Arene-Perfluoroarene Interactions in Solution

Abstract

A systematic study of arene-perfluoroarene interactions in solution is presented. Using a combination of NMR titration experiments, X-ray crystallography, and computational analysis, we analyze the effects of fluorination, substituents, ring size, and solvation on the arene-perfluoroarene interaction. We find that fluorination, extension of the π systems, and enhancement of solvent polarity greatly stabilize the stacking energy up to 3 orders of magnitude (K_a = <1 to 6000 M^-1), with the highest K_a achieved for the interaction of water-soluble variants of perfluoronaphthalene and anthracene in buffered D₂O (pD = 12). Combining computational and experimental results, we conclude that this impressive binding energy is a result of enthalpically favorable electrostatic and dispersion interactions as well as the entropically driven hydrophobic effect. The enhanced understanding of arene-perfluoroarene interactions in aqueous solution sets the stage for the implementation of this abiotic intermolecular interaction in biology and medicine.

Figure 1.

(a) Ground state geometries of arene-arene interaction. (b) Ground state geometry of benzene-perfluorobenzene interaction. (c) Key stabilizing factors for arene-perfluoroarene interactions in solution. (d) Overview of studies reported herein, focusing on properties that affect arene-perfluoroarene interactions in solution using titration, crystallography, and computation.

Figure 2.

Arenes (a) and perfluoroarenes (b) for measuring binding affinities in organic and aqueous solution. Arenes 1a, 2a, and 3a were prepared for titration experiments. Arenes 1b, 2b, and 3b were prepared for crystallography. Simple perfluorobenzene (4) and perfluoronaphthalene (5a) were used in titration experiments in organic solvents. Functionalized perfluoronapthalene 5b was used in titration experiments in aqueous solvents. (c) Six arene-perfluoroarene complexes of varying sizes employed to study the ring size, fluorination, substituent, and solvation effects in arene-perfluoroarene interactions.

Figure 3.

(a) Representative binding affinity determination experiment using compounds 2a and 5a. (b) ¹H NMR titration of complex 2a·5a in CD₃OD. Chemical shifts shown are the aromatic region of arene 2a. *Octafluoronapthalene impurities. (c) Representative binding isotherm. Arene aromatic signals were monitored and fitted using a 1:1 binding equilibrium equation in IgorPro.

Figure 4.

Crystal structures of arene-perfluoroarene complexes. Ellipsoids are shown at 75% probability level and the principal ellipses are shown with black lines. Cocrystals are obtained by slow evaporation of 1,2-dichloroethane and hexane (for 2b·4 and 3b·4), 1,2-dichloroethane and diethyl ether (for 1b·5a and 3b·5a), and 1,2-dichloroethane and toluene (2b·5a) from 1:1 mixtures of arenes and perfluoroarenes at overall 0.2 M concentrations.

Figure 5.

Experimental and computational results of fluorination effects. (a) Experimental comparison of arene-arene (K_a (X = D)) and arene-perfluoroarene (K_a (X = F)) interaction in CD₃OD. Dotted line indicates when K_a = 1 M⁻¹ and the gray area indicates NMR detection limit (K_a < 1 M⁻¹). Blue = guest is perfluoroarene. Orange = guest is perdeuteroarene. (b) Methodology of computational analysis of the fluorination effect using truncated 2b·5a. (c) Energy decomposition analysis (second generation ALMO-EDA) on the cocrystal structure, 2b·5a, and truncated computed structure, 2b·C₁₀H₈. Total interaction energies and energy breakdowns are calculated using B97M-V and revPBE functionals with the def2-svpd basis set. Energies in kcal mol⁻¹. ΔE_elec = electrostatic. ΔE_disp = dispersion. ΔE_Pauli = Pauli repulsion. ΔE_pol = polarization. ΔE_CT = charge transfer. ΔE_int = total interaction energy.

Figure 6.

Computational study of substituent effects. (a) Scheme of computational analysis on the substituent effects using truncated 2b·5a. (b) Energy decomposition analysis (second generation ALMO-EDA) on the cocrystal structure, 2b·5a, and truncated computed structures, C₁₀H₈·5a and (MeOH)₂·5a. Total interaction energies and energy breakdowns are calculated using B97M-V and revPBE functionals with def2-svpd basis set. Energies in kcal mol⁻¹. ΔE_elec = electrostatic. ΔE_disp = dispersion. ΔE_Pauli = Pauli repulsion. ΔE_pol = polarization. ΔE_CT = charge transfer. ΔE_int = total interaction energy.

Figure 7.

Experimental and computational study of ring size effects. (a) Experimental K_a measurements of 6 differently sized arene-perfluoroarene complexes in CD₃OD. K_a’s are plotted against the number of combined arene and perfluoroarene rings within the arene-perfluoroarene interactions. Dotted line indicates when K_a = 1 M⁻¹ and the gray area indicates NMR detection limit (K_a < 1 M⁻¹). Orange = K_a values for arene·4 in CD₃OD. Blue = K_a values for arene· 5a in CD₃OD. (b) Energy decomposition analysis (second generation ALMO-EDA) on the cocrystal structures, 2b·4, 3b·4, 1b·5a, 2b·5a, and 3b·5a. (c) Linear free energy relationship (LFER) between calculated ΔE_disp or ΔE_elect and experimental ΔG_MeCN–d3.

Figure 8.

Experimental study of solvation effects. Graph of K_a with increasing solvent polarity and salt effect. Total salt concentrations were kept at 20 mM.