We describe a direct and asymmetric aldol-like reaction between a wide range of N-acyl-1,3-oxazolidine-2-thiones and cobalt-protected propargylic acetals catalyzed by a chiral nickel(II) complex leading to syn β-alkoxy derivatives. This overcomes longstanding limitations associated with acetals from aliphatic aldehydes, selectively providing syn aldol adducts in excellent yields as single stereoisomers (dr >97:3, er up to >99:1). Furthermore, the cobalt fragment enables downstream intramolecular Pauson-Khand cyclizations, granting rapid access to densely functionalized bicyclic architectures.

Parallel asymmetric total syntheses of eliglustat and C2-epi-eliglustat are reported. Both approaches feature a common key step, which involves a stereocontrolled TMSOTf-mediated aldol-like reaction of azidoacetyl thioimides with dibenzyl acetals of aromatic aldehydes catalyzed by chiral nickel(II) complexes. It is worth noting that the structure of dibenzyl acetals plays a key role in the stereochemical outcome of some of these reactions, as supported by theoretical calculations. Overall, this strategy enables the independent manipulation of the amino and hydroxy functional groups and favors the isolation of enantiomerically pure products.

A new approach to the synthesis of all of the potential stereoisomers of β-alkoxy-α-amino acids derived from phenylalanine, tyrosine, tryptophan, and other β-aryl counterparts is reported. Such a method hinges on direct and asymmetric Lewis acid-mediated aldol-like reactions of N-azidoacetyl thioimides with dialkyl acetals from aromatic aldehydes catalyzed by chiral nickel(II) complexes. This produces at will both the corresponding syn and anti adducts, which can be smoothly converted into enantiomerically pure intermediates such as dipeptide fragments. In turn, computational calculations have unveiled clues for a better understanding of such a stereocontrolled carbon-carbon bond-forming transformation.

The green and safe polymer HEC confers bio-interactive properties to Ag-Nps that, together with the small size and positive ζ potential, increase their biological reactivity towards zebrafish embryos.

Abstract The EU-project ASINA is testing Low-Cost Particulate Matter Sensors (LCPMS) for industrial monitoring of the concentration of airborne particles, with the purpose of integrating this sensor technology within the data collection layer of Digital Twins (DTs) for manufacturing. This paper shows the results of field performance evaluations carried out with five LCPMS from different manufacturers (Alphasense OPC-N3, Plantower 9003, Sensirion SPS30, Sensirion SEN55 and Tera Sensor NetxPM), during several field sampling campaigns, conducted in four pre-commercial and commercial pilot lines (PLs) that manufacture nano-enabled products, belonging to the ASINA and OASIS H2020 EU-projects [2,28]. Field tests consisted of deploying LCPMS in manufacturing process, measuring in parallel with collocated reference and informative instruments (OPS TSI 3330/CPC TSI 3007), to enable intercomparison. The results show the complexity and differential response of the LCPMS depending on the characteristics of the monitored scenario (PL). Overall, they exhibit uneven precision and linearity and significant bias, so their use in industrial digital systems without proper calibration can lead to uncertain and biased measurements. In this sense, simple linear models are not able to capture the complexity of the problem (non-linear systems) and advanced calibration schemes (e.g. based on machine learning), applied “scenario by scenario” and in operating conditions as close as possible to the final application, are suggested to achieve reliable measurements with the LCPMS.

In order to reach a sustainable future and meet the UN’s Sustainable Development Goals (UN SDGs), business model innovation (BMI) needs to explore theoretical and practical intersections of the traditional innovation management (IM) and new product development (NPD) processes with sustainability considerations. New environmental and health policy ambitions such as those presented in the European Green Deal and the EU Chemicals Strategy for Sustainability (CSS) challenge traditional IM theories on BMI and NPD processes. The Safe-and-Sustainable-by-Design (SSbD) concept is a central element of the CSS and demands a novel approach that integrates innovation with safety, sustainability and circularity of materials, products and processes without compromising their functionality or their technical and/or commercial viability. Importantly, adopting such a concept can prevent regrettable substitutions, future liability and brand image issues for companies. To achieve this, companies must design products with minimal environmental impact, adopt circular economy principles, and ensure social responsibility throughout the value chain, whilst economic viable. By doing so, companies contribute to economic, environmental, and social sustainability. In this perspective, a conceptual framework is proposed on how to achieve sustainable BMI and NPD by integrating traditional IM tools with SSbD using life cycle thinking principles considering external and internal drivers.

