We report a novel strategy for the high-efficiency preparation of macrocyclic diblock copolymers at relatively high concentrations via the combination of supramolecular self-assembly and "selective" click reactions, relying on the fine control of spatial accessibility between terminal reactive groups. The linear precursor, alpha-alkynyl-omega-azido heterodifunctional poly(2-(2-methoxyethoxy)ethyl methacrylate)-b-poly(oligo(ethylene glycol) methyl ether methacrylate), linear-PMEO(2)MA-b-POEGMA-N(3), self-assembles into micelles with PMEO(2)MA cores and POEGMA coronas at elevated temperatures. The spatial separation between reactive alkynyl and azide groups precludes click reactions within micelle entities. On the other hand, due to the unimer-micelle exchange equilibrium and the fact that unimer concentration is typically low (critical micellization concentration, CMC), click reactions occur exclusively for unimers. This eventually led to complete intramolecular cyclization of all linear precursors.

Two novel double hydrophilic multiblock copolymers of N,N-dimethylacrylamide and N-isopropylacrylamide, m-PDMAp-PNIPAMq, with varying degrees of polymerization (DPs) for PDMA and PNIPAM sequences (p and q) were synthesized via consecutive reversible addition-fragmentation chain transfer (RAFT) polymerizations using polytrithiocarbonate (1) as the chain transfer agent (Scheme 1), where PDMA is poly(N,N-dimethylacrylamide) and PNIPAM is poly(N-isopropylacrylamide). The DPs of PDMA and PNIPAM sequences were determined by 1H NMR, and the block numbers, i.e., number of PDMAp-PNIPAMq sequences (n), were obtained by comparing the molecular weights of multiblock copolymers to that of cleaved products as determined by gel permeation chromatography (GPC). m-PDMA42-PNIPAM37 and m-PDMA105-PNIPAM106 multiblock copolymers possess number-average molecular weights (Mn) of 4.62x10(4) and 9.53x10(4), respectively, and the polydispersities (Mw/Mn) are typically around 1.5. Block numbers of the obtained multiblock copolymers are ca. 4, which are considerably lower than the numbers of trithiocarbonate moieties per chain of 1 (approximately 20) and m-PDMAp precursors (approximately 6-7). PDMA homopolymer is water soluble to 100 degrees C, while PNIPAM has been well known to exhibit a lower critical solution temperature (LCST) at ca. 32 degrees C. In aqueous solution, m-PDMA42-PNIPAM37 and m-PDMA105-PNIPAM106 multiblock copolymers molecularly dissolve at room temperature, and their thermo-induced collapse and aggregation properties were characterized in detail by a combination of optical transmittance, fluorescence probe measurements, laser light scattering (LLS), and micro-differential scanning calorimetry (micro-DSC). It was found that chain lengths of PDMA and PNIPAM sequences exert dramatic effects on their aggregation behavior. m-PDMA105-PNIPAM106 multiblock copolymer behaves as protein-like polymers and exhibits intramolecular collapse upon heating, forming unimolecular flower-like micelles above the thermal phase transition temperature. On the other hand, m-PDMA42-PNIPAM37 multiblock copolymer exhibits collapse and intermolecular aggregation, forming associated multimolecular micelles at elevated temperatures. The intriguing aggregation behavior of this novel type of double hydrophilic multiblock copolymers argues well for their potential applications in many fields such as biomaterials and biomedicines.

