Ab initio study of the selective alkylation of m-cresol with tert-butanol catalyzed by SO3H-functionalized ionic liquids

Article abstract of DOI:10.1016/j.cattod.2009.07.089

Our previous work showed that for catalytic alkylation of m-cresol with tert-butanol (TBA) SO₃H-functionalized ionic liquids exhibited several characteristic advantages over conventional catalysts. This work investigated the reaction mechanism of the alkylation of m-cresol with tert-butanol catalyzed by the SO₃H-functionalized ionic liquid (IL) through quantum chemical calculation in combination with the experimental studies. The experimental results showed that 2-tert-butyl-5-methyl phenol (2-TBC), 4-tert-butyl-3-methyl phenol (4-TBC) and tert-butyl-m-cresol ether (TBMCE) products were all primary products, while 2,6-di-tert-butyl-3-methyl phenol (2,6-DTBC) was a secondary product. The calculation results indicated that the selectivities of the products depended on the fundamental natures of the reactive sites, including the orbital overlap, the Coulomb and the steric effect in the interaction between the tert-butyl ion ([t-C₄H₉]⁺) and the m-cresol; the TBMCE was dynamically favored but not thermodynamically stable, while the C-alkylated products, especially 2-TBC, were the thermodynamically preferred products; the IL played an important role in generating the [t-C₄H₉]⁺ from the TBA and the final products from the intermediates.

Full text of DOI:10.1016/j.cattod.2009.07.089

Catalysis Today 149 (2010) 232–237
Contents lists available at ScienceDirect
Catalysis Today
journal homepage: www.elsevier.com/locate/cattod
Ab initio study of the selective alkylation of m-cresol with tert-butanol
catalyzed by SO3H-functionalized ionic liquids
Jinxia Zhou a,b, Xiumei Liu a, Shuguang Zhang b, Jingbo Mao b, Xinwen Guo a,
*
a State Key Lab of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116012, China
b College of Environmental and Chemical Engineering, Dalian University, Dalian 116622, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Our previous work showed that for catalytic alkylation of m-cresol with tert-butanol (TBA) SO3H-
functionalized ionic liquids exhibited several characteristic advantages over conventional catalysts. This
work investigated the reaction mechanism of the alkylation of m-cresol with tert-butanol catalyzed by
the SO3H-functionalized ionic liquid (IL) through quantum chemical calculation in combination with the
experimental studies. The experimental results showed that 2-tert-butyl-5-methyl phenol (2-TBC), 4-
tert-butyl-3-methyl phenol (4-TBC) and tert-butyl-m-cresol ether (TBMCE) products were all primary
products, while 2,6-di-tert-butyl-3-methyl phenol (2,6-DTBC) was a secondary product. The calculation
results indicated that the selectivities of the products depended on the fundamental natures of the
reactive sites, including the orbital overlap, the Coulomb and the steric effect in the interaction between
the tert-butyl ion ([t-C4H9]+) and the m-cresol; the TBMCE was dynamically favored but not
thermodynamically stable, while the C-alkylated products, especially 2-TBC, were the thermodyna-
mically preferred products; the IL played an important role in generating the [t-C4H9]+ from the TBA and
the final products from the intermediates.
Available online 26 August 2009
Keywords:
m-Cresol
Alkylation
Tert-butanol
Ionic liquid
Frontier orbital theory
ß 2009 Elsevier B.V. All rights reserved.
1. Introduction
butylation of m-cresol over the ionic liquid catalysts can be
conducted at lower reaction temperature. The reaction results
2-Tert-butyl-5-methyl phenol (2-TBC) is a precursor for a
number of commercially important antioxidants and a light
protection agent for bisphenols and thiobisphenols. 2-TBC is also
used to prepareimportant UV absorber and muskambrette, which is
a perfume fixation agent [1]. Many kinds of acid catalysts have been
used for the synthesis of tert-butylated m-cresol, such as H2SO4 [2],
Al-MCM-41 [3] and mesoporous solid superacids UDCaT [4].
