Guided Discovery of H-Bond-Directed Reaction Divergence: A Teaching Lab on Anomalous Cyclization in Cyclic Sulfites

This pedagogical module transforms an unexpected research discovery─hydrogen-bond-directed reaction divergence─into a three-week inquiry-based lab for upper-level undergraduate students. Students synthesize chiral cyclic sulfite 1 and confront cognitive conflict when intramolecular cyclization (avg 81% yield, n = 30) occurs instead of the predicted methylation. Through guided analysis of 1 H NMR shielding (Δδ = −2.24 ppm for shielded O(3)–H(3)) and crystallographic data (O(3)···O(4) distance of 2.888 Å, O(3)–H(3)···O(4) bond angle of 160.22°), they discover how an intramolecular S═O···H(3)–O(3) hydrogen bond shields reactive sites, diverting reaction pathways. Quantitative assessment shows 93% proficiency in mechanistic reasoning and 87% mastery of 1 H NMR shielding analysis. The experiment fosters four key skills: (1) advanced synthesis techniques (Grignard, anhydrous techniques), (2) spectroscopic interpretation, (3) structural database mining (CCDC), and (4) mechanistic logic construction.