Ionic-liquid supported oxidation reactions in a silicon-based microreactor

Article abstract of DOI:10.1016/j.tetlet.2005.11.147

The combination of microfabrication and reaction engineering techniques has the potential to produce powerful microreactors. In a microreactor, aqueous buffers provide high electroosmatic mobility and no external pumping is required. While numerous reactions have been demonstrated to be highly efficient in microreactors, so far there has been no report on the epoxidation of cyclohexene in a microreactor. This is mainly due to the reduced solubility of cyclohexene in aqueous media. The greater volatility of cyclohexene leading to long reaction times is another reason. To improve the solubility of cyclohexene in the reaction buffer, a water soluble ionic-liquid 1-butyl-3-methylimidazolium tetrafluoroborate was used, also for the first time in microreactor work. In this letter, four different catalysts (i.e., manganese(II) and copper(II) complexes of Schiff and reduced Schiff bases) were synthesized and used for the oxidation reactions considered. The reactions were monitored by gas chromatography/mass spectrometry. The microreactor performance was evaluated by comparing with a conventional (batch scale) reaction. Catalytic activities and yields were found to be relatively high for the copper(II) complexes as compared with the conventional route.

Full text of DOI:10.1016/j.tetlet.2005.11.147

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 957–961
Ionic-liquid supported oxidation reactions in a
silicon-based microreactor
Chanbasha Basheer,a Muthalagu Vetrichelvan,b Valiyaveettil Suresha,b, and
*
Hian Kee Leea,*
aDepartment of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore
bSingapore–MIT Alliance, E4-04-10, 4 Engineering Drive 3, Singapore 117546, Singapore
Received 13 September 2005; revised 22 November 2005; accepted 29 November 2005
Available online 20 December 2005
Abstract—The combination of microfabrication and reaction engineering techniques has the potential to produce powerful microre-
actors. In a microreactor, aqueous buffers provide high electroosmatic mobility and no external pumping is required. While numer-
ous reactions have been demonstrated to be highly efficient in microreactors, so far there has been no report on the epoxidation of
cyclohexene in a microreactor. This is mainly due to the reduced solubility of cyclohexene in aqueous media. The greater volatility of
cyclohexene leading to long reaction times is another reason. To improve the solubility of cyclohexene in the reaction buffer, a water
soluble ionic-liquid 1-butyl-3-methylimidazolium tetrafluoroborate was used, also for the first time in microreactor work. In this
letter, four different catalysts (i.e., manganese(II) and copper(II) complexes of Schiff and reduced Schiff bases) were synthesized
and used for the oxidation reactions considered. The reactions were monitored by gas chromatography/mass spectrometry. The
microreactor performance was evaluated by comparing with a conventional (batch scale) reaction. Catalytic activities and yields
were found to be relatively high for the copper(II) complexes as compared with the conventional route.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
dures for selective oxidation of olefins is still a subject
of practical and theoretical interest.
