In the Laboratory

JChemEd.chem.wisc.edu • Vol. 77 No. 4 April 2000 • Journal of Chemical Education 511

Epoxide Chemistry: Guided Inquiry Experiment WEmphasizing Structure Determination and Mechanism

H. G. Krishnamurty,* Niveta Jain, and Kiran SambyDepartment of Chemistry, University of Delhi, Delhi-110007, India; *Hari@mantraonline.com

The merits of discovery-based and puzzle-solving labo-ratory exercises have been discussed from a pedagogicalpoint of view in this Journal and laboratory experimentsexemplifying this approach have been published (1). Herewe report an operationally simple puzzle-solving exercise,which we have used in our instructional laboratories to helpstudents develop mechanistic reasoning, problem-solvingskills, and critical thinking. The central theme of the experi-ment is the chemistry of epoxides, a subject on which veryfew laboratory experiments are available.1 With suitablemodifications, the experiment is appropriate at both theundergraduate and graduate levels.

The Experiment

The experiment consists of three steps: (i) preparation ofchalcone 1, (ii) preparation of chalcone epoxide 2, and (iii)reaction of chalcone epoxide with hot alkali (see Scheme I).

The Puzzle

What is the structure of the product resulting from the actionof hot alkali on chalcone epoxide?

The experiment described here results in a product whosestructure is not easily amenable to prediction. Systematicchemical and spectroscopic analysis leads to its correctstructure. Students will face a puzzling four-line signal inthe NMR spectrum, which is a clue to its structure. Finally,a stepwise mechanism to explain the formation of 6 can bedeveloped using lecture-based organic chemistry concepts.2

65

4 3

NaOH, ∆

1 2

NaOH-H2O2

βα

O

Ha

Hb

O

OH

Hb

Ha

O O

OH

OH

O

O

O

CC CH2O

OH OH

Scheme I

This experiment is based on the work of Sir Robert Robinsonmore than six decades ago (2). It provides an opportunityfor students’ involvement and discussion of many topics such

as (i) the aldol condensation, a very important and funda-mental reaction in chemistry, (ii) carbanion formation, (iii)The Claisen–Schimdt reaction, (iv) epoxidation, particularlythe difference between an isolated alkene and a conjugatedalkene, (v) conjugate addition (1,4-addition), (vi) stereo-selectivity, (vii) benzil–benzilic acid change, (viii) oxidativecleavage of α-hydroxy acid (Malaprade oxidation), and (ix)organic spectroscopy.

Experimental Procedure

trans-Benzalacetophenone (Chalcone) 1This is prepared as described by Ellern (3), with minor

modification.mp 56–57 °C; IR (KBr): 1660, 1600, 1440, 1320, 1200,990, 740 cm�1; 1H NMR (60 MHz, CDCl3, δ): 6.9 (d,J = 17 Hz, 1H, Ha), 7.3–7.9 (m, 11H, Hb, and Ar H)

trans-Chalcone Epoxide 2CAUTION: Hydrogen peroxide is corrosive and can cause

bleaching. Avoid contact with skin. Use protective gloves for safety.Chalcone epoxide 2 is prepared by treating a mixture of

chalcone in ethanol and hydrogen peroxide (30%) with dilutesodium hydroxide (10%) (20 min at 30°, 10 min at roomtemperature). The epoxide is crystallized from a small vol-ume of ethanol.

mp 88–90 °C (lit. mp 89–90° [4]); IR (KBr): 1686,1593, 1453, 1410, 1351, 1236, 1006, 891, 751 cm�1;1H NMR (60 MHz, CDCl3, δ): 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)

Reaction of Chalcone Epoxide with Hot AlkaliPlace 500 mg of chalcone epoxide in a round-bottomed

flask and add ethanolic sodium hydroxide (10 mL, 10%).The solid nearly dissolves and forms a turbid yellow solution.Reflux the mixture gently over a suitable heat source for 1 h(the solution turns dark orange within 15 min). Cool thereaction mixture, filter, and acidify with dilute HCl. Collectthe precipitated solid by suction filtration. Dissolve the solid insaturated aqueous NaHCO3, filter to remove the small amountof a colored sticky insoluble material, and then acidify (diluteHCl). Crystallize it from ethanol–water (0.40–0.45 g).

mp 161–162 °C; IR (KBr): 3437, 3030, 2925, 1722,1493, 1454, 1264, 1189, 1101, 1075, 878, 793 cm�1;1H NMR (500 MHz, CDCl3–DMSO-d6, δ): 3.15 (d,J = 14 Hz, 1H), 3.50 (d, J = 14 Hz, 1H), 7.15–7.45 (m,10H, Ar H); EIMS m/z: 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), 55 (21.3); found: C, 74.51%, H, 5.50%;C15H14O3 requires C, 74.38%, H, 5.78%.

