Cyclamen aldehyde synthesis: Aldol condensation followed by hydrogenation over ruthenium catalyst

Article abstract of DOI:10.1007/s11164-015-1948-y

Cyclamen aldehyde is a fragrant substance with the scent of cyclamen or lily-of-the-valley. In this work, the desired cyclamen aldehyde was prepared by twostep synthesis. At the first step, aldol condensation of 4-isopropylbenzaldehyde and propanal was carried out. The influence of used catalyst (potassium hydroxide and sodium methoxide) and propanal amount were tested. Propanal was used in excess and it was added to the reaction mixture dropwise (to prevent its self-condensation to 2-methylpent-2-enal). Resulting mixture of 4-isopropylbenzaldehyde and forcyclamen aldehyde was hydrogenated using different Ru/C catalysts. The products detected in hydrogenation reaction mixture were: desired cyclamen aldehyde, cyclamen alcohol and forcyclamen alcohol. The influence of catalyst type and amount, reaction temperature and hydrogen pressure on the reaction course was tested. The highest yield (19.4 %) was obtained using pressure 10 MPa, temperature 110 °C and 2 wt% of catalyst Ru/C.

Full text of DOI:10.1007/s11164-015-1948-y

Res Chem Intermed
DOI 10.1007/s11164-015-1948-y
Cyclamen aldehyde synthesis: aldol condensation
followed by hydrogenation over ruthenium catalyst
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Eva Vrbkova Tomas Skypala Eliska Vyskocilova
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Libor Cerveny
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Received: 16 October 2014 / Accepted: 3 February 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract Cyclamen aldehyde is a fragrant substance with the scent of cyclamen or
lily-of-the-valley. In this work, the desired cyclamen aldehyde was prepared by two-
step synthesis. At the first step, aldol condensation of 4-isopropylbenzaldehyde and
propanal was carried out. The influence of used catalyst (potassium hydroxide and
sodium methoxide) and propanal amount were tested. Propanal was used in excess
and it was added to the reaction mixture dropwise (to prevent its self-condensation
to 2-methylpent-2-enal). Resulting mixture of 4-isopropylbenzaldehyde and forcy-
clamen aldehyde was hydrogenated using different Ru/C catalysts. The products
detected in hydrogenation reaction mixture were: desired cyclamen aldehyde, cy-
clamen alcohol and forcyclamen alcohol. The influence of catalyst type and amount,
reaction temperature and hydrogen pressure on the reaction course was tested. The
highest yield (19.4 %) was obtained using pressure 10 MPa, temperature 110 °C
and 2 wt% of catalyst Ru/C.
Keywords Cyclamen aldehyde ꢀ Forcyclamen aldehyde ꢀ Hydrogenation ꢀ Aldol
condensation
Introduction
Cyclamen aldehyde (2-methyl-3-(4-iso-propylphenyl)propanal) is used as a fragrant
substance for its fresh flower smell (cyclamen, lilac and violet). It is used as a
surrogate of the currently utilized favorite and cheap analogue of cyclamen
aldehyde, namely lily aldehyde (2-methyl-3-(4-tert-butylphenyl)propanal), which
was classified as a possible mutagenic agent [1]. Lily aldehyde is frequently used in
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E. Vrbkova (&) ꢀ T. Skypala ꢀ E. Vyskocilova ꢀ L. Cerveny
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Department of Organic Technology, Institute of Chemical Technology, Technicka 5,
Prague 166 28, Czech Republic
e-mail: eva.vrbkova@vscht.cz
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E. Vrbkova et al.
detergents, soaps, etc. Another use of cyclamen aldehyde is as an intermediate in
fungicide synthesis [2]. Cyclamen aldehyde can be prepared by aldol condensation
