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1 9 9 6 S P R I N G E R - V E R L A G N E W Y O R K , I N C . 1 0 . 1 0 0 7 / s 0 0 8 9 7 9 6 0 0 3 4 a

1 Portions of this work were presented at the 211th National Meeting of the American Chemical Society, New Orleans,

LA, March 24, 1996.

L a b o ra t o r ie s a n d De mo n s t ra t io n s

Rheosmin (RaspberryKetone) and Zingerone,and Their Preparation byCrossed Aldol-CatalyticHydrogenation Sequences1LEVERETT R. SMITHDepartment of ChemistryContra Costa CollegeSan Pablo, CA [email protected]

The articleincludes

backgroundinformation on

the targetcompounds and

the syntheticmethods used

reparations of the two closely-related natural productsrheosmin (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 conden-sation of 4-hydroxybenzaldehyde with acetone gives an adduct(4-(4'-hydroxyphenyl)-3-buten-2-one), which is hydrogenatedcleanly 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 tozingerone. The article includes background information on thetarget compounds and the synthetic methods used, along withexperimental procedures and IR and NMR data on thecompounds encountered.

P


1 9 9 6 S P R I N G E R - V E R L A G N E W Y O R K , I N C . S 1 4 3 0 - 4 1 7 1 ( 9 6 ) 0 3 0 3 4 - 8

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

Background to the Synthetic Sequences and the Target CompoundsVanillin, a pleasant compound for laboratory exercises [1619], has long been known toundergo 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'-hydroxy-3'-methoxyphenyl)-2-butanone), a substance originally identified as a major flavor ofginger [20, 21]. Although zingerone was later indicated mainly to be an apparent resultof a retro-aldol decomposition of a precursor in the plant [22], the compound hasmaintained a modest phytochemical and medicinal interest [2328]. Another phenolicaldehyde, 4-hydroxybenzaldehyde (itself a natural product), condenses with acetone togive 4-(4'-hydroxyphenyl)-3-buten-2-one, a precursor to rheosmin (4-(4'-hydroxyphenyl)-2-butanone) [29, 30], a substance colloquially called the raspberryketone [31]. Although rheosmin has been known as a flavor substance since the 1920sand 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 widercommercial use as a fragrance additive, came in more recent decades. The toxicology ofrheosmin has been investigated [38, 39], as has its insect attractant [40, 41] andolfactory qualities [42, 43]. The structural similarity between rheosmin and zingeronesuggests a similar biogenesis [31], and studies have shown similar metabolic fates for



Vanillin, R = OCH34-Hydroxybenzaldehyde, R = H

O

OHR

H

OHR

O

OHR

O

acetone

OH-H2/Rh

Zingerone, R = OCH3Rheosmin, R = H

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

Discussion of the Preparative Crossed-Aldol and Hydrogenation ReactionsVanillin and 4-hydroxybenzaldehyde react fairly readily with acetone at roomtemperature, but (unlike benzaldehyde and other nonphenolic aromatic aldehydes) tooslowly to finish in one laboratory period. Presumably, anions of phenolic aldehydes areless readily attacked by the acetone enolate ion than neutral molecules would be;suggestions for a related molecular modeling exercise appear in the ExperimentalSection. Literature reports of the condensation of vanillin with acetone typically involvea 24-hour reaction time. Leaving the blood-red homogeneous mixture more than two orthree days results in a lower-quality product. The literature procedure can be modified toproceed cleanly over the course of one week, by changing the solvent ratio and using ahigher 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 thenext. Similar differences in condensation conditions for 4-hydroxybenzaldehyde make aqualitatively similar, but more modest, difference in the results. To allow flexibility insetting up, both 24-hour and one-week procedures are given for each crossed-aldolreaction, on two different scales. The 0.25-g-scale procedures (indicated assemimicroscale) were fully class-tested; the 60-mg-scale procedures (indicated asmicroscale) were checked (duplicate runs) by the author. With either starting material,the product obtained appears pure spectroscopically, although the crude 4-hydroxybenzaldehyde/acetone adduct is typically somewhat discolored. Thevanillin/acetone adduct is easily recrystallized from ethanol/water. With a little more



