Cooperative Catalysis of an Alcohol Dehydrogenase and Rhodium-Modified Periodic Mesoporous Organosilica

Article abstract of DOI:10.1002/anie.201904116

The combined use of a metal-complex catalyst and an enzyme is attractive, but typically results in mutual inactivation. A rhodium (Rh) complex immobilized in a bipyridine-based periodic mesoporous organosilica (BPy-PMO) shows high catalytic activity during transfer hydrogenation, even in the presence of bovine serum albumin (BSA), while a homogeneous Rh complex exhibits reduced activity due to direct interaction with BSA. The use of a smaller protein or an amino acid revealed a clear size-sieving effect of the BPy-PMO that protected the Rh catalyst from direct interactions. A combination of Rh-immobilized BPy-PMO and an enzyme (horse liver alcohol dehydrogenase; HLADH) promoted sequential reactions involving the transfer hydrogenation of NAD⁺ to give NADH followed by the asymmetric hydrogenation of 4-phenyl-2-butanone with high enantioselectivity. The use of BPy-PMO as a support for metal complexes could be applied to other systems consisting of a metal-complex catalyst and an enzyme.

Full text of DOI:10.1002/anie.201904116

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Accepted Article
Title: Cooperative Catalysis of an Alcohol Dehydrogenase and
Rhodium-Modified Periodic Mesoporous Organosilica
Authors: Tomoki Himiyama, Minoru Waki, Yoshifumi Maegawa, and
Shinji Inagaki
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10.1002/anie.201904116
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COMMUNICATION
Cooperative Catalysis of an Alcohol Dehydrogenase and
Rhodium-Modified Periodic Mesoporous Organosilica
Tomoki Himiyama, Minoru Waki, Yoshifumi Maegawa, and Shinji Inagaki*
Abstract: The combined use of a metal complex catalyst and an
enzyme is an attractive concept, but typically results in mutual
inactivation. A rhodium (Rh) complex immobilized in a bipyridine-
based periodic mesoporous organosilica (BPy-PMO) shows high
catalytic activity during transfer hydrogenation in the presence of a
model protein, bovine serum albumin (BSA), while a homogeneous
Rh complex exhibits reduced activity due to direct interaction with
the BSA. The use of a smaller protein or an amino acid instead of
BSA revealed a clear size-sieving effect of the BPy-PMO that
protected the Rh catalyst from direct interactions. A combination of
Rh-immobilized BPy-PMO and an enzyme (horse liver alcohol
dehydrogenase; HLADH) successfully promoted sequential
reactions involving the transfer hydrogenation of NAD+ to give NADH
followed by the asymmetric hydrogenation of 4-phenyl-2-butanone
based on the generation of NADH with high enantioselectivity. This
result indicates the significant compatibility of Rh-immobilized BPy-
PMO with HLADH. The use of BPy-PMO as a support for metal
complexes could potentially be applied to various other systems
consisting of a metal complex catalyst and an enzyme.
example, an oxovanadium complex immobilized on the pore
surfaces of mesoporous silica was used together with lipase for
the dynamic kinetic resolution of racemic alcohols.4 The size-
sieving effect of the mesopores improved the compatibility of the
metal complex and the lipase, indicating that the undesired
interaction between the vanadium catalytic center and the
enzyme were reduced. Developing a mesoporous support
capable of forming a variety of metal complexes on its pore
surfaces would allow the simultaneous use of a wide variety of
metal complex catalysts and proteins.
Combinations of metal complex catalysts with enzymes are
expected to provide a new approach to achieving unique
chemical transformations.1 Artificial metal complexes can exhibit
catalytic activities that are rarely obtained from natural enzymes,
while enzymes can allow highly selective catalysis. One
approach for their combination is direct linkage of transition
metal ions to protein surfaces to form hybrid biocatalysts, which
showed high enantioselectivity for the reactions missing from
nature’s toolbox.2 Another approach is using both a metal
complex and an enzyme simultaneously to achieve one-pot
cascade reactions in sequential steps. This approach is
interesting but a crucial issue for the combined use due to the
mutual inactivation of metal complexes and enzymes via
nonspecific interactions (Figure 1a). Several strategies have
been developed to overcome this problem and enable the
combined use of metal complexes and enzymes, based on
compartmentalization.3
Figure 1. (a) Mutual inactivation between a protein and a metal complex. (b) A
schematic representation of Rh@PMO. The rhodium catalytic centers inside
the mesopores are protected via the size-sieving effect to avoid inactivation by
the protein.
