Synthesis of raspberry ketone via Friedel-Crafts alkylation reaction catalyzed by sulfonic acid-functional ionic liquids

Article abstract of DOI:10.1134/S0965544118010152

Phenol and butanolone catalyzed by different SO₃H-functionalized ionic liquids (ILs) for synthesis of raspberry ketone (RK) had been investigated. The influences of different ionic liquids, reaction time, reaction temperature, reactant ratio, t

Full text of DOI:10.1134/S0965544118010152

ISSN 0965-5441, Petroleum Chemistry, 2018, Vol. 58, No. 1, pp. 56–61. © Pleiades Publishing, Ltd., 2018.
Synthesis of Raspberry Ketone via Friedel-Crafts Alkylation Reaction
Catalyzed by Sulfonic Acid-Functional Ionic Liquids1
Wang Wang, Zhenzhen He, Conghao Li, Zhixiang You, and Hongyun Guo*
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, Zhejiang, China
*e-mail: guohy63@163.com
Received February 16, 2017
Abstract⎯Phenol and butanolone catalyzed by different SO3H-functionalized ionic liquids (ILs) for synthe-
sis of raspberry ketone (RK) had been investigated. The influences of different ionic liquids, reaction time,
reaction temperature, reactant ratio, the amount of ionic liquid were investigated. The yield of raspberry
ketone was 82.5% under the optimum reaction condition. In addition, the ILs (3-sulfo)propyltriamine bisul-
fate ([TEA-PS][HSO4]) can be recycled up to five consecutive times without loss of activity. This method had
the advantages of mild conditions, high product yield, easy to separate from the product, as well as environ-
mentally friendly procedure. At the same time, the possible reaction mechanism was discussed.
Keywords: phenol, butanolone, SO3H-functionalized ionic liquid, raspberry ketone, recycle, reaction mech-
anism
DOI: 10.1134/S0965544118010152
INTRODUCTION
supercritical and near-supercritical water [16]. Liquid
acid catalysts cause equipment corrosion and environ-
mental pollution while solid acids deactivate rapidly
due to the build-up of coke. Although cation-
exchange resins show a good performance, thermal
stability and fouling of the resins are also the major
problems.
With the development of society and the improve-
ment of our living standard, Fragrances are part of the
daily life and can be found application in many con-
sumer goods like household cleaners, perfumes, oils or
even food [1]. To satisfy the growing demand for syn-
thetic fragrances, raspberry ketone is absolutely essen-
tial as an important compound. In 1957, raspberry
ketone was discovered by Schinz and Seidel [2, 3] as
primary aroma component of red raspberries as it was
already indicated by the name of this compound.
Raspberry ketone has a large application potential in
perfumery, cosmetics and as a food additive for soft
drinks and sweets. As an important raw material and
fine chemical intermediates, raspberry ketone is not
only for the preparation of food and flavors daily fla-
vor, but also for the synthesis of pharmaceuticals [4]
and dye [5]. The derivatives of raspberry ketone have
therapeutic effect on influenza [6]. Since natural
abundance of raspberry ketone is very low with only
1–4 mg/kg raspberries, so it has to be prepared by syn-
thesis [7, 8]. There are many methods for synthesis of
raspberry ketone, catalysts are used for this reaction
include Lewis acids, such as AlCl3 and BF3 [9], Brφn-
sted acids, such as H3PO4, H2SO4, HF, HClO4 [10],
cation-exchange resin [11], mesoporous materials
[12], zeolites [13, 14], molecular sieves [15], and also
However, there is little information available in lit-
erature about synthesis of raspberry ketone catalyzed
by ionic liquids. Ionic liquids are new kind of solvent
which is entirely composed of ions. Their use as an
environmentally benign alternative for conventional
solvents has received much attention [17–23].
