Understanding zwitterionic ring-expansion polymerization through mass spectrometry.

Zwitterionic ring-expansion polymerization (ZREP) is a polymerization method in which a cyclic monomer is converted into a cyclic polymer through a zwitterionic intermediate. In this review, we explored the ZREP of various cyclic polymers and how mass spectrometry assists in identifying the product architectures and understanding their intricate reaction mechanism. For the majority of polymers (from a few thousand to a few million Da) matrix-assisted laser desorption/ionization time-of-flight mass spectrometry is the most effective mass spectrometry technique to determine the true molecular weight (MW) of the resultant product, but only when the dispersity is low (approximately below 1.2). The key topics covered in this study were the ZREP of cyclic polyesters, cyclic polyamides, and cyclic ethers. In addition, this study also addresses a number of other preliminary topics, including the ZREP of cyclic polycarbonates, cyclic polysiloxanes, and cyclic poly(alkylene phosphates). The purity and efficiency of those syntheses largely depend on the catalyst. Among several catalysts, N-heterocyclic carbenes have exhibited high efficiency in the synthesis of cyclic polyesters and polyamides, whereas tris(pentafluorophenyl)borane [B(C6F5)3] is the most optimal catalyst for cyclic polyether synthesis.

Mass spectrometry of dendrimers.

Mass spectrometry (MS) has become an essential technique to characterize dendrimers as it proved efficient at tackling analytical challenges raised by their peculiar onion-like structure. Owing to their chemical diversity, this review covers benefits of MS methods as a function of dendrimer classes, discussing advantages and limitations of ionization techniques, tandem mass spectrometry (MS/MS) strategies to determine the structure of defective species, as well as most recently demonstrated capabilities of ion mobility spectrometry (IMS) in the field. Complementarily, the well-defined structure of these macromolecules offers major advantages in the development of MS-based method, as reported in a second section reviewing uses of dendrimers as MS and IMS calibration standards and as multifunctional charge inversion reagents in gas phase ion/ion reactions.

Regioselective Palladium-Catalyzed Chain-Growth Allylic Amination Polymerization of Vinyl Aziridines.

Organometallic-mediated chain growth polymerization of readily accessible chemical building blocks is responsible for important commercial and technological advances in polymer science, but the incorporation of heteroatoms into the polymer backbone through these mechanisms remains a challenge. Transition metal π-allyl complexes are well-developed organometallic intermediates for carbon-heteroatom bond formation in small-molecule catalysis yet remain underexplored in polymer science. Here, we developed a regioselective palladium-phosphoramidite-catalyzed chain-growth allylic amination polymerization of vinyl aziridines for the synthesis of novel nitrogen-rich polymers via ambiphilic π-allyl complexes. The polymerization accessed a linear microstructure with four carbons between each nitrogen, which is challenging to achieve through other chain-growth polymerization approaches. The highly regioselective allylic amination polymerization demonstrated the characteristics of a controlled polymerization and was able to achieve molar masses exceeding 20 kg mol-1 with low dispersities (D̵ < 1.3). The identification of the polymer structure and well-defined chain ends were supported by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and chain extension experiments demonstrate opportunities for building more complex materials from this method. A Hammett study was performed to understand the role of the catalyst and monomer structure on regioselectivity, and the data supported a mechanism wherein regioselectivity was primarily controlled by the ligand-metal complex. Postpolymerization desulfonylation provided access to a novel polyamine that demonstrated broad anticancer activity in vitro, which highlights the benefits of unlocking novel polyamine microstructures through regioselective chain-growth allylic amination polymerization.

Separation, identification, and confirmation of cyclic and tadpole macromolecules via UPLC-MS/MS.

