Mechanistic insights into trithiocarbonate degradation during the RAFT polymerization of N-arylmethacrylamides are reported. Previous work by our group showed significant RAFT agent degradation during the polymerization of N-arylmethacryloyl sulfonamides at 70 °C. Herein we report the influence of methacrylamide structure on trithiocarbonate degradation during the RAFT polymerizations of N-phenylmethacrylamide (PhMA) and N-benzylmethacrylamide (BnMA) in DMF at 70 and 30 °C. UV-vis spectroscopy revealed trithiocarbonate degradation occurs exclusively after covalent addition of monomer to the RAFT agent, with 60% trithiocarbonate degradation occurring after 12 h during the polymerization of PhMA at 70 °C compared to only 3% degradation measured during the polymerization of BnMA under identical conditions. Small molecule analogues of trithiocarbonate-functional poly(PhMA) and poly(BnMA) were synthesized by single monomer unit insertion and the kinetics and byproducts of degradation investigated by in situ 1H NMR analysis at 70 °C. Trithiocarbonate degradation was ultimately shown to occur by N-phenyl-promoted, N-5 nucleophilic attack on the terminal thiocarbonyl by the ultimate methacrylamide unit.

We show that many of the nucleophiles (catalysts, reducing agents, amines, thiols) present during "one-pot" aminolysis/thiol-maleimide end-group functionalization of RAFT polymers can promote side reactions that substantially reduce polymer end-group functionalization efficiencies. The nucleophilic catalyst 1,8-diazabicyclo[5.4.0]undec-7-ene and the reducing agent tributylphosphine were shown to initiate anionic polymerization of N-methylmaleimide (NMM) in both polar and nonpolar solvents whereas hexylamine-initiated polymerization of NMM occurred only in high-polarity solvents. Furthermore, triethylamine-catalyzed Michael reactions of the representative thiol ethyl 2-mercaptopropionate (E2MP) and NMM in polar solvents resulted in anionic maleimide polymerization when [NMM]0 > [E2MP]0. Base-catalyzed enolate formation on the α-carbon of thiol-maleimide adducts was also shown as an alternative initiation pathway for maleimide polymerization in polar solvents. Ultimately, optimal "one-pot" reaction conditions were identified allowing for up to 99% maleimide end-group functionalization of dithiobenzoate-terminated poly(N,N-dimethylacrylamide). Much of the work described herein can also be used to ensure near-quantitative conversion of small molecule thiol-maleimide reactions while preventing previously unforeseen side reactions.

(Graph Presented). The controlled RAFT polymerization of a library of pH- and CO2-responsive methacryloyl sulfonamides (MSAs) that possess pKa values in the biologically relevant regime (pH = 4.5-7.4) is reported. Initial polymerizations were conducted at 70°C in DMF with 4-cyano-4-(ethylsulfanylthiocarbonylsulfanyl)pentanoic acid (CEP) or 4-cyanopentanoic acid dithiobenzoate (CTP), resulting in polymers of broad molecular weight distributions (Mw/Mn > 1.20). As well, chain extension of a poly(methacryloyl sulfacetamide) (pSAC) macro-CTA at 70°C was unsuccessful, indicating a loss of "living" chain ends during polymerization. However, by conducting the RAFT polymerization of MSAs at 30°C with 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile), polymers with narrow molecular weight distributions (Mw/Mn < 1.15) and improved chain end retention were obtained. Homopolymers of each MSA derivative were synthesized, and the influence of the sulfonamide R group on monomer pKa and pH-dependent polymer solubility was determined during these studies. The facility by which these controlled poly(MSAs) can be prepared via low-temperature RAFT without the need for functional group protection and the resulting pKa-dependent pH- and CO2-responsive properties point to significant potential in areas including drug and gene delivery and environmental remediation.

Polyisobutylene (PIB)-based bottlebrush polymers were synthesized via ring-opening metathesis polymerization (ROMP) of norbornene- and oxanorbornene-terminated PIB macromonomers (MM) initiated by Grubbs third-generation catalyst ((H2IMes2)(pyr)2(Cl)2Ru=CHPh) (G3). While both MMs reached greater than 97% conversion as measured by 1H NMR, the rate of propagation of PIB norbornene was measured to be 2.9 times greater than that of PIB oxanorbornene MMs of similar molecular weight (MW). The slower rate of propagation of the oxanorbornene MM was attributed to interaction between the electron-rich oxygen bridge and the metal center of G3, which slowed but did not inhibit polymerization. Both types of MMs demonstrated controlled/"living" polymerization behavior, and brush polymers with MWs up to ∼700 kg/mol with narrow dispersity (≤ 1.04) were achieved.

