Racemization of ion pairs

Racemization of neutral substrates by solvolysis through an ion-pair or ion-dipole reaction intermediate will rarely be observed for reactions in water, because few substrates will meet the following strict requirements for the observation of racemization  

The situation is different for solvolysis reactions in most other solvents, where the intermolecular interactions between ions at an ion pair are stronger than the compensating interactions with solvent that develop when the ion pair separates to free ions. This favors the observation of racemization during solvolysis. There are numerous reports from studies on solvolysis in solvents with relatively low dielectric constant such as acetic acid, of polarimetric rate constants (ka, s-1) for racemization of chiral substrates that greatly exceed the titrimetric rate constant (fct, s-1) for formation of acid from the solvolysis reaction.15 

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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... 

Entry 4 shows that reaction of a secondary 2-octyl system with the moderately good nucleophile acetate ion occurs wifii complete inversion. The results cited in entry 5 serve to illustrate the importance of solvation of ion-pair intermediates in reactions of secondary substrates. The data show fiiat partial racemization occurs in aqueous dioxane but that an added nucleophile (azide ion) results in complete inversion, both in the product resulting from reaction with azide ion and in the alcohol resulting from reaction with water. The alcohol of retained configuration is attributed to an intermediate oxonium ion resulting from reaction of the ion pair with the dioxane solvent. This would react until water to give product of retained configuratioiL When azide ion is present, dioxane does not efiTectively conqiete for tiie ion-p intermediate, and all of the alcohol arises from tiie inversion mechanism. ... 

The ion-pair concept thus predicts that SmI reactions can display either complete racemization or partial inversion. The fact that this behavior is generally found is evidence that ion pairs are involved in many SnI reactions. There is much other evidence for the intervention of ion pairs ... 

This tetranuclear complex was first prepared by Jorgensen (2), and was resolved into optical isomers by Werner (5), who thereby disposed of the vitalist contention that organic carbon is an essential concomitant of optical activity. Werner named the complex hexol after the bridging ligands. The structure of this tetranuclear species has now been established by an X-ray crystal-structure analysis of the racemic salt (52). The complex racemizes fairly readily and rates of racemization depend heavily on pH the first-order rate constants at pH 2.0, 7.0, and 8.1, are respectively, k = 2 x 10 6, 2 x 10 3, and 4 x 10 2 sec-1 at 22"C. Tartrate and selenate decrease the rate of racemization, probably as a result of ion pairing between the hydroxo bridges and the anions (56). 

Excess of rate of racemization over rate of product formation supports the idea of ion pairs that can return to substrate nevertheless, as it is possible that some, or even most, of the ion pairs return without racemizing (Scheme 4), considerable doubt remains about kt, the rate of formation of the ion pairs. The difficulty is that there is no way to detect the event represented by kt if it is followed immediately by k t. We shall know that something has happened only when kt is followed by kT or by kv. If k t competes with these processes, some ionization will go undetected. 

There has been a study of the influence of ion-pairing reagents and solvents on the stability of the hydroxide adduct (11) of the diethylamide of 3,5-dinitrobenzoic acid e.g. (11) is stabilized by quaternary ammonium salts in benzene. The resulting methodology has been used to perform highly enantioselective biphasic kinetic resolutions of several racemic electron-deficient amides.50... 

For (58) and (60) keq was found to equal krac80,82. Thus it appears that internal return in allylic systems results in racemization and complete oxygen equilibration. However, this result is also consistent with an ion pair (63) which retains coordination of the ether oxygen to the carbon atom from which it departed. (63) would produce an equimolar mixture of (62a) and (62b). Determination of the 180 distributions of both recovered enantiomers from the solvolysis of (60) revealed identical scrambling, i.e. rapid interconversion of ion pairs (63) and (64)S2 With (55), however, predominant product formation from (63) was indicated by excess carbonyl-180 in the inverted ester and excess ether-180 in the ester of retained configuration80. ... 

