1
An Overview of NHCs

Matthew N. Hopkinson1 and Frank Glorius2

1 Freie Universität Berlin, Institut für Chemie und Biochemie, Takustr. 3, 14195 Berlin, Germany

2 Westfälische Wilhelms-Universität Münster, Organisch-Chemisches Institut, Corrensstr. 40, 48149 Münster, Germany

Since the unambiguous isolation of the first free N-heterocyclic carbene () IAd in 1991 by Arduengo et al. [1], these compounds have received a huge amount of attention from across the chemical community [2]. As stable examples of coordinatively unsaturated, electronically deficient carbene compounds, much of the earlier interest resulted from their status as academic curiosities. However, as studies were conducted on their properties and reactivity, the full potential of NHCs in many different areas of chemistry was revealed. As strong s-donors to metal centers, NHCs are nowadays widely used as ancillary ligands in organometallic chemistry including in industrially important catalytic transformations [3], rivaling phosphines, and cyclopentadienyls in this role. Many NHC-metal adducts are also attracting attention in materials science and as potential metallopharmaceuticals [4]. The strong binding properties and stabilizing features of NHCs have also led to many applications not involving metals. For example, boron-NHC adducts have been widely studied in a number of different contexts [5], whereas some classes of p-accepting NHCs have been shown to activate small molecules such as ammonia [6]. It is the reactivity of NHCs as organocatalysts, however, that forms the basis of this book [7]. First observed by Ukai et al. in a thiazolium salt-mediated benzoin condensation in 1943 [8], NHCs have proved efficient catalysts for umpolung reactions of aldehyde substrates, reacting via so-called Breslow intermediates, which can be considered acyl anion equivalents [9]. Alongside these processes, alternative transformations involving a wide range of different reactivity modes with both aldehydes and other substrate classes are possible with the application of chiral NHCs often allowing for high levels of enantioselectivity [10]. The scope and diversity of NHC organocatalysis continue to expand at a rapid pace and detailed summaries highlighting that the major reaction classes and current research trends are to be found in the subsequent chapters of this book. In this introductory chapter, we instead provide a general overview of NHCs, highlighting their common structural features and properties and briefly summarizing some of their uses outside of organocatalysis. The major synthetic routes to commonly employed NHC organocatalysts are discussed while a particular focus is given to understanding and comparing the various electronic and steric properties of different classes of NHC.

1.1 General Structure of NHCs

1.1.1 Classes of NHCs and Related Stable Carbenes

The definition of what constitutes an NHC is often subject to different interpretations, and many classes of carbene compounds have been labeled NHCs in the literature. For the sake of clarity, we consider an NHC as any compound featuring a carbene center as part of a heterocyclic ring containing at least one nitrogen atom. Many different carbenes satisfy these criteria, and a selection of some of the most important classes of NHC is shown in Figure 1.1. The first reported compound IAd (1a), isolated by Arduengo et al. [1], is an example of an imidazolylidene NHC (1). The carbene center in this species is situated between the two nitrogen atoms in an aromatic imidazole heterocycle. Imidazolylidenes of this type were the focus of many of the early studies on NHCs, and they continue to find applications across many areas of chemistry. Derivatives featuring aromatic nitrogen substituents such as mesityl (IMes, 1b) and 2,6-diisopropyl (IPr or IDipp, 1c) are particularly widely used as ligands for transition metals and feature in catalysts for cross-coupling reactions and other important transformations. Related to imidazolylidenes but often displaying different reactivity are their saturated imidazolinylidene analogs 2. These species also feature two nitrogen atoms adjacent to the carbene center in a five-membered heterocycle, yet are not aromatic. The first free imidazolinylidene NHC SIMes (2a) was prepared by Arduengo et al. [11], and this compound, which again features N-mesityl substituents, has since found a widespread use as a ligand for ruthenium in Grubbs' second-generation olefin metathesis catalysts [3f, u]. Benzimidazolylidenes 3 possess a benzene ring fused onto an imidazolylidene NHC while derivatives with larger ring sizes such as six-membered tetrahydropyrimidinylidenes 4 or various ring-sized N,N´-diamidocarbenes (s, 5) have been prepared. These latter compounds, pioneered by Bielawski and coworkers, have been shown to activate small molecules such as ammonia and undergo insertion into alkenes in a similar manner to classical triplet carbenes [12].

Figure 1.1 Some important classes of NHC with selected examples.

There is also no requirement for two nitrogen atoms in the heterocycle, and various NHC classes featuring an alternative heteroatom such as oxygen (oxazolylidenes, 6) or sulfur (thiazolylidenes, 7) in place of one nitrogen are accessible. Thiazolylidenes (7) have been particularly widely used as organocatalysts with the original report by Ukai et al. in 1943 making use of such a species, although the involvement of a free carbene as a catalyst was at that time not acknowledged [8]. NHCs 8, which feature one nitrogen as the only heteroatom in a pyrrolidinylidene ring, were introduced by Bertrand and coworkers [13] and are commonly referred to as cyclic (amino)(alkyl)carbenes () or cyclic (amino)(aryl)carbene () depending on the nature of the carbon substituent adjacent to the carbene center [14]. These compounds are more p-accepting than other classes of NHCs and have proved useful for stabilizing sensitive p-block species and even organic radicals [15]. There are also classes of NHCs that feature more than two nitrogen atoms in the heterocyclic ring. Triazolylidenes 9 have found a particularly widespread use as organocatalysts and can be considered the NHCs of choice for many transformations. Examples of widely employed triazolylidenes include 1,3,4-triphenyl-4,5-dihydro-1H-1,2,4-triazol-5-ylidene () (9a) [16], which is also often referred to as the Enders carbene and N-pentafluorophenyl (9b) or N-mesityl-substituted bicyclic systems (TMes, 9c). A further attractive feature of triazolylidene organocatalysts is the relative abundance of chiral derivatives such as compound 9d, which allows enantioselective reactions to be realized. In addition to considering the range of different NHC ring sizes and substitution patterns, distinct NHC structures can be accessed by generating the carbene center at different positions. Although the carbene carbon is normally situated between the two nitrogen atoms in imidazolylidenes 1, it is also possible to generate the carbene at the 4-position. In this case, a neutral, non-zwitterionic resonance structure cannot be drawn, and the species is referred as a mesoionic or "abnormal" carbene () 10 [17]. When the carbene center is not situated adjacent to a nitrogen atom, the species is called a "remote" NHC () 11 [18].

Although the above classes of compounds satisfy all the criteria for NHCs listed above, it is important to remember that many related non-NHC compounds have also been reported that possess similar structural features (Figure 1.2) [19]. For example, acyclic derivatives often known as acyclic diamino carbenes (s) (12) that do not feature a nitrogen heterocycle or species where the nitrogen has been replaced by a different heteroatom such as phosphorus have been synthesized [19, 20]. A free acyclic carbene species 13 stabilized by adjacent phosphorus and silicon substituents was in fact reported by Bertrand and coworkers in 1988, three years before the isolation of a free NHC [21]. Cyclopropenylidene compounds (14) featuring exocyclic nitrogens were also more recently synthesized by Bertrand and coworkers [22], while extended "bent allene" species such as 15 have themselves been used as ligands [23]. These compounds can be considered as acyclic carbenes stabilized by NHCs.

Figure 1.2 Selected related classes of stable carbene.

1.1.2 Structural Features Common to All NHCs

As shown in Figure 1.3 for the representative imidazolylidene IMes (1b), there are several structural features that are common to all classes of NHCs. These features each play a role in stabilizing the carbene moiety and variations in their structure or...