Deprotonation of carbon acids

Deprotonation of carbon acids by Oz in the presence of O2 (i.e. when 02 is formed in situ by bubbling O2 through the catholyte) can lead to oxidative conversion of the carbon acid by reaction between the deprotonated substrate and the excess O2 [107,121-123], in some cases by consumption of less than stoichiometric... 

Table 1 alicyclic Representative intrinsic rate constants (kQ) and intrinsic barriers ( AGj) for the deprotonation of carbon acids by secondary amines ... 

One of the consequences of the imbalanced nature of the transition state is that the polar effect of a remote substituent may either increase or decrease the intrinsic barrier whether there is an increase or decrease depends on the location of the substituent with respect to the site of charge development. Let us consider a reaction of the type shown in Equation (4). In this situation an electron-withdrawing substituent Z will decrease AG or increase ka. This is because there is a disproportionately strong stabilization of the transition state compared to that of the product anion due to the closer proximity of Z to the charge at the transition state than in the anion. As discussed earlier, this also leads to an exalted BrlAnsted aCH value and is the reason why aCH > Pb for the deprotonation of carbon acids such as 11-13 and others (Table 2). 

The three-step procedure described here illustrates a convenient, general route to di-tert-alkylamines. Extensive purification or Isolation of intermediates is not required. The reactions are easily monitored. Only in the final step is the exclusion of air and moisture necessary. It should be noted that tert-butyl-tert-octylamine is considerably more hindered than 2,2,6,6-tetramethylpiperidine. tert-Butyl-tert-octylamine is inert to methyl iodide, while 2,2,6,6-tetramethylpiperidine gives a white precipitate of the pentamethylammonium iodide within minutes upon treatment with methyl iodide at room temperature. The extreme hindrance of this amine has been exploited in the selective deprotonation of carbon acids and in other reactions.10... 

The equilibrium constant for deprotonation of carbon acids is equal to the ratio of the rate constants for formation and reaction of the product carbanion (Scheme I.IA-C). In recent years, kinetic methods have been used to provide solid values of the pKaS for ionization of a wide range of weak carbon acids. These experiments are, in principle, straightforward and require only the determination or estimate of two rate constants - one for the slow and thermodynamically unfavorable generation of the carbanion, and a second for fast downhill carbanion protonation. 

The barrier to thermodynamically unfavorable deprotonation of carbon acids (AGfl, Fig. 1.1) in water is equal to the sum of the thermodynamic barrier to proton transfer (AG°) and the barrier to downhill protonation of the carbanion in the reverse direction (AGr Eq. (1.2)). The observation of significant activation barriers AGr for strongly thermodynamically favorable protonation or resonance stabilized carbanions shows that there is some intrinsic difficulty to proton transfer. The Marcus equation defines this difficulty with greater rigor as the intrinsic barrier A, which is the activation barrier for a related but often hypothetical thermoneutral proton transfer reaction (Fig. 1.2B) [46]. 

The Marcus intrinsic barriers for deprotonation of carbon acids to form enolates that are stabilized by resonance delocalization of negative charge from carbon to oxygen are larger than for deprotonation of carbon acids to form carbanions where the charge is localized mainly at carbon. 

As bases. Formation of magnesium enolates from a-chloro-a-arenesulfinylcar-boxylic acid derivatives involves desulfinylation with a Grignard reagent. f-Butyl Grignard reagents are preferred in certain circumstances for the deprotonation of carbon acids. This method has been applied to a synthesis of chiral jS-hydroxy esters from arenesulfinylacetic esters. ... 

