A Naked Eye and Fluorescence Turn-on Sensor for Smartphone Assisted Solid and Solution Phase Sensing of Highly Toxic Triphosgene.

A naked eye and fluorescence turn-on 1,8-naphtahlimide based chemosensor,1, possessing Schiff base linkage was utilized for the rapid detection of highly toxic triphosgene. The proposed sensor selectively detected triphosgene over various other competitive analytes including phosgene with the detection limit of 6.15 and 1.15 µM measured using UV-vis and fluorescence spectrophotometric techniques, respectively. Colorimetric changes observed in solution phase were processed by image analysis using smartphone leading to on-site and inexpensive determination of triphosgene. Further, solid phase sensing of triphosgene was carried out by 1 loaded PEG membranes and silica gel.

Rapid and Mild Lactamization Using Highly Electrophilic Triphosgene in a Microflow Reactor.

Lactams are cyclic amides that are indispensable as drugs and as drug candidates. Conventional lactamization includes acid-mediated and coupling-agent-mediated approaches that suffer from narrow substrate scope, much waste, and/or high cost. Inexpensive, less-wasteful approaches mediated by highly electrophilic reagents are attractive, but there is an imminent risk of side reactions. Herein, a methods using highly electrophilic triphosgene in a microflow reactor that accomplishes rapid (0.5-10 s), mild, inexpensive, and less-wasteful lactamization are described. Methods A and B, which use N-methylmorpholine and N-methylimidazole, respectively, were developed. Various lactams and a cyclic peptide containing acid- and/or heat-labile functional groups were synthesized in good to high yields without the need for tedious purification. Undesired reactions were successfully suppressed, and the risk of handling triphosgene was minimized by the use of microflow technology.

High sensitivity of graphdiyne nanoflake toward detection of phosgene, thiophosgene and phosogenoxime; a first-principles study.

The sensing properties of 2D carbon materials are well explored for various gaseous analytes, however, the detection of toxic chemicals e.g., phosgene (Ph), thiophosgene (ThP) and phosogenoxime (PhO) are rarely studied. To the best of our literature survey, only a single study is found for the adsorption of phosgene on 2D carbon nanoflake (graphyne). This motivated us to explore the sensitivity of graphdiyne (GDY) nanoflake for the detection of phosgene and couple of its derivatives. Therefore, we have performed a density functional analysis to simulate the comparative interaction between phosgene, thiophosgene and phosogenoxime with graphdiyne nanoflake. The interaction behaviours are estimated by interaction energies, (symmetry adopted perturbation) SAPT0 analysis, (noncovalent interaction index) NCI analysis, molecular orbital analysis, natural bond orbital (NBO) charge transfer and UV-Vis absorption analysis. The obtained results demonstrate the trend in sensitivity of graphdiyne for analytes is PhO@GDY > ThP@GDY > Ph@GDY. The sensible justification for the particular observation is provided by the energy gaps between HOMO and LUMO orbitals in term of %sensitivity. The %sensitivity is in complete accord with the aforementioned trend. In addition, results suggest that graphdiyne based sensor for detecting phosgene and derivatives are better in sensitivity in comparison with already reported graphyne sensor.

Fluorescent Chemosensor for Dual-Channel Discrimination between Phosgene and Triphosgene.

As highly toxic and accessible chemical reagents, phosgene and triphosgene have become a serious threat to public safety. So, it is highly desirable to develop facile methods to detect and recognize them. In this article, a novel fluorescent chemosensor, Phos-4, has been constructed with 1,8-naphthalimide as the fluorophore and 2-(2-aminophenyl)imidazol as the recognition sites for discrimination between phosgene and triphosgene in a dual-channel mode for the first time. Owing to the difference in electrophilicity between chlorocarbonyl and trichloromethoxycarbonyl, the sensing reaction of Phos-4 with phosgene undergoes two carbamylations to afford a cyclic product with green fluorescence, and only one carbamylation occurs for triphosgene to form a noncyclic product with blue fluorescence. The sensor Phos-4 exhibits high sensitivity (the limit of detection, 3.2 nM, for phosgene, and 1.9 nM, for triphosgene) and high selectivity in solutions. Furthermore, facile test papers containing Phos-4-embedded nanofibrous membrane have been fabricated by the electrospinning technology. The test papers can provide visual and selective detection of phosgene with a lower limit of detection (42 ppb) and a faster response (≤10 s) in the gas phase over those in solutions. The test paper with Phos-4 is promising to be a practical detection tool of gaseous phosgene.

Instantaneous Detection of Trichlorinated Carbon via Photo-Induced Electron Transfer toward Chemosensor for Toxic Organochlorides.

