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3 THE CHEMICAL EDUCATOR

ISSN 1430-4171 http://journals.springer-ny.com/chedr 10.1007/s00897960034a

1996 SPRINGER-VERLAG NEW YORK, INC.

Laboratories and Demonstrations

Rheosmin (Raspberry Ketone) and Zingerone, and Their Preparation by Crossed Aldol-Catalytic Hydrogenation Sequences1
LEVERETT R. SMITH Department of Chemistry Contra Costa College San Pablo, CA 94806-3195 lsmith@viking.dvc.edu

The article includes background information on the target compounds and the synthetic methods used

reparations of the two closely-related natural products rheosmin (raspberry ketone, 4-(4'-hydroxyphenyl)2-butanone) and zingerone (4-(4'-hydroxy-3'methoxyphenyl)-2-butanone), are well-suited for the introductory organic laboratory. The crossed-aldol condensation of 4-hydroxybenzaldehyde with acetone gives an adduct (4-(4'-hydroxyphenyl)-3-buten-2-one), which is hydrogenated cleanly over rhodium on alumina to form rheosmin. Condensation of vanillin with acetone gives 4-(4'-hydroxy-3'methoxyphenyl)-3-buten-2-one, which is hydrogenated to zingerone. The article includes background information on the target compounds and the synthetic methods used, along with experimental procedures and IR and NMR data on the compounds encountered.

Portions of this work were presented at the 211th National Meeting of the American Chemical Society, New Orleans, LA, March 24, 1996.

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1996 SPRINGER-VERLAG NEW YORK, INC.

Introduction

The wide occurrence and many variants of aldol-type processes have long made them a prominent part of organic chemistry [13], and thus of the chemical education literature [411]. Various laboratory texts include crossed-aldol reactions, usually preparations of benzalacetone and benzalacetophenone derivatives, starting from such compounds as benzaldehyde, piperonal, nitrobenzaldehyde, or anisaldehyde. These go smoothly, and they easily allow students to isolate pure crystalline products in a single laboratory period, although the main use of the adducts obtained may be purely academic. Experiments that demonstrate catalytic hydrogenation, also important, have received extensive coverage over the years [1215]. To make organic laboratories more appealing, more preparations involving natural products might be attractive additions to the repertoire, even if the experimental procedures do not always lend themselves so readily to finishing within one laboratory period. This paper discusses crossedaldol/catalytic-hydrogenation sequences leading to the closely-related natural products zingerone and rheosmin, both of which work well as organic laboratory targets.

Background to the Synthetic Sequences and the Target Compounds

Vanillin, a pleasant compound for laboratory exercises [1619], has long been known to undergo a facile crossed-aldol reaction with acetone to give 4-(4'-hydroxy-3'methoxyphenyl)-3-buten-2-one, which can be hydrogenated to zingerone (4-(4'-hydroxy3'-methoxyphenyl)-2-butanone), a substance originally identified as a major flavor of ginger [20, 21]. Although zingerone was later indicated mainly to be an apparent result of a retro-aldol decomposition of a precursor in the plant [22], the compound has maintained a modest phytochemical and medicinal interest [2328]. Another phenolic aldehyde, 4-hydroxybenzaldehyde (itself a natural product), condenses with acetone to give 4-(4'-hydroxyphenyl)-3-buten-2-one, a precursor to rheosmin (4-(4'hydroxyphenyl)-2-butanone) [29, 30], a substance colloquially called the raspberry ketone [31]. Although rheosmin has been known as a flavor substance since the 1920s and is on the U.S. FDAs GRAS (generally regarded as safe) food additives list [32], its characterization in raspberries and other natural sources [31, 3337], as well as wider commercial use as a fragrance additive, came in more recent decades. The toxicology of rheosmin has been investigated [38, 39], as has its insect attractant [40, 41] and olfactory qualities [42, 43]. The structural similarity between rheosmin and zingerone suggests a similar biogenesis [31], and studies have shown similar metabolic fates for

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H O acetone HO R Vanillin, R = OCH3 4-Hydroxybenzaldehyde, R = H OHHO R

O H2/Rh HO R

Zingerone, R = OCH3 Rheosmin, R = H

the two compounds [44, 45]. It should be noted that the synthetic precursors, the crossed-aldol adducts (dehydrorheosmin and dehydrozingerone), are obscure natural products in their own right, having been identified as minor plant metabolites [23, 46].

