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EXPERIMENT2

39Preparation of an a,B-nnsaturateo r"tlifvia Michael and Ardor condensation Reactions

CrystallizationMichael reaction (conjugate addition)Aldol condensation reaction

This experiment illustrates how two important synthetic reactions can be combined toprepare an a,p-unsaturated ketone, 6-ethoxycarbonyi_:,s_aipr,"nyl_2_cyclohexenone. Thefirst step in rhis svnthesis r_s 119dir; hvj;;;

"*u.rutyr'i.;;;;;," addition of erhyr aceto_acetate to tans-chalcone (aMichael aidition reaction). Soaium rr"yaroxide serves as a sourceof hvdroxide ion to catatvzethe reaction.;r; ;;."*lJrr"#iJ,ioo "n

and Et are abbre_viations for rhe phenyl and ethyt g."r;;, ;;pecrively.Il

)

l

I

OOilll-c. -cEt-o- -cui -ar,Ethyl acetoacetate

f?-C-- -C -Ph' --c- 'ph

NaOH---_J

OOIl il

-C.. -c -Et-o- - cH- -cH,iorll

-CH'- - C -Ph CH, -ph

I

HChalcone

The second step of the synthesis is a base-cat alyzed.aldol condensation reaction. Themethyl group loses a grotgn in the presence of base, ura ,rr" .".rriing methyrene carbanionnucleophilically attacks ,t:*"lrr gr;;;. A stable ,i*-."-u"."d ring is formed. Etha-nol supplies a proton to yield tt e afioiinteLediate.

OOitit-C - -C -Et-O- 'CH- 'CH, . NaoH ,Iolit

-cH. -c\P{ tF6 ph

oil

oII-C- -aEt-o- 'cH- \

I

-cHPh\ -c--CH, 'Ph

cHz

I -o,

'Barium hydroxide has also been used as a caElyst (see References)

tIJddddi;,F7tfIt7F;;;;;;i!;;;;;;;;f,,fd;f,irlql

tlI I _,oH-cH'-. -c ---

Ph cHz Ph

Experiment 39: Preparation of an .,.-lJnsaturated Ketone Via Michael and Aldol Condensation Reactions - a Small-Scale Approach -

Pavia

Finally, the aldol intermediate is dehydrated to form the final product, 6-ethoxycar-

bonyl-3,5-diphenyl-2-cyclohexenone. The a,B-unsaturated ketone that is formed is very

stable because of the conjugation of the double bond with both the carbonyl group and a

phenyl group.

ooil ll

-C-- -C-Et-o' -cH - -cHr

Required Reading

ooIttl-C-.- -c--------+ Et-O- -CH' 'CH

tiltil-cH- -c ---

Ph cHz Ph

6-Ethoxycarbonyl-3,5-diphenyl-2-cyclohexenone

+ HzO

Review: Techniques 7 ,8, ll, and 12

Special lnstructions

The sodium hydroxide catalyst used in this experiment must be kept dry. Be sure to

keep the top on the bonle when not in use.

Suggested Waste Disposal

Dispose of all aqueous wastes containing ethanol in the bottle designated for aqueous

wastes. Ethanolic filtrates from the crystallization of the product should be poured into the

nonhalogenated organic waste container.

/Votes to the lnstructor

The trans-chalcone (Aldrich Chemical Co., No. 13,612-3) should be finely ground for

use by the class. The 95Vo ethanol used in this experiment contains 57a water.

