Empirical Guidelines for the Development of Remote Directing Templates through Quantitative and Experimental Analyses

Abstract

The ability to differentiate and selectively activate remote C−H bonds represents a perennial challenge in the field of C−H activation. Since its first report in 2012, a now-established "directing template" (DT) approach remains demonstrably effective for the functionalization of remote C−H bonds. As selectivity is hypothesized to be principally determined by the optimal positioning of the reactive catalyst to a target C−H bond, a DT's spatial factors are particularly important toward achieving high selectivity, though a systematic study on its requisite factors remain unelucidated. Through an in-depth analysis of 119 structurally unique published remote DTs, this report summarizes the key factors that are central toward achieving high selectivity at defined aryl positions, which are experimentally corroborated through the development of new aliphatic meta and para-selective DTs for electronically unbiased arenes. These empirical rules, which summarize key distance and geometric factors, are expected to be useful tools for the future development of site-selective arene C−H activation as well as other reactions that rely on covalent/noncovalent DT-mediated remote regioselection.

Insight into the effect of contact ion pairs on C-H bond activation for the synthesis of Ru(III)-NHC complexes: A combined experimental and computational study

“…[15][16][17][18][19] However, ion pairs have not been extensively studied in regioselective or site-selective processes employing transition metals, because they are often thought to lack the directionality required to obtain high degrees of positional control when compared to hydrogen bonds. [20][21][22][23] Recent development in organometallic chemistry have increased the importance of counteranion effects brought by ion-pairing. 24 In the imidazolium-based salts, the formation of H-bonds is primarily facilitated by the hydrogen atoms on the imidazolium ring.…”

Asymmetric Remote meta-C–H Activation Controlled by a Chiral Ligand

“…The successful development of this method is valuable because it may also suggest important clues for understanding directing template-assisted remote meta -C–H activation of arenes, which have been well developed in the past decade after Yu’s seminal work . Moreover, this asymmetric C–H activation strategy might be versatile in principle because a variety of non-asymmetric transformations have been realized with the template-directed remote C–H activation strategy using MPAA ligands. − …”

Pd(ii)-catalyzed meta-C–H bromination and chlorination of aniline and benzoic acid derivatives

“…8 a However, the meta -C–H halogenation of anilines is still a formidable challenge since the conventional highly reactive sites are ortho / para positions. Although there have been several significant strategies disclosed for meta -C–H functionalization of arenes 9–28 and a few of them have been applied for aniline derivatives by the groups of Gaunt, 10 Yu, 11 Ackermann, 12 Phipps, 13 a Nakao, 14 and others 15 as well as our group, 16 to date, only a single 29 report on meta -C–H halogenation ( i.e. chlorination) of aniline derivatives has been disclosed by the Yu group using a substituted pyridine as the DG for the initial ortho -C–H activation and modified norbornene as the mediator for subsequent meta -C–H chlorination (Scheme 1b).…”