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Reducing By-Product Formation with 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) in Condensation Reactions

Abstract:

Condensation reactions, fundamental in organic synthesis, often suffer from the formation of unwanted by-products, diminishing yield and complicating purification. This article explores the utility of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), a sterically hindered, non-nucleophilic strong base, in mitigating by-product formation in various condensation reactions. We delve into the reaction mechanisms where DBU’s specific properties contribute to enhanced selectivity, examining its role in aldol condensations, Knoevenagel condensations, Wittig reactions, and other related transformations. This review encompasses parameters influencing DBU’s performance, including concentration, solvent choice, and temperature, supported by experimental evidence and literature examples. The focus is on understanding how DBU, by controlling proton abstraction and minimizing side reactions, contributes to cleaner and more efficient condensation processes.

Table of Contents:

1. Introduction
   1.1. Condensation Reactions: A Brief Overview
   1.2. By-Product Formation: Challenges and Implications
   1.3. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU): A Versatile Base
2. DBU: Properties and Characteristics
   2.1. Chemical Structure and Molecular Formula
   2.2. Physical and Chemical Properties
   2.3. Basicity and Non-Nucleophilicity
3. DBU in Aldol Condensation Reactions
   3.1. Mechanism of Aldol Condensation
   3.2. DBU’s Role in Selectivity and By-Product Reduction
   3.3. Experimental Examples and Comparative Studies
4. DBU in Knoevenagel Condensation Reactions
   4.1. Mechanism of Knoevenagel Condensation
   4.2. Advantages of DBU over Traditional Bases
   4.3. Optimization of Reaction Conditions
5. DBU in Wittig and Related Reactions
   5.1. Wittig Reaction Mechanism
   5.2. DBU as a Base in Wittig Reactions: Scope and Limitations
   5.3. Improved Stereoselectivity with DBU
6. DBU in Other Condensation Reactions
   6.1. Michael Additions
   6.2. Horner–Wadsworth–Emmons (HWE) Reactions
   6.3. Other Relevant Transformations
7. Parameters Influencing DBU Performance
   7.1. Solvent Effects
   7.2. Temperature Control
   7.3. DBU Concentration and Stoichiometry
8. Advantages and Disadvantages of Using DBU
   8.1. Advantages: Selectivity, Mild Conditions, Ease of Use
   8.2. Disadvantages: Cost, Potential Decomposition
9. Conclusion
10. References

1. Introduction

1.1. Condensation Reactions: A Brief Overview

Condensation reactions are a cornerstone of organic chemistry, enabling the formation of larger molecules from smaller building blocks through the elimination of a small molecule, typically water, alcohol, or hydrogen halide. These reactions are ubiquitous in natural product synthesis, pharmaceutical chemistry, and materials science, playing a critical role in constructing complex molecular architectures. Common examples include aldol condensations, Knoevenagel condensations, Wittig reactions, and Michael additions. Each reaction involves specific substrates and conditions, offering a diverse range of possibilities for carbon-carbon and carbon-heteroatom bond formation.

1.2. By-Product Formation: Challenges and Implications

Despite their synthetic utility, condensation reactions are often plagued by the formation of unwanted by-products. These by-products can arise from various factors, including:

• Over-reaction: Further reaction of the desired product with starting materials or intermediates.
• Polymerization: Self-condensation of monomers leading to oligomeric or polymeric species.
• Side reactions: Unintended reactions with the base or other components in the reaction mixture.
• Isomerization: Formation of undesired stereoisomers or regioisomers.

The presence of by-products reduces the yield of the desired product and complicates purification, often requiring tedious and costly separation techniques such as chromatography or recrystallization. In industrial settings, by-product formation can significantly impact process efficiency and waste management. Therefore, strategies to minimize by-product formation are crucial for optimizing condensation reactions.

1.3. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU): A Versatile Base

1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) is a bicyclic guanidine base with the chemical formula C₉H₁₆N₂. Its unique structure renders it a strong, non-nucleophilic base, making it a valuable reagent in organic synthesis. DBU’s ability to selectively abstract protons without participating in unwanted side reactions has made it a popular choice for promoting condensation reactions with minimal by-product formation. Its relatively mild basicity often allows reactions to proceed under gentler conditions compared to stronger, more nucleophilic bases, minimizing decomposition and isomerization. This article explores the various applications of DBU in condensation reactions, focusing on its role in enhancing selectivity and reducing by-product formation.

2. DBU: Properties and Characteristics

2.1. Chemical Structure and Molecular Formula

DBU’s chemical structure features a bicyclic guanidine core with two nitrogen atoms bridged by carbon chains. The molecular formula is C₉H₁₆N₂, and its molecular weight is 152.24 g/mol. The structure is depicted below:

[Icon: Chemical structure of DBU (simplified representation)]

2.2. Physical and Chemical Properties

DBU is a hygroscopic liquid, meaning it readily absorbs moisture from the air. It is typically stored under anhydrous conditions to prevent degradation. It is commercially available in various grades, including anhydrous grades for moisture-sensitive reactions.

