Introduction

Since decades, calixarenes act as prominent building blocks for the design of supramolecular inclusion compounds [1, 2]. Whereas it is a well-known fact that the chemical modification of the upper and lower rim of the chalice clearly influences the inclusion potential, until recently less was known about the effect of a bridge modification on the supramolecular properties. In this latter respect, we showed that either one [3–8] or two [9, 10] bridge substituents on opposite methylene units of the parent tetramethoxycalix[4]arene 1 (Fig. 1) exercise a distinct influence on the molecular conformation of the host as well as on the supramolecular architecture of the crystal packing. In a more detailed examination, a single small lateral substituent like ethyl or COOH seems to reduce the close packing of the crystal due to the higher dissymmetry of the chalice leading to straightened guest channels capable of solvent inclusion [8]. A conformational change upon attachment of a second lateral substituent transform symmetry from partial cone to 1,2-alternate, resulting in dense packing with highly reduced solvent accessible voids [10]. In this study involving subsequent substitution of the bridge monosubstituted calixarenes 2–5, we compare the recently described bridge dimethylated derivative 6 [10] with three new acetonitrile solvates of equal bridge-disubstituted calix[4]arenes (7–9). Thereby, the focus is on comparison of their crystal packing depending on growing spatial demand of the substituent, i.e. ethyl (7), allyl (8) and benzyl (9) including isostructurality and packing density calculations. It can be applicable in a special case of crystal engineering being adequately described as “synthon engineering”.

Fig. 1
figure 1

Chemical structures of the compounds studied in this article

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Experimental

Melting points were measured on a microscope heating stage Nagema (Wägetechnik Rapido Radebeul) and are uncorrected. IR spectra were recorded on a Nicolet Avatar 370 DTGS (Thermo) using ATR technique (wave numbers given in cm−1). 1H- and 13C-NMR spectra were obtained from a Bruker Avance 500 at 500.1 MHz (1H) and 125.8 MHz (13C) with TMS as internal standard. Fixation of the conformationally mobile bridge monosubstituted calix[4]arenes 2–5 is achieved by addition of NaI/acetonitrile-d 3 (cone conformer) and for the bridge-disubstituted calix[4]arenes 6–9 by immediate dissolving of the obtained crystals (1,2-alternate conformer). Chemical shifts are presented in ppm (δ). Mass spectra were recorded on a LCMS-320 spectrometer (Varian) in the ESI modus. Solvents were purified and dried following standard procedures.

The basic p-tert-butyltetramethoxycalix[4]arene 1 was synthesized using the literature known protocol [11] starting from p-tert-butyltetrahydroxycalix[4]arene. The calixarenes 6–9 were prepared following the literature protocol [9] by subsequent lithiation and substitution procedure via the bridge monosubstituted pendants 2–5. Analytical data of compounds 2–4 as well as 6–8 can be found in the literature [9, 12].

2-Benzyl-5,11,17,23-tetra-tert-butyl-25,26,27,28-tetramethoxycalix[4]arene (5)

Calixarene 1 (1.4 g, 2.0 mmol) in 80 ml dry THF; n-BuLi (5.2 ml, 8.4 mmol, 1.6 M in n-hexane) and benzyl bromide (2.8 g, 1.9 ml, 16.0 mmol) were used [12]. Yield: 1.05 g (65 %) as white solid (mp 165–169 °C). 1H-NMR (CDCl3): 7.41 (d, 2H, 4 J HH = 1.9 Hz, ArH), 7.15 (s, 4H, ArH), 7.15–7.13 (m, 7H, ArH), 4.87 (t, 1H, 3 J HH = 8.1 Hz, CHCH2Ph), 4.27 (d, 1H, 2 J HH = 12.5 Hz, ArCH2Ar), 4.22 (d, 2H, 2 J HH = 12.4 Hz, ArCH2Ar), 4.16 (s, 6H, OCH3), 3.81 (s, 6H, OCH3), 3.42 (d, 2H, 3 J HH = 8.1 Hz, CH2Ph), 3.43 (d, 2H, 2 J HH = 12.5 Hz, ArCH2Ar), 3.37 (d, 1H, 2 J HH = 12.4 Hz, ArCH2Ar), 1.25 (s, 18H, C(CH3)3), 1.20 (s, 18H, C(CH3)3).

