Following Sharpless' visionary characterization of several idealized reactions as click reactions, the materials science and synthetic chemistry communities have pursued numerous routes toward the identification and implementation of these click reactions. Herein, we review the radical-mediated thiol-ene reaction as one such click reaction. This reaction has all the desirable features of a click reaction, being highly efficient, simple to execute with no side products and proceeding rapidly to high yield. Further, the thiol-ene reaction is most frequently photoinitiated, particularly for photopolymerizations resulting in highly uniform polymer networks, promoting unique capabilities related to spatial and temporal control of the click reaction. The reaction mechanism and its implementation in various synthetic methodologies, biofunctionalization, surface and polymer modification, and polymerization are all reviewed.

Thiol–Ene Click Chemistry

Department of Chemistry, Department of Radiology, Washington University in Saint Louis, Saint Louis, Missouri 63130, Department of Chemistry, Texas A&M University, College Station, Texas 77842, Cancer Center Karolinska, Department of Oncology-Pathology CCK, R8:03 Karolinska Hospital and Institute, SE-171 76 Stockholm, Sweden, and Department of Chemistry and Biochemistry, Department of Materials, and Materials Research Laboratory, University of California, Santa Barbara, California 93106

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Applications of Orthogonal “Click” Chemistries in the Synthesis of Functional Soft Materials

The photopolymerization of mixtures of multifunctional thiols and enes is an efficient method for the rapid production of films and thermoset plastics with unprecedented physical and mechanical properties. One of the major obstacles in traditional free-radical photopolymerization is essentially eliminated in thiol–ene polymerizations because the polymerization occurs in air almost as rapidly as in an inert atmosphere. Virtually any type of ene will participate in a free-radical polymerization process with a multifunctional thiol. Hence, it is possible to tailor materials with virtually any combination of properties required for a particular application. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 5301–5338, 2004

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/pola.20366

Thiol–enes: Chemistry of the past with promise for the future

As a tribute to Professor Charlie Hoyle, we take the opportunity to review the impact of thiol-ene chemistry on polymer and materials science over the past 5 years. During this time, a renaissance in thiol-ene chemistry has occurred with recent progress demonstrating its unique advantages when compared with traditional coupling and functionalization strategies. Additionally, the robust nature of thiol-ene chemistry allows for the preparation of well-defined materials with few structural limitations and synthetic requirements. To illustrate these features, the utility of thiol-ene reactions for network formation, polymer functionalization, dendrimer synthesis, and the decoration of three-dimensional objects is discussed. Also, the development of the closely related thiol-yne chemistry is described. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 743–750, 2010

