Functionalised N-Heterocyclic Carbene Complexes

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Functionalised N-Heterocyclic Carbene Complexes

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Functionalised N-Heterocyclic Carbene Complexes OLAF KÜHL Institute for Biochemistry, Ernst-Moritz-Arndt University of Greifswald, Germany

A John Wiley and Sons, Ltd., Publication

This edition first published 2010 © 2010 John Wiley & Sons Ltd Registered office John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, United Kingdom For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com. The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. 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, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for every situation. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Kühl, Olaf. Functionalised N-heterocyclic carbene complexes / Olaf Kühl. p. cm. Includes bibliographical references and index. ISBN 978-0-470-71215-3 1. Ligands. 2. Heterocyclic compounds. 3. Transition metal complexes. I. Title. QD474.K825 2009 541'.2242—dc22 2009042558 A catalogue record for this book is available from the British Library. ISBN: 9780470712153 Set in 10/12 Times Roman by MPS Limited, A Macmillan Company, Chennai, India Printed and bound in Great Britain by Antony Rowe Ltd, Chippenham, Wiltshire

Contents Abbreviations

vii

Introduction

1

Chapter 1 The Nature of N-Heterocyclic Carbenes 1.1 Synthesis 1.1.1 Synthesis of the Imidazolium Salts 1.1.2 Closing the Ring 1.1.3 Synthesis of the Free Carbenes 1.1.4 Synthesis of Transition Metal Complexes of NHC 1.2 Properties of NHC 1.2.1 The Internal Electronic Structure 1.2.2 Basicity of NHC 1.2.3 Steric Properties 1.2.4 The Carbene-Metal Bond 1.2.5 Decomposition Pathways References

7

Chapter 2 Why Functionalisation? 2.1 Phosphane Mimic 2.2 Hemilability 2.3 Chirality 2.3.1 Planar Chirality 2.3.2 Axial Chirality 2.4 Ligand Geometry 2.5 Catalysis 2.5.1 Allylic Alkylation 2.5.2 Coupling Reactions 2.5.3 Olefin Metathesis 2.5.4 Polymerisations 2.5.5 Organocatalysis References

39

Chapter 3 N-Heterocyclic Carbenes with Neutral Tethers 3.1 Amine Functionalities 3.1.1 Heteroaromatic Functional Groups

55

vi

Contents

3.1.2 Oxazolines 3.1.3 Imino Functional Groups 3.1.4 Amino Functionalised NHC 3.2 Oxygen-Containing Groups 3.3 Phosphane Functionalities 3.4 Bis-Carbene Ligands 3.5 Tris-N-Heterocyclic Carbene Ligands 3.6 Pincer Carbenes References Chapter 4 N-Heterocyclic Carbenes with Anionic Functional Groups 199 4.1 Oxygen-Containing Groups 4.2 Nitrogen-Containing Groups 4.3 NHC Ligands Incorporating Cp Moieties 4.4 Transition Metal NHC Complexes Involved in the Activation of C-H Bonds 4.5 Immobilisation of the Catalyst 4.6 Sulfur-Containing Functional Groups References Chapter 5 Chiral N-Heterocyclic Carbenes References

279

Chapter 6 Natural Products 6.1 Thiazole 6.1.1 Isolation and Stability of Thiazolylidene 6.1.2 Benzothiazoles 6.1.3 Metal Complexes 6.2 Amino Acids 6.3 Purines and Xanthines 6.4 Carbohydrates 6.5 Miscellaneous References

309

Index

347

Abbreviations

acac ad ampy anti BARF Benz BIMCA BINAP BINOL bipy boc BoxCarb Bun But CAAC cod coe COMP Cp Cp* Cy p-cymene dba DIPP DMA DMF DMSO DNA dppe dppf EDA ee Et EWG fac

acetylacetonate adamantyl 2-aminomethylpyridine antiparallel orientation {B[3,5-(CF3)2C6H3]4}benzyl 3,6-di-tert-butyl-1,8-bis(imidazol-1-yl)carbazole 1,1’-binaphthylphosphane 1,1’-binaphthyldiol bipyridyl tert-butoxycarbonyl bisoxazoline carbene n-butyl tert-butyl cyclic alkyl amino carbene 1,5-cyclooctadiene cyclooctene conjugated organometallic polymer cyclopentadienyl pentamethyl cyclopentadienyl cyclohexyl p-isopropyl toluene trans,trans-dibenzylideneacetone 2,6-diisopropyl aniline dimethyl acetamide dimethyl formamide dimethyl sulfoxide deoxyribonucleic acid bis-diphenylphosphinoethane 1,1’-bis(diphenylphosphino)ferrocene 1,1-ethanediol diacetate enantiomeric excess ethyl electron-withdrawing group facial

viii

Abbreviations

Fc η Hex HOMO IEt IL Im IMes IPri κ KHMDS LDA MAC MAO Me mer Mes MFILC nbd NBS NHC NHC-S NMP Np NTf OAc OTf ox-NHC PCET PHOX pri py pybox RNA ROMP ROP SHOP syn Taz Tbp TEP thf tht TIME TIMEN

ferrocenyl hapto, hapticity hexyl highest occupied molecular orbital 1,3-diethyl imidazolylidene ionic liquid imidazole, imidazolium 1,3-dimesityl imidazolylidene 1,3-diisopropyl imidazolylidene kappa potassium hexamethyldisilazane lithium diisopropylamine monoaminocarbene methylaluminoxane methyl meridonal mesityl multi-functionalised ionic liquid composition norbornadiene N-bromosuccinamide N-heterocyclic carbene(s) sulfur functionalised NHC N-methyl-2-piperidone neopentyl bis(trifluoromethanesulfonyl)amide acetate triflate oxazoline functionalised NHC proton coupled electron transfer phosphino-oxazoline isopropyl pyridyl pyridyl bisoxazoline ribonucleic acid ring opening metathesis polymerisation ring opening polymerisation Shell Higher Olefin Process parallel orientation thiazolylalanine trigonal bipyramidal Tolman Electronic Parameter tetrahydrofuran tetrahydrothiophene tris-[2-(3-alkylmethylimidazolium-1-yl)ethyl]methane tris-[2-(3-alkylmethylimidazolium-1-yl)ethyl]amine

Abbreviations

TOF Tol Tolyl TON Tp TsO VE VSEPR Xyl

turnover frequency tolyl toluenyl turnover number tris-pyrazolyl borate tosylate valence electrons valence shell electron pair repulsion xylyl

ix

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Introduction

The chemistry of N-heterocyclic carbenes (NHC) and particularly their transition metal complexes is considerably older than the isolation of the first free NHC by Arduengo et al. in 1991 [1]. In 1968 Öfele [2] and Wanzlick and Schönherr [3] independently published the first transition metal NHC complexes. Whereas Öfele reacted an imidazolium salt with a transition metal hydride, Wanzlick and Schönherr reacted the imidazolium salt with a transition metal acetate (see Figure I.1). Lappert developed the thermolysis of an electron-rich olefin in the presence of a transition metal complex as another way to synthesise these compounds [4]. When, in 1975, Clarke and Taube published their findings on carbon coordinated purine transition metal complexes [5], transition metal NHC complexes with functionalised NHC made their debut in biochemistry. The chemistry of carbenes from natural products became firmly established following the discovery that the catalytic activity of thiamine (vitamin B1) is based on the intermediate formation of a carbene derived from thiazole [6–9] (see Figure I.2). However, lacking a stable free carbene, the chemistry of transition metal carbene complexes stayed on the very fringes of inorganic chemistry. This changed dramatically after the publication of the first free stable carbene by Arduengo et al. [1]. Several theoretical publications describing the electronic and steric properties of the new compound class and their bonding to transition metals in the long known (over 20 years) complexes appeared [10–15]. Applications were soon found following Herrmann’s landmark review concerning the use of NHC in catalysis [16]. The first catalytic experiments with transition metal NHC complexes were performed by Lappert et al. some 10–15 years earlier [17]. In particular, the discovery that NHC were better σ-donors than phosphanes gave the coordination chemistry of NHC ligands great momentum and many reactions hitherto performed by transition metal phosphane complexes were now reported for their NHC analogues [16,18–20]. Limitations and new opportunities were rapidly appearing. McGuinness et al. showed the elimination of the ‘stable, inert’ spectator NHC ligand from the transition metal

Functionalised N-Heterocyclic Carbene Complexes. Olaf Kühl © 2010 John Wiley & Sons, Ltd.

2 Introduction

Ph

Ph

N ⫹

N Ph

[Hg(OAc)2]

Ph

N

CO N

N

⫹

Hg

N

Ph

N

CO

N

Ph

N

Ph N [Pt(PEt3)Cl2]2

N

N

CO Cr CO

Ph

N

Ph

⫺

⫹

N Ph

[HCr(CO)5]

OC

N

Cl

Pt

PEt3 Cl

N

Ph

Figure I.1 Synthesis of the first transition metal NHC complexes.

Ph

Introduction Organocatalysis with thiamine

R1 N

R2

S

O OH

R1 N

R2 R1

O

N

R2

⫺

-H

⫹

PhCHO, H

⫹

R1

R3

N

R2

OH

S

R3

:

S Ph

⫹

H

⫹

Ph Ph *

H OH

⫹

Ph

R3

3

Ph

S R3 R1

PhCHO

N

R2

S

Ph OH

R3

Taube's ruthenium carbene complex 2⫹

2⫹

2⫹

NH [H+]

N H3N H3N

Ru

HN

NH3

H3N

NH3

H3N

OH2

NH Ru OH2

CO

HN

NH3

H3N

NH3

H3N

NH Ru CO

NH3 NH3

Figure I.2 Examples of NHC in organocatalysis and as ligands from natural sources.

in catalytic reactions [21,22] and the possibility to generate a transition metal NHC catalyst complex in ionic liquids (imidazolium salts) from the reverse reaction [23] (see Figure I.3). Although NHC ligands were well established within the mainstream of inorganic chemistry by the mid 1990s, the difficulties in obtaining and handling them as free carbenes prevented their universal application. Phosphanes can be easily distributed commercially and in fairly large quantities; free NHC ligands cannot. However, their imidazolium salt precursors can be and with less difficulty than their phosphane counterparts. It was therefore no surprise to see a new, even bigger, surge in NHC chemistry following the landmark discovery of Lin and Wang in 1998 that imidazolium salts can be transferred into their silver(I) carbene complexes upon reaction with Ag2O [24,25]. The reaction is tolerant to many functional groups and the silver(I) NHC complex acts as a carbene transfer agent for the synthesis of almost any transition metal [26] (see Figure I.4).

4

Introduction ⫹

L N

Pd

⫹

L

L

Me

N

N

N

L

L

Pd

Me

⫹

Me

N

N Me

⫹

L

Pd

N

[PdL2]

N

Figure I.3 Decomposition of transition metal carbene complexes through reductive elimination.

But N

Au

[Au(SMe2)Cl]

Cl

N

But

But N ⫹

Ag2O

N

Ph Ag

Cl Ph

N

N

Ph

Ph

But N

N

Cl Pd

[Pd(cod)Cl2] N

Cl

N But

Ph

Figure I.4 NHC transfer from silver(I) carbene complexes to other transition metal centres.

It is somewhat ironic that the trend in metal NHC complex chemistry reverts back to the old traditional protocols of Öfele and Wanzlick, the reaction of an imidazolium salt with a transition metal complex in the presence of a weak base. Öfele and Wanzlick had the base incorporated in the transition metal complex, Lin did the same, but it can be provided externally as K2CO3, NaOAc, NEt3, pyridine or almost any other known base. The driving force

Introduction

5

in this reaction is of course the formation of the transition metal NHC bond, a fact already perceived by Öfele, Wanzlick and Lappert. These ‘old’ protocols are also compatible with many functional groups on the imidazolium salt and it has become customary to deprotonate functionalised imidazolium salts in the presence of simple transition metal salts in order to synthesise transition metal carbene complexes of functionalised carbenes. Functionalised carbenes can anchor free carbenes to the metal site, introduce hemilability, provide a means to immobilise transition metal carbene catalysts, introduce chirality, provide a chelate ligand or bridge two metal centres. NHC can be attached to carbohydrates and camphor, derived from amino acids and purines, and they can be used as organocatalysts mimicking vitamin B1 or as weak ‘solvent’ donors in lanthanide chemistry. There are many possibilities which are still only scarcely explored. This book makes an attempt to introduce major trends in functionalised NHC ligands to the reader and to assist them in their attempts to develop and apply their own functionalised carbenes. An extensive, but not conclusive, list of references is provided at the end of each chapter to direct the reader from this introductory book to the original literature and to the many scientists who laid the foundations in this field.

References 1. See the references listed at the end of Chapter 1.

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1 The Nature of N-Heterocyclic Carbenes

There are essentially three different types of transition metal carbene complexes featuring three different types of carbene ligands. They have all been named after their first discoverers: Fischer carbenes [27–29], Schrock carbenes [30,31] and Wanzlick–Arduengo carbenes (see Figure 1.1). The latter, also known as N-heterocyclic carbenes (NHC), should actually be named after three people: Öfele [2] and Wanzlick [3], who independently synthesised their first transition metal complexes in 1968, and Arduengo [1] who reported the first free and stable NHC in 1991. Fischer carbene complexes have an electrophilic carbene carbon atom [32] that can be attacked by a Lewis base. The Schrock carbene complex has a reversed reactivity. The Schrock carbene complex is usually employed in olefin metathesis (Grubbs’ catalyst) or as an alternative to phosphorus ylides in the Wittig reaction [33]. The NHC are different from both other types. They form transition metal complexes that are essentially inert, although exceptions are known. Their exceptional stability derives from their intrinsic stabilisation from the N-C pπ-pπ bonding interaction of the nitrogen atoms flanking the carbene carbon atom. The p orbital of the carbon is thus partially filled and no longer available for nucleophilic attack. Also, it does not have a lone pair of its own with which it could possibly engage in a nucleophilic interaction of its own. Hence, it remains unreactive taking the middle ground between the opposing reactivities of Fischer and Schrock carbenes. It is this apparent lack of reactivity that meant that the transition metal NHC complexes received little attention in their early history.

Functionalised N-Heterocyclic Carbene Complexes. Olaf Kühl © 2010 John Wiley & Sons, Ltd.

8

Functionalised N-Heterocyclic Carbene Complexes

X

N

R

R

X R

MLn Fischer

R

MLn

N

MLn

Wanzlick - Arduengo

Schrock

Figure 1.1 Bonding in Fischer, Wanzlick–Arduengo and Schrock carbene transition metal complexes.

1.1 Synthesis The easiest way to arrive at a NHC or its complexes is to use an appropriately substituted azolium salt as the starting material [18]. As many of these imidazolium salts may not be commercially available or may prove to be too expensive, difficult to store or too dry, it is best to be familiar with their synthesis. Although arguably the most popular route to NHC is via the azolium salt, there are many other options for their synthesis. An excellent and comprehensive overview of the synthesis of NHC and some of their complexes can be found in Hahn [34]. An interesting route to tri- and tetracarbenes is provided by the template controlled cyclisation of isocyanides, a method pionered by Lappert and coworkers [35,36] (see Figure 1.2).

1.1.1 Synthesis of the Imidazolium Salts There are two general methods to generate the required imidazolium salt: (i) substitution on the imidazole ring; and (ii) synthesis of the imidazole ring with the substituents already in place [18].

R

R

C MX2

N

R OEt

H2N

H N EtO

H

OEt

M

EtOH H H

M N H

N

OEt

N

H

4 Figure 1.2 Template synthesis of transition metal NHC complexes using isocyanides.

4

The Nature of N-Heterocyclic Carbenes R K N

R

N

N XCH2R'

RX KX

H

N

N

9

X

N

R'

Figure 1.3 Synthesis of an imidazolium salt starting from imidazole.

(i) Substitution on the imidazole ring The first substituent is usually introduced on the nitrogen atom by reacting potassium imidazolide with an alkyl halide to obtain the 1-alkylimidazole [37]. The second substituent is subsequently introduced by reacting the 1-alkylimidazole with a second equivalent of a (different) primary alkyl halide (see Figure 1.3). Advantage: Two different substituents can be introduced and thus unsymmetrically substituted NHC can be obtained using this route. Disadvantage: The method is limited to primary alkyl halides as secondary and tertiary alkyl halides are subject to unwanted elimination reactions. (ii) Synthesis of the imidazole ring When substituents other than primary alkyls are required on the nitrogen atoms of the imidazole ring, the imidazole ring has to be synthesised from glyoxal, formaldehyde and a primary amine in the presence of an acid [38] (see Figure 1.4). Now, all substituents are available as long as pendant functional groups do not interfere with the ring forming reaction. Advantage: Most symmetrically N,N’-disubstituted imidazolium salts can be synthesised using this method.

R O R

O H2N

NH2 O

X

N R

HX

H

N R

Figure 1.4 Synthesis of an imidazolium salt via the assembly route.

10

Functionalised N-Heterocyclic Carbene Complexes

C H 2R ' O

O

NH4X

H2N

N H

R

O

X

N

N

R'CH2X

H

N R

R

Figure 1.5 Synthesis of an unsymmetrically substituted imidazolium salt via the imidazole assembly route.

Advantage: By changing the acid, the anion of the imidazolium salt can be chosen [39]. Thus, halides can be avoided or iodide introduced depending on further requirements. Disadvantage: Only symmetrically N,N’-disubstituted imidazolium salts are accessible. For the synthesis of unsymmetrically N,N’-disubstituted imidazolium salts, method (ii) has to be modified. This is achieved by using 1 equiv. of ammonium chloride and 1 equiv. of the primary amine resulting in the formation of N-substituted imidazole. Subsequent reaction with a primary alkyl halide [method (i)] yields the desired unsymmetrically N,N’disubstituted imidazolium salt [40,41] (see Figure 1.5). Note: This method is limited in its substitution pattern regarding the second substitution by the same disadvantage as method (i). With the knowledge of the two principle methods of synthesis, we can now turn our attention towards modifications of the ring itself and the substituents on it. There are a range of different NHC available that fall within the range of carbenes covered by this book. These include saturated and unsaturated, annulated and chiral NHC and NHC whose carbene carbon atom is not part of a five-membered ring [36] as well as NHC with heteroatoms in positions 4 and 5 of the imidazole ring [42] (see Figure 1.6).

1.1.2 Closing the Ring A very important and versatile method en route to a NHC is the ring closure reaction with ortho-formate [18,34,36,43] (see Figure 1.7). Here a suitable diamine is reacted with a triester of formic acid resulting in a N=CH-N group that can be deprotonated to form a carbene. Advantage: Carbenes based on four-, five- and six-membered rings become available. Advantage: A broad range of substitution patterns on the ring are accessible. The method is particularly suitable for NHC that have ‘uncommon’ substituents in the 4,5-position [44], an unusual scaffold [45,46], annulated rings [47–49], are saturated [50] or have readily available diamino precursors [51,52].

The Nature of N-Heterocyclic Carbenes R

R

R

N

N

N :

:

N

N

:

N R

R

R

N

:

11

N R

R R

R R'

R'

*

N

R R2N

N

*

:

* N

R'

B

:

: B

N R2N

R

*

N

N

R'

R

R

Figure 1.6 Examples for different NHC frameworks.

1.1.3 Synthesis of the Free Carbenes The free carbene is usually generated from the imidazolium salt precursor by reaction with a strong Brønstedt base like potassium (sodium) hydride [53], potassium tert-butylate (with catalytic amounts of DMSO) [54], MN(SiMe3)2 (M = Li, Na, K) [55] or BuLi [56]. An elegant method to generate the free carbene is the reaction of the imidazolium salt precursor with sodium hydride in liquid ammonia. In contrast to other solvents, liquid ammonia dissolves both, the imidazolium salt and the base (NaH) providing a medium for smooth, efficient deprotonation and carbene formation in high yields [57,58] (see Figure 1.8). boc NH

boc BrCH2CH2NHMes

N

HN

Mes HCl

PPh2

PPh2

HC(OEt)3 N

NH2

PPh2

N

H2N

Mes PPh2

Figure 1.7 Ring closure to an imidazolium salt with triethyl-orthoformate.

Mes

12

Functionalised N-Heterocyclic Carbene Complexes R

R N

N

NH3 (1)/NaH

H

N

X

:

NaX/H2

N R

R

Figure 1.8 Deprotonation of an imidazolium salt with sodium hydride in liquid ammonia.

Advantage: Many transition metal carbene complexes can only be synthesised using the free carbene. The method is not limited by suitable anions or oxidation states associated with the transition metal compound used as starting material. Disadvantage: The strong bases used are incompatible with many functional groups in the pendant sidechains. Disadvantage: Several transition metal carbene complexes can be synthesised directly from the imidazolium salts without the need to isolate the free carbene. An alternative to the imidazolium salts as starting materials is the elimination of an alcohol from 2-alkoxy-1,2-dihydro-1H-imidazoles that are accessible by reaction of vicinal diamines with ortho-esters of formic acid [59–61] (see Figure 1.9).

R N

R

R N

NaOMe MeOH

N

H ΔT

N

OMe

N R

N R

R R

R

NH

N HC(OEt)3

NH R

:

N R

Figure 1.9 HNC via alcohol thermolysis – a similar method to triethyl-orthoformate.

The Nature of N-Heterocyclic Carbenes R

O

H2N

R

13

OH

S

H2N

R

R

N

N S

KC8 N

N R NHR

R

Cl

NHR

:

S

Cl

Figure 1.10 Synthesis of a free NHC via the thione route.

Disadvantage: Thermal decomposition of the 2-alkoxy-1,2-dihydro-1H-imidazole often leads to dimerisation of the NHC and the corresponding tetraaminoethylenes are formed instead. There are of course a range of methods of less general application. One that is of considerable importance is the reduction of imidazol-2-thiones, accessible from the reaction of thioureas and α-hydroxyketones or alternatively o-phenylene diamines and thiophosgene [62] (see Figure 1.10). Disadvantage: The reduction of the thione often fails or the C=S group is directly reduced to a methylene carbon rather than a carbene.

1.1.4 Synthesis of Transition Metal Complexes of NHC Today, transition metal complexes of NHC are mainly formed using four methods: (i) reaction of a transition metal complex with a free carbene (preformed or generated in situ); (ii) reaction of an imidazolium salt with a transition metal complex possessing a basic anion or entity; (iii) by using a carbene transfer agent; and (iv) by reacting an imidazolium salt with a transition metal salt in the presence of a weak base (see Figure 1.11). (i) Reaction of a transition metal complex with a free carbene Deprotonation of an azolium salt with a strong base renders the free carbene which can then be reacted with a suitable transition metal complex to yield the transition metal carbene complex. In many cases, the NHC is not isolated, but prepared in situ prior to adding the metal complex. Advantage: The choice of transition metal complexes as starting materials is far greater than with any other method, save that using carbene transfer agents. Disadvantage: The choice of carbene is limited by the tolerance of functional groups towards strong bases.

14

Functionalised N-Heterocyclic Carbene Complexes R N

2

:

⫹

[Pd(cod)I2]

N R R

R

N 2

N

⫹

⫹

Pd(OAc)2 N

R

R R

[Pd(cod)I2]

N ⫹

Ag2O

2

N

I R

PdI2

R

N ⫹

N Pd

N

2

R

I

K2CO3 R

AgI

N

N

R

R

N 2

⫹

N R

Figure 1.11 Synthesis of transition metal NHC complexes using basic transition metal complexes.

(ii) Reaction of an imidazolium salt with a transition metal complex possessing a basic anion or ligand The deprotonation of an azolium salt to form a carbene requires a base. This base can be supplied as the anion of a transition metal compound, in which case the azolium salt is deprotonated in situ and the carbene formed coordinates to the metal generating the NHC transition metal complex. This method works best if a coordinating anion, such as bromide or iodide, is supplied with the azolium salt. This method was successfully applied using acetates [64,65], acetylacetonates [66,67], alkoxides [16,68,69] and [Pd2(dba)3] [70]. In fact, the first NHC transition metal complex reported by Wanzlick and Schönherr in 1968 [3] used mercury(II) acetate and 1,3diphenylimidazolium perchlorate as the starting materials. An interesting variant is the in situ preparation of transition metal alkoxides from the corresponding halogenides and subsequent reaction with an azolium salt to form the NHC transition metal complex [69]. This works particularly well with rhodium, iridium and ruthenium where [(η4-cod)MCl]2 (M = Rh, Ir) and [Cp*RuCl]2 are readily available [57,58,71]. Advantage: A mild method to prepare NHC transition metal complexes in high yields. Advantage: Transition metal complexes with chelating bis-carbenes featuring acidic methylene protons in the linker unit can be readily prepared, when the isolation of the free carbene using strong bases would be far more difficult.

The Nature of N-Heterocyclic Carbenes

15

Disadvantage: When the azolium salt does not contain a coordinating anion, this anion has to be provided by adding LiI or a similar salt. Synthesis using a transition metal hydride One of the first publications of a NHC transition metal complex, published by Öfele in 1968, was the reaction of an imidazolium salt with [HCr(CO)5] to form [Cr(Me2Im)(CO)5] with the formation of hydrogen [2]. The method can also be used with other transition metal hydrides, such as [IrH5(PPh3)2] [63]. Advantage: There are no purification problems as the elimination product, hydrogen, is a gas. Disadvantage: There is only a limited number of transition metal hydride complexes available as starting material. Disadvantage: The method leads to the formation of a salt, with a cationic metal carbene complex, unless the anion of the azolium salt can coordinate to the metal. This is a disadvantage because cationic transition metal NHC complexes are subject to carbene decomposition pathways, unless they are stabilised as a chelating bis-carbene [21,22]. The silver(I) oxide method One of the most generally used methods to prepare a NHC transition metal complex is the reaction of an azolium salt with silver oxide to form the silver carbene complex [24,25,72]. It is so general that it has its own name, the silver(I) oxide (Ag2O) method [25,26]. Of course, oxide is a base and thus it falls under the heading of reactions with basic transition metal compounds, but the silver carbene complexes are usually only synthesised because the silver atom coordinates only weakly and can easily be replaced by another metal of choice. It is therefore known as a carbene transfer agent. Advantage: The silver carbene complex can usually be synthesised using undried solvents and with exposure to air. Advantage: The method is compatible with most functional groups. (iii) Synthesis using a carbene transfer agent Silver carbene complexes are the most commonly used carbene transfer complexes [83]. Other carbene transfer agents include lithium adducts [56], potassium complexes [53], molybdenum carbene complexes [83,84] or chromium carbene complexes [85]. (iv) Reaction of an imidazolium salt with a transition metal salt in the presence of a weak base The concept of Wanzlick (and Öfele) to react the imidazolium salt with a basic transition metal complex can be modified – and generalised – by separating the base and the transition metal complex. In this case, an equilibrium between the imidazolium salt and its deprotonated form, the carbene, is established. Although the equilibrium is very much on the side of the imidazolium salt, by far the weaker conjugate acid, the reaction is shifted towards the carbene by strong coordination of the NHC ligand to the transition metal. Examples for weak bases used in this context include Na2CO3 [73], K2CO3 [74–77], Cs2CO3 [78], NEt3 [79,80], pyridine [76] and NaOAc [81,82]. (v) Other Methods There are two standard methods to generate transition metal NHC complexes that originate from the times when stable free carbenes were not accessible and thus the NHC had to be generated within the coordination sphere of the metal. These are the reaction of suitable transition metal complexes with electron-rich tetraaminoethylenes [4,18,86,87] and a

16

Functionalised N-Heterocyclic Carbene Complexes R N

R

N R

N

R

N

2CO

[Fe(CO)5]

R

R OC

N

N

N

Fe

CO CO

CO

R

N R CO H N

But PhCHO[PhNH3]ClButNC[NEt4][(NC)Cr(CO)5]

HN

OC

CO CO

N

H2O [NEt4]Cl

Cr CO Ph

Ph

Figure 1.12 Transition metal NHC complexes via thermolysis of electron-rich olefins or isocyanide template synthesis.

template reaction using isocyanides as the building block for the imidazole ring [88–90] (see Figure 1.12). Today, they are all but displaced by modern alternatives, although for cyclic tetracarbenes the isocyanide route is still the method of choice [35,91,92].

1.2 Properties of NHC 1.2.1 The Internal Electronic Structure The stability of NHC is often described in terms of the singlet–triplet gap which is the energy difference between the singlet ground state and the triplet excited state [16] (see Figure 1.13). When this difference is small, then there is a strong tendency for the NHC to dimerise forming tetraaminoethylenes. The stable NHC have typically singlet– triplet gaps above 65 kcal mol–1 [11,93]. What is the reason for this stability and how is the carbene centre stabilised electronically? The first stable NHC ever isolated was 1,3-diadamantyl-1H-imidazol-2-ylidene, an unsaturated carbene with bulky substituents on the nitrogen atoms [1] (see Figure 1.14). It

N

N

⌬E

N

N

Singlet

Triplet

Figure 1.13 The singlet–triplet gap.

The Nature of N-Heterocyclic Carbenes

17

N

N N

:

:

:

N

N

N

Figure 1.14 A series of the first three frameworks of free carbenes: steric protection, sterically unprotected unsaturated NHC, sterically and electronically unprotected, saturated NHC.

was thought that steric and electronic factors contributed to its stability and its reluctance to dimerise. It is easy to imagine that the bulky adamantyl substituents would prevent the two carbene carbon atoms from approaching each other and forming a C=C double bond. It is equally easy to count the 6 π-electrons (two from the C=C double bond and four from the two nitrogen lone pairs) and assume that there is aromaticity due to a delocalised 6 π-electron system [10,11,94]. However, the isolation of N,N’-dimethyl substituted NHC [54] and the first saturated NHC, 1,3-dimethyl-1H-imidazolin-2-ylidene by Arduengo et al. in 1995 [95] cast serious doubt as to the validity of the need for steric or aromatic stabilisation in these carbenes. Two independent theoretical studies by Boehme and Frenking [10] and Heinemann et al. [11] in 1996 as well as a later one by Tafipolski et al. [94] gave an excellent account of the stabilising factors and the differences between saturated and unsaturated NHC. The first question that needed answering was whether the unsaturated NHC are indeed aromatic. The Hückel rule states that aromatic systems are monocyclic, homonuclear, planar and possess a delocalised 4n+2 π-electron system [96]. Unsaturated NHC fulfil all the criteria except homonuclearity, which would make them heteroaromatic compounds. However, there was doubt as to the delocalisation of the 6 π-electron system. Although there are 6 π-electrons, their distribution is extremely unequal, the backbone carbon atoms C4 and C5 contribute one π-electron each, the nitrogen atoms provide a lone pair each, but the carbene carbon atom C2 gives none. Can there be a true delocalisation in such circumstances?

18

Functionalised N-Heterocyclic Carbene Complexes

N

N

N

N

N C-N electron withdrawal

N-C back donation

N C-N electron withdrawal N-C back donation

Figure 1.15 Electronic stabilisation of NHC.

Delocalisation of the 6 π-electron system in unsaturated NHC would have consequences in the thermodynamic, structural and magnetic data and the charge density within the p orbitals of the ring atoms [11]. From thermodynamic considerations one can learn that the main contribution to the stability of the NHC comes from a combination of the large electron-withdrawing effect of the electronegative nitrogen atom on the σ-electrons of the C-N single bond paired with a πN-πC backdonation via the p orbitals [97] (see Figure 1.15). The presence of a C=C double bond in the backbone provides additional thermodynamic stabilisation of at least 20 kcal mol–1 [11]. The structural analysis shows that in the unsaturated NHC the C4-C5 and N3-C4 bonds are shorter but the C2-N bonds longer than in the unsaturated NHC, as is expected in a delocalised 6 π-electron system. The N1-C2-N3 bond angle at the carbene carbon atom is larger in saturated than in unsaturated NHC corresponding to a higher percentage of s character for the C2-N bonds of saturated compared with unsaturated NHC [10]. Of course, the differences in the C4-C5 and N3-C4 bond lengths are as expected for the introduction of a formal C=C double bond, but the relative lengths of the C2-N bonds need further explanation. The difference does not lie in a stronger pπ-pπ contribution for the saturated carbene, but in the fact that the larger s character in the hybrid orbitals of the carbene carbon atom of the saturated NHC results in a larger Coulomb attraction between N and C2 [10]. The anisotropy of the magnetic susceptibility Δχ is regarded as a criterion for an aromatic ring current [11] and it was found that magnetic anisotropy for unsaturated NHC is only slightly lower than for imidazole, but much greater than for saturated NHC [10]. The effect is significantly smaller even for unsaturated NHC than for typical aromatic compounds like benzene, but shows that unsaturated NHC possess partial aromatic character. A charge density analysis reveals that the carbene carbon atom of the unsaturated carbene has a higher absolute and relative pπ(C2) occupancy than the saturated counterpart [10] indicating a larger π delocalisation for the unsaturated NHC. Note: The π interactions ‘undoubtedly enhance the stability of the unsaturated compounds over the saturated analogues’ [95].

The Nature of N-Heterocyclic Carbenes

N

N

N 10- electron system

19

N 6- electron system N-C-N allyl system

Figure 1.16 6 (10) π-electron system or 2 (6) π-electron + N-C-N allyl system.

Note: ‘The electron donation of the neighbouring lone pairs is sufficient (but necessary and still dominating) and ... the delocalisation in [unsaturated NHC] provides merely an additional but not a necessary thermodynamic stabilisation’ [10]. Note: The stability of NHC is electronic rather than steric in nature. We now know what a monocyclic carbene on the basis of an imidazole ring looks like electronically. We can safely assume that carbenes derived from triazolium and even tetrazolium salts have similar principal characteristics. However, does this hold true for carbenes synthesised from benzimidazolium salts and other annulated NHC? Could it be that a benzaimidazol-2-ylidene has an electronic structure that consists of a benzene ring and a N-C-N allyl system with 4 π-electrons (see Figure 1.16). The answer is not a clear ‘yes’ or ‘no’ decision. The truth is that one trend for annulated carbenes goes in the direction of saturated or even acyclic carbenes [98–100]. Annulation usually results in the destabilisation of the carbene centre and it becomes increasingly more difficult to isolate the free carbene [47,50] if the annulated ring system is extended from benzene to naphthene and phenanthrene [101,102]. The incorporation of nitrogen atoms in the annulated ring system usually enhances the destabilising effect. The destabilisation of the carbene by the effect of annulation results in a smaller singlet–triplet gap. 1,3-Dineopentyl-1H-benzimidazol-2-ylidene, an annulated carbene with intermediate singlet–triplet gap, shows an interesting equilibrium between the monomeric free carbene and the dimer form, a tetraaminoethylene [103] (see Figure 1.17). But

But

N

But

But

N N

N

But

:

N

But

N

N

: N

But

Figure 1.17 Equilibrium between electron-rich olefin and free NHC.

But

20

Functionalised N-Heterocyclic Carbene Complexes

Figure 1.18 Abbreviated molecular orbital scheme of an annulated NHC ligand. Copyright Wiley-VCH Verlag GmbH & Co KGaA. Reproduced with permission.

Photoelectron spectroscopy reveals that the highest occupied molecular orbital (HOMO) in NHC is the lone pair in the sp2 hybrid orbital of the carbene carbon atom (see Figure 1.18). However, a molecular orbital with π symmetry centred around the N-C-N heteroallyl system is of almost equal energy. This gives the carbene the ability to engage in π-face donor interactions with the transition metal fragment. For unsaturated NHC these π-face donor interactions are more favourable than for saturated ones [104].

1.2.2 Basicity of NHC Knowing that the free carbenes can be synthesised from the azolium salts by abstraction of the H2-proton with a strong base, it is not a surprise that the NHC themselves are very strong Brønstedt acids [105–110]. This behaviour follows the well-known rule that a weak acid (the azolium cation) has a strong conjugate base (the carbene). Just how strong a base these carbenes are may not be that easy to determine. A classical Brønstedt base is defined within the medium water where the pH value is restricted by the autoprotolysis equilibrium of water itself, limiting the pH range to values of 0–14. Water will protonate a carbene to the azolium salt [111], but the hydroxide ion leads to decomposition reactions under ring opening [108,112]. How, then, can we determine the actual basicity of these carbenes? One method was proposed by Alder et al. [105] who reacted 1,3-diisopropyl-4,5-dimethylimidazol2-ylidene with acidic hydrocarbons with known pKa values in (CD3)2SO and monitored the reaction by 1H-NMR spectroscopy. Whereas indene (pKa 20.1) was completely deprotonated, the weaker acids 9-phenylxanthene (pKa 27.7) and triphenylmethane (pKa 30.6) were not deprotonated at all. With fluorene (pKa 22.9) and 2,3-benzofluorene (pKa 23.5) mixtures of the two acid/conjugate base couples carbene/imidazolium and hydrocarbon/anion were obtained. Integration of the signals in these spectra led to the calculation of the pKa value of 24.0 for 1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene in DMSO-d6. Denk and Rodezno found that the carbene 1,3-di-tert-butylimidazol-2-ylidene reacts rapidly with DMSO-d6 under H/D exchange of the ring protons. The deuterated carbene

The Nature of N-Heterocyclic Carbenes But H

But

N D

:

H

N

H

D

H

H

D

N D

N

But

But

But

N

H

N

D

N

But

H

But

But

D

D

D

D

N

But

N

D D

N

But

But

D H

N But

D

H

D D

N

But

N

D

N

D

But

21

N :

H But

N But

Figure 1.19 H/D exchange in an imidazolium/NHC system.

1,3-di-tert-butyl-4,5-dideutero-imidazol-2-ylidene was isolated from the reaction mixture [108] (see Figure 1.19). Given that DMSO is not an inert solvent for NHC, although 1,3-diisopropyl-4, 5-dimethylimidazol-2-ylidene, the carbene used by Alder et al., has no ring protons and thus is not subject to H/D exchange in DMSO-d6, Kim and Streitwieser have investigated the basicity of NHC in THF using UV-Vis spectroscopy [106]. They used three different hydrocarbon indicators, 9-phenyl-2,3-benzafluorene, 3,4-benzafluorene and 9-benzylfluorene, all of which have slightly different UV-Vis spectra for the neutral and the anionic species. Like Denk and Rodezno, they used 1,3-di-tert-butylimidazol-2-ylidene as the carbene and found a pKa value of 20.0 in THF for this carbene. As 1,3-diisopropyl-4,5dimethylimidazol-2-ylidene, the carbene used by Allen et al., is actually an isomer of 1,3di-tert-butylimidazol-2-ylidene, the basicity of the two NHC should be roughly identical within experimental error. The difference of four pH units is a clear indication that the measured basicity is dependent on experimental conditions, in this case mainly the choice of solvent. This was already observed by Alder et al. when they reacted 1,3-di-tertbutylimidazol-2-ylidene with 9-phenylfluorene (pKa 18.5 in THF), fluorene and indene in THF [105] (see Figure 1.20). Whereas the deprotonation of fluorene failed, 9-phenylfluorene and indene were deprotonated giving a pKa value upwards of 18.5 in accordance with the findings of Kim and Streitwieser. We conclude that it is easier to generate the free carbene from the imidazolium salt in THF rather than in DMSO. However, Arduengo et al. tell us that it is advantageous to add a catalytic amount of DMSO in the reaction between imidazolium salts and KOBut in THF to facilitate the removal of the proton [54]. The anion of DMSO, generated in small amounts, is a better proton scavenger for imidazolium salts than the potassium tertbutoxylate itself. Looking at the reaction of an imidazolium salt with mercury(II) acetate to form the [Hg(NHC)2] complex, the original reaction of Wanzlick and Schönherr [3], we are left with a small mystery. Why could the weak conjugate base acetate (pKa 4.75 in water) deprotonate the much weaker acid imidazolium?

22

Functionalised N-Heterocyclic Carbene Complexes

9-phenyl-2,3-benzafluorene

3,4-benzafluorene

9-benzylfluorene

Figure 1.20 Three annulated aromatic compounds used as indicators to measure the basicity of NHC.

Note: The strong M-NHC bond facilitates deprotonation of the azolium salt enabling the use of weak anionic bases like acetate. The exceptionally strong basicity of the NHC is reflected in their equally great nucleophilicity. A convenient way to measure the electronic properties of ligands is through the A1 carbonyl stretching frequencies of the corresponding transition metal carbonyl complexes [113]. The standard is known as the Tolman Electronic Parameter (TEP) and is derived from the [Ni(CO)3L] complex of the ligand. Many different transition metal carbonyl complexes have been used and conversion tables as well as theoretical methods for the computation of TEP values are available [113,114]. In general, NHC have lower TEP values than phosphorus-containing ligands [19,107,115], even lower than 2056 cm–1, the TEP value of the most basic trialkyl phosphane PBut3 [115]. The accepted interpretation is that these carbene ligands are very strong σ-donors and weak π-acceptors [107]. However, π-donation of NHC ligands towards transition metals is also discussed [104,109], a property that is generally not attributed to phosphanes. An interesting aspect is the relative net electron donicities of carbene ligands. In a series of N-stabilised carbenes [C(NPri2), SIMes, Imes], Herrmann et al. showed that unsaturated NHC are better net donors than saturated NHC and sometimes can even outperform the acyclic and more basic carbene ligand C(NPri2)2 [57,104,107] (see Figure 1.21). A similar observation was made by Dorta et al. [19]. However, the absolute differences between the net donicities of these different carbene ligands are very small and are unlikely to play a major role in catalyst performance [19]. Note: There are no significant differences in the electronic properties of NHC ligands deriving from N-substitution or indeed unsaturation versus saturation issues [19]. Note: The electronic properties of NHC ligands are affected by annulation [50]. The same conclusion concerning the M-NHC bond structure and strength can be drawn from bond parameters derived from X-ray structure determinations of transition metal NHC complexes [109,116,117].

The Nature of N-Heterocyclic Carbenes R

Pri N

Cl

Rh

Pri

CO

R

N

Cl

Rh

CO

N

CO

N R

Pri

(CO) 2057

Rh

CO

N

N

Cl

CO

CO Pri

23

R

2081

2076

cm1

Figure 1.21 Evaluation of NHC σ-donicity using IR spectroscopy.

The interesting electronic properties of NHC and their azolium precursors can be seen in the 1H- and 13C-NMR spectra for the H2 and C2 atoms. Since the H2 atom of an azolium salt is essentially acidic, the corresponding chemical shift will be observed downfield, typically at δ = 8–11 ppm (see Figure 1.22). There is a correlation between the proton chemical shift and the ease of deprotonation [50]. The precursor of the acyclic carbene bis(diisopropylamino)carbene, N,N,N’,N’’-tetraisopropylformamidinium chloride has a proton chemical shift of δ = 7.60 ppm [118], significantly upfield of the normal range for azolium salts. The carbon chemical shifts of the azolium salts can be found at the downfield end of the aromatic range at δ = 140–160 ppm and the carbenes themselves about Δδ = 100 ppm downfield of the imidazolium salts. Coordination to transition metals brings the carbon chemical shift upfield from the value of the free carbene. Whereas the C2 resonance in [Cp*Ru(NHC)Cl] complexes are typically around δ = 200 ppm [116], the same signal in [Ag(NHC)Cl] complexes can be found at δ = 170–190 ppm [50] (see Figure 1.23). The dependence of the C2 chemical shift of a coordinated carbene on the nature of the carbene is given in Denk et al. [107] for a series of rhodium NHC complexes as δ = 211.9 ppm for a saturated NHC, δ = 195.9 ppm for a benzannulated NHC and δ = 182.6 ppm for an unsaturated NHC. The corresponding bis-(diisopropylamino)carbene complex is given as δ = 233.8 ppm, the most downfield and Δδ = 21.7 ppm upfield from the free carbene [118].

But

But

N

N But

N

N

(1H) 9.71

N

N

But

N

N But

But 9.92

10.50 ppm

Figure 1.22 The influence of annulation in 1H-NMR spectroscopy.

24

Functionalised N-Heterocyclic Carbene Complexes R

Pri N

Cl

Pri Pri

N

Rh

Cl

Rh

N

N

R

Pri 233.79

211.9

R

R

N

Cl

Rh

N

Cl

Rh

N R

195.9

N

R 182.6 ppm

Figure 1.23 The influence of annulation in 13C-NMR spectroscopy.

Note: The carbene carbon atom of a NHC is observed as a characteristic downfield signal in the 13C-NMR spectrum.

Note: The carbene carbon atom of a coordinated NHC is observed upfield from the corresponding free carbene in the 13C-NMR spectrum. Note: Silver complexes of NHC typically experience the largest coordination chemical shift in the 13C-NMR spectrum.

1.2.3 Steric Properties The description of the steric properties of phosphanes using the Tolman cone angle [113] proved to be an excellent concept capable of explaining many phenomena in the coordination chemistry of phosphanes and their applications, especially in homogenous catalysis. That there is a steric influence connected with NHC was noticed very early, in fact it was thought that the steric hindrance introduced by the N-mesityl substituents was a contributing factor in the isolation of the first stable carbene in 1991 as opposed to dimerisation to the known tetraaminoethylenes [1]. It is comparatively easy to divide the N-substituents into bulky and nonbulky ones, but it is far more difficult to justify the decision in borderline cases and even more difficult to quantify the findings in a similar way to the Tolman cone angle, which gives a single value that can be calculated as the sum of the three contributing substituents on phosphorus. In short, the Tolman cone angle is valid for symmetrical and unsymmetrical (tertiary) phosphanes [113].

The Nature of N-Heterocyclic Carbenes

25

NHC are not cone-shaped, but can be described as wedges or fences. They usually have a flat centre and spreading wings – often the N-substituents are referred to as wingtips [19,116,119–122]. A NHC has two relevant angles in the coordination sphere of a metal, one connected with the wingspan and one connected with the effective ‘height’ of the carbene, a parameter largely determined by the wings as the N-substituents protrude beyond the flatness of the imidazol centre. A rather facile way to divide NHC ligands into bulky and nonbulky is by looking at their trans-[M(NHC)2X2] (L = Ni, Pd, Pt; X = Cl, Br, I) complexes. Sterically undemanding NHC ligands arrange coplanar and perpendicular to the MC2X2 plane, whereas sterically demanding NHC show substantial deviations from coplanarity [123]. As early as 1999, Nolan proposed a set of two angles to describe the steric impact of NHC on the coordination sphere of a transition metal, AH (for the height) and AL (for the length) of the carbene ligand described as a ‘fence’ [116] (see Figure 1.24). Nolan et al. developed this concept on a series of [Cp*Ru(L)Cl] (L = NHC, PCy3, PiPr3) complexes and felt the need to point out that AL depends on the value of the Ru-NHC bond length, although Δ˚< 1˚ for ΔRu-C < 5 pm. It should also be pointed out that the arithmetic average of AH and AL, at least for the bulkier carbenes, is roughly equal to the Tolman cone angle of the two phosphane ligands used in the study. It is also interesting to note that for N-aryl substituents the AL value largely depends on the para-substituent and the AH value on the ortho-substituent (o-tolyl would have the same AH value but a smaller AL value than mesityl). These parameters did not gain widespread recognition within the carbene community and in 2003 Nolan et al. introduced a modified parameter, termed % Vburr [19,120,121]. The parameter % Vburr combines the two angles AH and AL into one parameter that merely gives what ‘amount of volume of a sphere centred on the metal (is) buried by overlap with atoms of the NHC ligand’ [121] (see Figure 1.25). Advantage: All the steric impact is compacted into one simple number. Advantage: % Vburr values for phosphanes are easily computed. Disadvantage: NHC with different steric properties can have the same % Vburr value.

N P

Cone shaped phosphane

N

Wedge shaped NHC

Figure 1.24 The angular dependance of the steric influence: phosphane and NHC ligands.

26

Functionalised N-Heterocyclic Carbene Complexes

N

N

M

300 pm

Figure 1.25 A graphical description of the steric demand – like an umbrella in the midday sun.

Consider the two phenanthrene annulated NHC in Figure 1.26, they differ only in the position of the methyl group in the tolyl N-substituent. They have the same % Vburr value, but the o-tolyl substituted one is a monomeric NHC whereas the p-tolyl isomer is a dimeric tetraaminoethylene at ambient temperature [124]. The AH, AL nomenclature is able to distinguish between the two and explain the monomeric or dimeric structure. The greater AH value introduced by the o-methyl group is sterically active, whereas the greater AL value introduced by the p-methyl group is sterically inactive. It is worth mentioning that Müller and Vogt have recently reintroduced the AH, AL concept for phosphinine ligands that have similar steric characteristics to NHC [119]. They call the two different angles the occupancy angles α and β, but the definitions are almost identical and they point out that the arithmetic average of α and β is very close to the Tolman cone angle Θ for tertiary phosphanes. Advantage: The two dimensions that are subject to steric influence by the NHC ligand are well separated. Disadvantage: The occupancy angles are dependent on the M-C bond length and thus different for different metal atoms.

p-Tol

p-Tol

N

N

N

N

N

N

:

p-Tol

p-Tol

Figure 1.26 Significant structural differences in a pair of NHC with the same % Vburr value.

The Nature of N-Heterocyclic Carbenes

27

The occupancy angle shares this disadvantage with other geometry-based ligand parameters such as the natural bite angle introduced for chelating bisphosphane ligands [125–127] and of course the % Vburr value. The reason lies in the definition of these parameters. They all depend to some degree on the bond length between the metal and the ligating atom. The longer this bond length, the smaller % Vburr and the smaller the occupancy angles α and β. Therefore, metal atoms with larger radius, like Mo, W and Ru, have a smaller % Vburr and occupancy angles for the same ligands than metals with a smaller radius, like Cu and Ni.

1.2.4 The Carbene-Metal Bond Two types of transition metal carbene compounds are traditionally referred to by the names of the scientists who first made them, namely E. O. Fischer [27] and R. R. Schrock [30]. The discovery of the first transition metal NHC complexes by Öfele [2] and Wanzlick [3] falls in between the other two, but did not receive the same amount of recognition at the time (see Figure 1.27). The structures and reactivities of Fischer and Schrock carbenes can be explained by interactions of singlet and triplet carbenes with suitable metal d orbitals without any stabilisation from neighbouring nitrogen atoms at the carbene carbon atoms [14,128–132]. In this model, Fischer carbenes can be described as resulting from a σ-donor interaction of the singlet carbene lone pair into the empty dz2 orbital of the metal. The metal than uses its full dxz orbital for a π-backdonation into the empty p orbital of the carbene carbon atom [129]. Characteristically, Fischer carbenes are found with low valent (late) transition metals and a carbene ligand where at least one of the two substituents carries a π-donor group [14,132], usually a heteroatom or phenyl substituent [131]. Typical representatives are 18-electron species like [Cr(CO)5{=C(OMe)Ph}] [130,131]. In contrast, Schrock carbenes are electron deficient [10 to 16 valence electrons (VE)] early transition metal complexes with the metal atom in a high oxidation state and carbene substituents that are limited to alkyl groups and hydrogen [131]. Their bonding situation can be described in terms of the interaction of a triplet carbene with a triplet metal fragment resulting in a covalent double bond [132]. Tantalum complexes like [(np)3Ta=CHBut] and [Cp2(Me)Ta=CH2] are representative of Schrock carbenes.

Mes EtO Ta

CH3 CH2

Ph

OC

N

CO

Au

Cr CO

OC

N

CO Mes

Schrock

Fischer

Wanzlick/Arduengo

Figure 1.27 Three different transition metal carbene complexes.

Cl

28

Functionalised N-Heterocyclic Carbene Complexes

Fischer carbenes possess electrophilic carbene carbon centres (they react with nucleophiles) whereas Schrock carbenes show opposite reactivity, and have nucleophilic carbene centres (that react with electrophiles) [14,131]. What then is the nature of the metal (M)-NHC bond? As NHC are internally stabilised by N→Ccarbeneπ-donations, a simple answer would be that they are pure σ-donors and π-backdonation from the transition metal is negligible. The dπ-pπ M→C backdonation would have to be delivered into an already (partially) filled p orbital at the carbene carbon atom. Indeed, for a relatively long time (in the short history of NHC transition metal complexes), Wanzlick (Arduengo) carbenes were considered to be pure σ-donor ligands [14,132], but more recently, a somewhat larger degree of metal→carbene π-backdonation [129] has begun to emerge. Today, it is widely accepted that metal→carbene π-backdonation can be responsible for up to 20–30% of total M→C bond strength in transition metal NHC complexes [73,132,133]. Note: NHC can engage in metal→carbene π-backbonding to some degree, but it is not necessary for the exceptional stability of the M-NHC bond. That this is so can be seen from the investigation of some beryllium NHC complexes [13,134] where the carbene was seen to replace bridging chloride ligands and coordinate to the Be2+ cation despite the lack of suitable electrons for π-backbonding on the beryllium atom. Corresponding to the low degree of metal→carbene π-backbonding in transition metal NHC complexes, the M-C bond in these compounds is very long and has to be regarded as a single bond [115] despite a π-backbonding degree of up to 20–30%. Occasionally, an additional π-donor bond from the carbene to the metal is discussed [104]. Such a bond is principally possible since NHC possess an occupied orbital of π-symmetry immediately below the sp2-hybridised HOMO lone pair. This would contribute to the great (σ/π) donor strength of the NHC ligands.

1.2.5 Decomposition Pathways Originally, it was believed that NHC behave strictly as donor spectator ligands [16,18] and do not react either with the substrate, the metal or any other substituent or ligand on the metal they are bonded to. However, it has been emerging for some years that NHC are not as straightforward a ligand class as many chemists wished to believe [22]. In 2001, McGuinness et al. showed transition metals (calculated for Pd) carrying a NHC ligand and an alkyl or aryl group cis to it can undergo concertive reductive elimination with the formation of C2-substituted imidazolium salts [21]. The reaction is exothermic (about – 4 kcal mol–1) and originates from a four coordinate palladium(II) complex where the C2-pπ orbital is perpendicular to the plane of the metal and thus correctly orientated to interact with the methyl (aryl) group and the dxy orbital of the metal. After formation of the C2-CR bond (R = alkyl, aryl) the imidazolium ring separates from the metal. Of course, the opposite has also been observed whereby an imidazolium salt oxidatively adds to a transition metal complex. [135,136]. This was first noticed in catalytic reactions involving transition metal phosphane complexes as catalysts and imidazolium based ionic liquids. Unexpected improvements in catalytic performance prompted investigations to find out whether the phosphane ligands had been replaced by more electron-rich NHC

The Nature of N-Heterocyclic Carbenes

29

[137]. In a theoretical and experimental study, McGuinness et al. described the oxidative addition of an imidalium cation to zerovalent d10 metals [23] and came to the conclusion that addition on chelated Pd(0) is favoured over linear [Pd(PR3)2] complexes and that C2-X (X = I, Br, I) activation on the imidazolium cation is much easier than C2-H and C2-Me activation with the methyl group beeing the least reactive. Disadvantage: Deactivation of catalyst due to concertive reductive elimination of the NHC ligand and the catalytically active alkyl or aryl group. Note: Carrying out the reaction in an imidazolium-based ionic liquid is believed to minimise the effect of reductive elimination as oxidative addition of the solvent is favoured instead [23]. A similar mechanism might operate in the activation of an azolium salt by a transition metal compound forming the metal carbene complex. However, since a basic substituent on the metal (acetate, alkoxide, hydride) usually reacts with the H2-proton, the proton is removed from the reaction as the conjugate acid and reductive elimination does not occur. In many catalytic reactions, a methyl or hydride substituent on the metal increases the reactivity of the catalytic system and thus the presence of such a substituent is normally highly desired. When this methyl or hydride group is cis to the NHC ligand or can move into the cis position relative to the NHC ligand during the course of the reaction, reductive elimination might occur in a facile manner [22]. Note: The presence of a positive charge on the metal facilitates reductive elimination. Note: Electron-rich ligands decrease the rate of reductive elimination. This is in line with the observation that neutral complexes are more stable than cationic ones. Note: Sterically bulky ligands accelerate reductive elimination. Not surprisingly, chelating carbene ligands show greater stability with regard to reductive elimination than monodentate carbene ligands [22]. However, even transition metal complexes with bis-carbene ligands can suffer degradation by reductive elimination (see Figure 1.28). Note: Chelating carbenes are significantly more stable towards reductive elimination than monodentate NHC. Note: It is possible to prepare stable cis-dimethyl compounds of nickel(II) and palladium(II) with chelating bis-NHC ligands [138,139]. This is an important observation, since functionalised carbenes usually possess a sidechain with a coordinating functional group. Thus, functionalisation normally introduces added stability to the catalyst. There are two possible mechanisms to this observed elimination, simple reductive elimination and a migratory insertion/decomplexation sequence [22]. Normally, a simple reductive elimination mechanism is observed [140], but occasionally a migratory

30

Functionalised N-Heterocyclic Carbene Complexes

N

N N

N

150 C

N

N Pd

Pd

Mes

N

N

Mes N

MeCN

Pd NCMe

N

DMSO

N

T C2H4/CO

N

N

N

N

N

DMSO

Pd

N R

R

Mes

N Mes

Figure 1.28 Reductive elimination and oxidative addition.

insertion/decomplexation sequence could be proven [141]. This migratory/decomplexation mechanism follows closely the process observed in CO/ethylene copolymerisation catalysis. This is hardly surprising, since NHC are isoelectronic to CO and isonitriles. A second, very important decomposition pathway involves the activation of C-H bonds on the N-alkyl [142–147] or N-aryl [148–151] sidechains. Occassionally, even C-C activation in the sidechain is observed [152]. Similar C-H activation is observed in transition metal phosphides, especially when the phosphorus ligand has a SMes substituent [153]. The activation of C-H bonds on the N-aryl substituents in transition metal NHC complexes was observed by Lappert et al. in 1979 when they reacted aryl substituted tetraaminoethylenes with the ruthenium complexes [RuCl2(PPh3)3], [RuCl(NO)(PPh3)2] and [RuCl3(NO)(PPh3)2] in xylene at 140 ˚C [149]. That elevated temperatures are not required for the activation of C-H bonds on N-aryl substituents in the case of ruthenium was shown by Enders et al. [151,154] when they reacted 2-phenyl-5R-triazolium perchlorate with [(η6-cymene)RuCl2]2 at ambient temperatures and observed ortho-metallation on the phenyl ring. A similar reaction was reported by Baratta et al. using trans,cis[RuHCl(PPh3)2(ampy)] and 1,3,4-triphenyl-4,5-dihydro-1H-1,2,4-triazol-5-ylidene [148] in refluxing toluene. Ruthenium not only activates C-H bonds in the N-sidechain of the NHC ligand, but also C-O [146], C-Cl [C12] and C-C bonds [152]. Reaction of [(η6-cymene)RuCl2]2 with

The Nature of N-Heterocyclic Carbenes

31

the functionalised imidazolium salts [MesICH2CH2X]Cl (X = Cl, OMe) results in the loss of the functional group X and formation of a RuCNCC-metallacycle [146]. Whereas activation of the C-Cl and C-O bonds were facile and could be achieved at ambient temperature, the activation of the C-C bond required a reaction time of 16 days in refluxing benzene (80 ˚C) [152]. In a very recent computational study, Diggle et al. have calculated the activation barriers for C(aryl)-X activation (X = H, F, OH, NH2, CH3) as 0 (H), 9 (F), 12 (OH), 20 (NH2) and 21.3 kcal mol–1 (CH3), respectively [155]. In comparison, the activation barrier for C(sp3)-H is 6.6 kcal mol–1 [156]. C-X activation occurs under reaction conditions relevant for homogenous catalysis [157], but does not always result in decomposition as C-H activation is often reversible and can be exploited in catalytic transfer hydrogenations involving alcohols [156]. Note: The possibility of C-X activation is extremely important, when functionalised NHC are used as ligands, especially with late transition metals. It is interesting to note that C-H activation on ruthenium NHC complexes is not limited to intramolecular protons located in the N-sidechain of the carbene, but occurs intermolecularly as well. Leitner et al. reacted [MesIRuH4PCy3] with toluene-d8 at ambient temperature and observed a rapid H/D exchange reaction involving the four hydride hydrogen atoms on ruthenium, the methyl protons of the mesityl substituents of the carbene ligand and the deuterium atoms on the meta positions of toluene-d8. The ortho-, para- and methyl-deuterium atoms of the solvent did not participate [145]. This C-H activation is not limited to ruthenium, but occurs frequently in corresponding iridium, rhodium, nickel, palladium and platinum complexes [147] and was recently reported for a ytterbium complex [144]. Nolan et al. have even reported double C-H activation in a rhodium(III) complex carrying two NHC ligands [142,143]. The starting material is a rhodium(I) species, [Rh(coe)2Cl]2 that undergoes mono or double C-H activation after reaction with IBut depending on reaction conditions. The double C-H activated, square pyramidal, 16 VE complex [Ru(I’But)2Cl] (I’But = IBut with one hydrogen missing) is obtained in benzene and can be transformed into the corresponding square planar, 14 VE complex [Ru(I’But)2]PF6 by chloride abstraction with AgPF6 in methylene chloride [142]. Note: Activation of C-H bonds in the N-sidechains of NHC ligands is a frequently occurring phenomenon. Note: Most instances of C-H, and C-X (X = C, O, Cl), activation have been observed with late transition metals, i.e. those frequently used in homogenous catalysis. An interesting observation was made by Morris et al. [158,159] who reported that the electron-rich system [Ru(IBut)(PPh3)2H] showed no inclination for intramolecular C-H activation. It seems that the same electronic preferences are working for reductive elimination and C-X activation. A third decomposition pathway is decomplexation. In principle, NHC ligands can dissociate from the metal complex, although the M-NHC bond is significantly stronger than the M-phosphane bond [116,160]. Well known examples for decomplexation of NHC ligands

32

Functionalised N-Heterocyclic Carbene Complexes

are a special family of second generation Grubbs’ catalysts first published by Weskamp et al. [161]. During the initiation period one of the two NHC ligands dissociates and thus activates the catalysts. An improvement in catalyst design was then introduced by the Grubbs group with a mixed IMes/PCy3 ruthenium catalyst for olefin metathesis whereby only the phosphane ligand dissociates [162] (see Figure 1.29). However, not all NHC ligands are equally stable as an example from the Grubbs group shows, whereby a triazolium substituted ruthenium catalysed decomposed yielding a bisphosphane ruthenium complex and a triazolium salt [163] even at room temperature. The first decomplexation reaction involving substitution of a ruthenium coordinated NHC ligand by trimethyl phosphite was reported by Lappert et al. [87] in the reaction between [Ru(SIMe)4Cl2] with trimethyl phosphite yielding [Ru(SIMe)4{P(OMe)3}2Cl2]. Displacement of a coordinated NHC ligand by phosphanes was also reported for rhodium complexes in the reaction between [Rh(IMes)(PPh3)2Cl] and PPh3 in dichloroethane [164] with subsequent alkylation of the carbene at C2 (see Figure 1.30). A similar reaction occurs with bis-diphenylphosphinoethane (dppe) as the phosphane in refluxing xylene [165].

Ph

Ph

T Cl

PCy3

Ru

initiation Cl

Cy3P

catalysis Cl

Ru

Cl

Cy3P

Cy

Ph

N

Cy Cy

Ru

N

T

N

catalysis

Cl

initiation Cy

Ru

N

N

Cy

Cl

T Ph

N

Ru Cl

Cl

Cy

Cy

N

Ph

N

Cl

initiation

Cl PCy3

Cy

Figure 1.29 The second generation Grubbs’ catalyst.

The Nature of N-Heterocyclic Carbenes

33

Ph N

N

Cl

N

Ph3P

Cl Rh

dppe PPh3

N N

N Cl N

Ph2P

N

Ru

Ph2P

Rh

PPh2 PPh2

N Ph

P(OEt)3

N

N

Cl P(OEt)3

N (EtO)3P

Ru N Cl N

Figure 1.30 Replacement of NHC ligands by phosphanes and phosphites.

The picture becomes even more complex when a series of [Pd(NHC)2] and [Pd(NHC)PR3] (R = Cy, tolyl) complexes [166] are considered. Reaction of [Pd(IBut)2] with PTol3 yields the mixed complex [Pd(IBut) PTol3] after dissociation of a carbene ligand even at ambient temperature. The more basic phosphine ligand PCy3 reacts even faster resulting in the monophosphane complex within 15 min at room temperature.

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The Nature of N-Heterocyclic Carbenes

37

140. D. S. McGuinness, M. J. Green, K. J. Cavell, B. W. Skelton, A. H. White, J. Organomet. Chem. 565 (1998) 165. 141. A. A. Danopoulos, N. Tsoureas, J. C. Green, M. B. Hursthouse, Chem. Commun. (2003) 756. 142. R. Dorta, E. D. Stevens, S. P. Nolan, J. Am. Chem. Soc. 126 (2004) 5054. 143. N. M. Scott, R. Dorta, E. D. Stevens, A. Correa, L. Cavallo, S. P. Nolan, J. Am. Chem. Soc. 127 (2005) 3516. 144. G. M. Ferrence, A. J. Arduengo III, A. Jokisch, H.-J. Kim, R. McDonald, J. Takats, J. Alloys Comp. 418 (2006) 184. 145. D. Giunta, M. Hölscher, C. W. Lehmann, R. Mynott, C. Wirtz, W. Leitner, Adv. Synth. Catal. 345 (2003) 1139. 146. R. Cariou, C. Fischmeister, L. Toupet, P. H. Dixneuf, Organometallics 25 (2006) 2126. 147. M. J. Chilvers, R. F. R. Jazzar, M. F. Mahon, M. K. Whittlesey, Adv. Synth. Catal. 345 (2003) 1111. 148. W. Baratta, J. Schütz, E. Herdtweck, W. A. Herrmann, P. Rigo, J. Organomet. Chem. 690 (2005) 5570. 149. P. B. Hitchcock, M. F. Lappert, P. L. Pye, S. Thomas, J. Chem. Soc., Dalton Trans. (1979) 1929. 150. G. T. S. Andavan, E. B. Bauer, C. S. Letko, T. K. Hollis, F. S. Tham, J. Organomet. Chem. 690 (2005) 5938. 151. D. Enders, H. Gielen, J. Organomet. Chem. 617–618 (2001) 70. 152. M. Prinz, M. Grosche, E. Herdtweck, W. A. Herrmann, Organometallics 19 (2000) 1692. 153. E. Hey-Hawkins, S. Kurz, J. Organomet. Chem. 479 (1994) 125. 154. D. Enders, H. Gielen, G. Raabe, J. Runsink, J. H. Teles, Chem. Ber. 130 (1997) 1253. 155. R. A. Diggle, A. A. Kennedy, S. A. McGregor, M. K. Whittlesey, Organometallics 27 (2008) 938. 156. R. A. Diggle, S. A. McGregor, M. K. Whittlesey, Organometallics 27 (2008) 617. 157. V. Dragutan, I. Dragutan, L. Delaude, A. Demonceau, Coord. Chem. Rev. 251 (2007) 765. 158. S. Burling, G. Kociok-Köhn, M. F. Mahon, M. K. Whittlesey, J. M. J. Williams, Organometallics 24 (2005) 5868. 159. K. Abdur-Rashid, T. Fedorkiw, A. J. Lough, R. H. Morris, Organometallics 23 (2004) 86. 160. W. A. Herrmann, M. Elison, J. Fischer, C. Köcher, G. R. J. Artus, Angew. Chem. Int. Ed. 34 (1995) 2371. 161. T. Weskamp, W. C. Schattenmann, M. Spiegler, W. A. Herrmann, Angew. Chem. Int. Ed. 37 (1998) 2490. 162. M. Scholl, T. M. Trnka, J. P. Morgan, R. H. Grubbs, Tetrahedron Lett. 40 (1999) 2247. 163. T. M. Trnka, J. P. Morgan, M. S. Sanford, T. E. Wilhelm, M. Scholl, T. Choi, S. Ding, M. W. Day, R. H. Grubbs, J. Am. Chem. Soc. 125 (2003) 2546. 164. D. Allen, C. M. Crudden, L. A. Calhoun, R. Wang, J. Organomet. Chem. 689 (2004) 3203. 165. M. J. Doyle, M. F. Lappert, P. L. Pye, P. Terreros, J. Chem. Soc., Dalton Trans. (1984) 2355. 166. L. R. Titcomb, S. Caddick, F. G. N. Cloke, D. J. Wilsona, D. McKerrecher, Chem. Commun. (2001) 1388.

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2 Why Functionalisation?

Having familiarised ourselves with the electronic and steric properties of NHC, we might well ask ourselves what purpose the functionalisation of this ligand class might serve and with this in mind, what functional groups will be useful? No general answer can be given for the multitude of potential purposes. However, as one of the main applications of NHC is as ligands for transition metal complexes in catalytic processes, it is not surprising that a main drive for functionalisation has been the development of bidentate ligands on the basis of functionalised carbenes. The success of monodentate carbenes in catalysis has its reasons in their superior electron donicity [1–5] compared with the phosphane ligands. Introducing a functional group into the carbene necessarily mitigates this advantage as the additional functional group will have a lower electron donicity than the carbene itself. The expected properties of the functional group will therefore have to compensate for this apparent disadvantage. However, if seen from another perspective, a decisive advantage can be envisaged. A known functionalised bidentate ligand can be upgraded by substitution of a donor group with a NHC moiety.

2.1 Phosphane Mimic Conceptionally, the carbene group is often seen as a phosphorus mimic [6,7] and has similar donor properties as phosphanes, although usually with a higher electron donicity. The development of functionalised carbene ligands closely follows that of functionalised phosphane ligands [8,9]. In many cases, successful P,N bidentate ligands are transformed into the corresponding C,N bidentate ligands [9–11]. Of course, the concept can be adapted for other donor atom combinations like C,C [12,13], C,P [8,14] or C,O [15–18] (see Figure 2.1). Thus, we see NHC ligands with pendant amino, amido, ether, aryloxy, alkoxy and cyclopentadienyl (Cp) functional groups, to name just a few (see Figure 2.2). In phosphane Functionalised N-Heterocyclic Carbene Complexes. Olaf Kühl © 2010 John Wiley & Sons, Ltd.

40

Functionalised N-Heterocyclic Carbene Complexes

PPh2 O

O N

Fe

OH

P

R'

PPh2 Ph2P

N

N

Phosphinophenol

R

R

Fe

R'

Pybox

Bu N

Pigiphos

O

:

N

N

OH

⫹

N

N O

Fe N

N

N

:

Ph2P

PPh2

BoxCarb

NHC analogue

Fe

Ph2P

NHC analogue

O N

PHOX

Ph

Figure 2.1 Some functionalised NHC and their phosphane (amine) analogues.

N

⫹

N N

N

Fe

N

N

⫹

O

Ph

N

⫹

N

N

⫹

O

N

N DIPP Ph

HN N

N

N

⫹

O

N

N

N Mes

⫹

⫹

N

N

⫹

Ph

Ph

HO N

O

HN

Et

Et

But Et

O

N

⫹

N

O

Et O

Ph

⫹

O

O

N

O

N

⫹

N ⫹

N

Ar PPh2 N N ⫹

N

N

⫹

O

Figure 2.2 Some functionalised imidazolium salts.

Why Functionalisation?

41

ligands, the sidechain functional group serves multiple purposes and these purposes are mirrored in carbene chemistry. Functional groups are introduced for hemilability, carriers of chirality, modification of bite angles, the establishment of a specific ligand geometry or simply to fine tune the electronic or steric properties of the ligand [19–25].

2.2 Hemilability The concept of hemilability calls for a ligand with at least two donor functions; one donor group binds strongly to the metal and the other only weakly [19]. The weak donor has the ability to leave the coordination sphere of the metal in the course of the (catalytic) reaction, thus creating a free coordination place for the substrate (see Figure 2.3). However, since the weak donor is tethered to the strong donor and therefore remains in the vicinity of the metal, it can recoordinate and stabilise the metal complex in the absence of substrate. The concept is often used for the precatalyst in catalytic reactions. This principle can be adapted for carbene ligands. In combination with a hard donor group like an amino or oxo group, the functional carbene becomes a hemilabile bidentate ligand. Whether the NHC moiety serves as the anchor or as the hemilabile end of the ligand depends on the metal it is intended to bind to (see Figure 2.4). The s-block and early transition metals are only loosely bound to the carbene end and need to be anchored to the hard functional group [27,28], whereas late transition metals and many p-block elements bind strongly to the carbene end meaning that the functional group will have to be designed as the hemilabile part of the ligand [29,30].

O Ph Ph

Ph P

⫹CO

OC Rh

P

Ph

⫺CO

P

Ph

Ph

OC Rh

Ph

O

Ph

P

Cl

CO

Cl O

O

N Ph

P

P Ni

Ph Ph

N

N Ph Ph

Ph Ph

Ph

Ph Ph

Ph N

Ph

Ph

N

P Ni P

P

Figure 2.3

P

P

N

O

Ph Ph

N

P Ph

N

O

Two transition metal complexes featuring hemilabile phosphane ligands [19,26].

