General Concepts and Stereochemistry: Acidity, Aromaticity, Chirality, Topicity and Conformational Analysis

Acid strength is decided by the stability of the conjugate base. Electronegativity and hybridisation: C–H acidity rises with s-character, ethane (pKa ≈ 50) < ethylene (44) < acetylene (25). Induction falls off with distance: CF₃COOH (0.2) < ClCH₂COOH (2.9) < CH₃COOH (4.8). Resonance delocalises the charge: phenol (10) is far more acidic than cyclohexanol (16), and a p-NO₂ group lowers phenol’s pKa to 7.1 because the nitro group accepts the phenoxide charge directly; acetylacetone’s central CH₂ (9) is acidified by two carbonyls. Aromaticity can be decisive: cyclopentadiene (pKa ≈ 16) is as acidic as water because its anion is a 6π aromatic ring, while cycloheptatriene (≈ 36) gives an antiaromatic-leaning 8π anion. For substituted benzoic acids electron-withdrawing groups raise acidity (p-nitrobenzoic acid 3.4 < benzoic 4.2 < p-methoxybenzoic 4.5), and almost any ortho substituent raises it (the ortho effect: the carboxyl is twisted out of conjugation with the ring).

Basicity is quoted as the pKa of the conjugate acid (pKaH). A lone pair in an sp orbital (nitriles) is much less basic than one in sp² (pyridine, pKaH 5.2) or sp³ (piperidine, 11.1). Delocalisation lowers basicity: aniline (4.6) is a far weaker base than cyclohexylamine (10.6), and in pyrrole the nitrogen lone pair is part of the aromatic sextet, so pyrrole is barely basic (pKaH ≈ −3.8, protonated on carbon). Delocalisation of the protonated form raises it: guanidine (13.6) and amidines such as DBU are strong neutral bases because their conjugate acids share the charge over three or two nitrogens. In water, methylamines are ordered Me₂NH > MeNH₂ > Me₃N > NH₃ because solvation of the ammonium ion competes with the inductive effect; in the gas phase the order is simply Me₃N > Me₂NH > MeNH₂ > NH₃.

Aromatic stability in physical properties. Benzene’s heat of hydrogenation (−208 kJ/mol) is about 152 kJ/mol less than three times that of cyclohexene (−120 each), the classic measure of its resonance energy. The aromatic ring current deshields protons outside the ring (benzene δ 7.3) and strongly shields those inside, as in [18]annulene (inner H near δ −3). Charge separation that creates aromatic rings produces large dipole moments: azulene (1.0 D, blue) behaves as a cyclopentadienide fused to a tropylium, and tropone and cyclopropenone are unusually polar and basic at oxygen because their protonated forms are aromatic cations.

A molecule is chiral when it is not superimposable on its mirror image, which is the same as having no improper axis Sₙ. The commonest cause is a stereocentre (a carbon with four different groups), labelled R or S by the Cahn–Ingold–Prelog rules: rank the substituents by atomic number (at the first point of difference, duplicating atoms for multiple bonds), view with the lowest-ranked group pointing away, and read 1 → 2 → 3 clockwise as R. Chirality without a stereocentre is examined too: axial chirality in allenes abC=C=Cab and in biaryls with bulky ortho groups whose rotation is hindered — atropisomers such as 6,6′-dinitrobiphenyl-2,2′-dicarboxylic acid and BINOL, separable when the rotation barrier exceeds about 90 kJ/mol; planar chirality in trans-cyclooctene and substituted ferrocenes; and helical chirality in hexahelicene.

Enantiomers rotate plane-polarised light equally and oppositely. The specific rotation [α]ᵀ_λ = α/(l·c), with the observed rotation α in degrees, the path length l in decimetres and c in g/mL. The composition of a mixture is expressed as enantiomeric excess, ee = ([major] − [minor])/([major] + [minor]) × 100%, which for an ideal sample equals the optical purity [α]_obs/[α]_pure × 100%. So 80% ee is a 90:10 mixture, and a racemate (0% ee) is optically inactive. With several stereocentres, n centres allow at most 2ⁿ stereoisomers, fewer when meso forms (achiral, with an internal mirror plane) exist: 2,3-dibromobutane has three (a pair of enantiomers and a meso form), tartaric acid three. Diastereomers — stereoisomers that are not mirror images — have different physical properties; relative configuration is described as erythro/threo or syn/anti on a zig-zag chain, and E/Z (CIP ranking) for alkenes.

