Heterocyclic Compounds and Biomolecules

The Hantzsch–Widman system builds a name from a prefix for each heteroatom — oxa (O), thia (S), aza (N), in that order of priority — and a stem giving ring size and saturation: three-membered -irene/-irane (N: -irine/-iridine), four -ete/-etane (-etidine for N), five -ole (unsaturated) and -olane (saturated; -olidine for N), six -ine (for N) and -inane or -ane (for O and S). So oxirane is ethylene oxide, thiirane the sulfur analogue, azetidine the saturated four-membered amine, 1,3-oxazole and 1,3-thiazole the O,N and S,N five-membered rings, and 1,3-diazole is imidazole. Numbering starts at the highest-priority heteroatom (O > S > N) and gives the other heteroatoms the lowest locants. Many rings keep trivial names that are also accepted: furan, thiophene, pyrrole, pyridine, pyrimidine (1,3-diazine), pyrazine (1,4-diazine), pyridazine (1,2-diazine) and pyrazole (1,2-diazole).

Fused bicyclic systems are named by prefixing the attached ring to the base component and lettering the fusion bond: indole is benzo[b]pyrrole, benzofuran benzo[b]furan, benzothiophene benzo[b]thiophene; quinoline is benzo[b]pyridine with N at position 1 and isoquinoline benzo[c]pyridine with N at 2; purine fuses pyrimidine with imidazole. Fused rings keep conventional numbering: in indole N is 1 and the reactive carbon is C3; in quinoline C4 is para to N and C5/C8 are the peri positions of the benzene ring.

In furan, pyrrole and thiophene each ring atom contributes one p orbital and the heteroatom supplies a lone pair, giving six π electrons over five atoms: aromatic, planar and π-excessive. Aromatic stabilisation falls as the heteroatom becomes more electronegative and holds its lone pair more tightly: benzene > thiophene > pyrrole > furan; furan is the least aromatic and behaves as a diene in Diels–Alder reactions with maleic anhydride. Because the ring carbons carry extra π density, electrophilic substitution is far faster than for benzene — pyrrole > furan > thiophene > benzene — and occurs at C2, where the σ-complex has three resonance forms including one with the positive charge on the heteroatom (C3 attack gives two). Pyrrole is so reactive that it polymerises in strong acid, so mild reagents are used: Vilsmeier–Haack formylation (DMF/POCl₃), acetylation with Ac₂O, nitration with acetyl nitrate. Pyrrole’s N–H is weakly acidic (pKa ≈ 17.5), and the anion alkylates on N or C.

Preparation. The Paal–Knorr synthesis cyclises a 1,4-dicarbonyl compound: with acid (or P₂O₅) to a furan, with ammonia or a primary amine to a pyrrole, and with P₄S₁₀ or Lawesson’s reagent to a thiophene. The Knorr pyrrole synthesis condenses an α-amino ketone with a β-keto ester, and the Hantzsch pyrrole synthesis combines an α-halo ketone, a β-keto ester and ammonia. Industrially furfural (from pentose-rich biomass by acid dehydration) is the gateway to furan.

Pyridine is isoelectronic with benzene; the nitrogen lone pair lies in an sp² orbital in the ring plane, not in the π system, so pyridine is aromatic and basic (pKaH 5.2) and is a good ligand and nucleophilic catalyst. The electronegative nitrogen makes the ring π-deficient: electrophilic substitution is very sluggish (made worse by protonation of N in acidic media) and goes to C3 under forcing conditions; the N-oxide, activated at C4, is the practical detour. Conversely, nucleophiles attack C2 and C4, where the negative charge of the intermediate can sit on nitrogen: the Chichibabin reaction (NaNH₂) gives 2-aminopyridine with loss of H⁻, and 2- and 4-halopyridines undergo S_NAr easily. The Hantzsch pyridine synthesis condenses two equivalents of a β-keto ester, an aldehyde and ammonia to a 1,4-dihydropyridine, oxidised to the pyridine.

