Mechanism of 8‑Aminoquinoline-Directed Ni-Catalyzed C(sp3)–H Functionalization: Paramagnetic Ni(II) Species and the Deleterious Effect of Carbonate as a Base

Studies into the mechanism of 8-aminoquinoline-directed nickel-catalyzed C­(sp3)–H arylation with iodoarenes were carried out, to determine the catalyst resting state and optimize catalytic performance. Paramagnetic complexes undergo the key C–H activation step. The ubiquitous base Na2CO3 is found to hinder catalysis; replacement of Na2CO3 with NaO t Bu gave improved catalytic turnovers under milder conditions. Deprotonation of the 8-aminoquinoline derivative N-(quinolin-8-yl)­pivalamide (1a) at the amide nitrogen using NaH, followed by reaction with NiCl2(PPh3)2 allowed for the isolation of complex Ni­([AQpiv]-κN,N)2 (3) with chelating N-donors (where [AQpiv] = C9NH6NCO t Bu). Complex 3 is a four-coordinate disphenoidal high-spin Ni­(II) complex, excluding short anagostic Ni-- t Bu hydrogen interactions. Complex 3 reacts with the paddle-wheel [Ph3PNi­(μ-CO2 t Bu)2]2 (6·PPh 3 ) or t BuCO2H to give insoluble {[AQpiv]­Ni­(O2C t Bu)}2 (5). Dissolution of 5 in donor solvents L (L= DMSO and DMF) gave a paramagnetic intermediate assigned by NMR as [AQpiv]­Ni­(O2C t Bu)­L (5·L) and equilibrium reformation of 3 and 6·L. DFT calculations support this equilibrium in solution. Both 3 and 5 undergo C–H activation at temperatures as low as 80 °C and in the presence of PR3 (PR3 = PPh3, P i Bu3) to give Ni­(C9NH6NCOCMe2CH2-κN,N,C)­PR3 (7·PR 3 ). The C–H functionalization reaction orders with respect to 7·P i Bu 3 , iodoarenes, and phosphines were determined. Hammett analysis using electronically different aryl iodides suggests a concerted oxidative addition mechanism for the C–H functionalization step; DFT calculations were also carried out to support this finding. When Na2CO3 is used as the base, the rate determination step for C–H functionalization appears to be 8-aminoquinoline deprotonation and binding to Ni. The carbonate anion was also observed to provide a deleterious NMR-inactive low-energy off-cycle resting state in catalysis. Replacement of Na2CO3 with NaO t Bu improved catalysis at milder conditions and made carboxylic acid and phosphine additives unnecessary. Complex 3 and its functionalized analogues were observed as the catalyst resting state under these conditions.