Acidities kinetic

Hydrogen kinetic acidity ol thiazolium ions and thiazole has received much attention since Breslow (419,420) and Ingraham and Westheimer... 

The electronic influence of the 4-substituent corresponds to a relative increase in the kinetic acidity of the C-5 proton when an electron-withdrawing group (R=Ph) is situated at the 4-position and to a relative increase in the kinetic acidity of the 2-methyl group when an electron-donating group (R = Me) is at the same position (Table 1-59). 

In the El cb mechanism, the direction of elimination is governed by the kinetic acidity of the individual p protons, which, in turn, is determined by the polar and resonance effects of nearby substituents and by the degree of steric hindrance to approach of base to the proton. Alkyl substituents will tend to retard proton abstraction both electronically and sterically. Preferential proton abstraction from less substituted positions leads to the formation of the less substituted alkene. This regiochemistry is opposite to that of the El reaction. 

It has been found that there is often a correlation between the rate of deprotonation (kinetic acidity) and the thermodynamic stability of the carbanion (thermodynamic acidity). Because of this relationship, kinetic measurements can be used to construct orders of hydrocarbon acidities. These kinetic measurements have the advantage of not requiring the presence of a measurable concentration of the carbanion at any time instead, the relative ease of carbanion formation is judged from the rate at which exchange occurs. This method is therefore applicable to very weak acids, for which no suitable base will generate a measurable carbanion concentration. 

There have been numerous studies of the rates of deprotonation of carbonyl compounds. These data are of interest not only because they define the relationship between thermodynamic and kinetic acidity for these compounds, but also because they are necessary for understanding mechanisms of reactions in which enolates are involved as intermediates. Rates of enolate formation can be measured conveniently by following isotopic exchange using either deuterium or tritium ... 

Nitroalkanes show a related relationship between kinetic acidity and thermodynamic acidity. Additional alkyl substituents on nitromethane retard the rate of proton removal although the equilibrium is more favorable for the more highly substituted derivatives. The alkyl groups have a strong stabilizing effect on the nitronate ion, but unfavorable steric effects are dominant at the transition state for proton removal. As a result, kinetic and thermodynamic acidity show opposite responses to alkyl substitution. 

The easiest access to most benzyllithium, -sodium, or -potassium derivatives consists of the deprotonation of the corresponding carbon acids. Hydrocarbons, such as toluene, exhibit a remarkably low kinetic acidity. Excess toluene (without further solvent) is converted into benzyllithium by the action of butyllithium in the presence of complexing diamines such as A. Af.Af.jV -tetramethylethylenediamine (TMEDA) or l,4-diazabicyclo[2.2.2]octane (DABCO) at elevated temperatures1 a procedure is published in reference 2. 

For the deprotonation of less acidic precursors, which do not lead to mesomerically stabilized anions, butyllithium/TMEDA in THF or diethyl ether, or the more reactive, but more expensive,. seobutyllithium under these conditions usually are the most promising bases. Het-eroatomic substitution on the allylic substrate, which docs not contribute to the mesomeric or inductive stabilization often facilitates lithiation dramatically 58. In lithiations, in contrast to most other metalations, the kinetic acidity, caused by complexing heteroatom substituents, may override the thermodynamic acidity, which is estimated from the stabilization of the competing anions. These directed lithiations59 should be performed in the least polar solvent possible, e.g.. diethyl ether, toluene, or even hexane. 

Kresge et a/.498 have drawn attention to the fact that detritiation of [3H]-2,4,6-trihydroxy- and [3H]-2,4,6-trimethoxy-benzenes by concentrated aqueous perchloric acid gives correlations of log rate coefficient with — H0 with slopes of 0.80 and 1.14 respectively. Protonation to give the carbon conjugate acids is, however, governed by h0lA0 and h0l 9S, respectively, which suggests that the difference in kinetic acidity dependence is a property of the substrate and should not be interpreted as a major difference in mechanism. The kinetic difference can be eliminated by an appropriate comparison of kinetic and equilibrium acidity dependencies. In equation (230)... 

A different approach to the problem of hydrocarbon acidity, and hence carbanion stability, is that of Shatenshtein and Shapiro, who treated hydrocarbons with deuterated potassium amide and measured the rates of hydrogen exchange. The experiments did not measure thermodynamic acidity, since rates were measured, not positions of equilibria. They measured kinetic acidity, that is, which compounds... 

