Isohexide-Based Tunable Chiral Platforms as Amide- and Thiourea-Chiral Solvating Agents for the NMR Enantiodiscrimination of Derivatized Amino Acids.

New arylamide- and arylthiourea-based chiral solvating agents (CSAs) were synthesized starting from commercially available isomannide and isosorbide. The two natural isohexides were transformed into the three amino derivatives, having isomannide, isosorbide, and isoidide stereochemistry, then the amino groups were derivatized with 3,5-dimethoxybenzoyl chloride or 3,5-bis(trifluoromethyl)phenyl isothiocyanate to obtain the CSAs. Bis-thiourea derivative containing the 3,5-bis(trifluoromethyl)phenyl moiety with exo-exo stereochemistry was remarkably efficient in the differentiation of NMR signals (NH and acetyl) of enantiomers of N-acetyl (N-Ac) amino acids in the presence of 1,4-diazabicyclo[2,2,2]octane (DABCO). Nonequivalences in the ranges of 0.104-0.343 ppm and 0.042-0.107 ppm for NH and acetyl groups, respectively, allowed for very accurate enantiomeric excess determination, and a reliable correlation was found between the relative positions of signals of enantiomers and their absolute configuration. Therefore, a complete stereochemical characterization could be performed. Dipolar interactions detected in the ternary mixture CSA/N-Ac-valine/DABCO led to the identification of a different interaction model for the two enantiomers, involving the formation of a one-to-one substrate/CSA complex for (S)-N-Ac-valine and a one-to-two complex for (R)-N-Ac-valine, as suggested by the complexation stoichiometry.

A Squaramide-Based Organocatalyst as a Novel Versatile Chiral Solvating Agent for Carboxylic Acids.

A squaramide-based organocatalyst for asymmetric Michael reactions has been tested as a chiral solvating agent (CSA) for 26 carboxylic acids and camphorsulfonic acid, encompassing amino acid derivatives, mandelic acid, as well as some of its analogs, propionic acids like profens (ketoprofen and ibuprofen), butanoic acids and others. In many cases remarkably high enantiodifferentiations at 1H, 13C and 19F nuclei were observed. The interaction likely involves a proton transfer from the acidic substrates to the tertiary amine sites of the organocatalyst, thus allowing for pre-solubilization of the organocatalyst (when a chloroform solution of the substrate is employed) or the simultaneous solubilization of both the catalyst and the substrate. DOSY experiments were employed to evaluate whether the catalyst-substrate ionic adduct was a tight one or not. ROESY experiments were employed to investigate the role of the squaramide unit in the adduct formation. A mechanism of interaction was proposed in accordance with the literature data.

Tunable Excimer Circularly Polarized Luminescence in Isohexide Derivatives from Renewable Resources.

Organic compounds showing circularly polarized luminescence (CPL) are at the forefront of novel applications and technologies. Here we show the synthesis and chiroptical properties of pyrene and perylene derivatives of inexpensive chiral scaffolds: isomannide and isosorbide. Low-intensity ECD spectra were obtained, suggesting the absence of chromophore interaction in the ground state, except in the case of isomannide bis-perylenecarboxylate, whose ECD spectrum showed a positive exciton couplet. All isomannide derivatives, with the only exception of the one containing a pyrenecarboxylate and a perylenecarboxylate, exhibited excimer CPL spectra, whereas isosorbide derivatives did not show any CPL. Isomannide derivatives bearing two pyrenecarboxylate or two pyrenylacetate groups showed positive CPL emission with dissymmetry factors up to 10-2 , which depends on the conformational freedom of the appended units. The CPL sign, Stokes shift and order of magnitude of dissymmetry factor were reproduced by excited-state calculations on a representative compound. Interestingly, the mixed derivative containing pyrenic units with different spacing from the isomannide scaffold showed an oppositely signed excimer band with respect to the homo-substituted derivatives.

Renewable Resources for Enantiodiscrimination: Chiral Solvating Agents for NMR Spectroscopy from Isomannide and Isosorbide.

