Computational study of the mechanism of amide bond formation via CS₂-releasing 1,3-acyl transfer

Abstract

Reactions of thiocarboxylic acids and dithiocarbamate-terminal amines provide a linker-traceless method for amide bond formation under mild conditions, whereas the reaction mechanism is not clear. A systematic study was performed herein with density functional theory (DFT) calculations to elucidate the detailed mechanism, the substitution effect on the proposed CS2-releasing 1,3-acyl transfer and the differences between CS2- and CO2-releasing 1,3-acyl transfer. Relevant results indicate that this type of reaction proceeds via the nucleophilic addition of an in situ generated dithiocarbamic acid on thiocarboxylic acid, H2S elimination, rate-determining 1,3-acyl transfer and CS2 release. For the generation of secondary amides via the 1,3-acyl transfer, a thiocarboxylic acid- or dithiocarbamic acid-assisted pathway, in which both the carbonyl group and amide nitrogen are activated, is the most favored. For the generation of tertiary amides, MeOH-assisted carbonyl-activation is the most favorable pathway. N,N-Dialkyl substitution of the mixed anhydride intermediate promotes the 1,3-acyl transfer by the steric effect. In contrast, N-phenyl substitution and using thiobenzoic acid as a substrate slow down 1,3-acyl transfer by both the conjugation effect and steric effect. Furthermore, CS2-releasing 1,3-acyl transfer was found to be favored over CO2-releasing 1,3-acyl transfer in the aspects of both kinetics and thermodynamics mainly because the S-COR bond is weaker than the O-COR bond.

Computational Study of Mechanism and Thermodynamics of Ni/IPr-Catalyzed Amidation of Esters

“…Newman and coworkers recently disclosed a Ni/IPr-catalyzed amidation of ester under Lewis acid-free conditions [ 54 ] ( Scheme 1 c). This transformation attracts our mechanistic interests [ 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ]; particularly for the Lewis-acid free Ni-mediated C–O bond cleavage and C–N bond formation. Here we report a computational study on the mechanism of Ni/IPr-catalyzed amidation of ester and the thermodynamic equilibrium of amidation.…”

N‐Carboxyanhydrides (NCAs): Unorthodox and Useful Reagents for Amide Synthesis

“…The mechanistic proposal offered by the authors proceeds via addition of thioacids 30 to the dithiocarbamate intermediate. Transthioesterification of the two species to form a transient thia‐NCA intermediate (not observed) is supported by a separate computational study, [7a] which can undergo elimination of CS 2 to generate the amide product 31 . Overall, a wide variety of amides were prepared including histidine‐, tyrosine‐, tryptophan‐ and asparagine‐containing dipeptides without the use of side‐chain protecting groups and without detectable erosion of ee (Scheme 8).…”

Topology of electrostatic potential and electron density reveals a covalent to non-covalent carbon–carbon bond continuum

“…For a limited set of data, an exploratory MESP topology analysis is conducted for atom-atom interactions such as C-N, C-O, C-S, N-N, O-O, and S-S, in molecules from diverse experimental and theoretical investigations. [94][95][96][97][98][99][100] The study takes into account the covalent, non-covalent, and borderline cases. In all cases, the magnitude of the positive eigenvalue l v1 showed relatively large values compared to the magnitude of both l v2 and l v3 , wherein l v2 D l v3 .…”