The Kinetics of Deprotonations

For discussion of deprotonations of organic compounds both the rate of deprotonation and the equilibrium acidity must be considered. Equilibrium acidities are expressed by the pFCa value, which is defined as follows for an acid AH  

The degree of dissociation of an acid in water can be easily estimated with the Henderson-Hasselbach equation. When the pH of the solution equals the pKa of an acid, then the acid is 50% dissociated ([AH] = [A ]) for each integer by which the pH differs from the pKa the ratio [A ]/[AH] will increase or decrease by a factor of 10  

Equilibrium acidities are usually determined by titration, either with indicators of known plCa [24] or by following the extent of dissociation spectroscopically (e.g. by UV-spectroscopy [35]). Kinetic acidities, i.e. the rates of deprotonation of acids, can be determined by measuring rates of racemization[36] or rates of H-D or H-T exchange [37, 38], by chemical relaxation experiments (e.g. T-jump method [35, 39]), or by H NMR (line broadening and saturation recovery [40]). 

The rate of deprotonation of an acid by a base depends on their structures [41], on the solvent and temperature, and on the difference (ApKa) between the pKa of the acid and that of the base. When acid and base have the same pfCa (ApKa=0) the change of free energy for proton transfer becomes zero and the reaction becomes thermoneutral. Under these conditions the rate of proton transfer is limited only by the so-called intrinsic barrier [34], which is particularly sensitive to structural changes in the reaction partners [39]. When ApKa increases, the rate of proton transfer also increases and approaches a limiting value, which depends on the structures of the acid and base and on the experimental conditions. For normal acids (O-H, N-H) in water the rate of proton transfer becomes diffusion-controlled (ka=10loL mol-1 s 1) when ApKa 2, but in aprotic solvents the limiting proton transfer rate can be substantially lower [42]. 

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Knowing the equilibrium constants for the protonation of the amino and imidazole nitrogens, and the kinetics of deprotonation of the C(2) carbon of imidazole, it was possible to investigate nitrogen-protonation microequilibria and the C(2)-deprotonation microkinetics of histidine, histamine and other related compounds164. 

In the course of pulse radiolysis studies of purine and pyrimidine bases, Fielden et al. (1970) and Greenstock et al. (1973b) have been able to follow the kinetics of deprotonation of these compounds by OH- produced in the irradiated aqueous solution. The observation is made possible by the difference in ultraviolet absorption between the neutral and basic forms. The rate constants for deprotonation were found to be (1-2) x 101 0 M s-1 and those for the protonation of the anion by H+, 4 x 1010 M I s-1. 

The kinetics of deprotonation leading to the enamine had been investigated by several groups using isotope exchange kinetics24-27, as well as triiodide trapping of the... 

Figure 9.27. Kinetics of Water Deprotonation. The kinetics of deprotonation and protonation of the zinc-bound water molecule in carbonic anhydrase.

Benzothiazoles.— The kinetics of deprotonation at the C-methyl group in the benzothiazolium salt (590 X = and in the benzoselenazolium (590 ... 

Chapters 1 and 2. Most C—H bonds are very weakly acidic and have no tendency to ionize spontaneously to form carbanions. Reactions that involve carbanion intermediates are therefore usually carried out in the presence of a base which can generate the reactive carbanion intermediate. Base-catalyzed condensation reactions of carbonyl compounds provide many examples of this type of reaction. The reaction between acetophenone and benzaldehyde, which was considered in Section 4.2, for example, requires a basic catalyst to proceed, and the kinetics of the reaction show that the rate is proportional to the catalyst concentration. This is because the neutral acetophenone molecule is not nucleophihc and does not react with benzaldehyde. The much more nucleophilic enolate (carbanion) formed by deprotonation is the reactive nucleophile. 

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 ... 

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 ... 

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 effect of HMPA on the reactivity of cyclopentanone enolate has been examined.44 This enolate is primarily a dimer, even in the presence of excess HMPA, but the reactivity increases by a factor of 7500 for a tenfold excess of HMPA at -50° C. The kinetics of the reaction with CH3I are consistent with the dimer being the active nucleophile. It should be kept in mind that the reactivity of regio- and stereoisomeric enolates may be different and the alkylation product ratio may not reflect the enolate composition. This issue was studied with 2-heptanone.45 Although kinetic deprotonation in THF favors the 1-enolate, a nearly equal mixture of C(l) and C(3) alkylation was observed. The inclusion of HMPA improved the C(l) selectivity to 11 1 and also markedly accelerated the rate of the reaction. These results are presumably due to increased reactivity and less competition from enolate isomerization in the presence of HMPA. 

Some of the details of the mechanism may differ for various catalytic systems. There have been kinetic studies on two of the amination systems discussed here. The results of a study of the kinetics of amination of bromobenzene using Pd2(dba)3, BINAP, and sodium r-amyloxide in toluene were consistent with the oxidative addition occurring after addition of the amine at Pd. The reductive elimination is associated with deprotonation of the animated palladium complex.166... 

Acetylene is sufficiently acidic to allow application of the gas-phase proton transfer equilibrium method described in equation l7. For ethylene, the equilibrium constant was determined from the kinetics of reaction in both directions with NH2-8. Since the acidity of ammonia is known accurately, that of ethylene can be determined. This method actually gives A f/ acid at the temperature of the measurement. Use of known entropies allows the calculation of A//ac d from AG = AH — TAS. The value of A//acij found for ethylene is 409.4 0.6 kcal mol 1. But hydrocarbons in general, and ethylene in particular, are so weakly acidic that such equilibria are generally not observable. From net proton transfers that are observed it is possible sometimes to put limits on the acidity range. Thus, ethylene is not deprotonated by hydroxide ion whereas allene and propene are9 consequently, ethylene is less acidic than water and allene and propene (undoubtedly the allylic proton) are more acidic. Unfortunately, the acidity of no other alkene is known as precisely as that of ethylene. 