effort the 4-hydroxybenzaldehyde/acetone adduct can be recrystallized from wateralone; although a single recrystallization does not give a melting range that matches the112 C reported by Mannich and Merz [30], purity nonetheless appears excellent, andsatisfactory 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 palladiumand 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 beforecrystallization [20]. Mannich and Merz pointed out [30] that the ketone products werestable to the hydrogenation conditions they used, so the alcohol was perhaps generatedvia an initial 1,4-hydrogenation, followed by saturation of the resulting enol.Purifications are, of course, appropriate exercises for students of organic chemistry, butthe difficulty of obtaining pure products in high yield made these particularhydrogenation-purification approaches unattractive for the introductory organic course.Previous experience [48] in which rhodium had given cleaner reactions than palladiumor platinum, led to trying rhodium in this case with excellent results. Hydrogenation israpid using 0.5% rhodium on alumina (commercial pellets were ground in a porcelainmortar); crude products are obtained in high yield and high spectroscopic purity (basedon comparison of IR and 60-MHz proton NMR with those of commercial material) withno evidence of overhydrogenation. Different texts present varied apparatus forhydrogenations [49-51]; a slight modification (Figure 1) of Williamsons invertedgraduated cylinder reservoir [51] was used here, for its ease of setup and simplicity inmonitoring hydrogen uptake. Rheosmin can be purified further by recrystallization fromwater; 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 isa little more expensive than platinum or palladium, a 25-gram bottle of 0.5% catalystwill suffice for hundreds of hydrogenations. The 0.5% rhodium on alumina also offersthe advantage of being pale enough that the disappearance of the starting materialsyellow color is clearly visible as the hydrogenation approaches completion. As with thecrossed-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



10 mL flask

stirbar

Claisenadapter

rubber septum

pan ofwater

100 mLgraduate

PVC tubing

FIGURE 1. SEMIMICROSCALE HYDROGENATION APPARATUS

the students prepare aldol adducts by the semimicroscale procedure, then performhydrogenations on microscale. Before the laboratory (preferably!), or while thehydrogenation is in progress, students should be asked to calculate the expected uptakeof hydrogen.

Alternative Preparations of Rheosmin and ZingeroneBased on yields and convenience, the reactions selected and adapted for this laboratoryexercise appear to be the methods of choice for rheosmin and zingerone. There arehowever, other methods reported for both compounds. Rheosmin has also beensynthesized from phenol by Amberlyst-15-catalyzed addition of 3-buten-2-one [53].Zingerone has been prepared several additional ways. These include reduction anddecarboxylation of ethyl vanillylideneacetoacetate [52]; reaction of 4-benzyloxy-3-methoxybromomethylbenzene 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-N-methylpropanamide [55]; and by Amberlyst-15-catalyzed addition of 3-buten-2-one to 2-



methoxyphenol [53]. If structural variants were desired, some of the alternatives mightoffer advantages. Students in an advanced organic laboratory might find a comparison ofthe alternate methods to be an interesting and challenging exercise; however, we havenot pursued this option.

Experimental SectionPreliminary remarksThe experimental procedures that follow are based on the expectation that students willpreviously have had a laboratory-based general chemistry course, that they will haveencountered a variety of basic organic laboratory operations before this exercise, andthat 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 thatinstructors using these procedures will be experienced in the standard organic teachinglaboratory setting, and that instructors will check out laboratory procedures before usingthem in their classes. Commonly-accepted laboratory safety precautions, including butnot limited to the use of appropriate safety goggles or safety glasses, are to be followedthroughout.

Semimicroscale condensation of vanillin with acetoneThe 24-Hour (Literature) VariantA 13 100-mm Pyrex screw-cap culture tube (or, if preferred, a test tube with a tightly-fitting stopper) is charged with 0.25 g (1.65 mmol) of vanillin and 1.0 mL (14 mmol) ofacetone. The tube is swirled to dissolve the solid; 1.0 mL of 10% (w/v) (2.5 M) aqueousNaOH (caution: caustic!) is added; then, the tube is immediately capped and shakenvigorously to give a clear yellow solution (it later gradually darkens to red). The mixtureis allowed to stand at room temperature for 2448 hours. For workup, the tube isopened; 5.0 mL of 3 M aqueous HCl is added, then the tube is re-closed and shakenvigorously to get yellow suspended crystals (slight warming of the mixture may beevident due to the acid-base neutralization). Suction filtration, followed by rinsing with afew mL of water, gives material, which after air-drying, has a mp of 124127 C. Wastedisposal note: The acidic aqueous filtrate contains acetone and reaction byproductsand must, therefore, be placed in the organic solvent waste container. If requested bythe instructor, the filtrate should be neutralized with sodium bicarbonate prior topouring it into the waste container. The solid product can be recrystallized bydissolving it in hot ethanol, adding an almost equal volume of hot water, and cooling;