2,14-Dibenzyl-5,11,17,23-tetra-tert-butyl-25,26,27,28-tetramethoxycalix[4]arene (9, 1,2-alternate)

Bridge monobenzyl substituted calixarene 5 (0.48 g, 0.6 mmol) diluted in 40 ml dry THF, TMEDA (0.62 ml, 0.48 g, 4.0 mmol) in 40 ml dry THF, n-BuLi (2.2 ml, 3.4 mmol, 1.6 M in n-hexane) and benzyl bromide (0.52 ml, 0.78 g, 4.6 mmol) were used. Yield: 0.38 g (71 %) as colourless microcrystalline powder. 1H-NMR (CDCl3): 7.21 (d, 2H, 4 J HH = 2.3 Hz, ArH), 7.15–7.14 (m, 8H, ArH und ArHBz), 7.09–7.04 (m, 6H, ArHBz), 7.00 (d, 2H, 4 J HH = 2.3 Hz, ArH), 4.86 (t, 2H, 3 J HH = 8.0 Hz, CHCH2C6H5), 3.77 (s, 4H, ArCH2Ar), 3.31 (d, 4H, 3 J HH = 8.0 Hz, CH2C6H5), 2.76 (s, 12H, OCH3), 1.26 (s, 36H, C(CH3)3). 13C-NMR (CDCl3): 154.2, 144.2, 141.3, 137.7, 132.6, 129.2, 128.1, 126.0, 124.7, 122.8, 59.9, 41.2, 37.5, 37.2, 34.1, 31.5. IR: v = 2954, 2927, 2901, 2866, 2821, 1479, 1455, 1431, 1392, 1361, 1288, 1243, 1202, 1173, 1077, 1016, 961, 870, 798, 751, 743, 698, 644, 603, 592, 538, 505. MS(ESI): calcd. for C62H76O4 (884.57); found: 907.6 (M + Na)+ m/z. Anal. calcd. C%: 84.12, H%: 8.65; found: C%: 83.85, H%: 8.54.

X-ray structure determination

Single crystals of 7–9 suitable for X-ray diffraction were obtained by slow solvent evaporation and cooling of hot solutions of the respective calixarenes in acetonitrile/CHCl3 (1:1). Diffraction data were collected on a Bruker APEX II diffractometer with MoKa radiation (λ = 0.71073 Å) using ω- and φ-scans. Reflections were collected for background, Lorentz and polarisation effects. Preliminary structure models were derived by application of direct methods and were refined by full-matrix least squares calculation based on F 2 for all reflections [13]. All hydrogen atoms were included in the models in calculated positions and were refined as constrained to bonding atoms. Crystal data and details of structure determination and refinement can be found in Table 1.

Table 1 Crystal data and selected details of the data collection and refinement calculations of new compounds 6–9
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Isostructural and packing density calculations

The cell similarity index (π) has been calculated as π = [(a + b + c)/(a′ + b′ + c′) − 1], where a, b, c and a′, b′, c′ are the orthogonalized lattice parameters of the compared crystals [14, 15]. In the event of great similarity of two unit cells, the value of π is close to zero. For the calculation of the isostructurality index [I(s)], I(s) = |Σ(∆R i)2/n)0.5 − 1| × 100 [14, 15], the distance differences between the crystal coordinates of the identical non-H atoms of the host calixarene were used, taking into account both the differences in the geometry of the molecules and the positional differences caused by rotation and translation. The calculated molecular overlay [16] or molecular isometricity index [I(m)] [14, 15] is a direct measure of the degree of approximate isomorphism of the two molecules. It is calculated by the same equation as I(s) completed by least squares fitting of the positions occupied by the identical atoms of the two molecules resulted in the superposition of the molecules. The Kitaigorodskii packing index (KPI) [17] as well as further density calculations were performed using the implementation of Platon [18].

