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The Isomerization of Safrole: A Review

by Rhodium
Introduction
Many ways of isomerizing safrole (3,4-Methylenedioxyallylbenzene) into isosafrol
e (3,4-Methylenedioxy- propenylbenzene) can be found in the literature. The isom
erizations, which in all reviewed cases are catalytic, often have high yields, b
ut differs greatly in easiness and reaction times. The availability and costs of
the catalysts also differ over a broad range.
The reaction, which is general for the conversion of nearly all allylbenzenes (l
ike safrole, apiole, dillapiole and elemicin) to their corresponding propenylben
zene isomer, is usually carried out by heating the allylbenzene together with an
inorganic catalyst or catalyst mixture under reflux, with or without the use of
a solvent. After the reaction is finished, the catalyst is removed by filtratio
n, any solvent removed under vacuum, and the residue is distilled to purify the
propenylbenzene from unreacted allylbenzene and polymerized material.
Physical properties
Compound
Melting Point
Boiling Point
Safrole
11°C
232-234°C
trans-Isosafrole
8.2°C
253°C (760mm), 179.5°C (100mm),
135.6°C (20mm), 85-86°C (3.5mm)
cis-Isosafrole
-21.5°C
77-79°C (3.5mm)
The isomerization always gives a mixture of both cis- and trans- isomers of the
propenylbenzene (approx 30:70 using standard hydroxide ion catalyzed isomerizati
on). The trans-propenylbenzene is thermodynamically more stable than the cis-pro
penylbenzene, so with longer reaction times, the ratio of the trans-isomer is in
creased in respect to the cis. As increasing the reaction time beyond the necess
ary for converting the allylbenzene will lower the yield of the product propenyl
benzenes (due to side reactions), so attempts to influence this ratio is usually
not made. Because the reaction produces mixture of isomers rather than a single
compound, the boiling point of the propenylbenzene is never sharp. In the case
of isosafrole, the trans isomer boils at approx 10°C higher than the cis, so the i
sosafrole isomers are usually collected as a mixture over a temperature range, r
ather than trying to collect each fraction separately. In spite of a certain err
orneous statement in Total Synthesis II For all practical purposes, cis- and tra
ns-isosafrole reacts just the same, so there is no real point in separating the
isomers.
Potassium Hydroxide Catalyzed Isomerization
Vacuum Reflux
Using only KOH as catalyst and doing the reflux under vacuum with no solvent1 is
preferable for several reasons. First, the vacuum helps removing the water (~15
%) present in the KOH, and the lower reflux temperature prevents excessive side
reactions.
Experimental
Potassium hydroxide (10-12g, 1-2 mole%) was added to 800g safrole (from sassafra
s oil fractionally distilled twice) situated in a 2000ml round-bottomed flask (n
ever fill a flask more than half full), equipped with an efficient reflux conden
ser, and with the top of the condenser attached to a vacuum source of approximat
ely 10-20 mbar capacity. Magnetic stirring was initiated in the flask, and the s
uspension was brought to reflux under vacuum, which was typically attained at ap
proximately 120°C. The reflux was continued overnight, the vacuum source disconnec
ted, and the reflux condenser was replaced by a fractional distillation setup wi
th a vigreux column and the isosafrole was distilled, again with good magnetic s
tirring. Refraction index measurements shows the reaction to be mostly completed
after approximately 3 hours, but the reaction was still typically refluxed over
night. Stronger vacuum means longer reaction times, because of lower reflux temp
erature. Bigger reactions than 1000ml of safrole that have the tendency to bump
violently, apparently magnetic stirring isn't good enough anymore. For our indus
trially oriented bees: using a capillary to introduce a stream of air bubbles, c
omparable to good old-fashioned vacuum distillation should work to circumvent th
e batch size limitation.
The KOH residue in the distillation flask can be reused to isomerise another bat
ch of safrole. The vacuum limits reflux (=reaction) temp and also helps in remov
ing water formed by the reaction of KOH with the safrole. The higher the tempera
ture, the faster this reaction will be over. As a rule of thumb, half the vacuum
means lowering the boiling point about 10°C. A substance boiling at 200°C at 1000mb
ar (athmospheric) will boil at 190° at 500mbar, 180° at 250mbar, 170°C at 120 mbar, 16
0°C at 60 mbar, 150°C at 30mbar and so on. This is not exact, but can be used to est
imate the expected boiling points roughly. Magnetic stirring is absolutely neces
sary. Don't do this with more than 1L safrole, strong bumping was experienced wi
th bigger amounts. Use distilled safrole! When there's too much water present, r
eaction fails. Distill the iso with column, preferrably collecting the middle 80
%. Recycle the first and last 10%.
