Substituent‐Guided Routing in Chemical Reaction Networks

Metabolism is a complex chemical reaction network (CRN) that distributes reaction flux across multiple pathways, and mimicking such routing is of central interest in the design of synthetic out‐of‐equilibrium systems. Here, we investigate a chemically driven transient oligoesterification network in which subtle structural modifications of 4‐hydroxybenzoic acid monomers give rise to markedly different routing behaviors. Strongly electron‐withdrawing substituents positioned ortho to the phenolic hydroxy group act as molecular traffic directors by modulating its nucleophilicity and thereby selectively enabling or suppressing specific reaction channels. This substituent‐guided pathway selection directly links molecular structure to network routing and provides a programmable strategy for wiring synthetic CRNs in ways reminiscent of biological metabolic organization. These findings demonstrate how chemical modification can reconfigure network connectivity and advance the rational design of complex synthetic CRNs.