Renewable Molecular Flasks with NADH Models: Combination of Light-Driven Proton Reduction and Biomimetic Hydrogenation of Benzoxazinones

Article abstract of DOI:10.1002/anie.201702926

Using small molecules with defined pockets to catalyze chemical transformations resulted in attractive catalytic syntheses that echo the remarkable properties of enzymes. By modulating the active site of a nicotinamide adenine dinucleotide (NADH) model in a redox-active molecular flask, we combined biomimetic hydrogenation with in situ regeneration of the active site in a one-pot transformation using light as a clean energy source. This molecular flask facilitates the encapsulation of benzoxazinones for biomimetic hydrogenation of the substrates within the inner space of the flask using the active sites of the NADH models. The redox-active metal centers provide an active hydrogen source by light-driven proton reduction outside the pocket, allowing the in situ regeneration of the NADH models under irradiation. This new synthetic platform, which offers control over the location of the redox events, provides a regenerating system that exhibits high selectivity and efficiency and is extendable to benzoxazinone and quinoxalinone systems.

Full text of DOI:10.1002/anie.201702926

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Communications
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International Edition: DOI: 10.1002/anie.201702926
German Edition: DOI: 10.1002/ange.201702926
Host–Guest Systems
Renewable Molecular Flasks with NADH Models: Combination of
Light-Driven Proton Reduction and Biomimetic Hydrogenation of
Benzoxazinones
Liang Zhao, Jianwei Wei, Junhua Lu, Cheng He,* and Chunying Duan*
Abstract: Using small molecules with defined pockets to
catalyze chemical transformations resulted in attractive cata-
lytic syntheses that echo the remarkable properties of enzymes.
By modulating the active site of a nicotinamide adenine
dinucleotide (NADH) model in a redox-active molecular flask,
we combined biomimetic hydrogenation with in situ regener-
ation of the active site in a one-pot transformation using light as
a clean energy source. This molecular flask facilitates the
encapsulation of benzoxazinones for biomimetic hydrogena-
tion of the substrates within the inner space of the flask using
the active sites of the NADH models. The redox-active metal
centers provide an active hydrogen source by light-driven
proton reduction outside the pocket, allowing the in situ
regeneration of the NADH models under irradiation. This
new synthetic platform, which offers control over the location
of the redox events, provides a regenerating system that exhibits
high selectivity and efficiency and is extendable to benzox-
azinone and quinoxalinone systems.
dinucleotide (NADH).[8,9] In terms of the availability, atom
economy, and by-product removal, the combination of light-
driven proton reduction to regenerate the active sites is
a promising approach that has not been reported in the field
of renewable and recyclable NADH mimics.[10,11] From
a catalytic perspective, the challenges in developing one-pot
catalytic processes include the combination of photoredox
catalysis and hydrogenation catalysis, in addition to the
compatibility between the dynamic kinetics and reaction
intermediates and the synergy of the inside and outside redox
processes.
Through direct modulation of two tridentate chelating
donors at the meta sites of a central dihydropyridine amido
(DHPA) mimic relative to the active site of an NADH model,
metal-organic macrocycles that contain redox-active nickel-
(II) nodes for photocatalytic proton reduction and renewable
active sites of a NADH model system for the hydrogenation
of benzoxazinones were prepared (Scheme 1), and their
catalytic performance was evaluated. We envisioned that
the modified pocket in the molecular flask would strongly
interact with substrates that will then react with the active
sites of the NADH mimics to produce the hydrogenation
product and NAD+ mimics in the inner space of the pocket.
Redox-active metal centers provide the possibility of photo-
catalytically reducing protons,[12] forming active H-atoms that
interact with the NAD+ mimics, and regenerating the active
sites for another cycle. Controlling the location of the reaction
cycles could be a promising approach to provide reactions
Catalytic synthetic methods that are inspired by natural
enzyme prototypes that react under an ambient atmosphere
and use benign solvents and clean energy are a major
endeavor in synthetic chemistry.[1] To match the efficiency
and selectivity of enzymatic systems, chemists use small
molecules with defined hydrophobic cavities that emulate the
properties of enzyme active sites to catalyze specific chemical
transformations.[2,3] An exciting area in this research includes
the incorporation of transition-metal moieties as redox-active
vertices that mimic the highly evolved and finely tuned
natural photocatalytic systems by catching organic dyes in the
pocket.[4,5] Such a separation of the redox events by the inner
and outer spaces of the cavity provides a new synthetic
platform that combines photocatalytic reduction with a spe-
cific hydrogenation reaction.
