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N-Heterocyclic Carbenes: From Laboratory Curiosities to Efficient Synthetic Tools

N-Heterocyclic Carbenes: From Laboratory Curiosities to Efficient Synthetic Tools

by Guy Bertrand (Contribution by), Silvia Diez-Gonzalez (Editor), James J Spivey (Editor), Mareike Jahnke (Contribution by), Ekkehardt Hahn (Contribution by)

Over the last fifteen years, N-heterocyclic carbenes (NHCs) have mostly been used as ancillary ligands for the preparation of transition metal-based catalysts. Compared to phosphorus-containing ligands, NHCs tend to bind more strongly to metal centres, avoiding the necessity for the use of excess ligand in catalytic reactions. The corresponding complexes are often


Over the last fifteen years, N-heterocyclic carbenes (NHCs) have mostly been used as ancillary ligands for the preparation of transition metal-based catalysts. Compared to phosphorus-containing ligands, NHCs tend to bind more strongly to metal centres, avoiding the necessity for the use of excess ligand in catalytic reactions. The corresponding complexes are often less sensitive to air and moisture, and have proven remarkably resistant to oxidation. Recent developments in catalysis applications have been facilitated by the availability of carbenes stable enough to be bottled, particularly for their use as organocatalysts. This book shows how N-heterocyclic carbenes can be useful in various fields of chemistry and not merely laboratory curiosities or simple phosphine mimics. NHCs are best known for their contribution to ruthenium and palladium-catalysed reactions but the scope of this book is much broader. The synthesis of NHC ligands and their corresponding metal complexes are covered in depth. Moreover, the biological activity of NHC-containing complexes, as well as an overview of their theoretical aspects are included. Such metal species are further examined, not only in terms of their catalytic applications, but also of their stereoelectronic parameters and reactivity/stability. Finally, special attention is given to the hot topic of organocatalysis. The book will be of interest to postgraduates, academic researchers and those working in industry.

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Royal Society of Chemistry, The
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Catalysis Series , #6
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6.40(w) x 9.30(h) x 1.40(d)

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N-Heterocyclic Carbenes

From Laboratory Curiosities to Efficient Synthetic Tools

By Silvia Díez-González

The Royal Society of Chemistry

Copyright © 2011 Royal Society of Chemistry
All rights reserved.
ISBN: 978-1-84973-042-6


Introduction to N-Heterocyclic Carbenes: Synthesis and Stereoelectronic Parameters


Institut für Anorganische und Analytische Chemie, Westfälische Wilhelms-Universität Münster, Corrensstrasse 30, D-48149 Münster, Germany

1.1 Introduction

Chemists have been fascinated with carbenes for more than 150 years. The simplest member of this class of compounds, possessing a neutral divalent carbon atom and six electrons in its valence shell, is methylene, CH2. Numerous attempts to isolate methylene or related compounds failed, although 'carbenic reactivity' of methylene derivatives was described in connection with cyclopropanation reactions as early as 1953.

Even if free carbenes could not be isolated, carbene complexes have been known for a long time. The first complex with a heteroatom-stabilized carbene ligand, most likely unrecognized as such, was prepared as early as 1925 by Tschugajeff (English transcription, Chugaev). Tschugajeff's 'red salt' 1 was obtained by the reaction of the tetrakis(methylisocyanide) platinum(II) cation with hydrazine. The 'yellow salt' 2 was formed upon treatment of 1 with HCl in a reversible reaction. The determination of the molecular structures of 1 and 2 in 1970 demonstrated that these compounds were correctly described as diaminocarbene complexes (Scheme 1.1).

In 1964, Fischer prepared and characterized unambiguously the first metal carbene complex 3 obtained by nucleophilic attack of phenyl lithium at tungsten hexacarbonyl followed by O-alkylation. This was followed by Schrock's synthesis of a high oxidation state metal alkylidene complex 4 obtained by α-hydrogen abstraction from tris(neopentyl) tantalum(V) dichloride (Scheme 1.1).

Parallel to these efforts, Wanzlick tried to prepare a stable N-heterocyclic carbene by α-elimination of chloroform from 5. The free carbene, however, could not be isolated and instead its dimer, the entetraamine 6=6, was always obtained (Scheme 1.2). Wanzlick's initially postulated cleavage of the entetraamine according to 6=6->2×6 could not be demonstrated conclusively. Cross-metathesis experiments with differently N,N'-substituted entetraamines failed, excluding an equilibrium between the monomer 6 and the dimer 6=6 (Scheme 1.2).

