POROUS CHIRAL MATERIALS AND USES THEREOF

Abstract

A porous chiral material of formula [M(L).sub.1.5(A)].sup.+X.sup. wherein M is a metal ion; L is a nitrogen-containing bidentate ligand; A is the anion of mandelic acid or a related acid; and X.sup. is an anion

Claims

1. A porous chiral material of formula [M(L).sub.1.5(A)].sup.+X.sup. wherein M is a metal ion; L is a nitrogen-containing bidentate ligand; A is the anion of mandelic acid or a related acid; and X.sup. is an anion.

2. A porous chiral material according to claim 1 wherein M is selected from a group consisting of: cobalt, chromium, iron, nickel, manganese, calcium, magnesium, cadmium, copper and zinc.

3. A porous chiral material according to claim 1 wherein L is selected from a group consisting of: 4,4-bipyridine, 1,2-bis(4-pyridyl)ethane, and 4,4-bipyridylacetylene.

4. A porous chiral material according to claim 1 wherein A is the anion of (S)-()-mandelic acid.

5. A porous chiral material according to claim 1 wherein X.sup. is a triflate ion.

6. (canceled)

7. A material of formula [M(L).sub.1.5(A).sup.+]X.sup.G.sub.n wherein M is a metal ion; L is a nitrogen-containing bidentate ligand; A is an anion of mandelic acid or a related acid; X.sup. is an organic anion; G is a guest molecule; and n is from 0 to 5.

8. (canceled)

9. A crystalline sponge comprising a porous chiral material of formula [M(L).sub.1.5(A)].sup.+X.sup..

10. A method of separating enantiomers, the method comprising contacting a composition comprising a mixture of enantiomers with a material of claim 1.

11. (canceled)

12. A method of separating enantiomers according to claim 10, the method comprising passing a composition comprising the mixture of enantiomers through a chromatography column comprising as a stationary phase a chiral porous material of formula [M(L).sub.1.5(A)].sup.+X.sup. wherein M is a metal ion; L is a nitrogen-containing bidentate ligand; A is an anion of mandelic acid or a related acid; and X.sup. is an anion.

13. A method of separating enantiomers according to claim 12, the method comprising: (a) passing a composition comprising the mixture of enantiomers through a chromatography column comprising as a stationary phase a chiral porous material of formula [M(L).sub.1.5(A)].sup.+X.sup.; (b) contacting the composition comprising the mixture of enantiomers with a crystalline chiral porous material of formula [M(L).sub.1.5(A)].sup.+X.sup. for a period sufficient for the composition to equilibrate; and (c) obtaining the crystal structure of the material obtained in step (b), thereby identifying an enantiomer.

Description

EXAMPLES

[0162] All reagents and solvents were commercially available and used as received.

[0163] Instrumentation

[0164] Powder X-Ray diffraction was performed on a PANalytical X'Pert MPD Pro using Cu K (=1.5418 ) radiation with a 1D X'Celerator strip detector. Single crystal data were collected on a Bruker Quest PHOTON 100 CMOS system equipped with a Cu K INCOATEC Imus micro-focus source (A=1.5418 , T=100(2) K). Thermogravimetric analysis was performed using a TA Instruments TGA-Q50 at a constant rate of 5 C./min from 25 C. to 550 C. SEM images were taken by Hitachi SU-70 and JEOL JSM-7500F systems with high resolution. Gas chromatographic measurements were performed on a GC-14B (Shimadzu, Japan) system with flame ionization detector. Nitrogen (99.999%) was used as the carrier gas. A -DEX 225 capillary column (30 m long0.25 mm i.d.0.25 m film thickness, Supelco Inc.), a Chirasil L-Val capillary column (25 m long0.25 mm i.d.0.12 m film thickness, Agilent Technologies), and a Cyclosil-B capillary column (30 m long0.32 mm i.d.0.25 m film thickness, Agilent Technologies) were employed as commercial columns for comparison.

[0165] X-Ray Structure Analysis

[0166] This was carried out using standard techniques known to those skilled in the art. In all cases indexing was performed using APEX2 Data integration and reduction were performed using SaintPlus 6.01 as provided by Bruker. Absorption correction was performed by multi-scan method implemented in SADABS. Space groups were determined using XPREP implemented in APEX2. Structures were solved using Patterson Method (SHELXS-97), expanded using Fourier methods and refined on F.sup.2 using nonlinear least-squares techniques with SHELXL-97 contained in APEX2, WinGX v1.70.01 and OLEX2 v1.2.6 programs packages. All non-H framework atoms as well as ordered guest molecules and anions were refined anisotropically and without restraints or constraints. Atoms of disordered guest molecules have been found from difference Fourier map and were initially refined freely, however due to overlap of disordered parts the restraints have been used to impose feasible geometry on molecules. The targeted distances have been taken from CSD Database.