Simple microfluidic analytical systems offer many funda-
mental and practical advantages in organic synthesis
and a range of applications have been developed in
many different areas.1,2 The motivation for using
micro-analytical devices includes low sample consump-
tion, fast analysis times and high-throughput. These
environmentally friendly methods are ideal for screening
catalytic efficiency and also to quantify intermediate
products.3–5
Ionic liquids have been employed as solvents or catalysts
in many such catalytic processes.11 Additionally, ionic
liquids provide an ideal medium for reactions that
involve reactive ionic intermediates. Due to the stabiliza-
tion of charged intermediates by ionic liquids, they can
promote enhanced selectivities and reaction rates and
are finding increasing applications in organic synthe-
sis.12,13 Moreover, ionic liquids uniquely integrate many
valuable properties including high polarity, low visco-
sity, high liquid temperature range, high thermal stabil-
ity, wide tunability, immiscibility with certain organic
solvents and no effective vapour pressure. The main
advantages of ionic liquid catalysis are greatly enhanced
reaction rates, higher activity at lower temperature and
higher selectivity. It is believed that the non-volatile
characteristic of ionic liquids allows product separation
from the catalyst without the formation of azeotropes,
therefore reducing contamination of the product.14,15
Electrochemical synthesis in microreactors provides an
attractive approach to organic synthesis, avoiding toxic,
expensive organic solvents, and often providing unique
pathways to control the reactant and product distribu-
tion.1,6 Catalytic oxidation of hydrocarbons is an impor-
tant process.7 Organometallic complexes are considered
to be very effective catalysts for the epoxidation of ole-
fins.8–10 The development of simple and efficient proce-
*
In this study, silicon-based microreactors were fabri-
cated using standard photolithographic procedures and
Corresponding authors. Tel.: +65 6516 2995; fax: +65 6779 1691;
e-mail addresses: chmsv@nus.edu.sg; chmleehk@nus.edu.sg
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.147

958
C. Basheer et al. / Tetrahedron Letters 47 (2006) 957–961
utilized to perform the epoxidation of cyclohexene for
the first time in microfluidic work using the ionic liquid
(1-butyl-3-methylimidazolium tetrafluoroborate [bmim]-
[BF4]). The performance of various types of catalysts
such as Schiff-base and reduced Schiff-base complexes
of Cu(II) and Mn(II) complexes were investigated.
Reactions were monitored using gas chromatography/
mass spectrometry (GC/MS) and the yields were
compared with those from bulk scale epoxidation. To
the best of our knowledge, this is also the first report
of the epoxidation of cyclohexene in a silicon-based
microreactor.
lected by filtration, washed with cold isopropanol fol-
lowed by diethyl ether and dried in air for 30 min. The
crude Schiff base was recrystallized from ethanol, fil-
tered and dissolved in methanol (50 mL). Sodium boro-
hydride (0.85 g, 22.6 mmol) was added slowly in
portions. After refluxing for 2 h, the reaction mixture
was cooled and quenched with water (20 mL). Methanol
was removed and the reduced ligand was extracted with
dichloromethane (3 · 30 mL). The combined organic
extracts were washed with water; the organic layer was
dried over anhydrous sodium sulfate and concentrated
to yield a brown, oily liquid of the pure ligand.
1
Ligand L2: Yield = 1.89 g (45%). H NMR (300 MHz,
2. Experimental
CDCl3), d: 8.62 (d, pyridyl, 2H, J = 6 Hz), 8.45 (d,
pyridyl, 2H, J = 7.6 Hz), 7.91 (t, pyridyl, 2H, J = 7.6
Hz), 7.70–7.60 (m, aromatic, 2H), 7.32 (m, pyridyl,
2H), 7.30–7.10 (m, aromatic, 2H), 4.50 (s, –H2C–,
4H). 13C NMR (75 MHz, CDCl3), d: 158.8, 149.0,
136.8, 136.7, 122.0, 121.7, 119.3, 112.2 (aromatic), 49.8
(–H2C–). IR (NaCl plates), t cmꢀ1: 3342 (amine N–H
stretch), 3056, 3011 (aromatic C–H stretch), 2926,
2853 (alkane C–H stretch), 1987, 1889, 1851, 1778 (aro-
matic overtones and combination bands), 1594, 1570
(aromatic C@C stretch), 1511 (amine N–H bend), 1274
(C–N stretch). EI-MS (m/z) 290.1 (M+, calculated
formula weight 290.37).
2.1. Fabrication of the microreactor
A silicon-based T-shape microreactor (Fig. 1) was fabri-
cated using standard photolithographic techniques,
based on Pattekar and Korthareꢀs work.16
2.2. Synthesis of ligand and complexes
2.2.1. Synthesis of copper(II) and manganese(II) com-
plexes of L1. The synthesis of the ligand, L1 and its
complexes of both copper and manganese are reported
elsewhere.17
2.2.3. Synthesis of copper(II) and manganese(II) com-
plexes of L2. The metal salts MnCl2 and CuCl2Æ2H2O
were used as starting materials. Both complexes were
prepared similarly. 0.7 mmol of each metal chloride
was dissolved in methanol (5 mL) and added dropwise
to a solution of reduced Schiff base ligand (L2) in dichlo-
romethane. The resulting solutions were stirred over-
night at room temperature. The solid products
deposited were collected by filtration and dried in air.