42

Functionalised N-Heterocyclic Carbene Complexes But

But N(SiMe3)2

N Y

N(SiMe3)2 N

N(SiMe3)2

Ph3P=O

Ph

:

N

But

N

N(SiMe3)2

Y

But

O N

N

P Ph Ph

N H But

N

OH Ag

⫹

But

HO H N

N

Figure 2.4 Two transition metal complexes with hemilabile functionalised NHC ligands.

In the concept of hemilabile functionalised NHC ligands, typical anchor groups for hemilability at the carbene end are amides, alkoxides (aryloxides) and the Cp ligand family. In particular, the Cp functional group is an excellent anchor for early transition metals, whereas the amide and alkoxide functionalised carbenes are often used for lanthanide metals. Hemilability of the carbene moiety can be avoided, if a second anchor group is introduced. Examples include two pendant aryloxy [31] or amido groups [32,33] (see Figure 2.5).

Ph

Ph

But

But O

N

N

O

Ti

Cl But

N

N

N But

Ar

N

Zr Cl Cl

Ar

Figure 2.5 Weakly coordinated NHC ligands stabilised by anchoring aryloxide and alkylamide groups.

Why Functionalisation?

43

When the labilities are reversed, that is when the NHC group is used as the anchor, ligand design again orientates itself on the successful hemilabile bidentate phosphanes. Now, we encounter pendant ether [34,35], tertiary amino [36,37], pyrido [11,38–40], imino [41–44] and carbonyl groups [30,45] in the sidechain.

2.3 Chirality As we have seen in Chapter 1, it is very difficult to introduce chirality in the immediate vicinity of the carbene centre [23,24,46]. An elegant way to circumnavigate this is to introduce a functional group on the carbene that can act as the carrier of chirality in the metal complex (see Figure 2.6). Excellent examples are a Cp scaffold for planar chirality [47–49] or the binaphthyl group for axial chirality [50–52]. The tether itself can be used as the chiral backbone as is the case in functionalised carbenes derived from 1,2-diamino cyclohexane [53,54]. A good and usually inexpensive source for the introduction of chirality into a ligand is the exploitation of the so-called chiral pool. The easiest way of course is the utilisation of a chiral primary amine during the synthesis of the imidazole ring. One step further along that route, naturally occurring chiral building blocks like amines, amino acids, and carboxylic acids can introduce a functional group and an asymmetric centre with defined chirality into the carbene (see Figure 2.7).

2.3.1 Planar Chirality Planar chirality is usually associated with disubstituted aryl ligands coordinated to a metal atom [55] (see Figure 2.8). In this arrangement, the arene scaffold is fixed in space (by coordination to the metal atom) and the position of the two substituents on the arene ring

SiMe3 N

N

N

⫹

N

⫹

Mes

Fe

N

HO

N

⫹

⫹

N

N

Cy

Cy

Figure 2.6 NHC donors on standard chiral scaffolds.

R1 N R2

⫹

N

Ph

* ⫺

Ph N

⫹

N

R

N ⫹

N

COO

Figure 2.7

Introduction of chirality and functionality into the NHC ligand.

⫺

COO

44

Functionalised N-Heterocyclic Carbene Complexes

N

⫹

N Ru

N Fe

N

Cl

⫹

N

Cl

Fe

Ph

N

Ph

O

Figure 2.8 Planar chiral NHC ligands (complexes). The Ru complex is not actually chiral, but removal of either of the ortho-methyl groups would make it so.

relative to each other becomes distinguishable. An image and its mirror image evolves; the molecule becomes chiral. A popular planar chiral spectator group is the ferrocenyl (Fc) moiety that can be easily attached to other functional groups including a carbene [23,47,48]. Planar chirality on the basis of a metal coordinated benzene ring is likewise possible and was realised with ruthenium as the arene coordinated metal atom [56–58]. Another possibility is the use of [2,2]-paracyclophane as the planar chiral scaffold [59–61].

2.3.2 Axial Chirality Axial chirality can be introduced by various methods. In organic chemistry, axial chirality can occur when a carbon atom is simultaneously part of two double bonds like in the allene system. The same rules as in asymmetric carbon atoms apply, except that now the atom is drawn out into a R1R2C=C=CR3R4 axis, the allene system [62]. In practical terms, axial chirality often occurs when free rotation along an axis in the molecule is sufficiently hindered. A well known example is the binaphthyl system where free rotation around the common bond can be prevented by introducing bulky substituents in the 2,2’-positions. If these substituents are NHC, then an axial chiral bis-carbene results [50,51,63].

2.4 Ligand Geometry The geometry of the ligand or rather the substitution pattern the ligand establishes in the coordination sphere of the metal is of great importance for the reactivity of the resulting metal (catalyst) complex. Two classic ligand structures enforce a meridonal (mer) or facial (fac) coordination pattern on the metal, with significant consequences for possible applications. In modern NHC chemistry these two patterns are realised by two carbene entities substituted in the 2,6-position of a pyridine or in the 1,3-position of a benzene ring for the mer or pincer geometry and a tripod arrangement of three NHC moieties on a boron or an arene scaffold for the fac geometry, respectively (see Figure 2.9). Both ligand classes are modelled on long established ligands, the pincer ligands with amino, phosphane or ether sidechains on a pyridine or benzene base for the mer geometry [64–66] and the scorpionate ligands (tris-pyrazolylborates) for the fac geometry [67–69].

Why Functionalisation? N

H N N

⫹

N

N ⫹

N

N

⫹

N

⫺

N

But

⫹

N

B

45

N

⫹N

But

N ⫹

N

⫹

N But

pincer or mer

Figure 2.9

tripodal or fac

Imidazolium salts with mer or fac geometry.

The tris-carbene ligand family with fac geometry points its three wingtip groups downwards around the metal shielding it effectively from the approach of any but small substrates. Its main application is therefore the activation of small molecules, including the activation of dioxygen and proton coupled electron transfer (PCET), a reaction normally performed by certain enzymes [70,71].

2.5 Catalysis Soon after the first isolation of a stable carbene, homogenous catalysis became a major field of application for this new ligand class [72,73]. For some time, simple monodentate NHC like the archetypical IMes all but dominated the scene. This is hardly surprising as NHC were a new ligand class whose properties were investigated in virtually every catalytic reaction. When publications with these readily available carbenes began to proliferate, protocols for functionalised NHC were developed and these hybrid ligands were then used in catalysis. Early applications included coupling reactions like Heck [74], Sonogashira [75] and Suzuki–Miyaura [76–78]. As could be expected, early attempts were rather ordinary with respect to yields and turnover rates.

2.5.1 Allylic Alkylation Definition: A reaction whereby an alkyl group is transferred from an organometallic compound to an organic compound containing an (activated) allyl group. A typical reaction involves an in situ generated copper(I) catalyst with an NHC ligand and dialkylzinc [79–81] or EtMgBr [82] as the alkyl source (see Figure 2.10). A typical substrate is the prochiral cyclohexenone [83–85]. Chiral carbenes are therefore preferred and the introduction of an additional functionality (besides an element of chirality) on the carbene is not immediately obvious. Note: In contrast, functional groups with the potential to react with the alkylating agent would be disadvantageous to say the least.

46

Functionalised N-Heterocyclic Carbene Complexes

N

⫹

HO N Mes N

⫹

Ph O

N

⫹

N

N

Ph O

EtMgBr NHC/Cu(OTf)2

Figure 2.10

*

Allylic alkylation using copper complexes with functionalised NHC.

2.5.2 Coupling Reactions Catalytic coupling reactions and in particular Suzuki–Miyaura, Sonogashira and Heck reactions, have long been favourite applications for NHC ligands (see Figure 2.11). A simple explanation is that these aryl–aryl couplings have achiral products and thus standard achiral NHC are sufficient as a starting point. In addition, Wanzlick–Arduengo carbenes are very strong σ-donor and weak π-acceptor ligands providing electron-rich metal centres, indeed more electron rich than the customary phosphane complexes [7,86–88]. Some mechanistic aspects of these coupling reactions led to the advantages of additional functional groups on the carbene being investigated. Is it better to use cis-biscarbene complexes, trans-biscarbene complexes, monocarbene complexes or catalysts generated in situ? Oxidative addition (electron-rich metal centre) is considered to be the rate limiting step in the catalytic cycle with sterically demanding ligands helpful in product formation (reductive elimination). Would a sterically demanding, electron-rich ligand like a bulky carbene be the answer? Since Suzuki–Miyaura coupling reactions are easy to perform, functionalised carbenes have often been tested in this catalysis, but with mediocre to poor results [89–91]. In retrospect, this is easily understood, since the best results are obtained for bulky transbiscarbene complexes and functionalised NHC usually provide cis-chelate complexes [92]. However, the Suzuki–Miyaura reaction was used to evaluate the electronic properties of annulated carbenes [93,94].

2.5.3 Olefin Metathesis Olefin metathesis has been the success story for NHC in homogenous catalysis with the Nobel Prize being awarded in 2005 [95–97] for its part in the development of this benchmark reaction. Second generation Grubbs’ catalysts of course contain NHC instead of phosphane ligands (see Figure 2.12). Despite the award of the Nobel Prize, olefin metathesis is still one of the greatest challenges for the application of carbenes in homogenous catalysis: asymmetric olefin metathesis is still waiting for a major breakthrough.

Why Functionalisation?

47

R N Pd N

n

R

Br

R

R

N

Tol

N

Pd

Pd N

n

Tol

N

Ph

n

Br

R

R

HO

HO B

B

Br

HO

HO

Figure 2.11

Proposed mechanism for the Suzuki–Miyaura reaction.

DIPP Cy

Ph

N Ph

N Cl

Ru

PCy3 Cl

Cy3P

N

Ru Cl

Cl

But

Ph O O

PCy3 But

Cy 1st generation Grubbs

Figure 2.12

2nd generation Grubbs

Mo

Schrock

Some typical catalysts for the olefin metathesis reaction.

48

Functionalised N-Heterocyclic Carbene Complexes

Functionalised NHC could make a significant contribution towards achieving this breakthrough. Obviously, a chiral catalyst would be necessary and introducing a chiral NHC instead of the achiral one currently in use in second generation Grubbs’ catalysts does not require much imagination. However, it might be better to additionally anchor the carbene to the ruthenium atom using a pendant functional group on the carbene sidechain, for instance an OH group. This strategy has recently been employed by Hoveyda et al. [98,99]

2.5.4 Polymerisations α-Olefins can be polymerised or oligomerised using early or late transition metal catalysts. Of interest are the electron-rich, late transition metal catalysts with phosphane ligands rather than the electron-deficient, early transition metal Ziegler–Natta catalysts. Since NHC are excellent phosphane mimics, the use of functionalised carbenes as ligands in olefin polymerisation catalysts would be self evident. An excellent model reaction is the commercially used Shell Higher Olefin Process (SHOP), initially developed by Keim [100–102]. Here, enolisable ketophosphanes are used as ligands for nickel(II) catalysts (see Figure 2.13). A variant of this is the use of phosphino phenol ligands introduced by Heinicke [103–105].

2.5.5 Organocatalysis Definition: The term organocatalysis describes a catalytic reaction where the catalyst is an organic molecule. NHC can be used as organocatalysts in reactions where a nucleophile is needed as the catalyst (see Figure 2.14). The role of azolium salts such as imidazolium and thiazolium in benzoin and acyloin condensations was first recognised by Ukai et al. as early as 1943 [106–108]. Related reactions are the Stetter reaction [109] (see Figure 2.15), acylation and transesterification [106]. The mechanism for these reactions was proposed by Breslow in 1958 [110,111] involving a carbanion at C2 of the thiazole ring as a key intermediate. Today it is recognized that this ‘carbanion’ is better represented as the NHC generated from thiazolium by deprotonation [112]. The archetypical organocatalyst for these reactions is thiamin (vitamin B1) and the mechanism for the thiamin catalysed benzoin condensation recognising a carbene as the active catalyst is shown in Figure 2.15 [113].

Ph Ph N Ph O

N

Ni py

hP

NHC analogue

Figure 2.13

P

O

Ph

Ni Mes

Ph3P

Ph

SHOP-catalyst

The SHOP catalyst and its NHC analogue.

Why Functionalisation? O

PriO

⫺

O

⫹

[TiCl(OPri)3] N

N

N

N

N

O

⫹

OPri

Ti

KH N

OPri

O K

49

N

H

O

N

O

:

or

O

O⫺

N

O

N

O OH

O

O

O N

N ⫺

H

O⫺

N

O

⫹

O

O

N

O

O O

H

O

O

⫺

Figure 2.14 Organocatalytic ring-opening polymerisation of lactide with a hydroxyethyl functionalised NHC compound as catalyst.

R1 N

R2

H

⫹

S R3 -H

Ph

⫹

O *

R1

OH

Ph

N

R2

: R1 O N

R2

S

⫺

PhCHO,H

Ph

R1 H N

R2

⫹

OH ⫹

OH

S R3

⫹

R3

S

Ph R3 R1

PhCHO

Ph N

R2

OH S R3

Figure 2.15 Proposed mechanism for the Stetter reaction.

Ph

50

Functionalised N-Heterocyclic Carbene Complexes

Recently, the asymmetric variants of the Stetter [114–118], crossed-benzoin [114, 117–120], and transesterification [121] reactions have attracted great interest as asymmetric nucleophilic acylation processes. A prerequisite for asymmetric catalysis is the availability of a chiral catalyst. Introduction of chirality into the thiamin framework follows the same principles as that for the related imidazolium systems, mainly the introduction of a chiral centre next to the nitrogen atom of the thiazole ring [117].

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69. S. Trofimenko, Chem. Rev. 93 (1993) 943. 70. R. E. Cowley, R. P. Bontchev, J. Sorrell, O. Sarracino, Y. Feng, H. Wang, J. M. Smith, J. Am. Chem. Soc. 129 (2007) 2424. 71. L. Nieto, F. Ding, R. P. Bontchev, H. Wang, J. M. Smith, J. Am. Chem. Soc. 130 (2008) 2716. 72. W. A. Herrmann, Angew. Chem. 114 (2002) 1342. 73. W. A. Herrmann, C. Köcher, Angew. Chem. 109 (1997) 2256. 74. M. Oestreich (Ed.), The Mizoroki-Heck Reaction, John Wiley & Sons, Ltd, Chichester, 2009. 75. K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 16 (1975) 4467. 76. N. Miyaura, K. Yamada, A. Suzuki, Tetrahedron Lett. 20 (1979) 3437. 77. N. Miyaura, A. Suzuki, J. Chem. Soc., Chem. Commun. (1979) 866. 78. N. Miyaura, A. Suzuki, Chem. Rev. 95 (1995) 2457. 79. K.-S. Lee, K. Brown, A. W. Hird, A. H. Hoveyda, J. Am. Chem. Soc. 128 (2006) 7182. 80. A. O. Larsen, W. Leu, C. N. Oberhuber, J. E. Campbell, A. H. Hoveyda, J. Am. Chem. Soc. 126 (2004) 11130. 81. Y. Lee, K. Akiyama, D. G. Gillingham, M. K. Brown, A. H. Hoveyda, J. Am. Chem. Soc. 130 (2008) 446. 82. B. E. Ketz, X. G. Ottenwaelder, R. M. Waymouth, Chem. Commun. (2005) 5693. 83. H. Clavier, L. Coutable, L. Toupet, J.-C. Guillemin, M. Mauduit, J. Organomet. Chem. 690 (2005) 5237. 84. H. Clavier, L. Coutable, J.-C. Guillemin, M. Mauduit, Tetrahedron: Asymmetry 16 (2005) 921. 85. D. Martin, S. Kehrli, M. D. Augustin, H. Clavier, M. Mauduit, A. Alexakis, J. Am. Chem. Soc. 128 (2006) 8416. 86. D. G. Gusev, Organometallics 28 (2009) 763. 87. R. A. Kelly III, H. Clavier, S. Giudice, N. M. Scott, E. D. Stevens, J. Bordner, I. Samardjiev, C. D. Hoff, L. Cavallo, S. P. Nolan, Organometallics 27 (2008) 202. 88. T. Weskamp, V. P. W. Böhm, W. A. Herrmann, J. Organomet. Chem. 600 (2000) 12. 89. C.-Y. Liao, K.-T. Chan, Y.-C. Chang, C.-Y. Chen, C.-Y. Tu, C.-H. Hu, H. M. Lee, Organometallics 26 (2007) 5826. 90. C.-Y. Liao, K.-T. Chan, J.-Y. Zeng, C.-H. Hu, C.-Y. Tu, H. M. Lee, Organometallics 26 (2007) 1692. 91. M. K. Samantaray, V. Katiyar, K. Pang, H. Nanavati, P. Ghosh, J. Organomet. Chem. 692 (2007) 1672. 92. O. Kühl, Chem. Soc. Rev. 36 (2007) 592. 93. M. G. Organ, S. Avola, I. Dubovyk, N. Hadei, A. S. B. Kantchev, C. J. O’Brien, C. Valente, Chem. Eur. J. 12 (2006) 4749. 94. C. J. O’Brien, E. A. B. Kantchev, C. Valente, N. Hadei, G. A. Chass, A. Lough, A. C. Hopkinson, M. G. Organ, Chem. Eur. J. 12 (2006) 4743. 95. R. R. Schrock, Angew. Chem. 118 (2006) 3832. 96. R. H. Grubbs, Angew. Chem. 118 (2006) 3845. 97. Y. Chauvin, Angew. Chem. 118 (2006) 3824. 98. A. H. Hoveyda, A. R. Zhugralin, Nature 450 (2007) 243. 99. J. J. Van Veldhuizen, S. B. Garber, J. S. Kingsbury, A. H. Hoveyda, J. Am. Chem. Soc. 124 (2002) 4954. 100. R. Bauer, H. Chung, P. Glockner, W. Keim, H. Zwet, US Patent No. 3 635 937, 1972. 101. J. Heinicke, M. Köhler, N. Peulecke, W. Keim, P. G. Jones, Z. Anorg. Alg. Chem. 630 (2004) 1181. 102. W. Keim, Angew. Chem. 102 (1990) 251. 103. J. Heinicke, E. Musina, N. Peulecke, A. A. Karasik, M. K. Kindermann, A. B. Dobrynin, I. A. Litvinov, Z. Anorg. Alg. Chem. 633 (2007) 1995. 104. J. Heinicke, N. Peulecke, M. Köhler, M. Z. He, W. Keim, J. Organomet. Chem. 690 (2005) 2449.

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53

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3 N-Heterocyclic Carbenes with Neutral Tethers

In this chapter, we will look at NHC with neutral donor atoms in the sidechain. Most examples deal with nitrogen-containing functional groups, oxygen-containing functional groups with phosphanes coming next. When we consider a second or even third carbene as the functional group, we arrive at the bis- and tris-carbene ligands. A section will deal with pincer carbenes, where the carbene is either flanked by two pyridyl groups (N-C-N pincer) or the central pyridine is flanked by two carbene units (C-N-C pincer).

3.1 Amine Functionalities There are three main groups of neutral nitrogen functionalised NHC, those with aromatic amines in the sidechain, those with oxazolines and those that contain imine groups (see Figure 3.1). Most of the substituents bearing amine functionalities are covered in Chapter 4, which discusses NHC with anionic tethers that are usually deprotonated in the course of carbene formation or ligating to a metal. It is probably not surprising that most NHC bearing a nitrogen heteroaromatic functional group are actually pyridyl functionalised NHC. The second most popular group are oxazoline functionalised ones due to the excellent ligating properties of oxazolines and the ease with which chirality can be introduced into oxazolines – actually in closer proximity to the metal atom than is possible with NHC themselves.

3.1.1 Heteroaromatic Functional Groups Pyridine functionalised NHC are reminiscent of the pybox family of ligands [1], the pyridine bis-oxazolines, pyridine functionalised phosphanes [2–4] or even the bipy, bipyridyl, Functionalised N-Heterocyclic Carbene Complexes. Olaf Kühl © 2010 John Wiley & Sons, Ltd.

56

Functionalised N-Heterocyclic Carbene Complexes R N

: N

N

N

N

:

:

N N N

N R

R

N

N O

N

:

R

N

N

N R'

N

R

Figure 3.1 Amine functionalised N-heterocyclic amines.

PPh2

O

O N

R'

N

N

N

R

R

R'

py.phosphane

pybox

N

N

bipy

Figure 3.2 Some chelate ligands with amine functional groups.

ligands [5–7] (see Figure 3.2). A distinguishing feature of the py-NHC ligands is the ease with which their silver(I) complexes can be formed [8–11] and even more the ability to use these silver(I) carbene complexes as carbene transfer agents. With additional (N)-donor groups in place and keeping in mind the preference of silver(I) to coordinate to amines [12],

N-Heterocyclic Carbenes with Neutral Tethers

57

a great range of structural motifs emerged from these pyridine functionalised carbenes that ultimately developed applications of their own. The combination of carbene based chelate ligands and closed shell cations like silver(I) and gold(I) with a natural tendency to form d10-d10 intermetallic interactions, termed argentophilicity [13,14] and aurophilicity, respectively, led to transition metal carbene complexes of the group 11 metals with polymeric structures and interesting optical properties [15–19]. A combination of silver(I) and gold(I) [15], which are of the same size [20], produces a dipolar d10-d10 intermetallic interaction due to the difference in electronegativity of the two metals [20] that often leads to a shorter metal–metal separation than observed for homonuclear systems [21,22]. Reaction of a monopyridyl functionalised imidazolium salt with AgBF4 in the presence of a base (NaOH), a variant of the Ag2O method since Ag2O is usually synthesised from AgNO3 and NaOH, yields a silver(I) bis-carbene complex with two pendant pyridyl functional groups [15] (see Figure 3.3). Carbene transfer to gold(I) and subsequent addition of another equivalent of AgBF4 yields first the gold(I) and then the mixed Au(I)/Ag(I) dinuclear complex. Note: Gold(I) apparently prefers the carbenes whereas silver(I) is content with the pyridine ligands. Obviously, addition of further AgBF4 to the mono-silver complex activates coordination to pyridine and formation of the dinuclear silver(I) complex. However, the dinuclear complex is in equilibrium with a trinuclear, triangular complex (see Figure 3.4).

N

N N

AgBF4/NaOH

Au(tht)Cl

N

N

N

N

Ag

N

N

N

N

N Au

N

N

N

AgBF4

N

N

Au N

N Ag

N

N

Figure 3.3 Synthesis of a transition metal carbene complex with Ag–Au interactions.

58

Functionalised N-Heterocyclic Carbene Complexes

N

N

N

N

N

N 3

Ag

Ag

Ag

N 2

N

Ag

N N

N

Ag

N

N N N

Figure 3.4 Equilibrium between the dinuclear and the trinuclear silver(I) carbene complex.

Note: The trinuclear complex contains coordination places on silver that are presently occupied by acetonitrile solvent molecules. These are available for the coordination of a second pendant pyridyl group. Introduction of a second pendant pyridyl group on the carbene ligand makes two things possible: a solvent free trinuclear complex [17] and the complexation of the two pyridyl groups of the same carbene ligand by a silver(I) cation leaving the carbene functionality vacant to act as a monodentate carbene ligand [16]. The synthesis follows the same protocols as for the monopyridyl functionalised carbenes (see Figure 3.5). As we have seen previously, there is a subtle equilibrium between the trinuclear Ag3 and the dinuclear Ag2 complex whereas this equilibrium was not observed in the mixed dinuclear AuAg complex. Similarily, the mixed trinuclear AuAg2 complex apparently exists only in the open form shown in Figure 3.5 and not in the triangular form shown in Figure 3.4 [16]. When the stoichiometry is changed, i.e. only 1 equiv. of AgBF4 is used instead of 2 equiv., a polymeric chain like structure is obtained instead of the monomeric trinuclear one [16,23,24]. The chain is formed by bridging pyridyl substituents and d10-d10 intermetallic interactions between Au and Ag cations. Interestingly, only one of the two pyridyl substituents of a given carbene coordinated to silver with the missing coordination site on silver occupied by an acetonitrile solvent molecule (see Figure 3.6). Note: Not only the stoichiometry is changed, but also the linker between imidazole and pyridine is shortened (down to zero). It is maybe not surprising that when the second pyridyl substituent is omitted, the polymeric chain-like structure is preserved [18,19]. However, we may remember that the same reaction, with the same stoichiometry, but with the methylene-linker in place yielded discrete dinuclear and trinuclear molecules [15] (see Figures 3.3 and 3.4). Note: The main application of these polymeric chain-like mixed Ag/Au functionalised carbene complexes uses their luminescent behaviour.

N-Heterocyclic Carbenes with Neutral Tethers

N

N

N

N N N

N

N

N

N

N

N

AgBF4

Ag

NaOH

N

Ag

N

0.5 Ag2O

N

N

Ag

Ag

N

N

N

N N

59

N

N

N

Au(tht)Cl

MeCN N

N N

N

N N

2 AgBF4

Au N

N N

N

N

N

Ag

N Au

N

N

Ag

N NCMe

Figure 3.5 Synthesis of silver(I) carbene complexes using carbene ligands with two pendant pyridyl groups.

N N

N

N ⴙ

N Au

Ag MeCN

N N

N

N

N

N AgBF4

N

N

ⴙ

ⴙ

N

N

Py NCMe

ⴙ

Au

ⴙ

Ag MeCN

Py N

N

N

ⴙ

Au

Ag

N N

N

N

N N

Figure 3.6 The polymeric chain-like structure of a mixed Ag/Au functionalised carbene complex.

A rather interesting phenomenon occurs when pyridine functionalised imidazolium iodide is used to generate the silver(I) complex using the Ag2O method. In this case, Wang et al. isolated a trinuclear silver complex consisting of three bis-carbene silver(I) units bonded to the same central iodide anion (see Figure 3.7) where the pyridyl substituents remain pendant [25]. The corresponding copper(I) adduct of pyridine functionalised carbene carrying only one pendant functional group shows interesting structural dependencies on the size of the wingtip group, the tether length and even the solvent used for crystallisation [26] (see

60

Functionalised N-Heterocyclic Carbene Complexes Py

Py

N

N

N

N

Ag

N

I N

N

Ag

Ag

N

Py

Py N Py

N N

N Py

I2

Figure 3.7 A trinuclear silver(I) carbene complex with C3-symmetry and noncoordinating pyridyl groups.

Figure 3.8). The DIPP wingtip group is evidently too bulky or the tether too short to allow more than a monomeric structure, whereas with a Mes substituent, the molecule has a choice between a dimeric structure with Cu-Cu interactions (CH2Cl2/ether) and a polymeric chain structure (CDCl3). The coordination geometry of silver and gold complexes is often linear. When we go to group 10 metal complexes, however, we would expect square planar (Ni, Pd, Pt) or tetrahedral (Ni) geometries [20]. This is indeed the case. Reacting a palladium(II) salt with one equivalent of a monopyridyl functionalised NHC results in the expected palladium carbene complex with a chelating pyridyl carbene ligand [27,28] (see Figure 3.9). Abstraction of the halide with silver(I) triflate yields an unexpected tetrameric metallacycle. In the metallacycle, the carbene and pyridine ligands are mutually trans leaving the methyl and triflate groups equally trans to each other. In order to adopt this configuration around palladium, the chelating ligand not only has to decoordinate, presumably with the pyridine as the leaving group, but the methyl or triflate (bromide) ligand ends up in a different position as well. It is difficult to reconcile this mechanistically, but one way of doing it would be the abstraction of bromide by silver, coordination of triflate, cleavage of pyridine and subsequent coordination of the pyridine on a different palladium atom, in between the methyl and triflate ligands. Of course, other sequences are possible. Note: In the absence of base, no carbene forms and the ligand coordinates with the pyridine end only leaving the imidazolium end pendant If a palladium(II) allyl complex is used as the palladium precursor, there is no electronic need for the pyridine ligand to coordinate to the metal [29]. It therefore remains pendant and the pyridyl functionalised NHC ligand coordinates in monodentate fashion with its carbene

N-Heterocyclic Carbenes with Neutral Tethers

N

N Cu Br

N

61

Br

N

Cu N

N

N

N

N

N

Cu

N DIPP

N

Br

DIPP CH2Cl2/Et2O

Cu2O

N

N

N

CDCl3

N

N Mes

N Mes

Cu N

Br

N

N Mes Cu N

Br

N

N Mes Cu

Br

Figure 3.8 Structures of pyridyl functionalised NHC copper(I) complexes, dependent on the wingtip group. Br Pd

N

DIPP N

DIPP

N

N

N

N

PdCl3 F3C But

Pd N

Pd But

N

Me

O

Br 4

O

O

N

N N

AgO2CCF3

F3C

O

Pd

N Me

N N

But

N

N

But

Me N

Pd

O

CF3

N O

Me N

N

Pd N

O O

But CF3

Figure 3.9 Structures of palladium(II) pyridyl functionalised carbene complexes.

62

Functionalised N-Heterocyclic Carbene Complexes

end only. Only after abstraction of the chloride ligand with AgBF4 does the pyridine end coordinate to palladium forming a cationic chelate complex [30–32]. The pyridine end can be substituted by a comparatively weak phosphane ligand, PPh3 (see Figure 3.10). It is possible to introduce chirality into the carbene backbone. An interesting approach comes from Michon et al. [33] who synthesised a bis-quinoline substituted chiral imidazolidin-2-ylidine using enantiomerically pure (1R,2R)-diaminocyclohexane and (1R,2R)diphenylethylenediamine as starting materials (see Figure 3.11). The ligands were then utilised to generate the copper(I) carbene and the palladium(II) amido complexes, respectively. Of course, the heteroaromatic sidegroup is usually not strong enough as a donor ligand to replace chloride from a palladium(II) centre [31,34]. Coordination of the sidearm can be achieved by silver halide abstraction using a suitable silver salt [31], using a silver carbene complex as the silver source [31,34,35] or reacting the imidazolium salt directly with [Pd(OAc)2] [36] and therefore in the absence of halide (PF6- was used as the imidazolium counterion). Reacting 2 equiv. of the silver complex of the functionalised carbene with [Ni(PPh3)2Cl2] yields the bis-carbene nickel(II) complex with the two carbenes and pyridines in cis-position and thus pyridine and carbene trans to each other [37]. There are no free coordination sites available and the chloride anions are uncoordinated (see Figure 3.12). However, under catalytic conditions, the pyridyl unit can be expected to be hemilabile [38]. In this case, the pyridine end dissociates but does not leave the vicinity of the metal since it is tethered to the metal-coordinated carbene end. The metal complex can now use the free coordination site for (catalytic) reactions and subsequently, the pyridine end coordinates again to the metal stabilising the catalyst. The authors used this system in the Mes

Mes

Mes

N

N Ag-AgI2

[Pd(allyl)Cl]2 N

N

AgBF4

Pd Cl

N Pd

N Mes

N

N

N Mes

Mes PPh3

Mes N Pd N

PPh3 N Mes

Figure 3.10 Synthesis and behaviour of a palladium(II) pyridyl functionalised carbene allyl complex.

N-Heterocyclic Carbenes with Neutral Tethers R

R

R

Br

H2N

N

NH2

R

NH

[Pd]

HN

N

N

HC(OEt)3

[Pd(OAc)2]

R

N

N

N

R

Ph

N

N

Ph

N Pd

KOBut N

Cu

CuI

N

63

N

N

N

N

I

Figure 3.11 Copper(I) and palladium(II) complexes of quinoline functionalised carbene ligands. Mes

Mes

N Br

Mes

N

Ag N

Br

2

N

Ag N

Mes

Br

N

N

Mes

N

N

N Ni

[Ni(dme)Br2]

Br

Ni

N

N

N N

N

Mes N

2

Ag N

Br

N

N

N N

[Ni(PPh3)2Cl2]

Ni

N

N N

Figure 3.12 Synthesis of nickel(II) pyridyl functionalised carbene complexes.

polymerisation of norbornene and ethylene using methylaluminoxane (MAO) as cocatalyst, presumably to create a Ni-methyl bond as the starting point for the catalytic reaction. Activity for norbornene was reported as high and that for ethylene as moderate. Reaction of only 1 equiv. of ligand of course yields a neutral chelate complex with two halide ligands on the metal centre [39]. Note: Introduction of a bulkier wingtip group (Mes for methyl) does not change the overall structure of the complex or its composition.

64

Functionalised N-Heterocyclic Carbene Complexes

Note: The chelate effect is strong enough to exclude all other ligands (PPh3, Cl and Br as well as the usually weak ether ligand). Using rhodium(I) and iridium(I) precursor complexes [40,41] should result in pyridine functionalised carbene complexes similar to those from the isoelectronic [29] palladium(II) and nickel(II) complexes. This can be seen in a recent publication by Wang et al. [42] where a pyridine functionalised imidazolium salt is transformed into the silver carbene complex and subsequently reacted with [Ir(cod)Cl]2 to form the corresponding iridium(I) carbene complex with a pendant pyridyl group that coordinates to the iridium centre only after chloride abstraction with AgBF4 to form the cationic complex (see Figure 3.13). However, the group 9 metals have the ability to form octahedral complexes when in the +3 oxidation state. In that case the structural difference appears to be that the metal(III) bis-carbene complexes have additional axial halide ligands compared with the square planar metal(I) bis-carbene complexes (see Figure 3.14). Not surprisingly, these rhodium and iridium carbene complexes were tested for their catalytic behaviour in the transfer hydrogenation of benzophenone and acetophenone (M +3), the hydrosilylation of alkynes (M +1) and also the catalytic cyclisation of acetylenic carboxylic acids (M +1). Hydrogenation works better for iridium than rhodium and for aromatic than for aliphatic ketones [40,43,44]. The iridium(I) complex is the first iridium catalyst showing activity for the cyclisation of acetylenic carboxylic acids [40]. The results for the hydrosilylation reactions were very moderate. Introduction of a bulky pyridyl ligand again results in a reduced ligating ability of the pyridine functionality [41], which this time could be visualised using the rhodium(I) cod complexes instead of the palladium allyl ones (see Figure 3.5). From Figure 3.15 it is clear that the bulky, ortho-Mes substituted, pyridine donor cannot displace an anionic ligand (chloride, azide) from the coordination sphere of the rhodium(I) centre. Likewise, the bulky pyridine donor is displaced by triphenyl phosphane, whereas the

Mes

Mes

N

N

N

N

AgBF4 Ir

N

N

[Ir(cod)Cl]2

Mes

N Ir

Ag

N

N

Cl

I 2

CO

N

N

Mes

Ir N

OC

CO

Figure 3.13 Synthesis and structure of iridium(I) carbene complexes featuring pyridine functionalised NHC ligands.

N-Heterocyclic Carbenes with Neutral Tethers

65

N 0.5 [M(cod)Cl]2

M N N N

N But

Ag2O N But

But N

Cl

M Rh, Ir

N

N

0.25 [M(coe)2Cl]2 M N

N Cl N But

Figure 3.14 Synthesis of rhodium and iridium pyridyl functionalised carbene complexes.

N

N

Mes Ag-AgI2

N [Rh(cod)Cl]2

2

But

Mes N Cl

Mes

AgBF4

Rh

N

N N

Rh

N

But

N NaN3

But P(OMe)3

PPh3

Mes

CO

N N3 Rh N

Mes Mes N

N

But

Ph3P

Mes Rh

N

N N

N But

Rh

CO CO

N

N (MeO)3P

Rh

P(OMe)3 N

But

P(OMe)3

N But

Figure 3.15 The coordination behaviour of a bulky pyridyl functionalised carbene ligand in the coordination sphere of rhodium(I).

66

Functionalised N-Heterocyclic Carbene Complexes

small carbonyl ligand displaces the weakly bound cod ligand instead. Triphenyl phosphite was seen to displace both the pyridine and the olefin donor groups. If the Cp is introduced as an additional spectator ligand on iridium, pseudo octahedral complexes [29] are formed where the Cp ligands can be said to occupy three coordination sites on iridium contributing three lone pairs (anionic electron count) in three donor bonds towards the metal. In this description, the iridium centre has still three vacant coordination sites to complete the octahedron. All three additional ligands need to be trans to the facially binding Cp ligand. Examples are provided by Peng et al. [45] (see Figure 3.16) and Gnanamgari et al. [46] (see Figure 3.17). Mes N Mes

N

Mes Cl

Ag2O

Ir

N

Cl

CDCl3

Ir

N

Cl

N

[Cp*IrCl2]2 N

N

N N

KPF6

Figure 3.16 Synthesis and structure of an iridium(III) carbene complex featuring a pyrimidine functionalised NHC ligand.

N

Bun N

Bun

N

Ag2O

N

N

Ru

Cl

[Ru(p-cumene)Cl2]2

N N

N

Mes N

Mes

Ag2O N

N

Cl [Cp*IrCl2]2

N

Ir

N

N

N N

Figure 3.17 Synthesis and structure of iridium(III) and ruthenium(II) carbene complexes featuring a pyrimidine functionalised NHC ligand.

N-Heterocyclic Carbenes with Neutral Tethers

67

Note: The iridium(III) and the ruthenium(II) complexes in Figure 3.17 are isoelectronic and almost isostructural (within the limit of a five-membered versus a six-membered aromatic ring system as the spectator ligand). An interesting example for abnormal coordination [47,48] is observed in an iridium(II) complex reported by Faller and coworkers [49,50]. The complex is formed in the reaction of a pyridyl functionalised imidazolium salt with a metal hydride, [IrH5(PPh3)2], a seven coordinate iridium(V) hydride complex (see Figure 3.18). The authors claimed that the abnormal coordination is favoured because of the steric strain at the metal centre of the chelate complex [50]. The chelate ligand bite angle [51–53] in the iridium(III) carbene complex is reported to be 89.3(2)˚ [49] compared with 84.5(1)˚ and 87.2(1)˚ in Liu’s rhodium(I) complexes [41] and 85.0(3)˚ and 86.2(3)˚ in Peris’ rhodium(II) complexes [40]. Using monodentate ligands, the corresponding angle widens to 97.4(3)˚ [50]. Note: The chelate carbene complex with normal carbene coordination (C 2) has a smaller bite angle and is therefore more strained than the chelate carbene complex with abnormal carbene coordination (C 4) Note: The chelate carbene complexes with normal carbene coordination (C 2) do exist. They have even bulkier wingtip groups (tert-butyl instead of isopropyl) and a more crowded equatorial plane since the abnormally coordinated (C 4) carbene chelate ligands are ‘faced’ with sterically uniquely undemanding hydride ligands. Four years after Gründemann et al.’s original observation [49], Peris and coworkers [40] proved that steric strain is not the decisive factor in the abnormal coordination of the carbene in these particular iridium(III) hydride complexes. We may well suspect that differences in X

N N

X

N

H

Ir

N

Ph3P

N R

R

H

Ir

PPh3

PPh3

H R

N

Ph3P

2 H2

N

X

N [IrH5(PPh3)2]

H N

a

b

R

X

% a

b

Me

Br

91

9

Me

BF4

45

55

Pri

Br

84

16

Pri

BF4

0

100

Figure 3.18 Normal versus abnormal coordination in the iridium(III) hydride complex of a pyridyl functionalised carbene ligand.

68

Functionalised N-Heterocyclic Carbene Complexes

oxidation states (+5 compared with +1 and +3) and especially the reaction pathway will contribute significantly. It needs to be remembered that both Peris [40] and Liu [41] first generate the normally coordinated silver complex and transfer the ‘normal’ carbene to the group 9 metal, whereas Gründemann et al. generated the ‘abnormal’ carbene in the coordination sphere of iridium from the imidazolium salt and under abstraction of 2 mol of hydrogen (acid/base and redox reaction). However, the steric demand of the wingtip group does have an influence upon the distribution between normal and abnormal coordination in the product [54]; the bulkier the wingtip group, the more abnormal coordination is observed in the product. These iridium(III) hydride complexes are rare examples of transition metal carbene complexes where the pyridine functionalised carbene ligand coordinates in an abnormal fashion. The corresponding group 8 complexes synthesised by Kaufhold et al. [55] and Yi it et al. [56] have the familiar normal coordination mode. There is a rich variety of synthetic routes in their generation (see Figure 3.19). Yi it et al. [56] start from the electron-rich olefins and react those with a suitable ruthenium(II) precursor following a protocol originally introduced by Lappert et al. [57–59]. Kaufhold et al. react the imidazolium salt directly with ruthenium(III) chloride. The reducing agent is probably the solvent ethylene glycol. Interestingly, when a sterically undemanding wingtip group like methyl is used, the product is the tris-carbene complex [60]. Reaction of the free carbene with [Ru(p-cymene)Cl2]2 was not successful. In the case of iron(II), however, synthesis N

N

N

N

N

Cl

N

[Ru(C6Me6)Cl2]2

Ru

N

N

N

N

N

N

Cl

N RuCl3

N

N

N

N

C

C

Ru

N X

C

X N

N

Ru

C N

N C

[Fe(PPh3)2Cl2] N N

:

N

N

Fe

NCMe NCMe

N C

N

Figure 3.19 Synthesis of ruthenium and iron pyridyl functionalised carbene complexes.

N-Heterocyclic Carbenes with Neutral Tethers

69

was achieved by the reaction of the free carbene with [Fe(PPh3)2Cl2] [55]. In both cases, the reaction was accompanied by an anion exchange reaction. Mas-Marzá et al. synthesised a very interesting ligand featuring two carbene and one pyridine donor groups anchored to the same CH backbone unit [61] in an attempt to create a new hemilabile tridentate ligand with fac geometry. Unfortunately, the pyridine group either does not coordinate at all (in the presence of strongly coordinating donor solvents like DMSO) or in a [2+1] bridging mode (in the presence of weakly coordinating solvents like acetonitrile). What happens when the structural motifs of a NHC and a pyridine donor ligand are combined to form tridentate or tetradentate ligands, either in catena or in cyclic form? The answer can be seen in Figure 3.20, where we see a pincer complex, a saddle shaped complex from the cyclic ligand and a helical complex formed by the tetradentate catena ligand, respectively. The nickel and palladium complexes of the catena ligand were synthesised by Chiu et al. [62], whereas the cyclophane structure of the silver(I) complex was reported by Garrison et al. [63] to be a dimer. The two silver(I) cations coordinate to two carbene donors only, one from each cyclophane. Changing one of the pyridine rings for an aliphatic carbon bridge does not change the structural motif [64], as can be expected since the missing pyridine donor did not participate in the coordination. The same structural motif was retained even in a pincer type ligand architecture [65]. When one of the pyridine donors of the cyclophane ligand is replaced by a sterically demanding N-methylpyrrole unit (the methyl substituent would point into the cavity), a complex consisting of two ligands and four silver(I) cations is formed, in which the silver(I) cation coordinates to two carbene and one pyridine donors [66]. These cyclophane ligands – featuring two carbene and two pyridine donor groups – do act as tetradentate ligands towards transition metals. Baker et al. [67] reported the respective nickel(II) complex after reaction of the free ligand (bis-imidazolium salt) with nickel(II) bromide in the presence of sodium acetate as base. An even more interesting question arises with pyridine functionalised carbene ligands featuring two different heteroaromatic wingtip groups. This is the case with the pyridine and pyrimidine functionalised carbenes synthesised by Ye et al. [68]. From our knowledge of organic chemistry [69,70], we remember that the introduction of a nitrogen atom into a N N N N N

N M

N

N

N N

X

N

M

M N R

N

R

pincer complex

N N

N N

saddle shaped complex

helical complex

Figure 3.20 Architectures of complexes of multidentate, pyridine functionalised NHC ligands.

70

Functionalised N-Heterocyclic Carbene Complexes

six-membered aromatic ring system like benzene makes the resulting heterocycle electron poor. The corresponding five-membered ring (pyrrazole) would be electron rich. Of course, pyrimidine with two nitrogen atoms is even poorer in electrons than pyridine with one nitrogen atom in the aromatic ring. Note: In a mixed pyrimidine/pyridine functionalised carbene, the chelate complex is formed by coordination of the pyridine donor and not the pyrimidine donor. In the absence of a second coordinating wingtip group, pyrimidine donors can coordinate to a transition metal [71,72]; known examples include mercury(II) [71], palladium(II) [72], platinum(II) [72] and nickel(II) [72]. Interestingly, mercury(II) and silver(I), both known for their linear coordination geometry in carbene complexes, show different coordination geometries when bonded to a carbene ligand functionalised with a pyrimidine and a carboxylic acid amide functional group. The mercury(II) cation appears to be four coordinate with two carbene and two pyrimidine units from two ligands coordinating to the metal, whereas pyrimidine coordination is missing from the analogous silver(I) complex. In the structures of the platinum(II), palladium(II) and nickel(II) complexes, interesting differences can be seen [72]. In each case 2 equiv. of ligand were reacted with 1 equiv. of the metal. In the case of palladium, only one carbene ligand was coordinated in chelate fashion yielding [Pd(κ2-L)Cl2], whereas both carbene ligands coordinated to platinum, but only one as a chelate yielding [Pt(ι2-L)(ι1-L)Cl]. Only one of the pyrimidine units could exclude the halide ligand forming a monocationic complex. The case of nickel is even more complex. Here a [Ni(κ2-L)2Cl]2 complex is formed with two chelating ligands per nickel atom, an octahedral geometry around nickel and chloride bridges that give the complex the appearance of a dimer (see Figure 3.21). NHC ligands with five-membered heteroaromatic functional groups include pyrazole. Wang et al. [73] and Chiu et al. [74] linked the imidazole ring of the carbene with one of the nitrogen atoms of a pyrazole ring using an alkyl tether. These ligands form chelate complexes with palladium(II) [73], but act as bridging monodentate ligands to silver(I) centres [74]. When a pyrazole ring is used as a scaffold to two pendant carbene donor groups, dimetallic complexes can be formed [75] (see Figure 3.22). Similar complexes were also synthesised for nickel, rhodium and iridium [76,77]. Appreciable metal–metal interactions could not be observed in any of these complexes, with the exception of argentophilic [77,78] or aurophilic [79] interactions. As with other functionalised carbenes, these pyrazole bridged ones have precedences, in this case amine [80,81], phosphino [82] and Cp [83] functionalised pyrazole ligands. It may obviously be tempting to modify the pyrazole bridge to a pyridazine one [84], going from a five-membered to a six-membered heteroaromatic system and lowering the electron donicity of the bridge unit in the process [69,70]. When Scheele et al. did just that [85,86] they found that the pyridazine ligand does not coordinate, at least not to mercury(II) [85].

3.1.2 Oxazolines Oxazolines are another important class of ligands with a nitrogen donor group [87]. They can be regarded as cyclic imines [70]. Phosphinooxazoline ligands [38,88–92] are of course the

N-Heterocyclic Carbenes with Neutral Tethers

N

2

[Pd(NCMe)2Cl2]

N

N

N

N

N

71

Mes

Mes

N

Pd

N

Cl

AgCl

Cl

[Pt(cod)Cl2] [Ni(PPh3)2Cl2]

N

N

N

Mes

N N

N

N

N

N

N

Pt

N

N

N Cl

Mes

Cl

N

Ni

Ni

Mes N

Mes

N Mes

Cl N

N

N

N

N Mes

N

N

N

Figure 3.21 Complexes of nickel(II), palladium(II) and platinum(II) with pyrimidine functionalised carbene ligands.

Cl

Cl N

N

N

N

R

R

N

N N

N

N

N

R

O O

HCl / EtOH

R

N

N

N

N

N

NH

H2O

R

R

N

N

N HN

NH

N

R

Ag2O [Pd(allyl)Cl]2

N N R

N Pd

N Pd

N

N R

Figure 3.22 Dinuclear complexes using bridging pyrazole functionalised carbene ligands.

72

Functionalised N-Heterocyclic Carbene Complexes

ligands on which the oxazoline functionalised NHC ligands were modelled [93]. The oxazoline functionality is a privileged ligand family [94–97] meaning that this ligand shows excellent performance in many catalytic reactions. This in itself would be sufficient to explain its prominent inclusion in the growing arsenal of functional groups as substituents in NHC. Another is the ease of introduction into the carbene as a so-called module [93,98–101] using 2-halo-oxazolines and the chiral centre in the 4-position of the oxazoline ring, directly adjacent to the nitrogen donor atom (and thus one bond closer than in NHC itself). Oxazoline-modified NHC ligands are presently divided into three categories, those without a linker between imidaol-2-ylidene and oxazoline [93,98,99,101–103], those with such a linker (usually a methylene or ethylene bridge) [100,101,103–105] and NHC with annelated oxazoline substituents (benzoxazoline) [99] (see Figure 3.23). Note: The benzoxazoline system has no chiral centre. Note: Figure 3.23 shows different orientations for the oxazoline ring in the ethylene bridged system compared with the other two. Consequently, the chiral centre is now in the bridge rather than on the wing. What is the rationale behind the different architectures of oxazoline functionalised carbenes? One important consideration is the rigidity of the ligand scaffold. The rigidity is one of the main parameters that determine the actual structure of the catalyst during the catalytic reaction and so ultimately determines the product distribution to a large extent. However, the comparatively small and inflexible bite angle [51–53] limits the ligand’s compatibility with a large range of potential catalyst metals [100]. Introducing a linker unit makes more transition metals accessible, but at the expense of more dynamic behaviour of the ligand backbone resulting in a loss of stereocontrol during catalysis and leading to a less favourable distribution of enantiomers and/or isomers in the product. The compromise seems to be a sterically demanding linker unit that sterically prevents or at least limits puckering during catalysis [100]. Another important aspect is the position of the chiral centre relative to the ligand scaffold and relative metal centre. In most successful, chiral and chelating bisphosphane ligands the centre(s) of chirality is(are) situated on the backbone linker between the two phosphorus donor groups (see Figure 3.24). The ethylene tethered oxazoline functionalised carbene ligand depicted in the middle of Figure 3.23 mirrors this general architecture, whereas the linker free ligand on the left has the chiral centre on the wing of the oxazoline group, a position that is less effective in chiral phosphane chelates [106,107]. The benzoxazoline unit is of course achiral and thus unsuitable for asymmetric catalysis.

N

O N N

R1

N

O N

N N

R

R2

N N

R2

without linker

O

R1

with ethylene linker

benzoxazoline functionalised

Figure 3.23 Oxazoline functionalised NHC.

N-Heterocyclic Carbenes with Neutral Tethers

73

H PPh2

PPh2

O *

PPh2

*

*

H

*

PPh2

*

H

H

O

PPh2 PPh2

DIOP

CHIRAPHOS

NORPHOS

Figure 3.24 Some successful, chiral, chelating bisphosphane ligands.

H

Br

O

Br(CF2)2Br

N

N

N

R

N

N

N

O N

R'

R' R

R

O

BuLi

R or

R

N

N

O R

N But

N

N

O N Pri

Figure 3.25 Modular synthesis of oxazoline functionalised NHC without linker group.

It is also an annulated donor ligand and as such more electron deficient compared with the nonannulated species [108]. Given that most catalytic reactions require electron-rich donor ligands [29], these benzoxazoline functionalised carbenes seem to be a poor choice for catalytic applications. Linker-free oxazoline functionalised NHC can be synthesised using a modular approach. In this modular approach, a standard alkyl or aryl substituted imidazole (module 1) is reacted with a 2-halo substituted oxazoline (module 2) to form the corresponding oxazoline functionalised imidazolium salt (see Figure 3.25). In a second step, the oxazoline functionalised NHC can then be reacted with a suitable metal precursor to form the corresponding transition metal carbene complex [93,98,102] (see Figure 3.26). It is interesting to note that the substituent on the oxazoline side of the chelate ligand might be crucial for the structure of the copper(I) bromide adduct (see Figure 3.26). An isopropyl group results in a polymeric structure where the bidentate oxazoline functionalised NHC ligand bridges two copper(I) centres. If the isopropyl group is substituted for two methyl substituents, a discrete dimeric structure is formed. However, these two isolated examples are not sufficient proof for a definitive steric influence of the substituent on the oxazoline ring on the structure of the compound. It is possible that both structures are energetically similar and preference for either would be determined by external factors rather than a small steric influence.

74

Functionalised N-Heterocyclic Carbene Complexes

Mes

N

O

N

Mes

[Rh(µ-OBut)(NBD)]2

O

N

N

Mes

N

Rh

Bu

Br

N

N N

KPF6 t

Rh

O N But

But

Mes

Mes

N

O

N

N N

N

O N

N

N

Cu

O

Br

N

Cu N

O

N

Cu

CuBr

N

N Br

O

N

Mes

Mes

N N

Br

Br O

Mes

Cu

N

CuBr

N

N

O

N N

Mes

Mes

Figure 3.26 Synthesis and structures of transition metal NHC complexes with tetherless oxazoline functionalised NHC ligands.

César et al. have investigated the Berry pseudorotation prevalent in five coordinate rhodium complexes [93] (see Figure 3.27). The product distribution in the rhodium catalysed hydroformylation of 1-olefins is often dependant on the coordination pattern of the bidentate spectator ligand [53], i.e. whether it coordinates equatorial/equatorial or

Mes Br

N

N

O

Rh

N

Br Rh

N O

N

N Mes

O N N

Mes

N N

N

O

Br Rh

Rh

Br

N

Mes

O N N

N

Mes Rh

Br

Figure 3.27 Berry pseudorotation in five coordinate rhodium(I) complexes with linker-free oxazoline functionalised NHC ligands.

N-Heterocyclic Carbenes with Neutral Tethers

75

equatorial/axial on the rhodium atom in a trigonal bipyramidal complex. In this sense, the fluxional behaviour of the oxazoline functionalised NHC ligands might be disadvantageous for catalytic reactions, both for the regioselectivity and the stereoselectivity. In the asymmetric hydrosilylation of prochiral dialkylketones and arylketones [98] César et al. achieved excellent yields (90–99%) and enatiomeric excess (ee) values (88– 91%) with arylalkylketones after abstraction of the halide substituent from the rhodium precatalyst using AgBF4. Note: Abstraction of the bromide substituent creates a cationic, four coordinate and square planar rhodium(I) complex. Oxazolin-2-ylidenes can also be used directly for coordination to metal atoms [109], but then they are not functionalised and therefore not covered by this book. However, it may be interesting to note that their generation is possible as a template synthesis in the coordination sphere of transition metal complexes using a functionalised hydroxyisocyanide [110,111] or the reaction of an epoxide with a hydrogen isocyanide complex [112]. Benzoxazole functionalised NHC ligands can be synthesised by the familiar modular approach [98]. It should be remembered that annulation results in a decrease of the net donor strength of the ligand [108,113] which is likely to be a disadvantage in many catalytic reactions. Similarily, the chiral centre in the parent oxazoline ring becomes an achiral bridgehead atom in the benzoxazoline system. Note: The benzoxazoline functionalised NHC are typically achiral and thus unsuitable for asymmetric catalysis. In a hydrosilylation reaction of styrene and 1-octene as substrates, Poyatos et al. used a benzoxazoline functionalised NHC as ligand and obtained the products in lower yields, but similar selectivity to comparable platinum(0) carbene complexes [99]. One could argue that the lower yield is due to the unfavourable electronic properties introduced by annulation, but the experimental evidence is so far not sufficient to draw such a conclusion. Introduction of a linker group between the imidazole ring and the oxazoline unit requires an elaborate synthetic strategy [100,103–105]. In the first step, the oxazoline ring is synthesised, but with a linker in the 2-position and a functional group capable of adding to the imidazole ring at the end of the linker. This functional group can either be a halogen [103,105] (see Figure 3.28) or a hydroxyl group [103,105] (see Figure 3.29). Schneider et al. go the opposite route by first introducing a functionalised linker on the imidazole ring and then using the functional group on the linker to build the oxazoline ring [100] (see Figure 3.30). Although introduction of a linker unit provides greater flexibility of the ligand in terms of accessibility of more transition metal fragments, this flexibility is bought at the expense of rigidity in the ligand backbone [100]. As the rigidity is a key factor in the regio- and stereoselectivity of the ensuing transition metal complex in catalysis, introduction of a more flexible linker unit generally results in decreased catalytic performance. To counter this, Schneider et al. have introduced methyl substituents on the methylene linker unit to stiffen the backbone of bidentate oxazoline functionalised carbene ligands [100]. Catalytical experiments have not been reported with this ligand so far and we are left with experimental evidence for ligands that are unmodified in the linker unit. Powell et al.

76

Functionalised N-Heterocyclic Carbene Complexes O Cl HO

Cl

1

1

N

N

N H

R

N

Cl

Cl

HO

O

O

O

R1

R1

N R2

NH2

R

H2N

CO2Me

H N

Ad

CO2Me

AdC(O)Cl

OH

O

CO2Me

H N

Ad

NaBH4

O

OH

CO2Me

TsCl Ad

Ad I

N

TsO

N

KI O

O

Figure 3.28 Synthesis of an alkyl halide functionalised chiral oxazoline. O

CO2Me R1

OH

CO2Me

O Cl

CO2Me

O

cyclisation OH

H2N

R1

N

N H R1

reduction

O

N R1

O

N

OTs

R2 -imidazole

O

N

N R2

OH

TsCl

R

N

1

R1

Figure 3.29 Synthesis of an oxazoline functionalised chiral imidazolium salt from serine.

have reported the catalytic hydrogenation of E-1,2-diphenylpropene using a series of precatalysts [Ir(cod)(ox-NHC)]BARF where the oxazoline functionalised carbene ligand carried an ethylene linker and was modified in the steric demand of its substituent in the 2-position of the oxazoline unit [105]. The NHC wingtip group was chosen to be DIPP, a sterically demanding aryl substituent. Both yield and chiral resolution (ee) increased with increasing steric demand of the substituent (from 13% ee for phenyl to 98% ee for adamantyl) [105]. Shortening of the linker group from ethylene to methylene has significant effects [104]. As test reaction serves the hydrogenation of E-2-(4-methoxyphenyl)-2-butene with the

N-Heterocyclic Carbenes with Neutral Tethers

N

NH

N

N

Br

+

H2N

N

N

OH

O

N

O

O

77

O

O Et

Et

Et

OH

cyclisation

N R

N

N

O N

N

RX

O N

Figure 3.30 Synthesis of an oxazoline functionalised chiral imidazolium salt from valinol.

corresponding iridium catalyst. The most striking difference is the enantiomer prevalent in the product; whereas the catalyst with the ethylene linker produces the (S)-enantiomer in up to 91% ee, the catalyst with a methylene linker produces the mirror image, the (R)enantiomer, in up to 85% ee. Closer inspection reveals that the orientation of the chiral centre was changed in going from the ethylene to the methylene linker and thus reversal of the product’s enantiomeric distribution can be expected. Also, the orientation of the oxazoline ligand is important. If the linker unit is attached to the C2-atom of the oxazoline ring, then the chiral resolution (ee) is generally lower then when the linker unit is attached to the C4-atom (backbone) of the oxazoline ring. It should be remembered that swapping the adjacent C/O positions in the oxazoline ring effectively moves the chiral centre from C2 to C4 and thus from an (internal) bridge position to an (external) wingtip position. Note: The (internal) bridge position produces the greater chiral resolution (ee) compared with the (external) wingtip position of the asymmetric centre. Combination of a linker-free and a dimethyl-methylene linked oxazoline functionalised NHC ligand leads to the tridentate BoxCarb ligand [101] (see Figure 3.31). In principle, the methylene linked oxazoline functionalised ligand (pybox analogue) is synthesised first and subsequently quarternisation of the imdazole ring is achieved by a 2-bromo-oxazoline to yield the final BoxCarb ligand. The tridentate BoxCarb ligand was used to synthesise the corresponding carbene complexes of silver(I), rhodium(III) and palladium(II) [101]. Interestingly, the potentially tridentate BoxCarb ligand coordinates in a bidentate fashion only in the case of the silver(I) complex and it is the linker-free oxazoline ring that remains pendant. The coordination

78

Functionalised N-Heterocyclic Carbene Complexes OH

OEt

OEt

NH

N

H N

(S)-valinol

N

Br O

N

O

N

O

N

cyclisation O N O

N

N

Br

O

N N

O N

N

N

Figure 3.31 Synthesis of the tridentate BoxCarb ligand.

of the BoxCarb ligand to the square planar palladium(II) centre is identical to that in the octahedral rhodium(III) complex, mer as expected (see Figure 3.32). No catalytic reactions to evaluate the stereodirecting properties of this new ligand class have yet been reported in the literature. NHC are extensively used as spectator ligands in ruthenium catalysed olefin metathesis reactions [115–117]. To introduce chirality in a rigid framework, Hoveyda and Zhugralin used a functionalised, axial planar NHC to replace the monodentate standard IMes ligand generally used in achiral protocols [118]. The asymmetric olefin metathesis is still in its infancy and hence, chiral bidentate and functionalised carbenes can prove valuable ligands to promote this reaction. However, since a Grubbs’ olefin metathesis catalyst (see Figure 3.33) consists of a pentacoordinated ruthenium complex where the ruthenium centre carries the reactive carbene ligand and the spectator NHC together with a sacrificial neutral donor ligand and two anionic substituents (usually chloride), any functionalised NHC ligand needs to have an anionic functional group rather than a

O N

N

N

N

N

O

O N

N

O

O

Ag O

Br N

Br

N

Pd

N

Rh

N Br

Cl

Figure 3.32 Transition metal complexes of the tridentate BoxCarb ligand.

Br

N

N-Heterocyclic Carbenes with Neutral Tethers

PCy3 Ru

Mes

N

N

Mes

Cl Cl

Mes Ru

N

79

N

Cl Ru

Cl OPri

Cl O

OPri OPri

Mes

N

N O

: N

Figure 3.33 Achiral and chiral ruthenium catalysts for olefin metathesis reactions.

neutral one. For this reason, an oxazoline functionalised NHC is probably not the right ligand for this catalytic reaction. Poyatos et al. synthesised a ruthenium carbene complex with an oxazoline functionalised NHC ligand [119]. This ruthenium(II) complex is formed by the reaction of the silver(I) complex of a linker-free oxazoline functionalised carbene ligand with [Ru(p-cymene)Cl2]2 dimer as the ruthenium(II) source (see Figure 3.34). As the p-cymene usually occupies three coordination sites on the ruthenium centre, the bidentate ox-NHC ligand and a further chloride substituent complete the octahedral coordination sphere on the metal forming a cationic complex. The remaining chloride substituent can be removed by abstraction with AgPF6 to generate a dicationic complex where the sixth coordination site is occupied by a water molecule. Oxazoline functionalised carbene ligands can also be synthesised using a common planar chiral scaffold as platform for both functional groups (see Figure 3.35). Here, pseudoortho-dibrominated [2,2]-paracyclophanes are transformed in a multi-step synthesis to the corresponding oxazoline functionalised carbenes [120]. Again, the carbene ligand is modelled on the bisphosphino analogues [121–123]. The ligands were used to synthesise the respective iridium(I)-cod complexes that were then subsequently used in the asymmetric hydrogenation of prochiral olefins, mainly derivatives of styrene. The chiral resolution (ee) was generally poor to just about moderate ranging from 4 to 46% ee. It is interesting to note that higher conversion resulted in lower chiral resolution, irrespective of whether the temperature or the hydrogen pressure was modified. It is equally interesting that catalyst systems with chiral oxazoline units featured lower chiral resolution performances than those with achiral oxazoline units. Apparently, there are conflicting chiral elements within the ligand design, a phenomenon often observed with ligands featuring multiple chiral elements, especially of differing dimensionality.

80

Functionalised N-Heterocyclic Carbene Complexes But

O

N

N

Mes

N

N

Ag2O

But

N

Ag

O

Br N Mes

[Ru(p-cumene)Cl2]2

N

Mes

Cl

N

Ru

O

N

But

Figure 3.34 Synthesis of a ruthenium(II) oxazoline functionalised NHC complex. O

O

Br N

N

BuLi/CO2 LiAlH4 Br Br

PBr3 Br

R-imidazole R

N

O

N (Rp) - enantiomer

N

N

O

N (Sp)-enantiomer

N R

Figure 3.35 Synthesis of a chiral planar oxazoline functionalised carbene featuring a [2,2]paracyclophane backbone.

N-Heterocyclic Carbenes with Neutral Tethers

81

3.1.3 Imino Functional Groups Imino functionalised carbene ligands provide a nitrogen functional group where the nitrogen is part of a double bond, but not embedded in a heteroaromatic ring system. The existence of the C=N double bond creates the possibility of Z/E isomerism and thus a potential complication in the utilisation of imino functionalised NHC as chelate ligands. Furthermore, in principle the imino group can tautomerise to an enamine when the imino group is linked by a methylene (or higher) group to the imidazole ring of the carbene entity (see Figure 3.36). In this case, the nitrogen binds as an amide onto the metal atom. These cases are described in Chapter 4. In order to prevent enamination, different strategies can be employed. The easiest way is to eliminate the extra CH2 unit that causes enamination in the first place. To this effect, imino functionalised imidazolium salts were developed that have the imino functionality directly attached to the imidazole ring of the NHC unit (see Figure 3.37). Note: Elimination of the CH2 linker unit shortens the ring size of the resulting metallacycle from six to five. This changes the geometrical parameters of the potential catalyst: ligand bite angle, steric demand of ligand substituents on the coordination sphere of the active centre, and electronic effects due to conjugative double bonds. But N

N

N Mes

N

N

[Rh(cod)Cl]2

Mes

But NH

AgBr2

Ag

Rh

ⴙ

Mes N N N But

[Pd(NCMe)2Cl2] N

N Mes

But

But

Cl

Z

Pd

N N

ⴙ

N

NH

Cl

Mes But

E Mes

N N

ⴙ

N

Figure 3.36 Imino/enamino tautomerism and coordination as an anionic chelate ligand.

82

Functionalised N-Heterocyclic Carbene Complexes

Cl N

N

But

Ph

N

+

But

N

N

Ph

N

Ph

Ph

DIPP Ph N

O

O

DIPP-NH2

DIPP SOCl2

N

N

N

N

DIPP Ph

Cl

Ph

N H

Ph

Cl

N

O N

N

DIPP-NH2 Ph

N

N

Figure 3.37 Linker-free imino functionalised NHC ligands.

Note: The possibility of Z/E isomerism is retained in the linker-free imino functionalised NHC ligand. Note: The linker-free imino group should possess better coordination properties to the metal since it is in closer proximity to it. However, enamination can enable anionic binding which as a single bond can prove to be stronger than a donor bond. Coordination of the imino functionalised carbene ligand to the transition metal is usually achieved indirectly, by the silver oxide route [124–128], rather than via the free carbene [129]. Interestingly, when Steiner et al. attempted coordination via the free carbene, they observed a 1,2-shift of the functionalised wingtip group on the imidazole ring that can be described as an intramolecular nucleophilic substitution reaction on the imino carbon atom [129] (see Figure 3.38). However, if KN(SiMe3)2 is used as the base, no 1,2-shift of the imino functionalised wingtip group was observed and the free carbene isolated and characterised. The crystal structure of the E isomer was reported [130]. Note: The choice of base in the generation of the free carbene can be critical. Similar to other nitrogen functionalised carbene ligands, the imino functionalised ones usually coordinate to the silver atom with their carbene carbon atom only leaving the imino group pendant. Coordination of the ligand to another transition metal can then occur in a monodentate or a bidentate fashion, although a bidentate chelate complex is preferred when the coordination site would otherwise stay vacant. In particular, palladium carbene complexes with these imino functionalised NHC ligands are known where the metal is coordinated to one chelating ligand and those where the metal is bonded to the carbene carbon atoms of two ligands, with the imino groups pendant (see Figure 3.39).

N-Heterocyclic Carbenes with Neutral Tethers

83

DIPP

DIPP

N

N

Ph

N

:

KH

Ph

N

N

N

1,2-shift DIPP N N Ph N

Figure 3.38 1,2-shift of the imino wingtip group on an imino functionalised carbene.

R

N

N

N

DIPP

Ag DIPP

N

N R

N

[Pd(cod)Cl2]

2 [Pd(cod)Cl2]

Mes

N N

N

N Cl Pd

N Cl DIPP

Pd N

Cl

N

N

Cl Mes

N

DIPP

Figure 3.39 Synthesis of palladium(II) complexes of imino functionalised NHC.

DIPP

84

Functionalised N-Heterocyclic Carbene Complexes

Note: The palladium(II) chloride adduct is practically insoluble in common organic solvents, but chloride abstraction with AgOTf yields a cationic complex that is soluble in acetonitrile – the method is recommended for the purification of these compounds [126]. The weak donicity of the imino group is clearly demonstrated by an example of an imino functionalised NHC ligand with a methylene linker group [126]. Here, the addition of a donor solvent results in the increasing dissociation of the imino functional group from the metal centre according to the donor strength of the solvent: DMSO > MeCN > THF > MeNO2 (see Figure 3.40). The solvent dependency of the hemilability of imino functionalised NHC ligands can be seen in an apparent ligand exchange process whereby the anionic substituents on the palladium centre change places [128] (see Figure 3.41). The ligand exchange mechanism is believed to contain a hemilabile on/off step and either isomerisation or pseudorotation of the palladium entity. Note: Isomerism in the ligand sphere of palladium(II) carbene complexes with imino functionalised carbene chelate ligands is observed with moderately donating solvents like THF and acetonitrile as the solvent has to be hemilabile itself. The methyl substituents were introduced by reacting the silver carbene complex with a suitable methylated palladium precursor, either [Pt(SMe2)Me2]2 [125] or [Pd(cod)ClMe] [128]. Generation of a monocationic and even a dicationic palladium complex with a chelating imino functionalised NHC ligand is possible using a silver(I) salt (see Figure 3.42) [128] which gives rise to the expectation that ligand exchange reactions involving the introduction of anionic substituents other than halides and methyl groups might be possible. A glimpse of such a protocol was given with the purification method introduced by Netland et al. [126] involving the abstraction and reintroduction of a chloride ligand. Seeing the dicationic complex in Figure 3.42 that is stabilised by two solvent molecules (weakly coordinating acetonitrile) immediately raises the expectation that two imino functionalised NHC ligands should in principle be able to coordinate in a chelate fashion to the same metal atom. This is realised in a trigonal bipyramidal rhodium(I) complex, where the two carbene moieties are in the axial position [130] (see Figure 3.43).

N N N Cl

N

solvent

Cl

Pd Pd Cl

N

Ar

N

solvent

Cl

Ar

Figure 3.40 Solvent dependency of the chelating ability of imino functionalised NHC ligands.

N-Heterocyclic Carbenes with Neutral Tethers

85

N N Me Pd Cl

N

THF

THF

Ar

Mes

N

isomerisation at Pd

N

N

Pd Ar

N

Mes

N

Pd Cl

THF

Ar

N

THF

Cl

N

N N

N Pd

THF Cl

N

Cl

Pd

pseudorotation

THF

N Ar

Ar

Figure 3.41 Ligand exchange mechanism on the palladium(II) centre featuring a hemilabile imino functionalised carbene ligand. N

N

N Me Pd N

AgPF6 MeCN

AgPF6

N

Cl N DIPP

N

Me Pd NCMe DIPP

MeCN

N N

NCMe Pd NCMe DIPP

Figure 3.42 Cationic palladium complexes with a chelating imino functionalised NHC ligand.

Note: The trigonal bipyramidal rhodium(I) complex in Figure 3.43 is a rare example of a trigonal bipyramidal bis-carbene complex where the carbene ligands are in the right, axial, position. Normally, steric constraints force the (bulky) carbene ligands in the electronically less favoured equatorial positions [131]. Although the main emphasis with imino functionalised carbene ligands is on their silver(I) complexes, as carbene transfer agents, and on late transition metal complexes – palladium,

86

Functionalised N-Heterocyclic Carbene Complexes

N

N

But

Ph N

Rh

Ph N

[Rh(cod)Cl]2

:

N

But

Ph N Ph N [Rh(CO)(PPh3)Cl]

N

Ph

Ph N

Rh

N CO

Ph

Ph

t

Bu

But

N

N

Figure 3.43 Synthesis and structure of rhodium(I) carbene complexes with imino functionalised NHC ligands.

platinum and rhodium – there are also some few examples for other transition metals employed in their coordination chemistry. Steiner et al. have presented a tungsten(0) complex prepared by reaction of the free carbene and [W(CO)5THF] with photochemical decarbonylation [132]. The resulting tungsten(0) complex has a straightforward structure, with a chelating imino functionalised carbene ligand and four carbonyl ligands to complete the octahedron. It is perhaps time to discuss the reasons for the interest these imino functionalised carbene precursors have received as potential ligands in complexes of the catalyst metals. A very obvious reason of course is the fact that the imino group coordinates in a hemilabile fashion to the transition metal. As such, there is an equilibrium between a chelate complex and one where the NHC ligand is monodentate and has the imino group pendant. This of course is a preferred situation in catalysis since the chelate complex serves as a stable precatalyst that makes a free coordination site available for the incoming substrate under catalytic conditions. This situation is illustrated in Figure 3.41 with a solvent molecule in place of the substrate. The hemilabile behaviour of this ligand class also explains why the focus of the coordination chemistry of these ligands has been almost exclusively on the catalyst metals palladium, platinum and rhodium. In terms of ligand development, imino functionalised carbenes mimic the all nitrogen donor ligands bis-imines (N,N) and bis-imino pyridines (N,N,N) [129] (see Figure 3.44) and can be seen as an extension of a series of somewhat older functionalised carbenes: oxazoline functionalised NHC [133], pyrido functionalised NHC [134,135] and bis-carbene pyridines

N-Heterocyclic Carbenes with Neutral Tethers

R N

R

N

N

N,N,N

N

R

:

R

87

N N

N

N,C,N R R

R

R

R R

R

R

N

N,N

N

:

N

N,C N

N R

R

R

R

Figure 3.44 Development shift from all-nitrogen donor ligands to nitrogen donor modified NHC ligands.

