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Chemistry and Technology of Carbodiimides
Chemistry and Technology of Carbodiimides Henri Ulrich C 2007 John Wiley & Sons, Ltd. ISBN: 978-0-470-06510-5
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Chemistry and Technology of Carbodiimides
HENRI ULRICH
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C 2007 Copyright
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[email protected], or faxed to (+44) 1243 770620. 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. 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. Other Wiley Editorial Offices John Wiley & Sons Inc., 111 River Street, Hoboken, NJ 07030, USA Jossey-Bass, 989 Market Street, San Francisco, CA 94103-1741, USA Wiley-VCH Verlag GmbH, Boschstr. 12, D-69469 Weinheim, Germany John Wiley & Sons Australia Ltd, 42 McDougall Street, Milton, Queensland 4064, Australia John Wiley & Sons (Asia) Pte Ltd, 2 Clementi Loop #02-01, Jin Xing Distripark, Singapore 129809 John Wiley & Sons Ltd, 6045 Freemont Blvd, Mississauga, Ontario L5R 4J3, Canada Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Anniversary Logo Design: Richard J. Pacifico Library of Congress Cataloging-in-Publication Data Ulrich, Henri, 1925– Chemistry and technology of carbodiimides / Henri Ulrich. p. cm. Includes bibliographical references. ISBN 978-0-470-06510-5 (cloth) 1. Carbodiimides. I. Title. TP248.C24.U57 2007 2007013946 661 .894–dc22 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN 978-0-470-06510-5 Typeset in 10/12pt Times by Aptara Inc., New Delhi, India Printed and bound in Great Britain by Antony Rowe Ltd, Chippenham, Wiltshire This book is printed on acid-free paper responsibly manufactured from sustainable forestry in which at least two trees are planted for each one used for paper production.
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Contents
Preface Acknowledgements 1
2
xiii xv
General Introduction
1
1.1
5
References
Alkyl- and Arylcarbodiimides
9
2.1
Introduction
9
2.2
Synthesis of Alkyl- and Arylcarbodiimides
10
2.2.1
From Thioureas, Isothioureas and Selenoureas
10
2.2.2
By Dehydration of Ureas
16
2.2.3
From Isocyanates or Isothiocyanates
17
2.2.4
From Cyanamides
25
2.2.5
By Nitrene Rearrangements
25
2.2.6
From Haloformamidines or Carbonimidoyl Dihalides
28
2.2.7
By Thermolysis Reactions
29
2.2.8
By Miscellaneous Other Methods
33
2.3
References I
36
2.4
Reactions of Alkyl- and Arylcarbodiimides
41
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2.4.1
Oligomerization and Polymerization
41
2.4.2
Cycloaddition Reactions
46
2.4.3
Reaction of Ylides with Carbodiimides
76
2.4.4
Insertion Reactions
78
2.4.5
Nucleophilic Reactions
83
2.4.6
Heterocycles from Carbodiimides
104
2.4.7
Use of Carbodiimides In Condensation Reactions
113
2.4.8
Miscellaneous Reactions
125
References II
130
Unsaturated Carbodiimides
147
3.1
Introduction
147
3.2
Synthesis of Unsaturated Carbodiimides
148
3.2.1
From Thioureas
148
3.2.2
From Unsaturated Isocyanates
148
3.2.3
From Unsaturated Iminophosphoranes and Isocyanates or Isothiocyanates
148
By Other Methods
154
3.2.4 3.3
3.4 4
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Reactions of Unsaturated Carbodiimides
154
3.3.1
Polymerization Reactions
154
3.3.2
Cycloaddition Reactions
154
3.3.3
Other Reactions
162
References
162
Halogenated Carbodiimides
165
4.1
165
Introduction
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4.2
4.3
4.4 5
vii
Synthesis of Halogenated Carbodiimides
165
4.2.1
From α-Haloisocyanates
165
4.2.2
By Halogenation of Carbodiimides
166
4.2.3
From Carbonimidoyl Dichlorides or Imidoyl Chlorides
166
4.2.4
By Other Methods
167
Reactions of Halogenated Carbodiimides
168
4.3.1
Cycloaddition Reactions
168
4.3.2
Nucleophilic Reactions
169
4.3.3
Other Reactions
170
References
171
Acyl-, Thioacyl- and Imidoylcarbodiimides
173
5.1
Introduction
173
5.2
Synthesis of Acyl-, Thioacyl- and Imidoylcarbodiimides
174
5.2.1
From Thioureas
174
5.2.2
From Ureas
176
5.2.3
From Isocyanates
177
5.2.4
From Carbonimidoyl Dichlorides or Chloroformamidines
178
5.2.5
From Cyanamides
179
5.2.6
From Other Carbodiimides
179
5.2.7
By Other Methods
179
5.3
Reactions of Acyl-, Thioacyl- and Imidoylcarbodiimides
180
5.3.1
Cycloaddition Reactions
180
5.3.2
Other Reaction
180
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180 183
6.1
Introduction
183
6.2
Synthesis of Silicon Substituted Carbodiimides
183
6.2.1
From Cyanamides
183
6.2.2
From Ureas
184
6.2.3
From Isocyanates and Isothiocyanates
184
6.2.4
From Silylamines
185
6.2.5
From Other Carbodiimides
186
6.2.6
By Other Methods
186
6.4
8
References
Silicon Substituted Carbodiimides
6.3
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Reactions of Silicon Substituted Carbodiimides
187
6.3.1
Oligomerization Reactions
187
6.3.2
Cycloaddition Reactions
188
6.3.3
Other Reactions
190
References
191
Nitrogen Substituted Carbodiimides
195
7.1
Introduction
195
7.2
Synthesis of Nitrogen Substituted Carbodiimides
195
7.3
Reactions of Nitrogen Substituted Carbodiimides
198
7.4
References
198
Phosphorous Substituted Carbodiimides
199
8.1
Introduction
199
8.2
Synthesis of Phosphorous Substituted Carbodiimides
199
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9
10
ix
8.2.1
From Thioureas
199
8.2.2
From Iminophosphoranes
200
8.2.3
From Carbonimidoyl Dichlorides
200
8.2.4
From Cyanamides
201
8.2.5
From Other Carbodiimides
202
8.2.6
By Other Method
203
8.3
Reactions of Phosphorous Substituted Carbodiimides
203
8.4
References
204
Sulfur Substituted Carbodiimides
205
9.1
Introduction
205
9.2
Synthesis of Sulfur Substituted Carbodiimides
205
9.2.1
From Thioureas or Ureas
205
9.2.2
From Carbonimidoyl Dichlorides or Imidoyl Chlorides
206
9.2.3
By Fragmentation Reactions
207
9.2.4
From Other Carbodiimides
208
9.2.5
By Other Methods
208
9.3
Reactions of Sulfur Substituted Carbodiimides
209
9.4
References
210
Metal Substituted Carbodiimides
213
10.1 Introduction
213
10.2 Synthesis of Metal Substituted Carbodiimides
214
10.2.1
From Cyanamides
214
10.2.2
From Isocyanates
215
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10.2.3
From Other Carbodiimides
216
10.2.4
By Other Methods
217
10.2.5
Synthesis of Metal Carbodiimide Adducts
218
10.3 Reactions of Metal Substituted Carbodiimides
222
10.4 References
223
Cyclic Carbodiimides
227
11.1 Introduction
227
11.2 Synthesis of Cyclic Carbodiimides
229
11.2.1
From Cyclic Thioureas
229
11.2.2
By Nitrene Rearrangement
230
11.2.3
From Bisaryliminophosphoranes and Isocyanates or Isothiocyanates
231
11.3 Reactions of Cyclic Carbodiimides
12
236
11.3.1
Nucleophilic Reactions
236
11.3.2
Oligomerization Reactions
237
11.3.3
Cycloaddition Reactions
238
11.3.4
Other Reactions
240
11.4 References
241
Polymeric Carbodiimides
243
12.1 Introduction
243
12.2 Isocyanate Terminated Polycarbodiimides
243
12.3 Oligomeric Carbodiimides
247
12.4 Linear Homopolymers via Addition Across the C N Bonds
248
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xi
12.5 Polymers Derived from Unsaturated Carbodiimides
250
12.6 Linear Polymers
251
12.7 Crosslinked Homo- and Copolymers
252
12.8 Modification of Linear Polymers with Carbodiimides
253
12.8.1
Crosslinking of Polymers
253
12.8.2
Modification of Linear Polymers
254
12.8.3
Modification of Crosslinked Polymers
254
12.9 References
255
Applications of Carbodiimides
259
13.1 Introduction
259
13.2 Applications in Organic Synthesis
260
13.3 Biological Applications
261
13.3.1
Antibiotic Synthesis
261
13.3.2
Protein and DNA Synthesis
261
13.3.3
Modification of Proteins
264
13.3.4
Crosslinking of Proteins
266
13.3.5
Carbodiimides in Pharmaceuticals, Herbicides and Pesticides
267
13.4 Polymer and Industrial Applications
268
13.4.1
Use in Polymer Synthesis
268
13.4.2
Use in Polymer Applications
269
13.4.3
Polymer Modifications
271
13.4.4
Carbodiimides as Stabilizers
271
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13.4.5
Carbodiimides in Dye Applications
272
13.4.6
Other Applications
273
13.5 References
274
Index
283
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Preface
Carbodiimides are the diimides derived from carbon dioxide, and they are extensively used in the formation of peptide amide bonds from carboxylic acids and amines. This reaction was utilized by the Nobel laureate Sheehan in the total synthesis of penicillin. He also was the first to use water soluble carbodiimides to crosslink gelatin. Khorana, another Nobel laureate, demonstrated that carbodiimides can also be used in the synthesis of nucleotides. Today, carbodiimides are used extensively in the synthesis and modification of proteins. Proteomics is the new frontier of chemical research. I became involved in carbodiimide chemistry in my research work on isocyanates at the former Donald S. Gilmore Research Laboratories of the Upjohn Company in North Haven, CT. Carbodiimides are readily synthesized from isocyanates using a phospholene oxide catalyst. This reaction can be conducted without a solvent, and the byproduct is carbon dioxide. We used this reaction in the manufacture of a liquid version of MDI (4,4 -diisocyanatodiphenylmethane), which today is sold in huge quantities worldwide. By reacting MDI with dicarboxylic acids in a vented extruder we manufactured a family of thermoplastic polyamide elastomers, which are sold today by the Dow Chemical Company. Also, N-sulfonylcarbodiimides were synthesized for the first time in our laboratories. They are the precursors of the antidiabetic sulfonamides, such as Upjohn’s Tolbutamide (Orinase). Because of the close relationship of isocyanates with carbodiimides we studied many linear and cyclic carbodiimide reactions, especially their cycloaddition reactions. This book reviews the technical literature on carbodiimides with emphasis on the last decades of the old century and the new century. The carbodiimides are subdivided into alkyl and aryl isocyanates, which cover a major portion of the book. The remaining chapters are carbodiimides with unsaturated substituents, halogenated carbodiimides, acyl-, thioacyl- and imidoylcarbodiimides, silicon substituted carbodiimides, nitrogen substituted carbodiimides, phosphorous substituted carbodiimides, sulfur substituted carbodiimides, metal substituted carbodiimides, cyclic carbodiimides, polymeric carbodiimides and application of carbodiimides. The last chapter includes the numerous biochemical applications of carbodiimides, and the chapters on silicon substituted carbodiimides and metal substituted carbodiimides include their role as precursors for ceramic materials.
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Environmental considerations, spectroscopic properties, and the toxicology of carbodiimides are discussed in the general introduction. The text should prove valuable to researchers and technologists in organic and biochemistry, especially in the new emerging fields of proteomics and nanotechnology. The future of these vibrant fields with endless possibilities is bright indeed.
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Acknowledgements I would like to acknowledge the contributions of my former co-workers at the Donald S. Gilmore Research Laboratories of the Upjohn Company, especially Dr R.H. Richter and B. Tucker who were involved in the synthesis and cycloaddition reactions of carbodiimides; Dr L.M. Alberino who participated in the synthesis of polycarbodiimides; Dr K. Onder and Dr W.J. Farrissey, Jr, who played a major role in the development of thermoplastic polyamides based on carbodiimide chemistry; Dr H.W. Temme and Dr C.P. Smith, who developed novel polymeric catalysts for the conversion of isocyanates into carbodiimides; and A. Odinak, who developed the liquid MDI process. I would especially like to acknowledge the encouragement of the late Dr A.A.R. Sayigh. In the initial carbodiimide research the valuable contributions of Prof. Dr W. von EggersDoering of Harvard University are acknowledged, and special thanks go to Prof. Dr D.M. Crothers, the former Chairman of the Chemistry Department of Yale University in New Haven, Connecticut, who allowed my access to Yale’s fine technical libraries, which helped immensely in the compilation of the literature to this book. Last but not least I would like to thank my wife Franziska for her patience, constant encouragement and support of this undertaking.
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1 General Introduction
Carbodiimides are a unique class of reactive organic compounds having the heterocumulene structure R N C N R. They can be formally considered to be the diimides of carbon dioxide or the anhydrides of 1,3-substituted ureas, and they are closely related to the monoimides of carbon dioxide, the isocyanates. The substituent R can be alkyl, aryl, acyl, aroyl, imidoyl or sulfonyl, but nitrogen, silicon, phosphorous and metal substituted carbodiimides are also known. The unsubstituted carbodiimide HN C NH is isomeric with cyanamide, H2 NCN. Mono substituted carbodiimides, generated in the thermolysis of 1-substituted tetrazoles, can be isolated at liquid nitrogen temperature but isomerize to the cyanamides at higher temperatures.1 Cyanamide is a relevant molecule in prebiotic chemistry, and it was recently shown that water-ice catalyzes the rearrangement of cyanamide to carbodiimide. Carbodiimide could act as a condensation agent in the assembly of amino acids into peptides.2 In the peptide synthesis, using substitued carbodiimides as condensation agents, formation of L L bonds is favored over D D bonds by a ratio of 6:1.3 Carbodiimides are widely used to mediate the attachment of biomarkers to polypeptides. Examples include carbodiimides with ferrocenyl substituents. Also, peptides are covalently modified with ferrocenecarboxylic acid using EDCCl and N-hydroxy-succinimide to promote the coupling to surface lysines. They also mediate the attachment of substituents to single walled nanotubes (SWNTs) and multiwalled nanotubes (MWNTs). Also, microdots are attached to virus molecules using a water soluble carbodiimide. The attachment of viral DNA to gold particles is used in the manufacture of a new type of vaccine. The first synthesis of carbodiimides was reported by Weith in 1873.4 However, carbodiimides were already synthesized by Hinterberger5 and Zinin6 in 1852, and Biziro7 in 1861. The earlier authors obtained carbodiimides by desulfurization of 1,3-disubstituted thioureas’ but did not recognize their structure. Carbodiimides are exceedingly useful compounds in organic synthesis. Of particular significance is their use as dehydrating agents in the synthesis of β-lactam antibiotics, Chemistry and Technology of Carbodiimides Henri Ulrich C 2007 John Wiley & Sons, Ltd. ISBN: 978-0-470-06510-5
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Chemistry and Technology of Carbodiimides
nucleotides and peptides. In 1953, Khorana and Todd8 reported the use of carbodiimides, especially dicyclohexylcarbodiimide, in the synthesis of ortho- and pyrophosphate esters. The use of carbodiimides in the synthesis of peptides was reported by Sheehan and Hess in 1955.9 Sheehan and Henery-Logan used dicyclohexylcarbodiimide in the total synthesis of penicillic acid in 1957.10 Sheehan published a book on the synthesis of penicillin in 1982.11 He also used a water soluble carbodiimide to crosslink gelatin.12 Merrifield received the nobel price in 1985 for the synthesis of polypeptides using polymeric substrates.13 Dicyclohexylcarbodiimide (DCC) is used in this automated stepwize synthesis of polypeptides to activate the carboxyl group. The Merrifield method allows the synthesis of polypeptides, such as ribonuclease A, consisting of 124 amino acids. Oligonucleotides are also synthesized using a carbodiimide in the automated condensation step.14 Carbodiimides are also ‘zero length’ protein crosslinking agents, which promote formation of covalent crosslinks between reactive side groups of amino acids, but do not remain as a part of the crosslink. Also, blocked carbodiimides are used as crosslinking agents.15 The most widely used carbodiimides are dicyclohexylcarbodiimide (DCC) and diisopropylcarbodiimide (DICDI). Carbodiimides with primary alkyl substituents are usually less stable. The most stable aliphatic carbodiimide is di-t-butylcarbodiimide. For racemization free esterifications, peptide couplings and for dehydration reactions bis[[4-(2,2dimethyl-1,3-dioxolyl)]methyl]carbodiimide (BDDC) was introduced in 1994.16 Another group of important aliphatic carbodiimides are the water soluble aliphatic carbodiimides. They usually contain a tertiary amino group in the side chain. Numerous carbodiimides with one alkyl substituent having a terminal t-amino group attached to the side chain have been synthesized. They are usually converted to the more water soluble quaternary ammonium salts by alkylation with MeI or other alkylating agents. Examples include N-ethyl-N -(3-dimethylaminopropyl)carbodiimide (EDC), and its hydrochloride (EDCCl, sometimes referred to as EDAC). For the solid phase synthesis of peptides a polymeric version of EDC was obtained by treating Merrifield resins with EDC in DMF at 100 ◦ C or in refluxing acetonitrile.17 Polyamine carbodiimides combining the phosphate activating property of EDC with the DNA binding property of spermine have also been synthesized from the corresponsing thiourea and HgO.18 Another useful carbodiimide is ferrocenylcarbodiimide (FCDI) which reacts with guanine and thymine bases of single stranded DNA.19 Also, a bipyridyl-tagged carbodiimide, used as a chelating tag, was synthesized.20 In the aromatic series, carbodiimides having a substituent in the o-position are preferred. Examples include N,N -di-o-tolylcarbodiimide and N,N -di-2,6-diethylcarbodiimide, the latter being a useful stabilizer for polyester based polyurethanes.21 The use of carbodiimides in organic synthesis includes the Moffat oxidation of primary alcohols to aldehydes using a dicyclohexylcarbodiimide/DMSO adduct as reagent. Also, conversion of alcohols or phenols into hydrocarbons via hydrogenation of acylisoureas derived from the corresponding carbodiimide adducts is a useful reaction. Furthermore, aldoximes, on treatment with carbodiimides, are converted into nitriles, and numerous uses of carbodiimides as condensation agents or catalysts are known (see Chapter 13). Another useful synthetic method for the synthesis of complex heterocyclic compounds is the aza-Wittig reaction, involving carbodiimides as intermediates.22 This reaction was discovered by Staudinger and Hauser in 1921.23 Carbodiimides have also found use as agricultural chemicals and pharmaceutical intermediates. For example,
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General Introduction
3
N-arenesulfonyl-N -alkylcarbodiimides are precursors of the antidiabetic sulfonyl ureas.24 Sulfonylureas are also potent herbicides. Carbodiimides are used in numerous industrial applications. Their reactivity with carboxylic acids is being utilized in the stabilization of many polyester based polymers. For this purpose sterically hindered aromatic carbodiimides are used.25 Isocyanato substituted oligomeric and polymeric carbodiimides are also being used in some polymer applications.26 The elimination of chlorofluorocarbons (CFCs) as blowing agents for rigid polyurethane insulation foams prompted the development of partially or totally carbon dioxide blown foams based on polymeric isocyanates, having polycarbodiimide segments in their backbone structure. The use of efficient carbodiimide catalysts in combination with the more costly HFCs (hydrogen containing fluorocarbons) affords partially carbon dioxide blown rigid foams. Of course, low density open cell carbodiimide foams are also obtained from polymeric isocyanates using a phospholene oxide catalyst.27 The reaction of 4,4 -diphenylmethane diisocyanate (MDI) with a carbodiimide catalyst is used to formulate a liquid MDI product for RIM (reaction injection molding) and thermoplastic polyurethane elastomer applications.28 The use of dicarbodiimides as monomers in polyaddition reactions have not as yet found wide utility. However, polymers containing carbodiimide groups are known, and further nucleophilic reactions of these polymers with numerous substrates are reported. Carbodiimides, generated in situ from isocyanates are used as catalyst in the formation of polyamides from diisocyanates and dicarboxylic acids.29 Also, homoleptic lanthanide amidinates, made from carbodiimides, exhibit high catalytic activity for the ring opening polymerization of ε-caprolactone at room temperature.30 Polymeric nanoaggregates are the result of self-assembly of block copolymers. For example, PEO-b-PAA on reaction with EDC methiodide undergoes self-association to form short rods, vesicles, encapsulated spheres and long fibers.31 The attachment of nanotubes and microdots to engineered viruses is also mediated using EDC.32 Review articles on carbodiimides were published by Khorana in 1953,8 by Kurzer and Douraghi-Zadeh in 1967,33 by Mikolajczyk and Kielbasinski in 198134 and by Williams and Ibrahim in 1981.35 Carbodiimides containing silicon, germanium, tin and lead substituents were reviewed by Gordetsov and coworkers in 1982,36 N-functionalized carbodiimides by Vovk and Samarai in 199237 and polycarbodiimides by Pankratov in 1993.38 A review on the synthesis of heterocycles by the aza-Wittig reaction appeared in 1991.39 Aliphatic and aromatic carbodiimides are liquids or solids at room temperature. The stability of substituted dialkylcarbodiimides increases as follows: RCH2 < R2 CH < R3 C.40 Dimethylcarbodiimide should be used freshly prepared, but it can be stored for several days below room temperature. Unsaturation in the aliphatic substituents decreases the stability of carbodiimides. For example, diallylcarbodiimide is unstable. In the aromatic carbodiimides, the solid products are more stable than the liquid products. N-alkyl-N -arylcarbodiimides are less stable than diarylcarbodiimides. The introduction of electron attracting groups into the aromatic substituents seems to increase the polymerization tendency of the resulting carbodiimide. In contrast, electron donating substituents on the aromatic ring of arylalkylcarbodiimides enhance their reactivity with carboxylates.41 The cumulative bonds in carbodiimides are not linear. X-ray studies show bond angles variing from 166◦ to 170◦ for N,N -diaryl- as well as N-aryl-N -alkylcarbodiimides.42 The bonding of the N C N bond may be due to steric interaction between the two
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Chemistry and Technology of Carbodiimides
nitrogen substituents. A geometry search, using the INDO method, revealed that the lowest energy state of dimethylcarbodiimide has a dihedral angle of 90◦ .43 The configurational flexibility of diisopropylcarbodiimide has been studied by 1 H-NMR measurement.44 Carbodiimides are best characterized by their infrared spectra, which show a very strong absorption between 2150 and 2100 cm−1 attributable to the N C N stretching.45 Aliphatic carbodiimides give rise to a single peak in the 2140–2125 cm−1 range, while aromatic carbodiimides exhibit two bands in this region. Vibrational dynamics of the N C N stretching in DCC was investigated by the transient grating method.46 The Raman spectrum of carbodiimides shows a strong absorption at 1460 cm−1 which can be attributed to the symmetric vibrations.47 In 13 C-NMR spectra the chemical shift of the sp-hybridized center carbon is approximately 135 to 140 ppm.48 This signal can be used to differentiate between carbodiimide and cyanamide structures, because in cyanamides the signal appears at 112 to 117 ppm. Dicyclohexylcarbodiimide shows a single signal in the 14 N-NMR spectrum indicating a symmetric structure.49 The 15 N-NMR spectra of carbodiimides were also investigated and the chemical shift is about 270 ppm. It was found that the spectrum of N-ethyl-N -(3-dimethylamino)propylcarbodiimide hydrochloride indicated the presence of three isomers.50 At neutral pH, the cyclic forms account for approximately 7 %. Similar results were obtained in another NMR study.51 A study of the conformation of DCC by 1 H-NMR at low temperature showed that the carbodiimide group exerts a significant preference for the equatorial position.52 The He(I) photoelectronic spectrum of dimethylcarbodiimide shows bands at 9.5, 11.55 and 12.26 eV; the first maximum consists of two ionizations representing two orbitals on the N C N part with both π and n character.53 Also, electron energy loss spectra of DCC, polysilyl- and polytitanylcarbodiimides are recorded.54 The UV absorption spectrum of dimethylcarbodiimide in heptane solution shows a strong band at 206.6 nm and three bands at 247.5, 254 and 260 nm due to the allowed n–π transitions polarized perpendicularly to the plane of the CNC angle.55 The extinction coefficient of 1-ethyl-3-(3-dimethylamino)propylcarbodiimide (EDC) in water is ε (214 nm) = 6 × 103 L/mol/cm. The UV assay is used for testing of side reactions.56 Also, 13 C and 15 N-labeled EDC were synthesized.57 Substituent effects on the stability of carbodiimides show that electron negative substituents, such as F, Cl, OH and NH2 destabilize carbodiimides, while electropositive substituents increase the stability of carbodiimides. However, the electronegative substituent NO2 stabilizes carbodiimides by a π -acceptor complex.58 Carbodiimides have chiral structures similar to allenes, i.e., they can exist in optically active forms. Schloegl and Mechtler60 were the first to report a partial optical separation of N,N -diferrocenylcarbodiimide into enantiomers by chromatography on acetylated cellulose, but other authors doubt the validity of these results. According to theoretical calculations a separation of carbodiimide enantiomers is not possible.59 N,N diferrocenylcarbodiimide was also obtained in optically active form by kinetic resolution in the reaction with (-)-S-6,6 -dinitrodiphenic acid.60 Cervinka and coworkers isolated both enantiomers of (R,S)-N,N -bis(α-phenylethyl)carbodiimide, and they found that they undergo racemization at room temperature.61 A recent study on the racemization mechanism of macrocyclic carbodiimides indicates that the open chain as well as the large ring carbodiimides racemize by nitrogen inversion or trans-rotation, while medium size cyclic carbodiimides racemize by cis-rotation.62
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5
The cycloaddition of chiral (-)menthylcarbodiimide with prochiral ketenes affords chirally selective cycloadducts.63 In the reaction of an optically active alcohol with dicyclohexylcarbodiimide complete inversion of the configuration occurs after hydrolysis.64 Treatment of arenesulfenic acids with alcohols, thiols or secondary amines in the presence of optically active carbodiimides affords the corresponding optically active arenesulfenic acid derivatives.65 DCC is used to convert an optically active selenoxide into the corresponding optically active selenimide with TsNH2 .66 Carbodiimides are used in the laboratory as stabilizing agents, coupling agents and as condensation agents and a potential for exposure exists during these operations. The aliphatic carbodiimides are reported to be irritating to the skin, eyes and the respiratory tract. Contact dermatitis caused by DCC was reported.67 DCC has a higher contact hypersensitivity in the mouse ear swelling test than DICDI.68 Exposure to diisopropylcarbodiimide can cause temporary blindness.69 The mammalian toxicity of carbodiimides is low. For example, DCC has a LD50 in rats of 2.6 g kg–1 .70 DCC also shows antitumor activity in mice.71 The oral LD50 of diisopropylcarbodiimide in mice is 36 mg/Kg. Carbodiimide (EDC) modified glycosaminoglycans are a new class of anticancer agents.72 EDC hydrochloride, when administered to animals, exerts a carcinostatic effect on experimental tumors.73 Di(triphenylmethyl)carbodiimide is more toxic to a malignant than a normal cell line. EDC is used in the preparation of a meningococcal group C polysaccharide-tetanus toxoid conjugate used as human vaccine.74 No epidemiological studies have associated carbodiimides with cancer risk in humans.
1.1
References
1. G.I. Yrazo, J. Elguero, R. Flammang and C. Wentrup, Eur. J. Org. Chem. 2209 (2001) 2. F. Duvernay, T. Chiavassa, F. Barget and J.P. Aycard, J. Am. Chem. Soc. 126, 7772 (2004) 3. H.R. Kricheldorf, M. Au and T. Mang, Int. J. Pept. Protein Res. 26, 149 (1985) 4. W. Weith, Ber. Dtsch. Chem. Ges. 6, 1395 (1873) 5. Hinterberger, Jahresber. Fortsch. Chem. 629 (1852) 6. N. Zinin, Jahresber. Fortsch. Chem. 628 (1852) 7. J. Biziro, Jahresber. Fortsch. Chem. 497 (1861) 8. H.G. Khorana, Chem. Rev. 53, 145 (1953) 9. J.C. Sheehan and G.P. Hess, J. Am. Chem. Soc. 77, 1067 (1955) 10. J.C. Sheehan and K.R. Henery-Logan, J. Am. Chem. Soc. 79, 1262 (1957) 11. J.C. Sheehan, “The Enchanted Ring, the Untold Story of Penicillin”, MIT Press, London, England (1982) 12. J.C. Sheehan and J.J. Hlavka, J. Am. Chem. Soc., 79, 4528 (1957) 13. R.B. Merrifield, Angew. Chem. 97, 801 (1985) 14. S.A. Narang, Tetrahedron 39, 3 (1983) 15. D.S.T. A-Lim, A.H.M. Scholman, R. Addink, K. te Niejenhuis and W.J. Mijs, Polym. Bull. 35, 9 (1995) 16. F.S. Gibson, M.S. Park and H. Rapoport, J. Org. Chem. 59, 7503 (1994) 17. M.C. Desai and L.M. Stephens Stramiello, Tetrahedron Lett. 34, 7685 (1993)
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18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29.
G. V. Kiedrowski and F.Z. Doerwald, Liebigs Ann. Chem. 787 (1988) K. Mukumoto, T. Nojima and S. Takenaka, Nucl. Acids Symp. Ser. 49, 231 (2005) E. Convers, H. Tye and M. Whittaker, Tetrahedron 60, 8729 (2004) B. Tucker and H. Ulrich, US Pat. 3,345,407 (1967) H. Wamhoff, J. Dzenis and K. Hirota, Adv. Heterocycl. Chem. 55, 129 (1992) H. Staudinger and E. Hauser, Helv. Chim. Acta 4, 861 (1921) A.A.R. Sayigh, H. Ulrich and J.B. Wright, US Pat. 3,422,021 (1969) W. Neumann and P. Fischer, Angew. Chem. Int. Ed. 1, 621 (1962) K. Wagner, K. Findeisen, W. Schaefer and W. Dietrich, Angew. Chem. 93, 855 (1981) H. Ulrich and H.E. Reymore, J. Cell. Plast. 21, 350 (1985) H.W. Bonk, H. Ulrich and A.A.R. Sayigh, J. Elastoplast. 4, 259 (1972) K. Onder, in “Reaction Polymers”, W.F. Gum, W. Riese and H. Ulrich, eds., Hanser Verlag, New York, 405–452 (1992) Y. Luo, Y. Yao, Q. Shen, J. Sun and L. Weng, J. Organomet. Chem. 662, 144 (2003) C. Gu, D. Chen and M. Jiang, Macromol. 37, 1666 (2004) N.G. Portney, K. Singh, S. Chaudhary, G. Destito, A. Schneemann, M. Manchester and M. Ozkan, Langmuir 21, 2098 (2005) F. Kurzer and K. Douraghi-Zadeh, Chem. Rev. 67, 107 (1967) M. Mikolajczyk and P. Kielbasinski, Tetrahedron 37, 233 (1981) A. Williams and I.T. Ibrahim, Chem. Rev. 81, 589 (1981) A.S. Gordetsov, V.P. Kozyukov, I.A. Vostokov, S.V. Sheludyakova, Y.I. Dergunov and V.F. Mironov, Russ. Chem. Rev. 51, 485 (1982) M.V. Vovk and L.I. Samarai, Russ. Chem. Rev. 61, 297 (1992) V.A. Pankratov, Russ. Chem. Rev. 62, 1119 (1993) N.I. Gusar, Russ. Chem. Rev. 60, 146 (1991) E. Schmidt, W. Striewsky and F. Hitzler, Liebigs Ann. Chem. 560, 222 (1972) W.L. Mock and K.J. Ochwat, J. Chem. Soc., Perkin Trans 2 843 (2002) A.T. Vincent and P.J. Wheatey, J. Chem. Soc., Perkin Trans 2 687, 1567 (1972) D.R. Williams and R. Damrauer, J. Chem. Soc. (D) 1380 (1969) F.A.L. Anet, J.C. Jochims and C.H. Bradley, J. Am. Chem. Soc. 92, 2557 (1970) G.D. Meakin and R.J. Moss, J. Chem. Soc. 993 (1957) H. Maekawa, K. Ohta and K. Tonigawa, J. Phys. Chem. A 108, 9484 (2004) P.H. Mogul, Nuclear Sci. Abstr. 21, 47,014 (1967) F.A.L. Anet and I. Yavari, Org. Magn. Res. 8, 327 (1976) J.D. Ray, L.H. Piette and D.P. Hollis, J. Chem. Phys. 29, 1022 (1958) I. Yavari and J.D. Roberts, J. Org. Chem. 43, 4689 (1978) T. Tenforde, R.A. Fawwaz, N.K. Freeman and N. Castagnoli, J. Org. Chem. 37, 3372 (1972) C. Bushweller and J.W. O’Neil, J. Org. Chem. 35, 276 (1970) S. Schouten and A. Oskam, Inorg. Chim. Acta 22, 149 (1977) O. Lichtenberger, J. Woltersdorf, N. Hering and R. Riedel, Z. Anorg. Allg. Chem. 626, 1881 (2000) G. Rapi and G. Sbrana, J. Am. Chem. Soc. 93, 5213 (1971) N. Wrobel, M. Schinkinger and V.M. Mirsky, Anal. Biochem. 135 (2002) T. Pouyani, J. Kuo, G.S. Harbison and G.D. Prestwich, J. Am. Chem. Soc. 114, 5972 (1992)
30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57.
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58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74.
7
D. Tahmassebi, J. Chem. Soc., Perkin Trans 2 613 (2001) Z. Simon, F. Kerek and G. Ostrogovich, Rev. Ruoum. Chim 13, 381 (1968) K. Schloegl and H. Mechtler, Angew. Chem. 78, 606 (1966) O. Cervinka, V. Dudek, Z. Stihel and J. Zikmund, Coll. Czech. Chem. Comm. 44, 2843 (1979) P. Molina, M. Alajarin, P. Sanchez-Andrada, J.S. Carrio, M. Martinez-Ripoll, J.E. Anderson, M.L. Jimeno and J. Elguero, J. Org. Chem. 61, 4289 (1996) C. Belzecki and J. Krawczyk, J. Chem. Soc., Chem. Commun. 302 (1977) J. Kaulen, Angew. Chem. 99, 800 (1987) J. Drabowicz and M. Pacholczyk, Phosphorus Sulfur, 29, 257 (1987) T. Shimizu, N. Seki, H. Taka and N. Kamigata, J. Org. Chem. 61, 6013 (1996) T.E. Hoffman and R.M. Adams, J. Am. Acad, Dermat. 21, 436 (1989) B.B. Hayes, P.C. Gerber, S.S. Griffey and B.J. Mead, Drug Chem. Toxicol. 21, 195 (1998) R.C. Meyer, Chem. Eng. News 68(45), 2 (1990) W. Aumueller, Angew. Chem. 75, 857 (1963) M.E. Roberts, D.E. Rounds and S. Shankman, Texas Rept. Biol. Med. 19, 352 (1961); C.A. 56, 9368 (1962) C.Y. Pumphrey, A.M. Theus, S. Li, R.S. Parrish and R.D. Sanderson, Cancer Res. 62, 3722 (2002) A.B. Moshnikova, V.N. Afanasyev, O.V. Proussakova, S. Chernychov, V. Gogvadze and I.P. Beletsky, CMLS, 63, 229 (2006) E.C. Beuvery, G.J. Speijers, B.I. Lutz, D. Freudenthal, V. Kanhai, B. Haagmans and H.J. Derks, Dev. Biol. Stand. 63, 117 (1986)
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2 Alkyl- and Arylcarbodiimides 2.1
Introduction
The alkyl-, alkylaryl- and diarylcarbodiimides are the diimides derived from carbon dioxide, however, no direct formation of carbodiimides from amines and carbon dioxide is known. Interestingly, carbodiimides can be obtained from amines and carbon dioxide via a switterionic titanium complex (see Section 2.2.8).1 The major starting materials for the synthesis of carbodiimides are isocyanates, 1,3-disubstituted ureas or 1,3-disubstituted thioureas. The synthesis of isocyanates requires the use of the toxic carbonyl chloride or its oligomers. A book on the synthesis and reactions of isocyanates appeared in 1996.2 Symmetrical carbodiimides, i.e., molecules with the same substituent on both nitrogen atoms, are best prepared from alkyl or aryl isocyanates in the presence of a phospholene oxide catalyst, the byproduct being carbon dioxide gas. No solvent is required for this reaction. Unsymmetrical carbodiimides or alkylarylcarbodiimides are also obtained from isocyanates, either by reaction with amines and subsequent dehydration of the intermediate 1,3-disubstituted ureas, or by reaction of isocyanates with iminophosphoranes (aza-Wittig reaction). Iminophosphoranes can also be used to synthesize symmetrical carbodiimides. In this case they are reacted with carbon dioxide, thereby mimicking the synthesis of carbodiimides from amines and carbon dioxide. Another useful synthesis of unsymmetrical carbodiimides, not requiring the use of carbonyl chloride, is the reaction of carbonimidoyl dihalides with amines. The synthesis and chemistry of carbonimidoyl halides was reviewed in 1968.3 Isothiocyanates are also major starting materials for carbodiimides either by converting them into 1,3-disubstituted thiourea intermediates, which are subsequently desulfurized, or by treating them with iminophosphoranes. In many of the carbodiimide reactions N,N -dicyclohexylcarbodiimide (DCC) is used. However, N,N -diisopropylcarbodiimide (DIPCD) is also often used. Aliphatic carbodiimides, having secondary alkyl groups as substituents, are more stable than carbodiimides Chemistry and Technology of Carbodiimides Henri Ulrich C 2007 John Wiley & Sons, Ltd. ISBN: 978-0-470-06510-5
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with primary alkyl groups as substituents. N,N -di-t-butylcarbodiimide is the most stable aliphatic carbodiimide, but it is also the least reactive. For example, in N-methyl-N -tbutylcarbodiimide cycloaddition reactions occur across the less sterically hindred C N bond (see Section 2.4.2.1) Steric as well as electronic factors determine the reactivity of carbodiimides. For example, N-alkyl-N -arylcarbodiimides with substituents R NMe2 or Me in the p-position of the aryl group react faster than N-alkyl-N -arylcarbodiimides with R NO2 in the p-position.4 Often reactions of carbodiimides are performed in an aqueous system requiring the use of water soluble carbodiimides. The workhorse in this application is N-ethyl-N -(3dimethylaminopropyl)carbodiimide (EDC) and its hydrochloride salt (EDCl).5 However, many other water soluble carbodiimides are also used. Nobel laureat Sheehan used water soluble carbodiimides in the synthesis of penicillins. Also, oligomeric and polymeric carbodiimides are used extensively in solid state chemistry as shown in Chapter 12. A major use of DCC is in the formation of peptide bonds, as demonstrated by the Nobel laureat Khorana in 1955.6 His discovery of the reaction of dibenzyl phosphate with DCC to give tetrabenzyl pyrophosphate laid the foundation for most of his work with nucleotides.
2.2
Synthesis of Alkyl- and Arylcarbodiimides
2.2.1 From Thioureas, Isothioureas and Selenoureas The synthesis of carbodiimides by desulfurization of 1,3-disubstituted thioureas is the most general method of synthesis because dialkyl-, alkylaryl- and diarylcarbodiimides with the same or different substituents are obtained. The desulfurization of N,N -disubstituted thioureas 1 with yellow mercuric oxide is the classical method of synthesis of carbodiimides 2 used by Weith in 1873.7 RNHCSNHR + HgO −−→ RN C NR + HgS + H2 O 1 2
(2.1)
The reaction proceeds best in benzene or acetone, but xylene and carbon disulfide have also been used as solvents. Since water generated in the reaction may add to the carbodiimide to form a urea, dehydrating agents, such as CaCl2 , Na2 SO4 , MgSO4 or MgCO3 are added to the reaction mixture. For example, N-cyclohexyl-N -isopropyl-carbodiimide is obtained in 80 % yield by conducting the desulfurization in the presence of MgSO4 .8 The water can also be removed by azeotrope distillation. However, the water is not detrimental in the synthesis of aliphatic carbodiimides.9 Also, several N-(tosylmethyl)carbodiimides 4 are prepared similarly from the corresponding thiourea 3.10 4-MePhSO2 CH2 NHCSNHR + HgO −−→ 4-MePhSO2 CH2 N C NR 3 4
(2.2)
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Alkyl- and Arylcarbodiimides R
[%]
mp ◦ C (bp)
Me CMe3 CPh3 C6 H11 Ph
95 75 90 90 94
Oil (115/0.01 Torr) 138–139 Oil Oil
11
In addition to dialkyl-, alkylaryl- and diarylcarbodiimides, heterocyclic carbodiimides, such as 1,4-dioxan-2-ylcarbodiimides 6 are obtained by desulfurization of the corresponding thiourea 5.11
O
O NHCSNHR + HgO
O
N
O
5
C
(2.3)
NR
6
R
[%]
bp ◦ C/Torr
i-Pr Ph
71 65
111–112/10 169–171/10
This method is also used in the synthesis of 13 C and 15 N labeled EDC, which is obtained in 57 % yield.12 Symmetrical and unsymmetrical glycosyl carbodiimides are also obtained in good yields in the desulfurization of the corresponding thioureas with HgO.13 Bis-Boc-carbodiimide is obtained similarly as an intermediate in the reaction of N,N -di (t-butoxycarbonyl)thiourea with primary amines in the presence of Et3 N in DMF.14 A spin labeled carbodiimide derivative 8 is synthesized from the thiourea 7 and HgO.15
NHCSNHC6H11
N
+ HgO
N
N
N
C
NC6H11 (2.4)
N O
O 7
8
This carbodiimide is useful for probing protonation reactions in proton-pumping enzymes. Also, highly fluorescent N-alkyl- or N-aryl-N -[4-(5-phenyloxazol-2-yl)benzyl]carbodiimides 10 are prepared from the corresponding thioureas 9 and HgO.16 O
CH2NHCSNHR + HgO
Ph N
O CH2N
Ph
C
NR
N 9
10
(2.5)
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Chemistry and Technology of Carbodiimides R Et i-Pr Ph
mp ◦ C
[%]
41 59 78
58 70 53
Lead and silver oxide can also be used to affect desulfurization of thioureas. Generally, a 1.5 to 2.5 molar excess of the finely divided oxide gives optimal yields. The oxides and salts of other elements have also been used to affect the desulfurization of thioureas. Examples include zinc oxide and salts17 (ZnO, ZnCl2 , ZnSO4 ), aluminumoxide,18 arsenic oxide19 and lead salts.20 The desulfurization of thioureas is also accomplished by either sulfur dioxide or carbon disulfide. The reaction of thioureas21 or dilithium salts of thioureas22 with sulfur dioxide at 0 ◦ C affords carbodiimides in 38–81 % yield. Thermolysis of dilithio- or bis(bromomagnesio)thioureas, or reaction of the salts with carbon disulfide below room temperature also produces carbodiimides.23 Another useful method to convert thioureas into carbodiimides involves their reaction with reactive chlorine compounds, such as SOCl2 , SO2 Cl2 , SCl2 or S2 Cl2. The use of the sulfur chlorides involves chloroformamidines as intermediates (see Section 2.2.6).24 The reaction of thioureas 11 with methanesulfonyl chloride in methylene chloride in the presence of triethylamine/DMAP (4-dimethylaminopyridine) at room temperature produces carbodiimides 12 in 85–100 % yield25 RNHCSNHR + MeSO2 Cl −−→ RN C NR 11 12 R Ph Ph Ph Ph Ph 2-Cl-5-MePh
R1 Me i-Pr –CH2 CH2 Ph 2-furfuryl Ph n-Pr
(2.6)
[%] 91 97 97 85 95 100
Sheehan and Hlavka9 used benzenesulfonyl chloride and aqueous potassium carbonate to synthesize several N-alkyl-N -(aminoalkyl)carbodiimides 14 from the corresponding thioureas 13. RNHCSNH(CH2 )n NR12 + PhSO2 Cl −−→ RN C N(CH2 )n NR12 13 14
(2.7)
Di-2-pyridylsulfite has also been used to desulfurize thioureas. The yields of carbo- diimides RN C NR1 (R = R1 = n-Bu, C6 H11 , Ph and R = Ph, R1 = Me) are 76–90 %.26 The reaction of N,N -disubstituted thioureas 15 with phosgene (carbonyl chloride) affords aliphatic and aromatic carbodiimides 16 in good yields.27 For example, addition of phosgene
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13
in benzene or chlorobenzene to a suspension of the thiourea in the same solvents at 45 ◦ C, followed by heating to 125–133 ◦ C affords the listed carbodiimides.28 RNHCSNHR1 + COCl2 −−→ RN C NR1 + COS + 2 HCl 15 16 R Ph Ph 2-MePh 4-MePh a
R1
[%]
bp ◦ C/Torr
Ph Cyclohexyl 2-MePh 4-MePh
52 44 83 50
116–118/0.7 105–106/0.4 146–149/0.7 142–144/0.8a
(2.8)
m p 57–58 ◦ C
The use of an excess of carbonyl chloride has to be avoided because the intermediate chloroformamidines react with carbonyl chloride to give chloroformamidine-N-carbonyl chlorides. Heating of diarylthioureas with thiocarbonyl chloride also affords carbodiimides.29 Alkylchloroformates, upon reaction with thioureas at 5 to 10 ◦ C in the presence of triethylamine give low yields of carbodiimides. Other reactive chlorine compounds used in the synthesis of carbodiimides include 2,4dichloro-5-nitropyrimidine,30 1-chlorobenzothiazole,31 2-chlorobenzothiazole,32 2-chloro1-methylpyridinium iodide,33 N-phenylbenzimidoyl chloride,34 N-chloroamidines,35 N-acyl-N,N -dialkylchloroformamidine36 and cyanuric chloride.37 Sometimes the reaction is conducted in the presence of triethylamine. The Mukaiyama reagent (2-chloro-1-methylpyridinium iodide) is also used in the in situ reaction of amines with BocNHCSNHBoc to effect guanylation of amines.38 A polymer supported Mukaiyama reagent is also used in the guanylation reaction.39 In the reaction of thioureas with primary or secondary amines in the presence of CuSO4 /SiO2 / triethylamine in THF to produce guanidins, the corresponding carbodiimides are intermediates.40 Reaction of diarylthioureas 17 with azodicarboxylate in the presence of triphenylphosphine gives diarylcarbodiimides 18 in 40–81 % yield.41 EtOCON NCOOEt + RNHCSNHR −−→ RN C NR + EtOCONHNHCOOEt 17 18 (2.9) Azodibenzoyl reacts similarly to give carbodiimides.42 The desulfurization of thioureas can also be effected with triphenylphosphine in the presence of triethylamine and carbon tetrachloride. In this manner carbodiimides 19 are obtained in over 90 % yield.43 RNHCSNHR + Ph3 P + Et3 N + CCl4 −−→ RN C NR + Ph3 PS + HCCl3 + Et3 N HCl 19 (2.10)
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N,N -disubstituted thioureas 20 react with DCC to give a new carbodiimide 21 and N,N dicyclohexylthiourea. This reaction is an equilibrium reaction.44 RNHCSNHR + R1 N C NR1 ←→ RN C NR + R1 NHCSNHR1 20 21
(2.11)
This reaction is used to synthesize heterocyclic compounds from ortho-substituted phenylthioureas.45 A solid phase synthesis of 2-arylamino-6H-pyrano[2,3-f]benzimidazole-6-ones is accomplished by reacting polymer bonded o-dianilino intermediates with arylisothiocyanates and diisopropylcarbodiimide.46 The reaction of diphenylthiourea 22 with 2,4-dimethylphenyl cyanate affords diphenylcarbodiimide 23 in high yield.47 PhNHCSNHPh + ROCN−−→[ROC( NH) S C( NPh)NHPh] 22 −−→PhN C NPh + R1 OCSNH2 23
(2.12)
Thioureas as are also oxidized with excess alkaline hypochlorite below 0 ◦ C to give carbodiimides 24 in excellent yields.48 RNHCSNHR + 4 NaOCl −−→ RN C NR + 4 NaCl + Na2 SO4 + 2 H2 O 24
(2.13)
Alkali chlorites, NaCl2 O, in the presence of cuprous salts, can also be used for this oxidation.49 Oxidation of thioureas with dichlorodicyanobenzoquinone in the presence of sodium hydroxide also affords carbodiimides.50 Reaction of dialkylthioureas with sodium amide in refluxing toluene affords carbodiimides 25.51 The use of sodium hydride instead of sodium amide gives higher yields. RNHCSNHR + NaNH2 −−→ RN C NR + NaSH + NH3 25
(2.14)
The reaction of aliphatic thioureas 26 with benzylmagnesium chlorides gives carbodiimides 27 (R = Me, Pr, i-Pr) in 60–72 % yields.52 PhCH2 CH(R)NHCSNHCH(R)CH2 Ph + 2 PhCH2 MgCl 26 −−→PhCH2 CH(R)N C NCH(R)CH2 Ph 27
(2.15)
The photodegradation of 1-t-butyl-3-(2,6-diisopropyl)-4-phenoxyphenylthiourea affords the corresponding carbodiimide, which seem to cause its insecticidal properties.53 The thermal dissociation of S-alkyl-N,N -diphenylisothioureas into mercaptans and diphenylcarbodiimide was already discovered during the last century.54 Schlack and Keil51 utilized this reaction to synthesize several dicycloalkyl and bis-carbodiimides 29 by heating the isothioureas 28 at 125–240 ◦ C under vacuum (yields: 40–90 %). RNHC(SR1) NR −−→ RN C NR + R1 SH 28 29
(2.16)
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15
S,N,N-trimethyl-N -arylisothiourea 30, upon reaction with an isothiocyanate, produces a carbodiimide 31.55 This reaction involves a [2 + 2] cycloaddition reaction, followed by a cycloreversion to give the observed products. RN C(SMe)-NMe2 + R1 NCS −−→ RN C NR1 + Me2 NC(S)SMe 30 31
(2.17)
The reaction of diazine substituted t-butylthioureas 32 with methyl iodide under phase transfer conditions (1,2-dichloroethane/30 % NaOH) in the presence of tetrabutyl-ammonium bromide affords diazinyl substituted t-butylcarbodiimides 33 in 62–76 % yields.56 The reaction involves the intermediacy of the S-methylisothiourea derivative. RNHCSNH-t-Bu + MeI −−→ RN C N-t-Bu 32 33 R
[%]
1,2-diazinyl 1,3-diazinyl 1,4-diazinyl
62 70 67
(2.18)
Silver nitrate or mercuric chloride in DMF, in the presence of triethylamine, can also be used to convert the isothiourea derivatives into carbodiimides.57 Thermolysis of S-methyl-N-alkyl or aryl-N -cyanoisothiourea 34 (R Ph, Et, cyclohexyl) also generates the corresponding carbodiimides 35, which were trapped with methanol to give the isourea derivatives 36.58 RNHC(SMe) NCN −−→ [RN C NCN] −−→ RNHC(OMe) NCN (2.19) 34 35 36 The reaction of 1,3-substituted selenoureas in THF (6 hr reflux) and oxygen in the presence of DBU (1,8-diazabicyclo-[5,4,0]undec-7-ene) gives a 78 % yield of N-butyl-N -t-butylcarbodiimide from the corresponding selenourea. It is not necessary to prepare the selenourea because an 82 % yield of the same carbodiimide is obtained from t-butylisonitrile and n-butylamine using Se and DBU, followed by refluxing in the presence of oxygen.59 Oxidation of selenoureas 37 with NaIO4 in DMF (refluxing for one minute) affords carbodiimides 38 in moderate to good yields.60 4-MePhNHCSeNHR + NaIO4 −−→ 4-MePhN C NR 37 38 R
[%]
CH3 (CH2 )2 CH3 (CH2 )3 CH3 CH2 CH(Me)– Me3 C Ph 2-MePh
93 90 95 39 50 50
(2.20)
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2.2.2 By Dehydration of Ureas N,N -Disubstituted ureas 39 can be dehydrated with phosphorous pentoxide to give carbodiimides in good yields.61 For example, refluxing of 1,3-dicyclohexylurea and phosphorous pentoxide (five-fold excess) in pyridine affords DCC in 76 % yield. 1,3-diarylureas afford yields of 53–86 % under the same conditions. This reaction can also be conducted with triphenylphosphine in the presence of carbon tetrachloride and triethylamine,62 or with triphenylphosphine dibromide in the presence of triethylamine.62,63 to give carbodiimides 40. RNHCONHR1 + Ph3 PBr2 −−→ RN C NR1 39 40 R1
[%]
cyclohexyl n-Bu cyclohexyl Ph
66 72 70 75
R cyclohexyl Ph Ph Ph
(2.21)
Also, N,N -di-n-dodecylcarbodiimide (76 % yield), N-6-(4 -methoxybiphenyl-4-oxyhexylN -n-hexylcarbodiimide (60 % yield) and N-6-(4-methoxyphenylazo)phenyloxy)hexyl-N n-hexylcarbodiimide (70 % yield), monomers for liquid crystalline polyguanidines, are synthesized in the same manner.64 The triphenylphosphine dibromide can also be attached to a polymeric substrate.65 Also, phenyl dichlorophosphoridate, PhOP(O)Cl2 (55–60 % yield), phenyl N-phenylphosphoramidochloridate, PhOP(O)NHPhCl, (75–90 % yield) and phenyl chlorophosphoridate PhOP(O)OPhCl (70–80 % yield) can be used instead of Ph3 PBr2 in the reaction with ureas.66 The reaction of N,N -disubstituted ureas with phosphoryl chloride also affords carbodiimides67 Other reactive chlorine compounds also react with N,N-disubstituted ureas 41 to give carbodiimides. Examples include Me2 N+ CCl2 Cl− in the presence of triethylamine which affords carbodiimides 42 in good yields.68 RNHCONHR1 + Me2 N+ CCl2 Cl− + Et3 N −−→ RN C NR1 41 42 R t-Bu C6 H11 t-Bu C6 H11 Ph
R1
[%]
t-Bu C6 H11 1-naphthyl 1-naphthyl C6 H11
65 100 90 75 95
(2.22)
The reaction of N,N -dialkylureas 43 with p-toluenesulfonyl chloride in the presence of pyridine as hydrogen chloride scavenger and solvent gives carbodiimides 44. In this manner
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17
dicyclohexylcarbodiimide is obtained in 82 % yield.69 Also, N-(p- or m-vinylphenyl)-N isopropylcarbodiimide is synthesized similarly.70 RNHCONHR + RSO2 Cl −−→ RN C NR + C5 H5 N HCl 43 44
(2.23)
This reaction can be conducted under solid–liquid phase transfer catalytic (PTC) conditions using solid potassium carbonate as base and a liquid lipophilic quaternary ammonium salt as catalyst.71 Numerous carbodiimides with a side chain bearing a tertiary amino group, such as–(CH2 )n NMe2 , are obtained in this manner. Sheehan and coworkers used a modification of this procedure to synthesize several water soluble carbodiimides.72 Also, the Burgess reagent (Et3 N+ SO2 N− COOMe) is used at room temperature to convert N-aryl-N -tritylureas into the corresponding carbodiimides in yields of 85–91 %.73 The reaction of dialkylureas with phosgene affords mainly chloroformamidine hydrochlorides when the substituents on nitrogen are secondary or tertiary alkyl groups.74 Chloroformamidine hydrochlorides are readily converted to carbodiimides using a tertiary amine (see Section 2.2.6). N-o-carboxylphenyl-N -phenyl thiourea 45 upon reaction with HgO affords a carbodiimide, which undergoes intramolecular cyclization to give the shown heterocycle 46.75
H N
NHCSNHPh + HgO
NPh (2.24)
O
COOH O 45
46
2.2.3 From Isocyanates or Isothiocyanates 2.2.3.1 By Catalytic Conversion. Symmetrically substituted carbodiimides are best obtained by the catalytic conversion of two equivalents of isocyanates into a carbodiimide and carbon dioxide. This is the most convenient method of synthesis of symmetrically substituted carbodiimides, because the byproduct is carbon dioxide gas, and the yields approach quantitative. A solvent is not necessary and numerous isocyanates are readily available as starting materials.2 Heating of isocyanates above 150 ◦ C slowly produces carbodiimides. For example, heating of hexamethylene diisocyanate at 189–195 ◦ C for 20 hr produced 4–6 % of oligomeric isocyanate terminated carbodiimides, but in addition 18–20 % of isocyanate terminated isocyanurates were formed. The reaction is facilitated if a slow stream of nitrogen is passed through the boiling isocyanate.76 The unsymmetrical isocyanate dimer 47 was proposed as an intermediate in this transformation.
O 2 RN
C
O
RN
RN O
RN 47
C
NR + O
C
O
(2.25)
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In 1962 Campbell and Monagle77 at Du Pont discovered that cyclic phosphine oxides are excellent catalysts for the conversion of isocyanates into carbodiimides. The most effective catalyst is 1,3-dimethylphospholine -1-oxide (48). However, the more readily available 1-ethyl-3-methylphospholine 1-oxide78 and 1-phenyl-3-methylphospholine 1-oxide79 effect this conversion equally well. Other cyclic phosphorous compounds, such as 1-phenylphospholene-1-oxide80 (49), phosphetane 4-oxides81 (50) and 1,3-diazaphospholidine oxides82 (51) also convert isocyanates into carbodiimides. The reaction occurs at room temperature, but is best conducted below 60 ◦ C to avoid excessive formation of carbon dioxide.
NMe
MeN P Me
P O
Ph
(48)
P O
R
P R
O
(49)
(50)
(2.26)
O (51)
A study of the mechanism of this catalytic process revealed that the reaction proceeds by two [2+2] cycloaddition sequences via a phosphine imine (iminophosphorane) intermediate 52.83 The mechanism is consistent with the observation that O18 enriched phosphine oxide catalyst gives carbon dioxide with considerable O18 incorporation.84
R3P(O) + R1NCO
R3P O R´N
O
R3P
NR1 + CO2 (2.27)
52 The reaction is first order with respect to isocyanate and catalyst, and the reaction of the phosphine imine with isocyanate is the slow, rate determining process. All pentavalent P O compounds catalyze this reaction and the order of catalytic activity is phosphine oxide > phosphinate > phosphonate > phosphate.85 For example, addition of a catalytic amount of hexamethylphosphoric acid triamide increases the rate of conversion of phenyl isocyanate to diphenylcarbodiimide.86 The catalytic conversion of phenyl isocyanate to diphenylcarbodiimide, using isopropylmethylphosphonofluoridate, i-Pr(Me)P(O)F, a poor catalyst, exhibits a pseudo-zero order at 135 ◦ C.87 Triethylphosphate is used commercially to convert the solid MDI (4,4 -diisocyanatodiphenylmethane) partially into a carbodiimide modified liquid MDI.88 Several phosphorous compounds having a P S bond are also catalysts for this reaction. For example, heating of phenyl isocyanate with triphenylphosphine sulfide at 160 ◦ C affords diphenylcarbodiimide.89 Since triphenylphosphine sulfide was recovered unchanged, a different mechanism seems to be operative. A tricyclic P S compound, S P[N(Me)CH2 CH2 ]3 N, also catalyzes the transformation of isocyanates to carbodiimides.90 Triphenylarsine oxide and triphenylantimony oxide also catalyze the conversion of isocyanates into carbodiimides.2 The catalytic activity of the oxides of phosphorous, arsenic and antimony are in agreement with the dipole moments of
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the corresponding compounds, i.e., Ph3 As → O (5.50 D) > Ph3 P → O (4.31 D) > Ph3 Sb → O (2.0 D). Polymeric catalysts are also developed. For example, phospholene oxide modified divinylbenzene/styrene copolymers,91,92 as well as a polystyrene anchored triphenylarsine oxide93 catalyst were prepared. The solid phase catalysts can be removed by filtration after partial conversion of an isocyanate to the carbodiimide. Such a catalyst is useful for the preparation of carbodiimide modified liquid MDI (4,4 -diisocyanatodiphenylmethane) products, which are of considerable commercial interest. The catalytic conversion of aryl and alkyl isocyanates 53, using 2-ethyl-1,3-dimethyl1,3,2-diazaphospholidine -2-oxide (0.5 % by weight) at 180 ◦ C afforded the listed carbodiimides 54 in high yields.99 2 RNCO −−→ RN C NR + CO2 53 54
R
[%]
bp ◦ C/Torr
C6 H11 C18 H35 Ph 3-ClPh 2-MePh 2,6-Et2 Ph
77.5 100 82 93 84 83
96–98/0.3 118/0.7 174–176/1.4 128–130/0.3 189/0.5
(2.28)
mp ◦ C 50–53 43–46
Several metal carbonyl compounds 55 also catalyze the conversion of isocyanates into carbodiimides.94 This reaction also involves metal imine intermediates 56. M C O + RNCO −−→ M C NR + CO2 55 56
(2.29)
M C NR + RNCO −−→ RN C NR + M C O where M = Fe > W > Mo
(2.30)
Other catalysts effective in the conversion of isocyanates into carbodiimides include the naphthenates of Mn, Fe, Co, Cu and Pb,95 derivatives of metallic acetylacetonates,96 the alkoxides of titanium, zirconium and niobium97 and vanadium oxides or chlorides.98 Sterically hindered isocyanates are readily converted into carbodiimides upon heating in the presence of a catalytic amount of a strong base. For example, heating of 2,6-diethylphenyl isocyanate with a catalytic amount of potassium t-butoxide at 200– 250 ◦ C affords 90 % of 2,2 6,6 -tetraethyldiphenylcarbodiimide, bp 194–197 ◦ C/0.5 Torr.99 However, when phenyl isocyanate is treated with a catalytic amount of potassium tbutoxide at room temperature an exothermic reaction with exclusive formation of triphenylisocyanurate (phenyl isocyanate trimer) is observed. Applying this procedure to 2,2 ,6,
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6 -tetraethyldiphenylmethane diisocyanate 57 affords the diisocyanatocarbodiimide 58, mp 88–90 ◦ C.100
OCN
CH2
NCO
57
OCN
CH2
N
C
N
CH2
NCO
58
(2.31) Also, selective reaction of the para isocyanato group in 2,4-TDI 59 is observed using a phospholene oxide catalyst to form the diisocyanate 60, mp 113–115 ◦ C.101 NCO
CH3 OCN
CH3
N
C
N
OCN 59
CH3 NCO
60
(2.32) The structure of the starting isocyanate determines the rate of carbodiimide formation. Aliphatic isocyanates react slower than aromatic isocyanates. 2.2.3.2 By Aza-Wittig Reaction. In the reaction of heterocumulenes with iminophosphoranes, carbodiimides with different substituents on nitrogen are obtained. The reaction of iminophosphoranes 61 with isocyanates (X O) or isothiocyanates (X S) to give carbodiimides with two different substituents 62 was discovered by Staudinger and Hauser in 1921.102 Ph3 P NPh + RN C X −−→ PhN C NR + Ph3 P X 61 62
(2.33)
In later years this reaction became known as the aza-Wittig reaction and review articles appeared in the 1990s.103−105 In recent years the aza-Wittig reaction has been used extensively to synthesize complex heterocycles involving carbodiimides as intermediates. Symmetrically substituted carbodiimides are also obtained from iminophosphoranes and carbon dioxide or carbon disulfide, involving isocyanates or isothiocyanates as intermediates. Instead of the heterocumulenes di-t-butylcarbonate is also used in the reaction with iminophosphoranes. For example, bis(1-naphthyl)carbodiimide is obtained in 64 % yield using this procedure.106
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21
The P-alkyl iminophosphoranes are considerably more reactive than the P-aryl compounds, but iminophosphoranes with alkoxy or chloro groups are also known to participate in the reaction. N-alkyl- or N-aryltrichloroiminophosphoranes are usually obtained as four membered ring dimers, which on thermolysis generate the monomers. For example, thermolysis of the dimeric N-methyltrichloroiminophosphorane 63 in o-dichlorobenzene in the presence of phenyl isocyanate affords N-methyl-N -phenylcarbodiimide 64 in 57 % yield.107
MeN
PCI3
CI3P
NMe
[MeN=PCI3 + PhNCO]
MeN=C=NPh + POCI3
63
(2.34)
64
Heating of N-2-fluorophenyltrichloroiminophosphorane dimer generates the monomer, which is an active carbodiimide metathesis catalyst.108 An abnormal aza-Wittig reaction is observed in the reaction of a polymer bound iminophosphoranes with electron poor isocyanates, such as p-nitrophenyl isocyanate. With aliphatic isocyanates the regular aza-Wittig reaction occurs.109 Many other carbodiimides with two different substituents are conveniently synthesized from isocyanates and iminophosphoranes. For example, carbodiimides 67 with a phosphorous substituent in the α-position are obtained from the isocyanate 65 and the iminophosphorane 66 (R = i-Pr or Ph).110 CF3 PhC[P(O)(OEt)2 ]NCO + Ph3 P NR −−→ CF3 PhC[P(O)(OEt)2 ]N C NR 65 66 67 (2.35) Carbodimides 68, having sulfur containing substituents, are obtained similarly.111 ROCSSCR1 R2 NCO + Ph3 P NR3 −−→ ROCSSCR1 R2 N C NR 68 R
R1
R2
R3
[%]
Et n-Bu
Ph Ph
CF3 CF3
2,4,6-Me3 Ph 2,4,6-Me3 Ph
38 43
(2.36)
However, carbodiimides obtained from α-acetyl isocyanates 69 are unstable and rearrange to the N-substituted ureas 70.112 t-Bu(Ph)C(COCOR)NCO + Ph3 P NAr −−→ t-BuC(Ph) NCON(OCOR)Ar 69 70 (2.37) The reaction of sugar iminophosphoranes with CS2 or CO2 also affords N,N -bis(acetylglycosyl)carbodiimides in 47–86 % yield.113 Also, reaction of mono- and disaccharide isothiocyanates with iminophosphoranes affords the corresponding carbodiimides.114 Likewise, glycosyl iminophosphoranes react with isothiocyanates or sugar isothiocyanates to give the corrsponding carbodiimides.115 Bis-sugar carbodiimides are obtained in the
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reaction of 6-deoxy-6-isothiocyanato sugars with glycosyl iminophosphoranes.115 The tandem aza-Wittig reaction is used in many examples to construct sugar carbodiimides.116 Iminophosphorane attached to cyclodextrins reacts with sugar isocyanates to give the corresponding carbodiimides. When the cyclodextrin substituted iminophosphoranes are reacted with carbon dioxide bis(cyclodextrin)carbodiimides are obtained.117 The reaction of peracetylated glycopyranosyl azides 71 with trimethylphosphine in dry dichloromethane generates the corresponding glycosyl trimethyliminophosphoranes in situ, which react with carbon disulfide to give the symmetrical carbodiimides 72.118 R7 ON O R5 3 N C N 3 1 + Me3P + CS2 R R R6 O R4 R2 71 R1 H H H H OAc
72
(2.38)
R2
R3
R4
R5
R6
R7
OAc OAc NHAc OAc H
OAc OAc OAc OAc H
H H H H OAc
H OAc H H H
OAc H OAc OAc OAc
CH2 OAc CH2 OAc CH2 OAc H H
mp ◦ C
[%] 80 95 71 65 76
177–179 89–91 212–214 133–134 162–163
Also, reaction of sugar iminophosphoranes 73 with acetyl azide affords the sugar substituted carbodiimide 74.119 O
O O
O O
O
PPh3 + MeCON3
N
N
O
O
O
73
C
NMe
O 74
(2.39) Sugar isothiocyanates 75 are also converted with azides and triphenylphosphorous into sugar carbodiimides 76.120 AcOCH2
AcOCH2 O
O NCS + RCH2N3
AcO AcO
OAc 75
AcO
N
AcO
C
NCH2R
OAc 76
(2.40)
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23
The stable tropon-2-ylimino arsorane, -stiborane, and -bismuthorane undergo the aza-Wittig reaction. The order of reactivity is Bi > Sb > As > P.121 l-(triphenylphosphoroylideneaminomethyl)benzotriazole 77 reacts with Grignard reagents to produce substituted iminophosphoranes 78, which react with isocyanates to give carbodiimides 79.122
N
RX N
RCH2N
N
PPh3
RCH2N
NR1
C
(2.41)
PPh3 Mg
CH2N 77
78
79
Reaction of the same benzotriazole with thiolate in the presence of sodium or lithium, followed by reaction with isocyanates, generates thioalkyl substituted carbodiimides.123 The reaction of the diaziridinone 80 (R t-Bu) with triethylphosphite generates an isocyanate and a phosphine imine, which react with each other to give di-t-butylcarbodiimide 81 (90 % yield) and triethylphosphate.124
RN
NR + (EtO)3P
[RNCO + (EtO)3P
NR]
RN
C
O 80
NR + (EtO)3PO
81 (2.42)
Refluxing of two equivalents of aryliminophosphoranes 82 with carbon disulfide in benzene for two hours affords symmetrical diarylcarbodiimides 83 in excellent yields. The intermediate in this reaction is the corresponding isothiocyanate.125 2 RN PPh3 + CS2 −−→ RN C NR + 2 Ph3 PS 82 83
R
[%]
mp ◦ C (bp ◦ C/Torr)
Ph 2-MePh 3-MePh 4-MePh 4-ClPh 2-MeOPh 4-O2 NPh
75 80 91 84 93 77 89
(170/13) (140/1.1) (157/3) 55 54–55 72–73 165–167
(2.43)
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Chemistry and Technology of Carbodiimides
In a similar manner, the aryliminophosphorane 84 is converted with carbon disulfide into the symmetrical carbodiimide 85.126
Cl
SO2Ph N
Cl
SO2Ph
+ CS2
NCS
PPh3
84 Cl
(2.44)
SO2R C
N
N
RSO2
Cl
85 2.2.3.3 From Phosphoramidates. As well as iminophosphoranes phosphoramidates 86 also react with isocyanates to give carbodiimides 87 as shown by Wadsworth and Emmons in 1964.127 This is also a suitable method to synthesize carbodiimides with different substituents, from isocyanates. (EtO)2 P(O)NHR + R1 NCO −−→ RN C NR1 86 87 R cyclohexyl cyclohexyl
(2.45)
R1
[%]
t-Octyl Ph
84 60
ω-Dialkylaminoalkylphosphoramidates 88 are converted to ω-dialkylaminoalkylcarbodiimides 89 with isocyanates using a two phase system (K2 CO3 /xylene).128 (EtO)2 P(O)NH(CH2 )n NR2 + R1 NCO −−→ R1 N C N(CH2 )n NR2 88 89
(2.46)
R1
n
R2
R3
[%]
mp ◦ C(bp/Torr)
n-Bu cyclohexyl cyclohexyl cyclohexyl cyclohexyl cyclohexyl cyclohexyl Ph
3 2 3 3 2 2 3 3
Me Me Me Et
Me Me Me Et
75 90 89 83 82 86 84 78
75–79 (85–86/0.25) (105/0.1) (102/0.1) (120–122/0.1) (125–127/0.2) —a (91–95/0.08)
a
boils with decomposition
–CH2 CH2 OCH2 CH2 – –(CH2 )4 – –(CH2 )5 – Me
Me
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25
Reaction of isocyanates with the silylamine salt 90 affords the carbodiimide 91.129 RNCO + F3 SiN(Li)R1 −−→ RN C NR1 90 91
(2.47)
2.2.4 From Cyanamides Alkylation of monotritylcyanamide 92 with trityl chloride affords bis(trityl)carbodiimide 93.130 Ph3 CNHCN + Ph3 Cl −−→ Ph3 CN C NCPh3 92 93
(2.48)
With less sterically hindered substituents, mixtures of carbodiimides and disubstituted cyanamides are obtained. Carbodiimide 95 is also prepared from cyanamide and the olefin 94 with t-butyl hypochlorite, possibly through a free radical process.131
+ H2NCN + t-BuOCI
BuCH(CI)CH2N
94
C
NCH2CH(CI)Bu
95 (2.49)
Photolysis of t-butyl-N-chlorocyanamide 96 in the presence of cyclohexene gives a 22 % yield of carbodiimide 97.132 Cl t-BuN(Cl)CN +
hv
96
t-BuN
C
N
97
(2.50)
Numerous metal substituted carbodiimides are synthesized from cyanamides (see Sections 1.5 and 1.9)
2.2.5 By Nitrene Rearrangements The Tiemann rearrangement of amidoximes affords carbodiimides through a nitrene intermediate. For example, reaction of the shown amidoxime 98 with benzenesulfonyl chloride in pyridine affords N-phenyl-N -cyclohexylcarbodiimide 99 in 64 % yield.133 PhC(NHC6 H11 ) NOH + PhSO2 Cl−−→[PhC(NHC6 H11 ) NSO2 Ph] 98 .. −−→[PhC( NC6 H11 ) N .. ]−−→PhN C NC6 H11 99
(2.51)
Diarylcarbodiimides are similarly obtained from amidoximes and POCl3 in pyridine.134 The yields range from 51–74 %. Cyclic carbodiimides are also synthesized using the Tiemann rearrangement (see Section 11.2.3).