Despite the usefulness of organochlorides as raw materials for organic synthesis, they cause several issues in the human body, such as hepatic dysfunction, tumor, and heavy damage to the central nervous system. Especially when organochlorides contain three or more chlorinated carbons, they tend to be more toxic to the human body possibly owing to relatively high reactivity. Several electron donors (TPCAs) are designed to devise a novel detection system for toxic organochlorides containing trichlorinated carbons, and the detection mechanism of the devised sensor system is systematically identified by EPR measurement and the analysis of the solution after the detection of chloroform, which is used as a model compound. Since the detection system simultaneously utilizes the radical-generation capability and the low LUMO level of the trichlorinated carbon, it provides high selectivity against most of the common organic compounds including other organochlorides containing mono- or dichlorinated carbons, and the outstanding selectivity of the designed sensor has been verified with Mirex composed of numerous chlorinated carbons. In addition, the detection system exhibits immediate sensing capability because only electron transfer and radical reaction are involved in the detection process. Finally, when diphosgene is detected with the devised sensing platform, a noticeable change in fluorescence intensities can be identified within 5 s even for a diphosgene concentration of less than 1 ppm.

Triphosgene-pyridine mediated stereoselective chlorination of acyclic aliphatic 1,3-diols.

We describe a strategy to chlorinate stereocomplementary acyclic aliphatic 1,3-diols using a mixture of triphosgene and pyridine. While 1,3-anti diols readily led to 1,3-anti dichlorides, 1,3-syn diols must be converted to 1,3-syn diol monosilylethers to access the corresponding 1,3-syn dichlorides. These dichlorination protocols were operationally simple, very mild, and readily tolerated by advanced synthetic intermediates.

Characterization of the designer drug bk-2C-B (2-amino-1-(bromo-dimethoxyphenyl)ethan-1-one) by gas chromatography/mass spectrometry without and with derivatization with 2,2,2-trichloroethyl chloroformate, liquid chromatography/high-resolution mass spectrometry, and nuclear magnetic resonance.

RATIONALE: We describe the analytical characterization of the designer drug bk-2C-B, a cathinone derivative, contained in a seized tablet, in the absence of an analytical standard. METHODS: The analytical techniques employed include gas chromatography/mass spectrometry (GC/MS), without and with derivatization with 2,2,2-trichloroethyl chloroformate, liquid chromatography/high-resolution-MS (LC/HRMS) with an Orbitrap® analyzer, and nuclear magnetic resonance (NMR). LC/HRMS measurements consisted of accurate mass measurements of MH(+) ionic species under full scan conditions; comparison of experimental and calculated MH(+) isotopic patterns; examination of the isotopic fine structure (IFS) of the M+1, M+2, M+3 isotopic peaks relative to the monoisotopic M+0 peak; study of MH(+) collision-induced dissociation (CID) product ions obtained in fragmentation experiments. RESULTS: GC/MS analysis gave highly informative EI mass spectra, particularly after the derivatization of bk-2C-B with 2,2,2-trichloroethyl chloroformate. The application of LC/HRMS, allowing for accurate mass measurements at 100,000 resolving power, greatly enhanced analytical capabilities in structural characterization of this new designer drug. HRMS allowed us to obtain the accurate mass measurements of bk-2C-B MH(+) ionic species, with a mass accuracy of 2.19 ppm; fully superimposable experimental and calculated MH(+) isotopic patterns, with RIA1 and RIA2 values <4%; the IFS of the M+1, M+2, M+3 isotopic peaks relative to the monoisotopic M+0 peak completely in accordance with theoretical values. These findings enabled us to obtain the elemental composition formula of the seized drug. Furthermore, characteristic MH(+) CID product ions enabled the characterization of the bk-2C-B molecular structure. The presence of (79)Br and (81)Br isotopes in the substance molecule produced a characteristic isotopic pattern in most MS spectra. Lastly, NMR spectra allowed us to obtain useful information about the position of substituents in the designer drug. CONCLUSIONS: The combination of all the analytical techniques employed allowed the characterization of the seized psychoactive substance, in spite of the lack of a reference standard.

One-Step Synthesis of 2-Chloropyrimidin-4-ol Derivatives: An Unusual Reactivity of Thiophosgene.

A novel, high-yielding, one-step synthesis of 2-chloroquinazolin-4-ols and analogous bicycles from 2-aminoamides using thiophosgene is described. The scope of the reaction includes aminothioamides, amino acids, and fused heterocycle derivatives, furnishing quinazolines, oxazinones, and substituted fused pyrimidine bicycles, respectively. On the basis of observed results with substituted analogues, a mechanism for this transformation is thought to occur via an isothiocyanate intermediate followed by an unexpected chemoselective reaction of thiophosgene on the thiol intermediate.

Flow synthesis of ethyl isocyanoacetate enabling the telescoped synthesis of 1,2,4-triazoles and pyrrolo-[1,2-c]pyrimidines.