Mesoporous materials having uniform pores with nano-scale
diameters should exclude proteins larger than the pore
diameters. Taking advantage of this size-sieving effect, direct
interactions between a protein and a metal complex can be
avoided by locating the complex inside the mesopores. As an
Recently, we reported a periodic mesoporous organosilica
(PMO) containing 2,2’-bipyridine (BPy) ligands densely packed
on the pore surfaces (BPy-PMO).5a In this material, the BPy
groups can function as bidentate ligands for many different
metal complexes. To date, a variety of metal complexes have
been formed on these ligands, to obtain materials such as
Ir(cod)(OMe)(BPy) (cod: 1,5-cyclooctadiene), [Ru(bpy)2(BPy)]2+
(bpy: 2,2’-bipyridine), RuCl2(CO)2(BPy), [IrCp*Cl(BPy)]+ (Cp*:
pentamethylcyclopentadiene), Re(CO)3Cl(BPy) and MoO2Cl
(OH)(BPy).5 These immobilized metal complexes on the BPy-
PMO have exhibited efficient heterogeneous catalysis because
[*]
Dr. T. Himiyama, Dr. M. Waki, Y. Maegawa, Dr. S. Inagaki
Toyota Central R&D Laboratories, Inc.
Nagakute, Aichi 480-1192 (Japan)
E-mail: inagaki@mosk.tytlabs.co.jp
Dr. T. Himiyama
Current address : National Institute of Advanced Industrial Science
and Technology, Ikeda, Osaka 563-8577 (Japan)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201904116
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of the formation of the isolated metal complex center on the well-
defined pore surface and the ready diffusion of molecules in the
large pores (3.8 nm in diameter). Non-enzymatic regeneration of
NADH have been developed by using Rh catalysts such as
[RhCp*(bpy)Cl]Cl (Rh1).6 Hydride transfer takes place via key
intermediate of rhodium hydride complex in the formate-driven
mechanism, which was well investigated in previous literatures.7
The NADH drives an enzyme to catalyze an enantioselective
transformation. However, the Rh-complex catalyst is known to
strongly interact with proteins, leading to mutual inactivation,
meaning that a sequential reaction based on the combined use
of this catalyst and an enzyme is very difficult or impossible.1c,8
Here, we report the catalytic performance of Rh-immobilized
BPy-PMO (Rh@PMO) in the presence of a protein, as well as
the cooperative catalysis of an enzyme and Rh@PMO (Figure
1b). Rh@PMO was found to exhibit high catalytic activity during
transfer hydrogenation even in the presence of a protein having
a molecular size larger than the pore diameter, indicating the
were identified as type-IV, similar to those obtained from the
pristine BPy-PMO (Figure S6). Density functional theory pore
diameter (DDFT), Brunauer-Emmett-Teller surface area (SBET
)
and t-plot pore volume (Vt-plot) values were derived from the
isotherms and are summarized in Table 1. All three values were
slightly reduced following immobilization of the Rh complex,
suggesting the formation of Rh complexes in the mesopores of
the BPy-PMO.
The catalytic activities of the homogeneous material Rh1 and
of Rh@PMO were evaluated during the transfer hydrogenation
of 2-cyclohexen-1-one in the presence of BSA as a model
protein (Scheme 1). The homogeneous Rh1 showed high
catalytic activity, affording cyclohexanone in almost 100% yield
after 1.3 h in the absence of BSA (Figure S7a). However, the
addition of BSA to the homogeneous reaction solution drastically
reduced the activity due to the deactivation of the Rh1 via
nonspecific interactions with the BSA protein. The Rh@PMO
also exhibited good catalytic activity for this reaction in the
absence of BSA, although the reaction rate was lower than that
of the homogeneous Rh1 (Figure S7b). Interestingly, the activity
of the Rh@PMO was not greatly reduced when BSA was added.
