The Nitration of Phenacetin A Structured Project Approach to Teaching Organic Chemistry in Undergraduate Laboratory Classes Richard A. Russell and Robert W. Switzer, and Robert W. Longrnore School of Science and Technology. Bond University, Private Bag 10, Gold Coast Mail Centre. Queensland. 4217. Australia B. Hoang Dullon and Lesley Harland University College, University of NSW, Northcott Drive. Campbell. ACT 2600. Australia As part of a new teaching program1 we have introduced structured projects as an effective means of assessing laboratory skills in organic chemistry. In this program students comnlete a basic svnthesis and then initiate a related nseudo-research program that progressively challenges their exoerimental skills and their capacity to think as practicinp is based upon the poorl; brganic chemists. One such documented nitration of phenacetinZ4. The starting point for our exercise is to set students the task of nitrating phenacetin using a mixture of nitric and acetic acids. This establishes the basic synthetic technique and a t the same time yields a single product (2-nitrophenacetin) that is readilv purified. Students are asked to establish the identity o i t k s compound by any technique they choose. Most find bv 'H-NMR snectrosco~vthat the oroduct is a mononitro-derivative a i d identify i t through its meltine- noint5. At this point we provide the student with . authentic samples of 2-nitrophenacetin, 3-nitrophenacetin, and 2.5-dinitrophenacetin and ask them to check their dedudion by developing an analytical TLC separation and compare the standards with their samples3. Students are then set the task of devising a synthesis for the isomeric 3nitrophenacetin and preparing a pure sample of 'this comnound. Most students manaee.. eiven time. to find the kev ieference to this preparation4 and, having done so, are pr;vided with an Enelish translation6. Under the sunervision of a demonstrator &ey are then permitted to attempt the nitration of phenacetin in sulfuric acid rather than in acetic acid as suggested by the reference. Having obtained a crude product from the nitration, they develop a procedure for purifying the pr0duct.a task thatshould direct them bark to their earlier TLC analysis. At this point we provide no further input other than the necessary safety checks. The better students manage to find a wnrkahleseparation at least to the point of obtaining a pure sample of the minor product of the nitration, namely 2,5-dinitrophenacetin. The major product
168
Journal of Chemical Education
is much more demanding, for, although it elutes from a column of either alumina or silica t o afford a material seemingly analytically pure by TLC, this interpretation of the separation rewires considerable care. Onlv the better expe&entalistimanage to work their way beyond this point and obtain a pure sample of the 3-nitroisomer. Of this group of students there are usually one or two who speculate about the nature of the other product, which can be identified by careful spectroscopic analysis as 3,5-dinitr~~henacetini. The very best students of course resolve the problem totally. As a final means of eradine students we ask that thev devise a proof that conclu~velyestablishes the structure ofall their pure compounds. This is much more difficult for students a t this level but can be achieved by a consideration of the chemical shifts of the acetamido NH resonance and the aromatic protons8. On occasion, students have developed
' Bearman, R. J.; Russell, R. A. J. Chem. Educ. 1987, 64. 703.
The outcome of the nitration of phenacetin is remarkably sensitive to the reaction conditions3 and offers even more scope for projects than outlined in this paper. Oelschlaeger, H.: Welsch, Chr. Arch. Pharm. 1964, 297, 608. Reverdin, F. Helv. Chim. Acta 1927, 10, 3. These compounds are to be found in Dictionary of Organic Compounds. Ed. Heiibron, under the parent headings of nltrophenetidine. Beiistein lists them under nitro-acetamidophenetol, and Chemical Abstracts uses a variety of names depending on the volume searched. -~~ The original paper is in French and provides a worthy challenge to any linguist in the class, largely because it involves the use ot numer0.s outmode0 or at least infrequentlyused scmtificterms. Students are permitted to undertake their own NMR analysis using a 60-MHz spectrometer and in addition are provided with photocopies of spectra run at 300 MHz. All compounds are soluble in CDCIS. The acetamido orotons ortho to a nitro arouo resonate ataooroximately 6 10 ppm while those removed from-the'influenceof iniramolecuiar hydrogen bonding resonate at approxlmateiy 6 7.4 ppm.
