Racemization in SnI

The mechanisms by which sulfonate esters undergo nucleophilic substitution are the same as those of aUcyl halides. Inversion of configuration is observed in Sn2 reactions of aUcyl sulfonates and predominant inversion accompanied by racemization in SnI processes. 

Two additional examples of racemization in SnI reactions are given in Figure 7.16. 

Partial but not complete loss of optical activity in SnI reactions probably results from the carbocation not being completely free when it is attacked by the nucleophile. Ionization of the alkyl halide gives a carbocation-halide ion pair-, as depicted in Figure 8.8. The halide ion shields one side of the carbocation, and the nucleophile captures the carbocation faster from the opposite side. More product of inverted configuration is formed than product of retained configuration. In spite of the observation that the products of SnI reactions are only partially racemic, the fact that these reactions are not stereospecific is more consistent with a carbocation intermediate than a concerted bimolecular- mechanism. 

Enantiomerically pure 3-methyl-3-hexyl bromide and water react in SnI fashion to give racemic 3-methyl-3-hexanol. 

A-[Co(en)3l is not racemized in the presence of OH at high temperatures the observed loss of optical activity is associated with the formation of cis and trans [Co(en)2(OH)2] (164). This is in keeping with the observation that cis-[Co(en)2en(OH) (i.e., with one monodentate en ligand) in basic aqueous solution does not cyclize to form [Colenla] (165). In the presence of a large excess of free en, however, racemization is observed the rate is dependent on en concentration, and the complex exchanges ligands at about the same rate as racemization (164, 166). Carbon black catalyzed racemization follows the rate law V = Ai[Co(en)3 ]ads[OH ]ad8. where the concentrations refer to the amount of reactant adsorbed onto the surface of the catalyst, ki has a value of (9 1) X 10 M s at 25°C (167). An effect of [en] was observed but was attributed solely to the pH of the basic amine. The reaction on the surface of the catalyst was proposed to occur via the SnI(CB) mechanism. 

The ion-pair hypothesis in SnI reactions. The leaving group shields one side of the carbocation intermediate from attack by the nucleophile, thereby leading to some inversion of configuration rather than complete racemization. 

The rate of an SnI reaction depends only on the concentration of the alkyl halide. The halogen departs in the first step, forming a carbocation that is attacked by a nucleophile in the second step. Therefore, carbocation rearrangements can occur. The rate of an SnI reaction depends on the ease of carbocation formation. Tertiary alkyl halides, therefore, are more reactive than secondary alkyl halides since tertiary carbocations are more stable than secondary carbocations. Primary carbocations are so unstable that primary alkyl halides cannot undergo SnI reactions. An SnI reaction takes place with racemization. Most SnI reactions are solvolysis reactions The solvent is the nucleophile. 

FIGURE 7.57 Incomplete racemization is often found in SnI reactions. An excess of inversion is generally found. 

This lack of complete racemization in most SnI reactions is due to the fact that ion pairs are involved. Dissociation of the substrate occurs to give a structure in which the two ions are still loosely associated and in which the carhocation is effectively shielded from reaction on one side by the departing anion. If a certain amount of substitution occurs before the two ions fully diffuse apart, then a net inversion of configuration will he observed (Figure 12.12). 

In SnI reactions, racemization always occurs at a stereogenic center. Draw two products, with the two possible configurations at the stereogenic center. 

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 ... 

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 ... 

The SnI reactions do not proceed at bridgehead carbons in [2.2.1] bicyclic systems (p. 397) because planar carbocations cannot form at these carbons. However, carbanions not stabilized by resonance are probably not planar SeI reactions should readily occur with this type of substrate. This is the case. Indeed, the question of carbanion stracture is intimately tied into the problem of the stereochemistry of the SeI reaction. If a carbanion is planar, racemization should occur. If it is pyramidal and can hold its structure, the result should be retention of configuration. On the other hand, even a pyramidal carbanion will give racemization if it cannot hold its structure, that is, if there is pyramidal inversion as with amines (p. 129). Unfortunately, the only carbanions that can be studied easily are those stabilized by resonance, which makes them planar, as expected (p. 233). For simple alkyl carbanions, the main approach to determining structure has been to study the stereochemistry of SeI reactions rather than the other way around. What is found is almost always racemization. Whether this is caused by planar carbanions or by oscillating pyramidal carbanions is not known. In either case, racemization occurs whenever a carbanion is completely free or is symmetrically solvated. 

