Rates of deprotonation

Kinetic enolate- deprotonation of the most accessable proton (relative rates of deprotonation). Reaction done under essentially irreversible conditions. 

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. 

The kinetic method of determining relative acidity suffers from one serious complication, however. This complication has to do with the fate of the ion pair that is formed immediately on removal of the proton. If the ion pair separates and difiuses into the solution rapidly, so that each deprotonation results in exchange, the exchange rate is an accurate measure of the rate of deprotonation. Under many conditions of solvent and base, however, an ion pair may return to reactants at a rate exceeding protonation of the carbanion by the solvent. This phenomenon is called internal return ... 

The pK values determined are influenced by the solvent and other conditions of the measurement. The nature of the solvent in which the extent or rate of deprotonation is determined has a significant effect on the apparent acidity of the hydrocarbon. In general. 

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 ... 

Another technique is to measure the rate of halogenation of the carbonyl compound. Ketones and aldehydes in their carbonyl forms do not react rapidly with the halogens, but the enolate is rapidly attacked. The rate of halogenation is therefore a measure of the rate of deprotonation. 

Structural effects on the rates of deprotonation of ketones have also been studied using veiy strong bases under conditions where complete conversion to the enolate occurs. In solvents such as THF or DME, bases such as lithium di-/-propylamide (LDA) and potassium hexamethyldisilylamide (KHMDS) give solutions of the enolates in relative proportions that reflect the relative rates of removal of the different protons in the carbonyl compound (kinetic control). The least hindered proton is removed most rapidly under these... 

The pA of 1,3-dithiane is 36.5 (Cs" ion pair in THF). The value for 2-phenyl-1,3-dithiane is 30.5. There are several factors which can contribute to the anion-stabilizing effect of sulfur substituents. Bond dipole effects contribute but carmot be the dominant factor because oxygen substituents do not have a comparable stabilizing effect. Polarizability of sulfur can also stabilize the carbanion. Delocalization can be described as involving 3d orbitals on sulfur or hyperconjugation with the a orbital of the C—S bond. MO calculations favor the latter interpretation. An experimental study of the rates of deprotonation of phenylthionitromethane indicates that sulfur polarizability is a major factor. Whatever the structural basis is, there is no question that thio substituents enhance... 

Very significant acceleration in the rate of deprotonation of 2-methylcyclohexanone was observed when triethylamine was included in enolate-forming reactions in toluene. The rate enhancement is attributed to a TS containing LiHMDS dimer and triethylamine. Steric effects in the amine are crucial in selective stabilization of the TS and the extent of acceleration that is observed.18... 

If the amine carries a chelating substituent, as for 2-methoxyethylamine, the rate of deprotonation is accelerated. For any specific imine, ring substituents also influence the imine conformation and rate of deprotonation. These relationships reflect steric, stereoelectronic, and chelation influences, and sorting out each contribution can be challenging. 

Chelating ligands for magnesium were expected to influence the relative rate of deprotonation and addition [19], TMEDA gave a modest improvement in the reaction affording a 92 8 ratio of 3 61 under the best conditions. N,N -Dimethylimidazolidinone was not as effective in suppressing the formation of 61. No reaction was observed in DME, even on heating to 50°C. 

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. 

TABLE 12. Relative rates of deprotonation at 50 °C in cyclohexy-lamine, dihedral angle (C=C—C—H) as determined from force field calculations, and deduced equilibrium pAT sCHA values for several carbon acids0... 

The rates of silylation of AN with BSA (Chart 3.2) were estimated by the competitive reaction method (204). These rates change in parallel with the rates of deprotonation of these AN, determined by treatment with NaOH in aqueous methanol (213). 

