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1 / VOL. 1, NO.

3 ISSN 1430-4171
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1996 SPRINGER-VERLAG NEW YORK, INC. 10.1007/s00897960034a

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

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

1
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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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 crossed-
aldol/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'-hydroxy-
3'-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
3 / VOL. 1, NO. 3 ISSN 1430-4171
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1996 SPRINGER-VERLAG NEW YORK, INC. S 1430-4171 (96) 03034-8

H O O

O acetone H2/Rh
HO OH- HO
HO
R R R
Vanillin, R = OCH3 Zingerone, R = OCH3
4-Hydroxybenzaldehyde, R = H 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 4-
hydroxybenzaldehyde/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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100 mL
graduate
PVC tubing

rubber
septum

Claisen
adapter

pan
of
10 mL flask 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-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-
6 / VOL. 1, NO. 3 ISSN 1430-4171
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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 tightly-
fitting 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 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 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 (75-
MHz, 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 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 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 2-
mL 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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narrow-bore
25 mL Pasteur
graduate pipet filter
glass PVC tubing
adapter
rubber
septum
tubing
connector

Claisen Celite layer


adapter
glass wool
pan
of
water

5 mL vial,
with spinvane

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)-3-
buten-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 14/20-
joint 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 plastic-
to-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 soda-
lime 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 easily-
completed 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 concentration-
dependent. 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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