Recently, advancement in the field of ionic liquids
research provides another route to achieve task-spe-
cific ionic liquids in which a functional group is cova-
lently tethered to the cation or anion of the ionic liq-
uid, especially to the N atom in the triethylamine [24–
26]. When an alkane sulfonic acid group is covalently
tethered to the IL cation, the IL would be a strong
Brφnsted acid [27]. These SO3H-functionalized ionic
liquids have exhibited great potential in replacement of
conventional homogenous and heterogeneous acidic
catalysts because they are fluxible, nonvolatile, non-
corrosive and immiscible with many organic solvents
[28–30].
In this work, we firstly reported an efficient and
environmentally benign alkylation reaction of phenol
with butanolone using SO3H-functionalized ionic liq-
1
The article is published in the original.
56

SYNTHESIS OF RASPBERRY KETONE VIA FRIEDEL-CRAFTS ALKYLATION
57
uids as a substitute for conventional homogenous and
heterogeneous acidic catalysts. Then the reaction con-
ditions were optimized and selected. This work also
gave an insight into the proposed mechanism for the
alkylation of phenol with butanolone.
Preparation of SO3H-functional ILs [31]. In a typ-
ical procedure for the preparation of [TEA-PS] [X], a
mixture of ethyl acetate (250 ml) and 1,3-butanesul-
tone (0.5 mol) was charged into a round bottom flask
(500 mL) , then added triethylamine (0.5 mol) to the
round bottom flask. The resulting mixture was vigor-
ously stirred for 12 h at 60°C. The solid product was
washed with ethyl acetate (3 × 50 mL) after filtration,
and dried under vacuum (70°C, 0.1 MPa). Then, zwit-
terions (0.1 mol) were dissolved in 50 mL of deionized
water, and 0.1 mol of acid (sulfuric acid, hydrochloric
acid, p-toluenesulfonic acid, phosphoric acid) was
added dropwise with vigorous stirring, respectively
and the resulting mixture was stirred for an additional
8 h at 70°C. Extra water was removed by rotary evapo-
ration (70°C, 0.1 MPa), and SO3H-functional ILs
were obtained with a total yield of 68% (see
Scheme 1).
EXPERIMENTAL
Materials and reagents. All solvents and chemicals
in the experiment were commercially available and
used without further purification unless otherwise
stated. Triethylamine and 1,3-butane sultone were
purchased from Aladdin. The products were examined
using gas chromatography (Agilent 7890B; capillary
column: Agilent DB-5, 30 m × 0.25 m × 0.25 μm;
programmed oven temperature:100°C, held for 5 min,
ramped to 250°C at 5°C/min, held for 10 min; N2 car-
rier gas).
N
N
S
1,3-propane sulfonic lactone
HX
N
X
60ºC, 12 h
70ºC, 8 h
S
O
O
O
O
O
OH
TEA-PS
Scheme 1. The synthesis process of [TEA-PS][X] (X– =
[TEA-PS][X]
−
Cl–, PTSA–,
4− ).
H2PO
HSO4,
Characterization of ILs. The synthesized ILs were 129.40, 125.36, 60.18, 54.75, 52.65, 47.96, 47.23,
identified by 1H NMR and 13C NMR spectral data.
20.45, 17.20, 6.57.
(3-sulfo)propyltriethylamine phosphate ([TEA-
PS][H2PO4]) 1H NMR (500 MHz, D2O) δ 3.10–2.81
(m, 8H), 2.58 (t, J = 7.1 Hz, 2H), 1.78–1.63 (m, 2H),
0.89 (t, J = 7.2 Hz, 9H).13C NMR (126 MHz, D2O)
δ 60.06, 54.69, 52.64, 47.84, 47.19, 30.24, 26.84, 17.14,
6.61.
Reaction procedure. In a typical reaction, Phenol
(1, 0.5 mol), IL (0.03 mol) were added into a three-
necked round bottom flask equipped with magnetic
stirrer and butanolone (2, 0.1 mol) and dripped into
the above solution slowly. The resulting mixture was
heated to 50°C and magnetically stirred for 30 min
when the drop was completed. After the reaction was
completed (TLC detected), the upper organic phase
was separated from IL by decantation and analyzed via
gas chromatography (GC), IL was recovered from the
aqueous solution by removing water at 70°C under
vacuum for 6 h, and used directly for the next run (see
Scheme 2).
