Issue 36, 2024

A guide to bullvalene stereodynamics

Abstract

Here, we analyze the stereodynamic properties of bullvalenes using principal moments of inertia and exit vector plots to draw comparisons with commonly used ring systems in medicinal chemistry. To aid analyses, we first classify (i) the four elementary rearrangement steps available to substituted bullvalenes, which (ii) can be described by applying positional descriptors (α, β, γ, and δ) to the substituents. We also (iii) derive an intuitive equation to calculate the number of isomers for a given bullvalene system. Using DFT-modelled structures for di-, tri-, and tetrasubstituted bullvalenes, generated using a newly developed computational tool (bullviso), we show that their 3D shapes and the exit vectors available from the bullvalene scaffold make them comparable to other bioisosteres currently used to replace planar aromatic ring systems in drug discovery. Unlike conventional ring systems, the shapeshifting valence isomerism of bullvalenes gives rise to numerous shapes and substituent relationships attainable as a concentration-independent dynamic covalent library from a single compound. We visualize this property by applying population weightings to the principal moments of inertia and exit vector analyses to reflect the relative thermodynamic stabilities of the available isomers.

Graphical abstract: A guide to bullvalene stereodynamics

Supplementary files

Article information

Article type
Edge Article
Submitted
06 jun 2024
Accepted
23 aug 2024
First published
23 aug 2024
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2024,15, 14608-14617

A guide to bullvalene stereodynamics

R. A. Ives, W. Maturi, M. T. Gill, C. Rankine and P. R. McGonigal, Chem. Sci., 2024, 15, 14608 DOI: 10.1039/D4SC03700F

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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