However, these catalysts bear some disadvantages. The liquid acid
catalysts may cause equipment corrosion and environmental
pollution, and the solid acids usually deactivate rapidly due to coke
formation at high reaction temperature. Recently, functionalized
ionic liquids, known as environmentally benign catalysts, have been
investigated extensively [5–8]. In our laboratory, we have studied
the alkylation of m-cresol with TBA using SO3H-functionalized ionic
liquids as catalysts, and they have exhibited several characteristic
advantages over conventional catalysts [9]. The ionic liquids can be
recycled after the reaction. No significant deterioration of their
catalytic performance, including their activity and selectivity, was
observed. When compared with those solid acid catalysts, the tert-
showed that the alkylation of m-cresol with tert-butanol in ionic
liquids produced mixed products, including the isomers of tert-
butylated phenols in terms of the type of alkyls and the position of
alkyl substitute: mono C-alkylated products, dialkylated products
and tert-butyl-m-cresol ether (TBMCE). With increasing reaction
time the selectivity to 2-TBC increased rapidly and reached the
highest equilibrium level, while a significant decrease of the
selectivity to TBMCE and finally disappearance of TBMCE in the
products were observed.
The goal of this work was to investigate this reaction
mechanism involving the fundamental nature of the ionic liquid
with computational chemistry in combination with the experi-
mental study. The frontier orbital theory based on the quantum
chemical calculations has been applied to investigate the key steps
of the reaction pathway of the alkylation of m-cresol with TBA in
the acidic catalyst system at a molecular and atomic level,
especially those critical factors that determine the selectivities.
2. Experimental
2.1. Preparation of ionic liquids
* Corresponding author at: State Key Lab of Fine Chemicals, School of Chemical
Engineering, Dalian University of Technology, P.O. Box 39, No. 158, Zhongshan Road,
Dalian 116012, China. Tel.: +86 411 39893990; fax: +86 411 83633080.
E-mail address: guoxw@dlut.edu.cn (X. Guo).
The SO3H-functionalized ionic liquid (cation = (C2H5)3–N–
(CH2)4–SO3H; anion = HSO4) was synthesized according to the
0920-5861/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.cattod.2009.07.089

J. Zhou et al. / Catalysis Today 149 (2010) 232–237
233
literature [5–7]. Triethylamine and 1,4-butanesultone were mixed
by stirring for 12–24 h at 313–353 K. After the mixture solidified,
the solid (zwitterion) was washed three times with ethyl ether and
then dried under vacuum (393 K, 0.01 Torr). A stoichiometric
amount of sulphuric acid was added to the zwitterions precursor.
The mixture was stirred at 353 K for 8 h to form the ionic liquid.
The product was washed repeatedly with cyclohexane and ethyl
ether to remove residues, and dried under vacuum (393 K,
0.01 Torr); the ionic liquid (IL) is a viscous liquid at room
temperature.
2.2. Catalyst testing
The tert-butylation of m-cresol with TBA was carried out in a
glass reactor at 343 K. The typical loading amounts of reactants,
catalyst and solvent were m-cresol 6.0 mmol, TBA 6.0 mmol, ionic
liquid 1.0 mmol, cyclohexane 12 ml (m-cresol:TBA:IL = 6:6:1),
respectively. The mixture was stirred at the reaction temperature
for 1 h. Identification of the products was conducted on a HP6890/
5973 GC/MS with a HP-5MS column; quantitative analysis was
carried out on a 7890 GC (Shanghai Tianmei Co.) equipped with a
SE-30 column (30 m ꢀ 0.25 mm).
Fig. 1. Optimized geometries and the atomic charges of the [t-C4H9]+ and m-cresol.
performed using the Gaussian 03 program supplied by Gaussian,
Inc [13].
Thebindingenergydischargedbytheinteractionbetweenthem-
cresol and the [t-C4H9]+ were calculated according to the following
equation [14]:
3. Computational methods
D
E ¼ EAꢁB ꢁ ðEA þ EBÞ
(1)
3.1. Molecular cluster selections
where
D
E is the binding energy, EA and EB are the individual
energies of the m-cresol and the [t-C4H9]+ before bonding, res-
pectively, and EAꢁB is the energy of the corresponding intermediate
product.
