Cu(I)-catalyzed azide–alkyne 1,3-dipolar cycloaddition (CuAAC), popularly known as the “click reaction”, serves as the most potent and highly dependable tool for facile construction of simple to complex architectures at the molecular level. Click-knitted threads of two exclusively different molecular entities have created some really interesting structures for more than 15 years with a broad spectrum of applicability, including in the fascinating fields of synthetic chemistry, medicinal science, biochemistry, pharmacology, material science, and catalysis. The unique properties of the carbohydrate moiety and the advantages of highly chemo- and regioselective click chemistry, such as mild reaction conditions, efficient performance with a wide range of solvents, and compatibility with different functionalities, together produce miraculous neoglycoconjugates and neoglycopolymers with various synthetic, biological, and pharmaceutical applications. In this review we highlight the successful advancement of Cu(I)...

Cu-Catalyzed Click Reaction in Carbohydrate Chemistry

The engineering of catalysts with desirable properties can be accelerated by computer-aided design. To achieve this aim, features of molecular catalysts can be condensed into numerical descriptors that can then be used to correlate reactivity and structure. Based on such descriptors, we have introduced topographic steric maps that provide a three-dimensional image of the catalytic pocket-the region of the catalyst where the substrate binds and reacts-enabling it to be visualized and also reshaped by changing various parameters. These topographic steric maps, especially when used in conjunction with density functional theory calculations, enable catalyst structural modifications to be explored quickly, making the online design of new catalysts accessible to the wide chemical community. In this Perspective, we discuss the application of topographic steric maps either to rationalize the behaviour of known catalysts-from synthetic molecular species to metalloenzymes-or to design improved catalysts.

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Towards the online computer-aided design of catalytic pockets

Discovered in 2005, cyclic (alkyl)(amino)carbenes (CAACs) are among the most nucleophilic (σ donating) and also electrophilic (π-accepting) stable carbenes known to date. These properties allow them to activate a variety of small molecules and enthalpically strong bonds, to stabilize highly reactive main-group and transition-metal diamagnetic and paramagnetic species, and to bind strongly to metal centers, which gives rise to very robust catalysts. The most important results published up to the end of 2013 are briefly summarized, while the majority of this Review focuses on findings reported within the last three years.

Cyclic (Alkyl)(amino)carbenes (CAACs): Recent Developments

Mesoionic carbenes are a subclass of the family of N-heterocyclic carbenes that generally feature less heteroatom stabilization of the carbenic carbon and hence impart specific donor properties and

Mesoionic and Related Less Heteroatom-Stabilized N-Heterocyclic Carbene Complexes: Synthesis, Catalysis, and Other Applications.

The emergence of N-heterocyclic carbenes as ligands across the Periodic Table had an impact on various aspects of the coordination, organometallic, and catalytic chemistry of the 3d metals, including Cu, Ni, and Co, both from the fundamental viewpoint but also in applications, including catalysis, photophysics, bioorganometallic chemistry, materials, etc. In this review, the emergence, development, and state of the art in these three areas are described in detail.

N-Heterocyclic Carbene Complexes of Copper, Nickel, and Cobalt

The copper-catalyzed 1,3-dipolar cycloaddition of an azide to a terminal alkyne (CuAAC) is one of the most popular chemical transformations, with applications ranging from material to life sciences. However, despite many mechanistic studies, direct observation of key components of the catalytic cycle is still missing. Initially, mononuclear species were thought to be the active catalysts, but later on, dinuclear complexes came to the front. We report the isolation of both a previously postulated π,σ-bis(copper) acetylide and a hitherto never-mentioned bis(metallated) triazole complex. We also demonstrate that although mono- and bis-copper complexes promote the CuAAC reaction, the dinuclear species are involved in the kinetically favored pathway.

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Isolation of bis(copper) key intermediates in Cu-catalyzed azide-alkyne "click reaction".

Cyclic (alkyl)(amino)carbenes with a six-membered backbone were prepared. Compared to their five-membered analogues, they feature increased % Vbur and enhanced donor and acceptor properties, as evidenced by the observed n → π* transition trailing into the visible region. The high ambiphilic character even allows for the intramolecular insertion of the carbene into an unactivated C(sp3)-H bond. When used as ligands, they outcompete the five-membered analogues in the palladium-mediated α-arylation of ketones with aryl chlorides.

Highly Ambiphilic Room Temperature Stable Six-Membered Cyclic (Alkyl)(amino)carbenes.

A novel synthetic route gives access to mesoionic carbene and cyclopropenylidene supported gold chloride complexes. The corresponding cationic MIC-gold complex obtained by chloride abstraction allows for the first transition metal-catalyzed functionalization of both nitrogens of parent hydrazine.

Mesoionic Carbene‐Gold(I) Catalyzed Bis‐Hydrohydrazination of Alkynes with Parent Hydrazine

It has been previously demonstrated that stable singlet electrophilic carbenes can behave as metal surrogates in the activation of strong E-H bonds (E = H, B, N, Si, P), but it was believed that these activations only proceed through an irreversible activation barrier. Herein we show that, as is the case with transition metals, the steric environment can be used to promote reductive elimination at carbon centers.

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Reductive Elimination at Carbon under Steric Control.

Many organic and main-group compounds, usually acids or bases, can accelerate chemical reactions when used in substoichiometric quantities, a process known as organocatalysis. In marked contrast, very few of these compounds are able to activate carbon monoxide, and until now, none of them could catalyze its chemical transformation, a classical task for transition metals. Herein we report that a stable singlet ambiphilic carbene activates CO and catalytically promotes the carbonylation of an o-quinone into a cyclic carbonate. These findings pave the way for the discovery of metal-free catalyzed carbonylation reactions.

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Daniel R. Tolentino

Papers

Isolation of bis(copper) key intermediates in Cu-catalyzed azide-alkyne "click reaction".

Highly Ambiphilic Room Temperature Stable Six-Membered Cyclic (Alkyl)(amino)carbenes.

Mesoionic Carbene‐Gold(I) Catalyzed Bis‐Hydrohydrazination of Alkynes with Parent Hydrazine

Reductive Elimination at Carbon under Steric Control.

Realizing Metal-Free Carbene-Catalyzed Carbonylation Reactions with CO