of 4-isopropylbenzaldehyde and propanal (Fig. 1), which is usually performed using
inorganic basic catalyst (NaOH, KOH) [3, 4], but some research using heteroge-
neous catalyst are also available [5].
A product of aldol reaction, forcyclamen aldehyde (2-methyl-3-(4-iso-propy-
lphenyl)prop-2-enal), can be hydrogenated using different metal catalysts, e.g.,
palladium on active carbon, or different metals (nickel, rhodium, palladium) on
Al2O3 [5, 6]. Hydrogenation of forcyclamen aldehyde can give three possible
products: 3-(4-isopropylphenyl)-2-methylprop-2-en-1-ol (forcyclamen alcohol),
which can be isomerized to desired cyclamen aldehyde, e.g., using Fe(CO)5and
UV irradiation [7], the desired cyclamen aldehyde or the undesired product of
subsequent cyclamen aldehyde hydrogenation, cyclamen alcohol (3-(4-isopropy-
lphenyl)-2-methylpropan-1-ol) (Fig. 2). Some syntheses leading to non-racemic
cyclamen aldehyde have also been reported [8, 9].
Materials and methods
4-Isopropylbenzaldehyde (Acros), potassium hydroxide (Penta), sodium methoxide
(Sigma Aldrich), methanol (Penta), N,N0-dimethylformamide (Penta), toluene
(Penta), isopropylalcohol (Penta), diethylether (Penta), and different ruthenium
O
Fig. 1 Scheme of forcyclamen
aldehyde synthesis
O
+
O
H
O
III.
O
H
O
O
I.
II.
Fig. 2 Scheme of hydrogenation forcyclamen aldehyde to cyclamen alcohol (I), cyclamen aldehyde (II),
forcyclamen alcohol (III)
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Cyclamen aldehyde synthesis
Table 1 List of catalysts used
Name
Manufacturer
Solid support
Rutheium content (wt%)
Moisture (wt%)
Type 97
Type 698
Type 600
Johnson Matthey
Johnson Matthey
Johnson Matthey
C
4.62
4.84
4.90
54.90
2.30
SiO2
C
49.90
catalysts (Johnson Matthey; Table 1) were purchased from commercial sources and
used without purification. Propanal (Sigma Aldrich) was freshly distilled before
reaction (b. p. 46 °C).
Aldol reaction
The flask was charged with the catalyst and the solvent (3 ml) and 4-isopropylben-
zadehyde (1 ml, iPB) were added. The total amount of propanal was added
dropwise to the mixture in four portions at 0, 30, 60 and 90 min of the reaction.
Except for monitoring the influence of temperature, all experiments were performed
at room temperature (25 °C). When a higher temperature was used, the flask was
equipped with a condenser. Samples were neutralized by acetic acid, diluted with
ethanol, centrifuged and analyzed. At the end of the reaction, the reaction mixture
was also neutralized using acetic acid, washed with water, extracted using
diethylether and evaporated.
Hydrogenation
Hydrogenations were performed in an autoclave (volume 160 ml; Parr). A mixture
containing 4-isopropylbenzaldehyde (cca 10 wt%) and forcyclamen aldehyde (FCA,
ca. 90 wt%) was used for the hydrogenation. Autoclave was charged with an
appropriate amount of catalyst (active metal Ru; Table 1), 10 g of a mixture of
4-isopropylbenzadehyde and forcyclamen aldehyde and 90 ml of solvent, isopropy-
lalcohol. Samples taken during the reaction were centrifuged and analyzed.
Both samples from the aldol reaction and hydrogenation were analyzed using a
Shimadzu GC 17A chromatograph fitted with nonpolar column ZB-5 (60 m,
0.32 mm diameter, 0.25 lm film) and FID. Composition of reaction mixture was
also monitored using GC-MS Shimadzu 2010 fitted with nonpolar column.
Results and discussion
Aldol condensation
Reaction course
All results were compared after 180 min of the reaction (after 180 min from the
reaction starting, the maximal 4-isopropylbenzaldehyde conversion was reached in
all cases; Fig. 3). In all cases, selectivity decreased with conversion, which was
123