Indole reacts with electrophiles at C3, not C2: attack at C3 gives a σ-complex in which the positive charge is stabilised by nitrogen without disrupting the benzene ring. Indoles are made by the Fischer indole synthesis, in which an arylhydrazone of a ketone or aldehyde rearranges in acid through its ene-hydrazine by a [3,3]-sigmatropic shift, then cyclises and loses NH₃. Quinoline and isoquinoline combine a benzene and a pyridine ring: electrophiles attack the benzene ring (C5 and C8), nucleophiles the pyridine ring (C2 and C4 of quinoline, C1 of isoquinoline). Quinolines come from the Skraup synthesis (aniline, glycerol, conc. H₂SO₄ and a mild oxidant: glycerol dehydrates to acrolein, which undergoes conjugate addition, cyclisation and oxidation), the Doebner–Miller and the Friedländer synthesis (2-aminobenzaldehyde with a ketone). Isoquinolines come from the Bischler–Napieralski reaction (a β-arylethylamide with POCl₃ gives a 3,4-dihydroisoquinoline) and the Pictet–Spengler reaction (a β-arylethylamine with an aldehyde gives a tetrahydroisoquinoline), the latter mirroring alkaloid biosynthesis.

Monosaccharides are polyhydroxy aldoses or ketoses. The D/L label refers to the configuration of the stereocentre farthest from the carbonyl, compared with D-glyceraldehyde; it is unrelated to the sign of rotation. An open-chain aldohexose has four stereocentres and 2⁴ = 16 stereoisomers, eight D and eight L; D-glucose, D-mannose (its C2 epimer) and D-galactose (its C4 epimer) are the common ones. In solution glucose exists almost entirely as the six-membered pyranose hemiacetal, formed by attack of O5 on C1, which creates a new stereocentre, the anomeric carbon: the α-anomer (C1–OH axial, trans to CH₂OH in the Haworth projection) has [α]_D +112° and the β-anomer (C1–OH equatorial) +18.7°. Either dissolves and changes rotation to the equilibrium value +52.7° — mutarotation — with about 36% α and 64% β, the β favoured because all its substituents are equatorial despite the anomeric effect.

Reactions. Sugars with a free hemiacetal are reducing sugars: they reduce Tollens’ reagent and Fehling’s solution. Br₂ water oxidises an aldose to the aldonic acid; dilute HNO₃ oxidises both ends to the aldaric acid; NaBH₄ gives the alditol. Three equivalents of phenylhydrazine form an osazone at C1 and C2, so glucose, mannose and fructose, which differ only at C1–C2, give the same osazone. The Kiliani–Fischer synthesis lengthens the chain by one carbon (cyanohydrin, hydrolysis, reduction; two C2 epimers result), and the Ruff degradation shortens it. Alcohols under acid give glycosides (acetals), which do not mutarotate. Disaccharides: maltose is α-D-Glc-(1→4)-D-Glc and cellobiose β-D-Glc-(1→4)-D-Glc, both reducing; lactose is β-D-Gal-(1→4)-D-Glc, reducing; sucrose is α-D-Glc-(1→2)-β-D-Fru, joined through both anomeric carbons and so non-reducing; its hydrolysis changes the rotation from +66.5° to negative (invert sugar), because fructose is strongly laevorotatory.

The twenty coded α-amino acids (all L, i.e. S except cysteine, which is R) exist in water as zwitterions H₃N⁺–CHR–COO⁻: they are high-melting, water-soluble and poorly soluble in organic solvents. Each has pKa₁ (COOH, about 2) and pKa₂ (NH₃⁺, about 9–10), and side-chain ionisations for acidic and basic residues. The isoelectric point pI, where the net charge is zero and the amino acid does not move in electrophoresis, is the average of the two pKa values that bracket the neutral zwitterion: glycine (2.34, 9.60) has pI 5.97; aspartic acid (1.88, 3.65 side chain, 9.60) has pI (1.88 + 3.65)/2 = 2.77; lysine (2.18, 8.95, 10.53 side chain) has pI (8.95 + 10.53)/2 = 9.74.

