1H NMR-Based Framework for Estimating Molecular Formation Enthalpies of Organic Compounds

Abstract

We report a method for estimating standard enthalpies of formation (ΔHf°) directly from routine 1H NMR spectra. By combining spectral features with heteroatom-based functional motifs, accurate models were obtained (R2 ≈ 0.99; RMSE ≈ 5.5 kcal mol–1). The predictive performance was consistent across multiple validation approaches and comparable to established group contribution methods, while avoiding the need for knowledge of compound structure. The obtained formation enthalpies further enabled reasonable estimation of reaction enthalpies for representative organic transformations. Overall, the results demonstrate that routinely accessible NMR observables capture trends associated with molecular thermodynamic stability.