Industrial Chemistry Library, Volume 8
The Roots of Organic Development
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Industrial Chemistry Library, Volume 8
The Roots of Organic Development
Industrial Chemistry Library Advisory Editor: S.T. Sie, Faculty of Chemical Technology and Materials Science Delft University of Technology, Delft, The Netherlands
Volume 1
Progress in C1 Chemistry in Japan (Edited by the Research Association for C 1 Chemistry)
Volume 2
Calcium Magnesium Acetate. An Emerging Bulk Chemical for Environmental Applications (Edited by D.L. Wise, Y.A. Levendis and M. Metghalchi)
Volume 3
Advances in Organobromine Chemistry I (Edited by J.-R. Desmurs and B. Gdrard)
Volume 4
Technology of Corn Wet Milling and Associated Processes (by P.H. Blanchard)
Volume 5
Lithium Batteries. New Materials, Developments and Perspectives (Edited by G. Pistoia)
Volume 6
Industrial Chemicals. Their Characteristics and Development (by G. Again)
Volume 7
Advances in Organobromine Chemistry II (Edited by J.-R. Desmurs, B. Gdrard and M.J. Goldstein)
Volume 8
The Roots of Organic Development (Edited by J.-R. Desmurs and S. Ratton)
Industrial Chemistry Library, Volume 8
The Roots of Organic Development Edited by Jean-Roger
Desmurs
Rh6ne Poulenc Industrialisation, CRIT/Carrikres, 85 Avenue des Frbres Perret, 69192 Saint-Fons Cedex, France Serge Ratton
Rh6ne Poulenc Organic Intermediates Enterprise, 25 Quai Paul Doumer, 92408 Courbevoie Cedex, France
1996 ELSEVIER Amsterdam
~
Lausanne
~
New York --
Oxford --
Shannon
~
Tokyo
ELSEVlER SCIENCE B.V. Sara Burgerhartstraat 25 P.O. Box 211, 1000 AE Amsterdam, The Netherlands
ISBN: 0-444-82434-0 9 1996 Elsevier Science B.V. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior written permission of the publisher, Elsevier Science B.V., Copyright & Permissions Department, P.O. Box 521, 1000 AM Amsterdam, The Netherlands. Special regulations for readers in the USA - This publication has been registered with the Copyright Clearance Center Inc. (CCC), Salem, Massachusetts. Information can be obtained from the CCC about conditions under which photocopies of parts of this publication may be made in the USA. All other copyright questions, including photocopying outside of the USA, should be referred to the copyright owner, Elsevier Science B.V., unless otherwise specified. No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein.
This book is printed on acid-free paper. Printed in The Netherlands
FOREWORD It is our belief within RHONE-POULENC that the key to building long term customer relationship in our industry is superior technology backed up by outstanding service. Benefits of superior technology in Organic Chemistry are multiple : lower cost raw materials, shorter synthesis routes, improved yields, selectivity and kinetics, resulting in better productivity. Higher transformation rates of less hazardous materials leads to healthier, cleaner operations with reduced waste disposal issues. Last but not least, process safety is continually upgraded as more intimate knowledge of chemical reactions and other unit operations is achieved. For our worldwide customers such technical progress creates multifaceted value: reliability, shorter response time, more competitive economics, improved quality leading to faster registration, and safer and more environmentally responsible operations. Furthermore, it enables us to extend the use of this expertise to the adaptation of decisive physical or chemical properties of molecules to provide our customers with desired use properties. Making our overall skills available to customers to solve their problems is indeed the basis of our ,, Chimie Nouvelle ,, approach. In this spirit we expect and look forward to provide, along with our Organic Intermediates technology, whatever services are required to make our joint success complete : efficient pilot facilities, advanced analytical equipment with expert staff, toxicology and eco toxicology support, environmental services, formulation capabilities, ... we do this throughout the world. This is the way we aim to become your preferred partner in organic chemistry, to gain your confidence and be able to participate early in your most important projects. May this book demonstrate to all our existing or potential partners our commitment to top level organic chemistry. We are proud of the achievements and expertise of our teams. May our partners keep challenging them to build leaderships together.
Bertrand LOUVET Rh6ne-Poulenc Chemical Sector Executive vice-President
Ted ZIEMANN President of Rh6ne-Poulenc Organic Intermediates Enterprise
This Page Intentionally Left Blank
PREFACE It seems to us, symbolic, important, and above all promising for the furore, that the year in which Rh6ne-Poulenc holds its centenary celebrations also sees the publication of a scientific review, gathering together organic chemistry research carried out in common by groups from universities and other large organisations, and with Rh6ne-Poulenc research workers. The development of an industrial group, especially one such as Rh6ne-Poulenc, is directly linked to the possibility of innovation. For this, it is necessary to rely, not just on the groups own resources and strengths, but also on the research and discoveries made by external research bodies. The General Management of the Group, as far back as 1974, was aware of this need to have a closer association with upstream research, and so signed the first contract with the CNRS (National Research Centre). This was only the first step, although an important one, and several years passed before Rh6ne-Poulenc opened its research doors to the outside world. From 1981 until the present day, with the support and constant incitement of the Group managers, a network of collaborators has been set up, at first in France, and then abroad. This has required, from everyone involved, efforts regarding mutual understanding, always within a climate of trust. The first organised meetings were RP-CNRS symposia based on themes, and focusing on problems directly related to the Groups chemical interests (homogeneous catalysis, chemical reactivity, regioselectivity...) during which our research workers and those of the CNRS exchanged information and results and initiated future collaborations. Today these symposia have been replaced by ,, Journ6es RP-CNRS ,, where several themes are examined over a two day period, using a format akin to a seminar. It was then decided to modify these <, Journ6es Scientifiques ,,, originally reserved for Rh6ne-Poulenc research workers, by orienting them towards a particular theme (silicon chemistry, reactivity in organic chemistry, materials science, molecular biology, etc.) and by inviting, under the presidency of an internationaly renowned scientist, not only Rh6ne-Poulenc research workers, but also the best specialists from France and abroad, interested in the theme under examination, and by asking them to actively participate through written or oral presentations.
VII
The assessment of these ~ Journ6es ,, has been particularly positive, allowing on the one hand high-level research workers to discover our own research interests, and on the other, allowing the Group to take advantage of their expertise and to possibly have future Rh6ne-Poulenc scientists trained in their laboratories. At pratically the same time, Rh6ne-Poulenc set up a Scientific Council, assembling internationally renowned scientists, each working in the different areas of research relevant to the Group. The role of this council is essentially to provide ideas and propositions concerning the great scientific problems, as well as an external and independant audit, ready at any moment to notify the General and Scientific Management of any new discoveries or advances likely to modify the direction of our research. In 1987, the organisation of the Scientific Management was improved, with directors being nominated for the following three areas : chemistry (J.M. Lehn), physical-chemistry (P.G. De Gennes) and biology (C. H616ne), each being assisted by an internal consultant, establishing permanently the opening of our research to the external scientific world. Today, always with this same preoccupation, under the impetus of Philippe Desmarescaux, General Manager, and of Claude H616ne, now Scientific Director, this collaboration has culminated in the Bio-Avenir programme, which represents a model for the interaction between public research and industry. But let us return to the various themes presented in this book. They represent an image, albeit a rather incomplete one ; but an image which exemplifies this research in common, and of the results achieved by such a methodology. It must also be noted that everything which has just been evoked, has only been possible because of the enthusiasm, support, trust and the willingness to persevere, of all the research workers concerned, whatever their affiliation. Also, it must be added that the management of the large organisations, in particular the Management of the Chemical Sector of the CNRS, the Research Directors of our sectors as well as the group leaders of our Research Centres, have all contributed to this development through their encouragement and financial aid. This continuing exciting adventure is a long term exercise. Mutual respect, esteem and the desire to work together does not come over night. Time is needed in order to know one another, to ~ tame one another ,, as the fox in the ~, Little Prince ,, by Saim-Exup6ry said. It is also important, as we have seen, to allow enough time to set up high level competences in new areas, by accepting the failures which arrive at the start, perseverance often bringing about the sought after results, especially in the case of difficult scientific hurdles. VIII
Today this long term policy is bearing fruit. We wish that this book be the first of many in the area of chemistry and perhaps in other areas as well. Thank you, once again, to all those who made what was once only a wish, become a daily reality.
J.M. LEHN Nobel Prize Winner Presidem of the Sciemific Council
C. JEANMART Correspondant Member of the Academy of Sciences
IX
ACKNOWLEDGEMENTS We would like to thank the Rh6ne-Poulenc Organic Intermediates Enterprise for the financial backing that has enabled this book to be published, and especially Ted Ziemann, president of Rh6ne-Poulenc Organic Intermediates Enterprise. We would also like to thank : - M r s Th6r6se Fessetaud who co-ordinated all the authors and the company Proman. -The Mrs Marthe Di Rollo, Dominique Trouillet, Laurence Ouled and Elisabeth Di Rollo from Proman who did all the typing for this work. - Mrs Tavernier for her help in translating various articles. -The Mrs St6fanie de Rouville and Martine Pinard from the communications management of the chemicals sector for their help and advice. Lastly, we would like to thank all the authors for their work that enabled the publication of this book.
Jean-Roger DESMURS
Serge RATTON
CONTENTS
FOREWORD B. Louvet, T. Ziemann, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V PREFACE C. Jeanmart, J.M. Lehn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII ACKNOWLEDGEMENTS ..........................................................
X
INTRODUCTION J.R. Desmurs, C. H61~ne, D. Michelet, S. Ratton . . . . . . . . . . . . . . . . . . . . 1
SYNTHESIS ACYLATION Friedel-Crafts acylation : interactions between Lewis acids / acyl chlorides and Lewis acids / aryl ketones R. Ashforth, J.R. Desmurs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bismuth (III) salts in the Friedel-Crafts acylation J.R. Desmurs, M. Labrouill6re, J. Dubac, A. Laporterie, H. Gaspard, F. Metz . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3
15
Friedel-Crafts acylation of aromatics using zeolites M. Spagnol, L. Gilbert, D. Alby . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 COC12 catalyzed trifluoroacetylation of aromatics using trifluoroacetic anhydride J. Ruiz, L. Gilbert, D. Astruc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
XI
ALKYLATION Catalysis by rare earth phosphate II methanol in vapor phase
9 Selective O-methylation of phenols by
L. Gilbert, M. Janin, A.M. Le Govic, P. Pommier, A. Aubry ..... 48 Catalysis by rare earth phosphate III : Characterisation of samarium phosphate and samarium phosphate-cesium hydrogenophosphate as key catalysts for O-alkylation of phenols A.M. Le Govic, P. Pommier, A. Aubry, L. Gilbert, M. Janin ..... 62
AROMATIC FUNCTIONALISATION Selective functionalisation of fluoroaromatics via organosilicon intermediates B. Bennetau, P. Babin, J. Dunogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 Arylation of amines and alcohols catalyzed by nickel, copper or palladium complexes H.J. Cristau, J.R. Desmurs, S. Ratton, S. Rignol, M. Taillefer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 The isomerisation of 1,2,4-trichlorobenzene : a theoretical study S. Firkins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
CARBOXYLATION Carboxylation of hydroxy aromatic compounds I. Bonneau-Gubelmann, M. Michel, B. Besson, S. Ratton, J.R. Desmurs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
CHLORINATION Access to polychlorophenols, chemistry of intermediates J.R. Desmurs, S. Ratton, R. Jacquerot, J. Dananch6, B. Besson, J.C. Leblanc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 XII
Diastereoselective halogenations P. Duhamel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
ENZYMATIC CATALYSIS Enzymatic hydrolysis of adiponitrile into 5-cyanovaleric acid, an intermediate for Nylon 6 E. Cerbelaud, M.C. Bontoux, F. Foray, D. Faucher, S. Levy-Schil, D. Thibaut, F. Soubrier, J. Crouzet, D. P6tr6 .... 189
FLUORINATION Reagents with trifluoromethyl substituents H.G. Viehe, Z. Janousek . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201 Fluorination of aromatic compounds by halogen exchange with fluoride anions (,, Halex ,, reaction) B. Langlois, L. Gilbert, G. Forat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244 4-Fluorophenol : a key intermediate for agrochemicals and pharmaceuticals C. Mercier, P. Youmans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 Fluorodecarboxylation of arylchloroformate : a new access to fluoroaromatics H. Garcia, L. Gilbert, M.C. Perrod, S. Ratton, C. Rochin ....... 301 Mild trifluoromethylation of organic compounds C. Wakselman, M. Tordeux . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
FORMYLATION Formylation of aromatic compounds in superacidic medium L. Saint-Jalmes, C. Rochin, R. Janin, M. Morel . . . . . . . . . . . . . . . . . . . . 325
XIII
HYDROGENATION High selectivities in hydrogenation of halogenonitrobenzenes on Pd, Pt or Raney Nickel as catalysts G. Cordier, J.M. Grosselin, R.M. Ferrero . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
HYDROXYALKYLATION Influence of the cation in condensation of glyoxylic acid on phenols in aqueous hydroxide solution M.F. Wuthrick, C. Maliverney . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
HYDROXYLATION Selective access to hydroquinone ,, Fuchsone ,, route M. Costantini, E. Fache, D. Michelet, D. Manaut . . . . . . . . . . . . . . . . . . 350
NITRATION The mechanisms of nitration of phenol P. M6tivier, T. Schlama . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
368
OXIDATION Oxidation of alkylphenols to hydroxybenzaldehydes E. Fache, D. Laucher, M. Costantini, M. Beclere, G. Perrin-Janet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
380
Large pore Ti-Beta zeolite with very low aluminium comem : an active and selective catalyst for oxidations using hydrogen peroxide M.A. Camblor, M. Costantini, A. Corma, P. Esteve, L. Gilbert, A. Martinez, S. Valencia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
XIV
391
PEPTIDE SYNTHESIS Peptide synthesis by SAPPHO technology J.M. Bernard, K. Bouzid, J.P. Casati, M. Galvez, C. Gervais, P. Meilland, V. P6v6re, M.F. Vandewalle, J.P. Badey, J.M. Enderlin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405 A new and practical removal of allyl and allyloxycarbonyl group promoted by water-soluble Pd(0) catalysts S. Lemaire-Audoire, M. Savignac, J.P. Genet, J.M. Bernard .... 416
SAFETY Safety of chlorination reactions J.L. Gustin, A. Fines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
APPLICATIONS Sodium amide in organic synthesis J.M. Poirier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 445 Delivery systems for controlled release of active materials C. Prud'homme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469 Anisole : an excellent solvent J.R. Desmurs, S. Ratton . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481 The use of phenolic compounds as free-radical polymerization inhibitors F. Lartigue-Peyrou . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489
ANALYSIS Tracing back the origin of vanillin by SNIF-NMR G.J. Martin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506 XV
NMR under high gas pressure F. Metz, M. Lanson, A. Merbarch, U. Frey . . . . . . . . . . . . . . . . . . . . . . . . 528 Lactic derivatives
: methods for determining the optical purity of various
intermediates F. Marcenac, D. Bernard, F. Boyer, J. Chabannes, Y. Danion, M. Minfray, N. Peyre, E. Zandanel, M. Hillairet, J.C. Marsault, E. Pilot . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536
A U T H O R INDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 550
S U B J E C T INDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 552
XVI
INTRODUCTION JEAN-ROGER DESMURS a), CLAUDE H E L E N E b), DANIEL MICHELET b) AND SERGE RATTON c~ a) Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie, 85 Avenue des Fr~res Perret, 69192 Saint-Fons Cedex, France. b) Direction Scientifique, 25 Quai Paul Doumer, 92408 Courbevoie Cedex, France. c) Interm6diaires Organiques, 25 Quai Paul Doumer, 92408 Courbevoie Cedex, France.
This book is a collection of papers dealing with various aspects of inorganic chemistry: - from exploratory work on the reactivity and selectivity of new reactions to studies on the reaction mechanisms of well known reactions, -from work highlighting the potential of certain technologies for new reactions (bioconversion, organometallic catalysis, etc.), to studies illustrating the potential for synthesis of certain reactants (e.g. sodamide), -from work on the choice and development of industrial synthesis pathways for new Fine Chemical intermediates, to studies aimed at understanding chemical phenomena linked to process Safety, from work dealing with the treatment and formation of organic solids in order to tailor their properties, to development of analytical techniques enabling detection of the origin of products, - and work on the development of new analytical methods in order to provide better characterisation of reaction processes and products. The diversity of topics covered in this book clearly shows the scope required nowadays, in terms of fields of knowledge and expertise, to enable the development of new processes and to the industrialisation and commercialisation of new intermediates. The speed with which the complex new process or product development procedure must take place, starting from exploratory research right through to the launch of the industrial production process, implies the contribution of numerous scientific disciplines, in other words the existence of major centres of competency, as well as perfect harmony between all the experts involved. -
The major centres of competency in Organic Chemistry, the foundation of Rh6ne-Poulenc Group Chemicals Sector's technical activity, are the fruit of many years of basic research. This type of research is often initiated by Rh6ne-Poulenc Group's Sciemific Direction or benefits from its support before being fully taken over by the Chemicals sector for confirmation of new concepts and scientific orientation towards high potential targets. Fundamental type research is often performed in association with the CNRS and internationally renowned university laboratories. This book contains a certain number of articles written by joint RP - University Laboratory teams, which is a good illustration of the spirit of trust that motivates researchers who are getting to know and appreciate one another more and more.
FRIEDEL-CRAFTS ACYLATION : INTERACTIONS B E T W E E N L E W I S ACIDS / ACYL C H L O R I D E S AND L E W I S ACIDS / ARYL K E T O N E S
REBECCA ASHFORTH AND JEAN-ROGER DESMURS Rh6ne-Poulenc
Industrialisation,
Centre
de
Recherche,
d'Ing6nierie
et
de
Technologie, 85 Avenue des Fr6res Perret, B.P. 62, 69192 Saint-Fons Cedex, France.
INTRODUCTION The Friedel-Crafts acylation reaction is one of the most important in aromatic chemistry used in particular to prepare aryl ketones (eqn. 1) 0 + R'
R--C
+ \C1
HC1
(1)
R'
The reaction is catalysed by a Lewis acid such as AIC13, FeC13, TIC14, SbC15, NbC15, etc (refs. 1-5). The major drawback of the Friedel-Crafts reaction lies in the need to use the Lewis acid in stoichiometrical quantities relative to the acetone formed, which in industrial terms poses large effluent problems. The use of stoichiometrical quantities of Lewis acid results in the formation of a complex at the end of the reaction between the aryl ketone formed and the Lewis acid. ~__C/?
/
.....MCln
u
To resolve the effluent problem, much work has been performed investigating the conditions or catalysts that enable the Friedel-Crafts acylation to be performed with catalytic quantities of Lewis acid. Whilst the Friedel-Crafts acylation mechanism remains to be accurately determined (ref. 6) it is reasonable to postulate four stages. The activation of acid chloride by the Lewis acid (eqn. 2). O
0,,
R--C//'\ C1
+
MCln
"-
R--C ~ \
(2)
%'MCln / CI"
The reaction of the activated acid chloride with the aromatic compound to give a complex (eqn.3). 0E~....... MCln_
-~
+
O,
R--C ~" """MCln
R'
R
~
\cr"'"
~
1
(3)
R'
The aromatisation of the complex (eqn. 4).
| O..........,.AICI3
/0 ............,-MCIn C,, R,,,-"" +HC1
~
R'
(4)
The decomplexation between the Lewis acid and the aryl ketone formed (eqn. 5). o .....M C h
R,~\ ~ /
+ xR
R,/k
/
R
MCln
(5)
The Friedel-Crafts acylation with catalytic quantities of Lewis acid requires a knowledge of the equilibria (2) and (5).
INTERACTIONS W I T H LEWIS ACIDS OF M E T A L HALIDE TYPE Complexation of acid chlorides D.E.H. Jones and J.L. Wood (ref. 7) used infrared spectroscopy to study the
chloride complexes of acidic A1CI3. The study of the complexation of acetyl chloride by the various metal halides (Table 1) was performed by measuring the variation of the vibration intensity (CO) at 1808 cm -1.
Table 1. Complexation of acetyl chloride in equimolar mixtures of CH3COC1 and metal halides (infrared). Lewis acid
% acetyl chloride a) complexed by the Lewis acid
A1CI3
94
AIBr3
Insoluble 79
All3 SnC14 SnC12 TiC14
13
FeCI3
Insoluble
GaC13
b)
89
SbC15
b)
84 21
SbCIs NbC15
b)
22
a) 0.2 M solution in CHzC12 b) Precipitation after 30 minutes These results obtained using IR are confirmed with NMR in accordance with the method described by G. Sartori (ref. 8) (Table 2).
Table 2. NMRS3C of acetyl chloride in equimolar mixtures of CH3COC1and metal halides a) Lewis acid
~13C (C --" 0)ppm
A~13C (C = 0)ppm
170.3 1,OM
A1C13
207.4
36.7
SnC14
170.8
0.2
TIC14
171.0
0.7
Solvent 9CD2C12 NMR Bruker AMX 300
As described by G. Sartori (ref. 8), NMR shows that acetyl chloride is either found free or in a 1"1 complex with A1C13.
Complexation of ketones The complexation of p-methyl acetophenone 1 with various metal halides has been determined using infrared by monitoring the change in vibration intensity (CO) at 1683 m -1 (Table 3).
H
3
C
~
O
Table 3. Complexation of p-4-methyl acetophenone 1 with equimolar mixtures of (1) and metal halides.
Lewis acid
% of complexed p-methyl acetophenone
A1C13
83
A1Br3
85
All3
100
SnC14
82
SnC12 TiC14
100
FeC13
100
GaC13
b)
100
SbC15
b)
100 38
SbC13 NbC15
b)
100
Ti(OCH(CH3)2)4 a) 0.2 M solution in CH2C12 b) Precipitation
All metal halides have electron deficiencies which complex the acetophenone. The data obtained by infrared are perfectly confirmed by N M R (Table 4).
methyl
Table 4. NMR13C of 4-methyl acetophenone 1 with equimolar mixtures of 1 and metal halides. Lewis acid
~13C (C -- 0) ppm
A~13C (C = 0) ppm
197.7 1,0M
A1C13
214.9
17.2
SnC14
209.3
11.6
GaC13
215.3
17.6
197.9
0,2 M
A1C13
214.6
A1Br3
215.4; 215.6
16.7 [
17.5; 17.7
!
All3
214.9
17.0
SnC12
Insoluble
TIC14
Precipitation
FeC13
Paramagnetic
SbC15
Precipitation
SbC13
200.2
2.3
NbC15
215.5
17.6
As opposed to acetyl chloride, we can observe a continuous change in the chemical shift of the carbon in the carbonyl group given in Figure 1 as a function of a varying aluminium chloride / 4-methyl benzophenone ratio.
A1C13 Me
~
1,30
1,20
1,00
1
_ ~ _ = i
i
i
0,80
0,60
!
.
.
.
.
.
l
.
,,
,
,,,,
0,50
_
0,30
/
0,20
....
J_ ! 0,16 0,10
. Fig. 1.
._.
.
.
.
.
[
Pure p-MePhCOMe
$13C of the CO in 4-methyl acetophenone as a function of the aluminium chloride / 4methyl acetophenone ratio. 9
A similar change is also seen in NMR of 27A1 (Fig. 2)
AI I C=O
1,30
0,80 9
,
,
=
0,50 ,,
,
,
,
,
J
i
i,,
0,20 ppm
120
100
80
Fig. 2. S27A1 as a function of the A1C13 / 4-methyl acetophenone ratio.
These observations could be due to the existence of several complexes of different stoichiometry and geometry as suggested by various pieces of work (refs. 9,10).
KETONE-CHLORIDE
COMPETITION
RELATIVE
TO
THE
COMPLEXATION OF LEWIS ACIDS NMR and IR studies have enabled us to show that equilibria (2) and (5) were strongly shifted towards the complex form, O
// R--C \C1
O,,
+
MCln
_..
"--
R--C ~" .......MCln
(2)
\ C1"''"
0 .....MCln
~~__c//0
"R
+ MCIn (5)
We have sought to determine the competitive behaviour of a mixture of acetyl chloride and 4-methyl acetophenone relative to metal halides. Table 5 shows a considerable favouring of 4-methyl acetophenone when a Lewis acid equivalent quantity is added to an equimolar solution of 4-methyl acetophenone and acetyl chloride.
Table 5. The degree of complexed 4-methyl acetophenone measured by infrared in an equimolar mixture of 4-methyl acetophenone and acetyl chloride.
Lewis acid
% complexed p-MePhCOMe
A1C13
92
A1Br3
92
All 3
100
SnC14
96
13
TiC14
100
14
FeC13
62
30
GaC13
100
16
SbC15
100
29
SbC13
42
12
NbC15
100
% Complexed CH3COCI
SnC12
a)
0.2 M solution of 4-methyl acetophenone in CH2C12, 0.2 M of CH3COC1 / 0.2 M metal halide T = 25.
An increase in the CH3COC1 / 4-methylacetophenone ratio, 5"1 instead of 1"1 does not change the degree of complexed ketone (Table 6) which shows that the interaction between ketone and Lewis acid is much greater than the interaction between the acid chloride and the Lewis acid in the case of the metal halides studied.
12
Table 6.
Degree of complexed 4-methyl acetophenone measured by infrared using a mixture of acetyl chloride (5 eq.), 4-methyl acetophenone (1 eq.).
Metal halide
% complexed p-MePhCOMe
A1C13
88
A1Br3
100
All3
100
SnC14
86
SnC12 TiC14
100
FeC13
69
GaC13
100
SbC15
76
SbC13
37
NbC15
84
CONCLUSION Complexation with aryl ketone is much favoured by using conventional Lewis acids such as metal halides. In solution, the equilibrium (5) is in fact totally shifted towards the complex form at ambient temperature.
R'
// C \R
+
MCln
....MCIn
..~
(5) R '''~
/
~R
Because of this, the Friedel-Crafts acylation catalysed by metal halides such as A1C13, FeC13, TiCI4, etc. requires near stoichiometric quantities of Lewis acids.
To make Lewis acids catalytic for the Freidel-Crafts reaction various solutions can be considered : 9 Finding weaker metal halides such as BiC13 (ref. 11) in order to limit the complexation with aryl acetone and favour complexation with the chlorine in the acid chloride, 9 Using solid catalysts in order to hinder aryl ketone complexation (ref. 12), 9 Using less complex forming salts than metal halides with aryl acetone in the same way as rare earth triflates (refs. 13, 14), 9 Increasing acylation temperature (ref. 4) but this is often a source of secondary reactions.
References 1. C. Friedel, J.M. Crafts, Bull. Soc. Chim. Fr., 27,482, (1877). 2. C. Friedel, J.M. Crafts, Bull. Soc. Chim. Fr., 27,530, (1877). 3. A. Noguchi, T. Ikawa, Y. Shimada, J. Org. Syn. Chem. Japan, 39, 714, (1966). 4. I.P. Tsukervanik, N.V. Veber, Dold. Akad. Navk. SSSR, 180, 892, (1968). 5. J.J. Scheele in "Electrophilic Aromatic Acylation", Thesis, Delf, (1991). 6. J. March in "Advanced Organic Chemistry, Reactions, Mechanisms and Structure" 4 ed., J. Wiley, pp , New York, (1992). 7. D.E.N. Jones, J.L. Wood, J. Chem. Soc. (A), 3132, (1971). 8. F. Bigi, G. Casmati, G. Sartori, G. Predieri, J. Chem. Soc. Perkin Trans II, 1319, (1991). 9. S. Starowieyski, S. Pasynkiewicz, A. Sporzynski, A. Chwojnowski, I. Organometal. Chem., 94, 361 (1975). 10. N.L. Chikina, Yu. V. Kobdazhnyl, G.A. Osipov, Zh. OBBshch Khim, 45, 1354, (1975). 11. J.R. Desmurs, M. Labrouill6re, J. Dubac, A. Laporterie, H. Gaspard, F. Metz. This book. 12. M. Spagnol, L. Gilbert, D. Alby. This book. 13. A. Kawada, S. Mitamura, S. Kabayashi, J. Chem. Soc., Chem. Commun. 1157, (1993). 14. L. Hachiya, M. Moriwaki, S. Kobayashi Tetrahedron Lett. 36, 409, (1995).
B I S M U T H (III) SALTS IN F R I E D E L - C R A F T S A C Y L A T I O N
JEAN-ROGER DESMURS a), MIREILLE LABROUILLERE b), JACQUES DUBAC b) ANDRE LAPORTERIE b) HAFIDA GASPARD b~ AND FRAN(~OIS METZ a~ a) Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie des Carri6res, 85, Avenue des Fr6res Perret, BP 62, 69192 Saint-Fons Cedex, France. b) H6t6rochimie Fondamentale et Appliqu6e (URA CNRS 477), Universit6 Paul-Sabatier, 118 route de Narbonne, 31062 Toulouse Cedex, France.
INTRODUCTION The acylation reaction is one of the most important reactions in organic chemistry (ref. 1) (eqn. 1). The substituted atom Y is generally hydrogen, but can be an organometallic group of silyl type (refs. 2, 3). ZY
-~
z--C--R II 0
(1)
This reaction involves an acylating reagent (acyl halides, carboxylic acids or anhydrides) in the presence of an activator, usually a Lewis acid. However, as a result of the complexation of this Lewis acid with the formed ketone, more than one mole of catalyst is required per mole of reagent. It cannot be reused because the ketone is isolated after hydrolysis of the complex. Such is the dilemma of Friedel-Crafts acylation (refs. 4-6) in the presence of the traditional catalyst, aluminum chloride (eqn. 2). ArH + RCOX + A1C13
~
Ar~C--R + HX II O ... A1C13
H-,O -
CX- c~ o c (o), R_..)
~
Ar~CO--R
+
Alsalts
(2)
Consequently, a lot of research has been carried out in this area in order to find convenient catalysts, i.e. those able to activate the acylating reagent while giving labile complexes with ketones, in particular in hot conditions. Ferric chloride is the most common catalyst when the reaction is achieved in this manner (refs. 7, 8). With this same view, Friedel-Crafts acylation in the presence of small quantities of catalysts (for example FeC13), is strongly activated by microwave irradiation, in particular when the catalyst is on a graphite substrate (ref. 9). Other recent works concerning the catalytic acylation of aromatic ethers concern : - t h e use of Lewis acid-lithium or silver salt (AgC104 or AgSbF6) systems (ref. 10), boron (ref. 11) or metallic triflates (ref. 12), the latter being reusable catalysts, or also zinc chloride on a clay substrate ("Clayzic") (ref. 13) ; the study of the regiochemistry of the acylation of 2-methoxynaphtalene in the presence of metallic chlorides (ref. 14) ; and the preparation of 4-alkanoylaryl-benzylethers (ref. 15). Catalysis by Br6nsted acids requires very strong concentrations (refs. 4-6), and is restricted to the more stable reagents and substrates. In this respect, anisole is not acylated with a good yield in presence of 1 % of triflic acid (ref.tl6). -
-
R E C E N T RESULTS CONCERNING CATALYSIS BY BISMUTH (HI) SALTS Whilst numerous metallic salts are used in catalysis, some of them have been relatively little studied. Such is the case of bismuth (III) salts including the chloride. Bismuth, relatively inexpensive, with a metallic character marldedly more pronounced than that of As or Sb, and giving much less toxic derivatives (ref. 17), might play an increasing role in catalysis, in particular for the substitution of some industrial catalysts affected by stricter standards on wastes. Many works concern Bi (V) compounds in stoichiometric oxidations involving the BiV/Bi m redox pairing (ref. 18). The use of Bi (III) compounds in organic reactions is less developed, but the literature includes some references, especially for the catalytic oxidation of alkenes or arenes (Bi (III) complexes and molybdates) (refs. 19-23), acyloins (Bi203/AcOH) (ref. 24), and in oxidative cleavage of epoxides (Bi (III) mandelate / DMSO) (ref. 25), ~-glycols (Ph3Bi / NBS) (ref. 26), and ~-ketols (Bi (III) mandelate) (ref. 27).
Concerning BiC13, this weak Lewis acid proved an unexpected catalyst in the Mukaiyama-cross aldol and -Michael reactions from enoxysilanes (ref. 28), because other metallic chlorides (TIC14, A1C13, SnC14...) and stronger Lewis acids, are required in stoichiometric proportion for these reactions (ref. 29). On the other hand, more recently, i has been shown that : the BiC13 catalytic activity in these reactions could be considerably enhanced by addition of some metallic iodides (ref. 30) ; the coupling of aldolisation and halogenation reactions, giving 13-haloketones or -esters, is possible owing to these catalytic systems (ref. 31) ; these Bi (III) halide systems allow strong Lewis acid sensitive compounds to be used (furane cpds) (ref. 32). Moreover, BiC13 on its own acts as catalyst for the Knoevenagel reaction (ref. 33) and is a strong activator of the Si-C1 bond (ref. 34). Associated with some metals (A1, Fe, Zn), BiC13 gives Bi(0) which is a catalyst for the allylation of aldehydes and amines (ref. 35), and for the reduction of aromatic nitro compounds to azoxy compounds (ref. 36). When associated with sodium borohydride, BiC13 gives an efficiem system for the selective reduction of nitroarenes and azomethines (ref. 37). As far as catalysis of acylation is concerned, BiC13 has been little studied. Two references report the use of this salt for the acetylation of toluene (ref. 38) and for the benzoylation of anisole (ref. 39), with average results for the latter, but poor for toluene. More recently, Le Roux and al. showed that BiC13metallic iodide systems efficiently catalyze the acylation reaction of enoxysilanes and allylsilanes for which they represent the first known catalysts (refs. 30b, 40). Although involving organosilanes, these last results encouraged us on to investigate the catalytic approach of Friedel-Crafts acylation using bismuth (III) salts, on their own, associated with co-catalysts, or on a substrate. We present here our initial results (ref. 41). -
-
-
BISMUTH (III) SALTS IN THE FRIEDEL-CRAFTS ACYLATION OF AROMATIC ETHERS Anisole is a reactive aromatic substrate for acylating reagents. For large extent, the recent works of Scheele (ref. 42) focus on this compound. Therefore, in order to give good comparison, we have chosen to carry out our first tests on Friedel- Crafts acylation using anisole 1 (eqn. 3).
MeO-~
RCOX_ HX -~ M e O ~ C R
+ MeO-~ o
(3)
/
RC [I O
2
3_
X = CL OC (O) R R = Me (a), Me2CH (b), Me3C (e), Me (CH2)4(d), Ph (e)
Acylation of anisole by acyl chlorides The reaction between anisole and acyl chlorides (eqn. 3, Z = C1) was carried out with an excess of aromatic substrate, without solvent (Table 1).
Table 1. Acylation of anisole by acyl chlorides (eq. 1, E = C1)a Entry
Catalyst (% mol)
R
Conditions b
Yield (%)~
1
BiC13 (10)
Me
50~
2h
60
;
50 d
2
BiC13 (10)
Me2CH
85~
6h
100
;
87 d
3
BiC13 (1)
Me2CH
85 ~
6h
40
4
BiC13 (10)
Me3C
85~
6h
90
;
80 a
5
BiC13 (10)
Ph
85~
6h
100
;
90 d
6
Claybis c (5) f
Me
50~
lh
50
7
Claybis: (5) f
Me2CH
70~
2h
92
;
85 d
8
Claybis c (5) f
MeaC
70~
2h
90
;
80 d
9
Bi203 (5)
Me2CH
85~
4h
90
;
80 d
l0
Bi203 (0.5)
Me2CH
85 ~
4h
35
a. b. c. d. e. f.
Without solvent; anisole / RCOC1 = 4/1; heating in an oil bath. Temperature of the oil bath. Conversion toward RCOCI ; 2_a,b,c,e / 3 a,b,c,e > 90/10 Yield in isolated product after aqueous workup. BiC13 / K 10 Montmorillonite prepared as "Clayzic" (ref. 13). 5% mol. in BiC13.
The Bi (III) salts, used bath chloride and oxide, gave comparable or often better results to those previously described in the literature. For instance, in the same experimental conditions Scheele observed 40 to 50% conversion of acetyl chloride in presence of 25 % mol. of catalyst (FeC13, TiCI4, SnCI4) (ref. 42). We have obtained 60 % conversion of acetyl chloride with only 10 % mol. of BiC13 (Table 1, entry 1). With a less volatile reagent, isobutyryl chloride, the reaction temperature can be increased, and the conversion was quantitative after 6h of heating at 85~ (Table 1, emry 2). In this case, 1% mol. of BiC13 led to 40 % conversion (entry 3). Isovaleryl chloride and benzoyl chloride also gave high yields (entries 4, 5). With the oxide Bi203, the yields are comparable to those obtained with the chloride (entries 9, 10). Deposited on K 10 Montmorillonite ("Claybis"), BiC13 becames more active than ZnC12 (ref. 13), the acylation reaction takes place at lower temperature and with a shorter reaction time (entries 7, 8), with only 5 % mol. of BiC13equivalent. Furthermore, some experiments with various Bi (III) salts and organometallic derivatives (for example : bismuth oxychloride, -acetate, salicylate, -carbonate oxide, -zirconate, -germanium oxide, triphenylbismuth) have shown that these derivatives are also catalysts for the acylation of anisole by acyl chlorides (ref. 41). Comparative tests were carried out with some catalysts under the same experimental conditions (Table 2). BiC13 is the most efficient of the 4 metallic chlorides used (Table 2, entries 1-6), but the difference is more pronounced with the oxides (entries 7-10), a point that will be turned to account and discussed further.
Table 2. Acylation of anisole by catalystsa Entry
Catalyst (% mol)
hexanoyl chloride. Comparative tests with various
Reaction time
Y/d (%)b 65
1
BiCI3 (5)
6h
2
BiC13 (10)
6h
87
3
SbC13 (10)
6h
27
4
FeC13 (5)
6h
58
5
FeCI3 (10)
6h
44
6
ZnC12 (5)
6h
46
7
Bi203 (5)
4h
80
8
Sb203 (5)
4h
20
9
Fe203 (5)
6,5h
< 5
10
ZnO (5)
6,5h
60
a. Without solvent 9anisole / RCOCI = 4/1 9heating at 80~ in an oil bath. b. In isolated product after aqueous workup; 2 d / 3 d > 90/10.
A study of solvents (Table 3) shows that dichloromethane associated with ether (10/1) gives acceptable yields, but benzene, not acylated in these conditions, and nitromethane give better yields. BiC13 is soluble in these last two solvents, at room temperature in MeNO2, and the reaction proceeds in homogeneous conditions.
Acylation of anisole by acid anhydrides Table 4 reports the results using 10 % tool. of BiC13 with acetic and isobutyric anhydrides as reagents (eq. 3, Z = OC(O)R). The acetylation of anisole by (MeCO)20 is outstanding (Table 4, entries 1,2), particularly by refluxing, towards acylation by MeCOC1 (Table 1, entries 1,6). On the other hand, acylation with (MezCHCO)20 is more difficult than with MezCHCOC1. The oxide Bi203 is not an acylation catalyst with an acid anhydride as reagent. However, the addition of chlorine-mobile agent to Bi203 gives an efficient catalytic system, for example Bi203,6 MeCOCI (5 % mol) or BieO 3, 6 Me3SiC1 (5 % mol). In the acylation of anisole by acetic anhydride, bismuth trichloride appears as a better catalyst than iron and zinc chlorides (Table 4, entries 2,5,6).
20
Table 3. Acylation of anisole by acyl chlorides RCOC1 in the presence of a solvent a Entry
Catalyst (% tool)
R
Solvent Conditions
Conversion ( ~o)b
1
BiC13 (5)
Me
28
2 3 4 5
BiC13 (10) Bi203 (5) BiC13 (10) Bi203 (5)
Me Me Me Me2CH
6
BiC13 (10)
Me2CH
CH2C12, Et20 (10/1) reflux, 3h MeNO2, 80~ 2h CH2C12, Et20 (10/1) reflux 4h C6H6, reflux 4h
7
Bi203 (5)
Me2CH
C6H 6,
8
BiC13 (10)
Me2CH
MeNO2, reflux 3,5h
a. b. c.
40 55 80 70 70 85 968c
reflux 4h
90" 80c
Anisole / RCOC1 = 1/1.2. Conversion toward anisole" 2 a,b / ~ a,b > 90/10. Yield in isolated product after aqueous workup.
Acylation of veratrole The acylation of 1,2-dimethoxybenzene or veratrole was carried out in the same conditions
as those of anisole,
either using acyl chlorides
or acid
anhydrides (eqn. 4) (Table 5). MeO MeO
MeO /N~
RCOX
MeO~N~~_C[
R
o
_4
5 x = EL OC(O)R R = Me (a), Me2CH (b)
21
(4)
Table 4. Acylation of anisole by acid anhydrides (eq. 1, Z = OC(O)R) a.
Entry
Catalyst (% mol)
R
Conditions
Conversion ( %)b
1 2 3 4 5 6
BiC13 (10) BiC13 (10) BiC13 (10) BiC13 (10) FeC13 (10) ZnC12 (10)
Me Me Me2CH Me2CH Me Me
85~ c, 6h reflux, 3h 85~ r 6h reflux, 3h reflux, 6h reflux, 6h
87 100 67 75 70 66
a. b. c.
Without solvent 9anisole / (RCO)20 = 4/1. Conversion toward the acid anhydride; 2 a,b / 3 a,b > 90/10. Temperature of the oil bath.
Bismuth chloride is a good catalyst for veratrole acylation by RCOC1 (entries 1,2), but the crude product may contain about 5 % of an impurity idemified (GC-MS) as compound 6, which would arise from cleavage of an ether group by HC1. The reaction is more difficult with acid anhydrides (entries 4,5) relative to anisole (Table 4, entries 2,4). MeO
M e O ~ c o
R
22
Table 5. Acylationof veratrolea Entry
Catalyst (% mol)
Acylating reagent
Conditions b
Conversion ( %)c
1
BiCI3 (10)
MeCOCI
50~
lh
2
BiC13 (10)
Me2CHCOC1
85~
6h
80 100 " 88 d
3
Bi203 (5)
Me2CHCOC1
85~
4h
70
4
BiC13 (10)
(MeCO)20
140~
7h
65
5
BiC13 (10)
(Me2CHCO)20
140~
7h
24
a. b. c. d.
958 d
Without solvent; veratrole / acylating agent = 4/1 ; heating in an oil bath. Temperature of the oil bath. Conversion of 5 toward acylating agent. Yield in isolated product after aqueous workup.
Mechanistic aspects The mechanistic aspects of Friedel-Crafts acylation have been widely developed, in particular concerning identification of the intermediate complexes between the acylating reagent and the catalyst (refs. 1, 5, 6, 43). The general opinion is that these species exist in solution as an equilibrium mixture of ionic (oxocarbenium salts) and molecular (donor-acceptor complexes) forms whose relative concentrations depend on solvent and temperature. As a result of the insolubility of bismuth chloride in chloromethanes, a spectrometric study of RCOC1-BiC13 mixtures has been carried out in nitromethane. An equimolecular mixture of MeCOC1-BiC13 in MeNO2 (0.2 mol. 1-1) analyzed by infrared spectrometry showed the lack of characteristic absorptions of oxocarbenium ions around 2200-2300 cm -1 (refs. 43, 44), but a marked modification of the carbonyl stretching absorption. Two bands at 1715 and 1756 cm -1 took the place of the strong band at 1810 cm -1 of the free acetyl chloride, indicative of the perturbed carbonyl frequency of a dative structure C =O-+BiC13 (ref. 43). Multinuclear NMR has been very useful for the analysis of these complexes (ref. 43), in particular for the acetyl chloride-aluminum chloride system (ref. 45). A 1H and 13C-NMR study has been achieved with nitromethane solutions of acetyl chloride-BiC13 system (Table 6). Experiments using carbon 13 labelled acetyl-13C2 chloride in CD3NO 2 prove the existence of only one coordination
species. Indeed, the 13C-NMR spectra show one carbonyl signal (doublet) at low field (A6 = 6 ppm) of the carbonyl signal of free acetyl chloride, and one methyl signal (doublet) at high field (A6 = -13 ppm) of the methyl signal of free acetyl chloride. With two equivalents of BiC13, the acetyl chloride appears completely complexed. The chemical shifting of the protons of the methyl group is not influenced by the complexation. With 4-methoxyacetophenone 2, a similar experiment in nitromethane shows any modification of the chemical shift of the 13C-carbonyl signal after introduction of BiC13. Addition of MeCOC1 to this mixture causes the appearance of the characteristic signals of MeCOC1-BiC13 interaction. The actual stoichiometry of the RCOC1-BiC13 complex will be possible to define after further studies and its eventual isolation. Owing to the low basicity of bismuth, its interaction with the chlorine atom of RCOC1 must be envisaged. This would also explain the preferential complexation of BiC13 with acyl chlorides relative to ketones, that is the key of a catalytic system for FriedelCrafts acylation. We must point out the possibility of rt complexes between BiC13 and aromatic compounds (ref. 46). Considering the lability of these complexes, these interactions do not play a prominent role in the mechanism of FriedelCrafts acylation, but they can improve the solubility of bismuth salts.
Table 6. N M R data for acetyl-13C2 chloride-BiC13 a mixtures.
Mixtures
51H
513C (Me) b
513C(O)b
MeCOC1
2.66
33.9
172.5
33.9 20.6
172.5 176.5
20.9
178.8
MeCOC1, BiCI3
MeCOC1, 2 BiC13
a.
b.
2.67
Chemical shifts relative to TMS (ppm) 9 solvent CD3NO2 " t e m p e r a t u r e doublet, Ij(13C/13C) = 56 Hz.
24
300K.
A remarkable and somewhat surprising result is the catalytic activity of numerous bismuth (III) derivatives for the acylation of anisole by acyl chlorides. This result is indicative of likely oxygen-chlorine exchange between the Bi-O bond containing compound and acyl chloride giving BiC13, the true active species.This exchange is also involved in the Bi203-MeCOC1 and Bi203Me3SiC1 systems, active catalyst with acid anhydrides.
CONCLUSION Whilst bismuth (III) chloride is an efficient catalyst for the aromatic ether acylation by acid chlorides or anhydrides, it is not strong enough to carry out the acylation of non activated aromatics. However, the potential of using a wide range of Bi (III) salts as catalysts (ref. 41), in particular the oxide, the oxychloride and the carboxylates, all non hygroscopic compounds, offers advantages, and is indicative of the great versatility of Bi (III) derivatives. Moreover, the Bi salts obtained after hydrolytic workup are directly reusable. The para-selectivity of the described acylations is very high. In the case of the bismuth (III) salt, the ortho effect (refs. 42, 47), with its disadvantages, does not appear. Since the molecular chemistry is well developed, it seems to us possible to undertake the synthesis and study of the catalytic power of new bismuth (III) derivatives containing suitable ligands to activate the Lewis acidity of this element.
References
1. a) J. March, "Advanced Organic Chemistry. Reactions, Mechanisms, and Structure", 4th edition,Wiley, pp. 487-495,539-542, 598-599, New York, (1992). b) R. Taylor, "Electrophilic Aromatic Substitution", J. Wiley, New York, (1990) ; and references therein. 2. a) I. Fleming, J. Dunogu~s, R. Smithers, Organic Reactions, 37, 57, 148-154, (1989). b) I. Fleming, J. Dunogu~s, R. Smithers, Organic Reactions, 37,446-474, (1989). 3. B. Benneteau, J. Dunogu~s, Synlett, 171, (1993). 4. J. March, ~ Advanced Organic Chemistry, Reaction, Mechanisms and Structure ,,, 4th edition, pp. 539-542, J. Wiley, New York, (1992). 5. G.A. Olah in "Friedel-Crafts Chemistry", Wiley, New York, (1973) and references therein.
25
6.
a) b)
.
8.
9.
a)
b) c) 10. a)
b) c) 11. 12. a)
b) 13. a)
b) 14. 15. 16. 17. 18. 19. 20. 21. a) b) c) 22. 23. 24. a)
b) 25. a)
b)
H. Heaney in "Comprehensive Organic Synthesis", B.M. Trost, ed., Pergamon, Oxford, Vol. 2, 733, (1991). G.A. Olah, R. Krishnamurti, G.K.S. Prakash, id., Vol. 3, 293, (1991) ; and references therein. D.E. Pearson, C.A. Buehler, Synthesis, 533, (1972). M. Desbois, R. Gallo, J.F. Scuotto, FPt2 534 905 and FP 2 534 906, (1982), (to Rh6ne-Poulenc). R. Laurent, Th~se, Universit6 Paul-Sabatier, Toulouse, N ~ 1913 (1994) ; M. Audhuy-Peaudecerf, J. Berlan, J. Dubac, A. Laporterie, R. Laurent, S. Lefeuvre, French application N~ 94 09073, (1994) ; C. Laporte, R. Laurent, A. Laporterie, J. Dubac, Unpublished results. T. Mukaiyama, T. Ohno, T. Nishimura, S. Suda, S. Kobayashi, Chem. Lett., 1059, (1991). T. Mukaiyama, K. Suzuki, J.S. Han, S. Kobayashi, Chem. Lett., 435, (1992). K. Suzuki, H. Kitagawa, T. Mukaiyama, Bull. Chem. Soc. Jpn., 66, 3729, (1993). T. Mukaiyama, H. Nagaoka, M. Ohshima, M. Murakami, Chem. Lett., 165, (1986). A. Kawada, S. Mitamura, S. Kobayashi, J. Chem. Soc., Chem. Commun. 1157, (1993) A. Kawada, S. Mitamura, S. Kobayashi, Synlett, 545, (1994). A. Corn61is, A. Gerstmans, P. Laszlo, A. Mathy, I. Zieba, Catal. Letters, 6, 103, (1990). A. Corn61is, P. Laszlo, S. Wang, Tetrahedron Lett., 34, 3849, (1993). S. Pivsa-Art, K. Okuro, M. Miura, S. Murata, N. Nomura, J. Chem. Soc. Perkin Trans. 1, 1703, (1994). W. Grammenos, W. Siegel, K. Oberdorf, B. Mueller, H. Sauter, R. Doetzer DE 4 312 637, (1994) (to BASF) ; Chem. Abstr., 122, 9662, (1995). F. Effenberger, G. Epple, Angew. Chem. Int. Ed., 11,300, (1972). N. Sax Irving, R.J. Bewis in "Dangerous Properties of Industrial Materials", pp. 283,284, 522,523, Van Nostrand Reinhold, (1989). D.H.R. Barton, J.P. Finet, Pure Appl. Chem. 59, 937, (1987) and references therein. J.M. Br6geault, M. Faraj, J. Martin, C. Martin, New. J. Chem., 11,337, (1987). M.M.J. Wolfs, P.A. Batist, J. Catal., 32, 25, (1974). J.L. Callahan, R.K. Grasselli, E.C. Milleberger, H.A. Strecker, Ind. Eng. Chem., Proc. Res. Dev., 9, 134, (1970). R.K. Grasselli, J.D. Burrington, Ind. Eng. Chem. Proc. Res. Dev., 23, 393, (1984). A.B. Anderson, D.W. Ewing, Y. Kim, R.K. Grasselli, J.D. Burrington, J.F. Brazdil, J. Catal., 96, 222, (1985). T. Hayakawa, T. Tsunoda, H. Orita, T. Kameyama, H. Takahashi, K. Fukuda, K. Takehira, J. Chem. Soc., Chem. Commun., 780, (1987). D.D. Agarwal, K.L. Madhok, H.S. Goswani, React. Kinet. Catal. Lett., 52, 225, (1994). W. Rigby, J. Chem. Soc., 793, (1951). C. Djerassi, H.J. Ringold, G. Rosenkranz, J. Amer. Chem. Soc., 76, 5533, (1954). T. Zevaco, E. Dunach, M. Postel, Tetrahedron Lett. 34, 2601, (1993). V. Le Boisselier, E. Dunach, M. Postel, J. Organomet. Chem., 482, 119, (1994).
26
26. 27. 28. a)
b) 29. 30. a)
b) 31. 32. a) b) 33. 34. a) b) 35. 36. 37. 38. 39. 40. a) b)
41. 42. 43. 44. a) b) c) d) e) 45. a) b) c)
D.H.R. Barton, J.P. Finet, W.B. Motherwell, C. Pichon, Tetrahedron, 42, 5627, (1986). V. Le Boisselier, C. Coin, M. Postel, E. Dunach, Tetrahedron, 51, 4991, (1995). H. Ohki, M. Wada, K. Akiba, Tetrahedron Lett., 29, 4719, (1988) ; M. Wada, E. Takeichi, T. Matsumoto, Bull. Chem. Soc. Jpn., 64, 990, (1991). T. Mukaiyama, Angew. Chem. Int. Ed., 16, 817, (1977). C. Le Roux, H. Gaspard-Iloughmane, J. Dubac, J. Jaud, P. Vignaux, J. Org. Chem., 58, 1835, (1993). C. Le Roux, Th6se, Universit6 Paul-Sabatier, N ~ 1532, (1993). C. Le Roux, H. Gaspard-Iloughmane, J. Dubac, J. Org. Chem., 59, 2238, (1994). C. Le Roux, M. Maraval, M.E. Borredon, H. Gaspard-Iloughmane, J. Dubac, Tetrahedron Lett., 33, 1053, (1992). C. Le Roux, H. Gaspard-Iloughmane, J. Dubac, Bull. Soc. Chim. Fr., 130, 832, (1993). D. Prajapati, J.S. Sandhu, Chem. Lett., 1945, (1992). M. Labrouill6re, C. Le Roux, H. Gaspard-Iloughmane, J. Dubac, Synlett, 723, (1994). M. Labrouill6re, C. Le Roux, H. Gaspard-Iloughmane, J. Dubac, Bull. Soc. Chim. Fr., (in press). M. Wada, H. Ohki, K. Akiba, Tetrahedron Lett., 27, 4771, (1986). H.N. Borah, D. Prajapati, J.S. Sandhu, A.C. Ghosh, Tetrahedron Lett., 35, 3167, (1994). H.N. Borah, D. Prajapati, J.S. Sandhu, J. Chem. Res., Synop., 228, (1994). O.C. Dermer, D.M. Wilson, F.M. Johnson, V.F. Dermer, J. Org. Chem., 63, 2881, (1941). I.P. Tsukervanik, N.V. Veber, Dokl. Akad. Nauk SSSR, 180, 892, (1968). Le Roux, H. Gaspard-Iloughmane, J. Dubac, Xth Intern. Symp. on Organosilicon Chem., Poznan, August 15-20, P31, (1993). J. Dubac, C. Le Roux, H. Gaspard-Iloughmane in "Organosilicon Chemistry (Proceedings of the Xth Intern. Symp.)", B. Marciniec, J. Chojnowski, Ed. ; Gordon and Breach, Langhorne, Pen, USA, (in press). J. Dubac, M. Labrouill~re, Andr6 Laporterie, J.R. Desmurs, French application, N o 94 10253, (1994). J.J. Scheele in "Electrophilic Aromatic Acylation", Tech. Hogeech, Delft, Neth. (1991) ; Chem. Abstr. 117, 130844, (1991). B. Chevrier, R. Weiss, Angew. Chem. Int. Ed., 13, 1, (1974). G.A. Olah, S.J. Kuhn, W.S. Tolgyesi, E.W. Baker, J. Amer. Chem. Soc., 84, 2733, (1962). D. Cassimatis, J.P. Bonnin, T. Theophanides, Can. J. Chem. 48, 3860, (1970). A. Germain, A. Commeyras, A. Casadevall, Bull. Soc. Chim. Fr., 3177, (1972). A. Germain, J.L. Pascal, J. Potier, Can. J. Chem., 55, 3096, (1977). G.A. Olah, A. Germain, A. White in "Carbonium Ions", G.A. Olah, P.V.R. Schleyer, Ed.; Wiley, New York, Chap. 35, (1976). J. Wilinski, R.J. Kurland, J. Amer. Chem. Soc., 100, 2233, (1978). B.Glavincevski, S. Brownstein, J. Org. Chem., 47, 1005, (1982). F. Bigi, G. Casnati, G. Sartori, G. Predieri, J. Chem. Soc. Perkin Trans 2, 1319, (1991).
27
46. a)
G. Peyronel, S. Buffagni, M. Vezzosi, Gazz. Chim. Ital., 98, 147, (1968).
b) H. Schmidbaur, T. Probst, B. Huber, G. MOiler, C. Kriiger, J. Organomet. Chem., 365, 53, (1989).
c) H. Schmidbaur, J.M. Vallis, R. Nowak, B. Huber, G. MOiler, Chem. Ber., 120, 1829 and 1837, (1987).
d) I.M. Vezzosi, A.F. Zanoli, L.P. Battaghia, A.B. Corradi, J. Chem. Soc. Dalton Trans 191, (1988).
e) W. Frank, J. Schneider, S. Mtiller-Becker, J. Chem. Soc., Chem. Commun., 799, 47.
(1993). A. Corn61is, P. Laszlo, S.F. Wang, Catal. Lett. 17, 63, (1993).
28
FRIEDEL-CRAFTS ACYLATION OF AROMATICS USING ZEOLITES
MICHEL SPAGNOL, LAURENT GILBERT AND DANIEL ALBY Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie, 85 Avenue des Fr6res Perret, B.P. 62, 69192 St Fons Cedex, France
INTRODUCTION The Friedel-Crafts acylation as well as the related Fries rearrangemem of aromatics are methods of choice in todays organic chemistry for synthesizing aromatic ketones as reactive intermediates for the production of fine chemicals. The conventional method of preparation of these aromatic ketones is the homogeneous Friedel-Crafts acylation of aromatic hydrocarbons with carboxylic acid derivatives using Lewis acids (A1C13, FeC13, BF3, ZnC12, TIC14) or Bronsted acids (polyphosphoric acid, HF). For this purpose, stoichiometric to excess amounts of the catalyst are required for the reaction to proceed (ref. 1). On an industrial scale, the use of metal halides type acids, which are preferred catalysts, is particularly penalizing. Indeed, during the workup of acylation mixtures, catalysts are distroyed and produce relatively large amounts of hydrochloric acid in the off-gas or in the effluent. This hydrochloric acid, which as to be disposed of, originates both from the catalyst and also from the acyl chloride employed for the acylation. In addition, to this disposal as a considerable environmental problem, the corrosion problem, due to the hydrochloric acid, must be solved. Therefore, a process that could be both environmemally friendly and also inexpensive, with respect to the disadvantages indicated, is clearly desirable. This article presents an alternative to the classical Friedel-Crafts catalysis using heterogeneous catalysts such as zeolites as we believe them to be ultimate catalysts for the future production of aromatic ketones.
29
RESULTS AND DISCUSSION
Literature Background Although much attention has been recently given to zeolites in the area of catalysis (petrochemistry in particular), there are few examples in the literature of the utilisation of solid acids such as clay (ref. 2) or zeolite (ref. 3) catalysts to the acylation of aromatics. On the other hand, the Fries rearrangement of phenylacetate has been well described (ref. 4). Y-faujasite-type zeolite exchanged with Ce 3+ cation have shown remarkable reactivity in the acylation of aromatic hydrocarbons such as toluene, especially when use in conjunction with straight-chain carboxylic acids (C12-C20) as acylating agents (ref. 3f). In all cases, excellent para selectivity is observed that can be explained by invoking a shape-selectivity argument. HY and Hb are also effective para-selective catalysts in the acylation of anisole by phenylacetyl and phenylpropanyl chloride without any noticeable demethylation reaction occurring (ref. 3e). In this particular article, the modification of catalyst parameters such as the influence of the level of Na + exchanged of the zeolite as well as the Si-to-A1 ratio has been examined (eqn. 1).
OCH3
OCH3
o
+ C1/~CH2Ph
catalyst
(1)
78~ CC14 H2Ph !
It was found that the initial rate for the formation of the aromatic ketone 1 is a linear correlation of the Na + exchanged indicating that all the acid sites are active in catalysing the acylation reaction. Therefore, a material does not need to have very strong acid sites to exhibit high activity. On the other hand, it is better to use a zeolite with a high framework Si-to-A1 ratio in order to insure a good reaction. Very interesting Friedel-Crafts acylation reactions using zeolites can also be found in the work of Bayer's team (ref. 3d) as well as Prins (ref. 3c). In both cases, work was realized on activated aromatics such as anisole. In the latter, Hb were found to exhibit particularly hight activity and selectivity independently of the Si-to-A1 ratio of the zeolite.
30
When examining in detail these results it appeared very difficult for us to build upon these experimental results as the reaction condition differ drastically from one paper to the other. This prompted us to reinvestigate the scope and limitation of the Friedel-Crafts acylation using heterogeneous solid as catalysts in trying as much as we could to rationalized the observed effects.
Catalysis Experiments We first focus our attention on the batch acylation of anisole in the liquid phase by
fixing
primary
parameters
anisole/acylating agent,
(acylating
agent,
solvent,
temperature,
ratio
% weight of catalyst), varying only the nature of the
catalyst. These parameters were chosen according in part to ref 3c. The results are presented in Table 1. Table 1. Acylation of anisole by acetic anhydridea OCH3
OCH3 cata
+ Ac20
~
+ CH3COOH
90~ 6 h H3
Entry
Catalyst
Yield (%) b
Selectivity(%)
1
HZSM5
12
> 98
2
H Mordenite
29
> 98
3
Hb
70
> 98
4
HY
69
> 98
5
exchanged clay
14
> 98
6
A1 clay
16
,,
> 98 ..
7
H3PW6Mo6040
21
> 98
a) reaction conditions 9molar ratio anisole/acetic anhydride = 5, 10% weight of powerded catalyst, 90~ 6h. b) yields were determined by GC using an internal standard. Eventhough all the catalysts tested show a very high selectivity, zeolite are clearly the preferred catalysts to carry out this reaction under mild conditions. 31
Among them the HY and Hb exhibit the best activity as previously reported (refs. 3c, 3d). Optimisation of the reaction parameters underlines the following trends" In general, an increase of the molar ratio anisole/acetic anhydride, the amount of catalyst as well as the temPerature, is benefitial for the activity. In changing the substrate to a more activated aromatic such as veratrole, the following results were obtained. Table 2. Acylation of veratrole by acetic anhydridea OCH3
OCH 3 CH3
10 % cata +
OCH3
Ac20
+ CH3COOH
90~ 6 h
3
Entry
Catalyst
Yield (%) b
Selectivity( %)
1
HZSM5
12
> 98
2
H Mordenite
25
> 98
3
Hb
53
> 98
4
HY
95
> 98
a) reaction conditions " molar ratio veratrole/acetic anhydride = 5, 10% weight of powerded catalyst, 90~ 6h. b) yields were determined by GC using an internal standard. For this reaction, only zeolite catalysts were found to show some activity which are presented in Table 2. HY not only stand out as the best material, but in this case, the reaction was much faster, in accordance with the classical electrophilic substitution rules of more activated substrate. The Hb which was as active as the HY in the case of anisole is now much less active with veratrole (entry 3 and 4), underlining the effect of secondary parameters related to the catalyst itself. Such parameters includes, the structure of the zeolite, the size and the shape of the pores, the diffusion and chimisorption of both the substrate and the acylating agent. H mordenite (entry 2) are not very active due to the monodimensional structure which disfavor bimolecular reaction. On the other hand, HZSM5, Hb and HY have a tridimensional structure which pore sizes and intersection volumes are presented in Table 3. 32
Table 3. Intersection volume and pore sizes for HZSM5, Hb, HY. Entry
pore sizes
Zeolite
[010] [100] [001] [100]
HZSM5 2
Hb
3
HY
5.3 x 5.6 5.1 x 5.5 7.6 x 6.4 5.5 x 5.5 [111]
intersection volume (A3) 150 310 1700 (supercage)
The acylation reaction should proceed through a Wheland type intermediate formed presumably within the intersection of the pores. If we compared the size of these intermediates with the intersection volume (Table 4) we can draw the following conclusion" Table 4. Volume and size of the postulated intermediate Entry
Weyland interm.
size (AxAxA)
volume (A3)
10 x 5.8 x 5.0
290
10.4 x 8.0 x 5.3
440
0CH3
CH3
OCH3 ~
.~~/OCH3
H//~CH3 O
In the HZSM5, the intersection volume does not allow the intermediate to be formed and therefore, everything seems to happen at the outer surface of the catalyst. With this in mind, it is interesting to note that the yield obtained in the case of anisole and veratrole is the same indicating that the acylation of anisole on
.)..3
HZSM5 might also proceed at the surface of the catalyst. The same observation can also be made in the case of H mordenite. The volume intersection of Hb is well suited for the acylation of anisole (compare Table 3 entry 2 with Table 4 entry 1) which is slightly superior to HY in term of activity, where the Weyland intermediate does not beneficiate from the confinement effect (ref. 5). On the other hand, it appears clearly that the acylated intermediate, in the case of veratrole can not be formed in the Hb, this intermediate being bigger than the allowed intersection volume. However, this situation is not encountered when HY are employed explaining the good catalytic results observed. In order to compare the versatility of this new process with classical FriedelCrafts reactions, we examined the reaction of anisole with benzoic anhydride: The results are presented in Table 5. Table 5: Benzoylation of anisole catalyzed by zeolitesa OCH3
?CH3 10 % cata
+
(PhCO)20
+ PhCOOH
90~ 6 h h
Yield (%)
b
Entry
Catalyst
Selectivity (%)
1
HZSM5
13
> 98
2
Mordenite
16
> 98
3
Hb
13
> 98
4
HY
15
> 98
a) reaction conditions 9molar ratio anisole/benzoic anhydride - 5, 10% of powdered catalyst, 90~ 611. b) Yields were determined by GC using an internal standard. Eventhough, selectivity was found to be very high in all cases, the activity was low. It appears obvious from these experiments that the benzoylation of anisole is independent on the pore sizes of the zeolites. Taking into account the size of the postulated Wheyland intermediate, calculated to be around 604 A3, and the intersection volume of the different zeolites (Table 3), one can clearly see that none of the tested catalysts have the required space to allow 34
the formation of the reactive intermediate. In addition, the same yield obtained in all cases reinforces this argument suggesting that the reaction only happens at the outer surface of the catalysts. Any attempts in trying to optimize the reaction by varying primary parameters, failed. Having examined the influence of the size of the acylating agent, we focused our attention on the use of acylchlorides as potential partners for the zeolite catalyzed process. The results are presented in Table 6. Table 6. Acylation of anisole using acylchloridesa OCH3
OCH3 10 % cata
+ RCOCI
~ 90~
Entry
R
Catalyst
1
CH3
Mordenite
+ HC1
6h
Yield (%)
b
6 . . .
2
CH 3
Hb
0
3
CH 3
HY
7
4
C6H5
Mordenite
0
5
C6H5
Hb
0
6
C6H5
HY
6
,.,
a) reaction conditions 9molar ratio anisole/acylchloride = 5, 10% of powdered catalyst, 90~ 6h. b) Yields were determined by GC using an internal standard. There is no reaction when an acylchloride is used in conjunction with a zeolite independently of its structure. This observation might suggest that the Bronsted acidity of the zeolite is no well suited for acylchloride as opposed to typical lewis acid such as aluminium chloride.
35
In order to understand this reactivity difference, we carry out 13C NMR experiments, examining the C = O shift of an anhydride or an acylchloride when complexed with a Lewis acid (A1C13) or a Bronsted acid (HC104) (Table 7).
Table 7. 13C NMR complexation Experiments
D d'~C (ppm)
CH3COC1
dl3(c =O) (lmol/1; CD2C12) 170.6
2
CH3COC1-A1C13
207.4
36.4
3
CH3COC1-HC104
184.6
14
4
(CH3CO)20
166.9
5
(CH3CO)20-A1C13
171.7
4.8
6
(CH3CO)20-HCIO4
179
12.1
7
(CH3CO)20-AIC13-CH3COC1
171.5
4.6
8
(CH3CO)20-HC1Oa-CH3COC1
184.3
13.7
Entry
Substrate
1
These X3C NMR experiments fit the observed results we obtained " a) Bronsted acids activate more strongly acetic anhydride than Lewis acids do (compare entry 6 and 7). b) On the other hand, Lewis acids exhibit a high complexation affinity with acylchloride compare to Bronsted acids (entries 2 and 3) which may in part accounts for the low reactivity observed in the case of zeolites. This may suggest that doping the zeolite with Lewis acid might improve the reaction. We therefore engaged our effort toward the synthesis and the test of zeolites exchanged with metals such as cobalt, zinc or cerium. The results are presented in Table 8 : Table 8. Acylation of anisole with acetylchloride catalyzed by metal exchanged Y-zeolites OCH3
OCH3 10 % cata
+ CH3COC1
+ HC1 90~ 6 h H~3 36
Entry
Catalyst
Yield (%)
1
CoY
25
2
ZnY
25
3
CeY
27
,.
The results obtained are slightly higher than the crude zeolite itself (compare Table 6, Entries 1-3 and Table 8). However, one" can not clearly conclude on the advantage of using these type of exchanged catalysts as analysis of the reaction mixture after reaction show significant amount of metal in solution. One can therefore expect the leaching of one of the metal to be excluded by including the metal in the zeolite framework.
CONCLUSION We have demonstrated that anisole and veratrole can be very efficiently acylated in liquid phase by acetic anhydride with zeolite catalysts under mild conditions, without undergoing demethylation, giving rise only to the para isomer. The pore sizes of the zeolite was found to be a critical parameter in order to ensure a good reactivity. This reactivity was correlated with comparing the volume of the Weyland's Friedel-Crafts intermediates and the intersection of the pore sizes of the catalyst. The nature as well as the structure of the acylating agent is essential and it was found that acylchloride, at this point, do not work in the reaction. In general, we have shown, using NMR technics, that acetic anhydride is well activated by Bronsted type acids whereas acylchlorides have a higher propensity to be activated by Lewis acids. In addition, this acylating reaction turns out to be very "environmentally friendly" process compared to the classical Friedel-Crafts reaction catalyzed by aluminium chloride, generating only byproducts such as acidic acid which can easily be recovered and recycled.
37
References
1.
2.
a) b) c) d) e)
3.
4.
a) b) c) d) e) f) a) b) c) d)
5.
e) a) b)
G.A. Olah in "Friedel-Crafts and related reactions", Wiley-Interscience, Vol. I-IV, New York, (1963-1964). G.A. Olah in "Friedel-Crafts Chemistry", Wiley-Interscience, New York, (1973). A. Corn61is, P. Laszlo, S. Wang, Tetrahedron Lett., 34, 3849, (1993). A. Corn61is, P. Laszlo, S. Wang, Catalysis Lett., 17, 63, (1993). P. Laszlo, A. Mathy, Helv. Chim. Acta, 70, 577, (1987). J.A. Clark, A.P. Kybett, D.J. Macquarrie, S.J. Barlow, P. landon, J. Chem. Soc., Chem. Comm. 1353, (1989). B. Chiche, A. Finiels, C. Gauthier, P. Geneste, J. Graille, D. Pioch, J. Mol. Cat., 42, 229, (1987). For a general reference see : P.B. Venuto, Microporous Materials, 2, 297, (1994). V. Paul, A. Sudalai, T. Daniel, K.V. Srinivasan, Tetrahedron Lett., 35, 2601, (1994). G. Harvey, A. Vogt, H.W. Kouwenhoven, R. Prins, Catalysis, 363, (1993). US 4,960,943, (1990), (to Bayer). A. Corma, M.J. Ciment, H. Garcia, J. Primo, J. Appl. Catal., 49, 109, (1989). B. Chiche, A. Finiels, C. Gauthier, P. Geneste, J. Org. Chem., 51, 2128, (1986). I. Neves, F. Jayat, Magnoux, G. Perot, F.R. Ribeiro, M. Gubelmann, M. Guisnet, J. Mol. Catalysis, 93, 169, (1994). A.H.G. Vogt, H.W. Kouwenhouten, Collect. Czech. Chem. Comm. 57, 853, (1992). Y. Pouilloux, J.P. Bodibo, I. Neves, M. Gubelmann, G. Perot, M. Guisnet, Stud. Surf. Science Cat., 59, 513, (1991). C.S. Cundy, R. Higgins, S.A.M. Kibby, B.M. Lowe, R.M. Paton, Tetrahedron Lett., 30, 2281, (1989). Y. Pouilloux, N.S. Gnep, P. Magnoux, G. Perot, J. Mol. Catalysis, 40, 231, (1987). E.G. Derouane, J.M. Andr6, A.A. Lucas, J. Catal., 110, 58, (1988). E.G. Derouane, Catalytica Highlights, 18, 4, (1992).
38
CoCI 2 CATALYZED TRIFLUOROACETYLATION OF AROMATICS USING TRIFLUOROACETIC ANHYDRIDE
JAIME RUIZ a), LAURENT GILBERT b) AND DIDIER ASTRUC a) a) Laboratoire de Chimie Organique et Organom6tallique, URA CNRS N ~ 35, Universit6 Bordeaux I, 351 Cours de la Lib6ration, 33405 Talence C6dex, France b) Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie, 85 Avenue des Fr~res Perret, B.P. 62, 69192 Saint-Fons C6dex, France.
ABSTRACT Trifluoroacetic anhydride (TFA) reacts at room temperature with anisole in the presence of COC12 as catalyst to give regiospecifically p.methoxytrifluoroacetophenone and 4,4'-dimethoxydiphenyle. The experimental conditions (anisole / TFA ratio) can orientate the system towards either reaction. Para-methylanisole reacts under these conditions to give exclusively trifluoroacetylation in ortho position with respect to the methoxy group without formation of a dimer. Similarly, 13-methoxynaphthalene reacts to give regiospecifically 1-trifluoroacetyl, 2-methoxynaphthalene. Meta-dimethoxybenzene exclusively gives 1,3-dimethoxy, 4trifluoroacetyl benzene. Veratrole does not react, probably because of the formation of a stabilized chelate complex with Co n. The reaction medium oxidizes ferrocene to ferricinium without trifluoroacetylation whereas 1,2,3,4-tetramethylbenzene is inert, which indicates the requirement of at least one methoxy substituent.
INTRODUCTION Fifty years ago, Simons et al. synthesized trifluoroacetophenone for the first time (eqn. 1, refs. 1,2). Since then, the trifluoroacetylation of aromatic compounds has continuously attracted the interest of chemists (refs. 3-16). Indeed, the classic Friedel-Crafts reaction (refs. 1,2) requires sub-stoichiometric quantities of aluminium chloride and trifluoroacetylchloride whose boiling point, - 27~ makes it difficult to use. Moreover, some F/C1 exchange between trifluoro-acetophenone 39
and aluminium chloride is suspected. The trifluoroacetylation of activated aromatics such as azulene (ref. 6), anthracene (ref. 7), thiophene (refs. 8,9), furanne (refs. 9,10), pyrrole (refs. 8,9,11), indole (ref. 9),N,N-dimethylaniline (refs. 9,12), pyrogallol trimethyl ether (ref. 9) can proceed using trifluoroacetic anhydride (TFA) at 200~ (refs. 6,7) or the triflate at 80~ (eqn. 2, ref. 8). Trifluoroacetophenones are more easily synthesized by reaction between a Li, Mg, Zn or Mn derivative and trifluoroacetic acid or ethyl - or Li trifluoroacetate (eqn. 3, refs 14-20). Another recent method uses 2-trifluoroacetoxypyridine, but requires the recycling of the compound (eqn. 4, ref. 21).
CF3COC1 + ArH
A1C13
~
ArCOCF3
(1)
+
CF3CO2SO2CF 3 +
80~
44 h .
COCF 3
(2)
I
H CF3COX + ArM
~
CF3COAr +
(3)
MX
X = OH, OR, C1, OCOCF3
+ ArH OCOCF3
Given problems, drawback search for ArH
A1C13 - 10~
~
CF3COAr +
- 0~
(4) O
the broad field of application of Friedel-Crafts reactions and the above in particular the formation of large quantities of aluminic waste, a major for industry, considerable investigation has recently been undertaken in catalysts (eqn. 5, refs. 22-31).
+ (RCO)20
cat.
ArCOR
+ RCO2H
40
(5)
For instance, Iqbal has published a preliminary result for the acylation of anisole catalyzed by COC12 involving the intermediacy of arene radical cations as shown by the formation of duplication products (eqn. 6, ref. 31). OMe
OMe
OCOCH3
OMe
.----M +
+ CH3COC1
.____. COCH3
.---,
+ ((~~~---~~~
COCH3
/
+ CH3COCOCH3 (6)
.
MeO
Until now, no research has been reported on truly catalytic trifluoroacetylation. We report here the first results on the CoG12 catalyzed trifluoroacetylation of anisole and other mono - and dimethoxyaromatics using TFA. We know that 1,3,5trimethoxybenzene can be trifluoroacetylated by TFA due to the production of CF3CO + according to equation (7) whereas resorcinol (1,3-dimethoxybenzene) is inert (refs. 8,32).
(CF3CO)20
-..
---
CF3C O + , CF3CO2-
(7)
RESULTS Anisole reacts at room temperature with TFA in the presence of CoC12 as the catalyst. For instance, in the presence of five equivalents of TFA for one equivalent of anisole in the presence of 10 % CoC12, we have obtained 34 % of p-trifluoroacetylanisole and 54 % of dimerization in para position. The dimerization of anisole reported to occur in the course of the acetylation reaction is referred to the ortho structure, which we have not found. The difference in structure (para versus ortho) can be due either to a mechanistic difference or to an erroneous attribution. The variation in the proportions of anisole and TFA in the reaction medium has a dramatic influence on the competition between the trifluoroacetylation and dimerization pathways. For instance, the reaction between one equivalent of anisole and one equivalent of TFA at 100~
regiospecifically leads to the para-dimerization
of anisole with a 96 % yield (eqn. 8).
41
CH30-~
+ (CF3CO)20 1 eq.
1 eq.
COC12 10 %.._ C H 3 0 ~ ~ ~ / ~ _ O C H 3 100~ 15 h. 96 %
(8)
Thus, it appears that a large excess of TFA should lead to the exclusive formation of p-trifluoroacetophenone. Indeed, a 80-fold excess of TFA (as solvent) leads to a 25 % yield of trifluoroacetophenone after one month at room temperature without formation of the dimer (the only other product being anisole). Under the same conditions, at 100~ in 15 days, the yield of p.trifluoroacetophenone is 96 % (eqn. 9). OCH3 ~
OCH3 + (CF3CO)20 excess
C~ 10% 100~ 15 d.
~
+ CF3CO2H COCF3 96 %
(9)
This reaction is totally inhibited by ligands such as CH3CN or PPh 3, a strong indication for the coordination of the reactants to cobalt, thus for an inner-sphere mechanism. When the reaction is carried out at 150~ an insoluble black tar is formed. In p.methylanisole, the para position at which trifluoroacetylation occurs in anisole is now blocked by the methyl substiment. With 5 equivalents of TFA, we have obtained the product resulting from the exclusive regiospecific trifluoroacetylation in ortho position with respect to the methoxy group without formation of a dimer (eqn. 10). The yield is lower than in the case of anisole, however, if the reaction time is only 15 h. at 100~ and unreacted p.methylanisole can be recovered.
42
( CH3
OCH3 + (CF3CO)20 C~ 10 % IO0~ 15 h.
COCF3
CH3 1 eq.
+ CF3CO2H
CH3 5 eq.
40 %
(10)
Since no dimer was formed in this case, we re-investigated the acetylation reported in the literature to give the ortho-ortho dimer (ref. 31). The only compound found under the conditions mentioned in the literature (ref. 31) is the one resulting from o-acetylation along with the starting material, but the ortho-ortho dimer was again not observed. We have carried out reactions with other substrates, in particular 13-methoxynaphthalene. The reaction is remarkably facile and leads to 1-trifluoroacetyl 2-methoxynaphthalene as the only reaction product, in 68 % yield (eqn. 11). In this case, the most reactive position is position 1 (the position para with respect to the methoxy group is now blocked). Reactivity in position 6 has been observed in a limited number of cases, for the acetylation, especially when zeolites are used (ref. 33).
COCF3 ~ O C H 3 +
1 eq.
(CF3CO)20
COC12 10 % 100~ 15 h.'-
1 eq.
~ O C H 3 ~
+ CF3CO2H
68 %
(11)
Finally, we have investigated the CoC12 catalyzed trifluoacetylation using TFA for dimethoxyaromatics : veratrole (ortho-dimethoxybenzene) and meta-dimethoxybenzene. Veratrole did not react despite several attempts (eqn. 12) and metadimethoxybenzene is the subject of trifluoroacetylation in the position ortho/para (eqn. 13).
43
~
OCH3 OCH3
COC12 10 % + (CF3CO)20
X
w
no reaction
(12)
100~
veratrole 1 eq.
5 eq.
OCH3
(~CH3 CoC12 10 % + (CF3CO)20 OCH3
~ 100~
+ CF3COzH OCH3
15 h.
COCF3 1 eq.
5 eq.
87 %
(13)
In spite of the activation in para positions by the methoxy group in veratrole, such positions are not sufficiently reactive although there is no steric effect. Under the
same
reaction
conditions,
ferrocene
is oxidized to
ferricinium
but
no
trifluoroacetylation product is found. Durene does not react (eqns. 14 and 15). Since COC12 is not an oxidant, this confirms the intermediate formation of oxidizing Co nI species by reaction between COC12 and TFA.
~
CH3 CH3
CoC12 10 % + (CF3CO)20
CH3
/N/ N
"-
IO0~
CH3 1 eq.
5 eq.
44
no reaction
(14)
+
Fe
CoCle 10 % ~-100~
+ (CF3CO)20
1 eq.
2 eq.
~ Fe
X-
(15)
(X- = C1- or OAc-)
MECHANISM It appears that a methoxy substituent on the aromatic ring is necessary to make the CoC12 catalyzed trifluoroacetylation by TFA work. The lack of reactivity of veratrole is not clear but it is possible that the purple Co II (veratrole) "+ complex which forms is too stable to react because of its chelate structure. Indeed, the para position with respect to the first methoxy group should be even more reactive in veratrole as compared to anisole. An essential mechanistic feature is the inhibition of the reaction by coordinating solvents such as acetonitrile or by other ligands such as triphenylphosphine. This inhibition by ligands indicates that coordination of the substrates is a key step in this process. The formation of dimers and ferricinium indicates that Co IH species are formed (eqns. 16-19). > [CoIIIc12(CF3CO)] + [(CoIIIc12(CF3CO2)]
2 [COIIC12] + (CF3C0)20
(16)
It is also clear that these Co nI species can either oxidize the aromatic or react by electrophilic attack (refs. 34,35). The aromatic dimer is formed as a result of this monoelectronic oxidation : [CoIIIc12(O2CCF3)] + PhOCH 3 PhOCH3~
+ PhOCH 3
> [COIIC12] + (PhOCH3) "+, CH3CO 2-
> dimer H + H +
dimer H + [CoIII(o2CCF3)]----~ dimer + CFaCO2H + Con
45
(17) (18) (19)
The real mechanistic alternative is indeed whether the C-C bond is formed by a classic electrophilic attack (eqn. 20) or by the interaction of [ColII(c1)2(COCH3)] with the radical cation of the aromatic (eqn. 21). PhOMe + [ComC12(COCF3)] PhOMe"+ + [CoIIIc12(COCF3)]
> p-CF3COPhOCH3 + [CoIII(c1)] q-HC1
(20)
> p-CF3CPhOCH3 + [ColICI2] -k- H +
(21)
The latter possibility has been suggested by Iqbal in the case of the Co II catalyzed
acetylation
of
anisole
by acetylchloride
(ref.
31).
However,
no
experimemal support of the mechanism has been provided so far. Oxidation and electrophilic attack can be competitive pathways or oxidation can be a common pathway for both dimerization and trifluoroacetylation.
CONCLUSION We have reported here the catalyzed trifluoroacetylation of methoxyaromatics by TFA for the first time. No solvent is used in the reaction (coordinating solvents inhibit the reaction). In the case of anisole, variations of the experimental conditions allow to selectively lead to either paradimerization or trifluoroacetylation. Given the inconvenience of the production of large quantities of aluminium waste in the A1C13 induced process and the delicate handling of trifluoroacetic chloride due to its boiling point o f - 27~
the finding reported here should prove very practical for
the trifluoroacetylation of methoxyaromatics on the industrial scale.
References .
2. 3. 4 5 6 7 8 9 10. 11. 12.
J.H. Simons, E.O. Ramler, J. Am. Chem. Soc., 65,389, (1943) J.H. Simons, W.T. Black, R.F. Clark, J. Am. Chem. Soc., 75, 5621, (1953) D.D. Tanner, A. Kharrat, J. Am. Chem. Soc., 110, 2968, (1988) P.J. Wagner, M.J. Thomas, E. Puchalski, J. Am. Chem. Soc., 108, 7739, (1986) O. Ichitani, S. Yanagida, S. Takamuku, C.J. Pac J. Org. Chem., 52, 2790, (1987) A.G. Anderson, R.J. Anderson, J. Org. Chem., 27, 3578, (1962) W.H. Pirkle, D.L. Sikkenga, M.S. Pavlin, J. Org. Chem., 42,384, (1977) R.K. Mackie, S. Mhatre, J.M. Tedder, J. Fluorine Chem., 10, 437, (1977) S. Clementi, F. Genel, G. Marino, J. Chem. Soc. Chem. Commun., 498, (1967) V.G. Gluckhovtsev, Y.V. II'In, A.V. Ignatenko, L.Y. Brezhnev, Isz. Akad. Nauk., SSSR, Ser. Khim. (Engl. Transl.), 2631, (1988) W.D. Cooper, J. Org. Chem. 23, 1382, (1958) M. Hojo, R. Masuda, E. Okada, Tet. Lett. 28, 6199, (1987) 46
13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35.
T.R. Forbus, J.C. Martin, J. Org. Chem. 44, 313, (1979) R. Stewart, K.C. Teo, Can. J. Chem. 58, 2491, (1980) P.J. Wagner, R.J. Truman, A.E. Puchalski, R. Wake, J. Am. Chem. Soc., 108, 7727, (1986) X. Creary, J. Org. Chem., 52, 5026, (1987) G. Friour, G. Cahiez, J.F. Normant, Synthesis, 37, (1984) S. Sibille, V. Ratovelomanana, J. P6richon, J. Chem. Soc. Chem. Commun., 283, (1992) D. Naumann, M. Finke, H. Lange, W. Dukat, W. Tyrra, J. Fluorine Chem., 56, 215, (1992) X. Creary, J. Org. Chem., 52, 5026, (1987) T. Keumi, M. Shimada, M. Takahashi, H. Kitajima, Tet. Lett. 1990, 783. M. Hiro, K. Arata Chem. Lett., 325, (1978) K. Nomita, Y. Sugaya, S. Sasa, M. Miwa, Bull. Soc. Chim. Japn., 53, (1981) T. Yamaguchi, A. Mitoh, K. Tanabe, Chem. Lett., 1229, (1982) F. Effenberger, G. Epple, Angew. Chem. Int. Ed. Engl., 11,300, (1972) F. Effenberger, F. Steegmiller, Chem. Ber., 121, 117, (1988) T. Mukaiyama, H. Nagaoka, M. Ohshima, M. Murakani, Chem. Lett. 165, (1988) T. Mukaiyama, T. Ohno, T. Nishimura, S.J. Han, S. Kobayashi, Chem. Lett., 1059, (1991) T. Mukaiyama, K. Suzuki, S.J. Han, S. Kobayashi, Chem. Lett., 435, (1992) A. Kawada, S. Mitamura, S. Kobayashi, Synlett, 545, (1994) J. Iqbal, M.A. Khan, N.K. Nayyar, Tet. Lett., 5179, (1991) J.-P. Begu6, D. Bonnet-Delpon, Tetrahedron Report N ~ 290, Tetrahedron, 47, 3207, (1991) G. Harvey, G. M/ider, Collect. Czech. Chem. Commun., 57,862, (1992) J.K. Kochi in "Metal-Catalyzed Oxidation of Organic Compounds" Academic Press, New York, pp. 120-133, (1981) D. Astruc in "Electron Transfer and Radical Processes in Transition-Metal Chemistry" VCH, Chapter 7, New York, (1995)
47
CATALYSIS BY RARE EARTH PHOSPHATE II 9 SELECTIVE O - M E T H Y L A T I O N OF PHENOLS BY M E T H A N O L IN VAPOR PHASE
LAURENT GILBERT a) MARCELLE JANIN a) ANNE-MARIE LE GOVIC b) PASCALE POMMIER b) AND ALAIN AUBRY b) a) Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie, 85 Avenue des Fr~res Perret, B.P. 62, 69192 Saint-Fons, France b) Rh6ne-Poulenc Recherches, Centre de Recherches d'Aubervilliers, 52 rue de la Haie Coq, 93308 Aubervilliers Cedex, France
ABSTRACT Vapor phase catalytic alkylation of phenols with methanol was carried out on various phosphates as catalysts. The best activity and selectivity was observed on boron, rare-earth and niobium phosphate. With boron phosphate, the reaction is very selective for O-alkylation even at high temperature. On this catalyst omethoxy-phenol is selectively obtained from 1-2-dihydroxybenzene. With rareearth phosphate calcinated at 400~ and with niobium phosphate, O-alkylation selectivity decreases with an increase of reaction temperature. For rare-earth phosphates it is possible to improve the selectivity by calcination at higher temperature or by a wetness impregnation of cesium hydrogenophosphate. An explanation of these results is proposed.
INTRODUCTION Alkylaryl ethers have distinctive, pleasant odors flavors which make then valuable for the perfume and flavor industries. They are also valuable intermediates for agrochemicals, pharmaceuticals, food preservatives and antioxidants (ref. 1). Among those products, 2-methoxyphenol 1 (guaiacol) is especially interesting as it is used as intermediate for the synthesis of important food additives like vanilline.
48
The most versatile method of preparation is the williamson ether synthesis (ref. 2) particularly by reaction of sodium phenate with halogen derivatives of hydrocarbons. To obtain a higher reactivity, this reactant can be substituted by a dialkyl sulfate or dialkylcarbonate but those alkylating agents scarcely contribute to a more economic process. The preparation of methylarylether by reaction between phenols and methanol was the object of many studies as such a process present main advantages on an economic point of view due to the lower cost of methanol compare to methylchloride and an environmental advantage due to the limitation, and even the total removal of saline effluents. However, to be an attractive one, such a process needs to be highly selective in O-alkylated products with a strict limitation of Calkylated by-products. Numerous studies concerning O-alkylation of phenol were reported (refs. 3-9). Described catalysts belong to all the catalyst families 9oxides (ref. 3) ; phosphates (refs. 4, 5) ; metallosilicates (ref. 6) ; aluminophosphates (ref. 7) ; ion exchange resin (ref. 8). On the other hand, the selective mono-O-alkylation of diphenols was little reported and mainly in patent literature (ref. 9). The main studies deal with synthesis of guaiacol by methylation of 1-2-dihydroxybenzene 2 (catechol) (eqn. 1) catalyzed by boronphosphate eventually doped or supported (ref. 9). The main difficulties of this reaction consists in physical instability of the catalyst which is eluted in the reaction stream conducting to the formation of methylborate as a byproduct which has to be separated. It is then needed to add some new catalyst continuously. We have studied the O-alkylation of catechol in guaiacol by solid-gas catalysis. In this reaction, 1,2-dimethoxybenzene 3 (veratrole) can be produced as a coproduct and also some C-alkylated derivatives as by-products. We have chosen to mainly study phosphates derivatives and to realize a large screening of catalysts. In the preoccupation to screen all the periodic classification of the elements, we have tested numerous metallic phosphates that we have arbitrarily classified as a function of the cation valence. As far as it was possible, we have limited the synthetic routes of catalysts to one or two to be able to compare their intrinsic activity.
~~]
OCH 3
OH
.,~ OH
catalyst +
+
CH3OH vapor phase
2
1
49
H20
(1)
EXPERIMENTAL Catalysts preparation : the various metallic phosphates were prepared by wet synthesis except for niobium oxide phosphate which was obtained from CBmm. According to the solubility of the metallic precursor, two synthetic routes were used: - precipitation (for a totally soluble precursor) - dissolution, reprecipitation (for a less soluble precursor) For precipitation, the synthetic process consists of addition of orthophosphate anions to an aqueous solution of the metallic salt. The precipitated metallic orthophosphate was then recovered by filtration, then washed, dried at l l0~ and then calcinated at various temperature. By this method CaHPO4, FePO4, Ce(HPO4)2, Zr(HPO4)2 were obtained. The dissolution, reprecipitation process consists of preparing a metallic salt suspension of known solubility and in adding to it an aqueous orthophosphate anion solution in order to displace the following equilibrium: M x Ly
+
z Hz-n PO4 n+
-"
"-
Mx H(z-n)PO4
+
Y L t-
with nz = ty
n from 1 to 3 L = CO32-, OH-, C204 z-
The metallic orthophosphate is then recovered using the same workup as reported for the precipitation method. Phosphates of rare earth metals were prepared by this method using rare earth carbonates as precursors, boron phosphate starting from orthoboric acid, and yttrium phosphate from yttrium oxyde. Cesium phosphate synthesis is a little special due to its high solubility in water and cesium phosphate crystals were obtained by water evaporation from an aqueous solution of cesium hydrogenophosphate resulting from the neutralization of an aqueous solution of cesium hydroxyde by phosphoric acid. Crystalline structure (DRX) and specific surface area (BET method) were systematically determined on the dried and calcinated catalysts at 400~ Rare earth phosphates were more precisely characterized and the results are reported in the following paper (ref. I0). Catalytic tests 9The reactions were performed in a vapor phase tubular quartz reactor packed with the catalyst (stationary bed) and heated in a shell oven under nitrogen at the test temperature. During the catalyst's reactions screening were performed between 250 and 390~ using 2.5 ml of catalyst. After thermal 50
equilibria has been reached, nitrogen was introduced via volumetric flow meter (1 l/h). A catechol solution (2.25 mmol/g) in methanol (molar ratio CH3OH / C 6 H 6 0 2 = 10) was introduced with the aid of a syringe at a flow of about 5.5 g per hour. The reaction products were collected and were analysed by liquid chromatography.
RESULTS AND DISCUSSION Catalytic activity of metallic phosphate
Table 1 summarize the catalytic performances of metallic orthophosphates at 270~ The main following conclusions can be then extracted : - calcium phosphate has no activity
- generally the other metallic phosphate are selective for the O-alkylated products. Cesium hydrogenophosphate presents the lowest selectivity but as for zirconium and cerium IV hydrogenophosphate the measurement of selectivity is rather imprecised due to a low activity. Moreover with cesium hydrogenophosphate another difficulty is linked to its high physical instability and so a rapid decrease of the conversion, - in those conditions cerium III and samarium phosphate are the only catalysts giving a significant (# 5 %) yield of veratrole, - the best activities are obtained for boron, rare earth (lanthanum, samarium, cerium) phosphates and niobiumoxyphosphate. All those conclusions are simplified in Figure 1 which show that in terms of productivity, trivalent and pentavalem metallic phosphates are the most active catalysts for this reaction. On the other hand, if we reported the activity as a function of specific surface area (Figure 2) we observed a very high activity of cesium hydrogenophosphate, all the other active catalysts showing a comparable activity.
Table 1. Activity of metallic phosphates
Phosphate
S BET(m2/g)
Cs2HPO4 <0,5 (400~ CaHPO4
WHSV (hl)
RX
2,1
Cs4P207
Conversion Selectivity
(%) 11
53
12
(dry)
21
(400~
Ca2P207
137
(400~
quadratic
2,3
20
100
LaPO4
100
(dry)
hexagonal
1,7
60
98
92
(400~
CePO4
123
(dry)
hexagonal
1,7
60
92
112
(400~
124
(dry)
hexagonal
1,8
72
96
107
(400~
YPO4 i
SmPO 4 !
BPO4
cubic
Selectivity
guaiacol (%) veratrole (%) 0
2,6
16
(400~
quadratic
2,9
37
99
34
(dry)
monoclinical
3,6
11
85
i
31,,
(400~
Ce(HPO4)2i
22
(dry)
Ce(HPO4)2
3,5
13
(400~
CeP207
5
(400~
monoclinical
2,8
7
61
0
121
(400~
amorphous
3,3
62
99
0
!
FePO4
Zr(HPO4)2 NbOPO4
!
Fig. 1. Influence of phosphate nature on yield in guaiacol
52
100
Fig. 2. Catalytic activity at 270~ per unit surface
Influence of the reaction temperature on selectivity in O-alkylated products The influence of temperature on the selectivity was examined systematically. This study had not drown an interesting catalytic activity for catalyst which are weakly active at 270~ but had shown some important variation in selectivity for the more active catalysts : boron, lanthanum, cerium III, samarium phosphate and niobium oxyphosphate. Catalytic results for those catalysts as a function of the temperature are reported in Table 2 and selectivity in O-alkylated products is simplified on Figure 3. For BPO4 (Table 2, entry 1) an increase in the temperature leads to an increase of the activity without loss in guaiacol selectivity. This activity increase did not permit to obtain the di-O-alkylated product with a significant yield, the conversion being still limited. Those results are in good agreement with the published results (ref. 9). With rare earth phosphates (Table 2, entries 2, 3, 4) as catalysts, an increase in the reaction temperature leads to an high increase of the activity, the catechol conversion being nearly complete at 300~ Then a consistent amount of di-Oalkylated products are producted. On the other hand, selectivity in O-alkylated products drops in a significant manner on behalf of C alkylated derivatives. For NbOPO4 (Table 2, entry 5), an increase in the temperature leads to a low increase of the activity, but as for rare earth phosphate, we observed for temperature higher than 330~ an important fall down of selectivity in O-alkylation. 53
Fig. 3. Selectivity in O-alkylated products Those catalysts (REPO4, NbOPO4) are more active, productively speaking, than boron phosphate but they also favored C-alkylated products, mainly at high temperature. The influence of catalyst calcination temperature was studied in the case of samarium phosphate as those products show a thermal phase transition between 600 and 700~
(ref. 10). Catalytic results are summarized in Table 3.
Table 3. Influence of samarium phosphate calcination temperature on selectivity in Omethylation of catechol
Temp. (of)
" smPO] Calcinated at 400~ (SS = 107 rn2/g) Conversion Selectivity (%) (%) Guaiacol
Selectivity (%) Veratrole
StoP04 calcinated at 700~ (SS = 39 m2/g) Selectivity Conversion Selectivity (%) (%) (%) Veratrole Guaiacol
300
88
88
12
77
95
5
330
92
60
10
83
91
9
360
94
35
5
95
90
9
Samarium phosphate calcinated at 700~
and then of monoclinical structure,
shows a very promissing activity and selectivity in O-alkylated products even at high conversion of catechol.
54
Table 2. Catalytic results as a function of temperature
Reaction temperature
Reaction temperature
27( )~
300~
0
o~ ~,-~
~D
Entry
Phosphate nature
Reaction temperature
d = a
330~
...., 0
o ._
-~ -~
._. -9
";,~
r~ .~
0
~ ~
._>
o rn
5~
|
i
BPO4
37
99
99
58
99
99
76
98
100
60
98
98
77
98
98
82
64
64
60
92
97
79
89
100
95
24
28
72
96
99
88
88
100
92
6C
70
62
99
99
63
92
92
64
68
68
....
LaPO4 (ex carbonate)
CePO4 SmP04 (ex carbonate) NbOPO4
55
Cesium hydrogenophosphate presents a remarkable catalytic activity since its specific surface area is very low. However, this solid cannot be used as a catalyst due to its physically instability under the reaction conditions. We, therefore, focussed our attention in trying to support this catalyst, supports being chosen among the one active in the reaction : BPO4, REPO4 (RE = Sm, La) and NbOPO4. The different catalysts are prepared by wetness impregnation. Initially, we have fixed arbitrarily the cesium hydrogenophosphate content to 10 % in weight. This value is superior to the one needed to generate a monolayer and we can therefore observe, the intrinsic activity of the supported cesium hydrogenophosphate. Table 4. Catalytic activity of Cs2HPO4 impregnated metallic phosphate Entry
Catalyst
Temperature
Conversion
(~ 1
LaPO4
300 '
98
330
l'
82
.....
64
360
i
88
57
0 '
0 0
300
52
98
0
(Cs 10 % p/p)
330
86
88
10
360
97
64
26 12
S m P O 4,
4
Cs2HPO4
(Cs 10 % p/p)
5
77
Selectivity Veratrole (%)
LaPO4, CszHPO4
SmPO
4
Selectivity Guaiacol(%)
(%)
BPO4
300
88
88
330
ii
92
60
360
'
94
" '
35
10 '
5
300
71
100
0
330
90
90
10
360
98
75
24
300
58
99
0
330
76
98
2
360
83
96
3
BPO4, Cs2HPO4
300
18
100
(Cs 10 % p/p)
330
30
100
360
32
100
0
300
52
92
0
330
63
68
0 i
7
8
NbOPO4
NbOPO4,Cs2HPO
|
i
|
0
0
360
64
38
0
300
51
98
2
330
59
86
360
61
81
4
(Cs 10 % p/p)
i
56
Boron phosphate, as previously seen, effectively catalyzed the O-alkylation of catechol to guaiacol (Table 4, entry 5). At different temperature, the reaction leads selectively to guaiacol. The consecutive reaction of veratrole formation being limited even at high conversion. The impregnation of this catalyst by cesium hydrogeno-phosphate gives rise to an heterogeneous product as it was demonstrated by the RX, STEM analysis. The cesium is concentrated in amorphous zones without any interaction with the boron phosphate crystallites. The obtained catalyst presents a lower activity but still an excellent selectivity in guaiacol (Table 4, entry 6). Niobium phosphate exhibits a lower selectivity in Oalkylated products, in particular at high temperature (360~ (Table 4, entry 7). The impregnation of this catalyst by cesium hydrogenophosphate leads to an uniform cesium distribution. The activity of niobium phosphate is not greatly enhanced while the selectivity is increased (Table 4, entry 8). However, cesium hydrogenophosphate interacts mildly with niobium phosphate since it is eluted under the reaction conditions. In the case of rare earth phosphates (Table 4, entries 1-4), the impregnation by cesium hydrogeno-phosphate does not modify noticeably the activity. However the selectivity in O-alkylated products is greatly enhanced. At high conversion one can also observed the formation of veratrole in significative amount by consecutive O-alkylation of guaiacol. Those catalysts having a good activity as well as selectivity were further characterized. The results of this studies are presented in the following article (ref. 10). The influence of the cesium hydrogenophosphate content was examined in the case of lanthanum phosphate. Figure 1 presents the selectivity observed at 330~ for a 80 % conversion. 100 8O ~,
60
~
4o
~
2o 0
I
0
3
6
9
12
Content of Cs2HP4 (% p/p)
15
Fig. 1. Influence of cesium hydrogenophosphate content
5?
