A Ligand-Dissociation-Involved Mechanism in Amide Formation of Monofluoroacylboronates with Hydroxylamines

Abstract

Acylborons, as a growing class of boron reagents, were successfully applied to amide ligation and showed potential in chemoselective bioconjugation reactions in recent years. In this manuscript, a density functional theory (DFT) study was performed to investigate the mechanism of the amide formation between monofluoroacylboronates and hydroxylamines. An updated pathway was clarified herein, including water-assisted hemiaminal formation, pyridine ligand dissociation, elimination via a six-membered-ring transition state, and water-assisted tautomerization. The proposed mechanism was further examined by applying it to investigate the activation barriers of other monofluoroacylboronates, and the related calculations well reproduced the experimentally reported relative reactivities. On the basis of these results, we found that the ortho substitution of the pyridine ligand destabilizes the acylboron substrates and the hemiaminal intermediates by steric effects and thus lowers the energy demand of the ligand dissociation and elimination steps. By contrast, the para substitution of the pyridine ligand with an electron-donating group enhances the coordination of the ligand by electronic effects, which is a disadvantage to the ligand dissociation and elimination steps. The ligand bearing a rigid linkage blocks the rotation of the pyridine ligand and makes ligand dissociation difficult.

A novel and stable hydroxylamine salt generated from betaine hydrochloride and its application in the synthesis of cyclohexanone oxime

“…23,24 Recently, the M06 method has often been utilized to investigate processes involving BH and hydroxylamine. 14,[25][26][27][28] The geometries of each species involved were fully optimized at the level of 6-31+g(d,p) in the gas phase. Frequency analyses were conducted with the same basis set to confirm that the optimized structures were ground states without imaginary frequency.…”

Acyl metalloids: conformity and deviation from carbonyl reactivity

“…Subsequent elimination via a sixmembered-ring transition state, and final water-assisted tautomerization generates the corresponding amide (36). 37 The Please do not adjust margins Please do not adjust margins utility of this ligation strategy was emphasized through the development of a traceless, templated amide forming process that proceeds at low micromolar concentrations in aqueous media. 38 Bode and coworkers also demonstrated an amide formation process between primary amines or amides with KATs (4) promoted by simple chlorinating agents, such as 1,3-dichloro-5,5-dimethylhydantoin (DCH) and 1,3,5-trichloroisocyanuric acid (TCCA) (Scheme 10a).…”

“…Subsequent elimination via a six-membered-ring transition state, and final water-assisted tautomerization generates the corresponding amide ( 36 ). 37 The utility of this ligation strategy was emphasized through the development of a traceless, templated amide forming process that proceeds at low micromolar concentrations in aqueous media. 38 …”

Double-Regiodetermining-Stages Mechanistic Model Explaining the Regioselectivity of Pd-Catalyzed Hydroaminocarbonylation of Alkenes with Carbon Monoxide and Ammonium Chloride

“…Given our interest in the amide bond formation and Pd-catalyzed cross-couplings with CO, we also conducted a DFT study to investigate the HAC reactions reported by Huang . Different mechanistic insights were discovered for the Pd-catalyzed couplings of mono-substituted alkenes, CO, and NH 4 Cl with P­( t Bu) 3 and xantphos as ligands.…”