A structureeactivity relationship study on the Wacker oxidation of stilbenes at ambient condition

Article abstract of DOI:10.1016/j.jorganchem.2013.05.008

To evaluate which structural elements of the stilbenes are responsible for their activity on the Wacker oxidation, a series of stilbenes with various functional moieties and substitution patterns were considered. In this regard, it is found that the oxidation rate of stilbenes strongly depends on their structures to give the corresponding carbonyl compounds. Consequently, the ortho position of alkene and methoxy groups plays a key role in the complexation with PdCl2. The oxidation process is clean with high selectivity of product and low percentage of byproducts.

Full text of DOI:10.1016/j.jorganchem.2013.05.008

Accepted Manuscript
A Structure-Activity Relationship Study on the Wacker Oxidation of Stilbenes at
Ambient Condition
Hossein Reza Darabi, Mohsen Mirzakhani, Kioumars Aghapoor, Khosrow Jadidi,
Laleh Faraji, Nader sakhaee
PII:
S0022-328X(13)00385-9
10.1016/j.jorganchem.2013.05.008
JOM 18030
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 6 February 2013
Revised Date: 24 April 2013
Accepted Date: 10 May 2013
Please cite this article as: H.R. Darabi, M. Mirzakhani, K. Aghapoor, K. Jadidi, L. Faraji, N. sakhaee,
A Structure-Activity Relationship Study on the Wacker Oxidation of Stilbenes at Ambient Condition,
Journal of Organometallic Chemistry (2013), doi: 10.1016/j.jorganchem.2013.05.008.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Highlights:
1- The study on Wacker oxidation of cyclic and internal stilbenes with PdCl2.
2- The study of the structural elements of the stilbenes on the Wacker Oxidation.
3- The oxidation rate of stilbenes was strongly depended on their structures.
4- The ortho position of alkene and methoxy groups on stilbenes plays a key role.
5- Cyclic stilbene shows a higher efficiency due to host-guest complexation.

ACCEPTED MANUSCRIPT
A Structure-Activity Relationship Study on the Wacker Oxidation of Stilbenes at Ambient
condition
Hossein Reza Darabi,a,*Mohsen Mirzakhani,a Kioumars Aghapoor,a Khosrow Jadidi,b Laleh
Faraji,b Nader sakhaeeb
aNano & Organic Synthesis Lab., Chemistry & Chemical Engineering Research Center of Iran, Pajoohesh Blvd., km
17, Karaj Hwy, Tehran 14968-13151, Iran. Tel.: +98 21 44580720; Fax: +98 21 44580762
* Email: darabi@ccerci.ac.ir; r_darabi@yahoo.com
bChemistry Department, Faculty of Science, Shahid Beheshti University, Evin, 1983963113, Tehran, Iran

ACCEPTED MANUSCRIPT
Graphical abstract synopsis
A Structure-Activity Relationship Study on the Wacker Oxidation of Stilbenes at Ambient
condition
Hossein Reza Darabi,a,*Mohsen Mirzakhani,a Kioumars Aghapoor,a Khosrow Jadidi,b Laleh
Faraji,b Nader sakhaeeb
aNano & Organic Synthesis Lab., Chemistry & Chemical Engineering Research Center of Iran, Pajoohesh Blvd., km
17, Karaj Hwy, Tehran 14968-13151, Iran. Tel.: +98 21 44580720; Fax: +98 21 44580762
* Email: darabi@ccerci.ac.ir; r_darabi@yahoo.com
bChemistry Department, Faculty of Science, Shahid Beheshti University, Evin, 1983963113, Tehran, Iran
It is found that the Wacker oxidation rate of stilbenes strongly depends on their structures and, consequently, the ortho position of alkene
and methoxy groups plays a key role in the complexation with PdCl2. The oxidation process is clean with high selectivity of product and
low percentage of byproducts.