[136]. The few catalytic applications reported so far using imino functionalised NHC gave very ordinary results and given the isomerisation behaviour depicted in Figure 3.41, it is not expected that performance in asymmetric applications will be satisfactory. Imino functionalised NHC ligands are not as straightforward as they may seem. Some surprises can occur. One such surprise is the concomitant bromination of the gold(I) centre to gold(III) and the functionalised carbene ligand, both the methylene tether unit and aromatic substituent on the imino nitrogen atom (see Figure 3.45) reported by Samantaray et al. [137]. The mechanism of this bromination is not entirely clear, but a proposed pathway, provided by the authors of the original publication, states the oxidation of the gold(I) centre to a gold(III) centre as the first step. As the second step, bromination of the methylene group (in its tautomeric, olefinic form as an enamine) is proposed. The third step – amino aided bromination of the aryl substituent in the para position – completes the triple bromination process (see Figure 3.46). It is interesting to note that the three-step oxidation process follows conventional reaction processes only in its first step, the oxidation of gold(I) to gold(III). The sidechain bromination is not SSS (sunlight, boiling temperature, sidechain) and the aryl bromination is not KKK (cold, catalyst, nucleus), the established reaction conditions for such bromination reactions [69,70]. Although the hemilabile behaviour of the imino functional group together with an apparent isomerisation process on palladium may make it difficult to achieve high chiral resolution (ee) in asymmetric catalysis, Bonnet and Douthwaite developed an imino functionalised carbene ligand system based on the diamino cyclohexane framework that has achieved ees of up to 92% in palladium catalysed allylic alkylation reactions using (E)-1,3-diphenylprop3-en-1-yl acetate and dimethylmalonate [138].The chiral imidazolium salt is synthesised in a three-step procedure starting from 1,2-diamino cyclohexane (see Figure 3.47). The key step undoubtedly is the generation of the imidazole ring from one of the two imino groups in the second step of the protocol.

88

Functionalised N-Heterocyclic Carbene Complexes Pri Pri

Ph

Br

Ph

Br N

N Au

Br

Ag

Cl

N Br

N

Pri

N

Pri

Pri

[Au(SMe2)Cl]

Ph

N

Br

Br2

N

N Au

Cl

N

Pri

Figure 3.45 Bromination of a gold(I) imino functionalised carbene complex. Pri

Ph

Pri

N

Br2

N

Pri

Ph

N

Cl

Pri

Br

Ph

Au

Br

N

Pri

Pri

Pri

Br

Br

N

N Au

Br

N

Br

Br-Br

NH Br

N Br

Au

Ph

N

HBr

N Br

Br Pri

Au Br

N

Pri

HBr

Ph

Pri

Br

Ph

Br

NH Br

Br-Br

Br Pri

N

N

N Br

Au Br

N

Br Pri

Au Br

N

Figure 3.46 Proposed reaction mechanism for the triple bromination of a gold(I) carbene complex with an imino functionalised NHC ligand.

Note: A dialkyl substituted imino group gives much better chiral resolution than the standard aryl substituted ones. Note: Substituents on the imino group can be changed by hydrolysis followed by recondensation with the appropriate dialkylketone. The same research group has developed this ligand system further by introducing an additional hydroxyl group onto the imino aryl substituent [139]. This results in a salene

N-Heterocyclic Carbenes with Neutral Tethers

TosCH2NC

RBr

Ph

Ph N

N

N

Ph

N

N

N

Ph

Ph

89

Ph

N

N

R

H 2O

Ag2O R1 R1

Ph N

O

R2

N

Ph N

R2

NH2

N

N

R

R

Ph N

N AgBr

Ph

N R

Figure 3.47 Synthesis of a chiral imino functionalised NHC ligand from a 1,2-diamino cyclohexane scaffold.

functionalised NHC ligand and raises the question of whether the anionic N,O chelate ligand or the neutral C,N coordination mode prevails. Indeed, the ligand can and does on occasion act as an anionic tridentate C,N,O ligand with pincer geometry. The synthesis of the salene functionalised NHC ligand follows the established procedure (see Figure 3.47) using 3,5-di-tert-butyl-2-hydroxybenzaldehyde as the carbonyl compound. Coordination to silver(I) (Ag2O method), palladium(II) (reaction with palladium(II) acetate) and iron(II) is as expected (see Figure 3.48). Even the N,O coordination in the iron(II) complex does not come as a complete surprise, as these positions are available in the silver(I) carbene complex that acts as the starting material. Furthermore, it has to be remembered that iron has an affinity for oxygen and nitrogen donors. The coordination behaviour of the rhodium(I) centre towards this potentially tridentate C,N,O ligand, however, is maybe a little bit unusual. The explanation is rather straightforward. The phenoximine part of the ligand has a hydroxyl group in close proximity to the imino nitrogen atom. In fact, within the imidazolium salt and the silver(I) complex one can assume the existence of an intramolecular hydrogen bond between the hydroxyl group and said imino nitrogen atom resulting in a six-membered ring, which of course is a stabilised geometry. This intramolecular hydrogen bond deactivates the imino nitrogen atom preventing coordination of a metal centre by it. This intramolecular hydrogen bond system is retained in the neutral rhodium(I) complex (as seen in the crystal structure) and the hydroxyl group cannot be cleanly deprotonated by a common base (NEt3, NaOH, KOBut). Chloride abstraction by a silver salt results in nitrogen rather than oxygen coordination of the phenoximine part of the ligand. Note: Intramolecular hydrogen bonds can shield potential donor sites and effectively reduce the denticity of the ligand.

90

Functionalised N-Heterocyclic Carbene Complexes

Ph

Ph N

Ph N

N

N

Br

But

O

N

AgBF4

Pd

H

N

N

N

[Pd(OAc)2]

Pd N

But

O

MeCN

But

O But

But

But

Ag2O

Ph N Ph N N

N Rh

N AgBr O

N

OH

But Ph

H

But

t

Bu

[Fe(N{SiMe3}2)2] N

But

N

N

[Rh(cod)Cl]2 CF3

NaB

But

AgBr

Ph CF3

But

O Fe

But N

4

N

O

N

AgBr

N But

Cl H Rh O

But But

N

N

Ph

Figure 3.48 Coordination behaviour of a potentially tridentate C,N,O salene functionalised imidazolium salt.

3.1.4 Amino Functionalised NHC In principle, the imino functionalised imidazolium salts can and have been used to synthesise amino functionalised NHC ligands, simply by reduction of the imino functionality [69, 70]. Another possibility would be Bonnet and Douthwaite’s elegant procedure [138] that we have already seen in Figure 3.47. Shi and Qian [139] followed, two years after Bonnet and Douthwaite, a somewhat more complicated route starting with 1,2-diamino cyclohexane, arriving at the amino functionalised (and acetyl protected) imidazolium salt after five steps (including a palladium catalysed hydrogenation) (see Figure 3.49) compared with Bonnet and Douthwaite’s facile three-step route to the N-unprotected imidazolium salt [138,140]. Of course, the carbene unit synthesised by Shi and Qian is benzannulated instead of nonannulated, but that should be disadvantageous for the intended catalytic application [108,141,142]. The amino functionalised imidazolium salt was then used to prepare a palladium NHC complex that was used in the Suzuki–Miyaura coupling between phenylboronic acid and phenyl bromide, albeit with rather moderate success. Note: The efficiency of the catalyst cannot be evaluated in the absence of a cross-coupling product since homocoupling of the arylboronic acid usually occurs in the absence of a defined catalyst. Flahaut et al. published [143,144] a method for the synthesis of a chiral amino functionalised NHC ligand that takes advantage of the facile synthesis of imino functionalised

N-Heterocyclic Carbenes with Neutral Tethers

91

F

NH2

NO2

NO2 NH

NH2

NO2

Ac2O/HOAc

NH

NH2

[Pd]/H2

NH

NH

NH2

NH

O

O

HC(OEt)3

N

O

N Pd

O

I

I

HN

Pd

N

[Pd(OAc)2]/ NaI

N

NH

N

N

MeI

NH

NH

N O

N

O

Figure 3.49 Synthesis of a dimeric palladium(II) carbene complex featuring a chiral amino functionalised NHC ligand.

carbenes. A simple reduction with sodium borohydride [70] converts the imino group to a secondary amine (see Figure 3.50). The linchpin of this synthesis is the presence of a chiral centre in the imino functionalised imidazolium salt, introduced by preparing the Schiff base from a chiral primary amine. Since the imino group is prochiral, reduction with sodium borohydride results in two enantiomers. They can be separated by simple crystallisation due to the presence of a second chiral centre turning the enantiomers into diastereomers. Although a second asymmetric carbon atom enables enantiomeric purification by crystallisation, the yield of the desired diastereomer is determined by the ease with which the reducing agent (BH4-) can approach either side of the N=C double bond. The determining factor here is an intramolecular hydrogen bond between the H2 proton of the imidazolium ring and the imino nitrogen atom. Whilst this intramolecular hydrogen bond hinders the free rotation of the wingtip group around the C-N bond and thus locks the C=N double bond in space, chiral resolution is ultimately achieved by the geometry around the asymmetric carbon atom. In Figure 3.50, the respective phenyl group is shown to point below the C=N double bond making it easier for the BH4- moiety to attack from above. This reaction sequence favours the observed (S,S) enantiomer over the alternative (S,R) enantiomer. Note: An intramolecular hydrogen bond can be stereodirecting in an otherwise achiral hydrogenation reaction. The obtained amino functionalised imidazolium salts could be used to generate the corresponding palladium(II) carbene complexes using the silver(I) complexes as carbene transfer agents. Application of these palladium(II) complexes (predominantly in situ) in asymmetric allylic alkylation reactions between (E)-1,3-diphenylprop-3-enyl acetate and dimethyl malonate (a standard reaction for this catalytic process [145]) gave up to 80% ee,

92

Functionalised N-Heterocyclic Carbene Complexes Ph

N

N Mes

N

N

H

Mes Ph N

N

H2N

Ph

O

NaBH4

Ph HN

attack from above

N Ph

Ph

Mes NaBH4

major (S,S)

attack from below

N

N Mes

Ph HN

minor (S,R) Ph

Figure 3.50 Synthesis of a chiral amino functionalised NHC ligand by reduction of a chiral imino functionalised imidazolium salt using NaBH4.

but with low reaction rates. Flahaut et al. gave the weak π-acidity of NHC as the reason for the low reaction rates since this should disfavour the nucleophile addition step [144]. In view of recent findings concerning the π-acidity of NHC ligands (see Chapter 1) this explanation may be slightly too simplistic to be convincing. A second source of amino functionalised imidazolium salts is the quest for functionalised ionic liquids [146,147]. Wan et al. used a piperidine functionalised imidazolium salt as a base in a palladium catalysed Heck reaction in an ionic liquid medium. The system was designed such that the phosphane ligand, the base and the solvent were all imidazolium based ionic liquids [148] (see Figure 3.51). Given the fact that imidazolium based ionic liquids can act as carbene precursors for coordination to transition metals [149] that coordinate better than phosphane ligands (with cationic substituents in the present case), it is far from certain which is actually the ligand in that carefully designed system. From the three components, the 2-phosphino substituted imidazolium salt cannot serve as a ‘normal’ carbene ligand, but both the amino functionalised imidazolium salt (given the role as the base) and the nonfunctionalised imidazolium salt can act as carbene ligands and would enhance the catalytic activity of the system, if they did [149]. Furthermore, the amino functionalised imidazolium salt would stabilise the Pd(0) species due to its hemilabile behaviour. One should use these ionic liquid systems with caution. A truly hemilabile amino functionalised NHC ligand was introduced by Jiménez et al. who synthesised a series of rhodium(I) compounds using ammonium functionalised imidazolium salts as starting materials [150] (see Figure 3.52). Interestingly, initially an ionic rhodium(I) compound was obtained that did not contain a carbene-rhodium bond. The rhodium carbene complex could be obtained after further deprotonation and coordination of the amine sidearm to the metal occurred only after chloride abstraction with AgBF4. The inability of the amino functionality to displace the chloride substituent on the rhodium centre is proof of its weak donor ability and thus its hemilabile behaviour. This is

N-Heterocyclic Carbenes with Neutral Tethers

93

PPh2

N

N

N

N

N

base

"ligand"

N

N

solvent

Figure 3.51 A multi-functionalised ionic liquid composition (MFILC) containing an amino functionalised imidazolium salt for the Heck reaction of aryl iodides and bromides.

N

N

N

NaH [Rh(cod)Cl]2

Cl

Rh

N

Cl

N NH

2 KOH NaH [Rh(cod)Cl]2

N

N

Rh

N

AgBF4

N

Rh

Cl

N N

Figure 3.52 Synthesis of rhodium(I) carbene complexes using an amino functionalised NHC as ligand.

not surprising as we have seen similar coordination patterns in the complexes of pyridine functionalised NHC ligands where the heteroaromatic functional groups are better donors than the tertiary amines employed by Jiménez et al. These rhodium carbene complexes were successfully employed as catalysts in the hydrosilylation of terminal alkynes. It was found that selectivities improve when the remaining wingtip group on the imidazole ring is small.

94

Functionalised N-Heterocyclic Carbene Complexes

Note: Neutral complexes with amino functionalised NHC ligands are more active than cationic ones. Amino functionalised imidazolium salts can be protected at the amino group turning them into amido functionalised imidazolium salts with a pendant neutral amido group [151–153] – as opposed to an anionic one that is the result of the deprotonation of an amino group. Obviously, the direction of this carboxylic acid amido group within the wingtip group of the imidazolium salt can be either way – an acetylated amine [151,154–156] or the amide of a carboxylic acid [152,153,157] (see Figure 3.53). Formation of transition metal carbene complexes of these functionalised imidazolium salts is principally possible following the silver(I) oxide route and subsequent carbene transfer to a suitable transition metal precursor complex. However, it was observed that silver(I) oxide, being a base, can at times deprotonate the carboxylic acid amide functional group turning the amido functionalised NHC ligand into a bridging anionic bidentate ligand. Carbene transfer of this bidentate ligand to gold(I) is possible under retention of the structure (see Figure 3.54). Note: Protection of the amino group during synthesis of the amino functionalised imidazolium salt can become necessary as the amino group can itself react with the functionalised aminoalkyl halide (see Figure 3.55). Belokon et al. have published a somewhat intricate protocol for the N3-methylation of a histidine isomer, itself an imidazolium derivatised α-amino acid [158] (see Chapter 6). The amino group can be N-boc protected and the resulting imidazolium salt reacted with silver(I) oxide to yield the corresponding silver(I) carbene complex. The functional groups in the wingtip group (carboxylate and N-boc amide) do not coordinate to the silver centre (see Figure 3.56).

HN

MeI N

But

HN

N

N

N But

O

O ΔT

H2N Cl H N N

N

Ph

But

N

N

But NH

O

Ph N

O

Figure 3.53 Neutral amido functionalised imidazolium salts.

N

N-Heterocyclic Carbenes with Neutral Tethers

N

2

95

N But N H

O O N

O But

N

Ag2O

N H

N

2Ag2O

Ag

But

H N

N

But

N

N Ag

Ag

N

But

N

N

O

[Au(SMe2)Cl]

O N

O But

N

N

N H

Au H N

N

O

[Au(SMe2)Cl]

But

N

Au But

N

But

N

N

Au

N

N

N

O

O

Figure 3.54 Amide deprotonation during the synthesis of amino functionalised silver(I) carbene complexes.

H

HBr

N

H2N

H2 N N H

N

N

73 %

Br N

+

N

7%

N

+

+

H2 N H2 N

N

N +

N H

N

N

2 21%

1%

Figure 3.55 Possible side reactions in the synthesis of amino functionalised imidazolium salts.

NHC ligands that possess amino functionalities as substituents in wingtip aryl groups that are clearly intended to modify the electronic properties of this aryl group rather than influence the coordination behaviour of the NHC ligand by introducing a second potential donor function are not considered further in this chapter. An example of this kind of NHC ligand is the 1,3-bispara-dimethylaminobenzyl-benzimidazol-2-yliden ligand found in Özdemir et al. [159].

3.2 Oxygen-Containing Groups Neutral, oxygen-containing functional groups can be introduced in the form of ethers, esters, ketones and sometimes even alcohols (see Figure 3.57), although the latter are

96

Functionalised N-Heterocyclic Carbene Complexes

N

H2N

COO

N

N

O

O

N

COO

N H

But

Ag2O

N N O Ag O

N H

COO

But

Figure 3.56 The silver complex of an N-boc protected imidazolium derivatised α-amino acid.

usually intended to serve as anionic alkoxides or for the coupling of the carbene moiety onto polymeric supports. Introduction of the functional group onto the imidazole ring can be effected by the traditional route, the quarternisation of a 1-substituted imidazole with a functionalised alkyl halide or alternatively, one of several special methods like the reaction of a N-substituted imidazole with an epoxide, a terminal alkyne or an individual strategy for the synthesis of a NHC embedded into a macrocyclic crown ether type molecule (see Figure 3.58). Of course, the underlying strategy is almost always the same; the nucleophilic nitrogen atom of the imidazole ring attacks the substrate displacing a substituent on the corresponding electrophile. For all the similarities between phosphanes and carbenes [160], this difference in their synthetic routes is what most clearly distinguishes their chemistries. Furthermore, the reactivity of most oxygen-containing functional groups [69,70] makes special strategies for the synthesis of their transition metal complexes necessary, since the strong bases required to generate the free carbenes would attack the functional group first [161]. The most important method for the generation of the respective transition metal complexes is the silver(I) oxide method [8–11], but other longer established protocols like the reaction of the functionalised imidazolium salt with a transition metal acetate [162,163] or an electron-rich olefin [58,164] are possible. We will discuss alcohol and ether functionalised NHC first, followed by furan functionalised ones. After a brief glimpse into Bertrand’s noncyclic biaryl amino carbenes, we will turn towards macrocyclic, crown ether type examples and finally to NHC bearing a carbonyl group in the sidechain.

N-Heterocyclic Carbenes with Neutral Tethers

97

Et O

Et

Et O O N

N

Et

N

O

N N

N

O

N

N

O Ph

N

N

O

HO N O

N

O

N

N

Figure 3.57 Structures of neutral oxygen functionalised NHC imidazolium salts. HO

O

HO MeI

N

HN

N

N

N

N

Et O

O

Br

HN

N

Et

O Et N

O

O

N

O Et N N

N NH

N

O

N

O

N

N CO2Me

N N

LiAlH4

Bun HO

N

N

TsOBun

HO

N

N N

NH

N

N

N N

N

Bun

N

N N

Figure 3.58 Synthesis of oxygen functionalised imidazolium salts.

Note: The epoxide method provides a hydroxyl functionalised imidazolium salt where the imidazolium and the hydroxyl group are in the 1,2-position with respect to each other. Note: The epoxide is usually prochiral yielding a racemic hydroxyl functionalised imidazolium salt. Note: The racemic hydroxyl functionalised imidazolium salt can be purified (isolation of one enantiomer only) by standard chiral resolution techniques, i.e. via the tartrate.

98

Functionalised N-Heterocyclic Carbene Complexes

The epoxide method can be used with epoxides of acyclic [165–168] and cyclic [169–172] alkenes with a visible bias for cyclohexene oxide as the epoxide of choice. The epoxide is usually reacted with unsubstituted imidazole creating a neutral molecule. If the epoxide is reacted with an N-substituted imidazole, a zwitterionic molecule is created as the hydroxide functional group in the sidearm lacks the imidazole NH hydrogen atom to be protonated. In this case, addition of one equivalent of acid provides protonation to the alcohol and the counteranion for the formation of the imidazolium salt. This approach has several consequences for the synthetic strategy and the design of the final functionalised imidazolium salt. Reaction of the epoxide with imidazole limits the choice for the other wingtip group. Usually that means quarternisation of the imidazole with a primary alkyl halide. However, this primary alkyl halide can itself be functionalised providing the opportunity for a twofold functionalised imidazolium salt and thus carbene. The other alternative is choice of the second wingtip group, including aryl substituents, with limitation to innocent substituents, i.e. those that do not react with the epoxide themselves. Among the earliest examples for the successful application of the epoxide method is a publication from Glas et al. [169] in which they introduce the reaction of imidazole with cyclohexene oxide, subsequent quarternisation with methyl iodide and the derivatisation of the hydroxyl functional group to an ester (see Figure 3.59). Note: The reaction proceeds with 100% trans selectivity. Note: Esterification of the hydroxy functionalised imidazole was achieved by an enzyme catalysis reaction (C. antarctica) [173–175]. Keeping in mind that the hydroxy functionalised imidazolium salt is a racemic mixture, we would expect more than one stereoisomer for a transition metal carbene complex using this ligand. This becomes further complicated when the transition metal complex contains two carbene ligands – a homochiral and a heterochiral complex become possible. In the square planar coordination environment of palladium(II), the steric implications become very visible. The steric demands of the methyl and cyclohexanolyl wingtip groups are significantly

HO

O

HN

HO MeI

N

N

N

N

N

lipase B (C. antarctica) isopropenyl acetate

O

O

O MeI N

N

O N

N

Figure 3.59 Synthesis and derivatisation of a hydroxy functionalised imidazolium salt.

N-Heterocyclic Carbenes with Neutral Tethers

99

different and thus, the two functionalised carbene ligands align themselves antiparallel and trans to each other (see Figure 3.60). The OH group is a hydrogen bond donor and forms hydrogen bonds to the iodide atom of the Pd-I bond (crystal structure) and probably, as a hydrogen acceptor, with the H2-atom of the imidazolium ring. Whereas Glas et al. required the isolation of the hydroxy functionalised imidazole prior to generating the imidazolium salt, Ray et al. developed a protocol whereby the hydroxycyclohexyl group and the second sidechain could be introduced in a one-pot (but two-step) process without the need to isolate the intermediate first [170,172]. A second difference is the utilisation of the silver(I) oxide method and subsequent carbene transfer by Ray et al. as opposed to the palladium(II) acetate method employed by Glas et al. Using this new, improved protocol, Ray et al. could introduce a benzyl [170], ketyl [170] and carboxylic acid amide [172] functionality through the second wingtip group (see Figure 3.61). OH

N

N

[Pd(OAc)2]

I

N

N

Pd

N

N

HO

I

OH

I

N

N

HO

N

Pd

I

N

HO

heterochiral

homochiral

Figure 3.60 The heterochiral and homochiral palladium(II) carbene complexes of a cyclohexanolyl functionalised NHC ligand. Ph N

Ph

N H

O

N

N HO

N

O

Cl

N

O HO

Figure 3.61 One-pot synthesis of doubly functionalised imidazolium salts starting from cyclohexene oxide.

100

Functionalised N-Heterocyclic Carbene Complexes

Note: The introduction of an electron-withdrawing group (EWG) like a ketyl functionality increases the acidity of the H2-proton on the imidazolium ring significantly [170,176]. The increased acidity of the H2-proton can be seen in the extent of the downfield shift of this proton in the 1H-NMR spectrum – up to and beyond 10 ppm [170,176], irrespective of whether the EWG contains an electronegative heteroatom or is an annulated aromatic ring system (e.g. benzimidazole). Synthesis of transition metal carbene complexes is achieved by the silver(I) oxide method and subsequent transfer to the next transition metal (in this case gold) (see Figure 3.62). Two different types of silver(I) carbene complexes are realised, the monocarbene and bis-carbene complexes. Transfer of the carbene to a gold(I) centre does not always occur with retention of structure as only the gold(I) monocarbene complexes are observed. The gold(I) complexes of the hydroxycyclohexyl functionalised carbene ligands were tested for their ability in the ring opening polymerisation (ROP) of L-lactide under solventfree melt conditions [177,178]. Ray et al. also introduced an aromatic version of the hydroxycyclohexyl functionalised imidazolium salt by replacing the cyclohexyl ring with a benzyl group [171]. The methylene linker group becomes necessary since an alkyl halide is required to attach the functionalised sidegroup to the imidazole ring [179]. Synthesis of the imidazolium salt is straightforward and formation of the transition metal carbene complexes follows the silver(I) oxide route to the gold(I) and the palladium(II) complexes, the latter as the typical trans isomer [131] (see R

Ph

O N N

N

N HO HO Ag2O

R

Ag2O

O

Ph

N N

OH

N Ag

Cl

R Ph, NHBut

N

HO

HO

Ag

N N

Ph

R O

Ph

[Au(SMe2)Cl] N N HO

[Au(SMe2)Cl]

N Au

Cl

N

Au

Cl

HO

Figure 3.62 Silver(I) and gold(I) carbene complexes using hydroxycyclohexyl functionalised NHC ligands.

N-Heterocyclic Carbenes with Neutral Tethers

101

But N Au MeO

But

N

Br

N

N

Ag2O

MeO

[Au(SMe2)Cl]

But

N

Cl

N

OMe

Ag MeO

N

N But

[Pd(cod)Cl2]

But N

Cl

N

OMe

Pd MeO

N Cl

N But

Figure 3.63 Synthesis of 2-methoxybenzyl functionalised imidazolium salts and their transition metal complexes.

Figure 3.63). The palladium(II) complex was used in the Suzuki–Miyaura cross-coupling reaction between phenylboronic acid and benzyl bromide, 2-bromo and 4-bromo benzaldehyde, respectively [180–182]. The rationale behind the introduction of the ortho-methoxy group is its ability to behave as a hemilabile ligand, which is likely to stabilise the palladium(0) catalyst species – after reductive elimination of the product in the catalytic cycle – by intermittently occupying the otherwise empty coordination sites preventing formation of palladium black. Yang et al. used a similar protocol (an ether functionality supported on a primary alkyl halide carrier) to introduce an acetal on either side of the imidazole ring generating an ether functionalised ionic liquid (IL) imidazolium salt [183] (see Figure 3.58). The anion could be varied without loss of the IL property (melting point below 100 ˚C) [184]. Synthesis of the transition metal carbene complexes (palladium) was done by carbene transfer from the corresponding silver(I) complexes or by reaction with the metal acetate (nickel) [162] (see Figure 3.64). Note: Depending on stoichiometry, reaction conditions and coligands, monocarbene and bis-carbene as well as dimeric palladium(II) carbene complexes can be synthesised. The palladium(II) complexes were used in the Heck reaction between aryl halides and styrene using either water or DMF as the solvent. Whenever comparison is possible, the yields for the aryl bromides were significantly better than for the analogous chlorides. It may be interesting to note that the dimeric μ-chloride bridged palladium complex is not coplanar, but displays a butterfly structure with respect to its two square planar palladium environments.

102

Functionalised N-Heterocyclic Carbene Complexes Et

Et O

Et

O N

O

O

Et O

N

Et

O

Et

Et

Ni

Br Ag2O

O

Et

Et O

N

Et Ag

O

N

N

O

O N

Br

Et

Et O

Et O

N

N

O

Et O

O Et

[Ni(OAc)2]4H2O

Et

Et O

N

N

O

Et O

O Et

Et

[Pd(MeCN)2Cl2]

[Pd(MeCN)2Cl2] O

Et O

Et

O O

N

N

O

O

Et

Cl

Pd

Pd

Cl

Cl

N

N O

Et

N

O Et

O

O Et

Pd

PPh3

N

O O

N

Et O

N

N Cl

Et

Cl

Et

Et O

O

Pd

Cl PPh3

Et

O

Et Cl

Et Cl

Et

Et

O Et

O

N

Et O Et

O Et

Et

Figure 3.64 Synthesis of nickel(II) and palladium(II) carbene complexes with acetal functionalised NHC ligands.

Note: The imidazolium salts and the palladium(II) complexes can be reversibly hydrolysed to the corresponding aldehyde functionalised compounds (see Figure 3.65). Another example for methoxy functionalised imidazolium salts comes from the group of Çetinkaya [185,186] featuring an n-alkyl tether. Çetinkaya et al. use the traditional route to transition metal carbene complexes employing the electron-rich olefins as carbene source [57–59]. Thermal cleavage of the olefinic double bond in the presence of the metal precursor complex yields the desired transition metal carbene complex (see Figure 3.66). Using this method, Çetinkaya et al. synthesised rhodium(I) [185,186] and ruthenium(II) [185] complexes. Incorporation of a furan moiety as a carbene wingtip group was introduced by Nielsen et al. The synthesis is facile enough starting with a bromination (NBS) of 2,5-dimethylfuran and subsequent reaction with two equivalents of N-substituted imidazole to yield a bis-imidazolium furan [187] (see Figure 3.67). The silver(I) complexes of the furan functionalised bis-carbene ligands were used for the palladium catalysed aryl amination of p-bromotoluene with morpholine as the amine and [Pd(dba)2] as the precatalyst employing an in situ protocol. Performance of the catalyst was poor, but increased somewhat with additional bulk on the wingtip groups (Me < But< Mes) and the reaction time. The latter indicates that the catalyst, formed in situ, is stable under catalytic conditions and remains active over prolonged reaction times. Another bis-carbene bearing an oxygen-containing functional group was synthesised by Diéz-Barra et al. [188] employing a hydroxyethyl functional group on the backside of

N-Heterocyclic Carbenes with Neutral Tethers

103

Et Et

O

O

O

Et N

O

dil HCl

O

N

N

T

HO

OH

[H2O]

O

N

N

HO

OH

N

Et

O

Et

Et

O

Et

O

O

O

N

N

O

Pd Cl

Cl

Et O

Pd Cl N

O

dil HCl

Cl

T

N

Cl

O

Pd Cl

Cl HO

N

O

O

Et

Cl

C

Pd N

Et

O

Et

[H2O]

OH

N

N

HO

Et Cl

HO

OH

N

N

Pd Cl

Pd Cl N

N

OH

OH HO

Figure 3.65 Acetalisation and hydrolysis of acetale/aldehyde functionalised imidazolium salts and their palladium(II) complexes.

O O

MeO N

O

OMe

N

MeO

OMe

N

N

N

N

MeO

OMe

O

N

N

O

[Rh(cod)Cl]2

[Rh(cod)Cl]2

O

[Ru(p-cumene)Cl2]2

O

O

O N

N

N

Cl

Cl Ru Cl

Rh

Rh N

Cl

N N

O O

MeO

MeO

OMe

Figure 3.66 Rhodium(I) and ruthenium(II) carbene complexes with methoxyalkyl functionalised NHC ligands.

the methylene linker unit (see Figure 3.68). The intentional application for these ligands does not seem to be additional donicity and thus a potentially tridentate ligand, but rather a structurally innocent functional group for the generation of dendrimers [189] or alternatively to attach the ligand to a polymeric support [190].

104

Functionalised N-Heterocyclic Carbene Complexes

O

N

O

Br

Br Br

O

O

N

N

N

N

N

N

N

N O

Ag

Ag

O

Ag2O

AgBF4 N

O N

N

N

N

N

Figure 3.67 Synthesis of furan functionalised imidazolium salts and their silver(I) complexes.

N

N NH

N

O

N N

CO2Me

Bun

N

N

HO

N

LiAlH4

N

N

HO

N

TsOBun

N N

NH

O

N N

N

N

N N

Bun

N

N

N

[Pd(OAc)2] KBr

Bun N Br N Pd

OH

Br N Bun

N

Figure 3.68 Synthesis of a backside hydroxyethyl functionalised bis-imidazolium salt and its palladium(II) complex.

Note: The palladium(II) complex exists in two conformational forms, with the hydroxyethyl group in axial (major) and equatorial (minor) positions of a six-membered palladacycle with boat conformation. Both conformers are in equilibrium with each other. Another NHC ligand with a backside hydroxy functional group was introduced by Buchmeiser and coworkers with the intention to use the hydroxy group to attach the NHC ligand to a polymeric support [161,191]. Attachment to the polymeric support was achieved

N-Heterocyclic Carbenes with Neutral Tethers

105

by an ester linkage and the NHC ligand used to form a second generation Grubbs’ catalyst for olefin metathesis. Ether functionalities on carbene ligands can also stabilise monoaminocarbenes (MACs) [192–194], which again have phosphane predecessors [195–197] (see Figure 3.69). This particular MAC features a biphenyl backbone with two ortho-methoxy groups on one of the two phenyl rings. The methoxy groups cannot only coordinate in hemilabile fashion onto the transition metal in a transition metal carbene complex of the ligand, but concomitantly impede rotation around the biphenyl axis. This introduces axial chirality [69] and renders the MAC a potential ligand for asymmetric catalysis. Note: The cationic complex in Figure3.69 features a rare Pd--O contact that is caused by an unavoidable close proximity between the palladium atom and one of the methoxy groups rather than an affinity of the palladium centre for the oxygen donor. The cyclic variety of MACs are called cyclic alkyl amino carbenes (CAACs) and have an excellent steric element [198]. With a cyclohexyl wingtip group on the carbon end of the carbene – known as a ‘wall of protection’ – they can sterically block one side of the transition metal centre in a transition metal carbene complex effectively introducing outstanding regioselectivity and stereoselectivity in catalytic processes [198] (see Figure 3.70). Note: Sterically demanding substituents on the cyclohexyl wingtip group of CAAC prevent the conversion between conformers and establish an enantiomerically pure ligand and thus superior performance in asymmetric catalysis. The introduction of ether functional groups into the backbone (see Figure 3.70) brings us back to NHC. We essentially look now at an imidazolium ring with two oxazoline type rings annulated to it. The structure is semi-flexible meaning that the annulated rings can tilt and thus shape the available space around the carbene centre. In other words, the conformation of the annulated rings determines the steric demand of the wingtip groups on the carbene centre and thus on the transition metal coordinated to it [199,200]. Similar to our position on amino functionalised carbenes, we will not discuss those oxygen functionalised carbenes whose oxygen functionality merely modifies the wingtip group electronically without having a real bearing on the transition metal itself. An example of such a NHC ligand is given in Özdemir et al. [201] – in this case a p-methoxyphenyl wingtip group.

N

N

N Li

MeO

OMe

[Pd(allyl)Cl]2

Cl O

Pd O

N AgBF4 O

Pd O

Figure 3.69 Structures of MACs and their palladium(II) allyl complexes.

106

Functionalised N-Heterocyclic Carbene Complexes O O

O

O N N

N

:

N

: N

N

:

:

but: N

:

only one conformation possible

Figure 3.70 CAAC and NHC with cyclohexyl wingtip groups.

By far more interesting are polyether functionalised imidazolium salts, especially those that lead to metallacrown ether functionalised carbene ligands. Development of this particular ligand class follows the by now familiar pattern of adapting an existing functionalised phosphane to the corresponding carbene. Here, the favourable properties of metallacrown ether functionalised phosphanes in catalytic processes [202–205] leads to the development of similarly functionalised NHC ligands. Winkelmann et al. used the presence of two hydroxy groups on each of their two wingtip substituents to form a bowl shaped carbene ligand, where the alkyl ends of the ether groups fill in the sides of the regular aryl substituted NHC ligands to form a bowl [206,207] (see Figure 3.71). The tethered alkyl chains shield the carbene from above and from below, exactly those positions of greatest vulnerability in the metal–carbene system. Note: Decomposition to a 2-alkyl-imidazolium salt requires close proximity and a certain geometrical grouping to occur in catalytic systems with transition metal carbene complexes (see Chapter 1). The synthesis of the ligand system is very elegant and involves 2,6-dihydroxy-nitrobenzol as the starting material. The reduction of the oxalic acid diamide to a substituted diamino

N-Heterocyclic Carbenes with Neutral Tethers OH

O NO2

HO

O NO2

OH

107

SnCl2/EtOH

NH2

O

O

Cl

O

O

Cl

O O HN

O O

NH

O HN

O

O

LiAlH4

O

NH O

O

HC(OEt)3

O

O

N O

N

PCy3 Cl Ru Cl PCy3 Ph

O

O

N O

ⴙ

N O

O

Figure 3.71 Synthesis of a concave, ether functionalised imidazolium salt.

ethane derivate effectively limits this protocol to the synthesis of saturated NHC ligands. (Note the use of a first generation Grubbs’ catalyst in the key olefin metathesis step that leads to the double linkage of the two wingtip groups.) The ligand was then used to form a variety of transition metal carbene complexes [207] (see Figure 3.72). Interestingly, more than one method for the formation of transition metal carbene complexes was successfully employed: presence of an inorganic base (K2CO3) to deprotonate the imidazolium salt and the silver(I) oxide method with subsequent carbene transfer to rhodium(I), iridium(I) and copper(I), respectively. The silver(I) and copper(I) carbene complexes were used for the cyclopropanation of styrene and indene with 1,1ethanediol diacetate (EDA) giving very poor conversion with silver (< 5%) and quantitative yields with copper. The diastereomeric ratio (endo/exo) was more favourable with silver than with copper giving almost a pure diastereomer for the silver catalysed reaction of indene. The development of crown ether functionalised imidazolium salts starts from the consideration that it is possible to link one polyether chain with two imidazolium units at the end points. Since a transition metal can coordinate two imidazolium salts in trans fashion [131,162,208], two of these (poly)ether functionalised bis-carbenes can form a macrocyclic crown ether type ligand system with two transition metal carbene linkages. In favourable cases, a pincer type C,O,C tris-coordination to the same transition metal is conceivable, but may not be very likely when the great affinity of late transition metals to NHC ligands and the ‘aversion’ of these same late transition metals to ether donor ligands is taken into account. However, hemilabile stabilisation of transition metal complexes in catalytic processes can certainly be hoped for.

108

Functionalised N-Heterocyclic Carbene Complexes

O

O

N

Ag2O

N

O O

O

O

N

N

O CuCl

O

O

O

O

O

Ag

Cu Cl

Cl N

PdCl2 K2CO3

Cl

N

N

[M(cod)Cl]2

O O

N

N O Cl

Pd

O

O O O Cl

N

O

Cl

N

N

CO O

O

O

N

N

Cl

M

M

O CO CO

M Rh, Ir

Cl

Figure 3.72 Formation of transition metal carbene complexes with the concave ether functionalised imidazolium salt shown in Figure 3.71.

Nielsen et al. have introduced a monoether linked bis-carbene [209] modelled on an amino linked bis-carbene ligand that acts as a C,N,C pincer ligand in a corresponding palladium(II) complex [156]. Synthesis of the ether linked bis-carbene is facile and involves the reaction of the 1-ω-dichloro-diethylether with 2 equiv. of methylimidazole. Subsequent reaction with silver(I) oxide and carbene transfer to suitable transition metal precursor complexes affords the corresponding complexes (see Figure 3.73). Note: The palladium(II) complex in Figure 3.73 shows no Pd-O coordination despite the existence of a ‘free’ coordination site owing to chloride abstraction by the silver carbene complex. Coordination of the weak donor acetonitrile is preferred. Note: The ether linked bis-carbene ligand does not act as a pincer ligand towards late transition metals. Modification of the remaining wingtip group does not alter the general properties of this ligand type. Wang et al. chose to exchange the sterically innocent methyl group with sterically more demanding 1-naphthylmethylene and 9-anthracenylmethylene groups [210] describing the same structural pattern in the silver(I) complexes already seen in Figure 3.73. Reaction of this silver carbene complex with [Au(SMe2)Cl] afforded the corresponding isostructural gold(I) complex. Introduction of a polyether linkage follows the same synthetic protocol, although Liu et al. chose to use N-substituted benzimidazole instead of the non-annulated analogue [211]. Again, the ether groups do not coordinate to the transition metal, but the benzene rings of the benzimidazole moieties are found to be involved in π-π stacking interactions in the solid-state structures of the compounds. Of course, the introduction of annulation in the benzimidazole derived carbenes changes the electronic properties of the carbene ligand significantly [108,113]. It is worth mentioning that given a stoichiometric ratio of 1:1 between transition metal and chelating bis-imidazolium salt, it becomes possible to form

N-Heterocyclic Carbenes with Neutral Tethers

N Cl

109

N N

Cl

O

N

N

N

O

Ag2O

O N

N

N

N O

N

N

[Pd(NCMe)2Cl2]

Ag

N

Pd Cl

N

Ag

N

O N

N

N

N

Figure 3.73 Synthesis of an ether linked bis-imidazolium salt and its transition metal carbene complexes.

mononuclear carbene complexes when the polyether bridge is long enough to coordinate as a chelate rather than in bridging mode (see Figure 3.74). Note: The cationic mercury(II) carbene complex in Figure 3.74 shows Hg-O distances that are consistent with Hg-O bond lengths in mercury crown ether complexes [212] Note: The neutral HgI2-carbene complex in Figure 3.74 shows no such Hg-O distances. Wang et al. experience similar results in their attempt to elongate their monoether linkage further to di- and triether linkages [213]. Their 1-naphthylmethylene and 9-anthracenylmethylene wingtip groups, although sterically more demanding than a sec-butyl group, do not impede the formation of mononuclear chelate complexes. Carbene transfer from silver(I) to gold(I) is again facile producing isostructural group 11 carbene complexes. No Ag-O or Au-O interactions were observed. Similar carbene complexes of silver(I) and gold(I) are observed when catechole is used as the scaffold. Synthesis of the bis-imidazolium salt follows the established protocol with bis-iodoethyl catechole and N-(1-naphthylmethyl)-imidazole as the starting materials [214]. Reaction with silver(I) oxide and subsequent carbene transfer to copper(I) iodide yields the corresponding silver(I) and copper(I) carbene complexes. Other oxygen-containing functional groups include carbonyl functionalities like aldehydes, ketones, carboxylic acids and esters. An excellent overview was published by McGuinness and Cavell [215]. Synthesis of the functionalised imidazolium salts is once again facile and is achieved by the reaction between methylimidazole and the appropriately substituted alkyl halide (see Figure 3.75). Reaction of the functionalised imidazolium salt with silver(I) oxide and subsequent carbene transfer affords the corresponding palladium(II) complexes. When the stoichiometry between carbene and palladium is 2:1 the expected

110

Functionalised N-Heterocyclic Carbene Complexes O

N

O

N

N

N HgI2

[Hg(OAc)2]

KOBut

KOBut

O

N

I

Hg

N

Hg N

N

Ag2O

N

O

O

N

O

N

N

I

I

I

I O

N

I Hg

Hg

I

I

O N

Ag N

N

Figure 3.74 Chelating bis-NHC ligands and their transition metal complexes. E tO

O Et

Ph N

N

N

S NCMe O

N

N

O

N

N

Ag2O

S

Pd

S

A g 2O

N

Et Ph N

N

EtO

O

O

AgBF4

Ag

N

O

[Pd(NCMe)2Cl2]

Et

O

N

N Ag

N O

Ph

N N

[Pd(NCMe)2Cl2]

N

N Pd

Cl

N

OEt Cl

N

Et O

[Pd(cod)MeCl] Ph

N

2 [Pd(cod)MeCl]

O

N

N

Cl

Pd

Cl

O

N

Cl

N EtO

EtO

N

O

Ph

O

Pd N

N Pd

OEt Pd

Cl N

N

O

Cl

O O

N

N

OEt

Figure 3.75 Synthesis of silver(I) and palladium(II) carbene complexes from carbonyl functionalised imidazolium salts.

N-Heterocyclic Carbenes with Neutral Tethers

111

bis-carbene complex with pendant keto groups is observed. This is as expected, but noncoordination of the keto functionality persists even when the stoichiometry is changed to 1:1. In this case palladium prefers a chloro-bridged dimer rather than coordination of the carbonyl oxygen donor. Another interesting observation is the formation of the cis isomer when [Pd(NCMe)2Cl2] is used as the palladium source, but the trans isomer with [Pd(cod)MeCl] as the starting material. Note: The cationic palladium(II) carbene complex prefers the weak donor acetonitrile over the chelate carbonyl oxygen donor. A few years earlier, Herrmann et al. published a carboxylic ester functionalised imidazolium salt that was synthesised directly from imidazole and bromoacetic acid ethyl ester [216]. Owing to its method of synthesis the imidazolium salt is C2-symmetric with two ester functional wingtip groups. Generation of the rhodium(I) and palladium(II) carbene complexes was realised by reaction of the imidazolium salt with a rhodium alkoxide precursor or with palladium(II) acetate in the presence of NaOEt and NaI (see Figure 3.76). The silver(I) oxide method had not been discussed in the literature at the time [11].

O

EtO O

O

2

N

EtO

O OEt

N

Rh

N

Rh O

Br

N

O

Rh

NaOMe MeOH

O

MeO

NaOEt NaI

OEt

N

O

Br

O

EtO

N

Pd

I

Rh

N

N

OEt

Al

OMe

KOH H N

I

N

HN

O

I

Pd

I EtO

O

O

O N

N

O

OEt O

Br

Rh N

Rh

PPh3

Br

N

N

O

O HN O

O EtO

O N

N

I Pd

OEt

PPh3

I

Figure 3.76 Ligand substitution reactions on a rhodium(I) carbene complex with an ester functionalised carbene ligand.

112

Functionalised N-Heterocyclic Carbene Complexes

Note: The rhodium(I) carbene complex can be used for extensive ligand modification reactions. Amongst these are hydrolysis of the ester, exchange of the alcohol of the ester and synthesis of the amide. Again, an iodo bridge is preferred over carbonyl oxygen coordination in the palladium(II) complex. The iodo bridge is easily cleaved upon addition of a donor ligand like PPh3 and the ester functionality can be modified using standard textbook procedures [69,70]. Herrmann et al. exchanged the alcohol under basic catalytic conditions (NaOMe, methanol) in a transesterification reaction to the methyl ester, hydrolysed the ester function to the free carboxylic acid with one equivalent of KOH and performed an aminolysis to the corresponding amide with dimethylaluminium isopropylamide [217]. A monoester functionalised NHC was successfully employed by Fürstner et al. [218] in a second generation Grubbs’ catalyst [116,219] for olefin metathesis reactions. As usual for such catalysts, the NHC sits trans to the phosphane in the base of a square pyramidal geometry around the ruthenium centre with the phenylylidene located in the apex [131]. Ketone functionalised carbenes were introduced by Yu et al. [220] and Ketz et al. [221]. Yu et al. used the carbene transfer method via the silver(I) carbene complex, although free carbenes with acidic methylene groups (i.e. enolisable ketones) can be isolated [222]. The respective rhodium(I) carbene complex is isostructural to the one synthesised by Herrmann et al. featuring an ester functionalised carbene (see Figure 3.76). The corresponding nickel carbene complexes show a different behaviour [221,223]. Here, the keto group of the imidazolium salt is enolisable leading to an anionic chelate carbene ligand with similar properties to Keim’s SHOP catalysts [224,225]. Without proper precautions, two carbenes are coordinated to the nickel centre and both keto groups coordinate as alkoxides effectively blocking all the available coordination sites and making the resulting nickel complex inactive in catalytic reactions. A similar chelate coordination pattern is observed in the reaction of the keto functionalised imidazolium salt with nickelocene [223]. The coordination of amido functionalised carbene ligands, where the amido function is introduced by the acetylation of an amino functionalised imidazolium salt, to transition metals has already been discussed in Section 3.1. Here it suffices to mention that the synthesis is similar to other carbonyl functionalised NHC ligands and their transition metal complexes. A suitable example is given in Rivera and Crabtree [226]. A most interesting class of oxygen functionalised NHC ligands was presented by Cesar et al. [227] when they reacted a 1,3-aminoimine (formamidine) with a monosubstituted malonic acid [228,229]. The result is a zwitterionic six-membered betaine that can be deprotonated to an anionic NHC ligand and coordinated to transition metals (see Figure 3.77) This approach makes the synthesis of neutral zwitterionic transition metal carbene complexes possible, with valuable advantages over cationic complexes [230]. The concept was previously applied to N, P and S ligands [231,232] and has a carbene precursor in Roesler’s backbone boron substituted NHC ligands [233]; the latter has not been coordinated to transition metals yet. Note: The formally cationic rhodium(I) centre in Figure 3.77 stabilises itself with an aryl π-interaction to one of the wingtip Mes groups.

N-Heterocyclic Carbenes with Neutral Tethers But

But HO

OH

O

H N

Mes

N

But

O

O

BuLi

Mes N

O

O

O

N

N Mes

Mes

N Mes

:

Mes

113

KHMDS

[Rh(cod)Cl]2 [CpFe(CO)2I]

But

But

O

O

N

O

O

O

N

N Mes

But

O

Mes

[Ag(PPh3)OTf]

Rh

N

Mes

N Mes

OC OC

Fe

N

Mes

Mes Ag

PPh3

Figure 3.77 Synthesis of an anionic NHC and its transition metal complexes.

3.3 Phosphane Functionalities So far [234], we have limited ourselves to ‘unreactive’ neutral functional groups following the ‘historic’ evolution in functionalisation of NHC that confined itself to tertiary amines like pyridine [235], ester, keto and ether functionalities [236], oxazolines [237] and phosphines [238]. We will later see that recently researchers have discovered the suitability of stronger nucleophiles such as alcoholates [239] and secondary amides [240]. But, as in phosphine chemistry the ‘golden rule’ of functionalised carbenes is to introduce the functional group first and generate the carbene (phosphine) last [237]. Having introduced the ‘golden rule’ of phosphine chemistry to its carbene analogues we will proceed to break it several times in the following brief summary of routes to synthesise phosphino functionalised carbenes. The best way to synthesise an imidazolium salt is to react an N-substituted imidazole with an alkyl or aryl halide [235]. Thus, it is a good idea to utilise a functionalised alkyl halide. The functional group can then be used to introduce the phosphino group. This approach was used by Yang et al. [238] and Lee et al. [241] in their synthesis of N-aryl, N’-diphenylphosphinoethyl imidazolium salts (see Figure 3.78). The first step is the reaction between the N-substituted imidazole and 1,2-dihaloethane (halogen = Br [238], Cl [241]) followed by the introduction of the phosphino group utilising HPPh2 and KOBut in DMSO as polar solvent. The reaction can be carried out using imidazole itself and 2 equiv. of 1,2-dichloroethane [242]. The product is the N,N'-bis-chloroethyl imidazolium salt that can be converted into the N,N'-bis-diphenylphosphinoethyl imidazolium salt as above by reaction with HPPh2 and KOBut in DMSO. Another interesting approach starts

114

Functionalised N-Heterocyclic Carbene Complexes

N

N

BrCH2CH2Br

N

N

thf

ⴙ Br

HPPh2/KOBut

N

N

ⴙ PPh2

dmso

Br ⴚ

Br

ⴚ

Figure 3.78 Introduction of a phosphino group onto the sidechain of an imidazolium salt.

TosMIC/K2CO3

PhCHO

Ph N

H2N

N

NH2

N

N

Ph

Ph Ph N TosMIC tosylmethyl-isocyanide

Ph

RBr N

Ph

Ph

ClPPh2/NEt3

NH P

N

Br

N Ph Ph

HCl(aq)

P N

N

NH

NH2

Ph Ph

N

R

Figure 3.79 Synthesis of a phosphino carbene with a chiral backbone.

with the chiral diamine 1,2-diaminocyclohexane (see Figure 3.79) [243]. One of the amino groups is used to synthesise the imidazole ring. During imidazole ring formation the other amino group needs to be protected (as imine). After the amino group is liberated by acid catalysed hydrolysis, the phosphino group is introduced by reaction with ClPPh2 in the presence of triethylamine as auxiliary base to bind the HCl that is formed during the reaction. We have now broken the ‘golden rule’ since we still need to form the imidazolium salt by reaction with a suitable alkyl halide. This can be achieved by standard procedures. In this particular case, the initial attempt was indeed to introduce the phosphino group last, but reaction of the imidazolium salt with ClPPh2 in the presence of triethylamine as auxiliary base gave a mixture of several phosphine-containing species and the alternative route was used with success. Obviously, the phosphino group can be introduced into the alkyl or aryl halide before it is reacted with the substituted imidazole breaking the ‘golden rule’ yet again. This route was employed by Focken et al. [244] and Wang et al. [245]. Focken et al. introduced the planar chiral [2,2]-paracyclophane substituent onto the imidazole, but not before introducing a phosphino group onto the [2,2]-paracyclophane group (see Figure 3.80). It should be noted that this interesting pathway calls for the enantiopure pseudoortho-dibromo-[2,2]-paracyclophane to be reacted with 1 equiv. of butyl lithium (BuLi) and then ClPPh2 to introduce one phosphino group only. A second equivalent of BuLi followed by reaction with CO2 and reduction with LiAlH4 introduces a hydroxymethyl group that

N-Heterocyclic Carbenes with Neutral Tethers

Br

PPh2

BuLi/ClPPh2

PBr3

PPh2

1) BuLi; 2) CO2

Br

Br

PPh2

N

N Ar

3) LiAlH4

OH

PPh2

Br

Br

115

N

N

Ar

Figure 3.80 Stepwise introduction of a phosphino group and an imidazolium salt on a chiral paracyclophane.

can be converted into the respective halide and then used to form the imidazolium salt. The additional C1 unit introduced by CO2 gives the substituent the required flexibility to act as an efficient chelate ligand. A similar protocol was developed by Wang et al. starting from benzaldehyde, N,Ndimethylaminomethyl benzene was formed, lithiated in the ortho position and reacted with ClPPh2 to introduce the phosphino group. Then the amino group is substituted with chloride and the molecule reacted with the respective imidazole to generate the mono- or bisphosphino imidazolium salt (see Figure 3.81). A principal question of course is, what can be achieved by preparing a mixed NHC/phosphane chelate ligand or a ligand system containing a monodentate NHC and a monodentate phosphane? At first glance, one might think that the advantage of substituting a phosphane ligand for a NHC in a catalyst (NHC are better net donors than phosphanes [246]) would be accumulative meaning that the advantage becomes greater for each phosphane substituted by a NHC. On further consideration however, we will remember that ligand tuning is the art of finding a ligand (phosphane or NHC or other) that is just right for the application in hand. In the case of phosphanes we fine-tune by carefully selecting the substituents on phosphorus for their electronic and steric impact on the catalyst metal [247–249]. With NHC ligands, we should do the same. It is not unreasonable to expect that for certain catalytic applications the best ligand might be the one slightly more electron rich than the most suitable phosphane ligand currently available. In such a case of course, it might be best to substitute only one of the two phosphane ligands by a NHC. It might be better still to provide a phosphino functionalised NHC to exploit the chelate effect. Note: The second generation Grubbs’ catalyst [Ru(PCy3)(IMes)(=CHPh)Cl2] [117] employs a phosphane and a NHC and is activated by loss of the PCy3 ligand. The Herrmann variant [Ru(IMes)2(=CHPh)Cl2] [116] is inferior simply because it would have to lose one of the two NHC ligands, a process that takes longer because NHC bind stronger than phosphanes. The Grubbs’ catalyst requires a vacant coordination site to become active. In the active species, the NHC ligand is superior to the phosphane, simply because of the greater net electron donicity. In many other C-C and C-N coupling reactions, the picture is different.

116

Functionalised N-Heterocyclic Carbene Complexes N

N 1) BuLi; 2) ClPPh2

Cl ClCOOEt

PPh2

N

PPh2

N

NH

N

N

N

Cl PPh2

N

Ar

N Ar Cl

Ph2P

PPh2

Figure 3.81 Stepwise introduction of phosphino groups onto the imidazole ring.

There, a balanced compromise between the oxidative addition and reductive elimination steps needs to be found. Roland et al. [250] explain the preference for mixed NHC/phosphane systems in the Tsuji–Trost reaction [143] with the electronic situation in the reaction intermediate, a cationic allylpalladium complex that acts as the electrophile. Its electrophilic properties are naturally diminished when the net electron donicity [251] of its constituting ligands is increased (NHC versus phosphane) [243]. It has therefore become a successful strategy to combine the electron rich and coordinatively stable NHC ligand with a phosphane ligand featuring improved π-acceptor ability [243,252,253]. The accepted mechanism for the Tsuji–Trost reaction illustrates these findings (see Figure 3.82) [254]. A similar situation prevails in other C-C and C-N coupling reactions since they also contain a PdL2 key intermediate. It is therefore no surprise that mixed NHC/phosphane ligand systems have been employed for the Mizoroki–Heck, Suzuki–Miyaura and Stille reactions [238,255–258]. In all these cases, the incorporation of a phosphane ligand instead of the second NHC ligand improves the activity of the catalytic reaction. Similar results are reported for the allylic alkylation of dimethylmalonate using mixed NHC/phosphane palladium catalysts [252]. We will now proceed by looking into the Suzuki reaction and the allylic alkylation reaction in more detail as key examples for the influence of mixed NHC/phosphane ligand systems on the performance of catalytic coupling reactions. The preparation of a mixed NHC/phosphane palladium(II) complex can be achieved by simply reacting [Pd(PPh3)3] with a 2-chloro-imidazolium salt [259]. Oxidative addition of the C-Cl bond yields the palladium(II) coordinated carbene and eliminates 2 mol of phosphane (see Figure 3.83). The cationic and neutral palladium(II) carbene complexes are in equilibrium with each other documenting the comparative lability of the Pd-PPh3 bond. The 2-chloro-imidazolium salt is accessible from the corresponding thione that can be synthesised by Kuhn’s method [260] from the diamine. Using a chiral 1,2-diaminocyclohexane scaffold produces a chiral saturated carbene.

N-Heterocyclic Carbenes with Neutral Tethers L X

PdL2

117

L X

Pd

Oxidative addition X

L

Pd

L

either/or L Pd

L

Pd

L

Nu

L

L Nu

Decomplexation

Pd

Reductive elimination

PdL2

L

L

Nu

Nu

Pd

L

Nu

PdL2

Figure 3.82 The mechanism of the Tsuji–Trost reaction.

C(O)Cl2

C(S)Cl2 NH

HN

But

But

N

But

But

But

N

N

But

N

Cl

S

[Pd(PPh3)4]

But

N Ph3P

N Pd Cl Cl

But

PPh3

But

N Ph3P

N

But

Pd PPh3 Cl trans

Cl

But

N Ph3P

N

Pd Cl PPh3

But Cl

cis

Figure 3.83 Facile preparation of a mixed NHC/PPh3 palladium(II) system.

Note: Kuhn’s thione method to prepare free NHC can be amended to produce 2-chloroimidazolium salts that can in turn be used to synthesise transition metal carbene complexes by oxidative addition. A more conventional arrangement is the reaction of an imidazolium iodide (or alternatively imidazolium chloride in the presence of NaI) with palladium(II) acetate as reported by Herrmann et al. [255] (see Figure 3.84). The Pd2I2 unit is subsequently cleaved by a phosphane yielding the desired mixed NHC/phosphane palladium(II) complex.

118

Functionalised N-Heterocyclic Carbene Complexes N

N

N

Pd [Pd(OAc)2]/NaI

I

N

I

I

N

Pd N

I N

PPh3

I

N Pd I

PPh3

Figure 3.84 A conventional route to mixed NHC/phosphane palladium(II) complexes.

Note: Herrmann et al. observed an equilibrium between the mixed NHC/phosphane palladium(II) complex and the two homoleptic complexes [Pd(PR3)2I2] and [Pd(NHC)2I2]. The ratio is given as 7:3. This would mean that three different palladium(II) complexes are potentially present in a catalytic reaction. Note: The above means that the Pd-NHC bond in [Pd(NHC)2I2] can relatively easily be cleaved in order to sustain the equilibrium. This poses the question, what exactly is the catalytically active species in these reactions? Herrmann et al. provide experimental results towards the answer. They carried out the pilot reactions – Suzuki–Miyaura, Heck and Stille – with the phosphane-free palladium complex [Pd(NHC)I]2 and the mixed NHC/phosphane palladium complex [Pd(NHC)(PR3)I2]. The bisphosphane complexes [Pd(PR3)2I2] are known to decompose to palladium black under the reaction conditions employed [255]. The Suzuki–Miyaura reaction proved to be indifferent to the catalyst when p-bromoacetophenone and phenylboronic acid were used as substrates. In the Stille reaction, for the same target product, the situation was drastically different. Here, the dimer [Pd(NHC)I]2 achieved only 11% of the yield given by the mixed catalyst [Pd(NHC)(PR3)I2], while the Mizoroki–Heck reaction between styrene and phenyl bromide again gave an indifferent result (92:87%). In a Suzuki–Miyaura reaction between phenylboronic acid and p-chlorotoluene, the results were very interesting. Here, [Pd(PCy3)2I2] gave the faster conversion (60 min versus 2.5 h) compared with [Pd(NHC)(PCy3)I2], but the latter had the greater yield (100:90%). The [Pd(NHC)2I2] complex fared very poorly with about 40% conversion after 5 h. Türkmen and Cetinkaya achieved similar results in the Suzuki–Miyaura reaction between p-bromotoluene and phenylboronic acid using either [Pd(NHC)(PPh3)Cl2] or [Pd(NHC)2Cl2] as defined catalyst [256]. The mixed NHC/phosphane complex gives consistently the same or significantly better yields. Liao et al. used a carboxylic acid amide functionalised carbene and a phosphane in a mixed NHC/phosphane palladium(II) catalyst [261]. The system shows the usual ligand exchange behaviour meaning that the PPh3 ligand can be substituted by PCy3. This made it possible to study the influence of the phosphane ligand on the performance of the catalyst. In the Suzuki–Miyaura reaction between phenylboronic acid and p-chloroacetophenone, the yield changes dramatically. When PCy3 is chosen as the phosphane ligand, then quantitative yield is observed (for both the saturated and unsaturated NHC), but in the case of PPh3 the yield drops to 8% (unsaturated NHC) or even 4% (saturated NHC). When

N-Heterocyclic Carbenes with Neutral Tethers [Pd(allyl)Cl]2 3 mol% additive (PPh3) dimethyl malonate (3 eq)

OAc * Ph

MeO2C

119 CO2Me

*

Ph DIPP N

N

Ag Cl Et

8.5 mol%

Ph

Ph

Ph

HN Ph

Figure 3.85 The use of the mixed NHC/phosphane ligand system in the Tsuji–Trost allylic alkylation reaction.

the sterically more demanding o-methoxy-phenylboronic acid is chosen together with the electron rich p-bromomethoxybenzene as substrate, the yield is high with only marginal differences on the choice of phosphane (86:92%). Flahaut et al. investigated the potential of chiral amino functionalised carbene ligands in the Tsuji–-Trost reaction [252]. In the absence of phosphane, the system (see Figure 3.85) generated the product in 33% yield after 2 days. The addition of 7 mol% (2.3 equiv.) PPh3 resulted in complete conversion after just 1 h. The assumption is that the phosphane replaces the hemilabile amino sidearm carrying the chiral information. This is confirmed by a rapid drop in ee (76% down to 10%). After noting this phenomenon, Flahaut et al. proceeded to investigate monodentate, nonfunctionalised and achiral NHC ligands in the Tsuji–Trost reaction, with and without phosphane additive. They found no reaction without phosphane and very low reactivity in the absence of carbene. Apparently, both ligands are needed for high reactivity. Interestingly, the reaction can be performed even at low phosphane loadings. When 0.5 equiv. of PPh3 (relative to palladium) were used, the reaction still went to completion, but took much longer. Not surprisingly, the nature of the carbene also plays a major role. Best results (conversion and reaction rates) were obtained when at least one of the wingtip groups on the carbene was reasonably small. Even the replacement of a methyl group by a benzyl one increases the reaction time to completion by a factor of six. When it is replaced by DIPP, it no longer reaches completion, but the reaction comes virtually to a stop after 5 min (56%). After 90 min it is still at only 58% completion. The catalyst is not only active in the Tsuji–Trost reaction (allylic alkylation), but also in the corresponding amination reaction. This was shown by the reaction of (E)-1,3-diphenylprop3-en-yl acetate with benzylamine that resulted in two products (see Figure 3.86). Modification of the base (K2CO3 98%; KOH 68/16%) suppresses the by-product. It was originally reported that NHC-palladium complexes are unsuitable for nitrogen nucleophiles in these catalytic coupling reactions [262], but soon after, the reaction could be performed, albeit with a low activity [263] under anhydrous conditions. When biphasic conditions are employed, the amination reaction becomes reasonably active (reaction time 4–6 h; near quantitative yield) [250,252]. Note: The Tsuji–Trost reaction works best with mixed NHC/phosphane ligands and under biphasic conditions.

120

Functionalised N-Heterocyclic Carbene Complexes Ph

Ph

[Pd(allyl)Cl] 22.5mol% additive (PPh3) 5mol% benzylamine (2eq)

OAc

O

Ph Ph

Ph Mes

N

N

NH

6 mol%

Ph Ph

Ph Ag

Ph

Major

Minor

I

Figure 3.86 Allylic amination using mixed NHC/phosphane palladium(II) catalysts.

Note: The corresponding amination reaction has only been reported with good yield using NHC-palladium systems when biphasic conditions were employed. We conclude that the addition of phosphanes to palladium(II)-NHC complexes is advantageous with respect to reaction times, yield and completion ratio for a wide range of catalytic coupling reactions including Tsuji–Trost, allylic amination, Suzuki–Miyaura, Heck and Stille. Chang et al. investigated the amination of benzyl alcohol in benzyl alcohol using an iridium catalyst with mixed NHC/phosphane ligands (see Figure 3.87). A systematic comparison between the catalytic system in the presence or absence of phosphane was not reported and we have to rely on a single entry for judgement [264]. This single entry indicates that the addition of phosphane might determine the nature of the product rather than the feasibility of the catalytic process as such. With phosphane addition, the product distribution is in favour of N-benzylaniline (47:32%), whereas in the absence of phosphane the major product is the Schiff base (61:24%). Another important factor is the choice of base, with KOH being the clear favourite for the formation of N-benzylaniline. Note: In the present case, the excellent π-acceptor ligand carbonyl is replaced by the good but weaker π-acceptor ligand phosphane. Note: The better π-acceptor PPh3 gives a higher N-benzylaniline to Schiff base ratio than the weaker π-acceptor ligand PCy3. Note: There is no clear relationship between electronic ligand properties and product distribution. A steric contribution of the coligand (CO, PR3) is expected. We will now turn our attention towards the synthesis and application of phosphane functionalised carbenes. A very interesting class of ligands is based on the ferrocene [265–267] scaffold. Cp functionalised carbenes will be discussed in Section 4.3 and we will find our ferrocene functionalised carbenes there as well. However, the synthesis of the ligands involves a strategy to introduce the phosphane and carbene moieties onto the ferrocene scaffold in a way that optimises results despite the fact that both groups are best introduced last. An elegant synthesis comes from Gischig and Togni [268,269] starting from the diastereoselective ortho functionalisation of (R)-N,N-dimethyl-1-ferrocenylethylamine which is a standard method to introduce central (already in the starting material) and planar (owing to the second substituent on the Cp ring) chirality on the ferrocene scaffold [267,270–272] (see Figure 3.88).

N-Heterocyclic Carbenes with Neutral Tethers Ph N

N Cl

[Ir(cod)Cl]2

Ag I N

Ph

Ph

Ph

N Cl

CO

N

N

Ph

N Cl

PR3 Ir

Ir

2

Ir

CO CO

N

Ph

Ph

121

PR3 CO

Ph

Ph N Cl HO

NH2

N

Ir PR3 CO

Ph

NH

N

Figure 3.87 Amination of benzylic alcohol using a mixed NHC/phosphane iridium catalyst.

NMe2

1) BuLi 2) ClPPh2 3) AcOAc

OAc PPh2

N

NH

Fe

Fe

N

Fe

N

PPh2

Ph2P

Fe

1) NaOBut 2) [Ru(PPh3)3Cl2]

Fe PPh2

NCMe N

Fe

P Ph2

Fe

N Ru

Ph2P

Cl [OEt3]PF6 acetonitrile

N

Ru

PPh2

Cl

N NCMe

Cl

Fe

mer "fac"

Figure 3.88 Synthesis of a carbene analogue of pigiphos.

Note: The conversion of the dimethylamino group to the acetate becomes necessary because introduction of the imidazole would otherwise result in the oxidation of the phosphane [273]. Comment: Seo et al. [273] performed their reaction in acetic acid, which might well have been glacial acetic acid. Gischig and Togni [268,269] repeated it initially with acetic acid and then improved it by using acetic acid anhydride. The time of addition of imidazole might be decisive to prevent oxidation of phosphorus. The substitution reaction itself proceeds with retention of configuration at the stereogenic centre irrespective of which functional group is replaced (NMe2 or OAc).

122

Functionalised N-Heterocyclic Carbene Complexes

Introduction of the imidazole results in the symmetric, disubstituted imidazolium salt [268], whereas the monofunctionalised compound is accessible when an N-substituted imidazole is used [273,274]. The symmetric, difunctionalised imidazolium salt was the target in Barbaro and Togni’s synthesis of a pigiphos [275] analogue. We once again encounter a case where the development of a functionalised carbene follows in the wake of the successful application of a (functionalised) phosphane. The main difference between pigiphos and its carbene analogue is the symmetry: pigiphos is C1-symmetric (owing to the cyclohexyl rest) and the carbene analogue has C2 symmetry (NHC have only two wingtip groups resulting in the scrapping of the symmetry relevant cyclohexyl group). It is interesting to note that the pigiphos ligand adopts a fac-like coordination mode on the square pyramidal ruthenium(II) complex, unlike the Grubbs’ catalyst where the two phosphanes (NHC) and the ylidene (=CHPh) are meridonially arranged [276–278]. The mer (pincer) geometry is restored upon halogen abstraction and acetonitrile coordination to form an octahedral complex with the two acetonitrile ligands trans to each other. Incidentally, this is reminiscent of the archetypical pincer geometry displayed by the corresponding palladium(II) complex which is isoelectronic to the square pyramidal ruthenium(II) complex. The empty coordination site below the base of the pyramid in this complex is approached by a hydrogen atom of the wingtip methylene group in a so-called remote agostic interaction [279]. Phosphino functionalised carbenes do not need to be used in situ or the carbene complexes generated without the formation of the free carbene. Danopoulos et al. have isolated and structurally characterised a phosphino functionalised carbene after deprotonation of the corresponding imidazolium salt with KN(SiMe3)2 [280], a feat repeated by Hodgson and Douthwaite using a chiral imidazolium salt [243]. The more popular routes towards transition metal phosphino functionalised carbene complexes avoid the formation of the free carbene and apply one of several in situ methods. Lee et al. reacted the phosphino functionalised imidazolium salt with palladium(II) chloride in the presence of sodium acetate as base [241,281] resulting in the expected palladium(II) chelate complex. An alternative route to the same phosphino functionalised imidazolium salt was introduced by Tsoureas et al. [282]. It involves the reaction of an N-arylimidazole with (ω-bromoalkyl) diphenylphosphine oxide followed by reduction with trichlorosilane (see Figure 3.89). They proceeded to synthesise the corresponding palladium(II) carbene complex and investigated the reactivity of this complex. It could be shown that the dimethyl and dibromo complexes could be synthesised and that from them cationic complexes featuring diverse π-donor ligands are accessible (see Figure 3.90). O

O P Br

Ph Ph

N

N

Ar Ar

N

P N

Ph Ph

SiHCl3

Ar

N

PPh2 N

Figure 3.89 Syntheses of a phosphino functionalised imidazolium salt using the silane reduction route.

N-Heterocyclic Carbenes with Neutral Tethers Ar

Ar Br

N

Ph2P

Pd

MeCN N Pd

Br PPh2

1)KN(SiMe3)2 2) [Pd(cod)Cl2]

123

AgBF4

NCMe PPh2

N

N

N 1) KN(SiMe3)2 2) [Pd(tmed)Me2]

Ar

Ar N

N

N

Pd PPh2

Ar

MeI

N I

N Pd

P Ph

1) BARF 2) MeCN

I

I Ph

1) BARF 2) PMe3 1) BARF 2) py

Ar MeCN N

Ar

Pd PPh2

N

Ar N

py

N

Pd

Me3P

Pd PPh2

PPh2

N

N

Figure 3.90 Reactivity of a palladium(II) phosphino functionalised carbene complex.