This curve shows that an excellent selectivity in O-alkylated products is obtained starting at about 5 % of Cs2HPO4. This value corresponds to the cesium hydrogeno-phosphate quantity which is necessary to obtain a monolayer. The increase in the cesium hydrogenophosphate content does not lead to a lower activity. The study of O-methylation of phenol as well as 1,4-dihydroxybenzene in anisole and 4-methoxyphenol respectively and the condensation of catechol with ethylene glycol demonstrates that the use of L a P O 4 , Cs2HPO4 as a catalyst is a powerfull methodology to selectively access numerous alkylarylethers. Results are presented in Table 5. Table 5. O-alkylation of phenols catalyzed by LaPO 4, Cs2HPO 4
Reaction OH
OCH3
Catalyst
Reaction conditions
Results
LaPO 4 Cs2HPO 4
MeOH/PhOH = 10
Conversion = 53 %
0 = 360~
(8 % p/p)
tc# ls. OH
OMe
LaPO 4 Cs2HPO 4 (8 % p/p)
OH
MeOH/H20/H Q = 16/7/1
Selectivity = 90 % o-cresol
10 %
Conversion = 25 % Selectivity = 94 %
0 = 330~
OH
tc# ls.
OH
HO
LaPO 4 Cs2HPO 4
Ethylene
Conversion = 100 %
(8 % p/p)
Glycol/PC = 10w1
Selectivity = 98 %
0 = 330~ tc# ls.
DISCUSSION The sum of results published in the literature on phenol alkylation using methanol are not clear and one cannot easily conclude to the relation between the acidity and the basicity of the catalyst and the selectivity in O or C alkylated products. However it seems that O-alkylation products can be obtained by the use of acidic catalysts (ref. 11). An increase of the acidity of oxide type catalysis (ref. 3) or mixed aluminium phosphate-alumina (ref. 12) gives rise to an increase of selectivity in O-alkylated products. However for strongly acidic catalysts Calkylated products, which are the more thermodynamically stable, can be obtained either by isomerization or by reaction between phenol and methylarylether. 58
On mildly acidic catalysts, C-alkylated products can also be obtained by competitive reaction on residual basic sites. This latter mechanism is generally evidenced by examining the regioselectivity of the reaction, a mechanism involving a basic site leading to the ortho isomer via a surface phenolate. When strongly basic catalysts are used, C-alkylated products are mainly formed. O and C-alkylation mechanisms necessitate the cooperation between acid and basic site in order to activate at the same time phenol and methanol. With this results in mind, we believe that it is now possible to explain the observed datas. The catalysts having shown the best activity are acidic catalysts. The niobium phosphate has a high activity (ref. 13) that may originate from the low selectivity in O-alkylated products at high reaction temperature. Rare earth phosphates calcinated at 700~ (ref. 10) and boron phosphate which have a medium acidity correlate well with a good selectivity in O-alkylation. In the case of rare earth phosphate calcinated at 400~ the decrease in selectivity while increasing the reaction temperature is due to the presence of basic sites on the catalyst. On the other hand, the good to excellent selectivity in O-alkylated products observed with cesium hydrogenophosphate alone or supported is difficult to explain. Indeed this catalyst is exclusively basic. The absence of C-alkylated products by the reaction between guaiacol and methanol tends to suggest that the guaiacolate intermediate at the surface has a different behaviour on lanthanum phosphate as well as lanthanum phosphate doped with cesium hydrogenophosphate.
59
R
OH
~
B~(~)~OCH3
OH I
~OCH3
R
o•R
H\o/CH3 [ ~ R
path A
A~
H(E) MeOI--I
H|
R
"-
R R
pathBr_
Ho
~
CH3~o/H e
!e
MeOI-I = I A ~ _ ~
@
H20
%oc.3
OCH3 H20
,
R
Scheme 1. Proposed mechanism for the basic catalysis alkylation of phenol
In addition, cesium hydrogenophosphate has an interaction with the rare earth phosphate as it was demonstrated by further characterization. The mechanism in basic catalysis goes via a phenolate anion that can be chemosorbed either by an acidic site (path A) or on a neighbouring Lewis acid site (path B). Methanol will be activated by an acid site and therefore will be able to react in O or C alkylation. The C alkylation will be favoured as the acidic site chemosorbing the phenolate will be harder. For example, the excellent selectivity in O-alkylated products observed on cesium hydrogenophosphate is due to the softness of the cesium ion,
60
(A e = Cs 9 in path B), while path A seem to be favoured (A 9 = La3e) on LaPO4 calcinated at 400~
CONCLUSION In this study, we have demonstrated that boron,
niobium and rare earth
phosphates are excellent catalysts for the selective O-alkylation of pyrocatechine in guaiacol and veratrole.
The reaction is conducted in the vapor phase using
methanol as the alkylating agent.
In the case of rare earth phosphates
the
calcination temperature has a very important effect on the selectivity of the reaction. This phenomenon,
linked to the synthetic procedure,
is due to the
residual basicity on the rare earth phosphate calcinated at 400~
Wetness
impregnation of rare earth phosphate by cesium hydrogenophosphate give rise to very active as well as selective catalysts.
References
1. Kirk Othmer Encyclopedy, 4th Edition, John Wiley, Chap. 9, p. 860, New York, (1995). 2. J. March in "Advanced organic chemistry", 4th Edition, John Wiley, pp. 386-387, (1992). 3. T. Kotanigawa, M. Yamamoto, K. Shimokawa, Y. Yoshida, Bull. Chem. Soc. Jpn. 47, 950, (1974). A.B. Mossman, US 4.611.084 (25/11/1985), (to AMOCO Corp). D. Farcassu, US 4.487.976, (30/08/1982), (to EXXON US). 4. F. Nozaki, I. Kinuira, Bull. Chem. Soc. Jpn, 50, (3), 614, (1977). 5. P. Pierantozzi, A.F. Nordguist, Appl. Catal., 2!, (2), 263, (1986). F.M. Bantista, J.M. Campelo, A. Garcia, D. Luna, J.M. Marinas, A. Romero, J.A. Navio, M. Macias, Appl. Catal. A, 99, (2), 161, (1991). M. Marczewski, G. Perot, M. Guisnet et al. (Eds), in "Studies in surface science and catalysis", p. 273, Elsevier (Science Publishers BV ?), Amsterdam, (1988). E. Fischer, O. Skiner, G. Wih, Wiss. Z. Univ. Rostock, Naturwiss, Reihe, 39, (7), 67, (1990). V. Durgakumari, S. Narayanan, L. Guczi, Catal. Letters, 5, 377, (1990). G.A. Olah, J. Kaspi, J. Org. Chem., 43, 16, (1978). Y. Shioni, Y. Nakamura, T. Manabe, S. Furusaki, M. Matsuda, M. Saito, EP 509927, (16/04/1992), (to Ube Industries). S. Furusaki, M. Matsuda, M. Saito, Y. Shiomi, (03/04/1991), (to Ube Industries). S.P. Bhatnagar, A. Prakash, S.C. Misra, M.S. Raiker, IN 158895, (18/11/1983), (to Reckitt and Colman). 10. A.M. Le Govic, A. Aubry, L. Gilbert, P. Pommier, M. Janin, following paper in this issue. 11. F.M. Bautista, J.M. Campelo, A. Garcia, D. Luna, J.M. Marinas, A. Romero, Applied Catalysis A: , 99, 161, (1993). 2. E. Santa Cesaria, D. Grasso, Applied Catalysis, 64, 83, (1990). 3. A. Florentino, P. Cartraud, M. Magnoux, M. Guisnet, Applied Catalysis, 89, 143, (1992). R.L. Martins, W.J. Schitine, F.R. Castro, Catalysis today, 5, 483, (1989). .
CATALYSIS BY RARE E A R T H P H O S P H A T E lII. C H A R A C T E R I S A T I O N OF SAMARIUM P H O S P H A T E AND SAMARIUM P H O S P H A T E - C E S I [ ~ H Y D R O G E N O P H O S P H A T E AS KEY CATALYSTS FOR O - A L K Y L A T I O N OF P H E N O L S
ANNE-MARIE LE GOVIC a~, PASCALE POMMIER a~, ALAIN LAURENT GILBERT b~AND MARCELLE JANIN b~
AUBRY a~,
a) Rh6ne-Poulenc Recherches, Centre de Recherches d'Aubervilliers, 52 rue de la Haie Coq. 93308 Aubervilliers Cedex, France b)Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie, 85 Avenue des Fr~res Perret, BP 62, 69192 Saint-Fons Cedex, France
SUMMARY Samarium phosphates, impregnated or not by cesium hydrogenophosphate, selective catalysts for O-alkylation of phenols, have been characterised by various techniques. This study has shown that : the cesium salt added by wetness impregnation (10 % w/w) has a sintering effect on its calcination. The examination of structural and textural datas shows that the cesium does not enter the crystalline network. The cesium salt is uniformly distributed on the crystalline surface and the special morphology of samarium phosphate makes the cesium retained in the porosity of the solid. - Samarium phosphate has an intrinsic acidic activity which can only be observed on products calcinated at a temperature of 700~ and which therefore possess a -
monoclinic structure. Samarium phosphate calcinated at lower temperatures, with an hexagonal structure has acido-basic characteristics highly dependant on the synthetic route use : - a totally basic activity is observed for samarium phosphate being neutralized with ammonia after precipitation.
62
products which have not been treated according to the previous step present an acidic activity -
- the addition of cesium by wetness impregnation on the dry catalyst produces a totally basic behavior.
INTRODUCTION Even if the use of rare-earth phosphates in heterogeneous catalysis for fine chemicals has been reported from more that 20 years, those catalysts were little characterized. Recently, doping those catalysts with cesium salts has greatly improved the activity, selectivity of the transformation as well as the life time of the catalysts (refs. 1,2). Particularly, a synergism between cesium hydrogenophosphate and samarium phosphate has been observed for the O-alkylation of dihydroxy-benzene (ref. 2). We described in this paper some characterizations of this solid doped or not, that may allow to explain catalytic results.
EXPERIMENTAL Samarium phosphate was prepared by wet synthesis starting from samarium carbonate (Sm2(CO3)3, originated RP). Precipitation of phosphate by phosphoric acid is conducted at 80~ by addition of a samarium carbonate suspension in a vessel containing phosphoric acid. After the end of the addition, the solid could be treated by ammonia at pH - 9. Cesium hydrogenophosphate is introduced by wetness impregnation of the dried (110~ solid. Transmission microscopy is realized using a Philips CM30 apparatus at 300 KV. DRX spectra were realized on a diffractometer Philips 1700 by scanning between 5 to 70 ~ at l~ Porous distribution is determined by mercury intrusion after elimination of gas over night at 200~ in an oven (Autopore II 9220 V3.01). Acidobasic properties characteristics of solids were estimated by studying the reactivity of 2-methyl 3-butyn-2-ol (MBOH) (ref. 3).
RESULTS AND DISCUSSION I n f l u e n c e of th e c e s i u m salt on t h e r m a l stability
We have compared the specific surface area thermal evolution of samarium phosphate just dried or samarium phosphate impregnated by cesium hydrogeno63
phosphate (10 % w/w) between 400~ and 800~ Results are reported in Figure 1 and Table 1 and show a sintering effect of the cesium salt.
Table 1. Specific surface area of SmPO4, SmPO4, Cs2HPO4 as a function of calcination temperature SmP04 (m2/g)
SmPO4, Cs2HPO 4 (m2/g)
dried
124
91
400
107
84
500
97
67
700
39
10
Temperature (~
140 ;pecific surface area 9 (m2/g) 120 100 80
--0--
60
SmP04
SmP04, Cs2HP04
I
40 20
200
,
|
.
,
,
|
300
400
500
600
700
800
Temperature (~
Fig. 1. Specific surface area of SmPO4" SmPO4, Cs2HPO 4 as a function of calcination temperature
64
~ T I V E
I~IOll
vl
+ tnil'mltofl.
I I -i
0I~4ETER
9e x t ~ m l l ~
IHii-i t-
.....
__
_..,
.
.
.
0.:'
O.l
..... iillili I1 i'~"il~ i.~ ,
-,
......
. i
l!t~'--,r ..... i ~1"t-I-i~;--!
-.' .... tbt4.-t-,~-/~if.bt-l-i-i .... ! _i /!lit 1/i!Iilili ]
9
l
i iO
,, !i
:i
roLL._!.......~--
100
~ --
.
-
I-
( licromtt~s
~ ii'i _L~_L.., O.Ol
O.
i
OIiUtr[l~
~io
•
.
i!ll ! /IIIIILL~__$___!
.4
'..
i
)
Porous repartition of SmPO4
"3
CUHUt.ATIVE IHTRU6IOH + tntJ~ltOn
vl
OIAHETEH
m ixt.r~ston
' ,.I_4~H_~L y i
, i l t I i.~. ~il]ill
ili]i
i ! t
1.,11, i I
I [tNitl! i [ i,li!!t, ,l!I tt ,~,~i[!
I !l!i]li I-! -~--~l!Ii-[~ii i iii!i!'il !, !it~i!t!i!l .
O.II
0.1
il
II
I
~
'
t0
ti
.. .tiltlii
1!1:! ~tli~li liilli
'
!t:~
ilil .
t
i!i[!li
.~!.!!!!!, ~!i!i!l i .. o. !
1
oz.uq~n~.
Fig. 3.
t
LIiLLLl~
l
l!il i !/
111,~,~ I :
Porous repartition of SmPO4, Cs 2 HPO4
65
( eicroutar~
)
0.01
,
For the same thermal treatment (fixed duration and temperature), specific surface area of SmPO4, Cs2HPO4 are systematically weaker of about 20 m2/g (or even 30 m2/g) than those of SmPO4. On an other hand, we have checked that the ammonia treatment has no effect on specific surface area. Those results have been maked up, in the case of solid calcinated at 500~ by porosity measuremem and by electronic microscopy analysis. 9 Poro$imetry
9 samples expand a porous volume of 0,69 cm3/g with a
microporous volume of 0,20 cm3/g. Introduction of cesium lower the porous volume without any change in the porous repartition (Table 2, Figs. 2 and 3).
Table 2. Porous repartition of SmPO, and SmPO4, Cs2HPO4 Porous volume Medimn pore Medium pore between 0,1 rn diameter (m) diameter (A) and 37 A
Catalyst
Total porous voltt3Ine (cm /g)
Porous volume between 30 ~,d 0,1 m (cm/g)
SmPO4
0,69
0,45
0,20
15
65
SmPO4, Cs2HPO4
0,56
0,40
0,16
12
7o
Electronic microscoov The sintering effect of the cesium salt has been made visible by transmission electronic microscopy. Comparison of electronic microscopic stereotypes of product calcinated at 500~ (6 h.) without (Fig. 4) or with Cs2HPO4 (Fig. 5) leads to the following remarks 9 SmPO4 is formed of agglomerated polydispersed small stick of size between 10 -
and 100 nm. In the case of SmPO4, the periphery of those sticks is well defined (frame -
bones). - In the case of SmPO4, Cs2HPO4, the periphery of the sticks is badly defined and they are linked by amorphous zone of molten aspect enriched in cesium, as shown on cartography analysis (Fig. 6). The STEM-EDS cartography analysis does not show if the cesium is uniformly widespread on each cristallite or if it creates a solid solution in the cristalline structure of the phosphate. It is the reason why a DRX structural analysis was realized.
66
Samarium phosphate precipitates as an hexagonal phase and shows a phase transition between 600 and 700~
to form a more closed monoclinic phase. Those
results are in good agreement with schneider's published datas (ref. 4) reviewing crystalline structure studies about rare earth orthophosphates. Rare earth orthophosphates can be subdivided into several families according to their crystalline structures and the polymorphic modification as a function of the temperature. The first family regroups light rare earth (so called ceric phosphates) including the following elements : La, Ce, Pr, Nd, Sm, Eu. Those phosphates are dimorphiques. Indeed, they precipitate at low temperature under hexagonal phase and evoluate at higher temperature to the thermodynamically stable phase, the monoclinic one, isomorphic to monasite CePO4. The phase transition temperature is accompanied by an exothermic phenomena linked to the cation ionic radius and is higher as the cation radii is lower (ref. 5). 9 DRX DRX studies of SmPO4 and SmPO4, Cs2PO4 calcinated at various temperatures (between 200 and 800~ show that cesium has no visible effect on crystalline structure of products : the crystalline phase transition (from hexagonal to monoclinic) occurs between 600 and 700~ independently on the presence of cesium (Table 3) - the mesh parameters are similar for SmPO4 and SmPO4, CszHPO4 (Table 4) DRX shows no formation of cesium pyrophosphate which is usually obtained as -
early as 300 ~ The complete analysis of the crystalline structure by DRX and EXAFS of impregnated structure shows that the cesium does not enter the crystalline network in SmPO4. The comparison of those results and the electronic microscopy analysis leads to the conclusion that the cesium is uniformly distributed on crystallite surface and that the excess of cesium is retained in the porosity of the solid, probably as amorphous cesium phosphate.
67
Fig 5. Electronic microscopy of
SmPO4,CsHPO 4 68
Fig. 6-2.
STEM - EDS cartography of Sm PO4, Cs2HPO 4 | localisation of P 69
Fig. 6-3.
STEM - EDS cartography of Sm PO4, Cs2HPO4 | localisation of Cs
ACIDO-BASIC PROPERTIES Characterization of SmPO4 We have examined the influence of surface chemistry of SmPO4 on its acidobasic properties. Characterization by reactivity of MBOH was realized for product treated at pH = 9 with an ammoniacal solution or not. The MBOH test permits to determine without any doubt the acido-basic characteristic of surface site. We have reported in Table 5, methylbutynol conversion at the 12th pulse and the acidic (A), basic activities (B) and activity due to acid base pairs (B) obtained for each samarium phosphate. The evolution of acido properties - conversion of MBOH and selectivity in the various products formed as a function of preparation methods and calcination temperatures are reported Figures 7 and 8. 9 The acidic selectivity is the sum of selectivity in 3-methyl 3-buten-l-yne (MBYNE) and in prenal which are formed on acidic sites. 9 The basic selectivity is the selectivity in acetone or acetylene which are formed on basic sites.
70
9 The acid base pairs selectivity is the sum of selectivity in 3-hydroxy 3-methyl butan-2-one,
in 3-methyl 3-buten 2-one and methylisopropylketone which are
formed supposedly to be on acid-base pairs.
Table 5. Acidobasicity of samarium phosphate determined by reaction of MBOH Calcination
Conversion of
temperature
MBOH (%)
Catalyst
A
B
AB
dried
11
94
1
5
500~
14
97
1
2
700~
30
98
1
1
dried
27
2
98
-
treated by an
500~
24
7
93
-
ammoniacal solution
700~
91
8
1
SmPO4
dried
0,7
_
_
_
Cs2HPO4 (10 % p/p) ,,
500~
0,5
SmPO4,
dried
32
100
Cs2HPO4 (10 % p/p)
500~
39
100
S m P O
S m P O
4
4
(treated by an ammoniacal solution) If we compare products calcinated at 500~
SmPO4 without treatment has a
totally acidic behaviour while the sample treated at pH = 9 as a totally basic behaviour. The basic behaviour observed for SmPO4 treated at pH = 9 indicates the presence of residual anions coming from the ammoniacal neutralization step. When calcinated at 700~
both products present comparable behaviour with an
higher acidity for the phosphate not treated. At 700~
we find the intrinsic acidic
activity of samarium phosphate. SmPO4, Cs2HPO4 was also characterized by the MBOH test. Results reported in Table 5 show that the presence of the cesium salts exalt the surface basicity. The addition of the cesium salts induces a totally basic like behaviour of this catalyst. The observed difference in activity should be interpreted with some caution due to the high basic activity of cesium oxide, the presence of which, even in small quantities, can not be excluded.
Conversion of MBOH (%)
40-, 3O
A w
--43- SmPO4 without treatment
,.,
20-
SmPO4 treated at pH = 9
100~ [ i
0
100
200
300
400
500
600
700
Calcination temperature of SmPO4 (~ A
4030 J
- - u - SmPO4 without treatment 20~, SmPO4 treated at pH = 9
L
10~ ~
,
v
0' 200
100
300
400
500
600
700
Calcination temperature of SmPO4 (~
A 9activity = mmol MBOH transformed per surface unit and per hour Fig. 7. Acido-basic properties of samarium phosphate
SmP04 Selectivity (%) 100 80
60
--{3----o- % MBYNE (Acidity) ~
I,
40
~
2o
~ 100
% Prenal (Acidity)
200
300
400
500
600
700
Calcination temperature of SmP04 (~
72
SmPO4 treated at pH = 9 Selectivity (%) 100 80 -i L
60
- - o - % Acetylene (basicity) i
40 ~
- - I - % MBYNE (acidity)
% Acetone (basicity) r
20O~ _20100
:
% Prenal (acidity)
v
200
300
400
500
600
700
Calcination temperature of SmPO 4 (~
Fig. 8. Acido-basic properties of samarium phosphate 9selectivity on each catalyst
CONCLUSION This study leads to the following conclusions. Cesium salt added by wetness impregnation (10 % w/w) has a sintering effect on the calcination of samarium phosphate. The examination of structural and textural data shows that the cesium does not enter the crystalline network. The cesium salt is uniformly distributed on crystallites surface and the special morphology of samarium phosphate makes the cesium retained in the porosity of the solid. Samarium phosphate has an intrinsic acidic activity which can only be observed on products calcinated at 700~ and therefore with a monoclinic structure. Samarium phosphates calcinated at a lower temperature, with an hexagonal structure has acido-basic characteristics highly dependant on the synthetic route used - a totally basic activity is observed for samarium phosphate being neutralized with ammoniac after preparation - products which have not been treated according to the previous step present an acidic activity the addition of cesium by wetness impregnation on the wet product gives it a -
totally basic activity.
73
References 1. P.J. Tirel, C. Doussain, L. Gilbert, M. Gubelmann, H. Pernot, J.M. Popa, Studies in surface science and catalysis, 78,693, (1983) 2. L. Gilbert, M. Janin, A.M. Le Govic, P. Pommier, A. Aubry, Preceeding paper in this issue 3. H. Lauron-Pernod, F. Luck, J.M. Popa, Applied Catalysis, 78,213, (1991) 4. L. Niinist6, M. Leskelii in "Handbook on the Physics and Chemistry of rare earth" F.A. Gschneider, J.R. Eyring, L. Eyring Eds., Vol. 9, Chapter 59, p. 91. 5. R. Kijkowna, Nieorg. Zwiazki Fosforowe, 7,239, (1976)
74
SELECTIVE FUNCTIONALISATION ORGANOSILICON INTERMEDIATES
OF
FLUOROAROMATICS
VIA
BERNARD BENNETAU a), PIERRE BABIN b) AND JACQUES DUNOGUES a) a) Laboratoire de Chimie organique et organom6tallique (URA 35 CNRS), Universit6 Bordeaux I, 351, Cours de la Lib6ration, 33405 Talence, France b) Laboratoire de Pharmacie chimique, Universit6 Bordeaux II, Place de la Victoire, 33000 Bordeaux, France
INTRODUCTION The importance of fluorinated organic compounds is demonstrated by the increase in the number of published novel compounds prepared during the last two decades. This fact reflects the interest of scientists, both academic and industrial, in utilizing fluorine to modify the physical and chemical properties of organic compounds. The introduction of fluorine increases thermal and oxidative stability, lipophilicity and also closely mimics hydrogen in particular from a sterical point of view. These properties range from the high stability of fluorinated polymers to the enhanced properties of agrochemicals and phamaceuticals. For instance, organofluorine compounds have been used as lubricants, refrigerants, fire extinguisher agents, inhalation anesthesics and surfactants. Otherwise, many fluoroaromatics find wide use in biomedical applications (ref. 1), agrochemicals and pharmaceuticals (ref. 2) because their efficacy is improved by the presence of fluorine (lower dosage, lower toxicity and increased selectivity). The regioselective functionalisation of fluoroaromatics or the selective introduction of fluorine into aromatic molecules under mild conditions are of great importance to the chemical industry and are a considerable challenge to organic chemists. So, the regio- and stereospecific requirements have created needs for developing special reagents and procedures; many strategies to introduce fluorine into a fluorinated aromatic ring or to introduce substituents into fluoroaromatics have been developed.
75
The aim of the present account is to provide comprehensive, if not exhaustive, highligths of the selective functionalisation of fluoroaromatics, and in a few cases, electrophilic fluorination of arylsilanes. E L E C T R O P H I L I C CLEAVAGE REACTIONS OF CARBON SILICON BONDS IN FLUORO-ARYLSILANES WITH OR WITHOUT FRIEDELCRAFTS CATALYSTS Eaborn et al. (ref. 3) have shown that the displacement of the trimethylsilyl moiety in aryl(trimethyl)silanes by electrophiles was analogous to that of hydrogen in electrophilic aromatic substitution :
iMe3
RO
iMe3 E+ -..
Nu"~
R
slow
~
R
0E
+ Me3Si~Nu
fast
Scheme 1.
Moreover, the efficacy of the ipso factors for a series of electrophilic desilylation processes gave rise to the expectation that aryl(trimethyl)silanes might be successfully employed for synthetic purposes; this was confirmed by many works reviewed in 1993 (ref. 4). With fluoroaromatics, the ipso effect of the trimethylsilyl group was involved for regiospecific electrophilic substitutions. For example, the increasing sophistication of nuclear medicine techniques has presented challenges to the synthetic chemist involved in the preparation of imaging agents labeled with radionuclides. In order to compare their utility as substrates for regiospecific aromatic halogenation, some para-substituted aryltrimethylsilicon,-germanium, and -tin compounds were treated with no-carrier-added (n.c.a.) 77Br and 131I (ref. 5). Results are summarized in Scheme 2 :
76
Radiochemical yield (%) F
F
MMe3
.A.
77Br
131I
Si
18
<10
Sn
81
96
Ge
51
88
X
i) "77Bror 131I" M = Si, Ge, Sn Scheme 2. It was observed that the rate of aromatic halodemetalation decreases in the sequence Sn > Ge > Si. On the other hand, only few examples of direct electrophilic fluorination of aromatics have been reported since the ability of fluorine to behave as an electrophile
is not
easily
achieved;
however,
radiofluorination
of
aromatic
compounds has been described but, in the reactions which have been reported, it is apparent that strong electron-donating groups are required on the aromatic ring when mild fluorinating reagents are used. Nevertheless, without activating groups, an alternative route to 18F-labeled radiopharmaceuticals, using 18F-labeled reagents has
been
proposed,
involving
arylsilanes
(ref. 6).
The
scope
of
this
fluorodemetalation reaction as well as the influence of the metal displaced and of aromatic substituents has been studied (ref. 7). The reaction is given and the yields mentioned in Scheme 3. Chemical yield (%) Y
Y i CF3
MMe3
18F
i) [18F]-F2 or [18F]-CH3CO2F M = Si, Ge, Sn Y = F, CF3 Scheme 3.
77
Sn
Ge
Si
74
56
30.5
35
10.5
2.5
As previously noted (ref. 5), yields are lower when arylgermanium or -silicon derivatives are used. However, for activated aromatic systems, it was pointed out that aromatic halodesilylation proceeds under convenient conditions and arylsilanes being less expensive than their germanium and tin analogues and much less toxic than the corresponding aryltins. Another example of electrophilic fluorination of fluoro(trialkyl)silanes by acid-catalyzed metal-metal exchange is given below (ref. 8): X
X
X
ArF (%) 43
CF3 SiMe3
<5
F
i) Pb(OAc)4 9BF3.Et20 9room temp. X = F, CF3 Scheme 4. More recently, the electrophilic cleavage of carbon-silicon bonds in neutral hexacoordinated silicon compounds such as diorgano(phtalocyaninato)silicons, [(Pc)Si (RX)(R2)], with N-bromosuccinimide, halogens, copper (II) halides and 3chloroperbenzoic acid was reported (ref. 9). Only one example concerns with fluorinated aromatics ( R ~ or R 2= C6H4CF3) and in this case, the yield was very low (14% at the best). In this area, an original method for the regiospecific functionalisation of fluorobenzene in ortho- or para-position has been proposed (refs. 10-13) according to Scheme 5 :
78
F
F
Me3Si~ E i v Yield
F
F
I
O
~--~
F SiMe~i
Me3Si/ "<,/ 65 %
J
MeCO PhCO
Me3Si~/SiMe3
68 52 51 32
Br I
" .~
%
64 % F
F
I
Me3Si~ Me3SiCI / Li / THF 0-5~
Yield
9 h') aromatisation 9
m')E-CI iv)KF / DMF/ H20 " v) CF3CO2H/ CC14
%
MeCO PhCO Me3SiOSO2 HzNSO2 I
Scheme 5. The silylation of the fluorobenzene can also be achieved by electrochemical reduction (ref. 14). As the ipso effect is sometimes ineffective with strong-electron donating groups, advantage of the possible electrophilic substitution of the allylsilane intermediate was taken to perform the acylation of phenols in the meta position according to Scheme 6 (refs. 15 - 17) : OMe
O i, ii
iv
iii
e3Si F
OH
O
E
E F 72 %
F Yield
i) Me3SiC1 / THF / 0-5~ 9ii) H30 + / H 2 0 iii) E-C1 9iv) CuBr2-LiBr / CH3CN, reflux
MeCO PhCO
Scheme 6.
79
60 50
(%)
Yield
MeCO PhCO
70 77
(%)
Another important way to polysubstituted aromatics and, of course, fluoroaromatics, is provided by proton abstraction from activated arenes. The organometallic intermediates are generated by hydrogen/metal exchange (ref. 17) (with common reagents such as phenyl- or butyllithium). The regiochemistry is provided by various directing metalation groups, usually heteroelements or halogens (F, CF 3 or C1). However, when electrophiles are not compatible with lithium reagents or when the reaction requires higher temperatures, e. g. fluoroaromatics and weak electrophiles, this route is not possible because of the formation of benzynes. So, an attractive alternative for the functionalisation in position-2 of 1,3disubstituted benzenes involving arylsilanes has been proposed (refs. 18, 19) according to Scheme 7 :
x. Y
X
.Y
1)RLi i, ii S
~
/
l
e
3 E
X ~ , Y
X=CI'Y=F X=Y=F
Yield (%) 90 90
E+
J,.
E=~ X=CI'Y=F X=Y =F
i) n-BuLi(1.1 equiv.), THF,-75~ ii) Me3SiC1(1.1 equiv.) 94N HC1 Scheme 7.
80
MeCO 92 90
I SO3SiMe3 (%) 70 80 70 80
As a part of recent investigations in the chemistry of arylisoxazoles and arylpyrazoles, respectively used as herbicides (ref. 20) and fungicides (ref. 21), fluorinated acetophenones were prepared (ref. 22) following a similar methodology (Scheme 8) : SiMe3
COMe
i
ii Y
X = F ; Y =C1 X = F ; Y = Br
Yield (%) 83 88
Y Yield (%) 75 75
i) n-BuLi (1.1 equiv.), THF, -78~ ; Me3SiC1 (4 equiv.) ; 4N HC1 ii) AIC13,MeCOC1, 0-25~ CH2C12 Scheme 8. E L E C T R O P H I L I C CLEAVAGE REACTIONS OF CARBON SILICON BONDS IN FLUOROARYLSILANES W I T H N U C L E O P H I L I C CATALYSTS Reports in the literature on reactions of aldehydes with trimethylsilyl(pentachloro)- ou trimethylsilyl(pentafluoro)benzenes (ref. 23) under thermal conditions (the cleavage of the Ar-Si bond being be rate-determining step) have led to the assumption (ref. 24) that a mechanism different from that formulated by Eaborn (ref. 3) might be operative in these cases. However, 2nitrophenyl(trimethyl)silane, as phenyltrimethylsilane, does not react thermally with benzaldehyde even upon heating at 100~ in DMF for three days. But, if a nucleophilic catalyst (potassium tert-butanolate, potassium- or cesium fluoride ) is added, electrophilic substitution proceeds a t - 6 0 ~ within 1 h in 92% yield (with t-BuOK). The reaction was extended to some other substituted benzenes and, among them, o-fluoro(trimethylsilyl)-benzene (ref. 25).
soe3 F
F + PhCHO
OH
i 76%
1)KOCMe3 / DMF / H20 Scheme 9.
In the presence of furan, elimination to dehydrobenzenes takes place as a competitive reaction in the base-catalyzed carbodesilylation (ref. 26). Elimination is preferred with decreasing leaving tendancy of the halides (I > Br > > C1 > F) 9 OH
_~SiMe3 CO R + R1CHO+ v "X i) KOCMe 3 / DMF / H20
i
_~/[~ph r_- R
@ + R
X = F, C1, Br, I R 1 -- H, Pr Scheme 10. Attack of the base, at the silicon atom, is postulated as the first step in the reaction sequence with subsequent dissociation of the pentacoordinated intermediate in the rate-determining step; the carbanion thus liberated would rapidly react with benzaldehyde. Because the C-Si bond is not enough polarized, activation is required by fluoride ions to form a pentacoordinated silicate which is assumed to be a soft nucleophile or generates a nucleophilic anion species (ref. 27) :
I ArmSi m I
F
OH
~ ..,,,
Ar--Si
Ar"
R--CHO
~
Ar
F
Scheme 11. It must be mentioned that the existence of the free postulated carbanion is not absolutely necessary since a concerted mechanism, without elimination of Me3SiF, leads to the same result 9
..,,|
Ar~Si
I"
+ E-Nu
~
~
Ar-E + Me3Si-N
I[
F
F (regenerated)
Scheme 12. As an example, the behaviour of benzyltrimethylsilane which adds solely in 1,2position to the chalcone (ref. 28), in the presence of fluoride ion, strongly suggests that the free carbanion is not formed. With polyhaloarylsilanes and
non-enolizable
aldehydes,
using
tris(diethylamino)sulfonium difluorotrimethylsilicate (TASF) as the catalyst, the corresponding benzhydrols are obtained (ref. 29) upon hydrolysis as shown below: OH RCHO + Me3Si-Ar
i, ii ~
R/J',.. Ar 44-89 %
i) TASF, THF - ii) HC1-MeOH
R =
Ph,
PhCH
=
CH2
9t-Bu
9
Ar = C6F5 93,5-C12-C6F3 94-H-C6F4 94-n-Bu-C6F4 Scheme 13. In the presence of a catalytic amount of potassium cyanide-18-crown-6 complex, treatment
of C6Fs-SiMe3
with enolizable
ketones,
gives
the
corresponding
trimethylsilyl enol ethers (ref. 30). The cross-coupling reaction is defined as the reaction of an organometallic compound R-M with an organic compound R'-X (wherein X is a leaving group) to give a coupled product R-R'. Although various organometallic compounds with M = Mg, B, A1, Zr, Sn, Cu, etc. have been studied extensively, a few of them fulfill all the criteria generally required. Organosilicon compounds also couple with organic halides or triflates in the presence of a fluoride ion promoter and a palladium catalyst (ref. 31). However, with aryl(trialkyl)silanes,
sometimes for electronic reasons, the
reaction does not take place. In order to reduce the electron density on the silicon atom, alkyl groups were replaced by fluorine. The fluorine effect could be explained as follows: i) the van der Waals radius of fluorine is roughly comparable to that of hydrogen and hence the fluorine-substituted silyl group is not so bulky than the trimethylsilyl one; ii) electronegativity of fluorine favours the formation of the reactive pentacoordinated silicate, enhances the Lewis acidity of the silicate and
favours also a nucleophilic assistance. The reaction is quite general (ref. 32) and so alkyl-, alkynyl-, alkenyl- and, of course, arylsilanes were used. Unsymmetrical fluorinated biaryls have been prepared by the cross-coupling reaction of aryl(alkyl)difluoro-silanes and aryl iodides (refs. 33, 34) 9
Arl-Si(R)F 2 + Ar2-I
,-,
~
i) n3-C3H3PdC1)2(5 mol % 9 KF (2 equiv.) 9D M F Here reported 9 Arl = C6Ha-CF 3 R = Me
Arl-Ar 2
Ar2 3-MeO-C6H 4 3-HOCH2-C6H 4 4-AcO-C6H 4
Yield (%) 52 67 47
Scheme 14.
As indicated with a strong electron-withdrawing group such as C F 3 , the reaction gave lower yields of products. When the coupling reaction of aryl(alkyl)difluorosilanes and aryl iodides is carried out under an atmospheric pressure of carbon monoxide, unsymmetrical fluorinated diaryl ketones were obtained (refs. 35, 36) : O
O "
o
)F2
+
CF 3
I
CF 3
i) CO (1 atm) 9nLC3H3PdC1)2(2.5 mol %) KF (1.1 equiv.)" DMI, IO0~
38 %
Scheme 15.
More recently, the scope of the reaction has been extended and further mechanistic aspects have been discussed (ref. 37). Cleavage of C-Si bonds of organosilicon compounds is continually receiving much attention in view of its versatile utility in organic synthesis. With functional silicon compounds such as fluoro-, chloro-, alkoxy-, and aminosilanes, the oxidative cleavage of C-Si bonds, giving corresponding alcohols (ref. 38) (Scheme 16), is of special interest for the 84
synthesis of natural products because of the wide presence of hydroxyl groups in these molecules : i R-SiX 3 +
H202
~
R-OH
i) 30 % H202 / KF / (KHCO3) / MeOF / THF SiX3 = SiMe2H, SiMenF3_n, SiM%CI3_., SiMen(OR)3_. Scheme 16.
Peracids and peroxides are also used as oxidizing reagents, but the most characteristic feature is that the presence of at least one heteroatom (or functional group) on silicon is essential for performing the oxidation. In this context, an attractive route to fluorinated phenols was proposed according a two-step pathway : 1) synthesis of aryl(methyldiethoxy)silanes
from
bromoarenes
tetraethoxy(dimethyl)disilane (ref. 39) as depicted (Scheme 17 and Table 1) : Br
SiMe(OEt)2
Y i) (EtO)2MeSiSiMe(OEt)2 ; Pd (Ph3)4 / A X = H, Y = F, CF 3 X=F, Y = F , OMe Scheme 17. Table 1. Silylation of Bromoarenes Bromoarenes
Arylsilanes
Yield (%)
3-CF3-C6H4OH
3-CF3-C6H4SiMe(OEt)2
80
4-CF3-C6H4OH
4-CF3-C6H4SiMe(OEt)2
70
2-F-C6H4OH
2-F-C6H4SiMe(OEt)2
80
3-F-C6H4OH
3-F-C6H4SiMe(OEt)2
80
4-F-C6H4OH
4-F-C6H4SiMe(OEt)2
61
2,4-FzC6H3OH
2,4-F2C6H3SiMe(OEt)2
65
3,5-F2C6H3OH
3,5-F2C6H3 SiMe(OEt)2
75
3-F-4-MeO-C6H3OH
3-F-4-MeO-C6H3SiMe(OEt)2
45
85
and
Fluorinated arylsilanes are conveniently prepared from fluorinated bromoarenes and disilanes in the presence of palladium catalysts (refs. 40- 42) and especially from hexamethyldisilane (refs. 40,41). 2) oxidative cleavage of the C-Si bond was achieved with hydrogen peroxide (ref. 43) as follows (Scheme 18 and Table 2) : StMe(OEt)2
OH
X
~ Y
X Y
i) 30 % H202 (2.4 equiv.) ; CzH5OH ;KF (1 equiv.) X = H, OMe, F Y = F, CF 3 Scheme 18.
Table 2 Oxidative Cleavage of Fluorinated Silylbenzenes Arylsilanes
Phenols
3-CF3-C6H4SiMe(OEt)2
3-CF3-C6H4OH
60
4-CF3-C6H4SiMe(OEt)2 2-F-C6H4SiMe(OEt)2 3-F-C6H4SiMe(OEt)2 4-F-C6H4SiMe(OEt)2
4-CF3-C6HnOH 2-F-C6H4OH 3-F-C6H4OH 4-F-C6HaOH
62 75 60 56
2,4-F2C6H3S i M e ( O E t ) 2 3,5-F2C6H3SiMe(OEt)2 3-F-4-MeO-C6H3SiMe(OEt)2
2,4-F2C6H3OH 3,5-F2C6H3OH 3-F-4-MeO-C6 H3OH
60 70 70
.
.
.
.
.
.
.
.
Yield (%)
86
Concerning the oxidation cleavage of the C-Si bond (Scheme 18), a possible mechanism was proposed (ref. 38) (Scheme 19) 9 x
x .
I .Si .........R x~ "~R'
F
H202
....... R
-..
X~Si
]
X ~ S i .... O 7 0 H !
J
[ "~R' F
.
-
.
.
.
.
x
x Zi ,/
~. ..eR
si H
H20
R--OH
i "~R' F
Scheme 19. The oxidative cleavage of the C-Si bond may be also explained (ref. 43) as below 9 ~+
x X/
x
.Si .........Ph "~Me
X--
X ~/ [ M
i<,~h F
[PhOH]
H3O+
~
x ~.-OH i6
-
_
H
F
Ph~OH
Scheme 20. When oxidation with hydrogen peroxide leads to undesired products, it is noteworthy that the bistrimethylsilylperoxide, for which a very cheap and convenient synthesis was proposed (ref. 44), may be successfully used (ref. 43). The behaviour of bis(trimethylsilyl)peroxide supports the second interpretation. Indeed, the replacement of HO-OH by Me3SiO-OSiMe 3 in the first mechanism involves, in the last step, the reaction of Me3SiOSiMe3 on the pentacoordinated silicon moiety which seems very unlikely. The present reaction offers a high synthetic utility since functional groups on the aromatic ring, sensitive to organometallic reagents, are compatible; moreover, it
87
involves a disilane, readily available, since obtained by ethoxylation of industrial disilane residue. This account, focalized on the regioselective functionalisation of fluorinated arylsilanes, illustrates the potentialities of the organosilicon chemistry in the aromatic series. Considering the results here reported, this way constitutes an attractive alternative to the other methods usually involved for the electrophilic substitution.
ACKNOWLEDGEMENTS The authors are indebted to Drs. N. Crenne and S. Ratton for their constant support and stimulating discussions and Rh6ne-Poulenc Chimie is aknowledged for his financial support.
References 1. Biomedical Aspects of Fluorine Chemistry; R. Filler, Y. Kobayashi ; Eds.; Kodansha Ltd.; Tokyo, (1982). 2. R.E. Banks, D.W.A. Sharp, J.C. Tatlow, Eds, Fluorine : The First Hundred Years ; Elsevier Sequoia : New York, (1986). 3. C. Eaborn, J. Organometal. Chem. , 100, 43 (1975). 4. B. Bennetau, J. Dunogu~s, Synlett, 175 (1993) and refs. therein. 5. S.M. Moerlein, H.H. Coenen, J. Chem. Soc. Perkin Trans. I, 1941, (1985). 6. M. Speranza, C.-Y. Shiue, A.P. Wolf, D.S. Wilbur, G.J. Angelini, Fluorine Chem., 30, 97, (1985). 7. H.H. Coenen, S.M. Moerlein, J. Fluorine. Chem., 36, 63, (1987). 8. G.V. De Meio, J.T. Pinhey, J. Chem. Soc. Chem. Commun., 1065, (1990). 9. K. Tamao, M. Akita, H. Kato, M. Kumada, J. Organometal. Chem., 341, 165, (1988). 10. B. Bennetau, M. Krempp, J. Dunogu~s, S. Ratton, Tetrahedron Lett., 31, 6179 (1990). 11. B. Bennetau, J. Dunogu6s, M. Krempp, EP 349 373, (1989), (to Rh6ne-Poulenc Chimie). 12. B. Bennetau, M. Krempp, J. Dunogu6s, S. Ratton, Tetrahedron, 46, 8131, (1990). 13. B. Bennetau, J. Dunogu6s, M. Krempp, FR 2 633 287 (1989), (to Rh6ne-Poulenc Chimie). 14. C. Biran, M. Bordeau, D. Deffieux, J. Dunogu6s, M.P. L6ger-Lambert, FR 2 681 866, (1993), (to Rh6ne-Poulenc Chimie). 15. B. Bennetau, F. Rajarison, J. Dunogu6s, P. Babin, Tetrahedron, 50, 1179, (1994). 16. B. Bennetau, P. Babin, F. Rajarison, J. Dunogu6s, FR 2 668 484, (1992), (to Rh6ne-Poulenc Chimie). 17. For a general review, see Snieckus, V. Chem. Rev., 90, 879, (1990). 18. B. Bennetau, F. Rajarison, J. Dunogu6s, P. Babin, Tetrahedron, 47, 10843, (1993). 19. B. Bennetau, P. Babin, J. Dunogu6s, EP 385 874, (1990), (to Rh6ne-Poulenc Chimie). 20. B. Bennetau, P. Cain, US 5 334 753, (1994), (to Rh6ne-Poulenc Agriculture). 21. R. Cantegril, D. Croisat, P. Desbordes, F. Guigaaes, J. Mortier, R. Peignier, J.P. Vors, WO 9 322 287, (1993), (to Rh6ne-Poulenc Agrochimie). 22. J. Moyroud, J.L. Guesnet, B. Bennetau, J. Mortier, Tetrahedron Lett., 36, 881, (1995). 23. A.F. Webb, D.S. Sethi, H. Gilman, J. Organometal. Chem., 21, 61, (1970).
88
24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44.
F. Effenberger, W. Spiegler, Angew. Chem. Int. Ed. Engl., 20, 265, (1981). F. Effenberger, W. Spiegler, Chem. Ber., 1!8, 3872, (1985). F. Effenberger, W. Daub, Chem. Ber., .124, 2113, (1991). K. Tamao, Yuki Gosei Kagaku Kyokai Shi, 48, 457, (1990) ; Chem. Abstr., 113, 114375, (1990). B. Bennetau, M. Bordeau, J. Dunogu~s, Bull. Soc. Chim. France, 11-90, (1985). M. Fujita, M. Obayashi, T. Hiyama, Tetrahedron, 44, 4135, (1988). O.A. Vyazankina, B.A. Gostevskii, N.S. Vyazankin, J. Organometal. Chem., 292, 145, (1985). A. Hallberg, C. Westerlund, Chem. Lett., 1933, (1982). Y. Hatanaka, T. Hiyama, Synlett, 845, (1991), and refs. therein. Y. Hatanaka, S. Fukushima, T. Hiyama, Chem. Lea., 1711, (1989). T. Hiyama, Y. Hatanaka, JP 03058942, (1991), (to Sagami Chemical Research Center). Y. Hatanaka, T. Hiyama, Chem. Lett., 2049, (1989). T. Hiyama, Y. Hatanaka, JP 03258744, (1991), (to Sagami Chemical Research Center). Y. Hatanaka, K.I. Goda, Y. Okahara, T. Hiyama, Tetrahedron, 50, 8301, (1994). K. Tamao, T. Hayashi, Y. Ito, ,, Frontiers of Organosilicon Chemistry ,,, Royal Society of Chemistry ; Cambridge, 197, (1991), and refs. therein. S. Cros, B. Bennetau, J. Dunogu6s, P. Babin, J. Organometal. Chem., 468, 69, (1994). P. Babin, B. Bennetau, J. Dunogu6s, FR 2 677 358, (1992), (to Rh6ne-Poulenc Chimie). P. Babin, B. Bennetau, M. Theurig, J. Dunogu/~s, J. Organometal. Chem., 446, 135, (1993). H. Matsumoto, K. Yoshihoro, S. Nagashima, H. Watanabe, Y. Nagai, J. Organometal. Chem., 128,409, (1977), and refs. therein. S. Prouilhac-Cros, P. Babin, B. Bennetau, J. Dunogu6s, Bull. Soc. Chim., 000, (1995). P. Babin, B. Bennetau, J. Dunogu6s, Synth. Commun., 22, 2849, (1992).
89
ARYLATION OF AMINES AND ALCOHOLS CATALYZED BY NICKEL, COPPER OR PALLADIUM COMPLEXES
HENRI-JEAN C R I S T A U a),, JEAN-ROGER DESMURS b) , SERGE RATTON c) SANDRINE RIGNOL a) AND MARC TAILLEFER a) a) Laboratoire de Chimie Organique E.N.S.C.M. (Unit6 de Recherche Associ6e au CNRS n ~ 458), 8 rue de l'Ecole Normale, 34053 Montpellier Cedex, France. b) Rh6ne Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie, 85 avenue des Fr6res Perret, 69192 Saint-Fons Cedex, France. c) Interm6diaires organiques, 25 quai Paul Doumer, 92408 Courbevoie Cedex, France.
ABSTRACT The arylation reaction of primary and secondary amines has been investigated using nickel or palladium complexes as catalysts, and bromo- or chloroarenes as arylating agents. Among the complexes tested, the more efficient catalyst is the bis (bipyridyl) nickel (II) bromide, bipy2NiBr 2, which affords for example high yields in the arylation of allylamine with m-bromotrifluoromethylbenzene. The reduction of the haloarene, sometimes observed with the nickel complexes, becomes predominant with palladium catalysts whatever the complex used. For the arylation of primary or secondary alcohols, the same nickel complex, bipy2NiBr2 (in presence of base, particularly KHCO3), prove to be the more active catalyst, even in regard to various usual copper catalysts. The reaction affords good yields in alkylarylethers, under relatively mild conditions. An attempted mechanism, based on a catalytic cycle with a nickel(I) active species, is formulated on account of earlier mechanistic investigations described in the literature. Lastly, an unexpected aminolysis of nitriles catalyzed by the nickel (II) bromide, which affords an interesting new way to amides, is described.
90
INTRODUCTION The arylation of nucleophiles or electrophiles is particularly importam in the field of industrial synthesis (ref. 1). However, to meet the actual needs for sophisticated aromatic compounds, these classical reactions present numerous limitations. So for example, in the arylation of nucleophiles (ref. 2) : on the one hand the scope of substrates obtainable by the direct SNAr mechanism is restricted by the necessary presence of electron withdrawing groups on the starting aryl halide, on the other hand, the arylation of strongly basic nucleophiles through the "aryne mechanism", although applying to non activated haloarenes, suffers most often from the lack of regioselectivity associated to the possibility of cine substitution. In absence of activating substituents or even more in the presence of electrondonating groups, a catalysis with transition metal complexes, mainly with the copper complexes is used (ref. 1) : for example in the Ullmarm diaryl ether synthesis by arylation of aroxide nucleophiles, in the Goldberg synthesis of Narylamides or imides, or further in the Hurtley arylation of enolates... However, the presence of secondary reactions such as the reduction of the haloarenes, and the sometimes drastic reaction conditions can restrict the industrial applications of the copper catalysis. At the moment, works are still in progress to make the copper systems more efficiem (ref. 1). But promising solutions to the arylation of nucleophiles by non-activated haloarenes can also be found using other catalytic systems, for example complexes of palladium or nickel. Examples are already known mainly in the arylation of soft nucleophiles such as thiolates or selenolates (refs. 3, 4, 5), but their generalization to the more difficult cases of chlorinated arylating agents and/or hard nucleophiles was scarcely investigated. The present work situated in this general context, deals with the arylations catalyzed by nickel or palladium complexes, of hard oxygen or nitrogen nucleophiles, using bromo-or chloroarenes (eqn. 1). If necessary, the comparison with the copper systems was also undertaken (ref. 6). cat. [Pd], [Cu] or [Ni] Ar~X
+
H--Nu
~ - HX
X - Br, C1 Nu = NRR', OR"
Ar--Nu
(1)
RESULTS AND DISCUSSION Arylation of amines As previously pointed out, till now few works have been done in the field of arylation using nickel or palladium systems (refs. 5, 7). Only one detailed study (ref. 7) concerns the arylation of amines by haloarenes using nickel (0) or nickel (II) complexes as catalysts : with bromobenzene, ammonia does not react and usually the arylation yields (indeed the GC-conversion rates of a tenfold excess of amine into arylamine) are rather low (12-38 %), even if the best results mentionned for dimethylamine and piperidine reach 57-85 % yield. In the same way, except in isolated cases (ref. 8), palladium does not seem to have been used for the arylation of this type of hard nucleophiles. The arylating agents chosen to realize our investigations are halo (trifluoromethyl)-benzene, the aminolyse of which presenting an industrial interest. Nickel-Catalysis A preliminary comparison of various nickel compounds as catalysts was made, in the same operating conditions (18h, 160~ in monoglyme), for the arylation of allylamine by m-trifluoromethylbromobenzene (eqn. 2) (Table 1). [Ni] cat
F3C
+ H2N--CH2--CH=CH2 -
\
_ ~ ~ F3C monoglyme 18 h / 1 6 0 ~
Br
+ HBr
(2)
NH--CH2~CH=CH2
Table 1. Arylation of allylamine by m-trifluoromethylbromobenzene, catalyzed by nickelcomplexes (eqn.2). Entry
[Ni] a)
Cat. b)(%)
Yield c) (%)
1
Ni(PPh3)4 bipy2NiBr2 NiC12 NiBr2 pheneNiBr2
5 5 5 10 10
5 50 20 22 30
2 3 4 5 a)
Nickel complex : "bipy" and "phen" mean respectively 1,10-phenanthroline. b) Catalyst molecular ratio to the starting aryl halide. c) G.C. yield (formation rate) in m-F3C-C6H4-NHCH2-CH=CH2. 92
2,2'-bipyridine
and
In the presence of a nickel (0) complex such as Ni(PPh3)4 the arylation of allylamine occurs in a very low yield (5 %). With nickel (II) salts or complexes, the yields are higher and the best results are obtained for bipyzNiBr 2 (50%) or to a less extent for phen2NiBr e (30%). It is noteworthy that Cramer and coll. (ref. 7) pointed out, on the contrary, that "diamines which coordinate strongly to nickel (II) interfered in the reaction of dimethylamine with chlorobenzene and reduced by a factor of ten (ethylenediamine) or even inhibit (o-phenamroline) the arylation". According to the first results, the reactivity of some primary or secondary amines towards m-bromo or p-chlorotrifluoromethylbenzene has then been tested in presence of bipy2NiBr2, used in catalytic amount (eqn. 3) (Table 2).
_•
F3C
+ H--NRR' X
bipy2NiBr2 (5 % molar) ~monoglyme
F3C---~(..) ) + H--X (3) \ - / "NRR'
X = m-Br, p-C1 Table 2. Arylation of amines catalyzed by bipy2NiBr2 (eqn. 3) ~) emry
7
ArX Conv. b) (%)
H-NRR'
m-F3C-C6H4Br 95
- ~ ~
T (~ Time (h) 160~ 18h
9
p-F3C-C6H4C1 85
10
p-F3C-C6H4C1 37
H2N-CH2Ph
95
m-F3C-C6H4NHCHzCH= CH2
75
160 ~ 48h
m-F3C-C6H4NH-CH2Ph
46
200~ 18h
p_F3C__C6H4__N/---~
H2N-CHzPh
N ~
m-F3C--C6H4I N / - - ~
Yield (%)
160~ 48h
m-F3C-C6H4Br H2N-CH2CH =CH2 75 m-F3C-C6H4Br 75
Product
200~ 18h
77
c)
a) Operating conditions 9ArX (2 mmol), catalyst (0.1 mmol), amine (20 mmol). b) Conversion rate of aryl halide. c) Formation of the reduction product F3C-C6H5 9yield 16%. In the operating conditions used, the piperidine and allylamine are arylated in high yields (respectively 95 % and 75 %) by m-trifluoromethylbromobenzene with a complete selectivity (entries 6 and 7). 93
To the best of our knowledge, it is the first example of the direct arylation of allylamine catalyzed by a nickel complex (ref. 9). For benzylamine (entry 8) the arylation reaction with m-trifluoromethylbenzene remains the main process (yield 46 %). The only other fluorinated product observed, but the starting compound, is the trifluoromethylbenzene (29 %). In a parallel way, the arylation reaction is apparently accompanied by a partial amine dehydrogenation into the corresponding imine 1, whose formation could explain the presence of N-benzylidene benzylamine 2, and dibenzylamine 3, this last one being detected in small amount. These results are described in the Scheme 1 in which the nickel complex could act as a catalyst for the (de)-hydrogenation processes (refs. 10, 11).
PhCH2NH2
[Ni]
PhCH2NH2
~ H2 + [PhCH=NH] !
PhCH2NHCH2Ph ~ 3_
H2 /[Nil']
PhCH=N--CH2Ph 2_
- NH3
1 [P:::NHCH2Phl
Scheme 1. Amine dehydrogenation catalyzed by nickel complexes. Good results are also obtained from the chlorinated arylating agent on account of its lower reactivity (the reaction takes place at 200~ instead of 160~ for the bromoarene). So the arylation of piperidine by p-chlorotrifluoromethylbenzene occurs in 77 % yield with a 90 % selectivity (entry 9). This result is somewhat surprising taking into consideration Cramer's work (ref. 7), who noticed that the arylation reaction of p-chlorotrifluoromethylbenzene by a secondary amine such as dimethylamine, in presence of NiC12 as catalyst, did not occur. The piperidine is also a secondary amine, therefore, it appears that the complex bipy2NiBr 2, likely owing to the presence of o-donor n-acceptor ligands, has a better efficiency than NiC12 in such reactions. However, still with p-chlorotrifluoromethylbenzene and the same nickel catalyst, benzylamine gives only the reduction product (entry 10) 9 in the competition between arylation and (de)-hydrogenation process, the last one overbalance owing to the less efficient arylating agent. The reduction of the aromatic substrates, sometimes observed with the nickel complex bipy2NiBr2, becomes predominant in presence of palladium catalysts even for the good arylating agents as shown in the following paragraph. 94
Palladium-Catalysis The reactivity of various primary or secondary amines with p-chloro or mbromo-trifluoromethylbenzene has been investigated in the presence of various Pd(0) or Pd(II) complexes (Scheme 2) (Table 3). The conversion of trifluoromethylphenyl halide _44 is almost quantitative (90100 %), in heterogeneous (Pd/C), as well as in homogeneous conditions [ ( P h 3 ) n P d , bipyPdCl2, (Ph3P)zPdC12] (Scheme 2). However, the product of the nucleophilic arylation is formed only in very low yield, in both palladium(0) and palladium(II) catalysis. On the other hand, whatever the complex used, the formation of the reduction product, the trifluoromethylbenzene, is important, even with apparently a moderate yield (which can be explained by a partial loss of trifluoromethylbenzene, a highly volatile product " Any other aromatic product apart 6 and 7 cannot be detected in the reaction mixture). / CH2R' F3C _ @ X F3C 2 mmol
CH2R' / + H--N \R 20 mmol
R
[Pd] cat. 5 %
6 (< 10 %)
monoglyme 180~
919 h
/--'---x
F3C__~~~
+
\~J/ _4a "p-Cl 4 b 9m-Br
+ HX
~--N=CH--R']
5 7_ (30-70 %)
8
[Pd] cat. 9Pd/C, (Ph3P)4Pd, bipyPdCl2, (Ph3P)2PdC12
H--N
/ \
H--
H--
Ph
H2N.-"'N~
R 5
5a
5b
5c
Scheme 2. Arylation of amines catalyzed by palladium complexes
The mechanism which can be proposed for the observed reduction is similar to the one indicated for the reduction of a haloarene by an alcohol, catalyzed by the palladium (ref. 12). In the case of a palladium(0) catalysis, the different steps of this mechanism are shown in the following Scheme 3, involving in particular the dehydrogenation of the amine [the same reactions performed without any amine leads to exclusive formation of the reduction product _7 in a very low yield ( < 5 %).
95
7
~
Pd(O) ~ ~
-
.~---- Ar--X
(a)~,,X ~
(a) Ar~Pd--H
4_
Ar~Pd--H
R
I
( -~
I
I 8
H--N--CH2R" 5_
(d) H--X H
Ar~Pd--N(CH2R')R
I N--R Ar~Pd ..~- II CH--R"
(e)~
Scheme 3. Attempted mechanism for the reduction of haloarenes (for clarity, those ligands attached to palladium which do not participate in the reaction are not indicated). The mechanism would proceed through an oxidative addition of the haloarene on a palladium(0) moiety (step a). The palladium(II) species formed in this way reacts with an amine equivalent to lead to an aminopalladiated entity (step b). This last one, after 13 elimination (step c) (ref. 13) and dissociation of an imine (step d) (ref. 14), leads by reductive elimination (step e) to the in situ reduced aromatic product with regeneration of the catalytically active species (Scheme 3). In the case of a palladium(II) catalysis, the same mechanisms can be considered, because a lot of Pd(II) complexes, such as (Ph3P)2PdC12 or PdCI2 are reduced in situ into palladium(O) under similar experimental conditions (ref. 14). In order to avoid the concurrent dehydrogenation of amines into intermediate imines, the starting amines have been chosen without mobile hydrogen a to nitrogen (t-butylamine and aniline). Under similar conditions, even in presence of m-bromotrifluoromethylbenzene _4 b, and at high temperature (200~ no reaction occurs, whatever the complex used, [(Ph3P)4Pd or (Ph3P)2PdC12]. Similarly, ammonia is not arylated by p-bromotrifluoromethylbenzene.
96
Arylation of alcools To improve the results of the amines arylation, several experiments were carried out on the catalytic SYstem. Concerning the solvent for example, the 2methoxyethanol was used in place of the usual 1,2-dimethoxyethane in order to reach a better solubility of the nickel(II) precursors : but, in this case, besides the expected arylated amines, the reactions afford also some amounts of the 2methoxyethoxyarene. The literature does not mention such arylation of alcohol catalyzed by nickel complexes ; accordingly, it was interesting to investigate this new way for the synthesis of alkylarylethers. The first experiments concerning the catalytic system demonstrate the necessity of use of a nickel complex in presence of base (eqn. 4) (Table 3).
N C ~ B r
+ HO~(CH2)2OMe
[Ni] (7 % mol.) ~ NC NPr3 / reflux 66 h + (- Pr3NHBr)
O(CH2)2OMe (4)
Table 3. Necessity of the presence of both nickel complex and base to perform the arylation of 2-methoxyethanol (eqn. 4) a) Entry 11 12 13
Catalyst
bipyzNiBr2 bipyENiBr2
Base b)
ArBr Conv. c) (%)
Yield d)
Pr3N
<5 <5 80
0 0 80
Pr3N
a) Operating conditions : ArX(1 mmol), catalyst (0.07 mmol), amine (1 ml), 2-methoxyethanol (6 ml). b) In order to avoid secondary reactions, the tri-n-propylamine (a tertiary amine) was chosen. c) Conversion rate of arylbromide. d) Isolated yield. Concerning their catalytic activity, various nickel complexes were investigated specially in regard to the influence of the nitrogen, oxygen or phosphorus ligands (Table 4).
97
Table 4. Comparison of the activity of various nickel catalysts for the arylation of 2methoxyethanol (eqn. 4) ~) Catalyst b) Yield (%) c)
Coordinating Atom en2NiBr2 11%
bipy2NiBr2 80 %
phen2NiBr2 31%
(dppe)NiBr2 a) 21%
bdpNiBr2 a) 14%
Ni(PPh3)4 a) <5%
NiBr2 e) 38 %
Ni(acac)2 8%
Ni(OAc)2 6%
a) Operating conditions : see table 3. b) The abbreviations for the ligands are usual : en (ethylenediamine), bipy (2,2'-bipyridine), phen (1,10-phenanthroline), dppe [1,2-bis (diphenylphosphinoethane)], bdp [ 1,2bis (diphenylphosphino) benzene], acac (acetylacetonate). c) Isolated yield. d) Phosphonium salts corresponding to the arylated ligands were detected after precipitation of the reaction mixtures in ether. e) The nickel bromide, NiBr2, in solution is probably complexed with the 2-methoxyethanol. As for the arylation of amines, the best results have been obtained here with the bipy2NiBr2 complex, probably owing to the cy-donor/Tt-acceptor properties of the 2,2'-bipyridyl ligand (to the 1,10-phenantroline ligand belong similar electronic properties, but in this case the lower yields are probably related to a lower solubility). Concerning the other cy-donor /Tt-acceptor phosphorus ligands, the low yields (5-21 %) are probably induced by a concurrent arylation of the phosphine destroying the starting complex during the reaction 9such phosphine arylations are already described in the literature (ref. 15) and phosphoniums salts were actually detected in the reaction mixture at the end of the reaction. In order to compare the new nickel catalytic system with the classical copper catalysis used for the arylation of alcohols (ref. 16), several experiments were performed with various copper catalysts (eqn. 5) (Table 5). [Cu] (7 % mol.)
NC--~Br
+ HO~(CH2)2OMe
[Cu] = Cu (I) or Cu (II)
-- NC NPr3 / reflux66 h + (- Pr3NHB-r)
98
O(CH2)2OMe (5)
Table 5. Comparison of the activity of various copper catalysts for the arylation of 2methoxyethanol (eqn. 5) a) Coordinating Atom b)
Catalyst
Yield (%) o
CuBr e)
4 0 0 0 6 12
CuCI(PPh3)3 phen2CuBr CuBr2 a) Cu(acac)2 Cu(OAc) 2 a) b) c) d)
For the operating conditions and the ligands abbreviations : see table 4. Nature of the coordinating atoms bounded to the copper halogenide moiety. Isolated yield. The copper bromide is assimilated to an oxygen complex in the mixture. All the copper(I) or copper(II) complexes exhibit a very low activity (the yields
are less than 12 %), under the same conditions already used successfully with the nickel complexes (affording up to 80 % yield). Indeed, as the catalysis with copper is likely working through an intermediate cuprous alcoholate, the poor results obtained with the copper complexes are probably connected with the absence of alcoholates under the catalytic conditions used. To improve the nickel catalyzed arylation of alcohols and to reach a lower temperature and/or a shorter time as well as a smaller ratio of catalyst, the influence of the base was investigated more thoroughly, using the bromobenzene as arylating agent (in order to avoid any secondary reaction on the cyano group of the pbromobenzonitrile used in the preliminary investigations) (eqn. 6) (Table 6).
--~Br
+ HO--(CH2)2OMe
bipy2NiBr2 or CuBr (7 % molar) / ~ (X(~//X--O(CHz)2OMe base / reflux
99
(6)
Table 6. Influence of the base on the nickel or copper catalyzed arylation of 2-methoxyethanol (eqn. 6) ~) Catalyst
bipy2NiBr2
CuBr
Base
Pr3N d)
K2CO3
K H C O3
KOAC
K2CO3
KHCO3
Time (h)
66
20
20
20
20
20
Yield (%) b), c)
40
70
100
10
40
< 5%
a) Operating conditions : PhBr (1 ml), bipy2NiBr2 (0.07 mmol), base (1.1 mmol), 2-methoxyethanol (6 mmol). b) GC. yield. c) In all cases a full conversion of the starting arylhalide into arylated alcohol is observed. d) 4.4 mmol. The best results were obtained for the potassium carbonates, specially for the hydrogenocarbonate
which
affords
a
quantitative
yield
in
1-phenoxy
2-
methoxyethane, after only 20 h. It must be pointed out that, in this case too, the comparison experiments Ni
vs.
Cu prove the better catalytic activity of the nickel complex (the difference of the results, Ni
vs.
Cu, is higher for KHCO 3 than for K2CO 3 demonstrating probably the
specific sensitivity of the copper catalysis to the alcoholate concentration (higher for K2CO 3 than for KHCO3). Using the best operating conditions previously determined but with a half quantity (3.5 %) of the nickel complexe, the scope of the arylation of alcohols was roughly investigated by changing the alcohol and the arylating agent (eqn. 7) (Table 7). /R ArX
+
HO--CH
\R'
bipy2NiBr, - (3 59 % molar) 20 h,
125oC
/R ~
(- HX)
100
Ar--O--CH
\R'
(7)
Table 7. Influence of the substrate on the bipy2NiBr2 catalyzed arylation of alcohols (eqn. 7) HO-CHRR'
ArX
Yield b) (%)
MeOCH2CH2OH nPrMeCHOH BuOH BuOH BuOH BuOH BuOH
C6HsBr C6HsBr d) C6HsBr p-MeOC6H4Br p-HOC6H4Br C6H5C1 c) p-F3CC6HnC1
100 40 100 90 0 30 100
,..
a) b) c) d)
Operatingconditions : ArX (1 mmol), alcohol (6 ml). G.C. yield. Reactiontime : 4 days. Reactiontime: 7 days.
Primary alcohols can be arylated in excellent yields by bromoarenes, even with electron donating substituents (for example by p-bromoanisole) with the exception of the p-bromophenol (which is probably transformed in the much less reactive pbromophenolate). Although less reactive, the chloroarenes can also act as arylating agents for the primary alcohols and the yields can even by excellent if electron withdrawing substituents are present on the phenyl ring. Secondary alcohols, such as 2-pentanol, can also be arylated by bromobenzene, even if the arylation is more difficult (the yields are lower even after a longer time); but, it must be pointed out that the selectivity towards bromobenzene continues to be excellent (100 %).
Attempted mechanism for the catalyzed arylation of hard nucleophiles The mechanism of the amines or alcohols arylation catalyzed by nickel(II) complexes has not been elucidated until now (refs. 7, 17), even though the arylation of nucleophiles catalyzed by nickel(0) complexes is better understood. In this last case it is generally admitted that the reaction proceeds by an oxidative addition step, followed by a nucleophilic substitution, and then a reductive elimination of the arylation product (Scheme 4). According to the work of Kochi (ref. 18), the oxidative addition of the haloarene on a nickel(0) complex takes place through a monoelectronic transfer from the metal to the aryl halide with simultaneous formation of a nickel(I) intermediate, the actual catalyst of the reaction (ref. 6).
101
-L Ni ~ 3
Ni ~ 4 --.
~
+L
~
ArX
+ [ (NilL3") (ArX ~ ]
I Ar--Nu I
+ [ (NilL2 ~) ( A r X ' ) ]
+
[ ArNi 1~INuL2~ ] [ (ArX~) ]
[ArNin XL2 ] Nu [ ArNinNuL2 ] , ~ ~ . . . . . . . . _ . . _ _ _ _ . ~ X
Scheme 4. Attempted mechanism for the arylation of hard nucleophiles catalyzed by Ni(0) complexes. In the case of the amines or alcohols arylation catalyzed by nickel(II), it is possible, as a result of a thermal dismutation of the nickel(II) into nickel(I) and nickel(Ill) ; to consider the similar intervention of a nickel(l) complex as a catalytically active species ; but then the formation of this intermediate still has to be proved. Another possibility of mechanism is based on an oxidative addition process directly on the nickel(II) entity (ref. 4d). However this reaction, well known for the metals in their low oxydation degrees is disadvantaged by higher oxydation degrees, and further it would result in a transient nickel(IV) complex, a non usual oxidation degree for this metal.
Aminolysis of nitriles As an unexpected result of our investigations on the arylation of amines, a new catalysis with nickel complexes was pointed out for the aminolysis of nitriles 9 indeed, in the reaction of the p-bromobenzonitrile with the 4-phenylpyridine in the presence of catalytic amounts of NiBr2, in addition to the expected arylamine, the amide resulting from the aminolysis of the cyano group (and subsequent hydrolysis during the work-up) was isolated (eqn. 8). 102
Ph----(
NiBr2 (cat. 3.5 % mol.)
/
N--H + Br
diglyme reflux" 14 h
CN
~ Ph----(
/ ~ N---~(..__~)//K----CN
(8)
(62 %) 0 \
/
N (15%)\
)------Ph /
The usual ways to obtain amidines (or amides after subsequent hydrolysis) by addition of primary or secondary amines to nitriles are : (i) the metallation of the amines, to improve their nucleophilicity (refs. 19, 20), (ii) the acidic activation of the nitriles to increase their electrophilicity either by H C 1 / R O H (the Pinner method (refs. 20, 21), or by a Lewis acid such as A1C13 (ref. 22). In other respects, the cyano group coordinated on various tervalents (Co, Rh, Ir, Ru) or divalents (Pt, Pd, Ni) transition metals can undergo nucleophilic addition in the coordination sphere with modification of the nitrogen ligand which remains coordinated on the metal (refs. 23, 24, 25). But, till now, to the best of our knowledge, there is no example for the aminolysis of nitriles catalyzed by nickel complexes. This reaction was investigated using the 2-phenylethylamine as substrate and by analyzing, for facility reasons, the amides resulting from the hydrolysis of the corresponding amidines, after the reaction (if the conditions used are anhydrous) or during the reaction (performed in presence of water) (eqn. 9) (Table 8).
R--CN + R'NH2
NiBr2 (cat. 3.5 % rnol_) [ /,tN--R' ""- l R - - C 140~ " 65 h \NH--R'
H20
//O -~ R--C (9) (- R'NH2) \NH--R'
Of course, it must be pointed out that the reaction of benzonitrile with the amine needs the nickel catalysis : the reaction without NiBr2 affords only tiny amounts of the N-substituted benzamide.
103
Table 8. Aminolysis of nitriles catalyzed by NiBr2 [eqn. (9) 9R ' N H 2 = Ph(CHz)2NH2] R-CN
~ ~
Amide
H20
Yield (%)
o
CN
60 XNH(CH2)2Ph
o ---CN
55 ~%H(CH2)2Ph
%Br,
O
Nc-4
66 a)
Ph(CH2)2NH
O N C ~ C N
O
/ Ph(CH2)2NH
\
/
\ NH(CH2)2Ph
60
O \XC--(CH2)4 m C N /
NCm(CH2)4mCN
50 b)
Ph(CH2)2NH a) As secondary product, the arylated amine Ph(CH2)2NH-pC6H4-CN (17%) is also formed in the reaction. b) The reaction affords also 10 % of a "Thorpe-Ziegler-like" cyclization product 9 Ph(CH2)2NH CN The amides are obtained in good yields starting from (un)-substituted benzonitriles. For example with the terephtalonitrile the interesting diamide N,N'-bis (2-phenylethyl)terephtalamide is obtained in good conditions (an extension of this reaction starting from diamines could lead to the formation of polyamides). However, the same reaction performed with adiponitrile, affords mainly the monoamide as the monoaminolysis product. This nitrile aminolysis reaction, involving a nickel catalysis, permits moreover to obtain the synthesis of N,N'-disubstituted amidines, the classical methods leading only to the corresponding N-unsubstituted amidines.
104
CONCLUSION In the following figure are summarized the differem transformations discussed before : bromoarenes (but also in some cases chloroarenes) can be transformed into aromatic hydrocarbons
or into more interesting industrial products
such as
arylamines or arylethers. cat. Pd ~ i ArH [ HNR2 <
ca .
ArBr (ou ArCl) ROH
"
i
cat. Ni (or Cu) ~ ]ArOR ]
All these transformations show that arylbromides, by using metallic catalysts such as palladium, nickel or copper complexes, can exhibit a diversified reactivity like their aliphatic analogs. Particularly, among the catalysts used, the bipy2NiBr2 complex is the more efficient catalyst for the arylation of primary or secondary amines. Moreover with the same catalyst, the first examples of arylation catalyzed by a nickel complex for primary or secondary alcohols have also been obtained. Accordingly the arylation of nucleophiles catalysed by the nickel(II) complex
bipy2NiBr2 can
be considered as a good synthetic tool and at least as an interesting
alternative to the usual copper catalysis. References
1. a) L. Krumenacker, S. Ratton, Actualit6 Chimique, 5, 29, (1986). b) A.J. Paine, J. Am. Chem. Soc., 109, 1496, (1987). a) J. March in "Advanced Organic Chemistry", Edit. J. Wiley & Sons, 3rd Edition, pp. 576-598, (New-York), (1985). b) A.S. Abd-E1-Aziz, C.C. Lee, A. Piorko, R.G Sutherland, J. Organomet. Chem., 348, 95, (1988). c) M.F. Semmelhack, H. Rhee, Tetrahedron Lett., 34, 1395, (1993). d) T. Hattori, J. Sakamoto, N. Hayashizaka, S. Miyano, Synthesis, 199, (1994). 3. J.R. Dalton and S.L. Regen, J. Org. Chem., 44, 4443, (1979). 4. a) Migita, Shimizu, Asami, Shiobara, Kato, Kosuigi, Bull. Chem. Soc. Japan, 53, 1385, (1980). b) H.J. Cristau, B. Chabaud, A. Ch6ne, H. Christol, Synthesis, 892, (1981). c) H.J. Cristau, B. Chabaud, R. Labaudini6re, H. Christol, Organometallics, 4, 657, (1985). d) H.J. Cristau in "Advances in Organobromine Chemistry", Vol. I, Edit. J.R. Desmurs, B. Gerard, Elsevier, pp. 233-244, Amsterdam, (1991). 5. E.C. Hughes, F. Veatch and V. Elersich, Ind. Eng. Chem., 42, 787, (1950). .
105
.
.
8.
a) b)
10. 11. 12. 13. 14.
15. 16. a) b) c) d) 17. a) b) 18. 19 a) b) 20. 21. 22. a) b) 23. 24. a) b) 25.
H.J. Cristau, J.R. Desmurs in "Advances in Organobromine Chemistry", Vol. II, Edit. J.R. Desmurs, B. Gerard, M. Goldstein, Elsevier, pp. 117, Amsterdam, (1994). R. Cramer, D. R. Coulson, J. Org. Chem., 40, 2267, (1975). H. Nakajima, A. Yokoyama, JP 61,171,456 (1987), Chem. Abstr., .106, (1987), 66883d (arylation of ammonia with p-dibromobenzene : yield 12 %). A. S. Guram, S.L. Buchwald, J. Am. Chem. Soc., !16, 7901, (1994), (palladium catalyzed aromatic amination of in situ generated aminostannanes). D. L. Boger, S.R. Duff, J.S. Panek, M. Yasuda, J. Org. Chem., 50, 5782, (1985), (formation of aryl-nitrogen bond by treatment with an excess of palladium(0) complex). Y. Beziat, H.J. Cristau, J.R. Desmurs, S. Ratton, FR 8902755, (1990), (to Rh6nePoulenc Chimie). Eur. Pat. Appl., .1!4, 163702s, (1991). A. Venot, Bull. Soc. Chim. Fr., 4736, (1972). J. Von Braun, G. Blessing, F. Zobel, Ber., 56, 1988, (1923). Y. Tamam, Y. Yamada, K. Inoue, Y. Yamamoto, Z. I. Yoshida, J. Org. Chem., 48, 1286, (1983). S.I. Murahashi, N. Yoshimura, T. Tsumiyama and T. Kojima, J. Am. Chem. Soc., 105, 5002, (1983). Indeed, by-products were isolated and identified as typical for the evolution of the expected imines : from 5a, the N,N'-pentamethylene bispiperidine ; from 5b, the fully dehydrogenated 4-phenylpyridine ; and from 5c a "trimeric" derivative, the 2-ethyl 3,5 dimethylpyridine. D.V. Allen, I. Novell, L.A. March, Tetrahedron Lett., 23, 5479, (1982). H. Weingarten, J. Org. Chem., 29, 3624, (1964). A.L. Williams, R.E. Kinney, R.F. Bridger, j. Org. Chem., 32, 2501, (1967). R.G.R. Bacon, J.R. Wright, J. Chem. Soc.(C), (1969) 1978. R.G.R. Bacon, R.S. Renninson, J. Chem. Soc.(C), 312, (1969). L. Cassar, J. Organomet. Chem., 54, C 57, (1973). L. Cassar, M. Fo/t, J. Organomet. Chem., 51,381, (1973). T.T. Tsou, J.K. Kochi, J. Am. Chem. Soc., 101, 6319, (1979). F.C. Cooper, M.W. Partridge, J. Chem. Soc., 255, (1958). J.A. Gautier, M. Miocque, C. Fauran, A.Y. Le Cloarec, Bull. Soc. Chim. Fr., 200, (1970). R.L. Shriner, F.W. Neumann, in Patai, "The Chemistry of Amidines and imidates", Wiley, p. 359, New-York, (1975). F.C. Schaefer, G.A. Peters, j. Org. Chem., 26, 412, (1961). P. Oxley, M.W. Partridge, W.F. Short, J. Chem. Soc., 1110, (1947). F.C. Cooper, M.W. Partridge, Org. Synth., 36, 64, (1956). F.A. Cotton, G. Wilkinson in "Advanced Inorganic Chemistry", fifth edition, Wiley, p. 361, New-York, (1988). P. Paul, K. Nag, Inorg. Chem., 26, 1586, (1987). P. Paul, K. Nag, J. Chem. Soc., Dalton Trans., 2373, (1988). B.C. Challis, A.R. Butler, in Patai, "The Chemistry of Amino Group", Wiley, p. 289, New-York, (1968).
106
THE ISOMERISATION OF 1,2,4-TRICHLOROBENZENE : A THEORETICAL STUDY
SIMON FIRKINS Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie, 85 Avenue des Fr6res Perret - B.P. 62 - 69192 Saint-Fons Cedex France
INTRODUCTION Theoretical techniques have been applied to the problem of the isomerisation of 1,2,4-trichlorobenzene (124TCB). Semi-empirical methods have been used to study three proposed mechanisms for the isomerisation of 1,2,4-trichlorobenzene into 1,2,3 and 1,3,5-trichlorobenzene as well as examining the thermodynamic stabilities of protonated species and final products. Comparison with experimental observations has been possible.
HYPOTHESES CONCERNING THE ISOMERISATION REACTION MECHANISM Ionic, via 1,2 intermolecular shift The isomerisation of 1,2,4-trichlorobenzene in this mechanistic scheme would begin by protonation, and would be followed by a 1,2 shift passing via a chloronium ion.
107
Cl
H "*
~
c,
"
I
Cl
Cl
,,.Cl
~
CI
Cl
Cl
Cl ~
b,~
4"
Cl
Cl
Cl
Cl
~ CI l
[ ~ CIl Cl
H
Cl
H §
_..
~
+ H§
H
"Cl
Cl
Homolytic scission after protonation In this case, following protonation of the 1,2,4-trichlorobenzene, homolytic scission of the protonated species occurs, with the formation of a radical cation and a chlorine radical. Next, the chlorine radical would attack either the radical cation or the chlorine radical in order to produce a protonated species which would then deprotonate to form a new trichlorobenzene. H Cl
CI + c , . _
Cl [ ~
CI
~ Cl
~H+
_
+
CI
CI
Cl
Cl
CI
CI
Cl
Cl
+ Cl" ~,
~
Cl ~ H
""-
+ H+ Cl
H
Ionic, dissociative This mechanism would involve, after protonation, a chloride ion leaving the ring thus forming a neutral aromatic and a C1 § This cation would then attack the ring in order to form a new protonated species.
108
H
Cl -..,
c,
+ Cl + ~,,
~
Cl
Cl
Cl
CI
C l - ~
...C
+ H+
Cl
Cl
Cl
Cl [~Cl
Cl
~ C I
_,.......
+ Cl +
,
H Cl
~
+ H§ Cl
M E T H O D S USED FOR THE CALCULATIONS Drawing of the molecules In order to draw the molecules, the CHEM-X (ref. 1) suite of programs was used. This software also interfaces the graphic environment with the programs which perform the calculations. Calculation of optimised structures and energies The optimised geometries and energies of the neutral, protonated and radical molecules, as well as the transition states were calculated at the semi-empirical, PM3 (ref. 2) level of theory using the program MOPAC (ref. 3), version 6.0.
RESULTS AND THEIR INTERPRETATION Isomeric distribution of neutral molecules Calculations carried out on the neutral molecules give the following values for the energies 9
109
Cl
I E =
- 1706,98743 eV
E =
- 1706,94755 eV
E =
- 1707,02296 eV
c,
c.
This leads to the following order of stability 9 Cl
CI
Cl
c,.Gc,
c.
increasing stability
Using these energies, and the Boltzmann equation, it is possible to calculate the isomeric
distribution of
1,2,3
and
1,3,5-trichlorobenzene
at the time
of the
isomerisation of 1,2,4-trichlorobenzene. Cl
c,
_
Cl
+
Cl
Cl
CI Cl
Theoretical distribution These
results
16,2 %
are very close to those obtained
3 1/2 hours.
110
83,8 %
after a reaction
time
of
CI
Cl
Cl
c,
Cl
.
Cl Cl TT1,2,4 -- 36,7 %
RT1,2.3 = 18 %
RT1,3.5 = 57,9 %
Experimental distribution
23,8 %
76,2 %
Isomeric distribution of protonated species The
following
energies
are
obtained
from
calculations
on the
protonated
species 9 Cl
cI
1 cl
Cl - 1714,20984
E/ev AE/kcalmol -~
HH
+ 3,6
H
values
and
I~Hcl
Cl
CI - 1713,66541
- 1713,75184 + 4,4
these
Cl
~cl
Ol - 1713,94434
Using
- 1713,95052
Cl
Cl
+ 0,1
once
Cl
Cl
Cl - 1714,10547 + 2,4
Cl
H
i cl
+ 2,0
again,
the B o l t z m a n n
equation,
the
relative
d i s t r i b u t i o n o f each m o l e c u l e can be calculated. W i t h respect to the m o s t a b u n d a n t species, the two active m o l e c u l e s , m e a n i n g those w h i c h allow the f o r m a t i o n of i s o m e r s , h a v e relative c o n c e n t r a t i o n s of 2.4 10 .3 and 2.6 10 -5. These values are by no m e a n s ridiculous for this type of reaction.
111
Comparison of the mechanisms leading to the formation of 1,2,3
and
1,2,4-trichlorobenzene In order to compare the mechanisms, the energies of all protonated species and intermediates have been calculated with respect to the active protonated forms.
Formation of 1.3,5-trichlorobenzene CI
+ CI §
N
Mechanism 3 (dissociative, ionic)
+ 95,1 kcal mo1-1 CI
+ CI
Mechanism 2 (single electron transfer)
+ 44,7 kcal mo1-1 CI
Mechamsm 1 (intramolecular, ionic) H
+ 23,0 kcal mo1-1
ci
ci
ci
+ 13,1 kcal mol-1
0 k c a l mo1-1
112
Formation of 1,2,3-trichlorobenzene
N
Mechanism 3 (dissociative, ionic)
Mechanism 2 (single electron transfer)
~ ~
Cl
+
el §
+ 91,4 kcal mol-~ Cl+
Cl"
+ 38,2 kcal mo1-1 CI
G Y Mechanism 1 (intramolecular, ionic)
+ 17,7 kcal mo1-1
CI
CI
CI
H
0 kcal mo1-1
+ 2,4 kcal mol-1
C o m p a r a i s o n of the different mechanisms for the formation of 1,2,3 and
1,3,5-trichlorobenzene Taking into account the energy difference between the two active protonated forms (4.5 kcal tool-l), the following diagram is obtained 9
113
CI
CI
[ ~
+ CI§
Cl
Mechanism 3
+ CI§
+ 45,1 kcal mol -] CI
~
+ 9 5 , 9 kcal mo1-1
Cl
Cl
+
Cl
Mechanism 2
Cl+
cI
+ 4 4 , 7 kcal mo1-1 CI
+ 42,7 kcal mol 1 CI
c,~ ~-c'
Mechanism 1
"
+ 23,0 kcal mol 1
"CI
+ 22,2 kcal mol -]
CI ci '
+ 13,1 kcal mol -]
H
cI
ci
I
H
CI + 6 , 9 k c a l mo1-1
cl
4,5 kcal mo1-1
0 kcal mo1-1
DISCUSSION The general conclusions drawn from these calculations are : - The 1,2 intramolecular shift is the most favorable of the mechanisms. - The ionic, dissociative mechanism is very unlikely. - The mechanism which proceeds via the formation of radicals appears difficult, but cannot be excluded as a possibility at high temperatures. - The thermodynamically stable product is the 1,3,5-trichlorobenzene,
but the
energy difference between the isomers is reasonably small. - The activation energies for the formation of both 1,2,3 and 1,3,5-trichlorobenzene are very close, indicating that a mixture of products would probably be produced.
114
EXPERIMENTAL RESULTS Initial Composition
124TCB : 98.8 %
After 1 hour of 124TCB : 86.2 % reaction at 450~
123TCB : 0.7 %
135TCB : 0.4 %
123TCB : 10.2 %
135TCB : 2.9 %
- The isomerisation is observed with an acidic zeolite at 400-500~ - No evidence is found to support the mechanism involving homolytic fission (single-electron transfer). -
It seems probable that the intramolecular mechanism operates within the acidic
zeolite environment.
CONCLUSIONS The intramolecular ionic mechanism is the most energetically favorable, although the radical mechanism could be considered possible in the gas phase at elevated temperatures, despite the lack of experimental evidence thus far. The dissociative mechanism is very unlikely, with an activation energy of approximately 90 kcal mo1-1. The thermodynamically favoured species is 1,3,5-trichlorobenzene, but due to comparable activation energies, the formation of a certain quantity of 1,2,3-trichlorobenzene seems reasonable. Therefore, in order to favorise the formation of 1,2,3-trichlorobenzene, it was thought necessary to limit further isomerisation of this compound, that is, to defavorise the protonation of 1,2,3-trichlorobenzene. In order to do this, the use of solid catalysts (eg. zeolites) which can introduce a selectivity based on size and shape at the protonation stage seems the best option. The experimental results obtained from such an approach validate this hypothesis.
References
1. CHEM-X Chemical Design Ltd, Roundway House, Cromwell Park, Chipping Norton, OX7 5SR, Grande-Bretagne 2. J.J.P. Stewart, J. Comp. Chem., 10, 221, (1989) 3. J.J.P. Stewart, Frank J. Seiler Reasearch Laboratory, U.S.A.F., CO 80840
115
C ARBOXYLATION OF HYDROXY AROMATIC COMPOUNDS
ISABELLE BONNEAU-GUBELMANN a), MURIELE MICHEL b), BERNARD BESSON c), SERGE RATTON a) AND JEAN-ROGER DESMURS b) a) Rh6ne-Poulenc Recherches, Centre de Recherches d'Aubervilliers, Rue de la Haie Coq, 93308 Aubervilliers, France. b) Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie, 85 Avenue des Fr~res Perret, 69192 Saint-Fons Cedex, France. c) Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie, 24 Avenue Jean-Jaur~s, B.P. 166, 69151 D6cines-Charpieu Cedex, France. d) Interm6diaires Organiques, 25 Quai Paul Doumer, 92408 Courbevoie Cedex, France.
INTRODUCTION The carboxylation of hydroxyaromatic compounds in the form of alkaline salts (the Kolbe Schmitt reaction) is well known and applied in the synthesis of acids such as salicylic acid, para-hydroxybenzoic acid and ortho-cresotinic acid. It was in 1860 that Kolbe first produced salicylic acid by heating a mixture of phenol and sodium in the presence of carbon dioxide at atmospheric pressure. In the years that followed, the importance of CO2 pressure, temperature of the system and the role of water was highlighted. Consequently, this reaction, that is often known as ,, the Kolbe Schmitt reaction ,, has given rise to several variants :
116
Table 1. Kolbe, Kolbe Schmitt and Marasse reactions Conditions T P (CO2) Bar ~
Reactions
Name
-
180-200
Kolbe
5-7
120-200
KolbeSchmitt
20-100
150-250
Marasse
50
200-250
modified Marasse
COONa
COONa
~
OH + K2CO3 + C O 2 (excess)
,~-
''-
(,(,),)---'-OH COOK
)'---OM + M2CO3 + CO
,-.
~
~___~OM
+ HCOOM
(M = K ou Na) COOM
The Kolbe Schmitt reaction is different from the Kolbe reaction due to the CO2 pressure.
Increasing this pressure in fact shifts the equilibrium towards the
salicylate form (single salt).
THERMODYNAMIC CONSIDERATIONS
Theoretical calculations (on phenol) These thermodynamic calculations were performed using Thergas software for the following reaction" OH
OH
+ CO2
~ COOH
The thermodynamic values were calculated by the additive nature of the bonds and correspond to the hypotheses of a gas phase reaction. The software does not take account of phenol salts. 117
Table 2. Thermodynamic data (according to Thergas) T (K) o R
(kcal.mol-1)
AG~ (kcal.mo1-1)
298
398
- 29,59
- 30,78
11,70
14,72
498 - 31,61
17,84
598
698
- 32,13
- 32,67
21,03
24,26
Strictly speaking the phenol carboxylation reaction is exothermic. AG~ is positive and increases as a function of temperature : this shows that the direct carboxylation of phenol is impossible ; it is essential to perform the reaction using a phenate.
Measured data (on potassium phenate) This thermodynamic data is taken from the description of a Ueno process (ref. 1) for the preparation of para-hydroxybenzoic acid. OK
OK
OH o
AH (x~ (298 K) = - 7 kcal.mo1-1 (1)
+ CO2
(solid)
OK
(gas)
OH
COOK
OH
OK o
AH (2) (298 K) = 0 kcal.mo1-1
COOK
(2)
COOK
The formation of the bisalt A is exothermic.
MECHANICAL CONSIDERATIONS Principle It has been shown that the carboxylation reaction of phenol, that has previously been salified, occurs through an electrophilic substitution mechanism, via a complex formed between the phenol, the CO2 molecule and the alkaline metal (ref. 2). 118
In theory, this reaction takes places in two stages (Fig. 1) 9 -
the carboxylation of phenate (eqn. 3) and
- restructuring between the carboxylate / phenate / phenol (eqn. 4).
OM
OM,CO2 (3)
+ CO2
OM
OM.CO2
OH (4)
COOM (M = Na or K) Fig. 1. Mechanism for the carboxylation of phenol The intermediate has been represented in simplified form. In fact two hypotheses exist for the structure (refs. 3, 4) but neither has been definitively proven.
,M,, & ............ ::o
I
OM.CO2
o
Complex formation
J OCOOM Formation of phenyl carbonate
The reaction passing through a metallic complex is that most commonly described in literature. In any case the key intermediate is the bisalt.
119
OM
~
.COOM
Mechanisms for the carboxylation of sodium phenate and potassium phenate (Figs. 2, 3) are given below. OH
ONa
aq
~, .......Na.
ONa
~o ....C~O
+ CO2
OH
,COONa +
ONa
_
ONa
.COONa +
~ OH
,COONa
(6)
OH (7)
Kinetic and them~dymmic product (stable)
Fig. 2. Carboxylation of sodium phenate
120
OH
OK +
KOH aq
(8)
+ H2~O
OK
OH
~
(~ ......... K ,,
+ ,o ,,,, + CO2 -.,
OH
"-
.......C"~O
OK
OK
COOK
(9)
OH (10)
Kinetic product (stable)
OK
OK
OK COOK +
2 ~~~,./COOK
(11) COOK OK
OK
OK
OOK +
(12)
"~ 2
COOK
COOK Thermodynamic product (stable)
Fig. 3. Carboxylation of potassium phenate In summary 9 The key intermediate in all cases is the metallic bisalt. In the case of sodium, this bisalt can be respresented as a cyclic complex with 6 thermally stable centres. 121
+
Na~) -0" 0 \ONa
The carboxylation of sodium phenate gives excellent selectivity in producing salicylic acid. As far as potassium is concerned, bipotassium salicylate is not thermally stable and restructures itself intermolecularly to form tri-potassium isophthalate and potassium phenate. This mechanism has been proven and the intermediates have been identified (ref. 4). The carboxylation of potassium phenate gives excellent selectivity in producing parahydroxybenzoic acid.
PARAMETERS GOVERNING THE REACTION Cation type As has been described above, the key imermediate is the bimetallic salicylate : - With small (hard) cation Li + and Na +, this bisalt has a metallo complex structure with 6 thermally stable centres which leads to a carboxylation process. -With large cations (soft) K +, Rb +, Cs +, this bisalt is not thermally stable and parahydroxybenzoic acid is formed via isophtalate to phenate. This mechanism is possible with potassium and is favoured at low CO2 pressures (~ 1 bar) and at high temperatures ( > 180~ Temperature
The temperature influences both the reactivity of the phenate and the selectivity, as shown in Table 3.
122
Table 3. The influence of temperature 9carboxylation of potassium phenate Selectivities (%)
T (~
Yield (%)
,,,
140 190 210 250
A.S. 59 29 6
pHBA 41 70 94 > 98
39 43 48 > 48
Conditions 9 Bulk carboxylation Duration 9salification 1 h30mn Carboxylation 4h P (CO2) = 1 bar These values show clearly the thermal restructuring of bipotassium salicylate in parahydroxybenzoic acid, as shown in figure 3. C O 2 pressure The minimum required pressure for the carboxylation of phenate corresponds to the dissociation pressure of the complex formed between the phenol, the alkaline metal and the CO2 molecule, and to the applied temperature (ref. 5). Between 120~
and 160~
the dissociation pressure of the complex (sodium phenate CO2)
is around 4 bars. At a given temperature, an increase in CO2 pressure, above this minimum value has no effect on the system selectivity, but it can favour the reaction kinetics. The role of water
The presence of traces of water leads to a reduction in yields (Table 4). Table 4. The influence of residual water in the phenol / phenate mixture on the carboxylation yield H20 content (ppm)
Yield loss (%)
5O0 5 000
1.25 12.5
In fact, any molecule of water present, breaks down the phenate into a molecule of alkaline hydroxide, which then consumes some CO2, to regenerate water (eqns. 13-15).
123
OM
OH
2 ~
+2
2 MOH
+
CO 2
H20
,~.
+ 2 MOH
"~
(13)
M2CO3 + H20
OM
(14)
OH
+H20+CO22
+ M2CO 3
(15)
The water can also form in situ by 9 2 MOH
+ CO 2
~,
"~
M2CO3
+
H20
(16)
Ueno (ref. 5) draws attention to the fact that the production of water can also be due to a parasite etherification process (eqns. 17, 18). OH
~
O - - ~
+
H20
(17)
OH + CO 2 +
2 H20
(18)
II o
The influence of the system The carboxylation reaction of phenol requires total anhydricity. This condition can be fulfilled : - either in solid phase : good selectivity will be achieved is the gas / solid exchanges are efficient. These conditions requires the use of special technology.
124
- o r in suspension in an inert solvent (biphenyl ether, kerosene, di-or terphenyl, etc.). - or in a phenol phase system.
SYNTHESIS OF OTHER HYDROXYAROMATIC COMPOUNDS The influence of substitute core groups
The reactivity of the substrate is influenced by the steric space requirement and the core substitute groups. - An alkyl group (either ortho or para) favours the ortho-carboxylation of the phenol group. - A donor group (NH2, OCH3, OH, X, etc.) enables good yields to be achieved ( > 80%). An acceptor group (NO 2, CN, COOR, etc.) will inhibit the reaction. The differences in reactivity and orientation are summarised in Table 4.
-
125
Table 5. The influence of substituents (ref. 6) Substituents
Majority product
Substrate
HO--@R
Conditions
H O - ~ R HOOC
Yield
Ref.
t ~ = 160- 220~ P = 4 0 - 100 b dur6e = 4 - 8 h
25 h 85 %
(7) (8) (9) (10) (11) (12)(13)
t ~ = 125- 175~ P = 100b dur6e=4-8h
70~83 %
(7) (8) (9) (12) (13) (14) (15) (16)
t ~ = 200~ P = 40b dur6e = 6 h
37 %
(13)
t ~ = 200~ P = 40b dur6e = 6 h
3O %
(7) (13) (17) (18)
t ~ = 210oC P = 35 b dur6e = 40 h
17 %
(18) (19) (20)
t ~ = 250~ P= 30b dur6e = 5 h
90 %
(7)
t ~ = 180~ P=63b dur6e = 5 h
84 %
(7) (21) (22)
t~ =90-225~ P = 8 - 100b dur6e = 4 - 43 h
5-90 %
(7) (13) (23) (24) (25) (26)
t ~ = 210~ P =40b dur6e = 4 h
0-19%
HOOC Alkyl (CH3,
_ ~ OH
C2H5"" ")
R
R R
R
R
R'
R
HOOC
R'
HOOC HO-~R' R
Phenyl
HO@~R'
R
.o-@~ HOOC
HOOC Donor (NH2, OMe, OH, X...)
Ho- G HOOC ~
Acceptor (NO2, CN, COOR...) HOOC
126
(13)
CONCLUSIONS The carboxylation reaction of phenol by CO2 is well known and industrially developed using various technologies. Chemically speaking the key parameters are shown in Table 6. Selectivity
Key parameters Cation P (CO2) T~
ortho
para
Na
K
equilibrium shift 130 + 50
210 + 30
a
Three main technology types can be used : - fluidised bed, ,, LIST ,, reactor, -
in a dispersion system,
- bulk.
References
1. ,, Liquid crystal polymers ,,, SRI, report N~ 86 C. 2. J. March in ,, Advanced Organic Chemistry ,,, 3ieme Edition, John Wiley, p. 491-492, NewYork, (1985). 3. R. Schmitt, J. Prakt. Chem., 397, (1885). 4. A.J. Rostron, A.M. Spivey, J. Chem. Soc., 39, (1964). 5. Ueno Ryuzo, Masada Yoshiyasu, EP 254 596, (1986). 6. A.S. Lindsey, H. Jesrey, Chem. Rev., 583, (1957). 7. O. Bame, G.F. Adamson, J. Org. Chem., 19, 510, (1954). 8. F. Beilstein, A. Kuhlberg, Ann., 156, 206, (1870). 9. B.I.O.S. Final report N ~ 664, His Majesty's Stationery Office, London. 10. D. Cameron, H. Jeskey, J. Org. Chem., 15,233, (1950). 11. R. Ihle, J. Prakt. Chem., 2 (14), 443, (1876). 12. P. Spika, Gazz. Chim. Ital., 8, 421, (1878). 13. F. Wessely, K. Benedikt, Monatsh, 81, 1071, (1950). 14. C. Brunner, Ann., 351,320, (1907). 15. A. Engelhardt, J. Russian. Phys. Chem. Soc., 1, 220, (1869). 16. M. Filiti, Gazz. Chim. Ital., 16, 126, (1886). 17. R.C. Fuson, J. Corse, J. Amer. Chem. Soc., 63, 2645, (1941). 18. L. Palfray, Bull. Soc. Chim., 956, (1948). 19. J.A. Jesurun, Ber., 19, 1414, (1886). 20. H. Kolbe, E. Lautemann, Ann., 115,201, (1860). 21. Heyden, Fabrik, German patent 61125, (1891) ; Frdl 3,828. 22. H. Schwazz, Ber., 13, 1643, (1880). 23. M. Calvin, US 2 493 654, (1950) ; CA. : 44, 2559, (1950).
127
24. L.N. Ferguson, R.R. Holmes, J. Amer. Chem. Soc., 72, 5315, (1950). 25. V.M. Rodionov, Bull. Acad. Sci. U.R.S.S., Classe Sci. Chim., 3 (421), (1940) ; C.A. : 35, 5101, (1941). 26. L. Varnholt, J. Prakt. Chem., 2 (36), 19, (1897).
