Experimental and Theoretical Studies on the Reactions of Aliphatic Imines with Isocyanates.

In the context of a project aiming at the replacement of the 3-substituted ß-lactam ring in classical ß-lactam antibiotics by an N(3)-acyl-1,3-diazetidinone moiety, we have investigated the reaction of isocyanates with imines derived from allyl glycinate and differently substituted propionaldehydes. Imines of aromatic aldehydes with anilines have been reported to react with acyl isocyanates to give 1,3-diazetidinones or 2,3-dihydro-4H-1,3,5-oxadiazin-4-ones, via [2+2] or [4+2] cycloaddition, respectively. However, neither of these products was formed with imines derived from allyl glycinate and 2-(mono)methyl propionaldehydes. α,α-Dimethylation of the imine enabled the [4+2] cycloaddition pathway, but the desired 1,3-diazetidinone products were not observed. Surprisingly, the imines obtained from thioesters of 2,2-dimethyl 3-oxo propionic acid reacted with aryl isocyanates or with benzyl isocyanate to give 5,5-dimethyl-2,4-dioxo-6-(aryl-/alkylthio)tetrahydropyrimidines, via thiol displacement and re-addition to a putative six-membered iminium intermediate. These experimental results obtained for the reactions could be rationalized by DFT calculations. In addition, we have shown that N(3)-acyl-1,3-diazetidinone and 2,3-dihydro-4H-1,3,5-oxadiazin-4-one products can be distinguished based on experimental IR data in combination with theoretical reference spectra employing the IR spectra alignment (IRSA) algorithm. This discrimination was not possible by means of 1 H, 13 C, or 15 N NMR spectroscopy.

Novel tetrahydronaphthalen-1-yl-phenethyl ureas: synthesis and dual antibacterial-anticancer activities.

Cancer and antibiotic-resistant bacterial infections are significant global health challenges. The resistance developed in cancer treatments intensifies therapeutic difficulties. In addressing these challenges, this study synthesised a series of N,N'-dialkyl urea derivatives containing methoxy substituents on phenethylamines. Using isocyanate for the efficient synthesis yielded target products 14-18 in 73-76% returns. Subsequently, their antibacterial and anticancer potentials were assessed. Cytotoxicity tests on cancer cell lines, bacterial strains, and a healthy fibroblast line revealed promising outcomes. All derivatives demonstrated robust antibacterial activity, with MIC values ranging from 0.97 to 15.82 µM. Notably, compounds 14 and 16 were particularly effective against the HeLa cell line, while compounds 14, 15, and 17 showed significant activity against the SH-SY5Y cell line. Importantly, these compounds had reduced toxicity to healthy fibroblast cells than to cancer cells, suggesting their potential as dual-functioning agents targeting both cancer and bacterial infections.

Multifold Post-Modification of Macrocycles and Cages by Isocyanate-Induced Azadefluorination Cyclisation.

We present the multiple post-modification of organic macrocycles and cages, introducing functional groups into two- and three-dimensional supramolecular scaffolds bearing fluorine substituents, which opens up new possibilities in multi-step supramolecular chemistry employing the vast chemical space of readily available isocyanates. The mechanism and scope of the reaction that proceeds after isocyanate addition to the benzylamine motif via an azadefluorination cyclisation (ADFC) were investigated using DFT calculations, and a series of aromatic isocyanates with different electronic properties were tested. The compounds show excellent chemical stability and were fully characterised. They can be used for subsequent cross-coupling reactions, and ADFC can be used directly to generate cross-linked membranes from macrocycles or cages when using ditopic isocyanates. Single-crystal X-ray (SC-XRD) analysis shows the proof of the formation of the desired supramolecular entity together with the connectivity predicted by calculations and from 19F NMR shifts, allowing the late-stage functionalisation of self-assembled macrocycles and cages by ADFC.

Reconstruction of exposure to methylene diphenyl-4,4'-diisocyanate (MDI) aerosol using computational fluid dynamics, physiologically based toxicokinetics and statistical modeling.

