Capturing the Effect of Exact Exchange in Thio-Michael Additions with a Machine-Learned Functional at Meta-GGA Cost
Year: 2026
Type: preprint
Abstract: Semilocal density-functional approximations fail to describe the formation of anionic enolates in thio-Michael additions, the bond-forming step of covalent-inhibitor warheads; range-separated hybrids, which reintroduce long-range exact exchange, are required. Across the published CCSD(T)validated reaction pathways of eight warheads, we show that Skala—a deep-learned semilocal functional containing no exact exchange—matches the range-separated hybrid reference for the activation barriers, enolate geometries and relaxed reactant structures, outperforming the global hybrid B3LYP at meta-GGA cost. The one signature it does not reproduce is the orbital one: its Koopmans ionization potential stays at the semilocal scale, because the ionization-potential theorem constrains the exchange potential, not the energy. Skala thus captures the effect of exact exchange in the total energy, from training data alone.
Source: ChemRxiv
Institution: University of Nottingham
Language: English
Subfield: Atomic and Molecular Physics, and Optics
Field: Physics and Astronomy
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7214730341