ACCEPTED MANUSCRIPT
A Structure-Activity Relationship Study on the Wacker Oxidation of Stilbenes at
Ambient Condition
Hossein Reza Darabi,a,*Mohsen Mirzakhani,a Kioumars Aghapoor,a Khosrow Jadidi,b
Laleh Faraji,b Nader sakhaeeb
aNano & Organic Synthesis Lab., Chemistry & Chemical Engineering Research Center of Iran, Pajoohesh
Blvd., km 17, Karaj Hwy, Tehran 14968-13151, Iran. Tel.: +98 21 44580720; Fax: +98 21 44580762
* Email: darabi@ccerci.ac.ir; r_darabi@yahoo.com
bChemistry Department, Faculty of Science, Shahid Beheshti University, Evin, 1983963113, Tehran, Iran
Abstract: To evaluate which structural elements of the stilbenes are responsible for their activity on the Wacker oxidation, a
series of stilbenes with various functional moieties and substitution patterns were considered. In this regard, it is found that the
oxidation rate of stilbenes strongly depend on their structures to give the corresponding carbonyl compounds. Consequently,
the ortho position of alkene and methoxy groups plays a key role in the complexation with PdCl2. The oxidation process is
clean with high selectivity of product and low percentage of byproducts.
Keywords: The Wacker oxidation, Stilbene, Structure-activity relationship
1. Introduction
Oxygenation of olefins is one of the most straightforward routes for the synthesis of
carbonyl compounds. The original Wacker oxidation, using Pd/Cu catalyst system, is a
powerful method for converting terminal olefins to the corresponding methyl ketones. [1-
15] Besides its industrial importance, this transformation has found widespread
1

ACCEPTED MANUSCRIPT
applications in synthetic chemistry, and is continually used in fields relating to catalysis
and natural product synthesis. [16-18]
Up to now, the Wacker oxidation reaction suffers from Pd deactivation, high catalyst
loading, and a limited substrate scope. [1-18] Consequently, different attempts can be
found in the literature in order to eliminate the aforementioned drawbacks. Many of them
are related to the heterogenization of the palladium catalyst system over different
supports such as zeolites [19], pore glass [20], montmorillonite [21], polymers [22, 23],
and TiO2. [24]
On the other hand, to facilitate the reoxidation of the Pd0 species by O2 and prevent its
precipitation into inactive metal, cocatalysts, such as copper, heteropolyacids, [25, 26] or
benzoquinone,[27] Fe(III)/Fe(II) [28], and PdCl2-DMA system [29] have been reported.
Moreover, tert-butylhydroperoxide (TBHP) was used as the primary oxygen source. [30]
As known in the Pd(II)-catalyzed direct-O2 coupled reactions, it has been known that
either a solvent or ligand plays significant role in accelerating the reaction. [31-33]
In the oxidation of cyclic and internal olefins, however, this system shows low activity
and selectivity, producing large quantities of organic chlorides. [34] For example, a new
complex of molybdovanado phosphate with palladium acetate leads only to 19% yield of
cyclopentanone from the oxidation of cyclopentene. [35] Highlighted example of internal
olefins oxidation is a PdCl2-DMA system which shows a highly efficiency and
regioselectivity without the need for additional co-catalysts or reducing reagents. [36, 37]
This methodology needs a PdCl2-DMA system preparation at 10 atm pressure followed
by oxidation process under 3 atm of O2 and 80 °C heating for 10-20 h.
2

ACCEPTED MANUSCRIPT
Compared with the impressive development of internal alkenes, the Wacker oxidation of
stilbenes 1 has a little been explored thus far. In the best of our knowledge, there are only
two reports on the oxidation of stilbene (only 1e) in the presence of peroxides. The first
report was focused on the effect of perfluorinated ligand in a biphasic solvent system
which gave 73% yield of 2e. [38] The second report relies on the efficiency of a new
ligand, leading to 2e in 22% yield together with 20% benzaldehyde after 48 h oxidation at
35 °C. [12]
The objective of this paper is to study the structural elements of the stilbenes which are
responsible for their observed activities on the Wacker Oxidation. In this context, the
different kinds of stilbenes, including cyclic stilbenes and linear stilbenes, for the Wacker
oxidation was investigated in detail.
2. Experimental
2.1. Materials and methods
13
1H and C NMR spectra were recorded on a Bruker-500. All NMR samples were run in
CDCl3 and chemical shifts are expressed as ppm relative to internal Me4Si. Mass spectra
were obtained on a Fisons instrument. Substrates are commercially available and used
without further purification.
2.2. General procedure for the Wacker reaction of stilbenes
A 5-mL, two-necked, round-bottomed flask is fitted with a magnetic stirrer. The flask is
charged with a mixture of stilbenes 1 (0.1 mmol), palladium chloride (0.1 mmol) and
3

