Oxidation of Thymol and Carvacrol to Thymoquinone with KHSO5 Catalyzed by Iron Phthalocyanine Tetrasulfonate in a Methanol–Water Mixture

Article abstract of DOI:10.1007/s10562-016-1850-2

Abstract: The oxidation of thymol and carvacrol to thymoquinone with potassium peroxymonosulfate (KHSO₅) catalyzed by iron phthalocyanine tetrasulfonate (FePcTS) in a methanol (4.0?mL)–water (0.5?mL) mixture has been carried out. In a typical reaction, the amounts of the substrate, oxidant, and catalyst were 0.300, 0.600, and 1 × 10^?3 millimoles, respectively. Ninety-nine percent conversions of thymol in 1?h and of carvacrol in 30?min were achieved at ambient temperature. The major product of both oxidation reactions was thymoquinone (2-isopropyl-5-methylbenzoquinone, TQ) and the reactions also yielded polymeric products poly(2-isopropyl-5-methyl-1,4-phenylene oxide) and poly(5-isopropyl-2-methyl-1,3-phenylene oxide). These polymers are novel and not reported before. When H₂O₂ or Bu^tOOH was used as the oxidant, the yield of TQ was <1 %. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s10562-016-1850-2

Catal Lett
DOI 10.1007/s10562-016-1850-2
Oxidation of Thymol and Carvacrol to Thymoquinone
with KHSO Catalyzed by Iron Phthalocyanine Tetrasulfonate
5
in a Methanol–Water Mixture
1
1
1
1
Tuğçe Günay · Yasemin Çimen · R. Bengü Karabacak · Hayrettin Türk
Received: 24 May 2016 / Accepted: 20 August 2016
©
Springer Science+Business Media New York 2016
Abstract The oxidation of thymol and carvacrol to thy -
moquinone with potassium peroxymonosulfate (KHSO 5)
catalyzed by iron phthalocyanine tetrasulfonate (FePcTS)
in a methanol (4.0 mL)–water (0.5 mL) mixture has been
Keywords Phthalocyanine tetrasulfonate ·
Peroxymonosulfate · Thymol · Carvacrol ·
Oxidation < Processes and reactions
carried out. In a typical reaction, the amounts of the sub
-
−
3
strate, oxidant, and catalyst were 0.300, 0.600, and 1 ×10
1 Introduction
millimoles, respectively. Ninety-nine percent conversions
of thymol in 1h and of carvacrol in 30min were achieved at
ambient temperature. The major product of both oxidation
reactions was thymoquinone (2-isopropyl-5-methylbenzo -
quinone, TQ) and the reactions also yielded polymeric prod-
ucts poly(2-isopropyl-5-methyl-1,4-phenylene oxide) and
poly(5-isopropyl-2-methyl-1,3-phenylene oxide). These
polymers are novel and not reported before. When H O or
The chemical conversion of abundant and cheap natural
products is a convenient way to produce more valuable
and useful compounds [1–3]. Thymoquinone is one of such
compounds. Although thymoquinone can be isolated from
the essential oils of a few aromatic plants, it can also be pro-
duced from the oxidation of thymol or carvacrol which are
p-methane type aromatic monoterpenes [4]. Recently, some
publications have reported the antitumor [ 5], hepatopro -
tective [6] and membrane lipid peroxidation inhibition [ 7]
activity of thymoquinone. Because thymoquinone can only
be obtained from limited number of plants such as Nigella
sativa [8, 9] and Monarda fistulosa [10], its facile synthesis
from cheap and abundant chemicals has great demand. In
2
2
t
Bu OOH was used as the oxidant, the yield of TQ was<1%.
Graphical Abstract
the synthesis of thymoquinone from natural product pre
cursors and other chemicals, metallo porphyrins, phtha
locyanines and some other metal complexes were used as
oxidation catalysts.
