Copolymerization of ß-Butyrolactones into Functionalized Polyhydroxyalkanoates Using Aluminum Catalysts: Influence of the Initiator in the Ring-Opening Polymerization Mechanism.

Within bioplastics, natural poly(3-hydroxybutyrate) (PHB) stands out as fully biocompatible and biodegradable, even in marine environments; however, its high isotacticity and crystallinity limits its mechanical properties and hence its applications. PHB can also be synthesized with different tacticities via a catalytic ring-opening polymerization (ROP) of rac-ß-butyrolactone (BBL), paving the way to PHB with better thermomechanical and processability properties. In this work, the catalyst family is extended based on aluminum phenoxy-imine methyl catalyst [AlMeL2], that reveals efficient in the ROP of BBL, to the halogeno analogous complex [AlClL2]. As well, the impact on the ROP mechanism of different initiators is further explored with a particular focus in dimethylaminopyridine (DMAP), a hardly studied initiator for the ROP of BBL. A thorough mechanistic study is performed that evidences the presence of two concomitant DMAP-mediated mechanisms, that lead to either a DMAP or a crotonate end-capping group. Besides, in order to increase the possibilities of PHB post-polymerization functionalization, the introduction of a side-chain functionality is explored, establishing the copolymerization of BBL with ß-allyloxymethylene propiolactone (BPLOAll), resulting in well-defined P(BBL-co-BPLOAll) copolymers.

Alkali metal⋯methyl short contacts in aluminates: more than agostic interactions.

Knowing the nature and strength of noncovalent interactions is key to enhancing the synthetic methods and catalytic processes in which they are involved. We present herein the synthesis and characterization of a novel aluminium sodium oximate compound, followed by a comprehensive computational study of the sodium⋯methyl interaction that appears in its crystal structure. Our experimental results have been compared to a large set of structural data retrieved from the Cambridge Structural Database in order to assess the main geometrical preferences of these interactions. Moreover, representative model systems have been studied at the DFT level and the topology of their electron density analysed by means of QTAIM. Although alkali metal⋯methyl short contacts have been traditionally considered as agostic interactions, we have demonstrated here that the physical origin of the attraction relies on the electron-rich carbon atom bound to aluminium and its interaction with the cation.

Synthesis and applications of the sulfur containing analogues of cyclic carbonates.

Cyclic thiocarbonates are the sulfur containing analogues of the well-studied cyclic carbonates and are relatively poorly explored despite their potential applications and intriguing reactivities. To date, application of these organosulfur compounds has included their use as monomers for polythiocarbonate synthesis (their ring-opening is more readily achieved and more selective than the corresponding cyclic carbonates) and as reactive intermediates for the preparation of a range of higher-value sulfur containing compounds. Despite these uses, the synthesis of these compounds is far less explored and developed than their non-sulfur analogues. Here, we provide an overview of the state-of-the-art, both recent and historical, for the synthesis of a range of cyclic mono-, di- and tri-thiocarbonates (both five and six-membered rings), with selected examples of their reported applications also highlighted.

Chemoselective cycloadditions to epoxide derivatives of erucic acid with CO2 and CS2: controlled access to value-added bio-derived compounds.

The potential for application of bio-derived molecules in our everyday lives is attracting vast interest as attention moves towards development of a truly circular and sustainable economy. Whilst a large number of molecules are naturally available and contain a variety of functional groups, few of these compounds are able to be immediately transferred to applications where they can directly replace established oil-derived species. This issue presents both a challenge and an opportunity for the synthetic chemistry community. This study demonstrates how erucic acid, a molecule containing an olefin and a carboxylic acid, which is readily available from commonly cultivated rapeseed oils, can be used as a platform to be chemoselectively converted into a range of value-added compounds using established and high yielding synthetic procedures. In particular, the work showcases approaches towards the chemoselective (and in cases regioselective) oxidation with m-CPBA and incorporation of cyclic carbonate and cyclic dithiocarbonate functionalities which have potential to be employed in a range of applications. Expedient routes to unusual derivatives containing both cyclic carbonate and cyclic dithiocarbonates are also presented taking advantage of the distinct reactivities of the two different epoxides in the intermediate compounds. This work also provides a rare example of the synthesis of internal cyclic dithiocarbonates. These new products have potential to be applied as monomers in the growing field of bio-based non-isocyanate polyurethane synthesis.

