Article pubs.acs.org/crystal
Ammonium Salts of Lithocholic Acid: Structures and Kinetics Luigi R. Nassimbeni,*,† Nikoletta B. Báthori,‡ and Tanith-Lea Curtin† †
Centre for Supramolecular Chemistry Research, Department of Chemistry, University of Cape Town, Private Bag, Rondebosch 7701, South Africa ‡ Crystal Engineering Unit, Department of Chemistry, Faculty of Applied Sciences, Cape Peninsula University of Technology, P.O. Box 652, Cape Town, 8000, South Africa ABSTRACT: Lithocholic acid (LCA) forms salts with n-propylamine (PPA) and sec-butylamine (sec-BUAM). The structure of (LCA−)(PPA+)·EtOH has been elucidated. LCA completely resolves sec-butylamine and the structure of (LCA−)((R)-BUAM+) has a similar packing arrangement. The kinetics of enclathration of LCA with PPA and the kinetics of decomposition of both compounds have been measured.
1. INTRODUCTION Lithocholic acid (LCA) is one of the bile acids, which consist of a steroidal skeleton and a flexible side chain. The skeleton can accommodate up to three hydroxyl groups and two methyl groups which give rise to hydrophilic and lipophilic faces respectively. The best known examples are cholic acid (CA) and deoxycholic acid (DCA), which are excellent host compounds and form inclusion compounds with a wide variety of guest molecules. The structures and packings of the bile acids and their derivatives have been reviewed,1,2 and the packing coefficients of the host cavities, a measure of the molecular recognition between the host and guest, have been discussed. LCA, however, is not a good host compound and Miyata2 states that attempts to form inclusion compounds with more than 100 organic compounds all failed. The Cambridge Structural Database (Version 5.33) only lists two structures, that of the apohost3 and that of its melaminium salt.4 In this work we present the structures of the salts formed by reacting LCA with n-propylamine (PPA) and sec-butylamine (BUAM), as well as their kinetics of enclathration and decomposition. The atomic numbering scheme for the host and guests is given in Scheme 1.
the instability of the compound which was used in powdered form for the thermal analysis and which is discussed later. The structure is characterized by layers of the lithocholate anions and the propylammonium/EtOH moieties, as shown in Figure 1b. The structure of (LCA−)((R)-BUAM+) crystallizes in the space group P21 with Z = 2. The BUAM+ cation was disordered in two positions (59% and 41%), and both positions were occupied by the R enantiomer. There is no evidence of the S enantiomer of sec-butylamine in the structure. Therefore complete resolution has been achieved. The structure of the asymmetric unit is shown in Figure 2a, which also displays the N+···O− contacts. The packing is similar to that of the previous structure (Figure 2b).
3. THERMAL GRAVIMETRY The thermal gravimetry curve for the decomposition of (LCA−)(PPA+)·EtOH is shown in Figure 3. The decomposition takes place in two steps. The first step A is due to desorption of the EtOH (calc. 10.9%, expt. 9.7%). This is followed by a plateau B and the second decomposition due to the loss of the n-propylamine (calc. 13.6%, expt. 12.5%). The thermal gravimetry curve for the decomposition of (LCA−)(BUAM+) is shown in Figure 4, which displays a single mass loss due to the sec-butylamine (calc. 16.3%, expt. 16.0%). For both the ammonium salts, the onset of the amine-release reaction is significantly greater than the normal boiling points of the respective amines (bp PPA = 48 °C, bp BUAM = 63 °C), testifying to the enhanced stability of the respective salts.