In the discussion of the relative acidity of carboxylic acids in Chapter 1, the thermodynamic acidity, expressed as the acid dissociation constant, was taken as the measure of acidity. It is straightforward to determine dissociation constants of such adds in aqueous solution by measurement of the titration curve with a pH-sensitive electrode (pH meter). Determination of the acidity of carbon acids is more difficult. Because most are very weak acids, very strong bases are required to cause deprotonation. Water and alcohols are far more acidic than most hydrocarbons and are unsuitable solvents for generation of hydrocarbon anions. Any strong base will deprotonate the solvent rather than the hydrocarbon. For synthetic purposes, aprotic solvents such as ether, tetrahydrofuran (THF), and dimethoxyethane (DME) are used, but for equilibrium measurements solvents that promote dissociation of ion pairs and ion clusters are preferred. Weakly acidic solvents such as DMSO and cyclohexylamine are used in the preparation of strongly basic carbanions. The high polarity and cation-solvating ability of DMSO facilitate dissociation... 

Deprotonation of the acidic a carbon of the amino acid gives an intermediate a-keto add imine. .. 

Scheme 28 Oxidative conversion of carbon acids initiated by deprotonation by superoxide.

Nucleophilic addition of the metal-stabilized pyrrolium complexes is readily achieved with borohydride and cyanide ion. The scope of this reactivity is bracketed by the diminished electrophilicity of the iminium carbons and the acidity of the ammine ligands, which prevents the use of strongly basic nucleophiles. Competing deprotonation of the acidic pyrrolium ring protons is observed primarily only with 3//-pyrrolium complexes or when bulky nucleophiles are used. 

The basicity of LDA is so high that it is even possible to generate bisenolates from /3-diketones and /3-ketoesters (Figure 10.7). Even carboxylates can be deprotonated at the a carbon if the strongest organic bases are employed (Figure 10.8). In contrast, the twofold deprotonation of phenylacetic acid by ethylmagnesium bromide is not com-... 

When HX is a carbon acid the value of the rate coefficient, ) for a thermodynamically favourable proton transfer rarely approaches the diffusion limit. Table 1 shows the results obtained for a few selected carbon acids which are fairly representative of the different classes of carbon acids which will be discussed in detail in Sect. 4. For compounds 1—10, the value of k i is calculated from the measured value of k, and the measured acid dissociation constant and, for 13, k, is the measured rate coefficient and k1 is calculated from the dissociation constant. For 11 and 12, both rate coefficients contribute to the observed rate of reaction since an approach to equilibrium is observed. Individual values are obtained using the measured equilibrium constant. In Table 1, for compounds 1—10 the reverse reaction is between hydronium ion and a carbanion whereas for 11, 12 and 13 protonation of unsaturated carbon to give a carbonium ion is involved. For compounds 1—12 the reverse reaction is thermodynamically favourable and for 13 the forward reaction is the favourable direction. The rate coefficients for these thermodynamically favourable proton transfers vary over a wide range for the different acids. In the ionization of ketones and esters, for which a large number of measurements have been made [38], the observed values of fe, fall mostly within the range 10s—101 0 1 mole-1 sec-1. The rate coefficients observed for recombination of the anions derived from nitroparaffins with hydronium ion are several orders of magnitude below the diffusion limit [38], as are the rates of protonation and deprotonation of substituted azulenes [14]. For disulphones [65], however, the recombination rates of the carbanions with hydronium ion are close to 1010 1 mole-1 sec-1. Thermodynamically favourable deprotonation by water of substituted benzenonium ions with pK values in the range —5 to —9 are slow reactions [27(c)], with rate coefficients between 15 and 150 1 mole-1 sec-1 (see Sect. 4.7). 

Carbon acids can serve as good examples for the principles of acidity. Often organic reactions in basic media start with deprotonation of an acidic C-H, so we will need to... 

Efficient catalysis of deprotonation of strongly acidic carbon that undergoes rela-... 

It has been proposed that part or all of the intrinsic barrier for deprotonation of a-carbonyl carbon is associated with the requirement for solvation of the negatively charged oxygen of the enolate anion [80]. However, the observation of small intrinsic barriers for deprotonation of oxygen acids by electronegative bases to form solvated anions [31] suggests that the requirement for a similar solvation of enolate anions should not make a large contribution to the intrinsic barrier for deprotonation of a-carbonyl carbon. 

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