E u g e n e J. Volker Ernest Pride' a n d C h a r l e s Hough2 Shepherd College Shepherdstown. WV 25443
Drugs in the Chemistry Laboratory The conversion of acetaminophen into phenacetin
Laboratory experiments involving drugs are of unusually high interest t o many chemistry students and especially t o those majoring i n t h e allied health or life science fields. T h e experiment described here, in which acetaminophen (I) is converted into phenacetin (II), has been used successfully a t Shepherd College in a n introductory chemistry course for nurses and in t h e oreanic chemistrv lahoratorv. This e x ~ e r i ment is often praised by t h e students for its "relevance" hemuse it ~ deals .-~ ~with - - medications from evervdav . " life familiar t o most of t h e m under various trade names. Roth (I) ,-,and (11) , , a r e antiovretic .. analeesics available overthe-counter singly or in combination with other drugs, usually asnirin a n d caffeine. For examole. . . D a t r i P a n d Tvleno1"consist of (I) a s t h e only active ingredient; Vanquish" and Excedrin" contain (1) and Emoirin" contains (11) in combination with other physiologicall; active substances. As can be seen from their structural formulas, (I) a n d (11) are chemically clusely related, uhtmicctin h e w an rthrr that can h e h t a i n e d try the O - . ~ l k \ , l ; i t ~ofmaretsm~ncgphcn. ~~~
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H-o+NH-C-CH,
(6). An alternative'procedure for the preparation of phenacetin is described by Adams e t al. (7) and is shown below. A~IHCII~~IIOAE
cH,-CH--O+W
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This acylation reaction provides a suitable experiment for students interested in doina- additional work in t h e area of drug synthesis.
a,-cH.uvn. 01,-C-"H-ml!nOu.
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substitution closelv related t o the Williamson synthesis, a reaction discussed hvirtually all organic chemistr; texts, and focuses attention on the structural difference between the two drugs. In our laboratory program this experiment is part of a sequence relating t o pharmaceuticals which also includes t h e isolation of caffeine from tea (2),t h e synthesis of aspirin from salicylic acid ( 3 ) ,the determination of the molecular weight of aspirin by titration ( 4 ) ,t h e qualitative separation of commercially available analgesic drug mixtures by tlc (51, and the quantitative separation of such mixtures by extraction
I
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II
CH,-CH--O+NH-C-CH,
Experimental A 25- or 50-ml round-bottomed flask is charred with 1.51 e (10
(11)
I t is interesting to note t h a t ingestion of (11) results in its metaholic transformation in t h e human body t o (I) which is the reverse of the reaction shown in t h e equation. T h e acetaminophen so produced is t h e compound responsible for t h e analgesic effect ( 1 ). In the experiment a t hand, the phenolic alcohol group of acetaminophen is alkylated with ethyl iodide using the basic catalyst K2C03. Either reagent grade acetaminophen3 or commercial tablets of this substance may he used as t h e starting material. T h e phenacetin produced is identified by its mp, mixed m p with commercial material, and its ir and nmr spectra. If desired, the reaction can he followed by tlc. The experiment is simple, inexpensive, a n d sufficiently rapid so t h a t i t can he done in one 3-hr laboratory period."t illustrates a technique of ether formation by a nucleophilic 'Undergraduate research participant in chemistry. Undergraduate research participant in chemistry. 3The acetaminophen used in our laboratory was obtained from the Aldrich Chemical Co., Milwaukee. WI; the phenacetin from Matheson. Coleman, and Bell Inc.. Norwood. OH. O u r practice. however, is to start the refluxing process at thebesinning of a laboratory period which is devoted mainly to other experiments. The reaction vessel is then stored and workup begun during the next laboratory period. "Using the information on the container for the proprietary preparation availahle to us and weighing the table-ts. weights uf 2.5'2 g (1)atril") and 2 . 1 8 ~ Wylenol') were fbund to be equivalent. "t is necessary to test tof'ind
