Feb 26, 2024

A Comprehensive Guide to Enamine: Synthesis, Hydrolysis and Reactions

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

  1. Synthesis of Enamines
  2. Hydrolysis of Enamines
  3. Applications in Organic Synthesis
  4. Comparison of Enols, Enolates and Enamines
  5. Enamine Catalysis
  6. 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

Synthesis of enamine
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;

Mechanism of formation of enamine
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;

Mechanism of hydrolysis of enamine
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.

Michael Addition of Enamine
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. 

Mechanism of Michael Addition of Enamine
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.

Alkylation of Enamine
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.

Acylation of Enamine
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.

Halogenation of enamine
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;

Comparison of Enols, Enolates and Enamines
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.

Asymmetric Aldol Reaction of Enamines
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.

Asymmetric Aldol Reaction of Enamines
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.

Intramolecular Aldol Reaction
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.

Asymmetric Diels Alder Reaction
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.

1,3-dipolar Cycloaddition Reactions of Enamines
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

  1. Substitution Reactions
  2. Aldol Reaction
  3. Pericyclic Reactions

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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