Acidity kinetic versus thermodynamic

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... 

Formation of a highly electrophilic iodonium species, transiently formed by treatment of an alkene with iodine, followed by intramolecular quenching with a nucleophile leads to iodocyclization. The use of iodine to form lactones has been elegantly developed. Bartlett and co-workers216 reported on what they described as thermodynamic versus kinetic control in the formation of lactones. Treatment of the alkenoic acid 158 (Scheme 46) with iodine in the presence of base afforded a preponderance of the kinetic product 159, whereas the same reaction in the absence of base afforded the thermodynamic product 160. This approach was used in the synthesis of serricorin. The idea of kinetic versus thermodynamic control of the reaction was first discussed in a paper by Bartlett and Myerson217 from 1978. It was reasoned that in the absence of base, thermodynamic control could be achieved in that a proton was available to allow equilibration to the most stable ester. In the absence of such a proton, for example by addition of base, this equilibration is not possible, and the kinetic product is favored. 

This process illustrates the concept of kinetic versus thermodynamic control of a reaction, with naphthalene-1-sulfonic acid being the kinetic product and the 2-sulfonic acid the thermodynamic product. The energy changes associated with these processes are illustrated in Figure 12.1. 

Primary arylamines and p-ketoesters react in the presence of strong acid to provide 2-quinolones (Knorr reaction), whereas their thermal reaction yields 4-quinolones (Conrad-Limpach reaction). These reactions present a typical example of kinetic versus thermodynamic control, which has been employed in the synthesis of many quinolone derivatives for more than a century. 

What does all of this mean The reaction of 2-pentanone with LDA in THF at -78°C constitutes typical kinetic control conditions. Therefore, formation of the kinetic enolate and subsequent reaction with benzaldehyde to give 34 is predictable based on the kinetic versus thermodynamic control arguments. In various experiments, the reaction with an unsymmetrical ketone under what are termed thermodynamic conditions leads to products derived from the more substituted (thermodynamic) enolate anion. Thermodynamic control conditions typically use a base such as sodium methoxide or sodium amide in an alcohol solvent at reflux. The yields of this reaction are not always good, as when 2-butanone (37) reacts with NaOEt in ethanol for 1 day. Self-condensation at the more substituted carbon occurs to give the dehydrated aldol product 38 in 14% yield. Note that the second step uses aqueous acid and, under these conditions, elimination of water occurs. 

That we are dealing here with kinetic versus thermodynamic control was demonstrated with (Z)-3-iodoacrylic acid, which can easily be obtained from propiolic acid [240]. 

SCHEME 16.7 Kinetic versus thermodynamic acidity of nitroalkenes. 

In the 1960s changes in the U V spectrum as a function of protein structure came under intense study. Characteristic alterations in the aromatic region were used to monitor protein denaturation. Both kinetic and thermodynamic parameters for the unfolding process can be studied via spectrophotometry. The basis for the spectral changes has been attributed to the influence of the environment in the vicinity of Tyr and Trp on their absorbance. In the native state, these relatively hydrophobic amino acids are most often buried inside the hydrophobic protein core, but upon denaturation, they become exposed to the aqueous buffer environment. Model studies with aromatic amino acids, their analogs, or small peptides containing Phe, Tyr, and Trp demonstrated the environmental effects of a hydrophilic versus hydrophobic solvent system. 

Parallel chemistry is observed with the trimethylene methane complexes 10.136 (Scheme 10.34)." In this case, however, the cationic tv -complex 10.137, although observable by NMR at low temperature," cannot be isolated. It could be trapped with nucleophiles, but different nucleophiles gave different types of product. Allyltrimethylsilane gave a new trimethylene methane complex 10.138," while methanol yielded an if -diene complex 10.139. The different structural types produced, trimethylene methane versus diene complex, are likely to be due to kinetic and thermodynamic control as addition of methanol would be expected to be reversible under acidic conditions. 

The comparison of I —> N and N —> I may also be explained by the buffered pH in the diffusion layer and leads to an interesting comparison between a process under kinetic control versus one under thermodynamic control. Because the bulk solution in process N —> I favors formation of the ionized species, a much larger quantity of drug could be dissolved in the N —> I solvent if the dissolution process were allowed to reach equilibrium. However, the dissolution rate will be controlled by the solubility in the diffusion layer accordingly, faster dissolution of the salt in the buffered diffusion layer (process I—>N) would be expected. In comparing N—>1 and N —> N, or I —> N and I —> I, the pH of the diffusion layer is identical in each set, and the differences in dissolution rate must be explained either by the size of the diffusion layer or by the concentration gradient of drug between the diffusion and the bulk solution. It is probably safe to assume that a diffusion layer at a different pH than that of the bulk solution is thinner than a diffusion layer at the same pH because of the acid-base interaction at the interface. In addition, when the bulk solution is at a different pH than that of the diffusion layer, the bulk solution will act as a sink and Cg can be eliminated from Eqs. (1), (3), and (4). Both a decrease in the h and Cg terms in Eqs. (1), (3), and (4) favor faster dissolution in processes N —> I and I —> N as opposed to N —> N and I —> I, respectively. 

Reactions of carbocations with free CN- occur preferentially at carbon, and not nitrogen as predicted by the principle of hard and soft acids and bases.69 Isocyano compounds (N-attack) are only formed with highly reactive carbocations where the reaction with cyanide occurs without an activation barrier because the diffusion limit has been reached. A study with the nitrite nucleophile led to a similar observation.70 This led to a conclusion that the ambident reactivity of nitrite in terms of charge control versus orbital control needs revision. In particular, it is proposed that SNl-type reactions of carbocations with nitrite only give kinetically controlled products when these reactions proceed without activation energy (i.e. are diffusion controlled). Activation controlled combinations are reversible and result in the thermodynamically more stable product. The kinetics of the reactions of benzhydrylium ions with alkoxides dissolved in the corresponding alcohols were determined.71 The order of nucleophilicities (OH- MeO- < EtO- < n-PrCT < / -PrO ) shows that alkoxides differ in reactivity only moderately, but are considerably more nucleophilic than hydroxide. 

The older literature on the electrochemistry of dioxygen in acidic media attributes the difference between the thermodynamic potential for the four-electron reduction (O2/H2O, +1.23 V versus NHE Fig. 2-1) and the observed value at a freshly activated platinum electrode [+0.67 V versus NHE, Eq. (2-23)] to overvoltage (or kinetic inhibition). Likewise, the difference between the thermodynamic potential for the two-electron reduction (O2/HQOH, +0.70 V versus NHE, Fig. 2-1) and the observed value at passivated electrodes [+0.05 V versus NHE, Eq. (2-22)] was believed to be due to the kinetic inhibition of the two-electron process. 

Sulfonation Phenol reacts with concentrated sulfuric acid to yield mainly the orthosulfonated product if the reaction is carried out at 25 °C and mainly the para-sulfonated product at 100 °C. This is another example of thermodynamic versus kinetic control of a reaction (Section 13.10A) ... 

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