Synthesis of an azo-Mn(II) complex with mild pH control using a microfluidic device

Article abstract of DOI:10.1039/c7ra06089k

This study describes the synthesis of an azo-Mn(ii) complex requiring an accurate pH control. The reaction conditions for the delicate azo-Mn(ii) complex could be precisely controlled using a microfluidic device. The microfluidic method showed the followi

Full text of DOI:10.1039/c7ra06089k

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Synthesis of an azo-Mn(II) complex with mild pH
control using a microfluidic device
Cite this: RSC Adv., 2017, 7, 39576
a
a
a
a
Daiki Tanaka, * Shunsuke Sawai, Dong Hyun Yoon,
Tetsushi Sekiguchi,
b
a
Takashiro Akitsu and Shuichi Shoji
This study describes the synthesis of an azo-Mn(II) complex requiring an accurate pH control. The reaction
conditions for the delicate azo-Mn(II) complex could be precisely controlled using a microfluidic device. The
microfluidic method showed the following advantages over the conventional method: the concentration of
the pH-control reagent was reduced (1/15), the reaction time was remarkably decreased from 4 h to less
Received 1st June 2017
Accepted 31st July 2017
ꢀ
than 1 s, and the reaction temperature was lowered from 40 to 23 C. Moreover, the microfluidic device
suppressed the oxidation of the compound and did not require cooling to remove the heat of reaction.
In addition, the conventional method uses harsh pH control, whereas the microfluidic device permits
mild pH control.
DOI: 10.1039/c7ra06089k
rsc.li/rsc-advances
Herein, we propose a new synthetic method for a very simple
azo-metal complex using a microuidic device. Chemical
1
. Introduction
Azo-metal complexes have attracted attention from many processes using microuidic devices can be highly efficient. For
researchers in recent years. Azo compounds have important example, Priest et al. reported the microuidic solvent extrac-
2
+
uses in biofuel cell electrodes and solar power applications and tion of Cu ions from particle-laden aqueous solutions using
as cell markers. For example, Lim et al. designed a heptame- 2-hydroxy-5-nonylacetophenone as an alternative to conven-
10
thine-azo conjugate as a near-infrared uorescent probe to tional solvent extraction. Furthermore, Kitamori and co-
monitor mitochondrial glutathione with low background auto- workers described the determination of carbamate pesticides
1

uorescence and serve as a cell marker. However, the synthesis such as carbaryl, carbofuran, propoxur, and bendiocarb using
of azo-metal complexes remains challenging and is still an a microuidic device developed for efficient solvent extrac-
1
1,12
active area of research. For instance, Grirrane et al. and Zhang tion.
and Jiao have reported that gold nanoparticles supported on downscaling reaction vessels as well as the advantages of the
titanium dioxide (TiO
) and nanoparticulate cerium dioxide continuous-ow microuidic approach over conventional
CeO
) catalyse the aerobic oxidation of aromatic anilines to methods, as illustrated by a number of examples of organic
aromatic azo compounds. Takeda, Minakata, and co-workers reactions carried out in microuidic devices.
demonstrated the oxidative homodimerization of aniline under group reported the use of a microuidic device in the photo-
Brivio et al. and deMello et al. reviewed the effects of
2
(
2
2,3
13–16
The Lumley
4–6
various conditions. Monir et al. reported the development of chemical oxidation of cholesterol, a-terpinene, and citronellol
an efficient method for the synthesis of aromatic azo under ow conditions, and the results were compared with
compounds in high yields through the phenyliodine(III) diac- those of similar batch reactions. Miller et al. described the
17
etate (PIDA)-mediated oxidative dehydrogenative coupling of rapid and high-yielding carbonylative cross-coupling reactions
7
anilines. Einaga, Akitsu, and co-workers systematically inves- of aryl halides to form secondary amides using a glass-
18
tigated organic/inorganic hybrid materials composed of metal fabricated microuidic device. Gunther and Jensen reviewed
complexes and azo compounds in poly(methyl methacrylate) the ow characteristics in multiphase micro- and nanoscale
8