Product 34 predominates in the polar aprotic solvent (acetonitrile), while in the polar protic solvent (methanol) products 35 are formed preferentially. The different products are caused by the relative rate of deprotonation against desilylation of the aminium radical, that is in turn governed by the action of enone anion radical in acetonitrile as opposed to that of nucleophilic attack by methanol. In an aprotic, less silophilic solvent (acetonitrile), where the enone anion radical should be a strong base, the proton transfer is favoured and leads to the formation of product 34. In aprotic solvents or when a lithium cation is present, the enone anion radical basicity is reduced by hydrogen bonding or coordination by lithium cation, and the major product is the desilylated 35 (Scheme 4). 

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... 

Rates of deprotonation of a simple ketone (89) by lithium diisopropylamide (LDA) in THF at -78 °C show a first-order dependence on ketone, and an order of 0.58 ( 0.06) in base. Alternative pathways involving the LDA monomer and its solvent-complexed dimer (90) are considered. 

Results of a theoretical study of 1,3-prototropic rearrangement of 1-methylindene, catalysed by ammonia and MesN in water and in cyclohexane, have confirmed earlier predictions that the proton moves freely over the indene ring once it has been abstracted by the base. The relative rates of deprotonation, ion-pair collapse and ion-pair rearrangement have been estimated and discussed in each case. 

It is found that quaternary salts of 1,3-azoles are deprotonated at C-2 in the same way. Rates of deprotonation are considerably faster because of the influence of the quaternary centre that provides a favourable inductive effect. The conjugate base bearing opposite charges on adjacent atoms is termed an... 

The simplest case in which the relative rates of deprotonation determine the enantiomeric ratio of product is only given when the intermediate carbanionic species are... 

Bertini-Gross and Beak demonstrated in a broad study that conformationally restricted bicyclic carbamates undergo rapid diastereoselective deprotonation with s-BuLi/TMEDA". The proton closest to the carbonyl group is preferentially removed. Competition experiments gave information about the relative rates of deprotonation. Scheme 3 summarizes some second-order competitive efficiencies. 

TMEDA is added as a co-solveni to promote the rate of deprotonation of 2-hthiofuran by BuLi. 

In a kinetic study of the acylation of toluene, with p-xylene and the corresponding perdeutero compounds with aroyl triflates, correlation was found between the primary kinetic isotope effect and the ortho para ratio.35 Different conformations of the bent cr complexes36 for the two isomers resulted in a much higher rate of deprotonation and rearomatization for the para isomer. By appropriately selecting reaction conditions and thereby affecting the ratio of the two conformations, unusually high amounts of ortho products may be obtained.37,38... 

These points have been pursued in detail for two reasons. The first is to indicate the level of uncertainty in deriving pATas when the rate of deprotonation falls significantly short of its relaxation limit and the structure-reactivity correlation for the alkene conjugate base of the cation is insufficiently defined. The second is that the identity of the rate constants for 2-propene and 2-butene still imply a difference of 0.3 log units between 2-propyl and 2-butyl cations. In so far as this difference corresponds with the small difference in geminal interaction of the OH groups, the implication is that as measured by their HIAs the two ions have the same stability (cf. discussion on p. 25). In conclusion, the preferred pATR for the 2-propyl cation is listed below with the more secure values for the /-butyl and ethyl cations. 

NOB studies on nicotine in trifluoroacetic acid, when the rate of deprotonation is slow on the NMR time scale, enable assignment of signals to be made to the diastereoisomeric salts [295] and [296]. The... 

The different biological properties of NO and HNO can be partially explained by the high reduction potential for NO and the slow rate of deprotonation of HNO. However, HNO is a mild reductant (163, 164), and biomolecules such as ferricyt c (170) and SOD (83, 84) are reduced, at least formally, by HNO donors, resulting in formation of free NO. The relevance of these and other reactions that have been observed with purified biomolecules to the complex, heterogeneous environments of cells and tissue can be determined by elucidation of the chemical biology of HNO. This process includes identification of potential reactions, mechanistic determinations, and systematic comparisons of relative reaction rates, particularly for modification of biological targets in relation to consumption pathways. 

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