Acidity of phosphonium salts

Most of the pKa values for the phosphonium salts have been determined by potentio-metric measurements in the case of / -ketophosphonium salts562 (Table 13). The acidity of these phosphonium salts depends not only on the R and R groups of the carbonyl chain, but also on the other substituents linked to the phosphorus562 564. Particularly for the cyclic phosphonium salts, the pKa value can vary significantly depending on the different steric and electronic (even transannular) effects on the phosphorus atom564  

In addition, the acidities of phosphonium salts vary in relation to the solvent in a typical way for onium salts in the case of various water-ethanol mixtures, the acidity decreases as the proportion of ethanol increases and then reincreases in pure ethanol562. Further, there are great differences between the pKa values measured in two different solvents562  

The kinetic acidity of phosphonium salts was first studied by NMR measurements of the hydrogen-deuterium exchange rate for a series of phosphonium salts565  

The results indicate that the kinetic acidity is markedly lower for phosphonium salts than for the corresponding nitroalkanes, but cannot be correlated with pKa values. In contrast, the measurement of kinetic acidity using double potential step chronoamperometry180 allowed the determination of pka values for a series of phosphonium salts corresponding to semi-stabilized or non-stabilized ylides  

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By 1989 Mukaiyama had already explored the behaviour of phosphonium salts as Lewis acid catalysts. It was possible to show that the aldol-type reaction of aldehydes or acetals with several nucleophiles and the Michael reaction of a,j3-unsatu-rated ketones or acetals with silyl nucleophiles gave the products in good yields with a phosphonium salt catalyst [116]. In addition, the same group applied bisphosphonium salts as shown in Scheme 45 in the synthesis of ]3-aminoesters [117]. High yields up to 98% were obtained in the reaction of A-benzylideneaniline and the ketene silyl acetal of methyl isobutyrate. Various analogues of the reaction parteers gave similar results. The bisphosphonium salt was found to be superior to Lewis acids like TiCl and SnCl, which are deactivated by the resulting amines. 

In summary, there are now several examples of phosphonium salt-based Lewis acids as catalysts known, which have shown a good catalytic activity. However, an asymmetric catalyzed reaction with an enantiopure phosphonium salt has not been reported yet. 

In a 1985 patent by Hoffmann-La Roche, the Wittig condensation was also the crucial step in assembling isotretinoin (1, Scheme 2). Under the optimized conditions, 1.03 equivalents of phosphonium salt 8 was condensed with 1 equivalent of hydroxybutenolide 9 in the presence of 1.25 equivalents of 2 N KOH in isopropanol at -30°C for 1 to 1.5 h. The product (91.5% total yield) consisted of 75.9% of 2-cis-4-cis-vitamin A acid (10) and 16.7% of isotretinoin (1). Without separation, the mixture of 10 and 1 was subjected to palladium-catalyzed isomerization conditions the mixture was heated at 50°C for 1 h in acetonitrile in the presence of 0.10 mol% of palladium(n) nitrate, four equivalents (based on palladium nitrate) of triphenylphosphine and 2... 

Smith 63> has recently reported a new mechanism for the initiation by quaternary phosphonium salts. This mechanism assumes interaction of the acidic hydrogen atom of the alkyl group of phosphonium salts with epoxy oxygen as a nucleophile ... 

Despite the early use of phosphonium salt melts as reaction media [12, 18, 25], the use of standard ionic liquids of type 1 and 2 as solvents for homogeneous transition metal catalysts was described for the first time in the case of chloroaluminate melts for the Ni-catalyzed dimerization of propene [5] and for the titanium-catalyzed polymerization of ethylene [6]. These inherently Lewis-acidic systems were also used for Friedel-Crafts chemistry with no added catalyst in homogeneous [7] as well as heterogeneous fashion [8], but ionic liquids which exhibit an enhanced stability toward hydrolysis, i. e., most non-chloroaluminate systems, have been shown to be of advantage in handling and for many homogeneously catalyzed reactions [la]. The Friedel-Crafts alkylation is possible in the latter media if Sc(OTf)3 is added as the catalyst [9]. 

In a variation, high yields of phosphonium salts (77%) have been claimed to be obtained from the reaction of white phosphorus and benzyl halides, XC Y nClA2 with the aid of metal or metal salt (CuCl) catalysis The reaction may also be carried out in a high boiling solvent. Here dialkylation prevails and tlie phosphinic acid (PhCH2)2P(O)OH is isolated after hydrolysis... 

Scheme 4.2 Acid catalysed hydrolysis of phosphonium salts...

The formation of guanidino side products is not critical for the stepwise solid-phase synthesis of standard peptides, in which a preactivation of reactive amino acids is conducted. However, if activation in situ is carried out or activation of hindered amino acids, protected peptides, or a carboxylic moiety before a cycli-zation step is performed, the use of phosphonium salts may be more efficient. For slow activation reactions, the addition of more coupling reagent (e.g., PyAOP) during the course of the reaction is advisable because the coupling derivative is hydrolyzed after a few minutes. 

We and others have found that CH2CI2 is an excellent solvent for acidic dihydrogen and dihydride compounds. Methylene chloride has a low dielectric constant so that monocationic complexes will usually form 1 1 ion pairs below 0.01 M and higher aggregates above this concentration. Several pK/ of metal hydride complexes in CH2CI2 anchored to the pKa fl of phosphonium salts or other acids have been reported (e.g. see Table 1.2 from our work) they fall in the range from about -5 to 12 [23,30,49-52]. These are actually ion-pair pK values because they have not been corrected for the effects of ion-pairing. 

The Homer-Wadsworth-Emmons reaction is also a useful option for producing olefins in the solid phase. Supported stabilized phosphonoactates, as they are more acidic than phosphonium salts, can readily give the corresponding ylides with weak bases such as DBU, DIPEA, EtaN. One still has to make sure that these reaction conditions are chemoselective. Both types of reactions, Wittig and Homer-Wadsworth-Emmons, have been successfully used in cyclative and/or functionalizing cleavage. 

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