Reaction mechanism of solvated n-BuLi with thiophene in THF: A theoretical and spectroscopic study

Abstract

It is widely known that organolithium reagents, such as n-BuLi, play an important role in chemistry. Therefore, the role the reagent undergoes in any chemical system is an important aspect to investigate. Hence, this work originated on the prospect of better characterising the reactivity and behaviour of n-BuLi in an aprotic solvent. It this theoretical study, a conformation search protocol designed for analysis of a large set of low energy conformers was implemented in order to select the lowest energy conformers (LECs) of several solvated and unsolvated species of n-BuLi in THF. Furthermore, the protocol was enhanced to incorporate DFT empirical dispersion to improve the accuracy of the structural geometries; they compared well with those computed at the MP2 level. The computed LECs were used to investigate the 1) oligomerisation, 2) solvent effects, 3) mixed-aggregate stabilities and 4) theoretical 1-dimensional NMR data of n-BuLi in THF. From these data, the different equilibrium aggregation states of n-BuLi were characterised at �78�C and the oligomerisation was found to be induced by the coordination of THF. The favoured and most stable dimer and tetramer n-BuLi species are both tetra-solvated. Following the theoretical analysis on the structural behaviour of n-BuLi in THF, 1-dimensional 1H, 13C, and 7Li NMR were generated experimentally with which to compare alongside literature. A complete comparison between the data sources provided a concluding synergy confirming the reported mixed-aggregation of n-BuLi in THF solution. Use of a reaction modelling protocol (involving two unique solvation models) was implemented for the full investigation into the reaction mechanism of n-BuLi with mono-halogenated (bromine and chlorine) thiophene in THF. The reaction analysis yielded full characterisation of the reaction energy profiles and stationary points for over twenty unique chemical reaction systems. The reaction study shows that the mechanism for which lithium�halogen exchange occurs through the formation of the ate-complex (when a Lewis acid combines with a Lewis base whereby the central atom (from the Lewis acid) increases its valence and gains a negative formal charge) as proposed in the literature. The stability of the ate-complex is dependent on how well the halogen can accommodate a negative charge and the degree of lithium interaction. Hence, bromine has favourable reactivity over chlorine as the generated TSs along the reaction energy profile are significantly more stable. This work opens up a new field in theoretical/computational studies of reaction mechanisms involving n-BuLi in countless organic synthetic reactions reported to-date.