Thiol-isocyanate reaction

Scheme 2.4 Step-growth polymerization via the thiol-isocyanate reaction, yielding poly(thiourethane)s. (Reproduced with permission from AJ. Inglis and C. Bamer-Kowollik, Ultra rapid approaches to mild macromolecular conjugation, Macromolecular Rapid Communications, 2010, 31, 14, 1247-1266. Wiley-VCH Verlag GmbH Co. KGaA.)...

The use of the base-catalyzed thiol-isocyanate reaction in the quantitative preparation of m-end functional polymers was also recently reported (Li et al, 2009). Here, RAFT polymerization was used to prepare poly (A, N- diethylacrylamide), the dithioester end group of which was transformed into a thiol moiety by aminolysis. Subsequent end-group modification of the resulting thiol-terminated polymer was achieved in an overnight, ambient temperature and oxygen-free reaction with one of a collection of commercially available isocyanates in the presence of triethylamine (Figure 2.11a). 

It is important to note that the thiol-isocyanate reaction is not orthogonal to the base-catalyzed Michael addition of thiols to alkenes, as was observed by Lowe when attempting to conjugate 2-isocyanoethyl methacrylate, although this system still showed significant selectivity towards the thiocarbamate adduct (Li et al, 2009). Furthermore, it should be noted that isocyanates are very reactive (and toxic) compounds that can react with hydroxyl functionality. 

Figure 2.11 (a) Aminolysis of a polymer chain formed via RAFT polymerization and reaction of the resulting thiol with an isocyanate - the subsequent treatment with tris(2-carboxyethyl)phosphine (TCEP) is to regain thiol-capped polymers from possible disulfide species (b) real-time kinetics of the thiol-isocyanate reaction, monitored by FT-IR spectroscopy (Li et at., 2009). (Reprinted with permission from H. Li, B. Yu, H. Matsushima et aL, The thiol-isocyanate click reaction Lacile and quantitative access to omega-end-functional poly(N,N-diethylacrylamide) synthesized by RALT radical polymerization, Macromolecules, 42, 17, 6537-6542, 2009. 2009 American Chemical Society.)... 

Shin, J., Matsushima, H., Chan, J.W., and Hoyle, C.E. (2009) Segmented polythiourethane elastomers through sequential thiol-ene and thiol-isocyanate reactions. Macromolecules, 42,3294. 

In the presence of catalytic amount of a base (such as triethylamine (NEtj)), thiols are deprotonated to thiolate anions, which react with isocyanates forming thiourethanes. The thiol-isocyanate reaction is fast and proceeds readily without any side product even in the presence of water, alcohol, or amines. The most common base used for this reaction is l,5-diazabicyclo(4.3.0)non-5-ene (DBN). The reaction has the potential to be used more often as a very effective conjugation method (Scheme 1.14). 

Another type of activated double bond is found in isocyanates and isothiocyanates. Methylisocyanate was responsible for a disaster in Bhopal, India, in 1984 when approximately 40 tons of the gas were accidentally released leading to the death of thousands of people and injury to many more. Some have called this the worst industrial accident in history. Methylisocyanate reacts with nucleophiles as shown in Figure 8.18—in this case with a thiol. This reaction is reversible, and therefore a glutathione conjugate can act to... 

The isocyanate group is very reactive and will condense with other active compounds containing hydrogen, like amines and thiols. Products resulting from such reactions, respectively, are the ureas and thiocarbamates. With amines the rate of reaction is somewhat faster than with hydroxyl compounds, while that with thiols is slower. However, a wide variety of catalyst systems (many based on amines and organometallic compounds) is available for the acceleration of isocyanate reactions. 

Iwakura and Okada 64) interpret the mechanism and kinetics of the fert-amine catalyzed reactions of isocyanates with n-butanethiol and n-dodecanethiol somewhat differently. They found that the catalyzed reaction was strictly first order with respect to the thiol, isocyanate, and... 

R.M. Hensarling, S.B. Rahane, A.P LeBlanc, B.J. Sparks, E.M. White, J. Locklin, et al.. Thiol-isocyanate chck reactions rapid development of functional polymeric surfaces, Polym. Chem. 2 (2011) 88-90. 

