**N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline**
**Definition**
N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (commonly abbreviated as EEDQ) is an organic compound widely used as a reagent in organic synthesis, particularly for the selective modification of amines. It functions primarily as a coupling agent and an amine-protecting reagent in peptide synthesis and other chemical transformations.
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## Introduction
N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) is a heterocyclic compound characterized by a quinoline core structure that is partially saturated and substituted with ethoxycarbonyl and ethoxy groups. It is a member of the dihydroquinoline family and is notable for its utility in organic chemistry as a reagent that facilitates the formation of amide bonds and the protection of amine functionalities.
EEDQ is valued for its mild reaction conditions, selectivity, and efficiency in coupling reactions, making it a reagent of choice in peptide synthesis and other applications requiring the activation of carboxylic acids or the protection of amines. Its chemical properties and reactivity profile have been extensively studied, contributing to its widespread adoption in synthetic organic chemistry.
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## Chemical Structure and Properties
### Molecular Structure
EEDQ consists of a quinoline ring system that is partially hydrogenated at the 1,2-positions, resulting in a 1,2-dihydroquinoline framework. The nitrogen atom at position 1 is substituted with an ethoxycarbonyl group (-COOEt), while the carbon at position 2 bears an ethoxy substituent (-OEt). The molecular formula of EEDQ is C14H16N2O4.
The presence of the ethoxycarbonyl group on the nitrogen and the ethoxy group on the adjacent carbon imparts unique reactivity to the molecule, enabling it to act as an electrophilic reagent toward nucleophilic amines.
### Physical Properties
– **Appearance:** EEDQ typically appears as a white to off-white crystalline solid.
– **Molecular Weight:** Approximately 272.29 g/mol.
– **Melting Point:** Generally reported in the range of 70–75 °C.
– **Solubility:** It is soluble in common organic solvents such as dichloromethane, chloroform, and ethyl acetate, but has limited solubility in water.
– **Stability:** EEDQ is relatively stable under dry, inert conditions but can hydrolyze in the presence of moisture, leading to decomposition.
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## Synthesis
### General Synthetic Routes
The synthesis of N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline typically involves the reaction of 2-ethoxy-1,2-dihydroquinoline with ethyl chloroformate or related ethoxycarbonylating agents. The process generally proceeds via nucleophilic substitution at the nitrogen atom, introducing the ethoxycarbonyl group.
A representative synthetic pathway includes:
1. Preparation of 2-ethoxy-1,2-dihydroquinoline by partial hydrogenation or selective functionalization of quinoline derivatives.
2. Reaction of the 2-ethoxy-1,2-dihydroquinoline intermediate with ethyl chloroformate under controlled conditions to yield EEDQ.
The reaction conditions are optimized to minimize side reactions and maximize yield, often involving the use of inert atmospheres and anhydrous solvents.
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## Applications
### Use as a Coupling Agent
EEDQ is primarily employed as a coupling reagent in organic synthesis, especially in the formation of amide bonds between carboxylic acids and amines. Unlike other coupling agents such as carbodiimides (e.g., DCC), EEDQ offers several advantages:
– **Mild Reaction Conditions:** EEDQ facilitates coupling at ambient temperatures without the need for strong activating agents.
– **Reduced Racemization:** In peptide synthesis, EEDQ minimizes racemization of chiral centers, preserving stereochemical integrity.
– **Selective Activation:** It selectively activates carboxylic acids toward nucleophilic attack by amines, reducing side reactions.
The mechanism involves the formation of an activated ester intermediate, which then reacts with the amine to form the desired amide bond.
### Amine Protection
In addition to its role as a coupling agent, EEDQ can act as an amine-protecting reagent. It temporarily modifies amine groups to prevent unwanted reactions during multi-step syntheses. The ethoxycarbonyl group introduced by EEDQ can be removed under mild acidic or basic conditions, restoring the free amine functionality.
### Peptide Synthesis
EEDQ has found particular utility in peptide synthesis, where the formation of peptide bonds requires efficient and selective coupling of amino acids. Its ability to reduce racemization and operate under mild conditions makes it suitable for synthesizing peptides with sensitive or complex sequences.
