Rapid and accurate molecular deprotonation energies from quantum alchemy

Abstract

We assess the applicability of alchemical perturbation density functional theory (APDFT) for quickly and accurately estimating deprotonation energies. We have considered all possible single and double deprotonations in one hundred small organic molecules drawn at random from QM9 [Ramakrishnan et al., JCTC, 2015]. Numerical evidence is presented for 5160 deprotonated species at both HF/def2-TZVP and CCSD/6-31G* levels of theory. We show that the perturbation expansion formalism of APDFT quickly converges to reliable results: using CCSD electron densities and derivatives, regular Hartree–Fock calculations are outperformed at the second or third order for ranking all possible doubly or singly deprotonated molecules, respectively. CCSD single deprotonation energies are reproduced within 1.4 kcal mol⁻¹ on average within third order APDFT. We introduce a hybrid approach where the computational cost of APDFT is reduced even further by mixing first order terms at a higher level of theory (CCSD) with higher order terms at a lower level of theory only (HF). We find that this approach reaches 2 kcal mol⁻¹ accuracy in absolute deprotonation energies compared to CCSD at 2% of the computational cost of third order APDFT.