Selecting a finite structure that not only represents the real
state perfectly but also saves computational cost is very important
[10–12]. For the reaction studied here, the key step might be the
electrophilic substitution reaction of tert-butyl ion (termed as [t-
C4H9]+) with the H+ on the aromatic ring or the hydroxyl group of
m-cresol. The reaction could produce many kinds of products
theoretically, but our experiments showed that the main product
was 2-TBC, followed by 4-TBC. TBMCE was a special product which
was first formed in a significant amount and then disappeared
gradually. The selectivity of the alkylation is mainly dependent on
the natures of the active sites of m-cresol. Considering the
computational economy as well as essential structural and
chemical information of the system studied in this work, our
calculation was focused on the interaction between [t-C4H9]+ and
m-cresol, assuming that the [t-C4H9]+ attacked the O1 atom, C2
atom and C4 atom of m-cresol (see Fig. 1) to form three
intermediates (intermediates A–C) and then the final products
(TBMCE, 2-TBC and 4-TBC), respectively.
In this reaction, it is believed the IL plays an important role both
in the generation of the [t-C4H9]+ through the elimination of the
hydroxyl group from the TBA and in the formation of the final
products by removal of the H+ from the Intermediates. So the
catalytic effect of the ionic liquid is also studied in this
computational work. First the structures of the cation and the
anion of the IL were optimized and analyzed, and then the possible
interacting structures between the IL and the TBA or the
intermediates were constructed, optimized and analyzed.
4. Results and discussion
4.1. Experimental result
Fig. 2 shows the results of the selectivities as a function of the
conversion. When the conversion was near zero, all the three
products, 2-TBC, 4-TBC and TBMCE, were detected. With increase
in the conversion of m-cresol, the selectivity to 2-TBC increased
rapidly and the selectivity to 4-TBC rose slightly, while the
selectivity to TBMCE dropped rapidly and eventually disappeared.
Therefore, it was believed that 2-TBC, 4-TBC and TBMCE products
were the primary products, while 2,6-DTBC was a secondary
product. The product distribution of this electrophilic substitution
reaction is mainly related to the active sites of m-cresol which have
their characteristics in terms of the Coulomb force, the frontier
3.2. Computational method
The Møller–Plesset perturbation theory (MP2) at the 3-21G
level was selected for the geometry optimization, the frequency
calculation and the atomic charge analysis of the reactants, the
intermediates and the final products. The geometries were
calculated with a complete structural optimization. And then,
the optimized structures were used for the energy calculation and
the frontier orbital analysis at the MP2/6-311++G** level; the zero-
point-vibration-energy (ZPE) corrections were done on the base of
the MP2/3-21g frequency results. All these calculations were
Fig. 2. Product distribution at different conversions. Reaction conditions: m-cresol
(20 mmol):TBA:IL3 (6:6:1) molar ratio; 343 K; cyclohexane: 12 ml.

234
J. Zhou et al. / Catalysis Today 149 (2010) 232–237
Fig. 3. Optimized geometries of the intermediates and the final products.
orbital distribution and the stereo-hindrance effect. These aspects
will be discussed thoroughly according to the computational
results.
electrophilic effect. This would result in a fast formation of the
intermediate A, and then the product TBMCE, which is in
agreement with the experimental observation. The charges of
the carbon atom in the aromatic ring are not identical. Among C2,
C3 and C4, C2 takes on the highest amount of negative charge,
followed by C4 and C3. This means that among those three active
sites, C2 has the highest superiority in Coulomb attraction.
4.2. The Coulomb force discussion
The optimized molecular geometries of [t-C4H9]+ and m-cresol
are shown in Fig. 1, and the optimized structures of the
intermediates (A–C) and final products (TBMCE, 2-TBC and 4-
TBC) are shown in Fig. 3. [t-C4H9]+ has an approbatory plane
structure, in which the central carbon atom takes on positive
charge while the other three carbon atoms show negative charges.
