Internal proton return

HMPT). These results were explained by a postenohzation complex 210 (Figure 10.19), in which the protonated amide base is still in close contact with the enolate. The attack of the methyl iodide preferentially takes place from the less hindered it-face of the double bond. With LHMDS, the approach of the electrophile is hindered by the bulky TMS-groups, and an internal proton return from the amide base to the enolate becomes a competing process. The consequences of the reprotonation are low yields of methylated products and the recovery of the corresponding amount of starting material. 

An unusual case of internal proton return in a highly chirotopic environment was reported for the L-alanine derivative ( + )-2. On deprotonation with less than one equivalent of LDA in the presence of lithium bromide, and alkylation with iodomethane, 3 is isolated in which the methyl group has entered the ring from the less hindered side (sec also Section 2.1.4.2.). However, complete epimerization of the side chain occurred during this alkylation reaction. Deprotonation first produces the ester enolate. This enolate is selectively reprotonated from the less hindered side by internal proton transfer which produces the starting material for the alkvla-tiony5a. 

Internal proton return to lithium enolates from secondary amines which are coordinated to the lithium ion has been used for diastereoselective (Sections 2.1.3.6. and 2.1.4.2.) and enantioselec-tive (Section 2.1.6.1.2.) protonations. A remarkable example of enantioselective internal proton return, with the exclusion of any additional proton source, occurs with racemic Naproxen amides 1l63a. 

The ACPC deaminase (EC 4.1.99.4) converts ACPC to 2-oxobutyrate 124, and incubation with (IS)- and (lR)-[2,2- H2]ACPC, which leads to labeling in the methyl and the C-3 positions, respectively, showed that it was the bond to the 2-pro-S carbon that was cleaved in the process (341). This is the bond made on biosynthesis of ACPC. A mechanism for the process is suggested in Scheme 90, and the indication of internal proton return suggests operation... 

The use of chiral lithium amide bases in combination with achiral protonating agents provides as striking argument for the internal proton return in mixed eno-late aggregates. The concept was verified first by Hogeveen and Zwart [233] and thereafter studied intensively by Vedejs and coworkers who used Lewis acids for reprotonation [234]. The method is illustrated for the deracemization of naproxen amide 466 that is converted into a mixture of cis- and traws-enolates 468 in the ratio of 93 7 by treatment with 2 equiv. of s-butyllithium, followed by 2 equiv. of... 

Vedejs E, Lee N. Lewis acid induced internal proton return enantiocontrolled protonation of an amide enolate. J. Am. Chem. Soc. 1991 113 5483-5485. 

Related work in our group led to the synthesis of the cyclophanes 21-23 (Scheme 7) [20]. It was found that 21 adopted the syn conformation exclusively and 23 adopted the anti conformation exclusively. However, cyclophane 22 was observed to exist in a ca. 6 1 antv.syn ratio at equilibrium. The two conformers can be separated by flash chromatography and the return to the equilibrium ratio monitored by H NMR. Noteworthy here is the direct observation of an anti to syn flip of a [2.2]metacyclophane. There have been only two other reports of such anti to syn flips [21], Also noteworthy is the chemical shift of the internal proton of the inner ring of anti-22, which appears at S 3.03. 

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 ... 

This process is referred to as internal return, i.e., the base returns the proton to the carbanion faster than exchange of the protonated base with other solvent molecules occurs. If internal return is important under a given set of conditions, how would the correlation between kinetics of exchange and equilibrium acidity be affected How could the occurrence of internal return be detected experimentally ... 

A Global scheme for solvolysis 2 Clocks for reactions of ion pairs 3 Addition of solvent to carbocation-anion pairs i Protonation of a carbocation-anion pair 11 Isomerization of ion pair reaction intermediates Reorganization of ion pairs in water 13 Internal return of isotopically labeled ion pairs Racemization of ion pairs 22 Concluding remarks 24 Acknowledgements 24 References 24... 

Protonation of the leaving group anion, which prevents internal return of the ion pair to reactant, and has the effect of making substrate ionization irreversible. 

In view of the above, several workers, notably Zoltewicz, have stressed the likely importance of the internal return mechanism (Scheme 12) for proton-transfer reactions from heterocyclic compounds. 

The demonstration that stars are capable of such nuclear fertihty is based upon a combination of knowledge from what appear to be widely separated areas of physics. One of these concerns the internal structure of stars, telling us the temperature and pressure at different depths. The other concerns the probabilities at different energies of all the possible reactions between various nuclei, and between those nuclei and protons or neutrons. In the latter case, the acquisition of the relevant data was greatly accelerated by the Second World War. The beauty of nuclear astrophysics rests upon the success of this marriage and the complementarity of the two disciplines it brings together. The nuclear butterfly has returned to its stellar chrysalis. 

