Nitration and Nitrosation

Electrophilic nitration and nitrosation of aromatics are fundamental synthetic organic reactions and are well understood in terms of mechanism/ On the other hand, similar nitration and nitrosation of alkanes were only studied in the 1970s and 1980s. 

TABLE 6.1. Nitration and Nitrolysis of Alkanes and Cycloalkanes with NO2+PF( 

1-adamantanol are by-products indicating that the pentacoordinate carbocation can also cleave to the 1-adamantyl cation (hydride abstraction). These results show the nonlinear nature of the ionic intermediate.  

The nitronium ion is also capable of acting as an oxidizing agent effecting hydride abstraction from a variety of functionalized alkanes. The oxidation of diarylmethyl methyl ethers is best illustrated involving pentacoordinate carbocations [Eq. (6.44)]. 

The nitrosonium ion (NO ), the electrophilic species formed in nitrous acid media, is also a particularly effective hydride abstracting agent. Cumene reacts with NO+ to give various condensation products that involve intermediate formation of the cumyl cation. °The formation of the cumyl cation in a nonlinear hydride transfer reaction involves a pentacoordinate carbocation [Eq. (6.45)]. 

A large number of quantum chemical studies have been devoted to this topic. However, as we wiU see, there are still open questions regarding the mechanistic details of the nitration reaction. We will start this survey with two seminal articles from 2003 that were written independently of each other. 

and this results in only one broad minimum on the PES, the ic-complex. The results show that the nitrosonium reaction has a different mechanism compared to nitration and that eare should be taken when interpreting other S Ar reactions based on structures of complexes between arenes and NO.  

At this point, it may be appropriate to summarize our current understanding of the mechanism for gas-phase nitration of aromatics. The reaction can proceed via the formation of two intermediates before the formation of the a-complex. The first is a ring-centered coordinated x-complex that is intermediate in energy between the separated reactants and the a-complex. The second is the C-atom coordinated x-complex that is only slightly higher in energy than the a-complex. 

FIGURE 4.1 Structures of stationary points in the gas-phase nitration of benzene optimized at the M06-2X/6-31 lG(d,p) level. Bond lengths in angstroms and bond angles in degrees. 

Whereas the second type of complex seems to be omnipresent in aU nitrations, the first has not been found in all theoretical studies, and its stability generally decreases with increasing activation of the aromatic nucleophile. There seems to be a consensus that some degree of SET is present in nitrations and that this is most prominent for activated aromaties. However, there is little theoretical support for the interpretation of the C-atom coordinated jc-eomplex as an SET eomplex. 

That numerous 2-amino-5-nitrothiazole derivatives exhibit antiamebic, antihistomonal, antitrichomonal, and antischistosomal properties (see Section VI.2) explains the large number of nitration reactions reported. Nitration in a mixture of concentrated nitric and concentrated sulfuric acids IS among the most common experimental methods (16, 27, 58, 374-377). 

2-Amino-4-mesitylthiazole (179) cannot be nitrated, in contrast with 2-amino-4-f-Bu-thiazole (194). Nitration is also reported to fail with ethyl-2- acetamidothiazol yl -4-carboxylate (58). 

2-Dimethylaminothiazole reacts as 2-aminothiazole with nitrating reagents (375. 384), but the other dialkylaminothiazoles (32a, 32b, 32c p. 32) are reported to be cleaved rather than nitrated (385). 

Experimental requirements for the isolation of these nitramino derivatives are developed in Ref. 87. They rearrange easily to ring nitro-substituted isomers (see Section V.6). In the 2-aminothiazole series, nitration may proceed through direct electrophilic substitution competing with rearrangement of nitramino derivatives. Dickey et al. have shown that the rearrangement proceeds rapidly in 96% sulfuric acid at 2(fC, but in 85% sulfuric add it is very slow so. according the concentration of add various mechanisms can participate in the formation of the 5-nitro derivative. 

Recent results for the quantitative nitration of 2-alkylthiazoles (386) suggest that a reinvestigation of the nitration of amino derivatives would be worthwhile. 

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Nitroethanes. See under Ethane, Nitrated and Nitrosated Derivatives in Vol 6, E143-Rff... 

The formation of the Wheland intermediate from the ion-radical pair as the critical reactive intermediate is common in both nitration and nitrosation processes. However, the contrasting reactivity trend in various nitrosation reactions with NO + (as well as the observation of substantial kinetic deuterium isotope effects) is ascribed to a rate-limiting deprotonation of the reversibly formed Wheland intermediate. In the case of aromatic nitration with NO, deprotonation is fast and occurs with no kinetic (deuterium) isotope effect. However, the nitrosoarenes (unlike their nitro counterparts) are excellent electron donors as judged by their low oxidation potentials as compared to parent arene.246 As a result, nitrosoarenes are also much better Bronsted bases249 than the corresponding nitro derivatives, and this marked distinction readily accounts for the large differentiation in the deprotonation rates of their respective conjugate acids (i.e., Wheland intermediates). 