Test two apparently identical groups by replacing each in turn with a new group. If the two products are identical, the groups are homotopic (the protons of CH₂Cl₂, related by a C₂ axis); if they are enantiomers, the groups are enantiotopic (the CH₂ protons of ethanol, related only by a mirror plane); if they are diastereomers, the groups are diastereotopic (the CH₂ protons of 2-butanol, or the two methyls of an isopropyl group attached to a stereocentre). Homotopic and enantiotopic nuclei are equivalent in NMR in an achiral solvent; diastereotopic nuclei are chemically inequivalent and can have different shifts and couple to each other. Enzymes, being chiral, distinguish enantiotopic groups: in the oxidation of ethanol by alcohol dehydrogenase only one CH₂ hydrogen is removed.

The same classification applies to the two faces of a trigonal centre. The faces of acetone’s C=O are homotopic; those of acetaldehyde are enantiotopic, labelled Re and Si by the CIP order of the three substituents seen from each face (clockwise = Re); addition of a nucleophile to one face gives one enantiomer. A carbonyl next to an existing stereocentre has diastereotopic faces, and attack on them gives diastereomers in unequal amounts — the basis of the Cram and Felkin–Anh models of the synthesis chapter.

Rotation about C–C single bonds interconverts conformations. In ethane the eclipsed form lies about 12 kJ/mol above the staggered, mostly from torsional strain. In butane the anti conformer is lowest, the gauche about 3.8 kJ/mol higher (a steric CH₃/CH₃ interaction), and the fully eclipsed form about 19 kJ/mol above anti. Heteroatoms change the preferences: in 1,2-difluoroethane and in ethylene glycol the gauche form is favoured (the gauche effect and intramolecular hydrogen bonding).

Cyclohexane adopts a strain-free chair in which every C–C bond is staggered; the boat is about 29 kJ/mol higher and the twist-boat about 23. Each carbon has one axial and one equatorial position, and ring flipping exchanges them. A substituent prefers the equatorial position, avoiding 1,3-diaxial interactions; the free-energy preference is its A-value: about 7.3 kJ/mol for CH₃ (95% equatorial at 298 K), 9 for i-Pr and more than 20 for t-Bu, which effectively locks the ring. For disubstituted rings: trans-1,2 and cis-1,3 and trans-1,4 can put both groups equatorial, whereas cis-1,2, trans-1,3 and cis-1,4 must have one axial. trans-Decalin is rigid and cannot flip; cis-decalin flips. In pyranoses an electronegative group at the anomeric carbon prefers the axial position — the anomeric effect (n_O → σ*C–X).

Conformation controls reactivity when a reaction has strict geometric demands. E2 elimination needs the H and the leaving group anti-periplanar, which in cyclohexanes means both axial. Neomenthyl chloride, whose Cl is axial in the favoured chair, eliminates fast and gives mainly the more substituted 3-menthene (Zaitsev); menthyl chloride must first flip to put Cl axial, reacts about 200 times more slowly, and then has only one anti-periplanar hydrogen, so it gives only 2-menthene. In rigid systems, axial and equatorial isomers differ in S_N2, oxidation and ester-hydrolysis rates.

Neighbouring-group participation (anchimeric assistance) is internal nucleophilic attack by a group positioned anti to the leaving group. It shows as a rate enhancement and as retention of configuration, the result of two successive inversions. trans-2-Acetoxycyclohexyl tosylate solvolyses several hundred times faster than the cis isomer and gives the trans product through a bridging acetoxonium ion; a β-aryl group forms a phenonium ion; and a suitably placed C=C can accelerate ionisation enormously — anti-7-norbornenyl tosylate reacts about 10¹¹ times faster than the saturated 7-norbornyl ester.

A reaction is stereospecific when stereoisomeric starting materials give stereoisomerically different products because of the mechanism: anti addition of Br₂ converts cis-2-butene into racemic (2R,3R)/(2S,3S)-2,3-dibromobutane and trans-2-butene into the meso compound; S_N2 inverts; syn-dihydroxylation with OsO₄ turns a cis-alkene into a meso or erythro diol. A reaction is stereoselective when one stereoisomer forms in preference to others that could form: reduction of 4-tert-butylcyclohexanone by LiAlH₄ gives about 90% of the trans (equatorial) alcohol by axial attack, while the bulky L-selectride attacks equatorially and gives mainly the cis (axial) alcohol.