An unprecedented Dianin clathrate structure with Z ′ ( host ) = 16

Please do not adjust margins a. Wolfson Centre for Materials Processing, Brunel University, Kingston Lane, Uxbridge, Middlesex UB8 3PH, UK, Tel: +44 (0)1895 265337; Fax: +44 (0)1895 203376; Email: chris.frampton@brunel.ac.uk. b. Department of Medical Chemistry, College of Medicine, University of Duhok, Duhok, Kurdistan Region, Iraq. c. Chemistry Department, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia d. Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, Scotland, UK, Tel: +44 (0)141 330 4479; Email: david.macnicol@glasgow.ac.uk †Electronic Supplementary Information (ESI) available: Full 1400608-1400611, 1400701experimental details and crystal structure data. [CCDC 14006081400611, 1400701, [2(295 K, 200 K, 371 K and 90 K), 3(120 K)]]. For ESI and crystallographic data in CIF or other electronic formats see DOI: 10.1039/x0xx00000x Received 00th January 20xx, Accepted 00th January 20xx


Introduction
Elucidation of the crystal structure of the clathrates formed by 4-p-hydroxyphenyl-2,2,4-trimethylchroman 1, widely known as Dianin's compound 1 , has allowed interpretation of results from very wide ranging studies of these fascinating inclusion compounds 2 .In addition, the availability of this detailed structural information has provided the key to the successful design and synthesis of new host molecules related to parent 1, for example 2 and 3.For many years the structural situation appeared completely defined and a basic tenet relating to all the Dianin's clathrates was that they all crystallised in what one may now aptly term the classical clathrate space group, with hexagonal unit cell axes, a ca.27 Ǻ and c ca. 11 Ǻ, and with universally Z′(host) = 1.A true closed-cage clathrate structure, arising from astute consideration of space group and associated unit cell dimensions alone, was assigned to the adducts of 1 in 1955 3 , however it was not until the end of the Scheme 1.
1960's that detailed X-ray diffraction studies 4 fully characterised the clathrate structure 5,6 of 1. Closed hour glassshaped cavities were found to be formed between C3i [3 ]  symmetric, (12) , [OH]6 hexameric host units stacked infinitely along the c-axis.At around this time also, exactly parallel and independent results were found 7,8 for the closely related isostructural clathrates of thiachroman 2, and the structure 9 of the stable isostructural apohost, (empty cage), form of 1 followed immediately from an electron density map phased on the atomic coordinates of the EtOH clathrate of 2. The consistent host packing, in space group 3 , Z′(host) = 1, found for all the known clathrate structures of these hosts engendered the view that this packing mode was universal for all clathrates of 1 and 2. This perception was buttressed by the knowledge that many host molecules structurally related to 1 and 2 also form isomorphous, although not in all cases isostructural, host lattices which are analogous to those of 1 and 2, invariably with Z′(host) = 1.Examples of such hosts are the selenachroman 3  dihydroxyphenyl)-2,2,4-trimethylchroman 12 ; and a 2-normethyl analogue 13 of 1.The first indication that this packing might not, in fact, represent a unique clathrate potential energy minimum came from the reported unit cell dimensions 10 of the EtOH clathrate of 3, which showed relative to the expected dimensions, c essentially remained unchanged but a effectively doubled with a = 57.42(1)Å and c = 10.871(1)Å; however, all attempts to solve this structure were unsuccessful owing to the fact that only X-ray photographic data were available at that time.In 2009 Jacobs and coworkers 14 published the structure of the ethylenediamine clathrate of compound 1 which interestingly also demonstrated a unit cell which was doubled in a relative to the archetypal Dianin's cell which contained two distinct unit types wherein one unit contained neutral guest molecules and the second contained partially ionised guests.More recently, Lee et al 15 have studied the iso-propanol (IPA) clathrate of 1 in the temperature range 15 K to 299 K and also found a corresponding cell where doubling of the a axis for this compound occurred just below 180 K with the low temperature form retaining the trigonal space group 3 , but now with Z′(host) = 4, rather than Z′(host) = 1 characteristic of the archetypal trigonal Dianin's clathrate structure.Cooling to 15 K did not induce any further transformation of the unit cell.We now report novel temperature-dependent behaviour for the 3:1 (host:guest) IPA clathrates of 2 and 3, the direct thiaand selenachroman counterparts of parent 1; and in addition for the remarkable novel polar and chiral (3:1) IPA clathrate 6 having quasiracemic host components R-Dianin's compound, 4 and S-Thia-Dianin's compound, 5.For 2 and 3 we describe below a further ultimate quadrupling of the a axis compared with standard Dianin's clathrates, producing a hexagonal unit cell with volume increased by sixteen times containing 288 host and 96 IPA guest molecules and featuring 16 host molecules of 2 or 3 in the asymmetric unit., i.e.Z′(host) = 16.
Differential scanning calorimetry (DSC) studies have revealed two reversible commensurate phase changes for the IPA clathrate of 2. Above the higher-temperature transition at ca. 368 K, approximately 14 K prior Please do not adjust margins Please do not adjust margins to guest loss and final melting, we have defined the archetypal Dianin's cell, Z'(host)=1, for 2.

