Thiol-maleimide addition reaction

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. 

Scheme 2 Michael addition reaction of acrylates, vinylsulfones, and maleimides with thiol...

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.

Several PEG reagents are available for site-specific PEGylation with protein cysteine thiols. mPEG-maleimide reacts to form a stable sulfide linkage via a 1,4-addition reaction of the thiol to the a,) -unsaturated site on the maleimide moiety [24]. 

For a carbohydrate microarray, a glass slide is modified by the thiol group as solid support. Carbohydrates in the form of glycosylamines are converted into maleimide via a hydrocarbon tether chain and covalently bound to the glass surface by hetero-Michael addition reaction (Park and Shin, 2(X)2) between the thiol group and the maleimide moiety of the glycosyl derivative (Fignre 14.4C). 

The stereochemistry of the thiol is important. Steiic effects have been used to explain the differences in rates of reactivity of RCjHiSH (R = H, 2-/-Bu, 4-/-Bu) in addition reactions with N-ethyl maleimide or displacement of 2,4-(02N)2C,H8S- from 2,4-(03N)2q,H3SSEt ... 

Non-peptide self-assembly stractures for cell immobilization can also be created using Watson-Crick base pairing principle. Four-arm (star-shaped) PEG end terminated with thiol thymine (T-SH) and thiol adenine (A-SH) was synthesized using maleimide via Michael-type addition reaction, which formed hydrogel via intermo-lecular hydrogen bonding of nucleotide base pairs. This hydrogel was successfully used to encapsulate adipose-derived stem cells (ASCs) [69],... 

Michael addition reactions alcohols with maleates, 46 with fumarates, 63 MA with acetylacetone, 235 MA derivatives, 65, 66 in maleamic acid cyclization, 83 with maleates, 63 maleates with thiols, 506 maleic anhydride, 65, 229 maleimides with amines, 512 Mitsubishi process, MA production, 29... 

Michael addition is a facile reaction between nucleophiles and activated olefins and alkynes in which the nucleophile adds across a carbon-carbon multiple bond [25], For the preparation of hydrogels, the hydroxyl, thiol or amine functionalities have been reacted with vinyl sulfones [26-28], acrylates [29-31], acrylamides [32], and maleimides [33, 34] (Scheme 2). 

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