Combined Experimental and Theoretical Study of the Mechanism and Enantioselectivity of Palladium- Catalyzed Intermolecular Heck Coupling

Abstract

The asymmetric Heck reaction using P,N-ligands has been studied by a combination of theoretical and experimental methods. The reaction follows Halpern-style selectivity; that is, the major isomer is produced from the least favored form of the pre-insertion intermediate. The initially formed Ph-Pd(P,N) species prefers a geometry with the phenyl trans to N. However, the alternative form, with Ph trans to P, is much less stable but much more reactive. In the preferred transition state, the phenyl moiety is trans to P, but significant electron density has been transferred to the alkene carbon trans to N. The steric interactions in this transition state fully account for the enantioselectivity observed with the ligands studied. The calculations also predict relative reactivity and nonlinear mixing effects for the investigated ligands; these predictions are fully validated by experimental testing. Finally, the low conversion observed with some catalysts was found to be caused by inactivation due to weak binding of the ligand to Pd(0). Adding monodentate PPh3 alleviated the precipitation problem without deteriorating the enantioselectivity and led to one of the most effective catalytic systems to date.

BINAP versus BINAP(O) in Asymmetric Intermolecular Mizoroki–Heck Reactions: Substantial Effects on Selectivities

“…[8, 9k] A recent quantum-chemical study even showed that, in one example, the migratory insertion of 1 occurs from the least-favored intermediate. [29] The consistently high ee values obtained with iPr 2 NEt as base corroborate, at least, that BINAP(O) acts as a bidentate ligand, and the minor deviations in the ee values of 2 and 3 (both R configuration) do not support a kinetic-resolution pathway.…”

Thiadiazolidine 1-oxide systems for phosphine-free palladium-mediated catalysis

“…24 Computational studies of the effects of halides or acetates have been published by Shaik 25 and by Norrby. 26 Some very interesting results showing high activity of palladium in the presence of acetate anions were published by Reetz 27 and by de Vries. 28 In view of these reports, we decided to run the same experiments in the absence of any ligand, as it is plausible that the active palladium species does not contain the ligand.…”

Computational Studies of Synthetically Relevant Homogeneous Organometallic Catalysis Involving Ni, Pd, Ir, and Rh: An Overview of Commonly Employed DFT Methods and Mechanistic Insights

“…224 This means that the major isomer is formed from one of the higher energy pre-insertion intermediates (Scheme 10). While the trans Ph−N arrangement is more favorable over the trans Ph−P arrangement, the higher barrier of the subsequent furan insertion and the lower stability of the formed carbopalladated species make the trans Ph−N pathway less productive.…”