Stereochemistry to Deduce Mechanism

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Chapter: Organic Chemistry : Stereochemical and Conformational Isomerism

In the above discussion of stereoselectivity the mechanisms of various reactions have been used to rationalize why some are stereoselective and some are not.


In the above discussion of stereoselectivity the mechanisms of various reactions have been used to rationalize why some are stereoselective and some are not. Thus the bromination of olefins proceeds via a bridged bromonium ion interme-diate and gives only trans addition across the double bond [reactions (6.2) and (6.3)]. In contrast, the addition of HBr across a double bond gives a carboca-tion intermediate that does not maintain the facial integrity of the olefin and is thus much less stereoselective [reaction (6.1)]. In these examples the mechanism of the reaction is used to explain and understand the diastereoselectivity that is observed. There are many other examples (usually in textbooks) where the mech-anism of a reaction is used to rationalize the stereoselectivity of the process. To do this requires that the mechanism be known with certainty.

In most cases in the real world of chemistry both currently and historically, the reverse order is followed; that is, the mechanism is deduced with certainty only after the stereoselectivity has been determined. Because the stereochemical out-come of a chemical reaction is experimentally determined, it provides a powerful tool for examining the intimate spatial details of transition states and for deter-mining how a reaction takes place at the molecular level. As such stereochemical studies have had a huge impact on the elucidation of reaction mechanisms.

In addition to bond breaking and charge buildup in the transition state, stere-ochemical changes during a reaction provide insight into the structural require-ments of the activated complex of the rate-determining step. If a reaction is stereospecific, that is, if only one stereoisomer is formed in a reaction, then there is likely to be a particular spatial relationship between groups that is required for efficient product formation. (The key here is the term “efficient” because reactions can sometimes proceed if the correct spatial relationship is not obtain-able, but they will go much more slowly.) If a reaction is stereoselective, that is, if one stereoisomer is the major but not exclusive product, then one particular spatial relationship is favored over another in the product-forming step. If the stereoselectivity of a reaction can be understood, then key structural elements in the activated complex can often be identified.

Several common examples show the power of this reasoning. The reaction of osmium tetroxide with olefins followed by reduction gives diols resulting exclu-sively from syn addition to the double bond. The reaction is hence stereospecific The addition stereochemistry is clearly seen in cyclic olefins, but it is also seen in acyclic olefins where single diastereomers are produced [reaction (6.4)].

The results from the cyclic series show that both oxygens come from the same side of the double bond, probably from a single OsO4 molecule. The results in the acyclic series demonstrate that both oxygens add to the ends of the double bond at the same time. If one oxygen added first, an intermediate with a sin-gle carbon – carbon bond would be formed which could isomerize by rotation around that bond. The observation of complete diastereoselectivity requires that both C–O bonds be formed simultaneously. Thus a concerted addition across the double bond is the most reasonable pathway consistent with these results. The stereochemical analysis is shown below for the cis starting material.

An analogous analysis for the trans olefin would predict only the d,l diastereomer for concerted addition of OsO4 to the π bond, but the same meso – d,l mixture would be obtained if the addition were stepwise.

Contrast the above syn addition of osmium tetroxide with the well-known anti stereochemistry found in the addition of bromine to alkenes. Cyclic systems give only trans addition in most cases, and acyclic olefins give single diastereomers that depend on the geometry of the starting olefin. These results are consistent with one bromine adding to one face of the olefin to give a bridged ion which maintains the stereochemistry of the original olefin. Bromide ion adds from the opposite face to give a single diastereomeric dibromide product.

Walden inversion was the term given to the change in stereochemistry observed in bimolecular nucleophilic substitutions. For example, reaction of (2S)-2-triflyloxyesters with sodium azide gives (2R)-2-azidoesters.

Inversion of configuration requires that the nucleophile adds electrons to the σ orbital of the carbon – triflate bond from the side opposite that bond. As required by the stereochemistry, formation of the bond from azide to carbon is concurrent with cleavage of the carbon leaving group bond.

If racemization were observed, it could only be due to a cleavage of one of the bonds to the chiral center prior to carbon – nitrogen bond formation or subsequent to it. This could occur by (a) enolization of the starting triflate, (b) an ionization of triflate to a carbocation and then nucleophilic attack by the azide, or (c) enolization in the azido product. The fact that clean inversion occurs means not only that the substitution by azide occurs with inversion but also that none of these other processes is significant under the reaction conditions since they would lead to racemized product.

The stereoelectronic requirements of groups undergoing base-promoted elimination is also easily seen by stereochemical studies. Treatment of trans-2-methylcyclohexyl tosylate gives 3-methylcyclohexene as the major product while treatment of cis-2-methylcyclohexyl tosylate gives the more stable 1-methylcyclohexene as the only product.

These data are consistent with the favored transition state having an antiperiplanar relationship between the proton being removed and the leaving group. In a six-membered ring, this can only occur when they both are diaxial. In the trans isomer, the conformation in which the tosylate is axial only has a proton at C-6 axial and antiperiplanar. Thus elimination occurs across C-6 and C-1 to give only 3-methyl cyclohexene. In the cis isomer, the conformation in which the tosylate group is axial has antiperiplanar hydrogens at both C-2 and C-6. Elimination could proceed in either direction; however, removal of the proton at C-2 is favored because the more stable olefin product is produced.

These examples show the power of stereochemical information in pinpointing structural elements of activated complexes. Combined with other types of mech-anistic information, even the most intimate mechanistic details can be clarified in many cases. For example, consider the solvolysis in ethanol of 3-phenyl-2-tosyloxy butane in which the replacement of the tosylate group by a solvent nucleophile is noted.

While this appears to be a simple substitution reaction, the details can be further explored. It was found that this reaction proceeded by a first-order rate law, which suggests an ionization pathway (Sn1) for the substitution. However, when a group of substituted aromatic compounds were investigated, plots of the rate constants (log kZ/ kH) gave a much better correlation with σZ+ than with σz and ρ+ = −1.3. This Hammett study reveals that a positive charge is developed on the aromatic ring in the transition state of the rate-determining step. About the only way for this to happen is for the phenyl ring to interact with the positive charge produced by the ionization of the leaving group.

The use of the 2R,3R isomer led to formation of only 2R,3R-2-ethoxy-3-phenylbutane. Thus the configuration at each chiral center was retained in the product. These stereochemical data rule out simple ionization and solvent capture as a reaction mechanism since this would lead to a mixture of 2R and 2S configurations. From these observations it has been postulated that the phenyl group assists ionization of the leaving group by electron donation to produce a bridged ion.

The bridged ion has a positive charge delocalized over the aromatic ring as required by the σZ+ correlation. Furthermore the solvent nucleophile can only add from the side opposite the bridging phenyl group, leading to retention of configuration as the stereochemical results demand.

Stereochemical studies can be an indispensable adjunct to other types of mech-anistic investigations for unraveling the details of reaction processes. They allow the positions of atoms or groups in a molecule to be tracked through a reaction, thereby revealing the spatial requirements of the reaction.

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