Nitrosopyrrolidine formation

Evidence exists that the relative solubility of amines and inhibitors in heterogeneous oil-water systems could be decisive in formation of nitrosamines and blocking these reactions, Nitrosopyrrolidine formation in bacon predominates in the adipose tissue despite the fact that its precursor, proline, predominates in the lean tissue (5,6,7). Mottram and Patterson (8) partly attribute this phenomenon to the fact that the adipose tissue furnishes a medium in which nitrosation is favored, Massey, et al, (9) found that the presence of decane in a model heterogeneous system caused a 20-fold increase in rate of nitrosamine formation from lipophilic dihexylamine, but had no effect on nitrosation of hydrophilic pyrrolidine. Ascorbic acid in the presence of decane enhanced the synthesis of nitrosamines from lipophilic amines, but had no effect on nitrosation of pyrrolidine. The oil-soluble inhibitor ascorbyl palmitate had little influence on the formation of nitrosamines in the presence or absence of decane. 

Co. and 20 mM nitrite in water, pH 3, 25 C, 60 min reaction], it was nitrosated to yield 3.62 mM 2,6-dimethyl-N-nitrosomorpho-line (DMNM), which was a 10% greater yield than that for a similar nitrosation of morpholine to give NMOR. This indicated a slightly larger rate constant for DMNM than for NMOR formation (3). Crude DMM is a 2 1 mixture of the cis and trans isomers ( 0). GC analysis of the product of the kinetic run showed that the 2 isomers were nitrosated at similar rates. Cis-DMNM [retention time (RT), 320 sec] was well separated from NMOR (RT, 430 sec), but trans-DMNM (RT, 405 sec) was not. Accordingly, we prepared pure cis-DMM, b.p. 133 C, by spinning-band fractional distillation of crude DMM and used it in the analytical procedure. The RT of N-nitrosopyrrolidine (NPYR) was 390 sec. 

The extent of formation of these NOC depends upon the presence of nitrogen oxides present in the atmosphere during the manufacturing cycle. The major contaminants are NDMA, A-nitrosodiethylamine (NDEA), A-nitrosopyrrolidine (NPYR), NMOR, A-nitrosodiphenylamine (NDPhA), A-nitrosopiperidine (NPIP) and A-nitrosodibutylamine (NDBA)68. NMOR was found in the hot process areas NDMA occurred in tube production areas in which NDPhA was being used as retarder and tetramethylthiuram disulphide as an accelerator. Figure 12 shows a proposed reaction scheme of formation of NOC in the rubber industry and subsequent exposure67. 

The photochemistry of certain A-substituted heterocycles has also been studied. As part of a continuing investigation of the photolysis of A-nitroso compounds in solution, the conversion of A-nitroso-3-azabicyclo[3.2.2]nonane (65) into the oxime (66) by photolysis in the presence of acid was reported.58 N-Nitrosopyrrolidine is similarly transformed. The mechanism of this reaction is said58 to involve elimination of NOH with the formation of an imine as intermediate, and, in fact, in the photolysis of 2-ethyl-A-nitrosopiperidine (67), the tetrahydropyridine (68) is the major product. This mechanism certainly does not operate in the photolysis of iV-nitroso-2-azacyclo-octanone, which can be rationalized on the basis of an intramolecular hydrogen transfer [Eq. (16)].59 Acyclic iV-nitrosoamides behave in a similar fashion to IV-nitrosoamines.60... 

Mirvish (15) showed that weak bases are more easily N-nitrosated than strong bases under mildly acidic conditions. Since the secondary amine nitrogen on the 1,3-thiazolidine ring is much less basic (pKa 6.3) than in the pyrrolidine ring (pKfl 11.3), the formation of N-nitroso-l,3-thiazoline should be favorable and hence would be predicted to occur in products such as bacon where N nitrosopyrrolidine is of major concern. 

Chung, F.L. and Hecht., S.S. (1983) Formation of cyclic l.N2-adducts by reaction of deoxyguanosine with a-acetoxy-N-nitrosopyrrolidine, 4-(carbethoxynitrosamino)butanal, or crotonaldehyde. Cancer Res., 43, 1230-1235. 

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