The amide functionality is found in a wide variety of biological and synthetic structures such as proteins, polymers, pesticides and pharmaceuticals. Due to the fact that synthetic amides are still mainly produced by the aid of coupling reagents with poor atom-economy, the direct catalytic formation of amides from carboxylic acids and amines has become a field of emerging importance. A general, efficient and selective catalytic method for this transformation would meet well with the increasing criterias for green 10 chemistry. This review covers catalytic and synthetically relevant methods for direct condensation of carboxylic acids and amines. A comprehensive overview of homogeneous and heterogeneous catalytic methods is presented, covering biocatalysis, Lewis acid catalysts based on boron and metals as well an assortment of other types of catalysts.

Amidst the green: A green, mild and effective protocol for the direct formation of secondary and tertiary amides from non‐activated carboxylic acids and amines in good to excellent yields by employing ZrCl4 as the catalyst is presented (see scheme). The amide coupling protocol proved to be suitable for scaled up syntheses, and the mild reaction conditions conserve the enantiopurity of chiral starting materials.

The arylation of secondary acyclic amides has been achieved with diaryliodonium salts under mild and metal-free conditions. The methodology has a wide scope, allows synthesis of tertiary amides with highly congested aryl moieties and avoids the regioselectivity problems observed in reactions with (diacetoxyiodo)benzene.

The reduction of amides gives access to a wide variety of important compounds such as amines, imines, enamines, nitriles, aldehydes and alcohols. The chemoselective transformation into these functional groups is challenging due to the intrinsic stability of the amide bond; nevertheless, the ability to reduce highly stable carboxamides selectively in the presence of sensitive functional groups is of high synthetic value for academic and industrial chemists. Hydride-based reagents such as LiAlH or diboranes are today the most commonly used compounds for amide reductions, and apart from the substantial amount of waste generated using these methods, they lack tolerance to most other functional groups. This tutorial review provides an overview of the recent progress made in the development of chemoselective protocols for amide reduction and gives an insight to their advantages and drawbacks.

The mechanism of the zirconium-catalyzed condensation of carboxylic acids and amines for direct formation of amides was studied using kinetics, NMR spectroscopy, and DFT calculations. The reaction is found to be first order with respect to the catalyst and has a positive rate dependence on amine concentration. A negative rate dependence on carboxylic acid concentration is observed along with S-shaped kinetic profiles under certain conditions, which is consistent with the formation of reversible off-cycle species. Kinetic experiments using reaction progress kinetic analysis protocols demonstrate that inhibition of the catalyst by the amide product can be avoided using a high amine concentration. These insights led to the design of a reaction protocol with improved yields and a decrease in catalyst loading. NMR spectroscopy provides important details of the nature of the zirconium catalyst and serves as the starting point for a theoretical study of the catalytic cycle using DFT calculations. These studies indicate that a dinuclear zirconium species can catalyze the reaction with feasible energy barriers. The amine is proposed to perform a nucleophilic attack at a terminal η-carboxylate ligand of the zirconium catalyst, followed by a C-O bond cleavage step, with an intermediate proton transfer from nitrogen to oxygen facilitated by an additional equivalent of amine. In addition, the DFT calculations reproduce experimentally observed effects on reaction rate, induced by electronically different substituents on the carboxylic acid.

The chemoselective reduction of amides in the presence of other more reactive reducible functional groups is a highly challenging transformation, and successful examples thereof are most valuable in synthetic organic chemistry. Only a limited number of systems have demonstrated the chemoselective reduction of amides over ketones. Until now, the aldehyde functionality has not been shown to be compatible in any catalytic reduction protocol. Described herein is a [Mo(CO)6 ]-catalyzed protocol with an unprecedented chemoselectivity and allows for the reduction of amides in the presence of aldehydes and imines. Furthermore, the system proved to be tunable by variation of the temperature, which enabled for either C-O or C-N bond cleavage that ultimately led to the isolation of both amines and aldehydes, respectively, in high chemical yields.

Tertiary amides are efficiently reduced to their corresponding enamines under hydrosilylation conditions, using a transition-metal-free catalytic protocol based on t-BuOK (5 mol %) and (MeO)3SiH or (EtO)3SiH as the reducing agent. The enamines were formed with high selectivity in good-to-excellent yields.

The increasing energy demand calls for the development of sustainable energy conversion processes. Here, the splitting of H2O to O2 and H2, or related fuels, constitutes an excellent example of solar-to-fuel conversion schemes. The critical component in such schemes has proven to be the catalyst responsible for mediating the four-electron oxidation of H2O to O2. Herein, we report on the unexpected formation of a single-site Ru complex from a ligand envisioned to accommodate two metal centers. Surprising N-N bond cleavage of the designed dinuclear ligand during metal complexation resulted in a single-site Ru complex carrying a carboxylate-amide motif. This ligand lowered the redox potential of the Ru complex sufficiently to permit H2O oxidation to be carried out by the mild one-electron oxidant [Ru(bpy)3](3+) (bpy = 2,2'-bipyridine). The work thus highlights that strongly electron-donating ligands are important elements in the design of novel, efficient H2O oxidation catalysts.