IL-7R is essential for leukemia-initiating cell activity of T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy resulting from the dysregulation of signaling pathways that control intrathymic T-cell development. Relapse rates are still significant, and prognosis is particularly bleak for relapsed patients. Therefore, development of novel therapies specifically targeting pathways controlling leukemia-initiating cell (LIC) activity is mandatory for fighting refractory T-ALL. The interleukin-7 receptor (IL-7R) is a crucial T-cell developmental pathway that is commonly expressed in T-ALL and has been implicated in leukemia progression; however, the significance of IL-7R/IL-7 signaling in T-ALL pathogenesis and its contribution to disease relapse remain unknown. To directly explore whether IL-7R targeting may be therapeutically efficient against T-ALL relapse, we focused on a known Notch1-induced T-ALL model, because a majority of T-ALL patients harbor activating mutations in NOTCH1, which is a transcriptional regulator of IL-7R expression. Using loss-of-function approaches, we show that Il7r-deficient, but not wild-type, mouse hematopoietic progenitors transduced with constitutively active Notch1 failed to generate leukemia upon transplantation into immunodeficient mice, thus providing formal evidence that IL-7R function is essential for Notch1-induced T-cell leukemogenesis. Moreover, we demonstrate that IL-7R expression is an early functional biomarker of T-ALL cells with LIC potential and report that impaired IL-7R signaling hampers engraftment and progression of patient-derived T-ALL xenografts. Notably, we show that IL-7R-dependent LIC activity and leukemia progression can be extended to human B-cell acute lymphoblastic leukemia (B-ALL). These results have important therapeutic implications, highlighting the relevance that targeting normal IL-7R signaling may have in future therapeutic interventions, particularly for preventing T-ALL (and B-ALL) relapse.

NHC-CDI Betaine Adducts and Their Cationic Derivatives as Catalyst Precursors for Dichloromethane Valorization.

Zwitterionic adducts of N-heterocyclic carbene and carbodiimide (NHC-CDI) are an emerging class of organic compounds with promising properties for applications in various fields. Herein, we report the use of the ICyCDI(p-Tol) betaine adduct (1a) and its cationic derivatives 2a and 3a as catalyst precursors for the dichloromethane valorization via transformation into high added value products CH2Z2 (Z = OR, SR or NR2). This process implies selective chloride substitution of dichloromethane by a range of nucleophiles Na+Z- (preformed or generated in situ from HZ and an inorganic base) to yield formaldehyde-derived acetals, dithioacetals, or aminals with full selectivity. The reactions are conducted in a multigram-scale under very mild conditions, using dichloromethane both as a reagent and solvent, and very low catalyst loading (0.01 mol %). The CH2Z2 derivatives were isolated in quantitative yields after filtration and evaporation, which facilitates recycling the dichloromethane excess. Mechanistic studies for the synthesis of methylal CH2(OMe)2 rule out organocatalysis as being responsible for the CH2 transfer, and a phase-transfer catalysis mechanism is proposed instead. Furthermore, we observed that 1a and 2a react with NaOMe to form unusual isoureate ethers, which are the actual phase-transfer catalysts, with a strong preference for sodium over other alkali metal nucleophiles.

Aluminates with Fluorinated Schiff Bases: Influence of the Alkali Metal⁻Fluorine Interactions in Structure Stabilization.

New heterometallic aluminium-alkali metal compounds have been prepared using Schiff bases with electron withdrawing substituents as ligands. The synthesis of these new species was achieved via the reaction of AlMe3 with the freshly prepared alkali-metallated ligand. The derivatives formed were characterized by NMR in solution and by single crystal X-ray diffraction in the solid state. Aluminate derivatives with lithium and sodium were prepared and a clear influence of the alkali metal in the final outcome is observed. The presence of a Na···F interaction in the solid state has a stabilization effect and the species [NaAlMe3L]2 can de isolated for the first time, which was not possible when using Schiff bases without electron withdrawing substituents as ligands.

Comparison of halogen bonding networks with Ru(ii) complexes and analysis of the influence of the XB interactions on their reactivity.

Coordination compounds of formula [Ru(Cl)2(CNR)4] are interesting building blocks for the preparation of halogen bonding supramolecular networks, since the chloride ligand is a good XB acceptor. When using I2 as the XB donor, an unexpected reaction on the ruthenium coordination sphere happens where the chloride ligands are substituted by iodides. The isolation of several intermediates with different substitution degrees and showing XB interactions in a solid state network evidenced the clear influence of the XB species in this unusual reaction process. The extension of the studies to bromine gave the analogous result, i.e. the substitution of the chloride ligands by bromides. Furthermore, changing the organic substituent in the isocyanide ligands from alkyl to aryl does not affect the outcome of the reaction; however the process is faster when the alkyl substituents are present. In the course of the study of these reactions we have isolated a whole range of XB-based networks were interactions such as ClI-I, BrBr-Br, II-I and IBr-Br are present, a systematic comparison of the XB structural features for the different networks isolated and the influence in their reactivity has been performed.

