Review pubs.acs.org/cm
The Thiol-Michael Addition Click Reaction: A Powerful and Widely Used Tool in Materials Chemistry Devatha P. Nair,† Maciej Podgórski,†,‡ Shunsuke Chatani,† Tao Gong,† Weixian Xi,§ Christopher R. Fenoli,§ and Christopher N. Bowman*,†,§,∇ †
Department of Chemical and Biological Engineering, University of Colorado, UCB 596, Boulder, Colorado 80303, United States Faculty of Chemistry, Department of Polymer Chemistry, MCS University, pl. Marii Curie-Skłodowskiej 5, 20-031 Lublin, Poland § Department of Chemistry and Biochemistry, University of Colorado, UCB 215, Boulder, Colorado 80309, United States ∇ Materials Science and Engineering Program, University of Colorado, Boulder, Colorado 80309, United States ‡
ABSTRACT: The key attribute of the thiol-Michael addition reaction that makes it a prized tool in materials science is its modular “click” nature, which allows for the implementation of this highly efficient, “green” reaction in applications that vary from small molecule synthesis to in situ polymer modifications in biological systems to the surface functionalization of material coatings. Over the past few decades, interest in the thiol-Michael addition reaction has increased dramatically, as is evidenced by the number of studies that have been dedicated to elucidating different aspects of the reaction that range from an in-depth analysis aimed at understanding the mechanistic pathways of the reaction to synthetic studies that have examined modifying molecular structures with the aim of yielding highly efficient thiol-Michael reaction monomers. This review examines the reaction mechanisms, the substrates and catalysts used in the reaction, and the subsequent implementation of the thiol-Michael reaction in materials science over the years, with particular emphasis on the recent developments in the arena over the past decade. KEYWORDS: thiol-Michael addition reaction, thiol-click chemistry, thiol-Michael addition reaction mechanism
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INTRODUCTION Michael Addition Reactions. The Michael addition reaction, which is broadly characterized as the reaction of an enolate-type nucleophile in the presence of a catalyst to an α, βunsaturated carbonyl, has a myriad and long history of implementation in reactions in organic synthesis to yield highly selective products in an efficient manner under environmentally friendly reaction conditions.1 More specifically, the Michael addition reaction is described as a special type of conjugate (1,4) addition in which the strong nucleophilic attack on the βcarbon of an α,β-unsaturated carbonyl results in a negatively charged enolate intermediate, that subsequently yields the Michael adduct, by protonating the catalyst. This thermodynamically favored, facile methodology to generate C−C, C−N, C−S, C−O, and other C−X bonds within the Michael product has been a workhorse reaction in small molecule organic synthesis for more than 125 years.1−4 Since being discovered by Arthur Michael in the late 1880s, the initial Michael addition reactions were carried out by him to explain the formation of a cyclopropane derivative as observed by Conrad and Kuthzeit in a reaction between diethyl 2,3-dibromopropionate with diethyl sodiomalonate.2,5 Michael was able to demonstrate that a reaction between ethyl 2-bromoacrylate and diethyl sodiomalonate also yielded the same cyclopropane derivative and correctly deduced that the same product could be obtained © 2013 American Chemical Society
from either reaction only if an addition reaction to the double bond of the acrylic acid were to take place. Since that time, a variety of different Michael addition reaction chemistries have been extensively discovered and implemented to build a comprehensive toolbox to include a range of efficient reactions that yield highly specific products.1−16 In addition to fulfilling the key criteria that qualifies this reaction as a highly modular “click” reaction with the ability to produce highly stereospecific and regiospecific products, the Michael addition reaction is a simple, robust, and highly effective reaction that can result in C−C bond formation under relatively facile reaction conditions. The Michael addition reaction paradigm includes the carbon-Michael reactions,6,7 oxa-Michael reactions,8−10 aza-Michael reactions,11−14 and the thiol-Michael reactions,15,16 all of which have been studied and implemented over the years in organic synthesis and in materials science. The Thiol-Michael Click Reaction. While the Michael addition reactions historically have been used ubiquitously in Special Issue: Celebrating Twenty-Five Years of Chemistry of Materials Received: July 3, 2013 Revised: August 15, 2013 Published: August 19, 2013 724
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Scheme 1. The Thiol-Michael Addition Reaction Falls within the Intersection of Two Powerful Reaction Methodologies: The Powerful Thiol-Click Reaction Paradigm and Michael Addition Reactionsa
a
The thiol-click reactions are characterized by their robust, self-limiting pathways and, combined with the Michael addition reaction, they yield a highly efficient, modular reaction mechanism. (The scheme is adapted with permission from Hoyle et al.18 Copyright 2010, Royal Society of Chemistry.)
