Molecular recognition of pyrazine N,N′-dioxide using aryl extended calix[4]pyrroles

Calix[4]pyrrole (C4P)-based systems have been extensively explored as binding agents for anions and ion pairs. However, their capacity to act as molecular containers for neutral species remains underexplored. We report here the molecular recognition of pyrazine N,N′-dioxide (PZDO) using a series of aryl extended C4Ps including three α,α-diaryl substituted C4Ps (receptors 1–3), an α,β-diaryl substituted C4P (receptor 4) and an α,α,α,α-tetraaryl substituted C4P (receptor 5). Single crystal structural analyses of the 2 : 1 host–guest complexes between receptors 1–3 and PZDO revealed that the C4P subunits exist in an unusual partial cone conformation and that the PZDO guest is held within electron-rich cavities formed by the lower rims of the individual C4P macrocycle. In contrast, receptor 5 was seen to adopt the cone conformation in the solid state, allowing one PZDO molecule to be accommodated inside the upper-rim cavity. Evidence for guest-directed self-assembly is also seen in the solid state. Evidence for C4P–PZDO interactions in CD3CN/CD3OD solution came from 1H NMR spectroscopic titrations. Electrostatic potential maps created by means of density functional theory calculations were constructed. Density functional theory calculations were also performed to analyse the energetics of various limiting binding modes. On the basis of these studies, it is inferred that interactions between the ‘two-wall’ C4P derivatives (i.e. receptors 1–4) and PZDO involve a complex binding mode that differs from what has been seen in previous host–guest complexes formed between C4Ps and N-oxides. The present study thus paves the way for the further design of C4P-based receptors with novel recognition features.


Fig. S3
Mole ratio plot for the interaction between 1 and PZDO. The result is consistent with a 1:1 binding stoichiometry.

Fig. S4
Least-squares non-linear fitting of the changes in the chemical shift corresponding to the H1 peak of 1 as a function of added PZDO. The solid lines were obtained from non-linear curve-fitting to a 1:1 binding model using the www.supramolecular.org web applet. obtained from a non-linear curve-fitting using Eq. S1.

Fig. S8
Mole ratio plot for the interaction between 2 and PZDO. The result is consistent with a 1:1 binding stoichiometry.

Fig. S9
Least-squares non-linear fitting of the changes in the chemical shift corresponding to the H2 peak of 2 as a function of added PZDO. The solid lines were obtained from non-linear curve-fitting to a 1:1 binding model using the www.supramolecular.org web applet.

Fig. S10
Least-squares non-linear fitting of the changes in the chemical shift corresponding to the H2 peak of 2 as a function of added PZDO. The solid lines were obtained from non-linear curve-fitting to a 2:1 binding model using the www.supramolecular.org web applet. was obtained from a non-linear curve-fitting using Eq. S1.

Fig. S13
Mole ratio plot for the complexation between 3 and PZDO. The result is consistent with a 1:1 binding stoichiometry.

Fig. S14
Least-squares non-linear fitting of the changes in the chemical shift corresponding to the H3 peak of 3 as a function of added PZDO. The solid lines were obtained from non-linear curve-fitting to a 1:1 binding model using the www.supramolecular.org web applet. was obtained from a non-linear curve-fitting using Eq. S1.

Fig. S18
Mole ratio plot for the complexation between 4 and PZDO. The result is consistent with a 1:1 binding stoichiometry.

Fig. S19
Least-squares non-linear fitting of the changes in the chemical shift corresponding to the H4 peak of 4 as a function of added PZDO. The solid lines were obtained from non-linear curve-fitting to a 1:1 binding model using the www.supramolecular.org web applet.

Fig. S20
Least-squares non-linear fitting of the changes in the chemical shift corresponding to the H4 peak of 4 as a function of added PZDO. The solid lines were obtained from non-linear curve-fitting to a 2:1 binding model using the www.supramolecular.org web applet.

Fig. S25
Changes in the chemical shift corresponding to H6 peak of 6 as a function of the added PZDO. The red solid line was obtained from a non-linear curve-fitting using Eq. S1.

Fig. S26
Mole ratio plot for the complexation between 6 and PZDO. Although difficult to ascertain with certainty, the result is deemed consistent with a 1:1 binding stoichiometry.

Fig. S27
Least-squares non-linear fitting of the changes in the chemical shift corresponding to the H6 peak of 6 as a function of added PZDO. The solid lines were obtained from non-linear curve-fitting to a 1:1 binding model using the www.supramolecular.org web applet.

Fig. S28
Least-squares non-linear fitting of the changes in the chemical shift corresponding to the H6 peak of 6 as a function of added PZDO. The solid lines were obtained from non-linear curve-fitting to a 2:1 binding model using the www.supramolecular.org web applet.

