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.

中文翻译：

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苯甲酸间位 C-H 官能化的构象灵活模板的实验和计算开发

通过实验和计算工作设计了用于苯甲酸间位 CH 烯化的构象灵活模板。新设计的模板有利于银-钯异二聚体低势垒过渡态，并证明当天然底物的功能手柄和目标 CH 键之间的距离减小时，延长模板以实现元选择性是可行的。对邻位、间位和对位 CH 裂解过渡态的分析确定，新模板构象优化了间位过渡态中腈和钯-银二聚体之间的相互作用，使钯能够以中等强度裂解间位 CH 键。良好的产率和高区域选择性。区域选择性完全由模板控制，和动力学实验表明，在存在单保护氨基酸配体的情况下，速率增加了 4 倍。使用所有可访问的 CH 激活过渡态的 Boltzmann 分布，可以以合理的准确性计算预测许多研究模板中的元选择性。报告的结构和畸变能可用于进一步开发模板，用于迄今为止未探索的芳烃底物的间位 CH 活化。