Handling fluorinated gases as solid reagents using metal-organic frameworks

Abstract

Fluorine is an increasingly common substituent in pharmaceuticals and agrochemicals because it improves the bioavailability and metabolic stability of organic molecules. Fluorinated gases represent intuitive building blocks for the late-stage installation of fluorinated groups, but they are generally overlooked because they require the use of specialized equipment. We report a general strategy for handling fluorinated gases as benchtop-stable solid reagents using metal-organic frameworks (MOFs). Gas-MOF reagents are prepared on gram-scale and used to facilitate fluorovinylation and fluoroalkylation reactions. Encapsulation of gas-MOF reagents within wax enables stable storage on the benchtop and controlled release into solution upon sonication, which represents a safer alternative to handling the gas directly. Furthermore, our approach enables high-throughput reaction development with these gases.

Fig. 1. Delivery of fluorinated gases using MOFs.

(A) Examples of drug-like molecules bearing fluoroalkyl and fluoroalkenyl groups. (B) Fluorinated gaseous building blocks. (C) Streamlined synthesis using VDF (6). (D) Overview of gas reagent delivery strategies, including balloons, generation from molecular precursors, and release from porous materials (this work). (E) The volume of 1 mmol of an ideal gas compared to 1 mmol of gas contained in a MOF (Mg₂(dobdc) with a crystallographic density of 0.909 g/cm³ (25, 26) and one gas molecule per metal site).

Fig. 2. Fluorinated gas adsorption in open metal site materials.

(A) Comparison of storage capacity and binding enthalpy for VDF in porous materials. (B) Comparison of storage capacity (blue) and binding enthalpy (red) for fluorinated gases in Mg₂(dobdc). (C) Magic-angle spinning ¹⁹F solid-state NMR spectrum of VDF–Mg₂(dobdc) (blue) compared to solution-state ¹⁹F NMR spectrum of VDF in THF (red). (D) Rietveld refinement of VDF–Mg₂(dobdc). Measured diffraction data (blue), fitted pattern (red), and the difference (black) are shown. Weighted residual factor (R_wp) = 11.9%. Inset: Structural model for VDF–Mg₂(dobdc). THF: tetrahydrofuran.

Fig. 3. Delivery and synthetic transformations of VDF and HFP.

NMR yields were determined by ¹⁹F NMR using fluorobenzene as an internal standard. Isolated yields are shown in parentheses. See supplementary information for experimental details. (A) Percentage of VDF delivered to solution (determined by ¹⁹F NMR) from freshly prepared VDF–Mg₂(dobdc) or wax-encapsulated VDF–Mg₂(dobdc). (B) Scope of Pd-catalyzed defluorinative coupling of VDF and (hetero)arylboronic acids using VDF–Mg₂(dobdc). The yields in the first row correspond to reactions using freshly prepared VDF–Mg₂(dobdc) that was dispensed using a solid-addition funnel. The yields in the second row (wax) correspond to reactions using VDF–Mg₂(dobdc) wax capsules that were left on the benchtop for 24 h and then broken to dispense VDF–Mg₂(dobdc). (C) Pd-catalyzed defluorinative coupling of HFP and arylboronic acids using HFP–Mg₂(dobdc). (D) Performance of VDF–Mg₂(dobdc) in defluorinative coupling with 4-biphenylboronic acid after storage under different conditions. *Wax capsule was cut open prior to dispensing VDF–Mg₂(dobdc). DMF: N,N-dimethylformamide.

Fig. 4. Generalizability of gas–MOF delivery.

NMR yields were determined by ¹⁹F NMR spectroscopy using fluorobenzene as an internal standard. Isolated yields are shown in parentheses. See supplementary information for experimental details. The yields in the first row correspond to reactions using freshly prepared gas–Mg₂(dobdc) that was dispensed using a solid-addition funnel. The yields in the second row (wax) correspond to reactions using gas–Mg₂(dobdc) wax capsules that were left on the benchtop for 24 h and then broken to dispense gas–Mg₂(dobdc). (A) Scope of Negishi coupling of (hetero)aryl halides and VDF–ZnCl•TMEDA synthesized from VDF–Mg₂(dobdc). *Pd(PPh₃)₄, †8 h, 10 mol% XPhos Pd G3, ‡18 h, 10 mol% XPhos Pd G3, §11 h, 10 mol% XPhos Pd G3. DMF: N,N-dimethylformamide, TFA: trifluoroacetate, dtbbpy: 4,4′-di-tert-butyl-2,2′-dipyridyl, Ph: phenyl, THF: tetrahydrofuran, Et₂O: diethyl ether, OTf: trifluoromethanesulfonate, TMEDA: tetramethylethylenediamine, Me: methyl, Ts: p-toluenesulfonyl. (B) Scope of Pd-catalyzed Heck coupling of (hetero)aryl bromides and TFP using TFP–Mg₂(dobdc). *XantPhos Pd G3 (2 mol%) and tetrabutylammonium bromide (1 equiv.). (C) Scope of Fe-catalyzed trifluoromethylation of (hetero)arenes using TFMI–Mg₂(dobdc). †0.15 mmol FeSO₄·7H₂O, 50 °C, §50 °C. Fc: ferrocene, DMSO: dimethyl sulfoxide.