erable work has been devoted to studying the relative reactivity of thiols with numerous substrate/catalysts combinations and subsequently designing and formulating reaction conditions that efficiently yield a highly selective product, thereby ensuring that the advantages of the “click” nature offered by thiols have been exploited and implemented in chemistries in a range of diverse fields that span the spectrum of chemical, biochemical, biological, physical, and engineering applications, to name a few.1,18,20,21,23,24 Thus, while a library of possible thiol reactions have been developed and used to formulate and create a range of thiol-based engineering materials with bespoke physical, mechanical, and chemical properties, we will limit our discussion in this paper to the versatile and powerful thiolMichael click reaction. Within materials science applications, the thiol-Michael addition reaction offers an enhanced level of control over reaction parameters to ensure both spatial and temporally modifiable materialsbe it the in vivo surface modification of biomaterials or photolithographic patterning of a substrate.25−28 Therefore, it is of no surprise that, over the past two decades with the resurgence of thiol-chemistries at large, the thiol-Michael addition reaction or the conjugate addition of thiols or thiolate anions, to electron-deficient CC bonds has garnered significant attention, primarily due to its facile, powerful nature. Furthermore, even in very dilute systems such as those necessary for polymer−polymer conjugation or polymer end group-functionalization, both the nucleophile- and base-catalyzed thiol-Michael addition mechanisms do not lead to the formation of significant side products, such as the radical−radical termination products formed in radicalmediated thiol-ene reactions.21,23 This ability to proceed to quantitative conversion without side product formation even under dilute conditions renders the thiol-Michael addition the reaction of choice for many materials chemistry applications. Considerable efforts have been dedicated to the understanding of the thiol-Michael addition reaction pathway along with the development of novel catalyst systems capable of achieving high yields from the facile hydrothiolation of an activated CC bond with readily available reagents such as
organic synthesis, their implementation in materials applications, surface modification, polymer modification, and polymer synthesis has largely arisen in parallel to the broader implementation of click chemistry in materials. Here, we focus on a specific Michael addition reaction that has arguably generated the highest level of recent interest and implementation in materials chemistry applications, including those ranging from bimolecular synthesis to surface modification to engineering adhesives and laminates to dendrimer synthesis and block polymer conjugation: the thiol-Michael addition reaction. Since the first report of the thiol-Michael addition reaction in the 1960s by Allen et al.,17 it has quickly become an indispensible tool for organic synthesis, and it has been the focus of increasing fundamental analysis and practical implementation in polymer chemistry and materials development.18 The versatility afforded by the weak sulfur−hydrogen bond enables the thiolMichael addition reaction to be initiated using a wide-range of precursor materials. Over the years, the thiol-Michael addition reaction has been tailored to progress under mild, solventless reaction conditions using mild catalysts to yield a highly efficient, modular click reaction.1,18,19 Historically referred to as mercury-scavenging mercaptans, the presence of the highly reactive sulfur within the thiol functional group has ensured its use in applications that require enhanced physical and chemical properties, e.g., sulfur has been used to cross-link polymers since the advent of the Industrial Revolution.18 The inherent electron density of the S atom ensures that thiols react under facile reaction conditions via mildly catalyzed processes with numerous substrates, although the high thiol reactivity is sometimes seen as a disadvantage that compromises the orthogonality and specificity necessitated by the click paradigm. In fact, numerous thiol-X reactions have been broadly classified as click reactions in which the thiol reacts via pathways as diverse as radical-mediated thiol-ene reactions, amine-catalyzed thiol-epoxy reactions, thiourethane-forming thiol-isocyanate reactions, and thiol-halide reactions, among others as illustrated in Scheme 1.18,20−22 However, over the past decade and in an attempt to develop enhanced control and specificity of these reactions, consid725
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Scheme 2. The Base-Catalyzed Thiol-Michael Addition Reaction Pathway Shows the Hydrothiolation of an Activated CC Bond via the Addition of the Anion across the Electron-Deficient Beta-Carbon of the Enea
a
Note that, in the thiol-Michael nucleophilic pathway, the nucleophile undergoes conjugate addition to the activated CC bond, generating the strong intermediate carbanion, which, in turn, deprotonates the thiol, which subsequently undergoes thiol-Michael addition. (The scheme is adapted with permission from Xi et al.36 Copyright 2012, American Chemical Society.)
