Deciphering a Reaction Network for the Switchable Production of Tetrahydroquinoline or Quinoline with MOF-Supported Pd Tandem Catalysts

Article abstract of DOI:10.1021/acscatal.0c00899

A mechanistic study of heterogeneous tandem catalytic systems is crucial for understanding and improving catalyst activity and selectivity but remains challenging. Here, we demonstrate that a thorough mechanistic study of a multistep reaction can guide us to the controllable selective synthesis of phenyltetrahydroquinoline or phenylquinoline with easily accessible precursors. The one-pot production can be achieved, catalyzed by a well-defined, bifunctional metal-organic framework-supported Pd nanoparticles, with only water as the side product. Our mechanistic study identifies six transient intermediates and ten transformation steps from the operando magic angle spinning nuclear magnetic resonance study under 27.6 bar H2. In particular, reactive intermediate 2-phenyl-3,4-dihydroquinoline cannot be observed with conventional chromatographic techniques but is found to reach the maximal concentration of 0.11 mol L-1 under the operando condition. The most probable reaction network is further deduced based on the kinetic information of reaction species, obtained from both operando and ex situ reaction studies. This deep understanding of the complex reaction network enables the kinetic control of the conversions of key intermediate, 2-phenyl-3,4-dihydroquinoline, with the addition of a homogeneous co-catalyst, allowing the selective production of tetrahydroquinoline or quinoline on demand. The demonstrated methods in this work open up new avenues toward efficient modulation of reactions with a complex network to achieve desired selectivities.

Full text of DOI:10.1021/acscatal.0c00899

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Article
Deciphering Reaction Network for the Switchable Production of
Tetrahydroquinoline or Quinoline with MOF-Supported Pd Tandem Catalysts
Long Qi, Jingwen Chen, Biying Zhang, Renfeng Nie, Zhiyuan Qi, Takeshi Kobayashi,
Zongbi Bao, Qiwei Yang, Qilong Ren, Qi Sun, Zhiguo Zhang, and Wenyu Huang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c00899 • Publication Date (Web): 17 Mar 2020
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Deciphering Reaction Network for the Switchable Production of
Tetrahydroquinoline or Quinoline with MOF-Supported Pd Tandem
Catalysts
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Long Qi,a,‡,* Jingwen Chen,b,c,‡ Biying Zhang,b Renfeng Nie,b Zhiyuan Qi,b Takeshi Kobayashi,a
Zongbi Bao,c Qiwei Yang,c Qilong Ren,c Qi Sun,c Zhiguo Zhang,c,* Wenyu Huanga,b,*
a U.S. DOE Ames Laboratory, Iowa State University, Ames, Iowa 50010, USA
b Department of Chemistry, Iowa State University, Ames, Iowa 50010, USA
c Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological
Engineering, Zhejiang University, Hangzhou 310027, China
KEYWORDS: tandem catalysis, reaction network, metal-organic frameworks, metal nanoparticles, operando spectroscopy,
mechanistic study.
ABSTRACT: Mechanistic study of heterogeneous tandem catalytic system is crucial, but remains challenging, for the
understanding and improving catalyst activity and selectivity. Here, we demonstrate that a thorough mechanistic study
of a multistep reaction can guide us to the controllable selective synthesis of phenyltetrahydroquinoline or
phenylquinoline with easily accessible precursors. The one-pot production can be achieved, catalyzed by a well-defined,
bifunctional metal-organic framework-supported Pd nanoparticles, with only water as the side product. Our mechanistic
study identifies six transient intermediates and ten transformation steps from the operando magic angle spinning NMR
study under 27.6 bar H2. In particular, reactive intermediate 2-phenyl-3,4-dihydroquinoline cannot be observed with
conventional chromatographic techniques but is found to reach the maximal concentration of 0.11 mol L-1 under the
operando condition. The most probable reaction network is further deduced based on the kinetic information of reaction
species, obtained from both operando and ex situ reaction studies. This deep understanding of the complex reaction
network enables the kinetic control of the conversions of key intermediate, 2-phenyl-3,4-dihydroquinoline, with the
addition of a homogeneous co-catalyst, allowing the selective production of tetrahydroquinoline or quinoline on demand.
The demonstrated methods in this work open up new avenues towards efficient modulation of reactions with complex
network to achieve desired selectivities.
consuming
trial-and-error
experiments.
The
INTRODUCTION
establishment of complex reaction networks, including
reactants, intermediates, and favored and unwanted
products, would help to elucidate the underlying
principles of such transformations and, in turn, guide the
design of efficient catalytic systems.
The concept of tandem catalysis, whereby sequential
chemical conversions catalyzed by multiple active sites in
one pot give desirable product selectively, has gained
significant interest for the selective catalytic production of
chemicals and fuels.1 This interest is based on the
prospects of boosting the atom economy, as costly
intermediate separations and purification processes could
be avoided. Identified among the 5 priority research
directions for catalysis science by U.S. DOE in 2017,2 a
significant challenge is how to direct convoluted
transformations through the desired routes for the target
product in a complexed reaction network, given that
tandem catalysis typically involves multiple transiently-
evolved intermediates. Thus far, optimization of reaction
conditions has relied mainly on laborious and time-
Probing the reaction network requires but is not limited
to: (1) identifying reaction species, (2) deconvoluting
individual reaction paths, and (3) understanding the
reversibility and rates of interconversions. However, due
to the co-presence of solid catalysts, reaction solution,
and reactive gas, an in-depth study of heterogeneous
tandem reactions and the associated complexed reaction
network is rather challenging, in particular when
intermediates are unstable upon sampling. Even for stable
species, the limited number of intermittent sampling at
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high temperature and pressure greatly restricts the data
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density to delineate the reaction network accurately.
