Thiol-maleimide reaction

Figure 20.4 Reduction of the disulfide bonds within the hinge region of an IgG molecule produces half-anti-body molecules containing thiol groups. Reaction of these reduced antibodies with a maleimide-activated enzyme creates a conjugate through thioether bond formation.

As electron-rich olefins are more reactive, vinyl-sulfones are the most reactive species and are capable of reacting with thiols, amines, and even with small nucleophilic alcohol groups. Less reactive are acrylamides and acrylates, which are reactive towards amines and thiols. Maleimides are the least reactive of the mentioned species and allow selective addition of thiols in the presence of amines in the pH range 6.5-7.5. However, hydrolysis of the imide, especially at elevated pH values [35], may be a concern for certain applications. The mentioned Michael addition reactions do not require organic solvents and can be carried out at physiological temperature and pH [36], In acidic conditions, the reaction is either very slow or does not proceed because protonation removes the nucleophilic form in the case of amines, and the thiolate anion is usually the active species in Michael additions involving thiols [25],... 

Fig. 2. Important reactions involved in the generation of thiol-maleimide links. All of these reactions proceed under neutral conditions. (A) Free sulfhydryl groups undergo additional reactions with maleimide groups. (B) Thioacetate protection groups may be hydrolyzed with hydroxylamine. (C) 2-Pyridyldisulfide protecting groups are reduced by DTT.

Scales, C.W. Convertine, A.J. McCormick, C.L. Fluorescent labeling of RAFT-generated poly(N-isopropylacrylamide) via a facile maleimide-thiol coupling reaction. Biomacromolecules 2006, 7 (5),... 

In a first article [17], the authors described the synthesis of AA (with furan-furan end groups) and AB (with furan-maleimide end groups) monomers using the thiol-ene reaction between 10-undecenoic acid and 2-furanmethanethiol. Monomers bearing two terminal furan rings were reacted with bismaleimides, and monomers bearing furan and maleimide end groups were self-polymerised as described in Chapter 7. 

A3 + B2 system), leading to branched or crosslinked materials iii) monomers incorporating furan and maleimide end groups (AiB or AB2 structures), which led to hyperbranched structures. In all cases, the thiol-ene reaction between 10-undecenoic acid and 2-furanmethanethiol was the main strategy to prepare the desired monomers. Corresponding DA polymerisations are discussed in Chapter 7. Scheme 6.5 illustrates the synthetic procedures adopted for all these monomers. 

Implementation of these concepts to polymers based on vegetable oils [8] started with a set of studies in which 10-undecenoic structures were converted into bis- and tri-furan monomers, as well as AB, AB2 and AiB homologous structures bearing furan and maleimide moieties [9-11]. Syntheses of these monomers were carried out using thiol-ene reactions in conjimction with more conventional couplings, as discussed in Chapter 6 (the mechanisms are illustrated in Scheme 6.5). 

A real synthetic strength of the TEC reaction is its versatility with respect to ene substrates that can be used and include both activated and nonactivaed species such as norbomenes, (meth)acryl-ates, maleimides, and allyl ethers to name but a few (Yu et al., 2009). Recent examples describing the application of the thiol-ene reaction in the polymer/materials eld include the use in thioether dendrimer synthesis (Killops et al., 2008), convergent star synthesis (Chan et al., 2008), synthesis of multifunctional branched organosilanes (Rissing and Son, 2008), and modi -cation/functionalization of wide range of polymers (Justynska and Schlaad, 2004 Killops et al., 2008). 

L. BUhet, O. Gok, A.P. Dove, A. Sanyal, L.T.T. Nguyen, P.E. Du Piez, Metal-free functionalization of linear polyurethanes by thiol-maleimide coupling reactions, Macromole-cnles 44 (October 25, 2011) 7874-7878. 

Figure 1.5 Bioconjugation of synthetic polymers by targeting thiols (cysteine residues) (a) Michael addition between thiols and maleimides, and (b) thiol-ene reaction. ...

Pounder, R.J., Stanford, M.J., Brooks, P. et al. (2008) Metal free thiol-maleimide Click reaction as a mild functionalisation strategy for degradable polymers. Chemical Communications, 5158. 

The coupling reaction proceeded smoothly under relatively mild conditions with the aldehyde/l,3-dione ratio near to 1 1. The reaction was monitored by gel permeation chromatography (GPC) and found to be completed within 3 h [33]. As reported in the literature, to produce a similar copolymer from two polymer chains via accepted click reactions (CuAAC, thiol-maleimide, etc.) typically takes from 4 h to 2 days, depending on various conditions such as room temperature [74, 102], heating [81, 100], or photomediation [101], Thus, the Biginelli reaction can stitch polymer chains together as efficiently as traditional click reactions. 

The Michael addition reaction of amines and thiols with bismaleimides or functionalized monomaleimides is a versatile tool ia the synthesis of chain-extended maleimide-terroinated prepolymers. These prepolymers generally are soluble ia organic solvents from which they can be processed to prepreg and molded to high quaUty, void-free laminates. 

The acrylic compounds, maleimides, dimaleimides, and thiols are known as direct cross-hnk promoters, since they enter directly into the cross-linking reaction and become interconnecting molecular links [243]. 

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