Nitrenium ions formation

In addition to solvolysis and nitrenium ion formation, Af-aLkoxy-A-chloroamides (2) also undergo bimolecular reactions with nucleophiles at nitrogen. Not only is the configuration destabilized by the anomeric effect, it also parallels that of a-halo ketones, where halogen on an sp carbon is activated towards reactions by the adjacent carbonyl. This rate-enhancing effect on 8 /2 processes at carbon is well-known, and has been attributed to conjugation of the p-orbital on carbon with the carbonyl jr-bond in the S 2 transition state stabilization of ionic character at the central carbon as outlined by Pross as weU as electrostatic attraction to the carbonyl carbon. The transition states are also affected by the nature of the nucleophile. ... 

Figure 13.8. Nitrenium ion formation versus concerted rearrangement.

Figure 13.23. Nitrenium ion formation by heterolysis of iV-hydroxylamines in strong acid.

Figure 13.24. Nitrenium ion formation by decomposition of azides in acidic solution.

Nitrenium ions and direct electrophilic aromatic amination (cyclic nitrenium ions, formation of N-heterocycles by intramolecular amination, N-aminopyridinium salts) 05ZOR487. 

The mechanistic dichotomy for conversion of ACC to ethylene seems clear from the large body of work presented above. Formation of N-heteroatom derivatives leads to the nitrene or nitrenium ion and results in a concerted mechanism, while electron transfer/free radical oxidants lead to a radical cation and result in a non concerted mechanism. Despite the significant evidence in favor of the radical pathway, reference to N-hydroxylation and nitrenium ion formation as a key step in ethylene biosynthesis has persisted, particularly in the plant physiology literature (2, 43-46). The sequence similarity of the EFE and several hydroxylase enzymes (vide supra) has only added fuel to this fire. However, consideration of the mechanisms for known hydroxylation processes makes the intermediacy of N-hydroxy-ACC very unlikely. 

More recently Hand et al. (ref. 9) have studied the decomposition reaction of N-chloro-a-amino acid anions in neutral aqueous solution, where the main reaction products are carbon dioxide, chloride ion and imines (which hydrolyze rapidly to amine and carbonyl products). They found that the reaction rate constant of decarboxylation was independent of pH, so they ruled out a proton assisted decarboxylation mechanism, and the one proposed consists of a concerted decarboxylation. For N-bromoamino acids decomposition in the pH interval 9-11 a similar concerted mechanism was proposed by Antelo et al. (ref. 10), where the formation of a nitrenium ion (ref. 11) can be ruled out because it is not consistent with the experimental results. Antelo et al. have also established that when the decomposition reaction takes place at pH < 9, the disproportionation reaction of the N-Br-amino acid becomes important, and the decomposition goes through the N,N-dibromoamino acid. This reaction is also important for N-chloroamino compounds but at more acidic pH values, because the disproportionation reaction... 

In 1984, we demonstrated that A-alkoxy-A-acyl nitrenium ions 15 could be generated by the reaction of A-alkoxy-A-chloroamides 14 with Lewis acids such as Ag + and Zn2+ and used these to form heterocycles by intramolecular aromatic substitution reactions (Scheme 2).90 In this manner, several novel A-acyl-3,4-dihydro-2,l-benzoxazines 16a and A-acyl-4,5-dihydro-( I //,3//)-2,1-benzoxazepines 16b were made. Subsequent work91,92 and that of Kikugawa93 96 produced numerous syntheses involving alkoxynitrenium ions including formation of natural products.97 99... 

Population of the <7 n-oac orbital weakens the bond rendering it unstable, resulting in formation of a resonance-stabilised nitrenium ion (Fig. 14c). 

The arguments presented herein lend the strongest support to SN2 attack by G-N7 at the amide nitrogen of /V-acyloxy-/V-alkoxyamides and for pathway (i) in Scheme 23 rather than pathway (iii) in which, once bound to DNA, the mutagens undergo SnI formation of reactive nitrenium ion. 

Novak et al. <1998JA1643> devised a novel approach to amino-substituted tctrazolo[ 1,5-tf Jpyridine which provides a really unique pathway (Scheme 34). These authors studied the possibility of formation of nitrenium ions from the pivaloylhydroxylamine 143 and found that if azide anion is present in the main reaction route is the formation of tetrazolo[l,5-tf]pyridine 146. The authors concluded that the first intermediate is the formation of the carbonium cation 144 which captures the azide anion to yield 2-azidopyridine 145, that is, the valence bond isomer of the product 146. 

There has been considerable interest in the chemistry of hydroxylamines, since it is believed52 that the carcinogenicity of some arylamines results from the formation of the TV-hydroxy species, which in turn generate nitrenium ions that react in a conventional electrophilic sense with nucleic acids. 

Fig. 4.8. Formation of mutagenic N-hydroxyamines from arylamides. Pathway a via deacetylation and subsequent IV-hydroxylation. Pathway b via IV-hydroxylation and subsequent deacetylation. Pathway c via N-acetoxy arylamine produced by IV,0-acyltransferases. [99]. Activation of hydroxylamines and hydroxylamides by O-sulfation is not shown. In all cases, the ultimate electrophile may be a nitrenium ion.

