The Malonic Ester Synthesis in the Undergraduate Laboratory Bernard E. Hoogenbwm, Phillip J. Ihrlg, Arne N. Langsjoen, Carol J. Linn, and Stephen D. Mulder Gustavus Adolphus College, St. Peter, MN 56082 The versatile reactions of diethvl malonate Vmalonic ester") represent an important lectire topic for the introductorv course in oreanic chemistrv. Althoueh i m ~ o r t a nsvnt the"tically and me>hanistically, these reactions are only r&ely performed in the introductory laboratory because of problems associated with the necessary reaction conditions and with the isolation and purification of high-boiling liquid products. For example, assembly of apparatus to maintain anhydrous conditions and an inert atmosphere is time consuming and requires equipment usually not available for large sections of beginning students. The seemingly simple preparation of sodium ethoxide to promote alkylation of diethyl malonate might well consume an entire lab period for a beginning organic chemist, unless performed on a micro scale. Extended reflux periods also tend to reduce student attentiun and involvement. In particular, removal of solvent and distillation of liauid products at reduced pressure are not easily, and perhaps noisafely, accomplishedhy large lab sections of beginning students. Using starting materials of a higher molecular weight range leads to easily isolated solid products and alleviates many difficult handling problems. We have found that solid diphenyl malonate (DPM, I), rather than liquid diethyl malonate, is a useful starting compound to illustrate the elegant chemistry involved in the classic "mhlonic ester synthesis". Syntheses using 1 to 20 mmol quantities of DPM (1) can easily be completed in a 3-4-h laboratory period. The preparation of DPM (1) is accomplished in about 30 min by warming a mixture of malonic acid, phenol, and phosphorous oxychloride.
The cou~line of DPM (1) with henzenediazonium chloride produces ihe Ghenylhyd&one of diphenyl mesoxalate (3), which is readilv reduced to diphenvl acetamidomalonate (4).
1 + Ph-N2+
-
CL-
Ph-NH-N=C
\COOPh 3
This material (4) also forms a nucleophilic carbanion in the presence of anhydrous potassium carbonate in anhydrous acetone. Like diethyl acetainidomalonate, 4 is a useful intermediate in the synthesis of amino acids.
5
AcOH
+ 2HOPh + C02
DPM(1) also condenses under the same conditions (anhydrous K2C03in acetone) with avariety of salicylaldehydes to produce heterocyclic coumarin derivatives. Phenyl esters of other carboxylic and many sulfonic acids may he prepared by a similar procedure on any scale. Variations on this procedure constitute instructive exercises in themselves. DPM (1) readily forms its nucleophilic carbanion in the Dresence of solid anhvdrous potassium carbonate suspended In acetone. These simple conditions promote the alkylation of DPM (1) with primary alkyl halides.
-
COOPh
+ HOPh + H20
~ r /
\cHcoo~ P~CH~'
These procedures can he adapted to any scale without major modifications of equipment or conditions. To minimize isolation and purification problems when working on a small scale (0.1 to 10 mmol), reacting materials should be
Under the same conditions, diethyl malonate fails to react or reacts slowly.
Resented as a poster for the 23rd Great Lakes Regional Meeting of the American Chemical Society. Nonhern 11 inois University, DeKalo. IL. May 31, 1990.
PhCH2 \C/COOPh P~CH~' 2
COOP^
KOH
~2
PhCH2
Volume 88 Number 8 August 1991
689
weighed o n a n analytical balance, and TLC should be used when possible to determine completeness of reactions.
