E_min: A First-Principles Thermochemical Descriptor for Predicting Molecular Synthesizability

Area of Science:

• Computational Chemistry
• Chemical Synthesis
• Materials Science

Background:

• Predicting the synthesizability of novel molecules is a persistent challenge in chemistry.
• Current methods often rely on heuristic approaches, which can be limited in accuracy.

Purpose of the Study:

• To introduce a novel, accurate, and physically meaningful method for predicting molecular synthesizability.
• To validate a new thermochemical descriptor based on first-principles calculations.

Main Methods:

• Introduction of E_min, defined as the energy difference between a molecule and its lowest energy constitutional isomer.
• Application of the E_min descriptor to a dataset of 134,000 molecules from the QM9 dataset.
• Evaluation of E_min's predictive power both independently and in conjunction with existing methods.

Main Results:

• The E_min descriptor demonstrates high accuracy as a standalone predictor of molecular synthesizability.
• Incorporating E_min reduced incorrect "synthesizable" predictions by up to 52% when augmenting common prediction techniques.
• The study highlights the complementary nature of first-principles thermochemistry and heuristic stability approximations.

Conclusions:

• E_min offers a robust, first-principles-based approach to enhance the prediction of chemical synthesizability.
• This method provides a valuable tool for accelerating the discovery and design of new molecules.
• The findings open new avenues for developing advanced synthesizability prediction models.