Synthesis of insoluble polystyrene-supported flavins and their catalysis in aerobic reduction of olefins

Article abstract of DOI:10.1002/pola.28536

2′,4′-p-Vinylbenzylideneriboflavin (2′,4′-PVBRFl) was prepared as a flavin-containing monomer and copolymerized with divinylbenzene and styrene or its p-substituted derivatives such as 4-acetoxystyrene, 4-vinylbenzyl alcohol, and 4-vinylbenzoic acid to give the corresponding non-functionalized and functionalized PS-DVB-supported flavins PS(H)-DVB-Fl, PS(OAc)-DVB-Fl, PS(CH₂OH)-DVB-Fl, and PS(COOH)-DVB-Fl, respectively. PS(OH)-DVB-Fl was also prepared by hydrolysis of PS(OAc)-DVB-Fl under basic conditions. These novel flavin-containing insoluble polymers exhibited characteristic fluorescence in solid state, except PS(OH)-DVB-Fl, and different catalytic activities in aerobic reduction of olefins by in situ generated diimide from hydrazine depending on their pendant functional group. For example, PS(H)-DVB-Fl was found to be particularly effective for neutral hydrophobic substrates, which could be readily recovered by a simple filtration and reused more than 10 times without loss in catalytic activity. On the other hand, PS(OH)-DVB-Fl and PS(COOH)-DVB-Fl proved to be highly active for phenolic substrates known to be less reactive in the reaction with conventional non-supported flavin catalysts.

Full text of DOI:10.1002/pola.28536

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Synthesis of Insoluble Polystyrene-Supported Flavins and
Their Catalysis in Aerobic Reduction of Olefins
1
Yukihiro Arakawa,1 Risa Kawachi,1 Yoshihiko Tezuka,2 Keiji Minagawa,1,3 Yasushi Imada
1Department of Applied Chemistry, Tokushima University, Minamijosanjima, Tokushima 770-8506, Japan
2Department of Optical Science and Technology, Tokushima University, Minamijosanjima, Tokushima 770-8506, Japan
3Institute of Liberal Arts and Sciences, Tokushima University, Minamijosanjima, Tokushima 770-8502, Japan
Correspondence to: Y. Imada (E-mail: imada@tokushima-u.ac.jp)
Received 5 January 2017; accepted 27 January 2017; published online 00 Month 2017
DOI: 10.1002/pola.28536
ABSTRACT: 20,40-p-Vinylbenzylideneriboflavin (20,40-PVBRFl) was
prepared as a flavin-containing monomer and copolymerized
with divinylbenzene and styrene or its p-substituted derivatives
such as 4-acetoxystyrene, 4-vinylbenzyl alcohol, and 4-
vinylbenzoic acid to give the corresponding non-functionalized
and functionalized PS-DVB-supported flavins PS(H)-DVB-Fl,
PS(OAc)-DVB-Fl, PS(CH2OH)-DVB-Fl, and PS(COOH)-DVB-Fl,
respectively. PS(OH)-DVB-Fl was also prepared by hydrolysis
of PS(OAc)-DVB-Fl under basic conditions. These novel flavin-
containing insoluble polymers exhibited characteristic fluores-
cence in solid state, except PS(OH)-DVB-Fl, and different cata-
lytic activities in aerobic reduction of olefins by in situ
generated diimide from hydrazine depending on their pendant
functional group. For example, PS(H)-DVB-Fl was found to be
particularly effective for neutral hydrophobic substrates, which
could be readily recovered by a simple filtration and reused
more than 10 times without loss in catalytic activity. On the
other hand, PS(OH)-DVB-Fl and PS(COOH)-DVB-Fl proved to be
highly active for phenolic substrates known to be less reactive
in the reaction with conventional non-supported flavin cata-
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lysts.
2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A:
Polym. Chem. 2017, 00, 000–000
KEYWORDS: aerobic oxidation; catalysis; flavin; fluorescence;
heterogeneous polymers
fluorinated or hydrophobic aliphatic chains could be immobi-
lized onto solid supports such as fluorous silica gel, reversed
phase silica gel and polyethylene pellet and used them as
reusable heterogeneous photocatalysts for oxidation of ben-
zyl alcohols in water.8 However, since they are noncovalent
immobilizations, it is probably not so easy to apply them to
other reactions requiring organic solvents or additional
reagents without catalyst leaching. Thus, a readily reusable
insoluble polymer-supported flavin catalyst potentially
available for comprehensive reactions has so far not been
developed.