(3-sulfo)propyltriamine
bisulfate
([TEA-
PS][HSO4]) 1H NMR (500 MHz, D2O) δ 2.78–2.56
(m, 8H), 2.44–2.21 (m, 2H), 1.47 (dd, J = 9.1, 4.5 Hz,
2H), 0.66 (s, 9H).13C NMR (126 MHz, D2O) δ 59.86,
54.46, 52.41, 47.59, 46.95, 29.97, 26.55, 16.88, 6.32.
(3-sulfo)propyltriethylamine hydrochloride ([TEA-
PS][Cl]) 1H NMR (500 MHz, D2O) δ 3.27–2.95 (m,
8H), 2.74 (t, J = 7.1 Hz, 2H), 1.95–1.78 (m, 2H), 1.05
(t, J = 7.2 Hz, 9H). 13C NMR (126 MHz, D2O)
δ 60.15, 54.74, 52.66, 47.94, 47.23, 30.25, 26.95, 17.20,
6.60.
(3-sulfo)propyltriethylamine
p-toluenesulfonate
([TEA-PS][PTSA]) 1H NMR (500 MHz, D2O) δ 7.39
(dd, J = 5.1, 3.0 Hz, 2H), 7.04 (d, J = 4.8Hz, 2H),
3.02–2.78 (m, 8H), 2.65 (dd, J = 6.8, 4.0 Hz, 3H),
1.94–1.83 (m, 2H), 1.80–1.66 (m, 2H), 0.91 (d, J =
3.9 Hz, 9H).13C NMR (126 MHz, D2O) δ 142.19,
PETROLEUM CHEMISTRY Vol. 58 No. 1 2018

58
WANG WANG et al.
O
O
RK
HO
3
2,4-DRK
OH
O
IL
HO
+
HO
Solvent-free,heat
1
2
O
O
2,6-DRK
OH
O
Scheme 2. Synthesis of raspberry ketone by ILs. RK—raspberry ketone; 2,4-DRK—2,4-Double replace raspberry ketone;
2,6-DRK—2,6-Double replace raspberry ketone.
RESULTS AND DISCUSSION
Effect of reaction time. Figure 1 shows the yield of
different products as a function of reaction time for
alkylation of phenol with butanolone at 50°C with a
molar ratio of phenol to butanolone of 5 : 1. In the
early stages of the reaction, the products were RK,
2,4-DRK, 2,6-DKR, other products were very few. As
the reaction going on, the RK was decreased, the 2,4-
DRK and 2,6-DKR were slightly increased. Figure 1
also shows clearly that the reaction reached an equilib-
rium level after 180 min. In the process of reaction,
ionic liquid could be well miscible with reactants,
reaction was in a homogeneous phase. After butano-
lone addition was completed in an hour, the raspberry
ketone content was the highest in the next 30 min, that
is to say, 90 min is the best reaction time. Therefore we
determine the optimal reaction time is 90 min.
Effect of different ILs. The experiments were car-
ried out at a molar ratio of phenol/butanolone = 5/1
for two reasons: (i) to avoid the formation of large
amounts of by-products, such as the oligomers of 1-
butylene-2-keto, 2,4-Double replace raspberry
ketone; 2,6-Double replace raspberry ketone, diphe-
nyl ether ketone, raspberry ketone isomers; and (ii) to
diminish the influence of the water formed by the
dehydration of butanolone in situ. At the same time,
the slight excess of phenol is enough to have a crucial
influence on the alkylation reaction [32]. The influ-
ence of different ionic liquids on the catalytic activity
in alkylation of phenol with butanolone was shown in
Table 1.We can see the yield from ionic liquid [TEA-
PS][HSO4] as catalyst (entry 1) was slightly better than
other ionic liquids (entries 2–4),which indicated that
the anionic (HSO4) improved the catalytic perfor-
mance [33], due to sulfuric acid is a strong acid.
