Superelectrophiles reactivities

Phosphonium groups are well known for their ability to stabilize adjacent anionic sites (i.e., Wittig reagents), but the results with the dicationic species indicate that phosphonium groups can also destabilize adjacent cationic groups producing their superelectrophilic reactivities. 

Based on related observations, it was concluded that the superelectrophile 234 is not involved in the phenylation reaction. However, weak interaction (solvation) of the nitrile lone pair (i.e., 235) with the superacid may generate increasing dipositive character and the observed superelectrophilic reactivity. 

The observed electrophilic reactivity is indicative of superelectrophilic activation in the dication 173. Other ammonium-carboxonium dications have also been reported in the literature, some of which have been shown to react with benzene or other weak nucleophiles (Table 4).1 42b 57-60 Besides ammonium-carboxonium dications (175-179), a variety of N-heteroaromatic systems (180-185) have been reported. Several of the dicationic species have been directly observed by low-temperature NMR, including 176, 178-180, 183, and 185. Both acidic (175, 180-185) and non-acidic carboxonium (176-177) dicationic systems have been shown to possess superelectrophilic reactivity. The quinonemethide-type dication (178) arises from the important biomolecule adrenaline upon reaction in superacid (entry 4). The failure of dication 178 to react with aromatic compounds (like benzene) suggests only a modest amount of superelectrophilic activation. An interesting study was done with aminobutyric acid... 

Various sulfonium and carbosulfonium ions show remarkably enhanced reactivity upon superelectrophilic activation, similar to their oxygen analogs so do selenonium and telluronium ions. The alkylating ability of their trialkyl salts, for example, is greatly increased by protosolvation. 

In these (and other) solid superacid catalyst systems, bi- or multi-dentate interactions are thns possible, forming highly reactive intermediates. This amounts to the solid-state equivalent of protosolvation resulting in superelectrophilic activation. 

In summary, we have shown that stable cationic charge centers can significantly enhance the reactivities of adjacent electrophilic centers. Most of the studied systems involve reactive dicationic electrophiles. A number of the reactive dications have been directly observed by low temperature NMR. Along with their clear structural similarities to superelectrophiles, these dicationic systems are likewise capable of reacting with very weak nucleophiles. Utilization of these reactive intermediates has led to the development of several new synthetic methodologies, while studies of their reactivities have revealed interesting structure-activity relationships. Based on the results from our work and that of others, it seems likely that similar modes of activation will be discovered in biochemical systems (perhaps in biocatalytic roles) in the years to come. 

More recent studies with superacidic systems (TfOH, TfOH—SbF5), used also in the Gattermann reaction, indicated that strong acids significantly increase reactivities of benzene with benzonitrile.33 104 It is concluded that the superelectrophilic 14 dication formed as a results of protonation of 13 is the reactive species in the Houben-Hoesch reaction. 

Since the inception ofthe superelectrophilic concept in the 1970s1 and 1980s 2 first formulated as protosolvation of cationic intermediates, superelectrophiles as highly reactive dicationic and tricationic intermediates have been successfully observed and characterized.3-5 Consequently, selected examples of superelectrophiles are also covered in this chapter where appropriate, whereas various organic transformations, in which the involvement of superelectrophilic intermediates is invoked or superelectrophiles are observed, are treated in Chapter 5. 

As already mentioned and shown, considerable experimental and theoretical evidence has been collected over the last decades, which supports the idea of superelectrophilic activation, that is, protosolvation1 2 or de facto protonation of cationic intermediates.3-5 Examples of superelectrophiles as highly reactive dica-tionic (doubly electron-deficient) and tricationic intermediates were discussed in Chapter 4. 

