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The Synthesis of Lactones from pAroylpropionic Acids Lawrence McGahey Union College. Schenectady. NY 12308 Most of the "big" organic lecture texts discuss lactone nomenclature, synthesis, and the role of ring size in cyclization of hydroxyacids. In contrast, few laboratory experiments about lactones have been published for use in the introductory organic course. T h e experiments described here give students experience in short, multistep syntheses using reactions covered in most elementary organic courses and demonstrate reactions of difunctional compounds. Friedel-Crafts acylation of toluene with succinic anhydride affords 4-oxo-4-(p-toly1)butanoic acid (I), the starting material for all the lactone syntheses:
Reaction 1demonstrates the creation of a heterofunctional compound from monofunctional starting materials. Unsaturated lactone 2 forms on heating 1with acetic anhydride, possibly by reaction of the en01 with a mixed anhydride:
sis is the purification of lactone 4 by recrystallization from ethyl acetate-hexane because the scale of work is small and the lactone is highly soluble in the ester solvent. I n studying difunctional compounds students learn that a reaction a t one functional group can produce an intermediate that reacts with the other functional group, sometimes leading to an unexpected product. T o demonstrate this principle, lactone 4 can also be prepared by NaBH4 reduction of the methyl ester of ketoacid I:
Synthesis of 1 according to eq 4 not only illustrates the interaction of the intermediate alkoxide with the ester but also exemplifies Fischer esterifiration and the selective reduction of ketones in the presence of esters. Comparable yieldsof J areobtainal~leby either synthesis3or 4, the major losses ucrurring during the rerrystallization. It is orohablv nor oossihle for studenrs to carry out all of the experiments described here because of time constraints and the limited amount of 1 available. One approach is to have students work in pairs and compare resultsof syntheses 3 and 4. Experimental Procedures
A beautiful color change attends reaction 2; i t is also amenable to being performed on a small scale and makes a good structure-determination or "mechanism" problem. Reduction of the sodium salt of 1 with NaBHa yields 4hydroxy-4-p-tolylbutanoicacid (3). which upon heating cyclizes to 4, y-p-tolyl-y-butyrolactone:
Synthesis of 1 The literature method for preparing 8-benzoylpropionic acid2was adapted. A dry 250-mL round-bottomed flask equipped with a n addition funnel, condenser (no water flow needed), and an efficient trap" for HCI is charged with 6.8 g (68 mmol) suceinie anhydride. Reagent toluene (50 mL, 471 mmol) briefly dried over anhydrous CaClz (6 g) is then added; the anhydride does not completely dissolve. Anhydrous AICh (20 g, 150 mmol) is carefully added through a powder funnel to the anhydride-toluenemixture, and the other glassware (well-greased joints!) and gas trap are connected to the flask. The contents of the flask are thoroughly mixed by vigorous swirling for about 5 min at room temperature and then heated on a steam bath with frequent swirling for 30-45 min. Next, the reaction mixture is well chilled bv swirline in an ice hath (check the pas trap first to avoid suckingwater into ihe system upon cooling).water (50 mT.\ the funnel to the reaction mixture ....., ir .. added thrnwh . ..~ .~ ~ - ~addition ~ w p r 15 XI m i n , this step is quite exothrrmie and lherated much H('1 theinitial additionof HrOshould bcattempledrautious1y.AnadditionoiI ImL I2MHC'ifollows.\Vhantheco~~trnrsoI the flask are cold and HCI evolution has ceased, the flask is removed from the ice hath, and thegas trapand other glasswarearedetached. Any solid stuck to the bottom of the flask should be carefully dislodeed with a soatula (not a glass rod). The flask is euuippedfor aimnle"diatil1atio~of thetoluene-water azeotrooe. ~ncethehvdrorarlwn i i rrrnuvrd, the hut ~(IUCOUL r r ~ i d wis poured intouL30-mL beaker and coolpd in an rce hath. To rhr rryarallrzed rrudr krrnnr~d ~~~~