Results and discussion

The successive lithiation technique has been proven to be a reliable synthetic route to yield calix[4]arenes with two different or equal substituents on opposite methylene bridges [9, 10]. Both in CDCl3 solution as well as in the solid phase such 2,14-disubstituted calix[4]arenes adopt the rare 1,2-alternate conformation, which is also the case for the title compounds 7–9 (Fig. 2). Whereas most of the recently discussed structures of bridge-disubstituted calix[4]arenes bear two different bridge substituents and approach nearly symmetrical arrangement, perfect centrosymmetry can only be realised if the two bridge substituents are the same, i.e. methyl (6) [10], ethyl (7), allyl (8) and benzyl (9). In all obtained crystal structures 6–9, the calixarene host is arranged by the symmetry centre (space group P-1 of 6, and P21/c or P21/x of 7–9, Table 1). There is half of the host molecule in the asymmetric unit. The host exposes two cavities on both sides capable of two acetonitrile guest molecules. This realises a host:guest ratio of 0.5:1, which is a newly occurring stoichiometry compared to related structures. Although the geometrical parameters of the host in the different structures seem to be only slightly affected by the type of lateral substituent (Table 2), the cell volume clearly increases with growing size of the attached group (2480.12(17) Å3 in 7–2816.01(11) Å3 in 9, Table 1). Anyhow, the structure of the benzyl derivative 9 is slightly different from the other two which is attributed to the different hydrogen-bond system owing to the larger size and geometry of the benzyl group. The crystals of the ethyl (7) and allyl (8) substituted calixarenes are isostructural.

Fig. 2
figure 2

ORTEP representation of the molecular inclusion structures 7–9 at the 40 % probability level

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Table 2 Calculated metrical parameters of calixarene hosts 6–9 and values of the solvent accessible voids, respectively, packing coefficients [17] for all examined structures
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Commonly, in all three solvate structures (Fig. 2), the lower rim methoxy groups point outside the chalice, qualified only for intermolecular interactions (Table 3). This fact is attributed to the included acetonitrile molecules, since a related guest-free structure of the allyl-substituted calixarene 8 shows two methoxy groups pointing into the cavity [9]. Worth to mention, the inclusion of guest molecules can affect the molecular conformation of the calixarene, which has already been demonstrated recently for a related system [19].

Table 3 Intermolecular distances and angles of possible hydrogen-bond type interactions in the compounds 7–9
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In the isostructural pair 7/8 (Fig. 3a) the terminal methyl group of the acetonitrile, in accordance with different bridge-disubstituted structures, is C–H···O hydrogen bonded [20] to the methoxy oxygens of the calixarene, maintaining several C–H···π interactions [21–23] (Table 3). In addition, the acetonitrile nitrogen displays the acceptor of a methoxy hydrogen from the neighbouring calixarene host resulting in known molecular chains along the crystallographic b direction. Although the allyl group is able to act as a hydrogen donor, no supramolecular interconnection involving this bridge substituent is observed. Also in the crystal structure 9 (Fig. 3b) the terminal methyl group of the acetonitrile guest is stabilized by the C–H···O contacts including the methoxy groups of the calixarene core. However, differently to 7 and 8, the lateral benzyl substituents are in weak C–H···N interaction with the acetonitrile guests as well. The participation of the lateral substituent in the secondary interaction system has already been observed in structures possessing a bulky or polar bridge substituent [10]. The guest position is strengthened by C–H···π interactions to the host, while a methoxy hydrogen (H16) is π-bonded to a neighbouring calixarene (Table 3).

