Data and Molecular Fingerprint-Driven Machine Learning Approaches to Halogen Bonding

The ability to predict the strength of halogen bonds and properties of halogen bond (XB) donors has significant utility for medicinal chemistry and materials science. XBs are typically calculated through expensive ab initio methods. Thus, the development of tools and techniques for fast, accurate, and efficient property predictions has become increasingly more important. Herein, we employ three machine learning models to classify the XB donors and complexes by their principal halogen atom as well as predict the values of the maximum point on the electrostatic potential surface (V_S,max) and interaction strength of the XB complexes through a molecular fingerprint and data-based analysis. The fingerprint analysis produces a root-mean-square error of ca. 7.5 and ca. 5.5 kcal mol^–1 while predicting the V_S,max for the halobenzene and haloethynylbenzene systems, respectively. However, the prediction of the binding energy between the XB donors and ammonia acceptor is shown to be within 1 kcal mol^–1 of the density functional theory (DFT)-calculated energy. More accurate predictions can be made from the precalculated DFT data when compared to the fingerprint analysis.