Reactive Intermediate Chemistry

phases has proved controversial. The high bond dissociation energy of silicon– halogen and silicon–oxygen bonds has ruled out traditional SN1 solvolyses as a route to these intermediates. The reactive intermediates 92 and 93 decay by heterolytic cleavage of a silicon–carbon bond. The LFP studies of these reactions, however, have shown that even in the weakly nucleophilic solvents acetonitrile (92)86 and HFIP (93)87 the C–Si cleavage occurs with solvent participation at the silicon so that no free silyl cation is formed. Mayr et al.88, on the other hand, have concluded that hydride transfer from R3SiH to diarylcarbenium ions in CH2Cl2 does proceed to give R3Siþ as an intermediate.

Lambert et al.89 summarized the history of the attempts by his group and others to observe R3Siþ under stable ion conditions. Hydride transfer from R3SiH to salts of carbocations such as the trityl cation does occur and has been used extensively. Initial studies involved silanes such as Ph2MeSiH and the perchlorate salt of the trityl cation. The products were found to be covalent, that is, R3Si OClO3. Switching to alkylthiosilanes such as (i-PrS)3SiH to take advantage of stabilization by the sulfur led to conducting solutions, but the products were complexes with the solvent. This conclusion was based upon 29Si NMR chemical shifts that were typically in the range of 30–50 ppm, far upfield from a value 300 ppm calculated for the free silyl cation. The trityl counterion was then changed to (C6F5)4B and the hydride transfer performed in aromatic solvents such as benzene and toluene. Once again, the value of the 29Si resonance, 80–100 ppm, led to the conclusion that there was coordination with the solvent, which was verified by a crystal structure of the toluene complex of the Et3Siþ (C6F5)4B salt 94. This revealed a toluene ring geometry that was essentially unperturbed and a C Si bond distance

˚ ˚

of 2.18 A, considerably lengthened from the normal distance of 1.85 A. The silicon portion, however, was not planar, which is consistent with tetracoordination. Thus, while the borate counterion was well removed, there was loose coordination to the toluene. Studies by the Reed90 group with halocarboranes as the anion produced similar materials described as ‘‘closely approaching a silyl cation.’’ Here there was coordination between the silicon and halogen atom of the counteranion. Although the silicon–halogen distance was long, the geometry around the silicon was still not planar, as required for the free cation.

Et +

Et

Si (C6F5)4 B−

32 CARBOCATIONS

In addition to its interesting structure, the triethylsilylium–aromatic complex has proved useful in preparing other cations. Reaction with 1,1-diphenylethylene, for example, provided the cation 95, the first example of a persistent b-silyl substi-

tuted carbocation (i.e., where decomposition by loss of the silyl group did not occur).91

½Et3Siþ ðC6F5Þ4B &ArH þ CH2 CPh2 ! Et3SiCH2CPhþ2 ðC6F5Þ4B ð26Þ

95

Lambert then turned to the mesityl (2,4,6-trimethylphenyl) group Mes, in which the two ortho methyl groups provide steric hindrance that might prevent coordination. Trimesitylsilane, (Mes)3SiH, did not transfer its hydride, however, presumably because the carbocation could not approach close enough. In what has been termed the ‘‘allyl leaving-group approach,’’ trimesitylallylsilane was prepared. Its reaction in C6D6 with the b-silyl carbenium salt 95 led to the first free silyl cation 96,92 with a chemical shift of 225 ppm in good agreement with the computed value of 230 ppm. This reaction presumably proceeds via electrophilic addition to the terminal end of the allyl group to give an intermediate 97, followed by cleavage of the silyl cation. Other examples of silyl cations have more recently been reported.93 A crystal structure of a carborane salt of (Mes)3Siþ has confirmed that it has a free three-coordinate silyl cation.94

