Unexpected Periodicity in Cationic Group 5 Initiators for the Ring-Opening Polymerization of Lactones.

ε-Caprolactone (ε-CL) adducts of cationic, amine tris(phenolate)-supported niobium(V) and tantalum(V) ethoxides initiate the ring-opening polymerization of lactones. The Ta(V) species prepared and applied catalytically herein exhibits higher activity in the ring-opening polymerization (ROP) of ε-caprolactone than the previously reported, isostructural Nb(V) complex, contradicting literature comparisons of Nb(V)- and Ta(V)-based protocols. Both systems also initiate the ROP of δ-valerolactone and rac-ß-butyrolactone, kinetic studies confirming retention of higher activity by the Ta congener. Polymerizations of rac-ß-butyrolactone and δ-valerolactone were previously unrealized under Group V- or Ta-mediated conditions, respectively, although the former has afforded only low molecular weight, cyclic poly-3-hydroxybutyrate. Cationic ethoxo-Nb(V) and -Ta(V) δ-valerolactone adducts are also reported, demonstrating the facility of δ-valerolactone as a ligand and the generality of the synthetic method. Both δ-valerolactone-bearing complexes initiate the ROP of ε-caprolactone, δ-valerolactone, and rac-ß-butyrolactone. Accordingly, we have elucidated trends in reactivity and investigated the initiation mechanism for such systems, the insertion event being predicated upon intramolecular nucleophilic attack on the coordinated lactone by the adjacent alkoxide moiety. This mechanism enables quantitative, stoichiometric installation of a single monomer residue distinct from the bulk of the polymer chain, and permits modification of polymer properties via both manipulation of the molecular architecture and tuning of the polymerization kinetics, and thus dispersity, through hitherto inaccessible independent control of the initiation event.

Coordination of ε-Caprolactone to a Cationic Niobium(V) Alkoxide Complex: Fundamental Insight into Ring-Opening Polymerization via Coordination-Insertion.

We report three niobium-based initiators for the catalytic ring-opening polymerization (ROP) of ε-caprolactone, exhibiting good activity and molecular weight control. In particular, we have prepared on the gram-scale and fully characterized a monometallic cationic alkoxo-Nb(V) ε-caprolactone adduct representing, to the best of our knowledge, an unprecedented example of a metal complex with an intact lactone monomer and a functional ROP-initiating group simultaneously coordinated at the metal center. At 80 °C, all three systems initiate the immortal solution-state ROP of ε-caprolactone via a coordination-insertion mechanism, which has been confirmed through experimental studies, and is supported by computational data. Natural bond orbital calculations further indicate that polymerization may necessitate isomerization about the metal center between the alkoxide chain and the coordinated monomer. The observations made in this work are expected to inform mechanistic understanding both of amine tris(phenolate)-supported metal alkoxide ROP initiators, including various highly stereoselective systems for the polymerization of lactides and of coordination-insertion-type ROP protocols more broadly.

Sustainable Syntheses of Paracetamol and Ibuprofen from Biorenewable ß-pinene.

Scalable processes have been developed to convert ß-pinene into 4-isopropenylcyclohexanone, which is then used as a feedstock for the divergent synthesis of sustainable versions of the common painkillers, paracetamol and ibuprofen. Both synthetic routes use Pd0 catalysed reactions to aromatize the cyclohexenyl rings of key intermediates to produce the benzenoid ring systems of both drugs. The potential of using bioderived 4-hydroxyacetophenone as a drop-in feedstock replacement to produce sustainable aromatic products is also discussed within a terpene biorefinery context.

A Highly Active and Selective Zirconium-Based Catalyst System for the Industrial Production of Poly(lactic acid).

The biodegradable, aliphatic polyester poly(lactic acid), PLA, is a leading bio-based alternative to petrochemical-derived plastic materials across a range of applications. Widely reported in the available literature as a benchmark for PLA production via the bulk ring-opening polymerization of lactides is the use of divalent tin catalysts, and particularly tin(II) bis(2-ethylhexanoate). We present an alternative zirconium-based system that combines an inexpensive Group IV metal with the robustness, high activity, control, and designed compatibility with existing facilities and processes, that are required for industrial use. We have carried out a comprehensive kinetic study and applied a combined experimental and theoretical approach to understanding the mechanism by which the polymerization of lactide proceeds in the presence of this system. In the laboratory-scale (20 g) polymerization of recrystallized racemic d,l-lactide (rac-lactide), we have measured catalyst turnover frequencies up to at least 56,000 h-1, and confirmed the reported protocols' resistance toward undesirable epimerization, transesterification, and chain scission processes, deleterious to the properties of the polymer product. Further optimization and scale-up under industrial conditions have confirmed the relevance of the catalytic protocol to the commercial production of melt-polymerized PLA. We were able to undertake the efficient preparation of high-molecular-weight PLA on the 500-2000 g scale, via the selective and well-controlled polymerization of commercial polymer-grade l-lactide under challenging, industrially relevant conditions, and at metal concentrations as low as 8-12 ppm Zr by weight ([Zr] = 1.3 × 10-3 to 1.9 × 10-3 mol %). Under those conditions, a catalyst turnover number of at least 60,000 was attained, and the activity of the catalyst was comparable to that of tin(II) bis(2-ethylhexanoate).

