RegioSQM20

RegioSQM20 predicts the regioselectivity of electrophilic aromatic substitution (EAS) reactions in heteroaromatic systems to identify reactive sites and estimate qualitative reactivity.

Key Features:

• Semiempirical quantum-mechanical calculations: Uses the open-source semiempirical tight-binding program xTB to compute proton affinities at potential reactive sites, replacing the previously used closed-source MOPAC.
• Tautomer consideration: Identifies and analyzes low-energy tautomeric forms of input molecules and provides regioselectivity predictions for each form, increasing reported prediction success from 90.7% to 92.7%.
• Qualitative reactivity prediction: Assigns qualitative reactivity levels (low, medium, high) based on the proton affinity at the reaction center with the highest value.
• Comparative benchmarking: Benchmarks performance against machine-learning models WLN (Struble et al.) and IBM RXN (Schwaller et al.), reporting comparable success rates for entire datasets excluding tautomers, with WLN noted as faster while RegioSQM20 offers more comprehensive predictions by considering tautomers.

Scientific Applications:

• EAS regioselectivity prediction: Predicts likely sites of electrophilic aromatic substitution in heteroaromatic molecules.
• Tautomer-sensitive analysis: Evaluates how low-energy tautomers alter reactive site predictions in heteroaromatic systems.
• Synthetic planning and mechanism studies: Supports design and optimization of synthetic pathways and helps interpret EAS reaction mechanisms in computational chemistry and cheminformatics contexts.

Methodology:

Performs xTB semiempirical tight-binding calculations to compute proton affinities at potential reactive sites, enumerates and evaluates low-energy tautomers, assigns qualitative reactivity (low/medium/high) based on the highest proton affinity, and benchmarks results against WLN and IBM RXN.