lms as non-crystalline solids that could be converted into systems, measurement methodology, and how these charac-
9
19
chiral Schiff base complexes and made to regularly align.
teristics could be utilized in microuidic applications.
Kanai et al. described a sheath ow multi-sample injector that
methods is complicated because it requires a metal catalyst and allowed concentration-conserving sample injection using a step-
However, the synthesis of azo compounds via conventional
20
strict control of the atmosphere and temperature.
wise ow to reduce the dilution of the sample reagent. We have
previously established the synthesis of metal complexes and
21,22
a
protein–metal complexes using microuidic devices.
The
Research Organization for Nano & Life Innovation, Waseda University, 120-5
Research Development Center, 513 Waseda-tsurumakicho, Shinjuku-ku, Tokyo synthesis of the metal complexes using the microuidic device
1
62-0041, Japan. E-mail: d.tanaka@aoni.waseda.jp
required a shorter reaction time and no temperature or atmo-
b
23,24
Department of Chemistry, Faculty of Science, Tokyo University of Science, 1-3
Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
spheric control.
Furthermore, the conventional synthesis of
39576 | RSC Adv., 2017, 7, 39576–39582
This journal is © The Royal Society of Chemistry 2017

View Article Online
Paper
RSC Advances
Fig. 1 pH control in the conventional method.
Fig. 2 Three-step synthesis of the azo-Mn(II) complex.
azo compounds requires harsh pH adjustments using high
concentrations of hydrochloric acid and sodium hydroxide.
However, highly concentrated reagents lead to decomposition of
the compounds (Fig. 1). In addition, these conventional methods
require cooling to remove the heat of reaction.
2
.2.1 Synthesis of azo compound (step I). The synthesis
À1
was performed under cooling with ice. Aniline (250 mmol L
reagent A) and sodium nitrite (250 mmol L , reagent B) were
added dropwise to an aqueous HCl solution (5.62 mol L
under stirring for 30 min to form the diazonium compound.
,
À1
À1
)
À1
In this study, we demonstrate the use of a microuidic device
to synthesise azo compounds under milder conditions than
those utilized in conventional methods. According to previous
studies, microuidic devices can permit a more than 10 000-
Then, o-vanillin (250 mmol L , reagent C) was added to the
solution of the diazonium compound, which was neutralised
using NaOH, and the resulting mixture was stirred for 30 min to
afford an orange compound that was identied as the azo
23,24
1
fold increase in the rates of chemical reactions.
We, there-
compound via the IR, FAB-MS, and H-NMR analysis.
fore, focused on the high reactivity that could be achieved with
a microuidic device. The device is likely to reduce the required
concentration of pH-adjustment reagents. Moreover, the
microuidic device allows reactions to be performed at the
interface between reagents. The reagents are supplied one aer
another, and the reactants for each step are synthesised in
a stepwise manner. Thus, localised excess chemical reactions
do not occur. Furthermore, the conventional method requires
complicated operations, thus making the synthesis difficult.
However, the use of a microuidic device eliminates the need to
control these operations and allows the convenient and user-
friendly synthesis of azo-Mn(II) complexes.
2
.2.2 Synthesis of azo ligand (step II). The azo compound
À1
(
(
40 mmol L ) was added dropwise to a solution of (1R,2R)-
+)-1,2-diphenylethylenediamine (20 mmol L , reagent D) dis-
solved in methanol (50 mL), and the resulting mixture was
stirred at 40 C for 2 h to afford an orange solution of the ligand.
À1
ꢀ
2
.2.3 Synthesis of azo-Mn(II) complex (step III). Mn(II)
À1
acetate tetrahydrate (20 mmol L , reagent E) was added to the
abovementioned solution to obtain a red solution of the complex.
Aer being stirred for 2 h under N gas, the complex was ltered
2
off as a red prismatic precipitate (Fig. 3), and the product was
analysed via UV-vis spectroscopy, TOF-MS, H-NMR, and XRD.
1
2.3 Synthesis with the microuidic device
2
.3.1 Design and fabrication of the microuidic device.
2
. Experimental
The designs of the simple Y-junction and X-junction devices
used in this study are shown in Fig. 4. The width of the channel
2.1 Materials and measuring equipment
The chemicals and reagents were of the highest grade
commercially available (Tokyo Chemical Industry; Kanto
Chemical) and used as received without further purication.
The products were analysed by infrared spectroscopy (IR; FT/IR-
6200, JASCO), ultraviolet-visible spectroscopy (UV-vis; U-3900,
Hitachi), fast atom bombardment mass spectrometry (FAB-
MS; JMS-BU25, JEOL), time-of-ight mass spectrometry (TOF-
1
MS; JMS-T100LC, JEOL), proton NMR spectroscopy ( H-NMR;
ECX500, JEOL), and X-ray diffraction (XRD; RINTUltima3,
Rigaku). The conventional synthesis and the synthesis con-
ducted using the microuidic device were compared.
2.2 Conventional synthesis
As shown in Fig. 2, the azo-Mn(II) complex was synthesised in
25
three steps following the method reported by Akitsu et al.
Steps I, II, and III represent the syntheses of an azo compound,
azo ligand, and azo-Mn(II) complex, respectively. Steps II and III
were performed under a nitrogen atmosphere.
Fig. 3 Synthetic scheme for the azo-Mn(II) complex.
RSC Adv., 2017, 7, 39576–39582 | 39577
This journal is © The Royal Society of Chemistry 2017

