Inclusion with Mixed Guests: Structure and Selectivity Ayesha Jacobs,† Luigi R. Nassimbeni,*,† Kanyisa L. Nohako,† Hong Su,‡ and Jana H. Taljaard§ Department of Chemistry, Faculty of Applied Sciences, Cape Peninsula UniVersity of Technology, P.O. Box 652, Cape Town 8000, South Africa, Department of Chemistry, UniVersity of Cape Town, Rondebosch 7701, South Africa, and Department of Chemistry, Nelson Mandela Metropolitan UniVersity, Port Elizabeth 6000, South Africa
CRYSTAL GROWTH & DESIGN 2008 VOL. 8, NO. 4 1301–1305
ReceiVed October 18, 2007; ReVised Manuscript ReceiVed December 11, 2007
ABSTRACT: The structures of the inclusion compounds formed by the host 9-(2-naphthyl)-9H-xanthen-9-ol (H) with 1,4-dioxane (DIOX), cyclohexanol (CYOL), and cyclohexanone (CYONE) have been elucidated. The selectivity profile of the host with respect to the guest pairs dioxane/cyclohexanol and dioxane/cyclohexanone have been analyzed, as well as the mixed guest compound H · ½DIOX · 1CYONE. Thermal analysis and kinetics of desorption of these inclusion compounds have been performed and correlated with the structures. Introduction The process of molecular recognition can be studied by analyzing the selectivity of a host compound by a particular guest. Thus when a host H reacts with a guest G in solution: H + nG S H · nG
(1)
the equilibrium constant, K, can be evaluated from a knowledge of the activities of the host–guest complex and those of the free species. Chemists often approximate the activities to concentrations, in which case K ) [H · nG]/[H][G]n and the standard Gibbs free energy ∆G° ) -RT ln K is a measure of the molecular recognition occurring in the host–guest reaction, if one defines the standard state as 1 mol dm-3. The selectivity of a host binding two particular guests G1 and G2 is given by the thermodynamic selectivity ) KG1/KG2, and for reactions in solution this is discussed by Steed, Turner and Wallace in their recent book entitled Core Concepts in Supramolecular Chemistry and Nanochemistry, which reviews the basic concepts that underpin host–guest chemistry.1 However, when the host–guest compound precipitates from the saturated solution of the mother liquor, the evaluation of ∆G for the equilibrium reaction is more difficult, as it involves the accurate determinations of the solubilities of the host in the guest mixtures. This task is laborious and usually impractical due to the paucity of the host material. We have therefore adopted the concept of a selectivity coefficient KA:B, first enunciated by Ward2 and defined as KA:B ) (KB:A)-1 ) ZA/ZB * XB/XA, where for two guests A and B, XA, XB are the mole fractions in the liquid mixture and ZA, ZB are the mole fractions of the guests in the crystal. It is thus possible to analyze the selectivity coefficient of a host for a particular guest A, over the complete range of compositions of mixtures of guests A and B, by varying the mole fraction XA of the starting mixture systematically from 0 to 1. The crystals derived from each mixture are analyzed, and the mole fractions ZA, ZB of the enclathrated guests are determined by a suitable analytical technique. * To whom correspondence should be addressed. E-mail: nassimbenil@ cput.ac.za. † Cape Peninsula University of Technology. ‡ University of Cape Town. § Nelson Mandela Metropolitan University.
Figure 1. Enclathration selectivity profiles for two guests A and B where (a) represents zero selectivity, with KA:B ) 1; (b) A is preferred to B over the whole range, KA:B ≈ 6 and (c) the selectivity is concentration dependent.