sodium methoxide, weak organobases such as NEt3, and nucleophiles such as phosphines being the most widely used catalyst systems. Lewis acids such as gandolinium triflate-based tetrafluoroborate also successfully initiate the thiol-Michael addition reactions.29 Moghaddam et al.30 demonstrated that a mixture of KF/Al2O3 could yield an efficient ionic liquid to catalyze the thiol-Michael reaction while Movassagh et al.31 examined ideal conditions under which the thiol-Michael addition reaction could proceed in the absence of a solvent. Gao et al.32 further studied the efficiency of molecular iodine to successfully catalyze both aromatic and aliphatic thiol-Michael additions with 1,4-unstaturated carboxylic acids. However, by far, the most efficient catalysts with the propensity for minimal side reactions that have been used to initiate the thiol-Michael addition reactions are the base and nucleophile-based catalysts. We briefly examine the significant studies that clearly elucidate the thiol-Michael addition base-catalyzed pathway and the thiol-Michael nucleophilic addition pathway. It is of note that both the pathways, the nucleophile-mediated thiol-Michael reactions and the traditional base-catalyzed reactions, are extremely rapid and give quantitative yields of specific products in bulk conditions under ambient conditionsall veritable hallmarks of an ideal “click” reaction. Given the gamut of reactions involving thiols, it is important to note that the reactivity of a specific thiol used in a reaction plays an important role in dictating the reaction kinetics and the product specificity. Generally, thiols are divided into aromatic thiols, thioglycolates (thioacetates), thiopropionates, and aliphatic thiols, and based on the pKa and other attributes of the thiol, its reactivity in a Michael addition reaction can vary significantly (Scheme 3).18 It is important to note that based on the nature of the basic thiol group and the corresponding thiyl and thiolate species, the highly efficient thiol-based reactions occur with a variety of very useful and readily available organic substrates.20
The remainder of this article will initially elaborate on the two distinct mechanistic pathways through which the thiolMichael reaction proceeds to yield the Michael adduct and address various aspects that impact each thiol-Michael addition reaction pathway, its kinetics, and product formation. Subsequently, the implementation of the reaction in different applications and synthetic methodologies along with the possibilities that this reaction has opened up, be it in terms of molecular synthesis, the formation of cross-linked polymer networks, or other aspects relevant to materials chemistry, will be detailed in the following discussions.
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THIOL-MICHAEL ADDITION MECHANISMS AND CATALYSTS Base-Catalyzed Thiol-Michael Addition. As illustrated in Scheme 2, the base-catalyzed Michael addition reaction involves the use of catalytic amounts of a base (e.g., an amine) to facilitate the reaction between a thiol and an electron-deficient vinyl group to yield a thioether addition product. The basecatalyzed thiol-Michael addition reaction and its historical implementation in organic synthesis is well-documented.1 In the traditional base-catalyzed thiol-Michael addition reaction pathway, the reaction kinetics and yield of the thioether product have been shown to depend on factors such as the strength and concentration of the base catalyst, the thiol pKa, the steric accessibility of the thiol and the nature of the electron withdrawing group coupled to the CC bond. Additional factors such as the polarity of the solvent and the pH of the solvent further affect the kinetics of the reaction in solution reactions. Typically, as illustrated in Scheme 2, the reaction pathway is as follows: in the presence of a common base such as triethylamine, a proton from the thiol is abstracted to generate a thiolate anion, along with a conjugate acid. The thiolate anion is generally a strong nucleophile, which initiates the addition of 726
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Scheme 3. Range of pKa Values for Different Thiol Types That Are Commonly Used in Organic Reactionsa
a This pKa range shows that the thiol pKa values generally fall between 7 and 11 for aromatic thiols, thioglycolates (thioacetates), thiopropionates, aliphatic thiols, and cysteine thiols.
the rate of the thiol-Michael addition reaction between hexanethiol and hexyl acrylate was tremendously affected by the pKa values of organocatalysts. Therefore, triethylamine (TEA, with a pKa = 10.8) gave an apparent rate constant of 2.8 × 10−6 mol L−1 s−1 with 0.057 mol % concentration, whereas 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), which has a pKa of 13.5, had a rate constant of 5.5 × 10−3 mol L−1 s−1, despite the catalyst concentrations being 2 orders of magnitude less than that of triethylamine. However, the authors imply that this significant difference in the reaction rate is not only from high basicity of 1,8-diazabicycloundec-7-ene (DBU) and DBN, but also their ability to act as a nucleophile and react via an alternative pathway. As previously mentioned, the pKa of the thiol along with its structure are important factors that impact the reaction rate in thiol-Michael reactions. However, by employing a strong nucleophile as a catalyst instead of a base, the dependence of the reaction on the pKa of the thiol used can be limited. When initiating via the nucleophilic reaction pathway, a strong nucleophile is used to generate a strong base via the nucleophilic attack on a Michael acceptor (the activated ene), which, in turn, generates the intermediate zwitterionic enolate base that is responsible for deprotonating the thiol. The high reactivity of the resulting thiolate anion ensures rapid reaction kinetics, even in the presence of trace protic species such as water. Although both the base and nucleophile-catalyzed mechanisms have been studied over the years, recently, much attention has been focused on understanding the nucleophilic thiol-Michael addition pathway as a means for improving various characteristics of the thiol-Michael reaction. Nucleophile-Catalyzed Thiol-Michael Addition. Indepth mechanistic studies by Liu et al.37 and Chan et al.38 established that, while both a base and a nucleophile are capable of successfully catalyzing the thiol-Michael addition reaction, phosphines were able to catalyze the thiol-Michael addition reaction with (meth)acrylates with minimal side reactions, and, in comparison with a base, nucleophilic phosphines catalyzed the reaction much more rapidly and efficiently.37−39 The study systematically examined the impact of the thiol-(meth)acrylate Michael addition reaction, with regard to the nucleophile type, solvent, and substrate, on the reaction mechanism and kinetics.40 However, unless used in catalytic quantitates, phosphines were also seen to initiate side reactions by reacting with the vinyl group. As Chan et al.38,39 and Liu et al.37 have shown, in the nucleophile-mediated pathway, the nucleophile itself does not catalyze the reaction; instead, it reacts with the electron-deficient CC bond to generate a strong base.