View Article Online
RSC Advances
Paper
concentrations below 1/15, aniline did not dissolve in the
aqueous solution. We, therefore, decided to conduct the subse-
quent synthetic experiments at a concentration of 1/15 because
this mild pH control does not lead to the decomposition of the
azo compound.
2.3.3 Synthesis of the azo compound (step I). A simple
Y-junction channel was used for step I (Fig. 4a). The azo
À1
compound was synthesised using aniline (250 mmol L
,
À1
reagent A), sodium nitrite (250 mmol L , reagent B), and
o-vanillin (250 mmol L , reagent C). Aniline was dissolved in
an aqueous HCl solution (0.37 mol L ), and o-vanillin was
dissolved in an aqueous NaOH solution (0.37 mol L ). This
À1
À1
À1
Fig. 4 Device design and fluidic experiments. (a) Y-junction device. (b) synthetic step was performed in the two channels of the
À1
X-junction device.
Y-junction microuidic device at a ow rate of 2 mL min . The
synthesised azo compound was ltered and analysed via IR,
FAB-MS, and H-NMR (Table 2).
1
Table 1 Preliminary experimental conditions for pH control
2.3.4 Synthesis of the azo ligand (step II). In step II of the
synthesis, a Y-shaped microuidic device was used (Fig. 4a). The
HCl concentration
Synthesis result
À1
ligand was synthesised from the azo compound (40 mmol L
,
À1
À1
À1
À1
À1
À1
step I product) and (1R,2R)-(+)-1,2-diphenylethylenediamine
1
1
1
1
1
1
/1 (5.62 mol L
/2 (2.81 mol L
/5 (1.12 mol L
/10 (0.56 mol L
/15 (0.37 mol L
/20 (0.28 mol L
)
)
)
Failure
Failure
Failure
Success
Success
Insoluble (aniline)
À1
À1
(20 mmol L , reagent D) at a ow rate of 2 mL min (Table 2).
2.3.5 Synthesis of the azo-Mn(II) complex (step III). The
azo-Mn(II) complex was synthesised from the azo ligand and
)
)
)
À1
Mn(II) acetate tetrahydrate (20 mmol L , reagent E), both of
which were dissolved in methanol. Step III of the synthesis was
performed in the second channel of the X-junction microuidic
device (Fig. 4b). This synthesis was performed directly aer step
II with no treatment, with the outlet from step II connected to
was approximately 500 mm, and the depth was approximately
00 mm. The device was fabricated via the standard so litho-
graphic technology. Reagents and solutions were introduced by
1
À1
the ligand inlet for step III. The ow rate was 4 mL min . Aer
the synthesis, the solvent was evaporated to afford the product,
24
a syringe using a syringe pump.
.3.2 Preliminary experiments – synthesis of the azo
1
which was analysed by UV-vis spectroscopy, TOF-MS, H-NMR,
2
and XRD (Table 2). However, XRD measurement data could
not be obtained.
compound (step I). We conducted preliminary experiments to
determine the appropriate concentration of the pH-adjustment
reagent for the uidic experiments (Table 1). The preliminary
À1
concentrations of HCl and NaOH selected were 1/1 (5.62 mol L ),
3
. Results and discussion
À1
À1
À1
À1
1
1
/2 (2.81 mol L ), 1/5 (1.12 mol L ), 1/10 (0.56 mol L ), and
/15 (0.37 mol L ) as compared to those used in the conven- The FAB-MS results show the mass-to-charge ratio (m/z: [256.08
+
tional method. The synthetic experiments failed at the concen- + H] ) of the products obtained aer step I for both the
trations 1/1, 1/2, and 1/5, and only black decomposition products conventional method and the microuidic device method
1
were obtained. The synthetic experiments at the concentrations (Fig. 5). In addition, the H-NMR spectra of the products ob-
1/10 and 1/15 afforded orange compounds. Moreover, at the HCl tained from the two methods were consistent (Fig. 6).
Table 2 Summary of the synthetic conditions
Conventional method
Microuidic device
À1
À1
Reagent concentration (step I), HCl and NaOH for pH control
Reagent concentration (step I), azo compounds
Reagent concentration (steps II and III), azo-metal complex
Reaction temperature (step I)
Reaction temperature (steps II and III)
Flow rate
5.62 mol L
0.37 mol L
À1
À1
250 mmol L
250 mmol L
À1
À1
20 and 40 mmol L
20 and 40 mmol L
23 C (R.T.)
23 C (R.T.)
2 and 4 mL min
ꢀ
ꢀ
ꢀ
0–5 C
ꢀ
40 C
À1
—
Stirring time (step I)
Stirring time (steps II and III)
1 h
4 h
—
—
Atmosphere
Synthesis scale
Analytical method for the azo compound (step I)
Analytical method for the metal complex (step III)
N
50 cm
2
Air
0.002 cm
3
3
1
IR, FAB-MS and H-NMR
UV-vis, TOF-MS, H-NMR and XRD
1
39578 | RSC Adv., 2017, 7, 39576–39582
This journal is © The Royal Society of Chemistry 2017