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 inHz): 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 VariantA 13 100-mm Pyrex screw-cap culture tube is charged with a 5-mm glass bead (to aidin 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; thesolid phase gradually turns to a filamentous gold mass under a maraschino-redsupernatant. Workup is as above with the note that after HCl is added the mixture isshaken until the original solid is gone, replaced by fine yellow crystals.

Microscale condensation of vanillin with acetoneThe 24-Hour VariantA 5-mL reaction vial with Teflon-lined screw-cap closure is charged with a spinvane, 60mg (0.39 mmol) of vanillin, and 0.25 mL of acetone. The mixture is magnetically stirredto dissolve the solid; then, 0.25 mL of 10% (w/v) aqueous NaOH (caution: caustic!) isadded. 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, withrapid stirring, 1.0 mL of 3 M aqueous HCl is added. The initially-oily mixture gives afine yellow crystalline suspension after 12 min of stirring. The crystals are isolated bysuction filtration, using three 2-mL portions of water to complete transfer and wash thesolid. Information on waste disposal and product characterization is noted in thesemimicroscale procedure.

The 1-Week VariantA 5-mL reaction vial with Teflon-lined screw-cap closure is charged with a spinvane, 60mg (0.39 mmol) of vanillin, and 0.40 mL of acetone. The mixture is magnetically stirredto dissolve the solid; then, 0.125 mL of 20% (w/v) aqueous NaOH (caution: caustic!) isadded. The vial is tightly capped, and the mixture is stirred to give a uniform slurry (ca.



20 s), then allowed to stand at room temperature. After one week, the vial is opened, thespinvane is loosened with a spatula, and 1.0 mL of 3 M aqueous HCl is added with rapidstirring. The initially-oily mixture gives a fine yellow crystalline suspension after 24min of stirring. The crystals are isolated by suction filtration, using three 2-mL portionsof water to complete transfer and wash the solid. Information on waste disposal andproduct characterization is noted in the semimicroscale procedure.

Semimicroscale condensation of 4-hydroxybenzaldehyde with acetoneThe 24-Hour VariantA 13 100-mm Pyrex screw-cap culture tube is charged with 0.25 g (2.05 mmol) of 4-hydroxybenzaldehyde 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 iscapped and shaken to get a clear dark amber solution; the solution is left to stand for 2448 hours. Within 24 hours, the mixture turns to an orange-red semisolid mass. Forworkup, the mixture is treated with 5.0 mL of 3 M aqueous HCl, recapped, and shakenvigorously (one to several minutes) until the initially oily suspension yields a slurry ofcrystals. If the suspended oil does not crystallize within five minutes, addition of a smallseed crystal and further shaking should be effective. The mixture is suction filtered, andthe filter cake is washed with a few mL of cold water. Waste disposal note: The acidicaqueous filtrate contains acetone and reaction byproducts and must, therefore, beplaced in the organic solvent waste container. If requested by the instructor, the filtrateshould be neutralized with sodium bicarbonate prior to pouring it into the wastecontainer. Air drying of the product gives fine brown crystals, generally with m.p. 97101 C, whose IR and NMR spectra typically indicate high purity. Recrystallizationfrom 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 (75-MHz, CDCl3): 201, 159, 145, 131, 126, 124, 116, and 27 ppm.

The 1-Week VariantCharge 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. Afterswirling to dissolve the solid, add 0.50 mL of 20% (w/v) (5 M) aqueous NaOH (caution:



caustic!). The tube is immediately capped and shaken vigorously. The mixture sets upalmost instantly, but shaking gives a loose amber to tan slurry. The tube is left to stand atroom temperature for one week. Workup, as noted above, gives a fine tan crystallinematerial of mp 102109 C.