Discussion of the Preparative Crossed-Aldol and Hydrogenation Reactions

Vanillin and 4-hydroxybenzaldehyde react fairly readily with acetone at room temperature, but (unlike benzaldehyde and other nonphenolic aromatic aldehydes) too slowly to finish in one laboratory period. Presumably, anions of phenolic aldehydes are less readily attacked by the acetone enolate ion than neutral molecules would be; suggestions for a related molecular modeling exercise appear in the Experimental Section. Literature reports of the condensation of vanillin with acetone typically involve a 24-hour reaction time. Leaving the blood-red homogeneous mixture more than two or three days results in a lower-quality product. The literature procedure can be modified to proceed cleanly over the course of one week, by changing the solvent ratio and using a higher concentration of aqueous hydroxide, to give a slurry which reacts more slowly. The reaction can quickly and easily be set up by students one week, then continued the next. Similar differences in condensation conditions for 4-hydroxybenzaldehyde make a qualitatively similar, but more modest, difference in the results. To allow flexibility in setting up, both 24-hour and one-week procedures are given for each crossed-aldol reaction, on two different scales. The 0.25-g-scale procedures (indicated as semimicroscale) were fully class-tested; the 60-mg-scale procedures (indicated as microscale) were checked (duplicate runs) by the author. With either starting material, the product obtained appears pure spectroscopically, although the crude 4hydroxybenzaldehyde/acetone adduct is typically somewhat discolored. The vanillin/acetone adduct is easily recrystallized from ethanol/water. With a little more

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effort the 4-hydroxybenzaldehyde/acetone adduct can be recrystallized from water alone; although a single recrystallization does not give a melting range that matches the 112 C reported by Mannich and Merz [30], purity nonetheless appears excellent, and satisfactory for the subsequent hydrogenation. Catalytic hydrogenation of the ,-unsaturated ketones, to give zingerone and rheosmin, can give more difficulty than the condensation. Literature reports appear of palladium and Raney nickel giving significant over-hydrogenation to give alcohols as byproducts, in 1520% yield, which complicates cleanup and isolation of pure ketone products [30, 36, 47]. Platinum has also been used, but vacuum distillation was required before crystallization [20]. Mannich and Merz pointed out [30] that the ketone products were stable to the hydrogenation conditions they used, so the alcohol was perhaps generated via an initial 1,4-hydrogenation, followed by saturation of the resulting enol. Purifications are, of course, appropriate exercises for students of organic chemistry, but the difficulty of obtaining pure products in high yield made these particular hydrogenation-purification approaches unattractive for the introductory organic course. Previous experience [48] in which rhodium had given cleaner reactions than palladium or platinum, led to trying rhodium in this case with excellent results. Hydrogenation is rapid using 0.5% rhodium on alumina (commercial pellets were ground in a porcelain mortar); crude products are obtained in high yield and high spectroscopic purity (based on comparison of IR and 60-MHz proton NMR with those of commercial material) with no evidence of overhydrogenation. Different texts present varied apparatus for hydrogenations [49-51]; a slight modification (Figure 1) of Williamsons inverted graduated cylinder reservoir [51] was used here, for its ease of setup and simplicity in monitoring hydrogen uptake. Rheosmin can be purified further by recrystallization from water; zingerones low melting point (ca. 40 C) makes crystallization difficult [30, 52], but ether and petroleum ether have been used for this purpose [20, 30]. While rhodium is a little more expensive than platinum or palladium, a 25-gram bottle of 0.5% catalyst will suffice for hundreds of hydrogenations. The 0.5% rhodium on alumina also offers the advantage of being pale enough that the disappearance of the starting materials yellow color is clearly visible as the hydrogenation approaches completion. As with the crossed-aldol reactions, hydrogenation procedures are included on two different scales. An alternative to suction filtration, using a Celite-packed column made from a pipet, appears in the microscale hydrogenation procedure; for variety, one may wish to have

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1996 SPRINGER-VERLAG NEW YORK, INC.

