Inter- and Intra-Molecular Organocatalysis of SN2 Fluorination by Crown Ether: Kinetics and Quantum Chemical Analysis.

Young-Ho Oh,Dong-Wook Kim,Sung-Woo Jang,Sungyul Lee,Chul-Hee Kim,Wonhyuck Yun,Sung-Sik Lee

doi:10.3390/molecules26102947

Young-Ho Oh, Dong-Wook Kim + Show 5 more

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https://doi.org/10.3390/molecules26102947

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Abstract

We present the intra- and inter-molecular organocatalysis of SN2 fluorination using CsF by crown ether to estimate the efficacy of the promoter and to elucidate the reaction mechanism. The yields of intramolecular SN2 fluorination of the veratrole substrates are measured to be very small (<1% in 12 h) in the absence of crown ether promoters, whereas the SN2 fluorination of the substrate possessing a crown ether unit proceeds to near completion (~99%) in 12 h. We also studied the efficacy of intermolecular rate acceleration by an independent promoter 18-crown-6 for comparison. We find that the fluorinating yield of a veratrole substrate (leaving group = −OMs) in the presence of 18-crown-6 follows the almost identical kinetic course as that of intramolecular SN2 fluorination, indicating the mechanistic similarity of intra- and inter-molecular organocatalysis of the crown ether for SN2 fluorination. The calculated relative Gibbs free energies of activation for these reactions, in which the crown ether units act as Lewis base promoters for SN2 fluorination, are in excellent agreement with the experimentally measured yields of fluorination. The role of the metal salt CsF is briefly discussed in terms of whether it reacts as a contact ion pair or as a “free” nucleophile F−.

Highlights

Accepted: 12 May 2021SN 2 reactions [1–13] are such fundamental chemical transformations that have been studied for so long that the mechanism of this important and useful process is usually considered to be perfectly understood
The slightly larger observed yield for fluorination of 1 preFigure 1 depicts our present scheme designed to verify the effects of crown ethers on sented in Figure 1 may indicate that a small portion of 2 and 3 does not form 1:1 complex
We carried out intramolecular SN 2 fluorination of 1 promoted by the fused crown ether unit, in comparison with the SN 2 fluorination of 2

Summary

Introduction

SN 2 reactions [1–13] are such fundamental chemical transformations that have been studied for so long that the mechanism of this important and useful process is usually considered to be perfectly understood. It was commonly assumed that the counter-cation is sufficiently far from the nucleophile, so that the countercation/nucleophile may be considered to be a solvent-separated ion-pair In this regard, some useful wisdom has been frequently invoked concerning the role of counter-cation and solvent for SN 2 reactions: alkali metal cations are considered to be inefficient as countercation, and protic solvents (water, alcohols) are to be avoided because of the harmful hydrogen bonding through –OH with the nucleophile. We examine the mechanisms of fluorination for the reactants to estimate the role of intramolecular crown ether unit in 1 and the two methoxy groups in 2 for enhancing the SN 2 rates. Our calculations illustrate that the mechanisms of these observed kinetics are such that the crown ether units act as Lewis base promoters [17–22,29] for SN 2 fluorination. Brief discussion is given concerning the role of the metal salt CsF in relation to whether it reacts as a contact ion pair [30] or not

Materials and Methods

Intra- and inter-molecular

From the role of

Results

Conclusions