INTRODUCTION Flavoenzymes such as monooxygenase and
DNA photolyase containing flavin cofactors play a pivotal
role in biological redox systems in nature.1 Catalytic func-
tions of these flavoenzymes have inspired chemists to use
the active center, the isoalloxazine ring of flavin cofactors,
for developing simple flavin molecule-catalyzed metal-free
redox reactions for organic synthesis.2 Although various
biomimetic flavin-catalyzed organic reactions have been
reported, they have not yet reached the stage of practical
application. One of the unsolved issues responsible for such
limitation is efficient recovery and reuse of the flavin cata-
lysts. In general, immobilizing catalysts on an insoluble sup-
port can be highly effective since it allows for not only easy
recovery and reusability of the catalysts as well as facile
product isolation but also the development of continuous
flow synthesis.3 Nevertheless, it is surprising that the immo-
bilization of flavin catalysts onto an insoluble support via
covalent bond has remained unexplored so far, although
there have been several reports on the synthesis and appli-
Reduction of olefins is among the most fundamental molecu-
lar transformations in organic synthesis. The most commonly
used method for olefin reduction today is arguably that with
molecular hydrogen catalyzed by a transition metal such as
Pd and Pt because of its high efficiency and reliability, even
though noble metal catalysts and risky H2 gas are required.9
Meanwhile, olefin reduction by diimide, NH 5 NH, is known
as an alternative method where in principle NH 5 NH has to
be generated in situ due to its high lability.10 In this respect,
there is no doubt that hydrazine, NH2NH2, is the most
cation of linear soluble polymer-supported flavins.4–7 Konig
€
and coworkers reported that flavin molecules bearing
Additional Supporting Information may be found in the online version of this article.
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attractive NH 5 NH generator, because it is much cheaper
than other candidates, such as anthracene diimide and aryl-
sulfonylhydrazide,10 and H2O is the sole byproduct of oxida-
tion of NH2NH2 by O2. We previously introduced an efficient
way for the generation of NH 5 NH by the aerobic oxidation
of NH2NH2 with synthetic flavin catalysts, which led us to
the development of a convenient and safe method for the
flavin-catalyzed aerobic reduction of olefins.11 Combination
of the inherent chemoselectivity of diimide reduction10 and
the redox catalytic activity of flavin molecules has allowed
for efficient reduction of various olefins including those not
applicable in typical metal-based hydrogenation under mild
conditions, as demonstrated by us11 and others,12 which is
highly environmentally benign because of utilizing metal-free
organocatalyst (flavin) and nonhazardous terminal oxidant
(O2) and producing nontoxic wastes (N2 and H2O). The
synthetic utility of the flavin-catalyzed olefin reduction fur-
ther led us to develop readily reusable insoluble polymer-
supported flavin catalysts to render it even more practical.
were corrected for the spectral response of the optical system
using quinine bisulfate and N,N-dimethylaminonitrobenzene as
a standard.13 GC analyses were carried out on a Shimazu
GC-2010 by using a DB-1 glass capillary column (0.25 mm 3
30 m).
Materials
Riboflavin (Kanto Chemical), hydroquinone (nacalai tesque), p-
toluenesulfonic acid monohydrate (TsOH•H2O, TCI), dimethyl
2,20-azobis(2-methylpropionate) (MAIB, Wako Chemical),
hydrazine monohydrate (Wako Chemical, nacalai tesque), 4-
phenyl-1-butene (Kanto Chemical), o-allylphenol (Kanto Chem-
ical), DMF (nacalai tesque), and acetonitrile (nacalai tesque)
were commercially available and used without further purifi-
cation. 2,20-Azobis(isobutyronitrile) (AIBN, Wako Chemical)
and 4-vinylbenzoic acid (TCI) were purified by recrystalliza-
tion from methanol. 4-Acetoxystyrene (Sigma Aldrich, Japan)
was purified by washing with 0.1 N sodium hydride and water.
Styrene (nacalai tesque) and divinylbenzene (DVB, Wako
Chemical) were purified by distillation under reduced pres-
sure. 4-Vinylbenzaldehyde diethyl acetal14 and 4-vinylbenzyl
alcohol15 were prepared according to the reported procedure.
In this article, we present the first insoluble organic polymer-
supported flavins and their use as an efficient and reusable
catalyst for aerobic reduction of olefins with hydrazine. We
have chosen poly(styrene-co-divinylbenzene) (PS-DVB) as a
support, because the corresponding polymeric catalysts can be
designed from comonomers and easily prepared by radical
copolymerization.3 We initially show the synthesis of new
flavin-containing styrene monomer, 20,40-O-p-vinylbenzilidene
riboflavin (20,40-PVBRFl), and then its radical copolymeriza-
tion with divinylbenzene and styrene or p-functionalized sty-
rene derivatives to prepare poly(styrene-co-divinylbenzene-
co-20,40-PVBRFl) (PS(R)-DVB-Fl) bearing a different pendant
group (R). Finally, we detail the catalytic activities as well as
reusability of PS(R)-DVB-Fl in aerobic reduction of olefins
with hydrazine.