Results and Discussion
Thia-Dianin's IPA clathrate, 2 For the IPA clathrate of the thiachroman analogue 2, full single crystal X-ray structure datasets were collected at 371 K, 295 K, 200 K and 90 K.The crystal structure of the thiachroman clathrate at 295 K is isostructural/isomorphous with the published low temperature forms, (100 K and 15 K), of the IPA clathrate of Dianin's compound 15 and with similar unit cell

b O,c a
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Thermal Analysis
Given that the IPA clathrate of host 2 at 295 K is isostructural with the corresponding clathrate of 1 at 100 K, we have sought to establish if the primary archetypal Dianin cell could be observed for the former clathrate above room temperature and encouraging results were obtained from the DSC traces shown in Figure 3.The upper trace shows a low energy event of 4.532 J g -1 with onset temperature of 368.90 K compatible with the anticipated transition, with a second larger endothermic event attributable to guest loss and subsequent melting.The origin of the former event was confirmed by the hysteresis shown in the middle trace of Figure 3, (Endotherm onset 368.29 K, energy 4.522 J g -1 , exotherm onset 368.65 K, energy 3.364 J g -1 ).Accordingly, a   temperature gave a unit cell consistent with the 295 K structure and showed that no significant guest loss had occurred during high-temperature data collection.It was also possible to observe the lower temperature reversible phase transition, (lower trace), by cooling the sample to 90 K and 6, (290 K) 6, (90 K) Formula C18H20O2, C18H20O1S1, 0.66(C3H8O1) Please do not adjust margins Please do not adjust margins allowing the temperature to increase naturally.The exothermic phase transition was observed at 182.23 K with an associated energy of 14.15 J g -1 .

Quasiracemate, 6
In a recent paper 17 we described the retention of robust clathrate forming ability of a quasiracemate formed from the R-enantiomeric form of Dianin's compound 4, and the Senantiomeric form of Thia-Dianin's compound 5 which were obtained by chiral HPLC chromatography; this quasiracemic system was shown to undergo supramolecular assembly to form a polar clathrate lattice which was stable even in the absence of a consolidating guest component.Seeking a direct parallel with the above novel temperature-dependent phenomena we also investigated the IPA clathrate of this quasiracemic host system, 6, as a function of temperature.The structure at 290 K exactly parallels that of 1 itself at this temperature forming an archetypal Dianin's unit cell with a = 27.658(2)Å and c = 10.956(1)Å, space group 3 with a total of 18 molecules in the unit cell.Lowering the temperature to 90 K results in the formation of the first doubled unit cell with a = 55.0808(9)Å and c = 10.8542(2)Å, space group 3 where there are now four independent chroman hosts, 4, and four independent thiachroman hosts, 5, in the asymmetric unit of structure.
The absolute stereochemistry of the quasiracemate was confirmed at both temperatures through the Flack parameter 0.024(5) and 0.006 (7) at 290 K and 90 K respectively, see Figures 5 and 6.An important feature of the conformation of all the host molecules described above is the proximal relationship of the p-hydroxyphenyl substituent and its syn related methyl group; it may be noted that this conformation avoids a short contact between the syn related which is present in the structures of the enantiomerically pure non-solvated components 17 .In all the isomorphous clathrate structures described above there are columns located on the three-fold proper rotation axis, comprised of infinitely stacked hexameric host units.Throughout the transformations, all host molecules of a given conformation maintain a fixed uniform distribution with respect to the c-axial direction.The temperature-dependent cell transformations correspond to a progressive 'wedging apart' of the trigonal columns; the column separations for 2 being 16.31 Å, 32.62 Å and 64.54 Å for 371 K, 295 K and 90 K respectively.These columns are shown in green in Figures 1, 2 and 4 and the emergence of the inter-column molecules suggests the possibility of storage of other molecules, for example pharmaceutical actives, in related clathrates.A recent excellent review 20 highlights the current interest in high Z' structures.For very high Z' cases, the Cambridge Structural Database (CSD) 21 , Version 5.38 update February 2017, shows that currently out of over 876,000 entries there are only 73 unique crystal structures with Z' greater or equal to 10 and 21 with Z' greater or equal to 15.It is of interest, therefore, to record that the value Z'(host) = 16 found for 2 (and 3) represents to our knowledge a current universal maximum for all purely organic clathrates, i.e. not including low density metal organic frameworks and indeed is among the highest known for all purely organic crystals.The value of Z at 288 is also the highest known for all structures in the database, the current maximum being 192.

Experimental Section Preparation of compounds and clathrates
Compounds 1 2 , 2 16 and 3 10 were all synthesized according to established procedures and compounds 4 and 5 were obtained via the optical resolution of 1 and 2 respectively according to the procedure in reference 17.Clathrates of 1, 2 and 3 were prepared by recrystallisation of the unsolvated materials from neat IPA.Cocrystallisation of equimolar quantities of 4 and 5 from neat IPA yields the novel polar quasiracemic clathrate 6.