Advanced techniques as noteworthy as operando magic
angle spinning NMR spectroscopy (MAS-NMR)3 has
proven to be unique for detailed structural and kinetic
information of multiphasic systems at both high
temperatures and high pressures.4,5 Accordingly,
operando MAS-NMR techniques provide the opportunity
for monitoring the reaction intermediates and ultimately
mapping out the reaction networks. To elaborate the
feasibility of our plan, we choose a model tandem catalytic
system for the production of tetrahydroquinoline (THQ)
or quinoline, where the first chemical conversion is the
Claisen-Schmidt condensation of 2-nitrobenzaldehyde
(NBA) and acetophenone (ACP) to nitrochalcone, followed
by its reductive intramolecular cyclization, Scheme 1. This
reaction is ideal not only because the production of THQ
and quinoline architectures, widely existing in bioactive
natural products,6 can serve as key pharmaceutical
ingredients,7-13 and THQ is essential building block of
hydrogen-storage materials,14-16 but also due to the
involvement of multiple transiently-evolved intermediates
as a result of the concurrent reduction of several
functionalities (i.e., -NO2, C=C, C=O, C=N, and arenes)
during reductive cyclization.
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Scheme 1. Kinetic control in the selective synthesis of
PTHQ and PQ catalyzed by Pd/UiO-66.
RESULTS AND DISCUSSION
Production of PTHQ with bifunctional Pd/UiO-66
MOFs have attracted great attention as solid acid
catalysts.17-20 Modifying the organic linkers or
immobilizing metal nanoparticles also introduces other
active sites.21-23 The co-existence of different active sites
can enable tandem catalysis of two or more consecutive
steps in one pot to eliminate unnecessary
In order to thoroughly study this tandem reaction and
gain insights into the fundamental principles behind, a
stable, well-defined catalyst is necessary. Metal-organic
frameworks (MOFs) give great promises for the
integration of multiple active species for tandem catalysis.
By judiciously selecting the metal centers/clusters and
ligands of the MOF, a microenvironment is created, which
can be used to introduce other catalytic species further
and to aid the catalytic process. Considering that active
species with acidity and hydrogenation capability are
separation/purification
steps
and
boost
atom
economy.1,24
In the multistep synthesis of PTHQ (Scheme 1), we first
carried out the Claisen-Schmidt condensation between
ACP (1) and NBA (2) at 100 °C with three different acidic
MOFs, including UiO-66(Zr), HKUST(Cu), and MIL-101(Cr).
The structural characterization results of these three MOFs
are shown in Figures S1-S2. UiO-66 shows the highest
catalytic activities achieving quantitative yield of ortho-
nitrochalcone (4) in 3 h, Figure 1. The high activity could
be owing to the combined efforts of Lewis acidic Zr with
missing ligand and Brønsted site by the μ3-OH in the
SBU.25,26 The strong Lewis acidity has been demonstrated
in the Meerwein‐Ponndorf‐Verley (MPV) reduction of
prenol and furfural.27 MIL-101 with coordination-
unsaturated Cr sites show only 8% conversion in 3 h,
which is much less active compared to UiO-66. Lewis
acidic HKUST-1 is inefficient in promoting the
condensation reaction, although it is active in catalyzing
the Friedländer reaction for the synthesis of quinoline.28 In
comparison, an inorganic solid acid, -Al2O3, was
examined and found nearly inactive as well. Therefore,
UiO-66 is chosen as the acidic catalyst for the multistep
reaction.
needed
to
accomplish
the
aforementioned
transformations, we constructed a bifunctional catalyst by
supporting Pd nanoparticles (NPs) on an acidic metal-
organic framework (MOF), Pd/UiO-66, Scheme 1. Using
the advanced operando spectroscopic method, we
detected and quantified key intermediates (under 27.6 bar
H2 at 40°C), in particular, the reactive 2-phenyl-3,4-
dihydroquinoline and (E)-3-(2-(hydroxyamino)phenyl)-1-
phenylprop-2-en-1-one that cannot be detected by ex-
situ sampling methods. Significantly, the obtained
mechanistic information was then utilized to unravel the
high selectivity in the phenyltetrahydroquinoline (PTHQ)
synthesis for the Pd/UiO-66 catalyst. More importantly,
the mechanistic insights further allowed us to switch the
selectivity of the product between PTHQ and
phenylquinoline (PQ) by adding a co-catalyst. These
results provide a new insight for manipulating complex
transformations.
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O
OH
O
O
condensation of –NH2 and –OH via nuclear substitution to
form PTHQ directly after reduction of both C=C and C=O.
Pd/UiO-66
CHO
- H2O
1
2
3
CH3
b
a
NO2
NO2
OH
Path II
4
ACP, 1
3
4
5
NBA, 2
N
H
NH2
NO2
6
7
8
9
O
O
Path I
Path III
Path IV
O
N
N
NH2
NO2
4
PQ, 5
10
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NH2
OH
N
NH2
H
PTHQ, 6
Scheme 2. Reductive cyclization of 4 to PTHQ catalyzed
by Pd/UiO-66, showing four possible cyclization paths.
Possible reactant H2 and product H2O are omitted.
Figure 1. Conversion of NBA versus reaction time for the
MOF-catalyzed Claisen-Schmidt condensation reaction.
Reaction conditions: NBA (0.2 mmol), ACP (0.4 mmol),
catalyst (5 mg), toluene (1 mL), 100 °C. The lines are added
only to guide the eye.