4.3. Carbocations in Zeolites95

Zeolites are porous aluminosilicate caged structures that can have both Brønsted and Lewis acid sites approaching superacid strengths. These structures play an important role in the petroleum industry because of their ability to catalyze transformations of hydrocarbons in reactions that proceed by way of carbocation intermediates. This has led to a considerable interest in observing such species within the zeolite framework. Relatively stabilized cations such as triarylmethyl, xanthylium, dibenzotropylium, and cyclopentenyl cations can be observed as persistent ions in acidic zeolites, where they have been characterized in similar manners as in superacids, that is, by solid-state NMR, IR, and UV–vis spectroscopy. Less stable cations such as cumyl cations and the 9-fluorenyl cation do not persist. However, such ions have recently been studied as transient intermediates using LFP with diffuse reflectance detection.96 These studies provide information about the reactivity of carbocations generated within the zeolite cavities. There are some interesting differences from reactions in homogeneous solution associated with both the active and passive influences of the zeolite environment. In the former sense, the zeolite

can directly participate in cation decay by direct participation as a nucleophile, leading to framework-bound products. In the latter sense, the zeolite can have significant effects on the reactions with added nucleophiles, slowing down diffusional encounter but enhancing the reactivity once the nucleophile is in the same cage in the zeolite.

4.4. Carbocations in Carcinogenesis

Most chemical carcinogens share the property of forming DNA adducts, a lesion, which if not repaired, can lead to mutagens and cancer. While some carcinogens form these adducts via radical chemistry, the more common mechanism is one where DNA reacts as a nucleophile.97 The carcinogen is either an electrophile or is converted by metabolism into an electrophile. Of these, there are several important systems where the electrophile is a delocalized carbocation. Scheme 1.9 summarizes two of the widely studied examples. The polycyclic aromatic hydrocarbon (PAH) carcinogens, typified by benzo[a]pyrene (98),98 undergo metabolic activation to a diol epoxide (99), that (possibly in the presence of DNA)99 undergoes acid-catalyzed ring opening to a delocalized benzylic-type cation (100). Tamoxifen (101) (Ar ¼ C6H4-4-OCH2CH2NMe2), an antiestrogen employed in the treatment of breast cancer, causes a small number of endometrial cancers. A mechanism has been implicated involving allylic hydroxylation, followed by sulphation to the ester 102. This ester is short lived, undergoing SN1 ionization to the allylic cation 103.100 As is typical of delocalized carbocations, 103 and the benzylic cations derived from the PAHs alkylate deoxyribonucleic acid (DNA) at the exocyclic amino groups of adenine and guanine to give relatively stable adducts such as 104. This behavior

contrasts dramatically with that of SN2 alkylating agents, which react principally at N7.97

Scheme 1.9

Benzylic-type cations derived from PAHs have been studied under superacid conditions, where, not surprisingly, they are relatively stable.101 Lifetimes in water of diastereomeric forms of the benzo½a&pyrene derivative (100) have been determined by the azide clock approach to be 50 ns.98 The tamoxifen cation 103 has

34 CARBOCATIONS

been studied directly by LFP; this has a lifetime at pH 7 of 25 ms.100 As nucleophiles, guanine and adenine in monomeric forms do not compete effectively with water for such cations.102 There are indications, however, that when incorporated in DNA they are significantly more nucleophilic.97 The reasons for this are a subject of current investigation. It has been suggested that in the double helix the hydrogen-bonded partner functions as a general base catalyst removing one of the NH protons at the same time as the cation reacts.103 There are also indications that delocalized cations preassociate in some manner with DNA before reaction occurs.104

4.5. Carbocations in Biosynthesis

The isoprene pathway produces a diverse range of natural products such as terpenes and steroids. A number of complex biochemical transformations are involved, many of which have been proposed to involve short-lived carbocation intermediates. Two recent studies provide a brief introduction.

The enzyme isopentenyl diphosphate: dimethylallyl diphosphate isomerase catalyzes a key early step whereby 105 is isomerized to 107 (Eq. 28, OPP ¼ diphosphate). A number of studies, including a recent crystal structure,105 have led to a mechanism whereby an intermediate tertiary carbocation 106 is formed by protonation by a cysteine residue C67. Deprotonation is proposed to involve a metal bound glutamate E116 facing the cysteine in the active site. An interesting aspect of the enzyme is the requirement for a tryptophan residue W161, which is suggested to stabilize the cationic intermediate through quadrupole-charge interaction with the indole p electrons.