the anion across the electron-deficient beta-carbon of the ene to yield an intermediate carbon-centered anion which, being a strong base, abstracts a hydrogen from the conjugate acid to yield the thioether as a product. The base catalyst is also regenerated in the process and the anionic propagation step has been shown to proceed rapidly in the absence of interference from protic sources such as water or alcohol. Although the susceptibility of the base-catalyzed mechanism to other protic species in comparable concentrations of the catalyst, such as a strong acid, can be considered a drawback of this pathway, the significance of this reaction in organic synthesis and engineering applications is well-established, as inferred from its extensive use in applications that range from organic synthesis to substrate modification, several examples of which are highlighted later.33−35 The rate-limiting step of the thiol-Michael addition reaction pathway is generally the nucleophilic attack of a thiolate anion on the electron-deficient vinyl. Therefore, the rate of reaction (Rrxn) is written as eq 1: R rxn = k[R−S−][vinyl]
(1)
−
where [R−S ] denotes the thiolate anion concentration and can be derived from the equilibrium established between the thiol and base (eq 2): Keq =
[R−S−][B+−H] [R−SH][B]
(2)
Therefore, ⎛ [B] ⎞ R rxn = kKeq ⎜ + ⎟[R−SH][vinyl] ⎝ [B −H] ⎠
(3)
Therefore, the overall reaction rate of the thiol-Michael reaction depends on (i) the basicity of the catalyst, (ii) the acidity of the thiol, and (iii) the electrophilicity of the vinyl. Given that the range of thiol pKa values spans from 4.13 for 2,4,6-trinitrothiophenol to 11.2 for tert-pentylmercaptan, the specific catalyst chosen to mediate a particular reaction should be chosen carefully.22 In the case of a strong base catalysti.e., when the pKa of the conjugate acid of the base catalyst is much higher than that of thiolthe concentration of the thiolate anion generated will be approximately equal to that of the base catalyst and provide the highest reaction rate, which is now a pseudo-first-order reaction in the vinyl concentration.1 In the case of a weaker base, the concentration of the thiolate anion generated will now be dependent on the equilibrium between the thiol and the base catalyst. Chan et al.35 have shown that 727
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Figure 1. Two key kinetic profiles that suggest a nucleophilic pathway for the reaction between the hexyl acrylate and hexanethiol are shown here. The first reaction (panel a) shows the kinetic profiles observed in the presence of primary, secondary, and tertiary amines, represented by triethylamine (open squares, □), dipropylamine (filled squares, ■), 0.43 mmol hexylamine (open circles, ○), and 0.75 mmol hexylamine (filled circles, ●). The second reaction (panel b) shows the kinetic profiles for the reaction of hexyl acrylate with hexanethiol in a solvent (benzene) with four different phoshphines: tri-n-propylphosphine (P-n-Pr3) (open squares, □), dimethylphenylphosphine (PMe2Ph) (filled squares, ■), methyldiphenylphosphine (PMePh2) (filled circles, ●), and triphenylphosphine (PPh3) (open circles, ○).The tertiary phosphine was observed to be more reactive than the primary amine when present in half the concentration of the amine. (The figures 1a and 1b are reprinted with permission from Chan et al.35 Copyright 2010, American Chemical Society.)
Scheme 4. Factors To Be Considered When Selecting an Initiating System for Thiol-Michael Click Reactionsa
a
Predictably, the efficiency of the initiating systems depends on the specific thiol, the ene, the catalyst type, and the concentration, along with the reaction conditions that are chosen.
initiation of a seemingly base-catalyzed thiol-Michael addition reaction. The reaction of hexyl acrylate and hexanethiol was carried out in the presence of triethylamine, dipropylamine, or hexylamine. As would be expected from the basicity of the amines, the kinetic profiles of the model reaction between hexanethiol and hexyl acrylate catalyzed by one of the three different amines, hexylamine, n-dipropylamine, and NEt3 should follow the order nPr2NH > NEt3 > HexNH2, with the n-dipropylamine catalyzing the reaction at the fastest rate: however, the observed kinetic profile of the catalyzed reaction was HexNH2 > NEt3 > nPr2NH2. These differences could not be explained merely by the difference in pKa between the secondary and tertiary amines used in this experiment (∼0.4 pKa). Significantly, when the observed results were viewed in terms of the relative nucleophilicity of the amines, the kinetic data followed a profile that was consistent with the observed
Therefore, in this case, the reaction kinetics are dependent on the nucleophilicity of the catalyst, because the higher the nucleophilicity of the catalyst, the larger the number of active thiolate anion intermediates that can be generated. Another aspect of this pathway is that it is nominally an anionic chainlike mechanism with an anionic intermediate, since there are no other protic species other than the thiols present in the reaction.33,38,40 Specifically, Chan et al.35 studied phosphine-centered nucleophiles such as tributyl phosphine and dimethylphenyl phosphine and the role they play in the nucleophilic thiolMichael addition pathway. In a defining study that described a commonly noted but little-explored phenomenon, they observed from the experimentally determined kinetic profiles that the reaction catalyzed by hexylamine (HexNH2) was seen to proceed to completion rapidly within the initial 500 s of 728
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Scheme 5. Free-Energy Profiles of Base- and Nucleophile-Initiated Pathways for Trimethyl Phosphine-Catalyzed Thiol-Michael Additiona
a
These profiles indicate that the base-catalyzed pathway has significantly higher activation energy, compared to the nucleophile pathway for the phosphine catalyst, adding additional evidence and explanation in favor of the nucleophilic pathway. (The scheme is adapted with permission from Wang et al.42 Copyright 2013, Elsevier.)
