Assessment of Computational Tools for Predicting Supramolecular Synthons

Bhupinder Sandhu,Abhijeet S Sinha,Ann Mclean,Christer B Aakerӧy,John Desper

doi:10.3390/chemistry3020043

Bhupinder Sandhu, Abhijeet S Sinha + Show 3 more

Open Access

https://doi.org/10.3390/chemistry3020043

Copy DOI

Journal: Chemistry	Publication Date: May 3, 2021
Citations: 6	License type: CC BY 4.0

Affiliation: Kansas State University

Abstract

The ability to predict the most likely supramolecular synthons in a crystalline solid is a valuable starting point for subsequently predicting the full crystal structure of a molecule with multiple competing molecular recognition sites. Energy and informatics-based prediction models based on molecular electrostatic potentials (MEPs), hydrogen-bond energies (HBE), hydrogen-bond propensity (HBP), and hydrogen-bond coordination (HBC) were applied to the crystal structures of twelve pyrazole-based molecules. HBE, the most successful method, correctly predicted 100% of the experimentally observed primary intermolecular-interactions, followed by HBP (87.5%), and HBC = MEPs (62.5%). A further HBC analysis suggested a risk of synthon crossover and synthon polymorphism in molecules with multiple binding sites. These easy-to-use models (based on just 2-D chemical structure) can offer a valuable risk assessment of potential formulation challenges.

Highlights

Hydrogen-bond energies for each combination of synthons is presented in Table 1, See
Molecular conformational analysis using DFT B3LYP (6-311++G** basis set in vacuum) shows that P1–P12 with amide functionality occur as trans instead of cis isomer as the stable conformation, which was further confirmed based on a Cambridge Structural Database (CSD) search
These results indicate that even though A + F is geometrically constrained, as seen in CSD search, it can still form experimentally

Summary

Introduction

At the core of the crystal structure of most organic molecular solids is the supramolecular synthon [2,3,4,5], a “structural unit within supermolecules which can be formed and/or assembled by known or conceivable synthetic operations involving intermolecular interactions”, introduced by Desiraju in 1995 [2]. The synthon can serve as a valuable starting point for identifying the most likely ways in which molecules will aggregate [19,20] This means that an important step towards predicting a crystal structure often involves finding the most likely synthons in molecules with competing molecular recognition sites, Scheme 1. A key question in crystal engineering is, given a molecular structure, can we predict its crystal structure [1]? At core that of theif crystal structure of mostarray organic molecular in solreasonable to the assume a particular structural is abundant a database, it may reflect thermodynamic of a given crystalsupermolecules packing array, as well as a kinetic ids is the supramolecular synthon [2,3,4,5], astability “structural unit within which preference of its formation.

Results

Discussion

Conclusion