Molecular Machine Learning for Chemical Catalysis: Prospects and Challenges.

ConspectusIn the domain of reaction development, one aims to obtain higher efficacies as measured in terms of yield and/or selectivities. During the empirical cycles, an admixture of outcomes from low to high yields/selectivities is expected. While it is not easy to identify all of the factors that might impact the reaction efficiency, complex and nonlinear dependence on the nature of reactants, catalysts, solvents, etc. is quite likely. Developmental stages of newer reactions would typically offer a few hundreds of samples with variations in participating molecules and/or reaction conditions. These "observations" and their "output" can be harnessed as valuable labeled data for developing molecular machine learning (ML) models. Once a robust ML model is built for a specific reaction under development, it can predict the reaction outcome for any new choice of substrates/catalyst in a few seconds/minutes and thus can expedite the identification of promising candidates for experimental validation. Recent years have witnessed impressive applications of ML in the molecular world, most of them aimed at predicting important chemical or biological properties. We believe that an integration of effective ML workflows can be made richly beneficial to reaction discovery.As with any new technology, direct adaptation of ML as used in well-developed domains, such as natural language processing (NLP) and image recognition, is unlikely to succeed in reaction discovery. Some of the challenges stem from ineffective featurization of the molecular space, unavailability of quality data and its distribution, in making the right choice of ML model and its technically robust deployment. It shall be noted that there is no universal ML model suitable for an inherently high-dimensional problem such as chemical reactions. Given these backgrounds, rendering ML tools conducive for reactions is an exciting as well as challenging endeavor at the same time. With the increased availability of efficient ML algorithms, we focused on tapping their potential for small-data reaction discovery (a few hundreds to thousands of samples).In this Account, we describe both feature engineering and feature learning approaches for molecular ML as applied to diverse reactions of high contemporary interest. Among these, catalytic asymmetric hydrogenation of imines/alkenes, β-C(sp 3 )-H bond functionalization, and relay Heck reaction employed a feature engineering approach using the quantum-chemically derived physical organic descriptors as the molecular features─all designed to predict the enantioselectivity. The selection of molecular features to customize it for a reaction of interest is described, along with emphasizing the chemical insights that could be gathered through the use of such features. Feature learning methods for predicting the yield of Buchwald-Hartwig cross-coupling, deoxyfluorination of alcohols, and enantioselectivity of N , S -acetal formation are found to offer excellent predictions. We propose a transfer learning protocol, wherein an ML model such as a language model is trained on a large number of molecules (10 5 -10 6 ) and fine-tuned on a focused library of target task reactions, as an effective alternative for small-data reaction discovery (10 2 -10 3 reactions). The exploitation of deep neural network latent space as a method for generative tasks to identify useful substrates for a reaction is demonstrated as a promising strategy.