# Nucleophilic Fluorination of a Secondary Alkyl Bromide with KF(18‐Crown‐6) and Bulky Diols: Microsolvation Causes Chemoselectivity Inversion in the Free Energy Profile

## TL;DR

This study shows how adding specific alcohols improves fluorination reactions of certain chemical compounds.

## Contribution

The study identifies bulky diols that significantly enhance SN2 selectivity in nucleophilic fluorination reactions.

## Key findings

- Bulky diols like BDMb-F6 increase SN2 pathway preference by 5.6 kcal mol−1.
- TBOH-F3, pinacol, and BDMb-F6 improve SN2:E2 selectivity compared to TBOH.
- Microsolvation of fluoride ion by hydrogen bond donors explains the chemoselectivity inversion.

## Abstract

Fluoride ion solvated in polar aprotic solvents works like bases and reacts with secondary alkyl bromide substrates mainly via E2 reactions, with minor formation of SN2 fluorination products. The use of KF combined with crown ether increases the SN2 yield. However, secondary substrates remain a challenge for nucleophilic fluorination. It has recently been demonstrated that crown ethers combined with the fluorinated tert‐butyl alcohol (TBOH) TBOH‐F3 can increase the KF salt reactivity and selectivity toward SN2 reactions. These observations can be explained by the microsolvation of the fluoride ion with hydrogen bond donor species. This study explores computationally the effect of bulky diols in the reaction of KF(18‐crown‐6) with 2‐bromopropane as a model substrate. This study investigates the microsolvation by TBOH, TBOH‐F3, and the bulky diols pinacol and BDMb‐F6, aimed at evaluating their effect on the SN2:E2 product ratio. Considering the competitive pathways, results show that TBOH is the least effective, while bulky alcohol TBOH‐F3, pinacol, and BDMb‐F6 favor the SN2 pathway by 0.5, 1.6, and 5.6 kcal mol−1. Thus, the study's findings indicate that pinacol and especially the BDMb‐F6 diol are highly promising alcohols for achieving greater SN2:E2 selectivity in nucleophilic substitution reactions utilizing KF(18‐crown‐6).

The combination of crown ether with strong hydrogen bond donor bulky diols enhances reactivity and SN2 selectivity in challenging fluorination reactions of secondary alkyl bromide substrates.© 2025 WILEY‐VCH GmbH