-
-
Martins et al. [ 11] used various manganese(III) por
phyrin catalysts in the oxidation of thymol, carvacrol and
p-cymene with H O and found that thymoquinone was
-
2
2
the major product in the oxidations. Milos [ 12] reported
the oxidation of oregano essential oil containing thymol
Electronic Supplementary Material The online version of this
article (doi:10.1007/s10562-016-1850-2) contains supplementary
material, which is available to authorized users.
and carvacrol with KHSO and H O catalyzed by iron(III)
5
2
2
tetraphenylporphyrin and iron(III) phthalocyanine. Thy
moquinone was found to be the main or one of the main
products. Milos obtained complete substrate (thymol and
-
ꢀ
Yasemin Çimen
yasemincimen@anadolu.edu.tr
1
carvacrol) conversions within 1h when KHSO was used as
Department of Chemistry, Faculty of Science,
5
Anadolu University, 26470 Eskişehir, Turkey
oxidant. Ay et al. [ 13] studied thymol oxidation with H O
2
2
1
3

2
T. Günay et al.
catalyzed by µ-dihydroxo-bis(2,6-pyridinedicarboxylatoaq
uachromium(III)) complex. The conversion of thymol was
2
0–25% and the selectivity of thymoquinone was 100 %.
Skrobot et al. [14] reported the oxidation of carvacrol and
thymol with H O catalyzed by free and Y zeolite-entrapped
2
2
manganese(III) tetra(4- N-benzylpyridyl)porphyrin (MnT -
BzPyP). The homogeneous and heterogenized MnTBzPyP
complexes were active in the oxidation of carvacrol and
thymol. The oxidation of carvacrol (<25 % conversion)
and thymol (<18 % conversion) yielded thymoquinone
with 100 % selectivity. Santos et al. [15] investigated the
5
−
catalytic activity of Keggin-type anions [BW O ] and
[
1
2
40
III
6−
Mn (H O)BW O ] for the oxidation of monoterpenes
2 11 39
(
geraniol, nerol, (+)-3-carene, thymol and carvacrol) by
Fig. 1 Sodium salt of iron phthalocyanine tetrasulfonate
using H O . The conversions were in the 35–4 0% range after
2
2
3
h however thymoquinone formed only in small amounts in
all reactions. Uliana et al. [16] reported the oxidation of 11
mono-phenols to para-benzoquinones catalyzed by cobalt,
nickel, copper and vanadium salen type complexes.
Metallophthalocyanines are attractive catalysts for the
oxidations or degradations of various organic substrates
because of high catalytic activities in the reactions and
easy preparations in large scale with low cost. Chemis-
try and catalytic activities of metallophthalocyanines and
mechanistic aspects of the reactions involving them are
recently reviewed by Sorokin and Kudrik [17], Calvete et
al. [18], and Zagal et al. [19]. Furthermore catalytic acti-
vation of peroxymonusulfate by cobalt phthalocyanine for
elimination of dyes [20], the oxidations of four phenolic
compounds with various oxidants using Co(II) and Fe(II)
phthalocyanine catalysts [21], the oxidation of 2,3,6-tri-
methylphenol and 2-methyl-1-napthol with tert-butyl
hydroperoxide catalyzed by supported iron phthalocya-
nine [22] and the oxidation of tetrabromobisphenol A by
peroxymonusulfate catalyzed by an iron(III) phthalocya-
nine tetrasulfonic acid [23] are recently published reports
related to our study.
Fig. 2 Major products of the oxidation of thymol and carvacrol
The GC analyses of the oxidation reaction mixtures of
thymol and carvacrol were carried out on a Thermo-Trace
GC Ultra Gas Chromatograph equipped with an FID detec-
tor and a Permabond SE-54 capillary column (ID: 0.32mm,
film thickness: 0.25 µm, length: 25 m). The mass spectra
were taken with a GC–MS (Thermo Finnigan Polaris Q).
The visible spectra were obtained using a Shimadzu 2450
1
13
UV–Vis spectrophotometer. H NMR,
C NMR, and
gHSQCAD NMR spectra of the products were taken using a
400 MHz Agilent NMR spectrometer. The GPC analyses of
the polymeric oxidation products were performed on a GPC
(Agilent 1100 Series) fitted with a RI detector and PLgel
5 μm MIXED-C 200×7.5 mm column.
Herein, we report the oxidation of thymol and carvacrol
with KHSO catalyzed by iron phthalocyanine tetrasulfo -
5
nate in a CH OH-H O mixture. To the best our knowledge,
3
2
this catalyst‒oxidant system was not used before in the oxi-
dation of thymol and carvacrol.
