Investigations on the factors influencing selectivity in reactions of nucleophiles containing multiple reactive sites

Sheehy, Kevin J.

Restriction lift date: 2026-09-30

Investigations on the factors influencing selectivity in reactions of nucleophiles containing multiple reactive sites

dc.check.date	2026-09-30
dc.contributor.advisor	Byrne, Peter
dc.contributor.author	Sheehy, Kevin J.	en
dc.contributor.funder	Irish Research Council	en
dc.date.accessioned	2023-06-15T10:17:50Z
dc.date.available	2023-06-15T10:17:50Z
dc.date.issued	2023-01-06	en
dc.date.submitted	2023-01-06
dc.description.abstract	A fundamental goal in organic chemistry is to be able to understand and rationalise why chemical processes occur as they do. Naturally, therefore, an understanding of the factors that govern regioselectivity in chemical reactions is of paramount importance – i.e., if a compound contains more than one reactive site, which one is preferred, and why? An ambident chemical species is defined as one whose molecular entities each possess two alternative and strongly interacting reactive centres which may partake in a reaction. These centres are connected in such a way that reaction at either site greatly reduces the favourability of a subsequent attack at the second site. Reliably accounting for the regioselectivity observed in reactions of ambident nucleophiles and electrophiles is a challenge laden with difficulties and potential pitfalls. In this thesis, the concept of hard and soft acids and bases (HSAB), which is commonly applied to organic reactivity in an attempt to rationalise and predict the reactivity of these substrates, is found to be an inadequate and misleading simplification of the myriad factors which determine the outcome of the reactions of ambident nucleophiles. This conclusion is drawn from rigorous examination of reactions of various ambident nucleophiles, such as enolates and diazine N-oxides. The preferred site of alkylation of diazine N-oxides by representative hard and soft alkylating agents was established conclusively using the underutilised 1H–15N HMBC NMR technique in combination with other NMR spectroscopic methods, giving outcomes which could not be explained in the context of the hard/soft acid/base (HSAB) principle. In lieu of this, a Marcus theory-based approach was used instead to rationalise these results, utilising calculated values of Marcus intrinsic barriers (ΔG‡int) and ΔrG° to derive Gibbs energies of activation (ΔG‡) values for the processes of N- and O-methylation. These values, as well as those derived directly from DFT calculations, closely reproduced the observed experimental N- vs. O-alkylation selectivities for methylation reactions of pyrazine N-oxides and pyrimidine N-oxide, thereby demonstrating the value in alternative approaches to rationalising the outcomes of reactions of ambident nucleophiles. A novel approach to rationalising ambident reactivity is proposed herein which analyses reactions of enolates in which the Marcus theory-based approach described above has limited use. The first steps towards the construction of this model are taken in this thesis, involving the close examination of alkylation reactions of enolates and the determination of values of ΔG‡ for the competing processes of O- and C-alkylation. This model reveals defining characteristics in the Gibbs energy profile diagrams which describe the reactions of ambident nucleophiles, enabling a greater understanding of the factors which dictate site selectivity in these reactions.	en
dc.description.status	Not peer reviewed	en
dc.description.version	Accepted Version	en
dc.format.mimetype	application/pdf	en
dc.identifier.citation	Sheehy, K. J. 2023. Investigations on the factors influencing selectivity in reactions of nucleophiles containing multiple reactive sites. PhD Thesis, University College Cork.
dc.identifier.endpage	514
dc.identifier.uri	https://hdl.handle.net/10468/14595
dc.language.iso	en	en
dc.publisher	University College Cork	en
dc.rights	© 2023, Kevin J. Sheehy.
dc.rights.uri	https://creativecommons.org/licenses/by/4.0/
dc.subject	Ambident nucleophile
dc.subject	Marcus theory
dc.subject	Gibbs energy
dc.subject	Enolate
dc.subject	Rate constant
dc.subject	Selectivity
dc.title	Investigations on the factors influencing selectivity in reactions of nucleophiles containing multiple reactive sites
dc.type	Doctoral thesis	en
dc.type.qualificationlevel	Doctoral	en
dc.type.qualificationname	PhD - Doctor of Philosophy	en