Intriguing I2 Reduction in the Iodide for Chloride Ligand Substitution at a Ru(II) Complex: Role of Mixed Trihalides in the Redox Mechanism.

The compound [Ru(CN(t)Bu)4(Cl)2], 1, reacts with I2, yielding the halogen-bonded (XB) 1D species {[Ru(CN(t)Bu)4(I)2]·I2}n, (2·I2)n, whose building block contains I(-) ligands in place of Cl(-) ligands, even though no suitable redox agent is present in solution. Some isolated solid-state intermediates, such as {[Ru(CN(t)Bu)4(Cl)2]·2I2}n, (1·2I2)n, and {[Ru(CN(t)Bu)4(Cl)(I)]·3I2}n, (3·3I2)n, indicate the stepwise substitution of the two trans-halide ligands in 1, showing that end-on-coordinated trihalides play a key role in the process. In particular, the formation of ClI2(-) triggers electron transfer, possibly followed by an inverted coordination of the triatomic species through the external iodine atom. This allows I-Cl separation, as corroborated by Raman spectra. The process through XB intermediates corresponds to reduction of one iodine atom combined with the oxidation of one coordinated chloride ligand to give the corresponding zerovalent atom of I-Cl. This redox process, explored by density functional theory calculations (B97D/6-31+G(d,p)/SDD (for I and Ru atoms)), is apparently counterintuitive with respect to the known behavior of the corresponding free halogen systems, which favor iodide oxidation by Cl2. On the other hand, similar energy barriers are found for the metal-assisted process and require a supply of energy to be passed. In this respect, the control of the temperature is fundamental in combination with the favorable crystallizations of the various solid-state products. As an important conclusion, trihalogens, as XB adducts, are not static in nature but are able to undergo dynamic inner electron transfers consistently with implicit redox chemistry.

Correction to "N-Heterocyclic Carbene-Carbodiimide (NHC-CDI) Betaines as Organocatalysts for ß-Butyrolactone Polymerization: Synthesis of Green PHB Plasticizers with Tailored Molecular Weights".

[This corrects the article DOI: 10.1021/acscatal.3c05357.].

Pyridine-4-thiol as halogen-bond (HaB) acceptor: influence of the noncovalent interaction in its reactivity.

The study of pyridine-4-thiol as a halogen-bond (HaB) acceptor has allowed the isolation of its cocrystal with the HaB donor IC6F4I, namely, 1,2,4,5-tetrafluoro-3,6-diiodobenzene bis(pyridin-1-ium-4-ylsulfanide), C6F4I2·2C5H5NS (1), where the S atom is the HaB acceptor, while the pyridine position is blocked by the proton. Furthermore, the S atom acts a dual acceptor and also establishes an interaction with the pyridinium proton from an adjacent molecule. The presence of these interactions in 1 contributes to the stabilization of the zwitterionic form. This pre-organization seems to have an influence on the reactivity of the compound since when left in dichloromethane solution, an unusual activation of the C-Cl bond is observed that leads to the formation of the bis[(pyridin-1-ium-4-yl)sulfanyl]methane dication, while the Cl atoms are still present as chloride counter-ions, i.e. 4,4'-[methanediyldi(sulfanediyl)]dipyridinium dichloride, C11H12N2S22+·2Cl- (2). In the crystal structure of 2 it is observed that the S atom is now acting as the donor part of a chalcogenide bond with the chloride anions.

σ-Hole triel bonds in aluminium derivatives.

This communication reports the synthesis and X-ray characterization of a new mononuclear aluminium compound exhibiting an intramolecular σ-hole triel bonding interaction. It is compared with a dinuclear aluminium compound, previously reported by us, where the aluminium atoms participate in two concurrent σ-hole triel bonding interactions. To our knowledge, such behaviour has not been previously described in the literature.

Group 13 salphen compounds (In, Ga and Al): a comparison of their structural features and activities as catalysts for cyclic carbonate synthesis.