2
.2 Oxidation of Thymol and Carvacrol
2
2
Experimental
In a typical experiment, a methanol solution of 7.5× 10−
M
thymol or carvacrol (4.0 mL, 0.300 mmol) and an aqueous
−
3
−3
2
.1 Reagents and Instrumentation
solution of 2.0× 10 M FePcTS (0.5 mL, 1.0× 10 mmol)
were mixed in a 25 mL round-bottomed-flask. After addi-
tion of Oxone (0.1844 g, contains 0.600 mmol active
Iron phthalocyanine tetrasulfonate (FePcTS) was prepared
as its sodium salt using the procedure given in the litera
ture [24] (Fig. 1). Thymol (Merck), carvacrol (Sigma) and
KHSO as Oxone (Aldrich) were used as received. The
other reagents were research grade.
-
component KHSO ) to the reaction mixture, the reac-
5
tion mixture was stirred magnetically for a certain period
of time at ambient temperature. Then the organics in the
reaction mixture was immediately extracted three times
5
1
3

Oxidation of Thymol and Carvacrol to Thymoquinone with KHSO 5 Catalyzed by Iron Phthalocyanine…
3
Fig. 3 The GC chromatogram of the reaction mixture of the oxidation of thymol
Fig. 4 The GC chromatogram of the reaction mixture of the oxidation of carvacrol
1
00
with 2 mL of dichloromethane. Before the GC analysis, a
known amount of naphthalene was added to the extract as
9
8
7
6
5
4
3
2
1
0
0
0
0
0
0
0
0
0
0
an internal standard. The amounts of the residual substrate
and product thymoquinone (TQ, Fig. 2) in the extract were
calculated using their peak areas in the chromatograms,
the amount of internal standard and GC detector response
factors. TQ was identified by the GC–MS Software, with
spiking injection of an authentic sample of TQ as well as
comparing its MS spectra with the MS spectra of TQ given
in the literature. Furthermore the product TQ was isolated
0
50
100
150
200
with a column chromatographic separation using a 50
CH Cl -petroluem ether eluent and characterized with
%
H
Time (min)
1
2
2
NMR spectroscopy.
Fig. 5 Conversion of thymol and carvacrol and yields of TQ dur
-
ing the oxidations: (filled blue circle ) Thymol, (filled green triangle)
Carvacrol, (filled red square) TQ (from conversion of thymol), (open
red triangle) TQ (from conversion of carvacrol). Reaction condi-
Polymeric products (Fig. 2) of thymol and carvacrol were
isolated from the reaction mixture with centrifugation and
then washed with water and methanol to remove oxidant,
tions: thymol or carvacrol =0.300 mmol, KHSO = 0.600 mmol,
5
−
3
substrate and other impurities. Structural characteriza
-
FePcTS= 1.0 × 10 mmol, Volume =4.5 mL (8:1 methanol–water
mixture)
tions of both polymers were made with NMR spectroscopy
1
3

4
T. Günay et al.
techniques and their average molecular masses were deter -
mined with GPC analysis.
In recycling of FePcTS, the same conditions as described
above were employed for the oxidations After each cycle,
first organic materials in the reaction medium were extracted
with CH Cl , then new portions of thymol or carvacrol and
2
2
KHSO were added to the medium. After extractions to
5
replace methanol extracted by CH Cl , a small portion of
2
2
methanol was added to make the reaction medium 4.5 mL.
3
Results and Discussion
3
.1 Oxidations of Thymol and Carvacrol
The oxidation of thymol and carvacrol with potassium per -
oxymonosulfate (KHSO ) catalyzed by FePcTS has been
5
investigated. The reactions were carried out in a 4.5 mL
methanol–water (8:1 v/v) mixture at room temperature.
