Methyl isocyanates

A contact insecticide with the trade name Sevin . White solid, m.p. 142 C. It is prepared by reaction of I-naphthol with methyl isocyanate or with phosgene and a base. 

There are three types of TAP emissions continuous, intermittent, and accidental. Both routine emissions associated with a batch process or a continuous process that is operated only occasionally can be intermittent sources. A dramatic example of an accidental emission was the release of methyl isocyanate [624-83-9] in Bhopal, India. As a result of this accident, the U.S. Congress created Tide III, a free-standing statute included in the Superfund Amendments and Reauthorization Act (SARA) of 1986. Title III provides a mechanism by which the pubHc can be informed of the existence, quantities, and releases of toxic substances, and requires the states to develop plans to respond to accidental releases of these substances. Eurther, it requires anyone releasing specific toxic chemicals above a certain threshold amount to aimuaHy submit a toxic chemical release form to EPA. At present, there are 308 specific chemicals subject to Title III regulation (37). 

More recently, a commercial process has been introduced for the manufacture of methyl isocyanate (MIC) which involves the dehydrogenation of /V-m ethyl form am i de [123-39-7] in the presence of palladium, platinum [7440-06-4], or mthenium [7440-18-8], at temperatures between 50—300°C (31). Aprotic solvents, such as ben2ene [71-43-2], xylenes, or toluene [108-88-3], may optionally be used. A variation of this synthesis employs stoichiometric amounts of palladium chloride [7647-10-1], PdCl2. 

Low boiling isocyanates, such as methyl isocyanate [624-83-9] are difficult to prepare via conventional phosgenation due to the fact that the A/-alkyl carbamoyl chlorides are volatile below their decomposition poiat. Interestingly, A/-ethyl carbamoyl chloride decomposes at its boiling poiat whereas the A/-propyl carbamoyl chloride is thermoly2ed cleanly into isocyanate and hydrogen chloride. 

A convenient method for the synthesis of these low boiling materials consists of the reaction of /V,/V-dimethy1iirea [96-31-1] with toluene diisocyanate to yield an aUphatic—aromatic urea (84). Alternatively, an appropriate aUphatic—aromatic urea can be prepared by the reaction of diphenylcarbamoyl chloride [83-01-2] with methylamine. Thermolysis of either of the mixed ureas produces methyl isocyanate ia high yield (3,85). 

X5lenol is an important starting material for insecticides, xylenol—formaldehyde resins, disinfectants, wood preservatives, and for synthesis of a-tocopherol (vitamin E) (258) and i7/-a-tocopherol acetate (USP 34-50/kg, October 1994). The Bayer insecticide Methiocarb is manufactured by reaction of 3,5-x5lenol with methylsulfenyl chloride to yield 4-methylmercapto-3,5-xylenol, followed by reaction with methyl isocyanate (257). Disinfectants and preservatives are produced by chlorination to 4-chloro- and 2,4-dich1oro-3,5-dimethylpheno1 (251). 

Naphthol is mainly used in the manufacture of the insecticide carbaryl (59), l-naphthyl A/-methyicarbamate/ iJ-2j5 - (Sevin) (22), which is produced by the reaction of 1-naphthol with methyl isocyanate. Methyl isocyanate is usually prepared by treating methylamine with phosgene. Methyl isocyanate is a very toxic Hquid, boiling at 38°C, and should not be stored for long periods of time (Bhopal accident, India). India has developed a process for the preparation of aryl esters of A/-alkyl carbamic acids. Thus l-naphthyl methylcarbamate is prepared by refluxing 1-naphthol with ethyl methylcarbamate and POCl in toluene (60). In 1992, carbaryl production totaled > 11.4 x 10 t(35). Rhc ne-Poulenc, at its Institute, W. Va., facihty is the only carbaryl producer in United States. 