128
ACCESS TO POLYCHLOROPHENOLS : CHEMISTRY OF INTERMEDIATES
JEAN-ROGER DESMURS a), SERGE RATTON b), RENE JACQUEROT a), JEAN DANANCHE a), BERNARD BESSON a) AND JEAN-CLAUDE LEBLANC ~ a) Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie, 85 Avenue des Fr6res Perret, B.P. 62, 69192 Saint-Fons Cedex, France. b) Interm6diaires Organiques, 25 quai Paul Doumer, 92408 Courbevoie Cedex, France. c) Rh6ne-Poulenc Chimie, B.P. 17, 38800 Le Pont-de-Claix, France.
INTRODUCTION U.S. production between 1977-1980, shown in Table 1, illustrates the industrial importance of these aromatic derivatives, used either as synthesis intermediates, or active components for some agrochemical compounds or pharmaceuticals specialities.
129
Table 1. Production levels and uses of chlorophenols (ref. 1) Product
US production t/year
Uses
a few thousands tons
intermediates
23000
intermediates
19000
fungicide used in wood protection formulations
OH ~ C 1
OH CI
C1 OH C1
C1
C1
The agrochemicals sector provides the main outlets for chlorophenols, as shown in Table 2 which shows a few well-know products.
130
Table 2. Shows agrochemical and pharmaceuticals specialities prepared from chlorophenols. Structure
Trade-mark
C1 24 D Acid (herbicide)
I~~-O--CH2COOH C1 ~ H3 C1----~,,),/x----O--CH--COO H
Dichloroprop (herbicide)
C1 /-.~ ~ CH3 C1 - - - - ~ . ) / ~ O--~~)//x--- O-- CH-- COOH3
Hoelon (herbicide)
C1 Bifenox (herbicide)
CI-~O~~N~--NO2 COOCH3 CI c3.7
C1-----{(
) )---O--CH-~--CH2--N
\~_;(
-
~C1
_
,c_N.~N
O//
Sportak (fungicide)
\--/
C1 // O~CH2~CH2~NH--NH~CxNH2
\ -(X
Guanochlor (antihypertensor)
C1 CI
C1
NH--
Diclofenac (analgesic)
CH2CO2H
131
Generally a (trichlorophenols,
quality problem is created when heavy chlorophenols tetrachlorophenols and pentachlorophenols) are processed.
Impurities such as polychlorophenoxyphenols, polychlorodibenzodioxins, polychlorodibenzofurans and polychlorodihydroxybiphenyls, are quite often found in some industrial products. Table 3 below shows the influence of the structure of the series of dibenzodioxins on the DL 50 (refs. 2, 3) (number and position of the chlorine atoms). Table 3. Shows LD 50 by mouth of various polychlorodibenzodioxins. DCDD
TCDD HCDD (2,3,7,8 isomer) (mixed isomers)
OCDD
r j 0.114 mg/kg
mouse
0.022 mg/kg
J
rat
> 1000 to 2000 mg/kg
guinea-pig {
J
0.045 mg/kg
> 4000 mg/kg
100 mg/kg > 1000 to 2000 mg/kg
0.0006 mg/kg 0.0021 mg/kg
J rabbit
I
0.115 mg/kg (0.275 mg/kg) - through percutaneous route > 0.252 mg/kg through intraperitoneal route
2,3,7,8-Tetrachlorodibenzodioxin 1 has a toxicity clearly above that of all the other compounds of this series. Thus it is imperative that industrial products are free of this impurity or its precursors.
132
Literature on this subject tells that chlorophenols cause these unwanted byproducts to form (refs. 4, 5, 6) when exposed to thermal, photochemical or basic conditions (eqn. 1). OH + C1
Cim
~
C
H
CI~ + 2HCI (1) ~
"O"
But information provided in the literature is not sufficient to explain how these by-products, observed during experiments carried out on chlorination reactions, are formed. Consequently our objective was to study chemical phenomena occurring during the phenol chlorination process in order to understand how by-products were formed with the aim of reducing the amount formed.
HYPOTHESIS It seems that the creation of polychlorophenoxyphenols, polychlorodibenzofurans or polychlorodibenzodioxins is closely related to the varying degrees of chlorination. During the mono and dichlorination of phenol, no parasite chemistry appears. But if we introduce a third and especially a fourth or fifth chlorine atom within the aromatic core then a problem is created. This is problably linked to the high activating quality of the OH group which tends to orientate an electrophilic substitution - in an ortho or para positioning (Fig. 1).
"x
cl
OH
cl
Cl
OH
cl
Fig. 1. Activated position towards an electrophilic attack of chlorine When the carbon has already been substituted by an atom, ipso attack leads to some polychlorinated
gem-dichlorocyclohexadienones (Fig.
133
2).
0
0 C1
0
CI~.~C1
C I ~ C I
C1
C1
0
0 ,C1
C
C1
C1
~1
"1
Fig. 2. Polychlorinatedgem-dichlorocyclohexadienones generated by chlorination of 2,4 or 2,6dichlorophenols or 2,4,6-trichlorophenol We assumed for this process that gem-dichlorocyclohexadienones were actual intermediates acting in the formation of chlorophenols (eqn. 2) containing one or two atoms of chlorine in meta position relative to the OH group. 0
C1
OH
.C1
.~
C I ~ C 1 (2)
isomerisation y
"C1
C1 but they could also be the precursors of polychlorophenoxyphenols (eqn. 3)
0 C1
OH CI+CI
CI
0 .9 . C I ~ C I condensation "- ~CU. ~"
C1 + HCI
OH 9 _~ C I - . ~ C 1 (3)
C1
y o
CI
CI
CI
Cl
134
"C1
or polychlorodibenzodioxins (eqn.3)
OH I
?
+ HCI
d
+clQ
I
CI
or polychlorodibenzofurans (eqn.5)
135
1) Red 2) -HC1
(4)
and polychlorohydroxydiphenyls (eqn. 6) O C1
OH ~~/C1
CI
OH 9
C
+
l
~
~
+ HC1 C1
(6)
k~.,.OH C1
To verify these hypotheses, we have successive by performed the following actions : - synthesising polychlorinated gem-dichlorocyclohexadienones ; - developing a method of analysis enabling characterization and quantitative analysis of the products ; - d e m o n s t r a t i n g that polychlorinated gem-dichlorocyclohexadienones existed within chlorination reaction masses, and establishing how the formation of gemdichlorocyclohexadienones and that of polychloro by-products were correlated ; - examining the reactivity of polychlorinated gem-dichlorocyclohexadienones.
SYNTHESIS
OF
POLYCHLORINATED
GEM-DICHLOROCYCLOHEXA-
DIENONES
Polychlorinated gem-dichlorocyclohexadienones can be obtained through the action of t-butyl hypochlorite (ref. 7), hypochlorous acid (ref. 8) or chlorine in acetic acid (refs. 9, 10) with a chloro phenol. OH C1
C1
O 1 I C I ~ C 1
O CI
C1 (7)
ch c1 + tBuOC1
ch c1 + tBuOH
n=0.1 or2 The methods described by P. SVEC (ref. 6) enabled us to prepare 2,4,4,6-tetrachlorocyclohexa-2,5-dien- 1-one 2, 2,3,4,4,6-pentachlorocychlohexa
136
2,5-dien- 1-one 3, 2,3,4,4,5,6-hexachlorocyclohexa-2,5-dien- 1-one 2,3,4,5,6,6-hexachlorocyclohexa-2,5-dien- 1-one 5. 0
0
C1
C1
C1
0
CI
C1
and
0
C I ~ C 1
CI.~~C1
CI"Ol./~.cI'CI~..
C1
C1 C1
2
ANALYSIS
3
OF
4
POLYCHLORINATED
5
GEM-DICHLOROCYCLOHEXA-
DIENONES
As our aim was to bring to light the polychlorinated gem dichloro cyclohexadienones, within chlorination reaction masses, one of the most important parts of our study was to develop an efficient method of analysis capable of detecting traces amounts of these intermediates. The only items of interest to be found in the literature are those provided by P. SVEC and coll. fiefs. 6, 11) using gas phase chromatography in c.c.m.. P. SVEC and V. KUBELKA (ref. 11) observed that the polychlorinated gemdichlorocyclohexadienones were broken down in gas phase chromatography. This result was confirmed in the laboratory by work performed on different gas phase chromatography columns which showed almost quantitative reversion of the polychlorinated gem-dichlorocyclohexadienones back to the initial state of chlorophenol (eqn. 8). For this reason GPC cannot be used. 0 C1
OH C1
G P C - 2 0 0 to 250 ~
C1
CI
(8) C1
Some polychlorinated gem-dichlorocyclohexadienones were separated by P. SVEC (6) using thin-layer chromatography on a silica plate with eluants of hexane, cyclohexane, and benzene type. Using hexane as an eluant it was possible to transpose this separation of elements to HPLC with a silica column (Fig. 3). 137
Column : HIBAR MERCK Si 60 (5 u) ; L = 12.5 cm Hexane eluant
t N
m
h
\D
Y)
N
*I /, -
-. ?'
rr.
r-
..-.
Fig. 3. Chromatogram of the separation of polychlorinated gem-dichlorocyclohexadienonesand gem-dichlorocyclohexenones with silica column 138
These separation conditions proved difficult to handle, especially for chlorination masses, since the large quantities of chlorophenols introduced caused the base line to shift rapidly. This resulted in any quantitative analysis being impossible. These circumstances obliged us to research into other conditions using HPLC. We observed that the polychlorinated gem-dichlorocyclohexadienones were eluted (Fig. 4) when placed under the conditions that we used to quantitatively analyse the chlorophenols, but unfortunately the retention periods were interfering with those of the chlorophenols (Fig. 5).
139
,.j],
"el.,...,
7, *'2. i
-... *. :21
r. r, !
-
u-.
--.
~.~ I--
i.-.,
~4
,2.-, L.L.I
,-,-, L , J
J
~
i.."~-
r'_L~_
."
L"-: ".'-'
C':,CI
I
(..-_" o- -o
,2,-_. ;'%
,--,
~-" k - J L.~ 9 .,:-P.-..4
,., "2". :-~
_.,
Fig. 4. 2,4,4,6-Tetrachlorocyclohexa-2,5-diene-l-one on coiunm R.P. 18 e l u a n t methanol- acetate buffer pH 4.1 (78.22) 140
,.j],
"el.,...,
7, *'2. i
-... *. :21
r. r, !
-
u-.
--.
~.~ I--
i.-.,
~4
,2.-, L.L.I
,-,-, L , J
J
~
i.."~-
r'_L~_
."
L"-: ".'-'
C':,CI
I
(..-_" o- -o
,2,-_. ;'%
,--,
~-" k - J L.~ 9 .,:-P.-..4
,., "2". :-~
_.,
Fig. 4. 2,4,4,6-Tetrachlorocyclohexa-2,5-diene-l-one on coiunm R.P. 18 e l u a n t methanol- acetate buffer pH 4.1 (78.22) 140
Because similar retention periods are used for some chlorophenols and polychlorinated gem-dichlorocyclohexadienones a problem of peak times was created and it was necessary to use a double detection method enabling differentiation of both products. In order to obtain the best possible sensitivity and specificity for the polychlorinated gem-dichlorocyclohexadienones, we opted for electrochemical detection based on reduction of gem-dichlorocyclohexadienones at an imposed potential o f - 0 volt (Fig. 6). ,.C1 O"
0 C1
C1
C1
00 C1
C1 ~
C1
C1|
+ 2 e-
~~.
C1
~
+ C1| C1
C1|
The chlorophenols,
(9)
(10) cyclohexadienones,
benzoquinones
and chlorophenoxy-
phenols are analysed using UV detection. Simultaneous electrochemical detection enables specific analysis of electro active compounds in reduction. This analytical technique proved to be very efficient as only one injection provided us with all the required information on the composition of the reaction masses.
142
8.67 9.95 11.48 14.14-
2 , 3 , 6 - T r i c h l o r o p-benzoquinone Chloranil 2,4,4,6-Tetrachlorocyclohexa2,5-dien-l-one 2,4,6-Trichlorophenol
15.9218.33 19.67 -
2,3,4,4,6-Pentachlorocyclo hexa-2,5-dien-l-one 2,3,4,6-Tetrachlorophenol Pentachlorophenol
O
E O
~i!j;I ~ r. 9o
<>
~ ~
.--.
,i
"~ .
-
.-, .
.
.
:,
"
.
.
7.
.
" 9 r.~, ..'~ ..,-"
'i , -
!
"i.
Fig. 6. Benzoquinones, cyciohexadienones and phenols mixture in UV and electrochemical detection 143
The limit of detection of polychlorinated gem-dichlorocyclohexadienones by HPLC using equipment fitted with a double detection system, UV and electrochemical, is approximately 0.01% in a synthetic chlorophenol mixture.
D E T E C T I O N OF POLYCHLORINATED GEM-DICHLOROCYCLOHEXADIENONES WITHIN THE CHLORINATION MASS Since the analytical method we used enabled us to detect down to 0 . 0 1 % of polychlorinated gem-dichlorocyclohexadienone in a chlorophenol mixture, we were able to detect this compound in a chlorination reaction mass. This confirmed some of the assumptions we had made when we started work on the subject. Detection of the polychlorinated gem-dichlorocyclohexadienones was performed by means of numerous tests and only one example of the chlorination of 2,4,6-trichlorophenol in the presence of A1C13 (ref. 12) is described below : OH C1
OH CI + C12
MC13
~ C1
i1
(11)
1
C1
C1
2,4,6-Trichlorophenol and A1C13 are heated to a temperature of 100~ Then chlorine is introduced at the rate of 5 1/hour. Samples of the product are taken at the following times : corresponding to each of the respective, introduced quantities of chlorine : 164.6 mM (equivalent 0.5) 329.2 mM (equivalent 1) 658.4 mM (equivalent 1.5) 987.6 mM (equivalent 2) The formation of 2,4,4,6-tetrachlorocyclohexa-2,5-dien-l-one is observed from the very first sample. Formation of dichlorobenzoquinone, trichlorobenzoquinone, tetrachloro-phenol and polychlorinated phenoxyphenols is also observed (Fig. 7).
144
0
c 0 .L(
a
m N C
m 0
I !
I
,
Fig. 7. Chromatogram of the chlorination of 2,4,6-trichloropheno1 after introduction of 0.1 of chlorine equivalent 145
During the 2,4,6-trichlorophenol chlorination process (Fig. 8), the concentration of 2,4,4,6-tetrachlorocyclohexa-2,5-dien-l-one remains more or less constant while a marked increase of other impurities is noted. From these results, the following observations can be made : -Chlorophenoxyphenols and other polychlorinated impurities were released when the polychlorinated
gem-dichlorocyclohexadienones were
generated in the reaction
mixture. This fact confirms our hypothesis that polychlorinated
gem-dichlorocyclo-
hexadienones are probably the cause of the parasite chemistry. - The
content
of
polychlorinated
gem-dichlorocyclohexadienones
remains
approximately constant afterwards, and this fact supports our assumption that intermediates for the reaction with one or two chlorine atoms in meta position could be used. Whilst these initial results showed us that our assumption was correct, we still had to demonstrate that the polychlorinated gem-dichlorocyclohexadienones, placed under the conditions of the chlorination process, were capable of producing the different products observed during the experiment. An in-depth study conducted on the reactivity of the polychlorinated
gem-dichlorocyclohexadienones confirmed
these facts.
146
During the 2,4,6-trichlorophenol chlorination process (Fig. 8), the concentration of 2,4,4,6-tetrachlorocyclohexa-2,5-dien-l-one remains more or less constant while a marked increase of other impurities is noted. From these results, the following observations can be made : -Chlorophenoxyphenols and other polychlorinated impurities were released when the polychlorinated
gem-dichlorocyclohexadienones were
generated in the reaction
mixture. This fact confirms our hypothesis that polychlorinated
gem-dichlorocyclo-
hexadienones are probably the cause of the parasite chemistry. - The
content
of
polychlorinated
gem-dichlorocyclohexadienones
remains
approximately constant afterwards, and this fact supports our assumption that intermediates for the reaction with one or two chlorine atoms in meta position could be used. Whilst these initial results showed us that our assumption was correct, we still had to demonstrate that the polychlorinated gem-dichlorocyclohexadienones, placed under the conditions of the chlorination process, were capable of producing the different products observed during the experiment. An in-depth study conducted on the reactivity of the polychlorinated
gem-dichlorocyclohexadienones confirmed
these facts.
146
REACTIVITY
OF
GEM-DICHLOROCYCLOHEXA-
POLYCHLORINATED
DIENONES
Since 2,2,4,6-tetrachlorocyclohexa-3,5-dien-l-one changes very rapidly, when in chlorophenol medium, to give 2,4,4,6-tetrachlorocyclohexa 2,5-dien 1-one (eqn. 12), we deliberately restricted the scope of our study to only deal with this last compound. This was because we wanted to avoid analysis of mixtures for which the interpretation would have been very difficult. 0 Cl~....~C1 ~ T ~ "C1
0 70~
C1
,Cl (12)
"~ trichlorophenol
C1 Thus we examined in turn : - the intrinsic thermal stability of polychlorinated gem-dichlorocyclohexadienones, -the thermal stability of polychlorinated gem-dichlorocyclohexadienones within chlorophenols, - the behaviour of polychlorinated gem-dichlorocyclohexadienones with acids, -the action of water and chlorine on polychlorinated gem-dichlorocyclohexadienones.
T H E R M A L STABILITY OF POLYCHLORINATED GEM-DICHLOROCYCLOHEXADIENONES Literature does not provide any information on this subject. Before studying the reactivity itself, it seemed important to us to know the range of temperatures which could be used, by examining the basic thermal stability of these compounds (Table 4). Since a chlorination process takes 8 hours on average, we opted to use this time period to perform all trials necessary to conduct the study.
148
Table 4. Percentage of polychlorinated gem-dichlorocyclohexadienonestransformed after heating for 8 hours at different temperatures. Temperatures Cyclohexadienones
Melting point
70~
125 ~
180~
O
C1y
[~,CI
C1/
122 ~
0 %
0 %
100 %
112 ~
0%
0%
100
106 ~
0 %
0 %
100 %
~C1
C1
,C1
%
xCl 0 C1
Cl
When heated throughout, polychlorinated gem-dichlorocyclohexadienones remain stable up to a temperature of 150~ and do not produce the impurities observed during the chlorination process. At a temperature of 180~ the formation of polychlorodibenzodioxins is observed with several break-down products.
149
Table 5. Amount of dioxins in ppm formed after heating polychlorinated gem-dichlorocyclohexadienones for 8 hours at a 180~ 0
0
i
ci
Dioxins
CI~
i Cl
0 CI
C I ~ ~C1
Cl~
c1
C1/
C1
C
1,3,6,8-Tetrachlorodibenzodioxin
10
not detected
not detected
2,3,6,8-Tetrachlorodibenzodioxin
not detected
not detected
not detected
Pentachlorodibenzodioxins
16
1
3
Hexachlorodibenzodioxins
8
40
< 3
Heptachlorodibenzodioxins
50
1000
< 3
Octachlorodibenzodioxin
140
260
4200
THERMAL
STABILITY
OF
POLYCHLORINATED
GEM-DICHLORO-
CYCLOHEXADIENIONES IN CHLOROPHENOLS Since polychlorinated
gem-dichlorocyclohexadienones possibly
formed during
the process of chlorination are in contact with chlorophenols, we determined their stability in the presence of chlorophenols. This experiment was performed with mixtures of 1 mM of polychlorinated
gem-dichlorocyclohexadienonesand
10 m M of
chlorophenols heated for 8 hours at different temperatures. Obtained results indicate the strong influence of the type of phenol and polychlorinated
gem-dichlorocyclohexadienones on
the changes in reaction mixture.
This is the reason why we will distinguish : a) the process related to phenols containing chlorine atoms with a 2.4.6 position from that b) of phenols containing at least one hydrogen with a 2.4.6 position.
Process performed with chlorinated atoms with a 2.4.6 position In the presence of 2,4,6-trichlorophenol, 2,3,4,6-tetrachlorophenol or pentachlorophenol no significant transformation of the cyclohexadienone 2 occurs when performed at temperatures up to 150~
(refer to tables 4, 5, 6).
150
Table 6. Percentage of 2,4,4,6-tetrachlorocyclohexa-2,5-dien-l-one 2 transformed after heating for 8 hours at different temperatures. Melting point of phenol
Phenols
temperature 9 125~
70~
180~
OH
c' 7c 65~
2%
114~
4%
173~
4%
C! OH CI~,~ CV' ' ~
C1 I~ CI OH
CI.~
C1
4%
100 %
Cl~'~~C1 CI
At 180~ 2,3,4,6-tetrachlorocyclohexa-2,5-dien-l-one 2 in isomerizes to tetrachlorophenol 6 with a 75 % yield. 0 C1
pentachlorophenol
OH ,C1
180o
C1
,C1 (13)
Pentachlorophenol
C1 C1
2
6__
151
With pentachlorocyclohexadienone 3, we observe the same stability.
C1
C1
C1
Table 7. Percentage of 2,3,4,4,6-pentachlorocyclohexa-2,5-dien-l-one heating for 8 hours at different temperatures.
3 transformed after
Temperatures Phenols
Phenol melting point
70 ~ C
65 ~
5 %
114 ~
3%
173 ~
2%
125 ~ C
180 ~ C
2%
99 %
OH Cl~/~]./CI
C1 OH CI.~
/CI
Cl OH CI~
CI
c1
When the process is performed at 180 ~
with pentachlorophenol, an exchange
reaction can be observed with 2,3,4,4,6-pentachlorocyclohexa-2,5-dien-l-one
3
leading to the formation of tetrachlorophenol and 2,3,4,4,5,6-hexachlorocyclohexa2,5-dien- 1-one _4.
152
Parallel to this reaction, an isomerization process of 2,3,4,4,6-pentachlorocyclohexa-2,5-dien-l-one 3 in pentachlorophenol _7 takes place. Hexacyclohexadienone 4 i s even stable up to 180~
as indicated in the Table 8.
O C I ~ C 1
CIcl cl'c1 Table 8. Percentage of 2,3,4,4,5,6-hexachlorocyclohexa-2,5-dien-l-one _4 transformed after heating for 8 hours at different temperatures. Temperatures Phenol
Phenol melting point
70 ~ C
65 ~
2 %
114 ~
2%
173 ~
1%
125 ~ C
180 ~ C
2 %
2%
OH C1
C1
CI OH
C1~ CI
OH
civic CI.~
C
Cl
153
At first sight, polychlorinated
gem-dichlorocyclohexadienones seem
to have
thermal stability in the presence of trihalogenated phenols in 2.4.6 position. But detailed analysis of the reaction mass - now possible thanks to the development of the analytical method described above - shows that in all the cases a 3 to 15 % formation of polychloro phenoxyphenols occurs. After heating for 8 hours at 70~ the 2,4,4,6-tetrachlorocyclohexa-2,5-dien-l-one
2
(lmM)
in 2,4,6-tetrachloro-
phenol (10 mM), the following products : 2,4-dichloro 6-(2,4,6-tetrachlorophenoxy) phenol 8 and 2,6-dichloro 4-(2,4,6-trichlorophenoxy) phenol 9 (Fig. 9) are detected within the reaction mass.
~
"
1JV
~
'
~
.
.
: :.,,,: ~~,.~. ... . ...-.. ----t
.
0 CI~CI
. o
g ~
- ' "~"': " . . . . . . . ....
_ .... ".--
J
"
_ -
J
CI~
"C! OH
CI ~ C I C1
CI CI"~Oc_ ~ CIHO - o~
~
~
CI
~
CI
CI
Fig. 9. Chromatogram of a mixture of tetrachloroclohexadienone 2 and 2,4,6-trichlorophenol after being processed for 8 hours at a temperature of 70~ 154
C,o C,
OH
oH
C1
C1
C1 CI
0
C1
C1
C1
C1
9
8
The formation of phenoxyphenols 8 and 9 at 70~
which was only observed
with the mixture of tetrachlorocyclohexadienone, 2,4,6-trichloro-phenol (Table 4) seemed
to
be
a
transformation
of
the
2,4,6-trichlorophenol
catalysed
by
tetrachlorocyclohexadienone. Table 9. Formation of phenoxyphenols after a heating for 8 hours, on different mixtures of products.
Reactants initial composition in %
OH CI~ 0 C1 0/ 7C1 C1CI~C1CI CI
CI
C1
c,
O
0%
not detected
not detected
2%
9.6 %
6.4 %
not detected
not detected
100 % O
OH
CICI~C1CI +CI~ ~CI CI 10,5 %
89,5 %
OH
7.c, 100 %
155
Phenoxyphenols 8 and 9 are the result of an attack by SN2 or SN' 2 of 2,4,6-trichlorophenol on cyclohexadienone 2 with intermediate formation of polychlorophenoxycyclohexadienones 10 and 11.
0 (SN'2 C1
OH
I~C1
+
C1
C1~ N/C ]--~~'~SN 2
2_
Cl
C1
0 CI~ /u,,. ~C1
(16)
0 C1 C1
.C1
+
]~
' 0 ~ C1
C1
C1
C1
C1 1_!
As a second step the polychlorophenoxycyclohexadienones 10 and 11 oxidise 2,4,6-trichlorophenol back to tetrachlorocyclohexadienone 2 and polychlorophenoxyphenols 8 and 9.
156
cl*cl
+
A
c1
11
+
“0c1 c1
C1
Ci
3
c1 8
This mechanism shows the catalytic role of polychlorinated dichlorocyclohexadienone 2 explained in a different way. (Fig. 10)
157
gem-
OH
0 CI
/CI
O Cl
Cl
9
Cl
/
C1 C1
"~
- HCl
CC1~IO~ C1
C1
Fig. 10. Catalytic process of the formation of polychlorophenoxyphenols At temperatures up to 150~ for 7 hours, chlorophenols on their own do not produce any chlorophenoxyphenols. At the same temperature and time as above, polychlorinated gem-dichlorocyclohexadienones do not produce any chlorophenoxyphenols and consequently are stable products. A mixture of 2,4,6-trichlorochlorophenol and polychlorinated gem-dichlorocyclohexadienones produces some polychlorophenoxyphenols. A balance of this reaction indicates that the polychlorophenoxyphenols formed are the result of the condensation of the two chlorophenol molecules. Polychlorinated gem-dichlorocyclohexadienones have a catalyst function. This very important result shows the essential part played by the polychlorinated
gem-dichlorocyclohexadienones
in the parasite chemistry of the chlorination of
phenols.
Process performed with chlorophenols containing at least one hydrogen atom in a 2,4,6 position Apart from their greater reactivity, the behaviour of these chlorophenols with polychlorinated gem-dichlorocyclohexadienones is close to that of trihalogenated chlorophenols with a 2.4.6 position.
158
In this case too, the development of the mixture is a function of both the phenol (number and position of the chlorine atoms) and the polychlorinated gem-dichlorocyclohexadienone. Table 10. Percentage of transformed cyclohexadienones after heating 1 mM cyclohexadienones in 10 mM of phenol at 70~ for 8 hours.
of
% of transformed cyclohexadienones
Phenol
--OH
CI
C1
O CI~C1
O C I ~ C I
C1CI~-CI
C1CI~-cfCI
100 %
100 %
53 %
100%
15 %
7%
100 %
100%
49 %
10%
10%
6%
70 %
18%
7%
C1
C I @ O H C1
C1 CI
The reactivity of polychlorinated gem-dichlorocyclohexadienones decreases as the number of chlorine atoms increases. Most of the by-products formed during these reactions belong to the polychloro phenoxyphenols category. This is shown in the following example with the 2,4-dichlorophenol.
159
0
OH
C1
C1
CI
C1 C1 12 % yield
2
12
C1
C1
HO
c1
C1
+ C1
27 % yield C1
13 C1
C1
+ C1
6 % yield 9
el
C1
HO
C1
C1 8 % yield
8
C1
C1
C1 + C1
OH
26 % yield
C1
The
formation of the
condensation
of
SN 2 and
structures 12 SN' 2 of
and 13 is easily explained by
2,6-dichlorophenol
on
the
tetrachlorocyclo-
hexadienone 2, via phenoxycyclohexadienones 14 and 15 (eqns. 19, 20). 2,4,6-Trichlorophenol is the result of an intramolecular transfer of the chlorine according to the following equations "
160
.CI
0
OH
V
OH
" 0 ~ c1
~
Cl
C1
1
Cl
Cl
Cl
1__4
1__2
0
OH
CI
+
CI
OH
1
C1
OH C1
CI
+ C1
C
C1
0
C
13
0 C1
OH C1
CI
[ Cl OH
1
C1 ~
2
(20)
(21)
2
el
C1
The 2,4,6-trichlorophenol thus formed produces polychloro phenoxy phenols 8 and 9 through the process described in the previous section. Equations 19, 20 and 21 show the capacity of 2,4-dichlorophenol to be chlorinated by the ipso intermediates which results in consumption of polychlorinated gem-dichlorocyclohexadienones. This explanation easily demonstrates that phenols with a smaller amount chlorine appear to have the highest reactivity. As soon as they reach 70~
phenols with low chlorine content (phenol,
monochlorophenols, dichlorophenols) produce polychloro phenoxyphenols in the presence of polychlorinated gem-dichlorocyclohexadienones. In this case there is some consumption of polychlorinated
gem-dichlorocyclohexadienones.
161
BEHAVIOUR OF P O L Y C H L O R I N A T E D GEM-DICHLOROCYCLOHEXAD I E N O N E S W I T H ACIDS Chlorination of 2,4,6-trichlorophenol to tetrachlorophenol or pentaclorophenol is usually performed with an acid (refs. 12, 13). For this reason it was important to observe
the
reactivity
of
polychlorinated
gem-dichlorocyclohexadienones
in
chlorophenols in the presence of acids. To do this we studied the behaviour of a mixture containing the following components at 70~ - 1 mM of a polychlorinated
:
gem-dichlorocyclohexadienone
- 10 mM of a phenol - 2 mM of acid As the type of phenol used is mainly responsible for the formation of products, we will distinguish - as we did for the thermal stability - trihalogenated phenols in 2.4.6 position, and phenols containing at least one hydrogen atom in position 2.4.6.
Process performed with phenols containing chlorine atoms with a 2.4.6. position In the presence of either a Lewis acid or a strong Bronsted acid, the main reaction observed is the isomerization of polychlorinated
gem-dichlorocyclohexa-
dienone to chlorophenols (eqns. 22, 23). 2,4,6-Trichlorophenol acts as a solvent in this process.
0 C1
OH C1
AIC13(2.5 mM) 70 ~ - 8 h ~ C I ~ / ~ C 1 2,4,6-Trichlorophenol (10 mM)
Yield = - 90 %
(22)
Yield =-~ 80 %
(23)
CI
2
Cl
OH C I ~ C 1
C%l.>
A1C13(2.5 mM) 70 ~ - 8 h 2,3,4,6-Tetrachlorophenol (10 mM)
E1~
C1 C1
162
When performed under similar conditions, gaseous hydrochloric acid formed during the chlorination process hardly creates any isomerization of polychlorinated gem-dichlorocyclohexadienones to chlorophenols. This difference in reactivity explains why it is necessary to use either a strong acid or a Lewis acid to reach the tetra or penta stage. The yield produced by isomerization varies according to the nature of the acid used. This is shown in the table below : Table 11. Reactivity of 2,4,4,6-tetrachlorocyclohexa-2,5-dien-l-one 2 in the presence of acid at 70~ and for 8 hours. Yield relative to the introduced cyclohexadienone O
CI~ 7C!
Acid
C!~" ~C1
c,yyc, OH
OH
CI
CI
Cl
ci~
_2 transformed% without acid CF3SO3H cH3~so3rt
rho
2 %
1%
9,6 %
100 %
90 %
72 %
25,3 %
1,5 %
15 %
100 %
14,5 %
6,4 % 5,7 %
H2SO 4
at
98 %
0,8 %
7,5 %
HC10 4
at
70 %
100 %
1%
0,7 %
22 %
HC1
at 37 %
28 %
11,5 %
3,4 %
2,7 %
[A1C13
100 %
90 %
0,7 %
2,8 %
TIC14
99 %
90 %
7,4 %
6%
TiC13
50 %
2%
100 %
85 %
2,9 %
11,6 %
FeC13
l
The yield of the tetrachlorophenol, the nature and quantity of chlorophenoxyphenols vary according to the type of acid used. A1C13 appears to be the acid which produces the least parasite chemistry. This is confirmed by the chlorination experiments performed indicating that, generally, A1C13 is the best catalyst. Trifluoromethanesulphonic
acid
does
6-(2,4,6-trichlorophenoxy) phenol 9.
163
not
produce
any
2,4-dichloro
OH
C1
I
c1
_9
This result can be of interest since this type of chlorophenol is a precursor of polychlorodibenzodioxins. According to the polychlorinated gem-dichlorocyclohexadienone and acid used, the reaction mechanism is either intermolecular, or intramolecular. Consequently the transformation of 2,3,4,4,6-pentachlorocyclohexa-2,5-dien-1one 3 (1 mM) in the presence of A1C13 (2.5 mM) in 2,4,6-trichlorophenol (10 mM) leads to the formation of a unique product : 2,3,4,6-tetrachlorophenol. As a whole, this process appears to be intermolecular. 0
I I c l ~ c 1
OH
AIC13(2.5 raM)
c1
c1 (24)
2
CI~I " > ~ C 1 U" " 3
70~
8hr OH
C1
C1 CI
C1
1.68 mM intermolecular (10 mM) C1 The reaction starts off with chlorine transfer to pentachlorocyclo-hexadiene 3 with 2,4,6-trichlorophenol to produce some 2,3,4,6-tetrachlorophenol and tetrachlorocyclohexadienone 2 (eqn. 25).
164
O
c, c, +Cl CI~cI.~C
1
OH
OH
c,
c, c, c,+ CU
C1
0
.Cl (25)
T
C1
3
2
OH
A1Cl3
C1
,C1
2
CI CI
During the following step the cyclohexadienone 2 isomerizes to tetrachlororophenol in an intramolecular way. This last point was perfectly demonstrated by heating a mixture of tetrachlorocyclohexadienone 2 (1 mM) and 2,3,4,6-tetrachlorophenol (10 mM) in the presence of A1C13, at a temperature of 70 ~ for 8 hours. 0
OH
CI~CI+
CI~,/C1
(21/ "(21 2
CU
OH A1C13 C1
T C1
CI
absence of pentachlorophenol
(26)
C1 C1
As opposed to this, the transformation process of the same cyclohexadienone 3 (1 mM) under the same conditions with trifluoromethanesulphonic acid produces a mixture of 2,3,4,6-tetrachlorophenol and pentachlorophenol, by intermolecular and intramolecular processes. OH CI~CI
CF3SO3H(2.5 mM)
ClcI,,/~-Cl
70~ - 8 h OH CI~CI
CI
jCl?l~
OH [~Cl (27)
2
[
CI
CI~
CI
CI CI 0.5 mM 0.67 mM INTERMOLECULAR INTRAMOLECULAR
(10 mM)
CI 165
Results obtained can be explained by the following reaction mechanisms 9
C!
OH -- cICI~~CI CI
0......H|
0
CIcI~C! CI - H+
OH ~:~CI
CICI~CI CI
~MOLECULAR (28)
x ~~ CI Cl
~,,,,,,,H
OH CI~/CI+ H
CI
CIl ~ C i
OH CI
CU y CI
_-
C1/ y CI
Fig. 11. Intramolecularand intermolecular mechanisms To conclude, strong acids and Lewis acids transform polychlorinated gemdichlorocyclohexadienones in chlorophenols. Polychlorinated gem-dichlorocyclohexadienones are true intermediates in the formation of chlorophenols that have one chlorine atom in meta position of the OH. According to the reaction system used (nature of the acid, of the polychlorinated gem-dichlorocyclohexadienone, and of the polychlorophenol) either an intramolecular migration of the chlorine (isomerization) or a intermolecular transfer occurs. - I n addition to the transformation of polychlorinated gem-dichlorocyclohexadienones to polychlorophenols, formation of polychlorophenoxyphenols - in quantities varying according to the acid used in the process - also takes place. Process performed with chlorophenols containing at least one hydrogen atom in a 2.4.6. position When these
chlorophenols
are
used
to
run
the
process,
hardly
any
transformation of polychlorinated gem-dichlorocyclohexadienones in chlorophenols takes place.
166
O
OH
C1
C1
Acid
CI~
C1 (28)
X Chlorophenol containing at least 2.4.6
c1
C1
one hydrogen element in
The products formed are mostly polychlorophenoxyphenols and polychloro dihydroxybiphenyls, which are other families of by-products found in the chlorination masses. Polychloro dihydroxybiphenyls are mostly found with phenol and o'-chlorophenol (eqns. 30, 31). 0 Cl~/Cl
OH
AICI3(2.5 mM)
+ I~~..;.Cl
or
CF3SO3H (2.5 mM)
OH CI,,.~C1 (29)
70 ~ - 8 h
C1~
"CI
10 mM
1 mM
"~ C1
"C1
Yield
=2%
CI + CI
~
O
HO
CI Yield
OH
O
A1CI3(2.5 mM)
H C1 = -~60 %
C1
C1
OF
CF3SO3H(2.5 raM)
cl Icl c
1
+
70~ - 8 h
+C I ~ ~ ~ - O H /
HO
10 mM
1 mM
\ Yield
C1 = - 40 %
(30) 17
3 Preparation and characterization of the biphenyls was performed using the following technique.
167
CI
c1
c1
The formation of polychlorodihydroxybiphenylsis the result of a nucleophilic attack on the protonated form of the cyclohexadienone (Fig. 12).
168
o CI~
.H O"
o~ C1 -.. H+ ,._ C I. ' ~ ~ ,L, _ u C _I
C1
C1
OH
OH
OH
1 OH CI
.C1
C1
/~"~OH
Fig. 12. Mechanism of formation of polychlorodihydroxybiphenyls When the process is performed with 2,6-dichloro and 2,4-dichlorophenol, polychlorophenoxyphenols formed as well as polychlorodihydroxybiphenyls (eqn. 31).
169
cQcy$
1 rnM
NCI3 70"(2.5mM) - 8h
*
c1
CI 10 rnM
0.94 rnM
OH
I
c1 0.04 mM
0.18 rnM
Cl
c1
0.45 mM
CI
The formation of biphenyl 20 can be explained by the oxydation of 2,4-dichloro phenol by 2,4,4,6-tetrachlorocyclohexa-2,5-dien-l-one 2 (eqn. 32).
170
0 C1
OH C1
2
OH
CI +
~
2
+ 2 HC1
C1
2_
C1
CI
2
C1
(32)
C1
OH
r/"~
C1
CI
+
c1
20
Fig. 13. Mechanism of formation of biphenyls 20 Polychlorinated gem-dichlorocyclohexadienonesin the presence of a strong acid do not change into chlorophenols when processed in chlorophenols containing at least one hydrogen atom in ortho or para position. The main products formed are : polychlorophenoxyphenols and polychlorodihydroxybiphenyls.
REACTIVITY WITH WATER P. SVEC (ref. 6) demonstrated that polychlorinated
gem-dichlorocyclohexa-
dienones hydrolysed in halogenated benzoquinones. O C1
O c1
C1
c1 (33)
+ H20
Chlorinated benzoquinones are also a family of by-products produced during the chlorination of heavy chlorophenols (trichlorophenols, tetrachlorophenols, pentachlorophenols) (Fig. 13). We observed that the quantity of benzoquinones formed is linked to the presence of water contained in the reactants.
171
0 C1
OH C1
2
OH
CI +
~
2
+ 2 HC1
C1
2_
C1
CI
2
C1
(32)
C1
OH
r/"~
C1
CI
+
c1
20
Fig. 13. Mechanism of formation of biphenyls 20 Polychlorinated gem-dichlorocyclohexadienonesin the presence of a strong acid do not change into chlorophenols when processed in chlorophenols containing at least one hydrogen atom in ortho or para position. The main products formed are : polychlorophenoxyphenols and polychlorodihydroxybiphenyls.
REACTIVITY WITH WATER P. SVEC (ref. 6) demonstrated that polychlorinated
gem-dichlorocyclohexa-
dienones hydrolysed in halogenated benzoquinones. O C1
O c1
C1
c1 (33)
+ H20
Chlorinated benzoquinones are also a family of by-products produced during the chlorination of heavy chlorophenols (trichlorophenols, tetrachlorophenols, pentachlorophenols) (Fig. 13). We observed that the quantity of benzoquinones formed is linked to the presence of water contained in the reactants.
171
REACTIVITY WITH CHLORINE
Chlorine reacts with polychlorinated gem-dichlorocyclohexadienones to produce polychlorinated cyclohexenones (ref.6) (eqns. 34, 35). O
O + C1
~
(34)
C C1 l i ~
Clcl.>
c
O CI~C1 / ~ C 1 C1 C1 C1
O CI~/~/C1 Cll~fl - - / ~ C 1 C1~ ~ C1 C1
+ C12
~
cl
(35)
We were able to detect and segregate the polychlorinated cyclohexenones from the chlorination reaction masses. o CI~C1
O Cl~.~/C1 C1
C
o CI~/~/C1 C1
C1
C1~
"~ C1
"C1
This action again confirms the essential part played by the polychlorinated gemdichlorocyclohexadienones in the parasite chemistry.
CONCLUSION The development of an efficient analytical method enabled us to detect the presence of polychlorinated gem-dichlorocyclohexadienones in chlorination reaction masses. An in-depth study conducted on reactivity demonstrated that polychlorinated gem-dichlorocyclohexadienones had a very high degree of reactivity (Fig. 14), but above all explained how the mechanisms related to these compounds - which may have sometimes a catalytic quality - worked. 173
REACTIVITY WITH CHLORINE
Chlorine reacts with polychlorinated gem-dichlorocyclohexadienones to produce polychlorinated cyclohexenones (ref.6) (eqns. 34, 35). O
O + C1
~
(34)
C C1 l i ~
Clcl.>
c
O CI~C1 / ~ C 1 C1 C1 C1
O CI~/~/C1 Cll~fl - - / ~ C 1 C1~ ~ C1 C1
+ C12
~
cl
(35)
We were able to detect and segregate the polychlorinated cyclohexenones from the chlorination reaction masses. o CI~C1
O Cl~.~/C1 C1
C
o CI~/~/C1 C1
C1
C1~
"~ C1
"C1
This action again confirms the essential part played by the polychlorinated gemdichlorocyclohexadienones in the parasite chemistry.
CONCLUSION The development of an efficient analytical method enabled us to detect the presence of polychlorinated gem-dichlorocyclohexadienones in chlorination reaction masses. An in-depth study conducted on reactivity demonstrated that polychlorinated gem-dichlorocyclohexadienones had a very high degree of reactivity (Fig. 14), but above all explained how the mechanisms related to these compounds - which may have sometimes a catalytic quality - worked. 173
All the products formed from polychlorinated gem-dichlorocyclohexadienones in the presence of chlorophenols are indeed those identified in the chlorination of phenol. These results confirm our hypothesis, and prove the essential role of polychlorinated gem-dichlorocyclohexadienonesas reaction intermediates which can react to give either noble products (chlorinated phenols in meta), or unwanted condensation products (polychloro phenoxy phenols, polychloro dihydroxy biphenyls, etc.). Improvement of the quality of chlorophenols implies that the chemical evolution of the polychlorinated gem-dichlorocyclohexadienones is controlled during the chlorination reaction.
References 1. Kirk Othmer Encyclopedia of Chimical Technology Third Edition, John Wiley, Wol. 15, p. 916 ; vo1. 13, p. 39, Ed. 1981 ; vol. 5, pp. 797, 1979, (1981). Cahier de notes documentaires, 99, 243, (1980). 3. Chlorodioxins - Origin and Fak., p. 55, Advances in chemistry series - American Chemical Society. M. Kulka - Can. J. Chem., 39, 1973, (1961). 5. H.I. Joschek, S.I. Miller, J. Amer. Chem. Soc., 88 (14), 3269, (1966). 6. J.R. Plimmer, U.I. Klingebiel ; Science, 174, 407, (1971). 7. P. Svec, Th6se Pragues, (1973). 8. H. Miiller, H. Linde, J. Prakt. Chem., 4 (5), 77, (1957). 9. R. Fort, Ann. Chim., 13 (4), 203, (1959). 10. P. Svec, M. Zbirovsky, Collect. Czech. Chem. Comm., 4_9_0(10), 3029, (1975). 11. P. Svec, V. Kubelka, Fresenius Z. Anal. Chem., 277 (2), 113, (1975). 12. Monsanto, US 1213090 (1969), (to Monsanto). 13. JA 61' 7017 (1958), (to Toyana Chemical Industry Company). .
.
175
DIASTEREOSELECTIVE HALOGENATIONS
P. DUHAMEL Universit6 de Rouen, URA C.N.R.S 464 et I.R.C.O.F. 76821, Mont-Saint-Aignan Cedex, France.
INTRODUCTION Diastereoselective halogenations using removable chiral auxiliaries have been the purpose of recent significant developments, a-Halo aldehydes, or-halo ketones and c~-halo carboxylic acid derivatives are very useful precursors involved for total syntheses of pharmaceutical drugs and phytochemicals. In most cases, the biological activity is associated with one of the two enantiomers. So, diastereoselective halogenation of carbonyl compounds and carboxylic acid derivatives has attracted considerable attention in recent years, as a tool for the production of enantiomerically pure substances. The numerous examples of diastereoselective halogenation of compounds with non removable chiral adjuvants are outside the scope of this review.
ASYMMETRIC HALOGENATION OF KETONES VIA ENAMINES OF LPROLINE ESTERS K. Hiroi and S.I. Yamada have reported for the first time, in 1973, the asymmetric synthesis of ~ halo ketones by the diastereoselective bromination of ~-enamines of L-proline esters (ref. 1). Thus cyclohexanone was converted, via its enamine, to the (R)-2-bromo cyclohexanone (Fig. 1).
176
0
~'~COOEt
COOEt
' H
I Br2, CHC13, -15~
~
..Br
~COOEt
" (R) .., Aq. HC1 / benzene
Br-~,
.Br(R)
ee% :37 yield from cyclohexanone : 47 % Fig. 1. Asymmetric synthesis of (R)-2-bromo cyclohexanone
ASYMMETRIC HALOGENATION OF KETALS DERIVED FROM TARTARIC ACIDS ESTERS Asymmetric halogenation of chiral acetals has been realized by C. Giordano (refs. 2-7). Using alkyl esters of optically active tartaric acids as chiral auxiliaries, a high diastereoselectivity is obtained even at room temperature. The results are best explained by a fast electrophilic addition of bromine on the electron rich enol ether, originating from an acid-catalyzed equilibrium with the chiral acetal. If (2R, 3R)tartaric acid is involved, a S-configuration prevails at the new stereogenic center. Finally, cautious hydrolysis provides a set of 2-bromo alkyl aryl ketones, which can be obtained in enantiomerically pure form after crystallization (Fig. 2) :
177
MeOOC
COOMe
MeOOC
COOMe
H+ 0
O_
0
OH
Ar~
Ar~X~
Me
Me
Br2; CC14" 15~
MeOOC
O
COOMe
1~ H20, CH3SO3H, 20~ Ar
S) Me
2 ~ Crystallisation
0
0
Br
Ar~(s) Me
ee% > 9 8
64 < de % < 88 90 < yd % < 98
Ar" X = H, Me, iBu, C1
Fig. 2. Synthesis of enantiomerically pure 2-bromoalkyl aryl ketones
The diastereomeric ratio is only slightly affected by change of solvent (ref. 3) (Table 1).
178
Table 1. Solvent effect on the diastereoselectivity of the bromination MeOOC 0
COOMe
MeOOC
0 Br2
~
~
0
B
r
"MeO
COOMe 0 Me
(s)
MeO
Solvent
Temp. (of)
Reaction time (h)
Yd %
De %
Ethyl acetate
- 10
8.5
89
88
Toluene
- 10
2.5
88
86
Carbon tetrachloride
- 10
2.0
98
86
Carbon tetrachloride
+ 15
1.0
98
84
Dichloromethane
- 10
1.0
96
80
Owing to the simplicity, selectivity and economy of this new procedure, the c~bromo alkyl aryl acetals have been proposed as starting materials for the industrial production of some 2-aryl propionic acids such as the important pharmaceutical drugs, Ibuprofen and Naproxen. For instance, the preparation of enantiomerically pure Naproxen has been carried out, in one step, by means of the highly stereoselective Lewis acid catalyzed rearrangement of a starting a-bromo acetal, involving a 1,2-aryl shift (ref. 3) (Fig. 3) : MeOOC 0
COOMe O~
Ag+
Br"
1~ Ag+BF42~aq.HCl, 85~
COOH
M
e
O
~
MeO ee% >98
Enantiomerically pure NAPROXEN yield 993 %
Fig. 3. Synthesis of Naproxen
179
ASYMMETRIC
HALOGENATION
OF
CARBOXYLIC
ACIDS
DERIVATIVES PREPARED FROM C A M P H O R - 1 0 - S U L F O N I C ACID In the same way as enantiomerically pure ~-halo ketones, o~-halo esters have been prepared in high diastereomeric excesses by asymmetric halogenation of silyl ketene acetals generated from chiral esters 9So, a successfull procedure was first introduced in 1985, by W. Oppolzer (refs. 8,9), using derivatives of camphor-10sulfonic acid as chiral auxiliaries (Fig. 4).
Si
"',,
O H
R2
R2
NXS
X
O
2 ~ LDA, TMSCI
H SO2NR12 OTMS 84 < crude de% < 96 68 < crude yield % < 91
R1- cyclohexyl R2" Me nBu X 9 CI
Ph
C1,Br C1
iBu nCsH17 Br
After crystallisation 9 de% > 96
C1, Br
54 < yield % < 77 Fig. 4. Asymmetric halogenation of silyl enol ethers derived from camphor-10-sulfonic acid esters.
The
results,
c~-halo esters of (S) configuration,
are consistent with an
electrophilic addition of the "halonium" on the less hindered Si face of the 13carbon of the keten acetals. Obviously, a-halo esters with (R) configuration are obtained if the antipode of the aforementioned chiral auxiliary is used. It is noteworthy that this procedure not only affords crude a-halo esters in high diastereoisomeric excess but, allows, by a simple crystallisation, to obtain them, in quantitative diastereoisomeric excess. Similarly, using bornane [10,2] -sultam as a chiral auxiliary, provides, via the bromination
of
the
intermediate
boryl
enolates,
an
diastereoisomerically pure a-halo esters (ref. 10) (Fig. 5) :
180
alternative
route
to
R NO ~ "
Bu2BOTf . EtNiPr2 CH2C12,-5~
~ R
NBS ~ THF,-78~
R ~i N
Br
O 85 < de% < 100
Fig. 5. Asymmetric bromination of boryl enolates of bornane-10,2-sultams These diastereoisomerically pure derivatives were not converted in free a-halo carboxylic acids, but transformed into halohydrins, terminal epoxides (ref. 8) and c~-amino acids (refs. 9,10).
ASYMMETRIC HALOGENATION OF CHIRAL IMIDE ENOLATES Asymmetric halogenation of carboxylic acid derivatives has also been achieved by D.A. Evans (refs. 11,12) via chiral N-acyl oxazolidones. For instance, an Nacyl oxazolidone prepared by acylation of the (4S)-benzyl-2-oxazolidone chiral auxiliary derived from (S)-phenylalanine, is converted to its (Z)-dibutyl boron enolate, which is added to a NBS slurry, at low temperature (Fig. 6) : O 0 ~.~NH
O
O
.o R
Bn
O
\ ( Bn Bu2BOTf, iPr2NEt, CH2C12, -78~ Bu\ / Bu
O
O NBS CH2C12 -78~
\
(,
Br Bn
88 < de % < 92
o/B~o
\(
Bn R : Ph-CH2, iPr, iPr-CH2; tBu; allyl
Fig. 6. Asymmetric halogenation of chiral imide enolates. 181
The sense of asymmetric induction is consistent with an electrophilic bromination of the Si face of the boron enolate, yielding an c~-halocarboximide of (S) configuration and displaying a high level of diastereoselectivity. The c~-halo carboximides are not hydrolyzed to free carboxylic acids, but converted to c~-amino acids, by a procedure implicating the involvement of intermediate a-azido carboximides (refs. 11,12).
ASYMMETRIC HALOGENATION OF KETENE ACETALS DERIVED FROM ESTERS OF D-(+)-GLUCOSE DIACETONIDE Finally, free G~-chloro acids have been prepared in high enantiomeric excess by chlorination of silyl keteneacetals using D-(+)-glucose diacetonide as chiral auxiliary (refs. 13,14). The most outstanding features of this very efficient chiral auxiliary are the cheapness, and the easy hydrolysis of the final G~-halo esters, that allows the removal of the chiral auxiliary under nonracemising conditions : moreover, this compounds is non toxic and is commercially available. According to the usual procedure, the carboxylic esters of D-(+)-glucose diacetonide are converted into silyl ketene acetals. The chlorination by N-chloro succinimide (NCS) carried out in THF, at low temperature, provided ~-chloro esters, with a high diastereoselectivity. Hydrolysis without racemization to the free ~-chlorocarboxylic acids is best realized either in acidic conditions (aq. HC1), or using LiO2H. With the first method, the chiral auxiliary is also hydrolyzed, nevertheless it can be recovered undamaged in quantitative yield using the second method instead (Fig. 7) :
182
C1 R(S)~ R
~ i
i
J OH "~ O
OH
O 85 < 66 <
ee % < 95 yield % from
1 < 79
R 9Me, Pr, iPr, nBu, tBu...
/ O
LiOOH
TMSO
o oJ.v~
,~
~O---~ ]
LDA, C1SiMe3 ...~O. O
~'O~o/..~.
o R
NCS
~ THF, - 70~
THF, -70~
~.O.O
O
,o.)__ E 990-100 %
1
85 <
de
% < 95
Fig. 7. Asymmetric halogenation of silyl ketene acetals derivated D-(+)-glucose diacetonide.
It is noteworthy that the level of the enantiomeric excess and the configuration of the a-chloro esters, were found to be not affected by the double bond configuration. Thus, with the same chiral auxiliary, i.e. D-(+)-glucose diacetonide, the electrophilic attack proceeds always on the same Si-face of the silyl ketene acetal whatever the E or Z configuration of the starting material (Fig. 8). TMSO
TMSO
Me
O---
ot
1 ~ NCS
O..~ \
2 ~ LiOOH
~
O
Me ~
HO
, (~1 ee'90
Z
1~ NCS 2 ~ LiOOH
%
E
Fig. 8. 13-Controlled diastereoselective chlorination
183
At this stage, we have to answer the question : what happens if an c~-chloro acid of (R) configuration is desired instead of an (S) one ? According to the Latent Trigonal Center (L.T.C.) Concept (ref. 15) (Fig. 9 bis) asymmetric additions belong either to a-controlled or to 13-controlled reactions. In the first group (orcontrol), using the same chiral auxiliary, just changing the configuration of the starting enolate from E (or Z) to Z (or E) is enough to obtain a final product of opposite configuration. In the second group (13-control), asymmetric additions on enolates carried out with the same chiral auxiliary, lead to a final product of same configuration whatever the E or Z configuration of the double bond (Fig. 9). In this last case, availability of the two enantiomers of the chiral auxiliary is required, if the two final products of opposite configuration are wanted. C1+
C1+ C1 -~'cMe H
O2R*
(E)
(E)
C1+
C1+ C1 -~
Me~CO2R* (Z) a-Controlled Chlorination The E and Z isomers lead to different isomers
(Z) 13-Controlled Chlorination The E and Z isomers lead to the same isomer Fig. 9. Latent Trigonal Center (L.T.C.) concept (ref. 15)
184
LATENT TRIGONAL CENTER (LTC) CONCEPT (P. DUHAMEL)
or-control
13-control
Z and E lead to
Z and E lead to
different
the same
enantiomers
enantiomer
a and/or b = electrondonating groups; c, d = H, substituents: e = electrophilic species
185
Obviously, the chlorination of silyl ketene acetals belonging to the group of 13controlled asymmetric additions, it is necessary, if a-chloro acids with (R)configuration are wanted, to operate with the chiral auxiliary of opposite configuration, i.e., the very expensive L-(-)-glucose diacetonide. Whenever it occurs that the mirror image of a very cheap natural product is a very expensive molecule, as for instance L-(-)-glucose, it sounds like a good idea to look for its unnatural but cheap "chiral equivalent". Thus, it was shown in preliminary studies, that the furanic oxygen, and the two oxygenated functions in 1,2 positions of D(+)-glucose diacetonide are not essential for the efficiency of this chiral auxiliary. Therefore, the very expensive L-(-)-glucose diacetonide required for the asymmetric synthesis of (R)-a-chloro acids, can be successfully replaced by a simple enantiomerically pure molecule synthesised from cyclopentanone (ref. 16) (Fig. 10)
~
J
-
i D ( +)-Glucose diacetonide
0 0
.-.O
S L (-)-Glucose diacetonide
Chiral equivalent of L (-)-Glucose diacetonide
OH HO
OH OH D (+)-Glucose
HO
0
L (-)-Glucose
Fig. 10. Chiral equivalent of L-(-)-glucose diacetonide.
This partially undressed L-(-)-glucose behaves as the chiral equivalent of L-(-)glucose diacetonide affording ot-chloro propionic acid of (R)-configuration, with the same enantiomeric excess (Fig. 11) "
186
TMSO
O
" Memo
_
c1
/.I NCS \
ee "90 %
o..).._ O
O
OTMS H
Cl
i
ee-90 %
i
i
' (R)
!
~-,~ NCS ~
.~
Fig. 11. Asymmetric chlorination using chiral equivalent of L-(-)-glucose diacetonide.
Finally, the lowest enantiomeric excess obtained with c~-chloro propionic acid can be raised up to enantiomeric purity, by simply introducing a methylene group in place of the oxygen atom in the 5-position (ref. 16) (Fig. 12) 9 TMSO O 1o NCS, THF,-70~
HO ( S ) ~ / , Me i
2 o LiOOH
\
C1
o
X
O
CH2
ee
90 %
> 99 %
Fig. 12. Improvement of the stereoselection by modification of the chiral auxiliary
References
1. 2. 3. 4. 5. 6. 7. 8. 9.
K. Hiroi, S.I. Yamada, Chem. Pharm. Bull. (Tokyo), 21, 54 (1973). G. Castaldi, S. Cavicchioli, C. Giordano, F. Uggeri, Angew. Chem. Int. Ed. Eng., 25, 259, (1986). G. Castaldi, S. Cavicchioli, C. Giordano, F. Uggeri, J. Org. Chem., 52, 3018, (1987). G. Castaldi, S. Cavicchioli, C. Giordano, A. Restelli, EP 217, 375, (1987), (to Zambon S.p.a.). G. Castaldi, S. Cavicchioli, C. Giordano, A. Restelli, EP 217, 376, (1987), (to Zambon S.p.a.). G. Castaldi, C. Giordano, Synthesis, 1039, (1987). C. Giordano, L. Coppi, A. Restelli, J. Org. Chem., 55, 5400, (1990). W. Oppolzer, P. Dudfield, Tetrahedron Lett., 26, 5037, (1985). W. Oppolzer, R. Pedrosa, R. Moretti, Tetrahedron Lett., 27, 831, (1986). 187
10. 11. 12. 13. 14. 15. 16.
W. Oppolzer, Pure Appl. Chem., 62, 1241, (1990). D.A. Evans, J.A. Ellman, R.L. Dorow, Tetrahedron Lett., 28, 1123, (1987). D.A. Evans, T.C. Britton, J.A. Ellman, R.L. Dorow, J. Am; Chem. Soc., 112, 4011, (1990). L. Duhamel, P. Angibaud, J.R. Desmurs, J.Y. Valnot, Synlett, 807, (1991). P. Angibaud, J.L. Chaumette, J.R. Desmurs, L. Duhamel, G. PI6, J.Y. Valnot, P. Duhamel, Tetrahedron : Asymmetry, in press. P. Duhamel, L. Duhamel, C.R. Acad. Sci., 320 IIb, 689, (1995). J.L. Chaumette, J.Y. Valnot, unpublished results.
188
ENZYMATIC HYDROLYSIS OF ADIPONITRILE VALERIC ACID, AN INTERMEDIATE FOR NYLON 6
INTO
5-CYANO
EDITH CERBELAUD a), MARIE-CLAUDE BONTOUX a), FLORENCE FORAY a), DIDIER FAUCHER b), SOPHIE LEVY-SCHIL b), DENIS THIBAUT b), FABIENNE SOUBRIER b), JOEL CROUZET b) AND DOMINIQUE PETRE a) a) Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie, 85 Avenue des Fr&es Perret, BP 62, 69192 Saint-Fons Cedex, France. b) Rh6ne Poulenc Rorer Gencell, CRVA/IBV, 13, quai Jules Guesde, B.P. 14, 94403 Vitry-sur-Seine Cedex, France.
An industrial process must be economic and safe for the environment. The chemical hydrolysis of nitrile in acid is well known (ref. 1). Nearly all nitriles react with either basic or acid catalysts, but considerable quantities of inorganic salts are always produced as by-products. The only way to suppress these by-products is to produce the ammonium carboxylate under neutral pH and then to recover the ammonia by dissociation of the salt between the weak base and acid. Therefore, we suggest the route shown in Figure 1.
Nrt3 CN Adiponitrile
~"
CO2",NH4+
~'~"NH O
Ammonium 5-cyanovalerate
[NYLON 6[
Caprolactame
Fig. 1. The chemo-enzymatic route for caprolactame
Apart from the neutral pH, a second challenge for the catalyst is to select the cyano group of adiponitrile without affecting the one in ammonium 5-cyanovalerate (CVA). For these two main reasons, mild conditions and chemo-selectivity, we attempted enzymatic catalysis. 189
Microbial hydrolysis of organic nitriles has been found to proceed by two major enzymatic pathways (see figure 2). nitrile~
RCONH2
RCN
I amidase RCO2_,NH4+
Fig. 2. The two different enzymatic pathways for the hydrolysis of nitrile into ammonium carboxylate. The first pathway via the amide uses two different enzymes 9a nitrile hydratase and an amidase, and in the second one, the nitrile is directly hydrolysed
into
ammonium carboxylate by a nitrilase. When the enzymes are not pure, we often discriminate between the two routes by using the amide, a substrate which is present only in the first system. If we focus on the enzymatic hydrolysis of adiponitrile, we find that the literature contains references to a great number of strains producing these different enzymes (Table 1). Table 1: Strains hydrolysing the adiponitrile. Micro-organisms
Reference
Brevibacterium B222
Novo Industri (ref. 2) Yamada et al (ref. 3) ; Galzy et al (ref. 4) Godlust et al (ref. 5) Kikuchi et al (ref. 6) Yanase et al (ref. 7) Asahi Chem. (ref. 8) Novo Ind. (refs. 9, 10, 11) Nissei K.K. (ref. 12) Nippon Mining (ref. 13) Gutman et al (ref. 14) Yamada et al (refs. 15, 16)
Brevibacterium R312 Fusarium oxysporum f. sp. melonis Fusarium solani MN7030 Pseudomonas sp. 13 Rhodococcus AK-32 Rhodococcus sp. CH5 Rhodococcus sp. YK 196 Rhodococcus rhodochrous PA34 Rhodococcus rhodochrous NCIB 11216 Rhodococcus rhodochrous K22
Generally, the reaction products are not clearly identified and we cannot evaluate the selectivity. However, in both Brevibacterium strains isolated by P. Galzy, such an idemification was possible. With Brevibacterium R312, the CVA is a kinetic product and the best yield is 50% with other by-products such as 190
adipamic acid and adipamide being formed (ref. 4). In a patent, Novo Nordisk exemplified the hydrolysis of AdN in CVA using Brevibacterium B222 with a 90 % yield (ref. 1). With both these strains, the enzymatic system is composed of nitrile hydratases and amidases. The nitrile hydratase gene of Brevibacterium R312 is cloned, sequenced (ref. 17) and over expressed in Rhodococcus rhodochrous ATCC12674 (pKRNH2) (ref. 18). The best selectivity which can be hoped for with this nitrile hydratase is 93 % (ref. 4). Moreover, the cyanovaleramide with its poor solubility must not be accumulated and requires a biocatalyst with a superactivated amidase activity. The nitrile hydratase is less stable than amidase and the biocatalyst with these two enzymes would not be sufficiently robust for an industrial application. Consequently, we looked for a nitrilase which removes the problem of regulation between the two activities and give directly the CVA, a very soluble product. To design this biocatalyst, we followed four different steps : -finding the strains producing a nitrilase activity by microbiological screening starting from samples of earth, - selecting the best enzymes by purification and characterization, -overexpressing the nitrilase activity in a recombinant strain using molecular biology, - improving the selectivity of the enzymes by mutagenesis.
RESULTS Microbiological screening The following screening which allowed isolation of the correct nitrilases was initially designed to select enzymes degrading AdN into ammonium adipate (ADO). As the slow steps of this reaction were generally the hydrolysis of ionic compounds (ammonium adipamate (Adm) and ammonium 5-cyanovalerate), the sodium 5-cyano valerate was used as a unique nitrogen source for the selection pressure. The method of screening was very classical with four main steps " 1) enrichmem of earth samples with relevant strains in minimum liquid as an unique nitrogen source using sodium 5-cyano valerate . The earth samples were collected under peach, walnut, and almond trees and on different plants producing nitrile compounds. After three or four days of culture, the micro-organisms were collected and put again into the same fresh medium but with a higher CVA concentration. Thereafter, the CVA concentration was increased six times. 191
2) At each step of enrichment, the micro-organisms were isolated in a Petri dish using the medium A with 2 % agar-agar and then purified in the same medium. 3) To evaluate the strains that were isolated, each clone was cultivated in 3 ml liquid medium A using 1.5 g/1 CVA. The cells were collected by centrifugation and the pellets was added to 25 mM CVA and 50 mM pH 7 phosphate buffer. The best ones, seventy strains, were thus selected. 4) To confirm the performance of these strains, their activities for the production of AdO starting from CVA and AdN were measured and compared to those of B r e v i b a c t e r i u m R312. The four best ones were identified and are listed in Table 2.
Table 2. Strains issuing from the microbial screening having the best activities for the production of AdO starting from AdN and CVA. Specific activities (mole/h.kg dried cell) AdN CVA
Microorganisms
Brevibacterium R312
0,17
0,22
Comamonas testosteroni
2.9
1.6
Bacillus sp.
0.8 0.2 2.3
2.7 0.4 1.2
Brevibacterium sp. Comamonas acidovorans
Common conditions 9T~ 25 9[AdN] = [CVA] = 50 mM 950 mM Phosphate buffer pH 7 The C o m a m o n a s NIl activities were determinated on AdN and four putative intermediates 95-cyanovaleramide, CVA, adipamate and adipamide (Table 3). Table3. Comamonas NIl activity on adiponitrile, ammonium 5-cyanovalerate, 5-cyano valeramide, ammonium adipamate and adipamide Conditions [nitrile] [driedcell] mM (g/l) 50 3.4
Substrate Adiponitrile Ammonium 5-cyano valerate
37
Specific activity (mole/h.kg of DC) 8
13
2.2
Common conditions 950 mM phosphate buffer pH 7 - T~ = 25. During the AdN unique intermediate was detected. These CVA catalysed by a
hydrolysis into adipate, the ammonium 5-cyanovalerate was the product. Moreover, for the other compounds, no intermediate different kinetic data predicted a conversion of adiponitrile into nitrilase.
192
Putative nitrilase purification of Comamonas N i l
The purification steps were mainly carried out in 50 mM TrisHC1 buffer, pH 7.5, 1 mM dithioerythrytol. At each step, the nitrilase activity of the fractions was determinated at pH 7 and at 25 ~ of
10 m M
adiponitrile.
The protein
Commassie blue method. (Phasystem pharmacia|
in 10 mM phosphate buffer in the presence concentration
was determined
The protein pannel was analysed by SDS
by
the
PAGE
The data from each of the steps are listed in Table 4.
Table 4. Purification of the nitrilase of Comamonas NIl Activity
Yield
Purification Step
Vol. (rnl)
Protein (mg)
1- Crude extract
61
920
62
68
100
100
1
130
250
47
190
27
76
2.8
36
27
56
2100
2.9
90
30
4- Hydroxyapatite column
3
12
49
4100
1.3
79
60
5- Phenyl Superose
51
11
11
1000
1.1
18
15
6- Gel filtration
9
2.7
6.3
2300
0.3
10
34
2.9
1
1.2
1200
0.01
2
18
2- Q Sepharose FF
total specific protein activity (%) (kU) (U/protein mg) (%)
PF
,,
3- Gel filtration ,
, ,
7- Mono Q HR 5/5
Abbreviations 9U gmole/h 9Vol volume 9PF purification factor Apart from the nitrilase, two other enzymes were purified, a nitrile hydratase acting on ammonium 5-cyanovalerate (ref. 19) and an amidase acting on adipamate (ref. 20).These enzymes were separated on the Q sepharose fast flow column. Consequently, the specific activity after the second step was due to the nitrilase alone and would be higher than 9300 U/mg of pure nitrilase. Taking the purified protein, the N-terminal sequence of 27 amino-acids was determined by Edman automatic sequential degradation : Met
Lys
Asn
Tyr
1 Val 16
Pro
Thr
Val
Lys
Val
5 Phe
Met
Asn
Leu
Ala
Ala
Val
Glu
Ala
Thr
20
Val
Asp 25
193
Gin
Ala
Ala 15
10 Lys
Thr 30
A search of sequence libraries made it possible to find a 53 % identity with the nitrilase of Klebsiella pneumoniae active on Bromoxynil (ref. 21). The enzyme gave a single band of 38 kDa on SDS-PAGE and the native molecular weight was 490 kDa by gel filtration corresponding to dodecameric protein. Among the sixteen published nitrilases, 60 % have an average molecular weight of 550 kDa with an average monomeric unit of 41 kDa. The activity of the purified nitrilase was determined on differem nitriles at the optimal pH of 4 but also at pH 7 for adiponitrile and ammonium 5-cyanovalerate (Table 5). Table 5. Specific activity of pure nitrilase on some nitriles pH
Relative activity (%)
4
100
7
97
4
22
7
1.5
5-Cyano valeramide
4
28
Acrylonitrile
4
23
Propionitrile
4
6
Benzonitrile
4
4
Substrate Adiponitrile
Ammonium 5-cyano valerate
Common conditions 9acetate buffer 910 mM pH 4 " phosphate buffer 910 mM pH 7 9substrate 10 mM - T~ 25 9enzyme (step 6) 3 to 30 gg of protein/ml. For the adiponitrile, the nitrilase activity was independam of pH and for ammonium 5-cyanovalerate, the higher its ionic feature the worse the nitrilase activity. Therefore, the chemo-selectivity of the nitrilase between adiponitrile and ammonium 5-cyanovalerate was 64 % at pH 4 and 97 % at pH 7. The nitrilase activities were determined for other dinitriles and compared to that of adiponitrile (Fig. 3). For each compound, the chemo-selectivity was identical to that obtained for adiponitrile.
194
Legend: Fumaronitrile Glutaronitrile Pimelonitrile Sebaconitrile
(Fum) (Glu) (Pim) (Seb)
Succinonitrile (Nit) Adiponitrile (AdN) Azelaonitrile (Aze)
Fig. 3. Relative activities of nitrilase on dinitrile
Nitrilase cloning and overexpression of the nitrilase (ref. 22) Briefly, the genomic DNA of Comamonas Nil was digested with several restriction enzymes and analyzed by Southern blot using a 26 met probe synthesized from a NH2-terminal sequence. The best signal without ambiguity was obtained with an SstI-SstI fragment of about 4 kb. This fragment was cloned using pUC19 plasmid and the host strain, E. coli DH5c~. Two clones which had inserted, in both orientations, the same fragment of about 4.1 kb were analysed in detail. The nitrilase gene was carried by this 1194 bp insert and was sequenced (Fig. 3). An analysis of the sequence obtained made possible an open reading frame of 1064 bp, called the nitA gene, coding for 354 residues corresponding to the molecular weight of 38725 Da. This polypeptide comprises the NH2-terminal sequence used to synthesize the probe, as well as three internal sequences determined on tryptic fragments of the purified nitrilase. Optimal expression of nitA was obtained by using the E. coli P trp and the RBS of LcII gene to give the PXL2158 plamid. The E. coli TG1 (pXL2158) expressed a heterologous protein (38 kDa) representing approximately 30 % of total proteins of which only 10 % was found to be soluble. The solubilisation of the nitrilase was greatly improved with the co-expression of a E. coli GroE chaperone (ref. 23). For that, the plasmid pXL2035 was constructed by cloning into the vector pDSK519, the 2.2 kb fragment containing the groES and groEL genes coding for the two subunits of GroE. The E. coli 195
(pXL2158,2035) overexpressed the GroE which solubilizes the bulk of the nitrilase expressed from pXL2158. The activity of these different recombinant strains are listed in Table 6 and compared to those of the wild Comamonas Nil.
72
ct=9~162
tgaggaagacagca, RTG RRR RRT TRT CCT RCR GTC RRG GTR GCR GCR GTG CRR GCT ~ e t Lgs Rsn Tgr Pro Thr Ual Lgs Ual R l a R i o Ual Gin RIo
12~ 14
GCT CCT GTR TTT RTG RRT CTR O~O GCA RCR OTR GRT RRR RCT TOT RRO TTR RTR Rio Pro Ual Phe Met Rsn Leu Olu Rla Thr Ual Rsp L~$ Thr C~s Ly$ Leu I l e
102 32
GCR GRR GCR GCR TCT ~TG gOC OCC RRG GTT flTC GGC TTC CCR GRR GCR TTT RTT RIo Glu RI~ Rla Set Met Gly i l i a L~s Uai l l e GI~ Phe Pro O l u RIo Phe l i e
236 50
CCC GGC TRT CCR TRT TOG RTT TGG RCR TCR RRT RTG GRC TTC RCT GGR RTG RTO Pro Gig Tg~ Pro Tgr Trp l i e Trp Thr Set Rsn Met flsp Phe Thr GI~ Met Met
290 60
TGG GCC GTC CTT TTC RAG RRT OCO RTT ORR RTC CCR RGC RRR GRR GTT CAR CRR Trp R{a Ua| L~u Phe Lys ASh Rla l i e Otu l i e Pro Ser L~s G[u Ual Gin Otn
344 86
RTT RGT GRT GCT GC.R RRR RRG RRT OOfl GTT TRC GTT TGC OTT TCT OTR TCR GRG l i e Set Rsp Rio Rla Lgs Lgs Rsn Gig UoI Tgr UoI C~s UoI Set UoI Set GSu
398 104
Rflfl GRT RRT GCC TCG CTR TRT TT6 RCG CRR TTO TOO TTT GRC COG RRT GOT RRT Lgs Rsp Rsn R i o Set Leu Tgr Leu Thr Gin Leu TPp Phe Rsp Pro Rsn Gig Rsn
452 122
TTO RTT GGC RRO CRC RGO RRR TTC RRG CCC RCT ROT ROT GRR RGR OCT GTR TGG Leu l i e Gig Lgs His Rrg L~s Phe L~s Pro Thr Set Set Olu Rrg Rla Ual TPp
506 140
GGR GRT GGO GeT OGR RGC RTG OCT CCC OTR TTT RRR RCR GRG TRT GGG RRT CTT Ofg Rsp Gig Rsp Gig S i r Met RIa Pro Ual P h i Lgs ThP Olu T~P Oly Rsn Leu . . . .
56e 150
01g 01g Le~IIIG~nC~s
c ~ o r o e TGG GRR CRT GCT CTC CCR TTR RRC RTT GCG GCG RTG GOC Trp Glu H i s Rla Leu Pro Leu Rsn t i e RIo Rio Met Gig
614 176
TCR TTG RRC GRR CRG GTR CRT GTT 6CT TCC TGG CCfl GCC TTC GTC CCT RRR GGC Set Leu Rsn g l u Gin Ual H i s U=! Rla Ser Trp Pro Rla Phe Ual PPo Lgs Gig
668 194
GCR GTR TCR TCCRGR GTR TCR TCC flOC OTC TGT OCG TCT RCT flRT GCG RTG CflT Ala Ual Set Ser Rrg UoI S i r S i r Ser UoI C~s R i a Ser Thr Rsn Rla Met H i s
722 212
CRG RTC RTT ROT CRG TTT TRC OCO RTC AGC RAT CRG GTR TRT GTA RTT RTG TCR Gin l i e l i e S e t Gin Phi T~r RIo l i e Set Rsn Gin Uol Tgr UoI t l e Me~ Set
776 230
RCC FI~T CTC GTT GGC CRR GRC RTG RTT GRC RTG RTT GGG RRR ORT GRR TTT TCC Thr Rsn Leu U=I Gig Gin Rsp Met l i e Rsp Me~ l i e GIV L~s Rsp Glu Phe Set
830 248
RRR RRC TTT CTR CCG CTT GOT TCT OGR RRC RCR GCG RTT RTT TCT RRC RCC GGT Lgs Rsn Phe Leu Pro Leu GI~ Set Gig Rsn T h r R i o l i e l i e Set Rsn Thr Gig
884 256
ORG RTT TTG GCR TCfl RTT CCR CRR GRC GCG GRG GGR RTT GCT GTT GCR GRG RTT Olu l i e Leu i l i a Ser l i e Pro Gin Rsp Rio Olu Gig I l l RIo Uol RIo Olu l i e
038 284
ORC CTT RRC CRR RTR RTT TRT GOR RRG TOG TTR CTG ORT CCC GCC GOT CRT TRC ~sp Leu flsn Gin l i e l i e Tgr Gig Lgs Trp Leu Leu flsp Pro RIo Gig H i s T~P
992 3~2
TCT RCT CCC GGC TTC TTR RGT TTG RCR TTT ORT CRG TCT ORR CRT GTR CCC GTR Set Thr Pro Gi~ Phe Leu Set Leu Thr Phe Rsp Gin Set Olu H i s Uol Pro Uol
1046 320
RR~ RRR RTR GOT GAG CRG RCR ~ C CRT TTC RTC TCT TRT GRR GRC TTR CRT O~R L9$ LgS I10 O19 O(u Gin Thr Rsn His Phe t i e S e r ' T ~ r Olu Rsp Leu His Olu
1100 338
GAr RRR RTG GRT RTG CTR RCG RTT CCG COG ~GG COC GTR GeE RCR GCG TGR tcgc ~s~ L~s Met Rsp Met Leu Thr lie Pro Pro Rrg Fb-g Uol RIo Thr Rla
1155 354
cgcctctcggggcg~tcggttgctgatagcca~r
1194
ooG Go~ e r e
Fig. 4. Sequence of the nitrilase gene from Comamonas Nil 196
Table 6. Determination of the different recombinant strains expressing the nitrilase and their control strains on ammonium 5-cyanovalerate and adiponitrile Strain .
.
.
Substrate
Activity
.
Nature
(g/l)
Comamonas NIl
3,4
(U/kg de DC)
8
AdN CVA
2,2
E. coli (pXL2035)
0.06
AdN
E.coli (pXL2158)
0,24
AdN
270
1,2
CVA
8
0,06
AdN
1300
0,2
CVA
67
E.coli (pXL2158,2035)
Common conditions 950 mM phosphate buffer pH 7 9T~ 25-28, [substrate] = 50 mM. Abbreviations 9U moles of hydrolysed adiponitrile/h. 9DC dried cells. The activities of recombinant strains have confirmed the intensities of the bands on SDS-PAGE (data not shown). Compared to the wild strain Comamonas N I l , the activity was 160 times higher on AdN and 30 times on CVA. The different ratio between the rates on CVA and AdN was due to the presence of other enzymes which catalyse the transformation of CVA into AdO. The chemo-selectivity of recombinant strains was too weak to develop an industrial process.
Chemo-selectivity improvement of the nitrilase The mutagenesis of the pXL2158 plasmid was carried out in vitro using a mutagenic agent, the hydroxylamine which changes G,C into AT. The mutagenised plasmids were re-introduced into E. coli (pXL2035). The resulting strains were then screened in 96 well plates using a specific ammonia assay with Nessler's reactant. Among
the 560 clones, three of them had the same activity on adiponitrile and a
lower one on CVA compared to normal E. coli (pXL2158,2035). The nitrilases of two mutant clones, 12D1 and 1F3, were purified and the measurements of KM and Vm were carried out (Table 7).
197
Table 7. The kinetic constants, KM and Vm, of the mutant nitrilases Kinetics constants Nitrilase
AdN (pH7)
KM1
KM11
Chemoselectivity
(mM)
Vm 1 (Us)
(mM)
Vmll (Us)
(%)
4.1
2910
5
430
75
mutation 1F3
1.8
2500
1.2
8.6
99.3
mutation 12D1
8.8
3200
1.
6.6
99.5
4
500
nd
0.3
99.8
wild type ,,
CVA (pH5)
.
mutation 12D land 1F3
Common conditions 9AdN 100 mM phosphate buffer pH 7 , CVA 100 mM acetate buffer pH 5 9 T~ 25-28, [substrate] = 50 mM. Abbreviation 9Us gmole of substrate/h.mg of protein 9chemo-selectivity (VmI-VmlI)/(Vm I + Vm II)
Both mutagenised nitA, were sequenced. In each case, one mutation alone was found. Starting from both mutations, the double mutant was created by a site-directed mutagenesis. The resulting enzyme was purified and characterised (Table 7). Its chemo-selectivity was excellent but unfortunately the activity on adiponitrile was
lower. A l l the r e c o m b i n a n t w h o l e cells p r o d u c i n g the d i f f e r e n t nitrilases w e r e e v a l u a t e d
for the hydrolysis rate on AdN and for its chemo-selectivity (Table 8). Table 8. Activity of the whole cells producing the nitrilase and its mutants Conditions Substrate
Activity
Selectivity
(nature)
(g/l)
(raM)
(U/kg of DC)
(%)
E. coli (pXL2158,2035)
0,05 0,2
AdN CVA
2000 136
87
mutant 1F3
0,12 0,6
AdN CVA
870 7
98
mutant 12D 1
0,13 0,7
AdN CVA
970 7
99
double mutant 1F3-12D1
2,1 2,1
AdN CVA
83 0
100
Strains
Common conditions " 50 mM phosphate buffer pH 7 " T~ Abbreviation 9U mole of substrate/h 9DC dried cell 198
25-28 9[substrate] = 200 mM.
CONCLUSION Using the different methods, it was possible to design an excellent catalyst for a bulk product such as caprolactam. The first advantage of the biocatalysis in this route is able to carry out this reaction at neutral pH. The second is to selectively obtain the a,03-cyanoacid starting from the a,c0-dinitrile. No other type of catalysis can do this. For that, the following steps were carried out : 1- Finding a new enzyme by screening to transform directly the adiponitrile into ammonium 5- cyanovalerate 2- Eliminating the other activities (nitrile hydratase and amidase), 3- Over-expressing the nitrilase, 4- Solubilizing the nitrilase 5- Improving its selectivity. We
can
conclude
that
biocatalysis,
which
uses
diverse
sciences
such
as
microbiology, biochemistry and molecular biology, is a powerful method to design a catalyst and not only for the high value compounds but for bulk chemical compounds as well.
ACKNOWLEDGEMENTS This work has been performed as part of -Bioavenir program ,, financed by Rh6ne-Poulenc with the participation of the Minister for Research and Space, as well as the Minister of Industry and Trade.
References
1. J. March in ,, Advanced organic chemistry ,,, third edition, J. Wiley & Sons, pp. 788-789, New-York, (1985). 2. EP 178 106, (01/10/84), (to Novo Industri). 3. T. Nagasawa, K. Ryuno, H. Yamada, Biochem. Biophys. Res. Comm., 139 (3), 1305-1312, (1986). 4. J.L. Moreau, F. Bigey, S. Azza, A. Arnaud, P. Galzy, Biocatalysis, 10, 325, (1994). 5. A. Godlust, Z. Bohak, Biotechnol. and Appl. Biochem., 11,581, (1989). 6. M. Kuwahara, H. Yanase, Y. Ishida, Y. Kikuchi, J. Ferment. Technol., 58 (6), 573, (1980). 7. H. Yanase, T. Sakai and K. Tonomura, Agric. Biol. Chem., 46, 2925, (1982). 8. JP 4-341185, (12/11/90), (to Asahi Chemical). 9. K. Ingvorsen, B. Yde, S.E. Godfredsen, R.T. Tsuchiya, CIBA Found. Symp., 140, 16-31, (1988). 10. M.A. Cohen, J. Sawden, N.J. Turner, Tetrahedron Lett., 31 (49), 7223, (1990). 11. P. HOnicke-Schmidt, M.P. Schneider, J. Chem. Soc., Chem. Commun., 648, (1990). 12. Nissei Kagaku Kogyo JP 01074996, (16/09/87).
199
13. T.C. Bhalla, A. Miura, A. Wakamoto, Y. Ohba, K. Furuhashi, Appl. Microbiol. Biotechnol., 37, 184, (1992). 14. C. Bengis-Garber, A.L. Gutman, Appl. Microbiol. Biotechnol., 32, 11, (1989). 15. I. Watanabe, Y. Satoh, K. Enomoto, Agric. Biol. Chem., 51 (12), 3193, (1987). 16. M. Kobayashi, N. Yanaka, T. Nagasawa, H. Yamada, J. Bacteriol., 172 (9), 4807, (1990). 17. J.F. Mayaux, E. Cerbelaud, F. Soubriet, D. Faucher, D. Pdtr6, J. Bacteriol., 172, 6764, (1990). 18. EP 0502476, (04/03/91), (to Nitto chemical Ind. Co). 19. E. Cerbelaud, J. Crouzet, S. Levy-Schill, F. Soubriet, D. P6tr6, FR 93-09990 (10/08/93). 20. E. Cerbelaud, J. Crouzet, S. Levy-Schill, D. P6tr6, FR 93-1062, (27/01/93). 21. D. Stalker, WO 89-00193, (08/07/87). 22. S. Levy-Schil, F. Soubrier, A. M. Crutz-Le Coq, D. Faucher, J. Crouzet, D. P6tr6, Gene, 161, 15-20, (1995) 23. S.M. Hemmingsen, C. Woolford, S.M. Van der Vies, K. Tilly, D.T. Devenis, C.P. GeorgoPoulos, R.W. Hendrix, R.J. Ellis, Nature, 333,330, (1988).
200
REAGENTS WITH TRIFLUOROMETHYL SUBSTITUENTS
HEINZ GUNTER VIEHE AND ZDENEK JANOUSEK Laboratoire de Chimie organique, Bfitiment Lavoisier, Place Louis Pasteur 1, B- 1348 Louvain-la-Neuve, Belgium.
INTRODUCTION Reactivity or inertness from fluorine substitution 9The Electronegativity Effect
Fluorine substitution on carbon confers particular reactivity because of its particular properties : Fluorine as the most electronegative element forms very strong CF bonds which are sized to "cover" perfluorocarbons tightly. Polytetrafluoroethylene (Teflon) is one practical example illustrating the exceptional chemical and thermal stability of saturated perfluorocarbons in a sharp contrast to explosive tetrafluoroethylene or to fluoroacetylenes. The discovery that tert-butylfluoroacetylene oligomerised spontaneously (ref. 1) could be explained by ground state destabilisation resulting from combining electronegative sp-carbon with fluorine. The "Electronegativity Effect" (ref. 2) produces maximal thermodynamic stability for substituents on carbon with complementary polarity, whereas equal polarity generally leads to destabilisation (Scheme 1, ref. 3). F F
,
F
(it
F
F
F
F
F
F F
F
Scheme 1.
The high chemical reactivity of tetrafluoroethylene and also that of the safer trifluorochloroethylene permits smooth thermal biradical [2 + 2] cyclodimerisation or cycloadditions to C-C double or triple bonds. Useful fluorinated reagents are obtained, such as the trifluorochloro-cyclobutene esters arising from more facile 201
cycloaddition to captodative (ref. 4) ~x-thioether-acrylates followed by oxidative elimination of the thioether, rather than from propiolic esters in a single step (ref. 5).
COOR S--R CF-~--CFC1
COOR ~ S \ F
F
C O O R
F C1
F
F
F C1
COOR F
F
F
C1
Scheme 2. These "trifluorochloroethane-bridged" acrylates (or analogous tetrafluorocyclobutenes described below) combine the high reactivity of a strained and fluoroalkyl destabilised double bond with unusual thermal stability towards ring-opening due to the presence of fluorine atoms on sp3 carbon. Thermal ring opening to butadienes (ref. 5) occurs only at -- 500 ~ also because of the Electronegativity Effect by fluorine leading to destabilisation of the double bonds. The fluorine-destabilised multiple bonds also add nucleophiles easier than their chlorine analogs (ref. 6) and the direction of addition is opposite : From nucleophilic alpha-addition to fluorine and beta to chlorine results the relative ease of fluorine substitution inspite of the strong CF-bond, whereas the beta-adducts to chloroacetylenes form triple bonds by c~-elimination and rearrangement (ref. 7, Scheme 3). r~
R~S
RS|
1 I
RS|
Nucleophilic Halogen Substitution [3-Addition via c~-Addition
c~-Elimination
+ rearrangement
Scheme 3. Fluorosubstitution on saturated (sp3) carbon confers polarity together with chemical inertness and imparts lipophilicity, particularly by the CF 3- or Rf-group.
202
Therefore, the synthesis of reagents with CF3-substitution or generally with a Rf group is a challenging problem which elicits much current interest. In practice, CF3-groups are generally and industrially derived from CCI 3 by exchange with HF under relatively harsh conditions according to the Swartsreaction which is most often applied to C 1-hydrocarbons themselves or to activated CC13 groups next to carbonyl, vinyl or aryl moieties. This gives rise to CF 3substituted reagents themselves or to their derivatives such as shown in the Scheme 4.
C13C--Y
C13C--C6H5
//o C I 3 C - -\ C C1
F3C~C6H5
F3C--C\
C13C--CH--CH2
//O F3C~Y
F3C--CH:CH2
F Y = C1, SR, NR2, H Reagents with a CF3-Substiment C1
C1~Aryl
C2~
C3~
Scheme 4.
CF3-substituted reagents may be classified according to their number of carbon atoms. The C 1-reagents may furnish F3C-radicals, radical ions or ions. c2 reagents containing a CF 3 group may readily be obtained from trifluoroacetic acid or its aldehyde or alcohol. This report describes mainly C2-C4 CF3-substituted reagents derived from trifluoroacetic acid, trifluoroacetoacetate or from trifluoropropene. Several useful C2 reagents with CF3-substitution were obtained from N-tertiary trifluorothioacetamides as shown in the schemes to be detailed below. We have also elaborated the chemistry of the so far hardly studied trifluoroacetic dithioesters and of several CF3-substituted iminium salts (schemes 5a and 5b).
203
C2-Reagents with
CF 3
o
/
II F3C__C__OJ
HN\
O
ii
F3C~CH2~N
N-ten. -amides
Thioamide
Dithioesters
ch /
),
CF3-Iminium Salts . CF3-Mannich Salts ,,
.2V
CH3X I
J
Slj
i / F3C~C--N i \
i e/ F3C--C=N \ xe
Amide chloride
Thio amidium salt
Cl
Amine
S
/ \
II F3C~C~S~
Cl
\
ii
FsC--C--N
/ /
S
P2S5
/ \
F3CmC--N
He
i
H
i
cP
\
. CF3-Iminium Salts ,, ,, CFs-Mannich Salts ,,
F3C--C--N
\
R
/
Thio-aminal of Fluoral
J
Cl
!
F3C~ C - - N
I'/
e/ F3CmC--N i \
S"
Thioaminals
Scheme 5a.
CF3 Iminitma- Salts SIf
S/ NaBI-I4 I / r-- F3C--C--N \ CH3CN Hi
i e/ \
F3C~C--N |
F~C | /
F3C-C//O ) 2 0
C=N
ff
O II F3C~C~SR
I
F3C-,,~N ~
\
(~O--C~CF 3 II O
O~/CF 3
CI O 11 O--OH
/ F3C~CH2~N
F3C~CH2~N
\
\
95 %
Scheme 5b.
C3-reagents
were
obtained
from t r i f l u o r o b r o m o a c e t o n e
( S c h e m e 6).
204
or from t r i f l u o r o p r o p e n e
C 3 - Reagents o II F3C--CmCH2Br
$8 / HNR
CF3
CF3
~
o s II II F3C--C--C--NR 2
/
s~
CF3
CF3
s~
so2~
CF3 O
SO2~
Scheme 6.
C4-reagents from trifluoroacetoacetate and other reagents (Scheme 7) C4-Reagents
O F3C
]l
0
F3C~O
II I1 OR
NH2
N:
OR
Various Cn-Reagents CF3 ~
(O)n x = SR, COOR F
13-Trifluoroacetyl-lactam
F
Tetrafluoro-cyclobutene derivatives
L
0 II F3C~CH2~S
Trifluoroethyl-t-butylsulfoxide
CF3-Dipoles Scheme 7.
Trifluoromethyl substituted C2-reagents derived from trifluoroacetamide, -thioamide or-thioester Whereas the tertiary trifluoroacetamides obtained by aminolysis of methyl trifluoroacetate
are
rather
inert,
the
corresponding
205
thioamides
permit
an
S-alkylation to thioamidium salts and chlorination to amide chlorides (ref. 8, Scheme 8). The thioamidium salts react with hydride or other nucleophiles to give many useful intermediates. CF3-substitution on the carbon of the iminium function causes high reactivity arising from the captodative (ref. 9) functionality on the cation : CF3-destabilisation and amino-stabilisation. We have reported already on the trifluoroacetamide chloride as mainly covalem distillable liquid. This o~,ot'-dichloroamine comproportionates quantitatively on heating to give the ct,c~'-dichloro-isomer in contrast to alkyl or aryl analogs which undergo the von Braun dechloroalkylation (ref. 8, Scheme 8).
C1 i / F3C~C=N(~
_.,
C1 I / ,-- F3C_C_ N
C1 i / F3C--C--N
> 130~
ClI ) C1|
I-t)
I _HC1 C1 J / F3C~C--N e \
C1 i / R--C=N |
\
CI|
'. Cl)
H
+.c)/
x~HC1
I
C1, =
=
E
N
F3Cx
I
N
F 3 C ~ _~
|
E
E
E
E
C1 A
I
R--C=N~
- CH3C1 R = alkyl, aryl,
Scheme 8.
The 1,3 "dipolar" redox isomerisation of C-captor-substituted amide chlorides is general, first order and independent of solvent polarity : it is the fastest with the strongest captor groups (ref. 10). Since ionisation induced by counterion complexation of these amide chlorides blocks the isomerisation, either homolysis of CCl-bonds in cd-position or a concerned elimination to the interceptable dipole and readdition of HC1 could explain the reaction mechanism. But what is the driving force of the rearrangement ? Again the Electronegativity Effect (ref. 2) is certainly 206
an important factor together with sterical "decongestion". The electronegative chloride migrates away from electronegative neighbors. We have found now analogous 1,3-dipolar isomerisations of CF3-carbon substituted dithio-orthoamides (refs. 11, 12, Scheme 9). /MeMe S/ MeMe F3C_C=N/| MeSH~ F3C--C--NI/ \ I \ Me S\ Me X(9 Me
Me s/MIM e S/ Me S Me I jI II Toluene A~ F3C--C--N + F3C--C--N/ + F3C--C--N \ 8d. I \ HI \ Me Me H / S
,
- HX~ (DBU)
~
"
U
]-HS--Me [ J ] J
[
//
~
160o neat~
Ph
J
66 ~ "~ (37%
6%
2%
22 %
41%)
F3C~/" )
" o
2G- o I
Ph
Scheme 9. In refluxing toluene the main reaction is the 1,3-dipolar isomerisation apparently via the interceptable CF3-dipole. In neat phase at higher temperatures reduction to the thioaminal and elimination of dimethylsulfide become the major reactions. Further results arise from trifluorothioamidium salts with varying N-substitution. Addition of cyanide furnished substituted thioaminals with two captor substituents and their thermal behaviour was studied (refs. 1, 13, Scheme 10).
207
S/ R I / F3C~C=N \ |
KCN, CH3CN
S/ I
w..-
F3C--C--NR2 I C III N
25~ 2 hr
R
CH30~SO3 (~ Thermal isomerisation
/ S R = CH3
)
H
Toluene A 3 hrs, H2SO4 cat.
N
F3CC III N F3C.
12
hrs 0
100 % conversion
\
I
N.
N------C~
70%
O /)~N-- Ph
O I
Ph
But with R--C2H5 and ~NR2 = ~ N ~
no isomerisation in the absence ot~
X
H S ~ C 1
H F3C~C--N C III N
o F3C--C--N
190~
+ C1
(by the ESR)
I
C III N Scheme 10. Again a dipolar adduct to N-phenyl-maleinimide was obtained. Surprisingly, the NN-diethyl-trifluoromethyl-cyano or the pyrrolidino analog did not isomerise even at higher temperatures in refluxing xylene, whereas acid catalysis led to decomposition. At 190 ~ ESR signals showed homolysis of the C-S-bond (ref. 14). 2o8
Correspondingly, p-chlorothiophenol produced a reduction of the C-S-bond with formation of the pyrrolidino 3,3,3-trifluoropropionitrile, a derivative of alanine. For comparison, non-fluorinated thioamidium salts were also reacted with cyanide and both the phenyl- and the ten-butyl derivative were obtained, but instead of the dicyano thioaminal, mainly the (presumably radical) dimer was found (Scheme 11).
/ S
KCN, CH2C12
A, Toluene
\
12 hrs, 25~
i(9
C6H5
24 hrs
Sj / I--N|
KCN, CH2C12
/
A, Toluene
\
12 hrs, 25~
/ [--N| \
KCN, CH2C12
S/
/ S"
CF3~SO30
12 hrs, 25~
N
C6H5. C III N S/
N--=C
/
c III N
\
24 hrs
25~
\
N~C
\
C III N
III N
i(9
N=C
\
)
N
,,..._
/ C6H5
N
\
]
+ N~C------H
C III N major
C III N minor
/2
Scheme 11.
The three thioamidium salts differ in reactivity because of steric, electronic and polar substituent-effects, the thioaminals isomerised normally only in the ten-butyl case, lost the S-substituent by H-reduction in the phenyl derivative and yielded dimerisation of N,N-dimethyl amino and dicyanomethyl residue. The reduction of the C-phenyl derivative is suppressed when S-phenyl replaced S-methyl. Now the dipolar isomerisation occurs again (Scheme 12).
209
C1
t
/
1 PhS|
\
2 CN|
C6Hs~C=N (9
cf~
/ Ph S
.Ph / C6Hs~C--N I \ C III N
s-I
)
H I -~ C6Hs~C--N I \ C III N
Scheme 12. Possible intermediates are the dipoles for the isomerisation, the radical pairs for the dimerisation and for the reduction arising with the S-CH 3 group. Breaking the C-S bond could be accompanied or followed by formation of the interceptable dipole, the addition of RSH, the coupling or reduction depending on the relative stability of the intermediates. While further studies and the discussion are planned to be published elsewhere, it can be concluded that trifluorothioacetamides, their amidium salts, their amide chlorides,
their
thioacetals
and
1,3-dipoles
are
useful
reagents
with
CF 3-
substitution. The trifluoromethyl iminium salts, the trifluoroethyl-t-butyl sulfoxide, and the already mentioned trifluoro-dithioacetates are treated in the following sections.
T R I F L U O R O M E T H Y L IMINILWI SALTS As summarized already in the introduction these iminium salts of fluoral are readily available either with trifluoroacetic acid anhydride (TFAA) and N-oxide of trifluoroethylamine (Potier-Polonowsky reaction, ref. 15) or from N-O or N-S acetals formerly accessible by electrochemical amine oxidation and now by hydride reduction of thioamidinum salts (ref. 11). These "CF3-Iminium" salts can be isolated and even be distilled (X - CF3COO-) but they were most often used in situ.
/ F3C~C--N |
I
\
H
/ ~
F3C-CH--N
t
X
\
X| Scheme 13.
210
Thus condensation occurs with carbonyl activated methylene groups in high yields to [3-trifluorovinylcetones "trifluoroethylidenation" which are again useful CF3-reagents such as heterodienes for cycloaddition to vinylethers. "CF3-Iminium"-salts condense with aromatics or olefins (ref. 16) and even with those too little activated towards the parent Eschenmoser-B6hme iminium salts (Schemes 14, 15, 16).
Eschenmoser- B6hme IminiumSalt
e/
CH2=N
X|
\
Scheme 14. | R F3C--CH---N\
X|
R O
II
R = CH3
X = O--C--CF3
O
Ph1 ~ 0 ~ Ph
4d
25~ 5d CF3
CF3
76%
88% O
O 4d
CF3
CF3
84 %
88%
O A, CH2C12
O
~
CF3
F
3
C
~
4d 96 % O ~---OEt
A, CH2C12 10d
C
F3C
\-(
N (~/' COOEt
89%
Scheme 15. 211
CF3
R = ~CH2~CH2~O--CH2~CH2~
CF3 OJ /
CH2Ch 25~
/
0/--~NR, ---60% F3C
F3C CH2C12 25~
0
F,cA-o)
)
25~
~
O
CF3
Ph
CH3
88%
NR-, OCH3
CH2C12 80%
25~ F3
~y Scheme
---NR2
48%
45%
CH2C12
/N/
R2
CH2C122"5oC~ ~
F3 94 %
16.
TRIFLUORODITHIOESTERS This class of compounds is only scarcely known, such as the ethyl ester and its activity in a Diels Alder reaction (ref. 17). The already mentioned new preparation from the trifluorothioacetamidium salts with H2S or from the trifluoroacetamide chloride with successive HSR and HzS treatment produces these reactive compounds. Some examples of their synthesis and their high reactivity follow (ref. 18, Scheme 17).
212
S/
i
R
/
F3C--C-'N@
H2S R CH3 t-C4H9
\
|
S II F3CmCmS--R
CH2.,""~ CH2COOEt CH2--Ph o-C6Ha~COOMe
C1
F3c-c'=@
1. HSR
50 - 70 %
2. H2S C1|
:F:.
S II F3C~C~S~CH 3
95%
20~ neat N2CHCOOEt ether
F3C~~_~COOEt /S
P(OCH3)3 ether 100 %
H
F3C /S
COOEt H 92 %
/ Ph3P=C\
H
%
Sm
C
40- 50 % C
CF3
COOH COOH
@NH
I1
CF3
66 %
CH2C12 NEt 3
S|
,.CH3 S" F3C
SH
I H
t BuOK (cat) Scheme 17.
