Salt Effects on the Phase Behavior and Cocrystallization Kinetics of POCB-Water Mixtures.

Mixtures of water with polyoxacyclobutane (POCB) have a unique phase diagram which combines liquid-liquid equilibrium (LLE) at high temperatures and cocrystallization of a POCB-hydrate at low temperatures. Such cocrystal hydrate formation is extremely rare among polymers. We report on the effects of adding NaCl salt on the phase behavior of POCB-water mixtures and the kinetics of hydrate crystallization from such mixtures. Salt loadings of less than 0.1 wt % were found to greatly expand the LLE region. Salt loadings of ∼10 wt % were found to significantly decrease the melting temperature of the hydrate below its ∼37 °C value under salt-free conditions. The hydrate was found to be remarkably tolerant of salt and persists at room temperature even when equilibrated with salt-saturated water. Salt was found to slow down hydrate crystallization, and the degree of slowing was greater than that expected from the salt-induced decrease in undercooling due to melting point depression.

Chirality-Directed Regioselectivity: An Approach for the Synthesis of Alternating Poly(Lactic-co-Glycolic Acid).

We report the synthesis of alternating poly(lactic-co-glycolic acid) via a regioselective ring-opening polymerization of (S)-methyl glycolide. An enantiopure aluminum salen catalyst with binaphthyl backbone facilitates the regioselective ring-opening of this unsymmetrical cyclic diester exclusively at the glycolide acyl-oxygen bond site. This living, chain-growth polymerization is able to reach low dispersities with tailored molecular weights. Quantitative regioselectivity calculations and sequence error analysis have been established for this sequence-controlled polymer.

Learning from Peptides to Access Functional Precision Polymer Sequences.

Functional precision polymers based on monodisperse oligo(N-substituted acrylamide)s and oligo(2-substituted-α-hydroxy acid)s have been synthesized. The discrete sequences originate from a direct translation of side-chain functionality sequences of a peptide with well-studied properties. The peptide was previously selected to solubilize the photosensitizer meta-tetra(hydroxyphenyl)chlorin. The resulting peptidomimetic formulation additives preserve the drug solubilization and release characteristics of the parent peptide. In some cases, superior properties are obtained, reaching up to 40 % higher payloads and 27-times faster initial drug release.

Sequence-Controlled Polymers Through Entropy-Driven Ring-Opening Metathesis Polymerization: Theory, Molecular Weight Control, and Monomer Design.

The bulk properties of a copolymer are directly affected by monomer sequence, yet efficient, scalable, and controllable syntheses of sequenced copolymers remain a defining challenge in polymer science. We have previously demonstrated, using polymers prepared by a step-growth synthesis, that hydrolytic degradation of poly(lactic- co-glycolic acid)s is dramatically affected by sequence. While much was learned, the step-growth mechanism gave no molecular weight control, unpredictable yields, and meager scalability. Herein, we describe the synthesis of closely related sequenced polyesters prepared by entropy-driven ring-opening metathesis polymerization (ED-ROMP) of strainless macromonomers with imbedded monomer sequences of lactic, glycolic, 6-hydroxy hexanoic, and syringic acids. The incorporation of ethylene glycol and metathesis linkers facilitated synthesis and provided the olefin functionality needed for ED-ROMP. Ring-closing to prepare the cyclic macromonomers was demonstrated using both ring-closing metathesis and macrolactonization reactions. Polymerization produced macromolecules with controlled molecular weights on a multigram scale. To further enhance molecular weight control, the macromonomers were prepared with cis-olefins in the metathesis-active segment. Under these selectivity-enhanced (SEED-ROMP) conditions, first-order kinetics and narrow dispersities were observed and the effect of catalyst initiation rate on the polymerization was investigated. Enhanced living character was further demonstrated through the preparation of block copolymers. Computational analysis suggested that the enhanced polymerization kinetics were due to the cis-macrocyclic olefin being less flexible and having a larger population of metathesis-reactive conformers. Although used for polyesters in this investigation, SEED-ROMP represents a general method for incorporation of sequenced segments into molecular weight-controlled polymers.