A new family of chiral selectors was synthesized in a single synthetic step with yields up to 84% starting from isomannide and isosorbide. Mono- or disubstituted carbamate derivatives were obtained by reacting the isohexides with electron-donating arylisocyanate (3,5-dimethylphenyl- or 3,5-dimethoxyphenyl-) and electron-withdrawing arylisocyanate (3,5-bis(trifluoromethyl)phenyl-) groups to test opposite electronic effects on enantiodifferentiation. Deeper chiral pockets and derivatives with more acidic protons were obtained by derivatization with 1-naphthylisocyanate and p-toluenesulfonylisocyanate, respectively. All compounds were tested as chiral solvating agents (CSAs) in 1H NMR experiments with rac-N-3,5-dinitrobenzoylphenylglycine methyl ester in order to determine the influence of different structural features on the enantiodiscrimination capabilities. Some selected compounds were tested with other racemic analytes, still leading to enantiodiscrimination. The enantiodiscrimination conditions were then optimized for the best CSA/analyte couple. Finally, a 2D- and 1D-NMR study was performed employing the best performing CSA with the two enantiomers of the selected analyte, aiming to determine the enantiodiscrimination mechanism, the stoichiometry of interaction, and the complexation constant.

Synthesis of (Hyper)Branched Monohydroxyl Alkoxysilane Oligomers toward Silanized Urethane Prepolymers.

The aim of this work was the synthesis of (hyper)branched oligomers based on trialkoxysilane in various conditions and further application of them in order to modify the urethane prepolymers. Hydroxyl-terminated trialkoxysilane was used as a monomer for homo-condensation. It was obtained by reaction of 3-aminopropyl trialkoxysilane (APTES) with ethylene carbonate (EC). The reaction was based on the attack of amine at the carbonyl carbon atom followed by ring opening of the carbonate to give a urethane (carbamate) product. The next step was the condensation via substitution of ethoxy groups on silicon atom with the terminal hydroxyalkyl groups present in the primary product with the evolution of ethanol. Accordingly, the impact of temperature and type of catalyst on process efficiency was investigated. A quantitative analysis of reaction progress and products of the conversion of EC together with ethanol evolution was conducted by means of gas chromatography, which allowed us to determine the formation of monomeric product and, indirectly, of oligomeric products. It was found that at room temperature after 24 h, the majority of the monomeric product was isolated, whereas at elevated temperature in the presence of Ti-based catalyst, further condensation of the monomer into branched oligomers was preferred, and, moreover, the application of vacuum intensified that process. The obtained products were structurally characterized by 1H and 29Si NMR, MALDI-ToF and Gel Permeation Chromatography. Finally, two different alkoxysilane products, monomeric and oligomeric, were applied for modification of urethane prepolymer, forming silanized one (SPUR). The influence of the silanizing agent on the mechanical and thermal properties of the moisture-cured products was shown before and after additional conditioning in water.

Sugar-Based Ionic Liquids: Multifaceted Challenges and Intriguing Potential.

Carbohydrates represent a promising option in transitioning from oil-based chemical resources to renewable ones, with the goal of developing chemistries for a sustainable future. Cellulose, hemicellulose, and largely available monosaccharides already provide useful chemical building blocks, so-called platform chemicals, such as levulinic acid and hydroxymethyl furfural, as well as solvents like cyrene or gamma-valerolactone. Therefore, there is great anticipation for novel applications involving materials and chemicals derived from sugars. In the field of ionic liquids (ILs), sugar-based ILs have been overlooked for a long time, mainly on account of their multistep demanding preparation. However, exploring new strategies for accessing sugar-based ILs, their study, and their exploitation, are attracting increasing interest. This is due to the growing concerns about the negative (eco)toxicity profile of most ILs in conjunction with their non-sustainable nature. In the present review, a literature survey concerning the development of sugar-based ILs since 2011 is presented. Their preparation strategies and thermal behavior analyses, sorted by sugar type, make up the first two sections with the intention to provide the reader with a useful guide. A final overview of the potential applications of sugar-based ILs and their future perspectives complement the present analysis.

Ag-In-Zn-S alloyed nanocrystals as photocatalysts of controlled light-mediated radical polymerization.

We report on the first case of the use of nonstoichiometric ternary (Ag-In-Zn-S) semiconductor nanocrystals as photoinitiators and photocatalysts of methyl methacrylate (MMA) polymerization. Two types of nanocrystals were tested, differing in their composition and characterized by red (λmax = 731 nm) and green (λmax = 528 nm) photoluminescence, respectively. Exploiting their reducing properties and capability of free radical generation we demonstrate that under ultraviolet (UV) radiation they effectively photoinitiate radical polymerization of MMA whereas under visible light (blue or green) they act as photocatalysts of living radical polymerization.

Recent Advances in the Application of ATRP in the Synthesis of Drug Delivery Systems.