View Article Online
Paper
RSC Advances
Fig. 5 FAB-MS spectra of the azo compounds obtained in step I of the conventional method and using the microfluidic device.
À1
Furthermore, a peak corresponding to N]N (1590 cm ) was
The UV-vis spectra (Fig. 7b) revealed changes in the detected
observed in the IR spectra (Fig. 7a). These analytical data showed p–p* and charge-transfer transitions, which indicated that the azo-
that both the conventional and microuidic device methods Mn(II) complex had been obtained. In addition, the TOF-MS data
successfully afforded the azo compound. This result proved that showed peaks for the azo-Mn(II) complex (m/z: 741.2; Fig. 8).
1
the azo compound could be synthesised under mild pH control Moreover, the large peaks in the H-NMR spectra were consistent
using the microuidic device. The chemical reaction was (Fig. 9). Overall, these results indicated that the azo-Mn(II) complex
promoted using the microuidic device, and the reaction pro- had been successfully synthesised using the microuidic device.
ceeded even at a low HCl concentration. Moreover, the synthesis
in the microuidic device did not require temperature control conventional method, a large amount of solvent can be gradu-
Table 3) as the microuidic device allowed the reaction to occur ally evaporated to promote crystal growth. Conversely, a small
XRD measurement data could not be obtained. In the
(
at the interface. The reagents were supplied one aer another, and amount of solvent obtained using the microuidic device
the reactants for each step were synthesised in a stepwise manner. method rapidly evaporated. For this reason, the product herein
The synthesis of difficult azo compounds requiring control of pH was obtained as a powder rather than as a crystal, and the XRD
and temperature is also possible using microuidic devices.
We also tested a microuidic device with a channel width of
spectra could be adequately obtained.
Microuidic devices have been suggested to lead to high
200 mm. However, this device could not be used for the synthesis reaction rates. For steps II and III, the microuidic device was
because the azo compound immediately clogged the channels. operated at room temperature and the conventional method
ꢀ
Therefore, in the experiments reported herein, we synthesised was conducted at 40 C. In addition, the conventional method
the azo compound using a microuidic device with a channel required a reaction time of 4 h, whereas the reaction in the
width of 1 mm.
microuidic device completed in less than 1 s.
1
Fig. 6 H-NMR spectra of the azo compounds obtained in step I of the conventional method and using the microfluidic device.
This journal is © The Royal Society of Chemistry 2017
RSC Adv., 2017, 7, 39576–39582 | 39579