OBJECTIVES: This study employed computational fluid dynamics (CFD), physiologically based toxicokinetics (PBTK), and statistical modeling to reconstruct exposure to methylene diphenyl-4,4'-diisocyanate (MDI) aerosol. By utilizing a validated CFD model, human respiratory deposition of MDI aerosol in different workload conditions was investigated, while a PBTK model was calibrated using experimental rat data. Biomonitoring data and Markov Chain Monte Carlo (MCMC) simulation were utilized for exposure assessment. RESULTS: Deposition fraction of MDI in the respiratory tract at the light, moderate, and heavy activity were 0.038, 0.079, and 0.153, respectively. Converged MCMC results as the posterior means and prior values were obtained for several PBTK model parameters. In our study, we calibrated a rat model to investigate the transport, absorption, and elimination of 4,4'-MDI via inhalation exposure. The calibration process successfully captured experimental data in the lungs, liver, blood, and kidneys, allowing for a reasonable representation of MDI distribution within the rat model. Our calibrated model also represents MDI dynamics in the bloodstream, facilitating the assessment of bioavailability. For human exposure, we validated the model for recent and long-term MDI exposure using data from relevant studies. CONCLUSION: Our computational models provide reasonable insights into MDI exposure, contributing to informed risk assessment and the development of effective exposure reduction strategies.

Methylene diphenyl diisocyanate occupational exposure data in industry (1998-2020): A descriptive summary from an industrial hygiene perspective.

This paper provides an overview of airborne methylene diphenyl diisocyanate (MDI) concentrations in workplaces across North America and Europe. A total of 7649 samples were collected between 1998 and 2020 by producers of MDI during product stewardship activities at customer sites, primarily using validated OSHA or ISO sampling and analysis techniques. As would be expected from the low vapor pressure of MDI, 80% of the concentrations were less than 0.01 mg/m3 (1 ppb) and 93% were less than 0.05 mg/m3 (5 ppb). Respiratory protection is an integral part of Industrial Hygiene practices; therefore, its use was studied and summarized. While covering a variety of MDI applications, a large number of samples was obtained from composite wood manufacturing facilities, offering specific insight into potential exposures associated with different process sections and job types in this industry sector. Given the potential presence in industrial processes of MDI-containing dust or aerosols, future work should place increased emphasis on also investigating dermal exposure. The data reported in this paper provide valuable information for product stewardship and industrial hygiene purposes throughout the MDI-processing industry.

Ru3 (CO)12 -Catalyzed Modular Assembly of Hemilabile Ligands by C-H Activation of Phosphines with Isocyanates.

Hemilabile ligands have been applied extensively in transition metal catalysis, but preparations of these molecules typically require multistep synthesis. Here, modular assembly of diverse phosphine-amide ligands, including related axially chiral compounds, is first reported through ruthenium-catalyzed C-H activation of phosphines with isocyanate directed by phosphorus(III) atoms. High reactivity and regioselectivity can be obtained by using a Ru3 (CO)12 catalyst with a mono-N-protected amino acid ligand. This transformation significantly expands the pool of phosphine-amide ligands, some of which have shown excellent efficiency for asymmetric catalysis. More broadly, the discovery constitutes a proof of principle for facile construction of hemilabile ligands directly from the parent monodentate phosphines by C-H activation with ideal atom, step and redox economy. Several dinuclear ruthenium complexes were characterized by single-crystal X-ray diffraction analysis revealing the key mechanistic features of this transformation.

Behavior of Isocyanic Acid and Other Nitrogen-Containing Volatile Organic Compounds in The Indoor Environment.

Isocyanic acid (HNCO) and other nitrogen-containing volatile chemicals (organic isocyanates, hydrogen cyanide, nitriles, amines, amides) were measured during the House Observation of Microbial and Environmental Chemistry (HOMEChem) campaign. The indoor HNCO mean mixing ratio was 0.14 ± 0.30 ppb (range 0.012-6.1 ppb), higher than outdoor levels (mean 0.026 ± 0.15 ppb). From the month-long study, cooking and chlorine bleach cleaning are identified as the most important human-related sources of these nitrogen-containing gases. Gas oven cooking emits more isocyanates than stovetop cooking. The emission ratios HNCO/CO (ppb/ppm) during stovetop and oven cooking (mean 0.090 and 0.30) are lower than previously reported values during biomass burning (between 0.76 and 4.6) and cigarette smoking (mean 2.7). Bleach cleaning led to an increase of the HNCO mixing ratio of a factor of 3.5 per liter of cleaning solution used; laboratory studies indicate that isocyanates arise via reaction of nitrogen-containing precursors, such as indoor dust. Partitioned in a temperature-dependent manner to indoor surface reservoirs, HNCO was present at the beginning of HOMEChem, arising from an unidentified source. HNCO levels are higher at the end of the campaign than the beginning, indicative of occupant activities such as cleaning and cooking; however the direct emissions of humans are relatively minor.