Synthesis of 20,40-PVBRFl
Riboflavin (225 mg, 0.60 mmol), p-TsOH•H2O (114 mg, 0.60
mmol), and hydroquinone (0.4 mg, 3.6 lmol) were placed in
a heat-gun-dried 50 mL round bottom flask under a nitrogen
atmosphere. DMF (12 mL) and 4-vinylbenzaldehyde diethyl
acetal (309 mg, 1.5 mmol) were added, and the solution was
stirred for 3 h at 80 8C. The reaction mixture was diluted
with ethyl acetate (50 mL) and washed with water (3 3
30 mL). The aqueous layer was extracted with ethyl acetate
(3 3 30 mL), and the combined organic layers were dried
over MgSO4, which was filtered and concentrated under
reduced pressure. The resulting crude product was purified
by flash column chromatography on silica gel using a mix-
ture of MeOH:EtOAc 6:94 as eluent to afford 163 mg of
20,40-PVBRFl as yellow powder (56%): M.p. 180 8C
(decomp.); 1H NMR (600 MHz, DMSO-d6, d): 2.38 (s, 3H, 7-
CH3), 2.45 (s, 3H, 8-CH3), 3.45-3.53 (m, 1H, 30-CH), 3.55 (dt,
J 5 12, 5.9 Hz, 1H, 50-CH), 3.64 (ddd, J 5 9.6, 6.0, 1.6 Hz, 1H,
40-CH), 3.75 (ddd, J 5 11, 6.0, 1.5 Hz, 1H, 50-CH), 4.16 (ddd,
J 5 9.6, 7.5, 2.6 Hz, 1H, 20-CH), 4.68 (t, J 5 5.8 Hz, 1H, 50-OH),
4.76-4.94 (br, 1H, 10-CH), 5.11-5.23 (br, 1H, 10-CH), 5.23 (dd,
J 5 10.8, 0.6 Hz, 1H, -C 5 CH), 5.50 (s, 1H, -OCHO-), 5.64 (d,
J 5 5.4 Hz, 1H, 30-OH), 5.81 (dd, J 5 18, 0.6 Hz, 1H, -C 5 CH),
6.68 (dd, J 5 10.8, 17.4 Hz, 1H, -CH 5 C), 7.21 (d, J 5 8.4 Hz,
2H, m-H), 7.35 (d, J 5 7.8 Hz, 2H, o-H), 7.81 (s, 1H, 6-ArH),
8.01 (s, 1H, 9-ArH), 11.35 ppm (s, 1H, NH); 13C NMR (151
MHz, DMSO-d6, d): 18.7, 20.6, 46.2, 60.7, 63.3, 78.5, 81.8,
99.0, 114.7, 118.1, 125.4, 126.3, 130.4, 132.0, 133.7, 135.7,
136.1, 137.1, 137.2, 137.4, 145.6, 150.6, 155.3, 159.8 ppm;
IR (ATR): v 5 3491, 3322, 3162, 3012, 2829, 1716, 1650,
1574, 1532, 1497, 1421, 1402, 1349, 1259, 1226, 1180,
EXPERIMENTAL
General
Melting points were measured on an AS ONE ATM-01. NMR
spectra were recorded using a JEOL JNM-ECX-400 (1H, 400
MHz) and JNM-ECA-400 spectrometers (1H, 400 MHz) or a
Varian Unity-Inova 600 spectrometer (1H, 600 MHz and 13C,
151 MHz). The chemical shifts of 1H NMR and 13C NMR signals
are quoted relative to tetramethylsilane. IR spectra were
recorded on a JASCO IR-460 spectrometer with ATR unit. UV
spectra were recorded on JASCO V-550 spectrometer. Steady-
state emission and excitation spectra were recorded using a
Hitachi F-7000 spectrometer. The solid-state emission quantum
yield was measured using a BaSO4-coated integrating sphere
(69 mm internal diameter) with an exit port (20 mm diameter)
connected to a polychromator (Photal MCPD-1000), image
intensifier (Hamamatsu Photonics, C7039-02), and dual-cooled
CCD camera (Hamamatsu Photonics, C4880-17). Excitation ray
for solid-state emission was a diode laser (Coherent, Radius
405) or a high stability mercury xenon lamp (Hamamatsu
1132, 1082, 1011, 833 cm21
(e) 5 264 (34344), 360 (6351), 444 nm (8898); Fluorescence
Photonics, L2422) coupled with a monochromator (Photon emission: kmax (solid) 5 556 nm (kex 5 442 nm), kmax
; UV–vis (ethanol): kmax
Technology International, Model 101). All emission spectra
(ethanol) 5 516 nm (kex 5 442 nm); MS (DART): m/z 491.1
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([M 1 H] 1); Anal. calcd. for C26H26N4O6: C 61.41, H 5.55, N
11.02; found: C 61.58, H 5.42, N 11.09.
extractor and dried in vacuo to give 207 mg of poly(20,40-PVBRFl-
co-4-vinylbenzyl alcohol-co-DVB) (PS(CH2OH)-DVB-Fl) as yellow
solid (48%). The content of flavin unit in polymer was calculated
to be 0.15 mmol g21 based on the elemental analysis data: Anal.