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Chemistry and Technology of Carbodiimides
The reaction of the tetrazolium salt 100 in the presence of triethylamine to give diethylcarbodiimide 101 also involves a nitrene intermediate.135 Mono aryl substituted tetrazolium salts react similarly to afford N-aryl-N alkylcarbodiimides.136
NEt Cl + Et3N
EtN N
EtN
C
NEt (2.52)
N
100
101
Likewise, oxadiazolium salts 102 react with triethylamine to give carbodiimides 103 (R = n-Bu, cyclohexyl, Ph).137
NMe Cl + Et3N
RN
MeN
C
NR (2.53)
O O 102
103
The thermolysis of 2-methyl-5-phenyl-1,3,4-oxadiazol-2-(3H)-one 106 produces a nitrile imine intermediate 105 which rearranges to the carbodiimide 107.138 The same carbodiimide is obtained in the thermolysis of 2-methyl-5-phenyltetrazole 104.
N
O NMe
Ph
N
[PhC
NMe]
Ph
N N
O
N NMe
104
105
PhN
C
106
(2.54)
NMe
107 Also, 1,5-disubstituted tetrazoles are useful precursors of carbodiimides.139 The photolysis of 2,5-diphenyltetrazole affords diphenylcarbodiimide.140 The same carbodiimide is also obtained in 70 % yield on heating of 1,5-diphenyltetrazole at 210– 220 ◦ C.141 Thermolysis of 1-aryl-5-methyltetrazoles also affords carbodiimides.142 The thermolysis of 4,5-diaryl-1,2,3,5-thiaoxadiazole 1-oxide 108 gives diarylcarbodiimide 109 and sulfur dioxide on heating at 100 ◦ C143 . The examples listed below were obtained by thermolysis at 100–125 ◦ C for 10–30 minutes, the mesityl derivatives dissociate readily at room temperature.144
R NR1 N
RN
C
SO O 108
109
NR1 + SO2
(2.55)
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[%]
bp ◦ C/Torr
Me t-Bu Ph Ph Ph Ph 2,4,6-Me3 Ph Ph Ph Ph Ph
20 88 75 85 60 82 77 80 70 80 89
—a 73–75/760 121–122/0.5 —a —a 145–158/0.4 41–41.5b —a —a 135–138/0.2 46–47b
R Ph Ph Ph 4-MePh 2,4-Me2 Ph 2,4,6-Me3 Ph 2,4,6,-Me3 Ph 4-MeOPh 3-ClPh 4-ClPh 2,6-Cl2 Ph a b
27
The carbodiimides disproportionate on attempted vacuum distillation mp
Numerous N-2,4,6-trimethyl-3,5-dichloro-N -arylcarbodiimides are similarly obtained from the corresponding thiaoxadiazole 1-oxides in 60–80 % yield.145 A bis-phenylene1,2,3,5-oxathiadiazole-1-oxide was utilized as a blocked bis-carbodiimide in crosslinking reactions.146 Some metal substituted nitrile imines upon photolysis afford carbodiimides (see Section 10.2).147 A stabilized imidoyl nitrene was recently isolated.148 Photolysis of tetrazolethiones 110 affords dialkylcarbodiimides 111.149 Likewise, photolysis of 1-aryl-4-methyltetrazolethiones gives rise to the formation of N-aryl-N methylcarbodiimides.150
S R1N
NR
hv
RN
C
NR + N2
(2.56)
N N 110
111
Likewise, N-phenyl-N -methylcarbodiimide 113 is obtained in the photolysis of 5phenylimino-4-methyl-1,2,3,4-thiatriazoline 112.151
NPh S
MeN
hv
PhN
C
N N 112
113
NMe + N2 + S
(2.57)
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Pyrolysis of pyridine imidoyl-N-imines 114 also produces carbodiimides 115 in yields of 86–96 %.152
Ph Ph Ph
N
Ph
N
NR1
RN
C
NR1
(2.58)
+
Ph
N
Ph
R 115
114
2.2.6 From Haloformamidines or Carbonimidoyl Dihalides Chloroformamidines are intermediates in the conversion of carbonimidoyl dihalides to carbodiimides. Their hydrochlorides are also obtained in the reaction of N,N -dialkylureas or thioureas with phosgene or thionyl chloride (see Section 2.2.2). Secondary and tertiary alkyl groups favor the reaction of the ureas at oxygen to give the chloroformamidine hydrochlorides.153 An excess of phosgene has to be avoided because chloroformamidine hydrochlorides react with phosgene to give N,N -dialkylchloroformamidine N-carbonyl chlorides.74 Phosphorous pentachloride reacts similarly with the ureas to give chloroformamidine dihydrochlorides.154 Treatment of the chloroformamidine hydrochlorides 116 with bases, such as triethylamine, generate the carbodiimides 117.154 RNHC(Cl) NHR1 ]Cl + 2 Et3 N −−→ RN C NR1 + 2 Et3 N · HCl 116 117 R i-Pr C6 H11 Ph Ph 4-MeOPh
R1
[%]
i-Pr C6 H11 C6 H11 PhCH2 4-MeOPh
74 82 78 70 67
(2.59)
The phosgenation of N,N -dialkyl- and N-alkyl-N -arylureas at 110–120 ◦ C in chlorobenzene, followed by reaction with amines affords N,N ,N -trisubstituted guanidines via the intermediate chloroformamidines.155 Heating of chloroformamidines 118 causes isomerization to give carbodiimides 119.156
N
C(Cl)
NAr 118
Me2C(Cl)CH2N
C
NAr
119
N-Chloroamidines, upon reaction with silver oxide, also give carbodiimides.157
(2.60)
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N,N -dicyclohexylcarbodiimide is also obtained in good yield in the bromination of N,N -dicyclohexylformamidine with N-bromosuccinimide, in the presence of pyridine or with bromine in the presence of NaOH.158 The bromoformamidine is an intermediate in this conversion. Heating of carbonimidoyl dihalides with amines or amine hydochlorides affords carbodiimides. For example, heating of trifluoromethylcarbonimidoyl difluoride 120 with amines produces the corresponding trifluoromethyl substituted carbodiimides 121.159 CF3 N CF2 + RNH2 −−→ [CF3 N C(F) NHR] −−→ CF3 N C NR 120 121
(2.61)
The reaction involves formation of the fluoroformamidine as an intermediate. Also, heating of carbonimidoyl dichlorides with primary amine hydrochlorides in an inert solvent at 180 ◦ C under nitrogen affords carbodiimides.160 For example, arylcarbonimidoyl dichlorides 122 react with propylamine to give N-aryl-N -propylcarbodiimides 123.161 RN CCl2 + R1 NH2 · HCl −−→ RN C NR1 + 3 HCl 122 123
(2.62)
Instead of the second equivalent of the primary amine, triethylamine can also be used. For example, reaction of the sugar carbonimidoyl dichloride 124 with cyclohexylamine and triethylamine gives a quantitative yield of the carbodiimide 125.162 AcOCH2
AcOCH2 O N
AcO AcO
CCl2 + C6H11NH2 + Et3N
OAc 124
O N
AcO AcO
C
NC6H11
OAc 125
(2.63) In the high temperature chlorination of N-methylaniline 126 a mixture of tetrachlorophenylcarbonimidoyl dichloride 127 and perchlorodiphenylcarbodiimide 128 is obtained.163 PhNHMe + Cl2 −−→ C6 Cl5 N CCl2 + C6 Cl5 N C NC6 Cl5 126 127 128
(2.64)
2.2.7 By Thermolysis Reactions Heating of N-isopropyl-N phenylcarbodiimide at atmospheric pressure affords a mixture of N,N -diisopropyl-, N,N diphenyl- and the starting carbodiimide.164 Apparently, a thermal metathesis reaction occurs. Vanadium oxo [V(O)(O-i-Pr)3 ] and imido vanadium complexes [V(NPhMe)Cl3 ] are found to be catalysts for this metathesis reaction.165 Likewise, mixtures of aromatic and aliphatic carbodiimides undergo the carbodiimide metathesis reaction. Vanadium oxo complexes V(O)(O-i-Pr)3 are precatalysts which are converted into the reactive imido complexes V(NR)(O-i-Pr)3 during the reaction.
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The metathesis of symmetrical aliphatic carbodiimides is also catalyzed by tungsten imido complexes above 140 ◦ C.166 Other carbodiimide metathesis catalysts include Cr(II)/SiO2 ,167 iminophosphoranes,168 imido circonocenes,169 guanidine supported titanium complexes170 and group 14 amide complexes.171 Very efficient metathesis catalysts are iridium guanidate complexes, because treatment of two carbodiimides with 5 mol% of the catalyst at room temperature effects complete equilibration between the starting carbodiimides and the mixed carbodiimide within three minutes.172 Heating of equimolar amounts of two symmetrically substituted carbodiimides 129 and 130 in refluxing p-xylene in the presence of 3–7 mol% of catalyst affords equilibrium mixtures of carbodiimide 131 and reagents 129 and 130 in a ratio of 2:1.167 RN C NR + R1 N C NR1 ←→ RN C NR1 129 130 131
(2.65)
Heating of a carbodiimide with an isocyanate affects an exchange reaction with generation of an unsymmetrical carbodiimide and a different isocyanate. This equilibrium reaction works especially well when the generated isocyanate has the lowest boiling point and thus can be removed from the equilibrium mixture by continuous distillation. For example, heating of α-naphthyl isocyanate 132 with DCC and removal of cyclohexyl isocyanate affords N-α-naphthyl-N -cyclohexylcarbodiimide 133. The use of a second equivalent of α-naphthyl isocyanate affords di-α-naphthylcarbodiimide 134.173 Upon heating of diisocyanates, such as TDI and MDI, with diphenylcarbodiimide carbodiimide, terminated oligomers are obtained.174 RN C NR + R1 N C O ←→ RN C NR1 + RN C O 132 133
(2.66)
RN C NR1 + R1 N C O ←→ R1 N C NR1 + RN C O 134
(2.67)
An exchange reaction of a tellurium diimide dimer with t-butyl isocyanate affords di-tbutylcarbodiimide and N,N -bis(t-butyl)ureato dimer.175 The reaction of α-haloisocyanates 135 with N-trimethylsilyl-N -phenylcarbodiimide 136 at 80 ◦ C affords α-isocyanatocarbodiimides 137.176 RR1 C(Cl)NCO + Me3 SiN C NR2 −−→ RR1 C(NCO)N C NR2 + Me3 SiNCO 135 135 137 (2.68)
R CF3 CF3
R1
R2
[%]
Ph 4-MePh
Ph Ph
66 65
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The reaction of N-sulfinylamines 138 with isothiocyanates affords low yields of carbodiimides 139.177 RN S O + R1 N C S −−→ RN C NR1 + S + SO 138 139 Heating of two equivalents of phenyl isothiocyanate with di-t-butylsulfurdiimide affords N-t-butyl-N -phenylcarbodiimide in 72 % yield.178 The adducts derived from carbodiimides and nucleophiles also undergo thermal elimination reactions to regenerate the carbodiimide, and they are therefore of limited preparative value. For example, the elimination of hydrogen chloride from carbonimidoyl dichlorides is used in the synthesis of arenesulfonylcarbodiimides (see Section 9.2.2). Of course, isoureas and isothioureas also undergo elimination reactions. When the elimination of isothioureas is conducted in the presence of heavy metal ions, the insoluble metal mercaptides are precipitated to facilitate the in situ generation of the carbodiimides. Heating of several heterocyclic ring compounds gives rise to the formation of carbodiimides. For example, 3-methyl-2-phenyl-1-azirine 140 on treatment with 2,4,6trimethylbenzonitrile oxide affords the carbodiimide 141, mp 39–41 ◦ C.179
N Ph
Me + RC
N
O
RN
C
(2.69)
NCH(Me)COPh
140
141
In the reaction of nitrile oxides with phosphine imines, the five membered ring compounds 142 dissociate already at room temperature to give carbodiimides. For example, reaction of benzonitrile oxide with PhN P(OEt)3 affords diphenylcarbodiimide in 76 % yield.180 Ph PhC
N
O + PhN
P(OEt)3
N O PhN
N P(OEt)3
C
NPh + O
P(OEt)3
Ph 142
(2.70) In the reaction of 3-dialkylamino-2,2-dimethyl-2H-azirines 143 with isothiocyanates carbodiimides 144 are formed in high yields. The obtained carbodiimides are in equilibrium with a zwitterionic form 145.181 N
143
NMe2 + RNCS
N Me2NCSC(Me)2N 144
C
NR
NR
S Me2N 145
(2.71)
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For example, a 87 % yield of N-[α-(dimethylthiocarbamoyl) isopropyl]-N -isopropylcarbo -diimide 144 (R i-Pr), bp 112/0.05 is obtained in this manner.182 Also, many four membered ring heterocycles, on heating, produce carbodiimides. For example, 4-iminoazetidine-2-ones, obtained from thioureas and phosgene, undergo fragmentation on heating to form carbodiimides and carbonyl sulfide. Similarly, the [2+2] cycloadducts 146 derived from carbodiimides and isothiocyanates dissociate on heating to give the starting materials. In contrast, attachment of an arenesulfonyl or ethoxycarbonyl group causes fragmentation into a new set of heterocumulenes.183
NR RN
C
RN
NR + R1NCS
R1N
S
R1N
C
NR + RNCS
146 (2.72)
The use of N-methyl-N -t-butylcarbodiimide as a diagnostic tool results in the formation of t-butyl isothiocyanate on fragmentation because addition of the C S bond of the isothiocyanate occurs across the less sterically hindered C N group of the carbodiimide.183 1,2,3,3-tetraaryl-1,2-diazetidin-4-imines 147 dissociate on heating above 200 ◦ C to give diarylcarbodiimides 148 and benzophenone imines.184
NR
Ph2
NR
R1N
R1N
NR + Ph2C
C
147
NR
(2.73)
148
Heating of the 1,2-oxazetidine derivative 149 at 400 ◦ C under vacuum produces N-methylN -trifluoromethylcarbodiimide 150 and methyl isocyanate.185
NMe CF3N
MeN
O
C
NCF3 + MeNCO
(2.74)
NMe 149
150
Also, 1,2,4-oxazetidines 151 afford aromatic carbodiimides 152 on thermolysis.186
RN O
NR 151
RN
C
NR + H2O
(2.75)
152
Diazaphosphetidinones 153 dissociate on heating into a trichlorophosphazene and an isocyanate, which react with each other to generate a carbodiimide 154 and phosphoryl
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chloride.187
O RN Cl3P
RNCO + R1N
NR1
PCl3
RN
153
C
NR1 + Cl3PO
(2.76)
154
The diazepine derivative 155 affords diphenylcarbodiimide 156 on heating in decalin.188
O
O
Ph N NPh N Ph 155
PhN
NPh +
C
NPh
(2.77)
156
Thermolysis of tricyclohexyl guanidine at 280–320 ◦ C affords dicyclohexylcarbodiimide.145
2.2.8 By Miscellaneous Other Methods The insertion reaction of heterocumulenes can be used to synthesize carbodiimides having two different substituents. For example, the carbamate 157 derived from an isocyanate and bis(tributyltin)oxide can be reacted with an isothiocyanate to give a carbodiimide 158 with substituents derived from the isocyanate and the isothiocyanate.189
Bu3SnN(R1)COOSnBu3 + R2NCS
[Bu3SnSC(
NR2)N(R1)SnBu3]
157 R1N
C
NR2 + (Bu3Sn)2S
158
(2.78)
The photolysis of sulfilimine 159 affords N-phenyl-N -2,6-dimethylphenylcarbodiimide 160 in 26 % yield. N-phenyl-N -2,6-diethylphenyl- (18 %) and N-phenyl-2,6dichlorophenyl-carbodiimide (34 %) are similarly obtained.190 hv 2,6-Me2 PhN C(Ph)NSMe −− → 2,6-Me2 PhN C NPh 159 160
(2.79)
The photolysis of boryl substituted nitrilimines also affords the corresponding carbo -diimides.191
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Reaction of 3-chlorobenzothiazole-S-dioxide 161 with phenylurea in the presence of lithium carbonate affords an 85 % yield of the shown carbodiimide 162.192
O
O S N
+ H2NCONHPh
O2S
N
C
NPh
(2.80)
N
Cl 161
162
The reaction product derived from isonitriles and primary amines in the presence of Pd(II)Cl2 reacts with silver oxide to give carbodiimides 163.193 RNH2 + R1 NC−−→[PdCl2 (R1 NC)C(NHR)NHR1 ] −−→ RN C NR1 163 R n-Bu C6 H11 C6 H11 CH2 =CHCH2 Ph
R1
[%]
t-Bu t-Bu C6 H11 t-Bu t-Bu
85 94 68 80 77
(2.81)
In the palladium catalyzed reaction oxygen is also used in the presence of iodine (0.2 mol) and good yields of carbodiimides 164 are obtained.194 RNH2 + R1 NC −−→ RN C NR1 164 R t-Bu t-Bu cyclohexyl 4-MeOPh
(2.82)
R1
[%]
t-Bu cyclohexyl cyclohexyl cyclohexyl
86 76 67 67
Also, NiCl2 is used as catalyst in this reaction.195 For example, from 3-amino-5chlorobenzonitrile and t-pentylisocyanide the corresponding carbodiimide is obtained in 62 % yield. Even bulk gold is used to catalyze the reaction of isocyanides with primary amines in the presence of oxygen.196 The reaction of azides 165 with an isonitrile in the presence of iron pentacarbonyl as the catalyst, affords carbodiimides 166 in 50–60 % yield.197 RN3 + R1 NC −−→ RN C NR1 165 166
(2.83)
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Bis(trifluoromethyl)carbodiimide 168 is obtained by isomerization of perfluoro-2,4-diaza1,4-pentadiene 167.198 CF2 NCF2 N NCF2 ←→ CF3 N C NCF3 167 168
(2.84)
The reaction of alkyl halides with trimethylsilylcarbodiimide affords carbodiimides with adjacent heterocumulene groups. For example, reaction of α-chlorosulfilimines 169 with N-trimethylsilyl-N -phenylcarbodiimide 170 affords the functional carbodiimide 171.199 RCF3 C(Cl)NSO + Me3 SiN C NPh −−→ RCF3 C(NSO)N C NPh 169 170 171 R
[%]
bp ◦ C/Torr
Ph 4-MePh 4-ClPh
52 50 30
140/0.1 140/0/08 145/0.1
(2.85)
Likewise, reaction of α-chloro isocyanate 172 with N-trimethylsilyl-N -phenylcarbodiimide affords α-isocyanatocarbodiimides 173.200 RCF3 C(Cl)NCO + Me3 SiN C NPh −−→ RCF3 C(NCO)N C NPh 172 173 R
[%]
bp ◦ C/Torr
Ph 4-MePh EtOCO
66 65 61
95/0.06 105/0.05 110/0.09
(2.86)
In the exchange reaction of t-butylimido zirconocene complexes 174 with methyl isothiocyanate N-methyl-N -t-butylcarbodiimide 175 is obtained.201 Cp2 Zr(THF) N-t-Bu + MeNCS −−→ MeN C N-t-Bu 174 175
(2.87)
Likewise, imido tantalium complexes 176 undergo exchange reactions with N-t-butyl-N 2,6-dimethylphenylcarbodiimide to give bis-t-butylcarbodiimide 177 and the imido tantalium complex 178.202 CpCl2 Ta N-t-Bu + t-BuN C NR −−→ t-BuN C N-t-Bu + CpCl2 Ta NR 176 177 178 (2.88) Imido zwitterionic titanium complexes, Ti NAr[CH3 B(C6 F5 )3 ], undergo reaction with carbon dioxide to give isocyanates and symmetrical carbodiimides via a ligand metathesis
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reaction.1 Titanium imido complexes also react with CS2 to give a mixture of isothiocyanates and carbodiimides in a ratio of 3:1.203 The reaction of bis(triphenylstannyl)carbodiimide 179 with trityl chloride affords a 74 % yield of bis(triphenylmethyl)carbodiimide 180.204 Ph3 SnN C NSnPh3 + 2 Ph3 CCl −−→ Ph3 CN C NCPh3 + 2 Ph3 SnCl 179 180
(2.89)
The nickel carbodiimide complex 181 reacts with carbon monoxide to give carbodiimide 182 in 50 % yield.205
N CH2 Ph P Ni
N
+ 2 CO
PhCH2N
C
N
P
181
2.3
182
(2.90)
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H.J. Bestmann, J. Lienert and L. Mott, Liebigs Ann. Chem. 718, 24 (1968) C. Palomo and R. Mestres, Synth. 373 (1981) J. Kim, B.M. Novak and A.J. Waddon, Macromol. 37, 8286 (2004) A. Akelah, Synth. 413 (1981) C. Palomo and R. Mestre, Bull. Soc. Chim. 2136 (1989) H. Walther, German (East) Pat. 22,437 (1961); C.A. 58, 2382 (1963) T. Schlama, V. Gouverneur and C. Mioskowski, Tetrahedron Lett. 37, 7047 (1996) G. Amiard and R. Heymes, Bull. Soc. Chim. France 1360 (1956) H. Konogawa, M. Nanasawa, S. Uehara and K. Osawa, Bull. Chem. Soc. Jpn. 52, 533 (1979) Z.M. Jaszay, I. Petnehazy, L. Toke and B. Szajani, Synth. 520 (1987) J.C. Sheehan, P.A. Cruickshank and G.L. Boshart, J. Org. Chem. 26, 2525 (1961) M.R. Barvian, H.D. Hollis Shoewalter and A.M. Doherty, Tetrahedron Lett. 38, 6799 (1997) H. Ulrich, J.N. Tilley and A.A.R. Sayigh, J. Org. Chem. 29, 2401 (1964) G. Doleschall and K. Lempert, Tetrahedron Lett. 1195 (1963) T.W. Campbell, J.J. Monagle and V.S. Foldi, J. Am. Chem. Soc. 84, 3673 (1962) T.W. Campbell and J.J. Monagle, J. Am. Chem. Soc. 84, 1493 (1962) W.C. McCormack, US Pat. 2,663,736 (1955); C.A. 49, 7602 (1955) W.C. McCormack, Org. Synth. 43, 73 (1963) K. Issleib, K. Krech and K. Gruber, Chem. Ber. 96, 2186 (1963) J. Ackroyd and B.M. Watrasiewicz, Brit. Pat. 1,215,157 (1970); C.A. 75, 20,610 (1971) H. Ulrich, B. Tucker and A.A.R. Sayigh, J. Org. Chem. 32, 1360 (1967) J.J. Monagle, T.W. Campbell and H.F. McShane, J. Am. Chem. Soc. 84, 4288 (1962) J.J. Monagle and J.V. Mengenhauser, J. Org. Chem. 31, 2321 (1966) J.J. Monagle, J. Org. Chem. 27, 3854 (1962) H. Normant, Angew. Chem. 79, 1029 (1967) J.O. Appleman and V.J. DeCarlo, J. Org. Chem. 32, 1505 (1967) W.E. Erner and A. Odinak, US Pat. 3,384,653 (1968) L. Maier, Helv. Chim. Acta 47, 120 (1964) J. Tang, T. Mohan and J.G. Verkade, J. Org. Chem. 59, 4931 (1994) W. Schaefer, K. Wagner and H.D. Block, Germ. Pat. 2,552,340; C.A. 87, 58,978 (1977) C.P. Smith, US Pat. 4,068,055; C.A. 88, 121,930 (1978) C.P. Smith and G.H. Temme, J. Org. Chem. 48, 4681 (1983) H. Ulrich, B. Tucker and A.A.R. Sayigh, Tetrahedron Lett. 18, 1731 (1967) E. Dyer and R.E. Reed, J. Org. Chem. 26, 4677 (1961) J.W. Heberling, Jr., US Pat. 3,152,131 (1964); C.A. 62, 9073 (1965) K.C. Smeltz, US Pat. 3,426,025 (1969); C.A. 70, 69,007 (1969) M. Tani, A. Yoshida and H. Muro, Japan Kokai Tokkyo Koho 7, 966,656; C.A. 91, 157,347 (1979) B. Tucker and H. Ulrich, US Pat. 3,345,407 (1967) H. Ulrich, US Pat. 3,522,303 (1970) K.C. Schmelz, US Pat. 2,840,489; C.A. 52, 16290 (1958) H. Staudinger and E. Hauser, Helv. Chim. Acta 4, 861 (1921) H. Wamhoff, J. Dzenis and K. Hirota, Adv. Heterocycl. Chem. 55, 129 (1992)
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104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143.
39
N.I. Gusar, Russ. Chem. Rev. 60, 146 (1991) Y.G. Golobov and F. Kasukhin, Tetrahedron 48, 1353 (1992) P. Molina, M. Alajarin and P. Sanchez-Andrada, J. Org. Chem. 59, 7306 (1994) H. Ulrich and A.A.R. Sayigh, Angew. Chem. Int. Ed. 1, 595 (1962) S.A. Bell, S.J. Geib and T.Y. Meyer, J. Chem. Soc., Chem. Commun. 1375 (2000) C.E. Hoesl, A. Nefzi and R.A. Houghten, Tetrahedron Lett. 44, 3705 (2003) V.I. Gorbatenko, N.V. Melnichenko and L.I. Samarai, Zh. Obshch. Khim. 48, 1425 (1978); C.A. 89, 104,784 (1978) M.V. Vovk, M.M. Bretski and V.I. Dorokhov, Zh. Org. Khim. 25, 759 (1989) M.V. Vovk, V.I. Dorokhov and L.I. Samarai, Zh. Org. Khim. 22, 1784 (1986) A. Messmer, L. Pinter and F. Szega, Angew. Chem. Int. Ed. 3, 228 (1964) J.M.G. Fernandez, C.O. Mellet, V.M.D. Perez, J. Fuentes, J. Kovacs and I. Pinter, Tetrahedron Lett. 38, 4161 (1997) J.M.G. Fernandez, C.O. Mellet, V.M.D. Perez, J. Fuentes, J. Kovacs and I. Pinter, Carbohydr. Res. 304, 261 (1997) M.I. Garcia Moreno, J.M. Benito, C.O. Mellet and J.M.G. Fernandez, J. Org. Chem. 66, 7604 (2001) F. Charbonnier, A. Marsura, K. Rroussel, J. Kovacs and I. Pinter, Helv. Chim. Acta 84, 535 (2001) L. Kovacs, E. Osz and Z. Gy¨orgydeak, Carbohydrate Res. 337, 1171 (2002) E. Zbiral and W. Sch¨urkhuber, Liebigs Ann. Chem. 1870 (1982) P. Lin, C.L. Lee and M.M. Sim, J. Org. Chem. 66, 8243 (2001) M. Nitta, Y. Mitsumoto and Y. Yamamoto, J. Chem. Soc., Perkin Trans. 1 1901 (2001) A.R. Katritzky, J. Jiang and L. Urogdi, Synth. 565 (1990) A.R. Katritzky, J. Jiang and J.V. Greenhill, Synth. 107 (1994) F.D. Greene, W.R. Bergmark and J.F. Pazos, J. Org. Chem. 35, 2813 (1970) P. Molina, M. Alajarin, A. Arques and J. Saez, Synth. Comm. 12, 573 (1982) M. Takahashi and D. Suga, Synth. 986 (1998) W.S. Wadsworth and W.D. Emmons, J. Org. Chem. 29, 2816 (1964) Z.M. Jaszay, I. Petnehazy, L. Toke and B. Szajiani, Synth. 397 (1988) U. Klingbiel, Z. Naturfordch. 33B, 950 (1978) H. Bredereck and E. Reif, Chem. Ber. 81, 426 (1948) L. De Vries, US Pat. 3,769,344; C.A. 80, 36,725 (1974) R.S. Neale and N.L. Marcus, J. Org. Chem. 34, 1808 (1969) J.H. Boyer and P.J.A. Frints, J. Org. Chem. 35, 2449 (1970) J. Garapon, B. Sillion and J.M. Bounier, Tetrahedron Lett. 4905 (1970) R.A. Olofson, W.R. Thompson and J.S. Michelman, J. Am. Chem. Soc. 86, 1865 (1964) A.C. Rochat and R.A. Olofson, Tetrahedron Lett. 3377 (1969) R.A. Olofson and K.D. Lotts, Tetrahedron Lett. 3131 (1979) S. Fischer and C. Wentrup, J. Chem. Soc., Chem. Comm. 502 (1980) P.A.S. Smith and E. Leon, J. Am. Chem. Soc. 80, 4647 (1958) N.H. Toubro and A. Holm, J. Am. Chem. Soc. 102, 2093 (1980) P.A.S. Smith and E. Leon, J. Am. Chem. Soc. 80, 4647 (1958) Y.V. Shurukhin, N.A. Klyuev, I.I. Grandberg and V.A. Konehits, Chem. Heteroc. Comp. 20, 1177 (1984) P. Rajagopolan and B.G. Advani, J. Org. Chem. 30, 3369 (1965)
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144. A. Dondoni, G. Barbara and A. Battaglia, J. Org. Chem. 42, 3372 (1977) 145. P. Beltrame and C. Vintani, J. Chem. Soc. (B) 873 (1970) 146. D.S.T. A-Lim, A.H.M. Schotman, R. Addink, K. Te Niejenhuis and W.J. Mijs, Polym. Bull. 35, 9 (1995) 147. G. Bertrand and C. Wentrup, Angew. Chem. Int. Ed. 33, 527 (1994) 148. M. Granier, A. Baceiredo, H. Gruetzmacher, H. Pritzkow and G. Bertrand, Angew. Chem. 102, 671 (1990) 149. H. Quast and L. Bieber, Chem. Ber. 114, 3252 (1981) 150. R. Chhabra, M.R. Pokhrel and S. Rajat, Proc. 41st Midwest Regional ACS Meeting, Oct., 2006 151. H. Quast and U. Nahr, Chem. Ber. 118, 526 (1985) 152. A.R. Katritzky, P. Nie, A. Dondoni and D. Tassi, Synth. Comm. 7, 387 (1977); J. Chem. Soc. Perkin 1, 1961 (1979) 153. H. Ulrich, J.N. Tilley and A.A.R. Sayigh, J. Org. Chem. 29, 2401 (1964) 154. H. Ulrich and A.A.R. Sayigh, J. Org. Chem. 30, 2779 (1965) 155. D.F. Gavin, W.J. Schnabel, E. Kober and M.A. Robinson, J. Org. Chem. 32, 2511 (1967) 156. T.J. Giacobbe, D.A. Tomalia and W.A. Sprenger, J. Org. Chem. 36, 2142 (1971) 157. T. Fuchigami, E. Ichikawa and K. Odo, Bl. Chem. Soc. Jpn. 46, 1765 (1973) 158. S. Furumoto, Yuki Gosei Kagaku Kyokay Shi. 34, 499 (1976); C.A. 85, 176,906 (1976) 159. I.L. Knunyants, A.F. Gontar, N.A. Tilkunova, A.S. Vinigradov and E.G. Bykhovskaya, J. Fluorine Chem. 15, 169 (1980) 160. B. Anders and E. Kuehle, Angew. Chem. Int. Ed. 4, 430 (1965) 161. E. Kuehle, Angew. Chem. 81, 18 (1969) 162. T. Hassel and H.P. Mueller, Angew. Chem. 99, 368 (1987) 163. W. Zecher, H. Tarnow and H. Holtschmidt, Germ. Pat. 1,222,918 (1964) 164. I.G. Hinton and R.F. Webb, J. Chem. Soc. 5051 (1961) 165. K.R. Birdwhistell, J. Lanza and J. Pasos, J. Organomet. Chem. 584, 200 (1999) 166. K. Weiss and P. Kindl, Angew. Chem. 96, 616 (1984) 167. K. Weiss and K. Hoffmann, Z. Naturforsch. 42b, 769 (1987) 168. S.A. Bell, T.Y. Meyer and S.J. Gelb, J. Am. Chem. Soc. 124, 10698 (2002) 169. R.L. Zuckerman and R.G. Bergman, Organomet. 20, 1792 (2001) 170. T. Gan Ong, G.P.A. Yap and O.S. Richeson, J. Chem. Soc., Chem. Commun. 2612 (2003) 171. J.R. Babcock and L.R. Sita, J. Am. Chem. Soc. 120, 5585 (1998) 172. A.W. Holland and R.G. Bergman, J. Am. Chem. Soc. 124, 9010 (2002) 173. W. Neumann and P. Fischer, Angew. Chem. Int. Ed. 1, 621 (1962) 174. P. Fischer, W. Kallert, H. Holtschmidt and E. Meister, Germ. Pat. 1,145,353 (1963); C.A. 58, 12,732 (1963) 175. G. Schalle, T. Chivers, C. Jaska and N. Sandblom, J. Chem. Soc., Chem. Commun. 1657 (2000) 176. V.I. Gorbatenko, N.V. Melnichenko, M.N. Gertsyuk and L.I. Samarai, Zh. Org. Khim. 12, 2103 (1976) 177. T. Minami and T. Agawa, Tetrahedron Lett. 2651 (1968) 178. D.H. Clemens, A.J. Bell and J.L. O’Brian, Tetrahedron Lett. 1491 (1965) 179. V. Nair, Tetrahedron Lett. 4831 (1971)
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201. 202. 203. 204. 205.
R. Huisgen and J. Wulff, Tetrahedron Lett. 921 (1967) E. Schaumann and H. Behr, Liebigs Ann. Chem. 1322 (1979) E. Schaumann, E. Kausch and W. Walter, Chem. Ber. 110, 820 (1977) H. Ulrich, B. Tucker and A.A.R. Sayigh, J. Am. Chem. Soc. 94, 3484 (1972) M.W. Barker and R.H. Jones, J. Heterocycl. Chem. 9, 555 (1972) S.P. Makarov et al., Dokl. Akad. Nauk SSSR 142, 596 (1962), C.A. 57, 4528 (1962) C.K. Ingold, J. Chem. Soc. 87 (1924) H. Ulrich and A.A.R. Sayigh, J. Chem. Soc. 87 (1963) H.W. Hein, D.W. Ludovici, J.A. Pardoen, R.C. Weber, E. Bonsall and K.R. Osterhout, J. Org. Chem. 44, 3843 (1979) A.J. Bloodworth, A.G. Davies and S.C. Vasishtha, J. Chem. Soc. (C) 2640 (1968) T.L. Gilchrist, C.J. Moody and C.W. Rees, J. Chem. Soc., Perkin 1 1871 (1979) M. Arthur, H.P. Goodwin, A. Baceiredo, K.B. Dillon and G. Bertrand, Organomet. 10, 3205 (1991) H. Hettler, Tetrahedron Lett. 1791 (1968) Y. Itoh, T. Hirao and T. Saegusa, J. Org. Chem. 40, 2981 (1975) H. Pri-Bar, and J. Schwartz, J. Chem. Soc., Chem. Comm. 347 (1997) T. Kiyoi, N. Seko, K. Yoshino and Y. Ito, J. Org. Chem. 58, 5118 (1993) M. Lazar and R.J. Angelici, J. Am. Chem. Soc. 128, 10613 (2006) T. Saegusa, Y. Itoh and T. Shimizu, J. Org. Chem. 35, 3995 (1970) P.H. Ogden, Fr. Pat. 1,535,979; C.A. 71, 49,334 (1969) Y.G. Shermolovich and V.I. Gorbatenko, Zh. Org. Khim. 12, 1129 (1976) V.I. Gorbatenko, N.V. Melnichenko, M.N. Gertsyuk and L.I. Samarai, Zh. Org. Khim. 12, 231 (1976) R.L. Zuckerman and R.G. Bergman, Organomet. 19, 4795 (2000) P. Royo and J. Sanchez-Nieves, J. Organomet. Chem. 597, 61 (2000) H. Wang, H. Chan and Z. Xie, Organomet. 24, 3772 (2005) R.A. Cardona and E. Kupchik, J. Organomet. Chem. 43, 163 (1972) D.J. Mindiola and G.L. Hillhouse, J. Chem. Soc., Chem. Comm. 1840 (2002)
2.4
Reactions of Alkyl- and Arylcarbodiimides
180. 181. 182. 183. 184. 185. 186. 187. 188. 189. 190. 191. 192. 193. 194. 195. 196. 197. 198. 199. 200.
2.4.1 Oligomerization and Polymerization Carbodiimides undergo cyclooligomerization reactions. In this regard they are similar to isocyanates, the mono imides of carbon dioxide. For example, aliphatic carbodiimides undergo rapid dimerization catalyzed by tetrafluoroboric acid at room temperature to give salts of the cyclodimers 183. Neutralization with dilute sodium hydroxide, or better filtration through basic Al2 O3 , afford 1,3-dialkyl-2,4-bisalkylimino-1,3-diazetidines 184.206
NHR BF4 RN 2 RN
C
NR
NR RN
NR RN
NR RN
183
184
(2.91)
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[%]
mp ◦ C
n-Pr i-Pr C6 H11
70 90 95
90a 52 122.5
a
bp at 0.05 Torr
Salts of aliphatic carbodiimide dimers are also obtained in the reaction of carbodiimides with dimethyl sulfate. The cyclic dimer of dibenzylcarbodiimide, mp 102–103 ◦ C, was isolated in low yield from the distillation residue of the monomer.207 The crystal structure of 1,3-dicyclohexyl-2,4-bis(cyclohexylimino)-1,3-diazetidine, the cyclodimer of DCC, is recorded.208 In the mono P-substituted carbodiimide 185 dimerization occurs across the alkyl substituted C N bond to give the expected cyclodimer 186.209
Ph2P(O)N NR 2Ph2P(O)N
C
NR
(2.92)
RN NP(O)Ph2
185
186
Diazetidines 188 are also obtained in the reaction of 1,2,4-triazineiminophosphorane 187 with aryl isocyanates (yields: 55–75 %).210
Me
O
N
N
N
PPh3 + RNCO
Me
O
N
N
N
N NR
N SMe
O
Me
N
N
SMe RN N
N MeS 187
188
(2.93)
R
[%]
mp ◦ C
Ph 4-F-Ph 4-Cl-Ph 3-Me-Ph 3-MeOPh α-naphthyl
55 59 75 75 58 67
210–212 175–177 202–205 186–188 100–102 210–212
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The dimers are found to be Z,Z isomers 189, but small amounts of the E,E isomers 190 are also formed. Theoretical considerations favor the formation of the Z,Z isomers.211
R N
Het N
Het N
Me
O
R N
Het N
Het =
N
N R
N R
189
190
N
Het
N N
MeS (2.94)
Reaction of the diazetidines 188 with amines afford pentasubstituted biguanides.212 Dimers and trimers of N-ary-N -trifluoromethylcarbodiimides are obtained in their attempted synthesis.213 In N-aryl-N -trifluoromethylcarbodiimides the trimerization occurs across the aliphatic C N group. The dimerization of diphenylcarbodiimide is catalyzed by tributylphosphine. In this manner 1,3-diphenyl-2,4-diphenylimino-1,3-diazetidine 191, mp 162–163 ◦ C, is obtained in 71 % yield on heating of the carbodiimide at 90 ◦ C in the presence of tributylphosphine for 22 hrs.214 Heating of diphenylcarbodiimide at 165–170 ◦ C for 16 hrs. in the absence of the catalyst afforded 43 % of the dimer, indicating that the dimerization is a thermal process.
NPh PhN 2 PhN
C
NPh
(2.95)
NPh PhN 191
When tetrafluoroboric acid is added to aromatic carbodiimides quinazolium salts 192 are obtained, which on hydrolysis afford 3-aryl-2-arylamino-4-aryliminoquinazolines 193.206
NHPh BF4
N PhN
C
NPh
N
NPh PhNH 192
NHPh NPh
PhN
(2.96)
193
Heterocyclic substituted carbodiimides can undergo dimerization by a [2+4] cycloaddition process. For example, di-2-pyridylcarbodimide 194, generated in situ in the reaction of an iminophosphorane with CS2 and an isothiocyanate, affords the cyclodimer 195,
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mp 218–220 ◦ C in 94 % yield.215
N N N N
C
N
N
N N
194
N
N
N
(2.97)
N
195
In a similar manner [2+4] cycloadducts are formed in the generation of N-trifluoromethylN -(2-pyridyl)carbodiimide. Heating of diphenylcarbodiimide with N-methylhexamethyldisilazane affords the diphenylcarbodiimide trimer 196.216
NPh PhN 3 PhN
C
NPh
(2.98)
NPh PhN
N Ph 196
NPh
The more reactive N,N-dimethylcarbodiimide undergoes trimerization on standing at room temperature to give cyclotrimer 197, which on heating at 160–170 ◦ C isomerizes to form 2,4,6-tris-dimethylamino-1,3,5-triazine 198.217
NMe2
NMe 3 MeN
C
NMe
MeN MeN
NMe N Me 197
NMe
N Me2N
N N
NMe2
198 (2.99)
Dicarbodiimides have not gained the same prominence as diisocyanates as monomers for addition polymers. Dicarbodiimides are obtained from difunctional precursors, such as bis-thioureas. Another synthetic method is the conversion of diisocyanates with iminophosphoranes.218 The reaction can be conducted stepwise to give an isocyanatocarbodiimide as an intermediate. The reaction of sterically hindered aromatic diisocyanates with bases or phospholene oxide catalysts afford oligomeric carbodiimides having terminal isocyanate groups.219 If the catalytic conversion of 4,4 -diphenylmethane diisocyanate (MDI) is conducted in the
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presence of phenyl isocyanate as a chain stopper, predominantly linear oligomeric carbodiimides are obtained. This reaction is conducted in xylene at 120 ◦ C, using 1-phenyl-3methylphospholene-1-oxide as the catalyst.220 The resulting medium high molecular weight polymers showed improved processing most likely by the plasticizer effect of the lower molecular weight oligomers. However, rapid crosslinking occurs on heating to 200–250 ◦ C. The infrared spectra of the heated polymers show a decrease in carbodiimide absorption and the appearance of a new band due to a C N group at 1690 cm−1 , indicating the formation of cyclic dimers and trimers. The reaction of hexamethylene diisocyanate with a phospholene oxide catalyst affords low molecular weight trifunctional oligomers, in which the isocyanate and the carbodiimide groups are cotrimerized with the generated carbon dioxide to give six-membered ring cycloadducts. A diisocyanate byproduct is used as a masked isocyanate.219 Polyhexamethylenecarbodiimide, an insoluble condensation reagent for the synthesis of peptides, is obtained in the reaction of hexamethylene diisocyanate with a phospholene oxide catalyst in NMP. The isocyanate end groups are reacted with ethanol.221 Linear polycarbodiimides, upon reaction with adipic acid, form polyureides. For example, reaction of the 2,4-TDI derived carbodiimide with adipic acid in DMF produces the polymer, mp 295 ◦ C.222 Oligomeric carbodiimides are efficient stabilizers for polyesters or polyester containing polymers. The homopolymerization of aliphatic carbodiimides, using n-butyl lithium as catalyst in hydrocarbon solvents at room temperature, affords nylon-1 imides 199 (R Me, n-Bu, allyl, Ph), which have no commercial interest because unzipping occurs on heating. In the unzipping process the monomer is regenerated.223 The polymerization failed with DDC, diisopropylcarbodiimide and methyl-t-butylcarbodiimide. RN C NR ←→ − [ N(R) C( NR)− ]n 199
(2.100)
Using titanium catalysts, such as CpTiCl2 NMe2 , rigid rod or helical polycarbodiimides are obtained from dialkyl-, arylalkyl- and diarylcarbodiimides.224 Polycarbodiimides formed from optically active monomers show large increases and sign changes in their optical rotations, which is indicative of diastereoselictivity with respect to helical sense. More robust copper(I) and copper(II) amidinate complexes also initiate this living polymerization of carbodiimides.225 Vinyl polymers, bearing pendant carbodiimide groups 200, are obtained from N-(p- or m-vinylphenyl)-N -alkylcarbodiimides.226
N
C
NEt
N
C
NEt (2.101)
P 200 Polymers with pendant carbodiimide groups are also synthesized from crosslinked polystyrene.227 In this synthetic route crosslinked polystyrene beads are chloromethylated
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and converted to the amines. Reaction with isopropyl isocyanate gives the urea 201, which is treated with tosyl chloride and triethylamine to produce the carbodiimide polymer 202.
P
CH2NHCONHR
P
CH2N
C
NR (2.102)
201
202
Utilization of this polymer in peptide synthesis afforded only 60 % peptide, the remainder being the N-acylurea.228 However, the polymer is useful in the Moffat oxidation (see Section 2.4.3).229 Polymers derived from aromatic diisocyanates by a catalytic process are of considerable interest. These polymers have phosphine imine and isocyanate end-groups, which can lead to further reaction on heating. Wagner and coworkers14 obtained linear low molecular weight polymers from 2,4-TDI, using 1-methylphospholene-1-oxide as catalyst. These polymers can be reacted with a wide variety of nucleophiles to give poly(ureas), poly(acyl ureas), poly(formamidines) and poly(guanidines). Also, reaction of these polymers with acrylic or methacrylic acid affords polymers, which can be further crosslinked by a free radical type polymerization process. For example, diisocyanatocarbodiimides, upon reaction with polyols followed by reaction with amines give polyurethanes containing guanidine groups.230 Melt processable linear polycarbodiimides cannot be obtained in the polymerization of aromatic diisocyanates with a phospholene oxide catalyst.220 However, some of the high molecular weight polymers can be molded into clear tough films, but the tensile properties of these films decrease with increasing temperature.231 Because of the tendency of isocyanate terminated polycarbodiimides to crosslink on heating, it was of considerable interest to utilize them in the construction of thermoset polymers. Thus, reacting polymeric MDI (PMDI) with a phospholene oxide catalyst affords low density rigid open cell polycarbodiimide foams.232 The generated carbon dioxide is used as the blowing agent. As the component temperature is raised from 25 ◦ C to 80 ◦ C at a constant catalyst level, density decreases with a corresponding decrease in compressive strength. Foam friability also decreases with increasing component temperature. Poly(carbodiimide) foams are a new generation of isocyanate based polymers that have properties significantly different from polyurethane or polyisocyanurate foams. Of especial interest are their heat stability and flammability properties. Modification of poly(carbodiimide) foams with polyols afford hybride foams containing urethane sections. However, the thermal stabilities of the poly(urethane carbodiimide) foams are lower. Using isocyanate trimerization catalysts, such as 1,3,5-tris(3dimethylaminopropyl)hexahydro-s-triazine, in combination with the phospholene oxide catalyst gives poly(isocyanurate carbodiimide) foams with improved high temperature properties. The cellular poly(carbodiimide) foams derived from PMDI incorporate sixmembered ring structures in their network polymer structure.232
2.4.2 Cycloaddition Reactions 2.4.2.1 [2+2] Cycloaddition Reactions Across C N Bonds. Cycloaddition reactions of heterocumulenes are well known reactions.233 Like many of the other heterocumulenes carbodiimides form cyclodimers and cyclotrimers (see Section 2.4.1). The obtained dimeric
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47
species can be considered to be intermediates in the carbodiimide exchange reaction. [2+2] Cycloadducts derived from two different linear carbodiimides were first synthesized by Ulrich and coworkers in 1987.234 For example, N-(4-dimethylaminophenyl)N -methylcarbodiimide 203, acting as the nucleophile, reacts with N-(4-nitrophenyl)-N isopropylcarbodiimide 204, acting as the electrophile, to form the [2+2] cycloadduct 205 in 69 % yield. The reaction proceeds across the aliphatic substituted C N bond, most likely involving a dipolar intermediate. No other [2+2] cycloadducts were formed. Me2N
N
C
NMe + O2N
203
N
C
N-i-Pr
204 Me2N
(2.103) N NMe i-PrN N NO2 205
Cycloadducts derived from macrocyclic carbodiimides and diphenylcarbodiimide are also known (see Section 11.3.3). Aliphatic carbodiimides often react with heterocumulenes to form six-membered ring 1:2 cycloadducts. For example, DCC reacts with N-p-toluenesulfonyl-N cyclohexylcarbodiimide to give the 1:2 cycloadduct 207, mp 123–124 ◦ C in 93 % yield. The initially formed polar intermediate 206 reacts with a second sulfonylcarbodiimide molecule to give the final product.235 NR C RN RN
C
NR + 2 R1SO2N
C
NR
NR + R1SO2N
R1SO2N
C
NR
206 NR NSO2R1
RN RN
N
NR
SO2R1 207
(2.104)
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Similar [2+2+2] cycloadducts 208 are obtained in the reaction of arenesulfonyl isocyanates with aliphatic carbodiimides.235
NR2 2 RSO2N
C
O + R1N
R1N
NR2
C
O
NSO2R
(2.105)
O N SO2R 208
R1
R2
Me cyclohexyl cyclohexyl
t-Bu cyclohexyl cyclohexyl
R 4-MePh 4-MePh 3-ClPh
mp ◦ C
[%] 25 75 58
145–146 170–172 150–153
Similar six-membered ring 1:2 cycloadducts are obtained from aliphatic carbodiimides and aliphatic isocyanates, arenesulfonyl isocyanates and chlorosulfonyl isocyanates. The reaction of carbodiimides with alkyl- or arylisocyanates proceeds exclusively across the C N bond of the isocyanates to give 2-imino-1,3-diazetidine-4-ones 209 as evidenced by degradation studies.239 In the case of N-alkyl-N -arylcarbodiimides the reaction proceeds across the aliphatic C N bond. In Table 2.1 the [2+2] cycloadducts derived from carbodiimides and isocyanates are listed. p-Substituted N-aryl-N -alkylcarbodiimides undergo fastest reaction when the substituent is Me2 N > Me > H > O2 N . The reaction of an aryl isocyanate is fastest when the p-substituent is O2 N . Aliphatic isocyanates react considerably slower than aromatic isocyanates. Steric hindrance can also play a role in determining which C N bond participates in the [2+2] cycloaddition reaction. For example, in N-(4-dimethylaminophenyl)-N phenylcarbodiimide, addition occurs across the phenyl substituted C N bond, while in N(4-dimethylaminophenyl)-N -2,6-dimethylphenylcarbodiimide, reaction occurs across the 4-dimethylaminophenyl substituted C N bond. The [2+2] cycloaddition reaction of carbodiimides with isocyanates follows second order kinetics. Since aromatic carbodiimides react slower than aliphatic carbodiimides, heating at 100–125 ◦ C facilitates the reaction of the former. The 2:1 cycloadducts 210 derived from ethyl isocyanate and diethylcarbodiimide are obtained when bis(acetylacetonate) tin (II) is used as catalyst.241
NEt 2 EtNCO + EtN
C
NEt
NEt
EtN O
N Et 210
O
(2.107)
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Table 2.1 [2+2] Cycloadducts derived from Carbodiimides and Isocyanates
RN
C
O + R1N
NR2
C
NR2
R1N
(2.106)
NR
O
209 R
R1
R2
[%]
mp ◦ C
Ref.
Me Me Me Et C6 H11 Ph Ph Ph Ph Ph Ph Ph Ph Ph 4-O2 NPh 4-O2 NPh 4-O2 NPh 4-O2 NPh α-C10 H7
Me Me Me Et i-Pr i-Pr t-Bu Me Me Me Me Me Ph 2,6-Me2 Ph C6 H11 Me i-Pr 2-MePh i-Pr
Ph 4-MeOPh 4-(Me2 N)Ph Et i-Pr i-Pr t-Bu t-Bu Ph 4-ClPh 4-MeOPh 4-(Me2 N)Ph Ph 2,6-Me2 Ph C6 H11 4-O2 NPh 4-O2 NPh 2-MePh i-Pr
28 48 71 — — — — 45 54 47 85 68
35–36 66–67 145–146 38–40/0.1a oil 38 68 52 86–87 92–93 101–102 120–121 139–140 125–126 73–75 180–181 140–142 100–101 oil
234 234 234 236 237 237 237 238 234 234 234 234 239 234 240 234 234 240 237
a
30 — 90 86 30 —
bp ◦ C/Torr
The reaction of DCC with chlorosulfonyl isocyanate affords two products depending on the mode of addition of the reagents. When the isocyanate is added to the carbodiimide the [2+2] cycloadduct 211 is obtained, while addition of the carbodiimide to the isocyanate affords the six membered ring [2+2+2] adducts 212.242
NR O RN
C
NR + ClSO2NCO
ClSO2N NR RN 211
+
NR
ClSO2N O
N O SO2Cl 212 (2.108)
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Six membered ring 2:1 cycloadducts 213 are also obtained in the reaction of isocyanate salts with carbodiimides.243 O RR1C
N
O SbCl6 + R2N
C
C
NR2
RR1CHN
NCH2R3
R3CH2N
N R2 213
NCH2R3
(2.109)
The reaction of phenylcarbonyl isocyanate with carbodiimides at low temperatures affords oxazetidine imines 214 by addition across the C O bond of the isocyanate group.
NR1 RCONCO + R1N
C
R2N
NR2
(2.110)
O
RCON 214 R
R1
R2
[%]
mp ◦ C
Ref.
PhCO PhCO
t-Bu C6 H11
Me C6 H11
PhCO
Ph
Ph
81 — 54 —
114–115 138–139 142–143 132–138
238 244 243 245
Evidence for the proposed structure of the four membered ring [2+2] cycloadducts is provided by the retroreaction of the N-methyl-N -t-butylcarbodiimide adduct 215, which affords t-butyl isocyanate rather than methyl isocyanate expected for the isomeric structure.238
N-t-Bu MeN O
t-BuNCO + MeN
C
NCOPh
(2.111)
RCON 215 There is considerable discrepancy in the literature regarding the structures of the cycloadducts derived from carbonyl isocyanates and carbodiimides. For example, Arbuzov and Zobova245 claim that a cycloadduct, mp 132–138 ◦ C (dec.), derived from diphenylcarbodiimide and phenylcarbonyl isocyanate at 0 ◦ C has a diazetidinedione structure. Based on our findings an oxazetidine structure is indicated. Tsuge and Sakai246 obtain [2+4] cycloadducts 216 when the reaction of arylcarbonyl isocyanates with carbodiimides is conducted in refluxing benzene. Fom phenylcarbonyl isocyanate and N-phenyl-N -2-methylphenylcarbodiimide mixtures of [2+4] cycloadducts
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are obtained.
O RCONCO + R1N
NR2
N
NR2
C
R
(2.112)
NR1
O 216
R1
R2
[%]
mp ◦ C
Ph Ph 4-ClPh 4-MeOPh 4-O2 NPh C6 H11 C6 H11 C6 H11 C6 H11
Ph C6 H11 C6 H11 C6 H11 C6 H11 C6 H11 C6 H11 C6 H11 C6 H11
— 75 71 66.5 75 54 76 64 87
179–179.5 128–129 117–118 123–124 125–126 142–143 122–123 157–158 139–140
R Ph Ph Ph Ph Ph Ph 4-ClPh 4-MeOPh 4-O2 NPh
Phenylthiocarbonyl isocyanate reacts similarly with carbodiimides to give [2+4] cycloadducts 217. From N-phenyl-N -cyclohexylcarbodiimide and phenyl-thiocarbonyl isocyanate two isomeric [2+4] cycloadducts are obtained. Aliphatic thiocarbonyl isocyanates react similarly to give [2+4] cycloadducts.247 O
PhCSN
C
O + RN
C
NR
N
NR Ph
S
(2.113)
NR
217 The formation of [2+2] cycloadducts derived from isocyanate terminated MDI carbodiimide and MDI is commercially utilized to form a liquid MDI product. These types of cycloadducts are also present in polymeric MDI. The [2+2] cycloaddition reaction of isothiocyanates with carbodiimides generally proceeds across the C S bond of the isothiocyanate to give thiazetidine derivatives 218. However, in the reaction of methyl isothiocyanate with N-(4-dimethylaminophenyl)-N methylcarbodiimide a mixture of the thiazetidine derivative 218 and the isomeric iminodiazetidinethione derivative 219 is obtained. The structure of 219 was confirmed by X-ray crystallography.248
RN
C
S + R1N
C
NR2
NR2
R1N
+
NR2 R1N NR
S RN
(2.114)
S 218
219
The cycloadducts derived from isothiocyanates and carbodiimides are listed in Table 2.2.
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Chemistry and Technology of Carbodiimides Table 2.2 Cycloadducts derived from Isothiocyanates and Carbodiimides R
R1
R2
[%]
218 mp ◦ C
219 mp ◦ C
Ref.
Me Ph Ph 4-ClPh 4-MeOPh 4-Me2 NPh 4-O2 NPh 4-O2 NPh 4-O2 NPh
4-Me2 NPh Ph C6 H11 C6 H11 C6 H11 C6 H11 t-Bu i-Pr C6 H11
Me Me C6 H11 C6 H11 C6 H11 C6 H11 Me i-Pr C6 H11
t-Bu i-Pr C6 H11 Ph 2-MePh i-Pr C6 H11
Me i-Pr C6 H11 Ph 2-MePh i-Pr C6 H11
131–132 115–116 75–76 68–69 oil 67–68 91–92 51–52 73–75 75–76 87–88 56–58 152–153 181–182 130–131 oil 120–122
124–125 —b
4-MePhSO2 4-MePhSO2 4-MePhSO2 4-MePhSO2 4-MePhSO2 Ph2 P(S) Ph2 P(S)
48a 8 55 38 55 31 66 90 95 92 61 40 81 89 69 100 100
248 248 249 249 249 249 238 238 238 249 238 238 238 238 238 250 250
a b
Combined yield of 218 and 219 Was also present in the crude reaction mixture
Heating of the cycloadduct derived from 4-nitrophenyl isothiocyanate and dicyclohexylcarbodiimide causes cycloreversion to give the starting materials.249 In the reaction of phenylcarbonyl isothiocyanate and substituted phenylcarbonyl isothiocyanates, respectively, with carbodiimides, [2+4] cycloadducts 221 are usually obtained, but the [2 + 2] cycloadduct 220 is also formed when the reaction of DCC with phenylthiocarbonyl isothiocyanate is stopped at shorter reaction times.251 S NR NR N RN + RCONCS + RN C NR (2.115) S NR R O RCON
220
221
1-Thia-3-azoniabutatriene salts 222 react with carbodiimides to give the corresponding [2 + 2] cycloadducts 223 in 69–85 % yield.252
NR1 Me2NRC
N
C
S SbCl6
+
R1N
C
R1N
NR1
S Me2NRC
222
SbCl6
N 223 (2.116)
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Dialkylaminothiocarbamoyl isothiocyanates react with carbodiimides to give [2+4] cycloadducts.253 [2 + 2 + 2] Cycloadducts 225 are obtained in the reaction of the shown carbodiimide 224 with methyl- or benzyl isothiocyanate.254 The structure of the [2+ 2+2] cycloadducts were determined by X-ray crystallography.255
S Me2C(CSNMe2)N
C
R1N
NR + R1NCS
NR
S
N1 R
224
NC(Me)2CSNMe2
225 (2.117)
R
R1
[%]
mp ◦ C
Me Et i-Pr i-Pr PhCH2
Me Et Me PhCH2 PhCH2
23 14 51 44 16
155–157 96–98 166–168 165 73–75
Likewise, the heterocyclic isothiocyanate 226 reacts with DCC to give the expected [2+2] cycloadduct 227.256
NC6H11
C6H11N Me
Me
N
N
NCS + DCC
S
(2.118)
N S
S 226
227
Isoselenocyanates also undergo [2 + 2] cycloaddition reactions across their C Se bond with carbodiimides to give 1,3-selenazetidine-2,4-diimines 228.257
R1N
C
Se + R2N
C
NR2
NR2
R2N R1N
Se 228
(2.119)
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Chemistry and Technology of Carbodiimides R1 cyclohexyl cyclohexyl Ph Ph 4-ClPh 4-ClPh 4-BrPh 4-BrPh
R2
[%]
i-Pr cyclohexyl i-Pr cyclohexyl i-Pr cyclohexyl i-Pr cyclohexyl
88 99 84 98 97 88 99 98
In the reaction of N-(4-methylphenyl)diphenylimine 229 with diphenylcarbodiimide the [2 + 2] cycloadduct 230 is obtained.258
NPh Me
N
CPh2 + PhN
C
PhN
NPh
N
Ph2
Me 229
230 (2.120)
Also, metalimides, such as the pinacolate complex of iridium 231 undergo a [2+2] cycloaddition reaction with N,N -ditolylcarbodiimide to give the metalacycle 232.259
LIr
NR + R1N
C
NR1
231
LIr
NR
R1N
(2.121)
NR1
232
Similarly, imidozirconocene complexes 233 undergo the [2+2] cycloaddition reaction with carbodiimides to give the metalacycles 234.260
Cp2Zr(THF)
233
NR + R1N
C
NR1
Cp2Zr
NR
R1N
NR1
(2.122)
234
In the reaction of the P C N derivative 235 with diphenylcarbodiimide at −70 ◦ C the cycloaddition proceeds across the C P bond rather than the C N bond to give the
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[2 + 2] cycloadduct 236.261
N-t-Bu t-BuP
C
N-t-Bu + PhN
C
t-BuP
NPh
(2.123)
NPh PhN
235
236
In the reaction of DCC with the phosphaketene RP C O addition across the P C bond is also observed. Also, (tropon-2-ylimino)arsorane 237 reacts with diphenylcarbodiimide to give 238.262
O N
N
+ PhN
C
NPh
NPh
(2.124)
N
AsPh3
237
238
In situ generated stiborane and bismuthorane react similarly. 2.4.2.2 [2+2] Cycloaddition Reactions Across C C Multiple Bonds. Cycloadducts derived from carbodiimides and olefins or allenes are not known. However, the [2+2] cycloaddition of ketenes, R2 C C O, to carbodiimides affords 4-imino-2-azetidinones (β-lactames) 239 in high yield. Aliphatic carbodiimides show higher reactivity in comparison to aromatic carbodiimides, and the reaction proceeds across the aliphatic C N bond in N-alkyl-N -arylcarbodiimides.263 The cycloadducts obtained in this reaction are listed in Table 2.3. Also, reaction of N-trimethylsilyl-N -alkylcarbodiimides 240 with haloketenes affords β-lactams 241, which are easily desilated with absolute methanol to give halogenated 1-alkyl-4-imino-2-acetidinones 242.272
Me3SiN
C
NR + R1R2C
C
O
RN
NH RN
R1R2 O
240
NSiMe3
RR1 O
241
242
(2.126) The [2 + 2] cycloaddition reaction proceeds via an ionic linear intermediate, which can be intercepted when the reaction is carried out in liquid sulfur dioxide, for example, when diphenylketene is added to a solution of diisopropylcarbodiimide in sulfur dioxide at −78 ◦ C. On warming and evaporation of the sulfur dioxide a 90 % yield of 1,1-dioxo2-(N-isopropylimino)-3-isopropyl-5,5-diphenylthiazolidine 4-one 243, mp 119–122 ◦ C is
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Table 2.3 Cycloadducts derived from Ketenes and Carbodiimides
RR1C
C
O + R2N
C
NR3
R2N
NR3
RR1
O
(2.125)
239 R
R1
R2
R3
[%]
mp ◦ C (bp)
Ref.