Scheme 1. Atomic Numbering of the Host and Guests
The ensuing profiles are generally of three kinds and are shown in Figure 1. Figure 1a represents zero selectivity, KA:B ) 1 and is the result expected in situations where the structure of the inclusion compound is such that the topology of the space that accommodates the guest is sufficiently adaptable for either A or B, and the resulting structures form a series of solid solutions that are isomorphous. An example of the study of the enclathration of meta- and para-xylenes by the host cholic acid (CA), in which Miyata et al.3 elucidated the structures of a series of clathrates of CA with the mixed xylenes, and the selectivity profile slightly favored the para-xylene with a modest selectivity coefficient Kp-xylene:m-xylene = 2.5. Figure 1b shows the case where A is strongly preferred over B over the whole concentration range with a large selectivity coefficient. This is the situation where separation of the two guests is a practical proposition, and is particularly attractive for the pharmaceutical industry, where the separation of enantiomers is important. An example is the separation of
10.1021/cg7010343 CCC: $40.75 2008 American Chemical Society Published on Web 02/23/2008
1302 Crystal Growth & Design, Vol. 8, No. 4, 2008
Jacobs et al. Table 1. Crystal Data Table
compound structural formula molecular mass (g mol-1) data collection temp (K) crystal system, space group a (Å) b (Å) c (Å) R (°) β (°) Y (°) volume (Å3) Z Dc, calculated density (g cm-3) absorption coefficient µ (mm-1) F(000) crystal size (mm) theta range for data collection limiting indices reflections collected/unique data/restraints/parameters extinction coefficient goodness-of-fit on F2 final R indices [I > 2σ(I)] R indices (all data) largest diff peak and hole (e Å-3)
H · ½DIOX
H · 2CYOL
H · ½DIOX · 1CYONE
H · 2CYONE
C23H16O2 · ½C4H8O2 368.41 133(2) triclinic, P1¯ 9.0864(2) 9.4982(2) 10.8509(3) 84.116(1) 87.407(1) 89.219(1) 930.56(4) 2 1.315 0.085 388 0.05 × 0.11 × 0.18 2.72–25.64 -11,10; (11; -13,12 12119/5383 3145/0/258 0.033(6) 1.048 R1 ) 0.0383 wR2 ) 0.0921 R1 ) 0.0506 wR2 ) 0.1018 0.189 and -0.188
C23H16O2 · 2C6H12O 524.67 133(2) orthorhombic, Pn21a 12.2208(2) 14.3358(3) 16.2293(3) 90 90 90 2843.29(9) 4 1.226 0.078 1116 0.09 × 0.12 × 0.22 3.84–25.34 (14; (17; (19 31118/4982 4982/4/365 0.0043(9) 1.052 R1 ) 0.0469 wR2 ) 0.1092 R1 ) 0.0657 wR2 ) 0.1181 0.377 and -0.261
C23H16O2 · ½C4H8O2 · C6H10O 466.55 133(2) monoclinic, P21/n 9.5665(1) 8.7422(1) 29.1262(4) 90 95.523(1) 90 2424.58(5) 4 1.278 0.083 992 0.10 × 0.11 × 0.20 2.86–25.32 (11; (11; -35,34 8439/4421 4421/1/286 0.003(3) 1.109 R1 ) 0.0970 wR2 ) 0.2714 R1 ) 0.1258 wR2 ) 0.2948 1.325 and -1.046
C23H16O2 · 2C6H10O 520.64 173(2) triclinic, P1¯ 8.4229(2) 12.7825(3) 14.6721(3) 70.075(1) 89.937(1) 70.854(1) 1392.04(5) 2 1.242 0.080 556 0.09 × 0.11 × 0.13 1.88–25.42 (10; -13,15; -16,17 3282/16474 5044/0/291 0.007(6) 1.040 R1 ) 0.1526 wR2 ) 0.4021 R1 ) 0.1974 wR2 ) 0.4296 0.694 and -0.550
Table 2. Hydrogen Bonding Details structures H · ½DIOX H · 2CYOL H · ½DIOX · 2CYONE a
donor (D)-H · · · acceptor (A)
D · · · A (Å)
D-H (Å)
H · · · A (Å)
D-H · · · A (°)
O9-H9 · · · O1G O9-H9 · · · O1G1 O1G1-H1G1 · · · O1G2 O1G2-H1G2 · · · O9a O9-H9 · · · O1G1
2.790(2) 2.728(2) 2.730(2) 2.819(2) 2.800(4)
0.95(2) 0.97(1) 0.97(1) 0.97(1) 0.97(1)
1.87(2) 1.76(1) 1.77(1) 1.87(1) 1.86(1)
163(2) 177(3) 173(2) 167(3) 163(4)
Symmetry code: x - ½, y, -z + ½.
