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.

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.

Allogeneic IgG combined with dendritic cell stimuli induce antitumour T-cell immunity.

Whereas cancers grow within host tissues and evade host immunity through immune-editing and immunosuppression, tumours are rarely transmissible between individuals. Much like transplanted allogeneic organs, allogeneic tumours are reliably rejected by host T cells, even when the tumour and host share the same major histocompatibility complex alleles, the most potent determinants of transplant rejection. How such tumour-eradicating immunity is initiated remains unknown, although elucidating this process could provide the basis for inducing similar responses against naturally arising tumours. Here we find that allogeneic tumour rejection is initiated in mice by naturally occurring tumour-binding IgG antibodies, which enable dendritic cells (DCs) to internalize tumour antigens and subsequently activate tumour-reactive T cells. We exploited this mechanism to treat autologous and autochthonous tumours successfully. Either systemic administration of DCs loaded with allogeneic-IgG-coated tumour cells or intratumoral injection of allogeneic IgG in combination with DC stimuli induced potent T-cell-mediated antitumour immune responses, resulting in tumour eradication in mouse models of melanoma, pancreas, lung and breast cancer. Moreover, this strategy led to eradication of distant tumours and metastases, as well as the injected primary tumours. To assess the clinical relevance of these findings, we studied antibodies and cells from patients with lung cancer. T cells from these patients responded vigorously to autologous tumour antigens after culture with allogeneic-IgG-loaded DCs, recapitulating our findings in mice. These results reveal that tumour-binding allogeneic IgG can induce powerful antitumour immunity that can be exploited for cancer immunotherapy.

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.

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.

Th17 cells induce Th1-polarizing monocyte-derived dendritic cells.

In chronically inflamed tissues, such as those affected by autoimmune disease, activated Th cells often colocalize with monocytes. We investigate in this study how murine Th cells influence the phenotype and function of monocytes. The data demonstrate that Th1, Th2, and Th17 subsets promote the differentiation of autologous monocytes into MHC class II(+), CD11b(+), CD11c(+) DC that we call DCTh. Although all Th subsets induce the formation of DCTh, activated Th17 cells uniquely promote the formation of IL-12/IL-23-producing DCTh (DCTh17) that can polarize both naive and Th17 cells to a Th1 phenotype. In the inflamed CNS of mice with Th17-mediated experimental autoimmune encephalomyelitis, Th cells colocalize with DC, as well as monocytes, and the Th cells obtained from these lesions drive the formation of DCTh that are phenotypically indistinguishable from DCTh17 and polarize naive T cells toward a Th1 phenotype. These results suggest that DCTh17 are critical in the interplay of Th17- and Th1-mediated responses and may explain the previous finding that IL-17-secreting Th cells become IFN-γ-secreting Th1 cells in experimental autoimmune encephalomyelitis and other autoimmune disorders.

Exploiting the reversible covalent bonding of boronic acids: recognition, sensing, and assembly.

Boronic acids can interact with Lewis bases to generate boronate anions, and they can also bind with diol units to form cyclic boronate esters. Boronic acid based receptor designs originated when Lorand and Edwards used the pH drop observed upon the addition of saccharides to boronic acids to determine their association constants. The inherent acidity of the boronic acid is enhanced when 1,2-, 1,3-, or 1,4-diols react with boronic acids to form cyclic boronic esters (5, 6, or 7 membered rings) in aqueous media, and these interactions form the cornerstone of diol-based receptors used in the construction of sensors and separation systems. In addition, the recognition of saccharides through boronic acid complex (or boronic ester) formation often relies on an interaction between a Lewis acidic boronic acid and a Lewis base (proximal tertiary amine or anion). These properties of boronic acids have led to them being exploited in sensing and separation systems for anions (Lewis bases) and saccharides (diols). The fast and stable bond formation between boronic acids and diols to form boronate esters can serve as the basis for forming reversible molecular assemblies. In spite of the stability of the boronate esters' covalent B-O bonds, their formation is reversible under certain conditions or under the action of certain external stimuli. The reversibility of boronate ester formation and Lewis acid-base interactions has also resulted in the development and use of boronic acids within multicomponent systems. The dynamic covalent functionality of boronic acids with structure-directing potential has led researchers to develop a variety of self-organizing systems including macrocycles, cages, capsules, and polymers. This Account gives an overview of research published about boronic acids over the last 5 years. We hope that this Account will inspire others to continue the work on boronic acids and reversible covalent chemistry.

Preparation of stereoregular isotactic poly(mandelic acid) through organocatalytic ring-opening polymerization of a cyclic O-carboxyanhydride.

Poly(mandelic acid) (PMA) is an aryl analogue of poly(lactic acid) (PLA) and a biodegradable analogue of polystyrene. The preparation of stereoregular PMA was realized using a pyridine/mandelic acid adduct (Py⋅MA) as an organocatalyst for the ring-opening polymerization (ROP) of the cyclic O-carboxyanhydride (manOCA). Polymers with a narrow polydispersity index and excellent molecular-weight control were prepared at ambient temperature. These highly isotactic chiral polymers exhibit an enhancement of the glass-transition temperature (T(g)) of 15 °C compared to the racemic polymer, suggesting potential future application as high-performance commodity and biomedical materials.

T(H)1, T(H)2, and T(H)17 cells instruct monocytes to differentiate into specialized dendritic cell subsets.