We report the synthesis of quatrefoil-shaped star-cyclic polystyrene, star-cyclic PS, containing a polyhedral oligomeric silsesquioxane (POSS) core via the combination of atom transfer radical polymerization (ATRP) and click chemistry techniques. The obtained star-cyclic PS represents a new chain topology in the category of nonlinear-shaped polymers. Using octa(3-chloropropyl) polyhedral oligomeric silsesquioxane, POSS-(Cl)8, as the starting material, its azidation and subsequent click reaction with a slight excess of propargyl 2-bromobutyrate afforded octafunctional initiator, POSS-(Br)8. 8-arm star-linear PS-N 3 was obtained by the azidation of star-linear PS-Br, which was synthesized by the ATRP of styrene using POSS-(Br)8 as the initiator. Model reaction between α,ω-diazido-terminated PS (N 3-PS-N 3) and difunctional propargyl ether confirmed that bimolecular click cyclization reaction can effectively occur under highly dilute conditions. Next, intramolecular click ring closure of star-linear PS-N 3 was conducted under highly dilute conditions, using propargyl ether as the difunctional linker and CuBr/PMDETA as the catalyst, affording quatrefoil-shaped star-cyclic PS. Gel permeation chromatography (GPC), 1H NMR, and FT-IR analysis confirmed the complete consumption of azide moieties in star-linear PS-N 3 and that the coupling reaction proceeded via the intramolecular manner. Differential scanning calorimetry (DSC) results revealed that star-cyclic PS possesses higher glass transition temperature (T g) than that of star-linear PS, possibly due to the ring topology of PS arms in the former.

Two oppositely charged graft ionomers, P(MAA-co-AzPMA)-g-PNIPAM and P(QDMA-co-AzPMA)-g-PNIPAM, containing thermosensitive PNIPAM graft chains were successfully synthesized via a combination of atom transfer radical polymerization (ATRP) and “click” reactions, where PAzPMA, PMAA, PNIPAM, and PQDMA are poly(3-azidopropyl methacrylate), poly(methacrylic acid), poly(N-isopropylacrylamide), and poly(2-(dimethylamino)ethyl methacrylate) (PDMA) fully quaternized with methyl iodide, respectively. In aqueous solution, polyelectrolyte complexation between negatively charged backbone of P(MAA-co-AzPMA)-g-PNIPAM and positively charged backbone of P(QDMA-co-AzPMA)-g-PNIPAM leads to the formation of polyion complex (PIC) micelles consisting of polyion complex cores and thermoresponsive PNIPAM coronas. Upon addition of a difunctional cross-linker, propargy ether, PIC micelles can be facilely cross-linked via “click” reactions. The obtained covalently core-stabilized PIC micelles exhibit permanent stability against the addition of NaCl and pH changes, which are drastically different from that of non-cross-linked PIC micelles. Moreover, these novel types of stable PIC micelles exhibit thermoinduced dispersion/aggregation due to the presence of PNIPAM coronas, suggesting that their physical affinity to external substrates can be tuned with temperature. They might act as stable nanocarriers of charged compounds or highly efficient nanoreactors of polar compounds in the field of pharmaceutical formulation or biotechnology.

Double hydrophilic diblock copolymer, poly(N,N‐dimethylacrylamide)‐b‐poly(N‐isopropylacrylamide‐co‐3‐azidopropylacrylamide) (PDMA‐b‐P(NIPAM‐co‐AzPAM), containing azide moieties in one of the blocks was synthesized via consecutive reversible addition‐fragmentation chain transfer polymerization. The obtained diblock copolymer molecularly dissolves in aqueous solution at room temperature, and can further supramolecularly self‐assemble into core‐shell nanoparticles consisting of thermoresponsive P(NIPAM‐co‐AzPAM) cores and water‐soluble PDMA coronas above the lower critical solution temperature of P(NIPAM‐co‐AzPAM) block. As the micelle cores contain reactive azide residues, core crosslinking can be facilely achieved upon addition of difunctional propargyl ether via click chemistry. In an alternate approach in which the PDMA‐b‐P(NIPAM‐co‐AzPAM) diblock copolymer was dissolved in a common organic solvent (DMF), the core‐crosslinked (CCL) micelles can be fabricated via “click” crosslinking upon addition of propargyl ether and subsequent dialysis against water. CCL micelles prepared by the latter approach typically possess larger sizes and broader size distributions, compared with that obtained by the former one. In both cases, the obtained (CCL) micelles possess thermoresponsive cores, and the swelling/shrinking of which can be finely tuned with temperature, rendering them as excellent candidates as intelligent drug nanocarriers. Because of the high efficiency and quite mild conditions of click reactions, we expect that this strategy can be generalized for the structural fixation of other self‐assembled nanostructures. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 860–871, 2008