The efficient flow synthesis of important heterocyclic building blocks based on the 1,2,4-triazole and pyrrolo[1,2-c]pyrimidine scaffold has been achieved. Crucially, a telescoped continuous flow process was developed based on the reaction of N-formylglycine with triphosgene to deliver a stream of ethyl isocyanoacetate in situ, which subsequently yielded the desired heterocyclic entities in a telescoped reaction. Additionally, the functionalisation of the pyrrolo[1,2-c]pyrimidine core via subsequent SEAr reactions was studied revealing insight into a 'halogen dance' phenomenon associated with these medicinally relevant architectures.

A refined quartic potential energy surface and large scale vibrational calculations for S0 thiophosgene.

In this work we present a full 6D quartic potential energy surface (PES) for S0 thiophosgene in curvilinear symmetrized bond-angle coordinates. The PES was refined starting from an ab initio field derived from acc-pVTZ basis set with CCSD(T) corrections for electron correlation. In the present calculations we used our variational method that was recently tested on formaldehyde and some of its isotopomers, along with additional improvements. The lower experimentally known vibrational levels for 35Cl2CS were reproduced quite well in the calculations, which can be regarded as a test for the feasibility of the obtained quartic PES.

On readout of vibrational qubits using quantum beats.

Readout of the final states of qubits is a crucial step towards implementing quantum computation in experiment. Although not scalable to large numbers of qubits per molecule, computational studies show that molecular vibrations could provide a significant (factor 2-5 in the literature) increase in the number of qubits compared to two-level systems. In this theoretical work, we explore the process of readout from vibrational qubits in thiophosgene molecule, SCCl2, using quantum beat oscillations. The quantum beats are measured by first exciting the superposition of the qubit-encoding vibrational states to the electronically excited readout state with variable time-delay pulses. The resulting oscillation of population of the readout state is then detected as a function of time delay. In principle, fitting the quantum beat signal by an analytical expression should allow extracting the values of probability amplitudes and the relative phases of the vibrational qubit states. However, we found that if this procedure is implemented using the standard analytic expression for quantum beats, a non-negligible phase error is obtained. We discuss the origin and properties of this phase error, and propose a new analytical expression to correct the phase error. The corrected expression fits the quantum beat signal very accurately, which may permit reading out the final state of vibrational qubits in experiments by combining the analytic fitting expression with numerical modelling of the readout process. The new expression is also useful as a simple model for fitting any quantum beat experiments where more accurate phase information is desired.

Efficient amide bond formation through a rapid and strong activation of carboxylic acids in a microflow reactor.

The development of highly efficient amide bond forming methods which are devoid of side reactions, including epimerization, is important, and such a method is described herein and is based on the concept of rapid and strong activation of carboxylic acids. Various carboxylic acids are rapidly (0.5 s) converted into highly active species, derived from the inexpensive and less-toxic solid triphosgene, and then rapidly (4.3 s) reacted with various amines to afford the desired peptides in high yields (74%-quant.) without significant epimerization (≤3%). Our process can be carried out at ambient temperature, and only CO2 and HCl salts of diisopropylethyl amine are generated. In the long history of peptide synthesis, a significant number of active coupling reagents have been abandoned because the highly active electrophilic species generated are usually susceptible to side reactions such as epimerization. The concept presented herein should renew interest in the use of these reagents.

More protected vibrational states at the dissociation limit of SCCl2.

Local vibrational coupling models predict that intramolecular vibrational energy redistribution (IVR) is not completely statistical even at the dissociation limit of polyatomic molecules. Thus states protected from IVR and from rapid dissociation form regular progressions and can be assigned vibrational quantum numbers. We previously observed such regular progressions of states in vibrational spectra of the molecule SCCl2, but a discrepancy in the density of such states remained between theory and experiment. Here we show that the gap can be closed by observing and assigning additional vibrational transitions above the dissociation limit of SCCl2, and by carefully analyzing the theoretically expected density of protected states. The newly observed transitions originate from recently assigned and more highly excited vibrational levels in the B̃ electronic state, connecting to the X̃ ground state by different Franck-Condon factors. Based on our analysis of Franck-Condon activity, we conclude that theory and experiment agree within measurement uncertainty. Consistency between theory and experiment implies that even more protected states should be observed for larger molecules, leading to nonstatistical dissociation reactions.

Franck-Condon fingerprinting of vibration-tunneling spectra.