Monomer sequence in PLGA microparticles: Effects on acidic microclimates and in vivo inflammatory response.

Controlling the backbone architecture of poly(lactic-co-glycolic acid)s (PLGAs) is demonstrated to have a strong influence on the production and release of acidic degradation by-products in microparticle matrices. Previous efforts for controlling the internal and external accumulation of acidity for PLGA microparticles have focused on the addition of excipients including neutralization and anti-inflammatory agents. In this report, we utilize a sequence-control strategy to tailor the microstructure of PLGA. The internal acidic microclimate distributions within sequence-defined and random PLGA microparticles were monitored in vitro using a non-invasive ratiometric two-photon microscopy (TPM) methodology. Sequence-defined PLGAs were found to have minimal changes in pH distribution and lower amounts of percolating acidic by-products. A parallel scanning electron microscopy study further linked external morphological events to internal degradation-induced structural changes. The properties of the sequenced and random copolymers characterized in vitro translated to differences in in vivo behavior. The sequence alternating copolymer, poly LG, had lower granulomatous foreign-body reactions compared to random racemic PLGA with a 50:50 ratio of lactic to glycolic acid. STATEMENT OF SIGNIFICANCE: This paper demonstrates that changing the monomer sequence in poly(lactic-co-glycolic acid)s (PLGAs) leads to dramatic differences in the rate of degradation and the internal acidic microclimate of microparticles degrading in vitro. We note that the acidic microclimates within these particles were imaged for the first time with two-photon microscopy, which gives an extremely clear and detailed picture of the degradation process. Importantly, we also document that the observed sequence-controlled in vitro processes translate into differences in the in vivo behavior of polymers which have the same L to G composition but differing microstructures. These data, placed in the context of our prior studies on swelling, erosion, and MW loss (Biomaterials2017, 117, 66 and other references cited within the manuscript), provide significant insight not only about sequence effects in PLGAs but into the underlying mechanisms of PLGA degradation in general.

Cis-Selective Metathesis to Enhance the Living Character of Ring-Opening Polymerization: An Approach to Sequenced Copolymers.

The hydrolytic behavior and physical properties of a polymer are directly related to its constituent monomer sequence, yet the scalable and controllable synthesis of sequenced copolymers remains scarcely realized. To address this need, an enhanced version of entropy-driven ring-opening metathesis polymerization (ED-ROMP) has been developed. An unprecedented level of control is obtained by exploiting the kinetic and thermodynamic differences in the metathesis activity of cis- and trans-olefins embedded in large, unstrained macrocycles. First-order rate kinetics were observed, and polymer molecular weights were found to be proportional to catalyst loading. Computational analysis suggests that incorporation of a cis-olefin into the monomer backbone both introduces a thermodynamic driving force and increases the population of metathesis-active conformers. This approach offers a generally applicable method for enhancing living character in ED-ROMP.

The impact of monomer sequence and stereochemistry on the swelling and erosion of biodegradable poly(lactic-co-glycolic acid) matrices.

Monomer sequence is demonstrated to be a primary factor in determining the hydrolytic degradation profile of poly(lactic-co-glycolic acid)s (PLGAs). Although many approaches have been used to tune the degradation of PLGAs, little effort has been expended in exploring the sequence-control strategy exploited by nature in biopolymers. Cylindrical matrices and films prepared from a series of sequenced and random PLGAs were subjected to hydrolysis in a pH 7.4 buffer at 37 °C. Swelling ranged from 107% for the random racemic PLGA with a 50:50 ratio of lactic (L) to glycolic (G) units to 6% for the sequenced alternating copolymer poly LG. Erosion followed an inverse trend with the random 50:50 PLGA showing an erosion half-life of 3-4 weeks while poly LG required ca. >10 weeks. Stereosequence was found to play a large role in determining swelling and erosion; stereopure analogs swelled less and were slower to lose mass. Molecular weight loss followed similar trends and increases in dispersity correlated with the onset of significant swelling. The relative proportion of rapidly cleavable G-G linkages relative to G-L/L-G (moderate) and L-L (slow) correlates strongly with the degree of swelling observed and the rate of erosion. The dramatic sequence-dependent variation in swelling, in the absence of a parallel hydrophilicity trend, suggest that osmotic pressure, driven by the differential accumulation of degradation products, plays an important role.