Fast and accurate diffusion NMR acquisition in continuous flow.

FlowNMR spectroscopy has become a popular and powerful technique for online reaction monitoring. DOSY NMR is an established technique for obtaining information about diffusion rates and molecular size on static samples. This work extends the FlowNMR toolbox to include FlowDOSY based on convection compensation and use of a low-pulsation pump or flow effect correction, allowing accurate and precise diffusion coefficients to be obtained at flow rates up to 4.0 mL min-1 in less than 5 minutes.

Understanding the Effects of Cross-Linking Density on the Self-Healing Performance of Epoxidized Natural Rubber and Natural Rubber.

The demand for self-healing elastomers is increasing due to the potential opportunities such materials offer in reducing down-time and cost through extended product lifetimes and reduction of waste. However, further understanding of self-healing mechanisms and processes is required in order to develop a wider range of commercially applicable materials with self-healing properties. Epoxidized natural rubber (ENR) is a derivative of polyisoprene. ENR25 and ENR50 are commercially available materials with 25 and 50 mol % epoxidation, respectively. Recently, reports of the use of ENR in self-healing materials have begun to emerge. However, to date, there has been limited analysis of the self-healing mechanism at the molecular level. The aim of this work is to gain understanding of the relevant self-healing mechanisms through systematic characterization and analysis of the effect of cross-linking on the self-healing performance of ENR and natural rubber (NR). In our study, cross-linking of ENR and NR with dicumyl peroxide and sulfur to provide realistic models of commercial rubber formulations is described, and a cross-linking density of 5 × 10-5 mol cm-3 in sulfur-cured ENR is demonstrated to achieve a healing efficiency of 143% for the tensile strength. This work provides the foundation for further modification of ENR, with the goal of understanding and controlling ENR's self-healing ability for future applications.

Versatile Chemical Recycling Strategies: Value-Added Chemicals from Polyester and Polycarbonate Waste.

ZnII -complexes bearing half-salan ligands were exploited in the mild and selective chemical upcycling of various commercial polyesters and polycarbonates. Remarkably, we report the first example of discrete metal-mediated poly(bisphenol A carbonate) (BPA-PC) methanolysis being appreciably active at room temperature. Indeed, Zn(2)2 and Zn(2)Et achieved complete BPA-PC consumption within 12-18 mins in 2-Me-THF, noting high bisphenol A (BPA) yields (SBPA =85-91 %) within 2-4 h. Further kinetic analysis found such catalysts to possess kapp values of 0.28±0.040 and 0.47±0.049 min-1 respectively at 4 wt%, the highest reported to date. A completely circular upcycling approach to plastic waste was demonstrated through the production of several renewable poly(ester-amide)s (PEAs), based on a terephthalamide monomer derived from bottle-grade poly(ethylene terephthalate) (PET), which exhibited excellent thermal properties.

Comparison of Cyclic and Linear Poly(lactide)s Using Small-Angle Neutron Scattering.

Small-angle neutron scattering (SANS) experiments were conducted on cyclic and linear polymers of racemic and l-lactides (PLA) with the goal of comparing chain configurations, scaling, and effective polymer-solvent interactions of the two topologies in acetone-d 6 and THF-d 8. There are limited reports of SANS results on cyclic polymers due to the lack of substantial development in the field until recently. Now that pure, well-defined cyclic polymers are accessible, unanswered questions about their rheology and physical conformations can be better investigated. Previously reported SANS experiments have used cyclic and linear polystyrene samples; therefore, our work allowed for direct comparison using a contrasting (structurally and sterically) polymer. We compared SANS results of cyclic and linear PLA samples with various microstructures and molecular weights at two different temperatures, allowing for comparison with a wide range of variables. The results followed the trends of previous experiments, but much greater differences in the effective polymer-solvent interaction parameters between cyclic and linear forms of PLA were observed, implying that the small form factor and hydrogen bonding in PLA allowed for much more compact conformations in the cyclic form only. Also, the polymer microstructure was found to influence polymer-solvent interaction parameters substantially. These results illustrate how the difference in polymer-solvent interactions between cyclic and linear polymers can vary greatly depending on the polymer in question and the potential of neutron scattering as a tool for identification and characterization of the cyclic topology.

