Computational insight into Wilkinsonʹs complex catalyzed [2 + 2 + 2] cycloaddition mechanism leading to pyridine formation

An interesting reaction for the synthesis of aromatic carbo- and heterocycles is the transition-metal catalyzed [2 + 2 + 2] cycloaddition reaction. In this elegant and atom-efficient process three C–C or C–X (X = N, O, S…) bonds are formed in a single synthetic process. The [2 + 2 + 2] cycloaddition is catalyzed by a variety of organometallic complexes, including more than 15 different metals. In this work, we carry out computational studies of the reaction mechanism between two acetylenes and a nitrile to form substituted pyridines catalyzed by the Wilkinson complex. Our results show that initial oxidative addition between the two acetylene molecules is the rate-determining step. Oxidative addition between two acetylenes is more favorable than between acetylene and nitrile moieties. Our results are in agreement with the experimental finding that the formation of pyridines in some cases requires the use of an excess of nitrile. Nitriles with electron withdrawing substituents favor the incorporation of nitrile in the insertion process and improve the ratio of pyridine vs. benzene.