Amine-thiol-ene conjugation

Encouraged by the successful model reaction, implementation of the radical amine-thiol-ene conjugation in synthetic polymer science was envisaged. Consequently, several AB -type monomers containing both a double bond and a thiolactone unit were prepared. Upon aminolysis, these monomers form a reactive thiol-ene, which is consumed in the same medium in a stepwise polyaddition. It is clear that the nature of the introduced double bond and chemical linkage (amide, urethane, etc.) connecting the thiolactone and double bond determine both the reaction conditions and outcome of the two-step process, as well as the final properties of the synthesized polymers. 

Two different AB monomers, susceptible to radical amine-thiol-ene conjugation, were synthesized and successfully used in a photopolymerization, yielding linear polymers with either a pol3 thioether/pol3mrethane [48] or a polythioether/ polyamide backbone [48, 55]. 

However, conceptual issues directly related to the radical reaction in the one-pot process partially impede extension of the scope of the radical amine-thiol-ene conjugation. First, some functional groups (e.g., furan [119-123], double and triple bond) introduced via the amine are incompatible with this radical environment. Additionally, UV curing takes place upon decomposition of a photoinitiator (e.g., DMPA), but model studies revealed that some amines (e.g., benzylamine) react with the formed radical fragments, thus limiting the use of a photoinitiator [48]. 

In addition to the radical amine-thiol-ene conjugation, the one-pot combination of aminolysis of a thiolactone unit and a nucleophilic thiol-ene conjugation (Michael addition) (Scheme 5, pathway b) was explored. The Michael addition between a nucleophile (e.g., thiol, amine, or stabilized carbanion) and an activated double bond (e.g., imidazole, acrylate, vinyl sulfone) is often the key step in polymer... 

Double PPM of Poly thiolactone s One-Pot Process Through Nucleophilic Amine-thiol-ene Conjugation... 

The second approach for site-specific double PPM was performed using the polythiolactones prepared by random RAFT copolymerization of NIPAAM and thiolactone acrylamide monomer 7 (Scheme 12) [52]. The respective copolymers were subjected to additive-free nucleophilic amine-thiol-ene conjugation. A chloroform solution of the poly thiolactone at a concentration of 10 wt% was treated with the desired acrylate, followed by addition of the primary amine. Both reagents were used in a fivefold excess with respect to the number of thiolactone units (Scheme 15). 

Scheme 15 Double PPM of thiolactone-containing linear polymers in a one-pot approach using nucleophilic amine-thiol-ene conjugation...

The simplicity of the approach in terms of experimental set-up, together with the mild reaction conditions and the almost endless choice of amine/acrylate combinations, render the nucleophilic amine-thiol-ene conjugation a powerful and versatile PPM tool for site-specific double modification. The possibility for simultaneous introduction of chemical functionalities and solubility modulators provides paths to multifunctional tailor-made materials. 

An alternative route to disulfide formation is a thiol-disulfide exchange reaction [160, 167, 168] in the presence of a 2,2 -dipyridyl disulfide(or derivative) as a reactive disulfide. Two very recent studies revealed that the thiol-disulfide exchange reaction (pathway c in Scheme 5) offers better selectivity and control over the disulfide formation process. Moreover, the obtained mixed disulfide remains reactive towards thiols for further modification. In contrast to the above-described amine-thiol-ene conjugation, this approach is not 100% atom-efficient because 2-mercaptopyridine (or a derived structure) is released in the reaction medium. Monteiro and coworkers synthesized multifunctional nanostructures (worms and rods) with multiple chemical functionalities directly in water using a one-step RAFT-dispersion polymerization. The introduced functional handles originate from their presence in the R group on the CTA. In the case of thiolactone worms and rods, aminolysis with allylamine and subsequent one-pot scavenging of... 

Both variants of this one-pot two-step reaction sequence, following either the radical or nucleophilic pathways, are applicable, although the radical version has some limitations because of orthogonality issues when using functionalized amines. The nucleophilic amine-thiol-ene conjugation is particularly attractive because this 100% atom-efficient polymerization is a very mild process, occurring at ambient conditions without any additive or external trigger. 

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). 

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