Enamines,
play a crucial role in synthesizing a number of compounds with diverse
applications. In this blog post, we will dive into the fascinating world of
enamines, exploring their synthesis methods and reactions.
Key words: Enamine, Imine, Aldehyde, Ketone, Nucleophilic addition, Nucleophilic Substitution.
Table of Contents
- Synthesis of Enamines
- Hydrolysis of Enamines
- Applications in Organic Synthesis
- Comparison of Enols, Enolates and Enamines
- Enamine Catalysis
- Conclusion
1. Synthesis of Enamines
Enamines
can be synthesized through the condensation reaction between a secondary amine
and a carbonyl compound, typically an aldehyde or ketone. The reaction is catalyzed
by an acid, resulting in the formation of an imine intermediate, which is
subsequently tautomerized to the corresponding enamine.
Reaction Scheme
 |
| Figure 1: Synthesis of Enamine |
Mechanism
The mechanism of enamine of synthesis involves following steps;
Step 1: Protonation of the carbonyl oxygen to enhance electrophilicity of the carbonyl carbon.
Step 2: Nucleophilic addition of the secondary amine on carbonyl carbon to form iminium alcohol intermediate.
Step 3: Proton transfer to make OH to OH2 which is a good leaving group.
Step 4: Elimination of H2O as leaving group to form iminium ion intermediate.
Step 5: Proton abstraction from the adjacent carbon to make C=C and neutralize the charge of N atom. This process yields enamine compound. Complete mechanism is shown below;
 |
| Figure 2: Mechanism of Synthesis of Enamine |
2. Hydrolysis of Enamines
Enamine
hydrolysis under acidic conditions provides ketone compound. The mechanism of
hydrolysis of enamine in described below;
 |
| Figure 3: Mechanism of Hydrolysis of Enamine |
The involved
steps in hydrolysis of enamine are;
Step 1:
Protonation of C=C followed by formation of an imine intermediate.
Step 2:
Addition of H2O molecule on C=N bond to produce amino alcohol species
Step 3:
Proton transfer to make amine to ammonium group which is a good leaving group
Step 4:
Liberation of amine fragment and formation of oxonium ion.
Step 5:
Deprotonation of oxonium ion intermediate to form neutral species.
3. Applications in Organic Synthesis
3.1. Michael Addition
Enamines
participate in Michael addition reactions, particularly with α,β-unsaturated
carbonyl compounds. The enamine acts as a nucleophile, attacking the electrophilic
carbon of the double bond, leading to the formation of a new carbon-carbon
bond.
 |
| Figure 4: Michael Addition of Enamine |
Mechanism
of Michael Addition on α,β-unsaturated carbonyl compounds
Enamines
acts as nucleophile when reacts with α,β-unsaturated carbonyl compounds. This
process consists of two stages, first is addition of nucleophile on alkene
carbon to form imine intermediate. And the second step is hydrolysis of the
imine to produce 1,5-diketo compound. Hence expanding the molecular diversity
of the synthesized compounds.
The
mechanism of enamine addition and hydrolysis is shown below;
Step 1:
Attack of enamine (nucleophile) on alkene carbon, this results in
delocalization of pi electrons to form imine-enolate intermediate.
Step 2: Tautomerization
of enolate to form ketone intermediate.
Step 3: Hydrolysis
of imine functional group to produce ketone functionality. Here we will not
show the complete mechanism of hydrolysis of imine intermediate as we have
discussed earlier.
 |
| Figure 5: Mechanism of Michael Addition of Enamine |
3.2. Alkylation
Enamine have tendency to undergo Nucleophilic Substitution Reaction by using alkyl halide, where alkyl groups are transferred onto the carbon atom of the enamine. This results in the formation of a new carbon-carbon bond.
 |
| Figure 6: Alkylation of Enamine |
Mechanism
of Alkylation of enamines
The
alkylation of enamine also comprises two stages. First is nucleophilic
substitution of Cl atom by enamine to produce imine intermediate. Then second
stage is hydrolysis of imine intermediate to give final ketone compound.
3.3. Acylation
Enamine
undergo Nucleophilic Acyl Substitution reaction by using acyl chloride.
