Reactive Intermediate Chemistry

Figure 13.5. Nitrenium ions in DNA damaging reactions.

involving a number of processes beyond the initial DNA damaging step. The reader is referred elsewhere for a more comprehensive discussion of chemical carcinogenesis, including issues such as DNA repair, and specific genetic targets and cellular protection mechanisms.16–20

Certain aromatic amines were first recognized, on the basis of epidemiological data, to be correlated with bladder cancer, an otherwise rare condition. It is now known that the amines themselves are not the genotoxic agents. Instead it appears that these amines are converted by several tissue-specific enzymatic processes into arylnitrenium ions (11).18 It is these species that are thought to attack DNA at guanine bases, producing covalent adducts. A simplified mechanism is provided in Figure 13.5. It should be pointed out that the role of nitrenium ions in this process is somewhat controversial and alternative mechanisms involving cation radicals have also been advanced.

Both arylnitrenium and alkoxynitrenium ion intermediates have been incorporated into strategies for the chemical synthesis of complex molecules. There are several diverse reaction pathways employed in these reactions. Thus it is difficult to summarize this chemistry with a single reaction scheme. In general, though, the nitrenium ions serve as nitrogen-based electrophiles and form bonds either at the nitrogen or at a mesomeric positive center with various nucleophiles.21–26 The most promising (i.e., regiospecific and high yielding) reactions explicitly

designed to use nitrenium ion intermediates, involve the nitrenium ion center covalently linked to a p nucleophile, such as an aromatic ring (12, Fig. 13.6).24–26

Polyaniline is a repeating unit of benzene rings each joined by an N H group (13, Fig. 13.7). This polymer and its derivatives are of interest because they are electrically conductive when doped with oxidants. This material is prepared by oxidation of aniline electrochemically,27–30 enzymatically,31,32 or with simple chemical reagents.33–35 Polyaniline can be formally regarded as a polymer of

X X

N NR R

12

Figure 13.6. Nitrenium ions in synthesis.

N

13

Figure 13.7. Polyaniline formation.

phenylnitrenium ion. As such it occurred to early workers that the polymer forms when oxidation of aniline gives phenylnitrenium ion, which in turn adds to an aniline unit to provide phenylbenzidine.27,30 The chain could elongate through further oxidation to give a substituted nitrenium ion that would incorporate another

aniline, and so on. Others have argued that the mechanism can be explained by radical coupling processes.29,33,34

1.4. Nitrenium Ion History: Highlights of Pre-1984 Studies

Prior to the 1980s, most studies of nitrenium ions dealt with the question of their discrete existence. In essence, any transformation that goes from one stable molecule through a nitrenium ion intermediate, could also be formulated to occur in a concerted fashion (Fig. 13.8). This creates something of a ‘‘chicken-and-egg’’ problem. In the absence of any unambiguous data on nitrenium ion behavior, it was impossible to argue that observation of a given reactivity pattern was indicative of nitrenium ion formation. Likewise, one could not identify characteristic nitrenium ion reactions, because there were no conditions universally agreed to form nitrenium ions.

It is now apparent that nitrenium ions occur in a variety of contexts including the so-called Bamberger rearrangement 36–38 (i.e., acid-catalyzed isomerization of N- hydroxyaniline 14 to 4-aminophenol 15, Fig. 13.9), and the aforementioned catabolism of arylamines. The earlier workers, however, for the most part did not explicitly consider the possibility of such a species. Heller et al.39 were the first to present kinetic evidence for such an intermediate. Interestingly, they chose to represent it as the iminocyclohexadienyl cation (16), ‘‘With the customary ellipsis of allowing a single valency structure to represent mesomeric systems.’’

Figure 13.8. Nitrenium ion formation versus concerted rearrangement.

INTRODUCTION 601

Figure 13.11. Nitrenium ions in the rearrangment and elimination of benzhydryl azides.

Other evidence advanced in favor of alkyl nitrenium ions came from Agþ pro-

moted isomerization and solvolysis of various cyclic and bicyclic N-chloroamines (e.g., 20).40,41,46 A representative example is shown in Figure 13.12. It was argued

that the silver ion abstracted the chloride from the substrate creating a singlet nitrenium ion (21). Products were derived from 1,2-alkyl shifts to the apparent nitrenium nitrogen and subsequent trapping by either the solvent (22) or the chloride ion. While these products are consistent with formation of a free nitrenium ion, it was also acknowledged that they could be formed in a concerted fashion, whereby alkyl migration occurred concertedly with elimination of the chloride ion.

The formation of the parent amine 23 in these solvolysis reactions was considered to be the most definitive evidence for formation of a discrete nitrenium ion. Gassman and Cryberg41 postulated the following. (a) Initial Cl N bond heterolysis would occur adiabatically, generating the singlet nitrenium ion 21. (b) The triplet

Figure 13.12. Evidence for a discrete nitrenium ion intermediate.

602 NITRENIUM IONS

state 24 was either the ground state, or else it was very close in energy to the singlet.

(c) The trapping of the singlet nitrenium ion (accompanied by the alkyl migration) would compete with relaxation to the triplet state. Given these three assumptions, it was reasoned that collision of the nitrenium ion with heavy atom molecules would accelerate the singlet to triplet interconversion. This so-called heavy atom effect is, a well established phenomenon in photochemistry47 and photophysics,48 but at the time it was unknown in nitrenium ion chemistry.

