Learning Continuous Solvent Effects from Transient Flow Data: A Graph Neural Network Benchmark on Catechol Rearrangement

TL;DR

This paper introduces a new benchmark dataset and a graph neural network model for predicting reaction yields across continuous solvent mixtures, significantly improving accuracy over traditional methods.

Contribution

The work presents the Catechol Benchmark dataset and a hybrid GNN architecture that effectively models continuous solvent effects in reaction outcome prediction.

Findings

Hybrid GNN achieves an MSE of 0.0039, outperforming baselines.

Explicit molecular graph message-passing is crucial for generalization.

Continuous mixture encoding enhances model robustness.

Abstract

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.