We introduce Franck-Condon fingerprinting as a method for assigning complex vibration-tunneling spectra. The B̃ state of thiophosgene (SCCl2) serves as our prototype. Despite several attempts, assignment of its excitation spectrum has proved difficult because of near-degenerate vibrational frequencies, Fermi resonance between the C-Cl stretching mode and the Cl-C-Cl bending mode, and large tunneling splittings due to the out-of-plane umbrella mode. Hence, the spectrum has never been fitted to an effective Hamiltonian. Our assignment approach replaces precise frequency information with intensity information, eliminating the need for double resonance spectroscopy or combination differences, neither of which have yielded a full assignment thus far. The dispersed fluorescence spectrum of each unknown vibration-tunneling state images its character onto known vibrational progressions in the ground state. By using this Franck-Condon fingerprint, we were able to determine the predominant character of several vibration-tunneling states and assign them; in other cases, the fingerprinting revealed that the states are strongly mixed and cannot be characterized with a simple normal mode assignment. The assigned transitions from vibration-tunneling wave functions that were not too strongly mixed could be fitted within measurement uncertainty by an effective vibration-tunneling Hamiltonian. A fit of all observed vibration-tunneling states will require a full resonance-tunneling Hamiltonian.

One-step synthesis of biodegradable curcumin-derived hydrogels as potential soft tissue fillers after breast cancer surgery.

A one-step synthesis of a curcumin-derived hydrogel (curcumin content of 25-75 mol %) is reported. Curcumin is incorporated into the hydrogel backbone and cross-linked through biodegradable carbonate linkages. Curcumin as a part of the polymer backbone is protected from oxidation and degradation, while hydrogel hydrolysis results in the release of active curcumin. Nontoxic poly(ethylene glycol) and desaminotyrosyl-tyrosine ethyl ester are used to tune the hydrophilic/hydrophobic hydrogel properties. In this way, hydrogels with a wide range of physical properties including water-uptake (100-550%) and compression moduli (7-100 kPa) were obtained. Curcumin release is swelling-controlled and could be extended to 80 days. In vitro, curcumin-derived hydrogels showed selective cytotoxicity against MDA-MB-231 (IC(50) 9 µM) breast cancer cells but no cytotoxicity to noncancerous quiescent human dermal fibroblasts even at high curcumin concentrations (160 µM). One possible application of these curcumin-derived hydrogels is as soft tissue filler after surgical removal of cancerous tissue.

Radiosynthesis of [13N]dantrolene, a positron emission tomography probe for breast cancer resistant protein, using no-carrier-added [13N]ammonia.

Dantrolene (1) is a substrate for breast cancer resistant protein, which is widely distributed in the blood-brain-barrier, intestine, gall bladder, and liver. PET study with 1 labeled with a positron emitter can be used to visualize BCRP and to elucidate the effect of BCRP on the pharmacokinetics of drugs. The objective of this study was to label 1 using nitrogen-13 ((13)N, a positron emitter; half-life: 9.9min). Using no-carrier-added [(13)N]NH(3) as the labeling agent, we synthesized [(13)N]dantrolene ([(13)N]1) for the first time. The reaction of carbomyl chloride 2b with [(13)N]NH(3) gave an unsymmetrical urea [(13)N]3, followed by cyclization of [(13)N]3 to afford [(13)N]1. Due to its instability, 2b was prepared in situ by treating amine 5 with triphosgene in a ratio of 4 to 1 and used for subsequent [(13)N]ammonolysis without purification.

Acute nose-only inhalation exposure of rats to di- and triphosgene relative to phosgene.

Groups of young adult Wistar rats were acutely exposed to trichloromethyl chloroformate (diphosgene) and bis(trichloromethyl) carbonate (triphosgene) vapor atmospheres using a directed-flow nose-only mode of exposure. The exposure duration used was 240 min. The median lethal concentration (LC50) of diphosgene and triphosgene was 13.9 and 41.5 mg/m3, respectively. Based on the molar exposure concentrations, the LC50s of phosgene (previously published), diphosgene, and triphosgene were 0.07, 0.07, and 0.14 mmol/m3, respectively. Although the principal toxic mode of action of the volatile diphosgene was similar to phosgene gas, the vapor phase of triphosgene appeared to be different to that of phosgene and diphosgene based on a more persistent occurrence of signs of respiratory distress and a biphasic onset of mortality. While all substances caused mortality within 1 day postexposure, triphosgene induced a second phase of mortality 11?14 days postexposure. The vapor saturation concentration of triphosgene at ambient temperature is ?100 times its LC50. In summary, triphosgene-induced lung injury patterns are different from that of phosgene and diphosgene. More research is needed to close the substantial data gaps of triphosgene.

Diversity-oriented, one-pot, multi-component synthesis of substituted uracil derivatives.

With the emergence of high throughput screening of bioactive molecules, there is constant need for the development of new strategies for diversity-oriented synthesis. We describe here a novel one-pot multicomponent reaction for the synthesis of uracil derivatives using easily available starting materials. This new synthetic strategy provides easy access to diverse uracil derivatives in moderate to good yields.