Extrapolating from this work, Hoyle and colleagues combined this chemistry with thiol-ene reactions to achieve segmented polythiourethane elastomers (Shin et al, 2009). A simple mixing of di-thiol prepolymer, diisocyanate linker and a catalytic amount of triethylamine (0.03-0.1 wt%) resulted in 95% conversion of the isocyanate within 10 min. 

Li, H.B., Yu, B., Matsushima, H. et al. (2009) The thiol-isocyanate cUck reaction facile and quantitative access to omega-end-functional poly(N,N-diethylacrylamide) synthesized by RAFT radical polymerization. Macromolecules, 42,6537. 

Thiol groups can react with many chemical species with high yields under benign conditions and thus many thiol-related reactions, such as thiol-ene, thiol-yne, thiol-epoxy, thiol-isocyanate and thiol-halogen reactions, are considered to be chck-type reactions [63]. 

Hensarling RM, RahaneSB, LeBlanc AP, Sparks BJ, White EM, Locklin J, Patton DL (2011) Thiol-isocyanate click reactions rapid development of functional polymeric surfaces. Polym Chem 2 88-90... 

Polyurethanes are extremely versatile polymeric materials due to their elasticity, responsive nature toward impact, stretchability, and other possible physical manipulations. They have been utilized in various fields to make optical devices, adhesives, coatings, and also in many biomedical applications. Thiol-isocyanate click reactions have been used to generate polythiourethanes, a sulfur analog of polyurethane, in a very efficient way and in high yields [50]. 

Scheme 1.14 Tertiary-amine-catalyzed thiol-isocyanate click reaction.

Thiocarbamates, formed by reaction of a thiol with an isocyanate, are stable in acidic and neutral solutions and are readily cleaved by basic hydrolysis. The... 

A series of reactions was developed to transfer amines to ureido- and thioureido-derivatives for separation. The reaction of ureido-derivatives is widely used by the reaction with 1-phenylethyl isocyanate (PEIC) [8] or the naphthyl-analogue 1-(1-naphthyl)ethyl isocyanate (NEIC) [9]. Both reactions can be used not only for chiral amines but also for alcohols and thiols. 

Ketenes easily add water,alcohols, amines and thiols to give derivatives of phosphorylated carboxylic acids ( -7). Phosphorylated ketenes undergo reactions of cyclo"aadition to vinyl ethers,diazomethane,styrene, cyclopentadiene, etc. From phosphorylated ketenes other phosphorylated cumulenes can be obtained,for example allenes,isocyanates,ketenimines... 

The toxicity of methyl isocyanate comes as a surprise if its high sensitivity to hydrolysis is considered. But actually, it may reach its site of action in the human body largely undecomposed. This is due to the reversible addition of another nucleophile to this heterocumulene. The tripeptide gluthathione, which is supposed to protect the body against oxidizing agents, adds to the C=N double bond of the isocyanate by means of its thiol group whereby the thio-carbamate is formed. When the latter decomposes in a reversal to its formation reaction, it releases the intact toxic methyl isocyanate. 

Scavenger resins and polymer-bound reagents are routinely used to prepare medium-sized (500-1000 member) libraries. Polymer-bound isocyanates (9) and aldehydes (10) are used to remove amines from reaction mixtures, while polymer-bound thiols (11) are used to scavenge halides. 

Isocyanates react rapidly with thiol, amine, or hydroxyl groups resulting in thiourea, urea, and carbamate linkages, respectively (Scheme 9). Without the use of catalysts, the reaction is fastest for thiols that are most nucleophilic, followed by amines and alcohols. 

The isocyanate, SF5NCO, is easily hydrolyzed to SF5NH2 and C02, whereas SF5NCS is hydrolytically very stable. Both compounds undergo addition reactions with substrates containing easily replaceable hydrogen atoms, i.e., alcohols, thiols, and amines. With alcohols (thiols) the isocyanate and isothiocyanate give urethanes and thiourethanes, respectively. 

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