213
S~S
93%
REAGENTS FROM SUBSTITUENTS
TRIFLUOROPROPENE
WITH
~-SULFUR
The known ~-phenylsulfide 2 of trifluoropropene 1 can be oxidized to the sulfoxide 3 and further to the sulfone 4 and to its epoxide 5 (Scheme 18, ref. 18).
,/
CF3
.~ ~
CF3
1
.~
/
CF 3
._
/
CF 3
O / N,/CF3
SPh
SOPh
SOzPh
2
3
4
SOzPh 5
Scheme 18
Compouds 1-4 are useful for nucleophilic additions and for cycloadditions, whereas the epoxide 5 reacts well with 1,n bis-nucleophiles giving 2, 3, 4_ heterocyclisations (refs. 18, 19, 20). As we found, trifluoropropene -ct-thioderivatives are prone to 1,3 dipolar additions (ref. 21, Scheme 19). H ~/
CH2N2
2-4
N~
Et20 --- 2 hrs, 20~
I
N (O)n
n=l
(/b~p h
80~
N
N" / ~ .v
CF3
\\
CF3 - 100 %
n=0 n=2 N2CH--COOEt
66 %
distillable A ~ decomposition
EtOvC
//N,,N~H
2-4
76- 100 CF3 PhCHN2
/ ~
CF3 100 %
C6H6 ~
50~
PheUN 2 Et20
Ph .~
SPh
Ph ---~__ C (F3
A, 15 min. -
MeO~N~SiMe
3
CHzPh
~
SO2Ph
A, CH3COOEt ~ Ph\-'--,
S~a
CF3 O)nPh
2,3,4
65 - 84
H | , CH2C12 I
CH2Ph Scheme 19. 214
/CF 3 76 %
"7
SO2Ph
1,4 Cycloadditions to trifluoropropene derivatives Generally all derivatives 2-4 react, but the sulfone 4 gave nearly quantitative yields at mild temperatures (ref. 19, Scheme 20).
2
CF3 ~ S P h
A, C6H 6
+
72 %
24 hrs
3
+
@
4
+
~ \\
4
+
A,5dEt20---,-- endo - exo - isomers 98 %
Et20 ~ 20~ 1 d
q
endo - exo
A, CH2C12 4d "-
99 % (4 91)
~ C F 3 ~"SO2Ph
+
83
~
(..~.~CF3 "SO2Ph
9
99 %
17
Scheme 20. Michael addition of alcohols, thiols and amides expectedly gave high yields with all three sulfur derivatives 2-4 of trifluoropropene and interestingly the sulfoxide 3 furnished with thiophenol beyond the expected monoaddition the dithioacetal of trifluoropropanal (Scheme 21). CF 3
PhSH +
( //S~Ph O
PhmS
~
CF3
)
/
--100%
Ph~S
Scheme 21. Enamines revealed differentiation of reactivity towards 2-4. The more polar sulfoxide 3 and the sulfone 4 reacted with pyrrolidinocyclohexene or morpholinocyclopentene simply by addition, whereas the thioether 3 went further by HF elimination and bicyclisation. After hydrolysis the bicyclic ketones were isolated in good yields. Malonate reacted with 3 by addition followed by HF elimination. With 4 or fi only addition was observed. Acetone dicarboxylate reacted with 3 by addition followed by HF elimination and then by heterocyclisation to the difluoro-pyrane 215
derivative, whereas the sulfoxide furnished the substituted fluorobenzene and its phenol by hydrolysis (ref. 19, Scheme 22).
1) CH2Ch;, A , NEt3
3 2) HCliHzO
F
1) CH2C12, A, NEt;
4 or 5
55%
n=l n=2
1
2) HClIH2O
46%
1) CH2Cb, A, NEt3
3
2) HCI I H20 F
1) CH2C12, A , NEtj
4 or 5
n=l n=2
2) HCIiHzO
31% 68%
5
0
0
1 ) CH2C12, A , NEt3
n= 1
4 or 5 2) HCI/H20
Me0
Me0 0
0
216
(0)"
O 1) CH2C12, A, NEt3
P ooEt +phi2j_2oot
2) HCI / H20 F
~t~ ~
O
F
22 / 36 %
O 0
1) CH2C12, A, NEt 3 r
OH
0
0
OH
0
Meo ' OM O OMe
2) HC1 / H20 45/16%
Eto-~ O
Scheme 22.
HETEROCYCLISATION WITH orOR I3-TRIFLUOROMETHYL EPOXYSULFONES Generally nucleophilic 13-attack to epoxysulfones followed by sulfinate eliminations generates carbonyl groups. The crystalline cz-trifluoromethyl epoxysulfone 5 follows this pattern and is particularly useful as 1,2-biselectrophile in heterocyclisations (ref. 20, Scheme 23).
217
O ~ i , , , ~ CF3 PhS
74 % PhS
Q SO2Ph
CF3
5_ S II 5
+
CF3
S S.~N
H2N'~NH2
91%
NH2
'
+
O.
_ NH2
5
I H
+
~
46 %
NH2
5
CF3
+
N
CF3
~XSI~NH,
Scheme 23. The 13-trifluoromethyl epoxysulfone reacts with opposite regiochemistry and arose the still unanswered question of bis-trifluoromethyl derivatives related to the already mentioned and studied tetrafluorocyclobutene derivatives or of their trifluorochloroanalogs (Scheme 24). X F3C
CF3
X F
F
F
F (el)
Scheme 24.
218
T E T R A F L U O R O - AND T R / F L U O R O C I ~ O R O C Y C L O B U T E N E R E A G E N T S In agreement with the captodative concept, 2 + 2 cycloaddition of cd-olefins to trifluoroethylene via biradical intermediates is more facile than to captor-substituted olefines,
or
to
the
captor-substituted
acetylenes.
Phenylthioacetylene
reacts
smoothly and permits S-oxidation of the adducts (ref. 21, Scheme 25). SPh
=<
COOCH3
COOCH3
SPh
120~ 8 hrs
C1
80%
F
F
F -
F
C1
__S COOCH3
COOCH3
[Cl
190~ 16 hrs F
F
S--Ph 80~ 8 hrs 50%
F F
35%
S--Ph
KF, DMF
C1
80~, 30'
F
~S--Ph F F
F
Scheme 25. Both series of cyclic olefins with activation by the trifluorochloroethane (or tetrafluoroethane) bridge are interesting dieno- and dipolarophiles (ref. 22), leading to so far hardly accessible annelated structures (Schemes 26, 27).
219
Ph I
COOMe
F
c1 67 Yo
COOMe
F
G F
C
l
F
COOMe
F F F 70 Yo
180°C
7hrs
& I
Me
\
\
Scheme 26
220
F
F
51 %
O~s02Ph
i fX = F F--j i x J 65%
/SO2Ph
i
X
X=F 88%
F
F
r
F
S02Ph
F F
X=CI X=F
F
"--..i
85% "-.. 93%
SO2Ph i ' R T , neat phase, ~ 12 hrs F
F
Scheme 27. The
tosylate of trifluoroethanol
furnishes by
substitution and
subsequem
oxidation the tert-butylthioether and its sulfoxide as useful reagems for the attachmem of trifluoroethylthioethers or their sulfoxides to multiple bonds according to the following scheme (Scheme 28, ref. 19).
221
F3C--CH2OTos + HS
Nail, DMF 80 ~
O II ~ F3C--CH2~S 90%
F3C--CH2~S 72 % ~
TFA / T F A A ~ CH2C12/. . . . . . . . 40 ~
[
O
]
[
~"
"
F3C--CH2~S--O--C--CF3
\_/
F3C._._~
~/~ Oil S--.-/ O--C--CF 3
F3C_____N S
7-8" F3C
85%
0 II O~C--CF 3
~ d
O
" }
F3C--CH2~S~H
-
:
COOMe/
i
O F3C--CH2~{ / MeOOC
70%
82 %
II O--C--CF 3
/,,,,.,// F3C~S'~-~
1 A, Toluene
/
MeOOC
+ <
0~
O
,.CF3
+ isomer 83 % (7 : 3)
[I O F 3 C ~ S ~ ~ ~ \ O. ,.CF3 "C" II 0 Scheme 28.
222
94 %
H COOMe
87%
AMINOSULFURATION OF BROMOTRIFLUOROACETONE TO TRIFLUOROPYRUVIC THIOAMIDES Sulfur dissolved in DMF thionates in the presence of sec-amines methylene groups activated by a captor group. The halogen is then replaced by the amine, the overall sequence leading to thioamides. This is shown below for bromotrifluoroacetone (Scheme 29, refs. 23, 24). O
F3C
O
Br
$8, HNR2 DMF, 20~
NR2
~ F3C
I + F3C--CH
S
NR2
6
7 (trace)
Scheme 29. The yields of trifluoropyruvic thioamides 6 with common secondary amines are mostly fair and do not exceed 65 %. The reduction products - trifluorolactic thioamides 7 are formed in certain cases as by-products (about 5 %). Trifluoroacetone yields under the Willgerodt-Kindler conditions only 7 (30-35 %), besides other products. These lactic products 7 are therefore formed more expediently by reduction of 6 using ammonium formate at 100~ The reactivity of 6 as starting materials for the synthesis of heterocycles was explored, since the parent trifluoropyruvic acid (ref. 25) had already been used for this purpose. As it turned out, the heterocyclisations proceed sluggishly because of the low reactivity of the thioamide group and monocondensations at the highly reactive trifluoroacetyl group (e.g. imine or azine formation) can be observed. Thus only ortho-phenylenediamine gave the expected quinazoline in a 65 % yield upon heating the components at 120~ (Scheme 30).
6
N~
CF3
N
NR2
Scheme 30. The use of TIC14 did not facilitate the cyclisation and led to the formation of a double imine consuming 2 eq. of 6. Accordingly, primary amines form in the presence of TiCI4 the corresponding imines 8 and the same result is obtained when iminophosphoranes are applied (Scheme 31).
223
'
R'NH2, TiCI4
R'~ N
or qb3P= NR'
Zn, HOAc
HN
/NR2
F3C
.i R'
NR2
F3C
S
S
_8
9
Scheme 31. N,N dimethylhydrazine reacts in the same fashion, while hydrazine gave only 9 % of the azine together with the reduction product _7. The reduction of imines 8 yields the corresponding trifluoro-alanine derivatives 9. The hindered imines 8 are very stable and do not undergo [4+2] cycloadditions or addition of butyl-lithium, and even LiA1H4 reacts very sluggishly. Amines 9 are also only moderately basic but react with strong electrophiles as exemplified for phosgeniminium chloride (PI) (Scheme 32). NMe2
9_(R'= H)+
C1 ')==:~qMe2C1e CI/
N,~S "F3C
NR2
10 86% Scheme 32.
In this case the thioamide sulfur also participates and trifluoromethyl thiazole 10 is obtained in a very good yield. Amine 9 R = M e reacts similarly with phosgene to form the corresponding thiazolone in a 99 % yield. While 6 does not react properly with stabilized anions (Knoevenagel Reaction), organolithium and magnesium reagents give alcohols 11 in excellent yields (ref 26, Scheme 33).
1. R' Metal 6_
~ 2. NH4C1
OH [ //S F3C--C--C I \ R' NR2
11 ~ 80 %
Scheme 33.
224
11 (R = PhCH2)
SOC12 ~ or P205
CF3 P h ~ S
1. N2H4
R2N
~
2. S8 or MnO2
F3C NR2 ~N.N Ph I
H 12
13
86 %
Scheme 34. Compounds 11 can be chlorinated when R'=C6H 5 or benzyl. The latter eliminates HC1 to the corresponding trifluoromethyl cinnamic thioamide (12, Scheme 34). Compound 12 cyclizes with hydrazine to give a pyrazoline which can be dehydrogenated to afford pyrazole 13. Many trifluoromethylated pyrazoles are known as described in an excellent review (ref. 27). Alcohols 11 can be methylated using NaH/TfOMe. These methyl ethers could not be hydrolyzed to the corresponding Mosher acid. As the hydroxyl is now protected by an alkyl group, the thioamide moiety can be chlorinated to give the amide chloride 14. This unstable compound was directly cyclized with benzothiazole (Scheme 35). ~NH2
F3c
OMesI/// C12 I \ Me NMe2 1~
O[Mex~\~,/ C1 1 I Me Me2 C1| 14
"~"
"SH .._ ~ ~ ~ -
/QMe (, CF3 Me ~5
Scheme 35. The O-mesyl compound was prepared in view of the subsequent elimination which would give the interesting a-CF 3 acrylic thioamide. But in the basic medium used (Nail), the methyl of the mesylate was deprotonated and the anion cyclized at the thiocarbonyl function, thus leading to the unusual sultone structures 16 (refs. 28, 29, Scheme 36a).
225
/SO2~Me O' S F3C
SO2 NaH -~
/~ R
16
R = Me, Et, Bz, Allyl, Ph
Scheme 36a.
E T H Y L T R I F L U O R O A C E T O A C E T A T E (TFAE) AS A USEFUL BUILDING B L O C K IN H E T E R O C Y C L I C SYNTHESIS TFAE has already been largely studied as a very versatile synthon. It contains two electrophilic centers (ester and a trifluoroacetyl carbonyl) as well as a very activated methylene group. In pure phase it is enolized up to 90 %. A very good review on this and similar compounds exists in the literature (ref. 30). We have more particularly studied the primary enamine 17 and the diazoderivative 18 (Scheme 36b). Chemistry of ethyl-2-diazotrifluoroacetoacetate 18 In order to prepare larger amounts of 18 the method of Weygand and Bestmann
was used which involves the acylation of ethyl diazoacetate by trifluoroacetic anhydride (TFAA) (ref. 31, Schema 36b).
0
0
~ F3C
0 OEt
F3C
F3C~OEt
H2N
CO2Et
N2
17
TFAE
F3C
H.
/CO2Et
TFAA pyfid~
HO
CO2Et
0
N2
90 % Scheme 36b.
226
18 90 %
Diazo-tranfer upon TFAA works also properly. For mechanistical studies we have also prepared 15N marked 18 by using Na15NO2 and glycine (ref. 32). It was expected that 1-diethylaminoprop-l-yne would undergo a 1,3-dipolar cycloaddition with 18 leading first to trifluoroacetyl isopyrazole 19 which could then undergo a 1,5 sigmatropic shift (von Alphen-HiJttel rearrangement) (Scheme 37).
18 H3C
NEt2 ~
O # F3C~N~N E" ~__~\ Et2N
~ ~
9
\ 1--9
Scheme 37. In as much as the trifluoroacetyl group was absent in the final product, we concluded that the ynamine reacted in a [2 + 2] cycloaddition across the activated carbonyl. This would lead to oxetene 20 which could open to a diazo glutaconic derivative 21. Its cyclization in situ would afford the 3H-pyrazole 2__22and finally the observed N-carbamoyl pyrazole 23 (Schema 38).
18
O
Ynamine ,._
-NEt2
Me,_ / / ,._
F3CE 20
NEt2 O "/ - ' ~ )K"~N
CONEb
C/~YN2 F3 E 21
"
,.._
~N Me/ F3C
E 22
OF.E*2 Me~ _ _ _ _ ~N 23, 64%
1.5 F3C
E
Scheme 38. Subsequently, however, we have prepared a series of diazocompounds 21a,b closely ressembling 21, via the Wittig and Horner-Emmons-Wittig (HEW) olefination vide infra, and observed that none of them cyclized even upon heating. It 227
became obvious that 20 rearranges directly to 2_22. The latter undergoes a spontaneous 1,5-carbamoyl shift to give 23. Its structure was secured by X-ray crystallography. 23 undergoes very slowly another 1,5-carbamoyl shift, and also the carbamoyl group can be removed by methanol to give the parent pyrazole. Due to its enolic structure TFAE does not react with Wittig reagents and the like. This enolization is suppressed in 18 and a number of Wittig and HEW olefinations could be performed. It should be noted that strongly basic Wittig reagents lead only to decomposition. The results are summarized in the schemes 39 and 40. R
o
~ N 2 F3C
+
CO2Et
liaR
ether,r.t.
N2
~ F3C
PPh3
CO2Et 21
R = CO2Et, 88 %
R = CO2tBu, 56 % R=COMe, 77 % R = C N , E / Z = 1"2,86% Scheme 39.
O F3C~'~
N2 CO2Et
RI'~
R2
1. LiCkMeCN 2. EtN(iPr)2
F3C'@
N2 CO2Et
o~P(OEt)2 21
R ~ = H, R2 R 1 = H, R2 Ra = H , R 2 R1 = F, R2
-- CO2Et, 82 % = CO2tBu, 62 % =CN, E / Z = 1 : 2 , 8 4 % = CO2Et, 15 %
Scheme 40. Compounds 2_!_1 react with triphenyl phosphine to give the corresponding phosphazines. When the starting diazocompound carries a vinyl group substituted by a carbonyl function, an intramolecular Aza-Wittig reaction provides an interesting entry to CF3-substituted pyridazines 24 (Scheme 41, ref. 33). The results are similar when the reaction sequence is inversed, namely 18 is converted first to its phosphazine which is in turn olefinated as shown above. AzaWittig reactions are resumed in ref. 34 and the recent chemistry of the diazo group in ref. 35. 228
The parent diazo compound 18 is thermally very stable even in the presence of Rh-based catalysts, but one report (ref. 36) nevertheless describes the trapping of the carbene which may also react as a 1,3-dipol with ethyl vinyl ether at IO0~ under pressure (Scheme 42). R
R
R
Ph3P
O F3C
Ph3PO
O
2
F3C
--N-.XPPh3
F3C
E
N
Nil E
E
24 R = OEt, 83 %
R = tBu, 57 % R = M e , 64% Scheme 41.
COzEt OEt
Rh2(OAc)4
1___88 - - /
E t O ~ C F
100 ~ 8 h
3
Scheme 42.
R
R
R 0
700~ ,._
R
0
~v
F3C
2 E
R=OMe, 62% Scheme 43.
F3C
F3C
(9 E
E 9 R=Me, 68% " R-tBu, 0%
F3C
E 25 E= CO2Et
CF3-substituted diazoglutaconates are as inert as 18 and elegant reactions of H.M.L. Davies (ref. 37) performed on diazoglutaconates could not be materialised in our case. The flash vacuum pyrolysis (FVP) of our diazoglutaconates was more rewarding. While the starting material is recovered intact even at 450~ 700~
but at
the cyclization occurs to give CF3-furanes 25 (ref. 38, Scheme 43).
Pyridazones belong to the category of electron-poor azadienes and they could be 229
expected to react with electron-rich multiple bonds (refs. 39, 40). In practice, enamines gave only ill-defined products, but an ynamine in refluxing toluene gave pyridine 26 via loss of a nitrile (Scheme 44). R N F3C
+ Me
:
- NEt2
llO~
NIl E 2_!4
26
70 %
Scheme 44.
Chemistry of 2-benzyloximino TFAE The known oxime of TFAE was benzylated to form 27 which is another nonenolizable derivative of TFAE and is able to undergo the Wittig olefination (Scheme 45, ref. 38). Products 28 are formed in very good yields even with nonstabilized Wittig reagents. 0
N--OBu
~-~ F3C
E
R +
/~'Pq~3 R
~
~NOBu F3C E
27
28
Scheme 45.
Chemistry of hydrazones of TFAE H.J. Bestmann has prepared the phosphazine of TFAE from 18 and triphenyl phosphine. This compound is hydrolyzed by ZnC12/H20 to give the parent hydrazone 29 and it can be transformed to the corresponding tris carbonyl compound using HNO2 (ref. 41). In analogy to the studies by H. Neuenhoffer, we have N-acylated 29 by acid anhydrides to obtain crude N-acylhydrazones 30 in about 50 % yield (Scheme 46).
230
0
0
E
o
F3C
II
+ (R--C--Oh
~
F3C
0
N~NH2
N.
29
"N H
-~
~,.
R
F3C
HOAc
N
3O
3_!1
"~
N
R
Scheme 46.
1,5-bis-electrophiles
Intermediates 30 being
react with ammonia to give
1,2,4-triazines 31. These electron-poor azadienes give with enamines the corresponding CF 3- pyridines 32 via a loss of nitrogen (Scheme 47). With ynamine, one can observe two pathways which occur simultaneously : there is either a loss of N 2 giving pyridine 33 or a loss of cyanoformate leading to pyrimidine 34 (Scheme 48). As an exception, 31, R = Ph gives the corresponding pyrimidine as a unique product in a 79 % yield. E /N~ 31 +
110~
~n
R=Me R = Ph
F
3
~ 1 0-30 rain.
n = 1, n = 1,
N
C ~ ~...~
)n
32
R 71% 77 %
73 % 9 n = 2 , 78 % 9 n = 2 ,
Scheme 47.
F31L-N[[ NEtz
31 R=Me
Me
-
-
NEt2
--
Me
F3C-~/NEt2
N.. N Me
33 49% Scheme 48.
231
34 34%
The reactivity of ethyl-3-amino-4,4,4-trifluorocrotonate 1_7_7 The quite acidic TFAE reacts with ammonia to form only the corresponding ammonium enolate. This salt upon heating at 100~ for 1-2 h forms the desired enamine 1_7_7together with some trifluoroacetyl acetamide (15-20 %). Pure 17 is obtained upon careful distillation (Spinning Band) in a 7 1 % yield (refs 23, 42, 43), as a low melting (30-35~ solid. Its configuration Z (amino and ester groups are on the same side) was established by NMR-studies (ref. 44). Enamine 17 reacts with PI salts via condensation at the amino group which is followed by a de-chloroalkylation of the ester leading to cyclized products: 4-CF 31,3-oxazin-6-one 35 (refs. 23, 43, Scheme 49). The isomeric 2-CF3-1,3-oxazin-6ones 36 were studied by W. Steglich (ref. 45).
F3C
PI
HzN
CO2Et 17
CHCI3
=.j..S ~
F3C~O N.yO
35
N .~,.O
NR2 - 90 %
CF3 36
Scheme 49. The reactions of the Vilsmeier-Haack-Arnold reagent or N,N-dimethyl benzamide chloride stop at the azadiene stage and phosgene failed to react altogether. 35 Where dimethyl amino is replaced by a phenyl 37 could be prepared in high yield by N-benzoylation of 17, followed by chlorination of the amide using oxalyl chloride and subsequent heating at 130~ The N-trifluoroacetylated product of 17 could be chlorinated only with difficulty (PCI5/POC13) and the very stable imidoyl chloride hereby obtained failed to cyclize. Acetimidoyl chloride derived from 17 apparently did cyclize, but 35, R = Me instead of NR2 was hydrolyzed during the aqueous work-up. Surprisingly, dialkylamino oxazinones 35 and the 2-phenyl analogue 37 underwent cycloadditions with acetylene diester and ethyl propiolate, albeit under harsh conditions (reflux in xylene or chlorobenzene) (Scheme 50, refs. 23, 46). Other electron-poor dienophiles failed to react, as well as the electron-rich ones, where only decomposition was observed. The follow-up chemistry of 35 and 37 was studied and has led to numerous trifluoromethyl substituted heterocycles (refs. 43, 44).
232
F 3 C ~
O ~
R2
~. :::~
g
F 3 C ~ '"~---
R:
R1
R2
RI = N
/
R2 =H,E
yield - 80 %
3__~5,3__2_7
Scheme 50.
Aminolysis of benzoxazines 35, 37 Oxazinones possess an activated lactame moiety and react easily with nucleophiles. A general picture is given in the Scheme 51. Thus water gives the previously unknown trifluoro aminocrotonamide. Amines may yield different products according to their substitution and basicity. Primary amines and 35 lead usually to ring-opening followed by re-cyclization to pyrimidine-4-ones 37a. On the other hand, 35 gives ring-opened products 3.8. With primary amines a Michael addition can take place leading to the corresponding aminals 39. Aromatic amines react only once to furnish enamines 40. Pyrrolidino cyclohexene acted only as a source of pyrrolidine yielding 4_!1. Ethylene diamine gives rise to a cyclic aminal structure 4_22. Mono-substituted hydrazines react similarly to five-membered ring aminals 43 which eliminate readily the amide function present to give pyrazolones 43 (Scheme 51, ref. 44).
233
F3C'~~
O
O H. ~NMe2 "N O F3C~-.~NH R RHN
FsC H Nx~'~INR'2
N'~/Nx R, Ph
R"
\'0
O
38
37a
39
HNR'2 F3C H.N~N/"
~ II
Me2N" \'O
~
~ Pyrrolidinocyclohexene
O
4_,
j
FsC'x.~'~O
H20,A
N.~o
R= NMe2,Ph
R
F3C N~~..~[ NMe2 H2 O
2N(CH2)2NH2 0
'~NMe~
F3C
H2N(CH2)2NH2
H"N~ - - - - N H A r MezN..~O
H-_N'
F3c~O H..--N
O 40
O H.,"N"~R F3C~
N~H 42
H20,A
F3C"~
H~N"N"~::~O
H..N.N/~O
I R'
I R'
4__33
44
Scheme 5 1.
REACTION OF 3-AMINOCROTONATE 17 WITH ISOTHIOCYANATES AND SOME FOLLOW-UP REACTIONS Enamine 17 reacts smoothly at 20~ with isothiocyanates to furnish 4-trifluoromethyl thiouracils 45 (Scheme 52, ref. 44).
234
F3C
DMSO, 20oC~ F 3 C ~ O
C12 n , , F 3 C ~ O
tert. butyl OK
0oc
+ RN =C'--S H2N
CO2Et
N,~NR
!.7_7
N.~NR /
/
SH
SCI
4__55
4__66
R = Me, n-Butyl, Cyclohexyl, Phenyl, alkyl Yields 63 - 98 % Scheme 52. An analogous reaction with isocyanates has already been explored (ref. 47). The parent compound 45, R = H has been prepared from TFAE and thiourea as early as in 1948 (ref. 48) but N-substituted thioureas do not seem to react (ref. 47). Interestingly, 45 can be transformed to the versatile sulphenyl chloride 46 upon chlorination at 0~ At a higher temperature one observes also C-chlorination which can be avoided. Compounds 46 are not very stable, but they give all the typical reactions of sulphenyl chlorides, thereby leading to many interesting structures. The parent 45 behaves in a complete analogy to arenethiols (S-alkylation, Michael addition, S-oxidation and dimerisation). The nucleophilic reactivity of 17 can be increased by N-deprotonation and the best results were obtained with the in situ generated lithium salts. The latter react with acrylates by Michael addition and ring closure to give a single product. The problem of regioselectivity arises because the enamine anion 47 is delocalized and can react both at the nitrogen anion and/or at the enamine carbon. Both cases are known in the literature with similar substrates (ref. 49). These two pathways should lead to the isomeric dihydro co- or 7-pyridones (Scheme 53).
o
E
E
=(
RN_aack
F3C
R F3C
NH
Li |
R = H, Me -(CH2)2OH
C-attack
I
H
H 48
E
47
49
Scheme 53.
235
The differentiation between 48 and 49 by spectroscopical means is not obvious but the X-rays of the crystalline product derived from ethyl acrylate upon oxidation to pyridone (Scheme 54).
have
unambiguously
established
its
c~-pyridone
structure
50
Similar structures containing a cyano group at the 5-position have already been studied for their cardiotonic activity (ref. 50).
S8, A 49
E
~
~
50, 50 % F3C
I
O
H Scheme 54.
TRIFLUOROMETHYLATED
HETEROCYCLES
FROM
13-TRIFLUORO-
A C E T Y L A T E D LACTAMS AND BENZOLACTAMS Trifluoroacetylation of C-H acidic compounds using TFAA or methyl trifluoroacetate is a well-established process. It introduces a trifluoroacetyl group which is prone to various transformations. There is a number of reports dealing with trifluoroacetylation of ketones (ref. 51), lactones (ref. 52) and even of tertamides (ref. 53). In contrast, only one report deals with trifluoroacetylation of a cyclic lactame - N-methylpyrrolidone (NMP) (ref. 54), but it could not be duplicated. Finally, the best results for obtaining 52 are shown in the Scheme 55 (refs. 55, 56, 57). The occurrence of the gem-diol 51 is not surprising. F3C ,OH Nail O I
~ O H
F3C Dist.
CF3CO2Et
0
70~ at 0,1 Torr I
I
Me
Me
Me
NMP
51
52
Scheme 55. This procedure was extended to higher lactams and the N-substituent was also varied. Benzoannelated lactams gave also mostly satisfactory yields. 236
Compound 52 formed readily the corresponding hydrazone 53 which cyclized upon the treatment with POCI 3 to give dihydropyrrolopyrazole 54 (Scheme 56, ref. 58).
F3C
H|
H I
~N..Me
CF3
POCI3
52 + MeNHNH2
Tol, A
Pyr., 20~ I
\Me
M/
Me 53
54
Scheme 56. The corresponding N,N-dimethyl hydrazone and oxime of 52 were prepared as well. Hydrazine reacted normally with 52 leading to the corresponding hydrazone in a 74 % yield. With other trifluoroacetyl lactams and hydrazine or phenylhydrazine an interesting ring-opening of the lactame function, followed by ring-closure (RORC) occurred. This leads to unusual zwitterionic pyrazoles 55 (Scheme 57). 0
( ~
\\ C~CF3
RNHNH2 ,._
| MeH2Nn
~
CF3 55 60-70%
o I
I
Me
Me
Scheme 57. These compounds could not be ring-closed (enolate anion is a latent carbonyl) using a variety of conditions (ref. 58). Dihydrocompound 54 could be oxidized using MnO2 to the corresponding aromatic bicyclic product. Guanidine reacted also properly with 52. The intermediary guanidino enamine 56 could be isolated and it cyclized uneventfully to 57 in the presence of POC13 (Scheme 58, ref. 59).
237
HN F3C~ ~ N H 2 ,_.___~~N
Guanidine
52
~- ( N . ~
O,,H
F3C POC13
~/~N\
refll~ 1 hr ~-
Q,N,~N/--NH2
I
I
Me
Me
5___6673%
5__2_740%
Scheme 58. The reactions with benzamidine were less straightforward and needed harsher conditions (heating to 100~176 with the neat base) (Scheme 59). CF3
CF3
Ph
~
I
I
Me n= 1,2,3
Me 58 CF3
@ ~ N +
N ~i
CF3
H
N~ ' j ( C H 2 ) 4 - N I
-Me
Ph + PhJ 2"N " "~"> I~O I
Me 59
60
Scheme 59. Compound 58 is the expected intermediate which accompanied the cyclization product 59 (n = 1). With n = 3, none of the 58 was formed, 59 was present in 31% yield, together with 60 (41%). This compound arises through the opening of the lactam moiety. Generally, the isolated 58 could again be cyclized to 59 using POC13. The picture was quite similar with annulated benzo-lactams (ref. 59) which lead to tricyclic systems. As with TFAE, the corresponding enamine 61 could be prepared by the method of Swartz (refs. 42, 60). This versatile compound was reacted with amide chloride 238
of N-methyl piperidone to give the azadiene 62 (Scheme 60). Further cyclization did not occur. F3C.
F3cMeNN/~ H-~
@
:~
+ I
COC12
0
N
CHC13,A
I
Me
I
Me
Me
61
62
Scheme 60. Compounds 52 and homologues reacted invariably with 1,4-bis-nucleophiles such as ethylenediamine and 2-aminoethanol at the CF3CO group by forming oxazolidines 63 and imidazolidines 64 (Scheme 61, ref. 62). Similar behaviour was encountered with ethyl trifluoroacetoacetate (ref. 61). F3C H 63, x = o
XH
52 + H2N
reflux ~
~N~~
---~
64, X=NH
I
Me Scheme 61. RORC products 65 may also predominate when benzolactams are reacted with phenyl and methyl hydrazine (Scheme 62, ref. 63). The POC13 induced cyclization of 65 failed, but in one case 66 reacted by bridging to form a phospha-cycle 67 (Scheme 63, ref. 63).
F3C n
I
Me
O
F3C
H \N-Me
-
I
Me I
R n=l,2
65
Scheme 62. 239
52-71%
F3C
F3C
"Me
POCI3, reflux .[~"-;2N_p/O~ v
Me
67 30%
NH
M/
Me/ g XC1 66
Scheme 63. A recent study describes the behaviour of trifluoroacetylated (benzo) lactams toward 2-aminopyridine, 2-aminobenzimidazole and 3-amino-l,2,4-triazole (ref. 64).
Robinson annelation with 52 1,3-Dicarbonyl compound 52 being strongly acidic undergoes a Michael
addition with methyl vinylketone (MVK) and the intermediate products can be cyclized to spiro-cyclohexenone 68 (Scheme 64, ref. 65).
1. NaHcat 52 + MVK
-
~ Phil, 20~ 2. AcOH, piperidine Phil reflux
68
65%
F3 I Me
Scheme 64. The synthetic potential of 68 was explored further. Thus its trifluoroacetylation using LDA and ethyl trifluoroacetate gives 69 together with its gem-diol in a 56 % yield (Scheme 65, ref. 65). The cyclization with benzamidine gave 70 in low yield.
240
Ph O F3C
H
F3C benzamidine
68
/
"-
70
28 %
F3
~ N / ~ O CF3 Me
Me 69
Scheme 65. The picture was quite similar with annulated benzo-lactams (ref. 64) which lead to polycyclic systems. Aminothiophenol formed a spiro-compound using the vinyl ketone carbonyl. Compound 68 was subjected to another annelation with MVK to give the tricyclic spiro-ketone 71. It was also transformed to spiro-dienone 72 via a selenation-elimination process. O O
71 "
F3 I
Me
35%
(
/~
7__~2 70%
N I
Me
O
Scheme 66.
CONCLUSION The selection of results shows the usefulness of simple and readily available trifluoromethylated compounds deriving mainly from trifluoroacetic acid or trifluoropropene as CF3-carrying reagents. Such an approach avoids tedious C1-F exchange reactions and leads directly to convergent synthesis of more complex trifluoro-methylated molecules.
241
References
1. 2. 3.
4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. a) b) 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38.
H.G. Viehe, R. Mer6nyi, J.M. Oth, J.R, Senders, P. Valange, Angew. Chem., 76, 922, Int. Ed. Engl., 3,755, (1964). J.N. Harvey, H.G. Viehe, J. Prakt. Chem., 337, 253, (1995). G. Leroi, J.-P. Denispelaare, H. Ankadour, D. Temsamani, C. Wilante Bull. Soc. Chim. Belg., 367 (1994) and refs. cited. M.A. Plancquaert, Ph. Francois, R. Mer6nyi, H.G. Viehe, Tetrahedron Lett., 49, 72657268, (1991). J.L. Anderson, R.E. Putnam, W.H. Sharkey, J. Am. Chem. Soc., 83,382, (1961). H.G. Viehe, Angew. Chem., 79, 744 (1967); Int. Ed. Engl., 6, 767, (1967). S.Y. Delavarenne, H.G. Viehe, Chem. Ber., 103, 1198, (1970). M. Rover-Kevers, L. Vertommen, F. Huys, R. Mer6nyi, L. Stella, Z. Janousek, H.G. Viehe, Angew. Chem., 93, 1091 (1981), Int. Ed. Engl., 12, 1023, (1981). H.G. Viehe, Z. Janousek, R. Mer6nyi, L. Stella, Acc. Chem. Res., 18, 148, (1985). F. Huys, R. Mer6nyi, Z. Janousek, L. Stella, H.G. Viehe, Angew. Chem., 91, 650, (1979) ;Int. Ed. Engl., 18,615, (1979). C. At~s, part of PhD. work, 1994-1995. For a related observation see H. Ahlbrecht, W. Farnung, Synthesis, 336, (1977). See also the "1,3-dipole elimination" starting from bis(dialkylamino) malononitriles : W. Kantlehner, U. Greiner, Liebigs Ann. Chem., 963, (1990). Unpublished results in collaboration with R. Sustmann and H. Korth. C. At~s, Z. Janousek, H.G. Viehe, Tetrahedron Lett., 34, 5711, (1993). C. Beauve, M6moire de licence, UCL, (1994). H.C. Brown, R. Pater, J. Org. Chem., 27, 2852, (1962). W.J. Middelton, E.G. Howard, W.M. Sharkey, J. Org. Chem., 30, 1375, (1965). F. Laduron, part of Ph. D. work, 1991-1995. M. Redon, part of Ph.D. work, 1991-1995. F. Laduron, Z. Janousek, H.G. Viehe, J. Fluorine Chem. (1994), accepted. M.A. Plancquaert, M. Redon, Z. Janousek, H.G. Viehe, to be published. Ph. Francois, part of Ph.D. work, 1994-1995. C. Malivemey, H.G. Viehe, Tetrahedron Lea., 31, 6339, (1990). C. Malivemey, Ph. D. thesis, Louvain-la-Neuve (1990). M.E. Mustafa, A. Takaoka, N. Ishikava, J. Fluorine Chem., 30, 463, (1986). C. Maliverney, H.G. Viehe, B. Tinant, J.P. Declercq, Bull. Soc. Chim. Fr., 127, 843848, (1990). J. Elguero, A. Fruchier, N. Jagerovic, A. Werner, Organic Prep. and Proc. Int. (OPPI), 27, 33, (1995). C. Maliverney, R. Mer6nyi, H.G. Viehe, Bull. Soc. Chim. Belg., 99, 941, (1990). B. Tinant, J.P. Declercq, C.Malivemey, H.G. Viehe, Acta Cryst, C47, 2000, (1991). K.I. Pashkevich, V.I. Saloutin, Russian Chem. Reviews, 54, 1185, (1985). F. Weygand, H.J. Bestmann, Angew. Chem., 72,538, (1960). M. Guillaume, Z. Janousek, H.G. Viehe, Ch. Wynants, J-P. Declercq, B. Tinant, J. Fluorine Chem., 69, 253-256, (1994). M. Guillaume, Z. Janousek, H.G. Viehe, Synthesis (1995), accepted. S. Egushi, Y. Matsushita, K. Yamashita, Org. Prep. and Proc. Int., 24, 209, (1992). T. Ye, M.A. McKervey, Chem. Rev., 94, 1091, (1994). M.G. Hoffmann, E. Wenkert, Tetrahedron, 49, 1057, (1993). See for example : H.M.L. Davies, M.J. McAffee, C.E.M. Oldenburg, J. Org. Chem., 54,930, (1989). M. Guillaume, Ph.D. Thesis, Louvain-la-Neuve, 1994. 242
39. 40. 41. 42. 43.
D.L. Boger, Chem. Rev. 86, 781, (1986). H. Neuenhoffer, G. Werner, Liebigs Ann. Chem., 437, (1973) and 1955, (1973). H.J. Bestmann, O. Klein, Liebigs Ann. Chem., 97, (1964). F. Swarts, Bull. Sci. Acad. Belg., 5,671 and 680, (1926). M.A. Decock-Plancquaert, F. Evariste, N. Guillot, Z. Janousek, C. Maliverney, R. Mer6nyi, H.G. Viehe, Bull. Soc. Chim. Belg., 101,313, (1992). F. Evariste, Ph.D. Thesis, Louvain-la-Neuve, 1992. 44 W. Steglich, R. Jeschke, E. Nushbaum, Gazz. Chim. Ital., 116, 361, (1986) and the 45. references quoted. Evariste, N. C. Maliverney, R. Mer6nyi, H.G. Viehe, J. Prakt. Chem., 335, 35, 46. (1993). A.W. Lutz, S.H. Trotto, J. Heter. Chem., 9, 513, (1972) and US Patent 3981 715, 47. (1976). W.H. Miller, A.M. Dessert, G.W. Anderson, J. Am. Chem. Soc., 70, 500, (1948). 48. A.R. Katritzky, D.C. Oniciu, B. Mancheno, R.A. Barcock, J. Chem. Soc. Perkin 49. Trans. 1, 113, (1994). L. Mosti, P. Schenone, M. Lester, P. Doringo, R.M. Gaillon, D. Fraccarollo, Eur. J. 50. Med. Chem., 28, 853, (1993) and I1 Farmaco, 47,427, (1992). E.P. Kramarova, Yu.I. Bankov, I.F. Lutsenko, Zhur. Obshch. Khim., 45,478, (1975) ; 51. C.A. 82, 112129y, (1975); see also C.A. 108, 200234g, (1987) ; C.A., 112, 139043r, (1989). K.N. Allen, R.H. Abeles, Biochemistry, 28, 8466, (1989). 52. A.N. Fomin, V.I. Salutin, M.N. Rudaya, K.I. Pashkewich, Zhur. Org. Khim., 22, 53. 1603, (1986). I.L. Knunyants, Izv. Akad. Nauk SSSR, Ser Khim., 7, 1688, (1986). 54. J.-P. Bouillon, Ph.D. Thesis, Louvain-la-Neuve, 1994. 55. 56. a) J.-P. Bouillon, C. Maliverney, R. Mer6nyi, H.G. Viehe, J. Chem. Soc. Perkin Trans I, 2147, (1991). b) J-P Bouillon, C. At6s, C. Maliverney, Z. Janousek, H.G. Viehe, Org. Prep. Proced. Int., 26, 249-255, (1994). J-P. Bouillon, A-M. Frisque-Hesbain, Z. Janousek, H. G. Viehe, Heterocycles, 40, 661, 57. (1995). J-P. Bouillon, V. Bouillon, C. Wynants, Z. Janousek, H.G. Viehe, Heterocycles, 37, 58. 915-932, (1994). B. Tinant, J.-P. Declercq, J.-P. Bouillon, H.G. Viehe, Bull. Soc. Chim. Belg., 102, 59. 611, (1993). J-Ph. Bouillon, Z. Janousek, H.G. Viehe, Synth. Comm., (1995), accepted. 60. G.M.J; Sluszarczuk, M.M. Joulli6, J. Org. Chem., 36, 37, (1971). 61. J.-Ph. Bouillon, Z. Janousek, H.G. Viehe, B. Tinant, J.-P. Declercq, Bull. Soc. Chim. 62. Beiges, 103,655, (1994). J.-Ph. Bouillon, Z. Janousek, H.G. Viehe, B. Tinant, J.-P. Declercq, J. Chem. 63. Soc.,Perkin Trans. II, submitted. J-P. Bouillon, Z. Janousek, H. G. Viehe, Polish J. Chem., 68, 2315, (1994). 64.
243
FLUORINATION
OF
AROMATIC
COMPOUNDS
BY
HALOGEN
E X C H A N G E W I T H F L U O R I D E ANIONS ("HALEX" R E A C T I O N )
BERNARD LANGLOIS a~, LAURENT GILBERT b~ AND GERARD FORAT u~ a) Universit6 Claude B e r n a r d - Lyon I, Laboratoire de Chimie Organique 3, associ6 au CNRS, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne, France. b) Rh6ne-Poulenc
Industrialisation,
Centre
de
Recherche
et
d'Ing6nierie,
85 Avenue des Fr~res Perret - 69192 Saint-Fons, France.
GENERAL FEATURES Halogen exchange with a fluoride anion is one of the two main techniques to introduce a fluorine atom on an aromatic nucleus, which is a useful complement of diazotization of anilines in hydrogen fluoride or thermal decomposition
of
arenediazonium fluoroborates (Schiemann reaction). It is used on an industrial scale to produce, for example, 2,6-difluorobenzonitrile (the precursor of the insecticide Diflubenzuron) or 2,4-difluoroaniline (the precursor of Diflufenican or other herbicides). C1
F
F
C1
F
F
F o
\NH~
NH@
C1
F Diflubenzuron - (Philips Duphar)
244
NO2
KF
NO2 H2 w_ F - ~ Cat.
F ~ F
c1
NH2
r w.-
F
O
CF3 Diflufenican- (Rh6ne-Poulenc) Scheme 1. Industrial process involving a "Halex" step
The earliest experiments have been reported as soon as 1936 for the fluorination of polyhalobenzenes at very high temperature (ref. 1) but, to perform the reaction under more realistic conditions, an electron-withdrawing substituent is needed to activate the displacement of the leaving group. Mesomeric electron-withdrawing substituents are better than purely inductive ones and the following efficiencies have been observed : NO2 > pyridinic N > CN > CF3 > COX (X = Hal, OR) > CHO-~ COR > C1n These electron-withdrawing substituents must be located in ortho or para position to the leaving group and, sometimes, their efficiency can be enhanced by an halogen in meta position. Some comparative examples are given below (ref. 4) :
NO2 X
NO2
C1
~
X
F
DMF Table 1. Influence of substituents X
Conditions
ArF (%)
NO2
140-150~ / 0.5 h
77
CF3
160~ / 3.5 h
76
COzMe
155~ / 4 h
67
245
The leaving ability of the group to be displaced is as follows : R3N + > NO2 > C1 > Br
Displacement of ammonium moieties is of huge interest for the rapid synthesis, under very mild conditions, of 18F-labelled radio-pharmaceuticals useful for medical imaging. Following Clark's work and some others in the 80's (refs. 2,3) increasing interest is paid to fluorodenitration but this method is limited by the availability of 1,2 or 1,4 dinitrobenzenes. Thus, on an industrial scale, exchange of F for C1 is much preferred (ref. 5). The kinetics of chlorine displacement is strongly dependent on the position of the activating substituent : 4-chloronitrobenzene reacts faster than 2-chloronitrobenzene with potassium fluoride whereas, in 2,4-dichloronitrobenzene, chlorine in the 2-position is exchanged more rapidly than chlorine in the 4-position (refs. 4 - 8). These observations are consistent with an addition-elimination process involving an anionic adduct (Meisenheimer's complex) which has been observed by 1H and 19F NMR (ref. 9) or UV spectroscopy (ref. 3) :
E W G ~ C 1
-..
+F |
"-
EWG
-F|
~
C1 \
/
F
4--
-CI@
~
EWG
+ C1 @
EWG = electron-withdrawing group Scheme 2. Addition-elimination process for aromatic halogen exchange.
When located in 2- or 4-position to the chlorine atom, the nitro group stabilizes the Meisenheimer's adduct both by inductive and mesomeric effects, the latter one being predominant. To maximize this effect, the nitro group must be coplanar with the aromatic ring. This is not the case when a bulky chlorine atom is presem in ortho position : the nitro group is then twisted out the plane and 2-chloronitrobenzene is less reactive than 4-chloronitrobenzene. In 2,4-dichloronitrobenzene, mesomeric activation of 2- and 4- positions is affected to the same extend and inductive effect becomes predominant. Nevertheless, this effect decreases very fast with the distance so that the ortho position is more activated than the para one. Inductive activation by halogens can also explain the higher reactivity of 3,4-dichloronitrobenzene compared to 4-chloronitrobenzene. The same phenomenon has been observed with 2-chloropyridines (ref. 10) : 246
X2
X1 C1
Me2S02
Table 2. Inductive effects in the "Halex" reaction
X1
X2
Conditions
Fluoropyridine (%)
H
200- 210~
C1
201~
h
65
194~
h
70
C1
h
49.5
Concerning the effect of the magnitude of twisting in chloronitrobenzenes, we observed that 2,6-dichloronitrobenzene, in which the nitro group is more twisted than in 2,4-dichloronitrobenzene, does not react under conditions where the latter isomer is quite completely transformed (sulfolane / 180~ If the
Meisenheimer's
adduct
is
stabilized
by
/ 11 h). the
electron-withdrawing
substituent, it is also destabilized by +I~ interactions between the negative charge and the p-electrons of the two halogens. Thus, the formation of this adduct can be considered as an equilibrated process since +I~ effect is more pronounced with fluorine than with chlorine, which forms longer bonds than fluorine. On the other hand, as fluorine is more electronegative than chlorine, fluoroaromatics should be more electrophilic than chloroaromatics, and the second step in Scheme 2 could be also considered as an equilibrium. It will be seen that, under some conditions, chloroaromatics can be generated from fluoroaromatics and chloride anions. Nevertheless, reactions depicted in Scheme 2 are usually shifted to the right because C-F bonds are stronger than C-C1 ones (542 kJ/mol vs 339 kJ/mol) (ref. 11). The first " H a l e x " experiments have been carried out with neat chloroaromatics at high temperatures (400 - 500~
but the introduction of dipolar aprotic solvents
in the late 50's brought a dramatic improvement for the use of this process on a large scale under realistic conditions (0 ~ _< 2 0 0 - 250~
(ref. 4). It can be noticed
that protic solvents, which decrease the nucleophilicity of the fluoride anion by strong hydrogen-bonding, are less adapted than aprotic ones. Commonly used dipolar aprotic solvents are : dimethylsulfoxide (DMSO), tetramethylenesulfone (or 247
sulfolane), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), Nmethylpyrolidinone (NMP) or benzonitrile. For fluorodenitration, the following order of efficiency has been reported : DMSO > tetramethylenesulfoxide > DMAc > NMP > sulfolane (ref. 12). For other "Halex" reactions, DMSO remains the best solvent (provided that the reaction temperature is lower than 150~ but some changes can be observed in the order of efficiency for other solvents. It can be noticed that, under rather drastic conditions, some by-products can result from the solvent, for instance N,N-dimethylanilines from DMF (refs. 13,14) or thioanisoles from DMSO (ref. 15). Thus, because of its low cost, its thermal stability (up to 250~ and its high boiling poim (Eb760 -- 285~ sulfolane is often preferred. Potassium fluoride is the cheapest source of fluoride and is thus widely used on large scale. However, it is only slightly soluble in aprotic solvents and large difficulties arise from this fact both on a process point of view and on a fundamental point of view (concerning the elucidation of the mechanism). Thus, the "Halex" reaction has been also studied with organosoluble fluorides.
F L U O R I N A T I O N WITH ORGANOSOLUBLE FLUORIDES Tetraalkylammonium fluorides, commonly available, are soluble in a wide range of solvents. However, they are very hygroscopic (ref. 16) and several hydrates are known for Me4NF.nH20 (n 1,2,3,4), Et4NF.nH20 (n = 1,2,2.75,3,5), (n-C3H7)4NF.nH20 (n = 2,3,6), (n-C4H9)4NF.3H20 or BnMeaNF.H2 O (Bn = benzyl) (ref. 16). Among them, Me4NF.4H2 O, Et4NF.2H20, Bu4NF.3H20 and BnMe3NF.H20 are commercialy available. Even under high vacuum, complete dehydration fails at room temperature and Hoffman degradation occurs, under heating at 60~ when hydrogen is present in [3-position to the nitrogen centre (refs. 17,18) : | R3N_CH2~CH2~
R,
Fe
A
| R4N--CH2~CH2~R' Fe+ HF
R3N + R ' - C H - - C H 2
+ HF
| R4N--CH2~CH2~R'
HF2e
Azeotropic dehydration with benzene also fails (refs. 17, 18).
248
Table 3.
Dehydration of R4NF, nH20 according to (ref. 17) and (ref. 18)
R4NF, nH20
20~
Treatment
State
Residual water (Karl-Fischer)
Observed species (19F NMR) (see below)
none
solid
n=3
F-, nH20
solid
n = 2.5
F-, nH20
solid
n=2
F-, nH20 -at-HF2-(traces)
mbar/13h
lyophilization Bu4NF, 3H20
Me4NF, 4H20
20~
sieves
oil
F-, nH20 + HF2- (40-60%)
60~
mbar/20 h
oil
n =0.6
60~
mbar/27 h
oil
n = 0.2
HF 2-
45~
mbar/22 h
solid
n=2
F-, nI-I20
solid
n=2
F-, nH20
solid
n = 1
F-, H20
azeotropic (C6H6) BnMe3NF, H20
azeotropic (C6H6)
.
.
.
.
HF 2-
Hydrated tetraalkylammonium fluorides can be, nevertheless, used in " H a l e x " reactions but water, the nucleophilicity of which is enhanced by hydrogen-bonding with F-, competes
with the fluoride and delivers phenols and diaryl ethers as by-
products. A typical situation is shown below for 3,4-dichloronitrobenzene (ref. 17).
249
C1 O2N~-~-C1 1
C1 R4NF, nH20 Solvent/120~ (F-/Solv. = 1/25 mol/mol)
CI
O 2 N @ F
+ O 2 N @
2
OH
~
C1
Table 4.
Reaction of 3,4-dichloronitrobenzene with soluble hydrated tetraalkylammonium fluorides according to (ref. 17).
RaNF, nH20
BuaNF, 3H20
Solvent
Conv. 1 (%)
Yield 2 (%)
Sulfolane
60
42
20
4.29
56 43
20
3.11
20
3.91
DMSO DMF
Yield (3 + 4) Initial rate of (%) formation for 2 102.Vo (min-1)
Me4NF, 4H20
Sulfolane
60
48
12
4.85
Et4NF, 2H20
Sulfolane
55
45
10
4.17
BnMe3NF, H20
Sulfolane
52
47
5
2.41
Table 4 shows that : - The initial rate of formation of aryl fluoride, but also the yield of oxygenated by-products, increase with the water content of the reagent, -
The final yield of aryl fluoride increases with the solvent polarity,
-
The initial rate of formation of aryl fluoride increases when the solvent polarity
decreases. The effect of the water content in the ammonium fluoride is illustrated on Figure 1 (from (refs. 17,18))
250
NO 2
NO 2
1 BnMe3NF, n H20 CI
Sulfolane/120~ / 2 h F
100 80 "5 6O - - I - - Yield 2
4020 0
|
0
1
m
m w
|
I
2
3
4
n H20
Fig. 1.
Influence of water on the reaction of 3,4-dichloronitrobenzene with BnMe3NF, nH20 (refs. 17,18)
Thus, such extended side-reactions constitute a severe drawback for the use of hydrated alkylammonium fluorides in aromatic fluorination. This problem can be +
-
avoided by using other solvates of onium fluorides, especially species like RaM F , nHF and, for instance, BuaN+HF2 - (n = 1), BunN+H2F3 - (n = 2), Bu4N+H3F4 (n = 3), Bu4P+HF2 -, PhnP+HF2 - or Ph4As+HF2 -. These compounds are easily prepared from R4M § nH20 or R4M § by phase-transfer techniques (refs. 17,19 - 21) or ion-exchange on resins (refs. 17, 20, 22 - 27). However, their ability to displace aromatic chlorine is dramatically dependent on the degree of solvation of the fluoride, as shown on Figure 2 (refs. 17,18) :
251
NO2
NO2 Bu4NF, n HF (1 eq.) Sulfolane / 120~ 92 h. (HF2-/solv. = 1/25)
~]~C1 C1
80 60 O
E
40 2O
0
v
!
|
1
2
3
4
n (F-, n HF) Fig. 2. Influence of the degree of solvation in Bu4NF, nHF on the fluorinating power (refs. 17,18).
In practice, only monohydrogenofluorides are efficient for "Halex" reactions. Moreover, two equivalents of Bu4NHF 2 are needed to obtain quite quantitatively 2_ from 1 but, under the above conditions, the reaction is completely chemoselective (Fig. 3) (refs. 17,18).
252
NO2
NO2 Bu4NHF2
,._,._
Sulfolane 120~ 92 h
CI
C1
C1
100 80 6O 9
40 20 "V"
|
0
1
!
2
3
Mol.ratio Bu4NHF 2 / 1 Fig. 3. Influence of the excess of Bu4NHF2 on the fluorination yield
This p h e n o m e n o n can be explained by the f o r m a t i o n of n o n - r e a c t i v e highersolvated f l u o r i d e s w h e n the reaction p r o c e e d s 9
ArC1 + Q + HF2-
~-
Q + HF2- + HF ArC1 + Q + H2F3-
A r F + Q +CI + H F Q+H2F 3-
/N/ ~ ,.._
ArF
ArF + Q + C1- + Q + H2F3-
ArC1 + 2 Q+HF2
253
Fluorination yields are less sensitive to solvent effects with Bu4NHF 2 than with BuaNF, 3 H20 (Tables 4 and 5) but the same tendency is observed. It can be noticed that this effect can be correlated to the variation of 19F NMR chemical shifts for solvated F- in different solvents (see below). Thus, the measurement of 19F chemical shifts could be a fruitful guide to choose a convenient solvent for fluorination. C1 O2N
~ ~ _ _
CI
R4M +HF2-(2 eq.)
~ O2N
Solvent (HF2- / solv. = 1/25) 120~ / 2 h
_1
Table 5.
C1 F 2
Fluorination of 3,4-dichloronitrobenzene with onium hydrogenofluorides according to (ref. 17). Solvent
Yield 2 (%)
102.Vo (min1)
DMSO
92
7,34
DMF
91
8,08
Sulfolane
88
8,10
Bu4P+HF2-
Sulfolane
68
Ph4P+HF2
Sulfolane
44
Ph4As+HF2-
Sulfolane
60
RaM+HF2-
Bu4N+HF2
Table 5 clearly shows that ammonium hydrogenofluorides
are far better
fluorating agents than other onium hydrogenofluorides 9 BuNHF 2 > Bu4PHF 2 > Ph4AsHF 2 > Ph4PHF 2 As previously mentionned, the possibility of a reverse reaction, that is the formation of chloroaromatics from fluoroaromatics, must be investigated, especially with onium halides since, in this case, no solubility problem can disturb the eventual equilibria. Table 6 indicates that tetrabutyl ammonium or phosphonium chlorides, when
dried,
react to a very limited extend with fluoroaromatics,
even in
concentrated medium with very activated substrates like 2,4-dinitrochlorobenzene (ref. 17). 254
However, water enhances dramatically this " R e t r o - H a l e x " reaction but only when performed on very activated substrates (ref. 17). An explanation could be found in the fact that the fluoride anion can be far more strongly solvated than the chloride anion : hydration could thus be an effective driving force for the "Retro-Halex" reaction.
X
X + BunM+CI, xH20 Solvent ~ O 2 N - ~ C 1 120~ / 2 h (1 eq.)
O2N-~F
X + O2N~OH
Table 6. Displacement of aromatic fluorines by onium chlorides. X
NO2
C1
M
x(H20)
Solvent*
Conv. ArF (%)
Yield ArC1 (%)
Yield ArOH (%)
N
1
Sulfolane
52
44
8
DMF
80
68
12
N
0
DMF
8
P
0
DMF
13
N
1
Sulfolane
* CI- / Solv. = 1/2 (mol/mol)
As already noticed, the anionic fluorinated species are cominuously changing as the halogen exchange proceeds in homogeneous media and this reaction is sensitive to the nature of the solvent. In order to have a better knowledge of the process at every moment and to quantify the solvent-solute interactions, 19F N M R spectra of different solvated fluorides have been recorded in several solvents (refs. 17,18) (Table 7).
255
T a b l e 7.
C h e m i c a l shifts (19F N M R ) f o r s o l v a t e d f l u o r i d e s in d i f f e r e n t s o l v e n t s ( f r o m (ref. 17))
19F N M R ; 8 ( p p m vs. CHCl3)a'b); JHF ( H z ) o r Av ( H z ) |
Solvent
Bu4NF, 3 H20
Bu4NHF2
Bu4NH2F 3 d)
Bu4NH3F4 d)
MeaNF, 2 H20
MeaNF, 4 H20
EtaNF, 2 H20
2~C-VHg_
NMe-T, H20
HCONMe 2 DMSO
-93.2
- 131.7
- 152.0
- 104.0
- 143.8
- 160.2
- 99.7
-
108.6
-
101.9
(Av=12) DMSO-d6
- 150.1
- 161.8
(d,J=119) CH3COCH3
- 109.4
- 151.3
-
167.6
HCONHMe
- 113.2
- 144.3
-
163.6
CD2C12
- 118.7
- 1 5 3 . 8 c)
- 170.4
EEl 4
- 113.2
- 144.8
- 164.9
HMPT
- 114.1
- 150.4
- 168.2
MeCN
- 114.1
- 149.9
- 165.4
- 170.6
-
118.1
-
111.7
(Av= 10) -114.4
DMF
-149.4
- 166.3
-
112.6
(Av=10) - 116.1
DMAc
- 150.6
- 166.4
-
114.6
(Av=31) PhNO 2
-
116.5
- 153.0
- 164.5
-
119.4
(Av=32) PhCN
- 116.5
- 151.3
- 167.7
DMPU
- 116.5
-155.1
- 169.3
DMEU
-
118.1
- 155.8
- 168.8
- 120.4
- 155.9
- 168.4
Sulfolane
-114.3
-120.7 (zXv=40)
MeOH
- 147.4
C1CH2CH2C1
- 160.1
- 172.5
- 157.4
- 167.6
HMPT
= hexamethylphosphoramide
DMEU
= N,N-dimethylethyleneurea
;DMPU
a)
Singlet if no other indication provided
b)
F- / s o l v . = 1 / 5 0 ( m o l / m o l )
c)
becomes a doublet at- 56~
d)
large singlets
= N,N-dimethylpropyleneurea
(8 = - 1 4 2 . 5 p p m ; JHr = 120 H z )
256
;
- 97.4
The chemical shifts have been correlated satisfactorily with the solvent parameters AN (acceptor number (ref. 28)), DN (donor number (ref. 29)) and (dielectric constant) for a set of nine solvents (acetone, acetonitrile, DMF, DMAc, nitrobenzene, sulfolane, HMPT, benzonitrile, methanol) (ref. 17) (Fig. 4). The predominant weight of AN indicates clearly the basic character of solvated fluorides which, however, is strongly modulated by HF-solvation and can be quantified in that way. Thus, the correlation between the chemical shift and the reactivity of soluble fluoride anions could, in principle, allow to predict their fluorination efficiency in any solvent.
FLUORINATION WITH ALKALINE FLUORIDES Because of their price and availability, alkaline fluorides are the most attractive anionic fluorinating agents. Caesium fluoride is the most reactive of them but, because of its price, is only devoted to the preparation of products with very high added values. At the other bottom, lithium and sodium fluorides are completely unreactive. Thus, potassium fluoride, which presents the best ratio between cost and reactivity, is the most popular reagent to perform the "Halex" reaction on a large scale. In fact, no other inorganic fluorides than alkaline ones have been claimed for this technique. Taking into account that all inorganic fluorides and chlorides are sparingly soluble in aprotic solvents and that solubility could be a significant parameter in the "Halex" process, this point can be understood when looking at the lattice energy of solid inorganic fluorides and chlorides. Indeed, a reaction in which one reagent and one product are both in the solid state, must be favoured if the lattice energy of the product is larger than the lattice energy of the reagent. In fact, the lattice energies of fluorides are always larger than those of chlorides. This gap is partly balanced by a higher solvation energy for fluorides and a larger energy for C ~ F bonds (452 kJ/mol) than for C----C1 bonds (339 kJ/mol) (ref. 11). Nevertheless, minimizing the difference between lattice energies of chlorides and fluorides must favour the process. This difference lies between -196 and -83 kJ/mol for alkaline salts, between- 146 and-280 kJ/mol for alkaline earth salts and between-272 a n d - 1 8 8 kJ/mol for transition metal salts (ref. 31). Thus, alkaline fluorides appear to be the less unadapted reagents for substitutive aromatic fluorination. Some of their thermodynamic data are reported on Table 8.
257
BU4NF.3H20
Bu4NHF2
Y( I)=89.6+ I.16 AN+O. 14 DN+0.2 c
Y(2)= 144.3 + 0.29 AN -0.04 DN + O.14 r
170
150
165
140 E ca
'~ 160 130
Dr.l~
6 120
155
Sulfolanea
I
d
G
eL!
t.)
II0 I00
150 145
"
100
!
"
110
i
120
9
i
130
9
!
9
140
Y experimental (ppm)
140,
//" I
i
150
140
150
CI,BOH
9
l
160
Y expeMmental (ppm)
9
, _
170
Bu4 N H2. F3 Y(3)= 16 I.I +0.2 AN +0.09 DN +0.04 c
175
E e,t
170
4D U
>" 165
160 160
9
i
165
9
i
170
9
175
Y expeMmental (ppm) Fig. 4. Correlations between ]9F NMR chemical shifts of solvated fluorides and. solvent parameters (NEMROD program (ref. 30)).
258
ArC1 + MF
~
ArF + MCI
Table 11. Thermodynamic data for alkaline fluorides and chlorides
AEL (MC1-MF) a) AG~176
b) AH(ArC1---~ArF)c)
EL('MF)a)
EL(MC1)a)
(kJ/mol)
(kJ/mol)
(kJ/mol)
(kJ/mol)
(kJ/mol)
Li
1030
834
-196
194
+83
Na
910
769
-141
152
+28
K
808
701
-107
122
-6
Rb
774
680
-94
114
-19
Cs
744
657
-87
102
-26
Fr
715
632
-83
M
a) b) c)
-30
E L = lattice energy; according to (ref. 31) and (ref. 32) according to (ref. 33) according to (ref. 11)
Table 11 can only provide general tendencies since it cannot explain the fact that caesium fluoride is not much more soluble than potassium fluoride and, even, can be less soluble, as reported from our o w n measurements in Table 12.
259
Table 12. Apparent solubilities of caesium and potassium fluoride (electrochemical analysis of the supernatant solution after stirring for 1 h and decantation for 10 min at 0~
Solvent
[KF] (ppm) 40~
lO0~
[CsF] (ppm) 150~
40~
IO0~
150~
2,4-C12C6H4-NO2
23
65
Benzonitrile
42
105
25
24
10
DMAc
18
290
40
28
155
165
DMF
25
70
110
20
120
150
N,N-Diethyl acetamide
85
225
170
50
50
70
Acetonitrile
50
Sulfolane
44
490/190"
200
Sulfolane + 1% H20
70
100
240
Sulfolane + 5 % H20
30
130
130
NMP
81/20"
635/160"
360/140"
41
215
90
DMSO
20
70/80*
40
35
75
220
DMPU
135/20"
335/100"
140/70"
610
190
240
<1
m
20
m
48
135
230
// m
m
* Results from two experiments
These results are not completely accurate and reproducible since they are very dependent on the quality of the fluoride. Sometimes, the figures given in Table 12 do not constitute a real solubility value but the analysis of a ,, colloidal ,, suspension, as demonstrated from analyses before and after ultrafiltration of the supernatant solution: Table 13. Real solubility of potassium fluoride Solvent
[KF] before filtration
Sulfolane
44
DMSO
20
260
[KF] after filtration (• = 0.45 p m - Millipore HV)
Thus, solubility values from Table 12 (or other papers) must be taken with care for kinetic calculations, especially when relations for homogeneous systems are used. For instance, these values cannot be taken into account to explain the reported difference of reactivity between several alkaline fluorides in "Halex" reaction (ref. 17) C1
C1
_ _ ~ O2N
C1 leq.
+
MF
Sulfolane (2 eq.) ~ 150~ h
2eq.
M =Na
0 %
M=K M=Rb M = Cs
5% 6% 95 %
O2N
F
When we started to study this reaction, reported informations, which, on the other hand, were dispersed and sometimes difficult to link together, led us to think that the "Halex" process, when performed with alkaline fluorides, was more complex than already reported. Thus, we tried to quantify the effect of all significant parameters in a reliable way, in order to optimize the results, especially for the manufacture of 2,4-difluoronitrobenzene, and to have a deeper knowledge of the mechanism.
Fluorination with pure caesium fluoride
Caesium fluoride is really the most efficient fluoride since it reacts significantly with 2,4-dichloronitrobenzene (DCNB) at a temperature as low as 80~ and converts quite completely this substrate at 120~ whatever is the supplier of the fluoride. However, the rates of formation of the different products seem to be dependent on the origin of this fluoride (Table 14).
261
NO2
NO2
NO2 F+
C1 CsF (--- 3 eq.)/0~
NO 2 C~
.F
h ,,,..._
Sulfolane (CsF/Sulf. -- 0.5 wt/wt) C1
C1 DCNB
4CI2FNB
F 2C14FNB
F DFNB
Table 14. Aromatic fluorination with caesium fluoride CsF (origin)
0~
conv.DCNB (%)
Yield DFNB 4C12FNB + 2C14FNB (%) (%)
2C14FNB 4C12FNB
80
33.8
2.5
30.9
0.23
90
74.3
18.6
52.6
0.22
120
97.5
78.2
2.1
0.80
130
97.6
79.7
2.4
2.00
90
73.9
17.3
51.4
0.21
120
96.3
67.6
12.8
0.18
130
97.3
70.0
3.6
0.61
Fluka
120
94.3
50.9
26.4
0.17
Aldrich
120
95.9
58.0
18.5
0.18
Chemetall
Janssen
This dispersion could be related to the fact that caesium fluoride is very difficult to dry thoroughly (more than potassium fluoride). As a consequence, fluorination with CsF ~ 180~
is quite completely matched by the formation of oxygenated by-
products.
Fluorination with pure potassium fluoride
Influence of w a t e r Potassium fluoride
is also very hygroscopic
as shown in Figure
5 for
commercial KF submitted, at room temperature, to an atmosphere with a relative humidity of 50 % (ref. 17).
262
[ % H20 in KF (wt/wt)
40 ~.
....1o
30
I
J
I
20
KF Riedel de Ha/m
10 Time (h) 0,0
!
!
|
0,5
1,0
1,5
-
!
2,0
Fig. 5. Absorption of water by KF (Riedel de Ha6n) at 20~ under a 50% relative humidity (ref. 17)
The reverse process, that is drying, is far much more difficult because of very strong hydrogen bonds between water and the fluoride anion, which is the smallest and the most electronegative halide. As depicted in Figure 6, water contents below 0,4 % in weight are difficult to reach by usual techniques (ref. 17).
2~
k %H20 in KF
o
llO~ IB
Time (h) i
0
1
|
!
|
!
|
|
2
3
4
5
6
7
Fig. 6. Drying of KF at ll0~
under atmospheric pressure (ref. 17)
However, small amounts of water have been claimed to be beneficial for the " H a l e x " reaction (refs. 34 - 40) and we examined this point quantitatively. It is very clear that at 180~ dichloronitrobenzenes,
the temperature needed to get a valuable conversion of water
has
a
deleterious 263
effect
on
the
yield
of
fluorocompounds : whatever is its concentrations, water competes with F- and oxygenated by-products increase dramatically for water contents in KF above 1 % (by weight). Nevertheless, at lower temperatures, which usually deliver low conversions of the substrates and thus are not useful for industrial application, a m a x i m u m value is observed for both conversion and yield for a given water content
of KF which is dependent on the nature of the substrate and temperature (Table 15). Table 15. Influence of water on aromatic fluorination with K F Conditions
Substrate
O2N
ArF
yield
select.
(%)
(%)
A conv.
A select.
(relative)
(relative)
0.4 D~ 8.6
67.3 97.4 c)
67.3 92.1
100 94.6
+ 45 %
-5 %
Sulfolane / 150~ /4 h
0.4 ~)
11.7 13.4 c3
11.7 13.4 c)
100 100
+ 15 %
0 %
Sulfolane / 120~ / 11 h
0.4 o) 5.6 7.0
6.0 6.0 10.0 c)
4.2 5.2 6.0
70 86c~ 60
0 % + 67 %
+23 % -14 %
Sulfolane / 150~ / llh
0.4 D) 2.5
40.0 44.0 c~
35.0 38.0 c~
87.5 86.3
+ 10 %
-1%
DMF / 120~ 2h
a)
H20 in Conv. ArCI KF ( % wt/wt) (%) /
NO2 a)
O2N--~C1 c1 OzN C l - ~
a)
Cl
from (ref. 17)
b) standard condition
c) m a x i m u m value observed
It must be noticed that water does not influence yield and selectivity in the same way. On the other hand, separated analyses of the liquid and solid phases during reaction indicate that, for initial water contents of potassium fluoride below 1% wt, water remains on the solid. This observation is consistent with the fact that small additions of water on KF do not increase the solubility of this salt in aprotic solvents (Table 12). The effect of water could be rationalized by considering that water weakens the interaction between K § and F- at the surface of the solid and F- is thus more available for the reaction. But fluoride is consequently hydrated and becomes less nucleophilic.
This
dichloronitrobenzene,
could water
explain favours
that, to
during a larger
the extend
fluoration the
of
formation
2,4of
chlorofluoronitrobenzenes than the formation of difluoronitrobenzene. On the other
264
hand, this latter compound is more sensitive to hydrolysis than the former ones, so that the presence of water becomes rapidly a drawback concerning the final yield. It has been already reported that, with organosoluble ammonium chlorides, water favours the "Retro-Halex" reaction which competes with hydrolysis. Similar experiments showed that this process does not occur under heterogeneous conditions (aromatic fluoride and solid KC1 or CsC1 in aprotic solvent), whatever are the substrates, the solvent and the source of inorganic chloride, provided that the water content of the latter remains around or below 1 % by weight. This point has been confirmed independently in a very recent paper (ref. 41). However, when 10 % wt of water is added to potassium chloride, the "Retro-Halex" has been observed, though hydrolysis was the major process (ref. 17) : NO2
NO2
NO2 KC1 + 10 % H20 NO2
DMF/120~
+
+
heavy pdts
h NO2
F conv. = 42 %
('~'~
yields =
NO2
C1
OH
2 %
13 %
27 %
Influence of the solvent The nature of the aprotic solvent plays a crucial role for the aromatic fluorination with fluorides. Some accurate determinations have been performed either on 3,4-dichloronitrobenzene (ref. 17) (Table 16) or 2,4-dichloronitrobenzene (Table 17).
265
C1
O2N
C1 C1
Solvent (50 eq.) 160~ h
r-
O2 N
Table 16. Influence of the solvent on "Halex" reaction for 3,4-dichloronitrobenzene Solvent
Yield ArF (%)
103.Vo (min-1)
DMSO
100
28.1
HMPT
53
5.02
DMAc
45
3.73
Sulfolane
37
3.21
DMPU
34
3.01
DMEU
23
3.52
NMP
16
2.56
HMPT = Hexamethylphosphoramide" DMPU = N,N-dimethylpropyleneurea DMEU = N,N-dimethylethyleneurea
In all cases (Tables 16, 17), DMSO is the best solvent, concerning both kinetics and yields of the halogen exchange, but its sensitivity to bases and its poor thermal stability do not favour its use in practice. For other solvents, the scale of efficiency is somewhat dependent on the substrate (and may be, as a consequence, on the temperature). For instance, sulfolane is better than NMP in the case of 3,4dichloronitrobenzene and the reverse is true for 2,4-dichloronitrobenzene. Reactions are very slow in benzonitrile which, in practice, is devoted to " H a l e x " reactions on very stable substrates, like polychlorobenzenes, at temperatures above 300~
N,N-
dimethylethyleneurea (DMEU) and N,N-dimethylpropyleneurea (DMPU), claimed to replace advantageously the carcinogenic HMPT, halogen-exchange.
266
are not suited to aromatic
NO2
NO2 CI
NO2 F
KF (3 eq.)
NO 2 C1
.F
,,,,._
C1
Solvent (KF/solv. = 0.5 wt/wt) 0~ h
C1
F
F
,v
DCNB
DFNB
CFNB
Table 17. Influence of the solvent on "Halex" reaction for 2,4-dichloronitrobenzene conv. DCNB (%)
Yield DFNB (%)
Yield CFNB (%)
130
71.0
21.8
51.5
Sulfolane
130
3.4
0
3.4
Sulfolane
180
83.0
25.8
45.0
Sulfolane + DMSO2*
180
92.7
46.8
32.6
NMP
130
24.4
1.1
16.0
NMP
180
95.9
44.3
12.1
DMEU
180
92.4
4.3
6.2
DMPU
180
84.3
19.4
17.6
PhCN
180
6.1
0.2
0.9
Solvent
0~
DMSO
* DMSO 2 = dimethylsulfone
Influence of the reagent ratios Usually, the literature recommends to use 2 equivalents of fluoride for each chlorine to replace. However, we observed, for 2,4-dichloronitrobenzene at 180~ that 1.5 equivalent per chlorine are sufficient. For higher ratios, conversions and yields remain almost constant, except that hydrolysis of 2,4-difluoronitrobenzene increases a little because of the supplementary water brought with the excess of potassium fluoride.
Very recently, Smyth et al.
equivalents of potassium fluoride are needed,
(ref. 41) reported that 3.75
in D M F at 125~
to convert
completely D C N B to DFNB. Nevertheless, the ratio KF/substrate influences a little bit the isomeric ratio of chlorofluoronitrobenzenes
obtained
at the end of the reaction.
2C14FNB/4C12FNB moves from 1/5 (when K F / D C N B 267
=
For
instance,
1.5) to 1/3.8 (when
KF/DCNB = 3). This difference, concerning the kinetics of monofluorination, will be discussed later.
Fluorination with KHF2 As for the "Halex" reaction in homogeneous medium, it could be thought that potassium hydrogenofluorides would be a valuable alternative to potassium fluoride all the more so since its lattice energy is close to that of potassium chloride : E L (KX) = 808 (X = F), 703 (X = HF2), 701 (X = CI) (kJ/mol)
However, results are exactly the same, wether 3,4-dichloronitrobenzene is opposed to KHF2 (2 equivalents) or KF (2 equivalents) at 150~ or 180~ in sulfolane (ref. 17). With less reactive substrates like 2,4-dichloronitrobenzene, potassium hydrogenofluoride is far less effective than potassium fluoride (Table 18). Corrosion of the glass vessel by KHF2 is a supplementary drawback.
NO2
NO2
C1 KF, nHF (x eq.)
~
~ / F ['("-")"~ +
NO2 C1 +
F
Solvent (KF, nHF/solv. - 0 , 4 - 0,6 wt/wt) Cl
Cl
F
F
v
DCNB
CFNB
DFNB
Table 18. Aromatic fluorination with KHF 2
Solvent
130~ Sulfolane
DMSO
DMF
conv.DCNB Yield DFNB Yield CFNB
Conditions
180~
130~
130~
h
h
h
h
(%)
(%)
(%)
3.0
3.4
0
3.4
5.2
0.9
0
0.8
2.1
82.3
26.1
47.9
2.1
24.9
0.3
10.9
4.5
77.7
28.8
52.5
5.0
8.7
0.5
8.1
4.9
3.7 268
3.7
Fluorination by KF catalysed with CsF Comparison between Tables 14 and 15 clearly demonstrates that caesium fluoride is far more effective than potassium fluoride towards 2,4dichloronitrobenzene. As some papers reported about the addition of CsF as catalyst in the "Halex" reaction using KF (refs. 42 - 46), we quantified the behaviour of CsF-KF mixtures to look for some synergistic effect. It can be answered positively to this question when examining the reaction of KF-CsF mixtures with 2,4-dichloronitrobenzene at 130~ for 6 h in sulfolane (Fig. 7). As pure KF is not reactive under these conditions, line A was expected to represent the variation of DCNB conversion against the molar ratio of CsF in the fluorinating agent. However, curve B was obtained concerning the DCNB conversion and lines C and D represented the selectivities for chloronitrobenzenes and difluoronitrobenzene. Thus, a catalytic effect of CsF is really observed in sulfolane and is particularly interesting for molar ratios (CsF/CsF + KF) below 5 %, as detailed in Table 19. CsC1 and RbF, though being a little bit less effective, behave in the same way in sulfolane. However, the caesium effect is less pronounced in DMSO (Table 19). Concerning the role of the solvent in the "Halex" reaction, it can be observed that the scale of efficiency is not modified when the molar ratio of CsF remains lower than 8 % but, for larger ratios, all the solvents, except DMSO, tend to become similar. Some other inorganic fluorides (SbF 3, CdF 2, ZnF2) have a positive catalytic effect, though less pronounced than that of CsF, whereas AgF and CuC1 inhibit the reaction to a large extend (Table 20).
269
% ArF
100
90
8O
+
70
60
A-
50
40 /
30
20
10 % Mol 0
5
Fig. 7. A B C D
10
20
30
40
50
60
70
80
CsF CsF + KF 90
100
Fluorination of 2,4-dichloronitrobenzene with KF + CsF in sulfolane at 130~ 6 h (F-/DCNB = 3.0 mol/mol; F-/solvent = 0.3 to 0.5 mol/mol). Theoretical conversion of DCNB from CsF only Experimental conversion of DCNB Selectivity for chlorofluoronitrobenzenes Selectivity for 2,4-difluoronitrobenzene 270
for
~O2
NO2
C1
NO2
NO2
F
F
( I ~ + MX) (3 eq.) Solvent/6 h 0~ C1
C1 v
DCNB
CFNB
DFNB
Table 19. Catalysis of the "Halex" reaction with caesium or rubidium salts
Solvent
MX
MX MX+KF (%)
Conv. DCNB (%)
i i I
83.0
0.00
Yield DFNB (%)
Yield CFNB (%)
45.0
25.8
71.9
12.2
o
99.5
0.90 CsF Sulfolane (180~
CsC1
2.50
100
95.3
4.7
5.00
100
96.4
3.6
65.0
21.0
48.2
32.8
98.6
1.00
,
RbF
4.70
95.4 ,
DMSO (130~
CsF
0.00
71.0
51.5
21.8
1.01
94.3
53.9
37.9
2.50
95.0
55.7
36.3
6.50
96.9
64.0
31.3
271
Table 20. Catalytic effect of inorganic salts on "Halex" reaction MX KF+MX (%)
A (conv.DCNB) conv.DCNB (%)
A(DFNB) DFNB (%)
A(CFNB + DFNB) CFNB + DFNB (%)
10
+8
+ 33
-5
CdF2 (sulfolane 130~
+ 37
+71
+ 33
ZnF2* (sulfolane; 130~
+18
+43
+21
AgF (DMSO- 130~
-52
- 87
-55
CuC1 (DMSO" 130~
-53
- 92
-64
MX
SbF3 (sulfolane; 180~
* To be compared to (ref. 47)
Fluorination by KF with phase-transfer catalysts
Phase-transfer agents are the most popular catalysts for the " H a l e x " reaction with alkaline fluorides. All types of transfer agents have been claimed : tetraalkylammonium halides (refs. 34, 48), Aliquat 336 (ref. 49), branched pyridinium halides (eventually supported on a polymer) (refs. 50 to 53), tetraalkylphosphonium chlorides (refs. 42, 54 - 57) or bromides (ref. 12), crown-ethers (refs. 58, 59) eventually associated with Ph4PBr (refs. 43, 60), tris-(dioxa-3,6-heptyl)amine (TDA- 1) (ref. 61) or polyethyleneglycols (PEG) (ref. 62). All these references provide very dispersed indications. Thus, we wished to estimate quantitatively the effectiveness of some phase-transfer catalysts under the same conditions and to compare them to caesium fluoride. Indeed, onium salts improve dramatically the results for the substitutive fluorination of 3,4-dichloronitrobenzene in sulfolane at 120~ as shown from the relative initial rates (ref. 17) :
272
C1 O2N-~C1 Catalyst
:
C1 Sulfolanel20oc O2N~Q~-
Vo
=
1 (relative)
Bu4NC1
125
Bu4PC1 PhaPC1
111 114
PhnAsC1 18-crown-6
124 5
These figures indicate clearly that all onium salts, including tetraphenylarsonium chloride which has not been tested before, are far more effective than 18-crown-6 at 120~
in sulfolane. The same is true in DMSO. However, at 160~
the crow-
ether, which is more thermally stable than onium salts, becomes the best catalyst. In our hands, the following results were obtained with 2,4-dichloronitrobenzene (Table 21). The [2.2.2] cryptand is not more effective than tetramethylammonium chloride and cannot be used in very low concentrations (no effect for 0.02 %). Thus, its cost and toxicity preclude its industrial use. Other catalysts like TDA-1 or Et3N,3HF have no significant effect. Phtaloyl dichloride, though claimed to be useful for the "Halex" reaction (refs. 63, 64), does not bring any improvement in sulfolane, even at 180~
and, moreover, induces side-reactions in DMSO. The same is true for
polyethyleneglycols.
273
NO2 C11
NO2 KF (3 eq.)
NO2 F
NO 2 C1
Catalyst/solvent 0~ h
+
C1
+
C1 9
DCNB
~~~]/F
F -y
,,
F 9
CFNB
DFNB
Table 21. Influence of phase-transfer catalysts on the fluorination of 2,4-dichloronitrobenzene. Solvent
Sulfolane
0~
130~ 180~
DMSO
130~
Cata.
none MeaNC1 PI~PC1 Ph3SC1 none Me4NC1 none Me4NC1 Ph3SC1 Ph4AsC1 BnMe3NBr BnMe3NHF2 [2.2.2]
Cata ~(%) KF
Conv. DCNB (%)
Yield DFNB (%)
Yield CFNB (%)
0.0 4.1 1.3 1.5 0.0 3.0 0.0 2.2 3.9 3.9 4.1 4.4
3.4 78.6 83.7 46.7 83.0 90.5 71.0 100.0 99.0 100.0 99.9 98.7 100.0
0.0 26.8 32.2 6.2 25.8 35.2 21.8 93.1 65.6 66.6 76.8 71.5 85.3
3.4 47.7 43.1 33.3 45.0 35.6 51.5 1.8 18.6 0.6 9.2 18.0 2.8
1.45
Under conditions mentionned in Table 21, tetramethylammonium chloride is more effective than caesium fluoride to improve the " H a l e x " reaction on DCNB at 130~
(refs. 65 - 67). However, a synergistic effect is observed when combining
these two catalysts (Table 22).
274
Table 22.
Comparison of CsF and Me4NC1 as catalysts of the "Halex" reaction on DCNB (130~ h/3eq.KF/KF:Solv. = 0.5).
Solvent
CsF/KF (%)
DMF
24.0
Me4NC1/KF (%)
Conv. DCNB (%)
Yield DFNB (%)
Yield CFNB (%)
64.0
15.1
48.7
99.5
78.3
14.7
56.5
10.5
44.0
97.7
55.5
25.5
71.0
21.8
51.5
2.5 DMAc
23.0 31.2
DMSO
96.9
64.0
31.3
100.0
93.1
1.8
3.4
0.0
3.4
5
22.7
1.5
22.3
8.7
33.4
2.3
30.1
4.1
78.6
26.8
47.7
4.4
89.4
40.8
41.6
24.4
1.1
16.0
47.9
7.9
44.6
6.5 2.15
Sulfolane
NMP 8.0
C u r i o u s l y , the increase of conversions and yields due to the catalysts does not se e m to be s i m p l y c o r r e l a t e d to an increase of the K F solubilities (Table 23).
Table 23. Solubilities of KF and CsF in the presence of Me4NC1
[KF] (ppm)
Solvent 40~ *
[CsF] (ppm)
100~
150~
40~
100~
150~
Sulfolane
490/190
200
48
135
230
DMSO
70/80
40
35
75
220
Sulfolane + Me4NC1
250
650
140
290
800
DMSO + Me4NC1
5
330
90
110
250
* after filtration
275
The same remark has been reported by Rieux (ref. 17) and, very recently, by Smyth et al. (ref. 41) who observed that the solubility of KF in DMF is not proportional to the concentration of added cetyltrimethylammonium bromide.
Influence of the pre-treatment of KF As the
"Halex"
reaction using alkaline fluorides is carried out in an
heterogeneous system, the influence of the physical state of the solids must be taken into account. Several pre-treatments of potassium fluoride have been proposed to improve its performances which are evidently linked to the area of the solid surface. Spray-drying (refs. 68, 69) and freeze-drying (ref. 70) are now considered as more activating treatments of KF than calcination. Very recently, however, slow recrystallisation in methanol has been claimed to deliver a potassium fluoride which is even more effective than the spray-dried one (ref. 41). Some comparisons are given on Figure 8, Table 24 and Pictures 1 and 2. Table 24. Pre-activation of potassium fluoride Drying technique
Mean size of particles (~tm)
Specific area (m2/g)
Calcination
200-300
Spray-drying (30 %)
10-50
Freeze-drying (5 %)
38
Recryst. MeOH
Density (g/~)
Typical water content (%)
0.1
1.4-1.6
0.30
1.3
0.3-0.7
0.24
0.72
0.24
0.80
276
Picture 2. Spray dried potassium fluoride (ISC Co) 277
KF DMSO
CI~NO2
>
% ArF
F ~ N O 2
% ArF
freeze-dried KF
spray-dried KF
10o
lOO
SO t /
calcined KF
o
0
9
1
9
v
2
~
3
(from (ref. 68))
~
calcinedKF
0
4
5
h
0
1
2
3
(from (ref. 70))
4
5
h
Fig.8. Reactionprogresswithpre-treatedKF
For our part, we verified that spray-dried KF is more effective when obtained from a methanolic solution than from an aqueous solution, since, in the former case, the B.E.T. surface area is larger than in the latter one. Scanning electron microscopy (SEM), associated with differential calorimetric analysis, confirms that, in the latter case, small crystals of anhydrous KF are often aggregated by an ~ amorphous ,, coating of hydrated KF (KF, 2H20 ). SEM revealed also that potassium chloride, which is formed during the reaction, does not syncrystallize with potassium fluoride, the surface of which is available all along the reaction since most of KC1 crystals are segregated from KF crystals. Spray-dried potassium fluoride is known to aggregate rather rapidly (ref. 71) and absorption of carbon dioxide (0.4 to 2 %) have been claimed to prevem this phenomenon (ref. 71). However, in our hands, commercial spray-dried KF did not show any difference in structure and reactivity with calcined KF. Thus, we needed a technique which would be simple enough and as rapid as possible to activate potassium fluoride just prior use. Sonication and grinding in situ fulfill these criteria. Sonication is the most effective activating technique but grinding in the easiest to scale-up. Pre-sonication of potassium fluoride (20 kHz, 20 to 200 W/cm 2) deagglomerates efficiently the aggregates, the mean size of which decreases from 100 ~tm to 30 ~tm
278
as shown on Figure 9 (distribution in size) and Figure 10 (distribution in area). Sonification can be also carried out during the "Halex"
reaction, either in a
continuous mode or in a pulsed one which, though less energy-consuming, is more effective (Table 25). ,,,A,,~,,~ ,~,,c,,o,,~,,~, ~o~
, oo
~ - .........
pre
l'reat,
gO"
U5
, o2
, os
]
;
\
/
~ ~"
\
.i
~'o
~,-
~
~o 9
~ oo
, o2
, os
Fig. 9. Influence of sonication on the size of KF particles (Sympatec laser granulometer) t~loo
tot .:
(3_ ~q
(~
: "
(Z)
-
...
.. . . . . .
.
.
toe
,to3 US=O
...
.
................. '.
_ -
"
-
US=,I
O
i OOY,
::" .... "-
_ C) r,1 "
r~
tr
"
,,
-: . _ _.
\_
I
I
I
I
i
1
Fig. 10. Influence of sonication on the surface area of KF (Sympatec laser granulometer) 279
This activation mode deagglomerates the potassium fluoride all along the reaction but prevents also the growing of KC1 crystals (Pictures 4 and 5). NO2
NO2 C1
NO2
KF (3 eq.) DMSO Me4NC1 (0.1 eq.) 130~ min
C1
C1
F
F ,0
.t
DCNB
CFNB
DFNB
Table 25. Activation of the "Halex" reaction by sonication.
mode
Conv. DCNB (%)
Yield DFNB (%)
Yield CFNB (%)
None
43.8
4.0
34.3
Sonication (10 min) prior
79.0
30.0
49.0
67.1
13.9
52.0
84.0
34.0
47.0
Activation
reaction Sonication during reaction (continuous mode) Sonication during reaction (pulsed mode " 0.25 sec/sec)
Dynamic grinding of potassium fluoride, prior reaction, in a Netzsch grinder (LME1 type, 50~
1 h, 2620 rpm) decreases also dramatically the mean size of
KF particles, which drops from 65 ~tm to 11 ktm, and, consequently, the same chemical results can be reached within 3 hours instead of 4.5 hours without treatment. Grinding is not so effective as sonication concerning the reaction rate but allows to use more concentrated reaction media without increasing the stirring energy (Table 26). Microwave activation has been also tested but failed 9a sharp increase of the initial rate was observed but the reaction was rapidly blocked and side-reactions occurred. S.E.M. revealed that, in this case, potassium fluoride was coated by potassium chloride.
280
Picture 4. KC1 crystals after Halex reaction on DCNB for 30 nan at 130~ continuous sonication (leaflets = Me4NC1) 281
in DMSO with
NO2
NO2 ,C1
KF (3 eq.)
F .~
C1
NO2
NO2 C1
.F
+
Me4NCI (4 %) DMSO/130~
C1
DCNB
F
F
CFNB
DFNB
Table 26. Influence of the activation of KF Activation mode
Reaction duration (h)
Conv. DCNB (%)
Yield DFNB (%)
Yield CFNB (%)
None
4.5
99.7
90.3
9.4
100.0
92.0
8.0
100.0
92.0
8.0
Pre-sonication (10 mn) Pre-grinding (1 h)
Kinetic and mechanistic considerations Because of the high lattice energy of inorganic fluorides, substitutive fluorination with alkaline fluorides in aprotic solvents is always a two-phase reaction which is very dependent on the origin and the preparation of the solid reagent. In order to get new improvements, it is now necessary to have a better knowledge of the reaction at the molecular scale and, especially, to determine if the process is limited by physics (that means by the solubilization of the fluoride) or by chemistry. In the latter case, the problem is to know if the reaction occurs in the liquid phase or on the surface of the solid. Some insight could be given by kinetic measurements and comparison of the influences of the reaction parameters on rate values. Four cases must be considered depending on the rate-limiting step :
282
Table 27. Nature and consequences of the different rate-limiting processes.
Limitation
Consequences
Homogeneous process l . Casel
Rate-limiting step Physics
Interracial process Case 2
I
Solubilization of KF
Diffusion of substrate
rate order for ArC1 important parameters
1
9 Solvent 9 Temperature 9 PT catalysts 9 Surfacestate
Solvent Temperature
I Case4
I Case3 i Chemical reaction
Several
rate order for ArC1 important parameters
observations
argue,
]
1
9 Solvent 9 Temperature 9 PT catalysts (reactivity of F)
I
1
9 9 9 9
Solvent Temperature PT catalysts Surface state
on a qualitative point of view,
against the
hypothesis of an homogeneous process (cases 1 and 3) : -
Potassium hydrogenofluoride, which is more soluble than potassium fluoride,
does not provide better results under the same conditions. -
The reverse " H a l e x " reaction, which is possible with stoichiometric amounts of
tetraalkylammonium chlorides, does not occur with potassium chloride. -
It has been demonstrated that small amounts of water, which can be beneficial
to the " H a l e x " reaction, do not increase proportionally the solubility of potassium fluoride (Table 12) and remain located on the surface of the solid. -
In the same way, the solubility of F- cannot be correlated to the added amount
of onium salts as indicated in Table 23 and in the literature (ref. 41). Quantitative determinations show that ammonium salts are mainly located on the surface of the undissolved potassium fluoride (ref. 17). -
During
the
incomplete
fluorination of 2,4-dichloronitrobenzene,
the
ratio
between chlorofluoronitrobenzenes is dependent on the initial excess of potassium fluoride over DCNB. This fact is not compatible with an homogeneous process. On a quantitative point of view, it can be noticed from Table 16, that the initial rates cannot be correlated to the solvent parametres (DN, AN, ~, ~t.... ) as in homogeneous processes. 283
In order to choose between situation 1 and others, the solubilization rate of KF have been studied in DMSO and sulfolane at 160~ (Fig. 11)
50
160"C
E c~ o,.
v
i.i.
I
w
20 ~9
+
10
0
|
0
10
20
30
,
40
Sulfo1~ne
|
50
Minules
DMSO
6O
Fig. 11. Solubilisation rate of KF at 160~ (from ref. 17).
Surprisingly, the solubilization of KF is a slow process, the rate of which is of the same order of magnitude as that of the " H a l e x " reaction. Moreover, the lowest solubilization rate is observed in DMSO which, however, is the best solvent for fluorination.
Despite this contradiction,
such a solubilization
rate could be
consistent with case 1 (Table 27), concerning the rate-limiting step. However, a simple
treatment
of the
conversion
of
aryl
chloride
against
time
clearly
demonstrates that this process is first-order relative to ARC1. Such a result rules out case 1. The same conclusion has been drawn in a very recent paper (ref. 41). More sophisticated determinations are needed to choose between cases 2 and 4. Concerning the fluorination of 2,4-dichloronitrobenzene, the following scheme must be considered (Scheme 2) :
284
NO2
]
,C1
4F2C1NB ~O2
NO2
,C1
F
C1 DCNB
CI 2F4CINB
Scheme 2.
Provided that the second fluorinations are first-order (relative to the substrates) like the first ones, the following mathematical model can be settled 9 Y1 = 1- e "Kt
K = kll + k12
kll (e-Kt _e-k21 t) Y2 - k21 _ K
k 1 2 (e-Kt _e-k22t)
Y3 = k22_ K
y4=
ikllk21+k12k22-k21k22i( (k 21 - K) (k 22 - K)
where
Y1
"
-
e -Kt
-1) +
conversion of DCNB
Y2 = yield of 4F2C1NB Y3 = yield of 2F4C1NB Y4 -- yield of DFNB
285
k12 kll (e -k21t - 1) + k22 _ K k21_K
(e -k22t -1)
This system can be computed in order to fit the calculated curves Yn = f(Y1) with the experimental ones (figure 12) by optimization of the expression i=n
Z (Y4Y1exp. -Y4exp.) 2 +(Y3Ylexp.-Y3) 2 + (Y2Ylexp._ Y2exp.) 2 i=l The rate constants kij result from the fitting. The variations of kij with the reactions parameters can be thus estimated. In the hypothesis of an homogeneous process, all kij must be affected in the same way and k12/k11 as well as k22/k21 ratios must not change. According to this criterium, Table 28 demonstrates that the homogeneous hypothesis must be ruled out since k12/kll and k22/k21 vary with the origin of potassium fluoride, the dilution and the presence of CsF or Me4NC1. Thus, the whole process, including catalysis by CsF or onium salts, must be interpreted in terms of interfacial reactions.
286
I
!
!
Y,-4
~
NO,
0.8
NO2
NO2
..C!
KF Sulfolane 180~
~
NO~
+
C!
Ci
DCNB
4C12FNB
+ F
F
2CI4FNB
DFNB
0.6
0.'~
Y3
0.2 Y2
!
o
Exp.
t
0.6
o.~
= 3 . 5 8 D + 00 = 2 . 3 4 D + 00 = 2 . 2 0 D + 00
ka2/kll k21/kll k22/kll kll k12 k21 k22
o.P
= = = =
5.45D-02 1.95D-01 1.28D-01 1.20D-01 f
DFNB 2C14FNB 4C12FNB
+ X O
Calc.
Fig. 12. Yn = f(Y1) " calculated (solid lines) and experimental (o, + , x)
287
!
0.8
YI
~
NO2 C1
KF (3 eq.) Sulfolane 180~
O2
~
F
C1
CI
C1
NO2
NO2
F
F
F
Table 28. Rates constants against some reaction parameters 102.kll
Conditions
102.k12
102.k21
102.k22
kl2/kll
k22/k21
(1.mol-l.h-1) (1.mol-l.h-1) (1.mol-l.h"1) (1.mo1-1.h -1) Standard run KF type A
5.45
19.5
12.8
12.0
3.58
0.94
8.11
24.8
5.45
12.4
3.06
2.28
7.28
22.6
14.0
11.0
3.10
0.79
8.63
17.7
15.5
8.44
2.05
0.54
9.0
19.2
12.5
9.88
2.13
0.79
10.0
24.5
10.4
13.0
2.42
1.25
Standard but KF added in 4 times
5.58
19.0
13.1
9.42
3.40
0.72
Standard + 2.5 % CsF
11.3
37.5
29.1
20.8
3.32
0.71
Standard + 5.0 % CsF
12.1
39.2
36.1
21.6
3.25
0.60
Standard + 2.5 % Me4NC1
11.5
29.5
12.8
21.2
2.55
1.65
KF/solv. =0.47 KF type B KF/Solv. =0.47 KF type C KF/solv. =0.47 KF type D
I
KF/solv. = 0 . 4 7
KF type E KF/solv. =0.31 KF type A KF/solv. =0.31
A B C D E
= = = = =
I
Riedel de HaEn- calcined Riedel de HaEn- spray-dried by Rh6ne-Poulenc Aldrich- spray-dried Riedel de HaEn - dried in a Turbosphere (R.P.) Morita- spray-dried
288
This hypothesis is corroborated by the kinetic interpretation of experiments using KF which has been previously activated by sonication or grinding
9 some
pathways can be favoured over others depending on the surface state (Table 29) 9
NO2
NO2
C1
NO2
F
KF (3 eq.) Me4NC1 (4 %) DMSO/130~
C1
NO2
CI+
F
+ C1
F
F
Table 29. Influence of sonication and grinding on rate constants Activation
kll (h-1)
k12
k21
k22/k21
(h-1)
k22 (h-1)
kl2/kll
(h-1)
None
0.35
0.88
0.98
0.60
2.47
0.61
KF pre-treated by sonication (10 ran)
0.72
2.24
1.52
1.60
3.11
1.05
KF pre-treated by grinding (1 h)
0.37
1.66
0.60
0.89
4.49
1.48
,
,
The interfacial hypothesis has been also proposed independently and very recently by Smyth et al. (ref. 41) who correlate the rate constants with the Hammett parameters (P and o-) and found that the solubilization of KF cannot be the ratelimiting step since P is as large as + 6.4. To explain more accurately the observed phenomena, we propose the following model (Scheme 3) in which the reaction proceeds in a border-phase at the solidliquid interface. By analogy with Sasson (ref. 72), this phase could be named co-phase.
289
Ca--~ ~, )/'---r~ 2
phase Me 4.N §
. . . . . Ca
. . . .
9
r
(31
:~OG
~
.....
F"~
.~
F'J
F"
N§
KF K§
Ca
K§ F"
K§
4 - - . Ca"
.o
K§ Me,
+ "'NMe
.
§NMe 4
K* (31
F ~ ' ~ ' ~ Ca" + NMe 4 +
Me 4N*
Scheme
3. Border-phase
Ca-
NMe 4
model
This model can explain the results given by the kinetic study : -
The reaction occurs at the solid-liquid interface. Thus, the kinetic rates must
depend on the surface state of the solid and include an absorption term which can vary from one substrate to another one. With this hypothesis, the formation and consumption of 2C14FNB and 4C12FNB can vary independently with the surface state. -
Small amounts of water are known to favour the formation of the c0-phase
(ref. 72). - Inside the co-phase, which is mainly constituted by solvent, the rules of homogeneous chemistry can be applied. Thus, the reaction kinetics is dependent on the nature of the solvent and the concentrations, the conversion of the aromatic chloride is a first-order process and oniums salts, which concentrate in the c0-phase, are effective to enhance the nucleophilicity of fluoride anions. This last hypothesis is consistent with the 19 value ( + 6.4) given by Smyth (ref. 41) who, on the other hand, also determined activation parameters which are consistent with a Meisenheimer's process (AH ~ = 24.4 + 4 kcal/mol, AS~ = -14.3 + 2.2 kcal/mol).
290
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57. 58. 59. 60.
61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72.