Isocyanates may contribute to allergic contact dermatitis from diabetes devices and wound dressings.

BACKGROUND: Isocyanates are well-known occupational allergens, but can also be present in medical devices. OBJECTIVES: To highlight that contact sensitization to isocyanates might contribute to allergic contact dermatitis (ACD) from polyurethane (PU)-containing diabetes devices and wound dressings. PATIENTS AND METHODS: Nineteen patients with suspected ACD from diabetes devices and/or wound dressings were patch tested to an isocyanate series. Four wound dressings, six diabetes devices and four monomeric isocyanate patch test preparations were analysed with gas chromatography - mass spectrometry. RESULTS: Eight patients reacted to isocyanates and corresponding amines: 3 to isophorone diisocyanate (IPDI), 4 to 4,4'-diaminodiphenylmethane (MDA), 4 to 2,4-toluene diisocyanate (TDI) and 1 to polymeric methylene diphenyl diisocyanate (PMDI). Three of four wound dressings contained isocyanates (methylene diphenyl diisocyanate [MDI], TDI and/or IPDI), whereas five of six diabetes devices contained 4,4'-MDI, and one of them also IPDI. None of the medical devices contained 1,6-hexamethylene diisocyanate. Contrary to IPDI, and especially MDI, only the concentration of the TDI patch test preparation corresponded approximately (80%) to its label. CONCLUSION: Patch tests with isocyanates may be worth-while in patients with suspected ACD from PU-containing medical devices. Besides MDA, and PMDI, also TDI might potentially be a marker for MDI-sensitization.

Assessment of personal inhalation and skin exposures to polymeric methylene diphenyl diisocyanate during polyurethane fabric coating.

Methylene diphenyl diisocyanate (MDI) monomers and polymeric MDI (pMDI) are aromatic isocyanates widely used in the production of polyurethanes. These isocyanates can cause occupational asthma, hypersensitivity pneumonitis, as well as contact dermatitis. Skin exposure likely contributes toward initial sensitization but is challenging to monitor and quantitate. In this work, we characterized workers' personal inhalation and skin exposures to pMDI in a polyurethane fabric coating factory for subsequent health effect studies. Full-shift personal and area air samples were collected from eleven workers in representative job areas daily for 1-2 weeks. Skin exposure to hands was evaluated concomitantly with a newly developed reagent-impregnated cotton glove dosimeter. Samples were analyzed for pMDI by liquid chromatography-tandem mass spectrometry. In personal airborne samples, the concentration of 4,4'-MDI isomer, expressed as total NCO, had a geometric mean (GM) and geometric standard deviation (GSD) of 5.1 and 3.3 ng NCO/m3, respectively (range: 0.5-1862 ng NCO/m3). Other MDI isomers were found at much lower concentrations. Analysis of 4,4'-MDI in the glove dosimeters exhibited much greater exposures (GM: 10 ng/cm2) and substantial variability (GSD: 20 ng NCO/cm2; range: 0-295 ng NCO/cm2). MDI inhalation exposure was well below occupational limits for MDI for all the job areas. However, MDI skin exposure to hands was substantial. These findings demonstrated the potential for substantial isocyanate skin exposure in work settings with very low airborne levels. This exposure characterization should inform future studies that aim to assess the health effects of work exposures to MDI and the effectiveness of protective measures.

Toluene diisocyanate occupational exposure data in the polyurethane industry (2005-2020): A descriptive summary from an industrial hygiene perspective.

