LAB DOCUMENTATION
TITLE : EPOXIDE CHEMISTRY: GUIDED ENQUIRY EXPERIMENT EMPHASISING
STRUCTURE DETERMINATION AND MECHANISM
THE EXPERIMENT
The exercise consists of a three step organic synthesis. The sequence is (i) preparation of benzalacetopheone
(chalcone 1), (ii) preparation of chalcone epoxide 2 and (iii) the reaction of 2 with hot alcoholic sodium
hydroxide leading to a product labelled HA.
THE PUZZLE
What is the structure of the product HA? What is the mechanism of its formation?
CHEMICALS REQUIRED
Benzaldehyde, acetophenone, ethanolic sodium hydroxide solution (10%), hydrogen peroxide (30%).
EQUIPMENT
Common glassware and a suction filtration assembly.
DIRECTIONS
Prepare chalcone and chalcone epoxide according to the procedures in the hand-out.
The three step sequence should be completed in two lab sessions (3-4 hrs. each). Study the 1H NMR spectra of
chalcone and chalcone epoxide provided to you and deduce the corresponding structures including the relevant
stereochemistry.
Focus your attention on the structure determination of product HA using the given elemental analysis and
spectroscopic data. Carry out appropriate tests on HA to support the proposed structure. Then attempt to come
up with your own mechanistic rationalization. Perform an independent chemical degradation experiment as
directed by your instructor. An in depth discussion of the overall experiment will follow.
EXPERIMENTAL PROCEDURES :
Claisen – Schmidt reaction : Condensation of acetophenone with benzaldehyde : trans-Chalcone 1
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The preparation of chalcone illustrates the Claisen-Schmidt reaction. This reaction is an example of mixed aldol
condensation, which is a very important carbon-carbon bond forming reaction in organic synthesis.
NaOH
C6H5CHO + C6H5COCH3
[C6H5CH(OH)CH2COC6H5]
C6H5CHa = CHb COC6H5 + H2O
Chalcone is best prepared as described by Ellern (J. Chem. Edn, 1979, 56, 418) with minor modifications.
Dissolve sodium hydroxide pellets (1g) in not more than 1.5 ml of water in an Erlenmeyer flask. Add 25 ml of
methanol, cool to 20-22oC and add 6 mL (0.05 mole) of acetophenone and 5 ml (0.05 mole) of benzaldehyde
and swirl the flask. The homogeneous mixture turns yellow immediately and warms fairly rapidly to 30-35oC.
After 15 min., the mixture abruptly becomes turbid and then separates cleanly into two phases, the lower phase
being yellow and the upper phase nearly colourless. Chill the whole mixture, which results in the lower phase
becoming a cake of light yellow crystals. Separate the product by vacuum filtration, wash with cold water
several times and on a porous clay plate or on a filter paper in a desiccator using anhydrous calcium chloride as
a desiccant. This substance is sufficiently pure for the next step of epoxidation. Yield about 9.35 g (90%).
Caution : Chalcone may be toxic and irritant to skin. Avoid contact with skin.
M.P. 56 – 57OC
1R (KBr) : 1660, 1600, 1440, 1320, 1200, 990, 740 cm-1.
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H NMR (60 MHz, CDCl3):  6.9 (d, J = 17 Hz, 1H, Ha) 7.3 - 7.9 (m, 11H, Hb and Ar–H).
trans Chalcone epoxide (2):
In this experiment, the conversion of an ,-unsaturated ketone to an epoxyketone using alkaline hydrogen
peroxide is demonstrated. Note that an isolated olefinic bond undergoes epoxidation with peracids while the
conjugated olefinic compounds (enones) form epoxides by sodium hydroperoxide (an anionic agent). The
reaction is an example of 1,4-addition.
C6H5CO.CH
CH.C6H5
C6H5C
O
+
+ (Na )
CH
CH
O
_
OOH
C6H5
OH
C6H5C CH
_
O
CH
C6H5C
CH.C6H5
O
CH
C6H5
OOH
_
+ OH
O
2
Caution : Hydrogen peroxide is corrosive and can cause bleaching. Avoid contact with skin. Use protective
gloves for safety.
Place 3 g of benzalacetophenone (chalcone), 35 mL of ethanol and 2.8 mL of 30% hydrogen peroxide in an 100
mL Erlenmeyer flask. Swirl the mixture and add dropwise 6 mL of a 5% aqueous sodium hydroxide solution
over about 20 min. Cool the reaction mixture so that the temperature does not rise above 30 oC. After the
addition of the alkali is completed, alllow the mixture to stand for 10 min. Filter the cyrstalline chalcone
epoxide (suction), wash once with cold water and crystallise the crude product from a small volume of ethanol.
