o-Quinone methide as alkylating agent of nitrogen, oxygen, and sulfur nucleophiles. The role of H-bonding and solvent effects on the reactivity through a DFT computational study

The reactivity of the alkylating agent o-quinone methide (o-QM) toward NH3, H2O, and H2S, prototypes of nitrogen-, oxygen-, and sulfur-centered nucleo philes, has been studied by quantum chemical methods in the frame of DF the ory (B3LYP) in reactions modeling its reactivity in water with biological n ucleophiles. The computational analysis explores the reaction of NH3, H2O, and H2S with o-QM, both free and H-bonded to a discrete water molecule, wit h the aim to rationalize the specific and general effect of the solvent on o-QM reactivity. Optimizations of stationary points were done at the B3LYP level using several basis sets [6-31G(d), 6-311+G(d,p), adding d and f func tions to the S atom, 6-311 + G(d,p),S(2df), and AUG-cc-pVTZ]. The activatio n energies calculated for the addition reactions were found to be reduced b y the assistance of a water molecule, which makes easier the proton-transfe r process in these alkylation reactions by at least 12.9, 10.5, and 6.0 kca l mol(-1) [at the B3LYP/AUG-cc-pVTZ//B3LYP/6-311 + G(d,p) level], for ammon ia, water, and hydrogen sulfide, respectively. A proper comparison of an un catalyzed with a water-catalyzed reaction mechanism has been made on the ba sis of activation Gibbs free energies. In gas-phase alkylation of ammonia a nd water by o-QM. reactions assisted by an additional water molecule H-bond ed to o-QM (water-catalyzed mechanism) are favored over their uncatalyzed c ounterparts by 5.6 and 4.0 kcal mol(-1) [at the B3LYP/ 6-311 + G(d,p) level ], respectively. In contrast, the hydrogen sulfide alkylation reaction in t he gas phase shows a slight preference for a direct alkylation without wate r assistance, even though the free energy difference (Delta DeltaG(#)) betw een the two reaction mechanisms is very small (by 1.0 kcal mol(-1) at the B 3LYP/6-311 + G(d,p),S(2df) level of theory). The bulk solvent effect, evalu ated by the C-PCM model, significantly modifies the relative importance of the uncatalyzed and water-assisted alkylation mechanism by o-QM in comparis on to the case in the gas phase. Unexpectedly, the uncatalyzed mechanism be comes highly favored over the catalyzed one in the alkylation reaction of a mmonia (by 7.0 kcal mol(-1)) and hydrogen sulfide (by 4.0 kcal mol(-1)). In contrast, activation induced by water complexation still plays an importan t role in the o-QM hydration reaction in water as solvent.