Click Reactions in Organic Synthesis

Srinivasan Chandrasekaran

• Publisher: Wiley-VCH
• Year: 2016
• Print ISBN:
  9783527339167
• eBook ISBN:
  9783527694181
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Physical & Theoretical Chemistry

This book on click reactions to focus on organic synthesis, this reference work describes the click concept and underlying mechanisms as well as the main applications in various fields. As such, the chapters cover green chemical synthesis, metal-free click reactions, synthesis of pharmaceuticals, peptides, carbohydrates, DNA, macrocycles, dendrimers, polymers, and supramolecular architectures.
By filling a gap in the market, this is the ultimate reference for synthetic chemists in academia and industry aiming for a fast and simple design and synthesis of novel compounds with useful properties.

Chapter 1
Click Chemistry: Mechanistic and Synthetic Perspectives

Ramesh Ramapanicker and Poonam Chauhan

Search for reactions that can be used to link two or more diversely functionalized molecules with minimum effort and without the formation of side products has become increasingly important in the past 15 years. As organic molecules started to find their place as easily tunable and functional materials, the requirement of new conjugation reactions that can be used effectively by nonsynthetic organic chemists became unavoidable. Such a reaction should be easier to carry out, yield high selectivity, should be compatible with water and other protic solvents, and should lead to quantitative conversions. Click chemistry is a collection of such reactions that has evolved as an efficient tool for ligation, which gained quick acceptance in biotechnology, material and polymer science, medicinal chemistry, and so on. Among all the click reactions, copper-catalyzed 1,3-dipolar Huisgen cycloaddition (HDC) between a terminal alkyne and an azide is the jewel in the crown. Owing to its remarkable functional group tolerance, researchers can fearlessly introduce easily functionalizable groups such as hydroxyl, carboxyl, and amino groups into conjugate molecules using this reaction.

The concept of click chemistry was first introduced by Sharpless and coworkers in 2001 at the Scripps Research Institute [1]. Click chemistry is not limited to a set of organic reactions, but is a synthetic philosophy inspired by nature in terms of their efficiency, selectivity, and simplicity. Any reaction that can produce conjugate molecules efficiently from smaller units under simpler reaction conditions can be considered as a click reaction. The catchy term click refers to reactions that are modular in approach, efficient, selective, versatile in nature, give single product (high yielding), and can be performed in benign and easily removable solvents without the need for chromatographic purification. There are various reactions with different mechanisms that can be considered as click reactions, provided they follow a simple common reaction trajectory [1].

Sharpless first introduced the concept of click chemistry to provide an effective conjugation technique in drug discovery [2], but the concept and methodology were widely accepted, and click chemistry found its applications in almost all facets of research and technology, which employ organic molecules, such as polymer science [3], nanoscience [4], bioconjugation [5], and development of sensors [6] .

In this chapter, we have provided a detailed account of various click reactions with emphasis on their mechanisms and synthetic details. The discussions are based on the following classification of click reactions.

1.1 Cycloaddition Click Reactions

1.1.1 Azide–Alkyne Huisgen 1,3-Dipolar Cycloaddition

The classical HDC reaction between an alkyne and an azide is the most discussed among click reactions. Both alkynes and azides are unreactive under physiological conditions and undergo a cycloaddition reaction only at elevated temperatures (Scheme 1.1) [7, 8]. Although both alkynes and azide functions can easily be introduced on to the substrates, the cycloaddition reaction is highly exothermic (ΔH⁰ is between −50 and −65 kcal/mol) and has a high activation barrier of 25–26 kcal/mol (for methyl azide and propyne). Hence, the uncatalyzed reaction is generally slow and is not regioselective [9]. The difference between HOMO-LUMO energy levels of both azide and alkyne are comparable, thus both dipole HOMO and dipole LUMO pathways can operate in this reaction leading to a mixture of 1,4 and 1,5-triazole regioisomers. It is, however, observed that the use of electron-deficient terminal alkynes can impart 1,4-regioselectivity to a reasonable extent. These factors limit the use of uncatalyzed Huisgen cycloaddition as an effective conjugation technique.

Scheme 1.1 Huisgen 1,3-dipolar cycloaddition between alkynes and azides.

1.1.2 Copper-Catalyzed Azide–Alkyne Cycloaddition (CuAAC) Click Reaction

Sharpless [9] and Meldal [10] independently reported a Cu(I)-catalyzed version of the cycloaddition reaction between azides and terminal alkynes, which is 10⁷ times faster than the uncatalyzed reaction. The interaction between Cu(I) and terminal alkynes makes the latter a better 1,3-dipolarophile, enhancing its reaction with azides. The Cu(I)-catalyzed reaction is highly regioselective and only the 1,4-adducts are formed. The Cu(I)-catalyzed reactions can be carried out at room temperature and at a much faster rate.

Sharpless reported the possibility of using in situ generated copper(I), obtained through the reduction of copper sulfate pentahydrate (CuSO₄·5H₂O) with ascorbic acid, as an efficient catalyst for carrying out azide–alkyne conjugation reactions in solutions [9]. The reactions worked well when a mixture of water and an alcohol is used as the solvent. The solvent mixture allowed effective dissolution of the metal salt and the organic components needed to be conjugated. Meldal and coworkers reported a very practical application of azide–alkyne cycloaddition catalyzed with cuprous iodide in conjugating peptides through side chains or the backbone in solid phase [10]. Both reactions were selective for the formation of 1,4-disubstituted 1,2,3-triazoles and together revolutionized the concept of click reactions (Scheme 1.2).

Scheme 1.2 CuAAC click reaction.

In addition to being a stable linker, the triazole group has certain other advantages. On comparison with an amide bond, which was otherwise the most common linkage used, a triazole group exhibits certain interesting and unique properties. Unlike an amide bond, triazoles are not susceptible to hydrolytic cleavage. They cannot be reduced or oxidized under normal conditions. A triazole linkage, with an extra atom in its backbone, places the carbon atoms linked to 1- and 4-positions at a distance of 5.0 Å, while...

Table of contents

• Cover
• Title Page
• Copyright
• Table of Contents
• List of Contributors
• Preface
• Chapter 1: Click Chemistry: Mechanistic and Synthetic Perspectives
• Chapter 2: Applications of Click Chemistry in Drug Discovery and Development
• Chapter 3: Green Chemical Synthesis and Click Reactions
• Chapter 4: Synthesis of Substituted 1,2,3-Triazoles through Organocatalysis
• Chapter 5: Applications of the Cu-Catalyzed Azide–Alkyne Cycloaddition (CuAAC) in Peptides
• Chapter 6: Synthesis of Diverse Carbohydrate-Based Molecules using Click Chemistry
• Chapter 7: Azide–Alkyne Click Reaction in Polymer Science
• Chapter 8: Thiol-Based “Click” Chemistry for Macromolecular Architecture Design
• Chapter 9: Synthesis of Macrocycles and Click Chemistry
• Chapter 10: Modifications of Nucleosides, Nucleotides, and Nucleic Acids using Huisgen's [3+2] Azide–Alkyne Cycloaddition: Opening Pandora's Box
• Index
• End User License Agreement