Found: C 77.36, H 7.40, N 0.85; Fluorescence emission (solid):
Preparation of PS(H)-DVB-Fl
20,40-PVBRFl (39 mg, 0.08 mmol), styrene (367 mg, 3.52
mmol), DVB (52 mg, 0.40 mmol), and MAIB (18 mg, 0.08
mmol) was dissolved in DMF (2 mL) in a screw tube (18
mmID). The mixture was bubbled with nitrogen for 1 min
and stirred at 65 8C for 25 h under nitrogen atmosphere.
The resulting yellow gel was poured into ether and crushed,
then washed with ether, THF, and methanol by means of
Soxhlet extractor and dried in vacuo to give 214 mg of poly
(20,40-PVBRFl-co-St-co-DVB) (PS(H)-DVB-Fl) as yellow solid
(58%). The content of flavin unit in polymer was calculated
to be 0.12 mmol g21 based on the elemental analysis data:
Anal. Found: C 88.82, H 7.81, N 0.69; M.p. 180 8C (decomp.);
Fluorescence emission (solid): kmax 5 539 nm (kex 5 405 nm);
IR (ATR): v 5 3060, 3026, 2921, 2852, 1601, 1584, 1547,
1493, 1451, 756, 696, 541 cm21. Particle size of the polymer
was controlled by grinding and sieving prior to use as catalyst.
k
max 5 553 nm (kex 5 405 nm); IR (ATR): v 53322, 2921, 1540,
1511, 1419, 1211, 1011, 806 cm21. Particle size of the polymer
was controlled by grinding and sieving prior to use as catalyst.
Preparation of PS(COOH)-DVB-Fl
20,40-PVBRFl (39 mg, 0.08 mmol), 4-vinylbenzoic acid (527 mg,
3.56 mmol), DVB (52 mg, 0.40 mmol) and MAIB (18 mg, 0.08
mmol) was dissolved in DMF (2 mL) in a screw tube (18
mmID). The mixture was bubbled with nitrogen for 1 min and
stirred at 65 8C for 10 h under nitrogen atmosphere. The result-
ing yellow gel was poured into ether and crushed, then washed
with ether, THF, and methanol by means of Soxhlet extractor
and dried in vacuo to give 466 mg of poly(20,40-PVBRFl-co-4-
vinylbenzoic acid-co-DVB) (PS(COOH)-DVB-Fl) as yellow solid
(76%). The content of flavin unit in polymer was calculated to
be 0.13 mmol g21 based on the elemental analysis data: Anal.
Found: C 68.92, H 6.03, N 0.74; Fluorescence emission (solid):
Preparation of PS(OAc)-DVB-Fl
20,40-PVBRFl (78 mg, 0.16 mmol), 4-acetoxystyrene (1.14 g,
7.04 mmol), DVB (104 mg, 0.80 mmol) and AIBN (26 mg, 0.16
mmol) was dissolved in DMF (4 mL) in a screw tube (18
mmID). The mixture was bubbled with nitrogen for 1 min and
stirred at 65 8C for 18 h under nitrogen atmosphere. The result-
ing yellow gel was poured into ether and crushed, then washed
with ether, THF, and methanol by means of Soxhlet extractor
and dried in vacuo to give 869 mg of poly(20,40-PVBRFl-co-4-ace-
toxystyrene-co-DVB) (PS(OAc)-DVB-Fl) as yellow solid (65%).
The content of flavin unit in polymer was calculated to be 0.18
mmol g21 based on the elemental analysis data: Anal. Found:
C 74.73, H 6.46, N 0.98; Fluorescence emission (solid):
k
max 5 555 nm (kex 5 405 nm); IR (ATR): v 52921, 1684,
1608, 1576, 1540, 1507, 1419, 1240, 1177, 1105, 1017, 853,
803, 775, 705 cm21. Particle size of the polymer was controlled
by grinding and sieving prior to use as catalyst.
Typical Procedure for Aerobic Reduction of Olefins
Catalyzed by PS(R)-DVB-Fl
Hydrazine monohydrate (19 mg, 375 lmol) and acetonitrile
(0.7 mL) was mixed for 1 min under vigorous stirring. To the
mixture was added PS(R)-DVB-Fl (3.75 lmol, 3 mol %), an ole-
fin (125 lmol), and acetonitrile (0.3 mL), which was stirred at
30 8C for 14 h under air. The reaction yield was determined by
either GC analysis with absolute calibration or NMR measure-
ment using 1,3,5-trimethoxybenzene as an internal standard.
k
max 5 537 nm (kex 5 405 nm); IR (ATR): v 5 2923, 2849, 1754,
1505, 1367, 1130, 1186, 1164, 1014, 909, 844, 552 cm21
.
