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Synthesis, Photophysical Characterization, and Gelation Studies of a Stilbene–Cholesterol Derivative An Advanced Physical Organic Chemistry Laboratory H. Cristina Geiger,* David K. Geiger, and Christine Baldwin Department of Chemistry, State University of New York-College at Geneseo, Geneseo, NY 14454; *
[email protected] Organogels have received much attention in the recent research literature (1, 2). Organogels are low molar mass organic compounds with the ability to immobilize an incredible quantity of solvent. Some gelators exhibit the ability to gel several solvents at levels of 1% (w兾w) or below. Under these conditions one molecule of gelator may immobilize several thousand solvent molecules (3). Fibrous aggregation of low molar mass compounds formed by noncovalent interactions is responsible for gelation (4). The driving force for gelation usually involves hydrogen bonding, dipole–dipole, dipole–induced dipole, and London dispersion forces, noncovalent interactions between molecules with extended conjugation, and so forth. For stilbene–cholesterol based gelators, the driving forces for molecular aggregation are weak van der
O BrCH2
C
PPh 3 xylene
OCH3
Waals interactions developed by the stacking of cholesterol moieties and noncovalent π–π interactions between the aromatic rings in the stilbene (2, 3). This remarkable ability has important implications in the development of sensors, templates for organic synthesis, electrochemical techniques, and biological applications (5). However, based on a survey of popular introductory and organic chemistry texts (6–8) gels receive barely a mention in the crowded undergraduate curriculum. The laboratory is an excellent place to introduce the topic of gels. We describe a laboratory experience that combines organic synthesis, spectroscopy, and the physical characterization of an example of this interesting state of matter. Besides remarkable gelation ability, the final product displays
_ Br + PPh3C H2
O C
OCH3
2
1
O 1. K2CO3
2. CH3(CH2)7
O
THF/CH2Cl2
3
O C CH3(CH2)7
O
OCH3
4
KOH
O
EtOH
C CH3(CH2)7
OH
O 5
1. (CClO)2 CH2Cl2 /DMF 2. cholesterol/pyridine
O C CH3(CH2)7
O
O 6
(8OS-chol)
Scheme I. Synthesis of 4-octoxy-4’-(cholesteryloxycarbonyl) t-stilbene (8OS-chol).
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liquid crystal properties and thus provides for an opportunity to explore the characteristics of this class of compounds. Because of the confluence of different areas of chemistry, this series of experiments is appropriate for an advanced laboratory course. The students enrolled in our course are in their third or fourth year. Since there is not a specific text for the course, students are required to use the primary research literature (3, 4, 9, 10). The series of experiments is performed in three parts, as described below. Synthesis of 4-Octoxy-4’-(cholesteryloxycarbonyl) t-stilbene (8OS-chol) The synthesis starts with a Wittig reaction by using the bromo ester 1 and octyloxy benzaldehyde 3 to afford the stilbene ester derivative 4 (10), see Scheme I. During this synthesis the students will gain experience in working with moisture- and light-sensitive compounds. trans-Stilbene easily isomerizes to cis-stilbene when exposed to white light. The room lights must be dimmed or the use of yellow light (λ = 520 nm) is required. The progress of the reaction is monitored by TLC visualized by UV light (λ = 365 nm) and the final crude product is purified via recrystallization or silica gel column chromatography. The recrystallized stilbene ester is hydrolyzed by refluxing it in an alcoholic potassium hydroxide solution. Although this reaction is straight forward, purification of the acid 5 by recrystallization or column chromatography is necessary. The final step consists of the formation of the cholesterol compound 6. This esterification reaction is accomplished in two steps by a procedure reported in the literature (2, 3). During this final step, the formation of the acid chloride intermediate, the students are confronted with working with a moisture-sensitive compound. If the acid chloride is hydrolyzed, the yield of the stilbene ester will be small and the students will need to repeat the synthesis. With this series of linear syntheses, the students are given complete responsibility for the yields and care of their products. Students are warned to avoid using all of the material that they prepared in previous steps as they continue through the synthetic procedure. In case of an accident, they can repeat a specific step without the need of going back to the initial step. The overall yield is about 5% (80 mg). This quantity is enough for all of the analyses and gelation studies, each of which can be performed with 1 or 2 mg of compounds.
