An Overview of N-Heterocyclic Carbene: Properties and Applications

Abstract

In 1991, N-heterocyclic carbenes were isolated and characterised successful introduced an entirely new class of organic compounds for research. From these origin as scientific curiosities, N-heterocyclic carbenes today rank among organic chemistry’s most powerful tool, having a wide applicability in commercially important processes. In this chapter, we summarise the general properties and uses of N-heterocyclic carbenes in modern chemistry and demonstrates how these properties are being exploited.

1. Introduction

Carbenes, a fascinating family of carbon-containing compounds, are described as neutral compounds having a divalent carbon atom with a six-electron valence shell. Nevertheless, unbound carbenes are extremely unstable due to their incomplete electron octet and coordinative unsaturation, and they have only ever been thought of as highly reactive transitory intermediates in organic transformations like cyclopropanation. Despite attempts at synthesis dating back to 1835 [1], it wasn’t until groundbreaking investigations in the late 1980s and early 1990s that a free, uncoordinated carbene was finally isolated and given a clear characterisation [2]. Bertrand and colleagues described the creation of the first isolable carbene in a seminal study from 1988, stabilising it through advantageous interactions with nearby silicon and phosphorus substituents [3]. A nitrogen heterocycle with a carbene that can be isolated and “bottled” was described by Arduengo et al. three years later [4]. The remarkable stability and relatively easy synthesis of the first N-heterocyclic carbene (NHC), 1,3-di(adamantyl)imidazol-2-ylidene (IAd, compound labelled 1a), spurred an explosion of experimental and theoretical studies, with libraries of novel NHCs being synthesised and studied. These structural features were inspired by earlier insightful studies by Wanzlick [5] and O fele [6] on metal-carbene complexes. As more of the complex chemistry of these compounds has been uncovered and utilised as a result of these discoveries, NHCs have been raised from simply laboratory curiosities to substances of immense practical value. NHCs have several uses in some of the most significant catalytic transformations in the chemical industry as good ligands for transition metals, and their reactivity upon coordination to main group elements and as organocatalysts has opened up new study avenues.

In order to serve as an introduction and reference for researchers interested in investigating and using these significant chemicals, we have attempted to present a condensed review of the features and wide range of uses of NHCs in this chapter. Following a general overview of the structure and characteristics of NHCs, three sections are loosely divided to discuss NHCs’ reactivity and uses in contemporary chemistry. These sections cover their use as ligands for transition metals, when they are coordinated to p-block elements, and as organocatalysts. For further in-depth reading, each part includes a brief summary of the salient characteristics and essential applications, as well as references to seminal works and thorough expert evaluations. The discussion is highlighted by more thorough summaries of a few recent research that illustrate the state of the art today and anticipated developments as an increasing number of NHCs continue to find novel and interesting uses throughout the chemical sciences (Figure 1).

Figure 1.

Major applications of NHCs.

2. Structure and general properties of NHCs

NHCs are categorised as heterocyclic entities with at least one nitrogen atom and a carbene carbon inside the ring structure [7, 8]. Several diverse types of carbene compounds with varying substitution patterns, ring diameters, and levels of heteroatom stabilisation fit under these criteria [9]. The first known compound, IAd (1a), serves as an illustration of the general structures of NHCs in Figure 2. The exceptional stability of the carbene centre C2 can be partially explained by the overall electrical and steric impact of these structural characteristics.

Figure 2.

Structure of carbene.

NHCs typically have bulky substituents next to the carbene carbon, as shown in IAd by the two adamantyl groups attached to the nitrogen atoms. These substituents work to kinetically stabilise the species by sterically disfavoring dimerization to the corresponding olefin (the Wanzlick equilibrium). Yet, the nitrogen atoms’ ability to stabilise electrons is a much more crucial feature. The highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO), which are best defined as a formally sp2-hybridised lone pair and an unoccupied p-orbital at the C2 carbon, respectively, in NHCs such as IAd are different from conventional carbenes (Figure 3).