To test for the heavy atom effect, Gassman and Cryberg41 compared solvolysis reactions carried out with and without bromoform added as the heavy atom agent. Enhanced yields of the parent amine 23 were detected in the presence of both bro-

moform and 1,4-dibromobenzene, suggesting the operation of a heavy atom effect, and thus the formation of a discrete nitrenium ion. Later workers49–51 questioned

these findings. The proposed formation of the parent amine could also be explained by a competing process in which the Cl N bond of a protonated or metalated form of the amine fragments in a homolytic fashion. Regardless of the interpretation of these experiments, Gassman should be credited with firmly advancing the idea that singlet and triplet nitrenium ions could exist and that their chemical reactions would differ. As we shall see below, this idea has withstood the test of time, even if the original experiments that inspired it remain controversial.

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 Parker52 carried out cyclic voltammetry on N,N-di-(2,4-methoxyphenyl)amine (25) in acetonitrile with alumina added to suppress any adventitious nucleophiles. The voltammogram 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.

Serve53 carried out similar experiments with bis(2,4-dimethoxyphenyl)amine and bis(2,4,6-trimethoxyphenyl)amine. In the presence of 2,5-lutudine, a nonnucleophilic base, he detected a two-electron oxidation wave in cyclic voltammetry

Figure 13.13. Electrochemical oxidation of hindered amines gives nitrenium ions.

(CV) experiments. The product of this oxidation was identified as the corresponding nitrenium ion on the basis of its visible absorption band. The latter was shown to be distinct from the nitrenium dication band that was generated under acidic conditions. Also, the cyanide adduct (Fig. 13.13) was isolated and characterized by spectroscopy (1H NMR).

2. THEORETICAL TREATMENTS OF NITRENIUM IONS

The inherent instability of nitrenium ions makes them attractive candidates for study using various quantum-based computational methods. By using such methods, it is possible to predict a variety of molecular properties with useful accuracy at a reasonable cost. These properties include geometries, charge distributions, heats of formation, and relative energies of the singlet and triplet states, which are rather difficult to determine experimentally for short-lived species such as nitrenium ions. Generally, experimental measurements most readily provide stable product distributions, and in some cases, reaction rate constants and electronic spectra. Although it is also possible to theoretically determine transition state energies and geometries, and thus predict decay pathways, such calculations are presently either too demanding of computational resources or else so approximate as to be, at best, a qualitative guide. Thus computational studies are generally able to compliment experimental measurements. On the other hand, the lack of a common data set makes it difficult to assess the accuracy of the various computational approaches. A future challenge remains in finding experiments that either provide computationally accessible data and/or in developing computational procedures that can predict experimentally accessible data.

2.1. Parent, Alkyl-, and Halonitrenium Ions

In general, nitrenium ions have two low-energy electronic states of interest, the triplet state (designated triplet sp in Fig. 13.14), in which the nonbonding electrons have parallel spins and occupy separate orbitals, and the singlet state (designated singlet s2), in which the two nonbonding electrons are paired in the same orbital. The remaining singlets, sp and p2, are generally much higher in energy and are thus

Figure 13.14. Electronic configurations of simple nitrenium ions.

the parent. Also consistent with increased steric strain in the dimethylnitrenium ion

˚ ˚ singlet state is the increased N C bond length of 1.396 A compared with 1.364 A

in the monomethyl. In contrast the triplet N C bond lengths are much less affected

˚

by additional substitution, increasing by only 0.005 A in the dimethyl relative to the monomethyl nitrenium ion.

Interestingly, a recent gas-phase photoelectron spectroscopy (PES) study of dimethylnitrenium ion by Wang et al.67 would seem to be in conflict with the earlier calculations. These workers measured ionization of the dimethylamine radical to give various electronic states of the nitrenium ion. The first ionizing transition, which they attribute to formation of the nitrenium ion’s 1A1 state, occurs with a potential of 9.01 V. The transition to the 3B1 occurs at 9.65 V. If these assignments, which generally agree with DFT calculations run by the same group, are correct, then dimethylnitrenium ion is a ground-state singlet, with a rather substantial energy gap ( 17 kcal/mol). Of course, this study reports only the vertical gap, whereas the gap reported by Cramer and co-workers66 was adiabatic.

It is important to note that for methyl nitrenium ion the singlet state is not predicted at higher levels of theory to show a potential energy minimum. Rather this species is a transition structure that eliminates H2 without a barrier (Fig. 13.15). It seems likely that the difficulties encountered in attempting to study alkyl nitrenium ions might be traced to their propensity to rearrange or eliminate.

Gonzales et al.58 calculated energies and singlet–triplet energy gaps for some halogen and cyano substituted nitrenium ions. The effect of these substituents is to stabilize the singlet in preference to the triplet. This is attributed to the p-dona- tion and s-withdrawing effects of these groups. The cyano group has the more modest effect, reducing the gap by 1.6 kcal/mol. The halogens, fluorine, and chlorine have more pronounced effects reducing the gap by 29 and 24 kcal/mol, respectively. Depending on the theoretical method used the monohalogenated systems are either ground-state singlets or triplets, but in either case the energy difference between the states is small. The dihalo species are clearly ground-state singlets.68 Interestingly, the triplet state of the CN derivative gives a linear geometry and is probably best represented as a protonated 1,3-diradical.

Gonzales and co-workers69 extended their work on simple nitrenium ions, examining the reactions of several small, monosubstituted nitrenium ions (XNHþ, where X ¼ H, F, Cl, CN, and Me) with water. These computational studies (QCISD(T)/6– 311þþ G**) treated only the singlet states of the nitrenium ion. According to these calculations, each singlet nitrenium ion adds to water to form an O-protonated hydroxylamine intermediate (R2N OHþ2 ). No activation barrier was detected for

Figure 13.15. Singlet CH3NHþ is predicted to dissociate without a barrier.