Reactive Intermediate Chemistry

Figure 13.52. Macrocyclization through nitrenium ion/arene coupling.

Analogous methods have been applied to the synthesis of macrocycles. Abramovitch et al.24 obtained fair yields of a macrocyclic diarylamine (107) through N to para cyclization of a arylnitrenium ion (106) onto a thiobenzene group (Fig 13.52). In a related study, Abramovitch and Ye170 attempted the addition of an arylnitrene derivative to a tethered alkoxybenzene ring 108. The reaction actually produced the phenanthrene derivative 109. This apparent result is from the coupling of the meta position of the arylnitrenium ion to the 4-position of the proximal arylether. It is argued that the addition proceeds by an initial para to para cyclization to a five membered ring (110). Acylation by trifluoroacetic anhydride induces a 1,2-shift to give 111. The latter is deprotonated to give the observed product (Fig. 13.53).

There are several examples of arylnitrenium ion additions to alkenes (Fig. 13.54). For example, Dalidowicz and Swenton171 trapped N-acetyl-N-(4-methoxyphenyl)- nitrenium ion 112 with 3,4-dimethoxy-1-propenylbenzene and isolated products resulting from addition of the alkene to the ortho position of the nitrenium ion, giving cation 113, followed by its cyclization onto N (yielding 114) or the acetyl carbonyl group (yielding 115).

Similar results were obtained when diphenylnitrenium ion was trapped with various silylenol ethers and silyl ketene acetals (e.g., 116).172 In these experiments, a distribution of N-(117), p- (118), and o- (119) adducts were generated (Fig. 13.55). The ortho adducts underwent a cyclization reaction, producing an indolone derivative.

OO

Figure 13.53. Cyclization–rearrangement of a arylnitrenium ion.

115

Figure 13.54. Addition of an arylnitrenium ion to an alkene.

Figure 13.55. Addition of N,N-diphenylnitrenium ion to alkenes.

4.4. Singlet-State Reactions with Hydride Donors

This process has not been studied in detail. It has been shown that diphenylnitrenium ion reacts with various hydrocarbons and metal hydrides to give diphenyl amine.144 An analysis of the rate constants for these processes showed that the reaction was most likely a hydride transfer, rather than a hydrogen atom transfer (Fig. 13.56). Novak and Kazerani173 found a similar process in their study of the decay reaction of heteroarylnitrenium ions.

Figure 13.56. Hydride transfer.

4.5. Triplet-State Hydrogen Atom Transfer Reactions

Relatively little is known about the chemical reactions of triplet state nitrenium ions. In fact, the only reaction that is unambiguously assigned to this spin state is hydrogen atom transfer. The triplet state has two unpaired electrons. Intuitively, one might suspect that it would behave in a way similar to a free radical. To the extent that unambiguous data are available, this does seem to be the case.

N-tert-Butyl-N-(2-acetylphenyl)nitrenium ion was generated by photolysis of the corresponding anthranilium ion. This photolysis first creates a singlet state of the precursor. The latter partitions between ring opening, providing the singlet-state nitrenium ion, and intersystem crossing, providing the excited triplet state of the

precursor. The latter undergoes a ring opening creating the triplet nitrenium ion (Fig. 13.57).117,156,157

These reactions give three types of stable products: (1) adducts from the addition of nucleophiles (alcohols, water, halides) to the benzene ring, (120); (2) an iminium ion (121), apparently resulting from the 1,2-shift of methyl group, and (3) the parent amine (122). It was argued that 120 and 121 are specific products of the singlet state, whereas 122 is derived from the triplet state. These assignments are supported by several additional experiments. For example, it was shown that the yield of the triplet product was enhanced when the photolysis was carried out using triplet sensitization, but it was suppressed when a triplet quencher (a molecule that deactivates the excited triplet state of the precursor by an energy-transfer mechanism) was employed.117 Several other anthranilium ion generated nitreniuim

ions were investigated in this manner and they all showed qualitatively similar

behavior.118,156,157,174,175

Figure 13.57. Spin-specific chemistry of arylnitrenium ions.

632 NITRENIUM IONS

Figure 13.60. Attempt to protonate nitrosocompound gives dication.

Figure 13.61. Vinylidene nitrenium ion stabilized in superacid media.

ions can serve as weak bases due to their nonbonding electron pairs. For example, attempts to generate N-hydroxyl-N-phenylnitrenium ion 127 through the protona-

tion of N-nitrosobenzene 126 resulted in the formation of the dication (Fig. 13.60).176 Olah and co-workers177–179 did succeed in creating alkylidenenitren-

ium ions. This result was accomplished by treating cyanohydrins 128 with superacid, creating a-cyanocarbenium ion 129a, which can be regarded as a nitrenium ion on the basis of resonance structure 129b (Fig. 13.61).