The synthesis in eq 3 demonstrates the selective reductionof a ketone in the presence of an acid. Conversion of the ketoacid to its salt prevents acidolysis of the NaBH4 and allows water to be the reaction solvent. When the reduction mixture is acidified, hydroxyarid 3 usually oils out of sdution; since it crvstallires with difficulry, it is extrarted from the aqueous mixture. Lactone 4 does not form by spontaneous cyclization of 3 (as many lecture texts imply): thermal dehydration is required. This seems to be true of many y-aryl-yhydroxybutyric acids. The literature procedure' calls for heating 3 under a high vacuum, distilling out 4 as 3 cyclizes. The method employed here is better adapted to classroom use: refluxine the hvdroxvacid in toluene smoothly effects ring closure; n simple distillation then removes the toluenewater azcotrope. The malit challenging aspert of the synthe-
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'Julia. M.; Julia. S.;Bemont. B. BUN.Soc. Chim. France 1960,304. Somervilie,L. F.; Alien. C. F. H. In "Organic Synlheses"; Blatt, A. H., Ed.; Wiiey: New York, 1943; Coil Voi 2, p 81. A vacuum adapter (femalejoint open) atop the condenser connected to a glass tube inserted in the mouth of a water-filled 250-mL filter flask is adequate. The inlet tube must not dip below the water surface. The filter flasE is connected to an aspirator to draw off the HCi. Volume 63
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December 1986
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is added 5 mL 12 M HCI diluted to 15 mL with water; after stirring the mixture briefly, the solid is collected by suction filtration and washed with 20 mL cold water. T o remove the colored by-products and aluminum salts, the solid is heated cautiausly to boiling in a 250-mL beaker with 50 mL 15% Na2C08. The heaker is removed from the heat temporarily, 0.5 g decolorizing charcoal is stirred in, and the mixture reheated to boiling and filtered by suction through a pad of diatomaceous earth (2-3 g for a 7-em Buchner funnel). The filter cake is washed with 25 mL water, and the warm filtrate is transferred to a 400-mL beaker and slowly acidified with 15 mL 12 MHC1 in the hood (foaming). After cooling to 10 "C in an ice bath, the precipitated 4-oxo-4-@-tolyl)hutenoic acid is collected on a clean Buchner funnel, washed with 25 mL cold water, and pressed free of excess water. Severaldays of air drying is required. The yield is about 70%;rnp 117-126 OC ( l k 4 117 "C, 120 OC, 127 T , 129 T). The ketoacid may he recrystallized from l-propanol(2.5 mL/g dry), mp 122-127°C,70%recovery. IRspectrum (KBr): 2500-3400,16501725 cm-I. Synthesis of 2 A recrystallized sample of 1(1.9 g, 10 mmol) is mixed with 1.2 mL acetic anhydride in a 25-mL round-bottomed flask fitted with a condenser, and the mixture heated on the steam bath for 30 min. Upon cooling to room temperature, the orange solid crystallizes. It is collected by suction filtration; the reaction flask is washed with a small volume of cold methanol, and this is used to wash the crude lactone. Recrystallization from methanol (about 10 mL) affords a yield of -60%, mp 103-109 'C (lit5 111 "C). 