4-picoline from 3-picoline by inclusion with the host 2,2′dihydroxy-1,1′-binaphthyl.4 Figure 1c is the result obtained when the selectivity is concentration dependent, and the host favors the guest in greater concentration. This occurs in the separation of 3-aminobenzonitrile from 4-aminobenzonitrile by the host 1,1,6,6-tetraphenylhexa-2,4-diyne-1,6-diol.5 It is noteworthy that the selectivity
profiles obtained for this system give similar results whether carried out in solution or from direct solid–solid reactions. We now present the results of the competition experiments carried out with the host 9-(2-naphthyl)-9H-xanthen-9-ol (H) and the guests 1,4-dioxane (DIOX), cyclohexanone (CYONE), and cyclohexanol (CYOL), the structures of the inclusion compounds, their thermal stability, and their kinetics of desorption. The atomic numbering scheme is given in Scheme 1. Experimental Section
Figure 2. Crystal structure of H · ½DIOX: Projection viewed down [100]. All H atoms except the hydroxyl hydrogen on the host are omitted. The H-bonds are plotted as dotted lines.
Structure Analysis. Crystals of H · ½DIOX, H · 2CYONE, and H · 2CYOL were obtained by dissolving the host in excess of their respective guest and allowing slow evaporation. Crystals of H · ½DIOX · 1CYONE were grown from the guest mixture with XDIOX ) 0.5. Thermogravimetry (TG) was employed to establish the host/ guest ratios. The crystal data, X-ray intensity, data collection, and refinement details are given in Table 1. Cell dimensions were established from the intensity data measured on a Kappa CCD diffractometer using graphite-monochromated MoKR radiation. The strategy for the data collection was evaluated using COLLECT software,6 and for all structures, the intensity data were collected by the standard phi scan and omega scan techniques and scaled and reduced using the program DENZO-SMN.7 The structures were solved by direct methods and refined by full-matrix least-squares on F2 using SHELX-97 program packages.8 The program X-seed9 was used as a graphical interface. For structures H · ½DIOX, H · 2CYOL, and H · ½DIOX · 1CYONE, all the non-hydrogen atoms were positioned using direct methods and refined anisotropically; the hydroxyl hydrogens were located in the difference electron density maps and refined with simple bond-length constraints,10 and the remaining hydrogen atoms were fixed in positions and refined isotropically. The elucidation of the H · 2CYONE structure was difficult in that high-quality crystals were not obtained. We carried
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Crystal Growth & Design, Vol. 8, No. 4, 2008 1303
Figure 5. Crystal structure of H · ½DIOX · 1CYONE: Space-filling diagram projected down [010] showing the open channels. All atoms of guest molecules are omitted, and the host molecules are represented using van der Waals radii.
Figure 3. Crystal structure of H · 2CYOL: A host molecule lies on the imagined mirror plane with two cyclohexanol molecules that deviate from this. Only hydroxyl hydrogens are shown, and all other H atoms are omitted. The hydrogen bonds are plotted as dotted lines. O9‡ comes from a host molecule via symmetry operation x - ½, y, -z + ½.
guest in crystals were analyzed by NMR spectroscopy on a Varian Unity 400 MHz spectrophotometer. Appropriate integrations of the peaks were carried out: the host from a proton in the δ ) 8.1–8.3 region, the eight dioxane protons were identified at δ ) 3.64, the four CH2CO protons of cyclohexanone at δ ) 2.30 and the cyclohexanol from the multiplet at δ ) 3.53–3.61. Thermal Analysis and Kinetics. Both TG and differential scanning calorimetry (DSC) were performed on a Perkin-Elmer Pyris 6 system. Crystals were blotted and crushed for analysis. Experiments were conducted from 303 to 473 K using a nitrogen gas purge at 30 mL min-1. Samples were placed in open ceramic pans for TG and in crimped but vented pans for DSC. The kinetics of desorption for both the cyclohexanol and the cyclohexanone compounds were determined using non-isothermal methods. A powdered sample of the cyclohexanol compound was grown for the analysis, and the PXRD confirmed that it had the same structure as that of the crystal. For the cyclohexanone compound crushed crystals were used for the kinetics experiments. Attempts at growing a powdered sample resulted in mass losses that deviated from the expected result.
