Towards the design of chemical reactions: Machine learning barriers of competing mechanisms in reactant space

TL;DR

This paper introduces a machine learning model called R2B that predicts activation energies and transition states in chemical reactions rapidly and accurately, aiding in reaction design and understanding reactivity patterns.

Contribution

The R2B model is a novel ML approach that infers kinetic barriers from molecular graphs, demonstrating high accuracy and applicability to diverse organic reactions.

Findings

R2B predicts activation energies within 2.5 kcal/mol of CCSD references.

E2 reactions are favored in 75% of cases, with SN2 likely for specific nucleophile and substituent types.

Hammond's postulate applies to SN2 but not to E2 reactions.

Abstract

While sophisticated numerical methods for studying equilibrium states have well advanced, quantitative predictions of kinetic behaviour remain challenging. We introduce a reactant-to-barrier (R2B) machine learning model that rapidly and accurately infers activation energies and transition state geometries throughout chemical compound space. R2B enjoys improving accuracy as training sets grow, and requires as input solely molecular graph information of the reactant. We provide numerical evidence for the applicability of R2B for two competing text-book reactions relevant to organic synthesis, E2 and SN2, trained and tested on chemically diverse quantum data from literature. After training on 1k to 1.8k examples, R2B predicts activation energies on average within less than 2.5 kcal/mol with respect to Coupled-Cluster Singles Doubles (CCSD) reference within milliseconds. Principal component analysis of kernel matrices reveals the hierarchy of the multiple scales underpinning reactivity in chemical space: Nucleophiles and leaving groups, substituents, and pairwise substituent combinations correspond to systematic lowering of eigenvalues. Analysis of R2B based predictions of ~11.5k E2 and SN2 barriers in gas-phase for previously undocumented reactants indicates that on average E2 is favored in 75% of all cases and that SN2 becomes likely for nucleophile/leaving group corresponding to chlorine, and for substituents consisting of hydrogen or electron-withdrawing groups. Experimental reaction design from first principles is enabled thanks to R2B, which is demonstrated by the construction of decision trees. Numerical R2B based results for interatomic distances and angles of reactant and transition state geometries suggest that Hammond's postulate is applicable to SN2, but not to E2.