Anodic oxidation of benzenesulphenanilides 56 leads to cleavage of the nitrogen-sulphur bond in the radical-cation with the formation of a nitrenium ion, which deprotonates to the nitrene. The intermediate dimerises to a phenazine [168]. 

Scheme 2 Proposed pathways for C8-dG adduct formation by aryl nitrenium ions (a) and radical species (b).

Nitrenium ions (or imidonium ions in the contemporaneous nomenclature) were described in a 1964 review of nitrene chemistry by Abramovitch and Davis. A later review by Lansbury in 1970 focused primarily on vinylidine nitrenium ions. Gassmann s ° 1970 review was particularly influential in that it described the application of detailed mechanistic methods to the question of the formation of nitrenium ions as discrete intermediates. McClelland" reviewed kinetic and lifetime properties of nitrenium ions, with a particular emphasis on those studied by laser flash photolysis (LFP). The role of singlet and triplet states in the reactions of nitrenium ions was reviewed in 1999. Photochemical routes to nitrenium ions were discussed in a 2000 review. Finally, a noteworthy review of arylnitrenium ion chemistry by Novak and Rajagopal " has recently appeared. 

McEwan and co-worker" examined the acid-catalyzed decomposition of unsymmetrical benzhydryl azides 18 and some related species (Fig. 13.11). The aryl migration step showed very little discrimination between aryl rings with electron-donating and those with electron-withdrawing substituents. This low selectivity was judged to be more consistent with formation of a discrete nitrenium ion intermediate (19). These workers reasoned that a concerted migration would exhibit higher selectivity toward donor-substituted arenes, because in that mechanism the electrons from the arene would participate in the reaction. 

The formation of the parent amine 23 in these solvolysis reactions was considered to be the most dehnitive evidence for formation of a discrete nitrenium ion. Gassman and Cryberg" postulated the following, (a) Initial Cl—N bond heterolysis would occur adiabatic ally, generating the singlet nitrenium ion 21. (b) The triplet... 

Nitrenium ions can be viewed as products from two-electron oxidation of amines (Fig. 13.13) followed by loss of a proton. Thus they need to be considered as intermediates in the oxidation of amines. In two early studies, diarylnitrenium ions were shown to have formed in the oxidation of diarylamines. Svanholm and Parker carried out cyclic voltammetry on A,A-di-(2,4-methoxyphenyl)amine (25) in acetonitrile with alumina added to suppress any adventitious nucleophiles. The voltam-mogram revealed two sequential oxidation processes (1) formation of the cation radical 26, and (2) either the nitrenium ion 27 or its conjugate acid. In strongly acidic solution the latter was sufficiently stable that its absorption spectrum could be recorded. 

Nitrenium ions have also been generated through the decomposition of azides under acidic conditions (e.g., trifluoroacetic acid-arene solvent mixtures). There are two potential pathways for the formation of the nitrenium ion from the precursors (Fig. 13.24). The first involves initial dissociation of the azide 41 to give a singlet nitrene 42, followed by proton transfer to the latter to yield the primary nitrenium ion 43. The second involves acid-induced decompostion of the azide, whereby preprotonation of the azide (44) forms the primary nitrenium ion in a direct manner. As with the hydroxylamine route, this method is limited to acidic or protic media. 

The principal disadvantage to the aminopyridinium ion route is the accessibihty of the precursors. None are available commercially, and most require multistep syntheses giving relatively low yields. Another potential pitfall is the formation of the pyridine byproduct (54). Pyridines can function as nucleophiles, attacking the nitrenium ion and creating complex mixmres. Finally, pyiidinium ions are electron deficient and can serve as good ground-state electron acceptors. Many of the stable products generated from nitrenium ion reactions are amines and are relatively easy to oxidize. Thus, a potential problem is secondary reaction, whereby primary photoproducts are oxidized by the precursor. 

Photolysis in polar media (e.g., H20-MeCN mixtures) results in the same products observed from thermal generation. In addition, however, the parent amine, which is not observed in the thermal reactions, is formed photochemicaUy. This finding suggests that there may be a competition between heterolysis and homolysis in the photochemical reaction. It has also been suggested that the amine might result from formation of the triplet nitrenium ion. In any case this competing process along with the instability of the precursors has hmited interest in this photochemical route. 

The situation is different for alkylarylnitrenium ions. Haley first demonstrated that a A -l-adamantyl-A -(2-benzoylphenyl) nitrenium ion 62 (Fig. 13.36) could be generated by photolysis of an anthranilium ion." In this case, rearrangement of the adamantyl ring, to give products from hydrolysis of 63, competes with addition reactions, giving 64. Similar experiments carried out on A -tert-butyl-A -arylni-trenium ions also showed that the 1,2-shift of a methyl group competes with additions of nucleophiles to the aryl ring. In the latter cases, the formation of the alkylarylnitrenium ion was verified by LFP. 

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