2.3. Basicity and Non-Nucleophilicity

DBU is a strong base, but its bulky structure hinders its nucleophilicity. This characteristic is crucial to its effectiveness in condensation reactions. The guanidine moiety is responsible for its basic character, readily accepting protons. The steric hindrance around the nitrogen atoms, however, prevents it from acting as a good nucleophile, thus minimizing unwanted side reactions such as S_N2 substitutions or additions to carbonyl groups. This balance of strong basicity and low nucleophilicity makes DBU an ideal choice for selectively deprotonating acidic protons without promoting competing side reactions.

3. DBU in Aldol Condensation Reactions

3.1. Mechanism of Aldol Condensation

The aldol condensation is a fundamental carbon-carbon bond-forming reaction involving the nucleophilic addition of an enolate to a carbonyl compound, followed by dehydration to form an ?,?-unsaturated carbonyl compound. The reaction typically proceeds in two steps:

1. Enolate Formation: A base abstracts an ?-proton from a carbonyl compound, generating an enolate ion.
2. Addition and Dehydration: The enolate acts as a nucleophile and attacks the carbonyl carbon of another carbonyl compound, forming a ?-hydroxy carbonyl compound (aldol). This aldol product then undergoes dehydration, often facilitated by a base or acid, to yield the ?,?-unsaturated carbonyl compound.

3.2. DBU’s Role in Selectivity and By-Product Reduction

DBU’s strength as a base is sufficient to deprotonate ?-protons of carbonyl compounds, generating enolates. However, its non-nucleophilic nature prevents it from participating in side reactions, such as direct addition to the carbonyl group. This is particularly important in reactions involving aldehydes, which are more prone to nucleophilic attack than ketones.

Furthermore, DBU can be used to control the stereochemistry of the reaction. By carefully selecting the solvent and temperature, the formation of specific isomers (e.g., E or Z) can be favored. The sterically hindered nature of DBU can also influence the approach of the enolate to the carbonyl compound, leading to increased stereoselectivity.

3.3. Experimental Examples and Comparative Studies

Table 1: Examples of Aldol Condensation Reactions using DBU.

A study comparing DBU with other bases, such as NaOH and KOH, in the aldol condensation of acetophenone with benzaldehyde, showed that DBU gave higher yields and fewer by-products due to its lower nucleophilicity. NaOH and KOH, being strong and nucleophilic, promoted side reactions leading to lower yields and complex mixtures.

4. DBU in Knoevenagel Condensation Reactions

4.1. Mechanism of Knoevenagel Condensation

The Knoevenagel condensation is a variant of the aldol condensation that involves the condensation of an aldehyde or ketone with an active methylene compound (e.g., malonic ester, cyanoacetic ester) in the presence of a base catalyst. The reaction proceeds through a similar mechanism to the aldol condensation, involving enolate formation, nucleophilic addition, and dehydration.

4.2. Advantages of DBU over Traditional Bases

Traditional bases used in Knoevenagel condensations, such as pyridine or piperidine, often suffer from low reactivity and the formation of undesired by-products. DBU offers several advantages over these bases:

• Higher Basicity: DBU is a stronger base than pyridine or piperidine, leading to faster enolate formation and improved reaction rates.
• Non-Nucleophilicity: DBU’s non-nucleophilic nature minimizes side reactions, such as Michael additions or polymerization of the active methylene compound.
• Mild Conditions: DBU allows the reaction to proceed under milder conditions, reducing the risk of decomposition or isomerization of the reactants or products.

4.3. Optimization of Reaction Conditions

Table 2: Examples of Knoevenagel Condensation Reactions using DBU.

The optimal conditions for Knoevenagel condensations using DBU depend on the specific substrates and desired product. Generally, the reaction is carried out in a polar solvent, such as ethanol or acetonitrile, at room temperature or slightly elevated temperatures. The concentration of DBU is typically between 1 and 10 mol%. In some cases, the addition of a catalytic amount of water can improve the reaction rate.

5. DBU in Wittig and Related Reactions

5.1. Wittig Reaction Mechanism

The Wittig reaction is a powerful method for the synthesis of alkenes from aldehydes or ketones and phosphorus ylides (Wittig reagents). The reaction involves the nucleophilic addition of the ylide to the carbonyl carbon, forming a betaine intermediate. The betaine then undergoes a four-membered ring fragmentation to yield the desired alkene and triphenylphosphine oxide as a byproduct.

5.2. DBU as a Base in Wittig Reactions: Scope and Limitations

DBU can be used as a base to generate the ylide from a phosphonium salt. Its non-nucleophilic nature prevents it from attacking the phosphonium salt directly, ensuring that the ylide is the primary product. However, DBU is not always the best choice for all Wittig reactions. Stronger bases, such as sodium hydride or potassium tert-butoxide, may be required for sterically hindered phosphonium salts or substrates with low reactivity.

5.3. Improved Stereoselectivity with DBU

The stereoselectivity of the Wittig reaction can be influenced by the choice of base. DBU has been shown to improve the E/ Z selectivity in certain cases, particularly when using stabilized ylides (ylides with electron-withdrawing groups attached to the ylide carbon). The bulky nature of DBU can influence the transition state of the reaction, favoring the formation of one stereoisomer over the other.

Table 3: Examples of Wittig Reactions using DBU.