2. STRUCTURES Crystal data and experimental and refinement parameters are given in Table 1. The structure of (LCA−)(PPA+)·EtOH crystallizes in the space group P21 with Z = 2. We experienced difficulties with the refinement of this structure due to the severe disorder in the carboxylate moiety of the lithocholate anion and the propylammonium cation (Figure 1a). No hydrogen atoms were revealed at the nitrogen in the final difference electron density map. The ethanol solvate molecule was also severely disordered and exhibited very high temperature factors. This correlates with © 2012 American Chemical Society
Received: May 14, 2012 Revised: June 20, 2012 Published: July 11, 2012 4144
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Scheme 1. Atomic Numbering of Host (LCA, lithocholic acid) and Guest Compounds
a similar result was recorded for the kinetics of enclathration of n-propylamine by the host 9−9′-(biphenyl-4,4′-diyl)difluoren9-ol at 25 °C, which also followed the contracting volume equation and displayed a threshold pressure of 273 mbar.6 This phenomenon was also noted for the kinetics of inclusion of acetone vapor by the host trans-9,10-dihydroxy9,10-diphenyl-9,10-dihydroanthracene, which was carried out at 284, 293, and 303 K at vapor pressures ranging from 50 to 240 mbar, and for which we noted that the reaction displayed anti-Arrhenius behavior.7
Table 1. Crystallographic Data and Structure Refinement Parameters (LCA−)(PPA+)·EtOH
structure moiety formula Mr temperature (K) crystal size (mm3) crystal system space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z ρ (calcd) (Mg m−3) μ(Mo−Kα) (mm−1) theta range for data collection (deg) reflections collected no. of parameters no. unique data no. data with I > 2σ(I) final R (I > 2σ(I)) final wR2 (all data) S
(LCA−)((R)BUAM+)
(C24H39O3−) (C3H10N+)·0.7C2H6O 468.61 173(2) 0.18 × 0.15 × 0.10 monoclinic P21 10.935(3) 7.735(2) 17.905(4) 90.00 106.558(5) 90.00 1451.7(6) 2 1.072 0.069 1.94−26.59
(C24H39O3−) (C4H12N+) 539.69 173(2) 0.20 × 0.18 × 0.18 monoclinic P21 10.8444(5) 7.6936(3) 17.8268(8) 90.00 107.148(1) 90.00 1421.2(1) 2 1.051 0.066 1.97−28.42
19690 360 5707 4739 0.0773 0.2258 1.058
14051 297 3795 3302 0.0895 0.2748 1.260
5. KINETICS OF DECOMPOSITION As stated previously, the decomposition of (LCA − )(PPA+)·EtOH takes place as two separate events. However, the loss of EtOH shown in step A of Figure 3 is very rapid and occurs immediately when the crystalline sample is withdrawn from the mother liquor and dried on filter paper. This resulted in inconsistent % mass losses for the runs carried out at the various heating rates. We therefore normalized all our desorption curves to the plateau shown as B and analyzed the decomposition reaction of the resultant salt (LCA−)(PPA+). The curves obtained at different heating rates are shown in Figure 6a, and the corresponding semi logarithmic plots of log β vs 1/T for various stages of decomposition, shown in Figure 6b, yielded an activation energy Ea ranging from 147 to 190 kJ mol−1. Similar decomposition curves were obtained for the (LCA−)(BUAM+) compound and are shown in Figure 7a. The semi logarithmic plot in Figure 7b yielded an Ea ranging from 117 to 136 kJ mol−1. It is noteworthy that the activation energies of decomposition of inclusion compounds, where the host−guest systems are stabilized by hydrogen bonds, have generally lower values. Thus the desorption of 1,4-dioxane from its inclusion complexes with 2,2′-dihydroxy-1,1′-binaphthyl (BINAP) is ≈70 kJ mol−1, and the BINAP clathrates with dimethyl sulphoxide and acetone have activation energies of ≈86 kJ mol−1 and 56 kJ mol−1 respectively.8 The structures and kinetics of decomposition of the inclusion compounds formed by p-tertbutylcalix[4] and [6] arenes have been investigated. With the guests chlorobenzene and benzylamine, the activation energies range from 67 to 87 kJ mol−1.9 The kinetics of desorption of the inclusion compounds formed by the host 9-(2-naphthyl)-9H-xanthen-9-ol with cyclohexanol and cyclohexanone were also carried out by the nonisothermal method and yielded activation energies ranging from 77 to
4. KINETICS OF ENCLATHRATION. LCA WITH N-PROPYLAMINE For the formation of the (LCA−)(PPA+) salt, 100 mg of finely powdered LCA was exposed to the vapors of n-propylamine at fixed vapor pressures of 240, 280, 320, and 360 mbar. All runs were carried out at 25 °C. The kinetic curves obtained fitted the decreasing volume model5 R3: kobst = 1 − (1 − α)1/3
over a range of α = 0.0−0.85. The resultant plot of kobs vs p is shown in Figure 5. We note that there is a threshold pressure Po of 189 mbar below which the reaction does not take place. Interestingly 4145
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Figure 1. The asymmetric unit (a) and crystal packing (b) of (LCA−)(PPA+)·EtOH (host in gray, PPA in blue and ethanol in red).
Figure 2. The asymmetric unit (a) and packing arrangement (b) of (LCA−)(BUAM+).
