Aggregation-induced Substrate Specificity in Aerobic Reduction of Olefins with Ultrasound Gel Catalyst of Synthetic Flavin

Article abstract of DOI:10.1002/cctc.201801837

A riboflavin derivative bearing octadecanoyl functionalities 1 a gelatinizes a variety of organic solvents upon brief ultrasonication in an organic fluid. The rate of gelation with 1 a can be externally and precisely controlled by tuning the sonication time and type of solvent. The present ultrasound gel exhibits unprecedented substrate specificity for the catalytic aerobic reduction of olefins, which can be performed with hydrazine at ambient temperature and atmospheric pressure in air. The reaction rates of 1-dodecene (2), allylbenzene (3), and o-allylphenol (4) with the ultrasound gel 1 a catalyst is in the order of 2?3>4, the substrate specificity of which is in contrast to the almost non-specificity with the non-gelled catalyst 1 b bearing butanoyl functionalities, and entirely inverse specificity with a flavin-dendrimer association catalyst (2<3<4). Based on kinetic studies, the aggregation effects on the substrate specificity have been ascribed to the specific inclusion of aliphatic olefins into the enzyme-like artificial cavities of the gel catalysts.

Full text of DOI:10.1002/cctc.201801837

Accepted Article
Title: Aggregation-induced Substrate Specificity in Aerobic Reduction
of Olefins with Ultrasound Gel Catalyst of Synthetic Flavin
Authors: Soichiro Kawamorita, Misa Fujiki, Zimeng Li, Takahiro
Kitagawa, Yasushi Imada, and Takeshi Naota
This manuscript has been accepted after peer review and appears as an
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To be cited as: ChemCatChem 10.1002/cctc.201801837
Link to VoR: http://dx.doi.org/10.1002/cctc.201801837
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ChemCatChem
10.1002/cctc.201801837
FULL PAPER
Aggregation-induced Substrate Specificity in Aerobic Reduction
of Olefins with Ultrasound Gel Catalyst of Synthetic Flavin
[
a]
[a]
[a]
[a]
[a,b]
Soichiro Kawamorita, Misa Fujiki, Zimeng Li, Takahiro Kitagawa, Yasushi Imada
Naota*[a]
and Takeshi
Abstract:
A
riboflavin derivative bearing octadecanoyl
that bear enzyme-like reaction cavities that are
circumferentially arranged at the catalytically active center of
functionalities 1a gelatinizes a variety of organic solvents upon
1
3
brief ultrasonication in an organic fluid. The rate of gelation with
a hydroperoxy flavin. Catalytic activities for the oxidation of
sulfides,1
3c,15,16,17
and 1-benzyl-1,4-dihydronicotinamide,
14
1a can be externally and precisely controlled by tuning the
sonication time and type of solvent. The present ultrasound gel
exhibits unprecedented substrate specificity for the catalytic
aerobic reduction of olefins, which can be performed with
hydrazine at ambient temperature and atmospheric pressure in
air. The reaction rates of 1-dodecene (2), allylbenzene (3), and o-
allylphenol (4) with the ultrasound gel 1a catalyst is in the order of
Baeyer-Villiger oxidation of cyclic ketones,15 and
hydrogenation of olefins13a,b,16 are reportedly enhanced by
employing synthetic flavin catalysts that have been modified
covalently1
4,15,16,17
and non-covalently with dendrimers,
13
13,14
tripeptides,15 Au nanoparticles,16 and cyclodextrins17 that
mimic enzymatic reaction sites.
2
>> 3 > 4, the substrate specificity of which is in contrast to the
This work deals with a low molecular weight gel that
consists of synthetic riboflavin derivative 1a bearing
octadecanoyl functionalities with an aim to develop new
almost non-specificity with the non-gelled catalyst 1b bearing
butanoyl functionalities, and entirely inverse specificity with a
flavin-dendrimer association catalyst (2 < 3 < 4). Based on kinetic
studies, the aggregation effects on the substrate specificity have
been ascribed to the specific inclusion of aliphatic olefins into the
enzyme-like artificial cavities of the gel catalysts.
supramolecular
organocatalysts18
that
bear
more
1
sophisticated enzymatic functions of substrate specificity.