Monocytes and T helper (T(H)) cells rapidly infiltrate inflamed tissues where monocytes differentiate into inflammatory dendritic cells (DCs) through undefined mechanisms. Our studies indicate that T(H) cells frequently interact with monocytes in inflamed skin and elicit the differentiation of specialized DC subsets characteristic of these lesions. In psoriasis lesions, T(H)1 and T(H)17 cells interact with monocytes and instruct these cells to differentiate into T(H)1- and T(H)17-promoting DCs, respectively. Correspondingly, in acute atopic dermatitis, T(H)2 cells interact with monocytes and elicit the formation of T(H)2-promoting DCs. DC formation requires GM-CSF and cell contact, whereas T(H) subset specific cytokines dictate DC function and the expression of DC subset specific surface molecules. Moreover, the phenotypes of T cell-induced DC subsets are maintained after subsequent stimulation with a panel of TLR agonists, suggesting that T(H)-derived signals outweigh downstream TLR signals in their influence on DC function. These findings indicate that T(H) cells govern the formation and function of specialized DC subsets.

Monomerizing alkali-metal 3,5-dimethylbenzyl salts with tris(N, N-dimethyl-2-aminoethyl)amine (Me6TREN): structural and bonding implications.

The series of alkali-metal (Li, Na, K) complexes of the substituted benzyl anion 3,5-dimethylbenzyl (Me2C6H3CH2(-)) derived from 1,3,5-trimethylbenzene (mesitylene) have been coerced into monomeric forms by supporting them with the tripodal tetradentate Lewis donor tris(N,N-dimethyl-2-aminoethyl)amine, [N(CH2CH2NMe2)3, Me6TREN]. Molecular structure analysis by X-ray crystallography establishes that the cation-anion interaction varies as a function of the alkali-metal, with the carbanion binding to lithium mainly in a σ fashion, to potassium mainly in a π fashion, with the interaction toward sodium being intermediate between these two extremes. This distinction is due to the heavier alkali-metal forcing and using the delocalization of negative charge into the aromatic ring to gain a higher coordination number in accordance with its size. Me6TREN binds the metal in a η(4) mode at all times. This coordination isomerism is shown by multinuclear NMR spectroscopy to also extend to the structures in solution and is further supported by density functional theory (DFT) calculations on model systems. A Me6TREN stabilized benzyl potassium complex has been used to prepare a mixed-metal ate complex by a cocomplexation reaction with tBu2Zn, with the benzyl ligand acting as an unusual ditopic σ/π bridging ligand between the two metals, and with the small zinc atom relocalizing the negative charge back on to the lateral CH2 arm to give a complex best described as a contacted ion pair potassium zincate.

Synthesis and structural characterization of group 4 metal alkoxide complexes of N,N,N',N'-tetrakis(2-hydroxyethyl)ethylenediamine and their use as initiators in the ring-opening polymerization (ROP) of rac-lactide under industrially relevant conditions.

A series of N,N,N',N'-tetrakis(2-hydroxyethyl)ethylenediamine (TOEEDH4) ligand precursors and their group 4 metal complexes have been prepared. The complexes have been characterized by single-crystal X-ray diffraction and (1)H NMR spectroscopy, highlighting the ability to systematically vary the number of TOEED ligands within the system. Initial catalytic data for the solvent-free, ring-opening polymerization of rac-lactide (rac-LA), a promising degradable polymer produced from renewable resources, is reported. At 135 °C, it has been demonstrated that the activity of the complexes is enhanced by increasing the number of labile isopropoxide groups. When the temperature was further increased to 165 °C, all complexes demonstrated a far higher activity irrespective of the identity of the metal or number of labile initiator groups. Polymerization kinetics were monitored in real time using FT-IR spectroscopy with a diamond composite insertion probe and Ti4(TOEED)(O(i)Pr)12 was demonstrated to convert over 95% of the rac-LA within 160 min.

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).

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.

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.

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.

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.

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.

Exploiting σ/π coordination isomerism to prepare homologous organoalkali metal (Li, Na, K) monomers with identical ligand sets.

Tetraamine Me(6)TREN has been used as a scaffold support to provide coordinative saturation in the complexes PhCH(2)M⋅Me(6)TREN (M=Li, Na, K). The Li derivative displays a Li−−C σ interaction with a pyramidalized CH(2) both in the solid state and in solution, and represents the first example of η(4) coordination of Me(6)TREN to lithium. In the sodium derivative, the metal cation slips slightly towards the delocalized π electrons whilst maintaining a partial σ interaction with the CH(2) group. For the potassium case, coordinative saturation successfully yields the first monomeric benzylpotassium complex, in which the anion binds to the metal cation exclusively through its delocalized π system resulting in a planar CH(2) group.

Polyamine-stabilized sodium aryloxides: simple initiators for the ring-opening polymerization of rac-lactide.

Metalation of 2,4,6-tri(methyl)phenol ((Me)ArOH) and 2,6-di(tert-butyl)-4-methylphenol ((Bu)ArOH) with NaN(SiMe(3))(2) in toluene and in the presence of stoichiometric amounts of the polydentate amines N,N,N',N'-tetramethylethylenediamine (TMEDA) and N,N,N',N'',N''-pentamethyldiethylenetriamine (PMDETA) affords three new sodium aryloxide complexes [Na(µ-OAr(Bu))(TMEDA)](2) (3), [Na(µ-OAr(Me))(PMDETA)](2) (4), and [Na(OAr(Bu))(PMDETA)] (5). Complexes 3 to 5 have been isolated as crystalline materials in reasonable yields and characterized in the solid state by X-ray crystallography and in solution by NMR spectroscopy. Complexes 3 to 5 and the related [tris(2-dimethylaminoethyl)amine] (Me(6)TREN) derivatives [Na(OAr(Me))(HOAr(Me))(Me(6)TREN)] (1) and [Na(OAr(Bu))(Me(6)TREN)] (2), recently prepared in our group, are shown to be active as initiators for the ring-opening polymerization (ROP) of rac-lactide with benzyl alcohol as a co-initiator. However, during the course of the polymerization reactions intrachain and stereorandom transesterification side-reactions were observed under some of the experimental conditions tested.