100 mL graduate PVC tubing rubber septum

Claisen adapter

10 mL flask

pan of water

stirbar

FIGURE 1. SEMIMICROSCALE HYDROGENATION APPARATUS

the students prepare aldol adducts by the semimicroscale procedure, then perform hydrogenations on microscale. Before the laboratory (preferably!), or while the hydrogenation is in progress, students should be asked to calculate the expected uptake of hydrogen.

Alternative Preparations of Rheosmin and Zingerone

Based on yields and convenience, the reactions selected and adapted for this laboratory exercise appear to be the methods of choice for rheosmin and zingerone. There are however, other methods reported for both compounds. Rheosmin has also been synthesized from phenol by Amberlyst-15-catalyzed addition of 3-buten-2-one [53]. Zingerone has been prepared several additional ways. These include reduction and decarboxylation of ethyl vanillylideneacetoacetate [52]; reaction of 4-benzyloxy-3methoxybromomethylbenzene with the the anion of acetone dimethylhydrazone, followed by oxidative hydrolysis, then hydrogenolysis to remove the benzyl group [54]; by reaction of methyllithium with 3-(4'-hydroxy-3'-methoxyphenyl)-N-methoxy-Nmethylpropanamide [55]; and by Amberlyst-15-catalyzed addition of 3-buten-2-one to 2-

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methoxyphenol [53]. If structural variants were desired, some of the alternatives might offer advantages. Students in an advanced organic laboratory might find a comparison of the alternate methods to be an interesting and challenging exercise; however, we have not pursued this option.

Experimental Section

Preliminary remarks The experimental procedures that follow are based on the expectation that students will previously have had a laboratory-based general chemistry course, that they will have encountered a variety of basic organic laboratory operations before this exercise, and that they will be familiar with the standard precautions that go with the use of acids, bases, common solvents, and other laboratory reagents. A further expectation is that instructors using these procedures will be experienced in the standard organic teaching laboratory setting, and that instructors will check out laboratory procedures before using them in their classes. Commonly-accepted laboratory safety precautions, including but not limited to the use of appropriate safety goggles or safety glasses, are to be followed throughout. Semimicroscale condensation of vanillin with acetone The 24-Hour (Literature) Variant A 13 100-mm Pyrex screw-cap culture tube (or, if preferred, a test tube with a tightlyfitting stopper) is charged with 0.25 g (1.65 mmol) of vanillin and 1.0 mL (14 mmol) of acetone. The tube is swirled to dissolve the solid; 1.0 mL of 10% (w/v) (2.5 M) aqueous NaOH (caution: caustic!) is added; then, the tube is immediately capped and shaken vigorously to give a clear yellow solution (it later gradually darkens to red). The mixture is allowed to stand at room temperature for 2448 hours. For workup, the tube is opened; 5.0 mL of 3 M aqueous HCl is added, then the tube is re-closed and shaken vigorously to get yellow suspended crystals (slight warming of the mixture may be evident due to the acid-base neutralization). Suction filtration, followed by rinsing with a few mL of water, gives material, which after air-drying, has a mp of 124127 C. Waste disposal note: The acidic aqueous filtrate contains acetone and reaction byproducts and must, therefore, be placed in the organic solvent waste container. If requested by the instructor, the filtrate should be neutralized with sodium bicarbonate prior to pouring it into the waste container. The solid product can be recrystallized by dissolving it in hot ethanol, adding an almost equal volume of hot water, and cooling;

