Harnessing homolytic bond energetics to steer inverse radical design

Homolytic bond dissociation energy (BDE) governs radical formation and bond-breaking thermodynamics, yet in molecular design it is typically evaluated only after candidate structures are proposed. This project flips that logic: we treat BDE as a continuous generative design coordinate rather than a post-hoc descriptor, enabling distributional control over bond strength at the regime level rather than exact set-point attainment.

A BDE-conditioned transformer generates radical fragment pairs steered toward prescribed single-bond strength regimes (50-130 kcal mol\(^{-1}\)), achieving monotonic, rank-resolved energetic control with 81-94% validity and 84-92% novelty across targets. At the screening level, an MPNN trained on the same data provides high-throughput energetic ranking consistent with regime-level steering.

DFT validation at the M06-2X/def2-TZVP level on randomly sampled novel generations yields a target-attainment MAE of 12.7 kcal mol\(^{-1}\), consistent with regime-level steering and isolating generative accuracy from inter-functional offsets. Cross-functional evaluation at \(\omega\)B97X-D3BJ/def2-TZVP preserves energetic ordering (DFT-calculated means spanning \(\sim\)64 to \(\sim\)119 kcal mol\(^{-1}\)), indicating the learned BDE axis reflects transferable thermodynamic structure rather than functional-specific artifacts.

Spin-delocalization analysis further reveals a statistically significant correlation between radical localization and bond strength across the DFT-validated set. Motivated by PFAS remediation, the framework is extensible to higher-energy C-F bond strength regimes.

(Sheshanarayana & You, 2026)