D.W. Headford, J.W. Slater, R.L. Sunley, R.D. Bowden, M.B. Green, DE 2,425,239? (1973), (to I.C.I. Ltd.). T.P. Smyth, A. Carey, B.K. Hodnett, Tetrahedron, 51, (22), 6363, (1995). J.H. Clark, D.J. Macquarrie, Tetrahedron Lett., 28, 111, (1987). Y. Yoshida,Y. Kimura, Chem. Lett., 1355, (1988). Y. Yoshida,Y. Kimura, J. Fluorine Chem, 44, 291, (1989). Y. Yoshida,Y. Kimura, JP J 63 170,332, (1989), (to Ihara Chem. Ind. Co.) [Chem. Abstrt., 109, 230540]. H. Ito, V. Matsushita, T. Shimizu, N. Ishikawa, M. Shimizu, EP 259,663, (1986), (to SDS Biotech. K.K.) [Chem. Abstr. 109, 128588]. H. Momotake, JP 63 284,135A2, (1987), (to Mitsui Toatsu Chemicals Inc.), [Chem. Abstr., 110, 134341]. R.A North, GB 2,042,507, (1979), (to Boots Co. Ltd). C.R. White, U.S. 4,418,229, (1981), (to Mallinckrodt Inc.). D.J. Brunelle, D.A. Singleton, Tetrahedron Lett., 25, 3383, (1984). G.L. Cantrell, PCT Int. Appl. WO 87/04148, WO 87/04149 and WO 87/04150, (1986), (to Mallinckrodt Inc.). Y. Yoshida, Y. Kimura, Tetrahedron Lett., 30, 7199, (1989). G.L. Cantrell, U.S. 4,642,398, (1986), (to Mallinckrodt Inc.). R.A. Kuntz, U.S. 4,069,262, (1978), (to Du Pont de Nemours Co.) [Chem. Abstr., 88, 120762]. J. Maul, D. Tang, ED 180,057, (1984), (to Occidental Chem. Co.). S. Kumai, M. Sasabe, H. Matsuo, Japan. Kokai JP 60 228,436, (1984), (to Asahi Glass Co.) S. Kumai, M. Sasabe, H. Matsuo, Japan Pat. JP 85,228,436 (1984); S. Kumai, M. Sasabe, H. Matsuo, Japan Kokai JP 60 246,326 and Japan. Pat. JP 85,246,326 (1984). T.J. Giacobbe, U.S. 4,031,100, (1976), (to Dow Chem. Co.). F. Jeanne, A. Trichet, Informations Chimie, 155, 327, (1976). V.V. Aksenov, V.M. Platonov, I.M. Moryakina, P.P. Rodionov, V.P. Fadeeva, Izv. Akad Nauk SSSR, Ser. Khim., 690, (1987). Y. Yoshida, Y. Kimura, Japan. Kokai JP 63 170,332, (1986), (to Ihara Chem. Ind. Co.) [Chem. Abstr. 109, 230540]; Y. Yoshida, Y. Kimura, EP 289,942, (1988) (to Ihara Chem. Ind. Co.). G. Soula, R. Ramanadin, M. Roustan, EP 32,077, (1979), (to Rh6ne-Poulenc); G. Soula, R. Ramanadin, M. Roustan, EP 49,186, (1980), (to Rh6ne-Poulenc). T. Kitazume, N. Ishikawa, Chem. Lett., 283, (1978). S. Kumai, T. Seki, H. Matsuo, JP 60 237,051, (1984), (to Asahi Glass Co.). I.S.C. Chem. Ltd., DE 2,527,944, (1974), (to I.S.C. Chem. Ltd) B. Langlois, L. Gilbert, G. Forat, FR 2,664,590, (1990), (to Rh6ne-Poulenc Chimie). J.M. Grosselin, R. Baillard, G. Cordier, B. Langlois, L. Gilbert, G. Forat, EP 409,709, (1990), (to Rh6ne-Poulenc Chimie). G. Forat, L. Gilbert, B. Langlois, EP 467,742, (1991), (to Rh6ne-Poulenc Chimie). N. Ishikawa, T. Kitazume, T. Yamazaki, Y. Mochida, T. Tatsumo, Chem. Lett., 761, (1981). K. Suzuki, S. Hiyama and M. Ohashi, JP 63 010,737, (1986), (to Seimi Chem. Co.), [Chem. Abstr., 109, 73124]. Y. Kimura and H. Suzuki, Tetrahedron Lea., 30, 1271, (1989). N. Miki, U.S. 4,806,332, (1987), (to Hashimoto Chem. Ind. Co.), [Chem. Abstr., 110, 195823]. S. Dermeik, Y. Sasson, J. Org. Chem., 50, 879, (1985).
292
4-FLUOROPHENOL : A KEY INTERMEDIATE FOR AGROCHEMICALS
AND PHARMACEUTICALS
CLAUDE MERCIER
a)
AND PATRICK YOUMANS
b)
a~ Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie, 85 Avenue des Fr~res Perret, B.P. 62, 69192 Saint-Fons Cedex, France b) Rh6ne-Poulenc Chemicals, St-Andrew's road, Avonmouth, Bristol, BS11 9YF, England
INTRODUCTION 4-Fluorophenol is widely used intermediate in the industrial production of pharmaceuticals (Cisapride and Sabeluzole from Janssen, Sorbinil from Pfizer, Progabide from Synthelabo (Fig. 1) and more recently an agrochemical specialities (Fig. 2). The current methods described in the literature to prepare 4-fluorophenol are shown in Figure 3 (refs. 1 to 10) where fluorine atom introduction into the molecule occurs either during the initial (methods B, C, F, H) or final reaction steps (methods A, D, E, I). All these various methods display both economic or technologial benefit and disadvantages and none of them seems to be entirely satisfactory for the industrial production of this compound. To reach productivity and low cost target needed by the agrochemical market, much work is being carried out to find profitable methods for 4-fluorophenol production (refs. 1 - 10).
293
NH 2
Cisapride (Janssen) EP 76530 Gastroprokinetic
C1
OMe
OMe
Sabeluzole (Janssen) Cognition Enhancer
I
HN.~
0
0
Sorbinil (PFizer) EP 172 719 Amidiabetics
F
OH
Progabide (Synthelabo) EP 2400 Antiepileptic
O
C1
Fig. 1. Pharmaceutical products using 4-fluorophenol as an intermediate
294
Azoles (Fungicides) Bayer EP 22969 (1978)
,~--x\ N ~,,,, N
(Fungicide) Du Pont US 4497807 (1978)
SXN= = ~ 0 C1
F Br
O N
Triazolones (Herbicides) F.M.C. WO 8700730 (1985)
NCHF 2
RO
F
RO
O
Tetrahydrophtalimide s (Herbicides) Sumitomo EP 61741 (1981)
O
cl
4-Phenoxyquinoline (Fungicide) Dow-Elanco
C1
Fig. 2. Agrochemical families using 4-fluorophenol as an imermediate
295
NH-~ OH
Br (C1)
F NH2 OH
A l k a l ~ B) Hydrolysis N ~ %
OH
Sandmeyer ( D / (C) Hydrolysis ~ F l u o r o dediazoniation H
(A) Fluorination ~
OH
~
Fluorodealkylation R
(I) Hydroxylation ..
F
_A
h,.
F
Fluoro- ,/ , 4 decarboxylation/(H)
O
(F)
Bayer-Villiger Rearrangement F olysis
~H /
HN--OTs [
0 Fig. 3. Methods for preparation of 4-fluorophenol
Method A (direct fluorination) or method I (hydroxylation) starts from very cheap raw materials but present problems of regioselectivity and low yield. Fluoro dediazoniation (method D) starting from easily available raw material, presents poor selectivity and problems of technology, recycling on scale-up.
296
RESULTS AND DISCUSSION The only two industrial methods to produce 4-fluorophenol are currently using 4-fluoroaniline (method C) or 4-bromofluorobenzene (method B) as starting material, (Fig. 4).
Br (Cl)
I ,,
NO 2
C1
CI
F
4-FLUOROPHENOL 9
M
=
Mp =
F
112 48 ~ (WHITE)
186~ pKA = 9.92 (25~ Bp 760
~"
- H20)
Fig. 4. The industrial production and physical properties of 4-fluorophenol Both of the two industrial synthesis start, in fact, from the same raw material (Benzene) to access by similar chemistry (nitration, reduction, halogenation, etc.) in five steps to the production of 4-fluorophenol. Only a fine analysis of the global process in terms of effluent, technology required and quality of the product allows selection of the most suitable access. The alkaline hydrolysis of 4-bromobenzene (ref. 2a - 2b) needs very drastic conditions (-- 190~ 5-20 bar, in the best conditions) (ref. 2c) with effluent containing copper salt and stoichiometric amounts of barium bromide. Another main drawback of this process is the selectivity and specification with regard to isomers of 4-fluorophenol and content of phenol resulting from hydrogenolysis, as reported by M. Bedoukian (ref. 2a). As phenol is nearly impossible to remove from 4-fluorophenol (identical boiling point), on the quality point of view the best process is the one which does not produce phenol, 2 and 3-fluorophenol.
297
By Sandmeyer hydrolysis (ref. 3 a - 3e) (diazotisation, acidic hydrolysis without copper salts) the target specification (Table 1) is reached without difficulty but the process has two major drawbacks for industrialisation, as underlined in the recent patent from Octel Chemicals (ref. 3c) : safety and corrosion on using convention equipment.
Table 1. Standard specification for 4-fluorophenol Purity (assay):
99 % minimum
Impurities content : 2-Fluorophenol Phenol 3-Fluorophenol 4,4'-Difluorophenylether Any other impurities
0.1% max. (w/w) 0.1% max. (w/w) 0.1% max. (w/w) 0.2 % max. (w/w) 0.1% max. (w/w)
The preparation of phenols by hydrolysis of benzediazonium ions is well known in the literature (ref. 10). It involves the preparation of a diazonium salt, e.g. the diazonium hydrogenosulfate by treatment of the aniline hydrogen sulphate with sodium nitrite in dilute aqueous sulphuric acid, followed by hydrolysis in more concentrated aqueous sulphuric acid. The temperature of the hydrolysis is maintained at the boiling point of the aqueous acid by proper adjustment of the concentration of the sulphuric acid and the phenol formed removed from the reaction medium by means of steam distillation in order to minimise the coupling of the formed phenol with the diazonium salt introduced. In the production of 4-fluorophenol from 4-fluoroaniline (ref. 4a - 4g) a major problem arises with corrosion of glass lined vessels by hydrofluoric acid release. The hydrofluoric acid is considered to arise by nucleophilic displacement of the fluoride from the 4-fluorobenzene diazonium hydrogen sulphate (Fig. 5). This is not surprising since the diazonium group is one of the most electron withdrawing group known.
298
~
F
HSO4-
NH 2
OH
I
H2S04
H20 / H +
~
+ N2
NaNO 2 (0-5 o c ) F 1
HSO4"
OH
o. Tars
OH
_- F-
OH
O
+HSO4-
~
.....
Fig. 5. By products from the 4-fluoroaniline process
Octel Chemicals have patented a process to decompose the diazonium at nearly room temperature using a copper salt of hydroxy carboxylic acid, allowing them to use conventional glass lined reactors, but with poor productivity and problems of copper effluent in aqueous. In Rh6ne-Poulenc, using the classical technique (steam distillation) we have developed specific reactors to avoid the corrosion due to HF in this semicontinuous process and be able to reach a multitons production scale using our Salindres and Avonmouth facilities and obtaining competitive manufacturing costs due to a good integration on raw material.
CONCLUSION The data reported shows that 4-fluorophenol can be advantageously prepared from 4-fluoro-aniline in good yield and quality using conventional techniques. It is certainly the leading industrial production to be able to reach specification and price of the agrochemical market as well as the integration pollution control (IPC) regulation. 299
References 1. a S. Misaki, J. Fluorine Chem., 21, 191, (1982). b R.E. Banks, I. Sharif, J. Fluorine Chem., 55,207, (1991). c I. Takemoto and K. Yamasaki, Biosci. Biotechn. Biochem., 58,495, (1994). d T. Unemoto, Organic Synthesis, 69, 129, (1990). e R.E. Banks, US 5086 178, (20.09.90), (to Air Products). f JP 90 399 143, (12.12.90), (to Sumitomo). 2. a M.M. Bedoukian, R.J. Eber, W.E. Kuehlewind, R.E. Mc Arthur, J. Org. Chem., 26, 4641, (1961). b JP 04 208241 A, (30.11.90), (to Ihara Chem. Ind.). c DE 3430 554, (20.08.84), (to Hoechst). d US 4940 821, (10.07.90), (to Dow Chemical). e R.G. Pews, J.A. Gall, J. Fluorine Chem., 50, 377, (1990). f JP 89, 319 448 (to T.R.A.N.A.D.) g US 2934 569, (26.04.60), (to Olin). h JP 85 04, 144, (23.06.83), (to Cemral Glass). 3. a JP 62,238,226, (09.04.86), (to Nippon Kayagu). b G.C. Finger, J. Amer. Soc., 81, 94, (1959). c EP 596 684, (05.11.92), (to Octel Chemicals). d JP 91 246 244 A2, (01.11.91), (to Ihara Chem.). e JP 62,29544, (31.07.85), (to Nippon Kayagu). 4. a N. Yoneda, J. Fluorine Chem., 45, 106, (1989). b T. Fukuhara, N. Yoneda, K. Takamura, A. Suzuki, J. Fluorine Chem., 51,299 (1991) c P.H. Cheek, J. Amer. Chem. Soc., 71, 1863, (1949). d EP 430 434, (22.11.89), (to ICI). e K. Hisashi, Y. Yoda, JP 90143 335, (23.05.90), (to Mitsui Toatsu Chemicals). f N. Yoneda, T. Fukuhara, JP 89 233 232, (12.03.88), (to Mitsubishi Kasei Corp). g JP 84 204 143, (06.05.83), (to Morita Kagaku Kogyo). 5. S. Stavber, Z. Planinske, I. Kosir, M. Zupan, J. Fluorine Chem., 59, 409, (1992). 6. a L. Conte, M. Napoli, G.P. Gambaretto, A. Guerrato, F.M. Carlini, J. Fluorine Chem., 67, 41, (1994). b M. Gubelmann, EP 320 346, (11.12.87), (to Rh6ne-Poulenc Chimie). 7. W.R. Dolbier, L. Celewicz, K. Ohnishi, Tetrahedron Letters, 30 (37), 4929, (1989). 8. a H. Garcia, L. Gilbert, EP 427 603, (06.11.89), (to Rh6ne-Poulenc Chimie). 9. a M. Nango, Y. Kimura, JP 92 29950, (31.01.92), (to Ihara). b P. Partha, J. Amer. Chem. Soc., 113, 5322 (1991). c M. Gubelmann, P.J. Tirel, EP 341 113, (02.05.88), (to Rh6ne-Poulenc Chimie). 10. H. Wallach, A. Heusler, Annalen, 243,228, (1898).
300
FLUORODECARBOXYLATION OF ARYLCHLOROFORMATE : A NEW ACCESS TO FLUOROAROMATICS
HERVE GARCIA a~, LAURENT GILBERT a~, MARIE-CECILE SERGE RATTON b~AND CHRISTOPHE ROCHIN c~
PERROD a~,
a)Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie, 85 Avenue des Fr6res Perret, B.P. 62, 69192 Saint-Fons Cedex, France b) Interm6diaires Organiques, 25 quai Paul Doumer, 92408 Courbevoie Cedex, France c) Rh6ne-Poulenc Chemicals PO Box 46, Avonmouth Bristol BS 11 9VF, England
SU/VIMARY The catalytic fluorodecarboxylation of arylchloroformate to fluorobenzene and analogues has been achieved with high yield in an anhydrous hydrogen fluoride vapor phase flow reactor. This methodology can be successfully applied to various derivates, the main limitation being the stability of substituents under the reaction conditions. The best catalysts are chromium and aluminium oxyfluoride. The reaction proceeds between 300 and 400~ and occurs in a short space of time. The catalytic activity decreases by coking but can be fully recovered by an oxydative treatment at high temperature. An ionic mechanism is proposed.
INTRODUCTION The formation of carbon - fluorine bonds is always a challenging synthetic reaction. Direct fluorination with fluorine leads to fragmentation and highly fluorinated products, making this non selective route unsuitable for the preparation of fluorobenzene and analogues. Therefore the preparation of fluorobenzene, generally requiring the introduction of fluorine via an appropriately functionalized benzene derivative has held the attention of chemists for nearly a century (ref. 1). The Balz-Schiemann reaction (ref. 2) and the improved direct diazotisation of aniline with sodium nitrite and subsequent dediazoniation in hydrogen fluoride without isolation of the intermediate salt (ref. 3) are the main industrial ways to 301
prepare fluorobenzene and its substituted analogues. The main drawbacks of this reaction are the toxicity of starting aromatic amines, thermal instability of diazonium salt and the inevitable formation of water in the diazotation reaction. Therefore, much effort has been devoted to the research of new industrializable routes to fluorinated aromatics derivatives which are as far as possible versatile and without the drawbacks of classical processes. Among the reported reactions (refs. 4-7) aryl fluoroformate decarboxylation seems to be very attractive. Aryl fluoroformates are easily prepared from the corresponding phenol, phosgene and anhydrous hydrogen fluoride, which are widely available and cheap raw materials. The decarboxylation of arylchloroformate (ref. 8) or thiochloroformate (ref. 9) into the corresponding chloroaromatic and the decarboxylation of aliphatic fluoroformate occurs by an ionic mechanism (ref. 10). But, the arylfluoroformate decomposition by this mechanism does not lead to the formation of fluorinated aromatics but instead to phenols and tars (ref. 4a). Even if dinitrogen and carbon dioxide can be considered as similar leaving groups (ref. 11) and if the evolution of carbon dioxide from a carboxylium ion should provide a large exothermic driving force similar to that obtained by elimination of dinitrogen from the diazonium ion, it appears that arylfluoroformates are very resistant to decarboxylation. This is attributed to the higher stability of the ArOCO + cation which can undergo a Friedel-Crafts reaction rather than decomposing to phenyl cation. The thermal, selective, decarboxylation of arylfluoroformate was reported for the first time by Christe and Pavlath (ref. 4). The use of vapor phase conditions and of temperatures as high as 700 - 800~ permits the selective transformation even without catalyst. Under the conditions, the use of Pt gauze as the catalyst improves the selectivity of the reaction. Fluorobenzene can then be obtained with high yield (up to 90 %), but this methodology is of little versatility. Yields are much lower with substituted aryl fluoroformates (ref. 4b). Moreover, these temperatures are considered to be beyond the scope of common industrial practice and particularly for the preparation of fine chemicals. A major improvement was described by Ashton and Co. (ref. 5) which showed that the reaction could be driven in the vapor phase at 350~ noble metal supported on 7-alumina.
using as catalyst a
Fluorobenzene can then be obtained with initial yields of about 60 %. But, yields reported are rather low and the reaction is not general although for (2,4,6-trimethylphenyl)-fluoroformate the same yield can be obtained 4chlorophenylfluoroformate decomposition to the corresponding phenol and carbonate occurs. 302
The authors interpret the lack of selectivity in this case to a reaction between the fluoroformate and hydroxyl from the surface of ), alumina. Even if this conditions represent an important improvement, this technology is not applicable on an industrial scale as the catalyst deactivates irreversibly by fluorination (ref. 12). Moreover, if the use of fluorinated aluminas leads to the improvement of initial selectivity, it can not avoid the catalyst deactivation which is transformed during the course of the reaction to aluminium fluoride, a non selective catalyst (ref. 12).
RESULTS AND DISCUSSION We now report that the fluorodecarboxylation of arylchloroformates can be achieved in an anhydrous hydrogen fluoride vapor phase reaction using aluminium fluoride as a catalyst. Fluorobenzene 2 can be obtained with a yield greater than 95 %; the reaction is very selective as the only by products observed are chlorobenzene (less than 2 %) and phenol (less than 1 % ) (Scheme 1).
Off1
II
+
HF
O
A1F3 ' 3 0 0 ~
~
tc= is HF / c h l o r o f o r m a t e
+
CO 2
+
HC1
= 50
!
S c h e m e 1. F l u o r o d e c a r b o x y l a t i o n
F
2
Y i e l d _2_> 95
of phenylchloroformate
High yields are achievable by using an excess of anhydrous hydrogen fluoride as shown in Table I. The increase of this ratio to a value of 75 does not greatly improve the activity and selectivity.
303
Table 1 " Fluorodecarboxylation of phenylchloroformate-Influence of the ratio HF/C6HsOCOC1
A1203, 300~ OCOC1 + HF
Entry
Without
catalyst,
W
F +
HF/C6H5OCOC1
Yield (%)
1
18
76
2
56
94
3
74
97
CO 2
we do not obtain at this temperature
+
HC1
any fluorinated
derivatives (Table 2, emry 1). Several catalysts (Table 1) are suitable for the fluorodecarboxylation
of
phenylchloroformate
to
fluorobenzene;
such
as
oxyfluoride (AI, entry 2; Cr, entry 4; Zr, entry 5; Ti, entry 10) or fluorides (A1, entry 3; La, entry 6; Ce entry 7; Mg entry 9). The best activity and selectivity is observed using as catalyst aluminium fluoride or oxyfluoride (entries 2 and 3).
Table 2 9 Fluorodecarboxylation of phenylchloroformate - Influence of catalyst nature Entry
Catalyst
Temperature (~
Yield PhF (%)
1
without catalyst
400
2
A1203
300
> 95
3
A1F3
300
> 95
4
Cr203
300
70
5
ZrO2
300
46
6
LaF3
300
40
7
CeF3
300
40
8
ZnO
300
14
MgF2
400
14
TiO2
220
54
10
304
< 1
In contrast to the decarboxylation of arylfluoroformate, anhydrous hydrogen fluoride
vapor
phase
fluorodecarboxylation
of
alkylchloroformate
can
be
successfully applied to many substrats (Table 3). Cresylchloroformates react in a similar way as phenyl chloroformate (entry 1 to 3). The use of more electrodonating substituents like methoxy is also successfull eg for the synthesis of 4-fluoro anisole (entry 4). But, the obtained yield is modest due to demethylation of 4-fluoro anisole or of the starting material leading to tars. For electron withdrawing groups, reactivity is lower but fluoro-chloro, fluorobromo and difluorobenzene are prepared in high yield (entries 6 to 8). Table 3.
Fluorodecarboxylation of arylchloroformate on aluminium oxyfluoride
O--
OCOC1 + HF
~ Vapour phase
R
F + HC1 + CO2 R
Emry
Substituent (R)
1
2-CHs
300
> 95
2
3-CH3
300
> 95
Temperature (~
Yield (ArF) (%)
3
4-CH3
300
> 95
4
4-CH30
400
24
5
4-F
300
< 1
6
4-F
400
> 95
7
4-C1
300
85
8
4-Br
400
70
9
4-NO2
300
Traces
10
1-Ph
350
24
11
1-naphthyl
300
10
12
1-naphthyl
400
> 95
Tars are obtained starting from 4-nitrophenylchloroformate (entry 9); this substrate is mostly unstable under the chosen reaction conditions. 2-Phenyl phenyl chloroformate 3 reacts in a different manner leading to a mixture of
1-fluorobiphenyl 4
(yield 24
%,
entry
intramolecular acylation (yield 50 %) (Scheme 2).
305
10) and of 5 obtained by an
F~ O
Fluorodecarboxylation
II
_4
HF. Al203 ~.. / r 300~ Vapour phase
3
v Internal Friedel & Crafts 5 Scheme 2. Fluorodecarboxylation of 2-phenylphenylchoroformate
Finaly 1-fluoronaphthalene can be obtained with a very high yield from c~naphthylchloroformate (entry 12). The influence of reaction temperature was examined in the case of the decarboxylation of meta-tolylchloroformate 6 in 3-fluorotoluene _7. Results are given in Table 4 and Figure 1. To proceed, the reaction needs a minimum temperature. At low temperature (250~ obtained in rather significant quantities.
Table 4.
Fluorodecarboxylation of 3-tolylchloroformate - Influence of the temperature
~ / CH 3
Entry
entry 1), cresol and cresylcarbonate are
Temperature
(~
OCOC1 + HF
~
F
/ CH 3
6
+
CO2 + HC1
7
Yield (%)
Yield (%)
Yield (%)
Yield (%)
3-fluorotoluene
3-chlorotoluene
m-cresol
carbonate
1
250
78
0,6
10,5
10,5
2
300
92
2
6
0
3
350
90
6
3
1
306
Yield 8, 9, 10
Yield 7 m
100
- 30
90
-E}-- Yield 7 - ~ - Yield 8 Yield 9 Yield 10
20
80 70
10
60 0
50 250
20O
300
350
400 Temperature (~
Fig. 1
Influence of the temperature on the selectivity of fluorodecarboxylation of 3-
tolylchloroformate
m-Cresol 8 is probably obtained by decomposition of chloro (or fluoro) formate by anhydrous hydrogen fluoride following "
/~OCX CH 3
+ HF II O X = C1, F
~
~
H + FCOX
O
/ CH 3
8
Cresylcarbonate 9 result from an acylation of cresyl haloformate by ArOCO + cation 9
~--~OCX ,,
/ CH3
O X=C1, F
/ CH3
+ ~r~OCQ)
XO
,,
CH3
O 9
O
\
~
(~XQ
/ CH3
C II"X O
~ CH3
+ X2CO
CH3
An increase of temperature favours fluorodecarboxylation and limits this side reactions, the main coproduct becomes then 3-chlorotoluene 10 which results from a intramolecular decarboxylation. 307
~OCC1
""
II
/ CH3
~ , ~
O
/ CH3
The synthesis of fluorinated aromatics by starting from the phenol derivative has been derivatives (Table V) like diphenylcarbonate (entry 2), ot,c~,ct-trifluoroanisole (entry 5). selectively
C1
+ CO 2
10
the elimination of a small molecule successfully generalized to various (entry 1), phenylchlorothioformate The reaction proceeds also very
starting from phenylfluoroformate.
For each substrats, an acidic
activation (Lewis or Bronsted) is necessary to produce an activated intermediate, probably the cation ArOCO § or an analogue, by the liberation of phenol or hydrogen fluoride. Table V 9 Influence of the leaving group nature X ~ O ~ Y
HFvaporphaseA1203 ~-
Entry
F + COX + HY
Temperature (~
Yield (ArF) (%)
1
O
OPh
300
60
2
S
C1
300
91
3
O
F
300
> 95
4
C12
CI
400
23
5
F2
F
400
50
R E A C T I O N A L MECHANISM For the decarboxylation of arylfluoroformates, Christe and Pavlath suggest an internal nucleophilic substitution mechanism (Scheme 3). 0 OC --F
R
8+
8-
~
O
R
Scheme 3. Internal nucleophilic substitution mechanism 308
~ F
+
CO 2
This mechanism was preferred to a mechanism via the cation ArOCO § due to the high stability of the acylium cation. This cation does not decarboxylate under the usual conditions for the decarboxylation of arylchloroformate and alkylfluoroformate. Decarboxylation of arylfluoroformiate on 7-alumina (ref. 4d) or fluorodecarboxylation of arylchloroformate under anhydrous hydrogen fluoride did not seem to proceed via the same mechanism. Indeed, the high activation energy of the internal nucleophilic substitution explains why such high temperatures such as 700-800~ are needed. At lower temperatures, the reaction must proceed via a nucleophilic displacement of carbon dioxide in the cation ArOCO § To obtain a very high selectivity in fluoro aromatics, it is necessary to have available nucleophilic fluoride ; the lower selectivity obtained in decarboxylation of phenyl fluoroformate using aluminium fluoride as catalyst can be explained assuming that the fluoride is not nucleophilic enough to permit the reaction. This is in accordance with the necessity of a large excess of anhydrous hydrogen fluoride for the fluorodecarboxylation of arylchloroformate on aluminium fluoride. So, this methodology permits the preparation of aryl fluoroformate with various susbtituents. The use of a large excess of anhydrous hydrogen fluoride compensates for the lack of reactivity of some arylchloroformates.
OCX " 0
+
HF
~
CQ
XHF
R )~"J/
-------~
F
+CO2
+ HX
R
X = C1, F
Scheme 4. Bimolecular nucleophilic substitution mechanism
Also the transformation of phenol to fluorobenzene using a mixture of hydrogen fluoride and antimony pentafluoride has been previously described (ref. 7), we have shown that under our conditions phenol is not reactive. Fluorobenzene is thus produced mainly from phenylchloroformate or phenylfluoroformate. Scheme 5 shows the reaction routes for the main products :
309
OH
+HF/ "COF2 ' + HF
-
CO2 C1
~
~OF
~ -HC1 + -CO 2 " ~ ~
_
CO2
G Scheme 5. Fluorodecarboxylation of arylchloroformate 9product's filiation
The
reaction of substituted arylfluoroformate
regiochemistry
shows
a high retention of
in accordance with the proposed mechanism.
In the case of
fluorotoluene no isomerisation is observed under the reaction conditions.
310
C A T A L Y S T LIFE TIME The catalyst life time was examined in the case of 3-fluorotoluene preparation by fluorodecarboxylation of 3-methylphenylchloroformate decarboxylation. We observed a rapid deactivation of the catalyst after 5 hours of continuous running. This deactivation is linked to the formation of non volatile derivatives. After 5 hours the amount of carbon on the catalysis is 4 %. The catalyst activity can be recovered by calcination under air for 3 hr at 450~ In this way, several reaction - reactivation cycles have been realised without significant modification of the catalytic activity (Scheme 6). CH 3
CH 3
I
HF vapour phase
f"/"'N"l
A1203, 300~ OCOC1
Yield (%) 100
80 60 40 20
0
10
20
30
40
50
60
70
80
Duration on stream (h.)
Scheme 6. Fluorodecarboxylation of 3-methylphenylchloroformate 9catalyst life time
311
CONCLUSION The fluorodecarboxylation of arylfluoroformates in the vapor phase, under anhydrous hydrogen fluoride has been successfully realised by using catalysts such as aluminium fluoride or aluminium or chromium oxyfluoride. This transformation is quite versatile, the main limitation being the stability of substrates or products under the reaction conditions. The catalyst used, deactivates rapidly by coking but can be reactivated by a simple oxidative treatment. This new access to fluorinated aromatics derivatives appears to be an attractive industrial alternative to the diazotisation of anilines.
References
1.
R.D. Chambers in "Fluorine in Organic Chemistry", Wiley-Interscience, New York, (1973). 2. G. Balz, G. Schiemann, Ber., 60, 1186, (1927). H. Susdritsky in "Adv. in Fluorine Chem.", vol. 4, M. Stacey, J.C. Tatlow, A.G. Sharpe, Eds., Butherwerthesm, London, (1965) ; Organofluorine chemistry : principles and commercial applications, Banks, Smart, Tatlow Eds, Plenum Press, chap. 9, (1994). 3. R.L. Ferm, C.A. Van Der Werf, J. Am. Chem. Soc., 72, 4809, (1950). 4. a) K.O. Christe, A.E. Parlath, J. Org. Chem., 30, 3170, (1965). b) K.O. Christe, A.E. Parlath, J. Org. Chem., 30, 4104, (1965). c) K.O. Christe, A.E. Parlath, J. Org. Chem., 31,559, (1966). 5. D.P. Ashton, T.A. Ryan, B.R. Webster, B.A. Wolfmdale, J. Fluorine Chem., 27, 263, (1986), EP 118241, (1983) (to ICI). 6. N. Isvashenko US 3.499.942, (1966). I. Hisamoto, C. Maeda, M. Nishiwaki EP 57443 (1981), (to Daikin Kogyo) J.F. Bieron, D.Y. Tang, US 4792 618, (1984), (to Occidental Chem. Corp.). M. Tojo, S. Fukuoka, J 63054332 and J 63088146, (1986), (to Asahi Chem. Ind.). F.J. Weignet, US 4754 084, (1987), (to Du Pont de Nemours). 1) L. Gilbert, H. Garcia, B. Langlois 2) L. Gilbert, H. Garcia, C. Rochin 3) L. Gilbert, B. Langlois, FR 2647106, FR 2647107, FR 2647111, (1989), (to Rh6ne-Poulenc). 7. J.I. Darragh GB 1582427 (1976), (to ICI). 8. A. Werckmann, GE 857 350, (1943). 9. H. Erlingafeld, Angew Chem., 72, 836, (1960). 10. S. Nakanishi, J. Am. Chem. Soc., 77, 3099, (1955). 11. P. Beak, R.J. Trancik, D.A. Simpson, J. Am. Chem. Soc., 91, 5073, (1969). 12. M. Janin, B. Langlois, L. Gilbert, M.C. Perrod, Private communication
312
MILD T R I F L U O R O M E T H Y L A T I O N OF ORGANIC COMPOUNDS
CLAUDE WAKSELMAN AND MARC TORDEUX SIRCOB-CNRS, Equipe Fluor, B~timent Lavoisier, Universit6 de Versailles, 45 avenue des Etats-Unis, 78 000 Versailles, France
INTRODUCTION Numerous organic molecules bearing a trifluoromethyl group have found industrial applications as pharmaceutical or agrochemical products (ref. 1). They are classicaly prepared by the use of aggressive or toxic reagents. However, the understanding of the reactivity of a small fluorinated molecule has recently allowed the proposal of new trifluoromethylation ways in much milder conditions.
PROPERTIES OF FLUORINATED SUBSTITUENTS Owing to the extreme electronegativity of fluorine (4.0 on the Pauling scale), fluorinated groups behave inductively as electron-withdrawing substituents. The trifluoromethyl group shows an electronegativity (3.5) higher than that of the chlorine atom (3.0) (ref. 2). The inductive effect is balanced by the mesomeric one in trifluoromethoxy and trifluorothiomethoxy groups as for an halogen substiment (ref. 3). On the other hand, fluorination can exert an influence on the lipophilicity of organic molecules, particularly at positions adjacent to atoms or groups having electrons. Hansch constants derived from octanol/water partition coefficients of substituted benzenes (ref. 4) are summarized in Table 1.
313
Table 1. Hydrophobic constants of various substimems
Substituent
OCH 3
F
CH 3
SCH 3
C1
CF 3
OCF 3
SCF 3
n
-002
0.14
0.56
0.61
0.71
0.88
1.04
1.44
. ,
*
Hansch constants derived from octanol/ water partition coefficients of subtituted benzenes (ref. 4).
These data are more appropriate to the nonspecific equilibrium binding of the various compounds to tissues in general than to their genuine kinetics of absorption and distribution in living systems (ref. 5). They can explain the interest for the introduction of the trifluomethylated substituents CF3, OCF3, SCF3 (considered to induce a higher lipophilicity than chlorine) in pharmaceutical and agrochemical products.
CLASSICAL PREPARATIONS The industrial route employed for the elaboration of the trifluoromethyl group is based on an halogen exchange in hydrogen fluoride (Fig. 1) (refs. 1,2). Only very stable molecules can survive in such drastic conditions.
ArCC13
HF
~
ArCF 3
ArYCC13
HF
~
ArYCF3
(Y = O, S)
Fig. 1. Halogen exchange reactions
Numerous alternative preparations have been described (ref. 2). They often make use of toxic (CF3SC1) or fragile (CF3Cu, CF3SCu) reagents. Radical trifluoromethylation can also occur starting from the expensive trifluoromethyl iodide.
R E A C T I V I T Y OF T R I F L U O R O M E T H Y L HALIDES Trifluoromethyl halides CF3X (X = I, Br) are known to be resistam to nucleophilic attack on the carbon atom (refs. 6, 7). This behaviour is explained by the unusual polarisation of the C - X bond (Fig. 2) and also by steric effects and lone-pair repulsion forces associated with fluorine substituents. 314
5- S + CF3mX
( X = B r , I)
Fig 2: Polarization of the CF3-X bond
Pioneering studies showed that attack by strong nucleophiles (alcoholates...) on the larger halogen X can occur, as shown by the formation of fluoroform in protic medium (Fig. 3) (ref. 8). solvent Nu- + CF3X
~
NuX +
CF3
~
CF3H
Fig. 3. Halogenophilic attack
However, since the mid 1970s, some reactions of trifluoromethyl iodide with soft nucleophilic reagents, enamines (ref. 9), or thiolates (ref. 10), have been interpreted as single electron transfer (SET) processes (Fig 4, X = I) (refs. 9, 10,
11). Nu- + CF3X
N u " + [CF3X] 9
[CF3X] 9
X" + CF3"
Nu
[NuCF3] 9
o
+ CF 3 9
[NuCF3] . " + CF3X
NuCF3 + [CF3X] "
Fig 4. SET process with a charged nucleophile.
Trifluoromethyl bromide, produced as a fire extinguishing agent (refs .12, 13), is much cheaper than the corresponding iodide. Unfortunatly, its reactivity is much lower too. At that time, this bromide was considered as rather inert.
315
T R I F L U O R O M E T H Y L BROMIDE REACTIONS
1. First substitution reaction by thiolates Thiolates are powerful nucleophilic reagents. However, we observed no reaction when trifluoromethyl bromide is bubbled through a potassium thiophenoxide solution in DMF at room temperature. This failure was in agreement with the inertness reputation of this halide. Assuming that a mechanism involving radical anions (Fig. 4, X = Br) could occur, a minimal concentration of the halide should be necessary to maintain the chain process. In order to increase the amount of trifluoromethyl bromide in solution, we performed the reaction under pressure. Indeed, condensation occurred at room temperature in a glass apparatus under 23 bars (Fig. 5) (refs. 16,17). Inhibition of this condensation by nitrobenzene was clearly observed, in agreement with the SET process (Fig 4, X = Br). A similar trifluoromethylation of thiols by trifluoromethyl bromide in liquid ammonia under UV irradiation has also been described (ref. 18).
ArSK + CF3Br
ArSCF3 + KBr
Fig 5. Trifluoromethylation of potassium thiophenoxide.
2. Reaction with metals and carbonyl compounds We remarked that the first step of the radical-anion chain mechanism (Fig. 4) can be considered as a reduction of the halide by the nucleophile. Consequently, we tried to use well known reductants such as zinc. However, no reaction occurred when the halide is placed in the presence of zinc in various solvents. By analogy with the thiophenoxide condensation, we attempted the transformation in DMF under slight pressure. Consumption of the reagents was only observed when electrophilic substrates, such as carbonyl compounds, are present since the beginning of the reaction. These Barbier like condensations started more easily in pyridine than in DMF (ref. 19). Moderate yields were obtained with aldehydes as substrates (Fig. 6).
2-4 bars / CF3X RCHO + Zn
RCH(OH)CF3 lutidine
Fig 6. Barbier condensation with aldehydes. 316
The reaction was more difficult with ketones. In the case of acetone, no addition product was even observed. Curiously enough, the presence of this simple ketone initiated the formation of trifluoromethyl zinc derivatives (Fig. 7).
CF3Br + Zn
2-4 bars
CF3ZaaBr + (CF3)2Zn
pyridine acetone
Fig 7. Formation of trifluoromethylzinc derivatives.
When benzaldehyde was subsequently introduced into such a medium, no condensation
product
was
detected,
showing
that
these
strongly
solvated
organometallics are poorly reactive. In the case of an a-keto ester, the addition of the trifluoromethyl group occurred as expected to the keto group (Fig. 8).
2-4 bars RCOCOOEt + Zn + CF3Br
R
pyridine
CF3 !
COOEt
I OH
Fig. 8. Addition to ketoesters.
Simple esters did not lead to addition products. However, the Barbier procedure was effective, even at atmospheric pressure, when the ester was activated by an electron-withdrawing group; ethyl trifluoropyruvate and hexafluoroacetone were respectively obtained from diethyl oxalate and ethyl trifluoroacetate (Fig. 9). 2-4 bars EtO2CCO2Et + Zn + CF3Br
CF3CO2Et + Zn + CF3Br
~ EtO2CCOCF3 pyridine id.
~ CF3COCF3
Fig. 9. Reaction with activated esters.
317
Some acid anhydrides were also trifluoromethylated (Fig. 10). O ~
O
O 3-4 bars
+ Zn + CF3Br
pyridine
O Fig. 10. Trifluoromethylation of phtalic anhydride It is well known that iminium salts show a reactivity comparable to that of carbonyl compounds towards organometallics. Consequently, we tried a similar Barbier condensation with the Eschenmoser's salt, but without success (Fig 11).
3-4 bars CH2zN+Me2 + Zn + CF3Br
CF3CH2NMe2 pyridine
Fig. 11. Failure of the Barbier condensation with the Eschenmoser's salt This failure can shed some light on the nature of the intermediate involved in these Barbier condensations. In contrast to the case of carbonyl compounds, iminium ions do not present a partial negative charge able to coordinate with the metal. On the contrary, carbonyl adsorption leaves the possibility for these compounds to play the part of a ligand around the nascent organometallic, formed at the zinc surface, and to react in the coordination sphere. Following this interpretation, the nascent organozinc intermediate is not completly surrounded with pyridine. It can be more reactive than the strongly solvated organometallics detected in the pyridine-acetone medium (vide supra).
3. Chemical synthesis of triflic acid Barbier conditions were also employed thiocyanates (Fig. 12) (ref. 20).
RSCN + Zn + CF3Br
2-5 bars
RSCF3
pyridine Fig 12. Trifluoromethylation of thiocyanates
318
for
the
trifluoromethylation
of
Benzyltrifluoromethylsulfide, formed from benzylthiocyanate, can lead to triflyl chloride by oxidative chlorination under slight pressure (Fig. 13). Cleavage of the carbon-sulfur bond was easy in this example because the benzyl group is able to stabilize a positive charge. El2, 4 bars C6H5CH2SCF3
C6HsCH2C1 + CF3SOaC1
H20, 5~ Fig. 13. Formation of triflyl chloride by oxidative chlorination of benzyltrifluoromethylsulfide
Owing to a limited yield obtained in the preparation of
benzyltrifluoro-
methylsulfide another route to triflic acid was prefered " the direct Barbier condensation with sulfur dioxide (Fig. 14) (ref. 21). 3-4 bars SO2 + Zn + CF3Br
CF3SO2ZaaBr DMF
Fig. 14. Formation of zinc bromide trifluoromethanesulfinate In contrast to the carbonyl condensations, where no reaction occurred between the substrate and the metal, an initial attack on zinc by sulfur dioxide in DMF was actually observed. Then, introduction of trifluoromethyl bromide under slight pressure led to the formation of zinc triflinate. Homologous zinc sulfinates have been obtained from the much more reactive long-chain perfluoroall~l iodides when these halides were introduced at atmospheric pressure, before or after sulfur dioxide, in a suspension of zinc-copper couple in DMSO or DMF (ref. 22). This condensation was imerpreted as occurring at the metallic surface and was tought to involve an adsorbed organozinc intermediate (ref. 23). In order to check this hypothesis, we performed the following experiment : the supernatant liquid formed in the reaction of sulfur dioxide with zinc in DMF was transfered to a second flask containing perfluorohexyl iodide. Formation of the corresponding sulfinate was detected by NMR. Consequently, a reaction had occurred in this solution. Moreover, inhibition of sulfinate formation was noticed when nitrobenzene was mixed with the perfluoroalkyl iodide. These results can be interpreted by a single electron transfer process (Fig. 15) (refs. 19, 21) involving an intermediate trifluoromethyl radical.
319
~--
Zn + 802
Zn+ +
502 "-(
SO2 +
Br" +
~
1/2-O2SSO2) j,
SO2-- +
CF3Br
SO2-- +
CF3-
.~
CF3-
CF3SO2"
Fig. 15. SET prosess for the triflinate formation
This condensation with sulfur dioxide is rather peculiar. To the difference with carbonyl electrophiles, sulfur dioxide is more easily reduced than trifluoromethyl bromide. As already pointed out, initial consumption of zinc by this anhydride was obvious, producing the sulfoxylate radical anion which is known to be in equilibrium with the dithionite anion (Fig. 15). Incidentally, this salt mixed with sodium bicarbonate in aqueous acetonitrile was used for the transformation of liquid perhalogenoalkyl halides into their corresponding sulfinates (ref. 24). We have been able to transform the gaseous and poorly reactive trifluoromethyl bromide into sodium trifluoromethanesulfinate. However, the reaction conditions (Fig. 16) (ref. 25) were modified because no transformation occurred in the medium employed for the sulfinato-dehalogenation of the liquid halides. 13 bars
Na2S204
+ CF3Br +
Na2HPO4
-- CF3SO2Na DMF-H20
Fig. 16. Formation of sodium trifluoromethanesulfinate from sodium dithionite
The triflinate salt was also obtained with sodium hydroxymethanesulfinate (Rongalite) in the presence of sodium metabisulfite in anhydrous DMF (Fig. 17) (ref. 25). 3-5 bars NaO2SCH2OH
+ CF3Br +
Na2S205
~
CF3SO2Na
DMF Fig. 17. Formation of sodium trifluoromethanesulfinate from sodium hydroxymethanesulfinate
The triflinate salt can be transformed to its corresponding triflate derivative by oxidation with hydrogen peroxide, then to triflic acid by action of sulfuric acid (Fig. 18).
320
30 %
CF3SO2Na Fig. 18.
H20 2 H2SO4 ~ CF3SO3Na ~ CF3SO3H
T r a n s f o r m a t i o n o f s o d i u m triflinate to triflic acid
4. Trifluoromethylation of aromatic compounds We have interpreted the formation of zinc triflinate by a SET process (Fig. 15). In order to test for the presence of the electrophilic trifluoromethyl radical in this reaction, we have added anilines to the medium. Indeed, alkylation at electron-rich positions of the ring was observed (Fig. 19) (ref. 26). NH2
NH2
~/
Zn + SO2 + CF3Br, 3-5 bars Na2S203, DMF
NH2
/CF3 +
CF3
Fig. 19. Trifluoromethylation of aniline
In this experiment, a decimolar quantity of zinc and sulfur dioxide was used. In order to explain such a catalytic effect, we have considered that the sulfur dioxide which is formed in the medium (Fig. 15) can be reduced back to its radical anion by an intermediate cyclohexadienyl radical. This step could induce a chain formation of the trifluoromethyl radical (Fig. 20) (refs. 26, 27). X X X
~
CF3
cv3Br
X CF3
~
SO2 . .
CF3Br 9
~
I-i+
$02
~
"
"
Fig. 20. Radical trifluoromethylation of aromatic compounds
321
CF3Br
"~CF3
Other electron-rich aromatic compounds can be employed as substrates. Pyrroles were trifluoromethylated regioselectively at the 2-position (ref. 27). Recently, the system trifluoromethyl iodide-zinc-sulfur dioxide in DMF at low temperature was used for the trifluoromethylation of aminonaphtalenes and aminoquinolines (ref. 28). Computational results support the mechanism in which the electrophilic trifluoromethyl radical intertact with the aromatic ring at the sites with the greatest electron density of the HOMO orbitals. Similar trifluoromethylation reactions of anilines, phenols or pyrroles were performed in the presence of sodium dithionite (ref. 27).
5. Trifluoromethylation of disulfides Owing to the susceptibility of the weak sulfur-sulfur bond in disulfides to free radical attack, the trifluoromethylation of these compounds was attempted. Indeed, trifluoromethyl sulfides were obtained (Fig. 21) (ref 29).
SO2 9precursor RSSR
+
RSCF3
CF3Br Na2HPO4, DMF-H20
Fig. 21. Trifluoromethylation of disulfides
Experimems were performed with various sulfoxylate radical anion precursors: sodium dithionite, sodium hydroxymethanesulfinate or a mixture of sulfur dioxide with a reductant, such as zinc or sodium formate (refs. 29, 30).In contradistinction with the trifluoromethylation of aromatic compounds (Figs. 19, 20), a stoiechiometric amount of the sulfoxylate radical anion precursor was necessary. In the disulfide case, there is no intermediate able to reduce back the sulfur dioxide which is formed in the medium (Fig. 22). o
SO2"CF3
+ +
2 RS.
CF3Br RSSR
~
CF3" + X
+
~
RSCF3
RS.
~
RSSR
+
SO 2
Fig. 22. Mechanism of the disulfide trifluoromethylation
322
CONCLUSION For many years now, the reactivity of trifluoromethyl bromide has been underestimated. During the past decade the major breakthrough in this area has been the realisation that trifluoromethylation of organic compounds with this halide can be induced by mild reductants such as thiolates, zinc or sulfoxylate radical anion. Nowadays, a great variety of fluorinated products are available by these new methods
:
sodium
triflinate
trifluoromethyl-containing
and
aromatic
triflic
acid,
compounds,
trifluoromethylated ethyl
alcohols,
trifluoropyruvate,
trifluoromethylsulfides ....
AKNOWLEDGEMENTS Cooperation between Rh6ne-Poulenc and our CNRS team began with Dr. C. Kaziz and was kept on with Drs. J-C. Lanet and S. Ratton. We thank all of them for their interest in this research programm. Part of the work has been developed at the " Centre de Recherche, d'Ing6nierie et de Technologie des Carri6res " in Lyon. We thank Drs. B. Langlois, J-L. Clavel, R. Nantermet and the other members of the Rh6ne-Poulenc laboratory for this close cooperation. Similarly, we aknowledge the active participation of Dr. C. Francese during the preparation of her thesis in our laboratory.
References
1. R. E. Banks, B. E. Smart , J. C. Tatlow in " Organofluorine Chemistry: Principle and Commercial Applications ", Plenum Press, New York (1994). 2. M.A. McClinton, D. A. McClinton, Tetrahedron, 48, 6555, (1992). 3. L. M. Yagupolskii, A. Ya. Ilchenko, N. V. Kondratenko, Russian Chem. Rev., 43, 32, (1974). 4. C. Hansch, A. Leo in " Substituent Constants for Correlation Analysis in Chemistry and Biology ", Wiley, New York, (1979). 5. P.N. Edwards in ref. 1, p.530. 6. R.D. Chambers in " Fluorine in Organic Chemistry ", Wiley, New York, (1973). 7. C. Wakselman, A. Lantz, in ref. 1, p. 178. 8. J. Banus, H. J. Emeleus, R. N. Haszeldine, J. Chem. Soc., 60, (1951). 9. D. Cantacuzene, C. Wakselman, R. Dorme, J. Chem. Soc., Perkin Trans. 1, 1365, (1977). 10. V. N. Boiko, G. M. Schchupak, L. M. Yagupolskii, Zhur. Org. Khim., 1057, (1977). 11. C. Wakseman, J. Fluorine Chem., 59, 367, (1992). 12. Until now the main application of trifluoromethyl bromide was its use as Halon 1301 in aeronautic ( ref. 13).Unfortunatly, Halons are implicated in the depletion of stratospheric ozone. The participants of the 1992 Montreal Protocol Meeting in Copenhagen agreed to phase out Halon production by the year 1994, except for some essential fire-fighting uses. Research on alternative agents have been initiated in order to find new products with low or zero Ozone Depletion Potential. However, the numerous candidates examined so far present 323
13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29.
massive problems: toxicity (CF2I),harmful production of hydrogen fluoride on discharge into the hot flame (CF3CHFCF3, CF3CHF2, CF3H), atmospheric life time higher than a millenary (CF3CF2CF 3, CF3CF2CF2CF 3) (refs. 14, 15). Another question is related to the quantity of material needed to put out a fire owing to the lower efficiency of the alternative agents. This issue is crucial for aircrafts where weight carried is a critical factor. These difficulties explain why Halon 1301 is still in use. However, introduction of possible substitutes should leave important stocks of this classical extinguishing agent. Their use for trifluoromethylation reactions should be more useful than a simple destruction. C. Wakselman, A. Lantz, in ref. 1, p.185. R. E. Banks, J. Fluorine Chem., 67, 193, (1994). M. Freemantle, Chem. Eng. News, 29 , (september 19 issue, 1994); idem, 25 (january 30 issue, 1995). C. Wakselman, M. Tordeux, J. Chem. Soc., Chem. Comm., 793, (1984). C. Wakselman, M. Tordeux, J. Org. Chem., 50, 4047 (1985). N. V. Ignatev, V. N. Boiko, L. M. Yagupolskii, Zh. Org. Khim., 21,653, (1985). M. Tordeux, C. Francese, C. Wakselman, J. Chem. Soc., Perkin Trans. 1, 1951, (1990). M. Tordeux, C. Francese, C. Wakselman, J. Fluorine Chem., 43, 27, (1989). C. Wakselman, M. Tordeux, Bull. Soc. China., 868, (1986). H. Blancou, P. Moreau, A. Commeyras, J. Chem. Soc., Chem. Comm., 885, (1976). A. Commeyras, Ann. Chim. (Paris), 9, 673, (1984). W-Y. Huang, J. Fluorine Chem., 32, 179, (1986). M. Tordeux, B. Langlois, C. Wakselman, J. Org. Chem., 54, 2452, (1989). C. Wakselman, M. Tordeux, J. Chem. Soc., Chem. Comm., 1701, (1987). M. Tordeux, B. Langlois, C. Wakselman, J. Chem. Soc., Perkin Trans. 1, 2293, (1990). L. Strekowski, M. Hojjat, S. E. Patterson, A. S. Kiselyov, J. Heterocycl. Chem., 1413, (1994). C. Wakselman, M. Tordeux, J-L. Clavel, B. Langlois, J. Chem. Soc., Chem. Comm., 993, (1991).
324
FORMYLATION
OF
AROMATIC
COMPOUNDS
IN
SUPERACIDIC
MEDIUM
LAURENT SAINT-JALMES, CHRISTOPHE ROCHIN, ROBERT JANIN AND MARCEL MOREL Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie, 85 Avenue des Fr~res Perret, B.P. 62, 69192 Saint-Fons Cedex, France.
INTRODUCTION Chemists were always interested in introducing in one step a formylgroup into aromatic rings to obtain aldehydes 9 O II ArH ~ Ar~C--H Several methods to obtain aromatic aldehydes are well-known. For example the reaction between aromatics and : -disubstituted formamides in presence of phosphorus oxychloride : Vilsmeier-
Haack reaction (ref. 1), - chloroform in basic medium : Reimer-Tiemann reaction (ref. 2), - zinc cyanide in acidic medium (for example HCI) : Gattermann rea ction (ref. 3). Carbon monoxide and formic derivatives can also be used to make formylations of aromatic compounds (ref. 4) in acidic or superacidic medium. Superacidic medium are characterized as medium whose acidity is superior to those of H2SO 4 (100 %) (ref. 5). In these medium the acidity cannot be measured by pH. The ,, Hammet-Deyrup acidity function ,,, Ho (ref. 6), which shows the facility of protonation of a weak base by a superacid, allows to class the superacids (ref. 7) (Fig. 1).
325
H2SO4 100 %
10
11 12
13
tl I I I I L A
2,4
14
A
15
4~
16
17
18
19
20
1
I
I
I
A
A
Illlllllll A
21 22
I
I
23
I
24
25
I ~---HO A
A HF
HF/BF3
HF/SbF5 ( 1 0 0 / 1)
CF3CO2H
FSO3H/SbF5 (1 / 1)
CF3SO3H FSO3H CFsSOsH/SbF5
(90 / 10) Fig. 1. Hammet-Deyrupacidity scale Formylation
using carbon
monoxide
The first example of electrophilic formylation was reported by Gattermann and Koch in 1897 (ref. 8). They found that carbon monoxide and HC1 can react with alkylbenzenes in presence of A1C13 and cuprous chloride to give aldehydes (Fig. 2).
ArH + CO + HC1
mc~3 CuC1
0 II
Ar~C--H
Fig. 2. Gattermann-Koch reaction From this first example, others acidic systems have been studied to try to generalize this type of formylation and to study selectivities. Formylation of aromatic rings with carbon monoxide requires the use of superacidics to activate carbon monoxide by protonation and to protonate the formed aldehyde which is the thermodynamic driving force of the reaction. O II Even if the formyl cation H--Ce was never observed, the mechanism of formylation by CO / superacids seems to be an electrophilic one.
326
Highly basic aromatic rings can be protonated in superacid medium to give or-complex. In this case, the formylation rates of these basic compounds decrease, which is consistent with an electrophilic mechanism. The use of HF-BF 3 mixture as catalyst for aromatic formylation has been reported
mostly
in
the
patent
literature
(refs. 10, 11).
Formylations
of
alkylbenzenes can be obtained with good yields (Fig. 3).
+ CO
+
20 bars
HF + BF3 10 eq.
~
_ 25oc
1,2 eq.
(ref. 10)
2
79 % yield Fig. 3. Formylation of alkylbenzenes with CO / HF/BF 3 In the cases of phenols,
formylations by C O / H F / B F
3 system require
pressures of carbon monoxide of about 50 to 100 bars to obtain good yields (refs. 12, 13)(Fig. 4).
OH
OH + HF + BF3 50 eq.
CO 40 bars 40~ 1h
2 eq.
~
(ref. 13)
3_ 4
Fig. 4. Formylation of phenol with CO / HF / Others
catalysts
such
as
80%
BF 3
HF-SbF 5
(ref. 14),
HF-SbF 7
(refs. 15, 16),
HSO3F-SbF5 (ref. 17) have also been used to make formylation of alkylbenzenes with carbon monoxide. Triflic acid, alone (ref. 18) or in presence of Lewis acid (ref. 19), catalyses formylation of alkylbenzenes by CO. Even if CO is much more soluble in CF3SO3H than in H2SO 4, pressures of CO superior to 100 bars are required to have good yields in benzaldehydes if Lewis acids are not present (Fig. 5). 327
CH3
0
CH3 CO (1200 psi) + CF3SO3H 6 eqt
3,5 h- RT~
-~
79%
~H3
CH3 CO (1 atm) + CF3SO3H + SbF5 3, 5 h, 0~
:--
59%
Fig. 5. Formylation with CO / triflic acid
Formylation using formic derivatives Very few Friedel-Crafts methods equivalent to the acylation with acyl halides or anhydrides are available to make formylation, undoubtly because halides and anhydrides of formic acids are very unstable. Formyl chloride has been shown to be stable at less than-60~
(ref. 20).
Formic anhydride, which can be obtained from formic acid by deshydratation, is unstable above -40~ Formic anhydride gives formates with phenols but fails to formylate aromatic rings (ref. 21). Mixed anhydrides of formic acid with acids, such as acetic formic anhydride, are stable but give acetylation of aromatic compounds with evolution of carbon monoxide (ref. 22). Formyl fluoride is the more stable halide of formic acid. It can be prepared from formic acid with potassium fluoride and benzoyl chloride in 16 % yield (ref. 23), other fluorinating agents are also used such as KHF2 (ref. 22) (Yield : 35,4 %). Reaction of sodium formate with benzoyl fluoride give also formyl fluoride (ref. 24) with 36 % yield. Formyl fluoride in presence of boron trifluoride forms a complex which has been used in aromatic formylations of alkylbenzenes (ref. 22, Table 1).
328
Table 1. Formylation with HCOF / Aromatic
BF 3
Product
Benzene _7 Toluene Xylene Naphtalene 9
Yield, %
Benzaldehyde 8 Tolualdehyde Dimethylbenzaldehyde Naphtaldehyde 10
56 75 78 20 - ot isomer 67 - [3 isomer
Methyl formate, a stable and commercialy available compound, is a C-1 building block (ref. 25) and so can be a theoretical formylating agent. We have found that formylation of a large type of aromatic substrates can be obtained with fair to good yields using methylformate in the presence of HF-BF3 complex (ref. 26). The
aromatic
compound
and
methylformate
are
diluted
in
anhydrous
fluorhydric acid and a pressure of boron trifluoride is added to the mixture. Amounts
of boron
trifluoride
can be changed to increase
yields.
Table 2
summarizes the obtained results. Benzene
can
be
formylated
very
easily.
Fluorobenzene
gives
fluorobenzaldehyde with a total selectivity in para isomer. On the contrary chloro and bromobenzene are transformed in poor yield, and chloro and bromo toluenes 17 are obtained next to halobenzaldehydes 16, showing that methyl formate can act as an alkylating agent. Table 2. Formylation with H C O 2 C H 3 / HF /
Substrates
a)
HF
BF3 pressure at 0 ~
T~
BF 3
time
conversion %
Yields %
Major products CHO
40 eq.
10 bar
50 ~
6h
72
90 %
11 9
12
F 10 bars
60~
6h
95 %
2,5 bars
40 ~
4h
55 %
~ )
81%
40 eq. 13
51% CHO 9
14
. . .
329
Substrates a)
HF
BF3 pressure at 0°C
To
time
anversion %
Yields %
Major products CI
I
c1 I
40 eq.
10 bars
60°C
6h
15 %
+
9
--
40 eq.
?
40 eq.
50°C
5h
80 %
50 %
10 bars
50°C
5h
85 %
53 %
10 bars
30°C
5h
20 %
22
13 %
OH
5 bars
50°C
5h
90 %
(yo"
rcHo I
CHO
-
I
40 eq.
10 bars
50°C
4h
25 %
22
40 %
21
23
OCH;
0
II
5 bars
OH
&"'
bCH3
-0
15 %
OCHj
I
24
11 %
I
--
@ \
40 eq.
2.5 bars
25
40°C
4h
69 %
- --
a) in every case 1,3 eq. HC0,Me
330
CHO
49 %
Two by-products 27, 28, (Fig. 6) are obtained during formylation of diphenylether 18 next to diphenylaldehyde. The formation of 27 and 28 can be explained by hydride transfer (Fig. 6), a type of transfer in acidic medium already mentionned in literature (ref. 27).
C o-o
(y~
18
19
CHO
C< I
+
C
OH-.~.H
27
0
28
Fig. 6. Formation of by-products during formylation of diphenylether Formylation of guaiacol 20 gives not only vanilline 21 but also aldehyde 29 and surprisingly acetophenone 30 (Fig. 7).
~ OH
OH
OMe OMe
OMe
OH OMe
OMe
20 C yield
3 40 %
30 %
18 %
21
29
30
Fig. 7. Formylation of guaiacol with HCO2Me / HF / BF3 system In the case of anisole 22, acetophenone 31 is also observed (Fig. 8).
331
OCH3
OCH3
(~CH3
OCH3 CHO
v-
+
~
+
22
CH3 11% 24
15% 23
5 % 31
yield
Fig. 8. Formylation of anisole with HCO2Me / HF / BF3 system Phenol is not formylated with H C O 2 M e / H F / B F 3. On the contrary phenyl formate 32 gives by Fries rearrangment p-hydroxybenzaldehyde 33 (Fig. 9). Phenol does not give phenyl formate 32 with methyl formate in the presence of HF / BF 3 (Fig. 9). OH
HCO2Me, HF, BF3
/
X
~CHO o II O--C--H
HCO2Me, HF, BF3
X o II
O--C--H
OH I-IF/BF 3 33
32
CHO
Fig. 9. Formylation of phenol with HCOzMe / HF / BF3 1,3,5-Trimethoxybenzene and 1,4-dimethoxybenzene do not give formylation in our conditions, but demethylations of these compounds are noted. During the reaction, formation or carbon monoxide is noted, showing that methyl formate is, in part, decomposed in the reaction conditions. Two mechanisms can explained the reaction of formylation with methyl formate in HF / BF 3 medium.
332
In route A (Fig. 10), methyl formate is decomposed in CO and methanol. Carbon monoxide is protonated to give formylation of an aromatic ring. In route B (Fig. 10), methyl formate is protonated without decomposition and can be attacked by an aromatic ring to give formylation. 0 II H--C--O--CH 3
|
-H II H--C--O--CH3
xx,,,
Route A ~ , , -'/
RouteBH O" I
H--C--O--CH3 (9
CO + CH3OH + H+
O
R
OH
[
O
+]
H OCH3
~~
CHO
/( CH3OH
R R
Fig. 10. Mechanism of formylation with HCOzMe / HF / BF3 system Acetylated products which are formed during formylation of guaiacol or anisol are difficult to explain. We can suppose that methanol which is the by-product in the reaction of formylation with methyl formate is, in part, deshydrated in our superacid conditions to give the carbocation CH3 + (Fig. 11). This carbocation can be attacked by CO in a nucleophilic way, like in Koch-Haft formylation of aliphatic
333
O compounds, to give the acyl cation CH3
, which is attacked by aromatic rings
to give acetophenones.
CH3~OH
H§
+ H20
|
O CH3~ICI | R
0 R
CH3~ O Fig. 11. Supposed mechanism of acetylation 9a side reaction during formylation Why this acetylated compounds are only formed starting from guaiacol and anisol is not explained. In conclusion, formylation of aromatic rings can be obtained in HF-BF3 medium using methyl formate, a stable and cheap material. High pressures are not required to make these formylations.
Different
functionalized aromatic rings are formylated in our conditions with fair to good yields. Optimizations of the yields obtained will be studied in the future.
References .
2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
C. Jutz, Adv. Org. Chem., 9, part 1,225, (1976). H. Wynberg, E.W. Meijer, Org. React., 28, 1, (1982). W.E. Truce, Org. React., 9, 37, (1957). G.A. Olah, L. Ohannessian, M. Arvanaghi, Chem. Rev., 4, 671, (1987). R.J. Gillepsie, T.E. Peel, Adv. Phys. Org. Chem., 9, 1, (1972). L.P. Hammet, A.J. Deyrup, J. Am. Chem. Soc., 54, 2721, (1932). G.A. Olah, G.K.S. Prakash, J. Sommer in "Superacids", J. Wiley & Sons, (1985). L. Gattermann, J.A. Koch, Chem. Ber., 30, 1622, (1897). M. Tanaka, M. Fujiwara, H. Ando, J. Org. Chem., 60, 2106, (1995). S. Fujiyama, B.E. Patent 887021, (1981), (to Mitsubishi Gas Chem). S. Fujiyama, T. Kasahara, Hydrocarbon Process, 57, 147, (1978). 334
12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.
K. Kudo, N. Sugita, H. Teranishi, Y. Takezaki, Sekign Gakkaishi, 11,690, (1968). L. Weisse, R. Neunteufel, H. Strutz, EP 599148, (1992), (to Hoechst). J.M. Oelderik, A. Kwantes, GB 1 128 966, (1968), (to Shell). M. Tanaka, Y. Souma, J. Chem. Soc. Chem. Comm., 1551, (1991). M. Tanaka, M. Fujiwara, H. Ando, Y. Souma, J. Org. Chem., 58, 3213, (1993). M. Tanaka, J. Iyoda, Y. Souma, J. Org. Chem., 57, 2677, (1992). B.L. Booth, T.A. E1-Fekk~, G.F.M. Moori, J. Chem. Soc., Perkin I, 181, (1980). G.A. Olah, K. Laali, O. Faroqs, J. Org. Chem., 50, 1483, (1985). H.A. Staab, A.P. Datta, Ang. Chem. Int. Ed. Engl., 3, 132, (1964). G.A. Olah, Y.D. Vankar, M. Arvanaghi, J. Sommer, Ang. Chem. Int. Ed. Engl., 18, 614, (1979). G.A. Olah, S.J. Kuhn, J. Am. Chem. Soc., 82, 2380, (1960). A.N. Nesmejanov, E.J. Kahn, Chem. Ber., 67,370, (1934). A.I. Mashentseo, J. Gen. Chem. USSR, 1_.6_,203, (1946). J.S. Lee, J.C. Kim, Y.G. Kim, Applied Catalyst, 57, 1, (1990). C. Rochin, M. Crochemore, S. Ratton, EP 300861, (1988), (to Rh6ne-Poulenc Chimie). R.M. Roberts, J. Org. Chem., 52, 1591, (1987).
335
H I G H S E L E C T I V I T I E S IN HYDROGENATION OF H A L O G E N O N I T R O B E N Z E N E S ON Pd, Pt OR RANEY NICKEL AS CATALYSTS
GEORGES FERRERO
CORDIER,
Rh6ne-Poulenc
JEAN-MICHEL
Industrialisation,
Centre
GROSSELIN
de
AND
Recherche,
ROSE-MARIE
d'Ing6nierie
et
de
Technologie, 24 Avenue Jean Jaur~s, 69153 D6cines-Charpieu Cedex, France.
INTRODUCTION z
X NO2
y NH 2
+ 2 H20 X, Y, Z (CI, Br, F, CF3)
Aromatic haloamines have a wide range of applications in the production of pharmaceuticals and agrochemical substances. The main route to these haloanilines involves reduction from the corresponding nitro compounds either with group VIII metal catalysts and hydrogen or with iron and hydrochloric acid. Most of the time the reduction of halonitroaromatic to the corresponding amine is accompanied by simultaneous dehalogenation which lowers the yield and results in the formation of corrosive halogen acids. At least 2 families of haloanilines can be distinguished. One of these families is included molecules in which the fluorine atom is contained within a CF 3 group bonded to the benzene core. This CF 3 group is insensitive to hydrogenation under operating conditions that are commonly used to reduce the NO2 group in the nitrated precursor. The other family includes molecules containing at least one fluorine atom that is directly bonded to the aromatic core. Sometimes this aromatic core also contains chlorine atoms. These
fluorine and chlorine atoms can be removed under conventional
hydrogenation conditions for the NO2 group, by reaction with hydrogen. 336
Such hydrodehalogenation is often unwanted, but it is sometimes necessary, especially in terms of the chlorine atom when we want to obtain haloanilines from halogenonitrobenzenes. Such hydrodechlorination can occur at the same time as the hydrogenation of the NO2 group with the same catalyst. It can also occur after the hydrogenation of the NO2 group, possibly with a different catalyst.
HYDROGENATION CATALYSTS The literature is filled with various processes and catalyst compositions and systems for these transformations. Promoted platinum and sulfided platinum are the most selective group VIII metal catalysts but depending on reaction conditions and the nature of the halogenonitrobenzene, some undesirable halo-azo and azoxy compounds are left in the product (refs. 3, 11). Catalysts suppliers as Johnson-Mattey (ref. 12), A.G. Degussa (ref. 13) or Heraeus provide special platinum on carbon catalysts at industrial scale. Depending the reaction conditions they claim for these catalysts very high selectivities in halogenoanilines. One other well known catalyst for these hydrogenation is the Raney Nickel catalyst. This catalyst is a very attractive industrial catalyst because of its low cost compared to platinum. However it is also well known to cause extensive dehalogenation during the hydrogenation of halonitroaromatics (ref. 14). Numerous methods have been employed to overcome this problem including modification of the nickel catalyst by adding base (ref. 15) phosphorus (ref. 16), amines (refs. 17, 18) and various sulfided additives (refs. 19, 20). Since the catalytic systems in the literature were not suitable for our application, we tried to develop precious metal or Raney Nickel based catalysts which offer high performance (selectivity, activity and stability) for the hydrogenation of various. In the particular case of Raney Nickel, Rh6ne-Poulenc Chimie has patemed in 1990 Raney Nickel catalysts promoted by iodides (ref. 21) or thiourea (ref. 22).
Some Industrial Hydrogenation Processes One of the most common hydrogenation processes is the batch process in liquide phase with a slurry catalyst ; in a stirred tank reactor (STR) or in a loop reactor as Buss Loop for example.
337
This process decreases hydrodehalogenation especially on the chlorine atom which is one of the most removal. It increases heavy products formed by coupling reactions on intermediaries of hydrogenation and favours by-products coming from nucleophilic substitution on the aromatic fluorine atom. One other process is to proceed by nitro-compound injection at the same rate it is consumed. So there is no accumulation of intermediaries in solution. This process is also carried out in liquid phase with slurry catalyst in STR or loop reactors. It favours hydrodehalogenation and absolutely needs an adapted and selective catalyst.
It decreases heavy products
and especially suppresses
HF
formation coming from nucleophilic substitution on the aromatic fluorine atom.
Some results at Laboratory and Industrial scale The results given as examples in this paper have been obtained by the way of injection pressure as indicated previously. We
selected
five of the current
halogenonitrobenzenes
which
give very
representative pictures in selectivities and activities regarding the type of catalyst involved in hydrogenation. Table 1 gives the results obtained with 0.5 % Pd / A1203 and Table 2 with 0.4 g of 0.5 % Pt / A120 3. Table 1. Hydrogenation of halogenonitrobenzenes over 0.5 % Pd / A1203
Nitro compounds
1 ~mp. ~
4-CNB
353
Injection Yield % rate mole h-1 g-~ chlorides (catalyst) 1.2
4-FNB
373
1.25
3-C-4-FNB
333
0.55
1.05
13.5
3,5-DCNB
353
0.95
9.5
= = = =
0.12
Aniline 90.12 %
7
4-Fluoroaniline " 13 % 4-Chloroaniline 95 % Aniline" 6 % 4-Chloroaniline 911% 3-Chloroaniline 2.5 % 3-Chloroaniline 7.5 % Aniline 910 %
Aniline" 13 %
19
353
CNB DCNB FNB C-FNB
Other by-products
13
3,4-DCNB
Yield % in wanted halogeno aniline
Yield % fluorides
chloronitrobenzene dichloronitrobenzene fluoronitrobenzene chlorofluoronitrobenzene 338
,,,
-~ 85 99,8 ~75 i
85 85
Table 2. Hydrogenation of halogenonitrobenzenes over 0.5 % Pt / A1203 Injection Yield rate -1 % mole h -1 g C1(catalyst)
% F-
Other by-products
1.9
-
0.05
Aniline: 1.9 %
= 98
-
< 0.05
-
Aniline : traces
< 99,9
0.20
0.5
0
0.087
4-Fluoraniline : 0 . 5 %
= 99,4
353
0.26
0.75
-
0.12
4-Chloroaniline : 0.7 %
= 99.0
373
0.32
1.8
-
0.032
4-Chloroaniline : 1.4 %
= 98
Temp. (~
4-CNB
373
0.37
4-FNB
373
0.35
3-C 4-FNB
353
3,4-DCNB
Yield
Yield % in wanted halogeno aniline
Yield % Azo + Azoxy
Nitro compounds
Aniline : 0 . 2 % 3,5-DCNB
353
0.22
0.4
0.08
3-Chloroaniline : 0.4 %
= 99.5
375
0.31
0.5
0.035
3-Chloroaniline : 0.4 %
= 99.5
Hydrogenation on Raney Nickel W i t h R a n e y N i c k e l catalyst we p e r f o r m e d the h y d r o g e n a t i o n s first w i t h o u t and t h e n with selectivity p r o m o t e r s .
Hydrogenation on Raney Nickel without promoters At
preselected
injection
rates
of
the
halogenonitrobenzene
as
described
p r e v i o u s l y we c o m p a r e d the activity and selectivity for e a c h h a l o g e n o n i t r o b e n z e n e at 353 ~
T h e r e s u l t s w e r e as follows.
9 R E A C T I O N R A T E ( m o l e h -1 g-1 Ni) 3,5-DCNB
...........
3,4-DCNB 3-C-4-FNB
t .......... 0.18
t ............... 0.23
4-CNB
t ..........................
t ........
0.4
* TOTAL HYDRODEHALOGENATION 4-FNB 3,5-DCNB 3,4-DCNB
4-FNB
"-
0.7 Y I E L D (%) 3-C-4-FNB
4-CNB
-t ........... t .......... t ............. t .......................... 3 8 10 14
339
t ........ 21
H y d r o g e n a t i o n on Raney Nickel with promoters A calculated and optimized quantity of selectivity p r o m o t e r was added to the catalyst and solvent mixture before the halogenonitrobenzene was injected to obtain the best c o m p r o m i s e b e t w e e n reaction rate and selectivity because all the p r o m o t e r s tested partially deactivated the catalyst. Table 3 shows the comparative results obtained with 3,4-dichloronitrobenzene in the p r e s e n c e o f the previously k n o w n promoters (Na2S, thiophene, cyanoguanidine) and our n e w one, thiourea. Table 3. Effect of promoters on the hydrogenation of 3,4-dichloronitrobenzene Promoter
(P)
Catalyst
Yield % CI
g/1
Injection rate mole h -1 g-1 (catalyst)
(P)
g/1
Yield % mzo + Azoxy
Temp.
Pres.
~
bar
Yield % in wanted halogenoaniline
Cyanoguanidine
3.0
20
0.18
0.7
< 0.001
353
20
~ 99.3
Thiophene
0.3
20
0.18
3.5
< 0.001
353
20
~ 96.5
Na2S- 9 H20 Thiourea
3.3 1.0
20 20
0.18 0.18
0.4 0.4
< 0.001 < 0.001
353 353
20 20
= 99.5 ~ 99.5
??????????? as p r o m o t e r in halogenonitrobenzene hydrogenation. Table 4. Effect of thiourea on the hydrogenation of halogenonitrobenzenes over Raney Nickel Nitro compound
4-CNB 4-FNB 3-C-4-FNB 3,4-DCNB 3,5-DCNB
T
P
Thiourea Catalyst
~
bar
g/1
g/1
Injection rate mole h -1 g-1 (catalyst)
353 373 353 353 353
20 20 20 20 20
1.0 1.13 3.30 1.0 1.0
20 20 20 20 20
0.28 0.45 0.13 0.20 0.16
Yield % C1or F-
Yield Yield % % Azo + in wanted Azoxy halogenoaniline
_<0.001 0.6 < 0.05 0.7 0.4 0.25
= 99.4 ~100 = 99.3 ~ 99.4 = 99.7
Finally Table 5 shows that in the hydrogenation o f 3,4-dichloronitrobenzene o v e r R a n e y Nickel catalyst p r o m o t e d by thiourea, the catalyst may be recycled m a n y times without loss of activity or selectivity.
340
Table 5. Recycle of Raney Nickel promoted with thiourea in the hydrogenation of 3,4dichloronitrobenzene Cycle Number
1 2 3 4
T
P
~
bar
353 353 353 353
20 20 20 20
Injection rate moleh-~ g-1 (catalyst)
Yield % C1-
Yield % Azo + Azoxy
0.20 0.20 0.20 0.20
0.4 0.6 0.6 0.6
< 0.001 < 0.001 < 0.001 < 0.001
Sulphur Yield % in solution in 3,4-dichloro(ppm) aniline 13 8 8 8
99.5 99.4 99.4 -~ 99.4
DISCUSSION In all cases the most selective catalyst was Raney Nickel doped with thiourea which gave a hydrogenation selectivity up to 99 % without forming azo and azoxy compounds (_< 10 ppm). The thiourea to Raney Nickel ratio must be selected for each halogenonitrobenzene since each one was affected differently by this change in ratio. In all cases an increase in this ratio decreased the hydrogenation rate but also decreased the hydrodehalogenation side-reaction rate, but to different degrees for each substrate. Another important benefit of the promoter, thiourea, is that the Raney Nickel may be recycled many times without appreciable loss of either activity or selectivity. This was amply demonstrated on hydrogenation of 3,4-dichloronitrobenzene where 300 kg of the nitro compound was hydrogenated per kg of catalyst without loss of activity or selectivity.
CONCLUSIONS A new selectivity promoter, thiourea is efficient, for selective hydrogenation of halogenonitrobenzenes on Raney Nickel. This promoter stays on the catalyst which can be reused without loss of activity or selectivity. The activity of the thiourea doped Raney Nickel catalyst is good enough (0.1 - 0.5 x 103 mole h -1 kg -1 of catalyst, depending on the halogenonitrobenzene) for an industrial application. The 0.5 % Pt / A1203 catalyst is also a good catalyst for selective hydrogenation processes (more than 98.5 %) but it generates azo and azoxy compounds. With 3,4-dichloronitrobenzene the yield of these compounds can be reduced from 0.12 % to 0.03 % by increasing the temperature from 353 to 373 ~
This, however is done
at the cost of higher hydrodehalogenation, 1.8 % rather than 0.75 % at the lower 341
temperature. In the special case of 4-fluoronitrobenzene hydrogenation, the 0.5 % P d / A120 3 is the recommended catalyst on the basis of its selectivity, activity and high
productivity
and
stability.
This
catalyst can be
used
successfully
in
hydrogenation of 2-FNB or 2,4-DFNB. It gives selectivities close to 99.9 % wanted fluoroanilines and the productivity remaines very high. Like the 0.5 % Pt / A120 3, it is very easy to continuously separate from the liquid phase without loss of fine particles of catalyst and metal. From an industrial point of view Raney Nickel promoted by thiourea or by iodides is a very attractive catalyst especially in the hydrogenation of halogenonitrobenzenes containing chlorine atoms. This catalyst can works in batch or in continuous process in STR or loop reactors. In the case of the hydrogenation of fluoronitrobenzenes Pd catalysts are good catalyst. P d / A 1 2 0 3 catalyst is a very suitable catalyst but P d / C
can also work. The
choice depend only on the type of used process.
References .
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.
US 4 140 719, (1979), (to Merck). US 5 294 742, (1995), (to Hoechst). US 3 067 253, (1962), (to Dow Chemical). GB 1 498 722, (1978), (to ICI). JP 49 728, (1973), (to Mitsui Toastsu Kagaku). F.S. Dovell, H. Greenfield, J. Am. Chem. Soc., 2767, (1965). H. Greenfield, Ann. N.Y. Acad. Sci., 145, 108, (1967). EP 307 777, (1987), (to Bayer). EP 347 796, (1988), (to Hoechst). DE 3 811 919, (1988), (to Hoechst). US 5 068 436, (1991), (to Dupont de Nemours). F. King, Perf. Chem., 19, (1988). A. Str~itz, O.R.C.S., (1984). FR 2 245 615, (1974), (to Nippon Kayaku). GB 1 191 610, (1970), (to Bayer). H.C. Yao, P.H. Emett, J. Am. Chem. Soc., 84, 1086, (1962). H.D. Burge, D.J. Collins, B.H. Davis, Ind. Eng. Chem. Prod. Res. Dev., 19, 389, (1980). J. Wisniak, M. Klein, Ind. Eng. Chem. Prod. Res. Dev., 23, 44, (1984). V.I. Savchenko, T.V. Denisenko, S.Y. Sklyar, V.D. Simonov, Zh. Org. Khim., 11, 2149, (1975). FR 1 600 519, (1970), (to Bayer). FR 2 649 978 (1989), (to Rh6ne-Poulenc). FR 2 649 979, (1989), (to Rh6ne-Poulenc).
342
INFLUENCE OF THE CATION IN CONDENSATION OF GLYOXYLIC ACID ON PHENOLS IN AQUEOUS HYDROXIDE SOLUTION
MARIE-FRANCE WUTHRICK AND CHRISTIAN MALIVERNEY Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie - 85 avenue des Fr~res Perret- BP 62 - 69192 Saint-Fons Cedex France.
INTRODUCTION Hydroxy and alkoxy aromatic aldehydes are very important products, used primarily as flavors and fragrances, secondly as intermediates in the manufacture of agrochemicals, pharmaceuticals, cosmetics and in the electroplating industry, etc (ref. 1). Ortho and para hydroxybenzaldehydes, vanillin, ethyl vanillin, protocatechualdehyde, veratraldehyde and piperonal are the most important products. Different processes are proposed for the synthesis of aromatic aldehydes but only very few are satisfactory for industrial applications. The main processes for the manufacture of hydroxybenzaldehydes are based on the functionalisation of phenol, catechol and catechol derivatives (guaiacol, guetol .... ). Ortho substitutions can be specific, as in the condensation of phenyl metaborate with formaldehyde to give salicylaldehyde after catalytic oxidation of intermediate saligenin (ref. 2), but generally, condensations with carbon electrophilic reagents give mixtures of ortho and para isomers (ref. 3). The more interesting challenge is the regiospecific preparation of para substitution products for the manufacture of 4-hydroxybenzaldehyde, vanillin and ethyl vanillin. One of the classical methods is the condensation of a phenol with glyoxylic acid in basic media to give substituted mandelic acids as intermediates. The corresponding 343
aromatic aldehydes are obtained decarboxylation (ref. 4) (Fig. 1).
after
OH
homogeneous
catalytic
ONa
OH 02,
COOH
oxidative
cata
H20, OH"
NaOH OH
CHO
R = H, OMe, OEt COONa
Fig. 1.
Preparationof hydroxybenzaldehydesfrom phenols and glyoxylic acid.
The base usually used for the condensation between phenols and glyoxylic acid is sodium hydroxide. The reaction is selective for the para position, but the 2- and 4-hydroxymandelic acids produced are more reactive than the phenols, and the consecutive reaction is the formation of dimandelic acid (Fig. 2). OH
R O ~
+
CHOI
NaOH
COOH
H20
R = Me, Et
OH
OH
I
COOH
OH
I R O ~ o H
RO, +
RO
~
COOH OH
+
OOH "para . Fig. 2 .
.
.
.
ortho .
.
.
.
di"
Condensationbetween phenols and glyoxylic acid in basic media
To minimize dimandelic acid formation, the phenol is used in excess, generally two or more equivalents. Results are listed in Table 1 (ref. 5).
344
Table 1. Results for the condensation between 2-alkoxyphenols and glyoxylic acid (GA) in aqueous sodium hydroxide.
ArOH
molar ratio
Conv.
NaOH/(ArOH +GA) ArOH % guaiacol
0.95
47.5
Yield (/GA) %
Selectivity (/ArOH) %
para
ortho
di
para
ortho
di
84.2
5.2
8.7
86.5
5.3
9.5
molar ratio ArOH/glyoxylic acid (GA) = 2 9[H20 ] p/p = 82 % 935~ - 4 hours
Our goal was to increase the chemical yield and selectivity into the para mandelic acid.
T H E P A R A S E L E C T I V I T Y O F THE CONDENSATION Different parameters such as temperature, pH and the conversion of guaiacol have no effect upon paraselectivity. We thought that changing
the nature of the
base, in particular the steric hindrance generated by the cation around the phenol function, could increase the paraselectivity, even in aqueous solution, as proposed by the Japanese company UBE, with cyclodextrins (ref. 6). Unfortunately, no increase of paraselectivity has been observed ! In the same way, the replacement of sodium hydroxide by potassium hydroxide leads to bad results (ref. 7), especially because consumption of glyoxylic acid by the Cannizzaro dismutation (ref. 8). Normally, however, we can expect the paraselectivity to be improved when the size of the cation is increased. The literature mentions at least three cases 9 the Kolbe reaction (ref. 9), the Reimer-Tiemann reaction (ref. 10) and the hydroxymethylation of phenols in alcoholic media (ref. 11), where with hydroxide anion the para/ortho ratio is increased following the series of the cations N a + K + < Cs + < R4 N + .
345
<
Finally, we have discovered that the use of a tetra-alkylammonium hydroxide dramatically increases the paraselectivity of the reaction in aqueous media. Our initial results are listed in Table 2 (ref. 12).
Table 2. Increase of paraselectivity by the use of tetra-alkylammonium hydroxides. a)
conversion
cation (M +)
guaiacol %
para
ortho
di
47.5
86.5
5.3
4.5
NMe 4
38.5
96.0
2.7
1.0
NEt4
49.0
95.4
2.5
1.2
NPr4
40.0
95.6
3.3
1.1
NBu 4
21.3
95.9
3.0
1.1
NMe3Bz
33.0
95.0
3.9
1.0
Na b)
selectivity
(/guaiacol) %
a) MOH/(guaiacol +GA) = 1 , except for b) 90.95 " guaiacol/GA = 2 9 35 ~
93 h (except for b) " 4 h).
Differences in conversion are explained in certain cases by the heterogeneity of the mixture. Tetraethylammonium hydroxide was used for all of the following experiments. To have the best process using tetraethylammonium hydroxide, we have searched for those parameters giving the best yield and lowest price combined " influence of the quantity of base, guaiacol/glyoxylic acid ratio, concentration ....
INFLUENCE OF RATIO OF TETRAETHYLAMMONIUM HYDROXIDE Firstly, the amount of hydroxide (molar ratio Et4NOH/(guaiacol + G A ) ) has an influence on the rate of reaction : after four hours at 35~
conversion is at a
maximum for ratios between 0.75 and 0.9. To either side of this range (0.7 and 0.96), some glyoxylic acid remains and the corresponding yields are lower. If the reaction is continued, these increase negligably. 346
The yields increase regularly from ratio 0.7 to ratio 0.855 decreasing thereafter. The paraselectivity increases in the same way, from ratio 0.7 (93 %) to ratio 0.96 (97.2 %). T h e results of these experiments are listed in Table 3 and Figure 3. Table 3. Influence of molar ratio of tetraethylammonium hydroxide
Yield (/GA) %
Selectivity (/guaiacol) %
Et4NOH/
conv. %
guaia +GA
guaiacol
para
ortho
di
E
para
ortho
di
E
0.7
47.4
88.2
4.8
3.4
96.4
93.0
5.1
1.8
99.9
0.75
49.3
92.5
4.4
3.2
100.0
93.8
4.5
1.6
99.9
0.8
49.5
94.0
4.0
3.2
101.2
95.0
4.0
1.6
100.6
0.855
50.0
96.0
3.6
2.8
102.4
96.0
3.6
1.4
101.0
0.9
49.0
94.5
3.1
2.5
100.1
96.4
3.2
1.3
100.9
0.96
48.2
93.7
2.7
2.1
98.5
97.2
2.8
1.1
101.1
molar ratio guaiacol/glyoxylic acid = 2 935 ~
94 hours
95
85 --
Conversion
A
yield of para
of guaiacol
-
selectivity of para
75
65
55
§
45 0.7
0.75
0.8
0.86
0.9
0.96
ratio Et4NOH
Fig. 3. Conversion, yield and selectivity functions of molar ratio of hydroxide
347
INFLUENCE OF CONCENTRATION GLYOXYLIC ACID
AND M O L A R R A T I O G U A I A C O L /
Neutralisation of guaiacol with sodium hydroxide results in a guaiacol-sodium guaiacolate complex of which the solubility depends on temperature and dilution. To carry out the condensation with glyoxylic acid, it is necessary to have an homogeneous mixture. The temperature can be raised, but due to the Cannizzaro reaction of glyoxylic acid, it is economically decreases with dilution.
uninteresting, and productivity
If the analogous complex with tetraethylammonium hydroxide exists, it is completely soluble in all cases, and it is possible to increase productivity by increasing the concentration. Glyoxylic acid and quaternary ammonium hydroxide are sold in aqueous solution, at 50 % and 40 % weight respectively. To increase the concentration, the only possibility is to reduce the quantity of water initially mixed with guaiacol. Usually, for the process using sodium hydroxide, the initial mixture is composed of 1.25 mole of guaiacol per litre of distilled water (,~ Co >, = 1.25 mol/1). If the initial volume of water is divised by four (--> ,, Co ~> = 5 tool/l), the volume of the final mixture is reduced by one third. In
the
Table
4
are
listed
results
obtained
with
a
molar
ratio
Et4NOH/(guaiacol + G A ) = 0.855 after four hours at 35~
Table 4 . Influence of excess of guaiacol and concentration
guaiacol
yield (/GA) %
,, Co ,, conv.* %
/ GA
Selectivity (/guaiacol) %
guaiacol
para
ortho
di
E
para
ortho
di
E
2.5
5
98.2
96.0
3.6
2.4
102
97.7
3.7
1.2
102.6
2
1.25
100.0
96.0
3.9
3.0
103
96.0
3.9
1.5
101.0
1.75
5
98.1
93.0
3.2
3.5
99.7
95.4
3.2
1.8
100.0
1.5
2.5
96.8
91.3
3.2
4.4
98.9
94.4
3.2
2.3
99.9
,, Co ,, = number of moles of guaiacol / volume of water conv.* = observed conversion of guaiacol/theoretical maximum conversion and theoretical maximum conversion = 100 x molar ratio GA/guaiacol 348
CONCLUSION We have discovered that the use of tetra-alkylammonium hydroxide in place of sodium hydroxide increases dramatically the paraselectivity of the condensation between guaiacol and glyoxylic acid in aqueous media. The other advantages are the possibility to increase the productivity, increasing initial concentration, with a lower ratio of base. The new conditions for condensation can be used for other 2 alloxyphenols for example 2 ethoxyphenol.
References C. Maliverney, M. Mulhauser, "Hydroxybenzaldehydes" in Encyclopedia of Chemical Technology 4th ed., Vol.13, pp.1030-1042, John Wiley, New-York, (1994). 2. a) J. Le Ludec, DE 2,612,844, (1976), (to Rhbne-Poulenc). b) P.A.R. Marchand, J.B. Grenet, US 3,321,526, (1967), (to Rh6ne-Poulenc). 3. H. Wynberg, Chem. Rev., 60, 169 (1960). 4. P. Maggioni, F. Minisci, BE 85,993, (1979), (to Brichima S.P.A.). 5. I. Jouve, Internal Report. 6. T. Huemura, JP 54,061,142, (1979), (to UBE). 7. D. Nobel, Internal Report. 8. E.R. Alexander, J. Am. Chem. Soc., 69, 289 (1947). 9. A.S. Lindsey and H. Jeskey, Chem. Rev., 57,588 (1957). 10. H. Wynberg, Org. React. 28, 1-36 (1982). 11. H. Iwane, T. Sugawara, EP 485,613, (1990), (to Mitsubishi Petrochem)~ 12. a) D. Nobel, FR 92-08,578, (1992), (to Rhbne-Poulenc Chimie). b) C. Malivemey, Internal Report. 1.
349
SELECTIVE ACCESS TO HYDROQUINONE 9,, FUCHSONE ,, ROUTE
MICHEL COSTANTINI* DANIEL MANAUT a)
a)
ERIC FACHE
a)
DANIEL MICHELET
b)
AND
a) Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie, 85 Avenue des Fr~res Perret, B.P. 62, 69192 Saint-Fons Cedex, France. b) Rh6ne-Poulenc, Direction Scientifique, 25 Quai Paul Doumer, 92400 Courbevoie, France.
INTRODUCTION Hydroquinone (HQ, 4-hydroxyphenol) and catechol (PC, 2-hydroxyphenol or pyrocatechol) are industrially prepared using the following process paths 9 i) selective access to HQ by aniline oxidation using manganese dioxide in sulphuric medium (ref. 1) (Fig. 1).Yields are high, but the process suffers from the stoichiometric co-production of mineral salts [MnSO4, (NH4)2SO4,...) which is the cause of serious environmental problems : O 2 ~ N H 2
+ (NH4)2SO4 + 4 MnSO4 + 4 H20
+ MrlO2 + 5 H2SO4
o
O H2
2HQ
0 Fig. 1. Synthesis of HQ the from aniline
350
ii) selective access of HQ through autoxidation of p. diisopropylbenzene in corresponding dihydroperoxide, which is then converted in HQ and acetone through a acid catalysis (ref. 2) (Fig. 2). This is a complex process involving a very high conversion of diisopropylbenzene and co-production of corresponding hydroxyhydroperoxide and dicarbinol which compels the acid scission to be performed in the presence of hydrogen peroxide in order to convert these products to H Q : OH
O2 ~ HOO)
~
+2)=0
( OOH -''H+-~"2 OH
Fig. 2. Synthesis of HQ from diisopropylbenzene iii) Simultaneous access to HQ and PC through phenol hydroxylation by hydrogen peroxide in the presence of either a homogeneous or heterogeneous catalyst (Fig. 3). This process has been studied in more depth than other processes. It was the incentive for setting up the most recent and highest performance industrial plants. on
OH
+ H202
catalyst
~
OH
+
~,OH
+ H20
OH Fig. 3. Hydroxylationof phenol by hydrogen peroxide
Heterogeneous catalysis : The best known catalyst is titanium silicate - (TS-1) a synthetic zeolite of ZSM family which does not contain any aluminium and in which titanium atoms replace some silicium atoms within the crystal lattice (Ti/Si= 5 %) (ref. 3). A process based on this catalysis is used in Italy (ref. 4). Although its performance levels are good, and the HQ/PC ratio can be modified (ref. 5) the high cost of the catalyst and its uncertain lifetime are the major handicaps preventing its extension.
351
Homogeneous catalysis :
The old ,, Fenton ,, process (hydroxylation carried out
in aqueous medium with catalysis by Fe : yield <
60 % with formation of
resorcinol, difficult to separate from HQ) is not used any more. The discovery by Rh6ne-Poulenc of phenol hydroxylation by hydrogen peroxide catalysed by strong acids (perchloric, triflic, sulphuric acids) was a decisive contribution to the HQ and PC synthesis, as it avoids the drawbacks of the former processes (ref. 6). This hydroxylation is performed by simple contact of hydrogen peroxide with phenol in the presence of a strong mineral acid (AH) acting as catalyst. The acido-basic process of the reaction is schematized in Figure 4 :
A-H
+ H202
-..
"-
A-H
... H 2 0 2
-..
"-
... H 3 0 2 +
~
OH
H302 + +
A"
--,
"-
A'+
H302 +
OH
PHENOL - H20
H
H OH
+ A ~
A H + H Q + PC
(A)
Fig. 4. Hydroxylation of phenol by hydrogen peroxide catalysed by acids By-products (polyhydroxylated polyphenyls) are formed by addition of phenol and, most of all, of diphenols to the carbocations (A). So phenol conversion must be limited to approximately 5 % in order to obtain acceptable yields of ,, diphenols ,~ (HQ + PC)(80-85 %/H202 and 90 %/phenol). Since Rh6ne-Poulenc's process produces HQ and PC simultaneously, if must be very flexible in relation to the para/ortho isomeric ratio, to meet market needs. A major industrial objective is to acquire complete control of this ratio. Concerning this ratio, it should be noted that : 1. The HQ/PC ratio increases with the strength of the catalyst acid. Table 1. HQ / PC ratio versus strengh of acid catalyst ACIDS
pKa *
Ar SO3H
-- 0.7
HQ/PC
t ~/~ (min)
79 %
0.44
10
RT /
H202
H2SO 4
-"
1
80 %
0.50
10
HC10 4
< -1
85 %
0.70
3
352
RT = selectivity versus consumed product.
* in H 2 0
The weaker the AH acid is, the more it can be found in form of (A-, H § ion pairs linked to phenolic hydrogen and thus facilitating, under the action of H202, the ortho hydroxylation (Fig. 5).
OH
O / H ....A',
O/H ....A', H+
3o2.
A,n+ + { ~ OH ~
~ ~ J l fOlH + AH + H20
Fig. 5. Orthohydroxylation of phenol by hydrogen peroxide in the presence of a ,, weak acid ,~ This effect is still limited and insufficient to meet variations in requirements. 2. As apposed
to this,
co-catalysis by benzophenone
- as well as by all
benzophenones with electro-donating groups - noticeably increases HQ selectivity (ref. 7). This para-directing effect is notably reinforced by polar aprotic solvents with basicity less than that of benzophenone
co-catalyst (nitriles,
sulfolane,
propylene carbonate...) (ref. 8). Table 2. Hydroxylation of phenol by hydrogen peroxide, catalysed by acids. Effect of the use of ketones as co-catalysts. Effect of solvents. ketones (100 % / H:O2 max)
solvents (25 % / phenol max)
without benzophenone benzophenone benzophenone
without without CH3CN propylene carbonate without CH3CN
acetophenone acetophenone
Selectivity RT H202
Ratio HQ/PC
t 1/2 (min)
85 85 85 85
0.7 1.0 1.2 1.3
3 1 -
85 85
0.7 0.7
<< 1 -
Remark " Acetophenone has a very important kinetic effect without modifying the HO/PC ratio _
Study of the mechanism of this co-catalysis by benzophenones has shown (not published works) that the process involves hemipercetal ! most probably leading to 353
dioxiranne 2 which is a very reactive and paraselective entity by steric bulking of the two aryl groups (Fig. 6).
Ar
\
Ar C=O + H+ --'
"-
~2+OH
+ H20, Ar OH \/ -~"~ C Ar/ 'O--OH
+
H+
-H o
Ar ~
\ /i
O
oI 2_ - H+ I + PhOH HQ + Ar2C=O
Fig. 6. Hydroxylation of phenol by hydrogen peroxide catalysed by acids. Mechanism of co-catalysis by benzophenones A
relatively
high
HQ
paraselectivity
is
obtained
(HQ/PC = 1.2-1.3).
Unfortunately, sometimes it is not enough, which is why we conducted research to find a process that was more selective in terms of hydroquinone. 3. By heating
a phenol / benzophenone / CF3SO3H mixture (2 / 1 / 0.5
ratio, T = 70~
At = 19 hr) we isolated compound 3 ,< fuchsone ,,.
C--O +
/
CF3SO3H
molar
(filchsone) + H20
(conversion= 26 %)
0 /
(1)
(yield= 26 %)
The absence of any 'ortho'compound is of note. This means that it is a paraselective
condensation
(which
is
also
quantitative
relative
to
reactive
compounds). In addition, from a sample of fuchsone synthesized from Ar2CC12/Phenol (ref. 9), we have demonstrated that in the presence of the stoichiometry of hydrogen peroxide and traces of a strong acid, this fuchsone 3 quantitatively leads to HQ and benzophenone (which is then regenerated) 9
354
A r 2 C ~ O
+ H202
g HC104
~ Ar2C-O + HO
OH
(2)
CH3CN 3_ Thus, equations (1) and (2) show that it is possible to access HQ selectively from phenol/H202 'via' fuchsone (ref. 10) in two stages. One can conceive the possibility of significantly increasing the HQ selectivity of a diphenols industrial unit - either by introducing the required quantity of fuchsone to the hydroxylation medium, or by reacting fuchsone with H202, and then sending the formed HQ and benzophenone to the distillation part of the unit.
FUCHSONE SYNTHESIS Selection of acid catalyst Besides triflic acid, other acids may also be considered initially. Table 3 shows performances obtained with other acids (Bronsted and Lewis as well as heterogeneous solid acids) in arbitrary and non-optimized conditions.
355
Table 3 Entry
Benzophenone (mmol)
Acids (mmol)
1 2 3 4 5 6 7 8 9 10 11 12
100 100 100 100 200 100 100 100 100 100 100 100
HBr (14) HC1 (gas) HC104 (50) H4P207 (50) HF (4000) NAFION (50) US-Y K.O. AIC13 (50) TiC14 (50) ZnC12 (50) ZnC12 (50)
20 20 20
CFsSO3H (10) CFsCOOH (80) CHsSO3H (40)
I
13 14 15
0 (~
AT (h.)
75 75 70 150 80 145 150 150 80 80 140 140
23 5 28 3 3 1 5 2 4 3 18 22
Conversion Yield (Benzophenone) (Fuchsone) 12 0 ---1 36 9.5 --2 --1 16 6.5 0.5 0
--1 31 8 ---2 --1 9 1
23 23
22 traces 22
I
80 80 110
Phenol = 200 mmol for all the experiments, except emry 3 (300 mmol). Only the strong acids are active. On account of their performances and easy use sulphonic acids seem to be the best compounds for these catalysis fuchsone formation (CH 3 SO3H , Ar SO3H, p. CH 3 Ar SO3H ...). But a study was also conducted on some solid catalysts that are easy to recycle : sulphonic resins, zeolites, clays...
