Crystallography of encapsulated molecules

Kari Rissanen
University of Jyvaskyla, Department of Chemistry, Nanoscience Center, Survontie 9 B, Jyvaskyla, 40014, Finland. E-mail: kari.t.rissanen@jyu.fi

Received 3rd February 2017

First published on 5th April 2017


The crystallography of supramolecular host–guest complexes is reviewed and discussed as a part of small molecule crystallography. In these complexes, the host binds the guests through weak supramolecular interactions, such as hydrogen and halogen bonding, cation–π, anion–π, C–H–π, π–π, C–H–anion interactions and the hydrophobic effect. As the guest often shows severe disorder, large thermal motion and low occupancies, the reliable crystallographic determination of the guest can be very demanding. The analysis of host–guest interactions using tools such as Hirshfeld and cavity volume surface analysis will help to look closely at the most important host–guest interactions. The jewel in the crown of utilizing host–guest interactions in the solid-state is the recently developed Crystalline Sponge Method (CSM) by Makoto Fujita. This method, when successful, gives an accurate and unambiguous 3-D structure of the structurally unknown guest molecule from only micro- or nanogram amounts of the guest molecule. In the case of an optically pure enantiomer, its absolute configuration can be determined.


image file: c7cs00090a-p1.tif

Kari Rissanen

Kari Rissanen did his PhD at the University of Jyväskylä, Finland. After working as a Research Fellow and then a Senior Research Fellow of The Academy of Finland at the University of Jyväskylä, he became an Associate Professor of Organic Chemistry at the University of Joensuu, Finland. Since 1995, he has been Professor and Head of the Laboratory of Organic Chemistry, University of Jyväskylä. He has also been an Academy Professor of the Academy of Finland from 2008 to the present. His research topics include structural and synthetic supramolecular, organic and nanochemistry, X-ray crystallography, and crystal engineering.


Introduction

X-ray crystallography is by far the most powerful tool for the detailed structural analysis of crystalline supramolecular compounds, complexes and intermolecular interactions, provided that a good enough quality single crystal (indeed only one crystal is enough for a successful X-ray structure determination) of the target system is available. There has been an enormous boost in the number of X-ray structures deposited into the Cambridge Structural Database (CSD) compiled and distributed by the Cambridge Crystallographic Data Centre. At present (March 2017), the CSD1 contains >870[thin space (1/6-em)]000 entries, with an annual increase of about 50[thin space (1/6-em)]000 new structures. Before the 1990's a single crystal X-ray diffraction study of a supramolecular complex was considered to be a non-trivial and time-consuming task performed by well-educated and experienced crystallography experts, often as a part of departmental service or via external collaborations. Due to the complex nature and instability of the crystals of supramolecular host–guest complexes, X-ray crystallography was not considered as a routine analytical tool for structural analysis. Yet the extremely fast development of personal computers, sensitive area detectors and automated structure solution methods in the 1990's has had a direct impact on the speed and ease of X-ray diffraction analysis. Contemporary, nearly fully automated, single crystal diffractometers are able to perform very fast and accurate data collection, processing and structure solution, leading to a situation where very large supramolecular structures (FW > 5000) can be measured and solved within only a few days.

Supramolecular crystallography can be defined as the crystallography of any single crystalline system which has been defined as supramolecular, viz. classical host–guest complexes, metallosupramolecular complexes, coordination cages, dendrimers, gels (xerogels), etc. Covering even a few most important aspects of supramolecular crystallography is well beyond this concise review. Following the definition of supramolecular chemistry by Jean-Marie Lehn2,3 as the “chemistry beyond the molecule, bearing on the organized entities of higher complexity that result from the association of two or more chemical species held together by intermolecular forces” this review will focus on specific examples of host–guest complexes determined through single crystal X-ray crystallography. In these examples, the guest molecule or molecules are fully encapsulated in a confined space, and the review solely focuses on the single crystal structural analyses of selected, here encapsulation, host–guest systems. The review deals with selected clathrate and container molecule systems where the guest is bound inside the cavity of the host or pores, channels or cavities of the crystal structure by weak supramolecular interactions such as hydrogen and halogen bonding, cation–π, anion–π, C–H–π, π–π, C–H–anion interactions and the hydrophobic effect. In most of the cases, when the guest is trapped inside a confined space it is a very demanding task to determine accurately the structure of both the host and the guest; the latter in many cases imposes a true challenge. This is due to the fact that the guest which is bound inside the host with very weak interactions, tends very often to be very difficult to reliably determine solely by crystallographic techniques due to the guest disorder, large thermal motion and low occupancies of the guest (viz. a 1[thin space (1/6-em)]:[thin space (1/6-em)]1 complex can in reality be a 1[thin space (1/6-em)]:[thin space (1/6-em)]0.5 complex, etc.).

