Learning Continuous Solvent Effects from Transient Flow Data: A Graph Neural Network Benchmark on Catechol Rearrangement
This work addresses a critical problem in organic synthesis and process chemistry by enabling systematic interpolation and extrapolation across solvent spaces, though it is incremental as it builds on existing GNN and encoding techniques.
The paper tackles the challenge of predicting reaction outcomes across continuous solvent composition ranges by introducing the Catechol Benchmark dataset and evaluating various machine learning methods, with a proposed hybrid GNN-based architecture achieving an MSE of 0.0039, a 60% error reduction over baselines.
Predicting reaction outcomes across continuous solvent composition ranges remains a critical challenge in organic synthesis and process chemistry. Traditional machine learning approaches often treat solvent identity as a discrete categorical variable, which prevents systematic interpolation and extrapolation across the solvent space. This work introduces the \textbf{Catechol Benchmark}, a high-throughput transient flow chemistry dataset comprising 1,227 experimental yield measurements for the rearrangement of allyl-substituted catechol in 24 pure solvents and their binary mixtures, parameterized by continuous volume fractions ($\% B$). We evaluate various architectures under rigorous leave-one-solvent-out and leave-one-mixture-out protocols to test generalization to unseen chemical environments. Our results demonstrate that classical tabular methods (e.g., Gradient-Boosted Decision Trees) and large language model embeddings (e.g., Qwen-7B) struggle with quantitative precision, yielding Mean Squared Errors (MSE) of 0.099 and 0.129, respectively. In contrast, we propose a hybrid GNN-based architecture that integrates Graph Attention Networks (GATs) with Differential Reaction Fingerprints (DRFP) and learned mixture-aware solvent encodings. This approach achieves an \textbf{MSE of 0.0039} ($\pm$ 0.0003), representing a 60\% error reduction over competitive baselines and a $>25\times$ improvement over tabular ensembles. Ablation studies confirm that explicit molecular graph message-passing and continuous mixture encoding are essential for robust generalization. The complete dataset, evaluation protocols, and reference implementations are released to facilitate data-efficient reaction prediction and continuous solvent representation learning.