A CO₂-Catalyzed Transamidation Reaction

Abstract

Transamidation reactions are often mediated by reactive substrates in the presence of overstoichiometric activating reagents and/or transition metal catalysts. Here we report the use of CO 2 as a traceless catalyst: in the presence of catalytic amounts of CO 2 , transamidation reactions were accelerated with primary, secondary, and tertiary amide donors. Various amine nucleophiles including amino acid derivatives were tolerated, showcasing the utility of transamidation in peptide modification and polymer degradation (e.g., Nylon-6,6). In particular, N,O-dimethylhydroxyl amides (Weinreb amides) displayed a distinct reactivity in the CO 2 -catalyzed transamidation versus a N 2 atmosphere. Comparative Hammett studies and kinetic analysis were conducted to elucidate the catalytic activation mechanism of molecular CO 2 , which was supported by DFT calculations. We attributed the positive effect of CO 2 in the transamidation reaction to the stabilization of tetrahedral intermediates by covalent binding to the electrophilic CO 2 .

An ETS‐NOCV‐based computational strategies for the characterization of concerted transition states involving CO2

“…According to the experimental results, almost all the amides receive an acceleration, but the best results are obtained with Weinrab amides (N‐methoxy‐N‐methylamides), for which the activation energy is lower (experimental Δ H ǂ = 19.0 kcal/mol, theoretical Δ H ǂ = 21.0 kcal/mol). Anyway, a high temperature is generally required (around 80°C) 15 …”

“…The second interesting case is about the recently proposed interaction between an amide and CO 2 , which demonstrated to actively promote the trans‐amidation reaction (Scheme 2 ). 15 …”

“…The second interesting case is about the recently proposed interaction between an amide and CO 2 , which demonstrated to actively promote the trans-amidation reaction (Scheme 2). 15 According to the experimental and theoretical mechanistic studies, the CO 2 acts as a template, using its acidic site to bind the oxygen of the ester, forming a carbonate, and the basic site to establish a strong H-bond with the attacking amine. In the subsequent step, the carbonate group acts as a proton shuttle, abstracting a proton from the attacking amine and transferring it to the nitrogen of the amide, therefore allowing the release of the leaving group with the simultaneous regeneration of and π*(C 1 O 3 ); ii) from lp(N 1 ) to π*(C 2 O 1 ); and iii) from lp(C 1 O 3 ) to σ* (N 1 H 1 ) (Table S16).…”

“…In a different research line, we discovered that CO 2 can also act as a catalyst for the trans‐amidation reaction, taking advantage of its amphoteric nature. 15 Indeed, the carbon atom of the CO 2 can form a covalent bond with the carbonyl oxygen of the amide, making the carbon more electrophilic, while the oxygen of CO 2 can abstract a proton from a primary/secondary amine, in a concerted or stepwise way, making the incoming nucleophile stronger (Scheme 2 ).…”

“…According to the experimental results, almost all the amides receive an acceleration, but the best results are obtained with Weinrab amides (N-methoxy-N-methylamides), for which the activation energy is lower (experimental ΔH ǂ = 19.0 kcal/ mol, theoretical ΔH ǂ = 21.0 kcal/mol). Anyway, a high temperature is generally required (around 80 C) 15. For our model reaction (see FigureS5, Supporting Information), the concerted TS, TS amide (see Figure5), shows only one imaginary frequency (À307.3 cm À1 ) in which there are the concurrent formation of a bond between the carbon of CO 2 and the oxygen of the amide (C 1 O 1 = 1.580 Å) and the formation of the bond between the carbon of the amide and the nitrogen of the amine (C 2 N 1 = 1.924 Å), leading to the tetrahedral intermediate PC amide .…”