Treatment-refractory ulcerative colitis responsive to indigo naturalis.

BACKGROUND: Indigo naturalis (IN) is an herbal medicine that has been used for ulcerative colitis with an unclear mechanism of action. Indigo and indirubin, its main constituents, are ligands of the aryl hydrocarbon receptor (AhR). We assessed the safety, efficacy, and colon AhR activity of IN given orally to patients with treatment-refractory ulcerative colitis. The role of AhR in IN benefit was further evaluated with an AhR antagonist in a murine colitis model. METHODS: This open-label, dose-escalation study sequentially treated 11 patients with ulcerative colitis with either IN 500 mg/day or 1.5 g/day for 8 weeks, followed by a 4-week non-treatment period. The primary efficacy endpoint was clinical response at week 8, assessed by total Mayo score. Secondary endpoints included clinical remission, Ulcerative Colitis Endoscopic Index of Severity, quality of life, and colon AhR activity measured by cytochrome P450 1A1 (CYP1A1) RNA expression. RESULTS: Ten of 11 (91%) patients, including 8/9 (89%) with moderate-to-severe disease, achieved a clinical response. Among these 10 patients, all had failed treatment with 5-aminosalicylic acid, 8 patients with a tumour necrosis factor (TNF)-alpha inhibitor, and 6 patients with TNF-alpha inhibitor and vedolizumab. Five patients were corticosteroid dependent. Clinical response was observed in all five patients who had been recommended for colectomy. Three patients achieved clinical remission. All patients experienced improved endoscopic severity and quality of life. Four weeks after treatment completion, six patients had worsened partial Mayo scores. Four patients progressed to colectomy after study completion. Colon CYP1A1 RNA expression increased 12 557-fold at week 8 among six patients evaluated. No patient discontinued IN due to an adverse event. Concomitant administration of 3-methoxy-4-nitroflavone, an AhR antagonist, in a murine colitis model abrogated the benefit of IN. CONCLUSION: IN is a potentially effective therapy for patients with treatment-refractory ulcerative colitis. This benefit is likely through AhR activation. TRIAL REGISTRATION NUMBER: NCT02442960.

Synthesis, Properties, and Applications of Bio-Based Cyclic Aliphatic Polyesters.

Cyclic polymers have long been reported in the literature, but their development has often been stunted by synthetic difficulties such as the presence of linear contaminants. Research into the synthesis of these polymers has made great progress in the past decade, and this review covers the synthesis, properties, and applications of cyclic polymers, with an emphasis on bio-based aliphatic polyesters. Synthetic routes to cyclic polymers synthesized from bioderived monomers, alongside mechanistic descriptions for both ring closure and ring expansion polymerization approaches, are reviewed. The review also highlights some of the unique physical properties of cyclic polymers together with potential applications. The findings illustrate the substantial recent developments made in the syntheses of cyclic polymers, as well as the progress which can be made in the commercialization of bio-based polymers through the versatility this topology provides.

Ti(IV)-Tris(phenolate) Catalyst Systems for the Ring-Opening Copolymerization of Cyclohexene Oxide and Carbon Dioxide.

Titanium(IV) complexes of amino-tris(phenolate) ligands (LTiX, X = chloride, isopropoxide) together with bis(triphenylphosphine)iminium chloride (PPNCl) are active catalyst systems for the ring-opening copolymerization of carbon dioxide and cyclohexene oxide. They show moderate activity, with turnover frequency values of ∼60 h-1 (0.02 mol % of catalyst, 80 °C, 40 bar of CO2) and high selectivity (carbonate linkages >90%), but their absolute performances are lower than those of the most active Ti(IV) catalyst systems. The reactions proceed with linear evolution of polycarbonate (PCHC) molar mass with epoxide conversion, consistent with controlled polymerizations, and evolve bimodal molar mass distributions of PCHC (up to M n = 42 kg mol-1). The stoichiometric reaction between [LTiO i Pr] and tetraphenylphosphonium chloride, PPh4Cl, allows isolation of the putative catalytic intermediate [LTi(O i Pr)Cl]-, which is characterized using single-crystal X-ray diffraction techniques. The anionic titanium complex [LTi(OR)Cl]- is proposed as a model for the propagating alkoxide intermediates in the catalytic cycle.

