In order for chemical reactions to gain traction in new processes for polymerizations, synthesis, and polymer modifications it is desirable that they be simple, efficient, highly selective, yield a single product, and occur under mild and preferably ambient conditions. Such ‘Click’ chemistries have an incredible potential to achieve significant utilization and advancement in all basic disciplines of science and engineering but particularly in materials and polymer science. Among the toolbox of ‘Click’ chemistries, the thiol‐X reaction family’s utility for synthesis, polymerizations and functionalization are currently a topic of immense interest. Since thiols react to high yields under benign conditions with a vast range of other chemical functional groups, their utility extends to a vast number of applications in the chemical, biological, physical, materials and engineering fields. While in general the thiol‐X reaction chemistries are not new, many have only recently been recognized and exploited for their exceptional qualities in the polymer/materials field. As such, the thiol‐click chemistry is rapidly becoming heavily utilized and has the potential for enabling numerous advancements in polymerizations, polymer synthesis, and polymer modification. In this book, a wide range of various thiol‐X chemistries is highlighted over a range of topics for which they have been successfully used. Research spanning reaction chemistries such as the ubiquitous thiol‐ene, thiol Michael addition, thiol‐isocyanate and thiol‐halogen reactions are all discussed along with applications of these materials in systems ranging from tissue engineering matrices to surface modification and their implementation in reactions involving monomers derived from naturally occurring substrates.

The book begins with Chapter 1 by Bowman and coworkers which begins the discussion of specific applications of thiol‐X chemistries in polymer and materials science, particularly the radical‐mediated thiol reactions involving both vinyl and alkyne functional groups. This chapter highlights the thiol‐ene and thiol‐yne chemistry, particularly the polymerization reaction, as it is used in ideal network synthesis. The chapter begins with a general discussion and applications of such network materials followed by a more detailed account of the mechanism and kinetics associated with the thiol‐ene reaction including its functional group tolerance. A similar section follows that is focused on the thiol‐yne chemistry. Subsequently, the material properties of thiol‐ene/yne network materials are discussed followed by sections on applications and issues associated with odor, shelf‐life, and oxidative and photostability.

Chapter 2 by Lowe et al. details the use of the suite of thiol‐X chemistries for the preparation of end‐functional (co)polymers prepared via reversible addition fragmentation chain transfer (RAFT) radical polymerization. The chapter begins with an introduction to the RAFT mechanism in radical polymerization (general features and mechanism) and includes methods for effecting removal of thiocarbonylthio groups from (co)polymers. This ability to reduce the typical RAFT end groups to thiols renders this mechanism of polymer formation ideal for coupling with thiol‐X reactions. The introduction is followed by a short discussion on the possible thiol‐based chemistries than can, and have, been employed with thiol‐terminated RAFT (co)polymers and some of the issues associated with conducting such reactions with macromolecular thiols effectively. The remainder of the chapter discusses recent examples of thiol‐X chemistry that have been employed to modify RAFT polymers with an emphasis on end‐group functionalization. This discussion includes highlights of thiol‐Michael, thiol‐yne, thiol‐isocyanate, thiol‐epoxide, thiol‐halogen as well as thiol‐thiol coupling reactions. The chapter concludes with a summary and outlook for these reactions.

Shipp reviews the use of thiol‐X chemistries in the synthesis of degradable polymers in Chapter 3. In particular, thiol‐ene and thiol‐Michael chemistries have been widely used because of their ability to be high yielding, orthogonal and functional group tolerant. They also exhibit the capacity to be conducted under physiological conditions, thus allowing them to be utilized in vivo. Furthermore, a wide range of thiol‐containing systems, such as cysteine residues in peptides, can be incorporated into the polymeric material, thereby providing functionality that may be specifically tailored, e.g. for targeted delivery, degradation, adhesion or cell growth. Degradation of such polymers may be achieved through a number of bond scission processes, including hydrolysis (e.g. of ester linkages) but may also be catalyzed by enzymes. Continued interest in the development of new materials for tissue engineering and the delivery of therapeutics is bound to further the involvement of thiol‐X chemistries, and should see them become mainstays in the production of biomedical devices in the near future.