This article provides an overview of toluene diisocyanate (TDI) workplace air concentration data. Data were collected between 2005-2020 in workplaces across the United States, Canada, and the European Union by a number of different organizations, primarily using the sampling procedures published in OSHA Methods 42 and 5002. The data were then collated and organized by the International Isocyanate Institute. Air samples were collected from several market segments, with a large portion of the data (87%) from the flexible foam industry. The air samples (2534 in total) were categorized into "area" or "personal," and the personal samples were subcategorized into "task," "short term," and "long term." Most of the air sample concentrations (87%) were less than 5 ppb. However, the presence of airborne TDI greater than 5 ppb indicated the importance of respiratory protection in some situations; therefore, respirator use patterns were studied and summarized. Additionally, this article provides a summary of air sample concentrations at different flexible foam manufacturing job roles. The information on air sampling concentrations and respiratory protection during TDI applications collected in this paper could be useful for product stewardship and industrial hygiene purposes in the industries studied.

Methylenediphenyl diisocyanate lysine conjugates in the urine of workers exposed to methylenediphenyl diisocyanate.

Diisocyanates have long been a leading cause of occupational asthma. As control often relies on personal protective equipment and there is the potential for skin uptake, biological monitoring is often used to assess worker exposure. Current routine biological monitoring methods do not distinguish between a diisocyanate and the corresponding diamine exposure in urine samples; therefore, a specific urinary biomarker is desirable. Urine samples were obtained from a group of workers exposed to methylenediphenyl diisocyanate (MDI) where aerosol generation was unlikely. Lysine conjugates of MDI were extracted from urine by solid phase extraction; analysis was performed by liquid chromatography tandem mass spectrometry. Acetylated MDI-lysine (acMDI-Lys) conjugates were detected in 73% of samples tested from persons with exposure to MDI compared to 93% of samples that were positive for methylene dianiline (MDA) in hydrolysed urine. There was a weak but significant positive correlation between the two biomarkers (r2 = 0.377). This is the first report detecting and quantifying acMDI-Lys in the urine of workers exposed to MDI, and acMDI-Lys may be a useful non-invasive biomarker in discriminating between MDI and MDA exposures.

Health effects of exposure to isocyanates in a car factory.

OBJECTIVES: Isocyanates are known to induce occupational diseases. The aim of this work was to assess the health effects of exposure to isocyanates and to test the sensitivity of selected parameters for early detection of isocyanate-related allergic diseases. METHODS: In total, 35 employees from one factory were tested: 26 workers exposed to isocyanates (exposed group) and nine office workers (control group). All subjects filled in a questionnaire regarding possible health problems. Fractional exhaled nitric oxide (FeNO) and spirometry were measured for each subject at the same time during two consecutive working days. A urine sample was taken for a biological exposure test (BET). RESULTS: No significant difference was found between the exposed and control groups for spirometry parameters and FeNO. However, in the exposed group, FeNO was highly elevated (> 50 ppb) in five subjects (all reporting health problems at the workplace, all with normal spirometry and non-smokers). The BET revealed a significant difference (p < 0.001) between the exposed and control groups for 4,4´-methylenediphenyl diamine (MDA) in the urine. CONCLUSIONS: Our examination showed the usefulness of the BET in monitoring of workplace exposure to isocyanates and the importance of FeNO in monitoring of allergic inflammation of airways in non-smoking employees with normal spirometry.

A versatile way for the synthesis of monomethylamines by reduction of N-substituted carbonylimidazoles with the NaBH4/I2 system.

An economical and versatile protocol for the one-pot synthesis of monomethylamines by reduction of N-substituted carbonylimidazoles with NaBH4/I2 in THF at reflux temperature is described. This method used no special catalyst and various monomethylamines can be easily obtained in moderate to good yields from a wide range of raw materials including amines (primary amines and secondary amines), carboxylic acids and isocyanates. Besides, an interesting reduction selectivity was observed. Exploration of the reaction process shows that it undergoes a two-step pathway via a formamide intermediate and the reduction of the formamide intermediate to monomethylamine as the rate-determining step. This work can contribute significantly expanding the applications of N-substituted carbonylimidazoles.

Investigation of Masked N-Acyl-N-isocyanates: Support for Oxadiazolones as Blocked N-Isocyanate Precursors.

