High-Throughput Screening and Prediction of Nucleophilicity of Amines Using Machine Learning and DFT Calculations

Nucleophilic index (N_Nu) as a significant parameter plays a crucial role in screening of amine catalysts. Indeed, the quantity and variety of amines are extensive. However, only limited amines exhibit an N_Nu value exceeding 4.0 eV, rendering them potential nucleophiles in chemical reactions. To address this issue, we proposed a computational method to quickly identify amines with high N_Nu values by using Machine Learning (ML) and high-throughput Density Functional Theory (DFT) calculations. Our approach commenced by training ML models and the exploration of Molecular Fingerprint methods as well as the development of quantitative structure–activity relationship (QSAR) models for the well-known amines based on N_Nu values derived from DFT calculations. Utilizing explainable Shapley Additive Explanation plots, we were able to determine the five critical substructures that significantly impact the N_Nu values of amine. The aforementioned conclusion can be applied to produce and cultivate 4920 novel hypothetical amines with high N_Nu values. The QSAR models were employed to predict the N_Nu values of 259 well-known and 4920 hypothetical amines, resulting in the identification of five novel hypothetical amines with exceptional N_Nu values (>4.55 eV). The enhanced N_Nu values of these novel amines were validated by DFT calculations. One novel hypothetical amine, H1, exhibits an unprecedentedly high N_Nu value of 5.36 eV, surpassing the maximum value (5.35 eV) observed in well-established amines. Our research strategy efficiently accelerates the discovery of the high nucleophilicity of amines using ML predictions, as well as the DFT calculations.