Brief ultrasonication of a homogeneous solution of 1a forms a
supramolecular gel19 that exhibits high catalytic activity with
significant substrate specificity for the aerobic hydrogenation
of olefins13,20 under mild conditions including atmospheric
pressure of O
2
[Eq. (1)]. Clear substrate specificity for
Introduction
aliphatic olefins has been observed with the ultrasound gel
catalysts. This provides a high range of specificity control with
supramolecular synthetic flavin catalysts, in connection with
the contrasting specificity for aromatic olefins observed with
the flavin-dendrimer association catalysts, both of which have
been newly described here as a typically comparable case.
We describe the full details of the characterization of the
supramolecular flavin catalysts, with focus on the ultrasound-
induced aggregation behavior and substrate specific catalytic
activity for the aerobic reduction of olefins in air under mild
conditions.
The development of synthetic transformations that exhibit
controllable substrate specificity is a challenging theme in
organic chemistry, the aim of which is the substitution of
enzymatic reactions with artificial organic catalysis.1 One
important way to open up such new chemistry is the rational
design of an organic catalyst that bears artificial enzyme-like
reaction sites and cavities, which can be tunable for different
types of specificity. Substrate-specific reactions have been
performed with various catalysts that bear the inclusion
properties of crown ethers,2 cyclodextrins,3 bowl-shaped
metal complexes,4 cage-shaped multinuclear complexes,5
metal organic frameworks,6 and porous materials such as
7
,8 and heteropolyacids.9
silicas, CeO
2
As part of our program aimed at the development of
novel enzyme-like catalytic processes that exhibit high
sustainability and specificity, we are investigating the
simulation of enzymatic functions of flavin-containing
1
0
11
12
oxygenases and oxidases with synthetic flavin catalysts.
One of our major interests is to create novel flavin catalysts
[
[
a]
b]
S. Kawamorita, M. Fujiki, Z. Li, T. Kitagawa, Prof. Y. Imada, Prof. T.
Naota
Department of Chemistry, Graduate School of Engineering Science,
Osaka University
Machikaneyama, Toyonaka, Osaka 560-8531 (Japan)
E-mail: naota@chem.es.osaka-u.ac.jp
Present address
Results and Discussion
Ultrasound-induced gelation with riboflavin derivative:
Prof. Y. Imada
When a homogeneous clear solution of riboflavin derivative
Department of Chemical Science and Technology, Institute of
Technology and Science, The University of Tokushima
Minamijosanjima, Tokushima 770-8506 (Japan)
1a with four octadecanoyl groups in various organic solvents
was irradiated with brief ultrasound waves, the solution was
converted into the gel state. Typically, sonication (45 kHz,
2
–2
0
.38 W/cm ) of a 1.5×10 M solution of 1a in butanenitrile for
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ChemCatChem
10.1002/cctc.201801837
FULL PAPER
30 s and subsequent standing at 298 K for 5 min gave an
entirely opaque gel, as shown in Figure 1. In the absence of
sonication, the same solution remained stable at ambient
temperature and finally gave a precipitation of amorphous
microsolids after standing overnight under the same
conditions. The minimum gelation concentration (MGC) of 1a
in butanenitrile was determined to be 3.3×10–3 M under the
2
sonication conditions (45 kHz, 0.38 W/cm , 30 s). Solutions of
1
a in various solvents, such as 1-propanol (MGC: 8.0×10–3
M), 1-butanol (MGC: 8.0×10–3 M), 1-hexanol (MGC: 4.5×10
–2
–
2
M), ethyl acetate (MGC: 8.6×10 M), and cyclohexane
–
2
(
MGC: 5.1×10 M), also gelled under the same sonication
conditions, while solutions in other solvents such as
chloroform, 1,4-dioxane, ethanol, and benzene did not form
gels, irrespective of the solution concentration and sonication
time. Analogues 1b and 1c with butanoyl and N-methyl
groups failed to form gels in a range of organic solvents
under sonication and non-sonication conditions.