Synthesis in h o m o g e n e o u s liquid phase Kinetic approach
9 Our objective was merely to determine the main factors
governing the reaction (never to establish a quantitative and complete kinetic model). Kinetic measurements
were conducted at constant volume
(co-solvent
=
p. xylene) and with CF3-SO3 H as catalyst. It was observed that the rate of the phenol/benzophenone condensation is 9
V=k
[phenol] [acid] [benzoquinone] [Fuschsone] [H20]
356
Influenc~ of thiols 9 the presence of thiols enables great increase the catalytic activity to be achieved (initial rate multiplied by approximatively 10 for 20 nd % of thiol benzophenone), and to rapidly reach very high conversions of benzophenone (Table 4). -
Table 4
THIOL
At
Conversion TT (ArCOAr)
Yield RR (FUCHSONE)
without
0hr30 lhr 2hr 3hr 4hr
5.6 6.4 8 12 15.2
5.6 6.4 8 12 14
with
0hr30 lhr 2hr 3hr 4hr
34 42 53.5 59.6 62
30.5 38 49 53.5 57.5 .....
PHENOL / BENZOPHENONE / Ar SO3H / Ar2CH2SH = 10 / 1 / 2 / 0 or 0.1 in.moles
Kinetic plots are shown in Diagram 1. With C F 3 S O 3 H , the effect is even more marked with a total conversion of benzophenone within one hour, and almost complete selectivity in Fuchsone. / 70 60 50-40-30-20-10-0
\ TT (Ar2C=O)
OH
Diagram 1.
I
I
I
I
1H
2H
3H
4H
1. experiment 17 with thiol 2. experiment 16 without thiol
357
f
Time (R)
This kinetic effect is virtually independent of the use of a thiol, (except in the case of bulky aromatic or heterocyclic thiols and dithiols liable to form cyclic sulphurs or disulphurs). Remark : the azeotropic elimination of the formed H20 (by a co-solvent such as toluene) is another way of increasing the rate, but the kinetic gain obtained remains very small, without any great increase in benzophenone conversion. - By-products
9
Under
good
condensation
conditions
(e.g.
9
PhOH / Ph2C = O / CH3SO3H = 10 / 1 / 8 in moles, 110~ the only visible byproduct is the biphenol p, p'-Ar2C (ArOH) 2 obtained with a yield of less than to 1%. At higher temperatures (190~ a mixture of PhCH2Ph, Ph3CH, and probably also 4 are identified - identification by NMR and/or mass spectrometry- all these products are in trace amounts, and the preceeding biphenol still remains the main by-product.
~~==O These
compounds,
when treated
with H202, do not generate to HQ
or
benzophenone. -Fuchsone and Carbinol : Fuchsone 3 extracted from its synthesis medium (treatment with H20 and organic solvent such as AcOEt - separation and washing of the organic phase - elimination of AcOEt) is in fact a mixture of fuchsone (60 %) and the corresponding carbinol fi (40 %).
ArzC~O
+ H20
)H "- A r 2 C ~ O H
3_
5__
Pure fuchsone can be obtained by means of simple azeotropic dehydration (in boiling p-xylene). Recrystallisation is performed with n-hexane (P.F = 144 ~ C, NMR purity > 95 %). Pure carbinol can also be synthesized simply by performing complete hydration of the fuchsone - carbinol mixture in the presence of H20 / AcOEt/ H3PO4 with extraction and recrystallisation (PF = 180~
358
NMR purity = 100 %).
Fuchsone, as used throughout this document, refers to the mixture of fuchsone and carbinol. Optimization Table 5 below shows balances of all the experiments conducted to perform optimizations of the synthesis of fuchsone. Table 5 Reactive agents E n t r y . equiv, amounts Ph2CO THIOL 18
1
T~ of reaction
0.2
110
Yields h
Yields
TT RR RT Ph.CO Fuchsone Fuchsone
4
99.2
84.6
85.3
h
TT RR Ph.CO Fuchsone
.
.
.
RT Fuchsone
.
19
1
0.2
80
4
96.4
75.8
78.6
5
97.6
79.6
20
1
0.05
80
4
80
75
93.8
7
88.7
86
97
21
1
0.05
110
4
91
86.3
94.8
6
94.3
93.3
98.9
22
1
0
110
4
47
46.3
98.5
6
58
55.3
95.3
1
0.05
140
4
95
88
92.6
.
.
24
1.5
0.05
110
5
76.9
76
98.8
7
80.7
78.4
97.2
25
1
0.005
110
4
65.7
65
98.9
7
75
72.7
96.9
1
0.2
110
4
99
83.7
84.5
.
27
0.5
0
110
4
56.6
55.3
97.7
7
74
70.7
28
1
0
140
5
84.8
73
86.1
7
89.7
77.8
86.7
29
1
0
110
4
45.2
43.7
96.6
7
60.5
57.8
95.5
1
0
110
4
43.6
41.3
94.8
7
59
58.7
99.4 98.9
23
26
i
i
i
I
30*
.
.
81.6
.
.
. 95.5
2
0
110
4
34
33.5
98.5
7
44
43.5
32
2
0.005
110
4
41
40.5
98.8
7
50
50
100
33
2
0.05
110
4
59.5
58
97.5
7
66.5
65
97.7
34
2
0.1
110
4
67
64.5
96.3
7
74.5
67.5
90.6
35
3
0
110
4
22.3
22.3
100
7
30
30
100
31
i
Phenol = 10 equivalent amounts - CHaSO3H = 8 equivalent amounts T T = c o n v e r s i o n - R R = yields - R T - s e l e c t i v i t i e s * Recycling o f methasulfonic acid (trial 29)
Most of the time it appears that on one hand the selectivity of fuchsone decreases as the temperature rises, and on the other hand that the thiol concentration can be greatly reduced whilst retaining a marked kinetic effect and high selectivity (entries 20-21). But, strong acid can never be a catalyst in the real sense of the term, as observed
throughout
the
preceeding
experiments. 359
We
will
see
that
it is
stoichiometrically consumed to form a stable salt with the fuchsone, and it will become a catalyst only after the hydrolysing action of this salt releases fuchsone and acid (which can then be recycled). Synthesis mechanism for fuchsone " All the above experiments confirm the following process 9 Ar2C=O + R--SO3H --..
Ar2C+__OH,-O3S_R _..
"- Ar2C+OH + O3S--R (3)
2 'S OH OH
Ar2C+--OH + ArOH O3S--R
"O3S--R OH Ar2C
OH + R--SO3H
Ar2C~OH,-O3S--R
Ar2C
~ ....... ~
OH Ar2C
OH (4) + RSO3H
w-- A r 2 C ~ O H ,
A r 2 C @ O
OH +nH20 I ~ OH,O3S--R .,t-~ Ar2C
"O3S--R + H20 (5)
+ R--SO3H
(6)
OH + R--SO3H (7)
A r 2 C ~ O
Carbocation which results from protonation of benzophenone (eqn. 3) is paraselectively added to phenol (this paraselectivity results from the steric hindrance created by the two nuclei attached to the same carbon atom) to give carbinol (reaction 4). Carbinol under the action of a strong acid R-SO3H dehydrates immediately to produce a salt (eqn. 5) which is the stable form of fuchsone in this medium. The formation of this salt leads to the consumption of one mole of strong acid per mole of fuchsone formed (the acid is therefore not catalytic). 360
We are mistaken when we imagine, at first, that the use of a weaker acid would give a protonation of benzophenone (eqn. 3) without dehydrating the formed carbinol (eqn. 5). In reality this is impossible since the benzophenone is less basic (donor number DNN 17) (ref. 11) than carbinol (DNN 38). So protonation of benzophenone needs a strong enough acid causing the dehydratation of carbinol and the formation of a salt. Hydrolysing the salt (eqn. 7) is necessary to isolate the fuchsone (mixed with carbinol). The regenerated acid CH3SO3H remains in the aqueous phase, and the fuchsone is extracted by an appropriate organic solvent (e.g. : isopropyl ether). Trials conducted on the synthesis of the fuchsone at high temperatures, aiming to shift equilibrium (6) to the right, and to give back the catalytic acid, resulted in failure. This was confirmed by the I.R. study on the salt at variable temperature (1" 240~ in which there is no modification of spectra. The formation of the main by-product 6 is explained by the addition of phenol to the cationic part of the dissociated salt (eqn. 8) :
Ar2C~OH,
O3SCH3
--- A r 2 C L - ~ O H + CH3SO3 +A
H
OH (8)
__(~OH
Ar2C - .-
Ir 6_
OH A clear demonstration of the existence of the three equilibria was made : it was brought to light that this biphenol within a strong acid turns completely into fuchsone salt, and that fuchsone in a phenol system with low acidity leads quantitatively to the biphenol. The influence of thiols results from a rapid addition of this product to the protonated benzophenone Ar2C + - O H (A) to form an hemithioketal which immediately reacts to give a new electrophilic species (B) :
361
/ [ Ar2C+OH ] + A~SH
-..
OH
"~ ar2C
~.,
"-
[ Ar2C+---S--R ] + H20
\ S - - R + H+
(A)
03)
Fig. 7. Addition of thiols to the protonated benzophenone
This species fixes on the phenol and gives a sulphide (C) which - through proton action- releases the cation (D), and regenerates the thiol. SR
I
Ar2C+---S~ R
1
~
ArzC
OH
A r 2 C ~ O H
+ R--SH
(13)
_H§ (C)
(D)
The kinetic effect is explained by the fact that since (B) is more electrophilic than (A), the limiting step of the overall process (addition of A on phenol) is replaced by a quicker reaction (addition of B to the phenol).
Synthesis trials conducted in liquid phase and with heterogenous catalysis Processing of the heterogenous acid catalysts (sulphonic resin, zeolites, clays...) is conducted the same way as it is for homogeneous catalysis: the active acid parts are progressively blocked as 'fuchsone salts'. Regeneration of these parts takes place through hydrolysis which releases the formed fuchsone. Heterogeneous catalysis will have to work first in absorption (the salt is formed) and then in desorption (washing with H20 + organic solvent). Between each of the cycle the washing water is eliminated through drying. It was observed that the efficiency of acid parts of sulphonic resins (NAFION or BAYER K 2431 : 0.8 to 5 meq. H+/g resins) always remains low (1-1.5 mole of fuchosne/10 equivalent amounts H § and that the use of prohibitive quantities of resins is necessary. The same procedure applies to resins having very large pores (BAYER K 1221, LEWATIT 4 % DVB). With mineral solid acids, efficiency is lower than in the previous examples (zeolites, clays, metallic oxides ..... ).
362
Synthesis trials conducted in gaseous phase on mineral solid acid catalysts 9 A few trials were conducted on various solid acids (SiO 2 - A1203 - Nb205, HZSM-5, ...) " Phenol/benzophenone/Argon = 2 / 1 Hold up time = 1 to 4 sec.
/ 1 in moles 0 = 350~
WHSV = 2 - 3.5 h -1
(WHSV = weight hour space velocity Fuchsone is an instable product under these conditions which explains why it is always absent in the process, although benzophenone is always partly transformed. The process cannot be improved by reducing the hold up time.
R E A C T I O N O F F U C H S O N E W I T H H202 We saw before that H202 reacts stoichiometrically with fuchsone leading selectively to HQ and benzophenone (reaction 2). How does this reaction work ? .Co-catalysed hydroxylation of phenol by fuchsone. Influence of [Fuch~oneJ on RR .(diphenols) and on HQ/PC ratio. Several hydroxylation experiments of phenol (by H202/HC104) were conducted starting with increasing quantities of fuchsone. All the results are shown in Table 6 and Diagram 3. Table 6
Trials
BP/36 BP/37 BP/38 BP/39 BP/40 BP/41 BP/42 BP/43 BP/44
Conversion Selectivity Selectivity Selectivity TT RT RT RT PC/HQ (H202) (HQ) (PC) (DP)
(Fuchsone / (HC104 / (H202 H202)o HzO2)o phenol)o % mol % mol % mol 4.65 10.3 14.5 19.9 21.8. 33 57 77.2 101
0.95 0.85 0.95 0.80 0.88 0.75 0.89 0.87 0.80
5.35 5.0 5.2 5.25 4.4 5.3 4.65 4.7 5.1
1 1 1 1 0,5 0,5 0,5 0,5 0,5
99 100 100 100 100 100 100 100 100
DP " Diphenols 363
39.5 42.5 44.5 48 47.5 54 68.5 81 93.5
41.5 40 36 34.5 34.5 29 18 9 2
81 82.5 80.5 82.5 82 83 86.5 90 94.5
1.05 0.94 0.80 0.72 0.73 0.54 0.26 0.11 0.02
PC/HQ
Selectivity% RT (PC +HQ)
1,5
95
1
90
0,5
85
0
80 100
0
25
50
75
PC/HQ (2) RT (PC + HQ) / H202 (1)
ratio (Fuchsone / H202)o % MOL. Diagram 3. By increasing the initial ratio (fuchsone/H202) both the selectivity in HQ and the diphenol yield are also increased. These results show to what extent cost savings could be made by using a phenol process in parallel with a fuchsone plant functioning with a (H202/FUCHSONE) molar ratio = 1 and producing hydroquinone with much greater yields of phenol and H20 2 ( - - 9 5 % ) than those achieved (80 %/H202 and 88 %/phenol) using phenol hydroxylation with H202/HC104 (with or without benzophenone). Remark : when co-cocatalysis is performed using fuchsone, a modulation of the PC/HQ ratio can be obtained with a reduced circulation of benzophenone, this ratio being very much higher than when co-catalysis of benzophenone occurs on its own (ref. 7) (best result for benzophenone co-catalysis : (HQ/PC) - 1 (Diagram 4). Ratio PC/HQ
1,5 J......
0,5
0
I 10
i 20
i 30
i 40
Ratio (Benzophenone / H202) 0 % moI.
Diagram 4.
364
50
BENZOPHENONE I FUCHSONE
It is thought that within the hydroxylation process in which fuchsone is the cocatalyst, this product will first react with H202. It was demonstrated that fuchsone is approximatively 200 times more reactive than phenol, quantitatively producing HQ and benzophenone. Hydroxylation continues further in the presence of the formed benzophenone. Total selectivity of HQ is due to the ex-fuchsone HQ on one hand, and on the other hand to the co-catalysis of hydroquinone. The above indicates that fuchsone is a mixture of fuchsone and carbinol, and that these two compounds lead to the same compounds in the presence of H202. But it is to be noted that carbinol is 5 times less reactive than fuchsone (i.e. approx. 40 times more reactive than phenol). Important remark : Proper separation of the fuchsone from its synthesis medium (CH3SO3 H) is a key element ensuring the adequate oxidation of this product by H202 as the yields percentage will not exceed 30%, with a HQ/PC r a t i o - 0,5 in the presence of CH3SO3H. This demonstrates that the fuchsone salt does not react with H202 and that non-identified secondary reactions occur. Bv-oroduct of the oxidation of fuchsone 4-Hydroxy benzophenone (Yield = 1.5%) is the only by-product identified. Figure 9 shows its formation mechanism 9 ,,
A
,,OH O" H202~ Ar2CI~ O H
Ar2C~O
(1)~ +H + - H20
Ar2C+O~OH
H20
Ar2C--O + HQ
(14)
0+
4-'~0~ ---OH
_-
O
+ ArOH
Fig. 9. The main reaction is (1) as the nucleophilic group p-HO-Ar migrates more easily than the Ar group which is less nucleophilic.
365
FUCHSONE-SELECTIVE PROCESS IN HYDROQUINONE We thought it would be better to let the fuchsone dissolve in the appropriate solvent (isopropyl ether) until its transformation to HQ by H202 occurs, rather than isolating fuchsone in solid state and facing the various difficulties of this technique.
Synthesis of fuchsone Phenol / benzophenone / CH3SO3H = 10 / 1 / 8 in moles ; 0 = 110~ ; 7 h. The duration of the reaction can be be shortened by adding thiols (such as water-soluble HS (CH2)2SO3H which can be recycled using the same procedure as that for CH3SOaH ). Processing of the reaction mass Isopropyl ether and water are added to the above reaction mass (hydrolysis of the salt to fuchsone/carbinol with acid release) : the aqueous phase contains 97.5 % of introduced CH3SO3H with a small quantity of phenol and trace amounts of fuchsone. The organic phase contains almost the entire quantity of phenol which did not react, fuchsone (corresponding to a yield of 58.5 %/benzophenone) and the residual benzophenone (conversion = 59.8 %). Oxidation of fuchsone by H 2 0 2 : A trace amount of HC104 is added to the organic phase, and then the stoichiometric quantity of H202 is added dropwise. Temperature is maintained at 40~ for one hour. HQ with a yield of 100 % / fuchsone is obtained, together with benzophenone with 100 % recovery rate. Then this organic phase is sent towards the distillation section of the diphenols unit. Recycling of CI-I3803I-I : The aqueous phase containing CH3SO3H is first dehydrated at atmospheric pressure, then at reduced pressure. This action ends with a temperature of 176~ in the boiler at 50 tors). CH3SO3H recovery rate is approx. 97 %. Then this acid is recycled to the fuchsone synthesis process without any loss of either activity or selectivity.
366
CONCLUSION This fuchsone route allows increase, as required of the HQ selectivity of a RHONE-POULENC type diphenols unit, while yields versus H202 and phenol are also increased. It is based on the principle of working with two independent hydroxylation processes (phenol and fuchsone) before joining the two fluxes to continue the process. New finding~ are : the paraselectivity of the condensation of benzophenone on the phenol and high HQ selectivity, of oxidation of fuchsone by H202_ (and high benzophenone selectivity which becomes a catalytic compound). This process solves the problem raised by the flexibility of the HQ/PC ratio required by a unit producing HQ and PC at the same time.
References 1. 2. 3. 4. 5.
6.
a) b) a) b) a) b) c) a) b)
7. 8. 9. 10. 11.
a) b)
W.H. Sheard and co-workers, Ind. Eng. Chem. 44, 1730, (1952). M. Dorn and co-workers, EP 368.292 (09/11/1988), (to Peroxide Chemie). E. Nowak and co-workers, U.S. 4.463.198 (23/08/1982), (to Goodyear). M. Taramasso and co-workers, BP 2.024.790 (22/06/1978), (to Snamprogetti S.p.A.). A. Esposito and co-workers, FP 2.523.575 (19/03/1982), (Anic). G. Bellussi and co-workers, EP 200-260 (23/04/1985), (to Enichem Sintesi). M. Marinelli and wo-workers, FP 2.657.346 (19/01/1990), (to Enichem Synthesis) ; A. Thangaras, P. Ratnasamy and A. Kumar, J. Catal., 131,294 (1991). Y. Ben Taarit, C. Naccache, J. Mol. Catal., 68, 45, (1991). F. Bourdin, M. Costantini, M. Jouffret, G. Lartigau, FP 2.071.464 (30/12/1969), (to Rh6ne-Poulenc). J. Varagnat, Incl. Eng. Chem. Prod. Res. Dev, 15 (3), 212, (1976). M. Costantini, M. Jouffret, EP 480.800 (04/10/1991), (to Rh6ne-Poulenc). M. Costantini, D. Laucher, EP 558.376 (01/09/1993), (to Rh6ne-Poulenc). H. Burton, G.W.H. Cheesman, J. Chem. Soc., 1955, 3089. W.T. Lewis and co-workers, J. Am. Chem. S0c., 101, 5717, (1979). M. Costantini, D. Michelet, D. Manaud, EP 606.182 and 606.183 (08/01/1993), (to Rh6ne-Poulenc). Y. Marcus in ,, Ion Solvation ,,, John Wiley and Sons Ed., (1985).
367
THE MECHANISMS OF NITRATION OF PHENOL
PASCAL METIVIER AND THIERRY SCHLAMA Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie, 85 Avenue des Fr6res Perret, B.P. 62, 69192 Saint-Fons Cedex, France
INTRODUCTION Nitration of phenol is an old reaction that has been described for the first time in 1875 (ref. 1). Nitrophenols are of great interest for the industry since they can be used as precursors for dyes, pharmaceuticals (e.g. acetominophen), and agrochemicals (e.g. parathion, phosalone). Documents dating from 1898 (ref. 2) can be found in the archives of the Rh6ne-Poulenc company indicating the early industrial interest toward this reaction. To our knowledge, Rh6ne-Poulenc is the only company carrying out this reaction on a large industrial basis. This reaction has the reputation to be messy (ref. 3), and despite important studies, the different mechanisms involded in this reaction have not been completely solved. Two mechanisms are currently considered to be active in this reaction. The first one which is well established and has been fully studied in aqueous media involves two steps, nitrosation followed by and oxidation (Scheme 1). Nitrosation is an electrophilic aromatic substitution involving the nitrosonium ion and is mainly para selective (refs. 4, 5), and the oxidation is due to the nitrogen dioxide in equilibrium with nitrous acid and nitric acid. Two mechanisms involving nitrogen dioxide have been proposed for the oxidation step (ref. 6). This total paraselectivity can only be obtain in a two step procedure where nitrosation is performed in the absence of nitric acid followed by oxydation to paranitrophenol by addition of nitric acid to the mixture.
368
OH
OH
+
HNO 2
~N O"
OH
3
+
H20
+
HNO 2
+
H20
OH
I +
HNO 3
0-~ N
0~. N+ O-
OH
OH
+
HNO 3
r
..N+ 0
O-
Scheme 1. 9The nitrosation / oxydation pathway, a para selective route to nitrophenol
The reaction of phenol with nitric acid catalysed by nitrous acid conducts to mixture of para and ortho nitro phenols, with a varying ratio and low yield in aqueous media, and an unvariable 55/45 ortho/para ratio when the reaction is carried out in biphasic media. The biphasic procedure, named nitrous acid catalysed nitration of phenol in the literature has been first pointed out by Kagan and coworkers (ref. 7) and has been since, subject to many studies. J.H. Ridd and coworkers, have shown throught CIDNP effects (Chemical Induced Dynamic Nuclear Polarisation) in the nitration reaction that the mechanism involves the ArO'NO2 radical pair (ref. 8). M.J. Thompson and P.J. Zeegers (ref. 9), have correlated the ortho/para ratio of the nitration of various phenols with the unpaired electron spin density of phenoxy radicals using semi-empirical calculations and shown that they are in very good agreement with the experiments. They have proposed a mechanism in which the phenoxy radical is the key intermediate. In this mechanism the first step is an electron transfer with NO + as the transfer agent, followed by a deprotonation step leading to the phenoxy radical which than reacts with nitrogen dioxide to give the nitrophenols (Scheme 2). This mechanism, also 369
enables to explain the formation of the major side product which is benzoquinone. The phenoxy radical can be over oxidated throught another electron transfer step, leading to the phenoxonium cation which reacts with water to give hydroquinone and is then oxidised to benzoquinone.
HNO 2 +
H+
..,,
"-
H20
OH
+
NO +
OH
+
NO +
#
+
+
OH
O.
[~
~ ~
O,
+ H+ OH
+
NO
NO 2
+ 2 HNO 3
2 NO 2 +
H20
OH
...,
"-
3 NO 2 +
_..,
~
HNO 2 +
~
H20 HNO 3
OH
I [ ~
NO
+
HNO 3
~N/~_
+
H20
Scheme 2. 9Nitrous acid catalysed nitration of phenol, mechanism proposed in literature
Both mechanisms (nitrosation / oxydation and nitrous acid catalysed) involve an initial step with NO + as the reacting specy. In water, it would react as an electrophilic reagent and in organic media as an electron transfer acceptor. Results obtained in our laboratory are not in good agreement with this explanation, and we decided to try to identify more precisely the role of each active specy in this reaction. 370
RESULTS Experiments were carried out with different oxydation states of nitrogen to try to identify the species that are active in the different mechanisms. The approach chosen was to react phenol with NIII, NIV and NV in water and in organic media and to observe the different products that are formed. This basic procedure which seems simple needs to be undertaken caustiously. Nitrophenols are very pourly soluble in water (2 g/1 for orthonitrophenol at 20~
and tends to demix from
water giving two liquid phases. Since this reaction is considered to be messy, one must be sure that the carbon balance is correct so to avoid misinterpretation. All the reactions were carried out in relative dilute state ( 1 % ) and reaction medias are quenched with aqueous cold water containing sulfamic acid to destroy nitrous oxydes, and titration of products is done throught HPLC analysis. Nitrosation : In aqueous media, as described in literature (refs. 4, 5) the main reaction product is paranitrogophenol.
Side products are paranitrophenol and
orthonitrophenol (Table 1). Table 1. 9 Nitrosation of phenol in aqueous media with NaNO2 (2 equivalents) / H2SO4 system n2so4 (%) weight
42
Temperature (~
42
70
70
23
-4
25
Conversion
(%)
41.9
63.8
24.1
41.3
. . . . .
Paranitrosophenol
(%)
35.2
44.4
19.9
23.7
YIELD
Paranitrophenol
( %)
1.7
0.8
2.8
5.5
HPLC
Orthonitrophenol
(%)
0.6
0.3
0.6
0.2
98.6
88.4
titration
At 23~
Benzoqu inone
( %)
2,4-Dinitrophenol
(%)
2,6-Dinitrophenol
(%)
Carbon balance
(%)
0.5
96.1
91.7
paranitrophenol becomes as important as paranitrosophenol, whereas
orthonitrophenol remains very low. This can be explained by the dismutation equilibrium of NIII in water to give NIV and NII (ref. 10). This NIV specy can then oxidise the paranitrosophenol to give paranitrophenol. The small quantity of orthonitrophenol
formed
indicates clearly that the nitrosation mechanism
preponderant.
371
is
In organic media (Table 2) results are more surprising in that, that according to the proposed ,, nitrous acid catalysed ,, mechanism, one would not have predicted paranitrosophenol
to
be
the
main
product.
Particularly,
in
toluene
or
dichloromethane where biphasic nitration of phenol takes place very rapidly, no reaction is observed.
Table 2. 9 Nitrosation of phenol in acetonitrile media with NOBF4 CH3CN
Temperature (~ Conversion
(%)
50
3
-1
72
83
56.4
65
37.2
1.5
3.2
Paranitrosophenol (%)
44.3
YIELD
Paranitrophenol
(%)
1.56
HPLC
Orthonitrophenol (%)
0.8
titration
Benzoquinone
0.6
(%) 0.5
2,4-Dinitrophenol (%) 2,6-Dinitrophenol (%) Carbon balance
The
carbon
balance
84
75
(%)
is not very
good
when
83.8
reaction
takes
place,
so
interpretation must be cautious. But even if this carbon loss reveals an electron transfer from phenol to NO + , this reaction is slow and does not explains results obtained in ,, nitrous acid catalysed ,, nitration of phenol. Reaction of phenol with dinitrogen tetroxide (N204) : In contrast to nitrosation in organic media, reaction with N204 in organic media is fast and leeds to the caracteristic products of ,, nitrous acid catalysed ,, nitration (Table 3). A striking exemple is reaction in toluene where nitrosation does not take place whereas reaction occurs with N204 leading to nitrophenols, benzoquinone and no trace of paranitrosophenol.
Furthermore the ortho/para ratio is roughly invariable and
corresponds exactly to the expected ratio for ,, nitrous acid catalysed ,~ nitration. Dinitrophenol and especially 2,4-dinitrophenol is formed in small quantities during this
reaction.
We
have
looked
at the
compared
reactivity
of
ortho
and
paranitrophenol and show that paranitrophenol reacts more quickly with N204 than orthonitrophenol to give dinitrophenol.
Nitration of orthonitrophenol
occurs leads to a ratio of 65/35 in favour of 2,4-dinitrophenol. 372
when it
From these
experiments we can conclude that in organic medium, nitrogen tetroxide is the reagent involved in the first step of the nitration leading to the phenoxy radical.
Table 3.
9 Reaction of phenol using N204 in organic solvents Toluene ,,Temperature
(~
N204
Conversion
(%)
p aranitrosopheno! . (%)
CH2C12
CH3CN
Stflfolane
AcOEt
0
24
24
0
24
0
24
24
0
24
24
0.5
0.5
0.6
0.5
0.5
0.5
0.5
0.5
1.1
1.1
0.5
90
57.8
56.8
64.8
73.5
96.5
55.8
43.6
100
100
81.7
/
/
/
/
/
/
/
/
/
/
/
..Paranitrophenol
'% )
34.3
11.6
11.0
21.5
10.8
40.6
18.3
15.1
40.3
30.9
29.9
Orthonitrophenol
( %)
40.9
23.5
25.3
24.6
28.4
47.2
19.6
18.8
47.0
35.6
34.5
Benzoquinone
( %)
4.2
1.9
1.7
1.3
1.8
2.1
1.3
1.0
1.9
1.9
1.7
.2,4-Dinitrophenol
(%)
0.8
7.7
8.5
1.5
15.7
0.8
5.6
/
2.0
14
3.2
2,6- Dintrophenol
( %)
/
/
/
/
/
/
2.6
/
1.0
6.3
1.0
Carbon balance
(%)
90
86.5
89.4
84.6
83.3
94.4
91.7
91.6
92.0
88.7
88.5
54.0
54.8
54.8
51.6
51.8
53.7
50.8
55.5
53.2
48.3
51.8
(ONP+2,6-DNP) / 2; nitrophenols
Reaction w i t h .
N204 ~
aqueous media and DMSO : As described in literature,
introduction of N204 in an aqueous media results in an immediate dismutation to nitrous acid and nitric acid (ref. 10). As a result of this dismutation results of this type of reaction leads to the same results than with nitrous acid in diluted sulfuric acid, i.e. nitrosation is the predominent mechanism (Table 4), with no trace of benzoquinone. In dimethyl sulfoxide (DMSO), the same type of result is obtained. This means that D M S O behaves the same way than water toward N204. This is confirmed through literature results, N204 is known to racemise chiral sulfoxide (ref. 11), and that its action on an O18 maked sulfoxide leads to an oxygene exchange between the two molecules (ref. 12). The explanation of this reactivity passes throught the dismutation of N 204 in sulfoxides as described in Scheme 3.
373
Table 4. - Reaction o f . N204. in water and in DMSO with phenol
WATER
DMSO
Temperature
(~
24
24
24
N204
(eq.) (%)
0.5
0.5
0.5
38.5
26.7
42.1
Paranitrosophenol
(%)
26.8
23.8
14.3
Paranitrophenol
(%)
0.9
1.1
8.3
Orthonitrophenol
(%)
1.5
1.4
1.9
Benzoquinone
(%)
/
/
/
2,4-Dinitrophenol
(%)
2,6-Dinitrophenol
(%)
Carbon balance
(%)
Conversion
6.4
o,.
o
O
CH3-
N. "n-
~ S-:'-O"
'
~'
"~
C H~ S--O
CH3
O
CH 3
O
89.0
99.5
90
O II
N-. oN~O
O
9
N'-----O
""-
* S---O
CH 3
'N--O
I_ O
O~N*IO H3
/S*---Or, )
O~N'~OI_ ~
OH 3
N--O
O
CH3 S'-"-O/ CH 3
s'---oCH3 I
I
O~
"N II O
O~N-tO O~\ 4-
O ae
N*-"'-N" O O 9
I /
S---O
C,H3
Scheme 3. " Dismutation of N204 with DMSO 374
O-~ N
II O
Reaction of the nitronium ion in organic media : reaction of phenol with NO2 + in organic media leads to the same type of results than with N204 (Table 5). The formation of benzoquinone is systematically observed and the ortho/para ratio is again invariable.
A small quantity of paranitrosophenol
is observed which
corresponds to nitrosonium contained in the nitronium product used as starting material (-- 4 % for NO2SbF6).
Table 5. 9 Reaction of NO2+ in organic media CH3CN
CH2C12
Temperature
(~
24
24
24
Conversion
(%)
28.1
64.8
63.3
Paranitro sophenol
( %)
3.3
1.2
0.3
YIELD
Paranitrophenol
( %)
9.2
20
18.7
HPLC
Orthonitrophenol
( %)
12.0
24.0
21.8
(%)
1.85
2.6
0.3
TITRATION Benzoquinone 2,4-Dinitrophenol
( %)
4.4
2,6-Dinitrophenol
(%)
0.2
Carbon balance
(%)
Nitration agent (ONP + 2,6-DNP) / E nitrophenols (%)
99.0
93.1
83.0
NO2SbF6
NOzBF4
NO2SbF6
56,5 %
54,5 %
49 %
Reaction of $ulfonitric medium with ohenol " Reactions in sulfonitric media are carried out using either sulfamic acid or urea as nitrous acid scavenger. Results obtained with different sulfuric acidities are given in Table 6. With diluted sulfuric acid and a nitrous acid scavenger, no reaction takes place, indicating that nitric acid by itself is not an active specy. With 80 % sulfuric acid, where the nitronium ion begins to be significative (ref. 13), the results are the same than in organic media. With 70 % sulfuric acid, a non expected result is obtain, in that, the ortho/para ratio moves up to 65/35. In that case the reaction is more orthoselective than ever. With sulfuric acid concentration over 80 %, the preponderant reaction is sulphonation of phenol. With intermediate type sulfuric acids (30-60 %), after a varying induction time where no reaction takes place, the media turns suddenly to tars and results are not interpretable.
375
Table 6. : Reaction of phenol with various sulfonitric medium Nitrous acid scavenger
no
urea
urea
urea
urea
urea
H2S04 (%)
80
80
80
70
70
20
Temperature (~
24
24
0
0
24
24
Conversion (%)
100
100
78.2
35.7
83.5
2.8
Paranitrosophenol
0.1
/
/
0.4
0.3
/
YIELD
Paranitrophenol
32.8
35.1
35.1
11.8
27.3
/
HPLC
Orthonitrophenol
42.2
45.9
42.4
22.1
51.9
/
Benzoquinone
0.1
/
/
/
/
/
2,4-Dinitrophenol
5.5
2.8
/
/
/
/
2,6-Dinitrophenol
2.4
1.2
/
/
/
/
Carbon balance (%)
83.1
85.0
99.3
98.7
96.0
97.2
(ONP+2,6-DNP) / Z nitrophenols
53.8
55.4
54.7
65.0
65.0
/
TITRATION
GENERAL DISCUSSION From our results, it appears clearly that the first step in nitrous acid catalysed nitration of phenol is not a monoelectronic transfer from phenol to the nitrosonium specy, but rather a reaction with N204 leading to the formation of the phenoxy radical, nitrous acid and NO2. The mechanism that we proposed for this reaction of phenol with N204 passes throught the intermediate formation of phenylnitrate, which then decomposes homolytically to form the phenoxy radical and NO2 (Scheme 4). Semi-empirical calculation (MNDO, PM3) on the homolytic scission of phenylnitrate shows that the Enthalpy of reaction to give the phenoxy radical and NO2 is -1,7 kcal/mol and though should be spontanneous (ref. 14). The N204 reaction with phenol that we propose here is formally the same then the reaction of water (ref. 17) with N204 leeding to dismutation into nitrosonium nitrate, also the same than the desmutation reaction with DMSO (ref. 15) and aliphatic alcools. This mechanism corresponds also partially to the one proposed by R.G. Coombes (ref. 18) for the reaction of 2,4,6-trialkylphenol with nitrogen dioxide in organic solution.
376
O
II
H~
H~oc/N~,.O.
o-\
/
o-
N~---N *
+ N O 2-
O
Same reaction as described for aliphatic alcohols
O
II
H ~ O (." N~,.O.
0 / N~"~0 -
ROH ~
l
+ N O 2-
+
HN02
RONO 2
t 1
J
0
II Semi empirical calculations
I
&H = - 1,7 kcal/mol.
+ NO 2
i + NO 2
>
H
OH
~ t
[ ~
+
NO 2
45%
NO 2
55 %
Scheme 4. 9 Proposed mechanism for nitrous acid catalysed nitration of phenol
With the nitronium ion results indicate that the same intermediate phenylnitrate is formed, which then follows the same path to give 55/45 ortho/para mixture of nitrophenols (Scheme 5). It is interesting to note that in organic medium the N204 nitration of phenol is much faster than with the nitronium ion. This mechanism involving
the
initial
formation
of
the
phenylnitrate
which
decomposes
homolitycally to the phenoxyradical and NO2" has already been proposed by J.H. Ridd in the case of nitration of paranitrophenol with the nitronium ion (ref. 16).
H~O NO2 ~"
OH +
NO2 +
~
O"
NO 2
~
O ~
.
+ NO 2
.
OH ~
Scheme 5. 9 Proposed mechanism for the nitration of phenol with the nitronium ion
377
NO 2
The case of nitration with at 70 % sulfonitric mixture seems particular. In this zone of acidity, the main specy is neither the nitronium ion neither nitric acid but protonated nitric acid HzNO3 + (ref. 13). In this case one can invoque a cyclic transition state to explain the ortho selectivity that is observed.
CONCLUSION According to our results, three mechanisms can be effective in the nitration of phenol. The first one which has been well described is the nitrosation oxydation pathway,
which is paraselective and involves paranitrosophenol
as the key
intermediate. The two other mechanisms involve the same key intermediate : the phenoxy radical which combines with NO2 to give a 55/45 ortho/para nitration mixture. This intermediate can be formed either via fast reaction with dinitrogen tetroxide (N204), or slow reaction with the nitrosonium ion. The results we obtain suggest that the first step is the formation of the phenylnitrate intermediate, which undergoes an homolitic breakage of the oxygen-nitrogen bond leading to the phenoxy radical and nitrogen dioxide. In the case,
OH
I H20
N204
O
0
ONO 2
O
O.
~
0 OH
+
NO2
Scheme 6. 9 The ,, nitrous acid ,~ catalysed nitration of phenol - overall proposed mechanism of the biphasic procedure, the formation of N204 results from the well know reaction of nitric acid with nitrous acid. This N204 is then extracted to the organic media where fast reaction with phenol takes place as depicted in Scheme 6.
378
References
1. K6rner, Gazz. Chim. Ital., 4, 440, (1875). 2. L. Benda, Internal report, (April 1898), (to Soci6t6 Chimique des Usines du Rh6ne). 3. T. Mc Cullough, K. Kubena, J. Chem. Educ, 67,801, (1990). 4. C.A. Bunton, E.D. Hugues, C.K. Ingold, D.I.H. Jacobs, M.H. Jones, G.J. Minkof, R.I. Reed, J. Chem. Soc., 2628, (1950). 5. B.C. Challins, J.H. Higgins, A.J. Lawson, J. Chem. Soc., Perkin Tram. II, 1831, (1972). B.C. Challins, J. Chem. Soc. 03), 1971, 770 ; B.C. Challins, J.H. Higgins, J. Chem. Soc., Perkin Trans. II, 1597, (1973). 6. Y. Ogata, H. Tezuka, J. Org. Chem., 1968, 33, 3179 ; G.V. Bazanova, A.A. Stotskii, J. Org. Chem. USSR, 1427, (1981). 7. M. Ouertany, P. Girarg, H.B. Kagan, Tetrahedron Lett., 23, 4315, (1982). D. Gaude, R. Le Goaller, J.L. Pierre, Synth. Comm., !6, 63, (1986) ; M.J. Thompson, P.J. Zeegers, Tetrahedron Lett., 29, 2471, (1988). 8. A.H. Clemens, J.H. Ridd, J.P.B. Sandall, J. Chem. Soc., Perkin trans. II, 1667, (1984) ; M. Ali, J.H. Ridd, J.P.B. Sandall, S. Trevellick, J. Chem. Soc., Chem. Commun., 1168, (1987); J.H. Ridd, S. Trevellick, J.P.B. Sandall, J. Chem. Soc., Perkin trans. II, 573, (1992). 9. M.J. Thompson, P.J. Zeegers, Tetrahedron, 45, 191, (1989) ; M.J. Thompson, P.J. Zeegers, Tetrahedron, 46, 2661, (1990). 10. J.W. Mellor in ,, A comprehensive treatise on inorganic and theoretical chemistry ,,, Volume 8, Logman Editor, pp. 454-469 for nitrous acid, pp. 529-549 for nitrogen tetroxide. 11. S. Oae, N. Kunieda, W. Tagaki, Chem. & Ind., 1790, (1965). 12. C.R. Johnson, Jr D. Mc Cams, J. Am. Chem. Soc., 86, 2935, (1964) ; C. Lagercrantz, Acta Chem. Scand., 23, 3259, (1969). 13. D.S. Ross, K.F. Kuhlman, R. Malhotra, J. Am. Chem. Soc., 105, 4299, (1983) ; G.F. Scheats, A.N. Stachan, Can. J. Chem., 56, 1280-1283, (1978) ; R.B. Moodie, K. Schofield, P.G. Taylor, J. Chem. Soc., Perkin trans. II, 133, (1979). 14. Phenylnitrate is not described in literature. 15. C.R. Johnson, J.R.D. Mc Cant, J. Am. Chem. Soc., 86, 2935, (1964) ; C. Lagercrantz, Acta Chem. Scand., 23, 3259, (1969). 16. J.H. Ridd, H.A. Clemens, J.P.B. Sandall, J. Chem. Soc., Perkin trans. II, 1667-1672, (1984). 17. T.A. Turney, G.A. Wright, Chem. Rev., 59, 497, (1959). 18. R.J. Coombes, A.W. Diggle, S.P. Kempsel, Tetrahedron Lett., 34, 8557, (1993).
379
OXIDATION OF ALKYLPHENOLS TO HYDROXYBENZALDEHYDES
ERIC FACHE, DOMINIQUE LAUCHER, MICHEL COSTANTINI, MONIQUE BECLERE AND GILLES PERRIN-JANET Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie des Carri6res, 85, Avenue des Fr6res Perret, BP 62, 69192 Saint-Fons Cedex, France.
4-methylphenol is oxidized into p-hydroxybenzaldehyde by oxygen or air, in water / acetic acid media, in the presence of catalysts like Pd / C or Pd-Sn / C (66 % selectivity for total conversion). The former catalysts are not able to yield ohydroxybenzaldehyde from 2-methylphenol. However, good performances are reach with a Pd-Pt / C catalyst (60 % selectivity for total conversion )
INTRODUCTION Among hydroxybenzaldehydes, the o- and p- hydroxy isomers are the most important for commercial applications in agricultural, flavor and fragance, pharmaceutical or polymer fields (ref. 1). The two main processes for the manufacture of hydroxybenzaldehydes are both based on phenol. The most widely used process is the saligenin process. Hydroxybenzyl alcohols (o- and p- isomers) are produced from base - catalyzed reaction of formaldehyde with phenol (ref. 2). Air oxidation of these alcohols over a suitable catalyst (based on palladium or preferentially on platinum) produces hydroxybenzaldehydes (ref. 3). The Reimer Tiemann process allows the coproduction of o- and p- hydroxybenzaldehydes (ref. 4). Treatment of phenol with aqueous chloroform and sodium hydroxide leads to benzal chlorides which are rapidly hydrolyzed by alkaline medium to aldehydes. The previous processes need two chemical steps and produce salt effluents. More recently, the direct formation of hydroxybenzaldehydes by the oxidation of the corresponding alkylphenols was reported. However, the oxidation of 4- and 2methylphenol respectively into p- and o-hydroxybenzaldehydes remains difficult, leading very often to heavies. For instance, the catalytic systems used for the 38O
oxidation of substituted cresols (Table 1) are no efficient and / or no selective in the case of o- and p-cresols (ref. 6).
Table 1 : Usual catalytic systems for the oxidations of substituted cresols or derivatives
Catalysis type
Catalysts
Substrates
References
Basic
tBuOK (Stoichiometric reaction)
2,6-tert-butyl-4-methylphenol
5a
Homogeneous
Ce(OAc)3
2,6-tert-butyl-4-methylphenol 2,6-dimethoxy-4-mrthylphenol
5b
Homogeneous
Co(OAc)2 + Mn(OAc)2
3,4,5-trimethoxytoluene
5c
Homogeneous
CuC12 + amines or oximes
2,4,6-trimethylphenol
5d
Heterogeneous
Pd/C
2,4,6 trimethylphenol
5e
However, with cobalt or iron catalysts, good results are obtained when the phenol group is protected, either under its acetate form after reaction with acetic anhydride in an acetic acid medium (ref. 7), or as phenate when the oxidation takes place in a basic medium (at least three equivalents of base versus cresol) (ref. 8). These oxidations suffer from great drawbacks : in acetic medium, the reaction leads to poor selectivities at high conversions (acid formation) and needs one more step to recover the aldehyde under the phenolic form. The main limitation of the oxidation in basic media is the large coproduction of salt. Moreover, the oxidation of o-cresol appears more difficult than the p-cresol one. In this paper, we wish to report efficient methods to oxidize 4-methylphenol and 2methylphenol into the corresponding aldehydes which avoid the previous drawbacks.
OXIDATION
OF
4-METHYLPHENOL
IN
ACETIC
MEDIA
IN
THE
PRESENCE OF PALLADIUM-BASED CATALYSTS Oxidations of methylaromatic compounds, without phenolic group, in the presence of palladium based catalysts are well documented (ref. 9). Toluene (ref. 9), o-, m-, p-xylene (refs. 9c-e), mesitylene (ref. 9c), hexamethylbenzene (ref. 9c), o-methylanisole (ref. 9e) and p-methylanisole (ref. 9d) are among the main substrates which have been studied. The solvent of choice for the reaction is acetic acid and the main product is the corresponding benzylic acetate. Aldehyde 381
selectivity is low. According to our knowledge, the oxidation of 4-methylphenol in acetic acid medium has been reported only one time with a catalyst based on palladium, bismuth and chromium or manganese or silicium (ref. 10). Under these conditions, the main product is 4-hydroxybenzylacetate. As expected, we found that the oxidation of 4-methylphenol in acetic acid medium in the presence of Pd-Sn / C * catalyst leads to 4-hydroxybenzylic acetate with a good selectivity (Table 2, entry 2). The study of the reactionnal intermediates in such a medium shows the difficulty to oxidize the acetate into 4-hydroxybenzaldehyde under these conditions (Table 2, entry 5) while the esterification of alcohol by acetic acid is complete (Table 2, entry 3).
OXIDATION OF 4-METHYLPHENOL IN WATER / ACETIC MEDIA IN THE PRESENCE OF PALLADIUM-BASED CATALYSTS In the case of Pd-Sn / C catalysts, the addition of water to the acetic medium allows the shift of the oxidation selectivity from the acetate towards 4-hydroxybenzaldehyde (Table 2, entry 1). Moreover, in this new medium, 4-hydroxybenzylic alcohol is converted into 4-hydroxybenzaldehyde with 61% selectivity (Table 2, entry 4). The best selectivities in aldehyde are reached with media containing at least 50% in volume of water (Table 2, entries 1, 2, 6-7). At lower water concentration, 4-hydroxybenzylacetate is the main product of the reaction (entry 2). The presence of water is necessary to allow the equilibrium between 4-hydroxybenzylacetate, which is not oxidized, and 4-hydroxybenzylalcohol which is easily converted into 4-hydroxybenzaldehyde (Scheme 1).
OH~CH2OAc
~ ~
,IOH
NNN~
OH
OH
CHO
COOH
H20
O H ~ C H 2 O H / ~
Scheme 1 : Oxidation of 4-methylphenol in the presence of Pd-based catalysts in water-acetic acid media. 382
T a b l e 2. 9Oxidation o f cresols with palladium-based catalysts in acetic acid / water m e d i a
Ea'ms'
Substrate
AcOH/ H20
Catalyst
At (h)
ml/ml
Nature
mmol Pd
Conversion
Selectivities
%
1
2
3
%
1
p-cresol
25 / 25
Pd-Sn/C
0.25
2
87
2
9
64
9
2
p-cresol
50 / 0
Pd-Sn/C
0.25
0.25
84
5
70
10
3
3
4-hydroxybenzylalcohol 50 / 0
Pd-Sn/C
0.25
0.2
100
4
4-hydroxybenzylalcohol 20 / 30
Pd-Sn/C
0.25
1
100
-
-
61
7
5
4-hydroxybenzylacetate 50 / 0
Pd-Sn/C
0.25
2
35
-
-
47
11
100
6
p-cresol
40 / 10
Pd-Sn/C
0.25
2
93
3
27
50
6
7
p-cresol
10 / 40
Pd-Sn/C
0.25
2
76
1
7
60
8
8
p-cresol
25 / 25
Pd/C
0.15
2.5
55
8
20
61
5
9
p-cresol
25 / 25
Pd/C
0.15
21
99.5
e
e
66
31
10
o-cresol
25 / 25
Pd/C
0.15
4
95
-
-
-
4
11
o-cresol
25 / 25
Pd-Pt/C**
0.27
4
70
-
-
14
-
12
o-cresol
25 / 25
Pd-Pt/C
0.27
4
100
-
-
60
+BiO(NO3)
Rt/Bi=2.45
Substrate " 10 m m o l " K O A c " 10 m m o l
100~
9o x y g e n - 5 1/h.
! " 2 or 4 - h y d r o x y b e n z y l a l c o h o l 92 2 or 4 - h y d r o x y b e n z y l a c e t a t e 9 3 " 2 or 4 - h y d r o x y b e n z a l d e h y d e 94 - 2 or 4 - h y d r o x y b e n z o i c acid
383
CATALYSTS USED TO OXIDIZE 4-METHYLPHENOL IN WATERACETIC MEDIA Various Pd-based catalysts used in acetic acid / water media allow the oxidation of 4-methylphenol into 4-hydroxybenzaldehyde with good selectivity. The best results are obtained with two kinds of catalysts : Pd-Sn / C and prereduced Pd/C* (Table 2, entries 1 and 8). With total conversion of cresol, 4-hydroxybenzaldehyde can be obtained with an average selectivity of 65 %. 4-hydroxybenzoic acid is the main by-product (Table 1, entry 9). The key of the oxidation seems to be the oxidation degree of palladium which has to be as low as possible (reduction of Pd(OAc)2 by Sn (II) derivatives in the case of Pd-Sn catalysts, or reduction, for instance by hydrogen, in the case of Pd / C catalysts). Hence, in the transformation of 4-hydroxybenzylalcohol into 4hydroxybenzaldehyde, palladium behaves as a dehydrogenation catalyst and has to be at a low oxidation degree. Moreover, it is also well known that low oxidation state palladium is implicated in benzylic oxidations, via the cleavage of the benzylic C-H bond, while more electrophilic palladium with high oxidation degree favors the attack and functionnalization of the aromatic ring (ref. 11).
MAIN SIDE-REACTIONS IN THE CASE OF 4-METHYLPHENOL OXIDATION IN WATER / ACETIC MEDIA IN THE PRESENCE OF PALLADIUM-BASED CATALYSTS When initial concentration of 4-methylphenol is increased, the selectivity in aldehyde and more generally in the corresponding alcohol, acetate, aldehyde and acid decreases (Table 3). The loss of selectivity in concentrated media, is mainly due to polyethers like :
C H 3 ~ O(---CH2~ O)O- - CnH 2 ~ Formation of these compounds, not or poorly oxidable under the reactionnal conditions, is due to the nucleophilic reaction of 4-methylphenol on 4-hydroxybenzylalcohol or on the corresponding acetate. With these results, we can complete the reactionnal scheme (Scheme 2).
384
Table 3- Oxidation of p-cresol in water-acetic acid (1/1) media by palladium-based catalysts Influence of the concentration of p-cresol on the selectivity of the oxidation
[p-cresol] M
Conversion %
Selectivities 3
%
!+2+3+4
0.2
99.5*
66
97
2.0
80**
35
50
KOAc 910 mmol; Pd/C (3 % Pd, Pd 0.15 mmol), AcOH / H20 =25 / 25 ml; 100~ oxygen 95 1 / h., * 21 h and p-cresol 10 mmol, ** 26 h, p-cresol 110 mmol and KOAc 100 mmol.
1" 4-hydroxybenzylalcohol" 2- 4-hydroxybenzylacetate; 3 4-hydroxybenzaldehyde; 4_ :4-hydroxybenzoic acid.
~ Cresol
OH
1 Polyethers
/
HO--@CH2ObI
CHO
Scheme 2 9 Oxidation of 4-methylphenol in water-acetic acid media in the presence of palladium based catalysts 9
H o w e v e r , the formation of previous by-products can be strongly decreased by continuous injection of cresol in the medium in order to keep a low instantaneous concentration of cresol in the medium. M o r e o v e r addition of bismuth allows a significant increase on aldehyde selectivity (Table 4).
385
Table 4 " Oxidation of p-cresol in water-acetic acid (1/1) media by palladium based-catalysts. Continuous injection of cresol.
BiONO3/Pd
Conversion %
Selectivities % 3
1+2+3+4
0
96.5
50
70
0.3
93.8
65
82
KOAc " 28 mmol; Pd/C (3% Pd, Pd 0.15 mmol), AcOH / H20 = 12.5 / 12.5 ml- 100~ oxygen" 5 1 / h, 20 h initial p-cresol 4 mmol, injection of p-cresol 41 mmol (12 h). 1" 4-hydroxybenzylalcohol; 2 94-hydroxybenzylacetate" 3 94-hydroxybenzaldehyde; _4:4-hydroxybenzoic acid.
RECYCLING
O F C A T A L Y S T S ; E X A M P L E O F T H E O X I D A T I O N O F 4-
METHYLPHENOL The industrial reality of a catalyst is only achieved if it can be easily recovered and if it keeps its activity and selectivity. These conditions are nearly gathered only with Pd-Bi / C catalysts (Figs 1-2). Finally, it has been found that promotion of palladium by bismuth not only increases the selectivity in aldehyde but also limits the deactivation of the catalysts. Similar results have been published in the past decade on the partial oxidation of alcohols with similar catalytic systems (ref. 13). Various interpretations on the role of bismuth have been suggested : among them, resistance of Pd/C against overoxidation and surface orientation of the reactant suppressing the formation and strong adsorption of poisoning intermediates are also problably the main reasons of the improved performances in the oxidation of p-cresol.
386
100 90 80
l"
70 60
Conversion with Pd/C I ,[! Conversion with Pd/C + Bi
TT% 50
40 30 20 10 0
1
0
1
,
,
,
2
3
4
Recycle
Fig. 1 9 Influence on the activity with the recycling of catalysts Pd / C and Pd / C + Bi (conditions described in Table 4)
80 B
70
[l
60 50
I II Selectivity with Pd/C I m Selectivity with Pd/C + Bi
4O RT % 30 2O 10 0
1
2
3
4
Recycle
Fig.2 9 Influence on the selectivity with the recycling of catalysts Pd / C and Pd / C +Bi (conditions described in Table 4)
O X I D A T I O N OF O T H E R C O M P O U N D S IN W A T E R / A C E T I C ACID M E D I A IN T H E P R E S E N C E OF Pd B A S E D C A T A L Y S T S . C A S E OF 2 - M E T H Y L P H E N O L (ref. 14) Of course, previous catalytic
systems
allow
the
oxidation
of
other
methylaromafic compounds into aldehydes, especially compounds which are not phenolic
and
(p-methylanisole,
which
bear
electrodonnating
3,4-(methylenedioxy)toluene
groups
on
the
aromatic
for instance). However,
ring
different
catalytic methods already exist for the oxidation of these kinds of substituted cresols (Table 1). So, the new systems would be really interesting only if they allow the oxidation of substrates, which are very difficult to oxidize by classical methods. 387
Among these substrates, we can find not only 4-methylphenol but also 2-methylphenol. Unfortunatly, oxidation of 2-methylphenol with the previous catalysts (Pd-Sn/C and Pd/C) only gives small amounts of 2-hydroxybenzoic acid and heavies (table 2, entry 10). These heavies are polyethers probably obtained by reaction of o-cresol itself with 2-hydroxybenzylacetate or 2-hydroxybenzylalcohol. Apparently, palladium catalysts activate the benzylic C-H bond of o-cresol, but the oxidation of the intermediates seems less rapid than side reactions. On the other hand, we have check that platinum catalysts, which are known to be excellent catalysts for the oxidation of 2-hydroxybenzylalcohol into 2-hydroxybenzaldehyde in basic aqueous medium (ref. 3), is unable to activate efficiently the benzylic C-H bond of cresols. We synthesized bimetallic catalysts, Pd-Pt / C** , with the hope that palladium would activate benzylic C-H bond and platinum would accelerate the oxidation of intermediate alcohols. Effectively, this new catalyst allows to recover 2-hydroxybenzaldehyde with 14 % selectivity at 70% conversion (Table 2, entries 11-12). Addition of bismuth salts are known to improve the aldehyde yield in the saligenin process. With such additives, the selectivity of the aldehyde can reached 60% for a total cresol conversion. Of course Pd-Pt / C can also oxidize 4-methylphenol but it does not bring significant improvement compared to initial catalysts.
CONCLUSION So, we have discovered new and original catalytic conditions which allow an easy transformation of alkylphenols into the corresponding hydroxybenzaldehydes. Hence, 4-methylphenol is oxidized into p-hydroxybenzaldehyde by oxygen or air, in water / acetic acid media, in the presence of catalysts like Pd/C or Pd-Sn/C (66 % selectivity for total conversion). The former catalysts are not able to yield o-hydroxybenzaldehyde from 2-methylphenol. However, good performances are reach with a Pd-Pt/C catalyst (60 % selectivity for total conversion).
References
1. 2. 3. 4.
In ,, Encyclopedia of chemical Technology ~,, Kirk-Other, third edition, 13, pp.70, John Wiley (New-York), (1981). K.C. Eapen and L. M. Yeddanapalli, Makromol. Chem., 1968, 119, 4. J. Le Ludec, Ger Often 2,612,844, (1976), (to Rh6ne-Poulenc SA). H. Wynberg, Chem. Rev., 60, 169, (1969).
388
5.
a) b)
c) d)
e) 6. 7. 8.
9.
a) b) c) d)
e) 10. 11. 12. 13. 14.
A. Nishinaga, T. Itahara, T. Shimizu, T. Matsuura, J. Am. Chem. Soc., (1978), 100 (6), 1820. T. Yuschikuni, J. Mol. Catal., 1992, 72, 29 ; N. Kitajima, S. Sunaga, Y. Moro-Oka, T. Yoshikuni, M. Akada, Y. Tomotaki, M. Taniguchi, Bull. Chem. Soc. Jpn., 61, 1035 (1988). N. Kitajima, S. Sunaga, Y. Moro-Oka, T. Yoshikuni, M. Akada, Y.Tomotaki, M. Taniguchi, Bull. Chem. Soc. Jpn., 61,967, (1988). M. Shimuzu, Y. Watanabe, H. Orita, T. Hayakawa, K. Takehira, Bull. Chem. Soc. Jpn., 66, 251 (1993). M. Shimuzu, Y. Watanabe, H. Orita, T. Hayakawa, K. Takehira, Tet. Lea., 32 (18), 2053 (1991). K. Takehira, M. Shimuzu, Y. Watanabe, H. Orita, T. Hayakawa, Tet. Lett., 31 (18), 2607, (1990). U.S. 4, 915,875 (04/11/1986), (to Dow Chemical). S . N . Sharma, S. B. Chandalia, J. Chem. Tech. Biotechnol., 49, 141, (1990), and references therein. JP 63154644, (1986) (to Mitsui Petrochemical), JP 62242644 A, (1986), (to Mitsui Petrochemical). J. Dakka, D. A. Sheldon, NL. 9200968-A (1992) (to DSM NV) ; JP 2172940, 2172941 and 2172942 (1988) (to Sumitomo) ; T. A. Andrew, M. Needham, US. Pat. 4,453,016 (1982) and U.S. Pat. 4, 471, 140 (1984) (to Dow Chemical) ; K. Freimund RShrscheid, U.S. Pat. 4, 748, 278 (31/05/1988) (to Hoechst), EP 323290-A (1987) (to Air Liquide) ; A. Schnatterer, H. Flege, US. 4929766 (1989) and US.Pat. 5130493 (1991), (to Bayer), A. Nishinaga, T. Itahara and T Matsuura, Angew. Chem. Internat. Edit., 14 (5), 356, (1975). S.K. Tanielyan, R. Augustine, J. Mol. Catal., 87, 311, (1994). E. Benazzi, H. Mimoun, C. J. Cameron, J. Catal., 140, 311, (1993). E. Benazzi, C.J. Cameron and H. Mimoun, J. Mol. Catal., 69, 299 (1991). D.R. Bryant, J. E. McKeon, B. C. Ream, J. Org. Chem., 33 (11), 4125 (1968). A.B. Goel, Inorg. Chim. Acta, 129, L31, (1987). A. B. Goel, Inorg. Chim. Acta, 121, L l l , (1986). A. B. Goel, Inorg. Chim. Acta, 90, (1984), L15. C. H. Bushweller, Tet. Lett., 58, 6123 (1968). D.R. Bryant, J. E. McKeon, B. C. Ream, Tet. Lett., 30, 3371, (1968) Matsuda, Teruo and Shirafuji, Tamio, JP 7879832 (1976), (to Sumitomo Chemical Co, Ltd). J.E. Lyons, Catalysis Today,1988, 3, 245. J.F. Lepage, in ,< Catalyse de contact ,,, Tecnnip Editions, 1978. T. Mallat, Z. Bodnar, P. Hug and A. Baiker, J. Catal., 153, 131, (1995) and references therein. E. Fache, M. Costantini, D. Laucher, FR 9207950, (29/06/92) and FR 9303488, (26/03/93) (to Rh6ne-Poulenc).
Pd-Sn / C catalyst is obtained by adding to a solution of 2.44 g palladium (II) acetate (10 mmol, Johnson-Matthey), 9.82 g of potassium acetate (100 mmol) in 400 ml acetic acid firstly 20 g of Ceca 3S charcoal (optionally treated with concentrated nitric acid according to known procedure (ref. 9b)) and then 16.1 g tin (II) 2-ethylhexanoate (39,75 mmol, Strem). The suspension is vigourously stirred and heated at 100~ for 4 hours. After cooling, the catalyst is recovered by filtration, washed with acetic acid and water and dried 5 hours under reduced pressure (50 mbar) at 50~ (Pd : 4,3 %; Sn : 2%).
389
Pd / C catalysts are synthezised according to usual methods (ref. 12). For instance, catalyst can be prepared by adding to a solution of 0.32 g palladium (II) acetate (1.4 mmol, JohnsonMatthey) and 0.98 g of potassium acetate (10 mmol) in 100 ml acetic acid 5 g of ceca 3S charcoal (optionally treated with concentrated nitric acid according to known procedure9b). The suspension is introduced in a stainless steel autoclave, heated at 100~ under 20 bar of hydrogen for 15 hours. After cooling, the catalyst is recovered by filtration, carefully washed with water and dried 5 hours under reduced pressure (50 mbar) at 50~ (Pd : 3.5%). Immediatly before the oxidation, the catalyst is reduced by hydrogen (200~ hydrogen : 1 l/h, 2 hours) ** The Pd-Pt / C catalyst is prepared according to the procedure describe for Pd / C catalyst, by mixing with the palladium salt, a platinum (II) or (IV) salt (hexachloroplatinic acid for instance) in the ratio (Pd: 2.85 %; Pt : 0.25 %).
390
LARGE P O R E TI-BETA ZEOLITE WITH VERY LOW ALUM]NIUM CONTENT 9AN ACTIVE AND SELECTIVE CATALYST FOR OXIDATIONS USING HYDROGEN PEROXIDE
MIGUEL A. CAMBLOR a) MICHEL COSTANTINI b) AVELINO CORMA a) PATRICIA ESTEVE a) LAURENT GILBERT b) AGUSTIN MARTINEZ a) AND SUSANA VALENCIA
a)
a) Instituto de Tecnologia Quimica (CSIC-UPV), Avda. Los Naranjos s/n, 46071 Valencia, Spain. b) Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie des Carri~res, 85 Avenue des Fr~res Perret, B.P. 62, 69192 SaintFons Cedex, France.
ABSTRACT The new large pore Ti-Beta zeolite has been synthesized in a wide range of chemical compositions and its activity and selectivity in the epoxidation of olefins and the hydroxylation of phenol has been tested. Several new synthetic procedures have been developed yielding innovative materials with chemical compositions out of the range previously known for zeolite Beta and with a predesigned composition profile in the crystallites. Catalysts with a reduced A1 content of up to 0.1 A1 atoms per unit cell of 64 tetrahedra and below with all the A1 confined into the very inner core of the crystallites show a good activity in the epoxidation of n-hexane with an enhanced selectivity to the epoxide. Optimization of the catalyst and of the reaction conditions for the selective hydroxylation of phenol can yield a valuable catalyst for this industrially important reaction. INTRODUCTION Zeolites are microporous crystalline solids which find a wide variety of industrial applications in the fields of ion exchange and separation, purification and catalytic transformation of organic compounds. As heterogeneous catalysts, most of their uses have been as acid catalysts where the combination of high acidity, high specific surface area and the shape selectivity derived from the size and shape of their 391
microporous channel systems made zeolites outstanding materials with no competitors in catalytic cracking and other petroleum and petrochemical processes. This has been the field of zeolites for over 30 years. However, recent advances in zeolite science are spreading the interest of zeolites as catalyst for a number of applications other than acid catalysis, including base and oxidation catalysis and photochemistry. An increased importance of zeolite catalysis in commodities and fine chemicals production can be thus envisaged. The interest of zeolites as oxidation catalysts begun with the synthesis of TS-1 (titaniumsilicalite-1) (ref. 1) and the subsequent reports on its catalytic performance using hydrogen peroxide in the presence of water. TS-1 is an active and selective catalyst in the epoxidation of olefins, the hydroxylation of aromatics, the ammoxidation of cyclohexanone (with NH 3 and H202), the oxidation of alcohols to ketones (ref. 2) and even the oxidation of alkanes to alcohols and ketones (refs. 3, 4). It has the outstanding property of being highly active in the presence of water, in contrast to other heterogeneous catalysts, even if they have the same overall composition (like the TiO2/SiO2 catalyst of Shell) (ref. 5). This can be an effect of having Ti species confined into the hydrophobic microporous channels, or of having Ti in a special environment or coordination, and makes Ti-zeolites an important subject of study from both the academic and the industrial points of view. TS-1 has a medium pore channel (-5.5,4,) which imposes severe geometrical restrictions to the size of the organic substrates to be oxidized (ref. 6), and also restricts the use of oxidating agents to H202. To overcome this limitations Ti-zeolites with larger pores were desirable. Along these lines of thought we reported the first synthesis of a large pore zeolite, Ti-Beta, with a tridimensional system of large pore channels (7-6.5A) (ref. 7). It was shown that this material while having lower intrinsic activity than TS-1 for the oxidation of organic substrates small enough to have no restrictions to enter the TS-1 pores, is more active than TS-1 for carrying out the oxidation of larger compounds (ref. 8). Additionally, Ti-Beta is active in oxidation reactions using tertbutyl hydroperoxide (ref. 9). Up to now, all the Ti-Beta samples reported contain A1 in framework positions. This implies that in activated samples, besides the Ti Redox sites, acid sites associated to framework A1 will also be present. The presence of the acid sites or the associated A1 may negatively affect the oxidation activity, but it certainly can catalyze other reactions such as formation of diols from epoxides, and undesired polymerization reactions. It is therefore of clear interest to prepare A1 free Ti-Beta zeolite by direct synthesis. Here we report a synthesis strategy which has allowed us to produce Ti-Beta samples with a much higher Si/A1 ratio than any one reported up to now, together with predesigned zeolite crystals containing very low A1 content all of it located in the 392
inner core of the crystallites, while leaving Ti in the outershell. This was expected to influence the catalytic activity and selectivity of Ti-Beta, and the results will be presented here. EXPERIMENTAL
Synthesis The synthesis mixtures were prepared using tetraethylammonium hydroxide (40 % aqueous solution, Alfa or 35 % aqueous solution, Aldrich) with a very low alkali
cations
content
(Na < 2ppm,
K < 0.Sppm),
deionized
water,
tetraethylorthotitanate (TEOT) or tetrabutylorthotitanate (TBOT) as a source of Ti and amorphous silica (Aerosil 200, Degussa) or tetraethylorthosilicate (TEOS, Aldrich) as the source of silica. Depending on the synthesis method a source of aluminum can be directly added to the synthesis mixture (metal A1, aluminum halide, etc.) or incorporated in the seeds of aluminosilicate zeolite Beta. Four synthetic procedures were developed and Table 1 summarizes the typical ranges of chemical composition of the initial mixture and the typical results of the syntheses. The methods are denoted according to the nature of the silica source and, in one case, the use of seeds. The preparation of the reaction mixtures was as follows" Amorphous silica method - TEAOH was diluted in a certain amount of water and the TEOT and Aerosil were added sequentially under stirring. Finally, a solution of aluminum nitrate in TEAOH and water was also added. (ref. 10) TEOS method- TEOS is hydrolized in an aqueous solution of TEAOH with stirring, then TEOT is also hydrolized. Finally, a solution of aluminum nitrate in TEAOH and water is added and the mixture is left, while stirring, until all the ethanol formed in the hydrolisis is evaporated. (ref. 11) TEOS/seeds method - TEOS is hydrolized in an aqueous solution of TEAOH under stirring, then TEOT is also hydrolized and the mixture is left, while stirring, until complete evaporation of the ethanol produced. If desired, H202 can be added either before or after TEOT addition. Then seeds are added to the clear solution formed and the mixture is kept under stirring to get an homogeneous mixture. Typically, the amount of seeds is around 2.5-3 g of zeolite Beta crystals per 100 g of SiO2 in the reaction mixture. No A1 solution is added. (ref. 12) TiO2/SiO 2 cogel method - A TiO2/SiO 2 coprecipitate is used as the source of Si and Ti and this is wetness impregnated with a solution containing A1 and TEAOH. The TiO2/SiO 2 cogel is prepared by first hydrolizing TEOS in a mildly acidic solution (HC1). Then a solution of TBOT in isopropanol is added under stirring. The pH of the resulting clear solution is then rised to 6.0 by addition of a small amount of a base (typically, tetraethylammonium hydroxide or tetrapropylammonium hydroxide). This 393
causes the precipitation of the TiO2/SiO 2 cogel, which is then dried to 110~ The dried cogel is then wetness impregnated with a solution containing TEAOH and a source of A1. (ref. 13) The synthesis mixtures were crystallized by heating at the crystallization temperature (usually 135-145~ in PTFE lined stainless steel 60 ml autoclaves. During crystallization the autoclaves are rotated at 60 rpm. After quenching with tap water, the solids are recovered by centrifugation and washed with distillate water until pH < 9. Then the solids were dried at 100~ 580~
for several hours and calcined at
to remove the tetraethylammonium cations occluded into the zeolitic channels.
Characterization Phase purity of the zeolites was determined by conventional X Ray powder diffraction (XRD) methods using a Philips 1060 diffractometer with a graphite monochromator and a variable divergence slit operating in the constant area mode. Cu K~ radiation (k = 1.541A) was used. The crystallinity was determined by measuring the total area under the main diffracted peak (2 0 -- 22.5 o) and comparing it with that of a highly crystalline aluminosilicate zeolite Beta. The chemical composition was determined by atomic absorption spectroscopy using a Spectra A-10 Plus Varian spectrometer. The absence of Ti oxides out of the zeolite framework was checked by diffuse reflectance Uv/Visible spectroscopy (Shimadzu UV-210PC spectrophotometer, reference BaSO4). Catalytic tests 1-hexene oxidation was carried out at 50~ in a round bottom glass flask equipped with a condenser and a magnetic stirrer. In a typical run 33 mmol of 1hexene, 23.6 g of methanol and 0.8 g of H202 aqueous solution (35 wt %) are mixed in the flask and heated to the reaction temperature under vigorous agitation. Then 0.2 g of catalyst is added to the reaction mixture (time zero). The kinetics of the reaction was followed by taking aliquots at five reaction times (between 0.5 and 5 hours). The products were analyzed by gas chromatography using a capillary column (5 % methylphenylsilicone, 25 m length) and a FID detector. For the H202/1hexene ratio used the maximum conversion of 1-hexene would be 25 %. The catalytic oxidation of phenol with hydrogen peroxide was performed in a round-bottom flask equipped with a condenser and a magnetic stirrer. In a typical reaction, given amounts of catalyst, phenol and solvent were mixed in the flask and heated to 80~ under vigorous agitation. The reaction was started by dropwise addition of 35 wt % aqueous hydrogen peroxide solution using a perfusion pump (addition time --1 min.). The reaction was stopped at 3 h by cooling the flask to 394
room temperature and then, the mixture was filtered to remove the catalyst. When water was used as solvent, methanol was added before filtering to homogenize the mixture. Products were analized by HPLC in a Waters Associates 440 apparatus equipped with a UV detector (254 nm) using a 100 RP-18 column (5 ~tm, 125 mm.). The amount of unreacted hydrogen peroxide was determined in both cases by iodometric titration. RESULTS AND DISCUSSION
Design of the synthetic procedure Four methods have been developed for synthesizing highly crystalline zeolite TiBeta. The aim was to prepare a catalyst with as low Al content as possible, in view of the detrimental effect of the acid character and the hydrophilic nature of the material in the catalytic oxidations with H202. Two of these methods afford Ti-beta with Si/A1 ratios more than 50 % larger than those previously claimed for zeolite Beta (5-100). However, the A1 content was still high. Then we designed a synthesis procedure which, while producing Ti-Beta with very high Si/A1 ratios, yields a material with extreme chemical zoning: an inner core of aluminosilicate zeolite is covered by a titanosilicate outer shell. The following illustrates how this synthesis procedure was designed. The
first
methods
reported
for
the
synthesis
of Ti-Beta
involved
the
crystallization, without the aid of seeds, of synthesis mixtures prepared using one of two different sources of Si (amorphous silica (7) and TEOS (11)) in the absence of alkali cations. Both methods gave similar results (Table 1) except that the TEOS method produced, for the same crystallization time, temperature and overall chemical composition in the starting mixture, higher Si/A1 ratios in the final zeolite. That just means that TEOS is a more reactive silica source than Aerosil. However, the upper limit for the Si/A1 ratio of the zeolite was the same in both cases (--150) (14). The isomorphous substitution of Si by Ti was evidenced by XRD, IR, XANES and EXAFS, (ref. 15) and the catalysts were found active in the oxidation of alkanes to alcohols and ketones (ref. 7) and in the oxidation of olefins (ref. 11) using hydrogen peroxide or tert-bu~l hydroperoxide (ref. 9). However, when H202 was used as the oxidant selectivity to the epoxide was found to be low due to the presence of acid sites that catalyzed the addition of the solvent (usually methanol) to the oxirane ring (see below). Using tert-butyl hydroperoxide as the oxidant afforded -- 100% selectivity to the epoxide with a somewhat lower oxidation rate. (ref. 9)
395
Interestingly, we observed a competition between Ti 4+ and A13+ in the crystallization of zeolite Ti-Beta (ref. 14). This competition was reflected in the following facts : -the higher the A1 content in the initial mixture, the lower the Ti content in the zeolite.
-the higher the Ti content in the initial mixture, the lower the A1 content in the zeolite. -
the Si/A1 (or (Si + Ti)/A1) ratios of Ti-Beta largely exceed the upper limit previously
found for zeolite Beta synthesized from gels containing alkali cations in the absence of Ti (Si/A1 ---40) (ref. 16). - t h e surface chemical analysis (XPS) indicated that, for Ti-Beta samples with Si/A1 ratios higher than 100, the outer shell of the crystallites contained no A1 at all, contrarily to what is found in the absence of Ti. To explain this competition we hypothesized that Ti could play a role similar to that of A1 in the crystallization of zeolite Beta, that is, the creation of negative charges in the framework and thus its stabilization by interaction with the TEA § templating cations. This hypothesis was also supported by the fact that the amount of TEA § cations decomposing at T > 6 2 0 K in air (as determined by thermal analysis) was dependent on the total amount of A1 + Ti, rather than only on A1 (ref. 14). This hypothesis required the ability of zeolitic Ti to change its coordination number, something which obtained substantial support from XANES and EXAFS measurements (ref. 15). As a result from this early work we thought that zeolite Beta crystals can grow without the incorporation of a trivalent element (A1, Ga, B, Fe,...) provided that Ti is incorporated into the framework. This was actually supported by the fact that, as mentioned above, Ti-Beta samples with Si/A1 ratios higher than 100 have no A1 in its outer shell, which means that in the last steps of its crystallization these samples grow without A1 incorporation. Unfortunately, we were unable to synthesize Ti-Beta in the absence of aluminium (or other T3+), the conclusion being that a trivalente element is necessary for zeolite Beta to nucleate. Obviously, crystallization of pure titaniosilicate zeolite Beta without A1 could then be possible if the nucleation problem was solved. We have done this by seeding with highly active zeolite Beta seeds comprised of very small zeolite Beta crystals (typically --0.05 mm and below) showing good stability in the synthesis media (TEOS/Seed method) (ref. 12). In this way it is possible to synthesize highly crystalline zeolite Ti-Beta with Si/A1 ratios well above those obtained by other synthesis procedures, for example Si/A1 ratios about 1000. Additionally, as shown by XPS, the crystals obtained by this procedure consist of an inner core of 396
aluminosilicate composition (which are basically the seeding crystals) covered by an outer shell of titanosilicate composition and essentially free of A1. The Ti-Beta outer shell can account for up to about 97.5 % of the mass of crystals. Fig. 1 schematically illustrates the chemical zoning in these "second generation" Ti-Beta materials.
Fig. 1. Schematic representation of chemical zoning in Ti-Beta catalysts prepared by the TEOS/Seed method
Finally, we have developed still another synthetic procedure (TiO2/SiO 2 cogel method), aimed to afford very high yields of Ti-Beta zeolite using a small amount of tetraethylammonium hydroxide (ref. 13). The method consists in the crystallization of a TiO2/SiO 2 cogel after wetness impregnation with a solution containing A13+ and TEAOH. This method gives good results for intermediate Si/A1 ratios but it doesn't allow the synthesis of Ti-Beta with A1 contents as low as those obtained with the TEOS/Seed method (Table 1).
397
Table 1. Methods for the synthesis of zeolite Ti-Betaa Typical Ti-Beta products
Typical gel compositions Method
SiO2/A1203 H20/SiO2
Zeolite Betaa
30-800
10-15
Amorphous silica
50-800
10-15
TEOS/seeds TiO2/SiO2 cogel
c. d.
20400
Si/A1
%TiO2 Yieldd
0.3-0.5
1140
0
0-10
0.5
50-150
1-6
-- 10
1-6
--- 10
, . .
TEOS
a. b.
SiO2frio 2 TEAOH/SiO2
50-800
10-15
20400
0.5
50-150
400-2000 b
10-15
20-1000
0.5
100-1(130b 0.3-6 c
15-30
30-120
0.4
50-300
15-30
50-800
5
1-6
The synthesis of zeolite Beta with no Ti is included for comparison (16) All the A1 is incorporated to the synthesis mixture in the aluminosilicate zeolite Beta seeds, and is confined to the inner core of the final product. Ti is incorporated to the outer shell of the crystallites. g of zeolite per 100g of initial mixture. To further illustrate the differences between the methods, Fig. 2 and 3 show the
yield and the Si/A1 ratio, respectively, of the zeolite as a function of time of crystallization for synthesis runned by the four methods. Obviously, it is not possible to compare synthesis with the same chemical compositions because of the differences of the methods. Accordingly, in Fig. 2 and 3 we compare synthesis runs that gave, for every method, high Si/A1 ratios and high zeolite yields. In this figures it is seen how our
"classical" syntheses of Ti-Beta zeolite (amorphous silica and TEOS
methods)
have
been
surpassed
by the
new,
previously
unpublished
methods
(TEOS/seed and cogel methods), if the Si/A1 ratio of the zeolite and its yield are compared. Furthermore, the TEOS/seed method is the most versatile one in terms of varying the chemical composition of the zeolite, and thus we have prepared materials wich are essentially pure silica (A1 plus Ti contents below 0.2 atoms per unit cell of 64 tetrahedra).
398
g zeolite / 100 g gel 25
20
J
S
15
10
0
0
5
10
15
Time (days) Fig. 2. Variation of the yield of Ti-Beta zeolite as a function of crystallization time at 135~ Gels prepared by the amorphous silica (o), TEOS (+), TEOS/Seed (*) and cogel ( I ) methods
Si / A1 in zeolite 1.000
800
600
400
200 _____.-.+ O
L
0
5
10
15
Time (days) Fig. 3. Variation of Si/A1 ratio of Ti-Beta zeolite as a function of crystallization time at 135~ Gels prepared by the amorphous silica ( ) , TEOS (+), TEOS/Seed (*) and cogel (n) methods. 399
C A T A L Y T I C TESTS
Epoxidation of 1-hexene Table 2 lists results obtained in the oxidation of 1-hexene with H20 2 using representative Ti-Beta zeolites prepared by the new TEOS/seed and cogel methods. The influence of the A1 content of Ti-Beta on the selectivity to the epoxide is clearly seen in Table 2. For the same level of 1-hexene conversion, the lower the A1 content in the catalyst the higher the selectivity to the epoxide. This is a consequence of the presence of strong acid sites due to the presence of A104- units in the framework. These acid sites act as catalysts for the opening of the oxirane ring by addition of either water produced in the decomposition of H20 2 (to give the glycol product) or methanol (to give the methyl glycol ether). The relationship between the selectivity and the A1 contem for a given conversion is not linear, being the enhancemem in selectivity as the A1 content increases more remarkable, when the lower the A1 content is. Table 2. Influence of the A1 content of the Ti-Beta on the selectivity to epoxide during the oxidation of 1-hexene at -- 4 % hexene conversion Si / A1 ratio
epoxide selectivity (%)
43 300 470 550 700
3 43 61 73 85
The epoxide selectivity problem can be completely solved by exchanging the zeolitic H § by Na § The Na § form of the catalyst show a --100% selectivity to the epoxide, while only a minor decrease in the activity is found (Table 3). However, it should be considered the leaching of Na § with time.
400
Catalyst
Type
SilAl
%Ti02
L'ogel
43
4.2
Cogel
300
4.7
React ion Time (h) 0.5 I 2 3.5 5 0.5 1
TEOSIS
470
3.3
2 3.75 5 0.5 1
TEOS/S
TEOSIS
550
550 (Na')'
3.0
3.0
2 3.75 5 0.5 1 2 3.83 5 0.5 1
TEOSIS
700
6.3
2 3.83 5 0.5 1.2 2 3.5 5
Product selectivity (mol %)
1-c6
conver. (mol%) 2.32
i:::
9.13 10.97 3.68 6.25 9.47 13.72 15.66 1.84 3.25 5.35 8.10 10.22 2.00
i::;
1 1.20
12.12 1.10 2.41 5.03 11.03 12.93 7.02 12.17 16.37 19.93 19.68
1 I II I
I
I
I
1 1
I
1 I
I
I
Epoxide
Glycol
MGE
8.09 3.38 1.36 0.71 0.46 45.94 25.87 15.28 9.69 7.63 87.73 66.49 46.11 32.96 27.30 98.72 75.82 52.00 33.38 31.74 100.00 100.00 100.00 99.27 98.47 56.11 37.73 27.77 19. I7 8.59
0 0 0 0 0 0 0 0 0 1.47 0 0 0 0 3.15 0 0 0 0.35 2.09 0 0 0 0 0 0 0.9 4.40 5.66 7.13
91.91 96.62 98.64 99.29 99.54 54.06 74.13 84.72 90.31 90.90 12.27 33.51 53.89 67.04 69.55 1.28 24.18 48.00 66.27 66.17 0 0 0 0.73 1.53 43.89 61.37 67.83 75.17 84.28
H202 (niol %)
1 I I
Conv.
Selec.
10.94 23.51 36.79 50.95 58.09 17.80
80.95 63.09 67.85 68.35 72.02 78.61 77.76
I
I
75.93 7.76
78.42 90.94 80.38
I
I I
I I
52.83 8.23
74.03 92.12
30.34
79.49
59.66 4.72
76.88 88.92 81.16
I 1
59.66 35.90
82.91 84.39
72.5 I
97.40
94.10
90.22
a) Nat form of Ti-Beta zeolite, obtained by contacting the zeolite with a Na acetate solution under reflux conditions.
TON (moVmol of Ti 7.5 12.5 21.1 29.4 35.3 10.6 18.0 27.3 39.5 45. I 7.8 13.7 22.6 34.3 43.2 9.1 16.4 28.9 50.7 54.9 5.0 10.9 22.8 50.0 58.6 15.I 26.1 35.2 42.8 42.3
In addition to the effect on the product selectivity, it is seen in Table 3 that, for a given synthetic method, the activity (1-hexene and H202 conversion) as well as the selectivity of H202 increases as the A1 content of the zeolite decreases. These results show that the AI content of zeolite Ti-Beta is one of the most important factors in determining its activity and selectivity in oxidation reactions, and the benefits that the new methods of synthesizing Ti-Beta with low A1 content can provide.
Hydroxylation of phenol For this reaction a high selectivity to diphenols with a high para-selectivity is desired. It appears that both parameters are related, so generally the higher the selectivity to diphenols the lower the catechol/hydroquinone ratio. We have found with Ti-Beta catalysts that the synthesis procedure is very important in determining this relationship. Thus, as it is shown in Fig. 4 (hydroxylation using acetone as a solvent), with catalysts synthesized by the TEOS/seed procedure it is possible to obtain a much higher selectivity to diphenols for a given catechol/hydroquinone ratio.
Diphenols selectivity (mol/100rnol H202) 70
60
. . . . . . . . . . . . . . . . . . . .
'
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
a 9
40 .
.
.
.
w
.
.
.
.
.
.
.
.
.
.
.
30
20
1
1,1
1,2
1,3
1,4
1,5
1,6
1,7
1,8
1,9
2
2,1
2,2
CTOL/HO.
Fig. 4.
Selectivity to diphenols (in mol % relative to H202) vs catechol to hydroquinone ratio in the hydroxylation of phenol with H202 using several Ti-Beta catalysts. Phenol / acetone / U20 = 50 / 65 / 6.5 (mol) : Ti-Beta / phenol = 4.5 g/mol ; H202/phenol = 5 % (mol). Reaction temperature 80~ 3h Reaction time. Ti-Beta materials prepared by TEOS / Seed (=), cogel (11), aerosil (+) and TEOS (*) methods. 402
In Table 4 we presem the results of catalytic tests in several conditions using a TiBeta prepared by the cogel method. There it can be seen that water is a good solvent from the point of view of activity and selectivity and that it is possible to obtain about equimolecular amounts of catechol and hydroquinone while keeping the selectivity to diphenols above 50 %. Table 4. Hydroxylation of phenol using a Ti-Beta catalysta Results referred to H202 (molar)
Reaction conditions H20 Solvem (g) (g) 0.23 Acetone, '7.55 1.55 t-BOH, 7.4 t-BOH,7.4 9.4 9.4 18.8 18.8 18.8 CH3CN18.8 9.0 Dioxane, 1.6 -
T (~ 80 80 80 94 80 80 80 80 80 80
Time (h) 3 3 3 3 3 3 1b 3c 3 3
Conversion ( %) 94 95.5 98 100 98 100 98.5 100 94 97
HQ
CTOL
17.5 14 17 24.5 25 24.5 27 26.5 17.5 23
23 13 16 24.5 22 24.5 28.5 25 28.5 21
Total CTOL/HQ diphenols 40.5 1.3 27 0.95 33 0.92 49 1.0 47 0.88 49 1.0 55.5 1.05 51.5 0.94 46 1.6 44 0.91
a) 9.4g phenol; H202/phenol:5%mol 9 0.45g catalyst, Ti-Beta (cogel method), Si/A1 73, 3.4%TIO2. b) 0.9g catalyst c) 1.35g catalyst
CONCLUSIONS It has been presented here that there is not a unique Ti-Beta material, but the characteristics and catalytic performance strongly depend on chemical composition and synthesis procedure. Then, new synthesis procedures which allow to prepare samples with much lower A1 content than any one reported before have been developed. Moreover, by using highly reactive and stable seeds, crystals of Ti-Beta zeolite have been produced, which have an inner core of aluminosilicate composition, covered by an outer shell of Titanosilicate which accounts for about 98 % of the mass. These synthesis methods have lead to samples which present an improved catalytic behaviour for reactions such as olefin oxidation and phenol hydroxylation using H202 as oxidant.
403
References 1. M. Taramasso, G. Perego, B. Notari, U.S. 4 410 501, (1983). 2. U. Romano, A. Esposito, F. Maspero, C. Neri, M.G. Clerici, Stud. Surf. Sci. Catal., 55, 33, (1990). 3. T. Tatsumi, M. Nakamura, S. Negishi, H. Tominaga, J. Chem. Soc., Chem. Commun., 476, (1990). 4. Huybrechts, D.R.C., L. De Bruycker, P.A. Jacobs, Nature, 345,240, (1990). 5. R.A. Sheldon, J. Mol. Catal., 7, 107, (1980). 6. T. Tatsumi, M. Nakamura, S. Negishi, H. Tominaga, J. Chem. Soc., Chem. Commun., 476, (1990). 7. M.A. Camblor, A. Corma, A. Martinez, J. P6rez-Pariente, J. Chem. Soc., Chem. Commun., 589, (1992). 8. A. Corma, M.A. Camblor, P. Esteve, A. Martinez, J. P6rez-Pariente, J. Catal., 145, 151, (1994). 9. A. Corma, P. Esteve, A. Martinez, S. Valencia, J. Catal., 152, 18, (1995). 10. M.A. Camblor, A. Corma, J. P6rez-Pariente, Sp. Pat. 2,037,596, (1993). 11. M.A. Camblor, A. Corma, A. Martinez, J. P6rez-Pariente, S. Valencia, Stud. Surf. Sci. Catal., 82, 531, (1994). 12. M.A. Camblor, A. Corma, M. Costantini, L. Gilbert, J. P6rez-Pariente, S. Valencia, FR Pat. 95/01824, (to Rh6ne-Poulenc), (17/02/95). 13. M.A. Camblor, A. Corma, M. Costantini, L. Gilbert, J. P6rez-Pariente, S. Valencia, FR Pat 95/01823, (to Rh6ne-Poulenc), (17/02/95). 14. M.A. Camblor, A. Corma, J. P6rez-Pariente, Zeolites, 13, 82, (1993). 15. T. Blasco, M.A. Camblor, A. Corma, J. P6rez-Pariente, J. Am. Chem. Soc., 115, 11806, (1993). 16. M.A. Camblor, A. Mifsud, J. P6rez-Pariente, Zeolites, 11,792, (1991).
404
PEPTIDE SYNTHESIS BY SAPPHO TECHNOLOGY
JEAN-MARIE BERNARD, KAMEL BOUZID, JEAN-PIERRE CASATI, MARIE GALVEZ, CHRISTIAN GERVAIS, PIERRE MEILLAND, VIRGINIE PEVERE, MARIE-FRANCE VANDEWALLE, JEAN-PAUL BADEY AND JEAN-MARIE ENDERLIN
Rh6ne Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie, 85 Avenue des fr~res Perret, B.P. 62, 69192 Saint Fons Cedex, France.
INTRODUCTION Peptides are molecules very active at low concentration. They are used in pharmaceutical, agrochemical and nutritional areas. The synthesis of these compounds (ref. 1) is very dependant on the sequence and the quantity required. To synthesize short peptides, at high volume and low cost, chemist prefer to use the N carboxyanhydrides (NCA) of aminoacids, protected if necessary on the side chain reactive functional groups. This is the case for intermediates of angiotensing converting enzyme peptides such as L-alanyl-L-proline and Ne-(TFA)-L-lysyl-Lproline. This method is however very difficult to use repetitively for long peptides, because it gives quantities of oligomers (more than 2 - 3 %) at each coupling step and the purity of the final peptides is poor. This is the reason why peptide chemists, to decrease the problems of purification prefer for long peptides to use protecting groups (tert-butyloxycarbonyl (t-Boc), benzyloxycarbonyl (Z), fluorenylmethyloxycarbonyl (FMOC) .... ) and classical reagents such as T.B.T.U. (O-1H-benzotriazol-l-yl)-l,l,3,3-tetramethyl uronium tetrafluoroborate), B.O.P.(benzotriazol-l-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate and so on in polar solvents such as N,N-dimethylformamide or N-methylpyrrolidone. But this solvents are not compatible with the acidic deprotection reagents such as trifluoroacetic acid and 405
necessite many solvent exchange or precipitation at each coupling or deprotection step. That is the reasons these methods are long and expensive. Recently, we have searched new, for economical ways to synthesize long peptides. We have now developed new methodology to produce peptides at low cost, continuously and automatically without precipitation and isolation at different steps of the synthesis. The name of this process is SAPPHO (in french : Synth~se Automatis6e de Peptides en Phase HOmog~ne). Different peptides or peptide fragments have been synthesize by this technology. We present here the synthesis of fragments of the salmon calcitonin.
THE SAPPHO TECHNOLOGY SAPPHO is a powerful new innovative technology for the automated large scale synthesis of peptides in solution phase, which can lead to significant cost saving of up to 50 % compared to the traditional technologies (in homogeneous phase or Merrifield phase). SAPPHO technology which combines a modular approach to synthesis with an innovative solubilisation system guarantees 9 the simplicity and reproducibility of the synthetic process the direct synthesis of the final product in high purity on line quality control at each stage. The patented solubilisation system enables the same solvent to be maintained throughout each coupling cycle, thus avoiding any need for interim purification, precipitation or difficult solvent exchange. The solubilisation system comprises 9 An organic solvent, non miscible with water (ref. 2). - A phenolic additive to enhance solubility (ref. 2), which gives no side reaction with the peptides all along the coupling cycle. The additive gives hydrogen bonds with the amide groups of the peptide and decreases the interactions between the molecules of peptide.The major consequences are a better solubilisation of the peptides in the medium which permits synthesis at high molar concentration. - A lipophilic, non polymeric, aromatic carboxyl protecting group protector (ref. 3), having good solubility in the organic solvent, stable throughout the synthesis. This protecting group is easily cleaved at the end of the synthesis by classical reactions like saponification, hydrogenolysis or other technologies. The choice of this protecting group and the cleavage method is dependent of peptide sequence and functional alpha amino and side chains protecting groups. -
-
-
-
406
Each successive amino acid is coupled with the growing peptidic chain through the repetition of a simple 4 step cycle: coupling, extraction, drying, and deprotection of the alpha nitrogen protecting group. In the SAPPHO process, the N-tert-butyloxycarbonyl (N-t-BOC), the Nallyloxycarbonyl (N-ALLOC), and the N,N-diallyl can be used for the protection of the alpha amino function. The functional side chains can be protected by different classical orthogonal protecting groups. Different coupling reagents such as N-hydroxysuccinimide activated esters of amino acids, T.B.T.U. ((O-1H-benzotriazol-l-yl)-l,l,3,3-tetramethyl-uronium tetrafluoroborate), or N protected N carboxyanhydrides of amino acids (UNCA), and so on can be used in the SAPPHO technology. The excess of reagents (coupling reagents and N protected amino acids) is very low (10 to 20 %, compared with the excess used (400 to 600 %) in solid phase synthesis (Merrifield synthesis)). After the coupling step, the excess reagents are transformed into hydrophilic species eliminated with the co-products during aqueous washing. The N protecting group is cleaved by the appropriate patented method. (ref. 4). For the cleavage of the N-ALLOC protecting group, the drying step can be avoided. Quality control at each step of the cycle enables high yields of 97.5 % per cycle (more than 99.5 % for the coupling and deprotection steps) to be achieved and simplifies the final purification. The SAPPHO process also permits peptide fragment coupling. This technology has been successfully applied to the synthesis of various peptides (Leucine Enkephaline, Luteinising Hormone Releasing Hormone (L.H.R.H.), calcitonin fragments...).
CALCITONIN FRAGMENTS SYNTHESIS Salmon calcitonin is a calcium regulated hormone which inhibits the bone resorption of calcium ions. It is a polypeptide of 32 amino acids. The Salmon calcitonin is currently manufactured by solid or liquid phase synthesis. Two protected fragments of the salmon calcitonin (1 to 10 and 25 to 32) have been synthesized by the SAPPHO process. All the aminoacids have the L configuration.
407
P r o t e c t e d (1-10) salmon calcitonin
Boc~Cys~Ser(O- BzI)- Asn-- Leu--Ser (O-Bzl)--Thr (O-BzI)--Cys-- Val~ Leu--Gly--COOH !
I
S
S
I
t
P r o t e c t e d (25 - 32) s a l m o n calcitonin
HC1, Thr (O-Bzl)-Asn-Thr(OBzl)-Gly-Ser(OBzl)-Gly-Thr(O-Bzl)-Pro-O-GPC The structure of the GPC group (carboxylic protective group) is 9
O
SYNTHESIS OF P R O T E C T E D (25 - 32) SALMON CALCITONIN The procedure of Gisin (ref. 5) has been used for esterification of L proline.The cesium salt of the N-tBoc L-Proline reacts with the (3-phenoxybenzyl) 4 chloromethylbenzoate (CI-GPC), in N,N-dimethylformamide (DMF). (Fig. 1)
Cs §
o -o
CI
9
-o CI-GPC
80~ + CSCI
Fig. 1. Synthesis of the lipophilic ester of N-tBoc L-proline
Then, after deprotection of the N-tBoc group with dry HC1 gas, the protected N tBoc aminoacids are successively introduced, at room temperature, on the chlorhydrate of the lipophilic L-Proline ester, by using T.B.T.U. as coupling reagent and diisopropylethylamine (Fig. 2.). A 15 % excess of T.B.T.U and N tBoc amino acids is used for the coupling steps. 408
Thr
Asn Thr
Gly Ser
Gly Thr
Pro Boc-Pro-OGPC
Boc-Thr(OBzl) -Pro-OGPC Boc-Gly -Thr(OBzl) -Pro-OGPC Boc-Ser(OBzl)-Gly -Thr(OBzl) -Pro-OGPC Boc-Gly-Ser(OBzl)-Gly-Thr(OBzl) -Pro-OGPC Boc-Thr(OBzl)-Gly-Ser(OBzl)-Gly-Thr(OBzl) -Pro-OGPC Boc-Asn-Thr(OBzl)-Gly-Ser(OBzl)-Gly-Thr(OBzl) -Pro-OGPC Boc-Thr(OBzl)Asn-Thr(OBzl)-Gly-Ser(OBzl)-Gly-Thr(OBzl) -Pro-OGPC coupling reagent: TBTU / Room temperature//deprotection reagent: dry HC1 gas//SAPPHO process
Fig.2. Scheme of synthesis of protected (25-32) Salmon Calcitonin
The molar concentration of the peptide in the solvent ranges between 0.25 M/L for the dipeptide Boc Thr (O-Bzl) - Pro - GPC and 0.1 M/L for the octapeptide Boc Thr (O-Bzl) - A s n - T h r (O Bzl) - Gly - Ser (O-Bzl) - Gly -Thr (O-Bzl) - Pro OGPC. The co-products (hydroxybenzotriazol, N,N,N',N'- tetramethylurea and the excess of N tBoc amino acids) are eliminated by aqueous extractions. The N tBoc group is cleaved with dry HC1 gas which gives volatile co-products (CO2, isobutene and tButyl chloride) eliminated by distillation. Yields of each coupling and deprotection steps are always more than 99.5 %. The reaction times of coupling and deprotection are always, respectively, less than 6 hours and less than 2 hours. 100 g of the protected (25 - 32) salmon calcitonin is isolated by precipitation with diisopropyl ether (71.5 %). The high performance liquid chromatography (HPLC) profile of the crude product is given in Figure 3.
409
--\
\ ql I . 7~. ' ;4.,06 --'-~_
.~1
:," . : : j
,
~,
....... "~"
" ~ ,~: . $ 6
I ~
ClATG ~
.'3 31X Z : ~
Fig.3. HPLC Profile of protected (25 - 32) Salmon Calcitonin
S Y N T H E S I S O F P R O T E C T E D (1 - 10) S A L M O N C A L C I T O N I N The synthesis of this fragment has been synthesized, using procedure. (Fig. 4.) Cys
Ser
Asn
Leu
Ser
Thr
Cys
Val
Leu
the
same
Gly
Boc-Gly-OGPC Boc-Leu--- GIy-OGPC Boc-Val . . . . Leu --- Gly OGPC Boc-Cys(S-Acm)-Val . . . . Leu--- GIy-OGPC Boc-Thr(OBzl)-Cys(S-Acm)-Val . . . . L e u - - - Gly-OGPC Boc-Ser(OBzl)-Thr(OBzl)-Cys(S-Acm)-Val . . . . Leu --- G ly-OGPC Boc-Leu . . . . Ser(OBzl)-Thr(OBzl)-Cys(S-Acm)-Val . . . . Leu --- GIy-OGPC Boc-Asn---Leu . . . . Ser(OBzl)-Thr(OBzl)-Cys(S-Acm)-Val . . . . Leu --- GIy-OGPC Boc-Ser(OBzl)-Asn---Leu . . . . Ser(OBzl)-Thr(OBzl)-Cys(S-Acm)-Val . . . . Leu --- Gly-OGPC Boc-Cys(S-Trt)-Ser(OBzl)-Asn---Leu . . . . Ser(OBzl)-Thr(OBzl)-Cys(S-Acm)-Val . . . . Leu--- GIy-OGPC coupling reagent: T B T U / R o o m t e m p e r a t u r e / / d e p r o t e c t i o n
reagent: dry HCI g a s / / S A P P H O
Fig. 4. Synthesis of the protected (1-10) Salmon Calcitonin 410
process
We have observed that T.B.T.U. gives a little dehydration of the side chain of asparagine. This side reaction has been confirmed by synthesis of an authentic cyanoalanyl peptide and HPLC analysis. Optimisation conditions have been fc,und to decrease the level of this side reaction : low temperature, minimisation of the quantity of diisopropylethylamine used during the coupling step and use of hydroxysuccinimide ester of asparagine as the activated aminoacid. The cyano alanyl peptide can be eliminated by preparative HPLC at the end of the synthesis. The analysis data (Mass spectra and HPLC profile) of the crude protected (1-10) salmon calcitonin are given in Figure 5 and Figure 6. FAB+ Magnet EpM:243 File T e x t : K B - 1 5 9 7 - D M F / N B A 100%
Bpi:22003712
AutoSpecEQ
24311 .......
90.
TIC:99330400
Flags:NORM
50.00 ............
lo0.o0 .........
i 2i2E 0E7 8E7
80.
5E7
70
307.08
60
3E7 1
5o~ 40
91.00
6E6
30_
364.14
0
165.08
"'-STxo....
4
t , 14q~.15 661.26 l,.lt,i~.lt/ 4160.1~ 552,-2~08 27 [
20. 10
IE7
IIIdtll, ddJI, Ldt.lll .... k k . . ~ . L i ~ , , l
26o
-~--S~o . . . . .
4;0 ....
i6o ....
x100.00
100~
,.~, ~ ' ~ , _ l J . . . . . .
6;0 ....
759.37
90,.4
J,. _.i~,m,.i,_L . . . . .
7~o . . . .
.do ....
tx o . . . .
950 . . . .