H F Cl Cl Cl Cl Cl Br Me3 Si Me t-Bu
H H H Cl CN Me Ph Br Br Me COOEt
i-Pr i-Pr i-Pr C6 H11 C6 H11 C6 H11 C6 H11 C6 H11 i-Pr i-Pr
5 40 65 55 88 25 65 59 90 32 64
PhC(Me)2 H Me Et Ph Ph Ph Ph Ph Ph
COOEt 2-ClPh Ph Ph Ph Ph Ph Ph Ph Ph
i-Pr i-Pr i-Pr C6 H11 C6 H11 C6 H11 C6 H11 C6 H11 i-Pr i-Pr —a —b —a C6 H11 —a i-Pr Me Et Et t-Bu t-Bu i-Pr
Ph Ph
Ph Ph
t-Bu C6 H11
t-Bu C6 H11
Ph Ph Ph Ph Ph Ph
Ph Ph Ph Ph Ph Ph
Me2 NC(S)C(Me)2 Me2 NC(O)C(Me)2 PhCH2 Ph 4-MePh 4-MeOPh
i-Pr i-Pr PhCH2 Ph 4-MePh 4-MeOPh
— (50–51/0.7) — — — 61–62 86–88 121.5–122 (72/0.25)c 75–76 — — — — — 35–36 — — — — — — 108.5–109.5 — — 158–159 161 128–130 — — — —
264 265 266 267 268 264 264 264 269 264 270 270 270 264 271 265 263 263 263 263 263 263 264 263 263 264 271 271 263 263 263 263
a b c
(−) menthylcarbodiimide S-PhCHMeN= =C= =N-t-Bu In the reaction hydrolysis of the silyl group occurs
C6 H11 i-Pr t-Bu i-Pr t-Bu Ph 4-MePh i-Pr
74 55 37 57 70 30 71 22 30 80 88 75 88 90 45 59 49 60 48 62
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obtained.273
NR R RN
C
NR + Ph2C
C
N
O
NR
C
RN
SO2
SO2
O
CPh2
O
Ph
Ph 243 (2.127)
In the reaction of ketene with carbodiimides in sulfur dioxide the five membered ring thiazolidine-4-ones 244 are similarly obtained.274
NR1
R1N CH2
C
O + R1N
NR2 + SO2
C
(2.128)
SO2
O 244
R1
R2
[%]
mp ◦ C
C6 H11 PhCH2 PhCH2 PhCH2 4-MePh 4-MePh 3,5-Me2 Ph 2,4,5-Me3 Ph 4-ClPh 4-MeOPh
C6 H11 PhCH2 3,5-Me2 Ph 2,4,6-Me3 Ph PhCH2 4-MePh 3,5-Me2 Ph 3,5-Me2 Ph 4-ClPh 4-MeOPh
57 51 51 49 70 48 61 22 68 60
143–145 111.5 103 102 167–168 185–187 211–213 178–180 191.5 183
In the reaction of carbodiimides with chiral substituents with prochiral ketenes, β-lactams are obtained in a highly diastereoselective manner.270 The mesoionic oxazol-5-one 245 is in equilibrium with an acylaminoketene 246, which undergoes a [2+2] cycloaddition reaction with diisopropylcarbodiimide to give the cycloadduct 247, mp 159–160 ◦ C in 63 % yield.275 O O C
O Ph
Ph N Me 245
Ph
NR
O N Me 246
Ph
+ RN
RN C
NR
N(Me)COPh O
Ph 247
(2.129)
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[2+2] Cycloadducts 249 are also obtained in the reaction of bis(trifluoromethyl)thioketene 248 with carbodiimides.276
NR RN RN
C
NR + (CF3)2 C
C
S
(2.130)
(CF3)2
S 248
249
Diisopropylcarbodiimide reacts with 1,2-bistrifluoromethylacetylene 250 to form a [2+2] cycloadduct 251, which undergoes ringopening to give the linear adduct 252.277
N-i-Pr i-PrN
C
N-i-Pr + CF3C
iPrN
CCF3
CF3
F3C 250
251 i-PrN
C(CF3)C(CF3)
CHN
CMe2
252 (2.131) Reaction of the cyclobutane aluminum complex 253 with carbodiimides affords heterocycles 254.278
Me
Me AICl4 + RN Me
Me
Me C
NR
Me NR
Me Me
(2.132)
N
253
R
254
The cobalt catalyzed cycloaddition reaction of diphenylcarbodiimide with disubstituted acetylenes 255 affords the isomeric 2-imino-1,2-dihydropyridines 256 and 257.279
R2
R1 R2 PhN
C
NPh + 2 R1C
R1
+
CR2 R1
255
R2
R2 N Ph 256
NPh
R1
N Ph 257
NPh
(2.133) The same reaction is observed using bis(triphenylphosphan)diphenylcarbodiimide nickel as the catalyst.280
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Phenylacetylene reacts with diphenylcarbodiimide in the presence of Fe(CO)5 to give imidazoline derivatives 258 and 259.281 NPh PhN
NPh + PhC
C
PhN
CH
+
NPh
PhCH
NPh PhN NPh
PhCH
NPh
O
258
259
(2.134) The CO insertion product is obtained in low yield. A similar reaction is observed with diphenylbutadiyne and diphenylcarbodiimide.282 An exchange reaction occurs on treatment of the [2+2] cycloadduct obtained from a zirconocene imide and bis(trimethylsilyl)carbodiimide 260 and diphenylacetylene to form a new metalacycle 261. The latter reacts with diisopropylcarbodiimide to form the [2+2+2] cycloadduct 262.260 Cp2Zr
NtBu
Me3SiN
Cp2Zr
+ PhC
CPh
NSiMe3
NtBu + RN
Ph
260
C
NR
Ph 261 tBu
Cp2Zr
N
RN
(2.135) Ph Ph
NR 262
In contrast, reaction of bromophenylacetylene 263 and iron pentacarbonyl with diarylcarbodiimides at 90–100 ◦ C gives benzodiazepinone derivatives 264.283 NR
H N RN
C
NR + PhC
CBr + Fe(CO)5
NR Ph
263
C
O CPh
264
R
[%]
mp ◦ C
Ph 2-MePh 4-MePh
40 17 17
150–151 181–182 188–189
(2.136)
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In this reaction phenyl isocyanate is generated in an exchange reaction of the diphenylcarbodiimide with iron pentacarbonyl, and the unusual reaction product is formed from the carbodiimide, the isocyanate and two equivalents of the acetylene derivative. 2.4.2.3 [2 + 2] Cycloaddition Reactions Across Other Bonds. The reaction of benzoylsulfene 265, generated in situ, with DCC gives a mixture of the [2 + 2] cycloadducts 266 and the [2 + 4] cycloadducts 267.284
RN
NR + PhCOCH
C
RN
SO2
S
NR
+
O2S
265
O
O
NR COPh
Ph
NR
O 267
266
(2.137) The reaction of carbodiimides with carbon disulfide gives rise to the formation of isothiocyanates 269. The initially formed cycloadduct 268 undergoes a cycloreversion reaction to give the reaction products.285
NR RN
C
NR + S
C
RN
S
2 RN
C
S
S S 268
269 (2.138)
From cyclic carbodiimides and carbon disulfide the corresponding diisothiocyanates are obtained (see Section 11.3.3). A similar cycloreversion reaction is observed in the reaction of N-sulfinylamines 270 with carbodiimides which affords sulfonylcarbodiimides 271 (see also Section 9.2).286
RN
C
NR + R1SO2N
S
O
R1SO2N
270
C
NR + RN
S
O
271 (2.139) BF− 4
+
In the reaction of Me2 N SO 272 with aliphatic carbodiimides the initial [2+2] cycloadduct 273 is rearranged to give 1,2,4-thiadiazetidinium salts 274.287
RN
C
NR + Me2N
RN SO BF4 272
OS
NR BF4 NMe2 273
NMe2 BF4
RN OS
NR
274 (2.140)
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In contrast, diarylcarbodiimides react with 272 to give the heterocycles 275.288 X PhN
C
X + Me2N
N
OS
SO BF4
R BF4 N NMe2
N
272
O S
X
NR BF4 NMe2
N H 275
(2.141) Carbodiimides also add to the B N bond in (CF3 )2 B NMe2 to give the unstable cycloadduct 276, which rearranges at 20 ◦ C to give the metalacycle 277.289
R (CF3)2B
NMe2 + RN
C
NR
N RN
N
NR
B
CF3
N
B
NR
CF3 277
276
(2.142) Iminophosphoranes also undergo [2+2] cycloaddition reactions with carbodiimides to give phosphetidines. For example, reaction of Cl3 P N-tolyl 278 with diisopropylcarbodiimide gives the [2+2] cycloadduct 279.290
NR RN
C
NR + CI3P
RN
NR1
(2.143)
CI3P NR1 279
278
Likewise, reaction of the cyclic dimer of Cl3 P N-2-FPh with diisopropylcarbodiimide affords a 50 % yield of the cycloadduct 279 (R1 = 2-FPh).291 The iminophosphoranes catalytically metathesise C N bonds of carbodiimides via an addition/elimination process. The reaction of carbodiimides with aromatic aldehydes 280 affords isocyanates and benzylideneamines in an exchange reaction.292
RN
C
NR + R1CH 280
O
RN
C
O + RN
CHR1
(2.144)
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Similarly, N-trimethylsilyl-N -phenylcarbodiimide 281 reacts with aldehydes in the presence of fluoride ions to give the isomeric 1,3-oxazolidines 282 and 283.293
PhN NH Me3SiN
NPh + RCH
C
O
R
NPh
O
281
+
NH R
282
O 283 (2.145)
In contrast, the carbodiimide 284 reacts with benzaldehyde to give a 78 % yield of 5-phenyl2-(tritylamino)oxazole 285.294
N C
TsCH2N
NCPh3 + PhCH
O
Ph
NHCPh3
O 285
284
(2.146)
Carbodiimides also add to metal carbon bonds in metalorganic compounds. For example, cyclopentadienyl iron dicarbonyl 286 affords [2+2] cycloadducts 287 with diphenyl- and dicyclohexylcarbodiimide, respectively.295
RN
C
NR Cp
RN
NR + CpFe(CO)2
(2.147)
Fe O
286
CO 287
Also, pentacarbonyl(diphenylcarbene)tungsten 288 reacts with DCC or diisopropylcarbodiimide to give metathesis products, which may involve the [2+2] cycloadducts 289 as intermediates.296
NR (CO)5W
CPh2 + RN 288
RN C
NR
Ph2
W(CO)5
289 (CO)5W
C
NR + RN
CPh2 (2.148)
In the reaction of the titanium vinylmethyl derivative 290 with carbodiimides the [2+2] cycloadducts 291, derived from addition of the carbodiimide across the Ti C bond of the
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Cp2 Ti C CH2 intermediate are obtained in high yield.297
NR
Me [Cp2Ti
Cp2Ti
CH2]
C
+
RN
C
RN
NR
Cp2Ti
290
291 (2.149)
Cyclopentadienyl-bis(ethylene)cobalt reacts with carbodiimides to give bicyclic adducts (see Section 10.3) 2.4.2.4 [2+3] Cycloaddition Reactions. Carbodiimides also react as dipolarophiles in [2+3] cycloaddition reactions. For example, generation of diphenylnitryl imine 292 in the presence of diphenylcarbodiimide affords a spiro compound 293 as the result of the reaction of the initially formed [2+3] cycloadduct with a second equivalent of the nitrile imine.298
Ph NPh PhN
C
NPh + 2 PhC
N
NPh
PhN
NPh
PhN
NPh
PhN 293
292
(2.150)
Ph
Nitrile oxides 294 also react with carbodiimides to give the [2+3] cycloadducts 295.299
NR RN R1C(Cl)
NOH
[R1C
N
O] + RN
C
NR
294
R
O N 295 (2.151)
Similarly, nitrones 296 undergo this reaction, but the obtained oxadiazolidines 297 rearrange to give triazolidinones 298.300
NPh R2C
N(R)
O + PhN
C
NPh
O N R
296
O PhN
PhN R2
297
RN
NPh
R
R 298
(2.152) Several azoniaallene salts, generated in situ, undergo a [2+3] cycloaddition reaction with carbodiimides. For example, generation of 300 from the chloroalkylazo compound 299 in
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the presence of carbodiimides give 4,5-dihydro-5-imino-1H-1,2,4-triazolium salts 301 in 65–100 % yield.301
NR3
R1R2C(Cl)N
[R1R2C
NR3SbCl6] + R4N
N
299
NR5
C
300 R1 SbCl6
R2 N
NR3
R4N
NR5 301
(2.153)
The substituents R1 and R2 are alkyl and substituent R3 is 2,4,6-trimethylphenyl while the carbodiimides used are diisopropyl-, di-t-butyl-, dicyclohexyl- and diphenylcarbodiimide. Also, 4-ClPhC(Cl)=N+ =C(Cl)-4-ClPh SbCl− 6 302 reacts with diaryl- or alkylarylcarbodiimides to give labile 2,2-dichloro-1,3,5-triazinium salts 303.302
R1 R1(Cl)C
N
C(Cl)R1 SbCI6
+
RN
C
NR
R2N
NR3
Cl 302
R1
N
SbCl6
Cl 303 (2.154)
In a similar manner the 1-aza-2-azoniaallene salts derived from coumarin and camphor react with diisopropylcarbodiimide to give the [2+3] cycloadducts.303 Also, 1,3-diaza-2-azoniaallene salts 304 undergo the [2+3] cycloaddition reaction with diisopropylcarbodiimide or DCC to give 1,3,4,5-tetrasubstituted 4,5-dihydrotetrazolium salts. 305.304
ArN
N
N(Cl)Ar + SbCl5
[ArN
NAr SbCl6] + RN
N
304
C
NR
NR RN ArN
NAr
SbCl6
N 305 (2.155)
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Alkylene oxides and alkylene carbonates react with carbodiimides to give imidazolidine2-ones 306.305
RN
C
NR +
O
RN
NR (2.156)
O 306 However, using BuSnI2 /PPh3 as catalyst in this reaction, the isomeric iminooxazolidines 307 are obtained in 80–85 % yield.306
RN
C
NR +
O
RN
O (2.157)
RN 307 Aziridines 308 react with diarylcarbodiimides in the presence of bis(benzonitrile) palladium dichloride to give imidazolidine imides 309 in 40–94 % yield.307
NR
R2 RN
C
RN
NR +
NR1
N R1
(2.158)
R2 309
308
Likewise, 1-t-butyl-2-carbomethoxyazetidine 310 reacts with p-chlorodiphenylcarbodiimide in toluene at 130 ◦ C in the presence of bis(benzonitrile)palladium to give the tetrahydropyrimidine derivative 311.308
CO2R CO2R + ArN NR 310
C
NAr
NAr N R
(2.159)
NAr
311
2-Vinyloxirans react with carbodiimides in the presence of Pd(dba)3 to give iminooxazolidines in good yields.309 Better yields are obtained when unsymmetrical carbodiimides are used in this reaction. 2-Vinylaziridines react similarly with carbodiimides in the presence of Pd(OAc)2 and PPh3 to give the [2+3]cycloadducts in moderate to high yields.310 In contrast, 2vinylpyrrolidines 312 react with diarylcarbodiimides in the presence of palladium catalysts
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to give seven membered ring cyclic arylguanidines 313.311
+ RN
C
NR
NR
N R1 312
N R1 313
(2.160)
NR
Zirconaaziridines 314 react with carbodiimides via insertion into the Zr–C bond to give the metalacycle 315.312
NR3 R3N
R2
+ R3N
Cp2Zr N R1
NR4
C
Cp2Zr
R2
(2.161)
N R1 315
314
The reaction of carbodiimides with diazomethane313 and diazoalkanes314 afford triazole derivatives. For example, carbodiimides react with the diazomethanes 316 to give 5-amino1H-1,2,3-triazoles 317.315
NR RN
C
NR + R1R2C
RN
N2
R1R2
N
(2.162)
N 316 R1
R2
H H SnMe3
H SiMe3 SnMe3
R 4-MePh 4-MePh 4-MePh
317 mp ◦ C
[ %] 33 19 96
161–162 118–119 132
In the reaction of α-alkoxycarbonyl cycloimmonium N-aminides 318 with diarylcarbodiimides heterobetaines 319 are obtained.316
Me N
CO2Et
+ RN
O
Me N C
NR
NR N
N NH 318
N
NHR
319
Alkyl diazoacetates react with diisopropylcarbodiimide to give oxazolines.317
(2.163)
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In the reaction of HN3 with dibutylcarbodiimide the [2+3] cycloadduct 320 is obtained.318 NBu BuN (2.164) BuN C NBu + HN3 HN N N
320 Generation of the dipol 321 in the presence of a carbodiimide affords thiadiazolidines 322.319
N N MeN
MeN
S
S
NR1
R1N + R1N
C
NR1
S
MeN
RSO2N RSO2N
RSO2N 321
322 (2.165)
Ketenimine complexes 323 react with carbodiimides to give [2+3] cycloadducts 324 in low yield.320
NR W(CO)5N(C6H11)
C
C(OEt)Ph + RN
C
NR
EtO
RN NC6H11
Ph 323
W(CO)5 324 (2.166)
R
[ %]
mp ◦ C
C6 H11 Ph
24 7
156 80
The anionic [2+3] cycloaddition of 1,3-diphenyl-2-azaallyl lithium 325 with DCC gives the cycloadduct 326, which reacts with another equivalent of DCC to form the final product 327.321 NR NR RN RN Li PhCH-N-CHPh [Ph Ph] Ph Ph (2.167) N N Li RN NHR
325
326
327
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2.4.2.5 [2+4] Cycloaddition Reactions. In [2+2] cycloaddition reactions with carbodiimides sometimes [2+4] cycloadducts are produced as coproducts. Examples include the reaction of phenylcarbonyl isocyanate, phenylcarbonyl isothiocyanate and thiocarbamoyl isothiocyanate with carbodiimides to give [2+4] cycloadducts, discussed in Section 5.3.1. In the current section, mainly [2+4] cycloaddition of carbodiimides as dienophile with dienes derived from oxoketenes, generated in situ or masked oxoketenes, especially 2,3-diones investigated by Kollenz and his coworkers are discussed. Reaction of the metal substituted acetylene derivative 328 with diphenylcarbodiimide affords the [2+4] cycloadduct 329.322 In this unusual reaction diphenylcarbodiimide reacts as the diene, involving one of the aromatic double bonds, and the metal substituted acetylene derivative reacts as the dienophile.
PhHN PhN
C
NPh + Me3SnC
N
CN(Ph)Me Me3Sn N(Ph) Me 328
329 (2.168)
In contrast, diphenylcarbodiimide reacts with the o-quinodimethane 330 as dienophile in the [2+4] cycloaddition reaction to give the violet cycloadduct 331 in high yield.323
CN
CN NPh
H
+ PhN
SMe
C
NPh
NPh
(2.169)
NMe2 331
NMe2 330
In another version of a diphenylcarbodiimide cycloaddition reaction, it produces a [2+2+2] cycloadduct 333 in 78 % yield in its reaction with diethyl 2,4-bis(diethylamino)cyclobutadiene-1,3-dicarboxylate 332.324
NEt2
NEt2
EtO2C
EtO2C + PhN
CO2Et
Et2N 332
C
CO2Et
NPh
(2.170)
Et2N
N Ph 333
NPh
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Diketene reacts in its oxoketene configuration 334 with carbodiimides to give 2,3-dihydro2-imino-4-oxo-1,3-oxazines 335, via a [2+4] cycloaddition sequence.325
O O
O
C
O
+ RN
O
O
334
335
R1
mp ◦ C
Et iPr t-Bu t-Oct C6 H11 Ph Ph
82a 30 69 59.5–60 82–83 109.5 182–183
R Et iPr C6 H11 C6 H11 C6 H11 C6 H11 Ph a
NR
NR1
C
NR (2.171)
Bp at 1.0 Torr
Also, ethyl 2-methylmalonate 336 on treatment with DCC affords the ketene intermediate 337, which is trapped with a second equivalent of DCC to give the [2+4] cycloadduct 338.325 O
Me
C
EtOCOCH(Me)COOH + DCC
O
EtO 336
+ DCC
337 O Me EtO
NC6H11 O 338
NC6H11
(2.172)
The masked α-oxoketene 339 reacts with carbodiimides via a [2+4] cycloaddition reaction to give the cycloadduct 340. The reaction is conducted by heating the reagents at 120–130 ◦ C
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for 10 minutes. At that temperature the α-oxoketene is thermally generated.
O
O
R1
R1
O
R2
+ R3N
C
NR3
NR3 R2
O
NR3
O
339
340
(2.173)
R1
R2
R3
[ %]
mp ◦ C
Ref.
H H Me Me Ph H H Me Me Ph -(CH2 )3 -(CH2 )3 -(CH2 )3 -(CH2 )3 -
Me Ph Me Ph Me Me Ph Me Ph Me
cyclohexyl cyclohexyl cyclohexyl cyclohexyl cyclohexyl Ph Ph Ph Ph Ph i-Pr Ph 4-MePh 4-ClPh
81 86 76 70 64 45 64 47 35 67 76 92 72 79
81–93 118–118.5 132–133 162–163 126–127 176–177 153–165 129–130 175–177 165–166 84–86a 194–195 172–173 187–188
326 326 326 326 326 326 326 326 326 326 327 327 327 327
a
Bp at 0.15 Torr
In the reaction of isonitroso Meldrum’s acid with carbodiimides only cyanoformamidines are obtained in quantitative yields.328 The reaction of dipivaloylketene 341 with diisopropyl- or phenylisopropylcarbodiimide in n-hexane affords solutions of the [2+4] cycloadducts 342.329
O C
R
O
O + R1N
C
NR1
R
NR2
O
R
R
341 R t-Bu t-Bu MeO
O
R1
R2
i-Pr i-Pr t-Bu
i-Pr Ph i-Pr
O 342
NR2
[ %]
mp ◦ C
98 50 53
100–105 124–125 67
(2.174)
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In the absence of solvents 2:1 spiroadducts 343 are obtained.
O
O
O C
R
+ R1N
2 O
R
NR1 O
R
NR2
C
O
R
R
O2 R N
R O 343
O (2.175)
R
R1
R2
[ %]
mp ◦ C
t-Bu t-Bu
Me i-Pr
Me Ph
76 45
182–186 156–158
In contrast, the dimer of dipivaloylketene 344 (R = R1 = R2 = t-Bu) reacts with carbodiimides to give [2+2] cycloadducts 345. A mixed dimer obtained in the thermolysis of 4-pivaloyl- and 4-methoxycarbonyl-5-t-butylfuran-2,3-dione also undergoes the [2+2] cycloaddition with dialkylcarbodiimides.
O
O
O
R
O O
O
C R1
3 R2 + R N
C
O
R
NR3
O O R2CO
O
R1
O NR3
R3N 344
345
(2.176)
R t-Bu t-Bu MeO MeO
R1
R2
R3
[ %]
mp ◦ C
t-Bu t-Bu t-Bu t-Bu
t-Bu t-Bu t-Bu t-Bu
Me i-Pr Me i-Pr
76 58 15 35
144–145 150–152 112 121
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Generation of acyloxyketenes 347 from the mesoionic precursors 346 upon reaction with carbodiimides also afford [2+2] cycloadducts 348.330
Ar1
O
O
O
C O
O
Ar1
O
Ar1 OCOAr2
O + RN
C
NR RN
Ar2
NR
Ar2 346
347
348 (2.177)
N-acylketene imines 349 also react with carbodiimides to give [2+4] cycloadducts 350 in good yields.331
Me EtOOC(Me)C
NCOR + DCC
C
CO2Et
N R
O 350
349
(2.178)
NC6H11 NC6H11
3-Aryl-2-quinoxalinyl(aroyl)ketenes 351, generated in the thermolysis of 3-aroyl-2-(2-aryl4,5-dioxo-4,5-dihydro-3-furyl)quinoxalins, react with DCC to give the [2+4] cyclo-adducts 352 in 92 % yield.332
N
Ar
N
Ar
+ DCC O
N
351
O NC6H11
N
C O
Ar
Ar
O
NC6H11
352 (2.179)
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The 2,3-furanedione derivatives 353 react with diisopropylcarbodiimide to give [2+4] cycloadducts 355 derived from a rearranged imino derivative 354.333
O
Ph O
O
R
+ RN
C
O
NR
O
O
N R
RN
353
O
O 354
(2.180)
Ph
NR
O
O + RN
Ph
RN C
NR RN
O
O
O
N N R Ph H 355
The indicated reaction mechanism was verified by 17 O-labeling studies.334 Similar adducts are produced from other cyclic diketones (see Table 2.4). N-pyridyl-(2)-triphenylphosphine imine 356 reacts with diphenylcarbodiimide via a [2+2] cycloaddition reaction. The initially formed cycloadduct 357 undergoes a cycloreversion reaction to give N-phenyl-N -pyridylcarbodiimide 358, which reacts with diphenylcarbodiimide to give a [2+4] cycloadduct 359 (yield: 52 %, mp 263–265 ◦ C).337
N
PPh3 + PhN
N
C
Ph3P
NPh
N
N
PhN NPh
356
357 NPh N
PhN
C
N
358
N
+ PhN
C
NPh
(2.181)
NPh N
359
NPh
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Table 2.1 [2+4] Cycloadducts derived from Carbodiimides and Cyclic Diketones
Dione
Carbodiimide
Ref.
Cycloadduct Ph
O
O
Ph
MeN
C
NMe
335 N Me
MeN
O
O
O
O N Me
Ph
O
O
Ph
i-PrN
C
N-i-Pr
O
iPrN
336 N
iPrN
O
O
O
iPr
O
O Ph O
RSO2N
Ph
O
Ph
i-PrN
C
N-i-Pr
O
O
O O
RSO2N
336
N
iPrN
iPr RSO2 O
O
Ph Ph
O
N
i-PrN
C
N-i-Pr iPrN
S
N
Ph
O
336
iPr
O
Ph
O
O
SO2R O
O
N
MeN
C
S
NMe MeN
O 335
N N Me Ph Me
O
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Reaction of the 2,4-dipole 360 with diphenylcarbodiimide affords a [2+4] cycloadduct 361.338
S
S SMe
+ PhN
C
S
NPh
SMe N Me 360
N N Me Ph 361
NPh (2.182)
An intramolecular Diels–Alder reaction is observed on heating of suitably substituted arylcarbodiimides 362 to form the heterocycles 363.339
(2.183)
N
C
362
NPh
N H
N 363
Enynecarbodiimides 364 form biradical intermediates 365, which undergo intra-molecular cycloaddition on heating to give benzo[b]carbazoles 366.340
R
R
•
N C N
N •
N
364
365 R
N H
(2.184)
N
366 o-Thiobenzoquinone methide 367 generated by thermal ring-opening of 2H-benzo[b]-thiete reacts with carbodiimides (R = i-Pr, cyclohexyl, Ph) to give the [2+4] cycloadducts 368
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in 24–72 % yield.341
S
S
S
+ RN
C
NR
NR NR
367
368 (2.185)
2.4.3 Reaction of Ylides with Carbodiimides The reaction of ylides with carbodiimides usually produces linear 1:1 adducts. The adducts derived from DMSO and carbodiimides undergo a facile reaction with primary alcohols to give an aldehyde (Moffat oxidation). With phenols and carboxylic acids, alkylation products and esters, respectively, are formed. The oxidation proceeds under mild conditions and can be applied to sensitive compounds.342 Primary alcohols are oxidized solely to aldehydes without the formation of even trace amounts of carboxylic acids. The carbodiimide adducts generated from DMSO or the dimethylseleniumoxide343 adducts have structure 369 (X = S, Se).
RN
C
NR + Me2X
O
RN
C(OXMe2)NHR
(2.186)
369 The subsequent reaction of the adduct 369 with an alcohol gives rise to the formation of the aldehyde 370.344
RN
C(OSMe2)NHR + R2CHOH 369
O + MeSMe + RNHCONHR
R2C
(2.187)
370
In the reaction of phenol derivatives 371 with DMSO in the presence of DCC, o- and p-methylthiomethyl derivatives 372 are formed.345,346
CH2 OS
CH2SCH3
CH2SCH3 O
OH
(2.188)
CH3 371
372
When carboxylic acids are treated with DMSO in the presence of DCC, methyl-thiomethyl esters 373 are obtained.347
RN
C(OSMe2)NHR + R1COOH
R1COOCH2SCH3 373
(2.189)
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Starting with an optically active sulfoxide 374 the DCC reaction gives the optically active derivative 375 (5–29 % optical purity).348
O
COOH SOCH2Ph +
RN
C
O
NR S
374
H + RNHCONHR Ph
375 (2.190)
Reaction of the oxysulfonium intermediate 376 with sulfonamides gives S,S-dimethyl-Nsulfonylsulfilimines 377 in high yield.349 C(OSMe2)NHR + R1SO2NH2
RN
SMe2 + RNHCONHR
R1NSO2N 377
376
(2.191)
In a similar manner amines and carboxylic acid amides give S,S-dimethylsulfilimines and N-acyl-S,S-dimethylsulfilimines, respectively.350 Reaction of the dimethylselenium oxide adduct 378 with benzoylfluoroacetone 379 gives the selenium ylide 380.351 RN
C(OSeMe2)NHR + PhCOCH2COCF3 378
PhCOC(SeMe2)COCF3 + RNHCONHR
379
380
(2.192) The reaction of the carbon ylide 381 with diphenylcarbodiimide gives the expected linear adduct 382.352
CH2
OSMe2
+
PhN
C
Me2SOCHC(NHPh)
NPh
381
NPh
(2.193)
382
Thiazole ylides 383 react with carbodiimides in the presence of hydrogen chloride to form thiazoline salts 384.353
CH3 PHCH2N
S
NHR
RN
CH2CH2OH + RN
C
NR
PhCH2N
S
CH3 383
Cl
CH2CH2OH 384 (2.194)
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The reaction of phosphorous ylides 385 with diphenylcarbodiimides affords ionic adducts 386 which dissociate into exchange products.354
Ph3P PhN
NPh + Ph3P
C
Ph2
CPh2 PhN Ph3P
385
NHPh NPh + Ph2C
C
(2.195) NPh
386
Reaction of hexaphenylcarbodiphosphorane 387 with diphenylcarbodiimide affords ethylene-1,1-bis(triphenylphosphonium)-2,2-bis(phenyl amide) 388.355
Ph3P
C
PPh3
+
PhN
C
Ph3P
PPh3
PhN
NHPh
NPh
387
388
(2.196)
2.4.4 Insertion Reactions Heterocumulenes undergo insertion reactions with numerous substrates. In general, carbodiimides react faster than isocyanates and isothiocyanates, in that order.233 Insertions of carbodiimides into metal–hydrogen, metal–halogen, metal–nitrogen, metal–oxygen and metal–sulfur bonds are reported. Also insertions of carbodiimides into carbon–hydrogen bonds are known. Examples of insertion reactions include Grignard or alkyl lithium compounds which react with carbodiimides to give formamidines 389 after hydrolysis.356 PhN
C
NPh + PhMgBr
[PhN(MgBr)C(Ph)
NPh]
PhNHC(Ph)
NPh
389
(2.197) The 1:1 reaction between the magnesium amide 390 (R = i-Pr) and diisopropylcarbodiimide affords dinuclear amidinate complexes 391.357
Mg(NR2)2 + RN
R N C
NR
R N Mg
R2N N R
390
NR2 N R
(2.198)
391
Amidino-bridged mixed aluminum–magnesium complexes are obtained in the reaction of Al-Mg complexes with carbodiimides.358
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Aluminium amidinate complexes 392 are synthesized by addition of aluminum alkyls to aliphatic carbodiimides. Also, alkylation of carbodiimides with MeLi, followed by reaction with AlCl3 affords aluminum amidinate complexes 393.359,360
RN
C
NR
+
Alme3
R Me N + Al N Me R 392
Me
MeLi
NR Me
Li + AlCl3
NR
Me
(2.199)
R Cl N + Al N Cl R 393
Reaction of carbodiimides with organic aluminum complexes AlX2 Y (X = Cl, R; Y = Cl, NR2 ) affords the insertion products XYAlN(R)C(X)NR.361 Bis-trimethylsilylcarbodiimide reacts with AlMe3 to give the insertion product Me2 Al(NSiMe3 )2 CMe.362 Guanidinates and mixed amido guanidates of aluminum and gallium are obtained by carbodiimide insertion into Al and Ga amido linkages.363 Diarylcarbodiimides also insert into B Cl, B OR, B SR and B NR2 bonds. Examples include insertions into BCl3 , RBCl2 and R2 BCl.364 Sometimes double insertion reactions occur. BCl3 reacts with two equivalents of Carbodiimide to give the double insertion product 394.
RN
C
NR
+
BCl3
ClB[NRC( 394
NR)Cl]2
(2.200)
Thioboronites 395 react with DCC to form insertion products 396, which on hydrolysis give the shown S-alkylisothioureas 397.365 RN C NR + Bu2 BSBu −−→ [Bu2 N(R)C(SBu) NR] −−→ RNHC(SBu) NR 395 396 397 (2.201) Hydrosilanes 398 react with carbodiimides in the precence of palladium chloride by insertion into the Si H bond to give N-silylformamidines 399.366 RN C NR + Et3 SiH −−→ Et3 SiN(R)CH NR 398 399
(2.202)
A similar hydrosilylation occurs using R2 SiH2 .367 Also, reaction of trimethylcyanosilane 400 with carbodiimides in the presence of aluminum chloride affords the insertion product 401.368 RN C NR + Me3 SiCN −−→ Me3 SiN(R)C(CN) NR 400 401
(2.203)
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Insertion into a Si P bond is also observed. Reaction of alkylbis(trimethylsilyl)phosphanes 402 with alkylarylcarbodiimides affords the insertion products 403, which depending on the substituents can rearrange into the P C compounds 404.369 RP(SiMe3 )2 + RN C NR −−→ RP(SiMe3 )C( NR)N(SiMe3 )R 402 403 −−→ RP C[N(SiMe3 )R]2 404
(2.204)
Insertion reactions of carbodiimides are also observed with Sn OR or Sn NR2 bonds. For example, reaction of tributyltinmethoxide 405 with diarylcarbodiimides affords the expected insertion product 406.370 Bu3 SnOMe + RN C NR −−→ Bu3 SnN(R)C( NR)OMe 405 406
(2.205)
Bis(tributylstannyl)oxide370 and trimethylstannyldimethylamide371 react similarly. A recent example of a more elaborate tinalkoxide, 407 is used in the construction of a heterocyclic ring 408.372
CO2Me
CO2Me Br + RN
R3SnO
C
NR
R3SnN(R)C(
407
NR)O
Br
CO2Me O
NPh
(2.205)
NPh 408 Triphenylleadmethoxide 409 also undergoes an insertion reaction with diarylcarbodiimides to give 410.373 Ph3 PbOMe + RN C NR −−→ Ph3 PbN(R)C( NR)OMe 409 410
(2.206)
Titanium amides 411 and alkoxides also produce double insertion products, such as 412.374 Ti(NMe2 )4 + RN C NR −−→ (Me2 N)2 Ti[N(R)C( NR)NMe2 ]2 411 412
(2.207)
The insertion products of diphenylcarbodiimide into Ti(O i Pr)4 carry out metathesis reactions at elevated temperatures by undergoing insertion of a second equivalent of carbodiimide in a head to head fashion followed by an extrusion reaction.375 Also, insertion into a Ti C bond is observed in the reaction of CpTiMe3 with carbodiimides to form CpTiMe2 [NRC(Me)NR].376 Insertion into Ti C bonds is also observed in the reaction of DIPCD with imidotitanium alkyl cations.377
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81
Carbodiimides also insert into Ta N bonds in a mixed tantalium amido/imido complex.378 Pentacoordinated phosphoranes, such as 413, react with DCC or diisopropylcarbodiimide to give hexacoordinate phosphorus amidinates 414.379
CF3PCl4 + RN
C
NR
413
CF3 R N Cl P N Cl Cl R 414
Cl
(2.208)
Several metal amides Me3 MNMe2 415 (M = Si, Ge, Sn) undergo insertion of N-benzoylN -t-butylcarbodiimide to give 416.380 Me3 MNMe2 + PhCON C N-t-Bu −−→ PhCON(MMe3 )C(NMe2 ) N-t-Bu 415 416 (2.208) Thermolysis of the insertion products affords N-t-butyl-N -trimethylmetalcarbodiimide. Insertion of carbodiimides into Zr C bonds is also observed.381 Also, zinc bis-amides react with one equivalent of carbodiimide to give a zinc guanidate complex.382 Ruthenium, osmium and iridium hydrides insert N,N -di-p-tolylcarbodiimide into the metal–hydrogen bonds to give N,N -p-tolylformamidinato derivatives.383 Organomercury derivatives react with carbodiimides similarly. For example, phenyldichlorobromomethyl mercury 417 reacts with carbodiimides to give the expected insertion products 418.384 PhHgCCl2 Br + RN C NR −−→ PhHgN(R)C( NR)CCl2 Br 417 418
(2.209)
Bis-trimethylsilyl mercury 419 reacts with carbodiimides to give insertion products 420.385 Hg(SiMe3 )2 + RN C NR −−→ PhN(SiMe3 )C( NPh)HgSiMe3 419 420
(2.210)
The insertion of carbodiimides into copper halides may explain the catalytic effect of the copper salts on the reaction of carbodiimides with alcohols and amines.233 In the reaction of carbodiimides with barbituric acids 421 in DMSO at 150 ◦ C, insertion into the C H bond occurs with formation of 5-diaminomethylenebarbiturates 422.386
R1 N
O
R1 N + RN
O N R1 421
O
C
NR
O NHR
O
(2.211)
N R1
NHR O
422
Similarly, reaction of carbodiimides with malonates or acetoacetic esters affords the insertion products. For example, the shown malonic acid derivative 423 reacts with DCC to give
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the insertion product 424.387 O O + RN O O
C
O
NHR
O
NHR
NR
423
(2.212)
424
Also, acetylacetone reacts with diphenyl- or dicyclohexylcarbodiimide in the presence of nickel acetylacetonate to give N,N -substituted α,α-dioxoketene aminals.388 Acetoacetic esters389 , acetylacetone,351 or malonic acid esters390 react with carbodiimides to give amidines. Insertion of carbodiimides into cyclic anhydrides 425 catalyzed by a cationic hydroxy cluster affords seven membered ring insertion products 426 as shown for the reaction of the five membered ring anhydrides.391 O O
O + RN
NR C
O
NR
R1
R O
(2.213)
NR
1
O
425
426
R
R1
[ %]
i-Pr i-Pr cyclohexyl cyclohexyl
H Ph H Ph
70 60 30 25
In a similar manner N,N-dialkyl-1,3-diazocine-2,4,8-triones are formed from six membered ring anhydrides. From propionic anhydride and DCC, N,N -dicyclohexyl-N,N dipropionylurea is obtained in 25 % yield. In the reaction of 4-ethoxycarbonyl-5-phenyl-2,3-dihydrofuran-2,3-diones 427 with diisopropylcarbodimimide, insertion into the furan ring occurs to give the oxazepin-6,7-dione derivative 428 in 68 % yield.392 O O O O O EtO EtO + i-PrN C N-i-Pr O (2.214) Ph O O Ph N N-i-Pr i-Pr 428 427 The addition of N-nitrourethanes 429 to carbodiimides also afforts insertion products 430.393 RN C NR + O2 NNHCOOEt −−→ EtOOCN(R)C( NR)NHNO2 (2.215) 429 430
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Insertion of di-t-butylcarbodiimide into organolanthanite complexes (La = Er, Y, Gd) to give organolanthanide amidinates is also observed.394 Likewise, diisopropylcarbodiimide undergoes insertion into lanthanocene amides.395 However, diisopropylcarbodiimide does not react with lanthanocene guanidate complexes.396 In the reaction of Et2 Y(N-i-Pr2 )2 with DIPCD the double insertion product undergoes rearrangement reactions.396
2.4.5 Nucleophilic Reactions 2.4.5.1 Reactions with Water, Alcohols, Phenols and Other Hydroxy Compounds. Carbodiimides undergo nucleophilic reactions with a wide variety of nucleophiles. The polar forms of carbodiimides 431 and 432 demonstrate the nucleophilicity of the N-atoms as well as the electrophilicity of the center carbon atom. RN C NR1 ←→ RN C⊕ NR1 ←→ RN C⊕ NR 432 431
(2.216)
The reaction of carbodiimides with water to give the corresponding N,N -disubstituted ureas 433 is catalyzed by acids and bases.397 For example, acetic acid is an effective catalyst in the formation of ureas from sugar derived carbodiimides.398 RN C NR + H2 O−−→ RNHCONHR 433
(2.217)
The effect of substituents on the rate of hydration of diphenylcarbodiimides in an alkaline medium is as follows: m-Cl < m-CH3 CO < p-Cl < m-CH3 H > p-CH3 > p-(CH3 )2 N. In acidic media this order is reversed. The rate constants for the hydrolysis of N-ethyl- N -(dimethylamino)propylcarbodiimide (EDC) exhibit a pH dependence.399 The reaction of the thiocarbamoyl substituted carbodiimide 434 with water results in the formation of a thiourea 435, which subsequently undergoes cyclization to give the heterocycle 436.400
Me2NCSC(Me2)N
NCHMe2 + H2O
C
Me2NCOC(Me)2NHCSNHCHMe2
434
435
O NCHMe2 N H 436
+ Me2NH
(2.218)
S
Carbodiimides react with alcohols to give O-alkylisoureas 437. RN C NR + R1 OH−−→ RN C(OR1 ) NHR 437
(2.219)
The reaction is catalyzed by alkoxides,401 by copper salts,402,403 by HBF4 ,1 by ZnCl2 417 or Pd(II) halides.404 The HBF4 catalysis can only be used with di-t-butylcarbodiimide
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because with other carbodiimides dimerization is observed (see Section 2.4.1). In the reaction of propargyl alcohol with carbodiimides ring closure is observed to give 2-imino-4methyleneoxazolidines.405 In the case of diols 438 (n = 0 or 1) the copper salt catalyzed reaction produces cyclic adducts 439.406 RN 2 RN C NR + HOCH2(CH2)nOH (CH2)n + RNHCONHR RN O
438
439 (2.220)
In the reaction of N-trimethylsilylmethyl-N -arylcarbodiimides 440 with ethylene glycol in the presence of a CuI catalyst mainly the isourea 441 is formed.407 Me3 SiCH2 N C NAr + HOCH2 CH2 OH −−→ Me3 SiCH2 NNC( NAr)OCH2 CH2 OH 440 441 (2.221) Using cyclohexanediol, cyclic oxazoline derivatives are only obtained with trans isomers.408 Oxazolines are also obtained in the reaction of carbodiimides with ω-haloalcohols.409 Alkane-1,4-diols react with DCC in the presence of catalytic amounts of copper(l)chloride to give O-alkylmonoisoureas, which cyclize to yield tetrahydrofurans using trifluoroacetic acid.410 When carbodiimides are generated in situ in proximity of hydroxy groups they undergo intramolecular ring closure reactions to produce heterocycles in the case of suitable geometry.411 A similar ring closure is observed when a carbodiimide with an acylated hydroxy group in the β-position is treated with ammonia.412 O-alkylisoureas, formed in the reaction of carbodiimides with alcohols, are excellent alkylation reagents. For example, reaction of O-alkylisoureas 442 with anions of alcohols or phenols form the corresponding ethers 443 with formation of N,N -disubstituted ureas.413 RNH C(OR1 ) NR + R2 OH −−→ R1 OR2 + RNHCONHR 442 443
(2.222)
The mechanism of this reaction involves attack of alkoxy or phenoxy anions on the alkyl group in the O-alkylisourea, as evidenced by the use of O18 labelled ethanol in the formation of the O-alkylisourea 444. The recovered urea 445 contained the label.414 RN C NR + EtO18 H−−→ RNH C(O18 Et) NR −−→ RNHCO18 NHR + PhOEt 444 445 (2.223) Excellent yields of alkylaryl ethers 446 are obtained when phenols and alcohols are heated with DCC at 100–110 ◦ C for one to four days.415 ArOH + ROH + RN C NR−−→ ArOR + RNHCONHR (2.224) 446 The mechanism of this reaction involves formation of an intermediate 2-alkylisourea, which is attacked by the phenolate ion. Dialkylether formation from sugar alcohols also occurs in the presence of DCC albeit in low yields.416
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In the reaction of O-alkylisoureas with thiophenols the corresponding alkylarylthioethers are formed.417 The reaction of optically active secondary alcohols with DCC in dioxane or toluene affords O-alkylisoureas 447, which react with formic acid to produce the ester 448 with complete inversion of configuration. Hydrolysis of 448 produces the secondary alcohol 449 with inversion of configuration.418
NR H R1
H
OH + DCC
C R2
H C O
OC
NHR + HCOOH
C R1
O H C
R2
R2
R1 448
447
HO
H C R2
R1 449
(2.225) When acrylic or methacrylic acid are reacted with the optically active O-alkylisoureas the obtained esters can be polymerized to give optically active polymers. A review article on isoureas was published in 1995.419 The reaction of diarylcarbodiimides with weakly acidic phenols at 160 ◦ C affords the expected isourea derivatives.420 However, with strongly acidic phenols, such as picric acid, N,N,N -triarylureas 450 are obtained.421 RN C NR + R1 OH −−→ RNH C(OR1 ) NR−−→ RR1 NCONHR 450
(2.226)
The N,N,N -triarylurea derivatives result from rearrangement of the initially obtained isourea derivatives. DCC reacts in a similar manner.422 The anions of thioalcohols or thiophenols are also alkylated with O-alkylisoureas.423 O-alkylisoureas are also good alkylating reagents for amines. For example, reaction of thymine, thymidine and uridine with alcohols in the presence of DDC gives only Nalkylation products.424 O-alkylisoureas are also used in the esterification of carboxylic acids425 and dialkylphosphates.426 O-alkylisoureas derived from carbodiimides and suitably protected sugars are used in the glycosidation of a variety of organic compounds in the presence of CuCl.427 Hydrogenation of O-alkyl- or O-arylisoureas affords alkanes or arenes.428 This is a convenient procedure to convert alcohols or phenols into the corrsponding hydrocarbons. Dehydration of β-hydroxyketones and β-hydroxyesters with carbodiimides is used to introduce double bonds into organic molecules. For example, Corey and coworkers used this method in the synthesis of prostaglandins.429 For example, The shown β-hydroxyketone
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451 reacts with DCC in the presence of cupric chloride to give the α,β-unsaturated ketone 452.
NHCHO (CH2)6CN
NHCHO (CH2)6CN
C5H11 AcO
OH
+ DCC
C5H11 AcO
O
(2.227)
O 452
451
Dehyration of β-hydroxyesters also leads to the formation of α,β-unsaturated esters.430 In the reaction of γ -hydroxyketones431 453 or -hydroxyketones432 with DCC, cyclic products 454 are obtained resulting from intramolecular alkylation.
O
O + DCC
(2.228)
O
CH2OH 453
454
The dehydration of 4-hydroxycyclohexanone 455 with chiral carbodiimides affords only a racemic bicyclo-[3.1.0]-hexane-2-one 456.433
O
O + DCC
OH 455
(2.229)
456
In the reaction of hydroxyalkynes 457 with carbodiimides, oxazolidines 458 are isolated, resulting from cyclization of the initially formed isoureas.434
R2 R1C
CCH(OH)R2 + R3N 457
O C
NR3
R3N
N R3 458
CHR1
(2.230)
The reaction of α-hydroxycarboxylic acid esters 459 with two equivalents of carbodiimides in the presence of cupric chloride affords a mixture of an O-alkylisourea 460 and
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the oxazolidone 461.435
R1 R1CH(OH)COOR2 + 2 RN
NR +
RNHC(OR2)
NR
C
459
O RN
O
N R 461
460
(2.231) However, using α-hydroxycarboxylic acids 462 and carbodiimides affords oxazolidinediones 463.436
O NR1 R2C(OH)COOH +
R1N
C
NR1
R2
+ R1NH2
(2.232)
O
O 463
462
N-(β-hydroxy)amides are cyclized with DIPCD in the presence of a catalytic amount of Cu(OTf)2 to give 2-oxazolines.437 Similarly, N-(2-hydroxyethyl)thioamides and N(2-hydroxyethyl)thioureas are converted with DCC in refluxing acetonitrile to give 2oxazolines in 88–94 % yield.438 Benzo-fused heterocycles 465 (n = 0,1,2) are obtained from the thiourea derivatives 464 and DCC (Yields 81–92 %)
N
NHCSNHPh
NHPh
+ DCC
OH
(2.233)
O
n
n
464
465
Activated α,β-unsaturated carboxylic acids 466 undergo a domino condensation/azaMichael reaction to form hydantoins 467.439
R EtOCOC(R)
CHCOOH + R1N 466
C
NR1
R1N R1N
CO2Et O
O R
O CO2Et R1N
NR1 O 467 (2.234)
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The reaction with asymmetric carbodiimides are generally highly chemo- and regioselective, affording one single regioisomeric hydantoine.440 With some hydroxycarboxylic acids lactone formation is observed in the reaction with carbodiimides.441 Sometimes N-acylureas are formed as byproducts.442 For example, in the reaction of β-hydroxycarboxylic acids 468 with DCC, γ -butyrolactones 469 are produced.443
O OH
O
COOH
(2.235)
+ DCC 468
469
Ketoximes 470 and aldoximes react similarly to alcohols with carbodiimides to give isourea derivatives 471. The reaction can be conducted in the presence of NaOH, hydrofluoric acid,444 or copper salts.445 R2 C NOH + R1 N C NR1 −−→ R1 NHC(ON CR2 ) NR1 470 471
(2.236)
The adducts derived from aldoximes and carbodiimides are not stable. They undergo dissociation to give nitriles 472. This reaction is a useful synthetic route to produce nitriles from aldehydes and hydroxylamine in the presence of DCC and cupric salts in one step. The reaction of of the oximes with carbodiimides is best conducted in a two phase system (methylenechloride/water) using triethylamine, and the yields are almost quantitative.446 R1 CH NOH + RN C NR −−→ R1 CN + RNHCONHR 472
(2.237)
Carboxylic acid reacts with hydroxylamine in the presence of DCC and triethylamine to give hydroxamic acids 473.447 RCOOH + H2 NOH −−→ RCONHOH 473
(2.238)
However, hydroxamic acids, such as 474, react with carbodiimides to produce a nitrene intermediate 475, which undergoes the Lossen rearrangement to give an isocyanate 476.448 The latter reacts with the starting hydroxamic acid to give the adduct 477. ¨ ] −−→ PhNCO −−→PhCONHOCONHPh PhCONHOH + RN C NR −−→[PhCON ¨ 474 476 477 475 (2.239) The reaction can be stopped at the isocyanate stage by using an excess of N-benzylN -(3-dimethylamino)propylcarbodiimide at pH 5 and room temperature. In this manner a quantitative yield of the corresponding amine is obtained by hydrolysis of the isocyanate.449
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The cyclic anhydride 479 is obtained in 56 % yield from the carboxylic/hydroxamic acid precursor 478 and DCC in methylenechloride at 0 ◦ C.450
COOH O
O + DCC
NOH Ph 478
O
O
(2.240)
N Ph 479
Amide formation from carboxylic acids 480 with O-subsituted hydroxylamine hydrochlorides also proceeds in the presence of DCC to give the substituted hydroxamic acid 481 in 91 % yield.451
Cl Cl COOH
+ PHCH2ONH3 + Cl
−
O
480
NHOCH2Ph
481 (2.241)
Cyclic hydroxyimides 482 react with carbodiimides to form the expected isourea derivative, which undergoes further reaction with the starting material to give the isolated aminoacid derivative 483.452
O NOH + RN O 482
O
O C
NR
N
OCO(CH2)3 NHCOO
O
N O
483
(2.242) However, in the reaction of glutaric acid derivatives with CF3 CONH2 in the presence of EDC hydrochloride/HOBt, cyclic imides are obtained in yields of 58–92 %.453 DCC promotes the facile formation of organic carbonates from aliphatic alcohols and carbon dioxide at 310 ◦ K and moderate pressure.454 2.4.5.2 Reaction with Carboxylic and Inorganic Acids. The reaction of carbodiimides with carboxylic acids has dual character because acyl ureas 484 or acid anhydrides 485 are formed. Often mixtures of both products are formed. The product formation depends on the nature of the reagents and the reaction conditions. With aromatic carboxylic acids mainly N-acylureas are formed, and in the presence of tertiary amines the anhydride formation is inhibited.455 RN C NR + R1 COOH −−→ RN(COR1 )CONHR 484
(2.243)
RN C NR + 2 R1 COOH −−→ R1 COOCOR1 + RNHCONHR 485
(2.244)
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The obtained N-acylureas are crystalline compounds, and they can be used to characterize carboxylic acids. The recommended carbodiimide for this purpose is bis(4dimethylaminophenyl)carbodiimide.456 The carboxylic acids are regenerated from the Nacylureas by mild alkaline hydrolysis. Aliphatic carbodiimides usually form a mixture of the N-acylureas and the corresponding anhydrides, but again conducting the reaction in the presence of an organic base produces the N-acylureas exclusively.457 When a mixed aliphatic/aromatic carbodiimide is used, the N-acylurea resulting from attack on the less basic nitrogen is formed.458 The mechanism of N-acylurea formation seems to involve protonation of the carbodiimide, followed by attack on oxygen to give an O-acylurea. Subsequent intramolecular rearrangement affords the N-acylurea. This rearrangement was confirmed by independent synthesis of O-acylureas and study of their behavior.459 An intramolecular reaction occurs in the generation of O-carboxyl group containing diphenylcarbodiimides, which gives rise to the formation of cyclic O-acylureas.460 In the reaction of ferrocene carboxylic acid with DCC in THF at room temperature the O-ferrocenoylisourea is formed, which can be converted to the N-ferrocenylurea upon refluxing in dioxane.461 From ferrocene-1,1 -dicarboxylic acid and DIPCD, DCC or Nethyl-N -t-butylcarbodiimide in refluxing ethyl acetate (several weeks) the corresponding N-ferrocenylureas are obtained. When ferrocene-1,1 -dicarboxylic acid is heated with DIPCD, DCC or N,N -di-p-tolylcarbodiimides in the absence of solvent, short reaction times are required to give the same products.462 It was shown by radiochemical methods that O- and N-acylureas can form simultaneously.463 Spectroscopic and kinetic evidence for the formation of O-acylureas in the reaction of N-ethyl-N -(3 -trimethylammonio)propylcarbodiimide perchlorate with acetate buffers was obtained.464 Heating of carboxylic acids with diarylcarbodiimides at 80 ◦ C in benzene affords arylamides 486 in high yields. The aryl isocyanate coproduct 487 remains in the solvent.465 RCOOH + ArN C NAr −−→ RCONHAr + ArNCO 486 487
(2.245)
Likewise, α-alkoxycarbonylcarbodiimides 488 react with carboxylic acids to give αalkoxycarbonyl isocyanates 489 and arylamides 490.466 RR1 C(OCOR2 )N C NR3 + R4 COOH −−→ RR1 C(OCOR4 )NCO + R3 NHCOR2 488 489 490 (2.246) Under the above conditions the carbodiimides react with the carboxylic acid via N-acylation. The rate of reaction of DCC with aliphatic acids in THF depends on the acid strength, i.e., chloroacetic acid reacts considerably faster than acetic acid.467 It was also found that the higher the acid strength, the higher the yields of anhydride and urea. The reaction exhibits first order kinetics both in acid and in carbodiimide, and the rate determining step is the formation of the O-acylurea.468 Solvent effects are also observed in the reaction of DCC with acetic acid. The reaction rates are highest in THF, and the proportion of N-acylurea is also the greatest in THF.469 The kinetics of the reaction of the water soluble N-cyclohexyl-N -(4-methylmorpholineβ-yl) carbodiimide p-toluenesulfonate with carboxylic acid was also investigated.470 The
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water soluble carbodiimide N-ethyl-N -(3-dimethylamino)propylcarbodiimide reacts with acetic acid through a cyclic tautomeric form.471 Carboxylic acids 491 with electron withdrawing substituents (R = CN, COOEt, PO(OEt)3 , SO2 Ar) in the α-position undergo facile dehydration in the presence of carbodiimides to form the ketenes 492. When an equivalent of t-butanol is added the corresponding esters 493 are obtained in high yields.472 RCH2 COOH + DCC−−→ [RCH C O] + t-BuOH −−→ RCH2 COO-t-Bu 491 492 493 (2.247) In the reaction of formic acid 494 with DCC, the very unstable formic acid anhydride 495 can be obtained.473 RN C NR + HCOOH−−→ HCOOCOH + RNHCONHR 494 495
(2.248)
The reaction of phenylpropiolic acid 496 with DCC affords a condensation product 497.474
O PhC
C-COOH + RN
C
O + RNHCONHR
NR Ph
496
O
497 (2.249)
Also, when the reaction of 3,4-methylenedioxyphenylpropiolic acid 498 with DCC is conducted in dimethoxyethane below 0 ◦ C, it produces 6,7-methylenedioxy-1-(3 ,4 methylenedioxyphenyl)naphthalene-2,3-dicarboxylic acid anhydride 499.475
O COOH
O
+ DCC
2 O
O O O O
O O 498
499 (2.250)
The reaction of allenic acid 500 with carbodiimides affords tricycloundecatrienones 502.476 The reaction proceeds through the initially formed linear N-acylurea derivative 501.477
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Ph2C
C
C(Me)COOH + RN
C
NR
C
RN(Ph2C
C(Me)CO)CONHR 501
500
Me O N
NHPh O
502
(2.251) Dicarboxylic acids react with carbodiimides depending on their structure. From oxalic acid and carbodiimides the corresponding urea, carbon monoxide and carbon dioxide are obtained. This reaction was used by Zetzsche and Friedrich207 as a quantitative analytical method for the determination of carbodiimides. The carbodiimide content of polymer supported carbodiimides is also determined with oxalic acid.478 From α-disubstituted malonic acids 503 substituted barbiturates 504 are obtained.479 O R RR1C(COOH)2 + R2N
C
R2 N
NR2
O R1
503
(2.252)
N O R2 504
This reaction proceeds via formation of a cyclic anhydride 505, which reacts with carbodiimide to form a 1,3-oxazinedione 506. The latter rearranges to give the barbiturate 507.480 O
O Et2C(COOH)2 + DCC
O
Et
Et
NR
O
Et
Et O
O 505
N R 506
(2.253) O Et
R N O
Et
N R O 507
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Dicarboxylic acids with two or three methylene groups give cyclic anhydrides, while dicarboxylic acids with four or more methylene groups 508 (n = > 4) give bis-N-acylureas 509.481 HOOC (CH2 )n COOH + RN C NR 508 −−→ RHNCON(R)CO (CH2 )n CON(R)CONHR 509
(2.254)
However, cyclization to give 511 was observed in the reaction of 3,6,9-trioxaundecanoic dicarboxylic acid 510 with DCC. 510 was reacted with an aminomethylstyrene resin, which was also utilized in the solid phase synthesis of oligopeptides using diisopropylcarbodiimide/HOBt and carboxyl protected amino acids.482
O O
O
HO
O
O
(2.255)
O
O
O HO
O
+ DCC O
O
510
511
From hydroxycarboxylic acids, such as 512, in the presence of EDCCl, DMPA and HCl, the cyclic lactone 513 is formed.483
O O
OTBS
OH
TBSO
O
+ EDCCl
HO Me
Me
512
513 (2.256)
Also, macrolactonization of hydroxy acids is achieved using a polymer bound carbodiimide.484 The reaction of aliphatic carboxylic acids with hydrogen peroxide mediated by DCC affords diacyl peroxides 514 in good yields.485 2 RCOOH + H2 O2 + DCC −−→ RCO O O COR 514
(2.257)
When the reaction of the carboxylic acid with hydrogen peroxide mediated by DCC is conducted in the presence of a peracid the unsymmetrical diacyl peroxides 515 are obtained. RCOOH + R1 CO3 H + DCC −−→ RCO O O COR1 515
(2.258)
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In the reaction of the tartaric acid derivative 516 with peroxydodecanoic acid in the presence of DCC, the expected mixed anhydride 517 is obtained in 73 % yield.486 HOOCCH(OAc)CH(OAc)COOMe + C11 H23 CO3 H 516 −−→ MeOOCCH(OAc)CH(OAc)COOOCOC11 H23 517
(2.259)
Cyclic anhydrides are also obtained from maleic acid, o-phthalic acid and 2,3-seco-5acholestane-2,3-dioic acid.487 The mechanism of stabilization of polyesters by carbodiimides is based on their rapid reaction with carboxylic acids, generated in the hydrolysis of polyesters. Carboxylic acids are catalysts for further hydrolysis of the polyesters. In the reaction of carbodiimides with inorganic acids, usually the corresponding anhydrides are formed. For example, sulfinic acids 518 react with carbodiimides to give the corresponding anhydrides 519.488 Sulfonic acids react similarly. RSO2 H + R1 N C NR1 −−→ RSO2 OSO2 R + R1 NHCONHR1 518 519
(2.260)
Sulfinic acid amides are obtained in the reaction of sulfinic acids with amines in the presence of DCC.489 In the reaction of sulfuric acid with alcohols, thioalcohols and amines in the presence of DCC, the respective sulfates, thiosulfates and amides are obtained.490 The reaction of H3 PO4 with DCC, followed by alcohol affords (RO)2 P(O)H.491 Mono- and disubstituted phosphoric acids react with DCC to give pyrophosphates.492 For example, from dibenzylphosphonic acid 520 and DCC in diethylether, a 90 % yield of tetrabenzylpyrophosphate 521 is obtained. 2 (RO)2 P(O)OH + RN C NR −−→ (RO)2 P(O)OP(O)(OR)2 + RNHCONHR 520 521 (2.261) The carbodiimides used are DCC, di-p-tolyl- and di-t-butylcarbodiimide and the reaction is conducted in pyridine or tri-n-butylamine.356 A similar reaction is observed for phosphinic acids.493 In the coupling of two different phosphoric acids, all three pyrophosphates are obtained, usually in a ratio of 1:2:1, i.e., the unsymmetrical product is only obtained in up to 50 % yield. In the synthesis of adenosinetriphosphate (ATP) the monophosphate of adenosine was reacted with a large excess of DCC and phosphoric acid to give a 60 % yield of ATP, the major byproduct being the adenosine diphosphate.494 When aqueous solutions of adenosin-5 -mono-, di- or triphosphates are treated with EDC or N-cyclohexyl-N -(2-morpholinoethyl)carbodiimide the major product is diadenosine-5 5 -pyrophosphate. The yields of the pyrophosphates are greatly increased in the presence of Mg2+ ions.495
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The reaction of 5-adenylic acid 522 with aqueous ammonia in the presence of DCC affords an 87 % yield of adenosine 5-phosphoric acid amide 523.496
(HO)2 P(O)OCH2
O O B
H2N
+ DCC + NH3
OCH2
P
O B
OH HO
OH HO
522
OH
523 (2.262)
DCC is also used in nucleotide chemistry to esterify a sugar hydroxyl group with a phosphate group in another nucleotide or oligonucleotide unit. Also p-styrene based polymers with a pyridyl-2-ethanol end group are reacted in pyridine with 3 -O-acetyldesoxythimidine-5 -phosphate in the presence of DCC.497 The reaction of mono esters of phosphoric acid with alcohols or phenols, in the presence of DCC, affords phosphoric acid diesters in high yield.498 This reaction is widely used in nucleic acid chemistry. Amino acyl adenylates are obtained in the reaction of adenosine 5-phosphate (A5P) with free amino acids in aqueous pyridine, mediated by DCC. The linkage is an anhydride between the amino acid carboxyl group and the phosphate in A5P.499 Intramolecular cyclization of the adenosine derivative 524 with DCC in pyridine/DMSO affords a 50 % yield of the intramolecular ester 525.500
(HO)2P(O)OCH2
O B + DCC
OH
HO
O
OB
O P
(2.263)
O
HO
OH
524
525
Treatment of nucleoside 5-phosphates 526 with DCC at high dilution affords the cyclic phosphates 527.501 Without the high dilution the expected pyrophosphates are obtained.
(HO)2 P(O)OCH2 O R + DCC HO
OH
526 (R = Ade)
O
OR
O P
HO
(2.264)
O 527 (R = Ade)
OH
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Lactone 529 is also observed in the reaction of the carboxylic acid 528 with DCC in pyridine.502
O R
HOOC
OR
+ DCC O
HO
(2.265)
O
OH
OH
528
529
Also, treatment of the 3-aminoadenosine derivative 530 with EDC HCO3 , effects cyclization to form the 3-amido compound 531.503
O (HO)2P
O
O R
+ EDC HCO3
O H2N
OP
OH
O
OR
O P
O
O N H
O
O
P OH
O 530
531 (2.266)
Intramolecular dehydration of cis- or trans-2-hydroxycyclohexylphosphate 532 occurs, to give 533 using a carbodiimide for the condensation reaction.504
O O P(OH)2 + DCC OH 532
O
O P
O
(2.267)
OH
533
The stepwise formation of oligonucleotides involves the reaction of β-cyanoethyl nucleotides with suitably protected nucleotides in the presence of DCC.505 3 - And 5 -phosphorylation using pyridinium-2-cyanoethyl protected nucleotides in the presence of DCC is also observed.506 Also, N-ethyl-N -(3-dimethylamino)propylcarbodiimide (EDC) is used in self-replication experiments.507 Oligonucleotides containing phosphorothioate diesters with non-bridging sulfur react with EDC to form stable adducts, In contrast, oligomers with terminal phosphorothioate mono esters form highly reactive intermediates which react readily with nucleophiles.508
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From methylenediphosphonic acid 534 and DCC an anhydride, having a bird-cage structure 535, is obtained.509
O
O
P CH2 P
(HO)2PCH2P(OH)2
O
O O O P CH2 P O
534
(2.268)
O 535
Monoesters of phosphoric acid 536, in the presence of DCC, react with alcohols and phenols to give the corresponding phosphoric acid diesters in quantitative yield. This reaction is widely used in nucleic acid chemistry.510 The first step in this reaction is the formation of the cyclic metaphosphate trimer 537, which serves as an active phosphorylating agent.511
O 3 ROP(O)(OH)2 + RN
C
NR
536
P RO
O
O
O P
O P O OR
OR
(2.269)
537
The reaction of carbodiimides with phosphonothioic and phosphinothioic acid512 as well as phosphonoselenoic513 and phosphinoselenoic acids514 proceed in a similar manner. 2.4.5.3 Reactions with H2 S, H2 Se, Thioalcohols and Thiophenols. The reaction of carbodiimides with hydrogen sulfide515 538 (X S) or hydrogen selenide 538 (X Se)516 affords the corresponding thio-(539 X S) or selenoureas (539 X Se), respectively.
