The Stubborn Persistence of Toxic Solvents in Chemical Synthesis.

Solvents dominate the environmental footprint of chemical synthesis, yet their selection remains governed by precedent rather than sustainability. Here, we analyse 1.3 million classified reactions from 40 years of patent data, distinguishing for the first time between reaction, workup, purification, and analytical solvents. Despite decades of awareness of solvent hazards and the publication of influential solvent selection guides, we find no net reduction in the proportion of hazardous solvents used as reaction media. Dichloromethane usage has grown, and rising trifluoroacetic acid consumption intensifies concerns over per- and polyfluoroalkyl substances. Where regulations have removed specific solvents, chemists have defaulted to lateral substitution, replacing one hazardous solvent with another rather than adopting greener alternatives. We identify the reaction classes most dependent on each problematic solvent, providing a data-driven framework for prioritising targeted intervention over blanket regulation. Crucially, these findings expose systemic biases in historical datasets that threaten to turn AI solvent-prediction models into engines for proliferating outdated, hazardous practices rather than advancing sustainable chemistry.