Where acyl group is transferred to the carbon of enamine. This results in the
formation of a new carbon-carbon bond. After hydrolysis of the imine
intermediate to form 1,3-diketone compound.
 |
| Figure 7: Acylation of Enamine |
3.4. Halogenation
Enamine reacts with Chlorine gas to provide β-chloro immonium intermediate. The hydrolysis of iminium intermediate gives b-chloroketone.
 |
| Figure 8: Halogenation of Enamine |
3.5. Reaction of enamine with Carboxylic acid
Enamine reacts with deuterated acetic acid to provide deuterated iminium intermediate. The hydrolysis of iminium intermediate gives b-deutero-ketone. This method is useful for the isotopic labelling of ketone compounds for various biophysical studies.
 |
| Figure 9: Reaction of Enamine with Carboxylic acid |
4. Comparison of Enols, Enolates and Enamines
As we
know from the structure that enols, enolates and enamines are derived from
carbonyl compounds. Hence, they have resemblance in their structure. They
comprise similar properties as well. To compare the properties of the enols,
enolates and enamines please see the table below;
 |
| Table 1: Comparison of Enols, Enolates and Enamines |
5. Enamine catalysis
5.1. Asymmetric Aldol Reaction
In the
year 2000, List, Lerner and Barbas III showed that the enamines which are
derived from naturally occurring amino acid L-proline can be used as catalyst
for intermolecular Aldol reaction.1 We have discussed the reaction
and its mechanism with details in separate article. Here we understand the
representative example of Aldol reaction by using enamine catalysis.
 |
| Figure 10: Asymmetric Aldol Reaction |
According to the authors, the reaction proceeds through enamine intermediate. The enamine is more nucleophilic than that of corresponding enol. Also presence of the carboxylic acid group stabilizes the transition state of Aldol reaction through hydrogen bonding. Therefore, the catalyst (amino acid) is covalently attached to the substrate and it controls the stereochemical pathway of the intermolecular aldol reaction.
 |
| Figure 11: Transition State of Aldol Reaction |
Also, there are examples reported for the intramolecular Aldol reactions by enamine catalysis.2 Please see the reaction below, in which 1,5-diketone compound undergoes Aldol reaction via enamine catalysis followed by dehydration reaction to yield a, b-unsaturated ketone compound.
 |
| Figure 12: Intramolecular Aldol Reaction |
5.2. Asymmetric
Diels Alder Reaction3
In the year 2016, Yang and co-workers described enantioselective synthesis of bicyclic dihydropyrans by means of an organocatalytic oxa-Diels-Alder reaction in the presence of aqueous acetaldehyde. According to the authors the reaction proceeds through enamine intermediate. In this process the enamine intermediate reacts with the diene through the less sterically hindered Si face.
 |
| Figure 13: Asymmetric Diels Alder Reaction |
5.3. 1,3-Dipolar
Cycloaddition Reactions of Enamines and Azides
Enamines show
remarkably high reactivity in their 1,3-dipolar cycloaddition reactions with
aromatic azides to produce triazoline.4 However, the triazolines
are very unstable and immediately undergoes various ring transformations such
as substituted triazoles. Thus, 1,3-dipolar cycloaddition reactions of enamine
and azides provides good synthetic route for the preparation of triazole derivatives.
 |
| Figure 14: 1,3-Dipolar Cycloaddition Reactions of Enamine |
6. Conclusion
In
conclusion, enamines stand as indispensable entities in the realm of organic
chemistry, serving as both intermediates and end-products in various synthetic
pathways. Their synthesis methods and reactions open a vast array of
possibilities for designing novel compounds with applications across different
industries. Embrace the magic of enamines and unlock the potential for ground-breaking
discoveries in the world of organic synthesis.
See Also
References
1) List,
B.; Lerner, R. A.; Barbas, C. F., Proline-catalyzed direct asymmetric aldol
reactions. J. Am. Chem. Soc. 2000, 122 (10), 2395-2396.
2) Agami,
C.; Platzer, N.; Sevestre, H., Enantioselective cyclizations of acyclic
1,5-diketones. Bull. Soc. Chim. Fr. 1987, 358-360.
3) J. Li,
K. Yang, Y. Li, Q. Li, H. Zhu, B. Han, C. Peng, Y. Zhi, X. Gou, Chem. Commun.
2016, 52, 10617–10620.
4) Bakulev, V.A., Beryozkina, T., Thomas, J. and Dehaen, W. (2018), The Rich Chemistry Resulting from the 1,3-Dipolar Cycloaddition Reactions of Enamines and Azides. Eur. J. Org. Chem., 2018: 262-294.
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