A major concern in nitrenium ion research has been to characterize the lifetimes and reaction rates of these species in solution. Two techniques have been the mainstays of this research. The oldest and most generally applicable method to characterize arylnitrenium ion lifetimes in solution is to measure the relative yields of the stable products. The ratio of rate constants can then be inferred from the product ratios.

One specific embodiment of this approach has been to use the azide (az) clock method (Fig. 13.62).180–182 Azide ion (N3 ) is a very strong nucleophile (Nu) and is

thus assumed to react with most arylnitrenium ions at the diffusion—limited rate,

NHR

kaz [N3−]

N3

N

R

NHR

knuc[Nuc]

Nuc

Figure 13.62. Azide clock method for determining arylnitrenium ion reaction rate constants.

Figure 13.63. Lifetime of a nitrenium ion in aqueous solvent.

5 109 M 1 s 1. Direct measurements of azide trapping reactions have generally

validated this assumption (see Chapter 2). Except for highly stabilized nitrenium ions, kaz, is seen to fall in a narrow range of 4–10 109 M 1 s 1. 11,131,183 The yield

of azide adducts relative to the competing products can be used to estimate the rate constants for formation of the latter.

In view of the role of arylnitrenium ions in carcinogenic DNA damage, there has been much interest in their lifetimes in aqueous solution. Arylnitrenium ions that are rapidly consumed through hydrolysis are unlikely to have lifetimes sufficient

for them to diffuse through the cell, penetrate the nucleus and damage the DNA. Fishbein and McClelland84,184,185 trapped the 2,6-xylylnitrenium ion (130) gener-

ated in the Bamberger rearrangement (acid-catalyzed decomposition of the corresponding hydroxylamine) with N3 . On the basis of product ratios and the assumption that the reaction of azide was diffusion limited, it was concluded that the lifetime of this nitrenium ion in aqueous solution was 1.5 ns. Such a short lifetime implies that this nitrenium ion (Fig. 13.63) would probably not be able to efficiently attack DNA in an aqueous cellular environment.

Several representative selectivity values Sð¼ log½kaz=kw&Þ derived in this manner are listed in Table 13.4. In the main, para-substituted aromatic rings and alkenyl

TABLE 13.4. Relative Selectivities ðS ¼ log kaz=k2Þ

Derived from Azide Trapping of R1R2Nþa

a See Ref. 14.

634 NITRENIUM IONS

groups show the most profound effect on the selectivity. This effect is seen in the series of fluorenyl and 4-biphenylyl nitrenium ions that have S mostly in excess of 3.5, ranging as high as 6.59. Alkoxy groups, which are generally regarded as stronger donors, show more modest effects on the selectivity, falling in the range of 2.7– 3.7. Alkyl groups are even less effective in conferring aqueous stability, showing S values <1.0. N-Alkyl and N-acetyl groups have only modest effects on S usually increasing or decreasing it by <1 relative to H.

The azide clock approach has the advantage of being universally applicable to any arylnitrenium ion that can be generated in aqueous solution (azide salts are typically insoluble or sparingly soluble in nonaqueous media). This corresponds to the conditions regarded as most relevant to their toxicological behavior. The method can also be adapted to the study of trapping rate constants for reagents other than water. The major disadvantage of this approach is that it only can give accurate rate constants in cases where the assumption of diffusion limited trapping is valid and preassociation of the azide with the precursor does not occur,

Laser flash photolysis methods have also been applied to the study of nitrenium ion trapping rates and lifetimes. This method relies on short laser pulses to create a high transient concentration of the nitrenium ion, and fast detection technology to characterize its spectrum and lifetime The most frequently used detection method is fast UV–vis spectroscopy. This method has the advantage of high sensitivity, but provides very little specific information about the structure of the species being detected. More recently, time-resolved infrared (TRIR) and Raman spectroscopies have been used in conjunction with flash photolysis methods. These provide very detailed structural information, but suffer from lower detection sensitivity.

5.2. Ultraviolet–Visible Spectra of Nitrenium Ions

The first nitrenium ion to be examined using any flash photolysis method was the 4- dimethylaminophenylnitrenium ion (131).186 However, the workers who carried out these experiments apparently did not consider this species to be a nitrenium ion. It was generated by pulsed Xe lamp photolysis from the corresponding azide (132, Fig. 13.64), and was detected through its absorption at 325 nm. As the resonance structure 131 implies, this nitrenium ion (or quinonediimine) is especially stable. In fact, its lifetime exceeds 100 ms at neutral pH, and it decays through hydrolysis of the C N bond to give iminoquinone (133).

Figure 13.64. First arylnitrenium ion detected by direct spectroscopic methods.