Oksana Danylyuk

SOLID-STATE COMPLEXES OF WATER-SOLUBLE CALIXARENES WITH BIORELEVANT MOLECULES

Dissertation completed at the Institute of Physical Chemistry Polish Academy of Sciences within International Ph.D Studies Supervisor: Dr. hab. Kinga Suwinska

Warsaw 2007

Most importantly, I would like to sincerely thank my supervisor Dr. Kinga Suwinska for her guidance and support over the last years. I would like to thank Dr. Anthony Coleman and his group, in particular Dr. Adina Lazar, who have made significant contribution to this work. I would like to thank all colleagues from Department II accomodating. Finally, I would like to thank Volodja and Sofijka for being my inspiration, support and motivation. . 3 who have been very helpful and

Results described in this dissertation were partially presented in the following publications: Papers: 1. Lazar A. N., Danylyuk O., Suwinska K., Coleman A. W. Assembly modes in the solid state structure of the complexes of melamine mono-cations with paracalix[4]arene sulfonic acid and calix[4]arene dihydroxyphosphonic acid. New Journal of Chemistry, 2006, 1, 59. 2. Perret F., Bonnard V., Danylyuk O., Suwinska K., Coleman A. W. Conformational extremes in the supramolecular assemblies of para-sulfonatocalix[8]arene. New Journal of Chemistry, 2006, 7, 987. 3. Perret F., Gueret S., Danylyuk O., Suwinska K., Coleman A. W. A stepped bilayer packing motif for para-sulphonatocalix[4]arene: The solid-state structure of the para-sulphonatocalix[4]arenetriethylamine complex. Journal of Molecular Structure, 2006, 797, 1. 4. Lazar A., Danylyuk O., Suwinska K., Coleman A. W. The solid-state structure of calix[4]arene dihydroxyphosphonic acidL-lysine complex. Journal of Molecular Structure, 2006, 825, 20. 5. Lazar A., Danylyuk O., Suwinska K., Coleman A. W. The structure of the tetrapotassium salt of calix[4]arene dihydroxyphosphonic acid. Chemistry Journal of Moldova. General, Industrial and Ecological Chemistry, 2007, 2 (1), 98. Conference presentations: 1. Lazar A. N., Coleman A. W., Baggetto L. G., Michaud M. H., Suwinska K., Danylyuk O., Navaza A., Dupont N. Complexation and biology of calix[4]arenes diphosphonates. MoldavianPolishUkrainian Symposium on Supramolecular Chemistry, 1012 October 2005, Chisinau, R. Moldova, poster. 2. Perret F., Danylyuk O., Suwinska K., Coleman A. W. Anionic calix[8] arenes chemistry. MoldavianPolishUkrainian Symposium on Supramolecular Chemistry, 1012 October 2005, Chisinau, R. Moldova, poster. 3. Danylyuk O., Suwinska K., Lazar A. N., Perret F., Navaza A., Coleman A. W. Solid state structure of the complexes between antiseptic chlorhexidine and three

anionic derivatives of calix[4]arenes. 48 Konwersatorium Krystalograficzne, 29 30 czerwca 2006, Wrocaw, Poland, poster. 4. Danylyuk O., Suwinska K., A. N. Lazar, Coleman A. W. Solid state complexes of p-sulfonatocalix[n]arenes with biomolecules. XV-th Conference Physical Methods in Coordination and Supramolecular Chemistry, September 27October 1 2006, Chisinau, R. Moldova, oral. 5. Danylyuk O., Suwinska K., A. N. Lazar, Coleman A. Solid-state assemblies of calix[4]arene diphosphate with biorelevant molecules. XIth International Seminar on Inclusion Compounds. 10-15 June 2007, Kyiv, Ukraine, poster. 6. Danylyuk O., Suwinska K., A. N. Lazar, Coleman A. Solid-state assemblies of calix[4]arene diphosphate with biorelevant molecules. 49 Konwersatorium Krystalograficzne. 2830 czerwca 2007, Wrocaw, Poland, poster. 7. Danylyuk O., Suwinska K., A. N. Lazar, Coleman A. Solid state complexes of calix[4]arene diphosphate with chlorhexidine and pilocarpine. 24th European Crystallographic Meeting, 2227 August 2007, Marrakech, Morocco, poster.

TABLE OF CONTENTS 1 2 INTRODUCTION ............................................................................................... 9 LITERATURE REVIEW .................................................................................. 11 2.1 2.2 General overview of the calixarenes ...................................................... 11 Water-soluble calixarenes ...................................................................... 14 2.2.1 Synthesis of water-soluble p-sulfonatocalix[n]arenes and calix[4]arene diphosphate .......................................................... 15 2.2.2 Structural characterization of p-sulfonatocalix[4]arene complexes................................................................................... 15 2.2.3 Structural characterization of p-sulfonatocalix[6]arene complexes................................................................................... 26 2.2.4 Structural characterization of p-sulfonatocalix[8]arene complexes................................................................................... 29 2.2.5 Structural characterization of calix[4]arene diphosphate complexes................................................................................... 32 2.2.6 2.2.7 2.3 3 4 Biological activity of water-soluble calixarenes ........................ 35 Drug solubilization..................................................................... 37

Conclusions ............................................................................................ 38

EXPERIMENTAL ............................................................................................. 39 RESULTS AND DISCUSSION ........................................................................ 43 4.1 Solid-state complexes of p-sulfonatocalix[4]arene................................ 43 4.1.1 4.1.2 4.1.3 4.1.4 4.1.5 4.1.6 4.1.7 Crystal structure of p-sulfonatocalix[4]arene complex with melamine .................................................................................... 43 Crystal structure of p-sulfonatocalix[4]arene complex with triethylamine .............................................................................. 47 Crystal structure of p-sulfonatocalix[4]arene complex with triethyltetramine ......................................................................... 50 Crystal structure of p-sulfonatocalix[4]arene complex with norspermidine............................................................................. 53 Crystal structure of p-sulfonatocalix[4]arene complex with chlorhexidine.............................................................................. 58 Crystal structure of p-sulfonatocalix[4]arene complex with tetracaine .................................................................................... 62 Crystal structure of p-sulfonatocalix[4]arene complex with tamoxifen ................................................................................... 66 7

4.1.8 4.2

Crystal structure of p-sulfonatocalix[4]arene complex with piribedil ...................................................................................... 70

Solid-state complexes of p-sulfonatocalix[6]- and p-sulfonatocalix [8]arenes................................................................................................. 73 4.2.1 4.2.2 4.2.3 4.2.4 4.2.5 Crystal structure of p-sulfonatocalix[6]arene complex with bis(6-amino-hexyl)amine ........................................................... 73 Crystal structure of p-sulfonatocalix[6]arene complex with dimethylamine............................................................................ 75 Crystal structure of p-sulfonatocalix[8]arene complex with ciscyclo-hexanediamine ................................................................. 78 Crystal structure of p-sulfonatocalix[8]arene complex with dimethylamine............................................................................ 82 Crystal structure of p-sulfonatocalix[8]arene complex with butanediamine ............................................................................ 85

4.3

Solid-state complexes of calix[4]arene diphosphate.............................. 88 4.3.1 Crystal structure of calix[4]arene diphosphate potassium salt... 88 dimethylamine............................................................................ 91 4.3.3 Crystal structure of calix[4]arene diphosphate complex with melamine.................................................................................... 96 4.3.4 Crystal structure of calix[4]arene diphosphate complex with cadaverine ................................................................................ 100 4.3.5 Crystal structure of calix[4]arene diphosphate complex with L-lysine (I) ............................................................................... 103 4.3.6 Crystal structure of calix[4]arene diphosphate complex with L-lysine (II) .............................................................................. 106 4.3.7 Crystal structure of calix[4]arene diphosphate complex with chlorhexidine............................................................................ 110 4.3.8 Crystal structure of calix[4]arene diphosphate complex with pilocarpine................................................................................ 113 4.3.2 Crystal structure of calix[4]arene diphosphate complex with

4.4 5 6 7 8 8

The role of supramolecular complementarity in the formation of calixarene complexes with biorelevant molecules............................... 116

CONCLUSIONS.............................................................................................. 123 SUMMARY ..................................................................................................... 125 REFERENCES................................................................................................. 127 APPENDIX...................................................................................................... 135

INTRODUCTION
The biological world is rich in ordered assemblies of molecules. The forces

holding together these assemblies are van der Waals interactions, hydrogen bonding, - and cation interactions, metal coordination and hydrophobic effects. Nature has exploited these interactions in biorecognition and biomolecular organization for billions of years. These weak, noncovalent interactions are responsible for the protein folding, the selective transport of ions and small molecules across membranes, transduction of signals, enzymatic reactions, and the formation of larger aggregates. They are also the basis of one of the fastest-growing areas of research: supramolecular chemistry. The concepts of supramolecular chemistry are derived from biology and rely on the phenomena of molecular recognition and self-assembly: molecules (hosts) recognize complementary sites (functionality, geometry, size, etc.) on other molecules (guests) and associate into larger entities, supermolecules, via weak non-covalent interactions. Chemists, biologists, engineers, physicists, optical scientists and materials scientists are "architects" who apply the fundamental principles involved in the biological processes to design and fabricate artificial supramolecular systems. The design and synthesis of water-soluble, synthetic macrocycles as artificial receptors and biomimetic models for enzymes has been a major subject of interest in recent years. Self-assembly of such synthetic receptors with biorelevant molecules is a powerful tool for the understanding, modelling and mimicking of biological systems 1 and developing new materials with specific properties and functions 2. Along with the cyclodextrins, crown ethers and cryptands, the calix[n]arenes are one of the most important categories of supramolecular hosts 3. Compared to the cyclodextrins, the calix[n]arenes exhibit a high degree of steric flexibility which confers on them a large area of applications. There exist many conformational isomers of calixarenes, and a large number of cavities of different sizes and shapes, which can be involved in molecular recognition processes. It is well known that biogenic amines, amino acids, peptides, and proteins constitute one of the most fundamental substrates in biological and artificial processes. The family of calix[n]arenes is deeply involved in molecular recognition of these compounds 4, especially in the understanding of specific biomolecular interactions which play a key role in modern supramolecular chemistry 5. Water-soluble calixarenes are of interest in building up systems that mimic natural biological processes through the presence of hydrophobic pockets which can bind apolar guests. Moreover, they have 9

also been demonstrated to possess useful potential bio-activities ranging from enzyme inhibition through antithrombotic activity and antiviral activity to antibacterial properties. The theme of this dissertation is the investigation in the solid state of complexes of certain water-soluble calix[n]arenes with biologically relevant molecules. Of the rich chemistry of water-soluble calixarenes that have been synthesized in recent times, the p-sulfonatocalix[n]arenes (n = 4, 6, 8) and calix[4]arene diphosphate have been chosen due to their good aqueous solubility, low toxicity, interesting biological activities, and ability to generate a wide range of structural variations in solid state complexes. The presence of anionic groups and a hydrophobic cavity coupled with hydrogen bonding capability makes the anionic calixarenes complementary, in the sense of supramolecular chemistry, to many biorelevant molecules containing ammonium functions. The aim of the work is the X-ray structural analysis of solid-state complexes of water-soluble anionic calixarenes with organic mono-, di-, tri- and tetramines, amino acids (lysine) and different drugs (chlorhexidine, tetracaine, tamoxifen, piribedil and pilocarpine). The amines and amino acids are among the most important molecules in natural living systems. Amino acids are the basic structural building blocks of proteins and other biomolecules. Amines are formed during normal metabolic processes in living organisms and are present in everyday food products. Natural polyamines stabilize nucleic acids and stimulate their replication. Polyamines are essential for growth processes, and they have also been associated with carcinogenesis 6. The investigation of the interactions between water-soluble calixarenes and ammonium functions present in biomolecules is crucial for the understanding of the mechanisms of biological activity of the calixarenes, for the development new biomaterials, selective sensors, new therapeutics and smart drug delivery systems based on the water-soluble calixarenes. The co-crystals of calixarenes with pharmaceutically active molecules represent a great interest in the pharmaceutical domain. Since many drugs combine amine and hydrophobic residues in their structure, the anionic p-sulfonatocalix[n]arenes and calix[4]arene diphosphate are good candidates for drug complexation. The cocrystallization of drug with water-soluble calixarenes offers the opportunity to modify chemical and physical properties of API (active pharmaceutical ingredient) and to control drug conformation. Such co-crystallization can improve solubility, bioavailability and stability of pharmaceutically active molecules and/or remove polymorphism.

10

2
2.1

LITERATURE REVIEW
General overview of the calixarenes
Calix[n]arenes are cyclic oligomers of phenol, that can adopt various

conformations and form hydrophobic cavities. They are simple to prepare in high yields from inexpensive starting compounds and easy to modify. Calixarenes can be decorated with a wide variety of functional groups on the aromatic rings and/or the O-centres of the phenolic groups, the so-called upper (or wide) and lower (or narrow) rims of the calixarenes, respectively (Fig. 1b). In addition to their inclusion capability, qualifying them as potential nanoscale containers, the variety of properties of functionalized calixarenes coupled with their low cost and non-toxicity may allow their exploitation through multidisciplary areas of research as catalysts 7, extractants 8, semi-conductor materials 9, switchable systems for data storage 10,11 and sensors of bioactive compounds 12,13. a b Upper rim

Lower rim
Fig. 1. (a) Calyx krater with the death of Aktaion; (b) representation of calix[4]arene in cone conformation.

Calixarenes have a long history, stretching back to 1872 when Adolph von Bayer published the first results concerning the products obtained from the reaction of phenol with formaldehyde. But he was unable to isolate the product and determine its structure. In 1942 Alois Zinke, a professor of chemistry at the University of Graz in Austria and his co-worker Erich Ziegler discovered that the base-induced reactions of p-alkylphenols with formaldehyde yields cyclic oligomers. 30 years later C. David Gutsche and co-workers 14 reinterpreted the Zinke results and developed methods for synthesizing each of the three major cyclic oligomers in good and reproducible yields. It was also Gutsche who first proposed the name calixarenes for these molecules since the shape of the molecule resembled the Calyx krater vases of ancient Greece (Fig. 1a). The first crystal structure of the calix[4]arene was determined by Andreetti and coworkers from the University of Parma and published in 1979 15. 11

The simplified nomenclature of the calixarenes uses [n] to identify the number of phenolic units in the macrocycle, thus calix[4]arene contains four units. The nature and positions of substituents are given by sequential numeration and the appropriate term for the function is placed before the term calix[n]arene. Hydroxyl substituents follows again sequential numeration and are placed after the name calix[n]arene. For example, the cyclic tetramer derived from p-tert-butylphenol is called p-tertbutylcalix[4]arene, but its systematic name is 5,11,17,23-tetra-tert-butylcalix[4]arene25,26,27,28-tetrol. Calix[n]arenes are readily available with n equal to 4, 6 and 8 and less readily with n equal to 5 and 7, recently 9 and 10. Furthermore a large series of calixarenes with hetero atoms, different substituents and aromatic groups different from benzene exist. a b c d

Fig. 2. Four main conformations of the calix[4]arenes: (a) cone, (b) partial cone, (c) 1,2-alternate and (d) 1,3-alternate.

Another aspect of calixarene nomenclature relates to the conformations these molecules can adopt. It was recognized by Cornforth 16 that a calix[4]arene can exist in four conformations, which were later named by Gutsche 17 as cone, partial cone, 1,2-alternate and 1,3-alternate with idealized structures having C4v, Cs, C2h and D2d symmetry, respectively (Fig. 2). The nomenclature refers to the orientation of the arene rings with respect to one another. In the cone conformation, all arenes point up and form a cone-like structure, whereas in partial cone three arenes point up and one points down. Frequently, however, the actual molecule posseses conformations and symmetries differing from the ideal as the result of torsional changes in the arene rings orientation. For example, the cone conformation often assumes a pinched or flattened cone structure in which one pair of arene rings becomes almost parallel while the other pair splays outwards. Proton nuclear magnetic resonance (NMR) measurements of several calixarenes in solution show that they mainly exist in the cone conformation, but they are conformationally mobile at room temperature 18. Some control on the calixarene conformation can be achieved by introducing bulky substituents on the upper or lower

12

rim to inhibit rotation. The flexibility of the calixarenes can be also controlled by crystallization which allows a desired conformation to be fixed in the solid state. The calix[6]arene can exist in eight up-down conformations and numerous others in which one or more of the aryl rings projects outward from the average plane of the molecule, depending on the solvent, the nature of the complexed guest and on the functionalizations on the lower rim. However two conformations show higher stability, the 1,2,3-alternate or double partial cone 19,20 (also known as hinged) in which three adjacent oxygen atoms lie on the one side and the other three on the other side of the molecule or a pinched cone 21,22 (winged) conformation in which all of the oxygen lie on the same side of the molecule and two opposite methylene groups point to the center of the bowl. The much larger annulus of the calix[8]arenes, the possibility of 16 up-down conformations, and the numerous other conformations in which one or more aryl rings project out would appear to make these more flexible and complicated than calix[4]arenes. The calyx shape of the molecule completely disappears in most calix[8]arenes and a new conformation which has the architecture of a pleated loop is observed 23 (Fig. 3). The undulating pleated loop structure allows maximal hydrogen bonding with the OH groups lying above and below the average plane of the molecule.

Fig. 3. Pleated loop conformation of p-tert-butyl-calix[8]arene 24.

The cone conformation of calixarenes is flexible in its ability to accommodate various guests. Their conformational properties help in ligating guests which can be even much larger compared with the host molecule. Studies on inclusion properties 25,26 of calixarenes have shown that, in the presence of guest molecules, appropriately functionalized calixarene derivatives can self-assemble to form dimeric units, host capsules, suitable to include these small organic molecules. 13

Calixarenes possessing both hydrophobic and hydrophilic groups at the opposite rims are usually suitable for the formation of bilayer arrangements involving head-tohead and tail-to-tail interactions. For example, many bilayer structures have been reported for p-tert-butyl-calix[4]arenes 27, in which the presence of hydrophilic phenolic rim and hydrophobic core and upper rim has resulted in the antiparallel alignment of adjacent calixarene molecules.

2.2 Water-soluble calixarenes

The parent calixarenes are totally insoluble in aqueous solutions, and this property is the major problem for the calixarene use in biopharmaceutical applications. Different methods have been developed to obtain water-soluble calixarenes 28. Generally to induce aqueous solubility, the calixarenes need to be functionalized with groups containing positive or negative charges, or with neutral but highly hydrophilic groups. Functions such as carboxylates, phosphates, sulfonates or ammonium groups are used for such modification Three possible sites for the functionalization exist: at the phenolic functions, para-position to the phenolic groups and at the methylene bridges. The tetracarboxylic acid of p-tert-butyl-calix[4]arene, introduced by Ungaro and co-workers in 1984 was the first example of water-soluble calixarene 29. In the same year Shinkai reported the preparation of p-sulfonatocalix[6]arene 30. Following the preparation of the sulfonated tetramer and octamer 31, other anionic water-soluble derivatives containing nitro 32, phosphonic acid 33, and carboxyl 34 functions appeared. Water-soluble calix[n]arenes are a widely investigated class of compounds becoming increasingly important in the field of supramolecular chemistry. They offer interesting inclusion properties and a wide range of metal coordination complexes both in solution and in the solid state. The property of water-soluble calix[n]arenes to form inclusion complexes with different guest species in water, opened a new direction of applications. The guest molecules range from inorganic ions, through small organic molecules to amino acids, hormones, peptides and neurotransmitters 35. The molecular recognition properties of these amphiphiles are of interest in nanochemistry where they have potential applications in building up new synthetic materials 36,37, and in medicinal applications which include drug delivery, and sensing 38. Water soluble calixarenes have been shown to be useful as new surfactants to water-solubilise biomolecules such as carotenoids 39. 14

2.2.1

Synthesis of water-soluble p-sulfonatocalix[n]arenes and calix[4]arene diphosphate The synthesis of p-sulfonatocalix[n]arenes (n = 4, 6, 8) can be simply achieved

in two methods: the most common is sulfonation of p-H-calix[n]arenes as first described by Shinkai30,31 and there is also direct ipso-sulfonation of the p-tert-butylcalix[n]arenes (Fig. 4). Direct ipso-sulfonation is simpler than the method of Shinkai but the reaction is often perturbed by incomplete substitution and is used only for the obtaining of calix[8]arene derivatives because of the low solubility of

p-H-calix[8]arene. ipso-sulfonation
SO3H SO3H HO3S SO3H HO3S

sulfonation
SO3H SO3H SO3H

H2SO4 80C
OH OH OHHO OH OH OHHO

AlCl3 toluene
OH OH OHHO

H2SO4 100C
OH OH OHHO

Fig. 4. Synthesis of p-sulfonatocalix[n]arenes.

Calix[4]arene containing two dihydroxyphosphoryl groups on the lower rim have been synthesized by consecutive treatment of easily accessible diethoxyphosphoryl derivative with bromotrimethylsilane and methanol 40 (Fig. 5).

diethylchlorophosphate chloroform
OH OH OHHO EtO P O OEt EtO O OH OH O P O

bromotrimethylsilane methanol
OEt HO P O OH HO O OH OH O P O OH

Fig. 5. Synthesis of calix[4]arene diphosphate.

2.2.2

Structural characterization of p-sulfonatocalix[4]arene complexes Anionic p-sulfonatocalix[n]arenes possess the highest known solubility in

aqueous solutions among the water-soluble calixarene derivatives and are able to complex a wide range of inorganic and organic cations. p-Sulfonatocalix[4]arene has been found to have a solubility at least as great as 0.1 M.

15

Fig. 6. (a) Cone and (b) 1,3-alternate conformations of p-sulfonatocalix[4]arene.

The smallest and most conformationally constrained p-sulfonatocalixarene, tetramer C4S, often adopts a cone conformation with hydrophilic upper and lower rims, while the cavity and outer midsection are strongly hydrophobic (Fig. 6a). The cone conformation is stabilized by intramolecular hydrogen bonding among OH groups. p-Sulfonatocalixarene with its cone-shaped hydrophobic cavity serves as a molecular container for small organic molecules and ions, biologically significant amino acids and nucleotide bases, globular shaped organic molecules and transition metal complexes. Some X-ray crystal structures of p-sulfonatocalix[4]arene show 41,42 that water molecule inside the calixarene cavity is hydrogen-bonded to the cloud of the aromatic nuclei, a motif which may be commonly encountered in biological systems (the hydrophobic pockets of proteins). Anionic p-sulfonatocalix[4]arene has shown a great capacity to generate a wide range of structural motifs. Most commonly, p-sulfonatocalix[4]arenes are assembled in an antiparallel (up-down) fashion with sulfonate groups covering the surfaces of the bilayers which are separated by a hydrophilic layer containing the guest molecules and water. The ability of these molecules to intercalate cations in the hydrophilic layers between bilayers of p-sulfonatocalix[4]arenes led Atwood and Coleman 43 to name these systems organic clays. In a recent review
44

of

the

biochemistry

of

p-sulfonatocalixarenes, Coleman and co-workers

stated that the decision to liken the

solid state structures adopted by their hydrated alkali metal salts to organic clays, rather than phospholipid bilayers, may have led us away from the study of the biochemistry of these molecules. While the span of the calixarene bilayers, at 14 , is of the order observed in smectite and vermiculite (15 ) it is much less than the 40 or so observed for biological membranes. However, the ability to form bilayers indicates that 16

calixarenes, extended through upper or lower rim derivatization, have the potential to insert themselves in biological membranes to form permanent channels 45. Subsequent investigations on the solid state supramolecular complexes of p-sulfonatocalix[4]arene revealed the prevalence of bilayer structural motif (Fig. 7) and perturbations thereof. The solid state structures of the supramolecular complexes between p-sulfonatocalix[4]arene and a variety of organic cations, both aliphatic and aromatic, with different chain length and charge have been reported.

Fig. 7. Structure of the sodium salt of p-sulfonatocalix[4]arene showing the typical bilayer motif.

The complexation of quaternary ammonium cations by synthetic receptors has attracted extensive attention recently, especially after the discovery that neurotransmitter acetylcholine is bound to acetylcholine esterase thanks to cation- interactions. It was demonstrated that the N(CH3)3+ group of acetylcholine is held not by negatively charged anionic groups of the enzyme, but rather by aromatic residues creating a suitable -capsule for binding of the quaternary ammonium salt by cation interactions 46, thus highlighting the crucial role of weak cation- interactions in the recognition processes 47. The complex of p-sulfonatocalix[4]arenes with the tetramethylammonium cation 48 shows the stoichiometry 1:5. The calixarene exists in the form of pentanion with one deprotonated phenolic group. One of the tetramethylammonium cations is embedded into the calixarene cavity with one methyl group situated deeply inside the cavity. The distances between the carbon atom of the included methyl group to the centroids of the four aromatic rings are longer than those typically found for C-H aromatic hydrogen bonding. It is suggested that the position of the cation is stabilized by strong electrostatic interactions with the electron-rich sulfonato groups. The 17

remaining four tetramethylammonium cations and crystallization water molecules are situated in the region between the typical calixarene bilayer. In the complex with the trimethylanilinium cation the aromatic moiety of the guest is included into calixarene cavity 49 (Fig. 8). The ammonium cation is bound to an electrostatic pocket formed by two neighboring sulfonate groups. The three aromatic hydrogens of trimethylanilinium are in contact with the benzene -system. The phenyl ring of the trimethylanilinium cation is significantly inclined in the cavity. This conformation is favored to attain the maximal multipoint interaction with p-sulfonatocalix[4]arene through both hydrophobic and electrostatic forces. The complex features the typical clay-like bilayer structure, that is, the calixarene rings form two hydrophobic layers, and the sulfonate groups cover the surface of the bilayer. The ammonium cation of the guest is placed on the surface.

Fig. 8. Inclusion complex of C4S with trimethylanilinium cation.

The complex of p-sulfonatocalix[4]arene with choline reveals the inclusion of the guest cation in the macrocyclic cavity of the C4S 50. There are two independent complexes with different guest conformation in the asymmetric unit. In the first complex the choline is in an extended conformation while in the second one is disordered (s.o.f. = 0.75 and 0.25) and adopts two folded conformations. In both complexes the choline quaternary ammonium cation inserts its positively charged N terminal group inside the cavity of the receptor. The linear molecule emerges from the cavity with its hydroxyl pointing between two sulfonates framing a window. This contrasts with the structure of C4S with trimethylanilinium cation where the phenyl group is located in the cavity49. The very short contacts observed between the choline atoms and those of the calixarene groups are in line with strong interactions with the substrate and high stability of the complex in the solution. Leverd reported structural study on the three C4S complexes with ethylenediamine of different stoichiometry and charge balance41. In the first complex 18

water is included into the macrocyclic cavity and two ethylenediammonium dications are complexed outside the cavity of the calixarene. If 2.5 equivalents of ethylenediamine are added to C4S, water is expelled from the cavity by the deprotonation of one of the phenolic groups of the macrocycle and replaced by ethylenediammonium dication to form an inclusion complex. The asymmetric unit comprises two independent molecules of the calixarenes that differ from one another in the way that the guest resides in the cavity. Both incorporated ethylenediammonium dications are stabilized in their positions by donating six hydrogen bonds to sulfonate groups of the C4S or to water molecules. Interestingly, the addition of 3 equivalents of ethylenediamine leads to the proton exchange reaction between the diamine and the diammonium dication and therefore to the formation of monocation which can compete with the dication for the inclusion inside the cavity. In the resulting mixed complex the monocation is included in the cavity of p-sulfonatocalix[4]arene, while dications are situated outside the cavity. Four independent calixarenes are present in the crystal lattice, in each of which the monocation is bound in the same way. The NH3 end of the molecule points towards the exterior of the cavity, forming strong hydrogen bonds with oxygen atoms of either water molecules or sulfonate groups, while the other NH2 end is embedded in the cavity and interacts with the aromatic core by N-H weak hydrogen bond. Ncentroid distances range from 3.449(4) to 3.603(4) . Such amine interactions with aromatic faces are a matter of importance in the folding and recognition of biological polymers 51. The complexes of p-sulfonatocalix[4]arene with linear 1,4-butanediamine (putrescine), 1,5-pentanediamine (cadaverine), 1,5,10-triazadecane (spermidine) 52 and cyclic cis-1,2-cyclohexanediamine show the partial inclusion of the guest molecule within the host aromatic cavity. In all these structures, the organic cation is held inside the cavity by ammonium-sulfonate hydrogen bonds and alkyl-aromatic hydrophobic interactions. In the complexes with cadaverine and putrescine, two p-sulfonatocalix[4]arene molecules of the opposing layers form a capsule, which contains two diammonium guest molecules. In the case of much longer spermidine and bulky cyclohexanediamine molecules, no capsules are observed due to lateral displacement of one layer of the complex with respect to the other. This results in one sulfonate group of calixarene of one layer being positioned above the cavity of calixarene of the opposing layer. The spermidine trication extends outside the p-sulfonatocalix[4]arene cavity and forms p-sulfonatocalix[4]arene of the same layer. 19 hydrogen bond to an adjacent

The solid state complex of p-sulfonatocalix[4]arene with L-lysine shows the stoichiometry 1:2 53, in contrast to the situation in solution, where 1:1 complexation is observed 54. There are two independent calixarenes and four independent lysine molecules in the structure. For all the L-lysine molecules, the - and -amino groups show contacts indicative of N-HO hydrogen bonds with oxygen atoms on the sulfonate groups of the calixarenes, but they display different types of interactions. Of the four independent lysine molecules, three are found within the hydrophilic layer separating the typical p-sulfonatocalix[4]arene bilayer, while the remaining molecule spans this bilayer in a manner resembling biomolecules traversing a lipid bilayer (Fig. 9a). a b

Fig. 9. (a) Solid-state packing of C4S complex with lysine showing the lysine spanning the bilayer and (b) zigzag bilayer of the C4S complex with arginine.

For the complex with D-arginine the planar bilayer of p-sulfonatocalix[4]arene is replaced by a zigzag bilayer arrangement (Fig. 9b).The four crystallographically independent molecules of C4S form a cage which accomodates six independent arginines, each with different chain conformation 55. The structure contains a water channel diagonal to a zigzag bilayer of the host. For alanine, histidine and phenylalanine, racemic pairs of molecules are confined in capsules comprised of two p-sulfonatocalix[4]arenes 56 (Fig. 10a). For (S)-serine two chiral molecules are also confined in such capsules 57. The (S)-alanine and (S)-histidine form independent 1:1 complexes (Fig. 10b). For (S)-tyrosine, a -stacked chiral pair of isomers is encapsulated by p-sulfonatocalix[4]arene. A feature of all amino acid complexes is that the polar groups of the amino acids point away from the calixarene cavity. For all these complexes the classical bilayer motif of p-sulfonatocalix[4]arene is observed. 20

Fig. 10. (a) Molecular capsule formed by two molecules of C4S containing racemic pair of histidine molecules and (b) open inclusion complex of C4S with (S)-histidine.