Note: Reaction of the dimethyl palladium(II) carbene complex with excess methyl iodide leads to decomposition of the compound by reductive elimination of an imidazolium salt that remains pendant on the phosphane anchor [283]. Note: The route via the phosphane oxide was chosen because yields using the more common route (the reaction of N-arylimidazole with 1,2-dibromoethane and subsequent phosphonylation) were poor [238]. The decomposition of the dimethyl palladium(II) carbene complex with excess methyl iodide is a stepwise process. Although the authors [282] propose oxidative addition of methyl iodide on the palladium centre forming an octahedral palladium(IV) complex, it seems much more likely, with respect to the rarity of palladium(IV) compounds [284,285], that the first step is reductive elimination of an imidazolium salt, a decomposition pathway found to be fairly common after the initial publication of McGuinness et al. [283]. Oxidative addition of methyl iodide followed by reductive elimination of ethane would account for the accumulation of iodide ligands on the palladium centre and a Pd(0)/Pd(II) redox couple. However, in the last step, a six coordinate Pd(IV) centre still seems to be necessary (see Figure 3.91). Note: In all the electronic nonsymmetric square planar cationic complexes, the methyl group is found trans to the carbene. The palladium(II) complexes with chelating phosphino functionalised carbene ligands were successfully tested in catalytic reactions. Among these were the Heck reaction [238,282],

124

Functionalised N-Heterocyclic Carbene Complexes Ar

Ar

N

Ar

N

N

N

Pd

N

MeI

PPh2 Pd

P

N

I

I Pd

P

Ph

Ph

Ph

I Ph

MeI Ar

Ar N

C2H6

N

N

N I

I Pd

P Ph

I Ph

I

P Ph

I

Pd I

I

Ph

Figure 3.91 Decomposition of a palladium(II) phosphino functionalised NHC complex with excess methyl iodide.

ethylene/CO copolymerisation [282], Suzuki–Miyaura reaction [241], asymmetric allylic substitution [243] and asymmetric transfer hydrogenation [243]. Far more interesting, both as a ligand and as a synthetic route to prepare it, is the approach by Lang et al. to prepare a phosphino functionalised carbene complex of a transition metal [286] (see Figure 3.92). The phosphino functionalised carbene is generated in the coordination sphere of palladium(II) in a template [4+2] Diels-Alder reaction between a coordinated 1-phenyl3,4-dimethylphosphole and 1-vinylimidazole. The reaction only proceeds in the presence of palladium(II) and is faster with the benzylamine coligand than with the phosphole as coligand. The exo-cycloadduct is the sole product. Zhong et al. built their phosphino functionalised carbene ligand on a phenylene scaffold using o-fluoroaniline as the starting material [287] (see Figure 3.93). The fluoro substituent is used to introduce the phosphino group and then the amino group serves as the starting point for an elaborate protocol to build the imidazolium ring. Note: O-phosphinoaniline is used to synthesise an unsymmetric imidazolium salt. This protocol can serve as an alternative to the rather unspecific and not very well understood Gridnev protocol [288] that usually proceeds in moderate yield for the first substituent and, owing to its quarternisation step, is limited to imidazolium salts carrying at least one alkyl wingtip group [246,289]. Zhong et al. used their phosphino functionalised carbene ligands successfully in the palladium catalysed hydroarylation of bicyclic alkenes. Our now familiar phosphino functionalised imidazolium salt – Ph2PCH2CH2ImMes+– has attracted further attention to warrant a third route for its synthesis. Nolan and coworkers used arylimidazole, dibromoethane and KPPh2 and obtained a rather low yield (21%) [238], whilst Tsoureas et al. chose the reduction of the corresponding phosphane oxide with SiHCl3 under harsh conditions and had no control over the anion [282]. This prompted Wolf et al. to develop a third route [290], another modification of Nolan’s protocol [238].

N-Heterocyclic Carbenes with Neutral Tethers

Ph

P

125

Cl

Pd Cl

P

Ph

N Cl

N Cl

or N

N

Pd

N

Cl

Cl

Cl Cl

P Ph

Pd P Ph

Figure 3.92 Synthesis of a transition metal phosphino functionalised carbene complex starting from a coordinated phosphole. Boc

(Boc)2O

KPPh2

NH2

NH

NH2

F

PPh2

PPh2

H HC(OEt)3

N

H N

H N

Br

H N

Ar

H

Boc H Ar

MeOH/HCl

N

N

Ar

Ar PPh2

PPh2

PPh2

Figure 3.93 Synthesis of a phosphino functionalised imidazolium salt on an o-phenylene scaffold.

Instead of 1,2-dibromoethane, they chose to react 2-bromoethanol thus avoiding a possible quarternisation reaction with the loose bromoalkyl end of the Nolan protocol. The OH group is exchanged for mesylate that subsequently serves as a leaving group with the introduction of the phosphane functionality (see Figure 3.94). As a variant, the OH group can be exchanged for bromide using PBr3. Note: The exchange of the bromide anion for tetrafluoroborate becomes necessary to avoid loss of the product during aqueous workup. The yield increases from 13 to 96%. Wolf et al. used the phosphino functionalised imidazolium salt to react it with nickel(II) bromide forming the P-coordination product (see Figure 3.95). Attempts to deprotonate

126

N

Functionalised N-Heterocyclic Carbene Complexes OH

Br

HO

N

N

N

NaBF4 PBr3 MsCl NEt3

Br

N

N

MsO

N

N

HPPh2/KOBut

1) HPPh2/KOBut 2) SiHCl3

Ph2P

N

N

Figure 3.94 Another route towards phosphino functionalised imidazolium salts. Br Ph2P

N

NiBr2

N

Ni

Br P

Br Ph

N Ph

N

Figure 3.95 Synthesis of a nickel(II) phosphino functionalised imidazolium complex for use as catalyst in the Kumada–Corriu reaction.

the imidazolium salt with subsequent formation of the nickel chelate complex failed to produce a single pure and defined product. It may be noted that Danopoulos et al. arrived at the corresponding palladium(II) complex by reacting the palladium chelate complex with excess methyl iodide [282]. The NiX3L (X = Cl, Br; L = phosphino functionalised imidazolium salt) complexes were used in a Kumada–-Corriu reaction [291–295], a C-C cross-coupling reaction employing a nickel or palladium catalyst that transfers a Grignard reagent onto a substrate. We are in for a few surprises with the chemistry of rhodium and iridium. Let us stay with the phosphino functionalised imidazolium salt Ph2PCH2CH2ImMes+ and react it with the precursor complexes [M(cod)OEt]2 (M = Rh, Ir) [296]. As expected, the corresponding cationic phosphino functionalised carbene complexes are formed (see Figure 3.96). Note: In the case of rhodium(I), the system reacts with a substitution reaction (two CO ligands for one cod), but for iridium(I) an addition is observed.

N-Heterocyclic Carbenes with Neutral Tethers

Ph2P

N

[M(cod)OEt]2

N

127

Ph

Ph

P M

N

M Rh, Ir N

CO

CO

N Ph

P

Ph

N

CO

Rh

N

CO

P Ph2

Ir

CO

N

Figure 3.96 Rhodium(I) and iridium(I) complexes of a phosphino functionalised NHC ligand.

The coordination geometry of the five coordinate iridium(I) complex is distorted trigonal bipyramidal with the carbene and an olefinic bond of the cod ligand in axial positions. The carbene assumes its expected position (according to VSEPR [297]) [131] and the phosphane (tethered to the carbene as it is) is forced into an equatorial position. This leaves the CO ligand with a choice of either equatorial or axial. As we have already seen [282], the ligand with the least π-acceptor ability (methyl in [282]) is trans to carbene. That leaves our CO ligand in the equatorial position (cis to carbene) and an olefinic double bond from cod in the axial position (trans to carbene). Note: The structure of the five coordinate iridium(I) complex is just as expected, but we are still at a loss as to why it is formed at all. Replacement of the cod ligand by two CO ligands would have seemed more probable. The complexes were used in catalytic intramolecular hydroamination reactions resulting in the intramolecular cyclisation of aminoalkynes [298,299]. When the stoichiometry is changed and 2 equiv. of phosphino functionalised imidazolium salt reacted with 1 equiv. of rhodium(I), a homoleptic, cationic rhodium(I) complex is formed where the carbenes are trans to each other [300]. The corresponding reactions with iridium(I) precursors again behave differently. When the phosphino functionalised imidazolium salt is reacted with [Ir(cod)Cl]2, the phosphane adduct with a pendant imidazolium moiety is formed. A similar reaction with the more reactive [Ir(cod)(μ-H)(μ-Cl)2]2 yields a five coordinate iridium(I) complex that might be described as having square pyramidal geometry with the bromide in apical position and the carbene in ‘abnormal’ coordination mode [47–49] (see Figure 3.97).

128

Functionalised N-Heterocyclic Carbene Complexes

Ph Ph2P

N

N

[Ir(cod)(-H)(-Cl)2]2

N

P

Ph Ir Br

Mes N Mes

Figure 3.97 Synthesis of an iridium(I) complex with abnormally coordinated phosphino functionalised NHC ligand.

The reaction of a [2.2]-paracyclophanyl imidazolium salt (depicted in Figure 3.80) with [Ir(cod)Cl]2 yields the expected square planar and cationic iridium(I) complex [244] that can be used in the hydrogenation of functionalised alkenes with an ee of up to 89%. We know how to attach one phosphino function to an imdazole ring and can imagine from there how to attach the other. A substituted imidazole yields a chloroethylimidazolium salt if reacted with 1,2-dichloroethane. If the reaction is carried out with imidazole itself, two chloroethyl wingtip groups are introduced giving rise to two phosphinoethyl wingtip groups [242] (see Figure 3.98). Similarly two o-chloromethyl-phosphinophenylene molecules can be added to introduce the phosphinated wingtip groups directly [245]. Zhong et al. [287] reported that the route involving the reduction of the respective phosphane oxide with SiHCl3 failed in the reduction step. This observation had already been made by Wolf et al. [290]. Formation of the palladium(II) complexes can be achieved using standard protocols and resulting in square planar complexes with mer (pincer) chelate structure. The six-membered, very flexible metallacycles featuring alkyl linker chains display ‘chiral puckering’ that would make the use of chiral analogues difficult in asymmetric catalytic applications. Lee et al. [242] showed that the palladium(II) complex can be synthesised via the silver(I) oxide route with carbene transfer or directly with PdCl2 in the presence of a base. Abstraction of chloride with AgBF4 results in the formation of the corresponding dicationic complex after uptake of a ligating solvent molecule. The same principles can be applied when benzimidazole is used instead of the customary nonannulated imidazole. Hahn et al. [301] used a variant of the 1,2-dibromoethane method to introduce the bromoethyl wingtip group. By choosing 1-bromo-2-chloroethane they exploited the different reactivities of the two halogens. The bromo end reacts much faster avoiding the unwanted quarternisation reaction and thus improving the yield. Again, employment of the silver(I) oxide method yields the corresponding palladium(II) complexes after carbene transfer (see Figure 3.99). The now familiar abstraction of chloride results in the formation of the cationic complex after ligation of pyridine. These palladium and platinum (completely analogous to palladium) complexes were used in the C-C coupling reaction of aryl bromides carrying functional groups in the para position with styrene or n-butyl acrylate at elevated temperatures. Note: The pincer complexes are less active then those with monophosphinated carbene ligands.

N-Heterocyclic Carbenes with Neutral Tethers

129

Cl Cl Cl K2CO3

HPPh2

N

Cl

Cl

N

N

KOBut

N

N

NH

N

N

Cl

Ph2P

Cl

Me2NHCl

O

PPh2

BuLi PPh2Cl

N

[Ti(OPri)4]

N

PPh2

ClCO2Et

N

N N

PPh2

NH

Cl

K2CO3

Ph2P

PPh2

Figure 3.98 Synthesis of phosphino functionalised imidazolium salts carrying two phosphino wingtip groups. Cl

Cl Cl Cl

N

N

K2CO3

N H

Cl

N

Br

N

N

Cl HPPh2 KOBu PPh2

N

PPh2 Pd

N

PPh2

[Pd(cod)Cl2]

PPh2

N

Cl

t

Ag2O AgCl

N

N

N

PPh2

PPh2

Figure 3.99 Synthesis of doubly phosphino functionalised benzimidazolium salts and their transition metal complexes.

130

Functionalised N-Heterocyclic Carbene Complexes

N PPh2

N

Ag2O

PPh2

N

PPh2

Ag

N

N

Ph2P Ag

Ag

Ph2P N

Ph P

PPh2

N

N

[Rh(CO)2Cl]2

Ph

Rh

P Ph CO

Ph Cl

[Rh(cod)Cl]2

PPh2 Cl Rh Cl

N

N

N dmf,

Cl PPh2

PPh2 Rh

N

PPh2

PPh2 CH2Cl Cl

N Cl

CH2Cl2

Rh N

Cl PPh2

Figure 3.100 Synthesis of rhodium(I) and rhodium(III) complexes from doubly phosphino functionalised NHC ligands.

Switching from palladium to rhodium, we encounter some very interesting chemistry. Zeng et al. [302] reacted the tridentate PCP phosphino functionalised imidazolium salt with silver(I) oxide and subsequently transferred the carbene to rhodium(I) (see Figure 3.100). Careful selection of the rhodium precursor complex and reaction conditions enables tetrahedral, square bipyramidal and octahedral rhodium(I) and rhodium(III) complexes to be formed. As the authors explained, the activation of the C-Cl bond in methylene chloride in an oxidative addition reaction on rhodium(I) resulting in a rhodium(III) complex requires an electron rich rhodium(I) complex. The presence of a NHC ligand is advantageous in this respect. The structure of the trigonal bipyramidal rhodium(I) complex in Figure 3.100 (top right) could not be determined unequivocally, but using the same reasoning employed for the similar iridium complex from Figure 3.96, we favour the structure depicted in Figure 3.100 rather then the ligand arrangement drawn by Zeng et al. [302]. Note: We have found that it is of no particular importance whether the phosphino group or the imidazolium group is introduced last into the phosphino functionalised imidazolium framework, but it pays to generate the carbene after the phosphino groups are in place. Note: There is no rule without a possible exception. Consider the Diels-Alder reaction in Figure 3.92. We are left with a pendant chloroethyl sidearm that can be used to introduce a second phosphino group after the transition metal carbene is already formed.

3.4 Bis-Carbene Ligands A bis-carbene ligand has two equal (symmetric) or very similar (unsymmetric) donor centres. The situation is, once again, analogous to the corresponding diphosphane ligands on

N-Heterocyclic Carbenes with Neutral Tethers

131

which the bis-carbene ligands are modelled. We are therefore not surprised to encounter similar questions, considerations, challenges, applications and solutions. In particular, central questions will be about the tether length, the ligand preferred bite angle, bridging or chelating bonding mode, modification of electronic properties (symmetric or unsymmetric distribution) and the steric influence of the wingtip groups. These questions have been raised for diphosphane ligands and have been answered in numerous publications. A very central question is presented when one considers the tether lengths in relation to bridging or chelating coordination to metal centre(s). With carbenes the situation is doubtless different from that encountered in phosphanes. This follows directly from the shapes of the NHC (wedge) [303,304] and phosphanes (cone) [305–307] and their respective ligand bite angles [51,52,131]. One would expect that with the carbene lone pairs being in a more unfavourable direction to those in phosphanes, the tether in a bis-carbene needs to be longer than in a diphosphane in order to enable a cis chelate coordination on the same metal centre. We will therefore investigate first the relationship between the tether length in bis-carbenes and their ability to form chelate metal complexes. A first comparative investigation comes from Peris and coworkers [308,309] who synthesised a series of n-butyl substituted bis-carbenes with tether lengths ranging from one to four methylene units (n = 1–4). Reaction of these imidazolium salts with silver(I) oxide and subsequent carbene transfer to rhodium(I) – with [Rh(cod)Cl]2 as the rhodium source – gave the corresponding [Rh(cod)Cl] complexes, bridging (n = 1,2) and chelating (n = 3,4) [309] (see Figure 3.101). Neveling et al. [308] reported similar results with an even smaller wingtip group (Me) and n = 3. Confirmation for the assumption that the cut-off line between bridging and chelating coordination might lie just past the ethylene bridge comes from Lappert and coworkers [310,311]. They synthesised a saturated, ethyl tethered bis-carbene that contains an alicyclic electron-rich olefin as the carbene precursor. Thermolysis in the presence of [Ru(cod)Cl]2 as the rhodium(I) source affords the bridging dinuclear transition metal complex (see Figure 3.102). A tetracyclic analogue of the electron-rich olefin featuring two propyl tethers yielded a chelating

N N Bun

Cl

N

nN

n 1 4

N Bun

1)Ag2O 2) [Rh(cod)Cl]2

Rh Cl

N n

Rh

N

N

N

n

Bu

nN

Rh

N

n 3, 4 Bun

n 1, 2

N

Figure 3.101 Dependence of the coordination mode of bis-carbenes on the tether length.

132

Functionalised N-Heterocyclic Carbene Complexes

N

N N

N

N

N

Ph N

N N

[Rh(cod)Cl]2 Ph

Cl

Ph N

Rh [Rh(cod)Cl]2

Cl Rh

N

N

Ph

Rh

N

N

N

N

Figure 3.102 Bridging and chelating alkyl tethered rhodium(I) bis-carbene complexes derived from electron-rich olefins.

bis-carbene rhodium(I) complex under similar reaction conditions [312] in accord with our present assumption. A more detailed study from Leung et al. [313] significantly disturbs our present simplistic view on the tether length as the sole discriminator between bridging and chelating mode in these alkyl linked bis-carbene ligands. We half guessed already that the remaining wingtip group may not be as innocent as it appears and that its steric demands may come to play a major role in the outcome. So far, we have only considered sterically indifferent substituents (Me, n-Bu, benzyl in short unbranched alkyl groups). However, before we turn to this rather obvious factor, it might be profitable to muse over the reaction temperature. We have already seen that at room temperature, the product distribution in Figure 3.101 is bridging for n = 1,2 but chelating for n = 3,4. Performing the same reaction under reflux conditions (a modest rise in temperature to 40 ˚C since the solvent is CH2Cl2) affords only the bridging product, irrespective of the tether length. Changing the size of the wingtip group leads to a somewhat surprising result. Now, a chelate complex is only formed when n = 1 and longer tether lengths result in bridging complexes [313]. The reason lies in a closer proximity of the two bulky tert-butyl groups in a cis chelate complex when the tether is long. Unbranched alkyl groups are sterically innocent enough not to influence the structural outcome. For an iso-propyl wingtip group we observe a borderline behaviour. Now, the two possible complexes are observed in a 4:7 ratio in favour of the bridging complex. Another consideration involves the anion, taken to be noncoordinating in all cases. We mark that in all cases discussed here the rhodium(I) precursor complex is [Rh(cod)Cl]2, which has its coordinating anion chloride already in place. For the chelating complex, the chloride ligand is displaced by the second carbene creating a cationic rhodium(I) complex.

N-Heterocyclic Carbenes with Neutral Tethers

133

In the bridging complex, the chloride ligand is retained and the complex is neutral. It is now of import, how the second, noncoordinating anion, namely PF6-, is introduced. When it is introduced after the rhodium(I) precursor then n = 1 is the only chelating complex for carbenes with the tert-butyl wingtip group. When KPF6 is added before [Rh(cod)Cl]2, however, even n = 2 is a chelating complex in contrast to the assumption that longer tether lengths result in clashing bulky wingtip groups and thus bridging complexes. Note: The formation of bridging versus chelating bis-carbene transition metal complexes is a function of tether length, reaction temperature, steric demand of wingtip groups and the order of the addition of counter anions. It is only fair to add that another very important factor determining the outcome of the bridging versus chelating question must be the transition metal itself. The groups of Peris [309], Cetinkaya, Raubenheimer [310] and Crabtree [313] all investigated square planar rhodium(I) complexes with a metal preferred bite angle [306,307] of 90˚. The next most popular transition metals in this field are the ever present [314] silver(I) complexes and square planar palladium(II) complexes, the latter being expected to behave similar to their rhodium analogues. However, with silver things are different. Silver(I) carbene complexes are frequently found to realise linear (180˚) or trigonal planar (120˚) coordination environments [314]. A study by Lee et al. [315] confirms this as it finds a bridging complex with n = 2, a methyl wingtip group and most importantly, a trigonal planar geometry around silver(I). Note: The metal preferred bite angle is another important factor in the formation of either the bridging or the chelating complex. With the unsymmetric bis-carbene palladium(II) complexes coming from Foley’s research group, we are again on firm ground: a square planar metal complex and sterically innocent wingtip groups (methyl, benzyl, p-But-benzyl) let us suspect the preferred formation of a chelate complex and this is indeed what is observed [316]. Moving to the third main group (group 13) brings us into new territory, geometrically speaking. Here, we encounter trigonal bipyramidal coordination geometries (as expected from hypervalent 10-E-5 compounds [317,318]) that are accompanied by a metal preferred bite angle of 120˚ and tetragonal coordination geometries (as expected from VSEPR theory for 8-E-4 compounds [319,320]) accompanied by a metal preferred bite angle of 109.5˚. The chosen bis-carbene ligand has a sterically demanding wingtip group in tert-butyl and the structurally characterised [In(NHC)2Br3] complex is chelating with both NHC moieties in equatorial position [321]. The equally structurally characterised [InH3{NHC(CH2)2NHC}InH3] complex is bridging. Steric considerations clearly do not play a role as the InH3 moiety has obviously more space around the metal than the InBr3 moiety with the bulkier bromide ligand. However, InH3 prefers the tetrahedral 8-E-4 structure with only one vacant coordination site for the carbene over the trigonal bipyramidal 10-E-5 structure with two vacant coordination sites for NHC ligands (see Figure 3.103). The cause for the failure for the InH3 fragment to attain a coordination number of five is still unexplained [321,322], but is thought to be founded on the great nucleophilicity of the carbene that electronically satisfies the indium centre and makes the

134

Functionalised N-Heterocyclic Carbene Complexes

N N

:

N N :

But

But

But N H H

In

LiInH3

InBr3 N

N

Br N

H

H

In

H H

N

N But

In Br

N Br Bu

N Bu

t

t

Figure 3.103 Bridging tetrahedral (8-E-4) and chelating trigonal bipyramidal (10-E-5) group 13 carbene complexes with bis-NHC ligands.

realisation of hypervalent coordination geometries unnecessary. In the InBr3 adducts, the indium centre is naturally more electrophilic than in InH3 and thus hypervalency becomes desirable. The determining factor in these group 13 carbene complexes of whether the bridging or chelating bis-carbene complex is formed is the electronic requirements (ultimately the nature of the coligand) of the metal centre. Note: The electronic requirements (and thus the coordination number) of the metal centre is another important factor in the formation of either the bridging or the chelating complex. For once, annulation does not seem to play a major role in the outcome of the resulting transition metal carbene complexes. Hahn et al. [323] report on a cis-bis-carbene palladium(II) complex synthesised by thermolysis of the corresponding electron-rich olefin (n = 3; ethyl wingtip) in the presence of PdI2 and Demir et al. [324] report on the catalytic activity (Heck and Suzuki couplings) of in situ prepared bis-carbene palladium(II) complexes (n = 1–4; substituted arylmethylene wingtip groups). Since the activities are similar irrespective of the tether length, one is led to assume that cis chelate complexes are formed in the course of the reaction. Having seen that structural predictions are very difficult, we will now turn to the choice of transition metal. We have already seen the dependence of the coordination mode in square planar complexes on various factors and noticed the preference for polymeric chains with the silver(I) complexes owing to the linearly coordinated silver centre. Chiu et al. [325] reported on a series of arylmethylene and methyl wingtipped bis-carbene complexes of silver(I) (polymeric bridging) and palladium(II) (monomeric chelating). Carbene transfer to palladium was achieved in DMSO since solubility in CH2Cl2 was very poor.

N-Heterocyclic Carbenes with Neutral Tethers

135

O

O

O

Br

OH I

I

N

O

Pd

N

N

N

N

N OH

N HO

Pd I

I

[Pd(OAc)2]

N

HO N

OH

N

N

N

Figure 3.104 An immobilised cis-bis-carbene complex of palladium(II).

Note: The polymeric nature of these silver(I) bis-carbene complexes limits their solubility in most organic solvents including the standard CH2Cl2. Strong donor solvents like DMSO overcome this problem, probably by breaking the silver-halogen bridges. Schwarz et al. [326] synthesised a functionalised bis-imidazolium salt with hydroxy end groups on the wingtips [327,328] and used it in the formation of chelating cis-bis-carbene complexes of palladium(II) applied as catalysts in the Heck reaction. The functional groups were needed to immobilise the catalyst by attachment to a polymeric support [329] (see Figure 3.104). The main intention behind this work is of course the immobilisation of the catalyst in catalytic processes accompanied with retention of high activities, recovery of the catalyst and the prevention of leaching from the reaction vessel. Similar cis-bis-carbene chelate complexes of palladium(II) [327,330,331], but without the hydroxy functional groups on the wingtips, were used by the same research group for the copolymerisation of ethylene and CO. Once again, chelating bisphosphane complexes inspired the synthesis and application of their NHC counterparts [332,333]. The actual, defined catalyst precursors were the cationic complexes formed after halide abstraction with silver salts in acetonitrile as donor solvent. In a study involving [Ru(p-cymene)Cl2]2 as the transition metal precursor complex, Peris and coworkers [334] investigated the influence of the wingtip groups on the coordination behaviour of the second carbene unit. They found that the sterically demanding neo-pentyl group prevents the formation of a chelate leaving the second imidazolium unit pendant (see Figure 3.105).

136

Functionalised N-Heterocyclic Carbene Complexes

N

N N

N

N

N

[Ru(p-cymene)Cl2]2 NEt3

[Ru(p-cymene)Cl2]2 NEt3

N

But NH

N

t

Bu

N

Ru I

N

N

N N

potential steric congestion

Ru N

I N

I

Figure 3.105 Influence of the steric bulk of the wingtip group on the coordination behaviour of the second carbene unit at ruthenium.

The reason is most likely steric crowding between the wingtip groups and the alkyl substituents on p-cymene. Whilst the first carbene ligand adopts a ‘staggered’ conformation, the second must position itself ‘eclipsed’, which appears to be unfavourable for the bulky tert-butyl group of the neo-pentyl wingtip group. Poyatos et al. [335] found a curious reaction behaviour in the formation of rhodium bis-carbene complexes. Dependent on the availability of dioxygen (from nondegassed solvents), oxidation of rhodium(I) to rhodium(III) was observed accompanied by a change of coordination mode from bridging (Rh(I)) to chelating (Rh(III)) (see Figure 3.106). There is no obvious steric reason for such a difference in coordination behaviour, since the square planar geometry around rhodium(I) is similar to the octahedral environment of rhodium(III), but the strong nucleophilicity (π-donor strength) of the carbene might just sufficiently stabilise the rhodium(III) centre electronically to warrant chelate coordination. Crabtree and coworkers found a similar oxidation state dependent coordination behaviour for related iridium(I) and iridium(III) bis-carbene complexes [336]. Note: The coordination behaviour (bridging versus chelating) of transition metal biscarbene complexes can be dependent on the oxidation state of the metal centre. Chelating coordination is favoured by the higher oxidation state. Öfele et al. found group 6 bis-carbene carbonyl complexes to be invariably chelating, but their wingtip group was limited to methyl [337]. Another interesting class of bis-carbenes is derived from Trofimenko’s bis-pyrazolatoborate ligands [338–340] and contains a BH2-linker unit instead of methylene between the

N-Heterocyclic Carbenes with Neutral Tethers

N

N

NCMe

N

[Rh(cod)Cl]2

I

NCMe N

I

Rh

137

N

O2

N

N

N

[Rh(cod)Cl]2 Rh

N

N

I

I

Rh

N N

Figure 3.106 Dependence of the coordination mode (bridging versus chelating) on the oxidation state of the metal.

two imidazolium units. This renders the ensuing bis-carbene a monoanionic ligand overall (see Cesar’s monoanionic oxygen functionalised carbene, Section 3.2). The first such biscarbene was introduced by Fränkel et al. [341] and was used to synthesise and structurally characterise a variety of transition metal carbene complexes (see Figure 3.107), including those of palladium, platinum and gold. Publications on the coordination of these ligands to silver [342], gold [342] and nickel [343] followed sometime later. In the homoleptic complexes of group 10 metals, the two bis-carbene ligand units are coordinated in antiparallel fashion called a trans double-boat conformation [343]. The steric influence of the wingtip group can be seen in the magnetic properties of the complex as the nickel(II) compound with tert-butyl wingtips on the bis-NHC ligand no longer has square planar geometry but forms an octahedral complex with agostic B-H--Ni interactions completing the coordination sphere. The magnetism of the nickel(II) complexes changes from diamagnetic (square planar) to paramagnetic (octahedral) [20]. Alkyl chains are of course not the only scaffolds for bis-carbene ligands. Another obvious choice would be the benzene ring in its many substituted forms. An added advantage is the possibility for modifying the relative positions of the NHC unit in relation to each other by choosing ortho, meta or para functionalised benzene rings for the building of the ligand backbone. Examples for o-phenylene scaffolds for bis-carbene ligands come from the research groups of Peris [344,345] and Herrmann [346]. Synthesis of the bis-imidazolium salt is achieved by reaction of α,α’-xylene dichloride and the N-substituted imidazole. The rhodium(I) and iridium(I) complexes can then be made by addition of the imidazolium salt to a solution of [M(cod)Cl]2 (M = Rh, Ir) in ethanol or acetonitrile (with NEt3 as auxiliary base) (see Figure 3.108). The rhodium complexes were used successfully in the hydrosilylation of styrene [344] whereas both the rhodium and iridium complexes were used for the direct borylation of arenes making functionalised arylboronic acid esters accessible by a simple one-pot reaction [346]. The synthesis of the para isomer can be achieved in the same way as the ortho isomer. An elegant synthesis starting from 1,2,4,5-tetramethylbenzene and formaldehyde (see Figure 3.109) was published by Liu et al. [347]. Incorporation of benzimidazole instead of the customary imidazole changes the electronic properties of the carbene unit [107], which can be seen by the downfield shift of the H2 signal in the 1H-NMR spectrum [176].

138

Functionalised N-Heterocyclic Carbene Complexes N KBH4

2

N N

NH

N

N

N

RI

B H2

N N R

N

R

B H2

Ag2O R

R

1) BuLi

2) [Au(SMe2]Cl]

Ag

or 1) LDA

N

N

2) MCl2, M Pd, Pt

1) BuLi

N

N

R H2B

BH2

N

[Au(SMe2)Cl]

N

N

N Au

Ag

N

N

N

2) [Ni(PPh3)2Cl2]

R

R

N BH2

H 2B

N

N Au N

H2B

N

N N N N

N

N N

M

BH2 R

N

Figure 3.107 Transition metal carbene complexes with bis-imidazolatoborate derived carbenes.

N ⴙ

Cl

N

N N N

N

[M(cod)Cl]2

ⴙ

M

N Cl

N

N ⴙ

N

Figure 3.108 Synthesis of iridium(I) and rhodium(I) carbene complexes with bis-carbenes possessing an o-xylylene scaffold.

Note: The structure is certainly flexible enough to allow trans coordination. The carbene units can directly be fused to the phenyl ring by reacting 2-phenyl-1,3,4-oxadiazole with p- or m-phenylenediamine dihydrochloride in o-dichlorobenzene [348,349]. Quarternisation with adamantyl bromide and genesis of the carbene with ButOK or NaH follows standard procedures [350]. The CuX (X = Cl, I) complexes of this bis-carbene ligand have similar structures to the silver(I) complexes seen in Figure 3.109.

N-Heterocyclic Carbenes with Neutral Tethers Br

p-formaldehyde

Ag

Cl

N

Br

but

N

N

Ag2O N

N N

N

N

Br Ag

Ag

Ag

N N

HBr

N

139

Br

N

N

N

Cl

Figure 3.109 Synthesis of a silver(I) bis-carbene complex with a p-phenylene backbone.

A totally different approach to bis-carbene ligands on a cyclic scaffold comes from Burgess and coworkers [351]. They start from N,N'-dimethyl-1,2-diaminocyclohexane and acetylate this compound with chloroacetic acid chloride. Addition of an N-substituted imidazole yields the chiral bis-imidazolium salt (see Figure 3.110). Reaction with silver(I) oxide and carbene transfer to palladium(II) completes the reaction sequence. The ligand structure can be used, with minor alterations, to create a chiral cis-bis-carbene complex of palladium(II) featuring two amide substituents. Since both the denticity of the ligand and the wingtip group of the carbene unit can be changed with ease, it is more than appropriate to call this protocol a modular approach to trans (and cis) chelating bis-carbene ligands. A much more complex but still chiral bis-carbene ligand system was introduced by Veige and coworkers [352,353] based on the trans-9,10-dihydro-9,10-ethanoanthracene scaffold (see Figure 3.111) that has been used previously as a platform for chiral bidentate ligands [354,355]. Note: The sterically innocent methyl wingtip causes the formation of the corresponding electron-rich olefin and subsequently a chelating mononuclear rhodium(I) complex. The sterically only moderately more demanding isopropyl wingtip group is already spacious enough to prevent the formation of the electron-rich olefin and causes the generation of a bridging dinuclear rhodium(I) complex. Note: The electron-rich olefin is cleaved under mild conditions (25 ˚C) and does not require the elevated temperatures customarily encountered during these reactions [356,357]. Note: Chelating cis-coordination to rhodium(I) lowers the symmetry of the ligand from C2 to C1 in the complex. In a second publication, Veige and coworkers added to the theme by disposing of the linker between the trans-ethanoanthracene scaffold and the coordinating carbene units [353]. The protocol is surprisingly straightforward once the scaffold is equipped with two amino groups and follows standard reaction pathways (see Figure 3.112). The behaviour of this second ligand is absolutely analogous to the earlier one (equipped with a methylene linker unit). Deprotonation of the imidazolium salt is followed by

140

Functionalised N-Heterocyclic Carbene Complexes O H N Cl

Cl

O

Cl

O N

N H

N

N

N O

N

N

N Cl

N

N

N

O

O N

O N

O

Cl

Pd

O

O

NH

N

N N

N

PdCl2, ButOK

Pd

N

N

N

N

O

N

N

N NH

Ag

N

N

N

Cl

N

O

N

N N

N

N

O

Figure 3.110 Synthesis of a chiral bis-carbene complex of palladium(II) using the 1,2-diaminocyclohexane scaffold.

R R N N

N

N

N

N

N

N

[Rh(nbd)2]BF4

KN(SiMe3)2

KN(SiMe3)2

N

N N

Rh L

N L

[Rh(cod)Cl]2

N N :

N

N

: N

N

N

[Rh(cod)Cl]2

N

Cl L Rh L

Rh L

Cl L

Figure 3.111 Synthesis of chiral bis-carbenes based on a 9,10-ethanoanthracene scaffold and their transition metal complexes.

N-Heterocyclic Carbenes with Neutral Tethers N

NH2

glyoxal NH4Cl H2CO

H2N

N

141

N N

N N

N

MeI

N

NO2 F

NO2 H N

H N

NH2

NO2

H N

H N

N

NH2

N N HC(OEt)3

Pd/C, H2

N

MeI N N N N

Figure 3.112 Synthesis of chiral bis-carbenes based on a 9,10-ethanoanthracene scaffold and their transition metal complexes.

formation of the electron-rich olefin that can be cleaved under mild conditions upon addition of the rhodium(I) precursor complex. The chelating cis complex is formed in both instances (methyl wingtip group), although it is not clear from the original publication whether the nonannulated bis-carbene ligand indeed forms the electron-rich olefin as the reaction was carried out in situ. A third example comes from Clyne et al. [358] and concerns the axial chiral binaphthyl backbone [359,360], itself known from phosphorus chemistry [361]. The synthesis starts from the trifluoromethylsulfonato substituted binaphthyl with a Kumada coupling reaction [291,292] with methylmagnesiumbromide. Oxidation with NBS yields the methyl brominated derivative that can be attached to the imidazole ring. Subsequent methylation results in the bis-imidazolium salt that is deprotonated to the bis-carbene and coordinated to the transition metal halide (Pd, Ni), a rather straightforward reaction sequence (see Figure 3.113). The overall yield for the four-step reaction to the bis-imidazolium salt is surprisingly good (65%). Note: After going to all the trouble of creating an enantiomerically pure asymmetric catalyst, the authors tested it on an achiral Heck reaction, although they obtained the E-isomer of the product. The achiral analogue of the binaphthyl scaffold is the biphenyl backbone. An example comes from Chen et al. [362] who synthesised a bis-benzimidazolium salt starting from 2,2’-diaminobiphenyl (see Figure 3.114). In contrast to the bis-carbene in Figure 3.113, the

142

Functionalised N-Heterocyclic Carbene Complexes

MeMgBr [Ni(dppe)Cl2]

OTf

Br

NBS

OTf

N

Br

N H NaH

N

N

N N I

M

N

I

N

N

N ButOK MI2

N

N MeI

or N

M Ni, Pd

N

N

N

I Pd

N

I

N

Figure 3.113 Synthesis of an axial chiral bis-carbene on a binaphthyl scaffold.

Br NO2

NH2

N H H N

NH2

Pd-C/H2

NO2

NH2

N H H N

NO2

NH2

HC(OEt)3

N

N [M(cod)Cl]2 NaOAc

I

N

N

N

N MeI

N

O M

N

I O

M Rh, Ir

N

N

N

N

Figure 3.114 Synthesis of a bis-imidazolium salt with a biphenyl backbone and its transition metal complexes.

N-Heterocyclic Carbenes with Neutral Tethers

143

biphenyl derivative does not have a linker unit between the backbone and the carbene units. To achieve this, a ring-closing reaction with triethyl orthoformate [246] became necessary. Standard alkylation with methyl iodide and subsequent reaction with a transition metal (Rh, Ir) follows customary protocols. The rhodium(I) complex was found to be a moderately effective catalyst for the hydrosilylation of ketones with diphenylsilane. Direct arylation of methyl imidazole with 2,7-dichloronaphthyridine leads to a potentially tetradentate and practically tridentate bis-carbene ligand on a naphthyridine scaffold [363]. Reaction of the bis-imidazolium salt with silver(I) oxide in the usual way yields a linear trinuclear silver carbene complex with this tris-bridging ligand (see Figure 3.115). It is likely that the trinuclear arrangement of the silver(I) ions is forced by the geometry of the ligand making the observed argentophilic interactions [364–366] possible. Even a rod-like backbone derived from acetylene is conceivable and has been realised by Liu et al. [367] starting from 1,4-dichlorobutin-2. The usual reaction with methyl imidazole and subsequent reaction with silver(I) oxide and carbene transfer to gold(I) [Au(SEt2)Cl] makes the dimeric silver(I) and gold(I) complexes accessible featuring argentophilic and aurophilic interactions, respectively. Note: The acetylene backbone is not flexible enough to allow the formation of a chelate complex with silver or gold, both preferring a linear arrangement of ligands. The two carbene units can be embedded in a (macro)cyclic ring system known as a cyclophane. A standard procedure for the synthesis of such a system starts with α,α’-dibromoxylene and potassium imidazolide [368]. Cyclisation can be achieved by reacting the bis-imidazole compound with a second equivalent of α,α’-dibromoxylene (see Figure 3.116). The cyclic bis-imidazolium cyclophane can then be reacted with palladium(II) acetate to form the palladium complex [369,370]. The silver(I) and gold(I) complexes are accessible from the reaction with silver(I) oxide [371] and the usual carbene transfer reaction to gold(I) [372]. Reaction of the bis-imidazolium cyclophane with [M(cod)Cl]2 (M = Rh, Ir) in the presence of KOBut yields the corresponding cationic metal bis-carbene complex. Subsequent

Cl

N

N

N N N

N

N

N

N Ag2O Ag

N

N

Cl

N

Ag

N

N

NCMe Ag

N

N

Figure 3.115 Synthesis of a bis-imidazolium salt on a naphthyridine backbone and its silver(I) complex.

144

Functionalised N-Heterocyclic Carbene Complexes N

N

Br

N Br N

Br

N

NK

N Br

N

N

N [Pd(OAc)2]

N N N

Pd

Br Br

N

Figure 3.116 Synthesis of a bis-imidazolium cyclophane on a xylene backbone and its palladium(II) complex.

reaction with CO (replacement of cod) and triphenyl phosphane (replacement of one CO ligand) gives complexes that retain the chelate ligand, but change the auxiliary ligands (cod, CO, PPh3) (see Figure 3.117). The palladium(II) complex was used as a catalyst for the Heck reaction between 4bromoacetophenone and n-butyl acrylate [368]. Although the catalyst proved to be active in this reaction, it shows singularly low conversion rates (7%) and turnover numbers (TONs) (6600). Until now, we have looked at bis-carbene ligands that are intended to form chelate complexes. If the geometry of the two carbene units is changed – by using a different scaffold – then a bridging bis-carbene ligand can be synthesised. Preferred scaffolds are 4,4’-biphenyl, trans-phenylene, but also acetylene. The intention for these ligand systems is the generation of main-chain conjugated organometallic polymers (COMPs) [373,374] with interesting electronic and mechanical properties. The synthesis of bis-carbene ligands on a p-biphenyl scaffold starts with 3,3’-diaminobenzidine [375,376]. Ring closure to the bis-benzimidazole compounds can be achieved by at least two routes: (i) using thiophosgene [260]; and (ii) using formic acid (see Figure 3.118). The linchpin in the thiophosgene method is the reduction of the thione to the carbene, which in this case was achieved by KC8 (potassium or K/Na alloy are alternatives). This back-to-back bis-carbene ligand can then be used in the synthesis of main-chain COMPs. An example of generating a COMP using palladium(II) acetate as the transition

N-Heterocyclic Carbenes with Neutral Tethers

N

N

N

N [M(cod)Cl]2

M

N N

CO

M Rh, Ir

N N

N M

N N

CO

PPh3

CO

M

N N

N

N

145

PPh3 CO

N

Figure 3.117 Synthesis of transition metal complexes of bis-carbene cyclophane ligands with a xylene backbone. But NH2

NH 1) pivaloyl chloride 2) LiAlH4

t

Bu

HN

H2N

NH

NH2

But H2N

HN But

H2COOH,

Cl2C S But

N S

N

NH

But

HN

N N

But N N

S

But KC8

1) NaH 2) BuBr

But

N

N

:

Bu

t

Bu

N N

:

Bu

N N

Bu

t

Bu N But

N Bu

Figure 3.118 Synthesis of bis-carbene ligands on a 3,3’-diaminobenzidine scaffold.

metal source is given in Figure 3.119. This method is referred to by Boydston et al. [376] as the Herrmann–Schwarz–Gardiner method [331], but was employed earlier by Arduengo [377] and is indeed a variation of Wanzlick’s original mercury(II) carbene synthesis [162]. Note: Palladium(II) salts prefer the formation of trans-bis-carbene complexes with square planar coordination sphere [131] and thus constitute an ideal synthon for COMPs. The biphenyl scaffold can still freely rotate around the phenyl-phenyl axis which will ultimately result in an axial twisting within the COMP, a property that is not always tolerable. To prevent this internal axial twisting, a more rigid scaffold needs to be introduced. This can be achieved by going from a one-dimensional backbone (a C-C single bond) to a two-dimensional backbone

146

Functionalised N-Heterocyclic Carbene Complexes Ph

Bu N Bu

N

N N

Bu

N

N Ph Bu [Pd(OAc)2] Ph

Bu

Ph

Bu N

N

Br N

N Br Pd N

Pd Br N

N Bu

Br N Ph

Bu n

Ph

Figure 3.119 Generation of a COMP using bis-carbene ligands on a 3,3’-diaminobenzidine scaffold.

(a phenylene ring). An early example for such a rigid scaffold comes from Cai et al. [378]. Their back-to-back bis-imidazole ligand has methyl groups on both C2-positions of the ligand preventing the formation of carbenes. Thus, they formed coordination complexes of cobalt(II) utilising one of the tertiary nitrogen centres. Attempts to form polymers (not COMPs as coordination to the transition metal is via nitrogen not carbon) were not reported. The synthesis of the first Janus bis-carbenes (back-to-back carbenes with a symmetric spacer unit – phenylene) was reported by Bielawski and coworkers [376,379,380]. The synthesis of the bis-imidazolium salts starts with a palladium catalysed amination of 1,2,4,5-tetrabromobenzene. The resulting tetraamine can be cyclised with triethyl orthoformiate [381] or by reductive cyclisation of 2,5-diamino-1,4-benzoquinonediimine (obtained by aerobic oxidation) [382] (see Figure 3.120). Note: The 1,2,4,5-tetraaminobenzenes are sensitive to atmospheric oxygen and easily oxidise to mixtures containing p-benzoquinonediimines. The corresponding p-benzoquinonediimines can be synthesised in high yield by standard procedures. Monomeric transition metal complexes (silver and rhodium) of these Janus bis-carbenes were synthesised by standard procedures, either with reaction of the bis-imidazolium salt with silver(I) oxide or by preparing the free carbene by proton abstraction with LDA and subsequent reaction with [Rh(cod)Cl]2 [379] (see Figure 3.121). If the wingtip group is

N-Heterocyclic Carbenes with Neutral Tethers R Br

Br

R

HN

R

NH

[Pd]/RNH2

Br

HN

N

N

NH

R

R N

HC(OEt)3

Br

147

N

R

R

R

[O] [Pd(OAc)2]/PriOH R

R

HN

N

R

R N

N

p-formaldehyde

H 2C N

NH

R

R

N

N

R

R

Figure 3.120 Synthesis of Janus (back-to-back) bis-carbenes. But

But N

N

N

N

Ag2O

Cl

t

t

Bu

Bu

But

But N

N

N

N

Ag

Ag

Cl

But

But

LDA

N

N

N

N

But N

N

N Cl

N

N

Rh

Rh Cl

But

But

But

But

N

[Rh(cod)Cl]2

:

:

But

But

But

But

NaH KOBut

But

But N

N

N

: N But

N

: N

But

N

N

But O2

N N But

N

N

N

N

:

O

But

Figure 3.121 Synthesis of Janus (back-to-back) bis-carbene transition metal complexes.

chosen to be small enough, the electron-rich olefin is formed by dimerisation upon generation of the free carbene (proton abstraction with NaH/KOBut). The double bond can be cleaved by selective oxidation with oxygen to the corresponding urea derivative [383,384]. The aim with these ligands is the synthesis of electrically conductive, self-healing materials (polymers). Note: The ability of the M-NHC bond to reform even after reductive elimination of an imidazolium salt is the key property in the development of electrically conductive, self-healing materials from these ligands.

148

Functionalised N-Heterocyclic Carbene Complexes

N N

N

N

Ir

[Ir(cod)Cl]2

Cl

N Ir

N

Cl

[Ir(cod)Cl]2

N N N N

Ir

Cl Ir

[Rh(cod)Cl]2

N Rh

Cl

Cl

N H

Figure 3.122 Synthesis of spacer-free Janus bis-carbene complexes using triazole as the scaffold.

Even more elegant would be the synthesis of a scaffold-free, back-to-back bis-carbene ligand of truly Janus design. In principle that would be possible with an imidazole derived NHC, but it requires a normal and an abnormal coordination on the same ring – a highly unlikely and not very stable proposition. Instead, utilisation of the triazolium system might be more promising. This concept was realised by Mata and Peris [385] in a stepwise approach. A one-step protocol yields symmetrically substituted ‘Janus’ complexes, whereas a two-step protocol gives a true Janus complex with two different metals in an unsymmetrical molecule (see Figure 3.122). The key lies in the stoichiometry. These spacer-free Janus bis-carbene complexes were successfully employed in the intramolecular cyclisation of acetylenic carboxylic acids (4-pentynoic acid and 5-hexynoic acid) as well as the transfer hydrogenation of ketones and imines.

3.5 Tris-N-Heterocyclic Carbene Ligands Historically, the first tris-NHC ligand was developed by Dias at DuPont [386] immediately after the isolation of the first free carbene [387]. It was based on a 1,3,5-tris-imidazole substituted hexamethylbenzene (see Figure 3.123). The general development of this ligand class was subsequently based on the well known scorpionate ligands developed by Trofimenko [338–340]. The tris-pyrazolyl borate (Tp) ligand series was developed to replace the universal Cp ligand family in organometallic complexes [338]. The idea is as simple as it is attractive; the pyrazole is replaced by imidazole making it possible to use the Tp protocols to generate the tris-carbene precursor. Quarternisation of the three imidazole rings and generation of the carbene follows established NHC procedures [388] (see Figure 3.124) in as much as Meerwein’s salt is used as the alkylation agent. Note: Using Meerwein’s salt (R3O)BF4 as alkylating agent limits the choice of substituents to methyl and ethyl.

N-Heterocyclic Carbenes with Neutral Tethers

149

R N

R

:

R

N

N

N

:

:

N N N

N

N

:

N

N

R

N

R

CH

:

R

TIME

N

R

N

:

N

N

:

N

:

:

N

R

TIMEN

N R R

R

N R

N

R

B

N N

N

H

R

N

Cp R

B

:

H

R

R

N

:

R

N

N

R

N

N

:

Tp

HB(RIm)3

N R

R

Figure 3.123 Comparison of tris-NHC ligands with the geometries of Cp and Tp ligands.

3

N

H

N

B

3(R3O)BF4 N

N

N

R Me, Et

H

N

B

N N N

BF4 N BF4

R

N

N

3BuLi H

R

B

:

KBH4

N

R

N N

:

N

H

N

N

R

N

:

N

R

HB(RIm)3

R

R R 3

N

N

KBH4 NH

H

B

N N

N

R

N N Tp R

Figure 3.124 The Synthesis of HB(RIm)3 (R = Me, Et) and Tp.

From the HB(RIm)3 ligand family [389], it is only a small step to develop the HC(RIm)3 ligand family [390] on the lines of the analogous Tp derivatisation [338–340]. It is maybe surprising that this development took an astonishing twelve years to materialise. In the meantime, we witnessed the advent of a more flexible tris-NHC ligand family with a tethered HC- or N-backbone, TIME [388,391–393] and TIMEN [388,394–398], respectively.

Functionalised N-Heterocyclic Carbene Complexes N

But N

H

B

N N

N

N

But

N

Br 3BuLi But

H

B

N

:

Me3N.BHBr2

N 3

But

:

150

N

N

But

N Br

N

But

:

HB(RIm)3

N t

Bu

Figure 3.125 Synthesis of HB(ButIm)3.

The somewhat more complicated looking phenylene based tris-NHC ligands [386,399,400] are comparatively rare, but by no means redundant. The Tp ligand family shows some interesting characteristics [340,401]. Similar to the Cp ligands it is modelled on, the steric bulk of the ligand determines the accessibility of the monoligated metal complex. Whilst CpZrCl3 compounds with small Cp ligands can be synthesised following special protocols [402], similar TpMCl (M = Ni, Co, Zn) routes were not developed [401]. It is much easier to increase the steric bulk of the wingtip group to sterically prevent the addition of a second Tp ligand. In the case of the HB(RIm)3 ligand family, this is not quite as facile. The crucial step is the introduction of the wingtip group itself, which is done with Meerwein’s salt and is thus limited to small substituents (Me, Et). For the introduction of bulkier wingtip groups like tert-butyl, a new synthetic route had to be developed [403] (see Figure 3.125). This new route does not seem to have intrinsic limitations concerning size, although the only examples in the literature so far are tert-butyl [403,404] and mesityl [404]. Note: A bulky wingtip group is needed to produce a mono tris-NHC metal complex. Although the reaction of the monoanionic free carbene HB(RIm)3 ligand with a MX2 (M = Fe, Co; X = Cl, Br) salt produces M{HB(RIm)3}2 in the case of a small wingtip group, the evidence is not conclusive due to the small number of examples. However, given the close analogy to the isostructural and isotopological Tp ligands, it is expected that [M{HB(RIm)3}X] complexes can only be made with bulky wingtip groups R. The introduction of only one tris-NHC ligand with small wingtip groups is possible, if the other side of the metal atom is occupied by strong ligands like carbonyl as in [Mn{PhB(MeIm)3}(CO)3] [405]. The preference for either the tridentate or [2+1] coordination mode that gave the Tp ligand family its nickname ’scorpionates’ (after scorpions that have two pincers and a sting) is not evident in the coordination chemistry of the tris-NHC ligands. It has to be remembered that the tris-NHC ligand family mimics a tridentate ligand that coordinates via a nitrogen atom and not a phosphorus. Whereas the carbenes are taken to resemble the soft phosphane donor ligands, amines are much harder and thus have far different properties as ligands. Therefore, it does not come as a surprise that the tris-NHC ligands invariably coordinate in a tridentate fashion to the same transition metal atom in all compounds where the crystal structure could be determined. Note: HB(RIm)3 is a tridentate ligand and not a [2+1] dentate ligand like the Tp family of ligands. Note: PhB(RIm)3 can reversibly be turned into a bidentate ligand upon partial protonation.

N-Heterocyclic Carbenes with Neutral Tethers

151

Treatment of [Co{PhB(RIm)3}Cl] (R = But, Mes) with 1 equiv. of hydrochloric acid resulted in the formation of the partially protonated [2+1] complex [Co{PhB(RImH)(RIm)2}Cl2] (R = But, Mes) [404] (see Figure 3.126) Ligands of the HB(RIm)3 family are used for a variety of transition metals [389,390,403– 408] and main group metals [403,409]. Interestingly, utilisation of the silver oxide route [11,314] comes almost as an afterthought [390]. Generation of the free tris-carbene can be accomplished by the addition of a strong base like BuLi and reaction of the monoanionic tridentate ligands yields the appropriate metal complex under salt metathesis, usually LiCl [403,408] (see Figure 3.127). Note: Generation of the mono- or bis-{HB(RIm)3} iron(II) complex depends entirely upon the size of the wingtip group, methyl yields the bis-adduct whereas tert-butyl results in the mono-adduct. The tetrahedrally coordinated complex [Fe{HB(ButIm)3}Br] is isostructural to the main group compound [Mg{HB(ButIm)3}Br] [403] and the transition metal compound [Co{HB(ButIm)3}Cl] [404]. The smaller main group cation Li+ combined with the smaller tris-NHC ligand HB(EtIm)3 surprises us with a dinuclear [Li2{HB(EtIm)3}2] complex But

N N Ph

B

N

HCl

But

N

N

Ph

B

base

N

Co

Cl

N

But

But

N

N N

Co N

But

N

Cl

Cl

But

Figure 3.126 Reversible partial protonation of [Co{PhB(RIm)3}Cl] (R = But, Mes). N N

But

N Br

B

N

H

But

N

B

But

N

N

N

FeBr2 H

B

N

N Br

N

N

Fe Br

N

But

But

But

N

N

N

Mg

But

N

N 3MeMgBr

H

But

Br But

N N N 2

H

B

N

H N

N

6BuLi

B

N N

N

N

N

N Fe

FeCl2

N

N

N

N

B N

N

Figure 3.127 Synthesis of [Fe{HB(MeIm)3}2] and [Fe{HB(ButIm)3}Br].

H

152

Functionalised N-Heterocyclic Carbene Complexes

[409], where each Li cation shows tetrahedral coordination of four NHC entities and each HB(EtIm)3 ligand bridges two lithium cations (Figure 3.128). Although crystal structures of Li-NHC complexes are rare [409–423], the occurrence of two structures among the first four examples known [409] may be indicative of a special preference for bridging carbene coordination displayed by lithium. In general, bridging coordination for NHC ligands is rather exceptional [314] In comparison, the structures of the silver(I) and gold(I) complexes of [M3{HB(RIm)3}2Br] (M = Ag, Au; R = But, Mes) [390] (see Figure 3.129) are based on spectroscopic evidence and elemental analysis as well as the usually linear coordination of silver(I) and gold(I) by two NHC ligands [314–414]. The structures of the analogous copper(I) complexes [407] are of a more speculative nature and will not be discussed here. After monoligation to a [Co{PhB(ButIm)3}Cl] complex [404,406], the Co-Cl bond can be used to introduce another ligand. Addition of MeLi to [Co{PhB(ButIm)3}Cl] yields blue [Co{PhB(ButIm)3}Me] featuring a reactive Co-Me group [404]. Similarily, addition

N

R

N H

B

N

N Li

N RR

N

N

N

N H3B THF

N

N

Li

N

Li

B

H

But

Mes

N

O Li

N N

But

BH3 THF

N R R N Li

Li O

t

N t

Mes

Bu

Bu

N

R Et

N

R

Figure 3.128 Structures of [Li2{HB(EtIm)3}2] and two other Li-NHC complexes. H B

H

B

N

N N

N

N N

N

N R

R

R

R

N Ag

N R

Ag

R

N

N

Au

Br

Ag

N

R

Au

R

Br

Au

N R

R N

N

N

N

N B

R

R N

N

N N

N B

H

H

Figure 3.129 Structure of [M3{HB(RIm)3}2Br] (M = Ag, Au; R = But, Mes).

N-Heterocyclic Carbenes with Neutral Tethers

153

of LiNHBut to [Co{PhB(ButIm)3}Cl] yields dark green [Co{PhB(ButIm)3}NHBut] [406] (see Figure 3.130). All three cobalt(II) complexes are tetrahedral high spin. The dark green complex [Co{PhB(ButIm)3}NHBut] can further react with a radical proton abstractor (a phenol radical) to form the corresponding cobalt(III)-imido complex in a redox reaction that is reported to model a crucial step in the oxidation of water to elemental oxygen in the catalytic system of photosystem II [406] (see Figure 3.131). A similar iron(III) complex exists as well [415]. The original reaction is between a MnOH species and a tyrosine radical forming a MnO moiety. The process is known as a proton coupled electron transfer (PCET) and this reaction step is modelled by the process depicted in Figure 3.131. With this knowledge, it may not be so totally surprising that the orange [Mn{PhB(MeIm)3}(CO)3] [405], in contrast to the Tp analogue, is not air-stable, but is oxidised by oxygen to the homoleptic, dark-red-purple [Mn{PhB(MeIm)3}2](OTf)2 (see Figure 3.132). The mechanism of the reaction is unknown, but the initial step appears to be the oxidation of manganese(I) by diatomic oxygen. Similar to the Tp family of ligands, the monoanionic {HB(RIm)3} ligands can be derivatised by substituting the BH backbone with a CH group [338–340]. The result is a neutral {HC(RIm)3} ligand. Biffis et al. have used a known tris-benzimidazole compound [416] that becomes a suitable tris-NHC precursor upon triple quarternisation with Meerwein’s salt [390] (see Figure 3.133). This methane based tris-NHC ligand system behaves very similar to its boron based analogue. The most obvious difference is of course its neutral charge compared with the monoanionic borate ligand. As a consequence, the corresponding silver complex [Ag3{HC(MeBenzIm)3}2](BF4)3, although supposedly isostructural with the borate complex N

But

N Ph

B

But

N

N

N Co N

Cl But

MeLi

N

LiNHBut

But N

N Ph

B

But

N N

N

But

N

But

N

N Co

Me But

B N

Co N

Ph

N

N But

But

H

Figure 3.130 Reaction of [Co{PhB(ButIm)3}Cl] with MeLi and LiNHBut, respectively.

154

Functionalised N-Heterocyclic Carbene Complexes But

N N Ph

B

But

N

O Ph

But

N

N

But

N

But

B

But

But

N

N N

N

Co

Co N

N But

But

N

N But

H

But

Figure 3.131 Reaction of [Co{PhB(ButIm)3}NHBut] to [Co{PhB(ButIm)3}=NBut]. N N Ph

N Ph

B

CF3SO3

N

N

N

N Mn

I

O2

B

KOTf

CO

N

N

N

N IV Mn N

N

N

N

N CO

B

CO CF3SO3

Ph

N N

Figure 3.132 Oxidation of [Mn{PhB(MeIm)3}(CO)3] to [Mn{PhB(MeIm)3}2](OTf)2. BF4 N N

H

N

3 (Me3O)BF4

N

CHCl3 + K3CO3

3

N N

N

N

N

N

N N

N

BF4

BF4

N

Figure 3.133 Synthesis of HC(MeBenzIm)3.

[Ag3{HB(RIm)3}2Br] (R = But, Mes), has three anions compared with just one [390]. The complex [Ag3{HC(MeBenzIm)3}2](BF4)3, was reported to be hygroscopic and unstable. In fact, its instability in solution prevented the recording of its 13C-NMR spectrum [390]. This instability is likely connected with the reduced nucleophilicity of the annulated carbene [51,112] rather than with its methine backbone. Whilst the HB(RIm)3 ligand family is predestined to form complexes with fac geometry, a tris-NHC ligand with a tether between the backbone unit and the three NHC units would be at liberty to form complexes with either fac or mer geometry as well as being more flexible in the denticity. The overall shape of the ligand would no longer force a tridentate mononuclear coordination behaviour.

N-Heterocyclic Carbenes with Neutral Tethers

155

The scaffold that would support such a tethered tris-NHC ligand could either be a CH-, a N- or a bigger moiety like a benzene ring. In each case, the scaffold carrying three alkyl halides is reacted with the appropriate substituted imidazole to generate the tris-imidazolium salt precursor (see Figure 3.134) [386,391,393]. The tris-[2-(3-alkylmethylimidazolium-1-yl)ethyl]amine (TIMEN) ligand family has an ethyl spacer between the amine backbone and each of the three carbene units [394–398] that gives the ligand a certain degree of flexibility [395,397]. This flexibility can best be seen in the copper(I) [395] and rhodium(I) complexes [397]. The rhodium(I) and iridium(I) complexes of the isopropyl derivative TIMENiPr show a trinuclear [2+1] bridging coordination of the tris-NHC TIMEN ligand (see Figure 3.135) [397]. These group 9 complexes show the ability of the TIMEN ligand design to adapt to the requirements of the metal, in this case the need for two cis-bound ligands as the weak cod-ligand occupies the positions trans to the carbenes within the metal preferred square planar geometry. Similarly, the reaction of TIMEN with copper(I) results in two different complexes with different structures and stoichiometries [395]. Utilisation of the silver oxide route results in a trinuclear complex, whereas the use of the free tris-NHC carbene ligand results in a mononuclear complex (see Figure 3.136). Note: The difference is actually not in the use of the carbene transfer agent (the silver complex) versus the free NHC, but in the number of copper(I) ions added. Note: The steric bulk would actually favour formation of the mononuclear complex where the trinuclear one is observed.

N

Cl N

Cl N

N

N

3

N

H

3

N

N

H TIMM

Br

N

Cl

:

N

N

N Cl

N

KOBut

Cl N

N

N

N

N

N

:

N

:

Cl

N

:

N

N

:

Br

N

Cl

N

N

Cl

N

N

KOBut

N

But

:

N

H

N

N

Br

N Br

N

N But

But

Cl

N Br

Cl N

But

:

N

N

:

Cl

N

N

NaH/KOBut N

Cl

Br

:

N 3

But

But

N

N

TIMEN

Figure 3.134 Synthesis of TIMEN, TIMM and a tris-NHC ligand with a phenylene scaffold.

156

Functionalised N-Heterocyclic Carbene Complexes

N N Rh N

N

N

N

N Rh

N

N N

N

N

N Rh N

Figure 3.135 Structure of [{Rh(cod)}3(TIMEN)2].

N

N

N

N

N

N

N

N

N N

N N

1.5 Ag2O N

Cu

Cu

Cu N

N

3 CuBr

N

:

N

N

:

But

N

N

But

But

N

N

[Cu(MeCN)4]PF6

N

N

N

But

Cu

N

:

N

But

N

N

N

N

N

N

N

But

Figure 3.136 Synthesis of [Cu3(TIMENMe)2] and [Cu(TIMENt-Bu)].

N

N-Heterocyclic Carbenes with Neutral Tethers

157

Normally, the free ligand is employed in the synthesis of the various transition metal complexes of TIMEN [394–397] and thus the mononuclear complex is formed. It requires only little imagination to realise that the amino function of the scaffold can be employed for a weak fourth coordination when the need arises. In the complexes of Ni(0) [396], Co(I) [394] and Cu(I) [395] we expect tetrahedral coordination of the central atom with the amino group of the ligand occupying the fourth coordination site. This is actually observed in each instance with the exception of Ni(0) (see Figure 3.137). The Ni(0) complex shows trigonal planar coordination of the three carbenes only, whereas tetrahedral coordination is observed upon oxidation to Ni(I). The backbone amino functional group can be displaced from the coordination sphere of the Co(I) complex by a small molecule [395,398]. Reaction of [Co(TIMENxyl)]Cl with CO, CH2Cl2 or O2 results in the formation of [Co(TIMENxyl)(CO)]Cl, [Co(TIMENxyl)Cl]Cl and [Co(TIMENxyl)(O2)](BPh4), respectively (see Figure 3.138). The latter two reactions are one-electron oxidations yielding Co(II) complexes. Reaction of [Co(TIMENxyl)]Cl with p-tolylazide results in a Co(III) imine complex with loss of the backbone amine coordination in a two-electron oxidation reaction (see Figure 3.139). The Co(III) imine complexes then rearrange under insertion of the imine But Xyl

N N But

Xyl

N Co

N

Cu

N

N

N N

N N

N

N

N

But

But

N

N

But

But

N N

But

N

Xyl

Ni

N

N

N

But

But

N

N

N

Ni

N

N

N

N

Figure 3.137 Structures of the tetrahedral TIMEN adducts of Co(I), Cu(I), Ni(I) and Ni(0).

158

Functionalised N-Heterocyclic Carbene Complexes Xyl N

Xyl

Xyl N

Xyl

N

OC N

Co

N

Xyl

Co

N

N

Xyl

N Xyl

N

N

N

CO

O2

N

Xyl N

N

N

O O

N

NaBPh4

N

Co

Xyl

N

CH2Cl2

MeCN

N

N

N

Xyl N

Xyl N

Xyl

MeCN N

N Co

Xyl Xyl

2

Cl N

N

N

N

N Co

Xyl

N

NaBPh4

N

N

MeCN

N

N

Figure 3.138 Reaction of [Co(TIMENxyl)]Cl with CO, CH2Cl2, NaBPh4/MeCN and O2. Xyl

Xyl

N

N

Xyl

N

Xyl

I Co

N

N

N

N

Xyl N3

N

N

N N

Co

N

N

N

Xyl

N

Xyl N

Xyl

N

N

N N

Co 2 N

Xyl

III

N

Xyl

Xyl

N

N

N

N

II

Co

N

N

Xyl

I

N

Figure 3.139 Two-electron oxidation of [Co(TIMENxyl)]Cl with p-tolylazide.

N

N

N-Heterocyclic Carbenes with Neutral Tethers

159

nitrogen into the cobalt-carbene bond to form a cobalt(I) amido complex. Further oxidation results in a cobalt(II) amido complex as the final product. Note: In each case, the tetrahedral coordination on cobalt is retained, irrespective of the oxidation state. This can be interpreted as a sign for the geometrical preference of the ligand rather than the metal. Note: The electron-rich Ni(0) complex is only tricoordinate indicative of the auxiliary nature of the amine coordination in TIMEN. Removing the amino group from the backbone of the TIMEN ligand family results in a similar tethered tris-NHC ligand family called TIME that lacks the capacity for a weakly coordinating fourth donor group. The application of this new tris-NHC ligand family, the TIME ligands, has mainly been limited to group 11 metals, copper [392,417], silver [390–392] and gold [390,392] with the occasional rhodium (iridium) complex [393]. The question of whether the TIME ligands (see Figure 3.140) are tridentate or [2+1] ligands has not been answered with any degree of certainty, mainly because the transition metals employed had either a preference for bis-coordination [283,390–392] or the trigonal planar geometry of the copper(I) centre did not accommodate the tether length of the particular TIME ligand used [417]. The question of course is whether a copper(I) halide like CuCl or CuI would generate a tetrahedral [Cu(TIME)X] (X = Cl, Br, I) complex instead of the trigonal planar complex formed with the noncoordinating anion PF6- used (see Figure 3.141) [417]. Note: The coordination of TIME in [Cu2(TIMEt-Bu)2](PF6)2 is indeed [2+1] with the monodentate end coordinating in abnormal (with the C4-atom) mode. BF4 N N

CHCl3 K2CO3

3 H

N

3(Me3O)BF4

N

N N

N

N

N

N

N

N BF4

N

N

Br N

N

Br

Br

N

N

Br Br

N Br

N

Figure 3.140 Synthesis of TIME ligands.

N

BF4

N

160

Functionalised N-Heterocyclic Carbene Complexes But N

But

But

But

N

I

But

N Cu

N N

N

N

N N

But

Cu

N

N

N

N

N

N But

N

Cu N

But

N But

Figure 3.141 Theoretical tetrahedral coordination of [Cu(TIMEt-Bu)I] and actual trigonal planar coordination of [Cu3(TIMEt-Bu)2](PF6)2.

The silver, gold(I) and copper(I) complexes of TIME are found to be trinuclear complexes incorporating two ligand molecules [390–392] of the general formula [M3(TIME)2]X3 (M = Cu, Ag, Au; X = PF6-, BF4-) (see Figure 3.142). Note: The [M3(TIME)2]X3 complexes were used to determine the nature of the M-carbene bond. The bond was found to be stabilised by considerable π interactions between the electron-rich group 11 metals and the carbene p-π orbitals. The bonding in the rhodium(I) and iridium(I) complexes [M(cod)(TIMEn-Bu)]PF6 (M = Rh, Ir) [393] is very similar except that the metal centre requires only two monodentate ligands, which results in a monoprotonated bidentate [2+1] type ligand coordination (see Figure 3.142). Use of two metal precursors per ligand results in a [2+1] bridging coordination mode with a cationic and a neutral end (see Figure 3.143). Both complexes were successfully tested in the catalytic hydrosilylation of phenylacetylene. The benzene scaffold was used to create two different classes of tris-NHC ligands, open [386,400] and closed [399] ligands (see Figure 3.144). The open ligand is constructed by symmetrically substituting three methyl groups of hexamethylbenzene with imidazole rings. The closed ligand has two hexamethylbenzene units (top and bottom) symmetrically bridged by three imidazole rings creating a cage-like ligand.

N-Heterocyclic Carbenes with Neutral Tethers

X

N

M

161

N

N N N M

X

N N

N

N

M

N

N

X

N

Figure 3.142 Structure of the trinuclear TIME complexes [M3(TIME)2]X3 (M = Cu, Ag, Au; X = PF6-, BF4-). Bun N N Bun

NEt3/[M(COD)Cl]3 n

Bu

N

45C N

Cl

N M

N

N

N

Bun Bun N

MeOH

N Cl

Cl

M Rh,Ir Bun

N N

M

Cl

N

Bun RT

N Bun

Ag2O/[M(COD)Cl]2 N

N M

N

N Bun

Figure 3.143 Synthesis of the two rhodium (iridium) complexes [M(cod)(TIMEn-Bu)]Cl (M = Rh, Ir) and [(cod)M (TIMEn-Bu)Rh(cod)Cl]Cl (M = Rh, Ir).

162

Functionalised N-Heterocyclic Carbene Complexes N

Br

Br

N

N Br N

imidazole

Br

N

Br

Br

N

N

N

N

N

N N But N Br

N

But N

But

N

N

N

Br N

Br

N But

Figure 3.144 The open and closed tris-NHC ligands with a phenylene scaffold.

N N

N

N

N

Ag2O

N

Ag

N

N

N

N

N

N

But

But But

But

But :

N

N

N :

N

But

N Tl(OTf)

Tl

N N N

N

:

N N

N

Figure 3.145 Synthesis of a thallium(I) and a silver(I) tris-NHC complex using ligands with a phenylene backbone.

N-Heterocyclic Carbenes with Neutral Tethers

163

The open ligand [386] has been used to coordinate a thallium(I) cation in a nearly symmetrical, trigonal planar fashion [400] (see Figure 3.145), whereas the closed cage ligand [399] coordinated a silver(I) ion in its centre employing only two of the three carbene centres. Attempts to trap an iron(III) cation in the centre of the closed ligand failed. Instead anion exchange with occurrence of a [FeCl4]- anion was observed. Note: The failure to incorporate iron(III) into the cage of the closed ligand is no indication that such an incorporation may not be possible, but rather a sign that more research is needed to find a suitable route.

3.6 Pincer Carbenes The pincer ligand describes a tridentate, meridonially coordinating architecture whose design ensures a stable and rigid coordination within a plane defined by the ligand. The three donor atoms are in close proximity to each other resulting in small bite angles [51,52] usually below 90˚. The central scaffold is often a pyridine or benzene ring with two prongs (sidearms carrying the other two donor atoms) in 1,3-position to each other (m-phenylene or 2,6-disubstituted pyridine) (see Figure 3.146). Popular flanking donor groups in pincer ligands are phosphines [418–420], amines [421,422] and thioethers [423]. The resulting metal complexes of pincer ligands (the most stable ones are square planar d8-complexes from group 10 [421]) feature two five-membered metallacycles with the flanking donor groups trans to each other, a meridonal coordination geometry and the fourth site in the square occupied by either a halide or a Lewis base [424]. The rigid pincer geometry is employed when catalytic reactions are performed under very harsh conditions (Heck reaction) [425,426] in order to take full advantage of their enhanced stability. The introduction of carbene flanking groups instead of the weaker bonding phosphanes or somewhat hemilabile amines and thioethers [38] increases the thermal stability further.

N

N

N

N

N

N

N

N

N E

E

E

N

E

E PR2, SR, NR2

Figure 3.146 Structures of pincer ligands.