The nitrogen of aHphatic and aromatic amines is alkylated rapidly by alkyl sulfates yielding the usual mixtures. Most tertiary amines and nitrogen heterocycles are converted to quaternary ammonium salts, unless the nitrogen is of very low basicity, eg, ia tn phenylamine. The position of dimethyl sulfate-produced methylation of several heterocycles with more than one heteroatom has been examined (22). Acyl cyanamides can be methylated (23). Metal cyanates are converted to methyl isocyanate or ethyl isocyanate ia high yields by heating the mixtures (24,25). 

In many pyrimidine ring syntheses, it is possible or even desirable to isolate an intermediate ripe for ring-closure by the formation of just one bond. For example, ethyl 3-aminocrotonate (502) reacts with methyl isocyanate to give the ureido ester (503) which may be isolated and subsequently converted into 3,6-dimethyluracil (504) by the completion of one bond. However, viewed pragmatically, the whole synthesis involves the formation of two bonds and therefore is so classified. On such criteria, only two pyrimidine/quinazoline syntheses involve the formation of only one bond. 

A similar product is obtained from the reaction of anhydro-4(5)-hydroxy-l,2,3-triazolium hydroxide (398). In this case reaction with DMAD occurred in 1 hour in boiling benzene. Extrusion of methyl isocyanate from the initial 1 1 cycloadduct (399) occurred during the reaction giving (400). 

IntensiHcation This involves using so little hazardous material that it does not matter if it all leaks out. For example, at Bhopal, methyl isocyanate (MIC), the material that leaked and killed over 2000 people, was an intermediate for which it was convenient but not essential to store. Within a few years many companies had reduced their stocks of MIC and other hazardous intermediates. 

Substitution If intensification is not possible, then an alternative is to consider using a safer material in place of a hazardous one. Thus it may be possible to replace flammaole solvents, refrigerants, and heat-transfer media by nonflammable or less flammable (high-boiling) ones, hazardous products by safer ones, and processes which use hazardous raw materials or intermediates by processes which do not. As an example of the latter, the product manufactured at Bhopal (carbatyl) was made from three raw materials. Methyl isocyanate is formed as an intermediate. It is possible to react the same raw materials in a different order so that a different and less hazardous intermediate is formed. 

The insecticide carbaryl can be produced by several routes, some of which do not use methyl isocyanate, or which generate only small quantities of this toxic material as an in-process intermediate (Kletz, 1991b). One company has developed a proprietary process for manufacture of carbamate insecticides which generates methyl isocyanate as an in-situ intermediate. Total methyl isocyanate inventory in the process is no more than 10 kilograms (Kharbanda and Stallworthy, 1988 Manzer, 1994). 

At about 12 40 A.M. December 3, 1984, the accident occurred that took 2,500 lives at the Union Carbide (India) Ltd. (UCIL) operated pesticide plant. The first indication of process upset was when the control-room operator (CRO) noted that the temperature in a supposedly refrigerated tank storing methyl isocyanate gas (MIC), had risen to 77° F. The pressure, normally 2 to 25 psi was 55 psi. 

The worst disaster in the history of the chemical industry occurred in Bhopal, in the state of Madhya Pradesh in central India, on December 3, 1984. A leak of methyl isocyanate (MIC) from a chemical plant, where it was used as an intermediate in the manufacture of the insecticide car-baryl, spread beyond the plant boundary and caused the death by poisoning of more than 2,000 people. The official figure was 2,153, but some unofficial estimates were much higher. In addition, about 200,000 people were injured. Most of the dead and injured were living in a shanty town that had grown up next to the plant. 

Bhopal Methyl Isocyanate Incident Investigation Team Report, Union Carbide Corporation, Danbury, Conn., Mar. 1985. 

Reaction of the phenol with methyl isocyanate then gives physo-stigmine (36). ... 

Alkylation of the protected azetidinyl bromide 61 with the anion from m-trifluormethyl-phenol gives ether 62. Removal of the N-(alpha-methylbenzyl)- protecting group by catalytic hydrogenation gives the secondary amine 63. Reaction of that compound with methyl isocyanate gives the anticonvulsant urea fluzinamide (64) [14]. 

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