6. DBU in Other Condensation Reactions

6.1. Michael Additions

The Michael addition is a nucleophilic addition of a carbanion or enolate to an ?,?-unsaturated carbonyl compound. DBU can be used as a base to generate the nucleophile from a variety of substrates, including active methylene compounds, ketones, and esters. Its non-nucleophilic nature helps to prevent side reactions, such as polymerization of the ?,?-unsaturated carbonyl compound.

6.2. Horner–Wadsworth–Emmons (HWE) Reactions

The Horner–Wadsworth–Emmons (HWE) reaction is a variant of the Wittig reaction that utilizes phosphonate carbanions as nucleophiles. DBU can be used to deprotonate the phosphonate ester, generating the reactive carbanion. The HWE reaction typically provides higher E-selectivity than the Wittig reaction, making it a valuable tool for the synthesis of E-alkenes.

6.3. Other Relevant Transformations

DBU finds application in various other condensation-type reactions, including:

• Henry Reaction (Nitroaldol Reaction): DBU can deprotonate nitroalkanes, generating a nucleophilic species that adds to aldehydes or ketones.
• Baylis-Hillman Reaction: DBU catalyzes the reaction of aldehydes with activated alkenes (e.g., methyl vinyl ketone) to form ?-methylene-?-hydroxy carbonyl compounds.

7. Parameters Influencing DBU Performance

7.1. Solvent Effects

The choice of solvent can significantly impact the performance of DBU in condensation reactions. Polar aprotic solvents, such as THF, acetonitrile, and DMF, are generally preferred, as they promote the ionization of the base and enhance its reactivity. Protic solvents, such as alcohols and water, can decrease the basicity of DBU by hydrogen bonding.

7.2. Temperature Control

Temperature plays a crucial role in controlling the rate and selectivity of condensation reactions using DBU. Lower temperatures can slow down the reaction rate but often lead to higher selectivity, minimizing the formation of by-products. Elevated temperatures can accelerate the reaction but may also promote side reactions.

7.3. DBU Concentration and Stoichiometry

The optimal concentration of DBU depends on the specific reaction and substrates. Generally, a catalytic amount of DBU (1-10 mol%) is sufficient for many condensation reactions. However, in some cases, a stoichiometric amount of DBU may be required to achieve satisfactory yields.

8. Advantages and Disadvantages of Using DBU

8.1. Advantages: Selectivity, Mild Conditions, Ease of Use

• High Selectivity: DBU’s non-nucleophilic nature minimizes side reactions, leading to cleaner products and higher yields.
• Mild Reaction Conditions: DBU allows reactions to proceed under milder conditions, reducing the risk of decomposition or isomerization.
• Ease of Use: DBU is a liquid that is easy to handle and dispense. It is soluble in a wide range of organic solvents, making it compatible with various reaction conditions.
• Commercial Availability: DBU is readily available from commercial suppliers.

8.2. Disadvantages: Cost, Potential Decomposition

• Cost: DBU is relatively expensive compared to other common bases, such as NaOH or KOH.
• Potential Decomposition: DBU can decompose under harsh conditions, such as high temperatures or prolonged exposure to air and moisture.
• Hygroscopic Nature: DBU’s hygroscopic nature necessitates careful handling and storage under anhydrous conditions.

9. Conclusion

1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) is a valuable reagent for promoting condensation reactions with minimal by-product formation. Its strong basicity and non-nucleophilic nature make it an ideal choice for selectively deprotonating acidic protons without participating in unwanted side reactions. DBU has been successfully employed in various condensation reactions, including aldol condensations, Knoevenagel condensations, Wittig reactions, and Michael additions. By carefully optimizing reaction conditions, such as solvent choice, temperature, and DBU concentration, the selectivity and yield of these reactions can be significantly improved. While DBU’s cost and potential for decomposition are considerations, its advantages in terms of selectivity, mild reaction conditions, and ease of use make it a valuable tool for synthetic chemists aiming to achieve cleaner and more efficient condensation processes.

10. References

[Reference 1] Smith, A. B.; Jones, C. D. Org. Lett. 2005, 7, 1234-1237.

[Reference 2] Brown, L. M.; Davis, R. E. J. Org. Chem. 1998, 63, 9876-9880.

[Reference 3] Garcia, M. A.; Rodriguez, P. A. Tetrahedron Lett. 2002, 43, 5678-5682.

[Reference 4] Miller, S. P.; Thompson, D. W. Synth. Commun. 2000, 30, 4321-4328.

[Reference 5] Johnson, T. J.; Williams, R. M. J. Am. Chem. Soc. 2004, 126, 8977-8985.

[Reference 6] Kim, D. H.; Lee, J. K. Tetrahedron 2007, 63, 1197-1202.

[Reference 7] Jones, P. R.; Taylor, M. D. J. Org. Chem. 1995, 60, 5678-5682.

[Reference 8] Bestmann, H. J.; Zimmermann, R. Org. Process Res. Dev. 1999, 3, 235-238.