;0 ~
4E6
~ 2~.6 0E0
./=
2 2E7
2 0E7
9o_~ 8o~
1 8E7
1702 75
1 5E7
70-
1 3E7
60
1 IE7
50
_8
40
8E6
6 6E6
30
1425.62 i
lO.~
i
ii00
1200
1300
1400
.....
1579.74
1500
1600
[
]~..t "
i
~
'
.
4 4E6 2 2E6 ,L_. I
1700
...........
1800
Boc__ ?ys--Ser-- Asn- Leu--Ser-- Thr--?ys-- Val-- Leu--Gly OH SFrt
OBzl OBzl S-Acre
L.. 91 (100 %) (35 %) 243
[MH]+ = 1679 - B ~ [MNa]+ = 1701
S-Trt
1579 -Acm"-- 1508 ~
1425
Fig.5. Mass spectra of the crude protected (1-10) salmon calcitonin 411
_t
1900
~ __.~j_ 0 0 E O
2000
M/Z
"
E" Z
s:.
~, 2
. "
Fig. 6. H.P.L.C. profile of the crude protected (1-10) salmon calcitonin
The protected peptide is isolated, before disulfide bridge formation, by precipitation from its N-methylpyrrolidone solution (95.5 % yield) with water. After saponification in DMF, the carboxylic protected (1 - 10) salmon calcitonin fragment is isolated by precipitation with acidic aqueous medium. The precipitate is washed with acetonitrile to give a white powder (80.5 %). The scheme of the the disulfide bridge synthesis is shown in Figure 7. Different protecting groups (S-Trityl, S-Acetamidomethyl...) have been introduced on the cysteine side chains to optimise the reaction conditions of disulfide bridge formation. The conditions developed by Kamber and his group have been used to make the disulfide bridge (ref. 5). The best results have been obtained when we use S trityl on the L-cysteine and S-acetamidomethyl on the 7 cysteine in N,N-dimethylformamide in the presence of an excess of iodine (4 equivalents). The excess of iodine is eliminated with ascorbic acid. The final peptide is isolated by precipitation with water.
412
Boc--CysmSer(O-Bzl) - Asn~ Leu--Ser (O-Bzl)- Thr (OBzI)--Cys-- Val-- Leu~Gly--O nGPC I
I
SwTrt
SmAcm
R.T.
1
NaOH
Boc~Cys--Ser(O- Bzl)- Asn~ LeuwSer (O- Bzl)- Thr(OBzl)--Cysm Val-- Leu--GIy--COOH I
I
S--Trt
S--Acm DMF I R.T.
I2
Boc--Cys--Ser(O-BzI)-AsnmLeumSer (O-BzI)-Thr (OBzt)--Cys--ValmLeu--Gly--COOH I
I
S
S
1
I
Fig. 7. Synthesis of protected ( S - S) (1-10) salmon calcitonin
The protected (S - S) (1-10) salmon calcitonin is purified by preparative chromatography
on
silica
as
stationary
phase
with
a
solvent
mixture
(dichoromethane / methanol / acetic acid (93 / 7 / 2 v / v / v)) as eluent phase. After precipitation with water the pure product is analysed by HPLC
on
Lichrospher 100 RP 18 (125 x 4 mm) 5 micron as stationary phase and with a mobile phase (methanol / water / N,N-dimethylformamide / trifluoracetic acid 70 / 30 / 5 / 0.4 v / v / v / v). The D M F is introduced in the eluent phase to solubilise the protected ( S - S) (1-10) salmon calcitonin. The H P L C profile of the pure protected (S - S) (1-10) salmon calcitonin is shown in Figure 8.
413
,
|ll
.
.
.
.
II
,
II
".
9~ - 1 4 oeoo
~
"Jo,~
JPE
-1~.
:-: _
t i
,
.
.
.
.
.
.
|
.
7
oam ~111~
9
/
i
Fig. 8. HPLC profile of the pure protected (S - S) (1-10) salmon calcitonin
The protected (S - S) (1-10) salmon calcitonin has been successfully coupled on a (11-32) protected fragment grafted on a polystyrene resin. After final HF deprotection, the salmon calcitonin has been obtained with a better yield than stepwise synthesis on a polystyrene resin. A gain of 50 % of final salmon calcitonin is obtained using this procedure.
CONCLUSIONS We have demonstrated that the SAPPHO process is a new and powerful method of synthesizing peptides, at a low cost, with very good yield and purity. It is the first automated peptide synthesis technology which can be used to synthesize peptide or peptide fragments from 3 to 15 aminoacids.
414
References 1. a Methoden der Organischen Chemie / Houben Weyl 15 / 1 and 2 Published Georg Thieme Verlag Stuttgart, ( ) b Peptides / Gross Meienhoffer N~ c Principles of Peptide Synthesis - M. Bodansky Ed. Springer- Verlag 2, ( ) M.F. Maurice, M. Galvez, EP 0432022 (02/10/1989), (to Rh6ne-Poulenc Chimie). 3. J.M. Bernard, K. Bouzid, C. Gervais, EP 0421848, (02/10/1989), (to Rh6ne-Poulenc Chimie). 4. V. P6v~re, EP 0537089 (11/10/1991) (to Rh6ne-Poulenc Chimie), J.M. Bernard, E. Blart, J.P. Genet, M. Savignac, EP 0566459 (15/04/1992 ~ (to Rh6nePoulenc Chimie) J.M. Bernard, E. Blart, J.P. Genet, S. Lemaire-Audoire, M. Savignac, French Applications, N ~ 930423; N ~ 9304232 and N ~ 9304233, (09/04/1993), (to Rh6nePoulenc). 5. B.F. Gisin, Helv. Chim. Acta, 56,1476, (1973) 6.' B. Kamber and coll Helv. Chim. Acta. :51, 2061, (1968); Idem 53,556, (1970); Idem 54, 398, (1971)
415
A NEW AND PRACTICAL REMOVAL OF ALLYL AND ALLYLOXYCARBONYL GROUPS PROMOTED BY WATER-SOLUBLE Pd(0) CATALYSTS
SANDRINE LEMAIRE-AUDOIP~ a), MONIQUE SAVIGNAC GENET a) AND JEAN-MARIE BERNARD b)
a), JEAN-PIERRE
a) Laboratoire de Synth~se Organique associ6 au CNRS URA 1381, Ecole Nationale Sup6rieure de Chimie de Paris, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France b) Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie, 85 Avenue des Fr~res Perret, B.P. 62, 69192 Saint-Fons Cedex, France.
INTRODUCTION Among the usual protecting groups for amino, hydroxyl and carboxylic functions, the allyloxycarbonyl (Alloc) and the allyl moieties were largely developed during the last twenty years, since a new methodology using n-allyl palladium complexes was introduced for their cleavage (ref. 1). O II R~ z / C ~ o . ' " ' - . ~ Z=N,O
Pd(O)Ln
C02 NuH
\_ ....
I |
+ RZ |
_-
R--ZH
+
Pd(0)Ln
-,} ~ R _ Z Z " - . . ~ Pd(0)Ln Scheme 1. 416
In literature, various conditions involving different allyl scavengers such as formic acid (ref. 2), morpholine (ref. 3), tributyltinhydride (ref. 4), or potassium 2-ethylhexenoate (ref. 5) in anhydrous medium have been reported. However, these systems suffer some limitations, especially for the deprotection of secondary amines which leads to the competitive undesired reaction of N-allylation (Scheme 1, path (2)). Although recent progress has been made using silylated amines as allyl scavengers (ref. 6), a simple and unexpensive method for the cleavage of allyl carbamates derived from secondary amines would be of great interest. In addition, one of the greatest drawbacks of homogeneous metal catalysis is the separation of the reaction product from the active catalyst, which often requires costly and toxic procedures. A solution to this problem consists in anchoring the catalyst on an organic or inorganic polymer (ref. 7) insoluble in the reaction medium. Another elegant alternative consists in using water soluble ligands which once complexed to the metal make the catalyst poorly soluble in organic media. These systems combine the advantages of homogeneous and heterogeneous catalysis : easy separation of the product from the catalyst, high reactivity and high selectivity. At presem, sulfonated phosphines, e.g. TPPMS (ref. 8) and TPPTS (ref. 9), constitute the most widely used class of water soluble ligands. They found various industrial applications in the field of hydrogenation (ref. 10), hydroformylation (ref. 11), reduction of saturated and unsaturated aldehydes (ref. 12) and coupling reactions (ref. 13). In our continuing imerest in the area of palladium promoted reactions (ref. 14), we have developed a water soluble catalyst prepared in situ from Pd(OAc)2 and the water soluble ligand TPPTS. This system demonstrated high activity for various cross-coupling reactions in aqueous medium (ref. 15). We have also found that this catalyst allowed smooth and selective removal of allyl and Alloc groups in the presence of diethylamine as allyl scavenger, in homogeneous (CH3CN/H20) and biphasic (CaH7CN/H20) media (ref. 16). This palladium promoted deprotections proceed with high to quantitative yields, and the use of a two-phase system allows the reaction to occur with remarkable selectivity, in particular for the cleavage of allylcarbamates derived from secondary amines. Moreover, we developed the first efficient conditions for the chemoselective removal of allylcarbamates in the presence of substituted allyl carboxylates ; in the same way, allyloxycarbonates can be cleaved without affecting dimethylallylcarbamates in the same molecule (ref. 17).
417
RESULTS AND DISCUSSION
Deprotection of alcohols and carboxylic acids The cleavage of allyloxycarbonates was investigated in the presence of molar 2 % of Pd(0) catalyst and diethylamine as nucleophile ; our results are summarized in Table 1. Using 5 eq. of HNEt 2, primary alcohols such as (R)-citronellol were deprotected in homogeneous medium (CH3CN/H20) with excellent yield (emry 1). When HNEt 2 was replaced by formic acid, the yield and the rate of the reaction considerably decreased. The deprotection of allyloxycarbonates derived from secondary alcohols 2 was also performed under the above conditions (Pd(OAc)2 / TPPTS (1/2) tool 2 % ; HNEt2) to recover the parent molecules with good yield (entry 2). Moreover, our catalytic system allowed the selective and quantitative cleavage of the allyloxycarbonyl moiety from 6-O-Alloc-methyl-2,3-dibenzyl-ot-Lglucopyranoside 3 without affecting the other protecting groups present on the molecule (entry 3). The reaction was then carried out in a biphasic medium (C3HTCN/H20), and 1-menthol could be quantitatively deprotected within 30 minutes. Taking advantage of a two-phase system, we were able to recycle the water-soluble catalyst up to 10 times with no loss of efficiency, which is a major asset from an industrial view point (see scheme given in ref. 18). In addition, the use of HNEt2 as an unexpensive allyl scavenger is very attractive since both the allylated by-product and the excess of nucleophile are simply removed by evaporation, affording after extraction very clean crude products. The above procedure was also applied to the cleavage of allylic esters. In the presence of tool 2 % of Pd(OAc)2/TPPTS and 5 eq. of HNEt 2 in homogeneous medium, phenylacetic acid was rapidly deprotected, in quantitative yield (entry 5). In the same way, the allyl group was smoothly removed from the carboxylic acid of the base sensitive cephalosporine 6 with 93 % yield (entry 6).
418
Table 1. Deprotection of Alcohols and Carboxylic Acids using Pd(OAc)2/TPPTS catalyst F_my
!
Substrate
HNEt2! Solvent ' Cat (eq.) (mol %)
Product
[ Time l Yield i
I
o/A lloc
I
OH
CH3CN / H20
2.2
CH3CN / H20
2.2
CH3CN / H:O
~
5
94 a)
10
80
20
99
30
100
5
100
HO. ~ . . . . O7OCH3
Alloc O ~ . . . . O7OCH3
HO...... "// ......OCH2Ph OCH2Ph 3
---OH
(min.) i (%)
/
,
2.2 !
OAlloc
HO...... T ......OCH2Ph OCH2Ph
C3H7CN/ H20
2.2
CH3CN / H20
5
.-.
OH
4
D
5
_fA lj~,,,,x,~O~
5
~y
OH
a) with HCOOH as nucleophile 9t = 2.5 h" yld = 51%
Deprotection of primary and secondary amines Then, we have investigated the cleavage of allylcarbamates (Table 2). The reaction was first conducted on primary amines in homogeneous medium. Under treatment with mol 2 % of Pd(0) catalyst and 2.2 eq. of nucleophile N-Allocbenzylamine _7 was quantitatively cleaved to recover the parent molecule within 10 minutes (entry 1). However, when N-allyloxycarbonyl-N-methyl benzylamine 8 was allowed to react under the same conditions, the undesired reaction of N-allylation
419
I
occurred preferentially to give a (30/70) mixture of the free amine and the N-allylated side product 9 (entry 2). This competition between the nucleophile and the flee secondary amine for the capture of the rt-allyl palladium complex intermediate is explained by the mechanism of deprotection (Scheme 2). L.
"Pd~
o
L
|
I
II
R-.z~C-.o/'--.~
~
~'~..~,
CO~
Z=N,O L\pd~L |
I
Pd(O)Ln
A
b
R--ZH + Et2N / ' ' ' ~
Et2NH
Scheme 2. In the first step, oxidative addition of the zerovalem palladium species on the allyl moiety of the protected substrate leads to a rt-allyl complex, followed by decarboxylation of the carbamate. Then, intermediate A is trapped by the nucleophile (diethylamine in the present case) resulting in the deprotected product with regeneration of the palladium (0) species (path a). Nevertheless, when RZ- has a strong nucleophilic character, and this is the case of secondary amide bases, it also acts as an allyl trapping agent to give the undesired N-allylated side-product (path b). Anticipating that the reaction may be more selective in a biphasic system, the deprotection was carried out in C3H7CN/H20 (6/1) medium, with mol 5 % of Pd(0) catalyst ; under these conditions, the free secondary amine was quantitatively recovered without any undesired N-allylated product (entry 3). The use of a twophase system thus offers an interesting alternative for the efficient removal of 420
allylcarbamates derived from secondary amines, avoiding the competitive N-allylation. It is reasonable to think that in such a biphasic medium there is almost no contact between the catalyst present in the aqueous phase and the deprotected substrate liberated in the organic layer, resulting in an enhanced selectivity toward path a. Other protected secondary amines such as (1R, 2S)-N-allyloxycarbonylephedrine 10 and N-allyloxycarbonyl-L-proline !1 reacted equally well upon treatment with 5 fold excess of HNEt 2 (entries 4 and 5).
Table 2. Deprotectionof Primary and Secondary Amines using Pd(OAc)2/TPPTS catalyst F_my
Substrate
HNEt2 Solvent Cat (mol%)[ (eq.)
Product
Time Yield (mill.)
(%)
10
100
i
1
~/~All~ N
2"2 CH3 H20 CN/
0"5
(" l ~
"NH2
7 2
~
/~I AII~ Me
2
_8
2
CH3CN / H20
100 30 %
70 %
4
OH p h / ~I ! Me
5
C3H7CN/ H20
5
CH3CN / H20
100 %
0%
100
OH
_
ph.d./Me
Me/N~Albc 10
~N~"~COOH I Alloc 1_!1
2
15
100
15
100
Me/N~H
2.2
CH3CN / H20
'"'N Z C O O H i H
421
This efficient and unexpensive methodology thus allows the removal of allyl and allyloxycarbonyl groups from various substrates and the particularly mild conditions are compatible with polyfunctionalized molecules. Moreover, both Pd(O) catalyst and N-allyl diethylamine by-product are easily separated from the free alcohols, amines and carboxylic acids which are recovered in almost pure form.
Chemoselective removal of allylic protecting groups At this stage of our study, we have compared the rate of deprotection of several phenyl acetic allyl esters under the above homogeneous or biphasic aqueous conditions. We found that in (CH3CN/H20) medium the dimethylallyl group is cleaved at a lower rate than the cinnamyl group in the presence of 2 to 2.5 mol % of palladium (0). Under the same conditions, the allyl moiety is instantaneously removed. By comparison, in a biphasic system (C3HTCN/H20), the cinnamyl and the dimethylallyl groups remain imact in the presence of mol 5 % of Pd(0) water soluble catalyst, even after 3 days at room temperature ; whereas the allylic ester is still cleaved to give phenyl acetic acid in excellent yield. Based on these results we investigated the selective cleavage of an allylcarbamate in the presence of a dimethylallyl carboxylate in the same molecule (ref. 19).
0
O...~~/R1
Pd(OAc)2fI~PTS(12) mol 1% CH3CN/H20 HNEt2 5eq.
N 0~0~..,
mol 3 to 5 %
N I H
~
Pd(OAc)2flTPTS (1:2)
O~O..~~RI
o ..ou
CH3CN/H20 HNEt2 5 eq. I H
422
As shown in table 3, the allyloxycarbamate of isonipecotic acid 12 was selectively and quantitatively cleaved under homogeneous conditions, in the presence of 1% of Pd(0), without affecting the dimethylallyl carboxylate (entry 1). The resulting monodeprotected product 13 was then deprotected using a higher amount of catalyst (mol 5 %). The same scheme of selective deprotections was achieved on a base sensitive cephalosporin 14 (entry 2) ; with 2.5 % of water soluble catalyst the Alloc moiety was selectively removed to give the dimethylallyl carboxylate 15 within 30 minutes, and then the carboxylic acid was quantitatively recovered using 5 % of Pd(0).
423
Table 3. Selective Cleavage of Allyloxycarbamates in the presence of Substituted Allyl Carboxylates Entry
Substrate
Product
Time (min.)
Yield c) (%)
Product
Time (min.)
Yield d~
10
100
60
100
45
100
40
86
(%)
H 1
20
O....~O,,,,,N,~
96
H
H 13
12
.~.N/O...~NH
-S
O O ~ N ~/~CH3
H2N~ S " - . ] O ~ N/N......~CH3 30
100 a)
!_5
14
O
O
-(
H
~__
H
o
O H
H
4
-=-\Ph
18
99
17
16
o
30
19
a) Pd(0) 9mol 2.5 % 9b) solvent 9butyronitrile-water " c) crude product 9d) isolated yield
We also applied these conditions of selective deprotection on amino acids ; it was possible to cleave the N-allyloxycarbamate of the L-proline derivative 16 without affecting the carboxylic acid protected by the dimethylallyl moiety (entry 3). Nevertheless, when the dimethylallyl group was replaced by the cinnamyl group, the use of 1% of Pd(0) in homogeneous medium led to complete removal of the allyloxycarbonyl group with a certain amount of the deprotected carboxylic acid (ref. 20). In order to overcome this difficulty it was necessary to operate under biphasic conditions, in the presence of 1 % of catalyst, giving the expected cinnamyl-L-prolinate 17 in quantitative yield (entry 4). Then, the selective cleavage of aUyloxycarbonates in the presence of dimethylallylcarbamates was performed with high efficiency (Table 4). 0
H 0 0. ~. . ~ . . . ~ . . I
Pd(OAc)2/TPPTS(1:2) mol 5 %
)
C3H7CN/H20 HNEt2 5 eq.
N
Pd(OAc)2/TPPTS (1:2) mol 5 %
CH3CN/H20 HNEt2 5 eq.
;
OHI (C)
N
OH I N
A first attempt to cleave selectively the allyloxycarbonate from (1R, 2S)-(-)ephedrine doubly protected 20, under homogeneous conditions, using 1% of Pd(0), led to total deprotection of the amino function together with partial removal of the dimethylallyloxycarbonyl group. Taking advantage of a biphasic medium, the reaction was thus conducted in a butyronitrile-water system with 5 % of Pd(0) ; under these conditions, the allyloxycarbonyl group was smoothly removed from oxygen without affecting the dimethylallylcarbamate. In a second step, the amine could be deprotected using an homogeneous medium, with acetonitrile as cosolvent, to recover the parent molecule within 15 minutes, with 100 % yield
425
(entry 1). An other example on 1-(2-O-Allyloxycarbonylethyl)-N-dimethylallyloxycarbonyl piperazine 22 gave similar results, and thus confirmed the selective cleavage of an allyloxycarbonate in the presence of N-dimethylallylcarbamate in the same molecule (entry 2).
426
Table 4. Selective Cleavage of Allyloxycarbonates in the presence of Dimethylallyl carbamates Substate
Entry
Time (min.)
Product
Yield c~ (%)
Product
Time (rain.)
Yield dr (%)
15
100
O OH OH
ph.~,,,.,~CH3
ph,,."k-,,,,/CH3
p h ~ . . , . ~ CH3
CIt3/N
o ~ O ' ~
~
20
100 CH3
O
llq
21 20
U ) r o.~o~ O
J
H
I
iS
r OH
OH 23
22 a)
Pd(0) 9mol 5 % / butyronitrile-water / crude product 9b) Pd(0) 9mol 5 % / acetonitrile-water / isolated yield
\H
CONCLUSION In summary, we have developed a smooth and efficient methodology for the cleavage
of allyloxycarbonates,
allylcarbamates
and
allyl
carboxylates
using
Pd(OAc) 2 / TPPTS catalyst in aqueous medium. The free parent molecules are easily
isolated
from the reaction
mixture
by
simple
aqueous
work-up
and
extraction; they are generally pure enough to be used in another step without any further purification. Moreover, the use of a two-phase system (C3HvCN/H20) affords a valuable solution for the deprotection of secondary amines which are obtained without any N-allylated side product. In addition, in a biphasic medium the recycling of the active catalyst is particularly attractive from an industrial view point. Finally, chemoselective deprotection of bifunctional molecules containing differently substituted allylic groups was performed with high efficiency. Various applications of this technique are under investigation in our laboratory, especially in the field of peptide synthesis.
References
1.
J.W. Greene, P.G.M. Wut in ,~ Protective group in organic synthesis >,, Ed. John Wiley, New-York (1991). 2. a) I. Minami, Y. Ohashi, I. Shimizu, J. Tsuji, Tetrahedron Lett., 26, 2449, (1985). b) Y. Hayakawa, S. Wakabayashi, H. Kato, R. Noyori, J. Am. Chem. Soc., 11.2, 1691, (1990). 3. a) H. Kunz, H. Waldmann, Angew. Chem. Int., Ed. Engl., 23, 71, (1984). b) H. Kunz, H. Waldmann, U. Klinkhammer, Helv. Chim. Acta, 71, 1868, (1988). c) H. Kunz, C. Unverzagt, Angew. Chem. Int. Ed. Engl., 23,436 (1984). 4. a) F. Guib6, Y. Saint M'Leux, Tetrahedron Lett., 22, 3591, (1981). b) F. Guib6, O. Dangles, G. Balavoine, A. Loffet, Tetrahedron Lett., 30, 2641, (1989). c) O. Dangles, F. Guib6, G. Balavoine, S. Lavielle, A. Marquet, J. Org. Chem., 52, 4984, (1987). d) P. Boullanger, G. Descotes, Tetrahedron Lett., 27, 2599, (1986). 5. P.D. Jeffrey, S.W. McCombie, J. Org. Chem., 47, 587, (1982). 6. A. Mermouk, F. Guib~, A. Loffet, Tetrahedron Lett., 33,477, (1992). 7. P.W. Wang, M.A. Fox, J. Org. Chem., 59, 5358, (1994). 8. S. Ahrland, J. Chatt, N.R. Davies, A.A. William, J. Chem. Soc., 276, (1958). TPPMS = Triphenylphosphinomonosulfonate sodium salt. 9. E.G. Kuntz, US Patent 4 248 802 (1981), (to Rh6ne-Poulenc Industries) ; D. Sinou, Bull. Soc. Chim. Fr. (3), 480, (1987). TPPTS = Triphenylphosphinotrisulfonate sodium salt. 10. a) Y. Dror, J. Manassen, J. Mol. Catal., 2, 219-222, (1977). b) A.F. Borwski, D.J. Cole-Hamilton, G. Wilkinson, Nouv. J. Chim., 2, 137, (1978). c) F. Joo, Z. Toth, M.T. Beck, Inorg. Chim. Acta, 25, L61, (1977). d) C. Larpent, R. Dabard, H. Patin, Tetrahedron Lett., 28, 2507, (1987). C. Larpent, H. Patin, J. Mol. Cat., 61, 65, (1990). 11. a) W.A. Hermann, J. Kellner, H. Riepl, J. Organomet. Chem., 3_8_9_,103, (1990). b) P. Escoffre, A. Thorez, P. Kalck, J. Chem. Soc., Chem. Commun., 146, (1987).
428
12. a) E. Fache, F. Senocq, C. Santini, J.M. Basset, J. Chem. Soc. Chem. Commun., 1776, (1990). b) A. B6nyei, F. Joo, J. Mol. Catal., 58, 151, (1990). c) J.M. Grosselin, C. Mercier, G. Allmang, F. Grass, Organometallics, 10, 2126, (1991). 13. N.A. Bumagin, P.G. More, L.P. Beletskaya, J. Organomet. Chem., 371,397, (1989). 14. a) D. Ferroud, J.M. Gaudin, J.P. Gen6t, Tetrahedron Lea., 27, 845, (1986). b) J.P. Gen6t, J.M. Gaudin, Tetrahedron, 43, 5315, (1987). c) J.P. Gen6t, S. Jug6, S. Achi, S. Mallart, J. Ruiz-Mont6s, G. Levif, Tetrahedron, 44, 5263, (1988). d) J.P. Gen6t, S. Grisoni, Tetrahedron Lea., 29, 4543, (1988). e) J.P. Gen6t, J. Uziel, S. Jug6, Tetrahedron Lett., 29, 4559, (1988). f) J.P. Gen6t, M. Port, A.M. Touzin, S. Roland, S. Thorimbert, S. Tanier, Tetrahedron Lett., 33, 77, (1992). g) J.P. Gen6t, N. Kardos, Tetrahedron : Asymmetry, 5, 1525, (1994). 15. a) J.P. Gen6t, E. Blart, M. Savignac, Synlett, 715, (1992). b) E. Blart, J.P. Gen6t, M. Sail, M. Savignac, D. Sinou, Tetrahedron, 50, 505, (1994). 16. a) J.P. Gen6t, E. Blart, M. Savignac, J.M. Paris, Tetrahedron Lett., 34, 4189, (1993). b) J.P. Gen6t, E. Blart, M. Savignac, S. Lemeune, S. Lemaire-Audoire, J.M. Paris, J.M. Bernard, Tetrahedron, 50, 497, (1994). S. Lemaire-Audoire, M. Savignac, E. Blart, G. Pourcelot, J.P. Gen6t, J.M. Bernard, 17. Tetrahedron Lett., 35, 8783, (1994). The catalytic system can be recycled up to 10 times as presented in the following scheme 18. (the procedure is applied on N-methyl N-allyloxycarbonyl benzylamine), without loss of efficiency. After completion of the reaction, the first schlenck tube containing the free amine in the organic layer and the catalyst in the aqueous layer is linked, by a siphon tube, to another schlenck tube containing the protected amine dissolved in butyronitrile. The aqueous layer with the active catalyst is transferred under argon pressure into the second tube, over the fresh solution of N-allyloxycarbonyl-N-methyl benzylamine. aqueous layer catalytic system Argon --I~
II.,
I,II
Argon
~TC,.. Ph~N,H I
Me ~'~~mEt2 + HNEt2 C3HTCN V = 3ml Catalyst + H20 V -- 0.5 mi
T
)(
I ///'// ~__~
)(
429
Ph~N ~ ' ~ "] ~" l~le ~ ~HNEt,. (2.2 eq) ~C3HTCN V = 3ml
19.
20.
The doubly protected substrates are readily prepared by addition of allyl chloroformate on the amino function, followed by esterification of the carboxylic acid with the appropriate substituted allylic bromide in the presence of DBU. When the substrate was treated with mol. 1 % Pd(O) under homogeneous conditions, the cinnamyl carboxylate was partially cleaved, and the reaction led to a mixture of the selectively N-deprotected prolinate with the fully deprotected amino acid in a (65 : 35) ratio.
430
SAFETY OF C H L O R I N A T I O N REACTIONS
JEAN-LOUIS GUSTIN AND ALEXANDRE FINES Rh6ne-Poulenc, Centre de Recherche, d'Ing6nierie et de Technologie, 24 Avenue Jean Jaur~s - 69151 D6cines - France
ABSTRACT Chlorination reactions are part of various processes in the chemical industry, to manufacture heavy chemicals, specialty chemicals, pesticides and pharmaceuticals, in inorganic and organic chemistry. They are a valuable tool in organic synthesis. The hazard of processing chlorine involves : Gas phase explosion ; Runaway reaction or thermal explosion in the condensed phase. Gas phase explosion hazard with chlorine as an oxidizer is present in gas phase chlorination processes as well as in chlorinations in the condensed phase. Gas phase chlorination processes are mostly continuous processes operating in the flammable area. Gas phase explosion hazard is related to burner malfunctions. Where chlorination is made by chlorine injection in the liquid phase, gas phase explosion hazard is related to chlorine evolution in the vapour phase, giving a flammable mixture with the solvent or reaction mixture vapour. Here hazard assessment is achieved by comparing the gas phase composition with the flammable area of the gaseous mixtures. Auto-ignition is also considered because the autoignition temperature of gaseous mixtures containing chlorine is close to the ambient temperature. The relevant flammability data is obtained in a specially designed 20 litre sphere. The main features of this explosion vessel include : Hastelloy C 276 walls, central ignition with spark, hot wire or pyrotechnic ignition source, 200 bar pressure resistance, ambient to 300~ initial temperature, easily opened for frequent cleaning. This apparatus allows precise determination of the flammability limits, autoignition temperature, explosion overpressure, rate of pressure rise and flame -
-
speed. A review of flammability data in chlorine is given. 431
Runaway reaction hazard in chlorination reactions is related to a series of dangerous process situations or process deviations such as : Delay in reaction initiation -
-
Reaction mixture instability
- Production of unstable species like chloramines, nitrogen trichloride, chloro nitroso compounds. -
Demixion or segregation of unstable species in case of chlorination made in
aqueous solution, because the chlorinated compounds are less soluble in water than the initial reactant. A full review in runaway reaction hazard in chlorination reactions is given with examples from the literature and from the laboratory.
INTRODUCTION Quite similar to oxygen, chlorine is used as an oxidizer in a wide range of chemical processes where it is reacted with organic and inorganic compounds to produce chlorinated products or intermediates. A wide range of useful products are obtained such as bleach, metallic chlorides, reactive monomers to manufacture plastics, heat exchange fluids, chlorinated solvents and intermediates in organic synthesis to produce specialty chemicals, pesticides and pharmaceuticals. Chlorine is involved in a wide range of process situations including gas phase reactions in a burner or on a catalyst, solid/gas reactions in a fluid bed, gas/liquid reactions in a packed column, gas/liquid reactions by injecting chlorine in a liquid phase in a semi-batch process or in a continuous process. The reaction of chlorine takes place without catalyst, in the presence of a catalyst or in photochemical reactions. Compared to oxygen, chlorine is a more reactive gas because it is processed as a pure gas whereas oxygen is mostly reacted using air. More problems would occur with oxygen if the use of pure oxygen was widespread in the chemical industry. Compared to pure oxygen, chlorine is even more reactive. The self-ignition temperature of gaseous mixtures of organic vapours with chlorine is much lower than that of their mixtures with oxygen. Natural light can split the chlorine molecule to produce reactive chlorine radicals. Many reactions of chlorine take place near the ambient temperature. The combustion of iron in chlorine can be initiated at temperatures slighly above 100~ Chlorine is toxic to man and animals. Many chlorinated compounds are also toxic.
432
For all the above reasons, the chemical processes where chlorine is involved are submitted to careful safety studies where the specific chemical properties of chlorine are considered
T H E R M A L E X P L O S I O N HAZARD IN THE CONDENSED PHASE Chlorine is a strong oxidizer. Mixtures of chlorine and organic fuels may have a high energy content and are unstable. The thermal instability of condensed phases containing chlorine can appear in various process conditions " 9 When chlorine is injected in a liquid reaction mixture, the chlorination reaction may not start immediately allowing chlorine to accumulate in the reaction mixture. The reaction may start suddenly when a large concentration of chlorine is present in the reaction mixture and give a severe runaway reaction producing a large quantity of insoluble HC1. An example of such an induction period in chlorination is mentionned in the literature for the chlorination of ketones in methanol (ref. 1). To avoid this type of incident, the reaction onset should be checked before allowing a large concentration of unreacted chlorine to be
-
dissolved in the liquid phase. When chlorine is reacted with an organic fuel in a liquid reaction mixture, highly unstable substitution products may be obtained. This process situation is dangerous in two cases : if a high concentration of unstable chlorination product is obtained in the condensed phase if a chlorinated liquid phase separates from the bulk liquid phase segregation".
"by
The latter situation is frequent in the chlorination of aqueous solutions of organic reactants because the chlorinated products are less soluble in water than the initial reactants. Examples of this dangerous process situation are the synthesis of alcohol hypochlorites by injecting chlorine in an alcaline aqueous solution of alcohol. Traugott Sandmeyer described the synthesis of methyl and ethyl hypochlorites (refs. 2, 3) and suffered severe injuries. Roland Fort and Leon Denivelle (ref. 4) described the synthesis and properties of a series of other alcohol hypochlorites obtained following Sandmeyer's Method. The oxidation of organic compounds containing nitrogen in their formula (amines, amides, cyanides) using chlorine, gives unstable chloramines. The very unstable nitrogen trichloride is finally obtained. NC13 is only slightly soluble in 433
water and can separate from aqueous solutions giving a very sensitive dense oil. Liquid NC13 can detonate. NC13 can be obtained by chlorination of aqueous solutions containing ammonium ions. NC13 compound was first obtained by Pierre Louis Dulong (1785 1838) by chlorination of ammonium chloride solutions. Dulong was seriously injured by several explosions of liquid NC13. (ref. 5) At least one accident is known where liquid NC13 could separate in a wastewater treatment where bleach was used to oxidize cyanide ions. After an agitation failure, the actuation of a bottom valve triggered the detonation. Direct chlorination would lead to the same dangerous situation. The chlorination of organic compounds with a N - O bound will leave this chemical bound unaffected. The chlorination of oximes will give chloro oximes or chloronitroso compounds (refs 6, 7) which can demix from aqueous solutions giving an unstable dense oil. This ends in process situations similar to NC13 formation and demixion. 9 Accumulation of unstable chlorinated compounds in the bulk liquid phase. The accumulation of unstable chlorinated products in the bulk liquid phase is most likely when a solvent is used where this product is soluble. The most common example is nevertheless the accumulation of NC13 produced by electrolysis of KC1 or NaC1 salt containing ammonium ions, in a NC13 removal process using extraction in carbon tetrachloride. If NC13 is not continuously thermally decomposed, high NC13 concentrations in the CC14 solution are obtained with a potential runaway decomposition hazard. Such an incident is known in the literature (ref. 8). Note that the decomposition kinetics of NC13 in CC14 solutions is strongly influenced by the wall material. Recommendations When chlorine is reacted with organic reactants, specially if nitogen comaining compounds or ammonium ions are present, the possible formation of unstable chlorinated compounds should be considered. Any segregation of a separate phase from the bulk liquid is potentially dangerous and should be investigated carefully. The demixion of an unstable liquid phase may induce a high vapour pressure of the unstable product in the gas phase because the gas phase is in equilibrium with the separated unstable liquid. This problem should be considered. If no segregation occurs, the process situation is safer, however it is necessary to check for low concentration of unstable chlorinated compounds (NC13, alcohol hypochlorites, others...) in the bulk liquid phase. 434
GAS PHASE EXPLOSION HAZARD IN CI-~O INATION REACTIONS Gas phase explosion hazard is present when chlorine is mixed with a fuel in the gas phase. The fuel may be hydrogen, a solvent or organic vapour, ammonia, etc. When chlorine is reacted with a fuel in a burner, as in the manufacture of HC1 from Hydrogen and chlorine or in the manufacture of chlorinated solvents from hydrocarbons and chlorine, most incidents occur when the burner is set on-stream, either by lighting the burner with a pilot flame or by preheating the gas and the burner. Of course the gas mixture is in the flammable range and explosions occur due to maloperation. When chlorine is reacted with a fuel on a catalyst bed, maloperation will result in catalyst burn- out and/or gas phase explosion before or after the catalyst. Here the determination of the fuel gas flammable limits in chlorine are of interest if the feed gas is not in the flammable range in normal process conditions. When chlorine is injected or bubbled in a liquid phase containing a reactant and/or a solvent, chlorine evolution in the gas phase may produce a flammable mixture with the reactant, product, solvent or reaction mixture vapour. Here inertizing is difficult as in other oxidation processes because the oxidizer is bubbled through the liquid reaction mixture. As far as possible, it is recommended to keep the gas phase composition outside the flammable range. Various methods are used : 1) Lowering the fuel vapour pressure below the Lower Flammability Limit in chlorine by lowering the process temperature. 2) Raising the fuel vapour pressure above the Upper Flammability Limit in chlorine by raising the process temperature. 3) Inertizing the gas phase by flushing the reactor gas phase with an inert gas such as Nitrogen, CO2, HC1. To keep the reactor gas phase below the L.F.L. in chlorine (method 1) is the safer method where only proper temperature control is necessary. To keep the reactor gas phase above the U.F.L. in chlorine (method 2) may not be quite safe. On start-up the temperature must be set to the process normal value ensuring enough fuel vapour pressure before chlorine injection. If a condensor is used where the fuel vapour pressure is depleted, the gas flow composition may enter the flammable range. Glass condensors are better not used or protected from light. Inertizing (method 3) is a difficult technique when the chlorine flow evolving from the liquid reaction mixture may change. 435
If chlorine does not evolve in the gas phase in normal process conditions, an inert gas flush in the reactor gas phase is recommended (see below). If a chlorine flow evolves from the liquid reaction mixture unreacted, enough inert gas flush must be provided in the reactor gas phase to lower the chlorine concentration below the minimum oxidizer concentration (MOC) of the fuel flammable range. If HC1 is released in the gas phase, this gas contributes to the reactor gas phase blanketing. However one should take into account rapid changes in the process conditions, if the wanted chlorination reaction stops due to catalyst depletion or reactant consumption. More unreacted chlorine can be released in the gas phase, the HC1 production can disappear. Therefore monitoring of the gas phase chlorine concentration using a chlorine analyser is recommended.
SELF-IGNITION, DEFLAGRATION AND DETONATION IN THE GAS PHASE Self-ignitions of gaseous mixtures containing chlorine and a fuel, near the ambient temperature, are known. Self-ignitions can turn into severe deflagrations or detonations. Self-ignition occurs in mixtures with a composition both in the flammable range and outside the previously determined flammable range. This phenomenon can be explained as follows : - The self-ignition temperature of gaseous mixtures is not a clear-cut limit. It is best represented by an induction period versus temperature relation. Self-ignition will be observed at lower temperature if a longer induction period is allowed. - Near the self-ignition temperature, the flammable area is enlarged to a wide range of equivalence ratios. - When long induction periods are necessary, weak ignition sources can initiate the explosion, such as light, wall effects, tar deposits, catalyst deposits on the wall, NCI3 decomposition flame (refs. 5, 9). A combination of these influences may explain the above mentioned self-ignition phenomenon outside the flammable range. As an example, the self-ignition of gas phase mixtures of dioxane and chlorine was thoroughly investigated by F.
Battin-Leclerc (refs. 10, 11). Dioxane
is
sometimes mentioned as a solvent for chlorination processes (ref. 12) whereas selfignitions of dioxane + chlorine mixtures is easily obtained near the ambient temperature.
436
The flammable limits of dioxane + chlorine mixtures were determined in a 4.6 litre explosion vessel together with the explosion overpressures and maximum rates of pressure rise (ref. 12). The explosion overpressures obtained are of the same order of magnitude of that of explosion of gaseous fuel in air but half of the expected thermodynamic explosion overpressures in chlorine. The gas phase detonation of gaseous mixtures of dioxane and chlorine was successfully investigated in shock tubes by A. Elaissi (refs. 13, 14). This mixture was shown to be very sensitive to detonation compared to mixtures of fuel in air or oxygen. The full investigation of this example, chosen for convenience, shows that mixtures of organic fuels with chlorine can exhibit self-ignition followed by deflagration and detonation thus explaining violent explosions observed in the past.
EXPERIMENTAL SET-UP TO STUDY EXPLOSION LIMITS, EXPLOSION CHARACTERISTICS AND SELF-IGNITION OF GASEOUS MIXTURES A new explosion vessel, a 20 litre sphere, was built to investigate gas phase explosions with special attention for experiments using chlorine as an oxidizer (Fig. 1).
Fig. 1. 20 litres explosion vessel
437
This new facility allows the measuremem of : -
The flammability limits of gaseous mixtures using various ignition sources : single spark, fusing wire, chemical ignitors.
-
The explosion characteristics i.e. explosion overpressure and maximum rate of pressure rise.
- The laminar burning velocity deduced from the pressure-time history of the explosion. (ref. 15) The pressure is recorded at a rate of 20.000 Points/s. - The self-ignition temperature and induction period of gaseous mixtures, down to a few minutes. Sampling is possible to check for gas phase reaction. - Flash points in chlorine The main features of this explosion vessel are : - Hastelloy C276 walls to lower wall effects i.e. to prevent the reaction of chlorine with fuel before ignition, catalysed by stainless steel. - The vessel is made of two half-spheres connected through a flange assembly kept tight by clamps. The upper half-sphere is fixed, the lower half-sphere is movable, using a pneumatic jack, to allow quick opening of the vessel for frequent cleaning. Combustion in chlorine produces soot deposits on the walls, which may promote or prevent ignition of subsequent mixtures. Cleaning after each positive test is necessary to obtain reliable flammable limits in chlorine. The vessel design pressure is 200 bar, thus allowing initial pressure of 10 to 20 bar according to the expected explosion pressure. The vessel temperature can be set between ambient temperature and 300~ Mixing is ensured before ignition using a propeller mixer. Central ignition is made using spark, hot wire or a pyrotechnic ignition source.
REVIEW
OF
FLAMMABILITY
DATA
OF
GASEOUS
MIXTURES
CONTAINING C H L O R I N E Flammability
limits
A review of flammability limits of gaseous mixtures containing chlorine was first given by Mal'tseva, Roslovskii and Frolov (refs. 16, 17). The experimental set-up used to obtain these data was a double-wall vertical glass cylinder, 80 mm in diameter and 120 mm high. The experiment initial temperature was set by thermostating the vessel. The fuel was introduced after evacuation, and allowed to 438
vaporize. Then chlorine was admitted in the explosion vessel. Mixing was only by molecular diffusion (no stirring). A 10 min waiting time was observed before ignition by a spark. Our comment on this method is that the wall material is correct, mixing is poor or not effective and the waiting time before ignition is too long and may have allowed the mixture to react before ignition. The results are summarized in Table 1 for the reader convenience.
439
Table 1. Flammability limits of gaseous fuels in chlorine. Data of Mal'tseva (refs. 16, 17) Fuel
Temperature (~
LFL % vol
UFL % vol
Hydrocarbons |
i
CH4
20- 22
5,6
63,0
C2 H6
i20 - 22
,4,95
, 55,4
I
C3 H8
'20 - 22
!4,30
50,0
C4 H 10
20 - 22
3,31
49,5
i
C5 H12
i
|
120 - 22
2,42
43
i
Alcohols CH3 OH
70
13,8
73,5
C2 H5 OH
83
5,06
64,1
C3 H7 OH
102
3,03
51,5
C4 H9 OH
120
2,53
48,8
C5 Hll OH
143
il,98
37,6
i 105
' 27,62
82,0
122
15,83
56,0
I
Carboxylic acids H COO H |
CH3 COO H ,
,
i
,i
C2 H5 COO H
145
'9,33
50,8
C3 H7 COO H
170
7,81
49,8
C4 H9 COO H
190
5,84
48,8
CH3 C1
20
10,2
56,0
116,7 i
52,9
Chloro-alkanes CH2 C12
'50
CH C13
not combustible
C2 H5 C1
20
|
8,98
49,2 |
1-2 C2 H4 C12 !
100 J
i C2 H3 C13
] !
16,4
136,8
,
not combustible
C3 H7 C1
60
6,88
41,8
C3 H6 C12
100
9,95
35,0
C3 H5 C13
not combustible
C4 H9 C1
100
5,42
44,5
NB compositions are in percents by volume.
440
Dokter (ref. 18) and Medard (ref. 19) published some more data collected in Table 2, together with interesting discussions. Table 2. Flammability limits of gaseous fuels in chlorine. Data published by Dokter (ref. 18) and Medard (ref. 19). Fuel
Temperature
(~ H2
cn4 00 .. 200
CH4 CH4 CH3 C1 C~. H6 H2 CH4
20
cn4 cn4
200
UFL % vol 89 63 66
LFL % vol 3,5 5,51 3,6 0,6 10,2 4,95
C2 H6 C3 H8 CH3 C1 CH2 C12
(18) (18) (18) (18) (18) (18) (19) (19) (19) (19) (19) (19) (19) (19)
63 58,8 86 70
5,6 3,6 0,6 6,1 5 10 16
100
Ref
58 " 40 63 53
Further flammability data obtained either using our 4.6 litre stainless steel cylinder (ref. 12) (C) or our 20 litre Hastelloy C sphere,(S) are given in Table 3. Table 3. Flammability limits of gaseous fuels in chlorine Fuel
Temperature
CH3 C1 C3 H8 C3 H6 C12 MTBE 1-4 Dioxane CH3 c o o H Acetone Chlorobenzene Toluene 2 chloro toluene a chloro toluene c~ dichloro toluene c~ trichloro toluene 2 Fluoro toluene
25 70* 200** 60 80 120 60 130 160 150 160 160 160 100
(~
* Po = 1,7 Atmosphere abs. ** Po = 1,3 Atmosphere abs.
LFL % vol 7 2 4,5 2 2,5 5 4,5 7,5 3,5 5 4 6 9 4
UFL % vol 65 60 33 41 36 ...... 60 43,5 50 45
37
(C) = 4.6 litre cylinder (S) = 20 litre sphere 441
Apparatus (C) (S) (S) (C) (C) (c) (C) (S) (S) (C) (S) (S) (S) (C)"
Miscellaneous data can be found in the literature, like the flammability limits
of
benzene in chlorine (ref. 20) 9L F L = 8 % vol, UFL = 52 % vol. The experimental data is given under atmospheric initial pressure, unless otherwise specified.
Self-ignition temperatures Data on self-ignition temperature of gaseous mixtures of fuel and chlorine are given by Mal'tseva (ref. 17), Dokter (ref. 18) and others. A collection of data is given in Table 4. Table 4. Auto-ignition temperature of gaseous fuels in chlorine Fuel
AIT in chlorine Author (~
CH4
318
(17)
C2 H6
280
(17)
dimethyl ether
ambient
(17)
C 1-C3 carboxylic acids
300 - 320
(17)
C4-C7 carboxylic acids
230 - 190
(17)
C2-C4 carboxylic anhydrides
290- 215
(17)
C3-C5 ketones
325 - 205
(17)
C1-C8 alcohols
1225 - 210
(17)
C2-C7 aldehydes
,110 - 160
(17)
H2
207
(18)
CH3 C1
215
(18)
CH2 C12
, 262
(18)
C2 H6
205
(18)
C3 H6
150- 100
(18)
1,2 C3 H6 C12
180
(18)
Dioxane (0,26 ATA)
100
(10 - 11)
chloro benzene
> 165~
20 litre sphere
i
C3 H8 (1,7 ATA)
!
165 ~
20 litre sphere
1
|
I
C 3 H6 (1,7 ATA)
160~
. 20 litre sphere
442
CONCLUSION Owing to the importance of chemical reactions involving free chlorine in the chemical industry, the collection of experiences and experimental data is of great interest. This should contribute more to process safety than information on less dangerous chemicals or processes. It is surprising that only limited effort or support is devoted to collect safety data on chlorination reactions. The literature on the safety of chlorination reactions is very limited compared to the literature on oxidation reactions using oxygen. The authors hope that their contribution will promote further experimental work in this field. The new 20 litre explosion vessel, specially designed to study the flammability of gaseous mixtures containing chlorine as an oxidizer will allow the obtention of reliable data at a reasonnable cost, for a wide range of initial conditions.
References
1. 2. 3. 4. 5. 6. 7. 8. 9.
10. 11.
12.
13. 14. 15. 16. 17.
R.R. Gallucci, R. Going, J. org. chem., 46, 2532, (1981). T. Sandmeyer, Ber. XIX, 857, (1886). T. Sandmeyer, Ber. XVIII, 1767, (1885). R. Fort, L. Denivelle, C.R. Acad. Sci., 234, 1109, (1954). F. Baillou, Thesis dissertation, 27 Septembre 1990, Universit6 d'Orl6ans, France. Piloty, Steinbock, Ber. 35, 3113, (1902). W. Steinkopf, W. Mieg, J. Herold, Ber. 53, 1148 (1920). "Nitrogen Trichloride, a collection of reports and papers", The Chlorine Institute, Report n~ Ed.2, New York, (1975). F.Baillou, R. Lisbet,G. Dupr6, C. Paillard, J.L. Gustin, "Gas phase explosion of nitrogen trichloride : Application to the safety of chlorine plants and chlorination processes", 7th International Symposium on Loss prevention and Safety promotion in the Process Industries. Taormina, Italy, May 1992, Paper n ~ 106. F. Battin-Leclerc, Thesis dissertation, 15 Jan. 1991, INPL-ENSIC, Nancy, France, (1991). F. Battin-Leclerc, P.M. Marquaire, G.M. Come, F. Baronnet, J.L. Gustin, "Auto-ignition of gas phase mixtures of 1,4 Dioxane and chlorine", 7th International Symposium on Loss prevention and Safety promotion in the Process Industries, Taormina, Italy, May 1992, Paper n ~ J.L. Gustin, "Gas-phase explosions of mixtures of organic compounds with chlorine", 6th International symposium Loss prevention and Safety Promotion in the Process Industries, Oslo, Norway, June 19- 22, Paper n ~ 91, (1989). Abdelkrim Elaissi, "Propri6t6s explosives des m61anges 1,4 Dioxanne + chlore en phase vapeur", Thesis dissertation, University of Orleans, France, 14 March 1994. A.Elaissi, G. Dupr6, C. Paillard, paper presented at the 8th International Symposium Loss prevention and Safety promotion in the Process Industries, Antwerpen, (1995). D. Bradley, A. Mitcheson, Combustion and Flame, 26, 201-217, (1976). A.S. Mal'tseva, Yu. E Frolov, V.L. Sushchinskiy, The Soviet Chemical Industry, 1, 23-25, (1971). A.S. Mal'tseva, A.T. Rozlovskii, Yu. E. Frolov, Zhurnal Vses. Khim. Ob-va im. Mendeleeva, 19, 5,522-551, (1974). 443
18. T. Dokter, J. Hazardous Materials 10, 73-87, (1985). 19. L. Medard, Les explosifs occasionnels, i, pp. 172-173, Lavoisier Ed., Paris, (1987) 20. G. Calingaert, W. Burt, I.E.C., 43 (10), 1341, (1951).
444
SODIUM AMIDE IN ORGANIC SYNTHESIS
JEAN-MARIE POIRIER URA n ~ 464 du CNRS, UFR Sciences, Universit6 de Rouen et IRCOF, F-76821 Mont Saint Aignan Cedex, France.
Sodium amide, NaNH2 (mp 210~ is slightly soluble in liquid ammonia, about 1 mole per litre at -33~ NaNH2 is a powerful basic reagent and very useful in organic synthesis. This compound acts essentially as a deprotonating reagent but in some cases as a nucleophilic reagent. The acidic acetylenic proton of alkynes can be easily removed by treatment with sodium amide in anhydrous liquid ammonia and the resulting anion reacted with various electrophilic reagems (refs. 1-4). In the same manner, the anion of indole (ref. 5) is methylated leading to the 1-methylindole in high yield. Diphenyl methane is metallated by NaNH2 and alkylated in 90-95 % yields (ref. 6). The disodiosalts of 13-diketones have been prepared and alkylated (refs. 7-8) or acylated (ref. 9) (Fig. 1). These salts can be reacted with chloro- and bromoacid salts leading to dioxocarboxylic acids (ref. 10). The acid salts must be prepared beforehand because of the rapid reaction of an excess of NaNH2 with the halogen of the acid. Treated with 2 equivalents of NaNH2 in liquid ammonia, unsymmetrical 13-diketones lead to disodiosalts in which two alkylation sites are possible (refs. 1113). When R 1 = H , R 2 = Me (Fig. 1) the methylation is very selective on the a site (a " b = 89 911). Increasing the steric hindrance on the b site (R 1, R 2 - - Me) yields almost exclusively methylation on the a site (a : b = 99 : 1) except when the anion is stabilized by resonance (R 1 = H, R 2 = Ph), in this case the methylation takes place on the b site. With unsymmetrical f3-diketones the following rule of selectivity has been proposed (refs. 9, 12) : phenylacetyl > acetyl > propionyl > isobutyryl. This order is valid whatever the alkyl halide used and the authors suggest that it is also valid for acylation and carbonatation.
445
Sodium enolates of ketones have been prepared by reaction of these ketones with NaNH2. For example, the alkylation of the sodium enolate of cyclohexanone by allylbromide (Fig. 2) leads to 2-allylcyclohexanone accompanied by a little of the dialkylated product (ref. 14). Dimethyl ethynyl carbinol was obtained by reaction of the enolate of acetone (prepared by reaction of solid NaNH2 in ether) with acetylene. Although a prepared ketone enolate is used, this reaction can also be considered as an aldolisation reaction of the acetylide with acetone (ref. 15). Hauser and coll. react sodioenolates of ketones prepared in ether (ref. 16) with acid chlorides (Fig. 2). O
O
O O .-,-- / ~ J ~ ~ O
1) NaNH2
2) X(CH2)nCO2M 3) H +
OH
X =C1, Br n = 1-3,5,6,10 M =Li, Na 0 0 / / ~ / R 1
NaNH2~
R2 O
~
site b
O 1) NaNH2 2) CO2 3) H +
~
R
--O
R2
site a
O
R . ~ ~
--O
-0 -0 ~ R 1
O ~
OH O
R = Ph, Me, Ph(CH2)2, n-Bu, PhCH=CH, Ph2C=CH, H, OEt Fig. 1. Reaction of disodiosalts of diketones.
446
~
ONa //-,.,....,,Br
O NaNH2 ,.._ NH3 liq.
EhO
ONa
O
NaNH2
1) C2H2
NH3 liq.
2) H +
O RI~.,/R
2
NaNH2 0~ Et20
O R
~...I
O
ONa R I ~
O
R3COCI R2
R I ~ R 3 R2
R
C1
NaNH2 NH3
N
)<
R
O CH2OH
R = Me, Ph, PhCH2 Fig. 2. Reaction of sodium enolates of ketones. This reaction mainly leads to 13-diketones which do not react with acid chloride in their reaction conditions. With the use of a,13-unsaturated acid chlorides, the corresponding 13-diketones are prepared but in low yields (28-60%). The sodium enolates prepared in this way are also able to react with ethyl ester (ref. 17). With the use of dihalocompounds, cyclic ketones have been obtained (refs. 18, 19). In the case of (z-haloketones an intermediate epoxide is formed and may be opened. With c~-chloroketones, the reaction leads to an oxazoline (ref. 20). Esters can also be deprotonated by NaNH2 in liquid ammonia, the resulting enolates are then alkylated (refs. 21-23). In order to prepare trialkylacetic acid from acetic acid, this process does not give good results since an amide is obtained. To reduce this side reaction a bulky alkoxy group must be used (ref. 24). With the use of triethylcarbinol esters (the starting ester is prepared as described in Fig. 3), the trialkylacetic acids are obtained in fairly good yields. Sodium enolates of esters also give aldol reactions with ketones (ref. 25). Ethyl-, isopropyl- or t-butylacetate readily react with benzophenone to yield the corresponding [3-hydroxyesters (Fig. 3). Only one equivalent of NaNH2 and a short 447
reaction time is needed to reduce the retroaldol reaction. With the use of two equivalents of NaNH2 and a longer reaction time no aldol product is obtained. The aldol reaction is also possible with lithium amide. This reaction type is only possible with ketones which do not bear an a-hydrogen atom to the carbonyl group. With acetophenone, it is only the enolate of the ketone which is obtained. However, the enolate of ethyl chloroacetate can react with acetophenone (ref. 26) because of the following epoxidation cyclisation leading to a glycidic ester (Darzens condensation) (Fig. 3). Glutaramides have been prepared (ref. 27) by treatment of 13-substituted glutaric acid diesters with NaNH2 in liquid ammonia.
R2 Ph/~/OR1
1) NaNH2 / NH3 liq. / Et20
O
Et3COH
phi/OR1
2) R2Br
1) NaNH2 2) R1R2CHCOC1
0 OCEt3
R1 1) NaNH2 2) R3X 3) HE1
RI~o R2 Ph
-•OR 0
1) NaNH2 / NH3 liq. 2) Ph2CO
1) NaNH2
O
2) PhCOMe
Ph
/ O
I l OHl
Me~./O p h / ~ - . L i COOEt
~
R--(
CH2CO2Me
OR
NaNH2 / NH3
NH
CH2CO2Me O Fig. 3. Reactions of sodium enolates of esters.
448
OH
The sodium dianions obtained from acids, treated by NaNH2 in liquid ammonia are easily alkylated (refs. 28-30). These dianions have also been used for Michael addition with benzalacetophenone or ethyl cinnamate. A similar Michael addition (ref. 31) is also observed with the enolate of ethyl phenylacetate (Fig. 4). Nitriles can also be deprotonated with NaNH2 in liquid ammonia. The resulting anion was able to give aldol reaction followed by dehydration (ref.32) or an alkylation reaction (ref. 33).
O Ph/~
OH
1) NaNH2 (2 equiv.) / NH3 l i q . 2) RC1 ~ 3) H +
R /~f#O
Ph OH OH
R1
R2
1) NaNH2 (2 equiv.) / NH3 liq. . R2 Ph
OH 2) R I ~ O
3) H + Ph
ph/~CN
1) NaNH2 / NH3
p h @
2) Ph2CO
Ph CN
Fig.4. Alkylation or aldolisation reactions of sodium enolates of ketones and of nitriles.
Methylated pyridines and quinoleines have been metallated by NaNH2 in liquid ammonia. In this case the 4-methyl is deprotonated (Fig. 5) contrarywise to n-BuLi or PhLi which yields the deprotonation on the 2-methyl (refs. 34-36). These results have been interpreted by a coordination of the lithium by the nitrogen leading to the deprotonation of the 2-methyl. When the cation used (sodium) is not as effective as lithium in coordinating with nitrogen or when the solvents employed (ammonia or diisopropylamine) are more strongly basic and thus more strongly coordinating, the metallation of 4-methyl occurs. According to this hypothesis, the use of NaNH 2 in ether yields a mixture of the two anions. All these anions have been reacted with electrophilic reagents (alkyl halides, aldehydes, ketones or esters).
449
CH2-
CH3
R~CH3 ~ ~ ~ ' ~ ~
R~CH3 R =H, Me
~CH3
nBuLi or PhLi Et20, hexane CH2-
R
CH3 (,"1 ~ f 2 H 3
CH2NaNH2
r.-~" I~I~H
3
Fig. 5. Metallation of methylpyridinesand methylquinoleinesby NaNH2.
NaNH2 in HMPA reacts at 45-50~ with diphenyl imines. The anion is alkylated in medium yields. In this case, best results are obtained with the use of lithium diethylamide (ref. 37). Tosylhydrazones are converted into ethylenic compounds (Fig. 6) by treatment with NaNH2 in decaline (ref. 38). R"bin N Me/
NaNH2
R,,,,~
"NHTs
Fig. 6. Reaction of hydrazoneswith NaNH2. l-Sodiocyclopropene is instantaneously and quantitatively formed by addition of cyclopropene to a slight excess of NaNH2 in liquid ammonia. This anion can be alkylated (Fig. 7) in fair to good yields depending on the structure of the halide (high yield with primary unsubstituted halides). Dehydrohalogenation becomes a competing reaction in the case of secondary and tertiary halides (ref. 39). With the use of more than one equivalent of NaNH2 a dialkylation of the starting cyclopropene is obtained. 450
In some cases NaNH2 is described as an isomerisating reagent by deprotonation of dienes or alkynes (refs. 40, 41). Cyclopropenyl ketones or vinyl cyclopropyl ketones treated by NaNH2 in HMPA or DMSO (ref. 42) lead to the cis- and transcyclopropyl ketones (Fig. 7).
~
1) NaNH2 / NH3 l i q -
~/j
.R
2) RX
\ k(
NaNH2 ~ HMPA or DMSO
or COMe
COMe
-
':
+ COMe
COMe
Fig 7. Reaction of NaNH2 with cyclopropenyl derivatives.
NaNH2 is basic enough to deprotonate alkyl triphenyl phosphonium bromide. Mixture prepared from these bromides and powdered NaNH 2 can be stored upon addition of an etheral solvent. They immediately generate the ylide which then may be reacted with carbonyl compounds. The use of such "instant-ylide" mixtures offers several advantages, the most interesting are very good yields and particularly a high cis/trans ratio (refs. 43-47). This ratio can be enhanced with the modification of the substituents at the phosphorus atom (Fig. 8). NaNH2 is also a basic reagent of choice for dehydrohalogenation. Dehydrohalogenation is easily achieved by treatment of bromo- or chloroaliphatic or bromovinylic compounds with a suspension of NaNH2. For example stearolic acid (ref. 48), 10-undecynoic acid (ref. 49) or diethoxyacetylene (ref. 50) have been so prepared (Fig. 9). In the same conditions phenylacetylene has been obtained from 2-bromostyrene (ref. 51), 2-butyn-l-ol from 3-chloro-2-buten-l-ol (ref. 52) but more drastic conditions are required to prepare cyclohexylpropyne from the corresponding vinyl bromide (ref. 53).
451
R 1~
O
A.r3PCH2R2, Br
NaNH2
.v_
R1/~ R2 RI
Ar
R2
Ph Ph Ph 2-furyl 2-thienyl o, o ' -difluorophenyl o-tolyl
Me Et n-Pr Me Me Me Me
n-CsHll cis/trans 91/9 96/4 94.5/4.5 99/1 99/1 98/2
Ph cis/trans 87/3 96/4 96.5/3.5 91.5/8.5 81.5/18.5 99/1 94.5/5.5
Fig. 8 Cis / trans ratio of the ethylenic compounds prepared with "instant ylides". Propargylic aldehyde diethyl acetals have also been prepared in good yields by dehydrohalogenation of 2,3-dibromo-1,1-dialkoxy propane. The intermediate acetylide may be alkylated (Fig. 10) (refs. 3, 54). Inamoto and coll. (ref. 55) reported the first formation of a bridgehead alkene by dehydrobromination. When treated with NaNH2 in refluxing toluene the bromide (Fig. 9) gives the alkene in 52 % yield. The ready formation of this compound which violates the Bredt rule is considered to involve a planar cis elimination of bromine and the 2 - e x o hydrogen atom. 1-Chlorobicyclopropyl is dehydrochlorinated by NaNH 2 in liquid ammonia, the intermediate anion is then protonated by NH3 leading to bicyclopropylidene (ref. 56) a valuable intermediate in the synthesis of polycyclopropylidenes ( [n]rotanes). Cyclopropene acetals (Fig. 10) can be prepared from dichloroacetone (ref. 57). The first step needs 3 equivalents of NaNH2 (the use of a smaller amount of base results in the formation of the acetal of the chlorocyclopropanone), the third equivalent of NaNH2 is consumed by the formation of the sodium salt which can be alkylated (70-77% yield). Cyclopropenes have also been synthesized from allyl chlorides in various solvents (refs. 58-61). Results are summarized in Fig. 10. Methyl cyclopropenes are generally accompanied by 1,3-butadiene. It is to be noted that the use of KNH2 or of a complex base (NaNH2 /t-BuONa) with methallyl chloride leads to methylene cyclopropane (ref. 62).
452
Aziridines have been obtained from chloroallylamines by treatment with NaNH2 in liquid ammonia (Fig. 11). These reactions are highly dependent on the ratio amine-NaNH2 and in some cases the acetylenic amine becomes the major product (refs. 63, 64).
Br
~
O Br
OH
1) 3 NaNH2 / NH3 l i q .
/,/,4"~
2) HC1
O
OH
Br EtO~
./H
NaNH2
OEt
OEt
OEt OEt
<
OEt
OEt
NaNH2 / NH3 liq.
Br~OEt Br
(
OEt OEt
Br
C1
NaNH2 / Toluene
NaNH2 NH3 liq.
Fig. 9. Dehydrohalogenation with NaNH2.
453
3 NaNH2 O
CI--.~~--
RX w.--
O
C1
NH3 liq. C1
~
,,/C1
NaNH2 / THF
Na
~
R
//~ Me
~x,,,/C1
_~..~/C1
~~Cl
NaNH2,tBuONa / THF
~
NaNH2, NaOH / dioxane .._
/~~
NaNH2, NaOH / dioxane
A ,
%
"Me
Fig. 10. Dehydrochlorination with NaNH2.
x ~j/NHR
S-7 NaNH2/ NH3 l i q . "-
NHR N\ R
+
/
Fig. 11. Treatment of chloroallylamines with NaNH2.
13-Chloroacetals or ethers treated by NaNH2 lead to the corresponding acetylenic compounds (Fig. 12) by elimination of HC1 and ROH (refs. 65, 66). Acetylenic or ethylenic 1,4-bisethers undergo 1,4-elimination of ROH upon treatment with NaNH2 in liquid ammonia leading to 1,3-dienylethers or enyne ethers (refs. 6770). A similar reaction also occurs with acetals yielding an enyne or a cumulene (refs 71,72) according to the starting structure. Similar results are obtained with alkylthio derivatives, for example phenylthioacetylene has been obtained by dehydrobromination of the bromovinyl sulfide (ref. 73).
454
/•./OEt
C1
1) NaNH2 / NH3 liq.r_- R
OEt
1) 3 NaNH2 / NH3 liq.
R
OEt
2) RX
C1
O
~
2) NH4C1
~
OR
~
~.,,,,,j",x OH
1) NaNH2 / NH3 liq. 2) H20
R = Me, tBu, Ph
/
/
OR
NaNH2
OR
~OR OMe
EtOyO,~J
NaNH2
~C=C____~~Me
Fig. 12. Reaction of acetals and ethers with NaNH2. Treated with NaNH2, aromatic halides lead to the elimination of a hydrogen halide and the formation of benzyne (refs. 74-77). This reaction can be followed by the addition of the amide ion, resulting in the obtention of anilines. The reaction occurs on the two reactional centres of the benzyne. Using 14C labelled chlorobenzene leads almost to a 1"1 ratio of aniline 1-14C and 2-14C (Fig. 13). Fluorides are less reactive than chlorides which are less reactive than bromides. When the halobenzene bears a substituent there are several possibilities (Fig. 13). With a halogen in the meta position, two benzynes are possible, the direction of the elimination is predictable on the basis of which hydrogen is more acidic. With an ortho or a para substiment only one benzyne is produced but the amination takes place according to the nature of the substiment (refs. 74-79). Various anions (ketones enolates for example) are able to react with arynes (Fig. 13) leading to the phenylated compound (refs. 80, 81). When the anion is generated from the starting material, the reaction leads to a cyclisation product (refs. 82-84). These reactions are also possible with other aromatic compounds (ref. 85). 455
0 ]
NaNH2
. (7N
2 C
,H 2
X R
~
NaNH2
Favored if R is an electronwithdrawinggroup NH2 R~NH2 H2N
NH2
Favored if R is an electrondonatinggroup X __~
NaNH2
R
R~Z
ZO
,4
R NaNH2
_~
2
R4
- - ~ C 1 CN
NaNH2
~
~
R3
CN
Fig. 13. Arynes from haloaromaticcompoundsin the presence of NaNH2. In closely related conditions 2-bromothiophene leads to the migration of the bromine atom onto the 3-position (ref. 86) while KNH2 gives an amination on this site (refs. 87, 88). A similar reaction-type is also obtained with substituted bromothiophenes; a transhalogenation mechanism has been proposed (ref. 89) (Fig. 14). 456
Br
NH2 NaNH2
Me /~Br
/~Br Br
NaNH2
KNH2
/~XS,,~
Me
Me
~~
NaNH2 Br~
Fig 14. Reactionof bromothiopheneswithNaNH2.
With ammonium salts, NaNH2 can promote two possible rearrangements (ref. 90) : the Stevens rearrangement in which an alkyl group migrates from the quaternary nitrogen atom to the a-carbon atom of a second alkyl group and the Sommelet-Hauser rearrangement which involves migration to the ortho position of a benzyl quaternary ammonium salt. The Stevens rearrangement, which is an intramolecular process, is favoured if an electron withdrawing group (EWG) is present. When the substituent ZCH2 is an allylic group the migration can occur on the c~- and ~,-carbon atom (ref. 91). When the benzylic substituent is optically active, the migration is realized with retention of configuration in the two rearranged products (Fig. 15).
R3 +1 Z~N--R2 R1
NaNH2 ~
~R3 Z,,,,],/N" "R2 t R1
Z = EWG +/ ~//""N~
R Ph NaNH2 ~ _ ~ /
Ph J'x R
N[ j
Fig. 15. Stevensrearrangemem.
457
Ph
In the presence of NaNH2 benzylic quaternary ammonium salts generally lead to the Sommelet-Hauser rearrangement (refs. 90, 92-104). An ortho alkylation takes place via an exomethylene intermediate. If the two ortho and ortho' positions are methylated, the methylene compounds can be isolated (refs. 92, 93). The first anion formed in this reaction can be trapped at a very low temperature (-80~ in an aldol reaction for example (ref. 103). At -30~ occur (Fig. 16).
the isomerization and the rearrangemem
In some cases, the Stevens rearrangement or an elimination (when a 13-hydrogen atom is present) can compete with the Sommelet-Hauser rearrangement (ref. 104) as shown in Table I. + "XNMe3 NaNH2
~
+
~NMe2 H
~jNMe2
Fig. 16. Sommelet-Hauser rearrangement. Table I. Competition between the three reaction processes for the ammonium salts. +Me Ph~/~-.Me /
R Elimination
%
Sommelet-Hauser rearrangement %
Stevens rearrangement %
i-Pr
12
88
0
cyclopropyl
33
67
0
cyclobutyl
3
97
0
cyclohexyl
31
23
46
t-Bu
14
6
62
CH2CD3
24
76a
0
a) two rearranged products as shown in Fig. 17 below.
458
"'Me CH2CD3
NH3 liq. "-
,,Me + N\CH2CD3
/NMe2 CD3
Fig. 17. Products obtained by Sommelet-Hauserrearrangement. In some cases ring expansion has been obtained during the Sommelet-Hauser rearrangement (refs. 94, 100). This rearrangement also occurs with naphthalenic derivatives (Fig. 18) and with many other heterocyclic compounds (refs. 105-107). NaNH2 .---NH3 liq / " e
Me
+
CH2NMe3 (
~
Me NaNH2
~ '
CH2NMe2
CH2NMe2 @
+ CH2NMe3
NaNH2
~
I
Me
/~N
Me
I Me CN NaNH2
R
R
Fig. 18. Sommelet-Hauserrearrangementpromoted by NaNH2. When non-enolizable ketones are treated with NaNH2 in aromatic solvents (generally benzene or toluene) at reflux, the cleavage of a carbon-carbon bond is obtained leading to the formation of an amide and a hydrocarbon (ref. 108), this 459
process is called the Hailer-Bauer reaction. When an aryl alkyl ketone is used the aliphatic amide is generally obtained, c~,ot,et',c~'-Tetraalkyldiamides are easily prepared in this way from the following diketones (Fig. 19) by Hailer-Bauer reaction (ref.108). 1,1-Dialkyl-3-butenyl phenyl ketones treated in the Hailer-Bauer conditions yield the corresponding pyrrolidone by internal cyclization. In some cases such reactions have been reported not to be effective with commercial sodium amide. The use of NaNH2 with 1,4-diazabicyclo[2.2.2]octane (DABCO) increases the activity of commercially available NaNH2 avoiding the preparation of this reagent in liquid ammonia followed by evaporation of this solvent (ref. 109). Ar~= O
NaNH2
R
R.~O
+ ArH
NH2
R1
NaNH2
R2
..- R I . ~ O + R2H NH2
R1, R2 = alkyl P h ~ / P h O
NaNH2
H 2 N ~ N H 2
O
O
O
n=3to14 O ~
P
h R
R
/R
NaNH2 ~Me~ R
/~O N I
H
Fig. 19. Hailer-Bauerreaction of non-enolizableketones.
The cleavage of alicyclic phenyl ketones generally leads to benzene and alicyclic carboxamides. Nevertheless, the use of 1-methyl cyclopropyl phenyl ketone yields benzamide and a cyclopropane. Using this property with a chiral compound, Imposimato and Walborsky (ref. 110) have shown that this reaction proceeds with retention of configuration (Fig. 20). 460
Me
Me
_ _
~ Ph
_
.-
..
'~COPh
NaNH2
~ ~~'~H
Toluene Ph
(-)R
Ph
Ph
(+)s
Fig. 20. Hailer-Bauer reaction with cyclopropyl phenyl ketones. Originally the Hailer-Bauer reaction was designed to serve as a method for amides synthesis (ref. 108). More recently the process has been extended to the preparation of hydrocarbons by replacement of a benzoyl group by a hydrogen atom (ref. 111). Applied to optically active ketones (Fig. 21), the Hailer-Bauer rearrangement leads to the optically active hydrocarbons with about 45 % of retention (ref. 112) with NaNH2 (best results are obtained with the use of potassium t-butoxide). The selectivity can be enhanced with the use of refluxing n-butylamine as the solvent (ref. 113). O ~.,R Ph
'Ph
NaNH2 j,, PhCONH2 + benzene,reflux
~e~...,,R Ph
Me
NaNH2 PhCO solvent benzene butylamine
~
Ph,,
H % retention 44 82
Fig. 21. Preparation of hydrocarbons by Hailer-Bauer reaction.
When the starting ketone bears a double bond (Fig. 22) the reaction leads essentially to the expected hydrocarbon but accompanied by cyclic structures and "dehydro" product (ref. 114). A similar reaction-type is observed if a cyclopropane or a cyclobutane (ref. 115) is borne on the side chain (Fig. 22). These reactions are highly dependent on the nature of the solvent.
461
Me
Ph,,
O
Me 18%
NaNH2 benzene
Ph Me
62 %
~"
....Me
Ph,,,. Me 15% ~ M e
5% Ph ~
NaNH2 Me solvent benzene THF heptane
% 50 83 63
% 42 15 32
% 7 1 3
Fig. 22. Hailer-Bauer reaction with unsaturated- and cyclopropylketones. Owing to the interest of optically active C-centered organosilanes, Paquette and co-workers (refs. 116-118) have applied the Hailer-Bauer reaction to optically active non-enolizable c~-silyl phenyl ketones. An optically active silane (Fig. 23) was obtained with retention of configuration (96 to 98 %). These results are interpreted on the basis of an initial ~-silyl carbanion formation within a solvent shell that also encases benzamide. O Phi., Me3Si
0 R Me
NaNH2
ph/~
NH2
+ Me3Si
Me
R = n-Pe, PhCH2, Ph-CH2-CH2, CH2C=CMe2
P h C O ~ Me3Si,,,"~
j
Me
Me
Me
NaNH2 Me3Si~
Fig. 23. Hailer-Bauer reaction of ot-silylketones. 462
Me
The Cram cleavage of diphenylcarbinols (refs. 114, 115) is generally obtained with alkoxides but NaNH 2 can also be used leading in the following example (Fig. 24) to a mixture of rearranged products. This reaction has been explained by the formation of free-radical intermediates.
OH Ph ~
M
Me
NaNH2
Ph
4%
benzene
3%
29% Me
Me 16 %
15 %
Fig. 24. Cram cleavage of diphenylcarbinols with NaNH2. The reaction of 1, 2, 3, 4, 5-pentaphenyl carbinol with NaNH2 in isoamylether (IAE) at 173 ~
leads after quenching with water to an enone (Fig. 25). If H20 was
added at room temperature the kinetically controlled product was prepared while the thermodynamically controlled enone is observed by adding H20 at 173~ (ref. 119). Ph
Ph
Ph Ph O
,~
1) NaNH2 2) H20, RT
Ph
Ph
Ph
Ph Ph
1) NaNH2
OH
2) H20, 173 ~
Ph
Ph
Ph
Ph
Fig. 25. Reaction of polyphenyl carbinols with NaNH2. The
reaction
of
NaNH2
in
aprotic
medium
on
tri-
or
tetracyclic
benzocyclobutanols (Fig. 26) leads to a rearrangement of the cyclic structure into a phenylcyclohexanone or into a cyclooctanone depending on the polarity of the solvent. When R I = R 2 = M e a Hailer-Bauer rearrangement is observed on the octanone leading to an amide (ref. 120).
463
O
R1
R3
RI\ R2 R2 R3
NaNH2 ~ i x - -~ 16"
R3
Ph
solvent v
O
"R4
R4
R4
R5
R6
R5
R5
solvent
%
%
total yield(%)
R1-R6 = H
DME
70
30
70
R1-R6 = H
HMPA
100
0
70
R4 = Me, R1-R3, R5, R6 = H
DME
61
39
76
R4=Me, R1-R 3, R5, R6 =H
HMPA
80
20
75
DME
0
100
80
R1, R 6 = Me, R2-R 5 = H
Fig 26. Reaction of NaNH 2 with benzocyclobutanols. Finally like methyllithium (ref.
121) ammonium fluoride (ref.
122), tris-
(dialkylamino)sulfonium salts (ref. 123) or alkali alkoxides (ref. 124), alkali amides in liquid ammonia are able to cleave the silicium-oxygen bond of silyl enol ethers (refs. 125, 126) leading to enolates. The sodium enolate obtained (Fig. 27) by treatment of a silyl enol ether with NaNH2 can be equilibrated in the medium, leading to two alkylated products, nevertheless no polyalkylated species is detected. With the use of LiNH 2 only the expected reaction product is prepared but the use of KNH2 leads to a mixture of C-mono and dialkylated and O-alkylted products (ref. 125). OSiMe3
O 1) NaNH2 / NH3 l i q .
O +
33.8 %
O +
34.6 %
31.6 %
Fig. 27. Cleavage of a silicon-oxygen bond with NaNH2. Sodium alkoxides which also cleave the silicon-oxygen bond, can be produced
in-situ by reaction of NaNH2 with an alcohol. For example the sodium enolate of 464
prenal produced in this way can be reacted with aldehydes such as benzaldehyde (Fig. 28) yielding a dihydropyran and a silylated dihydropyran in high yield (ref.t127). These two compounds treated polyunsaturated aldehyde (refs. 124, 128).
in
acidic
OH
medium
lead
to
a
OSiMe 3
1) NaNH2 /ROH ~OSiMe3
2) PhCH O
Fig. 28. Reaction of the sodium enolate of prenal with benzaldehyde. NaNH2 is a powerful basic reagent which was widely used in chemical laboratories until lithium diisopropylamide was discovered and became more commonly used as it is much more soluble in classical solvents such as ether and tetrahydrofuran. NaNH2 is also a powerful reagent when associated with potassium t-butoxide to become a "complex base" (not described here) as shown by the research work of Caubere and co-workers (ref. 62). Nevertheless NaNH2 remains a widely-used reagent in the chemical industry as shown by the numerous patents using NaNH2 (316 between 1983 and 1993) reported in the literature.
References .
2. 3. 4. 5. 6. 7. .
9. 10. 11. 12. 13. 14. 15.
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468
DELIVERY SYSTEMS MATERIALS
FOR
CONTROLLED
RELEASE
OF
ACTIVE
CHRISTIAN PRUD'HOMME Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie des Carri~res, 85 avenue des Fr~res Perret, B.P. 62, 69192 Saint Fons Cedex, France
INTRODUCTION For many years, the major focus of active material related research has been the discovery and the synthesis of new molecules. In the last decades, increasing attention was devoted to the manner in which these compounds are delivered. There has been considerable interest in developing controlled-release systems in a wide range of applications such as drug delivery, crop and seed protection in agriculture, animal nutrition, food additives, dyes and inks, personal care, household products, detergents, chemical reagents, curing agents and catalysts. The benefits offered by controlled delivery are now well known. In pharmaceutical applications, drug administration may be improved by using a delivery system designed for continuously maintaining the plasma levels of the active molecule in a therapeutically desirable range. Drugs can be released in a precise and prolonged manner (up to over one year) without necessitating repeated and sometimes painful administration (i. e., injection). Harmful side effects can be reduced and patient compliance may be improved. Other advantages of controlledrelease technology in drug development include localized delivery to a particular compartment of the body, and preservation of active agents which have short lifetimes in the body. In agricultural area, standard procedures for administration of pesticides result in a great deal of waste. The use of controlled-release systems can reduce the necessary dosage, and facilitate handling problems related to toxicity hazard. In various kinds of applications, there is a need to protect active ingredients against chemical or physical degradation, or to mask unpleasant odor or taste. Materials which would react with one another on contact, or need to be protected 469
from light, moisture, microorganisms or oxygen, can be incorporated in a polymer system specially designed to isolate them during the storage period, and to release them to the application site at the desired moment. The composition of the structural material and the choice of the fabrication process are important in the preparation of controlled-release systems. Over the past decades, great advances have been made in the engineering of multicomponent, polymer-based, structural materials. These materials were designed to release active substances by different mechanisms (ref. 1) including diffusion, chemical control (polymer degradation) and solvent activation (swelling or osmotic pressure). In some cases, combinations of such mechanisms have been used. Experimental methods and theoretical analysis of mass transport phenomena in these materials have been developed (refs. 2,3). Various fabrication methods can be used in the preparation of controlled-release systems. These methods include molding and extrusion techniques, pan coating, encapsulation, and gellation procedures. The selection of the fabrication process is based on considerations like active agent's stability and solubility, compatibility of agent with other ingredients, desired size and shape of the final system, productivity and cost. The purpose of this paper is to give illustrative examples of the controlledrelease approach, and to discuss the principles and the challenges of this promising technology. The following examples are based on studies conducted in our laboratories. CONTROLLED RELEASE IN ANIMAL NUTRITION One typical example of a controlled-release approach is the Smartamine T M system for ruminants developed and commercialized by Rh6ne-Poulenc Animal Nutrition. Smartamine TM products are rumen-protected amino-acids which are added to the feed of dairy cows in order to increase the protein content of the milk. It is well known that some amino-acids are limiting in the diets of ruminants. It has been demonstrated that effective absorption of methionine and lysine in the digestive system of cattle improves growth in steers and milk production in dairy cows. However, when unprotected amino-acids are given as feed additives to ruminants, they pass first into the rumen where they are degraded by microorganisms. Consequently, they never reach the absorptive sites of the gastrointestinal tract and cannot be used by the animal for protein synthesis. This is the reason why investigators are searching for supplemental forms of methionine and lysine which are resistant to microbial degradation and subject to absorption in a post-ruminal part of the digestive system of ruminants (Fig. 1). 470
Various routes have been proposed to prepare protected amino-acids. The desired use and method of administration greatly affects the choice of the system. In this case, the size of the system should not exceed a few millimeters because of the transfer from the rumen to the abomasum.
GASTROINTESTINAL TRACT OF RUMINANTS
v
Fig. 1. Selection of the release mechanism A first critical problem was the ability to achieve a good stability in the rumen and to find a mechanism which would trigger a rapid and total release of the active ingredients in a post-ruminal site. To accomplish this, the protective material of the system was designed to be sensitive to a pH change in the medium along the gastrointestinal tract. Most controlled-release systems can be formulated in two basic configurations : matrices and reservoirs. In a matrix system, the active substance is uniformly distributed throughout a solid material. In a reservoir system, a core of active ingredient is surrounded by a wall. Reservoir systems include membrane systems which are of the greatest value to achieve constant and precisely controlled release rates. Smartamine TM is a multiparticulate reservoir system consisting of amino-acid cores surrounded by a pH-sensitive coating (Fig. 2). In the present case, the principal advantage of a reservoir system is to allow high amino-acid contents.
471
SMARTAMINE TM
HYDROPHOBIC INGREDIENTS (LIPIDS) COATING ~
"4" pH-SENSITIVE POLYMER
AMINO-ACID CORE
Fig. 2. A multiparticulate reservoir system The methionine and lysine monohydrochloride cores are produced by a meltbinder extrusion spheronization process. Particle diameters are ranging from 1.5 to 2.5 mm. The coating is composed of hydrophobic substances and a pH-sensitive polymer which is able to dissolve or swell in the acidic abomasal medium. The cores are coated in a fluid-bed coater using a solvent-free process (Fig. 3). AMINO ACIDS (POWDER) WET GRANULATION PRocEss I (EXTRUSION-SPHERONIZATION)l
pH-SENSITIVE POLYMER IN AQUEOUS SOLUTION OR EMULSION MELTED FATTY ACIDS
AMINO ACID CORES
! DISPERSION I
)
COATING EMULSION
COATED AMINO ACIDS
Fig. 3. A solvent-free encapsulation process The pH-sensitive ingredient is a copolymer of 2-vinylpyridine and styrene (ref. 4). At low pH values, this copolymer becomes hydrophilic because of the protonation of its pyridine pendent groups. It is synthesized by radical emulsion polymerization of a mixture containing 65 % 2-vinylpyridine by weight and 35 % styrene (Fig. 4). After polymerization, unreacted monomers are eliminated using a 472
specific treatment. The coating material contains 20% copolymer and 80% stearic acid. This system has been approved by the U. S. Food and Drug Administration and by the European Authorities. CH=CH2
CH=CH2
~CH-CH2--CH--CH2~ Na2S208
50~ styrene 35%
pH 13
2-vinylpyridine 65%
Copolymer
Fig. 4. Synthesisof the copolymer of 2-vinylpyridine and styrene The use of chitosan as a means of controlling the release of amino-acids has been also investigated by Rh6ne-Poulenc (ref. 5). Chitosan (deacetylated chitin) is extracted from shrimp and crab shells. It is known as a non-toxic, biodegradable polymer (Fig. 5). It is insoluble in water at neutral pH and has the capacity to dissolve at low pH values. Chitosan solutions are prepared by dissolving the polymer in dilute acetic acid. Stearic acid and oleic acid are the hydrophobic constituents in the chitosan-based coatings.
473
CH3 \
Chitin
--~ ~ C l q
HO~ c ,
H
~,
/
I NH \
C--O
H / H H HO~ / .Nil / [ C~[ ~C. ..C~
t~ .CH2OH ~C~]cH~O
"
c H
c
CH
/
fl ~H2OH
/- -
"O ~
o
CH2OH [ ~O
\\
CH
.... c "" I
~\
H
C--O
\
Poly-~ (1-4)N-acetylD-glucosamine
/ c
fl
C--O
Chitosan (partially deacetylated chitin) H ~C~
I
CH2OH . . .
I ~0 9 -"CH .
.,-,~C
nw
IH
. HO.
.
l
l~H2
.
/
H
--C~l
.
NH2
u ]"
~C. CH"--
~C~l ~O XO/ " -"CH'"-
C
C
i~I
iJ.i ~H20H
/
H
CH2OH ,
I
.... C
0
l
raw]
D-glucosamine (> 7O%)
C
1~_i2
i~I
R-,,,c~O I
Chitosan
salts
O-
H
CH20H
HO.~
ra +
u
H
/" NH3 /1' J .CH2OH jC:-... [ ~O C~[ ~C. ~.C~ [ ~O \ CH \ I CH I ~ O / \ CH \ \ CH \ / 0 ~ /JCH...~ / \ /CH~ \ / HO~ T I y T / "" HO~ T I Y .1 NH3 H H CHgOH I NH3 H H
+
--
,
"
O-
I
I-1
+
o
I
Fig. 5. Chitin and chitin derivatives
The coating emulsions are obtained by dispersing melted fatty acids (stearic acid or a mixture of stearic acid and oleic acid) in the chitosan solution or in the copolymer emulsion at 90~
The amino-acid cores are fluidized with hot air in the
coater. The coating emulsion is pumped through a spray nozzle, atomized with a high pressure air stream, wetting the surface of the cores (Fig. 6). The heat of the fluidizing air drives the water away from the layer, leaving the coating ingredients behind (Fig. 7).
474
ii i
9o ' ~ ~ COATING EMULSION '
o~L
I
o
0
90"C
i
I . ~
UIDIZED CORES
e
9Ip~I,ll
HEATEDFLUIDiZlNGAIR
Fig. 6. Spray-coating process
Fig. 7. Scanning electron micrograph of the coating (cross section, chitosan-coated methionine granules) In-vitro laboratory testing is important for the development of controlled-release systems. In-vitro protection of the coated amino-acids was evaluated by measuring the amount of methionine or lysine released from the particles at 40~
in a
phosphate buffer at pH 6. In-vitro release behavior was determined by dissolution test at 40~ in a buffer at pH 2. 475
These studies have shown that numbers of parameters such as the coating weight and the coating composition can significantly affect the protection/release properties of the coated granules. For example, high levels of oleic acid in the coating improve resistance to water at pH 6. The physical properties of the amino-acids are also important. Highly hydrophilic lysine hydrochloride is more difficult to protect than methionine, and requires higher coating weights and more oleic acid. The behavior of the system can be strongly influenced by the microstructure of the coating material. For the chitosan-comaining products, excellent protection in rumen and good release rate at pH 2 were achieved using very low levels of pHsensitive component (only 3 % chitosan) in the coating composition (Fig. 8). This result can be explained by the continuous network structure formed by chitosan salt. This microstructure was observed using electron microscopy, by examination of a thin section of the coating after dissolving the fatty acids in toluene (Fig. 9). The formation of this particular structure was determined by the choice of the coating process and the coating conditions.
100 % METHION!NE RELEASED 90 80 7O 60 50 40 30 2O 10 0
2
4
6
8
10
12 14 16
18 20 22
24
TIME (HOURS)
Fig. 8. In-vitro testing of rumen-protected methionine granules Release rate at pH 2 and pH 6 Methionine loading in coated granule 981%, coating weight" 8 % Coating composition" 87 % stearic acid, 10 % oleic acid, 3 % chitosan (acetate) 476
Fig. 9. Transmissionelectron micrograph of the chitosan microstructure of the coating The products were also tested by in-vivo techniques. For example, evaluation of the rumen stability was carried out using samples placed in porous nylon bags and incubated in the rumen and in the intestine of cows. In other experiments, the products were given orally to the animals and the levels of amino-acids in the GI tract and in the blood plasma were measured. The impact of the protected aminoacid intake on the quality of the milk production was also studied in collaboration with institutes and universities in different countries. The increase of protein production is significant (0.9 g to 1.7 g / liter / animal) and economically interesting for dairy farmers. The higher levels of protein in milk also improve cheese manufacturing. It can be expected that the use of the Smartamine TM system will expand into other areas, such as veterinary applications where medicaments cannot be orally administrated because the biologically active molecule is subject to degradation in the rumen.
CONTROLLED RELEASE OF IODINE SALTS FOR FIGHTING IODINE DEFICIENCY A second example of an application of the controlled-release technology developed by Rh0ne-Poulenc is the Rhodifuse | system (ref. 6). This system is commercialized by Rh6ne-Poulenc RORER for the treatment of iodine deficiency. Lack of iodine in the diet can cause serious disorders such as goiter and cretinism in adults, growth disorders in children, and fetal death in pregnant women. This 477
problem is affecting several hundred million people in the world. Fighting against iodine deficiency is a world-wide priority for international health authorities. Rhodifuse | Iode was designed to deliver sodium iodide in a source of drinking water continuously over a one-year period. It can be placed in a well to release a therapeutic supply of iodine (100 ~tg / day / individual) at a nearly constant rate. It is a modular matrix system which is composed of three polypropylene baskets, each of them containing three matrices (Fig. 10). The cylinder-shaped matrices are loaded with 30% NaI by weight. They are prepared by molding a dispersion of NaI powder in a two-component silicone RTV (platinum catalyzed).
Fig. 10. A modular matrix system The use of silicone elastomers for controlled release is well known. The delivery of contraceptive steroids has been one of the most widely studied applications. In these systems, the release of the drug occurs via the diffusion of the active molecules through the polymer network. Such a mechanism is not suitable for the delivery of water-soluble compounds like sodium iodide. In the case of Rhodifuse | lode, the release mechanism (refs. 7, 8) is based on the osmotic properties of NaI (Fig. 11). In a first step, water diffuses through the silicone matrix and starts dissolving the NaI particles which are embedded in the polymer. Gradually, the particle dispersion is changing into a dispersion of growing cavities filled with NaI solution. As a result of high osmotic pressure, the size of the cavities keeps increasing, creating high local stresses and causing polymer cracking. 478
Finally, the iodine salt escapes from the matrix through the water-filled interconnecting network of cracks and cavities which is generated by this mechanism. The release rate of NaI is influenced by the mechanical properties of the silicone elastomer, the size and the shape of the matrix, the initial loading of iodine salt and the size distribution of the salt particles. The same mechanism can be used to release molecules which are less hydrophilic than NaI. In this case, the active ingredient should be co-formulated with an osmotic agent like NaC1 (refs. 9,10).
Fig. 11. Release mechanism
Rhodifuse | has been successfully tested in African villages where drinking water had very low iodine contents. Normal urinary iodine levels were measured after six months of supplementation. A significant regression in the prevalence of endemic goiter was observed among the population after one year.
CONCLUSION Controlled release of active materials is an important area of research. Controlled-delivery systems offer a number of potential advantages in many fields of applications. The design and the development of a new controlled-release system require a multidisciplinary approach. Polymer and material sciences play an important role. The selection of the formulation and the choice of the fabrication process are critical. In many cases, ingredients used in formulations should satisfy 479
requirements related to toxicity, to biocompatibility and to biodegradation, especially when used in food, in feed, and in medical applications. Various physical and chemical phenomena, such as erosion, swelling, diffusion, dissolution, etc .... can be used to trigger and to control the release of the active agent. Theoretica! models are available to aid in the application of these phenomena to a specific problem. Zero-order release kinetics (constant release rates) are often desired. A good laboratory evaluation of the products is also needed in the development of controlled-release systems. Good correlations should be made between in-vitro and in-vivo experiments, because the release behavior is often affected by the surrounding medium.
References 1. R.S. Langer, Chem. Eng. Commun., 6, 1, (1980). 2. N. A. Peppas, Mathematical models for controlled release kinetics, in Medical Application of Controlled Release, R. S. Langer, D. L. Wise, (Eds), CRC Press, Vol. II, p. 169, Boca Raton, FL, (1984). 3. N. A. Peppas, Mathematical modelling of diffusion processes in drug delivery systems in Controlled Drug Bioavailability, Wiley, Vol. 1, Drug Product Design and Performance, V.F. Smolen, L.A. Ball, (Eds), 203, New York (1984). 4. C. Prud'homme, P. Bourrain, H. Porte, Proceed. Intern. Control. Rel. Bioact. Mater., 18, 548, (1991). 5. C. Prud'homme, Proceed. Intern. Control. Rel. Bioact. Mater., 21, 112, (1994). 6. G. Torres, Proceed. Intern. Control. Rel. Bioact. Mater., !8, 403, (1991). 7. V. Carelli, G. Di Colo, J. Pharmaceutical Sci., 72, 316, (1983) 8. R. Schirrer, P. Thepin, G. Torres, J. Mater. Sci., 27, 3424, (1992). 9. V. Carelli,, G. Di Colo, C. Guerrini, E. Nannipieri, Int. J. Pharm., 50, 181, (1989). 10. G. Di Colo, Proceed. Intern. Control. Rel. Bioact. Mater., 18, 317, (1991).
480
A N I S O L E : AN E X C E L L E N T S O L V E N T
JEAN-ROGER DESMURS a) AND SERGE RATTON b) a) Rh6ne-Poulenc
Industrialisation,
Centre de Recherche,
d'Ing6nierie
et de
Technologie, 85 Avenue des Fr~res Perret, BP 62, 69192 Saint-Fons Cedex, France. b) Interm6diaires Organiques, 25, quai Paul Doumer, 92408 Courbevoie Cedex, France.
INTRODUCTION For a few years, the number of solvents available for the synthesis industry has been
significamly
reduced
for
safety
and
security
reasons.
Environmemal
constraints on chlorinated solvents are constamly increasing (ref. 1). Consequently, chemists have had to research new solvents and anisole is mentioned in several of their works. There is no doubt that for the chemist anisole has interesting characteristics (ref. 2) as indicated below : melting point 937 ~ C boiling point : 154 oC solubility in water : 1.6 g/litre self-ignition temperature : 475 ~ as well as low toxicity 9 DL 50 (rat) : > 5,000 mg/kg DL 50 (rat) : 3700 g/kg This document aims to review of the use of anisole as a solvent.
481
ORGANIC SYNTHESIS
Grignard reaction Anisole, as a solvent, has been widely used in the Grignard reaction. R.N. Lewis and J.R. Wright (ref. 3) report that anisole, which is a slightly basic solvent, gives a quick reaction between Grignard's reagent and acetone.
+
Anisole
~MgCI
0
OH
Other authors also describe different synthesis reactions 9 via an organomagnesium compound in anisole (ref. 4 ) HO --N
/~ /
HO MeMgI Anisole
/ /
t=2h. T= 85~
or in ether/anisole mixtures (ref. 5).
oi< ~
MeMgI Ether Anisole
OH
1 -0,33 h
Organolithium condensation Besides lithiation of anisole, anionisations by butyllithium of more acidic compounds can be obtained (ref. 6).
482
BuLi (1,6 M) CuC12
S
~
~
Hexane/ Et20 / Anisole - 1 0 . 100 ~
(2 eq.)
Yield = 90 %
Halide exchange Anisole has been used to perform the synthesis of fluorinated compounds through halide exchange (ref.7).
~
"<'/
NO2 "Cl
ZnF2 (3,3 eq.) / Anisole
~ N O 2
t=gh. T=154 ~
"
"F
Yield =49 %
Hydrogenation Hydrogenation of nitroaromatic compounds was performed by W. Theilacker and Coll. in Anisole with platinium as catalyst (ref. 8). NO2
H2/Pt
t- h
-70o
H2N
Yield 965 %
Carbonylation Anisole as a solvent for the carbonylation reaction is described in many publications. 483
Hydroxycarbonylation of 4-chloroiodobenzene produce 4-chlorobenzoic acid with palladium as a catalyst (ref.9). NaO
O
i
CO /NaOH / PdCl2 (P~)3)2 ~
~/)
t=10h. T=80-90~ C1
C1
The preparation of methacrylate (ref. 10) or anydride was described by the Shell company (ref. 11).
O
"-J~-/~OH
CO /Pd(OAc)2 / Anisole
Conversion: 64 %
+ CH3OH
O
P= 39 bar t=2h. T =90~
O
Selectivity : 95 %
CO / Pd(OAc)2 / P~bO3 / Anisole "T = 115oc P=21 bar
O I [ ~ O J Selectivity :95 %
Peptidic synthesis The properties of anisole have been widely used for peptidic synthesis as shown in the works on synthesis carried out by T. Abiko and H. Sekino (ref. 12) Boc-Tyr(Bzl)Leu-GlnSer(Bzl)-Leu-NHNH2
Boc-Tyr(Bzl)-LeuGln-Ser(Bzl)-Leu NHNH2
+
Boc-Thr(Bzl)Ala-LeuLys(Z)Arg(Mts)-OBzl
TFA Anisole
Boc-Thr(Bzl)Ala-Leu-Lys(Z)Arg(Mts)-OBzl 484
Boc-Tyr(Bzl)Leu-GlnSer(Bzl)-LeuThr(Bzl)-AlaLeu-Lys(Z)Arg(Mts)-OBzl Boc-Tyr(Bzl)-Leu-GlnSer(Bzl)-Leu-Thr(Bzl)Ala-Leu-Lys(Z)-Arg(Mts)OBzl
by N. Fujii, A.Otaka, S. Funakoshi, K. Bessho, T. Watanabe, K. Akaji, H. Yajima (ref. 13), Z-Ala-GlyThr-AlaAsp(OBz)Cys(MBzl)PheTrp(Mts) ~
TTFA TFA Anisole ~
Z-Ala-GlyThr-AlaAsp(OBzl)Cys(S1)-PheTrp(Mts)Lys(Z)-Tyr~
or by H. Yajima, N. Fujii, S. Funakoshi, T. Watanabe, E. Murayama, A. Otaka (Ref. 24). Z-Ala-GIyThr-AlaAsp(OBzl)Cys(MBzl)PheTrp(Mts)@
TTFA TFA TMSOTf Anisole m-cresol ~ t2 = 3h 0~ Chromatography
H-Ala-GlyThr-Ala-Asp-Cys(S1)-PheTrp-Lys-TyrCys(S1)-ValOH (S1) @
De-protection of peptides was also performed in anisole by H.B. Arzeno and D.S. Kemp (ref. 15). Arg (N(omega) -Ans)-ProPro-Gly-PheSer-Pro-PheArg(N(omega) -Ans) Ans@
TFA (anhydrous) PhSMe Anisole t =4h 25~
Arg-Pro-ProGly-Phe-SerPro-Phe-Arg
Decarboxylation When heated with reflux of anisole for two and a half hours, 4-benzoyl 3carboxy-2-methylthio-pyrimidine decarboxylates giving 4-benzoyl-2-methylthio pyridine with a yield of 98 % (ref. 18).
485
0
OH 0
o Anisole T = reflux t = 2,5 h.
MeS
Several other examples of the decarboxylation of pyrimidine are cited by J. Arukwe and F. Undheim (ref. 16).
Esterification Gallic acid is esterified by lauric alcohol in a nitrobenzene and anisole mixture in the presence of 2-naphtalenesulfonic acid (ref. 17).
HO
OH ~ O H
ij
H +
0 ''~~OH
2-naphtalene sulfonic acid nitrobenzene-anisole "-
OH HO
OH +
H20
t = 20 h.
APPLICATIONS
Additive for fuel Anisole is mentioned in the literature as an additive for fuel. Introducing between 2 and 9 % of anisole produces, high octane ratings (ref. 18-20). The use of surfactants in solution with acetophenone or anisole (refs. 30 - 34) was also described.
Paint and varnish strippers Anisole is a solvent used in the composition of products to scour paints (ref. 21).
486
Binders Binders for sand moulds, which are based on an aqueous solutions of phenolic resins and aromatic ether, such as anisole, are described in the literature (ref. 22).
Paints, varnishes Anisole was also mentioned as a solvent for paints polyimide type (ref. 23), and polyester type (ref. 24) paints or those based on isocyanate (ref. 25). Mitsubishi (refs. 26-29) describes the use of anisole for oxygen-proof and damp-proof materials which have a protecting function.