Microscale condensation of 4-hydroxybenzaldehyde with acetoneThe 24-Hour VariantA 5-mL reaction vial with Teflon-lined screw-cap closure is charged with a spinvane, 60mg (0.49 mmol) of 4-hydroxybenzaldehyde, and 0.25 mL of acetone. The mixture ismagnetically 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 tohomogeneity (ca. 20 s), then allowed to stand at room temperature. After 24 hours thevial is opened and with rapid stirring 1.0 mL of 3 M aqueous HCl is added. If theinitially-oily mixture does not give solid after 510 min of stirring, a tiny seed crystal isadded 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 tocomplete transfer and washing of the solid. Information on waste disposal and productcharacterization is noted in the semimicroscale procedure.

The 1-Week VariantA 5-mL reaction vial with Teflon-lined screw-cap closure is charged with a spinvane, 60mg (0.49 mmol) of 4-hydroxybenzaldehyde, and 0.40 mL of acetone. The mixture ismagnetically 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 auniform slurry (ca. 20 s), then allowed to stand at room temperature. After one week, thevial is opened, the spinvane is loosened with a spatula, and 1.0 mL of 3 M aqueous HClis added with rapid stirring. If the initially-oily mixture does not give a solid productafter 510 min of stirring, a tiny seed crystal is added and stirring continued. A finegranular solid forms within 12 min after seeding. The crystals are isolated by suctionfiltration, using three 2-mL portions of water to complete transfer and wash the solid.Information on waste disposal and product characterization is noted in thesemimicroscale procedure.



Semimicroscale hydrogenation of 4-(4'-hydroxy-3'-methoxyphenyl)-3-buten-2-one tozingeroneCaution: 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 theexperiment. Gas cylinders must be properly secured and transported, and equippedwith appropriate pressure regulators. Particularly, if more than one source ofhydrogen is in use, it may be prudent to have students set up their apparatus in thefume hoods. Also note: methanol is toxic and can be absorbed through the skin; avoidskin contact and breathing of methanol vapor.

Please refer to Figure 1 for a diagram of the hydrogenation apparatus used. Clamp a 10-mL 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 ofpowdered 0.5% rhodium on alumina, and 4 mL of methanol. Next fit the flask with aClaisen adapter, the vertical tube of which is closed with a rubber septum, and thesidearm of which is connected to a ca. 60-cm length of polyvinylchloride (pvc, Tygonor equivalent) tubing. The other end of the tubing is stiffened by insertion of a ca.10-cmglass tube. In an adjacent water bath (a standard pneumatic trough works well) issuspended a 100-mL graduated cylinder, filled with water and with the open end downin the bath. The end of the tube is immersed in the water bath, but not under thegraduated cylinder. Via a syringe needle through the septum, with stirring, the apparatusis flushed gently with nitrogen for 12 minutes. Stirring is stopped, then the apparatus isflushed gently with hydrogen for 12 minutes, and then the end of the outlet tube ispushed up into the graduated cylinder. When the cylinder is nearly full of hydrogen, thegas flow is stopped and the inlet needle is removed. The starting volume is noted, andrapid stirring is started. Hydrogen uptake typically is complete within 40 minutes;complete reaction is indicated by cessation of hydrogen uptake and by disappearance ofthe solutions initial yellow color. After uptake ceases, the mixture is suction filteredthrough diatomaceous earth (Celite) in a small Bchner funnel or fritted filter usingseveral mL of methanol to rinse the flask and the filter cake. The filtrate is evaporated toa viscous oil by heating gently on a hot plate (in the fume hood) in a small tared beakerto which boiling chips have been added. IR and NMR spectra of the material thusobtained match those of commercial zingerone, although it may be difficult to induce theoil to crystallize. Addition of a tiny seed crystal and stirring with a spatula gives a waxysolid. Waste disposal note: Any waste methanol from the hydrogenations should go into



the organic solvent waste container. Filter cakes containing rhodium are to be placedinto the laboratory heavy-metal-waste solid container. Spectroscopic data: IR (neat thinfilm): 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, and29 ppm.