Therefore, the central carbon (C7) of [t-C4H9]+ is the active site in
the electrophilic substitution. M-cresol shows an aromatic
structure, in which the atomic net charges of O1, C2, C3 and C4
sites are ꢁ0.72, ꢁ0.29, ꢁ0.21 and ꢁ0.25, respectively. The O1 site
shows a high negative charge, so it can be postulated that the [t-
C4H9]+ is more prone to interacting with the O1 atom via an
4.3. The orbital distribution discussion
Besides the electrostatic interactions, the effect of orbital
overlap may also play a role in the reaction between m-cresol (an
electron donor) and [t-C4H9]+ (an electron acceptor) according to
the frontier molecular orbital theory. The typical phase of LUMO of
[t-C4H9]+ primarily embodies an unoccupied Pi orbital of the
central carbon atom, as shown in Fig. 4. The HOMO, the orbital next
to the HOMO (termed as HOMO-1) and the orbital next to the
HOMO-1 (termed as HOMO-2) of m-cresol (shown in Fig. 4) are
mostly composed of multitudinous Pi orbital of C atoms and little Pi
orbital of O1 atom. It is believed that the orbital overlap effect
between the symmetry-allowed occupied and unoccupied orbitals
mainly depends on two sides: one is the orbital coefficient, and the
other is the orbital energy gap. The orbital coefficient influences
the magnitude of electron density in each localized site, and the
active site of the m-cresol with a larger orbital coefficient can
donote more electrons to the LUMO of the [t-C4H9]+, forming a
stronger conjugation. On the other hand, the symmetry-allowed
orbitals might overlap with each other to a considerable extent
only if they are of comparable energy. So using the super-
delocalizability parameter (Sr) [15,16] to evaluate the orbital
overlap effect is preferred as it considers both the orbital
coefficient and the orbital energy. Sr is a reactivity index of
aromatic hydrocarbons (AH), proposed by Fukui as the following
formula:
!
c2jr
ej
m
X
Sr ¼ 2
j¼1
Here the term Sr is the superdelocalizability at position r, ej is the
bonding energy coefficient in the jth molecular orbital (eigenva-
lue), c is the molecular orbital coefficient at position r in the HOMO
Fig. 4. LUMO of the [t-C4H9]+ and frontal occupied molecular orbitals of m-cresol.

J. Zhou et al. / Catalysis Today 149 (2010) 232–237
235
Table 1
The total energies of the intermediates and products (A.U.).
Intermediate A
Intermediate B
Intermediate C
TBMCE
2-TBC
4-TBC
ꢁ502.4111086
Energy
ꢁ502.7255049
ꢁ502.7314033
ꢁ502.7297011
ꢁ502.4040175
ꢁ502.4181119
and m is the index of the HOMO. This descriptor can be used to
predict the relative reactivity of the atoms in aromatic hydro-
carbons. For the alkylation in this study, a site with a relatively
larger Sr will result in a stronger orbital overlap, and then form a
more stable covalent bond between the [t-C4H9]+ and m-cresol.
The Sr values of m-cresol on the O1 and C atoms are shown in
Fig. 5. Among the C2, C4 and O1 sites, the Sr of C2 is the largest,
followed by C4 and O1. According to Sr, it can be deduced that a
stable covalent bond between the [t-C4H9]+ and m-cresol can be
formed in C2 site, followed by that in C4, and the new bond formed
in the O1 site cannot be as strong as that in C2 or C4 site. This
conclusion is in agreement with the stabilities of the intermediate
products and the final products. Through comparison of the total
energies of the optimized structures (see Table 1), it was found that
the total energies of the intermediate B and the intermediate C
were 15.5 kJ/mol and 11.0 kJ/mol lower than that of the inter-
mediate A, respectively, and the total energy of 2-TBC and 4-TBC
were 37.0 kJ/mol and 18.6 kJ/mol lower than that of TBMCE,
respectively. This means the stability orders among these species
were intermediate B > intermediate C > intermediate A and 2-
TBC > 4-TBC > TBMCE.The stereo-hindrance effect discussionAn-
other factor that might affect the product selectivity is the stereo-
hindrance effect on the different active sites of m-cresol. The O1
site stands out of the aromatic ring and is not hindered by any
other functional groups, while the C2 and C4 sites are influenced by
the hydroxyl and the methyl, respectively. So it can be deduced
that the stereo-hindrance effects on these sites are: C4 site > C2
site > O1 site.
product TBMCE quickly. This is in agreement with the experi-
mental result that a large amount of TBMCE was formed at the
early stage of the reaction. However, intermediate A is not very
stable due to the weak orbital overlap effect in O1 site in spite of its
easy formation. Moreover, the O1 atom in TBMCE still takes a high
negative charge (ꢁ0.716) and is prone to being attracted by a
positive group, such as H+. This would result in a reversible
reaction between intermediate A and TBMCE. The geometry-
optimization results show that when a H+ approaches the O1 of
TBMCE, the distance between the O1 and the butyl-C of the [t-
C4H9]+ increases from 1.511 A to 1.614 A. This means that the [t-
C4H9]+ tends to leave and may rearrange to form intermediate B
and intermediate C. But the reverse reactions of the intermediates
to produce 2-TBC and 4-TBC are very difficult as the atomic net
charges of the C2 and C4 atoms are too low to interact with H+ ions.