Many complexes based on group 13 elements have been successfully applied as catalysts for the synthesis of cyclic carbonates from epoxides and CO2 and to date these have provided some of the most active catalysts developed. It is notable that most reports have focused on the use of aluminium-based compounds likely because of the well-established Lewis acidity of this element and its cost. In comparison, relatively little attention has been paid to the development of catalysts based on the heavier group 13 elements, despite their known Lewis acidic properties. This study describes the synthesis of aluminium, gallium and indium compounds supported by a readily prepared salphen ligand and explores both their comparative structures and also their potential as catalysts for the synthesis of cyclic carbonates. In addition, the halide ligand which forms a key part of the compound has been systematically varied and the effect of this change on the structure and catalytic activity is also discussed. It is demonstrated that the indium compounds are actually, and unexpectedly, the most active for cyclic carbonate synthesis, despite their lower Lewis acidity when compared to their aluminium congeners. The experimental observations from this work are fully supported by a Density Functional Theory (DFT) study, which provides important insights into the reasons as to why the indium catalyst with bromide, [InBr(salphen)], is most active.

Cyclopentadienyl-silsesquioxane titanium complexes: highly active catalysts for epoxidation of alkenes with aqueous hydrogen peroxide.

Titanium complexes bearing an unprecedented tridentate cyclopentadienyl-silsesquioxanate ligand provide a new class of efficient and selective catalysts for epoxidation of olefins with aqueous hydrogen peroxide under homogeneous conditions.

Rheology of Poly(glycidyl methacrylate) Macromolecular Nano Assemblies.

A recently reported combined polymerization process of glycidyl methacrylate, mediated by homometallic and heterobimetallic aluminium complexes, naturally produces nano-sized macromolecular assemblies. In this work, the morphological features and the rheological properties of these novel nanoassemblies are studied. The hydrodynamic sizes of the nanoparticles in the solution range from 10 to 40 nm (in numbers), but on a flat surface they adopt a characteristic thin disk shape. The dynamic moduli have been determined in a broad range of temperatures, and the time-temperature superposition applied to obtain master curves of the whole viscoelastic response from the glassy to the terminal regions. The fragility values obtained from the temperature dependence are of m ~40, typical of van de Waals liquids, suggesting a very effective packing of the macromolecular assemblies. The rheological master curves feature a characteristic viscoelastic relaxation with the absence of elastic intermediate plateau, indicating that the systems behaved as un-entangled polymers. The analysis of the linear viscoelastic fingerprint reveals a Zimm-like dynamics at intermediate frequencies typical of unentangled systems. This behaviour resembles that observed in highly functionalized stars, dendrimers, soft colloids and microgels.

Ring-Opening Polymerization of L-Lactide Catalyzed by Potassium-Based Complexes: Mechanistic Studies.

Two non-toxic potassium compounds, 1 and 2, with a commercial oximate ligand have been prepared and fully spectroscopically characterized. Their activity as catalysts for the ring-opening polymerization (ROP) process of LLA has been studied, showing that they are extremely active and able to polymerize the monomer in a few minutes. For derivative 2, the presence of a crown ether in the potassium coordination sphere affects the nuclearity of the compound and consequently its solubility, with both aspects having an influence in the polymerization process. Detailed studies of the polymerization mechanism have been performed, and an unusual anionic mechanism was observed in absence of a co-initiator. Indeed, the monomer deprotonation generates a lactide enolate, which initiates the polymerization propagation. On the contrary, when a 1:1 ratio of cat:BnOH is used, a mixture of mechanisms is observed, the anionic mechanism and the activated monomer one, while from a cat:BnOH ratio of 1:2 and over, only the activated monomer mechanism is observed.

Abrogation of Notch Signaling in Embryonic TECs Impacts Postnatal mTEC Homeostasis and Thymic Involution.