The catalytic activity was likely retained because the Rh catalyst
in the PMO was not deactivated by the BSA, as this large
protein (14 × 4 × 4 nm, 66 kDa) could not enter the mesopores
(which had a diameter of 3.7 nm). Hot filtration experiments
demonstrated that the Rh complex was strongly bound to the
Rh@PMO and thus was not leached out during the reaction
either in the absence or presence of BSA (Figure S8).
ability to tolerate
a large protein. The combined use of
Rh@PMO and an enzyme promoted sequential reactions
consisting of the transfer hydrogenation of NAD+ to NADH as
well as asymmetric hydrogenation using NADH with high
conversion and good enantioselectivity, indicating the
compatibility of the Rh@PMO and the enzyme.
Rh@PMO was prepared by mixing [RhCp*Cl2]2 and BPy-PMO
powder in MeOH according to a previously reported technique,
with some modifications.9 The use of MeOH instead of DMF
preserved the highly ordered mesoporous structure of the PMO
after immobilization of the Rh complex. Complexation of the Rh
was confirmed by UV-vis diffuse reflectance spectroscopy, X-ray
absorption fine structure spectroscopy (XAFS) and energy-
dispersive X-ray spectroscopy (EDX). The UV-vis spectrum of
the Rh@PMO contained a characteristic absorption band at 380
nm, attributed to the formation of [RhCp*(bpy)Cl]+ on the pore
surfaces (Figure S1). X-ray absorption near-edge spectroscopy
(XANES) and extended X-ray absorption fine structure (EXAFS)
Fourier transform analysis at the Rh K-edge of the Rh@PMO
generated data similar to those obtained from Rh1. This result
indicates that the oxidation states and coordination symmetries
of the Rh centers in the Rh@PMO and Rh1 were similar (Figure
S2). Curve-fitting analysis of the Rh K-edge EXAFS Fourier
transforms also demonstrated that both materials had a similar
local coordination structure (Figure S3 and Table S1 for curve
fitting). The EDX analysis of the Rh@PMO showed that the
molar proportion of Rh relative to BPy was 6.3%, which
corresponds to a concentration of the Rh complex in the BPy-
PMO of 0.22 mmol g-1 (BPy: 3.18 mmol g-1). The EDX maps
acquired from the Rh@PMO indicated that the Rh atoms were
homogeneously distributed over the PMO particles as well as
over the Si atoms (Figure S4).
Table 1. Physicochemical properties of BPy-PMO and Rh@PMO.
Material
SBET[a] / m2 g-1
DDFT[b] / nm
Vt-plot[a] / cm3 g-1
BPy-PMO
Rh@PMO
600
430
4.3
3.7
0.34
0.27
[a] Determined from the adsorption branches of the isotherms. [b] Determined
from the desorption branches of the isotherms.
The XRD pattern of the Rh@PMO presented low angle
reflections at 2θ values of 1.82°, 3.18° and 4.85° due to the two-
dimensional hexagonal lattice. Three additional peaks were also
present at scattering angles of 7.60°, 15.6° and 23.0° as a result
of the molecular-scale periodicity of the bipyridine groups inside
the pore walls. These results confirm that the original structure
of the BPy-PMO was preserved even after immobilization of the
Rh complex on the pore surfaces (Figure S5). The nitrogen
adsorption/desorption isotherms generated by the Rh@PMO
Scheme 1. Transfer hydrogenation of 2-cyclohexen-1-one by a rhodium
catalyst.