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purified material melts around 127128.5 C. Spectroscopic data: IR (KBr): 3300 (br, s), 3020 (vw), 2980 (vw), 1635 (s), 1585 (vs), 1510 (m), 1460 (w), 1425 (w), 1365 (m), 1300 (s), 1270 (vs), 1230 (w), 1185 (vs), 1125 (w), 1025 (m), 1010 (m), 980 (m), 880 (w), 840 (w), 830 (w), 760 (w), 680 (w) cm-1. 1H NMR (300-MHz, CDCl3, couplings in Hz): 7.4 (d, J=16, 1 H); 7.1-6.95 (m, 2 H); 6.9 (d, J=8, 1 H); 6.55 (d, J=16, 1 H); 6.45 (s, 1 H); 3.9 (s, 3 H); and 2.35 (s, 3 H) ppm. 13C NMR (75-MHz, CDCl3): 199, 148, 147, 144, 127, 125, 124, 115, 110, 56, and 27 ppm. The 1-Week Variant A 13 100-mm Pyrex screw-cap culture tube is charged with a 5-mm glass bead (to aid in shaking the slurried mixture), 0.25 g (1.65 mmol) of vanillin, and 1.5 mL (20 mmol) of acetone. After the solid has dissolved, 0.50 mL of 20% (w/v) (5 M) aqueous NaOH (caution: caustic!) is added. The tube is immediately capped and shaken to get a slurry (whitish, slowly turning orange). The tube is stored at room temperature for a week; the solid phase gradually turns to a filamentous gold mass under a maraschino-red supernatant. Workup is as above with the note that after HCl is added the mixture is shaken until the original solid is gone, replaced by fine yellow crystals. Microscale condensation of vanillin with acetone The 24-Hour Variant A 5-mL reaction vial with Teflon-lined screw-cap closure is charged with a spinvane, 60 mg (0.39 mmol) of vanillin, and 0.25 mL of acetone. The mixture is magnetically stirred to dissolve the solid; then, 0.25 mL of 10% (w/v) aqueous NaOH (caution: caustic!) is added. The vial is tightly capped, and the solution is stirred to homogeneity (ca. 20 s), then allowed to stand at room temperature. After 24 hours the vial is opened and, with rapid stirring, 1.0 mL of 3 M aqueous HCl is added. The initially-oily mixture gives a fine yellow crystalline suspension after 12 min of stirring. The crystals are isolated by suction filtration, using three 2-mL portions of water to complete transfer and wash the solid. Information on waste disposal and product characterization is noted in the semimicroscale procedure. The 1-Week Variant A 5-mL reaction vial with Teflon-lined screw-cap closure is charged with a spinvane, 60 mg (0.39 mmol) of vanillin, and 0.40 mL of acetone. The mixture is magnetically stirred to dissolve the solid; then, 0.125 mL of 20% (w/v) aqueous NaOH (caution: caustic!) is added. The vial is tightly capped, and the mixture is stirred to give a uniform slurry (ca.

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20 s), then allowed to stand at room temperature. After one week, the vial is opened, the spinvane is loosened with a spatula, and 1.0 mL of 3 M aqueous HCl is added with rapid stirring. The initially-oily mixture gives a fine yellow crystalline suspension after 24 min of stirring. The crystals are isolated by suction filtration, using three 2-mL portions of water to complete transfer and wash the solid. Information on waste disposal and product characterization is noted in the semimicroscale procedure. Semimicroscale condensation of 4-hydroxybenzaldehyde with acetone The 24-Hour Variant A 13 100-mm Pyrex screw-cap culture tube is charged with 0.25 g (2.05 mmol) of 4hydroxybenzaldehyde and 1.0 mL (14 mmol) of acetone. After the solid has dissolved, 1.0 mL of 10% (w/v) (2.5 M) aqueous NaOH (caution: caustic!) is added, the tube is capped and shaken to get a clear dark amber solution; the solution is left to stand for 24 48 hours. Within 24 hours, the mixture turns to an orange-red semisolid mass. For workup, the mixture is treated with 5.0 mL of 3 M aqueous HCl, recapped, and shaken vigorously (one to several minutes) until the initially oily suspension yields a slurry of crystals. If the suspended oil does not crystallize within five minutes, addition of a small seed crystal and further shaking should be effective. The mixture is suction filtered, and the filter cake is washed with a few mL of cold water. Waste disposal note: The acidic aqueous filtrate contains acetone and reaction byproducts and must, therefore, be placed in the organic solvent waste container. If requested by the instructor, the filtrate should be neutralized with sodium bicarbonate prior to pouring it into the waste container. Air drying of the product gives fine brown crystals, generally with m.p. 97 101 C, whose IR and NMR spectra typically indicate high purity. Recrystallization from boiling water (ca. 100 mL per gram) gives material that is light yellow in color, with melting ranges up to ca. 108 C. Spectroscopic data: IR (KBr): 3150 (br, s), 1660 (w), 1625 (s), 1600 (vs), 1575 (s), 1510 (m), 1435 (m/s), 1370 (m), 1330 (w), 1290 (m), 1250 (vs), 1200 (m), 1170 (s), 1100 (w), 1000 (m), 1075 (m), 860 (vw), 840 (w), 820 (w), 740 (w) cm-1. 1H NMR (300-MHz, CDCl3): 8.1 (br, 1 H); 7.5 (d, J=16, 1 H); 7.4 (d, J=8, 2 H); 6.9 (d, J=8, 2 H); 6.6 (d, J=16, 1 H); and 2.4 (s, 3 H) ppm. 13C NMR (75MHz, CDCl3): 201, 159, 145, 131, 126, 124, 116, and 27 ppm. The 1-Week Variant Charge a 13 100-mm Pyrex screw-cap culture tube with a 5-mm glass bead, 0.25 g (2.05 mmol) of 4-hydroxybenzaldehyde, and 1.5 mL (20 mmol) of acetone. After swirling to dissolve the solid, add 0.50 mL of 20% (w/v) (5 M) aqueous NaOH (caution:

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caustic!). The tube is immediately capped and shaken vigorously. The mixture sets up almost instantly, but shaking gives a loose amber to tan slurry. The tube is left to stand at room temperature for one week. Workup, as noted above, gives a fine tan crystalline material of mp 102109 C. Microscale condensation of 4-hydroxybenzaldehyde with acetone The 24-Hour Variant A 5-mL reaction vial with Teflon-lined screw-cap closure is charged with a spinvane, 60 mg (0.49 mmol) of 4-hydroxybenzaldehyde, and 0.25 mL of acetone. The mixture is magnetically stirred to dissolve the solid, then 0.25 mL of 10% (w/v) aqueous NaOH (caution: caustic!) is added. The vial is tightly capped, and the solution stirred to homogeneity (ca. 20 s), then allowed to stand at room temperature. After 24 hours the vial is opened and with rapid stirring 1.0 mL of 3 M aqueous HCl is added. If the initially-oily mixture does not give solid after 510 min of stirring, a tiny seed crystal is added and stirring is continued. A fine granular solid forms within 12 min after seeding. The crystals are isolated by suction filtration, using three 2-mL portions of water to complete transfer and washing of the solid. Information on waste disposal and product characterization is noted in the semimicroscale procedure. The 1-Week Variant A 5-mL reaction vial with Teflon-lined screw-cap closure is charged with a spinvane, 60 mg (0.49 mmol) of 4-hydroxybenzaldehyde, and 0.40 mL of acetone. The mixture is magnetically stirred to dissolve the solid, then 0.125 mL of 20% (w/v) aqueous NaOH (caution: caustic!) is added. The vial is tightly capped, and the mixture stirred to give a uniform slurry (ca. 20 s), then allowed to stand at room temperature. After one week, the vial is opened, the spinvane is loosened with a spatula, and 1.0 mL of 3 M aqueous HCl is added with rapid stirring. If the initially-oily mixture does not give a solid product after 510 min of stirring, a tiny seed crystal is added and stirring continued. A fine granular solid forms within 12 min after seeding. The crystals are isolated by suction filtration, using three 2-mL portions of water to complete transfer and wash the solid. Information on waste disposal and product characterization is noted in the semimicroscale procedure.

