And thermodynamic acidity

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 following table gives exchange rates in methanolic sodium methoxide for a number of hydrocarbons and equilibrium acidities for some. Determine whether there is a correlation between kinetic and thermodynamic acidity in this series of compounds. If so, predict the thermodynamic acidity of the hydrocarbons for which no values are listed. 

Related to the pyridine studies are the results of base-catalyzed hydrogen exchange in cyclobutabenzene derivatives, which suggest that cyclobutyl annelation increases both the kinetic and thermodynamic acidity at the a-position. The most significant study is the thermodynamic deprotonation/carboxylation reaction of cyclobutabenzene with amyl sodium/COj, in which only the a-carboxy isomer is formed (Figure 6). This is consistent with the value for the a-proton being several p units lower than that for the P-proton in cyclobutabenzene (38). 

The deprotonation of 5,6-dihydro-3-tnethyl-4//-l,2-oxazine with lithium dialkylamides or butyl-lithium as base proceeds with high regioselectivity at the 4-methylene protons due to the greater kinetic and thermodynamic acidity of these protons relative to the exocyclic methyl protons3. 

If a carbanion is thermodynamically accessible, but is subject to rapid quenching by internal return of C02 in the case of decarboxylation, or by a proton in carboxylation, or in a hydrogen/deuterium exchange reaction, then the carbanionic intermediate off the enzyme would give the appearance of greater basicity than its thermodynamic value would predict. The localized character of the carbanion at the 6-position of UMP requires that the proton that is removed by a base in solution initially remains closely associated, and therefore, to a great extent be transferred to the carbanion. This reduces the rate of exchange and creates a discrepancy between kinetic and thermodynamic acidities. 

Enolization of cationic ketones is accelerated by electrostatic stabilization of the enolate anion. Rate constants for water-, acetate-, and hydroxide ion-catalysed enolization of 2-acetyl- 1-methylpyridinium ion (94) have been measured13811 and compared with a 2-acetylthiazolium ion (95), a simple analogue of 2-acetylthiamine pyrophosphate.13811 For (94), qh = 1.9 x 102 M-1 s 1, about 1.1 x 106 times that for a typical methyl ketone such as acetone. Thermodynamically, it is >108 times more acidic (pAa values of 11.1 vs 19.3). These increases in kinetic and thermodynamic acidity are derived from through-bond and through-space effects, and the implications for enzymatic catalytic sites with proximal, protonatable nitrogen are discussed. The results for (94) suggest a pAa value of 8.8 for (95), a value that cannot be measured directly due to competing hydrolysis. 

The reader is reminded that other methods for measurement of p/fa values of weak acids exist, notably Streitwieser s method using cesium (lithium) cyclohexylamide in cyclohexylamine, which has been used to measure both kinetic and thermodynamic acidities (Streitwieser and Hammons, 1965 Szwarc et al., 1974). 

There are two additional features of the hydrocarbon, cyclopropene, which have not been considered and which may contribute to its reduced kinetic and thermodynamic acidity. First of all, the reversed sign (polarity) of the dipole moment of cyclopropene compared to other alkenes, including cyclobutene, and its larger than usual magnitude (0.455 D) , is indicative of significant electron shift from the double bond to the methylene group . This has been shown to be a result of electron transfer from the n c-orbital to the <7 component orbital . Related to this polarity reversal is the observation... 

As a consequence of the limitations just mentioned, attempts to characterize the kinetic basicity of preparatively used EGBs by determination of proton-transfer rates have mainly been done on the first-mentioned group of radical anions, particularly radical anions derived from azobenzenes, and the group of dianions derived from activated alkenes. At the same time, these type of measurements have been used to compare kinetic and thermodynamic acidities of weak organic acids. 

Scheme 3 Relative kinetic and thermodynamic acidity of sulfides and selenides...

Part V is devoted to the study of H transfers in organic and organometallic reactions and systems. In Ch. 18 Koch describes kinetic studies of proton abstraction from CH groups by methoxide anion, of the reverse proton transfer from methanol to hydrogen bonded carbanion intermediates, and of proton transfer associated with methoxide promoted dehydrohalogenation reactions. Substitutent effects, kinetic isotope effects and ah initio calculations are treated. Of great importance is the extent of charge delocalization in the carbanions formed which determine the kinetic and thermodynamic acidities. 

Substitution of CO by phosphines 145 The Dotz reaction 149 Rearrangement reactions with loss of CO 151 Photochemical reactions 153 Reactions at the carbene carbon 158 General features 158 Amine nucleophiles 159 Phospine and phosphite nucleophiles 167 Alcohols and alkoxide ion nucleophiles 171 Thiol and thiolate ion nucleophiles 179 Intramolecular nucleophilic reactions 191 Hydroxide ion and water as nucleophiles 194 Insertion reactions initiated by nucleophilic attack Acid-base reactions at the a-carbon 207 General features and methods 207 Kinetic and thermodynamic acidities 209 Effect of structure on pKa values 210 Intrinsic rate constants for proton transfer 219 Thermodynamic acidities in organic solvents 223 Hydrolysis of ionizable carbene complexes 228 Acknowledgments 232 References 233... 

The following table gives exchange rates in methanolic NaOCHj and pA values for some hydrocarbons. Determine if there is a correlation between the kinetic and thermodynamic acidity. 

In some solvents, such as K+- OR-DMSO, it can be shown that the internal return equilibrium characterized by k /k is fast relative to the dissociation process characterized by k2- In this process, the base returns the proton to the carbanion faster than the proton donor exchanges with other molecules from solution. If internal return is important under a given set of conditions, how might that affect the correlation between observed kinetic and thermodynamic acidity How can the occurrence of internal return be detected experimentally ... 

Br0nsted plots were used to evaluate the relationship of kinetic and thermodynamic acidities of metal carbonyl hydrides.Proton transfer reactions to anilines in acetonitrile were used to generate the rate and equilibrium data. Br0nsted... 

The effect of alkyl groups on the kinetic and thermodynamic acidity of nitroal-kanes shows opposing trends. Although alkyl groups retard proton abstraction, they stabilize the nitronate anion. These opposing trends can be traced to the fact that... 

In a-phenylthio-ketones the phenylthio-group enhances both the kinetic and thermodynamic acidity of the proton on the sulphur-bearing carbon. The position of equilibrium in equation (1) was determined by trapping with trimethylsilyl chloride and subsequent analysis under conditions in which the rate of silylation exceeded... 

Afefa-methoxy phenyloxazoline and secondary and tertiary benzamides 10 are deprotonated at the C2 position by -BuLi and s-BuLi/TMEDA [107,108], whereas metalation occurs exclusively ortho to the methoxy with a-ethoxyvinyllithium/HMPA [109]. These observations indicate that the directing effect of the DMGs result from both kinetic (coordination) and thermodynamic (acidity) factors. 

The observation of the unusual inverse order of kinetic and thermodynamic acidities of the simple nitroalkanes (nitromethane = NM, nitroethane = NE, and 2-nitropropane = 2-NP) during their reactions... 

The racemization at the a-carbon of acyclic compounds in most of the cases occurs through a base-catalyzed enolization, where an achiral enolate is formed as an intermediate. Consequently, it is of great importance to study and understand both the kinetic and thermodynamic acidity of the a-proton under reasonable reaction conditions. 

---