Selective Catalytic Synthesis of 1,2- and 8,9-Cyclic Limonene Carbonates as Versatile Building Blocks for Novel Hydroxyurethanes.

The selective catalytic synthesis of limonene-derived monofunctional cyclic carbonates and their subsequent functionalisation via thiol-ene addition and amine ring-opening is reported. A phosphotungstate polyoxometalate catalyst used for limonene epoxidation in the 1,2-position is shown to also be active in cyclic carbonate synthesis, allowing a two-step, one-pot synthesis without intermittent epoxide isolation. When used in conjunction with a classical halide catalyst, the polyoxometalate increased the rate of carbonation in a synergistic double-activation of both substrates. The cis isomer is shown to be responsible for incomplete conversion and by-product formation in commercial mixtures of 1,2-limomene oxide. Carbonation of 8,9-limonene epoxide furnished the 8,9-limonene carbonate for the first time. Both cyclic carbonates underwent thiol-ene addition reactions to yield linked di-monocarbonates, which can be used in linear non-isocyanate polyurethanes synthesis, as shown by their facile ring-opening with N-hexylamine. Thus, the selective catalytic route to monofunctional limonene carbonates gives straightforward access to monomers for novel bio-based polymers.

Correction: Waste not, want not: CO2 (re)cycling into block polymers.

Correction for 'Waste not, want not: CO2 (re)cycling into block polymers' by Sumesh K. Raman et al., Chem. Commun., 2019, 55, 7315-7318.

Waste not, want not: CO2 (re)cycling into block polymers.

A new way to combine two different polymerisation reactions, using a single catalyst, results in efficient block polymer synthesis. The selective polymerisation of mixtures of l-lactide-O-carboxyanhydride and cyclohexene oxide, using a di-zinc catalyst in a one-pot procedure, allows the preparation of poly(l-lactide-b-cyclohexene carbonate). The catalysis near quantitatively recycles the carbon dioxide released during polyester formation into the subsequent polycarbonate block, with an atom economy of up to of 91%.

Functional and informatics analysis enables glycosyltransferase activity prediction.

The elucidation and prediction of how changes in a protein result in altered activities and selectivities remain a major challenge in chemistry. Two hurdles have prevented accurate family-wide models: obtaining (i) diverse datasets and (ii) suitable parameter frameworks that encapsulate activities in large sets. Here, we show that a relatively small but broad activity dataset is sufficient to train algorithms for functional prediction over the entire glycosyltransferase superfamily 1 (GT1) of the plant Arabidopsis thaliana. Whereas sequence analysis alone failed for GT1 substrate utilization patterns, our chemical-bioinformatic model, GT-Predict, succeeded by coupling physicochemical features with isozyme-recognition patterns over the family. GT-Predict identified GT1 biocatalysts for novel substrates and enabled functional annotation of uncharacterized GT1s. Finally, analyses of GT-Predict decision pathways revealed structural modulators of substrate recognition, thus providing information on mechanisms. This multifaceted approach to enzyme prediction may guide the streamlined utilization (and design) of biocatalysts and the discovery of other family-wide protein functions.

Zirconium amine tris(phenolate): A more effective initiator for biomedical lactide.

Here a zirconium amine tris(phenolate) is used as the initiator for the production of polylactide for biomedical applications, as a replacement for a tin initiator (usually tin octanoate). The ring opening polymerization (ROP) was carried out in the melt at 130°C. The zirconium-catalyzed PLA (PLA-Zr) required 30min, resulting in a polydispersity index (PDI) of 1.17, compared to 1h and PDI=1.77 for tin-catalyzed PLA (PLA-Sn). PLA-Zr and PLA-Sn supported osteosarcoma cell (MG63) culture to the same extent (cell number, morphology, extracellular matrix production and osteogenic function) until day 14 when the PLA-Zr showed increased cell number, overall extracellular matrix production and osteogenic function. To conclude, the reduction in reaction time, controllable microstructure and biologically benign nature of the zirconium amine tris(phenolate) initiator shows that it is a more effective initiator for ROP of polylactide for biomedical applications.

