Mechanistic Elucidation of Zirconium-Catalyzed Direct Amidation

Abstract

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.

Low‐Temperature Reverse Water–Gas Shift Process and Transformation of Renewable Carbon Resources to Value‐Added Chemicals

“…In this work, the reaction was catalyzed by a Ru–Rh bimetallic catalyst with LiI as promoter in HMimBF 4 , as shown in Table . Acetic acid was the main product from the reaction of lignin and CO 2 and H 2 (Figures S6 and S7 in the Supporting Information) . At 140 °C, the output of acetic acid was as high as 0.16 g g −1 lignin, and the yield of acetic acid was 48.3 % based on the content of methoxy groups in the PA‐lignin (Table , entry 1), which is close to the reported values starting from CO and H 2 O in the literature …”

Zirconium catalyzed amide formation without water scavenging

“…In analogy with previously reported Group IV metal‐catalyzed amidation protocols,[5a,9] excess amine was beneficial for the reaction outcome and enabled a decrease in catalyst loading (see Supporting Information). As a result, 94% yield was observed in 48 hrs using 2 mol% catalyst and starting concentrations of 0.4 M and 0.8 M for 1a and 2a , respectively (Table , entry 8).…”

“…Aromatic acids reacted sluggishly even in the presence of a large excess of 2a and extended reaction times with benzoic acid giving rise to higher yields compared to analogues with either electron withdrawing or donating substituents ( 3f‐h ). This finding stands in contrast to the previously reported protocol catalyzed by ZrCl 4 , where electron‐poor benzoic acids reacted faster than more electron‐rich analogues . Although unexpected, this difference does not necessarily indicate different operating mechanisms between the dry and the non‐dry Zr‐catalyzed protocols and may result from differences in equilibria of ammonium carboxylate salts and/or other off‐cycle species.…”

Direct amidation of non‐activated carboxylic acid and amine derivatives catalyzed by TiCp2Cl2

“…In 2011, Whiting et al proposed the possible mechanism of uncatalyzed direct amidation through hydrogen-bonded dimeric carboxylic acid, [37] in 2017, Adolfsson et al elucidated the mechanism of zirconium-catalyzed direct amidation through a dinuclear zirconium species. [32] The normal Lewis acid mechanism of Ti (OBu) 4 -catalyzed esterification of acid and alcohol was proposed by Bonora et al in 1985. [39] As showed in Figure 5, when the phenylacetic acid was heated in THF under 70 C in the presence of 10 mol% catalyst and 4 Å molecule sieves to afford a small amount of the anhydride of phenylacetic acid after 10 hr.…”