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20.11 Protecting Groups of Aldehydes

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  • Protection of Aldehydes and Ketones

    Since alcohols, aldehydes and ketones are the most frequently manipulated functional groups in organic synthesis, a great deal of work has appeared in their protection / deprotection strategies. In this discussion let us focus on the classes of protecting groups rather than an exhaustive treatment of all the protections.

    Acetals as Protecting Groups

    The importance of acetals as carbonyl derivatives lies chiefly in their stability and lack of reactivity in neutral to strongly basic environments. As long as they are not treated by acids, especially aqueous acid, acetals exhibit all the lack of reactivity associated with ethers in general. Among the most useful and characteristic reactions of aldehydes and ketones is their reactivity toward strongly nucleophilic (and basic) metallo-hydride, alkyl and aryl reagents. If the carbonyl functional group is converted to an acetal these powerful reagents have no effect; thus, acetals are excellent protective groups, when these irreversible addition reactions must be prevented.

    In the following example we would like a Grignard reagent to react with the ester and not the ketone. This cannot be done without a protecting group because Grignard reagents react with esters and ketones.



    Silyl Ethers (R – OSiR3) as Protecting Groups of alcohols

    Often during the synthesis of complex molecules on functional group in a molecule interferes with an intended reaction on a second functional group on the same molecule. An excellent example is the fact that a Grignard reagent can't be prepared from halo alcohol because the C-Mg bond is not compatible with the acidic -OH group.

    When situations like this occurs chemists circumvent eh problem by protecting the interfering functional group. Functional group protection involves three steps:

    1. Blocking the interfering functionality by introducing a protecting group.
    2. Performing the intended reaction.
    3. Removing the protecting group and reforming the original functional group.

    There are several methods for protecting an alcohol, however, the most common is the reaction with a chlorotrialkylsilane, Cl-SiR3 This reactions forms a trialkylsilyl ether, R'-O-SiR3. Chlorotrimethylsilane is often used in conjuction with a base, such as triethylamine, The base helps to form the alkoxide anion and remove the HCl produced by the reaction. Another very useful example uses tert-butyldimethylsilyl chloride (TBDMSCl) and imidazole to protect the alcohol as a silyl ether.

    General Reaction

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    The silyl ether protecting group can be removed by reaction with an aqueous acid or the fluoride ion.

    By utilizing a protecting group a Grignad reagent can be formed and reacted on a halo alcohol.

    1) Protect the Alcohol

    2) Form the Grignard Reagent

    3) Perform the Grignard Reaction

    4) Deprotection


    Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)

    Prof. Steven Farmer (Sonoma State University)

    Dr. Layne A. Morsch - University of Illinois Springfield