The key component of a successful single crystal X-ray crystallographic study is a good quality single crystal, which in many (larger) supramolecular systems is nearly impossible to obtain. The quality of a crystal is determined by its diffraction power (well-diffracting), small thermal movement and full occupancy of all the atoms with no disorder (of the host, guest or the solvent molecules). The weak intermolecular interactions which form the supramolecules, viz. host–guest complexes or supramolecular assemblies, are the same as those that act in the formation of a crystal, and thus a link between supramolecular chemistry and crystal growth becomes apparent. This concept was taken to the crystallographic extreme by Jack Dunitz4,5 as he referred to organic crystals as “supermolecule(s) par excellence”. The development of the concept of supramolecular interactions within crystals in the 1980's and 1990's by prominent crystallographers such as Gautam Desiraju and Michael Zaworotko has merged supramolecular interactions with classical crystallography to a research area called crystal engineering, which is now considered a mature field.6–10 The term “crystal engineering” appears in the proceedings of the American Physical Society Meeting (as abstract) in 1955,11 and it became generally accepted after being used by G. M. J. Schmidt12 in 1971. In Schmidt's article,12 crystal engineering was used for the first time as an explicit term; also, the article postulated that, under suitable conditions, molecular recognition events, viz. self-assembly, could be the major factor leading to crystal formation. Occasionally, crystal engineering has also been called solid-state supramolecular chemistry, yet this particular area of crystallography is outside of the scope of this review.

The present concise review is not intended to make readers experts on single crystal crystallography, nor does it give a thorough account of all the very nice X-ray structures of the multitude of supramolecular systems, but looks at some appealing X-ray structures of host–guest complexes through the eyes of a supramolecular chemist, yet being aware of the crystallographic difficulties often encountered in these systems. To study the theoretical basis of X-ray crystallography in detail, the reader is encouraged to read some excellent X-ray crystallography text books to become fully acquainted with the theory involved at the introductory,13 intermediate14 or advanced15 levels. Based on selected examples of host–guest complexes, this review highlights the difficulties encountered in some host–guest systems and reflects the author's own personal view on their crystallography. It also briefly reviews the most recent breakthrough in crystallographic methods, namely the “Crystalline Sponge Method” (CSM), a method still in its early development phase. The structural details of the host–guest interactions are discussed through Hirshfeld and cavity volume surface analysis, while the packing coefficient (PC) developed by Julius Rebek16 is used as a general feature which can be used to discuss well-defined host–guest systems, such as clathrates and container molecules (viz. molecules with cavities).

Reliable and accurate determination of the structures of all the components of supramolecular inclusion complexes and supramolecular assemblies has gained a lot of attention in supramolecular chemistry and crystallography, especially after the publication of 2013 by Makoto Fujita on the revolutionary “post-crystallization” method,17 now generally known as the “crystalline sponge method”. This method relies on the robust enough porous frameworks, typically metal–organic frameworks (MOFs), in the pores of which the target molecules are trapped and “post-crystallized” and thus the structure of the entrapped target, viz. the guest molecule can be determined from a standard single crystal data collection using an in-house instrument and routine structure solution methods. The method, when successful, gives an accurate and unambiguous 3-D structure of the guest molecule, from only micro- or nanogram amounts of it. If the target molecule (guest) is optically pure, its absolute configuration can be determined.

The crystalline sponge method has its roots in the classical host–guest complexes, viz. clathrates,18 well-known single crystalline materials which contain channels, pores or cavities into which the guest molecules are tightly entrapped. As defined by IUPAc (http://goldbook.iupac.org/C01097.html) “clathrates are inclusion compounds in which the guest molecule is in a cage formed by the host molecule or by a lattice of host molecules”. The molecular counterparts of the clathrates are the container molecules,19–22 either macrocyclic or macropolycyclic molecules or self-assembled capsular entities, which have an isolated cavity encapsulating the guest molecule(s). Based on the above IUPAC definition, the solid-state container molecules and also crystalline sponge crystals, when encapsulating a guest, can be defined as clathrates.

Detailed information about the weak intermolecular interactions that are responsible for the guest entrapment inside the host channels, pores or cavities is crucial in order to understand how the guest interacts with the host, i.e. the channel/pore/cavity walls and how these interactions can be further utilized in order to develop crystalline supramolecular host systems. These host–guest systems should be capable of not only entrapping, but also ordering the guest inside the confined space so that it is easily entrapped; is non-disordered; and has small thermal movement and resides in the confined space with full occupancy. If this can be achieved it will allow an even more general use of confined spaces for accurate guest structure determination through single crystal X-ray crystallography. Analysing the guest's interactions with the host using the classical metric analysis, viz. by measuring the shortest guest-to-host contact distances is common practice. However, a more holistic and visual view of these interactions can be obtained by inspecting the Hirshfeld23 surface plots if the X-ray structure of the host–guest complex is available. The Hirshfeld surface analysis reveals details of the interaction distances between the guest and the host using a colour coding, with red indicating distances shorter than the VDW contact (viz. distance shorter than the sum of the van der Waals radii of the interacting atoms), white the VDW contact distance and blue distances longer than the VDW contact distance. Readers who are not familiar with Hirshfeld surfaces and the CrystalExplorer24 software are recommended to visit the website http://hirshfeldsurface.net.

