Chemistry · Organic chemistry · Year 2

Stereochemistry and conformations

Two “mirror” molecules with the same formula: why does one heal and the other harm?

The situation

In 1957 a sedative called thalidomide went on sale in West Germany to help pregnant women with morning sickness. Four years later it became clear that it had caused severe birth defects in children — about 10 000 babies were affected. The thalidomide molecule exists in two forms that are mirror images of each other: the formula, boiling point and colour are the same, and only the spatial arrangement differs, like a “right hand” and a “left hand”. Today many drugs on pharmacy shelves — esomeprazole, levofloxacin, levodopa — consist of only one “hand”. How can two molecules made of the same atoms act so differently in the body, and how do we tell them apart and measure them?

Topic

Stereochemistry and conformations. Pharmacy shelf: two “mirror-image” drugs with one formula — one heals, the other harms (the thalidomide tragedy); the saccharimeter at a sugar factory; in the laboratory, a molecule…

Key ideas

Chirality and R/S
Conformations
Optical activity

Formulas

E (φ) = \frac{V_{3}}{2} (1 + \cos 3 φ), V_{3} (C_{2} H_{6}) \approx 12 kJ/mol

Energy of rotation about the C–C bond in ethane: the eclipsed conformation ( $φ = 0 °$ ) is 12 kJ/mol higher than the staggered one.

\frac{n_{eq}}{n_{ax}} = K = e^{Δ G^{\circ} / R T}

Ratio of equatorial to axial conformers of a substituent on cyclohexane; $Δ G^{\circ}$ is the A-value (CH₃: 7.3 kJ/mol → 95 % equatorial).

2^{n}

Number of stereoisomers of a molecule with $n$ chiral centres (fewer if meso forms exist): for cholesterol $2^{8} = 256$ .

α = {[α]}_{D}^{20} \cdot l \cdot c

Polarimeter: angle of rotation $α$ (°), tube length $l$ (dm), concentration $c$ (g/mL) or density of the liquid.

e e = \frac{| n_{R} - n_{S} |}{n_{R} + n_{S}} \cdot 100 % = \frac{α_{meas}}{α_{pure}} \cdot 100 %

Enantiomeric excess (optical purity): $e e = 0$ for a racemate, 100 % for a pure enantiomer.

Theory

Conformations: free and hindered internal rotation

Parts of a molecule can rotate about a σ-bond; the spatial shapes produced by this rotation are called conformations (rotamers). They are easiest to see in a Newman projection: we look along the C–C bond, with the front atom as the centre and the rear atom as the circle. In ethane the form in which the H atoms hide one another (eclipsed) is ≈ 12 kJ/mol higher in energy than the staggered form: this comes from repulsion between the electron pairs of the C–H bonds and from hyperconjugation. The barrier is small: at 25 °C ethane rotates ≈ $10^{10}$ times per second, so the rotation is “free” and yet still has a barrier (“hindered”). In butane the CH₃ groups give four different shapes: anti (180°, the most stable), gauche (60°, +3.8 kJ/mol — the CH₃ groups are close together), CH₃/H eclipsed (+16) and CH₃/CH₃ eclipsed (+19 kJ/mol). At 25 °C butane is ≈ 69 % anti and ≈ 31 % gauche. In macromolecules the same internal rotation determines the flexibility of the chain: each bond can be trans or gauche, so the mean distance between the chain ends is proportional not to the length but to $\sqrt{N}$ ; an “independent” section containing several bonds is the statistical (Kuhn) segment. The ratio of the barriers (ΔE gauche–anti) sets the thermodynamic flexibility of the chain, and the height of the rotation barrier sets its kinetic flexibility (in detail — in the topic “Physics of macromolecules and polymer solutions”).