Around 1960, it was already known that unsaturated heterocyclic azolium cations reacted in a base-catalyzed H,D-exchange reaction. Hoping that the delocalization of the six π-electrons in such derivatives might stabilize the intermediately formed carbene species, Wanzlick attempted to prepare the free carbene 7 by deprotonation of tetraphenylimidazolium perchlorate with KOt-Bu (Equation (1.1)). Again, he could not isolate free 7 but its intermediate formation was demonstrated indirectly by identification of some of its reaction products with water or with [Hg(OAc)2]. Almost three decades later, Arduengo succeeded in the preparation of free 7 by the deprotonation method originally suggested by Wanzlick.

While up to 1990 all attempts to isolate a stable N-heterocyclic carbene failed, metal complexes of unsaturated imidazol-2-ylidenes were known as early as 1968. The first complexes of this type were obtained by in situ deprotonation of imidazolium salts using mercury(II) acetate or dimethylimidazolium hydridopentacarbonylchromate(–II) followed by coordination of the carbene to the metal center (Scheme 1.3). Shortly thereafter, the stabilization of the saturated imidazolin-2-ylidene in a metal complex was described by Lappert who treated electron-rich entetraamines of type 6=6 with coordinatively unsaturated transition metal complexes to obtain complexes with imidazolin-2-ylidene ligands (Scheme 1.3).

While Bertrand and co-workers described in 1988 the stable λ-phosphino-carbene 8, which did not act as a ligand, Arduengo et al. prepared in 1991 the first free and stable 'bottleable' N-heterocyclic carbene 9 by deprotonation of the corresponding imidazolium salt (Scheme 1.4). This deprotonation method was later supplemented by Kuhn, who introduced the reductive desulfurization of thiones for the preparation of stable imidazol-2-ylidenes.

The isolation of compound 9 demonstrated that free carbenes were not invariably unstable intermediates. Its isolation initiated an intensive search for additional stable N-heterocyclic carbenes (NHCs) leading to the isolation of derivatives with different heteroatoms in the carbene ring and different N-heterocyclic ring sizes. General aspects of the synthesis of NHCs and their coordination chemistry with transition metals, coinage metals, f-block metals and main group elements have already been reviewed. Additional reviews deal with selected classes of polydentate ligands containing NHC donor functions and chiral NHC ligands or NHCs as organocatalysts. Important aspects of carbene dimerization and catalytic applications of NHC complexes have also been reviewed.

1.2 Electronic Structure and Stabilization of N-Heterocyclic Carbenes

Carbenes are defined as neutral compounds of divalent carbon where the carbon atom possesses only six valence electrons. If methylene, CH2, is considered the simplest carbene, a linear or bent geometry at the carbene carbon atom can be considered. The linear geometry is based on a sp-hybridized carbene carbon atom leading to two energetically degenerated p orbitals (px, py). This geometry constitutes an extreme and most carbenes contain a sp2-hybridized carbon atom with a non-linear geometry at this atom. The energy of the non-bonding p orbital (py), conventionally called pπ after sp2- hybridization, does practically not change upon the sp->sp2 transition. The sp2-hybrid orbital, normally described as the σ orbital, possesses partial s-character and is thus energetically stabilized relative to the original px orbital (Figure 1.1).

The two non-bonding electrons at the sp2-hybridized carbene carbon atom can occupy the two empty orbitals (pπ and σ) with a parallel spin orientation leading to a triplet ground state (σ1pπ1, 3B1 state, Figure 1.1). Alternatively, the two electrons occupy the s orbital with an antiparallel spin orientation (σ2pπ0, 1A1 state). An additional, generally less stable singlet state (σ0pπ2, 1A1 state) and an excited singlet state with an antiparallel occupation of the pπ and σ orbitals (σ1pπ1, 1B1 state) are conceivable but of no relevance for the present discussion.

The multiplicity of the ground state determines the properties and the reactivity of a carbene. Singlet carbenes possessing a filled σ and an empty pπ orbital exhibit an ambiphilic behavior, while triplet carbenes can be considered as diradicals. The multiplicity of the ground state is determined by the relative energies of the σ and pπ orbitals as depicted in Figure 1.1. Quantum chemical calculations showed that an energy difference of about 2 eV is required for the stabilization of the singlet ground state (1A1), while an energy difference of less than 1.5 eV between the relative energies of the σ and pπ orbitals favored the triplet ground state (3B1).