For example, let s look at the stereochemistry of SnI reactions. We already saw that Sn2 reactions proceed via inversion of configuration. But SnI reactions are very different. Recall that a carbocation is sp hybridized, so its geometry is trigonal planar. When the nucleophile attacks, there is no preference as to which side it can attack, and we get both possible configurations in equal amounts. Half of the molecules would have one configuration and the other half would have the other configuration. We learned before that this is called a racemic mixture. Notice that we can explain the stereochemical outcome of this reaction by understanding the nature of the carbocation intermediate that is formed. 

SnI and Sn2 reactions produce almost the same products. In both reactions, a leaving group is replaced by a nucleophile. The difference in products between SnI and Sn2 reactions arises when the leaving group is attached to a stereocenter. In this situation, the Sn2 mechanism will invert the stereocenter, while the SnI mechanism will produce a racemic mixture. That s the main difference—the configuration of one stereocenter. It seems like a lot of work to go through to determine the configuration of one stereocenter (which matters only some of the time). 

Racemization of chiral a-methyl benzyl cation/methanol adducts. The rate of exchange between water and the chiral labeled alcohols as a function of racemization has been extensively used as a criterion for discriminating the Sn2 from the SnI solvolytic mechanisms in solution. The expected ratio of exchange vs. racemization rate is 0.5 for the Sn2 mechanism and 1.0 for a pure SnI process. With chiral 0-enriched 1-phenylethanol in aqueous acids, this ratio is found to be equal to 0.84 0.05. This value has been interpreted in terms of the kinetic pattern of Scheme 22 involving the reversible dissociation of the oxonium ion (5 )-40 (XOH = H2 0) to the chiral intimate ion-dipole pair (5 )-41 k-i > In (5 )-41, the leaving H2 0 molecule does not equilibrate immediately with the solvent (i.e., H2 0), but remains closely associated with the ion. This means that A inv is of the same order of magnitude of In contrast, the rate constant ratio of... 

Gas-phase intracomplex substitution in (R)-(- -)-l-arylethanol/CHs OH2 adducts. It is well established that bimolecular Sn2 reactions generally involve predominant inversion of configuration of the reaction center. Unimolecular SnI displacements instead proceed through the intermediacy of free carbocations and, therefore, usually lead to racemates. However, many alleged SnI solvolyses do not give fully racemized products. The enantiomer in excess often, but not always, corresponds to inversion. Furthermore, the stereochemical distribution of products may be highly sensitive to the solvolytic conditions.These observations have led to the concept of competing ° or mixed SNl-SN2 mechanisms. More recently, the existence itself of SnI reactions has been put into question. ... 

In the example shown, there is slightly more of the inverted product in the reaction mixture, though the effect is not especially large. In other recorded examples, up to about 80% of the product might be the inverted form. It follows that the Sn2 process is accompanied by complete inversion, whereas an SnI process will involve racemization or partial inversion. 

A stereochemical study of the synthesis of unsaturated 1,4-aminoalcohols via the reaction of unsaturated 1,4-alkoxyalcohols with chorosulfonyl isocyanate revealed a competition between an retentive mechanism and an SnI racemization mechanism, with the latter having a greater proportion with systems where the carbocation intermediate is more stable.254 An interrupted Nazarov reaction was observed, in which a nonconjugated alkene held near the dienone nucleus undergoes intramolecular trapping of the Nazarov cyclopentenyl cation intermediate.255 Cholesterol couples to 6-chloropurine under the conditions of the Mitsunobu reaction the stereochemistry and structural diversity of the products indicate that a homoallylic carbocation derived from cholesterol is the key intermediate.256 l-Siloxy-l,5-diynes undergo a Brpnsted acid-promoted 5-endo-dig cyclization with a ketenium ion and a vinyl cation proposed as intermediates.257... 

A detailed and elegant study of the SnI solvolysis reactions of several substituted 1-phenylethyl tosylates in 50% aqueous TEE has enabled the rates of (1) separation of the carbocation-ion pair to the free carbocation, (2) internal return with the scrambling of oxygen isotopes in the leaving group, (3) racemization of the chiral substrate that formed the carbocation-ion pair, and (4) attack by solvent to be determined.122... 

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