Pharmaceutical Chemistry · Short notes

Organic Pharmaceutical Chemistry: Short Notes & Cheat Sheet

Reaction mechanisms, aromaticity, acidity and basicity, and the heterocycles found in common drugs.

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Short notes

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Heterocycles and the drugs built on them

Recognising the ring system is often enough to answer a 'which class' question.

Substitution and elimination

SN2 is one step, its rate depends on both substrate and nucleophile, it inverts configuration (Walden inversion) and is fastest with methyl and primary substrates in polar aprotic solvents.
SN1 goes through a carbocation, its rate depends only on the substrate, it gives racemisation and is favoured by tertiary substrates in polar protic solvents.
Carbocation stability: tertiary > secondary > primary > methyl (benzylic and allylic cations are also stabilised).
E2 is one step and needs an anti-periplanar hydrogen. Elimination usually gives the more substituted alkene (Saytzeff's rule).

Aromatic chemistry

Hückel's rule: a planar, cyclic, fully conjugated ring with 4n + 2 π electrons is aromatic (benzene has 6).
Electrophilic aromatic substitution: nitration, halogenation, sulfonation and Friedel–Crafts reactions.
Activating ortho/para directors: –OH, –NH₂, –OR, –NHCOR, alkyl. Deactivating meta directors: –NO₂, –CN, –COOH, –CHO, –COR, –SO₃H.
Halogens are the exception: they deactivate the ring but direct ortho/para.

Acids, bases and carbonyls

Approximate pKa: carboxylic acids 4–5, phenols about 10, alcohols about 16. Electron-withdrawing groups increase acidity (trichloroacetic acid is far stronger than acetic acid).
Basicity: aliphatic amines > ammonia > aromatic amines (aniline's lone pair is delocalised into the ring). Amides are essentially neutral.
Aldol condensation needs an α-hydrogen. The Cannizzaro reaction happens with aldehydes that lack one (formaldehyde, benzaldehyde), which disproportionate into an alcohol and an acid.
Esters are made by acid-catalysed reaction of an acid with an alcohol and hydrolysed by acid or base (saponification).

Heterocycles in drugs

Pyridine is weakly basic (pKa about 5.2): isoniazid, nicotinamide. Pyrrole is not basic, because its lone pair is part of the aromatic sextet.
Imidazole is amphoteric: histidine, metronidazole, azole antifungals, cimetidine.
Quinoline: quinine, chloroquine and the fluoroquinolones. Isoquinoline: papaverine.
Purine: caffeine, theophylline, 6-mercaptopurine, acyclovir. Pteridine: folic acid and methotrexate.
Thiazole: thiamine. Fused β-lactam–thiazolidine: penicillins. β-lactam–dihydrothiazine: cephalosporins.

Cheat sheet

High-yield facts in one place. Cover the right-hand column and test yourself.

SN1 vs SN2

Feature	SN1 · SN2
Steps	Two (carbocation) · One
Rate depends on	Substrate only · Substrate + nucleophile
Stereochemistry	Racemisation · Inversion
Best substrate	Tertiary · Methyl / primary
Solvent	Polar protic · Polar aprotic

Directing groups

Group	Effect
–OH, –NH₂, –OR	Strongly activating, o/p
Alkyl	Weakly activating, o/p
Halogens	Deactivating, o/p
–NO₂, –CN, –SO₃H	Strongly deactivating, meta
–CHO, –COOH, –COR	Deactivating, meta

Memory aids

SN1 = 1 molecule in the slow step: Unimolecular: only the substrate is in the rate-determining step, so the nucleophile's concentration does not matter.

Exam traps

Pyrrole is not basic even though it contains nitrogen; pyridine is.
Halogens are ortho/para directors despite deactivating the ring.
Aniline is a much weaker base than methylamine.
Benzaldehyde undergoes Cannizzaro, not aldol, because it has no α-hydrogen.

Revised? Now test yourself.

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