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Semimicroscale hydrogenation of 4-(4'-hydroxy-3'-methoxyphenyl)-3-buten-2-one to zingerone Caution: Hydrogen gas is extremely flammable! Use only in a well-ventilated room, and do not use flames or other sources of ignition in the laboratory during the experiment. Gas cylinders must be properly secured and transported, and equipped with appropriate pressure regulators. Particularly, if more than one source of hydrogen is in use, it may be prudent to have students set up their apparatus in the fume hoods. Also note: methanol is toxic and can be absorbed through the skin; avoid skin contact and breathing of methanol vapor. Please refer to Figure 1 for a diagram of the hydrogenation apparatus used. Clamp a 10mL round-bottomed flask above a magnetic stirrer, and charge it with a magnetic stirbar, 0.25 g (1.30 mmol) of 4-(4'-hydroxy-3'-methoxyphenyl)-3-buten-2-one, 50 mg of powdered 0.5% rhodium on alumina, and 4 mL of methanol. Next fit the flask with a Claisen adapter, the vertical tube of which is closed with a rubber septum, and the sidearm of which is connected to a ca. 60-cm length of polyvinylchloride (pvc, Tygon or equivalent) tubing. The other end of the tubing is stiffened by insertion of a ca.10-cm glass tube. In an adjacent water bath (a standard pneumatic trough works well) is suspended a 100-mL graduated cylinder, filled with water and with the open end down in the bath. The end of the tube is immersed in the water bath, but not under the graduated cylinder. Via a syringe needle through the septum, with stirring, the apparatus is flushed gently with nitrogen for 12 minutes. Stirring is stopped, then the apparatus is flushed gently with hydrogen for 12 minutes, and then the end of the outlet tube is pushed up into the graduated cylinder. When the cylinder is nearly full of hydrogen, the gas flow is stopped and the inlet needle is removed. The starting volume is noted, and rapid stirring is started. Hydrogen uptake typically is complete within 40 minutes; complete reaction is indicated by cessation of hydrogen uptake and by disappearance of the solutions initial yellow color. After uptake ceases, the mixture is suction filtered through diatomaceous earth (Celite) in a small Bchner funnel or fritted filter using several mL of methanol to rinse the flask and the filter cake. The filtrate is evaporated to a viscous oil by heating gently on a hot plate (in the fume hood) in a small tared beaker to which boiling chips have been added. IR and NMR spectra of the material thus obtained match those of commercial zingerone, although it may be difficult to induce the oil to crystallize. Addition of a tiny seed crystal and stirring with a spatula gives a waxy solid. Waste disposal note: Any waste methanol from the hydrogenations should go into

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the organic solvent waste container. Filter cakes containing rhodium are to be placed into the laboratory heavy-metal-waste solid container. Spectroscopic data: IR (neat thin film): 3400 (br, vs), 3010 (vw), 2930 (m), 2840 (vw), 1690 (s), 1600 (m), 1500 (m), 1430 (s), 1360 (s), 1260 (vs), 1240 (s), 1150 (s), 1120 (m), 1030 (s), 930 (w), 860 (w), 810 (m), 790 (m) cm-1. 1H NMR (300-MHz, CDCl3): 6.8 (d, J=8, 1 H); 6.7 (s, 1 H); 6.65 (d, J=8, 1 H); 6.2 (br, 1 H); 3.85 (s, 3 H); 2.85-2.65 (m, 4 H); and 2.15 (s, 3 H) ppm. 13C NMR (75-MHz, CDCl3): 209, 146, 144, 132, 120, 114, 111, 55, 45, 30, and 29 ppm. Microscale hydrogenation of 4-(4'-hydroxy-3'-methoxyphenyl)-3-buten-2-one to zingerone Apparatus (Figure 2) is almost the same as for the the semimicroscale hydrogenation, except that a 5-mL 14/20-neck reaction vial with spinvane is used instead of the 10-mL flask with spinbar, and a 25-mL graduated cylinder is used as the hydrogen reservoir. To avoid having to make major volume corrections in hydrogen readings, a narrower polyvinylchloride plastic tube is used. A glass reducing connector, hand-drawn or made from a pipet, joins the narrow tubing to a short length of larger tubing on the Claisen adapter sidearm. For the hydrogenation the reaction vial is charged with a spinbar, 60 mg (0.31 mmol) of 4-(4'-hydroxy-3'-methoxyphenyl)-3-buten-2-one, 15 mg of powdered 0.5% rhodium on alumina, and 1.5 mL of methanol. The apparatus is flushed, the graduate filled, and the hydrogenation is carried out as described in the semimicroscale procedure. When the reaction is complete, the mixture is filtered through a short Celite column prepared from a Pasteur pipet (Figure 2). To prepare the column, a small plug of fine glass wool is pushed (from the wide end) into the pipet, so that the plug fits snugly into the constriction. Next, enough Celite is scooped into the pipet to make a ca. 1.5-cm layer. Before pipetting in the hydrogenation mixture, the tightness of the column should be checked by passing 12 mL of methanol through it; if the eluate is clear, the column is acceptable to use. The hydrogenation mixture is passed through the column, and the eluate is collected in a small beaker (previously tared with an added boiling chip); two 2mL portions of methanol are used to complete transfer from the vial and to rinse the column. Elution can be speeded by exerting gentle air pressure on the top of the column, using a pipet bulb or (more conveniently) a syringe pipetter. Evaporation, characterization of product, and waste disposal are as noted in the semimicroscale procedure.