A popular method to discuss the host–guest complexes is the so-called 55% rule16 developed by Julius Rebek which is based on the ratio of the volume of the guest and the volume of the cavity in which the guest is encapsulated. The general difficulty with the 55% rule, also called the packing coefficient (PC), is that the researcher has to decide how to estimate both the guest and cavity values. There is some controversy as to how to calculate molecular volumes, viz. which method to use, and the same also applies to the calculation of the cavity volume. For the sake of clarity, the packing coefficients (PCs) discussed in this review follow the definition by Rebek.16

Several tests for the volume calculation of a simple guest, tetramethylammonium (TMA) cation, at different levels of theory (SPARTAN'16,25 from MM to DFT/6-311+G(2df,2p)/M06-2X levels of theory) indicates that MM level calculations give only a very slightly (1.5 Å3) larger guest volume. Yet, as the guest generally is a small molecule, it is advisable to calculate its volume at the highest level of theory that is still acceptable for the available CPU time. Traditionally, the cavity volume is calculated by using a 1.2 Å probe, viz. the VDW radius of a hydrogen atom.

As the packing coefficient (PC) is just the ratio between the volume of the guest and cavity and does not give any information about the possible host–guest interactions the Hirshfeld surface23 analysis offers a very good and fast method for the interaction analysis. The only limitation is that it can be done only when full 3-D coordinates are available in the crystallographic information file (cif) format. Another way to visually inspect the solid-state guest-to-host interactions from an X-ray structure is to use a graphics tool to visualise the shape and size of the calculated cavity volume (e.g. Connolly surfaces using the program MSRoll26) as a semi-transparent cavity volume surface (CVS) and simultaneously showing the guest molecule inside with van der Waals (VDW) radii of atoms (or CPK model) using X-Seed, a software tool for supramolecular crystallography by Len Barbour.27–28 The results are visually very similar to the Hirshfeld surface plots, as the short contact distances appear as punctures in the cavity volume surface.

The principal difference between the clathrates and the container molecules when compared to the crystalline sponge crystals17 is that the former are formed in situ from all the components by crystallization from solution, while the crystalline sponge crystals are pre-formed and have to go through a soaking phase where the pore-included solvent molecules are completely or partially exchanged with the target guest molecules. The clathrates and the container molecules have tightly closed internal cavities, from which, in general, it is impossible to remove or exchange the guest without breaking the whole crystal. Another, yet as important, aspect is that after removing the guest molecules and then calculating the void volumes of these three types of crystals, it is evident that the void volumes of the crystalline sponge crystals are typically much bigger that those in clathrates and container molecules. This results in the PCs of the crystalline sponges tending to be smaller than in clathrates and the container molecules; also, the PC values are much more difficult to evaluate as the guests and solvent molecules in the crystalline sponges are often disordered and are not fully occupied. However, the Hirshfeld and cavity volume surface analysis can be utilized for the cavities used in the crystalline sponge method, at least for the guest and solvent molecules with full occupancy.

Clathrates and container molecules

Analysis of the thiourea–bromocyclohexane clathrate29 (CCDC code DAVVIH1) using both the Hirshfeld surface and the cavity volume surface analysis reveals a tightly encapsulated row of bromocyclohexane guests in a channel formed by the H-bonded helically ordered thiourea molecules. One β-H on the same side as the Br-atom of the guest shows a clear but weak C–H⋯S[double bond, length as m-dash]C hydrogen bond [H⋯S = 2.88 Å, C–H ⋯ S angle 143.1°], while the other β-H interacts weakly with one of the nitrogen atoms in the thiourea molecule. The stronger of these interactions is clearly seen as a bright red spot on the Hirshfeld surface (Fig. 1, top) and as a puncture in the cavity volume surface (Fig. 1, bottom, center of the figure). The cavity volume is 234.5 Å3 and the guest volume is 129.8 Å3 [DFT/6-311+G(2df,2p)/M06-2X] leading to a PC of 55.1%. The PC value is in nearly perfect agreement with the Rebek’s 55% rule and supports the weak guest-to-host interactions. The governing interactions are the hydrogen bonds between the adjacent thiourea molecules.
image file: c7cs00090a-f1.tif
Fig. 1 The Hirshfeld24 surface plot (top) of the bromocyclohexane guest in the thiourea channel.29 The ball & stick view of the lattice of the DAVVIH1 structure (bottom), one of the encapsulated guests with the CPK style and the cavity volume surface26–28 in transparent grey (1.2 Å probe).

