Probing OH/OH hydrogen bonds with titratable NMR isotope shifts

Methanol titrations of partially deuterated diols dissolved in non-polar solvents such as CD₂Cl₂ and benzene-d₆ provide ¹H NMR measurements of OH/OD isotope shifts, diagnostic for intact or non-intact intramolecular hydrogen bonds under conditions of increasing protic solvent concentration. 1,3- and 1,4-diols (1-3), each with conformationally favored intramolecular OH/OH hydrogen bonds, can be titrated to constant isotope shift values in the presence of excess methanol equivalents, providing evidence for intact intramolecular hydrogen bonds under these conditions. Conversely, isotope shifts in a conformationally labile anti-1,3-diol (4), 1,3-disiloxanediol (5), or 1,6-diol (6) titrated to zero when in the presence of excess methanol equivalents, consistent with intramolecular hydrogen bond rupture under these conditions. Additionally, the titration behavior of hydroxyl chemical shifts in diols and protected derivatives has revealed significant OH/OD isotope shifts in the absence of chemical shift differences (dOH_in = dOH_out) necessary for an equilibrium isotope effect, lending evidence for an intrinsic contribution to this isotope effect. OH/OD isotope shift titration thus provides a means for understanding the origins of these isotope effects and for probing the persistence of intramolecular OH/OH hydrogen bonds in response to an increasing intermolecular hydrogen bond reservoir provided by the protic solvent additive.