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Before carrying out the one-pot tandem synthesis of
PTHQ from NBA and ACP (discussed in a latter section),
we conducted reductive cyclization (Step 2) of 4 which
was isolated from the condensation reaction mixture (Step
1). Their concentration profiles follow pseudo-first-order
rate law when the hydrogen gas is of large excess and
catalyst concentration remains unchanged; therefore, the
results are presented as normalized concentrations in
Figure 2.30 The conversion of 4 was completed in 5 h with
56% yield to PTHQ at 40 °C under 27.6 bar H2, Figure 2A.
PQ is also formed from 4 (Figure 2A), reaching maximal
yields of 23% at 2 h. To determine whether the
hydrogenation of PQ is the major reaction path to PTHQ,
we tested the hydrogenation of PQ under the same
conditions. The PTHQ production from PQ was
significantly slower than that from 4, Figure 2B. These
results suggest that PQ is a side product rather than the
rate-limiting intermediate toward PTHQ, which is also
confirmed by the hydrogenation of 4 and PQ under
ambient-pressure H2 at 50 °C, Figure S3. Furthermore,
there is a mass loss with 4 as the reactant, which cannot
be accounted for with any peaks in gas chromatograms.
To introduce hydrogenation capability to the MOF, we
synthesized Pd NPs supported on UiO-66 via wetness
impregnation followed by reduction under flowing H2.29
The powder X-ray diffraction (PXRD) patterns show that
UiO-66 and Pd/UiO-66 match the simulated pattern of the
MOF (Figure S1A), indicating the MOF structure is
maintained after the loading of Pd NPs (2 wt%). The
Brunauer-Emmett-Teller (B.E.T.) surface areas of UiO-66
before and after loading Pd are 1800 and 1530 m2·g-1,
respectively (Figure S1C and Table S1). The micropore
volume of UiO-66 also decreases slightly from 0.50 to 0.46
cm3·g-1. X-ray diffraction peaks of Pd NPs were not
obvious, possibly due to the low metal loading. As shown
in the TEM images (Figure S1B), the Pd NPs are dispersed
uniformly mostly on the external surface of UiO-66 with
an average diameter of 4.2  0.7 nm. Kinetic studies
revealed that the catalytic activity of UiO-66 in the
Claisen-Schmidt condensation reaction only slightly
decreased after loading Pd NPs.
The production of PQ or PTHQ can be achieved via
cyclization after reduction of –NO2 in 4. The cyclization
can proceed in four possible paths (Scheme 2): (I)
condensation of –NH2 and C=O to form PQ as the direct
key intermediate; (II) condensation of –NH2 and –OH via
nuclear substitution to form intermediate 2-phenyl-1,2-
dihydroquinoline after reduction of C=O; (III)
condensation of –NH2 and C=O to intermediate 2-phenyl-
1,2-dihydroquinoline after reduction of C=C; and (IV)
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ACP on mechanistic study, 13C-labelled ACP was added
only in a slight excess.
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toluene
toluene
A
4-a
ACP-a
ACP-b
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h
1
2
195 193 188 186 137 135 25 23 21 19 17
13C  (ppm)
Figure 2. Time-resolved concentration profiles of Pd/UiO-66
catalyzed hydrogenation reaction of (A) 4 and (B) PQ at 40 °C
and 27.6 bar H2. Reaction conditions: substrate (0.2 mmol), 2
wt% Pd/UiO-66 (5 mg, ~ 0.5 mmol% Pd), solvent toluene (2
mL). Conversions were calculated based on analysis of GC
results. The lines are added to guide the eye.
Figure 3. Claisen-Schmidt condensation reaction of ACP and
NBA at 80 °C. (a) Arrays of direct polarization 13C MAS-NMR
spectra (MAS rate: 5 kHz, 8 scans per transient); (b) kinetic
analysis of time-resolved NMR spectra. The 5 mm NMR rotor
was loaded with ACP-,-13C2 (1.56 mg, 12.8 mol) and NBA
(1.61 mg, 10.7 mol) in 50 L toluene with 1 wt% Pd/UiO-66
(1 mg). The curvefits (solid lines) were obtained by fitting the
second-order rate equation.
Mechanistic study with operando MAS-NMR To
further maximize production of PQ or PTHQ, it is crucial
to understand the reaction network leading to their
formation, which is not obvious based on ex situ studies.
Previous works by Crabtree31 and Soós32 used
spectroscopic and DFT methods for the simple reduction
of quinolines to THQs using homogeneous catalysts.
Similar approaches cannot be readily applied to
heterogeneous catalytic systems due to the complexity of
the molecular transformation in our multiphasic reaction
systems. Therefore, we employed operando high-pressure
MAS-NMR studies to explore the reaction network.
In Step 1, the Claisen-Schmidt condensation was
conducted under air at 80 °C (Figure 3A). The ACP
resonances started to decrease in intensity with the
appearance of two new doublets at 187.4 and 126.5 ppm
(Figures 3A and S4), assigned to 4. A trace amount of β-
hydroxyketone intermediate
3 was detected when
The high-pressure MAS rotor33,34 was loaded with ACP,
NBA (0.83 equiv.) and Pd/UiO-66 in toluene. The ACP was
isotopically labeled at both a- and b- positions with 13C
(194.5 and 24.3 ppm, respectively), allowing fast-tracking
of molecular evolution with 13C NMR. Therefore, each
intermediate and product was detected as two doublets
lowering the reaction temperature to 60 °C, Figure S5. No
aldol product was observed between two acetophenone
molecules at both tested temperatures. At 12 h, the yield
of 4 was 80% based on ACP, and the selectivity was >99%;
besides, the total concentration stayed constant after 21
h. The concentration profiles of ACP and 4 were extracted
from the NMR arrays acquired at 80 °C (Figure 3A). The
1
due to JCC while the non-labeled positions remained
invisible. To avoid any possible influence of unreacted
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time-resolved data of ACP and 4 were curve-fitted with
second-order rate equations,35 Figure 3B. The pseudo-
second-order rate constants of ACP and compound 4
were almost identical: 2.7  0.1 M-1 h-1 and 2.6  0.2 M-1
h-1, respectively.
