Stereochemical evidence

Like the kinetic evidence, the stereochemical evidence for the SnI mechanism is less clear-cut than it is for the Sn2 mechanism. If there is a free carbocation, it is planar (p. 224), and the nucleophile should attack with equal facility from either side of the plane, resulting in complete racemization. Although many first-order substitutions do give complete racemization, many others do not. Typically there is 5-20% inversion, though in a few cases, a small amount of retention of configuration has been found. These and other results have led to the conclusion that in many SnI reactions at least some of the products are not formed from free carbocations but rather from ion pairs. According to this concept," SnI reactions proceed in this manner ... 

Studies of structure effects on rate have helped substantially to bring researchers to the present deep understanding (72,13) of the mechanism of elimination reactions. Beside stereochemical evidence, successful linear correlations have yielded the desired information. The published series of reactants and correlations are summarized in Table II. The fit of straight lines to experimental data is usually good or very good, and only a few points deviate significantly. Details of the correlations may be found in the original literature here we will concentrate on the values of the slopes. 

Stereochemical evidence for the mechanism of nucleophilic substitution at a tetracovalent phosphorus atom has been mainly forthcoming from the experiments of Michalski et a/.48-50 with esters containing thiophosphoryl centers. Until recently, the inaccessibility of suitable optically active phosphorus compounds precluded stereochemical investigations on the mechanisms of their hydrolysis. 

A general reaction of 1 -acyl-2- )r m-alkylaairidin B fa the pyrolytic rearrangement to an uneaturated amide1 . -SM (Eq, 72). Stereochemical evidence supports the view that the reaction involves the intramolecular aVdinination of a proton concerted with the opening, of the aziridine dug (transition state, XLVI). So... 

Chapter 8 (section C3) presents stereochemical evidence that the hydrolysis of /3-o-galactosides catalyzed by /3-galactosidase (equation 7.11) involves two successive displacements on the C-l carbon—i.e., involves an intermediate. Further evidence for an intermediate from partitioning experiments is presented in Table 7.10. There is constant partitioning between water and methanol.39-41... 

Stereospecificity is a hallmark of enzyme catalysis, so a knowledge of the basic principles of stereochemistry is essential for appreciating enzyme mechanisms. Stereochemical evidence can provide important information about the topology of enzyme-substrate complexes. In particular, the positions of catalytic groups on the enzyme relative to the substrate may often be indicated, as may be the conformation or configuration of a substrate or intermediate during the reaction. Further, comparison of the stereochemistry of the substrates and products may reveal the likelihood of intermediates during the reaction. 

Lysozyme and /3-galactosidase, which are both glycosidases, catalyze very similar reactions. Both enzymes are found to catalyze the alcoholysis of their polysaccharide substrates with retention of configuration at the C-l carbon (equation 8.25).14-17 This is consistent with the evidence presented in Chapter 7, section C3, that there is at least one (but probably only one) intermediate on the reaction pathway. However, kinetic isotope data are consistent with the interpretation that the intermediate in the reaction of /3-galactosidase is covalent and that there are two successive SN2 displacements, whereas the intermediate with lysozyme is a bound carbonium ion formed in an SN1 reaction (Chapter 16). The carbonium ion, unlike an analogous one in solution, reacts stereospecifically on the enzyme. Thus, the stereochemical evidence by itself has given no indication of the nature of the intermediate. 

Using rate, product, and stereochemical evidence, Hughes, Ingold, and their co-workers assigned mechanisms to a number of systems and pointed out that many cases could not be clearly categorized as either SW1 or S 2.7... 

Stereochemical evidence confirms that neither alkyl nor hydride provides anchimeric assistance in the pinacol rearrangement. Compounds 9 and 10 both... 

From the stereochemical evidence we might expect that the effect of substituents on the rate of bromination of substituted styrenes in polar solvents would not be cumulative.38 And, indeed, 23, 24, and 25, when brominated under the conditions of Table 7.7, have the relative rates shown. Furthermore, the logs of the rates of bromination of ring-substituted styrenes show a linear correlation... 

