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Q8.18(i):
Give plausible explanation for each of the following: (i) Cyclohexanone forms cyanohydrin in good yield but 2,2,6-trimethylcyclo-hexanone does not.

Solution :

Step 1: Structural Analysis of the Carbonyl Center

The formation of cyanohydrin involves the nucleophilic addition of the cyanide ion ($CN^-$) to the carbonyl carbon of a ketone. The reaction is represented as follows:

$C=O + HCN \rightleftharpoons C(OH)(CN)$

For the reaction to proceed with a good yield, the nucleophile must successfully attack the electrophilic carbonyl carbon ($C^{\delta+}$). This process is dictated by both electronic effects and, more critically in this instance, steric hindrance [Per Transition State Theory and VSEPR theory].

Step 2: Analysis of Cyclohexanone

In cyclohexanone, the carbonyl carbon is flanked by two secondary carbon atoms at the $\alpha$-positions. The structure is relatively open, allowing the $CN^-$ nucleophile to approach the carbonyl carbon along the Bürgi-Dunitz trajectory without significant repulsion from the ring substituents. The transition state is sterically accessible, leading to the formation of the cyanohydrin product.

Step 3: Steric Hindrance in 2,2,6-trimethylcyclohexanone

In 2,2,6-trimethylcyclohexanone, the introduction of methyl groups creates a congested environment:

  • Gem-dimethyl effect: The two methyl groups at the C2 position exert significant steric bulk, shielding one face of the carbonyl group.
  • Adjacent substitution: The methyl group at the C6 position provides additional steric crowding.

When the nucleophile ($CN^-$) attempts to attack the carbonyl carbon, it encounters severe van der Waals repulsions from these three methyl groups. [By the principles of Steric Inhibition of Nucleophilic Attack].

O Cyclohexanone (Open) O 2,2,6-trimethylcyclohexanone (Sterically hindered)

Step 4: Thermodynamic and Kinetic Considerations

The steric congestion in 2,2,6-trimethylcyclohexanone destabilizes the tetrahedral intermediate formed during the nucleophilic addition. Because the transition state energy is significantly increased due to steric strain, the rate of reaction becomes negligible. Furthermore, the equilibrium constant ($K_{eq}$) for the addition reaction is shifted heavily toward the reactants rather than the products [Per Le Chatelier's Principle and Thermodynamic Stability].

Feature Cyclohexanone 2,2,6-trimethylcyclohexanone
Steric Bulk Minimal High (3 Methyl groups)
Nucleophilic Approach Facile Severely hindered
Cyanohydrin Yield High Negligible

Final Solution: The formation of cyanohydrin in 2,2,6-trimethylcyclohexanone is prevented by severe steric hindrance caused by the three methyl groups at the $\alpha$-positions, which block the approach of the $CN^-$ nucleophile to the carbonyl carbon, thereby increasing the activation energy and rendering the addition reaction thermodynamically unfavorable.


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