Figure 3.

Molecular orbital diagram of NHC.

The nearby nitrogen atoms maintain this structure both mesomerically and inductively by contributing electron density into the vacant p-orbital and reducing the energy of the occupied s-orbital, respectively. Because NHCs are cyclic, this forces the carbene carbon into a configuration that is more sp2-like and favours the singlet state. The C-N bond lengths (1.37 A) found in IAd, which lie between those of its equivalent imidazolium salt (IAdH1, 1.33 A)4 and its C₂-saturated counterpart (IAdH2, 1.49 A) [10], reflect this ground-state structure and indicate that the C₂₂ nitrogen bonds have partial double-bond character. All classes of NHC can be stabilised using these broad principles, however the proportional importance of each effect differs from compound to compound (Figure 4).

Figure 4.

Different types of N-heterocyclic Carbenes.

Due to their partial aromaticity, NHCs generated from heteroaromatic compounds benefit from a higher level of stability. As less proximal steric bulk is required due to this effect, which has been estimated to be about 25 kcal/mol for model imidazol-2-ylidenes [11], the simple methyl-substituted NHC 1,3- di(methyl)imidazol-2-ylidene (IMe) is persistent in solution [12]. The first example of a stable carbene that does not benefit from aromaticity was described by Arduengo and coworkers in 1995 [13] and is known as 1,3-di(mesityl)imidazolin-2-ylidene (SIMes). Therefore, stabilising the carbene centre does not need two nearby nitrogen atoms [14]. Stable carbenes containing only one nitrogen substituent, as the series of cyclic (alkyl) (amino)carbenes (CAACs,) discovered by Bertrand et al. [15], have also garnered significant research interest. NHCs bearing alternate heteroatoms, such as sulphur and oxygen, are accessible. When the carbene centre is generated at places other than C2, similar compounds stabilised by a single nitrogen atom may arise. These mesoionic or “abnormal” carbenes, for which it is impossible to sketch a neutral, non-zwitterionic carbene resonance structure, tend to be more electron-donating than their “normal” equivalents and can exhibit a wide range of distinct characteristics [16, 17]. There have also been reports of remote NHCs, in which the carbene carbon is not located close to a nitrogen heteroatom. The characteristics of the carbene can be significantly influenced by the size and substitution pattern of the nitrogen heterocycle. Although while instances of NHCs with smaller or bigger ring sizes, such as N, N9- diamidocarbenes (DACs), have also been described, the greatest class of NHCs is still 5-membered rings. Due to the higher N-C-N bond angle in these later compounds, which in turn effectively moves the nitrogen substituents closer to the carbene centre, there is an increase in steric shielding. Bigger rings also have an electrical impact because the cyclic structure’s geometric constraints change the kind and extent of heteroatom stabilisation. It is also important to note that numerous related groups of stable carbenes exist, which, although not being NHCs, benefit from related methods of stabilisation. These include cyclic derivatives and cyclic species featuring different ring heteroatoms such as phosphorus instead of nitrogen [7, 14, 17].

Understanding the reactivity of NHCs is made possible by their ground-state electrical structure. The lone pair located in the plane of the heterocyclic ring of NHCs makes these compounds nucleophilic in contrast to the normal electrophilicity of the majority of transitory carbenes. The main effect of this property is that NHCs are inclined to function as s-donors and bind to a variety of metallic and non-metallic species. The extraordinary power and distinctive characteristics of these interactions, as well as their impact on the stability, structure, and reactivity of the resulting complexes or adducts, are what have driven NHC interest to such a high level. The following sections go into more detail about this extensive coordination chemistry and the various applications of NHCs that result from it.