Proced u re

Assembling the Apparatus. To a 50-mL round-bottom flask, add 1.2 g of finelyground trans-chalcone, 0.75 g of ethyl acetoacetate, and 25 mL 95% ethanol. Srarirl the

flask until the solid dissolves and place a boiling stone in the flask. Add 1 pellet (be-

L

::r.nmenr 39: Preparation of an ','-unsaturated Ketone via Michael and Aldol condensation Reactions - a small-scale Approach -Pavia

r]IltrtIIarltItIttttttttttD,,t,))),

tween 0'090 and 0.120 g) of sodium hydroxide. weigh the pellet quickly before itbegins to absorb water. Attach a reflux condenser to the round-bottom flask and heatthe mixture to reflux using a hot plate or heating mantle. once the mixture has beenbroughttoagentleboil,continuetorefluxthemixtureforatleastl hour.Duringthisreflux, the mixture will become very cloudy and solid may begin to precipitate. Themixture may bump during the reflux. lf this happens, the solid in the reaction flaskstarts to "erupt" and throws solid up into the reflux condenser. you will need to re-duce the temperature of the hot plate or heating mantle to avoid this problem.

lsolation of the crude Product. After the end of the reflux period, allow themixture to cool to room temperature. Add '10 mL of water and scratch the inside ofthe flask with a glass stirring rod to induce crystallization (an oil may form; scratch vig-orously)' Place the flask in an ice bath for a minimum of 30 minutes. lt is essential tocool the mixture thoroughly in order to completely crystallize the product. Becausethe product may precipitate slowly, you should alsoscritch the inside of the flask oc-casionally over the 3o-minute period and coor it in an ice bath.Vacuum filter the crystals on a Brichner funnel, using 4 mL of ice-cold water toaid in the transfer. Then rinse the round-bottom flask with 3 mL of ice-cold 95% etha-nol to complete the transfer of the remaining solid from the flask to the Bnchner fun-

l:l tll.,* th".r,rt"lr t t. Alternatively, the crystals may be dried for:n _ Lrrs Lry)rot> iltdy ug (]neo Tor5u mlnutes ln an oven set at 75-80"C. Weigh the dry product. The solid contains someSOdiUm hvdroxicle and <ndirrm rrrhnn:+^ .^,L:-L ^-^ ----- , : :: -' '--'iI-'l

anetIlovaloTLaIalyst.Placethesolidpffieeka:i.aad/fftofn..lji^,,.,,n.,lhi

reagent-grade acetone and stir the mixture with a spatura.2 Most of the solid oissotvJrr., |r I ivr D1 \ro'''Y

inacetone,butdonotexoectallofi+fnrli<cnl.,otl^:rllr-,..-:.-1,,'<in acetone, but do not expect all of it to dissolve. t, remove ,;j< ,__\ j

liquid and transfer it into one or more gtass centrifuge tubes, t"urinffi rr;;;;;j'.: (-7, -.t i', 'possible behind in the beaker' lt is impossible to .roid dr"*ing some solid up tnto tri" tr/ O-"1,,,,1.1'pipet, so the transferred liquid willcontain suspended solids, and the solution will bevery cloudy' You should not be concerned about the suspended solids in the cloudyacetone extract because the centrifugation step will clear the liquid completely. cen-trifuge the acetone extract for approximately 2-3 minutes, or until the liquid clears.Usin! a ctean, dry pasteur pipet, transfer;;;;;;*fr::f;:i;Lff;:t:,ff;;:

]tube to a dry, preweighed 50-mL Erlenmeyer flask. lf the transfer operation is done lcarefully, you should be able to leave the solid behind in the centrifuge tube. T.ie_sol Ii9s left..behind-in the beaker and centrifuge tube are inorganic materials related to I

Evaporate the acetone solvent by carefully hEating the flask in a hot water bath Iwhile directing a light stream of dry air or nitrogen into the flask. Use a s/or,zstream Iof gas to avoid blowing your product out of the frask. when the acetonglas*.pfr |rated, you may be reft with an oiry sorid in the bottom of the tr"st.Firatfr1r,"-iiry I

tqqqqqIqIaIaIeeIeeeOeeCoOalolqqq.lelqeCidTdd

i

t0 Experiment 39: Preparation of an '''-ljnsaturated Ketone Via Michael and Aldol Condensation Reactions - a Small-Scale Approach -Pavia

gen into the flask to remove all traces of acetone. Reweigh the flask to determine theyield of this partially purified product.