Table 8.1 is a thermodynamic acidity scale and applies only to positions of equilibria. For the distinction between thermodynamic and kinetic acidity, see p. 228. 

Finally, in many cases the acidity equilibria cannot be measured but the rate of proton transfer or transmetallation can be measured to give an ionic or ion pair kinetic acidity. Studies using the rates of proton transfer have included the use of isotopes such as tritium and deuterium5,6. The rate is then used to calculate the Brpnsted slope, a, by plotting the logarithm of the proton transfer rate against the pK, as determined by the equilibrium acidity, for a series of compounds. From this plot, the approximate pKa of an unknown compound can be determined by comparison of the same type of compounds. 

Streitwieser and Boerth studied the kinetic acidities of cycloalkenes with lithium cyclo-hexylamide (LiCHA) in cyclohexylamine for comparison with those of benzene and toluene66. The relative rates of deprotonation and the corresponding equilibrium pK values are tabulated in Table 12. These proton transfer transition states are stabilized by conjugation of the reacting C—H bond with the double bond. 

Systematic studies of the thermodynamic and kinetic acidity of metal hydrides in acetonitrile were carried out by Norton et al. [10, 11]. A review of the acidity of metal hydrides presents extensive tabulations of pKa data [12] only a few of the trends will be mentioned here. Metal hydrides span a wide range of pKa values considering only metal carbonyl hydrides shown in Table 7.1, the range exceeds 20 pfCa units. As expected, a substantial decrease in acidity is... 

The reaction presumably involves a cis, syn elimination. As Eq. 34 illustrates, regioselectivity can be controlled by choice of base 49). The higher kinetic acidity of the benzylic position of 20 determines the regioselectivity with a- non-hindered base whereas, steric hindrance directs the base to the methyl group. 

Several methods exist for the synthesis of intricate, commercially unavailable halopyridines. By taking advantage of the different kinetic acidity at each site [C(4) > C(3) > C(2)], Gribble and Saulnier deprotonated 3-halopyridine regioselectively at C(4) and quenched the resulting 4-lithio-3-halopyridine with iodine to give 4-iodo-3-chloropyridine [1],... 

The reaction proceeds via electrogenerated cationic species as its seen with the nonfluorinated amines, carbamates, and amides (Scheme 6.14). However, the regiochemistry of this anodic methoxylation is not governed by the stability of the cationic intermediates B and B (thermodynamic control) since the main products are formed via the less stable intermediates B. Indeed, this remarkable promotion effect and unique regioselectivity can be explained mainly in terms of a-CH kinetic acidities of the cation radicals formed by one-electron oxidation of the amines since the stronger the acidity of the methylene hydrogen, the easier the deprotonation. 

Recent studies of kinetic acidity involving nitrocarbon acids have included the following benzoate ion-promoted deprotonation of (3- or 4-nitrophenyl)nitromethane and (3,5-dinitrophenyl)nitromethane187 the deprotonation by various bases of a series of... 

Substituent effects on the -(aminoethyl)cyclohexenone photochemistry were carried out to study the relative kinetic acidities of the tertiary aminium radical47. The ease of the methylene hydrogen to be removed as H+ increased in the order of X = alkyl < Si(CH3)3 < C=CH (equation 13). 

An understanding of kinetic acidity is necessary in order to distinguish such mechanisms from other ways in which hydrogen may become attached to a substrate, e.g., hydrogen atom transfer, reaction 8, and hydride transfer, reaction 9. 

Table I. Thermodynamic and Kinetic Acidities of Metal Hydrides in Acetonitrile...

The kinetic acidity (rate constant for metal-to-metal proton exchange) also decreases down a column (Cr>Mo W) in the periodic table. This parallels the order of rates we have observed for the dinuclear elimination of methane from... 

Replacement of a hydride ligand by a methyl substituent decreases both the thermodynamic and the kinetic acidity of the remaining hydrogen, while its replacement by an additional Os(CO) H unit increases the thermodynamic acidity but decreases the rate of deprotonation. The same additional delocalization that decreases the pK of 0so(C0)oHo relative to that... 

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