Acid derivatives, phenols, polycyclic and heterocyclic aromatics | 5D: Structure, function, and reactivity of bio-relevant molecules | Chem/phys

Acid derivatives (anhydrides, amides, esters)

Acid derivatives such as anhydrides, amides, and esters originate from carboxylic acids by modifying the –OH group into another substituent. Their shared structure centers on the carbonyl (C=O), rendering them reactive toward nucleophiles and useful intermediates in organic synthesis. Each derivative exhibits distinct properties and reactivity based on its leaving group and resonance stabilization.

Nomenclature

Acid chlorides: Suffix “-oyl chloride” (e.g., ethanoyl chloride).

Anhydrides: Suffix “-oic anhydride” (e.g., ethanoic anhydride).

Amides: Suffix “-amide” (e.g., N-methyl ethanamide).

Esters: Suffix “-oate” (e.g., methyl ethanoate).

Physical properties

The C=O bond is polar, facilitating dipole-dipole interactions that raise boiling points compared to nonpolar alkanes.
Amides can hydrogen-bond via their N–H group, leading to even higher boiling points. This hydrogen bonding is crucial in protein secondary structures.
Esters, anhydrides, and acid chlorides generally lack hydrogen-bond donation but still benefit from dipole interactions.
IR spectra show characteristic C=O absorptions:
Acid chloride: Near 1800 cm⁻¹
Anhydride: Two bands between 1700–1800 cm⁻¹
Amide: N–H stretch ~3300 cm⁻¹, C=O ~1700 cm⁻¹
Ester: C=O ~1700 cm⁻¹ and a C–O stretch ~1200 cm⁻¹

Important reactions

Preparation:
- Acid chloride from carboxylic acid + $SOC l_{2}$
- Anhydride from two carboxylic acids (with heat) or from acid chloride + carboxylate
- Ester from acid chloride + alcohol, or from carboxylic acid + alcohol under acidic conditions
- Amide from acid chloride + amine
Nucleophilic substitution: A nucleophile attacks the electrophilic carbon of the carbonyl, displacing the existing leaving group (e.g., chloride in acid chlorides).
Hofmann rearrangement (amide to amine): The amide’s C=O is removed by alkyl or aryl migration to nitrogen.
Transesterification: An ester reacts with an alcohol to form a new ester.
Hydrolysis:
- Esters hydrolyze (saponification in base) to yield carboxylates and alcohols.
- Amides hydrolyze to yield a carboxylic acid and amine (though more vigorous conditions are often required).

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General principles

Relative reactivity of acid derivatives: Acid chloride > Anhydride > Ester > Amide. Acid chlorides have excellent leaving groups ( $C l^{-}$ ), whereas amides have very poor leaving groups ( $- N R_{2}$ ).
Steric effects: Bulky substituents near the carbonyl hinder nucleophilic approach.
Electronic effects: Good leaving groups stabilize negative charges via resonance or inductive pulls (e.g., carboxylate from an anhydride).
Strain (β-lactams): In β-lactams, the ring includes an amide linkage that lacks free rotation due to partial double-bond character. The forced ring geometry creates high ring strain, making β-lactams more reactive.

Phenols

Phenols are aromatic ring systems bearing a hydroxyl substituent. This positioning enhances acidity compared to typical alcohols, due to resonance stabilization of the resulting phenolate ion. They appear in various natural products and synthetic compounds, exhibiting strong antiseptic properties and serving as key intermediates in industrial chemistry.

Oxidation and reduction (e.g., hydroquinones, ubiquinones)
Certain phenols, particularly those with two hydroxyl groups in the ring, act as 2e⁻ redox centers.
In biology, they cycle between reduced hydroquinones and oxidized quinones (as in ubiquinones), enabling electron transport in respiratory and photosynthetic pathways. The ring system’s ability to accommodate these redox changes underpins numerous cellular processes.

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Polycyclic and heterocyclic aromatic compounds

Polycyclic aromatics contain fused benzene rings (e.g., naphthalene, anthracene) that display strong aromatic stabilization and characteristic reactivity patterns, such as electrophilic substitution.

Heterocyclic aromatics incorporate at least one heteroatom (nitrogen, oxygen, sulfur) into the ring, producing molecules like pyridine or pyrrole. These modifications significantly influence acidity, basicity, and electronic properties, broadening the range of chemical behavior.

Biological aromatic heterocycles

Many essential biomolecules feature heterocyclic aromatic structures. For instance, the nucleobases in DNA and RNA (purines and pyrimidines) possess conjugated ring systems crucial for base-pairing and genetic information storage.

Heterocycles also arise in vitamins, cofactors, and pigments, where their resonance and functional groups enable binding, catalysis, and light absorption in vital biochemical reactions.