This solvent composition provided a homogenous reaction
medium for the substrate and catalyst. However Oxone, the
source of the oxidant KHSO , was partially soluble in the sol-
5
vent mixture. The oxidations were monitored by GC analysis
quantitatively. In addition, both oxidations gave polymeric
products which were identified as poly(2-isopropyl-5-methyl-
1,4-phenylene oxide) (Polymer 1) from thymol and poly(5-
isopropyl-2-methyl-1,3-phenylene oxide) (Polymer 2) from
carvacrol. Formations of these polymeric products are sur
prising and these polymers have not been reported before in
-
the literature. Both substrates were not accounted in reactions
and the GC chromatograms of their reaction extract indicated
formations of some other products, possibly oxidative cou-
pling products of the substrates we did not identify (Figs. 3,
4). Oxidation of thymol and carvacrol did not proceed in the
absence of either KHSO or FePcTS. Dioxygen in air under
5
the reactions were carried out was not acted as an oxidant for
the reactions in the absence of KHSO5.
The optimal thymol and carvacrol conversions and TQ
selectivity were obtained when the amounts of the substrate,
−3
oxidant, and catalyst were 0.300, 0.600, and 1 × 10 mmol
for both oxidations, respectively. The percentages of the
residual thymol and carvacrol and of the yields of TQ as
a function of reaction time are shown in Fig. 5. Thymol
was oxidized ca. 99 % in the first 1 h and the yield of TQ
was about 18 %. Under similar conditions the conversion
of carvacrol reached ca. 99% in the first 30 min, and the
yield of TQ was about 32%. It appears from the time course
plot these high substrate conversions and TQ yields were
achieved much before the indicated times.
We also investigated how the concentrations of the oxi-
dant, substrate and catalyst affect the oxidation of thymol
and carvacrol. Results of the reactions carried out varying
oxidant, substrate and catalyst amounts are given in Table 1.
1
3

Oxidation of Thymol and Carvacrol to Thymoquinone with KHSO 5 Catalyzed by Iron Phthalocyanine…
5
Fig. 6 1H NMR spectra of a
Polymer 1 and b thymol
The entries 1–5 in Table 1 show the effect of the variation
(FePcTS:substrate:oxidant mole ratios = 1:300:600). The
conversions of the substrates significantly decreased with
both oxidants. When H O was used, the conversions of
of the amount of KHSO in both oxidation reactions. When
5
the amount of KHSO 5 was twice or more of the substrate
2
2
(
entries 1–3, Table 1), the conversion of thymol was nearly
thymol and carvacrol were about 24 % in 1 h and 16 % in
30 min, respectively. When Bu OOH was used, the conver-
t
completed in 1 h and of carvacrol in 30 min. The selectiv-
ity percentages of TQ were about 18–20 % for the thymol
oxidation and 20–31 % for the carvacrol oxidation. When
sion of thymol and carvacrol was about 75 and 6 8% , respec-
tively. The yield of TQ was <1 % in all these reactions and
a coupling product was the major product.
Although the aim of this study was to develop an efficient
catalyst–oxidant system for the synthesis of thymoquinone
from thymol and carvacrol, the reactions were observed to
the KHSO /substrate mole ratio was <2, the conversions of
5
both substrates and their TQ selectivity decreased (entries
4
, 5, Table 1). As the concentration of FePcTS decreased by
one-half (entry 6, Table 1), the conversions of the substrates
decreased slightly and yield of TQ did not change much com- produce some polymeric products as well. Quantitative an a- l
pared to outcomes of our standard reaction (entry 3, Table 1) .
Comparable results based on the amounts of TQ formed
ysis of the polymers was attempted for the standard reactions
only in which the mole ratios of FePcTS:substrate:KHSO 5
were obtained for the conversions of the substrates as well as were 1:300:600 and it was found that Polymer 1 formed
their TQ selectivity by changing the KHSO /substrate mole
only 3 mg (corresponding ca. 6.7 % conversion of thymol)
and Polymer 2 formed about 15mg (corresponding ca. 34 %
conversion of carvacrol). Figures 6 and 7 show the H NMR
5
ratio >2 while keeping the amount of KHSO as 0.600 mmol
5
1
(entries 3, 7–9, Table 1 ). It can be deduced from the results
given in Table 1 that the oxidation of carvacrol with the
spectra of thymol and its polymer (Polymer 1) and carvacrol
FePcTS‒KHSO catalytic system produced higher TQ selec- and its polymer (Polymer 2), respectively. The spectra of
5
tivity and faster reaction than the oxidation of thymol.
