Superelectrophiles dication intermediate

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. 

Although electrophilic reactions involving dications with deactivated arenes may suggest the formation of superelectrophilic intermediates, there are a number of well-known examples of monocationic electrophiles that are capable of reacting with benzene or with deactivated aromatic compounds. For example, 2,2,2-trifluoroacetophenone condenses with benzene in triflic acid (eq 12).13 A similar activation is likely involved in the H2SO4 catalyzed reaction of chloral (or its hydrate) with chlorobenzene giving DDT (eq 13). 

It was reported that arylpinacols (48a) can undergo a superacid-catalyzed dehydrative cyclization to give the aryl-substituted phenan-threnes (eq 27).23 Superelectrophilic intermediates were proposed in the conversion. Tetraarylethylene dications have been studied by several methods and were observed directly by NMR as well as by UV-vis spectroscopy and X-ray crystallography.28 The low temperature oxidation of tetraaiylethylenes gives the dicationic species (50, eq 28). 

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). 

Computational methods have also been used frequently to estimate the thermodynamic stabilities of superelectrophiles. These calculations have often involved the estimation of barriers to gas phase dissociation or deprotonation, and the proton affinities of conventional electrophilic intermediates. Other useful studies have calculated the heats of reactions for isodesmic processes. An interesting example of these calculations comes from a study of the protoacetyl dication (Cf COH2"1- ).42 In calculations at the 6-31G //4-31G level of theoiy, the protoacetyl dication (83) is estimated to react with methane by hydride abstraction with a very favorable... 

Similar oxygen stabilized ethylene dications were proposed in several types of superacid-catalyzed condensation reactions involving 1,2-dicarbonyl compounds. For example, 2,3-butanedione condenses in high yield with benzene and the superelectrophile (35) is considered to be the key intermediate, because the monoprotonated species (78) is not sufficiently electrophilic to react with benzene (eq 17).35 Several biologically important a-ketoacids were also found to generate superelectrophiles... 

Related classes of gitonic superelectrophiles are the previously mentioned protoacetyl dications and activated acyl cationic electrophiles. The acyl cations themselves have been extensively studied by theoretical and experimental methods,22 as they are intermediates in many Friedel-Crafts reactions. Several types of acyl cations have been directly observed by spectroscopic methods and even were characterized by X-ray crystal structure analysis. Acyl cations are relative weak electrophiles as they are effectively stabilized by resonance. They are capable of reacting with aromatics such as benzene and activated arenes, but do not generally react with weaker nucleophiles such as deactivated arenes or saturated alkanes. 

The dicationic species have also been obtained from /3-ketoacids, fi-ketoesters, and /-i-ketoamides in superacid solutions (Table 1, entries 2-4). Diprotonated acetoacetic acid (75) can be observed by low-temperature NMR under stable ion conditions.34 Likewise, diprotonated methylacetoacetate (77) can be observed by NMR at temperatures lower than — 80°C in FS03H-SbF5-SC>2 solution.35 With ethyl acetoac-etate in HF-SbFs, the equilibrium constant for the dication-monocation equilibrium has been estimated to be at least 107, indicating virtually complete conversion to the superelectrophile.35 The /3-ketoamide (78) is found to give the condensation products 95 in good yield from CF3SO3H and the superelectrophile 79 is proposed as the key intermediate in the condensation reaction (eq 25 ).27... 

Carboxonium-Ammonium and Related Dications A wide variety of species have been generated in which the 1,3-dicationic structure arises from carboxonium ion centers being adjacent (separated by one carbon) to an ammonium or related charge center. These intermediates may be described as reactive dications, yet they have been shown to exhibit electrophilic reactivities comparable to superelectrophiles. 

The different chemistry of the dications 99 and 101 seems to reflect the superelectrophilic nature of the gitonic dication. It has also been shown that simple peptides may be multiply protonated in acids like FSOsH-SbFs, generally being protonated at the terminal amino group, the carboxyl group, and at the peptide bonds. In a study of the chemistiy of /V-tosylated phenylalanine derivatives, the diprotonated intermediate (103) was proposed in a reaction with superacid CF3SO3H (eq 33).42... 

One of the proposed intermediates in this transformation is the super-electrophilic species (184), which undergoes deprotonation to give the 2-buten-oyl cation. Further evidence for the superelectrophile 184 is obtained from experiments in which the 2-butenoyl cation (185) is generated in DSOsF-SbFs. Significant deuterium incorporation is found at the a and y positions, suggesting equilibria involving 184-186. In a similar respect, formation of the 4-chloro-3-methylbutanoyl cation (187) in superacid leads to the two acyl dications (188-189, eq 57).69... 

The conversion is thought to involve formation of the carboxonium ion (77) by protonation of the carbonyl oxygen, and subsequent protonation then occurs at the C-H bond. The resulting carboxonium-carbonium dication (78) possesses the maximum possible charge-charge separation for this bicyclic framework. Subsequently, an intermediate carboxonium-carbenium dication (79) is produced, which isomerizes to the tertiary -carbenium ion, and deprotonation provides the product enone (80). Similar distonic superelectrophiles are proposed in other rearrangements of terpenes in superacid.28... 

A number of related distonic superelectrophiles have been generated from A-heteroaromatic compounds (Table 2). Vinyl-dications (111-112) have been produced from the ethynyl pyridines,40 while /V-alkenyl A-heterocycles provide dications (113-115).42a Vinyl-substituted A-heterocycles provide access to distonic superelectrophiles such as dication 116.39 Dications 117 and 118 are generated from their precursors, and both intermediates lead to efficient cyclization reactions with the adjacent... 

Interestingly, the comparable monocation (190) is not reactive towards benzene or cyclohexane. This is an indication of the superelectrophilic character of dication 188. The isomeric hydroxyquinolines and 5-hydroxy-isoquinoline react with 5-7 molar excess of aluminum chloride and cyclohexane at 90°C to give ionic hydrogenation products, and the corresponding distonic superelectrophiles (191-193) are proposed as intermediates. 

Many types of bis-sulfonium dications have been described in the literature, although little is known about the extent of superelectrophilic activation in these species. As an example, the dithioniabicyclo[2,2,2]octane dication (217) is produced by reaction of the bicyclic dithioether dication (216) with styrene derivatives (eq 75).72 Tertiary sulfonium dications (useful synthetic intermediates) have been prepared (eq 76).73... 

Superelectrophilic Activation or Superelectrophilic Solvation. Trifluoromethanesulfonic acid (triflic acid, TfOH) has been extensively employed as a superacid Ho= —14.1) in superelectrophilic activation (or superelectrophilic solvation), both concepts advanced by Olah. Superelectrophilic activations may occur when a cationic electrophile reacts with a Bronsted or Lewis acid to give a dicationic (doubly electron-deficient) superelectrophile. However, it should be recognized that the activation may proceed through superelectrophilic solvation without necessarily forming limiting dicationic intermediates. The frequently used depiction of protosolvated species as their limiting dications is just for simplicity. ... 

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