(a) Predict the products X and Y in the following reactions: (5×3=15 marks) (i) 1-allyl-2,2-dimethylcyclopropan-1-ol [figure]…

(a) Products X and Y

(i) Oxidative ozonolysis. The substrate printed is a cyclopropanol: C-1 of a cyclopropane ring carries the OH and an allyl group (–CH₂–CH=CH₂), and C-2 carries two methyl groups (1-allyl-2,2-dimethylcyclopropan-1-ol). Ozone cleaves the only C=C through the molozonide and then the ozonide. Oxidative work-up with H₂O₂ turns each H-bearing carbonyl fragment into an acid, so the internal alkene carbon becomes –COOH and the terminal =CH₂ becomes formic acid. The tertiary alcohol and the ring are untouched.

• X = 2-(1-hydroxy-2,2-dimethylcyclopropyl)acetic acid (C₇H₁₂O₃)
• Y = HCOOH (formic acid). An excess of H₂O₂ can oxidise it further to CO₂ + H₂O.

OC1(CC=C)CC1(C)C  >>  OC1(CC(=O)O)CC1(C)C  +  OC=O

(ii) Hell–Volhard–Zelinsky reaction. The acid is bicyclo[2.2.2]octane-2-carboxylic acid, and its α-carbon (C-2) carries one hydrogen. PBr₃ converts –COOH into the acyl bromide. The acyl bromide enolises far more readily than the acid does, and the enol takes up Br₂ at the α-carbon. X is therefore 2-bromobicyclo[2.2.2]octane-2-carbonyl bromide, which is isolated as 2-bromobicyclo[2.2.2]octane-2-carboxylic acid after aqueous work-up (racemic).

OC(=O)C1CC2CCC1CC2  >>  OC(=O)C1(Br)CC2CCC1CC2

(iii) Free-radical bromination of isobutane. The chain runs Br₂ → 2Br•, then Br• + R–H → HBr + R•, then R• + Br₂ → R–Br + Br•. Abstraction by Br• is endothermic, so the transition state is late and resembles the radical (Hammond), and radical stability (3° > 1°) decides the rate. At 127 °C, 3° and 1° hydrogens react with relative rates of about 1600 : 1 per hydrogen. Isobutane has 1 tertiary H and 9 primary H, so the 3° share is 1600/(1600 + 9) ≈ 99.4%.

• X (major, > 99%) = (CH₃)₃C–Br, 2-bromo-2-methylpropane
• Y (trace) = (CH₃)₂CH–CH₂Br, 1-bromo-2-methylpropane

(b)(i) Ring opening of 2,2-dimethyltetrahydrofuran by HI

A is 2,2-dimethyltetrahydrofuran. Heated with one equivalent of HI, the ring opens once to give 4-iodo-4-methylpentan-1-ol, (CH₃)₂C(I)–CH₂CH₂CH₂OH.

HI first protonates the ether oxygen to form an oxonium ion. The C–O bond that breaks is the one to the tertiary carbon, because its heterolysis gives a tertiary carbocation that is stabilised by hyperconjugation and by the +I effect of three alkyl groups. The primary C-5 would need an S_N2 attack, and that pathway is slower than S_N1 ionisation here. Iodide then captures the tertiary cation (S_N1), and the primary end is released as –CH₂OH. Only one equivalent of HI is present, so the primary alcohol is not converted into an iodide (excess HI would give the 1,4-diiodide).

CC1(C)CCCO1  >>  CC(C)(I)CCCO

(b)(ii) NBS, then NaOEt, on 1,2-dihydronaphthalene

The substrate in the image is 1,2-dihydronaphthalene: C-1 is benzylic CH₂, C-2 is allylic CH₂, and C-3=C-4 is conjugated with the ring.

• NBS, CCl₄ (Wohl–Ziegler). NBS keeps the Br₂ concentration low, so radical substitution wins over addition to the C=C. The H removed is the one at C-2. The C-2 radical is allylic, and through C-4 it is also benzylic, so it is the most delocalised radical available. Bromine is delivered at C-2, which keeps the styrene-type C=C intact. [A] = 2-bromo-1,2-dihydronaphthalene.
• NaOEt, EtOH, Δ (E2). Ethoxide removes an H from C-1 (benzylic and anti to Br) and bromide leaves to form C-1=C-2. The ring now has 10 π electrons, so elimination is driven by aromatisation. [B] = naphthalene.