The direct insertion of Zn into olefin-halide bonds is a challenge. When (E)-alkenyl iodides were treated with a very large excess of Zn nanoparticles, in the presence of Pd(PPh3)4, the dimerization was observed but, unexpectedly, yielding mainly Z,E-1,3-dienes. This apparently contrathermodynamic E-to-Z isomerization of organometallic intermediates is predicted to be general and is explained with the aid of DFT [principally M06/6-311+G(d,p)], MP2, and CCSD(T) calculations.

This report demonstrates a case study within the ASINA project, aimed at instantiating a roadmap with quantitative metrics for Safe(r) and (more) Sustainable by Design (SSbD) options. We begin with a description of ASINA’s methodology across the product lifecycle, outlining the quantitative elements within: Physical-Chemical Features (PCFs), Key Decision Factors (KDFs), and Key Performance Indicators (KPIs). Subsequently, we delve in a proposed decision support tool for implementing the SSbD objectives across various dimensions—functionality, cost, environment, and human health safety—within a broader European context. We then provide an overview of the technical processes involved, including design rationales, experimental procedures, and tools/models developed within ASINA in delivering nano-silver-based antimicrobial textile coatings. The result is pragmatic, actionable metrics intended to be estimated and assessed in future SSbD applications and to be adopted in a common SSbD roadmap aligned with the EU’s Green Deal objectives. The methodological approach is transparently and thoroughly described to inform similar projects through the integration of KPIs into SSbD and foster data-driven decision-making. Specific results and project data are beyond this work’s scope, which is to demonstrate the ASINA roadmap and thus foster SSbD-oriented innovation in nanotechnology.

The design of increasingly more efficient asymmetric aldol reactions is nowadays an active area of research. The present Chapter shows how well-established methods based on preformed enolates from chiral substrates coexist with advanced versions of the venerable Mukaiyama aldol reaction and with a broad array of new, direct, and catalytic variants developed during the last decade. All of them strive to provide highly stereocontrolled transformations that enable the synthesis of chiral targets under the premises dictated by the Atom Economy in Synthesis and Green Chemistry.

Background Silver (Ag) nanoparticles (NPs) are used increasingly in consumer and healthcare fabrics due to their antimicrobial properties. Abrasive leaching experiments have shown that AgNPs can be released during textile wear and cause a dermal exposure. Derived-no-effect-limit value for AgNPs ranges from 0.01 to 0.0375 mg/kg-body-weight, and thus, low exposures levels can cause relevant risk. Methods In this study AgNP release from textiles by artificial sweat immersion and mechanical stress was investigated. A mass balance model was used to calculate dermal Ag exposure and potential intake via percutaneous absorption and inadvertent (peri-)oral intake during wear of face mask, suit with a full body exposure and gloves. Mass flow analysis was performed for up to 8-h wear time and by using Ag penetration rate constants reported for fresh-, cryopreserved- and glycerolized skin grafts. Results Dermal intake risk characterization ratio (RCR) during 8-h wear time for glycerolized skin was up to 0.02 for face mask and 0.9 for full body wear in a worst-case condition. Wearing gloves for 1-h followed by single unintentional fingertip mouthing (contact area 11.5 cm2) resulted in an RCR of 0.0002. RCR varied depending on the type of textile-product, exposure wear duration and skin type. Conclusions This study provides a comprehensive assessment of AgNPs release from textiles and their potential impact on human dermal exposure and was essential for understanding the safety implications for different exposure scenarios and mitigating potential risks.

