Quantifying Through-Space Substituent Effects

Abstract

The description of substituents as electron donating or withdrawing leads to a perceived dominance of through-bond influences. The situation is compounded by the challenge of separating through-bond and through-space contributions. Here, we probe the experimental significance of through-space substituent effects in molecular interactions and reaction kinetics. Conformational equilibrium constants were transposed onto the Hammett substituent constant scale revealing dominant through-space substituent effects that cannot be described in classic terms. For example, NO₂ groups positioned over a biaryl bond exhibited similar influences as resonant electron donors. Meanwhile, the electro-enhancing influence of OMe/OH groups could be switched off or inverted by conformational twisting. 267 conformational equilibrium constants measured across eleven solvents were found to be better predictors of reaction kinetics than calculated electrostatic potentials, suggesting utility in other contexts and for benchmarking theoretical solvation models.

Keywords: electrostatic interactions; noncovalent interactions; substituent effects.

Figure 1

A) Molecular balances (1‐X) and B) pyridine derivatives (2‐X) used in the present investigation to quantify through‐space substituent effects on molecular interactions and reaction kinetics, respectively. The values listed under the structures of substituents a to n are the Hammett constants, σ _p(conf) determined from conformational equilibrium constants measured in [D₆]benzene at 298 K (Table 1) using the correlation shown in Figure 2 B. Errors in σ _p(conf)<±0.08 (see section S4 in SI). Color coding matches the use in subsequent figures.

Figure 2

A) Correlation between the calculated electrostatic potential in the position indicated (ESP_ipso) and the conformational equilibrium constants determined in [D₆]benzene at 298 K for the 1‐X series of 25 molecular balances shown in Figure 1 A. ESPs were calculated using B3LYP/6‐31G* on the 0.002 electron/Bohr³ isosurface. Electrostatic potentials determined using isolated (proton‐capped) X‐substituents (i.e. without through‐bond contributions) also correlated highly with the experimental data (R₂=0.89, Figure S1C). B) Correlation between known σ _p Hammett substituent constants and conformational equilibrium constants of balances 1‐X determined in [D₆]benzene at 298 K. Errors in −log₁₀(K _X/K _H) are <±0.08 (section S4 in SI).

Figure 3

A) Calculated electrostatic potential slice showing electro‐enhanced (δ−ve) and electro‐attenuated (δ+ve) regions in space surrounding nitrobenzene. B) Experimentally determined Hammett substituent constants σ _p(conf) quantified using the conformational preferences of series 1‐X demonstrate switching from electro‐enhancing to electro‐attenuating behavior upon changing the orientation of a nitro group. C) The strongly electro‐enhancing behavior of methoxy groups (left) can be switched off via a conformational twist induced by adjacent tert‐Bu groups (center). In contrast, hydroxyl groups in the same position exert a strong electro‐attenuating influence (right). Electrostatic potentials are scaled from −100 kJ mol⁻¹ (red) to +100 kJ mol⁻¹ (blue). Indicated electrostatic potential values correspond to ESP_ipso as defined in Figure 2 A at the positions indicated with arrows.

Figure 4

Effect of increasing solvent polarity on the conformational equilibrium constants −log₁₀(K _X/K _H) determined at 298 K for the 1‐X series of molecular balances shown in Figure 1. Data for eleven solvents are reported in Table 1.

Figure 5

A) Energetic contributions to the difference in free energy between two conformations of a molecular balance, ΔG where solvophobic effects are negligible. E _O and E _H correspond to the intramolecular interactions in the O‐ and H‐conformers, respectively; α_Ο, α_H, α_S, β_Ο, β_H and β_S are the hydrogen‐bond donor (α) and acceptor constants (β) of the O‐/ H‐conformers and the solvent, respectively.21a, 27 B) Correlation of calculated electrostatic potentials over the ipso‐carbon ESP_ipso vs. the solvent‐independent intramolecular interaction energy difference ΔE=E _H−E _O dissected using the same solvation model.

Figure 6

A) Relationship between calculated electrostatic potentials taken over the nitrogen atom (ESP_N) and the N‐methylation of the 17 pyridine derivatives shown in Figure 1 B in [D₆]acetone at 298 K. ESPs were calculated using B3LYP/6‐31G* on the 0.002 electron/Bohr³ isosurface. B) Correlation of electrostatic potentials in X‐substituted phenyl derivatives (ESP_ipso) vs. corresponding X‐substituted pyridine derivatives (ESP_N). C) Correlation of conformational equilibrium constants measured in the 1‐X balance series vs. rate constants for the N‐methylation of correspondingly substituted 2‐X pyridine derivatives, when both sets of measurements were performed in [D₆]acetone. D) Improved correlations were found between rate constants measured in [D₆]acetone and conformational equilibrium constants measured in five other solvents including tetrahydrofuran (R²=0.88 to 0.94, Figures S38–S39). All experiments were performed at 298 K.