Chapter 4 by Roth and Theato focuses on a specific functionalization method for (co)polymers employing simple thiol‐thiol coupling reactions resulting in disulfide linkages with an emphasis on the reaction of thiols with thiosulfonates yielding asymmetric disulfides. After the brief introduction, the chapter highlights the reactivity and synthesis of small molecule as well as polymeric functional thiosulfonates. This introduction is followed by a discussion on the modification of RAFT‐prepared (co)polymers that have been cleaved to the corresponding macromolecular thiols and is complementary to the discussion in Chapter 2 on the modification of such macromolecular thiols. Aside from the straightforward end‐group functionalization, the authors also highlight tandem end‐ and side‐group functional approaches employing a combination of thiosulfonate chemistry and nucleophilic acyl substitution of pentafluorophenyl (meth)acrylate (co)polymers as well the preparation of self‐assembled monolayers prepared with methyl methanethiosulfonate.

Jones and Haddleton highlight the use of the thiol‐Michael conjugate addition reaction in Chapter 5 as a method for the functionalization of polymers and as a route to polymer‐biomolecule conjugates. Beginning with conjugation reactions involving cysteine, the chapter moves on to highlight the use of maleimide substrates with an emphasis on (co)polymers bearing such Michael acceptors as chain end functionality available for post‐polymerization conjugation. This discussion is followed by a section highlighting alternative efficient Michael acceptors employed as bioconjugation handles on (co)polymers including the vinyl sulfone functional group and the ability to form disulphide bridges. Protein/peptide modification employing both radical and base‐mediated thiol‐ene reactions is then highlighted. The application of novel mono‐ and di‐bromomaleimides, in the small molecule as well as polymeric forms (as end‐groups), for the conjugation of cysteine species is then noted. The chapter concludes with two short sections on the application of thiol‐ene chemistry in siRNA and aptamer conjugation as well as antibody drug conjugates.

Chapters 6 and 7 by Son and coworkers and Perrier and coworkers, respectively, focus on the application of thiol‐ene and thiol‐yne chemistries for the synthesis of non‐linear (macro)molecules. Chapter 6 gives a broader overview on the use of thiol‐X chemistries for the synthesis of branched/star and dendritic species beginning with examples employing the thiol‐Michael reaction for coupling followed by approaches utilizing the radical thiol‐ene, radical thiol‐yne and even sequential thiol‐ene/yne reactions. In contrast, Chapter 7 is more specific and focuses exclusively on the application of the radical thiol‐yne reaction as a means of preparing dendritic (co)polymers.

Anseth and coworkers highlight the application of thiol‐X chemistries in tissue engineering applications in Chapter 8. Important features associated with cytocompatible monomer design are discussed as well as subsequent encapsulation in hydrogel formulations. The authors subsequently review the major thiol‐X chemistries that have been employed to prepare hydrogel cell scaffold systems, providing generalized methods for the synthesis of cell‐laden hydrogels via thiol‐X reactions. Distinct advantages and disadvantages of each of the approaches are discussed.

In Chapter 9, Du Prez and coworkers highlight thiolactone chemistry as a tool to fabricate tailor‐made polymer architectures using the thiol‐X approach. The use of thiolactone chemistry in polymer science has only been introduced very recently and in this chapter the potential virtues regarding versatility and synthetic scope are highlighted. Thiolactones are cyclic esters of mercapto‐acids. Their use provides a remarkable versatility of modular synthesis and modification by opening the thiolactones with a wide variety of functional amines to release thiol groups that can then react via any number of thiol‐click reactions. The structural features, synthesis and properties of homocysteine‐γ‐thiolactone and derivatives are highlighted. The use of thiolactones as functional handles along the backbone of a variety of linear polymers enables the use of a wide variety of amines for double, modular post‐polymerization modification consisting of aminolysis and thiol‐click reactions.