The first p-sulfonatocalix[4]arenenucleic acid base complex structure is the adenine complex with the stoichiometry 1:4 reported by Atwood et al. 58. The complex crystallizes with a water molecule exhibiting aromatic hydrogen bonding embedded within the hydrophobic calixarene cavity. The adeninium cations form a hydrogen bonded array in a layer external to the cavity. Two different bilayers exist in the structure; one of calixarene anions, where the sulfonato groups are directed into the hydrophilic layer, and the other of adeninium cations, where the protonated nitrogen is directed into the hydrophilic layer. These two bilayers are separated in part by thin layers of water molecules. Raston et al. 59 recently reported structures of supramolecular complexes of nucleic bases (guanine, cytosine) and related compounds (benzimidazole and 2-hydroxybenzimidazole) with p-sulfonatocalix[4]arene. For all the complexes, the nucleic acid bases are found both exo and endo to the cavity of p-sulfonatocalix[4]arene anions. In the case of guanine the guest dication perched above the cavity of C4S in the hydrophilic area of the overall bilayer structure. The guanine dication is above and almost coplanar with the plane defined by the four SO3- groups of each calixarene and is involved in N-HO hydrogen bonds to oxygens on the sulfonato groups and crystallization water molecules. In the mixed complex with guanine and cytosine, one cytosine cation is located within the C4S cavity and another cytosine along with a guanine dication situated outside the cavity. The endo cavity cytosine cations lie perpendicular to the base plane of phenolic oxygens of the C4S cavity with their polar groups radiating outwards and are hydrogen bonded to two sulfonato groups of the C4S. 21

The other cytosine and guanine cations -stack with the aromatic rings on the p-sulfonatocalix[4]arene anions. The presence of both guanine and cytosine exo to the calixarene cavity disrupts the usual bilayer structure formation, but the overall structure has the cavities of the C4S oriented in opposite directions. For the complex C4S with 2-hydroxybenzimidazole a pair of -stacked 2-hydroxybenzimidazole cations is encapsulated by a pair of p-sulfonatocalix[4]arene anions approximating as molecular capsule. Another 2-hydroxybenzimidazole cation is located in the hydrophobic layer outside the calixarene cavity. The benzimidazole complex crystallizes with a pair of -stacked benzimidazole cations encapsulated by C4S anions, like that for 2-hydroxybenzimidazole. The molecular capsule has the endo cavity benzimidazole cation hydrogen bonded to each of the calixarenes. Solution and solid state studies on the complexation of three isomeric 4'-(pyridyl)-terpyridines by p-sulfonatocalix[4]arene has recently been reported 60. The terpyridines are widely used as supramolecular tectons in molecular architectures and are gaining promise in medicinal chemistry as possible anticancer and antimicrobial agents 61. For the complex p-sulfonatocalix[4]arene4 -(2-pyridyl)-terpyridine the stoichiometry is 2:3. The asymmetric unit consists of two calixarene-terpyridine motifs separated by another molecule of terpyridine (Fig. 11). Three of the four pyridine rings in each terpyridine molecule are protonated, with the exception being the nitrogen atom on the central pyridine ring. Both calixarenes adopt the expected pinched cone conformation, with the cavity in each being occupied by the pyridine ring of terpyridine molecule. The calixarenes are arranged in an updown fashion, and are separated by molecules of 4'-(pyridyl)-terpyridine which are -stacked to two calixarenes from each of the motifs. The bilayer arrangement incorporating molecules other than calixarenes is unusual and has only been reported in a few instances for positively charged guest molecules53,62. The inclusion complex p-sulfonatocalix[4]arene4'-(3'-pyridyl)-terpyridine crystallizes with the 1:1 C4Sterpyridine ratio. The terpyridine molecule is included within the cavity of C4S via the terminal 4'-(2-pyridyl) ring. Pairs of calixarene terpyridine motifs related by an inversion centre are molecular-capsule like in arrangement shrouding in part two terpyridine molecules. Such molecular capsules have been noted for smaller pairs of amino acids and related molecules where the shrouding is more effective56,59.

22

Fig. 11. The asymmetric unit of C4S complex with 4 -(2-pyridyl)-terpyridine.

In the case of 4'-(4-pyridyl)-terpyridine, a molecular capsule is formed in which two calixarenes encapsulate one terpyridine guest molecule, with the terminal pyridine ring being exo to the calixarene cavities. As for the previous structures, the arm of the terpyridine in the cavity is associated with C-H interactions between the protons on pyridine ring and the 1,3-pair of calixarene phenyl rings. A salient feature of the structure is a slippage within the bilayer arrangement in respect to the hydrophilic and hydrophobic domains giving rise to an overall corrugated bilayer arrangement, and the calixarenes are unusually well separated from each other through bilayer intercalation of terpyridine molecules. Stacking interactions are a dominant feature in each of the inclusion complex structures, either for terpyridines in the calixarene cavities, or those included in bilayers. Many of the p-sulfonatocalix[4]arene capsules take on the form of Russian Matryoshka dolls 63, 64, i. e. the inclusion complexes of inclusion complexes which are unusual examples of second-sphere supramolecular complexation (host-within-host). These complexes are mainly formed at low pH (<4) in the presence of lanthanide(III) ions, which act to close the molecular capsules by coordinating with the sulfonate groups. Such Russian dolls are readily formed by combining sodium p-sulfonatocalix[4]arene with 18-crown-6 (Fig. 12a). Sodium cations included in the crown ether can have two trans-water molecules, or two trans-oxygen centers from sulfonate groups, one from each calixarene 65. The complex of Ln3+ and 18-crown-6 with p-sulfonatocalix[4]arene shows the new type of assembly known as ferris wheel. Ln3+ resides in the centre of an 23

18-crown-6 molecule. It is coordinated to all six oxygens of the crown ether and to the oxygen atom of one sulfonate group of the C4s molecule. The 18-crown-6 is cupped in the bowl of the calixarene 66 (Fig. 12b).

Fig. 12. (a) Russian doll superanionic capsule of C4S with 18-crown-6 and sodium cation; (b) ferris wheel structure of C4S complex with 18-crown-6 and lanthanum (III) cation.

It has also been reported that p-sulfonatocalix[4]arene can generate such structure variations as 2D coordination polimers 67 and helical arrays 68. Atwood and coworkers 69 have shown that C4S form large molecular assemblies of spectacular nanometer-scale spheroids or helical tubules. These giant spheroids adopt either icosahedral, or cuboctahedral geometries and have been touted as inorganic virus mimics due to their large internal volumes and similar geometries. For the complex of p-sulfonatocalix[4]arene with pirydine N-oxide in the presence of lanthanide(III) nitrate in the ration of 2:2:1, the hydrophobic regions of the calixarenes are aligned, and assembled in an up-up radially symmetric fashion along the surface of a sphere in the contrast to up-down fashion when forming a bilayer. The spheroidal array consists of 12 calixarenes arranged at the vertices of an icosahedron (Fig. 13a). The polar outer-shell surface of the sphere consists of the sulfonate head groups of calixarenes and bears a total charge of -48, the polar inner-shell surface of the nano-sphere comprises 48 phenolic hydroxyl groups, 12 of which are deprotonated. The cavities of the calixarenes are situated just below the polar surface of the sphere and constitute a series of hydrophobic pockets. Twelve pyridine N-oxide molecules penetrate the polar surface of the sphere and are bound within the hydrophobic pockets via -stacking interactions. Their oxygen atoms extend outwards and coordinate to La3+ ions above the sphere 24

surface. In the same system the helical tubular structure may be obtained when the ratio of the starting components is of 2:8:1. The calixarene molecules are arranged along the surface of a cylinder that is analogous to the spherical assembly in that there is a polar core, a hydrophobic mid-region constituting the tube, and a polar outer shell. However, the organic shell is no longer composed purely of calixarene molecules, but contains pyridine N-oxide molecules intercalated between the aromatic rings of adjacent macrocycles. a b

Fig. 13. Schematic representation of nanometre scale spheroids based on p-sulfonatocalix[4]arene: (a) twelve C4S molecules in the presence of pirydine N-oxide and lanthanide(III) nitrate assemble at the vertices of an icosahedron (shown by green faces within spheroid), (b) twelve C4S molecules in the presence of 18-crown-6 and praseodymium (III) nitrate assemble at the vertices of a cuboctahedron (shown by red faces within spheroid)64.

The replacement of pyridine N-oxide by 18-crown-6 and lanthanum nitrate for praseodymium (III) (or neodymium(III) or samarium (III) nitrate) in the above mentioned ternary system C4SguestLn results in a remarkably dissimilar spheroidal array consisting of 12 calixarenes arranged at the vertices of a cuboctahedron 70 (Fig. 13b). Praseodymium (III) ions are complexed by 18-crown-6 together with two transwater molecules, and form the core of upper rim to upper rim molecular capsule, similar to the trans-aqua 18-crown-6 complex of sodium65. In the extended structure these Russian dolls are arranged in the form of cuboctahedra. This arrangement results in the formation of pores in the spheroid shell which are occupied by water molecules. The internal volumes of the icosahedron and cuboctahedron differ by approximately 30% in favour of the cuboctahedron. Thus, changing the nature of the guest in the hydrophobic cavity of C4S (pyridine N-oxide to 18-crown-6) results in the expansion of the spheroid. In addition, the formation of pores in the outer shell of the spheroid associated with this change allows the tentative analogy to viral mimicry of the cowpea chloritic mottle virus that has been shown to behave in a similar manner under 25

particular pH control, a system that can be used to trap molecular material for study within the virion shell 71. The cuboctahedral arrangement appears to allow communication from the hydrophilic interior of the spheroid through the hydrophobic channels/pores to exo-hydrophilic region via the presence of water molecules within the voids. There is also one example of the p-sulfonatocalix[4]arene in 1,3-alternate conformation (Fig. 6b), stabilized as its bipyridinium salt 72. The calixarene is surrounded by eight 4,4'-bipyridinium cations. Four of these are situated about the 4-fold axis while the remaining four protrude into the small clefts beside the sulfonate headgroups. The former interact with the C4S by means of relatively strong C-HO hydrogen bonds and face to face aromatic - interactions while the latter form strong N-HO hydrogen bonds to the oxygens of the sulfonate groups. It is worth mentioning that this solid-state complex is completely insoluble in water, this is probably due to intricate network of non-covalent interactions that provide a high degree of stability to the crystal lattice, thereby compensating for the energy involved in disruption of the C4S cone conformation .

2.2.3

Structural characterization of p-sulfonatocalix[6]arene complexes The supramolecular solid-state chemistry of p-sulfonatocalix[6]arene (C6S) is

less documented, in contrast to C4S. p-Sulfonatocalix[6]arene has larger cavity and is more conformationally flexible than its calix[4]analogue, and can act as ditopic receptor to various guest molecules. p-Sulfonatocalix[6]arenes typically adopt an up-down double partial cone (1,2,3-alternate) conformation 73,74 (Fig. 14a). Of the thirteen C6S based supramolecular structures found in the Cambridge Crystallographic Data Base three show the calixarene in the up-up double cone conformation 75,76,77 (Fig. 14b). a b

Fig. 14. Conformations of p-sulfonatocalix[6]arene: (a) up-downdouble partial cone and (b) upupdouble cone.

26

The

transition-

and

lanthanide-metal

supramolecular

chemistry

of

p-sulfonatocalix[6]arene shows its great potential in the formation of different supramolecular architectures that deviate from the typical bilayer arrangement formed with C6S. The versatility in complex formation is clearly seen in the system C6S pyridine N-oxidemetal ion. In the presence of nickel(II) ions the calixarene in the double partial cone conformation acts as a ditopic receptor to two pyridine N-oxide molecules with hexaaquanickle(II) cations residing in the hydrophilic regions within the bilayer 78 (Fig. 15a). The bilayer arrangement is similar to that seen for the calixarene in both the corresponding sodium salt and parent sulfonic acid and assembles with the similar -stacking distances 79. Replacement of nickel(II) from the above system with lanthanide(III) metal results in the formation of the complex where there is one pyridine N-oxide molecule bound to one metal center79. Although a bilayer is present within the extended structure, it is quite different from the previous one and can be described as a corrugated bilayer (Fig. 15b). Examination of other lanthanide metal ytterbium(III) affords a hydrogenbonded array of a C6Spyridine N-oxideytterbium complex which has varied coordination modes within the extended structure74. There are two independent a b

Fig. 15. (a) Bilayer arrangement of C6S molecules in the C6Spyridine N-oxidenickel complex and (b) corrugated bilayers of C6S in the C6Spyridine N-oxidelanthanum complex.

supramolecular tectons, one of which has two octacoordinate ytterbium ions bound to opposing sulfonate groups of the calixarene with one pyridine N-oxide ligand also bound to the metal center while residing in the partial cone of the C6S. The second supramolecular tecton consists of one calixarene, again with two lanthanide metal centers coordinated to opposing sulfonate groups within the calixarene, but with two pyridine N-oxide ligands. Of the two pyridine N-oxide molecules coordinated to ytterbium ions, one resides in one partial cone of the calixarene, while the other resides in the partial cone of the nearest identical tecton. 27

Raston and co-workers76 have shown that some control on the C6S conformation can be achieved in the presence of varied stoichiometric amounts of 18-crown-6 and selected lanthanide(III) chlorides. The calixarene may adopt an up-up double cone conformation or centrosymmetric up-down double partial cone conformation, depending on the ratio of the guest used and the nature of the lanthanide metal. In the presence of smaller lanthanides, complex has a double molecular capsule arrangement with two p-sulfonatocalix[6]arenes shrouding two 18-crown-6 molecules (Fig. 16a), while for the larger lanthanides ferris wheel arrangement is observed (Fig. 16b). The two complexes have the calixarenes in the elusive up-up double cone conformation. In the presence of large excess of 18-crown-6 the C6S adopts the double partial cone conformation with the calixarene acting as divergent receptor towards disc-shaped crown ether molecules. a b

Fig. 16. (a) Molecular capsule of two C6S in up-up conformation shrouding two 18-crown-6 molecules and (b) C6S in up-down conformation acting as divergent receptor towards 18-crown-6 molecules.

The bis-molecular capsule motif is observed for the C6S complex with tetraphenylphosphonium cations77. The two calixarenes in the pinched up-up double cone conformation encapsulate tetraphenylphosphonium cation pair. Some of the phenyl groups of the tetraphenylphosphonium cations reside in the pseudo calix[3] cavities of the calix[6]arenes. The interaction of the cations with the calixarenes involves C-H contacts from the aryl para hydrogens of the guests to the aromatic rings of the calixarenes. The remaining aryl group from each of the included cations protrudes out of the capsule into the hydrophilic domain. In the extended structure the capsules are well separated from each other, in contrast to the usual bilayer arrangement where the calixarenes are -stacked. The complexation of L-leucine by p-sulfonatocalix[6]arene has been reported recently75. The C6SL-leucine stoichiometry is 1:6. The calixarene in the double cone 28

conformation serves as a host to two L-leucine molecules. The hydrophobic aliphatic tails of the amino acids reside in the cavities of the calixarene while the polar groups are positioned near the upper rim sulfonate groups of the host (Fig. 17). Four hydrogen bonding contacts are evident between oxygen atoms of the amino acids to closest sulfonate groups of the calixarene, two examples of which are shown in Fig. 17. There are several hydrogen bonding contacts between protonated nitrogen atoms of the
L-leucine molecules and C6S sulfonate groups. In addition to included L-leucine

molecules, the remaining amino acids occupy interstitial spaces within the extended structure. The p-sulfonatocalix[6]arenes are packed in bilayer helical chains and are held together by -stacking and C-H interactions.

Fig. 17. Inclusion complex of C6S with L-leucine showing double cone conformation of the calixarene and the hydrogen bonding from L-leucine molecules to sulfonate groups.

2.2.4

Structural characterization of p-sulfonatocalix[8]arene complexes While calix[4]arenes have been widely studied, p-sulfonatocalix[8]arene (C8S)

was exploited much less because of its more challenging chemistry and the inherent difficulties in obtaining single crystals and authentication using X-ray diffraction data coupled with their higher conformational flexibility. This calixarene has a theoretically much larger molecular cavity, and thus has great potential for enveloping large spherical guest molecules such as fullerenes 80 or globular shaped metal complexes in water soluble thin films 81, in catalysis and ion transport 82,83, or acting as a surfactant for nanoparticle stabilisation. The first structural study of p-sulfonatocalix[8]arene was reported by Raston et al. in 2005 84. The p-sulfonatocalix[8]arene adopts a pleated loop conformation, which does not contain a substantial molecular cavity and is similar to that found for p-tBu 85 29

and p-H-calix[8]arene 86. The charge of the calixarene is -10 (with two calixarene base hydroxyl groups deprotonated). In this conformation C8S molecule has four grooves on either side of the macrocycle and each groove is occupied by a 4,4'-dipyridine-N,N'dioxide molecule (Fig. 18). The guest molecules, some being europium bound and some non-coordinated, interact with the calixarene by a series of -stacking and C-H interactions. Clearly 4,4'-dipyridine-N,N'-dioxide is an excellent choice of guest for C8S as it fits well with the large host when it is in the pleated loop conformation. The calixarene acts as a linking unit in a complex 3D wavy brick wall coordination polymer.

Fig. 18. Complex of the p-sulfonatocalix[8]arene with 4,4'-dipyridine-N,N'-dioxide.

In the presence of tetraphenylphosphonium and trivalent ytterbium cations, p-sulfonatocalix[8]arene forms large 2D porous structure 87. The asymmetric unit comprises two calixarenes, nine tetraphenylphosphonium cations, a chloride anion and disordered ytterbium cations with partial occupancies. Charge neutrality for the system implies that some of the sulfonate groups are protonated. In this complex the calix[8]arene adopts an unusual conformation (Fig. 19a) where three neighboring phenyl rings adopt a pseudo partial cone, which is occupied by a phenyl ring of one guest tetraphenylphosphonium cation. The basic structural motif consists of two calixarenes shrouding three tetraphenylphosphonium cations in a skewed molecular capsule arrangement which are interspersed between an envelope of tetraphenylphosphonium cations (Fig. 19b). Two of the included guests have C-H interactions with a pseudo calix[3]arene cavity of the C8S. The structure is 30

complicated, consisting of pseudo molecular capsules of C8S forming an overall layered structure where the calixarenes are in bilayer arrangement. There are two kinds of criss-crossed large channels filled with water molecules and aquated ytterbium cations forming 2D porous structure. p-Sulfonatocalix[8]arene has been shown to form chalice-like cavity for the solid state inclusion of coordination complex tris(phenantroline)cobalt(III) ([Co(phen)3]3+) in the presence of trivalent ytterbium cations 88. The encapsulation of globular shaped [Co(phen)3]3+ cation results in a disruption of the calixarene hydrogen bond network associated with the phenolic moieties, and the wrapping of the flexible a b

Fig. 19. (a) Unusual conformation of C8S showing pseudo calix[3]arene cavity, (b) skewed molecular capsule of two C8S molecules shrouding three tetraphenylphosphonium cations.

host around the guest (Fig. 20). The guest cation is held within the calixarene cavity by O-H and C-H interactions. Additionally, two cations are associated externally to each supermolecule. The guest cations are held distant from each other through encapsulation by three calixarenes, with each calixarene acting as a heterotritopic receptor for [Co(phen)3]3+ cation. The calixarene is best described as a distorted version of the pleated loop conformation, with the phenolic hydrogen bond network breaking such that a C2 symmetrical chalice is formed that is similar to that found for a bismuth cluster complex of a p-tert-butylcalix[8]arene 89. The lower rim of the chalice is stitched together through the two hydrogen bonding interactions between the sulfonate group from one ring and phenolic oxygen atom from another ring in alternate conformation. Hydrogen bonding interactions between phenolic units are absent. The preorganisation requirement of the calixarene in forming the complex results in the formation of large diameter, negatively charged channels within the crystal lattice.

31

Fig. 20. (a) Distorted pleated loop conformation of C8S; (b) inclusion of [Co(phen)3]3+ within the C8S cavity.

It would appear that size or/and shape of the guest has the capacity to influence the shape of the p-sulfonatocalix[8]arene cavity adopted in the solid state. The mutually induced fit in host-guest complexes between conformationally flexible p-sulfonatocalix[8]arene and photolabile cholinergic ligands has been observed in solution 90. Both the host and the guests adapted to each other and selected the higher energy but correct geometric conformers so that the guest could fit favorably into the cavity of the host to give ditopic binding of both the aromatic ring and the cationic ammonium moiety of the guest (Fig. 21). This system with mutually induced fit represents an original example of adaptive supramolecular biomimetic chemistry.

complex guest host

Fig. 21. Adaptive supramolecular system of C8S with flexible guest molecule.

2.2.5

Structural characterization of calix[4]arene diphosphate complexes Calix[4]arene diphosphate (C4diP) is a water-soluble calix[4]arene derivative

with two polar functions on the lower rim. Due to the anionic character of these functional substituents, this calixarene generates astonishing architectures in the solidstate complexes with aliphatic and heterocyclic amines.

32

Fig. 22. Typical dimeric structural motif of C4diP.

In the solid state calix[4]arene dihydroxyphosphonic acid exists in the flattened cone conformation as an included head to head dimer (Fig. 22) 91. Intramolecular hydrogen bonding between the unsubstituted and substituted phenolic groups rigidifies the cone conformation of C4diP. The dimeric motif described by the interpenetrating of aromatic rings of facing calixarenes is present in all the reported structures. In the complex with propandiamine calixarene building block is present as an included head to head dimer, held together by intermolecular - interactions 92. One terminal ammonium function of the propandiamine is hydrogen bonded to two phosphonate groups of the same C4diP and water molecule, and the second one is hydrogen bonded to three phosphonate groups of three other calixarenes. C4diP dimers are assembled into hexameric tube forming an aqua-channel structure (Fig. 23a). While both ethanol and water molecules are present in the structure, the channel itself shows total selectivity for water. Ethanol molecules are situated external to the channel and are hydrogen bonded to phosphonate P=O groups. Disordered water molecules are located along the channel. The assembly shows strong structural analogy to the aquaporin water channel 93, making the structure a potent mimetic of biological membrane transport channels. The crystal structure of the C4diP complex with 1,6-diaminohexane shows encapsulation of a calixarene dimer within a three-dimensional matrix formed by the diamine molecules 94. Two phosphonate groups of each calixarene act as a type of molecular tweezers for two ammonium groups of the guest, one of which is held in place by direct hydrogen bonding to both phosphonate moieties and the second by a bridging water molecule and a directly bound phosphonate moiety. Eight diammonium cations form the walls of a hydrophobic cavity that is filled by calixarene dimer. The

33

Fig. 23. (a) Top view of the water channel along the [111] direction in the complex with propandiamine; (b) molecular packing of C4diP complex with phenantroline.

head to head embedded calixarene dimers are held together by face to face -stacking. The mismatch between the size of the dimer filling the cavity and the extended length of 1,6-diaminohexane is compensated by chain folding in the diamine, allowing the ammonium-ammonium distances to match the dimensions of the calixarene molecule. In the case of the heterocyclic diamine phenanthroline, a face-to-face aromatic stacked dimer of 1,10-phenantroline is held within a cage of eight hydrogen bonded calix[4]arene dihydroxyphosphonic acid molecules by face to face aromatic interactions and hydrogen bonding 95. The central ring of the each phenanthroline molecule undergoes face to face stacking with an aromatic ring of the calixarene. The molecules of phenanthroline are displaced with face to face stacking between the central ring and the non-protonated heterocycle. The trapped 1,10-phenanthroline is involved in a hydrogen bond via its protonated nitrogen atom and the deprotonated hydroxyl of the phosphonic acid. Multiple aromatic-aromatic interactions are present in the cage. The crystal packing shows planes of dimers of C4diP perpendicular to the c crystal axis, Fig. 23b. These planes are held together by network of hydrogen bonds. Recently Lazar et al. 96 reported a structural study on the calix[4]arene dihydroxyphosphonic acid complexes with bipyridyl ligands: 2,2'-bipyridine, 4,4'-bipyridine and 1,2-bipyridylethane. For the three complexes, the overall structure is based on layers of calixarene dimers alternated with hydrated layers of bipyridil molecules. All the complexes present - interactions between the biryridyl moieties and the calix[4]arene dihydroxyphosphonic acid. In the case of 4,4'-bipyridine and 1,2-bipyridylethane nitrogen atoms of the bipyridil ligands are protonated, while for the complex with 2,2'-bipyridine nitrogen atoms are probably not protonated. The structure 34

of the complex C4diP2,2'-bipyridine shows a simple intercalated monolayer of 2,2'-bipyridine parallel to the dimeric layer of the calixarenes. The compact network of hydrogen bonds formed between the water molecules and the hydroxyl groups of the phosphonic acid generates a hydrophilic cage for each bipyridine molecule. A major feature of the structure is the face to face aromatic-aromatic interactions between molecules of C4diP and 2,2'-bipyridine. In the case of 4,4'-bipyridine the position of the nitrogen atoms on the bipyridyl skeleton is favorable for hydrogen bond bridging between two molecules of calix[4]arene dihydroxyphosphonic acid to afford an extended solid-state network. The bridge is nonsymmetric with one nitrogen atom involved in direct hydrogen bonding to a phosphonate group and the other one, hydrogen bonded to a bridging water molecule. In the structure there is a competitive interplay between hydrogen bonding, aromaticaromatic interactions and steric effects generated by the constrained geometry of 4,4'-bipyridine. The network formed by the bridging molecules of 4,4'-bipyridine may best be described as a 1D ladder structure with the rungs formed by the dimers of C4diP. The complex of calix[4]arene dihydroxyphosphonic acid with more flexible 1,2-bipyridylethane shows strong similarities in the general nature of packing with the 4,4'-bipyridine, both having the 1D ladder network, however, the details demonstrates the relaxation of the structure comparing with 4,4'-bipyridine complex. In the structure, both aromatic rings of 1,2-bipyridylethane are involved in face to face stacking interactions with aromatic rings of other molecules of 1,2-bipyridylethane. The hydrogen bonding type interactions between C4diP and 1,2-bipyridylethane show the same alternation as observed in the structure C4diP4,4'-bipyridine. At one end of the molecule 1,2-bipyridylethane, one of the pyridinium groups is also involved in hydrogen bonding to a water molecule, but here the water molecule forms hydrogen bonfs with two opposing phosphonate groups.

2.2.6

Biological activity of water-soluble calixarenes In spite of extensive early work of the biological properties of the p-sulfonated

calixarenes, it is only very recently that interest in their biomedical potential has come to the fore again. This considerable interest in water-soluble calixarenes for biological and medical applications has resulted in many patents.

35

Hwang et al. 97 patented a method of treatment of infection by enveloped viruses such as HIV, herpes simplex and influenza viruses, with calix[n]arenes having polar substitutent: sulfonate, carboxylate or phosphate groups. The calix[n]arenes binds selectively to viral envelop protein and this binding blocks virus attachment to infectable cells, thereby inhibiting virus infectivity. p-Sulfonatocalix[n]arenes posses suitable antimicrobial activity against fungal and bacterial microorganisms 98. C4S, C6S and C8S were found to exhibit antimicrobial activity against Corynebacterium, Fusarium solani f. sp. mori (F.s-26), the fungal strains Rosellinia necatrix [R-8], and Colletotrichum dematium [C.d.8901]. Atwood 99 demonstrated the activity of different p-sulfonatocalix[n]arene derivatives as chloride channel blockers. This study shown that the inhibition of the ionic channels increases with the increasing size of the macrocycle. Chloride channel modulators may serve as effective pharmaceutical for treating respiratory, cardiovascular and gastrointestinal disorders. Droogmans 100 investigated the inhibition of volume-regulated anion channel present on cultured endothelial cells which allows the passage of ions depending on the membrane potential, using p-sulfonatocalix[n]arenes and their derivatives. The p-sulfonatocalixarenes induced a fast inhibition at positive potentials but were ineffective at negative potentials. At small positive potentials, p-sulfonatocalix[4]arene was a more effective inhibitor than p-sulfonatocalix[6]arene and calix[8]arene, which became more effective at more positive potentials. p-Sulfonatocalix[n]arenes and their derivatives have been shown to posses antithrombotic activity 101. The conformation flexibility and the number of SO3 groups of p-sulfonatocalix[n]arenes resemble chemical structure of anticoagulant heparin. The anti-thrombotic activity of the p-sulfonatocalix[n]arene derivatives is believed to proceed by a heparinoid like inhibitory effect on protease activity in the coagulation cascade. Pinhal et al 102 found that p-sulfonatocalix[8]arene stimulates the synthesis of heparan sulfate proteoglycan secreted by rabbit and human endothelial cells in culture. p-Sulfonatocalix[n]arenes have been shown to have potential in the diagnosis of prion-based diseases 103, such as bovine spongiform encephalopathy BSE in cattle (so called mad caw disease), scrappy in sheep, chronic wasting disease in deer and variant Creutzfeldt-Jacob disease in humans. Coleman et al. 104,105 investigated p-sulfonatocalix[n]arene complexation by bovine serum albumin (BSA), an arginine and lysine rich protein, using electrospray mass spectrometry, dynamic light scattering and atomic force microscopy. For anionic 36

p-sulfonatocalixarenes one strong and two weak binding sites were found on the protein surface. The strength of the interactions between the calixarene and BSA is inversely proportional to the size of macrocyclic ring: n = 4 > n = 6 >> n = 8. Although the calixarenes are currently not approved for use in medicines to date they have shown neither toxicity nor immune responses 106,107. These results provide promising signs that p-sulfonatocalixarenes could be useful in the field of biopharmaceutical applications.

2.2.7

Drug solubilization One way to increase the aqueous solubility of drugs is to use complexing agents

to form host-guest complexes. Among the complexing agents available, cyclodextrins are most widely used in drug formulations 108. Alternative complexing agents are calixarenes, widely studied for their inclusion properties towards different guest molecules. Yang has recently investigated the solubilizing effect of p-sulfonatocalix[n]arenes on the poorly water soluble drugs, nifedipine 109 (an important calcium channel blocker that is used extensively for the clinical management of a number of cardiovascular diseases), niclosamide 110 (an anthelmintic drug that is active against most tapeworms) and furosemide 111 (a high ceiling diuretic). The results show that the size of the p-sulfonatocalix[n]arene, the pH of solubility medium, and the concentration of the calix[n]arenes significantly changed solubility of the drug. In the case of nifedipine the p-sulfonatocalix[8]arene improved the solubility the most, while in the presence of p-sulfonatocalix[6]arene the solubility of nifedipine was decreased. Interestingly, for niclosamide the greatest increase in the aqueous solubility was observed when p-sulfonatocalix[6]arene was added. p-Sulfonatocalix[6]arene improved the solubility of furosemide the most followed by p-sulfonatocalix[8]arene, while p-sulfonatocalix[4]arene increased the solubility of furosemide the least. The authors suggest that the dimension of calix[6]arene is most optimal for the niclosamide and furosemide molecules because host-sizeselectivity does exist in host-guest type complexation with calixarenes 112. The increase in drug solubility afforded by the calixarenes was most probably the result of the incorporation of the non-polar portions of the drug molecule into the non-polar cavities of the calixarenes similar to drugcyclodextrin complexes 113. The other possible mechanisms involved in the

37

complexation between p-sulfonatocalix[n]arenes and drugs may be hydrogen bonding and electron donor-acceptor interactions. The effects of the cavity size of p-sulfonatocalix[n]arenes and pH on the stability and fluorescent properties of berberine, a clinically important natural isoquinoline alkaloid, have recently been studied 114. The weakest binding was observed for C4S and the strongest for C8S. The substantial increase of the association constants with the receptor size originates from the growing strength of the - electronic interaction between the host and guest aromatic rings. The high flexibility of C8S and its comparable size to berberine permit strong host-guest interaction. The authors demonstrated that this particularly strong binding to p-sulfonatocalix[8]arene, which leads to a significant fluorescence intensity increase, can be applied to detect even trace amount of berberine.

2.3

Conclusions
The use of water-soluble anionic calixarenes in supramolecular chemistry and

for the complexation of organic cations has grown considerably since the initial work of Shinkai on the binding and structure of the p-sulfonatocalix[4]arene complex with the trimethylanilinium cation. Water-soluble anionic calixarenes are capable of complexing small biologically active molecules, amino acids and proteins. The solid-state complexes of p-sulfonatocalix[4]arenes and calix[4]arene diphosphate studied thus far show a remarkable diversity of structure types: from traditional bilayers through zigzag bilayers, Russian doll capsules, Ferris wheel complexes to aqua-channel hexagonal structures for C4diP, and nanospheroidal and tubular assemblies for C4S. The larger p-sulfonatocalix[6]arene and the corresponding octamer show a great potential for the assembly of complicated superstructures in the solid state. The field of biopharmaceutical application of anionic calixarenes by their complexation to cationic groups present in biomacromolecules is just starting, but it can be expected to be of great importance in the future.