Figure 2 plots the conversions after 6 h as functions of the BSA
concentration for various catalysts. The conversion over the
homogeneous Rh1 decreased significantly with increases in the
BSA concentration, while the Rh@PMO maintained a high level
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10.1002/anie.201904116
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of conversion (over 80%) even at BSA concentrations up to 20
mg mL-1. This result shows the superior ability of the Rh@PMO
to tolerate the presence of the BSA protein. We also examined
the tolerance properties obtained with another mesoporous silica
solid support (FSM-16) and with silica gel. The Rh-complex
catalyst was grafted onto the surfaces of the FSM-16 and silica
hydride donor.5 Thus, the asymmetric hydrogenation of 4-
phenyl-2-butanone was promoted by a mixture of Rh catalysts
and HLADH in conjunction with NAD+ and formate (Figure S9).
The combination of homogeneous Rh1 and HLADH gave the
corresponding alcohol, (S)-(+)-4-phenyl-2-butanol, with a 71%
conversion and 96% ee after 20 h (entry 1 in Table 2). After a 42
h reaction, the conversion was improved to 80% but the
enantioselectivity was decreased to 87% ee (entry 2 in Table 2).
A precipitate was observed to form in the reaction solution after
20 h and the UV-vis spectrum of the supernatant of the reaction
solution showed no absorption that could be attributed to
HLADH (Figure S10). These results suggest that the HLADH
was deactivated due to its interaction with the Rh1 catalyst
during the reaction. Actually, the considerable amount of Rh was
detected in the precipitate by inductively coupled plasma (ICP)-
atomic emission spectrometry (AES) (Supporting Information).
The decrease in enantiomeric purity with time is attributed to the
deactivation of the HLADH and the subsequent formation of a
racemic product by the Rh1 because the Rh1 alone generates
racemic 4-phenyl-2-butanol (entry 3 in Table 2).
gel using
a molecular linker, to afford Rh@FSM-16 and
Rh@SilicaGel (Scheme S1). These supported Rh-complex
catalysts also demonstrated continued high levels of activity in
the presence of BSA (Figure 2). This occurred because the
FSM-16 and silica gel had pore diameters (4.7 and 5.4 nm,
respectively) that were smaller than the molecular size of the
BSA. However, the catalytic activity of the Rh@PMO was higher
than those of the Rh@FSM-16 and Rh@SilicaGel in the
absence or presence of BSA. The direct immobilization of the
Rh complex on the pore surfaces without a linker when using the
Rh@PMO is evidently advantageous in terms of preserving the
original activity of the homogeneous Rh1 catalyst, as has been
reported previously.5
The combined use of Rh@PMO and HLADH afforded the
corresponding alcohol in 69% conversion with >97% ee after 20
h (entry 4 in Table 2) and 91% conversion with a higher
enantioselectivity of >98% ee after 42 h (entry 5 in Table 2). The
UV-vis spectrum of the reaction solution after 20 h exhibited a
characteristic absorption band at 280 nm due to HLADH (Figure
S10), suggesting that HLADH was still active and capable of
generating the enantiomeric product even after 20 h. It is
therefore evident that the Rh catalyst in the pores of PMO was
protected from the direct interaction with the HLADH because
the pore diameters were smaller than the HLADH (10 × 6 × 4
nm).
Rh@PMO played a role in regeneration of cofactor NADH
from NAD+, which was confirmed by the experiment using no
HLADH (Figure S11). The regeneration efficiency was evaluated
by total turnover number (TTN), which was defined as mole
product per mole cofactor, in the combined reaction system of
Rh@PMO and HLADH. TTN were 2.4 – 5.7, which was not so
high but indicated the regeneration of NADH in the combined
reaction system (Table S2).
Figure 2. Conversions of 2-cyclohexen-1-one after 6 h in the presence of BSA
(0-20 mg mL-1). Catalyst; Rh1 (black), Rh@PMO (red), Rh@FSM-16 (yellow)
and Rh@SilicaGel (blue).
To further investigate the size-sieving ability of Rh@PMO, a
small protein, myoglobin (Mb, with a molecular size of 2 × 3 × 4
nm), and an amino acid, histidine (His), were used instead of
BSA (Figure 3). The addition of His almost completely quenched
the transfer hydrogenation reaction when using either Rh@PMO
or homogeneous Rh1 as the catalyst because the small His
molecules were able to enter the mesopores and coordinate with
the Rh complex to inactivate the catalyst. The addition of Mb
almost fully stopped the reaction in the case of the Rh1,
although the Rh@PMO catalyst retained some activity because
the Mb molecules are almost equal in size to the Rh@PMO
pores. These results clearly indicate the size-sieving property of
the Rh@PMO.