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HPLC separations for all t h e nitration products and t h i s technique, while not essential to the exercise, does provide some i&resting challenges in setting u p g r a d i e n t e l u t i o n programs. This structured project approach t o laboratory work, while m o r e demanding i n t e r m s of supervision, establishes an effective method of grading s t u d e n t s according t o their skills a n d at the s a m e time removes a degree of "recipe following" from organic chemistry laboratory classes. I n a d dition s t u d e n t s gain a feeling of independence a n d become masters of their own work.
and 3.5~ i t i o ~ h e n a c e t i n2.5-~initro-&thoxyacetaniIide, ). Dinitro-4-ethoxyacetanilide A solution of phenacetin (8.68 g, 48.5 m m ~ l e in ) ~concentrated sulfuric acid (22 mL) was placed in a three-necked 250-mL roundbottomed flask equipped with a thermometer, a magnetic stirrer, and a dropping funnel. The flask was cooled in an salt-ice hath and treated dropwise with an ice coldmixture of concentrated nitric acid (4.25 mL) in concentrated sulfuric acid (3.25 mL) while carefully maintaining the temperatwe of the stirred solution helaw 5 'C. The mixture was stirred for a further 30 min at 5 OC, then cautiously poured onto 200 g of crushed ice contained in a 500-mL beaker. The resulting solid was collected by filtration under reduced pressure, washed with 100 mL of cold water, and finally dissolved in diethyl ether (200 mL). The ethereal solution was successivelv washed with sodium bicarbonate (2 X 100 mL. -, 5%). .. water (2 X ib0 mL).. dried overmagneaiumsulf~te, and filtered. The solvent was removed from the filtrate under reduced pressure to afford a yellow-brown rolid (-3 g) that was dissolved in the minimum volume of chloroform and chromatographed, using chloroform, on a column of alumina. The was ohtained least polar product, 2,5-dinitro-4-ethoxyacetanilide, as a );ellow sohd that was rerry3tallired from aqueous ethanol as golden prisms (fin mg, 0.5'"ol mp 159-161 'C. Further elution of the column afforded s light.huff-colored rolid that was washed with a ~
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The scale of this reaction mav be reduced lor students with experience in manipulating small quantities of material. 'O Heilbron. I. Dictionary of Organic Compounds. 4th ed.: Eyre and Spottiswoode: London, 1965: Vol. 4. p 2476.
small volume of diethyl ether and recrystallized from ethanol to afford 3-nitro-4-ethoxyacetanilide as fine pale-buff-colored prisms (0.7 g, 6.4%), mp 123-124 "C'O. The combined ether washings and ethanalic mother liquors contained 3,5-dinitro-4-ethoxyphenacetin. A sample of this compound was purified by centrifugal thin-layer chromatography on silica using ethyl acetate as the eluant. The resulting 3.5-dinitro derivative crystallized as yellow-brown needles mp 147-148 D Cfrom aqueous ethanol. Alternatively the crude material may be directly chromatographed on silica gel (350 g) and the products eluted with ethyl acetatenight petroleum (1:3). In this case 3,5-dinitro-4-ethoxyaeetanilide (1.72 g, 13%)can he totally separated. Preparation of 2-Niho-4+thoxyacetanilide (2Nitrophenacetin) A solution of phenacetin (2 g, 11.2 mmol) in glacial acetic acid (40 mL) was placed in a 250-mL two-necked round-bottomed flask equipped with a reflux condenser, a dropping funnel, and a magnetic stirrer. Concentrated nitric acid (2.5 mL) was added dropwise to the vigorously stirred solution at ambient temperature, and the mixture then warmed to 90 OC in a water hath for 5 min. The orange solution was cooled to 15 "C, poured into ice cold water (120 mL), and the mixture stirred at 0 'C until crystallization was complete. The resulting yellow solid (1.9 g) was collected by filtration under reduced pressure and washed with cold water (100mL) and asample of the product recrystallized from water to afford golden prisms, mp 1OP105 '=CL0.
TLC Analysis of Products The best results were obtained wine Kieseleel 60 F m coated ulitea (.~ M a c k Art.5719) ~.develoued with Zthvl a c e b andkkical .. RI. values were ?-nitro (1).90),2,s-dinitnr (0.83), 3,s-dinitro r0.761.and R-nitro (0.54). A developing solvent of methanol. chloroform 11:40) gave less satisfactory rerults and failed to separate the 3-nitro and 3,5-dinitro derivatives. ~
HPLC Analysis of Products All the nitro derivatives were separated on a 5-pm Partisil column using a gradient elution profile commencing with ethyl acetate1 hexane (I:]) and progressing to ethyl acetate over a 5-min period at aflow rate of2 mL min-I. The eluant was monitored at a wavelength between 360 and 395 nm. Isocratic separations were achieved for uairs of comoounds: thus 2-nitro and 2.5-dinitro seuarated on a similar column using ethyl acetateheaane (1:1), whereas the more polar pair of producta were separated using ethyl acetate.
Volume 67
Number 2
February 1990
189
