Machine Learning Meets Mechanistic Modelling for Accurate Prediction of Experimental Activation Energies

Abstract

Accurate prediction of chemical reactions in solution is challenging for current state-of-the-art approaches based on transition state modelling with density functional theory. Models based on machine learning have emerged as a promising alternative to address these problems, but these models currently lack the precision to give crucial information on the magnitude of barrier heights, influence of solvents and catalysts and extent of regio- and chemoselectivity. Here, we construct hybrid models which combine the traditional transition state modelling and machine learning to accurately predict reaction barriers. We train a Gaussian Process Regression model to reproduce high-quality experimental kinetic data for the nucleophilic aromatic substitution reaction and use it to predict barriers with a mean absolute error of 0.77 kcal/mol for an external test set. The model was further validated on regio- and chemoselectivity prediction on patent reaction data and achieved a competitive top-1 accuracy of 86%, despite not being trained explicitly for this task. Importantly, the model gives error bars for its predictions that can be used for risk assessment by the end user. Hybrid models emerge as the preferred alternative for accurate reaction prediction in the very common low-data situation where only 100–150 rate constants are available for a reaction class. With recent advances in deep learning for quickly predicting barriers and transition state geometries from density functional theory, we envision that hybrid models will soon become a standard alternative to complement current machine learning approaches based on ground-state physical organic descriptors or structural information such as molecular graphs or fingerprints.

Prediction of Chemical Reaction Yields using Deep Learning

“…Our approach to yield predictions can be extended to any reaction regression task, for example, for predicting reaction activation energies [36,37,38], and is expected to have a broad impact in the field of organic chemistry.…”

Structure-Based Reaction Descriptors for Predicting Rate Constants by Machine Learning: Application to Hydrogen Abstraction from Alkanes by CH3/H/O Radicals

“…8,10 In this regard, many pioneering works have been performed to learn activation energies and minimum energy paths of chemical reactions. 7,[11][12][13][14][15][16][17][18] Meanwhile, some efforts have been paid to directly predict rate constants. 8 For gas-phase bimolecular reactions, Houston et al employed Gaussian Process Regression to train thermal rate constants using a dataset of 13 reactions over a large 4 temperature range.…”

Completion of Partial Reaction Equations

“…Deep-learning models applied to chemical reactions have received much attention in recent years: from the design of algorithms for forward reaction prediction [1][2][3] and retrosynthetic analysis [1,4,5] that help chemists plan the design and execution of chemical syntheses, to the generation of reaction fingerprints [6] and prediction of reaction classes [7,6], yields [8], or activation energies [9]. Several of the latter predictive models were trained on fully-specified reactions -i.e., they rely on all the reagents being specified, including solvents and catalysts.…”