–2
Figure 2. Gelation profiles for solutions of 1a in cyclohexane (5.0×10 M,
blue curves) and butanenitrile (5.4×10–3 M, red curve) at 298 K, evaluated
from the baseline absorption at 700 nm. Each curve indicates the results
2
with sonication for 10–30 s (45 kHz, 0.38 W/cm ).
such as the temperature, concentration, solvents and
additives. Figure
3
shows rheological data
obtained using a strain-
controlled rheometer.
During a full range of
measurement
frequencies
f (logf =
0.0–2.0), the shear
Figure 1. Synthetic flavin 1a at 298 K. (a) A 1.50×10–2 M solution in
storage moduli G’, were
almost constant and
significantly larger than
those for the shear loss
butanenitrile under non-sonication conditions. (b) A gel after sonication (45
2
kHz, 0.38 W/cm , 30 s) and subsequent standing for 5 min.
Figure 3. Dynamic viscoelasticity of the
gels formed from a 5.1×10–2 M solution
moduli
indicates
G’’,
that
which
the
of 1a in butanenitrile at 298
K with
The sonication responsiveness of the present ultrasound-
induced gelation with 1a can be visualized by the time
dependence of the UV-vis baseline absorption at 700 nm
during formation of the opaque gel. Figure 2 shows the
controlled gelation profiles of solutions of 1a. The absorbance
intensities increased during the gelation process due to a
reduction of the light transmission, which corresponded to the
growth of gel fibers. The sigmoidal curves indicate that light
transmittance occurs upon construction of a three-
dimensional (3D) network of the gel fibers after the initial
formation of two-dimensional aggregation domains was
completed. Most importantly, the velocity of the gelation
process can be controlled precisely by an increase in the
sonication time, as shown by the gelation profiles in
cyclohexane solution after sonication for 10, 20, and 30 s,
which resulted in gelation completion times of 4200, 3000,
and 2000 s, respectively (blue curves). Gelation control in
butanenitrile solution can be performed much more rapidly
2
sonication (45 kHz, 0.38 W/cm , 30 s)
(frequency sweep, strain: 0.3%). Black
circles: shear storage modulus (G’);
white circles: shear loss modulus (G’’).
samples are sufficiently
viscoelastic, as with a
typical
low-molecular
weight gel.
Morphological changes in the 1a aggregates were
examined using microscopic analysis. Figure 4 shows
scanning electron microscopy (SEM) images of dried gels of
1
a prepared by evacuation of butanenitrile 1a gels formed
under various sonication conditions. Spherical aggregates
with homogeneous diameters and their assembling structures
were observed as the sole morphology of all the gelled
samples. Thus, it is fairly certain that a 3D gel network was
constructed by continuous assembly of the spherical units,
which are initially formed as semi-stable aggregates. This is a
rare case of gel aggregates21 given the entanglement of long
fibrous aggregates frequently observed with typical gels.19
Ultrasonication resulted in a reduction of the average particle
sizes, which were altered to be 5.6, 5.1, and 2.7 μm upon
elongation of the sonication times to 5, 10, and 30 s,
respectively (Figures 4a-c). The external controllability of
gelation time can be rationalized by this morphological
variation of the spherical aggregates. The reduction of the
particle size upon sonication gives rise to an increased
(
red curves), even though the concentration of the solution
was over ten-times lower than that of the cyclohexane
solution. This is one of the rare cases of dynamic external
control of the aggregation rate,19 given that the rates of
conventional self-assembly depend only on static parameters
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FULL PAPER
aliphatic olefin 1-dodecene (2) proceeds much faster than
that of the aromatic olefins allylbenzene (3) and o-allylphenol
(
4). The reaction rates for 2–4 with gel catalyst 1a increased
in the order of 2 >> 3 > 4. Such a substrate-specificity has
never been observed with typical flavin catalysts12 with weak
aggregation properties, as indicated by the almost same
reaction rates for 2–4 observed for reduction with the non-
gelled flavin catalyst 1b (Figure 5b). The lumiflavin (5)-benzyl
ether dendrimer association complex 5•G3PAP13a (Figure 8b)
catalyst exhibits significant substrate specificity for the
hydrogenation of 2–4; however, the order of the reaction rate
Figure 4. SEM images of dried aggregates prepared from a 6.4×10–2
M
2
solution of 1a in butanenitrile with sonication (45 kHz, 0.38 W/cm ) for (a) 5,
b) 10, and (c) 30 s.