Preparation of PS(OH)-DVB-Fl
Reuse Test of PS(H)-DVB-Fl in Aerobic Reduction
of 4-Phenyl-1-Butene
A mixture of PS(OAc)-DVB-Fl (900 mg) and NH2NH2•H2O
(1.02 g, 20.3 mmol) in DMF (20 mL) was stirred at 30 8C for 3 h
in a screw tube (18 mmID). The resulting orange gel was poured
into water and crushed, then washed with water, methanol, and
ether by means of Soxhlet extractor and dried in vacuo to give
321 mg of poly(20,40-PVBRFl-co-4-hydroxystyrene-co-DVB)
(PS(OH)-DVB-Fl) as orange solid. The content of flavin unit in
polymer was estimated to be 0.18 mmol g21 because of quanti-
tative conversion judged by FTIR analysis: IR (ATR): v 5 3329,
3024, 2915, 1611, 1540, 1509, 1444, 1363, 1225, 1171, 1013,
905, 825 cm21. Particle size of the polymer was controlled by
grinding and sieving prior to use as catalyst.
A glass reactor with Teflon filter (MultiSynTech, V050TF118)
equipped with a Luer stopper (MultiSynTech, V000LS100) was
charged with PS(H)-DVB-Fl (61 mg, 7.4 lmol), 4-phenyl-1-
butene (33 mg, 0.25 mmol), NH2NH2•H2O (38 mg, 0.75 mmol),
and acetonitrile (2 mL). The mixture was agitated using a shaker
(125 rpm) at 30 8C under air. The reaction was monitored by GC
analysis. The reaction mixture was directly filtered from the glass
reactor and the remaining PS(H)-DVB-Fl was washed with ace-
tonitrile, THF, and ether, which was reused for the next reaction.
RESULTS AND DISCUSSION
Synthesis of Flavin-Containing Styrene Monomer
Preparation of PS(CH2OH)-DVB-Fl
20,40-PVBRFl (39 mg, 0.08 mmol), 4-vinylbenzyl alcohol
(477 mg, 3.56 mmol), DVB (52 mg, 0.40 mmol) and MAIB
(18 mg, 0.08 mmol) was dissolved in DMF (2 mL) in a screw tube
(18 mmID). The mixture was bubbled with nitrogen for 1 min
and stirred at 65 8C for 36 h under nitrogen atmosphere. The
resulting yellow gel was poured into ether and crushed, then
washed with ether, THF, and methanol by means of Soxhlet
Riboflavin (Vitamin B2) is readily available in commerce and
its diacetalized derivatives, such as 20,40:30,50-di-O-methylener-
iboflavin (DMRFl), have previously proven to be an active cat-
alyst for aerobic reduction of olefins with hydrazine (Fig.
1).11(b,c) Taking this into account, we decided to use riboflavin
as a starting material and introduce a styrene moiety to its
ribityl group through the 20,40- or 30,50-acetal linkage.
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FIGURE 1 Structures of riboflavin and DMRFl.
Such partial acetalization of the ribityl group often encounters
a synthetic problem even through its protection and deprotec-
tion. For example, Yashima and coworkers synthesized 20,40-O-
p-ethynylbenzilidene riboflavin as a monomer by the reaction
of 50-O-trityl riboflavin and 4-ethynylbenzaldehyde dimethyl
acetal followed by the deprotection of the trityl group in 11%
yield.7 By contrast, we found that riboflavin could be readily
converted into 20,40-PVBRFl and its 30,50-analogue in a ratio of
approximately 2:1 with a trace amount of diacetalized product
by treating with 2.5 equiv of 4-vinylbenzaldehyde diethyl ace-
tal and 1 equiv of TsOH•H2O in DMF at 80 8C for 3 hours, which
could be separated by a column purification to give 20,40-
PVBRFl in 56% yield (eq 1). The selective formation of 20,40-
PVBRFl can be probably explained by transacetalization–
SCHEME 1 Synthesis of PS(H)-DVB-Fl.
Functionalized PS-DVB-Supported Flavins
The choice of support polymer is crucial for developing effi-
cient polymer-supported catalysts since the catalytic reac-
tions take place in microenvironment created in the polymer
network.3 In view of the fact that the catalysis of neutral fla-
vin for the aerobic reduction of olefins involves the nucleo-
philic reduction of a flavin molecule with hydrazine as a
rate-determining step,11(c) PS-DVB was supposed to be too
hydrophobic as a support for the target reaction because of
the strong hydrophilicity of hydrazine. Thus, we designed
additional three polymeric flavins PS(CH2OH)-DVB-Fl,
PS(OH)-DVB-Fl, and PS(COOH)-DVB-Fl containing different
hydrophilic pendant groups in PS-DVB. 4-Vinylbenzyl alcohol,
4-acetoxystyrene or 4-vinylbenzoic acid was copolymerized
with divinylbenzene and 20,40-PVBRFl in the molar ratio of
88:10:2 under radical conditions to afford PS(CH2OH)-DVB-
Fl, PS(OAc)-DVB-Fl, and PS(COOH)-DVB-Fl, respectively, in
moderate to high yields (Scheme 2). The acetyl groups in
hydrolysis equilibria that results in thermodynamically more
stable 20,40-PVBRFl having a freely rotatable primary alcohol
group. The structure of 20,40-PVBRFl was fully characterized
by NMR (1H, 13C, COSY, HMBC, HMQC, ROESY), FTIR, mass
spectroscopy, and elemental analysis.
