Reaction Of Methyl Isocyanate Research Articles

Quantum-chemical study on reactions of isocyanates with linear methanol associates: VII. Effect of nonspecific solvation on the reaction of methyl isocyanate with linear methanol associates

The effect of nonspecific solvation on the reactivity of methyl isocyanate toward linear methanol associates and thermodynamic parameters of this reaction was studied at the B3LYP/6-311++G(df,p) level of theory in terms of the polarizable continuum model (PCM). Transformations in the liquid phase are more exothermic than in the gas phase. Change of the solvent nature leads to variation of the geometric parameters and intrinsic free energies of the reactants and transition states. Increase in solvent polarity is accompanied by increase in the degree of asymmetry and polarity of transition states. As the dielectric permittivity rises, the polar constituent of the Gibbs energy of solvation decreases, while its nonpolar constituent increases. Owing to the opposite variations of these constituents of the Gibbs energy of activation, the reaction is weakly sensitive to solvent polarity.

Quantum-chemical study on reactions of isocyanates with methanol associates: VI. Quantum-chemical characterization of the relative reactivity of linear and cyclic methanol trimers in the addition to methyl isocyanate

Quantum-chemical study on the reaction of methyl isocyanate with cyclic methanol trimer at the B3LYP/6-311++G(df,p) level of theory showed that the process involves concerted asymmetric transition state in which the formation of new N-H bond outstrips the formation of new C-O bond. The reaction of methyl isocyanate with linear methanol trimer was found to be both kinetically and thermodynamically more favorable than with cyclic trimer.

Quantum-Chemical Study on Reactions of Isocyanates with Linear Methanol Associates: III.* Reaction of Methyl Isocyanate with Linear Methanol Associates

Addition of linear methanol associates at the C=N and C=O bonds of methyl isocyanate was studied in terms of the B3LYP/6-311++G(df,p) hybrid quantum-chemical method. The addition at the C=N bond is more favorable than the reaction at the carbonyl group. All reactions involve late asymmetric cyclic transition states. The activity of the reacting system increases in parallel with the degree of methanol association. Isomerization of methyl hydrogen methylcarbonimidate into carbamate is catalyzed by methanol associates. Thermal decomposition of carbamates with formation of isocyanates can occur in autocatalytic mode.

N-methylcarbamoylated valine of hemoglobin in humans after exposure to N,N-dimethylformamide: evidence for the formation of methyl isocyanate?

N,N-Dimethylformamide (DMF) is reported to cause testicular germ-cell tumors in exposed workers. The reports, however, are not in line with results obtained in animal and in vitro experiments, where DMF was shown not to be mutagenic and also not to be carcinogenic. Considerable interest raised on the formation of a reactive intermediate, presumably methyl isocyanate (MIC), during metabolism of DMF in humans over the last years. We report the formation of N-methylcarbamoylated valine of hemoglobin (Hb) in blood samples from workers exposed to DMF in the polyacrylic fiber industry. N-Methylcarbamoylated Hb was formed by the reaction of MIC with Hb. For this purpose, Hb adducts were monitored by means of a modified Edman degradation involving the release of the N-terminal valine adduct in form of 3-methyl-5-isopropylhydantoin (MIH). For internal standardization of the method, 3-ethyl-5-isopropylhydantoin (EIH) was used. Separation and analysis of MIH and EIH were carried out by gas chromatography and mass spectrometry with electron impact ionization (GC/EI-MS). Hb adducts in form of MIH were quantified in blood samples from exposed persons in concentrations between 26.1 and 412.0 nmol of MIH/g of globin. The observed adducts were proven to be identical to those derived from the in situ reaction between Hb and MIC. Taken together with the fact that only N-methylcarbamoylated Hb can undergo ring closure to the corresponding hydantoin, the reaction is indirect evidence for the occurrence of MIC in vivo. The formation of MIC directly in the cell and its possible distribution through the human body may lead to critical effects after exposure to DMF. Adducts were determined not to be totally specific for exposure to DMF since an identical adduct was also found in blood samples from the general population. However, concentrations were lower by a factor of about 100. The sources for background adducts are currently unknown.

The antibody response to methyl isocyanate: experimental and clinical findings.

As a result of the industrial accident in Bhopal, India (December 1984) in which thousands of people were exposed to methyl isocyanate (MIC), concern was raised for possible long-term health effects. The well-recognized immunologic consequences of exposure to other industrial isocyanates prompted investigation of an antibody response to MIC. Using procedures which had been developed in this laboratory to evaluate isocyanate immunotoxicity, animal studies were undertaken to develop and test reagents which could be used to detect antibodies to MIC in the exposed population. Guinea pigs were injected with MIC in its reactive isocyanate form. Three weeks later, blood was drawn and serum evaluated using ELISA. To detect antibodies, an antigen was prepared by reaction of MIC with guinea pig serum albumin. Antibodies were detected in each of the four animals injected with MIC. Titers achieved were 1:5120 to 1:10,240. Inhibition assays revealed antibody specificity directed toward the MIC hapten. Analogous antigens prepared by reaction of MIC with human serum albumin were used to evaluate sera from individuals exposed in Bhopal to MIC. Antibodies were detected in 12 of 144 exposed persons. Antibodies were specific for MIC, as evidenced by inhibition assays, and belonged to the IgG, IgM and IgE classes. However, titers were generally low and transient and were found in persons having had the highest MIC exposures. Total IgE values of sera were not significantly different from those of control sera obtained from Bombay residents. The results indicate that exposure to methyl isocyanate resulted in production of specific antibodies. However, the low titers observed and the transient nature of the response suggest little health consequence should result form the antibody response.