Next, we investigated the sequential reactions involved in the
combined use of Rh@PMO and enzyme (Scheme 2). Horse
liver alcohol dehydrogenase (HLADH) is known to catalyze the
asymmetric hydrogenation of 4-phenyl-2-butanone in the
presence of NADH.7,10 In addition, Rh1 catalyzes the transfer
hydrogenation of NAD+ to NADH in the presence of formate as a
Figure 3. Conversions of 2-cyclohexen-1-one after 6 h in the absence (None)
and presence of His (2.0 mg mL-1), Mb (20 mg mL-1) or BSA (20 mg mL-1).
Catalyst; Rh1 (black), Rh@PMO (red).
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10.1002/anie.201904116
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BPy-PMO is an excellent support for the Rh complex and not
only prevents deactivation of the HLADH but also preserves the
high activity of the original Rh catalyst.
The principle of the combined use of Rh@PMO and HLADH
was also demonstrated for NADPH-dependent enzyme.
Rh@PMO also catalyzed reduction of NADP+ to NADPH in the
presence of formate (Figure S12). The mixture of Rh@PMO and
NADPH-dependent enzyme in conjunction with NADPH and
formate successfully catalyzed the asymmetric hydrogenation of
4-phenyl-2-butanone, giving the corresponding alcohol in 99%
conversion with 97% ee after 20 h (entry 10 in Table 2, and
Figures S12 and S13).
In conclusion, Rh@PMO shows high catalytic activity and
significant tolerance to the presence of BSA during the transfer
hydrogenation of 2-cyclohexen-1-one. The additions of His or
Mb in place of BSA completely or partly quench the reaction
when using Rh@PMO, demonstrating the size-sieving effect of
the PMO. A one-pot reaction involving the initial formation of
NADH followed by asymmetric hydrogenation using the NADH
was successfully performed by combining Rh@PMO and
Scheme 2. Asymmetric hydrogenation by combining Rh@PMO and HLADH.
Table 2. Asymmetric hydrogenation of 4-phenyl-2-butanone.
Entry
Catalyst
Reaction time
[h]
Conversion [%]
ee [%][a]
1
Rh1
20
42
42
20
42
20
42
20
42
20
71
80
95
69
91
60
71
65
71
99
96
HLADH.
The
reaction
gave
high
conversion
and
2
Rh1
87
enantioselectivity due to the compatibility of the two materials.
This method could be expanded for use with a variety of one-pot
reactions based on mixtures of metal complex-immobilized BPy-
PMO and enzymes.
3[b]
4
Rh1
0
Rh@PMO
Rh@PMO
Rh@FSM-16
Rh@FSM-16
Rh@SilicaGel
Rh@SilicaGel
Rh@PMO
>98
>98
>98
>98
92
5
6
Experimental Section
7
Hydrogenation of 2-cyclohexen-1-one. The reactions were performed
at 40 °C in a 0.10 M (pH 7.0) sodium phosphate buffer solution (2.0 mL)
containing 0.5 M formate, the Rh catalyst (0.20 µmol) and 2-cyclohexen-
1-one (20 µmol) as the substrate. The reaction mixture (100 µL) was
subsequently collected and extracted with ethyl acetate (500 µL) three
times. The organic phase was analyzed by gas chromatography using
phenol as an internal standard.
8
9
88
10[c]
97
[a] Positive ee indicates preferential formation of (S)-(+)-4-phenyl-2-butanol.
[b] The reaction was conducted without HLADH. [c] The reaction was carried
out with NADP+ and NADPH-dependent ADH instead of NAD+ and HLADH.
Asymmetric hydrogenation of 4-phenyl-2-butanone using HLADH.
