Atoms in a molecule are held together by covalent bonds, and rotation around single bonds allows one molecule to adopt several three-dimensional poses called conformations. Using infrared spectroscopy and X-ray analysis, Barton and Hassel showed that the lowest-energy conformation largely determines a molecule’s reactivity and physical properties. For example, they quantified why the chair form of cyclohexane is more stable than the boat form and demonstrated how this influences reaction mechanisms. Conformational analysis is now indispensable in drug design and polymer development and forms a cornerstone of stereochemistry education. Their work gave chemists the idea of a “moving 3-D model” of molecules and established a culture of thinking about reactions in spatial terms.

Barton employed NMR, IR, and X-ray crystallography to map energy profiles of allylic compounds and steroids, while Hassel used electron diffraction to elucidate the three-dimensional arrangement of cyclohexane derivatives. They decomposed intramolecular non-bonded interactions, such as 1,3-diaxial strain, into theoretical contributions and thereby created the systematic methodology of “conformational analysis.” This enabled quantitative prediction of stereospecificity in nucleophilic substitution and elimination reactions, the anomeric effect in sugars, and equilibrium constants between ring conformers. Stability assessments of conformers now serve as a prerequisite for QSAR studies and molecular dynamics, finding wide application in lead optimization and catalyst design. The conformation concept also dovetails with advances in quantum chemical calculations, underpinning Ramachandran plots and molecular force-field parameterization.

Barton and Hassel embedded conformational analysis within a thermodynamic and quantum-chemical framework, quantifying conformer preference via ΔG=ΔH-TΔS decomposition. Barton’s analysis of long-range NMR effects refined the Karplus equation by establishing empirically derived dihedral-angle-dependent parameters for ^3J_HH coupling constants. Hassel, in turn, inverted electron-diffraction intensity curves through Fourier transformation to obtain axial-plane radial distributions, achieving sub-degree accuracy (<1°) for cyclohexane chair angles. Their results feed directly into steric energy mapping using A-values and provide experimental validation for local MP2/DFT barrier calculations. They also underpin empirical support for Bürgi-Dunitz attack angles and inform debates over Felkin-Anh vs. Cornforth control in nitron cyclizations. Modern rotamer libraries and protein-ligand docking scoring functions ultimately rely on the higher-order extrapolation of their basic conformational insights.