Example 1Synthesis of [Co(biyp).SUB.1.5.(1S)].SUP.+.OTf.SUP. .(Material A)

[0167] Material A may be prepared by four different methods, as follows:

[0168] (i) Solvent Layering

[0169] A 5 mL methanol solution of 0.4 mmol Co(CF.sub.3SO.sub.3).sub.2.6H.sub.2O (180 mg) and 0.4 mmol of enantiopure (S)-mandelic acid (1S, 60.8 mg) was layered above a 5 mL 1,2-dichlorobenzene (DCB) solution of 0.6 mmol 4,4-bipyridine (bipy, 93.6 mg). The amount of bipy can be varied from 0.3-0.6 mmol (46.8-93.6 mg). A buffer solution of 5 mL 1:1 methanol/DCB was layered between the top and the bottom layers to allow for slow diffusion over 7 days. Red rectangular prismatic crystals were harvested and exchanged with dichloromethane (DCM) daily for 5 days to remove DCB. The resultant crystalline samples were stored in neat DCM prior to use in further experiments.

[0170] The crystal structure of [Co(biyp).sub.1.5(1S)].sup.+OTf.sup. is shown in FIG. 1.

[0171] (ii) Direct Mixing

[0172] 0.8 mmol Co(CF.sub.3SO.sub.3).sub.2.6H.sub.2O (360 mg) and 0.8 mmol of enantiopure (S)-mandelic acid (1S, 121.6 mg) was stirred in a 5 mL of methanol. A solution of 1.2 mmol bipy (187.2 mg) in 5 mL DCB was added to and stirred over one day. The amount of bipy can be varied from 0.6-1.2 mmol (93.6-187.2 mg). The pink nanocrystalline powder thereby obtained was filtered and washed with DCM (20 mL) 10 times. The resultant material was stored in neat DCM prior to use in further experiments.

[0173] (iii) Solvothermal Reaction

[0174] A solution of 0.8 mmol Co(CF.sub.3SO.sub.3).sub.2.6H.sub.2O (360 mg) and 0.8 mmol of enantiopure (S)-mandelic acid (15, 121.6 mg) was stirred in 5 mL methanol at 80 C. 1.2 mmol bipy (187.2 mg) dissolved in 5 mL DCB at 80 C. was added over one day with continuous stirring. The amount of bipy can be varied 0.6-1.2 mmol (93.6-187.2 mg). The pink powder thereby obtained was filtered and washed with DCM (20 mL) 10 times. The resultant material was stored in neat DCM prior to use in further experiments. [0175] (iv) Mechanosynthesis

[0176] 0.4 mmol Co(CF.sub.3SO.sub.3).sub.2.6H.sub.2O (180 mg) and 0.4 mmol enantiopure (S)-mandelic acid (1S, 60.8 mg) was ground in a mortar and pestle for 1 min. 0.6 mmol bipy (93.6 mg) was then placed in the mortar along with 20 L of DCB. The mixture was further ground for 1 minute and then transferred to an 85 C. oven for 15 min. The resultant powder was washed with DCM (10 mL) 5 times and stored in neat DCM prior to use in further experiments.

Example 2Fabrication of Capillary Column Coated with Material A

[0177] Fused silica capillary (30 m long0.32 mm i.d., Yongnian Optic Fiber Plant, Hebei, China) was pretreated according to the following recipe before dynamic coating: the capillary was washed with 1 M NaOH for 2 h, ultrapure water for 30 min, 0.1 M HCl for 2 h, and ultrapure water until the outflow reached pH 7.0.

[0178] The capillary was then dried with N.sub.2 at 100 C. overnight. Material A was coated onto the pre-treated capillary column via a dynamic coating method. 3 mL DCM suspension of material A (1 mg/mL) was first filled into the capillary column under gas pressure, and then pushed through the column at a constant N.sub.2 pressure of 20 KPa to leave a wet coating layer on the inner wall of the capillary column. After coating, the capillary column was settled for 2 h for conditioning under N.sub.2. Further conditioning of the capillary column was carried out using a temperature program: 30 C. for 10 min, ramp from 30 C. to 150 C. at a rate of 3 C. min.sup.1, and 150 C. for 2 h.