Chapter 10 by Boutevin and coworkers discusses a variety of different routes for utilizing thiol‐ene coupling reactions to synthesize oligomers or polymers with controlled functionality and molecular weight. This includes thiol‐ene radical coupling to synthesize both block and graft copolymer reactive precursors including both monofunctional and telechelic precursors. Monofunctional reactive precursors are achievable with either thiol or vinyl bearing compounds. The versatility of the thiol reactions enables utilization of a wide range of functional groups that may undergo additional condensation reactions. The functional groups also promote the ability to tailor for targeted precursor properties, such as hydrophilic, lipophobic, and adhesion. Telechelic precursors are achievable from the addition of a functional thiol to a vinyl group, addition of two functional thiols to non‐functional dienes, and the addition of non‐functional dithiols onto non‐functional dienes. Thiol‐ene radical coupling is also highlighted as a route to modify polymers containing vinyl groups on the backbone as a means to partially modify polymeric backbone properties. The synthesis of block copolymers and ionomers by thiol‐ene radical coupling is also discussed.

In Chapter 11, Stenzel presents different types of thiol‐X reactions and their use to create hybrids of synthetic polymers with nature’s natural building blocks such as sugars, peptides and proteins. Through the functionalization of soluble polymer chains, the aim is to combine the best properties of both to create new materials that enable the design of polymers that can take on the properties of synthetic polymers while also being bioactive. Glycopolymers are a class of commonly synthesized biomaterials and their direct polymerization is well established. Post‐polymerization modification of these polymers via thiol‐X reactions allows the production of libraries of glycopolymers with the same macromolecular architecture. Thiol‐X chemistry also generally provides a simpler and more benign synthesis procedure for these materials. Glycopolymers are common biomaterials and though their synthesis is well established, the use of thiol‐X reactions enables more facile synthesis routes and increased options for functionalization. Functionalization of glycopolymers with thiol‐X reactions has been achieved via several routes including thio‐halogen reactions, thio‐para fluoro reactions, and thiol‐ene and thiol‐yne reactions. Polymer‐peptide conjugates are another common biomaterial where enhanced bioactivity is envisaged through enhanced solubility that changes the mode of delivery as well as the aim to design new polymer hybrids. The synthesis of polymer‐peptide conjugates through the use of thio‐halogen reactions, thiol‐ene reactions, thiol‐vinylsulfone reactions, thiol‐maleimide reactions, and thiol‐pyridyl disulfide reactions is described and the various benefits of each are discussed. Utilizing similar conjugation chemistry to those employed for polymer‐peptide conjugates, thiol‐X reactions have also been used to synthesize polymer‐protein conjugates, polymer‐DNA conjugates, and polymer‐monoclonal antibodies conjugates.

In Chapter 12 Hensarling and Patton highlight the application of the suite of thiol‐X chemistries as a means of modifying surfaces. The authors highlight how these chemistries have been successfully employed to modify monolayers and ultrathin films, polymeric surfaces, microporous membranes, particle surfaces as well as biological surfaces. It is shown that these thiol‐based chemistries represent an extremely powerful set of tools for the efficient modification and patterning of the above surfaces and have established themselves as some of the preferred methods for achieving facile functionalization.

In Chapter 13, Liang et al. introduce the implementation of thiol‐ene/thiol‐yne radical mediated reactions as a means to achieve robust and patternable surface modification and functionalization. Thiol‐ene/yne reactions are compatible with a wide range of functional groups and exhibit good orthogonality with other common organic synthesis reactions. Hence, thiol‐ene/yne reactions represent a versatile approach for tailoring solid surfaces with specific properties, immobilizing macromolecules such as proteins, surface engineering, and patterning. Thiol‐ene reactions are discussed for surface immobilization of proteins for biochips, surface patterning functional organic monolayers, multilayer structures, polymer brushes, crosslinked polymer films, as well as bioorganic coatings. Tailoring of surface properties is also discussed via attachment of functionalized particles, functionalization of trialkoxysilanes, and biofunctionalization of nanoparticles. Similar to the thiol‐ene reactions, thiol‐yne reactions are also utilized for surface patterning and modification of biomaterials. Surface functionalization of silica‐based stationary phases is utilized to achieve different selectivities in chromatographic stationary phases. Thiol‐ene/yne reactions represent an ideal pathway to achieve a range of tailored surface functionalizations. In this chapter, the preparation of chiral (ionic exchange), reversed‐phase, mixed‐mode, and hydrophilic interaction stationary phases are highlighted.

Neil B. Cramer and Christopher N. Bowman, University of Colorado, USA

Andrew B. Lowe, University of New South Wales, Australia