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glass adapter rubber septum tubing connector

narrow-bore PVC tubing

25 mL graduate

Pasteur pipet filter

Claisen adapter pan of water 5 mL vial, with spinvane

Celite layer glass wool

FIGURE 2. MICROSCALE HYDROGENATION APPARATUS.

Semimicroscale hydrogenation of 4-(4'-hydroxyphenyl)-3-buten-2-one to rheosmin The apparatus, procedure, and precautions are the same as for the above semimicroscale hydrogenation to zingerone, except that 0.25 g (1.54 mmol) of 4-(4'-hydroxyphenyl)-3buten-2-one is used as starting material. The material obtained on evaporation usually crystallizes spontaneously (more rapidly if seeded) on cooling after evaporation of methanol; although it generally appears very pure by IR and NMR, it typically melts in the range of ca. 7478 C. Recrystallization from water (ca. 40 mL per gram) gives material melting at 8082 C. Spectroscopic data: IR (KBr): 3360 (vs), 3020 (vw), 2920 (w), 2870 (vw), 1685 (s), 1620 (m), 1600 (m), 1510 (w/m), 1440 (m), 1365 (s), 1320 (vw), 1290 (w), 1225 (vs), 1170 (m), 1105 (vw), 1040 (vw), 960 (vw), 875 (w), 830 (m), 765 (w/m), 730 (vw). 1H NMR (300-MHz, CDCl3): 7.05 (d, J=8, 2H); 6.95 (s, 1 H); 6.8 (d, J=8, 2 H); 2.9-2.7 (m, 4 H); and 2.15 (s, 3 H) ppm. 13C NMR (75-MHz, CDCl3): 210, 154, 132, 129, 116, 46, 30, and 29 ppm. Microscale hydrogenation of 4-(4'-hydroxyphenyl)-3-buten-2-one to rheosmin The apparatus (Figure 2), hydrogenation procedure, and filtration are the same as for the above microscale hydrogenation to zingerone, except that 60 mg (0.37 mmol) of 4-(4'hydroxyphenyl)-3-buten-2-one is used as the starting material. Evaporation,

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characterization of product, and waste disposal are as noted in the semimicroscale hydrogenation to rheosmin. Additional notes regarding the hydrogenation We used 10-mL flasks with 14/20 joints and a screw-on connector (No. MW-58-02 from Chemglass, 3861 N. Mill Rd., Vineland, N. J. 08360, USA). The microscale hydrogenation used a 5-mL reaction vial (Chemglass No. MW-80-05), also with 14/20joint and screw-on connector, with a spinvane (Chemglass No. CG-2008-11) designed for the conical bottom of the vial. The Claisen head (Chemglass No. MW-68-01) had a 14/20 base joint, an open-tubular direct-top inlet, and a 7/10 joint on the curved sidearm; clear polyvinylchloride (pvc, e.g., Tygon) tubing, 0.8-cm i.d., fit snugly over the outside of the 7/10 joint to give a gastight seal. Equivalent glassware is, of course, also available from other manufacturers. Other plastic tubing (e.g., PTFE or polyethylene) could be used, although harder plastics may make it more difficult to get gastight plasticto-glass seals; the use of latex rubber tubing is not advised, due to possible emission of trace contaminants which can poison the catalyst. As an economical alternative to the flask or reaction vial with Claisen adapter, a sidearm test tube could be used; use a long syringe needle to assure effective gas flushing. Other alternatives would be as described by Williamson [51] or Landgrebe [12]. As laboratory gas sources, we used a small cylinder of each gas; these, with their regulators, fit securely in the indented top of a heavy-duty 60 by 90 cm-laboratory cart. As students have their apparatus ready, the cart is wheeled around to deliver the necessary gases. Because the cylinders and the cart are available, this approach seems easier and cleaner than generating hydrogen (e.g., by zinc and acid); furthermore, it seems desirable that the students encounter first-hand the procedures and precautions that go with use of compressed gases. If bottled hydrogen is unavailable or inconvenient, a Kips apparatus could be used, or students could generate hydrogen individually. However, if multiple hydrogen sources are present in the laboratory, it is strongly recommended that students set up their apparatus in the fume hoods. Hydrogen generated by zinc and acid should probably be passed through a sodalime trap before use. Flushing with nitrogen is not strictly necessary, but it removes oxygen from the apparatus and thereby helps to minimize the amount of hydrogen flushing required. Comments on the molecular modeling exercise Both resonance theory and (more quantitatively) molecular modeling show how the charge on the phenoxide aldol substrate delocalizes all the way to the carbonyl oxygen,