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/pola.23824

The power of thiol-ene chemistry

s a hydrogen atom from the thiol to give hydroperoxide 96 and a thiyl radical, which propagates the chain. Hydroperoxide 96 is reduced in the presence of triphenyl phosphine to give the corresponding alcohol 91. The preference for the formation of cis-3,5-disubstituted 1,2-dioxolanes is in agreement with the Beckwith−Houk transition state model for 5-exo-trig cyclizations. Similarly, the addition of thiophenol onto 5methylhepta-1,3,6-triene 97 under an atmosphere of oxygen led to 1,2-dioxolane 98, isolated in 49% as a single diastereoisomer after treatment with triphenyl phosphine, together with minor amounts of linear alcohols 99 and 100 (Scheme 49, eq b). This reaction is remarkable for a number of reasons. First, the addition of the thiyl radical occurs exclusively at the terminal position of the conjugated diene system and not at the terminal alkene, thus highlighting the higher reactivity of conjugated dienes as compared to isolated alkenes. Second, intermolecular trapping of the resulting allyl radical is reversible and regioselective under these reaction conditions. Because of the reversibility of the reaction between the allyl radical and molecular oxygen, both ratios 1,4/1,2-addition and 1,2dioxolane/linear alcohols strongly depend upon the initial concentration in thiol. Accordingly, the 1,2-dioxolanes were obtained in good yields only in highly diluted solutions. Finally, the 5-exo-trig cyclization occurs in a completely stereoselective manner, with only one of the two diastereomeric peroxyl radical intermediates (101) undergoing cyclization, while the other one (102) either leads to linear alcohol 99 or fragments back the allyl radical (Scheme 49, eq b). The reversible reaction of allyl radicals with molecular oxygen was also demonstrated for carotenoid-derived carbon-centered radical generated by Scheme 47 Scheme 48. Application to the Preparation of Functionalized 1,2,4-Trioxanes Chemical Reviews Review dx.doi.org/10.1021/cr400441m | Chem. Rev. XXXX, XXX, XXX−XXX X addition of a thiyl radical to the conjugated polyene carotene. This process has been extended to include the more challenging 1,5-dienes, from which six-membered ring endoperoxides can be obtained. Bachi and co-workers applied the thiol−olefin cooxidation process to the total synthesis of antimalarial agent yingzhaosu A (Scheme 50) and its C14epimer, as well as the preparation of a series of active analogues, from readily available limonene 103. The overall process is extremely challenging in this case due to the particular structure of the diene, with the 6-exo-cyclization process being in competition with intermolecular hydrogen atom abstraction from the thiol, and also potentially with intramolecular hydrogen abstraction from the activated allylic position by the reactive oxygen-centered radical. As previously observed, addition of the thiyl radical takes place at the less hindered position, and due to the lack of stereocontrol during the trapping of the resulting carbon-centered radical, peroxyl radical 105 is formed as a 1:1 mixture of diastereoisomers (Scheme 50). The latter undergoes 6-exo-trig cyclization to give carbon-centered radical 106. Unlike the initial trapping with molecular oxygen, the 2,3-dioxabicyclo[3.3.1]nonane system of 106 allows a highly diastereoselective reaction for the second trapping with molecular oxygen from the less hindered face to give 107. Alcohol 104 is then obtained following hydrogen abstraction from the thiol by peroxyl radical 107 and reduction of the resulting hydroperoxide with triphenylphosphine. The yields of endoperoxides remain relatively low (ca. 20−30%, calculated on the diene); however, considering the accessibility and the cost of the reactants (thiophenol, limonene, and oxygen), this approach represents a very attractive access to these structurally complex endoperoxides, some of which exhibit very promising activity for the treatment of malaria. 3.3.2. Intramolecular Trapping of the Carbon-Centered Radical. 3.3.2.a. Fragmentation Reaction: RingOpening of Vinyl Cyclopropanes. The carbon-centered radicals generated by addition of a thiyl radical onto the C C bond of vinylcypropanes have been shown to undergo cyclopropane ring-opening. The resulting radical species can then be trapped by hydrogen abstraction from the thiol. This fragmentation is a very fast process with rate constants in the range 10−10 s−1 (310 K) for most of the cyclopropylcarbinyl radicals, which allows for the fragmentation process to compete favorably with intermolecular reactions, as well as with most intramolecular processes. Alternatively, the carboncentered radical resulting from the β-fragmentation of the cyclopropylmethyl radical can engage further in carbon−carbon bond-forming processes. The allylsulfide moiety allows for the addition of radicals with concomitant release of a thiyl radical, and very elegant processes using only substoichiometric amounts of a source of thiyl radicals have been developed for the rearrangement of vinylcyclopropanes (see section 5.2.1.e). In particular, under nonreducing conditions and in the presence of an external olefin, efficient annulation reactions have been achieved, giving access to polycyclic compounds. The carboncentered radicals generated by the thiol-mediated ring-opening Scheme 49 Scheme 50 Chemical Reviews Review dx.doi.org/10.1021/cr400441m | Chem. Rev. XXXX, XXX, XXX−XXX Y of vinylcyclopropanes could also be trapped to form a new carbon−heteroatom bond. Here again, annulations taking advantage of the allylsulfide moiety have been developed (see section 5.2.1.e). Landais, Renaud, and co-workers used vinyl cyclopentenes such as 108, easily prepared by monocyclopropanation of silylcyclopentadienes, as radical acceptors for photogenerated thiyl radicals. The reversible addition of the thiyl radical onto the CC bond of 108 leads eventually to cyclopropylcarbinyl radical 110, which undergoes fragmentation to give carboncentered radical 111, stabilized by the neighboring ester group. Hydrogen atom abstraction from the thiol then furnishes cyclopentene 109 and regenerates a thiyl radical that propagates the chain (Scheme 51, eq a). The addition of the thiyl radical at the β-carbon center takes place in a highly stereoselective manner, opposite to the bulky silyl group. The fate of the stabilized carbon-centered radical resulting from the fragmentation process depends upon the reaction conditions. For instance, Naito and co-workers reported the use of vinylcylopropyl oxime ethers such as 112 in domino reactions promoted by a thiol or a disulfide in the presence of triethylborane. The ring-opening of the cyclopropyl moiety is initiated by addition of a thiyl radical onto the terminal position of vinylcyclopropyl oxime ether 112. The stabilized carboncentered radical resulting from the fragmentation process reacts with triethylborane to form a boryl enamine 115 (Scheme 51, eq b). Depending on the reaction conditions, the latter can engage further in a radical oxygenation process, leading eventually to α-hydroxy oxime ether 113 after reduction of peroxyl radical 116 by the thiol (Scheme 51, eq b). Alternatively, 113 can react with aldehydes in an ionic aldol process to give β-hydroxy oxime ethers in a stereoselective manner, as illustrated by the preparation of 117 from 112 (Scheme 51, eq c). In the aforementioned reactions, the allylsulfide moieties generated upon addition of a thiyl radical onto the vinylcyclopropane unit remain intact at the end of the reaction. However, radical reactions taking advantage of the fragmentation of allyl sulfides upon addition of radical species are also well documented. Some examples of intermolecular additions, as well as cyclization and annulation processes, will be described in section 5.2.1.e. 3.3.2.b. Rearrangement and Cyclization of Nonconjugated Dienes. In the addition of thiyl radicals onto nonconjugated dienes, the CC bonds can either react independently or lead to rearrangements through intramolecular trapping of the carbon-centered radical generated in the initial addition step. In many cyclic dienes, addition occurs selectively at the more strained double bond, and products resulting from rearrangements are often observed. For example, the addition of thiophenol to 5-methylene-norbornene led to the exo addition products 118 and 119, together with tricyclic adduct 120. The latter results from the rearrangement of homoallyl radical intermediate 121 into cyclopropylcarbinyl radical 122 (Scheme 52). Similar rearrangements have been observed in norbornadiene derivatives where substitution at C-7 can influence facial selectivity, while substitution of the methylene bridge in 7,7-dimethylnorbornene proved to have no effect in directing the addition of thiophenol. The formation of cyclopropylcarbinyl radical intermediates in norbornadiene derivatives can also lead to other skeletal rearrangements, as illustrated by the addition of thiophenol to hexachloronorbornadiene 123, which results in the formation of 125, beside the expected 1:1 addition product 124 (Scheme 53, eq a). Following addition of the thiyl radical, presumably from the less hindered endo-face, and subsequent 3-exo-trig cyclization onto the neighboring CC bond, cyclopropylcarbinyl radical 126 undergoes fragmentation to give the more stable α-chlorosubScheme 51 Scheme 52 Chemical Reviews Review dx.doi.org/10.1021/cr400441m | Chem. Rev. XXXX, XXX, XXX−XXX Z stituted carbon-centered radical 127. The latter then abstracts a hydrogen atom from the thiol to give 125 (relative configuration not established) and a thiyl radical, which goes on to propagate the chain. Similar rearrangement was observed i n t h e add i t i on o f t BuSH on to 1 , 2 , 3 , 4 , 7 , 7 hexamethylbicyclo[2.2.1]heptadiene. Likewise, Hodgson and co-workers have observed complete skeletal rearrangements in the addition of thiophenol to 7-azabicyclo[2.2.1]heptadienes such as 128 (Scheme 53, eq b). Transa

