Experimental and Computational Development of a Conformationally Flexible Template for the meta-C-H Functionalization of Benzoic Acids

A conformationally flexible template for the meta-CH olefination of benzoic acids was designed through both experimental and computational efforts. The newly designed template favors a silver palladium heterodimer low barrier transition state, and demonstrates that it is feasible to lengthen templates so as to achieve meta-selectivity when the distance :between the functional handle of the native substrate and target C-H bond decreases. Analysis of the ortho-, meta-, and para-C-H cleavage transition states determined-that the new template conformation optimizes the interaction between: the nitrile and palladium silver dimer in the meta-transition state, enabling palladium to cleave meta-C-H bonds with moderate-to-good yields and generally high regioselectivity. Regioselectivity is governed exclusively by the template,;and kinetic experiments reveal that there is a 4-fold increase in rate in the presence of monoprotected amino acid ligands. Using a Boltzmann. distribution of all,accessible C-H activation transition states, it is possible to computationally predict-meta-selectivity in a number of investigated templates with reasonable accuracy. Structural and distortion energies reported may be used for the further development of templates for meta-C-H activation of hitherto unexplored arene substrates.