Nitrogen Tetroxide (N OJ an energetic and versatile oxidizer, nitrator, and nitrosator. Available as a liquid in steel cylinders and tank cars under moderate pressure (0 to 10 P g)... 

Owing to the susceptibility of indole, isoindole and pyrrole rings to oxidation (see Section 3.05.1.4) and acid-catalyzed dimerization and polymerization (see Section 3.05.1.2.2), the products of the reactions with nitrating and nitrosating agents are subject to the reaction conditions. 

A kinetic study of the nitration and nitrosation of l-methyl-2-phenylindolizine revealed that substitutions at the 3-position derive from an attack on the indolizine base while substitutions elsewhere involve attack on the conjugate acid (79JCS(P2)312>. 

Aromatic A A -dialkylamines react rapidly with HN02 and undergo ring nitration and nitrosative dealkylation both reactions are linked through the formation of a nitrosammo-nium ion R1 RiV—N=O (R1 = Ar, R2 = Aik). This nitorosoammonium ion then undergoes reversible homolysis to NO and a cation radical (Loeppky et al. 1998). 

In an inert solvent, bromine can replace a 3- or 4-hydrogen atom on the trithiapentalene system.50 81 Nitration and nitrosation in position 3 (or 4) can also be performed.50 However, attempted nitration or nitrosation of 2,5-diphenyl-l,6,6a/SIV-trithiapentalene led to simultaneous oxidation of S-l and nitrosation on C-3.50... 

Formation of the Wheland intermediate from the ion-radical pair as the critical reactive intermediate is common to both nitration and nitrosation processes. The nitrosoarenes (unlike their nitro counterparts) are excellent electron donors, as judged by their low Eox° as... 

Steric Control of the Inner/Outer-Sphere Electron Transfer 461 Thermal and Photochemical ET in Strongly Coupled CT Complexes 463 Electron-Transfer Paradigm for Arene Transformation via CT Complexes 465 Electron-Transfer Activation of Electrophilic Aromatic Substitution 469 Structural Pre-organization of the Reactants in CT Complexes 470 CT Complexes in Aromatic Nitration and Nitrosation 472 Concluding Summary 475 References 475... 

The difference in the electron affinities, A E, approximately equal to k 5, necessary for the formation of the intermediate complex, depends to a great extent on the degree of steric accessibility and coordinative unsaturation of the nitrating and nitrosating agents. 

An interesting aspect of phenol nitration and nitrosation in the presence of nitrite is that these processes are favoured with decreasing pH. The pH trend... 

In neutral solution, in contrast, phenol nitration and nitrosation are pho-toinduced processes since no thermal reaction has been observed between phenol and nitrite ion. The pH value where the thermal and photoinduced processes have similar importance is around 5.5. Thermal processes prevail at lower pH and photoinduced ones at higher pH [55,62]. 

Nitration and nitrosation of aromatic compounds are likely to be rather complex processes involving different pathways. Involved reactive species are NO2, N204, N2O3, NO2 + NO and HNO2. Aromatic nitration via such pathways is inhibited by electron-withdrawing substituents on the ring, such as Cl and the nitro group. As to the relevance of hydroxyl-mediated processes (nitration by OH + NO2, nitrosation by OH + NO), it can be expected to be quite low for the majority of the compounds. 

The role of aromatic photonitration and photonitrosation processes in natural waters is still not clearly understood. It is, however, very interesting to report that nitration and nitrosation of monolinuron have been observed upon photolysis of nitrate and nitrite at environmental concentration levels [144], Studies on the environmental importance of such reactions will indeed benefit from the use of HPLC-MS-MS techniques for both process studies and field analysis, as they allow much lower detection limits to be reached when compared with traditional HPLC techniques. In the case of process studies, it would be very interesting to determine the extent at which the pathways observed for the photonitration and photonitrosation of aromatic compounds at fairly high concentration levels can be extrapolated to environmental conditions. 

The photolysis of nitrate in surface waters and of nitrite in atmospheric hydrometeors is a relevant source of hydroxyl, while the assessment of the environmental importance of nitration and nitrosation processes needs further studies. Recent results, however, indicate that photonitration and photonitro-sation might play a more important role in the environment than previously suspected [144], All such processes are influenced by substrate and ion concentration and in some cases by the amount of dissolved organic matter. 

Farminer, A. F. and Webb, G. A., Nitration and nitrosation reactions of 7-nitro-1,3,5-tria-zaadamantane and derivatives, J. Chem. Sac. Perkin Trans. I. 940. 1976. 

S-Nitrosation and S-nitroso compounds 418 10 Nitration and nitrosation 422 Acknowledgements 424... 

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