toluene
A
1
2
3
4
ACP-a
12-a
PQ-a
PQ-b
5
In Step 2, the rotor, further charged with 27.6 bar H2,
was heated to 40 °C and maintained for 22 h. The high
pressure of H2 gas ensured a large excess of H2 (ca. 15 of
4 by mol). Resonances of 4 disappeared after 2 h with the
appearance of several sets of doublets, Figure 4. PTHQ
(55.1 and 30.1 ppm) and PQ (155.7 and 117.2 ppm) were
observed as expected products. Two doublets at 195.7
and 37.9 ppm are assigned to the a and b carbons in 7,
arising from the reduction of the C=C in 4, Scheme 3. The
chemical shift of 7 is confirmed with an authentic sample
of 7 (Supporting information).
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4-a
8-a
9-a
9-b
8-b
7-a
4-b
195 190 185 165 160 155
130 125 120 115
A new resonance at 121.4 ppm instantly appeared in the
first spectrum and disappeared within 2 hours, following
which an adjacent signal at 120.0 ppm first formed and
then disappeared. Pairing signals of these two new
resonances (121.4 and 120.0 ppm) also partially overlap
with 4-a (187.6 ppm), indicating the two new species
preserve both C=O and C=C functionalities. The lower
frequencies of the b carbons of these two new species are
mostly due to the reduction of the –NO2 group in 4.
Therefore, we can most likely assign the new peaks to 8
containing hydroxylamine and 9 with amine (Scheme 3).
Compound 8 is an unstable molecule, and its in situ
observation (up to 0.04 mol L-1) is seldom reported. Few
reports on the detection of phenylhydroxyamine are
available with in situ and ex situ NMR but not under
pressurized H2.36,37 The detections were only reported with
in situ IR spectroscopy under pressure (10 bar H2),38,39 but
its quantification was not achieved. The formation of
stable products and intermediates, PTHQ, PQ, 4, 7, and 9,
was also confirmed by ex situ HPLC-MS analysis of
samples taken from a batch reactor after 30 min operating
at 27.6 bar and 40 °C, Figure S6.
13C  (ppm)
toluene
ACP-b
B
PTHQ-a
PTHQ-b
7-b
12-b
56 54 52 42 40 38 36 34 32 30 28 26 24 22 20 18
13C  (ppm)
Figure 4. Arrays of direct polarization 13C MAS-NMR spectra
(8 scans per transient), recorded during reductive cyclization
of 4 at 40 °C under 27.6 bar H2, showing (A) 198 - 113 ppm
and (B) 58 - 17 ppm. The 5 mm NMR rotor, containing the
reaction mixture after Claisen-Schmidt condensation, was
pressurized with H2 at 22 °C. MAS rate: 5 kHz.
Compound 11, the further hydrogenation intermediate
from either 7 or 9, cannot be identified in the NMR
spectra, nor detected by either GC-MS or HPLC-MS. The
absence of 11 is possibly due to its low concentration as
it readily cyclizes. However, the detection of 7 can
indirectly prove the existence of 11 as a short-lived
intermediate. The carbonyl signals of 4, 7, 8, and 9 drift
slightly to lower frequency, mostly due to the interaction
of their carbonyls with side-product water.
In Figure 4, there is another set of two pronounced
doublets (163.7 and 22.7 ppm), which presumably can be
assigned to 2-phenyl-3,4-dihydroquinoline (12, in Path III,
Scheme 2), agreeing with the literature results.40
Compound 12 cannot be detected by traditional
chromatographic techniques,40 including TLC (Figure S7),
GC-MS, or HPLC-MS, most likely due to its instability.
Surprisingly, our operando NMR result shows the maximal
concentration of compound 12 is as high as 0.11 mol L-1
at 4 h. The direct identification of 12 was only once
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reported, but not quantified, during the direct based on operando NMR identified intermediates, is thus
1
2
3
4
5
6
7
8
hydrogenation of quinones catalyzed by homogeneous
Ru complex, using ESI-HRMS.40 This further demonstrates
the unique capability of operando MAS-NMR in detection
and quantification of reactive intermediates to construct
complex reaction networks, while ex situ methods can only
provide insufficient or even misleading information.
demonstrated in Scheme 3.
O
b
a
9
NO2
10
11
12
13
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17
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4
+ H2
+ 2 H2
- H2O
O
O
NO2
NHOH
8
7
- 2 H2O
O
- H2O
+ H2
+ 3 H2
Figure 5. Concentration profiles of 12, PTHQ, and sum of 4,
7, 8, and 9, extracted from MAS-NMR arrays (Figure 4). For
better presentation, only every 3rd data point is shown for all
curves except the sum of 4, 7, 8, and 9. The concentration
profiles of PTHQ and 12 were analyzed with biexponential
rate equations. The other line is added only to guide the eye.
O
NH2
NH2
11
- H2O
9
- H2O
b
a
+ H2
- H2
b
a
N
N
PQ, 5
12
+ H2
b
a
+ H2
N
H
N
H
PTHQ, 6
10
Scheme 3. Reaction networks of the Pd/UiO-66 catalyzed
hydrogenation of 4 for the synthesis of 6, as demonstrated
by the NMR study. Molecules in solid box are unstable
reaction
intermediates.
Solid
lines
represent
transformations identified from experimental evidence.
Dotted lines represent other possible transformations.
Figure 6. Time-resolved concentration profiles of Pd/UiO-66
catalyzed hydrogenation reaction of 7 at 40 °C and 27.6 bar
H2. Reaction conditions: 7 (0.2 mmol), 2 wt% Pd/UiO-66 (5
mg, ~ 0.5 mmol% Pd), solvent toluene (2 mL). Conversions
were calculated based on analysis of GC results. The lines are
added only to guide the eye.
