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SN2 - Second-order Nucleophilic Substitution

Isotopic Labeling Experiments in the Investigation of SN2 Reactions

An isotopic labeling experiment may provide evidence for the complete inversion of absolute configuration by an SN2 reaction. If a pure enantiomer of a chiral, optically-active alkyl iodide that contains only non-radioactive iodine atoms is treated with radioactive iodide I125 (γ emitter, half-life about 60 days), an SN2 reaction occurs. In this reaction, the non-radioactive iodide of the initial alkyl iodide is replaced by the radioactive iodide I125. By the workup, the released non-radioactive iodide and the radioactive iodide that has not been consumed by the SN2 reaction are then separated from the alkyl iodide. The alkyl iodide sample contains initial non-radioactive alkyl iodide and radioactive alkyl iodide, which has been produced through the SN2 reaction. The ratio of radioactive to non-radioactive alkyl iodide can be determined with the help of a scintillation counter. The ratio depends on the turnover of the SN2 reaction.

Fig.1
Isotopic labeling experiment.

How can it be proven by this experiment that complete inversion of configuration occurs in an SN2 reaction?

First of all, the specific rotation of the starting product, which should be a pure enantiomer, must be measured. The corresponding I125-substituted, radioactive enantiomer with the same absolute configuration displays almost the exact same specific rotation. If the turnover of the SN2 reaction is complete and the configuration is inverted, a pure, radioactive alkyl iodide is obtained, which is enantiomeric to the initial alkyl iodide. That is, the product has an absolute configuration that is the complete opposite of that of the starting product. Consequently, its specific rotation has the same value as the starting product's specific rotation though its sign is exactly the opposite. If the turnover is incomplete, the specific rotation of the product mixture (radioactive and non-radioactive alkyl iodide) is between the specific rotations of the pure enantiomers, and its value corresponds directly to the turnover. That is, if the turnover amounts to 50 %, for instance, the specific rotation is zero.

If a specific rotation of the product mixture that does not correspond in this way to the turnover is detected, in the SN2 reaction only incomplete inversion of configuration could have occurred. If the specific rotation had not been altered at all, complete retention would have been proven. Racemization would have been shown, if the specific rotation lies half way between the initial specific rotation of the starting product and the specific rotation that is expected depending on the turnover in the case of a complete inversion of configuration.

The isotopic labeling experiment in the investigation of the SN2 mechanism explained above cannot be carried out with primary alkyl iodides, as their carbon carrying iodine is not asymmetrically substituted. Therefore, it is also not optically active and the reaction cannot be investigated by observing the change in optical rotation. If the primary alkyl iodide is optically active, the chirality center can obviously not be the carbon carrying the iodine. Consequently, the specific rotation would not be altered even if complete inversion of the reaction center's configuration occurs. Tertiary alkyl iodides also prove to be unuseful for the isotopic labeling experiments in the investigation of SN2 reactions, as they virtually never react in SN2 reactions, but rather in SN1 reactions or eliminations instead.

Many isotopic labeling experiments have been carried out in order to investigate the stereochemistry of SN2 reactions. These experiments have proven that in pure SN2 reactions complete inversion always occurs.

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