38

3 EXPERIMENTAL
In this chapter the procedures for data collecting and processing, structure solution and refinement, and crystal structure analyses are described. There are several stages in which we can influence the final quality of structure model. One of them is selecting a good quality crystal of pure composition, appropriate size, and regular shape and with no large internal imperfections, such as cracks or twinning. The size of the crystal should be around 0.2-0.3 mm for organic compounds. For compounds containing heavier atoms it is recommended to use smaller crystals to reduce absorption effects. All complexes described along this dissertation were synthesized and most of them crystallized by the group of Dr. Anthony W. Coleman from the Institute of Biology and Chemistry of Protines in Lyon. Crystals were obtained by the slow diffusion of solvents or slow evaporation from water-alcohol (methanol or ethanol) systems. A few complexes were crystallized from DMF-alcohol mixtures. Single crystals suitable for X-ray crystallographic analysis were selected following examination under a microscope. The crystals were mounted on glass fibers with a small quantity of glue, because the amount of glue in the X-ray beam influences background considerably. Some of the crystals were scooped up in a tiny loop made of nylon and attached to a solid rod. The last stage in the selection was crystal prescanning on the diffractometer, i.e. making a few quick exposures and checking the images visually on spot size, shape and distribution. All measurements were performed at low temperature (100 K) in order to prevent crystal decomposition, reduce thermal vibrations, enhance signal-to-noise ratio and reduce dynamic disorder. When a crystal is mounted and exposed to an intense beam of X-rays, it scatters the X-rays into a pattern of spots or reflections. The relative intensities of these spots provide the information to determine the arrangement of molecules within the crystal in atomic detail. Single-crystal X-ray diffraction data for all compounds described along this dissertation, were collected on a Nonius KappaCCD diffractometer using MoK radiation ( = 0.71073 ). The first stage of the measurement was the determination of the unit cell on the base of ten frames made by crystal rotation for ten degrees (scan angle 1 per frame). Having the unit cell parameters and point group symmetry it was possible to calculate the strategy for data collecting, i.e. the number of frames grouped 39

in sets together with the time needed per degree of rotation to get a dataset with reflections upto a specific diffraction angle. The raw data collected from the diffraction experiment were integrated and scaled in order to obtain the indexed reflections with a consistent intensity scale. Data collecting and processing were carried out using the programs Collect 115, HKL2000 116, maXus 117. The structures were solved by direct methods using the programs SHELXS-97 118, SIR92 119, SIR97 120 and refined by full matrix least squares using the program SHELXL-97118. Unless specified, all non-hydrogen atoms were refined anisotropically. Hydrogen atoms were placed in geometrically calculated positions and refined as riding atoms. Hydrogen atoms of methyl and hydroxyl groups were refined in geometric positions for which the calculated sum of the electron density is the highest (rotating group refinement). The torsion angles were then refined during the least-squares refinement. All hydrogen atoms were refined isotropically with temperature factors 1.2 times those of their bonded atoms (1.5 times for methyl and hydroxyl groups). Where possible, the hydrogen atoms of amino groups were located on Fourier difference maps and refined with positional parameters. In the other case hydrogen atoms were placed in positions for which the calculated sum of the electron density is the highest. Where possible, hydrogen atoms of water molecules were located in the differential Fourier electron density maps. In the case of bad diffraction data and disorder the DFIX and DANG geometrical restraints were applied in order to retain the guest molecules geometry. Disordered atoms were refined with isotropic displacement parameters. All crystallographic calculations were conducted with the WINGX 121 program package. Program PARST 122 was used for calculating geometrical parameters (planes and angles) from the results of crystal structure analyses. Non-covalent interactions of -, Donor-H and C-HAcceptor type were calculated using the program PLATON 123. The geometric parameters of non-covalent interactions and hydrogen bonds are presented in the form of tables in the Appendix. All the figures were prepared using the X-Seed 124 interface. Thermal ellipsoids were drawn at 50% probability level. Hydrogen atoms that do not take part in hydrogen bonding and disordered atoms with lower occupancy were omitted for clarity. A consistent numbering scheme was used for the calixarene molecules in all structures. The calixarene molecule was divided into four functional groups (phenyl group with substituents and methylene group) carrying the labels A, B, C and D. Where there is more than one calixarene molecule in the asymmetric unit the labels are augmented with the numbers 1 and 2 for the second and third crystallographically 40

independent molecules, respectively. For the large C6S and C8S molecules the asymmetric unit comprises only half of the host molecule, so the phenolic rings carry the labels A, B, C (and D for C8S). Labels for the guest molecules carry the letters X, Y, Z and W.

41

42

RESULTS AND DISCUSSION

4.1 Solid-state complexes of p-sulfonatocalix[4]arene

4.1.1 Crystal structure of p-sulfonatocalix[4]arene complex with melamine
Melamine (1,3,5-triazine-2,4,6-triamine) (Fig. 24) has been widely used as precursor for supramolecular motifs such as cyclic rosettes 125, tapes 126 and ribbons 127. Melamine is a metabolite of cyromazine, a pesticide. It is formed in the body of mammals who have ingested cyromazine It was also reported that cyromazine is converted to melamine in plants 128. Melamine is used combined with formaldehyde to produce melamine resin, a very durable thermosetting plastic, and melamine foam, a polymeric cleaning product. Melamine is also used to make fertilizers. Melamine derivatives of arsenical drugs are potentially important in the treatment of African trypanosomiasis. In the complex p-sulfonatocalix[4]arenemelamine the asymmetric unit (Fig. 25) comprises one molecule of tetraanionic C4S, four melamine monocations (named as W, X, Y and Z) and fifteen water molecules from which six have partial occupancies. Charge equilibrium in the structure is realized by protonation of one aromatic nitrogen atom of each melamine molecule. Crystallographic data for the complex of C4S with melamine are presented in Table 1.

Fig. 24. Melamine monocation.

The solid-state structure of the complex is generated by bilayer motif of p-sulfonatocalix[4]arenes which are held together by - interactions and by hydrogen bond between phenolic and sulfonate groups of the neighboring calixarene molecule (Fig. 26). In Fig. 27, the complete network of hydrogen bonds generated by melamine monocations is presented. Normally, melamine has three centres for non-covalent linking each of which can donate two hydrogen bonds from each amine groups and accepts one on each aromatic nitrogen. However, in the current structure the protonation 43

Table 1. Crystal data and structure refinement for C4Smelamine.

Molecular formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size range for data collection Index ranges Reflections collected Independent reflections Completeness to = 22.02 Absorption correction Refinement method Data / restraints / parameters 2 Goodness-of-fit on F Final R indices [I > 2(I)] R indices (all data) Extinction coefficient Largest diff. peak and hole

C28H20O16S44C3N6H712.5H2O 1467.41 100(2) K 0.71073 Triclinic P a = 11.1991(6) = 75.286(4). b = 15.293(1) = 86.453(4). c = 19.008(1) = 82.786(3). 3 3122.3(3) 2 1.561 Mgm-3 0.258 mm-1 1532 0.20 0.05 0.03 mm3 2.72 to 22.02. -11 h 11, -16 k 16, -19 l 19 27163 7510 [Rint = 0.068] 97.8 % None 2 Full-matrix least-squares on F 7510 / 0 / 896 1.08 R = 0.069, wR = 0.148 R = 0.106, wR = 0.160 0.0022(4) 0.54 and -0.32 e-3

Fig. 25. Asymmetric unit of the C4S complex with melamine.

44

of one aromatic nitrogen atom occurs and it becomes the hydrogen bond donor. In the complex there are five pairs of hydrogen bonds between neighboring melamine monocations and four quintets of hydrogen bonds with solvent molecules or sulfonate groups of the calixarenes (for each melamine monocation). One of the melamine cations (Z) forms hydrogen bonds with four water molecules and only one with the sulfonate group, all the three other melamine monocations (X, Y and W) are hydrogen bonded with two solvent molecules and with three sulfonate groups. It is worth to note that protonated nitrogen binds only to water molecules.

Fig. 26. View of the molecular packing along the a axis showing planar bilayers of p-sulfonatocalix[4]arenes.

Fig. 27. View along b axis of the network of hydrogen bonds encountered by melamine monocations.

The melamine monocations are arranged into linear chains and interact by -stacking (distances between centroids of melamine molecules vary from 3.783(3) to 45

3.915(3) , while distances between melamine planes vary from 3.377(3) to 3.433(3) ).

Fig. 28. Sheets of melamine monocations formed by linear chains of -stacked aromatic rings.

The structure of the complex of p-sulfonatocalix[4]arene with melamine shows a wide variety of interactions. The anionic groups of the calixarene play significant role in the diversity of the non-covalent interactions between melamine monocations and their environment.

46

4.1.2 Crystal structure of p-sulfonatocalix[4]arene complex with triethylamine

The stoichiometry of the complex is 1:2:1:3 for p-sulfonatocalix[4]arene, triethylamine, acetone and water, respectively. Crystallographic data for the complex of C4S with triethylamine are presented in Table 2. p-Sulfonatocalix[4]arene is present in the flattened cone conformation with a C2v symmetry (cone angles between the opposite aromatic rings are 44.30(8) and 100.10(7)). Hydrogen bonds occur between the four phenolic hydroxyl groups at the lower rim (O-HO distances of 2.770(3), 2.697(3), 2.734(3) and 2.706(3) ). Oxygen atoms of two sulfonate groups and acetone molecule are disordered over two positions.

Fig. 29. Triethylamine cation

Triethylamine molecule appears in the form of cation (Fig. 29) and the host molecule is in the form of anion. To satisfy charge balance, C4S in the complex should possess two protonated sulfonate groups. Unfortunately, it was not possible to locate all hydrogen atoms from the Fourier difference map for this to be clarified. Triethylammonium cations are complexed in two different ways (Fig. 30). Both are complexed via strong hydrogen bond between protonated nitrogen and sulfonate oxygen atom of the calixarene (2.753(3) and 2.738(5) for guest molecules X and Y, respectively), but whereas triethylammonium cation Y is located inside the C4S with one ethyl group pointing into aromatic cavity and showing C-H interaction of 3.638(5) with one of the aromatic ring of the C4S, triethylammonium cation X is complexed outside the cavity also showing C-H interaction of 3.540(4) with one of the aromatic ring of the neighboring C4S. There are also some C-HO hydrogen bonds between ethyl groups of the guest molecules and sulfonate oxygens of the calixarene.

47

Fig. 30. View of the asymmetric unit of the C4S complex with triethylammonium.

The complex between p-sulfonatocalix[4]arene and triethylammonium cations shows a novel stepped bilayer solid-state packing motif. As compared to typical bilayer or zigzag bilayer structures of C4S in which - interaction are often observed between adjacent calixarene molecules, in this case no such interactions are observed. Water molecules are involved in hydrogen bonding with sulfonate groups of C4S molecules and stabilize crystal packing. A range of C-HO interactions between methylenic bridges and sulfonate oxygens, and between aromatic carbons and sulfonate oxygens of the calixarene molecules also exist.

Fig. 31. View of the molecular packing along the b axis showing the steppded structural motif of C4S complex with triethylammonium.

48

Table 2. Crystal data and structure refinement for C4Striethylamine.

Molecular formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size range for data collection Index ranges Reflections collected Independent reflections Completeness to = 26.43 Absorption correction Refinement method Data / restraints / parameters 2 Goodness-of-fit on F Final R indices [I > 2(I)] R indices (all data) Extinction coefficient Largest diff. peak and hole

C28H20O16S42C6H16N0.6C3H6O3H2O 1021.12 100(2) K 0.71073 Triclinic P a = 10.5834(4) = 101.232(2). b = 12.5167(3) = 104.252(1). c = 18.8183(6) = 91.789(2). 2361.6(1) 3 2 1.436 Mgm-3 0.281 mm-1 1076 0.35 0.20 0.05 mm3 2.62 to 26.43. -13 h 13, -14 k 15, -23 l 23 31489 9607 [Rint = 0.027] 98.8 % None 2 Full-matrix least-squares on F 9607 / 0 / 698 1.08 R = 0.057, wR = 0.162 R = 0.081, wR = 0.173 0.0003(9) 0.83 and -0.89 e-3

49

4.1.3 Crystal structure of p-sulfonatocalix[4]arene complex with triethyltetramine

Polyamines are present throughout nature in every kind of living cell, and are generally considered to be involved in important biochemical processes such as DNA, RNA, protein biosyntheses, cell division, and acclimation to environmental stress. Polyamines such as triethylenetetramine (TETA) have been used extensively in coordination chemistry as multi-dentate ligands, as well as in hydrogen bonded systems involving anion coordination 129.

Fig. 32. Triethyltetramine in its tetraprotonated form.

Fig. 33. Asymmetric unit of the C4Striethyltetramine complex (some solvent molecules omitted for clarity).

Crystallographic data for the complex of C4S with TETA are presented in Table 3. In the complex the asymmetric unit comprises one C4S molecule, one molecule of TETA, four methanol molecules (two of which with partial occupancy) and two water molecules (one with partial occupancy) (Fig. 33). The TETA molecule is

50

Table 3. Crystal data and structure refinement for C4Striethyltetramine.

Molecular formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size range for data collection Index ranges Reflections collected Independent reflections Completeness to = 23.26 Absorption correction Refinement method Data / restraints / parameters 2 Goodness-of-fit on F Final R indices [I > 2(I)] R indices (all data) Extinction coefficient Largest diff. peak and hole

C28H20O16S4C6H22N43CH3OH1.33H2O 1006.61 100(2) K 0.71073 Triclinic P a = 11.5484(2) = 100.398(1). b = 13.2547(4) = 96.521(1). c = 14.7716(4) = 96.889(2). 2186.7(1) 3 2 1.529 Mgm-3 0.304 mm-1 1058 0.25 0.1 0.05 mm3 2.59 to 23.26. 0 h 12, -14 k 14, -16 l 16 6089 6089 [Rint = 0.000] 96.9 % None 2 Full-matrix least-squares on F 6089 / 0 / 615 1.05 R = 0.080, wR = 0.224 R = 0.123, wR = 0.252 0.007(2) 1.12 and -0.80 e.-3

protonated at each of the four amino groups and the calixarene is in the form of tetraanion. One end of the polyamine is disordered over two positions. p-Sulfonatocalix[4]arene is present in the flattened cone conformation, cone angles between the opposite aromatic rings are 69.5(2) and 62.0(2). One of the phenolic oxygen atoms forms bifurcated hydrogen bond with the neighboring phenolic oxygen and water molecule, while the three others form typical hydrogen bonds with the neighboring phenolic oxygen atoms. The cavity of C4S is occupied by a methanol molecule, which forms C-H interaction of 3.745(8) with one of the aromatic rings of the host (Fig. 33). TETA molecule is complexed exo to the C4S cavity with one of its terminal ammonium group pointing to the window formed by sulfonate group of the C4S and hydroxyl group of the included methanol molecule. The complex is stabilized by a range of N-HO and C-HO hydrogen bonds between TETA and C4S.

51

The triethyltetramine molecule in the tetraprotonated form can donate ten hydrogen bonds. In this complex TETA tetracation shows nine hydrogen bonds with oxygen atoms of the sulfonate groups of six C4S molecules and one hydrogen bond with a hydroxyl oxygen of a methanol molecule (Fig. 34).

Fig. 34. View of the hydrogen bond network generated by triethyltetramine tetracation.

The complex features the typical clay-like bilayer structure (Fig. 35), that is, the calixarene molecules, held together by - interactions, form two hydrophobic layers, and the sulfonate groups cover the hydrophilic surfaces of the bilayer. The polyamine molecules and solvent are located in the hydrophilic zone between the bilayers.

Fig. 35. View of the molecular packing of C4Striethyltetramine complex along a axis.

52

4.1.4 Crystal structure of p-sulfonatocalix[4]arene complex with norspermidine

Norspermidine (bis(3-aminopropyl)amine) (Fig. 36) is a homologue of spermidine. While norspermidine has been found to occur naturally in some species of plants, bacteria, and algae, it is not known to be a natural product in humans as spermidine is. Norspermidine is being researched for its use as an antitumor medicine in cancer treatment 130.

Fig. 36. Bis(3-aminopropyl)amine trication.

Crystallographic data for the complex of C4S with bis(3-aminopropyl)amine is presented in Table 4. In the complex the asymmetric unit (Fig. 37) comprises three C4S molecules and four molecules of bis(3-aminopropyl)amine (named as W, X, Y and Z), in the presence of eight methanol molecules (five of which with partial occupancy) and fourteen water molecules (three of which are disordered). Each of the polyamine molecules is protonated at all three amino groups and the calixarene molecules are in the form of tetraanions. Residual electron density in the complex is associated with disordered solvent molecules. As expected, all three independent p-sulfonatocalix[4]arene molecules are present in the flattened cone conformation. Cone angles between the opposite aromatic rings are 41.7(1) and 85.0(1), 41.8(1) and 86.4(1), 37.7(1) and 80.3(1) for the three crystallografically independent C4S molecules. The phenolic oxygen atoms are involved in intramolecular hydrogen bonds, but, interestingly, in each C4S molecule one of the phenolic oxygen atoms is involved in hydrogen bonding to a water molecule and another one forms bifurcated hydrogen bond with the neighboring phenolic oxygen atom and the oxygen atom of the sulfonate group of the neighboring calixarene molecule. In the complex the norspermidine molecules adopt four different conformations. Additionally, the polyamine molecule Z is disordered over two conformations. Each of four norspermidines is in the form of trication and can potentially donate eight hydrogen bonds. The network of hydrogen bonding (Fig. 38) generated by the norspermidine 53

Table 4. Crystal data and structure refinement for C4Sbis-3-aminopropylamine.

Molecular formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size range for data collection Index ranges Reflections collected Independent reflections Completeness to = 23.26 Absorption correction Refinement method Data / restraints / parameters 2 Goodness-of-fit on F Final R indices [I > 2(I)] R indices (all data) Extinction coefficient Largest diff. peak and hole

3C28H20O16S44C6H20N35.43CH3OH13.39H2O 3175.03 100(2) K 0.71073 Triclinic P a = 16.6565(2) = 90.142(1). b = 17.9590(3) = 106.816(1). c = 26.2009(4) = 108.192(1). 7090.1(2) 3 2 1.487 Mgm-3 0.289 mm-1 3340 0.60 0.40 0.30 mm3 2.92 to 23.26. -18 h 18, -19 k 19, -29 l 29 38106 20184 [Rint = 0.032] 99.0 % None 2 Full-matrix least-squares on F 20184 / 0 / 1834 1.05 R = 0.065, wR = 0.168 R = 0.085, wR = 0.180 0.0003(1) 1.58 and -0.80 e-3

Fig. 37. Asymmetric unit of the C4Snorspermidine complex (solvent molecules omitted for clarity).

54

Fig. 38. Network of hydrogen bonds generated by norspermidine molecules.

molecules is highly complex, closely related to the conformational variations of each independent polyamine molecule in the system. Norspermidine molecule W forms four hydrogen bonds with sulfonate oxygen atoms, two with water molecules, one with methanol molecule and one bifurcated hydrogen bond with sulfonate oxygen and another methanol molecule. Norspermidine molecule X donates two hydrogen bonds with sulfonate oxygen atoms, two hydrogen bonds with water molecules, one bifurcated hydrogen bond with sulfonate oxygen atom and water molecule, one bifurcated hydrogen bond with sulfonate oxygen atom and oxygen atom of methanol molecule and one trifurcated hydrogen bond with two sulfonate oxygen atoms and oxygen atom of methanol molecule. Polyamine molecule Y forms four hydrogen bonds with sulfonate oxygen atoms, one with water molecules, one bifurcated hydrogen bond with two sulfonate oxygen atoms and two bifurcated hydrogen bonds with sulfonate oxygen atom and water molecule. Molecule Z, one end of which is disordered over two positions, forms six hydrogen bonds with sulfonate oxygen atoms, three hydrogen bonds with water molecules and one hydrogen bond with oxygen atom of methanol molecule. Polyamine molecule Y is partially included into macrocyclic cavity of one of the crystallografically independent C4S molecules (Fig. 39). The protonated amino groups of the guest are directed out of the cavity and are hydrogen bonded with sulfonate oxygen atoms of the host. The aliphatic chain of the norspermidine is located inside the cavity and interacts with the host by three C-H interactions. 55

Fig. 39. Inclusion complex of C4S with norspermidine molecule Y.

As is shown in the Fig. 40, each of the two others crystallografically independent calixarenes include simultaneously one end of norspermidine molecule (X or W) and methanol molecule. The disordered norspermidine molecule Z is located outside the C4S cavities. a
X

b
W

Fig. 40. Inclusion complex of C4S with: (a) norspermidine molecule X; (b) norspermidine molecule W.

The solid-state structure of the complex is generated by bilayer motif of p-sulfonatocalix[4]arenes (Fig. 41) which are held together by - interaction of 3.677(3) and by hydrogen bonds between phenolic and sulfonate groups of the neighboring calixarenes. Additionally, there is a range of C-H interactions between methylenic bridges and aromatic rings of the neighboring calixarene molecules, as well as intermolecular C-HO weak hydrogen bonds between aromatic carbons and sulfonate oxygen atoms of the neighboring calixarene molecule that further stabilize the structure. The norspermidine molecules are located in the hydrophilic region between the C4S bilayers and are mainly hydrogen bonded to sulfonate oxygen of calixarene molecules and solvent molecules.

56

Fig. 41. View of the molecular packing of the C4Snorspermidine complex.

57

4.1.5 Crystal structure of p-sulfonatocalix[4]arene complex with chlorhexidine

Chlorhexidine (Fig. 42) is an antiseptic agent of large spectra, its mechanism of action being the precipitation of bacteria cells 131. It is particularly efficient for plaque inhibition and gingivitis treatments. Chlorhexidine does not crystallize easily; no solidstate structure of chlorhexidine was reported until now. The idea to co-crystallize drug with the aid of water-soluble anionic calixarene proved successful, as starting from alcohol-water solution, the co-crystals of chlorhexidine with p-sulfonatocalix[4]arene were obtained.

Fig. 42. Chlorhexidine cation.

Crystallographic data for the complex of C4S with chlorhexidine is presented in the Table 5. In the complex p-sulfonatocalix[4]arene-chlorhexidine the asymmetric unit (Fig. 43) comprises one C4S molecule, one drug molecule, three methanol molecules (two of them disordered), and seven water molecules (one with partial occupancy). The charge of calix[4]arene molecule is -4 and chlorhexidine molecule is +4 (protonation of all four imine groups occurs). p-Sulfonatocalix[4]arene is present in the flattened cone conformation (cone angles between the opposite aromatic rings are 79.0(2) and 62.5(1)). Hydrogen bonds occur between the four phenolic hydroxyl groups at the lower rim. The solid-state structure of the complex is generated by bilayer motif of p-sulfonatocalix[4]arenes (Fig. 45) which are held together by - interaction between neighboring molecules with the distance of 3.639(3) and C-H interactions between methylenic bridge and aromatic cycle of the neighboring calix[4]arene. The organization into bilayers of p-sulfonatocalix[4]arene allows the partial inclusion of the active molecules in the calixarenic crown forming the complex of host-guest type. The inclusion of the alkyl chain in the aromatic cavity is favourised by C-H interactions that are formed with the aromatic ring of the host calixarene. The inclusion of the active 58

Table 5. Crystal data and structure refinement for C4Schlorhexidine.

Molecular formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size range for data collection Index ranges Reflections collected Independent reflections Completeness to = 23.26 Absorption correction Max. and min. transmission Refinement method Data / restraints / parameters 2 Goodness-of-fit on F Final R indices [I > 2(I)] R indices (all data) Extinction coefficient Largest diff. peak and hole

C28H20O16S4C22H34N10Cl22.67CH3OH6.33H2O 1442.31 100(2) K 0.71073 Triclinic P a = 15.3259(5) = 65.687(2). b = 15.9819(5) = 77.180(2). c = 16.1353(4) = 64.427(1). 3244.1(2) 3 2 1.477 Mgm-3 0.317 mm-1 1508 0.43 0.30 0.13 mm3 3.02 to 23.26. -17 h 17, -17 k 17, -17 l 17 34407 9240 [Rint = 0.044] 99.2 % None 0.9600 and 0.8757 2 Full-matrix least-squares on F 9240 / 0 / 913 1.03 R = 0.056, wR = 0.137 R = 0.083, wR = 0.148 0.0024(5) 0.89 and -0.62 e-3

molecule is additionally stabilized by formation of strong N-HO hydrogen bonds between amine or guanidinium groups of chlorhexidine and sulfonate oxygens of C4S. The network of intermolecular interactions generated by the chlorhexidine molecule is highly complex (Fig. 44). The chlorhexidine molecule in the protonated form has two bisguanidinium groups and donates 14 hydrogen bonds, from which 9 are with sulfonate oxygens of C4S molecules, 4 hydrogen bonds with water and 1 with methanol molecule. There are also C-H interaction between one of the methylenic groups of the drug molecule and one aromatic ring of the host of 3.455(6) and C-H interaction between methylenic bridge of calixarene and aromatic ring of chlorhexidine (3.564(5) ).

59

Fig. 43. Asymmetric unit of the C4Schlorhexidine complex .

Fig. 44. Network of hydrogen bonds generated by chlorhexidine molecule.

In the co-crystal with calixarene sulfonate, the chlorhexidine adopts V-shaped conformation. The characteristics shown by the calixarene host play a dominant role in the co-crystallization. The formation of the hostguest system is mainly guided by formation of a wide range of strong hydrogen bonds between guanidinium and amine groups of drug and sulfonate oxygens of the calix[4]arene. The solvent molecules also play an important role in the non-covalent interactions in the molecular complex and are non-negligible parameter influencing conformation of the chlorhexidine molecule.

60

Fig. 45. Molecular packing of the C4Schlorhexidine complex.

61

4.1.6 Crystal structure of p-sulfonatocalix[4]arene complex with tetracaine

Tetracaine (Fig. 46) is a potent local anesthetic 132. It is mainly used topically, in ophthalmology and as an antipruritic, and has been used in spinal anesthesia. In the p-sulfonatocalix[4]arenetetracaine complex the asymmetric unit comprises one C4S molecule, four tetracaine molecules and twelve water molecules (Fig. 47). The charge of the calix[4]arene is -4 and all tetracaine molecules are protonated at the tertiary amino groups.

Fig. 46. Tetracaine monocation.

Crystallographic data for the complex of C4S with tetracaine are presented in the Table 6. As expected, p-sulfonatocalix[4]arene is present in the flattened cone conformation (cone angles between the opposite aromatic rings are 76.6(2) and 44.6(2)). Hydrogen bonds occur between the phenolic hydroxyl groups at the lower rim. One of the phenolic oxygens is hydrogen bonded to water molecule.

Fig. 47. Asymmetric unit of the C4Stetracaine complex (solvent molecules omitted for clarity).

62

Table 6. Crystal data and structure refinement for C4Stetracaine.

Molecular formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size range for data collection Index ranges Reflections collected Independent reflections Completeness to = 21.96 Absorption correction Refinement method Data / restraints / parameters 2 Goodness-of-fit on F Final R indices [I > 2(I)] R indices (all data) Extinction coefficient Largest diff. peak and hole

C28H20O16S44C15H25N2O212H2O 1994.16 100(2) K 0.71073 Triclinic P a = 13.6142(3) = 97.689(1). b = 13.8938(4) = 102.933(1). c = 27.7955(9) = 98.489(2). 4991.5(2) 3 2 1.327 Mgm-3 0.182 mm-1 2112 0.25 0.17 0.03 mm3 2.67 to 21.96. 0 h 14, -14 k 14, -29 l 28 49126 12136 [Rint = 0.101] 99.6 % None 2 Full-matrix least-squares on F 12136 / 0 / 1242 1.06 R = 0.097, wR = 0.261 R = 0.151, wR = 0.289 0.0016(6) 1.38 and -0.68 e-3

One of the four independent tetracaine molecules is partially included into the C4S cavity with its dimethyloammonium group while the other three are complexed outside the cavity (Fig. 47). The included tetracaine molecule is held inside the cavity by two C-H interaction between one of the methyl group of the guest and aromatic rings of C4S (3.700(9) and 3.760 ) and hydrogen bond between ammonium nitrogen of included tetracaine (donor) and sulfonate oxygen (acceptor) with the distance of 2.808(7) . The host-guest system is additionally stabilized by weak C-HO interactions between included drug and sulfonate oxygens of C4S. Each of the independent protonated tetracaine molecule donates two hydrogen bonds (Fig. 48): included molecule X is hydrogen bonded to sulfonate oxygen of host C4S and water molecule, molecule Y is hydrogen bonded to oxygen atom of tetracaine molecule X and water molecule, in molecule Z ammonium nitrogen forms one bifurcated hydrogen bond with sulfonate oxygen of C4S and water molecule, and amine 63

nitrogen forms one hydrogen bond with oxygen atom of another symmetry related molecule Z, molecule W is hydrogen bonded with two water molecules. All these differences in non-covalent interactions result in slightly different conformations of the four tetracaine molecules. As shown on Fig. 49, the solid-state structure of the complex is generated by typical bilayer motif of p-sulfonatocalix[4]arenes, which are held together by - interactions. Double layers of tetracaine molecules containing water molecules from the crystallization medium separate the bilayers of C4S. The tetracaine molecules are held together by different types of interactions: strong N-HO hydrogen bond, weak C-HO hydrogen bond, indirect hydrogen bond through water molecules and C-H interactions. No aromatic-aromatic interactions between neighboring drug molecules are observed.

Z W X

Fig. 48. Hydrogen bonds formed by four independent tetracaine molecules.

64

Fig. 49. View of the molecular packing of C4Stetracaine complex along the b axis.

65

4.1.7 Crystal structure of p-sulfonatocalix[4]arene complex with tamoxifen

Tamoxifen (Fig. 50) is a member of a class of compounds known as selective estrogen receptor modulators that have the capability of acting as estrogen receptor agonists in some tissues and as antagonists in other tissues. Tamoxifen is used in the treatment of breast cancer 133 and is currently the world's largest selling drug for this condition. The Food and Drug Administration (FDA) also approve it for the prevention of breast cancer in women at high risk of developing the disease. Crystallographic data for the complex of C4S with tamoxifen is presented in Table 7. In the complex p-sulfonatocalix[4]arenetamoxifen the asymmetric unit (Fig. 51) comprises one C4S molecule, four tamoxifen molecules and nine water molecules, from which three are disordered and two have partial occupancy. One sulfonate group of the C4S molecule is disordered over two positions.

Fig. 50. Tamoxifen cation.

The charge of the calix[4]arene is -4 and all tamoxifen molecules are protonated at the tertiary amino groups in the same way as in the complex with tetracaine. p-Sulfonatocalix[4]arene is present in the flattened cone conformation (cone angles between the opposite aromatic rings are 74.9(2) and 43.9(2)). Two phenolic oxygen atoms form bifurcated hydrogen bonds with neighboring phenolic oxygens and water molecules. Each of the protonated drug molecules is donor of one N-HO hydrogen bond to the sulfonate oxygen atoms of the calix[4]arene. The tamoxifen molecule X is partially included into the calix cavity by dimethylammonium group (Fig. 51). The inclusion complex is stabilized by different types of non-covalent interaction: strong hydrogen bond between ammonium nitrogen of guest (donor) and sulfonate oxygen

66

Table 7. Crystal data and structure refinement for C4Stamoxifen.

Molecular formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size range for data collection Index ranges Reflections collected Independent reflections Completeness to = 20.82 Absorption correction Refinement method Data / restraints / parameters 2 Goodness-of-fit on F Final R indices [I > 2(I)] R indices (all data) Extinction coefficient Largest diff. peak and hole

C28H20O16S44C26H30NO8H2O 2358.72 100(2) K 0.71073 Triclinic P a = 13.8719(8) = 96.023(2). b = 14.1205(6) = 99.013(2). c = 32.001(2) = 98.644(3). 6067.2(5) 3 2 1.291 Mgm-3 0.156 mm-1 2496 0.25 0.1 0.05 mm3 2.93 to 20.82. -13 h 13, -14 k 14, -31 l 31 24606 12617 [Rint = 0.092] 99.4 % None 2 Full-matrix least-squares on F 12617 / 2 / 1550 0.90 R = 0.066, wR = 0.137 R = 0.148, wR = 0.157 0.0000(1) 0.81 and -0.33 e-3

(acceptor) of host C4S with the distance of 2.788(6) , C-H interaction between included methyl group of drug and one of the aromatic ring of C4S (3.827(7) ), weak hydrogen bonds of C-HO type (3.400(7) and 3.481(8) ). Three other tamoxifen molecules are complexed outside the C4S cavity. Two bilayers exist in the structure (Fig. 52); one of calixarene anions, where the sulfonato groups are directed into the hydrophilic layer containing also water molecules, and the second one of tamoxifen cations, where the dimethylammonium groups are directed into the hydrophilic layer. In the C4S bilayer neighboring calixarenes are held together by - interactions. The network of C-H hydrogen bonds is generated between tamoxifen molecules in the drug layer (Fig. 53).

67

Fig. 51. Asymmetric unit of the C4Stamoxifen complex (solvent molecules omitted for clarity).

Fig. 52. View of the molecular packing of the C4Stamoxifen complex along the b axis showing typical C4S bilayers separated by tamoxifen bilayer.

68

X Y

Z W

Fig. 53. Network of C-H interactions generated by tamoxifen molecules in the layer.

69

4.1.8 Crystal structure of p-sulfonatocalix[4]arene complex with piribedil

Piribedil is a piperazine dopamine agonist (Fig. 54). It is used in the treatment of Parkinson disease, particularly for alleviation of tremor 134. It has also been used for circulatory disorders and in other applications as a D2 agonist. Crystallographic data for the complex of C4S with piribedil is presented in Table 8. In the complex p-sulfonatocalix[4]arenepiribedil the asymmetric unit (Fig. 55) comprises one C4S molecule, one drug molecule and thirteen water molecules (one water molecule has partial occupancy). The oxygen atoms of one sulfonate group are disordered over two positions. The charge of calix[4]arene is -4 and charge of piribedil is +3. The charge balance is realized by additional complexing of one potassium cation.

Fig. 54. Piribedil cation.