catalysts although enhanced catalytic activity can be attained in the case of trialkylphosphines such as P-n-Pr3. Comparing Base and Nucleophile-Catalyzed ThiolMichael Additions. Scheme 4 captures the different bases and nucleophiles that are commonly utilized for catalyzing the thiolMichael reaction and the factors that are to be considered while choosing an optimal catalyst for the reaction. Here, generalized factors that are predictive of the success and mechanism of the thiol-Michael catalyst are indicated. Given the optimization that has been achieved for both the nucleophilic and base-catalyzed thiol-Michael addition reaction mechanisms, the ultimate choice of catalyst for the reaction will remain, essentially, dependent on application and environment. In comparison with the base-catalyzed mechanisms, the nucleophilic Michael addition reaction generally proceeds to high conversions efficiently with relatively low concentrations of the catalyst. Phosphorus-centered catalysts, particularly trialkylphosphines, are seen to be extremely reactive, even at lower catalyst loadings.41 Li et al.40 investigated the thiolMichael reaction incorporating methacrylates, which are a vinyl group with low reactivity under typical thiol-Michael addition reaction conditions, and demonstrated that the phosphine DMPP led to quantitative conversion of the reactants within less than an hour, while TEA (base) or n-pentylamine (Ncentered nucleophile) required several hours to achieve high conversion. Also, although generally, the low pKa values of thiols ensure that the thiol-Michael addition reaction is insensitive to ambient conditions such as moisture and proceeds in the presence of water or alcohol as a solvent, it is of note that both the nucleophilic pathway and the basecatalyzed reaction pathway are impacted by the presence of external acidic protons other than the thiol in the reaction. The
rapid kinetics of the primary amine-catalyzed system also having the highest nucleophilicity, thereby establishing that the kinetic profiles of the reaction corresponded instead to the nucleophilicity of the catalyst (see Figures 1a and 1b). Since phosphines are weaker bases than alkylamines, Chan et al.35 further compared the kinetic profiles from four different phosphines (P-n-Pr3, PMe2Ph, PMePh2, and PPh3) for the reaction between hexyl acrylate and hexanethiol. Although as predicted, the aryl substitution in the phosphine resulted in a drastic drop in the catalytic activity of the phosphine, in comparison with the primary amine, as previously noted, the primary amine (HexNH2) was observed to be less reactive than the tertiary phosphine (trialkyl phosphine), despite being at a concentration that was 2 orders of magnitude higher, in comparison with the tertiary phosphine! The overall reactivity of the phosphines ranked in the following order:35 P‐n‐Pr3 > PMe2Ph > PMePh 2 > PPh3
Based on these observations, the currently accepted mechanism for nucleophile-mediated thiol-Michael addition reactions was adopted, whereby the nucleophile initially undergoes conjugate addition to the activated CC bond to generate the strong intermediate carbanion, which, in turn, deprotonates the thiol to generate a thiolate anion, which subsequently undergoes thiol-Michael addition. The carbanion is regenerated in the process and proceeds to deprotonate the thiol, thereby resulting in the thiol-Michael product. Xi et al.36 built upon this work and found that nitrogen centered nucleophiles such as 1-methyl imidazole were also able to initiate the nucleophilic addition mechanism in thiol-Michael addition reactions. Primary alkylamines are also extremely potent nucleophilic 729
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nucleophilic pathway is seen to be more strongly impacted by external protic species, as the catalytic concentrations of nucleophiles used in the thiol-Michael reactions are orders of magnitude lower than a typical base catalyst. In fact, in extreme cases, the presence of protic species completely inhibits the nucleophile-mediated thiol-Michael reaction. As an illustration of the reaction differences, one direct comparison of the two pathways, i.e., the free-energy profiles for both the base and nucleophile catalyzed reaction with trimethylphenylphosphine, demonstrate the critical differences in the two possible pathways, as shown in Scheme 5. Uniquely, despite the significant differences in these two mechanisms and their attributes, under appropriate conditions, both the basecatalyzed and the nucleophile-mediated thiol-Michael reactions fit the criteria to qualify as highly efficient click reactions, in terms of reaction kinetics, regiospecificity, high selective product yield, and the use of facile ambient reaction conditions.