Advances in atom transfer radical polymerization (ATRP) have enabled the precise design and preparation of nanostructured polymeric materials for a variety of biomedical applications. This paper briefly summarizes recent developments in the synthesis of bio-therapeutics for drug delivery based on linear and branched block copolymers and bioconjugates using ATRP, which have been tested in drug delivery systems (DDSs) over the past decade. An important trend is the rapid development of a number of smart DDSs that can release bioactive materials in response to certain external stimuli, either physical (e.g., light, ultrasound, or temperature) or chemical factors (e.g., changes in pH values and/or environmental redox potential). The use of ATRPs in the synthesis of polymeric bioconjugates containing drugs, proteins, and nucleic acids, as well as systems applied in combination therapies, has also received considerable attention.

Systemic sclerosis sine scleroderma: clinical and serological features and relationship with other cutaneous subsets in a large series of patients from the national registry 'SPRING' of the Italian Society for Rheumatology.

OBJECTIVE: To describe demographic, clinical and laboratory features of systemic sclerosis sine scleroderma (ssSSc) in a large multicentre systemic sclerosis (SSc) cohort. METHODS: Data involving 1808 SSc patients from Italian Systemic sclerosis PRogression INvestiGation registry were collected. The ssSSc was defined by the absence of any cutaneous sclerosis and/or puffy fingers. Clinical and serological features of ssSSc were compared with limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc) subsets. RESULTS: Among patients with SSc, only 61 (3.4%) were classified as having ssSSc (F/M=19/1). Time from Raynaud's phenomenon (RP) onset to diagnosis was longer in ssSSc (3 years, IQR 1-16.5) than lcSSc (2 years, IQR 0-7), and dcSSc (1 year, IQR 0-3) (p<0.001). Clinical ssSSc phenotype was comparable to lcSSc, except for digital pitting scars (DPS) (19.7% vs 42%, p=0.01), but significantly milder than dcSSc, particularly for digital ulcers (DU) (6.6% vs 35.7%, p<0.001), oesophagus (46.2% vs 63.5%, p=0.009), lung (mean diffusion capacity for carbon monoxide 72.2±19.6 vs 62.4±22.8, p=0.009; mean forced vital capacity 105.6±21.7 vs 89.2±20.9, p<0.001) and major videocapillaroscopic alterations (late pattern 8.6% vs 47.6%, p<0.001). Moreover, in ssSSc the percentages of anticentromere and antitopoisomerase were comparable to lcSSc (40% and 18.3% vs 36.7% and 26.6%), but divergent respect to dcSSc (8.6% and 67.4%, p<0.001). CONCLUSION: The ssSSc is a quite rare disease variant characterised by clinico-serological features comparable to lcSSc, but significantly different from dcSSc. Overall, longer RP duration, low percentages of DPS and peripheral microvascular abnormalities, and increased anti-centromere seropositivity distinguish ssSSc. Further investigations based on national registries might provide useful insights on the actual relevance of the ssSSc within the scleroderma spectrum.

Grafted Lactic Acid Oligomers on Lignocellulosic Filler towards Biocomposites.

Lactic acid oligomers (OLAs) were in situ synthesized from lactic acid (LAc) and grafted onto chokeberry pomace (CP) particleboards by direct condensation. Biocomposites of poly (lactic acid) (PLA) and modified/unmodified CP particles containing different size fractions were obtained using a mini-extruder. To confirm the results of the grafting process, the FTIR spectra of filler particles were obtained. Performing 1HNMR spectroscopy allowed us to determine the chemical structure of synthesized OLAs. The thermal degradation of modified CP and biocomposites were studied using TGA, and the thermal characteristics of biocomposites were investigated using DSC. In order to analyse the adhesion between filler particles and PLA in biocomposites, SEM images of brittle fracture surfaces were registered. The mechanical properties of biocomposites were studied using a tensile testing machine. FTIR and 1HNMR analysis confirmed the successful grafting process of OLAs. The modified filler particles exhibited a better connection with hydrophobic PLA matrix alongside improved mechanical properties than the biocomposites with unmodified filler particles. Moreover, a DSC analysis of the biocomposites with modified CP showed a reduction in glass temperature on average by 9 °C compared to neat PLA. It confirms the plasticizing effect of grafted and ungrafted OLAs. The results are promising, and can contribute to increasing the use of agri-food lignocellulosic residue in manufacturing biodegradable packaging.

Chemical Structures, Properties, and Applications of Selected Crude Oil-Based and Bio-Based Polymers.