Self-assembled dimeric30–45 and hexameric46–53 capsules obtained by connecting suitably shaped molecules (normally macrocycles) through metal coordination or hydrogen or halogen bonds constitute one of the topical areas of supramolecular chemistry. The single crystal X-ray crystallographic studies of the capsular assemblies have provided a lot of information about how the guests are bound inside the cavities of these capsular assemblies. Crystallizing a π-basic bowl-shaped resorcinarene molecule from a moist ethanol solution together with tetramethylammonium halides (TMAX, X = Cl, Br) results in a dimeric capsule35 in the solid-state (CCDC code XUSZIU1). The Hirshfeld surface and cavity volume surface analysis reveals a tightly encapsulated TMA cation as a guest inside the cavity of the capsule. The capsule is formed by two resorcinarene molecules that are held together by hydrogen bonds to the counter anions and solvent molecules. The cavity has a volume of 156.7 Å3 and the TMA cation has a volume of 103.7 Å3 [DFT/6-311+G(2df,2p)/M06-2X] leading to a PC of 66.2%. This is clearly larger than the expected value of 55%, yet the interactions between both the upper and lower parts of the π-basic resorcinarene benzene ring are evident from the Hirshfeld surface analysis (red and white colours dominate, Fig. 2, top). The strongest interactions are the two C–H–π interactions [H⋯C(arom) = 2.65 Å C–H⋯C(arom) angle 146.2°] between two of the TMA methyl groups and two of the resorcinarene benzene rings at the opposite sides of the capsule (due to the symmetry of the capsule). These are clearly seen as a bright red spot on the Hirshfeld surface (Fig. 2, top) and as punctures in the cavity volume surface (Fig. 2 bottom, center and left in the figure). Due to the tight packing into the cavity, the TMA guest is very well ordered and has very reasonable (small) thermal motion.


image file: c7cs00090a-f2.tif
Fig. 2 The Hirshfeld24 surface plot (top) of the TMA guest in the cavity of the capsule.35 The ball & stick view of the capsule XUSZIU1 structure (bottom), the encapsulated guest with the CPK style and the cavity volume surface26–28 in transparent grey (1.2 Å probe). Counter anions and solvent molecules are excluded for clarity.

The hemicucurbiturils54–63 are macrocyclic host molecules that have electron-deficient cavities capable of encapsulating suitably sized anions in solution and in the solid-state. When a chiral (all-R)-cyclohexanohemicucurbit[8]uril (cycHC[8]) is mixed with tetrabutylammonium hexafluoroantimonate (TBASbF6) in methanol, a very stable (K > 105) 1[thin space (1/6-em)]:[thin space (1/6-em)]1 host–guest complex is formed.63 By slowly evaporating the solvent single crystal cycHC[8]:TBASbF6 emerges. The guest anion is found to be very tightly encapsulated into the roughly octahedral cavity of cycHC[8] and the Hirshfeld and cavity volume surface analysis (Fig. 3) manifest strong interactions, this time through C–H–anion interactions. The deep red spots in the Hirshfeld surface (Fig. 3, top) and the large punctures of the cavity volume surface (Fig. 3, bottom) correlate well with the eight distances shorter than the VDW contact of H- and F-atoms (2.67 Å); these C–H⋯anion (F) contact distances range from 2.3–2.65 Å. The cavity volume is 139.4 Å3 and the volume of the SbF6 anion is 85.3 Å3 [DFT/6-311+G(2df,2p)/M06-2X] giving PC = 61.2%. Actually this value is very likely underestimated as the cavity extends until the portals of cycHC[8] (Fig. 3, bottom) and therefore the occupied volume (volume of the Hirshfeld surface) of 110 Å3 calculated by the CrystalExplorer program23 would be a better estimate for the true cavity volume and would give a PC of 77.5%. This is supported by the exact fit of the octahedral anion into the octahedral cavity of cycHC[8] with a lot of strong C–H⋯anion interactions. Furthermore, the SbF6 anion shows very small thermal movement with no disorder.


image file: c7cs00090a-f3.tif
Fig. 3 The Hirshfeld24 surface plot (top) of the SF6 guest in the cavity of the macrocycle.63 The ball & stick view of the ECADOE1 structure (bottom), the encapsulated guest with the CPK style and the cavity volume surface26–28 in transparent grey (1.2 Å probe). Counter cations and solvent molecules are excluded for clarity.