Fig. 55. Asymmetric unit of the C4Spiribedil complex (some solvent molecules omitted for clarity).

p-Sulfonatocalix[4]arene is present in the flattened cone conformation (cone angles between the opposite aromatic rings are 41.0(2) and 80.0(2)). One of the phenolic oxygen atoms forms bifurcated hydrogen bond to the neighboring phenolic

70

Table 8. Crystal data and structure refinement for C4spiribedil.

Molecular formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size range for data collection Index ranges Reflections collected Independent reflections Completeness to = 23.26 Absorption correction Refinement method Data / restraints / parameters 2 Goodness-of-fit on F Final R indices [I > 2(I)] R indices (all data) Extinction coefficient Largest diff. peak and hole

C28H20O16S4C16H21N4O2K12.5H2O 1291.23 100(2) K 0.71073 Monoclinic P21/c a = 12.5249(4) b = 29.8223(9) = 120.257(1). c = 16.9631(5) 5472.9(3) 3 4 1.567 Mgm-3 0.350 mm-1 2680 0.25 0.08 0.03 mm3 2.65 to 23.26. 0 h 13, -33 k 0, -18 l 15 34066 7769 [Rint = 0.109] 99.0 % None 2 Full-matrix least-squares on F 7769 / 0 / 811 1.06 R = 0.082, wR = 0.228 R = 0.121, wR = 0.243 0.0009(4) 0.66 and -0.58 e-3

oxygen and water molecule, the second phenolic oxygen forms hydrogen bond with water molecule, the other two phenolic oxygens form typical intramolecular hydrogen bonds to the neighboring oxygen atoms. The piribedil molecule is partially included into the macrocyclic cavity of C4S via terminal positively charged pirimidine group (Fig. 55). The inclusion complex is stabilized by - interaction (3.968(4) ) between pirimidinium ring of the guest and the aromatic rings of the host. Additionally, two C-H and one C-HO hydrogen bonds further stabilize the complex. The protonated nitrogens atoms of pirimidinium group donate two hydrogen bonds (2.911(8) and 2.719(8) ) to water molecules. The protonated nitrogen of piperazine group forms hydrogen bond of 2.728(8) with the sulfonate oxygen of the neighboring calixarene.In the extended structure calixarenes are in up-down bilayer arrangement with the 1,3-benzodioxol rings of piribedil molecules embedded into the hydrophobic layers of C4S separating neighboring calixarenes (Fig. 56). 71

Fig. 56. View of the molecular packing of the C4Spiribedil complex showing C4S bilayers separated by piribedil layer.

72

4.2

Solid-state complexes of p-sulfonatocalix[6]- and p-sulfonatocalix [8]arenes

4.2.1 Crystal structure of p-sulfonatocalix[6]arene complex with bis(6aminohexyl)amine

Crystallographic data for the complex of p-sulfonatocalix[6]arene (C6S) with bis(6-aminohexyl)amine are presented in Table 10. The asymmetric unit (Fig. 57a) consists of half of the C6S in the form of anion, one bis(6-aminohexyl)amine guest in the form of trication and five water molecules. Two water molecules and oxygen atoms of two sulfonate groups of C6S are disordered over two positions. The bis(6aminohexyl)amine molecule is also disordered over two positions and was modeled (using DFIX and DANG commands in SHELXL-97 program) in order to retain its geometry. Residual electron density of 1.24 and 1.12 -3 is located near disordered oxygen atoms of sulfonate group indicating even higher disorder of those. The high R factor is due to poorly diffracting crystals and the disorder effect. a b

Fig. 57. (a) Asymmetric unit of the C6S complex with bis(6-aminohexyl)amine (symmetrygenerated atoms in green, water molecules omitted for clarity); (b) double partial cone conformation of C6S.

The p-sulfonatocalix[6]arene anion adopts the centrosymmetric up-down double partial cone conformation (Fig. 57b) with one of the phenolic oxygen atoms forming hydrogen bond of 2.567(8) with the sulfonate oxygen atom of the neighboring C6S molecule. Each partial cone of C6S acts as a host for bis(6-aminohexyl)amine cation leading to 1:2 hostguest inclusion stoichiometry. The amino groups of the guests are situated near the anionic sulfonate groups of the C6S. The complexation is mainly guided by N-HO hydrogen bonding between ammonium nitrogen atoms of the guest and sulfonate oxygen atoms of the host. 73

Table 9. Crystal data and structure refinement for C6Sbis(6-aminohexyl)amine.

Molecular formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size range for data collection Index ranges Reflections collected Independent reflections Completeness to = 21.97 Absorption correction Max. and min. transmission Refinement method Data / restraints / parameters 2 Goodness-of-fit on F Final R indices [ I> 2(I)] R indices (all data) Extinction coefficient Largest diff. peak and hole

C42H30O24S62C12H32N310H2O 853.92 100(2) K 0.71073 Triclinic P a = 11.8372(4) = 106.721(2). b = 12.2645(4) = 111.948(2). c = 15.1670(6) = 91.773(2). 1932.74(12) 3 1 1.467 Mgm-3 0.271 mm-1 900 0.30 0.20 0.05 mm3 2.99 to 21.97. -10 h 12, -12 k 12, -15 l 15 21525 4656 [Rint = 0.034] 98.7 % None 0.9866 and 0.9232 2 Full-matrix least-squares on F 4656 / 16 / 502 1.85 R = 0.135, wR = 0.396 R = 0.155, wR = 0.415 0.000(5) 1.241 and -0.718 e-3

In the extended structure, the C6S layers are separated by layers of bis(6aminohexyl)amine cations (Fig. 58). The calixarene anions are held together by hydrogen bond between the phenolic oxygen atom of one C6S and sulfonate oxygen atom of the neighboring host, and C-HO interactions between aromatic carbon atoms and sulfonate oxygen atoms.

Fig. 58. Molecular packing of the C6Sbis(6-aminohexyl)amine complex along the c axis.

74

4.2.2 Crystal structure of p-sulfonatocalix[6]arene complex with dimethylamine

Crystallographic data for the complex of C6S with dimethylamine are presented in Table 10. The asymmetric unit consists of half of the C6S in the form of anion, three dimethylamine cations (usual DMF impurity) named as X, Y and Z and one DMF molecule (Fig. 59). The p-sulfonatocalix[6]arene anion adopts the centrosymmetric up-down double partial cone conformation and provides two identical binding sites for DMF guests leading to 1:2 host-guest inclusion stoichiometry. One of the methyl group of the included DMF molecule points to the centre of macrocyclic cavity and interacts with the host by two C-H interactions of 3.633(5) and 3.521(7). Interestingly, one of the phenolic oxygen atoms of the C6S anion forms hydrogen bond (2.839(6) ) with the carbonyl oxygen atom of the included DMF molecule.

Fig. 59. Asymmetric unit of the C6S complex with dimethylamine and DMF (symmetry-generated atoms in green).

Three dimethylammonium cations are complexed exo with respect to the twopseudo cavities of C6S by N-HO hydrogen bonding. Cation Y is situated in the pocket between two neighboring sulfonate groups. The nitrogen atom of the secondary ammonium group of the guest Y forms one hydrogen bond (Fig. 60) with the sulfonate oxygen atom of the neighboring C6S molecule and one bifurcated hydrogen bond with the oxygen atom of the sulfonate group framing a pocket and carbonyl oxygen of the DMF molecule. The methyl groups of the dimethylammonium cation form two C-HO hydrogen bonds of 3.514(9) and 3.308(8) with the sulfonate oxygen atoms of the 75

Table 10. Crystal data and structure refinement for C6Sdimethylamine.

Molecular formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size range for data collection Index ranges Reflections collected Independent reflections Completeness to = 21.26 Absorption correction Refinement method Data / restraints / parameters 2 Goodness-of-fit on F Final R indices [I > 2(I)] R indices (all data) Extinction coefficient Largest diff. peak and hole

C42H30O24S66C2H8N2C3H7NO 766.89 100(2) K 0.71073 Triclinic P a = 12.2408(5) = 87.975(2). b = 12.4420(5) = 70.696(2). c = 12.8054(5) = 75.688(2). 1781.2(1) 3 1 1.430 Mgm-3 0.277 mm-1 812 0.4 0.25 0.05 mm3 3.04 to 21.26. -12 h 12, -12 k 12, -13 l 13 22771 3941 [Rint = 0.033] 99.5 % None 2 Full-matrix least-squares on F 3941 / 0 / 466 1.15 R = 0.065, wR = 0.141 R = 0.079, wR = 0.147 0.0018(8) 0.955 and -0.444 e-3

host. Cations X and Z present the same type of hydrogen bonding by forming hydrogen bond with the sulfonate oxygen atom of the C6S and bifurcated hydrogen bond with the two sulfonate oxygen atoms of the second C6S molecule. As shown in Fig. 61, the overall structure reveals layered character of the packing, however, there are not clear hydrophobic and hydrophilic regions in the structure. The neighboring calixarenes are held together by O-HO hydrogen bond between phenolic oxygen atom (donor) of one C6S molecules and sulfonate oxygen atom (acceptor) of the second C6S molecule with the distance of 2.592(5) .

76

Fig. 60. Hydrogen bonding generated by dimethyammonium cations.

Fig. 61. View of the molecular packing along the a axes showing hydrogen bonding between the neighboring C6S molecules.

77

4.2.3 Crystal structure of p-sulfonatocalix[8]arene complex with cis-cyclohexanediamine

Crystallographic data for the complex of p-sulfonatocalix[8]arene (C8S) with 1,2-cyclohexanediamine is presented in Table 11. The asymmetric unit (Fig. 63) of the complex has the stoichiometry 1:4:8 p-sulfonatocalix|8]arene:cyclohexanediammonium:water. The calixarene in the complex with cyclohexanediamine lies at an inversion centre. For the complex of C8S with 1,2-cyclohexanediamine the crystals were probably twinned. In electron density maps we might have seen a shadow of the second component, especially 4 large peaks of 6 e-3. Under such conditions refinement did not converge, and the R factors are very large. Anyway, the resolution of the most important information, concerning the mutual interactions of the host and guest molecules and complex formation, was achieved. a b

Fig. 62. Conformation of p-sulfonatocalix[8]arene in the cyclohexanediamine complex: (a) top view; (b) side view.

The p-sulfonatocalix[8]arene anion adopts an inverted double partial cone conformation (Fig. 62), in which four sulfonate groups are pointing up and the other four are pointing down from the mean plane of the molecule forming two pseudo calix[4] cavities. Hydrogen bonds exist not only between vicinal hydroxyl groups (2.73(1) and 2.67(1) ), but also between the sulfonate group of one inverted p-sulfonatophenol group and the hydroxyl group of the neighboring inverted cone (2.60(1) ). The dimensions of the two partial cones are identical, and are similar to those observed for the p-sulfonatocalix[4]arene. The inclusion of the 1,2-cyclohexanediammonium cation is similar to that reported for the complex of this dication with p-sulfonatocalix[4]arene. As is seen in Fig. 63, cyclohexanediammonium cations are complexed in two different manners. The first one (molecule X) has its hydrocarbon ring included into the molecular cavity of the

78

Table 11. Crystal data and structure refinement for C8Scyclohexanediamine.

Molecular formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size range for data collection Index ranges Reflections collected Independent reflections Completeness to = 27.92 Absorption correction Refinement method Data / restraints / parameters 2 Goodness-of-fit on F Final R indices [I > 2(I)] R indices (all data) Extinction coefficient Largest diff. peak and hole

C56H40O32S84C6H16N28H2O 1037.10 100(2) K 0.71073 Monoclinic P21/a a = 12.5225(1) b = 25.6792(3) = 102.421(1). c = 14.5478(2) 4568.14(9) 3 2 1.508 Mgm-3 0.293 mm-1 2176 0.25 0.20 0.05 mm3 2.98 to 27.92. 0 h 16, -33 k 33, -19 l 18 21233 10809 [Rint = 0.068] 98.6 % None 2 Full-matrix least-squares on F 10809 / 0 / 592 2.69 R = 0.235, wR = 0.618 R = 0.264, wR = 0.623 0.013(4) 6.07 and -1.39 e-3

calixarene, with one ammonium head group interacting with sulfonate function of the host via hydrogen bond (N-HO distance of 2.77(1) ). The guest is held inside the cavity by C-H and C-HO interactions. The cyclohexanediammonium cation Y is included between two calixarenes and interacts with them via N-HO and C-HO hydrogen bonds. Both cyclohexanediammonium dications are donors of six hydrogen bonds (Fig. 64). The cyclohexanediammonium X forms two hydrogen bonds with water molecules, three hydrogen bonds with sulfonate oxygens of C8S molecules and one bifurcated hydrogen bond with two oxygens of sulfonate groups. The cyclohexanediammonium cation Y forms two hydrogen bonds with water molecules, two hydrogen bonds with sulfonate oxygens of the calixarenes, one bifurcated hydrogen bond with water molecule and sulfonate oxygen, and bifurcated hydrogen bond with two oxygens of sulfonate groups.

79

Fig. 63. Asymmetric unit of the C8Scyclohexanediamine complex (symmetry-generated atoms in green).

The specific conformation of the macrocycle is reflected in the mode of assembly of the structure. The anionic p-sulfonatocalix[8]arenes are packed in the rippled bilayers (and are held together by - (3.655(7) ) and C-HO (3.27(2) ) interactions between the neighboring molecules (Fig. 65). The ammonium groups of the cyclohexanediammonium cations point towards the hydrophilic zone between the C8S bilayers.

Fig. 64. Network of hydrogen bonding generated by cyclohexanediammonium cations.

80

Fig. 65. View along the a crystal axis of the rippled bilayer of C8Scyclohexanediammonim complex.

81

4.2.4 Crystal structure of p-sulfonatocalix[8]arene complex with dimethylamine

Crystallographic data for the complex of C8S with dimethylamine are presented in Table 12. The asymmetric unit consists of half of the C8S molecule in the form of anion, four dimethylammonium cations named as X, Y, Z and W, and one DMF molecule (Fig. 67). The p-sulfonatocalix[8]arene adopts a conformation (Fig. 66) in which three of the phenolic rings point up from the mean plane of the molecule, three point down and the other two of the phenolic rings are self-included in the macrocyclic cavity forming intramolecular hydrogen bonds between phenolic oxygen atoms acting as donors and sulfonate oxygen atoms acting as acceptors with the distance of 2.855(6) . In this conformation the typical hydrogen bonding between vicinal hydroxyl groups does not exist. a b

Fig. 66. C8S conformation in the dimethylamine complex: (a) top view; (b) side view.

This centrosymmetric C8S conformation provides two pairs of identical binding sites for two dimethylammonium cations named as W and two dimethylammonium cations named as Y leading to 1:4 host-guest inclusion stoichiometry (Fig. 68). Cations Y are located in the identical grooves formed by two phenolic rings pointing up and two phenolic rings pointing down and form hydrogen bond between ammonium nitrogen atom and sulfonate oxygen atom of the host with the distance of 2.820(7) . Cations W are situated between two included phenolic rings on each side of the macrocycle and form hydrogen bonds to the oxygen atoms of two sulfonate groups of 2.780(7) and 2.847(7) . The complexation is additionally stabilized by C-HO hydrogen bond (3.446(9) ) between methyl carbon atom of the cation W and one of the phenolic oxygen atom of the host. The cations X and Z are complexed between the neighboring C8S molecules by N-HO hydrogen bonding. Both cations form one bifurcated hydrogen bond with two 82

Table 12. Crystal data and structure refinement for C8Sdimethylamine.

Molecular formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size range for data collection Index ranges Reflections collected Independent reflections Completeness to = 20.81 Absorption correction Refinement method Data / restraints / parameters 2 Goodness-of-fit on F Final R indices [I > 2(I)] R indices (all data) Extinction coefficient Largest diff. peak and hole

C56H40O32S88C2H8N2C3H7ON 998.15 100(2) K 0.71073 Triclinic P a = 11.508(1) = 74.999(7). b = 12.816(1) = 89.037(6). c = 17.421(2) = 67.018(6). 2274.5(4) 3 1 1.457 Mgm-3 0.287 mm-1 1056 0.20 0.20 0.10 mm3 2.60 to 20.81. -11 h 11, -12 k 12, -17 l 17 9241 4723 [Rint = 0.113] 99.2 % None 2 Full-matrix least-squares on F 4723 / 0 / 599 0.93 R = 0.062, wR = 0.103 R = 0.129, wR = 0.118 0.0024(5) 0.26 and -0.30 e-3

sulfonate oxygen atoms and one normal hydrogen bond also with sulfonate oxygen atom. The network of hydrogen bonds generated by all four crystallografically independent dimethylammonium cations is presented in the Fig. 69.

Fig. 67. Asymmetric unit of the C8S complex with dimethylamine (symmetry-generated atoms in green).

83

W Y W

Fig. 68. Inclusion complex of C8S with dimethylamine.

As shown in Fig. 70, the overall structure reveals the layered character of the packing, similar to that observed for C6S-dimethylamine complex. There are not distinct hydrophobic and hydrophilic layers in the structure.

Z Y

X Fig. 69. Hydrogen bonding generated by four independent dimethylammonium cations.

Fig. 70. Molecular packing of the C8Sdimethylamine complex along a axes.

84

4.2.5 Crystal structure of p-sulfonatocalix[8]arene complex with butanediamine

Crystallographic data for the complex of C8S with 1,4-butanediamine are presented in Table 13. The unit cell of the complex consists of the following stoichiometry 1:3:1:2 p-sulfonatocalix[8]arene:1,4-butanediammonium:methanol:water. For the complex, only sulfur and hydroxyl oxygen atoms were refined anisotropically due to bad diffraction data, caused both by small, plate-shaped crystals and low resolution due to a high degree of disorder. Data were corrected using the PLATON SQUEEZE procedure for disordered solvent molecules, which were not located in the electron density maps. The butanediammonium cations were modeled using DFIX and DANG commands (SHELXL-97) in order to retain the correct geometry. As shown in Fig. 71, the p-sulfonatocalix[8]arene molecule adopts an almost planar conformation, in which all sulfonate groups are pointing out from the cavity; each phenolic hydroxyl group forming hydrogen bonds with its vicinal neighbors (2.67(1) to 2.73(1) ). The macrocycle has an average external diameter of near 20 (distance is measured between opposite pairs of sulfonate groups). The average internal diameter is near 7 . a b

Fig. 71. Conformation of C8S in the butanediamine complex: (a) top view; (b) side view.

Four orthogonal grooves are present on both faces of the macrocycle. In a similar manner to that observed by Raston et al. in the structure of the complex of C8S in a pleated loop conformation with 4,4'-dipyridine-N,N' dioxide, each groove of the macrocycle contains a butanediammonium cation or a phenyl group of the neighboring

85

Table 13. Crystal data and structure refinement for C8Sbutanediamine.

Molecular formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size range for data collection Index ranges Reflections collected Independent reflections Completeness to = 18.79 Absorption correction Refinement method Data / restraints / parameters 2 Goodness-of-fit on F Final R indices [I > 2(I)] R indices (all data) Extinction coefficient Largest diff. peak and hole

1C56H40O32S83C4H14N22CH3OH2H2O 905.94 100(2) K 0.71073 Monoclinic C2/c a = 24.3724(9) b = 22.2422(8) = 119.279(2). c = 23.340(1) 11035.9(8) 3 4 1.091 Mgm-3 0.230 mm-1 3784 0.30 0.20 0.07 mm3 2.65 to 18.79. -22 h 22, -20 k 20, -21 l 21 16344 4256 [Rint = 0.062] 99.2 % None 2 Full-matrix least-squares on F 4256 / 21 / 367 2.13 R = 0.186, wR = 0.472 R = 0.201, wR = 0.487 0.0014(7) 0.94 and -0.47 e-3

C8S molecules. Two of the three independent butanediammonium cations X and Z are complexed on the one face of the macrocycle, while the third one Y is situated on the other face of the macrocycle (Fig. 72), remaining two grooves on that side are occupied by phenyl rings of the neighboring C8S molecules. As shown in Fig. 72, cation Z forms two hydrogen bonds by its ammonium group with oxygen atoms of two sulfonate groups of the host (2.75(3) and 2.91(3) ). Complex assembles with channels along the b axis which are occupied by disordered methanol molecules, Fig. 73a. However, the view perpendicular to the b axis reveals the complexity of the packing. It now becomes apparent that two sets of cavities are generated (Fig. 73b). The first set of cavities represent channels of an oval geometry containing one butanediammonium cation in a folded conformation and disordered methanol molecules. The cavity walls are formed mainly of sulfonate groups and are therefore highly hydrophilic. The second set of square cavities intersect and connect the first set. The butanediammonium cations in an elongated form are located within these 86

Fig. 72. Inclusion complex of butanediammonim cations in the grooves of C8S.

cavities, with the ammonium head groups pointing out of them. Calixarene molecules are held together via C-HO hydrogen bonds between methylenic bridges and sulfonate groups (distances from 3.33(4) to 3.55(3) ). a

Fig. 73. View along the: (a) b axis; (b) [101] direction showing two different cavities.

87

4.3

Solid-state complexes of calix[4]arene diphosphate

4.3.1 Crystal structure of calix[4]arene diphosphate potassium salt

Crystallographic data for the potassium salt of C4diP are presented in Table 14. The asymmetric unit comprises one calix[4]arene diphosphate dianion, two potassium cations, one methanol molecule and eleven water molecules (Fig. 74). The calixarene molecule is deprotonated on each phosphonate group and retains flattened cone conformation. The cone angles between substituted phenolic rings and unsubstituted ones are 30.9(5) and 74.7(4). As in all structures involving calix[4]arene dihydroxyphosphonic acid studied by myself and those found in the literature, the characteristic generic motif is the dimeric association of two molecules of calixarene by interdigitating of the aromatic core (Fig. 74b). Here the angle formed by the p-carbon atoms describing interdigitation is 163.0(1). As expected, the potassium cations are solvated and are complexed exo with respect to C4diP cavity (Fig. 74a). a b

163.0

Fig. 74. (a) Asymmetric unit of the potassium salt of C4diP; (b) dimeric motif of C4diP molecules.

From a general point of view, the complex adopts a 1D architecture based on layers of dimeric units characteristic to calix[4]arene diphosphate, and are held together by the potassium cations ion-paired with the deprotonated oxygen atoms of the phosphate groups. Thus, infinite bridges of electrostatic interactions are connecting the dimeric units of C4diP. A stepped-like organization is observed, as represented in Fig.
75a, a perpendicular view to this motif shows parallel packing of sheets of dimers (Fig.

75b).

88

Table 14. Crystal data and structure refinement for C4diPpotassium.

Molecular formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size range for data collection Index ranges Reflections collected Independent reflections Completeness to = 18.92 Absorption correction Max. and min. transmission Refinement method Data / restraints / parameters 2 Goodness-of-fit on F Final R indices [I > 2(I)] R indices (all data) Extinction coefficient Largest diff. peak and hole

C28H20O10P2K2CH3OH11H2O 890.83 100(2) K 0.71073 Monoclinic P21/c a = 15.5758(7) b = 13.0023(7) = 111.067(4). c = 19.385(1) 3663.4(3) 3 4 1.615 Mg/m-3 0.437 mm-1 1872 0.25 0.10 0.10 mm3 2.80 to 18.92. 0 h 14, 0 k 11, -17 l 16 23811 2869 [Rint = 0.240] 98.5 % None 0.9576 and 0.8987 2 Full-matrix least-squares on F 2869 / 0 / 536 1.09 R = 0.090, wR = 0.218 R = 0.130, wR = 0.240 0.0000(10) 0.67 and -0.39 e-3

The electrostatic interactions between the phosphate oxygens and K+ cations are multiple with distances being: 2.24(1), 2.286(9), 2.315(9), 2.39(1) and 2.88(1) . Eight water molecules are coordinated to the complex by electrostatic interactions. Some of them form hydrogen bonds with phenolic oxygens or with oxygen atoms of the phosphate groups of C4diP, while some others are hydrogen bonded between them. The remaining three water molecules and methanol molecule are hydrogen bonded to phenolic oxygen atoms or to the coordinated water molecules. The solid state structure of the potassium salt of calix[4]arene diphosphate represents the first result of cation binding by C4diP, where the major driving force is the attraction between oppositely charged species. Apparently simple, the structure of potassium salt of calix[4]arene diphosphate presents a high degree of complexity, from the point of view of non-covalent interactions present in the complex, of the architecture achieved and of the effective cationic binding. 89

Fig. 75. View of the molecular packing: (a) along the c axis showing layers ofC4diP dimers; (b) double chains along b axis.

90

4.3.2 Crystal structure of calix[4]arene diphosphate complex with dimethylamine

Crystallographic data for the complex of C4diP with dimethylamine are presented in Table 15. The unit cell comprises two molecules of calix[4]arene diphosphate, three dimethylamine cations (X, Y and Z), one tetramethylammonium cation (usual DMF impurities) and one DMF molecule, Fig. 76.

Fig. 76. Asymmetric unit of the C4diP complex with dimethylamine.

Both C4diP molecules are in the form of dianions with deprotonated hydroxyl groups of the phosphonic acid substituents. The charge equilibrium is realized by complexation of three dimethylammonium and one tetramethylammonium cations from the crystallization mixture. Two crystallografically independent C4diP molecules adopt different conformations, Fig. 77. For the first C4diP molecule in the typical flattened cone conformation the dihedral angles between the substituted phenolic rings and the unsubstituted phenolic rings are 26.6(2) and 78.0(2), respectively. Intramolecular hydrogen bonding between the unsubstituted and substituted phenolic groups (2.879(6) and 2.858(6) ) rigidifies the cone conformation of C4diP molecule. The second crystallografically independent C4diP molecule adopt an unusual conformation where two substituted phenolic rings are inclined to the centre of the macrocyclic cavity (dihedral angles between the substituted phenolic rings and the unsubstituted ones are 23.1(2) and 125.5(2), respectively). Because of the strong deformation of the typical

91

Table 15. Crystal data and structure refinement for C4diPdimethylamine.

Molecular formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size range for data collection Index ranges Reflections collected Independent reflections Completeness to = 26.38 Absorption correction Refinement method Data / restraints / parameters 2 Goodness-of-fit on F Final R indices [I > 2(I)] R indices (all data) Absolute structure parameter Extinction coefficient Largest diff. peak and hole

2C28H24O10P23C2H8NC3H7NOC4H12N 1450.35 100(2) K 0.71073 Orthorhombic Pna21 a = 33.9505(3) b = 15.5238(4) c = 13.6156(7) 7176.4(4) 3 4 1.342 Mgm-3 0.182 mm-1 3072 0.30 0.20 0.20 mm3 2.74 to 26.38. -42 h 0, 0 k 19, 0 l 17 39772 7626 [Rint = 0.129] 99.5 % None 2 Full-matrix least-squares on F 7626 / 1 / 916 1.05 R = 0.070, wR = 0.185 R = 0.092, wR = 0.197 0.22(15) 0.0008(4) 0.720 and -0.662 e-3

flattened cone conformation, this C4diP molecule also presents very interesting type of intramolecular hydrogen bonding (Fig. 78a). One of the phenolic oxygen atoms acts as donor of hydrogen bond with carbonyl oxygen atom of DMF molecule (2.654(7) ) and acceptor of the hydrogen bond with the second phenolic oxygen atom (2.939(6) ). The calixarene molecule is flexible at the level of aromatic core and can adapt itself in order to allow the most favorable interactions with the local environment. Two crystallografically independent C4diP molecules form dimeric unit (Fig. 78b), where two substituted phenolic rings of the C4diP molecule in the deformed cone conformation penetrate the macrocyclic cavity of the second C4diP molecule in the flattened cone conformation. This dimer differs significantly from the typical dimeric unit usually described by the interdigitation of the phenolic rings and is often, but not always, composed of two symmetry related C4diP molecules.

92

Fig. 77. Conformations of two crystallografically independent C4diP molecules: (a) side view; (b) top view.

Fig. 78. (a) 1,3-Intramolecular hydrogen bonding in C4diP molecule; (b) dimeric structural motif of C4diP formed from two crystallografically independent molecules.

The overall structure is based on the C4diP layers with anionic surface alternating with layers containing dimethylammonium and tetramethylammonium cations, as well as DMF molecules (Fig. 79). One of the three dimethylammonium cations (cation X) intercalate into the hydrophobic core of the bilayer. The guest is situated in a cage formed by four molecules of C4diP (Fig. 80a), which are held together by intermolecular hydrogen bonding between neighboring phosphonic acid groups.Methyl groups of the included dimethylammonium cation point towards hydrophobic walls formed by the phenyl rings of the four C4diP molecules (the shortest C-H distance of 3.848(9) ), while ammonium group points towards hydrophilic bottom formed by four phosphonic acid groups generating two N-HO hydrogen bonds of 2.743(8) and 2.730(8) . Two C-HO hydrogen bonds (3.241(8) and 3.353(9) )

93

formed between methyl groups of the guest and oxygen atoms of the phosphonic acids of the C4diP molecules further stabilize structure of the complex. a

Fig. 79. View of the molecular packing of the C4diP complex with dimethylamine: (a) along the c axis; (b) along the b axis.

The remaining guest molecules are located in the cationic layer between the C4diP bilayers. The nitrogen atoms of the dimethylammonium cations Y and Z are hydrogen bonded to oxygen atoms of the phosphonic acid groups of two calixarenes from different bilayers, Fig. 80b. The DMF molecule forms C-HO hydrogen bond (3.315(9) ) between the carbonyl carbon atom (donor) and phenolic oxygen atom (acceptor) of the C4diP molecule. The complex of the calix[4]arene diphosphate with dimethylammonium and tetramethylammonium cations in the presence of DMF shows a novel type of C4diP self-assembling by forming an unusual dimeric structural motif. This is the first solid-

94

state structure with C4diP assembling differently from the typical dimeric unit characteristic for C4diP complexes obtained from alcohol-water systems.

Fig. 80. (a) Top view of the dimethylammonium cation in the molecular cage formed by four C4diP molecules; (b) hydrogen bonding generated by the guest molecules located in the cationic layer.

95

4.3.3 Crystal structure of calix[4]arene diphosphate complex with melamine

Crystallographic data for the complex of C4diP with melamine are presented in Table 16. The asymmetric unit comprises one molecule of calix[4]arene diphosphate, three melamine mono-cations (X, Y and Z), nine water molecules and one ethanol molecule (all solvent molecules have full occupancies), Fig. 81. Charge equilibrium in the structure is realized by protonation of one aromatic nitrogen of each melamine molecule. Calix[4]arene diphosphate is present in the flattened cone conformation, the dihedral angles formed by the substituted phenolic rings and by the unsubstituted phenolic rings are 34.0(1) and 85.7(1), respectively. The phenolic oxygen atoms of C4diP are involved in intramolecular hydrogen bonding (2.797(4) and 2.725(4) ).

Fig. 81. View of the asymmetric unit of the C4diP complex with melamine.

The solid-state structure of the complex is generated by bilayer motif of calix[4]arene diphosphate molecules (Fig. 82). The bilayers are formed by interpenetrated dimers of C4diP. The dimeric motif is described by the interdigitation of the phenolic rings, with the interdigitated p-carbon atom forming an angle of 153.6(1) with the two p-carbon atoms of the interpenetrating calixarene. The bilayer is also stabilized by strong PO-HOP hydrogen bond of 2.542(4) between the neighboring phosphate groups. The dimeric layers of calixarene alternate with sheets of parallel chains of melamine mono-cations two of which (Y and Z) are facing the phosphonic groups (chain 1) and another one (X) intercalated between the two (chain 2). The network of hydrogen bonds that characterizes chain 1 and its environment involves (Fig. 83a): 96

Table 16. Crystal data and structure refinement for C4diPmelamine.

Molecular formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size range for data collection Index ranges Reflections collected Independent reflections Completeness to = 21.98 Absorption correction Refinement method Data / restraints / parameters 2 Goodness-of-fit on F Final R indices [I > 2(I)] R indices (all data) Extinction coefficient Largest diff. peak and hole

C28H20O10P23C3N6H79H2O C2H5OH 1171.05 100(2) K 0.71073 Monoclinic P21/c a = 22.1727(9) b = 12.4313(7) = 103.281(3). c = 19.508(1) 5233.3(5) 3 4 1.486 Mgm-3 0.177 mm-1 2472 0.28 0.15 0.03 mm3 3.00 to 21.98. -23 h 23, -13 k 13, -20 l 20 55429 6336 [Rint = 0.064] 99.0 % None 2 Full-matrix least-squares on F 6336 / 0 / 751 1.00 R = 0.057, wR = 0.098 R = 0.101, wR = 0.110 0.00187(19) 0.24 and -0.32 e-3

three solvent molecules and two phosphonate groups per melamine monocation. Chain 2 shows hydrogen bonds to water molecules only (Fig. 83b). The protonated nitrogen atoms are involved in hydrogen bonds with oxygen atoms of phosphonate groups (chain 1) and with water molecules (chain 2). Double hydrogen bonding between the melamine mono-cations is present in the chains (N-HN distances from 2.966(5) to 3.133(5) ), but much weaker than these found for the melamine complex with p-sulfonatocalix[4]arene from 2.904(7) to 3.063(7) (see 4.1.1). The melamine monocations are coplanar and form tapes that are parallel to the dimeric layer of calix[4]arene diphosphate. Perpendicular to those tapes melamine mono-cations generate continuous zigzag chains characterized by shifted face-to-face interactions (Fig. 84). The - stacking of melamine mono-cations is more compact (values between 3.620(2) and 3.770(2) ) than in the complex with calix[4]arene sulfonate (3.783(3) to 3.915(3) ). Distances between melamine planes vary from 3.212(3) to 3.351(3) . 97

Fig. 82. View of the molecular packing along the b axis showing layers of C4diP dimers in the complex with melamine.

chain 1

chain 2

Fig. 83. View along c axis of the network of hydrogen bonds encountered by melamine monocations: (a) for the chain 1, (b) for the chain 2.

