M. Elena Peña

Reactivity of nucleophilic nitrogen compounds towards the nitroso group

We discuss the reactivity of 43 nucleophilic nitrogen compounds towards the nitroso group of N-methyl-N-nitrosotoluene-p-sulfonamide (MNTS), and in some cases with alkyl nitrites. The series of nucleophiles considered is structurally very varied, includes members exhibiting the alpha effect, and covers 8 pKa, units and a range of reactivities of almost five orders of magnitude. The values of solvent isotope effects and activation parameters have been measured and throw light on the, structure of the transition states involved. Reactivities do not correlate well with the basicity of the nucleophile, largely owing to the behaviour of primary amines, ammonia and nucleophiles with an alpha effect. Application of the curve crossing model suggests a relationship with vertical ionization potentials. The relationship with Ritchies N+ scale is discussed, and interesting correlations with the reactivities of the same nucleophiles in various other chemical processes are noted.

Evidence for concerted acid hydrolysis of alkyl nitrites

The results of studying the acid hydrolysis of methyl, ethyl, isopropyl, butyl, tert-butyl, pentyl, 2-bromoethyl, 2-chloroethyl and 2-ethoxyethyl nitrites in water show that the reaction is not, as widely accepted in the literature, catalysed by nucleophiles (Cl–, Br–, etc.), but is however subject to general acid catalysis. These findings, and the observed values of the solvent isotope effect, suggest that the substrate is protonated in the rate-controlling step of the reaction. Further, the relative reactivities of the various substrates investigated suggest a concerted mechanism in which the proton transfer occurs concurrently with the breaking of the O–N bond via a slightly imbalanced transition state.

Kinetics and mechanism of the nitrosation of N-acetyltryptophan and of the denitrosation of N-acetyl-N1-nitrosotryptophan

Both the formation and the denitrosation of N-acetyl-N1-nitrosotryptophan have been studied kinetically in aqueous solution at 25 °C at acidities between 1 M-HClO4 and pH 4. A value of 850 l mol–1 has been obtained for the equilibrium constant for the formation of N-acetyl-N1-nitrosotryptophan. At acidities ([H+]) greater than 0.1 M the rate constants for both nitrosation and denitrosation increase linearly with the concentration of acid, and the reaction rates are unaffected by the addition of nucleophiles (Br– and SCN–). The results are consistent with a mechanism for nitrosation where the rate-limiting step is the proton transfer from the protonated N-nitroso species to the medium. For denitrosation the corresponding protonation of the nitrosamine is rate-limiting. These conclusions are confirmed by the results obtained when the reactions are carried out in heavy water. However, in the pH range 1–4 the rates of both nitrosation and denitrosation are independent of the acidity of the medium and are again unaffected by the presence of nucleophiles or buffers. It is suggested that in this region nitrosation occurs at C-3. This is followed by deprotonation and an internal NO migration from C to N which is rate-limiting. This mechanism also accounts for earlier results on the denitrosation reaction at even lower acidities (pH 4–7), where acid catalysis and nucleophilic catalysis are found. Results of experiments in heavy water are compatible with this mechanism.

Decomposition of N-methyl-N-nitrosotoluene-p-sulphonamide in basic media: hydrolysis and transnitrosation reactions

The decomposition of N-methyl-N-nitrosotoluene-p-sulphonamide (MNTS) has been studied in basic and neutral water–alcohol mixtures. In alkaline media and when OH– was the nucleophile, the known hydrolysis reaction in which OH– attacks the SO2 group was observed; this reaction was first order in both OH– and MNTS. In the presence of ammonia, hydroxylamine, hydrazine, or primary, secondary or tertiary amines, a transnitrosation reaction took place in which the additional nucleophiles attacked the nitrogen atom of the MNTS NO group; this reaction was first order in both MNTS and free amine. In particular, MNTS proved to be as efficient as some alkyl nitrites for the nitrosation of secondary amines in neutral or alkaline media, in which conventional nitrosating agents do not exist. Similar reaction rates were observed for the more basic tertiary amines (which gave NO2– among the final products). Primary amines underwent rather slower reactions, with the exception of hydroxylamine and hydrazine, the nucleophilic nature of which is increased by the α effect. We discuss the relative reactivities of the various amines in terms of their basicity and vertical ionization potentials, and we report the effect of the proportion of alcohol in the medium on the rates of both hydrolysis and transnitrosation reactions.

