(a) (i) Tropolone is aromatic, but fulvene is non-aromatic. Why? (ii) Explain with example pseudo-aromaticity. (b) Identify the…

(a)(i)

Tropolone is aromatic because its planar, cyclic, conjugated seven-membered ring behaves as a tropylium system with 6 π-electrons, satisfying Hückel’s 4n+2 rule (n = 1). Although it is a neutral molecule, its aromatic character is best understood through significant dipolar resonance contributors where the carbonyl oxygen bears a negative charge and the ring carbons bear a positive charge, creating a continuous cyclic delocalization of 6 π-electrons (a tropylium-type cation). In contrast, fulvene is non-aromatic. While it possesses 6 π-electrons in total (only 4 of them within the ring), the exocyclic double bond disrupts the cyclic conjugation required for aromaticity. A dipolar resonance structure places a positive charge on the exocyclic carbon and a negative charge on the ring, but it is only a minor contributor (fulvene's dipole moment is only about 0.4 D), and it does not result in a stable, closed-shell aromatic sextet within the ring itself. The ring in fulvene behaves more like a diene than an aromatic system, lacking the thermodynamic stability and bond-length equalization characteristic of aromatic compounds.

(a)(ii)

Pseudo-aromaticity is the property of certain cyclic, conjugated systems that show a part of the stabilisation characteristic of aromatics although they do not strictly satisfy Hückel's rule in a symmetric, fully delocalised ground state. Such molecules acquire aromatic character through charge-separated (dipolar) resonance forms, and they show pronounced bond-length alternation, low resonance energies and retention of some polyene (addition) chemistry. Classic example: cyclopropenone. One of its dipolar resonance forms contains the 2π-electron cyclopropenyl cation (Hückel-aromatic, n = 0) with the negative charge on oxygen; the carbonyl is strongly polarised, the C–C bonds have marked double-bond character, and the compound is far more stable than a strained cyclopropanone (it resists hydration in water) — which is why it is called pseudo-aromatic. Tropone and tropolone are likewise described as pseudo-aromatic: their 6π tropylium-cation resonance form (n = 1) gives partial aromatic stabilisation without complete bond equalisation. In some textbooks the term is also applied to aromatic transition states, e.g., the cyclic 6π-electron transition state of the Diels–Alder reaction.

(b)

The sequence converts acetylcyclohexane into (Z)-1-cyclohexylbut-1-ene by the standard ketone → alkyne → cis-alkene route:

M — 1-(1,1-dichloroethyl)cyclohexane (the gem-dichloride). PCl₅ converts the ketone into the gem-dichloride: chloride attacks the P(V) centre to give a chlorophosphorane-type intermediate, which loses POCl₃ to leave the CCl₂ group.

N — ethynylcyclohexane (1-cyclohexylethyne). Three equivalents of NaNH₂ are used: the first two effect the double dehydrohalogenation of the gem-dichloride (via 1-chloro-1-cyclohexylethylene) to give the alkyne as its sodium acetylide; the third equivalent removes the remaining acidic ≡C–H proton so that the mixture is completely deprotonated. The acid work-up (HA) then regenerates the terminal alkyne.

O — 1-cyclohexylbut-1-yne (the internal alkyne). NaNH₂ deprotonates the terminal alkyne to the acetylide, which is alkylated by C₂H₅Br in an SN2 reaction.

P — H₂ over Lindlar catalyst (Pd/CaCO₃ deactivated with quinoline, or poisoned with lead). Syn (cis) addition of hydrogen across the triple bond gives the (Z)-alkene, (Z)-1-cyclohexylbut-1-ene, as drawn.

(c)

The reaction of neomenthyl chloride with sodium ethoxide in ethanol proceeds by an E2 elimination. Neomenthyl chloride is the isomer of 3-chloro-1-methyl-4-isopropylcyclohexane in which the chlorine atom is axial in the most stable chair conformation. For E2 elimination the β-hydrogen must be anti-periplanar to the leaving group; in this chair the axial chlorine at C3 is anti-periplanar to the axial hydrogen at C2 and, most importantly, to the tertiary hydrogen at C4.

Elimination towards C2 gives 2-menthene (p-menth-2-ene, disubstituted), whereas elimination towards C4 gives 3-menthene (p-menth-3-ene, trisubstituted). The major product is 3-menthene (≈78%) together with about 22% of 2-menthene, in agreement with the Zaitsev rule: the more substituted — and therefore more stable — internal alkene is formed preferentially. The anti-periplanar geometry is readily satisfied for both the C2–H and the tertiary C4–H, but removal of the tertiary C4–H delivers the trisubstituted alkene, so 3-menthene predominates. Its epimer menthyl chloride must first ring-flip to place the chlorine axially and then eliminates much more slowly, giving mainly the non-Zaitsev alkene, 2-menthene; hence the striking difference between the two chlorides.

