Towards Isotope Effect Calculations in the Supramolecular Age

: Drawing Conclusions from Model systems to Develop our Understanding of Large-Scale Interactions

Abstract

Isotope effects have been widely employed in the understanding of reactions, mechanisms and chemical change for decades. Herein is presented an evaluation of isotope effect theory in the context of contemporary computational studies. Model systems are used to illustrate the importance of considering the reacting system as part of the full environment, as opposed to a free subset of molecules, independent of the surroundings. B3LYP/aug-cc-PVDZ studies suggest the methyl cation exhibits unusual properties when exposed to a dielectric continuum, signifying that the UA0 continuum solvation cavity model can lead to erroneous results. Further B3LYP, M06 and MP2 studies on the anharmonicity of the C-H bond, and its influence on calculated vibrational frequencies and isotope effects show significant variation from benchmark values for the M06/6-31G+(d),aug-cc-PVDZ and aug-cc-PVTZ electronic structure methods. In combination with the polarised continuum model, anharmonic corrections applied to B3LYP/6-31+G(d) produces erroneous results, leading to the recommendation of avoiding these groupings of options within the same calculation method. A B3LYP/aug-cc-PVDZ study of an explicitly solvated ‘cluster’ system consisting of a methyl cation surrounded by five molecules of water, highlight the importance of interactions other than the commonly-considered donor-acceptor distances in methyl transfer reactions, in determining isotope effects and thereby, reactivity. Moreover, detailed kinetic isotope effect computations employing the recently redeveloped SULISO suite of isotope effect and vibrational characterisation software identify hydrogen bonding interactions perpendicular to the methyl transfer axis, as conceivably contributing to 3% variations recently used to support the compression hypothesis, and observed in isotope effects from experiment. The cutoff model, as postulated by Wolfsberg and Stern, and recently redeveloped by Williams, is applied to the methyl cation cluster system to identify degrees of freedom with significant contributions to the isotope effect, and therefore reactivity of the moiety. External degrees of freedom are seen to govern important contributions to the isotope effect, indicating that extreme care must be taken when applying the cutoff procedure to molecular Hessians. Reductio ad absurdum studies of cutoff levels show a major influence on the calculated isotope effects; the accuracy of the calculation of the reaction coordinate frequency and associated components significantly affect the accuracy of the isotope effects obtained. The theory implicit in the SULISO suite of software is applied to alternative systems. Isotope effects for a ruthenium-catalysed C-H activation catalytic cycle are computed and used to deduce the nature of catalysis and the most influential structures within. C-H activation is found to proceed by formation of an agostic intermediate, before conversion and final dissociation of products, with the observed KIE of 2.22 agreeing well with the calculated value of 2.17. The impact of dispersion corrections (D3 Grimme dispersion with Becke-Johnson damping), and their alternative implementations is described, suggesting that care must be taken when employing dispersion in terms of energetic corrections as opposed to including structural considerations. Dispersion is then considered as an effect on isotope effects calculated from QM/MM Hessians on catechol-o-methyltransferase. Isotope effects themselves vary insignificantly between methods, however the structures of the QM region and energetics indicate a contribution from dispersion corrections when included in the optimisation routine. A set of guidelines for future calculations of isotope effects in large, supramolecular systems acts as a conclusion, unifying the outcomes of each study included herein.

Date of Award	12 Dec 2017
Original language	English
Awarding Institution	University of Bath
Sponsors	Engineering and Physical Sciences Research Council
Supervisor	Ian Williams (Supervisor)