The pH-induced micellization kinetics of poly(glycerol monomethacrylate)-b-poly(2-(dimethylamino)ethyl methacrylate)-b-poly(2-(diethylamino)ethyl methacrylate) (PGMA-b-PDMA-b-PDEA) in the presence of salt (NaCl) was investigated by stopped-flow light scattering and fluorescence, and the results were compared to those obtained with salt-free solutions. Upon jumping from pH 4 to 12, this triblock copolymer forms micelles that consist of a central PDEA core, shielded by a PDMA inner shell and a PGMA outer corona. For micelle formation in the presence or absence of salt, all relaxation curves recorded by stopped-flow light scattering can be well fitted with a double-exponential function, leading to a fast relaxation time constant (τ 1 ) and a slow relaxation time constant (τ 2 ). The fast process (τ 1 ) is associated with the formation of quasi-equilibrium micelles, while the slow process (τ 2 ) is associated with micelle formation-breakup, approaching the final equilibrium state. Both processes occur much more slowly on initial addition of NaCl and then level off at higher salt concentrations (>0.5 M NaCl). The concentration dependence of τ 2 revealed that the mechanism of micelle formation/breakup process transforms from unimer insertion/expulsion in the absence of salt to micelle fusion/fission in the presence of high NaCl concentrations. This is because the PGMA corona and PDMA inner are less highly hydrated and the PDEA core is more compact in the presence of salt, thus favoring micelle fusion/fission instead of unimer insertion/expulsion. Relaxation curves obtained with stopped-flow fluorescence using pyrene as a probe can be well-fitted with a single-exponential function, and the relaxation time (τ py ) was in agreement with τ f , the relaxation time of the overall micellization process as detected by stopped-flow light scattering. Compared to the kinetics obtained with salt-free solutions, the micelle dissociation kinetics in the presence of salt resulting from a pH jump from 12 to 4 reveals a drastically different two-stage process with the two stages separated by a delay time of a few seconds.

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A series of thermoresponsive double hydrophilic (AB)(n) multiblock and ABA triblock copolymers of N,N-dimethylacrylamide (DMA) and N-isopropylacrylamide (NIPAM) with varying sequence lengths were synthesized via successive reversible addition-fragmentation chain transfer (RAFT) polymerizations by employing polytrithiocarbonate as the chain transfer agent. Previously, we reported that multiblock copolymers in dilute aqueous solutions can form either unimolecular or multimolecular micelles at elevated temperatures depending on the relative chain lengths of PDMA and PNIPAM sequences (Zhou et al. Langmuir 2007, 23, 13076-13084). In this follow-up work, we further explored and compared the chain architectural (multiblock vs triblock) and Hofmeister effects (addition of various sodium salts) on the gelation behavior of multiblock and ABA triblock copolymers at high concentrations and attempted to establish a correlation between the aggregation behavior and gelation properties of multiblock copolymers at low and high polymer concentrations, respectively. It was found that only m-PDMA(p)-PNIPAM(q) multiblock copolymers with PDMA and PNIPAM sequence lengths located within a specific range can form physical gels at elevated temperatures. Rheology measurements revealed that multiblock copolymers possess considerably lower critical gelation temperatures (CGT) and higher gel storage modulus, G'(gel), as compared to those of PNIPAM-b-PDMA-b-PNIPAM triblock copolymers possessing comparable sequence lengths. The addition of inorganic sodium salts can effectively facilitate thermogelling for multiblock and triblock copolymers, resulting in decreasing CGTs and critical gelation concentrations (CGCs) in the order of Hofmeister series with increasing hydration capabilities. The unique thermogelling behavior of aqueous multiblock copolymer solutions in the absence and presence of inorganic salts, as compared to that of ABA triblock copolymers, augurs well for their potential applications in various fields such as biomaterials and biomedicines.