Steric and electronic effects of the α substituents at the carbene carbon atom control the multiplicity of the ground state. It is generally accepted that the singlet ground state is stabilized by σ-electron withdrawing, generally more electronegative substituents. This negative inductive effect causes a lowering of the relative energy of the non-bonding σ orbital, while the relative energy of the pπ orbital remains essentially unchanged. Substituents with σ-electron donating properties decrease the energy gap between the σ and the pπ orbital and thus stabilize the triplet ground state.

In addition, mesomeric effects play a crucial role. The substituents at the carbene carbon atom can be classified into different categories depending on their π donor/π acceptor properties. Singlet carbenes of type X2C:, substituted with two π donors X, are strongly bent at the carbene carbon atom. The interaction of the π-electron pairs at the α substituents with the pπ orbital at the carbene carbon atom raises the relative energy of this orbital. The relative energy of the σ orbital at the carbene carbon atom is not affected by the π-interaction. Consequently, the σ–pπ energy gap becomes larger leading to a further stabilization of the bent singlet ground state. The interaction of the π electrons of the substituents with the pπ orbital at the carbene carbon atom leads to some extent to the formation of a four-electron three-centre π system where the X–C bonds acquire partial double-bond character (Figure 1.2). Important members of this class of compounds are the dimethoxycarbenes and the dihalocarbenes. The most important singlet carbenes stabilized by two π donors are the N-heterocyclic carbenes. The bonding situation in N-heterocyclic carbenes derived from five-membered heterocycles has been discussed in detail.

1.3 N-Heterocyclic Carbene Ligands

The isolation of the first stable N-heterocyclic carbenes and their successful use as ancillary ligands for the preparation of various metal complexes initiated an intensive search for new NHC ligands by variation of the size of the hetero- cycle, the heteroatoms within the cycle and the substituents at the nitrogen atoms of the heterocycle and the heterocycle itself. Access to Nheterocyclic carbenes is largely controlled by the availability of suitable NHC precursors. Most NHCs are prepared by deprotonation of azolium cations found in imidazolium, triazolium, benzimidazolium, imidazolinium or thiazolium salts or by reductive desulfurization of imidazol-, benzimidazol- and imidazolin-2-thiones. In addition, stable NHCs have also been obtained from various imidazolidines by thermally induced a-elimination reactions (Scheme 1.5). The preparation of suitable azolium salts, 2-thiones and imidazolines is presented in this section, followed by the description of methods for the liberation of the free NHCs from these compounds. Imidazol-2-ylidenes are the most widely used NHC ligands and therefore special emphasis is placed on synthetic procedures leading to these unsaturated NHC ligands featuring a five-membered diaminoheterocycle.

1.3.1 Synthesis of NHC Precursors

Several methods for the preparation of imidazolium salts 10 (Scheme 1.6) have been described. The two most common routes are the alkylation of the nitrogen atoms of imidazole and the multi-component reactions of primary amines, glyoxal and formaldehyde giving symmetrical N,N'-substituted azolium salts (Scheme 1.6a and b). The second method is particularly useful for the synthesis of imidazolium salts bearing aromatic, very bulky or functionalized N,N'-substituents. Unsymmetrically substituted imidazolium salts can be obtained by either stepwise alkylation of imidazole (Scheme 1.6a) or by combination of a multi-component cyclization with a subsequent N-alkylation reaction (Scheme 1.6c). N-Arylated imidazole derivatives can also be prepared from imidazole via a copper-catalyzed Ullman-coupling reaction. Imidazolium salts bearing two different aryl substituents at the nitrogen atoms or bisoxazoline-derived imidazolium salts leading to NHC ligands with a flexible steric bulk have also been described.

The saturated imidazolinium salts of type 11 (Scheme 1.7) can be obtained by alkylation of dihydroimidazole or by the cyclization reactions between N,N'-dialkyl-α,β-ethyldiamines with orthoesters (Scheme 1.7a). A multi-component reaction leading to unsymmetrical derivatives of type 11, which is particularly interesting for the synthesis of imidazolinium salts with substituents at the C4 and C5 positions of the heterocycle, was reported by Orru and co-workers (Scheme 1.7b). Also, the reaction of stable N-(2-iodoethyl)-arylammonium salts with an amine and triethylorthoformiate was reported to yield various imidazolinium salts of type 11 (Scheme 1.7c).

