Host–guest complexes of conformationally flexible C-hexyl-2-bromoresorcinarene and aromatic N-oxides: solid-state, solution and computational studies

Host–guest complexes of C-hexyl-2-bromoresorcinarene (BrC6) with twelve potential aromatic N-oxide guests were studied using single crystal X-ray diffraction analysis and 1H NMR spectroscopy. In the solid state, of the nine obtained X-ray crystal structures, eight were consistent with the formation of BrC6-N-oxide endo complexes. The lone exception was from the association between 4-phenylpyridine N-oxide and BrC6, in that case the host forms a self-inclusion complex. BrC6, as opposed to more rigid previously studied C-ethyl-2-bromoresorcinarene and C-propyl-2-bromoresorcinarene, undergoes remarkable cavity conformational changes to host different N-oxide guests through C–H···π(host) interactions. In solution phase CD3OD/CDCl3 (1:1 v/v), all twelve N-oxide guests form endo complexes according to 1H NMR; however, in more polar CD3OD/DMSO-d6 (9:1 v/v), only three N-oxides with electron-donating groups form solution-phase endo complexes with BrC6. In solid-state studies, 3-methylpyridine N-oxide+BrC6 crystallises with both the upper- and lower-rim BrC6 cavities occupied by N-oxide guests. Computational DFT-based studies support that lower-rim long hexyl chains provide the additional stability required for this ditopic behaviour. The lower-rim cavity, far from being a neutral hydrophobic environment, is a highly polarizable electrostatically positive surface, aiding in the binding of polar guests such as N-oxides.


III Computational study IIIa General Information
Molecular mechanics analysis of the complexes between three C-hexyl-2-bromoresorcinarene (BrC6), C-ethyl-2-bromoresorcinarene (BrC2) and C-propyl-2-bromoresorcinarene (BrC3) hosts and N-oxide 3 were initially carried out using Jaguar/Maestro software package [9] and OPLS-2005 force field. In order to make sure that we were adequately screening the conformer space of the complexes in these simulations, no constraints were applied on either N-oxide or acetone molecules.
The low energy conformer of 3@BrC2, 3@BrC3, and 3@BrC6 complexes were then optimized using the Gaussian 09 suite [10] of programs at the density functional theory (DFT) level with M062X/6-31G(d,p) [11] within the IEF-PCM solvation model [12]. All of the optimized complex geometry were confirmed by frequency calculations as minima with zero imaginary frequencies.
Single point calculations were performed on these optimized structures using long-range corrected (LRC) exchange-correlation functional with inclusion of dispersion correction, ωB97X-D in order to obtain a more accurate treatment of stacking type interactions [13].
A topological analysis of the electron density was performed with Bader's quantum theory of atoms in molecules (QTAIM) using the AIM2000 software [14].
Of note, the energies implemented in Table 2 are not interaction energies. We believe that calculated and predicted interaction energy for more than three components (out N-oxide, in Noxide, as well as acetone molecule with receptor) won't be much accurate due to basis set superposition errors" (BSSEs) and "basis set incompleteness errors" (BSIEs) and in our idea the counterpoise correction of interaction energy for removing these errors won't be effective to completely remove the errors. The reported energies in Table 2, obtained from quantum theory of atom in molecule (QTAIM) only shows the contributions of different possible non-covalent interactions on energetic aspect and stability of the calculated structures and provide a basis to explain the presence of these attractive interactions in the systems and distinguish them from weak interactions. As mentioned in Table 2 (See manuscript), electron density p(r) and Laplacian of the electron density ∇ 2 p(r) at the BCP, is related to bond order and in turn bond strength. E (X) is the energy [15] of those bonds (vary from 2.9 to 11.0 kcal/mol for H-bonds and 0.8 to 1.9 kcal/mol for other classes of non-covalent interactions) which is calculated from following equation. Although, they have important role in energetic aspect of complex, they are not the interaction energy.
Where Vc is the potential energy density and the kinetic energy density at the BCP. Table S3: Isodesmic reaction schemes for comparing relative energy of the 3@BrC2, 3@BrC3 and 3@BrC6 complexes.

S6
S7 Figure S1: The plotted molecular graph and topological properties 3@BrC6 complex by QTAIM analysis. μL of the 20 mM stock solution and diluted to a final volume 450 μL with a concentration 6.6 mM.

IIIb. DFT Calculated host-guest complex geometries for 3@BrC2
For the 1:1 host-guest, aliquot 300 μL of host and 150 μL of guest were mixed to final volume 450 μL to give a concentration 6.6 mM.