RN
C
NR + H2X 538
RNHCXNHR
(2.270)
539
75
Se selenoureas are obtained from carbodiimides and 75 [Se] hydrogen selenides.517 Selenoureas are also obtained in yields of 56 to 93 % from carbodiimides and LiAlHSeH in the presence of hydrogen chloride.518 Thioalcohols react with carbodiimides to give isothioureas 540. Elimination of thiourea can occur if an acidic β-hydrogen is available.519 RN C NR + R1 SH −−→ RNH C(SR1 ) NR 540
(2.271)
Especially useful is the reaction of carbodiimides with 2-mercaptoethanol because rapid reaction with EDC occurs with rates similar to the reaction of carboxyl groups with EDC.520
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α-Acylamino-β-thiopropionic acids 541 react with carbodiimides to give β-propiothiolactones 542.521
R1NHCH(CH2SH)COOH
+ RN
C
NR
O
R1NHCH S
541
+ RNHCONHR
542
(2.272) Thiophenols react with carbodiimides at 0 ◦ C to form the expected S-arylisothioureas. However, at 80–100 ◦ C different reaction products are observed.522 α-Mercaptocarbonyl compounds 543 react with carbodiimides to give thiazole derivatives 544.523
NR EtCOCH2SH + RN
C
RN
NR
(2.273)
S
Et 543
544
Thioglycolic acid 545 reacts with carbodiimides to give thiazolidinones 546.524
R2C(SH)COOH + R1N
NR1
R1N C
NR1
R 545
(2.274)
S
O
R 546
A carbodiimide (DCC) mediated synthesis of 4-thiazolidinones 547 using amines, aldehydes and mercaptoacetic acid affords yields of 80–95 %.525
R1 RNH2 + R1CHO + HSCH2COOH + DCC
RN S
O
(2.275)
547 Monothiocarboxylic acids 548 react with DCC to give either diacylsulfides 549 or N-acylN,N -dicyclohexylthioureas 550.526 RCOSH + RN C NR −−→ RCOSCOR+ RN(COR)CSNHR 548 549 550
(2.276)
The thiourea derivative is the major reaction product when thioacids containing electron acceptor groups in the molecule are used (R = 4-O2 NPh, ClCH2 etc.). In the reaction of dithiocarboxylic acids 551 with DCC the unstable dithioacetylsulfide 552 is formed, which undergoes dimerization to give a mixture of 1,3,5,7tetramethyl-3,4,6,8,9,10-hexathiaadamantane 553 and cis- and trans-2,4-dimethyl-2,
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4-bis-thioacetylthio-1,3-dithietane 554.527 2 MeCSSH + RN C NR −−→ [MeCSSCSMe] + RNHCSNHR−−→ 551 552
Me Me
S
S
Me
+
S
S
MeCSS S
Me
S S
(2.277)
Me
Me 553
SCSMe
554
In the reaction of substituted dithiobenzoic acids 555 with DCC, stable dithioacyl sulfides 556 are isolated in 75–85 % yield.528 ArCSSH + RN C NR −−→ ArCSSCSAr + RHNCSNHR 555 556
(2.278)
Dithiocarbamic acids 557, generated in situ from aliphatic amines and carbon disulfide, react with carbodiimides to give isothiocyanates 558 in 70–99 % yield.529 RNHCSSH + R1 N C NR1 557 −−→[R1 NHC(SCSNHR) NR1 ]−−→RNCS + R1 NHCSNHR1 558
(2.279)
2.4.5.4 Reactions with Ammonia, Amines, Amine Derivatives and Azides. Ammonia, primary and secondary amines react with carbodiimides to give guanidine derivatives.530 For example, from primary amines the guanidine derivative 559 is obtained. RN C NR + R1 NH2 −−→ RNHC( NR1 )NHR 559
(2.280)
The formation of the corresponding guanidines from diisopropylcarbodiimide and 2,4,6triethylaniline is catalyzed by V(N-2,6-Pr2 C5 H3 )Cl3 .531 Carbodiimides are generated as intermediates in the solid phase synthesis of oligomeric guanidines from protected thioureas and resin bonded amines in the presence of EDCCl.532 Also, a polymer bound triamine is used in combination with a polystyrene bound carbodiimide to produce guanidines.533 Libraries of guanidinocarboxylic acids were prepared by trapping of solution phase carbodiimides by polymer supported amines or by reacting polymer supported carbodiimides with solution phase amines.534 The lithium salts of the chiral (S)-2(N,N-dialkylaminomethyl)pyrrolidines react with diisopropylcarbodiimide to give chiral guanidines.535 Also, arenesulfonylthioureas are converted to substituted guanidines using EDC to mediate the reaction with amines.536
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Carbamic acid salts 560, generated in situ from primary amines and carbon dioxide, react with DCC in the presence of triethylamine to give 1,3-disubstituted ureas 561 and dicyclohexylurea.537 1 1 1 1 RNHCOO− RNH+ 3 + R N C NR −−→ RNHCONHR + R NHCONHR 560 561
(2.281)
The reaction of carbodiimides with amino substituted boron clusters afford guanidiniumundecahydro-closo-dodecaborates in good yields.538 Imines react similarly to amines with carbodiimides.539 Aminoalcohols 562 (n = 2,3), containing a primary amino group, react with carbodiimides to give 1,3-oxazoles 563.540
H2N(CH2)nOH + 2 RN
C
NR
[RNHC(NH(CH2)nOH)
NR
562 RNH (2.282)
NR O
HN
n
563 When carbodiimides are used in a molar ratio of 2:1 with respect to the aminoalcohol, addition occurs on both functional groups with subsequent cyclization. Salts of amino alcohols react similarly. Reaction of diarylcarbodiimides with aziridine 564 give 1-(N,N -diarylamidino)aziridines 565, which rearrange to 1-aryl-2-arylamino-2-imidazolines 566 on prolonged heating with potassium iodide.541
N H
+ RN
C
NR
RNH
C
NR
KI
RN
(2.283)
N
564
N NHR
565
566
Mercaptoethylamines react with diarylcarbodiimides to give bis-adducts 567 at room temperature. Heating to 100 ◦ C causes cyclization to give 2-arylamino-1,3-thiazolines 568.542
H2N(CH2)2SH + RN
C
NR
NR)NH(CH)2SC(
RNHC(
NR)NHR
567 N
S (2.283)
NHR 568
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Treatment of tricarboxylic acids with H2 NOBz HCl in the presence of EDC affords the corresponding trishydroxamic acids.543 Reaction of carboxylic acids with N,O-dimethylhydroxylamine 569, using DCC, affords the expected hydroxamic acid derivatives 570.544 RCOOH + MeNHOMe −−→ RCON(Me)OMe + RNHCONHR 569 570
(2.284)
The reaction of secondary sulfonamides with carboxylic acids in the presence of DCC and 4pyrrolidinopyridine affords N-tosylamides.545 Also intramolecular cyclization to lactames is achieved using DCC. Thioamides 571 react with carbodiimides to give nitriles 572.546 RN C NR + R1 CSNH2 −−→ R1 CN + RNHCSNHR 571 572
(2.285)
The reaction of thiocarboxylic acid amides 573 with carbodiimides affords 1,2,4-triazoles 574.547
Me H2NN(Me)CSSMe + RN
HN C
NR
S
SMe NR
RNH
573
N
(2.286)
N NMe S
N R
RNH
574 Reaction of unsaturated ketoamines 575 with diarylcarbodiimides, in the presence of NaH in DMF, affords the heterocyclic compound 576.548
NR3 R1CH(NH2)
CHCOR2 + R3N
C
NR3
N
NR3 R1
575
R2 576
(2.287)
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Guanidines react with equimolar amounts of carbodiimides to give disubstituted biguanids 577.549 H2 NC(NH2 ) NH + RN C NR −−→ RNHC( NR)NHC( NH)NH2 577
(2.288)
Heating of the biguanide with carbodiimide at 100 ◦ C in DMF affords substituted melamines.549 N,N -diaminoguanidine 578 reacts with carbodiimides in DMF to give 4-aryl-3,5di(arylamino)-579 and 3-amino-4-aryl-5-arylamino-1,2,4-triazoles 580.550
H2NNHC(
NH)NHNH2 + RN
C
NR
578 N N RNH
N R
N N NHR + RNH
579
N R
(2.289)
NH2
580
Hydrazine reacts with carbodiimides to give mono- and diadducts, the latter cyclize under more drastic conditions to form 1,2,4,-triazoles.551 Phenylhydrazine 581 reacts similarly with carbodiimides to give the 1,2,4-triazole derivative 582.
PhNHNH2 RN
C
NR
PhNHNHC(
PhN NH
NR)NHR RN
581
N R 582
NR
(2.290) Diphenylcarbodiimide reacts with excess thiosemicarbazide 583 to give the mono addition product 584 in high yield.552 H2 NNHCSNH2 + RN C NR −−→ RNHC( NR)NHNHCSNH2 583 584
(2.291)
Semicarbazides react in a similar manner. The reaction of carbodiimides with Nmethylhydroxylamine affords the expected guanidine derivative resulting from the reaction of the – NH group.553 In the reaction of carbodiimides with cyanamide 585, 1,2-disubstituted 3cyanoguanidines 586 are obtained.554 When the reaction is conducted in the presence of triethylamine the isomeric adduct 587 is obtained.555 RN C NR + H2 NCN −−→ RNHC(NHCN) NR or RNHC(NHR) NCN 585 586 587 (2.292)
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Carbodiimides react with hydrogen cyanide to give 1-cyano-N,N -disubstituted formamidines 588.556 RN C NR + HCN −−→ RNHC(CN) NR 588
(2.293)
The reaction product obtained from diphenylcarbodiimide and hydrogen cyanide is an intermediate in Sandmeyers indigo synthesis.557 HCN can also be eliminated from αaminocarboxylic acid nitriles 589 to give 1-cyano-N,N -disubstituted formamidines 590 and imines 591.435 RN C NR + R2 C(CN)NHR −−→ RNHC(CN) NR+ R2 C NR 589 590 591
(2.294)
N-silylated 1-cyano-N,N -disubstituted formamidines 592 react with DCC to give substituted imidazole derivatives 593.435
Me3SiN RN(SiMe3)C(CN)
NR + R1N
C
NR1
NR
R1N
NR
(2.295)
NR1 593
592
The reaction of the glycosylcarbodiimide 594 with HN3 proceeds in a regioselective manner to give 1-(β-glycosyl)-5-amino-1H-tetrazole 595.558
RNH N O N
t-BuSi(Me)2O
C
NR + HN3
O
O 594
O N
t-BuSi(Me)2O
O
N N
O 595 (2.296)
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Diphenylcarbodiimide reacts with trimethylsilyl azide 596 to give a silylated tetrazole derivative 597.559
N N PhN
NPh + Me3SiN3
C
PhN(SiMe)
N
(2.297)
N Ph 597
596
When diarylcarbodiimides are reacted with sodium azide and acid chlorides in the presence of a phase transfer agent, N-acyltetrazoles 598 are obtained in 55–74 % yield.560
N N RN
C
NR + NaN3 + R1COCI
RN(COR1)
N N R
(2.298)
598 Diaminouracil derivatives 599 react with cinnamic acids (R = NO2 , OCH3 , Br), in the presence of EDCCl to give carboxamido compounds 600.561
O NH2
N O
+ N H
CH
CH
COOH
NH2 R
599 R
(2.299)
O NH N O
O N H
NH2 600
2.4.6 Heterocycles from Carbodiimides Carbodiimides readily undergo reactions across their C N bonds to form heterocycles. For example, in their di- and trimerization reactions four and six membered ring N-heterocycles are obtained (see Section 2.4.1). Also, numerous four, five and six membered ring heterocycles are formed in the cycloaddition reactions of carbodiimides, often in excellent yields (see Section 2.4.2). Nucleophilic reactions of carbodiimides sometimes give rise to
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the formation of heterocycles (see Section 2.4.5). When carbodiimides are generated in the proximity of vinyl groups, cyclization reactions also often occur. For example vinylcarbodiimides undergo annelation reactions to unsaturated heterocycles (see Section 3.3.2) Acyl-, thioacyl- and imidoylcarbodiimides readily undergo [2+2] and [2+4] cycloaddition reactions with formation of heterocycles (see Section 5.3.1). Also, adjacent C N groups, as in pyridine substituted carbodiimides, cause cyclization with formation of heterocycles. When carbodiimides are generated in the proximity to suitably substituted OH, SH, or NHR groups, subsequent cyclization can give rise to the formation of heterocycles. This reaction is used to synthesize heterocycles 602 from ortho substituted thioureas 601 (X = O, S, NH).562
NHCSNHR
C
N
NR
+ DCC XH
XH (2.300)
601 N NHR X 602
Similarly, generation of the carbodiimide in proximity to a carboxyl group leads to cyclization. For example, the N-o-carboxyphenyl-N -phenyl urea 603 upon reaction with HgO affords the carbodiimide 604 which undergoes intramolecular cyclization to give the heterocycle 605.460
NHCONHR
N
C
NR
+ HgO COOH
COOH
603
604 (2.301)
H N
NR O
O 605
The cyclization of 603 is also achieved when the urea precursor is treated with a polymer supported EDC.563
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The heterocyclic urea derivative 606 (R = OCOCH2 Ph or H) with an o-substituted carboxyl group, on treatment with DCC, also cyclizes with formation of 607.564
COOH
N
O N
HO
O N
O
NHCONHR + DCC
O N
HO
N
NHR
OH
HO
OH 607
HO 606
(2.302) 2-Cyanoarylcarbodiimides react with ammonia to give quinazoline derivatives.565 In the reaction of aromatic or heterocyclic carboxylic acids with adjacent reactive groups with two equivalents of carbodiimides also heterocycles are readily obtained. For example, salicylic acid 608 reacts with aliphatic carbodiimides to give benzoxazine derivatives 609, together with the corresponding urea.566
O COOH + 2 RN
C
NR
NR
OH
O 609
608
+ RNHCONHR
NR (2.303)
Anthranilic acid reacts with aromatic carbodiimides similarly to give 3-substituted 1,3quinazoline-2,4-diones.567 A similar cyclization occurs in the reaction of 4-hydroxy-6-nitroquinoline-3-carboxylic acid 610 with DCC to give the oxazine derivative 611.568
NR O
OH COOH
O2N
O2N
O
+ DCC N 610
NR
N 611 (2.304)
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Hydroxycarboxylic acids 612 also react with carbodiimides to give oxazine derivatives 613.569
OH
Cl
+ RH
O
C
NR
O
Cl NR
O
COOH O 612
NR O
613
(2.305)
O
The reaction of thiosalicyclic acid 614 with two equivalents of carbodiimides may involve a thioacylketene intermediate 615, which undergoes a [2+4] cycloaddition reaction with the second equivalent of the carbodiimide to give the cycloadduct 616.570
O COOH
C + RN
C
+ RN
NR
SH
C
NR
S
614
615 O NR S
NR
616 (2.306) Ester groups adjacent to the carbodiimide are also used to effect ring closure to form heterocycles. For example, reaction of o-carboxyethyldiarylcarbodiimides 617 with hydrazine afford 3-amino-2-arylaminoquinazolin-4(3H)-ones 618 in 72–81 % yield.571
O CO2Et
N
+ H2NNH2 N 617
C
NAr
N 618
NH2 NHAr
(2.307)
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Generation of the carbodiimide from the 3-amino group in 618, followed by ring closure affords 1,2,4-triazolo[5,1-b]quinazolin-9-(3H)-ones in 63–88 % yield. Similarly, reaction of carbodiimide 619 with secondary amines in the presence of a catalytic amount os EtONa affords 2-dialkylamino-5,6,7,8-tetrahydrobenzothieno[2,3d]pyrimidine-4(3H)-ones 620 in high yields.572
O CO2Et
NAr
+ HNR2 S
N 619
C
NAr
S 620
N
NR2 (2.308)
Tetrabutylammonium fluoride promotes the intramolecular nucleophilic attack of the ester group. Oxazoline-5-ones 622 are obtained from carbodiimide 621 in this manner. The reaction is conducted at room temperature in THF and yields of 55–75 % are obtained.573
CO2Et N
C
O + Bu4F
NAr
N
O
(2.309)
NHAr 621
622
In case of o-carboxylic ester groups, such as in 623, ring closure to give 3,1-benzoxazin4-ones 624 is observed. The yields in this tetrabutylammonium fluoride promoted reaction are 50–55 %.
O CO2Et N C 623
+ Bu4F NAr
O
(2.310)
NHAr N 624
The heterocyclic carbodiimide 625, generated in the aza-Wittig reaction reacts with an
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alcohol to give the heterocycle 626.574
+ ROH
+ PhNCO
PPh3
N
N
CO2Et
N
CO2Et
N
C
N
N
NPh
625 O N
(2.311)
NR OR N 626
N
When instead of the ester group an arylamido group adjacent to the iminophosphorane group is present, reaction with arylisocyanates affords the carbodiimide which undergoes ring closure with formation of 2,3-disubstituted pteridin-4(3H)-one derivatives 627.575 O
O N
NHR N
N
N
NHR
+ ArNCO
PPh3
C
N
N
NAr
(2.312)
O N
NR N
N
NHR
627
Ring closure and annelation occurs when the heterocyclic carbodiimide 628 is generated in the presence of phthalazine to give the new heterocycle 629.576
N
N N Et 628
C
NR +
N
N N
N
N
N
Et 629
N NHR
(2.313)
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o-Aminothiophenols 630 react with carbodiimides to give mono and diadducts which cyclize to form 2-arylaminobenzothiazoles 631.577
NH2 + RN
N C
NR
NHR
(2.314)
S 631
SH 630
In the reaction of 2,2 -diaminobiphenyl 632 with DCC or DIPCD, 6-cyclohexylamino- or 6-isopropylamino-5H-dibenzo[d,f][1,3]diazepine 633, respectively, are obtained.578
NH
NH2 NH2 + RN
C
NHR
NR
(2.315)
N
633
632
Some carbodiimides, generated in the aza-Wittig reaction, readily undergo further reactions with groups adjacent to the cumulene group. For example, the heterocyclic carbodiimide 634 undergoes intramolecular cyclization involving the adjacent nitro group to form imidazo[4,5-d][1,2,3]triazoles 635.579
Et N
N
N
NO2
Me
PPh3
+ RNCO
Et N
N
N
NO2
C
NR
Me
634 Et N
N
N
N
Me
NR
635 (2.316)
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Heating of the iminophosphorane 636 with isocyanates to generate the carbodiimide in toluene affords pyridothionopyridazine derivatives 637.580
Ph Ph
N N
N
S
PPh3
+ RNCO
CO2Et 636
(2.317)
Ph Ph
N N
N
NHR
S 637
CO2Et
Carbodiimides generated in situ in the proximity of a hydroxy group as in 638 undergo intramolecular ring closure reactions to give heterocycles, such as 639.581
O
HO N3
N Me
N
C
NR
+ RNCO N Me 638 NHR O
N
N Me 639 (2.318)
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A similar ring closure is observed when the carbodiimide with an acylated hydroxy group in the β-position 640 is treated with ammonia to give the heterocycle 641.582
NHR OAc C
N
HN
NR
N (2.319)
+ NH3
640
641
Polymer bound 1,3,4-oxadiazoles 643 are obtained from substituted hydrazides 642 in DMF (100 ◦ C/18 h) in the presence of diisopropylcarbodiimide in 60–78 % yield.583
P
NH
NH
O
O
NHCO
R 642
(2.320)
N N NHCO
P
R O 643
From suitably constructed amine heterocycles annelation of diarylcarbodiimides can occur. For example, the aminodehydrotriazinone derivative 644 reacts with diarylcarbodiimides to give triazolotriazinones 645 on refluxing in toluene.584
N H2N
N
Me
N
+ ArN N H 644
C
NAr
ArN
N
Me
N
O
(2.321)
O ArNH 645
Heating of diarylcarbodiimides with o-nitro substituents in bromobenzene affords benzotriazoles. For example, an 85 % yield of 2-(o-nitrophenyl)benzotriazole 647 is obtained from 2,2 -dinitrodiphenylcarbodiimide 646.585
N N
C
N O2N
NO2 646
N H ON 2 647
(2.322)
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Mesoionic compounds are formed when carbodiimides, generated in an aza-Wittig reaction, are in proximity of a C S bond. For example, reaction of the iminophophorane 648 with an isocyanate or an isothiocyanate produces the mesoionic compound 649.586
S
S Ph N N
Ph
+ RN
S
C
N
X
+ −
S
(2.322)
N
PPh3
NR
648
649
Similarly, pyrido[2,1-b]-1,3,4-thiadiazolium-2-amenates are obtained by cyclization of carbodiimides, generated in situ, from thioureas.587 Also, reaction of N-aminoheterocycles 650 with arylcarbodiimides affords fused mesoionic 1,2,4-triazoles 651.588
Ph Ph
Ph
+
−
N
S
NH2 650
+ RN
C
NR
Ph
N
+ −
NR
(2.323)
N NHR 651
The carbodiimide mediated preparation of tricyclic pyrido[3 ,2 :4,5]pyrrolo[1,2c]pyrimidine is a key step in the preparation of the marine alkaloid variolin B.589
2.4.7 Use of Carbodiimides In Condensation Reactions 2.4.7.1 Esterification of Acids using Carbodiimides. The formation of anhydrides from carboxylic acids, thiocarboxylic acids, sulfonic acids and phosphorous acids are discussed in Section 2.4.5.2. In this section only special cases of anhydride formation are described. Mixed anhydrides of amino acids and adenylic acid are produced from the corresponding acids using DCC as the condensation agent.590 Mixed anhydrides not containing amino acids, such as butyryl adenate,591 adenosine 5 -phosphosulfate 592 and p-nitrophenylthymidine-5-phosphate593 are also obtained. Reaction of a mixture of carboxylic acid and an alcohol or thioalcohol with a carbodiimide at room temperature affords the corresponding ester 652 in high yield. The reaction is best conducted in methylenechloride as solvent, using DMAP (4-dimethylaminopyridine) as the catalyst.594 RCOOH + R1 XH + RN C NR −−→ RCOXR1 + RNHCXNHR 652 where X = O, S.
(2.324)
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Even the sterically hindered 2,4,6-trimethylbenzoic acid is esterified with methanol under these conditions. Carboxylic acids containing α-halogen atoms are best esterified with DCC without a solvent or base.595 Long chain ω-hydroxy acids, such as 653, are converted to the corresponding macrolactones 654 in 95 % yield using DMAP hydrochloride.596 HO(CH2)14COOH + DCC
(CH2)n
O
(2.325)
O 654
653
The 17 membered ring lactone is also obtained in 96 % yield, while shorter chains produce lower yields. Under similar conditions without DMAP hydrochloride, mixtures of the lactones and linear polymers are obtained.597 The direct esterification of undec-10-enoic acid with phenylalkanols using DCC and 4-(N,N-dimethylamino)pyridine affords the corresponding esters in quantitative yields.598 Esterification of the secondary alcohol 655 with long chain aliphatic acids in the presence of DCC and DMAP affords the dioxane esters 656 in yields of 80–93 %.599 O HO
O + RCOOH
RCOO
(2.326)
O 655
O 656
The formation of ketene intermediates facilitates the carbodiimide mediated esterification reaction with alcohols and phenols when carboxylic acids with an electron withdrawing group in the α-position are used as substrates.472 The reaction fails when highly sterically hindered substrates are used. From t-butanol and 1-phenylcyclohexane-1-carboxylic acid or 2,4,6-trimethylbenzoic acid, respectively, only the dianhydrides of the carboxylic acids are obtained. Better yields of the thiolesters are obtained by first reacting the carboxylic acid with 1-hydroxybenzotriazole in the presence of DCC, followed by reaction with the thioalcohol.600 A number of sugar esters are obtained in a similar manner.601 The use of DCC in the polycondensation of aliphatic dicarboxylic acids and diols is also reported. These polyester are biodegradable surface active compounds.602 Phenolic esters are obtained similarly. The presence of a nitro group in the aromatic nucleus and the use of pyridine as solvent facilitates the reaction. This reaction is recommended for the characterization of phenols.603 2,4,5-Trichlorophenyl-,604 pentachlorophenyl-,605 4nitrophenyl-606 and thiophenyl esters607 of N-acylamino acids are prepared in this manner. These aromatic esters are used in the stepwise lengthening of peptides. du Vigneaud and coworkers608 synthesized lysine vasopressin from a nonapeptide which they prepared stepwise using the nitrophenyl ester method. Room temperature esterification of dicarboxylic acids and diphenols are also carbodiimide mediated using the 1:1 complex derived from DMAP and p-toluenesulfonic acid as catalyst.609 Methacrylic acid is also esterified with phenols using carbodiimides and DMPA to mediate the reaction.610 The esterification of ferrocene-1,1 -dicarboxylic acid with substituted phenols to produce hexacatenar substituted ferrocenes, which are thermotropic liquid crystals, is also mediated by carbodiimides.611
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Poly(vinyl alcohol) is esterified with 2-mercaptobenzothiazole acetic acid or N-(mnitrobenzoyl)-L-methionine using DCC to mediate the reactions.612 Also, single walled and multiple walled carbon nanotubes were functionalized with poly(vinyl alcohol) in esterification reactions using DCC. The PVA as well as the functionalized nanotubes are soluble in DMSO allowing wet casting of nanocomposite thin films.613 Esters derived from hydroxyalkyl hexa-peri-hexabenzocoronenes and 9,10-anthraquinone-2-carboxylic acids are prepared using EDC and DMAP to construct self-assembly donor-acceptor dyads.614 The diazo acetic acid 657 is esterified with alcohols under neutral conditions in the presence of DCC and a catalytic amount of DMAP to give the corresponding esters 658 in high yields.615 HOCOC(N2 )COMe + ROH −−→ ROCOC(N2 )COMe (2.327) 657 658 The reaction of mono- and polynucleotides with high concentrations of sorbitol mediated by EDC results in the esterification of terminal phosphate groups.616 The esterification of N-protected amino acids with alcohols mediated by carbodiimide is also accomplished in the presence of DMAP.617 Oximes 659 are also acylated with carboxylic acids using DCC as condensation agent to give the O-acylated derivatives 660.618 RCOOH + HON CPh2 + RN C NR −−→ RCOON CPh2 + RNHCONHR 659 660 (2.328) In the reaction of glutaric acid derivatives with CF3 CONH2 in the presence of EDC hydrochloride/HOBt cyclic imides are obtained.619 2.4.7.2 Formation of β-Lactams, Peptides and Oligonucleotides. The intramolecular cyclization technology to form β-lactams using DCC in the condensation reaction was used by Sheehan and Henery-Logan in the total synthesis of penicilline in 1957. They also found that N-trityl penicilloates are cyclized with diisopropylcarbodiimides.620 Other βlactames, such as cephalothin lactone621 and (−)-thienamicin622 are similarly constructed. The latter synthesis proceeds in a stereospecific manner and DCC is used in combination with triethylamine to give a 93 % yield of the β-lactam 661. OH CH3CH(OH)CH(COOH)CH(NH2)CH2COOH
CO2CH2Ph
CH3 NH O 661
(2.329) Carbodiimides are also used in the enantioselective synthesis of 3-substituted 4-(alkoxycarbonyl)-2-azetidinones from malic acid.623 DCC is used in the the synthesis of nocardicin A.624 Penam, 4-thiazabicyclo[3.2.0]heptan-7-one, and 2,3-disubstituted derivatives utilize EDCCl in the cyclization steps.625 β-Lactams are also obtained in the [2+2] cycloaddition reaction of ketenes with carbodiimides (see Section 2.4.2.1). The synthesis of β-lactam peptide analogues of melanostatin uses EDCCl, HOBt and Et3 N in the construction of amide derivatives.626
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Sometimes the β-lactam precursors are constructed using DCC in the protection of the carboxylic acid group by reacting it with benzylhydroxylamine.627 N-tosyllactams are obtained similarly using DCC and 4-pyrrolidinopyridine to effect ring closure. Medium sized cyclic β-lactames are obtained via an intramolecular Staudinger ligation using DCC or EDC in the presence of Dabco.628 In 1955 Sheehan and Hess629 and Khorana630 showed independently that suitably blocked amino acids are condensed with amino acids in the presence of carbodiimides to produce carboxylic acid amides 662 under mild conditions. MeCONHCH(R)COOH + H2 NCH(R1 )COOR2 −−→ MeCONHCH(R)CONHCH(R1 )COOR2 662
(2.330)
The mechanism of the carbodiimide initiated coupling reaction involves a proton transfer followed by addition of the carboxylic acid to form the O-acylisourea 663. This reactive intermediate attacks the amino group to form the corresponding amide bond. However, 663 can undergo a rearrangement to give the N-acylurea 664, and it can also react with another molecule of the carboxylic acid to give the symmetrical anhydride 665 which is also an excellent acylating agent. When the carboxylic acid is an N-carboxamide (acetyl, benzoyl or a peptide chain) or a carbamate α-amino acid (Boc, Fmoc), the O-acylisoureas also can undergo an intramolecular cyclization to give the 5(4H)-oxazolone derivatives 666. The latter are also acylating agents, but not as powerful as 663 or 665. MeCONHCH(R)COOH + R1 N C NR1 −−→
R1N
C
NHR1
O
R1N
CH(R)NHCOMe O O 663
O R3
C
C
CH(R)NHCOMe 664
R
O O
CONHR1
R3
665
N Me O 666
O
MeCONHCH(R)CONHCH(R1)COOR2 662
R3 MeCONHCH(R)N-acetylated threonine derivatives form isolable 5(4H)-oxazolone derivatives.631
(2.331)
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The O-acylisourea 667 can be trapped by a nucleophile present in the reaction, usually a hydroxylamine derivative to give a more stable reactive ester 668. Racemization can occur involving the enol form of 668.
R1N
C
NHR1
+ R2R3NOH
CH(R)NHCOMe
O
MeCONHC(R)COONR2R3 668
O 667 (2.332) One of the drawbacks of the carbodiimide method is the formation of N-acyl-N,N disubstituted ureas as a side reaction. The problem of N-acylurea formation is enhanced when long reaction times are required. Also racemization can occur under the reaction conditions.632 The problem of N-acylurea formation is resolved by using a reactive nucleophile, such as N-hydroxybenzotriazole (HOBt), Cl-HOBt, Nhydroxysuccinimide or N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide, which also tends to suppress the racemization reaction. Also, ethyl-1-hydroxy-1H-1,2,3-triazole4-carboxylate (HOTC) is used in the solid phase peptide synthesis using Fmoc chemistry.633 Racemization also decreases according to carbodiimide structure in the order DCC > N-benzyl-N -ethylcarbodiimide > N-p-tolyl-N -ethylcarbodiimide > Nphenyl-N -ethylcarbodiimide.634 However, N-hydroxybenzotriazole can also catalyze diazetidine formation, another undesired byproduct.635 Often the use of excess carboxylic acid in the coupling reaction leads to anhydride formation being the major reaction.636 For example, benzyloxycarbonylamino acids react with DCC to give the corresponding dianhydrides.637 Also, an excess of the reactive nucleophile should be avoided. The amount of an 0.1 equimolecular excess is recommended.638 Solvents also have an effect on racemization.639 In addition to DCC and EDC many other aliphatic carbodiimides are used in peptide synthesis. Examples include N-t-butyl-N -methylcarbodiimide (BMC), N-tbutyl-N -ethylcarbodiimide (BEC), N,N -dicyclopentylcarbodiimide and N-cyclohexyl-N isopropylcarbodiimide (CIC). DCC, diisopropylcarbodiimide, BMC and BEC perform similarly in peptide synthesis.640 N-cyclohexyl–N -isopropylcarbodiimide (CIC) is comparable or even better than DCC for mediation of peptide bond formation in solid phase synthesis. Also, the solubility of the derived urea in dichloromethane is useful in the standard procedure.641 Polymeric carbodiimides are also used in peptide synthesis. For example, a polymeric carbodiimide with a N-cyclohexyl-N -phenyl endgroup is used in the synthesis of a metalloproteinase inhibitor.642 The modified carbodiimide method, using N-hydroxysuccinimide is called the Wuensch-Weygand method.643 Koenig and Geiger, in 1970 proposed the use of Nhydroxybenzotriazole.644 3-Hydroxy-4-oxo-3,4-dihydroquinazoline and 3-hydroxy-4-oxo3,4-dihydrobenzo[d]-1,2,3-triazine are also used.644 Other N,N-diacylhydroxylamines,
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ethyl 2-hydroximino-2-cyanoacetate645 and tosyl-hydroxylamine646 are also proposed as co-nucleophiles. 6-Chloro-1-hydroxybenzotriazole is more reactive than HOBt.647 A variety of N-protection groups are utilized in conjunction with carbodiimide/Nhydroxybenzotriazole coupling. In addition to the Boc (t-Butoxycarbonyl) group, the pnitrocinnamoyloxycarbonyl (Noc)648 group, and the ferrocenylmethyl (Fem) group are also used for the protection of amino groups.649 Also, the use of DMAP as an additive to carbodiimides in peptide synthesis is often advantageous.650 For example, the Fmoc amino protecting group is used in the solid phase synthesis of scorpion neurotoxin II using DCC or diisopropylcarbodiimide in the coupling reactions.651 Peptides play a key role in the post genomic era, but amide bonds are also present in many other organic compounds of biological interest. Nonapeptides are constructed using DCC and N-hydroxybenzotriazole,652 this method is also used in the synthesis of prothimosin α(pro Tα), a polypeptide consisting of 109 amino acids.653 In the latter reaction the coupling is conducted using DMSO as solvent. Similarly, glycoproteins are synthesized, but in this case piperidine/DMF is used as solvent.654 The synthesis of cyclosporin, a cyclopeptide formed from 11 amino acids also uses DCC in the formation of the heptapeptide intermediate.655 Sugarcarboxylic acids656 and sugaramines657 are also coupled using DCC and N-hydroxysuccinimide. These reactions are useful to construct peptidoglycolipids. Glycopeptides are also obtained by coupling sugar amines with N-protected amino acids. For example, in the reaction of glucosamine 669 with asparagin in the presence of DCC the corresponding amide 670 is obtained.658
AcO O NH2 + PhCH2OCONH(COOBzI)CH2COOH
AcO AcO
NHAc 669 AcO
(2.333)
O NHCOCH2CH(COOBzI)NHCOOCH2Ph
AcO
NHAc
AcO 670
Glycolipids are similarly synthesized using DDC and HOBt.659 Bicyclic azasugar glycomimetics related to castanospermin are prepared from sugar carbodiimides via aminooxazoline derivatives.660 EDC is also used to couple cattle serum albumin with a synthetic glycopeptide. DCC is used to activate hydroxyl groups in sugars.661 The coupling of nitroxide spin labeled species to monosaccharides is also accomplished using DCC.662
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The synthesis of peptides in an aqueous system can be achieved using water soluble quaternary ammonium group containing carbodiimides. Sheehan and coworkers used this method to couple N-phthaloglycine and glycine ethyl ester to a dipeptide,663 and to couple a linear tripeptide to form a cyclohexapeptide.664 Attempts are also made to increase the water solubility of the protected amino acids. 2-Phosphonioethoxycarbonyl (Peoc) groups are useful for this purpose, because they can be hydrolyzed under mild alkaline conditions. The Geiger-Koenig method665 has to be modified to accomodate the hydrolytic instability of the Peoc group. Thus, reaction of 2-(methyldiphenylphosphonio)ethoxycarbonyl leucine 671 with phenylalanine t-butyl ester in the presence of N-hydroxy-benzotriazole and Ncyclohexyl-N -β-(N-methylmorpholino)ethylcarbodiimide p-toluenesulfonate affords the Peoc-dipeptide ester 672 in 82 % yield.666 MePh2 P+ CH2 CH2 OCOLeuOH + H-Ph-O-t-Bu 671 −−→ [MePh2 ]Peoc-Leu-Ph-O-t-Bu 672
(2.334)
The deblocking can be conducted in quantitavive yield, using trifluoroacetic acid at room temperature. Another protection group used in combination with EDC is the 3-(3pyridyl)allyloxycarbonyl (Paloc) group.667 In this reaction DAEC is used in combination with N-hydroxybenzotriazole. Also, template controlled ligation of peptide nucleic acids is possible using EDC in an imidazole buffer.668 The highest selectivity is obtained using a peptide condensation that forms an abasic site.669 An example is the following reaction which produces the peptide 673.
AcN
CCG GlyCOOH + H2 N Gly GGC + EDC −−→
AcN
CCGGlyGlyGGC 673
(2.335)
Protected amino acid peptides are also conjugated to guanine rich oligonucleotides using EDC. For example, the N-protected amino acid 674 reacts with H2 N DNA (DNA = GGTGG where T is modified deoxyuridine) in the presence of EDC to give the amide 675.670 P COOH + H2 N DNA + EDC −−→ PCONH DNA 674 675
(2.336)
Cyclic peptide nucleotide hybrids with various ring sizes are obtained by intramolecular condensation of 3 -N-aminoacyl/peptidyl-5 nucleotides using EDCCl.671 A series of norbornene derivatives containing nucleic acid bases (thymine, adenine, guanine or uracil) are
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prepared as monomers for ring-opening metathesis polymerization (ROMP) using EDC. An example is the adenine derivative 676, which reacts with the norbornene derivative 677 to give the monomer 678.672
NHBoc
O
N
N N
N
N
+ H2N
O OH
+ EDC O
676
677 (2.337)
NHBoc N
N
O
O N
N
NH
N
O 678
Also, a high load soluble oligomeric carbodiimide is synthesized using the ROMP polymerization procedure (see Section 12.2).673 Oligothiopeptides can be synthesized using N-methyl-N -(3-dimethylamino)propylcarbodiimide and N-hydroxybenzotriazole.674 Polycyclic peptide antibiotica (lantibiotica) are also constructed using a water soluble carbodiimide and N-hydroxybenzotriazole.675 Cyclic peptides are synthesized using EDC/HOAt.676 α,α-Disubstitued α-amino acids are obtained in the reaction of carboxylic acids with 3-amino-2H-azirines. The coupling of these carboxylic acids utilizes N-cyclohexyl-N -[2-(4-methylmorphline-4-ylium)ethyl]carbodiimide p-toluenesulfonate in the presence of campher-10-sulfonic acid as the catalyst.677 Also, DCC in combination with zinc chloride is used in this reaction. Segmented coupling and stepwise peptide assembly is also accomplished using diisopropylcarbodiimide and 1-hydroxy-7-azabenzotriazole.678 The most widely used method to construct polypeptides is the use of a polymeric substrate to achieve multiple reactions. The Merrifield polypeptide synthesis on a polymeric substrate (crosslinked polystyrene) as the solid phase, revolutionized the synthesis of sequential polypeptides. The initial attachment of a protected amino acid to chloromethyl group containing polystyrene is achieved with triethylamine followed by hydrolysis to give 679 (Scheme 2.338, Step A). After removal of the protecting group, coupling of
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another protected amino acid with the polymeric substrate is conducted using DCC to activate the carboxylic acid group to form 680 (Scheme 2.338, Step B). Deprotection and further coupling of another protected amino acid can be repeated many times. Finally, the synthetic polypeptide 681 is removed from the crosslinked polymer using HBr, HF or CF3 COOH (Scheme 2.338, Step C). The removal of the polypeptide can also be effected with ammonia, thereby producing a polypeptide having a carboxylic acid end group.
BocNHCH(R)COOH + CICH2
P
BocNHCH(R)COOCH2
(Step A)
P
679 H2NCH(R)COOCH2
P
+ BocNHCH(R1)COOH
BocNHCH(R1)CONHCH(R)COOCH2
P
(Step B)
680 BocNHCH(R1)CONHCH(R)COOCH2
P
(Step C)
H2NCH(R1)CONHCH(R)COOH 681 (2.338) In the solid phase reaction the anhydride formation is the predominant pathway.679 Reaction with radioactive DCC has shown that less than 0.2 % of the polymer-bound amine reacts directly with the reagent.680 Other polymeric substrates, such as poly(N,N-dimethylacrylamide)681 and graft polymers derived from hydroxyl group containing crosslinked polystyrene and ethylene oxide682 are also used as solid phases. In the latter example diisopropylcarbodiimide is used in the coupling reaction. Also, diisopropylcarbodiimide/HOBt is used in the solid phase synthesis of polypeptides. Ammonium salts derived from polymer bound N-hydroxysuccinimide are also used in the EDC mediated amidation reaction.683
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7-Deazaxanthine-9-propionic acid 682 undergoes cyclization in the presence of EDCCl to give a 92 % yield of triazaacenaphthalene-5,6,8(4H,7H)-trione 683.684
O
O
HN HO
HN
N HOOC
N
+ EDCCl
O
682
N
N
(2.339)
O 683
The tricyclic compound 683 is a labile compound, which undergoes hydrolysis in water to regenerate 682. Repeated addition of EDCCl demonstrates the complete reversibility of the intramolecular acylation reaction. Linear soluble PEG (polyethylene glycol) is used as a liquid phase in the synthesis of polypeptides. In this case the esterification of the carboxylic acid group of the N-protected amino acids with the terminal – OH groups of PEG can be conducted using DCC685 or a water soluble carbodiimide to give 684.686 Reaction of 684 with a different N-protected amino acid produces 685. PEG OH + HOOCCH(R)NHBoc −−→ PEG OCOCH(R)NH2 684 PEG OCOCH(R)NH2 + HOOCCH(R1 )NHBoc
(2.340)
−−→ PEG OCOCH(R)NHCOCH(R1 )NHBoc 685
Using the automated stepwise method of synthesis on a solid phase allows the synthesis of polypeptides consisting of up to 120 amino acids. The final polypeptide is purified by HLPC (high pressure liquid chromatography). O-glycopeptides are also constructed on a solid phase using DCC and N-hydroxybenzotriazole in DMF.687 Also, solid phase synthesis of peptides containing α,β-didehydroamino acids are common. In this case the carbodiimide affects dehydration to generate the α,β-didehydroamino acids 686. For example, the water soluble carbodiimide EDC hydrochloride (EDCCl) is used in this dehydration reaction, also using CuCl as catalyst.688
R1 CH(OH)CH(NHCbz)COOR2 + RN C NR −−→ R1 CH C(NHCBz)COOR2 686 (2.341)
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EDCCl is also used in the coupling of the two heterocyclic amino acids 687 and 688 to form the amide 689 in 93 % yield.689
O COOH O
N NHBoc 687
CO2Et +
S
N NH2 688
NH O
N
S N
NHBoc
CO2Et
689
(2.342)
Other examples of this type of reaction include the use of the water soluble Ncyclohexyl-N -(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate or diisopropylcarbodiimide.690 EDCCl is also used in the N-formylation of isoserin 690 with formic acid to give the N-formyl derivative 691.691
EtOCOCH(OH)CH2 NH2 + HCOOH + EDCCl −−→ EtOCOCH(OH)CH2 NHCHO 690 691 (2.343)
Also treatment of N-diphenylmethylene-β-hydroxyamino acid methyl ester 692 with diisopropylcarbodiimide in the presence of CuCl achieves formation of the α,β-didehydro amino acid esters 693.692 R2 (OH)CH(N CPh2 )COOMe + RN C NR −−→ R2 C C(N CPh2 )COOMe 692 693 (2.344)
Nonapeptide linear amides are also often synthesized using the carbodiimide method. Examples include the synthesis of norcardicine A693 and the synthesis of renin inhibitors.694 The total synthesis of a trifluoromethyl (Tfm) analogue of pepstatin uses EDCCl/HOBt in the condensation steps.695 In the stepwise or block synthesis of polynucleotides, carbodiimides also play an important part. An example is the synthesis of the dinucleotide phosphate thymidyl-3 ,
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5 -thimidine 694 mediated by DCC in anhydrous pyridine.696
TrO
TrO
O
T
O −
+ O HO
P
O
O
OH
T
O
T
O −
O
P
O
O
O
T
AcO AcO 694 (2.345) The carbodiimide is also used to convert nucleotide phosphates into protected derivatives using 2-cyanoethanol or p-(triphenylmethyl)aniline. Carbodiimides are often used in the crosslinking of proteins. They are a family of ‘zero length’ protein crosslinking agents, which promote the formation of covalent crosslinks between reactive side groups of amino acids, but do not remain as part of the crosslinks. The ‘zero length’ protein crosslink can occur between carboxyl groups (available in aspartic acid or glutamic acid) and -amino groups (available in lysine) and intra- as well as intermolecular crosslinks can be formed. The water soluble EDC is used in the crosslinking of dermal sheep collagen697 and hyaluronic acid.698 When it is used in conjunction with N-hydroxysuccinimide on cellularized ovin carotid arteries, it has been noted that pH control alters the type of crosslinking produced.699 The absence of pH control may have favored the formation of interfibrillar or intermolecular crosslinks in collagen as well as involvement in other extracellular matrix components (proteoglycans and glucosaminoglycans). When the carboxyl groups on mucopolysaccharide chains become involved in EDC induced crosslinking with collagen, they form a proteoglycan or glycosaminoglycan ‘glue’ between fiber layers. Carbodiimides are also used to crosslink bioprosthetic materials to enhance their stability prior to implantation. For example, anticalcification treatment for porcine bioprosthetic valves can be conducted using carbodiimides. Carbodiimides are also used to investigate the conjugation of proteins in structural studies.700 Also, quantification of carboxyl groups in proteins can be achieved with carbodiimides.701 Numerous examples of proteine modification by carbodiimides are discussed in Section 13.2.3. 2.4.7.3 Carbodiimide Mediated Formation of Polyamides. A commercially interesting method to produce polyamides consists of reacting diisocyanates with dicarboxylic acids.
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This reaction is conducted in the presence of a phospholene oxide catalyst, generating carbodiimide species in situ, which undergo reaction with the dicarboxylic acids. In this manner segmented block polyamide elastomers and semicrystalline engineering plastics are produced from 4,4 -diphenylmethane diisocyanate (MDI) and aliphatic dicarboxylic acids, such as azelaic acid, and acid-terminated aliphatic polyester, polycarbonate or polyether prepolymers.702 The carbodiimide mediated polymerization can be conducted in a polar solvent or better continuously in a vented extruder.703 Isomeric mixtures of methylphospholene oxide (MPO) and dimethylphospholene oxide (DMPO) are used as catalysts.704 This technology was developed in the late 1970s at the D.S. Gilmore Research Laboratories of the Upjohn Co., and the thermoplastic poly(esteramide) elastomers and the copolyamides were commercialized in the 1980s. The dicarboxylic acids react with MDI to form the hard segments, while the carboxylic acid terminated prepolymers react with MDI to give the soft segments. The thus obtained poly(esteramides) and poly(etherester amides) are thermoplastic elastomers with better thermal properties than thermoplastic polyurethane elastomers. The copolyamides obtained from MDI and mixtures of adipic and azelaic acid are high melting crystalline polymers. Copolymers containing 20–30 % of adipic acid show an eutectic Tm of approximately 240 ◦ C. These MDI derived copolyamides have mechanical properties comparable to transparent nylons and polycarbonates, including high notched Izod impact strength. Formulating copolyamides from mixtures of isophthalic- and azelaic acids is also possible. In this case a portion of the isophthalic acid is prereacted with 2,4-TDI to depress the crystallinity of the IPA/MDI blocks.705 Copolymers with 50–60 % IPA display thermal and mechanical properties similar to polysulfone with significantly better yield strength. A semicrystalline engineering thermoplastic derived from azelaic acid has a Tg at 135 ◦ C and a Tm at 290 ◦ C.706 Random copolyamides are also obtained from MDI or TDI with mixtures of isophthalic acid and 4,4 -oxydibenzoic acid.707 Multiblock copolymers are also obtained by reacting a mixture of isophthalic acid and azelaic acid with MDI to form a prepolymer, which is subsequently reacted with α,ω-bis(10-carboxy-decyl)polydimethylsiloxane.708 Carbodiimides (DIPCD, DCC) are also used as activating compounds in the anionic polymerization of caprolactam to nylon 6.709
2.4.8 Miscellaneous Reactions Cyclic nitrones 695 react with di-t-butylcarbodiimide in the presence of a catalytic amount of tetrafluoroboric acid by dehyration to give the heterocycle 696.710
N 695
+ RN
C
NR
N
O
+ RNHCONHR
696
(2.346)
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Unsaturated aminoacid esters 698 are obtained in the reaction of carbobenzoxy protected α-hydroxyamino acid esters 697 with diisopropylcarbodiimide in the presence of CuCl.711 RCH(OH)CH(NHCbz)COOR1 + RN C NR −−→ RCH C(NHCbz)COOR1 697 698 (2.347) The reaction of carbodiimides with hydrogen chloride affords chloroformamidine hydrochlorides 699.712 RN C NR + 2 HCl −−→ RNHC(Cl) NHR]+ Cl− 699
(2.348)
Suitably substituted carboxylic acids 700 can be dehydrated with DCC to give the heterocycle 701.713 NR
NR O
NO2 + DCC
NH OH
O
NO2
N
700
701
(2.349) Carboxylic acid chlorides react with carbodiimides to give N-acychloroformamidines 702.714 Further reaction of the N-acylchloroformamidines with thiosemicarbazide affords 1,3,4-thiadiazoles.715 RN C NR + R1 COCl −−→ RN(COR1 )C(Cl) NR 702
(2.350)
Diisopropylcarbodiimide reacts with α-halo carboxylic acid chlorides to give the same chloroformamidines, which on hydrolysis cyclize to form 5-oxazolidinones.716 Carbonyl dichloride (phosgene),717 phosphoryl chloride,718 phosphorus trichloride,719 thiophosgene,719 thionyl chloride,719 sulfur dichloride719 and cyanuric chloride720 react with carbodiimides to give the expected chloroformamidine derivatives. In the reaction of carbodiimides with two equivalents of carbonyl chloride N,N -disubstituted chloroformamidine N-carbonyl chlorides 703 are obtained. RN C NR + 2 COCl2 −−→ RN(COCl)C(Cl)NR 703 R
[%]
bp ◦ C/Torr
n-Bu cyclohexyl 2-MePh
98 100 99
86/0.5 140–142/0.8 oil
(2.351)
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Dichloromethylene ammonium chloride 704 also reacts with carbodiimides to give chloroformamidinium salts 705.721 Me2 N+ CCl2 ]Cl− + RN C NR −−→ RN C(Cl)N(R)C(Cl) N+ Me2 ] Cl− 705 704 (2.352) The chloroformamidinium salts are utilized in the synthesis of heterocyclic compounds. Parabanic acid derivatives 706 are obtained in the reaction of carbodiimides with oxalyl chloride.722
RN
C
NR + (COCl)2
O
O
RN
NR
Cl
(2.353)
Cl 706
In contrast, reaction of methyloxalyl chloride with carbodiimides affords the imidazolidine2,4,5-trione derivative 707.723
RN
C
NR + CICOCOOMe
O
O
RN
NR
Cl
OMe (2.354)
O
O NR + MeCl
RN O 707
Addition of dimethyldithionooxalate to dialkylcarbodiimides affords 4,4 -dimethyloxyimidazolidine-2,5-dithione.724 Six-membered ring heterocycles 708 are obtained in the reaction of carbodiimides with malonyl chloride.725 Hydrolysis of the dichlorodihydropyrimidine-diones affords barbituric acid derivatives.726
O RN
C
NR + ClCOCR2COCl
R
R O
RN
NR
Cl
Cl 708
(2.355)
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The reduction of carbodiimides affords formamidines 709. Examples include reaction with NaBH4 727 or catalytic hydrogenation.728 RN C NR + H2 −−→ RNH CH NR 709
(2.356)
Hydrogenation of dialkylcarbodiimides in the presence of ruthenium clusters affords trialkylguanidines 710.729
2 RN C NR + H2 −−→ RNHC(NHR) NR + RNHCH3 710
(2.357)
The electrochemical reduction of diphenylcarbodiimide in acetonitrile affords diphenylmethane diamine.730 The reaction of carbodiimides with lithium powder resulted in a reductive coupling.731 Oxidation of di-t-butylcarbodiimide with m-chloroperbenzoic acid in methylene chloride affords a 20 % yield of the diaziridinone 711.732 Similar treatment of DCC gives no diaziridinone. O
O RN
C
NR + R1CO3H
RN
O C
NR
RN
C
NR
RN NR 711
(2.358) Oxidation of DCC with pertrifluoroacetic acid affords N-trifluoromethyl-N,N dicyclohexylurea.733 Reaction of aliphatic carbodiimides with 98 % H2 O2 produces peroxycarboximidic acid 712, which can be used to oxidize arenes to arene oxides.734 RN C NR + H2 O2 −−→ RNHC(OOH) NR 712
(2.359)
Also, 30 % H2 O2 in the presence of carbodiimides and mild bases or acids is used to epoxidize olefins.735 Ozonolysis of carbodiimides produces mainly ketones, isocyanates, cyanamides and oxygen.736
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Heating or irradiation of carbodiimides causes rearrangement to give cyanamides 713.737 RN C NR −−→ R2 NCN 713
(2.360)
Symmetrical glycosyl cyanamides are obtained from symmetrical glycosyl carbodiimides on treatment with SnCl4 . Also, allylcarbodiimide 714 on treatment with Pd(dba)2 rarranges to the allylcyanamide 715.738 4-MeOPhN C NCH2 CH CH2 −−→ 4-MeOPhN(CN)CH2 CH CH2 714 715
(2.361)
Photolysis of some N,N -dialkylcarbamoyl azides in the presence of carbodiimides leads to the trapping of the generated dialkylamino isocyanates by the carbodiimides to form five membered ring mesoionic 5-(dialkylamino)-1,2,4-triazoles.739 α-Alkoxycarbonylcarbodiimides 716, obtained from the corresponding isocyanates and N-arylphosphine imines, isomerize to give N-alkylidene-N -acylureas 717.740 αAlkoxycarbodiimides having a CF3 substituent are stable in the carbodiimide configuration 716.741 RR1 C(OCOR2 )N C NR3 −−→ RR1 C NCON(COR2 )R3 716 717
(2.362)
Epimerization of reducing sugars occurs in neutral solution using DCC. For example, fructose on heating with DCC in anhydrous methanol gives mixtures of glucose, manose and psicose.742 Heating of DCC with methyl iodide affords the N-methylated carbodiimide salt 718 in 75 % yield.743 RN C NR + MeI −−→ RN+ (Me) C NR]I− 718
(2.363)
The salt is used as reagent to convert alcohols into alkyl iodides. This reaction proceeds with inversion of configuration on the C atom bearing the – OH group. N-Methyl-N,N di-t-butyl-carbodiimide tetrafluoroborate is used as condensation agent in the synthesis of ethers and esters.744 In the reaction of alkyl lithium and carbon monoxide with carbodiimides, acylation of the carbodiimide with formation of 719 is observed.745 RN C NR + R1 Li + CO −−→ RNHC(COR1 ) NR 719
(2.364)
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Reaction of carbodiimides with nitromethane in the presence of NaH in DMF affords 1-nitro-2,2-bisaminoethylenes 720.746 RN C NR + MeNO2 −−→ (RNH)2 C CHNO2 720
(2.365)
Pentacarbonyl(hydroxymethylcarbene)chromium (0) 721 reacts with DCC to give an isonitrile complex 722 and ketenimine 723.747
RN [Me(OH)C]Cr(CO)5 + RN 721
C
NR
RNC Cr(CO)5 + RN C CH2 722 723 (2.366)
DCC is used to mediate the reaction of molybdenum oxometalates α-[Mo8 O26 ]4− with aromatic amines to give a monofunctionalized organoimido derivative.748
2.5
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3 Unsaturated Carbodiimides
3.1
Introduction
Carbodiimides with a double bond in conjugation to the C N bond conceivably could undergo vinyl polymerization to give homopolymers with pendant carbodiimide groups. However, N-methyl-N -vinylcarbodiimide decomposes within a few hours due to formation of oligomeric or polymeric species.1 Vinylcarbodiimides with a secondary or tertiary carbon substituent on one nitrogen atom ought to be more stable, thus allowing selective vinyl polymerization. Vinyl polymers with pendant carbodiimide groups are obtained by polymerizing N-(p- or m-vinylphenyl)-N -alkylcarbodiimides,2 or by converting polymers with pendant urea groups into the corresponding polycarbodiimides.3 Diallylcarbodiimide is unstable; however, enyne carbodiimides are often stable. In recent years carbodiimides with heterocyclic substituents have been generated in situ, using the aza Wittig reaction.4 When the carbodiimide is attached to a nitrogen heterocycle in the α-position, the carbodiimide is generally not stable. For example, dipyridyl-(2) carbodiimide undergoes a [2+4] cycloaddition reaction to form a cyclic dimer (see Section 3.1.1). Several N-heterocyclic substituted carbodiimides, generated in situ, are trapped with suitable dienophiles or they undergo intramolecular electrocyclization or Diels–Alder type reactions with neighbouring groups. Some heterocyclic mono- or dicarbodiimides with conjugated C C bonds are stable. Also, carbodiimides with a C N bond in conjugation to the cumulative system undergo [2+4] cycloaddition reactions with suitable dienophiles (see Section 5.3.1).
Chemistry and Technology of Carbodiimides Henri Ulrich C 2007 John Wiley & Sons, Ltd. ISBN: 978-0-470-06510-5
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Chemistry and Technology of Carbodiimides
3.2
Synthesis of Unsaturated Carbodiimides
3.2.1 From Thioureas The reaction of the thiourea 1 with methanesulfonyl chloride in the presence of triethylamine and DMPA in methylenechloride at 0 ◦ C affords an 86 % yield of the enyne carbodiimide 2.5
Ph
Me
Ph
Me Me
Me N
NHCSNH
C
N (3.1)
Me
Me
1
2
Also, 1,3-bis-(2-vinyloxyethyl)thiourea is converted into N,N -bis-(2-vinyloxy)ethylcarbodiimide using HgO in methylene chloride.6
3.2.2 From Unsaturated Isocyanates Unsaturated isocyanates 3 are converted into bis-unsaturated carbodiimides 4 using a phospholene oxide catalyst.7 RR1 C C(Ph)NCO −−→ RR1 C C(Ph)N C NC(Ph) CR1 R 3 4
R
R1
[%]
bp ◦ C/Torr
Me Pr Ph
Me H H
80 82 80
134–135/0.02 164/0.03 145–148/0.04
(3.2)
3.2.3 From Unsaturated Iminophosphoranes and Isocyanates or Isothiocyanates The reaction of unsaturated iminophosphoranes 5 with arylisocyanates affords mono unsaturated carbodiimides 6. The compounds are stable at room temperature in acetonitrile solution, but they cannot be distilled under vacuum. RCH CR1 N PPh3 + R2 NCO −−→ RCH CR1 N C NR2 5 6
(3.3)
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Unsaturated Carbodiimides R
R1
R2
H H Me Me C6 H11 C5 H11 Ph
H Ph Ph Ph Ph Ph Ph
Ph Ph Ph 4-MePh Ph 4-MePh Ph
4-MePh 4-MeOPh 4-ClPh Ph
Ph Ph Ph Ph
Ph Ph Ph 4-MePh
Ph Ph Ph 4-ClPh COOEt COOEt COOEt COOEt
4-MePh 4-MePh 4-MePh 4-MePh Ph Ph Ph Ph
MePh 4-MeOPh 4-ClPh Ph Ph 2,3-MeOPh PhCH= 4-Pyridyl a b
[%]
Ref.
51 70 86 70 80 64 97 46 64 94 38 75 70 70 54 92 —a —a —b
8 7 9 8 8 8 8 10 8 8 8 8 11 8 8 8 8 12 13 14 15
149
Intramolecular Cyclization occurs in this reaction. Also generated in situ and converted into 2-alkylamino-4Himidazolin-4-ones with aliphatic primary amines.16
As byproducts divinylcarbodiimides are formed.10 A better way to synthesize divinylcarbodiimides is the reaction of 5 with 6.12 In this manner N,N -bis[1-(4-methylphenyl)-2phenylvinyl]carbodiimide, mp 135 ◦ C, is obtained in 38 % yield. Also, reaction of (5,5-dimethyl-3-oxo-1-cyclo-hexenyl)iminotriphenylphosphorane 7 with isocyanates affords N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)-N -phenylcarbodimide 8.17 O O (3.4) PPh3 + RNCO
N
N
7
C
NR
8 R
[%]
n-Bu Ph 3-ClPh 1-naphthyl tosyl
42 84 54 46 40
N-(1,3,5-cycloheptatrienyl)-N -phenylcarbodiimide is obtained in 82 % yield from the corresponding iminophosphorane and phenyl isocyanate.8
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Likewise, reaction of the seven membered ring heterocyclic iminophosphoranes 9 with phenyl isocyanate gives the corresponding carbodiimides 10.18
R1
R1
R2
R2
R3 X
R3
(3.5)
X
PPh3 + PhNCO N C 10 9 X = O, R1 = COOEt, R2 = R3 = COOMe X = S, R1 = COOEt, R2 = R3 = H
N
NPh
Instead of phenyl isocyanate, phenyl isothiocyanate can also be used in the reaction with the iminophosphoranes.19 Heterocyclic dicarbodiimides 12 (X = CH, N) are obtained from the corresponding iminophosphorane precursors 11 in 53–75 % yield.20
Ph3P
N
X
N
PPh3 + RNCO
EtO2C
S
CO2Et
S
N 11
RN
C
(3.6)
N
EtO2C
S
N 12
C
N
X S
NR
CO2Et
When carbodiimides are generated from iminophosphoranes with adjacent reactive groups, intramolecular cyclization occurs. For example, reaction of the bis-iminophosphorane 13 with two equivalents of isocyanate affords the tricyclic compound 14.21
Me Ph3P
CO2Et
N CH
C(COOEt)N
N
PPh3 + 2 PhNCO
(3.7)
N Me 13
NHR 14
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151
Intramolecular cyclization also occurs in the reaction of the arylidene hydantoin derived carbodiimides 15, which cyclizes in situ to give imidazo[1,5-c][1,3]benzodiazepines 16.22 O
O
NH
NH
(3.8)
N
HN O N C NR
N
15
O
NHR
16
Also, the one pot reaction of heterocyclic bis-iminophosphoranes with one or two equivalents of aryl isocyanates leads to selective formation of fused heterocycles. For example, from the pyrazole derivative 17 either [1,3]-diazepines 18 or tricyclic ring systems 19 are formed. The latter reaction involves an intramolecular [2+2] cycloaddition of both carbodiimide substituents.23 CO2Et
Me 1 RNCO
N
CO2Et
NH N Ph
Me
N 18
N
PPh3
N N Ph
N
(3.9)
PPh3
CO2Et
Me
17 2 RNCO
NR N
N N Ph
NR
N 19
In the same manner 2-phenylthiazole and 2,3-substituted thiophene derived iminophosphoranes react with one eqivalent of aryl isocyanate to give fused 1,3-diazepines in 50–72 % yield, while with two equivalents aryl isocyanate the [2+2] cycloadducts are obtained in 50–61% yield.24 Likewise, reaction of the heterocyclic iminophosphorane 20 with isocyanates affords pyrimido[4,5-d]pyrimidines 21.25
O
O CO2Et
MeN O
N Me 20
N
PPh3 + RNCO
O NR
MeN O
N Me
N 21
OEt
(3.10)
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Chemistry and Technology of Carbodiimides
When the reaction of 20 with the isocyanate is conducted in the presence of pyridine, annelation to give 22 occurs.26
O
O CO2Et
MeN O
N Me 20
N
N
MeN
PPh3 + RNCO + C5H5N
O
N Me
NR
N 22
(3.11) The same reaction occurs with the five membered heterocyclic iminophosphorane 23 to form the annelated product 24.27
O PhN
O N Me
N
PPh3 + RNCO + C5H5N
N
PhN N Me
23
(3.12)
N 24
Fused pyrimidines, formed by a tandem aza-Wittig/electrocyclization reaction, are used in the synthesis of pyrazolo[3,4-d]pyrimidines, 1,2,3-triazolo[4,5-d]pyrimidines and thiazolo[4,5-d]pyrimidine derivatives.28 Ring closure also occurs in the reaction of the heterocyclic iminophosphorane 25 with an adjacent C N group to give the tricyclic compound 26.29
Ph
Ph
NC EtO
N N
S 25
CH
PPh3 + RNCO NR1
NC EtO
N N
NR NR1
S 26
(3.13)
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153
Unsaturated carbodiimides 27, generated in situ, can also be trapped with azo compounds to form 28 or with imines to give 29 via a [2+4] cycloaddition reaction.30
CO2Et
O EtOOCN
N
MeN
NCOOEt
O
O
N Me
MeN O
NCO2Et
N
NHR
28 N Me
C
N
NR
27
O PhCH
H
Ph NPh
MeN
NPh
O
N Me
N
NHR
29 (3.14) When the aza-Wittig reaction of 30 is conducted in the presence of a nucleophile ring closure is also observed to give 31.31
O N
CO2Et
N + RNCO +
N
N
NR
R1OH
PPh3
N
30
(3.15)
OR1
N 31
Tandem nucleophilic/intramolecular addition also occurs in the reaction of the iminophosphorane 32 (R = CO2 Me, CN) with isocyanates and nucleophiles (X = O, S, NR) to give 33.32
R R N 32
PPh3
NR1
+ R1NCO + R2XH N
(3.16)
XR2
33
From methyl 3-carboxypyridyl-2-iminophosphorane, aryl isocyanates and primary amines, (2-oxo-1,2-dihydropyridin-3-yl)-1,3,5-triazine derivatives are obtained.33
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Chemistry and Technology of Carbodiimides
3.2.4 By Other Methods The reaction of the vinyltetrazolium salt 34 with triethylamine affords the unstable N-vinylN -methylcarbodiimide 35.1 +
N
−
NMe BF4 N N 34
3.3
CH2
CHN
C
NMe
(3.17)
35
Reactions of Unsaturated Carbodiimides
3.3.1 Polymerization Reactions Vinyl polymers 36, bearing pendant carbodiimide groups, are obtained from N-(p- or mvinylphenyl-N -alkylcarbodiimides.2
N
C
N
NEt
C
NEt
P
(3.18)
36 For more examples of polymers derived from unsaturated carbodiimides see Section 12.4. Unsaturated carbodiimides also undergo oligomerization reactions. An example is the cyclodimerization of dipyridyl-(2)-carbodiimide 37. This carbodiimide cannot be isolated because it undergoes dimerization via a [2+4] cycloaddition reaction to give the cyclodimer 38.34
N N
N N
C
N N
N N
37
(3.19)
N
N N
N
38
3.3.2 Cycloaddition Reactions An example of a [2+2] cycloaddition reaction across two carbodiimide groups generated in a pyrazole system is shown Section 3.2.3. However, unsaturated carbodiimides often react as azadienes in [2+4] cycloaddition reactions (for example in the preceding reaction).