Cyclohexane, decalin and steroids

Cyclohexane is not flat: in the chair conformation all bond angles are ≈ 111° and all C–H bonds are staggered — there is no strain (small rings and ring strain — in the “Alkanes and cycloalkanes” experiment). Each carbon has one axial position (parallel to the axis of the ring) and one equatorial position (along the “equator” of the ring). When the ring flips (through the half-chair +45 → twist-boat +23 → boat +29 kJ/mol) all axial positions become equatorial and vice versa; at 25 °C this happens ~ $10^{5}$ times per second. An axial substituent clashes with the axial H atoms on carbons 3 and 5 (the 1,3-diaxial interaction = two gauche-butane interactions, 2 × 3.8 kJ/mol), so methylcyclohexane is 95 % equatorial and tert-butylcyclohexane 99.97 %. In decalin two chairs share a common bond: trans-decalin cannot flip, cis-decalin can. Steroids have a four-ring skeleton (rings A, B, C are six-membered, D is five-membered): cholesterol (zoosterol), the plant phytosterols (β-sitosterol), ergosterol of fungi (mycosterol), the sex hormones (testosterone, estradiol), corticosteroids (cortisol), bile acids, cardiac glycosides (digitoxin), steroid saponins and alkaloids. Cholesterol has 8 chiral centres — of the $2^{8} = 256$ stereoisomers only one is synthesised in nature; the trans fusion of the rings makes the molecule flat and rigid. Chemistry of cycloalkanes: small rings (cyclopropane, cyclobutane) open in addition reactions because of angle strain (with $H_{2}$ /Ni, $Br_{2}$ , HBr), whereas cyclopentane and cyclohexane undergo radical substitution like alkanes; cyclohexane is oxidised to cyclohexanol and cyclohexanone and then to adipic acid (the raw material for nylon); rings are synthesised by hydrogenating benzene, by the intramolecular Wurtz reaction and by the Diels–Alder reaction (school level — “Alkanes and cycloalkanes”).

Chirality, R/S and D/L

A molecule that cannot be superimposed on its mirror image is chiral (like a hand). The cause is often a carbon with four different substituents: a chiral centre (asymmetric atom). Stereoisomers that are mirror images of each other are enantiomers: their physical properties (boiling point, solubility, spectrum) are identical, they rotate the plane of polarised light by equal angles but in opposite directions, and they interact differently with other chiral substances (enzymes, receptors). The configuration is assigned by the Cahn–Ingold–Prelog rules: the substituents are ranked by atomic number (if equal, by the set of the next atoms; a double bond counts as a duplicated atom), the lowest-ranked one (4) is pointed away from the observer, and if the direction 1 → 2 → 3 is clockwise the centre is R (rectus), if anticlockwise — S (sinister). For sugars and amino acids the older D/L notation is used: in the Fischer projection (horizontal bonds towards the observer, vertical bonds away) the OH (or NH₂) on the lowest chiral centre is on the right for D and on the left for L. The amino acids in proteins belong to the L-series (alanine — S), and natural sugars to the D-series. Enantiomers are separated (resolution of a racemate) by crystallising diastereomeric salts formed with a chiral acid or base, by enzymes or by chiral chromatography (esters of amino acids, N-acyl and dinitrophenyl derivatives, the Edman reaction — in the topic “Amino acids and proteins”). Chirality is also present in macromolecules: the DNA double helix (B-form) is right-handed because it is built from D-deoxyribose residues — its mirror image (left-handed B-DNA made of L-deoxyribose) does not occur in nature. There is also a natural left-handed Z-DNA, but it is not the mirror image of the B-form — it is a different conformation.

Diastereomers, the meso form and geometric isomerism

Stereoisomers that are not mirror images are diastereomers: their physical properties differ. In tartaric acid, which has two chiral centres, (R,R) and (S,S) are enantiomers, while (R,S) has an internal plane of symmetry — the meso form: it has chiral centres, but the molecule is achiral and not optically active. So tartaric acid has 3 stereoisomers, not 4. An equimolar mixture of (R,R) + (S,S) is a racemate (racemic acid): it too does not rotate light. In 1848 L. Pasteur, using a magnifying glass, sorted crystals of a salt of racemic acid into two kinds — “right-handed” and “left-handed” crystals — and so was the first to separate enantiomers. Cis–trans (geometric) isomerism is also a kind of diastereomerism: in a ring or at C=C the substituents are on the same side (cis) or on opposite sides (trans) (school level — “Isomers and nomenclature”). Complex compounds also show geometric (cis/trans-[Pt(NH₃)₂Cl₂]) and optical (Δ/Λ-[Co(en)₃]³⁺) isomerism; in addition there are hydrate, ionisation, linkage (NO₂⁻ / ONO⁻), coordination and ligand isomerism, and conformational isomerism of chelate rings (in detail — “Complex compounds and ligands”). In polymers the order of the chiral centres along the chain is the tacticity: isotactic (all the same), syndiotactic (alternating), atactic (random); Ziegler–Natta catalysts give isotactic polypropylene.