In contrast to carbon-substituted isocyanates that are common building blocks, N-substituted isocyanates remain underdeveloped and reports on their N-acyl derivatives (i. e. amido-isocyanates) are exceedingly rare. Herein, amido-isocyanates were investigated in the context of syntheses of aza-tripeptide and hydantoins subunits starting from simple bench-stable precursors. A key finding is that the amido-isocyanate formed in situ cyclized to yield an oxadiazolone, and that under suitable reaction conditions this heterocycle is a traceless blocked (masked) N-isocyanate. Using organic bases as catalysts and upon heating, oxadiazolone formation is observed, and various nucleophiles to provide the desired aza-dipeptides or hydantoins in moderate to high yields. Further support for an amido-isocyanate intermediate was obtained using carboxylic acids as nucleophiles, affording N-acylhydrazide products.

Synthesis, antioxidant activity and bioinformatics studies of L-3-hydroxytyrosine templated N-alkyl/aryl substituted urea/thioureas.

A new series of urea/thiourea derivatives have been efficiently synthesized from the reaction of L-3-hydroxytyrosine with selective isocyanates/isothiocyanates and characterized by Infra-red, proton & carbon-13 nuclear magnetic resonance spectral and mass spectrometry studies. All the synthesized compounds have been screened for their antioxidant activity by 1,1-diphenyl1-2-picrylhydrazyl radical assay, ferric reducing antioxidant power assay and also studied their molecular docking interaction profiles against 1N8Q and 3NRZ enzymatic proteins. The in vitro antioxidant activity has further supported by quantitative structure activity relationship, absorption, distribution, metabolism, and excretion & toxicity studies, bioactivity studies & enzyme inhibition assay and identified that they were potentially bound to ASP490 & ASP361 aminoacid residue in chain A of 1N8Q protein and GLN1194 aminoacid residue in chain L of 3NRZ protein and are responsible for potential antioxidant activity. It is proved that urea derivatives linked with 4-fluoro & 4-nitro and thiourea derivatives linked with 3-chloro & 4-fluoro have exhibited promising antioxidant activity. In eventual synthesized compounds have been identified as potential blood-brain barrier penetrable compounds and proficient central nervous system active neuro-protective antioxidant agents as they have envisaged as easily penetrable to blood-brain barrier thresholds, a neuroprotective property.

Encoding Information into Polyethylene Glycol Using an Alcohol-Isocyanate "Click" Reaction.

In this article, the capability of encoding information using a homologous series of monodisperse monomethoxypolyethylene glycols (mPEG), with a number of ethylene oxide units ranging from nEO = 5 to 8, and monodisperse linear aliphatic isocyanates containing a number of CH2 units from 3 to 7, is demonstrated. The "click" reaction of the two corresponding homologous series yielded 20 different isocyanate end-capped polyethylene glycol derivatives (mPEG-OCONHR) whose sodiated adduct ion's nominal m/z values spanned from 360 to 548, providing an average ca. 8 m/z unit for the storage of one-bit information. These mPEG-OCONHR oligomers were then used to encode information in binary sequences using a 384-well MALDI sample plate and employing the common dried-droplet sample preparation method capable of encoding 20 bit, i.e., 2.5 byte information in one spot, was employed. The information stored in the spots was read by MALDI-TOF MS using the m/z value of the corresponding mPEG-OCONHR oligomers. The capability of the method to store data was demonstrated by writing and reading a text file, visualizing a small picture and capturing a short audio file written in Musical Instrument Digital Interface (MIDI) sequence. Due to the very large similarities in the chemical structures of the encoding oligomers and their "easy to be ionized" property, as well as their very similar ionization efficiencies, the MALDI-TOF MS signal intensities from each compound was so strong and unambiguous that complete decoding could be performed in each case. In addition, the set of the proposed encoding oligomers can be further extended to attain higher bit "densities".

Successful adjunctive treatment of compartment syndrome due to acute isocyanate inhalation using hyperbaric oxygen therapy: case report.