164

Functionalised N-Heterocyclic Carbene Complexes

Note: The C,N,C pincer ligands are neutral ligands and the corresponding palladium(II) complexes are cationic, whereas the C,C,C pincer ligands are monoanionic when coordinated to the metal and the corresponding palladium(II) complexes are neutral. This has consequences for the solubility of the complexes: [Pd(C,C,C)Cl2] has good solubility and [Pd(C,N,C)Cl]X has poor solubility in most organic solvents. Key factors in the design of carbene based pincer ligands are doubtless the linker unit between the aryl scaffold (benzene, pyridine) and the NHC moieties and the nature of the wingtip group on the flanking carbene donors (see Figure 3.147). This linker unit controls the bite angle (increase of bite angle from no linker to CH2-linker) and the rigidity of the pincer backbone (introduction of a linker unit enables a degree of flexibility or dynamic puckering within the now six-membered metallacycle). The influence of the wingtip group on the steric demand of this meridonal ligand class is self-evident. The very nature of the pincer design forces the wingtip groups into the space reserved for the fourth ligand, the space needed for the substrate and the room allocated for the catalytic reaction. Any sterically demanding wingtip group will directly restrict and shape the space available for the reaction influencing the regio- and stereoselectivity of the reaction. The para position of the central aromatic scaffold (benzene, pyridine) is available to modify the electronic properties of the central donor atom (C in a benzene scaffold, N in pyridine) [421] according to the well known influence of the first substituent (para) on the properties of the second substituent (ipso, meta) [69,70]. Note: The wingtip groups in transition metal pincer carbene complexes point away from the metal centre. This limits the steric influence of the wingtip groups on the metal’s coordination sphere. In particular, aryl ligands can align themselves perpendicular to the pincer plane creating two walls on either side of the fourth coordination site. R2 R2

N N N

R2

R1

R1

N R1

N N R1

N

Pd

N

N

N N R1

X

[Pd(OAc)2]

R2

NaI

N

N

N R1

N R1

N

Pd X

N N R1

Figure 3.147 Steric factors within transition metal pincer carbene complexes.

N-Heterocyclic Carbenes with Neutral Tethers

165

Before we look at the situation of d8-metals with a square planar coordination geometry, a quick glance at metals with a metal preferred bite angle of 180˚ and linear coordination geometry might be helpful. The typical carbene pincer ligand cannot support a metal with a linear coordination geometry. Apart from a coordination site mismatch – two sites on the metal and three on the pincer ligand – the two flanking carbenes are too close together to enable a bite angle of 180˚ and at the same time two M-C NHC bonds [51]. The system reacts by turning the pincer ligand into a bridging bis-monodentate ligand with only the NHC donors engaging the two metal centres. Two examples are silver(I) [427,428] and mercury(II) [429]. In both cases dimeric complexes are formed where the two metal atoms are roughly on top of each other with the ‘pincer’ ligands forming the first turn of a budding double helix. Accepting this structural motif, it is easy to imagine that the alternative for a linear coordination on the metal is a helical arrangement of the bridging ligand in an infinite chain structure (see Figure 3.148). A typical protocol for the preparation of a pincer carbene ligand starts from 2,6-dibromopyridine and the respective N-substituted imidazole to form the pincer imidazolium salt [430]. Standard protocols can then be used to liberate the free carbene or form the transition metal pincer carbene complex (see Figure 3.149). Wingtip groups include methyl [431–433], benzyl [432], n-butyl [430,432,433], but also DIPP [434] as a sterically more cumbersome aryl substituent. The wingtip group is not decisive for the catalytic activity, but can improve the solubility of the complex. The C,N,C pincer complexes of palladium(II) are monocationic and thus only poorly soluble. This changes somewhat with the introduction of n-butyl wingtip groups. Then they become soluble in chloroform, but not in CH2Cl2 [430].

N

N

N M

N

N

N

N N

N

N

N

N

M N MM

N

N

N

N

N

N N

N

M

N

N

N

N

N

N

M M Ag, Hg

N

N N

Dimer structure realised

Helix structure not realised

Figure 3.148 Structural alternatives for bis-carbene pincer ligands in linear coordination geometries of transition metals.

166

Functionalised N-Heterocyclic Carbene Complexes

N

N N

Br

N

Br

N

N

[Pd(OAc)2]

N

N

N

N

N

N

Pd

N

Br

Figure 3.149 Synthesis of a C,N,C pincer imidazolium salt and its palladium(II) complexes.

The main application of these palladium(II) pincer carbene complexes are in catalytic C-C coupling conditions under harsh reaction conditions. For this use, solubility is maybe not that important as low catalyst loadings are preferred and very high temperatures (up to 185 ˚C) required. Peris et al. describe the use of a palladium(II) pincer carbene complex as catalyst in the Heck reaction between iodobenzene and styrene in diethylacetamide (DEA, 184 ˚C) and dimethylacetamide (DMA, 165 ˚C) giving the yield of trans-stilbene as quantitative with 5 mol% catalyst loading within 1 h [431]. Even with 0.2 mol % catalyst loadings, good yields and turnover frequencies are still observed. The reaction still works satisfactorily when bromobenzene is used as the aryl halide. The following year, the same research group expanded their investigations to a range of different aryl halides (essentially p-tolyl, p-methoxyphenyl and p-halobenzaldehyde) [430]. They found a significant amount of cis-stilbene in most reactions monitored (14% for iodotoluene, 11% for methoxyphenyl bromide) and almost identical yields and product distribution for iodotoluene and methoxyphenyl bromide. The catalyst could be used in six consecutive cycles in the Heck reaction between 4-bromoanisole and styrene without any appreciable loss of activity. Immobilisation of the catalyst on clay (montmorillonite K-10) did not alter the catalytic properties of the system significantly [425], but served to improve the recyclability of the catalyst as the clay is easily removed from the reaction mixture [432]. The fact that the reaction can be performed in the presence of air and water adds to the appeal of the system. Extension of catalytic activities to the Sonogashira reaction [330,435] is possible and was done by Fernandez and coworkers [432] for the reaction of aryl iodides and aryl bromides with phenylacetylene in pyrrolidine (87 ˚C). The pyrrolidine serves as both solvent and base and the competing Glaser reaction (oxidative homocoupling of the phenylacetylene) [436–438] was surpressed by adding the alkyne slowly to keep its concentration down [439,440]. Yields were somewhat dependant on reaction temperature, base and solvent, but were generally high. In the nonimmobilised system of Loch et al. [430], yields were not appreciably different indicating that immobilisation with montmorillonite does not diminish the performance of the catalyst. Another interesting application was investigated by Tu et al. [433] when they enclosed their catalyst (essentially the same as everybody else’s as the pincer system does not lend itself to a great degree of modification) in a gel. A gel is formed when the solvent is incorporated into the compound structure by ‘swelling’, essentially through van der Waal’s interactions between the gelator and the solvent [441–444]. Long alkyl wingtip groups aid in this process [445,446]. In the case of the palladium pincer carbene complex, gel formation is caused by π-π stacking interactions of the pincer ligands creating alternating layers of stacked arenes and interwoven alkyl chains. The latter are probably responsible for the

N-Heterocyclic Carbenes with Neutral Tethers

167

observed swelling and gel formation by incorporating solvent molecules. The catalytic activity of the catalyst does not diminish in the gelation process and the catalyst can be recovered from the gel after the reaction. Danopoulos et al. reported the crystal structure of a palladium pincer carbene complex that is the product of intramolecular 1,2-methyl migration from palladium to the carbene carbon atom, a process also referred to as a migratory insertion of the carbene into the Pdmethyl bond [434] (see Figure 3.150). The importance of this compound stems from the fact that it was the first unambiguous experimental evidence for this process actually to take place after it had been suspected for several years with the suspicion being backed by several theoretical calculations [447–449]. Note: The palladium pincer carbene complex has only one flanking carbene group (on the right-hand side) and the complex is neutral (the left flanking group is an anionic substituent). When we go from palladium to nickel, we stay within group 10 and retain the square planar geometry common to most d8-complexes. We do not need to concern ourselves with the synthesis and structure of nickel(II) pincer carbene complexes. They are analogous to the palladium(II) homologues. However, in their applications, the Kumada–Corriu reaction [291,292] takes a prominent place besides the Heck and Suzuki reactions encountered also with palladium. Note: Since the pincer geometry calls for meridonal coordination, tetrahedral nickel(II) pincer carbene complexes are not expected to exist. Inamoto et al. [450] investigated the Kumada–Corriu reaction between p-tolylbromide and phenylmagnesiumhalide (Br,Cl) using the MeC,N,CMe nickel bromide complex as catalyst. Yields were good to very good with the biphenyl (the homocoupling product) as the only detected by-product. Interestingly, tolylchloride gave the better performance yielding 87% tolylphenyl and 9% biphenyl, whereas the ratio for tolylbromide as substrate was 70:23%. Using a combination of [Ni(acac)2] and the corresponding imidazolium salt to generate the catalyst led to a sharp decline of catalyst performance (product ratio 27:30%). Lower catalyst loading and higher reaction times resulted in a lower yield and increased biphenyl ratio indicating progressing catalyst decomposition (nickel black) in the course of the reaction. Extending the scope of the reaction to a greater range of substrates (aryl halides) confirmed the general trends known for the Kumada–Corriu reaction. Electron-rich and neutral aryl

:

N

N :

N N

N N

N

Pd N

i

Pr

N

N

Pd

N Pri

N Pri

Figure 3.150 1,2-methyl shift in a palladium pincer carbene complex.

Pri

168

Functionalised N-Heterocyclic Carbene Complexes

halides gave the cross-coupling product in good to high yields, whereas electron-poor aryl halides performed notably worse. A tolerance for silyl ethers was observed. Even aryl fluorides were active with this catalyst, but required increased reaction times [451,452]. The same nickel catalyst was also used for the Heck reaction between 4-bromobenzonitrile and butyl acrylate [453] as well as Suzuki coupling between substituted aryl halides (Cl, Br) and phenylboronic acid (see Figure 3.151). When going from group 10 (Ni, Pd) to group 9 (Co, Rh) transition metals, we do not necessaarily abandon our familiar d8-square planar complexes as nickel(II) and palladium(II) are isoelectronic to cobalt(I) and rhodium(I) [29]. However, cobalt(I) has the tendency to form tetrahedral complexes, a geometry that we declared to be unlikely for pincer carbene ligands. This leaves us with the very real possibility of a change of oxidation state for our new central metal atoms: rhodium(I) to rhodium(III) and cobalt(I) to cobalt(II) or cobalt(III), each accompanied with an increase of coordination number to five (trigonal bipyramidal, square pyramidal) or six (octahedral). Rhodium and cobalt are both known to perform these switches in their catalytic activities [454,455] or coordination chemistry [456]. Danopoulos et al. investigated the chemistry of the pincer carbene ligand coordinated to cobalt [457]. Starting with a cobalt(II) silylamide [12], they proceeded to oxidise the trigonal bipyramidal cobalt(II) pincer carbene complex to an octahedral cobalt(III) complex and reduced it to the square planar cobalt(I) complexes (see Figure 3.152). It is possible to change the geometry of the trigonal bipyramidal cobalt(II) complex to an octahedral

N

catalyst

N

N

Ni

N

N

Br NC NC

OBu

Heck

OBu

O

Br

O NC

NC

Suzuki

B

Br

OH

OH

BrMg

Kumada-Corriu

Br

O

O

Figure 3.151 Use of a nickel(II) pincer carbene complex in Kumada–Corriu, Heck and Suzuki coupling reactions.

N-Heterocyclic Carbenes with Neutral Tethers

N N

N

N

N

[Co{N(SiMe3)2}2]

N

N

Co N

DIPP

N DIPP

Br

169

II N

Br

DIPP

DIPP BrN(SiMe3)2

TlOTf [Na/Hg] N

N

Br

Co

N III

N Br

Br

N N DIPP

DIPP

TfO

N Co

N N MeLi

N Co

N Co

N DIPP

N

DIPP

OTf

N DIPP

I N

N N

py

N II

Br

N DIPP

I

DIPP

N DIPP

Figure 3.152 The redox and ligand exchange behaviour of a cobalt(II) pincer carbene complex.

variety by displacing the bromide ligands with triflate. Apparently, the weaker coordinating triflate ligands require an additional π-donor ligand (pyridine). On the cobalt(I) stage, the substitution of the bromide ligand by methyl does not result in the change of the coordination geometry. Evidently, square planar geometry is preferred over trigonal bipyramidal and neutral complexes over cationic ones. Reaction of the cobalt(II) complex with methyl lithium not only results in ligand exchange, but is also accompanied by reduction to cobalt(I). This behaviour is also seen in N,N,N pincer complexes of cobalt(II) [458,459]. Surprisingly, that does not indicate catalytic activity of any of these cobalt complexes in olefin polymerisation reactions. Note: A neutral trigonal bipyramidal complex is preferred over a cationic square planar one. Note: Cobalt is more flexible in its coordination geometry than the group 10 metal meaning that cobalt tolerates the coordination number five rather than a positive charge. Note: All cobalt(I), cobalt(II) and cobalt(III) pincer carbene complexes are neutral and soluble in common organic solvents (THF, toluene, but not hexanes). The corresponding rhodium(I) system was likewise investigated by the Danopoulos group [460] and revealed the diminished flexibility in the coordination geometry displayed by

170

Functionalised N-Heterocyclic Carbene Complexes

N

N

N

N

[Rh(C2H4)2Cl]2

N

N I

:

:

Rh N

N

N

N

Cl DIPP

DIPP

DIPP

DIPP

CD2Cl2 CO

N

Cl

N Rh

N Cl DIPP

N III CD2Cl

N N

N

DIPP

I Rh

N N

N CO DIPP

DIPP

Figure 3.153 Coordination geometries in rhodium pincer carbene complexes.

rhodium compared with cobalt (see Figure 3.153). The only two geometries observed were square planar for rhodium(I) and octahedral for rhodium(III), although rhodium is known to realise trigonal bipyramidal complexes in hydroformylation reactions [461]. The same reaction and complexes are observed when one of the flanking carbene groups of the pincer ligand is exchanged for a pyridine substituent. The resulting ligand is a N,N,C pincer ligand, a rather unusual ligand class, but halfway between a classic N,N,N pincer ligand and the new C,N,C ligand class. The properties of these N,N,C pincers should be very interesting, especially electronically as they introduce an electronic asymmetry into the complex and enable a further fine tuning of the electronic and coordination properties of pincer ligands. The synthesis of these N,N,C ligands is rather facile starting from 2-bromobipyridyl and N-DIPP-imidazole. In the reaction of the pincer imidazolium salt and [Rh(cod)Cl]2 in the presence of a weak base (NEt3), Poyatos et al. [462] obtained a rather interesting result. The rhodium(I) compound was not the 1:1 complex with pincer coordination, but a 2:1 (rhodium:ligand) complex with the ligand coordinating in bridging fashion (see Figure 3.154). The reason for this unusual behaviour might well be the sterically cumbersome leaving group 1,5-cod. A similar behaviour is observed in the coordination behaviour of bisphosphino urea ligands, where the sterically demanding ligand OC(NMePPhBut)2 coordinates as P,O-chelate ligand to the W(CO)4 fragments rather than in P,P-chelate mode due to the sterically demanding norbornadiene leaving group in the tungsten precursor complex [463,464]. The bridging bis-rhodium(I) complex was successfully employed in the hydrosilylation reaction between phenylacetylene (butylacetylene) and dimethylphenylsilane (trimethoxysilane).

N-Heterocyclic Carbenes with Neutral Tethers

N

N

N

N

[Rh(cod)Cl]2

N

N

Bu

Br

Br

Rh

N

Bu

N

N

Bu Rh

Bu

[Rh(cod)Cl]2

N

Bu N

Br

N Rh

N Br Bu

:

N

N

N :

N

171

N Bu

N III Br

N Bu

Figure 3.154 The pincer carbene ligand acting as a bridging ligand to two rhodium(I) moieties.

The pincer rhodium(III) complex was successfully employed in the transfer hydrogenation of cyclohexanone, acetophenone and benzophenone with isopropyl alcohol as the hydrogen source. Moving another triad further left in the periodic table, we arrive at ruthenium with its rich chemistry of bipy and terpy complexes. The terpy (tripyridyl) ligands are analogues of the C,N,C pincer ligands [465–467]. The ruthenium centre can easily coordinate one or two C,N,C pincer ligands meridonally. Poyatos et al. did precisely that, they synthesised a mono-pincer and a di-pincer ruthenium(II) complex starting from [Ru(cod)Cl2]2 as the precursor complex (see Figure 3.155) [468]. Not surprisingly, the CO ligand coordinates trans to the pyridine ring of the pincer ligand. Note: Triethylamine proved to be a better base in this particular synthesis than sodium acetate, sodium carbonate, sodium hydride or potassium tert-butanolate. The mono-pincer ruthenium(II) complex was successfully employed in the transfer hydrogenation of ketones (acetophenone, benzophenone, cyclohexanone) with isopropyl alcohol as the hydrogen source. The mono-pincer ruthenium(II) complex was successfully employed in the oxidative cleavage of olefins to aldehydes, dialdehydes or keto-aldehydes. The di-pincer ruthenium(II) complex was inactive in both catalytic reactions. Note: Since the pincer ligand coordinates strongly to transition metals and with two pincer ligands occupying six coordination sites on ruthenium, there are no free coordination sites for the catalytic reaction to take place.

172

Functionalised N-Heterocyclic Carbene Complexes

N N

N

[Ru(cod)Cl2]2

N

N

CO

NEt3

N

N

Ru

N

Bu

Br

N CO

Bu

Br

Bu

N Bu

NEt3

[Ru(cod)Cl2]2

N

C

N

N N Bu

N

Ru C

N Bu

Figure 3.155 Mono-pincer and di-pincer complexes of ruthenium(II).

The most important catalytic reaction associated with a ruthenium carbene complex is the ruthenium catalysed olefin metathesis [469–471]. It is therefore no surprise that pincer carbene complexes were employed for their activity in this reaction [472,473], although the pincer geometry is not compatible with the architecture of the Grubbs’ catalyst [474,475]. In particular, the Grubbs’ catalyst has an ylidene substituent and flanking that in the meridonal motif two phosphane ligands. If this structural motif is replaced by a pincer carbene ligand, the necessary initiation by loss of one of the phosphanes can no longer take place rendering the catalyst inactive. The catalyst therefore has to find another way to catalyse the olefin metathesis reaction. In a first model reaction, Danopoulos et al. [472] reacted a free pincer carbene ligand with [Ru(PPh3)3Cl2] and obtained the corresponding octahedral pincer carbene adduct (see Figure 3.156). The complex lacks the ylidene functionality necessary for activity of the complex in olefin metathesis. Instead, the compound was successfully employed in the transfer hydrogenation of cyclohexanone, acetophenone and benzylidene aniline. Reaction temperatures were mostly low to moderate (25–55 ˚C) and catalyst loadings in the range of 0.015 to 0.1% with TONs of only 150 to 8800. Danopoulos and coworkers [473] then developed a ruthenium(II) pincer carbene complex exactly on the lines described above starting from the Grubbs’ catalyst. Reaction with the free carbene ligand results in displacement of the phosphane ligands and coordination of the central pyridine unit changes the coordination geometry from square pyramidal to octahedral (see Figure 3.157). Again, utilisation of the N,N,C pincer framework results in the corresponding ruthenium complex. The C,N,C ruthenium(II) pincer carbene complex showed some activity in the olefin metathesis of norbornene, norbornadiene (catalyst loading 1 mol %), 1,5-cod, cyclooctene and diallylmalonate (catalyst loading 10 mol %). The N,C,N ruthenium(II) pincer carbene complex was not tested.

N-Heterocyclic Carbenes with Neutral Tethers

173

Cl Ph3P N N

N

Cl

N

N

PPh3 PPh3

Ru

N

Cl

N

Ru

:

:

N

N

DIPP

Cl

PPh3

N DIPP

DIPP

DIPP

Figure 3.156 A ruthenium(II) pincer carbene complex. Cl

PCy3 Ru

N N

N

Cl PCy3 Ph

N

N

Cl

N

N

Ru

:

:

DIPP

N

N DIPP

DIPP

Ph

DIPP

Cl

N

Cl

PCy3 Ru

N N

:

Cl Ph

N N

N

PCy3

Cl

N Ru

N

DIPP DIPP

N Cl Ph

Figure 3.157 Synthesis of a ruthenium(II) pincer carbene complex with the Grubbs’ catalyst as starting point.

Within the same triad, iron has the smaller ionic radius compared with ruthenium [20], although electronically and structurally the two elements should form the same complexes. They essentially do, but when a second pincer carbene ligand is coordinated, it coordinates with one NHC moiety in ‘abnormal’ coordination mode [476] as opposed to ruthenium, where both pincer carbene ligands are coordinated normally [468]. In the absence of coordinating anions (BPh4- instead of bromide) octahedral cationic complexes are formed instead of square pyramidal neutral ones (see Figure 3.158). The additional π-donor ligand compensates the positive charge electronically. Note: Steric constraints can result in the formation of ‘abnormal’ carbene complexes [47,48]. Note: The smaller ionic radius of iron compared with ruthenium can result in such a steric constraint The iron(II) pincer carbene dibromide complex undergoes interesting ligand substitution reactions, whereby the bromide substituents are replaced by several neutral ligands. At the same time, the iron(II) centre is reduced to iron(0) using sodium amalgam as reducing agent [477] (see Figure 3.159).

174

Functionalised N-Heterocyclic Carbene Complexes

N

N

N

N

:

N

N

N

:

DIPP

N

N

N

DIPP

DIPP

DIPP

[Fe(tmeda)Cl2]

[Fe(thf)1.5Cl2]

[Fe{N(SiMe3)2}2]

NaBPh4 N

N

C

Fe

N N

N N

DIPP

C

DIPP N

MeCN

N Fe

N

N

N

N

N

N

NCMe NCMe

Fe DIPP

DIPP

N Br

N Br DIPP

DIPP

Figure 3.158 Synthesis of iron(II) pincer carbene complexes.

N

N

N

Fe [Na/Hg]

N Br

CO

N Br DIPP

DIPP

[Na/Hg] PMe2

N

N

N

Fe N CO

N2

[Na/Hg]

N

N

N

Fe

CO

PMe3

N

PMe2

DIPP

DIPP

N

N

N2

DIPP

DIPP

CO

N

N

N

Fe N2

N N2 DIPP

N

ethylene DIPP N

N

N

Fe N N2

N C2H4

DIPP

Figure 3.159 Reactivity of th e iron(II) pincer carbene dibromide complex.

DIPP

N-Heterocyclic Carbenes with Neutral Tethers

175

The compounds serve as models for possible dinitrogen activation and have analogues with isostructural N,N,N iron pincer imine complexes [478]. However, dinitrogen activation and spectroscopic data concerning the M-N and N=N bond strengths do not necessarily coincide making it very difficult to predict the suitability of a given dinitrogen metal complex for the activation of dinitrogen [479] in envisaged stoichiometric or catalytic reactions (i.e. ammonia synthesis). McGuinness et al. [480] used the pincer carbene complexes of titanium(III), vanadium(III), chromium(III), iron(II), iron(III) and cobalt(II) for the oligomerisation and polymerisation of ethylene. The study limits itself to early (up to iron) transition metals since the platinum metals show 1,2-alkyl shifts from the metal to the carbene centre [434,481] resulting in reductive elimination and deactivation of the catalyst. The same might be true for the iron complexes, but titanium, vanadium and chromium all show high activities in the polymerisation of ethylene with a clearly observable influence of the pincer carbene wingtip groups on the performance of the chromium catalysts. Note: The transition metal (Ti, V, Cr, Fe) pincer carbene catalysts have no active hydride or alkyl ligands to start chain growth. Therefore activation with a cocatalyst is necessary (here MAO or Et2AlCl). Note: When the DIPP wingtip group in the pincer carbene ligand is substituted for the less sterically cumbersome isopropyl group, the ‘abnormal’ coordination mode in the di-pincer carbene complex of iron(II) is no longer observed. Another example for a defined pincer carbene chromium(III) catalyst for the oligomerisation of ethylene also comes from McGuinness et al. [482]. It is an example of a nonmetallocene polymerisation catalyst [483] that traditionally falls into the categories of chromium based Phillips and Union Carbide systems [484], nickel based SHOP catalysts [485] and titanium/aluminium based Ziegler-Natta catalysts [29]. The chromium(III) pincer carbene catalysts are highly active for the oligomerisation of ethylene and produce mainly α-olefins. Pugh et al. [486] published an equally facile synthesis for the transition metal pincer carbene complexes of titanium(IV), vanadium(II), chromium(II), manganese(II), niobium(III) and uranium(IV). It consists of treating the free carbene with the respective transition metal halide or the pincer imidazolium salt with the respective metal bis-trimethylsilylamide (see Figure 3.160). Figure 3.166 shows the reactivity and potential of these early transition metal pincer carbene complexes taking vanadium as an example. The broad range of compounds becomes possible owing to the rich redox chemistry of vanadium that makes different oxidation states easily accessible. Here, examples for vanadium(II), vanadium(III) and vanadium(IV) are shown. Abstraction of halogen is facile making the introduction of different π-donor ligands possible, even weak ones like acetonitrile. Although the V-NHC bond is weak, it is stabilised by the chelate effect and the pyridine anchor ligand in the middle of the pincer carbene scaffold. Oxidising and reducing agents do not interfere with the vanadium pincer carbene core, but the general weakness of the V-NHC bond (and that of the other early transition metal M-NHC bonds) are exposed by the susceptibility of the V-NHC unit to hydrolysis. Ligand exchange processes involving

176

Functionalised N-Heterocyclic Carbene Complexes

N

N

:

N

[V(tmeda)Cl2]

N :

DIPP

N

N

N

V

N

DIPP

Cl

DIPP

N

N3

N

N

N

Cl

DIPP

DIPP

Cl

N

N

V N

N

Cl

DIPP

[V(thf)3Cl3]

O

N N DIPP

Cl

N V Cl

N

N Cl

N DIPP

O

N N DIPP

Cl

N V O

AgBF4

N Cl

N DIPP

N

N MeCN V

N DIPP

N

O

NCMe

N DIPP

Figure 3.160 Synthesis of pincer carbene complexes of Ti(IV), V(II), Cr(II), Mn(II), Nb(III) and U(IV).

the pincer carbene ligand were not observed, even when strong donor ligands are offered [433]. Up to now, we have looked at pincer carbene ligands based on pyridine that do not feature a linker unit between the central pyridine ring and the flanking carbene units. Principally, a short linker unit is conceivable without compromising the pincer geometry. This geometry will be compromised as soon as the linker units become long enough to enable a fac coordination mode of the ligand. The ligand would then be able to switch coordination from pincer (mer) to tripodal (fac) making it all but useless for many applications that rely on the rigidity of the pincer scaffold. Therefore, the ready availability of the α,α’-dibromolutidine as starting material for C,N,C tridentate carbene ligands is by far not the only reason that this ligand class is the only other (apart from C,C,C pincer carbenes) pincer carbene ligand group. Simons et al. [487] used these pincer carbene ligands in the synthesis of silver(I), palladium(II) and rhodium(I) pincer carbene complexes (see Figure 3.167). Similar to the linker-free pincer carbene ligands, [Rh(cod)Cl]2 proved to be an unsuitable starting material to synthesise a rhodium(I) pincer carbene complex [462]. The ligand acted as bridging ligand to two [Rh(cod)Cl] units instead. Silver(I) carbene complexes are characterised by a broad range of different structures [314]. Hence, it is not surprising that Melaiye et al. [488] found an infinite chain structure as the underlying motif in a water soluble silver(I) pincer carbene complex (see Figure 3.168). Water solubility was achieved by the introduction of pendant hydroxyalkyl wingtip groups. Water solubility of the silver(I) pincer carbene is desirable when the compound is used as an antimicrobial agent in medical applications [489]. A third structural motif for silver(I) pincer carbene complexes is the dimer observed by Nielsen et al. [490] (see Figure 3.169). This dimeric structure becomes possible because of the flexibility introduced into the pincer structure by the linker unit, which acts as a hinge. It makes it possible for the NHC donor ligands to align themselves parallel to each other and perpendicular to the C-Ag-C vector of the silver coordination sphere. The dimer is considered to possess no argentophilic interactions as the Ag-Ag distance is 31 pm longer than the sum of the van der Waal’s radii (340 pm) [20].

N-Heterocyclic Carbenes with Neutral Tethers

N

N

Bu

N

N

Ag2O

N N Br

Br

177

N

ClAg

N

N

N

Bu

N

N

N

Bu

Bu

AgCl

Bu

[Pd(NCPh)2Cl2] [Rh(cod)Cl]2

N Cl

N

Rh

N

Cl Rh

N N

N

N

N

Bu

Pd Bu

N

N Cl Bu

Bu

Figure 3.167 Transition metal pincer carbene complexes of Ag(I), Pd(II) and Rh(I) featuring a pincer carbene ligand with a methylene linker unit.

Br

N

N N

N

N

N

N

OH

Ag2O

N

N

N

N

N

N

Ag

*

N

N

HO

OH

HO

OH n

Figure 3.168 Water soluble silver(I) pincer carbene complexes.

Carbene transfer to palladium yields the palladium complex [Pd(pincer)Me]Cl that undergoes a 1,2-methyl shift to form a pendant imidazolium salt at 150 ˚C in DMSO. This makes the pincer carbene ligand still relatively thermally stable with regard to reductive elimination. This is probably due to the difficulty encountered by the NHC unit in the pincer carbene ligand to orientate itself perpendicular to the pyridyl plane, the most favourable orientation for the reaction with the cis-methyl group. The flexibility of the pincer carbene ligand system can be seen from the crystal structures of their palladium complexes. The ligand without linker units features the central pyridine ring and the flanking NHC units strictly coplanar [431] whereas the linker unit introduces twisting of these three ring systems [490]. The flanking NHC units are now

178

Functionalised N-Heterocyclic Carbene Complexes

N

N

Ag2O

N

N

N

N Ag

N N

N

N

N

Ag

N

N

N

N

[Pd(NCMe)2MeCl]

N

N N

N

150C

N

N Pd

N DMSO

DMSO

N

d6-DMSO Pd N

N

Figure 3.169 A silver(I) pincer carbene complex with dimer structure.

tilted by 40–45˚, but in opposite directions, which is made possible by a corresponding tilting of the central pyridine ring. The palladium(II) pincer carbene complex showed good activity in standard Heck coupling reactions using activated aryl bromides, but was less effective with chlorides. An extension of the pincer concept to benzimidazole flanked systems and thus introduction of annulation [108,113], is expected to alter the electronic properties of the system, but not necessarily the structural implications. Annulation affects the backside of the pincer ligand’s flanking groups, an area that has no influence on the steric demand of the ligand towards a coordinated metal. Examples come from Hahn et al. [491] who synthesised the pincer imidazolium salt from α,α’-dibromolutidine and N-alkyl-benzimidazole using a standard protocol. Synthesis of the palladium(II) complex was then achieved with palladium(II) acetate in DMSO. The structure is similar to that of the palladium(II) pincer carbene complexes with nonannulated pincer ligands. Temperature dependant 1H-NMR spectroscopy

N-Heterocyclic Carbenes with Neutral Tethers

179

N N

N

N

N

N

Pd N

N Br R

R

Pd N R

N Br

R

Figure 3.170 Lutidine and pyridine bridged pincer carbene ligands with benzimidazole flanking groups.

shows a rapid equilibrium between the two possible tilting orientations even at room temperature. The palladium(II) pincer carbene complexes were employed in the Heck reaction between aryl bromides and iodides and styrene (α-methylstyrene). The robustness of the catalytic system towards air and moisture approaches levels suitable for commercialisation. Tu et al. bring the system back to the pyridine bridged C,N,C pincer carbene ligands (with benzimidazole flanking groups) [492] and thus take away the flexibility encountered in the lutidine bridged ones (see Figure 3.170). We would expect an even greater stability towards reductive elimination reactions involving 1,2-methyl shifts that result in the deactivation of the catalyst. However, experiments to test this have not been reported yet. Instead, Tu et al. report on the use of these catalysts in the Heck and Suzuki C-C coupling reactions. Suzuki coupling was performed in N-methyl-2-piperidone (NMP) at 140 ˚C between mostly aryl iodides and phenylboronic acid. In itself and considering the high reaction temperatures, this is hardly a taxing system, but the catalyst loading was a mere 10-4–10-7 mol % making the reaction economical from a catalyst viewpoint. The Heck reaction was performed under the same conditions (aerobic, NMP, 140 ˚C) demonstrating again the system’s indifference to air and moisture. The use of ary l iodides is unremarkable and the catalyst loading for the most part between 10-4 mol % and 10-7 mol % as well. A comparison between Tu’s pyridine bridged C,N,C pincer carbene ligand and the lutidine bridged one from Hahn’s group distinctly favours the more rigid Tu ligand over the conformationally flexible Hahn system. A totally different scaffold for the synthesis of anionic C,N,C pincer carbene ligands was recently proposed by Moser et al. [493]. They used 3,6-bis-tert-butylcarbazole [494] for the preparation of the pincer architecture. The key step here is the introduction of the iodo groups in 1,8-positions of the carbazole backbone. Introduction of the imidazole rings then follows established procedures. Owing to the reactivity of the central N-H group, introduction of the transition metal is achieved in a carbene transfer reaction from a rare lithium carbene complex [222,409,495–499] (see Figure 3.171). The [Rh(BIMCA)CO] complex, where BIMCA is 3,6-di-tert-butyl-1,8-bis(imidazol-1-yl)carbazole, has a very lowλ(CO) band of 1916 cm-1 in the IR spectrum indicative of either a very strong π-donor ability and/or a poor π-acceptor strength [251]. The enhanced nucleophilicity of the rhodium(I) centre (owing to the great π-donor strength of the NHC ligands and the carbazolide system)

180

Functionalised N-Heterocyclic Carbene Complexes But

But

But

But

N

NH

[Cu]-cat N H

N H

I

N H

N

I

N

N

N But

But

MeI

But

But

N N

N Rh N

CO

N

But

But

LDA N N

N [Rh(CO)2Cl]2

N

N

N H

N N

N Li N

Figure 3.171 C,N,C pincer carbene complexes with a 1,8-bis(imidazolyl)carbazolide scaffold.

is demonstrated by the facile oxidative addition of methyl iodide to the octahedral rhodium(III) complex. Note: The BIMCA scaffold results in a monoanionic C,N,C pincer carbene ligand that has the potential to create neutral rhodium(I) (with a neutral π-donor coligand) and palladium(II) (with an anionic, halide coligand) complexes with accompanying good solubility in most organic solvents. Labelling experiments with 13C-enriched CO were carried out to investigate the alleged lability of the CO ligand in the rhodium(I) BIMCA complex. The expected lability of the CO ligand comes from the observation of a distorted coordination of the CO ligand in the crystal structure of the complex. Both the N1-Rh-C(O) (161.0 pm) and the Rh-C-O (170.9 pm) bond angles deviate significantly from linearity giving the N1-Rh-C-O vector a distinct bent appearance. However, ligand exchange on the Rh(I) complex could not be observed using 13C-enriched CO as the 13C-NMR probe. Such a ligand exchange reaction could only be observed after oxidative addition of methyl iodide in the resulting rhodium(III) complex (see Figure 3.172). Note: The apparent enhanced nucleophilicity of the metal centre in transition metal BIMCA complexes paired with facile oxidative addition on the metal should make this pincer ligand system a prime candidate in those catalytic reactions where the oxidative addition is thought to be the rate limiting step (Suzuki, Sonogashira, Heck).

N-Heterocyclic Carbenes with Neutral Tethers But

But

181 But

But

MeI N

N N

N

I

N

I

N

III Rh

Rh N

N

CO

13CO

But

But

But

But

N

N N

N

I

N

Rh N

N

CO

X

13CO

N

13CO

N

I

III Rh

N

N

13CO

N

Figure 3.172 The reactivity of the rhodium(I) BIMCA complex.

The obvious extension to the C,N,C pincer ligands is the C,C,C pincer architecture that likewise has its predecessors in X,C,X (X = N, P, S) pincer ligands [430,500,501]. An example for a silver(I) complex of such a C,C,C pincer ligand comes from Chen et al. [502], who synthesised a bis-carbene ligand on the basis of α,α’-dichloroxylene and reacted the resulting bis-imidazolium salt with silver(I) oxide (see Figure 3.173). The ligand bridges two silver centres. Formation of the palladium(II) complex does not require the silver(I) complex, but can be achieved by reaction of the pincer imidazolium salt with [Pd2(dba)3] [136]. As already described for the corresponding C,N,C pincer complex, the C,C,C palladium(II) complex displays a conformational flexibility with δH# of 51.6 kJ/mol for the C,N,C pincer complex and 74.5 kJ/mol for the C,C,C pincer complex. This difference in enthalpies is unexpected and was explained later by the same authors [503] as stemming from a counter anionic

182

Functionalised N-Heterocyclic Carbene Complexes

N

N

Ag2O N

Cl

Cl

N

N

N

N

ClAg N

N

AgCl N

Figure 3.173 The silver(I) complex of a potential C,C,C pincer carbene ligand.

effect meaning that a coordinating counter anion lowers the activation barrier of the atropisomeric interchange. The coordinated, inner halide ligand does not have a noticeable effect on the interchange. Note: Since only the C,N,C pincer ligand forms cationic complexes with palladium(II), the C,C,C palladium(II) pincer carbene complex does not possess a counter anion that could assist in the atropisomerism. Both complexes were used in the Heck reaction between activated aryl halides (Br, Cl) and styrene. The C,N,C pincer complex was by far more active than the C,C,C counterpart and produced a higher ratio of trans-stilbene with a significantly greater yield (90:70%). The method of preparation is seemingly irrelevant as demonstrated by Danopoulos et al. [504]. They used three different routes to synthesise the same C,C,C palladium(II) pincer carbene complexes and showed in the process that all three methods can be applied to the linker unit free ligand as well (see Figure 3.174). Note: The 1,5-cod ligand did not prevent the formation of the chelate complex as was observed for the corresponding C,N,C rhodium(I) pincer carbene complex. This question of the 1,5-cod ligand and its role in assisting the formation of the bridging or hindrance in the attempted formation of the chelating C,C,C (C,N,C) pincer carbene complex is illustrated by a series of publications by Hollis and coworkers [505,506]. When the free carbene is reacted with [Rh(cod)Cl]2, the bridged complex is formed [505] (see Figure 3.175). The chelating complex is available, when the corresponding imidazolium salt is first reacted with [Zr(NMe2)4] and the resulting zirconium(IV) C,C,C pincer carbene complex reacted with [Rh(cod)Cl]2 in a carbene transfer reaction [506]. We note that the sterically cumbersome zirconium core and the sterically equally demanding 1,5cod ligand are apparently able to avoid each other during the formation of the chelating rhodium(I) complex. The free carbene, however, features only a sterically innocent central C-H group that is nonetheless unreactive with dimeric [Rh(cod)Cl]2 and sufficiently reactive with [Pd(cod)Br2] to form the chelating C,C,C pincer complex. Note: The formation of the bridging or chelating transition metal C,C,C pincer complex is evidently electronically controlled and connected with the transition metal’s ability to activate the central C-H bond.

N-Heterocyclic Carbenes with Neutral Tethers

N

183

N

N

N

Ag2O

ClAg

N

N

DIPP

DIPP

N

AgCl N

DIPP DIPP

[Pd(cod)Br2] N

N

N

N

N

N :

:

Br

N DIPP

DIPP N

DIPP

DIPP

[Pd2(dba3] [Pd(cod)Br2]

N

N Pd

N

N

Br DIPP

DIPP

Figure 3.174 Three routes to the same C,C,C palladium(II) pincer carbene complex.

N

N

N

I

N

I

Bu

N

I Rh

Zr

MeI

N

I

N

[Rh(cod)Cl]2

Bu

N

N I NHMe2 Bu

Bu N

Me2N Zr

N

N I NMe2 Bu

Bu

NHMe2 Bu Bu N

[Zr(NMe2)4] N

I

I Rh N

Bu

N

Rh I

I NH

N

N

N

N

N N Bu

N

N

N

[CuO]K2CO3

Bu

Br

Br

Bu

Rh

N Li

:

: Bu

N

[Rh(cod)Cl]2

N

N

N

Bu

Rh I

I Bu

N

N

N

N

Bu

Figure 3.175 Synthesis of the bridging and chelating rhodium(I) C,C,C pincer carbene complexes.

184

Functionalised N-Heterocyclic Carbene Complexes O HO HN

O N

LiAlH4

[Zr(NMe2)4]

N

N

N

NH2

H2N

Zr

N

N

Et

N X

HC(OEt)3 Et

Et

X

N X

Et

X = NMe2

Figure 3.176 C,C,C pincer carbene ligand with saturated flanking NHC groups.

N N Et Br

Br

Br

N

N

Br

N

N Et

Et

1)BuLi 2)[Pd2(dba)3]

N

N Pd N Et

Br

N Et

Figure 3.177 C,C,C pincer carbene ligands with flanking annulated NHC groups.

The two rhodium(I) C,C,C pincer carbene complexes were employed in the catalytic hydrosilylation of alkynes with comparable results concerning yield and regioselectivity. The corresponding C,C,C pincer carbene ligand with saturated flanking NHC groups is available from a multistep synthesis [506] (see Figure 3.176). The utilisation of benzimidazole in lieu of imidazole does not add significantly to the understanding of these C,C,C pincer ligands. However, Hahn et al. added an interesting facet to the synthesis of these ligands by choosing 1,α,α’-tribromoxylene as the entry point [507] (see Figure 3.177).

References G. Desimoni, G. Faita, P. Quadrelli, Chem. Rev. 103 (2003) 3119. P. Espinet, K. Soulantica, Coord. Chem. Rev. 193–195 (1999) 499. Z.-Z. Zhang, H. Cheng, Coord. Chem. Rev. 147 (1996) 1. G. R. Newkome, Chem. Rev. 93 (1993) 2067. H. Kobayashi, Y. Kaizu, H. Matsuzawa, H. Sekino, Y. Torii, Mol. Phys. 78 (1993) 909. C. Kaes, A. Katz, M. W. Hosseini, Chem. Rev. 100 (2000) 3553. U. S. schubert, C. Eschbaumer, Angew. Chem. Int. Ed. 41 (2002) 2892. I. J. B. Lin, C. S. Vasam, Comm. Inorg. Chem. 25 (2004) 75. I. J. B. Lin, C. S. Vasam, Can. J. Chem. 83 (2005) 812. A. T. Normand, K. J. Cavell, Eur. J. Inorg. Chem. (2008) 2781. H. M. J. Wang, I. J. B. Lin, Organometallics 17 (1998) 972. G. Jander, H. Blasius, Einführung in das anorganisch-chemische Praktikum, 15th edition, S. Hirzel Verlag, Stuttgart, 2005. 13. H. Schmidbaur, S. Cronje, B. Djordjevic, O. Schuster, Chem. Phys. 311 (2005) 151. 14. H. Schmidbaur, Gold Bull. 33 (2000) 3. 15. V. J. Catalano, A. L. Moore, Inorg. Chem. 44 (2005) 6558.

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

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4 N-Heterocyclic Carbenes with Anionic Functional Groups

4.1 Oxygen-Containing Groups We have already seen that many functionalised NHC ligands are modelled on previously known functionalised phosphanes. In the case of an oxygen-containing functional group where the oxygen atom can carry a (formal) negative charge, we can expect functionalised NHC ligands that resemble phosphinophenols [1,2], phosphinoalcohols [3–5] or phosphino carboxylic acids [6]. All these functionalised phosphane groups were employed as ligands in catalytic reactions. The rationale behind the concept of NHC ligands carrying anionic oxygen functional groups goes beyond the application in catalysis. NHC ligands do not bond strongly to the early transition metals [7] or alkaline earth metals [8]. However, both these groups of metals bind strongly to alkoxides or aryloxides. It is therefore reasonable to design functionalised NHC ligands with a view to an oxygen (nitrogen) based anchor group in addition to the somewhat loosely binding carbene unit. This results in the formation of a hemilabile chelate ligand [9]. Conversely, NHC bind strongly to the late transition metals (group 9 and group 10), metals that have only a low affinity to oxygen. Here, the oxygen-containing functional group serves as the hemilabile ligand [10]. We will therefore see a great versatility in the anionic tether and in the range of (transition) metal employed. Thiel and coworkers reacted imidazole with epoxycyclohexane to form the racemic hydroxycyclohexyl imidazole. Attempts to separate the enantiomers by kinetic resolution with lipase B of Candida antarctica and isopropenyl acetate as acylating agent [11,12] failed, but gave the racemic ester in high yields (see Figure 4.1). Alkylation was then Functionalised N-Heterocyclic Carbene Complexes. Olaf Kühl © 2010 John Wiley & Sons, Ltd.

200

Functionalised N-Heterocyclic Carbene Complexes

N N

N

MeI

OH

N

[Pd(OAc)2]

HO N

OH

N

I Pd I

N

N OH

O NH

lipase B (C. antarctica) is opropenyl acetate

N

O O N

N

N O

MeI

O

N

N

N

I Pd

[Pd(OAc)2] N

I

N O

O

O O

Figure 4.1 Synthesis of a hydroxycyclohexyl functionalised imidazolium salt and its palladium(II) complex.

achieved with methyl iodide in acetonitrile (alcohol as solvent greatly increases the reaction time [13]). The corresponding palladium(II) carbene complexes can be synthesised by reaction of the imidazolium salts with palladium(II) acetate. As expected, the oxygen functional groups do not coordinate to the palladium centre. Note: Use of epoxycyclohexane in a ring opening reaction with imidazole invariably results in racemic N-hydroxycyclohexyl imidazole. This of course presents a problem if the ligand is to be used in asymmetric catalysis. It seems that the racemic mixture of N-hydroxycyclohexyl imidazole is used in further reactions, normally even without mention of chirality [14,15]. Double functionalisation is facile, as the two wingtip groups need to be introduced stepwise. Ray et al. [14] used this opportunity to introduce a keto group in the second step by reacting N-hydroxycyclohexyl imidazole with chloracetophenone (see Figure 4.2). They then used the imidazolium salt to form the silver(I) complex by reaction with Ag2O [16]. Subsequent carbene transfer by reaction of the silver(I) carbene complex with [Au(SMe2)Cl] yields the corresponding gold(I) complex. Again, no coordination of oxygen to either metal was observed in the gold(I) and silver(I) carbene complexes. Oxygen contacts in silver(I) carbene complexes are known [17–19], but the structural diversity of gold(I) carbene complexes is much poorer [20] with only [Au(NHC)X] (X = halogen) and [Au(NHC)2]+ complexes known. The interest in functionalised carbene complexes of gold(I) derives not only from the longer known biological applications [21–23], but also from a recent interest in their performance in catalysis [14,15,24,25]. Ray et al. tested a series of nonfunctionalised, hydroxy functionalised and hydroxy/keto difunctionalised NHC ligands in the ROP of L-lactide [14]. There is no significant difference in the activities of the two functionalised NHC

N-Heterocyclic Carbenes with Anionic Functional Groups

O

Ph

N O

N

201

O

Cl

Ph

N

N

NH OH N

OH

Ag2O

Cl

O

Ph

Cl

Au

Ag N

[Au(SMe2)Cl]

N

N

OH

O

Ph

N

OH

Figure 4.2 Synthesis of a hydroxycyclohexyl functionalised imidazolium salt and its silver(I) and gold(I) complexes.

ligands in the gold(I) catalysed ROP of L-lactide. The results of the nonfunctionalised NHC ligand (derived from benzimidazole) are overshadowed by a moderate annulation effect [26,27]. Surprisingly, the benzannulated NHC ligand accelerates the catalytic reaction somewhat. That the method of synthesis of hydroxy functionalised carbene ligands is a general route is shown by a diversity of second wingtip groups. Apart from the methyl group [28] and keto group [14] discussed already, Ray et al. have shown that the introduction of an acetylamide functionality is likewise compatible with the previously introduced hydroxycyclohexyl group [15]. Preparation of the silver(I) and gold(I) complexes presented no surprises, but the resulting gold(I) catalyst was somewhat less active in the ROP of L-lactide than the previously described silver(I) carbene complexes. The epoxide method for the synthesis of hydroxy functionalised carbene ligands is neither limited to epoxycyclohexane nor to unsubstituted imidazole. Arnold et al. reacted N-tert-butylimidazole with 2-phenyl-epoxypropane and obtained a chiral and zwitterionic hydroxy imidazolium compound that was deprotonated to the corresponding dimeric lithium alkoxide NHC adduct by LiN(SiMe3)2 as the base (see Figure 4.3) [29]. Carbene transfer using CuX2 (X = Cl, OTf) as carbene acceptor yielded the copper(II) monocarbene and dicarbene adducts, respectively. Although often in NHC chemistry copper(I) precursors are employed to synthesise copper(I) catalyst complexes [30,31], copper(II) NHC complexes are rare [32]. Arnold et al. employed copper(II) salts specifically to generate NHC stabilised copper(III) complexes for copper catalysed conjugate addition reactions. They could isolate and characterise two copper(II) carbene complexes. A third was obtained in low yield and structurally characterised as having an oxide centre bridging four copper(II) atoms that are stabilised by an alkoxy functionalised bis-carbene [33,34]. Evidence of an intermediate copper(III) species could not be obtained, but neither can it be ruled out.

202

Functionalised N-Heterocyclic Carbene Complexes Ph O

O

H

N

⫺

O

N But

Ph N

But N

⫹

N

But

LiN(SiMe3)2

NH

MeI But Et2O H But

H LiN(SiMe3)2

N

H Li

OH

⫹

But

O

I

N

O

CuCl2

Li

N

N N

⫹

N

Cu O

N

N H

2

But

0.5 CuCl2 But H O

N

Cu

Cl thf

N

Figure 4.3 Synthesis of a hydroxycyclohexyl functionalised imidazolium salt and its copper(II) complexes.

The copper(II) carbene complexes were active in the conjugate addition to cyclohexenone using ZnEt2 as alkylation agent. The most efficient catalyst proved to be the monocarbene copper(II) complex with a tert-butyl wingtip group. Note: Whereas gold(I), silver(I) and palladium(II) did not show coordination by a neutral hydroxy functional group, copper(II) coordinates the anionic alkoxide functionalities [and even a O2− anion bridging four copper(II) centres]. The epoxide can provide another reactive functional group in order to engage two imidazole molecules in ‘simultaneous’ quarternisation reactions thus producing a hydroxy functionalised bis-imidazolium salt that can be used as a tridentate ligand. Such an example was reported by Arnold et al. in the reaction between 2 equiv. of N-tert-butyl imidazole and 2-phenyl-2-chloromethyl epoxide (see Figure 4.4) [33]. One N-tert-butyl imidazole molecule attacks the epoxide in a ring opening reaction and the other reacts with the chloromethyl end. The result is an imidazolium chloride from the latter and a zwitterionic imidazolium alkoxide from the former reaction. Reaction with silver(I) oxide and subsequent carbene transfer reaction to copper(I) iodide yields a dinuclear copper(I) carbene complex where the potentially tridentate ligand acts as a bidentate ligand to each copper(I) atom. The central alkoxide oxygen atom bridges both copper(I) centres.

N-Heterocyclic Carbenes with Anionic Functional Groups

203

Ph N

N

N

N

O

But

N

But

Cu

Cu But

t

Bu N

N N

O N

N

N

Cl

Ph

O

Ph

O

N N

N

N Ph

CuI

N

Ag2O Ag N

N O N

N Ph

Figure 4.4 Syntheses of a hydroxy functionalised bis-imidazolium salt and its silver(I) and copper(I) complexes.

Note: The epoxide method defines the tether length between the hydroxy group and the imidazole ring. The opening of the oxirane ring creates an ethylene tether that cannot be altered in length, but is modifiable in the substituents on the C2-linker. It should be noted that reaction of a hydroxy functionalised imidazolium salt does not necessarily result in carbene adduct formation of a tethered silver(I) alkoxide. Instead, it is possible that the hydroxy functionalised carbene can coordinate to the silver(I) cation as a neutral chelate ligand (see Figure 4.5) [35]. At first sight, the two hydroxy functionalised imidazolium salts in Figure 4.5 do not appear to be dramatically different. Also, the reaction conditions do not seem to be responsible for the formation of structurally different products. Still, the functionalised carbene ligand with an isopropyl wingtip group results in a deprotonated carbene that forms a simple neutral chelate complex with the silver(I) cation. Its counterpart with a sterically completely innocent methyl wingtip group forms a cationic silver(I) carbene complex where two neutral chelating hydroxy functionalised carbene ligands coordinate to the same metal. Apparently, coordination of two ligands is preferred by the metal cation, but sterically possible only when the wingtip group is methyl. Once the hydroxy functionalised imidazolium salt is formed, it can be deprotonised and reacted with various metal complexes to form (transition) metal carbene complexes. The hydroxy group ensures that the ligand can be coordinated even to metals that are normally reluctant to form stable carbene complexes. A good example is the deprotonation of a hydroxyethyl functionalised imidazolium salt with potassium hydride [36]. The potassium cation coordinates to the oxygen atom of the alkoxide sidechain and forms K4O4 cubes as structural elements (see Figure 4.6). The carbene end then coordinates to the respective

204

Functionalised N-Heterocyclic Carbene Complexes H O

But

Ag H

H OH

But

N

Ag2O

N

N

N

OH

But

N

N

Ag2O

N

N

H But

OH Ag

But

HO H N

N

Figure 4.5 The difference in the silver(I) carbene complexes, dependant on the size of the wingtip group.

N

N

N np

N O

N

K

O K

N

N

K np N np

O

O

K

N np

N

fht N

N np

N

np

N O

K

K

O

np K O N

K

thf

O thf N

np

KH OH

N

N

Figure 4.6 K4O4 structure of the potassium salt of a hydroxyethyl functionalised carbene.

N-Heterocyclic Carbenes with Anionic Functional Groups

205

potassium cation forming a metallacycle due to a chelate effect. That the formation of the K4O4 cube is indeed the key step and not the coordination of the carbene to the potassium cation is seen by a similar compound that is formed when KOH adds to the carbene centre of a naphthyl annulated carbene [37]. Here, the K4O4 cube is formed in the absence of a carbene. The potassium complex of the hydroxyethyl functionalised carbene, once formed, can then be used as a carbene transfer agent. Patel et al. employed this compound in the synthesis of titanium(IV) complexes used as catalysts in the polymerisation of lactides [38]. Synthesis of the catalyst is facile and involves the reaction of the potassium complex of the hydroxyethyl functionalised carbene with [Ti(OPri)4] (see Figure 4.7). Although the activity of the titanium(IV) carbene complex is considerably less then that of the potassium complex, the titanium complex acts as a masked NHC and thus a highly moisture and air stable NHC source [38]. The ring opening reaction is essentially an organocatalysed process whereby the imidazolium H2-proton attacks the carbonyl oxygen atom of the lactide electrophilicly and simultaneously the alkoxide end of the wingtip group attacks the endocyclic carbon atom of the lactide nucleophilicly causing ring opening. Cleavage of the H2--O hydrogen bond regenerates a catalytic species that is one monomeric unit longer than in the previous cycle. Alternatively, it is possible for the organocatalyst to attack the carbonyl carbon nucleophilicly as a carbene and simultaneously attack the endocyclic oxygen atom electrophilicly with the hydrogen atom of the wingtip group’s hydroxy functionality. Cleavage of the H--O hydrogen bond now generates a different species, the wingtip hydroxy group is still active, but the nucleophilic end is now the carboxylate group generated from opening of the lactide. The titanium(IV) complex just seen is not the only titanium carbene complex generated with this hydroxy functionalised NHC ligand. Arnold and coworkres reacted the potassium salt also with [Ti(thf)3Cl3], a titanium(III) precursor for which they established a new, cost efficient synthesis [39]. The product is a nonsymmetrical titanium(III) complex with octahedral geometry (see Figure 4.8). Two carbene units are coordinated trans to each other leaving the third carbene moiety mutually cis coordinated. The alkoxide groups follow suit. The symmetric alternative would be all carbene units coordinated trans to an alkoxide group. Since the second wingtip group can be chosen almost at will, synthesis of a bis-carbene ligand is comparatively facile. Two equivalents of the hydroxyethyl functionalised imidazole need to be reacted with a 1,ω-alkyl dihalide to generate the corresponding bis-imidazolium salt. Hemmert and coworkers employed this strategy using a methylene and a propylene tether, respectively [40]. These potentially four dentate ligands were then reacted with silver(I) oxide. As observed earlier [14,15], the hydroxy groups do not bind to the silver cations. Instead, two bis-carbene ligands coordinate to the same metal creating a situation whereby the silver(I) centre is homoleptically coordinated to four carbene donors, a rare situation [41,42]. Prühs et al. found an elegant application for a seemingly remote hydroxy group in the sidechain [43]. The remoteness of the hydroxy group implies a mode of introduction to the central imidazole ring different to the epoxide method developed by Arnold (hydroxyethyl) and Thiel (hydroxyhexyl). Indeed, Prühs et al. modified the classic method of imidazolium salt synthesis by using a bromoalkane as carrier for the hydroxy functional group. In this way, they reacted N-mesityl imidazole with 1-bromo-ω-hydroxyalkanes to obtain the

206

Functionalised N-Heterocyclic Carbene Complexes O

O K KH

N

N

N

N

[TiCl(OPri)3]

PriO O Ti

N

N

O

O

O

or

O

OPri

N

N

H

N

OPri

O

:

O

N

O OH

O

O

O N

H

N

N

O

O

O

O

N

O O

O O

H O

Figure 4.7 Organocatalytic ROP of lactide with a hydroxyethyl functionalised NHC compound as catalyst.

N-Heterocyclic Carbenes with Anionic Functional Groups

N

O

207

N

K [T i( thf ) 3C l 3] N

N

O

O N

Ti O N

NN

Figure 4.8 Synthesis of an octahedral titanium(III) NHC complex employing a hydroxyethyl functionalised carbene ligand.

corresponding imidazolium salts (see Figure 4.9). They were used as the NHC ligand in second generation Grubbs’ catalysts [44,45]. The remote hydroxy group was subsequently used to attach the catalyst to a polymeric support, with PhSiCl3 or MeSiCl3 as reactive linker groups, in an attempt to make the catalyst recyclable. Note: Functionalisation of a carbene with a hydroxy group on a variable length tether can be effected by reaction of an N-substituted imidazole with a bromo-alkanol. Keeping this in mind, we will now turn towards a multiple step synthesis of a hydroxyethyl functionalised imidazolium salt devised and developed with full knowledge of the above more facile protocols [46,47]. The synthesis starts with ethyloxalylchloride (see Figure 4.10). The two functional groups (ester and carboxylic acid chloride) have different reactivities that are used to introduce two different wingtip groups. In a first step, a nonfunctionalised amine was employed to prepare the carboxylic acid amide, ensuring that no potentially troublesome hydroxy group is present in the second step. Now, a (chiral) aminoalcohol is used to introduce the second wingtip group. Reduction of the unsymmetric oxalyl diamide with LiAlH4 yields the hydroxy functionalised diamine. Ring closure reaction with triethyl orthoformate yields the saturated, hydroxy functionalised (chiral) imidazolium salt. Note: Owing to the reduction step with lithium alanate, this protocol results in the synthesis of saturated NHC ligands that might be too labile in further catalysis reactions. The question may not be asked, but why develop a three-step synthesis when a one-pot protocol already exists? The answer, of course, is simple. The three-step synthesis provides a chiral ligand from an enantiopure aminoalcohol whereas the one-pot reaction provides an achiral ligand at best and otherwise a racemic ligand that proves hard to convert to an enantiopure ligand [28]. The enantiopure hydroxyethyl functionalised imidazolium salts were successfully employed in the asymmetric conjugate addition of alkyls to cyclohexenone [46,48,49]. In a comparative study, an unfunctionalised wingtip group chiral NHC, a backbone chiral saturated NHC and the hydroxyethyl functionalised saturated NHC (chiral centre on the

208

+

N

N

N

N

HO

Mes

⫹

HO

Ph Cy3P Ru PCy3 Cl Cl O

O

Ph

N

N

Si

Mes

O Cl

1) PhSiCl3 2) polymer

Ph Ru Cl

PCy3

N

N

Mes

HO Cl Ph Ru Cl

PCy3

Figure 4.9 Introduction of a remote hydroxy group with a bromoalkyl carrier and heterogenation of the resulting second generation Grubbs’ catalyst.

Functionalised N-Heterocyclic Carbene Complexes

Mes Br

N-Heterocyclic Carbenes with Anionic Functional Groups O

209

O MesNH2 OEt

Mes

OEt

Cl

N H O

O H2N

R OH

HO

O H N

Mes

R N

HC(OEt)3

N R

R

N H O OH

Figure 4.10 Synthesis of a chiral hydroxyethyl imidazolium salt.

hydroxyethyl tether) (see Figure 4.11) were employed in the conjugate addition of ethyl to cyclohexenone using copper(II) triflate as the catalyst precursor and EtMgBr as the ethyl transfer agent [49]. The best chiral resolution (68% ee) was obtained by the nonfunctionalised saturated NHC ligand, closely followed by the hydroxyethyl functionalised NHC (61% ee). However, the two catalysts afforded different enantiomers, the former the S(−) enantiomer the latter the R(+) enantiomer. This result seems to be representative. When alkyl substituted cyclohexenones were used as substrates the products had the same R/S distribution. The preferred enantiomer in the product seems to be largely independent of the copper(II) precursor or the ethyl source. When ZnEt2 was used instead of EtMgBr, a slightly higher ee value (75%) was obtained of the R(+) enantiomer [48]. For the substituted cyclohexenones, the chiral resolution was significantly higher with ZnEt2 than with the Grignard reagent (by 15–20% points). An interesting variant of the synthesis of a chiral hydroxyethyl functionalised imidazolium salt was likewise introduced by Clavier et al. [50]. Here, the authors used an α-amino acid from the chiral pool as starting block for the synthesis of a backbone chiral, saturated imidazole moiety (see Figure 4.12). N-boc protected (L)-valine was reacted with 2-tertbutylaniline to yield the corresponding amino acid amide. Subsequent deprotection and reduction with LiAlH4 affords the corresponding diamine that can be subjected to a ring closing reaction with triethyl orthoformate to the respective imidazole derivative. Reaction with the appropriate hydroxyalkyl halide completes the synthesis. There is no reason to believe that this protocol is limited to (L)-valine. It is likely to be a general route to the synthesis of backbone chiral, saturated NHC ligands, although certain

210

Functionalised N-Heterocyclic Carbene Complexes

N

⫹

HO N Mes N

Ph

O

⫹

N

⫹

N

N

Ph

O

EtMgBr NHC/Cu(OTf)2

*

Figure 4.11 Imidazolium salts employed in a comparative catalytic study concerning the conjugate addition of ethyl on cyclohexenone.

1) 2-But-aniline 2) hydrolysis 3) LiAlH4

O

NHBoc

1) dry HCl 2) HC(OMe)3

NH2

HO

N

NH

N

HO(CH2)2X

N

N

HO

X

Figure 4.12 Synthesis of a C4-chiral imdazolidinium salt from (L)-valine.

functional groups in naturally occurring α-amino acids are not compatible with the reduction step (LiAlH4) of the protocol. When the alkyl halide method is used to introduce a hydroxy functional group it can as easily provide two hydroxy functionalities in the same wingtip group. An example comes from Cai et al. who reacted N-methylimidazole with 3-chloro-2-hydroxypropanol to form the corresponding imidazolium salt (see Figure 4.13) that was then used in the palladium catalysed Heck reaction between phenyl iodide and ethyl acrylate [51].

N-Heterocyclic Carbenes with Anionic Functional Groups

N

N

Cl

211

OH OH

N

N

OH OH

Figure 4.13 Synthesis of a hydroxy functionalised imidazolium salt carrying two hydroxyl functionalities in the same wingtip group.

From alkoxide functionalised carbene ligands, it is only a small step towards aryloxide functionalised NHC ligands. Aihara et al. reported a phenoxide functionalised imidazolium salt that undergoes a 1,2-shift of one wingtip group to the C2-carbon atom upon deprotonation and generation of the free carbene [52] (see Figure 4.14). 1,2-migration is not usually observed for NHC, but has been reported previously for allyl wingtip groups [53] or triazole based NHC [54]. The synthesis of the ligand system starts with the stepwise alkylation of imidazole using 2-bromomethyl-4,6-di-tert-butylphenol, a classic synthetic route for imidazolium salts (see Chapter 1). The synthesis of transition metal carbene complexes with this ligand system becomes possible, when the imidazolium salt is deprotonated at low temperatures (−78°C) to the free carbene and immediately reacted with [Ti(thf)2Cl4], before the 1,2-migration step can occur. In this way, the corresponding octahedral titanium(IV) complex is prepared and can be further reacted with PhCH2MgCl to substitute the remaining chloride substituents by benzyl groups. Aihara et al. used the methylene linker between the phenol substituent and the imidazole ring as a means to attach the wingtip group to the backbone via the alkyl halide method (see Chapter 1). If the phenol group is to be directly attached to the imidazole ring, a different strategy needs to be employed. In Section 3.1, we saw that oxazolyl functionalised carbenes could be synthesised by making the oxazoline group from a substituted imidazole. Such a build-up strategy is not feasible in the present case as assembly of an aromatic ring is a complicated operation [55,56]. Instead Waltman and Grubbs chose the synthesis of a saturated imidazole system as a substituent of the phenol [47]. Note: This protocol for the linker-free synthesis of a phenol functionalised carbene ligand results in a saturated carbene backbone. The synthesis starts at ethyloxalyl chloride. Reaction with the appropriate aniline and triethylamine as auxiliary base results in a general synthon from which a second wingtip group can be introduced via reaction with a (functionalised) amine (see Figure 4.15). In the present case, the second amine is a o-hydroxyaniline that introduces the phenoxy

212

Functionalised N-Heterocyclic Carbene Complexes OH

OH

OH

But

But

Br

OH

But

N

But

N

Br

N

NH

But

But

But

But NaN(SiMe3)2

But

HO

ONa 1,2-shift

But

ONa

But

:

OH N

But

N

But

N

N But

But

But Ti(thf)2Cl4 Ph

Ph

But

But

But O

thf

O

Ti

Cl

But O

Ti

O

PhCH2MgCl

N

But

Cl Cl N

N

N

But

But

But

Figure 4.14 Synthesis of a phenoxy functionalised NHC and its titanium(IV) carbene complex. O

OEt

Cl

DIPP-NH2 DIPP

O

O

OEt

NH

O

NaOH DIPP

O

OH

NH

O

OH H2N

DIPP HO

HN O

HO LiAlH4

NH

HN

1-adamantol

OH

O

DIPP

HN

NH

DIPP

NH

Ph3P

Pd

O

O

HC(OEt)3 HO

N DIPP

⫹

N

KN(SiMe3)2

O

DIPP N

Ph3P

N Pd

Pd PPh3

Figure 4.15 Synthesis of a saturated phenoxy functionalised imidazolium salt.

N-Heterocyclic Carbenes with Anionic Functional Groups

213

functionality. Reduction of the carboxylic acid function with LiAlH4 yields the diamine that can be reacted with triethyl orthoformate to form the desired imidazolidene ring in the standard ring closure reaction. The additional adamantyl substituent on the phenol moiety was introduced by an acid catalysed reaction with 1-adamantol prior to the reduction step. The significance of this ligand is that it stabilises a Pd-alkyl group cis to the NHC ligand in a palladium(II) carbene complex. These transition metal carbene complexes with a cis alkyl ligand are still rare [57,58] owing to comparatively facile reductive elimination of an imidazolium salt [59] and formation of metal black. Stabilisation usually occurs by means of a chelating functionalised carbene ligand [60,61]. Shen and coworkers used Kawaguchi’s phenoxy functionalised carbene ligand for the preparation of nickel(II) [62] and iron (II) [63] carbene complexes. Using the same deprotonation method — NaN(SiMe3)2— they attempted the synthesis of a monocarbene nickel(II) complex that resulted in the formation of the homoleptic complex instead [62] (see Figure 4.16). Use of the correct stoichiometries significantly increased the yield. The synthesis of the corresponding iron(II) complex follows the same protocol and the same preference for the homoleptic bis-carbene iron(II) complex [63] (see Figure 4.17). The homoleptic iron(II) phenoxy functionalised carbene complex was used in the ROP of ε-caprolactone [64]. The polymerisation proceeds via a coordination–insertion mechanism [65–67] and the final product has the functionalised imidazolium unit as end group. Performance was riddled by poor control over number-average molecular weight and decreasing molecular weight with decreasing feedstock levels. This was attributed to interand/or intramolecular transesterification processes [65,66].

N N O

Ni

O N

N

OH

N

N

NaN(SiMe3)2 [Ni(PPh3)2Br2]

X

Ph3P O

Ni

Br N

N

Figure 4.16 Synthesis of a homoleptic nickel(II) carbene complex with a phenoxy functionalised NHC ligand.

214

Functionalised N-Heterocyclic Carbene Complexes

N N O

Fe

O N

N

OH

N

N

NaN(SiMe3)2 FeBr2

X Br O

Fe N N

Figure 4.17 Synthesis of a homoleptic iron(II) carbene complex with a phenoxy functionalised NHC ligand.

Sun et al. introduced another functionality, an imino group, into the linker unit [68]. The resulting phenoxyimino functionalised imidazolium salt is a potential tridentate ligand. Synthesis of the ligand starts with the corresponding salicylaldehyde and a 1-bromo-ω-aminoalkane to yield the imine with a pendant alkyl halide group for coupling to the imidazole unit (see Figure 4.18). Deprotonation with NaN(SiMe3)2 and subsequent reaction with [Ni(PPh3)2Br2] yields the nickel(II) carbene complex. The same result can be obtained, when the functionalised imidazolium salt is reacted with nickelocene. In this case, Cp acts as deprotonation agent [69,70]. The nickel(II) carbene complex was employed in the polymerisation of styrene. Milione et al. reacted the same phenoxyimino functionalised imidazolium salt with trialkyl alanes in an attempt to form the corresponding carbene complex of aluminium(III) [71] (see Figure 4.19). Reaction of the phenoxyimino functionalised imidazolium salt with AlMe3 proceeds smoothly with the hydroxy group reacting with the alane under elimination of methane. The imidazolium end does not react under methane elimination, but remains pendant. Aluminium carbene adducts are still rare [72–75] and are usually synthesised by a reaction between the alane and the free carbene. Another example for the coordinative behaviour of phenoxy functionalised carbene ligands comes from the Bielawski group [76]. They synthesised a phenoxy functionalised benzimidazolium salt starting from o-fluoro-nitrobenzene, which they reacted with o-hydroxyaniline. Reductive ring closure reaction with formic acid/formate and palladium/charcoal as catalyst

N-Heterocyclic Carbenes with Anionic Functional Groups

H2N

OH

215

OH

Br

Br N

O

N

N

N NaN(SiMe3)2

N Br O Ni

⫹

OH

[Ni(PPh3)2Br2]

N

N

N

N

Cp2Ni

Figure 4.18 Synthesis of a phenoxyimino functionalised imidazolium salt and its nickel(II) complex.

O

N

Al ⫹

OH

AlMe3 N

N N

N

⫹

N

Figure 4.19 Synthesis of an aluminium complex with a pendant imidazolium salt.

yields the corresponding phenoxy functionalised benzimidazole which can be quarternised to the respective benzimidazolium salt using n-butyl bromide (see Figure 4.20). Note: The ring closure reaction starting from a diamine yields the unsaturated system, benzimidazole, because the o-phenylene backbone provides the required double bond. Reaction of the phenoxy functionalised benzimidazolium salt with palladium(II) acetate affords the simple carbene adduct trans-[Pd(NHC)2Br2] without coordination of the hydroxy groups. Reaction of the initial palladium(II) adduct with sodium carbonate results

216

Functionalised N-Heterocyclic Carbene Complexes NO2

N

NH2 OH

NO2

N

NH

OH

OH F BuBr Bu N

N

OH Bu O O

N

N

Na2CO3

N

Pd

Pd N

Br

NBu

N

N Bu

OH

[Pd(OAc)2]

N

Br Bu

HO

Figure 4.20 Synthesis of phenoxy functionalised benzimidazolium salts and their palladium(II) complexes.

in the activation of the acidic OH-protons under HBr elimination (neutralised by soda) and formation of the chelate complex with the carbene units in cis coordination. The next step was the development of bifaced phenoxy functionalised imidazolium salts on a phenylene scaffold designed for the synthesis of main-chain organometallic polymers [76]. The synthesis follows closely the principles set out in Figure 4.20. The starting point is 1,5-dichloro-2,4-dinitrobenzene that is reacted with 2 equiv. of 2-aminophenol. Subsequent reductive cyclisation yields the bifaced bis-benzimidazole scaffold with the two phenoxy functional groups in place. Simple quarternisation provides the corresponding bifaced imidazolium salt that can be used to form a linear polymer chain with the bifaced phenoxy functionalised carbene ligand acting as a bridge between two consecutive metal centres (see Figure 4.21). Note: The ligand architecture ensures linear chain growth. Because the two NHC centres are at opposite ends of the same vector, a chelating coordination is de facto impossible. Note: Since the NHC donor is significantly stronger then the phenoxy end, coordination to the metal is dominated by the back-to-back carbene architecture. Note: If need be, metal coordination can be activated in two steps: (i) NHC ; and (ii) phenoxide ensuring a linear chain growth. The ruthenium catalysed olefin metathesis reaction is one of the most important catalytic reactions [77–79] and one that is distinctly underdeveloped for asymmetric applications [80]. Only a few concepts have been brought forward [80,81], of which the combination of a NHC ligand with a 1,1'-binaphthyl scaffold carrying a hydroxyl anchor group is the most promising to date.