The growing perspective of running out of crude oil followed by increasing prices for all crude oil-based materials, e.g., crude oil-based polymers, which have a huge number of practical applications but are usually neither biodegradable nor environmentally friendly, has resulted in searching for their substitutes-namely, bio-based polymers. Currently, both these types of polymers are used in practice worldwide. Owing to the advantages and disadvantages occurring among plastics with different origin, in this current review data on selected popular crude oil-based and bio-based polymers has been collected in order to compare their practical applications resulting from their composition, chemical structure, and related physical and chemical properties. The main goal is to compare polymers in pairs, which have the same or similar practical applications, regardless of different origin and composition. It has been proven that many crude oil-based polymers can be effectively replaced by bio-based polymers without significant loss of properties that ensure practical applications. Additionally, biopolymers have higher potential than crude oil-based polymers in many modern applications. It is concluded that the future of polymers will belong to bio-based rather than crude oil-based polymers.

Inferring experimental procedures from text-based representations of chemical reactions.

The experimental execution of chemical reactions is a context-dependent and time-consuming process, often solved using the experience collected over multiple decades of laboratory work or searching similar, already executed, experimental protocols. Although data-driven schemes, such as retrosynthetic models, are becoming established technologies in synthetic organic chemistry, the conversion of proposed synthetic routes to experimental procedures remains a burden on the shoulder of domain experts. In this work, we present data-driven models for predicting the entire sequence of synthesis steps starting from a textual representation of a chemical equation, for application in batch organic chemistry. We generated a data set of 693,517 chemical equations and associated action sequences by extracting and processing experimental procedure text from patents, using state-of-the-art natural language models. We used the attained data set to train three different models: a nearest-neighbor model based on recently-introduced reaction fingerprints, and two deep-learning sequence-to-sequence models based on the Transformer and BART architectures. An analysis by a trained chemist revealed that the predicted action sequences are adequate for execution without human intervention in more than 50% of the cases.

Effect of Electron-Beam Radiation and Other Sterilization Techniques on Structural, Mechanical and Microbiological Properties of Thermoplastic Starch Blend.

This work investigates the potential application of various sterilization methods for microorganism inactivation on the thermoplastic starch blend surface. The influence of the e-beam and UV radiation, ethanol, isopropanol and microwave autoclave on structural and packaging properties were studied. All the applied methods were successful in the inactivation of yeast and molds, however only the e-beam radiation was able to remove the bacterial microflora. The FTIR analysis revealed no significant changes in the polymer structure, nevertheless, a deterioration of the mechanical properties of the blend was observed. The least invasive method was the UV radiation which did not affect the mechanical parameters and additionally improved the barrier properties of the tested material. Moreover, it was proved that during the e-beam radiation the chain scission and cross-linking occurred. The non-irradiated and irradiated samples were subjected to the enzymatic degradation studies performed in the presence of amylase. The results indicated that irradiation accelerated the decomposition of material, which was confirmed by the measurements of weight loss, and mass of glucose and starch released to the solution in the course of biodegradation, as well as the FTIR and thermal analysis.

1D and 2D hybrid polymers based on zinc phenylphosphates: synthesis, characterization and applications in electroactive materials.

The synthesis, structure and properties of three hybrid polymers based on zinc arylphosphates are described in this study. Zinc bis(diphenylphosphate) (ZnDPhP) was obtained as needle-like crystals containing hexagonally packed, homochiral 1 ∞[Zn(DPhP)2/2] helical chains. The XRD and DSC studies revealed that upon heating, ZnDPhP undergoes a reversible thermal transition at ca. 160 °C with expansion mainly perpendicular to its c-axis. Zinc phenylphosphate hydrate (ZnMPhP-H) formed plate-like particles with an average thickness of less than 1 µm and much thinner nanolayers with a basal spacing of 15.5 Å. ZnMPhP-H was easily and reversibly dehydrated to its anhydrous form, ZnMPhP-A, which exhibited a somewhat larger basal spacing of 16.5 Å and the capacity for amine intercalation. The thermal decomposition of ZnDPhP or ZnMPhP-A began around 250 °C, resulting in the formation of solid mixtures of zinc phosphates and electron-conducting carbonaceous phases. The bulk electrical conductivities of the poly(vinylidene fluoride)-based composites containing the ZnDPhP pyrolyzates reached 0.1-0.2 S cm-1. Upon mixing with silicone oil, all the synthesized hybrid polymers formed fluids that exhibit significant negative electrorheological effects and have potential for application in electroresponsive smart materials. The application of an electric field during the crosslinking of such systems affected the viscoelastic properties of the resultant solid composites, while the cured systems showed rather small electrorheological effects.

Predicting retrosynthetic pathways using transformer-based models and a hyper-graph exploration strategy.