Results and Discussion
Figure 4. Crystal structure of H · 2CYONE: Space-filling diagram projected down the line 1j10 showing alternative layers of host and guest molecules. The atoms of guest molecules are represented using van der Waals radii with the host molecules in stick form. out several syntheses and analyzed three different crystals grown from different mother liquors. The results presented are from the best available crystal, which had a high mosaicity of 1.54°. While all the host atoms are well refined with anisotropic temperature factors, the guest molecules display considerable disorder, each yielding two positions for the carbonyl oxygens, which were assigned site occupancies of 0.5. The hydroxyl hydrogen as well as the H atoms on the guests were not included in the final model. The final R index was 0.155. We are, however, confident of the overall structure, with regard to the relative positions of the host and guest molecules and the hydrogenbonded interactions. Competition Experiments. These were carried out by dissolving 20 mg of the host in mixtures of the two guests: 1,4-dioxane/ cyclohexanone and 1,4-dioxane/cyclohexanol, so that the mole fraction of dioxane varies systematically from 0 to 1 in the liquid mixtures. The guest mixture was always in excess, with a host/total guest ratio of approximately 1:20. The solutions were allowed to crystallize, the ensuing crystals were dried on blotting paper, and the ratios of host/
H · ½DIOX crystallized in the space group P1¯, with the host in a general position and the 1,4-dioxane located on a center of inversion. The structure is stabilized by (host)O-H · · · O(DIOX) hydrogen bonds with d(O · · · O) ) 2.790(2) Å, and the guest molecules are located in highly constricted channels running in the [001] direction. The packing is shown in Figure 2. The metrics of the hydrogen bonds for all structures are given in Table 2. The structure of H · 2CYOL was initially solved in the space group Pnma with Z ) 4. This required the host molecule to lie on the mirror plane. However, the refinement was unsatisfactory, had a high R factor of 0.15, with the cyclohexanol guest molecule exhibiting apparent disorder and poor bond lengths and angles. We noted the E-distribution statistics were ambiguous, giving values intermediate between centric and acentric conditions. We therefore released the mirror symmetry and re-refined the structure in the space group Pn21a. This yielded a satisfactory final model, with credible bond lengths and angles and atomic temperature factors. Interestingly, the host still displays mirror symmetry, but the two cyclohexanol guest molecules deviate significantly from this, as shown in Figure 3. H · 2CYONE crystallized in the space group P1¯ with Z ) 2, so that all molecules are in general positions. There are two (host)O-H · · · O(CYONE) hydrogen bonds with d(O · · · O) ) 2.80(2) and 2.86(3) Å. The structure is characterized by alternating layers of host and guest molecules that are located on the (110) planes, as shown in Figure 4. H · ½DIOX · 1CYONE crystallized in the space group P21/n with Z ) 4, requiring the dioxane to be located on a center of symmetry.
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Jacobs et al.
Figure 6. (a) Selectivity profile of 1,4-dioxane/cyclohexanone showing the mole fraction ZDIOX in the crystal vs XDIOX in the mother liquor. (b) Triangular diagram showing the mole fraction of the host H Vs those of the two guests dioxane and cyclohexanone. The three clusters correspond to the three stoichiometries of the compounds obtained.
Figure 7. (a) Selectivity profile of 1,4-dioxane/cyclohexanol. (b) The triangular diagram shows that when XDIOX g 0.4, the scattered points correspond to mixtures of crystalline compounds.
