Naked and Self‐Clickable Propargylic‐Decorated Single‐Chain Nanoparticle Precursors via Redox‐Initiated RAFT Polymerization

Abstract

Protection of acetylenic monomers is a common practice to avoid parasitic side reactions during polymerization. Herein we report that redox initiated RAFT polymerization allows the direct, room temperature synthesis of a variety of single-chain nanoparticle precursors (displaying narrow molecular weight dispersity, M w / M n = 1.12 -1.37 up to M w = 100 kDa) containing well-defined amounts of naked, unprotected acetylenic functional groups available for rapid and quantitative intrachain crosslinking via metal-catalyzed carbon-carbon coupling (i.e. C-C "click" chemistry). To illustrate the useful "self-clickable" character of the new unprotected acetylenic precursors, single-chain nanoparticles have been prepared for the first time in a facile and highly-efficient manner by copper-catalyzed alkyne homocoupling (i.e.Glaser-Hay coupling) at room temperature under normal air atmosphere. a Supporting information for this article is available at the bottom of the article's abstract page, which can be accessed from the journal's homepage at http://www.macros.wiley-vch.de, or from the author.-2 - IntroductionAtom economy and waste reduction are two concepts emanating from green chemistry philosophy affecting current macromolecular synthesis strategies. [1,2] In addition, polymer versatility is increasingly imposed by several emerging Nanotechnology and Nanomedicine end-use applications (e.g. nanoimprinting lithography, theranostic nanomedicines). A good example is the synthesis of well-defined statistical copolymers with protected functional groups as precursors of individual, unimolecular nanoparticles through intrachain crosslinking. Single-chain nanoparticles are emerging soft nanomaterials with promisingproperties for different end-use applications such as processing additives, [3] blend compatibilizers, [4] artificial enzymes, [5] photostable bio-imaging agents [6] and drug / siRNAdelivery systems, [7] among others. Different routes for the synthesis of single-chain nanoparticles with size below 20 nm have been progressively introduced relying either on covalent [8] or noncovalent [9] intrachain crosslinking. Nevertheless, still a lack of nearly monodisperse precursors arising from commercial unprotected monomers allowing facile single-chain nanoparticle synthesis via highly-efficient functional group homocoupling (i.e."self-click" chemistry) persists.Among others, the acetylenic moiety has revealed as one of the more versatile functional groups in organic chemistry [10] showing multiple functionalization possibilities, spanning from old Glaser coupling [11] to relatively recent "click" chemistry procedures.[12] For linear macromolecular synthesis, however, protection of the acetylenic triple bond has been often necessary to avoid the alkyne side group to be involved in branching events and chain transfer reactions during radical polymerization. D´Lalelio and Evers [13] first reported that insoluble, crosslinked polymers were formed during radical polymerization of (metha)acrylic ester monomers containing acetyle...

Dynamic Single Chain Polymeric Nanoparticles: From Structure to Function

“…In non-dynamic SCPNs, intramolecular crosslinks are formed by covalent bond formation while in dynamic SCPNs the crosslinks consist of non-covalent or dynamic covalent bonds. In non-dynamic SCPNs, many different types of covalent bond formation have been applied successfully for the intramolecular crosslinking of the polymers (16)(17)(18)(19)(20)(21)(22)(23). In dynamic SCPNs, reversible covalent bonds such as disulfides (24) or acyl hydrazones (25) have been utilized as well as non-covalent bonds such as diamides (26), 2-ureido-pyrimidinones (UPys) (27), benzene-1,3,5-tricarboxamides (BTAs) (28), a combination of BTAs and UPys (29), BTA-bipyridines (30), cucurbit [8]uril (31), thymine-diaminopyridine (32), six-point cyanuric acid-Hamilton wedge interactions (33) and a combination of the last two (34).…”

Self-assembly of random copolymers

“…83, 84 Another interesting approach in intrachain homocoupling for SCNP formation has been applied by using alkyne functional groups that were activated in a rapid and highly efficient manner at room temperature. 85 Similarly, the self-assembly behaviour of linear poly(MMA- co -PgA) has been used to achieve SCNPs via metal-catalyzed C-C click covalent interactions. In addition, copper-catalyzed azide-alkyne cycloaddition, the so-called click chemistry, has also been used for the synthesis of bioconjugable poly(methyl methacrylate)-based single-chain nanoparticles.…”

Advances in Click Chemistry for Single-Chain Nanoparticle Construction

“…Covalent bonding interactions Vinyl [33,38,39,42] Radical coupling & Cross-Metathesis Benzocyclobutene [40,53] Diels-Alder reaction * Benzosulfone [9,28,41] Diels-Alder reaction * Azide + Protected alkyne [3,10,21,22,30,34] Copper-catalyzed [3+2] cycloaddition ** Carboxilic acid [54] Amide formation Isocyanate [23] Urea formation ** Enediyne [11,12,24,29] Bergman & Photo-Bergman cyclization Sulfonyl azide [31] Nitrene-mediated cross-linking Benzoxazine [36] Ring opening polymerization Alkyne [25] Glaser-Hay coupling * * C-C click chemistry. ** N-C click chemistry.…”

“…Further refinements of this technique were performed by Croce et al [28] in 2007 by introducing benzosulfone reactive groups instead of BCB moieties (see Figure 3) and by Dobish et al [53] in 2012 by developing substituted BCB functional groups reactive at lower temperatures (150 °C) (see Figure 4). A very recent breakthrough in intrachain homocoupling for single-chain nanoparticle formation has been the use of Glaser-Hay coupling (i.e., alkyne homocoupling) by Sanchez-Sanchez et al [25] involving naked, self-clickable alkyne functional groups that were activated in a rapid and highly efficient manner at RT, under oxygen atmosphere, in tetrahydrofuran (see Figure 5). This metal-catalyzed C-C click chemistry technique was possible thanks to the successful synthesis via redox-initiated RAFT polymerization of single-chain nanoparticle precursors containing well-defined amounts of naked acetylenic functional groups available for intrachain metal-catalyzed C-C coupling.…”