The success of carbocation chemistry lies in the stabilization of carbocations in a medium of low nucleophilicity. Superelectrophiles, in turn, are reactive intermediates generated by further protonation (protosolvation). This second protonation increases electron deficiency, induces destabilization, and, consequently, results in a profound increase in reactivity. In particular, charge-charge repulsive interactions6 play a crucial role in the enhanced reactivity of dicationic and tricationic superelectrophilic intermediates. As various examples of acidity dependence studies show, without an appropriate acidity level, transformations may occur at much lower rate or even do not take place at all. In addition to numerous examples of superacid catalyzed reactions, various organic transformations, in which the involvement of superelectrophilic intermediates is invoked or superelectrophiles are de facto observed in the condensed state, are also included in this chapter. 

Extending the concept of superacids to varied superelectrophiles has emerged as a productive new field in recent years (G. A. Olah and D. A. Klumpp, Superelectrophiles and Their Chemistry, Wiley-Interscience, Hoboken, NJ, 2008). Highly reactive and activated protosolvated or multiply charged superelectrophilic intermediates are involved in varied chemical reactions, many of them of substantial practical significance. 

Dinitrobenzofuroxan (DNBF) is known as a superelectrophile due to its high reactivity both as an electrophile and in its pericyclic addition reactions. NMR studies show that reaction with 2-aminothiazole and its 4-methyl derivative yield anionic carbon-bonded adducts such as (11) by reaction at the 5-position, whereas the 4,5-dimethyl derivative reacts via the exocyclic amino group. Kinetic studies of the first two compounds, both in acetonitrile and in 70 30 (v/v) water-DMSO, have been used to assess their carbon nucleophilicities and place them on the Mayr nucleophilicity scale.55 In a related study, the nucleophilic reactivity, in acetonitrile, of a series of indoles with both DNBF and with benzhydryl cations have been compared and used to determine nucleophilicity parameters for the indoles.56... 

These results can be interpreted in terms of protosolvation of the nitronium ion. While the monocationic nitronium ion is a sufficiently polarizible electrophile to react with strong nucleophiles such as olefins and activated arenes, it is generally not reactive enough to react with weak nucleophiles including methane. Partial or complete protonation of the nitronium oxygen then leads to the superelectrophilic species 8. The... 

Both types of dicationic species (9-10) exhibit the properties and reactivities of superelectrophiles. 

The concept of superelectrophilic activation was first proposed 30 years ago.20 Since these early publications from the Olah group, superelectrophilic activation has been recognized in many organic, inorganic, and biochemical reactions.22 Due to the unusual reactivities observed of superelectrophiles, they have been exploited in varied synthetic reactions and in mechanistic studies. Superelectrophiles have also been the subject of numerous theoretical investigations and some have been directly observed by physical methods (spectroscopic, gas-phase methods, etc.). The results of kinetic studies also support the role of superelectrophilic activation. Because of the importance of electrophilic chemistry in general and super-acidic catalysis in particular, there continues to be substantial interest in the chemistry of these reactive species. It is thus timely to review their chemistry. 

One of the defining features of superelectrophiles is the often-observed high level of reactivity towards nucleophiles of low strength.1 This experimental observation is frequently used as an indication for the involvement of a superelectrophiles. To illustrate, the following examples show how the electrophile s reactivity can be characterized to indicate superelectrophilic chemistry. 

Friedel-Crafts type reactions of strongly deactivated arenes have been the subject of several recent studies indicating involvement of superelectrophilic intermediates. Numerous electrophilic aromatic substitution reactions only work with activated or electron-rich arenes, such as phenols, alkylated arenes, or aryl ethers.5 Since these reactions involve weak electrophiles, aromatic compounds such as benzene, chlorobenzene, or nitrobenzene, either do not react, or give only low yields of products. For example, electrophilic alkylthioalkylation generally works well only with phenolic substrates.6 This can be understood by considering the resonance stabilization of the involved thioalkylcarbenium ion and the delocalization of the electrophilic center (eq 4). With the use of excess Fewis acid, however, the electrophilic reactivity of the alkylthiocarbenium ion can be... 