An Immunosuppressive Dendritic Cell Subset Accumulates at Secondary Sites and Promotes Metastasis in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) after complete surgical resection is often followed by distant metastatic relapse for reasons that remain unclear. In this study, we investigated how the immune response at secondary sites affects tumor spread in murine models of metastatic PDAC. Early metastases were associated with dense networks of CD11b+CD11c+MHC-II+CD24+CD64lowF4/80low dendritic cells (DC), which developed from monocytes in response to tumor-released GM-CSF. These cells uniquely expressed MGL2 and PD-L2 in the metastatic microenvironment and preferentially induced the expansion of T regulatory cells (Treg) in vitro and in vivo Targeted depletion of this DC population in Mgl2DTR hosts activated cytotoxic lymphocytes, reduced Tregs, and inhibited metastasis development. Moreover, blocking PD-L2 selectively activated CD8 T cells at secondary sites and suppressed metastasis, suggesting that the DCs use this particular pathway to inhibit CD8 T-cell-mediated tumor immunity. Phenotypically similar DCs accumulated at primary and secondary sites in other models and in human PDAC. These studies suggest that a discrete DC subset both expands Tregs and suppresses CD8 T cells to establish an immunosuppressive microenvironment conducive to metastasis formation. Therapeutic strategies to block the accumulation and immunosuppressive activity of such cells may help prevent PDAC progression and metastatic relapse after surgical resection. Cancer Res; 77(15); 4158-70. ©2017 AACR.

Ligands and complexes based on piperidine and their exploitation of the ring opening polymerisation of rac-lactide.

A range of ligands based upon 2-(aminomethyl)piperidine have been successfully complexed to Mg(ii), Zn(ii) and group IV metal centres. These complexes have been characterised both in solution and solid state with different coordination geometries realised dependant on the nature of the ligand. For the Mg(ii) and Zn(ii) complexes, M(1-2)2, were isolated and analysed by DOSY NMR spectroscopy. These ligands also furnished diastereomeric group IV complexes, M(1-2)2(OiPr)2. Group IV salalen and salan complexes, M(4-5)(OR)2 were also found to be diastereomeric in nature, with either ß-cis or α-cis geometriesrespectively. The tridentate ligand, 6H2, yielded five coordinate complexes with both Ti(iv) and Zr(iv). All complexes were screened for the ring opening polymerisation of rac-lactide under both solvent and melt conditions. For the Mg(ii) and Zn(ii) complexes, good activity was observed with Zn(1-2)2 demonstrating immortal polymerisation characteristics.

Restoring Retinoic Acid Attenuates Intestinal Inflammation and Tumorigenesis in APCMin/+ Mice.

Chronic intestinal inflammation accompanies familial adenomatous polyposis (FAP) and is a major risk factor for colorectal cancer in patients with this disease, but the cause of such inflammation is unknown. Because retinoic acid (RA) plays a critical role in maintaining immune homeostasis in the intestine, we hypothesized that altered RA metabolism contributes to inflammation and tumorigenesis in FAP. To assess this hypothesis, we analyzed RA metabolism in the intestines of patients with FAP as well as APCMin/+ mice, a model that recapitulates FAP in most respects. We also investigated the impact of intestinal RA repletion and depletion on tumorigenesis and inflammation in APCMin/+ mice. Tumors from both FAP patients and APCMin/+ mice displayed striking alterations in RA metabolism that resulted in reduced intestinal RA. APCMin/+ mice placed on a vitamin A-deficient diet exhibited further reductions in intestinal RA with concomitant increases in inflammation and tumor burden. Conversely, restoration of RA by pharmacologic blockade of the RA-catabolizing enzyme CYP26A1 attenuated inflammation and diminished tumor burden. To investigate the effect of RA deficiency on the gut immune system, we studied lamina propria dendritic cells (LPDC) because these cells play a central role in promoting tolerance. APCMin/+ LPDCs preferentially induced Th17 cells, but reverted to inducing Tregs following restoration of intestinal RA in vivo or direct treatment of LPDCs with RA in vitro These findings demonstrate the importance of intestinal RA deficiency in tumorigenesis and suggest that pharmacologic repletion of RA could reduce tumorigenesis in FAP patients. Cancer Immunol Res; 4(11); 917-26. ©2016 AACR.

Aluminium salalens vs. salans: "Initiator Design" for the isoselective polymerisation of rac-lactide.

We report the rationalised design of aluminium initiators and their application for ROP of rac-lactide (rac-LA). A very minor change to the ligand backbone (imine reduction) to give secondary amines was found to have a dramatic effect on activity and selectivity with isotactic PLA being realised.