The stilbene fatty acid cholesterol derivative, 8OS-chol, is capable of forming gels with several organic solvents at very low concentrations. The results of the gelation tests are shown in Table 1. 8OS-chol forms a gel with 1,2-dichloroethane, n-octanol, ethylacetate, and pyridine. The gel formed with 1,2-dichloroethane at 5 ⬚C crystallizes after warming to room temperature. Pyridine gives a stable gel at room temperature, but these gels are not studied because pyridine absorbs in the same region as the stilbene chromophore. n-Octanol is the best solvent for 8OS-chol. It forms a turbid gel a few seconds after cooling the isotropic phase to room temperature and it is stable up to several days. All gels prepared in this study are thermally reversible and most of them are turbid and stable for several months. The gel obtained at a level of 1% (w兾w) in n-octanol melts at 85–86 ⬚C. Spectroscopic Characterization of 8OS-chol Gels The best gel (2% in n-octanol, stable for several days) is selected for this analysis. A comparison of the absorption and emission spectra of the gel with the absorption and emission spectra of a dilute solution of the gelator (10᎑5 M in n-octanol) is made. The dilute solution is expected to show absorption and emission spectra corresponding to the stilbene chromophore (monomer). Any changes from these spectra observed for the absorption and emission spectra of the gel are due to the aggregation of the stilbene–cholesterol compound, which forms a 3D network of fibers during gelation (3). In this part of the laboratory, the students are introduced to the concept of molecular aggregation, absorption and emission spectroscopies, and the analysis of data using a spreadsheet.
Table 1. Gelation Ability of 8OS-chol Solventa
Physical Stateb
n-Hexane
I
Benzene
I
Toluene
R
Nitrobenzene 1,2-Dichloroethane Chloroform
R Gc I
Ether
I
Gelation Studies of 8OS-chol Gelator
THF
S
The gelation ability of the stilbene–cholesterol gelator in different organic solvents is investigated. A specific quantity of gelator, 0.5–2.0% (w兾w), is placed in a small-capped vial. A measured quantity of solvent is added and the mixture is heated near the boiling point of the solvent until all the gelator is dissolved. The warm solution is allowed to cool to ambient temperature. If gel formation does not occur after approximately 10 minutes, the solution is placed in the refrigerator. The melting temperature of the most stables gels are determined by heating the gel (in a capped vial) in a silicon oil bath. The temperature of the bath should rise at a rate of 2 ⬚C per minute. The transition temperature range is determined from the onset of gel melting until a homogeneous solution is obtained.
1,4-Dioxane
R
Ethylacetate
G
Acetonitrile
I
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Methanol
I
Ethanol
I
n-Butanol
R
n-Octanol
G
Pyridine
G
a
Gels are 0.5–2 % (w/w). All mixtures were heated above their phase transition temperatures and cooled to 5–20 ⬚C. b I = compound insoluble after heating, R = compound soluble after heating, but crystallizes at room temperature, S = gel not formed due to solubility, Gc = gel formed but crystals are observed, and G = stable gel at room temperature.
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The absorption spectra of each of the gels studied show an absorbance maxima at ∼330–340 nm. The absorption and emission maxima for a 2% n-octanol gel are shown in Table 2. In all cases, the absorption spectra of the gels (Figure 1) are broader than those of the corresponding monomer (10᎑5 M n-octanol solution). When heated, the gels dissolve and the solution becomes clear. The absorbance maxima of the gels and dilute solutions (monomers) occur at basically the same wavelength. For the emission spectra, the gels were excited at the wavelength maximum found in the absorption spectra (Figure 1). The gels examined, with absorbance maxima between 0.1–0.2, show emission spectra slightly redshifted from and broader than their respective monomer emission spectra. The emission intensities are sensitive to changes in the position of the slides containing the gel. Thus, the position should be held constant during all measurements. Another interesting experiment, depending on time available, is the study of the emission of a 2% (w兾w) gel in n-octanol as a function of temperature. The gel shows a 16fold increase in intensity compared to the isotropic phase (see Figure 2) (3). Hazard All manipulations should be performed in a working hood. The solvents are volatile, flammable liquids; there should be no open flames in the laboratory. Hydrochloric acid is corrosive. Eye protection and gloves should be worn at all times. Oxalyl chloride is a lachrymator and a highly toxic compound that reacts violently with water. It should be handled in a well-ventilated hood.