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Unsaturated Carbodiimides
155
Another example is the reaction of vinylcarbodiimides 39 with activated olefins, such as tetracyanoethylene, to afford the [2+4] cycloadducts 40.35
NR ArCH
C(Ph)N
NR + (NC)2C
C
(NC)2 C(CN)2
N
(NC)2 H
Ar 39
Ph
40 (3.20)
The [2+4] cycloadducts are also obtained from α-styrylcarbodiimide and tetracyanoethylene or N-(4-methoxyphenyl)maleimide. The reaction proceeds thermally or under Lewis acid promoted conditions.35 The reaction of the N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)-N -arylcarbodiimides 41 with 1-(1 -pyrrolidino)cyclohexene affords a mixture of the [2+4] cycloadduct 42 (46 %) and the pyrrolidine adduct to the starting carbodiimide 43 (41 %).
O + N 41
C
N
NR
O
O
(3.21)
+ N
NHR
N
C
NHR
N
42
43
A [2+4] cycloadduct is also obtained from N-(3-oxo-1-cyclohexenyl)-N -phenylcarbodiimide and 1-(1 -morpholino)cyclohexene.35 The reaction of the vinylcarbodiimide 44 with MeC CNEt2 at 0 ◦ C affords the [2+4] cycloadduct 45.12
NHPh
NPh C
N
+
EtO2C
MeC
Me
N
CNEt2
(3.22)
NEt2
EtO2C Ph 44
Ph 45
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Chemistry and Technology of Carbodiimides
Similarly, the vinylcarbodiimide 46 reacts with methyl acetylenedicaboxylate to give the [2+4] cycloadduct 47 in 20 % yield.35 NPh
NHPh
C N
+
MeOOC
CO2Et
N
CCOOMe
(3.23)
CO2Et 46
47
The [2+4] diastereoselective annulation of vinyl carbodiimides 48 to cyclic N-alkylimines 49 affords the S,S-diastereomer of the bicyclic dihydropyrimidine 50.36 This reaction is used in the synthesis of batzelladin alkaloids. H
MeO2C
+ C
N
Me
NCH2
N
OMe
48
CH2OR 49 H N
N H
(3.24)
CH2OR OMe
NCH2 50
Vinyl carbodiimides 51 also react with tosyl isocyanate to give [2+4] cycloadducts. When the reaction is conducted at room temperature in acetonitrile, addition across the C N bond of the isocyanate occurs to give 52. In contrast, reaction in refluxing benzene (15–30 hours) affords 53, resulting from addition across the C O bond of the isocyanate.35 NR1
NR1 N
+
N
NTos
Ar
H
O
Ph
C
NTos HN
O
Ph Ar 52
TosNCO
Ph
NR1
NR1 Ar 51
N
NR1
O NTos
Ph Ar
H
O
N
NHTos
Ph Ar 53
(3.25)
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157
Also, N-phenyl-N -pyridylcarbodiimide 54, generated in situ, reacts with diphenylcarbodiimide to give the [2+4] cycloadduct 55.37
NPh N
NPh (3.26)
PhN
C
+ PhN
N
C
N
NPh
NPh
N 54
55
Ferrocenyl substituted unsaturated carbodiimides 56, generated in situ, undergo intramolecular cyclization to give heterocyclic substituted ferrocenyl derivatives 57.38
CO2Et N
C
O NR
O (3.27)
N
Fe
Fe
NR
56
57
Likewise, cyclization to give 2-arylamino-3-ferrocenecarbonyl quinolines 59 occurs in the generation of the ferrocenyl carbodiimide 58.39
O
O
Fe
N C N
Fe
N
HN Ar
Ar 58
59
(3.28)
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Chemistry and Technology of Carbodiimides
The aza-Wittig reaction of iminophosphoranes 60 with isocyanates affords the carbodiimides 61, which undergo ring closure to give 2-aminopyridine derivatives 62.13
Ph
Ph
Ph
+ RNCO Ph3P
N
(3.29) RN
CO2Et
C
60
N
CO2Et
PhNH
N
CO2Et
62
61
Some substituted unsaturated arylcarbodiimides undergo intramolecular cyclization. For example, the vinyl carbodiimide 63 acts as an azadiene to undergo a 6 π -electrocyclization on heating at 140 ◦ C to form an intermediate, which rearomatizes to give 1-aminoisoquinolines 64.40
NR1
NR1 C
R2
N Ph
NHR1 R2
N
R2
N
Ph
(3.30)
Ph
63
64
Other intramolecular cyclization reactions involving arylcarbodiimides with an ortho vinyl group to form 2-aminoquinolines and pyrido[2,3-b]indoles are listed in Table 3.1. The latter reactions involve a [2+4] cycloaddition in which the carbodiimide intermediate acts as an azadiene and the C C bond of the ortho vinyl group acts as the dienophile. Calculated transition states for electrocyclization and cycloaddition reactions show that the mode of reaction depends on substituents, stereoelectronic, eutropic and steric factors.41 When the vinyl group on the aryl ring is separated by a methylene group, as in 65, rearrangement of the allyl to the vinyl group occurs to give 66, followed by electrocyclic ring closure reaction which produces 67.46
N C 65
NAr
N C 66
NAr
(3.31) N 67
NHAr
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Unsaturated Carbodiimides
159
Table 3.1 Intramolecular Cyclization Reactions of Unsaturated Arylcarbodiimides Carbodiimide
Cycloadduct
Ref.
R1
R1
R2
R2 N
C
NAr
42, 40
NHAr
N
R
R
Ar 42
N
C
N
N
N H
Ar
CO2Et
CO2Et
43
N
C
NR
NHR
N
R N
C
N
R
Me
NO2 N
N
N Ph
C
N H
22
N Ph
N
NHR
O NO2
MeN N Me
NO2 N
O
O
N
Me
NR
44
N
C
NR
NO2
MeN O
N Me
N
NHR
45
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Chemistry and Technology of Carbodiimides
Similarly, thermal treatment of the N-styrylcarbodiimide 68 affords the [4+2] cycloadduct 69 formed by initial rearrangement of the allyl to the vinyl group.
N
C
N
N
C
N
Ph
Ph
68
(3.32) Ph N H 69
N
When the ortho substituent on the aryl group contains a carbon–carbon triple bond in conjugation with the aromatic ring intramolecular cyclization also occurs. Such enyne carbodiimides, generated in situ, upon thermolysis or photolysis at room temperature, give indoloquinolines. For example, the enyne carbodiimides 70, generated from the corresponding thioureas, produce 6H-indolo[2,3-b]quinolines 71 upon heating in toluene.47
R1
R1
(3.33)
C
N
NR
N H
70
N 71
Photocyclization also occurs at room temperature in 91–95 % yield, when R1 = 4-O2 NPh or 4-NCPh.48 When in the enyne carbodiimide the N-phenyl terminus is blocked with methyl groups, as in 72, formation of the indoloquinoline 73 occurs upon photolysis with elimination of a methyl radical.5
Ph Me
Ph Me N
C
N Me
72
Me N H
(3.34)
N Me
73
The generation of heterocyclic enyne carbodiimides is more readily accomplished by reacting the enyne isocyanate derivative with suitable iminophosphoranes, followed by heating in refluxing p-xylene (see examples in Table 3.2).
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Table 3.2 Heterocyclic Compounds Obtained from Enyne Carbodiimides Carbodiimide
Heterocycle
[%]
Ref
O
44
49
N
58–69
50
N
30–32
47
N
30–48
47
45–71
51
25–60
47, 48
54–85
48
OMe N
C
NHPh
N
NPh
Ph
N
C N
R
N
N H
R
N
R
C
N
N
N H
N
N
R R N
C
N
N N H
R
N
R N
N
C
N
N H
N R
R
N
N N
C
N
N N H
N R
N
N
N
C
N
R
N
N
N H
161
N
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Chemistry and Technology of Carbodiimides
Also, p-phenylene diisocyanate 74 upon reaction of two equivalents of the iminophosphorane 75 and subsequent refluxing in p-xylene, affords the bis-heterocycle 76 in 66 % yield.40 R NCO + 2 OCN
N 74
PPh3
75 R N
C
N
(3.35) N
C
N R
N H
R
R
N
N
N H
76
3.3.3 Other Reactions N-Allyl-N -4-methoxyphenylcarbodiimide, on treatment with Pd(dba)2 , rearranges to the corresponding allylcyanamide.52
3.4
References
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Unsaturated Carbodiimides
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48. 49. 50. 51. 52.
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M. Schmittel, D. Rodriguez and J.P. Steffen, Angew. Chem. Int. Ed. 39, 2152 (2000) H. Li, J.L. Petersen and K.K. Wang, J. Org. Chem. 68, 5512 (2003) X. Lu, J.L. Petersen and K.K. Wang, J. Org. Chem. 67, 7797 (2002) G. Zhang, C. Shi, H.R. Zhang and K.K. Wang, J. Org. Chem. 65, 7977 (2000) S. Kamijo, T. Jin and Y.Yamamoto, J. Am. Chem. Soc. 123, 9453 (2001)
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4 Halogenated Carbodiimides
4.1
Introduction
Carbodiimides with halogenated substituents on the nitrogen atoms of the cumulative double bonds are not known. Apparently, dihalocyanamides are formed in attempts to synthesize N,N -dihalocarbodiimides. An example is the fluorination of cyanamide, which produces exclusively the highly explosive difluorocyanamide.1 Theoretical calculations on the hypothetical FN C NF have been published.2 Numerous examples of alkyl- and arylcarbodiimides having halogen substituents are known. For example, α-haloalkylcarbodiimides can exist in two isomeric forms depending on the other substituents. In N-perchloroethylN -alkylcarbodiimides the substituent determins the configuration. When R = t-Bu, the molecule is in the carbodiimide configuration 1. In contrast, when R = i-Pr or Ph, the molecules exist in the isomeric diazadiene configuration 2. When R = 2,4,6-Me3 Ph, a mixture of both isomers is encountered. CCl3 CCl2 N C NR ←→ CCl3 CCl N C(Cl) NR 1 2
(4.1)
Bis(perchloroethyl)carbodiimide exists in the diazadiene configuration. When the α-halo atoms are fluorine, the molecules are in the carbodiimide form.
4.2
Synthesis of Halogenated Carbodiimides
4.2.1 From α-Haloisocyanates The reaction of α-chloroisocyanates 3 with iminophosphoranes is a mild and efficient method of synthesis of α-halocarbodiimides 4.3 RR1 C(Cl)NCO + Ph3 P NR2 −−→ RR1 C(Cl)N C NR2 3 4 Chemistry and Technology of Carbodiimides Henri Ulrich C 2007 John Wiley & Sons, Ltd. ISBN: 978-0-470-06510-5
(4.2)
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Chemistry and Technology of Carbodiimides R
R1
R2
[%]
bp ◦ C/Torr
CCl3 CF3 CF3
H Ph 4-MeOPh
Ph Ph Ph
45 70 60
95/0.045 93/0.04 142/0.04
Also, in the reaction of the α-difluoro isocyanates 5 with iminophosphoranes Ph3 P NR (R = i-Pr, Ph, 2,4,6-Me3 Ph) the corresponding carbodiimides 6 are obtained in 40–60 % yield.4 CCl3 CF2 NCO + Ph3 P NR −−→ CCl3 CF2 N C NR 5 6
(4.3)
Likewise, unsymmetrical fluorine containing carbodiimides are obtained from α-hydroperfluoroisopropyl isocyanate.5 In contrast, reaction of perchloroethyl isocyanate 7 with Ph3 P NR affords the carbodiimide 8 only when R = t-Bu. When R = i-Pr or Ph the rearranged diazadienes 9 are obtained. In the case of R = 2,4,6-Me3 Ph, mixtures of 8 and 9 are obtained.4 CCl3 CCl2 NCO + Ph3 P NR −−→ CCl3 CCl2 N C NR −−→ CCl3 CCl N C(Cl) NR 7 8 9 (4.4)
4.2.2
By Halogenation of Carbodiimides
Chlorination of bis-1,2,2,2-tetrachloroethylcarbodiimide affords the perchlorinated compound, which is in the diazadiene configuration 10. Subsequent treatment of 10 with SbF3 in the presence of a catalytic amount of SbCl5 gives bis-1,1-difluoro-2,2,2trichloroethylcarbodiimide 11, bp 68 ◦ C/0.06 Torr, mp 37 ◦ C in 46 % yield.6 CCl3 CCl N C(Cl) NCCl2 CCl3 + SbF3 −−→ CCl3 CF2 N C NCF2 CCl3 10 11
(4.5)
Likewise, reaction of diazadiene 12 with CsF gives carbodiimide 13 rather than the expected perfluorinated diazadiene.4 CCl3 CCl N C(Cl) N-i-Pr + CsF −−→ CCl3 CF2 N C N-i-Pr 12 13
(4.6)
4.2.3 From Carbonimidoyl Dichlorides or Imidoyl Chlorides Unsymmetric alkyl(perfluoroalkyl)carbodiimides 15 are obtained in the reaction of perfluoroazaalkenes 14 with primary amines.7 Rf N CF2 + RNH2 −−→ Rf N C NR 14 15
(4.7)
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Reaction of pentafluorophenylcarbonimidoyl dichloride 16 with aniline hydrochloride affords N-pentafluorophenyl-N -phenylcarbodiimide 17.8 C6 F5 N CCl2 + 2 PhNH2 −−→ C6 F5 N C NPh 17 16
(4.8)
The reaction of 16 with n-butylamine or t-butylamine in acetonitrile at room temperature affords the corresponding carbodiimides in yields of > 70 %.9 Perfluoro-bis-carbonimidoyl difluoride 18 rearranges in the presence of fluoride ions to give bis(trifluoromethyl)carbodiimide 19.10 CF2 N CF2 N CF2 + F− −−→ CF3 N C NCF3 18 19
(4.9)
Aziridincarboximidoyl chlorides 20 isomerize to carbodiimides 21 at 40–60 ◦ C, or at room temperature in the presence of an acid catalyst.11
NAr ClCH2CH2N
N C Cl
C
NAr
(4.10)
20
4.2.4 By Other Methods The reaction of N,N -bis-alkylideneureas 22 with phosphorous pentachloride affords bis(αchloro)carbodiimides 23.12 RR1 C NCON CR2 R3 + PCl5 −−→ RR1 C(Cl)N C NC(Cl)R2 R3 22 23 R
R1
R2
R3
[%]
bp ◦ C/Torr
Ph Ph Ph Ph
CF3 CF3 t-Bu t-Bu
CF3 t-Bu t-Bu t-Bu
Ph t-Bu Ph t-Bu
85 70 70 70
115/0.05 125/0.03 172/0.03 145/0.03
(4.11)
Treatment of bis-alkylideneurea 24 with triphenylphosphine dibromide gives bis(α-bromo)carbodiimide 25.13 PhCF3 C NCON CPhCF3 + Ph3 PBr2 −−→ PhCF3 C(Br)N C NC(Br)PhCF3 24 25 (4.12) Heating of the perfluorinated azide 26 at 270–300 ◦ C affords bis(trifluoromethyl)carbodiimide 27.14 CF3 N C(N3 )CF3 −−→ CF3 N C NCF3 26 27
(4.13)
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Thermolysis of perfluoroalkyl(N-pentafluorosulfanyl)azidoazomethines 28 afford Nperfluoroalkyl-N -pentafluorosulfanylcarbodiimides 29 (R = CF3 , C2 F5 , NF2 CF3 ).15 RC(N3 ) NSF5 −−→ RN C NSF5 + N2 28 29
4.3
(4.14)
Reactions of Halogenated Carbodiimides
4.3.1 Cycloaddition Reactions N-Trifluoromethyl-N -arylcarbodiimides 30 undergo dimerization and trimerization on attempted synthesis to form 31(R = 4-MeOPh, 2,6-Me2 Ph) and 32 (R = Ph, 2,6-Me2 Ph), respectively. The cycloaddition reactions occur across the aliphatic C N bond.16
CF2N
CF2 + ArNH2
[CF3N
C
NAr]
30 ArN
NCF3
+
CF3N
ArN
CF3 N NAr NCF3
CF3N
NAr
(4.15)
NAr 32
31
When the reaction is conducted with 2-aminopyridine, the intermediate carbodiimide 33 undergoes a [4 + 2] cycloaddition reaction to form the triazine derivative 34.
N CF3N
C
N N
N
NCF3 NCF3
N
(4.16)
N
33
34
The α-chlorocarbodiimides 35, in the presence of N-ethyl-N,N-diisopropylamine, undergo a cyclocondensation reaction with 2-benzimidazolylacetonitriles at room
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temperature to give 1,2,3,5-tetrahydrobenzo[4,5]imidazo[1,2-e]pyrimidine 1-imino derivatives 36.17 ArN NH
Ar CF3
C
N N
C
NAr +
CF3 Ar
N CH2CN N R
N R
Cl 35
CN
36
(4.17)
4.3.2 Nucleophilic Reactions The reaction of bis-α-chlorocarbodiimides with 37 with alcohols, phenols or carboxylic acids in the presence of triethylamine affords the expected substitution products 38 and 39. However, reaction with amines gives diazadiene derivatives 40.18 ROH
PhCF3C(OR)N
C
NC(OR)PhCF3
38
PhCF3C(Cl)N
C
NC(Cl)PhCF3
RCOOH
PhCF3C(OCOR)N
C
NC(OCOR)PhCF3
39
37 R2NH
PhCF3C(NR2)N
C(NR2)N
CPhCF3
40
(4.18) On heating of the carbodiimide 41 in toluene a [2 + 4] cycloaddition occurs giving rise to the formation of 4-imino-1,3-benzoxazins 42. This reaction is the first example of an intra-molecular electrophilic substitution on the benzene ring by a carbodiimide group.19
NAr ArCF3C(OR)N 41
C
NH CF3
NAr O 42
(4.19)
Ar
In the reaction of N-perfluoroethyl-N -alkylcarbodiimides with mesidine (2,4,6trimethylaniline) imidoylcarbodiimides are obtained.20 Reactions of the same carbodiimides with RR1 CHNH2 leads to cyclization to give triazine derivatives.21
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The reaction of bis-α-chlorocarbodiimides 43 with carboxylic acids in the absence of triethylamine gives bis-alkylideneureas 44 and carboxylic acid anhydrides.22 RR1 C(Cl)N C NC(Cl)RR1 + R2 COOH −−→ RR1 C NCON CRR1 + (R2 CO)2 O 43 44 (4.20) Reaction of bis-α-chlorocarbodiimides with O,O-dialkyldithiophosphates in the presence of triethylamine results in a stepwise replacement of the α-chloro groups.23 However, reaction of α-chlorocarbodiimides with triethylphosphite affords carbodiimide phosphonates 45 and diazadienephosphonates 46.24 CF3 PhC(Cl)N C NPh + P(OEt)3 −−→ CF3 PhC[P(O)(OEt)2 ]N C NPh 45 + CF3 PhC N C( NPh)P(O)(OEt)2 46 (4.21) The reaction of α-chlorocarbodiimides with trimethylsilyl azide gives α-azidocarbodiimides 47.25 RR1 C(Cl)N C NCR2 + Me3 SiN3 −−→ RR1 C(N3 )N C NR2 47
(4.22)
4.3.3 Other Reactions Heating of the α-chlorocarbodiimide 48 at 180 ◦ C causes cyclization to give the triazine derivative 49.26
CF3
Ph
N PhCF3C(Cl)N
C
Cl 48
N
NPh N
CF3
(4.23)
Ph 49
When the same carbodiimide is heated with 3-substituted 1-phenylpyrazol-5-ones 50 in the presence of triethylamine the initially formed nucleophilic substitution product 51 undergoes cyclization to give 6-aryl-4-arylimino-1-phenyl-6-trifluoromethyl-1,4,5,
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6-tetrahydropyrazolo-[4,3-e][1,3]-oxazines 52.27
ArCF3C(Cl)N
NAr +
C
R
R
N
N
Ar N Ph 50
O
CF3
O
N Ph
N
C
NAr
51 CF3
R Ar N
NH NAr
O
N Ph
52 (4.24) N-2-chloroethy-N -arylcarbodiimides 53 react with oxalyl chloride to give chloroethylparabanic acids 54 after hydrolysis with water.11
O ClCH2CH2N
53
4.4 1. 2. 3. 4. 5. 6. 7. 8.
C
NAr + (COCl)2
ClCH2CH2N O 54
NAr
(4.25)
O
References M.D. Meyers and S. Frank, Inorg. Chem. 5, 1455 (1966) M.S. Cordon and H. Fischer, J. Am. Chem. Soc. 90, 2471 (1974) V.I. Gorbatenko, V.N. Fetyukhin and L.I. Samarai, Zh. Org. Khim. 12, 2472 (1976) V.I. Gorbatenko, Y.I. Matveev, M.N. Gertsyuk and L.I. Samarai, Zh. Org. Khim. 20, 2543 (1984) D.P. Deltsova, M.P. Krauskaya, N.P. Gambaryan and I.L. Knunyants, Russ. Chem. Bull. 16, 2005 (1967) Y.I. Matveev, V.I. Gorbatenko, L.I. Samarai, E.A. Romanenko and A.V. Turov, Zh. Org. Khim. 24, 986 (1988) A.S. Vinogradov, A.F. Gontar, E.G. Bykhovskaya and I.L. Knunyants, Zh. Vses. Khim. 28, 352 (1983); C.A. 99, 175,175 (1983) I.V. Kolesnikova, T.D. Petrova, V.E. Platonov, V.A. Mikhailov, A.A. Popov and V.A. Savelova, J. Fluorine Chem. 40, 217 (1988)
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9. I.V. Kolesnikova, T.D. Petrova, V.E. Platonov, T.G. Ryabicheva and V.A. Mikhailov, Zh. Org. Khim. 25, 1689 (1989), engl. p. 1523 10. P.H. Ogden and R.A. Mitsch, J. Am. Chem. Soc. 89, 5007 (1967) 11. D.A. Tomalia, T.J. Giacobbe and W.A. Spencer, J. Org. Chem. 36, 2142 (1971) 12. V.N. Fetyukhin, M.V. Vovk and L.I. Samarai, Synth. 738 (1979) 13. V.N. Fetyukhin, M.V. Vovk and L.I. Samarai, Zh. Org. Khim. 17, 1420 (1981) 14. A.F. Gontar, E.N. Glotov, A.S. Vinogradov, E.G. Bikhovskaya and L.I. Knunyants, Izv. Acad. Nauk, Ser. Khim. 700 (1985); C.A. 103, 87,459 (1985) 15. E.O. John, H.G. Mack, H. Oberhammer, R.L. Kirchmeier and J.M. Shreeve, Inorg. Chem. 32, 287 (1993) 16. W.T. Flowers, R. Franklin, R.N. Haszeldine and A.J. Perry, J. Chem. Soc., Chem. Commun. 14, 567 (1976) 17. M.V. Vovk, P.S. Lebed, V.V. Pirozhenko and I.F. Tsymbal, Zh. Org. Chem. 40, 1669 (2004) 18. M.V. Vovk, V.I. Dorokhov, V.V. Momot and L.I. Samarai, Zh. Org. Khim. 22, 1099 (1986) 19. M.V. Vovk, A.V. Bolbut, V.I. Dorokhov, P.S. Lebed and B.B. Koslesnik, Zh. Org. Khim. 36, 1739 (2000) 20. V.I. Gorbatenko, Y.I. Matveev and L.I. Samarai, Zh. Org, Chem. 23, 2385 (1987) 21. Y.I. Matveev, V.I. Gorbatenko, L.I. Samarai, S.V. Seveda, M.Y. Antipin and Y.T. Struchkov, Zh. Org. Khim. 23, 2390 (1987) 22. V.N. Fetyukhin, M.V. Vovk and L.I. Samarai, Zh. Org. Khim. 19, 1232 (1983) 23. V.N. Fetyukhin, M.V. Vovk and L.I. Samarai, Zh. Org. Khim. 21, 631 (1985) 24. V.I. Gorbatenko, M.V. Melnichenko and L.I. Samarai, Zh. Obshch. Khim. 48, 1425 (1978); C.A. 89, 109,784 (1978) 25. V.I. Gorbatenko, V.N. Fetyukhin, N.V. Melnichenko and L.I. Samarai, Zh. Org. Khim. 13, 2320 (1977) 26. M.V. Vovk, Zh. Org. Khim. 29, 1628 (1993) 27. A.V. Bolbut, V.I. Dorokhov, V.A. Sukach, A.A. Tolmachev and M.V. Vovk, Zh. Org. Khim 39, 1789 (2003)
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5 Acyl-, Thioacyl- and Imidoylcarbodiimides
5.1
Introduction
Acyl-, thioacyl- and imidoylcarbodiimides, having a C X (X = O, S, or NR) adjacent to the cumulative bond are usually not stable at room temperature. However, sterically hindered N-functional carbodiimides with aliphatic t-butyl groups or aromatic 2,6-dimethylphenyl groups are often more stable, and they are generated in situ, for subsequent reactions. For example, N-alkyl substituted imidoylcarbodiimides, RN C(Ph)N C NR1 are only stable as crystalline compounds for a short period of time. Even in chloroform solution they undergo subsequent reactions as indicated by the disappearance of the carbodiimide infrared band (see Table 5.1).1 In contrast, phenylimidoylcarbodiimides PhN C(R)N C NR, isomerize in solution to fom aminoquinazolines. Other imidoylcarbodiimides also undergo intramolecular rearrangements. For example, RR1 CHN C(CCl3 )N C NAr 1 undergoes a rearrangement to form dihydro-1,3,5-triazines 2.2
N
Cl3C [RR1CHN
C(CCl3)N 1
C
NAr]
N
NAr
R
R1 2
A review article on acyl-, thioacyl- and imidoylcarbodiimides appeared in 1992.3
Chemistry and Technology of Carbodiimides Henri Ulrich C 2007 John Wiley & Sons, Ltd. ISBN: 978-0-470-06510-5
(5.1)
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Chemistry and Technology of Carbodiimides Table 5.1 Disappearance of N C N Absorption of Aliphatic Imidoylcarbodiimides RN C(Ph)N C NR1 in CHCl3 R Me Me Me Me a
5.2
R1
Temp.
Time (hours or days)
Me I-Pr 2,6-Me2 Ph t-Bu
−6 ◦ C 61−62 ◦ Ca — —
2h 7h 10h 3d
bp of CHCl3
Synthesis of Acyl-, Thioacyl- and Imidoylcarbodiimides
5.2.1 From Thioureas All of the discussed carbodiimides have been synthesized by desulfurization of the corresponding thioureas. For example, reaction of alkylcarbonylthioureas with HgO afford the corresponding carbonylcarbodiimides in 60–90 % yield.4 Instead of HgO dibenzamido mercury is also used in the desulfurization of carbonylthioureas 3 to give the acylcarbodiimides 4.5 In the bottom two examples below (Scheme 5.2), the functional substituent on the nitrogen is an arylester group. RCONHCSNHR1 + [PhCONH2 ]2 Hg −−−→ RCON C NR1 3 4
R1
[%]
t-Bu C6 H11 t-Bu C6 H11
88 82 88 86
R Ph Ph PhO PhO
(5.2)
Carbodiimides with aliphatic ester substituents 5 are also obtained in moderate yields from the corresponding thioureas using carbonyl chloride in the presence of triethyl amine to affect the desulfurization.6 The ester carbodiimides have to be reacted immediately, because polymerization occurs after several hours. EtOCONHCSNHR + COCl2 /Et3 N −−−→ EtOCON C NR 5
R
[%]
bp ◦ C/Torr
i-Pr t-Bu C6 H11
42 45 37
60–62/0.01 63–65/0.01 80–82/0.01
(5.3)
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Also, 1-(alkoxycarbonyl)-3-(arylmethyl)thioureas 6 are converted to the corresponding acylcarbodiimides 7 using carbonyl chloride and Et3 N.7 ROCONHCSNHR1 + COCl2 /Et3 −−−→ ROCON C NR1 6 7
R1
[%]
PhCH2 4-MeOPhCH2 4-MeOPhCH2 (4-MeOPh)2 CH
100 94 100 54
R Et Et PhCH2 Et
(5.4)
The obtained ester carbodiimides also decompose slowly at room temperature. Carbonyl chloride is also used to convert N-acylthioureas into the corresponding carbodiimides.8 Amide substituents on the thioureas, upon desulfurization, give rise to the formation of carbamoylcarbodiimides 8. In this reaction cyanuric chloride in the presence of triethylamine is used to affect the desulfurization.9 For example, when R C6 H11 and R1 t-Bu, the corresponding carbamoylcarbodiimide, mp 119 ◦ C, is obtained in 82 % yield. R2 NCONHCSNHR1 + (ClCN)3 /Et3 N −−−→ R2 NCON C NR1 8
(5.5)
Carbamoylthiocarbodiimides 10 are similarly obtained from the corresponding thiourea 9 and cyanuric chloride in the presence of triethylamine.10 R2 NCSNHCSNHR1 + (ClCN)3 /Et3 N −−−→ R2 NCSN C NR1 10 9
R (C6 H11 )2 N (C6 H11 )2 N
R1
[%]
mp ◦ C
t-Bu 2,6-Me2 Ph
72 78
148 136
(5.6)
Imidoylcarbodiimides 11 are also obtained by desulfurization of the corresponding thioureas. For example, reaction of RN C(Ph)NHCSNHR (R = 2,6-Me2 Ph) with HgO affords the imidoylcarbodiimide, mp 104 ◦ C, in 88 % yield.11 Also, imidoylcarbodiimides containing one aliphatic substituent are obtained from the corresponding thioureas again using cyanuric chloride in the presence of triethylamine to affect the desulfurization.9 RC( NR1 )NHCSNHR2 + (ClCN)3 /Et3 N−−−→ RC( NR1 )N C NR2 11
(5.7)
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Chemistry and Technology of Carbodiimides R1
R2
[%]
mp ◦ C
2,6-Me2 Ph 2,6-Me2 Ph 2,6-Me2 Ph 2,6-Me2 Ph
C6 H11 C6 H11 Me C6 H11
75 85 81 88
43 60 110 117
R Ph 4-ClPh 4-O2 NPh 4-O2 NPh
The desulfurization of imidoylthioureas can also be conducted with triphenylphosphine, iodine and triethylamine.12 The same reagents are used in the desulfurization of 5-imino1,2,4-thiazolines 12 to give imidoylcarbodiimides 13.10
Ph
N
RN
S 12
+ PPh3 + l2 + Et3N
RN
C(Ph)N
C
NR1
(5.8)
NR1 13
R 2,6-Me2 Ph 2,6-Me2 Ph
R1
[%]
mp ◦ C
Me C6 H11
95 100
34 43
5.2.2 From Ureas The reaction of N-aziridinyliminoureas 14 with Ph3 P/CCl4 and triethylamine afford the Naziridinyliminocarbodiimides 15, which undergo electrocyclization to form 5,6-dihydro7H-imidazo[1,2-b][1,2,4]triazoles 16.13
N -N
C(Me)NHCONHR
N
N
C(Me)N
C
NR
Ph
Ph 14
15 Ph N
NPh
N N Me 16
(5.9)
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When R = COR1 , 5,6-dihydro[1,2,4]triazolo[5,1-d][1,3,5]oxadiazepine 17 is obtained.
Ph N
N
C(Me)NHCONCOR1 N
Ph
O N
R1 (5.10)
N N 17
Me
5.2.3 From Isocyanates Heating trichloromethylcarbonyl isocyanate 18 with a catalytic amount of phenylphospholene oxide affords a bis-trichlorocarbonylcarbodiimide 19.14 2 CCl3 CONCO −−−→ CCl3 CON C NCOCCl3 + CO2 18 19
(5.11)
However, heating of phenylcarbonyl isocyanate in the presence of a phospholene oxide catalyst gives 2,6-diphenyl-4-benzoylimino-1,3,5-oxadiazine 20.15
NCOPh N
2 PhCONCO Ph
N O 20
(5.12)
Ph
The reaction of α-haloisocyanates 21 with N-trimethylsilyl-N -carboxyethylcarbodiimide 22 affords estercarbodiimides 23 with an α-isocyanato group.16 R2 C(Cl)NCO + Me3 SiN C NCOOEt −−−→R2 C(NCO)N C NCOOEt 21 22 23
(5.13)
In the reaction of the iminophosphorane 24 with phenyl isocyanate the generated imidoylcarbodiimide 25 undergoes cyclization to give the tricyclic compound 26.17
Ph2C
N
N
C(Me)N
PPh3 + PhNCO
24 Ph N Me
Ph Ph
N N
(5.14)
C
NPh
Ph N N Me
25
NPh N
26
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5.2.4 From Carbonimidoyl Dichlorides or Chloroformamidines The reaction of the ester carbonimidoyl dichloride 27 with primary amines affords the corresponding estercarbodiimides 28 in good yields.18 EtOCON CCl2 + 2 RNH2 −−−→ EtOCON C NR 28 27
R
[%]
bp ◦ C/Torr
n-Bu i-Bu t-Bu C6 H11
54 50 60 52
64–65/0.01 68–70/0.01 65–67/0.01 78–81/0.01
(5.15)
Also, N-4-chlorophenylcarbonyl-N -t-butylcarbodiimide is obtained in a similar manner.19 The reaction of the bis-carbonimidoyl dichloride 29 with t-butyl amine affords the carbonyl dicarbodiimide 30.20 Cl2 C NCON CCl2 + 4 t-BuNH2 −−−→ t-BuN C NCON C N-t-Bu 29 30
(5.16)
In the reaction of H2 NCON CCl2 with t-butylamine the relatively stable N-t-Bu,N carbamoylcarbodiimide 31, mp 69 ◦ C is obtained in 64 % yield.21 Using aminoadamantan the corresponding carbodiimide, mp 124–126 ◦ C, is obtained in 80 % yield. H2 NCON CCl2 + 2 t-BuNH2 −−−→ H2 NCON C N-t-Bu 31
(5.17)
Chloroformamidines are intermediates in the above transformation of carbonimidoyl dichlorides with amines. Often, bases, such as triethylamine are used to affect their dehydrochlorination to give carbodiimides. For example, the substituted chloroformamidines 32 react with triethylamine to give the relatively stable imidoylcarbodiimide 33 (R = Et, i-Pr; R1 = 2,4,6-Me3 Ph).21 CCl3 C(NHR1 )NH C(Cl) NR + Et3 N −−−→ CCl3 C( NR1 )N C NR 32 33
(5.18)
Even methanol can be used for the dehydrochlorination of the chloroformamidines, as shown in the reaction of chlorodiazadienes 34 to give N-trichloromethylcarbonyl-N -alkylcarbodiimides 35.22 CCl3 C(Cl) N C(Cl) NR + MeOH −−−→ CCl3 CON C NR + MeCl + HCl 34 35 (5.19)
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179
5.2.5 From Cyanamides The reaction of RCONHCN with trimethylsilyl chloride affords the silyl substituted carbonyl carbodiimide 36.23 RCONHCN + Me3 SiCl −−−→[RCON(SiMe3 )CN] −−−→ RCON C NSiMe3 36 (5.20) The first carbonylcarbodiimide 38 was synthesized in 1922 in the reaction of the substituted cyanamide 37 with benzoyl chloride.24 HOCH2 CH2 NHCN + 2 PhCOCl −−−→ PhOCH2 CH2 N C NCOPh 37 38
(5.21)
5.2.6 From Other Carbodiimides In the reaction of carbodiimides with EtOCONCS the [2+2] cycloadduct 39 is obtained, which undergoes a reverse reaction to produce the estercarbodiimide 40.25
RN
C
NR + EtOCONCS NCO2Et
RN
EtOCON
C
S
NR + RNCS
(5.22)
RN 39
40
The reaction of bis-silyl- or stannylcarbodiimides 41 with carboxylic acid halides or anhydrides,26,27 affords carbonylcarbodiimides 42 having one silyl or stannyl substituent. R3 MN C NMR3 + R1 COX −−−→ R1 CON C NMR3 41 42
(5.23)
R3 M = Me3 Si, Bu3 Sn; R1 = Me, CF3 , Ph; X = Cl, RCOO
5.2.7 By Other Methods In the photolysis of azidoformat 43 in the presence of isonitriles several ester-carbodiimides 44 are obtained.28 EtOOCN3 + RNC −−−→ EtOCON C NR 43 44
R
[%]
t-Bu C6 H11
60 45
(5.24)
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The reaction of the1,2,4-oxadiazolium salts 45 with triethylamine affords carbonylcarbodiimide 46, (R = EtO, R1 = Me; R Ph, R1 = Et).29
O + − NR1 BF4 + Et3N
RCO
N 45
5.3
NR1
C
RCON
(5.25)
46
Reactions of Acyl-, Thioacyl- and Imidoylcarbodiimides
5.3.1 Cycloaddition Reactions Trapping of the imidoylcarbodiimide RN C(Ph)N C NR, 47 with isonitriles results in the formation of 4,5-diimino-imidazole 48.11
NR RN
C(Ph)N
C
NR + R1NC
N Ph
NR1
N R 48
47
(5.26)
In the absence of the trapping agent intramolecular ring closure to form aminoquinazolines occurs.
5.3.2 Other Reactions Reaction of the carbonylcarbodiimide 49 with SF4 affords the fluoroformamidine 50.26 CF3 CON C NSiMe3 + SF4 −−−→ CF3 CON C(F) N SF2 49 50
(5.27)
α-Carbodiimide esters 51 undergo nucleophilic reactions with amidines to give 2-aminoimidazolone derivatives 52.30
NHC(R1) N EtOCOCH(R)N
C
NR + R1C(
NH)NH2
R
NH
NPh (5.28)
O 51
5.4
52
References
1. J. Goerdeler and W. Eggers, Chem. Ber. 119, 3737 (1986) 2. Y. Matveev, Y.I. Gorbatenko, L.I. Samarai, S.V. Seveda, Y.M. Antipin and T. Struchkov, Zh. Org. Khim. 23, 2390 (1987)
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Acyl-, Thioacyl- and Imidoylcarbodiimides
3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.
181
M.V. Vovk and L.I. Samarai, Russ. Chem. Rev. 61, 297 (1992) BDR Pat. 12,405,195; Chem. Abstr. 67, 73,181 (1967) O. Mitsunobo, Bull. Chem. Soc. Jp. 45, 3607 (1972) R. Neidlein and E. Heukelbach, Tetrahedron Lett. 149 (1965) M.P. Groziak and L.B. Townsend, J. Org. Chem. 51, 1277 (1986) R. Neidlein and E. Heukelbach, Arch. Pharm. 300, 567 (1967) J. Goerdeler and S. Raddatz, Chem. Ber. 113, 1095 (1980) J. Goerdeler, H. Lohmann, R. Losch and S. Raddatz, Tetrahedron Lett. 2765 (1971) L. Capuano, V. Hammerer, and V. Huch, Liebigs Ann. Chem. 23 (1994) J. Goerdeler, J. Haag, C. Lindner, and R. Losch, Chem. Ber. 107, 502 (1974) K. Lee and S. Kang, Tetrahedron Lett. 36, 2815 (1995) B.A. Arbuzov, N.N. Zobova and O.V. Sofronova, Izv. Akad. Nauk SSSR Ser. Khim. 476 (1984) L.A. McGrew, W. Sweeny, T.W. Campbell and V.S. Foldi, J. Org. Chem. 29, 3002 (1964) V.I. Gorbatenko, N.V. Melchnichenko, M.N. Gertsyuk and L.I. Samarai, Zh. Org. Khim. 12, 2103 (1976) K.J. Lee, S.H. Kim, S. Kim, H. Park, Y.R. Cho, B.Y. Chung and E.E. Schweizer, Synth. 1057 (1994) M.V. Vovk, Zh. Org. Khim. 23, 2023 (1987) E. K¨uhle, Angew. Chem. 81, 18 (1969) R. Bunnenberg, J.C. Jochims and H. Haerle, Chem. Ber. 115, 3587 (1982) R.Bunnenberg and J.C. Jochims, Chem. Ber. 114, 2064 (1981) V.I. Gorbatenko, Y.I. Matveev and L.I. Samarai, Zh. Org. Khim. 23, 2385 (1987) A.M. Churakov, B.N. Khasanov, S.L. Ioffe and I.A. Tartakovskii, Izv. Aksd. Nauk SSSR, Ser. Khim. 650 (1982) E. Fromm and E. Honold, Chem. Ber. 55, 902 (1922) H. Ulrich, B. Tucker and A.A.R. Sayigh, J. Am. Chem. Soc. 94, 3484 (1972) W. Lidy and W. Sundermeyer, Chem. Ber. 109, 1491 (1976) V.F. Gerega, Y.I. Mushkin, Y.I. Baukov and Y.I. Dergunov, Zh. Obshch. Khim. 48, 1146 (1978) E. Kozlowska-Gramsz and G. Descotes, Tetrahedron Lett. 1585 (1982) D.M. Zimmerman and R.A. Olofson, Tetrahedron Lerr. 3453 (1970) M. Heras, M. Ventura, A. Linden and J.M. Villagordo, Tetrahedron 57, 4371 (2001)
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6 Silicon Substituted Carbodiimides
6.1
Introduction
Carbodiimides containing silicon, germanium, tin and lead substituents were reviewed by Gordetsov and coworkers in 1982.1 Some monosilylcarbodiimides, RN C NSiMe3, R = Me, Et, i-Pr, obtained from N-trimethylsilylamine and cyanogen chloride, are not stable and on standing rearrange to N-trimethylsilylcyanamides.2 However, when R = t-Bu or Ph no rearrangement is observed. Disilylcarbodiimides do not isomerize to disilylcyanamide. However, asymmetric disilylcarbodiimides rearrange on heating to give mixtures containing the symmetric disilylcarbodiimide. Bis-trimethylsilylcarbodiimide is used as a monomer in the synthesis of silicon carbodiimide polymers used as precursors for ceramics.3 Also, hard silicon carbonitride films are obtained by RF plasma-enhanced chemical vapor deposition of bis(trimethylsilyl)carbodiimide.4
6.2
Synthesis of Silicon Substituted Carbodiimides
6.2.1 From Cyanamides Reaction of gaseous silyl iodide 1 with silver cyanamide affords the disilylcarbodiimides 2 as colorless liquids stable at room temperature.5 2 HSiI + Ag2 NCN −−→ H3 SiN C NSiH3 + 2 AgI 1 2
(6.1)
Trialkyl- and alkoxysilyl halides react similarly with silver cyanamide6 or cyanamide and triethylamine.7 Also, Ph3 SiBr reacts with silver cyanamide to give bis(triphenylsilyl)carbodiimide.8 Similarly, disilyl chlorides, Me3 SiSi(R, R1 )Cl 3 react with silver cyanamide Chemistry and Technology of Carbodiimides Henri Ulrich C 2007 John Wiley & Sons, Ltd. ISBN: 978-0-470-06510-5
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to give the carbodiimide 4 in 90–95% yield (R = R1 = Me, n-Bu; R = Me, R1 = Ph; R = Me, R1 = SiMe3 ).9 2 Me3 SiSi(R, R1 )Cl + Ag2 NCN −−→ Me3 SiSi(R, R1 )N C N(R, R1 )SiSiMe3 4 3 (6.2) Substituted cyanamides 5 also react with trimethylchlorosilane in the presence of triethylamine to give the corresponding carbodiimides 6.10 RNHCN + Me3 SiCl −−→ Me3 SiN C NR 5 6 R
[%]
bp ◦ C/Torr
Ph COOEt
73 68
49/0.1 60/0.5
(6.3)
Also, N-trimethylsilyl-N -phenylcarbonylcarbodiimide is obtained from PhCONHCN and trimethylchlorosilane.11 Bis(trimethylsilyl)amine or 2,4,6-tris(trimethylsilylamino)-1,3,5triazine react with dicyanodiamide to give bis(trimethylsilyl)carbodiimide.12 Salts of phenylcyanamide react with R3 SiCl (R = Me, Ph) to give the carbodiimide R3 SiN C NPh.13 Instead of silyl halides also trimethylsilylcyanide is used. In this manner a 90 % yield of bis(timethylsilyl)carbodiimide is obtained from cyanamide and trimethylsilylcyanide (1 min, rt).14
6.2.2 From Ureas N,N-bis(trialkyl)ureas react with phenyllithium and trialkylsilyl chloride in refluxing benzene to give the corresponding carbodiimides.15
6.2.3 From Isocyanates and Isothiocyanates The reaction of the substituted iminophosphorane 7 with isocyanates or isothiocyanates produces the carbodiimides 8.16 Me3 SiCH2 N PPh3 + RNCX −−→ Me3 SiCH2 N C NR + X PPh3 8 7 R
X
[%]
bp ◦ C/Torr
Ph cyclohexyl Et
O O S
79 79 81
139/0.4 72–74/0.4 120/34
(6.4)
When two equivalents of the iminophosphorane are used with phenyl isocyanate, a 97 % yield of Me3 SiCH2 N C NCH2 SiMe3 , bp 77–80 ◦ C/23 Torr is obtained. The same carbodiimide is obtained from the iminophosphorane and Me3 SiCH2 NCO.17
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The reaction of tin-bis(trimethylsilyl)amido derivatives with isocyanates at −78 ◦ C gives the carbodiimides, RN C NSiMe3 , in 75–98 % yield.18 The tin-bis(trimethylsilyl)amido derivatives can be prepared in situ from Me3 SiNHR and n-BuLi, followed by SnCl2 .
6.2.4 From Silylamines The reaction of silylamines 9 with cyanogen chloride in diethyl ether affords mono silyl carbodiimides 10. On standing only the t-butyl and the phenyl derivatives are stable, the other derivatives rearrange to give the cyanamide isomers 11.2 RNHSiMe3 + ClCN −−→ RN C NSiMe3 + RN(CN)SiMe3 9 10 11
R
[%]
bp ◦ C/Torr
Me Et I-Pr t-Bu Ph
56 65 68 89 36
35/14 47/14 48/14 53/14 55/0.01
(6.5)
In the reaction of the sodium salt of bis(trialkylsilyl)amines 12 with phosgene, bis(trialkylsilyl)carbodiimides 13 are obtained.19 2 (R3 Si)2 NNa + COCl2 −−→ R3 SiN C NSiR3 + (R3 Si)2 O + 2 NaCl 12 13
(6.6)
Instead of phosgene, carbon dioxide,17 silicon tetraisocyanate,20 trialkylsilyl isocyanate,14 cyanogen halide21 or thiocyanogen22 can be used in this reaction. The reaction of phenylisocyanide dichloride with the lithium salt of bis(N-trimethylsilyl)amine affords Ntrichloromethylsilyl-N -phenylcarbodiimide.23 The reaction of hexamethyl disilazene with cyanoguanidine affords bis(trimethylsilyl)carbodiimide in 80 % yield.24 Also, reaction of t-butyl isocyanate with LiN(SiMe3 )2 14 affords N-t-butyl-N trimethylsilyl-carbodiimide 15 in 56% yield.25 t-BuNCO + LiN(SiMe3 )2 −−→ t-BuN C NSiMe3 14 15
(6.7)
Reaction of methyl-bis(trimethylsilyl) amine 16 with NC N S O at −70 ◦ C gives bis(trimethylsilyl)carbodiimide 17 in 80 % yield.26 (Me3 Si)2 NMe + NC N S O −−→ Me3 SiN C NSiMe3 + MeN S O 16 17
(6.8)
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6.2.5 From Other Carbodiimides Reaction of α-isocyanatocarbodiimides 18 with trimethylsilyliminotriphenylphosphorane affords N-trimethylsilyl-N -phenylcarbodiimide 19 and a urea derivative 20.27 RR1 C(NCO)N C NPh + Ph3 P NSiMe3 −−−→ Me3 SiN C NPh + RR1 C NCON PPh3 19 18 20
(6.9) Heating of bis(trimethylsilyl)carbodiimide with triphenylsilyl chloride at 245–250 ◦ C with simultaneous distillation of trimethylsilyl chloride gives bis(triphenylsilyl)carbodiimide 21 in 75 % yield.28 Me3 SiN C NSiMe3 + 2 Ph3 SiCl−−→ Ph3 SiN C NSiPh3 + 2 Me3 SiCl 21
(6.10)
Bis(trimethylstannyl)carbodiimide, upon heating with triisopropylchlorosilane29 or trimethylchlorosilane30 results in a stepwise replacement of the stannyl groups. Also, from bis-tributylstannylcarbodiimide and Me3 SiSi(Me)2 Cl a 65 % yield of the expected disilylcarbodiimide is obtained.9 The reaction of the bis(germyl)carbodiimide 22 with SiH3 Br affords the corresponding bis(silyl)carbodiimide 23.31 H3 GeN C NGeH3 + SiH3 Br −−→ H3 SiN C NSiH3 22 23
(6.11)
The insertion product derived from N-benzoyl-N -t-butylcarbodiimide and Me3 SiNMe2 undergoes thermolysis at 130 ◦ C to give N-t-butyl-N -trimethylsilylcarbodiimide in 68 % yield.32
6.2.6 By Other Methods Heating of N-trimethylsilyltetrazole 24 to 135 ◦ C affords bis(trimethylsilyl)carbodiimide, nitrogen and polymeric cyanamide.33 Me3SiNH
N SiMe3 N
N
N 24
Me3SiN
C
NSiMe3 + N2
(6.12)
Also, thermolysis of the heterocycle 25 affords monosilyl carbodiimides 26.34
SiMe3 RN OS
O
N 25
Me3SiN
C 26
NR + SO2
(6.13)
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Photolysis of the diazo compound 27 results in the formation of a P, Si substituted carbodiimide 28.35 (i-Pr2 N)2 P(S)C(SiMe3 ) N2 −−→ Me3 SiN C NP(S)(N-i-Pr2 )2 27 28
(6.14)
Also, metal substituted nitrile imines undergo a light induced rearrangement reaction to give silicon-boron, silicon-germanium, silicon-silicon, silicum-phosphorus, boron-boron, and germanium-germanium carbodiimides.36 An example is the formation of the Si, P carbodiimide 29.37 (i-Pr2 N)2 PC N −→ NSi-i-Pr3 −−→ i-Pr3 SiN C NP(N-i-Pr2 )2 29
6.3
(6.15)
Reactions of Silicon Substituted Carbodiimides
6.3.1 Oligomerization Reactions The first synthesis of oligomeric dialkylsilyl carbodiimides 31 dates back to 1964, when Pump and Rochow reacted disilvercyanamide suspended in diethylether or benzene with dialkyldichlorosilanes 30 (R1 = Me, Ph, OEt; R2 = Me, vinyl, Ph, OEt); the yields varied between 77 and 96 % and n varied between 6.4 and 8.4.38 R1 R2 SiCl2 + Ag2 NCN −−→ [R1 R2 Si NCN]n + 2 AgCl 30 31
(6.16)
The reaction of dichloromethylsilane with cyanamide affords a highly crosslinked polymer caused by hydrosilation reactions between the carbodiimide and the Si–H bond.39 Gels are obtained in the reaction of dimethylchlorosilane with bis(trimethylsilyl)carbodiimide. Using TiCl4 or Ti(NEt2 )4 with bis(trimethylsilyl)carbodiimide produces poly(titanium carbodiimides) as precursors for TiCN and SiCN composites.40 Disilylcarbodiimide polymers 33 are obtained from disilanes 32 and cyanamide in the presence of triethylamine.9 ClSi(Me)2 Si(Me)2 Cl + H2 NCN + Et3 N −−→ [Si(Me)2 Si(Me)2 NCN]n 33 32
(6.17)
Likewise, tetrachloro-1,2-dimethyldisilane reacts with bis(trimethylsilyl)carbodiimide to give Si/C/N gels. In the reaction of methyltrichlorosilane with bis(trimethylsilyl)carbodiimide in the presence of pyridine, a highly crosslinked ceramic precursor is also obtained.41 A 16 membered ring carbodiimide is obtained in the reaction of Me2 SiCl2 with cyanamide.42 In addition to the tetramer, oligomers with n = 2 to 7 are detected. Also, higher oligomeric carbodiimides are formed in the reaction of alkyl- and dialkyl silicon chlorides with cyanamide in the presence of pyridine.43 Also, from bis(trimethylsilyl)carbodiimide and silicon tetrachloride in the presence of pyridine, the silicon polycarbodiimide 34 is obtained.41 SiCl4 + 2 Me3 SiN C NSiMe3 −−→ [Si(N C N)2 ]n 34
(6.18)
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The polycarbodiimide 34 can be thermally decomposed at 1100 ◦ C under argon to form amorphous Si/C/N solids. Trichloroborazene reacts with bis(trimethylsilyl)carbodiimide to form non-oxide B/C/N gels. These gels consist of three-dimensional polymeric networks linked by carbodiimide groups.44 Similar polycarbodiimide hydrid gels are prepared from tris-s-triazines and bis(trimethylsilyl)carbodiimide.45 The viscoelastic properties of a gel system based on methyltrichlorosilane and bis(trimethylsilyl)carbodiimide have been reported.46
6.3.2 Cycloaddition Reactions In the [2+2] cycloadition reaction of haloketenes with N-alkyl-N -trimethylsilylcarbodiimides 35 the reaction occurs across the alkyl substituted C N group to give the cycloadduct 36.47
Me3SiN Me3SiN
NR +
C
R1R2C
C
NR
O
R1R2
(6.19)
O 36
35
The cycloadducts 36 are readily desylilated using methanol to form the corresponding imines. In the reaction of ketones48 and 1,4-quinones48,49 with bis(trimethylsilyl)carbodiimide in the presence of titanium tetrachloride reaction occurs across the C O bond to give cyanoimines. An example, is the reaction of the 1,4-quinone 37 with two equivalents of the carbodiimide in the presence of TCl4 to give the quinone diimines 38.
O O + 2 Me3SiN O
C
NSiMe3
NCN
O 37
O
(6.20)
O NCN 38 Similarly, from 2,3,7,8-tetramethylthianthrene-1,4,6,9-tetrone and the carbodiimide the corresponding tetra(cyanoimino) derivative is obtained.50 Heteroquinoides react similarly. For example, the heteroquinoide 39 reacts with two equivalents of bis(trimethylsilyl)carbodiimide in the presence of TiCl4 to give
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2,5-bis(cyanimino)-2,5-dihydrothieno[3,2-b]thiophenes 40 in moderate yields.51 R R S
O + 2 Me3SiN
O
S C
NSiMe3
NCN
NCN
S
S R
R 40
39
(6.21) The imido zirconocene complexed 41 react with bis(trimethylsilyl)carbodiimide to give [2+2] cycloadducts 42.52 Cp2Zr N-t-Bu Cp2Zr(THF) N-t-Bu + Me3SiN C NSiMe3 Me3SiN NSiMe3 (6.22) 42 41 In the reaction of bis(trimethylsilyl)carbodiimide with phenyl isocyanate, a six membered ring [2+2+2] cycloadduct 43 is obtained.53 NSiMe3 Me3SiN
NPh
Me3SiN
NSiMe3 + 2 PhNCO
C
O
N Ph 43
(6.23)
O
Cyclic 1:1 and 1:2 adducts are also obtained from bis(trimethylsilyl)carbodiimide and benzenesulfonyl isocyanate.54 However, reaction of the same carbodiimide with chlorocarbonyl isocyanate affords the triazine derivative 44.55 CI C
Me3SiN
N
N
NSiMe3 + CICONCO Me3SiO
N 44
OSiMe3
(6.24)
In the reaction of bis(trimethylsilyl)carbodiimide with the P N compound 45 the cycloadduct 46 is obtained, which rearranges to give the linear carbodiimide 47.56 Me3SiN
NSiMe3 + Me3SiN
C
P(
NSiMe3)N(SiMe3)2 45
N(SiMe3)2 Me3SiN
NSiMe3
P
Me3SiN
NSiMe3 46
N(SiMe3)2 Me3SiN
P
N
C
N(SiMe3)2 47
(6.25) NSiMe3
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In the reaction of α-chloroheterocumulenes, such as α-chloro-N-sulfinylamines (X = NSO)57 or α-chloro isocyanates (X = NCO)58 with bis(trimethylsilyl)carbodiimide displacement of the chloro group by a carbodiimide group is observed to give 48. RCF3 C(Cl)X + Me3 SiN C NSiMe3 −−→ RCF3 C(X)N C NSiMe3 + Me3 SiCl 48 (6.26)
6.3.3 Other Reactions Bis(trimethylsilyl)carbodiimide reacts with GaMe3 and InMe3 to give distillable 1:1 adducts. However, with AlMe3 the insertion product 49 is obtained.59 AlMe3 + Me3 SiN C NSiMe3 −−→ Me2 AlN(SiMe3 )C( NSiMe3 )Me 49
(6.27)
When bis(trimethylsilyl)carbodiimide is reacted with Me2 GaCl or Me2 InCl, oligomeric carbodiimides Me2 GaN C NSiMe3 or Me2 InN C NSiMe3 , respectively, are obtained.60 In the reaction of the same carbodiimide with thionyl chloride at −70 ◦ CNCN-S O is obtained in 60 % yield,25 and in the reaction with SF4 at room temperature F2 S NCN is formed in quantitative yield.61 Reaction of cyanuric halides 50 (X = F, Cl, Br or I) with bis(trimethylsilyl)carbodiimide affords oligomeric triazine structures 51 (X N C N ).62
X N
N
X
N 50
+ Me3SiN
C
NSiMe3
X N N N
X
N N
N
X N
N X
N
(6.28)
N X
N
N
N
N N
51 Similarly, tristriazine derivatives are obtained from trichloro-tris-triazine.
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The reaction of bis(trimethylsilyl)carbodiimide with SCl2 affords the mesoionic compound 52 in 81 % yield.63
Me3SiN
NSiMe3 + SCI2
C
S − Me3SiN + S Cl NSiMe3 Cl 52
(6.29)
Also, mesoionic compounds 53 are obtained in 70–77 % yield in the reaction of the same carbodiimide with RCON C(Cl)SCl.64
Me3SiN
C
NSiMe3 +
S
RCON RCON
C(Cl)SCl
+
NSiMe3 Cl
−
Me3SiN Cl 53 (6.30)
Phosphorousfluoroimides are obtained in high yields in the reaction of bis(trimethylsilyl)carbodiimide with PhPF4 and Ph2 PF3 , respectively.65 From PhPF4 the phosphorousfluoroimide 54 is obtained. Me3 SiN C NSiMe3 + PhPF4 −−→ PhPF2 NCN 54
(6.31)
The Si, P carbodiimide 55 is formed in the reaction of bis(trimethylsilyl)carbodiimide with P(S)F3 .66 Me3 Sii N C NSiMe3 + P(S)F3 −−→ Me3 SiN C NP(S)F2 + Me3 SiF 55
(6.32)
Reaction of (i-Pr)3 SiN C NSnMe3 with L2 TiCl2 affords L2 TiN C NSi(i-Pr)3 .67 N,N-Bis(glycopyranosyl)cyanamides are obtained from peracetylated aldoses and bis(trimethylsilyl)carbodiimide in the presence of SnCl4 .68 The reaction of bis(trimethylsilyl)carbodiimide with Li(2,4,6-tri-i-PrPh) affords a benzamidinato anion which on reaction with MeCl2 (Me = Nb, Ta) affords the niobium and tantalium benzamidinato complexes.69 Photolysis of tetra-t-butyldisilane in the presence of bis(trimethylsilyl)carbodiimide affords an insertion product.70
6.4
References
1. A.S. Gordetsov, V.P. Kozyukov, L.A. Vostokov, S.V. Sheludyakova, Y.I. Dergunov and V.F. Mironov, Russ. Chem. Rev. 51, 485 (1982) 2. I. Ruppert, Angew. Chem. 89, 336 (1977) 3. O. Lichtenberger, J. Woltersdorf and R. Riedel, Z. Anorg. Allg. Chem. 628, 596 (2002)
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4. Y. Zhou, D. Probst, A. Thissen, E. Kroke, R. Riedel, R. Hauser, H. Hoche, E. Broszeit, P. Kroll and H. Stafast, J. Eur. Cer. Soc. 26, 1325 (2006) 5. E.A.V. Ebsworth and M.J. May, J. Chem. Soc. 4879 (1961) 6. J. Pump and U. Wannagat, Liebigs Ann. Chem. 652, 21 (1962) 7. L. Birkhofer, A. Ritter and R. Richter, Tetrahedron Lett. 195 (1962) 8. G.M. Sheldrick and R. Taylor, J. Organomet. Chem. 101, 19 (1975) 9. G.A. Razuvaev, A.S. Gordetso, A.P. Kozina, T.N. Brevnova, V.V. Semenov, S.E. Skobaleva, N.A. Boxer and Y.I. Dergunov, J. Organomet. Chem. 327, 303 (1987) 10. V.I. Gorbatenko, M.V. Melnichenko, M.N. Gertsyuk and L. Samarai, Zh. Org. Khim. 12, 231 (1976) 11. A.M. Churakov, B.N. Khasanov, S.I. Ioffe and I. A. Tartokovskii, Izv. Akad. Nauk SSR, Ser. Khim. 650 (1982) 12. I.A. Vostokov, Y.I. Dergunov and A.S. Gordetsov, Zh. Obshch. Khim. 47, 1769 (1977); C.A. 87, 152,337 (1977) 13. H. K¨ohler and H.V. D¨ohler, Z. Anorg. Allg. Chem. 386, 197 (1971) 14. K. Mai and G. Patil, J. Org. Chem. 62, 275 (1987) 15. U. Wannagat and H. Seyfert, Angew. Chem. 77, 457 (1965) 16. O. Tsuge, S. Kanemasa and K. Matsuda, J. Org. Chem. 49, 2688 (1984) 17. G. Barbaro, A. Battaglia, P. Giorgianni, A. Guerrini and G. Seconi, J. Org. Chem. 60, 6032 (1995) 18. J.R. Babcock and L.R. Sita, J. Am. Chem. Soc. 120, 5585 (1998) 19. J. Pump and U. Wannagat, Angew. Chem. 74, 117 (1962) 20. U. Wannagat, J. Pump and H. Buerger, Monatsh. Chem. 94, 1013 (1963) 21. J. Hundeck, Angew. Chem. Int. Ed. 4, 704 (1965) 22. O.J. Scherer and M. Schmidt, Z. Naturforsch. 18b, 415 (1963) 23. K. Itoh, A. Nozawa and Y. Ishii, Tetrahedron Lett. 1421 (1969) 24. I.A. Vostokov, Y.I. Dergunov and A.S. Gordetsov, Zh. Obshch. Khim. 47, 1769 (1977) 25. I. Ruppert, V. Bastian and R. Appel, Chem. Ber. 108, 2329 (1975) 26. O.J. Scherer and R. Schmitt, Angew. Chem. 79, 691 (1967) 27. V.I. Gorbatenko, N.V. Melnichenko and L.I. Samarai, Zh. Org. Khim. 18, 2289 (1982) 28. J. Pump, E.G. Rochow and U. Wannagat, Monatsh. Chem. 94, 588 (1963) 29. G. Veneziani, R. Reau and G. Bertrand, Organomet. 12, 4289 (1993) 30. A.S. Gordetsov, Y.I. Dergunov and Y.I. Baukov, Zh. Obshch. Khim. 48, 473 (1978) 31. S. Cradock and E.A.V. Ebsworth, J. Chem. Soc. (A) 1423 (1968) 32. S. Matsuda, K. Itoh and Y. Ishii, J. Organomet. Chem. 69, 353 (1974) 33. L. Birkhofer and A. Ritter, Angew. Chem. 77, 114 (1965) 34. F. DeSarlo, A. Brundi A. Goti, A. Guarna and P. Rovero, Heterocycl. 20, 511 (1983) 35. M. Soleilhavoup, A. Baceiredo, D. Brigg and G. Bertrand, Inorg. Chem. 31, 1500 (1992) 36. G. Bertrand and C. Wentrup, Angew. Chem. Int. Ed. 33, 527 (1994) 37. F. Castan, A. Baceiredo, D. Brigg and G. Bertrand, J. Org. Chem. 56, 1801 (1991) 38. J. Pump and E.G. Rochow, Z. Anorg. Allg. Chem. 330, 101 (1964) 39. R. Riedel, E. Kroke, A. Greiner, A.O. Gabriel, L. Ruwisch and J. Nicolich, Chem. Mat. 10, 2964 (1998) 40. N. Hering, K. Schreiber, R. Riedel, O. Lichtenberger and J. Woltersdorf, Appl. Organomet. Chem. 15, 879 (2001)
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193
41. A.O. Gabriel and R. Riedel, Angew. Chem. 109, 371 (1997); Angew, Chem. Int. Ed. 36, 384 (1997) 42. A. Kienzle, A. Obermeyer, R. Riedel, F. Aldinger and A. Simon, Chem. Ber. 126, 2569 (1993) 43. R. Riedel, A. Greiner, G. Miehe, W. Dressler, H. Fuess, J. Bill and F. Aldinger, Angew. Chem. Int. Ed. 36, 603 (1997) 44. K.W. V¨olger, E. Kroke, C. Gervais, T. Saito, F. Babonneau, R. Riedel, Y. Iwamoto and K. Hirayama, Chem. Mater. 15, 755 (2003) 45. R. Riedel, E. Horvarth-Bordon, S. Nahar-Borchert and E. Kroke, Key Eng. Mater. 247, 121 (2003) 46. C. Balan, K.W. V¨olger, E. Kroke and R. Riedel, Macromol. 33, 3404 (2000) 47. L. Birkofer and W. Luckenhaus, Liebigs Ann. Chem. 1193 (1984) 48. A. Aum¨uller and S. H¨unig, Angew. Chem. 96, 437 (1984); Liebigs Ann. Chem. 142, 156 (1986) 49. T. Czekanski, M. Hanack, J.Y. Becker, J. Bernstein, S. Bittner, L. Kaufmann-Orenstein and D.J. Prelog, J. Org. Chem. 56, 1569 (1991) 50. M. Gonzales, P. de Miguel, N. Martiu, J.L. Segura, C. Seoane, E. Orti, R. Viruela and P.M. Viruela, Adv. Mater. 6, 765 (1994) 51. E. G¨unther, S. H¨unig, K. Peters, H. Rieder, H.G. von Schnering, J.U. von Sch¨utz, S. S¨oderholm, H.P. Werner and H.C. Wolf, Angew. Chem. 102, 220 (1990) 52. R.L. Zuckerman and R. G. Bergman, Organomet. 20, 1792 (2001) 53. Y.I. Dergunov, A.S. Gordetsov, I.A. Vostokov and V.F. Serega, Zh. Obshch. Khim. 44, 1523 (1974); C.A 81, 136,219 (1974) 54. Y.I. Dergunov, A.S. Gordetso, I.A. Vostokov and V.A. Galparin, Zh. Obshch. Khim. 45, 2234 (1975); C.A. 84, 44,291 (1976) 55. V.I. Gorbatenko, M.N. Gertsyuk and L.I. Samarai, Zh. Org. Khim. 13, 899 (1977) 56. R. Appel and M. Halstenberg, J. Organomet. Chem. 116, C13 (1976) 57. Y.G. Shermolovich and V.I. Gorbatenko, Zh. Org. Chem. 12, 1129 (1976) 58. V.I. Gorbatenko, N.V. Melnichenko, M.N. Gertsyuk and L.I. Samarai, Zh. Org. Khim. 12, 231 (1976) 59. R. Lechler, H.D. Hansen and J. Weidlein, J. Organomet. Chem. 359, 1 (1989) 60. P. Haag, R. Lechler and J. Weidlein, Z. Anorg. Allg. Chem. 620, 112 (1994) 61. W. Sundermeyer, Angew. Chem. 79, 98 (1967) 62. R. Riedel, E. Kroke and A. Greiner, Germ. Pat. DE 197 06 028.5 (1997) 63. H.U. H¨ofs, R. Mews, W. Clegg, M. Noltemeyer, M. Schmidt and G.M. Scheldrick, Chem. Ber. 116, 416 (1983) 64. R. Neidlein, P. Leinberger, A. Gieren and B. Dederen, Chem. Ber. 111, 698 (1978) 65. O. Glemser E. Niecke and J. Stenzel, Angew. Chem. 79, 723 (1967) 66. O. Glemser and E. Niecke, Z. Naturforsch. 23, 741 (1968) 67. G. Veneziani, S. Shimada and M. Tanaka, Organomet. 17, 2926 (1998) 68. L. Kovacs, E. Osz and Z. Gyorgydeak, Carbohydr. Res. 337, 1171 (2002) 69. C. Chen, L.H. Doerer, Y.C. Williams and M.L.H. Green, J. Chem. Soc., Dalton Trans. 967 (2000) 70. M. Weidenbruch, A. Lesch, K. Peters and H.G. v. Schnering, J. Organomet. Chem. 423, 329 (1992)
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7 Nitrogen Substituted Carbodiimides
7.1
Introduction
Nitrogen substituted carbodiimides are usually not stable in the carbodiimide configuration. Some derivatives can be distilled under vacuum, but on standing they undergo slow dimerization reactions. In one case of N-heterocyclic carbodiimides the 1,3-diazetidine diimine dimers are obtained instead of the monomers. Semiempirical calculations on the formation of 1,3-diazetidine diimine dimers of H2 N N C NMe confirm the Z,Z and E,E configurations of the dimers obtained.1 N-nitrosubstituted carbodiimides are more stable. The infrared spectra of nitrogen substituted carbodiimides show the typical carbodiimide absorption at 2070–2090 cm−1 . Sometimes, N-aminosubstituted carbodiimides are encountered as intermediates in the synthesis of heterocycles.
