Reactive Intermediate Chemistry

Generally speaking, substitution of an aromatic ring on the nitrenium ion center acts to stabilize the singlet state. This follows because the filled p orbitals on the aromatic ring raise the energy of the unfilled p orbital on the nitrenium ion center relative to the in-plane sp2 orbital. Thus it follows that additional p-donating groups on the aromatic ring are likely to further stabilize the singlet. Likewise, p acceptors are likely to counteract the effect of phenyl substitution and destabilize the singlet relative to the triplet.

These effects were examined in a DFT study by Sullivan et al.,74 who computedEst for a series of 4-substituted phenylnitrenium ions. The effects mostly followed the predicted trend. Interestingly, however, the nitro group stabilizes the triplet far less than the carbonyl groups (formyl, acetyl, carbomethoxy). The differences being 2.0 kcal/mol for the nitro compared with the unsubstituted system, and 6.6 kcal/mol for the formyl. The halogens, fluorine and chlorine, slightly stabilized the singlet, whereas alkoxy and amino groups provided substantial stabilization for the singlet. The results are given in Table 13.2. Another interesting result from the same study was an assessment of the effects of solvation on the stabilities of the singlet and triplet states. In most cases, it was found that the singlet state was preferentially stabilized relative to the triplet by 1–4 kcal/mol.

DFT-based calculations were carried out on a series of heteroarylnitrenium ions with nitrogens at various positions in the aromatic ring. Some results from this study are shown in Table 13.3.77 Several interesting results emerge. First, in contrast to the phenyl systems, the heteroaromatic nitrenium ions are slightly nonplanar in the singlet state and planar as triplets. Second, ring nitrogens stabilize the triplet

TABLE 13.2. Singlet–Triplet Energy Gaps in 4-Substituted

Phenylnitrenium Ions (X C6H4NHþ)a

XEst, (kcal/mol)

a See Ref. 74.

608 NITRENIUM IONS

TABLE 13.3. Singlet–Triplet Energy Gaps in

Heteroarylnitrenium Ions (ArNHþ)a

a See Ref. 77.

state relative to the singlet. In fact, the triazinyl and all of the pyrimidyl nitrenium ions are predicted to be ground-state triplets. The pyridyls also show smaller gaps than the phenyl system, but are predicted to be ground-state singlets. As with the arylnitrenium ions, solvation is predicted to stabilize the singlet by 0.5–5 kcal/mol relative to the triplet state. Finally, the heteroaromatic systems with ortho ring nitrogens (29) rearrange in a stepwise fashion, from the singlet state, forming N-hetero- arylnitriles (30, Fig. 13.18). These reactions occur in the singlet state. The predicted barriers range from 3–25 kcal/mol, with the triazenyl systems being the most facile.

More recent computational efforts have focused on mapping out reaction mechanisms, and to the extent possible, predicting product distributions in reactions. Novak and Lin78 determined the relative hydroxylation energies for a series of arylnitrenium ions and then attempted to relate these to experimental azide/water selectivity ratios (see Section 5). The former quantity was determined using a series of isodesmic reactions, wherein the E for hydroxide transfer from the adduct phenylnitrenium ion (31, Fig. 13.19) was used as a gauge for the relative hydrolytic stability of these nitrenium ions. The calculations (RHF/6-31G*) showed a good correlation between the hydroxylation energies and the product distributions observed when the same species were generated in aqueous solution in the presence of azide ion. Presumably, the rate of water addition correlates with the energy of hydroxide addition, and the rate constant for azide addition is constant.

Figure 13.18. Rearrangement predicted by DFT for 2-(1,3,5)-triazolylnitrenium ion.

31

Figure 13.19. Isodesmic reactions used to assess relative stability of arylnitrenium ions toward addition by water.

More recently, Sullivan and Cramer77 used DFT methods to model the addition of water to phenylnitrenium ion and N-acetylphenylnitenium ion (32, Fig. 13.20). This process was found to be endoergonic in the gas phase, presumably because the resulting oxonium ion 33 has a more concentrated positive charge than does the more delocalized singlet 32. However, when the effect of solvation was modeled, using a dielectric continuum, the reaction was predicted to exoergonic and barrierless. The authors point out that a small barrier might be present due to specific solvent–solvent and solvent–solute interactions, which are not considered in their solvation model.

Interestingly, it was also found that N-acetyl-N-arylnitrenium ions cyclize to form protonated benzoxazole derivatives (34).77 This reaction was found to have barriers of 4–11 kcal/mol in the gas phase. Although this finding has yet to be verified experimentally, it is significant in view of the fact that these nitrenium ions are frequently used in mechanistic studies of DNA damage.

One general, and as yet unsolved problem, is understanding and predicting the regiochemistry of arylnitrenium ion addition to DNA bases. This reaction is complicated because phenylnitrenium ion has four potential sites of addition (Fig. 13.21): the nitrenium center as well as the ortho and para ring carbons. Likewise, DNA has numerous sites for electrophilic addition. In guanine bases alone, there is a possibility for addition to N7, O6, N2, or C8.

Ford and Thompson79 used semiempirical methods to evaluate the relative stabilities of various nitrenium ion guanine adducts where the exocyclic 2-amino group of guanine is coupled to nitrogen and various ring positions of phenyl or

Figure 13.20. Reactions predicted by DFT for N-acetyl-N-arylnitrenium ions.

612 NITRENIUM IONS

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

of the decomposition mechanism. For simple hydroxylamines there are two basic sites: the nitrogen and the oxygen. Of these, the nitrogen is generally considered to be the more basic site. Thus any mechanistic study needs to account for O-proto- nated 38, N-protonated 39, and diprotonated precursor 40, as well as the formation of the nitrenium ion and its dication.85

Nitrenium ions have also been generated through the decomposition of azides under acidic conditions (e.g., trifluoroacetic acid–arene solvent mixtures).86,87 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.