Sequence Effects in Conjugated Donor-Acceptor Trimers and Polymers.

To investigate the sequence effect on donor-acceptor conjugated oligomers and polymers, the trimeric isomers PBP and BPP, comprising dialkoxy phenylene vinylene (P), benzothiadiazole vinylene (B), and alkyl endgroups with terminal olefins, are synthesized. Sequence effects are evident in the optical/electrochemical properties and thermal properties. Absorption maxima for PBP and BPP differ by 41 nm and the electrochemical band gaps by 0.1 V. The molar emission intensity is five times greater in PBP than BPP. Both trimers are crystalline and the melting points differ by 17 °C. The PBP and BPP trimers are used as macromonomers in an acyclic diene metathesis polymerization to give PolyPBP and PolyBPP. The optical and electrochemical properties are similar to those of their trimer precursors-sequence effects are still evident. These results suggest that sequence is a tunable variable for electronic materials and that the polymerization of oligomeric sequences is a useful approach to introducing sequence into polymers.

Sequence-Controlled Copolymers Prepared via Entropy-Driven Ring-Opening Metathesis Polymerization.

A new general synthetic approach to sequenced macromolecules was developed and applied to the synthesis of polymers comprising lactic acid (L), glycolic acid (G), and ε-caprolactone (C)-derived monomer units. The new method employs entropy-driven ring-opening metathesis polymerization (ED-ROMP) to prepare copolymers with embedded sequences and controlled molecular weights. Cyclic macromonomer precursors were prepared by ring-closing metathesis of ethylene glycol (Eg)-linked sequenced oligomers bearing terminal olefins. ED-ROMP of the resulting macrocycles using Grubbs' second generation catalyst yielded poly(CL-Eg-LC-Oed), poly(CLL-Eg-LLC-Oed), poly(LGL-Eg-LGL-Oed), and poly(LGL-Eg-LGL-Hed) (Oed = octenedioc acid; Hed = hexenedioc acid). Hydrogenation produced the saturated sequenced copolymers. Molecular weight was well-controlled and could be adjusted by varying the monomer-to-catalyst ratio. Mns of 26-60 kDa were obtained (dispersities = 1.1-1.3). The methodology proved general for three different sequences and two olefinic metathesis groups.

Chemical and Electrochemical Manipulation of Mechanical Properties in Stimuli-Responsive Copper-Cross-Linked Hydrogels.

Inspiration for the design of new synthetic polymers can be found in the natural world, where materials often exhibit complex properties that change depending on external stimuli. A new synthetic electroplastic elastomer hydrogel (EPEH) that undergoes changes in mechanical properties in response to both chemical and electrochemical stimuli has been prepared based on these precedents. In addition to having the capability to switch between hard and soft states, the presence of both permanent covalent and dynamic copper-based cross links also allows this stimuli-responsive material to exhibit a striking shape memory capability. The density of temporary cross links and the mechanical properties are controlled by reversible switching between the +1 and +2 oxidation states.

The effect of monomer order on the hydrolysis of biodegradable poly(lactic-co-glycolic acid) repeating sequence copolymers.