Thiyl Radicals in Organic Synthesis

The relationship between the photopolymerization rate of hydroxyalkyl acrylates and their structure has been investigated. The polymerization rates of hydroxyalkyl acrylates are significantly higher than those observed for typical monofunctional acrylate monomers and rival those of multifunctional monomers. By polymerizing at several temperatures, it was shown that the enhanced rates are directly proportional to the degree of hydrogen bonding. Apparently, termination rates are greatly reduced by hydrogen bonding, which is present in both the unpolymerized monomer and the final polymer film.

Influence of Hydrogen Bonding on Photopolymerization Rate of Hydroxyalkyl Acrylates

The photopolymerization of multifunctional thiol (trimethylolpropane tris(3-mercaptopropionate))/vinyl acrylate mixtures as a function of thiol content in the presence and absence of photoinitiators has been investigated using real-time FTIR, thin-film calorimetry, and 2D-COSY NMR. The addition of a multifunctional thiol to vinyl acrylate significantly enhances the conversion of the vinyl double bonds of vinyl acrylate due to the preferential addition of the thiyl radical to the vinyl group. Two separate free-radical polymerization processes, acrylate homopolymerization and thiol/vinyl ester copolymerization, occur simultaneously in thiol/vinyl acrylate mixtures. Thin-film calorimetry and 2D-COSY NMR results are consistent with real-time FTIR results, giving strong evidence for two simultaneous free-radical processes.

Thiol−Ene Photopolymerization Kinetics of Vinyl Acrylate/Multifunctional Thiol Mixtures

The relationship between the polymerization rate of various acrylates and methacrylates containing acid groups and their ability to hydrogen bond has been investigated by real-time infrared spectroscopy. The polymerization rate dependence on temperature of the acid-based acrylates and methacrylates is reduced compared to traditional (meth)acrylates with no groups capable of hydrogen bonding. For two of the acid containing monomers, polymerization rates actually decreased with an increase in temperature.

Tai Y. Lee

Papers

Influence of Hydrogen Bonding on Photopolymerization Rate of Hydroxyalkyl Acrylates

Thiol−Ene Photopolymerization Kinetics of Vinyl Acrylate/Multifunctional Thiol Mixtures

Photopolymerization of acid containing monomers: Real-time monitoring of polymerization rates