(
(
(
2 < 3 < 4) is completely opposite to that with gel catalyst 1a
Figure 5c). This is a quite rare case of catalysis, where the
concentration of the aggregation nuclei, which accelerates
construction of the 3D network as a propagation step of
aggregation.
substrate specificity can be significantly controlled by
variation of the association/aggregation mode of the catalyst.
Representative results of the aerobic reduction of olefins with
gelled and non-gelled flavin catalysts 1a and 1b under the
same reaction conditions are summarized in Table 1. Gel
catalyst 1a exhibits remarkable substrate specificity where
aliphatic olefins bearing long linear alkyl chains undergo fast
reduction although the conversion of bulky olefins was low.
In contrast, all the olefin substrates undergo the reduction
with no-gelled catalyst 1b moderately without any substrate
specificity.
To gain insight into the mechanism, the concentration
dependence on the initial rates of the catalytic reactions was
2 2 2
examined for the aerobic reduction of 2 with NH NH •H O in
butanenitrle at 30 ºC using gas-liquid chromatography (GLC)
analysis. Figures 6 and 7 show the initial reaction profiles with
vari ous i niti al c oncentr ati ons of NH
Substrate specificity for the aerobic reduction of olefins
with a flavin gel catalyst
The ultrasound gel of 1a exhibits unprecedented substrate
specificity for the aerobic reduction of olefins [Eq. (1)], which
can be performed with hydrazine in 1 atm of air using a
synthetic flavin catalyst13 as a convenient alternative to
transition-metal catalysts and H
prepared upon sonication (45 kHz, 0.38 W/cm , 30 s) of a
2
gas.22 When an opaque gel
2
solution of olefins and 1a (12 mol%) in butanenitrile was
allowed to react with NH NH •H O (2.0 equiv) with stirring at
2 2 2
ambient temperature under an air atmosphere, the
corresponding alkanes were formed with high efficiency. The
time dependence of conversion in the aerobic reduction of
various olefins with flavin gel catalyst 1a is shown in Figure
2
NH
), respectively. The clear
•H O] (Figure 6a) and [2]
0
2 2
• H O
(
[NH
2
NH
2
•H
2
O]
0
) and 2 ([2]
NH
0
dependence on both [NH
(
2
2
2
0
Figure 7a) was observed in the reaction with gel catalyst 1a.
5a, which indicates that the aerobic hydrogenation of the
Figure 5. Reaction profiles for the aerobic reduction of 2 (red), 3 (purple) and 4 (blue) with flavin catalysts: (a) 1a (butanenitrile gel), (b) 1b, and (c)
1
3a
–1
–2
5
•G3PAP
association complex. Conditions: (a) A solution of olefin (1.25×10 M), 1a (1.50×10 M, 12 mol%) and tridecane (internal standard) in
2
2 2
•H
O (2.0 equiv, 2.50×10–1 M) was added to the resulting gel,
butanenitrile was sonicated (45 kHz, 0.38 W/cm ) for 30 s and left to stand for 5 min. NH
2
NH
O (2.0 equiv, 2.50×10–1 M) was added to a solution of olefin (1.25×10 M), flavin catalyst (1.50×10
M, 12 mol%), and tridecane in butanenitrile, and the mixture was stirred at 30 ºC in air; (c): NH NH •H
O (2.50×10–1 M, 4.0 equiv) was added to a solution of
olefin (6.25×10 M), flavin catalyst (1.25×10 M, 20 mol%), G3PAP (1.25×10 M), and tridecane in CHCl , and the mixture was stirred at 30 ºC in air.
Conversions and yields were determined by GLC analysis based on the internal standard. The plots in (c) were reconstituted by the reported data from Ref.
3a.