Regulating a vacuum and keeping it constant is quite difficult. It's best to use
a diaphragm pump at full vacuum. Using a rotary vane oil pump here doesn't work
, because it pulls too much vacuum.
Isomerization with KOH/CaO9
If calcium oxide is added to a mixture of potassium hydroxide and safrole, the r
eaction becomes less water-sensitive as the CaO reacts with any water present to
form Ca(OH)2. The reaction is also very fast. The downside is that the CaO form
s a black insoluble gunk in the reaction flask, and has to be removed by vacuum
filtration with a filter aid before the isosafrole can be distilled off.
Experimental
100 grams of safrole was placed in a 250 ml RB flask fitted with a water-cooled
Allihn reflux condenser, and was heated with good stirring. When the solution st
arted to boil, 1 gram of KOH pellets was added through the condenser, and the sa
frole immediately took on a brown color. Next, 15 grams of CaO was also added th
rough the condenser, and the solution was allowed to reflux for 15 minutes, and
the heat was turned off, and the solution was poured into a beaker and was allow
ed to cool. The dark brown suspension was vacuum filtered through a pad of celit
e, and the filter cake was washed with 2x50 ml of CH2Cl2. The CH2Cl2 was removed
through distillation at atmospherical pressure, and unreacted safrole was also
distilled off at 240°C (bath temperature), and amounted to about 1 ml. The residue
was distilled at aspirator vacuum (~25 mmHg), and the isosafrole came over at 1
20-130°C as a water-white oil, weighing 70 grams (70%).
Base catalyzed isomerization using Microwave Heating4
Solvent
KOH
Reaction Time
(Std. reflux)
Yield
Reaction Time
(MW reflux)
Yield
EtOH
2 M
25 h
88%
240 min
90%
EtOH
4 M
5 h
98%
30 min
99%
EtOH (+ 2M KCl)
4 M
4 h
99%
20 min
99%
2-BuOH
2 M
4 h
95%
60 min
96%
1-BuOH
2 M
1 h
98%
20 min
99%
1-BuOH
4 M
15 min
99%
3 min
99%
Safrole and eugenol isomerization reactions were carried out under microwave irr
adiation at atmospheric pressure and homogeneous medium with various alcohols us
ed as solvents and different base concentrations. The rate reaction enhancement
shown was up to 13 times faster than conventional reflux.
To study the microwave irradiation effect over isomerization reactions of safrol
e at atmospheric pressure and homogeniuous medium, experiments with various alco
hols used as solvents and different base concentrations were carried out in an a
dapted microwave oven and in conventional reflux.
Experimental
The alcoholic alkaline solution is prepared by the prolonged stirring of 8.8g (o
r 4.4g for 2M) of KOH pellets in 30ml EtOH. The KOH and the alcohols were of ana
lytically purity grade. The alkaline solutions is placed in a RB flask provided
with reflux condenser then 4.0g of safrole is added and the solution heated.
The microwave oven used for this study was a 500W Continental 2001. the reflux s
ystem was pyrex and adapted through a hole in the ovens upper wall, having a dia
meter smaller than half wavelength to avoid microwave radiation escapes.
Potassium Hydroxide and Diethanolamine in 2-Ethoxyethanol 10
Addition of diethanolamine to the isomerization mixture and performing the react
ion in 2-Ethoxyethanol (ethylene glycol monoethyl ether) drastically reduces the
time needed for isomerization, as well as lowering the needed temperature, ther
eby lowering side-reactions occuring at higher temperatures
Experimental
1000g of safrole is added to 10g of potassium hydroxide and 50g of diethanolamin
e in 360g ethylene glycol monoethyl ether. The temperature is raised to 160-180°C
and held there for a few minutes while the isomerization takes place. After the
reaction the reaction mixture is poured into 1000ml water and neutralized with 2
5% sulfuric acid. The organic layer is separated and the aqueous layer extracted
with toluene and the extract added to the organic layer. After the toluene and
water was distilled off, isosafrole distilled over in 95% yield.
Potassium Hydroxide in n-Butanol13
To 91 mL (100g, 620 mmol) safrole were added 500 mL of a 3M solution of potassiu
m hydroxide in n-butanol* and the reaction mixture was stirred under reflux for
3 h. After cooling, the mixture was poured into a solution of 30 mL of concentra
ted hydrochloric acid and 200 mL of ice water. After neutralization, the organic
layer was washed with water and dried with anydrous Na2SO4. After removal of th
e excess n-butanol, the residue obtained was distilled under reduced pressure gi
ving 95 g (95%) of pure isosafrole as a colorless oil, with spectra in agreement
with the literature.
* Prepared by dissolving 84g KOH in 350ml n-butanol with stirring and slight hea
ting, and then diluting to 500ml with more n-Butanol.