the polymers indicated that the peaks of hydrogens of OH
groups and of one of aromatic protons on thymol and car -
vacrol are missing. Furthermore gHSQCAD NMR ( H/ C)
t
In addition, we have also used H O and BuOOH as oxi-
2
2
1
13
dant in place of KHSO in our standard reaction conditions
5
1
3

6
T. Günay et al.
Fig. 7 1H NMR spectra of a
Polymer 2 and b carvacrol
Scheme 1 Proposed mecha-
nism for oxidation of thymol to
form thymoquinone
spectra of the polymers revealed that only two aromatic
ring carbon atoms bear hydrogen atoms (Supplementary
material). These findings clearly prove the formations and
chemical structures of the polymers. The M and M molar
3.2 Proposed Mechanism for the Oxidation of Thymol
The mechanism of the oxidation thymol to form thymo-
quinone was proposed in Scheme 1 . The formation of the
w
n
masses of Polymer 1 and its PDI were 4611, 4323 g/mol and phenoxy radicals from phenols by some catalyst–oxidant
.07, respectively and Polymer 2 were 2763, 2580 g/mol systems is reported to be the first step in their oxidation
and 1.07, respectively.
1
IV
+
reactions by many authors [25– 27]. [Fe (O)PcTS] is the
1
3

Oxidation of Thymol and Carvacrol to Thymoquinone with KHSO 5 Catalyzed by Iron Phthalocyanine…
7
References
1
2
3
4
5
. Cavailero JAS, Nascimento GMS, Neves MGPMS, Silvestre
AJD, Vicente MGH (1996) Tetrahedron Lett 37:1893
. Silvestre AJD, Cavailero JAS, Silva AMS., Delmond B, Filliatre
C (1996) Heterocycl Commun 2:371
. Silvestre AJD, Cavailero JAS, Silva AMS, Delmond B, Filliatre
C (1997) J Chem Res., Synop. 228
. Dictionary of organic compounds, vol. 4, 6th edn (1996). Chap-
man & Hall, London
. Worthen DR, Ghosheh OA, Crooks PA (1998) Anticancer Res
1
8:1527
6
7
. Daba MH, Abdelrahman MS (1998) Toxicol Lett 95:23
. Houghton PJ, Zarka R, Delasheras B, Hoult JRS (1995) Planta
Med 61:33
−
3
8. Ghosheh OA, Houdi AA, Crooks PA (1999) J Pharm Biomed
Anal 19:757
Fig. 8 The visible spectra of 1 × 10 mmol FePcTS in the CH OH–
3
H O mixture containing 0.300 mmol thymol.a immediately after addi-
tion Oxone and after the reaction was started, b 1 min, c 5 min, d
5 min, e 30 min,f 45 min,g 1 h, h 2 h (The spectra were obtained after
diluting the mixtures 10 times with the CH OH-H O mixture 8-to-1
2
9
. Nergiz C, Otles S (1993) Food Chem 48:259
1
0. The Merck index of chemicals and drugs, Merck & CO, Rahway,
p 1046
1. Martins RRL, Neves MGPMS, Silvestre AJD, Silva AMS, Cava-
1
3
2
1
by volume)
leiro JAS, (1999) J Mol Catal A Chem 137:41
1
1
1
2. Milos M (2001) Appl Catal A Gen 216:157
catalytically active species to abstract the phenolic hydrogen
3. Ay B, Yildiz E, Jones S, Zubieta J (2012) Inorg Chim Acta 387:15
4. Skrobot FC, Valente AA, Neves G, Rosa I, Rocha J, Cavaleiro
JAS (2003) J Mol Catal A Chem 201:211
IV
+
from thymol. This species ([Fe (O)PcTS] ) was proposed
by Meunier et al. as the active species to abstract the phe-
nolic hydrogen and one electron from 2,4,6-trichlorophenol
15. Santos ICMS, Simões MMQ, Pereira MMMS, Martins RRL,
Neves MGPMS, Cavaleiro JAS, Cavaleiro AMV (2003) J Mol
Catal A Chem 195:253
[28–30] as well as by us in the oxidation of 2,3,6-trimethyl-
phenol [31]. Recently Sorokin et al. proved the formation of
1
6. Uliana MP, Vieria YW, Donatoni MC, Corrêa AG, Brocksom U,
Brocksom TJ (2008) J Braz Chem Soc 19:1484
IV
t
+
t
[
Fe (O)Pc Bu ] from FePc Bu and m -chloroperbenzoic
4 4
IV
+
acid that is an analogue [Fe (O)PcTS] [32]. Formations of
17. Sorokin AB, Kudrik EV (2011) Catal Today 159:37
18. Calvete MJF, Silva M, Pereira MM, Burrows HD (2013) RSC
Adv 3:22774
IV
III
II
−
Co (O)PcTS and Co (O)PcTS from Co PcTS by HSO
5
2
IV
2
IV
2
III
2
IV
and Pc -Fe -O-Pc -Fe (O) and Pc -Fe -O-Pc -Fe (O) by
tetrabutylammonium oxone were also reported [20, 33, 34].
