Theoretical and experimental studies on the divergent mechanisms of benzimidazole N-oxides formation.

FABRIZIO POLITANO; JORGE G. URANGA; NICHOLAS E. LEADBEATER; ELBA I. BUJÁN

Concon

Conferencia; 14th Latin American Conference on Physical Organic Chemistry; 2017

Recently we developed a synthetic methodology for the preparation of benzimidazole N-oxides using a two-step continuous flow process.[1] The first step consists of an SNAr reaction between 2,6-dinitrochlorobenzene and a primary amine, and the second step is a base-mediated cyclization reaction. Normally, the final products of this process are nitrobenzimidazole N-oxides (product 2 in figure) with the retention of the R group given from the amine precursor. However, when ethanolamine and ethylene-diamine were used, 7-nitro-1H-benzimidazole 3-oxide was obtained, implying the loss of CH2OH and CH2NH2 respectively. We have now developed experimental and theoretical studies in order to explain this unusual observation. Experimentally, we replicated the continuous flow conditions[1] in a microwave unit, performing one-pot two-step reactions at 120 ºC. The theoretical studies were performed employing DFT theory with the B3LYP functional and a basis set of 6-31+G*. The different steps were analyzed by employing a previous conformational search considering solvent effects in an implicit form in accordance with the IEFPCM model. The analysis was focused on the structure (1), already proposed as part of the mechanism for the formation of benzimidazole N-oxides,[2] calculating the reaction coordinates for both Path A (C-H bond cleavage) and Path B (C-C bond cleavage). We found that Path A is energetically favored by amines containing R1 groups; while, Path B is preferred for amines containing R2 groups. The theoretical studies allowed us to understand the structural and electronic factors determining the activation energies for the observed fragmentations. A good correlation between experimental results and theoretical results were found.