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

Abstract

A reação da hidroxilamina com acetato de fenila foi investigada teoricamente para se obter uma melhor compreensão do efeito alfa nas reações de nucleófilos neutros. Os cálculos foram feitos em nível B3LYP/6-311+G(2df,2p)//HF/6-31G(d) incluindo o solvente (água) em nível PCM/HF/6-31G(d). Os resultados mostram que um ataque direto da hidroxilamina leva a uma barreira de energia livre de ativação DG ‡ muito alta, em torno de 50 kcal mol -1. Uma segunda molécula de hidroxilamina pode catalisar o processo através de catálise bifuncional usando ambos os grupos NH 2 e OH simultaneamente. Esta catálise bifuncional reduz o DG ‡ para 19 kcal mol -1 e é capaz de explicar a relação de produtos cinético e termodinâmico observada experimentalmente.The reaction of hydroxylamine with phenyl acetate was theoretically investigated to shed light on the role of catalysis and the origin of the a-effect in this system. Calculations at the B3LYP/6-311+G(2df,2p)//HF/6-31G(d) level and the solvent effect included at the PCM/HF/6-31G(d) level predict that the direct attack of hydroxylamine to the carbonyl centre has a high DG ‡ barrier, close to 50 kcal mol -1. A second hydroxylamine molecule can catalyse the process through bifunctional catalysis using both the NH 2 and OH groups simultaneously. This dual bifunctional catalysis decreases the DG ‡ to 19 kcal mol -1 and is able to explain the experimentally observed kinetics and product ratio.

The role of ammonia oxide in the reaction of hydroxylamine with carboxylic esters

“…Our previous report has indicated that explicit water molecules can facilitate the hydroxylamine attack to the carboxylic ester. 4 We can notice that the overall kinetic barriers (theoretical and experimental) differ by only 1.3 kcal mol −1 , while the relative barriers are 1.5 kcal mol −1 (theoretical) and 1.9 kcal mol −1 (experimental). Furthermore, the special structure of the tetrahedral intermediates like MS1b and MS2 suggests that -OH and -NH 2 groups can act more efficiently than explicit water, because no entropic cost will be involved.…”

“…5 However, the barrier is very high and not competitive. Our previous report has indicated that explicit water molecules can facilitate the hydroxylamine attack to the carboxylic ester.…”

“…3 Their analysis suggests that the mechanism is compatible with the formation of the tetrahedral intermediate and its breakdown is the rate determining step. 5 The investigated bimolecular mechanisms have considered direct attack of the hydroxylamine nitrogen or oxygen atoms with simultaneous proton transfer to the carbonyl (Scheme 2). More recently, Mazera et al have reported kinetic studies on the reaction of hydroxylamine with five different derivatives of phenylacetate.…”

“…Mazera et al 4,5 have found that hydroxylamine can act as a bifunctional catalyst involving the oxygen and nitrogen atoms simultaneously. Mazera et al 4,5 have found that hydroxylamine can act as a bifunctional catalyst involving the oxygen and nitrogen atoms simultaneously.…”

Fragment‐Based Lead Discovery: Screening and Optimizing Fragments for Thermolysin Inhibition

“…Possible mechanisms of the ring formation are described and discussed in the literature in detail. [36][37][38] Biochemical testing of the novel fragments revealed an overall improvement of binding affinity along with convincing ligand efficiency: 30 a (K i = 930 mm), 30 b (K i = 315 mm), and 30 c 33 n.i. (K i = 128 mm), with ligand efficiencies of 0.32 kcal, 0.34 kcal, and 0.36 kcal, respectively ( Table 2).…”