Squalene synthase catalyzes the first committed step in cholesterol biosynthesis, condensation of two farnesyl diphosphates to form presqualene diphosphate (108), with subsequent rearrangement and reduction to squalene (112) (Eq. 29). It has been proposed that 108 ionizes to the cyclopropylcarbinyl cation 109, which rearranges via a cyclobutyl cation 110 (which may be a transition state) to a second more stable cyclopropylcarbinyl cation 111.106 Reductive ring opening produces squalene. The enzyme controls both the regioand stereochemistry of the reaction. Of interest are model studies suggesting that the rearrangement of 109 to 111 is a minor reaction channel without the enzyme, with the preferred reaction being rearrangement to the allylic cation 113. Within the active site of the enzyme, the

transition state for the cyclopropylcarbinyl–cyclopropylcarbinyl rearrangement must be stabilized by >7.9 kcal/mol relative to that of the competing rearrangement.

C11H19

+

C11H19

As a general comment, the cations that have been implicated in such biosyntheses are of the type for which analogues have been observed in superacids. However, many of these cations, (e.g., 106 and 109) would have a questionable existence as a free cation in an aqueous solution. This finding raises an interesting question whether they do have more than a fleeting existence within the active site of the enzyme. Does the enzyme provide some form of stabilization, such as that suggested when 106 is formed in the active site of isopentenyl diphosphate: dimethylallyl diphosphate isomerase?

5. CONCLUSION AND OUTLOOK

The study of carbocations has now passed its centenary since the observation and assignment of the triphenylmethyl cation. Their existence as reactive intermediates in a number of important organic and biological reactions is well established. In some respects, the field is quite mature. Exhaustive studies of solvolysis and electrophilic addition and substitution reactions have been performed, and the role of carbocations, where they are intermediates, is delineated. The stable ion observations have provided important information about their structure, and the rapid rates of their intramolecular rearrangements. Modern computational methods, often in combination with stable ion experiments, provide details of the structure of the cations with reasonable precision. The controversial issue of nonclassical ions has more or less been resolved. A significant amount of reactivity data also now exists, in particular reactivity data for carbocations obtained using time-resolved methods under conditions where the cation is normally found as a reactive intermediate. Having said this, there is still an enormous amount of activity in the field.

36 CARBOCATIONS

The roles of carbocations in commercially important hydrocarbon transformations are still not perfectly understood. The same can be said for carbocations in biological systems. Significant questions concerning reactivity still need to be explained. Why do so many reactions of carbocations show constant selectivity, in violation of the reactivity–selectivity principle? Is it possible to develop a unified scale of elec- trophilicity–nucleophilicity, in particular one that incorporates these parameters into the general framework of Lewis acidity and basicity. Finally, quite sophisticated synthetic transformations are being developed that employ carbocations, based upon insights revealed by the mechanistic studies.

SUGGESTED READING

G.K. S. Prakash and P. v. R. Schleyer, Eds., Stable Ion Chemistry, John Wiley & Sons, Inc., New York, 1997.

G.A. Olah, ‘‘100 Years of Carbocations and their Significance in Chemistry,’’ J. Org. Chem. 2001, 18, 5943.

Number 12 of Acc. Chem Res. 1983, where three papers discuss norbornyl cations.

C. D. Ritchie, ‘‘Cation–Anion Combination Reactions,’’ Can. J. Chem. 1986, 64, 2239.

R.A. McClelland, ‘‘Flash Photolysis Generation and Reactivities of Carbenium Ions and Nitrenium Ions,’’ Tetrahedron 1996, 52, 6823.

J.P. Richard, ‘‘A Consideration of the Barrier for Carbocation–Nucleophile Combination Reactions,’’ Tetrahedron 1994, 51, 7981.

H.Mayr, T. Bug, M. F. Gotta, N. Hering, B. Irrgang, B. Janker, B. Kempf, R. Loos, A. R. Offial, G. Remennikov, and H. Schimmel, ‘‘Reference Scales for the Characterization of Cationic Electrophiles and Neutral Nucleophiles,’’ J. Am. Chem. Soc. 2001, 123, 9500.

J.Lambert, ‘‘Preparation of the First Tricoordinate Silyl Cation’’ J. Phys. Org. Chem. 2001, 14, 370.

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