View Article Online
RSC Advances
Paper
Fig. 7 Spectroscopic measurements of the compounds. (a) IR spectra of the azo compounds (step I). (b) UV-vis spectra of the azo-Mn(II)
complexes (step III).
24
Mn(II) and Co(II) salen complexes using microuidic devices.
Table
3 Comparison between the microfluidic device and the
conventional method
In this study, the reaction time was too short for the reagents to
react with oxygen because they owed continuously into the
microuidic device. However, in the conventional method, the
reaction mixture was stirred, and metal acetate was oxidised.
Parameter
Conventional method
Microuidic device
À1
À1
pH control (step I),
HCl and NaOH
Reaction temperature
5.62 mol L
0.37 mol L
27
Furthermore, PDMS is not affected by alcohol. The quantities
that microuidic devices can handle are small although this
problem can be solved using multiple devices in parallel. In
microuidic devices, reactions occur rapidly and are isolated
from the air. Therefore, syntheses, which cannot be achieved via
conventional methods, such as simultaneous organic and
complex reactions, can be achieved using microuidic devices.
One drawback of the chemical synthesis using the microuidic
ꢀ
ꢀ
0–5 C
23 C (R.T.)
(
step I)
Reaction temperature
steps II and III)
ꢀ
ꢀ
40 C
23 C (R.T.)
(
Synthesis time (step I)
Synthesis time
1 h
4 h
1 s
1 s
(steps II and III)
Atmosphere
N
2
Air
+
device was the formation of a byproduct (m/z: [331.83 + H] )
derived from the azo compound, as shown in Fig. 5. In addi-
tion, the p–p* band in Fig. 7b indicated that the ligands were
mixed with the azo-Mn(II) complex. Furthermore, Fig. 9 indi-
cated that unreacted materials were mixed with the desired
products. However, this problem could be solved using
a microdroplet merging device, and we will investigate the use
of this device in our future work to prevent the inclusion of
unreacted materials.
Furthermore, the synthesis using the conventional method
needed to be performed under a N atmosphere, whereas it
could be performed under an air atmosphere using the micro-
2

uidic device. Zhang and Cloud reported that oxygen could
26
easily pass through a polydimethylsiloxane (PDMS) device.
However, Tanaka et al. have also described the synthesis of
Fig. 8 TOF-MS spectra of the azo-Mn(II) complex obtained in step III of the conventional method and using the microfluidic device.
39580 | RSC Adv., 2017, 7, 39576–39582
This journal is © The Royal Society of Chemistry 2017

View Article Online
Paper
RSC Advances
1
Fig. 9 H-NMR spectra of the azo-Mn(II) complex obtained in step III of the conventional method and using the microfluidic device.
4
S. Okumura, C. H. Lin, Y. Takeda and S. Minakata, J. Org.
Chem., 2013, 781, 2090–12105.
4
. Conclusion
An azo-Mn(II) complex was synthesised with mild pH control
using a highly reactive microuidic device. We successfully
synthesised azo compounds requiring temperature control and
pH control using a simple Y-junction microuidic device. In
addition, the microuidic device formed the azo-Mn(II) complex
in less than 1 s at room temperature, and the synthesis could be
performed under an air atmosphere. The microuidic device is
capable of chemical synthesis similar to the conventional
method although it is better suited to handling valuable and
dangerous reagents. In future work, we will synthesise azo-
5 Y. Takeda, S. Okumura and S. Minakata, Angew. Chem., Int.
Ed., 2012, 51, 7804–7808.
6 J. Belmar, M. Parra, C. Zu ˆa n ¨a iga, C. Pe ˆa rez, C. Mun ¨a oz,
A. Omenat and J. Serrano, Liq. Cryst., 1998, 26, 389–396.
7 K. Monir, M. Ghosh, S. Mishra, A. Majee and A. Hajra, Eur. J.
Org. Chem., 2014, 1096–1102.
8 Y. Einaga, R. Mikami, T. Akitsu and G. Li, Thin Solid Films,
2005, 493, 230–236.
9 Y. Aritake, T. Takanashi, A. Yamazaki and T. Akitsu,
Polyhedron, 2011, 30, 886–894.
metal complexes containing lysozyme as azo-metal complexes 10 C. Priest, J. Zhou, R. Sedev, J. Ralston, A. Aota, K. Mawatari
have optical isomerisation properties that may allow us to
and T. Kitamori, Int. J. Miner. Process., 2011, 98, 168–173.
achieve the goal of controlling fuel cells using light. It should be 11 T. Ito, K. Uchiyama, S. Ohya and T. Kitamori, Jpn. J. Appl.
noted that the amount of product generated using the micro-
Phys., Part 1, 2001, 40, 5469–5473.
uidic device is small. We intend to solve this problem by 12 A. Smirnova, K. Shimura and A. Hibara, Anal. Sci., 2007, 23,