Chemical peptide synthesis couples an N-protected amino acid to a C-protected one. The amine is protected as Boc (removed by TFA) or Fmoc (removed by piperidine); the carboxyl is activated with a carbodiimide such as DCC (often with HOBt to suppress racemisation through the oxazolone) or as an active ester; and side chains carry orthogonal protecting groups. In Merrifield solid-phase synthesis the C-terminal residue is anchored to a polystyrene resin, the chain is built from C to N by repeated deprotection and coupling, excess reagents are washed away, and the peptide is finally cleaved from the resin (HF for Boc chemistry, TFA for Fmoc chemistry).

Structure determination. Acid hydrolysis and an amino acid analyser give the composition. The N-terminus is identified by Sanger’s reagent (1-fluoro-2,4-dinitrobenzene) or, repeatedly, by the Edman degradation: phenyl isothiocyanate adds to the N-terminal amine and, in acid, cleaves that residue alone as a phenylthiohydantoin, leaving the shortened peptide for the next cycle. The C-terminus is found with carboxypeptidase. Longer chains are cut into overlapping fragments: trypsin cleaves after Lys and Arg, chymotrypsin after Phe, Tyr and Trp, and cyanogen bromide after Met. Disulfide bridges are located after cleaving them. Structural features: the amide bond is planar (partial C=N character) and usually trans; secondary structure is the α-helix (3.6 residues and 0.54 nm per turn, N–H···O=C bonds from residue i to i + 4) and the β-sheet; tertiary and quaternary structure follow. Nucleic acids: a nucleoside is a base on ribose or 2′-deoxyribose (β-N-glycoside), a nucleotide its phosphate ester, and the backbone links 3′ to 5′ through phosphodiesters. In double-stranded DNA the antiparallel strands pair A with T (two hydrogen bonds) and G with C (three), so A = T and G = C (Chargaff), in a right-handed B-form helix of about 10.5 base pairs per turn.

Lipids are the water-insoluble biomolecules: triglycerides (glycerol triesters of fatty acids, saponified by NaOH to glycerol and soaps), phospholipids (a phosphate head group on a diacylglycerol, which self-assemble into bilayers) and waxes. Natural unsaturated fatty acids have cis double bonds, which kink the chain and lower the melting point (oleic acid is liquid, stearic solid). Steroids share the tetracyclic cyclopenta[a]phenanthrene (perhydro-1,2-cyclopentenophenanthrene) nucleus of 17 carbons in rings A–D, usually all-trans fused; cholesterol, the bile acids, the sex hormones and the corticosteroids differ in oxidation pattern and side chain.

Terpenoids are built from C₅ isoprene units, joined mostly head-to-tail (the isoprene rule), biosynthetically from isopentenyl and dimethylallyl diphosphates. Classes by size: monoterpenes C₁₀ (limonene, menthol, citral), sesquiterpenes C₁₅ (farnesol), diterpenes C₂₀ (phytol, retinol), triterpenes C₃₀ (squalene, formed tail-to-tail from two farnesyl units and cyclised to lanosterol and then the steroids), and tetraterpenes C₄₀, the carotenoids. β-Carotene has eleven conjugated C=C bonds, which move its absorption into the visible and make it orange; central cleavage gives two molecules of retinal (vitamin A aldehyde). Alkaloids are basic, nitrogen-containing natural products, mostly from plants and mostly derived from amino acids, classified by their heterocyclic skeleton — pyridine and piperidine (nicotine, coniine), tropane (atropine, cocaine), quinoline (quinine), isoquinoline (papaverine, morphine), indole (reserpine, strychnine) and purine (caffeine) — and characterised by their basicity, which allows extraction into aqueous acid and precipitation with base.