Table S2
Bond lengths corresponding to various non-covalent interactions inferred from the crystal structures Note: 1. In the case that multiple bonds under one particular type of interaction were found in the crystal structures, the average bond lengths were calculated and reported.
2. The centroids of the aromatic rings were used to determine the bond lengths of C-H···π, O-H···π and donor-acceptor π-π interactions.
3. N/A (i.e. not available) indicates the absence of a particular type of non-covalent interactions. 6. X-ray experimental S10-S17 X-ray experimental for 12·PZDO:

12·PZDO
Single crystals of 12·PZDO were obtained as clusters of colourless prisms by vapour diffusion of n-heptane into a chloroform/methanol solution containing a mixture of receptor 1 and PZDO. The data crystal was cut from a larger crystal and had approximate dimensions of 0.35 × 0.10 × 0.05 mm. The data were collected on a Rigaku AFC12 diffractometer with a Saturn 724+ CCD using graphite monochromator with MoKα radiation source (λ = 0.71073 Å). A total of 1616 frames of data were collected using ω-scans with a scan range of 0.5° and a counting time of 37 seconds per frame. The data were collected at 100 K using a Rigaku XStream low temperature device. Details of crystal data, data collection and structure refinement are listed in Table S1. Data reduction were performed using the Rigaku Americas Corporation's CrystalClear version 1.40. The structure was solved by direct methods using SIR2004 and refined by full-matrix leastsquares on F 2 with anisotropic displacement parameters for the non-H atoms using SHELXL-2016/6. Structural analysis was aided by use of the programs PLATON and WinGX. The hydrogen atoms on carbon were calculated in ideal positions with isotropic displacement parameters set to 1.2xUeq of the attached atom (1.5xUeq for methyl hydrogen atoms). The hydrogen atoms bound to the pyrrolic nitrogen and the methanol oxygen atoms were located in a ΔF map and refined with isotropic displacement parameters.
Tables of positional and thermal parameters, bond lengths and angles, and torsion angles are in the CIF file. CCDC deposition number: 1976059.  X-ray experimental for 22·PZDO: Single crystals of 22·PZDO were obtained as clusters of yellowish prisms by vapour diffusion of n-heptane into a chloroform/methanol solution containing a mixture of receptor 2 and PZDO. The data crystal was cut from a larger crystal and had approximate dimensions of 0.29 × 0.15 × 0.13 mm. The data were collected on a Rigaku AFC12 diffractometer with a Saturn 724+ CCD using a graphite monochromator with MoKα radiation (λ = 0.71073 Å). A total of 901 frames of data were collected using ω-scans with a scan range of 0.5° and a counting time of 45 seconds per frame. The data were collected at 100 K using a Rigaku XStream Cryostream low temperature device. Details of crystal data, data collection and structure refinement are listed in Table S1. Data collection was performed using the Rigaku Americas Corporation's CrystalClear version 1.40. Unit cell refinement and data reduction were performed using Rigaku Oxford Diffraction's CrysAlisPro V 1.171.40.53. The structure was solved by direct methods using SHELXT and refined by full-matrix leastsquares on F 2 with anisotropic displacement parameters for the non-H atoms using SHELXL-2016/6. Structure analysis was aided by use of the programs PLATON, OLEX2 and WinGX. The hydrogen atoms on carbon were calculated in ideal positions with isotropic displacement parameters set to 1.2xUeq of the attached atom (1.5xUeq for methyl hydrogen atoms).
Some disordered solvent molecules centred near 0, 0, ½ could not be adequately modelled. The contributions to the scattering factors due to this solvent molecule were removed by use of the utility SQUEEZE in PLATON. PLATON was used as incorporated in WinGX. The crystal was also twinned. The twin law was determined using PLATON.
Tables of positional and thermal parameters, bond lengths and angles, and torsion angles are in the CIF file. CCDC deposition number: 1976060. X-ray experimental for 32·PZDO: Single crystals of 32·PZDO were obtained as yellow prisms by vapour diffusion of n-heptane into a chloroform/methanol solution containing a mixture of receptor 3 and PZDO. The data crystal had approximate dimensions of 0.21 × 0.13 × 0.094 mm. The data were collected at -173 °C on a Nonius Kappa CCD diffractometer using a Bruker AXS Apex II detector and a graphite monochromator with MoKα radiation (λ = 0.71073 Å). Reduced temperatures were maintained by use of an Oxford Cryosystems 700 low-temperature device. A total of 1767 frames of data were collected using ω-and fscans with a scan range of 0.6° and a counting time of 67 seconds per frame. Details of crystal data, data collection and structure refinement are listed in Table S1. Data reduction were performed using Bruker AXS, Inc's SAINT V827B. The structure was solved by direct methods using SHELXT and refined by full-matrix least-squares on F 2 with anisotropic displacement parameters for the non-H atoms using SHELXL-2016/6. Structure analysis was aided by use of the programs PLATON and WinGX. The hydrogen atoms bound to carbon atoms were calculated in idealised positions. The hydrogen atoms on the pyrrole nitrogen atoms and the oxygen atoms were observed in a ∆F map and refined with isotropic displacement parameters.
Data collection was performed using the Rigaku Americas Corporation's CrystalClear version 1.40. Unit cell refinement and data reduction were performed using Rigaku Oxford Diffraction's CrysAlisPro V 1.171.40.37a. The structure was solved by direct methods using SHELXT and refined by full-matrix least-squares on F 2 with anisotropic displacement parameters for the non-H atoms using SHELXL-2016/6. Structure analysis was aided by use of the programs PLATON and WinGX. The hydrogen atoms on carbon were calculated in ideal positions with isotropic displacement parameters set to 1.2xUeq of the attached atom (1.5xUeq for methyl hydrogen atoms).
Tables of positional and thermal parameters, bond lengths and angles, and torsion angles are in the CIF file. CCDC deposition number: 1976064.

