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In an effort to improve the predictability of retrosynthetic analysis, the simplifying assumption is implied that all functional groups of the same class react for all practical purposes with the same ease. Thus it is assumed that the classes: aldehydes, ketone, nitrile, nitro etc. display similarity in reaction. Sometimes a distinction is drawn between the functionality when attached to aryl as opposed to alkyl, but refinement rarely goes further than this. The combined particular electronic and steric effects in the vicinity of the functional groups is essentially ignored. Usually this simplification is a good one.

The more reactive group must usually be more than 100 times more reactive to obtain a quantitatively selective reaction. This can be seen to be true because to be essentially quantitative, when a reaction is 99% complete, the final 1% of starting material must be more reactive than the 99% of product, which could react further at the second functional group. If it is not that much more reactive, the reaction cannot expect to be quantitative (kinetic control assumed here).

This explains the widespread use of protecting groups to address the situation wherein a substrate contains two functionalities of the same type and the reaction of only a particular one is required.

There are situations however where it is documented that the same functional group in different environments react at usefully different rates. This can be the basis for separation of compound mixtures by reaction where the competition in reactivity is between the same nominal group in different substrates. Alternately, such a marked difference in reactivity can be the basis for a synthetic step which converts only one of two functional groups of the same class in an intramolecular competition.

For example suppose one is presented with a mixture of regioisomers, 4-methylethylbenzonitrile and 2-methylethyl-benzonitrile. Although each isomer contains a nominal nitrile, the nitrile groups are not equal in reactivity. It is reported that ortho substituted aryl nitriles do not readily for imidates by reaction with ethanol and anhydrous hydrogen chloride.

Thus if we were to treat a mixture of these nitriles with anhydrous hydrogen chloride in ethanol, we can expect only the para substituted compound to react and this can be used in a simple separation.

Another application can be found using the Zinn reduction of aryl nitro compounds to perform a selective reduction.

Thomas R. Nickson wrote a research article J. Org. Chem. 1986, 51, 3903-3904. The article taught that in the specific case of 3-trifluoromethyl toluene, when it is nitrated the compound formed in largest amount, the 2-nitro could be isolated in pure form because it was the only isomer than did not undergo the Zenin reduction with sodium sulphide and sulphur. Dr. Nickson however also taught that 3-methyl benzaldehyde and 3-methyl benzoic acid both nitrated preferentially in the 2 position. From my own experience I know that the compound 3,4-dichlorobenzaldehyde nitrates preferentially in the 2-position. It is possible that all 1,3-substituted compounds with one electron withdrawing group and one electron donating group nitrate preferentially in the 2 position AND may be separable by their failure to react in the Zenin reduction! Nickson tells us that one electron withdrawing group is advantageous to achieve a fast reduction but he was able to obtain 2-nitro m-xylene and separate it cleanly although in poor yield by reducing the other isomers but this reduction went slowly.

Also when the two substituents are both ortho-para directing the yield of the 2 isomer is much lower (10%) in the case of m-xylene. It is not clear whether the reaction scheme would work with two deactivating groups meta to each other.

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