Fig. 3
figure 3

Different packing architectures of calix[4]arenes with growing size of bridge substituents. a Motif in structure 7 and b motif in benzylated structure 9. The different coordination of the included CH3CN molecules is highlighted in orange (7) vs. magenta (9), while bridge residues are in light pink (Color figure online)

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There are individual voids available for the acetonitrile molecules in the calixarene structures 6–9. The voids are calculated in the absence and presence of guest molecules and become smaller with growing size of the lateral substituents (Table 2). Whereas four acetonitrile guests are needed to fill empty voids in the structure of 6 bearing two short methyl residues at the bridges [10], the number of included “spacer” guest molecules is reduced to antiparallel two in the structures of the higher homologues. The packing of molecules becomes denser in the later arrangement, as indicated by growing KPI indices calculated in the presence and absence of the guests as well (Table 2). Obviously, the available space within the lattice is exploited more efficiently in the series 7–8, than in 6, and consequently in the presence of the guest molecules the residually accessible volume is minimized to zero. The introduction of two benzyl residues (9) significantly alters the packing architecture, giving rise to additional secondary interactions of the bridge substituents.

The cell of the isostructural crystals 7 and 8 are similar, the cell similarity index is close to zero (π = 0.00338), while the structure with the same stoichiometry but significantly larger bridge substituents 9 differ markedly, i.e. 7/9: π = 0.04067 and 8/9: π = 0.04418.

The heavy atoms and the first carbon atom of the corresponding lateral substituent attached to the frame, present in the half of the centrosymmetric calixarene host molecules 6–9, were the subject of molecular similarity calculations (C26O2) [16]. The root mean square of the distance differences for the corresponding atoms of the compared fragments, as well as the largest distance of two corresponding atoms within a pair of molecules are calculated (Table 4). For the calculation of the overlay of the molecules (Fig. 4), the best molecular fit without consideration of the origin of the single left lateral carbon atom attached to the chalice is chosen. The influence of the spatial conditions of the bridge substituent on the calixarene geometry can be clearly extracted, which are largest for the pair 6/9, while calixarene host 6 fits well to the series of rather short bridge substituted calixarenes 7 and 8.

Table 4 Calculated molecular overlay of the calixarene frameworks (C26O2) (mercury). Upper right corner: root mean square of the distance differences of the corresponding atoms of the compared molecules (rmsD), bottom left corner (italic): the largest distance of two corresponding atoms of the compared molecules (maxD)
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Fig. 4
figure 4

Comparison of molecular conformation of the calixarene framework. The phenyl groups on the middle top are fitted in order to enhance the differences in the visualisation. Colour code of calixarenes: 6 (orange), 7 (light green), 8 (light blue) and 9 (pink) (Color figure online)

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Conclusion

Three new solvates of bridge-disubstituted tetramethoxycalix[4]arenes have been examined all consisting of the same 1:2 stoichiometry of the calixarene and the acetonitrile host–guest constituents. As the dominant packing motif remains, the crystal packing can be fine-tuned by synthetical modification of the peripheral methylene units. The increase of the sterical demand of the bridge substituents results in a more efficient utilisation of the crystal volume and a gradual reduction of residual empty voids of the lattice. If a size limit is exceeded, the bridge substituents are forced to participate in the supramolecular bonding system. This directed manipulation of the supramolecular packing architecture by appropriate synthetic adaptation of known synthons [24] can be seen as an extended case of “crystal engineering”, for which “synthon engineering” might be an appropriate designation.

Supplementary data

CCDC-883434 (7), CCDC-883435 (8) and CCDC-883433 (9) contain the supplementary crystallographic data for this article. These data can be obtained free of charge at www.ccdc.cam.ac.uk/data_request/cif [or from the Cambridge Crystallographic Data Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0) 1223-336033; e-mail: deposit@ccdc.cam.ac.uk].