Introduction: Isocyanates are the raw materials that make up all polyurethane products. Isocyanate is a powerful irritant to the mucosal membrane of the respiratory tract, eyes and skin. Pulmonary symptoms, especially occupational asthma, are predominant manifestations of isocyanate toxicity. Case report: We report mental changes and compartment syndrome complicated with rhabdomyolysis as an extraordinary manifestation of acute isocyanate toxicity observed in a patient during the waterproofing of a water tank. A 58-year-old man recovered consciousness after six hours in the emergency department and complained of severe pain in the lower leg. The results of his laboratory test showed that his serum creatine kinase (15,250 IU/L) level had increased. The tissue pressure in both the lower legs had increased to 180 mmHg/170 mmHg (right/left). We performed fasciotomy on the second day of hospitalization. The patient was provided hyperbaric oxygen (HBO2) therapy of 2.0 ATA for 90 minutes twice a day for seven days. His condition gradually improved over five months, and he did not require amputation. He had a mild neurological disorder in his foot and was transferred to a rehabilitation center five months after hospitalization. Conclusion: It is important to note that when working with isocyanate, non-specific complications such as a change in consciousness as well as compartment syndrome with rhabdomyolysis can occur in a confined space or high-temperature environment. In addition, we found that compartment syndrome caused by isocyanate toxicity can be effectively treated with fasciotomy and HBO2 therapy.

O-Isocyanates as Uncharged 1,3-Dipole Equivalents in [3+2] Cycloadditions.

1,3-Dipoles are commonly used in [3+2] cycloadditions, whereas isoelectronic uncharged dipole variants remain underdeveloped. In contrast to conventional 1,3-dipoles, uncharged dipole equivalents form zwitterionic cycloadducts, which can be exploited to build further molecular complexity. In this work, the first cycloadditions of oxygen-substituted isocyanates (O-isocyanates) were studied experimentally and by DFT calculations. This unique cycloaddition strategy provides access to a novel class of heterocycle aza-oxonium ylides through intramolecular and intermolecular cycloadditions with alkenes. This allowed a systematic study of the reactivity of the transient aza-oxonium ylide intermediate, which can undergo N-O bond cleavage followed by nitrene C-H insertion, and the formation of ß-lactams or isoxazolidinones upon varying the structure of the alkene or O-isocyanate reagents.

In silico and in vitro antioxidant activity profiles of urea and thiourea derivatives of 5-hydroxytryptophan.

A series of new urea and thiourea derivatives of 5-hydroxy tryptophan 3a-l was designed and synthesized from 5-hydroxy tryptophan (1) by treating various isocyanates 2a-g and isothiocyanates 2h-l in the presence of triethylamine (TEA) as a base. The antioxidant activities of the newly synthesized compounds were evaluated by using different in vitro assays such as 1, 1-diphenyl-2-picrylhydrazyl (DPPH), hydrogen peroxide (H2O2) and superoxide. The results obtained from the in vitro studies revealed that the compounds 3a, 3g, 3h, and 3l exhibited the significant high content of antioxidant activity. Besides, molecular docking studies indicated that, all the compounds 3a-l have formed higher binding energies with 3MNG protein than the reference compound 1. Among all the synthesized compounds, 3a, 3l, 3g, 3b, 3c and 3h have exhibited the highest dock scores than the rest of the compounds including the reference compound. Hence, it is concluded that the title compounds will open new vistas for the discovery of strong antioxidants and will stand as remarkable antioxidant moieties in future.

New Insights in Frustrated Lewis Pair Chemistry with Azides.

The geminal frustrated Lewis pair (FLP) tBu2 PCH2 BPh2 (1) reacts with phenyl-, mesityl-, and tert-butyl azide affording, respectively, six, five, and four-membered rings as isolable products. DFT calculations revealed that the formation of all products proceeds via the six-membered ring structure, which is thermally stable with an N-phenyl group, but rearranges when sterically more encumbered Mes-N3 and tBu-N3 are used. The reaction of 1 with Me3 Si-N3 is believed to follow the same course, yet subsequent N2 elimination occurs to afford a four-membered heterocycle (5), which can be considered as a formal FLP-trimethylsilylnitrene adduct. Compound 5 reacts with hydrochloric acid or tetramethylammonium fluoride and showed frustrated Lewis pair reactivity towards phenylisocyanate.