The effect of sequence on copolymer properties is rarely studied despite the precedent from Nature that monomer order can create materials of significant diversity. Poly(lactic-co-glycolic acid) (PLGA), one of the most important biodegradable copolymers, is widely used in an unsequenced, random form for both drug delivery microparticles and tissue engineering matrices. Sequenced PLGA copolymers have been synthesized and fabricated into microparticles to study how their hydrolysis rates compare to those of random copolymers. Sequenced PLGA microparticles were found to degrade at slower, and often more constant, rates than random copolymers with the same lactic to glycolic acid ratios as demonstrated by molecular weight decrease, lactic acid release, and thermal property analyses. The impact of copolymer sequence on in vitro release was studied using PLGA microparticles loaded with model agent rhodamine-B. These assays established that copolymer sequence affects the rate of release and that a more gradual burst release can be achieved using sequenced copolymers compared to a random control.

Manipulating Mechanical Properties with Electricity: Electroplastic Elastomer Hydrogels.

The dawn of the 21st century has brought with it an increasing interest in emulating the adaptive finesse of natural systems by designing materials with on-demand, tunable properties. The creation of such responsive systems could be expected, based on historical precedent, to lead to completely new engineering design paradigms. Using a bioinspired approach of coupling multiple equilibria that operate on different length scales, a material whose bulk mechanical properties can be manipulated by electrical input has been developed. The new macroscale electroplastic elastomer hydrogels can be reversibly cycled through soft and hard states while maintaining a three-dimensional shape by sequential application of oxidative and reductive potentials. This input changes the cross-linking capacity of iron ions within the gel matrix, between a poorly coordinating +2 and a more strongly binding +3 oxidation state. Inclusion of carbon nanotubes in the hydrogel preparation increases conductivity and decreases transition time.

Exploiting sequence to control the hydrolysis behavior of biodegradable PLGA copolymers.

Monomer sequence is a potentially powerful but underutilized tool for the control of copolymer properties. Sequence is demonstrated to dramatically affect the hydrolysis profile for the degradation of poly(lactic-co-glycolic acid) (PLGA), a member of the most widely used class of biodegradable polymers employed in biomedical applications. The nearly linear molecular weight loss profile and uniform thermal behavior throughout the course of the hydrolysis differ dramatically from the behavior that is exhibited by random copolymer controls with the same comonomer ratio.

Periodic incorporation of pendant hydroxyl groups in repeating sequence PLGA copolymers.

A series of repeating sequence poly(lactic-co-glycolic acid) copolymers (RSC PLGAs) has been prepared with the precise incorporation of a pendant benzyl-ether substituted monomer derived from serine. Copolymers were synthesized from the assembly of sequence-specific, stereopure dimeric, and trimeric segmers of lactic, glycolic, and (S)-3-benzyloxy-2-hydroxypropionic acids with controlled and varied tacticities. Deprotection of the hydroxyl groups was accomplished by catalytic hydrogenolysis to yield highly functionialized, hydrophilic polyesters. The (1)H and (13)C NMR spectra for all of the copolymers were consistent with sequence and stereochemical retention and lacked the signal broadening that is inherent with more random copolymers.

Iterative synthesis of heterotelechelic oligo(phenylene-vinylene)s by olefin cross-metathesis.

A novel iterative synthesis of heterotelechelic oligo(phenylene-vinylene)s using olefin cross-metathesis is reported. The metathesis homologation proceeds in good yields and allows for further functionalization, including the facile formation of donor-acceptor complexes and repeating sequence copolymers.

New insights into poly(lactic-co-glycolic acid) microstructure: using repeating sequence copolymers to decipher complex NMR and thermal behavior.

