CuMgAl hydrotalcite as an efficient bifunctional catalyst for the cross-dehydrogenative C–C coupling reactions under mild conditions

Article abstract of DOI:10.1016/j.apcata.2020.117771

CuMgAl layered double hydroxide compounds (CuMgAl-LDHs) have been synthesized, characterized and investigated in the aerobic CDC reactions. The results indicated that NH₃·H₂O coprecipitated CuMgAl LDH (N-CuMgAl-LDH) was able to effic

Full text of DOI:10.1016/j.apcata.2020.117771

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CuMgAl Hydrotalcite as an Efficient Bifunctional Catalyst for the
Cross-Dehydrogenative C–C Coupling Reactions under Mild
Conditions<!–<ForCover>Zhou W, Lu W, Wang H, Xia Z, Zhai S, Zhang
Z, Ma Y, He M, Chen Q, CuMgAl Hydrotalcite as an Efficient Bifunctional
Catalyst for the Cross-Dehydrogenative C–C Coupling Reactions under
Mild Conditions, Applied Catalysis A, General, doi:
10.1016/j.apcata.2020.117771</ForCover>–>
Weiyou Zhou, Wangmingzhu Lu, Hui Wang, Zhenzhen Xia,
Shaoyan Zhai, Zhong Zhang, Yuanjun Ma, Mingyang He, Qun Chen
PII:
S0926-860X(20)30364-1
DOI:
https://doi.org/10.1016/j.apcata.2020.117771
APCATA 117771
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Applied Catalysis A, General
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CuMgAl Hydrotalcite as an Efficient Bifunctional Catalyst for the
Cross-Dehydrogenative C–C Coupling Reactions under Mild
Conditions
Weiyou Zhou*, Wangmingzhu Lu, Hui Wang, Zhenzhen Xia, Shaoyan Zhai, Zhong Zhang, Yuanjun Ma,
Mingyang He*, Qun Chen
Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, Changzhou University, Changzhou 213164, China
*
Corresponding author. Fax: +86 51986330251.
E-mail address: zhouwy426@126.com (W.Y. Zhou); hemy_cczu@126.com (M.Y. He).
Graphical abstract
Highlights


CuMgAl LDH acts as an efficient heterogeneous catalyst for the CDC reaction.
Efficient heterogeneous catalyst for the CDC reaction between N-aryltetrahydroisoquinolines
and various C-H bonds.



NH3·H2O copreciptated CuMgAl hydrotalcite exhibites “acidic” surface property.
Redox-acidity dual function has been observed in the aerobic CDC reaction.
A probable reaction mechanism comprising an iminium ion intermediate was proposed.
Abstract: CuMgAl layered double hydroxide compounds (CuMgAl-LDHs) have been synthesized,
characterized and investigated in the aerobic CDC reactions. The results indicated that NH3·H2O
1

coprecipitated CuMgAl LDH (N-CuMgAl-LDH) was able to efficiently accelerate the CDC reactions
between the α-Csp3–H of N-aryltetrahydroisoquinolines and nucleophiles. A wide scope of
N-aryltetrahydroisoquinoline analogues and nucleophiles with different C–H bonds (Csp3–H, Csp2–H and
Csp–H) could be tolerated by the N-CuMgAl-LDH system. Compared with the sample using Na2CO3 as the
precipitant (C-CuMgAl-LDH), N-CuMgAl-LDH showed higher catalytic activity, which probably was due
to its higher surface acidity. Dual function of redox and acidity for the N-CuMgAl-LDH catalyst has been
observed in the CDC reaction. According to the obtained catalytic results, kinetic isotope effect experiment
and XPS analysis, iminium ion was proposed as the key intermediate, made possible by the cycle of Cu2+
and Cu+ under the aerobic conditions.
Keywords: CuMgAl hydrotalcite; cross-dehydrogenative-coupling reaction; tetrahydroquinoline;
bifunctional catalysis; surface acidity
1. Introduction
Cross-dehydrogenative-coupling (CDC) reaction has been a vital tool for constructing C–C bonds,
which avoids prefunctionalization of the substrates and provides an environmentally friendly synthetic
process with high atom economy [1,2]. In spite of the significant progress made in homogeneous catalytic
systems derived from metal salts or complexes of Cu [3-11], Co [12], Fe [13-16], Ru [17-19], Au [20] and
Rh [21, 22], etc, and in some metal-free systems [23-27], it is hard for homogeneous systems to achieve
sustainability and cost-effectiveness. Actually, some heterogeneous catalytic systems, including
nanoporous gold [28], magnetic nanoparticle-immobilized bipy-gold(III) complex [29],
graphene-supported RuO2 [30] and some photocatalyzed systems [31-36] have been described for the
transformation. However, most of these catalysts were based on noble metals or required complicated
preparation methods, and sometimes peroxides or additives were needed. Although SBA-15-support iron
terpyridine [37] and CuFe2O4 nanoparticles [38] have been developed for the CDC reaction, TBHP
(tert-butyl hydroperoxide) or benzoquinone analogues were required as additives in some cases. Therefore,
developing efficient and recyclable catalyst originated from available materials using molecular oxygen
without any additives for CDC reaction is still highly desirable. Furthermore, all the above heterogeneous
2