ACCEPTED MANUSCRIPT
aqueous methanol (MeOH/H2O = 10:1, 2.2 mL). An HCl solution is gradually added to
mixture to adjust the pH on 1-1.5. With the other outlets securely stoppered and wired
down, an oxygen-filled balloon is placed over one neck, and the flask is stirred at room
temperature to allow oxygen uptake. The solution is stirred vigorously at room
temperature under an oxygen balloon. After completion of the reaction (monitored by
TLC using ethyl acetate/hexane (3:7 v/v) or GC), dichloromethane was added to the
reaction mixture and the catalyst was recovered by filtration. The organic medium was
removed with rotary evaporator under reduced pressure. The crude products were
purified by column chromatography for products 2a–2k to afford pure products for
analytical measurements.
2.3. Selected spectroscopic data
2a: 1H NMR (300 MHz, CDCl3) δ 7.70-6.84 (8H, m, -Ar), 4.26 (2H, s, H-1), 3.92 (3H, s,
H-15), 3.75 (3H, s, H-16); 13C NMR (75 MHz, CDCl3) δ 200.47, 158.27, 157.47, 133.06,
131.26, 130.35, 128.12, 124.62, 120.53, 111.31, 110.30, 55.45, 55.28, 45.49.
2b: 1H NMR (300 MHz, CDCl3) δ 7.63-6.80 (8H, m, -Ar), 4.25 (2H, s, H-1), 3.88 (3H, s,
13
H-8), 3.79 (3H, s, H-16); C NMR (75 MHz, CDCl3) δ 197.39, 129.68, 129,63, 121.80,
121.34, 119.71, 115.05, 112.79, 112.39, 55.42, 55.18, 45.70.
2c: 1H NMR (300 MHz, CDCl3) δ 7.78-7.13 (8H, m,- Ar), 4.26 (2H, s, H-1), 2.48 (3H, s,
13
H-15), 2.28 (3H, s, H-16); C NMR (75 MHz, CDCl3) δ 201, 138.36, 137.83, 136.89,
133.37, 132.03, 131.36, 130.50, 130.37, 128.40, 127.28, 126.14, 125.68, 46.46, 21.27,
19.81.
4

ACCEPTED MANUSCRIPT
2d: 1H NMR (300 MHz, CDCl3) δ 7.84-7.06 (8H, m, -Ar), 4.25 (2H, s, H-1), 2.42 (3H, s,
H-16), 2.29 (3H, s, H-15); 13C NMR (75 MHz, CDCl3) δ 201(C-8), 46.46(C-1), 21.27 (C-
8), 19.8 (C-16).
1
13
2e: H NMR (300 MHz, CDCl3) δ 8.05-7.27 (10H, m,- Ar), 4.31 (2H, s, H-1); C NMR
(75 MHz, CDCl3) δ 197.66, 136.55, 134.52, 133.20, 129.48, 128.66, 128.63, 126.91,
45.51.
1
13
2f: H NMR (300 MHz, CDCl3) δ 8.14-7.27 (8H, m, -Ar), 4.40 (2H, s, H-1); C NMR
(75 MHz, CDCl3) δ 195.69, 138.87, 137.68, 134.56, 129.95, 129.77, 129.34, 128.83,
125.73, 125.92, 125.87, 125.73, 125.68, 125.28, 45.32, 29.71.
1
13
2g: H NMR (300 MHz, CDCl3) δ 7.88-7.12 (8H, m, -Ar), 4.22 (2H, s, H-1); C NMR
(75 MHz, CDCl3) δ 196.021, 135.01, 135, 132.07, 131.85, 131.20, 130.04, 128.66,
121.15, 44.76.
2k: 1H NMR (300 MHz, CDCl3) δ 7.54-6.88 (8H, m, -Ar), 4.35 (2H, s, H-1), 4.11 (4H, t,
H-11), 4.04 (4H, t, H-8), 2.13 (4H, m, H-9), 2.02 (4H, m, H-10); 13C NMR (75 MHz,
CDCl3) δ 202.73, 157.52, 156.91, 132.55, 131.78, 130.30, 129.63, 128.10, 125.24,
121.04, 120.60, 113.47, 112.37, 69.67, 69.08, 44.36, 27.42, 26.15.
3. Results and Discussion
3.1. Optimization of the model reaction
To study the role of stilbene structure, the basic parameters of classical Wacker reaction
such as high reaction temperature, medium to high pressure of O2 and reducing agents
were omitted. Note that the stoichiometric reaction without catalyst regeneration was
performed to evaluate which structural elements of the stilbenes are responsible for their
5