High molecular weight polyacrylonitrile (PAN) with low dispersity has been successfully synthesized utilizing reversible addition-fragmentation chain transfer (RAFT) polymerization. A comprehensive study was performed to understand the influence of reaction temperature, RAFT agent structure, and [M]0:[CTA]0[I]0 on the polymerization kinetics, molecular weight, and dispersity. Enhanced control is attributed to reduction of side reactions by conducting the polymerization at lower temperature, and optimizing the radical exchange between active and dormant states via appropriate selection of RAFT agent and initiator.

A postpolymerization modification strategy based on ambient temperature nucleophilic chemical deblocking of polymer scaffolds bearing N-heterocycle-blocked isocyanate moieties is reported. Room temperature RAFT polymerization of three azole-N-carboxamide methacrylates, including 3,5-dimethylpyrazole, imidazole, and 1,2,4-triazole derivatives, afforded reactive polymer scaffolds with well-defined molecular weights and narrow dispersities (Ä? < 1.2). Model analogues possessing the same N-heterocycle blocking agents with varied leaving group abilities were synthesized to determine optimal deblocking conditions. The reactivity of the azole-N-carboxamide moieties toward nucleophiles can be tuned simply by varying the structure of the azole blocking agents (reactivity order: pyrazole < imidazole < triazole). DBU-catalyzed reactions of thiols with imidazole- and 1,2,4-triazole-blocked isocyanate scaffolds were shown to occur rapidly and quantitatively under ambient conditions. Differences in reactivity of 1,2,4-triazole- and 3,5-dimethylpyrazole-blocked isocyanate copolymers with various nucleophiles at room temperature facilitated sequential and postpolymerization modification. This strategy advances the utility of blocked isocyanates and promotes the chemistry as a powerful postmodification tool to access multifunctional polymeric materials.

We report aqueous RAFT polymerization at pH = 0 mediated by a novel imidazolium-containing chain transfer agent. In 1 M HCl, unprecedented controlled polymerization and chain-extension of unprotected acyl hydrazide methacrylamides is achieved enabling the synthesis of well-defined acyl hydrazide functionalized polymer scaffolds of interest for dynamic covalent and bioconjugation strategies.

Self-assembled molecular nanostructures embody an enormous potential for new technologies, therapeutics, and understanding of molecular biofunctions. Their structure and function are dependent on local environments, necessitating in-situ/operando investigations for the biggest leaps in discovery and design. However, the most advanced of such investigations involve laborious labeling methods that can disrupt behavior or are not fast enough to capture stimuli-responsive phenomena. We utilize X-rays resonant with molecular bonds to demonstrate an in-situ nanoprobe that eliminates the need for labels and enables data collection times within seconds. Our analytical spectral model quantifies the structure, molecular composition, and dynamics of a copolymer micelle drug delivery platform using resonant soft X-rays. We additionally apply this technique to a hydrocarbon sequestrating polysoap micelle and discover that the critical organic-capturing domain does not coalesce upon aggregation but retains distinct single-molecule cores. This characteristic promotes its efficiency of hydrocarbon sequestration for applications like oil spill remediation and drug delivery. Such a technique enables operando, chemically sensitive investigations of any aqueous molecular nanostructure, label-free.

Amphoteric polysoaps have been prepared via statistical RAFT copolymerization using either methacryloyl sulfacetamide (mSAC) or methacryloyl sulfmethazine (mSMZ) and 4-hexylphenyl methylacrylamide (4HPhMA). These copolymers form pH- and CO2-responsive polymeric micelles capable of sequestering hydrophobic molecules in water. The composition and structure of the respective copolymers can be changed to tailor the onset and extent of CO2-dependent phase behavior. When CO2 is introduced into the system, resulting in carbonic acid formation, the pH drops below the pKa of the sulfonamide units along the copolymer backbone, and phase separation occurs. Purging with N2 results in an increase in pH and redissolution of the polysoap; this process can be repeated multiple times. The mSMZ polysoaps, which show complete phase transitions using this reversible process, were especially efficient in removing the model contaminants pyrene and 9-anthracenemethanol from water. The feasibility of recovering and reusing these copolymers is demonstrated, pointing to the potential utility of such CO2-responsive systems in water treatment and related environmental remediation applications.

GM1 ganglioside is known to promote amyloid-β (Aβ) peptide aggregation in Alzheimer's disease. The roles of the individual saccharides and their distribution in this process are not understood. Acrylamide-based glycomonomers with either β-d-glucose or β-d-galactose pendant groups were synthesized to mimic the stereochemistry of saccharides present in GM1 and characterized via ¹H NMR and electrospray ionization mass spectrometry. Glycopolymers of different molecular weights were synthesized by aqueous reversible addition-fragmentation chain transfer (aRAFT) polymerization and characterized by NMR and GPC. The polymers were used as models to investigate the effects of molecular weight and saccharide unit type on Aβ aggregation via thioflavin-T fluorescence and PAGE. High molecular weight (∼350 DP) glucose-containing glycopolymers had a profound effect on Aβ aggregation, promoting formation of soluble oligomers of Aβ and limiting fibril production, while the other glycopolymers and negative control had little effect on the Aβ propagation process.