Macrocyclic poly(glycidyl phenyl ether) (pGPE) synthesized via zwitterionic ring opening polymerization is typically contaminated by chains with linear and tadpole architecture. Although mass spectrometry (MS) analysis can readily confirm the presence of the linear byproduct, due to its unique mass, it is unable to differentiate between the cyclic and tadpole structures, which are constitutional isomers produced by backbiting reactions in monomeric or dimeric chains, respectively. To overcome this problem, ultraperformance reversed-phase liquid chromatography interfaced with electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) was employed. The separation achieved by UPLC revealed that the tadpole isomer elutes before the cyclic structure because of the increased polarity afforded by its distinctive substituents. The ratio of tadpole to cyclic species increased with the degree of polymerization, in agreement with the synthetic method used, as the potential for forming tadpole structures by backbiting is entropically favored in longer polymer chains. Once separated, the two isomers could be independently characterized by tandem mass spectrometry. The macrocyclic and tadpole species exhibit unique fragmentation patterns, including structurally diagnostic fragments for each structure.

Physical Evidence of Oil Uptake and Toxicity Assessment of Amphiphilic Grafted Nanoparticles Used as Oil Dispersants.

Herein, we report the toxicity evaluation of a new prototype dispersant system, silicon dioxide nanoparticles (NPs) functionalized with (3-glycidoxypropyl)triethoxysilane (GPS) and grafted poly(ε-caprolactone)-block-poly[oligo(ethylene glycol)methyl methacrylate mono-methyl ether] (NP-PCL-POEGMA). This serves as a follow up of our previous study where grafted silicon dioxide NPs functionalized with GPS and grafted hyperbranched poly(glycidol) (NP-HPG) were evaluated for reducing the toxicity in embryo, juvenile, and adult fish populations. In this study, the NP-HPG sample is used as a baseline to compare against the new NP-PCL-POEGMA samples. The relative size was established for three NP-PCL-POEGMA samples via cryogenic transmission electron microscopy. A quantitative mortality study determined that these NPs are non-toxic to embryo populations. An ethoxyresorufin-O-deethylase assay was performed on these NP-PCL-POEGMA samples to test for reduced cytochrome P450 1A after the embryos were exposed to the water-accommodated fraction of crude oil. Overall, these NP-PCL-POEGMA NPs better protected the embryo populations than the previous NP-HPG sample (using a protein activity end point), showing a trend in the right direction for prototype dispersants to replace the commercially utilized Corexit.

SpheriCal® -ESI: A dendrimer-based nine-point calibration solution ranging from m/z 273 to 1716 for electrospray ionization mass spectrometry peptide analysis.

RATIONALE: A calibration solution for mass spectrometry needs to cover the range of interest with intense and sufficiently narrowly spaced peaks. Limited options fulfilling this may lead to compromises between performance and ease of use. SpheriCal® -ESI was designed to combine high calibration performance for electrospray ionization (ESI) mass spectrometric analysis of peptides in positive mode with quick and easy use. METHODS: The developed calibration solution was tested using three mass spectrometers: two ion traps and one tandem quadrupole. The m/z errors of SpheriCal® -ESI itself and of a tryptic digest of cytochrome C were measured after calibration. The results were compared with those achieved with ESI Tuning Mix. The memory effects of the dendrimers, and contamination from Na+ in the calibration solution, were evaluated. RESULTS: SpheriCal® -ESI showed good shelf life as powder and was quickly reconstituted for use. Achieving intense and stable signals was straightforward. The accuracies and precisions were as expected for the instruments. SpheriCal® -ESI was more precise and at least as accurate as ESI Tuning Mix. The memory effects and Na+ contamination were found to be negligible in typical peptide solvents. In addition, the dendrimers showed predictable dissociations with product ions common to collision-induced dissociation in both ion trap and tandem quadrupole mass spectrometers. CONCLUSIONS: SpheriCal® -ESI provided easily accessible calibration by showing intense signals at low infusion rates and at source settings equal or similar to those used in peptide analysis. Nine calibration points in the range of interest gave precise and accurate results. Memory effects and contamination were negligible even without rinsing.

It is Better with Salt: Aqueous Ring-Opening Metathesis Polymerization at Neutral pH.