Diprotonated, superelectrophilic intermediates were suggested to be involved in both conversions. Considering protonated aldehydes, benzal-dehyde gives a carboxonium ion that is significantly resonance stabilized and thus unreactive towards aromatic substrates such as o-dichlorobenzene or nitrobenzene. Pyridinecarboxaldehydes, however, show much higher electrophilic reactivities due to their ability to form via TV-protonation the superelectrophile (5, eq 8).10 A similar situation is seen in the hydroxyalkylation reactions of acetyl-substituted arenes. Acetophenone is fully protonated in excess triflic acid, but the resulting carboxonium ion (6) is... 

Superelectrophilic activation has also been proposed to be involved, based upon the reactivity of carbocations with molecular hydrogen (a a-donor).16 This chemistry is probably even involved in an enzymatic system that converts CO2 to methane. It was found that A. A -menthyl tetrahy-dromethanopterin (11) undergoes an enzyme-catalyzed reaction with H2 by hydride transfer to the pro-R position and releases a proton to give the reduced product 12 (eq 15). Despite the low nucleophilicity of H2, cations like the tert-butyl cation (13) are sufficiently electrophilic to react with H2 via 2 electron-3 center bond interaction (eq 16). However, due to stabilization (and thus delocalization) by adjacent nitrogen atoms, cations like the guanidinium ion system (14) do not react with H2 (eq 17). 

As noted previously in Chapter 1, the electrophilic reactivities of acetyl salts increase dramatically as the acidity of the reaction medium increases. This was one of the observations that lead Olah and co-workers to first propose the concept of superelectrophilic activation, or protosolvation of the acetyl cation, in 1975.2 This seminal paper described the chemistry of acetyl hexafluoroantimonate (CHsCO+SbFg-) and the reaction with alkanes in various solvents. In aprotic solvents such as SO2, SO2CIF, AsF3, and CH2CI2, there was no reaction. However in HF-BF3, acetyl salts react with Ao-alkanes and efficient hydride abstraction is observed.27 This was interpreted by Olah as evidence for protonation of the acetyl... 

In several recent studies, nitro-substituted olefins have been shown to exhibit high electrophilic reactivities in superacid-promoted reactions.29 NMR studies have been used to identify some of the superelectrophilic intermediates in these reactions. For example, it was found that nitroethy-lene reacts with benzene in the presence of 10 equivalents of CF3SO3H to give deoxybenzoin oxime in 96% yield (eq 29). Since the reaction does not occur with only one equivalent of TfOH, it was proposed that the N,N-dihydroxy-iminium-methylium dication (51) is generated. In spectroscopic studies, l-nitro-2-methyl-l-propene (52) was dissolved in CF3SO3H, and at —5°C the stable dication (53) could be directly observed by and 13 C NMR spectroscopy (eq 30). 

Carboxonium ions are indicated to be involved in a number of super-electrophilic reactions. In several cases, the direct observation of the superelectrophiles and reactive dications has been possible using low... 

Mass spectrometric techniques also enable experimentalists to react dications and trications with neutral substrates in the gas phase to explore the chemical reactions of these multiply charged species. Although only a few superelectrophiles have thus far been examined experimentally for their gas phase chemical reactivities, other electrophilic gas phase reactions have demonstrated the potential of these methods. For example, the... 

In superacid catalyzed reactions of hydroxyquinolines and isoquinolines, dicationic superelectrophiles were proposed as intermediates in their reactions (see Table 4).35d In order to explain differences in relative reactivities between the isomeric superelectrophiles, the energies of the lowest unoccupied molecular orbitals Ultimo ), the square of the coefficients (c2) at the reactive carbon atoms, and the NBO charges (q) on CH groups were determined by MNDO and DFT computational methods. For example, 8-hydroxyquinoline (85) is found to be more reactive than 6-hydroxyquinoline (87) in the superacid catalyzed reactions with benzene and cyclohexane (eqs 47 -8). 

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