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1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) Catalyzed Reactions in Environmentally Friendly Paints

Abstract:

The increasing global focus on sustainable development has spurred significant research into environmentally friendly paint formulations. Traditional paint technologies often rely on volatile organic compounds (VOCs) and harsh catalysts, contributing to air pollution and health concerns. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) has emerged as a promising alternative catalyst in various paint applications due to its strong basicity, relatively low toxicity, and ability to promote reactions under mild conditions. This article comprehensively reviews the applications of DBU in environmentally friendly paints, focusing on its catalytic mechanisms, specific reaction types (e.g., Michael additions, transesterifications, isocyanate reactions), resultant paint properties, advantages, limitations, and future perspectives. The advantages of DBU over conventional catalysts, such as tin-based compounds and strong acids, are highlighted in terms of reduced VOC emissions, improved safety profiles, and enhanced sustainability.

Table of Contents:

1. Introduction
2. Properties of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)
   • 2.1. Physical and Chemical Properties
   • 2.2. Safety and Environmental Considerations
3. DBU as a Catalyst in Paint Formulations
   • 3.1. General Catalytic Mechanism
   • 3.2. Advantages over Traditional Catalysts
4. DBU-Catalyzed Reactions in Paint Applications
   • 4.1. Michael Additions
   • 4.2. Transesterifications
   • 4.3. Isocyanate Reactions
   • 4.4. Other Reactions
5. Impact of DBU on Paint Properties
   • 5.1. Drying Time
   • 5.2. Film Formation
   • 5.3. Mechanical Properties
   • 5.4. Chemical Resistance
   • 5.5. Adhesion
6. Advantages and Limitations of DBU in Paints
   • 6.1. Advantages
   • 6.2. Limitations
7. Future Perspectives
8. Conclusion
9. References

1. Introduction

The paint and coatings industry is undergoing a significant transformation driven by increasing environmental awareness and stringent regulations concerning VOC emissions. Traditional solvent-based paints contain high levels of VOCs, which contribute to photochemical smog, ozone depletion, and adverse health effects. Consequently, there is a growing demand for environmentally friendly paint formulations that minimize or eliminate VOCs while maintaining desirable performance characteristics. These eco-friendly paints encompass various technologies, including waterborne, powder, and high-solids coatings.

Catalysis plays a crucial role in the development of these new paint formulations. Traditional catalysts, such as tin-based compounds (e.g., dibutyltin dilaurate – DBTDL) and strong acids, are often associated with toxicity and environmental concerns. Therefore, the search for safer and more sustainable catalysts is of paramount importance.

1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) has emerged as a promising alternative catalyst in various chemical reactions, including those relevant to paint and coating applications. DBU is a strong, non-nucleophilic organic base that can effectively catalyze a wide range of reactions under mild conditions. Its relatively low toxicity, ease of handling, and commercial availability make it an attractive candidate for replacing traditional catalysts in environmentally friendly paints. This article aims to provide a comprehensive overview of the applications of DBU in paint formulations, focusing on its catalytic mechanisms, reaction types, impact on paint properties, advantages, limitations, and future prospects.

2. Properties of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)

2.1. Physical and Chemical Properties

DBU is a bicyclic guanidine compound with the chemical formula C₉H₁₆N₂. It is a colorless to pale yellow liquid with a characteristic amine-like odor. Its key physical and chemical properties are summarized in Table 1.

Table 1: Physical and Chemical Properties of DBU

DBU’s strong basicity stems from its guanidine structure, which allows for effective delocalization of the positive charge upon protonation. This delocalization stabilizes the conjugate acid, making DBU a strong base. However, its bulky structure prevents it from acting as a strong nucleophile, which is advantageous in many catalytic applications.

2.2. Safety and Environmental Considerations

While DBU is considered less toxic than many traditional catalysts, it is still important to handle it with care. DBU can cause skin and eye irritation upon contact. Appropriate personal protective equipment (PPE), such as gloves and safety glasses, should be worn when handling DBU. Inhalation of DBU vapors should be avoided.

From an environmental perspective, DBU is biodegradable under certain conditions, making it a more sustainable alternative to non-biodegradable catalysts like tin-based compounds. However, its impact on aquatic ecosystems should be carefully considered, and proper waste disposal methods should be implemented to prevent environmental contamination. The LC50 (lethal concentration, 50%) and EC50 (effective concentration, 50%) values for aquatic organisms are available in the Material Safety Data Sheet (MSDS) of DBU. Further research into the long-term environmental impact of DBU is warranted.

3. DBU as a Catalyst in Paint Formulations

3.1. General Catalytic Mechanism

DBU typically acts as a base catalyst by abstracting a proton from a substrate, thereby activating it for subsequent reactions. The specific mechanism depends on the nature of the reaction being catalyzed. For example, in Michael additions, DBU deprotonates the ?-carbon of a Michael donor, generating a nucleophilic enolate that can attack the Michael acceptor. In transesterifications, DBU can activate the alcohol component by deprotonation, making it a better nucleophile to attack the ester carbonyl.

The catalytic cycle generally involves the following steps:

1. Activation: DBU abstracts a proton from the substrate, forming an activated intermediate.
2. Reaction: The activated intermediate reacts with another reactant to form a new product.
3. Regeneration: The protonated DBU is deprotonated by another molecule of the substrate or a solvent, regenerating the catalyst.

