A conformationally adaptive macrocycle: conformational complexity and host–guest chemistry of zorb[4]arene

Large amplitude conformational change is one of the features of biomolecular recognition and is also the basis for allosteric effects and signal transduction in functional biological systems. However, synthetic receptors with controllable conformational changes are rare. In this article, we present a thorough study on the host–guest chemistry of a conformationally adaptive macrocycle, namely per-O-ethoxyzorb[4]arene (ZB4). Similar to per-O-ethoxyoxatub[4]arene, ZB4 is capable of accommodating a wide range of organic cations. However, ZB4 does not show large amplitude conformational responses to the electronic substituents on the guests. Instead of a linear free-energy relationship, ZB4 follows a parabolic free-energy relationship. This is explained by invoking the influence of secondary C–H···O hydrogen bonds on the primary cation···π interactions based on the information obtained from four representative crystal structures. In addition, heat capacity changes (ΔC p) and enthalpy–entropy compensation phenomena both indicate that solvent reorganization is also involved during the binding. This research further deepens our understanding on the binding behavior of ZB4 and lays the basis for the construction of stimuli-responsive materials with ZB4 as a major component.


Experimental section
General methods. All the reagents involved in this research were commercially available and used without further purification unless otherwise noted. Solvents were either employed as purchased or dried prior to use by standard laboratory procedures. 1 H NMR spectra were recorded on Bruker Avance-400 (500) spectrometers. All subtracted from each data set. All solutions were degassed prior to titration. The data were analyzed using the instrumental internal software package and fitted with a 1:1 binding model. Errors are smaller than ±10%. S3 Figure S9: ESI mass spectrum of 9-2PF 6 @ZB4. The result indicates 9-2PF 6 and ZB4 form a 1:1 complex. Figure S10: ESI mass spectrum of 10-2PF 6 @ZB4. The result indicates 10-2PF 6 and ZB4 form a 1:1 complex. S9 Figure S11: Non-linear curve-fitting of NMR titrations for the complexation between ZB4 and 6-PF 6 in the 1:1 mixture of CD 2 Cl 2 and CD 3 CN at 298 K. Nonlinear curve-fitting method used here has been reported. [1] Figure S12: Non-linear curve-fitting of NMR titrations for the complexation between ZB4 and 7-PF 6 in the 1:1 mixture of CD 2 Cl 2 and CD 3 CN at 298 K. S10 Figure S13: Non-linear curve-fitting of NMR titrations for the complexation between ZB4 and 8-PF 6 in the 1:1 mixture of CD 2 Cl 2 and CD 3 CN at 298 K.
The reflections for ZB4, 10 + @ZB4, 14 + @ZB4, 18 + @ZB4, 21 + @ZB4 and 18 + PF 6 were collected at 123 K with an Agilent Super-Nova dual wavelength diffractometer using mirror-monochromatized CuKα (λ = 1.54184Å) radiation. The data for 16 + @ZB4 were collected at 293 K with a Rigaku Saturn724 CCD diffractometer using mirror-monochromatized MoKα (λ = 0.71073Å) radiation. CrysAlisPro [2] was used for both data collection and processing. The intensities were corrected for absorption using analytical face index absorption correction method [3] for all the data. The structures were solved by intrinsic phasing method with SHELXT [4] and refined by full-matrix least-squares methods using SHELXL-2015 (or newer version). [5] All non-hydrogen atoms in the structures were refined with anisotropic thermal parameters. All hydrogen positions were refined using riding models.
The crystal of ZB4 was found to be a two-component nonmerohedric twin and HKLF5 refinement was applied. In the crystal structure there are two crystallographically independent molecules in the asymmetric unit. The first molecule shows disorder in two butyl groups. The terminal propyl moiety of one disordered butyl group and the terminal ethyl moiety of the other disordered butyl group were refined by splitting over two parts with refined occupancies. In the second ZB4 molecule only one butyl group shows significant disorder, in which the terminal propyl moiety was similarly splitted in two parts. Moderate geometric restraints were used to obtain chemically reasonable bond distances and angles, and stronger restraints (s = 0.01, st = 0.02) were applied to all atoms in disorders for reasonable ADPs. One additional geometric restraint was necessary to keep one disordered methylene hydrogen within reasonable distance from another methylene hydrogen of the same butyl group.