Nature has developed millions of redox systems in which
the redox process is catalyzed by numerous coenzymes.[6,7]
Taking advantage of modified prototypes and hydride reduc-
tion cofactors, chemists have developed a biomimetic hydro-
genation approach employing Hantzsch esters with relevant
compounds that function as mimics of nicotinamide adenine
[*] Dr. L. Zhao, J. Wei, J. Lu, Prof. C. He, Prof. C. Duan
State Key Laboratory of Fine Chemicals, Dalian University of
Technology
Dalian, 116024 (China)
E-mail: hecheng@dlut.edu.cn
Scheme 1. Schematic of the redox-active macrocycle with NADH
mimics showing the combination of biomimetic hydrogenation and
in situ regeneration of active sites through photocatalytic reduction in
a one-pot process.
cyduan@dlut.edu.cn
Supporting information for this article can be found under:
https://doi.org/10.1002/anie.201702926.
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with sufficient compatibility between the kinetics and reac-
tion intermediates.
2-one (Substrate 1), ESI-MS spectra exhibited a new peak at
m/z = 568.75 assigned to [Ni4(HZPB)3(H2ZPB)(1)2]5+ (Sup-
porting Information, Figure S3), suggesting the formation of
a 1:2 stoichiometric host–guest species. Microcalorimetric
titration[16] of host–guest complexation in the polar solvent
DMF with a higher solubility was carried out, revealing
a good n value of 2.0 from the curve fitting using the
“independent” model (Supporting Information, Figure S11),
corresponding to enthalpy (DH) and entropy (TDS) changes
for Ni-ZPBꢀ(1)2 of À0.49 Æ 0.03 and 29.2 kJmolÀ1, respec-
tively. The host–guest complexation species and the active
sites of NADH mimics are the basis for the biomimetic
hydrogenation within the pocket of macrocycle.
The ligand H2ZPB, which contains a central DHPA
backbone relative to the active site of the NADH model,
was synthesized by a Schiff-base reaction of 2-pyridylalde-
hyde and 1-benzyl-4-phenyl-1,4-dihydropyridine-3,5-dicarbo-
hydrazide. The reaction of the Ni(ClO4)2 and the H2ZPB
gives the redox-active macrocycle Ni-ZPB. Single-crystal
structure analysis revealed the formation of a tetranuclear
macrocycle with four central DHPA moieties. The macrocycle
Ni-ZPB is positioned on a C2 axis through the connection of
four ligands and four redox-active nickel ions in an alternating
fashion (Figure 1).[13] The edges of the tetragon formed by the
The evaluation of catalytic reactions first focused on the
hydrogenation of benzoxazinones. For a solution containing
1 and Ni-ZPB as the NADH mimics, the conversion reached
95% (racemates, no further separation for the two enantio-
mers) in the presence of ascorbic acid (H2A). Using the salt
Ni(ClO4)2 or H2A alone gave a trace amount of the product,
and loading an identical amount of the ligand itself yielded
only a small amount of product. A control experiment using
a benzoxazinone with bulky substituents, 2, 3-(4’-(tert-butyl)-
[1,1’-biphenyl]-4-yl)-6-(4-(tert-butyl)phenyl)-2H-1,4-benzo-
xazin-2-one, with a size larger than that of the pocket of Ni-
ZPB, yielded 17% of product under the same conditions.
Clearly, compound Ni-ZPB is responsible for the biomimetic
hydrogenation reaction, providing an efficient and confined
space for size or shape selectivity (Supporting Information,
Figure S18).[17]
The active sites of the NADH mimics in the macrocycle
could be regenerated by adding reducing agents.[18] In the
presence of Na2S2O3 as a reducing agent, a loading of 0.1%
mol ratio of Ni-ZPB resulted in 96% conversion for the
hydrogenation of 1. Thus, Ni-ZPB was considered to be
a renewable molecular flask and an efficient catalyst to
promote the hydrogenation. Under saturated reaction con-
ditions, 1 in high concentration (Kass[1]2 > 100) exhibited
pseudo zero-order kinetics of the product formation. When
the concentrations of Na2S2O3 and Ni-ZPB were fixed, the
initial turnover frequency (TOF) of the hydrogenation
reaction did not change as the substrate concentration
decreased (Figure 2a and the Supporting Information, Fig-
ure S19). When the concentrations of Na2S2O3 and 1 were
fixed, the initial rate constant for hydrogenation exhibited
a linear relationship with the concentration of Ni-ZPB
(Figure 2b and the Supporting Information, Figure S20).
The catalytic behavior is a Michaelis–Menten mechanism,
and the rate of the reaction depends on the concentration of
the host–guest species, rather than the concentration of the
substrates.