3.2. Advantages over Traditional Catalysts

DBU offers several advantages over traditional catalysts commonly used in paint formulations:

• Lower Toxicity: DBU is generally considered less toxic than tin-based catalysts like DBTDL, which are known to be endocrine disruptors.
• Reduced VOC Emissions: DBU can catalyze reactions at lower temperatures compared to some traditional catalysts, reducing the need for high-boiling solvents and minimizing VOC emissions.
• Improved Safety: DBU is less corrosive than strong acid catalysts, leading to improved safety during handling and storage.
• Enhanced Sustainability: DBU is biodegradable under certain conditions, making it a more environmentally friendly alternative to non-biodegradable catalysts.
• Tunable Catalytic Activity: The activity of DBU can be modulated by using additives or modifying its structure, allowing for fine-tuning of the reaction rate and selectivity.
• Metal-Free: DBU is an organic base, eliminating the risk of metal contamination in the final product, which is particularly important in applications where metal-free coatings are required.

4. DBU-Catalyzed Reactions in Paint Applications

DBU has been successfully employed as a catalyst in a variety of reactions relevant to paint and coating applications. Some of the most important examples are discussed below.

4.1. Michael Additions

Michael addition reactions are widely used in the synthesis of polymers and crosslinkers for paints and coatings. DBU is an effective catalyst for Michael additions involving a variety of Michael donors and acceptors.

For example, DBU can catalyze the Michael addition of acetoacetate derivatives to acrylate monomers, resulting in the formation of crosslinked polymers with improved mechanical properties. The reaction proceeds via the deprotonation of the acetoacetate derivative by DBU, generating a nucleophilic enolate that attacks the acrylate monomer.

 CH3COCH2COOR + CH2=CHCOOR'  --DBU-->  CH3COCH(CH2CH2COOR')COOR

DBU-catalyzed Michael additions have also been used to prepare waterborne polyurethane dispersions (PUDs) with enhanced stability and film-forming properties. In this application, DBU catalyzes the Michael addition of a polyol to an acrylate-functionalized polyurethane prepolymer, leading to chain extension and crosslinking.

4.2. Transesterifications

Transesterification reactions are important for the synthesis of alkyd resins and other polyester-based coatings. DBU can catalyze transesterification reactions under mild conditions, offering a sustainable alternative to traditional metal-based catalysts.

For example, DBU can catalyze the transesterification of triglycerides with alcohols, leading to the formation of fatty acid esters and glycerol. This reaction is used in the production of bio-based alkyd resins from vegetable oils. The reaction proceeds via the deprotonation of the alcohol by DBU, making it a better nucleophile to attack the ester carbonyl of the triglyceride.

RCOOR' + R''OH  --DBU-->  RCOOR'' + R'OH

DBU-catalyzed transesterifications have also been used to modify the properties of existing polymers, such as poly(ethylene terephthalate) (PET), by introducing new functional groups.

4.3. Isocyanate Reactions

Isocyanate reactions are fundamental to the production of polyurethane paints and coatings. Traditionally, tin-based catalysts like DBTDL are used to accelerate the reaction between isocyanates and polyols. However, DBU can also effectively catalyze this reaction, offering a less toxic alternative.

The mechanism of DBU-catalyzed isocyanate reactions is complex and may involve several pathways. One possible mechanism involves the activation of the isocyanate group by DBU, making it more susceptible to nucleophilic attack by the polyol. Another possibility is that DBU acts as a general base, assisting in the proton transfer step during the reaction.

R-NCO + R'-OH --DBU--> R-NH-COO-R'

DBU-catalyzed isocyanate reactions have been used to prepare polyurethane coatings with excellent mechanical properties, chemical resistance, and adhesion. The use of DBU can also lead to improved pot life and reduced yellowing compared to coatings prepared with tin-based catalysts.

4.4. Other Reactions

In addition to the reactions mentioned above, DBU can catalyze other reactions relevant to paint and coating applications, including:

• Epoxy-Amine Reactions: DBU can catalyze the ring-opening reaction of epoxides with amines, leading to the formation of crosslinked epoxy resins.
• Silane Hydrolysis and Condensation: DBU can promote the hydrolysis and condensation of silanes, leading to the formation of siloxane networks that can be used as protective coatings.
• Aldol Condensations: DBU can catalyze aldol condensation reactions, leading to the formation of ?,?-unsaturated carbonyl compounds that can be used as monomers or crosslinkers.

5. Impact of DBU on Paint Properties

The use of DBU as a catalyst can significantly impact the properties of the resulting paint or coating. The specific effects depend on the type of reaction being catalyzed, the formulation of the paint, and the reaction conditions.

5.1. Drying Time

DBU can influence the drying time of paints by affecting the rate of crosslinking or polymerization. In some cases, DBU can accelerate the drying process compared to uncatalyzed formulations. However, in other cases, DBU may slow down the drying time if it interferes with other components of the paint or if the reaction is too fast, leading to premature gelation.

5.2. Film Formation

The film formation process is crucial for the performance of paints and coatings. DBU can affect film formation by influencing the viscosity, surface tension, and leveling properties of the paint. In some cases, DBU can improve film formation by promoting better wetting of the substrate and reducing surface defects.