White needles (2.58 g, 80%).
M.p. 88 – 90oc
IR (KBr) : 1686, 1593, 1453, 1410, 1351, 1236, 1006, 891, 751 cm -1.
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H NMR (60 MHz, CDCl3) :  4.15 (d, J = 2.5 Hz, 1H, Hb) 4.40 (d, J = 2.5 Hz, 1H, Ha), 7.2 – 7.5 (m, 8H, Ar-
H), 7.8 – 8.0 (m, 2H, Ar-H).
The reaction of chalcone epoxide with hot alkali
Place 0.5 g of chalcone epoxide in a round-bottomed flask and add ethanolic sodium hydroxide (10 mL, 10%).
The solid nearly dissolves and forms a yellow turbid mixture. Reflux the mixture gently with a suitable heat
source for 1 hr. During this time, the solution turns dark orange (within 15 min). At the end of the hour, cool
the reaction mixture, filter, and acidify with dilute HCl. Collect the precipitated solid by suction filtration.
Dissolve the solid in saturated NaHCO3 solution, filter to remove a small amount of coloured sticky insoluble
material and then acidify (dilute HCl). Collect the precipitate by suction filtration and crystallise it from
ethanol-water. The product is labelled HA. The yield is about 0.45 g (83%).
M.p. 161 – 162oC
IR (KBr) : 3436, 3030, 2925, 1721, 1493, 1453, 1263, 1189, 1101, 1074, 878, 793 cm -1.
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H NMR (500 MHz, CDCl3 – DMSO-d6 ) :  3.15 (d, J = 14Hz, 1H), 3.50(d, J = 14 Hz, 1H), 7.15-7.54 (m, 10H,
Ar-H).
EIMS (m/z, % abundance) : 197 (7.3), 178 (4.7), 151 (8.1), 106 (7.1), 105 (100), 92 (43.1), 91 (45.6), 77 (49.6),
57 (24.9) and 55 (21.3).
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Found C, 74.51; H, 5.50%. C15H14O3 requires C, 74.38; H, 5.78%.
Report Form
Use separate sheet for each compound prepared .
1.
Date
2.
Title of the experiment
3.
Purpose of running the reaction
4.
Reaction scheme
5.
Reagents and products
6.
Details of the actual procedure used
7.
Characteristic(s) of the product
8.
Analytical and spectral data
9.
Signature of the student
INSTRUCTOR NOTES :
The benzaldehyde, acetophenone, sodium hydroxide and hydrogen peroxide (30%) used in the experiment are
readily available in most labs and are used directly. Common glassware and equipment are required. No
special lab preparation is required. All the experiments are safe to do and no hazardous wastes are generated.
Copies of detailed experimental procedures should be made available to students. The m.p. of chalcone and
chalcone epoxide may be checked before the third step is taken up. The stereochemistry of the chalcone is
readily established as trans based on the coupling constant between the olefinic protons H a and Hb. While the
Ha proton can easily be identified as a doublet (J = 17Hz), the H b proton very often forms part of the aryl
hydrogen complex multiplet. A 300 MHz spectrum may improve the resolution and simplify interpretation. The
stereochemistry of the chalcone epoxide is also established as trans based on 1H NMR data (see lab summary).
The product of the action of hot alkali on chalcone epoxide is the major target for the structure determination
puzzle. The elemental analysis and spectroscopic data (IR, NMR, MS) may be provided to students to save time
or students may be asked to collect the data. A 200 MHz spectrum for the hydroxyacid HA is desirable
although a 100 MHz spectrum is satisfactory. The approach to solving the structural problem including, the
mechanism of the reaction, is outlined in lab summary. The EIMS (70eV) of compound HA can not be used to
derive its molecular mass. This is likely to be due to the instability and ease of fragmentation of the molecular
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ion (M+•). The conditions at which the MS is taken is also important. Fragment ion (M +• - H2O) may be
observed as the ion of highest mass. The following additional information is helpful.