The cyclohexanone guests are located in channels running in the [010] direction, and the dioxane is hydrogen bonded to the host with d(O · · · O) ) 2.800(4) Å. The packing, with the guests omitted, and with the host atoms represented using van der Waals radii is shown in Figure 5, which clearly displays the channels. The selectivity profile for the dioxane/cyclohexanone system is shown in Figure 6a, in which the mole fraction of the dioxane
included in the crystals, ZDIOX, is plotted against the mole fractions of dioxane, XDIOX, in the starting mixture. We note that for XDIOX 0–0.3 only cyclohexanone is included, then the compound H · ½DIOX · 1CYONE is formed when XDIOX ) 0.4–0.7, and finally only dioxane is included for XDIOX g 0.8. This steplike profile is unusual, although we have noted two other examples: the host trans-9,10-dihydroxy-9,10-bis(p-tertbutylphenyl)-9,10-dihydroanthracene forms inclusion compounds with DMF and DMSO of the type host · nDMF · (4n)DMSO, in which five distinct compounds were isolated;6 and the host 9,9′-(ethyne-1,2-diyl)difluoren-9-ol that includes ethanol and acetonitrile with a constant ratio of these guests over the whole range of the guest mixture.7 The selectivity profile shown in Figure 6a displays the relative amount of the two guests enclathrated for any given concentration of the guests in the starting solution. However, it suffers Table 3. Thermal Analysis Data
Figure 8. TG and DSC of H · 2CYONE.
inclusion compound
H · ½DIOX
H · 2CYOL
H · 2CYONE
H:G ratio TG (calc % mass loss) TG (exp % mass loss) DSC (Ton/K) A B
1:½ 11.9 11.6
1:2 38.2 38.4
1:2 37.7 36.5
395.8 463.4
368.1 457.3
353.8 461.6
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for different extents of decomposition varying systematically from 5 to 30%. The lines are practically parallel indicating an unchanging mechanism of desorption, corresponding to an activation energy range of 91.2–104.5 kJ mol-1. Similar results were obtained for the desorption of H · 2CYONE with an activation energy range of 77.4–92.2 kJ mol-1. Conclusion
Figure 9. Plot of -log β vs 1/T for H · 2CYOL.
from the weakness of not showing the host to guest ratios. We have therefore plotted the results on a triangular diagram the apexes of which represent pure host (H) and the two guests dioxane (DIOX) and cyclohexanone (CYONE) as shown in Figure 6b, where the stoichiometry is plotted as a mole fraction. The 11 results thus obtained cluster in three distinct groups as H · ½DIOX, H · ½DIOX · 1CYONE, and H · 2CYONE, which correspond to the stoichiometries of the crystal structures elucidated. The selectivity profile for the dioxane/cyclohexanol system is shown in Figure 7a and is different from that of the previous system, in that no new compound with mixed guests was obtained. For 0 e XDIOX e 0.3, only cyclohexanone is included and for XDIOX g 0.4 the ZDIOX rises steadily from 0.6 to 1. In this region we obtained mixtures of crystals of the pure H · ½DIOX (plates) and H · 2CYOL (needles) compounds. These were identified visually under the microscope and were confirmed by measuring their unit cell parameters. The corresponding triangular diagram shown in Figure 7b shows one cluster corresponding to the structure H · 2CYOL, a scattered plot of the mixture of crystals, and the compound H · ½DIOX. Thermal Analysis and Kinetics. The thermal analysis of H · 2CYONE is shown in Figure 8. The TG curve shows a single step loss for the guest release. DSC shows an initial complex endotherm, A, associated with the loss of the cyclohexanone, followed by the endotherm B due to the host melt. Similar thermal profiles were observed for H · ½DIOX and H · 2CYOL. Table 3 gives the details of the thermal analysis results. We monitored the kinetics of desolvation for both H · 2CYOL and H · 2CYONE. This was carried out using the method of Flynn and Wall13 in which the mass loss was recorded as a function of temperature (T) at selected heating rates (β) varying from 1 K min-1 to 20 K min-1. The plot of -log β versus T-1 for H · 2CYOL is shown in Figure 9. The graphs are plotted
When a given host compound is exposed to a mixture of guests, the ensuing crystalline inclusion compounds depend on the nature and relative proportions of the guests in the mother liquor. In the case of a single host and a binary mixture of guests, the stoichiometry of the ensuing clathrates is usefully represented on triangular diagrams, and a combination of NMR spectroscopy and X-ray crystallography elucidate and correlate the structural results. The latter are sensitive to the nature of the guests, and small variations in the host–guest interactions may give rise to significantly different results. Acknowledgment. We thank the NRF (Pretoria) and the CPUT for funding.
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