Example 3Inclusion of Racemates and Other Guest Molecules in Single Crystals of Material A

[0179] Multiple single crystals of [Co(byp).sub.135(1S)].sup.+OFT.sup. were submerged in excess amounts of neat racemates and other guest molecules at ambient temperature for a time sufficient to reach equilibrium, typically believed to be about 5 days from previous experiments. By placing multiple crystals in parallel, it increases the probability of selecting high quality crystal for SCXRD examination.

Example 4Microgram Scale Inclusion of Geraniol and Nerol in Material A

[0180] A 20 uL DCM solution of 17 mg geraniol or nerol was added to a 0.3 mL Qsertvial low adsorption vial. A single crystal of material A was placed at the bottom of the vial and submerged in the solvent. Then the vial was loosely capped to allow DCM evaporation over 2 days. The crystal was coated in immersion oil for transfer and mounting. The inventors were able to determine the crystal structures of these compounds for the first time. FIG. 7 shows the binding sites of geraniol (a) and nerol (d) in Material A. Structural formulae (b, e) and molecular structures (c, 0 of geraniol and nerol, respectively. Thermal ellipsoids are drawn at the 50% probability level.

Example 5Stability Test

[0181] The crystalline sample of desolvated material A was exposed to 40 C. and 75% relative humidity for 7 days in a desiccator. The condition was achieved by using a supersaturated aqueous solution of NaCl maintained at 40 C. After 7 days, the samples were removed from the desiccator and characterized by PXRD. The results showed that material A remained stable under these humidity conditions. The heat stability of the material A was tested by heating the material progressively to 300 C. Powder X-ray diffraction patterns were taken at various temperatures as the material was heated. The results shown in FIG. 8 demonstrate that the crystal structure of the material did not change following heating to 300 C.

Example 6Synthesis of Other Materials

[0182] The following further materials were prepared as follows:

[0183] [Co(bipy).sub.1.5(2R)][OTf] (Material B)

[0184] The same procedure as that used to prepare compound A was followed with the exception that (R)-2-chloromandelic acid (0.40 mmol, 740 mg, 2R) was used instead of (S)-mandelic acid (1S). Red rectangular prismatic crystals were obtained in 75% yield. A view of the crystal structure of [Co(bipy).sub.1.5(2R)][OTf].DCB is presented in FIG. 2. Guest molecules are omitted for clarity.

[0185] [Co(bipy).sub.1.5(3R)][OTf] (Material C)

[0186] The same procedure as that used to prepare compound A was following with the exception that (R)-3-chloromandelic acid (0.40 mmol, 740 mg, 3R) was used instead of (S)-mandelic acid (1S) and benzotrifluoride (BTF) was instead of DCB. Red rectangular prismatic crystals were obtained in 75% yield. The crystals aggregate as clusters which are not suitable for study by single crystal X-ray crystallography. The Zn(II) analogue, [Zn(bipy).sub.1.5(1S)][OTf].BTF, was synthesized by using Zn(OTf).sub.2.6H.sub.2O (150 mg). A view of the crystal structure of [Zn(bipy).sub.1.5(3R)][OTf].BTF is presented in FIG. 3. Guest molecules are omitted for clarity.

[0187] [Co(bipy).sub.1.5(4R)][OTf] (Material D)

[0188] The same procedure as that used to prepare compound A was followed with the exception that (R)-3-chloromandelic acid (0.40 mmol, 740 mg, 4R) was used instead of (S)-mandelic acid (1S) and benzotrifluoride (BTF) was used instead of DCB, was followed. Red rectangular prismatic crystals were obtained in 75% yield. A view of the crystal structure of [Co(bipy).sub.1.5(4R)][OTf].BTF is presented in FIG. 4. Guest molecules are omitted for clarity.

[0189] [Co(bipy).sub.1.5(13R)][OTf].BTF (Material E)

[0190] The same procedure as that used to prepare material A was followed with the exception that (R)-4-methylmandelic acid (0.4 mmol, 660 mg, 13R) was used instead of (S)-mandelic acid (1S) and benzotrifluoride (BTF) was used instead of DCB, was followed. Red rectangular prismatic crystals were obtained in 75% yield. A view of the crystal structure of [Co(bipy).sub.1.5(13R)][OTf].BTF is presented in FIG. 5. Guest molecules are omitted for clarity.