Phase Transfer Catalyzed Isomerization
This is a method of isomerising allylbenzenes to propenylbenzenes in aqueous con
ditions at only 70°C.5
Allylbenzene was isomerized to trans- and cis-propenylbenzene. The reaction was
run under varying conditions of mechanical stirring speed, PTC structure, initia
l catalyst concentration, temperature, catalyst counterion, and aqueous NaOH con
centration. Standard reaction conditions consisted of 1.42 M allylbenzene in tol
uene, 5 mol% tetrabutylammonium bromide (TBAB), 40-50% aqueous NaOH, 75°C and stir
ring speed of 850 rpm [at least 550 rpm is needed]. Other phase transfer catalys
ts can be used. But ethyl-tri-octyl-ammonium undergoes extensive decomposition w
ithin 1.5 h due to the available ethyl group being convenient for Hoffman elimin
ation [The same goes for quats containing methyl groups]. Quats below a minimum
organophilicity (eg. tetra-propyl-ammonium) are ineffective. Catalyst decomposit
ion may effectively stop the reaction at 70-98% conversion, depending on reactio
n conditions.
Solventless PTC variation7
In this reference there is a procedure for isomerization of safrole under solven
t-free conditions. The scale is low, but scaling up with some modifications shou
ldn't be a problem.
Experimental
To 10 mmol safrole (1.62g) are added 12 mmol of solid crushed KOH (480mg) and 5
mol% (168mg) Aliquat 336 (common PTC). After shaking vigoruosly, the mixture is
warmed to 80°C and held there for 5 minutes. After cooling 50ml CH2Cl2 is added an
d the the rxn mixture is filtered over 5g florisil. CH2Cl2 is removed under vacu
um and isosafrole is obtained in 96% yield after distillation.
Transition Metal Catalyzed Isomerization
Metal Salt
Amount
Rxn Time
Yield
RuCl3
200 mg
3 h
98%
RuBr3
10.7 mg
3 h
98%
OsCl3
38 mg
10 min
90%
According to this patent6, safrole isomerization can be effected with various tr
ansition element salts. A suspension of the specified amount of transition metal
salt in 50g safrole is heated to 130°C for some time, and then the mixture is dis
tilled to give isosafrole with a minimum (<5%) of safrole forerun. The following
are the amounts used, heating time and yields with selected salts tried by the
authors of the patent.
Water-soluble Ru(II) salts can also be used for the isomerization of allylbenzen
es, even at room temp15.
Experimental
Rhodium(III)Chloride Hemihydrate6
Ruthenium(III)chloride hemihydrate (1.68g, 7.75 mmol) was ground to a fine powde
r and added to safrole (450g, 2.75 mol) in a 1000ml RB flask fitted with a reflu
x condenser and the solution, which soon turned a greenish black, was stirred at
130°C for 4h. The black oil was distilled at the water pump to give 45g of safrol
e at 110-117°C, and the bulk of the oil distilled at 118-121°C yielding 360g of crys
tal clear isosafrole (90% yield based on the reacted safrole).
Rhodium(III)Chloride Trihydrate14
To safrole (20 g) in ethanol (5 ml) was added RhCl3·3H2O (100 mg). The temperature
was maintained at 20°C by cooling and after 2 h the mixture was poured into water
and extracted with ether. The usual work-up was followed by distillation; the y
ield of the fraction bp 130-132°C at 15 mmHg was 93%. The minimum amount of cataly
st for 20 g of safrole is 5 mg; complete transformation requires 24 h in this ca
se. The amount of the trans-isomer of safrole was about 80%.
Iron Pentacarbonyl2,3
Fe(CO)5 (iron pentacarbonyl) and NaOH has been shown to be a very effective cata
lyst pair, giving a 97% yield of isosafrole at 99% purity. A downside with this
method is that Fe(CO)5 is a both toxic and expensive reagent, but on the other h
and, the reaction is very rapid and the molar consumption of the catalyst is low
.
Experimental
Safrole (500g), iron pentacarbonyl (2.5g) and sodium hydroxide (1.6g) were mixed
in a one litre flask equipped with stirrer, thermometer and reflux condenser. T
he well-stirred reaction mixture was heated to 110°C at which temperature a vigoro
us reaction commenced, causing the temp. to rise to 180°C in 6 min. After cooling
the mixture, 250ml of 2N acetic acid were added. The organic layer was separated
from the aqueous phase and washed with brine to neutrality. After drying and ev
aporation of the solvent the mixture was distilled from a Claisen flask and gave
485g (97%) of isosafrole.
Disodium Iron Tetracarbonyl11
The reagent Na2Fe(CO)4 (prepared in situ in THF by the reduction of Fe(CO)5 with
sodium naphthalenide) reacts with safrole in the presence of CuCl to bring abou
t isomerization to trans-isosafrole in 87% yield. Reactions involving BrCH2CH2Br
in place of CuCl give similar results.