Figure 4. TG curve for (LCA − )(BUAM + ) at heating rate β = 8 °C min−1.
Figure 3. TG curve for (LCA−)(PPA+)·EtOH at heating rate β = 8 °C min−1.
104 kJ mol−1.10 We surmise that, for the compounds under study, the additional electrostatic forces that stabilize the (LCA−)(PROP+) and (LCA−)(BUAM+) ionic frameworks, and which are
supplementary to the van der Waals and hydrogen bonding interactions, render the compounds more stable, and thus yield higher activation energies of decomposition. 4146
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of the respective amines and gave rise to elevated activation energies of decomposition.
7. EXPERIMENTAL SECTION 7.1. Materials. The compounds were obtained from Sigma Aldrich, and they were used without further purification. 7.2. Preparation of Inclusion Compounds. Single crystals of (LCA−)(PPA+)·EtOH and (LCA−)(BUAM+) were obtained by dissolving the host in EtOH followed by the addition of excess n-propylamine or ± sec-butylamine respectively at room temperature. Considerable difficulties were encountered in producing crystals of good quality, despite variations in the method of preparation. Several crystals were tested on the diffractometer in order to obtain the best intensity data collection. The associated powders were obtained by the same method with the addition of stirring. 7.3. Single Crystal X-ray Diffraction. Diffraction data for both compounds were collected on on a Bruker DUO APEX II diffractometer11 with graphite-monochromated Mo Kα1 radiation (λ = 0.71073 Å) at 173 K using an Oxford Cryostream 700. Data reduction and cell refinement were performed using SAINT-Plus,12 and the space groups were determined from systematic absences by XPREP13 and further justified by the refinement results. In both cases, the structures were solved with the aid of X-Seed14 by direct methods using SHELXS9715 and refined using full-matrix least-squares/difference Fourier techniques using SHELXL-97. The hydrogen atoms bound to carbon atoms were placed at idealized positions and refined as riding atoms with Uiso (H) = 1.2 Ueq (Ar−H, CH2) or 1.5 Ueq (CH3). Diagrams and publication material were generated using PLATON16 and X-Seed. Experimental details of the X-ray analyses are provided in Table 1.
Figure 5. Plot of kobs vs pressure.
6. CONCLUSION LCA forms salts with n-propylamine and sec-butylamine. Their structures were elucidated and their thermal decomposition curves were recorded. The decomposition of (LCA−)(PPA+)·EtOH occurred in two steps, with an initial loss of EtOH followed by the decomposition of the salt. The first step is rapid and gave inconsistent mass losses, showing that the EtOH guest is loosely held by the salt framework. This was confirmed by the disordered nature of the EtOH molecule in the crystal structure and is consistent with its high atomic temperature factors. The decomposition of the ammonium salts occurred at temperatures significantly higher than the normal boiling points
Figure 6. (a) Decomposition curves at different heating rates β (°C min−1) and (b) the semi logarithmic plots of log β vs 1/T for (LCA−)(PPA+)·EtOH.
Figure 7. (a) Decomposition curves at different heating rates and (b) the semi logarithmic plots of log β vs 1/T for (LCA−)(BUAM+). 4147
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Crystallographic information files for each structure have been deposited with the Cambridge Structural Database (CCDC 880559 and 880560). 7.4. Kinetics of Enclathration. Measurements were carried out in an automated magnetic suspension balance designed and constructed by Barbour.17 The finely powdered sample of LCA was exposed to the guest vapor pressure under controlled conditions of temperature and vapor pressure, and the mass increase with time was recorded. The isothermal curves thus obtained were converted to extent of reaction (α) versus time curves, and these were fitted to various kinetic equations to establish the best fit for the model. 7.5. Kinetics of Decomposition. Thermal gravimetry (TG) data were collected on a TGA Q500 (TA Instruments), with a purge gas of dry nitrogen flowing at 50 mL min−1. The method of Flynn and Wall18 was employed to record the mass loss of the compounds at fixed heating rates, β, of 2, 4, 8, 16, and 32 °C min−1. Plots of log β versus 1/T yielded straight lines which allowed the estimation of the activation energy of the reaction.
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AUTHOR INFORMATION
Corresponding Author
*Fax: +27-21-6505419. Tel: +27-21-6505893. E-mail: luigi.
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors thank the NRF (Pretoria) and the University of Cape Town and the Cape Peninsula University of Technology for funding.
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REFERENCES
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