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E. Vrbkova et al.
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Cyclamen aldehyde synthesis
100
99
98
97
96
95
94
93
92
91
90
100
90
80
70
60
2-Methylpent-2-enal
50
40
30
20
10
0
4-Isopropylbenzaldehyde
Forcyclamenaldehyde
Side products
0
20
40
60
80
100
0
1
2
3
4
5
Conversion of iPB (%)
Time (hod)
(a)
(b)
Fig. 4 Reaction course (a) and the dependence of selectivity to forcyclamen aldehyde on conversion of
iPB (b) (molar ratio 4-isopropylbenzadehyde:sodium methoxide:propanal 1:0.05:1, 25 °C, solvent
methanol)
caused by formation of side products (Fig. 4a, b). The formation of these side
products is also the reason for stopping the conversion of iPB because the propanal
was consumed by the side reactions. The side products identified in the reaction
mixture were the products of the subsequent aldol reaction between forcyclamen
aldehyde and propanal [2,4-dimethyl-3-hydroxy-5-(4-isopropylphenyl)pent-4-e-
nal(III.), 2,4-dimethyl-5-(4-isopropylphenyl)pent-2,4-dienal(IV)]. The product of
aldolization [3-hydroxy-2-methyl-3(4-isopropylphenyl)propanal(I.)] between pro-
panal and 4-isopropylbenzaldehyde was also present in the reaction mixture
(content lower than 2 %), and was directly dehydrated to create the desired
forcyclamen aldehyde (II).
Due to the fact that iPB and propanal were used in the molar ratio 1:1, no
subsequent reactions took place and total conversion of iPB was not reached
because there was no other reactant in the reaction mixture. In Fig. 4b, the
selectivity as a function of iPB conversion is illustrated. The apparent formation of
by-products not before 40 % conversion is given by the detection limit of GC (5 %).
Influence of catalyst type and amount
Two types of basic catalysts were studied: 36 wt% water solution of potassium
hydroxide (Fig. 5a) and 33 wt% methanolic solution of sodium methoxide
(Fig. 5b). Ther heterogeneous system containing potassium hydroxide in water
was tested for comparison and because this synthesis type was used in the literature
[4]. Sodium methoxide seems to be a more active catalyst than potassium hydroxide
(concerning the same molar ratio to substrate). The higher activity of sodium
methoxide was caused by its higher basicity and the use of the homogeneous
reaction system compared to potassium hydroxide (two-phase system). Considering
the same 4-isopropylbenzaldehyde conversion (conversion of propanal was not
calculated because this reaction compound was in stoichiometric excess), the
selectivity was almost the same. Using larger amounts of the catalyst in the case of
123

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E. Vrbkova et al.
Conversion of iPB
Selectivity to FCA
Conversion of iPB
Selectivity to FCA
100
80
60
40
20
0
100
80
60
40
20
0
1:0.01 1:0.05 1:0.1 1:0.15 1:0.2
1:0.01 1:0.03 1:0.05 1:0.07 1:0.1
Molar ra(tiao )iPB:KOH
Molar rati(obiP)B:MeONa
Fig. 5 Selectivity and conversion using 36 wt% water solution of potassium hydroxide as catalyst
(a) and using 33 wt% methanolic solution of sodium methoxide as catalyst (b) (molar ratio
iPB:propanal = 1:3, 25 °C, solvent methanol, 180th min of reaction)
Table 2 Calculated TOFs at
Catalyst
KOH
Molar ratio iPB:catalyst
TOF (hod-1
)
10 min of the reaction (molar
ratio iPB:propanal = 1:3,
25 °C, solvent methanol)
1:0.15
1:0.2
0.01
0.09
0.49
0.55
0.46
0.35
MeONa
1:0.03
1:0.05
1:0.07
1:0.1
sodium methoxide compared with the molar ratio substrate:catalyst 1:0.05 led to the
formation of larger amounts of side products, while the highest conversion remained
the same (96 %). TOF at 10 min of the reaction was also calculated (Table 2). TOF
was evaluated as the initial rate of the reaction. Usually, the increase of reaction rate
with increasing catalyst amount is observed (that is the case of molar ratios 1:0.03
and 1:0.05; in these two cases, the formation of side products is suppressed). In the
case of the studied reaction with increasing catalyst amount (twice in the case
1:0.05–1:0.5), the autocondensation of propanal started to be the preferred reaction
due to the high amount of catalyst.
Influence of propanal amount
The influence of propanal amount was examined using two ratios: 4-isopropylben-
zadehyde:sodium methoxide of 1:0.1 (Fig. 6a) and 1:0.05 (Fig. 6b). From these
figures, it can be seen that the results are moreover in the range of measurement
error. The propanal amount significantly influenced the content of propanal
autocondensation product in the reaction mixture, but the main factor influencing
the 4-isopropylbenzaldehyde conversion and selectivity was the amount of catalyst
123