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... 

Ni(II) by strong oxidants, such as OH, Br and (SCN), produced by pulse radiolysis and flash photolysis. Rate constants are 10 M" s for oxidation by OH and Brf and = 10 M s for (SCN)f Ref. 259. The most popular means of production in both aqueous and nonaqueous solution is electrolytic, jjjg ligands which stabilize Ni(III) are cyanide, deprotonated peptides, amines and aminocarboxylates, a-diimines and tetraaza macrocycles, including porphyrins. Low spin d Ni(III) resembles low spin Co(II). The kinetics of the following types of reactions have been studied ... 

A kinetic smdy of the formation of zwitterionic adducts (28) from 1,3,5-trinitrobenzene and diazabicyclo derivatives indicates that reactions are surprisingly slow, with rate constants many orders of magnitude lower than those for related reactions with primary or secondary amines. The use of rapid-scan spectrophotometry was necessary to study the kinetics of reaction of 4-substimted-2,6-dinitro-A -n-butylanilines (29) with n-butylamine in DMSO the two processes observed were identified as rapid deprotonation to give the conjugate base and competitive a-adduct formation at the 3-position. The reactions of MAf-di-n-propyl-2,6-dinitro-4-trifluoromethylaniline (30), the herbicide trifluralin, and its A -ethyl-A -n-butyl analogue with deuteroxide ions and with sulfite ions in [ H6]DMS0-D20 have been investigated by H NMR spectroscopy. With deuteroxide a-adduct formation at the 3-position is followed by... 

It has usually been assumed that the lithiation step involves loss of TMEDA and reformation of a BuLi-anisole complex prior to the deprotonation itself. However, the kinetics of the deprotonation step are inconsistent with this proposition both TMEDA molecules remain part of the complex during the deprotonation, which may therefore involve no 0-Li coordination and be directed purely by the acidifying effect on nearby protons of the a-electron-withdrawing MeO substituent. ... 

In 1991, Kessar and coworkers demonstrated that the kinetic barrier could be lowered by complexing the tertiary amine with BF3, snch that i-BuLi is able to deprotonate the ammoninm compound, which can be added to aldehydes and ketones as shown by the example in Scheme 4a. Note the selectivity of deprotonation over vinyl and allyl sites. A limitation of this methodology is that the ylide intermediate does not react well with alkyl hahde electrophiles. To get aronnd this, a seqnence that begins with the stannylation and decomplexation shown in Scheme 4b was developed. The stannane can be isolated in 94% yield (Scheme 4b) and snbseqnently snbjected to tin-lithium exchange to afford an unstabilized lithiomethylpiperidine that is a very good nucleophile. However, isolation of the stannane is not necessary and a procedure was devised in which the amine is activated with BF3, deprotonated, stannylated, decomplexed from BF3 with CsF, transmetalated back to lithium and alkylated, all in one pot (Scheme 4c). ... 

A number of points should be considered to determine the most appropriate experimental conditions for the desired reaction and, to that end, the kinetics of hydrolysis and ionization of 4-methyl-2-phenyl-, 4-benzyl-2-phenyl-, and 4-benzyl-2-methyl-5(4//)-oxazolones have been investigated. Deprotonation of 5(477)-oxazolones in aqueous media, which leads to racemization of optically active 5(477)-oxazolones, is a fast process that competes with the ring opening. The difference between the rate constant for racemization and the ring opening is greater in solvents with dielectric constants less than water and thus, oxazolones racemize faster than they hydrolyze. 

McClelland and co-workers identified the initial adduct detected in laser flash photolysis experiments involving the reaction of 75g with d-G as 111 (Ar = 2-fluorenyl, Y = H, R = 2 -deoxyribose)." This identification was based on the absorption spectrum of the intermediate, which extends out to 400 nm suggesting a highly conjugated species, by the observed pXa of 3.9 of the intermediate, which is consistent with deprotonation of 111 to form 112, by the lack of dependence of the rate constant for decomposition of the intermediate on the nature of Ar for the intermediates derived from 75g, 75n, 75p, and 75q, and by the kinetics of the decomposition of the intermediate into the stable C-8 adduct 102, which includes a pH-rate profile that showed both ionization states were reactive, buffer catalysis of decomposition of the... 

The remarkable solvent isotope effect on the kinetics of oxidation of guanine by 2AP radicals has been detected in H2O and D2O solutions [14]. In H2O, the rate constants of G(-H) formation are larger than those in D2O by a factor of 1.5-2.0 (Table 1). This kinetic isotope effect indicates that the electron transfer reaction from guanine to 2AP radicals is coupled to deprotonation/ protonation reactions of the primary electron-transfer products (Scheme 1). 

The observation of the electrocatalysis in Fig. 1 suggests that the Ru(bpy)3 and guanine couples have similar redox potentials. Based on the kinetics of oxidation by a series of substituted Ru(bpy)3 complexes, we predicted that the redox potential of guanine was 1.1 V (all potentials versus Ag/AgCl) [17]. Later, equilibrium titrations performed by Steenken using known one-electron oxidants showed that the potential was 1.07 V at pH 7 [39], which also implied that the guanine deprotonates in our reaction. The issue of guanine deprotonation will be discussed in depth below. 

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