[0191] [Co(LB).sub.1.5(1S)][OTf] (Material F)

[0192] Material F was prepared by the following solvent layering method: A solution of 0.4 mmol Co(CF.sub.3SO.sub.3).sub.2.6H.sub.2O (180 mg) and 0.4 mmol of (S)-mandelic acid (1S, 60.8 mg) in 5 ml of methanol was layered above a buffer solution which had in turn been layered above a solution of 0.6 mmol 1,2-bis(4-pyridyl)ethane (LB, 110.4 mg) in 5 mL 1,2-dichlorobenzene (DCB). The amount of LB can vary from 0.3-0.6 mmol (55.2-110.4 mg). The buffer solution was 5 mL of 1:1 methanol/DCB. These solvent layers were allowed to diffuse over 7 days, at which point red rectangular prismatic crystals had formed. These crystals were harvested and exchanged with dichloromethane (DCM) daily for 5 days to remove DCB. The resultant crystalline samples were stored in DCM prior to further use.

[0193] The crystal structure of [Co(LB).sub.1.5(1S)][OTf].DCM is shown in FIG. 6. Guest molecules are omitted for clarity.

[0194] Crystallographic parameters for materials A to F are given in table 1:

TABLE-US-00001 TABLE 1 [Co(bipy).sub.1.5(1S)][OTf]DCB [Co(bipy).sub.1.5(2R)][OTf]DCB [Zn(bipy).sub.1.5(3R)][OTf]BTF [Co(bipy).sub.1.5(4R)][OTf]BTF formula C.sub.59.42H.sub.45.61Cl.sub.3.81Co.sub.2F.sub.6N.sub.6O.sub.12S.sub.2 C.sub.58.8H.sub.43.2Cl.sub.6CO.sub.2F.sub.6N.sub.6O.sub.12S.sub.2 C.sub.55.8H.sub.40Cl.sub.2F.sub.9N.sub.6O.sub.12.8S.sub.2Zn.sub.2 C.sub.57H.sub.49Cl.sub.2Co.sub.2F.sub.9N.sub.6O.sub.14S.sub.2 fw 1466.48 1534.47 1436.10 1465.90 T (K) 100(2) 100(2) 100(2) 100(2) cryst system Monoclinic Monoclinic Orthorhombic Monoclinic space group P2.sub.1 P2.sub.1 P2.sub.12.sub.12.sub.1 P2.sub.1 a () 10.3499(5) 10.3260(5) 10.2977(4) 10.1623(4) b () 25.4610(12) 25.5247(11) 22.9238(9) 25.6092(11) c () 11.4211(6) 11.4411(5) 25.5012(10) 11.4729(5) () 91.403(3) 91.155(2) 90 90.244(3) V (.sup.3) 3008.8(3) 3014.9(2) 6019.9(4) 2985.8(2) Z 2 2 4 2 Dc (g .Math. cm.sup.3).sup.a 1.308 1.382 1.386 1.394 (mm.sup.1) 7.281 8.171 3.286 6.709 F (000) 1490.0 1552.0 2905.0 1492.0 R.sub.int 0.0584 0.0523 0.0637 0.0746 GOF 1.045 1.118 1.101 1.054 R.sub.1 (I > 2(I)) 0.0509 0.0815 0.0689 0.0659 wR.sub.2 (all data) 0.1159 0.1875 0.2031 0.1456 .sub.max (e .sup.3) 0.77 0.84 2.38 0.52 .sub.min (e.sup.3) 0.64 0.76 0.57 0.55 Flack 0.048(4) 0.246(5) 0.150(6) 0.079(4) [Co(bipy).sub.1.5(13R)][OTf]BTF [Co(LB).sub.1.5(1S)][OTf]DCM formula C.sub.59H.sub.55Co.sub.2F.sub.9N.sub.6O.sub.14S.sub.2 C.sub.57.27H.sub.57.54Cl.sub.6.55Co.sub.2F.sub.6N.sub.6O.sub.12.77S.sub.2 fw 1425.07 1562.19 T (K) 100(2) 100(2) cryst system Monoclinic Monoclinic space group P2.sub.1 P21 a () 10.1791(3) 13.5720(4) b () 25.6037(8) 10.1658(3) c () 11.4781(4) 26.4276(8) () 90.4539(18) 103.3217(17) V (.sup.3) 2991.36(17) 3548.11(18) Z 2 2 Dc (g .Math. cm.sup.3).sup.a 1.347 1.189 (mm.sup.1) 5.874 7.140 F (000) 1460.0 1593 R.sub.int 0.0590 0.0739 GOF 1.089 1.079 R.sub.1 (I > 2(I)) 0.0655 0.0906 wR.sub.2 (all data) 0.1511 0.2163 .sub.max (e .sup.3) 0.60 0.87 .sub.min (e.sup.3) 0.53 0.86 Flack 0.173(5) 0.191(5) .sup.acalculated for activated materials.