7.2
Synthesis of Nitrogen Substituted Carbodiimides
The reaction of the N,N-dimethylamino semicarbazide derivative 1 with phosgene affords the chloroformamidine intermediate 2, which on treatment with sodium bicarbonate affords N-t-butyl-N -dimethylaminocarbodiimide 3, bp 150 ◦ C in 64 % yield.2 Me3 CNHCONHNMe2 + COCl2 −−−→ Me3 CN C(Cl)NHNMe2 1 2 −−−→ Me3 CN C NNMe2 3
(7.1)
On standing at room temperature, 3 undergoes dimerization to form two isomeric hetero-cyclic zwitterionic dimers.3 N-phenyl-N -dimethylaminocarbodiimide could not be obtained under similar conditions in pure form. Chemistry and Technology of Carbodiimides Henri Ulrich C 2007 John Wiley & Sons, Ltd. ISBN: 978-0-470-06510-5
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Reaction of diethyl N-dimethylaminophosphoramidate with t-butyl- or t-octyl isocyanate affords the corresponding carbodiimides 4 in 60 % yield.4 (EtO)2 P(O)NHNMe2 + RNCO −−−→ RN C NNMe2 + (EtO)2 P(O)OH 4 R
[%]
bp ◦ C/Torr
t-Bu t-Oct
60 60
65/15 115/15
(7.2)
The N-aminosubstituted carbodiimides 4 slowly dimerize on standing. Heating of the dimers regenerates the monomers. The reactions of N-substituted iminophosphoranes 5 with alkyl or aryl isocyanates proceed under mild conditions to give aziridin substituted carbodiimides 6 (R = H, Ph; R1 = Me, Ph, α-naphthyl), which are only observed in solution, and their yield is approximately 40 %.5
R Ph
R
H N H
N
PPh3
+
H N H
R1NCO Ph
5
NR1 (7.3)
C
N 6
An unstable bis-diaziridin substituted carbodiimide is obtained by reacting 5 with pentamethylene diisocyanate. The N-aminosubstituted carbodiimide 7, generated similarly, undergoes cyclization using HBF4 in ethanol as catalyst to give the thiazolium salt 8.6
PPh3 + RNCO
MeSCSN(Me)N
[MeSCSN(Me)N 7
C
NR]
+
N NH SMe
R S 8
BF4
−
(7.4)
In the reaction of the heterocyclic N-substituted iminophosphorane 9 with aryl isocyanates, 2-arylamino-1,2,4-triazolo[5,1-b]quinazolin-9(3H)-ones 10 are formed in 86– 94 % yield.7
O
O N
N
PPh3 + ArNCO
NHR1
N 9
N N N 10
Ar
N R1 (7.5)
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In the reaction of guanidine derivatives 11 with base, the aminocarbodiimides 12 are generated, which undergo dimerization to form triaminotriazoles (R1 = H), or are intercepted with aldehydes or ketones to give the corresponding semicarbazides 13.8 R1 NHC(NH2 )NHX + OH− −−−→ [R1 N C N NH2 ] + R2 R3 CO 11 12 −−−→ R1 NHCONHN CR2 R3 13
R1
R2
R3
X
[%]
H Bu Bzl
Ph Ph Me
H H Me
OSO3 H OSO3 H Cl
74 62 15
(7.6)
In the reaction of acylhydrazines with isothiocyanates, N-substituted thiourea derivatives 14 are formed, which react with a polystyrene based polymeric carbodiimide (PCD) to generate the nitrogen substituted carbodiimide 15, which cyclizes to form 2-amino-1,3,4oxazoles 16.9
RCONHCSNHR1 14
+
RCONH
PCD
N
C
NR1
15
R
N O
N NHR1 16
(7.7)
N-trimethylsilyl-N -dimethylaminocarbodiimide is obtained as an intermediate in the reaction of N,N-dimethyl-N -trimethylsilylhydrazine with cyanogen chloride. The isolated product is a [2+2] cycloadduct with the also-formed Me2 NNHCN.10 The reaction of silver cyanamidonitrate 17 with triorganostannyl chloride affords N-nitro substituted carbodiimides 18.11 Ag[NO2 NCN] + R3 SnCl −−−→ R3 SnN C NNO2 + AgCl 17 18
R
[%]
mp ◦ C
Me Ph
75 67
140 163
(7.8)
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7.3
Reactions of Nitrogen Substituted Carbodiimides
Attempts to synthesize N-heterocyclic substituted carbodiimides from 1,2,4-triazine imino-phosphoranes 19 and isocyanates result in the isolation of the corresponding 1,3-diazetidine imine dimers 20.12
Me
O
N
N
Me N
O
N
PPh3 + RNCO
N
N
N
N
NR
O
Me
N
N
N
SMe RN N
SMe
N MeS 19
20 (7.9)
The dimerization of N-t-butyl-N -dimethylaminocarbodiimide affords two isomeric dimers 21 and 22, having zwitterionic structures.3 NMe2 N
Me3CN 2 Me3CN
C
NNMe2
NCMe3 + Me2NN
+
Me
N
N −
Me 21
CMe2
Me
N
NCMe3
+
N
N −
Me 22
(7.10)
7.4
References
1. J. Bertran, A. Oliva, J. Jose, M. Duran, P. Molina, M. Alajarin, C. Lopez Leonardo and J. Elguero, J. Chem. Soc., Perkin Trans. 2, 299 (1992) 2. J.H. Cooley, E.J. Evain, R.D. Willet and J.T. Blanchette, J. Org. Chem. 54, 1048 (1989) 3. S. Sarker, J.H. Cooley, R.D. Willet and A.L. Rheingold, J. Org. Chem. 60, 476 (1995) 4. W.S. Wadsworth, Jr. and W. Emmons, J. Org. Chem. 29, 2816 (1964) 5. E. Keschmann and E. Zbiral, Tetrahedron 31, 1817 (1975) 6. P. Molina, M. Alajarin and A. Vidal, Tetrahedron Lett. 32, 5379 (1991) 7. M. Ding, Y. Chen and N. Huang, Eur. J. Org. Chem. 18, 3872 (2004) 8. A. Heesing and H. Schulze, Angew. Chem. 79, 688 (1967) 9. F.T. Koppo, K.A. Evans, T.L. Graybill and G. Burton, Tetrahedron Lett. 45, 3257 (2004) 10. I. Ruppert, Angew. Chem. 89, 336 (1977) 11. L. J¨ager, D. Tretner, M. Biedermann and H. Hartung, J. Organomet. Chem. 530, 13 (1997) 12. P. Molina, M. Alajarin, J.R. Saez, M. De la Concepcion Foces-Foces, F.H. Caro, R.M. Claramun and J. Elguero, J. Chem. Soc., Perkin Trans. 1, 2037 (1986)
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8 Phosphorous Substituted Carbodiimides
8.1
Introduction
The first phosphorus substituted carbodiimide was synthesized by K¨ohler and Kotte in 1973.1 The authors assumed that the molecules had a cyanamid structure. The correct carbodiimide structure was elucidated later.2 Solid carbodiimide modified phosphates are also known.3 An example is the synthesis of sodium cyanamido phosphates 1 and 2.4 P4 O10 + 6 Na2 [NCN] −−→ 2 Na3 [PO3 (NCN)] + 2 Na3 [PO2 (NCN)2 ] 1 2
(8.1)
Phosphorous substituted carbodiimides are less stable than most of the other carbodiimides. For example, the carbodiimides Ph2 P(O)N C NR cannot be distilled without decomposition. However, carbodiimides (EtO)2 P(O)N C NR can be purified by vacuum distillation.
8.2
Synthesis of Phosphorous Substituted Carbodiimides
8.2.1 From Thioureas Phosphorous substituted carbodiimides 4 are synthesized by dehydrosulfurization of the corresponding thioureas 3 with HgO.5 R2 P(O)NHCSNHR1 + HgO −−→ R2 P(O)N C NR1 3 4 Chemistry and Technology of Carbodiimides Henri Ulrich C 2007 John Wiley & Sons, Ltd. ISBN: 978-0-470-06510-5
(8.2)
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R1
[%]
Ph Ph Ph Ph Ph Ph EtO EtO
Me Et Pr i-Pr C6 H11 Ph i-Pr C6 H11
71 87 85 91 92 98 91a 87b
a b
bp 94–99 ◦ C/0.2 Torr bp 110–116 ◦ C/0.1 Torr
In a similar manner the carbodiimides (MeO)2 P(O)N C NR (R = Me, Ph) are obtained in quantitative yield.6
8.2.2 From Iminophosphoranes In the reaction of iminophosphoranes (EtO)2 P(O)CH2 N PPh3 5 with phenyl isocyanate, a 75 % yield of the expected carbodiimide 6 is obtained.7 (EtO)2 P(O)CH2 N PPh3 + PhNCO −−→ (EtO)2 P(O)CH2 N C NPh 5 6
(8.3)
From the iminophosphorane Ph3 P NCN and tertiary alkyl halides in the presence of antimony pentachloride the heterocumulene salts Ph3 P N+ C NR SbCl6 − (R = t-Bu or adamantyl) are obtained in excellent yields.8 The reaction of cyclic iminophosphoranes 7 with isocyanates produces a carbodiimide intermediate 8, which was characterized as the corresponding urea 9.9
O
(CH2)n N P
+ RNCO
(CH2)n N C
[Ph2P
NR]
Ph
Ph 7
(8.4)
8 O [Ph2P
(CH2)n NHCONHR 9
8.2.3 From Carbonimidoyl Dichlorides The reaction of phosphorous substituted carbonimidoyl dichlorides 10 with arylamines in the presence of triethylamine affords the corresponding carbodiimides 11. The reaction proceeds via the intermediate chloroformamidines.10 The dehydrochlorination of the intermediate chloroformamidine occurs in diethyl ether at room temperature. (RO)2 P(O)N CCl2 + R1 NH2 −−→ (RO)2 P(O)N C NR1 10 11
(8.5)
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Phosphorous Substituted Carbodiimides R
R1
bp ◦ C/Torr
i-Pr Ph
Ph 4-BrPh
115/0.1 83–85a
a
8.2.4
201
melting point
From Cyanamides
The silver salt of cyanamide reacts with BrF2 P or Ph2 P(X)Cl to give bis-phosphorous substituted carbodiimides. For example, a 52 % yield of bis(difluorophosphinyl)carbodiimide 12 is obtained from the silver salt of cyanamide and bromodifluorophosphine.11 Ag2 NCN + 2 BrF2 P −−→ F2 PN C NPF2 12
(8.6)
Likewise, pentavalent P-disubstituted carbodiimides 13 are obtained in the reaction of R2 P(X)Cl (X = O, S) with silver cyanamide.12 Ag2 NCN + 2 R2 P(X)Cl −−→ R2 P(X)N C NP(X)R2 13
(8.7)
The trivalent P-disubstituted carbodiimides are only obtained as AgCl complexes in this reaction. However, the AgCl complex of R2 PN C NPR2 can be converted to 13 (X = S). Also, Na[Ph2 P(O)NCN] reacts with R3 MeCl to give the carbodiimide 14.13 Na[Ph2 P(O)NCN + R3 MeCl −−→ Ph2 P(O)N C NMeR3 14 Me
R
[%]
mp ◦ C
Sn Si Sn Pb
Me Ph Ph Ph
100 100 90 100
132–134 152 148 201
(8.8)
In a similar manner the corresponding sulfur containing carbodiimides 15 are obtained in high yields. Na[Ph2 P(S)NCN + R3 MeCl −−→ Ph2 P(S)N C NMeR3 15 Me
R
[%]
mp ◦ C
Sn Si Sn Pb
Me Ph Ph Ph
85 100 82 100
133 108 132 186
(8.9)
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Reaction of the bis(diisopropylamino)thioxophosphoranylcyanamide Me3 SnCl adduct 16 with dichlorophenyloxophosphorane, in the presence of triethylamine, affords the phosphoryl bis-carbodiimide 17 in 82 % yield.14 (i-PrN)2 P(S)NHCN Me3 SnCl + PhP(O)Cl2 −−→ [(i-PrN)2 P(S)N C N]2 P(O)Ph 17 16 (8.10) The phosphoryl bis-carbodiimide 17 polymerizes in the solid state when stored for one week at 30 ◦ C. A thiophosphoryl bis-carbodiimide 19 is also obtained from the bis-cyanamide precursor 18 and bis(diisopropylamino)chlorophosphane with subsequent oxidation with elemental sulfur. Et2 NP(S)[NHCN Me3 SnCl]2 + (i-PrN)2 PCl −−→ [(i-PrN)2 P(S)N C N]2 P(S)NEt2 18 19 (8.11)
8.2.5 From Other Carbodiimides The reaction of bis(trimethylsilyl)carbodiimide with P(S)F3 at 140–150 ◦ C gives 35 % of the mono phosphorous substituted carbodiimide 20.15 Me3 SiN C NSiMe3 + P(S)F3 −−→ F2 P(S)N C NSiMe3 + Me3 SiF 20
(8.12)
Bis(trimethylstannyl)carbodiimide 21 can also be used in trans carbodiimidization reactions. For example, reaction of 21 with bis(diisopropylamino)chlorophosphane gives a 90 % yield of bis(diisopropylaminophosphanyl)carbodiimide 22.14 Me3 SnN C NSnMe3 + 2 (i-PrN)2 PCl −−→ (i-PrN)2 PN C NP(N-i-Pr)2 22 21
(8.13)
The same carbodiimide is obtained from cyanamide and bis(diisopropylamino)chlorophosphane in the presence of triethylamine (85 % yield), and from the N-cyano-Phydrogenoiminophosphorane Me3 SnCl adduct and bis(diisopropylamino)chlorophosphane (95 % yield). From Ph2 P(O)Cl or Ph2 P(S)Cl and bis(trimethylstannyl)carbodiimide the corresponding carbodiimides are also obtained. Also, N-trimethylstannyl-N -triisopropylsilylcarbodiimide 23 reacts with bis(diisopropylamino)-chlorophosphane to give the P, Si substituted carbodiimide, which was oxidized with elemental sulfur, to give the more stable thiophosphoryl carbodiimide 24.16 Me3 SnN C NSi(i-Pr)3 + (i-PrN)2 PCl −−→ (i-Pr)3 SiN C NP(S)(N-i-Pr) 23 24
(8.14)
Likewise, reaction of 23 with isopropylaminodichlorophosphane gives the bis(carbodiimido)phosphine, which is also isolated in the oxidized form 25. Me3 SnN C NSi(i-Pr)3 + i-PrNPCl2 −−→ [i-Pr3 SiN C N]2 P(S)NEt2 23 25
(8.15)
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The reaction of bis(trimethylsilyl)carbodiimide with the P N derivative 26 gives the [2+2] cycloadduct 27, which on long standing rearranges to the phosphorus substituted carbodiimide 28.17
Me3SiN
C
NSiMe3 + Me3SiN
NSiMe3)N(SiMe3)2
P(
26 N(SiMe3)2 Me3SiN
P
NSiMe3
Me3SiN
N(SiMe3)2 Me3SiN
NSiMe3
P
N
(8.16)
C
NSiMe3
N(SiMe3)2 28
27
8.2.6 By Other Methods Photolysis of the P-heterocycle 29 affords the bis(thiophosphoryl)carbodiimide 30.18
N N (i-PrN)2
P
S P(N-i-Pr)2
S 29
(i-Pr2N)2P(S)N
C
NP(S)(N-i-Pr2)2
(8.17)
30
The photolytic rearrangement of metal nitrile imines 31 also affords P-substituted carbodiimides 32.19 (I-PrN)2 P N −−→ NSi-i-Pr3 −−→ (i-Pr2 N)2 PN C NSi-i-Pr3 31 32
8.3
(8.18)
Reactions of Phosphorous Substituted Carbodiimides
Addition of hydrogen chloride or hydrogen cyanide to P-substituted carbodiimides affords the adducts 33 (X = Cl or CN).20 Ph2 P(O)N C NR + HX −−→ Ph2 P(O)N C(X)-NHR 33
(8.19)
The reactions of the bis-phosphino carbodiimide 34 with acetylenes afford [2+3] cycloadducts 35.21
(i-Pr2N)2PN
C 34
NP(N-i-Pr2)2 + RC
CR
(iPrN)2P
N 35
NP(N-iPr)2
(8.20)
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With two equivalents of the same acetylene derivative a bicyclic P-compound 36 is obtained.
R2PN
C
NPR2 + 2 R1C
N CR1
N
R 2P 1 R1 R R1 36
8.4 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.
PR2 R1
(8.21)
References H. K¨ohler and B. Kotte, Z. Chem. 13, 350 (1973) J. Kaiser, H. Hartung and R. Richter, Z. Anorg. Allg. Chem. 469, 188 (1980) L. J¨ager amd H. K¨ohler, Sulfur Rep. 12, 159 (1992) H. K¨ohler, Pure Appl. Chem. 52, 879 (1980) G. Tomaschewski, B. Breitfeld and D. Zanke, Tetrahedron Lett. 3191 (1969) H. K¨ohler and D. Glanz, Z. Anorg. Allg. Chem. 554, 123 (1987) F. Palacios, A.M. Ochoa deRetana, E.M. de Marigorta, M. Rodriguez and J. Pagalday, Tetrahedron 59, 2617 (2003) J.C. Jochims, M.A. Rahman, L. Zsolnai, S. Herzberger, and G. Huttner, Chem. Ber. 116, 3692 (1983) T. Sakai, T. Kodama, T. Fujimoto, K. Ohta and I. Yamamoto, J. Org.Chem. 59, 7144 (1994) G.I. Derkach and N.N. Liptuga, Zh. Obshch. Khim. 36, 461 (1966); C.A. 65, 634 (1966) D.W.H. Rankin, J. Chem. Soc., Dalton Trans. 869 (1972) A. Weisz and K. Utvary, Monatsh. Chem. 99, 2498 (1968) L. J¨ager, H. K¨ohler, A.J. Brusilovec and V.V. Scopenko, Z. Anorg. Allg. Chem. 564, 85 (1988) G. Veneziani, P. Deyer, R. Reau and G. Bertrand, Inorg. Chem. 33, 5639 (1994) O. Glemser and E. Niecke, Z. Naturforsch. 23, 743 (1968) G. Veneziani, R. Reau and G. Bertrand, Organomet. 12, 4289 (1993) R. Appel and M. Halstenberg, J. Organomet. Chem. 116, C 13 (1976) M. Soleilhavoup, A. Baceiredo, F. Dahan and G. Bertrand, Inorg. Chem. 31, 1500 (1992) F. Castan, A. Baceiredo, D. Bigg and G. Bertrand, J. Org. Chem. 56, 1801 (1991) G. Tomaschewski and D. Zanke, Z. Chem. 14, 234 (1974) G. Veneziani, R. Reau, F. Dahan and G. Bertrand, J. Org. Chem. 59, 5927 (1994) A. Baceiredo, R. Reau and G. Bertrand, Bull. Soc. Chim. Belg. 103, 531 (1994)
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9 Sulfur Substituted Carbodiimides
9.1
Introduction
Carbodiimides having a sulfur atom attached to one nitrogen atom of the cumulative arrangement are of relative recent vintage. For example, N-sulfonylcarbodiimides were first observed as intermediates in the reaction of chloramin T (sodium salt of N-chloro-4-methylbenzenesulfonamide) with cyclohexylisonitrile by Aum¨uller in 1963.1 The author noted that N-sulfonylcarbodiimides are too unstable to be isolated. A year later Ulrich and Sayigh synthesized N-sulfonyl-N -alkylcarbodiimides by reacting 1-sulfonyl-3-alkylthioureas with carbonyl chloride (phosgene) or phosphorous pentachloride.2 Contrary to Aum¨uller’s observation, N-arenesulfonyl-N -alkylcarbodiimides are stable, distillable liquids. They are precursors of the oral antidiabetic arenesulfonylureas, and reaction of the N-arenesulfonylN -alkylcarbodiimides with water in the body generates the active drugs.3 N-sulfurcarbodiimide salts, Ph2 S N(+) C NR SbCl6 − , are obtained in the reaction of Ph2 SNCN with t-alkyl chlorides in the presence of SbCl5 in 98–100 % yield.4 N-arenesulfonyl-N -alkylcarbodiimides undergo the regular reactions of carbodiimides, only the rates of reaction are generally slower than the rates observed with alkyl- or arylcarbodiimides. Also, oligomerization reactions are less frequent.
9.2
Synthesis of Sulfur Substituted Carbodiimides
9.2.1 From Thioureas or Ureas The dehydrosulfurization of 1-arenesulfonyl-3-alkylthioureas with HgO affords the corresponding N-sulfurcarbodiimides only in low yields (8–14 %).5 However, reaction of 1-arenesulfonyl-3-alkylthioureas with HgCl2 in the presence of primary amines affords sulfamoylguanidines in 90 % yield.6 The corresponding arenesulfonylcarbodiimides are intermediates in this reaction. Chemistry and Technology of Carbodiimides Henri Ulrich C 2007 John Wiley & Sons, Ltd. ISBN: 978-0-470-06510-5
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Better results are obtained using carbonyl chloride2 or phosphorous pentachloride7 in the reaction with the sulfonylthioureas. Intermediates in this reaction are chloroformamidines 1, which, on heating, eliminate hydrogen chloride to give N-sulfonyl-N -alkylcarbodiimides 2. RSO2 NHCSNHR1 + COCl2 −−→ RSO2 N C(Cl)NHR1 −−→ RSO2 N C NR1 2 1 (9.1) R
R1
[%]
bp ◦ C/Torr
Me Me Me Ph Ph 4-MePh 4-MePh
Et n-Pr n-Bu Et n-Bu Et n-Bu
68 73 79 47 40 40 47a
98–100/0.5 92/0.25 103–105/0.3 139–144/0.2 151–155/0.1 147–151/0,25 159–162/0.2
a
A 75 % yield is obtained using phosphorous pentachloride.
Similarly, N-p-toluenesulfonyl-N -cyclohexylcarbodiimide is obtained from the corresponding thiourea in 65 % yield.8 The dehydrochlorination of 1 can also be achieved using aqueous base.9 Bis(arenesulfonyl)carbodiimides are intermediates in the reaction of the corresponding chloroformamidines with hydrazine.10 N-arenesulfonyl-N -arylcarbodiimides are not obtained from the corresponding thioureas and phosgene because stable four membered ring 1,3-thiazetidine-2-ones are formed in this reaction. For example, 3-phenyl-4-toluenesulfonylimino-1,3-thiazetidine-2-one 3 is obtained in 97 % yield from the corresponding thiourea and phosgene.7
RSO2NHCSNHPh + COCl2
RSO2N
NPh (9.2)
S O 3
Thermolysis of 3 provides all of the expected fragmentation products. The reaction of 1,3-bis(pentafluorosulfanyl)urea 4 with phosphorous pentachloride affords bis(pentafluorosulfanyl)carbodiimide 5.11 SF5 NHCONHSF5 + PCl5 −−→ SF5 N C NSF5 4 5
(9.3)
9.2.2 From Carbonimidoyl Dichlorides or Imidoyl Chlorides The reaction of phenylsulfonylcarbonimidoyl dichlorides 6 with primary alkylamine hydrochlorides in chlorobenzene at 100–140 ◦ C affords N-phenylsulfonyl-N -
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alkylcarbodiimides 7.12 PhSO2 N CCl2 + RNH2 HCl −−→ PhSO2 N C NR 6 7 R
[%]
bp ◦ C/Torr
n-Pr i-Pr n-Bu t-Bu Me2 CHCH2
39 59 57 39 54
140–142/0.01 135–138/0.01 160–165/0.01 140–142/0.01 153–155/9.01
(9.4)
The reaction of imidoyl chlorides 8 with sodium azide in diglyme solution gives high yields of trifluorosulfonylcarbodiimides 9, which are unstable and undergo di- and trimerization reactions on standing.13 RC(Cl) NSO2 CF3 + NaN3 −−→ RN C NSO2 CF3 8 9
(9.5)
9.2.3 By Fragmentation Reactions S-alkyl-N,N,N -trialkylisothioureas 10 react with tosyl isothiocyanate to give ionic adducts 11, which sometimes undergo a [2+2] cycloreversion reaction to give Nsulfonylcarbodiimides 12 and dimethylthiourea.14 NMe2 C(SMe)NMe2 + RSO2NCS
R1N
−
R1 N
+
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RSO2N
SMe
11
RSO2N
C
NR1 + Me2NCSNH2
12
(9.6) R
R1
[%]
4-MePh 4-MePh
i-Pr t-Bu
50 54
Heating of the cycloadducts derived from arenesulfonyl isocyanates with dialkylcarbodiimides in refluxing o-dichlorobenzene gives rise to the formation of Nsulfonylcarbodiimides and the lower boiling alkyl isocyanate.15 For example, reaction of p-toluenesulfonyl isocyanate 13 with di-n-butylcarbodiimide affords N-p-toluenesulfonylN -n-butylcarbodiimide 14 in 42 % yield. Reactions with DCC and diisopropylcarbodiimide proceed similarly. RSO2 NCO + R1 N C NR1 −−→ RSO2 N C NR1 + R1 NCO 13 14
(9.7)
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Addition of N-sulfinyl-p-toluenesulfonamide 15 to methyl-t-butylcarbodiimide causes an exothermic reaction with formation of the exchange products 16 and 17.16 RSO2 NSO + MeN C N-t-Bu −−→ RSO2 N C N-t-Bu + MeNSO 15 16 17
(9.8)
The thermolysis of perfluoroalkyl(N-pentafluorosulfanyl)azidomethines 18 affords Nfluoroalkyl-N -sulfanylcarbodiimides 19 (Rf CF3 , C2 F5 ).17 Rf C(N3 ) NSF5 −−→ Rf N C NSF5 18 19
(9.9)
9.2.4 From Other Carbodiimides The reactions of metal substituted carbodiimides 20 with arenesulfonyl chlorides or arenesulfonyl isocyanates produce metal substituted N-sulfonylcarbodiimides 21 (R3 M Me3 Si, Et3 Ge, Bu3 Sn; X Cl, NCO).18 R3 MN C NMR3 + R1 SO2 X −−→ R1 SO2 N C NMR3 20 21
(9.10)
Likewise, a sulfenylated carbodiimide 23 is obtained in the reaction of N-trimethylsilylN -butylcarbodiimide 22 with R2 NSCl.19 Me3 SiN C NBu + R2 NSCl −−→ R2 NSN C NBu + M3 SiCl 22 23
(9.11)
In Section 9.2.3. Several carbodiimide based methods of synthesis of N-sulfonylcarbodiimides are described.
9.2.5 By Other Methods The reactions of arenesulfonyl isothiocyanates 24 with azides give thiatriazole derivatives 25. On heating of 25, N-sulfonylcarbodiimides 26 (R p-tolyl, R1 n-Bu, Bzl) are obtained which are identified by infrared spectroscopy and derivative formation.20
N N RSO2NCS + R1N3
24
RN RSO2N 25
S
RSO2N
C
26
NR1 + N2
(9.12)
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209
When 25 is thermolyzed in the presence of DCC a five membered ring cycloadduct 27 is obtained in high yield.21
C6H11N
N N S + DCC
RN
NC6H11
RN
RSO2N 25
S
(9.13)
RSO2N 27
Thermolysis of the cycloadducts 28 derived from tosyl isocyanate and nitrile oxides also affords N-sulfonylcarbodiimides 29. For example, N-p-toluenesulfonyl-N -2,4,6trimethylphenylcarbodiimide, mp 71–72 ◦ C, is obtained in 87 % yield.22
R
NSO2R1 R1SO2N
N O 28
NR + CO2
C
(9.14)
O 29
This reaction proceeds via a nitrene intermediate. Also, a nitrene intermediate is involved in the reaction of RC(Cl) NSO2 CF3 with sodium azide at room temperature, which affords Ntrifluoromethylsulfonylcarbodiimides. N-trifluoromethylsulfonyl-N -phenylcarbodiimide is also obtained in the reaction of PhN PPh3 with CF3 SO2 NCO.13
9.3
Reactions of Sulfur Substituted Carbodiimides
The nucleophilic reactions of N-sulfurcarbodiimides are similar to the nucleophilic reactions of other carbodiimides. However, oligomerization reactions are less pronounced. The cyclic dimer of N-p-toluenesulfonyl-N -phenylcarbodiimide 31 is obtained on dissociation of the cycloadduct 30 obtained in the outlined reaction.14 NMe2 RN + SMe R1N − NR2
+ TosN
C
Me2N
SMe
RN
NPh
NPh R1N
N R2 30
NTos
TosN NPh PhN NTos 31
(9.15) A trimeric six membered ring cyclotrimer 32 is formed from N-trifluoromethylsulfonyl-N 4-fluorophenylcarbodiimide, which is characterized by hydrolysis to the triazine derivative
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33, indicating that the trimerization proceeds across the aryl substituted C N bond.13
R N
CF3SO2N C
4-FPhN
NSO2CF3
RN
R N
O
NSO2CF3
RN
NR
O NR
O 33
NSO2CF3 32
(9.16) Six membered ring cycloadducts of N-sulfonylcarbodiimides with arenesulfonyl isocyanates and dialkylcarbodiimides are also known.15 Reactions of N-sulfonylcarbodiimides with cyclic amidines 34 afford mesoionic cycloadducts 35 or a new sulfonylcarbodiimide 36 depending on the substituents.23
RSO2N
C
NR1
Me2N
+
N R
Me
N − NSO2R
R Me
Me2N +
34 + R1N
N (9.17)
35
C(NMe2)C(R,Me)N 36
C
NSO2R
The reactions of N-arenesulfonylcarbodiimides with oxalyl chloride afford five membered ring 1-arenesulfonyl-2,2-dichloro-3-alkylimidazolidine-4,5-diones 37.7
O RSO2N
C
NR1 + (COCl)2
O
RSO2N
N R1
(9.18)
Cl Cl 37 In the reaction of N-arenesulfonyl-N -phenylcarbodiimides with HN3 , the initial linear adducts 38 rearrange to give 5-arenesulfonylamino-1-phenyl-1H-tetrazoles 39.24
PhN N RSO2N
C
NPh + HN3
[RSO2N
C(N3)NHPh] 38
RSO2NH
N N
39 (9.19)
9.4
References
1. W. Aum¨uller, Angew. Chem. 75, 857 (1963) 2. H. Ulrich and A.A.R. Sayigh, Angew. Chem. 76, 781 (1964) 3. A.A.R. Sayigh, H. Ulrich and J.B. Wright, US Pat. 3,422,201 (1969)
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211
4. J.C. Jochims, M.A. Rahman, L. Zsolnai, S. Herzberger and G. Huttner, Chem. Ber. 116, 3692 (1983) 5. R. Neidlein and E. Heukelbach, Tetrahedron Lett. 149 (1965) 6. J. Zhang and Y. Shi, Tetrahedron Lett. 41, 8075 (2000) 7. H. Ulrich, B. Tucker and A.A.R. Sayigh, Tetrahedron 22, 1565 (1966) 8. R.K. Gupta and C.H. Stammer, J. Org. Chem. 33, 4368 (1968) 9. T. Kodama, K. Uehara, K. Hisada and S. Shinohara, Yuki Gosei Kagaku Kyokai Shi 25, 493 (1967); C.A. 68, 12,620 (1968) 10. V.N. Sevastyanov and E.A. Abrazhanova, Zh. Org. Khim. 17, 91 (1981) 11. J.S. Thrasher, J.L. Howell and A.F. Clifford, Inorg. Chem. 21, 1616 (1982) 12. R. Neidlein, W. Haussmann and E. Heukelbach, Chem. Ber. 99, 1252 (1966) 13. L.M. Yagupolski, S.V. Shelyazhhenko, I.I. Malettina, V.N. Petzik, E.B. Rusanox and A.N. Chemega, Eur. J. Org. Chem. 1225 (2001) 14. E. Schaumann and E. Kausch, Liebigs Ann. Chem. 1560 (1978) 15. H. Ulrich, B. Tucker, F.A. Stuber and A.A.R. Sayigh, J. Org. Chem. 34, 2250 (1969) 16. H. Ulrich, B. Tucker and A.A.R. Sayigh, J. Am. Chem. Soc. 94, 3484 (1972) 17. E.O. John, H.G. Mack, H. Oberhammer, R.L. Kirchmeier and J.M. Shreeve, Inorg. Chem. 32, 287 (1993) 18. Y.I. Dergunov, V.F. Gerega, M.G. Ivanov and Y.I. Baukov, Zh. Obshch. Khim. 47, 1971 (1977) 19. R. Appel and M. Montenarh, Z. Naturforsch. 30B, 847 (1975) 20. G. L’abbe, E. van Look, R. Albert, S. Toppet, G. Verhalst and G. Smets, J. Am. Chem. Soc. 96, 3973 (1974) 21. G. L’abbe, G. Verhalst, C.C. Yu and S. Toppet, J. Org. Chem. 40, 1728 (1975) 22. A.A. Esipenko, V.N. Fetyukhin, F.G. Kramarenko, A.N. Chernega, L.I. Samarai and V.V. Pirozhenko, Zh. Org. Chem. 27, 1262 (1991) 23. E. Schaumann and S. Grabby, Liebigs Ann. Chem. 290 (1981) 24. L.F. Pronski, E.A. Abrazhanova and V.N. Sebatyanov, Vopr. Khim Technol. 33, 10 (1974); C.A. 82, 156,198 (1975)
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10 Metal Substituted Carbodiimides
10.1
Introduction
Metal substituted cyanamides and carbodiimides gained attention in recent years because they are precursors of ceramic materials. It was found that alkali metal cyanamides have the carbodiimide structure. Lithium carbodiimide, Li2 NCN, is obtained in the reaction of Li2 C2 with LiN at 600 ◦ C.1 Na2 NCN2 and K2 NCN3 are prepared from the alkali metal amides and alkali metal hydrogen cyanamides in a vacuum using liquid ammonia. RbHNCN is obtained in the reaction of cyanamide with rubidium amide in liquid ammonia.4 The alkali earth cyanamides, MgNCN, CaNCN, SrNCN and BaNCN also have the carbodiimide structure. CaNCN is prepared from calcium carbonate and HCN, while the other alkali earth carbodiimides are prepared from melamin and the corresponding metal nitrides.5 EuNCN is made from EuN, elemental carbon and sodium azide at 1030 ◦ C.6 Most metal cyanamides or carbodiimides are precipitated from aqueous cyanamide solutions, while others use organosilicon precursors, such as bis(trimethylsilyl)carbodiimide (see 6.2.4). Also, mixtures of metal halides, sodium cyanamide and sodium azide are precursors for the synthesis of novel carbodiimides, such as EuNCN and Me2 (NCN)Cl2 (Me Sr, Eu).7 Also, LiSr2 (NCN)I3 , the first empty tetrahedral strontium entity coordinated by carbodiimide, is obtained in this manner, using SrI2 , NaCN, NaN3 and Li in a ratio of 2:1:1:2 at 880 ◦ C.8 LiMe2 (NCN)Br3 (Me Sr, Eu) is similarly obtained.9 Likewise, Eu8 (NCN)5 I6 , a rare earth carbodiimide iodide containing tetrahedral Eu8 clusters is prepared in this manner.10 Complex three- and one-dimensional interpenetrating networks are formed in lithium europium carbodiimide iodides LiEu2 (NCN)I3 and LiEu4 (NCN)3 I3 .11 Ln2 O2 NCN (La, Ce, Pr, Nd, Sm, Eu and Gd) are also obtained from the rare earth metal oxides in the presence of carbon under flowing ammonia gas.12 Also, two rare earth metal chloride carbodiimide nitrides Ln2 Cl(NCN)N (Ln La, Ce) are obtained through solid state metathesis reactions between LnCl3 and Li2 NCN at 800 ◦ C.13
Chemistry and Technology of Carbodiimides Henri Ulrich C 2007 John Wiley & Sons, Ltd. ISBN: 978-0-470-06510-5
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Transition metal carbodiimides, such as MnNCN and CuNCN,14 and carbodiimides derived from zinc,15 mercury,16 silver17 and thallium18 are also known. A preceramic polymeric titanium carbodiimide is obtained in the reaction of TiCl4 with bis(trimethylsilyl)carbodiimide.19 Liganded carbodiimidotitanium complexes are obtained in the reaction of Cp2 TiCl2 with Me3 SnN C NSi(i-Pr)3 .20 Also, dicyclopentadienyl titanium (IV) diisocyanates are converted into carbodiimides with LiN(SiMe3 )2 .21 In group IIIa boron, aluminum, gallium and indium substituted carbodiimides are reported. In group IVa, silicon, germanium, tin and lead substituted carbodiimides have been synthesized, and the silicon substituted carbodiimides are treated in Chapter 6. In group Va, nitrogen and phosphorous substituted carbodiimides are treated in Chapters 7 and 8, respectively. Carbodiimides with one metal and one phosphorous substituent are described in the phosphorous substituted carbodiimide chapter (Chapter 8). Carbodiimides with group VIa substituents are the sulfur substituted carbodiimides, and they are described in Chapter 9. Carbodiimides with oxygen substituents are not known. Also, [1+2] and [2+2] cycloadducts of carbodiimides to liganded metal compounds are described in the current chapter. A review article on amidinate complexes appeared recently.22 The boron substituted carbodiimides are stable liquids or solids, and the 13 C signals of the center carbon atoms in boron carbodiimides are at 123–127.8 ppm. In the solid state, the boron substituted carbodiimides are almost planar, but the angle on the central carbon atom (127 ◦ ) and the nitrogen atoms (146 ◦ , 163 ◦ ) show that the molecules are not strictly linear.23 The digermyl carbodiimide, H3 GeN C NGeH3 , is a colorless liquid with a melting point of 10 ◦ C, which is stable at room temperature for several hours.24 Some metal substituted carbodiimides, such as bis(trimethylstannyl)carbodiimide have a structure intermediate between carbodiimide, cyanamide and ionic components.25 Carbodiimides with a ferrocene group in the molecule are synthesized because the reversible redox characteristic of ferrocene is useful as an electron-transfer indicator. Such molecules are used as biosensors (see 13.3.2). A review article on silicon, germanium, tin and lead substituted carbodiimides appeared in 1982.26
10.2
Synthesis of Metal Substituted Carbodiimides
10.2.1 From Cyanamides In the reaction of the lead salt of cyanamide 1 with gaseous H3 GeI, the corresponding carbodiimide 2 is obtained in 84 % yield.27 2 H3 GeI + PbNCN −−→ H3 GeN C NGeH3 1 2
(10.1)
The reaction of bis(triethylgermyl)oxide 3 with cyanamide affords bis(triethylgermyl)carbodiimide 4.28 (Et3 Ge)2 O + H2 NCN −−→ Et3 GeN C NGeEt3 3 4
(10.2)
Triethylgermyl chloride reacts with the lithium salt of cyanamide to give 4, bp 162 ◦ C/17 Torr, in 63 % yield.28 Similarly, trimesylgermyl chloride reacts with cyanamide to form
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Mes3 GeN C NGeMes3 , mp 237–238 ◦ C, in 75 % yield.29 Also, triethylgermyl-N,Ndiethylamine reacts with dicyandiamide 5 to give a 83 % yield of 4.30 Et3 GeNEt2 + HN C(NH2 )NHCN −−→ Et3 GeN C NGeEt3 5 4
(10.3)
Cyclic oligomers of dimesylgermylcarbodiimide, (Mes2 GeNCN)n , where n = 3 and 4 are synthesized from dimesylchlorogermanium with silver cyanamide in the presence of triethylamine or using lithium cyanamide.31 Silver cyanamide reacts with trimethylstannyl chloride 6 in refluxing benzene to give bis(trimethylstannyl)carbodiimide 7.25 AgNCN + 2 Me3 SnCl −−→ Me3 SnN C NSnMe3 6 7
(10.4)
Bis(triethylstannyl)carbodiimide is similarly obtained from the sodium salt of cyanamide and triethylstannyl chloride.32 Bis(triphenylstannyl)oxide 8 also undergoes reaction with cyanamide in acetonitrile to give an 88 % yield of bis(triphenylstannyl)carbodiimide 9, mp 98–100 ◦ C.33 (Ph3 Sn)2 O + H2 NCN −−→ Ph3 SnN C NSnPh3 (10.5) 8 9 The same oxide reacts with tritylcyanamide to give a 78 % yield of N-triphenylmethyl-N triphenylstannylcarbodiimide, and bis(tributylstannyl)oxide reacts with dicyandiamide to give a 98 % yield of bis(tributylstannyl)carbodiimide.27 The aliphatic tin oxide 10 also reacts with cyanamide to give an 81 % yield of the corresponding carbodiimide 11.34 [(Me3 SiCH2 )3 Sn]2 O + H2 NCN −−→ (Me3 SiCH2 )3 SnN C NSn(CH2 SiMe3 )3 10 11 (10.6) The reaction of triphenyllead hydroxide 12 with cyanamide affords a 77 % yield of bis(triphenyllead)carbodiimide 13.27 2 Ph3 PbOH + H2 NCN −−→ Ph3 PbN C NPbPh3 12 13
(10.7)
Several oligomeric metal carbodiimides are obtained from metal halides and salts of phenylcyanamide. For example, reaction of SbCl3 with KNCNPh 14 affords Sb(N C NPh)3 15, mp 271 ◦ C (dec.) in 41 % yield.35 3 KNCNPh + SbCl3 −−→ Sb(N C NPh)3 14 15
(10.8)
In a similar manner Tl(NCNPh)3 , Hg(NCNPh)2 , Cd(NCNPh)2 , Co(NCNPh)2 and Cu(NCNPh)2 are obtained.
10.2.2 From Isocyanates The reaction of liganded titanium diisocyanate with LiN(Si-i-Pr3 )2 affords the thermally and hydrolytically unstable carbodiimides Cp2 Ti(NCO)(NCNSi-i-Pr3 ) and Cp2 Ti(NCN-iPr3 )2 .21
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10.2.3 From Other Carbodiimides The reaction of R2 BCl with bis(trimethylsilyl)carbodiimide affords the diboron substituted carbodiimide 16.36 2 Bu2 BCl + Me3 SiN C NSiMe3 −−→ Bu2 BN C NBBu2 16
(10.9)
Likewise, borazene trichloride 17 reacts with bis(trimethylsilyl)carbodiimide to give 18, an oligomeric gel.36
Cl HN Cl
B
B N H 17
NH B
Cl
+ Me3SiN
C
NMe3
[(B3N3H3)(NCN)n ]m
(10.10)
18
The reaction of bis(trimethylsilyl)carbodiimide with two equivalents of chlorodiazaborolidines affords the diboron substituted carbodiimides 19 in 75–90 % yield.23 2 R2 BCl + Me3 SiN C NSiMe3 −−→ R2 BN C NBR2 19
(10.11)
bp ◦ C/Torr
R2 B
Me N 119/0.3
B N Me Me N B
142–143a
N Me BPh2 a
b
—b
mp ◦ C, the crystal structure shows a non linear B N C N B arrangement with a central N C N angle of 171.9 ◦ .37 from diphenylboronbromide, unstable white powder.
The reaction of N-t-Bu-N -trimethylsilylcarbodiimide with 2-chloro-1,3-dimethyl-1,3diazaborolidine affords N-t-butyl-N -diazaborolidin-2-ylcarbodiimide, bp 57 ◦ C in high yield.23
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217
In the reaction of Me2 GaCl with bis(trimethylsilyl)carbodiimide in n-hexane, the microcrystalline Me2 GaN C NSiMe3 is obtained. The gallium substituted carbodiimide is a low molecular weight oligomer, mp 58–61 ◦ C (dec.).38 Also, from LiN C NGeMe3 and Me2 GaCl, the oligomeric carbodiimide Me2 GaN C NGeMe3 , mp 46–49 ◦ C is obtained. The indium/germanium substituted oligomeric carbodiimide, Me2 InN C NGeMe3 , is obtained in a similar manner. The reaction of bis(trimethylsilyl)carbodiimide with AlCl3 , GaCl3 or InCl3 affords the corresponding metal/silyl carbodiimides, MeCl2 N C NSiMe3 .39 Bis(trimethylsilyl)carbodiimide reacts with two equivalents of GeH3 F to give the bisgermylcarbodiimide 20 in 95 % yield.40 2 GeH3 F + Me3 SiN C NSiMe3 −−→ H3 GeN C NGeH3 20
(10.12)
Heating of bis(trimethylstannyl)carbodiimide with triisopropylchlorosilane results in a stepwise replacement of the trimethylsilyl groups. Also, reaction of this carbodiimide with two equivalents of trimethylchlorosilane affords bis(trimethylsilyl)carbodiimide (85 % yield), and with tributylchlorostannane, bis(tributylstannyl)carbodiimide (90 % yield) is obtained. N-triisopropylsilyl-N -trimethylstannylcarbodiimide 21 reacts with bis(diisopropylamino)chlorophosphane to give the Si, P substituted carbodiimide 22.41 i-Pr3 SiN C NSnMe3 + (i-PrN)2 PCl −−→ i-Pr3 SiN C NP(N-i-Pr)2 21 22
(10.13)
Thermolysis of the insertion product of Me3 GeNMe2 with N-benzoyl-N -tbutylcarbodiimide at 150 ◦ C affords Me3 GeN C N-t-Bu, bp 76 ◦ C/18 Torr in 75 % yield.42 The reaction of antimony pentachloride with bis(trimethylsilyl)carbodiimide gives rise to the formation of SbCl4 N C NSiMe3 .43 Similarly, tantalum pentachloride reacts with bis-(trimethylsilyl)carbodiimide to form TaCl4 N C NSiMe3 .44
10.2.4 By Other Methods The reaction of t-butylimino-2,2,6,6-tetramethylpiperidinoborane 23 with thiourea affords the diboron substituted carbodiimide 24 in 45 % yield.45
N-B
N-t-Bu + H2NCSNH2 N
23
BN
C
NB
N
(10.14) 24
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The photolysis of substituted boron nitrile imines 25 affords mono- and diboron substituted carbodiimides 26 [R (i-Pr2 N)2 B, Si-i-Pr3 , P(i-Pr2 N)2 , P(S)(i-Pr2 N)2 ].46 (i-Pr2 N)2 BC N−−→NR −−→ (i-Pr2 N)2 BN C NR 25 26
(10.15)
Irradiation of silylgermyl nitrile imines 27 also affords the expected carbodiimides 28.47 i-Pr3 SiC N−−→NGe(SnMe3 )[CH(SiMe2 )2 Cp 27 (10.16) −−→ i-Pr3 SiN C NGe(SnMe3 )[CH(SiMe2 )2 ]Cp 28 The thermolysis of bis(trialkylstannyl)diazomethane 29 affords bis(trialkylstannyl)carbodiimides 30 in good yields.33 (R3 Sn)2 C N2 −−→ R3 SnN C NSnR3 29 30 R
[%]
Me t-Bu
45 70
(10.17)
Treatment of bis(trimethylstannyl)diazomethane with a catalytic amount of tetrakis(triphenylphosphine)palladium in THF at room temperature affords a 90 % yield of bis(trimethylstannyl)carbodiimide. The reaction of stannylamines 31 with isothiocyanates affords monostannyl substituted carbodiimides 32.48 (Me3 Sn)3 N + RNCS −−→ Me3 SnN C NR + (Me3 Sn)2 S 31 32 R
[%]
mp ◦ C
t-Bu C6 H11 Ph
92 97 94
113 159 136
(10.18)
10.2.5 Synthesis of Metal Carbodiimide Adducts The reaction of a variety of liganded metal derivatives with carbodiimides give [1+2] or [2+2] cycloadducts or more complicated products resulting from rearrangement or reductive coupling reactions. Also, amidinate complexes, which are sometimes obtained in the reaction of metal complexes with carbodiimides, are included. In Table 10.1 some of the [1+2] cycloaddition products obtained from liganded metal compounds and carbodiimides are listed.
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219
[1+2] Cycloadducts of Liganded Metal Compounds and Carbodiimides
Metal Compound
Carbodiimide
Cp2 V
Structure
NR
Cp2V
bis(p-tolyl)
Ref.
49
N R NPh diphenyl
Cr(CO)5
Cr(CO)5
50
C NPh
Cp2 Mo
bis(p-tolyl)
(Ph3 P)2 Ni
diphenyl
NR
Cp2Mo
51
N R NR
(Ph3P)2Ni
52
N R
X2 Pd(CNPh)2
NR
X2Pd
di-t-butyl
53
N R
In the reaction of DIPCD with (CO)5 W CRPh 33 a [2+2] cycloaddition acrosss the W C bond is observed to give the four membered ring cycloadduct 34.54
CRPh + RN
(CO)5 W
C
NR
(CO)5W
RPh NR
(10.19)
RN 33
34
Also, in the reaction of Na[CpFe(CO)2 ] with diphenylcarbodiimide, [2+2] addition across the iron-carbon is observed.55 Lithium N,N -diorganoamidinates 35 are obtained in the reaction of phenyl lithium with DCC or DIPCD.56 PhLi + RN C NR −−→ Li[PhC(NR)2 ] 35
(10.20)
The lithium amidinates are used as precursors for homoleptic lanthanide amidinates. Lanthanide amidinate complexes have a high catalytic activity in the polymerization of ethylene. They are also used in the manufacture of membranes.57 Lanthanide amidinate complexes 37 (La Er, Y, Gd) are also obtained from alkyl metal complexes 36 and
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di-t-butylcarbodiimide.58
N Cp2La-t-Bu + t-BuN
C
N-t-Bu
Cp2La
(10.21)
N 36
37
In the reaction of 2,6-diarylphenyllithium with DIPCD in diethyl ether, the corresponding amidinates are obtained.59 The reaction of DCC with t-BuPLi2 in THF at 20 ◦ C affords a tetranuclear lithium complex.60 The 1,3-dipolar addition of phenylazide to metal coordinated ligands affords carbodiimide ligands. An example is the reaction of the bis-azidopalladium complex 38 with two equivalents of 2,6-dimethylphenyl isocyanide to give the bis-carbodiimide complex 39.61 L2 Pd(N3 )2 + 2,6−Me2 PhNC −−→ L2 Pd(N C NR)2 38 39
(10.22)
Another reaction sequence encountered in metal carbodiimide interactions occurs in the reaction of iron pentacarbonyl 40 with dialkylcarbodiimides, resulting in the formation of dehydroguanidino iron carbonyl complexes 41.62
NR Fe(CO)5 + RN
C
RN
NR
(10.23)
NR
(CO)3Fe Fe(CO)3 41
40
Using N-methyl-N -t-butylcarbodiimide and 40, a mixture of two iron complexes 42 and 43 is obtained.63
N-t-Bu Fe(CO)5 + MeN
C
N-t-Bu
t-BuN
NMe
(CO)3Fe Fe(CO)3 42
N-t-Bu +
NMe
MeN
(CO)3Fe Fe(CO)3 43 (10.24)
Ferrocene substituted amidinate complexes are also known. For example, reaction of ferrocenyl lithium with DCC affords the lithium amidinate 44, which on hydrolysis gives the
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ferrocene substituted amidinate 45.64
N
Fe-Li + DCC
Fe
NHR Li + H2O
Fe
C
N
(10.25)
NR 45
44
Hydrogen isocyanide complexes 46, generated in situ, have been reacted with carbodiimides to give isocyanocarboxamidines 47.65 Fe(CN)Cp(CO)HCN + RN C NR −−→ Fe(CN)Cp(CO)CN C(NHR) NR 46 47 (10.26) From cyclopentadienyl-bis-(ethylene)cobalt and DCC the dicobalt complexes 48 and cyclopentadienyl cobalt oligomers are obtained.66 NR CpCo(C2H4)2 + RN
C
(10.27)
NR
RN
NR
Co
Co 48
Reaction of CpCo(CNCH2 Ph)(PMe3 ) with phenyl azide affords the carbodiimide complex CpCo(CNPh-PhCH2 N C NPh)(PMe3 ).67 Dinuclear copper amidinate complexes catalyze the homopolymerization of carbodiimides.68 From cyclopentadienyl titanium complexes 49 and di-p-tolylcarbodiimide, a product 50, derived from a reductive coupling reaction, is obtained.69 Cp2Ti(CO)2 + RN
C
NR
R N
R N
N R
N R
Cp2Ti
TiCp2
(10.28)
49 50 Titanium amidinate complexes 51 react rapidly at room temperature in toluene with carbon dioxide giving the 1:1 adducts 52.70 The complexes 51 are potentially useful for the extraction of carbon dioxide from air. R N Me
Cp + CO2
Ti N R 51
NR
Me
R Cp O N Ti N N R R 52
O
(10.28)
Titanium and zirconium amidinate complexes catalyze the polymerization of ethylene in the presence of methylalumoxan.71 Some ruthenium, osmium and iridium metal hydrides react with diarylcarbodiimides to give products containing N,N -diarylformamidinate ligands.72
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The Ru(II)phenyl complex, LRu(CO)(NCMe)(Ph), reacts with carbodiimides to give amidinate complexes.73 Also, the Ru(II) complex (PCP)Ru(CO)(PMe3 )(NHPh), where PCP = 2,6-(CH2 P-t-Bu)2 C6 H3 , reacts with carbodiimides to give four membered ring heterometalacycles 53.74
P
P CO Ru PMe3 + RN
C
CO N Ru
NR
NHR
N R
NHPh P
Ph
P
(10.29)
53 In the reaction of iridium complexes 54 with two equivalents of carbodiimides, mixtures of cyclic carbamate complexes 55 and organometallic guanidinates 56 are obtained.75
Cp
NR
Ir O + RN
O Me2
Me2 54
C
NR
O + RN Me2
O Me2 55
Cp Ir NR
(10.30)
NR 56
Complexes derived from Co and Rh afford only the cyclic carbamate complexes.76 The synthesis of square planar rhodium (I) complexes, trans-RhCl(RN C NR)(PCy3 )2 , where R p-tolyl, is also reported.77 The reaction of the iridium imido complex LIr(CN-t-Bu) with two equivalents of di-tbutylcarbodiimide affords LIr(RN C NR)(CNR).78 Silver dinuclear and trinuclear amidinate complexes are also known.57 Also, bis(amidinate) complexes are obtained by direct metallation of amidines.79
10.3
Reactions of Metal Substituted Carbodiimides
The reaction of bis(triphenylstannyl)carbodiimide 57 with thioamides results in the formation of nitriles 58.80 Ph3 SnN C NSnPh3 + RCSNH2 −−→ RCN 57 58
(10.31)
In the reaction of 57 with phenyl isothiocyanate, the isothiourea, 59 is obtained.81 Ph3 SnN C NSnPh3 + PhNCS −−→ PhN C(NHCN)SSnPh3 57 59
(10.32)
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The osmium cluster, H2 Os3 (CO)10 , reacts with DIPCD via addition across the C N bond of the carbodiimide.82 The photolysis of the rhodium carbodiimide complex 60 in liquid propylene affords the allyl derivative 61.83 LRd(CH2 CMe3 )(PhN C NCH2 CMe3 ) −−→ LRd(CH2 CMe3 )(CH2 CH CH2 ) 60 61 (10.33)
10.4
References
1. M.G. Down, M.J. Haley, P. Hubberstey, R.J. Pulham and A.E. Thunder, J. Chem. Soc., Dalton Trans. 1407 (1978) 2. M. Becker, J. Nuss and M. Jansen, Z. Anorg. Allg. Chem. 626, 2505 (2000) 3. M. Becker and M. Jansen, Solid State Sci. 2, 711 (2000) 4. M. Becker and M. Jansen, Naturforsch. 54b, 1275 (1999) 5. U. Berger and W. Schnick, J. Alloys Compd. 206, 179 (1994) 6. O. Reckeweg and F.J. Di Salvo, Z. Anorg. Allg. Chem. 629, 496 (2003) 7. W. Liao and R. Dronskowski, Z. Anorg. Allg. Chem. 631, 496 (2005) 8. W. Liao, J. V. Appen and R. Dronskowski, J. Chem. Soc., Chem. Commun. 2302 (2004) 9. W. Liao and R. Dronskowski, Z. Anorg. Allg. Chem. 631, 1953 (2005) 10. W. Liao, B.P.T. Fokwa and R. Dronskowski, J. Chem. Soc., Chem. Comm. 3612 (2005) 11. W. Liao, C. Hu, K. Kremer and R. Dronskowski, Inorg. Chem. 43, 5884 (2004) 12. Y. Hashimoto, M. Takahashi, S. Kikkawa and F. Kanamaru, J. Solid State Chem. 125, 37 (1996) 13. R. Srinivasan, M. Str¨obele and M. Meyer, Inorg. Chem. 42, 3406 (2003) 14. X. Liu, M. Krott, P. M¨uller, C. Hu, H. Lucken and R. Dronskowski, Inorg. Chem. 44, 3001 (2005) 15. M. Becker and M. Jansen, Acta Crystallogr. C57, 347 (2001) 16. G. Baldinozzi, B. Malinowska, M. Rakib and G. Durand, J. Mat. Chem. 12, 268 (2002) 17. X. Liu, P. M¨uller, P. Kroll and R. Dronskowski, Inorg. Chem. 41, 4259 (2002) 18. K.M. Adams, M.J. Sole and M.J. Cooper, Acta Crystallogr. 17, 1449 (1964) 19. O. Lichtenberger, E. Pippel, J. Woltersdorf and R. Riedel, Mat. Chem. Phys. 81, 195 (2006) 20. G. Veneziani, S. Shimada and M. Tanaka, Organomet. 17, 2926 (1998) 21. H. Pienio and H.W. Roesky, Z. Naturforsch. 44B, 94 (1989) 22. D.A. Kissounko, M.V. Zabalov, G.P. Brusova, and D.A. Lemenovskii, Russ. Chem. Rev. 51, 351 (2006) 23. W. Einholz and W. Haubold, Z. Naturforsch. 41B, 1367 (1986) 24. J.D. Murdoch and D.W.H. Rankin, J. Chem. Soc., Chem. Commun. 748 (1972) 25. R.A. Forder and G.M. Sheldrick, J. Chem. Soc., Chem. Commun. 1023 (1970) 26. A.S. Gordetsov, V.P. Kozyukov, L.A. Vostokov, S.V. Sheludyakova, Y.I. Dergunov and V.F. Moronov, Russ. Chem. Rev. 51, 485 (1982) 27. J.A. Drake, R.T. Hemmings and H.E. Henderson, J. Chem. Soc., Dalton Trans. 366 (1976)
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28. I.A. Vostokov and Y.I. Dergunov, Zh. Obshch. Khim. 40, 1666 (1970); C.A. 74, 142,005 (1971) 29. M. Dahrouch, M. Riviere-Baudet, H. Gornitzka and G. Bertrand, J. Organomet. Chem. 562, 191 (1998) 30. I.A. Vostokov, Y.I. Dergunov and A.S. Gordetsov, Zh. Obshch. Khim. 47, 1769 (1977); C.A. 87, 152,337 (1977) 31. M. Dahrouch, M. Riviere-Baudet, J. Satge, M. Mauzac, C.J. Cardin and J.H. Thorpe, Organomet. 17, 623 (1998) 32. V.F. Gerega, Y.I. Dergunov, A.V. Pavlycheva, Y.I. Mushkin and Y.A. Aleksandrov, Zh. Obshch. Khim. 40, 1099 (1970) 33. R.A. Cardona and E.J. Kupchik, J. Organomet. Chem. 34, 129 (1972) 34. O.S. Dyachkovskaya, L.P. Malysheva and N.N. Chuvatkin, Khim. Elementoorg. Soedin 4, 62 (1976); C.A. 88, 23,076 (1978) 35. H. K¨ohler and H.V. D¨ohler, Z. Anorg. Allg. Chem. 386, 197 (1971) 36. K.W. V¨olger, E. Kroke, C. Gervais, T. Saito, F. Babouneau, R. Riedel, Y. Iwamoto and T. Hirayama, Chem. Mat. 15, 755 (2003) 37. G. Sawitzki, W. Einholz and W. Haubold, Z. Naturforsch. 43B, 1179 (1988) 38. P. Haag, R. Lechler and J. Weidlein, Z. Anorg. Allg. Chem. 620, 112 (1994) 39. R. Lechler, Dissertation, University of Stuttgart, 1987 40. S. Cradock and E.A.V. Ebsworth, J. Chem. Soc. (A) 1423 (1968) 41. G. Veneziani, R. Reau and G. Bertrand, Organomet. 12, 4289 (1993) 42. S. Matsuda, K. Itoh and Y. Ishii, J. Organomet. Chem. 69, 353 (1974) 43. G. Rajca, W. Schwarz and J. Weidlein, Z. Naturforsch. 39B, 1219 (1984) 44. G. Rajca and J. Weidlein, Z. Anorg. Allg. Chem. 538, 361 (1986) 45. G. Geisberger, K. Neukirchinger and H. Noeth, Chem. Ber. 123, 455 (1990) 46. M.P. Arthur, H.P. Goodwin, R. Baceiredo, K.B. Dillon and G. Bertrand, Organomet. 10, 3205 (1991) 47. C. Leue, R. Reau, B. Neumann, H.G. Stammler, P. Jutzi and G. Bertrand, Organomet. 13, 436 (1994) 48. D. H¨assgen and D. Hajduga, Chem. Ber. 110, 3961 (1977) 49. M. Pasquali, S. Gambarotta, C. Floriani and A. Chiesi-Villa, Inorg. Chem. 20, 165 (1981) 50. W.P. Fehlhammer, A. Mayr and M. Ritter, Angew. Chem. 89, 660 (1977) 51. J. Okunda and G. Herberich, J. Organomet. Chem. 320, C-35 (1987) 52. H. Hoberg and J. Korff, J. Organomet. Chem. 150, C-20 (1978) 53. B.M. Byercroft and J.D. Cotton, J. Chem. Soc., Dalton Trans. 1867 (1973) 54. K. Weiss and P. Kindl, Angew. Chem. 96, 616 (1984) 55. E.T. Hessel and W.D. Jones, Organomet. 11, 1496 (1992) 56. J. Richter, J. Feiling, H. Schmidt, M. Noltemeyer, W. Br¨user and F.T. Edelman, Z. Anorg. Allg. Chem. 630, 1269 (2004) 57. B.S. Lim, A. Rathu, J.S. Park and R.A. Gordon, Inorg. Chem. 42, 7951 (2003) 58. J. Zhang, R.Y. Ruan, Z.H. Shao, R.F. Cai, L.H. Weng and X.G. Zhou, Organomet. 21, 1420 (2002) 59. J.A.R. Schmidt and J. Arnold, J. Chem. Soc., Dalton Trans. 2890 (2002) 60. E. Iravani, B. Neum¨uller and J. Grunenberg, Z. Anorg. Allg. Chem. 632, 739 (2006) 61. Y. Kim, Y. Kwak, Y. Joo and S. Lee, J. Chem. Soc., Dalton Trans. 144 (2002)
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225
62. N.J. Bremer, A.B. Cutcliffe, M.F. Farona and W.G. Kofron, J. Chem. Soc. (A) 3264 (1971) 63. J.D. Cotton and S.D. Zornig, Inorg. Chim. Acta 25, L-133 (1977) 64. J.R. Hagadorn and J. Arnold, Inorg. Chem. 36, 132 (1997) 65. E. Bar, W.P. Fehlhammer, W. Weigand and W. Beck, J. Organomet. Chem. 347, 101 (1988) 66. S. Stella, C. Floriani, A. Chiesi-Villa and C. Guastini, Angew. Chem. 99, 84 (1987) 67. G. H¨orlin, N. Mahr and H. Werner, Organomet. 12, 1775 (1993) 68. K. Shibayama, S. Seidel and B.M. Novak, Makromol. 30, 3159 (1997) 69. M. Pasquali, C. Floriani, A. Chiesi-Villa and C. Guastini, J. Am. Chem. Soc. 101, 4740 (1979) 70. E.A. Giuducci, R.A. Cowley, M.E.G. Skinner and P. Mountford, J. Chem. Soc., Dalton Trans. 1392 (2001) 71. D. Liguori, F. Grisi, I. Sessa and A. Zambelli, Macromol. Chem. Phys. 204, 164 (2003) 72. S.D. Robinson and A. Sahajpal, J. Organomet. Chem. 117, C-111 (1976) 73. J.P. Lee, K.A. Pittard, N.J. DeYonker, T.R. Cundari, T.B. Gunnoe and J.L. Petersen, Organomet. 25, 1500 (2006) 74. J. Zhang, B. Gunnoe and J. Petersen, Inorg. Chem. 44, 2895 (2005) 75. A.W. Holland and R.G. Bergman, J. Am. Chem. Soc. 124, 1910 (2002) 76. A.W. Holland and R.G. Bergman, Inorg. Chim. Acta 341, 99 (2002) 77. H.L.M. van Gaal and P.J. Verlaan, J. Organomet. Chem. 133, 93 (1977) 78. D.S. Glueck, F.J. Hollander and R.G. Bergman, J. Am. Chem. Soc. 111, 2719 (1989) 79. J. Li, L. Weng, X. Wei, D. Lin and J. Lin, J. Chem. Soc., Dalton Trans. 1401 (2002) 80. E.J. Kupchik and H.E. Hauke, J. Organomet. Chem. 97, 39 (1975) 81. R.A. Cardona and E.J. Kupchik, J. Organomet. Chem. 43, 163 (1972) 82. R.D. Adams, D.A. Katahira and J.P. Selegue, J. Organomet. Chem. 213, 259 (1981) 83. D.D. Wick and W.D. Jones, Organomet. 18, 495 (1999)
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11 Cyclic Carbodiimides
11.1
Introduction
The stability of homocyclic carbodiimides depends on the ring size. Larger than eight membered ring compounds are relatively stable. Attempts to isolate the seven membered ring cyclic carbodiimide have resulted only in the isolation of its [2+2] cyclodimer. Attempts to trap the six membered ring cyclic carbodiimide have been unsuccessful.1 Homocyclic carbodiimides 2 (n = 5, 6, 7, 10, 11) are synthesized by dehydrosulfurization of the corresponding cyclic thioureas 1, or better by ring expansion of cyclic amidoximes 3.
