2.7 Methods of Studying Reaction Mechanisms: Isotopes, Crossover, Trapping, Kinetic Isotope Effect

2.7.1 Kinetic and non-kinetic methods ★★

A mechanism is a hypothesis; each method below can disprove a proposed path, none proves one. A good answer names the method, the experiment, the observation and what it rules out.SN

2.7.2 Isotopic labelling ★★★

• Which C–O bond breaks in ester hydrolysis? Ethyl propanoate labelled in the alkoxy oxygen, EtCO–¹⁸OEt, with OH⁻ gives EtCOO⁻ (no label) and Et¹⁸OH: acyl–oxygen fission (B_Ac2), not alkyl–oxygen.SN
• Is the tetrahedral species a true intermediate? Label the carbonyl oxygen, stop the reaction half-way and recover the unreacted ester: it has lost ¹⁸O. Only an intermediate that lives long enough for a proton shift (making its two oxygens equivalent) and that can revert to ester explains this; a single transition state cannot IFoS 2023 Q1(b) 5m.SN

• R–COO⁻ + Br–CN → R–CN + Br⁻ + CO₂: use R–¹⁴COO⁻. The nitrile is radioactive and the CO₂ is not: the nitrile carbon is the old carboxyl carbon; only N comes from BrCN, whose carbon leaves as CO₂. Path: acyl cyanate → acyl isocyanate → four-membered ring → R–C≡N + CO₂ (the reverse test, Br¹⁴CN, gives ¹⁴CO₂) CSE 2021 Q1(a) 10m IFoS 2022 Q1(c) 5m.SN

• Benzyne (Roberts): chlorobenzene with ¹⁴C at C-1 and KNH₂ gives aniline with the NH₂ half on the labelled carbon and half on its neighbour. Direct displacement would put it only on C-1; a symmetrical intermediate with two equivalent ends, benzyne, explains 50 : 50 (Fig. 2.7.3).SN

2.7.3 Crossover experiments ★★★ 15 marks in 2024

• Design: run two substrates that differ in both parts that may separate (double labelling, isotopic or by a substituent), in one flask under the same conditions. Only the two “own” products → intramolecular. Crossed products (statistically, about as much as the own ones) → the pieces separate and recombine: intermolecular.SN
• Claisen rearrangement: heat allyl p-tolyl ether with 2-methylallyl phenyl ether: only 2-allyl-4-methylphenol and 2-(2-methylallyl)phenol form; no 2-allylphenol and no 2-(2-methylallyl)-4-methylphenol. The allyl group never leaves its ring: a concerted [3,3] shift CSE 2024 Q4(b)(i) 10m.SN

• Para-Claisen: with both ortho positions blocked (2,6-dimethylphenyl or 2-methoxy-6-methylphenyl allyl ethers) the first [3,3] shift gives a dienone that cannot tautomerise; a second [3,3] (Cope) carries the chain to the para carbon, then H⁺ shift gives the 4-allylphenol. Heated together, each ether gives only its own para product: still intramolecular. Two inversions of the allyl chain: a crotyl group arrives at para unchanged in connection IFoS 2024 Q2(a)(i) 5m.SN
• Contrast: the Fries rearrangement of aryl esters gives some crossed products (an acylium ion is free in part); the benzidine rearrangement gives none.

2.7.4 Isolating, detecting and trapping intermediates ★★

• Isolate it under milder conditions (N-bromoamide and isocyanate in the Hofmann reaction); detect it in situ: carbocations by ¹³C NMR in superacid (SbF₅–SO₂ClF), radicals by ESR, enols and enolates by UV/IR.SN
• Trap it: add a reagent that reacts with the suspected species faster than anything else and gives a product of known structure. Benzyne + furan → Diels–Alder adduct; carbenes + alkene → cyclopropane (stereospecific for singlet); radicals + TEMPO; carbocations + N₃⁻ or MeOH; enolates + D₂O or Me₃SiCl (the D or SiMe₃ marks the carbon that carried the charge, 2.7.8).SN
• H/D exchange rates report carbanion formation: the α-H of a cyclopropyl ketone exchanges ≈ 6 × 10³ times faster than that of a cyclopropenyl ketone; the cyclopropenyl anion would place 4 π electrons in a planar three-membered ring, antiaromatic, so that carbanion forms slowly IFoS 2021 Q3(a)(i) 5m.SN