Compound 12 can be formed either by intramolecular
condensation reaction of 11 or partial reduction of PQ,
Scheme 3. The latter is rather unlikely under the reaction
condition because the maximal concentration of PQ, 0.02
mol L-1 (yield: 8 %), was reached at 7 h, and further
conversion of PQ was not clearly observed, Figure S8.
Besides, all species before cyclization (4, 7, 8, and 9) were
almost consumed when 12 peaked, indicating
unobserved compound 11 is the major source of 12,
Figure S8. The concentration of PTHQ and 12 together
with the sum of 4+7+8+9 are shown in Figure 5. The rate
constant of 12 consumption (0.18 ± 0.01 M-1 h-1) matches
well with that of PTHQ production (0.16 ± 0.01 M-1 h-1),
obtained by curvefitting according to a consecutive
reaction kinetics with two pseudo first-order reactions,
which strongly suggests that PTHQ is mostly derived from
12. The complete network of the reductive cyclization,
To better benchmark the relative rates of
hydrogenation, experiments starting with identified
intermediate 7, in comparison to 4 and PQ, were also
conducted under two conditions, 40 °C with 27.6 bar H2
(Figure 6) and 50 °C with ambient H2 (Figure S3). Under
both conditions, the reaction of 7 is slower than
compound 4 but faster than PQ, because 4 can be
converted through two subsequent pathways (to 7 and 8),
Scheme 3. The rate of PTHQ production from 4 and 7
(Figures 2A and 6) is almost identical. Besides, the
concentration build-up was clearly observed for 12 but
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not for 11. Together, these results suggest the turnover- molecular-level understanding of reaction network in
1
2
3
4
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6
7
8
limiting step is most likely the hydrogenation of 12. PQ
cannot be directly produced from 9 because 9 preserves
the trans-configuration of corresponding starting material
catalysis.
co-catalyst
- 2 H
N
O
3
PQ, 5
4 with a large JHH coupling constant (15.5 Hz) of the
N
olefinic protons. Therefore, PQ is yielded as a result of the
Pd/UiO-66 catalyzed dehydrogenation of 12. Similar
dehydrogenation reactions have been reported as an
equilibrium enabled by Pd-based catalysts for reversible
hydrogen storage.41 The hydrogenation of 12 to PTHQ is
faster than the dehydrogenation of 12 to PQ in the
presence of H2.
+ H2
NO2
12
4
N
H
PTHQ, 6
P1
P2
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O
O
O
co-catalysts:
O
O
P
P
OH
O
OH
The mechanistic study clearly shows that Pd/UiO-66 can
selectively favor the PTHQ formation pathway with a lower
activation barrier, suggesting the advantage in using the
reductive intramolecular cyclization reaction, when
compared to the direct reduction of PQ. It should be
noted that the full conversion of PQ to PTHQ via 12 can
be achieved but under more forcing conditions (i.e.,
higher temperature).
Scheme 4. Hydrogenation of 4 with and without P1 and
P2 co-catalyst.
Table 1. Hydrogenation of different substrates catalyzed
by Pd/UiO-66 with and without co-catalystsa
yield (%)b
amou
nt
Selective production of PQ over PHTQ The
identification of reactive intermediates, i.e. 12, allows us
the ability of switching the product selectively from PTHQ
to PQ, by selectively enhancing the dehydrogenation of
12 to PQ. We employed two phosphoric acids as
homogeneous transfer hydrogenation catalysts (Scheme
4), P1 with two phenyls and P2 with an octahydro-BINOL
derivative. P1 and P2 have been widely applied in transfer
hydrogenation reactions with Hantzsch ester as the
hydrogen sources.42,43 More importantly, both P1 and P2
are inert in H2 activation44-46 and phosphoric acids do not
affect the structures and activity of Pd nanoparticles for
hydrogenation reactions,47 particularly when accessibility
of acid center in P2 is protected by sterically-restricting
neighboring group.48 Using the same reaction condition
in the MAS-NMR study, all reactions initiating with 4
reached 100% conversion in 19 h with or without the use
of co-catalysts, Table 1.
entr substrat
co-
catalyst
P
y
es
PTHQ
mol%
Q


2
1
2
3
4
5
6
4
95
82
70
23

1
4
4
P1
P2
P2

9
2
24
71
≤1
≤1
4
20

PTHQ

PTHQ
P2
20
a Reaction conditions: (1) 4 (0.1 mmol), 2 wt% Pd/UiO-66
(5 mg), toluene (1 mL), 40 °C, 27.6 bar H2, 19 h b All yields
are calculated by GC with mesitylene as the internal
standard.
CONCLUSION
In conclusion, we have employed operando high-pressure
MAS-NMR spectroscopy to construct the reaction
network and achieve product selectivity in the synthesis of
PTHQ and PQ. An acidic MOF-supported Pd NPs (Pd/UiO-
66) as a bifunctional catalyst is used to achieve the one-
pot tandem synthesis. The acidic sites in UiO-66 were
efficient in catalyzing the Claisen-Schmidt condensation
between NBA and ACP, and the in situ formed ortho-
nitrochalcone was reduced multi-stepwise by the
supported Pd NPs under H2, generating PTHQs in
moderate to high isolated yields. Multiple stable and
unstable intermediates were pinpointed and quantified
under the operando condition, which allows the clear
elucidation of the conversion pathways under 27.6 bar H2.