The manganese(II) complex was a brown precipitate
and the copper(II) complex, a green solid.
2.2.2. Synthesis of N,N0-bis(2-pyridyl methyl)benzene-
1,2-diamine,
L2. 2-Pyridylcarbaldehyde
(3.8 mL,
40.0 mmol) was added to a solution of 1,2-phenylenedi-
amine (2.16 g, 20.0 mmol) in isopropanol (40 mL)
(Scheme 1). The stirred solution began to deposit a yel-
low precipitate after 15 min. Stirring was continued for
1 h at room temperature and the precipitate was col-
2.2.4. Manganese(II) complex-(L2Mn). Yield = 35%.
IR (KBr pellet), t: 3432 (amine N–H stretch), 3067,
3017 (aromatic C–H stretch), 2983, 2917 (alkane C–H
stretch), 1594 (aromatic C@C stretch), 1304 (C–N
stretch). UV (MeOH), kmax: 241, 306.5 nm. ESI-MS
(m/z): 999.1 (M+, calculated formula weight 994.3). Ele-
mental analysis for [(Mn3L2Cl6)Æ2(H2O)], found: C, 43.1;
H, 3.5; N, 11.1. Calcd: C, 43.5; H, 4.1; N, 11.3.
Figure 1. Schematic diagram of microreactor. A, B and C are
reservoirs. Length of the channel is 3 cm, width 200 lm and 50 lm
depth. The channel was sealed with a glass plate.
Methanol
NaBH4/reflux 2 h
Isopropanol
Stir 1 h
+
2
HN
N
NH
N
CHO
N
N
N
H2N
NH2
N
N
L1
L2
N
N
HN
N
NH
N
M
M
N
N
X
X
X
X
M = Cu(II) or Mn(II); X = Cl or H2O
Scheme 1. Synthetic scheme for the ligands, L1 and L2.

C. Basheer et al. / Tetrahedron Letters 47 (2006) 957–961
959
2.2.5. Copper(II) complex-(L2Cu). Yield = 48%. IR
(KBr pellet), t: 3426 (amine N–H stretch), 3073, 3041
(aromatic C–H stretch), 2975 (alkane C–H stretch),
1596 (aromatic C@C stretch), 1298 (C–N stretch). UV
(MeOH), kmax: 241, 325 nm. ESI-MS (m/z): 669.9
(M+, calculated formula weight 662.2). Elemental analy-
sis for [(Cu2LCl4)Æ(H2O)(CH2Cl2)], found: C, 34.4; H,
3.0; N, 9.1. Calcd: C, 34.5; H, 3.4; N, 8.5.
2.3. Epoxidation of cyclohexene in the microreactor
The basic arrangement of the T-shaped microreactor
with reservoirs A, B and C, is depicted in Figure 1.
The reaction is shown in Scheme 2. Initially, the T-
shaped microfluidic channel was filled with 50 mM of
phosphate buffer solution (with 0.5% (v/v) of ionic
liquid) and 5% (w/v) of the Schiff catalyst.
Figure 2. GC/MS-SIM chromatograms generated by the epoxidation
of cyclohexene under optimized conditions in the microreactor (a);
bulk scale epoxidation in the presence of hydrogen peroxide (b); and a
blank experiment (without catalyst) (c). Peak identifications: [1].
cyclohexene, [2]. 1,2-cyclohexene-oxide, [3]. 2-cyclohexen-1-ol, [4]. 2-
cyclohexen-1-one, [5]. 2-hydroxy-cyclohexanone.
