Discovering New Reactions with N-Heterocyclic Carbene Catalysis.
Year: 2009
Type: article
Abstract: Inspired by advances in our understanding of biological processes, new reactions employing organic molecules as catalysts have grown significantly over the last two decades.1 In the broadest of terms, the most successful of these catalysts can be classified either as Bronsted acids,2,3 hydrogen-bond donors,4–7 or Lewis bases.8–11 Each of these catalytic manifolds activates substrates in biological settings and provides an inspiring blueprint to create smaller, synthetic versions of these impressive biocatalysts. Lewis base catalysis is presently an exciting area of research and encompasses a wide variety of strategies to initiate both established and new chemical processes.12,13 An elegant and key biological transformation utilizes the cofactor thiamine, a coenzyme of vitamin B1, to transform α-keto acids into acetyl CoA, a major building block for polyketide synthesis. In this process, a normally electron-deficient molecule (e.g., pyruvic acid) is converted into an intermediate that possesses electron density on the carbon atom that was initially part of the carbonyl system. These carbonyl or acyl anions are unusual since they have “umpolung” (reversed polarity) when compared to the initial keto acids. In 1954, Mizuhara and Handler proposed that the active catalytic species of thiamine-dependent enzymatic reactions is a highly unusual divalent carbon-containing species,14 later on referred to as an N-heterocyclic carbene (NHC). An alternative description of the active thiamine cofactor employs the term zwitterion, which can be viewed as a resonance form of the carbene description. This unique cofactor accomplishes fascinating Lewis base catalyzed transformations by utilizing the lone pair of electrons at C-2.
In the early 1960s, Wanzlick and co-workers realized that the stability of carbenes could be dramatically enhanced by the presence of amino substituents, and they attempted to prepare a carbene center at C-2 of the imidazole ring.15,16 However, only the dimeric electron-rich olefin was isolated. Later on, Wanzlick's group demonstrated that potassium tert-butoxide can deprotonate imidazolium salts to afford imidazol-2-ylidenes, which can be trapped with phenyl isothiocyanate and mercury salts.17–19 However, Wanzlick's group never reported the isolation of the free carbene. Following these results, Arduengo et al. isolated in 1991 a stable crystalline N-heterocyclic carbene by the deprotonation of 1,3-di(1-adamantyl)imidazolium chloride with sodium or potassium hydride in the presence of a catalytic amount of either potassium tert-butoxide or dimethyl sulfoxide.20 The structure was unequivocally established by single-crystal X-ray analysis, and the carbene was found to be thermally stable, which stimulated extensive research in this field.
The nature of the stabilization is ascribed to the steric and electronic effects of the substituents: The two adamantyl substituents hinder reactions of the carbene center with external reagents as well as prevent dimerization. In 1992, Arduengo et al. expanded this carbene class by successfully isolating the carbene from 1,3,4,5-tetramethylimidazolium chloride by treating the latter with sodium hydride and catalytic amounts of potassium tert-butoxide in tetrahydrofuran.21 The successful isolation of carbenes with less bulky substituents demonstrates that electronic factors may have greater impact on the stability of the carbene than steric ones. Such electronic factors operate in both the π and σ frameworks, resulting in a “push-pull” synergistic effect to stabilize the carbene. π donation into the carbene from the out-of-the-plane π orbital of the heteroatoms adjacent to C-2 stabilizes the typical electrophilic reactivity of carbenes. The electronegative heteroatoms adjacent to C-2 provide additional stability through the framework of σ bonds, resulting in a moderation of the nucleophilic reactivity of the carbene (Figure 1).22 The combination of these two effects serves to increase the singlet–triplet gap and stabilize the singlet-state carbene over the more reactive triplet-state one.
Figure 1
Proposed Stabilization of N-Heterocyclic Carbenes through σ and π Electronic Effects. (Ref. 22)
The electronic properties of NHCs are a key determinant of the unique reactivity of these catalysts. Lewis bases are normally considered as single electron-pair donors. However, the singlet carbenes of NHCs are distinct Lewis bases that have both σ basicity and π acidity characteristics. These attributes allow for the generation of a second nucleophile in the flask. Nucleophilic addition of the carbene to an aldehyde results in the formation of a new nucleophile. The “doubly” nucleophilic aspect is unique to the carbenes. The combination of these characteristics allows NHCs to react as powerful nucleophiles, which has driven the development of a distinct class of catalytic processes during the last decade. This review highlights our work in this young and promising field.
Source: PubMed
Authors: Eric M Phillips, Audrey Chan, Karl A Scheidt
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
Funder: National Institutes of Health
OpenAlex ID: W189855860