Miscellaneous Isomerization Catalysts
Sodium on Alumina8
Allylbenzenes can be isomerized to propenylbenzenes either in a batchwise or con
tinous mode by letting it react with a catalyst prepared by fusing activated alu
mina, sodium hydroxide and sodium metal. The catalyst can also be reused.
Experimental
Catalyst preparation:
In a 100 ml four-necked flask, activated alumina (50 g) was charged and stirred
at 380-400°C for 2 h under nitrogen. Sodium hydroxide (8.7g) was portionwise added
thereto at the same temperature, and the resultant mixture was stirred for 20 m
inutes. Then, metallic sodium (2.0 g) was portionwise added thereto, whereby the
mixture became black but turned gradually white. After being stirred for 2 hour
s, the reaction mixture was allowed to cool to give a catalyst product. The prod
uct was not ignited upon exposure to air, and generation of hydrogen was not see
n on admixture with water.
General Procedure :
In a 25 ml flask, safrole (5.0 g) was charged, and the atmosphere was replaced b
y nitrogen. The catalyst (1.0g) was added thereto, and the resultant mixture was
stirred at room temperature for 1h. After elimination of the catalyst by filtra
tion, the filtrate was distilled to give isosafrole (4.9 g), bp 135°C at 20 mmHg.
Continous operation:
In a reactor of 10 mm in inner diameter and of 50 cm in length, the catalyst (15
g) was charged under a nitrogen stream. Safrole was continuously introduced the
rein from the upper part at a rate of 1.1 g/min., and the reacted product was ta
ken out from the lower part. No depression in the catalytic activity was seen ev
en after introduction of 200 g of safrole. The product was confirmed to be 100%
purity of isosafrole by gas chromatography.
CoCl2/Ph3P/NaBH4 System12
The catalyst generated in situ using CoCl2/Ph3P/NaBH4 in a 1/3/1 ratio in THF at
-10°C isomerizes safrole into trans-isosafrole. Efforts to stop the reaction at t
he cis-alkene stages were unsuccessful. Furthermore, no isomerization occurs at
-40°C, and above 0°C the catalyst decomposes. When more than 20 mmol (3.25g) of safr
ole was used, a considerable amount of starting material remained unreacted.
Experimental
The THF was distilled over benzophenone-sodium immediately before use. Anhydrous
CoCl2 was prepared by heating CoCl2·6H2O at 110°C for 24h and further dried under v
acuum for 1h at 100°C.
NaBH4 (378mg, 10 mmol) was added under nitrogen during 15 min to a magnetically
stirred suspension of CoCl2 (1.3g, 10 mmol) and Ph3P (7.86g, 30 mmol) in THF (80
ml) at -10°C (bath temperature) and the mixture was stirred for a further 30 min.
Safrole (3.25g, 20 mmol) was injected and the mixture stirred at -10°C for 2 hour
s. Petroleum ether (200 ml) was added at -10°C followed by 2 N HCl (30 ml). The la
yers were separated and the aqueous layer was extracted with petroleum ether (2x
25 ml). The combined organic extracts were washed once with saturated sodium chl
oride solution (30 ml) and dried over anhydrous magnesium sulphate. The solvent
was evaporated and pentane (10 ml) was added to the residue to precipitate the P
h3PBH3 complex and most of the Ph3P. The solvent was evaporated from the filtrat
e and the residue was distilled to give trans-isosafrole in 80% yield (2.6g, 16
mmol).
Propenylbenzene can also be prepared using this procedure by instead of safrole
adding allylbenzene (2.36g, 20 mmol) to the reaction mixture. After distillation
trans-propenylbenzene is recovered in 81% yield (1.92g, 16.2 mmol).
References
 1. Osmium, communication at The Hive (1998)
2. Chem. Abs. 66, 85716y (1967)
3. Rec. Trav. Chim. Pays-Bas 86, 31-32 (1967)
4. Syn. Comm. 27(24), 4335-4340 (1997)
5. J. Org. Chem. 48, 1022-1025 (1983)
6. US Pat 4,138,411
7. Syn. Comm. 23(10), 1379-1384 (1993)
8. US Patent 3,852,305
9. Chem. Abs. 47, 9360c (1953), Chem. Abs. 47, 10005h (1953)
10. British Patent 525,705
11. J. Organomet. Chem. 491, 263-266 (1995)
12. J. Organomet. Chem. 319, 113-117 (1987)
13. J Braz Chem Soc 11(4), 371-374 (2000), J. Pharm. Sci. 81(12), 1219-1222 (1
992)
14. J. Chem. Soc. Perkin Trans. 1, 359-363 (1977)
15. T. Karlen and A. Ludi, Helv. Chim. Acta 75, 1604-1605 (1992)