Single Crystal X-ray Diffraction
Variable temperature single crystal X-ray structure data for the iso-propanol clathrate of 2 and the iso-propanol clathrate of the polar quasiracemic host 6 were collected on an Agilent Supernova Dual Source, Cu at Zero, Atlas CCD diffractometer equipped with an Oxford Cryosystems Cobra cooling device.The data was collected using mirror monochromated CuKα radiation, (λ = 1.54178Å).Crystal structure data for the isopropanol clathrate of 3 was collected on a Siemens SMART IK diffractometer equipped with an Oxford Cryosystems Cryostream cooling device.The data were collected using graphite monochromated MoKα radiation, (λ = 0.71069Å).Structures were typically solved and refined with the SHELX 18 suite of programs.Unless otherwise stated, hydrogen atoms attached to carbon were placed geometrically and allowed to refine with a riding isotropic displacement parameter.Hydrogen atoms attached to a heteroatom were located in a difference Fourier synthesis and were allowed to refine freely with an isotropic displacement parameter.Temperaturedependent crystal structure data for compounds 2, 3 and 6 has

Thermal Analysis
Differential scanning calorimetry, (DSC), data were collected on a TA Instruments Q2000 equipped with a 50-position autosampler.The calibration for thermal capacity was carried out using sapphire and the calibration for energy and temperature was carried out using certified indium.Typically, 0.5 -3 mg of each sample, in a pin-holed aluminium pan, was heated at 10 °C/min from 25 °C to 300 °C.A purge of dry nitrogen at 50 ml/min was maintained over the sample.The instrument control software was Advantage for Q Series v2.8.0.394 and Thermal Advantage v5.5.3 and the data were analysed using Universal Analysis v4.5A.

Conclusions
The temperature-dependence of the structure of members of the Dianin host series, enclathrating iso-propanol, is a general phenomenon extending through the parent, 1 thiachroman 2 and selenachroman 3 individual host members to a polar quasiracemic counterpart 6; and is not limited to a single commensurate thermal phase transition.This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Please do not adjust margins

Figure 1 .
Figure 1.Structure of the IPA clathrate of 2 at 295 K viewed down the c-axis.The disordered IPA guest molecules around a 3 symmetry position are omitted for clarity.The ordered IPA guest molecules are shown in mauve.The host molecules are coloured according to cage type.Type I, green, Type II, red.
dimensions 10 to the EtOH clathrate of 3 with an observed doubling of the a unit cell axis with a = 56.4934(4)Å and c = 10.9041(1)Å and a retention of the trigonal space group 3 .The asymmetric unit features Z′ (host) = 4 and 4/3 IPA guests.In common with the 100 K Dianin's clathrate there exist two distinct hydrogen-bonded host units, illustrated in Figure 1.The first is a classical [OH]6 hexameric Type I host unit, between two of which stacked infinitely along the c-axis, are located two IPA guest molecules close to the 3-fold proper rotation axis, which are statically disordered around a point of 3 symmetry; the second unit, Type II, is an eight-membered hydrogen-bonded composite unit, located on point of 1 symmetry, comprised of six molecules of 2 and two centrosymmetrically-related guest molecules which are incorporated in the 16 hydrogen bonded motif.In this unit there are three crystallographically-independent O,c a b This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Please do not adjust margins

Figure 2 .
Figure 2. Structure of the IPA clathrate of 2 at 90 K viewed down the c-axis.The disordered IPA guest molecules around a 3 symmetry position are omitted for clarity.The ordered IPA guest molecules are shown in mauve.The host molecules are coloured according to cage type.Type I, green, Type II, red, Type III, purple and yellow.

Figure 3 .
Figure 3. (Top), DSC Thermogram of the IPA clathrate of 2, showing the phase transition to the archetypal Dianin cell with an onset temperature of 368.90 K. (Bottom), DSC Thermogram of the IPA clathrate of 2, showing the phase transition to the archetypal Dianin cell to be reversible.

Figure 4 .
Figure 4. Structure of the IPA clathrate of 2 at 371 K viewed down the c-axis.The disordered IPA guest molecules around a 3 symmetry position are omitted for clarity.The host molecule is coloured according to a Type I cage type, green.
is © The Royal Society of Chemistry 20xx

Figure 5 .
Figure 5. Structure of the IPA clathrate of the quasiracemate, 6 at 295 K viewed down the c-axis.The disordered IPA guest molecules around a 3 symmetry position are omitted for clarity.The host molecules are coloured according to enantiomer, S-Thia-Dianin's, orange and R-Dianin's, red.

Figure 6 .
Figure 6.Structure of the IPA clathrate of the quasiracemate, 6 at 90 K viewed down the c-axis.The disordered IPA guest molecules around a 3 symmetry position are omitted for clarity.The ordered IPA guest molecules are shown in mauve.The host molecules are coloured according to enantiomer, S-Thia-Dianin's, orange and R-Dianin's, red

Table 2 .
Crystallographic data for the IPA Clathrates of the quasiracemate 6.