This report, the second of its kind from ASINA project, aims at providing a roadmap with quantitative metrics for Safe(r) and (more) Sustainable by Design (SSbD) solutions for titanium dioxide (TiO2) nanomaterials (NMs). We begin with a brief description of ASINA’s methodology across the product lifecycle, highlighting the quantitative elements, such as the Key Performance Indicators (KPIs). We then propose a decision support tool for implementing SSbD objectives across various dimensions—functionality, cost, environment, and human health safety. This is followed by the main innovative findings, a consolidation of the technical processes involved, design rationales, experimental procedures, tools and models, used and developed, to deliver photocatalytic depolluting surfaces by spray- finishing techniques based on TiO2 NMs formulations. The roadmap is thoroughly described to inform similar projects through the integration of KPIs into SSbD methodologies, fostering data-driven decision-making. While specific results are beyond this report's scope, its primary aim is to demonstrate the roadmap (SSbD know-how) and promote SSbD-oriented innovation in nanotechnology. Finally, we provide a comparison of the approaches followed in two case studies that target different industrial sectors. This case-specific SSbD assessments provide a concrete exemplification of the addressed methodology that contributes to the efforts towards attaining a common roadmap for implementing SSbD solutions aligned with the EU’s Green Deal objectives.

Oxocarbenium cations are key intermediates for the stereo-controlled construction of carbon-carbon bonds. In particular, we have developed a wide range of stereoselective aldol-like processes that take advantage of the high reactivity of the oxocarbenium species arising from acetals, glycals, and orthoesters with metal enolates. This Account describes the development and optimization of such processes, together with other significant contributions, with a particular emphasis on their application to the synthesis of natural products.

Background Silver (Ag) nanoparticles (NPs) are used increasingly in consumer and healthcare fabrics due to their antimicrobial properties. Abrasive leaching experiments have shown that AgNPs can be released during textile wear and cause a dermal exposure. Derived-no-effect-limit value for AgNPs ranges from 0.01 to 0.0375 mg/kg-body-weight, and thus, low exposures levels can cause relevant risk. Methods In this study AgNP release from textiles by artificial sweat immersion and mechanical stress was investigated. A mass balance model was used to calculate dermal Ag exposure and potential intake via percutaneous absorption and inadvertent (peri-)oral intake during wear of face mask, suit with a full body exposure and gloves. Mass flow analysis was performed for up to 8-h wear time and by using Ag penetration rate constants reported for fresh-, cryopreserved- and glycerolized skin grafts. Results Dermal intake risk characterization ratio (RCR) during 8-h wear time for glycerolized skin was up to 0.02 for face mask and 0.9 for full body wear in a worst-case condition. Wearing gloves for 1-h followed by single unintentional fingertip mouthing (contact area 11.5 cm2) resulted in an RCR of 0.0002. RCR varied depending on the type of textile-product, exposure wear duration and skin type. Conclusions This study provides a comprehensive assessment of AgNPs release from textiles and their potential impact on human dermal exposure and was essential for understanding the safety implications for different exposure scenarios and mitigating potential risks.

Direct and stereodivergent Michael additions of N-acyl 1,3-thiazinane-2-thiones to α,β-unsaturated aldehydes catalyzed by chiral nickel(II) complexes are reported. The reactions proceed with a remarkable regio-, diastereo-, and enantioselectivity, so access to any of the four potential Michael stereoisomers is granted through the appropriate choice of the chiral ligand of the nickel(II) complex. Simple removal of the heterocyclic scaffold furnishes a wide array of either syn or anti enantiomerically pure derivatives, which can be exploited for the asymmetric synthesis of biologically active compounds, as demonstrated in a new approach to tapentadol. In turn, a mechanism, based on theoretical calculations, is proposed to account for the stereochemical outcome of these transformations.

The relative thermodynamic stability of two series of enamines has been examined using DFT (mainly M06-2X), MP2, and CCSD(T) calculations, supplemented by 1H NMR spectroscopy in some cases. The basicity of enamines derived from pyrrolidine and various carbonyl compounds has been computationally compared in the gas phase and in water; the results indicate which enamines or iminium ions may predominate in nonpolar and polar acidic media when pyrrolidine and two or more carbonyl groups or carbonyl compounds are present in the reaction flask. The relative basicity of a second series of enamines, from propanal and chiral pyrrolidines or imidazolidin-4-ones, has also been investigated; this sheds light on the main intermediates that should be expected when two or more secondary amines are present in acid-catalyzed aldehyde reactions. Non-covalent interactions explain the stability of folded side-chain conformers of O-silylated prolinol enamines, according to the predictions of M06-2X, omega B97X-D, and B3LYP-D3 (but not B3LYP). The significant stability of iminium ions containing appropriate electron-donating atoms or groups accounts for the basicity of the corresponding enamines. These findings pave the way for the future development of dual aminocatalytic processes.