Basic hydrolysis of N-[N′methyl]-N′-nitroso(aminomethyl)]benzamide in aqueous and micellar media

Abstract The kinetics of the alkaline hydrolysis of N-[N′-methyl-N′-nitroso(aminomethyl)]benzamide (NMAB) in the presence of surfactants have been studied. Incorporation of the substrate to the anionic surfactants inhibit the reaction, with electrostatic effects severely reducing the OH− concentration around the micelle. The cationic surfactants catalyze it. The reaction was studied in the presence of inert-ion cationic surfactants with different carbon chain lengths, and with the corresponding reactive-ion surfactants. For the inert-ion surfactants the results fit the pseudophase ion exchange model, similar rate constants in the micellar phase and similar competition among Br− and OH− ions for the micellar surface, independently of the surfactant, being observed. The micelle-substrate association constant increases with increasing surfactant hydrophobicity, however. These data show that hydrophobic forces predominate in the association between micelle and substrate and that the reaction occurs in the Stern layer, the characteristics of which do not depend on the length of the carbon chain. For the reactive-ion surfactants the data fit the ion exchange model or a mass-action model, the low constant for the micelle-substrate association not permitting discrimination between the two models. A method of discrimination based on comparison of the results with those obtained for the inert-ion micelles is used. The comparison suggests treating the data obtained with the mass-action model.

Kinetics and mechanism of the formation and decomposition of N-nitrosoamides and related compounds

Kinetic studies of the nitrosation reactions of ethyl N-ethylcarbamate, N,N′-dimethylurea, and 2-imidazolidone have shown that all are subject to primary solvent isotope effects and to general base catalysis with bases of pKa in the range 0.6–4.6. Both these features are indicative of a slow proton transfer. The characteristics of this proton transfer and the reactivity of the substrate depend to a large extent on the nature of the substrate: for ethyl N-ethylcarbamate the Bronsted plot is linear (β= 0.34) and the solvent isotope effect is 5.5; for N,N′-dimethylurea the curved Bronsted plot suggests that the reaction with acetate ion is diffusion-controlled, and the isotope effect is 3.2 in the absence of added base and 1.1 when the reaction is catalysed by acetate; for 2-imidazolidone the slightly curved graph of reaction rate against base concentration shows the proton donor to be an intermediate in the steady state, and the solvent isotope effects for the uncatalysed and acetate-catalysed reactions are 2.9 and 1.4, respectively. These facts suggest that the protonated intermediate has a near-zero pKa value. Complementary studies of the denitrosation of N-nitroso-N-methylurea, N-nitroso-N,N′-dimethylurea, and N-nitroso-2-imidazolidone have shown that the rate-controlling step of each of these reactions is protonation of the substrate. These data, together with those from the nitrosation experiments, imply a pKa of ca.–12 for the nitroso-amide. The discrepancy between the two results suggests that nitrosation initially takes place at the oxygen atom; this is followed first by a slow proton transfer and subsequently by a fast internal rearrangement to produce the thermodynamically more stable N-nitroso-amide.

Kinetic study of the nitrosation of 3-substituted indoles

Kinetic studies of the nitrosation reaction of three 3-substituted indoles (3-methylindole, indol-3-yl acetate and indole-3-acetic acid) show that the final state is an equilibrium between the reactants (nitrous acid and indole derivative) and the 1-nitroso derivative. Values of the rate constants for the nitrosation of the three indoles and denitrosation of the corresponding nitrosoindoles as well as values of the equilibrium constants have been obtained. The almost complete insensitivity of the reaction rates to medium acidity, the absence of catalysis by the usual catalysts of nitrosation (halides) and the high reactivity at low acidities, are in contrast to the kinetic characteristics of other N-nitrosation reactions. This atypical behaviour is discussed in terms of possible reaction mechanisms.