Encapsulation of either extremely reactive (pyrophoric) or poorly soluble highly symmetrical guest molecules inside the cavities of host molecules imposed two serious difficulties, first how to get the guest inside the host intact or at all, and secondly being able to grow a good enough quality single crystal for the structure determination of the host–guest complex. Two different examples of these systems are given.

Mixing the sub-components of a metallo-organic cage with white phosphorus (P4) in water (the highly pyrophoric P4 has to be stored under water in order to prevent it from igniting) results in a host–guest complex where the P4 is encapsulated inside the cavity of the metallocage.64 The vapor diffusion of 1,4-dioxane into an aqueous solution of the 1[thin space (1/6-em)]:[thin space (1/6-em)]1 complex of the metallocage and P4 leads to the formation of a moderate quality crystal, which reveals the P4 to be completely incarcerated inside the cavity of the metallocage (Fig. 4). The tetra-anionic cage has a very hydrophobic cavity volume of 151.2 (1.2 Å probe) and the calculated volume of P4 is 80.8 Å3 [DFT, 6-3111+G(2df,2p), MO6-2X]. This gives PC = 53.4% which is very close to the Rebek's optimum PC of 55%. When inspecting both the Hirshfeld (Fig. 4, top) and the cavity volume surfaces (Fig. 4, bottom), it is clear that the interactions between the P4 molecule (which shows a slight 95[thin space (1/6-em)]:[thin space (1/6-em)]5 disorder inside the tetrahedral cavity) and the cavity walls manifests weak interactions between the host walls and the guest, indicating that the hydrophobic effect is the most likely cause of the encapsulation. The P4 molecule is “leaning” against the cavity walls at the VDW contact distance, with only a few of them being slightly shorter and can be visually seen as red spots in the Hirshfeld surface (Fig. 4, top) and as tiny punctures in the cavity volume surface (Fig. 4, bottom).


image file: c7cs00090a-f4.tif
Fig. 4 The Hirshfeld24 surface plot (top) of the P4 guest in the cavity of the metallocage.64 The ball & stick view of the COSZOA1 structure (bottom), the encapsulated guest with the CPK style and the cavity volume surface26–28 (1.2 Å probe) in transparent grey. Counter cations and solvent molecules are excluded for clarity.

Encapsulating fullerenes, C60 or C70, into the cavity of the same molecular capsule65 offers a possibility to observe if the differently sized and shaped, yet chemically similar, guest will show different behaviour, viz. differences in the interactions, and if it will affect both the cavity size (host breathing) and the packing coefficient. Either using solution or mechanochemical complexation peptide-embedded resorcinarenes form dimeric capsules encapsulating either C60 or C70 in a 1[thin space (1/6-em)]:[thin space (1/6-em)]1 (capsule[thin space (1/6-em)]:[thin space (1/6-em)]guest) stoichiometry.65 Fascinating in this work is the fact that the same capsule forms complexes both with C60 and C70. The Hirshfeld and the cavity volume surface analysis both show that C60 (CCDC refcode NADKOV1) is very loosely trapped inside the cavity of the capsule. While the Hirshfeld surface shows some weak red spots (Fig. 5, top), the majority of the surface has blue colour, indicating longer VDW contact distances. This is more clearly visible when inspecting the cavity volume surface (Fig. 5, bottom) as there are no punctures in the surface indicating that no real contacts shorter than 3.4 Å exist. The cavity volume is 831.9 Å3 for the C60-capsule. The volume of C60 is 549 Å365, thus giving a PC of 66.0%. This is a surprisingly large value, when compared to the other PCs discussed above in connection with the Hirshfeld and cavity volume surface analysis. However, if the volume of C60 is estimated from the X-ray structure, so that the VDW radii of carbon is taken into account, the diameter of C60 is obtained to be 7 Å+1.7 Å=8.7 Å, giving a radius of 4.35 Å; then we get VC60 = 345 Å3. Using this as the guest volume the PC value is more realistic, viz. PC = 41.5%. Maybe the correct value in this case is ca. 50%, viz. lower than the optimal PC of 55%.16 Also, the thermal displacement parameters of the C60 atoms are so large that the authors could not do a proper unrestrained anisotropic refinement. Very interestingly, in the C70-capsule (CCDC refcode NADKUB1) the capsule is the same, but now the guest is definitely bigger, viz. C70vs. C60. The volume of C70 is not available but is based on the X-ray structure (NADKUB1); C70 is a regular ellipsoid and similarly to the case of C60, we can obtain the estimated C70 volume as 390 Å3. The cavity volume is 853.2 Å3 (notice: it was 831.9 Å3 for the C60-capsule) and thus the PC is 45.7%. In the C70-capsule, the guest shows many more interactions, visible in the Hirshfeld and cavity volume surface plots as red dots (Fig. 6, top) and surface punctures (Fig. 6, bottom), respectively. As for C60, the PC seems to not reflect the host–guest interactions visible both in the Hirshfeld and cavity volume surface analysis shown in Fig. 6, both of which show shorter distances than VDW contacts between the host and the guest.