Kinetic and stereochemical evidence helped to establish carbocation intermediates in organic reactions. These species, however, were generally too short-lived and could not be directly observed by physical means. 

Cram s original studies287 established, based on kinetic and stereochemical evidence, the bridged ion nature of (3-phenylethyl cations in solvolytic systems. Spectroscopic studies (particularly1H and 13C NMR)288-291 of a series of stable long-lived ions proved the symmetrically bridged structure and at the same time showed that these ions do not contain a pentacoordinate carbocation center (thus are not nonclassical ions ). They are spiro[2.5]octadienyl cations 111 (spirocyclopropylbenzenium ions)—in... 

The study of gas-phase acid-induced nucleophilic displacement on 2,3-dihalobutanes has provided stereochemical evidence for the occurrence of cyclic chloronium and bromo-nium ions (X = Cl, Br), but not fluoronium ions17. Protonation or methylation of the neutral 2,3-dihalobutane by a suitable acid GA+ produces a halonium intermediate 2, which in the presence of water ultimately leads to the corresponding halohydrin neutral product (Scheme 4). Analysis of these neutral products indicated that the reaction proceeds with retention of configuration when X = Cl, Br and with inversion of configuration when X = F. The results were rationalized by the mechanisms sketched in Scheme 4, namely direct bimolecular nucleophilic displacement by H20 on 2 when X= F and intramolecular nucleophilic displacement to convert 2 into the cyclic halonium ion 3 (with inversion of configuation) followed by bimolecular nucleophilic displacement on 3 (with inversion of configuration) when X = Cl and Br. 

Stereochemical evidence supports the fact that the reaction of the stereoisomers 9 and 10 takes place through an effectively planar benzylic radical, which is preferentially attacked from the face remote from the a-ethyl group. Because of the presence of geminal alkyl groups a to the reaction site, the reaction fails with nucleophiles such as the anions derived from 2-nitropropane and 2-ethylmalononitrile and with sodium p-toluenesulphi-nate. 

The solvent acts as a kinetically significant nucleophile in the overall solvolysis process for many simple secondary substrates, and this appears to be the major cause of the variation in relative rates with changes in solvent (Table 2, p. 11). This conclusion is supported by the quantitative correlations discussed in Section 6. The stereochemical evidence further suggests that, even when the magnitude of nucleophilic solvent assistance is less than a rate factor of 10 at 25°, solvolyses (e.g. of cylcohexyl tosylate in formic acid) can proceed with essentially complete inversion of configuration. These results are consistent with an SN 2 mechanism and the evidence for ion pair intermediates can then be considered in one of two ways. 

This chapter ends with a survey of the role of stereochemistry in the determination of mechanism. Though we have left stereochemistry to the last, it is one of the most important tools in unravelling complex mechanisms. You have already seen how inversion of configuration is a vital piece of evidence for an Sn2 mechanism (Chapter 17) while retention of configuration is the best evidence for participation (Chapter 37). You have seen the array of stereochemical evidence for pericyclic mechanisms (Chapters 35 and 36). The chapters devoted to diastereoselectivity (33 and 34) give many examples where the mechanism follows from the stereochemistry. We shall not go over that material again, but summarize the types of evidence with new examples. The first example looks too trivial to mention. 

The experiments also provide stereochemical evidence that a carbocation is an intermediate in both reactions. Both starting materials are ns-decalins but the product is a frans-decalin. The carbocation intermediate has no stereochemistry and can react with the nitrile from either face. Axial attack is preferred and it gives the stable frcws-decal in. The formation of the carbocation is shown only by the Beckmann fragmentation formation from the alcohol by the S l mechanism is obvious. 

Buchwald SL, Pliura DH, Knowla JR (1980) Stereochemical evidence for pseudorotation in the reaction of a phosphoric monoester. J Am Chem Soc 106 4916-4922... 

Hoang L, Bahmanyar S, Houk KN, List B (2003) Kinetic and stereochemical evidence for the involvement of only one proline molecule in the transition states of proline-catalyzed intra- and intermolecular aldol reactions. J Am Chem Soc 125 16-17... 

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