N
NH (CH2)n
S
(CH2)n C
NH 1
(CH2)n
(11.1)
NHOSO2R
N 2
N
3
Several labile seven membered ring cyclic and bicyclic carbodiimides are formed by rearrangement of singlet nitrenes either via flash vacuum pyrolysis of the nitrene precursors, tetrazolo[1,5-a]pyridines, at 480 ◦ C and subsequent trapping at −198 ◦ C, or by photolysis in an argon matrix.2 In this manner 4 was observed and trapped with methanol or diisopropylamine to give 1,3-diazepine derivatives (see also Section 11.3).3 The seven membered ring bicyclic carbodiimide 5 could not be observed. However, the isomeric carbodiimide 6, generated from 2-quinolylnitrene or 1-isoquinolylnitrene, was observed by infrared at 77 K.4 Likewise, the seven membered ring bicyclic carbodiimide 7 was observed in an argon matrix on photolysis of tetrazolo[1,5-c]quinazoline.5 Also, in an argon matrix Chemistry and Technology of Carbodiimides Henri Ulrich C 2007 John Wiley & Sons, Ltd. ISBN: 978-0-470-06510-5
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dichlorodehydrotetrazepine 8 was detected.6
N
N
N
N
N
N N
4
N 7
N 6
5
Ph Cl
N Cl
N N
N 8 (11.2)
In contrast, the seven membered ring tricyclic carbodiimide 9, obtained in the pyrolysis of tetrazolophenanthridene, is stable to −40 ◦ C and it dimerizes to give the [2+2] cyclodimer 10 in high yield.7
N
N (11.3)
N
N
N
N 10
9
Generation of 10 from the corresponding bis(iminophosphorane) using Boc2 O in the presence of DMAP, resulted in the formation of the corresponding cyclic urea derivative. However, low yields of 10 are also obtained from bis(iminophhosphoranes) and isothiocyanates. The bicyclic nine membered ring carbodiimide 11 is stable at room temperature.1 Also 12 is obtainable in the dehydrosulfurization of the corresponding cyclic thiourea, and 13 is a stable solid, but the tricyclic carbodiimide 14 has only been postulated as an intermediate.8
N 11
N N
C 12
N
N
N
13
N
N 14
(11.4)
Stable macrocycles with one or two carbodiimide groups in the ring have been synthesized by Molina and his coworkers (see Section 11.2.3).
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11.2
229
Synthesis of Cyclic Carbodiimides
11.2.1 From Cyclic Thioureas The homocyclic carbodiimides 16 were first synthesized by Behringer and Meier in 19579 by dehydrosulfurization of cyclic thioureas 15 with HgO.
N
NH (CH2)n
S
HgO
(CH2)n C
NH
(11.5)
N
15
16
In the reaction of 15 (n = 5) with HgO in methylenechloride in the presence of sodium sulfate, we obtained 16 (n = 5) in > 80 % yield.1 Macrocyclic bis-thioureas 17, on treatment with Ph3 P and CCl4 /Et3 N, afford cyclic biscarbodiimides 18.10
O
NH
NH
n
S NH
O
NH
N
O
N
O
n
N
S
n
N
(11.6)
n
17
18
n
[%]
mp ◦ C
1 2 3
50 65 52
56 61 34–35
The macrocyclic bis-carbodiimides are stable low melting solids. The cyclic thiourea 19, upon reaction with HgO affords the cyclic carbodiimide 20, but the compound has not been isolated in pure form.11
CH2N
CH2NH S
(11.7)
CH2N
CH2NH 19
20
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11.2.2 By Nitrene Rearrangement The modified Tiemann rearrangement of cyclic amidoxime derivatives 21 (where R = Me, Tos) using aqueous potassium hydroxide is also used to synthesize the listed homocyclic carbodiimides 22.
N N
(CH2)n
+ KOH
(CH2)n C
NHOSO2R
N
21
n 5 6 7 10 11 a
(11.8)
22
[%]
bp ◦ C/Torr
Ref.
> 90 74 73.3 84 24 87
—a 48–49/0.5 48/0.85 60–63/0.5 72/0.1 85–86/0.1
1 1 12 1 1 1
could not be distilled
Treatment of 7,8,9,10-tetrahydro-6-(hydroxyamino)benzo[b]azoc-5-ene 23 with aqueous potassium hydroxide affords 4,5,6,7-tetrahydobenzo-1,3-diazonine 24 in 27 % yield.1
+ KOH (11.9)
N C N
N NOSO2Me 23
24
Thermolysis of 2-azidopyridine 25 at 480 ◦ C generates the nitrene, which rearranges at low temperature to the cyclic carbodiimide 26. At −70 ◦ C the carbodiimide band in the infrared spectrum disappears and the isolated product is 2-cyanopyrrol 27.2
N 25
N3
N
N
N
N 26
N H 27
CN
(11.10)
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The carbodiimide 26 is also trapped with methanol or diisopropylamine to give the corrsponding 1,3-diazepine derivatives (see also 11.3.1). Similar thermolysis of the heterocyclic azide 28 affords the cyclic carbodiimide 29, which is stable up to −40 ◦ C. Above this temperature it undergoes a [2+2] cyclodimerization reaction.
N N
(11.11)
N
N3
28
29
Photolysis of the matrix isolated 2-azido-4,6-dichlorotriazine 30 affords the cyclic carbodiimide 31.6
Cl
N N
Cl N
N
Cl
Cl N
N
(11.12)
N N3 30
31
11.2.3 From Bisaryliminophosphoranes and Isocyanates or Isothiocyanates The reaction of bisaryliminophosphoranes with di-t-butylcarbonate (Boc)2 O in the presence of 4-dimethylaminopyridine, or carbon dioxide results in the formation of an intermediate isocyanate, which reacts with the second –N PPh3 group to form a cyclic carbodiimide or a cyclic dicarbodiimide. Reaction of the bisaryliminophosphorane with carbon disulfide generates a bis-isothiocyanate which undergoes reaction with the bisaryliminophosphorane to give the corresponding cyclic dicarbodiimide in high yield. Examples of these reactions are listed in Tables 11.1 and 11.2. A heterocyclic ring annulated carbodiimide is generated from a bisaryliminophosphorane and trapped with phenyl isocyanate.16 When the bisaryliminophosphorane 32 is first converted with carbon disulfide into the corresponding diisothiocyanate 33 and subsequently reacted with another equivalent of the
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Table 11.1 Macrocyclic Carbodiimides Bisaryliminophosphorane
Carbodiimide
(CH2)n
N
[%]
mp ◦ C
Ref.
2
77
140–142
13 14
4
40
134–136
14
98
89–91
15
7
147–149
14
50
86–88
14
2
67
oil
13
3
55
oil
13
98
oil
13
(CH2)n
N
Ph3P
n
C
N
PPh3
CH3
N
CH3 N
N
N C N
PPh3
Ph3P
O
O N
N
N
N
C
PPh3
Ph3P O
O
O
N
N Ph3P Boc
Ph3P
N Ph3P
N
Boc
nN
N
C
N
PPh3
O
nN
N
N
C
N
PPh3
Boc
Boc
N
N N PPh3
N
C
N
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Table 11.2 Macrocyclic Dicarbodiimides Bisaryliminophosphoranes
Carbodiimides
n
[%]
mp ◦ C
Ref.
25
182–184
14
43
207–209
14
45
210–212
14
O O N Ph3P
N Ph3P
N Ph3P
N PPh3
PPh3
PPh3
N
C
C
N
N O
N
N
N
N
N
C
C
N
N
N
N
C
C
N
N
(Continued )
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Table 11.2 Macrocyclic Dicarbodiimides (Continued) Bisaryliminophosphoranes
N
N
N
C
C
PPh3 N
N
N
Ph3P
N
N
Ph3P
PPh3
n [%] mp ◦ C
Carbodiimides
N
N
C
C
N
N
Ref.
84 104–106 14
40 199–201 13
O O N N C C N N
N N
Ph3P PPh3 O
20 248–250 13
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Table 11.2 Macrocyclic Dicarbodiimides (Continued) Bisaryliminophosphoranes
Carbodiimides
n
[%]
mp ◦ C
Ref.
2
10 97 40
234–235 234–235 145–147
14 13 14
71
217–218
14
50
—a
13
(Ch2)n
N
(Ch2)n
N
Ph3P
PPh3
N
N
C
C
N
N
(Ch2)n
4
O O N
N
Ph3P
PPh3
N
N
C
C
N
N O Boc N
Boc N N Ph3P
N
N
N
C
C
N
N
PPh3 N Boc
a
not reported
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bisaryliminophosphorane, the macrocyclic dicarbodiimides 34 are obtained.
+ (CH2)n
(CH2)n N Ph3P
N
N
N
PPh3
C
C
S
S
32
33
(CH2)n N
N
C
C
N
N (CH2)n
34
11.3
(11.13)
Reactions of Cyclic Carbodiimides
11.3.1 Nucleophilic Reactions The photolysis of azide 35 for 80 minutes in dioxane methanol solution at room temperature affords a 92 % yield of the distillable 1H-1,3-diazepine 36. Using diisopropylamine as the trapping agent a 76 % yield of the corresponding diisopropylamino derivative is obtained.
CF3
CF3 F3C
N 35
N3
+ MeOH N
N
N
N OMe 36 (11.14)
Numerous 1,3-diazepines containing mono- and bis-trifluoromethyl, chloro, alkoxy and dialkylamino groups have been prepared in this manner.17
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The reaction of macrocyclic dicarbodiimides with water affords the expected bis-ureas. With ammonia and primary and secondary alkylamines macrocyclic bis-guanidines are obtained in high yield.18
11.3.2 Oligomerization Reactions Seven membered ring cyclic carbodiimides, such as 1,3-diazahepta-1,2-diene1 37 and tetramethyl-1,3-diazahepta-1,2-diene19 are not stable in solution, but rapidly form dimers and oligomers. For example, from 37 the cyclodimer 38 formed by a [2+2] cycloaddition reaction and the cyclic trimer 39 are formed.1
N N
N
N N
N
(11.15)
N
N
N
37
N
N
+
38
N
39
Treatment of methylenechloride solutions of 1,3-diazacyclonona-1,2-diene and 1,3-diazacyclotetradeca-1,2-diene with a catalytic amount of tetrafluoroboric acid affords mixtures of dimeric and oligomeric species.1 From the seven membered ring tricyclic carbodiimide generated in the thermolysis of tetrazolophenanthridene only its cyclodimer has been isolated. The thermolysis of tetrazolo[1,5-c]quinazoline 40 generates the cyclic iminocarbodiimide 41 which forms a different cyclodimer 42.5
N N N N N 40
Ph
Ph N N
N 41 Ph
N N
N N
N
N Ph 42
(11.16)
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11.3.3 Cycloaddition Reactions The unstable 1,3-diazahepta-1,2-diene was trapped with diphenylcarbodiimide to give the [2+2] cycloadduct in 74 % yield.1 The larger ring cyclic carbodiimides also afford the [2+2] cycloadducts 43 with diphenylcarbodiimide.
N
N
(CH2)n C + PhN
C
NPh
(CH2)n
NPh
N
N
(11.17)
NPh
43
n
mp ◦ C
4 6 7 11
103–104 107–108 135–136 158–160
Cyclic carbodiimides also undergo a facile [2+2] cycloaddition reaction with alkyl- and aryl isocyanates to give the cycloadducts 44. With aryl isocyanates the reaction is exothermic and is completed within several minutes.
N (CH2)n C + RNCO
N (CH2)n
NR N
N 44
n
R
[%]
mp ◦ C
Ref.
4 4 5 5 5 6 7 11
Me ClCH2 CH2 4-O2 NPh Ph 4-ClPh Ph Ph Ph
37 48 70 —b —b —b —b —b
—a —a 109–111 —a 65 74–75 54–56 90
20 20 20 1 1 1 1 1
a b
colorless liquid almost quantitative
(11.18)
O
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The cycloaddition reaction of 4,5,6,7-tetrahydrobenzo-1,3-diazonine 45 with phenyl isocyanate occurs across the aliphatic C N bond to give 46.1
+ PhNCO N
N
N
N
O
(11.19)
N Ph
45
46
Trapping of 1,3-diazahepta-1,2-diene with 4-nitrophenyl isothiocyanate affords the [2+2] cycloadduct albeit in very low yield (1.3 %).20 The reaction of cyclic carbodiimides 47 (n = 4, 5), generated in situ, with carbon disulfide, results in the formation of the diisothiocyanates 48 in 23–28 % yield.19
N (CH2)n C
CS2
N (CH2)n
S N
SCN
(CH2)n NCS
(11.20)
S
N 47
48
Cyclic carbodiimides 49 (n = 5, 6, 11) react with phenyl-, phenethyl- and diphenylketene to give the [2+2] cycloadducts 50 in yields of > 90 %.21
N (CH2)n C + R2C
N C
O
(CH2)n
R2 (11.21)
N
O
N 49
50
From 49 (n = 5) and two equivalents of phenethyl- or diphenylketene, bis-adducts 51 are obtained in high yield.
O N (CH2)n C + 2 R2C N
C
O
N
R2
N
R2
(CH2)n
(11.22)
O 51
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Using chloromethyl- and dichloroketene, acylureas 52 rather than the cycloadducts are formed. COCHCl2
N
N
(CH2)n C + Cl2C
C
(CH2)n
O
N
O
(11.23)
N 52
11.3.4 Other Reactions The reaction of 1,3-diazacyclodeca-1,2-diene 53 with hexafluoroacetone affords a six membered ring 1:2 cycloadduct 54.1 N
N (CH2)n C
CF3
O
(CH2)n
+ (CF3)2CO
N
N
F3C 54
53
O
CF3
(11.24)
CF3
Cyclic carbodiimides also undergo a rapid reaction with phosgene in methylenechloride to form the expected adducts 55, which on hydrolysis give cyclic allophanoyl chlorides 56.22 N (CH2)n C + COCl2
N (CH2)n
NH
Cl (CH2)n
Cl
N
O Cl
N
(11.25)
N O
O 56
55
n
[%]
mp ◦ C
7 10 11
93 82 97
147–148 72 65–67
The reaction of cyclic carbodiimides with oxalyl chloride affords bicyclic parabanic acid derivatives 57 (when n = 11) or spiro(oxazolisine) derivatives 58 (when
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n = 5 or 6).23 O N (CH2)n C
+ ClCOCOCl
N
O (CH2)n O
Cl N
Cl
N
Cl
N
+ (CH2)n
O Cl O Cl
N O
Cl 58
57
(11.26)
Methyloxalyl chloride reacts with cyclic carbodiimides (n = 6) to form the spirobi(oxazolidine) derivative 59.23
OMe
O
Cl
N (CH2)n C
+ ClCOCOOMe
(CH2)n
N
O
N
O
N
(11.27)
OMe O
Cl 59
11.4
References
1. R. Richter, B. Tucker and H. Ulrich, J. Org. Chem. 48, 1694 (1983) 2. C. Wentrup and H.W. Winter, J. Am. Chem. Soc. 102, 6159 (1980) 3. C. Wentrup, A. Reisinger, G.G. Quiao and P. Visser, Pure & Appl. Chem. 69, 847 (1997) 4. A. Kuhn, M. Vosswinkel and C. Wentrup, J. Org. Chem. 67, 9023 (2002) 5. C. Wentrup, C. Thetas, E. Tagliaferri, H.J. Lindner, B. Kitschke, H.W. Winter and H.P. Reisenauer, Angew. Chem. 92, 556 (1980) 6. A.G. Bucher, F. Siegler and J.J. Wolff, J. Chem. Soc., Chem. Commun. 2113 (1999) 7. G.I. Yranzo, J. Elguero, R. Flammang and C. Wentrup, Eur. J. Org. Chem. 2209 (2001) 8. M.D. Baucin, A. Popescu, A. Simion, C. Dragnici, C. Maugra, D. Mihauescu and M. Procol, J. Anal. Appl. Pyrolysis 48, 129 (1999) 9. H. Behringer and H. Meier, Liebigs Ann. Chem. 607, 67 (1957) 10. N.G. Lukyanenko, T.I. Tirichenko and V.V. Limich, Synth. 928 (1986) 11. R.R. Hiatt, M.J. Shaio and F. Georges, J. Org. Chem. 44, 3365 (1979) 12. R. Damrauer, D. Soucy, P. Winkler and S. Eby, J. Org. Chem. 45, 1315 (1980) 13. P. Molina, M. Alajarin and P. Sanchez-Andrada, Tetrahedron Lett. 34, 5155 (1993) 14. P. Molina, M. Alajarin and P. Sanchez-Andrada, J. Org. Chem. 59, 7306 (1994)
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15. P. Molina, M. Alajarin, P. Sanchez-Andrada, J.S. Cario, M. Martinez-Ripoll, J.E. Anderson, M.I. Jimeno and J. Elguero, J. Org. Chem. 61, 4289 (1996) 16. P. Molina, A. Arques and A. Alias, J. Org. Chem. 58, 5264 (1993) 17. A. Reisinger and C. Wentrup, J. Chem. Soc., Chem. Commun. 813 (1996) 18. P. Molina, M. Alajarin and P. Sanchez-Andrada, Tetrahedron Lett. 36, 9405 (1995) 19. T. Hadribata, Dissertation, University of Hamburg, 1980 20. Y. Lotfy Aly, Dissertation, University of Hamburg, 1987 21. W.T. Brady and C.H. Shieh, J. Heterocycl. Chem. 22, 357 (1985) 22. R. Richter, B. Tucker and H. Ulrich, J. Org. Chem. 46, 5226 (1981) 23. R. Richter and E. Barsa, J. Org. Chem. 51, 417 (1986)
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12 Polymeric Carbodiimides
12.1
Introduction
Macromolecules with carbodiimide linkages in their repeat units are obtained from aliphatic and aromatic diisocyanates using a phospholene oxide catalyst. However, instead of linear polymers, only crosslinked thermosets are obtained in this manner. In contrast, linear polymers with pendant carbodiimide units are obtained from poly(vinyl azide) by subsequent reaction with triphenylphosphine to form poly(phosphine imines) followed by reaction with monoisocyanates to generate the linear poly(carbodiimides). The homopolymerization of carbodiimides affords polyguanidines, which are nylon-1 imides. Because of their thermal instability, the homopolymers have found no utility as industrial polymers. Polyguanidines are also obtained in the reaction of hexamethylenebis(t-butylcarbodiimide) with diamines. The polyaddition reactions of bis-carbodiimides with dialcohols and dithiols also produce the corresponding addition polymers. In the reaction of hexamethylene-bis(t-butylcarbodiimide) the polyaddition reactions proceed across the less sterically hindered C N bond. Masked bis-carbodiimides, which are thermally unblocked, are also used in crosslinking reactions. Oligomeric metal substituted carbodiimides have found utilities in the formation of ceramic materials. High-load soluble oligomeric carbodiimides are obtained by ROM (ring opening metathesis) polymerization. Such soluble carbodiimide oligomers are used as coupling reagents for esterification, amidation and dehydration of carboxylic acids. Polymeric substrates with carbodiimide end groups are often used in solid phase amidation reactions in peptide synthesis.
12.2
Isocyanate Terminated Polycarbodiimides
The reaction of diisocyanates with a phospholene oxide catalyst in a hydrocarbon solvent at room temperature produces thermoset polymers.1 For example, reaction of MDI 1 with a Chemistry and Technology of Carbodiimides Henri Ulrich C 2007 John Wiley & Sons, Ltd. ISBN: 978-0-470-06510-5
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phospholene oxide catalyst should produce the linear polymer 2, but crosslinked polymers are obtained instead.
OCN
NCO + Cat.
CH2 1
(12.1)
CH2
N
C
+ CO2
N n
2
The generation of the carbodiimide groups in the presence of excess isocyanate groups leads to the formation of four membered ring cycloadducts 3, which can react further with isocyanate or carbodiimide to give the thermally stable six membered ring cycloadducts 4 or 5, respectively. The formation of 4 or 5 accounts for the observed crosslinking.
RNCO + RN
C
NR
O
RN
+ RNCO
NR RN 3 O RN
NR NR RN
RN
N R 4
O
C
(12.2)
RN NR NR RN O N R 5
The thermoset polymers are usually obtained in quantitative yields. They are tough and can be molded into clear, tough films. Reaction of the polycarbodiimides with mono amines gives rise to the formation of polyguanidines. Also, conversion into polyureas with water, polythioureas with hydrogen sulfide and poly(O-alkylisoureas) with alcohols is known.2 The polycarbodiimides, having isocyanate end groups, are living polymers, because chain scission can occur by a reversible cycloaddition process. The formation of the 2:1 cycloadducts (isocyanate:carbodiimides) 4 from 3 and another mole of isocyanate occurs in the presence of a catalytic amount of HCl.3
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Using highly hindered aromatic diisocyanates, such as 6, with a phospholene oxide catalyst produces oligomeric carbodiimides 7.4
R OCN
R NCO
N
C
N + CO2
R
R
R
R
6
(12.3)
n
7
Some oligomers contain isocyanate end groups, while others are virtually free of isocyanate end groups, and crosslinking via cycloaddition to the carbodiimide end groups is prevented by steric hindrance. From 3,3 ,5,5 -tetraethyldiphenylmethane-4,4 -diisocyanate 8, in the presence of 2-ethyl-1,3-dimethyl-1,3,2-diazaphospholine-2-oxide, a low yield of the diisocyanate 9, mp 88–90 ◦ C is obtained.5
OCN
NCO 8
OCN
N
C 9
N
NCO
(12.4)
Oligomeric carbodiimides are efficient stabilizers for polyester, polyester based polyurethanes, polyether based polyurethanes and polyether based poly(urethane ureas). Oligomeric carbodiimides are commercially available under the trade name Stabaxol from Rhein Chemie, a subsidiary of Bayer. In Table 12.1, the carbodiimides and oligomeric carbodiimides used in the stabilization of polyester based polymers are listed.6 The polymer lifetime of polyester based polyurethanes with 3 % of monomeric carbodiimide added is increased ten fold at 35 ◦ C.7 When the less hindered 2,4-tolylene diisocyanate is reacted with a phospholene oxide catalyst linear oligomeric carbodiimides are obtained which have been reacted with a variety of nucleophiles to give poly(ureas), poly(acyl ureas), poly(formamidines) and poly-(guanidines) by addition across the N C N group. Also, reaction of the oligomeric carbodiimides with acrylic or methacrylic acid affords linear polymers, which can be further polymerized by free-radical type processes.8 Also, reaction of the carbodiimide oligomers obtained from 2,4-TDI with adipic acid in DMF produces a polyureid.9 Using the aliphatic hexamethylene diisocyanate 10 with a phospholene oxide catalyst at 20–50 ◦ C, the generated carbon dioxide is incorporated into the isocyanate
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Chemistry and Technology of Carbodiimides
Table 12.1 Carbodiimides and Oligomeric Carbodiimides Used as Stabilizers for Polyester Based Polymers Structure
N
C
N
N
C
N
N
C
N
Mol. Weight
Trade Name
222
Stabaxol E 443
362
Stabaxol 1
3000
Stabaxol P
10,000
Stabaxol P-100
n
N
C
N n
terminated oligomers 11 and 12.8 Conducting the reaction at 150–160 ◦ C causes formation of crosslinked polymers. O OCN(CH2)6NCO
OCN(CH2)6
N O
10
N(CH2)6NCO O
O 11
O + OCN(CH2)6N O
O N
O
(CH2)6 N(CH2)6NCO O 12
N
N(CH2)6NCO O
O
(12.5)
When the reaction of hexamethylenediisocyanate is conducted with a phospholene oxide catalyst in NMP, followed by reacting terminal isocyanate groups with ethanol, a polymer
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is obtained, useful as an insoluble condensation catalyst for polypeptides.10 In order to obtain linear processable polymers from the non hindered aromatic diisocyanate MDI, 13, the polymerization is conducted in the presence of a mono isocyanate, such as phenyl isocyanate, as a chain stopper. In this manner oligomeric carbodiimides 14 are obtained.11 The polymerization is conducted in xylene at 120 ◦ C, using 1-phenyl-3-methyl-2-phospholene oxide as the catalyst.
PhNCO
+ OCN
NCO 13
N
C
N
N
C
N n
14
(12.6)
The solubility of the obtained oligomers in xylene decreases as the molecular weight increases.The resultant oligomers show improved processing over the very high molecular weight intermediates, while still maintaining good thermal stability and good mechanical properties. The improved processability of the medium high molecular weight polymers may be the result of the plasticizer effect of the lower molecular weight oligomers present in the product. A study of the viscoelastic properties of all polymers, using modulustemperature plots has shown that all materials undergo a crosslinking reaction at 200– 250 ◦ C. The infrared spectra of the heated polymers shows a decrease in carbodiimide absorption at 2130 cm−1 , and the appearance of a new band at 1690 cm−1 , indicative of cyclic dimers or trimers of carbodiimides. Instead of phenyl isocyanate other aromatic monoisocyanates can be used as chain terminators. Examples include o-tolyl, p-methoxyphenyl and 2,6-diethylphenyl isocyanates. A negative working photoresist system is obtained using a oligocarbodiimide derived from 2,4-TDI and a phospholene oxide catalyst. m-Tolylisocyanate is used as the chain stopper. To this soluble linear polycarbodiimide a photoamine is added, which generates 2,6-dimethylpiperidine on irradiation. The generated secondary amine causes crosslinking via guanidine formation.12
12.3
Oligomeric Carbodiimides
Oligomeric dialkylsilylcarbodiimides, [R2 SiNCN]n , where n = 6–8, were first prepared by Pump and Rochow in 1964,13 by reacting dialkylsilylchlorides with silver cyanamide. Cyclic oligomeric carbodiimides, such as the 16 membered planar ring [(CH3 )2 SiNCN]4 are obtained similarly from dialkylsilylchlorides and cyanamide in THF in the presence of pyridine.14 Oligomeric methylsilanes, [CH3 HSiNCN]n , where n = 21–27 are also prepared from dichloromethylsilane and cyanamide in the presence of triethylamine.15 Similarly,
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disilanes react with cyanamide in the presence of triethylamine to give disilylcarbodiimide oligomers 15, n = 7–9.16 ClSi(Me)2 Si(Me)2 Cl + H2 NCN + Et3 N −−→ −[ Si(Me)2 Si(Me)2 NCN− ]n (12.7) 15 Silicondicarbodiimide oligomers, [Si(NCN)2 ]n are obtained from silicon tetrachloride and bis(trimethylsilyl)carbodiimiide.14 Germaniumdicarbodiimide is obtained similarly from GeCl4 and bis(trimethylsilyl)carbodiimide. Also, cyclic oligomers of dimesitylgermaniumcarbodiimide are obtained from dimesityldichlorogermanium and cyanamide in the presence of triethylamine or lithium cyamamide.17 Also, reaction of BCl3 with bis(trimethylsilyl)carbodiimide affords the corresponding boron carbodiimide oligomers.18 The reaction of borazine trichloride with bis(trimethylsilyl)carbodiimide affords crosslinked B/C/N oligomers 16.19 Cl
HN Cl
B
B N H
NH B
Cl
+ 1.5 TMSN
C
NTMS
[(B3N3H3)(NCN1.5]n 16
(12.8)
Similar crosslinked oligomers are obtained from cyanuric halides and bis(trimethylsilyl)carbodiimide. The oligomeric metal substituted carbodiimides are used as precursors for ceramic materials. High load, soluble oligomeric carbodiimides are obtained by ROM polymerization of N-cyclohexyl-N -(2-succinimidoethyl)carbodiimide 17 using a ruthenium catalyst to give 18, n = 50, 100 and 150.20
n
+ Cat.
O
O N
N 17
C
(12.9)
O
O N
NC6H11
N
C
NC6H11
18
The soluble oligomeric carbodiimide is used as a coupling reagent for esterification, amidation and dehydration of carboxylic acids.
12.4
Linear Homopolymers via Addition Across the C N Bonds
The homopolymerization of aliphatic carbodiimides affords nylon-1 imides 19. The thus obtained poly(guanidines) are of no interest as industrial polymers because unzipping occurs on heating.21 RN C NR −−→ −[ N(R) C( NR)−]n 19
(12.10)
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However, using titanium catalysts, such as CpTiCl2 NMe2 or CpTiCl2 (OR), rigid rod or living helical poly(guanidines) are formed from dialkyl-, arylalkyl-, and diarylcarbodiimides.22 From the chiral monomer 20, the optically active helical poly(guanidine) 21 is obtained using CpTiCl2 (O-i-Pr) as catalyst.23
N N N
C
n
(12.11)
N
20
21
The poly(carbodiimide) 21 displays a specific rotation similar to the monomer. Solutions (20 %) of poly(N,N -di-n-hexylguanidine), using Cp-TiCl2 NMe2 as catalyst in the polymerization reaction, form a layered smectic structure.24 Permanently optically active poly(guanidines) 23 (R = Me, n-Hexyl or Ph) are obtained from an achiral carbodiimide monomer 22 using an optically active titanium catalyst.25
N N
C
NR
(12.12)
N n
R 22
23
Poly[N-methyl-N -(2-methyl-6-isopropylphenyl)carbodiimide] maintains its chiral conformation even at elevated temperatures, and poly[-N-dodecyl-N -1-naphthylcarbodiimide] displays birefringent cholesteric mesophases. Stable helical polyguanidines are obtained from the same carbodiimide using chiral titanium catalysts in the polymerization.26 Also, using a chiral titanium catalyst chirooptical switching polyguanidines are obtained from N-(1-anthranyl)-N -octadecylcarbodiimide.27 Liquid crystalline polyguanidines 25 are obtained from the carbodiimide 24 also display a lyotropic nematic texture caused by strong dipolar–dipolar interaction between the main chain and side chains.28
CH3(CH2)5N
C
N(CH2)6O
N
N
OMe
24 OR
N N (CH2)5 CH3 25
n
(12.12) Polyguanidines 25 (R = Ph-Ph-OMe) exhibit thermotropic liquid crystalline behavior.
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The polyguanidines are living polymers, and they undergo depolymerization on heating to 150–240 ◦ C to generate the monomers. The chiral polymer obtained from (R)-(+)-Nmethyl-N -(α-phenylethyl)carbodiimide undergoes decomposition as indicated by TGA at about 190 ◦ C, while the racemic polymer decomposes 40 ◦ C lower.29 Poly(N-ethyl-N -α-phenylethylcarbodiimide) forms lyotropic liquid crystals in organic solvents which allows fabrication of ordered films for electro-optical applications.30 The titanium complexes are sensitive to high temperatures and the presence of oxygen or water. A more robust catalyst system is based on Cu(I) and Cu(II) amidinate complexes.31 Also, dinuclear copper amidinate complexes are used in the polymerization of carbodiimides.
12.5
Polymers Derived from Unsaturated Carbodiimides
Vinyl polymers 26 bearing pendant carbodiimide groups, are obtained from N-(p- or ovinylphenyl)-N -alkylcarbodiimides.32
N
C
NEt
N P
C
NEt
(12.13)
26
Polymers with pendant carbodiimide groups 27 are also synthesized from crosslinked polystyrene.33 In this synthetic route crosslinked polystyrene beads are chloromethylated and converted to the amines. Reaction with isopropyl isocyanate gives the corresponding ureas, which are treated with tosyl chloride and triethylamine to produce the crosslinked polycarbodiimides. This polymer is used in the polymer supported Moffatt oxidation of alcohols into aldehydes or ketones using benzene/DMSO.34 PCH2 Cl + NH3 −−−→ PCH2 NH2 + RNCO −−−→ PCH2 NHCONHR −−−→ PCH2 N C NR 27
(12.14) Also, reaction of the aminomethyl polystyrene with cyclohexylisocyanate affords a polymer bound urea, which is converted into the carbodiimide using Ph3 PBr2 . Reaction of the polycarbodiimide with methanol affords an O-alkylisourea which is used in the O-alkylation of carboxylic acids.35 When aminomethyl polystyrene is reacted with dialkylcarbodiimides, the corresponding polyguanidines are obtained which exhibit high selectivity towards Au(CN)2 − ions.36 Also, reaction of chloromethyl polystyrene with EDC affords the polymeric EDC hydrochloride 28. This polymer is used in the coupling of amino acids with carboxylic acids (yield: 72–100 %).37 PCH2 Cl + Me2 NCH2 CH2 CH2 N C NEt −−−→ PCH2 N+ (Me)2 CH2 CH2 CH2 N C NEt Cl− 28 (12.15)
PEDC is also applied to esterify carboxylic acids with N-hydroxysuccinimide or pentafluorophenol.38 Also, reaction of PEDC with heterocyclic carboxylic acids affords the corresponding anhydrides, which are converted with aniline derivatives into hetero-cyclic carboxamides.39
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Also, polymer bound thioureas 29 are converted into carbodiimides 30 using Mukaiyama’s reagent (2-chloro-1-methylpyridinium iodide) in the presence of triethylamine. This polymer is used in the solid phase synthesis of 2-aminoimidazolinones.40 PCH2 OCOCHRNHCSNHR1 −−→ PCH2 OCOCHRN C NR1 29 30
(12.16)
Another polymer supported carbodiimide is PCH2 O(CH2 )3 N C NC6 H11 (PSCDI), designed for optimizing the polymer supported formation of polypeptides.41 This polymer is used in conjunction with HOBt, the latter being easily removed with a supported carbonate base.42 The aza-Wittig reaction is also used to form polymers with pendant carbodiimide groups. For example, reaction of the polymeric azide 31 with benzyl isothiocyanate and triphenylphosphine gives the corresponding carbodiimide 32, a precursor for oligomeric guanidines.43 POCOCHNHCOPh-4-CH2 N3 −−→ POCOCHNHCOPh-4-CH2 N C NCH2 Ph 31 32 (12.17) Polymer supported carbodiimides are also used in the reaction of N,N -bis(t-butoxycarbonyl)thiourea with polymer supported triamines to give N,N -bis(t-butoxycarbonyl)protected guanidines.44 Polycarbodiimide methacrylates are obtained from the corresponding urea methacrylates. These polymers are utilized in the reaction with waterborne carboxylic acid containing acrylic polymers to produce waterborne polymers with methacrylic functonality.45 The carbodiimide content in polymer supported carbodiimides can be determined using oxalic acid.46
12.6
Linear Polymers
Linear carbodiimides with pendant carbodiimide groups are obtained by reacting polymeric azides derived from vinyl azide 33 with triphenylphosphine to form poly(phosphine imines) 34, which are subsequently converted to polycarbodiimides 35.47 − [ CH2 CH− ]n N3 + PPh3 −−→ −[ CH2 CH−]n N PPh3 + RNCO 33 34 −−→ −[ CH2 CH−]n N C NR + P(O)Ph3 35
(12.18)
The polyaddition reaction of hexamethylene-bis(t-butyl)carbodiimide 36 with diols, such as 1,4-butanediol, 1,10-decandiol, cyclohexanedimethanol and p-xylene glycol affords poly(O-alkylisoureas) 37.48 t-BuN C N(CH2 )6 N C N-t-Bu + HOROH 36 −−→ −[ NHC( N-t-Bu)N(CH2 )6 NHC( N-t-Bu) ORO− ]n 37
(12.19)
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Similarly, reaction of 36 with 4,4 -dimercaptobiphenyl affords poly(S-alkylisothioureas). Also, reaction of m- and p-phenylene bis(t-butyl)carbodiimide and p-phenylene bis(2,6dimethylphenyl)carbodiimide with hexamethylenediamine and nonamethylenediamine affords the corresponding addition polymers (polyguanidines).49 Poly(N-carbamoylamides) 39 are obtained from p-phenylene bis(t-butyl)carbodiimide 38 and sebacic acid.50 t-BuN C N-Ph-N C N-t-Bu + HOOC(CH2 )8 COOH −−→ −[ N-Ph-NCO(CH2 )8 CO−] 38 39 (12.20) Thiophene-2,5-bis-iminophosphoranes are converted to the corresponding bis-carbodiimides using aryl isocyanates but the bis-carbodiimides were converted in solution to the corresponding bis-guanidines.51 Bis-carbodiimides are also used to crosslink butadiene/acrylonitrile copolymers containing carboxyl groups.52 Also, blocked dicarbodiimides are used in the crosslinking of carboxyl functional poly(methacrylates).53 Dicarbodiimides are also obtained from gem diisocyanates54 or bisiminophosphoranes,55 but due to the proximity of the functional groups such monomers are not useful as monomers for carbodiimide derived polymers. For example, reaction of phenyltrifluoromethyl diisocyanate with triphenyliminophosphoranes affords gem dicarbodiimides 40.54 CF3 PhC(NCO)2 + 2 Ph3 P NR −−→ CF3 PhC(N C NR)2 40
12.7
(12.21)
Crosslinked Homo- and Copolymers
Cellular poly(carbodiimides) derived from polymeric isocyanate (PMDI) can be continuously produced using a phospholene oxide catalyst.56 As the component temperature is increased from 25 ◦ C to 80 ◦ C at a constant catalyst level, foam densities decrease with increasing component temperatures, with an expected corresponding decrease in compressive strength. The foam friability also decreases with increasing component temperature. Poly(carbodiimide) foams are a new generation of isocyanate derived polymers that have properties significantly different from polyurethane or polyisocyanurate foams. The most important property distinctions are high temperature resistance, improved flame resistance and low smoke. No external blowing agent is needed, because the generated carbon dioxide gas is utilized to expand the foam. Because of the predominantly open cell structure of these foams very little change in k factor (insulation value) occurs on aging. Modification of the poly(carbodiimide) foams, using polyols as comonomers, is possible, but the excellent thermal and flammability properties are reduced. Poly(carbodiimide isocyanurate) foams can also be continuously produced using 1,3,5-tris(3-dimethylaminopropyl)-hexahydro-s-triazine as the cocatalyst. Other trimerization catalysts, such as potassium 2-ethylhexanoate and quaternary ammonium carboxylate (Dabco TMR 2) are also used as cocatalysts in the formation of poly(carbodiimide isocyanurate) foams.57
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The recent trend to eliminate chlorofluorocarbon (CFC) blowing agents in rigid foam manufacture prompted a new look at PMDI derived foams containing partial carbodiimide structure. Since carbon dioxide, generated in carbodiimide formation from PMDI can be used as a blowing agent, significant reductions in the use of CFC or HCFC blowing agents can be achieved. The partial carbodiimide containing rigid foams are readily made by adding small amounts of a phospholene oxide cocatalyst to the formulation. In this manner poly(urethane) and poly(isocyanurate) foams are made containing carbodiimide as well as carbodiimide/isocyanate adducts in their backbone structure. New polyols are also formulated to be used in the formation of carbodiimide containing rigid foams.58
12.8
Modification of Linear Polymers with Carbodiimides
12.8.1 Crosslinking of Polymers Carbodiimides are members of a series of ‘zero-length’ protein crosslinking reagents, which promote the formation of covalent crosslinks between reactive side groups in amino acids, but do not remain as part of the crosslink.59 Examples of reactive side groups in amino acids include lysine, aspartic acid and glutamic acid. Carbodiimides have also been investigated for crosslinking bioprosthetic materials in order to enhance their stability prior to implantation. For example, EDC is used as a crosslinking agent to stabilize extracted ovine dermal collagen.60 Lysozyme and α-chymotripsin, when treated with EDC undergo intermolecular crosslinking to give thermostable proteins.61 Also, stability is improved in hemoglobin used in transfusion.62 Protein thiol groups also react with water soluble carbodiimides.63 For example, papaine is modified at residue cysteine 25.64 Tyrosine residues are also modified with carbodiimides.65 Enzymes, such as creatin kinase, have been grafted to collagen film by using water soluble carbodiimides.66 The pH optimum for coupling collagen to acrylic acid polymers is 4.4.67 Carbodiimides are also used to couple ovalbumin to mouse cells68 and melibionic acid to serum albumin.69 Protein immobilization with polyethylene grafted with polyacrylic acid in the presence of EDC has also been achieved.70 Exo-D-galacturonase is immobilized by coupling to a polyacrylamide type support activated by a water soluble carbodiimide.71 Poly(γ -glutamic acid) hydrogels are prepared from poly(γ -glutamic acid) and alkanediamines in the presence of water soluble carbodiimides.72 The crosslinking of thiolated and deacetylated gellan gum is mediated by carbodiimide to bind L-cysteine covalently to the gum.73 Thermally stable hydrogels are also obtained from aqueous gellan gels by partly crosslinking with EDC.74 Dopa modified PEG hydrogels as bioadhesives are also prepared using a carbodiimide mediated coupling reaction.75 Carbodiimides are also used to crosslink wool,76 hair in permanent wave composition,77 and bovin lutotropin.78 Similarly, carbodiimides are used as gelatin hardeners promoting crosslinking via a reaction of carboxyls with amino groups.79 Also, gelatin hydrogels are crosslinked with water soluble carbodiimides.80 Carbodiimides are also used as fixing agents. For example, intestinal glucagon has been preserved using water soluble carbodiimides.81 Fixation by carbodiimide treatment is also useful as an ultrastructure preservative for electron microscopy.82
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Crosslinking of scaffolding material for tissue regeneration based on collagen and hyaluronic acid is conducted using EDC.83 Also, artificial skin substitutes are being developed using EDC as crosslinker for grafting onto patients with severe burns.84 Resin bound carbodiimides are used in the formation of diphenol monomers used in the synthesis of tyrosine derived pseudo polypeptides.85
12.8.2 Modification of Linear Polymers Linear polymers containing carboxyl or sulfonic acid groups can be crosslinked with carbodiimides. Polymers with pendant carbodiimide groups have been used and synthesized as drying agents. Also, many other modified polymers with carbodiimide segments in the polymer backbone have been synthesized. For example, crosslinked organosilicon carbodiimide polymers are used in insulating coatings and high temperature paints.86 Crosslinked carbodiimide containing polymers with electrical insulation properties are made from MDI and a phospholene oxide catalyst.87 Addition of about 1 % of the linear MDI derived polycarbodiimide to nylon improves the relative melt strength and viscosity.88 Polycarbodiimides are also used as fiber reinforcements89 and in strengthening of glass fiber compositions.90 Acrylic binding sites for copolymerization are also synthesized using EDC.91 Likewise, poly(vinyl alcohol) is esterified with levulinic acid mediated by DCC using 4-pyrrolidino pyridine as the catalyst.92 Syndiotactic poly(methacrylic acid) is esterified with alcohols to give alternating ester linkages using carbodiimides.93 Strong acid catalysts cause random esterification. Water soluble carbodiimides are also used to couple ethyl glycinate with poly(acrylic acid).94 Hydroxyalkyl methacrylate gels, on treatment with carbodiimide and dimethyl sulfoxide, produce aldehyde group containing polymers which are used as carriers for biologically active compounds.95 A 1:1 mixture of a carbodiimide containing latex polymer (t-butylcarbodiimidoethyl methylmethacrylate) and a carboxylic acid containing latex polymer (2-ethylhexyl methacrylate) showed that polymer interdiffusion occurs faster than crosslinking.96 Also, cyclohexylcarbodiimidoethyl methacrylate and t-butylcarbodiimidoethyl methacrylate have been prepared, and these monomers are used to prepare carbodiimide functionalized latex particles for emulsion polymerization.97
12.8.3 Modification of Crosslinked Polymers Rod-shaped supramolecular assemblies comprising of triblock copolymers are transformed into spheres with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide. Subsequent intramicellular crosslinking with 2,2 -(ethylenedioxy)bis(ethylamine) preserves the intermediate morphology.98 Short life core-shell structured nanoaggregates are formed by self-assembly of PEO-b-PAA in water. The polymeric nanoaggregates exist as intermediates in aqueous solution with a shelf life of 1–3 weeks. The unique self association and self dissociation feature can be used as a carrier for controllable drug release. The nanoaggregates can be stabilized by further reaction with a diamine and EDC methiodide.99 Nanoparticle amino acid conjugates are obtained from carboxylic acid precursors with diisopropylcarbodiimide.100
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12.9 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35.
255
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13 Applications of Carbodiimides
13.1
Introduction
Numerous applications for carbodiimides in organic chemistry and especially in bioorganic chemistry are known. Even one multimillion ton/year application, the manufacture of liquid MDI (4,4 -diisocyanatodiphenylmethane) involves carbodiimides in low concentration as intermediates. The liquefaction of MDI is accomplished by catalytically generating carbodiimide linkages which undergo subsequent [2+2] cycloaddition with isocyanate groups. The formation of the cycloadducts in low concentrations lowers the melting point of MDI. Liquid MDI is easier to handle in most MDI applications. All MDI producers are using this process, which was pioneered at the D.S. Gilmore Research Laboratories of the Upjohn Co. In the early 1960s.1 The generation of catalytic amounts of carbodiimides from diisocyanates is also applied in the manufacturing of polyamides from MDI and dicarboxylic acids and/or dicarboxylic acid terminated prepolymers. These thermoplastic polyamides are produced continuously by reaction polymerization using a vented extruder to remove the carbon dioxide byproduct.2 Thermoplastic polyamides are manufactured today by the Dow Chemical Co., which purchased the Chemical Division of Upjohn in 1980. Oligomeric carbodiimides derived from sterically hindered aromatic diisocyanates are used as stabilizers for polyester based polymers because the carbodiimide groups in the oligomers, or in sterically hindered diisocyanates, mop up HCl, which catalyzes the depolymerization of polyesters. The carbodiimide stabilizers are commercially available under the tradename Stabaxol from Rhein Chemie, a subsidiary of Bayer. The most widely used carbodiimides are N,N -dicyclohexylcarbodiimide (DCC) and the water soluble N-ethyl-N -(3-dimethylamino)propylcarbodiimide (EDC) and its hydrochloride salt (EDCCl). Also, analogs of DCC, such as the fluorescent N-cyclohexylN -(1-pyrenyl)carbodiimide (PCD) and the paramagnetic N-cyclohexyl-N -(2,2,6,
Chemistry and Technology of Carbodiimides Henri Ulrich C 2007 John Wiley & Sons, Ltd. ISBN: 978-0-470-06510-5
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6-tetramethylpiperidineoxy)carbodiimide are used in protein applications to mark the reactive sites in the macromolecules. At the age of genomics and proteomics, carbodiimide mediated protein engineering is of considerable importance. Natural proteins and enzymes are readily modified or crosslinked to influence their behavior. The carbodiimide mediated inter- or intramolecular crosslinking of proteins is highly useful because no foreign molecules are introduced. Carbodiimides are ‘zero length’ crosslinkers. Peptide based pharmaceuticals use carbodiimides in their manufacture and this market will increase considerably over the current low level. ELISA (enzyme-linked immunosorbent assay) based on the gen-antigen reaction also uses carbodiimides to link attachments to the macromolecules.
13.2
Applications in Organic Synthesis
The reactions of carbodiimides outlined in Section 2.4 demonstrate the use of carbodiimides in organic synthesis. In the current chapter only some of the more important applications are highlighted. In view of the rapid reaction of carbodiimides with water they are often used in dehydration reactions. Major examples are the intra- and intermolecular esterification reactions of carboxylic acids, and the formation of peptides from carboxylic acids and protected amino acids. Especially, dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide (DIPCD) are often used in carbodiimide mediated reactions because the corresponding urea byproducts are insoluble in most organic solvents and water, and therefore are readily removed by filtration. Also, water soluble carbodiimides, such as N-ethyl-N -(3-dimethylamino)propylcarbodiimide (EDC) or its hydrochloride (EDCCl, sometimes referred to as EDAC) are often used in these reactions. EDC reacts with carboxyl groups at pH of 4.0–6.0, but loses its reactivity at lower pH.3 Sometimes solid phase reactions are conducted using carbodiimide terminated linear or crosslinked polymers. Carbodiimides also play a role as building blocks of numerous N-heterocycles. Examples are the cycloaddition reactions of carbodiimides.4 In the formation of [2+2] cycloadducts N-methyl-N -t-butylcarbodiimide is used as a marker to determine the mode of addition of isocyanates or isothiocyanates to carbodiimides.5 In these reactions addition across the C N or the C O bond of the isocyanate or across the C N or the C S bond of the isothiocyanate can occur. Addition to the N-methyl-N -t-butylcarbodiimide always proceeds across the N-methyl double bond. Also, the retroreaction of the [2+2] cycloaddition reaction of carbodiimides can afford a different set of heterocumulenes.6 Carbodiimides are also excellent dipolarophiles in [2+3] cycloaddition reactions. For example, 1,2,3,4-tetrazolium salts are obtained from dialkylcarbodiimides and 1,3-diaza1-azoniaallene salts.7 An important reaction of carbodiimides leading to bicyclic N-heterocycles is the azaWittig reaction.8 Often carbodiimides with unsaturated substituents are generated in situ and subsequent cyclization reactions afford the N-heterocycles. Many of these reactions are reported by Molina,9 Saito10 and Wamhoff.11 In the aza-Wittig reaction iminophosphoranes react with heterocumulenes (CO2 , CS2 , RNCO and RNCS) to generate carbodiimides, which often undergo subsequent reactions.
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In recent years, the metathesis reactions of carbodiimides, catalyzed by metal imido complexes, have been investigated. These reactions are useful to convert symmetrical carbodiimides into carbodiimides with different substituents (see Section 2.4.2.1). The solid phase synthesis of many organic molecules utilizes carbodiimide mediated reactions. An example is the synthesis of 1,4-benzodiazepine-2,5-dione using EDCCl in NMP in a key synthesis step.12 Often carbodiimides are used in the synthesis of complex proteins. A recent example is the synthesis of the tripeptide backbone of the novel immunosuppressent sanglifehrin A.13 In the synthesis of the marine alkaloid, variolin B, the formation of an annelated pyrimidine ring is achieved using a carbodiimide mediated cyclization process.14
13.3
Biological Applications
13.3.1 Antibiotic Synthesis The use of carbodiimides as mediators in biological condensation reactions is of considerable importance. Sheehan received a Nobel price for the first total synthesis of phenoxymethyl penicillin using DCC to effect the β-lactam ring closure reaction.15 Diisopropylcarbodiimide was used two years later to achieve the ring closure reaction in the synthesis of trityl penicillin.16 The Sheehan carbodiimide method was also used in the synthesis of other β-lactam antibiotics. Examples include the total synthesis of cephalothin lactone,17 the total synthesis of cefotaxin18 and the stereospecific construction of thienamycin.19 DCC is also used to prereact carboxyl groups with O-benzylhydroxylamine prior to βlactam ring closure.20 A water soluble carbodiimide in combination with HOBt is used in several steps of the total synthesis of nisin, a pentacyclic polypeptide.21 Carbodiimides are also used for amide bond formation in the synthesis of the antiviral antibiotic distamycin A.22 Similarly, carbodiimides are used in the synthesis of a model depsipeptide lactone related to quinoxaline antibiotics.23 In the last synthesis, DCC in the presence of pyridine is used in the depsipeptide bond formation. The chemical modification of the peptide antibiotic J25 also involves the use of a carbodiimide.24 The crosslinking of the major porin MspA of Microbacterium smegmatis is accomplished with EDC to crosslink carboxyl groups. The crosslinking limits the cell wall permeability of the microbacterium.25
13.3.2 Protein and DNA Synthesis Proteins play a key role in the post-genomic and proteomic era. Currently, over 200 new peptide based drugs are in different stages of development. Peptides represent about 1 % of the total active pharmaceutical ingredients with a market of $300–500M per year.26 Some of the new peptides utilize DCC/HOBt as coupling agents on a commercial scale. The majority of peptide drugs, up to 13–15 amino acids, are synthesized using the solution approach (Boc chemistry and DCC/HOBt). Also, solid phase Fmoc chemistry and fragment condensation approaches are being used. For example, Fuzeon, a peptide drug which docks on the surface of the HIV virus and blocks the virus from entering into a human blood cell, is produced by a combination of solid phase and solution phase methodologies.27
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The carbodiimides most often used in protein synthesis and reactions are DCC, EDC and DIPCD, in combination with 1-hydroxybenzotriazole (HOBt), 7-azabenzotriazole (HOAt), 6-chloro-1-hydroxy-benzotriazole (Cl-HOBt), N-hydroxysuccinimide or the water soluble sodium N-hydroxysuccinimide-3-sulfonate as coupling additives. The intermediate ester derived from the reaction of the initial O-acylisourea with Cl-HOBt is more reactive than the HOBt derived ester. The use of the coupling additives reduces racemization, and solvents of low dielectric constant, such as CHCl3 or CH2 Cl2 , also minimize the formation of epimers. The racemization prone serine can be coupled using Cl-HOBt with less than 2 % racemization.28 Sometimes, copper-(2)-chloride is used in conjunction with HOBt to prevent racemization.29 Often, the choice of carbodiimide used is of importance. For example, the synthesis of dipeptide esters containing a C-terminal Lproline proceeds well with DIPCD, while low yields of the dipeptides are obtained using DCC.30 Also, very high molecular weight polypeptides (mol. weight >1 000 000) are prepared from lower molecular weight polypeptides using carbodiimides as the condensing agents.31 Sheehan32 and another Nobel laureate Khorana33 showed independently that the mild carbodiimide mediated synthesis is very useful in the condensation reaction of N-blocked amino acids with a different amino acid to form a peptide bond. The O-blocking of carboxylic acid groups in peptide synthesis with amino nucleophiles, such as glycine esters or amides,34 or novel silicon containing protective groups35 is also mediated by carbodiimides. Likewise, alcohols are protected with 4-benzyloxybutyric acid, using EDC/DMPA.36 Of course, the availability of functional groups, such as carboxyl, hydroxyl, amino, thiol and imidazoles in proteins and enzymes allows interaction with carbodiimides. Often water soluble carbodiimides containing quaternary ammonium groups or tertiary amine hydrochloride groups (such as EDCCl) are used in these reactions. For example, Sheehan and coworkers used this variation to react N-phthaloglycine with glycine ethyl ester to form the corresponding dipeptide,37 and to couple a linear tripeptide to a cyclic hexapeptide.38 Also, nonapeptides are constructed using DCC/HOBt.39 This method is also used in the construction of prothimosin,40 a polypeptide containing 109 amino acids, and in the synthesis of cyclosporin.41 Using EDC/HOBt, human angeonin, midkine and the 228 residue aequoria green fluorescent protein have been synthesized.42 The Merrifield type of polymer terminated carbodiimides are often used in the solid phase synthesis of peptides. The number of carboxyl groups in a protein can be determined using a carbodiimide reaction.43 For example, 15 of the 17 carboxyl groups in α-chymotripsin have been coupled with ethyl glycinate using a water soluble carbodiimide.44 Nucleic acids are modified with ferrocenyl carbodiimide. For example, in single stranded DNA, the guanine bases react less readily than the thymine bases in borate buffer at 37 ◦ C.45 Also, poly (dT), where T = thymine, is immobilized on a carbodiimide mediated self assembly monolayer on a gold surface.46 Carbodiimides are frequently used to attach ferrocene as a microsensor to self assembled monolayers. An example are the ferrocene modified polyamidoamine (PAMAM) dendrimers, which are combined with gold nanoparticles to be used as chemical sensors. The PAMAM dendrimers are covalently attached to the mercaptoundecanoic acid mixed with a mercaptoundecanol self assembled monolayer.47 Such ferrocenyl tethered dendrimers are also tested as immunosensors.48 Also, self assembled amine substituted ferrocene monolayers are covalently bound to acid terminated silicon surfaces.49
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A step-by-step surface assembly utilizes poly-N-succinimidyl acrylate attached to a gold coated AFM (atomic force microscope) tip in conjunction with a silicon surface functionalized with a primary amino group. Retracting the AFM tip breaks the Au–C bond, leaving the polymer attached to the silicon surface.50 Organothiols chemisorbed on gold surfaces are especially useful for electrochemical and chemical studies. For example, carboxylic acid terminated monolayers are often used. An example is the attachment of cytochrome C with its side chain lysine groups to acid terminated self assembled monolayer gold electrodes.51 Carbodiimide mediated esterification of ferrocene-1,1 -dicarboxylic acid with phenols is used to construct thermotropic liquid crystals.52 Dextran bound adenosine, inosine and nebularine derivatives are synthesized by coupling of their 2 ,3 -O-(4-carboxyethyl-1-methylbutylidene) cyclic acetals with 6-aminohexyl- or 12-amino-dodecanyldextran using EDC.53 Carbodiimides are also used in the formation of DNA functionalized single walled carbon nanotubes (SWNT).54 The reactive sites in the SWNTs are caused by reacting them with a mixture of H2 SO4 /HNO3 (3:1). In this reaction carboxylic acid end groups are introduced, which allows DCC mediated coupling with amino terminated self assembled monolayers.55 Also, covalent coupling of quantum dots to multiwalled carbon nanotubes is accomplished with carbodiimides.56 Hybrids made by coupling inorganic carbon nanotubes and quantum dots with engineered viruses are also made using EDC as a zero length crosslinker.57 The viral networks are produced by covalent amide linkages between carboxyl groups on the nanotubes or quantum dots with primary amines from lysine residues in the virus protein coat. Unused EDC is quenched with 2-mercaptoethanol. Polymeric carbon nanocomposites are often functionalized with matrix polymers. An example is the functionalization of SWNTs and MWNTs with poly(vinyl alcohol) using a carbodiimide mediated esterification reaction.58 Also, poly(ethylene-co-vinyl alcohol) is used for this purpose to produce DMSO soluble functionalized SWNTs.59 In a similar manner poly(m-aminobenzene sulfonic acid) is covalently bonded to SWNTs to form water soluble graft copolymers.60 Ultrathin hydrogels are prepared from poly(vinyl amine-co-N-vinylformamide) and poly(acrylic acid) using EDC.61 Such soluble functionalized nanotube/PVA composites are used as an electrode for glucose sensing.62 Oligonucleotide probes are attached to polycarbodiimide treated glass via UV irradiation. In this manner oligonucleotide based microarrays are constructed.63 Carbodiimide terminated dithiolane self assembly momolayers (SAMs) are constructed on a gold surface with 6-mercaptohexanol. Only, poly(dT) has been immobilized on the surface of the SAMs through a specific reaction of the free imino group in thymine with the carbodiimide.46 Unprotected polynucleotides are derivatized using a water soluble carbodiimide in imidazol buffer to give a 5 -phosphorimidazolide.64 The exposure of polynucleotides to carbodiimides does not result in breakage of phosphodiester bonds or damage to the nucleotide bases. Aminophenyl boronic acid modified hydrogel beads are used for nucleotide isolation. The carboxyl groups on the gel bead surface are activated with EDC.65 A triple helix forming collagen model peptide and a thermosensitive elastin derived pentapeptide are copolymerized using EDCCl and HOBt in DMSO.66 A comparison of BrCN and EDC in assembling modified DNA duplexes and DNA–RNA hybrids shows that higher yields are obtained with the slower reacting EDC.67
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13.3.3 Modification of Proteins It is possible to modify and improve natural proteins and enzymes with protein engineering. EDC is often used in the chemical modification of biocatalysts, such as proteases, ribonuclease and glucose oxidase.68 The carbodiimide allows the alteration of amino acid side chains thereby generating new enzymes via covalent modification of existing proteins.69 For example, enzyme inhibitors can be covalently bonded to enzymes thereby lowering their reactivity. Carbodiimides are generally utilized as carboxyl activating agents for amide bonding with primary amines. Protein nanoparticles are modified by reacting them with L-cysteine and cystaminiumdichloride using a water soluble carbodiimide.70 Also, CdTe nanocrystals stabilized with thioacids or aminothiols are prepared using a water soluble carbodiimide.71 Radioactive glycine has been used to label carboxyl groups in blood coagulation factor VIII.72 N-terminal glutamic acid or aspartic acid can be modified with methyl glycinate to give a product, which can be distinguished analytically from glutamine and aspargine.73 Also, hemin has been derivatized similarly using a water soluble carbodiimide.74 Bovin trypsin has been modified with semicarbazide in the presence of a carbodiimide probably involving carboxyl groups.75 Also, monoamine derivatives of α, β or γ cyclodextrins are introduced into trypsin. The thus modified trypsins are more resistant to autolysis and show some increase in esterase activity.76 Ribonucleases are also modified by attaching aminoethanol, taurin and 1,2-diaminoethane to approximately six to eight of the 11 available carboxylates using EDC.77 The modified enzymes lose activity and the cytotoxicity is increased. The reaction of a carbodiimide alone with a protein can lead to deactivation, but since O-acylureas are labile to hydrolysis, reactivation occurs in the presence of water. Therefore, permanent deactivation of an enzyme caused by carbodiimide involves other pathways.78 Other examples of the reaction of carboxyl groups in proteins in the presence of carbodiimide include yeast enolase,79 acetylcholin esterase,80 L-glutamate dehydrogenase,81 an insect midgut trehalase,82 bovin β-lactoglobulin A,83 human serum albumin,84 bovin serum albumin,85 casein,86 and an acid proteinase87 from Aspergillus awamori. The introduction of thiol groups onto the surface of human serum albumin nanoparticles is also accomplished using EDC. This method is used to calculate the amount of free carboxyl groups on the surface of the nanoparticle.88 Pepsinogen is modified with DCC at four sites, while pepsin reacts at three.89 Pepsin is also modified with a carbodiimide containing a dye molecule,90 or the carboxyl group in pepsin is reacted with colored hydrophobic amines using a carbodiimide for the coupling reaction.91 Two to three carboxyl groups of serine pepsin, upon modification with tritium labled DCC, lead to an approximately 70–80 % loss of activity.92 Phenothiazine labled poly(ethylene oxide) has been attached to the lysine residues in glucose oxidase.93 An endo-1,4-β-xylanase (xylanase A), obtained from Schizophyllum commune, is rapidly deactivated using 1-(4-azonia-4,4-dimethylpentyl)-3-ethylcarbodiimide iodide, indicating that the reactive site in the enzyme is a carboxyl group.94 Xylanase A is of importance for the conversion of hemicellulosic biomass into fermentable products. Covalent immobilization of enzymes increases their stability while lowering their activity. Also, their storage stability is notably higher. The synthesis of arginine from citrulline, ATP and argenino-succinate synthetase may involve a carbodiimide intermediate.95
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Membrane ATPases have also been inhibited by carbodiimides. This reaction is associated with the membrane lipoprotein.96 Carbodiimide binding proteins have been isolated from bacterial membranes,97 chloroplasts,98 animal liver mitochondria,99 bovine heart mitochondria,100 molds101 and yeasts.102 The site of carbodiimide attack in the protein is probably in the hydrophobic region because only lipophilic carbodiimides are effective inhibitors.103 The addition of methyl glycinate protects erythrocyte membrane ATPase against carbodiimide inhibition.104 The inhibition reaction of carbodiimides may involve an O→N acyl shift in the initially formed O-acylurea. Carbodiimides are also used in immunoassays to identify and quantify analytes using antibody–antigen reactions, such as the ELISA (enzyme-linked immunosorbent assay) reactions. For example, medroxyprogesterone acetate with no immunogenicity has been coupled with serum albumin as the carrier protein.105 Also, collagen has been crosslinked and heparinized with EDC and N-hydroxysuccinimide, to measure the binding and release of fibroblast growth factor. Growth factors are proteins which promote proliferation and migration of cells.106 Antisera specificities to EDC adducts of proteins and N-acylurea EDC derived protein carriers are also studied using ELISA.107 The release characteristics and bioactivity of gelatin-tricalcium phosphate membranes covalently immobilized with nerve growth factors using a carbodiimide have also been determined.108 Liposome surfaces are modified with antibodies using EDC. The modified liposomes bind effectively to antigenic target cells.109 Anibody conjugated liposomes are used to transport and brain target encapsulated drug molecules.110 Thiol groups in proteins also react with water soluble carbodiimides. For example, papain is modified at cysteine 25.111 Also, free thiol groups in buckwheat α-glucosidase are protected by reacting them with a carbodiimide.112 Tyrosine residues are also modified with carbodiimides, and the inactivation of yeast hexokinase is reversed by hydroxylamine.113 Water soluble carbodiimides inhibit the transcription of supercoiled PM2 DNA with E. coli B RNA polymerase.114 Modification of the lactose permease of E. Coli with carbodiimides shows a preference for hydrophobic carbodiimides (DCC) over hydrophilic carbodiimides. In carbodiimide modification of EmrE, a small multidrug transporter in E. Coli, DIPCD modification indicates that Glu-14 is the target of the reaction.115 Polynucleotides react with positively charged water soluble carbodiimides much faster than do the monomers, owing to their electrostatic effect.116 Enzymes, such as creatine kinase, have been grafted on to collagen films by using water soluble carbodiimides.117 Porcine intestinal collagen has been crosslinked with EDC in acetone to provide a remodelable scaffold.118 EDC crosslinking of collagen/elastin matrices is also used to prepare flat scaffolds.119 Also, coupling of collagen to acrylic acid polymers has been studied.120 Collagen sponges, crosslinked with EDC and hexamethylenediamine, were used to study their biological stability.121 Treatment of the sponges with EDC markedly increased their resistance to collagenase digestion. Grafting of poly(methacrylic acid) modified gelatin or collagen to poly(L-lactic acid) films is also accomplished using EDC.122 A surgical adhesive is made from porcine collagen, polyglutamic acid and EDC.123 Also, a gelatin hydrogel, crosslinked with EDC has been found to be useful as a bioadhesive.124 The in vivo blood compatibility of EDC crosslinked and heparinized collagen is improved.125 The use of the carbodiimide method of binding chymotripsin to carboxymethyl-cellulose has also been investigated.126
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Carbodiimides are also employed to couple ovalbumin to mouse spleen cells,127 and melibionic acid to serum albumin.128 Aldehyde dehydrogenase, on treatment with DCC, loses its activity as dehydrogenase, but maintains its esterase activity.129 Crosslinking with EDC stabilizes the superoxide, generating respiratory burst oxidase in human plasma membranes.130 Hyaluronic acid, a linear polysaccharide abundant in connective tissue, in the extracellular matrix and in the vitreous body of the eye, contains carboxyl groups in its Dglucuronic acid segments. Surface treatment of flexor tendon autografts with EDC derivatized hyaluronic acid gelatin polymer decreases the digital work of flexion and tendon gliding.131 Modification of hyaluronic acid with aromatic amines, such as amino salicyclic acids, is also accomplished using EDC.132 Interestingly, reaction of hyaluronic acid with EDC in the presence of primary amines affords only the N-acyl urea derivatives, as proven by 13 C- and 15 N-labeling experiments.133 Water soluble carbodiimides are also used in the depolymerization of polyuronides via reduction of their carbodiimide activated carboxyl groups.134 Water soluble spin-labeled carbodiimides react with nucleosides. For example, poly(uridylic) acid is modified on the pyrimidine nitrogen.135 Low concentrations of carbodiimides modify the effector portion of the β-adrenergic receptor of the adenylyl cyclase system in frog erythrocytes.136 DCC blocks the catecholamine activation of adenylyl cyclase in turkey erythrocytes.137 Polymeric fluorescent dyes containing a carboxyl group are used for labeling of proteins via attachment to the amino group of the protein. The reaction is mediated by EDC.138 Also, stereospecific dehydration of threo-β-hydroxy-α-amino acid derivatives is achieved with EDC in the presence of CuCl2 .139
13.3.4 Crosslinking of Proteins Carbodiimides are zero length crosslinking agents which mediate amide bond formation between carboxylic acid groups and amino groups present in the protein. The crosslinking reaction can be intramolecular or intermolecular. Intramolecular crosslinking is often used in the study of the folding of proteins. Intermolecular crosslinking of proteins can be accomplished with carbodiimides by reacting with carboxyl groups forming an intermediate that can be stabilized upon reaction with amines to form a peptide bond without a spacer. Water soluble carbodiimides are often used in crosslinking reactions. The classical example of crosslinking of proteins is the reaction of gelatine using 1-ethyl-3-(2-morpholinyl)-4-ethyl)carbodiimide metho-ptoluenesulfonate.140 The water soluble carbodiimide EDCCl is often used in crosslinking reactions because it is soluble up to 100 mg/ml in water. Carbodiimides react with carboxyl groups in an acidic buffer (pH 4.7–7.5) to form an intermediate O-acylisourea. The O-acylisourea can rearrange to the N-acylurea or it can hydrolyze in aqueous solution. Therefore, stabilization of the intermediate is often necessary for further coupling reactions with an amine. The nucleophiles most often used as a stabilizer are HOBt (N-hydroxybenzotriazole), N-hydroxysuccinimide or sodium N-hydroxysuccinimide-3sulfonate, which produce the most stable intermediate esters by trans-esterification. Many other nucleophiles can also be used. To reduce intramolecular coupling to lysine residues, the carbodiimide mediated coupling should be performed in a concentrated protein solution at a low pH using a large excess of the nucleophile.