The relative simplicity with which libraries of structurally varied analogues may be created and researched is another appealing aspect of NHCs. Synthetic approaches to NHCs profit from years of study on the synthesis of heterocyclic compounds since, in the majority of situations, the carbene is produced following deprotonation of the matching cationic heterocyclic azolium salt [18]. The steric and electrical characteristics of the resultant carbene may be easily changed for most classes of N-heterocycles by simply changing the starting materials in a modular synthetic procedure. With various kinds of heterocycles having essentially varied steric needs, the nitrogen-substituents or other groups located next to C2 have the most impact on the steric environment at the carbene centre. The heterocycle class is the main factor controlling the NHC electronics, however the ring backbone substitution pattern is also crucial. The evaluation of these characteristics enables straightforward comparisons between NHCs as well as between NHCs and other related compounds like phosphines, enabling better informed choice of the best carbene for any particular application [19, 20].

3. Coordination of NHCs to transition metals

The vast majority of N-heterocyclic carbene applications require coordination to transition metals (Figure 5). About 20 years prior to the discovery of a free NHC, Wanzlick [5] and Ofele [6] separately synthesised imidazol-2-ylidene-containing species carrying mercury(II) and chromium(0), respectively, in 1968. These reactions resulted in the first instances of NHC-metal complexes. Before IAd was isolated, Lappert and colleagues had carried out insightful experiments in the early 1970s [21]. As was already indicated, NHCs aptitude as ligands for transition metals may be explained by the fact that they naturally possess the capacity to donate an official sp2-hybridised lone pair into an orbital of the transition metal.

Figure 5.

Coordination of NHC to transition metals.

Many groups have investigated the complete nature of bonding in these complexes, and Cavallo and colleagues [22] and D’ez-Gonzalez and Nolan [23] have both written reviews on the issue. While p-back-bonding into the carbene p-orbital and p-donation from the carbene p-orbital may not have a significant impact, s-donation is still the most significant factor in metal–ligand interaction. For instance, Frenking and coworkers determined that group 11 metal-imidazol-2-ylidene and imidazolin-2-ylidene complexes account for around 20% of the total bond energy [24]. In practice, metal-C-coordination is typically depicted as a single bond rather than a double bond in actuality, with p-contributions limited to delocalization inside the NHC ring (often depicted by a curved line between the ring heteroatoms). This illustration highlights the distinctions between NHCs and traditional Fischer or Schrock carbene ligands and most accurately captures the experimentally found potential for rotation around the metal-C-bond. NHCs were previously thought of potential analogues for this common class of auxiliary ligand in transition-metal coordination chemistry because of their strong s-donor and relatively weak p-acceptor features, which resemble the coordination properties of phosphines [25].

4. Medicinal and materials applications of NHC-metal species

Organometallic materials can be developed because of the great thermal stability of metal-NHC complexes and the possibility to customise their steric and electronic properties [26]. In order to create organometallic complexes within the material’s pores, imidazolium salts have been effectively coordinated to transition metals when used as linker molecules in metal–organic frameworks [27]. It is also possible for transition-metal complexes with hydrophobic long alkyl chain N-substituents to self-assemble into extremely air- and moisture-resistant liquid crystals that are thermally stable after the clearing point [28]. Many studies have been conducted on the addition of NHC-metal complexes to the side chains or primary chain of polymers. Bielawski and colleagues created a number of distinct palladium(II) and platinum(II) organometallic polymers A using benzene-linked bis(NHC) units which exhibit self-healing qualities due to the intrinsic reversibility of metal–ligand coordination [29]. The conjugated bis-NHC linkers in these materials, which enable electronic interaction between the two coordinated metal centers, make them promising as electrical conductors. There have also been reports of NHC-transition metal complexes that function as phosphors and other photoactive substances [30]. The therapeutic uses of NHC-transition-metal complexes as metallopharmaceuticals have received more attention in recent years, with silver(I) and gold(I) species showing particular promise as antibacterial and anticancer agents, respectively [31]. A variety of Gram-positive and Gram-negative bacteria are resistant to several imidazol-2- and imidazolin-2-ylidene-Ag complexes, which have astonishingly low minimum inhibitory concentration values (10 mg/ ml²¹). These species often remain therapeutically active for longer than the usual reference AgNO₃, which might be explained by a delayed release of active Ag¹ ions from the NHC-stabilised complexes. Based on the targeting of mitochondria, NHC -metal species containing gold have demonstrated potential as anticancer medications. Since anticancer action is heavily dependent on penetration across the mitochondrial membrane, it is essential for these systems to be able to precisely control the lipophilicity of the complexes by change of the N-substituents on the NHC. The cationic gold(I) complexes were demonstrated to induce apoptosis by selective inhibition of the selenoenzyme thioredoxin reductase, which is over expressed in many human cancers in a seminal publication by Berners-Price, Filipovka and co-workers (Figure 6) [32].