Solvent-induced mechanistic changes in nitrosation reactions. Part 2. Effect of acetonitrile–water mixtures in the nitrosation of ureas

The nitrosation of 1,3-dimethylurea in acetonitrile–water mixtures has been studied kinetically. The results obtained show that the addition of acetonitrile until the medium holds 70% acetonitrile by weight inhibits the reaction. The reaction is not catalysed by chloride ions in these circumstances, and the reaction mechanism is probably the same as in pure water. Addition of acetonitrile to a solution already containing more than 70% acetonitrile increases the reaction rate, and catalysis by halides becomes possible. The change in reaction mechanism this suggests was studied in detail in a medium containing 90% acetonitrile. The reaction rate increases non-linearly with increasing halide concentration and acidity, but seems to tend to the same limiting value in all cases, depending only on the nitrous acid and urea concentrations. Nitrosyl halides are therefore good nitrosating agents of ureas, though the catalytic efficiency of the different halides is the reverse of that in water, probably because of solvation-induced changes in their nucleophilicity. The tendency of the reaction rate towards a limiting value is evidence that the mechanism changes with the catalyst or acid concentration. In the limit, the reaction rate will only depend on nitrous acid and urea concentrations; this is consistent with a limiting step consisting of the rearrangement of the ‘nitrosourea’, the nitroso group transferring from the more nucleophilic O atom to the N atom. Thus, there is direct kinetic evidence that the nitrosation of amides occurs initially on oxygen.

The mechanism of the nitrosation of α-amino acids: evidence for an intramolecular pathway

The results of a kinetic study of the nitrosation of sarcosine, proline, cysteine, and the ethyl ester of sarcosine are reported. Under the conditions in which sarcosine and proline were studied, both first- and second-order terms were found for nitrite dependence. The experimental results are interpreted by a mechanism which involves NO+ and N2O3 as direct nitrosating agents, while the effect of acidity changes on the first-order term for nitrite shows that the N-nitroso compound is also formed in a parallel reaction in which a slow intramolecular rearrangement follows the attack of NO+ on the carboxylate group of the amino acid. This pathway is confirmed by the absence of such a parallel reaction in the nitrosation of the ethyl ester of sarcosine. The influence of acidity on the nitrosation of cysteine shows that S-nitrosation is brought about by the reaction of NO+ with both the N-protonated, HSCH2–CH(NH3)–CO2H, and zwitterion, HSCH2–CH([graphic omitted]H3)–CO2–, forms of the amino acid. The values obtained for the bimolecular rate constants are compatible with diffusion control, the difference between the values for both forms of the amino acid being explicable in terms of charges of the reagents.

NUCLEOPHILIC REACTIVITY TOWARDS 'NORMAL' AND AMBIDENTATE ELECTROPHILES BEARING THE NITROSO GROUP

Bimolecular rate constants for the reactions of N-methyl-N-nitrosotoluene-p-sulfonamide (MNTS) and 2-ethoxyethyl nitrite (EEN) with oxygen nucleophiles [HO–, CF3CH2O–, HO2–, CH3(CO)NHO– and ClO–], sulfur nucleophiles (SO32–, SCN–, thiourea, cysteine, S2O32– and HS–) and I– have been determined. For MNTS, ‘soft’ nucleophiles react at the nitroso group, whereas ‘hard’ nucleophiles react at least in part at the sulfonyl group. A discussion on the validity of nucleophilicity scales (N+ and n) is carried out and clearly for soft nucleophiles (N- and S-nucleophiles and I–) there is a good correlation with N+ with a slope close to 1 which implies a frontier orbital controlled reaction and a markedly diradicaloid transition state. For reactions at the sulfonyl group (O-nucleophiles), nucleophilic reactivity is better explained using the n scale which can be rationalized in terms of a larger electrostatic contribution to the interaction energy.