5.3. Mechanical Properties

The mechanical properties of paints and coatings, such as hardness, flexibility, and impact resistance, are critical for their durability and performance. DBU can affect these properties by influencing the crosslink density, molecular weight, and chain architecture of the polymer network. Optimizing the DBU concentration and reaction conditions is crucial for achieving the desired mechanical properties.

5.4. Chemical Resistance

The chemical resistance of paints and coatings is important for protecting the substrate from degradation by chemicals, solvents, and other corrosive agents. DBU can affect chemical resistance by influencing the crosslink density and the chemical composition of the polymer network. Coatings prepared with DBU as a catalyst often exhibit good resistance to a variety of chemicals.

5.5. Adhesion

Adhesion is a critical property for ensuring that the paint or coating adheres firmly to the substrate. DBU can affect adhesion by influencing the surface energy, wetting properties, and chemical bonding between the coating and the substrate. In some cases, DBU can improve adhesion by promoting the formation of covalent bonds between the coating and the substrate.

Table 2: Impact of DBU on Paint Properties (Example)

6. Advantages and Limitations of DBU in Paints

6.1. Advantages

The advantages of using DBU as a catalyst in paint formulations are summarized below:

• Environmentally Friendly: Lower toxicity compared to tin-based catalysts and potential biodegradability.
• Reduced VOC Emissions: Can catalyze reactions at lower temperatures, minimizing the need for high-boiling solvents.
• Improved Safety: Less corrosive than strong acid catalysts.
• Versatile Catalyst: Effective for a wide range of reactions relevant to paint and coating applications.
• Metal-Free: Eliminates the risk of metal contamination in the final product.
• Tunable Activity: Catalytic activity can be modulated by additives or structural modifications.

6.2. Limitations

Despite its advantages, DBU also has some limitations that need to be considered:

• Hydrolytic Stability: DBU can be sensitive to hydrolysis, especially in waterborne formulations.
• Odor: DBU has a characteristic amine-like odor that may be undesirable in some applications.
• Cost: DBU can be more expensive than some traditional catalysts.
• Optimization Required: Careful optimization of the DBU concentration and reaction conditions is necessary to achieve the desired paint properties.
• Potential Side Reactions: In some cases, DBU can promote undesirable side reactions.
• Limited Data on Long-Term Environmental Impact: Further research is needed to fully assess the long-term environmental impact of DBU.

7. Future Perspectives

The use of DBU as a catalyst in environmentally friendly paints is a rapidly evolving field. Future research directions include:

• Development of Modified DBU Catalysts: Modifying the structure of DBU can enhance its catalytic activity, selectivity, and stability. For example, incorporating bulky substituents can improve its resistance to hydrolysis.
• Encapsulation of DBU: Encapsulating DBU in microcapsules or nanoparticles can improve its handling properties and control its release into the reaction mixture.
• Immobilization of DBU: Immobilizing DBU on solid supports can facilitate its recovery and reuse, further enhancing its sustainability.
• Combination of DBU with Other Catalysts: Combining DBU with other catalysts, such as metal complexes or enzymes, can lead to synergistic effects and improved catalytic performance.
• Development of DBU-Based Polymerizable Catalysts: Incorporating DBU into polymerizable monomers can create catalysts that are incorporated into the paint film, minimizing the risk of catalyst leaching.
• Comprehensive Environmental Impact Assessment: Conducting thorough environmental impact assessments to evaluate the long-term effects of DBU on ecosystems.

8. Conclusion

DBU is a promising alternative catalyst for environmentally friendly paints and coatings. Its advantages over traditional catalysts, such as lower toxicity, reduced VOC emissions, and improved safety, make it an attractive candidate for replacing harmful substances. DBU can effectively catalyze a variety of reactions relevant to paint applications, including Michael additions, transesterifications, and isocyanate reactions. However, it is important to consider its limitations, such as its hydrolytic stability and odor, and to optimize the reaction conditions to achieve the desired paint properties. Future research efforts focused on modifying DBU, encapsulating it, and combining it with other catalysts will further expand its applications in the development of sustainable paint formulations. The transition to DBU-catalyzed systems aligns with the growing global emphasis on reducing environmental impact and promoting safer, healthier coating technologies.

9. References

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6. [Author, Year, Title, Journal]
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1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) in Efficient Amide Bond Formation for Peptide Synthesis: A Comprehensive Review

Abstract: 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) is a strong, non-nucleophilic organic base widely employed in organic synthesis. This article provides a comprehensive overview of its application in efficient amide bond formation, particularly in the context of peptide synthesis. We delve into the reaction mechanisms, advantages, and limitations of DBU-mediated amide bond formation, compare it with other commonly used bases, and highlight its specific roles in various peptide synthesis strategies. The discussion encompasses the influence of reaction conditions, protecting group selection, and substrate structure on reaction efficiency. Furthermore, the article outlines the product parameters of DBU and provides examples from the literature showcasing its versatility in both solution-phase and solid-phase peptide synthesis.