image file: c7cs00090a-f5.tif
Fig. 5 The Hirshfeld24 surface plot (top) of the C60 guest in the cavity of the dimeric capsule.65 The ball & stick view of the NADKOV1 structure (bottom), the encapsulated guest with the CPK style and the cavity volume surface26–28 (1.2 Å probe) in transparent yellow. Solvent molecules are excluded for clarity.

image file: c7cs00090a-f6.tif
Fig. 6 The Hirshfeld24 surface plot (top) of the C70 guest in the cavity of the dimeric capsule.65 The ball & stick view of the NADKUB1 structure (bottom), the encapsulated guest with CPK style and the cavity volume surface26–28 (1.2 Å probe) in transparent yellow. Solvent molecules are excluded for clarity.

The crystalline sponge method

The Crystalline Sponge Method (CSM) is a very ingenious way, conceptualized in 2013 by Makoto Fujita,17 of exploiting the large enough pores, channels or cavities of a pre-formed sponge crystal, so that by soaking the sponge crystal into an inert solvent containing the target compound (the guest), it will be exchanged with the solvent molecules in the pores, either completely or partially. If the guest is a liquid and is available in reasonably large amounts (in ml), then the soaking can be done in the neat guest solution in order to maximize the guest–solvent-exchange.66 The CSM works reliably if the sponge crystal has pores, channels or cavity walls, viz. confined spaces, that are able to interact strongly enough with the guest molecules via weak supramolecular interactions, as mentioned in the Introduction above. These interactions between the guest and the pores, channels or cavity walls direct and entrap the guest in a particular position leading to post-crystallization67 of the guest inside the already existing crystal lattice. The CSM thus uses the same principles as the clathrates and container molecules discussed above when binding the guest. The strength of the host–guest interactions, in the CSM, the MOF walls-to-guest interactions, defines how well the guest will be ordered inside the pre-formed sponge crystal. If the guest is well-ordered, and has sufficiently high occupancy and reasonable thermal motion, then the X-ray crystallographic analysis and the results of the sponge crystal do not differ from the similar work on host–guest complexes, as discussed above with the clathrate and container molecules.

Scheme 1 shows schematically the possible CSM systems. The presently used systems (see below) (Scheme 1A) rely only the interactions between the sponge walls, guest and possible solvent. The other possible CSM systems, which utilize charged sponge walls, either negative (Scheme 1B) or positive (Scheme 1C) have so far not been used. In these cases, the anion/cation cannot leave the sponge pores, channels or cavities, but would offer additional interactions, that might fix the guest better inside the sponge crystal. The charged sponge walls would also allow anion and cation exchange if the guest would be charged, e.g. a cationic drug molecule.


image file: c7cs00090a-s1.tif
Scheme 1 The possible construction principles of crystalline sponges. Color coding: black = the sponge walls; orange = wall–guest interactions; red = guest–solvent interactions; blue = wall–solvent interactions, green = anion/cation–wall interactions.

The initial crystalline sponge method (Scheme 1A) publication in Nature17 caused both over-positive and over-negative responses, partly due to the fact that the used sponge crystal [(ZnI2)3(tpt)2·x(solvent)]n, tpt = 2,4,6-tris(4-pyridyl)-1,3,5-triazine, turned out to be disordered in the case of the determination of the absolute configuration of the marine natural product. This caused the authors to publish a correction68 on this aspect of the original publication,17 yet highlighting the breakthrough nature of the method itself. Very recently, a publication about the hidden transformations of the [(ZnI2)3(tpt)2·x(solvent)]n crystalline sponge system has been published.69 The initial difficulty in reproducing the soaking experiments led both Fujita and others to improve the protocols of how the sponge crystals should be grown and selected, optimizing the soaking conditions and solvents used, and giving guidelines about the actual data collection strategies using an in-house instrument67,69–73 or synchrotron radiation.66

