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3.9: Protecting Groups in Organic Synthesis

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    One of the major problems in organic synthesis is the suppression of unwanted side reactions. Frequently the desired reaction is accompanied by reaction at other parts of the molecule, especially when more than one functional group is present. Functional groups usually are the most reactive sites in the molecule, and it may be difficult or even impossible to insulate one functional group from a reaction occurring at another. Therefore any proposed synthesis must be evaluated at each step for possible side reactions that may degrade or otherwise modify the structure in an undesired way. To do this will require an understanding of how variations in structure affect chemical reactivity. Such understanding is acquired through experience and knowledge of reaction mechanism and reaction stereochemistry.

    To illustrate the purpose and practice of protecting groups in organic synthesis, let us suppose that the synthesis of cis-2-octene, which we outlined in Section 13-7, has to be adapted for the synthesis of 5-octyn-1-ol. We could write the following:

    Roberts and Caserio Screenshot 13-10-1.png

    However, the synthesis as written would fail because the alkyne is a weaker acid than the alcohol (Section 11-8), and the alkynide anion would react much more rapidly with the acidic proton of the alcohol than it would displace bromide ion from carbon:

    Roberts and Caserio Screenshot 13-10-2.png

    The hydroxyl group of 4-bromo-1-butanol therefore must be protected before it is allowed to react with the alkynide salt. There are a number of ways to protect hydroxyl groups, but one method, which is simple and effective, relies on the fact that unsaturated ethers of the type Roberts and Caserio Screenshot 13-10-3.png are very reactive in electrophilic addition reactions (Section 10-4). An alcohol readily adds to the double bond of such an ether in the presence of an acid catalyst:

    Roberts and Caserio Screenshot 13-10-4.png

    The protected compound is a much weaker acid than the alkyne, and the displacement reaction can be carried out with the alkynide salt without difficulty. To obtain the final product, the protecting group must be removed, and this can be done in dilute aqueous acid solution by an \(S_\text{N}1\) type of substitution (Sections 8-7D and 8-7E):

    Roberts and Caserio Screenshot 13-10-5.png

    Contributors and Attributions

    John D. Robert and Marjorie C. Caserio (1977) Basic Principles of Organic Chemistry, second edition. W. A. Benjamin, Inc. , Menlo Park, CA. ISBN 0-8053-8329-8. This content is copyrighted under the following conditions, "You are granted permission for individual, educational, research and non-commercial reproduction, distribution, display and performance of this work in any format."

    This page titled 3.9: Protecting Groups in Organic Synthesis is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by John D. Roberts and Marjorie C. Caserio.