Nitrosamines stability

Gold and Linder (17) studied the esterase catalyzed hydrolysis of A-(-)-acetoxymethyl-(l-phenylethyl)nitrosamine. They found that the stereochemistry of 1-phenylethanol produced in the reaction was the same as that observed in the base catalyzed hydrolysis of the nitrosamine and also of N-(l-phenylethyl)nitrosocarbamate. These results indicated that the same diazotate was produced in all three reactions. The fact that no irreversible inhibition of the enzymatic hydrolysis of the nitrosamine was observed, while extensive irreversible inhibition was obtained with the nitrosocarba-mate, led these workers to conclude that the a-hydroxynitro-samine produced by the hydrolysis had sufficient stability to diffuse away from the active site of the enzyme. 

N-Nitrosamine inhibitors Ascorbic acid and its derivatives, andDC-tocopherol have been widely studied as inhibitors of the N-nitrosation reactions in bacon (33,48-51). The effect of sodium ascorbate on NPYR formation is variable, complete inhibition is not achieved, and although results indicate lower levels of NPYR in ascorbate-containing bacon, there are examples of increases (52). Recently, it has been concluded (29) that the essential but probably not the only requirement for a potential anti-N-nitrosamine agent in bacon are its (a) ability to trap NO radicals, (b) lipophilicity, (c) non-steam volatility and (d) heat stability up to 174 C (maximum frying temperature). These appear important requirements since the precursors of NPYR have been associated with bacon adipose tissue (15). Consequently, ascorbyl paImitate has been found to be more effective than sodium ascorbate in reducing N-nitrosamine formation (33), while long chain acetals of ascorbic acid, when used at the 500 and lOOO mg/kg levels have been reported to be capable of reducing the formation of N-nitrosamines in the cooked-out fat by 92 and 97%, respectively (49). 

Possible exposure to pesticide-derived N,-nitroso compounds depends on environmental processes that influence formation, movement, and degradation of the compounds. Although laboratory studies have shown the feasibility of environmental nitrosamine formation, there has been little evidence that it is an important process. Nitrosamines vary greatly in their environmental stabilities, but all seem to be susceptible to one or more modes of decomposition including photolysis, microbiological degradation, and plant metabolism. 

Used in combination with other accelerators, the dithiophosphates reduce the risk of bloom and the formation of nitrosamines. Generally reversion stability is improved. The copper dithiophosphate will cause discolouration and contact staining. 

The diffusion-limited electrochemical oxidation of V-nitrosamines in an aqueous pH 1.5 buffer was demonstrated at a GCE coated with a film of mixed valence ruthenium oxides, stabilized by cyano crosslinks. This electrode was used in a potentiostatic amperometric detector for FIA and HPLC, to allow the determination of representative N-nitrosamines (278a, 278c and 278d) for 278c, LOD was 10 nM and RSD 2% at 0.80 pM... 

A H NMR spectrum of /V,/V-dimethylnitrosamine (38) was obtained as early as 1957, and the free energy of activation for rotation was determined to be ca. 23 kcal/mol at 215°C (74). This high a barrier in nitrosamines is reasonable because the canonical structure 39 is stabilized by the strongly electron-donating ability... 

As seen in Figure 13-24, secondary amines react directly with acidic sodium nitrite to form a nitrosamine. (These compounds are very, very toxic.) Primary amines react under similar conditions to form unstable diazonium salts (see Figure 13-25). Diazonium salts readily lose the very stable N2 to form reactive carbocations that are useful in a number of synthetic pathways. Figure 13-26 shows the resonance stabilization of a diazonium ion. 

X) for VIII (13) y iii) theoretical calculations indicating unusually high contributions of the polar resonance form VII (15) and iv) association with a proton or metal ion at the nitroso oxygen, the site of the highest electron density (14). The structure of nitrosamines is more realistically represented by the resonance hybrid VIII which explains the extraordinary stability of nitrosamines towards acids and bases in contrast to the lability of nitrosamides I under dilute acidic and basic conditions. ... 

An unique result of the electronic structure of the nitrosamine function is that it can apparently stabilize a positive or negative charge at the carbon adjacent to the amino nitrogen in a manner similar to the benzylic system. Hie stereoelectronic control of electroj ilic substitutions at the Or-position, to be discussed later, requires an orbital interaction of the nitrosamine function with the anionic electrons. Hie reactiv-... 

