Thiol-yne addition

Click reactions are an attractive means to synthesize SCNPs due to their high efficiency, high functional group tolerance, and mild reaction conditions. Copper-mediated azide-allgme cycloaddition, thiol-ene addition, thiol-yne addition, and amine-isocyanate addition" click reactions have been used to synthesize cross-links and form SCNPs. 

This concept was refined by the research group of Li, who employed the thiol-yne reaction instead of the olefin cross-metathesis reaction as key step [60]. In this case, the carboxylic acid component served as anchor, whereby terminal alkynes were introduced by the remaining components (5-hexyn-l-al and propargyl isocyanoacetamide). Interestingly, thiol-yne addition of 3-mercaptopropionic acid to the pendant alkynes enabled not only the incorporation of further carboxylic acids, but also resulted in additional branching. Therefore, the second generation dendrimer, synthesized in three steps, exhibited 16 peripheral triple bonds. Moreover, this concept offers the opportunity to introduce structural diversity into the dendrimer architecture because the use of only one alkyne-functionalized compound in the Passerini-3CR still results in branching due to the thiol-yne reaction. Here, a structural sequence of employed phenylacetaldehyde and 2-nitrobenzaldehyde was demonstrated. 

Stereoselectivity of radical addition is not limited to sulfonyl radicals. The (rani-addition has also been observed for tin, bromine, chlorine, and silyl radicals. Varying degrees of selectivity has been observed for addition of carbon-centered radicals, depending on the substituents size and effect on the inversion barrier. Because the importance of negative hyperconjugation decreases for radicals in comparison to the anions, the barriers for inversion decrease in parallel. As a result, the selectivity can erode under conditions when trapping of the radical is slower than the equilibration, e.g. in the thiol-yne click reaction, which often provide a mixture of E and Z-vinyl sulfides. ... 

Nurmi et have attached a functional thiol by Michael addition TEC at a polymer chain end, followed by CuAAC reaction of the pendant alkynes from the monomer units, further demonstrating orthogonality between CuAAC and TEC. Yu etal have synthesized alkene- and alkyne-terminated PNIPAAm for reaction by thiol-ene, or the closely related thiol-yne, chemistry. These polymers were then functionalized with commercially available thiols, and NMR spectroscopy showed complete consumption of the allyl or propargyl protons with concomitant appearance of unique resonances for the added thiols. Integration of these peaks demonstrated that thiol-yne chemistry provided full double functionalization, while thiol-ene provided full stoichiometric conversion. 

The mechanism of the thiol-yne reaction resembles that of its thiol-ene sister. However, a second possible cycle involving further addition of a thiol into the remaining doublebond reaction is also possible in the thiol-yne version (Scheme 6.17) [49]. As a matter of fact, this second cycle is, by definition, a thiol-ene radical coupling. 

Only a few studies on oleochemistry have been reported until now. Similar to the effects seen with the thiol-ene reaction, one can take advantage of this interesting tool for the synthesis of novel monomers to be polymerised further by classical methods. Also, the possibility of two thiol groups reacting with one ethynyl group via two-step addition makes thiol-yne click polymerisation an interesting method for the preparation of hyperbranched polymers. 

Under radical-mediated conditions, a thiol also adds to a yne. The radical thiol-yne reaction can be considered as a sister reaction to the radical thiol-ene reaction because it possesses characteristics virtually identical to tiiose of the radical thiol-ene reactions. As with the thiol-ene reaction, the thiol-yne reaction, in general, proceeds rapidly under a variety of experimental conditions in an air atmosphere at ambient temperature and humidity, selectively yielding the mono or bisaddition products with little to no clean up required. In the case of the double addition products formed imder radical conditions, the reaction of two equivalents of thiol with a terminal alkyne is itself a two-step process (Fig. 12.32). The rst, slower, step 1 involves the addition of thiol to the CsC bond to yield an intermediate vinylic radical that subsequently imdergoes chain transfer to... 

TEP involves a stoichiometric reaction of a multifunctional olefin and a multifunctional thiol (e.g. thiol-vinyl ether, thiol-allyl ether, thiol-acrylate and thiol-yne). The reaction is a step-growth addition of the thiol to the double bond [1.46a]-[ 1.46c] formation of a thiyl radical, addition of the thiyl to the ene structure, regeneration of a thiyl, etc. termination occurs through recombination and disproportionation reactions. 

Figure 2.10 (a) The UV-promoted radical addition of thiols to alkynes - the thiol-yne reaction (b) kinetics of the thiol-yne reaetion monitored via FT-IR spectroscopy (Chan et ai, 2009a). DMPA 2,2-dimethoxy-2-phenylacetophenone. (Reprinted with permission from J.W. Chan, C.E. Hoyle and A.B. Lowe, Sequential phosphine-eatalyzed, nucleophilic thiol-ene/radical-mediated thiol-yne reactions and the facile orthogonal synthesis of polyfunctional materials, Journal of the American Chemical Society, 131, 16, 5751-5753, 2009. 2009 American Chemical Society.)... 

