Cockroft, Scott

Lusby, Paul

Smoliar, Ivan

2024-12-17T10:26:57Z

2024-12-17T10:26:57Z

2024-12-17

Intramolecular hydrogen bonds (IMHBs) are fundamental non-covalent interactions that profoundly influence molecular structure and reactivity. They affect the physico-chemical properties, molecular geometry, shape, and conformation of systems ranging from small molecules to nucleic acids and proteins, from catalysts to materials. For these reasons, the formation or disruption of IMHBs is used by chemists to modulate the structural, chemical and biological properties of a given compound. Therefore, the ability to predict the viability of formation of IMHBs, their stability and conformational changes upon their formation is key for rational design of new compounds with various applications. This thesis delves into the complexities of IMHBs, exploring their role in dictating the electronic, geometric, and conformational characteristics of molecular systems. A significant focus is placed on the predictive modelling of IMHB formation, stability, and the resulting conformational dynamics. Chapter 1 Presents a critical re-evaluation of selected unusual cases of IMHB reported in the literature. In the case of intramolecular interactions, the rigidity of bond lengths and rotational angles of the molecule restrict the geometrical freedom of the fragments that engage in Hbonding. Such bonds lack the liberty to adjust their geometries fully, restricting their ability to maximise the potential for attraction or minimise repulsive forces. Intramolecular systems, where hydrogen bond donors (HBD) and acceptors (HBA) are in close proximity, often display apparently H-bonded geometries. While these arrangements might seem to suggest H-bonding interactions, they often possess characteristics that question their apparent strength or even their existence. This review examines systems characterised by such unconventional hydrogen bonds — those that feature awkward H-bonded geometries and/or involve non-classical HBDs and HBAs. A central aspect we address is the true nature of these interactions: do these bonds, as reported, exhibit strengths comparable to conventional hydrogen bonds or are these geometries a consequence of minimising the otherwise repulsive intra-fragment contacts? Chapter 2 Presents the study of intramolecular hydrogen bonds formed by ortho-substituted phenols within the context of formamide molecular torsion balances. By means of NMR spectroscopy we analyse the propensity of the ortho-substituted phenols to undergo conformational change and engage in an IMHB with the amide carbonyl group. The chapter investigates how variations in ortho-substituents affect the IMHB formation, providing insights into the subtleties of molecular conformation governed by the close-range interactions of the phenolic OH with the proximal R-group. Computational double-mutant-cycle analysis allows us to link the experimentally observed conformer ratio of the molecular balances to the attractive and repulsive energies of the formamide, OH and R interactions. We present a model that the observed net energies to be dissected into three individual components. Those are the strength of the formamide…OH hydrogen bond, which is governed substituent effect of the Rgroup; and the energies of the OH…R and HO…R interactions. This work confirms the critical role of IMHBs in dictating the conformational equilibrium of these molecular balances and highlights the critical importance of short-range HO…R repulsion, in the ortho-substituted phenols, which accounts for the significant amount of the observed conformational behaviour. Chapter 3 Delves into the nature and energetics of Resonance-Assisted Hydrogen Bonds (RAHBs), a subject that has sparked considerable debate in the realm of molecular interactions. Utilizing a blend of SAPT energy decomposition analysis, along with NPA atomic charges, we examined a diverse array of intramolecular hydrogen-bonded systems, including both RAHB and non-RAHB variants. Our analysis reveals that RAHBs, despite their perceived uniqueness, are governed by the same fundamental physical phenomena as conventional hydrogen bonds. We address the longstanding ambiguity in defining RAHB, balancing between structural and energetic perspectives. Our findings confirm that the interplay between hydrogen bond and π-conjugated systems, often considered a hallmark of RAHB, is not exclusive to this bond type. Hence, we challenge the notion that RAHBs are a distinctly separate class of interaction. By extending our investigation to encompass both RAHB and non-RAHB structures, we highlight the similar behaviour exhibited by these systems. Contrary to the common classification of RAHBs as a unique interaction type, our work situates them within the broader spectrum of hydrogen bonds, underscoring their similarities to more conventional interactions.

https://hdl.handle.net/1842/42906

http://dx.doi.org/10.7488/era/5459

en

The University of Edinburgh

intramolecular hydrogen bonds

IMHB

hydrogen bond formation

molecular balances

functional groups

H-bonded state

non-H-bonded state

RAHBs

Intramolecular hydrogen bonds

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy