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 S_N1 or S_N2:

Substitution of small rings

Small rings are notoriously slow S_N2 substrates. Why? Recall that the transition state for an S_N2 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 S_N2 will be much slower. They cannot adopt this geometry very easily, and the transition state energy will be incredibly high.

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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 S_N2 reaction can occur, even though the conformation itself is higher in energy.

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Proper overlap of orbitals

For an S_N2 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.

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Substitution of epoxides

Nucleophilic substitution that results in the opening of epoxides (three-membered rings containing oxygen) can be both S_N2-like or S_N1-like depending on the reaction conditions. Under basic or neutral conditions, the nucleophile will attack via S_N2 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 S_N1 reaction.

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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.

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The reaction between an alkoxide (conjugate base of an alcohol) and an alkyl halide or sulfonate results in an S_N2 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.

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S_N1/S_N2 competition

Secondary carbons will undoubtedly exhibit features of both S_N1 and S_N2 reactivity. While S_N1 reactivity is normally reserved for tertiary carbons, and S_N2 reactivity for primary carbons, there is considerable overlap for secondary carbons. Using different reaction conditions can normally force one or the other mechanism.