The structure of the complex of calix[4]arene diphosphate with melamine shows a high degree of complexity. The presence of polar groups of the calixarene and numerous solvent molecules seems to be the main factors generating such variety in the non-covalent interactions that rigidify the complex.

98

Fig. 84. Sheets of melamine mono-cations along a axis formed by zigzag chains of -stacked aromatic rings.

99

4.3.4 Crystal structure of calix[4]arene diphosphate complex with cadaverine

Cadaverine (1,5-pentanediamine) (Fig. 85) is a foul-smelling toxic diamine produced by protein hydrolysis during putrefaction of animal tissue 135. Cadaverine is the decarboxylation product of the amino acid lysine. It is also produced in small quantities by living beings. Crystallographic data for the complex of C4diP with cadaverine are present in Table 17. The asymmetric unit of the complex (Fig. 86) comprises two dianions calix[4]arene diphosphate, two 1,5-pentanediamine dications, three water molecules (one with partial occupancy) and five methanol molecules (three molecules with partial occupancies). Both guest molecules are disordered over two positions.

Fig. 85. 1,5-Pentanediamine dication.

Fig. 86. Asymmetric unit of the C4diP complex with cadaverine.

The conformation of the two independent calix[4]arene molecules can be described as flattened cone. The cone angles between substituted phenolic rings and unsubstituted ones are 26.3(1), 108.3(2) for the first and 26.7(1), 100.7(2) for the

100

Table 17. Crystal data and structure refinement for C4diPcadaverine.

Molecular formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size range for data collection Index ranges Reflections collected Independent reflections Completeness to = 23.27 Absorption correction Refinement method Data / restraints / parameters 2 Goodness-of-fit on F Final R indices [I > 2(I)] R indices (all data) Extinction coefficient Largest diff. peak and hole

2C28H20O10P22C5H16N23.55CH3OH2.45H2O 1519.92 100(2) K 0.71073 Triclinic P a = 13.0916(3) = 112.960(1). b = 15.9633(5) = 93.643(2). c = 18.7215(6) = 91.505(2). 3589.9(2) 3 2 1.406 Mgm-3 0.190 mm-1 1603 0.35 0.15 0.13 mm3 2.55 to 23.27. -14 h 14, -17 k 17, -20 l 20 42142 10259 [Rint = 0.040] 99.2 % None 2 Full-matrix least-squares on F 10259 / 0 / 923 1.09 R = 0.067, wR = 0.166 R = 0.102, wR = 0.185 0.0016(6) 0.86 and -0.53 e-3

second crystallographically independent C4diP molecule, respectively. The cone conformation is stabilized by intramolecular hydrogen bonding between the phenolic hydroxyl groups acting as H-bond donors and the oxygen atoms connected to phosphonic acid groups as H-bond acceptors. As expected, complex is based on the interdigitating aromatic-aromatic stacked dimeric motif. The angles of interpenetration are 168.9(2) for the first and 152.5(2) for the second crystallographically independent dimer, respectively. The cadaverine dications are situated in the hydrophilic layer containing also solvent molecules from the crystallization mixture. The network of hydrogen bonds encountered by cadaverine dications is shown in Fig. 87. Cadaverine molecule X forms five hydrogen bonds with calix[4]arene diphosphate molecules from different layers and one hydrogen bond with water molecule, while cadaverine molecule Y forms only three hydrogen bonds with C4diP, one hydrogen bond with methanol molecule and one with 101

water molecule. The differences in local environment result in different conformations of guest molecules.

Fig. 87. Network of hydrogen bonds encountered by cadaverine dications.

Fig. 88. Molecular packing of C4diPcadaverine complex along a axis.

The solid-state structure of the complex is generated by typical bilayer motif of calix[4]arene diphosphate molecules (Fig. 88). The dimeric units of C4diP molecules from neighboring layers form hydrogen bonds. Each of the calixarenes is hydrogen bonded with two calixarenes from the neighboring layer.

102

4.3.5 Crystal structure of calix[4]arene diphosphate complex with L-lysine (I)

L-Lysine (Fig. 89) is an essential amino acid and is a basic building block of all

proteins. L-Lysine plays a major role in calcium absorption, building muscle protein, recovering from surgery or sports injuries, and the body's production of hormones, enzymes, and antibodies.

Fig. 89. L-Lysine cation.

Crystallographic data for the complex of C4diP with L-lysine are presented in Table 18. The structure was described as disordered in centrosymmetric space group, thus admitting that only the average structure was determined 136. The asymmetric unit of the complex (Fig. 90) comprises one C4diP molecule, one L-lysine molecule disordered over two positions and one water molecule. The calixarene molecule adopts flattened cone conformation. The cone angles between substituted phenolic rings and unsubstituted ones are 41.8(2) and 83.9(1), respectively. The charge of C4diP molecule is 1 with one deprotonated phosphonic acid group. The phenolic oxygen atoms are involved in intramolecular hydrogen bonding that stabilizes the flattened cone conformation.

Fig. 90. Asymmetric unit of the complex of C4diP with L-lysine.

103

Table 18. Crystal data and structure refinement for C4diPL-lysine (I).

Molecular formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size range for data collection Index ranges Reflections collected Independent reflections Completeness to = 24.79 Absorption correction Refinement method Data / restraints / parameters 2 Goodness-of-fit on F Final R indices [I > 2(I)] R indices (all data) Extinction coefficient Largest diff. peak and hole

C28H23O10P2C6H15N2O2H2O 748.64 100(2) K 0.71073 Triclinic P a = 10.3670(3) = 76.243(2). b = 11.1923(5) = 84.958(2). c = 16.2935(7) = 67.183(2). 1692.6(1) 3 2 1.469 Mgm-3 0.201 mm-1 788 0.20 0.10 0.10 mm3 3.12 to 24.79. -12 h 12, -13 k 13, -19 l 19 26026 5751 [Rint = 0.063] 98.9 % None 2 Full-matrix least-squares on F 5751 / 0 / 535 1.22 R = 0.090, wR = 0.180 R = 0.120, wR = 0.189 0.0100(17) 0.44 and -0.37 e-3

The structural motif of calixarene is based on typical dimeric unit of C4diP molecules (Fig. 91). The angle of interdigitation is 153.4(1). Neighboring dimeric units are connected by strong hydrogen bond between neighboring phosphate groups (PO-HOP 2.537(5) ). There are no aromatic-aromatic interactions between neighboring dimers. The C4diP molecules are packed in typical bilayer (that can be also considered as monolayer of C4diP dimers). The calixarene molecules from neighboring layers interact by strong hydrogen bond (PO-HOP 2.557(5) ). Double chains of L-lysine molecules are situated into the hydrophilic layer between calixarene bilayers. One amine group of amino acid is protonated. The polar groups of L-lysine form five hydrogen bonds with oxygen atoms of phosphonic acid groups of C4diP molecules from two neighboring layers and one hydrogen bond with water molecule (Fig. 92). No contacts between amino acid molecules are observed.

104

Fig. 91. View of the molecular packing showing layers of calix[4]arene diphosphate dimers in the complex with L-lysine.

Fig. 92. View of the hydrogen bonding formed by L-lysine molecule.

105

4.3.6 Crystal structure of calix[4]arene diphosphate complex with L-lysine (II)

Crystallographic data for the complex of C4diP with L-lysine are presented in Table 20. The asymmetric unit of the complex of C4diP with L-lysine is generated by the complicity of four molecules of calix[4]arene dihydroxyphosphonic acid with three molecules of lysine (named as X, Y and Z), in the presence of two molecules of ethanol and seven water molecules, Fig. 93. As expected, all four independent molecules of C4diP are present in the cone conformation. The phenolic oxygen atoms of calixarene molecules are involved in intramolecular hydrogen bonds except for one C4diP molecule where one of the unsubstituted phenolic oxygen atoms is involved in hydrogen bonding to a water molecule. In another C4diP molecule one of the phenolic oxygens forms a bifurcated hydrogen bond. The cone angles formed between the substituted phenolic rings and between the unsubstituted ones for the four crystallografically independent C4diP molecules are given in Table 19. It was difficult to estimate the real protonation state of the C4diP molecules because of the structure complexity.
Table 19. Cone angles formed between the substituted phenolic rings and between the unsubstituted ones for the four C4diP molecules

Cone angle, Molecule 1 Molecule 2 Molecule 3 Molecule 4

substituted unsubstituted 26.3(3) 28.1(3) 29.7(3) 27.3(3) 105.9(3) 106.7(3) 103.2(3) 111.0(3)

The presence of four independent molecules of C4diP as building elements of the complex induces formation of two structural dimeric units characterized by interdigitation of the aromatic crowns of two opposite calixarene molecules. Thus, the two angles formed by the p-carbon atoms describing the interdigitation are of 166.0(3) and 165.8(3). The general topology of the complex is guided by the layer of two dimeric units of calixarene molecules and by the large network of hydrogen bonds generated by the molecules of lysine. The dimeric units of calixarene molecules from neighboring layers form hydrogen bonds by one of the hydroxyl units of the phosphonic acid groups of 2.487(8) . 106

Table 20. Crystal data and structure refinement forC4diP L-lysine (II).

Molecular formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size range for data collection Index ranges Reflections collected Independent reflections Completeness to = 26.40 Absorption correction Refinement method Data / restraints / parameters 2 Goodness-of-fit on F Final R indices [I > 2(I)] R indices (all data) Absolute structure parameter Extinction coefficient Largest diff. peak and hole

4C28H24O10P23C6H15N2O22C2H5OH7H2O 2979.42 100(2) K 0.71073 Monoclinic P21 a = 10.7864(4) b = 29.3591(7) = 91.974(1). c = 21.8747(8) 6921.4(4) 3 2 1.430 Mgm-3 0.197 mm-1 3126 0.22 0.10 0.10 mm3 2.61 to 26.40. 0 h 13, 0 k 36, -27 l 27 45902 14400 [Rint = 0.128] 99.4 % None 2 Full-matrix least-squares on F 14400 / 1 / 1835 1.02 R = 0.078, wR = 0.186 R = 0.147, wR = 0.220 -0.04(13) 0.0011(3) 1.04 and -0.71 e-3

Fig. 93. Asymmetric unit of the C4diP complex with L-lysine (some solvent molecules omitted for clarity).

107

In the complex the L-lysine molecules adopt three different conformations. Additionally, amino acid Z is disordered over two conformations. All L-lysine molecules are in ionic form with protonated amine groups and deprotonated carboxylic groups, as denoted by the hydrogen bonds formed with the molecular environment. The hydrogen bonds of the polar groups of L-lysine, in this solid-state system, are mainly formed with the molecules of calixarene diphosphate. The network of intermolecular interactions generated by the amino acid is highly complex, closely related to the conformational variations of each amino acid in the system. Lysine Y forms dimer with Lysine X by N-HO hydrogen bond of 2.83(1) , while five other interactions are present with the hydroxyl groups of the phosphonic acid moieties of three C4diP molecules, Fig. 94. Lysine X donates all hydrogen bonds to the hydroxyl groups of the phosphonic acid moieties of the C4diP molecules. The final lysine Z, besides the hydrogen bonds with three C4diP molecules with the phosphonate groups and unsubstituted phenolic oxygen atom, forms three hydrogen bonds with water molecules. The arrangement of the three independent molecules of lysine generates a 1D ladder network, Fig. 95. Double chains of lysine molecules X and Y characterize the main framework, while the interconnection between these parallel chains is assured by the third lysine, Z.

Fig. 94. Network of hydrogen bonds developed by the three independent L-lysine molecules.

108

Fig. 95. Representation of the 1D ladder network generated by the arrangement of L-lysine molecules along the b axis showing hydrogen bonds involving the L-lysine molecules X and Y.

As it may be observed from the general packing (Fig. 96), the topology of this solid-state structure is characterized by the layer of calixarene dimers, intercalated with heterogeneous layer of L-lysine molecules. It is worth to mention that in this particular complex, a zigzag layer of dimers of C4diP molecules replaces the normally observed motif of planar layer of dimers. More than that, in the system, molecules of ethanol break down the continuity of the dimeric layer, intercalating between neighboring dimeric units. This zigzag assembly presented by the molecules of C4diP is related, on one hand, to the diverse non-symmetric hydrogen bonds formed with the three independent lysine molecules and, on the other hand, by the presence of the solvent molecule in the layer.

Fig. 96. Molecular packing of the complex of C4diP with L-lysine along a axis.

109

4.3.7 Crystal structure of calix[4]arene diphosphate complex with chlorhexidine

Biological activity and importance of chlorhexidine was described in Chapter 4.1.5. Crystallographic data for the complex of C4diP with chlorhexidine are presented in Table 21. The asymmetric unit comprises two C4diP molecules (one in the form of dianion and the second in the form of tetraanion), one chlorhexidine molecule, six methanol molecules and eight water molecules (Fig. 97). The charge balance in the co-crystal is achieved by protonation of four imine groups of chlorhexidine and by complexing two potassium cations. The calixarene molecules adopt flattened cone conformation with dihedral angles between substituted phenolic rings and unsubstituted ones of 30.0(5) and 79.5(5) for the first crystallografically independent calixarene, and 28.9(5) and 76.9(5) for the second one.

Fig. 97. Asymmetric unit of C4diP complex with chlorhexidine.

The typical C4diP dimeric unit is composed of two crystallographically independent molecules with the angle of interdigitation of 156.9(1). Due to the interdigitation of two calixarenes forming a dimeric unit, the possibility of inclusion of the active molecule in the aromatic cavity is eliminated. The chlorhexidine is thus complexes outside the cavity, its guanidinium and amine moieties being involved in hydrogen bonds with the polar phosphonate groups of the C4diP molecules (Fig. 98). 110

Table 21. Crystal data and structure refinement for C4diPchlorhexidine.

Molecular formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size range for data collection Index ranges Reflections collected Independent reflections Completeness to = 18.90 Absorption correction Refinement method Data / restraints / parameters 2 Goodness-of-fit on F Final R indices [I > 2(I)] R indices (all data) Absolute structure parameter Extinction coefficient Largest diff. peak and hole

2C28H24O10P2K2C22H34N10Cl26CH3OH8H2O 2074.78 100(2) K 0.71073 Monoclinic Cc a = 26.444(1) b = 13.126(1) = 109.506(6). c = 31.572(3) 10329.8(2) 3 4 1.334 Mgm-3 0.288 mm-1 4344 0.30 0.20 0.15 mm3 2.68 to 18.90. -24 h 24, -11 k 11, -28 l 28 25164 7645 [Rint = 0.063] 98.2 % None 2 Full-matrix least-squares on F 7645 / 2 / 1250 1.00 R = 0.068, wR = 0.161 R = 0.101, wR = 0.177 0.48(9) 0.00038(13) 0.65 and -0.31 e-3

There are also two hydrogen bonds between chlorhexidine nitrogen atoms (donors) and water molecules. The overall structure of the complex is based on the layers of calix[4]arene dimers alternating with hydrophilic layers containing drug molecules and solvated potassium cations (Fig. 99). The aromatic rings of chlorhexidine intercalate into the hydrophobic layers of C4diP molecules and separate neighboring calixarenes. This induced assembly allows interactions of the aromatic chlorophenyl rings of chlorhexidine with the aromatic rings of calix[4]arene dihydroxyphosphonic acid molecules (edge to face interaction with the shortest C-HC distance of 3.593 and edge to edge interaction with the shortest C-HC distance of 3.243). There is also one weak hydrogen bond between aromatic carbon of chlorophenyl ring of drug and phosphonate oxygen of calixarene with C-HO distance of 3.30(2) .

111

Fig. 98 Network of hydrogen bonds generated by chlorhexidine molecule

All these variations in interactions between the crystallizing agent calix[4]arene and chlorhexidine coupled with typical solid-state self-organization of C4diP induce specific S-shape conformation of the active molecule in the co-crystals.

Fig. 99. Molecular packing of C4diP complex with chlorhexidine.

112

4.3.8 Crystal structure of calix[4]arene diphosphate complex with pilocarpine

Pilocarpine (Fig. 100) is a naturally occurring alkaloid obtained from the leaves Pilocarpus jaborandi, a South American shrub. By mimicking the effects of acetylcholine, pilocarpine acts as a stimulant of the parasympathetic nervous system. It is used in the treatment of some types of glaucoma 137. Pilocarpine stimulates the secretion of large amounts of saliva and sweat and is used to treat dry mouth (xerostomia).

Fig. 100. Pilocarpine molecule.

Crystallographic data for the complex of C4diP with pilocarpine are presented in Table 22. The asymmetric unit comprises two C4diP molecule, one pilocarpine molecule, four water molecules and five methanol molecules from which two have partial occupancy and one is disordered over two positions. The calixarene molecules retain flattened cone conformation. The cone angles made by substituted phenolic rings and by unsubstituted ones are 28.0(3) and 75.7(3), respectively, for the first symmetrically independent calixarene, and 25.8(3) and 69.5(3) for the second one. The phenolic oxygen atoms are involved in intramolecular hydrogen bonding that stabilizes the flattened cone conformation. The residual electron density map has not shown the protonation of the nitrogen atoms of the pilocarpine. So, the most probably, the C4diP molecules are in the dihydroxyphosphonic acid form. As expected, the complex is based on the interdigitating dimeric motif of the two symmetrically independent C4diP molecules held together via C-H interactions. The angle of interpenetration is 164.5(2). The overall structure of the complex is based on the layers of calix[4]arene dimers alternating with hydrophilic layers containing pilocarpine and solvent molecules (Fig. 101). C4diP molecules are mainly hydrogen bonded by their phosphonate groups to solvent molecules and C4diP molecules from the neighboring layer. 113

Table 22. Crystal data and structure refinement for C4diPpilocarpine.

Molecular formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size range for data collection Index ranges Reflections collected Independent reflections Completeness to = 23.28 Absorption correction Refinement method Data / restraints / parameters 2 Goodness-of-fit on F Final R indices [I > 2(I)] R indices (all data) Absolute structure parameter Extinction coefficient Largest diff. peak and hole

2C28H26O10P2C11H16N2O23.83CH3OH4H2O 1556.60 100(2) K 0.71073 Monoclinic P21 a = 15.5227(5) b = 13.0524(4) = 109.434(2). c = 18.8840(7) 3608.0(2) 3 2 1.433 Mgm-3 0.195 mm-1 1627 0.20 0.15 0.15 mm3 2.96 to 23.28. 0 h 17, 0 k 14, -20 l 19 33427 5442 [Rint = 0.103] 99.4 % None 2 Full-matrix least-squares on F 5442 / 2 / 971 0.98 R = 0.069, wR = 0.177 R = 0.108, wR = 0.195 0.0(2) 0.0013(9) 0.59 and -0.38 e-3

Fig. 101. View of the molecular packing of the C4diP complex with pilocarpine.

114

Fig. 102. Asymmetric unit of the C4diP with pilocarpine (some solvent molecules omitted for clarity).

A major feature of the structure is face-to-face aromatic-aromatic interaction (Fig. 102) between imidazole ring of pilocarpine and aromatic rings of two C4diP molecules from different layers (3.748(8) and 3.757(7) ). There is also one C-HO hydrogen bond of 3.47(2) between pilocarpine molecule and phosphonate oxygen of the C4diP molecule, and one C-HO hydrogen bond of 3.28(2) between pilocarpine and water molecule.

115

4.4

The role of supramolecular complementarity in the formation of calixarene complexes with biorelevant molecules
Supramolecular complementarity (complementarity of size, shape and charge

between host and guest) plays a dominant role in the formation of host-guest complexes between anionic water-soluble anionic calixarenes and a range of biorelevant molecules with amino groups. Water-soluble calix[4]arenes with predefined macrocyclic cavities carrying anionic groups at the upper or lower rim are good complexing agents for organic amines. Pharmaceutically active molecules that combine aromatic rings, amino and hydrophobic residues in their structure are predisposed to the complexation with anionic calixarenes posessing hydrophobic cavities and multiple sites for cation binding. In the case of p-sulfonatocalix[4]arene (C4S) molecule the sulfonate groups on the upper rim enlarge the size of the cavity. For the calix[4]arene diphosphate (C4diP) molecule, two phosphonate group on the lower rim act as a type of molecular tweezer for cationic groups of the guests. The cone conformation for p-sulfonatocalix[4]arene and calix[4]arene diphosphate molecules, usually stabilized by intramolecular hydrogen bonding between the phenolic groups at the lower rim, is quite rigid, but certain flexibility is still present at the level of aromatic core (cone flattening), so the calix[4]arene molecules adapt themself slightly in order to allow the most favourable interactions with the local environment. C4diP

C4S

Fig. 103. Schematic representation of the p-sulfonatocalix[4]arene and calix[4]arene diphosphate showing polar parts of the molecules.

Various non-covalent interactions may contribute to the formation of host-guest complexes between anionic water-soluble calixarenes and a range of biorelevant molecules with amino groups described in this dissertation. These interactions are: strong and weak hydrogen bonding, - interactions and C-H interactions.

116

p-Sulfonatocalix[4]arene complexes The nature of the complexation (inclusion in the macrocyclic cavity or exo complexation) strongly depends on the nature of the guest, while stoichiometry of the complex depends rather on the charge balance. For example, in the case of melamine that does not posses significant hydrophobic groups, four independent melamine monocations (the stoichiometry of the complex is 1:4) are complexed outside the C4S cavity which is occupied by disordered water molecule. Such water inclusion was previously observed in a few structures of p-sulfonatocalix[4]arene41,42. In the 1:1 p-sulfonatocalix[4]arene complex with hydrophilic triethyltetramine (four amino groups separated by ethyl groups) the guest in the form of a tetracation is also complexed external to the host cavity. In this case the hydrophobic cavity is occupied by a methanol molecule. Interestingly, for the 3:4 p-sulfonatocalix[4]arene complex with another polyamine molecule, norspermidine (bis(3-aminopropyl)amine with three amino groups separated by propyl groups) which is more hydrophobic than triethyltetramine, three different types of complexation are observed. One of the crystallografically independent p-sulfonatocalix[4]arene molecules forms an inclusion complex with one triamine guest, while the remaining two host molecules include simultaneously one end of a norspermidine molecule and a methanol molecule. The last bis(3-aminopropyl)amine guest is complexed external to the host cavities. In the case of 1:2 complex (charge balance undefined) with relatively hydrophobic triethylamine one of the independent guest cations is included in the p-sulfonatocalix[4]arene cavity and the second one is complexed outside the cavity. For the p-sulfonatocalix[4]arene complexes with drugs containing aromatic rings, amine and hydrophobic residues in their structure, the partial inclusion of the active molecule into the macrocyclic cavity of the host is observed. For the chlorhexidine and piribedile the stoichiometry of the complexes is 1:1. In the case of chlorhexidine the aliphatic chain of the drug is situated in the p-sulfonatocalix[4]arene cavity, while for the piribedile the pirimidine ring of the drug is included in the host cavity. For the tamoxifen and tetracaine the stoichiometry of the p-sulfonatocalix[4]arene complexes is 1:4 to satisfy the charge balance. In both complexes only one of the four crystallographically independent drug molecules is included into the p-sulfonatocalix[4]arene cavity by its terminal dimethylammonium group, while the other three are complexed external to the cavity. 117

Complexation of pharmaceutically active molecules is favourized by the complementarity in polarity of the two species: cationic amines of drugs and anionic acids of p-sulfonatocalix[4]arene. The formation of host-guest systems is mainly guided by the formation of strong hydrogen bonds between the ammonium or guanidinium nitrogen atoms of the guests and sulfonate oxygen atoms of the host. The inclusion of the guests is additionally stabilized by a range of weak C-HO, C-H and - interactions. All the complexes show bilayer packing motif of the p-sulfonatocalix[4]arene molecules arranged in alternating up-down antiparallel fashion. The p-sulfonatocalix[4]arene molecules are held together by different types of interactions: - interactions, hydrogen bonds between phenolic and sulfonate groups, C-H and C-HO interactions. In the complexes with chlorhexidine and piribedile the aromatic rings of the guests protrude into hydrophobic part of the p-sulfonatocalix[4]arene bilayers. In the complex with triethylamine the new type of stepped bilayer packing motif was observed.

p-Sulfonatocalix[6]- and p-sulfonatocalix[8]arene complexes In the complexes with bis(6-aminohexyl)amine and dimethylamine

p-sulfonatocalix[6]arene molecule adopt typical centrosymmetric up-down partial cone conformation in which it posseses two pseudo cavities for guest inclusion leading to 1:2 host-guest inclusion stoichiometry. Surprisingly, in the complex with dimethylamine the p-sulfonatocalix[6]arene molecule includes two dimethylformamide (DMF) solvent molecules, while the dimethylammonium cations are complexed external to the cavity. The flexible p-sulfonatocalix[8]arene molecule could be induced to change its conformation significantly by different types of guest molecules. The concept of induced fit is very helpful for illustrating and understanding interesting binding behaviour of this host molecule. The induced fit model of the interaction between enzyme and a substrate was introduced from biological processes to supramolecular systems for explaining the binding behaviour of artificial receptors. The induced fit theory was described by D. E. Koshland 138 and is a development of Fischers wellknown lock and key theory. In the contrast to classical lock and key model where complementary groups are rigidly positioned, in the induced fit model the enzyme changes shape when it reacts. In supramolecular chemistry induced fit is understood in a broad sence by the way in which the introduction of the guest induces conformational 118

changes of the host, and by the way the changed conformation of the host or guest becomes much more adapted for guest binding. In the complex with bulky 1,2-cyclohexanediamine p-sulfonatocalix[8]arene adopts an inverted double cone conformation with two identical partial cones occupied by two guest cations. For the linear 1,4-butanediamine the host is in a conformation of almost planar macrocyclic rings with grooves occupied by elongated 1,4-butanediammonium cations. Structures of these two complexes represent two conformational extremities in the molecular structure of p-sulfonatocalix[8]arene. Such guest induced adaptability of p-sulfonatocalix[8]arene confirms the solution and modelling studies of the p-sulfonatocalix[8]arene complexes with inhibitors of cholinesterases that are formed through mutually induced fit (both host and flexible guest adapt to each other), thus mimicking very closely the binding occuring in the active site of cholinesterases (Fig. 104).

complex guest host

Fig. 104. Mutually induced fit in host-guest complex of C8S with photolabile cholinergic ligands.

In the complex with the small dimethylamine molecule p-sulfonatocalix[8]arene adopts an intermediate conformation between the double inverted cone and the almost planar macrocyclic ring with three of the phenolic rings pointing up from the mean plane of the molecule, three pointing down and the other two of the phenolic rings being self-included in the macrocyclic cavity. In this conformation typical hydrogen bonding between neighboring phenolic rings does not exist. In the contrast to the similar structure of p-sulfonatocalix[6]arene with dimethyamine in the presence of DMF, in the p-sulfonatocalix[8]arene complex host includes dimethyammonium cations, while DMF molecules are complexed exo to the cavity. The host-guest inclusion stoichiometry of the p-sulfonatocalix[8]arene complexes is dependent on the guest size and shape and is: 1:2 for cyclohexanediamine, 1:6 for butanediamine and 1: 4 for dimethylamine. 119

Calix[4]arene diphosphate complexes For the calix[4]arene diphosphate complexes due to the interdigitation of two calixarenes forming a dimeric unit, the possibility of inclusion of the guest molecule in the aromatic cavity is eliminated. The guest molecules are thus complexed outside the cavity with their amino groups being involved in hydrogen bonding with the anionic phosphonate groups of the host. In the complex with melamine the host-guest stoichiometry is 1:3, and melamine monocations form continuous zigzag chains in contrast to the linear chains in the p-sulfonatocalix[4]arene complex. For the cadaverine complex the stoichiometry is 1:1. The solid-state structure of both complexes is generated by typical bilayer motif of calix[4]arene diphosphate molecules separated by hydrophilic regions containing guest molecules and solvent. Calix[4]arene diphosphate forms two different solvates with L-lysine: the first 1:1 calix[4]arene diphosphateL-lysine complex contains water from the crystallization mixture and the second one with the stoichiometry 4:3 contains water and ethanol. The major feature of these two complexes is hydrogen bonding between polar groups of amino acid and phosphonate groups of the host. But the complexes differ significantly by the mode of packing: in the first complex the calix[4]arene diphosphate molecules are packed in typical bilayers separated by double chains of amino acid molecules, while in the second complex lysine molecules generate a 1D ladder network and zigzag layer of calix[4]arene diphosphate dimers replaces the normally observed motif of planar layer, moreover, molecules of ethanol break down the continuity of the dimeric layer, intercalating between neighboring dimeric units. Such interesting variations in the assembly mode are probably caused by the the flexibility of the amino acid chain and availability of many complementary hydrogen bonding sites in the molecule of calix[4]arene diphosphate. Typical solid-state self-organization of calix[4]arene diphosphate into dimeric units induce a specific conformation of the flexible chlorhexidine molecule in the complex. In contrast to the chlorhexidine complex with p-sulfonatocalix[4]arene where it adopts V-shaped conformation due to the partial inclusion in the host cavity, in the presence of calix[4]arene diphosphate the pharmaceutically active molecule is in the S-shaped conformation with aromatic rings intercalating into the hydrophobic layers of calix[4]arene diphosphate molecules and separating neighboring calixarenes.

120

A major feature of the calix[4]arene diphosphatepilocarpine complex structure is face-to-face aromatic-aromatic interaction between imidazol ring of drug and aromatic rings of two calix[4]arene diphosphate molecules. Surprisingly, there are no direct hydrogen bonds between pilocarpine and calixarene phosphonate groups. The calix[4]arene diphosphate complex with dimethylamine obtained from alcohol-DMF system shows a higly interesting structure with two crystallografically independent calix[4]arene diphosphate molecules adopting different conformations: the first calix[4]arene diphosphate molecule is in the typical flattened cone conformation, while the second one adopts unusual conformation where two substituted phenolic rings are inclined to the centre of the macrocyclic cavity and 1,3-intramolecular hydrogen bonding occures at the lower rim.