Table 2. Maximum Absorption and Emission Intensities of 8OS-chol Gel and Dilute Solution (10᎑5 M) in n-Octanol Medium
Absorption/nm
Emission/nm
Gel
338a
417
Solution
340
408
a
Broad spectrum.
Figure 1. Absorption and emission spectra of 8OS-chol (2% w兾w) gel and 10᎑5 M solution in n-octanol. Emission spectra are at lower energy (larger wavelength) than the corresponding absorption spectra.
Evaluation The progress is evaluated at each of the three steps using reports that include introduction and conclusions sections. For the first report, the synthetic part, students are directed to include a scheme of the reactions using a structure-drawing program, a description of the experimental procedure indicating the amounts of reagents used and obtained (in grams and mmol), and the yields in grams and percentages for each of the isolated products. Analyses of IR and 1H NMR spectra of each product are included. The second report includes a table with the results of the gelation studies and the selection of the most stable gel to be analyzed by spectroscopy. The final report must include a study of the photophysical properties of the most stable gel (aggregate) compared with the dilute solution (monomer). The students submit a paper that should contain all their work and be written as if it were to be submitted for publication. The culmination of the project is an oral presentation of their experimental results. Conclusions Not all undergraduate students have the opportunity to do research during their junior or senior year. This laboratory sequence provides a close approximation to that experience. Students are expected to attend to their experiments (e.g., remove the heat from a reaction, obtain NMR spectra 108
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Figure 2. Emission spectra of 8OS-chol (2% w兾w) gel as a function of temperature.
and melting points, etc.) outside of the regularly scheduled laboratory period. One faculty member, meeting 4 hours a week, can run this lab with 10–12 students. All students enrolled in this advanced laboratory will go through the steps involved in a research project. The faculty member provides guidance and instruction, but, after the first few weeks of the semester, the students are independent and proceed at different paces. The progress will depend on the individual student. Some students will need to do more purification steps than others (more chromatography); some students will
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have low yields in one step and will need to repeat a synthesis, and so forth. In any case, this experience will mimic the way that research is carried out and students not only will gain advanced synthetic skills but also experience the responsibility associated with a research project. W
Supplemental Material
Detailed experimental instructions for the synthesis of the gelator and notes for the instructor, including a laboratory schedule, are available in this issue of JCE Online. Literature Cited 1. Terech, P.; Weiss, R. Chem. Rev. 1997, 97, 3133–3159. 2. Murata, K.; Aoki, M.; Susuki, T.; Harada, T.; Kawabata, H.; Komori, T.; Ohseto, K.; Ueda, K.; Shinkai, S. J. Am. Chem. Soc. 1994, 116, 6664–6676.
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3. Geiger, H. C.; Stanescu, M.; Chen, L.; Whitten, D. G. Langmuir 1999, 15, 2241–2245. 4. Wang, R.; Geiger, H. C.; Chen, L.; Swanson, B.; Whitten, D. G. J. Am. Chem. Soc. 2000, 122, 2399–2400. 5. Simmons, B. A.; Taylor, C. E.; Landis, F. A.; John, V. T.; McPherson, G. L.; Schwartz, D. K.; Moore, R. J. Am. Chem. Soc. 2001, 123, 2414–2421. 6. Silberberg, M. S. Chemistry: The Molecular Nature of Matter and Change, 3rd ed.; McGraw Hill; New York, 2003. 7. McMurry, J. Organic Chemistry, 6th ed.; Brooks/Cole: Monterey, CA, 2004. 8. Wade, L. G., Jr. Organic Chemistry, 5th ed.; Prentice-Hall: Upper Saddle River, NJ, 2003. 9. Vaday, S.; Geiger, H. C.; Cleary, B.; Perlstein, J.; Whitten, D. G. J. Phys. Chem. B. 1997, 101, 321–329. 10. Mooney, W. F.; Brown, P. E.; Russell, J. C.; Costa, S. B.; Pedersen, L. G.; Whitten, D. G. J. Am. Chem. Soc. 1984, 106, 5659–5667.
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