We present an extension of our Molecular Transformer model combined with a hyper-graph exploration strategy for automatic retrosynthesis route planning without human intervention. The single-step retrosynthetic model sets a new state of the art for predicting reactants as well as reagents, solvents and catalysts for each retrosynthetic step. We introduce four metrics (coverage, class diversity, round-trip accuracy and Jensen-Shannon divergence) to evaluate the single-step retrosynthetic models, using the forward prediction and a reaction classification model always based on the transformer architecture. The hypergraph is constructed on the fly, and the nodes are filtered and further expanded based on a Bayesian-like probability. We critically assessed the end-to-end framework with several retrosynthesis examples from literature and academic exams. Overall, the frameworks have an excellent performance with few weaknesses related to the training data. The use of the introduced metrics opens up the possibility to optimize entire retrosynthetic frameworks by focusing on the performance of the single-step model only.

Tunable coordination of a tropos phosphite for fine-tuning of the Rh catalyzed asymmetric addition of phenylboronic acid to cyclohexenone.

Using the deoxycholic acid derived tropos biphenylphosphite as a Rh(i) chiral ligand different complexes are obtained, depending on the Rh : L molar ratio, that give rise to the formation of different chiral products in the asymmetric addition of phenylboronic acid to cyclohexenone.

Uncatalyzed conjugate addition of organozinc halides to enones in DME: a combined experimental/computational study on the role of the solvent and the reaction mechanism.

Both aryl and alkylzinc halides prepared by direct insertion of zinc into organic halides in the presence of LiCl underwent the conjugate addition reaction to nonenolizable unsaturated ketones in excellent yield, provided that DME was used instead of THF as the solvent. Diffusion NMR measurements highlighted that the species undergo considerable aggregation under the experimental conditions used in the synthetic procedure, but no substantial differences have been found between the two solvents. Density functional theory calculations, prompted by the experimental aggregation study, revealed an unexpected reaction mechanism, where the coordinating capabilities of DME stabilize a transition state involving two organozinc moieties, lowering the activation energy of the reaction with respect to that seen for THF, enough to explain the fast and quantitative reactions observed experimentally and the different behaviors of the two solvents.

On the Absolute Stereochemistry of Tolterodine: A Circular Dichroism Study.

Tolterodine (1) is a potent muscarinic receptor antagonist used in the treatment of overactive urinary bladder (OAB) syndrome. Tolterodine is chiral and it was patented, and is currently marketed, as the l-tartrate salt of the (R)-enantiomer. However, the existing literature does not offer an ultimate proof of a stereoselective mode of action of 1. A second open stereochemical issue concerns the absolute configuration (AC) of 1. Neither the original patents nor subsequent studies have established the AC of 1 in an unambiguous way, although the AC of the l-tartrate salt of 1 was assigned by X-ray diffractometry. Finally, neither electronic nor vibrational circular dichroism (ECD and VCD) spectra of 1 are reported so far. We performed a thorough ECD/VCD study of 1 in different solvents and at variable temperatures. Solvent and temperature dependence highlighted the existence of moderate flexibility which was confirmed by molecular modelling. ECD calculations with time-dependent density functional theory (TDDFT) accurately reproduced the experimental spectra and allowed us to confirm the AC of 1 in an independent way.

Mechanistic insights into the tropo-inversion of the biphenyl moiety in chiral bis-amido phosphites and in their palladium(ii) complexes.

Chiral bis-amido phosphites L1 and L2 containing a diaminobiphenyl unit and a chiral alkoxy group derived from either (-)-menthol or 3-acetoxy deoxycholic methyl ester have been synthesised. Both L1 and L2 react with PdCl2(NCPh)2 affording di- or mononuclear derivatives with formula trans-[Pd(µ-Cl)Cl(L)]2 (1a, L = L1; 1b, L = L2) or trans-PdCl2(L)2 (2a, L = L1; 2b, L = L2) depending on the Pd : L molar ratio. The crystal structure of (M,P)-1a confirms the trans arrangement of the ligand L1 and shows an unusual puckering of the Pd2(µ-Cl)2 core (θ 46°). Both the ligands L1 and L2 and their complexes (1 and 2) are fluxional in solution as a consequence of the tropo-inversion of the diaminobiphenyl unit. For L1, L2, 1a and 2a a combined study including variable temperature 31P{1H} NMR spectroscopy and line shape analysis, Eyring plots and DFT calculations have shed light on the mechanism of the tropo-inversion.

Ring-closing olefin metathesis of 2,2'-divinylbiphenyls: a novel and general approach to phenanthrenes.

[reaction: see text] The ring-closing olefin metathesis (RCM) of 2,2'-divinylbiphenyls, using a second-generation RCM ruthenium-based catalyst, leads to differently substituted phenanthrenes in quantitative yield under very mild reaction conditions, independent of both nature and position of the groups present on the biphenyl moiety.