121

122

CONCLUSIONS
Water-soluble anionic p-sulfonatocalix[n]arenes (n = 4, 6, 8) and calix[4]arene

diphosphate show a great capability to complex bioactive guest molecules containing ammonium functions. The typical self-organisation shown by the calixarene in the solid-state further imposes a specific complexation of the guest molecules: the organization into bilayers of p-sulfonatocalix[4]arene allows the partial inclusion of the guest in the calixarene cavity, while the interdigitation of two calix[4]arene diphosphate molecules forming a dimeric unit eliminates the possibility of guest inclusion in the macrocyclic cavity. In all structures proton transfer from sulfonic or phosphonic acid groups of the host onto nitrogen atom of the guest molecule is observed. So negatively charged receptors form complexes with positively charged guests. In the p-sulfonatocalix[4]arene complexes the guest and solvent molecules compete for being included in the aromatic cavity of the calixarene. The inclusion of the solvent (water or methanol) was observed in the complexes with melamine and triethyltetramine. Such competition was clearly seen in the complex with bis(3aminopropyl)amine (norspermidine) where two types of inclusion complexes were observed: one of the crystallografically independent p-sulfonatocalix[4]arene molecules includes one triamine guest, while the remaining two p-sulfonatocalix[4]arene molecules include simultaneously one end of norspermidine molecule and methanol molecule. For the p-sulfonatocalix[4]arene inclusion complexes with bis(3aminopropyl)amine, triethylamine, chlorhexidine, tetracaine, tamoxifen and piribedil the hydrophobic parts of the guest molecules (aliphatic or aromatic) are located in the aromatic cavity and are held in the place by C-H or - interactions. The position of the organic amine in the cavity allows maximal N-HO hydrogen bonding between the guest polar groups and sulfonate groups of the host. Both exo and endo complexation of organic amines is mainly guided by a range of direct hydrogen bonds between cationic groups of guests and sulfonate groups of the host. For all the calix[4]arene diphosphate complexes the guest molecules are situated external to the macrocyclic cavity and are hydrogen bonded to the phosphonate groups of the host. It was shown that calix[4]arene diphosphate forms two complexes with
L-lysine of different stoichiometry (1:1 and 4:3) and solvation state. It was established

that calix[4]arene diphosphate shows a novel type of self-assembling by forming 123

unusual dimeric structural motif in the complex with dimethylammonium and tetramethylammonium cations in the presence of dimethylformamide. The solid-state structure of all the complexes described during the length of this thesis are generated by bilayer motifs of the calixarene molecules. Some deviations from the typical bilayer organizations were observed: stepped bilayer for the p-sulfonatocalix[4]arene complex with triethylamine or the zigzag bilayer for the calix[4]arene diphosphate complex with L-lysine. The anionic p-sulfonatocalix[4]arene and calix[4]arene diphosphate proved to be good crystallization agents for a range of pharmaceutically active molecules (antibiotics, anticancer and anesthetic). For the p-sulfonatocalix[4]arene complexes with drugs the partial inclusion of the active molecule in the aromatic cavity was observed, while for the calix[4]arene diphosphate the exo complexes are formed. Hydrogen bonding between polar groups of drug and sulfonate or phosphonate groups of the calixarene is usually the dominant interaction in the formation of the complexes with the exception of calix[4]arene diphosphatepilocarpine complex where the face-to-face aromatic-aromatic interaction between imidazol ring of drug and aromatic rings of calix[4]arene diphosphate molecules is responsible for the complexation. The range of weak -, C-H and C-HO interactions between the drug and calixarene further rigidifies the structure of the complexes. The crystallization of the drugs with the aid of water-soluble calixarenes provides an opportunity to modify different characteristics of the active molecule: to improve stability, crystallize amorphous drugs, prevent polymorphism, increase solubility. The co-crystallization of an active pharmaceutical ingredient (API) with different calixarenes gives the possibility to change and control the conformation of the drug: the flexible chlorhexidine molecule adopts V-shaped conformation in the p-sulfonatocalix[4]arene complex and S-shaped in the calix[4]arene diphosphate complex. The use of the calixarenes as co-crystal formers with drugs has great potential in the pharmaceutical domain 139 due to their solubility in water and low toxicity. It was shown that the large p-sulfonatocalix[8]arene molecule can significantly adapt its conformation to the structure of the complexed molecule: from almost planar macrocyclic ring for long butanediamine to double inverted cone for bulky cyclohexanediamine. This ability of changing conformation by the induced fit mechanism confirms the strong promise of this molecule for biopharmaceutical applications.

124

SUMMARY
Self-assembly of water-soluble synthetic receptors with biorelevant molecules is

a powerful tool for the understanding, modelling and mimicking of biological systems and developing new materials with specific properties and functions. Water-soluble calix[n]arenes are deeply involved in molecular recognition of biorelevant compounds, they are of interest in building up systems that mimic natural biological processes and in medicinal applications which include drug delivery and sensing. The aim of this work is the X-ray structural analysis of solid-state complexes of water-soluble anionic calixarenes with organic amines, amino acids and pharmaceutically active molecules. The p-sulfonatocalix[n]arenes (n = 4, 6, 8) and calix[4]arene diphosphate have been chosen due to their good aqueous solubility, low toxicity, interesting biological activities and ability to generate a wide range of structural variations in the solid state. Twenty one solid-state complexes of watersoluble calixarenes with different guest molecules are described in this dissertation. Structural analysis of solid-state complexes of p-sulfonatocalix[4]arene shows that the nature of the complexation (inclusion in the macrocyclic cavity or exo complexation) strongly depends on the nature of the guest. In the complexes with hydrophilic melamine and triethyltetramine the inclusion of the solvent (water or methanol) into the hydrophobic calixarene cavity is observed, while the amine molecules are complexed outside the calixarene cavity. For the p-sulfonatocalix[4]arene complexes with bis(3-aminopropyl)amine, triethylamine and pharmaceutical molecules the hydrophobic parts of the guests are located in the host cavity and are held in the place by C-H or - interactions. Large p-sulfonatocalix[6]arene and p-sulfonatocalix[8]arene have been shown to include two or more guest molecules into the cavity. Moreover, p-sulfonatocalix[8]arene can significantly adapt its conformation to the structure of the complexed molecule: from almost planar macrocyclic ring for long butanediamine to double inverted cone for bulky cyclohexanediamine. This ability of changing conformation by the induced fit mechanism confirms the strong promise of this molecule for biopharmaceutical application. For calix[4]arene diphosphate the guest molecules are complexed outside the cavity with their amino groups being involved in hydrogen bonding with the anionic groups of the host. It was shown that in the DMFalcohol system calix[4]arene 125

diphosphate adopts unusual conformation with two substituted phenolic rings being inclined to the centre of the macrocyclic cavity. The various non-covalent interactions contribute to the formation of host-guest complexes between anionic water-soluble calixarenes and a range of biorelevant molecules with amino groups described in this dissertation. The complexation is mainly guided by direct hydrogen bonds between cationic groups of guests and sulfonate or phosphonate groups of the host. The complexation is additionally stabilized by the range of weak C-HO, C-H and - interactions between guest and host. All the complexes show bilayer packing motif of the calixarene molecules. The calixarene molecules are held together by different types of interactions: hydrogen bonds, -, C-H and C-HO interactions. In some complexes deviations from the typical bilayers are observed: stepped bilayer for the p-sulfonatocalix[4]arene complex with triethylamine or the zigzag bilayer for the calix[4]arene diphosphate complex with
L-lysine.

The water-soluble p-sulfonatocalix[4]arene and calix[4]arene diphosphate proved to be good crystallization agents for the range of pharmaceutically active molecules (chlorhexidine, tetracaine, tamoxifen, piribedil and pilocarpine). The crystallization of the drug with the aid of water-soluble calixarenes provides opportunity to modify and improve characteristics of the pharmaceutically active molecule, to change and control the conformation of the drug.

126

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APPENDIX

Structure p-sulfonatocalix[4]arenemelamine
Table 23. Hydrogen bonds for C4Smelamine ( and ).

D-H...A O(1A)-H(1A)...O(1D) O(1C)-H(1C)...O(1B) O(1C)-H(1C)...O(4C)1 O(1B)-H(1B)...O(8W)2 O(1B)-H(1B)...O(1A) O(1D)-H(1D)...O(3W)3 O(1D)-H(1D)...O(1C) N(3X)-H(3X)...O(1WA) N(4X)-H(4X1)...N(3Y) N(4X)-H(4X2)...O(3B) N(5X)-H(5X1)...O(3B)4 N(5X)-H(5X2)...O(3D)5 N(6X)-H(6X1)...N(2X)5 N(6X)-H(6X2)...O(10W) N(2Y)-H(2Y)...O(2W)6 N(6Y)-H(6Y1)...N(1X) N(6Y)-H(6Y2)...O(9W) N(5Y)-H(5Y1)...N(1W)7 N(5Y)-H(5Y2)...O(3D)4 N(4Y)-H(4Y1)...O(2B) N(4Y)-H(4Y2)...O(2A)8 N(2Z)-H(2Z)...O(4W)6 N(2W)-H(2W)...O(7W)6 N(4Z)-H(4Z1)...O(6W) N(4Z)-H(4Z2)...O(5W) N(4W)-H(4W1)...O(2C)9 N(4W)-H(4W2)...O(2D)10 N(5Z)-H(5Z1)...N(1Z)7 N(5Z)-H(5Z2)...O(5W)7 N(5Z)-H(5Z2)...O(4W)6 N(6W)-H(6W1)...N(3Z)6 N(6W)-H(6W2)...O(6W)6 N(6W)-H(6W2)...O(7W)6 N(6Z)-H(6Z1)...N(3W)6 N(6Z)-H(6Z2)...O(3C)4 N(6Z)-H(6Z2)...O(2C)4 N(5W)-H(5W1)...N(1Y)7 N(5W)-H(5W2)...O(3A)6 O(2W)-H(2WA)...O(4W) O(2W)-H(2WB)...O(1WC)9 O(2W)-H(2WB)...O(9W)6 O(3W)-H(3WA)...O(4C)9 O(3W)-H(3WA)...O(2C)9 O(3W)-H(3WB)...O(2D)10

d(D-H) 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 1.15 1.06 1.06 1.22 1.22 1.20

d(H...A) 1.96 2.04 2.46 1.98 2.50 1.99 2.34 1.84 2.19 2.20 2.41 2.31 2.12 1.93 1.84 2.06 1.97 2.06 2.34 2.30 2.28 1.97 1.92 2.08 2.08 2.12 2.23 2.06 2.14 2.53 2.02 2.07 2.65 2.14 2.01 2.65 2.08 1.95 1.73 1.74 2.26 1.64 2.43 1.64

d(D...A) 2.792(6) 2.786(6) 2.887(6) 2.704(5) 2.969(6) 2.678(6) 2.865(5) 2.709(7) 3.063(7) 2.899(6) 2.995(6) 3.015(7) 2.982(7) 2.736(7) 2.702(6) 2.943(7) 2.823(7) 2.939(7) 2.925(6) 3.145(6) 3.051(6) 2.747(6) 2.779(6) 2.945(6) 2.948(6) 2.919(6) 3.027(6) 2.936(7) 2.816(6) 3.172(7) 2.904(7) 2.760(7) 3.342(7) 3.024(7) 2.878(6) 3.240(7) 2.956(7) 2.828(6) 2.848(7) 2.639(19) 2.979(7) 2.749(6) 3.350(6) 2.819(6)

<(DHA) 170.1 147.2 112.2 143.6 116.5 138.4 121.2 168.3 171.7 136.5 124.2 137.2 166.5 151.7 165.6 176.2 163.3 174.3 123.8 159.9 146.3 146.5 165.1 167.6 168.5 150.0 150.1 174.8 133.1 130.8 177.1 134.8 135.9 176.8 168.3 125.4 177.0 172.5 160.6 139.8 123.7 148.7 130.7 165.8 135

O(4W)-H(4WA)...O(2WA) O(4W)-H(4WB)...O(2D)9 O(5W)-H(5WA)...O(4A)8 O(5W)-H(5WB)...O(3W) O(6W)-H(6WA)...O(8W)8 O(6W)-H(6WB)...O(4C)9 O(6W)-H(6WB)...O(3C)9 O(7W)-H(7WA)...O(2B) O(7W)-H(7WB)...O(3A) O(8W)-H(8WA)...O(2B)11 O(8W)-H(8WB)...O(2A) O(9W)-H(9WA)...O(3B)4 O(9W)-H(9WA)...O(4D)5 O(9W)-H(9WB)...O(2C)4 O(10W)-H(10A)...O(3D) O(10W)-H(10B)...O(4B)11 O(10W)-H(10B)...O(2A)

1.01 0.93 1.14 0.91 0.97 1.11 1.11 0.91 0.82 1.06 0.94 0.85 0.85 0.85 1.04 1.16 1.16

1.78 1.87 1.63 1.90 1.83 1.98 2.17 1.96 1.98 1.74 1.84 2.05 2.66 1.96 1.81 2.02 2.30

2.746(6) 2.795(6) 2.761(6) 2.805(5) 2.790(6) 2.988(6) 3.048(6) 2.840(6) 2.736(6) 2.781(6) 2.770(5) 2.775(6) 3.100(6) 2.764(6) 2.745(6) 2.902(6) 3.127(6)

157.9 173.9 174.8 172.6 167.1 149.6 134.3 162.1 152.2 166.4 169.4 143.4 114.0 158.5 148.0 129.4 125.7

(1) -x+1,-y-1,-z+1; (2) -x,-y,-z+1; (3) -x+1,-y,-z+1; (4) -x+1,-y,-z; (5) -x,-y,-z ; (6) -x+1,-y+1,-z; (7) -x+2,-y+1,-z; (8) x+1,y,z; (9) x,y+1,z; (10) x+1,y+1,z; (11) x-1,y,z

Table 24. - interactions for C4Smelamine ( and ).

Cg(I)Cg(J) AA1 CC2 WX3 WZ XY3 Y...Z

d(Cg(I)Cg(J)) <(Cg(I) Cg(J)) 3.429(3) 0.00 3.733(3) 0.02 3.915(3) 4.20 3.783(3) 8.36 3.799(3) 5.32 3.829(3) 2.35

<(Cg(I)Cg(J)Cg(I)) 19.12 24.91 30.38 26.64 22.48 28.12

<(Cg(I)Cg(J)Cg(J)) 19.12 24.91 26.18 23.46 25.35 26.47

(1) -x,-y,1-z; (2) 1-x,-1-y,1-z; (3) 1-x,1-y,-z

Table 25. C-HO interactions for C4Smelamine ( and ).

D-H...A C4B-H4B...O4D1 C4C-H4C...O2WA2 C4B-H4B...O4D3

d(D-H) 0.95 0.95 0.99

d(H...A) 2.51 2.57 2.52

d(D...A) 3.455(7) 3.481(8) 3.488(7)

<(D-H...A) 172 161 166

(1) 1+x,y,z; (2) x,-1+y,z; (3) -x,-y,1-z

136

Structure p-sulfonatocalix[4]arenetriethylamine
Table 26. Hydrogen bonds for C4Striethylamine ( and ).

D-H...A O(1A)-H(1A)...O(1B) O(1A)-H(1A)...O(4C)2 O(1D)-H(1D)...O(1A) O(1C)-H(1C)...O(1D) O(1B)-H(1B)...O(1C) N(1X)-H(1X1)...O(3D) N(1X)-H(1X1)...S(1D) N(1Y)-H(1Y1)...O(4A) N(1Y)-H(1Y1)...O(4A1) N(1Y)-H(1Y1)...S(1A) O(1W)-H(1W1)...O(4C) O(1W)-H(1W1)...S(1C) O(1W)-H(2W1)...S(1D)1 O(2W)-H(1W2)...O(3A) O(2W)-H(1W2)...O(4A1) O(2W)-H(1W2)...O(4A) O(2W)-H(1W2)...S(1A) O(2W)-H(2W2)...O(3B1)3 O(2W)-H(2W2)...O(3B)3 O(2W)-H(2W2)...S(1B)3

d(D-H) 0.84 0.84 0.84 0.84 0.84 0.91(3) 0.91(3) 0.92(4) 0.92(4) 0.92(4) 0.68(4) 0.68(4) 1.36(4) 1.15(5) 1.15(5) 1.15(5) 1.15(5) 1.11(5) 1.11(5) 1.11(5)

d(H...A) 2.04 2.64 1.90 1.98 1.91 1.85(4) 2.93(4) 1.83(4) 1.90(4) 3.02(4) 1.85(4) 2.88(4) 2.30(4) 1.67(5) 1.80(5) 2.66(5) 2.67(5) 1.41(5) 1.81(5) 2.75(5)

d(D...A) 2.770(3) 3.080(3) 2.706(3) 2.734(3) 2.697(3) 2.753(3) 3.794(3) 2.738(5) 2.765(5) 3.872(3) 2.516(3) 3.496(2) 3.469(2) 2.605(6) 2.826(7) 3.583(7) 3.726(3) 2.489(5) 2.728(5) 3.651(3)

<(DHA) 144.6 114.0 160.7 149.3 156.6 171(3) 160(3) 169(3) 157(3) 154(3) 169(5) 152(4) 142(2) 134(4) 146(4) 137(3) 152(3) 161(4) 136(3) 138(3)

(1) -x-1,-y,-z; (2) x+1,y,z; (3) -x,-y+1,-z+1

Table 27. C-H interactions for C4Striethylamine ( and ).

C-H... C4X-H4X1...B1 C1Y-H1Y2...B

(1) -1+x,-1+y,z

d(C-H) 0.99 0.98

d(H...Cg) 2.61 2.67

d(C...Cg) 3.540(4) 3.638(5)

<(C-H...Cg) 156 168

Table 28. C-HO interactions for C4S triethylamine ( and ).

D-H...A C1X-H1..O4D C6Y-H6Y1...O3C C6Y-H6Y2...O2A11 C2X-H2X2...O3C2 C6X-H6X1...O2B3 C3Y-H3Y2...O3D C3X-H3X3...O2C2 C7A-H7A2...O3C4 C7A-H7A1...O2A15 C4D-H4D...O4B2 C4B-H4B...O4D6 C2C-H2C...O4D6

d(D-H) 0.98 0.99 0.99 0.99 0.99 0.98 0.98 0.99 0.99 0.95 0.95 0.95

d(H...A) 2.50 2.55 2.45 2.52 2.60 2.46 2.59 2.47 2.38 2.55 2.55 2.53

d(D...A) 3.425(4) 3.440(4) 3.141(8) 3.165(4) 3.372(6) 3.400(4) 3.411(4) 3.428(4) 3.341(7) 3.452(6) 3.421(4) 3.380(3)

<(D-H...A) 157 150 126 123 135 161 141 164 164 159 153 150 137

(1) -x,1-y,1-z; (2) x,-1+y,z; (3) -1+x,-1+y,z; (4) 1+x,y,z; (5) 1-x,1-y,1-z; (6) x,1+y,z

Structure p-sulfonatocalix[4]arenetriethyltetramine
Table 29. Hydrogen bonds for C4Striethyltetramine ( and ).

D-H...A O(1D)-H(1D)...O(1W)4 O(1D)-H(1D)...O(1C) O(1A)-H(1A)...O(1D) O(1C)-H(1C)...O(1B) O(1B)-H(1B)...O(1A) N(3X)-H(3X)...O(4B)5 N(3X)-H(3X1)...O(2D) N(3X)-H(3X1)...O(4D)6 N(2X)-H(2X)...O(2A)5 N(2X)-H(2X1)...O(4A)7 N(4X)-H(4X1)...O(2M)4 N(4X)-H(4X2)...O(4D) N(4X)-H(4X3)...O(2C)5 O(1W)-H(1W)...O(2C) O(1W)-H(1W1)...O(2D)2 O(2M)-H(2M)...N(4X)4 O(1M)-H(1M)...O(4C)8 N(1X)-H(1X3)...O(1M)5 N(1X)-H(1X4)...O(3C)1 N(1X)-H(1X5)...O(4M)9 N(1X)-H(1X5)...O(3B)7 N(1X1)-H(1X6)...O(3C)1 N(1X1)-H(1X7)...O(4A)7 N(1X1)-H(1X8)...O(3B)7

d(D-H) 0.84 0.84 0.84 0.84 0.84 0.95(7) 1.02(6) 1.02(6) 1.07(7) 0.83(7) 1.02(8) 0.78(8) 1.26(9) 0.86(8) 0.82(7) 0.84 0.84 0.91 0.91 0.91 0.91 0.91 0.91 0.91

d(H...A) 1.96 2.45 1.91 1.93 1.83 1.85(7) 2.03(6) 2.54(6) 1.77(7) 2.03(7) 2.09(8) 2.16(9) 1.61(9) 2.01(8) 2.04(8) 2.24 2.55 2.41 1.68 2.21 2.45 2.11 2.26 1.80

d(D...A) 2.664(6) 2.951(5) 2.709(5) 2.689(6) 2.672(5) 2.768(7) 2.762(7) 3.149(7) 2.731(7) 2.815(8) 2.842(9) 2.881(8) 2.837(8) 2.823(6) 2.800(6) 2.842(9) 3.009(13) 3.101(17) 2.590(13) 2.791(11) 3.101(14) 2.988(11) 3.095(10) 2.687(10)

<(DHA) 141.0 118.6 158.9 150.4 176.5 164(5) 127(5) 118(4) 148(5) 159(7) 129(6) 153(9) 164(6) 158(7) 155(7) 128.5 115.3 132.5 174.8 120.8 128.7 162.3 153.1 165.8

(1) x+1,y,z; (2) x-1,y,z; (3) -x,-y,-z+2; (4) -x+2,-y+1,-z+1; (5) -x+2,-y,-z+1; (6) -x+3,-y,-z+1; (7) x+1,y,z1; (8) -x+1,-y,-z+1; (9) x+2,y,z-1

Table 30. - interactions for C4Striethyltetramine ( and ).

Cg(I)Cg(J) AA1 CC2

d(Cg(I)Cg(J)) <(Cg(I) Cg(J)) 3.804(4) 0.00 3.514(3) 0.00

<(Cg(I)Cg(J)Cg(I)) 28.72 21.71

<(Cg(I)Cg(J)Cg(J)) 28.72 21.71

(1) 3-x,1-y,2-z; (2) 2-x,1-y,1-z Table 31. C-H interactions for C4Striethyltetramine ( and ).

C-H... C2M-H2M3D1
(1) 2-x,1-y,1-z

d(C-H) 0.98

d(H...Cg) 2.99

d(C...Cg) 3.745(8)

<(C-H...Cg) 135

138

Table 32. C-HO interactions for C4Striethyltetramine ( and ).

D-H...A C3X-H1...O2D C3X-H1...O4D1 C2X-H2...O1M2 C4X-H3...O2D C4X-H3...O3M3 C7B-H7B1...O3C4 C7A-H7A2...O3B5 C5X-H5X1...O2B2 C6X-H6X1...O4C C6X-H6X2...O3D C1M-H1M1...O3A C1M-H1M2...O2B6 C2X-H2X2...O2C3

d(D-H) 0.99 0.99 0.95 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.98 0.98 0.95

d(H...A) 2.58 2.56 2.55 2.55 2.59 2.58 2.53 2.58 2.28 2.46 2.31 2.17 2.58

d(D...A) 3.199(7) 3.137(7) 3.21(1) 2.928(7) 3.535(1) 3.559(9) 3.481(9) 3.30(1) 2.917(9) 2.964(8) 3.03(2) 2.71(1) 3.532(8)

<(D-H...A) 121 117 127 102 160 171 160 129 121 111 130 114 177

(1) 3-x,-y,1-z; (2) 2-x,-y,1-z; (3) 1+x,y,z; (4) 2-x,1-y,1-z; (5) 2-x,1-y,2-z; (6) -1+x,y,z

Structure p-sulfonatocalix[4]arenenorspermidine
Table 33. Hydrogen bonds for C4Snorspermidine ( and ).

D-H...A O(1A1)-H(1A1)...O(1W) O(1B1)-H(1B1)...O(1A1) O(1C1)-H(1C1)...O(1B1) O(1C1)-H(1C1)...O(4B1)1 O(1A)-H(1A)...O(6W)2 O(1A)-H(1A)...O(1D) O(1B)-H(1B)...O(1A) O(1C)-H(1C)...O(4D2) O(1C)-H(1C)...O(1B) O(1D1)-H(1D1)...O(1C1) O(1D)-H(13A)...O(1C) N(3W)-N(3W1)...O(2C1)3 N(3W)-N(3W1)...O(2M)3 N(3W)-N(3W2)...O(5W) N(3W)-N(3W3)...O(2M) N(1W)-H(1N1)...O(4C1) N(1W)-H(2N1)...O(8W)3 N(1W)-H(3N1)...O(4B) N(2W)-H(2W1)...O(4B2)4 N(2W)-H(2W2)...O(4A1)3 O(1D2)-H(1D2)...O(1A2) O(1A2)-H(1A2)...O(8W)3 O(1A2)-H(1A2)...O(1B2) O(1B2)-H(1B2)...O(1C2) O(1C2)-H(1C2)...O(4B) O(1C2)-H(1C2)...O(1D2)

d(D-H) 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.94(5) 0.94(5) 0.90(6) 0.84(5) 1.04(5) 0.91(6) 0.97(6) 0.91(5) 0.98(5) 0.84 0.84 0.84 0.84 0.84 0.84

d(H...A) 1.94 1.87 2.26 2.33 1.95 2.51 1.86 2.13 2.33 1.88 1.86 1.98(5) 2.49(5) 1.98(5) 2.08(6) 1.76(6) 1.87(6) 1.84(6) 2.00(5) 1.92(5) 1.90 1.96 2.41 1.92 2.10 2.41

d(D...A) 2.687(4) 2.692(4) 2.805(4) 2.988(5) 2.679(4) 2.941(4) 2.677(4) 2.785(4) 2.816(4) 2.713(4) 2.697(4) 2.859(5) 3.079(5) 2.798(5) 2.879(5) 2.798(5) 2.762(5) 2.784(5) 2.816(5) 2.806(5) 2.731(4) 2.685(4) 2.829(4) 2.739(4) 2.763(4) 2.842(4)

<(DHA) 147.4 165.7 122.7 135.3 143.8 112.7 163.9 135.0 117.2 169.5 170.6 155(4) 121(4) 150(4) 160(5) 174(4) 170(5) 165(4) 149(4) 150(4) 169.5 144.7 111.7 163.7 136.0 113.0 139

N(1X)-H(1X1)...O(1M)2 N(1X)-H(1X1)...O(3C2)4 N(1X)-H(1X1)...O(2C2)4 N(1X)-H(1X2)...O(11W)3 N(1X)-H(1X3)...O(2C) N(2X)-H(2X1)...O(2D1) N(2X)-H(2X2)...O(5W) N(3X)-H(3X2)...O(1W)4 N(3X)-H(3X2)...O(2A)5 N(3X)-H(3X3)...O(4M) N(3X)-H(3X3)...O(4B1)3 N(2Y)-H(2Y1)...O(3A2)4 N(2Y)-H(2Y1)...O(3C) N(2Y)-H(2Y2)...O(3C2)4 N(1Y)-H(1Y2)...O(2D2)4 N(1Y)-H(1Y2)...O(7W)6 N(1Y)-H(1Y1)...O(3D) N(1Y)-H(1Y3)...O(3D2)7 N(3Y)-H(3Y1)...O(3B2)4 N(3Y)-H(3Y2)...O(4W)8 N(3Y)-H(3Y3)...O(2C) N(3Y)-H(3Y3)...O(3W) N(1Z)-H(1Z1)...O(6W)6 N(1Z)-H(1Z2)...O(4C)9 N(1Z)-H(1Z3)...O(4D2)4 N(2Z)-H(2Z4)...O(5M) N(2Z)-H(2Z3)...O(2A1)5 O(1M)-H(1M)...O(3A)10 O(2M)-H(2M)...O(3A1)3 O(1W)-H(1W1)...O(4D1)11 O(1W)-H(1W2)...O(4A)11 O(5W)-H(5W1)...O(3D1) O(5W)-H(5W2)...O(2B) O(6W)-H(6W1)...O(2B2)4 O(6W)-H(6W2)...O(4A1)3 O(8W)-H(8W1)...O(2A2)12 O(8W)-H(8W2)...O(4D)5 O(11W)-H(11W)...O(3B2)1 O(11W)-H(11Q)...O(2B1) N(3Z)-H(3Z3)...O(13W) N(3Z)-H(3Z4)...O(3D1)5 N(3Z)-H(3Z5)...O(2W) N(3Z1)-H(3Z7)...O(3A) N(3Z1)-H(3Z8)...O(3D) O(8M)-H(8M)...O(10W)13 O(4M)-H(4M)...O(2C2)4

0.92(6) 0.92(6) 0.92(6) 0.90(6) 0.93(6) 0.94(5) 0.93(5) 0.91 0.91 0.91 0.91 0.93(5) 0.93(5) 0.76(5) 0.96(6) 0.96(6) 1.14(6) 1.14(6) 0.91 0.91 0.91 0.91 0.96(6) 1.19(6) 0.83(6) 0.92 0.92 0.84 0.84 0.74(6) 0.90(6) 0.87(6) 0.77(6) 0.90(6) 0.79(5) 0.88(6) 0.73(6) 0.92(7) 0.61(7) 0.91 0.91 0.91 0.91 0.91 0.84 0.84

1.99(6) 2.45(5) 2.60(5) 1.98(6) 1.94(6) 1.95(6) 2.33(5) 2.15 2.39 2.16 2.42 2.11(5) 2.45(5) 2.08(5) 2.19(6) 2.28(6) 1.84(6) 1.65(6) 1.93 2.29 2.08 2.35 1.93(6) 1.65(6) 1.95(6) 1.78 1.87 1.97 2.14 2.03(6) 1.83(6) 1.94(6) 2.05(6) 1.82(6) 1.97(6) 1.80(6) 2.03(6) 1.88(7) 2.18(7) 2.17 2.04 2.25 1.92 2.12 1.90 1.97

2.814(6) 2.960(5) 3.101(5) 2.857(6) 2.861(5) 2.891(6) 2.987(5) 2.843(6) 2.970(6) 2.931(9) 2.955(7) 2.861(5) 2.934(5) 2.804(5) 2.973(5) 2.848(6) 2.977(6) 2.785(5) 2.809(5) 3.037(9) 2.859(5) 2.939(6) 2.826(5) 2.837(6) 2.782(5) 2.622(10) 2.776(6) 2.808(5) 2.899(4) 2.766(5) 2.715(5) 2.785(5) 2.808(4) 2.716(4) 2.761(4) 2.672(5) 2.751(5) 2.796(6) 2.799(5) 2.735(13) 2.866(10) 2.861(12) 2.804(11) 3.026(11) 2.733(9) 2.733(6)

148(5) 115(4) 115(4) 163(5) 170(5) 177(5) 127(4) 132.6 121.3 142.6 118.0 137(4) 113(4) 159(5) 139(5) 117(4) 174(4) 171(5) 162.9 138.8 142.6 122.1 155(5) 175(5) 177(6) 151.4 167.7 171.2 150.2 172(6) 166(5) 165(5) 169(6) 174(5) 173(5) 170(5) 172(6) 177(6) 177(10) 119.7 150.4 124.3 164.5 173.0 171.8 149.8

(1) -x,-y+1,-z+1; (2) x,y+1,z; (3) -x+1,-y+1,-z+1; (4) x+1,y,z; (5) -x+2,-y+2,-z+1; (6) x+1,y+1,z; (7) -x+1,-y+2,-z; (8) -x,-y+1,-z; (9) -x+2,-y+2,-z; (10) x,y-1,z; (11) -x+1,-y+2,-z+1; (12) x+1,y,z+1 (13) x-1,y,z-1

140

Table 34. - interactions for C4Snorspermidine ( and ).

Cg(I)Cg(J) A1A1
(1) 1-x,2-y,1-z

d(Cg(I)Cg(J)) <(Cg(I) Cg(J)) 3.677(3) 1.97

<(Cg(I)<(Cg(I)Cg(J)Cg(I)) Cg(J)Cg(J)) 23.73 21.90

Table 35. C-H interactions for C4Snorspermidine ( and ).

C-H... C7B1-H14AB11 C7B-H14CD2 C7C-H21BC2 C5W-H5V1B13 C7C2-H21FB C4Y-H4Y1C24 C4Y-H4Y2A24 C5Y-H5Y2...B24 C2M-H4M2...D11

d(C-H) 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.98

d(H...Cg) 2.94 3.00 2.92 2.91 2.97 2.93 2.83 2.84 2.99

d(C...Cg) 3.366(6) 3.442(6) 3.579(5) 3.748(6) 3.464(6) 3.913(5) 3.805(5) 3.750(5) 3.606(5)

<(C-H...Cg) 107 109 125 143 112 173 170 154 122

(1) -x,1-y,1-z; (2) 1-x,2-y,-z; (3) 1-x,1-y,1-z; (4) 1+x,y,z

Table 36. C-HO interactions for C4Snorspermidine ( and ).

D-H...A C7D-H28A...O6W1 C7D1-H28C...O1W C2D1-H23B...O2B C6W-H6V2...O3B12 C3W-H3V2...O3B C4W-H4V1...O3C1 C2A2-H2C...O2D3 C4B2-H11C...O2B14 C7A2-H7C2...O8W2 C1X-H81...O3B C3X-H87...O11W2 C4X-H4X1...O4A C4X-H4X2...O3B12 C2Y-H96...O2D25 C1Y-H97...O5M C6Y-H6Y1...O3A25 C1Z-H1Z1...O7W5 C2Z-H2Z2..O2D25 C4Z-H4Z1...O4D C4Z-H4Z2...O4C15 C6Z-H6Z2...O3A16 C4M-H4M6...O1D15

d(D-H) 0.99 0.99 0.95 0.99 0.99 0.99 0.95 0.95 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.98

d(H...A) 2.54 2.53 2.34 2.41 2.46 2.54 2.44 2.43 2.56 2.51 2.37 2.30 2.57 2.59 2.49 2.41 2.56 2.54 2.50 2.50 2.51 2.55

d(D...A) 3.504(6) 3.499(6) 3.266(5) 3.315(7) 3.187(6) 3.428(6) 3.312(6) 3.334(6) 3.511(6) 3.460(6) 3.183(7) 3.168(6) 3.073(6) 3.331(6) 3.310(9) 3.220(6) 3.406(8) 3.358(6) 3.485(8) 3.259(9) 3.30(1) 3.32(1)

<(D-H...A) 166 166 163 152 130 149 153 158 161 161 139 146 111 132 140 139 143 140 177 134 136 136

(1) x,1+y,z; (2) 1-x,1-y,1-z; (3) 1-x,2-y,-z; (4) -x,1-y,1-z; (5) 1+x,y,z; (6) 2-x,2-y,1-z

141

Structure p-sulfonatocalix[4]arenechlorhexidine
Table 37. Hydrogen bonds for C4Schlorhexidine ( and ).

