Mechanistic Insights into Direct Amide Bond Formation Catalyzed by Boronic Acids: Halogens as Lewis Bases

Abstract

Get the water out! DFT calculations predict water elimination from a tetrahedral intermediate to be the rate determining step in the title reaction. This transformation is calculated to be highly stereoselective, yielding cis amides as the kinetic products (see scheme). The superior activity of ortho‐halophenyl boronic acids results from the Lewis basic character of halogen atoms.

The Uncatalyzed Direct Amide Formation Reaction – Mechanism Studies and the Key Role of Carboxylic Acid H‐Bonding

“…More importantly, it is clear that highly charged zwitterionic species are not involved in the direct amide formation reaction, and indeed, this may even extrapolate to the boronic acid-catalyzed reaction variants. [20] DFT calculations suggest that a plausible mechanism for intermolecular direct amide formation proceeds through the existence of carboxylic acid hydrogen-bonded dimers, which are not only known to persist even at elevated temperatures but are likely to be highly favourable in nonpolar solvents. The role of such hydrogen-bonded dimers, as demonstrated in Scheme 3, is to enable both carboxylic acid activation towards nucleophilic attack by the amine, and to allow the reaction to proceed through to a neutral intermediate such as 8, which, according to the calculations, is energetically accessible.…”

Boron Ester‐Catalyzed Amidation of Carboxylic Acids with Amines: Mechanistic Rationale by Computational Study

“…Based on the literature, [14][15][16][17] the amidation is expected to start by the condensation of boron ester with carboxylic acid and the release of CF 3 CH 2 OH (Figure 1). In this step, the ligand exchange on the tetrahedral B2 generates the carboxylic acidcontaining species B3,f rom which the BÀOCOMe bond and CF 3 CH 2 OH are concertedly formed via TS1.T he trigonal bipyramidal transition state TS2 in which MeNH 2 is still attached to the boron centert op romote the cleavage of the BÀOR bond was considered.…”

“…on boron ester-catalyzed amidation, many efforts have previously been devoted to boron acid-catalyzed amidation. The density functional theory (DFT) studies from Marcelli, [15] Fu, [16] and co-workers on boron acid-catalyzeda midation support the formationo fa mide rather than catalystr egeneration as the rate-determining step. Very recently,t he studyf rom Whiting et al indicated that the reaction rate has ap ositive dependence on the amine concentration whereas the increase of carboxylic acid concentrationh as an egative effect on the reaction rate in boronic acid-catalyzed amidation.…”

Boronic Acid-Catalyzed Reactions of Carboxylic Acids

“…Marcelli's DFT calculations imply the formation of an acylborate intermediate 32 en route to an ortho-aminal transition state (TS-34) shown in Scheme 11 [40]. Strangely, according to the theoretical transition state, a water molecule is involved in the ortho-aminal breakdown.…”