The thermal and boron-catalysed direct amide formation reactions: mechanistically understudied yet important processes

Abstract

Despite the amide formation reaction being one of the key cornerstone reactions in organic chemistry, the direct amide formation is both little used and little explored. Acceptance of the feasibility and general applicability of the reaction depends upon the ability of researchers to bring it into the mainstream by development of: (1) an understanding of the mechanism of the reaction; and (2) the design of catalysts which promote the reaction on a wide range of substrates and under ambient conditions. From the earliest report of the direct amide formation in the 19th century, there have been relatively few reports of mechanistic studies, though it is clear that there is not a simple relationship between ease of direct amide formation and the pK(a) of the carboxylic acid and amine, or whether salt ammonium carboxylate formation is important. Consequently, direct amide formation has historically been run under higher temperature conditions. However, more recently, stoichiometric and catalytic boron compounds have been developed that considerably reduce the reaction temperatures under which direct amide formation will proceed. Limited attempts at mechanistic studies point to the formation of acyloxyborate or boronate species acting essentially as mixed anhydrides, though the exact order of these systems remains to be categorically determined.

Catalytic amide formation from non-activated carboxylic acids and amines

“…10 As mentioned above, it is well-known that amides can be formed by the thermal treatment of a carboxylic acid and an amine without any catalyst present, generally at reaction temperatures of >140 ºC. 11 Recently, it was shown that a significant amount of the 15 amide product can be formed even at lower temperatures, usually with azeotropic removal of water. 12,13,14 The yields of the thermal amidation reaction is highly substrate dependent, as well as dependent on temperature, substrate concentration, solvent and other reaction parameters.…”

Possible Evidence of Amide Bond Formation Between Sinapinic Acid and Lysine-Containing Bacterial Proteins by Matrix-Assisted Laser Desorption/Ionization (MALDI) at 355 nm

“…Unlike our previous hypothesis of covalent attachment at the side chain of cysteine residues [42], we have concluded that the attachment is more likely to occur at the side-chain of lysine residues (and the N-terminus) as a result of formation of a solid phase ammonium carboxylate salt during the MALDI sample preparation. We propose that the rapid heating and/or dipole/electromagnetic interaction during the laser pulse result in equilibrium retrogradation of the dry salt followed by nucleophilic attack of the lysine amine at the carbonyl carbon of the SA resulting in amide bond formation with concomitant loss of water (dehydration) [45][46][47]. Such a mechanism was proposed for amide bond formation by microwave irradiation of neat mixtures of primary amines and carboxylic acids where it was proposed that a transition state dipole/electromagnetic interaction (i.e., a non-thermal process) was primarily responsible for facilitating amide bond formation [46].…”

Direct Hydrogenation of Nitroaromatics and One‐Pot Amidation with Carboxylic Acids over Platinum Nanowires

“…However, this procedure requires elevated temperatures owing to the formation of unreactive carboxylate-ammonium salts as the intermediates. [7,8] Recently, Whiting and co-workers [8] reviewed the use of efficient boron-based catalysts for this transformation. However, these catalysts also display some disadvantages: synthesis of the boron complex catalysts is not trivial, and separation of the products from the reaction mixture can be difficult because they are homogeneous catalysts.…”