Since 1971, we have been engaged in the synthesis of g-substituted dialkyl N-nitrosamines, namely -hydroxy N-nitrosamines. Because of the presumed high reactivity of these alcohols, it seemed desirable to have them in a stabilized form, e.g. as esters. In 1970 Franck and his group reported a method to convert tertiary amines into dialkyInitrosamines in the presence of 2-nitropropane, cuprous ion and oxygen 9). If the amine is substituted with different alkyl groups, these groups are cleaved statistically (Eq. 1). 

This section will discuss experiments designed to synthesize phosphates of a -hydroxylated nitrosamines. These investigations shed some light on the thermal stability of a -substituted nitrosamines. 

The major health concern regarding use of curing salts is the possibility of nitrosamine formation in the cured products. Nitrite ion appears to be the precursor compound required for nitrosamine formation, rather than NO. Inclusion of reductants such as ascorbate, now required in bacon, lowers nitrite level in the product and increases the level of NO available for cured meat color formation and stability. 

Thus, DINA is seen from the above data to be markedly less stable to heat than Tetryl. This lack of stability was indicated to be due to the presence of an impurity, Di(nitroxylethyl)-nitrosamine, which might be removed by heating Uses, DINA has been proposed as a nonvolatile plasticizer for NC, and its use in place of NG has been suggested. Kincaid... 

Although 3-amino-l,2,4-thiadiazoles (e.g. the 5-phenyl homolog) fail to yield nitrosamines under the usual conditions,126 5-nitrosamines are well known.81, 5,190,191 Thus, 3-alkoxy-,8 3-alkylthio-,85 3-dialkyl-amino-,87 and 3-alkylsulfonyl-5-amino-86 (243) as well as 3-aryl-5-arylamino-l,2,4-thiadiazoles,74 on treatment with the calculated quantity of sodium nitrite in dilute mineral acid, or concentrated formic acid, yield crystalline nitrosamines (244). Their unusual stability has permitted a close study of their formation and properties. 170 Their positive Liebermann reaction85,87,170 and the results of their methylation (outlined in the reaction scheme) show that nitro-sation occurs in the side-chain and not in the nucleus.170... 

Alkylsulfonyl-5-nitrosamines have an increased stability-range in acidic media and require acids of high concentration (e.g. 80% sulfuric acid) for their conversion into the diazonium salts.86... 

Amines. Nitrated ond Njtrited, Analytical Piece dwes. Many of the procedures used for the analytical determination of amines are applicable to nitramines and nitrosamines(see Refs under Amines). Detn of the nitro-gcoup in nitramines is given in Org Analysis 2(1954X78,80, 8c 85 Addnl Refs aJI.V.Grachev, ZavodLab 12,434 (1946) CA 41,1177(1947) (Direct detn of nitres-amines) b)CJ.Ovenston CA.Parker, JSG 66, 394 5(194 CA 42,2771(1948) (Detn of nitros-amine content of propellants stabilized with sy nidi ethyldi phenyl urea) cJK. Kohlrausch, ActaFhys-Austriaca 1,292(1948) CA 42,6665(1948)... 

Detn of nitrosamine content in proplnts stabilized with Et Center)17)R. Dalbert, MP... 

We examined the thermal decomposition of a number of nitramines in dilute solution and in the melt phase. The nitramines included acyclic dialkyl mononitramines, where the dialkyls were methyl, ethyl, propyl and isopropyl cyclic mononitramines (N-nitro-pipeiidine and N-nitropyrrolidine) and cycle multifunctional nitramines (N-dinitropiperazhe l,3-dinitro-l,3-diazacyclo-pentane l,3-dinitro-l,3-diazacycbhexane RDX and HMX). For all nitramines, the predominant condensed-phase product was the nitrosamine though the amount formed depending on the nitramine and the phase of the thermolysis. The common trigger in the decompositions was N-N02 ho mo lysis, but the fate of the resultant amine radical depended on the phase. In solution the radical was stabilized sufficiently so that it resisted further decomposition and, instead, reacted with NO to form nitrosamine. In vapor or condensed phase, the amine radical underwent further reaction therefore,... 

Interactions with Closure Systems. Elastomeric and plastic container and closure systems release leachable compounds into the liquid dosage form, such as nitrosamines, monomers, plasticizers, accelerators, antioxidants, and vulcanizing agents [44], Each type of container and closure with different composition and/or design proposed for marketing the drug or physician s samples has to be tested and stability data should be developed. Containers should be stored upright, on their side, and inverted in order to determine if container-closure interactions affect product stability [6,45]. 

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