Cleaning agents Anisole is one of the substitutes to chlorinated or fluorinated solvents used as cleaning agents (refs. 30, 31).
CONCLUSION Anisole, a compound easily produced by methylation of phenolate, has chemical and physical characteristics, low toxicity and low cost which make it worth being systematically
examined
by
the
chemists
working
either
on
synthesis
or
applications.
References .
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
R. Rapp - L'Actualit6 Chimique, 62 (November 1994) MSDS Rh6ne-Poulenc - Version 3 (September 16, 1994) R.N. Lewis, J.R. Wright, J. Amer Chem. Soc., 7__A,1253, (1952) R.M. Anker, A.H. Cook, J. Chem. Soc, 58, (1946) J. Rigaudy, J.M. Farthouat, Bull. Soc. Chim. Fr., 1266, (1954) A. Berlin, G.A. Pagani, F.S. Sannicolo, J. Chem. Soc. Chem. Comm. 22, 1663, (1986) JP 3284135, (1989), (to Mitsui Toatsu Chem.). W. Theilacker, W. Berger, P. Popper, Ber. Deutsch Chem., 89, 970, (1956) X. Huang, J.L. Wu Chem. Ind, 17, 548, (1990) E. DRENT, EP 293053 (1988) (to Shell) E. DRENT, EP 186 228 (1986) (to Shell) T. Ab;,ko, H. Sekino, Chem. Pharm. Bull, 35, (5), 2016, (1987) N. Fujil, A. Otaka, S. Funakoshi, K. Bessho, T. Watanabe, K. Akaji, H. Yajima, Chem. Pharma. Bull; 35 (6), 2339, (1987) H. Yajima, N. Fujii, S. Funakoshi, T. Watanabe, E. Murayama, A. Otaka, Tetrahedron 44 (3), 805, (1988) H.B. Arzeno, D.S. Kemp, Synthesis, (1), 32, (1988) 487
16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26 27. 28. 29. 30. 31.
J. Arukwe, JF. Undheim, Acta. Chem. Scan. B, 4__.00(7), 588, (1986). N. Yokoyama, JP 06192667 ,(1994), (to Nippon Oil Co). R.G. Temple, N.R. Gribble- Prep. Pap., Am Chem. Soc., Div. Fuel Chem., 37 (4), 1829, (1992) H.G. Unzelman, Oil Gas J., 89 (19), 44, (1991) J.P. Lallier, S. Fouqay- EP 93-401372 (June 2nd, 1992), (to ELF Atochem). K. Kiuchi, H. Funada, A. Kura, S. Nikai, JP 04118148 (1990) (to KAO CORP.) T. Kigami, A. Morinaga, JP 05059169 (1990) (to Mitsubishi) T. Kigami, A. Morinaga, EP 367493 (1988) (to Mitsui) T. Kigami, A. Morinaga, JP 04029964 (1990) (to Nippon Paint) A. Hiroshi, T. Nishikawa, K. Sonada, A. Yoshiko, H. Adachi, Y. Aiba, FR 2659343 (1989) (to Mitsubishi Denki K.K.). Y. Aiba, H. Adachi, E. Adachi, JP 040663883 (1990) (to Mitsubishi Denki K.K.). H. Adachi, S. Yamamoto, DE 4138180 (1990), to Mitsubishi Denki K.K.) S. Yamamoto, H. Adachi, DE 4117667 (1990) (to Mitsubishi Electric Corp.). T. Yasukochi, S. Akimoto, JP 0311496 (1989), (to Nippon Oil and Fats Co.). G. Ferroni, C. Khouzam, WO 921346 (1991) (to Silvani Antincendi S.P.A.).
488
THE USE OF PHENOLIC COMPOUNDS POLYMERIZATION INHIBITORS
AS
FREE-RADICAL
FRANCOISE LARTIGUE-PEYROU Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et Technologie, 85 Avenue des Fr6res Perret, 69192 Saint-Fons Cedex, France.
de
INTRODUCTION The inhibition of radical polymerization is very important in the chemical industry for preventing premature polymerization during the manufacture, storage and transportation of unsaturated monomers such as vinyl monomers which polymerize with a radical mechanism. Runaway polymerization during these steps may accelerate autocatalytically and, in extreme cases, may generate substantial heat and pressure which can cause considerable damage. Though less dramatic but more commonly encountered, slow unwanted polymerizations during storage or transportation may lead to an unusable monomer due to the internal build up of polymer over time. In order to avoid unwanted polymerization, various (high reactivity) inhibitors can be used. According to their function, these can be classified as follows : (a) storage and transportation inhibitors (monomer stabilizers), (b) process inhibitors used during the manufacture of the monomer (e.g. distillation), (c) short-stop inhibitors used for "killing" (or stopping) the polymerization very quickly, (d) retarding inhibitors used for regulating the polymerization in progress, (e) inhibitors used to stop a polymerization when the desired conversion has been obtained and to increase the stability of the polymer (e.g. antioxidants). In points (a) to (c), the aim is to completely stop the polymerization with inhibitors in relatively low concentration (5 ppm to 2000 ppm by weight based on monomer). On the other hand, for applications (d) and (e) the inhibitors (or retarders) are used in relatively high concentration. In this article, only the two main points (a) and (b) will be discussed. 489
The performance of inhibitors varies depending upon their conditions of use. Therefore, inhibitors which are preferred for monomer manufacturing may not be suitable, for example, for storage conditions. The key to monomer stability lies in selecting the proper types and amounts of polymerization inhibitors. Worldwide, phenolic compounds are used in large scale.
OVERALL MECHANISMS OF INHIBITION
Overview of free-radical polymerization In order to explain how inhibitors work, we need to quickly describe the mechanism of free radical polymerization encountered for the ethylenically unsaturated monomers. For more details, several reviews (refs. 1-7) also described free radical polymerization. Under normal conditions, we have four elementary steps : Initiation, Propagation, Transfer and Termination.
Initiation step X ~ 2R" R" + M --> RM" In these equations, X and M are initiator and monomer, respectively, R" is the primary radical and RM" is the propagating radical. The free radical can be generated by a thermal process or by dissociation of an initiator such as benzoyl peroxide or azobisisobutyronitrile These radicals are reactive enough to react with the monomer giving the first propagating radical RM'. Propagation step RM" + M RM 2" +
M
--~
RM 2" ---> RM 3"
RMn" + M --> RM'n+I RM'n is the propagating radical. The propagation reaction occurs during the continuous addition of monomer. This reaction will grow the polymer chain as long as the monomer is available in the medium.
Chain transfer step RM n" + AH ---> RMnH + A" 490
RM n H is the polymer chain containing n monomer units and AH is a chain transfer agent or an inhibitor. The active radical site is transfered to another molecule.
Termination step by radical combination
RM n"
+
RMm ~
--~
RMn+mR
by disproportionation
RM n.
+
RM m"
--~
RMnH
+ Pm
Pm is a polymer chain. These two reactions lead to radical destruction.
General concepts of inhibition Inhibitors are substances that stop radical polymerization. Those have quite a rapid action on initiator and propagator radicals. They transformed them either into a non radical form or into a radical with low reactivity in propagation reaction. They will block the radical polymerization over a so-called induction period that will vary according to its concentration in the reaction environment and to the experimental conditions (temperature, catalyst, etc.). Beyond this induction period, polymerization will occur at the same rate as it would if the inhibitor was not present. (ref. 8). The reaction scheme for ideal inhibition is set out below X --> 2 R" R"
+
Z
-->
inactive product (rate constant kz)
This reaction competes with the chain-growth process :
R" + M --> RM" (rate constant kp) On this basis, it is then possible to determine an inhibition constam. This constant requires an exact kinetical analysis of each separate process, which has not been carried out in most cases. Generally only the ratio kz/kp is obtained. Some values (refs. 9 - 11) are shown in Table 1.
491
Table 1. Inhibition constants at 50~ Inhibitor Nitrobenzene
Monomer Styrene Methyl acrylate
z = kz/kp 0.326 0.00464
1,4-Dinitrobenzene
Vinyl acetate Styrene
11.2 13.52
1,3,5-Trinitrobenzene
Vinyl acetate (45~ Styrene
68.5 64.2
Methyl acrylate
0.204
p-Benzoquinone
Vinyl acrylate Styrene
404 518
Acrylonitrile
0.91
Methyl methacrylate Styrene
5.7 2040
Chloranile Copper (II) chloride
Methyl methacrylate (44~
0.26
Styrene
11000
Acrylonitrile (60~
100
Diphenylpicrylhydrazine (DPPH) Hydroquinone
Methyl methacrylate (60~ Methyl methacrylate (44~ Vinyl acetate
1027 2000 0.7
1,2,3-Trihydroxybenzene 2,4,6-Trimethylphenol Oxygen
Vinyl acetate Vinyl acetate Styrene
5 0.5 14600
Methyl methacrylate
33000
Phenol
Methyl acrylate
0.0002
p-Nitrophenol
Vinyl acetate Methyl acrylate
0.012 0.0649
References 9, 10 and 11.
It can be noticed that the inhibition constant kz/kp initially varies considerably as a function of the reactivity and the polarity of the chain growth radical. It is therefore difficult to extrapolate the efficiency of an inhibitor for a given monomer such as styrene to other monomers, for instance of acrylic type. Furthermore, as this table shows, oxygen is one of the strongest known free radical inhibitors : it acts on alkyl radicals to form peroxy radicals. However, these peroxy radicals can also graft onto the monomer to form an oxidized polymer. The 492
fact is that oxygen can have a dual role : one as an inhibitor (blocking the alkyl radicals in the reaction medium) and the other as polymerization initiator. To illustrate this,
we can try to diagramatically represent an inhibition
mechanism that is close to reality (Scheme 1).
X
~- [R~
02
~
ROO*
M
~
RO2M 9
02
RO2MOO ZH
@
z
RM
Scheme 1. Inhibition mechanism of free-radical polymerization
In fact the inhibition mechanism is much more complex than showed above since the propagating radicals can be alkyl radicals and/or peroxy radicals.
THE RANGE OF M O L E C U L A R INHIBITORS Radical polymerization inhibitors are therefore molecules that are able of reacting with the radicals present in the monomer (either alkyl radicals or peroxy radicals) to give very low reactive radicals which will stop the chain growth. It should be noted that the formation of these products (inert in terms of the polyaddition reaction) can result from several basic and consecutive reactions. This is why inhibition mechanism can sometimes be rather complex. Generally speaking, the chemical structures of these free radical inhibitors can be classified into two main family (ref. 12) : -
acceptor type radical inhibitors,
-
donor type radical inhibitors.
Acceptor type radical inhibitors Acceptor radical inhibitors will be capable of oxidizing the alkyl radicals R" by accepting an hydrogen atom or even an electron by means of an addition
493
mechanism. They are more reactive in an oxygen deficient environments. The main chemical families are presented below.
Quinones Quinones are the most extensively studied inhibitors of radical polymerization and they represent an important inhibitor class. They have complex behaviour and numerous inhibition mechanisms. Even if some details are not yet fully understood, it is now accepted that the main mode of reaction is an addition of the propagating radical to the oxygen of the quinone, as in the following reaction : Rn" + O
~
O
~
R n O @ O *
This aryloxyl radical may terminate a second chain as follows R n O ~ O
~
+ Rm~
.~
RnO~ORm
According to F.Tudos's investigations (ref. 13) on styrene polymerization, quinones can be divided into three groups : Benzoquinone and its non-halogen-substituted derivatives (1,4-Benzoquinone (BQ), 2-Me-BQ, diMe-BQ, triMe-BQ, tetraMe-BQ, MeiPr-BQ, diiPr-BQ, Bu-BQ etc...) - Halogen-substituted derivatives of benzoquinone (C1-BQ, Chloranil, etc...) Quinones with condensed ring systems (Naphtoquinone, Anthraquinone, Phenanthrenequinone etc...) -
-
Aromatic nitro compounds This class includes compounds such as : nitrobenzene, (di)nitrobenzenes, dinitrophenols, (di)nitrocresols or even (di)nitro(alkyl)phenols or cresols. Generally, these compounds are more effective with electron-rich monomers (vinyl acetate or styrene) but have very little effect on methyl methacrylate or methyl acrylate. Here again there are several inhibition mechanisms (ref. 14).
494
Nitroso compounds This inhibitor class can be broken down into two sub-groups: -
aromatic nitroso compounds type O N - ~ ~ ) ~
with R = H, Me, Et, OH,
R
or Nitrosonaphtol, 2-methyl
OMe, C1, p-NH2, NHCH3, NMe2, N(Alkyl), NPh2 4-nitrosophenol, Me-nitrosophenol
- N-nitroso compounds (N-nitrosodiphenylamine, N-nitrosophenylhydroxylamine, Cupferron...)
Metal salts A number of metal salts are well known to be radical inhibitors under certain conditions. In fact besides the rather pro-degrading nature of metal reactions 3+ 2+ + [ Fe + RH ~ Fe + H + R ~ ], metals salts may performed stabilization reactions depending on the redox potential of the system in question. Metal salts may also have some radical-trapping type stabilizing reactions. This is often the case for copper ions:
Cu
2+
+ R" ~
Cu
+
+ R
+
9
For example propagating radicals derived from acrylonitrile could be terminated by Fe(III), Mo(III), Ti(III), Cr(II)...
Other inhibitors Besides these main products, other inhibitors can also be mentioned such as : - dibenzofulvene derivatives - aromatic azo compounds - phenylacetylene - pyridinic derivatives etc...
Donor type radical inhibitors Donor radical inhibitors tend to reduce peroxy radicals by giving an hydrogen atom or an electron by transfer. They act most favourably in oxygen-rich environments. The main chemical families are presented below.
Phenolic compounds Phenolic compounds (phenol, hydroquinone, hydroquinone monomethylether, methylhydroquinone,
tertbutylhydroquinone, 495
catechol,
tertbutylcatechol
etc...)
represent the major class of polymerization inhibitors for vinyl monomers. Phenols inhibition mechanism can be represented as follows : ROO ~
+ HO ~
X
~
ROOH +
"O
X
Phenolic inhibitors in this case exhibit a so called oxygen synergy. This reaction is much more rapid than the transfer reaction on an alkyl radical. Moreover, the slightest trace of oxygen will very rapidly form a peroxy radical from an alkyl radical. Aromatic amines
Alkyl diphenylamines, alkyl p-phenylenediamines, phenothiazine are the main amines which are used.
~
.oo-
~
N H - R '
ROOH +
R
,
The same oxygen synergy as with phenolic inhibitors is exhibited with diphenyl aromatic compounds and phenylene diamine compounds (ref. 15). However, phenothiazine is a rather different case. Indeed it is well known that phenothiazine directly reduces alkyl radicals and not peroxy radicals (ref. 16), and that it works better in anaerobic environments (ref. 17). A lky lh y drox y lamin e s RO0~
+
\ N-OH
/
~
ROOH
\ N --0"
+
/
This type of compound (diethylhydroxylamine, dibutylhydroxylamine etc...) can form both a donor and an acceptor inhibitor system since the nitroxylated radicals that are so-formed are excellent acceptor inhibitors. They may therefore have either function according to the operating conditions in which they are used. Metals salts
It is again the redox potential of the environment that will determine whether certain metal salts act as donor inhibitors, as is the case for copper ions e.g. Cu
+
+
H
+
+ ROO ~
--)
Cu
2+
496
+
ROOH
THE USE OF P H E N O L I C INDUSTRY
INHIBITORS
IN THE VINYL M O N O M E R
The importance of phenolic inhibitors in the vinyl monomer industry. The role of phenolic compounds as stabilizers and antioxidants has been studied very extensively in polymers and copolymers (refs. 18, 19). Many papers are devoted to this problem. Studies have been made on the optimization of phenolic structure based on hydroquinone (ref. 20) or catechol (ref. 21) as an antioxidant in polypropylene for example. Others have dealt with the influence of the polarity or stearic effect for different phenolic compounds or substituted phenols on the kinetics of antioxidation reactions - for example in polyvinyl acetate (ref. 22). Lastly, many papers have discussed on kinetic effects. However, it is rather surprising that this type of product has not represented a major role as an inhibitor of the radical polymerization of vinyl monomers. No indepth theoretical research has been published, as it is the case of antioxidants, specifically dealing with the inhibition of monomers. The sparse information that is available is limited to a few papers and reviews. This is indeed less surprising since the problem of stabilization of vinyl monomers (particularly styrene, butadiene, (meth)acrylates, etc...) during manufacture and storage is as important as the commercial stabilization of polymers. The fact is that all vinyl monomers tend to polymerise very easily, especially at high temperatures. During their industrial production, a purification operation is generally needed to obtain products of the required purity. Since distillation is the most commonly used process to perform this purification; inhibition of the polymerization of vinyl monomers during distillation (sometimes carried out at high temperature) is of great importance. If polymerization takes place during this distillation step, the formation of high molecular weight compounds of different structures may occur and cause deposits on the internal surface of processing equipment, often rendering it inoperative. This undesirable effect results in a loss of monomer, limits plants efficiency, increases security risks and lowers product quality. Inhibitors used in these processes belong to various classes of compounds. The principal selection criteria of such "process-inhibitors" are the radical trapping efficiency and the ease of separation from the final product. The consumption of the phenolic inhibitors used during this process step is either on their own or mixed with other inhibitors from different families and represents around 50 % of the total consumption of process inhibitors. 497
On the other hand, the stabilization of monomers for storage in the factory or during road, rail or sea transportation, is a great problem in terms of monomer quality, and especially in terms of safety. Indeed, for all vinyl monomers, the polymerization reaction is exothermic and autocatalytic once initiated. It is therefore very difficult to have storage equipment that can withstand such pressures (ref. 23). The main selection criteria for such "package-inhibitors" are their effectiveness at ambient temperature, their colourlessness and their ability to be removed before polymerization or to be overcome by the use of moderate amounts of initiator under the customer's polymerization conditions. At the present time, phenolic inhibitors are greatly preferred by all the major production companies in the vinyl monomer industry. Therefore the consumption of phenolic inhibitors represents over 95 % of the consumption of package inhibitors. As mentionned in the introduction, inhibitors which are preferably use during manufacturing may not be suitable under stockage conditions. In any case the choice of phenolic products is clearly manifest. In fact, in the vinyl monomer industry, over 50 % of the polymerization inhibitors (process and package) are phenolic compounds.
Synergistic effect with oxygen. The particularity of the phenolic inhibitors used in industry, is their synergistic effect with oxygen. These inhibitors require a minimum amount of oxygen in order to be as effective as possible. This effect has been described in literature for the stabilization by hydroquinone or paramethoxyphenol of acrylic acid (refs. 24, 25), methacrylic acid (ref. 17), methyl methacrylate (ref. 26), vinyl acetate (refs. 27, 28) and styrene (refs. 29, 30). The effect occurs due to the extremely rapid reaction of the first alkyl radical with oxygen [R" + 02 ~ either termination reaction
ROO'], several orders of magnitude faster than [R ~ + ZH --> RH + Z ~ or propagation
[R" + M - - ~ RM'] e.g.. for methacrylic acid kl = 20,000 kp. The resulting peroxy radical reacts very rapidly with the phenolic inhibitor in a termination step. Industrially, the presence of oxygen in the production lines arises from the contact between hydrocarbons and air, or gases containing oxygen and in systems operating at reduced pressure as a consequence of leaks in the equipement. Therefore inhibitors which work in aerobic conditions are the most common. Generally for storage and transportation of such monomer, contact with air or a 50/50 nitrogen/air mixture is maintained. 498
Specifications
for
radical
polymerization
inhibitors
There are a certain number of factors to consider when selecting an inhibitor to avoid unwanted polymerization. The main key factors to take into account are : -
the operating environment (distillation column, reboiler, condenser, tank, drum,
etc) -
the nature of chemical compounds in the operating system (liquid, gas, pH,
reactivity of these products with inhibitors) -
temperature and pressure
-
presence of oxygen
-
ecotoxicity with respect to recycling or elimination of process effluents. Consequently the characteristics of a process inhibitor and a package inhibitor
are not the same. The main factors in selecting a process-inhibitor and a packageinhibitor are summarized in the Table 2.
Table 2. Characteristics of process inhibitor and package inhibitor Inhibitor Process-inhibitor Concentration range 20 ppm to 1% - trapping efficiency Characteristics ease of separation from the final product - solubility in crude monomer, raw material and coproducts - thermal stability - volatility degradability - toxicity ease of handling - price
-
-
to -
Package inhibitor 2 ppm to 2000 ppm trapping effectiveness color formation solubility ease of handling ease of removal or ability override toxicity
Selection of an inhibitor must therefore be made carefully while keeping in mind these characteristics. Several phenolic compounds may have the right profile in each inhibitor category and not effecting the quality and cost of monomer production. Amongst other things, this explains the success of phenolic inhibitors in the vinyl m o n o m e r industry.
499
Examples of phenolic inhibitors for few vinylic monomers
Styrenic m o n o m e r s Styrenic monomers are the aromatic vinyl monomers such as styrene, vinyltoluene, a-methylstyrene and divinylbenzene (DVB). Styrene is one of the most important monomers produced by the chemical industry today. It is separated from the products of dehydrogenation of ethylbenzene by a multi-stage rectification. The process inhibitors for styrene are mainly nitroaromatic compounds or aromatic amines and phenolic compounds such as ptertbutylcatechol or 2,6 ditertbutylhydroxytoluene mixed with other radical acceptor inhibitor. Regarding stabilization for storage and transportation of these monomers, the best known inhibitor is paratertbutylcatechol (p-TBC) which is widely used by every styrenic monomer producer. It imparts no color, but does require a minimum of 15 - 20 ppm oxygen. It is easy to remove prior to polymerization by alkaline washing, by distillation or by passing through an activated alumina column. The amount of p-TBC varies between 12 and 50 ppm for styrene, vinyltoluene and amethylstyrene and could rise to about 1000 ppm for DVB. An illustration of the effectiveness of p-TBC is shown in Figure 1.
500
25-
J
20
J
15
J
10
J
J
J
J J
J _
0 ppm
J
ppm m
_ 0,2.' TIME (hours)
Figure 1. Styrene polymerization at IO0~
Influence of concentration of p-TBC
Butadiene The most important source of butadiene world-wide is C4 fractions obtained as a by-product from the cracking of naphta and gas oil for ethylene. Butadiene a colourless flammable gas, may polymerize in three ways briefly described as : to a liquid dimer which appear in small quantities during storage. However, the major portion tends to remain dissolved in the liquid. - to a dark rubber-like heavy polymer usually formed in the liquid phase. This type can cause trouble by plugging lines and equipment. to a crystalline-like white polymer called "popcorn" usually formed in the vapour phase. It causes severe trouble by plugging up refining still columns, valves, pumps, pipes. -
-
Different process-inhibitors may be used during manufacturing depending on each producer. The most widely used phenolic process-inhibitor is the p-TBC with a mixture of other non phenolic process-inhibitors, p-TBC is the best inhibitor for retarding the "popcorn seed" formation.
501
On the other hand, p-TBC is generally used in the final butadiene product between 70 and 150 ppm. The 2,6-ditert-butylhydroxytoluene (BHT) could also be used as an alternative.
(Meth)acrylic acid and (Meth)acrylates Acryclic acid is obtained by the catalytic oxidation of propylene and acrylates (methyl acrylate, ethyl acrylate, butyl acrylate, 2-ethylhexyl acrylate...) by alcohol esterification of the acid. The preparation of methacrylic acid involves the acidic hydrolysis of acetone cyanohydrin and methyl methacrylate is obtained by a similar process involving the methanolysis of acetone cyanohydrin. During their manufacture, these very reactive monomers are found in very diverse chemical systems with great acidity (H2SO 4 may be a catalyst) or basic pH (caustic soda may be a neutralizer). Process inhibitors are also often mixed with inhibitors from different chemical families that are capable of being effective in each system that is encountered. Industrially, inhibitors as diverse as benzoquinone, cupferron, manganese or cerium salts, hydroxylamine, copper alkyldithiocarbamate, hydroquinone, phenothiazine, etc. may also be used. The current worldwide trend is to use a mixture of phenothiazine and hydroquinone as a process inhibitor system. For package inhibitors, manufacturers use hydroquinone (HQ), hydroquinonemethylether or paramethoxyphenol (HQMME or PMP), 2,4-dimethyl 6-tertbutyl phenol and BHT as an alternative. However the most common is the hydroquinonemonomethylether due to its colourlessness and its efficiency (ref. 31). As an example, the concentration of PMP in the products usually varies between 10 and 300 ppm for methyl acrylate and methacrylic acid respectively. In summary, Table 3 presents a certain number of phenolic inhibitors that are used either during the process or storage of the main monomers including vinyl monomers such as acrylonitrile, vinyl acetate or acrolein.
502
Table 3. E x a m p l e of few phenolic inhibitors in vinyl monomer
Inhibitor
Formula
HQ
+ + OH
OH
OH
OCH3
acrylic acid
*
methyl acrylate
*
ethyl acrylate
*
butyl acrylate
*
2-ethylhexyl acrylate
*
methacrylic acid
*
methyl methacrylate
*
ethyl methacrylate
*
2-ethylhexyl methacrylate
*
acrylonitrile
*
vinyl acetate
PMP
TBC
OH
BHT
2,4-diMe 6tBu Phenol
OH
OH
CH3
CH3
*
vinylidene chloride acroleine
*
styrene c~-methylstyrene
vinyl toluene divinylbenzene butadiene isoprene chloroprene
CONCLUSION The inhibition of radical polymerization is important in the chemical industry to prevent unwanted polymerization of vinyl monomers during processing, storage and transportation. Having discussed some of the principles of free-radical polymerization, a brief overview of possible inhibition mechanisms is presented. A short summary of the major classes of radical inhibitors gives an idea of the wealth of choice of chemical compounds available for use in this application. Owing to specifications for industrial inhibitors and the attractive intrinsic properties of 503
phenolic compounds, these inhibitors are the most common class used in this industrial application world-wide. In fact phenolic inhibitors are either used on their own or mixed with other inhibitors from different chemical families. In virtually all vinyl monomer synthesis processes they are either as a process or as a package inhibitor. Finally, a brief overview of some phenolic products used for this application is presented for a few vinyl monomers.
References
1. G.Odian in "La Polym6risation Principes et applications", Polytechnica, Paris, (1994). 2. G.C.Eastmond in "Comprehensive chemical kinetics", Bamford, Tipper, Eds Elsevier, Vol 14A, pp127- 152, Amsterdam, (1976). 3. P.J. Flory in "Principles of polymer chemistry", Comell Univ. Press, Ithaca, New York (1953). 4. G.E.Ham in "Vinyl polymerization", Ed Ham, Dekker, New-York, (1967). 5. J.C.Bevington in "Comprehensive Polymer Science" Allen, Bevington, Eds Pergamon Press, Vol 3, Ch.6, pp 65, (1989). 6. J.C. Bevington in "Radical polymerization", Academic Press, (1961). 7. Encyclopedia of Polymer Science and Engineering, Wiley, Vol 13, New York, (1988). 8. J.C.Bevington, N.A.Ghanem, H.W.Melville, J.Chem.Soc., 2822, (1955). 9. Encyclopedia of polymer science and technology, Wiley, Vol 7, pp 658, New York, (1969). 10. J.Brandrup, E.H.Immergut in "Polymer Handbook", Interscience publishers, (1975). 11. G.C.Eastmond in "Comprehensive chemical kinetics", Bamford, Tipper, Eds Elsevier, Vol 14A, pp153, Amsterdam, (1976). 12. F.Tudos, Z.Fodor, M.Iring in "Oxidation inhibition in organic materials", Eds Pospisil, Klemchuk, Vol II, p. 219, CRC, (1990). 13. F.Tudos, T.Foldes-Berezsnich, Prog. Polym.Sci., 14, 717-761, (1989) 14. G.C.Eastmond in "Comprehensive chemical kinetics" Eds Bamford, Tipper, Eds Elsevier, Vol 14 A, Chapter 2, p. 104, Amsterdam, (1976). 15. R.E.Winkler and E.B.Nauman, J.Polym.Sci., Polym. Chem.Ed, 26, 2853, (1988) 16. L.B.Levy, J. Polym. Sci., Polym. Chem. Ed., 23, 1505, (1985). 17. A.Nicolson Plant/Operations Progress, 10 (3), 171, (1991). 18. Atmospheric oxidation and antioxydants, G.Scott Eds Elsevier (1993). 19. Oxidation inhibition in organic materials, J. Pospisil, P. P. Klemchuk Eds, CRC Press (1990). 20. J.Pospisil, L.Kotulak, L.Taimr in "Stabilization of polymers and stabilizer processes advances in chemistry series 85, R. F. Gould Ed., American Chemical Society Publications, Chapter 14, (1968). 21. J.Pospisil, L.Kotulak, L.Taimr in "Stabilization of polymers and stabilizer processes advances in chemistry series 85, R. F. Gould Ed., American Chemical Society Publications, Chapter 13, (1968). 22. M.Simonyl, F.Tudos, J.Pospisil, Eur.Polym.J.,3, 101, (1967). 23. J.L.Gustin, P.Vandermarliere presented at the " 7th International Symposium on Loss Prevention and Safety Promotion in the Process Industries", Taormina, Italy 4 - 8 May 1992. 24. L.B.Levy Plato/Operations Progress, 6 (4), 188-189, (1987). 25. J.J.Kurland, J. Polym. Sci., Polym. Chem. Ed., 18, 1139, (1980). 26. R.G.Caldwell, J.L.Ihrig, J. Am. Chem.Soc., 84, 2878, (1961). 27. L.B.Levy, Process Safety Progress, 12 (1), 47, (1993). 5o4
28. 29. 30. 31.
L.B.Levy, L.Hinojosa, Journal of Applied Polymer Science, 45,537, (1992). G.L.Batch, C.W.Macosko, Thermochimica Acta, 166, 185- 198 (1990). A.A.Miller, F.R.Mayo, J.Am.Chem.Soc., 78, 1017, (1956). L.S.Kirch, J.A.Kargol, J.W.Magee, W.S.Stuper Plant/Operations Progress, 7 (4), 270-274, (1988).
505
T R A C I N G B A C K T H E O R I G I N O F V A N I L L I N BY S N I F - N M R
GERARD J. MARTIN Universit6 de Nantes - Laboratoire de R6sonance Magn6tique Nucl6aire et R6activit6 Chimique -URA CNRS/472 - France
INTRODUCTION A chemically pure compound, such as 99.99 % vanillin, is in fact a complex mixture of isotopomers, themselves a combination of isotopes of the elements concerned (C, H and O), and distributed according to their isotopic abundances. Probability rules predict 884736 isotopomers of vanillin molecule, C8H80 3. At the
natural abundance of the stable isotopes of C, H and O (Table 1) the light isotopomer of vanillin, 12C 81H816r'-'3, has an occurrence probability of 0.90685, whereas the heavy isotopomer, 13C82H81803, has only a 6.4478 E-55 chance of occurring in nature. In other words, we would have to produce a mass of vanillin much larger than the mass of the Sun to be able to observe its heavy isotopomer !
Table 1.
Isotopic abundances (in ppm) of the natural isotopes of H, C and O. The boxes indicates the nuclei which have a non-zero magnetic moment and may be studied by NMR. The brakets indicates radioactive nuclei.
1
1H 2 1
H
OXYGEN
CARBON
HYDROGEN
999844.26
155.74
10-10
12 6C
988887.67
16
O
997625.81
17 8~
373.00
8
13 6C
11112.33
[1% 6 ]
10-6
506
18 8~
2001.9
From a practical point of view, NMR spectroscopy is able to observe 13 isotopomers of vanillin containing one heavy isotope (8 for 13C and 5 for 2H, Fig.l a, l b), and in extreme signal-to-noise conditions, may detect the double natural labels 2H-13C. On the other hand, Isotope Ratio Mass Spectrometry (IRMS) and Liquid Scintillation Counting (LSC) or Tandem Mass Spectrometer Ion Accelerator (TMSIA) lead to overall contents in 2H, 13C, 180 and 3H, 14C respectively. This isotopic fingerprint is a very powerful means for assigning the origin of vanillin and can also provide useful indications on the transformation processes undergone by the raw materials and precursors of vanillin, since the isotopic abundances of a given chemical species do not follow random distributions bqt obey well defined physical, chemical or biochemical laws.
So I yen'l"
I
2
3
Ref.
4
, , I , , , , i , , W , l , l , w | ' ' ' W l W W ' ~ l t0.0 9.0 8.0 7.0 6.0 PPN
5.0
~
'
l
w
' ' 4.0
5
~
l
w
' ' 3.0
'
21
.0
'
9
Fig. la. Fig. 1.2H (Fig. la) and ]3C (Fig. lb) NMR spectra of vanillin sample prepared from guaiacol, recorded at 11.4 T 507
So I v e n t
i
DD~
9 "
2
'
9
I
180
9 "'
'
',
i
160
"
,
3
'~
4
9
~
t 0
,-
5
.,
6
i..
i
120
i..
7
~
T.
i
t00
,
~
,
i
80
9
""
r
9
Fig. lb.
The thermodynamic and kinetic isotope effects which are always associated with a transformation (i.e. distillation, chemical reaction...), induce varying degrees of isotopic fractionation of the product with respect its substrate. However, these differences in isotopic composition may be very small and accurate and precise quantitation methods are required if NMR Spectroscopy or Mass Spectrometry are to be used for isotopic analysis. The following points will be presented successively to illustrate the ability of isotopic analysis to trace back the origin of vanillin : i - NMR and isotopic methodologies. ii - Authentication of the natural or synthetic status of vanillin : the analytical aspect. iii - Explanation of the isotopic fractionation observed 9the mechanistic aspect.
508
]
60
9
M E T H O D O L O G Y O F I S O T O P I C ANALYSIS BY N M R S P E C T R O S C O P Y Individual resonances in {1H} decoupled 2H, 13C... spectra correspond to well defined isotopomers and their abundances are directly proportional to the signal intensities. In the case of the 2H-spectrum of vanillin, five signals are observed at 11.4 T
H~
1 "C~ O
3
4
6
08CH3 OH since even at this high field, the H 3 and H7 resonances are deceptively equivalent. The chemical shifts are presented in Table 2. Table 2. Chemical shifts of vanillin in ppm/TMS Site
1
2
3
4
5
6
7
8
82H/TMS
9.8
/
7.2
7
8.1(OH))
/
7.2
4
5X3C/TMS
153.2
91.7
88.5
77.1
114.6
110
72.1
17.6
For curve fitting procedures, it is more conveniem to assign isotopomers in decreasing chemical shift order which give respectively 9 for 2H Isotopomer :
1
2
3
4
5
Chemical shift : 1 for 13C
5
3,7
4
8
Isopotomer
1
2
3
4
5
6
7
8
Chemical shift
1
5
6
2
3
4
7
8
The assignment of 2H and 13C signals to the isotopomers of vanillin presents no difficulties.
On the other hand a precise and accurate determination of line
intensities is a considerable challenge. Precision depends mainly on the signal-tonoise ratio (S/N) achievable in a reasonable period of time which in turn is a function of the acquisition time, AQ, the delay between pulses, PD, and the number 509
of scans, NS. In the case of the 2H spectrum of vanillin, a value of 3.4s for AQ easily fulfills the condition of complete relaxation of the nuclei after a 90 ~ pulse width (PW) and a minimum of 2400 scans are required to obtain a (S/N) value higher than 200 for most of the isotopomers examined at 11.4T. To limit random errors which could be associated to short term instabilities of the spectrometer, a given spectrum is repeated three times. Using an automatic sample changer, three vanillin samples can therefore be studied in 24 hours. The sensitivity requirements of 13C spectroscopy are somewhat less severe than for 2H-NMR. Usually, S/N values higher than 200 are obtained for 13C isotopomers in 2 hours at l l.4T for a mixture of vanillin and relaxation reagents. (AQ=6.8s N S = 128 and P W = 9 0 ~ (ref. 1). The precision of the intensity determination, expressed in terms of repeatability (mean standard deviation of NE replications of NS scans) is of the order of 0.5 % to 2 % in relative values depending on the nature of the isotopomer and for a given treatment of the FID's. Analytical methods used for quality control purposes must also be accurate. Accuracy is defined as the closeness of agreement between the true value and the mean of a series of replicates. Reference materials certified by international organizations are available for judging the accuracy of an analytical procedure. As far as NMR spectroscopy is concerned, systematic errors which are frequently related to the lack of accuracy arise mainly during the acquisition step and in the treatment of the FID's. In order to minimize bias in signal acquisition, oversampling and very stable decoupling procedures are recommended, and, to obtain very reproducible intensity values, an operator independem curve fitting procedure should be implemented in the analytical sequence. The Interliss algorithm developed in Names (ref. 2) iterates in the complex plane from the raw frequency spectrum obtained after Fourier transformation without any phasis nor base line correction. The reproducibility of the FID treatment is thus optimized and small differences in the line intensities of different samples can be clearly shown. The 2H isotope ratios of vanillin are usually obtained by internal referencing from the signal intensity according to equation (1).
(D / H) i =
PwsMvmwsSi (D / H)ws
(1)
PiVMwsmvSwstv
where m, M, Pi and S are respectively the weights of products used and their molecular weights, the number of equivalent hydrogen in position i and the signal
510
intensity of the vanillin sample V and of the working standard WS. (D/H)ws is the isotope ratio of the reference used as the working standard and tv the weight/weight parity of vanillin. The site-specific isotope ratios (D/H)i are related to the overall isotope ratio (D/H) of the whole vanillin sample, obtained by IRMS after combustion of the product, by equation (2). n
Z Pi(D / H)i (D/H)i= i n ZPi
(2)
i
where the summation is carried out on the n isotopomers observable at the field considered. (D/H)i may therefore also be computed from IRMS data, (D/H), if for any reason, the NMR spectra of vanillin are run without addition of the working standard ws 9 n
fi
(D / H) i = Z. P i l l1 (D/H)
(3)
1
fi is the observed molar ratio of isotopomer i computed from the ZH-NMR spectrum
fi-
Si n ZSi
(4)
i
Equations 1 to 4 apply for all elements considered and the isotope ratio R, which are related to the isotopic abundance A R -
A A-1
(5)
are usually reported with respect to the international references V. Smow (2H and 180) and PDB (13C). The isotope ratios of these standards (Rref) were determined by rigourous international studies (Table 1) and are also used to define a relative scale of isotopic contents 5, expressed in per mil (%0):
511
5i =
((Ri))
Rref - 1 * 1000
(6)
Equations 3 and 4 are recommended to determine the Site-specific Isotope Ratios of carbon, since the existence of differential residual Nuclear Overhauser Enhancements in vanillin samples doped with Cr(AcAc)3 may induce more or less significant bias. To conclude this section, it should be recalled that data treatment is an important part of the analytical approach. The results of a SNIF-NMR experiment constitute a matrix of data where the variables are the isotope ratios or signal intensities of the different isotopomers and the individuals are the NE observations for a given sample. In this sense, SNIF-NMR is a second-order procedure (ref. 3) and multi-variate analysis is the appropriate method for evaluating the results if a linear behaviour of the variables may be assumed. When the whole set of vanillin samples from different origins is considered, we are faced with the necessity of choosing a classification procedure and defining belonging rules. A first approach which assumes a Gaussian distribution of the measurements is based on the computation of the Mahalanobis distances (ref. 4) from the means and the variances of the different groups considered. d2(M) = (~--g) C -1 (x-g)
(7)
where C is the variance-covariance matrix of the n isotope ratios measured for the n authentic vanillins of the group, ~t the vector mean of the group and x the coordinates of the unknown. It is recommended to associate to d(M) a probability P which will delineate the contour of the group as a function of Z2(et;n). In fact, the Mahalonobis distance gives a default classification since it does not take into account the random errors of measurement and the non Gaussian contribution in the distribution of the data. A better way to determine wether an unknown belongs to a reference group and to compute any mixture composition is to carry out a Monte-Carlo simulation (ref. 5). An overall belonging probability P is computed in the form of the summation of the different Gaussian distributions associated to each of the different measurements which constitute the reference group R. However it happens frequently that an unknown does not belongs frankly to a group of well defined origin but is in fact a mixture (A) of several origins (m) : 512
(8)
A = a 1 + a 2 ........ a m
The measurement function R M (1,n) determined on the unknown is a linear combination of the n isotope ratios Rij of the m origins and A is readily computed from the least square solution
A = ( R R ) -1 R -1
RM
(9)
A multi-variate probability may also be computed if we include the dispersion (variance) of the reference group by computing the Mahalanobis distances between the unknown and well defined mixtures of vanillins from different origins. It is obvious that the same limits as those described for the classification step apply to this procedure and a Monte-Carlo simulation should refine the determination of the mixture composition. The only drawback of the Monte-Carlo approach is the computation time since in the case of four isotope ratios measured for three groups of vanillins, a 1% precision requires 10Ell tests, i.e. one week of computation for a 60 MHz-Pentium based micro-computer (ref. 5) ! Even if the Mahalanobis distance gives less precise results, it is preferable to the Monte-Carlo simulation for most routine analyses.
A U T H E N T I C A T I O N OF V A N I L L I N S F R O M D I F F E R E N T O R I G I N S : THE
ANALYTICAL APPROACH The vanillin market is in fact shared by two products : the natural vanillin contained in vanilla beans, an extremely highly priced (~ 4000 $/kg) and scarce product, and the synthetic (from phenols) or hemisynthetic (from lignin) vanillins which are produced in large quantities and are relatively cheap (40 $/kg). According to the main food industry regulations in the European Union and the USA, a flavour is said to be natural (Table 3) only if the raw material comes from the living pool and if physical or biochemical processes only have been involved during the different manufacturing steps.
513
Table 3.
Classification of the status of a food additive (i.e. aroma) as a function of the nature of the raw material and process used in its manufacture
RAW MATERIAL Living
PRODUCT CLASSIFICATION Natural
Natural
Artificial
(named botanical)
(oiotechnological
(hemisynthetic)
product) Fossil
Artificial
Artificial
Artificial
(Biotechnological
(synthetic)
product) Process
Biotechnical
Physical
Chemical
Obviously, such a situation is likely to encourage cupidity and in the food industry fairly substantial quantities of vanillin ex-lignin have been mislabelled as natural. Various compositional criteria have been developed in an attempt to combat such fraud but give the considerable price difference between both qualities of vanillin, adjusting the chemical composition of adulterated samples to resemble that of the natural product was not a great price to pay. As far as stable isotope analysis is concerned,
13C-IRMS would have been a choice method to detect such
adulteration, since, as shown in Table 4, there is a very significant difference between natural 613C ---20.5 %o and hemisynthetic vanillin (613C -- -28 %o).
514
Table 4.
SNIF-NMR determination of the isotope ratios of vanillin isopotomers 1
2
3
4
5
Total
VN
130
(a)
160
200
130
145
VL
110
(a)
130
175
110
130
VG
350
(a)
140
150
2H Isotopomer .,
ppm/V.SMOW
,
X3CIsotopomer VN %o/PDB
%o/V.SMOW
8
Total
-45
-10
-50
-20 -28
VL
-55
-20
-55
-50
-20
-85
-30
1
2
3
Total
VN VL
,
160
2 to 7
VG 180 Isopotomer (b) I
120
1
2O (c)
(c)
L vc (a)
(c)
16 18
Due to fast chemical exchange with lable hydrogens of the medium this site is irrelevant for authentivation of vanillins
(b)
SMRI determination
(c)
Not yet available
Unfortunately, the natural product is heavier than its synthetic counterpart and it is relatively easy and not prohibitively expensive to add a small quantity of
13C
enriched vanillin to the synthetic product. From this point of view, vanillin exlignin is preferred to vanillin ex-guaiacol since the quantity of labelled material required is lower. Applying isotopic dilution equations, it is apparent that less than 13 one hundred milligrams of 99% C-labelled vanillin are required to transform l kg vanillin ex-lignin into lkg natural vanillin ! As early as the 1980's, it was possible to purchase 0.1g of such enriched compounds for 300 to 600 $, depending on whether the carbonyl, methoxy or ring was labelled. This rendered invalid the ~13Ccriterion for authenticating vanillins and lead to the investigation of deuterium NMR as a potential method to discriminate between synthetic and natural products (ref. 6). As shown in Table 4, the deuterium finger print of natural vanillin exhibits large differences to those of its synthetic analogues. The Mahalanobis distance dM between the gravity centres of natural and guaiacol vanillin is twenty times larger than between those of natural and lignin vanillin. However, even in this less favourable case, dM is much greater than the 99% probability contour of the natural vanillins defined by Z2(0.99 ; 4). 515
It is even possible to characterize the addition of 5 % lignin vanillin in the natural product at a 95 % confidence level. In fact the existence domain of a given group defined by 4 isotope ratios is a hyper-ellipse and it is more convenient to represent the populations of the three main groups of vanillin in a plane constructed from the two canonical functions D~ and D2. Figure 2 illustrate the ability of 2H-NMR to discriminate between the vanillin groups. Since three groups are involved, the whole variance is distributed in only two orthogonal directions. The main axe D1 is closely related to the deuterium content of the formyl group, whereas the second function D2 makes a clear distinction between natural and lignin vanillin. The classification is 100% complete at a 99.9 % confidence level.
516
b...,.
to
o
I0.00
26.70%
o 8.00 <
/
6.00 0
=_
. ..::\
j "
j -
[]
r'l
4.00 I:1
0
2.00
vanillins ex-bean$
0.00~
......
F t
[]
....
I ......
--
[. . . . . . .
I
.
"
6
rl
i:l
-2.00
[] /,
[]
"a ~ i : l
'
~..J.
o
lib
/
B
.. "73.3o
I:1
//-
a
-~
vanillins ex-guaiac01
-4.00 o
\
I:1
[]
. o
,
-6.00 -8.00 -8.00
~
da
a
a
vanlllinsex-lignln -6.00
-4.00
-2.00
0.00
2.00
4.00
6.00
8.00
10.0
A careful examination of each group enables some of them to be split into characteristic sub-groups. For example, beans grown in the Madagascar and Comor area exhibit significant differences with those found in the Eastern Pacific area. The case of hemisynthetic and synthetic vanillins is also worth a specific mention and their investigation brings to light some interesting mechanistic aspects. Lignin vanillins may be split into two subgroups according to the value of (D/H)1. Since the 2H content of this group is related to that of the propanoid fragment of lignin, the sub-group characterized by low (D/H)1 values could be associated to raw materials grown in very northern areas. The group containing the vanillins synthetized form phenols via guaiacol is clearly split into three subgroups in the plane of the first two canonical functions (Fig. 3) but a careful examination of the upper cluster shows that three samples are situated above the D1, D2 plane (z coordinate : 4.35) and all the other samples lie below (z coordinate : -1.45).
518
e4
I
Hi
9
~s
t
i
mmim
m
-
.. .
.
.
.
,w
v
0
i
I
Fig. 3. Representation of vanillins ex-guaiacol in the plane of the two discriminant functions 519
In the case of synthetic vanillin, the discriminant functions were computed from four (D/H)i and one (13C/12C) ratios. Indeed the 613C value may be a good criterion for distinguishing chemical substances from a C1 or C2 origin and in the case of lignin vanillin, it seems that there is no special interest to enrich guaiacol in 13C ! Groups 1 and 2 have similar (D/H)i values for the ring hydrogen, but they are characterized by different (D/H)I and 813C ratios. The differences between the samples belonging to the subgroups 3a and 3b are mainly related to the existence of specific 2H and 13C contents of the methoxyl fragment.
MECHANISTIC EXPLANATION OF THE ISOTOPIC FRACTIONATION OBSERVED IN VANILLIN The gross variations of ~3C content in natural and fossil materials may be easily rationalized. In the living pools, the three main groups of products with 813C values turning around-10 %0,-20 %o a n d - 3 0 %o may be associated to three basic different photosynthetic metabolisms C4, CAM and C3. Natural vanillin is extracted from Vanilla Planifolia Andrews or Vanilla Tahitensis Moore, species belonging to the orchydea family which has a crassulacean acid metabolism (CAM). Hemisynthetic vanillins are mainly elaborated from plants having a C3 metabolism for example, pinetrees (vanillin ex-lignin) or clove oil (vanillin ex-eugenol). On the other hand, the ~3C content of materials from a fossil origin is roughly centred around -28%0 for products synthetized from C2, C3 olefins or naphta but may be strongly depleted in 13C if there are prepared from natural gas. These are primary factors that explain the more important differences in 13C content ; more subtle variations however may be observed and depend essentially on the existence of 13C/12C kinetic isotope effects (KIE). As far as deuterium is considered, the largest isotopic fractionations observed are mainly related to environmental effects for natural products and to KIE for synthetic materials. It is therefore worth considering now the mechanism of isotopic fractionation during a chemical transformation, and to illustrate this with the case of aromatic formylation.
520
ISOTOPIC FRACTIONATION ASSOCIATED TO THE F O R M A T I O N OF AN AROMATIC ALDEHYDE FUNCTION From a general point of view, the mass and isotopic balance of a chemical transformation will govern the observed ffactionation between product (P) and substrate (S). (10)
A(So) = XpAp + (1- Xp)A(Soo) where n
XpAp = ~xiA(Pi) i
Pl P2
Pi So Pn Scx:, The isotopic fractionation ~(Pi) of Pi with respect to So is given by 9 (11)
A(So) ~(Pi) -
A(Pi)
and in the case of 2H, the isotopic abundance A may be safely replaced by the isotopic ratio R. It is interesting to express ~(Pi) in terms of the two main parameters of a chemical reaction, P, the transformation rate and k/k* the kinetic isotope effects (KIE) where * stands for the heavy isotope " ("
k*'~
[1 - ( l - P ) k / (12) Or(p)
P
521
and the fractionation between the remaining substrate (Soo) after the reaction and So is given by 9
(k, )
1 _ (1 - O) --s
(13)
a(s) This simple model is valid in fact for 13 isotope effects and does not take into account the existence of intermolecular competitive reactions which occur frequently in transformations involving C-H bond breaking (refs. 7, 8). Indeed the abstraction of a hydrogen atom from a group in the substrate having n equivalent germinal and m equivalent vicinal positions AHn BHm, involves a set of different isotope effects nkH
AHn BHm + ..............
YHn-IBHm + ZH
(a)
YHn-2DBHm + ZH
(b)
YHn-IBHm + ZD
(c)
YHn-IBHm-1 D + ZH
(d)
ot AHn-1 BDHm + ............
AHnBHm-1D + ...........
Neglecting any 13KIE, the isotopic fractionation of the remaining substrate c~(Soo) is given by (ref. 8)
VlIkD/+(n-l)[k~I ] 1] 1 _ (1- p)Ln\kH j n ~,~HH)- J
(14)
~(s) and for the product or(p) we have
r I
_o)Lni,ks )
]1-(11
_ n rI
(k~i/k
OL(kD/ kH) + ( n -
I
1I L
g) 1)(k~
/
r ( ~ (k ~ "~]] I Lt kD /+(n-1)l ~H III n /kH)Jll
I
]
(15)
kH) J
For example, the oxidation of toluene into benzyl alcohol will involve a primary and a secondary KIE and the isotopic fractionation observed may be very large.
522
In organic chemistry, the aromatic formylation reactions show great diversity and several hundred examples may be found in the literature (ref. 9) although only a few reactions are of any industrial interest. It should be kept in mind, however, that very highly priced 2H, 13C or 130 enriched vanillins are required to adulterate the synthetic commercial vanillins in order to match the isotopic contents found in vanilla beans. From this point of view, some exotic formylation reactions may be of great interest for the fraudsters. Basically, we may consider three kinds of aromatic formylation which are likely to involve significant differences in the nature of isotopic fractionation : the direct formylation of an aromatic ring, which leads frequently to significant -
carbon isotopic discrimination -
the oxidative formylation of hypohypsic aromatic substrates in which oxygen
fractionation may occur the reduction of oxidized aromatic substrates, carboxylic acids and derivatives. -
In these three categories of reactions, greater or lesser hydrogen fractionation is observed, the larger effect being related to reactions involving proton abstraction. As far as KIE of aromatic formylations are concerned, most of the works published deal with the determination of kn/kD. A recent review (ref. 10) has drawn up an inventory of kH/kD values for typical formylation precursors and reactions -
hydroxylation of toluene : Radical proton abstraction catalyzed by transition metals involves strong KIE
(kH/ko = 5 to 7). When the transition state is relatively dissymmetric, the KIE value is decreased to 2 or 3. halogenation of toluene : Radical halogenation by NBS or hypohalides induces a strong KIE (4.5 to 6) and at a low temperature (212 K), values up to 16 were observed. Conversely, the high temperature (376 K) chloration by C12 is characterized with a small effect (1.8). - oxidation of benzylic alcohols : The subsequent oxidation of the hydroxymethyl group into aldehyde shows very large variations in the KIE values according to whether proton abstraction is concerted with C-O bond formation (kH/kD = 1.6) or wether the tunnelling effect -
contribution is great ( k H / k D -- 5 0 ) . However oxidations with chromium derivatives have normal primary KIE (5 to 6). Similar values are observed during the oxidation of benzylamines -
oxidative breakage of C =C double bonds :
523
The transformation of styrene derivatives into substituted benzaldehyde (chromate, ferrocyanide, ozone ...) is characterized by an inverse KIE of the order of 0.8 to 0.98 - decarboxylation of aromatic ct-hydroxy acids : Substituted mandelic acids are key compounds in the synthesis of vanillin from phenols. However, the KIE observed during the oxidative degradation of mandelic acid into benzaldehyde is extremely dependent on the experimental conditions. Strong KIE (4 to 9) are measured in the presence of chromic or ferric acids but small values (1 to 2) are observed with NaOC1, N-bromo acetamide or vanadium V. To conclude, it is interesting to discuss in more detail the synthesis of vanillin from 4-hydroxy-3-methoxymandelic acid. According to scheme 1, glyoxylic acid reacts with guaiacol to give the substituted mandelic acid.
524
|
| ethylene
naphta
maleic anhydrid
biomass
ethanol (D/H)(cH2) = 120 to 140 ppm
ff-~CH3OH methyl fumarate (D/H)(CH=) = 140 to 150 ppm
glyoxal
l
methyl glyoxylate
glyoxylic acid (B) (D/H)(CHO) = 500 to 550 ppm
glyoxylic acid (A) (D/H)(cHO) = 220 to 240 ppm OH 130 ~ / O C H 3 130
130 ppm
OH 135 ~
OCH3
130 ~
130 ppm
HO-CH-COOH
/ OH
OH
135
~
OCH3
135 130
130 " ~ 1 3 0
CHO
CHO
350 to 400 ppm
210 to 230 ppm
Vanillin B
Vanillin A Scheme 1. 525
The isotopic fractionation observed may be rationalized in the light of the previous considerations. Glyoxylic acid may be synthesized from maleic anhydride or from ethanol : in these compounds the CH= and CH2- groups have nearly the same (D/H) value, of the order of 140 ppm. Methyl fumarate (the substrate) is oxidized with a small inverse KIE into glyoxylic acid A (the product) which is slightly enriched in 2H. On the other hand, the oxidation of the methylene group of ethanol into the formyl group of glyoxal is characterized by a strong direct KIE : the leaving hydrogen is depleted in 2H but the remaining atom in the substrate (glyoxylic acid B) is strongly enriched. When glyoxylic acids A and B react with guaiacol, we observe indeed two different vanillins A and B which have very different isotope ratio values for the formyl group, the other isotopomers of the aromatic ring remain unchanged during the reaction.
References 1. V. Caer, M. Trierweiler, G.J. Martin, M.L. Martin, Determination of site-specific carbon isotope ratios at natural abundance 13C-NHR Spectroscopy, Anal. Chem., 63, 2306, (1991) 2. Y.L. Martin, A Global Approach to Accurate and Automatic Quantitative Analysis of NMR Spectra by Complex Least-Squares Curve Fitting. Journal of Magnetic Resonance, Series A 111, 1-10 (1994) 3. K.S. Booksh, B.R. Kowalski, Theory of Analytical Chemistry : A guiding theory of analytical chemistry can be used to specify what information can be extracted from the data produced by an analytical instrument or method, Anal. Chem., 66, 782A, (1994) 4. P. Dagnelie in "Analyse statistique h plusieurs variables", Les Presses Agronomiques de Gembloux, 1982. 5. Y.L. Martin, Ph. D Thesis, Paris, (1995). 6. C. Maubert, C. Gu6rin, F. Mabon, G.J.Martin, D6termination de l'origine de la vanilline par analyse multidimensionnelle du fractionnement isotopique naturel sp6cifique de l'hydrog~ne, Analysis, 16, 434, (1988) 7. L. Melander, W.H. Jr. Saunders in "Reaction Rates of Isotopic Molecules" John Wiley & Sons, New York, (1979). 8. a) M.L. Martin, G.J. Martin in "Deuterium NMR in the study of Site-specific Natural Isotope Fractionation (SNIF-NMR). NMR Basic Principles and Progress", Ed. H. #Gtinther Springer-Verlag, Heidelberg, 23, 1, (1990). b) G.J. Martin, S. Hanneguelle, G. Remaud Parfums, Cosm6tiques, Ar6mes, 94, 95, (1990) 9. J. March in "Advanced organic chemistry : reactions, mechanisms and structure"; (IV~ - John Wiley & Sons, New York, (1992). 10. G. Heck, Ph D Thesis, Nantes, (1995). 11. Craig H., Isotopic standards for carbon and oxygen and correction factors for massspectrometric analysis of carbon dioxide, Geochim. Cosmochim. Acta, 12, 133-149, (1957). 12. Craig H., Standard for reporting concentrations of deuterium and oxygen-18 in natural waters, Science, 133, 1833-1834, (1961). 13. Gonfiantini R., Standards for stable isotope measurements in natural compounds, Nature, 271,534-536, (1978). 526
14.
15. 16.
17. 18. 19.
Guillou C. and Martin G.J., Characterization of reference tetramethylurea (TMU) for the determination of the H/D ratio in alcohols by SNIF-NMR, Commission European Communities, BCR Information, 1993, EUR 14396EN. Martin G.J. and Naulet N., Precision, accuracy and referencing of isotope ratios determined by NMR, Fresenius Z. Anal. Chem., 332, 648-651, (1988). Martin G.J., Trierweiler M., Ristow R., Hermann A. and Belliardo J.J., The certification of the three reference ethanols by SNIF-NMR : BCR Certified Reference Material CRM123, Commission European Communities, BCR Information, 1994, EUR14396EN, EUR15347EN. O'Leary M.H., Carbon isotopes in photosynthesis, Bioscience, 38, 328-336, (1988). Olsson I.U., Radiocarbon variations and absolute chronology , Nobel Symposium 12th Proc., Wiley Ed., New York, 1970. Stuiver M. and Polach H., Discussion of 14C data, Radiocarbon, 19, 355-363, (1977).
527
NMR UNDER HIGH GAS PRESSURE
FRANCOIS METZ FREY b)
a)
MARC LANSON
a)
ANDRE MERBACH
b)
AND URBAN
a) Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie, 85 Avenue des Fr6res Perret, B.P. 62, 69192 Saint-Fons Cedex, France. b) Universit6 de Lausanne, Institut de Chimie Min6rale et Analytique, BCH, CH- 1015 Lausanne, Switzerland.
NMR UNDER HIGH GAS PRESSURE : WHY ? A fine understanding of reaction mechanisms is of crucial importance to the control and optimisation of chemical processes. On account of this, various spectroscopic techniques for mechanistic studies and reaction monitoring have been continuously developed. However, in situ analytical techniques still remain rare in the case of reactions involving liquids under high gas pressure, for example reactions in which a gaseous reactant is used (carbonylation, hydrogenation, carboxylation, phosgenation, chlorination,) or reactions performed at high temperatures in closed vessels in which an autogenic pressure results. Among the techniques, high pressure NMR seems the most promising. Although it has the disadvantages of relatively low sensitivity and a long time scale, the multinuclear chemical shifts and couplings can provide detailed structural, kinetic and dynamic information. As a result, this technique has recently been developed.
NMR UNDER HIGH GAS PRESSURE : HOW ? High-pressure NMR experiments have been performed for more than 40 years using techniques ranging from hydrostatic methods employing hydraulic presses and titanium alloy vessels to the use of glass and sapphire tubes. In this article we will focus on sapphire tubes because they represent the only high-pressure NMR tool we are utilising. 528
Sapphire tubes, fastened to titanium alloy heads, were described in 1985 by C. Roe (ref. 1) and utilised to perform experiments at pressures of up to about 130 bar and a temperature range of-100~ to 150~ This arrangement has recently been improved by Merbach's group (ref. 2). The single-crystal sapphire tube (od " 10 mm ; id 98 mm) is glued to a titanium alloy flange with an epoxy adhesive. A Ti alloy valve assembly allowing pressurisation is then screwed into the flange and a sample volume of 3 - 5 ml is obtained. The entire tube and valve assembly weigh approximatively 50 g and generally spins in a commercial cryo-magnet. Even though the tubes have a flat bottom and do not meet the specifications of typical NMR tubes, 1H line widths obtained on a 300 MHz instrument are about 1 Hz. For obvious security reasons, the tube is fastened before pressurisation in a Plexiglas | protective casing, also designed in Lausanne (Figs. 1, 2). It is then possible to pressurise the assembly (Pmax up to 100 bar) (ref. 3), agitate it on a shaking unit in order to ensure a good gas to liquid transfer, and heat it (Tmax = 200 ~ with a specially adapted heating mantle. Thus, the complete sequence for a high pressure NMR experiment proceeds as follows 9 introduction of the solution into the sapphire tube and closing of the titanium alloy valve, fastening of the assembly into the protective casing, pressurisation to the working pressure with the desired gas, agitation and optional heating, - NMR analysis (possibly at variable temperature). -
-
-
-
529
Fig. 1. Drawing of a high-pressure sapphine tube by Merbach et al. 530
i lil,x i, ,is \"\\
I
,.'\
.~'
I
I
\\
~~
~,
"" xl,
,
,.\, ~
-": ,.',,
,.x, \,, ,<, ,.'x
?4
\\
,.N
I
\\
',4" ,.x, \\
i.'~' "b ,
" o
I
"5 I I
r- -i 9
I
'
'
L-1--
o
I
1 I 1
Fig. 2. H P N M R sapphine tube in its protective casing
531
NMR U N D E R H I G H G A S P R E S S U R E : POSSIBILITIES The applications of high pressure NMR are numerous and various : examples from studies carried out at the RP Research Centre include : - d e t e r m i n a t i o n of the solubility of gases (CO, CO2, butadiene, propylene) at variable pressure and temperature, - k i n e t i c monitoring of chemical transformations involving liquids under high gas pressure or systems evolving autogenic pressure. The experiment being performed in a closed vessel, it is essentially product-conservative and ensures therefore a quantitative analysis, - detection, identification and quantification of catalytic intermediates : for example, the organophosphorus palladium complex, HPdBr(PPh3)2, has been detected for the first time and identified in situ during the carbonylation of bromobenzene (ref. 3), a model reaction for the access to phenolic aldehydes by hydrogenocarbonylation (Scheme 1), (Fig. 3). -visualisation of exchange processes between free and bonded forms of a gaseous molecule (examples in organic and organometallic systems).
pd(PPh3) 4
Pd(PPh3) 2 + 2 PPh 3
Pd(PPh3) 2 + PhBr
PhPdBr(PPh3)2
PhPdBr(PPh3)2 + CO
Ph(CO)PdBr(PPh3) 2
Ph(CO)PdBr(PPh3)2 + H 2
PhCHO + HPdBr(PPh3)2
HPdBr(PPh3) 2 + R3N
Pd(PPh3) 2 + R3NHBr
Scheme 1. Palladium- catalysed hydrogenocarbonylation of bromobenzene
532
i
i i
(b)
_J 5
0
8
-5
-10
Fig. 3. 1H NMR spectrum in [2H8] thf of the products of the reaction between t r a n s PhPdBr(PPh3)2 and H2 (gas) after depressurisation at -50~ Insert is an expeansion of the metal hydride region at (a) 25 ~ (b) -50~
N M R U N D E R H I G H GAS P R E S S U R E : C O N C L U S I O N High pressure NMR allows the large potentialities of
"classical"
NMR
spectroscopy to be extended to reactions involving a high gas pressure (gaseous reactants or autogenic pressure). This attractive new field has been illustrated by a few, non-limiting examples. Last but not least, since the sapphire tubes we have described are transparent, they constitute a perfect screening autoclave allowing the reaction mixture under pressure to be continuously visualised. One is thus able to record any interesting phenomena such as colour changes and product or catalyst precipitation or solubilisation occuring during the reaction.
533
(f)
(e)
(d)
(c)
'
~ 9
~
(b)
~ " ' ~ 2O
(a)
0
App. 3. In situ 31P NMR spectra of the reaction between trans Ph(CO)PdBr(PPh3)2 and H2 (gas 9 80 bar) at 60~ to give trans HPdBr(PPh3) 2. The asterisked peak is due to trans PdBr2(PPh3) 2. t = 0 (a), 2 (b), 4 (c), 6 (d), 8 (e) and 10h (f). 534
References 1. D.C. Roe, J. Magn. Reson., 63,388-391, (1985). 2. G. Laurenczy, L. Helm, A. Ludi, A. Merbach, Helv.Chim. Acta, 74, 1236-1238, (1991). G. Laurenczy, L. Helm, A. Ludi, A. Merbach, Inorganica Chimica Acta, 189, 131, (1991). 3. G. Laurenczy, A. Merbach, J. Chem. Soc., Chem. Commun., 187, (1993). The burst pressure of the sapphire tubes was checked in a safe environment : a sapphire tube was loaded with - 2 ml water, fastened in its protective casing and placed in a bunker box behind a safety pane. It was then pressurised with 200 bar N2 (cylinder pressure) without any change. The pressure was raised with a water pump ; at approximatively 550 bar, the tube was ejected out of the flange (without any damage !) because the adhesive gave way. The experiment was repeated and the same results were observed. Thus, limiting the working pressure to 100 bar offers a reasonable margin of safety. 4. B.T. Heaton, S.P. Hebert, J.A. Iggo, F. Metz, R. Whyman, J. Chem. Soc. Dalton Trans., 3081, (1993).
535
LACTIC
DERIVATIVES
: METHODS F O R D E T E R M I N I N G THE O P T I C A L
PURITY OF VARIOUS INTERMEDIATES
FRANCOISE MARCENAC
a)
DIDIER BERNARD
a)
FERNANDE BOYER
a)
JACQUES CHABANNES a) YVES DANION a) MICHEL MINFRAY a) NICOLE PEYRE a) EUZEBE ZANDANEL a) MARGUERITE HILLAIRET t,) JEAN-CLAUDE MARSAULT b) AND ELIANE PILOT b) a) Rh6ne-Poulenc Industrialisation, Centre de Recherche, d'Ing6nierie et de Technologie, 85 Avenue des Fr~res Perret, B.P. 62, 69192 Saint-Fons Cedex, France. b) Rh6ne-Poulenc Chimie, B.P. 30, 79500 Melle, France.
INTRODUCTION Optically active esters of a-chloropropionic acid are precursors of agrochemical compounds. These esters are prepared from lactic acid using the synthesis path described in Figure 1. D-lactic acid is obtained by fermentation. Initially, this compound was esterified to methyl lactate which itself was transformed to (L) c~methyl chloropropionate (c~-CPM). The content of the minority enantiomer in these three compounds was of between 1.5 and 2.5 %. In order to meet market needs, Rh6ne-Poulenc has had to produce very high optical purity D-lactic acid on one hand and esterify it to isobutyl lactate on the other. This product is then transformed to the corresponding a-chloropropionate. The detection limit of the minority enantiomer in the three compounds must be as low as possible (0.1% for lactic acid and 0.5 % for both esters). Methods for determining the optical purity (= minority enantiomer / E of the two enantiomers) have considerably evolved over the years. The use of chiral stationary phases both in gas chromatography (GC) and in liquid chromatography (LC) and the development of enzymatic techniques have enabled the required detection limits to be achieved. This article summarizes on all the methods that we have developed and on those that we have chosen to check the purity. 536
~COOH Fermentation
.
OH D-lactic acid ~Esterification x ~COOiBu
~.COOMe .
OH D-methyl lactate
1
OH D-isobutyl lactate
1
Chlorination
.~COOiBu
.~COOMe
C1 L-isobutyl chloropropionate
C1 L-methyl chloropropionate
Fig. 1. Diagramrepresenting the synthesis of esters of ot-chloropropionic acid from lactic acid
LACTIC ACID
Summary of the methods developed Table 1 summarises all the methods for the determination of the optical purity of lactic acid as well as their respective advantages and drawbacks.
Enzymatic method The method used was developed to check L-lactic acid in biological and food systems (ref. 1). In the presence of L-lactate dehydrogenase (L-LDH), L-lactic acid (lactate) is oxidized by nicotinamide-adenine dinucleotide (NAD) to pyruvate (eqn. 1).
L-lactate + NAD+ _..
L-LDH
"-
pyruvate + NADH + H+
(1)
The equilibrium of these reactions lies almost completely on the side of lactate. However, by trapping the pyruvate in a subsequent reaction catalyzed by the enzyme glutamate-pyruvate transaminase (GPT) in the presence of L-glutamate, the equilibrium can be displaced in favour of pyruvate and NADH (eqn. 2). 537
GPT Pyruvate + L - ~ t e
--.
"-
L-alanine + c~-ketoglu~ate
(2)
The amount of NADH formed in the above reaction is stoichiometric with the concentration of L-lactic acid for D-lactic acid, respectively. The increase in N A D H is determined by means of its absorbance at 340 nm. This method gives the L-lactic acid content in the sample. In order to calculate the optical purity, the lactic acid title is performed using reverse phase liquid chromatography. The detection limit of L-lactic acid is extremely low ( < 0 . 0 5 % )
and the
accuracy is of the order of 5 relative % for contents of L-lactic acid in D-lactic acid of between 0.1 and 0.5 %.
GC method with a cyclodextrine type CSP (Analysis of methyl o-Trifluoroacetyl lactate type derivatives) Analysis of the lactic acid is performed using a double derivatization of the sample. Table 1. Summary of the methods for determining the optical purity of lactic acid Disadvantages
Advantages enzymatic method
Direct method, very sensitive, very high specificity
detection limits L/L + D %
Provides the L-lactic acid content The lactic acid title is performed using HPLC
0.05 %
GC on cyclodextrine type CSP of the O-TFA derivative of methyl lactate
Analysis of methyl lactate O-TFA form. Good resolution between the two enantiomers Good reproducibility
Requires double derivatization with the use of diazomethane
LC on Daicel WH CSP
Direct method
Detection limit too high
around 1%
GC on cyclodextrine type CSP of a dioxolanone type derivative
No racemization of the sample on derivatization
Difficult integration of the peaks Derivatization of the sample
<0.5%
538
0.1%
esterification of the acidic group with diazomethane. - esterification of the alcohol group with trifluoroacetic anhydride. The methyl ester is obtained of O-trifluorinated acetyl lactic acid. These two derivatization reactions are non racemizing. The separation of the two enantiomers of the derivative compound is obtained by GC on a chiral stationary phase (CSP) comprising a -
derivative of y-cyclodextrine. (Fig. 2) The derivative corresponds to the octakis (2,6 di O pentyl-3-O trifluoroacetyl) y-cyclodextrine These CSP were developed by D.W. Armstrong (refs. 2-4). The developed method enables the two enantiomers of the derivative compound to be completely resolved (Fig. 3). The detection limit of L-lactic acid is extremely low ( < 0 . 0 5 % ) and the accuracy is of the order of 5 relative % for contents of L-lactic acid in D-lactic acid of between 0.1 and 0.5 %. Analytical
method
using LC on a CSP
The two enantiomers are directly separated using liquid chromatography. A chiral stationary phase is used comprising a silica substrate on which is fixed an amino acid. The mechanisms developed are of the "ligand exchange" type. The distinction between two enantiomers is possible due to the formation of mixed diastereoisomerical complexes (chiral solute - transition metal - amino acid fixed on the silica substrate). The transition metal is added to the mobile phase. (Fig. 4) The direct method does not provide sufficient resolution between the two lactic acid enantiomers to achieve the required detection limits. This method was not able to be used to check industrial samples (Fig. 5).
539
O6R R6Q
O
,3 ,
/
O
OR2
~, "~ O"~
~ O ~ ~
OR3
~
"0
R~o'V
OR3
D r', ~ O~,
\(~o~
~-~/
~--.,-, OR3 u..
R30 ~
~6o.~~.
~o4 ~o6.
o~o~ -~~OR3
/I---O O
o~i~ OR2 9 R 3
~ / / ~
~6o~ ~o o~o/"'o'
o'6~ ,
R60 R2 = R 6=pentyl R3 = trifluoroacetyl Fig. 2
Structure of the derivative of 7-cyclodextrine used as a stationary phase
Derivatized D-lactic acid containing 2.5 % of L-lactic acid i
/ f f
i
Fig. 3
Separation of the enantiomers of methyl lactate O-TFA using GC. Chromatographic conditions ; column : Chiraldex GTA (length = 30 m, internal diameter : 0.25 mm Column temperature : 75~ injector : 150~ detector ; 200~ carrier gas : hydrogen. The retention time of the D-enantiomer is 3.3 minutes, that of the L-enantiomer is 4 minutes. 540
O
H " ~ ~ON~ .,~....---O\ / ._Cu2+ \ N-'-"--"-~ ~ n CO
pr~..x
-\
K
H
SILICA GEL
D-AMIN0 ACID
O
H " ~ / ~\ / '~ ,~.---- O"\ ..Cu2+, N -'------~ ~ CO SPACER ~ ~ /,," "-,,, SILICA GEL
\
H
~ R
L-AMINO ACID
B
Fig. 4
Representation of the ternary complex forming during the analysis of chiral solutes by "ligand exchange" (in this case the chiral is an amino acid)
Lactic a c i d - I L / L + D
L
= 1.5 %
L
Fig. 5
Direct separation of lactic acid enantiomers using an LC column 9 Daicel Chiralpak WH, 250 mm x 4.6 mm 9 eluant " CuSO4 = 0.25 mmol/1, p H = 5 . 6 9 flowrate 9 1 ml/min 9detection UV, ~, = 235 nm. 541
GC analytical method for lactic acid enantiomers derivatized in the form of dioxolanones This method was proposed by P. Husek (ref. 5) and involves the analysis of the lactic acid in the form of dioxolanone using GC on a chiral stationary phase comprising a derivative of the [3-cyclodextrine heptakis (2,3,6 tri O methyl) 13cyclodextrine. The derivatization reaction is as follows 9
HO
.J,Q, COOH
+
Lactic acid The
/ CF2C1 O===q CF2Cl
""F'--O,,~CF2Cl
.~
0~.~-0"
+ H20
"CF2C1
Dichlorotetrafluoroacetone
tested
method
did
not give
sufficient
resolution between
the
two
enantiomers of the derivative to enable the required detection limits to be achieved.
Discussion and conclusion Among the four methods tested, only the first two give the required detection limits. Comparative analyses have been carried out with the two methods. The results are given in Table 2. The correlation between results is excellent. Both methods appear to be fully complementary (correlation coefficient = R = 0.999) (Fig. 6). CORRELATION OF DATA
2.5
ENZYMATIC METHOD
2.0
1.5
1.0
0.5
0
Fig. 6
0
0.5
1.0 1.5 CHROMATOGRAPHY
2.0
2.5
Correlation of results obtained using the enzymatic and chromatographic methods. The results given are for [L-lactic / (L-lactic + D-lactic) x 100].
542
Table 2 Comparison of the results obtained using the enzymatic and chromatographic methods for the analysis of various samples of D lactic acid obtained by fermentation. [L-lactate content = (L-lactic / L-lactic + D-lactic) x 100] Sample
Chromatographic
Enzymatic
N~ N~ N~ N~ N~ N~ N~ N~ N~ N ~ 10 N ~ 11
0.34 % 0.46 % 0.40 % 0.39 % 0.43 % 0.39 % 2.3 % 0.43 % 0.40 % 0.23 % 0.94 %
0.33 % 0.43 % 0.38 % 0.37 % 0.39 % 0.38 % 2.3 % 0.38 % 0.39 % 0.20 % 0.93 %
,,
L A C T I C A C I D E S T E R S ( M E T H Y L AND I S O B U T Y L E S T E R S )
Summary of the developed methods Table 3 summarises the various methods for determining the optical purity of lactic acid with their respective advantages and disadvantages. GC m e t h o d with a cyclodextrine CSP (Analysis of methyl o-Trifluoroacetyl lactate type derivatives) Analysis of the lactic acid is performed after esterification of the alcohol group with trifiuoroacetic anhydride. The analytical conditions are identical to those described in Figure 3. Figure 7 represents the separation of the enantiomers of the isobutyl ester of lactic acid (O trifluoroacetyl derivative). Under these analytical conditions the detection limit of the L-enantiomer in the D-enantiomer is around 0.1% and the accuracy is of the order of 5 relative % for L-enantiomer coments in D-enantiomer of between 0.1 and 0.5 %.
Analytical method using LC on a "Pirkle" type C S P The enantiomers of m e t h y l , ethyl, isopropyl esters of lactic acid can be directly separated using a "Pirkle" chiral stationary phase. This phase comprises NH 2 grafted silica onto which is fixed 3-5-dinitrobenzoyl phenyl glycine using ionic bonds (Fig. 8). 543
NO2 ~Si-O
~Si~CH2~CH2~CH2~NH3
|
@
NO2
Fig. 8. Structure of the stationary phase used.
Table 3. Recap of the methods for determination of the optical purity of methyl and isobutyl esters of lactic acid.
Advantages
Disadvantages
detection limits L/L + D %
Enzymatic method after hydrolysis of the ester by lactic acid
Very sensitive, very high specificity method, identical to the method for analysing lactic acid
Requires hydrolysis of the ester. The lactic acid contem is measured using HPLC.
<0.1%
GC on cyclodextrine type CSP of the O-TFA derivative of the lactic acid ester
Acceptable resolution between the two enantiomers
Requires double derivatization
LC on Pirkle CSP
Direct method
Reproducibility problems
GC on a conventional column using a "Mosher " type derivative
No racemization of the sample on derivatization
Long and difficult derivatization
Good reproducibility of the method
Analysis on a conventional column
544
<0.3%
Unknown column stability over time
around 0.5 %
<0.5%
?
D-isobutyl lactate L-isobutyl lactate
Fig. 7
Separation of the enantiomers of isobutyl lactate O . T F A by GC. Analytical conditions identical to those described in figure 3. Retention time of the D-enantiomer 97.9 min. 9of the L-enantiomer " 7.5 min.
L
S
~
.......
~
~
---
~ Fig. 8
"
9 ...
-===-=----
R ~
S
Methyl
Ethyl
Isopropyl
R
Direct separation of the enamiomers of methyl, ethyl and isopropyl esters of lactic acid by LC on CSP of "Pirkle" type (racemic mixtures). Column : Pirlde ionic - L phenyl glycine, 250 cm x 4.6 rnm, 3~tm ; Eluant : (Heptane / Ethanol) : (99.5 0.5); Flow rate : 1 ml / min ; detection ; U V , ~. = 210 nm. 545
The stationary phase used is specially prepared for the analysis of lactic acid ester enantiomers. Indeed, conventional commercial CSP's contain D-phenyl glycine. With this type of substrate, the "L" enantiomers are eluted after the "D" enantiomers. Because of this, the detection limits of the "L" enantiomer in the "D" enantiomer are greater than 1%. The use of a CSP containing L phenyl glycine enables the elution order to be reversed for the enantiomers (L then D) and in this way to reduce the detection limits to 0.5 %. However, this limit is still greater than the required values and the method has therefore been discarded. Conventional
G C m e t h o d : a n a l y s i s of ,, M o s h e r ,, d e r i v a t i v e s
The lactates to be analysed are converted to esters of (S) methoxytrifluoromethyl acetic acid (or Mosher (S) acid)) by the reaction described in figure 10 (refs. 6,7,8). The diastereoisomers that are thus obtained are separated using GC on a semicapillary column using a polymethyl phenyl siloxane phase. Chromatograms corresponding to the separation of the enantiomers of derivatives of methyl and isobutyl esters of lactic acid are presented in Figure 11. The method developed is non racemizing and gives results comparable with those given by GC on cyclodextrine type CSP.
F3
OMe : COOH
OMe F3
~f/COOR
!,.._
OH R = Me, iBu Fig. 9. Derivatization reaction of lactic acid esters.
546
"
O~ COOR
Methyl D
7 f
D
t Isobutyl
Fig. 10. Separation of the "Mosher" derivatives of methyl and isobutyl esters of lactic acid Column : JW DB17, 30 m x 0.537 mm, film : 1 ~tm ; column temperature : 10 min at 160~ then 160 to 260 ~ at 4 ~ / min ; injector temperature : 220~ ; detector temperature : 220~ ; Detection FID.
Discussion Among the methods developed, only the LC method was rejected due to its lack of sensitivity and accuracy. Nonetheless, the four methods gave very similar results as shown in Table 4 for the analysis of isobutyl lactate samples.
ESTERS OF a - C H L O R O P R O P I O N I C A C I D Two methods using GC on chiral stationary phases were developed. Both enabled direct analysis of the two esters of (z-chloropropionic acid. The first of these used a non-polar stationary phase containing a chiral metal complex ("Ni-R-Cam"). This phase was developed by a German university (SchiJrig) and was not a commercial by available. It was therefore discarded. The second method used GC on a CSP comprising a derivative of f~-cyclodextrine (heptakis (30 acetyl, 2-6 di O pentyl) ~-cyclodextrine). It enables direct separation of the methyl and isobutyl esters of a-chloropropionic acid.
547
The detection limits of the D enantiomer in the L enantiomer are of around 0.5 % and are compatible with the values required to check industrial samples. Figure 12 shows an chloropropionate samples.
example
of analysis
of methyl
and
isobutyl
a-
GENERAL CONCLUSION In order to meet market requirements, it is necessary to produce high optical purity lactic acid derivatives (greater than 99.5 %). To do this, the methods used to check these derivatives have had to be redefined so as to achieve the required detection limits. Every possible approach for analysing the enantiomers has, at one time or another, been assessed, these being : - the specific method for one enantiomer (enzymatic method) -
direct analysis methods on chiral stationary phases, both in GC and LC
- analytical methods on CSP after transformation to a derivative -
formation of diastereoisomers and analysis using conventional GC methods. According to the type of product, one or even several of these approaches has
been proven to be suited to the problems to be resolved. Over ten methods have been developed, assessed and chosen or eliminated according to their performance levels. The broad-based nature of this study has enabled the problems linked with the analysis of chiral molecules to be extensively understood, enabling progress to be made in this field. Table 4 Comparison of the results obtained by the various methods developed analysis of various isobutyl lactate samples.
during the
L / L + D(%) Isobutyl lactate N~ N~ N~ N~ N~
Enzymatic method 0.23 0.51 0.44 2.30 1.90
GC on CSP
LC on CSP
GC on Mosher esters
0.24 0.47 nd 2.40
0.21 ~0.5 0.47 2.20
nd 0.47 0.43 2.26
1.84
548
1.88
1.98
Methyl chloropropionate 9D / D + L = 2.4 %
/----- .
tll I
II
D
7f_
Isobutyl chloropropionate 9D / D + L = 1.9 % ,
,,
f Fig. 11 Chromatograms corresponding to the analysis of methyl and isobutyl chloropropionate enantiomers (industrial samples) Chromatographic conditions : column : Lipodex D, 50 m x 0.25 mm, column temperature (85~ (methyl ester), 65~ (isobutyl ester), Injector temperature : 150~ Detector temperature : 220~ detection FID
References 1. Methods of enzymatic food analysis, Boehringer Mannhein Biochemica, (1984), technical document. 2. D.W. Armstrong, H.L. Jin, J. Chrom., 502, 154, (1990). 3. D.W. Armstrong, W. Li, J. Pitha, Anal. Chem., 62,214, (1990). 4. W. Li, H.L. Jin, D.W. Armstrong, J. Chrom., 509, 303, (1990). 5. Chrompack News, 2, (1990). 6. J.A. Dale, D.L. Dull, H.S. Mosher, J. Org. Chem., 34, 2543, (1969). 7. J.A. Dale, H.S. Mosher, J. Amer. Chem. Soc., 95,512, (1973). 8. P. Mohr, L. R6sslein, C. Tamm, Helv. Chim. Acta, 70, 142, (1987). 9. V. Schurig, R. Weber, J. Chrom., 217, 51, (1981).
549
AUTHOR
INDEX
F
A Alby D. Ashforth R. Astruc D. Aubry A.
Fache E. Faucher D. Ferrero R.M. Fines A. Firkins S. Foray F. Frey U.
29 3 39 48,62
G Galvez M. Garcia H. Gaspard H. Genet J.P. Gervais C. Gilbert L. Grosselin J.-M. Gustin J.L.
B Babin P. Badey J.P. Beclere M. Bennetau B. Bernard D. Bernard J.M. Besson B. Bonneau-Gubelmann I. Bontoux M.C. Bouzid K. Boyer F.
C Camblor M.A. Casati J.P. Cerbelaud E. Chabannes J. Cordier G. Corma A. Costantini M. Cristau H.J. Crouzet J.
75 405 380 75 536 405,416 116,129 116 189 405 536
405 301 15 416 405 29,39,48,62,301,391 336 431
H Hillairet M.
536
J
391 405 189 536 336 391 350,380,391 90 189
D Dananche J. Danion Y. Desmurs J.R. Dubac J. Duhamel P. Dunogues J.
350,380 189 336 431 107 189 528
129 536 3,15,90,116,129,481 15 176 75
Jacquerot R. Janin M. Janin R. Janousek Z.
129 48,62 325 201
L Labrouillere M. Lanson M. Laporterie A. Lartigue-Peyrou F. Laucher D. Leblanc J.C. Le Govic A.M. Lemaire-Audoire S. Levy-Schil S.
15 528 15 489 380 129 48,62 416 189
M Maliverney C. Manaut D. Marcenac F. Marsault J.C.
E Enderlin J.M. Esteve P.
405 391
550
343 350 536 536
Martin G.J. Martinez A. Meilland P. Merbach A. Mercier C. Metivier P. Metz F. Michel M. Michelet D. Minfray M. Morel M.
506 391 405 528 293 368 15,528 116 350 536 325
P Perrin-Janet G. Perrod M.C. Petre D. Pevere V. Peyre N. Pilot E. Poirier J.M. Pommier P. Prud'homme C.
380 301 189 405 536 536 445 48,62 469
R Ratton S. Rignol S. Rochin C. Ruiz J.
90,116,129,301,481 90 301,325 39
S Saint-Jalmes L. Savignac M. Schlama T. Soubrier F. Spagnol M.
325 416 368 189 29
T Taillefer M. Thibaut D. Tordeux M.
90 189 313
V Valencia S. Vandewalle M.F.
391 405 551
Viehe H.G.
201
W Wakselman C. Wuthrick M.F.
313 343
Y Youmans P.
293
Z Zandanel E.
536
SUBJECT INDEX
A Acetic anhydride 20 Acetominophen 368 Acetyl chloride 8,19 Acidity 325 Acido-basic properties of samarium phosphate 72 Acrylonitrile 194 Acylation of anisole 18,31 Acylation of aromatics ethers 17 Acylation of 1,2-dimethoxybenzene 21 Acylation of phenols 79 Acylation of veratrole 21,32 Acylchloride 35 Additive for fuel 486 Adipamate 192 Adipamide 192 Adiponitrile 189,192 A1C13 5,144,163 Alcohol hypochlorites 434 Alkylation mechanisms 60 Alkylation of phenols 62 Alkylation of sodium enolates of ketones 449 Alkylation of sodium enolates of nitriles 449 Allyloxycarbonates 417 Aluminium chloride 15 Aminoacids 405 Aminolysis of nitriles 102 Ammonium 192 Analysis of polychlorinated gem dichloro cyclohexadienones 137 Aniline 350 Animal nutrition 470 Anisole 17,32,481 Aromatic halodemetalation 77 Arylation of alcohols 90 Arylation of allylamine 92 Arylation of amines 90 Arylation of 2-methoxyethanol 97 Arylsilanes 80 Asymmetric halogenation of carboxylic acids 180 Asymmetric halogenation of chiral imide 181 Asymmetric halogenation of ketals 177 Asymmetric halogenation of ketene acetals 182 Asymmetric halogenations of ketones 176 Authentication of vanillins 513 Auto-ignition 431
552
B Balz-Schiemann reaction Barbier condensation Bayer-Villiger Rearrangement Benzonitrile Benzoquinone Benzoylation of anisole BiC13 Binders Bi203 Bipy2NiBr2 Bismuth salts Boltzmann equation Boron phosphate Bromobenzene (R)-2-Bromo cyclohexanone 4-bromofluorobenzene Bronsted acid Bu4NHF2 Butadiene 2-Butyn- 1-ol
301 319 296 194 372 34 17 487 20 93 16 110 55 92 176 297 162 252 501 451
C 261 407 407 345 189 117 326 483 532 116 116 120 118 121 120 48,62 51 50 350,495 50 163 70 474 473 433 144
Caesium fluoride Calcitonin Calcitonin fragments synthesis Cannizzaro dismutation Caprolactame Carbon dioxide Carbon monoxide Carbonylation Carbonylation of bromobenzene Carboxylation Carboxylation of hydroxy aromatic compounds Carboxylation of phenate Carboxylation of phenol Carboxylation of potassium phenate Carboxylation of sodium phenate Catalysis by rare earth phosphate II Catalytic activity of metallic phosphate Catalytic tests Catechol Cesium hydrogenophosphate CF3SO3H Characterization of SmPO4 Chitin Chitosan Chloramines Chlorination of 2,4,6-trichlorophenol 553
Chlorination of oximes Chlorine Chlorine injection Chlorobenzene 4-Chlorophenyl fluoroformate Cisapride Claybis Cleaning agents Cleavage of allyloxycarbamates Cleavage of allyloxycarbonates Cleavage of a silicon-oxygen bond with NaNH2 CO2 CoC12 Comamonas Nil Combustion Complexation of Lewis acids [3-Controlled diastereoselective chlorination Controlled release Controlled release of active materials Controlled release of iodine salts Copolymer of 2-vinylpyridine and styrene Copper Cram cleavage CsC1 5-cyano valeric acid Cyanovaleramide ~,-Cyclodextrine
434 431 431 93 302 294 19 487 424 418 464 116 44 196 432 11 183 469 469 477 473 90 463 269 189 192 540
D Decarboxylation Decarboxylation of arylfluoroformate Deflagration Deprotection of alcohols Deprotection of carboxylic acids Deprotection of primary amines Deprotection of secondary amines Detonation Dehydrobromination Dehydrohalogenation Dehydrohalogenation with NaNH2 Diastereoselective halogenations Dibenzodioxines Dichlorobenzoquinone 2,4-Dichloronitrobenzene 3,4-Dichloronitrobenzene 2,4-Dichloro 6-(2,4,6-tetrachlorophenoxy) phenol 2,6-Dichloro 4-(2,4,6-trichlorophenoxy) phenol Diflubenzuron Diflufenican
485 302 436 419 419 419 419 436 452 452 453 176 132 144 268 340 154 154 244 245
554
2,4-Difluoroaniline 2,6-Difluorobenzonitrile Digestive system of ruminants 1,2-Dihydroxybenzene Diisopropylbenzene Dimandelic acid 1,2-Dimethoxybenzene Dimethylamine Dinitrogen tetroxide 2,4-Dinitrophenol Dynamic grinding of potassium fluoride
271 244 471 49,351 351 344 49 93 372 372 280
E Electrochemical reduction Electrophilic substitution Enzymatic hydrolysis Enzymatic hydrolysis of adiponitrile Enzymes Epoxidation of 1-hexene Esterification Ethyl trifluoroacetoacetate Ethyl trifluoropyruvate Ethyl vanillin Explosion
79 79 189 190 190 400 486 226,239 317 343 431
F FeC13 Ferric chloride Flammability limits Fluorination Fluorination by KF catalysed with CsF Fluorination by KF with phase-transfer catalysts Fluorination of aromatic compounds Fluorination of 3,4-dichloronitrobenzene Fluorination with alkaline fluorides Fluorination with KHF2 Fluorine 4-Fluoroaniline Fluoroaromatics Fluoroarylsilanes Fluorobenzene 1-Fluorobiphenyl Fluorodecarboxylation Fluorodecarboxylation of arylchloroformate Fluorodecarboxylation of phenylchloroformate Fluorodecarboxylation of 2-phenylphenylchloroformate Fluorodecarboxylation of 3-tolylchloroformate 1-Fluoro naphthalene 555
13,163 16 438 296,301 269 272 244 254 257 268 201 297 301 81 301,309 305 296 301 303 306 306 306
4-Fluoronitrobenzene 4-Fluorophenol Formation of triflyl chloride Formyl cation Formylation Formylation of alkylbenzenes Formylation of aromatic compounds Formylation of phenol Free-radical polymerization inhibitors Friedel-Crafts acylation Friedel-Crafts reaction Fuchsone Functionalisation of fluoroaromatics
342 293,296 319 326 326 327 325 327 489 3 15,39,302 354 75
G Gas chromatography Gas phase explosion hazard in chlorination Gattermann-Koch reaction Glyoxylic acid GPC Grignard reaction Guaiacol Guaiacol vanillin Guetol
536 435 326 343 137 482 348 515 343
H Halex reaction Halide exchange Hailer-Bauer reaction Hammet-Deyrup acidity scale HC1 HC104 Heptachlorodibenzodioxins 2,3,4,4,5,6-Hexachlorocyclohexa-2,5-dien 1-one 2,3,4,5,6,6-Hexachlorocyclohexa-2,5-dien 1-one Hexachlorodibenzodioxins Hexacychlohexadienone Hexafluoroacetone HF/BF 3 High pressure NMR Hoffman degradation HPLC H2504 Hydrogen fluoride Hydrogenation Hydrogenation catalysts Hydrogenation of 3,4-dichloronitrobenzene Hydrogenation of halogenonitrobenzenes 556
247 483 460 326 163 163 150 137 137 150 153 317 327,332 528 248 137,413 163 309 483 337 340 336
Hydrogen peroxide Hydroquinone Hydroxybenzaldehydes 4-Hydroxybenzaldehyde 4-Hydroxybenzoic acid 4-Hydroxybenzylacetate 4-Hydroxybenzylalcohol Hydroxylation Hydroxylation of phenol
354,391 350,495 380,382,385 343 385 382,385 384,385 296 351,391,401
I 266 492 166 537 537 107 509 521 506
Influence of the solvent on "Halex" reaction Inhibition constants Intramolecular migration of the chlorine L-Isobutyl chloropropionate D-Isobutyl lactate Isomerisation of 1,2,4-trichlorobenzene Isotopic analysis by NMR Isotopic fractionation Isotopomers
K 268 456 17 117 116
KHF 2 KNH2 Knoevenagel reaction Kolbe reaction Kolbe Schmitt reaction
L L-alanyl-L-proline L-lactate dehydrogenase Lactic acid enantiomers Lanthanum phosphate Latent Trigonal Center Concept Leucine Enkephaline Lewis acids L.H.R.H. Liquid chromatography Lignin vanillin L-lactate dehydrogenase D-Lactic acid L-Lactic acid Lower Flammability Limit Luteinising Hormone Releasing Hormone Lysine
537 541 59 184 407 4,15,29,163 407 536 515 537 536 537 435 407 472
557
M Mechanism for the carboxylation of phenol Mechanism for the nitration of phenol Mechanism of arylation Meisenheimer's complex Merrifield synthesis Metallation of methylpyridines Metallation of methylquinoleines Methanol Methionine 2-Methoxy-phenol 4-Methyl-acetophenone 2-Methyl-3-butyn-2-ol Methylbutynol conversion L-Methyl chloropropionate Methyl formate Methylhydroquinone Methyl lactate D-Methyl lactate 2-Methylphenol Michael addition Minimum oxidizer concentration Molecular inhibitors Morpholohy of samarium phosphate Mosher derivatives m-trifluoromethylbromobenzene Mutagenesis
119 377 101 246 407 450 450 48 472 344 11 63 70 537 332 495 536 537 38O 449 436 493 62 546 92 197
N 445,449,452 179 515 53 57 90 93 372 368 190 368 433 305 368 371 368 368 23,528 495 495
NaNH 2 Naproxen Natural vanillin Niobium oxyphosphate Niobium phosphate Nickel Ni(PPh3)4 Nitration of orthonitrophenol Nitration of phenol Nitrile hydratase Nitrogen dioxide Nitrogen trichloride 4-Nitrophenyl chloroformate Nitrosation Nitrosation of phenol Nitrous acid Nitric acid NMR N-Nitrosodiphenyl N-Nitrosophenylhydroxylamine 558
O O-Alkylation of catechol O-Alkylation of guaiacol O-Alkylation of phenols Octachlorodibenzodioxins O-methylation of catechol O-methylation of 1,4-dihydroxybenzene O-methylation of phenols Onium hydrogenofluorides Optical purity of lactic acid Oragnolithium condensation Orthonitrophenol Overexpression of the nitrilase Oxidation Oxidation of alkylphenols Oxidation of 4-methylphenol Oxidative cleavage of fluorinated silylbenzenes
49,57 53 49,62 150 54 58 48 254 538 482 371,372 195 380,394 38O 381 86
P Paints Paints and varnishes strippers Palladium Paranitrophenol Paranitrosophenol Parathion p-Chlorotrifluoromethylbenzene Pd(OAc)2/TPPTS 2,3,4,4,6-Pentachloro cyclohexa-2,5-dien 1-one Pentachlorodibenzodioxins Peptides Peptides synthesis Peptidic synthesis Phenol Phenothiazine Phenoxycyclohexadienones 2-Phenylethylamine 2-Phenyl phenyl chloroformate Phosalone Piperonal "Pirkle" chiral stationary phase Polychlorodibenzodioxines Polychlorodibenzofurans Polychlorophenols Polychlorophenoxyphenols Polychlorinated gem dichloro cyclohexadienones Polytetrafluoroethylene Potassium fluoride Pre-activation of potassium fluoride Preparation of hydroxybenzaldehydes 559
487 486 90,384 368 371 368 93,94 421 136 150 406 405 484 368,495 496 161 103 3O5 368 343 543 132 132 129,132 156 136 201 257 276 344
Progabide Propionitrile Proposed mechanism for the alkylation of phenol Protocatechualdehyde Protonation
294 194 60 343 108
R Raney Nickel 337 Rare earth phosphates 53 RbF 269 Reaction of acetals with NaNH2 455 Reaction of bromothiophenes with NaNH2 457 Reaction of disodiosalts of diketones 445 Reaction of hydrazones with NaNH2 450 Reaction of sodium enolates of esters 448 Reaction of sodium enolates of ketones 447 Reactivity of polychlorinated gem dichloro cyclohexadienones 148 Reimer-Tiemann reaction 325,345 Release of amino-acids 473 Release of iodine salts 477 Retro-Halex reaction 255 Rhodifuse 477 Robinson annelation 240
S Sabeluzole Safety of chlorination reactions Salicylic acid Salmon calcitonin Samarium phosphate Samarium phosphate-cesium hydrogenophosphate Sandmeyer hydrolysis Sapphire tubes Sappho technology Schiemann reaction Self-ignition Silicone elastomers Silylation of bromoarenes Silylation of fluorobenzene Smartamine Sodium amide Sodium hydroxymethanesulfinate Sodium trifluoromethanesulfinate Solubility of gases Sommelet-Hauser rearrangement Sonication Sorbinil Specific surface area 560
294 431 122 410 53,62 62 296 528 405 244 436 478 85 79 470 445 320 320 532 457,458 280 294 63
Stevens rearrangement Styrene Styrenic monomers Superacidic medium Superacids Synthesis of aryl(methyldiethoxy)silanes Synthesis of 4-fluoroanisole Synthesis of polychlorinated gem dichloro cyclohexadienones Synthesis of triflic acid Synthesis of zeolite
457 492,500 500 325 326 85 305 136 318 398
T 273 TDA 495 Tertbutylcatechol 495 Tertbutylhydroquinone 248 Tetraalkylammonium fluorides 393 Tetrabuty lorthotitanate 148 2,2,4,6-Tetrachlorocyclohexa- 3,5-dien- 1-one 136,148 2,4,4,6-Tetrachlorocyclohexa-2,5-dien- 1-one 150 1,3,6,8-Tetrachlorodibenzodioxin 150 2,3,6,8-Tetrachlorodibenzodioxin 132 2,3,7,8-Tetrachlorodibenzodioxin 144 Tetrachlorophenol 164 2,3,4,6-Tetrachlorophenol 346 Tetraethylammonium hydroxide 393 Tetraethylorthosilicate 393 Tetraethylorthotitanate 433 Thermal explosion Thermal stability of polychlorinated gem dichlorocyclohexadienones 148 260 Thermodynamic data for alkaline fluorides 163 TIC13 163 TIC14 392 Titaniumsilicalite 417 TPPTS 107 1,2,4-Trichlorobenzene 107 1,3,5-Trichlorobenzene 144 Trichlorobenzoquinone 134 2,4,6-Trichlorophenol 328 Triflic acid 39 Trifluoroacetic anhydride 42 Trifluoroacetophenone 236 Trifluoroacetylation 39 Trifluoroacetylation of aromatics 43 1-Trifluoroacetyl 2-methoxynaphthalene 212 Trifluorodithioesters 205 Trifluoroethyl-t-butylsulfoxide 163 Trifluoromethanesulphonic acid 217 c~-Trifluoromethyl epoxysulfone 218 13-Trifluoromethyl epoxysulfone 561
Trifluoromethyl iodide Trifluoromethylation Trifluoromethylation of aniline Trifluoromethylation of aromatic compounds Trifluoromethylation of disulfides Trifluoromethylation of phtalic anhydride Trifluoromethylation of potassium thiophenoxide Trifluoromethylation of thiocyanates Trifluoromethyl bromide Trifluoromethyl halides Trifluoromethyl iminium salts Trifluoropyruvic thioamides Trifluorothioamidium salts Tris-(dioxa-3,6-heptyl)amine
322 313 321 321 322 318 316 318 315,320 314 210 223 207 272
U 435
Upper Flammability Limit
V 343,506 48 487 343 49 232 325 472
Vanillin Vapor phase Varnishes Veratraldehyde Veratrole Vilsmeier-Haack-Arnold reagent Vilsmeier-Haack reaction 2-Vinylpyridine
W 416 34
Water-soluble Pd(O) catalysts Wheyland intermediate
Y 50
Yttrium phosphate
Z 30,391 319 19
Zeolite Zinc triflinate ZnCI2
562