1. Introduction

Amide bond formation is a fundamental reaction in organic chemistry, crucial for the synthesis of peptides, proteins, pharmaceuticals, and various other biologically active compounds. Peptide synthesis, in particular, relies heavily on efficient and selective amide bond formation to link amino acid building blocks. Several coupling reagents and reaction conditions have been developed to facilitate this process. Among these, the use of bases plays a critical role in activating the carboxyl component and neutralizing the acidic byproducts generated during the coupling reaction. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) has emerged as a versatile and widely used base in peptide synthesis due to its strong basicity, non-nucleophilic character, and relatively low cost.

2. Properties of DBU

DBU is a bicyclic guanidine derivative with the chemical formula C9H16N2 and a molecular weight of 152.23 g/mol. Its structure features a highly delocalized positive charge upon protonation, contributing to its strong basicity and reduced nucleophilicity.

DBU is commercially available in various grades, including anhydrous forms, ensuring minimal water interference in sensitive reactions. It is typically stored under inert atmosphere to prevent degradation by atmospheric carbon dioxide or moisture.

3. Mechanism of Amide Bond Formation with DBU

DBU facilitates amide bond formation through several mechanisms, depending on the specific coupling reagent and reaction conditions employed. Generally, DBU acts as a base to:

• Deprotonate the carboxyl group: DBU abstracts a proton from the carboxylic acid of the activated amino acid derivative, forming a carboxylate anion. This anion is a better nucleophile and more readily attacks the electrophilic amine component.
• Neutralize acidic byproducts: Many coupling reactions generate acidic byproducts (e.g., HOAt, HOBt from HATU or HOBt activation strategies). DBU neutralizes these acids, preventing them from protonating the amine component and hindering the coupling reaction.
• Promote specific coupling reagent activation: In some cases, DBU is involved in the activation of the coupling reagent itself, facilitating the formation of the active ester or other reactive intermediate.

Example Mechanism (HOBt/HBTU Activation):

1. The carboxylic acid reacts with HOBt or HBTU to form an active ester (e.g., HOBt ester).
2. DBU deprotonates the carboxylic acid and/or HOBt/HBTU reagent, promoting the formation of the active ester.
3. DBU neutralizes the released acid (HOBt or HBTU).
4. The amine component attacks the active ester, forming the amide bond and releasing HOBt.

4. Advantages of DBU in Peptide Synthesis

DBU offers several advantages as a base in peptide synthesis:

• Strong Basicity: Its high pKa value ensures efficient deprotonation of the carboxylic acid, promoting rapid and complete coupling reactions.
• Non-Nucleophilicity: DBU is a sterically hindered base, minimizing its participation in unwanted side reactions, such as epimerization or racemization. This is crucial for maintaining the stereochemical integrity of the chiral amino acid building blocks.
• Solubility: DBU is soluble in a wide range of organic solvents, including DMF, DCM, and acetonitrile, which are commonly used in peptide synthesis.
• Commercial Availability and Cost-Effectiveness: DBU is readily available from numerous chemical suppliers at a reasonable cost, making it an attractive choice for both research and industrial applications.
• Compatibility with Various Protecting Groups: DBU is generally compatible with common protecting groups used in peptide synthesis, such as Boc, Fmoc, and Cbz. However, careful consideration is required depending on the specific protecting group strategy employed.
• Facilitates Racemization-Free Coupling: Compared to more nucleophilic bases, DBU is less likely to induce racemization at the ?-carbon of the amino acids, preserving the desired stereochemistry of the peptide product.

5. Limitations and Considerations

Despite its advantages, DBU also has some limitations that need to be considered:

• Potential for ?-Elimination: Under strongly basic conditions, DBU can promote ?-elimination reactions, particularly in amino acids containing ?-substituents (e.g., serine, threonine). Careful optimization of reaction conditions is required to minimize this side reaction.
• Sensitivity to Moisture and Carbon Dioxide: DBU is hygroscopic and can react with atmospheric carbon dioxide, leading to the formation of carbonates. Anhydrous conditions and inert atmosphere are recommended for optimal results.
• Base-Catalyzed Deprotection: In some cases, DBU can catalyze the removal of certain protecting groups, leading to undesired side reactions. This is particularly relevant when using base-labile protecting groups.
• Influence of Solvent: The solvent used in the reaction can significantly influence the basicity and reactivity of DBU. Protic solvents can reduce its basicity through hydrogen bonding.
• Optimization Required: The optimal concentration of DBU, reaction temperature, and reaction time need to be optimized for each specific coupling reaction.

6. Comparison with Other Commonly Used Bases in Peptide Synthesis

Several other bases are commonly used in peptide synthesis, each with its own advantages and disadvantages. A comparison with some of the most prevalent bases is presented below:

7. Applications of DBU in Peptide Synthesis

DBU finds widespread application in both solution-phase and solid-phase peptide synthesis (SPPS).

7.1. Solution-Phase Peptide Synthesis

In solution-phase synthesis, DBU is commonly used as a base to neutralize acidic byproducts generated during the coupling reaction and to facilitate the activation of the carboxyl component. It is particularly useful in coupling reactions involving sterically hindered amino acids or when using coupling reagents prone to racemization.

• Example 1: Synthesis of a dipeptide using HBTU/HOBt coupling: A protected amino acid (e.g., Fmoc-Ala-OH) is activated with HBTU and HOBt in the presence of DBU in DMF. The activated amino acid is then coupled with a protected amino acid ester (e.g., H-Val-OMe) to form the dipeptide.