Solvolysis of (44) gives the doubly destabilized cation (45), which shows a preference for internal return.89 Compound (44) is 109 times less reactive than is (46), of which 106 is attributed to the antiaromaticity of (45) and 103 to the presence of the electron-withdrawing CF3.89 The similarity of the destabilized cation (47) and the doubly protonated species (48) is demonstrated by the similar electrophilic cyclizations that these species undergo.90 Double-bond protonation was not observed.90 Compound (49) undergoes aniline-catalysed ring closure as shown to give (50), rather than the expected isomer (51).91... 

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. 

We can consider decarboxylation reactions in terms that are analogous to those in proton transfer reactions the reactivity of the carbanion in carboxylation reactions is analogous to internal return observed in proton transfer reactions from Bronsted acids. Kresge61 estimated that the rate constant for protonation of the acetylide anion, a localized carbanion (P A 21), is the same as the diffusional limit (1010 M s1). However, achieving this rate is highly dependent on the extent of localization of the carbanion. Jordan62 has shown that intermediates in thiazolium derivatives are also likely to be localized carbanions, which implies that protonation of these intermediates could occur at rates approaching those of other localized carbanions. 

We have presented evidence that pyrrole-2-carboxylic acid decarboxylates in acid via the addition of water to the carboxyl group, rather than by direct formation of C02.73 This leads to the formation of the conjugate acid of carbonic acid, C(OH)3+, which rapidly dissociates into protonated water and carbon dioxide (Scheme 9). The pKA for protonation of the a-carbon acid of pyrrole is —3.8.74 Although this mechanism of decarboxylation is more complex than the typical dissociative mechanism generating carbon dioxide, the weak carbanion formed will be a poor nucleophile and will not be subject to internal return. However, this leads to a point of interest, in that an enzyme catalyzes the decarboxylation and carboxylation of pyrrole-2-carboxylic acid and pyrrole respectively.75 In the decarboxylation reaction, unlike the case of 2-ketoacids, the enzyme cannot access the potential catalysis available from preventing the internal return from a highly basic carbanion, which could be the reason that the rates of decarboxylation are more comparable to those in solution. Therefore, the enzyme cannot achieve further acceleration of decarboxylation. In the carboxylation of pyrrole, the absence of a reactive carbanion will also make the reaction more difficult however, in this case it occurs more readily than with other aromatic acid decarboxylases. 

The one-base mechanism is characterized by the retention of the substrate-derived proton in the product (internal retum).30) With this criterion, reactions catalyzed by a-amino-c-caprolactam racemase,323 amino acid racemase of broad specificity from Pseudomonas striata333 have been considered to proceed through the one-base mechanism. However, such internal returns were not observed in the reactions of alanine racemases from K coli B,33) B. stearothermophilus,263 and S. typhirmaium (DadB and /1/r).263 The internal return should not be observed in the two-base mechanism, because the base catalyzing the protonation to the intermediate probably obtains the proton from the solvent. But the failure of the observation of the internal return can be also explained by the single-base mechanism in which exchange of the proton abstracted from the substrate a-carbon with the solvent is much faster than its transfer to the a-carbanion. Therefore, lack of the internal return does not directly indicate the two-base mechanism of the alanine racemase reaction. 

In conclusion, it is apparent that the use of the Br nsted coefficient as a measure of selectivity and hence of transition state structure appears to be based on extensive experimental data. However, the many cases where this use of the Br nsted coefficient is invalid suggest that considerable caution be used in drawing mechanistic conclusions from such data. The limitations on the mechanistic significance of a require further clarification, but the first steps in defining them appear to have been taken. The influence of change in the intrinsic barrier and variable intermolecular interactions in the transition state, both of which will result in a breakdown of the rate-equilibrium relationship, as well as internal return appear to be some of the key parameters which determine the magnitude of the Br nsted coefficient in addition to the degree of proton transfer. 

The reaction does not involve internal return and the rate of exchange, as discussed above, refers to a proton transfer step. This mechanism applies to most carbon acids in aqueous solution and the expected general base catalysis is observed, (ii) k2 < fe t, feobs = kxk2/k- - The observed rate coefficient is composite and the rate of exchange does not refer to a simple proton transfer step. It has been argued that the reaction will then show catalysis by hydroxide ion only and not by general bases when carried out in aqueous solution [26]. This arises because the rate of reaction depends upon the equilibrium concentration of intermediate in eqn. (11) which will depend upon the concentration and basicity of B. It... 

The observed rate coefficient for exchange (L = H, D, or T) is fe bs = k k2 /(kh. ] + k2)- If the primary isotope effect on k2 is different from that on k1 and k... j it is argued that the experimental isotope effects feob s tklb s and feobs/ ob s will not be related by the Swain—Schaad relation, kH/kT = (feH/feD)1442 which is derived with reference to a single-step proton transfer [115, 128]. The size of the discrepancy will depend upon the value of /e, /fe , the amount of internal return. In the analysis of isotope effects for triphenylmethane exchange it is assumed that k2=k2 = k2 since this represents a diffusion step. By introducing aT = k- i /k2 and Kl = k /k j eqns. (82) and (83) are obtained. A third equation (84)... 

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