# Influence of Halogen Atoms and the Reactivity of Nucleophiles on Reactions of Tetrahydropyran and Tetrahydrofuran Acetals with C‑Nucleophiles: Hyperconjugation and Inductive Effects

## TL;DR

This paper explores how halogen atoms and nucleophile reactivity affect the stereoselectivity of acetal substitution reactions.

## Contribution

The study reveals how hyperconjugation and inductive effects influence stereoselectivity in acetal reactions with C-nucleophiles.

## Key findings

- Fluorine-substituted tetrahydropyran acetals produce 1,2-cis products due to hyperconjugative effects.
- Chlorine- and bromine-substituted acetals yield 1,2-trans products due to stronger inductive effects.
- Five-membered-ring acetals show similar stereoselectivity trends but with different reactivity patterns.

## Abstract

Tetrahydropyran acetals bearing a fluorine atom adjacent
to the
acetal carbon atom can undergo highly stereoselective substitution
reactions with nucleophilic alkenes to give the 1,2-cis products. By contrast, the chlorine- and bromine-substituted acetals
give the 1,2-trans products. These results can be
understood by considering oxocarbenium ion intermediates and their
conformational preferences, which are dictated by hyperconjugative
effects from axial substituents, with F ≪ H < Cl < Br.
Reactions of the corresponding five-membered-ring acetals are also
1,2-cis selective in the case of fluorine and 1,2-trans selective with chlorine- and bromine-substituted acetals,
but selectivities showed different trends of reactivity vs selectivity.
The reactions with the five-membered-ring acetal were interpreted
as requiring anomeric halides as reactive intermediates because of
the conditions required to obtain substitution products.