Figure 1: Different strategies to direct SEAr reactions from above and underneath aromatic rings.
From: Precise through-space control of an abiotic electrophilic aromatic substitution reaction
(a) Proposed5 mechanism of through-space control in dimethylallyl tryptophan synthase (DMATS). The enzymatic pocket is illustrated schematically in blue. Note how (i) the precise positioning of the dimethylallyl cation inside the enzyme as well as (ii) a [C–H···N] hydrogen bond in the Wheland intermediate likely play a role in determining the selectivity of the reaction. (b) Placing a negatively polarized fluorine atom above the centre of an aromatic ring activates9 two symmetrically equivalent positions on the ring for SEAr reactions. On the other hand, carbonyl groups located directly above two atoms of an aromatic ring (c,d, this work) can precisely direct the substitution to one specific location. Key stabilizing interactions involving electron donation from O/N lone pairs to carbocations and positively polarized H/N atoms are illustrated with dashed lines.
