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

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 S_N2 fluorination products. The use of KF combined with crown ether increases the S_N2 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 S_N2 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 S_N2: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 S_N2 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 S_N2:E2 selectivity in nucleophilic substitution reactions utilizing KF(18-crown-6).

Keywords: crown compounds; density functional calculations; fluorine; hydrogen bonds; solvent effects.

Figure 1

FDA‐approved drugs containing primary and secondary alkyl fluorides.

Figure 2

Reactivity of the fluoride ion under different conditions.

Figure 3

Schematic representation of the KF(18C6) complex microsolvated by different alcohols, ROH, for the S_N2 nucleophilic fluorination reaction with 2‐bromopropane, and how the microsolvated environment can increase S_N2:E2 selectivity, according to the Gibbs free energy profile, ΔG.

Figure 4

Free energy profile in acetonitrile solution for the reaction KF(18C6) + iPrBr + TBOH. The more stable transition states in each step are shown: TS(E2anti) and TS(S_N2)‐TBOH, respectively. Calculations using a composite method: ωB97M‐V/ma‐def2‐TZVPP for electronic energy, X3LYP/ma‐def2‐SVP for optimization, frequencies, and conductor‐like polarizable continuum model (CPCM) for solvation free energy. Units of kcal mol⁻¹, 1 mol L⁻¹ standard state.

Figure 5

Free energy profile in acetonitrile solution for the reaction KF(18C6) + iPrBr + TBOH‐F3. The more stable transition states in each step are shown: TS(E2anti) and TS(S_N2)‐TBOH‐F3, respectively. Calculations using a composite method: ωB97M‐V/ma‐def2‐TZVPP for electronic energy, X3LYP/ma‐def2‐SVP for optimization, frequencies, and CPCM for solvation free energy. Units of kcal mol⁻¹, 1 mol L⁻¹ standard state.

Figure 6

From left to right: optimized geometries in acetonitrile solution of the KF(18C6)‐DIOL, KF(18C6)‐BDMb‐F6 complexes, and the [KF(18C6)‐BDMb‐F6]₂ dimer. Interaction energies were calculated from the separated species with KF in the gas phase using the ωB97M‐V/ma‐def2‐TZVPP level of theory for electronic energy.

Figure 7

Free energy profile in acetonitrile solution for the reaction KF(18C6) + iPrBr + 2,3‐DIOL. The more important transition states in each step are shown: TS(E2anti), TS(S_N2)‐DIOL, and TS(E2anti)‐DIOL. Calculations using a composite method: ωB97M‐V/ma‐def2‐TZVPP for electronic energy, X3LYP/ma‐def2‐SVP for optimization, frequencies, and CPCM for solvation free energy. Units of kcal mol⁻¹, 1 mol L⁻¹ standard state.

Figure 8

Free energy profile in acetonitrile solution for the reaction KF(18C6) + iPrBr + BDMb‐F6. The more important transition states in each step are shown: TS(E2anti), TS(S_N2)‐BDMb‐F6, and TS(E2anti)‐BDMb‐F6. Calculations using a composite method: ωB97M‐V/ma‐def2‐TZVPP for electronic energy, X3LYP/ma‐def2‐SVP for optimization, frequencies, and CPCM for solvation free energy. Units of kcal mol⁻¹, 1 mol L⁻¹ standard state.