fabricating an integrated device that should enable practical
chemical synthesis.
103–107.
13 M. Brivio, W. Verboom and D. N. Reinhoudt, Lab Chip, 2006,
6
, 329–344.
1
1
1
1
1
4 A. J. deMello, Control and detection of chemical reactions in
microuidic systems, Nature, 2006, 442/27, 394–402.
5 M. Neumann and K. Zeitler, Org. Lett., 2012, 14/11, 2658–
Conflicts of interest
There are no conicts to declare.
2
661.
6 C. A. Serra and Z. Chang, Chem. Eng. Technol., 2008, 31/8,
099–1115.
Acknowledgements
1
7 E. K. Lumley, C. E. Dyer, N. Pamme and R. W. Boyle, Org.
Lett., 2012, 14/22, 5724–5727.
8 P. W. Miller, N. J. Long, A. J. de Mello, R. Vilar, J. Passchierc
and A. Geec, Chem. Commun., 2006, 546–548.
This work was partially supported by a Grant-in-Aid for the
Scientic Basic Research (A) (No. 16H02349) from the Japanese
Ministry of Education, Culture, Sports, Science and Technology
(MEXT), and the authors would also like to thank the MEXT
1
2
9 A. Gunther and K. F. Jensen, Lab Chip, 2006, 6, 1487–1503.
0 M. Kanai, S. Ikeda, J. Tanaka, J. S. Go, H. Nakanishi and
S. Shoji, Sens. Actuators, A, 2004, 111, 32–36.
Nanotechnology Platform Support Project of Waseda University.
References
21 D. H. Yoon, A. Jamshaid, J. Ito, A. Nakahara, D. Tanaka,
T. Akitsu, T. Sekiguchi and S. Shoji, Lab Chip, 2014, 14,
1
2
3
S. Y. Lim, K. H. Hong, D. I. Kim, H. Kwon and H. J. Kim,
J. Am. Chem. Soc., 2014, 136, 7018–7025.
A. Grirrane, A. Corma and H. Garc ´ı a, Science, 2008, 322,
3050–3055.
22 D. Tanaka, D. H. Yoon, T. Sekiguchi, S. Shoji and T. Akitsu,
ISMM 2014, Singapore, 2014, pp. 243–246.
1661–1664.
C. Zhang and N. Jiao, Angew. Chem., 2010, 122, 6310–6313.
This journal is © The Royal Society of Chemistry 2017
RSC Adv., 2017, 7, 39576–39582 | 39581

View Article Online
RSC Advances
Paper
23 D. Tanaka, Y. Murakoshi, E. Tsuda, Y. Mitsumoto, 25 Y. Mitsumoto, N. Sunaga and T. Akitsu, SciFed Journal of
D. H. Yoon, T. Sekiguchi, T. Akitsu and S. Shoji,
Transducers 2015, Alaska, 2015, pp. 243–246.
4 D. Tanaka, W. Kawakubo, E. Tsuda, Y. Mitsumoto,
D. H. Yoon, T. Sekiguchi, T. Akitsu and S. Shoji, RSC Adv.,
Chemical Research, 2017, 1(1), 1–12.
26 H. Zhang and A. Cloud, Global Advances in Materials and
Process Engineering, Coatings and Sealants Section, Dallas,
2006.
2
2016, 6, 81862–81868.
27 A. Mata, A. J. Fleischman and S. Roy, Biomed. Microdevices,
2005, 7(4), 28.
39582 | RSC Adv., 2017, 7, 39576–39582
This journal is © The Royal Society of Chemistry 2017