After formation, the phenoxy radical from thymol is attacked
by another [Fe (O)PcTS] at the para-position carbon to the
carbon attached oxygen radical. Eventually Intermediate I in
the Scheme 1forms and rearranges into thymoquinone. A sim-
ilar mechanism can be drawn for the oxidation of carvacrol.
1
9. Zagal JH, Griveau S, Francisco Silva J, Nyokong T, Bedioui F
(2010) Coord Chem Rev 254:2755
20. Huang Z, Yao Y, Lu J, Chen C, Lu W, Huang S, Chen W (2016) J
Hazard Mater 301:214
2
IV
+
1. Saka EC, Çelik G, Sarkı G, Kantekin H (2016) J Incl Phenom
Macrocycl Chem 85:161
22. Zalomaeva OV, Ivanchikova ID, Kholdeeva OA, Sorokin AB
(2009) New J Chem 33:1031
2
3. Maeno S, Mizutani Y, Zhu Q, Miyamoto T, Fukushima M,
Kuramitz H (2014) J Environ Sci Health A 49:981
4. Weber JH, Busch DH (1965) Inorg Chem 4:469
5. Kolesnik IG, Zhizhina EG, Matveev KI (2000) J Mol Catal A
Chem 153:147
6. Trukhan NN, Romannikov VN, Paukshtis EA, Shmakov AN,
Kholdeeva OA (2001) J Catal 202:110
7. Palacio M, Villabrille PI, Romanelli GP, Vázquez PG, Cáceres
CV (2012) Appl Catal A Gen 417–418:273
3
.3 Recycling and Catalyst Degradation Study
2
2
In recycling of the catalyst FePcTS, it was observed that
both conversions percentages of thymol and carvacrol
dropped to <5 % in the second cycle. In FePcTS degrada -
tion study, the absorption spectra of the catalyst were taken
periodically for the oxidation of thymol. Figure 8 shows the
change in the visible spectra of the catalyst with time during
the oxidation. It appears that the decrease of the catalytic
activity of FePcTS in the catalytic-oxidant system in the
second cycle is due to degradation of catalyst in the first
cycle by the oxidant. Similar spectra were obtained during
the oxidation of carvacrol.
2
2
28. Sorokin A, Meunier B (1996) Chem Eur J 2:1308
2
9. Hemmert C, Renz M, Meunier B (1999) J Mol Catal A Chem
37:205
1
3
0. Sanchez M, Chap N, Cazaux JB, Meunier B (2001) Eur J Inorg
Chem 2001:1775
31. Çimen Y, Türk H, (2008) Appl Catal A Gen 340:52
3
2. Afanasiev P, Kudrik EV, Albrieux F, Briois V, Koifman OI,
Sorokin AB (2012) Chem Commun 48:6088
3. Neu HM, Zhdankin VV, Nemykin VN (2010) Tetrahedron Lett
3
5
1:6545
Acknowledgments This research was supported by Anadolu Unive-r
34. Sorokin AB (2013) Chem Rev 113:8152
sity Scientific Research Commission, Turkey (Grant No. 1505F313).
1
The authors would like to thank Dr. İlhami Çelik for taking the H
NMR and gHSQCAD NMR spectra.
1
3