Synthesis of Flavin-Containing Cross-Linked Polystyrenes
PS-DVB-Supported Flavin
We carried out radical copolymerization of styrene, divinylben-
zene, and 20,40-PVBRFl in the molar ratio of 88:10:2 using MAIB
as an initiator under heating and inert conditions (Scheme 1).
The copolymerization proceeded successfully, which was recog-
nized by gelation of the reaction mixture, to give PS-DVB-
supported flavin (PS(H)-DVB-Fl) in 58% yield after washing
with ether, THF, and methanol, followed by drying in vacuo. The
flavin loading of PS(H)-DVB-Fl was calculated to be 0.12 mmol
g
21 from its nitrogen content determined by elemental analysis.
In addition, the actual CHN content of PS(H)-DVB-Fl was in good
agreement with the theoretical value, indicating that the present
copolymerization took place according to the feed molar ratio.
SCHEME 2 Synthesis of PS(OAc)-DVB-Fl, PS(OH)-DVB-Fl,
PS(CH2OH)-DVB-Fl, and PS(COOH)-DVB-Fl.
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PS(OAc)-DVB-Fl were quantitatively hydrolyzed by a treat-
ment with an excess of hydrazine in DMF to give PS(OH)-DVB-
Fl, which was confirmed by IR spectroscopic data that showed
the disappearance of C 5 O absorbance at 1754 cm21 and the
appearance of –OH absorbance at 3329 cm21. The flavin load-
ings of PS(CH2OH)-DVB-Fl, PS(OAc)-DVB-Fl, and PS(COOH)-
DVB-Fl were estimated to be 0.15, 0.18, and 0.13 mmol g21
,
respectively, through elemental analyses.
Photophysical Properties of PS(R)-DVB-Fl
Flavins exhibit a characteristic absorption at ꢀ440 nm with
high molar absorptivities as well as an intense fluorescence
emission at ꢀ520 nm in solution state.1(g) Indeed, 0.1 mM
solution of 20,40-PVBRFl in ethanol emitted a bright light
under irradiation by a range of UV/Vis lights less than
ꢀ500 nm, and its fluorescence spectrum measured with an
excitation wavelength of 442 nm showed the maximum
emission peak (kmax) at 516 nm (Supporting Information Fig.
S9). Not surprisingly, the fluorescence peak of 20,40-PVBRFl
in solid state appeared at a slightly longer wavelength
(kmax 5 556 nm) with much lower intensity, due to concen-
tration quenching (Supporting Information Fig. S9). On the
other hand, the flavin-containing polymers including PS(H)-
DVB-Fl, PS(OAc)-DVB-Fl, and PS(COOH)-DVB-Fl were found
to emit light apparently in solid state under 365 nm UV light,
except PS(OH)-DVB-Fl (Fig. 2), which led us to explore their
emission properties in more detail. We carried out fluores-
cence measurements for all kinds of PS(R)-DVB-Fl in solid
state and determined their solid-state fluorescence quantum
FIGURE 3 Solid-state fluoresence spectra of PS(R)-DVB-Fl
(kex 5 405 nm). [Color figure can be viewed at wileyonlinelibrary.
com]
yield (/). As expected, a distinct fluorescence emission at
ꢀ550 nm was observed for PS(H)-DVB-Fl (kmax 5542 nm,
/ 5 10.6%), PS(OAc)-DVB-Fl (kmax 5 542 nm, / 5 16.5%),
PS(CH2OH)-DVB-Fl (kmax 5 552 nm, / 5 10.1%), and
PS(COOH)-DVB-Fl (kmax 5 552 nm, / 5 9.3%) using a 405-nm
excitation wavelength (Fig. 3), which would indicate that the
immobilized flavin molecules were distributed to the polymer
network rather homogeneously. By contrast, PS(OH)-DVB-Fl
exhibited almost no fluorescence emission. This is at least not
due to heterogeneous dispersion of flavins into the polymer,
given the fact that PS(OAc)-DVB-Fl showed the intense fluo-
rescence as mentioned above. Although a clear explanation for
the non-fluorescence of PS(OH)-DVB-Fl is not available at the
moment, we find it interesting because it may be caused by
some interactions between the immobilized flavin molecule
and phenolic hydroxyl groups, just like the situation in
flavoenzyme.16
Flavin-Catalyzed Aerobic Reduction of Olefins
Aerobic reductions of olefins were carried out with 3 equiv
of hydrazine monohydrate in acetonitrile under air at 30 8C
in the presence of 3 mol % of PS(R)-DVB-Fl under heteroge-
neous conditions to evaluate their catalytic activity, in which
the polymeric catalysts were ground and sieved to a defined
range of particle size prior to use (eq 2).