Aqueous ring-opening metathesis polymerization (ROMP) is a powerful tool for polymer synthesis under environmentally friendly conditions, functionalization of biomacromolecules, and preparation of polymeric nanoparticles via ROMP-induced self-assembly (ROMPISA). Although new water-soluble Ru-based metathesis catalysts have been developed and evaluated for their efficiency in mediating cross metathesis (CM) and ring-closing metathesis (RCM) reactions, little is known with regards to their catalytic activity and stability during aqueous ROMP. Here, we investigate the influence of solution pH, the presence of salt additives, and catalyst loading on ROMP monomer conversion and catalyst lifetime. We find that ROMP in aqueous media is particularly sensitive to chloride ion concentration and propose that this sensitivity originates from chloride ligand displacement by hydroxide or H2O at the Ru center, which reversibly generates an unstable and metathesis inactive complex. The formation of this Ru-(OH)n complex not only reduces monomer conversion and catalyst lifetime but also influences polymer microstructure. However, we find that the addition of chloride salts dramatically improves ROMP conversion and control. By carrying out aqueous ROMP in the presence of various chloride sources such as NaCl, KCl, or tetrabutylammonium chloride, we show that diblock copolymers can be readily synthesized via ROMPISA in solutions with high concentrations of neutral H2O (i.e., 90 v/v%) and relatively low concentrations of catalyst (i.e., 1 mol %). The capability to conduct aqueous ROMP at neutral pH is anticipated to enable new research avenues, particularly for applications in biological media, where the unique characteristics of ROMP provide distinct advantages over other polymerization strategies.

Limitations of ion mobility spectrometry-mass spectrometry for the relative quantification of architectural isomeric polymers: A case study.

Since their discovery, cyclic polymers have attracted great interest because of their unique properties. Today, the preparation of these macrocyclic structures still remains a challenge for polymer chemists, and most of the preparation pathways lead to an inescapable contamination by linear by-products. As the properties of the polymers are closely related to their structure, it is of prime importance to be able to assess the architectural purity of a sample. METHODS: In this work, the suitability of ion mobility spectrometry-mass spectrometry (IMS-MS) for the quantification of two isomers was investigated. A cyclic poly(L-lactide) was prepared through photodimerization of its linear homologue. Since IMS-MS can be used to differentiate cyclic polymer ions from their linear analogues because of their more compact three-dimensional conformation, the present work envisaged the use of IMS-MS for the quantification of residual linear polymers within the cyclic polymer sample. RESULTS: Using the standard addition method to plot calibration curves, the fraction of linear contaminants in the sample was determined. By doing so, unrealistically high values of contamination were measured. CONCLUSIONS: These results were explained by an ionization efficiency issue. This work underlines some intrinsic limitations when using IMS-MS in the context of the relative quantification of isomers having different ionization efficiencies. Nevertheless, the linear-to-cyclic ratio can be roughly estimated by this method.

Molecular Weight Control via Cross Metathesis in Photo-Redox Mediated Ring-Opening Metathesis Polymerization.

Photo-redox mediated ring-opening metathesis polymerization (photo-ROMP) is an emerging ROMP technique that uses an organic redox mediator and a vinyl ether initiator, in contrast to metal-based initiators traditionally used in ROMP. The reversibility of the redox-mediated initiation and propagation steps enable spatiotemporal control over the polymerization. Herein, we explore a simple, inexpensive means of controlling molecular weight, using alpha olefins as chain transfer agents. This method enables access to low molecular weight oligomers, and molecular weights between 1 and 30 kDa can be targeted simply by altering the stoichiometry of the reaction. This method of molecular weight control was then used to synthesize a functionalized norbornene copolymer in a range of molecular weights for specific materials applications.

Linear-Dendritic Alternating Copolymers.