Cyclamen aldehyde synthesis
100
80
100
80
60
40
20
0
60
40
Conversion of iPB
Conversion of iPB
Selectivity to FCA
20
0
Selectivity to FCA
1:1
1:2
1:3
1:5
1:1
1:2
1:3
Molar ratio iPB:propanal
Molar ratio iPB:propanal
(a)
(b)
Fig. 6 Comparison of selectivities and conversions using different amounts of propanal (molar ratio
iPB:sodium methoxide 1:0.1 (a) and 1:0.05 (b), 25 °C, solvent methanol, 180th min of reaction)
Table 3 TOF at 10 min of the
reaction (25 °C, solvent
methanol)
Molar ratio
iPB:MeONa
Molar ratio
iPB:propanal
TOF (hod-1
)
1:0.1
1:1
1:2
1:3
1:1
1:2
1:3
1:5
0.16
0.26
0.35
0.26
0.37
0.55
0.63
1:0.05
Fig. 7 Reaction results using
different solvents (molar ratio
iPB:sodium methoxide:propanal
1:0.05:1, 25 °C, 180 min of
reaction)
100
80
60
40
20
0
Conversion of iPB
Selectivity to FCA
Toluen
DMF
iPrOH MeOH
Solvent
discussed above. However, TOF values were also calculated (Table 3), and they
showed that the excess of propanal increased the reaction rate at the beginning of
the reaction.
123

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E. Vrbkova et al.
Table 4 Calculated TOFs in 10th min of the reaction (molar ratio iPB:MeONa:propanal = 1:0.05:1,
25 °C)
Solvent
TOF (hod-1
)
Selectivity at the
50 % iPB conversion
Solvent
basicity10 (SB)
Toluene
0.25
0.26
0.40
0.22
70
97
0.128
0.545
0.613
0.762
Methanol
N,N0-dimethylformamide
100
77
Isopropylalcohol
100
90
80
70
60
50
40
30
20
10
0
Cyclamenaldehyde
Cyclamenalcohol
Forcyclamenaldehyde
Forcyclamenalcohol
0
50
100
150
200
250
300
Time (min)
Fig. 8 Reaction course (110 °C, 10 MPa, 2 wt% of catalyst type 600)
Influence of the solvent
The influence of the solvent type was monitored (Fig. 7). Besides methanol, three
different solvents with different polarities were used. With the higher polarity of the
solvent, 4-isopropylaldehyde conversion increased. When a nonpolar solvent,
toluene, was used, more side products (high boiling) originated in the reaction
mixture. This means that the polarity of the solvent influences the formation of
2-methylpent-2-enal in the reaction mixture. TOF calculations (Table 4) showed
that other solvent properties (e.g., basicity that can work synergically with the
catalyst) influenced the reaction course. Using N,N0-dimethylformamide, more
propanal autocondensation product originated in the reaction mixture.
Hydrogenation
Hydrogenation of forcyclamen aldehyde results in the desired cyclamen aldehyde
(Fig. 8), which is subsequently hydrogenated to the undesired cyclamen alcohol.
Another by-product is forcyclamen alcohol. Hydrogenation was performed using
123

Cyclamen aldehyde synthesis
Table 5 Time to reach 40 % aldehyde conversion and the possible maximum yield
Entry
Catalyst
Amount of
catalyst (wt%)
Pressure
(MPa)
Temperature
(°C)
Time for 40 %
conversion (min)
Yield
(%)
1
Type 600
Type 600
Type 600
Type 600
Type 600
Type 600
Type 97
0.5
1
1
1
1
2
2
2
2
2
2
2
2
2
4
10
5
110
100
110
100
110
80
170
270
120
220
100
Not reached
210
260
230
100
50
14.9
6.9
2
3
5
10.6
2.9
4
10
10
5
5
13.7
1.6
6
7
5
100
100
100
110
120
100
110
110
110
6.5
8
Type 698
Type 600
Type 600
Type 600
Type 600
Type 600
Type 600
Type 600
5
12.1
4.8
9
5
10
11
12
13
14
15
5
10.9
16.9
6.4
5
10
10
15
10
180
70
19.4
13.8
18.2
50
40
the reaction mixture containing ca. 10 % of 4-isopropylbenzaldehyde and 90 % of
forcyclamen aldehyde obtained in the previous step. Different ruthenium catalysts
were studied: Type 97 (Ru/C, ruthenium content 4.62 %, moisture 55 wt%), Type
698 (Ru/SiO2, ruthenium content 4.84 %, moisture 2 %) and Type 600 (Ru/C,
ruthenium content 4.9 % moisture 50 wt%).
Reaction course
The reaction course of hydrogenation is recorded in Fig. 8. With forcyclamen
aldehyde, the amount was decreasing until 180 min of the reaction. Cyclamen
aldehyde acted as an intermediate, with maximum content around 70 % conversion
of forcyclamen aldehyde. Cyclamen aldehyde was continuously hydrogenated to
cyclamen alcohol. Forcyclamen alcohol was also identified in the reaction mixture
in a small amount because it is directly hydrogenated to cyclamen alcohol.
Influence of catalyst type
Using the three types of catalyst led to almost the same results: 20–23 % relative
concentration of cyclamen aldehyde at 300 min of the reaction under the same
reaction conditions (Table 5, rows 7, 8, 9). For the comparison, the two
characteristic values (Table 5) were chosen: the time to reach 40 % forcyclamen
aldehyde conversion and the possible maximum yield (maximum selec-
tivity 9 matching 4-isopropylbenzaldehyde conversion in percent). It can be seen
that the better results were obtained using the ruthenium catalyst supported on SiO2;
the catalyst with the supporting active carbon containing about 50 wt% of moisture
123