D-H...A O(1A)-H(1A)...O(1B) O(1B)-H(1B)...O(1C) O(1C)-H(1C)...O(1D) O(1D)-H(1D)...O(1A) N(1X)-H(1X)...O(3W)1 N(2X)-H(2X)...O(2D)2 N(2X)-H(2X1)...O(4W) N(3X)-H(3X)...O(4A)3 N(4X)-H(4X)...O(1W) N(4X)-H(4X1)...O(3C) N(5X)-H(5X)...O(3B) N(6X)-H(6X)...O(6W)4 N(7X)-H(7X)...O(2B)3 N(7X)-H(7X1)...O(2A) N(8X)-H(8X)...O(4D)5 N(9X)-H(9X)...O(4C)2 N(9X)-H(9X)...O(2C)2 N(9X)-H(9X1)...O(2M) N(10X)-H(10X)...O(4D)5 N(10X)-H(10X)...O(3D)5 O(1W)-H(1W)...O(3C)2 O(1W)-H(1W1)...O(2D)2 O(2W)-H(2W)...O(3A) O(2W)-H(2W1)...O(3A)3 O(3W)-H(3W)...O(4D)5 O(3W)-H(3W1)...O(2B)3 O(3W)-H(3W1)...O(4B)3 O(4W)-H(4W)...O(5W)3 O(4W)-H(4W1)...O(2C) O(5W)-H(5W)...O(1M)6 O(5W)-H(5W1)...O(4B)3 O(6W)-H(6W)...O(2C)3 O(6W)-H(6W1)...O(3M) O(2M)-H(2M)...O(2W)3

d(D-H) 0.77(5) 0.69(5) 0.65(5) 0.74(5) 0.69(5) 0.79(5) 0.89(5) 0.72(4) 0.80(4) 0.93(5) 0.84(4) 0.78(4) 0.96(6) 0.84(5) 0.81(5) 0.76(5) 0.76(5) 0.89(5) 0.81(5) 0.81(5) 0.85(5) 0.68(5) 0.91(5) 0.84(5) 0.89(5) 0.93(5) 0.93(5) 0.92(6) 1.10(6) 1.15(6) 0.80(6) 1.02(6) 0.83(6) 0.92(7)

d(H...A) 1.91(5) 2.02(5) 2.12(5) 1.96(5) 2.07(5) 2.29(5) 1.93(5) 2.04(5) 2.01(5) 1.99(5) 2.04(4) 2.12(5) 1.82(6) 2.04(5) 2.12(5) 2.57(5) 2.61(5) 1.84(5) 2.56(5) 2.65(5) 2.09(5) 2.29(5) 1.95(5) 2.10(5) 1.99(5) 2.06(5) 2.42(5) 1.89(6) 1.69(6) 1.80(6) 2.03(6) 1.97(6) 1.95(6) 1.78(7)

d(D...A) 2.643(4) 2.692(4) 2.719(4) 2.690(4) 2.750(5) 2.947(5) 2.810(5) 2.752(4) 2.799(5) 2.898(5) 2.847(4) 2.886(5) 2.785(5) 2.822(5) 2.890(5) 3.076(5) 3.290(5) 2.726(5) 3.120(5) 3.422(7) 2.898(4) 2.934(5) 2.853(4) 2.879(4) 2.877(5) 2.902(4) 3.219(5) 2.802(5) 2.778(5) 2.868(5) 2.808(5) 2.944(5) 2.774(5) 2.670(5)

<(DHA) 159(5) 168(6) 153(7) 167(5) 171(6) 142(4) 174(4) 177(5) 171(5) 164(4) 161(4) 171(5) 179(5) 156(5) 160(4) 125(4) 150(5) 174(4) 128(5) 162(5) 159(4) 161(6) 174(5) 153(5) 171(5) 150(4) 145(4) 171(5) 167(4) 151(4) 162(6) 159(5) 170(6) 162(6)

(1) x,y+1,z; (2) -x+1,-y+1,-z+2; (3) -x+1,-y+1,-z+1; (4) x,y,z+1; (5) -x+1,-y,-z+2; (6) -x+1,-y,-z+1

Table 38. - interactions for C4Schlorhexidine ( and ).

Cg(I)Cg(J) BB1
(1) 2-x,1-y,1-z

d(Cg(I)Cg(J)) <(Cg(I) Cg(J)) 3.639(3) 0.03

<(Cg(I)<(Cg(I)Cg(J)Cg(I)) Cg(J)Cg(J)) 23.42 23.42

142

Table 39. C-H interactions for C4Schlorhexidine ( and ).

C-H... C7C-H7C1D1 C7C-H7C2D1 C7D-H7D2X12 C11X-H11AA C12X-H12AD C22X-H22XC3

d(C-H) 0.99 0.99 0.99 0.99 0.99 0.95

d(H...Cg) 2.83 2.96 2.72 2.74 2.59 2.75

d(C...Cg) 3.259(5) 3.259(5) 3.564(5) 3.526(5) 3.540(5) 3.455(6)

<(C-H...Cg) 107 99 143 136 161 132

(1) 2-x,-y,2-z; (2) 1+x,-1+y,z; (3) -1+x,y,z Table 40. C-HO and C-HCl interactions for C4Schlorhexidine ( and ).

D-H...A C7B-H7B1..Cl2X11 C19X-H19X...O5W2 C2M-H2M1O4C1

(1) 1-x,1-y,2-z; (2) x,y,1+z

d(D-H) 0.99 0.95 0.98

d(H...A) 2.81 2.55 2.44

d(D...A) 3.509(5) 3.421(6) 3.252(4)

<(D-H...A) 128 152 140

Structure p-sulfonatocalix[4]arenetetracaine
Table 41. Hydrogen bonds for C4Stetracaine ( and ).

D-H...A O(1A)-H(1A)...O(8W)1 O(1B)-H(1B)...O(1A) O(1D)-H(1D)...O(1C) O(1C)-H(1C)...O(1B) N(2X)-H(2X)...O(11W) N(2W)-H(2W)...O(6W)2 N(1W)-H(1W)...O(1WA)2 N(2Y)-H(2Y)...O(2X) N(1Y)-H(1Y)...O(4W)3 N(1Z)-H(1Z)...O(4B)4 N(1Z)-H(1Z)...O(9W) N(2Z)-H(2Z)...O(2W)5 N(1X)-H(1X)...O(2A)

d(D-H) 0.84 0.84 0.84 0.84 0.73(8) 0.89 1.15(9) 0.92(8) 1.08(10) 0.84(8) 0.84(8) 1.01(8) 1.12

d(H...A) 1.98 1.93 1.97 1.99 2.34(8) 2.10 1.50(10) 2.03(9) 1.73(10) 2.10(8) 2.48(8) 2.00(8) 1.70

d(D...A) 2.756(7) 2.756(6) 2.746(5) 2.744(5) 3.051(9) 2.958(9) 2.642(11) 2.945(8) 2.788(11) 2.847(8) 3.039(7) 2.982(10) 2.808(7)

<(DHA) 153.7 168.6 153.6 149.4 166(9) 163.8 171(7) 175(7) 164(8) 148(8) 125(7) 164(6) 166.6

(1) -x+1,-y+1,-z; (2) x+1,y,z; (3) -x+1,-y+1,-z+1; (4) x,y-1,z; (5) -x+2,-y+1,-z+1

Table 42. - interactions for C4Stetracaine ( and ).

Cg(I)Cg(J) AA1 DD2

d(Cg(I)Cg(J)) <(Cg(I) Cg(J)) 3.792(4) 0.00 3.566(8) 0.02

<(Cg(I)Cg(J)Cg(I)) 23.96 23.08

<(Cg(I)Cg(J)Cg(J)) 23.96 23.08

(1) 1-x,1-y,-z; (2) -x,1-y,-z

143

Table 43. C-H interactions for C4Stetracaine ( and ).

C-H... C4W-H4W2X C12Y-H12EY1 C13X-H13BW C13Y-H13FW2 C14W-H14DX3 C15X-H15AZ C1X-H1X1D C1X-H1X2A

d(C-H) 0.99 0.99 0.99 0.99 0.99 0.99 0.98 0.98

d(H...Cg) 2.70 2.81 2.84 2.97 2.84 2.88 2.99 2.82

d(C...Cg) 3.61(1) 3.631(9) 3.733(9) 3.883(8) 3.75(1) 3.72(1) 3.700(9) 3.76(1)

<(C-H...Cg) 154 141 151 154 154 144 130 161

(1) 1-x,2-y,1-z; (2) -1+x,y,z; (3) 1+x,y,z

Table 44. C-HO interactions for C4Stetracaine ( and ).

D-H...A C7A-H7A2...O7W1 C7D-H7D1...O8W1 C8Z-H8ZO2W2 C10X-H10XO11W C11X-H11XO2A C2W-H2W1O2C3 C2W-H2W3O3B C1Y-H1Y1O2Z2 C1Y-H1Y3O2C4 C1Z-H1Z1O2Y5 C2Z-H2Z3O2Y5 C3X-H3X2O4C

d(D-H) 0.99 0.99 0.95 0.95 0.95 0.98 0.98 0.98 0.98 0.98 0.98 0.99

d(H...A) 2.48 2.30 2.57 2.57 2.43 2.44 2.47 2.37 2.38 2.52 2.39 2.32

d(D...A) 3.42(1) 3.273(9) 3.35(1) 3.33(1) 3.364(7) 3.21(1) 3.31(1) 3.28(1) 3.35(1) 3.37(1) 3.27(1) 3.18(2)

<(D-H...A) 160 168 140 137 167 136 144 154 169 146 150 146

(1) 1-x,1-y,-z; (2) 2-x,1-y,1-z; (3) 1+x,y,z; (4) 1-x,2-y,1-z; (5) 1-x,1-y,1-z

Structure p-sulfonatocalix[4]arene-tamoxifen
Table 45. Hydrogen bonds for C4Stamoxifen ( and )

D-H...A O(1C)-H(1C)...O(8W) O(1D)-H(1D)...O(1A) O(1D)-H(1D)...O(4W1)1 O(1A)-H(1A)...O(1WA)2 O(1A)-H(1A)...O(1B) O(1B)-H(1B)...O(1A) O(1B)-H(1B)...O(1WA)2 N(1W)-H(1W)...O(3D) N(1Z)-H(1Z)...O(4B1)3 N(1Z)-H(1Z)...O(4B)3 N(1X)-H(1X)...O(3A) N(1Y)-H(1Y)...O(3B) N(1Y)-H(1Y)...O(2B1)

d(D-H) 0.84 0.84 0.84 0.84 0.84 0.84 0.84 1.00(5) 1.09(6) 1.09(6) 0.88(6) 0.93 0.93

d(H...A) 2.05 2.14 2.23 2.04 2.38 2.23 2.59 1.79(5) 1.72(6) 1.81(6) 1.91(6) 1.95 2.11

d(D...A) 2.874(13) 2.883(6) 2.717(9) 2.722(6) 2.947(6) 2.947(6) 3.234(6) 2.772(6) 2.73(2) 2.861(14) 2.788(6) 2.794(9) 2.821(11)

<(DHA) 167.9 148.0 116.7 137.8 125.7 143.2 134.3 165(5) 151(5) 161(5) 172(6) 150.4 131.8

(1) -x+1,-y+1,-z; (2) x-1,y,z-1; (3) x+1,y,z

144

Table 46. - interactions for C4Stamoxifen ( and ).

Cg(I)Cg(J) AA1 DD2

d(Cg(I)Cg(J)) <(Cg(I) Cg(J)) 3.767(4) 0.03 3.982(4) 0.03

<(Cg(I)Cg(J)Cg(I)) 22.29 24.16

<(Cg(I)Cg(J)Cg(J)) 22.29 24.16

(1) -x,1-y,-z; (2) -x,-y,-z Table 47. C-H interactions for C4Stamoxifen ( and ).

C-H... C10W-H10WX2 C4Z-H4Z1W11 C16X-H16XZ32 C16Y-H16YW3 C16Z-H16ZX33 C2W-H2W2X1 C3X-H3X2Y1 C4X-H4X1...Y2 C1X-H1X2...A C4Y-H4Y2...Z24 C3Y-H3Y1...Z14

d(C-H) 0.95 0.99 0.95 0.95 0.95 0.98 0.99 0.99 0.98 0.99 0.99

d(H...Cg) 2.97 2.84 2.89 2.84 2.81 2.72 2.76 2.93 2.89 2.63 2.56

d(C...Cg) 3.696(7) 3.565(7) 3.765(7) 3.643(7) 3.643(7) 3.506(7) 3.712(7) 3.909(7) 3.827(7) 3.609(7) 3.523(6)

<(C-H...Cg) 134 131 153 143 146 137 161 170 161 169 165

(1) x,-1+y,z; (2) x,1+y,z; (3) 1+x,y,z; (4) -1+x,y,z Table 48. C-HO interactions for C4Stamoxifen ( and ).

D-H...A C7A-H7A2O1WA1 C3Z-H3Z2O2B2 C1W-H1W1...O2A C14Y-H14Y...O3C C2W-H2W1...O9W C2Z-H2Z3...O2D3 C4X-H4X2...O3D C1X-H1X1...O3D C4Y-H4Y1...O3A C2Y-H2Y1...O3C4 C2Y-H2Y2...O1Z4 C2Y-H2Y3...O7W4 C1Y-H1Y1...O3W4 C1Y-H1Y2...O3A C1Y-H1Y3...O4W4 C1Z-H1Z1...O4D3 C1Z-H1Z3...O2B2 C1Z-H1Z3...O1C5

d(D-H) 0.99 0.99 0.98 0.95 0.98 0.98 0.99 0.98 0.99 0.98 0.98 0.98 0.98 0.98 0.98 0.98 0.98 0.98

d(H...A) 2.41 2.50 2.57 2.36 2.58 2.59 2.53 2.51 2.57 2.55 2.56 2.43 2.52 2.50 2.41 2.52 2.45 2.47

d(D...A) 3.386(8) 3.106(9) 3.462(8) 3.146(8) 3.453(8) 3.519(8) 3.400(7) 3.481(8) 3.533(7) 3.352(8) 3.394(8) 3.30(1) 3.38(1) 3.355(9) 3.15(1) 3.359(8) 3.13(1) 3.063(8)

<(D-H...A) 168 119 151 141 149 159 147 170 164 140 143 147 147 146 132 144 126 118

(1) -1+x,y,-1+z; (2) 1+x,y,z; (3) x,-1+y,z; (4) -1+x,y,z; (5) 1-x,-y,-z

145

Structure p-sulfonatocalix[4]arenepiribedil
Table 49. Hydrogen bonds for C4Spiribedil ( and ).

D-H...A O(1A)-H(1A)...O(8W) O(1D)-H(1D)...O(1C) O(1B)-H(1B)...O(1A) O(1C)-H(1C)...O(1B) O(1C)-H(1C)...O(7W)10 N(3X)-H(3X)...O(2W)11 N(1X)-H(1X)...O(4D) N(4X)-H(4X)...O(13W)12 O(10W)-H(10W)...O(11W) O(10W)-H(100)...O(2A1)2 O(10W)-H(100)...O(2A)2 O(10W)-H(100)...O(2X)2 O(9W)-H(9W)...O(10W)13 O(9W)-H(9W)...O(2X)4 O(9W)-H(9W1)...O(6W)4 O(8W)-H(8W)...O(3C)14 O(8W)-H(8W1)...O(4B)8 O(12W)-H(12W)...O(4W) O(5W)-H(5W)...O(3A) O(5W)-H(5W)...O(3A1) O(5W)-H(5W)...O(4A1) O(5W)-H(5W1)...O(12W)

d(D-H) 0.84 0.84 0.84 0.84 0.84 0.88 0.91 0.99 1.05 0.83 0.83 0.83 0.95 0.95 1.07 0.95 0.81 1.13 0.99 0.99 0.99 1.06

d(H...A) 2.04 1.91 1.90 1.96 2.51 2.30 1.86 1.83 1.70 2.12 2.30 2.66 2.17 2.40 2.27 1.89 1.97 2.52 1.96 2.35 2.47 1.86

d(D...A) 2.815(7) 2.681(7) 2.732(7) 2.743(7) 3.024(8) 2.911(8) 2.728(8) 2.719(8) 2.702(7) 2.89(3) 2.964(19) 3.144(8) 2.750(7) 2.911(7) 3.114(7) 2.825(7) 2.758(7) 3.340(15) 2.935(14) 3.31(3) 3.27(3) 2.870(9)

<(DHA) 152.8 151.1 169.1 154.1 120.8 126.9 160.7 148.5 159.1 154.0 138.0 119.0 118.1 113.6 134.1 167.6 162.0 128.8 168.1 162.6 137.8 159.8

(1) -x+1,-y,-z+1; (2) -x+1,-y+1,-z+1; (3) -x+1,y+1/2,-z+3/2; (4) x-1,-y+1/2,z-1/2; (5) x,y,z-1; (6) -x+1,y-1/2,-z+3/2; (7) x,y,z+1; (8) x+1,-y+1/2,z+1/2; (9) -x+2,-y,-z+2; (10) x,-y+1/2,z-1/2; (11) -x+2,-y,-z+1; (12) x,y-1,z; (13) -x,y-1/2,-z+1/2; (14) x,-y+1/2,z+1/2 Table 50. - interactions forC4Spiribedil ( and ).

Cg(I)Cg(J) CX21
(1) 2-x,-y,1-z

d(Cg(I)Cg(J)) <(Cg(I) Cg(J)) 3.968(4) 8.19

<(Cg(I)<(Cg(I)Cg(J)Cg(I)) Cg(J)Cg(J)) 21.95 28.59

Table 51. C-H interactions for C4Spiribedil ( and ).

C-H... C14X-H14XD1 C16X-H16XB1

(1) 2-x,-y,1-z

d(C-H) 0.95 0.95

d(H...Cg) 2.52 2.93

d(C...Cg) 3.41(1) 3.81(1)

<(C-H...Cg) 156 155

Table 52. C-HO interactions for C4Spiribedil ( and ).

D-H...A C2B-H2BO2D1 C2D-H2DO2B2 C7D-H7D2O8W 146

d(D-H) 0.95 0.95 0.99

d(H...A) 2.59 2.39 2.60

d(D...A) 3.52(1) 3.30(1) 3.57(1)

<(D-H...A) 166 160 167

C7A-H7A1...O3D1 C10X-H10A...O13W3 C1X-H1X2...O4A C11X-H11B...O5W2 C9X-H9X1...O3W C12X-H12B...O6W2 C12X-H12B...O7W2 C9X-H9X2...O4C4 C8X-H8X1...O2C5 C8X-H8X1...O3C5

0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99

2.55 2.31 2.44 2.39 2.51 2.49 2.54 2.35 2.58 2.44

3.49(1) 3.26(1) 3.25(2) 3.31(1) 3.29(2) 3.29(1) 3.25(1) 3.14(1) 3.52(1) 3.26(1)

159 160 138 155 135 137 129 136 160 139

(1) -1+x,y,z; (2) 1+x,y,z; (3) x,-1+y,z; (4) 2-x,-y,1-z; (5) 1+x,y,1+z

Structure p-sulfonatocalix[6]arenebis(6-aminohexyl)amine
Table 53. Hydrogen bonds for C6Sbis6aminohexylamine ( and ).

D-H...A O(1C)-H(1C)...O(1A)1 O(1B)-H(1B)...O(1C) O(1A)-H(1A)...O(2B)2 N(1X)-H(1X1)...O(1W)3 N(1X)-H(1X1)...O(2C)4 N(1X)-H(1X2)...O(3A)5 N(1X)-H(1X3)...O(5W)6 N(2X)-H(2X3)...O(2B)7 N(2X)-H(2X4)...O(3W) N(3X)-H(3X5)...O(3B)8 N(3X)-H(3X4)...O(4W1) N(3X)-H(3X3)...O(4C)9 N(1)-H(1E)...O(3A1)5 N(1)-H(1F)...O(1W)3 N(1)-H(1F)...O(2C1)4 N(2)-H(2F)...O(3W1) N(2)-H(2G)...O(4W)8 N(3)-H(3C)...O(2W)7 N(3)-H(3D)...O(3B)8 N(3)-H(3E)...O(4W)

d(D-H) 0.84 0.84 0.84 0.91 0.91 0.91 0.91 0.92 0.92 0.92 0.92 0.92 0.91 0.91 0.91 0.92 0.92 0.94 0.94 0.94

d(H...A) 1.90 1.94 1.78 2.09 2.26 2.02 1.88 2.27 1.78 2.90 2.43 2.19 1.76 1.62 2.46 1.79 1.82 2.17 2.36 1.54

d(D...A) 2.612(7) 2.762(8) 2.567(8) 2.84(2) 3.14(3) 2.875(19) 2.78(2) 3.14(2) 2.69(3) 3.33(12) 2.86(12) 2.99(10) 2.65(3) 2.29(3) 3.01(3) 2.71(5) 2.59(4) 2.95(6) 3.15(6) 2.31(5)

<(DHA) 142.0 167.8 155.2 138.4 161.8 155.3 168.6 158.5 170.5 110.0 108.6 146.1 163.8 127.4 118.9 178.6 139.9 139.8 141.6 136.6

(1) -x-1,-y+1,-z+1; (2) -x,-y+1,-z+1; (3) x,y-1,z; (4) x,y-1,z-1; (5) x+1,y-1,z; (6) -x+1,-y,-z; (7) -x,-y,-z; (8) -x-1,-y,-z; (9) x-1,y,z-1 Table 54. C-H interactions for C6Sbis6aminohexylamine ( and ).

C-H... C1X-H1X4A1 C1-H1HA1

(1) -x,-y,-z

d(C-H)

d(H...Cg) 2.55 2.64

d(C...Cg) 3.44(3) 3.56(5)

<(C-H...Cg) 149 157

Table 55. C-HO interactions for C6Sbis6aminohexylamine ( and ).

D-H...A C2A-H2A...O2A1

d(D-H) 0.95

d(H...A) 2.55

d(D...A) 3.47(2)

<(D-H...A) 163 147

C4B-H4B...O4B2 C4C-H4C...O2A3 C12X-H12B...O3B4 C5X-H5X2..O1W5

0.95 0.95 0.99 1.00

2.53 2.57 2.55 2.50

3.42(1) 3.50(2) 3.31(1) 3.35(5)

157 164 133 143

(1) -1-x,1-y,-z; (2) -x,-y,1-z; (3) x,y,1+z; (4) -1-x,-y,-z; (5) -x,-y,-z

Structure p-sulfonatocalix[6]arenedimethylamine
Table 56. Hydrogen bonds for C6Sdimethylamine ([ and ].

D-H...A O(1B)-H(1B)...O(1C) O(1C)-H(1C)...O(4A)2 N(1Y)-H(1Y4)...O(1S)3 N(1Y)-H(1Y4)...O(2C) N(1Y)-H(1Y5)...O(3B)4 N(1X)-H(1X1)...O(4B) N(1X)-H(1X1)...O(2B) N(1X)-H(1X2)...O(3C)5 N(1Z)-H(1Z4)...O(3A)6 N(1Z)-H(1Z5)...O(3C) N(1Z)-H(1Z5)...O(2C)

d(D-H) 0.84 0.84 0.92 0.92 0.92 0.92 0.92 0.92 0.92 0.92 0.92

d(H...A) 1.80 1.75 2.13 2.34 1.93 2.00 2.49 2.00 1.93 2.07 2.32

d(D...A) 2.641(5) 2.592(5) 2.961(7) 2.806(6) 2.834(6) 2.916(6) 3.083(6) 2.773(7) 2.846(8) 2.861(7) 3.149(8)

<(DHA) 176.1 174.8 150.3 111.0 167.6 172.6 122.6 140.3 174.3 143.4 150.3

(1) -x,-y+2,-z+1; (2) x,y,z-1; (3) -x,-y+1,-z+1; (4) -x+1,-y+1,-z+1; (5) x,y,z+1; (6) x,y-1,z-1 Table 57. C-H interactions for C6Sdimethylamine ( and ).

C-H... C2S-H2S1C C2S-H2S2B

d(C-H) 0.98 0.98

d(H...Cg) 2.95 2.68

d(C...Cg) 3.633(5) 3.521(7)

<(C-H...Cg) 128 144

Table 58. C-HO interactions for C6Sdimethylamine ( and ).

D-H...A C2C-H2C...O3B1 C7A-H7A2...O1S2 C7B-H7B1...O3A3 C2Y-H2Y1...O4B C1Z-H1Z1...O2B1 C1Y-H1Y1...O4C4 C2Z-H2Z1...O4A1 C1X-H21...O4C4 C2X-H2X3...O4C4 C3S-H3S1...O2A5

d(D-H) 0.95 0.99 0.99 0.98 0.98 0.98 0.98 0.98 0.98 0.98

d(H...A) 2.42 2.49 2.43 2.39 2.43 2.58 2.58 2.49 2.59 2.42

d(D...A) 3.358(7) 3.429(7) 3.393(7) 3.308(8) 3.144(9) 3.514(9) 3.409(8) 3.374(9) 3.469(9) 3.369(7)

<(D-H...A) 169 158 165 156 129 160 142 150 150 164

(1) 1-x,1-y,1-z; (2) -x,2-y,1-z; (3) 1-x,2-y,1-z; (4) -x,1-y,1-z; (5) -x,2-y,2-z

148

Structure p-sulfonatocalix[8]arenecyclohexanediamine
Table 59. Hydrogen bonds for C8Scyclohexanediamine ( and )

D-H...A N(1X)-H(1X1)...O(3B)2 N(1X)-H(1X1)...O(4C)3 N(1X)-H(1X2)...O(2A)1 N(1X)-H(1X3)...O(4W) N(2X)-H(2X1)...O(4C)3 N(2X)-H(2X2)...O(3D)3 N(2X)-H(2X3)...O(3W) N(1Y)-H(1Y1)...O(2W)4 N(1Y)-H(1Y2)...O(3C)5 N(1Y)-H(1Y3)...O(1W)6 N(1Y)-H(1Y3)...O(4D)1 N(2Y)-H(2Y1)...O(3A)6 N(2Y)-H(2Y2)...O(1W) N(2Y)-H(2Y3)...O(2B)7 N(2Y)-H(2Y3)...O(2C)5 O(1B)-H(1B)...O(1C) O(1C)-H(1C)...O(1D) O(1D)-H(1D)...O(4A)

d(D-H) 0.91 0.91 0.91 0.91 0.91 0.91 0.91 0.91 0.91 0.91 0.91 0.91 0.91 0.91 0.91 0.84 0.84 0.84

d(H...A) 1.99 2.55 1.87 1.93 2.08 1.96 1.90 1.87 2.02 2.08 2.48 2.08 1.94 2.18 2.38 1.91 1.89 1.83

d(D...A) 2.789(14) 3.160(15) 2.771(14) 2.794(14) 2.989(15) 2.824(15) 2.757(16) 2.742(15) 2.871(16) 2.879(14) 3.018(14) 2.919(14) 2.811(16) 2.829(15) 3.016(15) 2.731(12) 2.666(12) 2.603(12)

<(DHA) 145.7 124.9 168.8 158.3 175.4 159.0 155.3 161.0 154.4 145.9 117.7 152.3 159.6 127.2 126.5 165.5 152.8 152.5

(1) -x,-y,-z+1; (2) -x,-y,-z+2; (3) -x+1,-y,-z+2; (4) x-3/2,-y-1/2,z-1; (5) x-1,y,z-1; (6) x-1/2,-y-1/2,z; (7) x-1/2,-y-1/2,z-1 Table 60. - interactions for C8Scyclohexanediamine ( and ).

Cg(I)Cg(J) BC1
(1) -1/2+x,-1/2-y,z

d(Cg(I)Cg(J)) <(Cg(I) Cg(J)) 3.655(7) 6.10

<(Cg(I)<(Cg(I)Cg(J)Cg(I)) Cg(J)Cg(J)) 15.93 10.19

Table 61. C-H interactions for C8Scyclohexanediamine ( and ).

C-H... C6X-H6X1B

d(C-H) 0.99

d(H...Cg) 2.97

d(C...Cg) 3.86(1)

<(C-H...Cg) 151

Table 62. C-HO interactions for C8Scyclohexanediamine ( and ).

D-H...A C1X-H1X...O3W1 C1Y-H1Y...O4D2 C2X-H2X...O4B C2Y-H2Y...O2C3 C7D-H7D2...O2D4 C3X-H3X1...O4W C4Y-H4Y2...O4A5 C5Y-H5Y1...O1B5 C6Y-H6Y2...O4D2

d(D-H) 1.00 1.00 1.00 1.00 0.99 0.99 0.99 0.99 0.99

d(H...A) 2.57 2.44 2.43 2.39 2.50 2.56 2.47 2.48 2.51

d(D...A) 3.30(2) 2.98(2) 3.30(2) 3.12(2) 3.27(2) 3.43(2) 3.46(2) 3.46(2) 3.14(2)

<(D-H...A) 130 113 145 129 135 146 175 171 121 149

(1) -x,-y,2-z; (2) -x,-y,1-z; (3) -1+x,y,-1+z; (4) 1-x,-y,1-z; (5) -1/2+x,-1/2-y,z

Structure p-sulfonatocalix[8]arenedimethylamine
Table 63. Hydrogen bonds for C8Sdimethylamine ( and ).

D-H...A O(1B)-H(1B)...O(3A)2 O(1D)-H(1D)...O(1S)1 O(1A)-H(1A)...O(3C) O(1C)-H(1C)...O(2D)3 N(1X)-H(1X1)...O(2A) N(1X)-H(1X2)...O(2B)4 N(1X)-H(1X2)...O(3B)5 N(1Z)-H(1Z1)...O(3D)6 N(1Z)-H(1Z1)...O(2B) N(1Z)-H(1Z2)...O(3B)7 N(1Y)-H(1Y1)...O(4B) N(1Y)-H(1Y2)...O(2D)6 N(1W)-H(1W1)...O(4C) N(1W)-H(1W2)...O(3C)1

d(D-H) 0.84 0.84 0.84 0.84 0.92 0.92 0.92 0.92 0.92 0.92 0.92 0.92 0.92 0.92

d(H...A) 1.94 1.91 2.07 2.05 1.81 2.05 2.41 1.94 2.61 1.96 1.90 1.88 1.97 1.97

d(D...A) 2.708(7) 2.590(6) 2.856(6) 2.701(6) 2.723(7) 2.795(8) 3.112(8) 2.764(7) 3.086(8) 2.864(7) 2.820(7) 2.789(8) 2.780(7) 2.847(7)

<(DHA) 150.6 136.5 154.9 133.7 169.9 137.2 133.5 147.5 112.5 168.2 172.6 170.0 146.1 159.6

(1) -x,-y,-z-1; (2) x-1,y,z; (3) x-1,y+1,z; (4) -x+1,-y,-z; (5) x+1,y-1,z; (6) x,y+1,z; (7) -x,-y+1,-z Table 64. C-H interactions for C8Sdimethylamine ( and ).

C-H... C3S-H3S3D1 C2X-H2X1A C1Z-H1Z3B2

(1) -1+x,y,z; (2) -x,1-y,-z

d(C-H) 0.98 0.98 0.98

d(H...Cg) 2.96 2.87 2.83

d(C...Cg) 3.415(9) 3.760(8) 3.722(9)

<(C-H...Cg) 110 152 151

Structure p-sulfonatocalix[8]arenebutanediamine
Table 65. Hydrogen bonds for C8Sbutanediamine ( and ).