Experimental Procedures Preparatlon of Dlphenyl Malonate ( 1) Using the method of Auger1, a mixture of 4.7 g (50 mmol) of phenol (caution: wear rubber gloves), 2.6 g (25 mmol) of malonie acid, and 5 mL of POCll (caution: corrosive vapor) is heated for 30 min on a steam hath in a hood (a large volume of HCI gas is evolved). Theeheny-redmixture is then cooled and poured with stirring onto a large volume (500 mL) of ice. When excess POC1, has been hydrolyzed, the resulting light green solid is removed by filtration and washed by stirring with 5%NaHCO:, solution and finally with water. The crude product is recrystallized from MeOH to produce 4.5 g (69%) of whiteerystels, mp 46.5-47.5 OC (lit.' mp 50 OC). Dilution of the MeOH filtrate with water to the cloud point provides additional product. Alkylation of Dlphenyl Malonate A mixture of 1.0 g (3.9 mmol) of DPM (I), 1.0 g (7.9 mmol) of benzyl chloride (Caution: lachrymator), 2.2 g (16 mmol) of anhyd KzCO:,,and 1.0g of Nal in 45 mL of anhyd MezCO is heated a t reflux and occasionally swirled (continuous stirring is better) for a period of 2-3 h or until TLC (CH~CIZ developer; Ip vapor visualization) indicates that 1has been consumed. The reaction mixture should be protected by a CaC12 drying tube from atmospheric moisture during the reflux period. After the reflux period, solid material is removed by suction filtration, and the solvent is removed by evaporation. The residual oily solid is acidified with 1O?kHC1. A yellow-brown color due to free Ip can be removed by the addition of a few crystals of solid NaHSOa. The insolublesolid (85%crude) is removed by filtration, rinsed well with water, and recrystallized from MeOH. The purified product (2, 0.55 g, 32%) melts at 150-151 'C. Using the following degradative experiment, it can he determined that this product is diphenyl dibenzylmalonate (2)2. Hydrolysis of Alkyl Derlvatlves of Dlphenyl Malonate The alkylation product (2,0.5 g) obtained by the above alkylation is dissolved in a solution of 0.5 g (6 pellets) of KOH in 6 mL of The mixture is heated (caution: wear gloves ethylene glycol (E.G.). and goggles) a t the boiling point for 5-10 min. The mixture is then diluted with 25 mL of water and acidified with 10% HC1. The resulting white solid is removed by suction filtration and recrystdlized from MeOH, affording 0.11 g, 40% yield. On the basis of its melting point (89 'C), this product is identified as dibenzylacetic acid (lit.%p 88-89 "C). Preparatlon of the Phenylhydrazone of Dlphenyl Mesoxalate
(3) A solution of 4.5 g (18 mmal) of DPM (1) in 45 mL of snhyd MerCO is swirled a t r w m temperature for 15 min with 7.5 g (54 mmol) of snhyd K2C03. The mixture is then chilled to 0-5 OC and treated dropwise (caution: wear rubber gloves) with a cold (0-5 OC) solution of benzenediszonium chloride prepared by diazotizing 2.34 g (18 mmal) of aniline hydrochloride in 18 mL of 1 M HCI with a solution of 1.24 g (18 mmol) of NaNOz in 15 mL of water. The addition of the diazonium salt is carried out with rapid stirring over a period of 15 min. Stirring is initially difficult but improves during the addition. When the addition is complete, the mixture is stirred for another 10 min and then poured into crushed ice. The resulting yellow solid ia removed by filtration and washed thoroughly with water. The crude product (6.0 g, 95%) is recrystallized from MeOH to vield 4.5 .. e (71%) . . of vellowoowdervsolid2..mD 148-149 "C. Materinl~uitahleforreductionu,&phenylacetarnidomal~~nate (1)may he uhtained simply by stirring the crude product with MeOH and filtering.
.
.