(d)(i)

The reaction of a carbene with cis-2-butene serves as a stereochemical probe to distinguish between singlet and triplet carbenes.

• Singlet Carbene: A singlet carbene has a filled sp² hybrid orbital (lone pair) and an empty p-orbital. It reacts with alkenes in a concerted, stereospecific manner. The carbene adds to the double bond in a single step, preserving the stereochemistry of the alkene. When a singlet carbene (e.g., :CH₂) reacts with cis-2-butene, it yields exclusively cis-1,2-dimethylcyclopropane. The orbital interaction involves the overlap of the alkene π-orbital with the empty p-orbital of the carbene and the alkene π*-orbital with the filled sp² orbital of the carbene, leading to simultaneous bond formation on the same face.
• Triplet Carbene: A triplet carbene has two unpaired electrons in orthogonal orbitals (one in an sp²-like orbital and one in a p-orbital). It reacts via a stepwise mechanism. First, one electron pairs with one electron from the alkene π-bond to form a single bond, generating a 1,3-diradical intermediate. This intermediate has a single bond between the former carbene carbon and the alkene carbon, allowing for free rotation around this C-C bond before the second bond forms. Consequently, the stereochemistry of the starting alkene is lost. The reaction of a triplet carbene with cis-2-butene yields a mixture of cis- and trans-1,2-dimethylcyclopropane. The lack of stereospecificity is the key diagnostic feature of triplet carbenes.

(d)(ii)

The reaction of para-bromophenol with NaNH₂ in liquid ammonia followed by acidic workup proceeds via a benzyne (aryne) mechanism.

1. Deprotonation: The strong base NaNH₂ deprotonates the phenolic -OH group to form a phenoxide ion.
2. Elimination: A second NH₂⁻ removes the ring proton ortho to bromine, and the resulting aryl anion expels the bromide ion from the para-position. This elimination is driven by the formation of a highly strained triple bond in the ring, known as 4-oxidobenzyne (or 3,4-dehydrophenoxide). The intermediate is a benzyne with a triple bond between C3 and C4 (numbering the oxygen as position 1, or C4 and C5 if numbering the ring carbons 1-6 with OH at 1).
3. Nucleophilic Attack: The amide ion (NH₂⁻) attacks the benzyne intermediate. The attack is regioselective. The negatively charged phenoxide oxygen is electron-releasing and destabilises a carbanion close to it. Attack at C3 (meta to O) places the developing negative charge at C4, para to and farther from O⁻, whereas attack at C4 (para to O) would place it at C3, nearer to O⁻. The aryl carbanion lies in an sp² orbital in the ring plane, so it cannot be delocalised onto the oxygen; this field effect decides the regiochemistry. Thus, NH₂⁻ attacks at C3.
4. Protonation: The resulting anion is protonated by ammonia to form the amine. Acidic workup protonates the phenoxide back to the phenol. The major product is m-aminophenol (3-aminophenol). The reaction demonstrates the elimination-addition mechanism characteristic of aryl halides with strong bases.

(e)

Protein denaturation is the loss of the native secondary, tertiary and quaternary structure of a protein, and hence of its biological activity, while the primary structure (the peptide bonds) remains intact. It is not hydrolysis.

• Temporary (reversible) denaturation: the unfolding agent disrupts hydrogen bonds, hydrophobic and ionic interactions and, sometimes, disulfide bonds, but the chain does not aggregate or become chemically modified, so the protein refolds when the agent is removed. Example: Anfinsen's classic experiment on ribonuclease A, which was unfolded by 8 M urea and β-mercaptoethanol (which reduces the four disulfide bonds). When urea and the thiol were removed slowly by dialysis and the cysteines re-oxidised in air, the enzyme regained nearly full activity with the correct disulfides, showing that the amino acid sequence contains all the information for folding. Mild changes of pH or temperature that unfold small proteins such as RNase or lysozyme are also reversible.
• Permanent (irreversible) denaturation: the unfolded chains aggregate or are chemically modified, so they cannot refold. Example: heating (boiling or frying) egg white: ovalbumin unfolds, exposes hydrophobic groups and forms new intermolecular disulfide bonds, giving an opaque, insoluble gel that does not revert on cooling. Other examples are the coagulation of milk proteins by heat and acid, precipitation by heavy-metal ions (Hg²⁺, Pb²⁺, Ag⁺) that bind thiol groups, and strong acids or alcohol used as disinfectants. In the RNase experiment, removing urea while the thiols were already oxidised produced "scrambled" disulfides and inactive enzyme, which shows how incorrect covalent cross-links can make denaturation effectively irreversible.