Precursor 12 for a N-heterocyclic diaminocarbene possessing a six-membered heterocycle was obtained from the reaction of a suitable 1,3-diamino-propane with triethyl orthoformiate (Scheme 1.7d). Related compounds with an aromatic backbone were obtained from diaminonaphthalene. While these methods are based on the ring closure by introduction of a CH+ fragment, Bertrand and co-workers presented a different approach based on the reaction of a 1,3-diazaallyl anion with compounds featuring two leaving groups. Amidinium salts with both six- or seven-membered heterocycles (12 or 13) were obtained by this method (Scheme 1.7e) which was further developed by Cavell and others to yield a variety of derivatives with different ring sizes and substituents at the nitrogen atoms.

Alternative precursors for the synthesis of NHCs are thiourea derivatives of type 14. Kuhn and Kratz first reported a facile method for the synthesis of symmetrically substituted imidazol-2-thiones by the reaction of 3-hydroxy-2-butanone with suitable thiourea derivatives (Scheme 1.8a). Related saturated imidazolin-2-thiones 15 or benzimidazol-2-thiones 16 were obtained by reaction of aliphatic or aromatic 1,2-diamino compounds with thiophosgene (Scheme 1.8b). Unsymmetrically substituted imidazolin-2-thiones 17 were obtained by the reaction of lithium-N-lithiomethyldithiocarbamates with aldimines and ketimines, respectively (Scheme 1.8c).

N-Heterocyclic carbenes can also be prepared by α-elimination from imidazolidines (see Scheme 1.5). Differently substituted imidazolidines or benzimidazolines were prepared by addition of alkali metal alkoxides to azolium salts or by condensation of suitable diamines with benzaldehydes bearing fluorinated aromatic rings. More exotic carbene precursors like 1,3-dimethyltetrahydropyrimidin-2-ium chloride were described by Bertrand and coworkers.

Reports on N,N'-donor-functionalized, chiral and polydentate N-heterocyclic carbenes appeared almost immediately after the reports on the preparation of the first stable NHCs. Herrmann's report on the first donor-functionalized imidazolium cations 18 and 19 (Figure 1.3) from 1996 was followed by a large number of publications dealing with imidazolium precursors for donor-functionalized carbene ligands. The preparation of NHCs from imidazolium precursors bearing acidic N-substituents like alcohols or secondary amines was of special interest. Studies by Arnold and coworkers demonstrated that alcohol functionalized imidazolium salts 20 (Figure 1.3) were readily accessible by nucleophilic opening of epoxides. Imidazolium salts 21 bearing N-s-amine substituents were also prepared. Fryzuk and coworkers succeeded with the synthesis of an N,N'-di(s-amine) substituted imidazolium salt. Indenyl- (22) and fluorenyl- (23) substituted imidazolium cations were also described (Figure 1.3).

A large number of differently bridged diazolium salts of type 24 (Figure 1.4) have been described. Compound 25, the precursor for an interesting biscarbene containing carbene and alcoholato donor functions, was prepared by Arnold et al. by the reaction of two equivalents of an N-alkylimidazole with a functionalized epichlorhydrin (Figure 1.4). Dibenzimidazolium salts are also known. Trisimidazolium salt 26 was first described by Dias and Jin, shortly thereafter followed by the description of trisimidazolium salts of type 27. Tripodal tris-imidazolium salts of types 26, 28 and 29 were prepared by Hu and Meyer.

The successful development of pincer ligands containing phosphine or amine donor groups by Milstein, and van Koten led to attempts to transfer this useful rigid ligand topology to tridentate ligands with NHC donor groups. Today, pyridine- (30), lutidine- (31), and phenylene-bridged 32 and 33 bis-imidazolium salts are known in addition to the diethyl amine-bridged derivative 36. The lutidine- and phenylene-bridged benzimidazolium salts 34 and 35 were also described (Figure 1.5).


Excerpted from N-Heterocyclic Carbenes by Silvia Díez-González. Copyright © 2011 Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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Meet the Author

Silvia Díez-González is a Senior Lecturer in the Department of Chemistry at Imperial College London, UK.

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