Thermodynamic acidities

Hthiated 4-substituted-2-methylthia2oles (171) at -78 C (Scheme 80). Crossover experiments at—78 and 25°C using thiazoles bearing different substituents (R = Me, Ph) proved that at low temperature the lithioderivatives (172 and 173) do not exchange H/Li and that the product ratios (175/176) observed are the result of independent metala-tion of the 2-methyl and the C-5 positions in a kinetically controlled process (444). At elevated temperatures the thermodynamic acidities prevail and the resonance stabilized benzyl-type anion (Scheme 81) becomes more abundant, so that in fine the kinetic lithio derivative is 173, whereas the thermodynamic derivative is 172. 

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... 

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. 

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. 

Predict the order of increasing thermodynamic acidity in each series of compounds ... 

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. 

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. 

The kinetic and thermodynamic properties of Fischer-type carbene complexes have also been addressed by Bernasconi, who relates the strength of the 7r-donor substituent to the thermodynamic acidity [95-101] and the kinetics and mechanism of hydrolysis and reversible cyclization to differences in the ligand X [96,102]. 

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. 

Fig. 17 Comparison of the electron acceptor properties of JV-nitropyridinium cations (XPyNO ) as measured by their E% values in relationship to the thermodynamic acidities of the corresponding hydropyridinium cations (XPyH+) as evaluated by their pXa values. Reproduced with permission from Ref. 235a.

While thermodynamically, the direct metalation of cyclopropane can be envisioned from a synthetic point of view, this approach has been rarely used. A major obstacle appears to be kinetics which can be overcome by incorporation of a hydroxyl group (see Eq. 16)17). In special cases, such as bicyclo [1.1.0] butane and methylenecyclopropane (Eq. 17) 18) the enhanced thermodynamic acidity is aceom-... 

Now the interesting question arose of whether the intermediate analogous to 215 but devoid of the methyl groups, that is, 3d2-l H-naphthalene (221), would also be interceptable, because 221 should show a high thermodynamic acidity owing to its conversion into the 2-naphthyl anion (224) on deprotonation and because of the use of the strong base KOtBu for the liberation of 221 from 3-bromo-l, 2-dihydro-naphthalene (220) (Scheme 6.52). In the event, the major product was indeed naphthalene. However, there were further products, namely the enol ether 223 and small quantities of 2,2 -binaphthyl (228) as well as 1,2-dihydronaphthalene (226). The overall yield amounted to 92% [137]. 

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... 

Directions for Future Work. The measurement of rates of proton transfer from a single acid to more bases differing only in thermodynamic base strength should allow the construction of BrjSnsted plots of kinetic versus thermodynamic acidity. The bases we have used at this early stage of development of the subject have involved different proton acceptor atoms and cannot be so used (although comparison of the Et N transfer rates of... 

The reactions discussed in the following sections take place in aprotic solvents, and reference to known or estimated thermodynamic basicities will relate to DM SO unless otherwise noted, since DM SO is the polar aprotic solvent in which most thermodynamic acidities have been measured [55-58]. Values of pK determined in DM SO can usually be assumed to parallel values in DMF [59, 60], MeCN, and other polar aprotic solvents whereas pK values (and relative pK values) related to water and other hydroxylic solvents can be very different. 

In acetonitrile (AN), the toluene cation-radical has high thermodynamic acidity, its pK is between -9 and -13 (Nicholas and Arnold 1982). In the same solvent (AN), neutral toluene has... 

If tautomerism occurs in dilute aqueous acid, then K and K l will be the thermodynamic acid ionization constants and (26) will hold thus... 

Benzylic compounds have—compared to the corresponding methyl derivatives—a higher thermodynamic acidity by 10 to 15 pATa units . Mesomeric stabilization requires a considerable flattening of the carbanionic centre towards sp hybridization (the sum of bond angles is 360° for sp and 328° for sp ). However, we should be aware that even if the carbanionic framework would be completely planar, the ion pair 209 is a planar-chiral species. For epimerization, the cation has to migrate from one face to the other one (equation 48). Due to a more facile flipping of the carbanionic centre and an easier formation of solvent-separated ion pairs, most of chiral benzyUithium compounds 208/ewi-208 racemize with great ease. 

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 formation of solely a-metallated species in benzocyclobutene after equilibration suggests an increased thermodynamic acidity at the a position. See Finnegan, R. A. J. Org. Chem. 1965, 30, 1333, and references therein. 

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. 

The regioselective DoM effects can be rationalized in terms of kinetic and thermodynamic control of the reaction (83T2009). The relative thermodynamic acidity (NaNH2/NH3/-25°C) of pyridine hydrogens... 

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