Computational Study of the Mechanism of Cyclic Acetal Formation via the Iridium(I)-Catalyzed Double Hydroalkoxylation of 4-Pentyn-1-ol with Methanol

The mechanism of Ir(I)-catalyzed double hydroalkoxylation of 4-pentyn-1-ol with methanol to form cyclic acetals has been investigated with density functional theory calculations. Using a model [Ir(PyP')(CO)(2)](+) catalyst (PyP' = 1-[2-phosphinoethyl]pyrazole) the key steps in the first hydroalkoxylation are shown to be (i) electrophilic activation of the alkyne at the cationic Ir(I) metal center; (ii) rate-limiting C-O bond formation via intramolecular nucleophilic attack by the pendant OH group at the C4 position of the bound alkyne; and (iii) facile H+ transfer to form an Ir-bound cyclic vinyl ether intermediate. The key C-O bond forming cyclization step is greatly facilitated by the presence of an external H-bonded MeOH molecule that stabilizes the positive charge that develops at the hydroxyl proton of the bound alkyne. External MeOH also plays a key role in the H+ transfer step, for which a number of kinetically competitive pathways corresponding to either retention of the hydroxyl proton in the product or exchange with solvent were identified. The second hydroalkoxylation is initiated from the Ir-bound cyclic vinyl ether intermediate and depends on the ability of that species to access an WO-alkyl form in which the beta-carbon carries a significant positive charge. Reversible C-O bond formation then occurs via nucleophilic attack of MeOH at the)beta-carbon and proceeds via a novel [3+2]-addition of the O-H bond over the {Ir-C-alpha-C-beta} moiety. This forms an Ir(III) hydrido-alkyl species, from which reductive elimination yields the final O,O-acetal product. This final reductive elimination is the rate-limiting step within the second hydroalkoxylation component of the cycle. The Ir(I)-alkyl intermediate can also access a MeOH-mediated C-H activation at the C-gamma position that leads to exchange with external MeOH. This accounts for the experimentally observed HID exchange at that position.