According to the experimental and computational results above,
a mechanism for the selective alkylation of m-cresol with tert-
butanol can be proposed, as shown in Scheme 1. The electrophilic
interaction of the [t-C4H9]+ with the hydroxyl group or the C2 and C4
atomsof m-cresol results in the formation of the products TBMCE, 2-
TBC and 4-TBC through intermediates A, B and C, respectively.
However, due to the higher electron density and the less stereo-
hindrance effect on the O1 atom, the formations of intermediate A
and the final product TBMCE are easy and fast, but they are not
stable. There is a reversible reaction between intermediate A and
TBMCE, so the TBMCE can reverse to intermediate A and that can
rearrange to intermediate B or C with B preferred due to its good
stability and short distance between O1 and C2 sites. With
increasing reaction time intermediates B and C are consumed
gradually by further reactions, and they will mainly be comple-
mented by the rearrangement of intermediate A formed by the
recombination of TBMCE and H+. This reaction chain will speed up
the reverse reaction from TBMCE to intermediate A. As a result, the
kinetically preferred O-alkylated product (TBMCE) disappears
gradually. Amongthoseproducts, 2-TBC, 4-TBCandTBMCEproducts
are all primary products, and 2,6-DTBC product is a second product
which is derived from 2-TBC. Between the two C-alkylated products,
2-TBC is the thermodynamically preferred product at the end.
Because of the stronger orbital conjugation and the Coulombic
interaction and the weaker stereo-hindrance effect of the [t-C4H9]+
with m-cresol on the C2 site than on the C4 site.
˚
˚
4.5. Mechanism discussion
From the analysis above, it is clear that each active site on m-
cresol has its particularity in the fundamental natures of the
Coulomb force, the orbital distribution and the stereo-hindrance
effect. Considering the higher negative charge and the weaker
stereo-hindrance effect on the O1 site, it is postulated that the
[t-C4H9]+ is more prone to interacting with the O1 atom in m-cresol
via an electrophilic effect, forming intermediate A and then the
4.6. The catalytic function of the ionic liquid
For this reaction, besides the key steps of the [t-C4H9]+
electrophilically adsorbing on the O1, C2 and C4 sites of m-cresol
and the formation the intermediates, other steps, such as the
departure of the hydroxyl group (–OHꢁ) from TBA to form the [t-
C4H9]+, or the removal of H+ from the intermediates and then the
generation of the final products, are also critical. The IL plays an
important role in these important steps. The optimized geometries
and the atomic charges of the cation and the anion of IL are shown
in Fig. 6. The O atoms take on negative charges and the S and H (H4,
H5) bear positive charges. In order to break the C7–O5 bond (see
Fig. 7) in TBA, it is helpful to have an electrophilic group to bond
with the O5 atom so that it can attract the electron and weaken the
C7–O5 bond. We have tried to conjugate H4 (in cation), H5 and S1
(in anion) with O5 (in TBA) in the initial-structure hypothesizers,
but the optimized structures shows that only the H4–O5
Fig. 5. The Sr values of m-cresol on the O1 and C atoms.

236
J. Zhou et al. / Catalysis Today 149 (2010) 232–237
Scheme 1. Proposed reaction network for alkylation of m-cresol.
Fig. 6. Optimized geometries and the atomic charges of cation and anion of IL.
Fig. 7. Optimized geometry of cation with TBA and anion with intermediate B.

J. Zhou et al. / Catalysis Today 149 (2010) 232–237
237
conjugation structure (see Fig. 7 ‘‘cation–TBA’’) could exist by
forming a strong hydrogen bond between H4 and O5, and this
hydrogen bond weakens the C7–O5 bond significantly since the
of m-cresol. The intermediate A and TBMCE are dynamically
favored but not thermodynamically stable, while the C-alkylated
products, especially 2-TBC, are the thermodynamically preferred
products. The IL plays an important catalytic role in generating the
[t-C4H9]+ from TBA and the final products from the intermediates.