Before we enter an in-depth discussion on the implementation of the thiol-Michael addition reaction, we briefly discuss the mechanism and utility of four specific, common thiolMichael addition reactions that have been extensively implemented in materials chemistry and organic synthesis and hold considerable promise for the future, namely, the thiolvinyl sulfone, thiol-acrylate, thiol-maleimide, and thiol-yne Michael addition reactions. Thiol-Vinyl Sulfone Systems. Vinyl sulfones react selectively and rapidly with thiols under Michael addition conditions in the presence of other vinyls such as acrylates, as demonstrated by Chatani et al.33 In fact, the propensity for the thiol-vinyl sulfone reaction has been utilized to develop several vinyl sulfonyl inhibitors that react with thiol-containing cysteine proteases that form the part of the life-cycle of parasites such as Trypanosoma cruzi, the organism that causes Chagas’ disease.47 The thiol-vinyl sulfone Michael addition proceeds both via the base-catalyzed pathway and the nucleophile-catalyzed pathway. The resulting stable thioether sulfone bond is not readily susceptible to hydrolytic degradation and, therefore, has found widespread implementation in applications that range from textile dyes to cell-responsive hydrogels in biological systems with tunable degradation properties.48,49 Hubbell and coworkers49 demonstrated that the mechanical properties of hydrogels formed via Michael addition of PEG vinyl sulfones with thiols present in cysteine residues could be modulated by varying the stoichiometry of the reactants. The resistance to hydrolytic degradation offered by the thioether sulfone bond overcomes problems associated with other carbonyl-conjugated vinyls such as acrylates and maleimides, which are shown to form thioether ester and succinimide bonds, respectively, after participating in Michael addition reactions. Thiol-(Meth)Acrylate Systems. The thiol-acrylate reaction is one of the most commonly used thiol-Michael reactions and has been implemented in dendrimer synthesis, degradable hydrogel formation, surface and particle modification, and block copolymer synthesis.50−53 Although methacrylates are less reactive to thiol-Michael addition than the corresponding acrylates, the ester formed as a result of the reaction is more hydrolytically stable than that of the thiol-acrylate product, which has been used to form hydrolytically degradable gels. The applicability of thiol-(meth)acrylate Michael addition polymers has been extensively demonstrated in bioengineering, including cell encapsulation, controlled drug delivery, and degradable hydrogels applications, most notably by Hubbell and co-workers,50 and Anseth and co-workers.54 Recently, Pritchard et al.55 demonstrated the formation of robust injectable hydrogels cross-linked via a conjugate Michael addition in aqueous media with mechanical properties that resemble soft tissue. In addition to the comprehensive characterization of the thiol-acrylate Michael addition by Chan et al.35 discussed earlier, Haddleton and co-workers40 systematically examined the thiol-(meth)acrylate Michael addition reaction to study the effects of the nucleophile type, solvent, and substrate. It was found that phosphines catalyzed the reaction much more rapidly than amines. Also, apart from the pKa of the thiol, the nucleophilicity and basicity of the catalyst used and the type of solvent in the reaction were shown to impact the reaction rate considerably with the use of dimethylsulfoxide (DMSO), which was found to be a key feature in enabling the thiol-methacrylate coupling. Thiol-Maleimide Systems. The thiol-maleimide Michael addition reaction has been widely implemented in biological
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THIOL-MICHAEL ADDITION MONOMERS AND SYSTEMS Generalized Molecular Substrates. Since a comprehensive discussion of the thiol-Michael addition reaction is incomplete without documenting its extensive applications in molecular and materials synthesis, the remaining part of this discussion will seek to highlight specific implementations of the thiol-Michael addition reaction toward synthesizing specific molecules, functionalizing surfaces, and forming polymer networks, among other materials chemistry applications. The included examples are by no means a comprehensive presentation of the many hundreds of thiol-Michael implementations from just the past few years, but rather are meant to be representative of the types of applications in which this reaction has been used. Independent of the different approaches that can be implemented to initiate the thiol-Michael addition reaction, such as utilizing a traditional base catalyst or a nucleophilic catalyst, it is also of note that the structure of the activated ene plays an important role in the kinetic profile of the subsequent reaction: typically, the more electron-deficient the CC bond, the more susceptible it is to a Michael addition reaction.22,38 Typical Michael acceptors in thiol-Michael addition reactions are electron-deficient enes such as acrylates, methacrylates, vinyl sulfones, and maleimides (see Scheme 6), as well as other Scheme 6. Reactivity of Commonly Utilized Vinyl Groups in Thiol-Michael Addition Reactions
electron-deficient ynes, such as ynones43 and propiolates.41,44−46 Therefore, the order of reactivity in terms of the CC bond reactivity is as follows:35 maleimide > fumarates > maleates > acrylates/acrylamides > acrylonitrile > crotonate > cinnamate > methacrylates/methacrylamides 730
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systems, primarily due to selectivity of the thiol-maleimide reaction in aqueous environments, the rapid kinetics associated with the reaction, and the stability of the thiol-maleimide product. The thiol-maleimide reaction has been used in the cross-linking of hydrogels, the fluorescent labeling of molecules and, more recently, for the ability of the succinimide thioether bonds to undergo retro reactions at high temperatures.56 The high reactivity of CC bond in maleimides is seen to be due to two main factors: (i) the bond angle distortion and the ring strain and (ii) the carbonyl groups being in the cisconformation. In highly polar solvents such as DMSO and dimethylformamide (DMF), the thiol-maleimide reaction proceeds in the absence of a catalyst as the formation of active species, i.e., the thiolate ion, is achieved due to the polarity of the solvent. NOTE: Some maleimides are known neurotoxins; therefore, considerable caution must be exercised in handling and implementing any reactions that utilize them.22 Thiol-Yne Michael Addition. Thiol-Michael addition reactions where electron-deficient ynes function as the Michael acceptors can be used in either small molecule synthesis as well as in the formation of monomers and in polymerization reactions. Similar to the thiol-Michael addition reactions with electron-deficient vinyls as Michael acceptors, these reactions are catalyzed by either bases or nucleophiles and the mechanism is quite similar to that described in Scheme 7.
