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.