Figure 6.

NHC showing medicinal properties.

5. NHCs as organocatalysts

A third significant class of applications, in which NHCs function as organocatalysts, has been made possible by their tendency to coordinate to carbon-electrophiles [33, 34]. The bulk of these reactions begin as a result of a carbene’s nucleophilic assault on carbonyl groups found in organic substrates. The majority of the transformations that NHCs mediate as organocatalysts involve an initial assault of the NHC onto a carbonyl group. The bulk of NHC-catalysed reactions use aldehydes as substrates, in addition to trans esterification and related transformations of esters, which are particularly relevant in the production of polymers. In these reactions, the functional group is umpolunged, and the carbonyl carbon behaves more like a transitory nucleophile than an electrophile. There are also other related transformations that include an umpolung at the b-position of α,β-unsaturated substrates. These procedures involve direct NHC assault on α,β-unsaturated esters as well as “conjugate umpolung” reactions of α,β-unsaturated aldehydes (Michael umpolung). Azolium intermediates with leaving groups in the a-position or those produced from aldehydes by in-situ oxidation constitute another family of reactions (Figure 7).

Figure 7.

NHC as organocatalyst.

The cationic N-heterocyclic fragment created by nucleophilic attack is electron-withdrawing by nature, which plays a crucial part in the adduct’s subsequent reactivity. An acyl azolium salt is produced in the case of esters by adding the NHC to the carbonyl and then releasing the alkoxy group. This species may interact with alcohols to produce transesterification products and is noticeably more electrophilic than the parent ester. In step growth and ring-opening polymer synthesis, reactions of this kind are often used, and NHCs provide an alternative to conventional organometallic catalysts and initiators [35]. Due to their strong Bronsted basicity, NHCs play a further role in these processes by hydrogen attaching to the alcohol and activating it for nucleophilic attack.

The nucleophilic attack of NHCs on aldehydes leads to the widest and most varied range of NHC-organocatalyzed reactions. The earliest instance of this type of transformation, which was reported in 1943 by Ukai and colleagues and included the homo-dimerization of aldehydes to benzoins catalysed by a thiazolium salt [36], was not well understood at the time. The mechanism of this method is based on the amphiphilic properties of an in situ produced NHC active catalyst, as suggested by Breslow in 1958 [37]. The previously aldehydic proton in the resultant compound is made acidic by the negative inductive impact of the cationic azolium group following the first nucleophilic assault of the NHC on the aldehyde. The enamine-like “Breslow intermediate”, which is nucleophilic at carbon as a result of p-donation from the ring heteroatoms.

The isolation and characterisation of representative samples taken from SIPr by Berkessel and coworkers [38] has recently validated the role of these species in NHC organocatalysis. In the aforementioned benzoin condensation, product production is caused by intermediate nucleophilic attack on another aldehyde equivalent followed by the elimination of the NHC. The aldehyde substrate’s natural reactivity is effectively flipped during the reaction (also known as “umpolung”), with the typically electrophilic carbonyl carbon serving as a momentary nucleophile. Hence, umpolung reactions of this kind are examples, and Breslow intermediates may be thought of as acyl anion equivalents [39].

