Nucleophilic substitution reactions of α-haloketones : a computational study

Abstract

This dissertation describes the computational modelling of reactions between α-haloketones and various nucleophiles. Nucleophilic substitution reactions of α-haloketones (also known as α- halocarbonyls in literature) are utilised in synthetic laboratories to obtain 1,2-disconnections; which are typically difficult to obtain otherwise. To gain insight into these reactions, DFT modelling was carried out in this project, with further understanding into these reactions being obtained using Quantum Fragment Along Reaction Pathway (QFARP) which is an extension of Interacting Quantum Atoms (IQA). The nucleophilic substitution reaction was modelled between α-bromoacetophenone (α- BrAcPh), to represent α-haloketones, and the common nucleophiles phenolate (PhO–) and acetate (AcO–). QFARP provided insight into the reactions which could not have been obtained with other computational approaches. It was shown that the reaction with AcO– results in greater destabilisation for the α-group of α-BrAcPh as compared to the reaction of PhO–, explaining the difference in activation energies for the reactions. Diatomic- and fragment-interactions provided awareness into the driving force of the reactions and showed how the hydrogens for the α-group of α-BrAcPh provide significant attractive interactions with the nucleophiles during the initial stages of the nucleophilic substitution reaction. Furthermore, reactions modelled between α-BrAcPh and MeO– was done, as experimental literature has reported the presence of two competing reactions: nucleophilic substitution and epoxidation. Modelling showed the two reactions have low activation energies which are comparable with another. Interestingly, the rate determining step for the epoxidation reaction is not the formation of the transition state structure but rather the rotational barrier which is required to allow the leaving group, bromine, to be trans to the carbonyl-O of α-BrAcPh. Previous reports indicated that the presence of an electron donating/withdrawing group on the phenyl ring of α-BrAcPh had a significant influence on the reaction rate and selectivity between the two reactions. These experimental observations correlated well with the modelling results when comparing the potential energy surfaces (PES) of the reactions. Analysis using QFARP was also applied to these reactions to gain a more fundamental understanding of the reactions and how they differ. While QFARP was not able to explain the selectivity with different substituents present, insight into the dominating interactions that are involved in the reactions was recovered.