Notch signaling is crucial for fate specification and maturation of thymus-seeding progenitors along the T-cell lineage. Recent studies have extended the role of Notch signaling to thymic epithelial cells (TECs), showing that Notch regulates TEC progenitor maintenance and emergence of medullary TECs (mTECs) in fetal thymopoiesis. Based on immunohistochemistry studies of spatiotemporal regulation of Notch activation in the postnatal thymus, we show that in vivo Notch activation is not confined to fetal TECs. Rather, Notch signaling, likely mediated through the Notch1 receptor, is induced in postnatal cortical and medullary TECs, and increases significantly with age in the latter, in both humans and mice, suggesting a conserved role for Notch signaling in TEC homeostasis during thymus aging. To investigate the functional impact of Notch activation in postnatal TEC biology, we used a mouse model in which RPBJκ, the transcriptional effector of canonical Notch signaling, is deleted in epithelial cells, including TECs, under the control of the transcription factor Foxn1. Immunohistochemistry and flow cytometry analyses revealed no significant differences in TEC composition in mutant (RPBJκ-KOTEC) and wild-type (WT) littermate mice at early postnatal ages. However, a significant reduction of the medullary region was observed in mutant compared to WT older thymi, which was accompanied by an accelerated decrease of postnatal mTEC numbers. Also, we found that organization and integrity of the postnatal thymic medulla critically depends on activation of the canonical Notch signaling pathway, as abrogation of Notch signaling in TECs led to the disruption of the medullary thymic microenvironment and to an accelerated thymus atrophy. These features paralleled a significant increase in the proportion of intrathymic non-T lineage cells, mostly B cells, and a slight decrease of DP thymocyte numbers compatible with a compromised thymic function in mutant mice. Therefore, impaired Notch signaling induced in embryonic development impacts postnatal TECs and leads to an accelerated mTEC degeneration and a premature thymus involution. Collectively, our data have uncovered a new role for Notch1 signaling in the control of adult mTEC homeostasis, and point toward Notch signaling manipulation as a novel strategy for thymus regeneration and functional recovery from immunosenescence.

Conjugated polymer nanostructures displaying highly photoactivated antimicrobial and antibiofilm functionalities.

This work reports the use of conjugated polymer nanostructures (CPNs) as photoactivated antimicrobial compounds against Gram-positive and Gram-negative microorganisms. Two representative CPNs of polythiophene (PEDOT) and polyaniline (PANI) were prepared as nanofibres with an average diameter of 40 nm and length in the micrometer range. Both CPNs exhibited strong antimicrobial activity under UVA irradiation with the same fluence rate as the UVA component of the solar spectrum. The effect was tested using the Gram-positive bacteria Staphylococcus aureus and the Gram-negative bacteria Escherichia coli. The reduction of colony forming units (CFUs) reached >6 log for PEDOT concentrations as low as 33 ng mL-1. For PEDOT nanofibers, a complete inhibition of S. aureus and E. coli growth was reached at 883 ng mL-1 and 333 ng mL-1 respectively. The photoactivation effect of PANI nanofibres on S. aureus and E. coli was also high, with a CFU reduction of about 7 log and 4 log respectively for an exposure concentration of 33 ng mL-1. The antimicrobial activity was only high under light irradiation and was almost negligible for bulk PEDOT and PANI. The effect of polymeric nanofibers could be attributed to the photoinduced generation of reactive oxygen species, which may induce cell membrane damage, eventually leading to bacterial impairment and inhibition of their biofilm forming capacity. CPN PEDOT and PANI coatings were able to keep surfaces free of bacterial attachment and growth even after 20 h of previous contact with exponentially growing cultures in the dark. PEDOT and PANI CPNs demonstrated good cytocompatibility with human fibroblasts and the absence of hemolytic activity. The materials demonstrated advantages in terms of broad antibacterial spectrum, biofilm inhibition, and the absence of acute toxicity for biomedical applications.

Polymeric ruthenium precursor as a photoactivated antimicrobial agent.

Ruthenium coordination compounds have demonstrated a promising anticancer and antibacterial activity, but their poor water solubility and low stability under physiological conditions may limit their therapeutic applications. Physical encapsulation or covalent conjugation with polymers may overcome these drawbacks, but generally involve multistep reactions and purification processes. In this work, the antibacterial activity of the polymeric precursor dicarbonyldichlororuthenium (II) [Ru(CO)2Cl2]n has been studied against Escherichia coli and Staphylococcus aureus. This Ru-carbonyl precursor shows minimum inhibitory concentration at nanogram per millilitre, which renders it a novel antimicrobial polymer without any organic ligands. Besides, [Ru(CO)2Cl2]n antimicrobial activity is markedly boosted under photoirradiation, which can be ascribed to the enhanced generation of reactive oxygen species under UV irradiation. [Ru(CO)2Cl2]n has been able to inhibit bacterial growth via the disruption of bacterial membranes and triggering upregulation of stress responses as shown in microscopic measurements. The activity of polymeric ruthenium as an antibacterial material is significant even at 6.6 ng/mL while remaining biocompatible to the mammalian cells at much higher concentrations. This study proves that this simple precursor, [Ru(CO)2Cl2]n, can be used as an antimicrobial compound with high activity and a low toxicity profile in the context of need for new antimicrobial agents to fight bacterial infections.