Current European (EU) policies, such as the Green Deal, envisage safe and sustainable by design (SSbD) practices for the management of chemicals, which cogently entail nanomaterials (NMs) and advanced materials (AdMa).

The current European (EU) policies, that is, the Green Deal, envisage safe and sustainable practices for chemicals, which include nanoforms (NFs), at the earliest stages of innovation. A theoretically safe and sustainable by design (SSbD) framework has been established from EU collaborative efforts toward the definition of quantitative criteria in each SSbD dimension, namely, the human and environmental safety dimension and the environmental, social, and economic sustainability dimensions. In this study, we target the safety dimension, and we demonstrate the journey toward quantitative intrinsic hazard criteria derived from findable, accessible, interoperable, and reusable data. Data were curated and merged for the development of new approach methodologies, that is, quantitative structure-activity relationship models based on regression and classification machine learning algorithms, with the intent to predict a hazard class. The models utilize system (i.e., hydrodynamic size and polydispersity index) and non-system (i.e., elemental composition and core size)-dependent nanoscale features in combination with biological in vitro attributes and experimental conditions for various silver NFs, functional antimicrobial textiles, and cosmetics applications. In a second step, interpretable rules (criteria) followed by a certainty factor were obtained by exploiting a Bayesian network structure crafted by expert reasoning. The probabilistic model shows a predictive capability of ≈78% (average accuracy across all hazard classes). In this work, we show how we shifted from the conceptualization of the SSbD framework toward the realistic implementation with pragmatic instances. This study reveals (i) quantitative intrinsic hazard criteria to be considered in the safety aspects during synthesis stage, (ii) the challenges within, and (iii) the future directions for the generation and distillation of such criteria that can feed SSbD paradigms. Specifically, the criteria can guide material engineers to synthesize NFs that are inherently safer from alternative nanoformulations, at the earliest stages of innovation, while the models enable a fast and cost-efficient in silico toxicological screening of previously synthesized and hypothetical scenarios of yet-to-be synthesized NFs.

INTRODUCTION:The current effort towards the digital transformation across multiple scientific domains requires data that is Findable, Accessible, Interoperable and Reusable (FAIR). In addition to the FAIR data, what is required for the application of computational tools, such as Quantitative Structure Activity Relationships (QSARs), is a sufficient data volume and the ability to merge sources into homogeneous digital assets. In the nanosafety domain there is a lack of FAIR available metadata.METHODOLOGY:To address this challenge, we utilized 34 datasets from the nanosafety domain by exploiting the NanoSafety Data Reusability Assessment (NSDRA) framework, which allowed the annotation and assessment of dataset's reusability. From the framework's application results, eight datasets targeting the same endpoint (i.e. numerical cellular viability) were selected, processed and merged to test several hypothesis including universal versus nanogroup-specific QSAR models (metal oxide and nanotubes), and regression versus classification Machine Learning (ML) algorithms.RESULTS:Universal regression and classification QSARs reached an 0.86 R2 and 0.92 accuracy, respectively, for the test set. Nanogroup-specific regression models reached 0.88 R2 for nanotubes test set followed by metal oxide (0.78). Nanogroup-specific classification models reached 0.99 accuracy for nanotubes test set, followed by metal oxide (0.91). Feature importance revealed different patterns depending on the dataset with common influential features including core size, exposure conditions and toxicological assay. Even in the case where the available experimental knowledge was merged, the models still failed to correctly predict the outputs of an unseen dataset, revealing the cumbersome conundrum of scientific reproducibility in realistic applications of QSAR for nanosafety. To harness the full potential of computational tools and ensure their long-term applications, embracing FAIR data practices is imperative in driving the development of responsible QSAR models.CONCLUSIONS:This study reveals that the digitalization of nanosafety knowledge in a reproducible manner has a long way towards its successful pragmatic implementation. The workflow carried out in the study shows a promising approach to increase the FAIRness across all the elements of computational studies, from dataset's annotation, selection, merging to FAIR modeling reporting. This has significant implications for future research as it provides an example of how to utilize and report different tools available in the nanosafety knowledge system, while increasing the transparency of the results. One of the main benefits of this workflow is that it promotes data sharing and reuse, which is essential for advancing scientific knowledge by making data and metadata FAIR compliant. In addition, the increased transparency and reproducibility of the results can enhance the trustworthiness of the computational findings.

