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-C–H 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.