In the Laboratory edited by
The Microscale Laboratory
R. David Crouch Dickinson College Carlisle, PA 17013-2896
Formation of α-Tetralone by Intramolecular Friedel–Crafts Acylation
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Michael S. Holden,* R. David Crouch, and Kathryn A. Barker Department of Chemistry, Dickinson College, Carlisle, PA 17013-2896; *
[email protected] The Friedel–Crafts acylation is one of the most wellknown of the named reactions. A large number of laboratory exercises of this transformation have appeared in this Journal (1). However, all of the published procedures are intermolecular reactions and many require an understanding of directing effects to predict the correct structure of the product. We sought to develop an intramolecular Friedel–Crafts lab in which an understanding of directing effects is not required, but which would deliver an easily isolable product. The formation of α-tetralone by the acid-induced cyclization of 4-phenylbutyric acid served our purposes (Scheme I).
O H COOH H3 O Scheme I. Formation of α-tetralone by the acid-induced cyclization of 4-phenylbutyric acid.
O
OH O COOH NH
OCH3
Hepalande
Inderal
O
Experimental
OH
O
Alphol Figure 1. Structures of drugs that use α-naphthol as a starting point.
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The ortho-disubstitution can be explained by a familiar concept—the ease of formation of a six-membered ring. Furthermore, the product is an interesting ring system and students can investigate some of the uses of α-tetralone and related compounds. For instance, the major industrial pathway for synthesis of α-naphthol involves the aromatization of α-tetralone. α-Naphthol is used as a starting point for the synthesis of a number of drugs, including the choleretic Hepalande, the adrenergic blocking agent Inderal, and the antirheumatic Alphol (2) (Figure 1). Use of α-tetralone in the Pfitzinger reaction (3) with isatin yields the quinoline-4carboxylic acid tetrophine (Scheme II); derivatives of this compound have been useful for treatment of autoimmune disease, psoriasis, organ transplant rejection, and chronic inflammation (4). α-Tetralone has been used as the starting material in the synthesis of the antidepressants Sertracine (5) and ABT-200 (6) (Figure 2). Recently, four new α-tetralones (aristelegone-A, -B, -C, and -D) have been isolated from the ornamental plant Aristolochiaceae (7). Our first efforts focused on the use of polyphosphoric acid (PPA) as the proton source, following the method of Snyder and Werber (8). Although this led to acceptable yields, the difficulties of having students work with PPA—the extreme viscosity makes it time-consuming to transfer—made for a less than desirable lab experiment. Matters were improved by having lab preps pre-measure the PPA into the glassware prior to the laboratory period but we felt that handing students a preweighed sample of one of the reagents lessens the quality of the lab experience. Eisenbraun and co-workers have reported the use of methanesulfonic acid (MSA) as a replacement for PPA in the synthesis of α-tetralones (9). As it is a free-flowing liquid MSA is much easier to handle than PPA. Workup conditions are also simplified. We have modified this method to the microscale formation of α-tetralone and have had great success.
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To a 5-mL conical vial equipped with spin vane and air condenser was added 1.5 mL MSA. With stirring, the acid was heated to 85–100 ⬚C. To the stirred acid was added 220 mg (1.34 mmol) of 4-phenylbutyric acid and the solution was stirred at the elevated temperature for 1 h. The reaction mixture was poured into 5 mL of ice cold water in a centrifuge tube and extracted with 2 × 3 mL of diethyl ether. The combined organic layers were washed with 2 mL of saturated aqueous NaHCO3 and then with 2 mL of water. The organic layer was passed through a pipet containing a one-half
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In the Laboratory
inch layer of silica gel topped by a one-half inch layer of magnesium sulfate or sodium sulfate. The pipet was rinsed with an additional 2–3 mL of ether. The solvent was removed in vacuo to yield α-tetralone as a clear, nearly colorless oil. Student yields ranged from 23–80% with an average yield of 60%. The NMR (10) and IR (11) of the product can be compared to literature spectra. Hazards MSA is corrosive and toxic. Diethyl ether is flammable, volatile and toxic; it should be dispensed in a properly functioning fume hood. No hazards are listed for α-tetralone or 4-phenylbutyric acid in the Aldrich catalog. Care must be taken during the extractions and washings as pressure may build in the vessel. Discussion Students often fixate on generation of alkyl and acyl cations by the reaction of alkyl and acyl halides with trihaloaluminum species, no doubt because textbooks concentrate on these methods. However, protonation of alkenes and carboxylic acids can also lead to cationic species and students learn that they have, in fact, seen this chemistry earlier in the organic chemistry course. As for the position of the new carbon–carbon bond, having the students look at the possible products from formation of a five- and six-membered ring quickly convinces them that only the six-membered ring can be formed. The experiment is easy to perform and fits nicely into a standard lab period, taking about 2.5–3 hours from start to finish. The major difficulty that students have is heating the system to an excessively high temperature. We have had students heat the system to over 180 ⬚C and still get product, although at low yields. Yields are also lowered if the chromatography–desiccant pipet is not washed with several milliliters of ether to rinse the product out of the column.