Preparatlon of Dlphenyl Acetamidomalonate ( 4 ) To a stirred slurry of 0.45 g (1.25 mmol) of 3 in 8 mL of glacial acetic acid and 2 mL of acetic anhydride (caution: lachrymator)
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Journal of Chernlcal Education
held a t room temperature by means of a water bath is added 0.5 g (7.7 mg-atom) of Zn dust. The mixture is swirled occasionally for 1h or until the yellow color of the original 3 is completely discharged. The mixture is then warmed slightly and filtered to remove excess Zn, rinsing the cake with several small portions of acetic acid. The clear colorless filtrate is diluted with water to the cloud point and allowed to stand a t room temperature to complete the crystallization. Filtration and rinsing with cold water affords 0.22 g (56%) of white solid, mp 122-123 'C. By working up all filtrates, yields up to 93% are obtainable. Recrrjtallizatian of the crude product from EtOH affords 0.29 g (74%) of pure diphenyl acetamidomdonate (4)" mp 122.5-123.5 OC.
Alkylation of Diphenyl Acetamldomalonate To a stirred solution of 2.2 g (7.0 mmol) of powdered 4.1.0 g (7.9 mmol) of benzyl chloride (caution: lachrymator), and 1g of NaI in 40mL of anhyd Me&O protected by a CaC12 tube is added 2.8g (20 mmol) of anhyd K~COI.The mixture is warmed a t reflux temperature for 1h. Removal of the solvent by evaporationleaves a dry solid. Rinsing with 5% HCI, filtration, and further rinsing with water affords 1.5 g (53%) of diphenyl acetamidohenzylmalonate (5)2, mp 133.5-136 'C. Recrystallization from EtOH yields 1.3 g (46%), mp 135-136 "C of pure material. Methylation of 4 with methyl iodide by a similar procedure produces diphenyl acetamidomethylmalonak?, mp 142-144 "C. Preparatlon of dl-Phenylalanlne from Dlphenyl Acetamidobenzylmalonate ( 5 ) A mixture of 2.5 g (6.2 mmol) of 5 and 30 mL of 6 M HCI is heated at partial reflux for 2 h to remove phenol as it is formed by codistillation with water. When the distillate no longer contains phenol (detected by FeCh and BrrH20 tests) and the volume of the hydrolysis mixture is about half its original volume, the hot pale-orange solution is filtered with charcoal and cooled. Filtration of the white solid and evaporation of the filtrate affords 1.2 g of crude product. Recrystallization from an EtOH-heptane mixture yields 0.77 g (75%) of product identified as dl-phenylalanine hydrochloride. In a similar manner 4 is converted in 43% yield to glycine hydrochloride; diphenyl acetamidomethylmalonate is converted to dlalanine hydrochloride in 94% yield. The amino acid hydrochloride salts produced by this method can be identified by IR spectra, mp behavior, and by TLC comparison with hydrochloride salts prepared from authentic and commercially available amino acids. Preparatlon of 3Carbophenoxy-6-bromocoumarln( 8 ) Approximately 0.1 g o f ~ o l i danhyd KKOi isadded toa solutron of 0.102 g t2 mmol) of 5.hromosalirylaldehyde and 0.512 g ( 2 mmd) of DPM (I) i n a minimum volume (about 5 mL, ofanhyd Me.CO. The mixture is stirred occasionally a t room temperatuie for about 20 min. Completeness of the reaction may be determined by TLC analysis (CHzC13 developer; Izvapor visualization). When the reaction is complete, the mixture is diluted with water. The solid is filtered and rinsed with 5% HCI and finally with water. Although it is usually obtained in nearly pure form, the product may he recrystallized, if necessary, from MezCO or MeOH. The purified product (0.61 g, 88%) has a melting point4 of 233-234 'C. Other salicylaldehydes react with DPM ( I ) in a similar manner'.
'
Bellstein's Handbuch der Organische Chemle; Springer: Berlin, 1923, Vol. 6, p 155. IR and NMR spectra and elementary (C,H.N) analyses were consistent with the structure assigned to this product. Bellstein's Handbuch der Organische Chemie; Springer: Berlin. 1926: Vol. 9, p 682. *H00genb00m. B. E.; El-Faghl. M. S.; Fink, S. C.; Ihrlg. P. J.; Langsjoen, A. N.; Linn, C. J.; Maehllng, K. L. J. Org. Chem. 1975, 40, 880-883.