In the Laboratory

512 Journal of Chemical Education • Vol. 77 No. 4 April 2000 • JChemEd.chem.wisc.edu

Results and DiscussionThe epoxidation of (E)–chalcone by alkaline hydrogen

peroxide gives a single product. The stereochemistry of theepoxide is readily established using the 1H NMR data. Theepoxide displays two doublets, one at 4.15 (Hb, J = 2.4 Hz)and the other at 4.40 (Ha, J = 2.5 Hz). The J values clearlyindicate that the epoxide is trans-chalcone epoxide (5). Thisreaction is an example of a stereoselective reaction (6 ).

The focus of the paper is on the reaction of the epoxide2 with hot alkali and determination of the structure of theproduct. We encourage students to use both chemical andspectroscopic data3 toward this end.

Students use the analytical values and derive the probablemolecular formula C15H14O3. The use and interpretation ofthe mass spectrum is deceptive and may not be taken up atthis stage. That the compound is an acid is evident from themethod of isolation. The degree of unsaturation (double bondequivalents) is calculated to be 9. Therefore it should havetwo phenyl rings and a carboxyl group. Inspection of theIR spectrum (Fig. 1) supports these inferences (1710 cm�1,C = 0) and also indicates the presence of a hydroxyl group(3436 cm�1, s). Thus, the compound is “likely to be ahydroxycarboxylic acid”. The following structures can nowbe proposed.

(D)(C)

(B)(A)

Ph CH CH

OH COOH

Ph Ph CH CH

Ph OH

COOH

Ph C CH2

OH

COOH

Ph

Ph C CH2

COOH

Ph

OH

Students now examine the 1H NMR spectrum and ruleout A, B, and C on the basis of predicted chemical shifts(see Fig. 2 and the experimental section). However, they areconfronted with four puzzling resonance lines between 3.00and 3.60, amounting to two protons. At this point, studentsare given a hint that the signal may be treated as an AB spinsystem and analyzed.4 Soon they recognize the nonequiva-

lence of the benzylic protons due to the presence of theadjacent stereogenic center bearing four different groups(structure D) (7). These considerations lead to the conclusionthat the hydroxyacid is likely to be D, that is, 2-phenyl-2-benzylglycollic acid 6 (Scheme I). Chemical tests on thecompound, such as Jones’s test and the periodic acid test,support the spectroscopic analysis

Periodic Acid Cleavage of Hydroxyacid 6An independent chemical conversion as proof of struc-

ture is oxidative decarboxylation of 6 by periodic acid (11).Our students have executed this reaction and identifieddeoxybenzoin (PhCOCH2Ph) by both melting point and IR.The overall sequence starting from chalcone (C6–C3–C6)leads to deoxybenzoin (C6–C2–C6).W

Mass Spectrum of 6The EIMS of 6 can now be rationalized as shown in Scheme

II. The absence of the parent peak (M+ 242) is noteworthy.The highest mass ion is m/z 197 [M+�–COOH] (Fig. 3).

+

6

m /z 105

m /z 197

m /z 151

m /z 91

+COOH

C

OH

Ph CH2

C

COOH

C

+OH

+OH

Ph

CH2

Ph

-[COOH]

C15H14O3 , M+ 242

Ph

Ph CH2 Ph

C O+ + PhCH3

Scheme II

Mechanism

The conversion of chalcone epoxide to the α-hydroxy-acid 6 is a mechanistic puzzle. Students clearly recognize that

Figure 1. IR spectrum of the α-hydroxyacid 6 in KBr. Figure 2. 1H NMR spectrum of the α-hydroxyacid 6 (500 MHz).

In the Laboratory

JChemEd.chem.wisc.edu • Vol. 77 No. 4 April 2000 • Journal of Chemical Education 513

a rearrangement is involved but they cannot readily decipherthe pathway. To begin, we direct the students to attempt tocome up with their own rationalizations.2

The reaction bears a certain relationship to benzil–benzilic acid rearrangement. Therefore, a 1,2-diketone islikely to be an intermediate in the reaction. The reaction isinitiated by alkali to give a diol and subsequent eliminationof water to form the diketone 5. The most characteristic prop-erty of the diketone is the ease with which it undergoes thebenzil–benzilic acid type of rearrangement. The rearrangementof the diketone to the hydroxyacid may involve either a phenylgroup migration or a benzyl group migration (Scheme I).