The reduction of 4-phenyl-1-butene (1a) using PS(H)-DVB-Fl
with particle size of 53–100 lm proceeded smoothly to give
butylbenzene (2a) in 86% yield and 98% yield after 24 and
48 h, respectively [Fig. 4(b), Run 1], in which a filter-equipped
glass reactor was used to operate the following catalyst recy-
cling process as efficient as possible [Fig. 4(a)].17 Solution
phase of the reaction mixture was filtered out and analyzed by
GC, whereas the residual solid catalyst was washed with
FIGURE 2 Photographs of PS(R)-DVB-Fl under room light or
UV irradiation (365 nm). [Color figure can be viewed at
wileyonlinelibrary.com]
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the effectiveness of PS(H)-DVB-Fl as a readily reusable as well
as highly active catalyst for the present reaction.
Next, we explored the catalytic functions of PS(CH2OH)-
DVB-Fl, PS(OH)-DVB-Fl, and PS(COOH)-DVB-Fl, which were
expected to be more effective than PS(H)-DVB-Fl as a cata-
lyst because of their amphiphilic properties. However, the
reduction of 1a to 2a catalyzed by any one of these function-
alized polymers with particle size of ꢁ53 lm was not com-
pleted even after 24 h (Table 1, Entries 2–4), while PS(H)-
DVB-Fl could efficiently catalyze the reaction (Entry 1) as
mentioned. Similar tendency in catalytic activity was
observed in the reduction of another simple olefin, ethyl 10-
undecanoate (1b), using PS(H)-DVB-Fl (Entry 6, 14 h, 96%)
and PS(OH)-DVB-Fl (ently 7, 14 h, 61%). The amphiphilicity
of the acid-functionalized polymers could actually be recog-
nized by apparent aggregation of the polymer particles in
the reaction mixtures containing an excess of hydrophilic
hydrazine. Nevertheless, only PS(H)-DVB-Fl, which is strong-
ly hydrophobic and therefore not aggregated, showed
extremely high activity, indicating that particle size is a more
crucial factor for reaction efficiency in this case. It is impor-
tant to note that, at least for the reduction of 1a, the catalyt-
ic functions of PS(CH2OH)-DVB-Fl, PS(OH)-DVB-Fl, and
PS(COOH)-DVB-Fl are not as excellent as PS(H)-DVB-Fl, but
still comparable with a homogeneous flavin catalyst, DMRFl
(Entry 5), despite their heterogeneity. This fact may be
explained by site-isolation effect of the flavin-containing
insoluble polymers in which each flavin molecule is isolated
from others, that is to say, redoxes of them do not affect
each other.
FIGURE 4 Aerobic reduction of 1a catalyzed by PS(H)-DVB-Fl:
(a) reaction and recycling protocol, (b) reusability of 1a (Run
1–11, 48 h; Run 12, 24 h; Run 13, 8 h). [Color figure can be
viewed at wileyonlinelibrary.com]
To use the acid-functionalized PS-DVB-supported flavins
effectively, we turned our attention to substrates bearing a
phenolic hydroxyl group. Given the fact that the rate-
determining step of the neutral flavin-catalyzed aerobic
reduction is the nucleophilic addition of hydrazine to fla-
vin,11(c) one can expect that such acidic substrates can be
unfavorable to the reaction system due to acid-base interac-
tion that lowers the nucleophilicity of hydrazine. Indeed, in
homogeneous reaction system with DMRFl as a catalyst, o-
allylphenol (1c) and p-vinylphenol (1d) underwent reduction
very slowly to give o-propylphenol (2c) and p-ethylphenol
(2d) in 19% yield (36 h, Entry 11) and in 4% yield (24 h,
Entry 15), respectively. On the other hand, our polymer-
supported flavin catalysts were found to exhibit significantly
higher activity for these acidic olefins than DMRFl. Particu-
larly effective were PS(OH)-DVB-Fl as well as PS(COOH)-
DVB-Fl over PS(H)-DVB-Fl. For example, the reduction of 1c
was catalyzed to furnish 2c in 42% (PS(H)-DVB-Fl, Entry 8),
72% (PS(OH)-DVB-Fl, Entry 9), and 76% yield (PS(COOH)-
DVB-Fl, Entry 10), respectively, after 36 h. An even more
distinct advantage of these acid-functionalized polymeric fla-
vins was observed in the reduction of 1d, which was con-
verted to 2d in 27% (PS(H)-DVB-Fl, Entry 12), 70%
(PS(OH)-DVB-Fl, Entry 13), and >99% yield (PS(COOH)-
DVB-Fl, Entry 14), respectively, after 24 h. These results
demonstrate that the acid-functionalized polymeric flavins
acetonitrile, THF, and ether, and dried in vacuo, and reused
[Fig. 4(a)]. Using this simple protocol, the excellent chemical
robustness and reusability of PS(H)-DVB-Fl could be demon-
strated [Fig. 4(b)]. Reactions from the 1st run to the 6th run
were carried out successively, in which quantitative yields of
2a were observed without exception. After the 6th run, the
reused polymeric flavin catalyst was preserved in a UV-
shielding amber desiccator for 3 months, and then the reuse
test was restarted to evaluate the storage stability of PS(H)-
DVB-Fl. The 7th run demonstrated that the catalytic activity
was not affected by the storage, which led us to further contin-
ue the reuse test until the 11th run under the same conditions.