Crystallization of Product. Crystallize tl;rgploduct using a minimum amount(approximatelySg mL) of toiting.g5% ethanorfhfidP'itr the sotid has dissotved, ailowthe flask to cool slightly. Scratch the inside of the flask with a glass stirring rod untilcrystals appear. Allow the flask to sit undisturbed at room temperature for a few min-utes. Then place the flask in an ice-water bath for at least 15 minutes.

Collect the crystals by vacuum f iltration on a B0chner funnel. Use three 1-mL por-tions of ice-cold 95% ethanol to aid in the transfer. Allow the crystals to dry until thenext laboratory period or dry them for 30 minutes in a 75-80'C oven. Weigh the dry6-ethoxycarbonyl-3,5-diphenyl-2-cyclohexenone and calculate the percentage yield.Determine the melting point of the product (literature value, 111-'112.C). Submit thesample to the instructor in a labeled vial.

Spectroscopy. At the option of the instructor, obtain the infrared spectrumusing the dry film method (Technique 25.4, p.878). You should observe absorbancesat 1734 and 1660 cm 1 for the ester carbonyl and enone groups, respectively. Com-pare your spectrum to that shown in this experiment. Your instructor may also wantyou to determine the proton and carbon NMR spectra. These may be run in CDCI3solvent.a

REFERENCES

Garcfa-Raso, A., Garcfa-Raso, J., Campaner, B., Mestres, R., and Sinisterra, J. v. 'An Improved pro-cedure fbr the Michael Reaction of Chalcones ." Synthesis (1992), 1037.

Garcfa-Raso, A., Garcfa-Raso, J., Sinisterra, J. V., and Mestres, R. "Michael Addition and AldolCondensation: A Simple Teaching Model fbr Organic Laboratory." Journal of Chemical Edu-cation, 63 (May 1986):443.

QUESTTONS

l. Why was it possible to separate the product from sodium hydroxide using acetone?2. The white solid that remains in the centrifuge tube after acetone extraction fizzes when hydrochlo-ric acid is added, suggesting that sodium carbonate is present. How did this substance form? Give abalanced equation for its formation. Also give an equation for the reaction of sodium carbonate withhydrochloric acid.3. Draw a mechanism for each of the three steps in the preparation of the 6-ethoxycarbonyl-3,5-diphenyl-2-cyclohexenone. You may assume that sodium hydroxide functions as a base and ethanolserves as a proton source.

3 The 9 nrl of ethanol indicated in the procedure is an approximation. You may need to add more hot or less hor 95Vo ethanolto dissolve the solid. Add boiling ethanol until the solid just dissolves.aProton NMR determined at 300 MHz: 1.05 ppm (riplet, 3H, I -- 7.1 Hz),2.95-3.05 ppm (multiplet, I H), 3.05-3.15 ppm(multiplet. I H),3.80ppm(multiplet,2 H),4.05 ppm(quartet, zH,J:7.lHz),6.57 ppm(doublet, I H,J = 2.0H2),and7 .30-7 .45 (multiplets, l0 H). Carbon NMR determined at 75 MHz: l7 peaks; 14.1,36.3,44.3,59.8, 61.1, 124.3, 126.4, 127.5,t27 .7, 129.0, 129.t, 130.7, 137.9, t41.2, I 58.8, I 69.5, and I 94.3 ppm.

Experiment 39: Preparation of an '''-unsaturated Ketone via Michael and A.ldol condensation Reactions - a Small-Scale Approach -Pavia

4' Indicate how you could synthes is trans-charcone. (Hint: See Experiment 3g).

o

Eso.=EoEgFdQ 40

4000 3500 3000 25oo 2ooo 1 500 1 000Wavenumbers

lnfrared spectrum of 6-ethoxycarbonyr-3,5-diphenyr-2-cycrohexenone, KBr.

500

30

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