Steric Modulation of Aromatic Compounds via Friedel–Craft Alkylation for Potential Reduction in Blood-Brain Barrier Permeability

Modulating blood–brain barrier (BBB) permeability is a crucial aspect of central nervous system (CNS) drug design. One strategy to decrease undesired BBB penetration involves the structural modification of drug molecules through the introduction of sterically bulky substituents. This study aimed to develop and evaluate a synthetic method for the selective introduction of tert-butyl groups onto an aromatic ring via Friedel-Craft alkylation, in order to investigate its potential to reduce BBB permeability. Acetanilide which synthesized from aniline was subjected to Friedel-Craft alkylation under mild conditions using tert-butyl chloride and aluminum chloride as reagents. Structural modification was confirmed via Fourier transform infrared spectrometer and nuclear magnetic resonance spectrometer. The tert-butyl group was successfully introduced, resulting in a substantial increase in molecular steric bulk. This approach may offer utility in the rational design of peripherally acting drugs by minimizing unintended CNS exposure.