ACCEPTED MANUSCRIPT
activity on the Wacker oxidation. Accordingly, we studied the oxidation of stilbene 1a at
1 atm O2 and room temperature after 12 h. In contrast, pH and type of solvents were
investigated.
Scheme 1. The optimized oxidation condition for the synthesis of 2a.
The combination of 1 equivalent of PdCl2 and methanol in pH = 1 exhibited the highest
activity on the oxidation of 1a, affording ketone 2a in 35% yield.
It was also found that solvents had some effect on this reaction and methanol was tested
to be the most efficient one based on the product yield. The use of ethanol in place of
methanol gave only 4% yield, whereas tetrahydrofuran (THF), acetonitrile,
dimethoxyethane (DMF), Ethylenediamine (EDA) and dichloromethane showed
absolutely no product. The increased loading of the PdCl2 from 1 to 4 equivalent of
substrate gave no considerable effect on the yield of product. The oxidation of 1a did not
proceed in the absence of water. Therefore, 1-1.5 equivalent of water is the suitable
choice for this reaction.
It is noteworthy that the PdCl2-catalyzed aerobic oxidation of 1a was resulted in the
formation of small amount of byproducts as elaborated in Scheme 2.
6

ACCEPTED MANUSCRIPT
Scheme 2. The relative percentage of 2a and by-products resulted from PdCl2-catalyzed oxidation of 1a.
3.2. Evaluation of the reaction scope
With the optimized reaction conditions in hand, we began to examine the scope of the
Wacker oxidation of stilbenes 1b-1h. As shown in Scheme 3, this transformation was
studied for a broad scope of substrates including various functional groups, such as
bromide, methoxy, methyl, nitril, and trifluoromethyl. The stilbenes 1b-1g were oxidized
to form the corresponding ketones 2b-2g in 5-10% yield. To obtain spectroscopic data,
the reactions were carried out in 72 h. Surprisingly, when the stilbene 1h was subjected to
oxidation condition, no product 2h was afforded even after 100 h reaction.
7

ACCEPTED MANUSCRIPT
Me
O
OMe
O
O
Me
Me
Me
MeO
2c
2b
2e
2d
O
O
O
CF3
Br
F3C
Br
2f
2g
NC
O
CN
2h
Scheme 3. The structures of 2b-2h.
The general finding revealed that the oxidation rate was substantially dependent on the
position and kind of substitute on phenyl rings. The close yields at the range 8-12% were
achieved for p-substituted substrates, regardless of electron-rich or electron-poor group
on the substrates. The oxidation rate of para-substituted stilbenes such as 1d (2d = 12%)
and 1g (2g = 10%) are similar to that of 1e (2e = 11%) and a little better than that of 1f
(2f = 7%).
However, the catalytic activity was dramatically reduced for o-substituted stilbenes 1c
and 1h in comparison with para-substituted stilbenes. Steric hindrance of methyl and
nitril groups about the alkene makes the rate of the oxidation reaction of 1c and 1h slow.
Therefore, the much higher yield of 2a rather than that of 2c (5%) and 2h (no reaction) is
due to the rate of palladium-alkene p-complex formation.
8