In the 12th run, we were finally aware of complete conversion
of 1a to 2a within 24 h, which was much faster than the reac-
tion using a fresh catalyst in the 1st run. Earlier monitoring of
the reaction in the 13th run revealed that the reaction was
completed already in 8 h. We supposed that this considerable
enhancement of the catalytic activity could be attributed to
increasing in the surface area of the solid catalyst as the reac-
tions were repeated. To confirm this assumption, we freshly
prepared PS(H)-DVB-Fl with particle size of ꢁ53 lm by care-
ful grinding and sieving, and used it as a catalyst for the same
reaction under identical conditions. As expected, nearly quan-
titative yield was observed in 9 h (Table 1, Entry 1), verifying
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TABLE 1 Flavin-Catalyzed Aerobic Reduction of Olefinsa
Entry
Substrate
Product
Catalystb
Time (h)
Yield (%)c
1
2
3
4
5
6
1a
1a
1a
1a
1a
2a
2a
2a
2a
2a
PS(H)-DVB-Fl
PS(CH2OH)-DVB-Fl
PS(OH)-DVB-Fl
PS(COOH)-DVB-Fl
DMRFl
9
95
68
76
61
56
96
24
24
24
24
14
PS(H)-DVB-Fl
7
8
1b
2b
PS(OH)-DVB-Fl
PS(H)-DVB-Fl
14
36
61
42
9
1c
1c
1c
2c
2c
2c
PS(OH)-DVB-Fl
PS(COOH)-DVB-Fl
DMRFl
36
36
36
24
72
76
19
27
10
11
12
PS(H)-DVB-Fl
13
14
15
1d
1d
1d
2d
2d
2d
PS(OH)-DVB-Fl
PS(COOH)-DVB-Fl
DMRFl
24
24
24
70
>99
4
a
b
c
Reactions were performed using 125 lmol of the olefin and 375 lmol
of hydrazine monohydrate in 1 mL of acetonitrile in the presence of
3 mol % of the catalyst under air at 30 8C.
Polymeric catalysts with particle size of ꢁ53 lm were used.
Determined by GC analysis (Entries 1–5) or 1H NMR measurement
(Entries 6–15) with internal standard.
are highly effective catalysts for the present aerobic reduc-
tion of olefins bearing a phenolic hydroxy group. This finding
can be explained by the high affinity of these flavin polymers
for hydrazine via acid-base interaction, which can make the
concentration of hydrazine on solid phase higher and that in
solution phase lower, and as a result, the rate-determining
nucleophilic addition of hydrazine to flavin favorable. Finally,
it should also be noted that, in the reduction of 1d to 2d,
PS(COOH)-DVB-Fl could be reused without loss in the activ-
ity at least 3 times (see Supporting Information).
the reaction unlike with the acid-functionalized PS-DVB-sup-
ported flavins, (iii) the acid functionalized PS-DVB-
supported flavins such as PS(OH)-DVB-Fl and PS(COOH)-
DVB-Fl have an enhanced affinity for hydrazine, which
allows for efficiently catalyzing the reduction of phenolic
hydroxyl group-containing olefins known as less reactive
substrates in conventional homogeneous system. Efficient
catalyst recovery and reuse were demonstrated with PS(H)-
DVB-Fl that could be readily recovered by a simple filtration
and reused without loss in activity at least until 13th run.
The results are currently leading us to the synthesis of
morphology-controlled flavin-containing insoluble polymers,
such as microspheres and mesoporous network polymers,
using other polymerization techniques, and their application
to the development of a continuous flow system for the pre-
sent aerobic reduction.
CONCLUSIONS
We introduced a novel flavin-containing vinyl monomer,
20,40-PVBRFl, and its copolymers, PS(R)-DVB-Fl, as efficient
and reusable heterogeneous catalysts for aerobic reduction
of olefins with hydrazine. The monomer was easily synthe-
sized from commercially available riboflavin in one step,
and the polymeric catalysts were readily prepared by free
radical solution copolymerization. Exploring the catalytic
activities of PS(R)-DVB-Fl in aerobic reduction of olefins
with hydrazine revealed that (i) PS(R)-DVB-Fl exhibit com-
parable activities to the non-supported counterpart DMRFl,
possibly because of flavin molecules dispersedly immobi-
lized onto supports as demonstrated by their characteristic
solid-state fluorescence, (ii) the non-functionalized PS-DVB-
supported flavin, PS(H)-DVB-Fl, is particularly effective for
aprotic substrates, which can be attributed to its strong
hydrophobicity not allowing for aggregation of itself during
ACKNOWLEDGEMENTS
This work was supported by Grant-in-Aid for Scientific
Research on Innovative Areas ‘Advanced Molecular Transfor-
mations by Organocatalysts0 from MEXT.
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