590 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS As predicted by the rate equation (33) for simple basic amines (pKa 5), the nitrosa- tion rate in water is maximum at pHmax = 3 to 3.4 (23, 24, 40, 63, 64) near the pKa of HNO2. For a given amine as the pH increases above pHmax the rate decreases, because the concentration of HNO2 decreases. As the pH decreases below pHmax the rate decreases, because the concentration of unprotonated amine decreases. At a given pH the rate of nitrosation increases as the basicity of the amine decreases, because of the higher relative concentration of unprotonated amine present. Thus, the following order of reactivity is found at pH 3.0: Amine •/NH OX /NH H=+N/•NH \ / pKa 11.2 8.7 5.57 Relative 1 930 180,000 rate (23, 33) Nitrosation of secondary amino acids (65, 66) occurs at an optimum pHm•x = 2.25 to 2.5 (34, 40). The reaction follows rate eq 14, but the pH-rate profile is changed by the fact that two amine species react--RNHCHR'CO=- and RNHCHR'CO2H. c. Tertiary Amines and Related Compounds. Tertiary amines have generally been regarded as inert to nitrosation, even though their conversion to secondary nitrosamines was reported over 100 years ago (67). Because dealkylation is required, the reaction occurs to a significant extent only at elevated temperatures in weakly acidic media (68-70). At 25øC and pH 3.4 nitrosation of tertiary amines is about 10,000 times slower than that of related secondary amines (23). The following mechanism has been proposed (23, 68, 69) for nitrosative dealkylation and nitrosamine formation: I ' N•0 + H•0 --HN0 R=N--CHR' I I ON H RzN•CH2R' + N=Oa N20a R•NNO ( R•NH + R'CHO H•O R,N=CHR' (15) With mixed tertiary alkyl aryl amines ring C-nitrosation also occurs (19). Two related compounds--the nitrogen acetal hexamethylenetetramine (71) and the drug antipyrine which has an eneamine structure (23, 72)--undergo N-nitrosation much more rapidly and extensively than normal tertiary amines. In both compounds at least one of the three N-substituents is in a higher oxidation state than in typical tertiary amines and nitrosation undoubtedly occurs by a different mechanism (70). d. Quaternary Amines and Amine Oxides. Quaternary ammonium compounds ap- parently react slowly with nitrite in acidic media. The initial dealkylation required ac- counts for their lower activity compared to tertiary amines and may not involve the nitrosating agent (73). The relative reactivity of secondary, tertiary and quaternary

NITROSAMINE CHEMISTRY 591 amines is indicated by the following data gathered for reaction of a ratio of 5 mol NaNO2/mol amine at 78øC and pH 5.6 for 4 hr (73). Amine % Yield of (CHa)2NNO (CHa)2NH 9.6 (CHa)aN 0.9 (CHa)4N + 0.6 (CHa)2NCH=CH=OH 1.6 (CHa)aN + CH= CH=OH 0.0002 Several naturally occurring quaternary ammonium compounds were found to be much less reactive than the tetramethylammoniurn ion (73). The tribenzylmethylarnmoniurn ion is reported to be unreactive under similar conditions (68). No nitrosation of 10 -a M hexadecyltrimethylammonium bromide by a 20-fold excess of nitrite at 25øC and pH 3.5 was observed after 40 min (44). Tertiary amine oxides in the presence of excess nitrite at pH 1 to 3 and temperature 25 to 75øC are converted to secondary nitrosamines to a greater extent than are tertiary amines (74). However, at 90 to 100øC and pH 4 to 5 both classes show similar reactivity (68, 70, 74). Two mechanisms that account for the change in relative reactivity with conditions have been proposed (70, 74). e. Secondary and Tertiary Amides. For secondary amides, as with amines, the nitrosation condition most widely investigated has been nitrite in aqueous acid. N-Alkyl ureas and carbamates are rapidly nitrosated at pH 1 to 2. The nitrous acidium ion is the main nitrosating agent for these and other amides (eq 16) and the reaction rate follows eq 17 (23, 39, 40). ZNHR + H2ONO + -- ZN(NO)R + H=O + H + (16) rate = k[ZNHR] [HNO=] [H +] (17) The reaction rate increases about ten times for each 1-unit drop in pH from 3 to 1 and does not show a pH maximum. At pH 2.5 nitrosation by NzOa contributes (39). In acidic aqueous media nitrogen substrates decrease in propensity toward nitrosation in the order 2-imidazolidone acyclic N-alkylurea N-arylurea N-alkylcarba- mate less basic dialkyl and secondary aromatic amines (pK• 9) and tertiary eneamines more basic dialkyl amines N-alkylamides, N-acylureas, N-alkylgua- nidines and tertiary amines (23). High yields of nitrosamides are obtained from reactions of amides with N=Oa (2) or SgO4 (28) in organic solvents. However, N-methylacetamide in aqueous solution at pH 13 does not react with added SzO4, conditions under which secondary amines are rapidly nitrosated (27). Apparently the weakly basic amide is too unreactive to compete with hydrolysis of the nitrosating agent. Nitrosation of tertiary amides in acidic aqueous solutions of nitrite at high concentra- tions and temperatures produce either nitrosamides or nitrosamines (23, 70, 75). Ni- trosation of trialkylureas gives the corresponding nitrosoureas. Dialkylnitrosamines are the major product from dialkyl- or trialkylthioureas, 1,1-dialkylureas, 1,1-dialkyl- 3-phenylureas and tetraalkylureas.