ACCEPTED MANUSCRIPT
To determine if ortho arrangement of methoxy and alkene is plausible, the alkene of 1b
with meta methoxy arrangement was subjected to the Wacker oxidation and gave 2b in
lower yield (10%).
These data shows that ortho arrangement of methoxy and alkene substitutions on the ring
plays a critical role on the complexation with PdCl2.
3.3. Structure-activity relationship
We considered two possible ways for the complexation of 1a with PdCl2. As shown in
Scheme 4, If PdCl2 interacts with both alkoxy groups, a steric hindrance is formed that
prevents the coordination alkene to PdCl2. A fast way to keep PdCl2 close to alkene group
is that one alkoxy group is take part in complexation with Pd ion.
Scheme 4. Two possible ways for the complexation of 1a with PdCl2.
An approach to proof this behavior is to use cyclic stilbene 1k in which, unlike 1a, the
aromatic rings are restricted from rotating. Based on x-ray analysis, 1k has coplanar
structure and one of the olefinic hydrogens is toward the cavity which may make a steric
hindrance to host Pd ion. [39]
To gain a favorable match of 1k and Pd ion, however, a mutual adaptation of host and
guest is needed to make an induced fit. The fit involves subtle changes in molecular
geometry of 1k allowing maximum attraction of the alkene and Pd ion. Therefore, more
9

ACCEPTED MANUSCRIPT
time is needed that molecule 1k may undergo suitable adjustment of its geometry on
guest inclusion to provide a greater stability of the complex.
While the results in Scheme 3 show the potential applications of the transformation,
understanding of the detailed reaction mechanism would be useful for further expansion.
Accordingly, 1k showed lower activity than that of 1a after 12 h oxidation (2k = 15%).
However, when the reactions prolonged to 72 h, a higher yield for 2k (70% yield) in
comparison with 2a (55%) was observed.
This inclusive data revealed that in addition to ortho arrangement of methoxy and alkene
substitutions on the ring, a suitable cavity plays a critical role on the increasing of
reaction yield.
4. Conclusions
Though the Wacker oxidation has been studied for about half a century, a detailed
mechanistic understanding of the process continues to be elusive because of the
utilization of added ions and co-oxidants.
In this study we designed some stilbenes 1 to provide a better understanding of the
structure-function relationships of the different substituent groups within the molecule. In
this regard, 1a was discovered as the most active hosts in which the ortho substitution of
10

ACCEPTED MANUSCRIPT
alkene and methoxy groups plays a key role in the activity. A further study shows that the
formation of host–guest complexation in cyclic stilbene 1k enhances the yield of 2k.
On the basis of these findings, we were able to provide a better understanding of the
structure-function relationships of the different substituent groups within the stilbene
molecule.
Further investigation on cyclic stilbenes is currently under investigation in our laboratory.
References
[1] G. O. Spessard, G. L. Miessler, Organometallic Chemistry; Prentice Hall: Upper Saddle River, (1997).
[2] J. M. Takacs, X. Jiang, Curr. Org. Chem, 7 (2003) 369–396.
[3] C. N. Cornell, M. S. Sigman, Inorg. Chem. 46 (2007) 1903–1909.
[4] V. Kotov, C. C. Scarborough, S. S. Stahl, Inorg. Chem. 46 (2007) 1910–1923.
[5] R. Jira, Angew. Chem. 121 (2009) 9196–9199; Angew.Chem. Int. Ed. 48 (2009) 9034–9037.
[6] J. Tsuji, Palladium Reagents and Catalysts; John Wiley & Sons: Chichester, (2004) pp 32–35.
[7] J.-E. Bäckvall, B. Åkermark, S. O. Ljunggren, J. Chem. Soc., Chem. Commun. (1977) 264–265.
[8] K. Zaw, P. M. Henry, J. Org. Chem. 55 (1990) 1842–1847.
[9] D. J. Nelson, R. Li, C. Brammer, J. Am. Chem. Soc. 123 (2001) 1564–1568.
[10] J. A. Keith, J. Oxgaard, W. A. Goddard, J. Am. Chem. Soc. 128 (2006) 3132–3233.
[11] J. A. Keith, R. J. Nielsen, J. Oxgaard, W. A. Goddard, J. Am. Chem. Soc. 129 (2007) 12342–12343.
[12] C. N. Cornell, M. S. Sigman, J. Am. Chem. Soc. 127 (2005) 2796–2797.
[13] T. Hayashi, K. Yamasaki, M. Mimura, Y. Uozumi, J. Am. Chem. Soc. 126 (2004) 3036–3037.
[14] J. Tsuji, Synthesis (1984) 369–384.
[15] J. M. Takacs, X. T. Jiang, Curr. Org. Chem. 7 (2003) 369–396.
[16] R. M. Trend, Y. K. Ramtohul, B. M. Stoltz, J. Am. Chem. Soc. 127 (2005) 17778–17788.
[17] C. N. Cornell, M. S. Sigman, Org. Lett. 8 (2006) 4117–4120.
[18] J. M. Lee, D. S. Ahn, D. Y. Jung, J. Lee, Y. Do, S. K. Kim, S. K. Chang, J. Am. Chem. Soc. 128
(2006) 12954–12962.
11