Extreme care was taken to ensure that air bubbles were
absent inside the microfluidic channel. This was checked
by measuring a constant current. The reactant (10 lL)
was introduced to reservoir A. The conditions included
a potential of 4 kV, (+) 200 lA to reservoir A and (ꢀ)
200 lA to reservoir C. Platinum wires were used as elec-
trodes. The reaction was monitored for 25 min at room
temperature.
ual reactant and products using standards. Based on the
calibration, reaction yields were calculated. Addition-
ally, controlled experiments were performed to check
the efficiency of the catalyst. Figure 2 shows the opti-
mized chromatograms of reactant and products.
2.4. Epoxidation of cyclohexene in bulk scale
The manganese(II) or copper(II) complex (4.4 mg) was
added to cyclohexene (0.11 mL, 1 mmol) in 50 mM
phosphate buffer containing 0.5% of [bmim][BF4] with
5% of the respective catalyst under a nitrogen atmo-
sphere at room temperature. The reaction was started
by the dropwise addition of 30% aqueous hydrogen per-
oxide (0.06 mL, 2 mmol) dissolved in acetonitrile
(0.5 mL). A control experiment was set up without any
metal complex. Epoxidation of cyclohexene was moni-
tored at different intervals (i.e., 1, 2, 3 and 5 h). After
completion of the reaction, the analytes were extracted
with diethyl ether and filtered, and reconstituted to
1 mL.
3. Results and discussion
3.1. Optimization of the epoxidation of cyclohexene in the
microreactor
The nature and relative yields of the products formed by
the catalytic oxidation of cyclohexene using a Schiff base
catalyst vary considerably depending on the conditions
and catalyst used. In order to optimize the reaction con-
ditions in the microreactor, analytical factors such as
addition of ionic liquid to the reaction medium, the
catalyst used (Cu(II) and Mn(II) complexes), applied
potential, current and reaction time, that might affect
the reaction conditions were studied.
2.5. Product mixture analysis
Analysis of the reaction mixture was performed on a
Shimadzu (Tokyo, Japan) QP2010 GC/MS system.
Initially, oxidation of cyclohexene was performed with a
phosphate buffer as the reaction medium. Due to the
low solubility of cyclohexene in the reaction medium,
less precise results and poor reaction yields were
obtained. This provided the impetus to perform the reac-
tion in a more favourable medium. Therefore, the
ionic liquid [bmim][BF4] was introduced (0.5% v/v) to
the buffer solution. A high concentration of 5% ionic
liquid did not give any improvement in the reaction. Since
The GC was fitted with
a
DB-5 column
(30 m · 0.32 mm i.d., 0.25 lm) from J&W Scientific
(Folsom, CA, USA). The detector was scanned over
the m/z range 50–500 to confirm the retention times of
the analytes. For determination of the reactants and
products, selected ion monitoring (SIM) was performed.
GC conditions were optimized initially and separate
quantitative calibration curves were plotted for individ-
OH
O
OH
Mn(II)/Cu(II) complex
O
O
2-cyclohexen
-1-one
2-hydroxy
cyclohexanone
1,2-cyclohexane 2-cyclohexen
oxide -1-ol
cyclohexene
Scheme 2. Epoxidation of cyclohexene.

960
C. Basheer et al. / Tetrahedron Letters 47 (2006) 957–961
the ionic liquid was miscible with the reaction medium
and reactant, more reproducible results were obtained.
Experiments were run across a voltage range of 1–5 kV
at a constant current of 200 lA to determine the opti-
mum potential at which the highest yield was obtained.
Figure 4 shows the influence of the applied voltage. As
can be seen, a maximum product yield was obtained at
4 kV.
Reaction time is one of the most important parameters
in the epoxidation of cyclohexene. The reaction time
was varied between 5 and 30 min at 100 lA current
and 5 kV applied potential and the reaction yield with
respect to time was monitored. A reaction time of
25 min appeared to be the optimum (Fig. 3).