The lecture discussion may now be completed by indicat-ing the acid-catalyzed rearrangement of the epoxide. House (9)showed that the chalcone epoxide 2 rearranges to 2-benzoyl-2-phenylacetaldehyde (α-formyl deoxybenzoin, 7) upon treatmentwith boron trifluoride etherate. Mechanistic investigationsbased on 14C-labeled substituted chalcone epoxides usingBF3�Et2O and also sulfuric acid as catalyst have established thatbenzoyl group and not phenyl group migration is involved5(10) (Scheme III).

7

Ph CO CH CH

O O

Ph Ph CO CH CH Ph

H

O CH CH

COPh

Ph

*14C labeled carbon

*+

*H+*

Scheme III

Project Merits and SummaryThis project has a number of educational merits. The

preparation of chalcone is a very common and popular labexperiment. The present work goes further, to teach aboutepoxidation and rearrangement reactions.

• All the starting materials are readily available in everylaboratory.

• Common lab glassware and equipment are used andno sophisticated instrumentation is needed.

• Chalcone, chalcone epoxide, and the hydroxyacids arecrystalline solids and obtainable in high yields.

• The exercise can be used as a multistep organic chem-istry experiment and a puzzle-solving exercise.

• All the reactions can be run on microscale.

• The students elucidate the structure following the sameprocedure used in research work. So they perceive thetask as relevant and meaningful. Such work is one partof the principle of learning through doing that under-lies lab work.

• The hydroxyacid illustrates an important structural(NMR) principle namely the nonequivalence of geminalhydrogens adjacent to a chiral center.

• Extensions of the project suitable for advanced coursesare numerous. The synthetic usefulness of the hydroxy-acids and the derived deoxybenzoins is another areaof interest (12). This experiment has been performedfor more than three years by several groups of under-graduate students using differently substitutedchalcones. The results are reproducible and successful.

WSupplemental MaterialDetailed experimental procedures for the periodic acid

cleavage of 6 and the acid-catalyzed rearrangement are avail-able in this issue of JCE Online.

Notes1. J. A. Ciaccio, in his articles in this Journal (8), made a

strong case for the need to devise laboratory experiments on thepreparation and reactions of epoxides, which are a synthetically use-ful class of compounds.

2. To facilitate this process, we give students a few hints duringthe lecture discussion at the end of the lab work, when the teacheris an active participant and guide.

3. The analytical and spectral data can either be given to thestudents to save time, or they may be asked to collect such data ingroups.

4. The analysis of the AB spectrum can be an extension ofthis project and is suitable for advanced organic chemistry labs.

Literature Cited1. Mauri, A. D.; Ricci, R. W. J. Chem. Educ. 1995, 72, 457–

459. Crouch, R. D.; Nelson, T. D. J. Chem. Educ. 1995, 72,A6–A7 and references cited therein. Jarret, R. M.; McMaster, P.D. J. Chem. Educ. 1994, 71, 1029–1031 and references citedtherein.

2. Baker, W.; Robinson, R. J. Chem. Soc. 1932, 1796–1806.3. Ellern, J. B. J. Chem. Educ. 1979, 56, 418.4. Weitz, E.; Scheffir, A. Chem. Ber. 1921, 54, 2344.5. Silverstein, R. M.; Bassler, G. C.; Morrill, T. C. Spectrometric

Identification of Organic Compounds, 5th ed.; Wiley: New York,1991; p 221.

6. House, H. Modern Synthetic Reactions; Benjamin: London,1972; p 306.

7. Silverstein, R. M.; Bassler, G. C.; Morrill, T. C. Op. cit.;pp 195–196.

8. Ciaccio, J. A.; Volpi, S.; Clarke, R. J. Chem. Educ. 1996, 73,1196–1198. Ciaccio, J. A. J. Chem. Educ. 1995, 72, 1037–1039.

9. House, H. O.; Reif, D. J.; Wilson, R. C. J. Am. Chem. Soc.1954, 76, 1235; 1956, 28, 2298.

10. Grisebach, H. Acad. Natl. Lincei 1964, 95–104.11. Jackson, E. L. Org. React. 1941, 2, 341.12. Devi, N.; Krishnamurty, H. G. Ind. J. Chem. 1994, 33B, 1187.

Figure 3. Mass spectrum of the α-hydroxyacid 6 (EIMS, 70 eV).