### Other Synthetic Applications
Beyond peptide synthesis, EEDQ is used in the preparation of various amides, esters, and heterocyclic compounds. It can facilitate intramolecular cyclizations and other transformations where selective activation of carboxylic acids or amines is required.
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## Mechanism of Action
The coupling reaction mediated by EEDQ proceeds through several key steps:
1. **Activation of Carboxylic Acid:** EEDQ reacts with the carboxylic acid to form an O-ethoxycarbonyl intermediate, which is a more reactive species than the free acid.
2. **Nucleophilic Attack by Amine:** The amine nucleophile attacks the activated intermediate, leading to the formation of an amide bond.
3. **Release of Byproducts:** The reaction releases ethoxyquinoline derivatives as byproducts, which can be removed by standard purification techniques.
The overall process is efficient and typically proceeds with high yields and minimal side reactions.
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## Advantages and Limitations
### Advantages
– **Mild Conditions:** EEDQ operates effectively at room temperature without harsh reagents.
– **Selectivity:** It selectively activates carboxylic acids, minimizing side reactions.
– **Low Racemization:** Particularly important in peptide synthesis to maintain stereochemical purity.
– **Ease of Handling:** Solid reagent with reasonable stability under dry conditions.
### Limitations
– **Moisture Sensitivity:** EEDQ can hydrolyze in the presence of water, requiring anhydrous conditions.
– **Byproduct Removal:** The quinoline byproducts may require careful purification steps.
– **Limited Solubility in Water:** Restricts its use in aqueous or highly polar media.
– **Cost:** May be more expensive compared to some other coupling agents.
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## Safety and Handling
EEDQ should be handled with standard laboratory precautions:
– **Personal Protective Equipment:** Use gloves, safety goggles, and lab coats.
– **Storage:** Store in a cool, dry place under inert atmosphere to prevent hydrolysis.
– **Hazards:** May cause irritation to skin, eyes, and respiratory tract; avoid inhalation and contact.
– **Disposal:** Dispose of waste according to local regulations, considering its chemical nature.
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## Analytical Characterization
### Spectroscopic Methods
– **Nuclear Magnetic Resonance (NMR):** ^1H and ^13C NMR spectroscopy are used to confirm the structure and purity of EEDQ.
– **Infrared (IR) Spectroscopy:** Characteristic absorption bands corresponding to carbonyl and ethoxy groups.
– **Mass Spectrometry (MS):** Confirms molecular weight and fragmentation pattern.
### Chromatographic Techniques
– **High-Performance Liquid Chromatography (HPLC):** Used to assess purity and monitor reaction progress.
– **Thin-Layer Chromatography (TLC):** Quick qualitative analysis during synthesis.
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## Related Compounds
EEDQ is part of a broader class of dihydroquinoline derivatives used in organic synthesis. Related reagents include:
– **N-Ethoxycarbonyl-1,2-dihydroquinoline (EDQ):** Similar reagent lacking the 2-ethoxy substituent.
– **Carbodiimides (e.g., DCC, EDC):** Alternative coupling agents with different reactivity profiles.
– **Other Quinoline-Based Reagents:** Used for selective activation and protection in organic synthesis.
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## Historical Context
The development of EEDQ as a coupling reagent emerged from the need for more selective and mild reagents in peptide synthesis during the mid-20th century. Its introduction provided chemists with an alternative to carbodiimide-based reagents, addressing issues such as racemization and side reactions. Over time, EEDQ has become a standard reagent in synthetic organic chemistry laboratories worldwide.
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## Conclusion
N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) is a valuable reagent in organic synthesis, particularly for the formation of amide bonds and the protection of amines. Its unique chemical structure and reactivity enable efficient coupling reactions under mild conditions with reduced racemization, making it especially useful in peptide synthesis. While it requires careful handling due to moisture sensitivity, its advantages have secured its place as a staple reagent in synthetic chemistry.
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**Meta Description:**
N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) is an organic reagent used primarily for amide bond formation and amine protection in organic synthesis, notable for its mild reaction conditions and selectivity.