It is also possible to generate similar nitrenium ions from arylazides and Lewis acids such as AlCl3. Takeuchi et al.88 found that when this decomposition was carried out in an aromatic solvent (e.g., benzene) good yields of N,N-diarylamines could be achieved. This was particularly true when the arylazides had electron withdrawing groups, which contrasts with the same arylnitrenium ions generated under protic conditions. Such metallonitrenium ions, or ‘‘nitreniumoids’’ have seen little study.

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

Figure 13.25. Nitrenium ions through heterolysis of N-chloroamines.

Gassman pioneered the use of N-chloroamines for the formation of both alkyl and arylnitrenium ions.10,40–44,46,89 Several examples are given in Figs. 13.10 and

13.12. In polar media, these precursors heterolyze to give chloride and the corresponding nitrenium ion (Fig. 13.25). The use of an anionic leaving group eliminates the requirement for strong acid. One disadvantage is that chloride is a very reactive nucleophile and tends to trap many nitrenium ions at the diffusion limit. In fact,

when arylnitrenium ions are generated by this route, isomers result from internal return of the chloride ion.44,90 This problem can be avoided, to some extent,

through the use of Ag(I) ions that form stable salts with chloride. Another potential pitfall is the possibility of competing N Cl homolysis, which generates aminyl radicals 45, rather than the desired nitrenium ion.91 This competing process complicates the elucidation of nitrenium ion behavior. It is probably for this reason that this route has been used only rarely in the last two decades.

Most recent investigations aimed specifically at the study of nitrenium ions have

employed the heterolytic cleavage of various esters of hydroxylamines 46 (Fig. 13.26).50,92–102 This method has the advantage of not requiring the introduc-

tion of acids to promote the reaction. Also, because the N O bond is stronger than the N Cl, it is less likely to result in homolysis. With sterically unhindered esters

(such as acetylhydroxylamines), complications can arise from acyl-transfer reactions, which generate the corresponding N-hydroxylamine 47.103–105 For this

reason, sterically hindered esters, such as pivaloyl 46 (Fig. 13.26, where R00 ¼ t-Bu), are often employed. As with the chlorides, internal return can also be a major decay pathway, particularly in less polar media.

Figure 13.26. Nitrenium ions through heterolysis of N-hydroxylamine esters.

614 NITRENIUM IONS

Figure 13.27. Nitrenium ions from chemical oxidants.

Various chemical oxidants have been applied directly to amines in order to generate nitrenium ion products (Fig. 13.27). For example Hoffmann and Christophe51 treated O-alkylhydroxylamines with m-(trifluoromethylphenyl)sulfonyl peroxide and generated stable products that they reasoned originated from the formation of a alkoxynitrenium ion. The latter was inferred to be formed from fragmentation of the corresponding sulfonate ester, although this precursor was not detected under

the reaction conditions. Wardrop and Basak,25 Wardrop and Zhang,26 as well as Kikugawa and Kawase,106,107 used a similar method wherein a N-alkoxyamide is

treated with bis(trifluoroacetoxy)iodobenzene. Again, neither the nitrenium ion nor its presumed ester precursor were isolated, but their formation was inferred from the final stable products. This general approach has proven to be very useful in

natural product synthesis.

Katrizky et al.108,109 employed N-aminopyridinium ions110,111 (48, Fig. 13.28) as thermal precursors of nitrenium ions. This route to nitrenium ions is attractive in that there is no net generation of charge. That is, a positively charged reactant gives a positively charged product (49) and a neutral byproduct (50). Thus it could be useful for generating these intermediates in nonpolar media. Unfortunately, these salts are generally less readily available than azides, hydroxylamines, or hydroxylamine esters. Also, their formation generally seems to require elevated temperatures and/or long reaction times. In some cases, concerted reactions, rather than the formation of free nitrenium ions, have been inferred.

3.2. Photochemical Methods

There has been considerable interest in photochemical methods for producing nitrenium ions. Photochemical routes hold several significant advantages over

Figure 13.28. Nitrenium ions from the thermolysis of N-aminopyridium ions.

616 NITRENIUM IONS

rearrangement products

R N triplet nitrene

Figure 13.30. Primary nitrenium ions through azide photolysis–nitrene protonation.

Thus nitrenium ion formation is favored by a spin-induced barrier to the deprotonation (Fig. 13.31). Obviously, the feasibility of this route requires that the protonation rate constant exceeds the sum of the ring-expansion and intersystem crossing rate constants. This assumption is the case for arylazide-derived nitrenium ions. For these species, the corresponding nitrenes are generally ground-state triplets, whereas the corresponding arylnitenium ions are ground state singlets.

Protonation of triplet nitrenes has yet to be demonstrated.

McClelland’s route has proven extremely useful.2,129–137 Aryazides are relatively easy to prepare, and azide photolysis produces N2 as the only byproduct. The disadvantages to this approach are (a) only primary, singlet-state nitrenium ions are accessible in this way; (b) the nitrenium ions can only be generated in polar and protic media (usually acidic aqueous solutions), and (c) the azido group does not significantly shift the absorption band of the aromatic ring to which it is attached. Consequently, it is often necessary to use low wavelength ultraviolet (UV) light to generate the nitrenium ion, which can create problems if various

3Ph-N-H

1Ph-N

11 kcal/mol

18 kcal/mol

3Ph-N

1Ph-N-H

Figure 13.31. Protonation of singlet nitrenes to give singlet nitrenium ions.