Engineered Nanomaterials (ENMs) have several uses in various industrial fields and are embedded in a myriad of consumer products. However, there is continued concern over the potential adverse health effects and environmental impacts of ENMs due to their unique physico-chemical characteristics. Currently, there are no specific international regulations for various ENMs. There are also no Occupational Exposure Limits (OEL) regulated by the European Union (EU) for nanomaterials in the form of nano-objects, their aggregates or agglomerates (NOAA). For ENMs the question of which metric to be used (i.e., mass, surface area, number concentrations) to determine the exposure is still not resolved. The aim of this work is to assess the worker exposure by inhalation in an industrial spray coating process by using all three metrics mentioned above. Two target ENMs (N-doped TiO2, TiO2N and AgNPs capped with a quaternized hydroxyethyl-cellulose, AgHEC) generated for industrial-scale spraying processes were considered. Results showed that the averaged particle number concentration (10-100 nm) was below 2.7 10(4) cm(-3) for both materials. The Lung Deposited Surface Area (LDSA) was in the range between 73 and 98 mu m(2)cm(-3) and the particle mass concentration (obtained by means of ICP-EOS off-line analysis) resulted below 70 mu g m(-3) and 0.4 mu g m(-3) for TiO2 and Ag, respectively. Although, the airborne particles concentration compared well with the NIOSH Recommended Exposure Level (REL) limits the contribution to the background, according to EN 17058 (Annex E) was significant (particularly in the particle number and PM1 mass concentrations). We successfully evaluated the worker exposure by means of the different airborne particles' metrics (number, surface and mass concentrations). We concluded that worker exposure assessment involving ENMs is a complex procedure with requires both real time and off-line measurements and a deep investigation of the background.

Background Adverse outcome pathways (AOPs) are conceptual frameworks that organize knowledge about biological interactions and toxicity mechanisms. They present a sequence of events commencing with initial interaction(s) of a stressor, which defines the perturbation in a biological system (molecular initiating event, MIE), and a dependent series of key events (KEs), ending with an adverse outcome (AO). AOPs have recently become the subject of intense studies in a view to better understand the mechanisms of nanomaterial (NM) toxicity. Silver nanoparticles (Ag NPs) are one of the most explored nanostructures and are extensively used in various application. This, in turn, has increased the potential for interactions of Ag NPs with environments, and toxicity to human health. The aim of this study was to construct a putative AOPs (pAOP) related to reproductive toxicity of Ag NPs, in order to lay the groundwork for a better comprehension of mechanisms affecting both undesired toxicity (against human cell) and expected toxicity (against microorganisms). Methods PubMed and Scopus were systematically searched for peer-reviewed studies examining reproductive toxicity potential of Ag NPs. The quality of selected studies was assessed through ToxRTool. Eventually, forty-eight studies published between 2005 and 2022 were selected to identify the mechanisms of Ag NPs impact on reproductive function in human male. The biological endpoints, measurements, and results were extracted from these studies. Where possible, endpoints were assigned to a potential KE and an AO using expert judgment. Then, KEs were classified at each major level of biological organization. Results We identified the impairment of intracellular SH-containing biomolecules, which are major cellular antioxidants, as a putative MIE, with subsequent KEs defined as ROS accumulation, mitochondrial damage, DNA damage and lipid peroxidation, apoptosis, reduced production of reproductive hormones and reduced quality of sperm. These successive KEs may result in impaired male fertility (AO). Conclusion This research recapitulates and schematically represents complex literature data gathered from different biological levels and propose a pAOP related to the reproductive toxicity induced by AgNPs. The development of AOPs specific to NMs should be encouraged in order to provide new insights to gain a better understanding of NP toxicity.