Theoretical investigation of von Braun and von Braun‐like reactions

Abstract

The von Braun reaction, discovered at the dawn of the past century, consists of the reaction between a tertiary amine and cyanogen bromide. It leads to the cleavage of a C-N bond with the formation of an N-dialkylcyanamide and an alkyl bromide and has been extensively used in organic synthesis. A detailed in silico study (PCM/DFT/B3LYP/6-31++G(d,p) calculations) of this venerable reaction has shown that in the first stage a zwitterionic adduct with a multi-bonded bromine atom is formed. The widely accepted mechanism involving an S N 2 reaction occurs in the second step, thus accounting for its selectivity. Quantum chemical calculations were performed for the von Braun-like reactions in systems formed by cyclic tertiary amines (N-alkyl azetidines). In these cases, the first stage is almost the same as in the classical von Braun processes, and selective S N 2 mechanisms can occur in the second step. This article thus reports a detailed in silico study of the reaction, first with 1-ethyl-1methylpropylamine 1 (R 1 =Me, R 2 = Et, R 3 = Pr, vide infra structure 10), as reported initially by von Braun, who observed the selective cleavage of the N-methyl group, and then with simplified analogues of 5 and 8, for which significant N-benzhydryl cleavage on one hand, and exclusive and diastereoselective ring opening on the other hand were observed. The key objective of this study was to understand the effect of the nature of the substituent at the nitrogen atom on the von Braun reaction mechanism, which in some cases results in only acyclic products and in others to a mixture of two products (substitution at the nitrogen atom and azetidine ring opening). 2. COMPUTATIONAL METHODS Density functional theory (DFT) calculations were performed using B3LYP exchange-correlation functionals,[11-13] together with the standard6-31G(d,p) basis set.[14] Geometry optimization was carried out using Berny's analytical gradient optimization method. Stationary points of the reaction minimum energy paths (MEPs) were characterized by frequencies calculations. MEPs were obtained via the gradient descent method from the transition states in forward and reverse directions of the transition vectors.

Diastereoselective ring cleavage of azetidines with cyanogen bromide

“…We previously carried out a detailed in silico study of the von Braun reaction applied to azetidine substrates to better understand the reaction pathways involved. 15…”