The optimum experimental conditions, involved a reac-
tion time of 25 min, an applied potential of 4 kV, an ap-
plied current of 200 lA and 5% of catalyst in a 50 mM
phosphate buffer containing 0.5% of [bmim][BF4]. Rep-
resentative results are summarized in Table 1. Compared
with the conventional synthesis, the microreactor experi-
ments provided higher reaction yields.
We evaluated the performance of the reaction with
respect to the applied current range from 75 lA to
250 lA at a constant potential of 5 kV for 25 min. The
reaction yield (% of conversion) increased with increas-
ing current up to 150 lA. At 200 lA, products were
obtained at comparably higher yields than the conven-
tional procedure.
The mechanism of the oxidation of cyclohexene involves
its double bond reacting readily with electrophilic radi-
cal cations.18,19 Oxidation is believed to be similar to
anodic oxidation of dienes18,20 and alkenes.21 Addition-
ally, Schiff complexes of Cu or Mn catalyse the oxida-
tion of cyclohexene to the corresponding ketones and
aldehydes.22 In the microreactor, both radical cations
and metal complex play significant roles in the oxidation
of cyclohexene.
40
20
0
The products obtained are 1,2-cyclohexene-1-oxide,
cyclohexanone; cyclohexen-1-one and 2-hydroxy-cyclo-
hexanone; and cyclohexen-1-ol is the main product in
both cases (microreactor and bulk). The transfer of an
oxygen atom from the oxometal complex to the allylic
radical gave the 2-cyclohexen-1-ol product. Further-
more, 2-cyclohexen-1-ol could be converted to cyclo-
hexen-1-one by loss of a proton. A similar type of
oxidation of cyclohexene to the epoxide, cyclohexenol
and cyclohexenone using iron phthalocyanines has been
reported elsewhere.23
5
10
15
20
25
30
reaction time (min)
1,2-cyclohexene-oxide
2-cyclohexen-1-one
2-cyclohexen-1-ol
2-hydroxy-cyclohexanone
Figure 3. Epoxidation of cyclohexene at various reactions time.
80
40
0
Comparing the manganese and copper complexes, the
copper complex could be a better catalyst for oxidation
of cyclohexene. The yield of oxidation products
obtained in the study is comparable with those reported
earlier24 via conventional procedures.
0
1
2
3
4
5
4. Conclusions
applied voltage (kV)
In conclusion, the Schiff and reduced Schiff base ligands,
L1 and L2 and their copper and manganese complexes
have been synthesized in good yields. The Schiff base
copper and manganese complexes (L1Cu and L1Mn)
and the dimeric copper and trimeric manganese com-
1,2-cyclohexene-oxide
2-cyclohexen-1-one
2-cyclohexen-1-ol
2-hydroxy-cyclohexanone
Figure 4. Epoxidation of cyclohexene at various applied potentials
under constant current and time (200 lA for 25 min).
Table 1. Percentage of product conversion in microreactor, bulk scale conversions are shown in parenthesis via Scheme 2
Products
Complex of L2
Complex of L1
Reduced Cu(II) complex
Reduced Mn(II) complex
Cu(II) Schiff
Mn(II) Schiff
1,2-Cyclohexene-oxide
2-Cyclohexen-1-ol
2-Cyclohexen-1-one
2-Hydroxy-cyclohexanone
Total conversion
5.5 (15.7)
22.0 (51.7)
2.3 (nd)
65.5 (10.9)
95.3 (78.3)
3.5 (15.9)
14.8 (45.0)
2.2 (4.5)
31.0 (5.3)
51.5 (70.7)
24.3 (28.1)
14.5 (6.1)
43.7 (11.1)
9.1 (9.4)
5.2 (16.1)
56.7 (2.6)
4.0 (3.3)
4.3 (nd)
70.2 (22.0)
91.6 (54.7)
nd = not detected.

C. Basheer et al. / Tetrahedron Letters 47 (2006) 957–961
961
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cyclohexene and systems. The microfluidic system
described here is an efficient and rapid cyclohexene
oxidation method. When the oxidation was carried out
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