˚
˚
length of the C7–O5 bond increases from 1.451 A to 1.514 A after
cation–TBA interaction. It is possible that both the C7–O5 bond and
the O2–H4 bond break and a H2O molecule is formed in the further
reaction of this step. The initial structures of the O2 in TBA
conjugating with H5 or S1 in anion after optimization take on a
hydrogen bond between the H5 in TBA and the O atom in anion
(except for O4), and this hydrogen bond has little contribution to
the C7–O2 bond breaking. Removing of H+ from the intermediates
is possible with an O atom in cation or anion to attract the H+. For
example, when the O3 in anion approaches the H2 in intermediate
B, the optimized structure (see Fig. 7 ‘‘anion–intermediate B’’)
shows that the H2 atom nearly departs from the C2 atom in
Acknowledgements
This project was sponsored by the Program for New Century
Excellent Talents in University (NCET-04-0268) and by the
Programme of Introducing Talent of Discipline to Universities.
The authors thank Dr. Xiaoliang Ma (Pennsylvania State Uni-
versity) and Prof. Shenmin Li (Dalian University) for fruitful
discussions.
intermediate B since the distance of H2–C2 in ‘‘anion–intermediate
References
+
˚
B’’ structure is 2.107 A. And the anion in combination with the H
will form a H2SO4 molecule. The new formed H2SO4 might give a H+
to the cation who has lost the H+. This H+ transfer is possible since
the IL is generated by the zwitterions precursor acquiring the H+
from the sulphuric acid. By then a catalysis cycle is completed.
[1] H. Fiege, A.G. Bayer, Ullmann’s Encyclopedia of Industrial Chemistry, 5th ed.,
VCH, 1991.
[2] J.K. Gehlawat, M.M. Sharma, J. Appl. Chem. 20 (1970) 93.
[3] V. Umainaheswari, M. Palanichamy, B. Arabindoo, Ind. J. Chem. 39A (2000) 1241.
[4] G.D. Yadav, G.S. Pathre, Micropor. Mesopor. Mater. 89 (2006) 16.
[5] A.C. Cole, J.L. Jensen, I. Ntai, K.L.T. Tran, K.J. Weave, D.C. Forbes, J.H. Davis, J. Am.
Chem. Soc. 124 (2002) 5962.
5. Conclusions
[6] J. Gui, X. Cong, D. Liu, X. Zhang, Z. Hu, Z. Sun, Catal. Commun. 5 (2004) 473.
[7] J. Gui, H. Ban, X. Cong, X. Zhang, Z. Hu, Z. Sun, J. Mol. Catal. A 225 (2005) 27.
[8] H.Y. Shen, Z.M.A. Judeh, C.B. Ching, Tetrahedron Lett. 44 (2003) 981.
[9] X. Liu, M. Liu, X. Guo, J. Zhou, Catal. Commun. 9 (1) (2008) 1.
[10] J. Zhou, Y. Zhang, X. Guo, W. Song, H. Bai, A. Zhang, Energy Fuels 20 (2) (2006) 778.
[11] N. Chen, R.T. Yang, Ind. Eng. Chem. Res. 35 (1996) 4020.
[12] J. Sauer, Chem. Rev. 89 (1989) 199.
[13] M.J. Frisch, et al., Gaussian 03 (Revision A.9), Gaussian, Inc., Pittsburgh, PA, 1998
(and 56 names).
[14] R.T. Yang, Adsorbents: Fundamentals and Applications, Wiley, New York, 2003, p.
208.
In this study, the quantum chemical calculation in combination
with experimental studies were used to investigate the funda-
mental natures of the alkylation of m-cresol with tert-butanol.
Among those products, 2-TBC, 4-TBC and TBMCE products are all
primary products, while 2,6-DTBC is a secondary product. The
selectivities of the products mainly depend on the fundamental
natures of the reaction active sites of m-cresol, such as the natures
of the orbital overlap, the Coulomb and the steric effect presented
in the interaction between the [t-C4H9]+ and the O1, C2 and C4 sites
[15] T. Ertan, I. Yildiz, B. Tekiner-Gulbas, K. Bolelli, O. Temiz-Arpaci, S. Ozkan, F.
Kaynak, I. Yalcin, E. Aki, J. Med. Chem. 44 (2009) 501.
[16] K. Chen, H. Xie, Z. Li, J. Gao, Bioorg. Med. Chem. Lett. 18 (2008) 53.