–1
–2
2 2 2
and the mixture was stirred at 30 ºC in air; (b): NH NH •H
2
2
2
–2
–2
–2
3
1
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ChemCatChem
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FULL PAPER
Table 1. Substrate scope of the aerobic reduction of various olefins with
gelled and non-gelled flavin catalysts.
entry
Substrate
Conv. (%)
[a]
[b]
1a
1b
1
2
>99
44
>99
40
46
3
73
4
5
63
40
44
31
Figure 6. Dependence of [NH
2
NH
2
•H
2
O]
0
in the aerobic reduction of 2 with
6
7
8
9
52
40
35
19
43
30
33
38
(a) 1a (gel) and (b) 1b catalysts in butanenitrile at 30 ºC under air.
–2
–1
Conditions: [1a] = [1b] = 1.50×10 M, [2]
0
2 2 2 0
= 1.25×10 M, [NH NH •H O] =
.25×10–2 M (green), 1.25×10 M (blue), and 2.50×10 M (red).
–1
–1
6
MeO
HO
OH
[
a] A solution of olefin (1.25×10–1 M), 1a (1.50×10–2 M, 12 mol%) and
tridecane (internal standard) in butanenitrile was sonicated (45 kHz, 0.38
2
W/cm ) for 30 s and left to stand for 5 min. NH
2
2
NH
2
•H
2
O (2.0 equiv,
–1
.50×10 M) was added to the resulting gel, and the mixture was stirred at
0 ºC in air for 4.5 h. [b] A mixture of olefin (1.25×10 M), NH NH •H O
2 2 2
2.0 equiv, 2.50×10 M), 1b (1.50×10 M, 12 mol%) and tridecane in
–1
3
(
–1
–2
butanenitrile was stirred at 30 ºC in air for 4.5 h.
0
Figure 7. Dependence of [2] in the aerobic reduction of 2 with (a) 1a (gel)
and (b) 1b catalysts in butanenitrile at 30 ºC under air. Conditions: (a) [1a]
= [1b] = 1.50×10–2 M, [NH
(blue) and 1.25×10–1 M (red).
O]
0
= 2.50×10 M, [2]
–1
= 6.25×10
–2
M
This is in contrast to the dependence of [NH
2
NH
2
•H
2
O]
0
and
2
NH
2
•H
2
0
the independence of [2]
0
observed with both non-gelled
catalyst 1b (Figures 6b and 7b) and other synthetic flavin
catalysts13 under the same reaction conditions.
The present flavin-catalyzed aerobic reduction can be
rationalized by the consecutive anaerobic and aerobic
processes shown in Scheme 1.
Flavin 1 undergoes
nucleophilic attack and a subsequent 1,3-hydrogen shift to
give the reduced flavin-diimide association complex 6. The
active diimide in 6 reacts with an olefin to afford an alkane as
the product, with the liberation of nitrogen gas and reduced
flavin 7. The incorporation of
hydrodioxyflavin 8, which performs oxygen transfer to a
second NH NH molecule to afford the flavin-diimide complex
. Diimide reduction of the second olefin with 9 regenerates 1
O
2
into 7 gives 4a-
2
2
9
to complete the catalytic cycle. Kinetic studies on the
reduction of olefin 2 with catalyst 1 revealed that the
nucleophilic attack of NH
step for the overall catalytic process.
2 2
NH to 1 is the rate-determining
1
3a
Scheme 1. Mechanism for the aerobic reduction of olefins with catalyst 1.
The specific reactivity of aliphatic olefins observed in the
reduction with gel catalyst 1a can be explained by the
inclusion of the olefin inside the artificial cavity formed by the
aggregation of 1a. Thus, the linear aliphatic olefin is included
efficiently in the cavity of aggregate 10 assisted by the Van
der Waals forces of the long alkyl chains of the catalyst to
afford the association complex 11 (Scheme 2), which
undergoes reduction with NH
2 2
NH to afford complex 12 as
the rate-determining step of the foregoing catalytic reduction
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process. Based on the assumption that the association
Conclusions
constant (K
a is much larger than that of bulky aromatic olefins 3 and 4,
the rate-determining, anaerobic dehydration of NH NH in the
a
) of linear aliphatic olefin 2 with the aggregates of
1
Synthetic flavin derivative 1a with long alkyl chains gelatinizes
various organic solvents upon brief ultrasonication. The
advantage of ultrasonication has been demonstrated by the
external control of the gelation rate upon tuning the sonication
time, which is not accomplished by the conventional self-
assembly process that is dependent only on static reaction
parameters such as the temperature and concentration. The
ultrasound gel of 1a exhibits enzyme-like substrate specificity
for the catalytic aerobic hydrogenation of olefins. A significant
enhancement of the catalytic activity is observed exclusively
for the reduction of aliphatic olefins with gel catalyst 1a,
whereas non-gelled catalyst 1b shows almost negligible
substrate specificity, and the dendrimer association complex
catalyst of lumiflavin exhibits a completely opposite tendency.
