Ab initio investigation of the kinetics and mechanism of the neutral hydrolysis of formamide in aqueous solution

Abstract

A hidrólise neutra da formamida em solução aquosa foi investigada por métodos ab initio de alto nível, incluindo o efeito do solvente pelo modelo contínuo polarizável (PCM). Considerou-se até quatro moléculas explícitas de água, sendo analisados os mecanismos envolvendo a formação do intermediário tetraédrico (stepwise mechanism) e o mecanismo de formação direta do ácido carboxílico via expulsão de amônia (concerted mechanism), estes com a participação de moléculas de água agindo como um catalisador bifuncional. Também foi investigado um mecanismo de catálise básica geral, com uma molécula de água agindo como base. Os cálculos em nível CCSD(T)/6-311+G(2df,2p)/ /MP2/6-31G(d) predizem que o mecanismo stepwise com duas moléculas de água no estado de transição é o mais favorável. Porém, a barreira de energia livre de 48,7 kcal mol-1 indica que a cinética é extremamente lenta e a reação não seria observada. Também analisamos o efeito do solvente sobre a geometria do estado de transição e notamos que esse efeito é de pouca importância na barreira energética. Testes com a teoria do funcional da densidade, usando o funcional B3LYP, mostram que conjuntos pequenos de funções de base como 6-31G(d) leva a barreiras de ativação extremamente subestimadas, enquanto que o uso do conjunto de funções de base 6-311+G(2df,2p) prevê barreiras próximas ao nosso melhor nível de cálculo. O presente estudo levanta dúvidas com relação a barreira experimental de 31 kcal mol-1 e sugerimos que a constante cinética k w reportada na literatura seja apenas um artefato matemático oriundo do ajuste de curvas. The neutral hydrolysis of formamide in aqueous solution involving up to four explicit solvent molecules was theoretically investigated using high level ab initio methods and including the bulk solvent effect through the Polarizable Continuum Model (PCM). We have analyzed cyclic transition states structures involving bifunctional catalysis and a general base catalysis structure. Both a stepwise mechanism with tetrahedral intermediate formation and a concerted mechanism were investigated. Our calculations at CCSD(T)/6-311+G(2df,2p)//MP2/6-31G(d) level predict an observable activation free energy barrier of 48.7 kcal mol-1 , corresponding to a stepwise water catalyzed mechanism with two water molecules into the transition state. Liquid phase geometry optimization was also performed, but the effect on the activation free energy is modest. Tests with density functional theory were carried out. The B3LYP/6-31G(d) calculation underestimates the barrier by 13 kcal mol-1 , whereas the B3LYP/6-311+G(2df,2p) method predicts an accurate barrier. The present study raises important questions about the reliability of the experimental activation free energy of 31.0 kcal mol-1 and suggests that the neutral hydrolysis of formamide does not take place at all.

Kinetic Solvent Effects in Organic Reactions

“…Integrating such methods with computational methods to calculate reaction rates in liquids, such as the continuum methods discussed in Section 3.2 and used in several of the discussed studies 24,52,54,73,78,79 , could provide a systematic approach to calculating many reaction rates in different solvents. This large volume of reaction rates could then be used to train a machine learning model to predict solvent effect from molecular properties.…”

Dual bifunctional catalysis and the α-effect in the reaction of hydroxylamine with phenylacetate

“…Previous studies on similar reactions have indicated that this level of theory is reliable. 21 Therefore, our gas phase calculations correspond to the B3LYP/6-311+G(2df,2p)//HF/6-31G(d) level. Because the reaction takes place in an aqueous solution, the solvent effect was included through the polarizable continuum model (PCM) [22][23][24][25] with atomic radii of 1.70 (C), 1.20 (H), 1.50 (O), 1.60 (N) and a scale factor of 1.20 for all atoms, as well as the dielectric constant of water.…”

“…Nevertheless, many previous studies have indicated that this process has a very high activation barrier for neutral nucleophiles and is viable only for ionic nucleophiles. 21,[28][29][30][31][32][33][34] In the case of neutral nucleophiles, water molecules or a second nucleophile molecule can act as a catalyst. In the reaction of hydroxylamine with phenylacetate, we found a similar situation.…”

Calculation of free-energy curves for the study of hydrolysis reactions in aqueous solution from ab initio potentials and molecular dynamics simulation

“…The hydrolysis of formamide is a reaction of primary importance since it can be considered as a model for the study of peptidic bonds. This reaction is catalyzed by both acids and bases, and neutral or water catalyzed hydrolysis is also possible [32][33][34][35][36][37]. Some experiments favour a base-catalyzed mechanism even in acid-catalyzed aqueous solution, but recent experiments [38] have allowed the neutral amide hydrolysis, although is generally accepted as being a slow and only very slightly exothermic process.…”

“…A number of theoretical studies have been devoted to the neutral hydrolysis of formamide, among which it is worth highlighting the work by Almerindo and Pliego [32], Antonczak et al [33,34] and the recent studies by Estiu and Merz [35] and Gorb et al [36].…”