Similar to the radical mediated thiol-yne reaction, in the thiol-yne Michael addition reaction, the thiols readily (with some exceptions43,45) add across the triple bond twice, although the second addition is reported slower by a factor of 103, in comparison to the first addition, which is different from the radical-mediated thiol-yne reaction wherein the second addition is often more rapid.46 Thus, unlike the thiolyne radical reaction, oftentimes, the single addition ene product from the thiol-yne Michael reaction can be isolated with good yields. Therefore, depending on the reaction conditions as well as the structures of the substrates, the electron-deficient yne can be selected to be either monofunctional (i.e., reacting with only a single thiol per yne) or difunctional where each yne reacts with two thiols, as is common in radical mediated thiol-yne reactions.45 Kuroda et al.43 reported making linear polymers from dithiol and diynone monomers. The thiols were only reacted with each ynone once to generate a vinyl-containing polymer with which subsequent radical-mediated thiol-ene reactions could be performed. Concurrently, the thiol can be reacted with the monoyne, as shown in Scheme 8, where the monoyne reacts twice to form a linear polymer.46 It is safe to conclude that the thiol-yne Michael addition reaction has not been used as extensively as other thiol-ene and thiol-Michael pathways, and the exploration of this reaction is still in its infancy.
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APPLICATIONS AND IMPLEMENTATION OF THIOL-MICHAEL CLICK REACTIONS Small Molecule Synthesis in Materials Chemistry. The thiol-Michael addition reaction has been important in the synthesis of small molecules and natural product formation for many decades. Historically, the facile nature of the reaction has seen the thiol-Michael reaction used in applications that range from the modification of small molecules in the PEGylation process (i.e., the conjugation reaction of thiol with poly(ethylene glycol) (PEG)) to molecular synthesis to functionalizing dendrimers with core−shell properties.57 The thioether bond generated during the thiol-Michael reaction is relatively weak and to a certain degree, a thermally reversible bond,17,58 which also makes it an ideal candidate as a thiol protecting group in synthesis. Specifically, Kuroki and co-workers59 used aryl vinyl sulfones to form thioether bonds within polymer networks and demonstrated that the installation of the thiol protecting groups within the network was relatively trivial due to the specificity of the click reaction. Upon treatment with a stronger base, tert-potassium butoxide, the thioether bond can be readily cleaved to regenerate the free thiol. Concurrently, ptoluenesulfonylacetylene was proven to be an efficient protecting group for thiols under similar reaction conditions.60
Scheme 7. The Thiol-Yne Michael Addition Reaction with Propiolate as a Typical Michael Acceptora
This scheme shows that both the first and the second thiol attacks are similar to a thiol-vinyl Michael reaction, with the second attack found to be 103 times slower in this system. (The scheme is adapted with permission from Kuroda et al.46 Copyright 1997, Elsevier.) a
Scheme 8. Synthesis of Linear Polymers from p-Xylene-α,α′-dithiol and Methylpropiolate (or Ethynyl Phenyl Ketone)a
a
Thiols react twice with the yne via thiol-Michael addition reactions. (The scheme is adapted with permission from Kuroda et al.46 Copyright 1997, Elsevier.) 731
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Scheme 9. Synthetic Outline for Forming 3-arm Star Polymers under Nucleophile-Catalyzed Conditions by Sequentially Reacting a RAFT-Prepared Poly(N,N-diethylacrylamide) Polymer via a Thiol-Vinyl Michael Click Reactiona
a
The terminal dithiocarbonate RAFT agent is reduced to a thiol, and its subsequent addition to the triacrylate core is then catalyzed by DMPP. (The scheme is adapted with permission from Chan et al.69 Copyright 2008, Royal Society of Chemistry.)
Scheme 10. The Michael Addition Reaction Was Used To Synthesize a Cyclodextrin-Centered Star Polymera
a
The polymer subsequently underwent modification of the CD-(SH)7 groups via a phosphine- or amine-catalyzed reaction. (The scheme is adapted with permission from Zhang et al.79 Copyright 2012, Royal Society of Chemistry.)