To determine whether the hydrogenation reaction oc-
curred inside the pocket of Ni-ZPB or outside, adenosine
triphosphate (ATP), an important compound in natural
systems that is inactive toward hydrogenation, was chosen
as an inhibitor.[19] The microcalorimetric titration curve
generated for Ni-ZPB upon addition of ATP revealed the
formation of a host–guest system. The higher DH (5.7 Æ
0.4 kJmolÀ1) and TDS (36.4 kJmolÀ1) changes compared to
those of the Ni-ZPB/1 system suggested that ATP was able to
Figure 1. Structures of the molecular macrocycles Ni-ZPB and Ni-PMB,
showing the coordination geometry of the ions and the direction of the
active site of the H2ZPB ligands. Nickel=cyan, oxygen=red, nitro-
gen=blue, carbon=white, and hydrogen=grey.
NADH-mimicking ligands that linearly bridge two metal ions
create an average Ni···Ni separation of circa 8.62 ꢀ, suggest-
ing that the cavity of the macrocycle is sufficiently large to
encapsulate planar aromatic substrates. Each nickel ion was
coordinated in a mer position with a pair of delocalized N2O
chelators to modify the redox potential to a region suitable for
electrochemical reduction of the proton. The DHPA moieties
on parallel edges of the macrocycle are positioned on the
same side, with another pair of DHPA moieties above or
beneath the macrocycle and with active sites positioned in the
interior of the pocket. These amide groups are located around
the charged pocket, providing enriched hydrogen bonding
triggers for the recognition and activation of substrate
encapsulation.[14] The close proximity between the encapsu-
lated substrate and active sites facilitates a direct H-transfer
reaction from the cofactor mimics to the substrate located
within the inner space of the pocket, ensuring size and shape
selectivity associated with the confining effects of the
molecular flask.[15]
The stability of Ni-ZPB in solution was characterized by
ESI-MS analysis. Intense peaks at m/z = 599.15, 624.14, and
649.13 are assigned to [Ni4(HZPB)4]4+, [Ni4(HZPB)3-
(H2ZPB)·ClO4]4+, and [Ni4(HZPB)2(H2ZPB)2·2ClO4]4+,
respectively. Upon addition of, 3-phenyl-2H-1,4-benzoxazin-
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Figure 2. Kinetics of the hydrogenation reaction in the Ni-ZPB/1/
Na2S2O3 system, showing a) the variation in turnover number (per
mole of the molecule Ni-ZPB) as the concentration of substrate
1 varies in the system containing Na2S2O3 (50.0 mm), H2A (0.10m),
and Ni-ZPB (10.0 mm) and b) the conversion of substrate 1 (10.0 mm)
as the concentration of Ni-ZPB varies in the system containing
Na2S2O3 (50.0 mm) and H2A (0.10m).
Figure 3. Turnover number per mole of the catalyst in a) the hydro-
genation of substrate 1 (10.0 mm) in a system containing Na2S2O3
(50.0 mm), H2A (0.10m), and catalyst (10.0 mm) and b) the hydrogen
2+
production in a system containing Ru(bpy)3 (1.0 mm), H2A (0.10m),
and catalyst (10.0 mm). Turnover number per mole of the catalyst in
c) the hydrogenation of substrate 1 (4.0 mm) and d) the hydrogen
production in systems containing Ru(bpy)32+ (1.0 mm), H2A (0.10m),
and catalysts (10.0 mm) in one-pot transformations. The magenta and
cyan bars show the absence and presence of ATP (20.0 mm), respec-
tively.
replace substrate 1 and become encapsulated in the pocket of
macrocycle. Upon addition of ATP to the reaction mixture,
the observed decrease in the turnover number (TON) from
820 to 140 confirmed that hydrogenation occurred within the
pocket of Ni-ZPB.[20] From a mechanistic viewpoint, the
encapsulation of the substrate into the pocket forced the
active sites into close proximity with substrate, enabling the
hydrogenation to occur efficiently and producing the NAD+
mimics. The product was driven out of the inner space of the
pocket by the fresh substrate molecules through an equilib-
rium-controlled, guest-exchange reaction, and the active sites
in the NADH mimics were regenerated by Na2S2O3 for
another transformation cycle. Direct microcalorimetric titra-
tion of Ni-ZPB upon addition of product 1a gave DH and
TDS values of À0.05 Æ 0.01 and 22.8 kJmolÀ1, respectively for
the host–guest complexation species. The fact that the free
energy change (DG) was 7.3 kJmolÀ1 smaller than that of
1 supported the idea that molecules of substrate 1 were able to
replace product 1a to form more stable supramolecular
species, suggesting that the substrate and Ni-ZPB are in
equilibrium with the substrate/Ni-ZPB complex.[21]
ure 3b). The location of the hydrogenation reaction in the
inner space of the pocket and the photoinduced electron
transfer outside the pocket of Ni-ZPB provide a new
approach that combines two chemical reactions in a one-pot
conversion.
