Secondary equilibrium isotope effects on acidity

This chapter reviews secondary equilibrium isotope effects (IEs) on acidity—primarily on the comparison of protium with deuterium—and addresses the IEs of 13C, 14C, 15N, and 18O. IEs provide a discriminating insight into molecular structure and reactivity. They involve only a minimum perturbation and can be directed at specific positions within a molecule. An alternative that focuses on molecular structure rather than vibrational frequencies is the nuclear–electronic orbital approach, which calculates equilibrium IEs by treating some or all nuclei quantum mechanically on the same basis as the electrons. The 18O IEs on the acidities of carboxylic and phosphoric acids are a combination of primary and secondary. They are primary to the extent that it is an 18O–H bond that is broken and secondary to the extent that an 18O remains in the carbonyl or phosphoryl bond. By generating proton-bound dimers and measuring their mode of dissociation, it is possible to measure secondary deuterium IEs on proton affinity. The protonated 2-pentanone is favored 2.1-fold over protonated 2-pentanone-3,3-d2, corresponding to a 0.16 kcal mol-1 greater proton affinity for the undeuterated isotopologue. IEs on acidity or basicity—including the secondary ones—must also affect the strength of hydrogen bonding, and IEs on hydrogen bonding reflect IEs on acidity or basicity. © 2010 Elsevier Ltd