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Targeting distal C–H bonds in arenes The Friedel-Crafts reaction is among the oldest in organic chemistry. For well over a century, chemists have relied on electronic effects intrinsic to aryl rings to append substituents at specific sites along the periphery. However, only in the past decade have they devised catalytic techniques that over-ride these preferences so that new groups usually drawn to the neighboring sites of an existing substituent instead wind up two or three carbons away. Dutta et al. review progress in this field, highlighting elaborate directing groups and mediators as well as sophisticated ligand design. Science, this issue p. eabd5992 A Review highlights methods to selectively substitute aryl rings two or three carbons away from an existing substituent. BACKGROUND Organic synthetic chemistry has facilitated the production of medicines, agrochemicals, food, polymers, dyes, and more through step- and atom-economical pathways. Most of these value-added products consist of complex molecular frameworks that can be constructed from simple starting materials by either functional group interconversion or installation of new functionality or coupling units. Incorporation of new functionality through direct replacement of a C−H bond, the most common constituent of organic molecules, has emerged as an attractive synthetic tool, particularly for its atom economy. However, to be useful, the process has to be highly regioselective to avoid costly time- and energy-intensive separations of similar product isomers. For aromatic and heteroaromatic ring substrates, regioselective C−H functionalization implies the installation of a functional group selectively at ortho-, meta-, or para-positions one, two, or three carbons away from a substituent that is already present. Traditional approaches to achieving this goal have relied on subtle reactivity differences arising from steric and electronic effects associated with each substituent. Although electronically controlled C−H functionalization of arenes by Friedel-Crafts reactions has been known for over a century, such methods often suffer from poor selectivity and limited substrate scope. A quest to find a putative reaction path that would override intrinsic electronic or steric bias is therefore an active research area. In the last three decades, there have been notable advances in the realm of proximal ortho-C−H functionalization with the assistance of a coordinating directing group. However, accessing distal meta- and para-C−H functionalization of electronically and sterically unbiased arenes remained elusive until much more recently. The development of suitable synthetic methods that enable distal meta- or para-C−H functionalization with prominent selectivity remains an active challenge for researchers in the synthetic chemistry field. ADVANCES Steric and/or electronic influences can be manipulated through the design of suitable catalysts, ligands, or reagents that alter the traditional patterns of regioselectivity. Several approaches have been implemented in the past decade for the selective functionalization of meta and para-C−H bonds along these lines. These include (i) σ-bond activation–assisted remote C−H functionalization, in which initial ortho-cycloruthenation plays a crucial role; (ii) template-assisted remote C−H functionalization; (iii) the use of a bifunctional template for remote C−H activation of heteroarenes; and (iv) remote C−H functionalization enabled by noncovalent interactions such as ion pairing and hydrogen bonding. Pairing palladium with a transient mediator in conjunction with a precise directing group has also emerged as a viable approach. Finally, nondirected remote C−H activation protocols that rely on cooperative catalysis, ligand, or reagent control of regioselectivity have been reported. OUTLOOK Emergence of the aforementioned distal C−H functionalization techniques has recast numerous synthetic routes to producing value-added chemicals. One of the major challenges associated with increasing the practicality of this chemistry is to discover more environmentally benign, cost-effective, scalable, and sustainable catalytic systems with very high turnover number. Expanding the catalytic toolbox in this fashion will enable the synthetic modification of hitherto inaccessible sites of organic molecules and enhance the discovery and manufacture of pharmaceuticals, agrochemicals, and other desired materials. Distal C−H functionalization of arenes. Transition metal catalysts paired with an optimal ligand, directing group (DG), and/or mediator can add a functional group (FG) two or three carbons away from an existing group (R) on an aryl ring. Transition metal–catalyzed aryl C−H activation is a powerful synthetic tool as it offers step and atom-economical routes to site-selective functionalization. Compared with proximal ortho-C−H activation, distal (meta- and/or para-) C−H activation remains more challenging due to the inaccessibility of these sites in the formation of energetically favorable organometallic pretransition states. Directing the catalyst toward the distal C−H bonds requires judicious template engineering and catalyst design, as well as prudent choice of ligands. This review aims to summarize the recent elegant discoveries exploiting directing group assistance, transient mediators or traceless directors, noncovalent interactions, and catalyst and/or ligand selection to control distal C−H activation.