Scheme 11. The Synthetic Process To Obtain End-Functionalized Glycopolymers Consisted of the Initial CCT of Glicydyl Methacrylate (GMA), Yielding Oligomers Followed by Three Sequential Click Reactions: The Thiol-Michael Reaction, the Epoxide Ring-Opening Polymerization, and the Copper-Catalyzed CuAAC Reactiona
a
The scheme is adapted with permission from McEwan et al.91 Copyright 2013, Royal Society of Chemistry. 732
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Scheme 12. Preparation of an End-Functionalized PNIPAm Monomer with Subsequent Modification To Yield a Michael Addition Product with Maleimide Groups and/or a Diels−Alder Adducta
a
The scheme is adapted with permission from Li et al.70 Copyright 2008, Wiley.
provide an efficient route for making linear and cross-linked polymers, dendrimers, hyperbranched polymers, and hydrogels from commercially available or easily synthesizable monomers via a step growth manner is further testimony to the “click” nature of the reaction. The synthesis of star polymers as demonstrated by Chan et al.38 via a thiol-vinyl Michael addition reaction demonstrates this powerful approach in which the nucleophilic, phosphine-catalyzed thiol-vinyl Michael addition reaction was used to enable convergent star synthesis with RAFT-prepared homopolymers. A convergent route to a 3-arm star polymer via the thiol-Michael addition reaction was demonstrated between RAFT-synthesized homopolymers and a trifunctional acrylate in which homopolymers of n-butyl acrylate or N,N-diethylacrylamide were prepared with 1-cyano1-methylethyl dithiobenzoate and 2,2′-azobis(2-methylpropionitrile) to obtain polymers with a polydispersity of 100 °C, and a wide range of mechanical properties was achieved by simple changes in the component concentrations. Extending the work of Hoyle, Nair and co-workers101,102 introduced polymer systems with two distinct sets of material properties by combining two orthogonal cross-linking reactions capable of generating distinct first- and second-stage polymers. The system reacted multifunctional thiols with an excess of multifunctional acrylates, initially via Michael addition, which left residual acrylates to be subsequently reacted via conventional radical photopolymerization. (The ability to form polymers with a wide range of nearly independent properties for polymers at each stage was achieved by proper selection of monomers and off-stoichiometric monomer ratios, which enabled a wide range of potential applications including shape memory polymers, lithographic impression materials, and optical materials with controlled refractive index patterns). Kloxin and co-workers103 recently followed up on this dual-cure approach to demonstrate that this methodology could also be used to buckle polymer networks in a photopatternable manner by using strongly attenuated light to initiate the second-stage acrylate photopolymerization. Thiol-Michael Addition-Based Hydrogels. Over the years, thiol-Michael addition-based hydrogels have been extensively used in biomedical applications.50,104−111 The facile and orthogonal nature of this reaction and its ability to yield a highly specific product under mild catalytic conditions, including the presence of water, salts, and oxygen, has numerous advantages for biological systems. Additional factors such as the absence of free thiols in the organic environment and the rapid kinetics of the thiol-acrylate and thiol-vinyl sulfone reactions, in comparison to the potential aza-Michael reactions, contribute to their extensive use. Furthermore, the ability to make thiol-functional monomers from cysteinecontaining peptides enables the incorporation of biological functionality into the backbone or as side chains in thiolMichael hydrogels. The ease of thiol-hydrogel formation under ambient conditions, along with insensitivity of the polymerization reaction to water and oxygen, has facilitated the application of these reactions in controlled drug delivery,55,105,109,112−117 tissue engineering,106,107,109,118−121 and hydrogel formation for tissue repair and reinforcement,53,107,111,122 among other applications. Hubbell and coworkers initially utilized the thiol-acrylate Michael addition reaction to form hydrogel-based biomaterials for controlled drug-delivery and tissue reinforcement applications. In their pioneering work, they demonstrated a degradable hydrogel formed via a thiol-Michael addition reaction of an aqueous
Scheme 23. (a) Surface Modification of MaleimideFunctionalized Gold Nanoparticles (AuNPs) Using ThiolMichael Addition (The scheme is adapted with permission from Zhu et al.,140 Copyright 2012, American Chemical Society), and (b) Conjugation of Thiol-Functionalized Nanotubes and Maleimide AuNPs Using Thiol-Michael Addition (The scheme is adapted with permission from Gobbo et al.141 Copyright 2013, Royal Society of Chemistry.)
to a decrease in molar mass, indicating that these materials are also biodegradable. (See Scheme 17.) Cross-Linked Polymer Networks Formed via ThiolMichael Addition. Cross-linked polymer networks, formed by the thiol-Michael addition reaction via step-growth polymerization reactions between multifunctional thiols and multifunctional activated vinyls result in uniform, homogeneous networks.26,51,97−99 As a result, the inherent homogeneity achieved via the step-growth polymerization results in a polymer with an increased capacity for mechanical energy absorption near its Tg value. An additional advantage of the step-growth-polymerization process is the delay that is achieved in attaining the gel point, which leads to the formation of a cross-linked network with the ability to flow for extended periods, resulting in a network with lower polymerizationinduced shrinkage stress. Indeed, conventional multiacrylate monomer polymerizations have experimental gel points of