The study of NHC-catalysed umpolung has advanced significantly over the past few decades, and [33, 34]. Figure 8 provide an overview of the main reaction classes. In general, pre-forming the free carbene is not necessary in reactions facilitated by NHC coordinated with the transition-metal complexes. Rather, the equivalent azolium salt precursor is often deprotonated in order to produce the active catalyst in situ. The creation of asymmetric variants utilising chiral NHCs has significantly increased the syntactic value of several of these transformations. The most successful enantioselectivity-inducing catalysts have been those based on the triazol-2-ylidene motif, with systems that include a chiral nitrogen substituent into a rigid polycyclic structure being commonly used.

Figure 8.

Different reactivity of Breslow intermediate.

One geometric isomer of the Breslow intermediate is preferred over the other when using these asymmetrical catalysts, and the electrophile approaches the least hindered enantiotopic face. Since the benzoin condensation is reversible, the Breslow intermediary may potentially attack other electrophiles nucleophilically. In particular, aldehyde addition reactions to activated alkenes, like Michael acceptors, have received a great deal of attention (the Stetter reaction). The researchers have been focusing on expanding the pool of appropriate olefinic coupling partners for this process [40]. Recently, the application of relatively electron-neutral styrene derivatives was accomplished utilising an electron-rich 2,6-dimethoxyphenyl N-substituted triazol-2-ylidene catalyst [41].

There are additional Breslow intermediate reactivity routes that do not need a formal umpolung at the carbonyl carbon [42]. For instance, removing a leaving group from the a-position can lead to the same kind of acyl azolium salts as those produced by adding NHC to esters. Similar species can also be produced via the direct in situ oxidation of the Breslow intermediate in the presence of an external oxidant or by pre-oxidised substrates like ketenes. Upon addition-elimination of a nucleophile, these intermediates may release the NHC fragment immediately, or they may first react as enolate or enone equivalents with the azolium moiety as a bystander [43].

The reactivity of α,β-unsaturated aldehydes is a potent and well-studied class of transformations. Because to the extended p-system of the Breslow-type intermediates produced with these substrates, nucleophilic attack may take place conjugately to produce products with an umpolung at the β-position (referred to as a “conjugate umpolung” [44]). In these methods, sterically demanding NHC catalysts that inhibit competitive functionalization at the traditional “carbonyl” position are frequently advantageous. The first conjugate addition of the NHC to the β-position as opposed to the carbonyl group occurs in another category of reactions with a,b-unsaturated carbonyl compounds. After this, the resultant adducts can react to produce products that are a- or b-functionalized as a consequence of chemistry of the Morita-Baylis-Hillman type or a formal umpolung at the b-position, respectively [45]. Accessing the umpolung reactivity seen with aldehydes from other kinds of substrates is one very fascinating topic of current study endeavour. Chi and coworkers recently published an exquisite proof of this idea in a number of annulation reactions of saturated aliphatic esters [46]. Figure 9 provides a mechanistic explanation for these events and illustrates how the critical diamino dienol Breslow-type intermediate is formed. The acyl azolium salt that results from the first nucleophilic addition-elimination of the NHC to the ester group tautomerizes to produce an enol species. The azolium group in this molecule has an electron-withdrawing property that makes the b-CH2 protons very acidic. If there is an excess of DBU base (where DBU is 1,8-diazabicyclo [5.4.0] undec-7-ene, 1.5–2 equiv.), deprotonation can take place to produce the homoenolate equivalent. The high degree of conjugation present in the resultant intermediate with b-aryl-substituted substrates can also help to explain the extraordinary selectivity for this deprotonation step over more traditional a-functionalization methods. The Breslow-type species, which may react as a nucleophile through conjugate umpolung to produce b-functionalized products, is comparable to that synthesised under standard circumstances using a,b-unsaturated aldehyde substrates.

Figure 9.

Mechanistic explanation for diamino dienol Breslow-type intermediate formation.

Aliphatic esters are often used as feedstocks in organic chemistry, but there are few other synthetic techniques for specifically activating the b-position of these substrates. This approach also permits high degrees of enantiocontrol during the annulation processes utilising the chiral triazol-2-ylidene catalyst, delivering five-membered heterocycles in enantiomeric ratios using enone, trifluoroketone, or hydrazone electrophiles (the reaction with enones is shown in Figure 10).

