Inversion in Sn2 reactions

The particular value that Ingold used for the rotation of optically pure 2-bromooctane has been questioned, but the basic idea of complete inversion in Sn2 reactions is established beyond question by study of systems other than alkyl halides and by elegant work involving radioactivity and optical activity (Problem 14, p. 488). 

Consequences of Inversion in Sn2 Reactions Further implications of material in Chapters 4 and 5. 

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

The important chemistry of alkyl halides, RX, includes the nucleophilic (SN) displacement and elimination (E) reactions discussed in Chapter 8. Recall that tertiary alkyl halides normally are reactive in ionization (SN1) reactions, whereas primary halides, and to a lesser extent secondary halides, are reactive in Sn2 reactions, which occur by a concerted mechanism with inversion of configuration (Sections 8-4 to 8-7). 

At carbon, most leaving groups are good in SN2 reactions these go with inversion. At carbon, most leaving groups are poor in SE2 reactions these go with retention. As for the SNi reaction, this is usually strongly assisted, e.g. in (129) and (130) by the formation of sulfur dioxide (Mackenzie, 1964 de la Mare, 1963). The stereo-... 

If this is all correct, then the vital 5 2 step should lead to inversion as it always does in Sn2 reactions. This turns out to be one of the great strengths of the Mitsunobu reaction—it is a reliable way to replace OH by a nucleophile with inversion of configuration. The most dramatic example is probably the formation of esters from secondary alcohols with inversion. Normal ester formation leads to retention as the C-O bond of the alcohol is not broken. 

The reaction usually proceeds with retention of configuration at the reacting centre. As in SN2 reactions going with retention (Chapter 37), this can mean only a double inversion. Coordination of Pd to the double bond of the allylic acetate occurs on the less hindered face opposite the leaving group and the nucleophile adds to the face of the 7t-allyl Pd cation complex opposite the Pd. The net result is displacement of the leaving group by the nucleophile with retention. Thereafter, the... 

Two additional examples of inversion of configuration in Sn2 reactions are given in Figure 7.10. 

One of the most important reasons for using tosylates instead of halides in Sn2 reactions is stereochemical. The Sn2 reaction of an alcohol via an alkyl halide proceeds with two Walden inversions—one to make the halide from the alcohol and one to substitute the halide—and yields a product with the same absolute stereochemistry as the starting alcohol. The S>j2 reaction of an alcohol via a tosylate, however, proceeds with only one Walden inversion and yields a product of opposite stereochemistry to the starting alcohol. Figure 17.9 shows a series of reactions on optically active 2-octanol that illustrates these stereochemical relationships. 

The stereochemistry of the direct substitution reaction has been the subject of some debate. Most recently, it has been reported that reactions of alkylheterocuprates proceed with high syn selectivity, while inversion of allenyl configuration, or anti selectivity, is observ in reactions of phenylcopper reagents. The degree of selectivity is variable and may be a reflection of product isomerization under the reaction conditions. Predominant anti stereoselectivity (anti syn ratios range from 91 9 to >99 1) is observed also in Sn2 reactions of allenyl halides (see Scheme 3), a finding that is consistent with the known preference for anti substitution of allylic substrates (see Section I.5.2.4.5). This method for al-kyne preparation has found application in the leukotriene area, and also for the synthesis of alkoxy al-kynes. ... 

The reaction is clearly not a simple Sn2 displacement of OH from R by PhC02, because HO is a really awful leaving group in Sn2 reactions and will not leave under these mild conditions, and besides, PI13P and DEAD are required for the reaction. But equally clearly, Sn2 displacement must happen at some point, or clean inversion at R could not occur. 

The so-called Walden inversion, an SN2 reaction shown in Figure 1, has been chosen as the model, since it is a well-studied reaction, from both a static and a dynamical point of view.26-36 In the present study, we limit our analysis to the gas-phase reaction, and we do not consider solvent effects that are known to strongly modify the potential energy surface (PES).29... 

Sn2 reactions lead to an inversion of stereochemistry. Nucleophilicity is decreased by protic solvents in SN2 reactions. The presence of a polar aprotic solvent is a clue that the mechanism is SN2. 

A study of the relative rates of reaction of lithium di-n-butylcuprate with a series of organic halides has shown that the relative reactivity of the halides is very similar to that exhibited in Sn2 reactions. Also, inversion of configuration occurs at the site of substitution. This evidence suggests that the transition state involves nucleophilic displacement of halide, but the details of the mechanism are still open to question. 

In reality, whereas full inversion of stereochemistry is always seen in Sn2 reactions, full racemization of stereochemistry in S l reactions is rare. Instead, partial inversion of stereochemistry is commonly found. In the solvolysis of l-phenylneojaentyl tosylate in acetic acid (Eq. n. 26), the reaction goes with 10% excess inversion. This observation is consistent with the participation of a contact ion pair. We already concluded that such a structure had to be an i ntermediate due to the results of competition kinetics. 

There are other common GO signs, or clues, in many Sn2 problems. Every time you see Sn2 you must think inversion —all Sn2 reactions go with inversion. There are also good nucleophiles that appear often in Sn2 problems. Cyanide (NC ), mercaptan (HS ), and thiolate (RS ) are good examples of ions that should make good nucleophile appear in your mental pull-down menu. 

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