90 MHz 'H NMR (CDC13,TMS): 6 2.3 (s, 3H), 3.3 (d, 2H, J = 3 Hz), 5.6 (t, 1H, J = 3 Hz), 7.1 (d, 2H, J = 7 Hz), 7.4 (d, 2H, J = 7 Hz). Synthesis of 4 Directly from 1 NaOH (1.3 g, 32 mmol) is dissolved in 25 mL Hz0 in a 125-mL Erlenmeyer flask, and 5 g 1 (26 mmol; unreerystellized ketoaeid is adequate) dissolved in the base. Any insoluble material (charcoal, filter acid) is removed by gravity filtration. NaBH4 (0.70 g, 18mmol) is added to the ketoacid salt solution in small portions aver 10-15 min; any lumps arecarefully broken up. (Workin hood; hydrogenis evolved-no flames!) The flask is lightly stoppered with a cork and set aside from ignition sources for 24 h. (A week's standing does no harm.) Excess reducing agent is destroyed by adding 5 mL acetone, swirling, and letting the solution stand 10-15 min. A cold HCl solution (11mL 12 MHCl poured over 25 mL ice) is slowly added to the reaction mixture: the hvdroxvacid (3) oils out. The mixture is ~extracted twice with25 m i ethe; (no flames!), the extracts dried with anhydrous MgS04, and the solvent removed by distillation or
on a rotnr). cvnpnratur. T o the residw i*added 20 mL t d u m e , and t h e m ~ t u r eis h e ~ t e d~ndrrrrfluxfirr?Omin. \ldter andmort ofrhe tuldme are then rrmwrd by drrtillntim The ia,t traces of tolume are removed under vacuum. The erude lactone may crystallize upon cooling and scratching. Crude4 is taken up in about 10mL hot ethyl acetate, any insolubles are removed hy filtration, and the filtrate concentrated to a volume of less than 5 mL; hexane (5-10 mL) or ligroin (6&70 OC) is then added to induce crystallization, and the solution is cooled in ice. The white needles are collected by suction filtration, washed with ligroin or hexane, end air-dried. Yields of 80% are obtainable hut may he lower if care is not exercised in recrystallization; the mother liquor should be saved for evaporation. Mp 67-74 "C (litz 72 T)90 MHz 'H NMR (TMS): 6 1.9-2.5 (m, 4H), 2.3 (s, 3H), 5.3 (m, l H ) , 7.1 (s, 4H). MS, mle (rel. ahund.): 176 (Mt, 691,161 (29). 121 (100),91 (48),56 (50).
Synthesis of 4 From 5 T o a solution of recrystallized 1 (6.0 g, 31 mmol) in 15-16 mL reagent methanol in a 50-mL round-bottomed flask is added 1mL H&On (18 M); the solution is then boiled under reflux 60-90 min. The esterification mixture is cooled briefly and carefully poured with stirring into a sodium carhonate solution (25 mL 15%Na2C03 25 mL H20) in a 250-mL beaker. Ice is added in portions to the stirred mixture (final total volume of 125 mL) to cause the ester to solidify. The granular solid collected by suction filtration is washed with 25 mLwater and set aside briefly on several thicknesses of filter paper; the damp ester can be reduced as below, or left to dry before proceeding. The dry erude ester has a m p of 4 2 4 8 OC. 90 MHz 'H NMR (CClr,TMS): 6 2.3 (s,3H), 2.55 (t, 2H, J = 6Hz), 3.1 (t, 2H, J = 6 Hz), 3.55 (s, 3H), 7.1 (d, 2H, J = 8 Hz), 7.75 (d, 2H, J = 8 Hz). The ester is dissolved in 25 mL 95% ethanol in a 125-mL Erlenmeyer flask by warming under the tap, 2 mL water is added, and the solution cooled to room temperature. NaBHl (0.35 g, 9.2 mmol) is added rapidly, with stirring to break up lumps of the reducing agent, and the solution left to stand 20 min. (Work in hood; no flames: hydrogen evolved!) The solution is heated to boiling on the steam bath, and 10 mL water is added, followed by 6 mL 10% HCI. The nearly clear solution is cooled in cold water to about room temperature and poured over -50 mL ice in a 250-mL beaker, and the mixture stirred to cause crystallization of 4. The lactone is collected by suction filtration, washed twice with 15 mL water, and dried before recrystallization from ethyl acetate-hexane (see above). The erude yield is 60-80s based on 1.
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de Barry Barnen, E.; Sanders, F. G. J. Chem. SOC. 1933,434 Walton, E. J. Chem. Soc. 1940,438.
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Journal of Chemical Education
Acknowledgment T h e a u t h o r t h a n k s the Chemistry Departments of Union College a n d t h e University of California, Berkeley, for support of t h i s work.