Microscale hydrogenation of 4-(4'-hydroxy-3'-methoxyphenyl)-3-buten-2-one tozingeroneApparatus (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-mLflask with spinbar, and a 25-mL graduated cylinder is used as the hydrogen reservoir. Toavoid having to make major volume corrections in hydrogen readings, a narrowerpolyvinylchloride plastic tube is used. A glass reducing connector, hand-drawn or madefrom a pipet, joins the narrow tubing to a short length of larger tubing on the Claisenadapter sidearm. For the hydrogenation the reaction vial is charged with a spinbar, 60mg (0.31 mmol) of 4-(4'-hydroxy-3'-methoxyphenyl)-3-buten-2-one, 15 mg of powdered0.5% rhodium on alumina, and 1.5 mL of methanol. The apparatus is flushed, thegraduate filled, and the hydrogenation is carried out as described in the semimicroscaleprocedure. When the reaction is complete, the mixture is filtered through a short Celitecolumn prepared from a Pasteur pipet (Figure 2). To prepare the column, a small plug offine glass wool is pushed (from the wide end) into the pipet, so that the plug fits snuglyinto the constriction. Next, enough Celite is scooped into the pipet to make a ca. 1.5-cmlayer. Before pipetting in the hydrogenation mixture, the tightness of the column shouldbe checked by passing 12 mL of methanol through it; if the eluate is clear, the columnis acceptable to use. The hydrogenation mixture is passed through the column, and theeluate is collected in a small beaker (previously tared with an added boiling chip); two 2-mL portions of methanol are used to complete transfer from the vial and to rinse thecolumn. 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 semimicroscaleprocedure.



glass adapter

5 mL vial,with spinvane

Claisenadapter

rubber septum

pan ofwater

25 mLgraduatenarrow-borePVC tubing

tubingconnector

glass wool

Celite layer

Pasteur pipet filter

FIGURE 2. MICROSCALE HYDROGENATION APPARATUS.

Semimicroscale hydrogenation of 4-(4'-hydroxyphenyl)-3-buten-2-one to rheosminThe apparatus, procedure, and precautions are the same as for the above semimicroscalehydrogenation to zingerone, except that 0.25 g (1.54 mmol) of 4-(4'-hydroxyphenyl)-3-buten-2-one is used as starting material. The material obtained on evaporation usuallycrystallizes spontaneously (more rapidly if seeded) on cooling after evaporation ofmethanol; although it generally appears very pure by IR and NMR, it typically melts inthe range of ca. 7478 C. Recrystallization from water (ca. 40 mL per gram) givesmaterial 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, 1H); 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 rheosminThe apparatus (Figure 2), hydrogenation procedure, and filtration are the same as for theabove 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,



characterization of product, and waste disposal are as noted in the semimicroscalehydrogenation to rheosmin.

Additional notes regarding the hydrogenationWe used 10-mL flasks with 14/20 joints and a screw-on connector (No. MW-58-02from Chemglass, 3861 N. Mill Rd., Vineland, N. J. 08360, USA). The microscalehydrogenation used a 5-mL reaction vial (Chemglass No. MW-80-05), also with 14/20-joint and screw-on connector, with a spinvane (Chemglass No. CG-2008-11) designedfor the conical bottom of the vial. The Claisen head (Chemglass No. MW-68-01) had a14/20 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 theoutside of the 7/10 joint to give a gastight seal. Equivalent glassware is, of course, alsoavailable 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 plastic-to-glass seals; the use of latex rubber tubing is not advised, due to possible emission oftrace contaminants which can poison the catalyst. As an economical alternative to theflask or reaction vial with Claisen adapter, a sidearm test tube could be used; use a longsyringe needle to assure effective gas flushing. Other alternatives would be as describedby Williamson [51] or Landgrebe [12]. As laboratory gas sources, we used a smallcylinder of each gas; these, with their regulators, fit securely in the indented top of aheavy-duty 60 by 90 cm-laboratory cart. As students have their apparatus ready, the cartis wheeled around to deliver the necessary gases. Because the cylinders and the cart areavailable, this approach seems easier and cleaner than generating hydrogen (e.g., by zincand acid); furthermore, it seems desirable that the students encounter first-hand theprocedures and precautions that go with use of compressed gases. If bottled hydrogen isunavailable or inconvenient, a Kips apparatus could be used, or students could generatehydrogen individually. However, if multiple hydrogen sources are present in thelaboratory, it is strongly recommended that students set up their apparatus in the fumehoods. Hydrogen generated by zinc and acid should probably be passed through a soda-lime trap before use. Flushing with nitrogen is not strictly necessary, but it removesoxygen from the apparatus and thereby helps to minimize the amount of hydrogenflushing required.