Example 7Separation of Enantiomers

[0195] The gas chromatography column of example 2 was used to separate enantiomers of the following compounds: (a) 1-phenylethanol, (b) 1-phenyl-1-propanol, (c) 1-phenyl-2-propanol, (d) -vinylbenzyl alcohol, (e) 2-phenylpropanenitrile, (f) 1-phenyl-1-butanol, (g) 1-phenyl-1-pentanol, (h) 1-phenyl-2-butanol, (i) -cyclopropylbenzyl alcohol, and (j) 2-phenylbutyronitrile.

[0196] The chromatograms for the separation of these compounds is shown in FIG. 9.

[0197] The separation was found to be superior to that achieved for the same racemic mixtures using three different types of known commercial chiral columns (-DEX 225, Cyclosil-B, and Chirasil L-Val). The comparative data is shown in table 2.

TABLE-US-00002 TABLE 2 Material A -DEX 225 Cyclosil-B Chirasil L-Val No. T.sup.a P.sup.b t.sup.c R.sup.d T.sup.a P.sup.b t.sup.c R.sup.d T.sup.a P.sup.b t.sup.c R.sup.d T.sup.a P.sup.b t.sup.c R.sup.d a 130 150 2.1 1.5 130 150 5.5 1.5 130 150 6.5 1.5 80 100 9.0 1.1 b 150 150 1.7 1.5 120 150 9.7 1.5 150 150 4.6 .sup.e 100 125 6.0 1.1 c 150 150 1.7 1.5 110 150 13 1.7 130 150 7.2 1.5 150 150 1.7 .sup.e d 140 150 2.1 1.4 120 150 11 1.9 140 150 7.5 1.2 100 150 5.0 0.5 e 150 150 2.4 1.4 115 150 13 1.5 150 150 4.2 2.2 150 150 1.5 .sup.e f 135 100 4.0 1.5 110 150 20 1.6 110 150 30 1.3 135 150 4.5 .sup.e g 150 100 3.0 1.4 150 150 8.0 .sup.e 150 100 13 1.7 100 150 12.0 0.8 h 130 150 5.0 1.5 150 150 6.0 .sup.e 130 150 11 1.5 80 150 12.0 1 i 150 150 3.5 1.5 130 150 15 1.7 150 150 9.0 .sup.e 100 150 12 0.3 j 150 150 2.5 1.4 120 150 14 0.4 150 150 5.4 2.2 150 150 2.0 .sup.e .sup.aseparation temperature ( C.), .sup.bN.sub.2 pressure (KPa), .sup.ctotal separation time (min), .sup.dresolution, .sup.ecannot be separated. All the separations were performed with optimized conditions.

Example 8

[0198] In order to gain insight into the nature of the supramolecular interactions between the analytes and the pores of material A, the inventors isolated and studied by SCXRD the ten host-guest compounds formed after crystals of material A were exposed for 5 days to the racemates used in example 7. Existing CSPs (e.g., polysaccharides and cyclodextrins) are not amenable to diffraction studies so the precise nature of preferred binding sites in a CSP has not yet been directly observed. That material A has an extra-framework cation enables its cavities to adapt to the guest. When coupled with its low symmetry space group, this adaptability allowed the inventors to observe the binding sites of material A using in high resolution using a conventional x-ray diffractometer. The absolute configurations of the preferred chiral guest molecules were unambiguously determined and validated thanks to the anomalous scattering effects of heavy atoms (Co and S). The host-guest binding sites are resolved for all 10 racemates. The absolute configuration of the chiral analytes was found to correspond with the longest retention time as confirmed by using an enantiopure reference standard for all 10 examples. The guest binding sites and absolute configuration of compounds b and c are shown in FIG. 10 and FIG. 11 respectively.

Example 9

[0199] The ability of material A to act as a chiral crystalline sponge to facilitate crystallisation and structure determination was tested successfully for the following further guest molecules: Dichloromethane, carbon disulphide, acetonitrile, 2-propanol, hexane, cyclohexane, toluene, 1,2-dichlorobenzene, allyl alcohol, allyl chloride, 1-bromopropane, 1-bromoheptane, 1-bromononane, 1-bromododecane, linalool, citral, citronellol and 1-decen-3-ol.