Sequence, which Nature uses to spectacular advantage, has not been fully exploited in synthetic copolymers. To investigate the effect of sequence and stereosequence on the physical properties of copolymers, a family of complex isotactic, syndiotactic, and atactic repeating sequence poly(lactic-co-glycolic acid) copolymers (RSC PLGAs) were prepared and their NMR and thermal behavior was studied. The unique suitability of polymers prepared from the bioassimilable lactic and glycolic acid monomers for biomedical applications makes them ideal candidates for this type of sequence engineering. Polymers with repeating units of LG, GLG and LLG (L = lactic, G = glycolic) with controlled and varied tacticities were synthesized by assembly of sequence-specific, stereopure dimeric, trimeric, and hexameric segmer units. Specifically labeled deuterated lactic and glycolic acid segmers were likewise prepared and polymerized. Molecular weights for the copolymers were in the range M(n) = 12-40 kDa by size exclusion chromatography in THF. Although the effects of sequence-influenced solution conformation were visible in all resonances of the (1)H and (13)C NMR spectra, the diastereotopic methylene resonances in the (1)H NMR (CDCl(3)) for the glycolic units of the copolymers proved most sensitive. An octad level of resolution, which corresponds to an astounding 31-atom distance between the most separated stereocenters, was observed in some mixed sequence polymers. Importantly, the level of sensitivity of a particular NMR resonance to small differences in sequence was found to depend on the sequence itself. Thermal properties were also correlated with sequence.

Mono- and terfluorene oligomers as versatile sensitizers for the luminescent Eu3+ cation.

We present the design, synthesis, and physical and photophysical characterization of Eu(3+) and Gd(3+) complexes formed with two ligands bearing either one or three fluorene sensitizer units. As a novel sensitizing approach, the oligomer length is used to control the energies of the triplet states of the sensitizer and to mediate the sensitizer to lanthanide energy transfer.

A palladium-catalyzed regio- and stereoselective four-component coupling reaction.

Pd(PPh(3))(4) catalytically assembles sulfenamide, alkyne, carbon monoxide, and diphenyl diselenide regio- and stereoselectively in a one-pot four-component coupling reaction to yield (Z)-beta-selenyl acrylamides. The reaction proceeds in good to excellent yields (60-95%) and is tolerant of a range of functional groups on both the nitrogen of the sulfenamide and the alkyne. Moderate selectivities ranging from 4:1 to 7:1 beta-selenyl to beta-sulfenyl acrylamide have been observed despite the initial concentration of 2:1 selenium to sulfur in the reaction. The chalcogeno selectivity was found to depend directly on CO pressure; increased pressure decreased selectivity for selenium over sulfur.

Proton as the simplest of all catalysts for [2 + 2] cycloadditions: DFT study of acid-catalyzed imine metathesis.

The mechanism of imine metathesis was studied as a prototype reaction for the impact that heteroatom substitution has on thermally forbidden [2 + 2] addition reactions using high-level density functional theory in combination with a continuum solvation model. The intuitively expected high activation barriers were confirmed for N-alkyl- and N-aryl-substituted imine reactants with transition state free energies of 78.8 and 68.5 kcal/mol, respectively, in benzene. The computed reaction energy profiles were analyzed to discover possible strategies for lowering the transition state energy. Protonation of the imine nitrogen was proposed as a possible catalytic route and was explicitly modeled. The computed reaction energy profile shows that protonation of one of the imine reactants has an enormous effect on the overall rate of metathesis and lowers the activation barrier by as much as 37.3 and 30.6 kcal/mol for the N-alkyl and N-aryl reactants, respectively. These results suggest that acid-catalyzed imine metathesis should be amenable at elevated temperatures. Furthermore, the protonation of both reactants of the metathesis reaction is predicted to be not productive owing to electrostatic repulsion of the reactants, thus suggesting that there should be an optimum pH for the catalytic turnover. A detailed analysis of the catalytic mechanism is presented, and the primary driving force for the catalysis is identified. Upon protonation of the imine nitrogen, the key [2 + 2]-addition step becomes asynchronous and one of the two intermolecular N-C bonds is formed before traversing the transition state, resulting in a substantial net decrease of the overall energy requirement. The general applicability of this intuitively understandable mechanism for designing structural features for lowering the energy of transition state structures is explored.

The regio- and stereoselective one-pot catalytic preparation of beta-selenyl acrylamides.

Pd(PPh(3))(4) is found to catalytically assemble sulfenamides, terminal aliphatic alkynes, carbon monoxide, and diphenyl diselenides regio- and stereoselectively in a single-pot reaction to produce good yields of beta-selenyl acrylamides. [reaction: see text]