C1Cc2ccccc2C=C1  >>  BrC1Cc2ccccc2C=C1  >>  c1ccc2ccccc2c1

(b)(iii) Alkenes from 2-chloro-2,3-dimethylpentane

2-Chloro-2,3-dimethylpentane is CH₃–CCl(CH₃)–CH(CH₃)–CH₂CH₃. Ethoxide brings about E2 elimination, and the β-hydrogens available are on C-1 (and the equivalent 2-methyl) and on C-3.

• Major (Saytzeff): 2,3-dimethylpent-2-ene, (CH₃)₂C=C(CH₃)CH₂CH₃. This alkene is tetrasubstituted, and the extra hyperconjugation makes it the most stable. C-2 carries two identical methyls, so there are no E/Z isomers.
• Minor (Hofmann): 2,3-dimethylpent-1-ene, CH₂=C(CH₃)–CH(CH₃)CH₂CH₃. It is 1,1-disubstituted and forms by loss of one of the six primary hydrogens.

Ethoxide is a small base, so the thermodynamically favoured Saytzeff alkene predominates.

(c)(i) Heterocycle syntheses and the Fischer indole mechanism

• (A) Quinoline – (3) glycerol, aniline, acid, nitrobenzene: Skraup synthesis.
• (B) Isoquinoline – (1) cinnamaldehyde, hydroxylamine, P₂O₅: cyclodehydration of cinnamaldoxime.
• (C) Indole – (2) acetaldehyde, phenylhydrazine, acid: Fischer indole synthesis.

Option (4), an α-halocarbonyl compound with thiourea, is the Hantzsch thiazole synthesis and has no match.

Mechanism of the Fischer indole synthesis:

1. Phenylhydrazine condenses with acetaldehyde to give the phenylhydrazone, PhNH–N=CH–CH₃.
2. Acid catalyses tautomerisation to the ene-hydrazine, PhNH–NH–CH=CH₂.
3. After protonation on the β-nitrogen, a [3,3]-sigmatropic rearrangement cleaves the weak N–N bond and joins the terminal CH₂ to the ortho carbon of the ring (the key C–C bond).
4. The resulting di-imine rearomatises by tautomerism to an ortho-substituted aniline carrying a –CH₂–CH=NH side chain.
5. The aniline NH₂ attacks the iminium carbon intramolecularly (5-exo cyclisation) to give a 2-aminoindoline (an aminal).
6. Acid then eliminates NH₃, and loss of a proton gives the aromatic indole.

Acetaldehyde phenylhydrazone itself cyclises poorly. In practice the parent indole is made from pyruvic acid phenylhydrazone, which gives indole-2-carboxylic acid, and that acid is then decarboxylated.

CC=NNc1ccccc1  >>  C=CNNc1ccccc1  >>  c1ccc2[nH]ccc2c1  +  N

(c)(ii) L-tyrosine to L-dopa

A second OH must be put at C-3, ortho to the phenol, without touching the (S) α-carbon. The free α-NH₂ would react with nitrous acid, and an o-hydroxy diazonium salt would close to a stable diazo-oxide, so all three groups are protected first.

1. Esterification and N-protection. SOCl₂/MeOH gives the methyl ester, and Ac₂O then gives the N-acetyl group: N-acetyl-L-tyrosine methyl ester.
2. O-Methylation. MeI with K₂CO₃ in acetone converts the phenol into the 4-methoxyphenyl derivative.
3. Nitration. HNO₃ in AcOH at low temperature puts NO₂ ortho to the strongly activating OMe, which is C-3.
4. Reduction. H₂ over Pd–C reduces the nitro group to the 3-amino compound.
5. Diazotisation and hydrolysis. NaNO₂/H₂SO₄ at 0–5 °C, then warm dilute H₂SO₄, gives the 3-hydroxy-4-methoxy derivative. The protected α-nitrogen is not attacked.
6. Global deprotection. Refluxing 48% HBr cleaves the aryl methyl ether and hydrolyses the amide and the ester. Neutralisation then gives L-dopa.

N[C@@H](Cc1ccc(O)cc1)C(=O)O  >>  COC(=O)[C@H](Cc1ccc(OC)cc1)NC(C)=O  >>  COC(=O)[C@H](Cc1ccc(OC)c([N+](=O)[O-])c1)NC(C)=O  >>  COC(=O)[C@H](Cc1ccc(OC)c(N)c1)NC(C)=O  >>  COC(=O)[C@H](Cc1ccc(OC)c(O)c1)NC(C)=O  >>  N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O

None of these steps makes or breaks a bond at the α-carbon, and strongly basic conditions, which could epimerise the ester, are avoided. The (S) configuration is therefore retained throughout. In the body the same change is catalysed by tyrosine hydroxylase (O₂, Fe²⁺, tetrahydrobiopterin), which hydroxylates L-tyrosine directly to L-dopa.