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8.7: Peculiarities in Substitution Chemistry

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    Finally, there are a few important features and/or exceptions that occur for substitution reactions, whether SN1 or SN2:


    Substitution of small rings

    Small rings are notoriously slow SN2 substrates. Why? Recall that the transition state for an SN2 reaction involves the formation of a pentacoordinate intermediate. The carbon atom in this intermediate will need to adopt a planar geometry, with bond angles of 120°. Because cyclopropyl rings have considerable angle strain (forced to be 60°), their rates of SN2 will be much slower. They cannot adopt this geometry very easily, and the transition state energy will be incredibly high.

    Screen Shot 2021-05-20 at 10.47.35 AM.png

    Substitution of cyclohexyl derivatives

    By contrast, when cyclohexane rings have a leaving group attached, substitution can occur, but only in a particular conformation. When the leaving group occupies an equatorial position, the \(σ^{*}_{C-X}\) is positioned over the inside of the ring. When a nucleophile approaches, it must pass through the center of the ring, where it is blocked by eclipsing hydrogens, and occurs more slowly. If the leaving group is axial, the SN2 reaction can occur, even though the conformation itself is higher in energy.

    Screen Shot 2021-05-20 at 10.48.05 AM.png

    Proper overlap of orbitals

    For an SN2 reaction, proper orbital overlap of the incoming nucleophile and the \(σ^{*}_{C-X}\) is needed. If this orbital is blocked, or otherwise inaccessible, the reaction will not occur. This can happen for neopentyl systems, bicyclic systems, or intramolecular substrates.

    Screen Shot 2021-05-20 at 10.48.09 AM.png

    Substitution of epoxides

    Nucleophilic substitution that results in the opening of epoxides (three-membered rings containing oxygen) can be both SN2-like or SN1-like depending on the reaction conditions. Under basic or neutral conditions, the nucleophile will attack via SN2 at the less highly substituted carbon atom. Under acidic conditions, the oxygen will protonate and then, if possible, open up to form a stable carbocation. This results in an SN1 reaction.

    Screen Shot 2021-05-20 at 10.48.17 AM.png

    Deprotonation of weak nucleophiles

    Weak nucleophiles like alcohols and water can be made more nucleophilic by deprotonation. This increases the HOMO of the nucleophile (increase in energy of nonbonding electrons). In some mechanisms, if a base is present, it is likely to deprotonate the acidic proton of the nucleophile to generate a more reactive species.

    Screen Shot 2021-05-20 at 10.48.23 AM.png

    The reaction between an alkoxide (conjugate base of an alcohol) and an alkyl halide or sulfonate results in an SN2 reaction that forms an ether. This is known as a Williamson ether synthesis, which is the first named reaction that you have come across. Name reactions are important reactions in organic chemistry that are described by the person who discovered them.


    Intramolecular substitution

    Reactions between electrophile and nucleophile can occur between two different exogenous species, but can also occur within the same molecule. Intramolecular reactions are faster than intermolecular reactions because there is very little entropic cost – the starting material is preorganized to react.

    Screen Shot 2021-05-20 at 10.48.27 AM.png

    SN1/SN2 competition

    Secondary carbons will undoubtedly exhibit features of both SN1 and SN2 reactivity. While SN1 reactivity is normally reserved for tertiary carbons, and SN2 reactivity for primary carbons, there is considerable overlap for secondary carbons. Using different reaction conditions can normally force one or the other mechanism.

    8.7: Peculiarities in Substitution Chemistry is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by LibreTexts.

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