4. Al-Tai, F. A.; El-Abbady, A. M.; Al-Tai, A. S. J. Chem. U.A.R. 1967, 10, 339–352. 5. Vukics, K.; Fodor, T.; Fischer, J.; Fellegvári, I.; Lévai, S. Org. Process Res. Dev. 2002, 6, 82–85. 6. Deshpande, M. N.; Cain, M. H.; Patel, S. R.; Singam, P. R.; Brown, D.; Gupta, A.; Barkalow, J.; Callen, G.; Patel, K.; Koops, R.; Chorghade, M.; Foote, H.; Pariza, R. Org. Process Res. Dev. 1998, 2, 351–356. 7. Wu, T-S.; Tsai, Y-L.; Damu, A. G.; Kuo, P-C.; Wu, P-L. J. Nat. Prod. 2002, 65, 1522–1525. 8. Snyder, H. R.; Werber, F. X. In Org. Syntheses, Collective Volume III, Horning, E. C., Ed.; John Wiley and Sons: New York, 1955; pp 798–800. 9. Premasagar, V.; Palaniswamy, V. A.; Eisenbraun, E. J. J. Org. Chem. 1981, 46, 2974–2976. 10. Pouchert, C. J.; Behnke, J. The Aldrich Library of 13C and 1H FT NMR Spectra; Aldrich Chemical Company: Milwaukee, WI, 1993; Vol. 2, p 810C. 11. Keller, R. J. The Sigma Library of FT–IR Spectra; Sigma Chemical Company: St. Louis, MO, 1986; Vol. 2, p 912D.
+ N H
COOH
N
Supplemental Material Instructions for the students and notes for the instructor are available in this issue of JCE Online. 1. For recent examples, see Miles, W. H.; Nutaitus, C. F.; Anderton, C. A. J. Chem. Educ. 1996, 73, 272. Newirth, T. L.; Srouji, N. J. Chem. Educ. 1995, 72, 454. Jarret, R. M.; Keil, N.; Allen, S.; Cannon, L.; Coughlan, J.; Cusumano, L.; Nolan, B. J. Chem. Educ. 1989, 66, 1056. 2. Kirk–Othmer Encyclopedia of Chemical Technology, 3rd ed.; Grayson, M., Ed.; John Wiley and Sons: New York, 1981; Vol. 19, pp 732–733. 3. The Pfitzinger is an old synthesis of quinoline-4-carboxylic acids from the reaction of isatin and α-methylene carbonyl compounds. The conditions are harsh: a concentrated solution of hydroxide in aqueous alcohol, isatin, and the α-methylene carbonyl compound are heated at reflux for several days. The mixture is treated with charcoal, filtered, and the product is precipitated by acidification with 50% acetic acid. For examples, see Hassner, A.; Stumer, C. In Organic Syntheses Based on Name Reactions and Unnamed Reactions; Baldwin, J. E.; Magnus, P. E., Eds.; Tetrahedron Organic Chemistry Series, Elsevier: Oxford, United Kingdom, 1994; Vol. 11, p 297.
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O
Pfitzinger
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Literature Cited
O
O
tetrophine Scheme II. Reaction of α-tetralone with isatin to yield the quinoline4-carboxylic acid tetrophine.
NH2Me Cl
H
N
Ph
O
MeSO3 O Cl Cl
Sertracine
ABT-200
Figure 2. Structures of drugs that use α-tetralone as a starting point.
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