For comparison, the analogous Zn-ZPB, with redox-
inactive zinc ions, and Ni-PMB (Figure 1b), with similar
structural features except for a benzene ring substituted at the
active site of the NADH model, were designed and prepared.
Control experiments consisting of an identical amount of the
redox-inactive Zn-ZPB did not produce any hydrogen under
the same photocatalytic experimental conditions, and loading
an identical amount of the reference compound Ni-PMB
produced 0.32 mL of hydrogen (TON of ca. 280 per mole of
Ni-PMB) (Figure 3b and the Supporting Information, Fig-
ure S14). Clearly, the redox-active nickel ions in our system
are dominant factors in catalyzing the proton reduction under
irradiation. ESI-MS spectra of Zn-ZPB and Ni-PMB solu-
tions containing 1 exhibited new peaks at m/z = 956.56 and
1262.27, respectively (Supporting Information, Figures S4 and
S5). These peaks are assigned to [Zn4(ZPB)(HZPB)3(1)2]3+
and [Ni4(PMB)2(HPMB)2(1)2]2+ ions, respectively, suggesting
the possible formation of complexation species in the reaction
mixture. Loading an identical amount of the analogous Zn-
ZPB resulted in the same catalytic efficiency, 95% conversion
of substrate 1, and 15% conversion of substrate 2. The
absence of active sites in Ni-PMB prevents any possibility of
hydrogenation transformation (Supporting Information, Fig-
ure S18).
The cyclic voltammogram of Ni-ZPB demonstrated that
the NiII/NiI and NiI/Ni0 reduction processes occurred at
À0.85 V and À1.08 V (versus Ag/AgCl), respectively.[22]
These potentials were within the range of the proton
reduction process (Supporting Information, Figure S16),
indicating the possibility of a redox-active Ni-ZPB catalyzing
proton reduction in aqueous systems. To localize the photo-
induced electron transfer and the proton reduction reaction
outside the pocket, Ru(bpy)32+ ions, with two positive charges
and a molecular size that is larger than the inner space of the
pocket in Ni-ZPB, were selected as the photosensitizer.
Under the optimized conditions, 0.53 mL of hydrogen (TON
of ca. 470 per mole of molecule Ni-ZPB) was generated after
2+
irradiation of a solution (5.0 mL) containing Ru(bpy)3
(1.0 mm), H2A (0.10m, ensuring that the reaction occurred
under stable reductive conditions) and Ni-ZPB (4.0 mm)
(Figure 3b and the Supporting Information, Figure S12). As
expected, the addition of ATP up to 20.0 mm did not affect the
efficiency of the photocatalytic hydrogen evolution (Fig-
A simple comparison of the kinetic behavior between the
hydrogenation reaction with Na2S2O3 and the light-driven
hydrogen evolution revealed that the redox-inactive Zn-ZPB
did not produce any hydrogen under the reaction conditions
but was able to accelerate the hydrogenation reaction within
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its pocket because of the presence of the active sites of the
NADH mimics. The redox-active Ni-PMB could reduce
protons to produce hydrogen under irradiation under the
experimental conditions but could not promote the hydro-
genation reaction because of the absence of the active sites of
the NADH mimics. Only the redox-active Ni-ZPB with
NADH mimic active sites could be used to catalyze the two
different kinds of transformations (Figure 3a,c).
In a simple model reaction, substrate 1 (4.0 mm) was
2+
added to a solution containing Ru(bpy)3 (1.0 mm), H2A
(0.10m), and Ni-ZPB (10.0 mm, 0.25% mol ratio of substrate
1), and a 97% yield of the hydrogenation product was
achieved (TON of ca. 390 per mole of molecule Ni-ZPB)
(Figure 3c). Concurrently, a quite lower volume of hydrogen
(0.09 mL, TON of ca. 80 per mole of molecule Ni-ZPB) was
generated. The total turnover number for both reactions
reached 470 moles per mole of Ni-ZPB. Upon the addition of
up to 20.0 mm ATP, the hydrogenation reaction of the Ni-
Figure 4. a) Turnover number (per mole of the molecule Ni-ZPB) for
the hydrogenation of substrate 1 at different concentrations by the
system containing Ru(bpy)3 (1.0 mm), H2A (0.10m), and Ni-ZPB
2+
(10.0 mm). b) Conversion in the hydrogenation of substrate
2+
1 (10.0 mm) by the system containing Ru(bpy)3 (1.0 mm), H2A
(0.10m), and different concentrations of Ni-ZPB.
