The carbonyl group C=O is a very versatile functional group in organic chemistry as it allows a wide — Organic Chemistry Chemistry Question
Carbonyl Chemistry
The carbonyl group C=O is a very versatile functional group in organic chemistry as it allows a wide range of chemical reactions among them some very useful C–C bond forming reactions. The deprotonation in the position to form an enolate and the attack of a nucleophile on the carbonyl C-atom are the two most important ways in which a C=O can react:
[VISUAL]
A lot of stereo- and regiochemical issues are associated with both these reactions, especially when the carbonyl compound is not symmetrical. Have a look, for example, at the following regioselective alkylation of 2-methyl-cyclohexanone (only mono-alkylation shall be considered):
[VISUAL]
LDA: lithium diisopropyl amide, Pr2NLi, a strong non–nucleophilic base
Write down the structures of A, A’, B and B’ (ignore stereochemistry here) and explain the different results of the two reactions with regard to the reaction conditions.
Model Answer
A:
B:
A':
B':
Explanation:
- NaOEt/EtOH, room temperature: Reversible deprotonation, thermodynamic control, more substituted enolate forms (A), leading to B.
- LDA, -78 °C: Irreversible deprotonation, kinetic control, the more acidic proton is removed, less substituted enolate forms (A'), leading to B'.
Why can butyllithium (BuLi) not be used for deprotonation?
Model Answer
BuLi can also act as a nucleophile and attacks the carbonyl C–atom. Therefore a non–nucleophilic base such as LDA has to be used.
Write down the mechanism of the formation of enamine C. What about regiochemistry here?
[VISUAL]
(Enamine formation from 2-methylcyclohexanone and pyrrolidine, catalyzed by p-TsOH, followed by reaction with a Michael acceptor to form D)
Model Answer
Mechanism of formation:
- Protonation of the carbonyl oxygen followed by nucleophilic attack of the pyrrolidine secondary amine onto the carbonyl carbon to form a hemiaminal.
- Proton transfer and elimination of water yields an iminium ion.
- Deprotonation from the less hindered alpha-carbon yields the enamine C.
Regiochemistry:
The formation of enamine preferentially occurs on the less substituted side because the more substituted enamine would suffer from steric hindrance, preventing a stable planar arrangement of the nitrogen lone pair with the double bond.
Explain with appropriate resonance structures why enamines react with electrophiles.
Model Answer
Enamines are nucleophilic because the nitrogen lone pair transfers electron density to the β-carbon, which can be illustrated via resonance structures:
[VISUAL]
(Resonance contributors showing the neutral enamine and the charge-separated iminium-enolate form with a negative charge on the β-carbon)
Write down the structure of the reaction product D (ignore stereochemistry here).
Model Answer
D is formed via a Michael addition of the enamine C to methyl vinyl ketone followed by hydrolysis. The structure of D is 2-methyl-6-(3-oxobutyl)cyclohexanone.
Consider the following reaction sequence for the synthesis of a coumarin derivative (nowadays solid phase bound acids such as Nafion H or Amberlyst are used as acid catalysts).
[VISUAL]
Write down the structure of E and explain its formation.
Model Answer
Structure of E: 4-methylcoumarin (C10H8O2)
Explanation of formation:
- Acid-catalyzed transesterification (lactone formation) via the attack of the phenol OH group onto the ester carbonyl, with elimination of MeOH.
- Subsequent acid-catalyzed dehydration (elimination of H2O) of the tertiary alcohol intermediate to give the fully conjugated 4-methylcoumarin derivative E.