Table 11.1-25 list examples in which certain additives have an unambiguous beneficial influence on selectivity and/or reaction rate. The enantiomerically enriched or pure compounds 1-9 have been prepared under the influence of mainly triethylamine or other bases. In case of 1 for the acetylation with 2,2,2-trichloroethyl acetate there was no reaction without triethylamine. For the formation of 5 the reaction time was shortened dramatically from ten days to three hours for 100% of conversion. In most cases there is no rationale for the effects of bases except the formation of ion-pairs between the added bases and traces of acids present in the reaction mixture. Only for the synthesis of 9 a systematic investigations demonstrates that triethylamine besides its racemizing properties (cf. Table 11.1-24) has a significant influence on the water activity of the reacting mixture[138]. In other cases, triethylamine has been used as an additive without comparing its influence with the results in its absence1 331. 

However, it has been pointed out81-83 that the high order with respect to nucleophile, as given in Table 9, is not compatible with such a mechanism. Indeed, Sommer reported the reaction to be third order in nucleophile but rationalized this in terms of ion-pair formation and solvation effects. Corriu has also pointed out that the energy of activation of racemization (Table 10) is smaller than that expected for pseudorotation (Table 7)82... 

When there is internal return, a deprotonation event escapes detection because exchange does not occur. One experimental test for the occurrence of internal return is racem-ization at chiral carbanionic sites that takes place without exchange. Even racemization cannot be regarded as an absolute measure of the deprotonation rate because, under some conditions, hydrogen-deuterium exchange has been shown to occur with retention of configuration. Owing to these uncertainties about the fate of ion pairs, it is important... 

The importance of ion pairing in amine nitrosation has been further demonstrated by Kirmse and Siegfried . They studied the nitrosation of the optically active 2-norbomamines, andconfirmed that the endo isomer 183 yields a mixture of 90% racemic exo alcohol 184 and 10% racemic endo alcohol 185. Formation of 184 is easily explained by formation of the... 

Schlosser [80] andVoyer [81] reported that N-Boc-N-methylbenzylamine 106 can be deprotonated with 5ec-BuLi in the presence of (-)-sparteine. The resulting organolithium can be trapped with electrophiles to provide a-substituted benzylamines 107 with high enantioselectivities (Scheme 31). Schlosser and coworkers showed that the reaction pathway of N-methyl-hl-Boc benzylamines 107 is an asymmetric deprotonation followed by racemization and asymmetric substitution, and provided rationalization of solvent effects in terms of ion paired species [80]. The enantioselectivity of this reaction sequence is highly dependent on the solvent, electrophile, and reaction time. 

At 100°C, /Ceq/fcrac = 2.3. If it is assuHied that ionization to p-nitrobenzoate ion completely randomizes the label, then /Cgq is a measure of the total ion-pair return, and k ac is a measure of the extent of racemization associated with this return. The greater rate of equilibration compared to racemization is indicative of ion-pair return with predominant retention of configuration. In the presence of added sodium azide (0.14 M), /Cgq is about the same, but k ac goes to zero. This means that the highly nucleophilic azide ion intercepts an intermediate that would return with racemization, but is not intercepting an intermediate that returns with retention of configuration. The intermediate that is more easily intercepted is the solvent-separated ion pair, and the intermediate that is difficult to intercept is the intimate ion pair. 

Many investigators have studied substitution at iron(II)-diimine complexes in binary aqueous mixed solvents and other investigators in aqueous salt solutions. Some years ago the results of addition of salts and a cosolvent were assessed, for [Fe(5N02phen)3] in water, t-butyl alcohol, acetone, dimethyl sulfoxide, and acetonitrile mixtures containing added potassium bromide or tetra-n-butylammonium bromide. " Now the effects of added chloride, thiocyanate, and perchlorate on dissociation and racemization rates of [Fe(phen)3] in water-methanol mixtures have been established. The main explanation is in terms of increasing formation of ion pairs as the methanol content of the medium increases, but it is somewhat spoiled by the (unnecessary) assumption of a mechanism involving interchange within the ion pairs. Kip values (molar scale) of 11,18, and 25 were estimated for perchlorate, chloride, and thiocyanate in 80% (volume) methanol at 298.2 K. These values may be compared with values of 20, 7, and 4 for association between [Fe(phen)3] and iodide, " [Fe(bipy)3] and iodide, " and [Fe(phen)3] and cyanide " " in aqueous solution (at 298.2,... 

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