Mutagenicity of methylisocyanate and its reaction products to cultured mammalian cells

Methylisocyanate (MIC) induced mutagenic responses in the absence of exogenous activation in the mouse lymphoma cell forward mutation assay at concentrations as low as 8–24 μM. MIC produced predominantly small mutant colonies, suggesting the possibility of clastogenic activity. The intermediate hydrolysis product, methylamine, was also mutagenic without exogenous activation but required several hundred-fold higher concentrations (ca. 3 mM). N, N′-Dimethylurea, the final product in the reaction of methylisocyanate and water, was totally refractory in either the presence or absence of S9 for concentrations up to 57 mM (5 mg/ml). The ethyl ester of N-methylcarbamic acid was also tested since it was the only available analogue to the highly reactive N-methylcarbamic acid intermediate. This compound was mutagenic only in the presence of S9 at doses exceeding 5–40 μM, which suggested the possibility that the free acid, produced by enzymatic hydrolysis, is also mutagenic. The mutagenic activity of the ester resulted solely in the production of small mutant colonies.

N-Methylcarbamoylphosphate, I. Synthese / N-Methylcarbamoyl Phosphates, I. Synthesis

Abstract Solutions of mono-and bis-N-methylcarbamoyl phosphates in non-aqueous solvents [e.g. acetonitrile, dimethyl formamide, chloroform) and, surprisingly, even in water are readily obtained by the reaction of methyl isocyanate with the solution of an appropriate mono-or dihydrogenphosphate. The course of the reactions and the limited stability of N-methylcarbamoyl phosphate ions in solutions can be monitored through 31P NMR measurements. Various types of compounds, including a coordination compound of cobalt could be isolated in crystalline form: [Et3NH]HX, KHX, NH4HX, Na2X · H2O, MgX · 4 H2O, CaX · H20, SrX · 2 H2O, BaX · H2O, ZnX · 5 H2O, CdX · 2 H2O, [(NH3)5CoX]ClO4, [Et3NH]Y, AgY · MeCN, X = MeNHC(O)OPO3, Y = [MeNHC(O)O]2PO2.

Bildung von Amidophosphaten und Amidophosphorsäure aus N-Methylcarbamoylphosphaten / Formation of Amidophosphates and Amidophosphoric Acid from N-Methylcarbamoyl Phosphates

Abstract The synthesis of various amidophosphates can be readily accomplished in aqueous solutions by the reaction of amines with solutions of sodium, potassium or ammonium N-methylcarbamoyl phosphate, prepared by the reaction of methylisocyanate with the corresponding hydrogen phosphates. Procedures for the synthesis of NH4[O3PNH3] and Ca[O3PNH2CH3]2 · 4 H2O are described in detail.

Synthesis and pharmacological evaluation of a series of analogues of 1-methylisoguanosine.

A series of analogues of the pharmacologically active marine natural product 1-methylisoguanosine (1) was evaluated for biological activity in muscle relaxant, cardiovascular, antiinflammatory, and antiallergic tests. Modifications at the 1 position produced the ethyl, n-butyl, n-octyl, and phenyl derivatives 3-6, respectively. Substitutions at the 8 position provided the bromo, hydrazino and amino compounds 9-11. Modification at the 5' position yielded the deoxy, iodo, and phosphate derivatives 15, 13, and 16, as well as the cyclic 3',5'-phosphate 17. The synthesis of the C-nucleoside analogue 19 was achieved from the beta-D-ribofuranosylcarboximidic ester 20. The acyclic analogue 29 and the beta-D-arabinofuranosyl derivative 35 were both synthesized by reaction of methyl isocyanate with the appropriately protected aminocyanoimidazole precursors 28 and 32. 1-Methylxanthosine (12), isoguanosine (7), and 2-methoxyadenosine (18) were also synthesized. At doses up to 100 mg/kg po, the 5'-phosphate 16, cyclic 3',5'-phosphate 17, and the O-methylated analogue 2-methoxyadenosine 18 were active in producing muscle relaxation and hypothermia. These compounds possessed antiallergic activity and produced dose-dependent falls in mean blood pressure and heart rate as did the 1-ethyl (3) and 1-n-butyl (4) analogues. In general, antiinflammatory activity paralleled the other results, except that the cyclic 3',5'-phosphate 17 was inactive at the dose tested, while the 3,5'-anhydronucleoside 14 was weakly active and displayed antiallergic effects.

High-pressure liquid chromatographic analysis of arylhydroxylamines after derivatization with methyl isocyanate

The quantitative analysis of micromolar levels of arylhydroxylamines in liver homogenates is described. The analyte is extracted from the biological medium with dichloromethane and then converted to the corresponding N-hydroxyurea by reaction with methyl isocyanate. The reaction product is stable both in the dry state and in solution. The derivatized mixture is separated by reversed-phase partition chromatography and teh hydroxylamine quantitated as the methylhydroxyurea by spectrophotometric monitoring of the column eluent at 254 nm. The method is specific for arylhydroxylamines in that the product is different from products formed by reaction of methyl isocyanate with alternate amine metabolites and metabonates.