Alcohol

The hydroxyl group is among the most prevalent functional groups in small-molecule drug discovery, present across a broad range of approved therapeutics and natural products. Its capacity to engage in hydrogen bonding, both as a donor and acceptor, makes it a versatile pharmacophoric element, contributing to target binding through direct interactions with residues in enzyme active sites and receptor binding pockets. Primary, secondary, and tertiary alcohols, along with their aromatic counterparts, phenols, each carry distinct electronic and steric profiles that influence potency, selectivity, and ADMET properties. Phenols, in particular, are widely exploited for their increased acidity and propensity to form strong hydrogen bonds with polar binding site residues.

Emerging synthetic techniques are exploiting the hydroxyl group in increasingly creative ways. In photochemistry, radical deoxyfunctionalisation strategies using visible-light photocatalysis enable C–O bond cleavage to form C–C and C–heteroatom bonds from readily available alcohol starting materials.

 Electrochemically, TEMPO-mediated anodic oxidation of primary and secondary alcohols to aldehydes, ketones, and carboxylic acids has gained significant traction as a practical and sustainable alternative to stoichiometric chemical oxidants, with demonstrated compatibility with sensitive substrates including propargylic and alpha-trifluoromethyl systems. 

The hydroxyl group appears frequently in FDA-approved drugs across multiple therapeutic areas. Atorvastatin (Lipitor, Pfizer), the widely prescribed HMG-CoA reductase inhibitor for hypercholesterolaemia, contains two secondary hydroxyl groups critical to its binding interaction with the target enzyme. More recently, Elacestrant (Orserdu, Stemline Therapeutics/Menarini), the first oral selective estrogen receptor degrader (SERD), received FDA approval in January 2023 for ESR1-mutated, ER-positive, HER2-negative advanced or metastatic breast cancer. The molecule incorporates a phenolic hydroxyl group within its tetrahydronaphthalene scaffold, contributing to its high-affinity estrogen receptor binding.

In organic synthesis, the hydroxyl group is central to a number of key named reactions.The Mitsunobu reaction enables stereospecific substitution of an alcohol with inversion of configuration, facilitating access to either enantiomer from a single alcohol precursor. Oxidation of primary and secondary alcohols using Swern conditions or Dess–Martin periodinane is a routine route to aldehydes and ketones, while the Barton–McCombie reaction provides deoxygenation via radical intermediates from secondary alcohols activated as xanthate esters.