Sugars and amino acids; optical activity

In solution glucose exists mainly as a six-membered pyranose ring: the C5–OH adds to the aldehyde group and C1 becomes a new chiral centre — two anomers, α (the C1–OH points down in the Haworth projection and is axial in the chair form) and β (up, equatorial). In β-D-glucopyranose all substituents are equatorial — which is why β predominates at equilibrium (≈ 64 %). When crystalline α-glucose dissolves in water, its rotation slowly changes from +112.2° to +52.7° — mutarotation: the ring opens and closes through the open chain until the α ⇌ β equilibrium is established (ring–chain tautomerism). In a polarimeter the light of a sodium lamp is polarised by the polariser, the chiral substance in the tube rotates the plane by $α = [α] l c$ , and the analyser is turned until the two halves of the half-shade field match. Aldohexoses with four chiral centres have $2^{4} = 16$ stereoisomers (8 D and 8 L); the ketohexose fructose has 3 centres and 8 stereoisomers. Sucrose rotates by +66.5° (to the right) and fructose by −92.4°; after hydrolysis the mixture rotates to the left — invert sugar. In sucrose both anomeric carbons are bonded, so it is a non-reducing disaccharide; maltose (α-1,4) and cellobiose (β-1,4) differ only in the configuration of one anomeric bond, yet human enzymes break down maltose and not cellobiose (deoxy- and amino sugars, ascorbic acid, lactose, raffinose — “Carbohydrates: glucose and starch”). The physics of optical activity — in the “Crystal optics” experiment. For amino acids D/L is defined relative to glyceraldehyde; enantiomeric purity $e e$ is measured with a polarimeter.

Chiral drugs, thalidomide and the limits of the model

The enzymes and receptors in the body are chiral, so enantiomers can act differently: (S)-carvone smells of caraway and cumin seed, (R)-carvone of spearmint; (S)-ibuprofen relieves pain, and the (R)-form is partly converted into (S) in the body. Thalidomide: in animal experiments the teratogenic effect (harm to the foetus) is linked more to the (S)-enantiomer, and the sedative effect to (R). But in the body the thalidomide enantiomers interconvert quickly (racemisation — the H on the chiral centre is acidic), so even giving only (R)-thalidomide could not have prevented the tragedy — do not replace this with the oversimplification “one enantiomer is good, the other is bad”. After the tragedy the rules for testing drugs were made much stricter. Model: molecules are drawn with real bond lengths and angles (1 Å ≈ 4.5 cm), conformation energies are experimental textbook values (smoothed with a Fourier series); the ring-flip path is schematic, using Cremer–Pople coordinates; rotation angles are for 20 °C and 589 nm; the mutarotation rate is a model value and time is sped up. Safety: the sodium lamp in the polarimeter gets hot; do not taste carvone or tartaric acid, and keep them out of your eyes.

Did you know?

In 1848 Louis Pasteur used a magnifying glass to sort small crystals of the sodium ammonium salt of racemic acid by hand into two piles: their solutions rotated polarised light by equal angles but in opposite directions. This was the first separation of enantiomers.
The two enantiomers of carvone differ in smell: (R)-carvone is the main odorant of spearmint oil, and (S)-carvone of caraway and cumin seed. The smell receptors in our nose are chiral as well.

Inside the experiment

The experiment starts from a real-life situation: you predict the result, change the controls, run the experiment and draw a conclusion. Inside are missions, theory, a quiz and a guided tour in which the camera moves and explains the key points.

More experiments in this section

Alcohols and ethers — Grade 10
Phenol, aldehydes and ketones — Grade 10
Acids, esters and soap — Grade 10
Carbohydrates: glucose and starch — Grade 10
Identifying organic substances — Grade 10
Radical and electrophilic mechanisms — Year 3
SN1, SN2 and elimination — Year 3
The aromatic ring and azo dyes — Year 3
Carbonyl compounds and synthesis — Year 3
Heterocycles and DNA — Year 3