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(a) Consider the following reactions : enter image description here

For these two reactions, the nucleophile attacks the less substituted carbon as it is less sterically hindered.

(b) Now consider the following reactions : enter image description here

For these three reactions, attack occurs on the more substituted carbon. I think the explanation for this is that in the transition state, the carbon undergoing attack has a slight cationic character, and can be somewhat stabilized by hyperconjugation, hence lowering the activation barrier for the reaction.

So my question is this : Among steric hindrance (a) and electronic considerations (b), which is the more dominant factor when deciding which carbon to attack? Is it related to the nucleophile used? Is it related to the nature of the heterocycle? Or is the ring-opening and nucleophilic attack non-concerted in some cases? Is it related to hard soft bases? Thanks for any answers in advance.

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1 Answer 1

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As evident by OP's given examples, the more dominant factor here is the strength of the nucleophile and the reaction conditions. For example, in $\bf{a}$, the nucleophiles are strong and reactions are under basic conditions (both Grignard reagents and acetylenides are basic). Thus, reaction mechanism is $\mathrm{S_N2}$ type so that nucleophile is attacking less hindreard carbon (recall the order of the $\mathrm{S_N2}$ is $\ce{CH3} \gt 1^\circ \gt 2^\circ \gt\gt 3^\circ$).

On the other hand, in $\bf{b}$, the nucleophiles are very weak and reactions are under acidic conditions (reaction should be acid-catalysed with weak nucleophiles; Ref.1 and 2). Thus, reaction mechanism is $\mathrm{S_N1}$ type so that nucleophile is attacking more hindreard carbon, wgich stabilized the partial positive charge (recall the order of the $\mathrm{S_N1}$ is $3^\circ \gt 2^\circ \gt\gt 1^\circ $ and noreaction with $\ce{CH3}$). The first two examples of $\bf{b}$ are not epoxides, but same principle applies:

Acid catalyzed epoxide

References:

  1. David Runciman Boyd and Ernest Robert Marle, "CXCVI.—The velocities of combination of sodium derivatives of phenols with olefine oxides," J. Chem. Soc., Trans. 1914, 105, 2117-2139 (DOI: https://doi.org/10.1039/CT9140502117).
  2. For further information, read this, this, this, and this.
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