Biological and Biochemical Relevance (Aromatic Substitution)

Aromatic iodination in hormone biosynthesis

• Tyrosine residues in thyroglobulin are enzymatically iodinated (EAS with I⁺ generated by thyroid peroxidase). Mono/di-iodotyrosines couple to give T₃/T₄ thyroid hormones—an in vivo example of directed aromatic substitution.

Aromatic hydroxylation (detox/activation)

• Cytochrome P450 enzymes oxidize aromatic rings to phenols, increasing polarity for excretion. Mechanistically radical/oxidative, but functionally installs –OH akin to a “substitution” that rearomatizes.

Pathological nitration

• Reactive nitrogen species (peroxynitrite, ·NO₂) nitrate tyrosine side chains → 3-nitrotyrosine (a biomarker of oxidative/nitrative stress). This parallels EAS nitration under biological conditions.

Azo linkages and prodrugs

• Diazonium coupling makes azo dyes; gut flora can reduce –N=N– to release active drugs (e.g., sulfasalazine → 5-aminosalicylic acid in colon). Shows how aromatic/azo chemistry is leveraged for site-specific delivery.

Synthesis of aromatic drugs

• Many APIs rely on controlled aromatic substitution (e.g., nitration/reduction/oxidation sequences to build PABA derivatives; guided EAS to set regiochemistry). Enzymes and synthetic routes both exploit directing effects to place substituents precisely.

Takeaway: Aromatic substitution patterns underpin hormone biosynthesis, metabolic activation/inactivation, stress markers, and drug design; biological systems enforce regioselectivity via enzymes, while synthetic chemists use directing groups and diazonium/Sandmeyer chemistry to access otherwise difficult substitutions.