N-Heterocyclic Carbenes with Anionic Functional Groups O2N

NO2

HN

NH

N

N

N

N

217

NH2 O2N

NO2

OH

HO HO Cl

OH

OH

Cl

BuBr

Bu

Bu Bu N

*

Pd

Pd N

O

Bu

N *

N [Pd(OAc)2]

N O

N HO

N

N OH

n

Figure 4.21 Preparation of an organometallic polymer using a bifaced phenoxy functionalised imidazolium salt.

The simpler architecture is the 1,1'-biphenyl scaffold, likewise introduced by Hoveyda and coworkers [19]. The synthesis of the imidazolium salt starts with a chiral diamine and a substituted, achiral biphenyl [82–84]. Subsequent introduction of a Mes substituent on the remaining primary amino end and ring closure reaction yields the chiral saturated imidazolium salt after hydrolysation of the methoxy group to liberate the phenolic hydroxy group (see Figure 4.22). Reaction with silver(I) oxide and carbene transfer to a Grubbs’ (Hoveyda) catalyst sets up the ruthenium catalyst complex. Note: The axial chirality of the 1,1'-binaphthyl scaffold is induced by the central chirality of the carbene unit [83,84]. This simplifies the issue of chirality from a synthetic point of view as the centrally chiral diamine is easier to purify than the axially chiral 1,1’-binaphthyl scaffold that would otherwise be required. Note: The 1,1'-biphenyl scaffold only becomes chiral through fixation of the phenoxy group onto the ruthenium centre. Carbene transfer from the silver(I) complex is not only possible to ruthenium(II) to form a catalyst suitable for asymmetric olefin metathesis, but also to copper(I) [17]. This provides a catalyst suitable for copper(I) catalysed conjugate addition of alkyl- and arylzinc reagents to β-substituted cyclic enones. The products, chiral cyclic ketones, are obtained in 88–95% isolated yield and 67–83% ee. Note: Diarylzinc reagents usually give somewhat lower yields and higher enantioselectivities than dialkylzinc reagents.

218

Functionalised N-Heterocyclic Carbene Complexes

Ph NH2

H2N

MeO

Ph

[Pd]/BINAP

+

I

MeO H N

Ph

MesBr

H2N

Ph

MeO H N

Mes N H

Ph

Ph

PBr3

HC(OEt)3

Mes Ph

N Ag2O N

O

Ru

O

N

Ph

Cl

Ph N Mes

Ph

HO Cl Ru O Cl Cy3P

Figure 4.22 Synthesis of a chiral ruthenium(II) carbene olefin metathesis catalyst on a 1,1’biphenyl scaffold.

To increase the rigidity of the 1,1'-biaryl scaffold and thus presumably improve the chiral resolution of the products, but also to enable the use of an unsaturated NHC unit, enantiopure 1,1'-binaphthyl can be used as the starting point for axial chirality in the ligand scaffold [85,86]. In a synthesis for a bis-carbene ligand on a 1,1'-binaphthyl scaffold (see Section 3.4) starting from 1,1'-diamino-binaphthyl, a side product with only one imidazole substituent is observed. The other amino group was exchanged for a hydroxy group during workup [85] (see Figure 4.23). Absence of racemisation was verified using the Mosher ester method [87].

NH2

N N

glyoxal, p-CH2O

NH2

OH

PriBr N

N

N Pri

N OH Rh

O

[Rh(cod)Cl]2

Figure 4.23 Synthesis of a hydroxy-binaphthyl functionalised imidazolium salt and its rhodium(I) complex.

N-Heterocyclic Carbenes with Anionic Functional Groups

219

The protocol leading to the unsaturated 1,1’-hydroxy-binaphthyl saturated NHC was a chance discovery, enabled by an aqueous workup procedure. The yield is only moderate (40%) and has to be separated from the main product, the targeted bis-imidazolium salt (51%). A better synthesis for this ligand might be desirable, although the saturated NHC equivalent is readily available [18,86,88,89]. The hydroxy-binaphthyl functionalised saturated imidazolium salt is readily avaliable from 1-amino-1'-hydroxy-binaphthyl in a reaction with a boc-protected mesitylamine aldehyde [86] (see Figure 4.24). The resulting Schiff base is reduced to the diamine by Na(OAc)3BH. Subsequent deprotection and ring closure reaction with triethyl orthoformate yields the corresponding hydroxy-binaphthyl functionalised saturated imidazolium salt. Reaction with silver(I) carbonate and subsequent carbene transfer to the ruthenium(II) precursor yields the asymmetric olefin metathesis precatalyst. The second wingtip group on the saturated imidazolium ring can be chosen almost at will and examples include Mes, DIPP and adamantyl [88]. These hydroxy-1,1'-binaphthyl functionalised NHC ligands can be used in asymmetric catalysis. Catalytic reagents performed with transition metal catalysts carrying these ligands include olefin metathesis [19,80,86], allylic alkylation [17,18,88] and hydrosilylation of ketones [85]. The performance of this ligand class in different catalytic reactions depends not only on the individual reaction, but also on the metal used. The rhodium NHC complex in Figure 4.23 catalyses the hydrosilylation of acetophenone with 98% conversion and boc

N

O boc N

NH2

N H OMe

OMe

Mes

HC(OEt)3

N OH

⫹

N Mes

Figure 4.24 Synthesis of a hydroxy-binaphthyl functionalised imidazolium salt.

220

Functionalised N-Heterocyclic Carbene Complexes

13% ee (S). In contrast, the corresponding iridium complex performs the same reaction with 50–60% ee (R) [85]. However, the observed reaction is actually hydrogen elimination from the tautomeric enol rather than proper hydrosilylation (the addition of a silane across a double bond). The allylic alkylation reactions were carried out with various substrates, among them an unsaturated phosphate [88], methyl cyclohexenone [17] and 1-octin [18] (see Figure 4.25). Catalyst performance (conversion and ee) was dependant on the bulk of the wingtip group, the existence of an anchoring anionic OH-group on the 1,1'-binaphthyl scaffold and the metal(s) used as catalytic centres (Ag, Cu) as well as the catalyst loading. A catalyst loading of 1% resulted in excellent conversion (>98%) only with a Mes wingtip group. Even then, ee could be improved by a catalysts loading of 10% (65–82% ee), the default value. The choice of wingtip group (DIPP, adamantyl, Mes) results in a drop of conversion rate (70, 18, <98%) and ee (52, 64, 82%) with the bulk of the wingtip group. Interestingly, in these findings for the substrate (left-hand side in Figure 4.25) the ligand was used in tenfold excess (comparable with phosphanes) [88]. When methyl cycloxenone is used as substrate [17], it becomes apparent that both conversion rate and ee improve when both silver(I) and copper(I) are present rather than just copper(I) alone. Although the hydroxy group is by far the most popular anionic oxygen containing functional group in functionalised NHC ligands, there are some examples for carboxylic

O

O

P

OEt OEt

O P Ph

O

Ph

OEt OEt

ZnEt2

ZnEt2

hex

O

Hex

Ph Et

Ph

Figure 4.25 Substrates for asymmetric allylic alkylation with hydroxy-1,1’-binaphthyl functionalised NHC ligands.

N-Heterocyclic Carbenes with Anionic Functional Groups

221

acid functionalised NHC [90–94] and even keto functionalised NHC that react with a suitable metal centre from the tautomeric enol form and thus result in carbene enolate complexes [95]. Ketz et al. synthesised a keto functionalised imidazolium salt using the standard protocol by reacting the appropriate N-aryl substituted imidazole with the respective keto halide [95]. Their intention was to use the corresponding nickel(II) carbene enolate complex in olefin polymerisation reactions similar to the phosphino enolates in the SHOP process [1–4]. It proved difficult to prepare the intended precatalyst with only one carbene enolate ligand attached to the nickel centre. Initially, the homoleptic complex with two carbene enolate ligands was formed. The authors pointed out that the high proportion of n-olefins is unusual. A similar protocol was used by Danopoulos et al. in the synthesis of a carboxylic acid functionalised imidazolium salt [90]. Reaction of N-DIPP-imidazole with chloroacetic acid trimethylsilyl ester provides the functionalised imidazolium salt. The silyl ester can be hydrolysed with methanol and the imidazolium zwitterion generated with liquid ammonia. The imidazolium zwitterion was then used to form the corresponding homoleptic palladium(II) complex after deprotonation of the imidazolium ring with LDA (LiNPri2) and subsequent reaction with palladium(II) acetate (see Figure 4.26). The structure holds no surprises, the two carbene units are coordinated trans and tilted against each other. Consequently, the carboxylate groups point into opposite directions positioning the bulky DIPP wingtip groups at maximum distance to each other and the six-membered rings formed by the chelate ligands have boat conformation.

DIPP

DIPP

DIPP N

Br N

OSiMe3

N

N

N

O

DIPP

MeOH

NH3/liq.

N

N

O

N

O

O OH

OSiMe3

O

1) LDA 2) [Pd(OAc)2]

O

N

DIPP

O N

Pd

N

O

DIPP

N O

Figure 4.26 Synthesis of a carboxylic acid functionalised palladium(II) NHC complex.

222

Functionalised N-Heterocyclic Carbene Complexes R O O

R

H2N OH

OH

R

O

N

H2O

O H2N HO

H

N O

OH O

R O

Figure 4.27 Synthesis of a (chiral) carboxylic acid functionalised imidazolium zwitterion.

The route used by Danopoulos et al. is a universal one meaning that the protocol can in principle be used to synthesise any other similar carboxylic acid functionalised imidazolium salt from a N-substituted imidazole and a primary alkyl halide bearing a carboxylic acid functional group. Introduction of chirality into the wingtip group is possible provided the centre of chirality is not the carbon atom bearing the halogen. In such a case, yields may be low and/or racemisation occurs. If chirality at this carbon atom is desired, it can be introduced using a chiral amino acid in the synthesis of the imidazolium salt itself (for a general protocol see Chapter 1) [91]. An early example, albeit with the achiral α-amino acid glycine, was provided by Kratochvil et al. They simply reacted glycine with glyoxal and formaldehyde in water (using the Arduengo protocol) to obtain the bis-carboxylic acid functionalised imidazolium zwitterion [92] (see Figure 4.27). In principle, this reaction should be extendable to other chiral aminoacids resulting in the corresponding enantiopure bis-carboxylic acid functionalised imidazolium zwitterions [96]. The concept can be adapted to the introduction of only one (chiral) carboxylic acid wingtip group, even without the introduction of a second one [94]. The adaptation comprises the dropwise addition of a mixture of ammonia, sodium hydroxide and the α-amino acid in water to a solution of glyoxal and formaldehyde in water at 50°C. Yields are moderate (but excellent compared with the 40–50% achieved by the parent protocol [97]). In the event, Strassner and coworkers [94] used the chiral carboxylic acid functionalised imidazole for the synthesis of the corresponding ester functionalised bis-carbene ligand and their palladium(II) complexes.

4.2 Nitrogen-Containing Groups The chemistry of NHC ligands with tethered anionic N-functional groups is comparatively young [98] and was started by the Arnold group [34] as a means to bind the NHC donor ligand to lanthanides. Although NHC were already known to coordinate to lanthanide metals,

N-Heterocyclic Carbenes with Anionic Functional Groups

223

the bond was so weak as to be reminiscent of a solvate complex [99–101]. The idea of the Arnold group provides an amide functional group as an anchor for a stable coordination to the lanthanide atom with the, in this case, weakly coordinating NHC donor unit tethered to it. Such ligand architecture assigns the labile role in a hemilabile chelate ligand to the NHC donor, a role it can only play with early transition metals and the lanthanides, but not the late transition metals where NHC donor ligands are known to be exceptionally strongly coordinating [102]. The possibility for the use of these amide functionalised carbene ligands in homogeneous catalytic applications was envisaged from the start [34]. Synthesis of amide functionalised NHC ligands is facile and follows a standard protocol of unsymmetrically substituted imidazolium salts (see Chapter 1). In the present case, Arnold et al. reacted N-tert-butyl-imidazole with N-tert-butyl-aminoethyl bromide hydrobromide [34]. Subsequent reaction with potassium hydride yields the amino functionalised carbene, probably in the form of a hydrogen bond stabilised zwitterion (see Figure 4.28). Stepwise reaction of the amino functionalised imidazolium salt hydrobromide first strips off the hydrobromide and then deprotonates the imidazolium ring (not the secondary amino group) to form a lithium chelate complex. But

But N

Br

N

⫹

But N

N

H

Br

⫹ NH2

But

H2N

⫺

But

KH

⫹

But

⫹

N

N

⫺

N

ButLi

N

N

But

N

N

But

But

But Br

Li

NH

ButLi

Br t

Bu

N

But

NH

But

NH

Li

N

⫹

Br

N

Br

Li

Li

Br

Br

⫹

NH

N

But

Figure 4.28 Synthesis of an amino functionalised imidazolium salt and its lithium carbene complex.

224

Functionalised N-Heterocyclic Carbene Complexes

Note: Chelate coordination to lithium is only possible for the amino carbene, but not for the amide imidazolium ligand. The formation of a tetracoordinated lithium atom in a dimer structure is probably the driving force for the formation of a carbene. Note: The Li2Br2 central ring is already present in the simple amino imidazolium adduct. Elimination of LiBr provides the chelate carbene adduct of lithium. The reaction of the amino imidazolium salt hydrobromide with silver(I) oxide yields the corresponding silver(I) carbene complex (see Figure 4.29) that has the same central structural unit as the lithium complex [35]. The diagonal relationship to magnesium can be activated when the amino functionalised imidazolium zwitterion is reacted with dimethyl magnesium (MgMe2) [103] (see Figure 4.30). The product is a homoleptic magnesium carbene complex. It is interesting to note that steric constraints result in an unsymmetric coordination mode for the carbene unit in the lithium and uranium, but not the magnesium complex. The magnesium cation is larger than its lithium counterpart, but more importantly, the tetrahedral coordination geometry implies a smaller ligand bite angle than for the trigonal geometry around lithium. In the equatorial plane of the uranium atom, the tert-butyl wingtip groups are far too bulky to avoid steric congestion and therefore twisting of the carbene ligands to relieve it.

But H2N

But

But

⫹

Br

Ag2O

⫹

N

NH

Ag But N

N

N

Figure 4.29 The silver(I) carbene complex of an amino functionalised imidazolium salt.

N

But N

N But

But

Li

Li

N

But

N

N U

Mg

N

N N

N

N

N

But

N But

But But O

N

N

N

N

But But

N

O

But

But

Figure 4.30 Chelate lithium, magnesium and uranium complexes of amido functionalised carbenes.

N-Heterocyclic Carbenes with Anionic Functional Groups

225

Note: These bent metal carbene geometries are clearly steric in origin. Having arrived at uranium as the coordinated metal, we are already past the lanthanides. It is necessary to take a break here and turn towards rare earth metal complexes with amino functionalised carbenes. Amongst the earliest examples are samarium and yttrium complexes of our already familiar amino functionalised imidazolium zwitterion from Figure 4.28. The synthetic route towards lanthanide complexes of amide functionalised carbenes relies on the elimination of MN(SiMe3)2 (M = K, Li, H) [34,103–105] from the corresponding lanthanide amide. It was not possible to use lanthanide halides as the starting point [104]. Bearing in mind the usefulness of the non-nucleophilic amide N(SiMe3)2− as an excellent leaving group, synthesis of the lanthanide carbene complexes is rather facile and involves the reaction between the amino functionalised carbene lithium bromide adduct and the lanthanide amide (see Figure 4.31). The presence of lithium halide can become a challenge as LiN(SiMe3)2 can be eliminated resulting in dimer formation via Ln-X-Ln halide bridges. An interesting feature of the lanthanide amide functionalised carbene complexes is their reactivity on the carbene backbone. The reaction of these carbene complexes with a strong base often results in the deprotonation of the carbene unit in C4/C5 position and subsequent substitution in this position. This can occur even when further N(SiMe3)2 groups are present on the lanthanide metal centre [105] (see Figure 4.32).

N

But

N

(Me3Si)2N But

Ce

Br

NH

NH

Br

Ce But

But

LiBr N(SiMe3)2

NH

NH

Br

N

Ce

[Ce{N(SiMe3)2}3]

Li

N

But

N

But N(SiMe3)2

N

N

But

N(SiMe3)2

N

But

LiI

N

But (Me3Si)2N But

N

Ce

I

NH

NH

I

Ce

But N(SiMe3)2

N

N

But

Figure 4.31 Synthesis of cerium(III) complexes of amino functionalised carbenes.

226

Functionalised N-Heterocyclic Carbene Complexes

But

But

But N(SiMe3)2

N

N(SiMe3)2

Y

But

N

N

N(SiMe3)2

Y

KC10H8 N

N(SiMe3)2

N(SiMe3)2 N

N

Y

SiMe3Cl

N

But

N

N(SiMe3)2

N

But

Me3Si

N

But

But N(SiMe3)2 N Sm

(Me3Si)2N But

N(SiMe3)2

N

But

Sm

O

KC10H8 N

N

N

DME

Sm

N O But N(SiMe3)2

N

N

But

Figure 4.32 Substitution reactions on lanthanide amide functionalised carbene complexes.

Note: Compare this behaviour with addition of salt (LiX) and subsequent loss of LiN(SiMe3)2. Another area, where NHC are employed advantageously, is the early transition metals. Here, the NHC units are able to stabilise high oxidation states as in [Ti(IMes)2Cl4] [106], [V(IMes)(O)Cl3] [107], [Re(IPri)4O2] [108] and [Tc(IEt)4N] [109,110]. Reaction of the commercially available [TiCl(OPri)3] with a lithium adduct of an amide functionalised carbene results in the substitution of an isopropyloxy substituent on titanium(IV) by the amide sidearm of the carbene. Simultaneous coordination of the carbene unit results in a five-coordinate chelate titanium(IV) complex [111] (see Figure 4.33). The choice of the lithium carbene adduct determines the number of OPri groups still present on the metal centre. The structures of these titanium(IV) carbene complexes are all distorted square pyramidal with the nitrogen atom in the apex, despite appearances regarding a trigonal bipyramidal structure in Figure 4.33. Another approach to amide functionalised carbenes starts with the intention to synthesise symmetrical ligands, with two aminoalkyl wingtip groups. There are two principal synthetic routes, both of which have been realised by the Fryzuk group [112,113]. Synthesis of a bisamide imidazolium salt follows a standard procedure (see Chapter 1) and subsequent reduction of the carboxylic acid amide to the amine is achieved by borane [112] (see Figure 4.34). Alternatively, the bis-amino imidazolium salt can be synthesised simply by reaction of 2 equiv. of the aminoalkyl chloride with imidazole [113] (see Chapter 1). Deprotonation with KN(SiMe3)2 yields the free carbene, presumably as a hydrogen bond stabilised imidazolium zwitterion similar to the monoamine functionalised carbene from the Arnold group [34].

N-Heterocyclic Carbenes with Anionic Functional Groups

227

But N Li

N

But OPri

[TiCl(OPri)3]

[TiCl(OPri)3]

Ti

Br N

OPri

N

But

But

N

OPri

[TiCl(OPri)

3]

N

But

N

Bu

N

OPri

LiBr

t

N

Br Ti

2 LiBr

But LiBr

OPri N

Br Ti

N

OPri But

N

Figure 4.33 Synthesis of chelate amide functionalised carbene complexes of titanium(IV).

N

O

N

O NH p-Tol

N

H3B-SMe2

HN p-Tol

NH p-Tol

N

N

N

KN(SiMe3)2

HN p-Tol

NH p-Tol

H

N p-Tol

Figure 4.34 Synthesis of an amino functionalised NHC ligand.

Synthesis of transition metal carbene complexes from these amine functionalised carbene ligands is surprisingly facile compared with the difficulties encountered by Arnold et al. Again, the reaction is best attempted utilising a transition metal amide or alkyl compound with concomitant elimination of the corresponding amine or alkane (see Figure 4.35). The respective chloro complexes can be synthesised by amide displacement with SiMe3Cl and the alkyl complexes retrieved by LiCl elimination using the transition metal chloride and a lithium alkyl as alkylation reagent. The pincer like diamino functionalised carbene ligand stabilises the group 4 metal sufficiently to perform a few very interesting insertion reactions with the M-Me bond. The reactions were performed with the hafnium rather than the zirconium complexes [113]. Small molecules used for these insertion reactions include isonitriles (aryl and alkyl) and CO (see Figure 4.36). Reaction of the hafnium carbene dimethyl complex with xylyl-isonitrile results in addition of this excellent donor ligand and subsequent insertion into the Hf-Me

228

Functionalised N-Heterocyclic Carbene Complexes

N

N

N

N

[Zr(CH2SiMe3)4]

N

Zr

Ar

Ar

Ar

NEt2

N

NEt2 Ar

N

Ar

Ar

Ar

Me3Si

N

Zr Cl

Cl

N

N

MeMgCl

N

Zr

Ar

Ar p-Tol, Mes

N

N

py

Cl

NC5H5

LiCH2SiMe3

N

Zr

Ar

SiMe3Cl

N

N

N

N Cl

H NH

N

N

N

[Zr(NEt2)4]

N Ar

Zr

Ar

N Ar

SiMe3

Figure 4.35 Synthesis and reactivity of amino functionalised carbene complexes of zirconium(IV).

N

N

N

N

Hf

Mes

N Mes

Mes

N

N

RNC

R

Hf

N Mes

CO 2 RNC RNC N

N

R N

N

N

Mes N

Hf

Mes

N

Hf O

Mes

N

N Mes

R R

Figure 4.36 Insertion of isocyanides and CO into the Hf-Me bonds of a dimethyl hafnium bis-amino functionalised carbene complex.

N-Heterocyclic Carbenes with Anionic Functional Groups

229

bond to form the respective η2-iminoacyl complex [114]. The reaction can be repeated with a second molecule of isonitrile. In this way, it is possible to synthesise a symmetrical and an unsymmetrical bis-η2-iminoacyl complex. Alternatively, the first η2-iminoacyl complex can be reacted with CO with formation of an eneamidolate metallacycle. The coordination chemistry of amino functionalised carbene is not limited to the early transition metals and the lanthanides. Douthwaite et al. have synthesised a tridentate ligand comprising two NHC units flanking a central secondary amine group using a multi-step protocol [115]. The protocol owes its multi-step nature to the need to protect the secondary amino group from competitive oligomerisation during attachment of the flanking imidazolium groups. This is achieved by introducing a benzyl protecting group onto the amino nitrogen atom that can later be removed by palladium catalysed hydrogenation (see Figure 4.37). Reaction with silver(I) oxide [16] and subsequent carbene transfer to palladium follows standard procedures (see Chapter 1) and yields a cationic palladium(II) complex featuring a neutral tridentate amino functionalised carbene ligand awaiting deprotonation of the amino functionality. Deprotonation of the amine proved difficult, with simple amines (NEt3, pyridine) not sufficiently basic to abstract the proton and a classic deprotonation agent for NHC ligands, KOBut, resulting in decomposition of the palladium complex. The predicament was finally resolved by using sodium hydride, a base sufficiently strong to deprotonate the amine, but resulting in the elimination of molecular hydrogen that is a gas and itself not acidic. It removes itself from the reaction and thus cannot decompose the palladium complex.

N

Cl

N

Cl N PhCH2Br

NH

N

N

But

N

But

⫹

t N Bu

Pd/C, H2

N

N

NH

Ph

Ph Cl

But

⫹

N

Cl

⫹

N

N

But

⫹

Ag2O

N N

N

Bu

N

t

NaH N

Pd

H

Cl

N

N ⫹

Pd

N Bu

But

t

AgCl

[Pd(MeCN)2Cl2]

Cl

NH AgCl

N

N

But

N

N

But N N

But

Figure 4.37 Synthesis of an amino functionalised carbene ligand featuring two NHC units and its palladium(II) complex.

230

Functionalised N-Heterocyclic Carbene Complexes

Note: Deprotonation of the palladium coordinated amine is difficult and dependant upon the choice of base. Sodium hydride is a strong base and upon abstraction of a proton produces molecular hydrogen, which evolves from the reaction without reacting with the palladium centre. The final neutral palladium(II) complex with the amide functionalised carbene ligand features two six membered metallacycles, just as the cationic not yet deprotonated one does. The amine nitrogen atom has four substituents (H, Pd and two C). Since the two metallacycles can adopt two distinct conformations that slowly flip into each other for steric reasons, the nitrogen atom appears chiral due to atropisomerism despite its overall C2-symmetry. The deprotonated complex lacks this feature, clearly visible in the respective NMR spectra. A very interesting amido functionalised carbene was prepared by Legault et al. [116] from N-mesitylimidazole and O-(2,4-dinitrophenyl)hydroxylamine, an electrophilic amination reagent [117]. The exo-amino group is subsequently acylated to afford a zwitterionic amido functionalised carbene (see Figure 4.38). Reaction with silver(I) acetate and sodium carbonate [a rare variant of the silver(I) oxide method] yields the silver(I) carbene complex as a dimer with a Ag-Ag bond. The silver(I) carbene complex can be used as a carbene transfer reagent to synthesise the homoleptic monomeric copper(II) carbene complex. Note: The silver (I) carbene complex features Ag-N amide bonds in a five-membered metallacycle with Ag-Ag bonds, but the copper(II) complex has Cu-O imino oxide bonds in a six-membered metallacycle and no Cu-Cu bonds. Note: Ag+ is known for its argentophilicity making Ag-Ag bonds more likely. The Ag+ ion also features a greater ionic radius compared with Cu2+. The copper(II) carbene complex does not display the usual tetrahedral geometry around the copper centre [118] owing to the Jahn–Teller effect, but an unusual distorted square planar

Mes

H 2N N

N

O

O2N

Mes

NO2

N

N

NH2

PhC(O)Cl

Mes

N

N

N

Ph

K2CO3 O

Ag2O

Mes Ph

N

Mes

N

O

N

N

N

N

O

CuCl2

Cu

Ph

O

Ag

Ph

N

N N

N

Ph

Ag

Mes

N O

N

Mes

Figure 4.38 An unusual amido functionalised carbene and its Ag(I) and Cu(II) complexes.

N-Heterocyclic Carbenes with Anionic Functional Groups

231

coordination geometry more familiar with the d8-complexes of the neighbouring divalent group 10 triad [119]. We have just seen a rather unusual functionalisation for a carbene, with the functional group’s nitrogen atom directly bonded to the nitrogen atom of the imidazole scaffold. The ‘normal’ functionalisation calls for a carbon linker group between the functional group and the imidazole backbone, the NHC unit. The reason is simply the ease of synthesis, apart from a higher degree of predictability with regard to the properties. Two isolated functional groups (amide and NHC) are just the sum of their individual properties. Elimination of the isolating spacer unit creates interaction between the two functional groups, with uncertain outcome. An example of a more standard, carboxylic acid amide functionalised imidazolium salt and its applications come from the Ghosh group [120]. They reacted chloroacetic acid anilide with N-mesityl imidazole and obtained the respective carboxylic acid amide functionalised imidazolium salt which was reacted with silver(I) oxide to form the corresponding silver(I) carbene complex featuring two trans-coordinated carbene ligands on the silver(I) ion (see Figure 4.39). The silver(I) carbene complex was used in the ROP of (L)-lactides [120]. Mechanistically, it is thought that the silver cation interacts with the carbonyl oxygen atom of the cyclic lactide. One of the carbene units then nucleophilicly attacks the carbonyl carbon atom resulting in C-O bond fissure and coordination of the oxygen atom on the silver cation. The role of the initial Ag-O=C interaction is to bring the lactide into position for nucleophilic attack by the carbene and to activate the carbonyl carbon atom for this attack (see Figure 4.40). Note: A C=O-Ag donor interaction transfers electron density from carbon via oxygen to silver and thus makes the carbonyl carbon atom more electrophilic. The amide functionalised carbene complex of silver(I) proved to be less effective in the melt polymerisation of (L)-lactide than the nonfunctionalised carbene complex (carboxylic acid amide group substituted by benzyl). The differences were only small and high conversion rates required high reaction temperatures. For lower temperatures (100–120°C) conversion rates were actually better for the functionalised carbene complex (but as low as 55–76%).

Ph NH O

Mes

Ph N

N

H N

P

HN O

Cl Mes

N

H N

N

Ag2O

Ph O

O

N N

Ag N

Mes

N

Mes

Figure 4.39 A carboxylic acid amide functionalised imidazolium salt and its silver(I) carbene complex.

232

Ph Ph

NH

NH

O HN

Ph

Ph

O

HN O

N ⫹

N O

N

⫹

N

Mes

O

N

N

Ag

Mes

O

Mes

O

Ag Mes

O

N

N

O

O

O O Ph

O

O O

NH

O

Ph O

HN O

N

N O

N Mes

O O

Ag Mes

N

n

Figure 4.40 Proposed mechanism for the ROP of (L)-lactide by a silver(I) complex of a carboxylic acid amide functionalised carbene.

Functionalised N-Heterocyclic Carbene Complexes

O

N-Heterocyclic Carbenes with Anionic Functional Groups

233 O

N

N

K2CO3

H N

N

Ph

Ph

Ph

N

N N

NiCl2

Ph

Ni

Ph N

O Ph

N O

Figure 4.41 Homoleptic nickel(II) complex of a carboxylic acid amide functionalised carbene.

Similar carboxylic acid amide functionalised imidazolium salts, with the same orientation but with different auxiliary wingtip group, were recently synthesised by Liao et al. [121]. They reacted their imidazolium salts with silver(I) oxide in DMF, a rather unusual solvent for this standard reaction, and managed to solve the crystal structures of several of the silver(I) carbene chlorides. The structure of the silver(I) carbene complex carrying a benzyl wingtip group, directly comparable with Ghosh’s mesityl one, was shown to be bonded to only one carbene unit, not two as in Ghosh’s compound. Since Liao et al. did not perform (L)-lactide ROP experiments, it remains unclear whether the structure of the silver(I) carbene complex has a bearing on the performance in catalysis. Liao et al. also synthesised an imidazolium salt carrying two carboxylic acid amide functionalities and generated its silver(I) carbene complex. It is distinguished by absolute linearity of the C-Ag-Cl vector and rather short Ag-C and Ag-Cl bond lengths. Carboxylic acid amide functionalised imidazolium salts can be reacted with group 10 halides directly in the presence of an inorganic base (e.g. K2CO3) to form homoleptic complexes (see Figure 4.41) [122]. Interestingly, the carbene units are cis to each other and not trans as would be expected (see Figures 4.30 and 4.38). The cis complexation is not aided by hydrogen bonding as the carboxylic acid amide functionality loses its proton upon complexation to nickel. The nickel(II) carbene complexes were used in the Suzuki–Miyaura cross-coupling reaction between phenylboronic acid and p-chloroacetophenone. The yield was low (10–15% depending on the carbene’s auxiliary wingtip group), but could be improved to quantitative (92–95% isolated) upon addition of 2 equiv. of PPh3. Reaction of the same functionalised imidazolium salt with PdCl2 produced interesting results [123]. In the presence of pyridine as base, the simple palladium(II) carbene adduct was formed (see Figure 4.42), but when K2CO3 was used as base, activation of the amide functional groups produced the corresponding homoleptic complexes, as a mixture of the cis and trans isomers. The occurrence of the trans isomer seems to be solvent dependent with the trans isomer formed only in DMF, but not in pyridine. A corresponding imidazolium salt carrying two carboxylic acid amide functionalised wingtip groups shows similar behaviour, but obviously without cis/trans isomers [123] (see Figure 4.43).

234

Functionalised N-Heterocyclic Carbene Complexes O Ph N

Ph

N

Ph

N H

Cl Pd Cl

pyridine

N

N

PdCl2

N

O

O

O

K2CO3

N

N NH Ph

Ph

N

N N

Pd N

Ph

Ph

Ph

N

Ph N

Ph

N

Pd N

Ph Ph

N

N

O

O less soluble

Figure 4.42 Synthesis of homoleptic palladium(II) carbene complexes using a carboxylic acid amide functionalised NHC ligand.

O

O

Ph

Ph N H

N

PdCl2 pyridine

O Ph

O N H

N H

N

PdCl2 K2CO3

Ph

N

N

N

N

N H

Cl Pd Cl N

N

O Ph

Pd N

N

O Ph

Figure 4.43 Synthesis of palladium(II) carbene complexes using a doubly carboxylic acid amide functionalised pincer NHC ligand.

N-Heterocyclic Carbenes with Anionic Functional Groups

235

Activation of the carboxylic acid amide proton occurs only after addition of potassium carbonate, similar to the reactivities observed with the monofunctionalised imidazolium salt in Figure 4.42.

4.3 NHC Ligands Incorporating Cp Moieties The Cp ligand family is easily the most popular spectator ligand in organometallic chemistry [119]. It combines an electron donicity of five electrons with the occupation of one to three coordination sites on the central metal atom [124]. In addition, the electronic and especially the steric properties of the Cp ligand can be modified almost at will [119] by introducing appropriate substituents on the five-membered ring. Recently, the modification of the Cp ring with pendant functional groups designed to turn the ligand into a hemilabile or constrained geometry bidentate chelate ligand moved into the area of ligand design [125,126]. Among the most important examples are Cp ligands with tethered phosphanes [125,126], amines [127], thioethers [126,128], ansa-bis-Cp ligands [129–133] and of course NHC modified Cp ligands [134–137]. A closely related, but neutral, ligand donating six rather than five (Cp) electrons is the tethered benzene ligand family [138]. The NHC modified ligand is mainly used in ruthenium complexes [139–142] and occasionally with chromium [143]. A completely different approach is the introduction of ferrocene as a wingtip group on the NHC ligand itself, either with [144,145] or without [146,147] a tether. The ferrocene group can be used to introduce a second, chelating functional group like a phosphane [148-150] or an oxazoline [151] as well as a second carbene [152,153]. Another possibility is the introduction of chirality either in the tether (central chirality) [154] or on the ferrocene itself (planar chirality) [154]. The ferrocenyl group introduces the unique steric and electronic properties of ferrocene [155–157] into the NHC ligand. The characteristic cylindrical shape of the Fc group effectively blocks one side on the NHC ligand [153,158] and the electronic properties of ferrocene render the NHC unit especially electron rich [159]. It is estimated that a Fc substituent can stabilise the carbene carbon atom in the same way as an amino group [159] making a Fc-C-Fc singlet carbene a viable target molecule in the quest for additional stabilised persistent singlet carbenes [159]. It is therefore hardly surprising that NHC ligands with Fc substituents that are directly bonded to the imidazole ring of the NHC have been synthesised in an attempt to optimise the positive influence of the Fc unit on the carbene [146,147]. A very interesting modification of the NHC ligand by a Cp moiety was recently introduced by Arduengo et al. [159–162]. Here, the Cp unit is back-to-back with the imidazole ring of the carbene. This way, the Cp and the NHC units can communicate electronically without steric interference from the Cp end. Of course, dinuclear complexes where one atom bonds to the carbene and the other forms a metallocene unit were synthesised [159,162]. An overview of the various Cp-modified NHC ligands is given in Figure 4.44. The prototype for Cp-modified NHC ligands comes, as usual for functionalised carbene ligands, from phosphane chemistry, in this case from the well known 1,1'-bis(diphenylphos phino)ferrocene (dppf) [163,164]. A recent example was introduced by Coleman et al. [165] using a synthetic route that is very similar to the protocol used for the formation of ferrocene

236

Functionalised N-Heterocyclic Carbene Complexes

N K

DIPP N

N

N

N

H

N

Ru

N

N

N

But

N

N N

R N

N

Fe

Fe

Fe

N

Fe

Fe

N

Fe

N

N

But

N N

N

N

R

N

N

R

N Fe

PPh2 O

Fe

Fe PPh2

Figure 4.44 Cp-modified NHC ligands.

functionalised imidazolium salts. The rationale behind the modification of the ligand with a ferrocene group is given to be superior catalytic activity of the resulting catalyst [164]. Note: ‘Transition metals containing ferrocene-based ligands . . . often show superior catalytic activity when compared to complexes containing other types of bidentate . . . ligands [165]’. The synthesis of Fc-modified imidazolium salts, as precursors for the carbene ligands, usually involves the reaction of a (substituted) imidazole with a ferrocenylmethyl halide [166], a classic route for functionalised NHC, the reaction of a (substituted) imidazole with ferrocenylmethyl trimethylammonium halide [166–170], the reaction of an imidazole functionalised diazonium salt with ferrocene [144] or the formation of the imidazole ring using hydroxymethylferrocene [171] or ferrocenylmethylamine [168] as starting materials (see Figure 4.45). The ferrocene group has been introduced for its special steric and electronic properties. It has a cylindrical shape and the potential to block a substantial portion of the metal’s coordination sphere making stereo- and regio-control possible in catalytic applications [166, 172–175]. Similarly, the ease with which ferrocene can be oxidised to the corresponding cation [176,177] makes it not only a standard in electrochemistry, but can have advantageous electronic effects as a substituent for carbenes as well [166].

N-Heterocyclic Carbenes with Anionic Functional Groups SiMe3

SiMe3

OH

Fe

CDI

N

SiMe3

N MeI

Fe

237

N

N I

Fe

CDI N, N'-carbonyldiimidazole

NMe3 I

Fe

N

R N

N

I

Fe

R

N

RI

NH2 NH4Cl HCHO glyoxal

Fe

N N Fe

Br H N Fe

N

N Fe

N

N MeI

Fe

N I

Figure 4.45 Synthesis of Fc functionalised imidazolium salts.

An interesting application for imidazolium salts has been the use as anion acceptors employing the C2-H2 group as a hydrogen bond donor [167,168,178]. It was claimed by the authors that one molecule of the Fc-modified imidazolium salt can bind either two halide anions or one nitrate or bisulfate anion [167]. It is only a small step from using functionalised imidazolium salts as anion receptors to applying these compounds as ionic liquids. After all, the rise of ionic liquids as versatile reaction media, green solvents and propellants is inextricably linked with the imidazolium scaffold [179–181]. It is therefore not surprising that the Shreeve group has extended their vast repertoire of imidazolium based ionic liquids by some Fc-modified ones [169] (see Figure 4.46) following the important discovery of an imidazolium based ionic liquid with a pendant [Co2(CO)6] group [182]. Note: The melting point and thus the generation of an ionic liquid depends largely on the choice of anion and the choice of the other wingtip group.

238

Functionalised N-Heterocyclic Carbene Complexes

N

N N Fe

N

Fe

NTf2

N

N

N

NTf

Fe

NTf2

NTf2

N

N

Figure 4.46 Some Fc-modified ionic liquid imidazolium salts.

The first report on the catalytic ability of palladium complexes with Fc functionalised NHC ligands came from the Beller group [183] closely followed by Demirhan et al. [170] (see Figure 4.47). Note: Unsymmetrically substituted carbenes often give higher regioselectivity. Beller’s group [183] tested Fc functionalised NHC ligands in the palladium catalysed telomerisation of 1,3-butadiene with methanol (see Figure 4.48) and found that some NHC ligands gave higher yields than phosphane ligands, but that unsymmetrically Fc functionalised NHC ligands gave the highest linear to branched (n:iso) ratios reported thus far. Interestingly, tethered Fc functionalised NHC ligands gave better results than those where Ph N N

I

Fe

Pd(OAc)2

Ph

[Rh(-OMe)(COD)]2 Ph

Fe N N

N

I

N

Pd I

Rh

N I

N Fe Ph

Fe

Figure 4.47 Some rhodium(I) and palladium(II) catalysts bearing Fc-modified NHC ligands.

N-Heterocyclic Carbenes with Anionic Functional Groups

telomers n/iso high

L

239

telomers n/iso low

Pd

2 2 MeO

L

⫺ L'

⫺

Pd

Pd

L

L

H⫹ L=

⫺

OMe

Pd ⫹ L'

L' ⫽

N ⫹

N

OMe Fe

Pd L

Fe

N

⫹

Fe

N

N ⫹ N Fe

N ⫹

⫹

N

N

N Fe

Fe

⫹

N

N

Fe

Figure 4.48 Fc functionalised NHC as ligands in the palladium catalysed telomerisation of 1,3-butadiene with methanol.

the ferrocene substituent was directly bonded to the imidazole ring. Evidently, the ferrocene substituent has the ability to entirely block the active metal centre preventing the reaction, if it is too close to the carbene carbon atom. Note: Imidazole based Fc functionalised NHC gave better results than benzimidazole based ones. Bildstein et al. have previously shown that Fc functionalised NHC (annulated and nonannulated) can be successfully employed to synthesise a broad range of transition metal complexes [166]. These include palladium, tungsten and mercury. Interestingly, two different species of mercury NHC complexes could be synthesised and structurally characterised (see Figure 4.49), with the dinuclear complex being the precursor for the mononuclear one. When coordinated to a gold centre, the Fc functionalised NHC ligand devised by Horvath et al. shows cytotoxic properties [144]. It is not quite clear what the role of the ferrocene substituent is since the ferrocene is in the para position of the phenyl wingtip group. One might think that such an architecture would render the Fc group sterically irrelevant and electronically somewhat of lesser importance. However, gold(I) phosphane and NHC complexes are known for their antitumour activity [184]. Of greater interest for catalytic processes is the introduction of planar chirality into the design of Fc functionalised carbenes coming from the Bolm group [171]. Planar chirality

240

Functionalised N-Heterocyclic Carbene Complexes N

Fe

N

Fe

I

N

N

I

I

Fe N

Hg(OAc)2

I Hg

2 Hg

Hg I

N

I

N

N

N

N

N I

Fe

N

Fe

Fe

Figure 4.49 Synthesis of transition metal NHC complexes with Fc functionalised carbene ligands.

can be generated in a ferrocene by introducing two substituents into the same Cp ring (see Figure 4.50). Bolm’s group realised this concept by introducing a trimethylsilyl group adjacent to the imidazole unit. They then proceeded to synthesise chromium(0) and rhodium(I) complexes and tested the rhodium complex in the hydrosilylation of acetophenone and propiophenone. However, products were obtained as racemates. Advantage: Introduction of a trimethylsilyl group not only generates planar chirality, but also significantly increases the solubility of the compound in nonpolar solvents.

N

N N

N

N

:

N :

SiMe3

Me3Si

Me3Si

S

S8 Fe

Fe

Cr(CO)6

Fe

[Rh(COD)Cl]2

N N

N

N Me3Si

Me3Si

Rh

Cr(CO)5

I

Fe Fe

Figure 4.50 Planar chiral, Fc functionalised NHC ligands and their transition metal complexes.

N-Heterocyclic Carbenes with Anionic Functional Groups

241

Introducing a second Fc substituent into the ligand system is not a principal improvement [158,185]. As we have seen, the effect of the ferrocene substituent is not that substantial. In contrast, symmetrisation can have adverse effects on the catalytic properties since unsymmetrical ligands often show the better results [183]. It is maybe more promising to use the ferrocene scaffold to introduce more than one donor functional group [145,148–154,186,187]. One obvious possibility is the introduction of two NHC units onto the ferrocene scaffold. There are three main possibilities, introduction on the same or on different [153] Cp rings and introduction on the same alkyl linker group [152] (see Figure 4.51). In both cases, no catalytic reactions were performed with the iridium(I) and palladium(II) complexes synthesised with these ligands. However, Peris and coworkers used the synthesis of their iridium carbene complex to show that the formation of the M-NHC bond is an oxidative addition that can be assisted by a weak base. This base does not deprotonate the imidazolium salt, but traps the protons formed in the process [152]. By far the most popular second donor group on Fc functionalised NHC ligands is a phosphino group, either on the same [145,154,185] or the other [186] Cp ring or with two phosphinoferrocenes flanking the imidazol-2-ylidene unit [148,149] (see Figure 4.52). The position of the phosphino group has obvious consequences for the chirality of the ligand. Placing it adjacent to the NHC unit on the same Cp ring introduces planar chirality (see Figure 4.50). Furthermore, the methyl linker unit can be used to introduce central chirality into the molecule. Note: Introduction of multiple elements of chirality can result in racemisation as the stereoselective influences of the different chiral elements may cancel each other.

Note: It may prove tedious to separate the individual enantiomers from the racemic mixture of the planar chiral compounds formed. Labande et al. tested the rhodium(I) complexes of diphenylphosphinoferrocenyl functionalised NHC ligands (Cp,Cp and Cp,Cp’ substitution) in the hydrosilylation of ketones finding these complexes of only moderate activity [186]. As no attempt was made for the chiral resolution of the catalysts prior to use in catalysis, the prochiral acetophenone could not be tested in asymmetric catalysis.

N N

N N

But

Fe

Fe R

N N

N

N

N

N

Fe N

N

But

not synthesised yet

Figure 4.51 Fc functionalised bis-NHC ligands.

R

242

Functionalised N-Heterocyclic Carbene Complexes

Fe

N

N

N

N

R N

N

R

Ph2P PPh2

PPh2

Fe Fe

Fe

PPh2

Figure 4.52 Fc functionalised NHC carrying a phosphino group on the ferrocene unit.

That the existence of multiple chiral elements in the catalyst complex are not always favourable for the chiral resolution in the product can be seen from a publication by Seo et al. [154], where the authors generated a rhodium(I) catalyst from a 1,2-diphenylphosp hino(methylimidazoliumalkyl) ferrocene in situ (see Figure 4.53) and used this catalyst in the asymmetric hydrogenation of itaconate. The catalyst was reported to be highly active, but the chiral resolution (ee) only 13%; the corresponding rhodium complex carrying two functionalised (bidentate) NHC ligands is entirely inactive [154]. The same ligand was used by Visentin and Togni [145] in the palladium catalysed allylic amination using racemic 1,3-diphenylallylethyl carbonate and either benzylamine or piperidine. The yields were rather low (32% and 58%, respectively) with very poor chiral resolution (5% ee of the S enantiomer).

N

N

N

N ⫹

Rh

Pd

PPh2 Fe

Ph ⫹

PPh2 Fe

Ph

Figure 4.53 Transition metal complexes from a central and planar chiral Fc functionalised NHC.

N-Heterocyclic Carbenes with Anionic Functional Groups

243

Fe Fe

N

⫹ P Ph2

Fe

N

N ⫹ Pd

N

N PPh2 MeCN

NCMe P Ph2

Fe Fe

N ⫹ Ru

Cu

PPh2 NCMe

Cu P Ph2

Cl

PPh2

I I

Fe

Figure 4.54 Transition metal complexes from a tridentate, central and planar chiral Fc functionalised NHC .

The diphenylphosphino group can be substituted by a phenylmercaptyl moiety [154] that would coordinate in chelate fashion to a rhodium centre, but only as a monodentate ligand (with the carbene) in the case of iridium. Interestingly, the rhodium complex, isostructural to the P functionalised complex, is absolutely inactive in the hydrogenation of itaconate whereas the corresponding phosphino functionalised catalyst was reported to be highly active [154]. Using two phosphinoferrocenyl wingtip substituents results in a carbene ligand of pincer type [148–150]. Again, an additional element of central chirality can be introduced in the linker group resulting in the presence of four chiral elements (two central and two planar) as well as virtual C2-symmetry, favoured in asymmetric catalysis. The ligand has been used by Gischig and Togni to synthesis copper(II), palladium(II) and ruthenium(II) complexes (see Figure 4.54). Some of the palladium(II) complexes were used in the asymmetric hydroamination of cyano olefins [150] with selectivities of up to 63 and 75% ee. Another favourite donor ligand is the oxazoline ring [188–190]. This ligand was introduced as a second donor function into a Fc functionalised NHC ligand by Bolm and coworkers [151]. With this second donor function, the ferrocene scaffold becomes a planar chiral backbone to the bidentate ligand, similar to the phosphino-modified ferrocene-NHC ligands. The oxazoline usually carries a central chiral carbon atom in the ring introducing a second chiral element (see Figure 4.55). Again, Bolm and coworkers used this ligand in the rhodium catalysed asymmetric hydrosilylation of acetophenone with almost quantitative yield, but almost no chiral resolution (0–6% ee). When the ferrocene unit is brought directly to the imidazole ring, without an intervening spacer, the steric bulk of the ferrocene group comes fully to bear upon the carbene carbon atom of the NHC and thus onto the metal centre of its transition metal complex [147,191,192]. Again, ligands with one [147] and two [191,192] ferrocene units are known and so are achiral [191,192] and planar chiral ones [192] (see Figure 4.56). Despite their apparent steric bulk, both the Fc and bis-ferrocenyl modified carbene ligands could be successfully applied in the synthesis of mono- and bis-carbene complexes of mercury(II) [147], tungsten(0) [147], palladium(II) [147,183,192] and silver(I) [191] (see Figure 4.57). Putting the ferrocene unit into direct contact with the central imidazol-2-ylidene ring opens up the possibility of electronic communication between the two systems either by an inductive or a mesomeric effect. The former becomes noticeable even if it may not be

244

Functionalised N-Heterocyclic Carbene Complexes

N

N

N

Fe

O

Figure 4.55 A central and planar chiral Fc functionalised NHC carrying an oxazoline unit.

N

N

N

Fe

Fe

N

N

Fe

N

N

Fe

Fe

Fe

N

Figure 4.56 Fc functionalised carbene ligands without linker units.

Fe N OC

CO N W CO N

N OC

Fe

Fe N OC W N OC

CO CO

N

CO N

Ag

Fe

N

N

Hg

N

N

N

N

Fe

Fe

Fe

Fe

Fe

Fe Fe

Fe I

N

N

Pd N

I

N

I

N I

I Pd

Fe

Pd

Fe Fe

N

N

N

PPh3

I

PPh3

Figure 4.57 Transition metal complexes of Fc functionalised NHC ligands without linker units.

N-Heterocyclic Carbenes with Anionic Functional Groups

245

significantly greater than other aromatic systems. The latter is certainly unnoticeable, since the relative position of the two aromatic ring systems is unfavourable due to the great bulk of the ferrocene. The two rings are essentially perpendicular to each other and thus there is no effective conjugation of their π-electron systems. Attempted catalytic asymmetric amide cyclisations analogous to those of Lee and Hartwig [193] proved the high activity of these palladium catalysts, but the chiral resolution was again low (9% ee) [192]. An interesting, Cp-annulated NHC ligand system was recently reported by Arduengo et al. [159–162] where the Cp ring is annulated at the back of the imidazole ring that is used to generate the carbene. This back-to-back architecture ensures direct communication between the metallocene and the NHC ligand. The expectation is for a direct communication between the two metal atoms via the ligand system [161] (see Figure 4.58). The ligand system can be synthesised from either imidazolidin-thione or from 2-chloro-methylimidazole (see Figure 4.59). The zwitterionic, annulated ligand system has two reactive centres, the Cp end and the NHC moiety. It is therefore reasonable to develop a strategy with regard to activating either end. Reaction of the Cp end with a suitable metal precursor can yield either a metallocene or a half sandwich complex. Both routes have successfully been applied (see Figure 4.47) [161]. Once the metallocene unit is formed, normal carbene reactions can be employed to synthesise transition metal carbene complexes. A good example is the reaction of the mono NHC-annulated ruthenocene with mercury(II) acetate (see Figure 4.60) where, depending on the stoichiometry, either the mono- or bis-adduct of mercury(II) is formed.

N

⫹

H

N [Cr(NCMe)3(CO)3] Cr OC

CO CO

⫺

N

⫹

N

H

N

⫹

H

N [Cp*Ru(NCMe)3]CF3SO3

Ru

⫺

CF3SO3

Figure 4.58 Metal–metal communication through the back-to-back annulated Cp-NHC ligand.

246

Functionalised N-Heterocyclic Carbene Complexes O

H

OH

N

N Cl

N

H

1) TsOH 2) LiAlH4

N

Cl

BuLi

Cl

N

H

OH

N

N S

N

TsOH

S

S

BuLi

N

N

N

O

N

(Me3O)BF4 Cl

N

N

Figure 4.59 Synthesis of a back-to-back annulated Cp-NHC ligand.

CF3SO3

Ru N

0.5Hg(OAc)2 N

N

Hg

N N

Ru

CF3SO3 H

N

Ru

N

CF3SO3

N excess 0.5Hg(OAc)2

HgOAc

Ru

CF3SO3

Figure 4.60 Synthesis of Cp-metallated annulated Cp-NHC ligands and their mercury(II) carbene complexes.

In general, the generation of the free Cp-annulated carbene is reported to be problematic as the free carbene is electron rich and thus very nucleophilic [161]. It might react with the electrophilic centres in the compound, the metal or auxiliary ligands like carbonyl groups preventing the isolation of the free carbene. It is thus better to synthesise the transition metal or main group NHC complexes without generating the free carbene first. This can be done by using an acetate (elimination of acetic acid) or by employing a 2-chloro derivative [159] in an oxidative addition reaction. Note: The thione can be synthesised from the Cp-metallated imidazolium salt. Note: Reduction of the thione to generate the free carbene is difficult and has not been achieved yet. Note: Generation of the free carbenes from the Cp-metallated imidazolium salts is problematic and has not been achieved yet. Generation of carbene adducts by standard methods is possible.

N-Heterocyclic Carbenes with Anionic Functional Groups

247

Using the 2-chloro-imidazole annulated Cp ligand, deprotonation of the Cp end and reaction with a suitable Cp*Ru precursor forms the appropriate annulated ruthenocene that can in turn be reacted with a palladium(0) source to form the dinuclear Ru/Pd complex (see Figure 4.61). The resulting Ru/Pd complex was then used in the Suzuki cross-coupling reaction of phenylboronic acid with p-benzoic acid (94%), p-bromophenol (83%) and p-bromoanisole (82%) in a 10% aqueous solution of acetonitrile in an effort to show that the ruthenocene annulation does not make catalysis impossible. The Cp ligand can also be employed as an anchor to an (early) transition metal [134,136,137] or a lanthanoid [134,135]. These developments follow immediately after the development of similar phosphino [125,126] or amino [127] functionalised Cp ligands, a trend that no longer can surprise us. The synthesis of the ligand precursor follows established routes for the formation of NHC pre-ligands. In a first step, the Cp ligand carrying an alkyl halide linker group is reacted with an N-substituted imidazole to yield the Cpmodified imidazolium salt (see Figure 4.62) [134,135,137]. Subsequently, the pre-ligand is stepwise deprotonated to yield first the free carbene and then the anionic Cp functionalised free NHC ligand [134,136]. Alternatively, and this procedure is preferred for the lanthanoid complexes [135], the imidazolium salt can be deprotonated in situ and reacted with a suitable trialkyl lanthanide or reacted without deprotonation with an anionic tetraalkyl lanthanide complex (see Figure 4.63). In this way, the indenyl tethered NHC complexes of yttrium, lutetium and scandium were synthesised [135] each still bearing two potentially reactive trimethylsilylmethyl substituents. The potential as single component or cationic (after activation with MAO) catalysts for the polymerisation of olefins was pointed out by the authors, but no studies have as yet been reported. The same can of course be said about the corresponding early transition metal complexes of titanium, zirconium, vanadium and chromium [134,136] where the synthesis of the proligands and the transition metal complexes were reported, but no catalytic studies performed.

MeCN

H N

NCMe NCMe Ru CF3SO3

N

N

[Pd(PPh3)4]

Ru

Cl

PPh3

N

Cl

N

N

Pd PPh3 Cl

Ru

Figure 4.61 Synthesis of the Ru/Pd coordinated Cp-annulated NHC ligand.

N N

N Br

KN(SiMe3)2

KN(SiMe3)2

DIPP

N

N

N

: N

DIPP

K

DIPP

Figure 4.62 Synthesis of the anionic Cp functionalised free NHC ligand.

DIPP N

248

Functionalised N-Heterocyclic Carbene Complexes

N :

N

LiCH2SiMe3

Mes

N

SiMe3

Me3Si

SiMe3

Sc

N

THF

THF

Mes

SiMe3 Me3Si

Sc

SiMe3

Li(THF)4

N

Sc Me3Si

SiMe3

Me3Si

N Mes

Figure 4.63 S63 Synthesis of rare earth complexes with Cp tethered functionalised NHC ligands.

The known crystal structures of these complexes show no undue strain upon the geometry inflicted by the tether length. Apparently, an ethyl bridge between the indenyl (fluorenyl) part of the ligand and the NHC unit is sufficiently long. In a comparative study between a tethered [135] and an untethered [194] nickel(II) complex (see Figure 4.64), no significant differences in the steric parameters were reported. However, a downfield shift of Δδ = 4.1 ppm (from 166.8 to 170.9 ppm) in the 13 C-NMR spectrum for the tethered complex was considered by the authors to be due to a chelate effect [135]. Since the Cp ligand family is an aromatic, anionic and (in the ionic counting method) sixelectron donor, it can isoelectronically be replaced by a neutral arene ligand [119]. Examples include ruthenium [139,140,142] and chromium [143] complexes (see Figure 4.65).

Ni

Ni

Br

Br N N

N N

Figure 4.64 A tethered and untethered nickel(II) complex bearing a Cp and a NHC ligand.

N-Heterocyclic Carbenes with Anionic Functional Groups

N

Ru

N

[Ru(p-cymene)Cl2]2

249

Cl Cl

Cl Cs2CO3

N

N O

O

Bun N

Bun N

N

Cl

Cl

Ag2O

N Cl Ru

N N

Ru Cl

Ru

Cl

Bun

Cl

N

N

Cr OC

CO CO

Figure 4.65 Ruthenium and chromium complexes of imidazolium-modified arene ligands.

An interesting aspect is the application of these arene functionalised imidazolium salts as organometallic ionic liquids [139,142,143] whereby the imidazolium salt functions as the ionic liquid itself [139,143] or as the ionic liquid compatible part of the compound using the transition metal arene complex as a catalyst in biphasic applications [142]. Note: It can be advantageous to block the C2 site of the imidazolium salt with an alkyl group to prevent carbene coordination on the metal centre. The basis of these applications as water soluble or aqueous-organic biphasic systems in catalysis is of course the stability of the transition metal NHC bond in aqueous solution first observed by Clarke and Taube [195]. In this context, formation of a ruthenium arene complex bearing a nontethered NHC ligand [196] follows the classic strategy to replace a phosphane ligand by a stronger bound carbene one. One of the first to realise the potential of this strategy in homogenous catalysis with ruthenium

250

Functionalised N-Heterocyclic Carbene Complexes

arene complexes was Joo. He developed a catalytic system that uses separate arene and NHC ligands on ruthenium to act as hydrogenation catalysts in aqueous solution (see Figure 4.66). Similar systems were independently developed by other research groups [139,140] using arene functionalised NHC ligands in an attempt to improve the catalytic system. Sémeril et al. developed a tethered system from an earlier untethered one [197] that was used in olefin metathesis reactions after initial loss of the arene (p-cymene) ligand (see Figure 4.67). Note: In hydrogenation reactions, catalysts with separate arene and NHC ligands performed better than tethered ones. Note: In hydrogenation reactions, catalysts with arene/phosphane ligands performed better than those with arene/NHC ligands. A system incorporating an arene ligand with pendant carbene and phosphino groups was introduced by Cadierno et al. [141], although the carbene functionality was not an NHC moiety.

Cl

Cl

Ru N

Cl

Ru

N

P N

N

N N

Bun

Bun

N

Figure 4.66 Ruthenium arene complexes bearing NHC ligands.

Mes

Mes Cl

Ru

Cl

Ru N

Cl

N

Cl

N N Mes

Mes proposed active olefin metathes is catalyst

precatalyst

Figure 4.67 The Precatalyst and the proposed active catalyst in an olefin metathesis system.

N-Heterocyclic Carbenes with Anionic Functional Groups

251

4.4 Transition Metal NHC Complexes Involved in the Activation of C-H Bonds Transition metal carbene complexes are widely used as catalysts in homogenous catalysis replacing the omnipresent transition metal phosphane complexes [198–201]. Many catalytic reactions involve the activation of a C-X bond where X is a halogen including the Suzuki–Miyaura [202–204], Mizaroki–Heck [205–207] and Sonogashira [208–211] reactions, another carbon including the olefin metathesis reaction [80,212], a boron as in the arylation of cyclohexenone [213] or a Si-H bond as in the hydrosilylation of olefins [214]. Given these desired reactions, it cannot be totally surprising if these transition metal carbene complexes at times activate C-H bonds as well, although the activation of a C-H bond is thermodynamically significantly more difficult than that of the more activated C-X bonds listed above. Even the activation of C-H bonds by transition metal carbene complexes has parallels in phosphane chemistry [215]. However, the reasons for the C-H activation by transition metal carbene complexes are still poorly understood and the reaction cannot as yet be predicted, although interesting applications in catalysis might be envisaged. Chilvers et al. [216] reacted a ruthenium(II) triphosphane hydride complex with a standard commercial carbene (with mesityl wingtip groups) under phosphane/NHC exchange (see Figure 4.68). The resulting ruthenium(II) carbene hydride complex was intended as a hydrogenation catalyst [217]. When reacting the complex [Ru(IMes)(PPh3)2CO(H)2] with CH2=CHSiMe3, an interesting observation was made. The ruthenium(II) complex does not react with the vinylsilane at room temperature, but does so at 100°C yielding the respective silane and an additional Ru-C bond after activation of one of the methyl groups on the mesityl wingtip groups. The ruthenium insertion into the C-H bond is reversible upon addition of 1 atm of molecular hydrogen at 75°C. If the C-H activated complex is heated at 110°C for a further 2 days, methane is eliminated with formation of a Ru-aryl bond [217].

PPh3

Mes

H

N

N

:

Ph3P Ru OC

Mes

N

Mes

H

N

Ph3P

PPh3

Mes

H Ru

OC

H PPh3

110C 2d

H2 Me3Si N

Mes N

Mes

N

N

Ph3P Ru OC

Ph3P OC

PPh3 H

Ru H PPh3

Figure 4.68 C-H activation in the wingtip group of a ruthenium(II) NHC complex.

252

Functionalised N-Heterocyclic Carbene Complexes

In the following year, Leitner and coworkers showed that this C-H activation process on the methyl group of a mesityl wingtip group can be observed at room temperature, when a suitable system is selected [218]. They used the carbene analogue [Ru(IMes)(PCy3) (H2)2(H)2] of Chaudret’s nonclassical ruthenium(II) hydride complex [Ru(PCy3)2(H2)2(H)2] [219,220]. Reaction of the ruthenium(II) carbene hydride complex with toluene-d8 at 25°C resulted in H/D exchange of all 12 o-methyl protons and all six Ru-H hydrides (see Figure 4.69). The para positions on the mesityl wingtip groups are not affected. The mesityl wingtip group is not the only substituent capable of C-H activation. When Baratta et al. reacted [Ru(PPh3)2(py-2-CH2NH2)(H)(Cl)] with 1,3,4-triphenyl-4,5-dihydro1H-1,2,4-triazol-5-ylidene in refluxing toluene, they observed C-H activation of a wingtip phenyl group and the evolution of molecular hydrogen [221] (see Figure 4.70). During the reaction, a reorganisation of the coordination sphere around ruthenium occurs. The three examples discussed so far all had a Ru-H hydride in common. This hydridic hydrogen atom was used to recombine with the proton from the wingtip group to form molecular hydrogen and a new Ru-C bond. The activation of a C-H bond on the wingtip group does not require the existence of a Ru-H moiety. Before the isolation of the first free NHC ligand by Arduengo et al. [222], Hitchcock et al. generated transition metal carbene complexes by thermal decomposition of electron-rich olefins in the presence of a suitable transition metal precursor complex [223–225]. When [Ru(PPh3)3Cl2] was used as the transition metal component, C-H activation of the wingtip group in the resulting ruthenium(II) carbene complex was observed, although no Ru-H bond was present in the starting material [225].

H3C

CH3 N

CD3 CH3

H3C CH3

H

H

H3C

D

N

N

D

D

D CH3

H 3C D

D

CD3

D

Ru H2

H2

D3C

CD3

N

Ru D2

D2

25°C, 5h

PCy3

D3C

PCy3

Figure 4.69 H/D exchange as a result of C-H activation on [Ru(IMes)(PCy3)(H2)2(H)2].

H Ph3P

N Ru

Ph3P Cl

N H2

Ph N N : N Ph Ph PPh3; H2

N

N N

Ph

Ru

N Ph3P Ph

Cl H2N

Figure 4.70 C-H activation of a phenyl wingtip group.

N-Heterocyclic Carbenes with Anionic Functional Groups

253

A purely alkyl wingtip group was employed by Dorta et al. using free IBut as the NHC ligand and [Rh(coe)2Cl]2 as the transition metal precursor complex [226,227] (see Figure 4.71). The reaction was reported to proceed stepwise and was dependant upon the choice of solvent. In pentane, only the carbene adduct without C-H activation was observed. In hexane, C-H activation in one NHC ligand only was observed, whereas in benzene C-H activation in the first NHC ligand was followed by C-H activation in the second NHC ligand. As the authors pointed out, an electron count of the three rhodium carbene complexes in Figure 4.71 reveals an interesting sequence. The simple rhodium(I) carbene adduct dimer is a square planar d8 16 VE complex, nothing out of the ordinary. The single C-H activated rhodium(III) complex in the middle is a distorted square pyramidal 16 VE complex with an additional agostic interaction to a proton of the wingtip tert-butyl group. This agostic interaction is thought to result in a proper C-H activation with loss of molecular hydrogen and formation of a distorted square pyramidal 16 VE complex without Rh-H groups. Abstraction of chloride from this complex, with AgPF6, results in the cationic, square planar 14 VE rhodium(III) complex shown at the bottom of Figure 4.71. Note: The square planar, cationic 14 VE rhodium(III) carbene complex in Figure4.71is supported and made possible by the strongly π-donating NHC ligands.

But N

Cl Rh

Rh

⫹

4

:

N

Cl

But

pentane

But

But

N Cl

But

Rh N

Cl N

N

N Rh

C6H6

hexane

But

C6H6

But H

Cl But N

N

N

C6H6

N

Rh

⫺H2

H

Cl But N

Rh N

N

H

t

Bu

H

AgPF6

N N

But

⫹ Rh

But N N

Figure 4.71 Single and double C-H activation in a rhodium(I) to rhodium(III) carbene complex.

254

Functionalised N-Heterocyclic Carbene Complexes

Up to now, we have seen the C-H activation in sterically demanding wingtip groups (tertbutyl, mesityl) or a wingtip group (phenyl) that can turn its C-H bond into the plane of the metal. As a consequence, it is easy to form the opinion that a sterically demanding wingtip group might be necessary. That is not the case. It is even possible to dispense of both steric bulk and aryl C-H bonds. An example is given by Arduengo and coworkers who used a combination of a tridentate Tp ligand and the sterically undemanding tetramethylimidazol2-ylidene NHC ligand on ytterbium(II) [228] (see Figure 4.72). Reaction of the starting ytterbium(II) complex [(TptBu,Me)Yb(thf)I] with the free carbene results in displacement of the coordinated solvent molecule, as expected. If the anionic substituent (iodide) in the starting complex is exchanged for a CH2SiMe3 group [229], reaction with excess of the free carbene proceeds under C-H activation of the methyl wingtip group and concomitant loss of not only the donor solvent molecule, but also tetramethylsilane (SiMe4). C-H activation is of course not uncommon with lanthanide-hydride and hydrocarbyl complexes [230–233] and thus the present example might not be completely unexpected. The corresponding Cp complexes (where the Tp spectator ligand is substituted by Cp) are known [234,235] and likewise undergo THF/NHC substitution. Note: In all these complexes, C-H activation is only observed when the CH2SiMe3 ligand is present as a facile leaving group (as SiMe4). We have seen that both aryl and alkyl wingtip groups can undergo C-H activation, preferably in Ru, Rh and Yb complexes. A key selector was the steric bulk of the wingtip group and thus the forced proximity of the C-H group relative to the metal centre. In some

H

H B

N N

N

N

But

Yb N

N

N

I

But

But

N

N

N

N

N

N

B

:

Yb

I

N

But

N But

N

THF t

Bu

KCH2SiMe3 H B

H B

N

But

N

N

N

N

N

But THF

:

SiMe3

But N

N N

N

N

Yb N

Yb N

N

N N

N But

But N

But

Figure 4.72 C-H activation in TpLnNHC complexes (Ln = lanthanide).

N-Heterocyclic Carbenes with Anionic Functional Groups

N N N

:

Cl

Cl

Ru

N

Ru

H PPh3 H

H

H Ph3P

255

PPh3

N

PPh3

N

CO Ph3P

PPh3 N Ph3P

N

Ru

Ru

CO PPh3

H Cl

H PPh3 H

H Cl

Figure 4.73 Agostic H-M interactions in a ruthenium(II) carbene complex that do not result in C-H activation.

instances, agostic H-M interactions could be observed prior to actual C-H activation and it is tempting to assume such agostic H-M interactions en route to insertion of the transition metal into the C-H bond. However, C-H activation does not always follow on the heels of an agostic H-M interaction, as was witnessed by Burling et al. in the case of certain ruthenium(II) NHC complexes incorporating hydride ligands and cyclohexyl wingtip groups with agostic hydrogen atoms [236]. Reaction of [Ru(PPh3)3(H)Cl] with ICy results in the displacement of a PPh3 phosphane ligand by the incoming carbene. The resulting ruthenium(II) carbene complex has pseudo-octahedral geometry with an agostic CH2 hydrogen atom of the cyclohexyl wingtip group occupying the sixth coordination site (see Figure 4.73). The agostic hydrogen sits trans to the hydride and two isomers are observed, one with the carbene trans to a phosphane and the other with the carbene trans to chloride. Reaction of this mixture of isomers with CO results in the coordination of CO in place of the agostic hydrogen and a single isomer with the carbene trans to chloride. It may be worth noticing that the ruthenium(II) carbene complex in Figure 4.73 is structurally and electronically very similar to the rhodium(III) carbene complex in Figure 4.71. Both are 16 VE complexes with an agostic H-M interaction trans to a M-H hydride ligand and both metals are known for their ability for C-H activation. In addition, ruthenium(II) is isoelectronic to rhodium(III) and they are direct neighbours in the fifth period of the periodic table. Furthermore, both agostic H-M interactions are part of alkyl wingtip groups, but only in the rhodium(III) complex is C-H activation actually observed, whereas the ruthenium(II) complex remains inactive. Another interesting example for C-H bond activation is provided by Dixneuf and colleagues who reacted [Ru(p-cymene)Cl2]2 with an imidazolium salt carrying a methoxyalkyl or chloroalkyl wingtip group in the presence of a deprotonating agent [237]. Carbene adduct formation proceeded as planned, but the hemilabile ether sidearm proved to be more reactive than anticipated. Elimination of HX and HCl produces an unsaturated five-membered metallacycle annulated to the carbene entity (see Figure 4.74). It is worth noticing that actually no Ru-H bond is involved in the C-H activation process. Instead,

256

Functionalised N-Heterocyclic Carbene Complexes X :

Mes

Mes

N

N

[Ru(p-cymene)Cl2]2

Cl

Ru Cl

N

BuLi

N

Mes

X

N HX HCl

or

N

:

BuLi X

Mes N

N

[Ru(p-cymene)Cl2]2

Mes

Cl

Ru

N N

Figure 4.74 Synthesis of Ru(II) NHC complexes using functionalised carbenes on a p-cymene ruthenium scaffold.

either a vinylcarbene is formed in the first step that adds to the ruthenium complex and then eliminates HCl in the coordination sphere of the metal (the hydrogen originating from the vinyl wingtip group) or alternatively, the free functionalised carbene is formed and coordinates to the ruthenium centre prior to eliminating both HCl and HX in the coordination sphere of the metal.

4.5 Immobilisation of the Catalyst The introduction of a functional group into the sidechain of a NHC ligand in catalytic applications can have other purposes than to improve the performance of the catalytic centre. The NHC scaffold can be used to attach the catalyst to a polymeric support and thus immobilise and semi-heterogenise the catayst. The intention behind this strategy is to recycle the catalyst and thus reduce the effective catalyst loading over time and to reduce the overall cost [238]. Of course, there are several opportunities to anchor the catalyst to a polymeric support. The most popular ones are the functionalisation of the Schrock carbene unit [239–243] and the functionalisation of the NHC unit [238]. The latter will interest us since it is the solution that falls within the scope of this book. Fürstner and coworkers have modified a ‘second generation’ ruthenium carbene complex used in olefin metathesis with a terminal hydroxy group in the sidechain (see Figure 4.75) [244]. The hydroxy group was then used to attach the NHC unit, and with it the catalyst, on a silicon support. Initially, a ‘second generation’ Grubbs’ catalyst had two NHC ligands and one is lost in the activation process. For practical reasons, the design has changed to one NHC and one PCy3 ligand, the latter being lost in the initiation period. In the present case it is necessary to have the tricyclohexyl phosphine unit instead of the second NHC to avoid loss of immobilisation with loss of ligand.