Herein, the design, synthesis, and characterization of an unprecedented copolymer consisting of alternating linear and dendritic segments is described. First, a 4th-generation Hawker-type dendron with two azide groups was synthesized, followed by a step-growth azide-alkyne "click" reaction between the 4th-generation diazido dendron and poly(ethylene glycol) diacetylene to create the target polymers. Unequal reactivity of the functional groups was observed in the step-growth polymerization. The resulting copolymers, with alternating hydrophilic linear and hydrophobic dendritic segments, can spontaneously associate into a unique type of microphase-segregated nanorods in water.

Evaluation of Amphiphilic Star/Linear-Dendritic Polymer Reverse Micelles for Transdermal Drug Delivery: Directing Carrier Properties by Tailoring Core versus Peripheral Branching.

The reverse micelle self-assembly of lipophile-functionalized poly(ethylene glycol) (PEG) dendrimer hybrids is probed for applications in carrier-mediated transdermal drug delivery. Under investigation are topologically diverse amphiphiles featuring controlled branching motifs at either the polymer core (one-, two-, and four-arm PEG) and the polar/nonpolar interface (peripheral dendritic generations 0-2). Thus, a systematic investigation of the effect of branching location (core vs peripheral) on carrier properties is described. Dye-encapsulation experiments verify these materials are capable of forming well-defined aggregates and solubilizing polar compounds. Further quantification of reverse micelle critical micelle concentration and dye loading capacity for the branched amphiphile library was obtained through spectroscopy characterization. Both core and peripheral branching are shown to significantly influence dynamic encapsulation behavior, with evidence of location-based contributions extending beyond multiplicity of branching alone. Finally, the in vitro transdermal diffusion of the reverse micelle carriers was investigated through Franz diffusion cell experiments using physiologically relevant juvenile porcine dermis. The permeation results, combined with previously reported aggregate size trends, show the complex relationship between polymer branching and transdermal transport, with the lowest core- and highest peripherally-branched amphiphilic analogs exhibiting optimal transdermal permeation characteristics for this set of branched carriers.

Synthesis and Self-Assembly of Amphiphilic Star/Linear-Dendritic Polymers: Effect of Core versus Peripheral Branching on Reverse Micelle Aggregation.

A series of branched polymers, consisting of a poly(ethylene glycol) (PEG) core and lipophilic peripheral dendrons, were synthesized and their self-assembly into reverse micelles studied toward the ultimate goal of carrier-mediated transdermal drug delivery. More specifically, this investigation systematically explores the structure-property contributions arising from location and extent of branching by varying the number of branch points at the core and the generation of dendrons at the polar/nonpolar interface. For branching at the core, PEGs were selected with one, two or four arms, with one terminal functionality per arm. For peripheral branching, end groups were modified with polyester dendrons (of dendritic generations 0, 1, and 2) for each of the three cores. Finally, lauric acid (LA) was used to esterify the periphery, yielding a library of branched, amphiphilic polymers. Characterization of these materials via MALDI-TOF MS, GPC and NMR confirmed their exceptionally well-defined structure. Furthermore, atomic force microscopy (AFM) and dynamic light scattering (DLS) confirmed these polymers' abilities to make discrete aggregates. As expected, increased multiplicity of branching resulted in more compact aggregates; however, the location of branching (core vs periphery) did not seem as important in defining aggregate size as the extent of branching. Finally, computational modeling of the branched amphiphile series was explored to elucidate the macromolecular interactions governing self-assembly in these systems.

The Synthesis of Cyclic Poly(ethylene imine) and Exact Linear Analogues: An Evaluation of Gene Delivery Comparing Polymer Architectures.

The delivery of genetic material to cells offers the potential to treat many genetic diseases. Cationic polymers, specifically poly(ethylene imine) (PEI), are promising gene delivery vectors due to their inherent ability to condense genetic material and successfully affect its transfection. However, PEI and many other cationic polymers also exhibit high cytotoxicity. To systematically study the effect of polymer architecture on gene delivery efficiency and cell cytotoxicity, a set of cyclic PEIs were prepared for the first time and compared to a set of linear PEIs of the exact same molecular weight. Subsequent in vitro transfection studies determined a higher transfection efficiency for each cyclic PEI sample when compared to its linear PEI analogue in addition to reduced toxicity relative to the branched PEI "gold standard" control. These results highlight the critical role that the architecture of PEI can play in both optimizing transfection and reducing cell toxicity.