Effect of reaction temperature. As can be seen from
Fig. 2, the reaction temperature we set is 40–80°C.
The yield of RK was up from 40 to 50°C, but it was
Table 1. Alkylation of phenol with butanolone in different ILsa
Yield of RK, %b
Yield of 2,4-DRK, %b
Yield of 2,6-DRK, %b
Entry
ILs
1
2
3
4
[TEA-PS][HSO4]
[TEA-PS][Cl]
[TEA-PS][PTSA]
[TEA-PS][H2PO4]
81.1
77.5
80.1
78.9
13.2
18.3
14.5
11.4
3.9
3.2
3.9
1.2
a
b
Reaction condiction: 50°C, phenol/but.nolone/ILs 5 : 1 : 0.03 mol/mol/mol, 5 h.
Yield was achieved by GC analysis.
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SYNTHESIS OF RASPBERRY KETONE VIA FRIEDEL-CRAFTS ALKYLATION
59
90
75
60
45
30
15
80
70
60
RK
2,4-DRK
2,6-DRK
RK
2,4-DRK
2,6-DRK
50
40
30
20
10
0
0.01
0.02
0.03
0.04
0.05
0.06
0
60 120 180 240 300 360 420 480
Time, min
Ionic liquids dosage, mol
Fig. 4. Influence of the amount of ionic liquids on alkyla-
tion of phenol with butanolone. Reaction conditions:
50°C, 90 min, phenol : butanolone = 0.5 : 0.1 mol/mol.
Fig. 1. Influence of reaction time on alkylation of phenol
with butanolone. Reaction conditions: 50°C, phe-
nol/butanolone/ILs ([TEAPS][HSO ])
5
:
1
:
4
0.3 mol/mol/mol.
RK
80
70
60
50
40
30
20
10
2,4-DRK
RK
2,4-DRK
2,6-DRK
2,6-DRK
80
70
60
50
40
30
20
10
0
0
40
50
60
70
80
Temperature, °C
2
3
4
5
Fig. 2. Influence of reaction temperature on alkylation of
1
phenol with butanolone. Reaction condictions: phe-
Run
nol/butanolone/ILs ([TEA-PS][HSO ])
5
:
1
:
4
0.3 mol/mol/mol, 90 min.
Fig. 5. Reaction conditions: 50°C, phenol : butanolone :
ILs = 5 : 1 : 0.2 mol/mol/mol, 90 min.
90
80
70
60
50
40
30
20
10
down firstly and then remained unchanged with
increase of temperature, and it reached the maximum
at 50°C. The possible causes of this phenomenon is
due to the adverse event increased when the tempera-
ture was too high, thus leading to the drop of RK yield.
The content of 2,4-DRK had a slight increase firstly
and then remained unchanged, however, the content
of 2,6-DRK had a slight decline continually. We have
done experiments at the lower temperature. At room
temperature, phenol is solid, experiment cannot be
carried out. Below 40°C, the ionic liquid viscosity is
large, low catalytic activity, no product generation.
Therefore, the best reaction temperature is 50°C.
RK
2,4-DRK
2,6-DRK
0
0.2
0.3
0.4
0.5
0.6
0.7
Phenol, mol
Effect of the reactant ratio. As is shown in Fig. 3, we
kept the amount of butanolone (0.1 mol) remained
unchanged and increased of phenol proportionally,
the content of RK increased and the content of RK
Fig. 3. Influence of the amount of phenol on alkylation of
phenol with butanolone. Reaction conditions: 50°C,
90 min, 0.1 mol butanolone, 0.03 mol ILs.
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60
WANG WANG et al.
reached to the maximum when the reactant ratio then the RK content had a slight decline with the
reached 5, then the content of RK was reduced with
the reactant ratio increased, which is possible that too
much phenol will have a dilution effect on catalyst,
and in consequence, reduce the activity of the catalyst.
