Kinetics and mechanism of hydrolysis of benzimidazolylcarbamates

Abstract

Através da carbamoilação do 2-aminobenzimidazole com diferentes cloroformatos substituídos, sintetizaram-se novos N- [1-(2-amino)benzimidazolil]carbamatos. Estudouse a hidrólise em meio aquoso destes carbamatos numa gama de pH compreendida entre 1 e 13, a uma temperatura de 25 ºC. Os parâmetros cinéticos avaliados levaram a concluir que até pH 4 a reação se processa por mecanismo que envolve o ataque bimolecular da água ao substrato N-protonado. Esta é a primeira vez que este comportamento é observado em carbamatos, sendo muito provavelmente devido à diferença de basicidade entre um dos azotos do anel de benzimidazolilo e o oxigênio da função carbamato. Para valores mais elevados de pH, os resultados são consistentes com um mecanismo B Ac 2, atuando a água como nucleófilo entre pH 4 e 7 enquanto que em pH superior o íon hidróxido é o nucleófilo.Synthesis of new 2-aminobenzimidazole-1-carbamates was accomplished by carbamoylation of 2-aminobenzimidazole using different substituted phenyl chloroformates. The aqueous hydrolysis of the new compounds was examined in the pH range 1-13 at 25 o C. The evaluated kinetic parameters led to the conclusion that up to pH 4 reaction proceeds by a bimolecular attack of water to the N-protonated substrate. This is the first time this behavior is described for carbamates, and can be ascribed to the higher basicity of the benzimidazolyl moiety when compared with the carbonyl oxygen. For higher values of pH, the results are consistent with a B Ac 2 mechanism with nucleophilic catalysis, but while between pH 4 and pH 7 water acts as the nucleophile, for pH> 7 the hydroxide ion is the acting species.

Preformulation Studies of Zidovudine Derivatives: Acid Dissociation Constants, Differential Scanning Calorimetry, Thermogravimetry, X-Ray Powder Diffractometry and Aqueous Stability Studies

“…The 5′- O -carbamate compounds 4 – 6 showed degradation reactions at an alkaline pH of 13.2, with k obs values of 1.04 × 10 −3 , 3.23 × 10 −3 and 1.96 × 10 −3 min −1 , respectively due to a base catalysis with a decreasing stability of 4 > 6 > 5 . Similar results were observed by Norberto et al for related compounds at different pH values [ 23 ].…”

Design, synthesis and evaluation of indole derivatives as multifunctional agents against Alzheimer's disease

“…Literature confirms that the propargylamine moiety is responsible for the MAO inhibitory properties of compounds containing this functional group. 29 The results obtained agree with this, as can be seen by the more potent IC 50 values upon inclusion of this moiety. The presence of a urea moiety (compounds 5 and 6) resulted in compounds that have comparably better inhibitory abilities than the carbamate compounds 7 and 8.…”

“…The carbamate on ladostigil is also open to acid hydrolysis and enzymatic metabolism, and once this metabolism takes place, it leaves a non-enzyme inhibiting neuroprotective molecule TV3279. 28,29 This loss of enzymatic ability may account for one of the reasons why ladostigil failed in Phase 2b AD clinical trials. In order to overcome these unfavourable properties of ladostigil a series of compounds structurally similar to ladostigil, but based on an indole structure was designed (1-8, Fig.…”

Basic hydrolysis of quinolinyl N,N‐dimethylcarbamates: a two‐step mechanism

“…Tertiary carbamates were also studied and previous results corroborated that predominant mechanism for basic hydrolysis is a B AC 2 addition–elimination mechanism with general base10 or nucleophilic catalysis 11. The first one is characterized by the direct attack on the carbonyl by the base originating an intermediate which is rapidly hydrolysed, and in the second one, there is a base‐assisted attack by a water molecule involving partial bond formation, on the carbonyl group.…”