Figure 10.

Reaction of NHC with enones.

6. Conclusions

One of the most significant achievements in contemporary chemical research is undoubtedly the discovery and development of N-heterocyclic carbenes. Since Arduengo and colleagues originally described the first “bottleable” NHC 23 years ago, significant research on the structure, coordination chemistry, and reactivity of these compounds by other groups has resulted in a wide range of applications in numerous industries. NHCs are currently the mainstays of organic and organometallic chemistry, competing with phosphines in the role of auxiliary ligands in transition metal catalysis and opening up new avenues in main-group chemistry and organocatalysis.

However, the rapid growth of NHCs is far from over, as our hope is evident from the examples of current research discussed in this review. NHCs continue to play a variety of novel functions in the chemical sciences in addition to their existing ones. Heterogeneous catalysis is one promising area where the strength of NHC-metal binding might provide improved stability of metallic colloids or surfaces with the potential to change the catalyst’s capabilities by in situ functionalization of the ligand. The growing usage of NHCs in metallopharmaceuticals may also be explained by the stability and strength of the metal–ligand connection as well as the ease with which one can modify the structural characteristics of organometallic complexes. The use of NHCs is becoming more widely accepted in domains where significant progress is also being achieved. Recent ground-breaking research in the field of organocatalysis has concentrated on the creation of novel reactivity pathways that broaden the spectrum of acceptable reaction partners beyond the conventional aldehydes.

The creation of novel NHCs with unique characteristics and reactivities is one of the main forces behind the most innovative research currently being conducted. In the area of homogeneous transition-metal catalysis, new chelating imidazolin-2-ylidene ligands on ruthenium catalysts have made it easier to catalyse Z-selective olefin metathesis, while recently created chiral NHC ligands have showed promise in asymmetric hydrogenation processes. The stability of hitherto inaccessible non-metallic species and the activation of tiny molecules have both been made possible by new classes of NHCs, such as DACs and CAACs, which have displayed an unheard-of reactivity. The recent report of an organic radical that had been stabilised by a CAAC and was “bottleable” serves as an example of how well CAACs are suited to this type of stabilisation. The future of NHCs appears to be highly promising given the significant advancements made over the previous two decades and the high calibre research now being carried out.

Acknowledgments

The authors are thankful to CSIR-IIIM Jammu to support this work.

Conflict of interest

The authors declare no conflict of interest.

Appendices and nomenclature

Ac

Acetyl

aq

Aqueous

Boc

tert-Butoxycarbonyl

Bu

n-Butyl

Bn

Benzyl

CAN

Ceric ammonium nitrate

CH₃CN

Acetonitrile

Cbz

Benzyloxycarbonyl

CuAAC

CuI-catalysed azide-alkyne cycloaddition

Cu(OAc)₂

Copper acetate

CuSO₄

Copper sulphate

Cy

Cyclohexyl

d.r.

Diastereomeric ratio

DCM

Dichloromethane

DIAD

Diisopropyl azodicarboxylate

DMF

Dimethylformamide

DMSO

Dimethylsulfoxide

Et

Ethyl

h

Hours

IPA

Isopropanol

m.p.

Melting point

Me

Methyl

mCPBA

Meta perchloro benzoic acid

min

Minutes

n-Bu

n-Butyl

NaN₃

Sodium azide

NH₃

Ammonia

NHC

N-heterocyclic carbene

Ph

Phenyl

Py

Pyridine

R_f

Retention factor

RT

Room temperature

TBS

tert-Butyldimethylsilyl

^tBu

tert-Butyl

TEA

Triethylamine

Tf

Trifluoromethanesulfonyl

TFA

Trifluoroacetic acid

THF

Tetrahydrofuran

Tosylate

p-Toluenesulfonate

Triflate

Trifluoromethanesulfonate

Ts

p-Toluenesulfonyl