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Chemical crosslinking of proteins in combination with mass spectroscopy is often used for the mapping of the three dimensional structures in proteins.141 An example is the crosslinking of hemoglobin.142 The authors also studied the structures of crosslinked neurofibrillary tangles isolated from the brain of an Alzheimer’s disease patient. Monobifunctional crosslinkers, synthesized in the carbodiimide mediated esterification of dicarboxylic acids in the presence of sodium N-hydroxysuccinimide-3-sulfonate, are used in the mapping of protein structures.143 The treatment of collagen fibers with carbodiimides leads to an increase in viscosity.144 Dendrimers, such as polypropyleneimine octaamine, are used in combination with EDC to crosslink collagen.145 Lysozyme and α-chymotripsin, when treated with water soluble carbodiimides, undergo intermolecular crosslinking to give thermostable proteins.146 α-Chymotripsin has also been inactivated using a water soluble carbodiimide.147 Carbodiimides are also used to crosslink wool,148 hair in permanent wave compositions149 and bovine lutotropin.150 Dynamin, a GTP-binding protein, on treatment with EDC, is crosslinked into a dimer.151 The resistance of biological tissues against enzymatic degradation is improved by carbodiimide crosslinking.152 The covalent coupling of a serine protease to a soluble–insoluble polymer (Eudragit) is also accomplished using a water soluble carbodiimide.153 Mycotoxins in foods often contain carboxyl groups suitable for carbodiimide mediated coupling with amino groups in proteins useful for developing immunoassay methods.154 Carbodiimides are also used as fixing agents. For example, intestinal glucagon has been preserved using a water soluble carbodiimide.155 EDC is also used for the fixation of fluorescent and non fluorescent calcium indicators.156 Fixation by carbodiimides is also useful as an ultrastructure preservative for electron microscopy.157 The fixation is most likely caused by crosslinking between carboxyl and amino groups. The structural binding site for the interaction of the carboxyl groups in the protein can be elucidated by mass spectroscopy.158
13.3.5 Carbodiimides in Pharmaceuticals, Herbicides and Pesticides Carbodiimides can be used as stabilizers in thiophosphate based pesticides to prevent hydrolytic degradation.159 Some carbodiimides show insecticidal and acaricidal properties.160,161 Diafenthiuron [1-t-butyl-3-(2,6-diisopropyl-4-phenoxyphenyl)thiourea], an effective insecticide and acaricide, may act via its derived carbodiimide. This transformation is accomplished by sunlight degradation in aqueous solution.162 The carbodiimide causes inhibition of ATP phosphorylation.163 An 3 H-labeled derivative of diafenthiuron, [phenoxy-4–3 H]diafenthiuron, has been prepared to study its photochemical and metabolic degradation.164 The biological activity of N-(pyrid-3-yl)thioureas toward spider mites is sensitive to the kinetics of the formation of the carbodiimides and their photochemical stability.165 Ectoparasiticidal activities are also observed in some carbodiimides.166 The acetylcholinesterase activity of houseflies is inhibited by phosphotriesters obtained from diethyl phosphate and phenols using DCC.167 The miticidal properties of some isothioureas may be due to a controlled release of the effective carbodiimide.168 An N-sulfonylcarbodiimide can be used as a masked oral
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antidiabetic drug, because the active sulfonylurea is generated upon reaction with water.169 Carbodiimides having fungicidal,170 nematocidal171 and antifoliant172 activities are also known. Some carbodiimides also have herbicidal properties.173 Cycloaliphatic carbodiimides are effective post emergence herbicides.174 In recent years thiolated polymers (thiomers) have been developed as oral drug delivery systems. Anionic thiomers are obtained from carboxylic acid groups containing polymers, such as poly(acrylic acid) and cysteine, using EDCCl to form covalent amide bonds. For example, from PAA450 and L-cysteine, thiolated polymers with self crosslinking properties have been developed with improved mucoadhesive properties. The self crosslinking is achieved by oxidative disulfide bonds in the reaction with mucus glycoproteins.175 Cationic thiomers are obtained from chitosan by reaction of thioglycolic acid with the primary amino groups in chitosan mediated by EDCCl. Thiomers are useful to formulate oral delivery systems for insulin, calcitonin and heparin.176 However, carbodiimide treated heparin may lose some of its anticoagulant properties.177 The potential of chitosan for the oral administration of peptides is also under consideration.178 Amphiphilic block copolymers used in the absorption of bile acids to lower cholesterol are also constructed using EDC in the coupling of PS-b-PAA with N,Ndimethylethylenediamine. Some diuretic alkyl- and arylguanidine analogs are synthesized using carbodiimide intermediates.179 Carbodiimide modified glycosaminoglycans were evaluated for anticancer properties. Heparin and chondroitin sulfate (CS) were exposed to EDC to generate the neoglycans neoheparin and neoCS, respectively. Both reduce cell viability by induction of apoptosis of myeloma and breast cancer cells in vivo.180 Chondroitin sulfate has also been covalently attached to collagen using EDC and N-hydroxysuccinimide.181 The use of ethanol during EDC crosslinking allows formation of defined porous collagenous matrices containing bioavailable CS.182 The use of organic solvents is also beneficial in the EDC crosslinking of hyaluronic acid films.183 EDC crosslinked collagen tissue has been found to be useful for corneal implantation.184 The crosslinked porcine derived collagen has optical clarity superior to human corneas. Neoglycoproteins as carriers for antiviral drugs are obtained using EDC for the drug conjugation.185 Carbodiimides are also used in immunoassay techniques for the detection of insecticides and herbicides. An example is the attachment of oppositely charged water soluble polyelectrolytes, using poly(methacrylate) as polyanion and poly(N-ethyl-4vinylpyridinium) as polycation, for attachment to the proteins using EDC in order to detect the herbicide simazine.186 The carbodiimide method (EDC, NHS) is also used for covalent attachment of lysine to wheat gluten.187
13.4
Polymer and Industrial Applications
13.4.1 Use in Polymer Synthesis In the polycondensation of aliphatic dicarboxylic acids with diols, DCC is used to mediate the reaction. In this manner biodegradable and surface active aliphatic polyesters are obtained.188 Also, hydroxycarboxylic acids derived from maleic or succinic acid are homopolymerized in the presence of EDCCl in DMF at room temperature. In this manner
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N-hydroxyethylmaleamide acid 1 is converted into the homopolymer 2.189 HOCH2 CH2 NHCOCH CH COOH + EDCCl −−−→ 1
[OCH2 CH2 NHCOCH CHCO ]n 2 (13.1)
The AB2 monomer, 3,5-bis-(3-hydroxypropyl-1-yl)benzoic acid is converted to a hyperbranched polyester using a carbodiimide to affect the polymerization. In this manner, soluble polyesters with molecular weights ranging from 500 to 11 000 and branching from 0.22 to 0.33 are obtained.190 Using hexahydroxybenzene as the core highly branched dendrimers are prepared with 4-hydroxybiphenyl-4 -carboxylic acid, followed by reaction with 3-PEO-5-PB substituted benzoic acid. All reactions are mediated by DIPCD.191 Carbodiimides are also used as catalysts in the formation of polyamides from dicarboxylic acids and diisocyanates. The carbodiimide catalyst is generated in situ from the diisocyanate using dimethylphospholene oxide as the catalyst.2 In this manner segmented thermoplastic poly(ether amides) and poly(ester amides) are obtained from the acid terminated monomers and diisocyanates by reaction polymerization processes. This reaction is best conducted in a vented extruder because carbon dioxide is the byproduct. The segmented polyamide elastomers are synthesized from MDI (4,4 -diisocyanatodiphenylmethane) and dicarboxylic acids and a carboxylic acid terminated aliphatic polyester, polycarbonate or polyether prepolymer with an average molecular weight of Mn = 500–5000. The dicarboxylic acids used as hard segment extenders are adipic and azelaic acid. Also, poly(ester amide) alloys are obtained using nylon-6,6 or polyesters (PEA/PBT). By using mixtures of adipic and azelaic acids as monomers in the reaction with MDI, transparent copolymers are obtained useful as engineering thermoplastics. Also, copolyamides obtained from mixtures of isophthalic (IPA) and azelaic acids and MDI/TDI mixtures have been made. TDI in combination with MDI is used to lower the melt temperature of the IPA/MDI blocks to allow thermoplastic processing. Sugar carbodiimides are key intermediates in the synthesis of some glycoconjugates.192
13.4.2 Use in Polymer Applications The chemistry of poly(carbodiimides) is discussed in Chapter 12, and because of the inherent problem of intermolecular crosslinking of linear polymer chains via cycloaddition reactions, only thermoset poly(carbodiimides) are of commercial importance. The high thermal stability of thermoset poly(carbodiimides) has prompted research into the feasibility of producing a new generation of thermally more stable foams derived from polymeric MDI (PMDI). We demonstrated in 1985 that low density poly(carbodiimide) and poly(carbodiimide isocyanurate) foams can be readily produced from PMDI using a phospholene oxide or a combination catalyst (phospholene oxide/tris(3-dimethylamino)propylhexahydrotriazine), respectively.193 It was demonstrated that open cell rigid foams with excellent thermal properties and low smoke densities can be produced on a commercial scale. Poly(carbodiimide isocyanurate) can also be made by mixing a carbodiimide groups containing prepolymer with a trimerization catalyst and a blowing agent.194 The recent trend to abolish chlorofluorocarbon (CFC) blowing agents in rigid foam manufacture has prompted a new look on PMDI derived foams containing partial carbodiimide structure. Since carbon dioxide, generated in carbodiimide formation, can be used
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as a blowing agent, significant reductions in the use of CFC or HCFC blowing agents can be achieved. The partial carbodiimide containing foams are readily made by adding small amounts of a phospholene oxide catalyst to the catalyst system. In this manner poly(urethane) and poly(isocyanurate) foams can be made containing carbodiimide as well as carbodiimide/isocyanate adducts in their backbone structures. New polyols have also been formulated to be used in carbodiimide containing foams or water blown foams.195 Polymers with pendant carbodiimide groups have been synthesized and used as solid phase dehydration agents. Many other modified polymers with carbodiimide segments in the polymer backbone have also been synthesized. For example, crosslinked organosilicon carbodiimide polymers are used in insulating coatings and high temperature paints.196 Crosslinked carbodiimide containing polymers with electrical insulating properties are made from MDI using a phospholene oxide catalyst.197 Addition of about 1 % of the linear MDI derived polycarbodiimide to nylon improves the relative melt strength and viscosity.198 Poly(carbodiimides) are also used as fiber reinforcements199 and in strengthening of glass fiber compositions.200 Poly(carbodiimides) are sometimes used as adhesive primers.201 Film forming carbodiimide homo- or copolymers have been used in microencapsulation techniques for pressure sensitive copy paper.202 Oligomeric acylureas are obtained from polyunsaturated carboxylic acids and carbodiimides as monomers for coatings.203 Artificial skin substitutes based on cultured autologous keratinocytes are crosslinked with EDC to increase their strength.204 Hyaluronic acid films, crosslinked with EDC, glycerol and 5 % Paclitaxel, prevent post surgical adhesion.205 The control of pH alters the type of crosslinking produced by EDC treatment of vascular grafts.206 A polyester arterial prosthesis has been coated with gelatin and crosslinked with a carbodiimide to improve properties.207 Crosslinked collagen tissue, using EDC and N-hydroxysuccinimide, is used in cornea implant applications.208 Dicyclohexylcarbodiimide is an inducer of permeability transition in mitochondria.209 Poly(dimethylsiloxane), on treatment with poly(ethylene glycol) mediated by carbodiimide, produces stable, hydrophilic, protein resistant coatings.210 Also, hydrogels, used as biological glue, are obtained from poly(L-glutamic acid) and gelatin mediated by a water soluble carbodiimide.211 The delivery of antibacterial proteins from prosthetic heart valves is also accomplished using EDC crosslinked gelatine hydrogels.212 The carbodiimide mediated coupling of acrylic polymers and collagen occurs via amino functional groups.213 A biocompatible high strength glue is prepared by EDC mediated reaction of citric acid with collagen.214 DOPA (3,4-dihydroxyphenylalanine) modified PEG hydrogels are prepared using a water soluble carbodiimide in their construction.215 Polyorganosilyl carbodiimides are obtained from silyl halides and cyanamide or bis(trimethylsilyl)carbodiimide. On pyrolysis at 1100 ◦ C they are converted into amorphous Si/C/N solids or polycrystalline silicon dicarbodiimides.216 Likewise, GaN is obtained from carbodiimide based polymeric precursors.217 Polymeric carbodiimide precursors for ceramic materials are also obtained from BCl3 218 and TiCl4 .219 Using Ti(NEt2 )4 as starting reagent, chlorine contaminations of the derived ceramic materials are avoided.220 Poly(carbodiimidogermylene), obtained from bis(triethylgermyl)carbodiimide and dichlorogermyl dioxane, is a semiconductor.221 Carbodiimides are also used to coat glass beads or modified polyacrylamide beads with polyamines.222 Imunologically active species can also be joined to glass treated with 3triethylsilylpropylamine using carbodiimides.223
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13.4.3 Polymer Modifications Syndiotactic poly(methacrylic acid) is esterified with alcohols to give alternate ester linkages using carbodiimides.224 The interaction of poly(2-ethylhexyl methacrylate) latex blend films containing either carboxyl or carbodiimide groups have been studied to assess the effect of polymer interdiffusion versus crosslinking.225 Water soluble carbodiimides are also used to couple ethyl glycinate with poly(acrylic acid).226 Treatment of carboxyl group containing crosslinked polystyrene resins with DCC causes further crosslinking via anhydride formation.227 Butadiene/acrylo nitrile copolymers with 0.09 % carboxyl group content have been crosslinked with the difunctional carbodiimide PhN C N(CH2 )6 N C NPh.228 The vulcanization of rubbers containing small amounts of carboxyl groups is also accomplished using carbodiimides.229 Polyoxymethylene has been prepared by polymerizing anhydrous monomeric formaldehyde with catalytic amounts of diisopropylcarbodiimide in toluene.230 The hardening of amino/carboxyl emulsion polymers can be conducted using ditolylcarbodiimide.231 Carbodiimides are also used as gelatin hardeners promoting crosslinking via a reaction of carboxyl with amino groups.232 Antifoggants are also formulated with carbodiimides.233 A thermographic process utilizing solid carbodiimides is also known.234 Silica coated with poly(ethyleneimine) is crosslinked with ethylenediaminetetracarboxylic acid mediated by EDCCl. The sorbent exhibits a high capacity for metal complexation and a good stability in an acidic medium.235 The modification of hydroxyl group containing polymers with carbodiimides affords more hydrophobic polymers.236 Cellulose, containing free hydroxyl groups, reacts with carbodiimides in the presence of copper salts to generate groups which can be dyed with acid dyes.237 Hydroxyalkyl methacrylate gels, on treatment with carbodiimide and DMSO, produce aldehyde group containing polymers which are used as carriers for biologically active compounds.238 Fluoro group containing aliphatic carbodiimides are used to impart oil and water repellent finishes to nylon and polyester fabrics239 and to leather materials.240 Gold nanoparticles are covalently linked to oligonucleotides using DIPCD to mediate the reaction. The gold nanoparticles are used as powerful biological sensors.241 Sequence specific detection of DNA is also accomplished with an electrochemical DNA sensor (E-DNA). The sensor is constructed by covalently attaching ferrocene, mediated by EDC, to a hairpin like DNA stem loop structure attached to a thiolated gold electrode. On hybridization with a complementary target sequence a large change in redox current is observed by separation of the ferrocene label from the electrode surface.242 A similar E-DNA sensor is constructed by carbodiimide mediated attaching of methylene blue (MB) to a DNA aptamer. On hybridization the MB end of the signaling probe allows the MB to collide with the electrode surface thereby generating a seven fold increase in redox current.243 Some aptamers are capable of distinguishing between on and off states of messenger RNA riboswitches.244
13.4.4 Carbodiimides as Stabilizers Oligomeric carbodiimides are useful stabilizers for ester based polymers, such as polyesters, polyester based polyurethanes, polyether based polyurethanes, polyether based poly(urethane ureas) and polycarbonates. The scavenging of carboxyl end groups or carboxyl groups, generated in the hydrolysis of polyesters, with carbodiimide prevents hydrolysis of the polymers caused by the catalytic effect of the carboxyl groups. Neumann
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and Fischer discovered this application in 1962, when they synthesized oligomeric carbodiimides from sterically hindered aromatic diisocyanates.245 The oligomeric carbodiimides are non volatile, resistant to extraction, and have good compatibility with many polyester or polycarbonate based polymers. For example, in a thermoplastic polyurethane elastomer, made from a high acid number poly(tetramethylene adipate) and MDI, 2 % of the carbodiimide stabilizer is sufficient to retain 90 % of its properties after nine weeks immersion in 70 ◦ C water. The unstabilized polymer completely disintegrates in the test.246 Also, addition of an oligomeric carbodiimide derived from MDI to poly(butylene terephthalate) stabilizes the melt viscosity of the polyester.247 The reaction kinetics between polyester acids and carbodiimides in polyester polyol and polyester polyurethanes is second order.248 It was also shown that the polymer lifetime increases to ten fold at 35 ◦ C in 100 % relative humidity by using 3 wt. % of a monomeric carbodiimide.249 Oligomeric carbodiimides can also function as chain mending agents, preventing loss of molecular weight. Optimal stabilizer packages for polyether based polyurethanes and polyether based poly(urethane ureas) also contain oligomeric carbodiimides in combination with antioxidants.250 Oligomeric carbodiimide stabilizers are commercially available under the trade name Stabaxol from Rhein Chemie, a subsidiary of Bayer. Bis-o-tolylcarbodiimide (Stabaxol E-443) is a liquid, while the oligomers derived from 2,2 ,6,6 tetraisopropyldiphenylcarbodiimide are waxy solids (Stabaxol M) and the polymers made from 2,6-diisopropylphenyl isocyanate and 2,4,6-triisopropylphenyl isocyanate as a chain stopper are solid powders (Stabaxol P, mol. weight 3 000 or P-100, mol. weight 10 000). Applications for the Stabaxol stabilizers include thermoplastic polyester urethanes, polyesteramide thermoplastic elastomers, castable polyester urethanes, polyester polyols, monofilament PET fibers, polycarbonates, polycarbonate/PET blends, EVA copolymers and poly(caprolactones).251 The thermal stabilization of poly(ethylene sulfide) is also accomplished with 4 % hexamethylenebis(t-butyl)carbodiimide and 2 % diphenylacetylene.252 Also, alternating carbon monoxide/ethylene copolymers are stabilized using aromatic carbodiimides.253 Carbodiimides have also been proposed as stabilizing agents for cinnamate ester based photo-polymers.254 Also, adhesion of the gelatinous photographic materials to a poly(ethylene terephthalate) support is improved through the addition of carbodiimides.255 The storage life of liquid polymeric isocyanates (PMDI) is improved by the addition of carbodiimides, which scavenge hydrolyzable chlorides. Solventless polyurethane coatings are also best formulated with carbodiimide modified MDI (Isonate 143-L). The carbodiimide group is generated on heating, and it can be utilized for further crosslinking or for stabilization of the polymer chains, especially in polyester based systems.256 Polyformaldehyde is stabilized by esterification of hydroxyl end groups with anhydrides or ketenes using carbodiimides to mediate the reaction.257
13.4.5 Carbodiimides in Dye Applications Fluorescent analogs of DCC are N-cyclohexyl-N -[4-(dimethylamino)-αnaphthyl]carbodiimide (NCD-4) and N-cyclohexyl-N -(1-pyrenyl)carbodiimide (PCD) which form fluorescent conjugates with mitochondrial electron transport particles or purified ATPase vehicles.258 N-cyclohexyl-N -(4-dimethylamino)-α-naphthylcarbodiimide
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inactivates the Ca2+ -ADPase, but addition of Mg2+ ADP protects against this inactivation.259 Also, the topographical organization of cytochrome b in the yeast mitochondrial membrane is determined with NCD-4.260 PCD is also used in site directed labeling of proteolipid (hydrophobic membrane proteins). PCD reacts specifically with protonated carboxyl groups to form stable, fluorescent N-acylurea end products.261 Also, site directed labeling of ATP synthases from I. tartaricus and E. coli is performed with PCD.262 The fluorescent carbodiimide is also used in the mapping of the chloroplast coupling factor in asolectin vesicles.263 Treatment of wool or hair with carbodiimides improves the wash fastness of applied dyes.264 The cosmetic qualities of bleached hair can be improved by treatment with N-cyclohexyl-N -(N-methylmorpholino)carbodiimide.265 N-ethyl-N -(3-trimethylammonio)propylcarbodiimide fixes the red dye 2-nitro-4[(βaminoethyl)amino]aniline to hair, most likely via an amide linkage.266 The coupling of a phosphorous dyestuff to cellulosic materials can also be accomplished using a carbodiimide.267 EDC also enhances the luminescence of poly(3,4,5-trihydroxybenzoate ester) dendrimers.268 The carbodiimide mediated attachment of dye molecules, such as 5(6)carboxyfluoresceine or rhodamine B to the model compound penylethylamine proceeds in 78 % and 63 % yields, respectively, using diisopropylcarbodiimide, three equivalents of pyridinium-p-toluenesulfonate (PPTS) and two equivalents of diisopropylethylamine (DIPEA). The above conditions are especially useful when the sodium salts of dyes are used. Examples are eosine Y, erythrosin B and phloxine B because yields of >90 % are obtained when the reactions are conducted in DMF in the presence of HOBt.269 Monodispersed chitosan conjugated Fe3 O4 nanoparticles are fabricated from chitosan via carbodiimide activation. The nanoparticles are useful for the removal of acid dyes.270
13.4.6 Other Applications An analytical HPLC method for methanol involves esterification with naphthylmethylamino-oxo-butanoic acid mediated by EDC and DMPA. The method can simultaneously determine methanol, ethanol and 1-propanol.271 Similarly, hydroxyl functions are labeled with 2-(prenyloxymethyl)benzoic acid using DCC and DMPA.272 Also, the simultaneous measurement of thyroxine and thyrotropin from newborn dried blood spot specimens is conducted using EDCCl and N-hydroxysuccinimide-3-sulfonate.273 Alginate hydrogel membranes, crosslinked with EDC, can be used in the pervaporation separation of ethanol–water mixtures.274 Asymmetric membranes, fabricated from poly(acrylonitrile-co-maleic acid) are immobilized with heparin and/or insulin in the presence of EDC to improve their surface properties.275 Also, poly(lactic acid)/poly(ethylene-co-vinyl acetate) nerve guide tubes are surface modified with elastin and laminin mediated by carbodiimides.276 Carbodiimide treatment potentiates the anticalcification effect of α-aminooleic acid on glutaraldehyde fixed aortic wall tissue.277 Diamine extended glutaraldehyde and carbodiimide crosslinks act synergistically in mitigating bioprosthetic aortic wall calcification. Amide crosslinking mediated by EDC is an alternative to glutaraldehyde fixation.278
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An improved system for the delivery of antisense oligonucleotides uses a carbodiimide mediated covalent conjugate with a copolymer of vinyl pyrrolidone and 2-hydroxyethyl methacrylate.279
13.5
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acids, esterification using carbodiimides 113–115 N -acyl-S,S-dimethylsulfilimines 77 α-acylamino-β-thiopropionic acids 98 acylcarbodiimides 173–181 reactions of 180 synthesis of 174–180 from carbonimidoyl dichlorides or chloroformamidines 178 from cyanamides 179 from isocyanates 177 from other carbodiimides 179 from thioureas 174–176 from ureas 176–177 N -acylchloroformamidines 126 N -acylketene imines 72 acyloxyketenes 72 N -acyltetrazoles 104 N -acylureas 88, 93 adenosine 5-phosphate (A5P) 95 adenosine-5-phosphoric acid amide 95 adenosinetriphosphate (ATP), synthesis of 94 5-adenylic acid 95 alcohols, reactions with alkyl- and arylcarbodiimides 83–89 aldehydes, aromatic 61 aldoximes 88 aliphatic carbodiimides homopolymerization of 45 infrared spectra 4 reactions with arenesulfonyl isocyanates 48 water soluble 2 Chemistry and Technology of Carbodiimides Henri Ulrich C 2007 John Wiley & Sons, Ltd. ISBN: 978-0-470-06510-5
aliphatic imidoylcarbodiimides, carbodiimide infrared band 173, 174 α-alkoxycarbonylcarbodiimides 90, 129 alkyl halides, reactions with trimethylsilyl carbodiimide 35 N -alkyl-N -[4-(5-phenyloxazol-2-yl)benzyl]carbodiimides 11 N -alkyl-N -trimethylsilylcarbodiimides, [2 + 2] cycloaddition reaction of haloketenes with 188 S-alkyl-N ,N ,N -trialkylisothioureas 207 alkylarylcarbodiimides 9 alkylbis(trimethylsilyl)phosphanes 80 alkylcarbodiimides reactions of 41–130 condensation 113–125 cycloaddition 46–76 heterocycles from 104–113 insertion 78–83 nucleophilic 83–104 oligomerization and polymerization 41–46 with ylides 76–78 synthesis of 10–36 by dehydration of ureas 16–17 by nitrene rearrangements 25–28 by thermolysis reactions 29–33 from cyanamides 25 from haloformamidines or carbonimidoyl dihalides 28–29 from isocyanates or isothiocyanates 17–25 from thioureas, isothioureas and selenoureas 10–15 O-alkylisoureas 84, 85
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Index
O-alkylmonoisoureas 84 1-(alkyoxycarbonyl)-3-(arylmethyl)thioureas 175 N -allyl-N -4-methoxyphenylcarbodiimide 162 aluminum amidinate complexes 79 amidines 82 amidoximes, Tiemann rearrangement of 25 aminals, N ,N -substituted α,α-dioxoketene 82 amines, reactions with carbodiimides 99 amino acyl adenylates 95 5-amino-1H-1,2,3-triazoles 66 3-amino-2-arylaminoquinazolin-4(3H)-ones 107 1-amino-isoquinolines 158 aminoalcohols, reactions with carbodiimides 100 aminoquinazolines 173 o-aminothiophenols 110 ammonia, reactions with carbodiimides 99 anhydrides 89, 113 carboxylic acid anhydrides 170 cyclic anhydrides 93, 94 anthranilic acid 106 N -(1-anthranyl)-N -octadecylcarbodiimide 249 antibiotics, synthesis of 261 antidiabetic drugs 268 arenesulfonyl isocyanates, reactions with aliphatic carbodiimides 48 N -arenesulfonyl-N -alkylcarbodiimides 3, 205 N -arenesulfonyl-N -phenylcarbodiimides, reaction with HN3 210 arenesulfonylcarbodiimides 31 reactions with oxalyl chloride 210 arenesulfonylthioureas 99 aromatic carbodiimides 2 infrared spectra 4 stability of 3 3-aroyl-2-(2-aryl-4,5-dioxo-4,5-dihydro3-furyl)quinoxalins 72 aryl isocyanates 42 1-aryl-2-arylamino-2-imidazolines 100 3-aryl-2-arylamino-4-arylimino-quinazolines 43 3-aryl-2-quinoxalinyl(aroyl)ketenes 72 6-aryl-4-arylimino-1-phenyl-6-trifluoromethyl1,4,5,6-tetrahydropyrazolo-[4,3-e][1,3]oxazines 170–171 N -aryl-N -[4-(5-phenyloxazol-2-yl)benzyl]carbodiimides 11 N -aryl-N -trifluoromethylcarbodiimides, dimers and trimers 43 2-arylamino-1,3-thiazolines 100 2-arylamino-3-ferrocenecarbonyl quinolines 157
2-arylamino-6H-pyrano[2,3-f]benzimidazole6-ones 14 2-arylaminobenzothiazoles 110 arylcarbodiimides 75 N -2-chloroethyl-N -arylcarbodiimides 171 o-carboxyethyldiarylcarbodiimides 107 reactions of 41–130 cycloaddition 46–76 oligomerization and polymerization 41–46 with ylides 76–78 synthesis of 10–36 by dehydration of ureas 16–17 by nitrene rearrangements 25–28 by thermolysis reactions 29–33 from cyanamides 25 from haloformamidines or carbonimidoyl dihalides 28–29 from isocyanates or isothiocyanates 17–25 from thioureas, isothioureas and selenoureas 10–15 see also diarylcarbodiimides; unsaturated arylcarbodiimides aza-Wittig reaction 2, 20–25, 251, 260 azides 34 2-azido-4,6-dichlorotriazine 231 azidoformat, photolysis of 179 aziridincarboximidoyl chlorides 167 aziridines 65 N -aziridinyliminoureas 176 azoniaallene salts 63, 64 barbiturates 92 5-diaminomethylenebarbiturates 81 batzelladin alkaloids 156 benzo[b]carbazoles 75 benzotriazoles 112 benzoyl-sulfene, reaction with DCC 60 biguanides 102 biological applications, of carbodiimides 261–268 bis-1,1-difluoro-2,2,2trichloroethylcarbodiimide 166 bis-1,2,2,2-tetrachloroethylcarbodiimide 166 N ,N -bis-(2-vinyloxy)ethylcarbodiimide 148 1,3-bis-(2-vinyloxyethyl)thiourea 148 bis-alkylideneureas 170 reactions with phosphorus pentachloride 167 triphenylphosphine dibromide 167 bis-α-chlorocarbodiimides 169, 170 bis-boc-carbodiimide 11 bis-carbodiimides 252 bis-N -acylureas 93 bis-sugar carbodiimides 21–22 bis-t-butylcarbodiimide 35
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Index bis-trichlorocarbonylcarbodiimide 177 bis-trimethylsilyl mercury 81 bis-trimethylsilylcarbodiimide 79, 183 N ,N -bis[1-(4-methylphenyl)2-phenylvinyl]carbodiimide 149 bis[[4-(2,2-dimethyl-1,3-dioxoyl)]methyl]carbodiimide (BDDC) 2 bis(4-dimethylaminophenyl)carbodiimide 90 bis(α-bromo)carbodiimides 167 bis(α-chloro)carbodiimides 167 bisaryliminophosphoranes, synthesis of cyclic carbodiimides from 231–236 2,5-bis(cyanimino)-2,5-dihydrothieno[3,2-b]thiophenes 189 N ,N -bis(glycopyranosyl)cyanamides 191 bis(perchloroethyl)carbodiimide 165 N ,N -bis(t-butoxycarbonyl)-protected guanidines 251 N ,N -bis(trialkyl) ureas 184 bis(trifluoromethyl)carbodiimide 35, 167 bis(trifluoromethyl)thioketene, reaction with carbodiimides 58 bis(trimethylsilyl)carbodiimide cyanoimines from 188 phosphorus substituted carbodiimides from 202, 203 reactions of 189, 190, 191 bis(trimethylstannyl)carbodiimide 202 bis(triphenylmethyl)carbodiimide 36 bis(triphenylsilyl)carbodiimide 186 bis(triphenylstannyl)carbodiimide 36, 186 bis(trityl)carbodiimide 25 blowing agents 269–270 boron carbodiimide oligomers 248 bovin trypsin 264 bromophenylacetylene 59 Burgess reagent 17 t-butyl isothiocyanate 32 1-t-butyl-2-carbomethoxyazetidine 65 N -t-butyl-N -dimethylaminocarbodiimide 198 N -t-butyl-N -phenylcarbodiimide 31 N -t-butyl-N -trimethylmetalcarbodiimide 81 t-butylimido zirconocene complexes, exchange reaction with methyl isothiocyanate 35 carbamic acid salts 100 carbamoylcarbodiimides 175 carbamoylthiocarbodiimides 175 carbodiimide foams 3 carbodiimide terminated dithiolane self assembly monolayers (SAMs) 263 carbodiimides 13 C-NMR spectra 4 15 N-NMR spectra 4 applications of 259–281
285
bond angles 3–4 cycloadducts derived from 52, 56 [2 + 2] 49 [2 + 4] 74 effect of substituents on stability of 4 halogenation of 166 with heterocyclic substituents 147 imidozirconcene complexes [2 + 2] cycloaddition reactions with 54 industrial applications 3 in pharmaceuticals, herbicides and pesticides 267–268 in polymer synthesis 269 protein and DNA synthesis 261–263 Raman spectra 4 reactions with ammonia, amines, amine derivatives and azides 99–104 dimethyl sulfate 42 isocyanate salts 50 phenylcarbonyl isocyanate 50 reactivity of 10 review articles on 3 structure of 1 synthesis of 1 acyl-, thioacyl- and imidoylcarbodiimides from 179 phosphorus substituted carbodiimides from 202–203 silicon substituted carbodiimides from 186 starting materials for 9 sulfur substituted carbodiimides from 208 toxicity of 5 uses of in attachment of biomarkers to polypeptides 1 in organic synthesis 1–2 as stabilizers for polyester based polymers 246 carbonimidoyl dichlorides 29 synthesis of acyl-, thioacyl- and imidoylcarbodiimides from 178 halogenated carbodiimides from 166–167 phosphorus substituted carbodiimides from 200–201 sulfur subsituted carbodiimides from 206–207 carbonimidoyl dihalides, synthesis of alkyl- and arylcarbodiimides from 28–29 o-carboxyethyldiarylcarbodiimides 107 carboxylic acid amides 116 carboxylic acids reaction of carbodiimides with inorganic and 89–97
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Index
carboxylic acids (Continued) reactions with hydrogen peroxide 93 reactions with N ,O-dimethyl-hydroxylamine 101 N -o-carboxylphenyl-N -phenyl thiourea 17 castanospermin 118 catalysts, for methathesis reactions 29–30 α-chloro isocyanate, reaction with N trimethylsilyl-N -phenylcarbodiimide 35 2-chloro-1-methylpyridinium iodide (Mukaiyama reagent) 13 N -chloroamidines 28 3-chlorobenzothiazole-S-dioxide 34 α-chlorocarbodiimide 170 p-chlorodiphenylcarbodiimide 65 N -2-chloroethyl-N -arylcarbodiimides 171 chloroethyl-parabanic acids 171 chloroformamidine hydrochlorides 17, 28, 126 chloroformamidines 126 synthesis of acyl-, thioacyl- and imidoylcarbodiimides from 178 chloroformamidinium salts 127 α-chloroheterocumulenes 190 α-chloroisocyanates 165 N -4-chlorophenylcarbonyl-N t-butylcarbodiimide 178 α-chlorosulfilimines 35 chondroitin sulfate 268 α-chymotripsin 267 collagen coupling to acrylic acid polymers 265 crosslinking of 124, 267 condensation reactions, use of carbodiimides in 113–125 copolyamides 125 copolymers, crosslinked 252–253 creatin kinase, grafting to collagen film 253 crosslinking agents 2 cyanamides 1, 129 fluorination of 165 N ,N -bis(glycopyranosyl)cyanamides 191 synthesis of acyl-, thioacyl- and imidoylcarbodiimides from 179 alkyl- and arylcarbodiimides from 25 phosphorus substituted carbodiimides from 201–202 silicon substituted carbodiimides from 183–184 1-cyano-N ,N -disubstituted formamidines 103 2-cyanoarylcarbodiimides 106 cyanoformamidines 70 1,2-disubstituted 3-cyanoguanidines 102 cyanoimines 188
cyclic carbodiimides 227–242 oligomeric 247 reactions of 236–241 cycloaddition 238–240 with methyloxalyl chloride 241 nucleophilic 236–237 oligomerization 237 with oxalyl chloride 240 with phosgene 240 synthesis of 229–236 by nitrene rearrangement 230–231 from bisaryliminophosphoranes and isocyanates or isothiocyanates 231–236 from cyclic thioureas 229 cyclic diketones, [2+4] cycloadducts derived from carbodiimides and 74 cyclic nitrones, reaction with di-t-butylcarbodiimide 125 cycloaddition reactions 46–76, 260 [2 + 2] 60–63 [2 + 2] across C N bonds 46–55 [2 + 2] across C C multiple bonds 55–60 [2 + 3] 63–67 [2 + 4] 68–76 of acyl-, thioacyl-, and imidoylcarbodiimides 180 of cyclic carbodiimides 238–240 of halogenated carbodiimides 168–169 of silicon substituted carbodiimides 188–190 cycloadducts 47 [2 + 2] 50 [2 + 2] derived from carbodiimides and isocyanates 49 [2 + 4] 50, 51 [2 + 4] derived from carbodiimides and cyclic diketones 74 derived from isothiocyanates and carbodiimides 52 derived from ketenes and carbodiimides 56 cyclobutane aluminum complex, reaction with carbodiimides 58 N -(1,3,5-cycloheptatrienyl)N -phenylcarbodiimide 149 N -cyclohexyl-N -(1-pyrenyl)carbodiimide (PCD) 272 N -cyclohexyl-N -(2,2,6,6-tetramethylpiperidineoxy)carbodiimide 259–260 N -cyclohexyl-N -[4-(dimethylamino)α-naphthyl]carbodiimide (NCD-4) 272 N -cyclohexyl-N -(4-methylmorpholine-betayl) carbodiimide p-toluenesulfonate 90 N -cyclohexyl-N -isopropyl-carbodiimide 10 N -cyclohexyl-N -(N -methylmorpholino)carbodiimide 273 cyclopentadienyl iron dicarbonyl 62
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Index cyclopentadienyl-bis(ethylene)cobalt 63 cycloreversion reactions 60 DCC (dicyclohexylcarbodiimide) 5, 9, 10, 29, 33, 259, 260, 261 1 H-NMR study 4 rate of reaction with aliphatic acids in THF 90 reactions with 3,4-methylenedioxyphenylpropiolic acid 91 3,6,9-trioxaundecanoic dicarboxylic acid 93 chlorosulfonyl isocyanate 49 dithiocarboxylic acids 98 formic acid 91 monothiocarboxylic acids 98 phenylpropiolic acid 91 N - p-toluenesulfonyl-N cyclohexylcarbodiimide 47 in synthesis of polypeptides 2 7-deazaxanthine-9-propionic acid 122 dehydration reactions 260 di-2-pyridylcarbodiimide 43 di-α-naphthylcarbodiimide 30 di-t-butylcarbodiimide 2 N ,N -di-t-butylcarbodiimide 10 diafenthiuron 267 N ,N -dialkyl-1,3-diazocine-2,4,8-triones 82 1,3-dialkyl-2,4-bisalkylimino-1,3-diazetidines 41 5-(dialkylamino)-1,2,4-triazoles 129 2-dialkylamino-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-ones 108 ω-dialkylaminoalkylcarbodiimides 24 ω-dialkylaminoalkylphosphoramidates 24 dialkylaminothiocarbamoyl isothiocyanates 53 dialkylcarbodiimides, stability of substituted 3 diallylcarbodiimides 147 N ,N -diaminoguanidine 102 5-diaminomethylenebarbiturates 81 4,5-diaryl-1,2,3,5-thiaoxadiazole-1-oxide 26 diarylcarbodiimides 25, 61, 79, 100 insertion reactions 79 reaction with acidic phenols 85 see also arylcarbodiimides; unsaturated arylcarbodiimides diarylthioureas 13 1,3-diaza-2-azoniaallene salts 64 1,3-diazacyclodeca-1,2-diene 240 1,3-diazahepta-1,2-diene 237 diazaphosphetidinones 32 1,3-diazaphospholidine oxides 18 diazetidines 42 dicarboxylic acids, reactions with carbodiimides 92
287
2,2-dichloro-1,3,5-triazinium salts 64 dichlorodehydrotetrazepine 228 dichloromethylene ammonium chloride 127 dichloromethylsilane 187 1,3-dicyclohexyl-2,4-bis(cyclohexylimino)1,3-diazetidine 42 N ,N -dicyclohexyl-N,N -dipropionylurea 82 N ,N -dicyclohexylcarbodiimide see DCC dicyclohexylcarbodiimide see DCC α, β-didehydro amino acid esters 123 α, β-didehydroamino acids 122 diethyl 2,4-bis(diethylamino)-cyclobutadiene1,3-dicarboxylate 68 diethyl N -dimethylaminophosphoramidate 196 diethylcarbodiimide 26 2,6-diethylphenyl isocyanate 19 N ,N -diferrocenylcarbodiimide 4 α-difluoro isocyanates 166 difluorocyanamide 165 N ,N -dihalocarbodiimides 165 2,3-dihydro-2-imino-4-oxo-1,3-oxazines 69 4,5-dihydro-5-imino-1H-1,2,4-triazolium salts 64 5,6-dihydro-7H-imidazo[1,2-b][1,2,4]triazoles 176 diisocyanatocarbodiimides 46 diisopropylcarbodiimide 2, 4, 5, 9, 61, 73, 83, 126, 260, 261 reaction with 1,2-bistrifluoromethylacetylene 58 dimesitylgermaniumdicarbodiimide oligomers 248 N -(5,5-dimethyl-3-oxo-1-cyclohexenyl)N -arylcarbodiimides 155 S,S-dimethyl-N -sulfilimines 77 S,S-dimethyl-N -sulfonylsulfilimines 77 4,4’-dimethyl-oxyimidazolidine-2,5-dithione 127 N -(4-dimethylaminophenyl)-N 2,6-dimethylphenylcarbodiimide 48 N -(4-dimethylaminophenyl)-N methylcarbodiimide 47 reaction with methyl isothiocyanate 51 N -(4-dimethylaminophenyl)-N phenylcarbodiimide 48 dimethylcarbodiimide 3, 4, 44 1,3-dimethylphospholine-1-oxide 18 2,2’-dinitrodiphenylcarbodiimide 112 1,1-dioxo-2-(N -isopropylimino)-3-isopropyl5,5-diphenylthiazolidine 4-one 55 DIPCD see diisopropylcarbodiimide 1,3-diphenyl-2,4-diphenylimino-1,3-diazetidine 43 1,3-diphenyl-2-azaallyl lithium 67
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Index
2,6-diphenyl-4-benzoylimino-1,3,5-oxadiazine 177 diphenyl-methane diamine 128 diphenylcarbodiimide 31, 33, 102, 128 [2 + 4] cycloaddition reactions 68 cycloaddition reaction with disubstituted acetylenes 58 effect of subsitutuents on rate of hydration 83 heating with N -methylhexamethyldisilazane 44 reaction with phenylacetylene 59 reaction with trimethylsilyl azide 104 4,4’-diphenylmethane diisocyanate (MDI) 3, 44 diphenylnitryl imine 63 dipivaloylketene 70, 71 dipyridyl-(2) carbodiimide 147 disilylcarbodiimide oligomers 187, 248 disilylcarbodiimides 183 α-disubstituted malonic acids 92 2,3-disubstituted pteridin-4(3H)-one derivatives 109 dithiocarbamic acids 99 dithiocarboxylic acids, reaction with DCC 98 di(triphenylmethyl)carbodiimide 5 divinylcarbodiimides 149 DNA, synthesis of 261–263 DNA functionalized single walled carbon nanotubes (SWNT) 1, 263 dyes, carbodiimides and 272–273 EDAC see EDCCl EDC 2, 4, 5, 96, 253 applications of 259, 260, 264, 273 rate constants for hydrolysis of 83 EDCCl 2, 5, 122, 123, 259, 260 applications of 259, 260 polymeric 250 enyne carbodiimides 75, 147 heterocyclic compounds derived from 160, 161 ethanol–water mixtures, separation of 273 ethyl 2-methylmalonate 69 2-ethyl-1,3-dimethyl-1,3,2-diazaphospholine2-oxide 245 1-ethyl-3-(3-dimethylamino)propylcarbodiimide see EDC 1-ethyl-3-methylphospholine-1-oxide 18 N -ethyl-N -(3-dimethylamino)propylcarbodiimide see EDC ethylene-1,1-bis(triphenylphosphonium)2,2-bis(phenyl amide) 78 ferrocene-1,1 -dicarboxylic acid 90, 114 O-ferrocenoylisourea 90 ferrocenyl carbodiimides 157
ferrocenylcarbodiimide (FCDI) 2 fixing agents 253 foams 3, 46, 252 formamidines 128 1-cyano-N ,N -disubstituted formamidines 103 Fuzeon 261 Geiger-Koenig method 117, 119 gem dicarbodiimides 252 germaniumdicarbodiimide 248 glycolipids 118 glycopeptides 118 glycosyl carbodiimides 11 1-(β-glycosyl)-5-amino-1H-tetrazole 103 guanidines N ,N -bis(t-butoxycarbonyl)-protected guanidines 251 reaction with carbodiimides 102 tri-alkylguanidines 128 tricyclohexyl guanidine 33 see also polyguanidines α-haloalkylcarbodiimides 165 haloformamidines, synthesis of alkyl- and arylcarbodiimides from 28–29 halogenated carbodiimides 165–172 reactions of 168–171 cycloaddition 168–169 nucleophilic 169–170 synthesis of 165–168 by halogenation of carbodiimides 166 from α-haloisocyanates 165–166 from carboimidoyl dichlorides or imidoyl chlorides 166–167 α-haloisocyanates reaction with N -trimethylsilylN -carboxyethylcarbodiimide 177 synthesis of halogenated carbodiimides from 165–166 haloketenes reaction with N -trimethylsilylN -alkylcarbodiimides 55 reactions with N -alkyl-N -trimethylsilylcarbodiimides 188 herbicides 268 heterobetaines 66 heterocumulenes cycloaddition reactions 46–47 insertion reactions 33, 78 heterocycles 260 enyne carbodiimides 160 from carbodiimides 104–113 six-membered ring 127
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Index heteroquinoides 188 hexamethylene diisocyanate 17 reaction with a phospholene oxide catalyst 45 hexaphenylcarbodiphosphorane 78 homocyclic carbodiimides, synthesis of 227 homopolymerization, of carbodiimides 243 homopolymers, crosslinked 252–253 hyaluronic acid 266 hydantoins 87 hydrazine 102 α-hydro-perfluoro-isopropyl isocyanate 166 hydrogen selenide 97 hydrogen sulfide 97 hydrosilanes 79 hydroxamic acids 88 hydroxy acids, macrolactonization of 93 4-hydroxy-6-nitroquinoline-3-carboxylic acid 106 hydroxycarboxylic acids 93, 107 4-hydroxycyclohexanone 86 imidazo[1,5-c][1,3]benzodiazepines 151 imidazo[4,5-d][1,2,3]triazoles 110 imidazolidine imides 65 imidazolidine-2-ones 65 imido tantalium complexes, exchange reactions with N − t-butyl-N -2,6dimethylphenylcarbodiimide 35 imido zwitterionic titanium complexes 35 imidoyl chlorides, synthesis of halogenated carbodiimides from 166–167 imidoyl dichlorides, synthesis of sulfur subsituted carbodiimides from 206–207 imidoylcarbodiimides 173–181 (2,4,6-trimethylaniline) imidoylcarbodiimides 169 reactions of 180 synthesis of 174–180 from carbonimidoyl dichlorides or chloroformamidines 178 from cyanamides 179 from isocyanates 177 from other carbodiimides 179 from thioureas 174–176 from ureas 176–177 imidoylthioureas, desulfurization of 176 imidozirconocene complexes, [2 + 2] cycloaddition reactions with carbodiimides 54 imines, N -acylketene 72 4-imino-2-azetidinones 55 iminophosphoranes 9, 20–21, 22, 61 bisaryliminophosphoranes 231–236
289
synthesis of phosphorus substituted carbodiimides from 200 unsaturated carbodiimides from 148–153 indoloquinolines 160 insertion reactions 33, 78–83 isocyanates [2 + 2] cycloadducts derived from 49 aryl 42 aza-Wittig reaction 20–25 catalytic conversion of 17–20 synthesis of acyl-, thioacyl- and imidoylcarbodiimides from 177 alkyl- and arylcarbodiimides from 17–25 cyclic carbodiimides from 231–236 silicon substituted carbodiimides from 184–185 unsaturated carbodiimides from 148 α-isocyanatocarbodiimides 30, 35 isocyanides 34 isonitriles 34 isonitroso Meldrum’s acid, reaction with carbodiimides 70 N -isopropyl-N -phenylcarbodiimide 29 isoselenocyanates, cycloaddition reactions across C Se bond 53 isoserin 123 isothiocyanates 9 [2 + 2] cycloaddition reactions 51 aza-Wittig reaction 20–25 catalytic conversion of 17–20 cycloadducts derived from 52 dialkylaminothiocarbamoyl 53 synthesis of alkyl- and arylcarbodiimides from 17–25 cyclic carbodiimides from 231–236 silicon substituted carbodiimides from 184–185 unsaturated carbodiimides from 148–153 t-butyl isothiocyanate 32 isothioureas 97, 207 synthesis of, alkyl- and arylcarbodiimides from 10–15 isoureas O-alkylisoureas 84, 85 O-alkylmonoisoureas 84 O-ferrocenoylisourea 90 poly(O-alkylisoureas) 251 ketenes 3-aryl-2-quinoxalinyl(aroyl)ketenes 72 acyloxyketenes 72 cycloadducts derived from 56 ketoximes 88
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Index
lactams 101 beta-lactams 55, 57 formation of 115–124 linear homopolymers, via addition across the C N bonds 248–250 linear polymers 251–252 crosslinking of 253–254 modification of 254 lysozyme 267 macrocyclic carbodiimides 232–235 racemization of 4 MDI (4,4’-diisocyanatodiphenylmethane) 259, 269 melibionic acid, coupling to serum albumin 266 (–)-menthylcarbodiimide 5 mercaptoethylamines 100 Merrifield polypeptide synthesis 120 metal imides, [2 + 2] cycloaddition reaction with N ,N -ditoylcarbodiimide 54 metathesis reactions 261 2-metcaptoethanol, reaction of carbodiimides with 97 methacrylic acid 114 methanol 273 methyl acetylenedicarboxylate 156 2-methyl-5-phenyl-1,3,4-oxadizol-2-(3H)-one 26 2-methyl-5-phenyltetrazole 26 N -methyl-N -t-butylcarbodiimide 32, 35 N -methyl-N -trifluoromethylcarbodiimide 32 N -methyl-N -vinylcarbodiimide 147 N -methylhydroxylamine 102 methyloxalyl chloride 127 reaction with cyclic carbodiimides 241 N -(4-methylphenyl)diphenylimine 54 Moffat oxidation 2, 46, 76 monosilylcarbodiimides 183 monosubstituted carbodiimides 1 monothiocarboxylic acids, reaction with DCC 98 monotritylcyanamide 25 1-(1 -morpholidino)cyclohexene 155 Mukaiyama reagent 13 N -α-naphthyl-N -cyclohexylcarbodiimide 30 neoglycoproteins 268 nitrene rearrangements synthesis of alkyl- and arylcarbodiimides by 25–28 cyclic carbodiimides by 230–231 nitrile oxides 63 nitriles 88, 101 1-nitro-2,2-bisaminoethylenes 130
nitrogen substituted carbodiimides 195–198 reactions of 198 synthesis of 195–197 nitromethane 130 nitrones 63 N -(4-nitrophenyl)-N -isopropylcarbodiimide 47 2-(o-nitrophenyl)benzotriazole 112 NMR studies 4 nonapeptide linear amides 123 nonapeptides 118 nucleophilic reactions of alkyl- and arylcarbodiimides 83–104 with ammonia, amines, amine derivatives and azides 99–104 with carboxylic and inorganic acids 89–97 with H2 S, H2 Se, thioalcohols and thiophenols 97–99 with water, alcohols, phenols and other hydroxy compounds 83–89 of cyclic carbodiimides 236–237 of halogenated carbodiimides 169–170 nylon-1 imides 45, 248 oligomeric carbodiimide stabilizers 272 oligomeric carbodiimides 245, 247–248 applications of 259 used as stabilizers for polyester based polymers 246 oligomeric dialkylsilylcarbodiimides 247 oligomeric methylsilanes 247 oligomerization reactions of alkyl- and arylcarbodiimides 41–46 of cyclic carbodiimides 237 of silicon substituted carbodiimides 187–188 oligonucleotides, formation of 2, 96 oligothiopeptides, synthesis of 120 oral drug delivery systems 268 organic synthesis, application of carbodiimides in 260–261 ovalbumin, coupling to mouse spleen cells 266 1,3,4-oxadiazoles, polymer bound 112 oxazetidine imines 50 oxazines 6-aryl-4-arylimino-1-phenyl-6trifluoromethyl-1,4,5,6tetrahydropyrazolo-[4,3-e][1,3]oxazines 170–171 2,3-dihydro-2-imino-4-oxo-1,3-oxazines 69 1,3-oxazoles 100 oxazolidinediones 87 5-oxazolidinones 126 oxazoline-5-ones 108
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Index oxazolines 66, 84 2-oxazolines 87 oximes 115 (2-oxo-1,2-dihydropyridin-3-yl)-1,3,5-triazine derivatives 153 N -(3-oxo-1-cyclohexenyl)-N phenylcarbodiimide 155 parabanic acid derivatives 127 PCD (N -cyclohexyl-N (1-pyrenyl)carbodiimide) 259 penicillin 2, 261 pentacarbonyl(diphenylcarbene)tungsten 62 pentacarbonyl(hydroxymethylcarbene)chromium 130 N -pentafluorophenyl-N -phenylcarbodiimide 167 pentafluorophenylcarbonimidoyl dichloride 167 pepsin 264 pepsinogen 264 peptides cyclic 120 synthesis of 1, 2, 115–124 N -perchloroethyl-N -alkylcarbodiimides 165 perfluoro-2,4-diaza-1,4-pentadiene 35 N -perfluoro-alkyl-N -pentafluorosulfanylcarbodiimides 168 perfluoro-bis-carbonimidoyl difluoride 167 perfluoroalkyl(N -pentafluorosulfanyl)azidoazomethines 168 pesticides 267 phenolic esters 114 phenyl isocyanate 60, 150 phenyl isothiocyanate 150 N -phenyl-2,6-dichlorophenylcarbodiimide 33 5-phenyl-2-(tritylamino)oxazole 62 1-phenyl-3-methylphospholene-1-oxide 45 1-phenyl-3-methylphospholine-1-oxide 18 3-phenyl-4-toluenesulfonylimino-1,3thiazetidine-2-one 206 phenyl-dichlorobromomethyl mercury 81 N -phenyl-N -2,6-diethylphenylcarbodiimide 33 N -phenyl-N -2,6-dimethylphenylcarbodiimide 33 N -phenyl-N -cyclohexylcarbodiimide 25, 51 N -phenyl-N -dimethylaminocarbodiimide 195 N -phenyl-N -methylcarbodiimide 27 N -phenyl-N -pyridylcarbodiimide 73, 157 phenyl-thiocarbonyl isocyanate 51 phenylacetylene, reaction with diphenylcarbodiimide 59 phenylcarbonyl isothiocyanate 52 phenylcarbonyl isothiocyanates, substituted, reaction with carbodiimides 52 p-phenylene diisocyanate 162
291
phenylhydrazine 102 phenylimidoylcarbodiimides 173 1-phenylphospholane-1-oxide 18 phenylurea 34 phosgene (carbonyl chloride) 12–13, 28 phosphanes, alkylbis(trimethylsilyl)phosphanes 80 phosphate thymidyl-3 ,5 -thimidine 123–124 phosphetane-4-oxides 18 phosphinic acids 94 phosphoramidates 24–25 phosphoric acids 94 phosphorus amidinates, hexacoordinate 81 phosphorus pentachloride 28 phosphorus substituted carbodiimides 199–204 reactions of 203–204 synthesis of 199–203 from carbonimidoyl dichlorides 200–201 from cyanamides 201–202 from iminophosphoranes 200 from other carbodiimides 202–203 from thioureas 199–200 phosphorusfluoroimides 191 photocyclization 160 polyamides, formation of 3, 124–125 polyamine carbodiimides 2 poly(carbodiimide) foams 46, 252 poly(carbodiimide isocyanurate) foams 252 polycarbodiimide methacrylates 251 polycarbodiimides from aromatic diisocyanates 46 from optically active monomers 45 isocyanate terminated 243–247 poly(carbodiimidogermylene) 270 poly(γ -glutamic acid) hydrogels 253 polyguanidines 243, 244, 250 liquid crystalline 249 optically active 249 see also guanidines polyhexamethylenecarbodiimide 45 polymeric carbodiimides 243–257 polymeric EDC hydrochloride 250 polymerization, of alkyl- and arylcarbodiimides 41–46 polymerization reactions, of unsaturated carbodiimides 154 polymers carbodiimides and 269–270 containing carbodiimide groups 3 crosslinking of 253–254 derived from unsaturated carbodiimides 250–251 modification of crosslinked 254 modification of 271 synthesis of 268–269
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Index
poly(N -carbamoylamides) 252 poly(N -docecyl-N -1-naphthylcarbodiimide) 249 poly(N -ethyl-N -α-phenylethylcarbodiimide) 250 poly[N -methyl-N -(2-methyl-6isopropylphenyl)carbodiimide] 249 polynucleotides, synthesis of 123 poly(O-alkylisoureas) 251 polyorganosilyl carbodiimides 270 polyoxymethylene 271 polypeptides, synthesis of 2 poly(S-alkylisothioureas) 252 polystyrene 45 poly(titanium carbodiimides) 187 polyurethanes 46 poly(vinyl alcohol) 115 β-propiothiolactones 98 proteins crosslinking of 124, 266–267 determining number of carboxyl groups in 262 modification of 264–266 synthesis of 261–263 pyrazolo[3,4-d]pyrimidines 152 pyridine imidoyl-N -imines, pyrolysis of 28 pyrido[2,1-b]-1,3,4-thiadiazolium-2-amenates 113 pyridothionopyridazine derivatives 111 N -pyridyl-(2)-triphenylphosphine imine 73 pyrimidines 152 pyrimido[4,5-d]pyrimidines 151 pyrophosphates 94 1-(1 -pyrrolidino)cyclohexene 155 ribonucleases 264 salicylic acid 106 1,3-selenazetidine-2,4-diimines 53 selenoureas 15, 97 synthesis of, alkyl- and arylcarbodiimides from 10–15 semicarbazide 102 silicon substituted carbodiimides 183–193 reactions of 187–191 cycloaddition 188–190 oligomerization 187–188 synthesis of 183–187 from cyanamides 183–184 from isocyanates and isothiocyanates 184–185 from other carbodiimides 186 from silylamines 185 from ureas 184
silicondicarbodiimide oligomers 248 silylamines, synthesis of, silicon substituted carbodiimides from 185 N -silylformamidines 79 spiroadducts 71 Stabaxol 272 stabilizers, carbodiimides as 271–272 N -styrylcarbodiimide 160 sugar carbodiimides 22 sugar isocyanates 22 sugaramines 118 sugarcarboxylic acids 118 sulfilimine, photolysis of 33 sulfinic acid amides 94 sulfinic acids 94 sulfonic acids 94 N -sulfonylcarbodiimide 267 N -sulfonylcarbodiimides 60, 205, 207 reactions with cyclic amidines 210 sulfonylureas 3 sulfur substituted carbodiimides 205–211 reactions of 209–210 synthesis of 205–209 by fragmentation reactions 207–208 from carbonimidoyl dichlorides or imidoyl chlorides 206–207 from other carbodiimides 208 from thioureas or ureas 205–206 symmetrical carbodiimides 9 syndiotactic poly(methacrylic acid) 254 1,2,3,3-tetraaryl-1,2-diazetidin-4-imines 32 tetrabenzylpyrophosphate 94 tetrabutylammonium fluoride 108 tetrachloro-1,2-dimethyldisilane 187 3,3 ,5,5 -tetraethyldiphenylmethane4,4 -diisocyanate 245 4,5,6,7-tetrahydrobenzo-1,3-diazonine 230, 239 tetramethyl-1,3-diazahepta-1,2-diene 237 2,3,7,8-tetramethylthianthrene-1,4,6,9-tetrone 188 tetrazolethiones 27 tetrazolophenanthridene 228 thermolysis reactions, synthesis of, alkyl- and arylcarbodiimides by 29–33 thermoplastic polyamides 259 thermoset polymers 243–244 thermotropic liquid crystals 263 1-thia-3-azoniabutatriene salts 52 1,3,4-thiadiazoles 126 thiadiazolidines 67 thiazole ylides 77 thiazolidinones 98 thioacylcarbodiimides 173–181
JWBK177-IND
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16:50
Index reactions of 180 synthesis of 174–180 from carbonimidoyl dichlorides or chloroformamidines 178 from cyanamides 179 from isocyanates 177 from other carbodiimides 179 from thioureas 174–176 from ureas 176–177 thioalcohols 97 thioamides 101 o-thiobenzoquinone methide 75 thioboronites 79 thiocarbonyl chloride 13 thiocarboxylic acid amides 101 thioglycolic acid 98 thiophene-2,5-bis-iminophosphoranes 252 thiophenols 98 thiosalicyclic acid 107 thioureas 1-(alkyoxycarbonyl)-3-(arylmethyl)thioureas 175 arenesulfonylthioureas 99 1,3-bis-(2-vinyloxyethyl)thiourea 148 N -o-carboxyphenyl-N -phenyl thiourea 17 oxidation of 14 reaction with chlorine compounds 12–13 synthesis of acyl-, thioacyl- and imidoylcarbodiimides from 174–176 alkyl- and arylcarbodiimides from 10–15 cyclic carbodiimides from cyclic 229 phosphorus substituted carbodiimides from 199–200 sulfur substituted carbodiimides from 205–206 unsaturated carbodiimides from 148 Tiemann rearrangement, of amidoximes 25 tin-bis(trimethylsilyl)amido derivatives 185 titanium amides 80 titanium imido complexes 36 N - p-toluenesulfonyl-N cyclohexylcarbodiimide 47, 206 N ,N - p-tolyformamidinato derivatives 81 tosyl isocyanate 156 N -tosylamides 101 N -tosyllactams 116 toxicity, of carbodiimides 5 tri-alkylguanidines 128 N ,N ,N -triarylureas 85 triazaacenphthalene-5,6,8(4H,7H)-trione 122 1,2,4-triazineiminophosphorane 42 1,2,4-triazoles 101 1,2,4-triazolo[5,1-b]quinazolin-9-(3H)-ones 108
293
tributyltinmethoxide 80 tricarboxylic acids 101 trichloroborazene 188 N -trichloromethylcarbonyl-N -alkylcarbodiimides 178 tricyclohexyl guanidine 33 tricycloundecatrienones 91 N -trifluoromethyl-N -(2-pyridyl)carbodiimide 44 N -trifluoromethyl-N -arylcarbodiimides 168 N -trifluoromethyl-N,N -dicyclohexylurea 128 trifluoromethylcarbonimidoyl difluoride 29 (2,4,6-trimethylaniline) imidoylcarbodiimides 169 2,4,6-trimethylbenzoic acid 114 trimethylcyanosilane 79 trimethylsilyl carbodiimide, reactions with alkyl halides 35 N -trimethylsilyl-N -alkylcarbodiimides, reaction with haloketenes 55 N -trimethylsilyl-N dimethylaminocarbodiimide 197 N -trimethylsilyl-N -phenylcarbodiimide 30, 35, 62, 186 N -trimethylsilylmethyl-N -arylcarbodiimides, reaction with ethylene glycol 84 N -trimethylsilyltetrazole 186 N -trimethylstannyl-N triisopropylsilylcarbodiimide 202 triphenylleadmethoxide 80 triphenylphosphine sulfide 18 1-(triphenylphosphoroylideneaminomethyl)benzotriazole 23 2,4,6-tris-dimethylamino-1,3,5-triazine 44 trityl penicillin 261 (tropon-2-ylimino)arsorane 55 trypsin 264 unsaturated aminoacid esters 126 unsaturated arylcarbodiimides intramolecular cyclization reactions 159 see also arylcarbodiimides; diarylcarbodiimides unsaturated carbodiimides 147–164 polymers derived from 250–251 reactions of 154–162 cycloaddition 54–162 polymerization 154 synthesis of 148–154 from thioureas 148 from unsaturated iminophosphoranes and isocyanates or isothiocyanates 148–153 from unsaturated isocyanates 148 α, β-unsaturated esters 86 unsymmetrical carbodiimides 9
JWBK177-IND
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294
July 19, 2007
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Index
ureas N -aziridinyliminoureas 176 dehydration of 16–17 synthesis of acyl-, thioacyl- and imidoylcarbodiimides from 176–177 silicon substituted carbodiimides from 184 sulfur substituted carbodiimides from 205–206
2-vinylaziridines 65 vinylcarbodiimides 105, 147 reaction with activated olefins 155 2-vinyloxirans 65
variolin B 113 vinyl polymers 250 N -vinyl-N -methylcarbodiimide 154
ylides, reactions with carbodiimides 76–78
water, reaction of carbodiimides with 83 Wuensch-Weygand method 117 xylanase A 264
zirconaaziridines 66