The reactions were carried out at 40 °C in a 0.10 M (pH 7.0) sodium
phosphate buffer solution (2.0 mL) containing 0.1 M formate, NAD+ (3.0
µmol), the Rh catalyst (0.60 µmol), HLADH (2.5 mg, 5 U) and 4-phenyl-2-
butanone (8.0 µmol) as the substrate. The reaction mixture (500 µL) was
subsequently collected and extracted with ethyl acetate (500 µL) three
times. The organic phase was analyzed by gas chromatography using
phenol as an internal standard.
Rh@FSM-16 and Rh@SilicaGel were also examined with
regard to the asymmetric hydrogenation in combination with
HLADH. The Rh@FSM-16 gave a high enantioselectivity of
>98%, similar to the Rh@PMO, but a lower conversion of 71%
after a 42 h reaction (entries 6-7 in Table 2). This high
enantioselectivity indicates that the FSM-16 also prevented
deactivation of the HLADH. However, the low conversion
confirms the reduced catalytic activity of the Rh complex when
immobilized on FSM-16 compared to BPy-PMO, as noted earlier.
The Rh@SilicaGel exhibited a low conversion of 71% together
with a relatively poor enantioselectivity of 88% ee after 42 h
(entries 8-9 in Table 2). The UV-vis spectrum showed that the
HLADH still remained in the solution after the reaction (Figure
S10). Therefore, the decrease in enantioselectivity could have
been caused by an undesirable interaction between the HLADH
and the silica gel, which had a disordered structure. The low
conversion is attributed to the poor activity of the Rh complex
when immobilized on silica gel. These results demonstrate that
Asymmetric hydrogenation of 4-phenyl-2-butanone using NADPH-
dependent ADH. The reactions were carried out at 40 °C in a 0.10 M
(pH 7.0) sodium phosphate buffer solution (2.0 mL) containing 0.1 M
formate, NADP+ (3.0 µmol), the Rh catalyst (0.60 µmol), NADPH-
dependent ADH (4 U) and 4-phenyl-2-butanone (8.0 µmol) as the
substrate. The reaction mixture (500 µL) was subsequently collected and
extracted with ethyl acetate (500 µL) three times. The organic phase was
analyzed by gas chromatography using phenol as an internal standard.
Acknowledgements
We thank Dr. Masamichi Ikai, Dr. Yasutomo Goto and Mr.
Satoshi Kosaka of Toyota Central R&D Labs. Inc. for performing
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10.1002/anie.201904116
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COMMUNICATION
138, 5781-5784; f) Y. Okamoto, V. Kohler, C. E. Paul, F. Hollmann, T.
R. Ward, ACS Catal., 2016, 6, 3553-3557;
the XAFS, TEM and ICP-AES analyses, respectively. The XAFS
work was performed at SPring-8 (BL14B2: proposals
2016B1617 and 2017A1822). This work was supported by JST
ACT-C, Japan (JPMJCR12Y1).
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Conflict of interest
a) M. Waki, Y. Maegawa, K. Hara, Y. Goto, S. Shirai, Y. Yamada, N.
Mizoshita, T. Tani, W. Chun, S. Muratsugu, M. Tada, A. Fukuoka, S.
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3846-3853; f) S. Ishikawa, Y. Maegawa, M. Waki, S. Inagaki, ACS
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The authors declare no conflict of interest.
Keywords: rhodium • mesoporous materials • heterogeneous
catalysis • hydrogenation • enzyme catalysis
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10.1002/anie.201904116
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
A rhodium complex immobilized in a
bipyridine-based periodic
mesoporous organosilica, Rh@PMO,
exhibited high catalytic activity during
transfer hydrogenation in the
Tomoki Himiyama, Minoru Waki,
Yoshifumi Maegawa, and Shinji
Inagaki*
Page No. – Page No.
presence of a protein, indicating
excellent tolerance for the protein
due to the size-sieving effect of the
PMO. A mixture of Rh@PMO and an
alcohol dehydrogenase promoted
sequential reactions to afford an
enantiomeric product with high
conversion and enantioselectivity.
Cooperative catalysis of an alcohol
dehydrogenase and rhodium-
modified periodic mesoporous
organosilica
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