N-Heterocyclic Carbenes with Anionic Functional Groups

257

N

N HO

Cl

Ru

Cl

P

Cy

Ph Cy

Cy

Figure 4.75 Grubbs’ catalyst with functionalised sidechain on the carbene.

Another possibility to anchor the NHC unit to a polymeric support is to attach the linker unit to the imidazole backbone rather than using the wingtip group for it. This approach was realised by Connon and Blechert with a saturated functionalised NHC ligand (see Figure 4.76) [245]. There is no real advantage to this approach other than having a saturated NHC as opposed to an unsaturated one. This facile solution for catalyst immobilisation follows a more complex approach reported by Mayr et al. [246]. This research group attached the imidazolium salt to a norbornene unit that was then subjected to a ring opening metathesis polymerisation (ROMP) reaction to form the polymeric NHC precursor (see Figure 4.77). The ROMP reaction had to be carried out with a molybdenum based Schrock catalyst because the ruthenium based Grubbs’ catalyst did not provide an endgroup that could be quantitatively capped with a suitable final endgroup.

Merrifield resin O

N

N

Ru

Cl

Cl

P

Cy

Ph Cy

Cy

Figure 4.76 Immobilisation through the NHC backbone.

258

Functionalised N-Heterocyclic Carbene Complexes

(OEt)3Si

CMe2Ph n O

[Mo] O

O O

O Ar Ar

N

N

BF4

Ar

N

N

BF4

O OH

O O

Si CMe2Ph

Si n

O

O Si O

Me

O

O

Si O Si O

OEt

O

Si

Ar

Si O Me OH OSiMe3

O

OSiMe3 Ar

N

Cl Cy3P

N

Ru

Ar

Cl Ph

Figure 4.77 Immobilisation of a Grubbs’ catalyst.

The triethoxysilane endgroup had to be introduced as the respective isocyanate and was then used to attach the polymer on the silicon support. In a final step, the NHC are formed and the ruthenium precursor loaded onto the polymer. Only 13% of the imidazolium sites are attached to ruthenium. The formation of this polymer supported Grubbs’ catalyst is doubtless a synthetic masterpiece, however, immobilisation of the Grubbs’ catalyst was achieved in a far less complicated manner only a few years later by a far simpler method by Fürstner and coworkers [244]. The triethoxysilyl endgroup is a popular functional group to bind the catalyst to a polymeric support [238]. Polymeric supports include silica gel, MCM-41 (mesoporous silica gel) and ITQ-2 (delaminated zeolite) [247]. Corma et al. used this approach to synthesise gold(I) and palladium(II) NHC complexes for Suzuki cross-coupling reactions between iodobenzene and various arylboronic acids (see Figure 4.78) [247]. The results were very modest at 35–80% dependent upon the substitution pattern of the arylboronic acid. Yields with gold(I) catalysts were marginally better than those for palladium(II) complexes. A similar strategy using a SiCl3 endgroup instead of a Si(OEt)3 one gives the same result. It is however interesting that the strategy can be adapted to the reverse reaction sequence regarding the synthesis of the catalytic complex. Wang and coworkers have set the polymer anchor first and then built the copper(I) NHC complex on this foundation [248,249]. By reacting p-trichlorosilyl-tolyl chloride with SiO2, they attached the future wingtip group onto the polymeric support. Reaction with N-alkyl(aryl)-imidazole generates the tethered imidazolium salt that can be converted into the immobilised copper(I) NHC complex using potassium tert-butylate as base and copper(I) iodide as the copper source (see Figure 4.79). The copper(I) complex was then used in the catalytic coupling reaction of phenylacetylene, paraformaldehyde and piperidine to PhCCCH2-piperidine giving an initial yield of 95% that drops down to 88% for the tenth consecutive cycle with recovery of the catalyst after every cycle.

N-Heterocyclic Carbenes with Anionic Functional Groups

O

Si(OEt)3

Si N

N

259

HO

O O

N

N HO HO

Au

Au

Cl

Cl O

Si(OEt)3

Si N

N

HO Cl

Pd

Cl

N

N HO HO Pd

Cl

L

O O

Cl

L

Figure 4.78 Immobilisation of the catalyst using a Si(OEt)3 endgroup.

OH

Cl

O

Si

OH Cl OH

Cl

Cl Si

O

Cl

O

N

N

N N

⫹

O O Si O

N

ButOK

N

Si Cu

I

CuI

O

O

O

Figure 4.79 Building the catalyst on the support.

Attachment of the catalyst by way of a hydroxy functionalised NHC was already envisaged by Herrmann et al. [250]. They described model complexes suitable for attachment of the imidazolium salt and thus the catalyst to a polymeric support, but did not actually carry out the immobilisation step. Attachment to the polymeric support via a hydroxy group is not as easy as it may seem since the polymeric support has itself hydroxy groups as the relevant functional groups. This makes it necessary to use RSiCL3 (R = Me, Ph) as reactive linker groups [244] or effective mediators to effect the linkage between the hydroxy functionalised carbene complex and the hydroxy functionalised polymeric support (see Figure 4.80). By using PhSiCl3 as reactive linker,

260

Functionalised N-Heterocyclic Carbene Complexes Mes Br

N

N

N

N

HO

Mes

HO

Ph Cy3P Ru PCy3 Cl Cl

O

O

Ph

N

N

Si

Mes

O Cl Ru Cl

1) PhSiCl3 2) polymer

Ph N

N PCy3

Mes

HO Cl Ru Cl

Ph

PCy3

Figure 4.80 Use of PhSiCl3 as reactive linker group to join the linker to the polymeric support.

Fürstner and coworkers [244] found a way to realise Herrmann’s concept of using a hydroxy functionality on the carbene wingtip group for effective immobilisation of the catalyst. It should be mentioned that many imidazolium salts are liquids at room temperature and thus fall into the general category of ionic liquids. An excellent overview of the techniques to attach ionic liquids onto solid supports is available by Mehnert [251]. Here, the interested reader is directed to the concept that ionic liquids cannot only be attached covalently to the support, but also by simple deposition of the ionic liquid phase containing the catalyst onto the support surface. In a more conventional approach, Zarka et al. attached a rhodium carbene complex onto an amphiphilic block copolymer [252]. The concept is simple and involves the utilisation of a hydroxyalkyl substituted NHC as a ligand for the rhodium(I) catalyst used in hydroformylation of 1-octene. The catalyst is then loaded onto a water-soluble, amphiphilic block copolymer by reacting the alcohol group of the catalyst with a carboxylic acid group of the block copolymer (see Figure 4.81). Attachment of the catalyst to a polymeric support can also be facilitated using a biscarbene as the ligand [253]. The bisimidazolium salt featuring a hydroxyalkyl sidechain on each of the two imidazolium units was reacted with palladium (II) acetate to form the neutral catalyst complex (see Figure 4.82). Immobilisation was then achieved by reacting the functionalised catalyst with 4-(bromomethyl)phenoxy-methyl polystyrene, known as Wang resin, as the polymeric support. A very interesting approach for the immobilisation of a catalyst comes from Meldal and coworkers who have incorporated the NHC into the growing peptide chain of a Merrifield synthesis (254). This is another example of attaching the wingtip group first on a polymeric support (Merrifield resin) and then attaching the imidazolium salt to the initial anchor (see Figure 4.83). There are a few alterations to the previous method. Here, the entire imidazolium salt unit is transferred and, more importantly, the polymer continues to grow after the incorporation of the imidazolium entities.

N-Heterocyclic Carbenes with Anionic Functional Groups OH

N

N

N

Rh

O

30

N

O

*

N

4 O

30

4

8

Br

N

N

N 4

O

261

O

N

N 4

4

N Br

O

O

Rh

O 8

*

4 O

N

OH

Figure 4.81 Immobilisation of anv NHC on a block copolymer. Polymer

Polymer

HO

N Br

Wangresin

N

N n Pd

N

Br n

O

OH

O

N

N Br

O

N

n Br

Pd Br

N

n HO

Figure 4.82 Immobilisation of an NHC using Wang resin.

Immobilisation is a viable concept when it does not appreciably lower the catalyst activity and when it can be facilitated by a simple method. A method is simple when the synthesis of the functionalised catalyst is not significantly more complicated than that of the nonfunctionalised catalyst. Additionally, the support should be commercially available or be obtained readily from a commercially available precursor [ 255 ].

262

Functionalised N-Heterocyclic Carbene Complexes R HO2C

N ⫹

N

I

R N

I

⫹

⫺

N

CO2H

N3

N3

[Red]

I

R N

⫹

N

⫺

CO2H

NH2

N

O

HN O

N

⫹

H N Ala

N

CF3CO2

⫺

O

Merrifield synthesis

Phe Ala Val

Ph O

HN H N

CF3CO2 N

⫺

⫹

N

Val

O Ph

O

Rink PEGA800

Figure 4.83 Immobilisation of the catalyst inside a peptide chain.

4.6 Sulfur-Containing Functional Groups Note: Due to the very limited scope of sulfur functionalised NHC ligands, we will discuss the neutral ligands alongside the anionic ones. The incorporation of sulfur functionalities into NHC wingtip groups has several consequences. Sulfur-containing functional groups are not that often encountered in catalytical applications [256,257], but several examples are reported [257]. They can be used as ligands in asymmetric catalysis when mounted on standard chiral scaffolds like 1,1'-binaphthyl (BINASR2, BIPHESR2) [258,259] or modelled on the DIOP ligand class (DIOSMe2) [260] (see Figure 4.84). The trend in the few examples where an NHC is functionalised with a sulfur-containing group does not necessarily reflect the choice of scaffold seen above, but the S functionalised NHC ligands do, in part, follow the general development of an S/P exchange in conventional functionalised phosphanes. The other major source for S functionalised NHC complexes of transition metals is the replacement of sulfur by a transition metal in certain π-sulfurane compounds. The NHC ligand, a tetrahydropyrimidine derivative, is only liberated during the reaction of the sulfurane with the transition metal precursor.

N-Heterocyclic Carbenes with Anionic Functional Groups

H

R

R

S

S

R

S

O

S

S

S

O R

H

DIOSMe2

BIPHESR2

BINASR2

263

Figure 4.84 Examples for chiral chelating sulfur donor ligands.

In a more conventional ligand design, Ros et al. used chiral N-trans-2,5-diphenylpyrrolidinyl imidazole as the starting point to introduce a thioether functionality on a primary alkyl halide carrier (see Figure 4.85) [261]. The thioether functionality becomes chiral upon coordination to palladium and the remote chirality effect of the other, the pyrrolidine wingtip group ensures that only one of the two possible sulfur based enantiomers is realised. Note: The remote chiral effect of the chiral trans-2,5-pyrrolidinyl substituent forces the prochiral thioether group to realise only one of the two possible enantiomers. Racemisation does not occur. Ph

Ph

N

N

N

N

Ag2O

N

N Ag Cl

Ph

S

S

Ph

Ph

Ph

Cl CyS

Ph

[Pd(cod) (allyl)]SbF6 Ph N

N

N S N

N

N Pd

Ph

Ph

Ph

Figure 4.85 Synthesis of thioether functionalised imidazolium salts and their silver(I) and palladium(II) carbenecomplexes.

264

Functionalised N-Heterocyclic Carbene Complexes

Note: The sulfur atom is prochiral: two different substituents and two electron lone pairs. After coordination, the palladium atom is the third different substituent and the remaining stereoactive lone pair results in an asymmetric sulfur atom. The corresponding thioether functionalised NHC without a second chiral wingtip group but an asymmetric carbon atom in the thioether sidearm was also synthesised by Ros et al. [261]. However, we will turn our attention towards a similar example from the same research group [262] where the NHC is pyrido[a] annulated [263]. The synthesis is again rather facile and follows standard procedures (see Figure 4.86). The chiral thioether precursor compound is accessible as the alcohol and needs to be treated with tetrabromomethane and PPh3 to generate the required primary alkyl bromide. Pyrido[a] carbenes and their homologues are usually not very stable [263–266], but the carbene can be isolated and stored readily enough [264,265]. In the present example, no free carbene is generated and stability is enhanced in the coordination sphere of silver(I) and palladium(II). Functionalisation of the NHC with a thiolate rather than a thioether can also be achieved, although by a somewhat more indirect route. To this end, Cabeza and coworkers reacted methyl levamisolium triflate, a synthetic antibiotic [267] based on the imidazothiazole scaffold, with [Pd(dba)2] in a thiazole ring opening reaction to give the corresponding palladium(II) coordinated chelating mercaptide functionalised NHC (see Figure 4.87) [268,269]. Br S

N Cy

N

N

N S Cy

Ag2O

N N [Pd(NCMe)2Cl2] Ag Br

N

S Cy

[Pd(cod)(allyl)]SbF6

N

Cl

Pd

S N

Cl

Cy

N

Pd

S Cy

Figure 4.86 Synthesis of thioether functionalised imidazolium salts having a pyrido[a] annulated wingtip group.

N-Heterocyclic Carbenes with Anionic Functional Groups

265

N PPh3

Ph S

N

PPh3

Pd Pd Ph3P

N

S

Ph N N

[Pd(dba)2]

Ph

N

S N Ph

bipy

S

N

Pd N

N

Figure 4.87 Synthesis of a mercaptide functionalised NHC palladium(II) complex by insertion of palladium into a C-S bond of levamisolium triflate.

Note: Addition of a second equivalent of phosphane is likely to break the S-Pd donor bond and yield the corresponding mononuclear complex. The thioether functionalised NHC transition metal complexes were used in the palladium(II) catalysed allylic substitution between 1,3-diphenylpropenyl acetate and dimethyl malonate to yield 1,3-diphenylpropenyl dimethylmalonate [261,262] (see Figure 4.88). The yields were good and the chiral resolution better than with most chiral carbene ligands in similar reactions (see Chapter 5). Not surprisingly, the remote chiral effect of the diphenylpyrrolidine wingtip group in Figure 4.85 gives significantly lower chiral resolution than the direct chiral effect of the asymmetric carbon atom in the thioether sidearm (Figure 4.86). A marked exception is benzoannulation on the pyrido[a] ring, which leads to 10% ee but no drop in yield. Similarly, substitution of the cyclohexyl group on sulfur with tert-butyl in Figure 4.85 results in a drop to 6% ee (from 72% ee), probably for steric reasons.

O OAc

O

O

Ph

O

O

O

O

[Pd(NHC-S)(allyl)]SbF6

Ph

O

NaH Ph

Ph

Figure 4.88 Palladium catalysed reaction between 1,3-diphenylpropenyl acetate and dimethyl malonate.

266

Functionalised N-Heterocyclic Carbene Complexes

A rather peculiar reaction, at least at first sight, occurs in the reaction of a nickel(II) bound dimercapto-diamino tetradentate ligand with CO (see Figure 4.89) [270–272]. The product is a sulfur functionalised NHC ligand coordinated to nickel(II). In a spot-the-difference analysis, one notes that the carbon atom of CO ends up as the C2-atom of the carbene and that two protons are abstracted from the two nitrogen atoms (presumably they form water with the carbonyl oxygen atom). We have therefore a ring closing reaction between the diamino ligand and CO mediated by nickel(II). Following these observations, Sellmann et al. developed a more rational reaction for the same complex by using the standard triethyl orthoformate as the ring closing reagent [272]. The dimeric product can of course be cleaved to a monomer by PPh3 as the better donor ligand (compared with a sulfide bridge). Note: The mercaptides compensate the positive charges on nickel(II) and give the ligand pincer geometry. A more conventional approach towards a sulphur functionalised NHC ligand is presented by Seo et al. [273] and follows the traditional phosphane route. Indeed, the thioether functionality takes the place of the phosphino group (see Figure 4.90). The final sulfur functionalised NHC ligand has already two chiral elements, an asymmetric carbon centre in the backbone and planar chirality associated with the Fc group. In addition, the thioether functionality is prochiral and becomes asymmetric upon coordination to a transition metal. H

H N

N

CO

Ni S

N

N

S S

H

Ni

S

S

Ni

S

H N

N NiCl2

SH

HS

N

N

HC(OEt)3

PPh3

N

N

Ni S

S PPh3

Figure 4.89 Synthesis of a mercaptide functionalised NHC ligand in the coordination sphere of nickel(II).

N-Heterocyclic Carbenes with Anionic Functional Groups

NMe2

NMe2 SPh

BuLi

N

N

N

SPh

MeI

PhSSPh

⫹

267

N ButOK [Rh(cod)Cl]2 AgBF4

N

N

ButOK [Ir(cod)Cl]2 AgBF4 N

⫹

N

Ir N

N

SPh

S

⫹

Rh

Ph

PhS

Figure 4.90 Synthesis of a thioether functionalised imidazolium salt on a ferrocene scaffold.

In the event, only the rhodium(I) complex features sulfur coordination, whereas the iridium(I) complex prefers a second carbene ligand over the sulfur mediated chelate effect. The two complexes were tested for their activity in the hydrogenation of dimethyl itaconate. The iridium complex was inactive and the rhodium complex showed 44% conversion with a disappointingly low chiral resolution of 18% ee (R). The corresponding phosphino functionalised NHC rhodium(I) complex reacted under milder conditions, but without improvement of chiral resolution, 13% ee (S). Before we discuss the sulfur functionalised NHC complexes derived from π-sulfurane compounds, we pause to reflect that sulfur functionalisation can have other intentions than to introduce a second donor group (hemilability, chelate effect). Moore et al. [274] introduced a sulfonato functionality into a NHC wingtip group to make the resulting transition metal carbene complexes water soluble. Introduction of the functional group was achieved in a modification of the epoxide method previously used by Arnold et al. [33] and Glas et al. [12] for the synthesis of alkoxide functionalised carbenes (see Section 4.1). Reaction of an N-substituted imidazole with 1,3-propane sultone [275] yields the sulfonato functionalised imidazolium compound as a zwitterion that can be reacted with silver(I) oxide and sodium chloride to generate the corresponding zwitterionic silver(I) sulfur functionalised carbene complex (see Figure 4.91). The N-alkyl, rather than N-aryl, substituted ligands proved to be unstable in their silver(I) carbene complexes and decomposed over time with deposition of elemental silver. Another interesting case of sulfur functionalised NHC complexes comes from Matsumura et al.’s synthesis of 2,3-disubstituted 6,7-dihydro-5H-2a-thia(2a-SII)-2,3,4a,7atetraazacy-clopent[cd]indene-1,4(2H,3H)-dithiones [276,277] (see Figure 4.92). Analogous

268

Functionalised N-Heterocyclic Carbene Complexes O O S

O N

Mes

SO3

N

N

Mes

N

Ag2O

SO3 N

Mes

NaCl

N

Ag

N

N

Mes

NaO3S

Figure 4.91 Synthesis of a water soluble sulfonato functionalised imidazolium salt and its silver(I) NHC complex.

S

S

Li

HN

NH

BuLi

N

Li

Ph S

O N

Cl

Ph

Li

O N

N

R - NCS

S

R

R

S

N

R - NCS

S N

N

S

N

N

S

Li

Ph

R N

O N

N

S

N

N R S

Figure 4.92 Synthesis of a π-sulfurane from perhydropyrimidine-2-thione.

π-sulfuranes on the basis of perhydroimidazole-thione rather than perhydropyrimidinethiones are also available [278]. Reaction of this 10-S-3 [279] tetraazapentalene derivative with [Pd(PPh3)4] or [Rh(PPh3)3)Cl] results in the formal substitution of sulfur by the transition metal accompanied by a redox reaction (see Figure 4.93) [280]. The endocyclic sulfur atom is transferred to a PPh3 ligand (oxidation of phosphorus to Ph3P=S). At the same time the transition metal is oxidised (palladium from 0 to +II; rhodium from +I to +III), which leaves sulfur to be reduced by four electrons (it is −II in Ph3P=S and thus must have been +II in the π-sulfurane starting material). It follows from this electron transfer analysis that the π-sulfurane is indeed better described as the sulfur complex of a doubly amide functionalised NHC ligand.

N-Heterocyclic Carbenes with Anionic Functional Groups R

R N

S Ph3P

N

S

N

Pd

and/or

[Pd(PPh3)4]

Ph3P

N

N S

N

Pd N

S

R

R

S N

269

N

N

R

S R N

N

R N

N

R S

S

[Rh(PPh3)3Cl]

PPh3 Cl Ph3P

S

N

N

N

N PPh3

or

Rh

Cl Ph3P

Rh N

S

R S

N R

Figure 4.93 Carbene transfer from sulfur to palladium and rhodium using a π-sulfurane.

Note: The π-sulfurane in Figure 4.92 is a very early and still rare example of a main group carbene complex using a functionalised NHC ligand. Note: The wingtip groups containing a sulfur and a nitrogen functionality elect to coordinate to the transition metal via its sulfur atom and not its nitrogen atom (as was the case with the main group element sulfur). Note: The graphical description of the π-sulfurane shows why the endocyclic sulfur is coordinated by nitrogen rather than by sulfur. In a trigonal bipyramidal geometry nitrogen is preferred over sulfur as the axial ligand. The phosphane ligand can be removed in 18% aqueous hydrochloric acid and subsequently replaced by pyridine [281]. The complex then features two mercaptide ligands on the palladium(II) atom confirming that sulfur coordination on the transition metal is indeed preferred over nitrogen coordination. This is even better seen, when the exocyclic thione sulfur atoms of the ligand are replaced by oxygen. Subsequent reaction with Wilkinson’s catalyst [Rh(PPh3)3Cl] reveals the metallophobic character of the carbonyl oxygen and the metallophilicity of the sulfur. This culminates in the failure to substitute the endocyclic sulfur and have it coordinate to rhodium(III) instead (see Figure 4.94) [282]. The reaction proceeds with loss of phenyl isocyanide, the reverse reaction to the synthesis of this 10-S-3 compound [276].

270

Functionalised N-Heterocyclic Carbene Complexes S

S

O

Et N

Ph N

N

S

N

N

S N

N

N

S N

N

N

N

Et

Ph O

O

O

[Rh(PPh3)3Cl]

[Pt(PPh3)4]

[Rh(PPh3)3Cl]

Et N

N

N Cl

Cl

N

O

S

Cl PPh3

N

N

N

Rh

Rh

Ph3P

N

N

N PPh3

Pt

Ph3P

PPh3

S

S

HN

Et

Ph O

O

Figure 4.94 Dependence of coordination and structure on the presence of thione or ketone. R

R N

R N

N

[(Ph3P)3Pd]

S

S

N

S

- Ph3PS

S

- PPh3 N

S

Ph3P

N

[Pd(PPh3)4]

S N

Pd

Ph3P

S

N

S

N

S N

N

N

R

R

R

R

R N

N

S

S Ph3P

N

N - Ph3PS

Pd

Pd Ph3P

S

N

S

N Ph3P

S N

N R

R

Figure 4.95 A tentative mechanism for the carbene transfer from sulfur to palladium.

N-Heterocyclic Carbenes with Anionic Functional Groups

271

A reaction mechanism for the replacement of the endocyclic sulfur atom by the transition metal in these π-sulfuranes was given by Manabe et al. on the basis of frontier electron density analysis [282] (see Figure 4.95). Iwasaki explained the mechanism on the energetically less favourable isomer featuring S-S rather than S-N bonds. It is well known that [Pd(PPh3)4] exists in equilibrium with [Pd(PPh3)3]. It is therefore tempting to assume that the first step is carbene transfer from sulfur to palladium. Following this, sulfur transfer from palladium to phosphane occurs, accompanied by a series of ligand rearrangements.

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5 Chiral N-Heterocyclic Carbenes

The introduction of chirality into the NHC framework follows different principles than that of traditional phosphane ligands. Whereas phosphanes are conically shaped [1] ligands with a tetrahedrally coordinated central phosphorus atom, NHC are planar disc-like ligands based on the aromatic imidazole system (see Chapter 1). It follows that phosphanes are asymmetric owing to a sterically active and stable lone pair, whereas the chirality in the ‘traditional’ NHC defines itself through a peripheral chiral element. This element can be an asymmetric atom (central chirality), an axial chiral element (an atropisomeric binaphthyl substituent) or planar chirality (double substitution on an aromatic ring system, planar chiral substituent). Combinations of these three types of chirality are possible and can be realised in a more or less facile protocol. Note: Chirality in NHC ligands is normally more remote than that in phosphane ligands, relative to the metal centre of an appropriate metal complex. The reason is the inherently achiral nitrogen atom adjacent to the carbene carbon atom. Note: Phosphanes can have an asymmetric phosphorus atom, but can NHC have an asymmetric carbene centre? Given that the asymmetric (carbon) atom has to be introduced two bonds away from the carbene carbon atom – the donor functionality of the ligand – there are two options for doing this: the exocyclic wingtip substituent and the endocyclic backbone atoms (C4 and C5). The latter are only available for the introduction of an asymmetric centre, when the NHC is saturated (the unsaturated NHC possesses only trivalent backbone carbon atoms). Figure 5.1 shows an overview of the various options for making NHC ligands chiral. Numerous reviews incorporate chirality of NHC ligands or are devoted to them. Excellent examples of the use of asymmetric transition metal NHC complexes in catalysis were given by Perry and Burgess [2] and César et al. [3], accompanied by chirality by an oxazoline wingtip group [4] and the use of chiral NHC in asymmetric alkylation reactions [5]. Functionalised N-Heterocyclic Carbene Complexes. Olaf Kühl © 2010 John Wiley & Sons, Ltd.

280

Functionalised N-Heterocyclic Carbene Complexes Ph

Ph

Ph N

central chirality

N R

N

⫹

N ⫹

N

Ph

N

R

N

axial chirality

⫹

⫹

N

⫹

N

HO

Mes N

⫹

N N

SiMe3 N planar chirality

⫹

N Fe

N ⫹

N

Figure 5.1 Examples of chiral NHC.

Note: Introducing more than one element of chirality (central, axial, planar) usually results in mediocre chiral resolution of products (% ee), probably owing to conflicting stereodirectivities of the individual chiral elements. We are already well accustomed with the historical relationship seen in the development of NHC ligands with special features. They often follow the example of successful phosphane ligands. Chiral NHC are no exception, although in key areas the very difference in shape between NHC and phosphanes prevents the development of NHC ligands as structural phosphane mimics. The axial (atropisomers with binaphthyl backbone [6,7]) and planar (ferrocene derivatives [8,9], [2,2]-paracyclophanes [10,11]) chiral examples, however, are styled on their phosphane predecessors [12–15]. We will first look at the unique options for NHC ligands before we turn to the more familiar phosphane mimics. Introduction of central chirality into the wingtip groups of the imidazole ring is challenging, since the carbon atom bonded to the nitrogen atom is the best choice for chiral induction in catalytic reactions. It is simply closest to the carbene carbon atom (three bonds away). The most facile protocol for the introduction of the wingtip group calls for the quarternisation of the imidazole nitrogen atom using an alkyl halide (see Chapter 1). Within this protocol, retention of chirality on the carbon atom carrying the halide (or complete inversion on this carbon atom) cannot always be guaranteed. A better alternative is therefore the use of chiral primary amines in the synthesis of the imidazolium ring system [16,17] (see Figure 5.2). The ring

Chiral N-Heterocyclic Carbenes

281

O Ph Ph

N NH2

2

⫹

⫹ O

O

Ph

N

H H

H O

Ph

Ph NH2

⫹

N O

H

NH4Cl

N

O H O

O

O

N

N

O

N

N ⫹

Figure 5.2 Synthesis of NHC with central chirality in the wingtip groups.

formation reaction proceeds without racemisation of the chiral primary amines [18–20]. By addition of 1 equiv. of ammonium chloride during the ring formation process, it is possible to introduce only one of the primary amines into the ring. This results in the formation of an asymmetrically substituted imidazole carrying one wingtip group only. The method is facile, but can be extended to accommodate almost any primary amine from the chiral pool, including functionalised derivatives. The alternative is the synthesis of a diamine or diimine with subsequent ring closure as is the case for a NHC ligand derived from a bisoxazoline [21]. The Arduengo imidazole synthesis protocol can only be used for symmetrical NHC or, in the Griednev variation, for unsymmetrical NHC with an imidazole scaffold [16,17]. When we extend the concept of NHC ligands with chiral wingtip groups to benzimidazole based NHC [22,23], we will have to alter the method of imidazole synthesis, in particular we need a different ring closure reaction since the benzene backbone makes the formation of a diimine intermediate impossible. This can be found in the triethyl orthoformate method [23,24] whereby a diamine is reacted with HC(OEt)3 to form the saturated imidazolidene ring system (see Chapter 1). The diamine can be synthesised in a double Buchwald–Hartwig amination [25,26] and thus with two different chiral primary amines, an unsymmetrical chiral benzimidazolium salt [22] can be formed (see Figure 5.3). Another NHC ligand class where the introduction of chiral wingtip groups through reaction of a precursor compound with a chiral primary amine is achieved in a facile manner is the one based on a six-membered tetrahydropyrimidine backbone [27,28]. The starting material in this case is 1,3-dibromopropane and the ring closure was achieved with formaldehyde instead of triethyl othoformate (see Figure 5.4).

282

Functionalised N-Heterocyclic Carbene Complexes Ph Br

H2 N

Ph

NH

H2N

Ph

Buchwald-Hartwig

NH

Ph

Ph N

HC(OEt)3

⫹

Buchwald-Hartwig

Br

Br

N

NH

Ph Ph

Figure 5.3 Synthesis of chiral NHC with a benzimidazole backbone.

Br

Br

H2N

Ph

H2C=O Ph

N H

N H

N

Ph

N Ph

Ph

NBS

N Ph

⫹

N Ph

Figure 5.4 Synthesis of chiral NHC with a pyrimidine backbone.

Note: The protocol can also be applied to 1,2-diaminoethane to form the corresponding imidazolidine system [29]. If the carbon atoms of the ethane (propane) backbone are chosen to be asymmetric, chirality is introduced into the ring rather than the wingtip groups. Naturally, one can imagine the introduction of a chiral alkyl linker unit bridging two NHC units. In this case, the analogy to bidentate chiral phosphanes is restored. Two examples of this come from the Marshall group [30,31] (see Figure 5.5). They used enantiomerically pure tartaric acid to synthesise an enantiomerically pure dioxalane or cyclopentane bridge [32,33] that could be attached to the imidazole rings via terminal bromide groups. The bridge is long enough to accommodate a trans coordination on ruthenium according to 13C-NMR spectral evidence [34], although for palladium(II) a cis coordination was observed. The trans coordination mode could be realised by extending the length of the bridge by one methylene unit on either side [31]. The situation becomes even more complicated when chelate complexes are considered. The chelate ligand forms a metallacycle with the central metal atom that can give rise to fluxional behaviour and thus to dynamic, interconverting conformations that add to the number of possible diastereomers [35–37]. A methylene bridged bis-carbene ligand forms a six-membered metallacycle with a bend-boat conformation [36]. In this conformation, the protons of the bridging methylene group are expected to be magnetically nonequivalent and exhibit an AB pattern in the 1HNMR spectrum. The rigidity of the conformation naturally depends on the type of transition metal complex, the coligands and the wingtip groups. Herrmann et al. determined

Chiral N-Heterocyclic Carbenes

O

283

O

N O

O

N N

Cy tartaric acid

N ⫹

⫹

N Br

Br

N Cy

Cy

N N Cy tartaric acid

Br

Br

N

N ⫹

⫹

N

N Cy

Cy

Figure 5.5 Synthesis of bis-NHC ligands with chiral, bridging linker units.

the steric implications of the wingtip groups on the coalescence temperature of a [Pd(LL)Br2] complex and found that ring inversion for methyl as wingtip group occurs at room temperature, a secondary carbon substituent coalesces at 128–154 ˚C and a tertiary carbon substituent requires temperatures in excess of 180 ˚C. It follows that the wingtip group may play a key role in catalytic complexes by not only defining the free space in the coordination sphere of the active metal centre, but by determining the rigidity of the conformation of the catalyst complex and thus adherence to a specific diastereomer. The influence of the coligand (halide) and wingtip group (steric bulk) on the coalescence temperature is caused by the necessity for the wingtip groups to pass the metal coordination plane during ring inversion. This is accompanied by the necessity for the wingtip groups to avoid the coligands (halides) and the metal. In this context, the size of the metal is of some consequence as it influences the bite angle [38,39] and the relative positions of the wingtip groups and coligands (through the M-C and M-X bond lengths). Note: In many catalytic processes, the coordination number on the catalytically active metal centre changes in the course of the catalytic cycle. This can increase the conformational flexibility of the chelate ligand in an intermediate sufficiently to result in unpredicted product racemisation. Note: Above estimates for coalescence temperatures are valid for [Pd(L-L)Br2] complexes only. In many coupling reactions the intermediate is a [Pd(L-L)] complex where the coalescence barrier is expected to be significantly lower.

284

Functionalised N-Heterocyclic Carbene Complexes

When the bridge between the two chelating carbene units is increased, the conformational flexibility of the metallacycle is increased in parallel. However, as it is no longer a sixmembered bend-boat conformation, its influence on the stereoselectivity concerning the product need not be of the same importance. A pincer ligand forming two such six-membered metallacycles [37], by necessity symmetry related, is far more interesting to consider (see Figure 5.6). Here, the central pyridine ring can rotate like a swinging door with the nitrogen atom acting as a hinge and the carbene units as stoppers. The result is a very flexible system that rapidly interconverts between two limiting structures that are symmetry related [35,37] and reduces the number of expected diastereomers by half. More importantly, this process can result in product racemisation and potentially renders the chiral chelating ligand system inefficient. Obviously, it is possible to introduce chirality into the wingtip group of a triazolium salt. Enders et al. [40] did precisely that and described the stereochemical consequences in a cis-bis-carbene complex of palladium(II) – square planar with two possible orientations of the unsymmetrical carbene ligands (see Figure 5.7). Not only does a mixture of cis- and trans-palladium complexes result from the reaction between the triazolium salt and palladium(II) acetate in the presence of sodium iodide [40], a result not in accord with previous observations with imidazolium salts [41,42], but the two unsymmetrical carbene ligands can orientate themselves anti (antiparallel orientation) and syn (parallel orientation) towards each other. This results in four different enantiomers without taking into account the stereochemistry of the chiral centre in the carbene’s wingtip. The distribution of the different isomers is very interesting. The triazolinylidene complexes are formed with 82 % trans and 8 % cis isolated yield with the corresponding imidazolinylidene complexes giving very similar results (89 % trans and 9 % cis). The imidazolinylidene complexes could not form syn and anti isomers as the symmetrical ligands were employed. With the imidazolinylidene complexes, however, the anti isomers were predictably favoured (trans: 28 % syn and 72 % anti; cis: 12 % syn and 88 % anti). The chiral wingtip group is sterically more demanding than the phenyl group on the other end and thus the anti isomer (the most bulky wingtip groups on opposite ends) is predominantly formed. R

R

N

N Pd N

N Br

N Br

N

N

Pd Br

Br

R

N N Pd

R

R

N

N ⫹

N

N Pd

Br

N

N

N R

⫹

N

Pd

Br

N R

N

N R

⫹

N

Br

N R

N R

Figure 5.6 Conformational flexibility of transition metal carbene chelate complexes.

Chiral N-Heterocyclic Carbenes

285

Ph Ph Ph

N

Ph

N

N

I

N

Pd

N

N Pd

N

Ph

N

N

anti

N

I

N

N

I

I

Ph Ph Ph trans

cis

Ph

Ph N

N

Ph

N

I

N

I

N N

N

syn

Pd

N

N

Ph

Ph

Ph

Pd I

N

N

I

N

Ph

Ph

Figure 5.7 Stereoisomers of palladium(II) carbene complexes with unsymmetrical, chiral triazolinylidene ligands.

Note: The existence of several stereoisomers in the formation of these transition metal complexes makes their use in asymmetric catalysis reactions very problematic. Losses in chiral resolution seem to be almost unavoidable. We would like to introduce at this point a few examples of wingtip group chiral imidazolium salts that are somewhat outside the mainstream. Pelegri et al. synthesised a difenchyl imidazolium salt [43] that is modelled on a dicamphyl imidazolium salt introduced by Lee and Hartwig [44] (see Figure 5.8). Both synthetic routes are similar with Pelegri et al. starting from fenchone and Lee and Hartwig from (-)isopinocamphenylamine, both available from the chiral pool. Lee and Hartwig’s dicamphyl imidazolium salt readily forms the palladium(II) carbene complex that can be used in the enantioselective formation of oxindoles. The corresponding difenchyl imidazolium salts do not react in the same way. They do not form the free carbene upon reaction with a strong base and they do not subsequently form the transition metal carbene complex either. Instead, they can be induced to form

286

Functionalised N-Heterocyclic Carbene Complexes

H2NOH

NaNO2 H2N NH2

O

N

OH

N

N

NO2 N

NaBH4

N ⫹

N

HC(OEt)3

NH

HN

Figure 5.8 Synthesis of a difenchyl imidazolium salt from fenchone.

the corresponding piperazinone with ring extension (formally insertion of CO into the C2-N bond). Another interesting approach to an NHC ligand with a chiral, bridging wingtip group was introduced by Perry et al. [45] and uses enantiomerically pure 1,2-diaminocyclohexane as the scaffold. Reaction with chloroacetic acid chloride and subsequently with DIPP-imidazole yields the imidazolium salt that can be reacted with silver(I) oxide [46] to the respective silver(I) NHC complex. Subsequent carbene transfer to palladium(II) renders the chiral palladium(II) carbene transfer that can be used in catalysis (see Figure 5.9). Note: The chiral carbene ligand in Figure 5.9 has its asymmetric centres far removed from the carbene carbon atom (five bonds). This yields a transition metal carbene complex with remote chirality that cannot be expected to efficiently transfer the chiral information to a prochiral substrate resulting in low chiral resolution (% ee) of the product. The situation can be changed by bringing the chiral centres closer to the catalyst metal (Pd). The most facile way to achieve this is to change the tertiary amine groups to secondary ones. This opens up the coordination of the respective nitrogen centres to palladium(II) as amides replacing the chloro ligands [45] (see Figure 5.10). Note: The palladium(II) carbene complex now has the asymmetric carbon atoms in close proximity to the catalytically active metal centre. However, there are no readily available free coordination sites for a substrate. Provision of free coordination sites only becomes possible after Pd-N bond fissure, accompanied by loss of chiral information on the catalytic centre. Both approaches are clearly not the ideal solution for the generation of an efficient asymmetric catalyst. The main challenge is to bring the asymmetric carbon atoms closer to

Chiral N-Heterocyclic Carbenes O

O Cl H N

O

N

N H

N

⫹

N

⫹

N

DIPP

N

DIPP

N

N

Cl

Cl

287

N DIPP

N

N Cl O

O

Ag2O

N

O

N

DIPP

N

O

N

DIPP

N Cl

Pd

Cl

N

[Pd(NCMe)2Cl2]

Ag ⫹

N N

DIPP N

N

DIPP N

O

N

O

Figure 5.9 Synthesis of palladium(II) and silver(I) carbene complexes using a chiral carbene ligand derived from 1,2-diaminocyclohexane. O

O N

⫹

N

N

DIPP N

NH PdCl2/KOBut

DIPP

Pd N

N

NH N O

N

N ⫹

DIP HP

N

DIPP O

Figure 5.10 Synthesis of a palladium(II) carbene complex using a chiral carbene ligand derived from 1,2-diaminocyclohexane.

the catalytically active metal centre. A possible solution could be ring closure of a N,N’-dialkyl-1,2-diaminocyclohexane entity to the corresponding saturated imidazolidinium salt with chiral ring atoms in the cyclohexyl backbone [47] (see Figure 5.11). Now, the asymmetric carbon atoms are only three bonds away from the catalytic metal centre in a transition metal carbene complex. Note: The solution depicted in Figure 5.11 provides a monodentate carbene that has lost the chelate effect present in the two previous options (Figures 5.9 and 5.10).

288

Functionalised N-Heterocyclic Carbene Complexes

NH

N

HN

N

1) But

Cl Bu

Cl

But

t

S

O

Pd

Cl

But

Cl

2) Cl

Ph3P

[Pd(PPh3)4]

Cl O N

But

⫹

Cl

N

But

Figure 5.11 A monodentate chiral carbene based on 1,2-diaminocyclohexane.

This brings us to the field of saturated NHC ligands with chiral centres in C4 and C5 positions. As the synthetic routes are limited and enantiomeric purity vital, the main challenge is purification of the chiral precursor compound, usually 1,2-diaminoethane with one or two substituents on the carbon atoms of the ethylene bridge to render these carbon atom(s) asymmetric [34,48,49]. A second route, of course, is the use of the 1,2-diaminocyclohexane scaffold, already mentioned above, that has added convenience owing to commercial availability. A convenient method for chiral carbene complexes is provided by oxidative addition of a C-Cl bond of a suitable precursor to a transition metal centre like palladium(0) [50]. The method has of course limited scope, since not all transition metals have appropriate precursor complexes in low oxidation states. Advantage: Usually better chiral resolution (% ee) of the product compared with unsaturated NHC with chiral wingtip groups. Disadvantage: Usually forms weaker transition metal carbene complexes compared with unsaturated NHC with chiral wingtip groups. Both (1R,2R)-1,2-diaminocyclohexane and (1R,2R)-diphenylethylenediamine can be used as starting materials for C4,C5 asymmetric, saturated carbene precursors [48]. Buchwald–Hartwig amination [26] then renders the appropriate secondary diamine precursor [51,52] that can subsequently be treated with triethyl orthoformate to facilitate ring closure to the corresponding chiral carbene precursor. Figure 5.12 shows the synthetic route from a chiral vic-diamine to the corresponding second generation Grubbs’ catalyst. The popularity of (1R,2R)-1,2-diaminocyclohexane and (1R,2R)-diphenylethylenediamine as starting materials for these chiral imidazolium salts originates from their ready availability from commercial sources. The question remains to be answered as to whether a different substituent on the backbone (the substituent that makes the backbone chiral) improves the properties of the ligand and thus ultimately increases the chiral resolution in the product of asymmetric catalysis. No study has been proposed yet, probably because such a remote group is not expected to influence the performance of any

Ph Ph

Ph

Ph

Buchwald-Hartwig

Ph

Ph

HC(OEt)3

BrMes H2N

Mes

NH2

NH

HN

N

Mes

Mes

Ph

Ph

Ru

Cl

Cy3P Ru Cl PCy3 Cl

Mes N

Cy3P

Cl

Cl

Ru

N

Cl

Ph

N N

Mes Mes

Ph

Buchwald-Hartwig HC(OEt)3

N

⫹

N

Mes

BrMes

Mes

NH

HN

Mes

NH2

289

Figure 5.12 Synthesis of chiral second generation Grubbs’ catalysts from chiral 1,2-diamines.

H2N

Chiral N-Heterocyclic Carbenes

Ph

Cy3P Ru Cl PCy3 Cl

Mes

Mes

Ph

Mes Cy3P

N ⫹

290

Functionalised N-Heterocyclic Carbene Complexes

asymmetric catalysis on its own. What is expected to make a difference is the size of the wingtip group. Here, the rule of thumb is the bigger, the better. Unfortunately, the Buchwald–Hartwig amination all but fails for amines bulkier than mesitylamine [49]. An alternative synthesis, suitable for bulky wingtip groups, was introduced by Mercer et al. [53]. The key feature of the synthesis is the reductive dimerisation of a Schiff base by a base metal (manganese, magnesium or zinc) in the presence of trifluoroacetic acid (see Figure 5.13). Advantage: Sterically more demanding wingtip groups than mesityl can be introduced into the carbene alongside chiral centres in the backbone (C4 and C5). Disadvantage: The major product is the undesired meso isomer. Additionally the rac form (minor product) needs to be resolved into at least one pure enantiomer. Note: Cross-coupling (not described yet and not selectively possible with the present reducing agent) produces different wingtip groups and prevents the meso form. Since the synthetic route of modifying the chiral 1,2-diamine apparently does not result in a high yield protocol for an endocyclical chiral carbene with bulky wingtip groups, a different approach was needed. This was recently provided by Zinner et al. [49,54]. They took the other way round starting from the corresponding diimine (with the bulky wingtip groups already in place [55]) and proceeded to introduce central chirality in the C4 and C5 position of the imidazole ring system (before cyclisation with triethyl orthoformate) (see Figure 5.14). The Grignard reagent not only introduces chirality into the backbone (by addition of tert-butyl groups to the double bonds), but also holds the diimine in place (as a chelate template for the two imino donor functions). The first addition is racemic, but the second is determined by the first asymmetric centre by a 1,2-effect [56,57]. Chiral resolution of the racemic mixture is achieved as the tartrate (enantiomerically pure tartaric acid is easily available from the chiral pool) [58]. Fractionated crystallisation of the diastereomers and subsequent liberation of the purified chiral 1,2-diamine with NaOH affords the chiral carbene precursor in two separate enantiomers. The degree of enantiomeric purity in the diamine can be monitored by 31P-NMR spectroscopy [59]. For this purpose, the diamine is reacted with PCl3 and subsequently with Ph

Ph

(rac); minor DIPP

NH

DIPP

⫹

excess metal (Mn, Mg, Zn) N

HN

excess TfOH Ph

Ph

Ph

(meso); major DIPP

NH

HN

DIPP

Figure 5.13 Synthesis of N-substituted chiral 1,2-diamines by reductive dimerisation.

ClMgBut

ClMgBut

But N

N

DIPP

But (rac)

DIPP NH

DIPP

M

HN

DIPP PCl3 (+) menthol S8

(+/-) tartaric acid NaOH

But

But

But

But

DIPP But

DIPP

NH

HN

DIPP

NH

HN

DIPP

P

(R,R) But

(S,S)

S

O

N DIPP DIPP

different 31P-NMR chemical shifts

But

N

S P

(S,S)

O But

N

Chiral N-Heterocyclic Carbenes

(R,R)

DIPP

N

DIPP

291

Figure 5.14 Synthesis and chiral resolution of chiral 1,2-diamines.

292

Functionalised N-Heterocyclic Carbene Complexes

[+]-menthol. Oxidation of the phosphorus compound with sulfur (S8) affords an easy to handle phosphorus compound with an additional chiral centre in the menthol substituent (actually three chiral centres). The chiral menthol group turns the racemic diamine into a mixture of diastereomers that have different chemical shifts in the 31P-NMR spectrum. This enables monitoring of the progress in enantiomeric purification by 31P-NMR spectroscopy and ultimately provides a means to synthesise a great variety of enantiomerically pure 1,2-diamines that can be turned into enantiomerically pure carbene ligands with bulky wingtip groups. The corresponding transition metal carbene complexes are accessible by standard protocols [54]. So far, we have considered protocols that result in chiral centres in the C4 and C5 position (actually always with the same substituent). Let us now turn to saturated carbenes that have only one chiral centre in the backbone. Figure 5.15 shows a procedure that utilises a chiral diamine derived from proline, a naturally occurring α-amino acid. Reaction with aniline to the corresponding amide and reduction with LiAlH4 yields the diamine used [60]. The actual synthesis of the chiral carbene then calls for reaction of the proline derived diamine with thiophosgene and subsequent S/Cl exchange with oxalyl chloride [50]. The 2-chloro imidazoles can then be used to form transition metal carbene complexes via oxidative addition on the metal centre. Another interesting and more general methodology to a carbene with only one chiral carbon atom in the backbone was introduced by Hahn et al. [61] (see Figure 5.16). Here, an arylamine is treated with n-BuLi and carbon disulfide to the corresponding thiocarbonic acid amide. Second deprotonation with sec-BuLi and subsequent reaction with an asymmetrically substituted Schiff base affords the imidazolidinone that can be reduced with Na/K alloy to the respective carbene. Chirality is introduced via the prochiral N=C bond of the Schiff base and the product is usually a racemate since no chiral discriminator is present in the formative step. Another synthetic route starting from a natural α-amino acid involves the utilisation of (L)-valine [62] (see Figure 5.17). N-boc protected (L)-valine was reacted with 2-tertbutylaniline to form the corresponding amino acid amide. Subsequent deprotection and reduction of the carbonyl group with LiAlH4 affords the diamine that can be transformed into the dihydroimidazole by ring closure with triethyl orthoformate. Quarternisation of the imino nitrogen atom and generation of suitable transition metal carbene complexes can then be realised following standard protocols (see Chapter 1).

Cl Cl2C=S N H

HN

Ph

O N

N

S

Cl O N

Ph

⫹

N

Ph

Cl

Figure 5.15 Synthesis of an enantiomerically pure carbene precursor from a proline derived diamine.

Chiral N-Heterocyclic Carbenes

293 Ar

Ar 1) n-BuLi Ar N

1) s-BuLi

Ar

2) CS2

2)

R N Ar'

H

S

SLi

N

R

N

R'

Na/K S

N

N

R

:

R'

N

R' Ar'

Ar'

Figure 5.16 Synthesis of a chiral carbene with only one asymmetric centre in the backbone. 1) 2-But-aniline

O

2) hydrolysis

1) dry HCl

3) LiAlH4

NH2

HO NHBoc

2) HC(OMe)3 N

NH

N

HO(CH2)2X

N

N ⫹

HO

X

⫺

Figure 5.17 Synthesis of a functionalised carbene precursor using (L)-valine as the starting material.

Note: Although only valine was used as the amino acid component and no transition metal carbene complexes were reported by the original authors, this method can be seen as general, at least for amino acids without reactive functional groups in the sidechain. It is, of course, possible to combine endocyclic (asymmetric centres in the imidazole ring) with exocyclic (asymmetric centres in the wingtip groups) chirality. The easiest way to do this is to combine the major protocols for each variety within a common synthetic sequence. Figure 5.18 shows a selection of popular and more recent examples for this kind of chiral carbenes [54,63–69]. The list of examples is astonishingly short. Note: The chiral information of endocyclic chirality adds to the positive effect of exocyclic chirality. A chiral transition metal carbene complex used in asymmetric catalysis performs better with exocyclic and endocyclic chirality present than with only one of the two elements in its chiral carbene.

294

Functionalised N-Heterocyclic Carbene Complexes Ph

But

But

N

⫹

Ph

N

N

N ⫹

Ph Ph

Ph

Ph Ph Ph

N

⫹

Pri

N

Pri anti orientation of iso-propyl groups in transition metal NHC complexes

Figure 5.18 Imidazolium salts with endocyclic and exocyclic chirality.

Having explored NHC ligands with central chirality and asymmetric carbon atoms in endocyclic and/or exocyclic positions, we now turn our attention to NHC ligands that incorporate axial chirality and thus convey chirality to the transition metal via atropisomerism. The most popular backbone for axial chirality is the 1,1’-binaphthyl unit, first introduced to asymmetric catalysis by Noyori and coworkers [70–72]. The most popular ligands of this class are BINAP [71,72], a chelate phosphane, and BINOL [73], a diol. The binaphthyl system becomes chiral when the substituents in 1,1’-positions are sufficiently bulky to prevent rotation around the naphthyl-naphthyl vector. The phenomenon is known as atropisomerism [74]. We again witness the successful development of a functionalised carbene ligand following in the footsteps of a phosphane model. This time it is Rajanbabu and coworkers who made the transition from phosphorous to carbon [75]. The synthetic route is depicted in Figure 5.19. The methylene linker in the original Rajanbabu ligand makes the ligand too flexible with the result that a mixture of trans and cis isomers of the palladium(II) complex is obtained. Asymmetric catalysis with such a ligand system cannot result in high enantiomeric excess (% ee) in the product. Note: Chirality in the ligand is not sufficient. The chiral information has to be conveyed to the substrate via the transition metal complex. Here, rigidity of the ligand scaffold is also required. A more rigid ligand scaffold was provided by Shi and coworkers [76] and Peris and coworkers [77] that solved the problem of structural isomers encountered with the more flexible ligand.

Chiral N-Heterocyclic Carbenes

Br

NH

N

N

n

N

N MeI

n

295

⫹

N

n

NaH n Br

nN

nN

N

⫹

N

n ⫽ 0,1 [Rh(cod)Cl]2 NaOAc KI

[Pd(OAc)2]

N

N N

N n

O

I n Pd I

nN N

I

Rh

I O

n N N

Figure 5.19 Axial chiral bis-carbene ligands based on the 1,1’-binaphthyl scaffold.

Hoveyda clearly based his 1,1’-binaphthyl derived functionalised carbene not on BINAP, the phosphane, but on BINOL, the diol. By exchanging one hydroxy group with a carbene moiety, he arrived at a ligand system that provides axial chirality, a rigid metallacycle with chelate effect, and an anionic anchor point [6,78] (see Figure 5.20). The synthesis starts with ß-methoxynaphthene that is brominated with NBS. Reaction with menthol protected α-hydroxy-ß-naphthocarboxylic acid generated the 1,1’-binaphthyl scaffold. This is reduced to the amine accompanied by hydrolysis of the methoxy group. Subsequent reaction with a protected aminomethylene aldehyde and ring closure with triethyl orthoformate affords the functionalised saturated imidazolium salt. The corresponding second generation Grubbs’ catalyst can be synthesised from the preligand by reaction with silver(I) carbonate and carbene transfer to ruthenium. The stereodirecting effect of the axially chiral 1,1’-binaphthyl ligand is assisted by the bulky wingtip group of the carbene (Mes) and the additional substituents of the benzylidenyl ligand that features prominently in the Grubbs’ catalyst (see Figure 5.12). It is not strictly necessary to introduce the 1,1’-binaphthyl backbone. For axial chirality, the biphenyl scaffold is sufficient, provided that rotation around the phenyl-phenyl axis is sufficiently hindered. Hoveyda combined this reduced axial chiral motif with additional central chirality in the imidazole backbone (C4 and C5) [6,7]. Synthetically, the task is accomplished by Buchwald–Hartwig amination of enantiomerically pure (1R,2R)diphenylethylenediamine with 1-methoxy-1’-iodo-biphenyl and subsequent reaction with mesityl bromide to introduce the bulky wingtip group on the second amino group of the chiral starting material. Ring closure reaction with triethyl orthoformate and hydrolysis of

296

Functionalised N-Heterocyclic Carbene Complexes Br MeO

N N

CF3

⫹

1) ClCF2CO2Me 2) NBS

HO

Mes

O

CF3

O

MeO

O

I

H2N

CF3

O

HO

O MeO

CF3

Figure 5.20 Synthesis of a chiral hydroxy functionalised imidazolium salt on an axially chiral 1,1’-binaphthyl scaffold.

the methoxy group affords the axial and central chiral hydroxy functionalised imidazolium salt (see Figure 5.21). Note: The 1,1’-biphenyl and the 1,1’-binaphthyl scaffolds have the same steric influence on the transition metal (ruthenium) centre of the second generation Grubbs’ catalyst. Therefore, the improved chiral resolution in the product is likely due to a favourite combination of axial and central chirality. Note: This could be a rare example where the influence of axial chiral elements and central chiral elements is additive. It is often the case that axial and central chirality cancel each other at least partially. Note: The influence of the axial chiral 1,1’-biaryl scaffold on the chiral resolution of the product is not well understood and the outcome for a given substrate cannot be predicted with confidence. Rajanbabu and coworkers [75] and Hoveyda and coworkers [6,7,78] have used the 1,1’biaryl scaffold to mount the NHC unit on it (as well as the additional functional group to complete the necessary chelate motif). Another possibility is presented by starting from the

Chiral N-Heterocyclic Carbenes

297

MeO I

Ph NH2

OMe

Ph

H2N

H N Ph

H2N Ph

Ph

Ph

MesBr N

N

Mes 1) PBr3 2) HC(OEt)3 OMe

Ph

OH

H N

Mes N H Ph

Figure 5.21 Synthesis of a chiral hydroxy functionalised imidazolium salt on an axially chiral 1,1’-biphenyl scaffold.

corresponding 1,1’-diaminobiaryl compound (the diamino version of BINOL) [79–81]. There are two possible strategies, exocyclic derivatisation (exchange of the hydroxy groups of BINOL with amino groups) [79,80] (see Figure 5.22) and endocyclic derivatisation (hydrogenation of bipyridine) [81] (see Figure 5.23). There are several large differences between the two resulting classes of NHC. The exocyclic carbenes are embedded in a seven-membered ring system with exposed nitrogen atoms. These nitrogen atoms carry wingtip groups like those of standard NHC ligands. The endocyclic carbenes are part of five-membered ring systems similar to the NHC based on imidazole. However, the nitrogen atoms are part of the biaryl ring system and thus do not possess modifiable wingtip groups. They are sterically defined. The synthesis of the exocyclic variant starts with 1,1’-dinitrobiphenyl which is reduced to the corresponding diamine [79,80] (see Figure 5.22). Subsequent Hartwig–Buchwald amination introduces the mesityl wingtip group. Ring closure with triethyl orthoformate was not successful. The authors then proceeded to introduce the wingtip group by acylation (with pivaloyl chloride [82]) followed by reduction with LiAlH4. Ring closure with triethyl orthoformate then proceeded smoothly at elevated temperature and prolonged reaction time. Unfortunately, the authors did not elaborate on the reasons for failure to synthesise the azolium salt with mesityl wingtips. The next challenge encountered was the formation of the free carbene ligand which failed irrespective of the base and reaction conditions. In each case decomposition of the azolium salt was the only result. A similar observation was made for certain electron deficient annulated

298

Functionalised N-Heterocyclic Carbene Complexes

NO2

NH2 Pd/C; H2

O2N

H2N

NHMes Hartwig-Buchwald MesHN MesBr

1) Cl(O)CBut

X

2) LiAlH4

HC(OEt)3 But

But

N H H N

Mes

N HC(OEt)3

N

⫹

⫹

N But

N Mes

t

Bu

Figure 5.22 Synthesis of a carbene precursor with an axially chiral backbone. But But NH2 NH2

1) Cl(O)CBut 2 )LiAlH4

HC(OEt)3

N H H N

N ⫹

N But But

Figure 5.23 Synthesis of a carbene precursor with an axially chiral backbone made from 1,1’-binaphthyl.

imidazolium salts [83,84]. Attempts to synthesise transition metal carbene complexes with the azolium salt carrying neopentyl wingtip groups all but failed, although the formation of a silver(I) acetate adduct was reported [79], albeit the method of its formation remains unknown. The authors explain this failure to synthesise the transition metal complexes by insufficient steric protection of the carbene centre (respectively, the metal-carbene bond) from the neopentyl groups whose bulky tert-butyl group can rotate away from the metal. The same authors then proceeded to synthesise the corresponding azolium salt based on the 1,1’-binaphthyl scaffold (see Figure 5.23) [79]. The same failure to synthesise either the free carbene or transition metal carbene complexes from it was established experimentally. Electronic destabilisation by a double annulation effect from the two phenyl (naphthyl) rings on the seven-membered azolium ring system is indeed the most likely explanation.

Chiral N-Heterocyclic Carbenes

299

This is confirmed by a very similar homologous germylene compound [85] that has two annulated quinoxaline units on an eight-membered germylene ring system. There, the germanium centre is sufficiently electron deficient to ligate a chloride anion, i.e. it acts as an electrophile not as a nucleophile. Steric protection can be provided by adamantyl wingtip groups that are introduced by the reaction of the 1,1’-diaminobiphenyl to the Schiff base (with 2-adamantone) followed by reduction with LiAlH4 [79,80] (see Figure 5.24). Ring closure with triethyl orthoformate to the corresponding azolium salt proceeds as usual and subsequent reaction with [Pd(allyl)Cl]2 in the presence of a suitable auxiliary base (potassium tert-butylate) yields the respective palladium allyl complex. The palladium(II) allyl complex can then be reacted with hydrochloric acid to form the [Pd(NHC)Cl2] dimer. Subsequent reaction with a silver(I) salt predictably breaks up the dimer under chloride abstraction and anion transfer from silver to palladium. One might ask for the rationale behind destroying the versatile and useful (for catalytic reactions) palladium-allyl bond. Maybe it was to show that the Pd-NHC bond can stand up to these reaction conditions, especially inertness to basic conditions and no carbene transfer from palladium to silver (see above). The endocyclic variant starts its synthesis with bipyridine that is reduced by hydrogenation using Raney nickel as the catalyst [81,86]. It may not be too well known, but bipyridine is actually prochiral since the carbon atoms forming the py-py bond have three different substituents and addition to the C=N double bonds thus creates

Ad NH2 1) 2-adamantone 2) LiAlH4

H2N

N Ad HN

NH ⫹

HC(OEt)3

Ad

N Ad

Ad ⫽

Ad N

1) KOBut 2) [Pd(allyl)Cl]2

Ad

TfO Pd

OTf

N

Cl

Ad

OH2

N

Cl

Pd

Pd

Cl

N

AgOTf

Ad N

Cl

N Ad

Ad Ad N AgOAc

Ad N AcO

Cl

HCl

Pd N

Pd

OH2

Ad

OAc

N

(rac) Ad

Figure 5.24 Synthesis of a carbene precursor with an axially chiral backbone and reactivity of its palladium(II) allyl complex.

300

Functionalised N-Heterocyclic Carbene Complexes

an asymmetric carbon in each piperidine ring. Naturally, there is symmetry there and together with the two stereocentres that means three enantiomers, the rac form (R,R and S,S) and the meso form (see Figure 5.25). Separation is achieved by protonation with hydrobromic acid and subsequent fractionised crystallisation [87]. Liberation with NaOH yields the rac form that can be resolved into the constituting enantiomers by a method originally developed by Alexakis et al. for 31P-NMR monitoring of the chiral purification process [59]. The ligand system can also be assembled using the corresponding benzoannulated bipiperidine backbone [81] (see Figure 5.26). The annulation effect [88,89] operates on the saturated piperidine ring and thus affects the carbene unit only in a significantly mitigated form. The result is the accustomed large σ-donor strength of a NHC ligand rather than the almost electrophilic behaviour of the exocyclic variant (see above). Steric protection is completely unnecessary – and structurally impossible as the NHC is embedded into a structurally flexible piperidine system. Coordination to transition metals is facile and can be achieved using standard protocols. It should be noted that the rhodium(I) 1,5-cod adduct reacts with CO under substitution of the cyclic olefin, a reaction observed with other NHC ligand systems. Note: The endocyclic variant reacts like a normal NHC whereas the endocyclic counterpart shows distinct electronic destabilisation that normally results in decomposition (free carbene and transition metal complexes).

N

⫹

NH HBr

Raney-Ni

⫹

NH2

NH

NH2 NaOH

⫹

H2

N

NH

⫹

NH2

⫹

rac

meso

N

NH 1) HBr 2) NaOH

O

NH

N

⫹

S

P N

NH

rac

S

P N

NH

NH2

O (S,S)

1) PCl3 2) L-menthol 3) S8

NH

(rac)

Figure 5.25 Synthesis of a carbene precursor with an axially chiral backbone made from 1,1’bipiperidine and its chiral purification.

Chiral N-Heterocyclic Carbenes

⫹

NH2

NH2

Cl

N

N HC(OEt)3

⫹

301

Rh

[Rh(cod)Cl]2 N

N

⫹

CO

Cl

N

Rh

CO CO

N

Figure 5.26 Synthesis of a carbene precursor with an axially chiral backbone made from benzannulated 1,1’-bipiperidine and its rhodium(I) complexes.

Chirality can be introduced into a transition metal carbene complex not only by an asymmetric (carbene) ligand, but also by an unsymmetrical one. A nice example is given by Enders et al. [90], who coordinated an unsymmetrical triazolium NHC to a square planar rhodium(I) complex and obtained an axial chiral rhodium(I) carbene complex (see Figure 5.27). The axial chirality becomes possible due to the square planar geometry around the rhodium(I) centre. It provides two L-M-L vectors. In a square planar arrangement, image and mirror image are identical, because rotating the plane by 180˚ causes the image to be superimposed onto the mirror image. Having an unsymmetrical NHC ligand perpendicular to the plane breaks the symmetry, because the wingtip groups are no longer identical and thus not superimposable. The result is axial chirality. Note: The only requirements for axial chiral transition metal carbene complexes are an unsymmetric carbene and a suitable metal geometry (e.g. square planar). Note: Axial chiral transition metal complexes may yield racemic products owing to a transition state with unsuitable metal geometry (e.g. trigonal planar or square bipyramidal). Although axial chirality may be more widespread owing to the 1,1’-binaphthyl scaffold, planar chirality is plainly rising in general usage. The chief requirement is a planar scaffold and a discriminator between the obverse and the reverse of said plane. A convenient scaffold answering this simple definition is the well known ferrocene. With the obverse blank and the reverse a CpFe unit, only two different substituents on the same Cp ring

302

Functionalised N-Heterocyclic Carbene Complexes

Ph

Ph N

N

N

N Ph

Rh

N

Cl

Rh

N

Ph

Rh

Ph

N

N

Cl

N

Cl

Ph

Ph

Ph

Rh

Ph

N

N Cl

Cl

Rh N N

N

Rh Cl

N

N

Ph

Ph

Ph View along the axis of chirality olefin - Rh - NHC

Figure 5.27 Axial chirality in a square planar rhodium(I) carbene complex caused by an unsymmetrical NHC ligand.

are required to introduce planar chirality. If one of these substituents is a NHC moiety, then the ligand is a planar chiral carbene. Bolm et al. [91] and Togni and coworkers [8,9] synthesised examples of these ligands. Bolm et al. introduced a trimethylsilyl group adjacent to the carbene moiety on the ferrocene scaffold (see Figure 5.28) starting from a central chiral ferrocenyl tolyl sulfoxide (FcS(O)p-Tol). The ligand was then shown to perform typical NHC reactions. Reaction with elemental sulfur affords the corresponding thione and reaction with [Rh(codCl]2 and [Cr(CO)6] the rhodium(I) and chromium(0) carbene complexes, respectively. In each case, the chirality is retained, since the chiral centre – the planar chiral ferrocene scaffold – is not implicated in the reaction. Note: The rhodium(I) carbene complex in Figure 5.27 is not only planar chiral (in the ferrocene scaffold), but also axially chiral (in the rhodium coordination plane). Togni’s synthetic route to a planar chiral (trimethylsilyl group on ferrocene) and central chiral (asymmetric carbon in the NHC-Cp alkyl linker) carbene ligand starts from a central chiral aminomethyl ferrocene (see Figure 5.29) [9]. Lithiation and subsequent reaction with trimethylsilyl chloride introduces planar chirality on ferrocene. Quarternisation of the dimethylamino group with methyl iodide enables reaction with imidazole to the double Fc substituted imidazolium salt which can then be deprotonated to the free carbene with potassium tert-butylate.

Chiral N-Heterocyclic Carbenes

N

N N

303

N

:

N

N :

SiMe3

Me3Si

Me3Si

S

S8 Fe

Fe

Fe

Cr(CO)6

[Rh(COD)Cl]2

N

N

N Me3Si

N Me3Si

Cr(CO)5

Rh I

Fe

Fe

Figure 5.28 Planar chiral, Fc functionalised NHC ligands and their transition metal complexes.

NMe2

Fe

⫹

NMe2

1) t-BuLi 2) SiMe3Cl

SiMe3

NMe3 MeI

SiMe3

Fe

Fe

N

N

N

N

: SiMe3 Fe

⫹

NH

N

NaOBut SiMe3 Me3Si

Me3Si Fe

Fe

Fe

Figure 5.29 Synthesis of a planar and central chiral, Fc functionalised NHC ligand.

304

Functionalised N-Heterocyclic Carbene Complexes

Asymmetric catalysis with these central and planar chiral functionalised carbenes is usually hampered by a low chiral resolution of the product [3]. Naturally, it is possible to synthesise a similar ligand system without central chirality and in fact without the unnecessary methylene linker unit. A suitable synthesis starts with planar chiral ferrocenyl aldehyde acetal (see Figure 5.30). Hydrolysis and oxidation of the acetal yields the corresponding carboxylic acid that is transformed into the azide and subsequently turned into the respective primary amine functionalised planar chiral ferrocene. A rather complex reaction sequence involving s-triazine, bromoacetaldehyde diethylacetal and boron trifluoride etherate eventually yields the desired doubly ferrocenyl substituted imidazolium salt that can be deprotonated with the usual potassium tert-butylate to the free carbene. The ligand was used to form a variety of palladium(II) carbene complexes with pyridine or a phosphane as coligand. Another way to introduce planar chirality into a NHC ligand is the use of [2,2]-paracyclophane wingtip groups [10,11,92]. A convenient starting point is the enantiopure (Rp)-4,12dibromo[2,2]-paracyclophane [93,94] (see Figure 5.31). A long sequence of substitution reactions leads to the final product. First, one bromide is exchanged with a hydroxy group by reaction with n-BuLi and boronic acid trimethyl ester. Next, methyl iodide is used for the methylation to a methoxy group. Subsequently, the focus of attention is shifted to the second bromide substituent. Lithiation with n-BuLi and reaction with formaldehyde results in chain elongation by one methylene unit. Hydroxy to bromide exchange is effected by reaction with phosphorus tribromide. At this point, the [2,2]-paracyclophane unit is sufficiently transformed to represent a primary alkyl bromide that can be used to quarternise N-methylimidazole to the corresponding imidazolium salt with a planar chiral wingtip group using standard procedures. O O

O

O O

N3

OMe Fe Fe

N

Fe

⫹

Fe

NH2

N

Fe

Fe

Figure 5.30 Synthesis of a planar chiral, Fc functionalised NHC ligand.

Chiral N-Heterocyclic Carbenes

OMe

OMe

OMe

Br

305

N ⫹

N

Br Br

Br

Ph N

⫹

N

OMe

N

N

⫹

N

⫹

N

Ph

Ph

Figure 5.31 Synthesis of a planar chiral, [2,2]-paracyclophane functionalised NHC ligand.

It is easy to realise that the first part of the [2,2]-paracyclophane transformation protocol introduces an arbitrary auxiliary functional group. Instead of a methoxy group, the introduction of a phosphane [95], a phosphane oxide [11], an aryl or an alkyl group [10] can be realised. Modification of this general principle is possible. Ma et al. [10] have synthesised a symmetrical carbene incorporating two [2,2]-paracyclophane wingtip groups, some with additional substituents on the paracyclophane. These additional substituents do not only alter the solubility properties of the catalyst complexes, but also prevent rotation of the planar chiral wingtip group around the crucial C-N bond axis. This keeps the wingtip groups carrying the chiral information within a defined sector of the catalyst metal’s coordination sphere, a vital prerequisite for the transfer of chiral information from the ligand via the metal centre to the substrate and thus the product. Bolm and coworkers introduced an additional central chiral wingtip group (CHPhMe) onto the other side of the imidazole ring [11] in an attempt to increase the chiral resolution in the product of asymmetric catalysis. For this effect, they reacted phenyl boronic acid with 4-chlorobenzaldehyde to give the corresponding chiral diarylmethanol. Chiral resolution was modest at best with no clear trend as to the additive or competitive nature of the two chiral elements present in the ligand. Note: Two different chiral elements in the same ligand can either enhance or neutralise each other. Ma et al. [10] chose a different catalytic reaction to show the chiral inducement of the planar chiral [2,2]-paracyclophane functionalised NHC ligand. The rhodium(I) catalysed reaction between a boronic acid and the prochiral cyclohexenone results in the addition of the boronic acid’s substituent to the olefinic double bond of cyclohexenone (see Figure 5.32). In the present case, the product is (S)-3-phenylcyclohexanone with 61–98 % ee. The lowest chiral resolution is observed with the least hindered [2,2]-paracyclophane group. To summarise, a large variety of different chiral elements and chiral wingtip groups were used in the synthesis and application of chiral NHC ligands. No clear trend can be

306

Functionalised N-Heterocyclic Carbene Complexes 1) [Rh(acac)(C2H4)2] N

Ph

⫹

N

N

N

2) PhB(OH)2 c-hexanone Ph

Ph

Rh Ph

Ph

O O

N

N

Ph Ph

Rh

O Ph

Ph

Figure 5.32 Utilisation of a planar chiral NHC in the asymmetric catalytic reaction between boronic acids and cyclohexenone using a rhodium(I) complex.

seen in the factors determining good or excellent chiral resolution in the products of any asymmetric catalytic reactions where these ligands are employed. Generally speaking, exocyclic chirality seems to be better than endocyclic chirality in imidazole based carbenes. Both causes of chirality seem to be additive rather than cancelling each other, but the same is not the case for other combinations of chiral elements. Axial chirality, especially when based on the 1,1’-binaphthyl scaffold seems to be favourable in asymmetric catalysis. However, no prediction can yet be made for specific ligand/substrate combinations. For planar chirality, the only convincing example up to date is the use of [2,2]paracyclophane wingtip groups and here auxiliary substituents on the paracyclophane enhance the chiral resolution, probably due to an additional atropisomeric effect, hindrance of rotation around the C-N bond.