In the structure of 10 + @ZB4, five of the eight butyl groups in the ZB4 molecule were significantly disordered. In two of them all atoms of the butyl group were refined by splitting over two parts, two terminal ethyl moieties in the butyl groups were refined by splitting over two parts, and in the other one terminal propyl moiety was split in two parts with refined occupancies. Moderate geometric restraints were used to obtain chemically reasonable bond distances and angles, and stronger restraints (s = 0.01, st = 0.02) were applied to few atoms for reasonable anisotropic displacement parameters (ADPs). The guest 10 + also shows a 1:1 disorder, in which the carbon atoms were refined over two positions with fixed occupancies. Moderate geometrical restraints S19 were also applied for the guest molecule. The PF 6 − anion is also disordered in that way that four fluorine atoms were refined over two positions with fixed 50:50 occupancies. The geometry of the anion is moderately restrained and only a few stronger ADP restraints (s = 0.01, st = 0.02) were applied to phosphorus and one fluorine atom. One additional geometric restraint was necessary to keep one disordered methyl hydrogen within reasonable distance from methyl hydrogen of the adjacent ZB4 molecule.
In the structure of 14 + @ZB4, four of the eight butyl groups were found to be disordered. Two terminal propyl moieties of the butyl groups were refined by splitting over two positions with fixed occupancies, while only one methylene (second from oxygen atom) in two other butyl groups were split. Moderate geometric restraints were used to obtain chemically reasonable bond distances and angles, and stronger restraints (s = 0.01, st = 0.02) were applied to all atoms in disorders for reasonable ADPs. The ADPs of one terminal methyl carbon were further restrained very strongly (s = 0.005, st = 0.01). The cocrystallized CH 2 Cl 2 molecule shows also disorder over two symmetrically equivalent positions and the ADPs of the other chlorine atom had to be restrained very strongly (s = 0.005, st = 0.01).
In 16 + @ZB4 four of the eight butyl groups in the ZB4 molecule were disordered and all atoms of the butyl group were refined by splitting over two parts with fixed occupancies. Moderate geometric restraints were used to obtain chemically reasonable bond distances and angles. The geometry of disordered butyl groups were moderately and the ADPs strongly restrained (s = 0.01, st = 0.02).
The crystal of 18 + @ZB4 is a merohedral two-component twin and refined accordingly with BASF parameter of 0.105. Half of the eight butyl groups in ZB4 show significant disorder. In two of them all atoms of the butyl group were refined by splitting over two parts, in one only the terminal ethyl moiety was split in two parts, and in other one only the terminal methyl moiety was split in two parts with refined occupancies. Moderate geometric restraints were used to obtain chemically reasonable bond distances and angles. The stronger restraints (s = 0.01, st = 0.02) were necessary to obtain reasonable ADPs for the carbon atoms. Also, similar ADP restraints were necessary for some carbon and oxygen atoms of ZB4.
In 21 + @ZB4, five of the eight butyl groups in the ZB4 molecule were disordered and then refined by splitting over two parts with fixed occupancies for the terminal one of two carbons based on the difference Fourier map. The geometry of disordered butyl groups were moderately and the ADPs strongly restrained (s = 0.01, st = 0.02). The O16 atom in the guest 21 + was also badly disordered. Its ADP was restrained very strongly (s = 0.005, st = 0.01). In addition, SQUEEZE [6] was used to treat the data due to the highly disordered solvent molecules (MeCN + CH 2 Cl 2 ).
In the crystal structure of 18 + PF 6 there is only a half molecule in the symmetric unit. It aimlessly crystallized out from one of the samples containing also ZB4 host (in 1:1 ratio). Its crystal structure is previously unknown, to the best of our knowledge, and is thus presented here.
The details of the data collection and refinement results are summarized as follows.