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among other places. Students can be asked to compare the charge distribution in the anions of vanillin and/or 4-hydroxybenzaldehyde with those in neutral (thus more susceptible to anionic attack) models such as 3,4-dimethoxybenzaldehyde (veratraldehyde) or 4-methoxybenzaldehyde (p-anisaldehyde), to get a clearer picture of what the nucleophile (the acetone enolate ion) sees as it approaches the substrates carbonyl carbon. Using HyperChem software, our students were asked to minimize structures by molecular mechanics using MM+, then do one-point semiempirical calculations with AM1, to find charge distributions in the anionic substrate and the nonionic model aldehyde. Molecular modeling results (structures labeled with atomic charges and with selected structural parameters), along with a brief discussion of the reactivity implications of the results obtained, were written by students as part of the overall laboratory report. A number of commercially available personal-computer based molecular modeling packages could be used to do the same exercise. Address for HyperChem inquiries: Hypercube, Inc., 419 Phillip St., Waterloo, Ontario, Canada N2L 3X2; phone 519-725-4040 or 800-960-1871; info@hyper.com; http://www.hyper.com. Miscellaneous concluding remarks for instructors, regarding the experimental procedures The authors preference was not to include expected yields in the handout given to students, but instructors will doubtless be interested in typical student results. For the semimicroscale aldol condensations: vanillin/acetone adduct: range 1984%, average 54%; 4-hydroxybenzaldehyde/acetone adduct: range 4391%, average 63%. For the semimicroscale hydrogenations: zingerone, 25100%, average 78%; rheosmin, 70 100%, average 90%. In advance of class use, semimicroscale trial runs by the author gave average yields of: vanillin/acetone adduct: 81%; hydroxybenzaldehyde/acetone adduct: 80%; zingerone: 100%; rheosmin: 99%. For the authors duplicate test runs on the microscale procedures, yields were: vanillin/acetone adduct: 71%, 67% (24 hr);74%, 74% (1 week); hydroxybenzaldehyde/acetone adduct: 65%, 64% (24 hr); 49%, 48% (1 week); zingerone: 98%, 94%; rheosmin: 97%, 100%. If one were to pick just one procedure to try with ones class, the vanillin/acetone aldol reaction is the more easilycompleted of the aldol reactions, and the hydrogenation to rheosmin gives more nicely crystalline material than does the hydrogenation to zingerone. On this basis, one could say that, overall, the two sequences are of comparable ease. Particularly for the microscale procedures, transfer of small volumes of solutions or solvents using small syringes tends to be easier and more precise than by using pipets. It is easy to scale up

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the aldol reactions if one simply wants to make material available for the class to hydrogenate. As an aid to proton NMR interpretation, students were asked to make complete assignments after generating an expected spectrum using the Beaker program. While Beakers NMR feature is relatively unsophisticated and often only approximates observed splittings and chemical shifts, the program is economical and easy to use, and students found it helpful. Address for Beaker inquiries: Brooks/Cole, 511 Forest Lodge Road, Pacific Grove, CA 93950-5098, USA; phone (408) 373-0728. Other software for calculating expected NMR spectra could, of course, be used instead of Beaker. In comparing NMR spectra obtained by various students, it will become apparent that the phenolic protons shift and peak shape are somewhat concentrationdependent. As a final thought, please keep in mind that the material presented in this paper is not graven in stone: users are encouraged to tailor procedural details, scale and apparatus to local circumstances and preferences. Supplemental information available from the author: Copies of IR and NMR (1H and 13 C) spectra of the crossed-aldol adducts, zingerone and rheosmin, will be sent on request.
ACKNOWLEDGMENTS

The author thanks the students of Chemistry 226227 for their enthusiasm, his colleagues for their encouragement, and the CCC Faculty Project Group for granting release time for this work.
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