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

Abstract

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.

Rational Development of Remote C−H Functionalization of Biphenyl: Experimental and Computational Studies

“…The Pd–Ag heterodimeric model gave an energetic barrier 5.7 and 10.0 kcal mol −1 lower than the Pd–Pd dimer and Pd monomer models, respectively. Our results are in accordance with previous studies of Pd‐catalyzed meta ‐selective C−H activation reactions,– in which the longer intrinsic length of a Pd–Ag complex compared with that of a monomeric Pd complex accommodates a more favorable coordination of the 2‐cyanobiphenyl substrate.…”

“…We compared the three possible Pd‐containing transition state (TS) species: monomeric Pd(OAc) 2 , dimeric Pd 2 (OAc) 4 , and heterodimeric PdAg(OAc) 3 . Interestingly, the Pd–Ag heterodimeric species gave lower activation barriers for the concerted metalation–deprotonation (CMD) C−H activation step –. Encouraged by the computational heterodimeric transition state, we envisioned that the installed U‐shaped template for the assembly of the large‐sized cyclophane transition state may not be necessary for meta ‐C−H activation.…”

Accessing Remote meta‐ and para‐C(sp2)−H Bonds with Covalently Attached Directing Groups

“…[21] Previous reports on the director-assisted meta-C À Ha ctivation of phenylacetic or hydrocinnamic acid positioned the target C À Hb ond at ad istance of 5o r6atoms from the carbonyl linker and at ad istance of 10 or 11 atoms from the nitrile group. [21] Previous reports on the director-assisted meta-C À Ha ctivation of phenylacetic or hydrocinnamic acid positioned the target C À Hb ond at ad istance of 5o r6atoms from the carbonyl linker and at ad istance of 10 or 11 atoms from the nitrile group.…”

Computational exploration of Pd‐catalyzed C–H bond activation reactions

“…In these two CMD models, the nitrile directing group of the template binds to one Pd or Ag, while the arene C–H bond is brought close to another Pd to undergo the acetate‐assisted C–H bond activation. The Pd–Ag heterodimeric model has also been applied to other systems …”