A Statistical-Chemometric Analysis Quantifying Impact of Stirring on Organic Reaction Yields: New Insights from the Huang et al. 2024 Data

Mechanical agitation (stirring) is a cornerstone of organic synthesis, but has received little scientific attention due to its “obvious” role in facilitating reactions. A very recent study by Huang and coworkers compared the isolated yields in approximately 600 paired stirred and unstirred reactions, across a range of standard synthetic reactions, and reported “almost no” differences. However, their study does not provide any quantitative metrics to estimate these differences. To more fully understand the magnitude of potential differences and to identify any reactions where yields do differ, a full multivariable statistical analysis was performed. Across all reaction types, in multivariable mixed models adjusted for reaction conditions including reaction scale, time, and reaction type, stirred reactions are associated with a 2.0 % (95% CI: 1.1 to 2.9%; p < 0.001) increase in isolated yield relative to unstirred reactions. Four reaction types also show statistically significant differences in individual mixed models. Cross-couplings (including Heck, Sonogoshira, and Suzuki reactions) showed a 2.1 % (95% CI: 1.4 to 2.9%; p < 0.001) increase in yield with stirring; electrochemical reactions (allylic C–H oxidation, silyl-Minisci) show a 3.0% (95% CI: 0.7 to 5.3%; p = 0.0091) greater yield; polar reactions (including the Fisher indole synthesis; Friedel-Crafts alkylations/acylations; Mannich reactions; Willamson ether synthesis; the Wittig reaction) show a 2.8 % increase (0.9 to 4.7%; p = 0.004) in yield in stirred versus unstirred reactions; and rearrangements (Claisen and Schmidt reactions), which overall show an 8.4% (95% CI: 6.5 to 10.4%; p < 0.001) increase in yield with stirring relative to unstirred paired reactions. Finally, to assess any interactions between overall yield and the impact of stirring, all reactions were classified using k-means cluster partitioning into three classes by paired yield; individual models for these classes show a clear gradient, where the lowest-yielding reaction group shows the largest overall increase in isolated yield (4.5%; 95% CI: 2.6 to 6.4%; p < 0.0001) with stirring. Stirring of moderate yield reactions is associated with a 1.6% (95% CI: 0.4 to 2.9%; p = 0.0082) increase in yield, while the highest yielding reactions show smaller effect sizes in stirred versus unstirred reactions (0.8% increase; 95% CI: 0.4 to 1.3%; p< 0.0001). These results suggest that while the overall changes in yields with stirring in these data for many reactions are modest, there is extensive variation of impact, and stirring is associated with real and practically important increases in isolated yields across a wide range of substrates and reaction manifolds. Future studies should incorporate design of experiment frameworks, to elucidate which reaction parameters drive these observed heterogeneous effects.