Through-Space Effects of Substituents Dominate Molecular Electrostatic Potentials of Substituted Arenes

Abstract

Model systems have been studied using density functional theory to assess the contributions of π-resonance and through-space effects on electrostatic potentials of substituted arenes. The results contradict the widespread assumption that changes in molecular ESPs reflect only local changes in the electron density. Substituent effects on the ESP above the molecular plane are commonly attributed to changes in the aryl π-system. We show that ESP changes for a collection of substituted benzenes and more complex aromatic systems can be accounted for mostly by through-space effects, with no change in the aryl π-electron density. Only when π-resonance effects are substantial do they influence changes in the ESP above the aromatic ring to any extent. Examples of substituted arenes studied here are taken from the fields of drug design, host-guest chemistry, and crystal engineering. These findings emphasize the potential pitfalls of assuming ESP changes reflect changes in the local electron density. Since ESP changes are frequently used to rationalize and predict intermolecular interactions, these findings have profound implications for our understanding of substituent effects in countless areas of chemistry and molecular biology. Specifically, in many non-covalent interactions there are significant, often neglected, through-space interactions with the substituents. Finally, the present results explain the perhaps unexpectedly good performance of many molecular mechanics force-fields applied to supramolecular assembly phenomena and π-π interactions in biological systems despite the neglect of the polarization of the aryl π-system by substituents.

Figure 1

Plots of the electrostatic potential of (a) benzene, (b) phenol, (c) anisole, and (d) planar nitrobenzene (left) and perpendicular nitrobenzene (right), mapped onto electron density isosurfaces (0.001 e/au³)

Figure 2

Plots of electrostatic potentials of monosubstituted benzenes (first and third row) and corresponding additive ESPs (second and fourth row). In each case, ESPs are mapped on electron density isosurfaces (0.001 e/au³) for the substituted benzene. The Hodgkin similarity index (H) is computed for the ESP values on the isodensity surfaces for the true and additive ESPs.

Figure 3

Front and back views of electrostatic potentials of aniline derivatives (top row) and corresponding additive ESPs (bottom row). ESPs are mapped on electron density isosurfaces (0.001 e/au³) for the substituted benzene. The Hodgkin similarity index (H) is computed for the ESP values on the isodensity surfaces for the true and additive ESPs.

Figure 4

Contour plots of the electron density, electron density difference versus benzene [Δρ = ρ(C₆H₅X) – ρ(C₆H₆)], electrostatic potential, and additive ESP for aniline, phenol, toluene, benzene, fluorobenzene, nitrobenzene, and hexafluorobenzene. The thick black line in the density and ESP plots denotes the electron density contour (0.001 e/au³) used to construct the isodensity surfaces in Fig. 2 and Fig. 3.

Figure 5

Plots of electrostatic potential of polysubstituted benzenes (top) and corresponding additive ESPs (bottom). In each case, ESPs are mapped onto electron density isosurfaces (0.001 e/au³) for the substituted benzene. The Hodgkin similarity index (H) is computed for the ESP values on the isodensity surfaces for the true and additive ESPs.

Figure 6

(a) Electrostatic potential of cryptolepine; (b) ESP of 7,9-dinitrocryptolepine and additive ESP of 7,9-dinitrocryptolepine constructed by adding the ESP of cryptolepine with the ESP of two HNO₂ molecules and mapped onto the electron density isosurface of dinitrocryptolepine. Density isosurfaces correspond to ρ = 0.005 e/au³. The Hodgkin index for the true and additive ESP plots is 1.00.

Figure 7

(a) ESP of molecular tweezers of Klärner and co-workers;, (b) ESP of anthraquinone; (c) ESPs (left) and additive ESPs (right) of two dinitroanthraquinones and 9-dicyanomethylene-2,4,5-trinitrofluorene. Density isosurfaces correspond to ρ = 0.001 e/au³. The Hodgkin similarity index (H) is computed for the ESP values on the isodensity surfaces for the true and additive ESPs.

Figure 8

ESP plot of 1,3,5-trisphenethynylbenzene (left) and plot of the true (middle) and additive (right) ESP of 1,3,5-tris(perfluorophenethynyl)benzene, mapped onto electron density isosurfaces (0.001 e/au³). The Hodgkins similarity index for the true and additive ESP plots is 0.78.

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