Malkin and Robinson [J. Chem. Soc., 1925, 369] prepared the diketone, a pale yellow solid (m.p. 65 oC), by
hydrolysis of -methoxychalcone. They also demonstrated its facile conversion to the hydroxyacid HA (6)
under the influence of alkali. Evidently, the diketone is not easy to isolate under the conditions of the hot alkali
reaction of the epoxide. However, Baker and Robinson could isolate the diketone derivative (minor) during the
reaction of 2',4'-dimethoxychalcone epoxide with alkali. This diketone gave the corresponding hydroxyacid on
reaction with hot alkali.
These observations lend credence to the role of the diketone as the reaction
intermediate.
+
H , H2O
NaOH
PhCOCH2OCH3
+
OCHPh
PhCO.C
CH.Ph
OCH3
PhCO.CO.CH2Ph
The Jones test (chromic anhydride – H2SO4) and the periodic acid tests are performed as described in “The
Systematic Identification of Organic Compounds” by R.L. Shriner; R.C. Fuson; D.Y. Curtin and T.C. Morill, 6 th
Ed., John Wiley and Sons Inc. New York, 1980.
OPTIONAL EXPERIMENTS:
The acid catalysed rearrangement of the chalcone epoxide and periodate cleavage of the hydroxy acid are
optional and left to the teacher's discretion.
Oxidative decarboxylation of HA with sodium periodate - Formation of phenylbenzyl ketone
(deoxybenzoin).
Dissolve the hydroxy acid HA (0.5 g) in an acetone – acetic acid – water mixture (10 mL, 3:2:1 v/v) and add
sodium periodate (1g, excess). Stir this mixture at room temperature for 5-6 hrs. Pour into ice water with
stirring, at which time an oily product separates out. Extract with diethyl ether, (10 mL x 3), wash once with
sodium hydrogencarbonate solution followed by water, and dry over anhydrous sodium sulphate. Filter or
carefully decant the ether and evaporate the solvent (hood). The deoxybenzoin is obtained as a gum. Crystallise
the residue from ethyl acetate, pale yellow needles m.p. 58-60oC (lit. m.p. 60oC).
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Periodic acid degradation of the hydroxy acid is useful and safe reaction. The product of the reaction is
phenylbenzylketone (deoxybenzoin) whose identity may be established by comparison with literature m.p. (R.L.
Shriner; R.C. Fuson; D.Y. Curtin and T.C. Morill, “The Systematic Identification of Organic Compounds” 6th
Ed., John Wiley and Sons Inc. New York, 1980.) IR and 1H NMR spectra may also be used. The interesting
point about the overall sequence starting from chalcone (C 6–C3–C6) to deoxybenzoin (C6–C2–C6) is the loss of
one carbon.
Acid catalysed rearrangement of chalcone epoxide - Formation of benzoylphenyl acetaldehyde
Prepare a solution of chalcone epoxide (0.3g) in 5 mL of dichloromethane and cool the solution to 05oC. Add boron trifluoride etherate (0.3 ml, excess) dropwise during 5 minutes. The color of the reaction
mixture turns yellow to orange immediately. Stir the solution at room temperature (25-30oC) for 15 minutes,
then add cold dilute hydrochloric acid and stir for 5 minutes. Separate the organic layer, wash once with water,
dry over sodium sulphate and remove the solvent (hood). The residue is a yellow-brown oil. It resists
crystallisation. It tends to solidify when thoroughly dried (vacuum) over 2-3 days. This material melts between
105-109oC. Careful recrystallisation from EtOAc-hexane gives a white solid m.p. 109-110oC (lit m.p. 11012oC, Wislicenus and Ruthing, Justus Liebigs Ann. Chemie, 379, 233, 261). The solid gives a wine red colour
with ferric chloride (test for enol) and readily forms a copper complex with addition of aqueous copper sulphate.
The rearrangement of chalcone epoxide to benzoylphenyl acetaldehyde is an exothermic reaction. Proper
control of temperature is essential or otherwise considerable decomposition may occur.
Post laboratory discussion
Students are required to review the following topics from prescribed books.
Aldol reaction, carbanion formation, Claisen-Schmidt reaction, epoxidation with special reference to
epoxidation of , -unsaturated carbonyl compounds, benzil-benzilic acid rearrangement and familiarity with
organic spectroscopy for structure determination. The instructor will be an active participant, guiding student
presentations with suggestions and explanations, and finally brings the whole project to a close.
CAS Registry Numbers
Acetophenone [98-86-2], Benzaldehyde [100-52-7], Hydrogen peroxide [7722-84-1], Sodium hydroxide pellets
[1310-73-2]
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