But the maximum of 2,4-DRK formation at 0.4 mol
(phenol) possible reason is that ionic liquid is excess,
according to the principle of phenol positioning,
ortho- and para-priority is occupied, so the amount of
2,4-DRK is large, but with the addition of phenol,
ionic liquid is diluted, para-priority is occupied, so the
maximum of RK formation at 0.5 mol (phenol), if
continue to add phenol, ionic liquid is excessively
diluted, the catalytic effect is reduced. there was an
obvious characteristic that 2,4-DRK and 2,6-DRK
were the minimum value when the rk content was the
maximum. thus we can come to such a conclusion that
the best raw material ratio is phenol : butanolone =
0.5 mol : 0.1 mol.
increase of the amount of ionic liquid. And the con-
tent of 2,4-DRK and 2,6-DRK had a similar change
rule. The side reaction is also increased at the same
time when catalyst dosage increases, so we must con-
trol the amount of the catalyst. Thus we can conclude
that the best amount of the catalyst is 0.02 mol.
Recyclability of ILs. In order to examine the regener-
ability of the ILs, we tried to recover the IL catalyst.
Because the ILs were stratified at the end of the reaction,
we could approximately get 90 percent of the ILs by
decantation easily, the remaining ILs were extracted by
n-hexane, then the recovered ILs were dried under vac-
uum for 5 h at 80°C and then reused for another cycle.
The same procedure was repeated five times. The IL was
1
assessed by H NMR spectroscopy and no traces of
products and reactant were detected. The results of the
recycling experiments are shown in Fig. 5. It could be
seen that ionic liquid [TEA-PS][HSO4] (1) was utilized
Effect of the amount of ILs. We can see in Fig. 4 that
the RK content was increased and reached to the max- repeatedly over five times without any apparent loss of
imum value when the amount of catalyst was 0.02 mol, catalytic activity.
O
O
H2O
O
O
O
HO
H+
+
N
S
O
H
2
CH2
O
HSO4
O
H
4
5
H
O
C
O
OH
N
HSO4
S
O
C
1
H
O
OH
(a) Carbocation attack
H+
O
H
C
N
S
O
HSO4
O
OH
C
C
O
(b) Alkene attack
O
HO
3
Scheme 3. The possible mechanism for catalytic synthesis of raspberry ketone.
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SYNTHESIS OF RASPBERRY KETONE VIA FRIEDEL-CRAFTS ALKYLATION
61
9. G. Sartori, F. Bigi, G. Casiraghi, G. Carnati, L. Chiesi,
The proposed mechanism for the alkylation of phenol
with butanolone [34]. The strong acidic ionic liquids
could protonate the hydroxyl group in butanolone
which can liberate H2O to form carbocation 4 [35].
The carbocation could either directly attack the ortho-
or para- position of phenol via formation of transition
state (a) as shown in Scheme 3 (which shows only
ortho-attack) to give the ortho- or para- alkyl phenol;
or it can undergo elimination of proton to form the
alkene 5 [36] which could also attack the ortho- or
para- position of phenol via formation of transition
state (b).
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In this study, SO3H-functional ionic liquids were
prepared and used for the synthesis of RK under sol-
vent-free conditions. The result demonstrated the
optimized conditions for this reaction were the molar
ratio of phenol : butanolone : ILs ([TEA-PS][HSO4]) =
5 : 1 : 0.2 at 50°C over 90 min, the biggest yield of RK
was 82.5% under these conditions. Furthermore, the
used IL catalyst could be easily recovered by simple
separation and reused up to five times without any
apparent reduction in its activity. Therefore, we come
to a conclusion that the alkylation of phenol with
butanolone catalyzed by Brφnsted acidic ionic liquid
([TEA-PS][HSO4]) indicates a great potential for pro-
ducing raspberry ketone.
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ACKNOWLEDGMENTS
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This work was financially supported by the
Research Foundation of Zhejiang Provincial Educa-
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