Investigation of Lysine-Functionalized Dendrimers as Dichlorvos Detoxification Agents.

Lysine-containing polymers have seen broad application due to their amines' inherent ability to bind to a range of biologically relevant molecules. The synthesis of multiple generations of polyester dendrimers bearing lysine groups on their periphery is described in this report. Their hydrolytic stabilities with respect to pH and time, their toxicity to a range of cell lines, and their possible application as nano-detoxification agents of organophosphate compounds are all investigated. These zeroth-, first-, and second-generation water-soluble dendrimers have been designed to bear exactly 4, 8, and 16 lysine groups, respectively, on their dendritic periphery. Such monodisperse bioactive polymers show potential for a range of applications including drug delivery, gene delivery, heavy metal binding, and the sequestration of organic toxins. These monodisperse bioactive dendrimers were synthesized using an aliphatic ester dendritic core (prepared from pentaerythritol) and protected amino acid moieties. This library of lysine-conjugated dendrimers showed the ability to efficiently capture the pesticide dichlorvos, confirming the potential of dendrimer-based antidotes to maintain acetylcholinesterase activity in response to poisoning events.

Letter: The potential of amine-containing dendrimer mass standards for internal calibration of peptides.

In order to ensure accurate mass determinations, MALDI-TOF mass spectrometers must be calibrated regularly. While peptides and proteins represent the most widely used calibration standards due to their monodispersity, known masses and availability, their limited shelf-life complicates their use. Recently, polyester dendrimer calibrants have been introduced as an alternative because, in addition to monodispersity and relative molecular masses as high as 30,000, they exhibit vastly improved stability and broad compatibility with both matrices and solvents. However, the use of these initially reported polyester dendrimers as internal calibrants for the analysis of peptides or proteins presents a unique problem because these dendrimers typically require ionization with metal cations, while amino acid-based compounds preferentially ionize via protonation of an amine. To address this complication, dendrimers bearing a single amine were prepared which demonstrate the ability to easily ionize via protonation with either acidic matrices or dilute solutions of trifluoroacetic acid. This class of amine-containing dendrimers shows promise as a calibrant system specifically designed for the internal calibration of peptides.

Efficient synthesis of high purity homo-arm and mikto-arm poly(ethylene glycol) stars using epoxide and azide-alkyne coupling chemistry.

High purity homo-arm and mikto-arm poly(ethylene glycol) (PEG) stars are successfully prepared by the combination of epoxide ring-openings and azide-alkyne click reactions. First, monohydroxy-PEG was modified via epoxide chemistry to bear one hydroxyl and one azide functionality at the same end. An alkyne-functionalized PEG chain was then coupled to the azide. Subsequently, the remaining hydroxyl could be reactivated to an azide again and again to enable stepwise addition of alkyne-functionalized polymer arms. The use of efficient reactions for this iterative route provides star polymers with an exact number of arms, and a tailorable degree of polymerization for each arm. Detailed characterization confirms the high purity of multi-arm polyethylene glycol products.

Elucidation of Dithiol-yne Comb Polymer Architectures by Tandem Mass Spectrometry and Ion Mobility Techniques.

Polymers have a wide range of applications depending on their composition, size, and architecture. Varying any of these three characteristics can greatly impact the resulting chemical, physical, and mechanical properties. While many techniques are available to determine polymer composition and size, determining the exact polymer architecture is more challenging. Herein, tandem mass spectrometry (MS/MS) and ion mobility mass spectrometry (IM-MS) methods are utilized to derive crucial architectural information about dithiol-yne comb polymers. Based on their unique fragmentation products and IM drift times, dithiol-yne oligomers with distinct architectures were successfully differentiated and characterized. Additionally, experimental collision cross-sections (Ω) derived via IM-MS were compared to theoretically extracted Ω values from molecular dynamics simulated structures to deduce the architectural motif of these comb oligomers. Overall, this work demonstrates the benefits of combining various mass spectrometry techniques in order to gain a complete understanding of a complex polymer mixture.

