Intermediates internal return

Studies of the stereochemical course of rmcleophilic substitution reactions are a powerful tool for investigation of the mechanisms of these reactions. Bimolecular direct displacement reactions by the limSj.j2 meohanism are expected to result in 100% inversion of configuration. The stereochemical outcome of the lirnSj l ionization mechanism is less predictable because it depends on whether reaction occurs via one of the ion-pair intermediates or through a completely dissociated ion. Borderline mechanisms may also show variable stereochemistry, depending upon the lifetime of the intermediates and the extent of internal return. It is important to dissect the overall stereochemical outcome into the various steps of such reactions. 

Neopentyl (2,2-dimethylpropyl) systems are resistant to nucleo diilic substitution reactions. They are primary and do not form caibocation intermediates, but the /-butyl substituent efiTectively hinders back-side attack. The rate of reaction of neopent>i bromide with iodide ion is 470 times slower than that of n-butyl bromide. Usually, tiie ner rentyl system reacts with rearrangement to the /-pentyl system, aldiough use of good nucleophiles in polar aprotic solvents permits direct displacement to occur. Entry 2 shows that such a reaction with azide ion as the nucleophile proceeds with complete inversion of configuration. The primary beiuyl system in entry 3 exhibits high, but not complete, inversiotL This is attributed to racemization of the reactant by ionization and internal return. 

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... 

The ion-pair intermediate must undergo internal return to reactant at a rate... 

Br than was the yield of the />ara-ester, 94. The differential effects of Br on the yield of these two products led to consideration of the mechanism of Scheme 42, in which three ion pair intermediates are invoked. Variation in the yields of the para-products as a function of [H ] and [Br ] led to estimates of the lifetimes for 95c of ca. 21 ps and for 96c of 0.25-0.5 ns. The estimated lifetimes suggest that both 92 and 95 should be thought of as tight ion pairs while 96 appears to be a solvent-separated ion pair. Internal return of 96 to the para-ester, 94, amounts to about 20% of the fate of 96 in the absence of Br, according to the fitting procedure, so this is apparently not an insignificant path for this ion pair. Curiously, 96 has about the same lifetime one would expect for the free ion, and it is not clear what role, if any, the free ion plays in this reaction. The authors did not include a preassociation path which would have accounted for some of the Br derived products. 

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. 

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. 

It may be argued that the evidence for ion pair intermediates is too indirect, since it has not been established that the ion pairs undergoing 18 O-scrambling or interned return are the same as those undergoing solvolysis. Evidence for ion pairs would then be explained by side-reactions and the solvolytic reactions for which nucleophilic solvent assistance is greater... 

Figure 9. Schematic representation of upper portion of potential eneigy surface for merging of substitution mechanisms. A Sjsj 1 mechanism. No nucleophilic solvation in transition state ion pair intermediate (possibly nudeophilically solvated) B Sn2 (intermediate). Transition state is nudeophilically solvated by solvent (SOH) intermediate is a nudeophilically solvated ion pair (see Fig. 8) C Classical Sn2. No energy minimum. In curves A and B, the second transition state may be of higher energy than the first in cases where internal return is important.

Winstein (1957c). They argued that during solvolysis of neophyl substrates [46, X = Cl, Br] internal return from the proposed phenonium ion-pair intermediate [47] would yield the tertiary derivative [48] (Fig. 13) and this would solvolyse rapidly. Thus, the titrimetric rate constants should correspond to the ionization rate constant k j (Fig. 2). Later neophyl tosylate [46, X = OTs] and its p-methoxy derivative were used (Smith et al., 1961 Diaz et al., 1968b Yamataka et al., 1973), and recently Schadt et al. (1976) defined as a scale of solvent ionizing power for tosylates, designated F2-AdOTs or Yqt, using eqn (5) but based on 2-adamantyl tosylate [6] instead of t-butyl chloride. A correlation of the rates of solvolysis of neophyl tosylate with F0 Xs (Fig. 14) is satisfactory (correlation coefficient... 

Other evidence to support the selection of 2-adamantyl tosylate as model compound has been discussed in Section 2 (p. 8), and the main conclusion can be summarized as follows. Independent evidence and the results in Fig. 15 firmly establish that nucleophilic solvent assistance cannot be appreciable for solvolyses of 2-adamantyl tosylate, since its response to solvents of widely varying nucleophilicities is almost exactly the same as 1-bicyclo [2,2,2] octyl tosylate [49] for which rearside attack is impossible if solvolyses of 2-adamantyl tosylate are anchimerically assisted, the extent of anchimeric assistance does not appear to be dependent on solvent (cf. Pritt and Whiting, 1975). In addition to these conclusions, the results in Fig. 14 suggest that internal return from intermediate contact ion pairs does not occur to a detectable extent for solvolyses of 2-adamantyl tosylate (see also Bentley and Schleyer, 1976). 

The large amounts of five- and six-membered cyclic tosylates, products of internal return (49% yield in one case 12a of Table 3) points also to a highly selective intermediate, although the reason for such a remarkable selectivity towards external nucleophiles is not clear. On the other hand, acetolysis of 6-phenyl-5-hexynyl brosylate, which is apparently anchimerically assisted by the triple bond (4>bs./ caic. = 1 6) yields only the five-membered ring product in addition to open-chain solvolysis products (13 of Table 3). The effect of the phenyl group in orienting the oyclization reaction would indicate that intermediate species like 43 may become important when R =Ph. 

The ion-pair intermediate must undergo internal return to reactant at a rate competitive with diffusional separation to free ions (k t > k-d 1.6 X 1010 s-1). 

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... 

First, the enzyme has at least two and probably three active-site basic groups involved in proton transfers to and from substrates, intermediates, and nascent products and all three bases are located on the si face of the substrate-PLP aldimine system as are the protons to be shuffled about, so all the proton transfers are likely to be economically suprafacial. Several pieces of stereochemical evidence suggest that the j5,y-olefinic PLP-p-quinoidal-a-anion (141) can rotate around its C(P)-C(ol) bond and also implicate that the cisoid isomer of this n complex and then the Z-isomer of the nascent aminocrotonate carry 80 % of the reaction flux. Furthermore, a 15% internal retention of the from the Pro-R methylene of ACPC (9) on B2H (85 % exchange with solvent, 15 % internal return) in the active site and the overall 22/78 H /H5 distribution at C(3) of the mono- and dideutero 2-ketobutyrate (138) products at C(3) are also noted. 

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