How Does Palladium-Amino Acid Cooperative Catalysis Enable Regio- and Stereoselective C(sp³)-H Functionalization in Aldehydes and Ketones? A DFT Mechanistic Study

Density functional theory computations have elucidated the detailed mechanism and intriguing selectivities of C(sp³)-H activation and arylation of aldehydes and ketones promoted by palladium-amino acid cooperative catalysis. The amino acid cocatalyst takes up the carbonyl substrate by a condensation reaction to form an imine-acid, which acts as a transient directing reagent and metathesizes with Pd(OAc)₂ (the precatalyst) to initiate active Pd(II) complexes. The reaction then proceeds through C-H bond activation, oxidative addition of Pd(II) by iodobenzene, and reductive elimination from Pd(IV) completing C-C bond formation, followed by ligand exchange to regenerate the active Pd(II) catalyst and release the arylated imine-acid which continues on hydrolysis to give the final product and regenerate the amino acid cocatalyst. The C-H activation step via concerted metalation-deprotonation (CMD), which is rate- and selectivity-determining, favors palladacyclic transition states with a minimum chelate ring strain and an optimal Pd(d)/C-H(σ) orbital interaction. This finding reveals the origins of the regioselectivities that favor (1) the benzylic C(sp³)-H over ortho-phenyl C(sp²)-H activation for aromatic aldehydes and (2) the β-primary C(sp³)-H over γ-primary C(sp³)-H activation for aliphatic ketones. Incorporation of a chiral amino acid into the catalyst allows for enantioselective benzylic C(sp³)-H arylation of aromatic aldehydes, and the enantioselectivity arises from steric and torsional strains that discriminate between the diastereomeric transition states. The computational results demonstrate rich experimental-theoretical synergy and provide useful insights for the further development of C-H functionalization and metal-organic cooperative catalysis.