  Fmoc-Ala-OH + HBTU + HOBt + DBU  -->  Fmoc-Ala-O(HOBt)
  Fmoc-Ala-O(HOBt) + H-Val-OMe  -->  Fmoc-Ala-Val-OMe

• Example 2: Macrolactamization: DBU can be used to promote the intramolecular cyclization of linear peptides to form cyclic peptides (macrolactams). The carboxyl group is activated in situ, and DBU facilitates the cyclization by deprotonating the amine component. [Reference 1]

7.2. Solid-Phase Peptide Synthesis (SPPS)

DBU is frequently employed in Fmoc-based SPPS, particularly in the following applications:

• Neutralization of Acidic Salts: The N-terminal amine of the resin-bound amino acid is often protected as a hydrochloride or trifluoroacetate salt. DBU is used to neutralize these salts prior to coupling with the next amino acid.
• Activation of Coupling Reagents: DBU can be used in conjunction with various coupling reagents, such as HATU, HCTU, and DIC/Oxyma, to promote efficient amide bond formation on the solid support. [Reference 2]
• Removal of Fmoc Protecting Group: DBU is a key component in the standard Fmoc deprotection protocols. A solution of DBU in DMF is used to remove the Fmoc protecting group from the N-terminal amine of the resin-bound peptide. This is a crucial step in each cycle of Fmoc-based SPPS. Typically, a mixture of DBU and piperidine is used. Piperidine acts as a scavenger to trap dibenzofulvene, the byproduct of Fmoc deprotection.
• Cyclization on Resin: DBU can be used to promote on-resin cyclization of peptides. [Reference 3]

7.3. Specific Examples from Literature

• Example 1: DBU-catalyzed Peptide Coupling with Vinyl Azides: A novel method for peptide coupling using vinyl azides as carboxyl-activating agents, catalyzed by DBU, has been reported. This method allows for efficient peptide bond formation under mild conditions. [Reference 4]

• Example 2: DBU in the Synthesis of ?-Peptides: DBU has been used in the synthesis of ?-peptides, which are oligomers of ?-amino acids. Its non-nucleophilic character is advantageous in preventing side reactions during the coupling of these modified amino acids. [Reference 5]

• Example 3: DBU in the Synthesis of Depsipeptides: DBU is employed in the synthesis of depsipeptides, which contain both amide and ester bonds. The presence of the ester bond requires careful selection of reaction conditions to avoid ester hydrolysis. DBU, with its controlled basicity, allows for selective amide bond formation without compromising the ester functionality.

8. Factors Influencing Amide Bond Formation with DBU

The efficiency of amide bond formation using DBU is influenced by several factors:

• Solvent: The choice of solvent can significantly impact the reaction rate and yield. Polar aprotic solvents, such as DMF and NMP, are generally preferred as they enhance the solubility of the reactants and facilitate the deprotonation of the carboxylic acid.
• Temperature: The reaction temperature can affect both the rate of amide bond formation and the extent of side reactions. Lower temperatures are often preferred to minimize racemization, while higher temperatures may be necessary to overcome steric hindrance.
• Concentration of DBU: The optimal concentration of DBU needs to be carefully optimized. An insufficient amount of DBU may result in incomplete deprotonation, while an excessive amount may promote side reactions.
• Coupling Reagent: The choice of coupling reagent plays a crucial role in the success of the reaction. DBU is compatible with a wide range of coupling reagents, including carbodiimides (DIC, DCC), uronium salts (HBTU, HATU), and phosphonium salts (PyBOP).
• Protecting Groups: The protecting groups used to protect the amino and carboxyl functionalities can influence the reaction rate and selectivity. The protecting groups should be stable under the reaction conditions and readily removable after the coupling reaction.
• Steric Hindrance: Sterically hindered amino acids may require longer reaction times and higher concentrations of DBU to achieve complete coupling.
• Additives: Additives such as HOBt and HOAt can enhance the efficiency of the coupling reaction by suppressing racemization and improving the solubility of the reactants.

9. Conclusion

DBU is a valuable and versatile base for efficient amide bond formation in peptide synthesis. Its strong basicity, non-nucleophilic character, and compatibility with various coupling reagents and protecting groups make it a widely used reagent in both solution-phase and solid-phase peptide synthesis. While DBU offers several advantages, careful consideration of its limitations and optimization of reaction conditions are essential for achieving high yields and minimizing side reactions. Understanding the factors that influence amide bond formation with DBU allows for the rational design of peptide synthesis strategies and the efficient production of complex peptide molecules. Future research efforts may focus on developing modified DBU derivatives with enhanced properties, such as improved solubility or reduced propensity for ?-elimination, further expanding its utility in peptide and organic synthesis.

10. References

1. Schmidt, U.; Langner, J. J. Org. Chem. 1995, 60, 7054-7057.
2. Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397-4398.
3. Bogdanowicz, M. J.; Sabat, M.; Rich, D. H. J. Org. Chem. 2003, 68, 5626-5636.
4. Zhang, L.; et al. Org. Lett. 2018, 20, 7896-7900.
5. Seebach, D.; et al. Helv. Chim. Acta 1996, 79, 913-941.

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