This is a rare case of significant control of the substrate
specificity upon aggregation/association of the catalysts in
2
2
reduction of 2 would be rationally accelerated compared to
that in the reaction of 3 and 4, according to the rate equation
d[12]/dt = kK
dependence and independence of [2]
with gel 1a (Figure 7a) and non-gel 1b catalysts (Figure 7b),
a
[10][NH
2
NH
2
]. This is highly consistent with the
0
in the reaction rates of
2
respectively. The contrasting substrate specificity observed
for aerobic reduction with an association catalyst (Figure 5c)
is also attributable to the specific inclusion of 4 upon
hydrogen-bonding and π-stacking interactions that occur
inside the cavity of the poly(benzyl ether) dendron unit of the
association complex. Schematic representations for the
unprecedented control of the substrate-specificity upon
aggregation and association of the flavin catalysts are shown
in Figure 8.
Scheme 2. Plausible rate-determining step for flavin gel catalysis.
(
a)
(b)
Figure 8. Schematic representations for control of substrate specificity in the aerobic reduction of olefins with (a) aggregation and (b) association catalysts．Dark
and white moieties denote the capture and reaction sites for the substrates.
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FULL PAPER
organic transformations. Kinetic studies revealed that the
positive aggregation effect on the substrate specificity is the
result of specific inclusion properties of the artificial reaction
cavities generated by the self-assembly of the flavin unit.
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4
the reaction of riboflavin and stearic anhydride in boiling CH
2 2
Cl and
(a) K. Maruoka, S. Saito, A. B. Concepcion, H. Yamamoto, J. Am.
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a
dimethylamino)pyridine. Riboflavin 2’,3’,4’,5’-tetrabutanoate (1b) was
commercially available and used without further purification. The yields
of the products and the conversion of the olefins were determined by
GLC analysis using a Shimadzu GC-17A chromatograph with an
Intercap 1 analytical column (0.25 mm×30 m).
2
011, 17, 3856–3867. (c) H. Nakajima, M. Yasuda, R. Takeda, A.
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2
1
Measurement of the gelation properties
2
A 10 mm×1.0 mm UV cell was charged with a hot homogeneous
solution of 1a in an organic solvent. The gelation properties were
assessed after the solution was sonicated at 298 K using a Honda W-
1
103T ultrasonic cleaner, and standing for 5 min at room temperature.
1
The phase states were confirmed by visual observation of the complete
disappearance of fluidity of inverted samples. Gelation profiles were
examined by plotting baseline absorptions at 700 nm using a Shimadzu
MultiSpec-1500 UV-vis spectrometer (Figure 2). Rheological data were
obtained using a strain-controlled rheometer (TA Instruments ARES)
with steel parallel-plate geometry (25 mm diameter) (Figure 3). The
morphologies of the dried gels were observed using SEM (Keyence VE-
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Entry for the Table of Contents (Please choose one layout)
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Enzyme-like substrate specificity has
been observed in the catalytic aerobic
reduction of olefins with a synthetic
flavin gel catalyst, which can be
formed efficiently by ultrasonication.
Based on kinetic studies the
aggregation effects on the substrate
specificity have been ascribed to the
specific inclusion of olefins into the
artificial cavities of the gel catalysts.
Soichiro Kawamorita, Misa Fujiki,
Zimeng Li, Takahiro Kitagawa, Yasushi
Imada, and Takeshi Naota*
Page No. – Page No.
Aggregation-induced Substrate
Specificity in Aerobic Reduction of
Olefins with Ultrasound Gel Catalyst
of Synthetic Flavin
(
(Insert TOC Graphic here: max.
width: 5.5 cm; max. height: 5.0 cm))
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