The mechanistic insights not only demonstrate a catalyst-
enabled route for efficient chemical transformation under
milder conditions but also allow us to selectively produce
Without any co-catalyst, 4 converted to PTHQ in high
yield with only 1% of PQ (Table 1, entry 1); nevertheless,
higher selectivity toward PQ (9%) was observed after
adding 2 mol% P1 (Table 1, entry 2). Changing the co-
catalyst to P2 (2 and 20 mol%) shifts the product
selectivity more obviously, increasing the yield of PQ to
24% and 71%, respectively (Table 1, entries 3 and 4). It
should be noted that the 71% yield of PQ was achieved
under 27.6 bar H2 in the presence of Pd. Furthermore,
reactions starting with PTHQ did not yield PQ (Table 1,
entries 5 and 6), suggesting PQ is solely generated from
12 in the presence of the co-catalyst. The success in the
mechanism-inspired switch of the products on demand
provides us an extra measure to achieve selective
synthesis which further demonstrates the importance of a
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high-resolution mass spectrometry; TLC, thin layer
chromatography.
PQ or PTHQ via kinetic control of the conversion of the in
situ observed key intermediate (12) employing
1
2
3
4
5
6
7
8
a
homogeneous co-catalyst in addition to heterogeneous
Pd/UiO-66. The demonstrated methodology, i.e.,
mechanistic study-guided design of catalytic systems, can
be well applied to other tandem reactions with complex
reaction network involving multi-step interconnected
transformations of various functional groups.
REFERENCES
(1)
Huang, Y.-B.; Liang, J.; Wang, X.-S.; Cao, R. Multifunctional
Metal–Organic Framework Catalysts: Synergistic Catalysis and
Tandem Reactions. Chem. Soc. Rev. 2017, 46, 126-157.
(2)
Li, X.; Zhang, B.; Tang, L.; Goh, T. W.; Qi, S.; Volkov, A.; Pei,
Y.; Qi, Z.; Tsung, C.-K.; Stanley, L.; Huang, W. Cooperative
Multifunctional Catalysts for Nitrone Synthesis: Platinum
Nanoclusters in Amine-Functionalized Metal–Organic Frameworks.
Angew. Chem., Int. Edit. 2017, 56, 16371-16375.
9
ASSOCIATED CONTENT
Supporting Information
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3)
Hunger, M.; Weitkamp, J. In Situ IR, NMR, EPR, and UV/Vis
Supporting Information is available free of charge on the ACS
Publications website. Examples for the synthesis of PTHQs
and PQs, structural characterization of catalysts
(physisorption and XRD), additional ex situ reactivity results,
operando NMR and related analysis, and characterization of
reaction species. (PDF)
Spectroscopy: Tools for New Insight into the Mechanisms of
Heterogeneous Catalysis. 2001, 40, 2954-2971.
(4)
Qi, L.; Alamillo, R.; Elliott, W.; Andersen, A.; Hoyt, D.; Walter,
E.; Sung Han, K.; Washton, N.; M Rioux, R.; A Dumesic, J.; L Scott, S.;
Walter, E.; Kee; Han, S. Operando Solid-State NMR Observation of
Solvent-Mediated Adsorption-Reaction of Carbohydrates in Zeolites.
ACS Catal. 2017, 7, 3489-3500.
(5)
Qi, L.; Chamas, A.; Jones, Z. R.; Walter, E. D.; Hoyt, D. W.;
AUTHOR INFORMATION
Washton, N. M.; Scott, S. L. Unraveling the Dynamic Network in the
Reactions of an Alkyl Aryl Ether Catalyzed by Ni/ γ -Al2O3 in 2-
Propanol. J. Am. Chem. Soc. 2019, 141, 17370-17381.
Corresponding Author
*lqi@iastate.edu
(6)
Katritzky, A. R.; Rachwal, S.; Rachwal, B. Recent Progress in
*zhiguo.zhang@zju.edu.cn
*whuang@iastate.edu
the Synthesis of 1,2,3,4-Tetrahydroquinolines. Tetrahedron 1996, 52,
15031-15070.
(7)
Salas, P. F.; Herrmann, C.; Orvig, C. Metalloantimalarials.
ORCID
Chem. Rev. 2013, 113, 3450-3492.
(8)
Wiesner, J.; Ortmann, R.; Jomaa, H.; Schlitzer, M. New
Long Qi: 0000-0002-1213-2946
Zhiguo Zhang: 0000-0003-1681-4853
Wenyu Huang: 0000-0003-2327-7259
Antimalarial Drugs. Angew. Chem., Int. Edit. 2003, 42, 5274-5293.
(9)
Mukherjee, S.; Pal, M. Medicinal Chemistry of Quinolines
as Emerging Anti-Inflammatory Agents: An Overview. Curr. Med.
Chem. 2013, 20, 4386-4410.
Author Contributions
(10)
Zemtsova, M. N.; Zimichev, A. V.; Trakhtenberg, P. L.;
Klimochkin, Y. N.; Leonova, M. V.; Balakhnin, S. M.; Bormotov, N. I.;
Serova, O. A.; Belanov, E. F. Synthesis and Antiviral Activity of Several
Quinoline Derivatives. Pharm. Chem. J. 2011, 45, 267-269.
‡ These authors contributed equally.
Notes
(11)
in Cancer Drug Discovery. Curr. Med. Chem. 2011, 18, 1488-1508.
(12) Afzal, O.; Kumar, S.; Haider, M. R.; Ali, M. R.; Kumar, R.; Jaggi,
M.; Bawa, S. Review on Anticancer Potential of Bioactive
Heterocycle Quinoline. Eur. J. Med. Chem. 2015, 97, 871-910.
(13) Musiol, R. An Overview of Quinoline as a Privileged
Solomon, V. R.; Lee, H. Quinoline as a Privileged Scaffold
The authors declare no competing financial interest.