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308 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95.

Functionalised N-Heterocyclic Carbene Complexes

S. C. Zinner, W. A. Herrmann, F. E. Kühn, J. Organomet. Chem. 693 (2008) 1543. G. A. Grasa, M. S. Viciu, J. Huang, S. P. Nolan, J. Org. Chem. 66 (2001) 7729. J. Alvaro, F. Grepioni, D. Savoia, J. Org. Chem. 62 (1997) 4180. K. Bembridge, M. J. Begley, N. S. Simpkins, Tetrahedron Lett. 35 (1994) 3391. E. J. Corey, D.-H. Lee, S. Sarshar, Tetrahedron: Asymmetry 6 (1995) 3. A. Alexakis, J. C. Frutos, S. Mutti, P. Mangeney, J. Org. Chem. 59 (1994) 3326. Organikum, 15th edition, VEB Deutscher Verlag der Wissenschaften, Berlin, 1984. F. E. Hahn, M. Paas, D. Le Van, T. Lügger, Angew. Chem. Int. Ed. 42 (2003) 5243. H. Clavier, L. Boulanger, N. Audic, L. Toupet, M. Mauduit, J.-C. Guillemin, Chem. Commun. (2004) 1224. J. Pytkowicz, S. Roland, P. Mangeney, J. Organomet. Chem. 631 (2001) 157. C. L. Winn, F. Guillen, J. Pytkowicz, S. Roland, P. Mangeney, A. Alexakis, J. Organomet. Chem. 690 (2005) 5672. F. Guillen, C. L. Winn, A. Alexakis, Tetrahedron: Asymmetry 12 (2001) 2083. A. Alexakis, C. L. Winn, F. Guillen, J. Pytkowicz, S. Roland, P. Mangeney, Adv. Synth. Catal. 345 (2003) 345. J. Pytkowicz, S. Roland, P. Mangeney, G. Meyer, A. Jutand, J. Organomet. Chem. 678 (2003) 166. J. Pytkowicz, S. Roland, P. Mangeney, Tetrahedron: Asymmetry 12 (2001) 2087. F. Grisi, C. Costabile, E. Gallo, A. Mariconda, C. Tedesco, P. Longo, Organometallics 27 (2008) 4649. P. Kocovsky, S. Vyskocil, M. Smrcina, Chem. Rev. 103 (2003) 3213. R. Noyori, Angew. Chem. Int. Ed. 41 (2002) 2008. R. Noyori, H. Takaya, Acc. Chem. Res. 23 (1990) 345. Y. Chen, S. Yekta, A. K. Yudin, Chem. Rev. 103 (2003) 3155. E. Eliel, S. H. Wilen, Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1993. D. S. Clyne, J. Jin, E. Genest, J. C. Gallucci, T. V. Rajanbabu, Org. Lett. 2 (2000) 1125. W.-L. Duan, M. Shi, G.-B. Rong, Chem. Commun. (2003) 2976. M. Albrecht, R. H. Crabtree, J. Mata, E. Peris, Chem. Commun. (2002) 32. J. J. Van Veldhuizen, D. G. Gillingham, S. B. Garber, O. Kataoka, A. H. Hoveyda, J. Am. Chem. Soc. 125 (2003) 12502. C. C. Scarborough, B. V. Popp, I. A. Guzei, S. S. Stahl, J. Organomet. Chem. 690 (2005) 6143. C. C. Scarborough, M. J. W. Grady, I. A. Guzei, B. A. Gandhi, E. E. Bunel, S. S. Stahl, Angew. Chem. 117 (2005) 5403. W. A. Herrmann, D. Baskakov, E. Herdtweck, S. D. Hoffmann, T. Banlaksananusorn, F. Rampf, L. Rodefeld, Organometallics 25 (2006) 2449. B. Gehrhus, M. F. Lappert, J. Heinicke, R. Boese, D. Bläser, Chem. Commun. (1995) 1931. O. Kühl, S. Saravanakumar, F. Ullah, M. K. Kindermann, P. G. Jones, M. Köckerling, J. Heinicke, Polyhedron 27 (2008) 2825. S. Saravanakumar, M. K. Kindermann, J. Heinicke, M. Köckerling, Chem. Commun. (2006) 640. O. Kühl, P. Lönnecke, J. Heinicke, New J. Chem. 26 (2002) 1304. F. Blau, Monatsh. Chem. 10 (1889) 375. Y. N. Forostyan, E. I. Efimova, I. I. Soroka, Zh. Org. Khim. 7 (1971) 2198. O. Kühl, K. Lifson, W. Langel, Eur. J. Org. Chem. (2006) 2336. F. Ullah, O. Kühl, G. Bajor, T. Veszpremi, P. G. Jones, J. Heinicke, Eur. J. Inorg. Chem. (2009) 221. D. Enders, H. Gielen, J. Runsink, K. Breuer, S. Brode, K. Boehm, Eur. J. Inorg. Chem. (1998) 913. C. Bolm, M. Kesselgruber, G. Raabe, Organometallics 21 (2002) 707. T. Focken, G. Raabe, C. Bolm, Tetrahedron: Asymmetry 15 (2004) 1693. H. J. Reich, D. J. Cram, J. Am. Chem. Soc. 91 (1968) 3527. K. Rossen, P. J. Pye, A. Maliakal, R. P. Volante, J. Org. Chem. 62 (1997) 6462. T. Focken, G. Raabe, C. Bolm, Tetrahedron: Asymmetry 15 (2004) 1693.

6 Natural Products

In this chapter, we will focus on three groups of NHC that are either generated from natural products like caffeine or thiamine or use starting materials that are the active centre of enzymes like thiazole in thiamine or are important building blocks in biopolymers like amino acids.

6.1 Thiazole The nonannulated parent compound thiazole has been implicated as the active centre of the naturally occurring enzyme thiamine (vitamin B1) [1,2]. It catalyses the decarbonylation of pyruvic acid to acetaldehyde and the benzoin condensation of aromatic aldehydes [3]. The mechanism of this reaction was first described by Breslow as early as 1958 [4]. Subsequently, the natural enzyme thiamine, found in yeast, was replaced by related nucleophiles like thiazole [5,6], triazole [7] and imidazole [8]. Reactions that follow this mechanism include the very important Stetter reaction (the benzoin condensation of aliphatic aldehydes), the Michael–Stetter reaction (a variant of the Stetter reaction where the aldehyde reacts with an α,β-unsaturated ketone) [1], transesterifications [9] or the acylation of alcohols [9,10]. All four reactions are carbene catalysed nucleophilic acylation processes. Note: NHC can be used as organocatalysts in carbene catalysed nucleophilic acylation processes. Note: The benzoin condensation is a condensation reaction of aromatic aldehydes catalysed by strong nucleophiles. Note: The Stetter reaction is a benzoin condensation using aliphatic aldehydes. Functionalised N-Heterocyclic Carbene Complexes. Olaf Kühl © 2010 John Wiley & Sons, Ltd.

310

Functionalised N-Heterocyclic Carbene Complexes

Note: The Michael–Stetter reaction is a benzoin condensation between an aliphatic aldehyde and an α,β-unsaturated ketone. Of great interest is the asymmetric variant of these reactions using chiral organocatalysts [11]. This interest was aroused very early since the product of the benzoin condensation, namely benzoin itself, first described by Wöhler and Liebig [11], carries a new asymmetric carbon atom (see Figure 6.1). Early attempts to use chiral thiazolium salts resulted in poor to medium ee and rather poor yields [11]. The strategy for the introduction of the asymmetric centre invariably positioned the chiral carbon atom on the N-sidechain, preferably directly adjacent (vicinal) to the nitrogen atom of the thiazole ring (see Figure 6.2). Such a strategy is of course rather obvious as it places the chiral centre closest to the reactive centre of the organocatalyst (the C2 atom of the thiazole ring). Note: Thiamine is not a chiral molecule. However, in yeast it is embedded in a chiral environment, a protein and thus can act as an asymmetric catalyst. The first asymmetric thiamine analogue, introduced by Sheehan in 1966, had the asymmetric carbon atom further removed from the thiazole ring [12] featuring a poor ee of only 2%. Moving the asymmetric centre directly adjacent to the nitrogen atom of the

R1 N

R2

H

S R3

Ph

-H

O

*

OH

R1

Ph

N

R2

: R1 O N

R2

PhCHO, H

S

R1

R3

Ph

H

N

R2 OH

S R3

OH

Ph

Ph

S R3

R1 PhCHO

Ph N

R2

OH S R3

Figure 6.1 The mechanism of the benzoin condensation according to Breslow [1,4].

Natural Products

311

O N

NH2 O

N

* Ph

*

N

N

H

S

HO

N

H

S

H

S

* *

*

*

*

N N

N

S

H

S

S

Figure 6.2 Structures of asymmetric organocatalysts derived from thiazole.

thiazole ring increased the ee to up to 52% as expected, but at the price of a sharp drop in the yield to a meagre 6% [13]. Subsequently, the yield could be improved to 48% [14] making the reaction viable as an asymmetric catalyst. Using a menthyl group on the thiazole ring increased the yield at the time to 20%, but at the expense of chiral resolution which dropped to 20% ee [15]. Research in the asymmetric benzoin condensation was clearly temporarily at a dead end with both ee values and yield fluctuating around somewhat mediocre numbers and no clear trend to optimise either. Introduction of the diamino cyclohexane scaffold, usually favoured in the effectiveness of chiral ligand architecture, did not yield the desired result as manifested by an ee of only 27% and a poor yield of 21% [16]. Note: The benzoin condensation is a carbene catalysed nucleophilic acylation process. Note: Increased nucleophilicity on the carbene carbon atom should improve the feasibility of the benzoin condensation. The Enders research group realised that an increased nucleophilicity on the carbene carbon atom would improve the benzoin condensation overall and might give the necessary impetus to break the apparent deadlock by initially increasing the yield and in its wake the chiral resolution. This was achieved by switching to triazole based NHC instead of the less nucleophilic thiazole based NHC (see Figure 6.3) [17–19]. The scheme proved to be successful as an ee of 75% (R) in 66% yield and a catalyst loading of 1.25 mol% could be achieved,

312

Functionalised N-Heterocyclic Carbene Complexes Ph Ph

N N

Ph

H

N

N

Ph

N

H

N N

N O

H

N

O

O

Figure 6.3 Some triazolium based chiral organocatalysts.

although ee and yield varied hugely with only small changes of substituents indicating that the steric and electronic factors governing yield and chiral resolution of this reaction were only poorly understood at the time. Note: The order of nucleophilicity is: thiazole < imidazole < triazole derived NHC.

Note: The order of acidity is: triazolium > thiazolium > imidazolium. Note: A chiral triazolium salt leads to higher yield and greater enantioselectivity than a chiral thiazole [20]. It is only a small step from the asymmetric benzoin condensation to the asymmetric Stetter reaction, the aliphatic variant of the benzoin condensation. The literature refers to the Stetter reaction when at least one of the two reactants is an aliphatic aldehyde. Normally, the reaction is performed as a cross-coupling reaction with two different reactants, one of which is not an aldehyde, but an α,β-unsaturated ketone. Strictly speaking, most thiazole catalysed reactions referred to as Stetter reactions are in fact Michael–Stetter reactions [21,22] (see Figure 6.4). The reaction received the name because Stetter used a Michael reagent, an acceptor with an activated double bond, as the second component of a crosscoupled Stetter reaction [11]. In an asymmetric Michael–Stetter reaction, the activated double bond is prochiral leading to a product with a new asymmetric centre. Enders first attempt to react butanal with a chalcone resulted in only 4% yield, but an ee of 39% [25] (see Figure 6.5). The steric concept was certainly valid, but the electronic properties clearly in want of improvement. Despite significant efforts to improve the yield and chiral resolution of the thiazolium catalysed asymmetric Michael–Stetter reaction, catalytic activity remained at the same dissatisfying low level [11]. A possible reason could be the irreversible reaction of the catalyst

Natural Products

313

O OSiR3

Ph

Ph Cy

O

*

N

*

N

H

O

* N

H

S

H

Ph N

S S

S

S

N

H

S

H

But N

But

Figure 6.4 Some thiazolium salts used in the Michael–Stetter reaction [11,23,24]. Ph

N

Ph

S

O

O

H

H

Ph

Ph

*

K2CO3

O

Ph

O

Figure 6.5 An asymmetric Michael–Stetter reaction using a chiral thiazolium salt as organocatalyst [11].

with the substrate to form stable adducts, a process that is known as catalyst poisoning in Organometallic Chemistry. This catalyst deactivation route could be shown for some closely related triazol-5-ylidenes [26] (see Figure 6.6). A possible route out of this apparent dilemma was shown by Enders et al. [27] in adapting the protocol of Ciganek [28] to an asymmetric intramolecular Stetter reaction. Favourable entropic effects result in increased yields and thus in an overall significantly improved reaction. Although initial studies were focused on triazolium based catalysts [11,29,30], the development of thiazolium based catalysts was not neglected [31]. An interesting new development came with the realisation of Miller that a range of enantioselective reactions for which peptides based on the imiodazole sidechain of histidine were used as organocatalysts could possibly serve as a model for the asymmetric intramolecular Michael–Stetter reaction as well [32]. To this end, Miller synthesised thiazole based peptidemodified organocatalysts that can be described as having a thio-histidine as the crucial amino acid (see Figure 6.7). The respective amino acid was reported as thiazolylalanine (Taz).

314

Functionalised N-Heterocyclic Carbene Complexes O O H[NHC]

H

CO2R2

1

R

base

R1

CO2R2

X

X X O, S, NMe

OMe H[NHC]

Ph N N N N

Ph N N

H

H

N

H

N

N Bn

Ph O

O

O

Figure 6.6 An asymmetric intramolecular Michael–Stetter reaction using triazolium based organocatalysts. H

OMe

N Ts O

S N

H

O R

* R2

H N

N H

R1

NHBoc

N R3

O O

N

S

S N

H

R4 H

Figure 6.7 Thiazole modified peptides as organocatalysts for the asymmetric intramolecular Michael–Stetter reaction.

Natural Products

315

Thiazolylalanine itself gave good enantioselectivity of up to 60–70% ee and poor to mediocre yield of 10–40%. Placing the thiazole group at the C-terminus of the short peptide chain reduced the enantioselectivity of the reaction, but the nature of the C-terminus amide played no major role. Significant improvement of yield (up to 67%) under retention of enantioselectivity (65–80%) could be achieved, when the thiazolylalanine group was incorporated into the middle of a short peptide chain [24,32]. The reaction depicted in Figure 6.6 could then be carried out with 13–45% yield and ees of about 70%.

6.1.1 Isolation and Stability of Thiazolylidene Although in situ generated thiazolylidene was used as an organocatalyst in benzoin condensation for decades and by yeasts since time immemorial, isolation of the first free thiazolylidene was achieved as late as 1996 by Arduengo et al. [2]. The differences to imidazolium derived NHC manifest themselves in the different properties introduced by the sulfur atom compared with the nitrogen atom. Sulfur is larger, disturbs the ring geometry and diminishes the pπ-pπ interactions between the heteroatom and the carbene carbon atom. It also carries no exocyclic substituent and thus can provide no steric shielding of the carbene centre. Thiazol-2-ylidenes are less well studied than their imidazole and triazol analogues. Only one isolated and structurally characterised example is known in the literature, the 3-(2,6-diis opropylphenyl)thiazol-2-ylidene synthesised by Arduengo et al. in 1997 [2] (see Figure 6.8). The parent compound, 2,3-dihydrothiazol-2-ylidene, was generated in an argon matrix at 10 K from thiazol-2-carboxylic acid as the starting material [33] (see Figure 6.9). Photochemical decarboxylation results in the formation of 2,3-dihydrothiazol-2-ylidene which reverts back to its thermodynamically stable isomer thiazol either under prolonged radiation at 250–420 nm or upon warming. The reactivity of the room temperature stable NHC 3-(2,6-diisopropylphenyl)thiazol2-ylidene is more interesting. Whereas imidazole derived NHC do not undergo reversible dimerisation, the thiazol NHC shows an acid catalysed monomer–dimer equilibrium at ambient temperature indicating that the stability of 3-(2,6-diisopropylphenyl)thiazol2-ylidene is just sufficient to exist in the monomeric form [2] (see Figure 6.10). It is the first monomer–dimer equilibrium observed for any NHC. The analogous 1,3-diphenyl-imidazol2-ylidene, described by Wanzlick as a dimer [34], was synthesised as a monomer by

S

N

Cl H

S :

KH -KCl / - H2

Figure 6.8 Synthesis of the first thiazol-2-ylidene.

N

316

Functionalised N-Heterocyclic Carbene Complexes H

H O

N

S

N

N

hν 254nm

hν 250-420nm

H

: S

S

O

Figure 6.9 Generation of 2,3-dihydrothiazol-2-ylidene in an argon matrix.

Pri Pri

Pri

Pri N :

2 S

N

S

S

N

[H]

Pri Pri

Figure 6.10 Acid catalysed monomer–dimer equilibrium of 3-(2,6-diisopropylphenyl) thiazol-2-ylidene.

Arduengo [35]. Some NHC derived from benzimidazole have since been found to undergo a similar equilibrium [36]. Note: Thiazol-2-ylidenes, although stable at ambient temperatures, readily dimerise reversibly to the respective electron-rich olefin. How close the stability of the monomeric 3-(2,6-diisopropylphenyl)thiazol-2-ylidene actually is at its dimerisation limit was demonstrated by Arduengo et al. in an attempt to synthesise the less bulky 3-(mesityl)thiazol-2-ylidene. When the monomer was generated at low temperatures using ButOK as the base, it dimerised at temperatures above 0°C in solution, whereas synthesis at ambient temperature using KH [same reaction conditions as for 3-(2,6-diisopropylphenyl)thiazol-2-ylidene] resulted in the dimer exclusively [2]. With a methyl group on the nitrogen atom, the intermediate carbene monomer could no longer be unequivocally detected even at low temperatures.

Natural Products H

R

Ph

Ph

:

R KOBut

N Ph

317

N

S

Ph ClO4

S

R Me, H, NO2

Figure 6.11 Syntheses of (2-aryl-4,5-diphenyl)isothiazol-3-ylidenes.

Recently, Schulze and coworkers synthesised a group of (2-aryl-4,5-diphenyl)isothiazol-3ylidenes (see Figure 6.11) by deprotonation of the respective isothiazolium perchlorates with ButOK as base [37]. The compounds are yellow solids that dimerise readily and show typical carbene reactions like insertion into NH bonds. The tendency to dimerise follows the known electronic properties of substituents on the phenyl ring on nitrogen (o-methyl thiazol-2-ylidene > imidazol-2-ylidene.

6.1.2 Benzothiazoles There are no examples of isolated and characterised stable benzothiazol-2-ylidenes found in the literature. That is not surprising since benzo-annulation decreases the stability of the free NHC [38] and thus facilitates dimerisation. As the nonannulated thiazole system is already prone to dimerisation, benzothiazol-2-ylidene can be expected to require very considerable steric shielding to make the isolation of the monomeric NHC possible. Thus, benzothiazolium salts are mainly used to synthesise the respective transition metal carbene complexes rather than the free ligands.

6.1.3 Metal Complexes Given that thiazole is the active centre in vitamin B1, thiamine has been the centre of intense research of its organocatalytic potential for decades; it might be surprising that only very few examples of transition metal NHC complexes are known that use thiazol-2-ylidene or its benzo-annulated analogue benzothiazol-2-ylidene. As we have seen above, one major reason is the instability of the free carbene leading to dimerisation instead. Another major contribution is the apparent inability of thiazol-2-ylidene to coordinate to silver(I) [39] making carbene transfer from silver salts to other transition metals impossible. Note: The most popular route to transition metal NHC complexes, the Ag2O method, is not available for thiazole and benzothiazole.

318

Functionalised N-Heterocyclic Carbene Complexes

Instead, only two reaction pathways are used to generate transition metal NHC complexes with thiazol-2-ylidene or benzothiazol-2-ylidene: (i) thermal cleavage of an electron-rich olefin in the presence of a suitable transition metal (see Figure 6.12) [40,41]; and (ii) deprotonation of a thiazolium or benzothiazolium salt in the presence of a transition metal (see Figure 6.13) [40,42–44]. The thermal route has little control over the outcome of the reaction in terms of the possible isomers (cis, trans) and is limited to those transition metal precursors that readily withstand the harsh reaction conditions. It does not have the potential for a general synthetic route. Calò et al. have reported a mixture of 12% cis isomer and 80% trans isomer using the deprotonation route [42]. Heating of the cis isomer in dimethyl acetamide (DMA) at 100°C afforded the trans isomer within 90 min indicating that the trans isomer is the thermodynamically preferred isomer. Raubenheimer et al. have developed a third route for transition metal NHC complexes with thiazol-2-ylidene, benzothiazol-2-ylidene and even isothiazol-5-ylidene ligands [45–49]. This method uses a thiazolyl transfer from lithium to a transition metal with subsequent protonation [47,49–54] or alkylation [41,45,46,48,51–56] of the nitrogen atom to generate the transition metal NHC complex. In this way, carbene complexes of copper(I) [41,45] (see Figure 6.14), gold(I) [46,50–53,55,56], iron(II) [47,54], group 6 metals(0) [48] and manganese(0) [49] could be obtained. Note: With copper(I) only the N-methylated complexes were stable, whereas protonation occurred at the C 2 carbene carbon atom. Whereas copper(I) thiazol-2-ylidene complexes are monocarbene and linear complexes that can form weak dimers in the solid state, the analogous gold(I) complexes could be synthesised as linear mono- or bis-carbene complexes. Since the metal requires a monoanionic ligand to balance its one positive charge, monocarbene complexes are normally neutral whereas the corresponding bis-carbene complexes are ionic. Partial protonation

N N S Et3P M Cl

N

Cl

Cl M Cl

S

T

S

M

PEt3 Cl

Cl

PEt3 N

M Pt, Pd S

M Cl

Cl PEt3

Figure 6.12 Thermal cleavage of an electron-rich olefin to form a transition metal benzothiazol2-ylidene complex.

Natural Products

319

N

2

H

Pd(OAc)2

S

N

S

N

Pd I

I

N

S

S

Pd

I

S

I N

Figure 6.13 Formation of a transition metal NHC complex by deprotonation of a benzothiazolium or thiazolium salt. N

N Li CuCl S

Li

N Cu

Cl

CF3SO3Me

S

Cu

Cl

S

Figure 6.14 Synthesis of copper(I) thiazol-2-ylidene complexes.

results in a neutral complex and full protonation in a cationic gold moiety whereas in the absence of protonation, the gold moiety is anionic but without carbene ligands [46] (see Figure 6.15). Note: In the gold(I) complexes in Figure 6.15, the carbene content can be controlled by the amount of acid added. Using the same synthetic route, Raubenheimer et al. could also prepare the analogous isothiazol-5-ylidene complexes of gold(I) [53] (see Figure 6.16). The reaction of [CpFe(CO)2Cl] with lithium isothiazol and subsequent methylation (protonation) with CF3SO3Me(H) to the respective isothiazol-5-ylidene complex of iron(II) follows the already familiar route [54]. The protonation of the thiazolyl ligand is so facile that it can even occur when cyclopentadiene is used as the ‘acid’ [47] (see Figure 6.17). Note the N-H-N hydrogen bond between the two benzothiazol ligands. An interesting sequence is the reaction between (benzo)thiazollithium and transition metal carbonyl complexes. As we have already seen in the case of Fe(II) [54], the

320

Functionalised N-Heterocyclic Carbene Complexes

N

N

N 2

[Au(tht)Cl]

Li

Au

Li

S

S

S

H

2HPF6

H

N

NBu4Br

N

N PF6

Au S

HCl

NBu4

N Au

S

S

S

H N

N Au

S

S

Figure 6.15 Influence of protonation on the gold(I) complex.

N 2

S Li

[Au(tht)Cl]

N

S

S

N

Au

Li

R H, Me

R N

2CF3SO3R

S

S Au

R N

CF3SO3

Figure 6.16 Formation of isothiazolyl and isothiazol-5-ylidene complexes of gold(I).

presence of a metal-halide bond facilitates the replacement of the halide by the thiazolyl moiety. This not only works for [CpFe(CO)2Cl], but equally well for [Mn(CO)5Br] [49]. However, reaction of [M(CO)5THF] (M = Cr, Mo, W) with aryllithium would normally result in the formation of Fischer carbene type complexes [48]. In the case of thiazollithium this is not the case. Instead, the substitution product is formed and N-methylation results in the generation of the carbene complex. When [Cr(CO)5THF]

Natural Products

321

FeCl2

Ph2P

PPh2

N

S

S

N

H

Cp

N Li

2 S

Fe

N

N

Fe

PPh2 PPh2

Ph2P S

S Ph2P

Figure 6.17 Synthesis of an iron(II) benzothiazol-5-ylidene complex using cyclopentadiene as the protonating agent.

is reacted with 4-methyl-thiazol, coordination to the metal occurs through the nitrogen atom and subsequent methylation results in 5(C)- and 3(N)-methylation of the thiazol ring (see Figure 6.18). Note: This reaction can serve as an alternative to the thermolysis of electron-rich olefins, in this case the dimers of thiazol-2-ylidene and benzothiazol-2-ylidene, developed by Lappert et al. [57,58]. [M(CO)5THF] N

N Li M = Cr, Mo, W

S

S

N

Cr(CO)5

N

M'(CO)5 S

S

1) BuLi

CF3SO3Me

M' = Mo, W

2) CF3SO3Me

N

N

N

M('CO)5 S

Cr(CO)5

+ S

Cr(CO)5 S

Figure 6.18 Reaction of [M(CO)5THF] (M = Cr, Mo, W) with 4-methyl-thiazollithium.

322

Functionalised N-Heterocyclic Carbene Complexes NC

N Li S

SLi

Figure 6.19 Equilibrium between the cyclic and acyclic form of 4,5-dimethyl-thiazollithium.

Note: Using lithiated thiazoles or benzothiazoles can result in low yields of the carbene complex precursor due to an equilibrium between the cyclic and acyclic forms [59] (see Figure 6.19). Utilisation of transition metal benzothiazol-2-ylidene and especially thiazol-2-ylidene complexes in homogenous catalysis reactions are very rare [42–44]. Calo et al. reported the use of bis-(3-methyl-benzothiazol-2-ylidene) palladium diiodide in the Heck reaction of aryl bromides and iodides with a catalyst loading of down to 10–4 mol% and near quantitative yields [42,44].

6.2 Amino Acids Amino acids are the monomers from which nature produces proteins and enzymes. As such, they form an important part of the chiral pool. Histidine contains an imidazole ring in the sidechain and thus is a logical target for the synthesis of functionalised and chiral NHC. Given that a primary amine, as found in natural amino acids, is a prerequisite for standard imidazole ring forming reactions [60], it is surprising that only a few protocols are found in the literature where an amino acid [61–66] or its respective alcohol [64,67] forms part of a reaction that leads to a carbene precursor. Hannig et al. used C- and N-protected histidine to synthesise a chiral imidazolium salt by quarternisation of the two ring nitrogen atoms with alkyl halides [63] (see Figure 6.20). Note: Alkylation of the imidazole ring with Meerwein’s salt results in the racemisation of the remote chiral centre in the backbone. Note: The protected histidine imidazolium salts have melting points of 39 and 55°C, respectively, qualifying them as chiral ionic liquids [63]. The n-propyl derivative was used as a chiral reaction medium (ionic liquid) to react αnaphthol with ethyl pyruvate in the presence of the Lewis acid CpZrCl3 resulting in a racemic mixture of products (see Figure 6.21). Apparently the chiral centre in the histidine backbone of the ionic liquid has no bearing on the steric situation around the active centre of the catalytic reaction. Disadvantage: The chiral centre of this histidine derived carbene precursor is in the backbone and thus too far removed from the carbene carbon atom to influence the outcome of a catalytic reaction.

Natural Products

323

O Br

2

MeO N

Ph

NH O

H

N

Br

O MeO N

Ph

NH N

O

O H

MeO N

Ph

NH I 2

H

N

I

O

Figure 6.20 Synthesis of a chiral imidazolium salt from the amino acid histidine.

O MeO Ph

OH O

O

N NH

O

H N Br

O OH O OH

+ O

CpZrCl3

rac

Figure 6.21 Hydroxyalkylation of α-naphthol with ethyl pyruvate in a chiral ionic liquid to a racemic product.

A second approach to incorporate the imidazole ring of histidine into a NHC ligand was proposed by Garrison et al. [61]. Here, the histidine would be the N-terminus of a peptide chain and already carries a substituent on the secondary amine nitrogen atom of the imidazole ring. Quarternisation with a pyridyl imidazolium salt by virtue of a pendant alkyl halide functional group is envisaged to generate the bis-imidazolium salt that can act as a C-N-C pincer ligand (see Figure 6.22). A model complex was actually synthesised, but in this model complex the peptide linker that would eventually carry the pharmaceutically relevant targeting group (TG) was replaced by an alkyl group. The validity of the peptide approach could not be proven. This experimental proof comes from the group of Meldal. This research group created a peptide embedded bis-imidazolium salt as a precursor for chelating bis-carbene

324

Functionalised N-Heterocyclic Carbene Complexes N N

N

N I

O

NH2

N

N

N

BPh4 NH

I

N

N

N

TG

R O TG: Targeting Group (formedical applications)

BPh4

NH2 NH

TG

Figure 6.22 Formation of a C-N-C pincer ligand from histidine.

ligands [62]. The strategy is essentially a solid-phase Merrifield synthesis whereby the imidazolium salt is introduced into the growing peptide chain as a bis-functionalised imidazolium salt with a carboxylic acid and a primary amine terminus. The primary amine was generated by reducing an azide group (see Figure 6.23). Advantage: Generation of a chiral pocket around the catalytically active metal centre. Advantage: The chiral pocket can easily be modified. Disadvantage: Multi-step synthesis of the bis-functionalised imidazolium salt. Disadvantage: Chiral centres removed from the carbene carbon atom and thus the catalytically active metal centre. Advantage: The NHC precursor is already immobilised on the Merrifield resin, but can readily be liberated. The key disadvantage of the three approaches presented in Figures 6.21–6.23 is the remoteness of the chiral centres from the C2-coordinated metal atom, the active centre in catalytic processes. Meldal and coworkers might have found an answer to this challenge by embedding their carbene ligands into a peptide chain. This approach is reminiscent of the coenzyme thiamine which is likewise embedded in a highly chiral protein providing a chiral environment. Bringing the chiral centre closer to the carbene carbon atom would mean making the carbon atom adjacent to the ring nitrogen atoms on the imidazole ring asymmetric (see Figure 6.24). There are two options: exocyclic or endocyclic. This can principally be achieved by incorporating the amino acid or its reduced form, the respective amino alcohol, into the imidazole ring [65] or the wingtip group [64,66,67]. Clavier et al. used the amino acid (L)-valine to synthesise a C4-chiral imdazolidinium salt for chiral molecular recognition studies [65]. The synthetic route utilises the C-terminus to form an amide. Subsequent reduction to the diamine and ring closure with trimethylorthoformate yields the chiral imdazolidinium salt (see Figure 6.25). Unfortunately, no transition metal complex was synthesised, although the combination of a pendant OH functionality and chirality in the backbone of the imidazolidin ring holds great promise for asymmetric homogenous catalysis.

Natural Products R HO2C

N

N +

325

I

R

N

N

I

CO2H

N3

N3

[Red]

I

R N

N

CO2H

NH2

N

O

O

N

O

H N Ala

N

HN CF3CO2

Merrifield synthesis

Phe Ala Val

Ph O

HN H N

CF3CO2 N N

Val

O Ph

Rink

O

PEGA800

Figure 6.23 Formation of a peptide embedded bis-imidazolium salt.

endocyclic

3 N

N

2

3 1 MLn

exocyclic

Figure 6.24 Asymmetric carbon atoms in 3-position to the metal (exocyclic and endocyclic).

326

Functionalised N-Heterocyclic Carbene Complexes

1) 2-But-aniline 2) hydrolysis 3) LiAlH4

O

HO NHBoc

1) dry HCl 2) HC(OMe)3

NH2

N

NH

N

HO(CH2)2X

N

N

HO X

Figure 6.25 Synthesis of a C4-chiral imdazolidinium salt from (L)-valine.

The research groups of Burgess [66], Bellemin-Laponnaz [67] and Pfaltz [64] utilised amino acids and/or the reduced form, the respective amino alcohol, to synthesise an oxazoline, which was then attached to an imidazole ring to form a chelating, chiral, functionalised carbene ligand. Each research group follows a different route. The earliest, and most complex, protocol is presented by Burgess and coworkers [66]. Starting from aspartic acid dimethylester, the amino group is acylated by adamantyl carboxylic acid chloride (see Figure 6.26). Reduction of the two ester groups, but not the amide function, with NaBH4 in ethanol followed by ring closure yields an oxazolinetosylate that is transformed into the iodide. A somewhat shorter approach by Nanchen and Pfaltz [64] starts with (S)-valinol and needs two steps to generate the chiral oxazoline chloride (see Figure 6.27). Note: In the Burgess route, the alkyl bridge (two carbon atoms) comes from the aspartic acid sidechain, whereas the Nanchen and Pfaltz route introduces the alkyl bridge with the chloroacetic acid chloride (linker length variable). Difference: Burgess attaches the alkyl bridge on the C 4 -atom of the oxazoline whilst Nanchen and Pfaltz use the C 2 . Note: The alkyl bridge can be introduced in the C 4 -position using the Nanchen and Pfaltz method, when serine is used as the starting material instead of valinol [64]. Bellemin-Laponnaz and coworkers use a different route [67]. They construct the oxazoline ring on the imidazole ring using valinol to introduce a second chiral centre (see Figure 6.28).

Natural Products H2N

CO2Me

H N

Ad

AdCOCl, NEt3

CO2Me

NaBH4,EtOH

H N

Ad

OH O

O

CO2Me

327

OH

CO2Me

TsCl, NEt3

TsO

I Ad

Ad

N

N

KI O

O

Figure 6.26 Synthesis of a chiral oxazoline substituent from aspartic acid.

HO ⫹

O

NEt3

O

HO

Cl

Cl

Burgess reagent

O

N

Cl

NH2 Cl

N H

Figure 6.27 Synthesis of a chiral oxazoline substituent from (S)-valinol.

(S)-valinol

2

N

NH

N

N

Br

N

N

OEt

NH

OEt

O

OH

O

O

1) MsCl, NEt3 2) NaOH, MeOH/H2O

N N O N

Figure 6.28 Synthesis of a chiral oxazolyl imidazolium salt from imidaolyl pivalic acid and (S)-valinol.

328

Functionalised N-Heterocyclic Carbene Complexes

The quest for oxazolyl substituted carbenes is fuelled by the excellent ligand properties of chelating oxazoline hybrid ligands in asymmetric catalysis. The benchmark ligand in this respect is phosphino-oxazoline (PHOX) [68–70], where the phosphino group takes the place of the NHC, a standard procedure in the development of carbene ligands from phosphorus analogues. In the present case, Nanchen and Pfaltz and Burgess and coworkers successfully employed the NHC-oxazoline ligands in the iridium catalysed asymmetric hydrogenation of arylalkenes. In addition, there exists a group of carboxylic acid functionalised carbene ligands that have the appearance of being derived from the amino acid glycine, but their synthesis was actually achieved by quarternising N-substituted imidazole with a bromoacetic acid ester [71,72]. A representative example for this synthetic route is presented in Figure 6.29. Direct reaction of glycine with glyoxal to form a carboxylate substituted imidazole ring results in a zwitterionic species where only one of the two carboxylic acid units is deprotonated [73,74] (see Figure 6.30). Note: Imidazolium salts can be generated directly from amino acids.

O N

N ⫹

O N

Br OEt Br

⫹

N OEt

⫺

Figure 6.29 Synthesis of a carboxylic acid functionalised NHC precursor (the glycine fragment is highlighted in bold).

O

O H 2N

OH

OH

N

O O H2N HO

⫹

H

N O

OH

⫺

O O

Figure 6.30 Synthesis of a zwitterionic imidazolium species from glyoxal and glycine.

Natural Products

329

6.3 Purines and Xanthines Xanthines are purines that carry carbonyl groups in 2- and 6-positions. Purines (and xanthines) are of great physiological importance as purine bases. Their coordination behaviour to metal cations is of great interest, since they are part of DNA and RNA. The important members of the family together with some derivatives are shown in Figure 6.31. The chemistry of transition metal carbene complexes with NHC derived from purines or xanthines has its roots in the synthesis of xanthinium betaines [75], the xanthine analogues of imidazolium salts. The synthesis is straightforward and involves the methylation of the xanthine with methyl tosylate (see Figure 6.32).

O

O

NH2 N

N

N H

N

N

HN

H2N

N H

N

adenine

N

HN

N H

N

guanine

hypoxanthine

O

O H N

N

HN

HN

O O

N H

N H

O

xanthine

N H

N H ureic acid

Figure 6.31 Some important purine derivatives. O

O O H N

HN

O

2

S

O

N H

N

N

HN

O

O

Figure 6.32 Methylation of xanthine.

N H

N

H

330

Functionalised N-Heterocyclic Carbene Complexes

This is a general method for the synthesis of xanthinium and guaninium salts [75–77]. The methylation agent can be changed to methyl iodide or dimethyl sulfate [76]. Instead of xanthine, 7,9-dimethyl-8-thioureic acid [76,78] can be used as the starting material. In the early days, metallation to a transition metal NHC complex was not attempted. This started in the mid 1970s when Taube and coworkers synthesised a ruthenium carbene complex [79] (see Figure 6.33) and realised that the imidazole can be replaced by a purine [80,81]. The reaction mechanism is similar to the one employed by Raubenheimer et al. for their chromium(0) thiazol-2-ylidene complex [48]. In the case of the ruthenium imidazol-2ylidene complexes, 4,5-dimethylimidazole stabilised the carbene complex compared with unsubstituted imidazole. Likewise, the carbonyl ligand in trans position was necessary to isolate and crystallise the complex. This can be expected, when an excellent σ-donor (NHC) is trans to an excellent π-acceptor (CO). Using the same reaction route, N-coordination and subsequent acid catalysed isomerisation to the C-coordinated carbene complex, Taube and coworkers could synthesise a broad range of purine derived ruthenium carbene complexes [80,81]. The structure of a caffeine carbene complex could be determined with X-ray crystallography (see Figure 6.34). Most of the compounds were characterised with spectroscopic methods, mainly UV-Vis spectroscopy, 2

2

NH [H]

N H3N

NH3

Ru

H3N

NH3

H3N

HN

NH

Ru

H3N

OH2

HN

CO

NH3

H3N

NH3

NH

Ru

H3N

OH2

NH3 NH3

CO

Figure 6.33 A ruthenium carbene complex using unsubstituted imidazole as carbene precursor.

O

O

N

N N N

O

O

[H]

N HN

N H3N

N

Cl Ru

H3N

NH3 Cl

H3N

Cl Ru

H 3N

NH3 Cl

Figure 6.34 Synthesis of a ruthenium carbene complex using caffeine as the carbene precursor.

Natural Products

331

using the differences between the charge transfer bands of N-coordinated and C-coordinated complexes as structure determinator. Compared with today’s 13C-NMR techniques and the difficulty of assigning NHC complexes on the grounds of the chemical shift values of the coordinated or uncoordinated carbene carbon atom correctly, the accuracy of assignments by Taube and coworkers on the basis of UV-Vis spectra alone is truly astounding. Although the reaction is successful with many representatives of the purine family, it relies on the protonation of the N9-nitrogen atom [81] meaning that substituents at N7 and N9 cannot be chosen at will, thus limiting the scope for steric, electronic and chiral diversification of a purine derived carbene ligand for application in homogenous catalysis. Furthermore, the NH functionality may have adverse effects in catalytic reactions and the yields of C-bound complexes are generally low. Note: Caffeine and theobromine formed exclusively C-coordinated (carbene) complexes. At the same time, Beck and Kottmair synthesised a mercury carbene complex using a methylated caffeine [75] as the starting material [82] (see Figure 6.35). This study was triggered by reports from Taube and coworkers [80,81] and Mansy and Tobias [83]. Attempts to synthesise a chromium pentacarbonyl complex with N9-methyl-caffeinium perchlorate according to the classic Öfele procedure [84] did not result in a defined product [82]. The mercury(II)acetate is the same starting material used by Wanzlick in his famous mercury carbene synthesis using 1,3-diphenylimidazolium perchlorate [85]. Note: The above mercury complex is the first purine transition metal carbene complex isolated in satisfactory yield. Buncel et al. [86] in a stepwise trimercuration of the hypoxanthine derivative inosine (see Figure 6.36) proposed a mechanism that takes account of the difference in reactivity of the available mercuration sites: N7 > N1 > C8. Interestingly, they had already proposed the existence of an ylidene (carbene) structure for the dimercurated compound. Using a similar methodology to Clarke and Taube [81], Clarke and coworkers synthesised the homologous osmium caffeine carbene complex [87]. As starting materials, they used a series of purines and purine analogues: 1-methylguanosine, 9-methylhypoxanthine, theophylline and caffeine. In all cases, the osmium coordinated to the imine nitrogen atom of the imidazole ring system. The exception was caffeine, which coordinated with the C8-carbon atom forming a carbene complex. The osmium moiety was synthesised

O O N 2

O

O

N

N

N

N

N

N

Hg(OAc)2

H

N

ClO4

Hg

ClO4

O

N

N

N

N

O

Figure 6.35 Synthesis of a mercury bis-carbene complex using N9-methylated caffeine as the carbene source.

332

Functionalised N-Heterocyclic Carbene Complexes O

O

N

HN

MeHgNO3

N

N

MeHgNO3

N

N

HgMe

MeHg

N

HN

N

N

O

HgMe

N

N

R

R

R

MeHgNO3

O

HgMe

MeHg

N

N

HgMe

N

N

R

Figure 6.36 Stepwise mercuration of a hypoxanthine derivative.

from the commercially available (NH4)2[OsCl6] by reduction with hydrazine hydrate to [Os(NH3)5(N2)]Cl2 [88,89]. Subsequent oxidation with bromine in neat triflic acid yields the starting material [Os(NH3)5(CF3SO3)](CF3SO3)2 [90,91]. The osmium carbene complex is then synthesised by reaction with the xanthine, addition of zinc amalgam and hydrochloric acid (see Figure 6.37). Note: Only when the N9-nitrogen atom is alkylated does the purine derivative coordinate with the C8-carbon atom forming a carbene complex. This can be seen in the behaviour of theophyline, theobromine and caffeine (see Figure 6.38). Whereas the N9-nitrogen alkylated xanthines theobromine and caffeine coordinate with the C8-carbon atom on the ruthenium [81] or osmium [87] metal, the N9 H ligand theophiline forms the N7-metal adduct in the first instance – with possible isomerisation to C8 coordination upon protonation [81].

O N

N

O

O

N

N

[Os(NH3)5CF3SO3](CF3SO3)2

N

N

H3N Os

HCl O

N

N

H3N

NH3 NH3

Cl3

NH3

H

Figure 6.37 Synthesis of an osmium carbene complex using 1,3,7-trimethyl xanthine as the carbene source.

Natural Products O

O

N

N

O

N H

N

Theophyline

O

O N

HN

N

N

N

Theobromine

333

N

O

N

N

Caffeine

Figure 6.38 Theophyline, theobromine and caffeine.

Whilst the first phase of purine carbene research was purely interested in the metal coordination of purines and the resulting applications in medicinal chemistry, biochemistry and pharmacology, a second phase emerged where the purine carbene precursor is considered as a potential carbene ligand in homogenous catalysis applications. This of course follows the realisation by Arduengo [92], Herrmann [93] and others that NHC are excellent donor ligands suitable for application in homogenous catalysis. The link between the two can be seen in a publication by Romerosa et al. [94], the first purine carbene complex of a metal from a group of late transition metals usually referred to as the catalyst metals (Rh, Ir, Ni, Pd, Pt). The synthesis is interesting, since the carbene was generated from 8-(methylthio)theopylline by palladium generated C-S bond cleavage (see Figure 6.39). Note: The compound in Figure 6.38 is not a palladium carbene complex but could be transformed into one by facile protonation (CF3 SO3 H ) or methylation (CF3 SO3 Me). Methylated caffeine [75,95,96] was reacted with silver oxide to generate the silver(I) bis-carbene complex [97] in near quantitative yield (see Figure 6.40). Carbene transfer to rhodium(I) using [Rh(cod)Cl]2 afforded the respective rhodium(I) carbene complex quantitatively. Note: The synthesis of the silver and the rhodium complex were carried out in air and the silver complex was generated in water. Although this reaction represents the first time that a purine base was deliberately reacted to generate a transition metal carbene complex, no application for this rhodium complex was reported. One could have envisaged catalytic trials. However, the efficiency of the silver oxide route for these purine base carbene precursors was recognised and their potential for the synthesis of late transition metal carbene complexes reported. Prompted by this publication, Schütz and Herrmann published their findings on rhodium and iridium purine carbene complexes in the same year [98]. They did not choose the popular silver oxide route, but the less popular alcoholate route (see Chapter 1). Here, the

334

Functionalised N-Heterocyclic Carbene Complexes O

O N N

S O

Cl Pd Cl

Cl Pd

N

PPh3

PPh3

O

N H

N

Ph3P

N

PPh3

N

S

N

NaOH, T O N O

H N

O Ph3P

N

N N

Pd PPh3

N O N

S

N

Figure 6.39 Synthesis of a palladium(II) theophylline-8-ylidene complex through C-S bond cleavage.

O

N

N

N O

N

O

O

H

N X

N

Ag2O

N

O

Ag

N N X N

N

N

O

X OSO3Me, PF6 [Rh(cod)Cl]2

Cl

O

N

Rh

N

N N O

X

Figure 6.40 Synthesis of a rhodium(I) carbene complex from methylated caffeine as starting material.

Natural Products

335

azolium salt is reacted with a transition metal alcoholate to generate the carbene complex accompanied by elimination of the alcohol. In preliminary reactions, the metal precursor is transformed into the ethanolate and sodium iodide added to provide a coordinating anion (see Figure 6.41). The cyclooctadiene ligand is easily replaced by two molecules of CO. The νCO stretching frequencies of the carbonyl ligands can be used to estimate the electronic properties of the 1,3,7,9-tetramethylxanthine-8-ylidene ligand. The electron donor ability is found to be less than for pyrimidine based carbenes [99] or imidazol-2-ylidenes [100]. It is also one of the strongest NHC π-acceptor ligands known [98]. Hypoxanthine can be methylated using methyl iodide [101] and the resulting 7,9-dimethyl-xanthinium salt reacted with [Rh(cod)OEt]2 to form the analogous rhodium(I) 7,9-dimethyl-xanthine-8-ylidene complex [98] (see Figure 6.42). Schütz and Herrmann concluded that the ligand properties of 7,9-dimethyl-xanthine-8-ylidene and 1,3,7, 9-tetramethylxanthine-8-ylidene are very similar. The crystal structure of the 1,3,7,9-tetramethylxanthine-8-ylidene rhodium(I) cyclooctadiene complex was reported by Herrmann et al. in 2006 [102] together with several other purine derived carbene complexes. The reaction conditions of their synthesis were slightly changed. [Rh(cod)OEt]2 was generated by dissolving [Rh(cod)Cl]2 in ethanol and adding NaH. The azolium salt was then added and the complex isolated after 1–2.5 days [102] (see Figure 6.43). Facile substitution of the cyclooctadienyl ligand by CO resulted in the synthesis of the corresponding carbonyl complexes.

Rh

Cl Cl

2 NaOEt

Rh

Et O

Rh

2

O Et

O

Rh

N

N

4

H

N

BF4

N

2(4)NaI

O

O N

I O

O N

N N

N

O

N O

N

Rh

N

N

O

N

N

O

CO

N N

N

Rh

N I

N

I

N

N

CO CO

N

O

Rh

O

N O

Figure 6.41 Synthesis of the rhodium (iridium) caffeine carbene complex using the ethanolate route.

336

Functionalised N-Heterocyclic Carbene Complexes

I O 0.5

Rh

O

H

N

NaI

⫹

Et O

⫹ HN

Rh

O Et

N

N

HN

N BF4

Rh

N

N

⫺

Figure 6.42 Synthesis of the corresponding hypoxanthine carbene complex.

X Rh N

Et O

0.5

N

H

Rh

Rh

X

N

O Et

N

CO

H2N

N

H N

N

Cl

N

H

Rh

N

2077

2078

CO

X

N

N

N N

H

CO

N cm1 N

N O

N

H

N

N N O 2080

O

N

H

N

HN N

2084

cm1

Figure 6.43 Synthesis of some purine derived rhodium(I) carbene complexes and their νCO stretching frequencies.

The authors pointed out that the 13C-NMR chemical shifts of the carbene carbon atoms could not be used as indicator for the electronic properties of the carbene ligands, but that the νCO stretching frequency of the corresponding rhodium(I) carbonyl complexes is a valid indicator. Both observations are in line with the recommendations of a recent review article [103]. Note: For the determination of electronic properties of ligands, νCO stretching frequencies of their metal carbonyl complexes are far more reliable than 13C-NMR chemical shifts.

Natural Products

337

Note: Despite the large variety in substituents in the pyrimidine ring, dimethylamino (+I), chloro (-I) and oxo (-M), the respective purine-8-ylidene ligands were remarkably similar in their electronic properties (Δ νCO of 7 cm-1) [102]. Using suitable reaction conditions, all four substituents on the square planar rhodium(I) starting material [Rh(cod)OEt]2 could be replaced by a 1,3,7,9-tetramethylxanthine-8ylidene ligand yielding a cationic tetrakisxanthine-8-ylidene rhodium(I) complex [102] (see Figure 6.44). The first purine-8-ylidene palladium complex was synthesised shortly afterwards by the Herrmann group [104]. Cleavage of a dimeric palladacycle with the azolium salt in the presence of sodium acetate (to preserve the acetate ligand on palladium) resulted in the respective monomeric palladium(II) carbene adducts (see Figure 6.45). Note: When DMA was used instead of DMSO, yields were drastically reduced, although the reaction temperature was kept under 90°C in each case. Note: The compounds can show cis/trans isomerism – discernible by two different signals in the 31P-NMR and the 13C-NMR (C8) spectra, respectively. The intention behind this research is the use of NHC stabilised palladacycles for use in homogenous catalysis [104], although the actual use in catalytic reactions was not reported yet. However, these compounds are designed to ‘combine the advantageous stability of palladacycles with the high σ-donor strength and steric demand of N-heterocyclic carbenes [93]’ [104]. The use of these NHC stabilised palladacycles in the Heck reaction was reported using other carbenes than those derived from purines [105]. The results were excellent with deactivated aryl bromides and activated aryl chlorides. The authors concluded that an efficient palladacycle catalyst should contain a single monodentate carbene ligand with good π-donor properties and bulky wingtip substituents [105]. This would seem to exclude the use of purine-8-ylidene ligands as these are described to be poor σ-donor and good π-acceptor carbene ligands [102]. It was shown that NHC ligands remain bonded on rhodium under hydroformylation conditions, meaning temperatures up to 100˚C and CO/H2 pressures of up to 50 bar [106,107]. After establishing that the performance of the electron-rich NHC ligands tetrahydropyrimidine-2-ylidene were unsatisfactory for hydroformylation reactions [107], Herrmann and coworkers tested their own, electron poor, purine-8-ylidene ligands in the hydroformylation of 1-octene [108] (see Figure 6.46). Although the performance was improved, the results were still significantly inferior to established phosphane ligands, in yield and turnover frequency (TOF). Selectivity is still low and the application of bulky wingtip substituents has no appreciable influence on the selectivity. Note: Selectivity issues in phosphane rhodium catalyst hydroformylation reactions are often discussed in terms of the ligand bite angle [109–111]. This feature is entirely absent in the monodentate NHC ligands discussed here.

338

O N

O O 2

Rh

Et O O Et

H

N

Rh

8

N

N N

BF4

N N

NaI 2

N

N

N

Rh

I

N

O

N N

O N

O

N

N O

Figure 6.44 Synthesis of a cationic tetrakisxanthine-8-ylidene rhodium(I) complex.

O

N N

N O

Functionalised N-Heterocyclic Carbene Complexes

O N

Natural Products

Ac O

0.5

Pd

H

N

O

H

N

BF4

N

N

P Pd

O Ac

P

Cl

339

NaOAc

NaOAc

N1

N

BF4

N

N O

OAc OAc

Pd P o-Tol

Pd

N

Cl

N

N

P

N

But

o-Tol

N

O

N

o-Tol

N

N

O

Figure 6.45 Synthesis of a palladacycle purine-8-ylidene complex.

O N N

N

O

N

N

Mes

N :

:

Mes N

N

: I Rh O

N

Rh N

N

N

I

R

N

R

N O

Figure 6.46 Carbene ligands employed in rhodium(I) catalyst hydroformylation reactions.

340

Functionalised N-Heterocyclic Carbene Complexes

6.4. Carbohydrates Carbohydrates are not only the most abundant biological molecules on earth [112], but are also used in many important biological processes and functions [113]. It might be surprising that it took so long for carbohydrate functionalised carbene ligands to be synthesised and investigated [113,114]. Very recently, Nishioka and Kinoshita and also Glorius independently synthesised the first examples of carbohydrate functionalised imidazolium salts and their transition metal NHC complexes. Peracetylated glucose, brominated in the 1-position, was reacted with N-methylimidazole to yield the corresponding carbohydrate functionalised imidazolium salt [114]. Reaction with silver(I) oxide and subsequently with [Cp*IrCl2]2 yields the silver(I) and iridium(III) NHC complexes, respectively (see Figure 6.47). The structural parameters of the Cp*Ir(NHC) complex are similar to those of analogous Cp*Ir(NHC) complexes featuring nonfunctionalised carbenes [115,116]. Glorius and coworkers used the same classic approach to synthesise their carbohydrate functionalised imidazolium salts and silver(I) NHC complexes thereof [113] (see Figure 6.48). They took the ligand derivatisation one step further by deprotecting the carbohydrate wingtip group with KCN in methanol. They used these carbohydrate functionalised imidazolium salts as organocatalysts in the organocatalysed formation of γ-butyrolactones by conjugate umpolung using cinnamaldehyde and α,α,α-trifluoroacetophenone as starting materials. The yields were satisfactory but the chiral resolution poor to moderate. The chiral resolution was independent of protection but depended upon the catalyst loading; high catalyst loading achieved the better ee.

OAc OAc N

N

O O

AcO AcO

AcO AcO

OAc

N

N

OAc

Br

Ag2O OAc OAc O AcO AcO

O

N

N

OAc

[Cp*IrCl2]2

AcO AcO

N

N

OAc Cl Cl

Ir Ag Br

Figure 6.47 Synthesis of a carbohydrate functionalised imidazolium salt and its transition metal NHC complexes.

Natural Products

341

OAc

O AcO AcO

N

N Mes

OAc

OAc

Ag O AcO AcO

AgOTf N

OAc

N Mes

AcO

Mes

DBU

N

OAc OAc

N O

OAc OAc [Pd(NCPh)2Cl2] O AcO AcO

N

N Mes

OAc Cl

Pd

Cl AcO

Mes N

OAc OAc

N O

OAc

Figure 6.48 Synthesis of transition metal complexes with carbohydrate functionalised NHC ligands.

The carbohydrate substituent possesses multiple stereocentres but what is more there are many different carbohydrates available in enantiopure form from which a ligand library can easily be synthesised to explore the potential of this interesting new ligand class in homogenous catalytic applications.

6.5 Miscellaneous NHC have become almost routine ligands in organometallic chemistry and a very broad range of applications has been developed. Excellent proof for this statement comes from the Wang group [117]. They modified the naturally occurring antitumour drug podophyllotoxin with an imidazole ring and used this imidazolium salt as the chiral carbene ligand in asymmetric allylic alkylation of rac-E-1,3-diphenyl allyl acetate and diethylmalonate (see Figure 6.49).

342

Functionalised N-Heterocyclic Carbene Complexes R N

OMs

OH

O

O

O

O

N

O

O O

MeO

O

MsCl, NEt3

MeO

OMe

CH3SO3

N O

O N R

O O

OMe OMe

OMe

MeO

OMe OMe

[Pd(allyl)Br]2 R N N CO2Et CO2Et

OAc Ph

Ph

EtO2C

[cat]

CO2Et

Pd Br

O

O Ph

Ph

O O

MeO

OMe OMe

Figure 6.49 Synthesis of the podophyllotoxin substituted carbene complex and the allylic alkylation reaction performed with it.

Note: The imidazole ring is introduced in a nucleophilic substitution with inversion of configuration (Walden inversion) at the six-membered alicycle. The defined catalyst shown in Figure 6.49 reached yields of up to 83% with ees of up to 79%. This was surpassed by catalysts prepared in situ with the same ligand, but Pd(OAc)2 and Pd2(dba)3 as palladium sources, respectively. These went up to 93% yield and 87% ee.

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Index

References to figures are given in italic type acetal complexes 102, 103 acetylamides 201 adenine 329 alkyl complexes 253 alkyl halides 76 allylic amination 120 aluminium complexes 214, 215 amides 112, 230 carboxylic acid 231–235 amination reactions 120 amines 40, 90–95 anionic 223–225 chirality and 43, 288–290 heteroaromatic 55–70 palladium 60–63 silver complexes 56–59 see also pyridyl complexes amino acids 96, 209–210, 292, 313–315, 322–328 anionic complexes 113 arenes 247–250 Arguendo synthesis 144–145, 281 aromaticity 17–18 aryloxides 211–213 aspartic acid 326, 327 axial chirality 44, 294–302, 301, 302 azolium salts 48 basicity 20–24 3,4-benzafluorine 22

benzimidazole 128, 178–179 benzimidazolium salts chiral 282 phenoxy 215–216 phosphino 129 benzoin condensation 309–312 benzothiazoles 317, 319–322 benzoxazolines 72–73 benzyl alcohol 120 9-benzylfluorine 22 BIMCA (3,6-di-tert-butyl-1,8-bis(imidazol-1yl)carbazole) 179–180, 181 binapthyl complexes 295–297 1,1-bipiperidine 300 bis-carbenes 130–131 anionic 203, 205–206 axial chiral 295–296 bridging and chelation 131–133 chiral 282–284 cyclic scaffold 137–142 diaminobenzidine scaffold 145 hydroxy 135 Janus 146–148 palladium 135 phenoxy 213 rhodium 136 xylene backbone 145 1,8-bis(imidazolyl)carbazolide 180 BoxCarb ligands 77–78

Functionalised N-Heterocyclic Carbene Complexes. Olaf Kühl © 2010 John Wiley & Sons, Ltd.

348

Index

Breslaw condensation 310 bromination, gold carbene complexes 86–87 4-bromoacetophenone 144 Brønsted basicity 20–22 caffeine 330–331, 331–332, 333, 334, 335 Candida antarctica Lipase B 199–201 carbene group ferrocenyl 244 as phosphorus mimic 39–41 carbene transfer agents 15 carbohydrates 340–341 carbon-hydrogen bond activation 31, 251–256 carbonyl functionalised complexes 109–110 carboxylic acid amide complexes 231–235 carboxylic acid complexes 221–222, 328 catalysis 45 allylic alkylation 45 catalyst immobilization 135, 166–167, 256–262 coupling reactions 46 organocatalysis 48 using phosphane complexes 115–120 using pincer complexes 166 see also Heck reaction; hydrosilylation; olefin metathesis; Sukuzi reaction CH bond activation see carbon-hydrogen bond activation chelate complexes 263 amine 56 biphosphane 73 bis-carbene 110 chiral 282–284 see also bis-carbenes; pincer complexes chelates 282–283 chiral complexes 1,1-bipiperidine 300 [2,2]-paracyclophane 304–305 planar 301–306 chirality 43, 62, 279–280, 280 1,2-diamines 288–290, 291 amino acid complexes 292 axial 44, 294–302, 301, 302 bis-carbenes 282–284 endo- and exocyclic 293–294, 297–300 hydroxyethyl imidazolium salts 206–210 phosphino compounds 113–115, 114 planar 43–44 wingtip groups 280–281 chromium complexes arene 249 ferrocenyl 240–241

pincer 175, 175–176 cobalt complexes pincer 168–169 scorpionate 151 TIMEN 157–159 conjugated organometallic polymers (COMP) 144–146, 146 copper complexes 61 amido 230 anionic 201–202 biphenyl 217–218 bis-carbene, hydroxy 203 pyridyl 63 thiazole 318–319 TIME 160, 161 TIMEN 155–156, 156 coupling reactions 46 see also Heck reaction; Suzuki reaction Cp see cyclopentadienyl crown ether functionalised complexes 107 cyclic alkyl amino carbenes (CAAC) 105 cyclohexyl functionalised complexes 106 cyclopentadienyl complexes 149, 236 anionic 235–250 back-to-back annulated 245–247 see also ferrocenes cyclophane 143 decomplexation 31–33 decomposition pathways 4, 28–33 deuterium 20–21 1,3-diadamantyl-1H-imidazol-2-ylidine 16–17 1,2-diamines 291 1,2-diamino cyclohexane 89, 90, 140, 287, 288 3,3’-diaminobenzene 145 Diels-Alder reaction 124 difenchyl complexes 285–286, 286 dimethyl sulfoxide (DMSO) 20–22 1,3-dineopentyl-1H-benzimidazol-2-ylidine 19–20 electronic structures 16–20 enamination 81–82 epoxycyclohexane 199–200 esters 12, 111–112 9,10-ethanoanthracene 140, 141 ethers 101, 105–110, 107, 109 ethylene 175 fac geometry see scorpionates fenchone 285–286 ferrocenes 120–122, 235–245

Index planar chiral 303 thioether 267–268 Fischer carbenes 8, 27, 28 ortho-formate 10 furans 102, 103 gels 166–167 glucose 340 glycine 222, 328 gold complexes ether 109 heteroaromatic amine 57 hydroxycyclohexyl 200–201 imido-functionalised 87, 88 scorpionate 152 thiazole 318–319, 320 TIME 160, 161 Grubbs’ catalysts 32–33, 112, 115, 172, 173, 208 chiral 289 immobilization 256–257, 258 guanine 329 hafnium complexes 228 HB(RIm)3 ligands 149–150, 151–154 Heck reaction 101, 118, 123–124, 144, 168, 179, 182, 251–256 hemilability 41–43 imino complexes 84–86, 85 Hermann-Schwartz-Gardiner synthesis see Arduengo synthesis hexadeuterio dimethyl sulfoxide 20–21 histidine 94–95, 322–324 hydrogen/deuterium exchange 20–21 hydrosilylation catalysts 75, 219–220 hydroxy functionalised complexes 98–100, 98 hydroxycyclohexyl functionalised complexes 99, 100–101 hypoxanthine 329, 331, 332, 335 imidaol-2-ylidine 72–73 imidaoyl pivalic acid 326, 327 imidazolium salts 3–5, 9, 15, 40, 199–200 amino 90–95, 95 amino functionalised, anionic 223–225 C-H bond activation 255–256 carbohydrate 340–341 carboxylic acid 221–222 carboxylic acid amide 231–233 catalyst immobilization 257–258 chiral 284–285, 294

crown ether functionalised 107 ethers 105–107 ferrocenyl 237, 267 from (L)-valine 209, 210 hydroxy 211 hydroxycyclohexyl 200–201 hydroxyethyl 207–210, 209 imino 87, 89 immobilization 260 iridium complexes 67 oxazoline 75–76 oxazolyl 327 oxygen-functionalised 97 peptide embedded 324–326, 325 phenoxy 212, 213 phenoxyimino 214–215, 215 phosphino 122, 124–126, 129 pincer 166 ruthenium complexes 330 sulfonato 267, 268 synthesis 8–10 thioether 263–264, 267 see also benzimidazolium salts imino functionalised complexes 81–89 palladium 83, 84 tautomerism 81 immobilization see catalysis, catalyst immobilization inosine 331, 332 ionic liquids 92, 237, 238, 260 iridium complexes 66–69, 66, 67 bis-carbene 136 C-H bond activation 31 phosphino 127–128, 128 pyridyl 64–66 TIME 160, 161 iridium hydrides 67–68 iron complexes imino functionalised 89 phenoxy 213, 214 pincer 173–175 pyridyl 68–69, 68 scorpionate 151–152 thiazole 319–320, 321 isocyanides 8 isothiazolyl 320 Janus bis-carbenes 146–148, 147 ketone functionalised complexes 112 Kummada-Corriu reaction 167, 168

349

350

Index

(L)-lactide 231, 232 lanthanides 224–225, 226, 247, 248 ligand exchange, pincer complexes 169 ligands 3 chiral geometry 44–45 electron donicity 22 see also individual ligand types; transition metal complexes linker units 75–77 lithium complexes, amino 223–224, 223 lutidine 179 magnesium complexes 224–225 magnetic susceptibility 18 manganese complexes 175–176 Meerwein’s salt 148 mer geometry see pincer complexes mercaptides see thiols mercury complexes 2, 331–332 Merrifield synthesis 260 mesityl complexes 251–252 metal complexes see lanthanides; transition metal complexes metathesis see olefin metathesis 2-methoxybenxyl complexes 101–102, 101 methylation 329 Michael-Stetter reaction 309–310, 314 Mizoroki-Heck reaction see Heck reaction monoaminocarbenes (MAC) 105 multidentate complexes 69–70 see also pincer complexes; scorpionates N-heterocyclic carbenes basicity 20–22 electronic structure 16–20 Fischer see Fischer carbenes frameworks 11 ligands see ligands Schrock see Schrock carbenes steric properties 24–27 synthesis 11–13 via imidazolium salts 8–10 via ring-closing 10 transition metal complexes see transition metal complexes Wanzlick-Arduengo see Wanzlick-Arduengo carbenes see also transition metal complexes nickel complexes

bis-carbene 137 C-H bond activation 31 carboxylic acid amide 233 ester 112 phenoxy 213, 213 pincer 167–168 pyrimidine 70, 71 sulfur-containing 266 TIMEN 159 niobium complexes, pincer 175–176 nitrogen functional groups 222–235 nuclear magnetic resonance (NMR) spectroscopy 23–24 nucleophilicity 22 olefin metathesis 46–48, 47, 112, 172, 216–219, 217, 250 oxazolines 78–79 oligomerisation 175 osmium 331–332, 332 oxazolines 70–79, 327 alkyl halide 76 BoxCarb 77–78 design considerations 72 ferrocenyl 244 oxazolines-2-ylidines 75 oxidation 28–29, 30 oxygen group functionalised complexes 95–97, 97 anionic 199–222 palladium complexes 62 acetalisation 103 amido 229–230 amino 91–92 bis-carbene 133, 135, 140 C-H bond activation 31 carbonyl functionalised 110 carboxylic acid 221 carboxylic acid amide 233–235, 234 chiral 287 chiral triazolidine 285 cyclohexanoyl 99, 101–102 ester 111–112 heteroaromatic amine 60–63 imino 89 imino functionalised 83, 84 phenoxy 215–216 phosphane 116–117, 118

Index phosphino 123–124, 123, 128 pincer 166, 167–168, 177–179, 178, 181–182, 183 purine 337, 339 pyrimidine 70, 71 theophylline-8-ylidine 334 thioether 265 [2,2]-paracyclophane 304–305 paracyclophanes 115 peptide chains 260, 262 perhydropyrimidine-2-thione 268 phenoxy functionalised complexes 212, 213 phenoxyimino complexes 214–216 phenyl groups, C-H bond activation 252–253 9-phenyl-2,3-benzafluorine 22 o-phenylene 137–139 p-phenylene 139, 162 phenylmagnesiumhalide 167 phosphane mimicry 39–41 phosphanes 3, 33, 112–130 catalytic applications 115–120, 123–124 ferrocenes 120–122 phosphino complexes 241–242, 242 phosphino oxazoline 328 phosphinophenol 40 phosphites 33 pigiphos 40, 121–122, 121 pincer complexes phosphino 128 pyridine with no linker 163–176 pincer-type complexes 163–184, 163, 243 applications 166–167 BIMCA 180–181 chiral 284–285 cobalt 168–169, 169 design considerations 164 histidine 324 preparation 165–166 structure 163–164 planar chirality 301–306, 303 ferrocenes 240–241 platinum complexes 2 C-H bond activation 31 pyrimidine 70, 71 podophyllotoxin 341–342 polyether functionalised complexes 106–107, 108–109 polymerisation 48, 175, 206 potassium complexes 204–205

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proton coupled electron transfer (PCET) 153 purines 329–339 pybox 40, 55–57 pyrazoles 71 pyridyl complexes 62–70, 63, 64, 65, 71, 264 see also pincer complexes pyrimidines 282 pyrrolidine 166 quinoline, copper and palladium complexes 63 rare earths see lanthanides reduction 29–30 reductive elimiation 4 rhodium complexes 333–335 axial chiral 302 bis-carbene 136 C-H bond activation 31, 253 caffeine 334, 335 chiral 305–306 cyclopentadienyl 253–254 ester 111–112 ferrocenyl 240 hydroxy-binapthyl 218, 219–220 imino 86, 89 Janus bis-carbene 146–147 methoxyalkyl functionalised 103 oxazoline 74–75 phosphino 126–127, 127, 130, 130 π-sulfurane 269 pincer 169–171, 177, 183 BIMCA 180–181, 181 purine 336–337, 336 pyridyl 64, 65 sulfur-containing 266–267 TIME 160, 161 TIMEN 156 using amino functionalised complexes 93 xanthines 333–335 ring-opening polymerisation 49, 206, 207–208 ruthenium complexes 3, 68, 218 arene 249 biphenyl 216–219 C-H bond activation 30–31, 251, 255 caffeine 330–331 decomplexation 32

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Index

ruthenium complexes (continued) imidazole 330 methoxyalkyl 103 oxazoline functionalised 80 pincer 171–172, 173 saddle complex 69 salts see imidazolium salts Schrock carbenes 27, 28 transition metal complex bonding 8 scorpionate ligands 150–163 see also TIME; TIMEN serine 76 Shell Higher Olefin Process (SHOP) 48 silver complexes 4, 100–101, 333–335 amide deprotonation 95 amido 230 amino 224 anionic 204 bis-carbene 133 hydroxy 203 carbohydrate 340 carbonyl functionalised 110 chiral 286, 287 ether 109 furan functionalised 102 heteroaromatic amine 56–59 hydroxycyclohexyl 200–201 Janus bis-carbene 146–147 pincer 176, 177, 178, 181–182 scorpionate 152, 153 thiazol-2-ylidine 317–318 TIME 160, 161 silver tetrafluoroborate 57 silver(I) oxide method 15, 59–60 sodium hydride 12 solvent effects 84 solvents 20–21 Sonogashira reaction 166 stability see hemilability steric effects 24–27, 224–225 chiral complexes 299 imino compounds 89 oxazoline complexes 72 pincer complexes 164–165 tris-carbenes 150 Stetter reaction 48, 49, 309–310, 312–313 sulfonato compounds 267, 268 sulfur functional groups 262–271 π-sulfurane 268–269

Suzuki reaction 46, 47, 118, 168, 168, 179, 233, 251 amino functionalised complexes and 90–91 tantalum complexes 27 telomerisation 238–239 thallium 162, 163 theobromine 333 theophylline 333 thiamine 3, 309 thiazoles 309–315 benzyl 317 metal complexes 317–322 thiazolylalanine 313–315 thiazolylidine 315–319 thioether complexes 263–264, 265 thiols 266, 243 thiolates 264 TIME ligands 159–160 TIMEN ligands 155–159 titanium complexes amide 225, 226 hydroxy 205, 207 phenoxy 212 pincer 175, 176 p-tolylazide 157, 158 transfer complexes 15 transition metal complexes 2, 57–60 carbohydrate 340–341 decomposition pathways 30–32 ferrocenyl 239–241 hemilabile 41, 42 metal-carbene bond 27–28 pincer 175–176 purines and xanthines 329–339 synthesis 13–16 thiazole 317–322 see also individual metals triazole 147, 148 trichlorosilane 258 tridentate ligands 69–70 triethoxysilane groups 257–258 triethyl-orthoformate 11 tris-[2-(3-alkylmethylimidazolium-1yl)ethyl]amines (TIMEN) 155–159 tris-carbene complexes 148–163, 162 tris-pyrazolyl borate (Tp) ligand 148–150, 149, 150–151 Tsuji-Trost reaction 117, 119

Index uranium complexes 175-176, 224–225 ureic acid 329 (L)-valine 209, 210, 292, 293, 324, 326 (S)-valinol 77, 326–328, 327 vanadium complexes 175–176 Wang resin 260, 261 Wanzlich-Arduengo carbenes 27

transition metal complex bonding 8 xanthines 329, 330–332 xylene 145 o-xylylene 138 zirconium complexes 228 zwitterions 222

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