Comments on the molecular modeling exerciseBoth resonance theory and (more quantitatively) molecular modeling show how thecharge on the phenoxide aldol substrate delocalizes all the way to the carbonyl oxygen,



among other places. Students can be asked to compare the charge distribution in theanions of vanillin and/or 4-hydroxybenzaldehyde with those in neutral (thus moresusceptible to anionic attack) models such as 3,4-dimethoxybenzaldehyde(veratraldehyde) or 4-methoxybenzaldehyde (p-anisaldehyde), to get a clearer picture ofwhat the nucleophile (the acetone enolate ion) sees as it approaches the substratescarbonyl carbon. Using HyperChem software, our students were asked to minimizestructures by molecular mechanics using MM+, then do one-point semiempiricalcalculations with AM1, to find charge distributions in the anionic substrate and thenonionic model aldehyde. Molecular modeling results (structures labeled with atomiccharges and with selected structural parameters), along with a brief discussion of thereactivity implications of the results obtained, were written by students as part of theoverall laboratory report. A number of commercially available personal-computer basedmolecular modeling packages could be used to do the same exercise. Address forHyperChem inquiries: Hypercube, Inc., 419 Phillip St., Waterloo, Ontario, Canada N2L3X2; phone 519-725-4040 or 800-960-1871; [email protected]; http://www.hyper.com.

Miscellaneous concluding remarks for instructors, regarding the experimentalproceduresThe authors preference was not to include expected yields in the handout given tostudents, but instructors will doubtless be interested in typical student results. For thesemimicroscale aldol condensations: vanillin/acetone adduct: range 1984%, average54%; 4-hydroxybenzaldehyde/acetone adduct: range 4391%, average 63%. For thesemimicroscale hydrogenations: zingerone, 25100%, average 78%; rheosmin, 70100%, average 90%. In advance of class use, semimicroscale trial runs by the authorgave average yields of: vanillin/acetone adduct: 81%; hydroxybenzaldehyde/acetoneadduct: 80%; zingerone: 100%; rheosmin: 99%. For the authors duplicate test runs onthe microscale procedures, yields were: vanillin/acetone adduct: 71%, 67% (24 hr);74%,74% (1 week); hydroxybenzaldehyde/acetone adduct: 65%, 64% (24 hr); 49%, 48% (1week); zingerone: 98%, 94%; rheosmin: 97%, 100%. If one were to pick just oneprocedure to try with ones class, the vanillin/acetone aldol reaction is the more easily-completed of the aldol reactions, and the hydrogenation to rheosmin gives more nicelycrystalline material than does the hydrogenation to zingerone. On this basis, one couldsay that, overall, the two sequences are of comparable ease. Particularly for themicroscale procedures, transfer of small volumes of solutions or solvents using smallsyringes tends to be easier and more precise than by using pipets. It is easy to scale up



the aldol reactions if one simply wants to make material available for the class tohydrogenate. As an aid to proton NMR interpretation, students were asked to makecomplete assignments after generating an expected spectrum using the Beakerprogram. While Beakers NMR feature is relatively unsophisticated and often onlyapproximates observed splittings and chemical shifts, the program is economical andeasy 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 insteadof Beaker. In comparing NMR spectra obtained by various students, it will becomeapparent that the phenolic protons shift and peak shape are somewhat concentration-dependent. As a final thought, please keep in mind that the material presented in thispaper is not graven in stone: users are encouraged to tailor procedural details, scale andapparatus to local circumstances and preferences.

Supplemental information available from the author: Copies of IR and NMR (1H and13C) spectra of the crossed-aldol adducts, zingerone and rheosmin, will be sent onrequest.

ACKNOWLEDGMENTS

The author thanks the students of Chemistry 226227 for their enthusiasm, hiscolleagues for their encouragement, and the CCC Faculty Project Group for grantingrelease time for this work.

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