Cu A AC) (Johnson et at, 2008), historically the first one that has been given this name, is up to now the most apphed method. However, despite the popularity of this reaction on a lab scale, its widespread use is limited by the presence of a cytotoxic transition metal and the need for potentially explosive azides. For that reason, a range of copper-ftee click approaches are now intensively studied, including thiol-ene/yne addition reactions and (ultrafast) hetero-Diels— Alder cycloaddition (HDA) reactions, which are believed to have great potential to become as popular as the CuAAC in the click chemistry toolbox (Lutz, 2008 Becer et ai, 2009). 

B2) were synthesized. Subsequently, hyperbranched polymers were formed by a thiol-yne click reaction under UV radiation at room temperature, whereby yields over 95% were reached within less than 2 h (Figure 8.9). Furthermore, the reaction was applied to RAFT polymerized linear polymers bearing an alkyne and a thiol group at the a and co end of the polymer, allowing subsequently formed hyperbranched polymer to incorporate additional functionalities. 

As with all condensation reactions, thiol-ene polymerizations are sensitive to the stoichiometry of the thiol- and ene-containing monomer substrates. Typically, the best results are obtained when there is a molar equivalent concentration of thiol and double bonds present. Recently, there has been a considerable effort to extend the photoinduced radical addition of thiols to alkynes (the so-called thiol-yne reaction). 

The thiol-yne coupling reaction is versatile, robust and can tolerate different functional groups due to its radical nature. It allows facile addition of two thiols to one alkyne group, which is suitable for constmction of complex polymer structures such as networks, dendrimers and hyperbranched polymers [63, 64]. Successful glycosylation of Unear polymers and dendrimers can be performed via radical-... 

Pdtzsch R, Komber H, Stahl BC, Hawker CJ, Voit BI (2013) Radical thiol-yne chemistry on diphenylacetylene selective and quantitative addition enabling the synthesis of hyperbranched poly(vinyl sulfide)s. Macromol Rapid Commnn 34 1772-1778... 

Pdtzsch R, Stahl BC, Komber H, Hawker CJ, Voit BI (2014) High refractive index polyvinylsulfide materials prepared by selective radical mono-addition thiol-yne chemistry. Polym Chem 5 2911-2921... 

Thiol-yne radical reactions follow a similar initiation step to that of thiol-ene reactions. After the initial addition of a thiol to the alkyne and formation of a vinyl radical with a P-thioether function, a hydrogen abstraction from another thiol molecule generates a new thiyl radical. Subsequent addition of a thiyl radical on the vinyl thioether forms another carbon radical, which abstracts a hydrogen from another thiol molecule to give a 1,2-dithioether, and the thiyl radical generated reenters the chain process (Scheme 1.11). The addition of the first thiol to the alkyne is the rate-limiting step, and the second thiol addition to the intermediate thiol-alkene is a faster step. Studies revealed that the second addition is approximately three times faster than the first addition [45]. 

In short, the thiol-yne radical click reaction is the formation of a 1,2-dithioether through double addition of thiols on to an alkyne. The reaction has largely been used to generate multifunctional polymer structures. Repetitive thiol-yne reactions are used to form multifunctional molecules, which are further used to make dendrimers [42] or hyperbranched polymers [46]. 

In reaetions with nueleophilie reagents diaeetylene behaves as aeetylene aeti-vated with aeeeptor group that is eommon to eonjugated polyynes. Therefore, the nueleophilie addition of amines, aleohols, and thiols oeeurs to its terminal position and leads to the formation of the eorresponding l-heteroalk-l-en-3-ynes readily involved in diverse eyelization reaetions. 

As mentioned in the introduction, l-heterobut-l-en-3-ynes, RXCH=CHC=CH (X = RN, O, S R = organic radical), are the nearest and most important diacetylene derivatives readily formed by nucleophilic addition of amines, alcohols, and thiols to diacetylene. In many heterocyclization reactions (especially those leading to fundamental heterocycles) l-heterobut-l-en-3-ynes behave as diacetylene synthetic equivalents, but unlike diacetylene, they are nonhazardous. Therefore, the syntheses of heterocycles therefrom are often more attractive in preparative aspect. 

Michael addition of pentM-yn-1-thiol to an activated alkyne produces co-yne vinylsulfides 424 as a separable mixture of the E and Z isomers. On treatment with -Uu (SnI I and a radical initiator, these substrates undergo a double radical cyclization accompanied by [(-fragmentation of the stannyl radical. The process is regio-, chemo-, and stereo-selective and produces the -isomer of the 5-substituted 3,4-dihydm-2//-thiopyran (Scheme 134) <1997JOC8630>. 

Alkynes react with thiols to give vinyl sulfides. With alkynes it is possible to add 1 or 2 equivalents of RSH, giving a vinyl sulfide or a dithioketal, respectively. Alternative preparations are available, as in the reaction of a terminal alkyne with Cp2Zr(H)Cl followed by PhSCl to give the vinyl sulfide with the SPh unit at the less substituted position (PhCH=CHSPh). The intramolecular addition of a thiol to an ene-yne, with a palladium catalyst, leads to substituted thiophene derivatives. ... 

Addition of thiols, with and without basic catalysis, occurs by nucleophilic attack at the non-fluorinated termini of 3,3,3-trifluoropropyne, 1,1,1-tri-fluoropent-2-yne, and AW-diethyltrifluoropropynylamine. It was noted that addition of alkoxide catalyst led to further nucleophilic attack by a second thiolate anion, e.g. 

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