D-H...A O(1A)-H(1A)...O(1D)1 O(1B)-H(1B)...O(1A) O(1C)-H(1C)...O(1B) O(1D)-H(1D)...O(1C) N(1Z)-H(1Z1)...O(4D1)3 N(1Z)-H(1Z2)...O(1M1) N(1Z)-H(1Z3)...O(4A1)2 N(1X)-H(1X2)...O(2A1)4 N(1Y)-H(1Y1)...O(2W) N(1Y)-H(1Y2)...O(3C) N(1Y)-H(1Y2)...O(4C1) N(1Y)-H(1Y3)...O(2C1)5 N(1Y)-H(1Y3)...O(4C)5

d(D-H) 0.84 0.84 0.84 0.84 0.91 0.91 0.91 0.91 0.91 0.91 0.91 0.91 0.91

d(H...A) 1.93 1.90 1.84 1.94 1.86 2.28 2.10 2.68 1.95 1.75 2.10 2.07 2.40

d(D...A) 2.732(12) 2.712(13) 2.670(13) 2.730(12) 2.75(3) 2.910(19) 2.91(3) 3.08(6) 2.83(4) 2.65(4) 2.81(4) 2.91(3) 3.15(3)

<(DHA) 158.3 162.1 167.4 155.4 165.0 126.3 148.9 107.4 159.5 171.1 133.2 152.6 141.0

(1) -x+1,y,-z+1/2; (2) -x+1/2,-y+1/2,-z; (3) x-1/2,-y+1/2,z-1/2; (4) x+1/2,-y+1/2,z+1/2; (5) -x+1,y,-z+3/2

150

Table 66. C-HO interactions for C8Sbutanediamine ( and ).

D-H...A C7A-H7A1...O2D1 C7B-H7B2...O3C12 C7C-H7C2...O4A3 C7D-H7D1...O2C4 C7D-H7D2...O3B14

d(D-H) 0.99 0.99 0.99 0.99 0.99

d(H...A) 2.37 2.52 2.54 2.50 2.56

d(D...A) 3.33(4) 3.46(3) 3.40(3) 3.47(3) 3.55(3)

<(D-H...A) 162 158 145 167 172

(1) -1/2+x,1/2-y,-1/2+z; (2) 1-x,1-y,1-z; (3) 1/2+x,1/2-y,1/2+z; (4) x,1-y,-1/2+z

Structure calix[4]arene diphosphatepotassium salt

Table 67. Hydrogen bonds for C4diPpotassium ( and ).

D-H...A O(1B)-H(1B)...O(1A) O(3A)-H(3A)...O(10W)4 O(1D)-H(1D)...O(1A) O(3C)-H(3C)...O(4W)5 O(1W)-H(1WA)...O(1B)3 O(1W)-H(1WB)...O(8W)2 O(2W)-H(2WA)...O(3C)6 O(2W)-H(2WA)...O(4W) O(2W)-H(2WB)...O(11W)7 O(4W)-H(4WA)...O(10W)8 O(4W)-H(4WB)...O(3C)6 O(5W)-H(5WB)...O(4C)9 O(5W)-H(5WA)...O(3A)1 O(6W)-H(6WA)...O(1M)1 O(7W)-H(7WA)...O(6W) O(7W)-H(7WB)...O(11W)10 O(8W)-H(8WA)...O(5W)9 O(8W)-H(8WB)...O(1W)1 O(9W)-H(9WA)...O(3A)4 O(10W)-H(10A)...O(11W) O(10W)-H(10B)...O(1M)10 O(11W)-H(11B)...O(7W)7 O(11W)-H(11B)...O(2W)10

d(D-H) 0.84 0.84 0.84 0.84 0.85 0.85 0.85 0.85 0.92 0.85 0.85 1.01 0.96 0.85 0.85 0.85 0.95 0.95 0.85 0.85 0.85 0.85 0.85

d(H...A) 2.15 1.93 2.13 2.54 2.00 2.39 2.13 2.24 2.35 2.05 2.78 1.67 2.14 2.04 2.64 1.98 2.40 1.90 1.95 2.03 2.24 2.01 2.43

d(D...A) 2.962(11) 2.65(2) 2.707(11) 3.00(3) 2.821(13) 2.810(14) 2.623(16) 2.83(3) 2.856(19) 2.53(3) 3.00(3) 2.676(12) 2.889(14) 2.68(3) 3.49(2) 2.72(2) 3.249(15) 2.810(14) 2.737(15) 2.72(2) 2.69(4) 2.72(2) 2.856(19)

<(DHA) 163.2 143.2 125.1 115.9 163.5 111.3 117.0 126.0 114.4 115.2 97.4 172.7 134.7 132.1 173.1 145.9 148.5 159.1 153.3 138.2 113.2 141.2 111.8

(1) x,y-1,z; (2) x,y+1,z; (3) -x+2,-y+1,-z; (4) -x+1,-y+1,-z; (5) -x+2,y-1/2,-z+1/2; (6) -x+2,y+1/2,-z+1/2; (7) -x+1,y+1/2,-z+1/2; (8) x+1,y,z; (9) -x+2,-y,-z; (10) -x+1,y-1/2,-z+1/2

Structure calix[4]arene diphosphatedimethylamine

Table 68. Hydrogen bonds for C4diPdimethylamine( and ).

D-H...A O(1C)-H(1C)...O(1B) O(1A)-H(1A)...O(1D)1 O(4B1)-H(4B1)...O(2D) O(4D1)-H(4D1)...O(2B)

d(D-H) 0.84 0.84 0.84 0.84

d(H...A) 2.08 2.04 1.77 1.78

d(D...A) 2.879(6) 2.858(6) 2.571(6) 2.602(7)

<(DHA) 158.5 163.4 159.7 167.6 151

O(3B)-H(3B)...O(3B1) O(3D)-H(3D)...O(3D1) O(1C1)-H(1C1)...O(1A1) O(1A1)-H(1A1)...O(1S) N(1X)-H(1X1)...O(2B) N(1X)-H(1X2)...O(2D) N(1Y)-H(1Y1)...O(4D)2 N(1Y)-H(1Y2)...O(2D1) N(1Z)-H(1Z1)...O(4B)3 N(1Z)-H(1Z2)...O(2D1)

0.84 0.84 0.84 0.84 0.92 0.92 0.92 0.92 0.92 0.92

1.67 1.70 2.35 1.82 1.82 1.83 1.76 1.85 1.75 1.84

2.461(7) 2.531(7) 2.939(6) 2.654(7) 2.743(8) 2.730(8) 2.665(8) 2.756(8) 2.663(9) 2.732(9)

156.6 169.0 127.8 169.2 176.7 166.9 166.2 167.1 169.7 163.9

(1) x,y,z-1; (2) -x+1,-y+1,z-1/2; (3) -x+1,-y+1,z+1/2 Table 69. C-H interactions for C4diPdimethylamine ( and ).

C-H... C1X-H1X1B C3S-H3S2A11

(1) 1-x,2-y,1/2+z

d(C-H) 0.98 0.98

d(H...Cg) 2.93 2.79

d(C...Cg) 3.848(9) 3.67(1)

<(C-H...Cg) 156 150

Table 70. C-HO interactions for C4diPdimethylamine ( and ).

D-H...A C1S-H1S...O1C1 C2-H2G...O2B1 C3-H3E...O4D1 C3-H3F...O4B2 C7C1-H7C2...O3D3 C7A1-H7A4...O3B C1X-H34...O3B1 C2X-H2X2...O3D1 C1Y-H39...O4B11

d(D-H) 0.81 0.98 0.98 0.98 0.99 0.99 0.98 0.98 0.98

d(H...A) 2.53 1.78 2.53 2.35 2.55 2.52 2.56 2.52 2.55

d(D...A) 3.315(9) 2.454(9) 3.06(1) 3.25(1) 3.382(8) 3.405(8) 3.353(9) 3.241(8) 3.36(1)

<(D-H...A) 162 123 114 152 142 148 138 130 140

(1) 1-x,1-y,-1/2+z; (2) 1-x,1-y,1/2+z; (3) x,1+y,z

Structure calix[4]arene diphosphatemelamine

Table 71. Hydrogen bonds for C4diPmelamine ( and ).

D-H...A O(1A)-H(1A)...O(1B) O(2D)-H(2DO)...O(2B)1 O(1C)-H(1C)...O(1B) O(1C)-H(1C)...O(3B) N(1X)-H(1X)...O(1W) N(6X)-H(6X1)...N(2X)2 N(6X)-H(6X2)...O(8W)3 N(6X)-H(6X2)...O(6W)4 N(4X)-H(4X1)...N(3X)5 N(4X)-H(4X2)...O(1W) N(4X)-H(4X2)...O(2W) N(5X)-H(5X1)...O(2W)2 N(5X)-H(5X2)...O(6W)2 152

d(D-H) 0.84 1.11 0.84 0.84 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88

d(H...A) 1.92 1.45 2.12 2.50 1.83 2.14 2.18 2.66 2.09 2.34 2.46 2.31 2.17

d(D...A) 2.725(4) 2.542(4) 2.797(4) 3.187(3) 2.678(4) 3.023(5) 2.882(5) 3.259(4) 2.966(5) 3.059(4) 3.165(5) 3.148(4) 3.003(5)

<(DHA) 158.9 166.0 136.9 139.7 159.7 176.4 136.8 126.5 174.6 138.5 137.0 158.6 157.5

N(1Y)-H(1Y)...O(3B) N(6Y)-H(6Y1)...N(2Z)4 N(6Y)-H(6Y2)...O(1S) N(4Y)-H(4Y1)...N(3Z) N(4Y)-H(4Y2)...O(4B) N(5Y)-H(5Y1)...O(9W)6 N(5Y)-H(5Y2)...O(3W)6 N(1Z)-H(1Z)...O(4D)7 N(6Z)-H(6Z1)...N(2Y) N(6Z)-H(6Z2)...O(3W)6 N(6Z)-H(6Z2)...O(4D)7 N(5Z)-H(5Z2)...O(1S)8 N(5Z)-H(5Z1)...O(8W) N(4Z)-H(4Z1)...N(3Y)8 N(4Z)-H(4Z2)...O(3D)7 O(1S)-H(1S)...O(3D)3 O(1S)-H(1S)...O(2D)3 O(1W)-H(1W1)...O(3B)3 O(1W)-H(1W2)...O(1D)3 O(1W)-H(1W2)...O(1A)3 O(2W)-H(2W1)...O(4D)3 O(2W)-H(2W2)...O(1C)3 O(3W)-H(3W1)...O(2B) O(3W)-H(3W1)...O(4B) O(3W)-H(3W2)...O(4W) O(4W)-H(4W1)...O(2W) O(4W)-H(4W2)...O(5W) O(5W)-H(5W2)...O(2B) O(6W)-H(6W1)...O(4W) O(6W)-H(6W2)...O(9W) O(7W)-H(7W1)...O(4B) O(7W)-H(7W2)...O(5W) O(8W)-H(8W2)...O(6W)9 O(8W)-H(8W1)...O(4B) O(9W)-H(9W1)...O(7W) O(9W)-H(9W2)...O(3D)10

0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.84 0.84 0.85 1.01 1.01 0.85 0.85 1.06 1.06 0.90 0.85 0.85 1.19 0.85 0.85 1.20 1.10 0.85 0.85 0.85 1.10

1.84 2.15 2.17 2.19 1.97 1.99 2.09 1.84 2.13 2.21 2.54 2.05 2.16 2.26 2.04 1.99 2.61 1.89 2.11 2.30 1.91 2.24 1.98 2.37 1.91 1.97 2.36 1.61 1.92 2.01 1.61 1.88 1.99 1.96 1.87 1.67

2.691(4) 3.023(5) 2.844(4) 3.063(5) 2.843(4) 2.806(4) 2.944(5) 2.691(4) 3.003(5) 2.886(4) 3.221(4) 2.908(4) 2.888(4) 3.133(5) 2.895(4) 2.770(4) 3.291(4) 2.722(4) 2.968(4) 3.079(4) 2.759(4) 3.048(4) 2.972(4) 3.201(4) 2.791(6) 2.799(5) 3.049(5) 2.779(4) 2.726(5) 2.821(4) 2.790(4) 2.897(5) 2.725(4) 2.731(4) 2.704(4) 2.755(4)

163.7 173.0 132.9 173.4 168.9 154.7 163.7 161.8 172.2 133.3 134.9 166.2 139.1 174.0 164.3 153.6 138.9 165.0 141.7 133.1 172.4 157.8 154.3 133.8 165.5 164.0 138.5 167.2 156.5 158.6 166.8 151.2 143.9 150.1 168.2 171.6

(1) x,-y+1/2,z+1/2; (2) -x+1,y-1/2,-z+1/2; (3) x,-y+1/2,z-1/2; (4) x,y-1,z; (5) -x+1,y+1/2,-z+1/2; (6) -x+1,-y+1,-z+1; (7) -x+1,y+1/2,-z+3/2; (8) x,y+1,z; (9) x,-y+3/2,z+1/2; (10) x,-y+3/2,z-1/2 Table 72. - interactions for C4diPmelamine ( and ).

Cg(I)Cg(J) XY1 XZ2 YZ2

d(Cg(I)Cg(J)) <(Cg(I) Cg(J)) 3.720(2) 4.39 3.620(2) 2.22 3.770(2) 2.38

<(Cg(I)Cg(J)Cg(I)) 30.29 27.68 29.12

<(Cg(I)Cg(J)Cg(J)) 26.20 25.53 27.29

(1) x,1/2-y,-1/2+z; (2) 1-x,1-y,1-z

153

Structure calix[4]arene diphosphatecadaverine

Table 73. Hydrogen bonds for C4diPcadaverine ( and ).

D-H...A O(1C1)-H(1C1)...O(1D1) O(1A1)-H(1A1)...O(1B1)1 O(2D1)-H(2D1)...O(4B)2 O(4B1)-H(4B1)...O(3D)3 O(2B)-H(2B)...O(1M)4 O(1A)-H(1A)...O(1D) O(1C)-H(1C)...O(1D) O(4D)-H(4D)...O(4M) O(4D)-H(4D)...O(2W) O(2M)-H(2M)...O(2B1)1 O(1M)-H(1M)...O(3D1)3 N(2Y)-H(2Y1)...O(3B1)5 N(2Y)-H(2Y2)...O(1W)6 N(2Y)-H(2Y3)...O(4M)6 N(2X)-H(2X1)...O(3W) N(2X)-H(2X2)...O(3D1) N(2X)-H(2X3)...O(3D1)1 N(2X1)-H(2X4)...O(3D1)1 N(2X1)-H(2X5)...O(3W) N(2X1)-H(2X5)...O(4B)2 N(2X1)-H(2X6)...O(3D1) N(1Y)-H(1Y3)...O(3D)7 N(1Y)-H(1Y2)...O(4D1)8 N(1Y)-H(1Y1)...O(2M)9 N(1X)-H(1N1)...O(2D1)1 N(1X)-H(1N2)...O(3B1) N(1X)-H(1N3)...O(3B)10

d(D-H) 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 1.08 0.92 1.08 0.91 0.91 0.91 0.91 0.91 0.91 0.91 1.11 1.11 0.95 1.00 1.06 1.17

d(H...A) 2.06 2.01 1.65 1.80 1.75 2.03 2.21 1.78 1.78 1.85 1.94 1.86 2.19 2.54 1.99 1.84 2.19 1.98 1.68 2.39 2.00 1.79 1.66 1.96 2.18 1.70 1.67

d(D...A) 2.876(4) 2.833(4) 2.477(4) 2.630(4) 2.574(4) 2.845(4) 2.937(4) 2.612(9) 2.553(6) 2.683(4) 2.773(5) 2.736(6) 2.761(7) 3.491(11) 2.869(12) 2.748(8) 2.983(8) 2.824(12) 2.291(15) 3.140(15) 2.894(13) 2.887(5) 2.734(5) 2.790(6) 2.898(5) 2.747(5) 2.815(5)

<(DHA) 163.2 165.6 167.9 167.9 165.3 163.7 144.8 169.4 151.4 169.4 171.5 135.1 119.0 145.7 160.8 177.1 144.9 154.1 121.3 139.2 168.9 168.5 163.6 144.5 126.9 167.9 166.6

(1) -x+2,-y+2,-z; (2) x+1,y+1,z; (3) -x+2,-y+1,-z; (4) x-1,y,z; (5) x-1,y-1,z+1; (6) -x+1,-y,-z+1; (7) -x,-y,-z+1; (8) -x+1,-y+1,-z+1; (9) -x,-y+1,-z+1; (10) -x+1,-y+1,-z

Table 74. C-H interactions for C4diPcadaverine ( and ).

Cg(I)Cg(J) BB1
(1) -x,1-y,1-z

d(Cg(I)Cg(J)) <(Cg(I) Cg(J)) 3.909(3) 0.02

<(Cg(I)<(Cg(I)Cg(J)Cg(I)) Cg(J)Cg(J)) 34.29 34.29

Table 75. C-HO interactions for C4diPcadaverine ( and ).

C-H... C2D1-H3A1 C3B-H3BD2 C2B-H2BC2 C4B-H4BA2 C3B1-H3B1D11 C1M-H1M3D13 C2M-H2M3B1 154

d(C-H) 0.95 0.95 0.95 0.95 0.95 0.98 0.98

d(H...Cg) 2.84 2.88 2.94 2.91 2.99 2.63 2.95

d(C...Cg) 3.765(5) 3.493(5) 3.801(6) 3.824(5) 3.681(5) 3.495(6) 3.691(6)

<(C-H...Cg) 165 124 152 161 131 147 134

(1) 1-x,1-y,-z; (2) -x,1-y,1-z; (3) 2-x,1-y,-z

Structure calix[4]arene diphosphateL-lysine (I)

Table 76. Hydrogen bonds for C4diPlysine (I) ( and ).

D-H...A O(1A)-H(1A)...O(1B) O(1C)-H(1C)...O(1D) O(2B)-H(2BO)...O(2D)1 O(3D)-H(3DO)...O(4B)2 O(1W)-H(1W)...O(1C) O(1W)-H(2W)...O(3B) O(1X)-H(1)...O(3B)#2 N(1X)-H(1N1)...O(4B)3 N(1X)-H(2N1)...O(1W)4 N(2X)-H(1N2)...O(3B)5 N(2X)-H(2N2)...O(2D)6 N(2X)-H(3N2)...O(4D)4

d(D-H) 0.86(6) 0.98(6) 0.85(6) 0.72(7) 0.86(7) 0.84(7) 0.87(6) 0.95(6) 1.09(6) 0.81(7) 0.96(7) 0.87(7)

d(H...A) 1.82(7) 1.70(6) 1.70(7) 1.84(7) 1.99(7) 2.09(7) 1.73(7) 2.01(6) 1.68(6) 2.16(7) 1.85(7) 1.96(7)

d(D...A) 2.673(5) 2.658(5) 2.537(5) 2.557(5) 2.841(6) 2.890(6) 2.585(5) 2.916(6) 2.723(7) 2.956(6) 2.796(6) 2.796(6)

<(DHA) 172(6) 168(6) 169(6) 171(7) 173(6) 161(6) 166(6) 159(5) 160(5) 170(6) 167(5) 161(6)

(1) x+1,y,z; (2) -x+1,-y,-z; (3) -x+1,-y-1,-z; (4) x,y-1,z; (5) x-1,y-1,z; (6) -x,-y-1,-z Table 77. C-H interactions for C4diPlysine (I) ( and ).

C-H... C5X1-H5Y2C1
(1) x,-y,-z

d(C-H) 0.99

d(H...Cg) 2.66

d(C...Cg) 3.58(1)

<(C-H...Cg) 155

Structure calix[4]arene diphosphateL-lysine (II)

Table 78. Hydrogen bonds for C4diPlysine (II) ( and ).

D-H...A O(1A)-H(1A)...O(1B) O(2B)-H(2B)...O(2E) O(1C)-H(1C)...O(2W) O(2D)-H(2D)...O(2D3) O(1A2)-H(1A2)...O(1D2) O(2B2)-H(2B2)...O(3W) O(1C2)-H(1C2)...O(1B2) O(3D2)-H(3D2)...O(1Z)1 O(1A3)-H(1A3)...O(1B3) O(3B3)-H(3B3)...O(1X) O(3B3)-H(3B3)...O(2X) O(1C3)-H(1C3)...O(1D3) O(4D3)-H(4D3)...O(3B2)2 O(1A1)-H(1A1)...O(1B1) O(1A1)-H(1A1)...O(1C1) O(3B1)-H(3B1)...O(1E) O(4D1)-H(4D1)...O(4B2)3 N(1Y)-H(1Y1)...O(3B) N(1Y)-H(1Y2)...O(4B1)

d(D-H) 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.91 0.91

d(H...A) 2.23 1.81 2.31 1.75 2.01 2.00 2.03 1.80 2.04 1.76 2.56 1.97 1.77 2.00 2.78 1.84 1.72 2.07 2.01

d(D...A) 3.026(8) 2.634(11) 2.842(8) 2.487(8) 2.807(9) 2.507(9) 2.795(9) 2.591(10) 2.787(9) 2.549(10) 3.263(9) 2.792(8) 2.599(10) 2.813(9) 3.110(8) 2.658(10) 2.520(8) 2.872(10) 2.851(9)

<(DHA) 159.3 166.8 121.9 145.8 156.9 118.2 150.4 156.2 148.5 155.5 142.3 164.1 168.5 163.6 105.7 164.5 159.1 146.0 153.8 155

N(1Y)-H(1Y2)...O(2X) N(1Y)-H(1Y3)...O(4D)3 N(2Y)-H(2Y1)...O(2D1) N(2Y)-H(2Y2)...O(2D2)4 N(2Y)-H(2Y3)...O(4B)3 N(1Z)-H(1Z1)...O(1A2)3 N(1Z)-H(1Z2)...O(6W) N(1Z)-H(1Z3)...O(4W) N(2Z)-H(2Z1)...O(1A3)5 N(2Z)-H(2Z2)...O(2D3)5 N(2Z)-H(2Z2)...O(2W)5 N(2Z)-H(2Z3)...O(4B3)5 O(1E)-H(1E)...O(3B3) O(2E)-H(2E)...O(2B) O(1W)-H(1W1)...O(4B3) O(1W)-H(2W1)...O(3B) N(1X)-H(1X1)...O(4B) N(1X)-H(1X2)...O(2B1) N(1X)-H(1X3)...O(2D1)1 N(2X)-H(2X1)...O(4B1)1 N(2X)-H(2X2)...O(3B3)1 N(2X)-H(2X2)...O(2B3)1 N(2X)-H(2X3)...O(4D) N(2X1)-H(2X5)...O(3B3)1 N(2X1)-H(2X6)...O(4D) N(2X1)-H(2X6)...O(2D)

0.91 0.91 0.91 0.91 0.91 0.91 0.91 0.91 0.91 0.91 0.91 0.91 0.84 0.84 1.12 1.04 0.91 0.91 0.91 0.91 0.91 0.91 0.91 0.91 0.91 0.91

2.34 1.85 1.90 1.98 1.89 2.23 1.80 1.85 2.21 2.13 2.31 1.88 1.77 2.20 1.47 1.50 2.09 1.95 1.87 1.92 2.31 2.40 1.96 2.58 2.01 2.56

2.834(10) 2.741(8) 2.805(10) 2.856(11) 2.784(10) 3.129(10) 2.700(9) 2.711(9) 3.057(10) 2.925(10) 2.877(8) 2.787(11) 2.607(10) 2.634(11) 2.559(8) 2.508(7) 2.970(7) 2.827(8) 2.775(6) 2.76(2) 3.02(2) 3.21(2) 2.86(2) 3.42(2) 2.84(2) 3.35(2)

113.7 165.9 176.9 161.2 168.5 171.2 167.9 157.0 154.9 145.7 120.0 175.5 174.4 112.0 161.3 162.9 162.2 162.4 174.4 151.6 135.3 148.2 168.2 154.0 151.8 144.9

(1) x-1,y,z; (2) x,y,z-1; (3) x+1,y,z; (4) x+2,y,z; (5) x,y,z+1 Table 79. - interactions for C4diPlysine (II) ( and ).

Cg(I)Cg(J) D2B11
(1) 1-x,1/2+y,1-z

d(Cg(I)Cg(J)) <(Cg(I) Cg(J)) 3.964(5) 2.41

<(Cg(I)<(Cg(I)Cg(J)Cg(I)) Cg(J)Cg(J)) 34.50 32.12

Table 80. C-H interactions for C4diPlysine (II) ( and ).

C-H... C3B-H3BD31 C4B-H4BC31 C3D2-H26D12 C2D2-H2D2A12 C4D2-H4D2C12 C3B3-H46D3 C2B3-H2B3...A3 C3B1-H68...B24 C2B1-H2B1...C24 C4B1-H4B1...A24 C4Y-H4Y1...A5 C6Y-H6Y2...C25 C2Z-H2Z...A36 C3Z-H3Z2...A25 156

d(C-H) 0.95 0.95 0.95 0.95 0.95 0.95 0.95 0.95 0.95 0.95 0.99 0.99 1.00 0.99

d(H...Cg) 2.89 2.90 2.89 2.95 2.98 2.92 2.93 2.95 2.96 3.00 2.76 2.98 2.75 2.88

d(C...Cg) 3.509(9) 3.796(9) 3.54(1) 3.832(9) 3.88(1) 3.55(1) 3.808(9) 3.62(1) 3.85(1) 3.86(1) 3.580(9) 3.61(1) 3.74(1) 3.83(1)

<(C-H...Cg) 124 158 127 155 158 125 155 128 156 152 141 122 171 160

C6Z-H6Z2...C6 C6X1-H6X4...C3

0.99 0.99

2.89 2.86

3.60(1) 3.43(2)

130 118

(1) 1-x,1/2+y,-z; (2) 1-x,1/2+y,1-z; (3) 1-x,-1/2+y,-z; (4) 1-x,-1/2+y,1-z; (5) 1+x,y,z; (6) x,y,1+z Table 81. C-HO interactions for C4diPlysine (II) ( and ).

D-H...A C7C-H7C1...O2D3 C7B3-H7B5...O1X C4Z-H4Z1...O1A31 C5Z-H5Z1...O7W C6Z-H6Z1...O4D31 C3X1-H3X4...O4B

(1) x,y,1+z

d(D-H) 0.99 0.99 0.99 0.99 0.99 0.99

d(H...A) 2.49 2.56 2.55 2.45 2.56 2.39

d(D...A) 3.19(1) 3.24(1) 3.53(1) 3.43(1) 3.32(1) 3.19(2)

<(D-H...A) 127 125 168 171 134 138

Structure calix[4]arene diphosphatechlorhexidine

Table 82. Hydrogen bonds for C4diPchlorhexidine ( and ).

D-H...A O(1A1)-H(1A1)...O(1D1) O(1A)-H(1A)...O(1D) O(1C1)-H(1C1)...O(1B1) O(1C1)-H(1C1)...O(1M) O(2B)-H(2B)...O(6M) O(1C)-H(1C)...O(1B) O(6M)-H(6M)...O(2D)1 O(1W)-H(1W1)...O(1A) O(1W)-H(1W2)...O(4B1) O(1W)-H(1W2)...O(4D) O(1M)-H(1M)...O(7W)2 O(1M)-H(1M)...O(1C1) O(3M)-H(3M)...O(2D1)3 O(7W)-H(7W1)...O(4D1)1 O(7W)-H(7W1)...O(1D1)1 O(7W)-H(7W2)...O(4D)1 O(7W)-H(7W2)...N(4X)4 N(10X)-H(10X)...O(3B1)5 N(9X)-H(9X1)...O(2B1)5 N(9X)-H(9X2)...O(2B)5 N(9X)-H(9X2)...N(7X) N(1X)-H(1X)...O(3B)6 N(7X)-H(7X1)...O(2D)7 N(7X)-H(7X2)...O(2D1)7 N(7X)-H(7X2)...O(4D1)7 N(4X)-H(4X1)...O(3W)8 N(4X)-H(4X2)...O(2D)8 N(6X)-H(6X)...O(3D)7 N(5X)-H(5X)...O(5W)8 N(2X)-H(2X1)...O(4D1)8 N(2X)-H(2X2)...O(3B)6

d(D-H) 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.86 0.69 0.69 0.84 0.84 0.84 0.99 0.99 1.20 1.20 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88 0.88

d(H...A) 2.01 2.03 2.21 2.52 2.01 1.95 1.86 1.97 2.58 2.60 2.13 2.43 2.03 1.79 2.65 1.82 2.53 1.95 2.49 2.24 2.48 1.93 2.17 2.46 2.62 2.14 2.09 2.06 2.30 1.96 2.30

d(D...A) 2.824(12) 2.837(13) 2.817(12) 3.159(13) 2.570(12) 2.732(13) 2.663(13) 2.780(13) 2.924(12) 3.257(14) 2.706(18) 3.159(13) 2.612(13) 2.730(14) 3.403(13) 2.819(13) 3.217(19) 2.771(15) 3.336(14) 3.050(16) 2.946(16) 2.791(16) 3.026(15) 3.232(15) 3.132(19) 2.886(16) 2.87(2) 2.921(16) 3.124(18) 2.835(16) 3.038(15)

<(DHA) 161.7 161.9 128.7 133.3 123.7 154.5 159.8 154.9 113.3 157.6 125.4 145.6 125.4 157.1 132.6 137.4 114.5 155.4 162.5 152.1 113.4 165.0 164.2 147.0 117.9 142.8 146.6 167.1 156.4 170.9 141.8 157

(1) x,y-1,z; (2) x,y+1,z; (3) x,-y+2,z+1/2; (4) x-1,-y+1,z+1/2; (5) x+1/2,-y+3/2,z-1/2; (6) x+1,-y+1,z-1/2; (7) x+1/2,-y+5/2,z-1/2; (8) x+1,-y+2,z-1/2 Table 83. C-H interactions for C4diPchlorhexidine ( and ).

C-H... C2B-H2BC11 C6M-H6M3B C3M-H3M2B12

d(C-H) 0.95 0.98 0.98

d(H...Cg) 2.98 2.85 2.65

d(C...Cg) 3.80(2) 3.74(2) 3.59(2)

<(C-H...Cg) 144 152 161

(1) x,2-y,-1/2+z; (2) x,1-y,1/2+z Table 84. C-HO interactions for C4diPchlorhexidine ( and ).

D-H...A C18X-H18X..O3B11 C5M-H5M2...O1W

(1) 1/2+x,3/2-y,-1/2+z

d(D-H) 0.95 0.98

d(H...A) 2.53 2.57

d(D...A) 3.30(2) 3.24(3)

<(D-H...A) 138 125

Structure calix[4]arene diphosphatepilocarpine

Table 85. Hydrogen bonds for C4diPpilocarpine ( and ).

D-H...A O(1C)-H(1C)...O(1D) O(1A)-H(1A)...O(1D) O(4B)-H(4B1)...O(4D)1 O(3D)-H(3D1)...O(2M1) O(4D)-H(4D1)...O(4B)2 O(3B)-H(3B1)...O(4W)1 O(1C1)-H(1C1)...O(1D1) O(1A1)-H(1A1)...O(1D1) O(4D1)-H(4D2)...O(4B1)3 O(4B1)-H(4B1)...O(4D1)4 O(3B1)-H(3B2)...O(1M) O(2D1)-H(2D2)...O(5M)3 O(2D1)-H(2D2)...O(4M)3 O(1M)-H(1M)...O(3D1)5 O(3M)-H(3M)...O(3W)1

d(D-H) 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84 0.84

d(H...A) 2.09 2.12 2.62 2.32 2.48 2.43 2.11 2.12 2.07 1.79 1.89 1.58 2.49 1.96 2.12

d(D...A) 2.860(9) 2.896(8) 3.284(13) 2.84(3) 3.284(13) 3.10(2) 2.833(9) 2.924(9) 2.461(9) 2.461(9) 2.615(11) 2.04(3) 3.30(3) 2.750(12) 2.79(2)

<(DHA) 152.2 152.5 136.9 120.5 159.6 136.8 143.9 159.9 107.5 135.7 144.4 111.0 163.6 155.9 136.5

(1) -x+1,y-1/2,-z+1; (2) -x+1,y+1/2,-z+1; (3) -x+1,y+1/2,-z; (4) -x+1,y-1/2,-z; (5) x,y-1,z Table 86. - interactions for C4diPpilocarpine ( and ).

Cg(I)Cg(J) AX A1X

d(Cg(I)Cg(J)) <(Cg(I) Cg(J)) 3.748(8) 4.58 3.757(7) 9.46

<(Cg(I)Cg(J)Cg(I)) 15.46 25.64

<(Cg(I)Cg(J)Cg(J)) 18.99 18.22

Table 87. C-H interactions for C4diPpilocarpine ( and ).

C-H... C3D-H3DD1 158

d(C-H) 0.95

d(H...Cg) 2.91

d(C...Cg) 3.50(1)

<(C-H...Cg) 122

C4D-H4DC1 C2B1-H2B1C C1M-H1M1B1

0.95 0.95 0.98

2.95 2.76 2.73

3.83(1) 3.62(1) 3.54(1)

154 152 139

Table 88. C-HO interactions for C4diPpilocarpine ( and ).

D-H...A C7X-H7X2..O4D1 C5X-H5X1...O2W1

(1)-x,1/2+y,1-z

d(D-H) 0.99 0.99

d(H...A) 2.48 2.37

d(D...A) 3.47(2) 3.28(2)

<(D-H...A) 172 152

159

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