2+
ZPB/1/Ru(bpy)3 system stopped, while the hydrogen evo-
Table 1: Conversion in the hydrogenation of substituted benzoxazinones
lution reaction recovered. The volume of hydrogen generated
reached the same value (0.53 mL) as that in the aforemen-
and quinoxalinones under light irradiation.[a]
2+
tioned Ni-ZPB/Ru(bpy)3 system (Figure 3d). These results
confirm that the addition of ATP as an inhibitor only stopped
the hydrogenation reaction that occurred in the inner space of
the pocket but did not quench the light-driven hydrogen
evolution that occurred outside the pocket of Ni-ZPB.
Control experiments showed that loading an identical
amount of the redox-inactive Zn-ZPB in the same combined
reactions resulted in little conversion to the hydrogenation
product, and no hydrogen was detected during the reaction
because the system did not produce hydrogen gas or active H-
atoms for regeneration of the active sites of the hydro-
genation catalyst. Loading an identical amount of Ni-PMB
did not yield any detectable hydrogenation products but
produced up to 0.30 mL of hydrogen, which was similar to the
2+
amount produced by the Ni-PMB/Ru(bpy)3 system under
the same conditions. Upon addition of up to 20.0 mm ATP, the
2+
volume of hydrogen produced by the Ni-PMB/1/Ru(bpy)3
system did not change, and no detectable hydrogenation
2+
product was observed because the Ni-PMB/1/Ru(bpy)3
system did not contain the active sites of the hydrogenation
catalyst.
When the concentrations of Ru(bpy)32+ and Ni-ZPB were
fixed, the initial TOF of the hydrogenation reaction did not
vary, even if the concentration of substrate 1 was changed
significantly (Figure 4a and the Supporting Information,
Figure S21). In contrast, the maximum turnover number for
the hydrogenation exhibits a linear relationship with the
concentration of substrate 1. The fixed initial turnover
frequency with varied concentrations of substrate 1 suggests
that the kinetic rate of the hydrogenation reaction depends on
the concentration of the host–guest species rather than the
substrate concentration. When the concentration of substrate
1 was fixed, the initial turnover frequency of the hydro-
genation reaction exhibited a linear relationship with the
concentration of Ni-ZPB (Figure 4b and the Supporting
Information, Figure S22). The superiority of such combined
systems that use clean energy to promote the hydrogenation
[a] Reaction conditions: substrate (4.0 mm), Ni-ZPB (10.0 mm), Ru-
2+
(bpy)3 (1.0 mm), and H2A (0.10m) in CH3CN/H2O solution (1:1 v/v,
pH 4.50), 12 h. The conversions were determined by 1H-NMR analysis of
the crude products.
reaction could be extended to several types of benzoxazi-
nones and quinoxalinones (Table 1).
From a mechanistic viewpoint, the modified pocket of Ni-
ZPB first encapsulates substrate 1. The host–guest system
enforces close contact between the active sites of the NADH
model and the encapsulated substrate molecule. The hydro-
genation reaction is localized in the inner space of the
molecular flask to give the hydrogenation product and the
NAD+ mimics. At the same time, the excited state of the
photosensitizer is positioned outside the flask, reducing the
redox-active catalyst to give active H-atoms for the in situ
regeneration of the active sites of the hydrogenation reagent
4
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renders a regenerating system that exhibits high efficiency in
the light-driven hydrogenation of benzoxazinones and qui-
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Keywords: biomimetic hydrogenation · molecular flasks ·
proton reduction · renewable active sites ·
supramolecular chemistry
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Manuscript received: March 21, 2017
Revised manuscript received: May 15, 2017
Version of record online: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Host–Guest Systems
In the pocket: Through modulation of the
active sites of NADH models in redox-
active molecular flasks, a new synthetic
platform that controls the location of
biomimetic hydrogenation and in situ
photocatalytic proton reduction to the
inner and outer spaces of the pocket,
respectively, was developed that echoes
the properties of enzymes for the one-pot
transformation of benzoxazinones and
quinoxalinones using light as a clean
energy source.
L. Zhao, J. Wei, J. Lu, C. He,*
C. Duan*
&&&& — &&&&
Renewable Molecular Flasks with NADH
Models: Combination of Light-Driven
Proton Reduction and Biomimetic
Hydrogenation of Benzoxazinones
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!