S43
X-ray experimental for 5·PZDO: Single crystals of 5·PZDO were obtained as thin colourless needles by vapour diffusion of n-heptane into a chloroform/ methanol solution containing a mixture of receptor 5 and PZDO. The data crystal was cut from a larger crystal and had an approximate maximum dimension of 0.1 mm. The data were collected on Beamline 5.0.3 at the Advanced Light Source at the Lawrence Berkeley National Laboratory. The synchrotron beamline produced a wavelength of 0.97741 Å. A total of 180 frames of data were collected using f-scans with a scan range of 1° and a counting time of 0.5 seconds per frame for frames collected with a detector offset of 0.0°. The data were collected at 100 K using an Oxford Cryostream low temperature device. Details of crystal data, data collection and structure refinement are listed in Table S1. Data collection was performed using the Beamline Operating Software, BOS/B3. The unit cell refinement and data reduction were performed using Agilent Technologies CrysAlisPro V 1.171.40.37a. The structure was solved by direct methods using SHELXT and refined by full-matrix least-squares on F 2 with anisotropic displacement parameters for the non-H atoms using SHELXL-2016/6. Structure analysis was aided by use of the programs PLATON and WinGX. The hydrogen atoms were calculated in ideal positions with isotropic displacement parameters set to 1.2xUeq of the attached atom (1.5xUeq for methyl hydrogen atoms).
A solvent void existed in a channel along x, 1/6, ½. The solvent molecules could not be adequately modelled. The contribution to the scattering due to the solvent was removed using SQUEEZE as found in PLATON.
Tables of positional and thermal parameters, bond lengths and angles, and torsion angles are in the CIF file. CCDC deposition number: 1976063.

Fig. S41
View of 5·PZDO showing the atom labelling scheme. Displacement ellipsoids are scaled to the 30% probability level. The methyl group hydrogen atoms have been removed for clarity.

S44
X-ray experimental for PZDO: Single crystals of PZDO were obtained as colourless needles by vapour diffusion of n-heptane into a chloroform/methanol solution containing PZDO. The data crystal had approximate dimensions of 0.43 × 0.16 × 0.07 mm.
The data were collected at -173 °C on a Nonius Kappa CCD diffractometer using a Bruker AXS Apex II detector and a graphite monochromator with MoKα radiation (λ = 0.71073 Å). Reduced temperatures were maintained by use of an Oxford Cryosystems 700 low-temperature device. A total of 556 frames of data were collected using ω-and f-scans with a scan range of 0.7° and a counting time of 29 seconds per frame. Details of crystal data, data collection and structure refinement are listed in Table S1. Data reduction were performed using Bruker AXS, Inc's SAINT V827B. The structure was solved by direct methods using SHELXT and refined by full-matrix least-squares on F 2 with anisotropic displacement parameters for the non-H atoms using SHELXL-2016/6. Structure analysis was aided by use of the programs PLATON and WinGX. The hydrogen atoms bound to carbon atoms were calculated in idealised positions. There are two crystallographically unique molecules in the asymmetric unit. One molecule resides on a crystallographic mirror plane of symmetry, whereas the other molecule resides around a crystallographic inversion centre.
Tables of positional and thermal parameters, bond lengths and angles, and torsion angles are in the CIF file. CCDC deposition number: 1976061.    Fig. S45 1 H NMR spectrum of 4 recorded in CD2Cl2. Note: Overlap of the peak at 1.54 ppm with the water peak at 1.53 ppm is thought to account for why the observed integral (i.e. 14.38) is slightly higher than the theoretical value (i.e. 12.00).

MS Spectrum Peak List
Obs. m/z