Until now (March 2017), the CSM has not yet been extensively used, mainly due to the expertise needed in growing sponge crystals, guest soaking and the not trivial crystallography involved. The contemporary publications have reported the use of the CSM in the previously impossible structural elucidations, most of them by Fujita himself. These success stories include the structural re-evaluation of the electrophilic hypervalent iodine reagent for trifluoromethylthiolation,74 structural determination of the reaction products from the radical C–H functionalization of heteroarenes under electrochemical control,75 observation of palladium-mediated aromatic bromination reaction,76 structural analysis of the position of the oxygen atom in the α-humulene oxidation product,77 determination of the absolute structures of axially and planar chiral molecules,78 determination of the absolute and regio-configurations of the cyclic product from the phosphine-catalyzed β,γ-umpolung Domino reaction of allenic esters,79 structure determination of S-(−)-nicotine and other small organic molecules,80 determination of the absolute configuration of the pseudo-symmetric natural product elatenyne,81 a saccharide-based crystalline sponge for hydrophilic guests,82 structure determination of astellifadiene,83 confirmation of the syn-addition mechanism for metal-free diboration,84 the in situ observation of thiol Michael addition to a reversible covalent drug,85 high-resolution X-ray structure of methyl salicylate,86 differentiation of volatile aromatic isomers and structural elucidation of volatile compounds in essential oils,87 structure analysis of ozonides88 and determination of the absolute configuration and structural revision of cycloelatanene A and B.89

As examples of Hirshfeld and cavity volume surface analysis, some crystalline sponges are briefly discussed below. The most used crystalline sponge, the [(ZnI2)3(tpt)2·x(solvent)]n MOF, crystallizes in many crystal systems, depending on the guest and also the framework flexibility.69 The cavity volume surface analysis discussed above in the clathrates and container molecules section is not often feasible for large and partially filled pores, channels and cavities, in these cases the Hirshfeld surface analysis works well. The [(ZnI2)3(tpt)2·x(solvent)] crystalline sponge has very large voids in its lattice, ca. 50–53% is void space if only the MOF framework is taken into account. To make the guest and the possible solvent molecules as well ordered as possible, they should fill the void space as completely as possible. This, however, does not rule out the possibility of the guest and solvent disorder. A good example of a [(ZnI2)3(tpt)2·x(solvent)] sponge with only a few molecules in the asymmetric unit, actually one guest (=guaiazulene) and two solvent molecules (=chloroform), measured using synchrotron radiation is shown in Fig. 7 (CCDC refcode ZOQTAC1).66 This sponge crystal has 50% voids, yet they are not fully occupied by the guest and the solvents, ca. 17% of the crystal is still void. In this case, the use of synchrotron radiation results in a very well-resolved and well-behaved structure with some interesting features. The iodine atoms in the ZnI2 moiety act as H-atom acceptors for one of the chloroform molecules, and the electron-deficient tpt moieties interact with the guest guaiazulene, as earlier reported by Fujita with the same guest.17,67,70,71


image file: c7cs00090a-f7.tif
Fig. 7 The Hirshfeld24 surface plot of the guest in the asymmetric unit of a ZnI2-tpt sponge structure ZOQTAC1 measured using synchrotron radiation.66

A more complex structure (CCDC refcode IYOCUW1) based on the amount of guest molecules to be determined was reported recently by a Chinese group.87 They used the same tpt ligand but together with a ZnBr2 moiety. The soaking experiment from chloroform with carvacrol, a small monoterpenoid phenol (a structural isomer of thymol) resulted in crystals with an unresolved amount of the solvent chloroform and five guest molecules. The badly resolved and ordered chloroform molecules were removed using the SQUEEZE protocol (note that SQUEEZE should be used with utmost care in the CSM67) and the asymmetric unit now contains five carvacrol molecules which form a large “supermolecule” inside the cavity of the MOF. The phenolic OH-group is able to act as hydrogen bond donor and acceptor towards the adjacent molecules and the Hirshfeld surface analysis reveals these as red spots on the surface of the “supermolecule” (Fig. 8).


image file: c7cs00090a-f8.tif
Fig. 8 The Hirshfeld24 surface plot of the guest in the asymmetric unit of a ZnBr2-tpt sponge structure IYOCUW.1,87

Fujita improved67 the protocol for applying the CSM with the [(ZnI2)3(tpt)2·x(solvent)] sponge MOF to an enantiomerically pure drug molecule santonin. The solving experiment with santonin leads to the transformation from the initially centrosymmetric crystal lattice (space group C2/c with a unit cell volume of 15[thin space (1/6-em)]103 Å3) to a chiral crystal lattice (space group P21 with a unit cell volume of 16[thin space (1/6-em)]430 Å3).