ACCEPTED MANUSCRIPT
[19] P. H Espeel, M. C. Thielen, P. A. Jacobs, J. Chem. Soc., Chem. Commun. 10 (1991) 669–671.
[20] J. P. Arhancet, M. E. Davis, B. E. Hanson, Catal. Lett. 11 (1991) 129–136.
[21] T. Mitsudome, T. Umetani, K. Mori, T. Mizugaki, K. Ebitani, K. Kaneda, Tetrahedron Lett. 47 (2006)
1425–1428.
[22] J. H. Ahn, D. C. Sherrington, Macromolecules 29 (1996) 4164–4165.
[23] H. G. Tang, D. C. Sherrington, J. Catal. 142 (1993) 540–551.
[24] K. M. Choi, T. Mizugaki, K. Ebitani, K. Kaneda, Chem. Lett. 32 (2003) 180–181.
[25] A. Lambert, E.G. Derouane, I.V. Kozhevnikov, J. Catal. 211 (2002) 445–450.
[26] A. Kishi, T. Higashino, S. Sakaguchi, Y. Ishii, Tetrahedron Lett. 41 (2000) 99–102.
[27] K. I. Matveev, N. B. Shitova, E. G. Zhizhina, Kinet.Catal. 17 (1976) 893–902.
[28] N. B. Shitova, L.I. Kuznetsova, K.I.Matveev, Kinet. Catal. 15 (1974) 72–99.
[29] T. Mitsudome, T. Umetani, N. Nosaka, K. Mori, T. Mizugaki, K. Ebitani, K. Kaneda, Angew. Chem.
118 (2006) 495–499; Angew.Chem. Int. Ed. 45 (2006) 481–485.
[30] J. M. Escola, J. A. Botas, J. Aguado, D. P. Serrano, C. Vargas, M. Bravo, Appl. Catal. A: Gen. 33
(2008) 137–144.
[31] S. S. Stahl, Angew. Chem., Int. Ed., 43 (2004) 3400–3420.
[32] S. S. Stahl, Science 309 (2005) 1824–1826.
[33] M. S. Sigman D. R. Jensen, Acc. Chem. Res. 39 (2006) 221–229.
[34] J. A. Cusumano, Chemtech 22 (1992) 482–489.
[35] K. Takehira, T. Hayakawa, H. Orita, Chem. Lett. (1985) 1835–1838.
[36] T. Mitsudome, K. Mizumoto, T. Mizugaki, K. Jitsukawa, K. Kaneda, Angew. Chem. Int. Ed. 49
(2010) 1238–1240.
[37] T. Mitsudome, S. Yoshida, Y. Tsubomoto, T. Mizugaki, K. Jitsukawa, K. Kaneda, Tetrahedron Lett.
54 (2013) 1596-1598.
[38] B. Betzemeier, F. Lhermitte, P. Knochel, Tetrahedron Letters 39 (1998) 6667–6670.
[39] H. R. Darabi, K. Jadidi, A. R. Mohebbi, L. Faraji, K. Aghapoor, S. Shahbazian, M.Azimzadeh, S.
Nasseri, Supramolecular Chem. 20 (2008) 327–333.
12