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E. Vrbkova et al.
seems to be the more active because the time for 40 % conversion was lower and so
was the possible maximal yield. The low yield means that the desired cyclamen
aldehyde is very rapidly subsequently hydrogenated to the undesired cyclamen
alcohol. For the following experiments, the catalyst Type 600 was chosen due to the
industry requirements.
Influence of temperature
Using lower temperatures (80, 100 °C), the rate of subsequent hydrogenation to
cyclamen alcohol was significantly lower. The reaction rate was higher using higher
temperatures (Table 5, rows 6, 9, 10, 11). The maximal yield was also higher using
higher temperatures. This was caused by the higher rate of C=C double bond
hydrogenation in the case of FCA compared with the rate of hydrogenation of the
C=O double bond. The difference between these hydrogenation rates was more
significant using the higher temperatures.
Influence of pressure
The influence of three different pressures on the reaction course was monitored
(Table 5, rows 10, 13, 14). With the increasing pressure, the reaction rate also
increased. The existence of nonlinear dependence of yield on the pressure could be
explained by the fact that, at low pressure as in the case of low temperature, the
hydrogenation rate of the C=C double bond and the C=O double bond are not so
different as in the case of higher pressures. But at even higher pressure (15 MPa),
the amount of hydrogen in the reaction mixture increased and also increased the rate
of C=O hydrogenation.
Influence of catalyst amount
Different amounts of catalyst were used to perform the reaction. The supposed trend
in the reaction rate was detected (Table 5, rows 1, 5, 13, 15). With increasing
catalyst amount, the time for 40 % conversion decreased which means a higher
reaction rate. The influence on the selectivity is not so apparent, but with higher
catalysts amounts (2 and 4 %), higher yields could be obtained.
From the results, it was obvious that the main influence on the yield was the
amount of hydrogen in the reaction. The amount of hydrogen was given by the
temperature (with increasing temperature, the solubility of hydrogen in the reaction
mixture increased) and by the pressure.
Conclusions
The optimal reaction conditions for the maximum yield of forcyclamen aldehyde
were found. The product may be used for the preparation of cyclamen aldehyde
which is a desirable compound in the fragrance industry. Two basic catalysts were
studied for the first step (forcyclamen aldehyde preparation) of the reaction and
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Cyclamen aldehyde synthesis
three Ru-based hydrogenation catalysts were tested in the second step (cyclamen
aldehyde preparation). The best reaction conditions were found as follows:
Aldol reaction: The best result (92 % selectivity to forcyclamen aldehyde, 90 %
conversion of 4-isopropylbenzaldehyde, i.e. 82,8 % yield of desired product) was
obtained using the following reaction conditions: molar ratio 4-isopropylbenzade-
hyde:sodium methoxide:propanal 1:0.05:1, 25 °C, solvent methanol, 180 min of
reaction. Sodium methoxide was preferred as a catalyst toward potassium
hydroxide, because of a higher reaction rate using the same amount of catalyst.
Atthe the the the higher temperatures, the formation of undesired products occurred,
and a higher molar excess of propanal led only to the increase of the reaction rate
and production of 2-methylpent-2-enal.
Hydrogenation: The desired product, cyclamen aldehyde, was subsequently
hydrogenated to cyclamen alcohol, and therefore coefficient maximal selectivity to
cyclamen aldehyde 9 4-isopropylbenzaldehyde conversion was taken as the most
important criteria. The highest selectivity (51 % at the 4-isopropylbenzaldehyde
conversion 38 %, i.e. yield 19.4 %) was obtained at 30 min of reaction using the
following conditions: 120 °C, 5 MPa and 2 wt% of catalyst Type 600.
Acknowledgment Word of thanks to the Ministry of education, youth and sports for financial support
from specific university research (MSMT No 20/2014).
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