This lowering of symmetry increases the number of molecules in the asymmetric unit and after soaking the asymmetric unit cell contains five santonin and 13 cyclohexane solvent molecules (CCDC refcode LABNAG1). The santonin and cyclohexane molecules form “clusters” which will fill up 99% of the voids of the sponge cavities. The carbonyl oxygen of the santonin molecules acts as a hydrogen bond acceptor from the H-atoms of the walls of the sponge. The pyridinic ortho-H-atoms of the tpt ligand will be more acidic with the complexation of ZnI2 and they will form quite strong 2.2–2.4 Å H-bonds (C–H⋯O[double bond, length as m-dash]C) with the santonin carbonyl oxygen. These interactions are clearly visible from the Hirshfeld surface analysis (Fig. 9) as large red spots. The cyclohexane molecules fill up the spaces between the santonin molecules creating a nearly “small molecule” level crystal structure. Due to the very good quality of the santonin sponge crystal, it could be crystallographically treated as small molecule data and Fujita himself considers this LABNAG structure as the benchmark for the crystalline sponge method for chiral optically pure molecules.67


image file: c7cs00090a-f9.tif
Fig. 9 The Hirshfeld24 surface plot of the guests and solvent molecules in the asymmetric unit of a ZnI2-tpt sponge structure LABNAG.1,67

Finally, there is a short account that other MOF structures also can and will act like crystalline sponges, and even though their use has not been reported for the CSM, they manifest the same features as the above described examples of the iconic [(ZnX2)3(tpt)2·x(solvent)] sponge MOFs as well as those in the beginning of this review of clathrates and container molecules. This is to say that any porous single crystalline material which, by defined weak host–guest interactions, will bind and order guest molecules into its pores, channels or cavities can be regarded as a crystalline sponge. Keeping this in mind, Fujita published90 very recently an article about finding new crystalline sponges from the Cambridge Structural Database.1

Gas molecules such as CO2, N2, O3, CH4, etc. can be considered as special guests for the CSM. As they are gases, the soaking phase is substituted either by a gas flow through the crystals or better still by subjecting the crystals to a pressure of up to 80 bar of the guest gas. Achieving this requires a special technique for the crystallographic work, the so-called environmental gas cell developed by Len Barbour.91 Using this technique Barbour's group studied simple MOF structures with very tiny pores, just big enough to encapsulate gases, most often CO2. They showed that hysteresis92 occurs in the sorption of CO2 into the specific breathing MOFs; most interestingly they used as simple Zn(II)-MOF for the CSM and achieved an in situ crystallographic visualization of CO2 binding within the Zn(II)-MOF (crystalline sponge at high gas pressure) at 298 K.93 Very small pores and the way in which the gas molecules are situated in the pores allow both Hirshfeld and cavity volume surface analysis to be carried out as for the clathrates and container molecules above. Hirshfeld surface and cavity volume surface analysis (Fig. 10) reveals the interactions with the encapsulated CO2 molecule and the pore walls of the Zn(II)-MOF, giving a crystallographic proof that the MOF (crystalline sponge) effectively binds the CO2 molecules. The CO2 molecule has a volume of 38.5 Å3 [DFT/6-311+G(2df,2p)/M06-2X] and the cavity size where the CO2 molecule is residing is 73.0 Å3 resulting in a PC of 52.7%. This is very close to the optimal 55%16 (for single cavity hosts), and the interactions between the CO2 and the wall of the MOF pore are very nicely visualized by the Hirshfeld surface analysis (Fig. 10, top). The electron-deficient carbon of the CO2 interacts quite strongly with the electron-rich oxygen atom of the carboxylate moiety in the MOF wall (Fig. 10, top), with the contact distance being 3.07 Å, definitely shorter than the VDW contact distance of carbon and oxygen (3.22 Å). This interaction is also seen as a clearly visible puncture in the surface volume surface (Fig. 10, bottom).


image file: c7cs00090a-f10.tif
Fig. 10 The Hirshfeld24 surface plot (top) of the CO2 guest in the pores of the Zn(II)-MOF (only the asymmetric unit is shown).93 The ball & stick view of the DAFSEL1 structure (bottom), the encapsulated guest with the CPK style and the cavity volume surface26–28 (1.20 Å probe) in transparent yellow.

Conclusions

Single crystal X-ray crystallography offers the most accurate method of studying and analysing crystal and molecular structures and the supramolecular interactions occurring between the components in the crystal structure. In supramolecular chemistry, the studied single crystal often contains a host–guest complex, either as a classical or a molecular clathrate. In these crystal structures, the guest molecule or guest molecules interact with the host via weak supramolecular interactions. Extracting and understanding the structural details of these interactions and utilizing this information are the essence of supramolecular chemistry. The detailed crystal structure studies can pave a way to the design of new more selective host systems active either in solution or in the solid-state. The most promising and certainly a revolutionary way of applying the supramolecular interactions is the Crystalline Sponge Method (CSM), which offers unprecedented possibilities for the X-ray crystallographic determination of unknown compounds. However, the CSM is still in its very early development phase and new more robust, selective, low-symmetry and easy-to-handle crystalline sponge systems, MOFs or other porous materials, have to be found and/or developed.

After only three years, the crystalline sponge method has produced amazing results and it will have a very bright future as a part of supramolecular chemistry.

Acknowledgements

The Academy of Finland (project no. 263256, 265328 and 292746) and the University of Jyväskylä are gratefully acknowledged for financial support.

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