Funding Sources
A
J.C., Z.B., Q.Y., Q.R. and Z.Z. are grateful for financial support
from the National Key R&D Program of China
(2016YFA0202900), the National Natural Science Foundation
of China (21878266, 21722609). J. Chen thanks Zhejiang
University for financial support. We thank the support from
Iowa State University. L.Q. and T.K. are supported by the U.S.
Department of Energy (DOE), Office of Basic Energy Sciences,
Division of Chemical Sciences, Geosciences, and Biosciences.
The Ames Laboratory is operated for the U.S. DOE by Iowa
State University under Contract No. DE‐AC02‐07CH11358.
W.H. appreciate the support from National Science
Foundation (NSF) grant CHE-1566445.
Scaffold in Cancer Drug Discovery. Expert Opin. Drug. Dis. 2017, 12,
583-597.
(14)
Heterocycles. Energ Environ. Sci. 2008, 1, 134-138.
(15) Sridharan, V.; Suryavanshi, P. A.; Menendez, J. C. Advances
Crabtree, R. H. Hydrogen Storage in Liquid Organic
in the Chemistry of Tetrahydroquinolines. Chem. Rev. 2011, 111,
7157-7259.
(16)
Scott, J. D.; Williams, R. M. Chemistry and Biology of the
Tetrahydroisoquinoline Antitumor Antibiotics. Chem. Rev. 2002, 102,
1669-1730.
(17)
Hu, Z.; Zhao, D. Metal-Organic Frameworks with Lewis
Acidity: Synthesis, Characterization, and Catalytic Applications.
CrystEngComm 2017, 19, 4066-4081.
ACKNOWLEDGMENT
We thank Gordon J. Miller for the use of the XRD instrument.
(18)
Hajek, J.; Vandichel, M.; Van de Voorde, B.; Bueken, B.; De
Vos, D.; Waroquier, M.; Van Speybroeck, V. Mechanistic Studies of
Aldol Condensations in UiO-66 and UiO-66-NH2 Metal Organic
Frameworks. J. Catal. 2015, 331, 1-12.
ABBREVIATIONS
NMR, nuclear magnetic resonance; HPLC, high-performance
liquid chromatography; ESI-HRMS, electro-spray ionization
(19)
Katz, M. J.; Mondloch, J. E.; Totten, R. K.; Park, J. K.; Nguyen,
S. T.; Farha, O. K.; Hupp, J. T. Simple and Compelling Biomimetic
ACS Paragon Plus Environment

Page 9 of 10
ACS Catalysis
Metal-Organic Framework Catalyst for the Degradation of Nerve
Agent Simulants. Angew. Chem., Int. Edit. 2014, 53, 497-501.
(20) Granadeiro, C. M.; Ribeiro, S. O.; Karmaoui, M.; Valenca, R.;
Ribeiro, J. C.; De Castro, B.; Cunha-Silva, L.; Balula, S. S. Production of
Ultra-Deep Sulfur-Free Diesels Using a Sustainable Catalytic System
Based on UiO-66(Zr). Chem. Commun. 2015, 51, 13818-13821.
(36)
Chen, G. X.; Xu, C. F.; Huang, X. Q.; Ye, J. Y.; Gu, L.; Li, G.;
1
2
3
4
5
6
7
8
Tang, Z. C.; Wu, B. H.; Yang, H. Y.; Zhao, Z. P.; Zhou, Z. Y.; Fu, G.; Zheng,
N. F. Interfacial Electronic Effects Control the Reaction Selectivity of
Platinum Catalysts. Nat. Mater. 2016, 15, 564-571.
(37)
Gao, Y. J.; Ma, D.; Wang, C. L.; Guan, J.; Bao, X. H. Reduced
Graphene Oxide as a Catalyst for Hydrogenation of Nitrobenzene at
Room Temperature. Chem. Commun. 2011, 47, 2432-2434.
(38)
M.; Hungerbuhler, K. In Situ Infrared Monitoring of the Solid/Liquid
Catalyst Interface During the Three-Phase Hydrogenation of
Nitrobenzene over Nanosized Au on TiO2. Phys. Chem. Chem. Phys.
2011, 13, 12463-12471.
(21)
Yang, Q.; Xu, Q.; Jiang, H. L. Metal-Organic Frameworks
Meet Metal Nanoparticles: Synergistic Effect for Enhanced Catalysis.
Chem. Soc. Rev. 2017, 46, 4774-4808.
Richner, G.; van Bokhoven, J. A.; Neuhold, Y. M.; Makosch,
(22)
Chen, L.; Luque, R.; Li, Y. Controllable Design of Tunable
9
Nanostructures inside Metal-Organic Frameworks. Chem. Soc. Rev.
2017, 46, 4614-4630.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(23)
Hosts for Nanoparticles. CrystEngComm 2015, 17, 199-217.
(24) Dhakshinamoorthy, A.; Garcia, H. Cascade Reactions
Catalyzed by Metal Organic Frameworks. ChemSusChem 2014, 7,
2392-2410.
Rosler, C.; Fischer, R. A. Metal-Organic Frameworks as
(39)
Corma, A.; Concepcion, P.; Serna, P. A Different Reaction
Pathway for the Reduction of Aromatic Nitro Compounds on Gold
Catalysts. Angew. Chem., Int. Edit. 2007, 46, 7266-7269.
(40)
Q.-H.; Xiang, J.; Yu, Z.-X.; Chan, A. S. C. Highly Enantioselective
Hydrogenation of Quinolines Using Phosphine-Free Chiral Cationic
Ruthenium Catalysts: Scope, Mechanism, and Origin of
Enantioselectivity. J. Am. Chem. Soc. 2011, 133, 9878-9891.