Crystallization-Induced Self-Assembly of Poly(ethylene glycol) Side Chains in Dithiol-yne-Based Comb Polymers: Side Chain Spacing and Molecular Weight Effects.

The chain architecture and topology of macromolecules impact their physical properties and final performance, including their crystallization process. In this work, comb polymers constituted by poly(ethylene glycol), PEG, side chains, and a dithiol-yne-based ring polymer backbone have been studied, focusing on the micro- and nanostructures of the system, thermal behavior, and crystallization kinetics. The designed comb system allows us to investigate the role of a ring backbone, the impact of varying the distance between two neighboring side chains, and the effect of the molecular weight of the side chain. The results reflect that the governing factor in the crystalline properties is the molar mass of the side chains and that the tethering of PEG chains to the ring backbone brings important constraints to the crystallization process, reducing the crystallinity degree and slowing down the crystallization kinetics in comparison to analogue PEG homopolymers. We demonstrate that the effect of spatial hindrance in the comb-like PEG polymers drives the morphology toward highly ordered, self-assembled, semicrystalline superstructures with either extended interdigitated chain crystals or novel (for comb polymers) interdigitated folded chain lamellar crystals. These structures depend on PEG molecular weight, the distance between neighboring tethered PEG chains, and the crystallization conditions (nonisothermal versus isothermal). This work sheds light on the role of chain architecture and topology in the structure of comb-like semicrystalline polymers.

Synthesis of Degradable Polysulfamides via Sulfur(VI) Fluoride Exchange Click Polymerization of AB-Type Monomers.

Polysulfamides are the -SO2- analogues of polyureas and form an intriguing family of polymers containing hydrogen-bond donor and acceptor groups. However, unlike polyureas, their physical properties are mostly unknown because of the scarcity of synthetic methods to access such polymers. Herein, we report an expedient synthesis of AB monomers for the synthesis of polysulfamides via Sulfur(VI) Fluoride Exchange (SuFEx) click polymerization. Upon optimization of the step-growth process, a variety of polysulfamides were isolated and characterized. The versatility of the SuFEx polymerization allowed structural modulation of the main chain through the incorporation of aliphatic or aromatic amines. While all synthesized polymers presented high thermal stability via thermogravimetric analysis, the glass-transition temperature and crystallinity were shown to be highly tied to the structure of the backbone between repeating sulfamide units through differential scanning calorimetry and powder X-ray diffraction. Careful analysis via matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and X-ray crystallography also revealed the formation of macrocyclic oligomers during the polymerization of one AB monomer. Finally, two protocols were developed to efficiently degrade all synthesized polysulfamides through either chemical recycling for polymers derived from aromatic amines or oxidative upcycling for those based on aliphatic amines.

Synthesis of cyclic dendronized polymers via divergent "graft-from" and convergent click "graft-to" routes: preparation of modular toroidal macromolecules.

Cyclic dendronized polymers represent a new class of polymers which exhibit a donut-like "toroidal" shape. Two previous unreported methods for preparing this architecture, the divergent "graft-from" and the convergent click "graft-to" approaches, are explored and the resulting products fully characterized. This route is particularly attractive because it enables production of exact linear and cyclic dendronized analogues, enabling direct comparison of their physical properties. In this preliminary work, the divergent "graft from" approach appears to lead to materials with broad PDI at high DP, whereas the "graft to" approach yields more well-defined dendronized cyclic polymers at larger DP. On the basis of reports to date, a combination of click cyclization followed by click "grafting to" provides the most versatile route for the synthesis of cyclic dendronized polymers.