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In nature, enzymatic pathways generate C_aryl−C(O) bonds in a site-selective fashion. Synthetically, C_aryl−C(O) bonds are synthesised in organometallic reactions using prefunctionalized substrate materials. Electrophilic routes are largely limited to electron-rich systems, non-polar medium, and multiple product formations with a limited scope of general application. Herein we disclose a directedpara-selective ketonisation technique of arenes, overriding electronic bias and structural congestion, in the presence of a polar protic solvent. The concept of hard–soft interaction along with in situ activation techniques is utilised to suppress the competitive routes. Mechanistic pathways are investigated both experimentally and computationally to establish the hypothesis. Synthetic utility of the protocol is highlighted in formal synthesis of drugs, drug cores, and bioactive molecules.

The regioselective conversion of C−H bonds into C−Si bonds is extremely important owing to the natural abundance and non‐toxicity of silicon. Classical silylation reactions often suffer from poor functional group compatibility, low atom economy, and insufficient regioselectivity. Herein, we disclose a template‐assisted method for the regioselectivepara silylation of toluene derivatives. A new template was designed, and the origin of selectivity was analyzed experimentally and computationally. An interesting substrate–solvent hydrogen‐bonding interaction was observed. Kinetic, spectroscopic, and computational studies shed light on the reaction mechanism. The synthetic significance of this strategy was highlighted by the generation of a precursor of a potential lipophilic bioisostere of γ‐aminobutyric acid (GABA), various late‐stage diversifications, and by mimicking enzymatic transformations.

The regioselective conversion of C−H bonds into C−Si bonds is extremely important owing to the natural abundance and non‐toxicity of silicon. Classical silylation reactions often suffer from poor functional group compatibility, low atom economy, and insufficient regioselectivity. Herein, we disclose a template‐assisted method for the regioselectivepara silylation of toluene derivatives. A new template was designed, and the origin of selectivity was analyzed experimentally and computationally. An interesting substrate–solvent hydrogen‐bonding interaction was observed. Kinetic, spectroscopic, and computational studies shed light on the reaction mechanism. The synthetic significance of this strategy was highlighted by the generation of a precursor of a potential lipophilic bioisostere of γ‐aminobutyric acid (GABA), various late‐stage diversifications, and by mimicking enzymatic transformations.