Wang, T.; Zhuo, L.-G.; Li, Z.; Chen, F.; Ding, Z.; He, Y.; Fan,
(25)
Frameworks. Chem. Rev. 2015, 115, 6966-6997.
(26) Hajek, J.; Caratelli, C.; Demuynck, R.; De Wispelaere, K.;
Jiang, J.; Yaghi, O. M. Brønsted Acidity in Metal–Organic
Vanduyfhuys, L.; Waroquier, M.; Van Speybroeck, V. On the Intrinsic
Dynamic Nature of the Rigid UiO-66 Metal–Organic Framework.
Chem. Sci. 2018, 9, 2723-2732.
(41)
Deraedt, C.; Ye, R.; Ralston, W. T.; Toste, F. D.; Somorjai, G.
A. Dendrimer-Stabilized Metal Nanoparticles as Efficient Catalysts for
Reversible Dehydrogenation/Hydrogenation of N-Heterocycles. J.
Am. Chem. Soc. 2017, 139, 18084-18092.
(42)
Brønsted
Organocatalytic Reduction of Quinolines. Synlett 2006, 1071-1074.
(43) Rueping, M.; Theissmann, T.; Raja, S.; Bats, J. W. Asymmetric
Counterion Pair Catalysis: An Enantioselective Brønsted Acid-
Catalyzed Protonation. Adv. Synth. Catal. 2008, 350, 1001-1006.
(44)
(27)
Hajek, J.; Bueken, B.; Waroquier, M.; De Vos, D.; Van
Speybroeck, V. The Remarkable Amphoteric Nature of Defective UiO-
66 in Catalytic Reactions. ChemCatChem 2017, 9, 2203-2210.
Rueping, M.; Theissmann, T.; Antonchick, A. P. Metal-Free
Acid Catalyzed Transfer Hydrogenation-New
(28)
Elena, P. M.; Jiří, Č. [Cu3(BTC)2]:
A
Metal–Organic
Framework Catalyst for the Friedländer Reaction. ChemCatChem
2011, 3, 157-159.
(29)
Li, X. L.; Guo, Z. Y.; Xiao, C. X.; Goh, T. W.; Tesfagaber, D.;
Huang, W. Y. Tandem Catalysis by Palladium Nanoclusters
Encapsulated in Metal-Organic Frameworks. ACS Catal. 2014, 4,
3490-3497.
Fleischer, S.; Zhou, S.; Werkmeister, S.; Junge, K.; Beller, M.
Cooperative Iron–Brønsted Acid Catalysis: Enantioselective
Hydrogenation of Quinoxalines and 2 H-1,4-Benzoxazines. Chem.—
Eur. J. 2013, 19, 4997-5003.
(30)
Davis, M. E.; Davis, R. J., Fundamentals of Chemical Reaction
Engineering. Courier Corporation: 2012.
(45)
Qin, J.; Chen, F.; He, Y.-M.; Fan, Q.-H. Asymmetric
(31)
Dobereiner, G. E.; Nova, A.; Schley, N. D.; Hazari, N.; Miller,
Hydrogenation of 3-Substituted 2H-1,4-Benzoxazines with Chiral
Cationic Ru-MsDPEN Catalysts: A Remarkable Counteranion Effect.
Org. Chem. Front. 2014, 1, 952-955.
S. J.; Eisenstein, O.; Crabtree, R. H. Iridium-Catalyzed Hydrogenation
of N-Heterocyclic Compounds under Mild Conditions by an Outer-
Sphere Pathway. J. Am. Chem. Soc. 2011, 133, 7547-7562.
(46)
Chen, Q.-A.; Gao, K.; Duan, Y.; Ye, Z.-S.; Shi, L.; Yang, Y.;
(32)
Erős, G.; Nagy, K.; Mehdi, H.; Pápai, I.; Nagy, P.; Király, P.;
Zhou, Y.-G. Dihydrophenanthridine: A New and Easily Regenerable
NAD(P)H Model for Biomimetic Asymmetric Hydrogenation. J. Am.
Chem. Soc. 2012, 134, 2442-2448.
Tárkányi, G.; Soós, T. Catalytic Hydrogenation with Frustrated Lewis
Pairs: Selectivity Achieved by Size-Exclusion Design of Lewis Acids.
Chem.—Eur. J. 2012, 18, 574-585.
(47)
Chase, Z. A.; Fulton, J. L.; Camaioni, D. M.; Mei, D.;
(33)
Walter, E.; Qi, L.; Chamas, A.; Mehta, H.; Sears, J.; L Scott, S.;
Balasubramanian, M.; Pham, V.-T.; Zhao, C.; Weber, R. S.; Wang, Y.;
Lercher, J. A. State of Supported Pd During Catalysis in Water. J. Phys.
Chem. C 2013, 117, 17603-17612.
Hoyt, D. Operando MAS-NMR Reaction Studies at High
Temperatures and Pressures. J. Phys. Chem. C 2018, 122, 8209-8215.
(34)
Chamas, A.; Qi, L.; Mehta, H. S.; Sears, J. A.; Scott, S. L.;
(48)
Rueping, M.; Antonchick, A. P.; Theissmann, T. A Highly
Walter, E. D.; Hoyt, D. W. High Temperature/Pressure MAS-NMRmr
for the Study of Dynamic Processes in Mixed Phase Systems. Magn.
Reson. Imaging 2019, 56, 37-44.
Enantioselective Brønsted Acid Catalyzed Cascade Reaction:
Organocatalytic Transfer Hydrogenation of Quinolines and Their
Application in the Synthesis of Alkaloids. Angew. Chem., Int. Edit.
2006, 45, 3683-3686.
(35)
Espenson, J. H., Chemical Kinetics and Reaction
Mechanisms. McGraw-Hill New York: 1995; Vol. 102.
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