catalytic systems have only been explored for limited types of substrate.
According to the proposed reaction path for the CDC reaction of N-aryltetrahydroisoquinolines [3, 33,
34], it is generally believed that iminium cation is firstly formed via oxidative dehydrogenation, and a
nucleophile attacks the intermediate to afford the coupled products. Copper salts and complexes have been
most extensively studied as catalysts for the CDC reactions, and the most notable examples are
CuBr/TBHP and CuCl2/O2, developed by Li’s [2,10] and Klussmann’s groups [3], respectively. Copper
species have been considered to be effective for the first reaction step and formation of iminium cation
[3-11], and base or acid is suggested to be helpful for the following nucleophilic reaction. On the other
hand, layered hydroxide compounds (LDHs), have been widely applied as catalyst in various reactions for
its adjustability of metallic composition and surface physicochemical properties [39-42]. In our recent
research, LDHs with different compositions have been found effective in the catalytic dehydrogenation of
alcohols [43-46] and N-heterocycles [47]. On the basis of the above analysis and our obtained results, we
envisioned that introducing Cu into LDHs structure might provide an efficient heterogeneous catalyst for
the CDC reaction between N-aryltetrahydroisoquinolines and various C–H bonds.
In the present study, CuMgAl LDHs were prepared respectively with NH3·H2O and Na2CO3 as the
precipitant, which would lead to different interlayer anions and varied surface properties. Although these
are the common reagents in preparing LDHs, rare study has been reported for the effect on the catalytic
activity in organic transformation. The prepared samples were then characterized and investigated in the
catalytic aerobic CDC reaction without any additives. Good results have been obtained for the present
catalytic system, and the bifunctional roles of the catalyst and possible reaction pathway have also been
discussed according to a series of controlled experiments.
2. Experimental
2.1 Chemicals
All the chemicals used were obtained from commercial sources.
N-phenyl-1,2,3,4-tetrahydroisoquinolines were synthesized from corresponding tetrahydroisoquinolines
and aryl halides according to the reported method [48]. 1-Deutero-2-phenyl-1,2,3,4- tetrahydroisoquinoline
(1a-d1) was synthesized according to the reported method [3], and the purity of 1a-d1 was 89% according to
1HNMR analysis.
3

2.2 Synthesis of CuMgAl LDHs
Taking N-CuMgAl-LDH as an example, solution (I) was prepared by dissolving Cu(NO3)2·6H2O (0.05
mol), Mg(NO3)2·6H2O (0.05 mol) and Al(NO3)3·6H2O (0.05 mol) in 150 mL deionized water. The solution
(II) and (III) were prepared by dissolving NaOH (0.04 mol) and NH3·H2O (25～28%, 20.0 g) in 100 mL
deionized water, respectively. Next, the solution (I) and (II) were added dropwise into solution (III) with
stirring (400 r/min) under 60 ℃and a pH=10±0.2 was maintained. The suspension was stirred for another 3
h. After being digested at 40 ℃for 14 h, the obtained precipitate was washed to neutrality. The powdery
N-CuMgAl-LDH sample was obtained after being dried at 70 ℃for 12 h. C-CuMgAl-LDH sample was
prepared through the same procedure by replacing the NH3·H2O with Na2CO3. Mg2Al-LDH was obtained
by similar procedure.
2.3 Characterization of CuMgAl LDHs
The structure and morphology of samples were confirmed by Powder X-ray diffraction (XRD, Rigaku
D/max 2500 PC X-ray diffractometer), scanning electron microscopy (SEM, JSM-6010plus/LV scanning
electron microscope) and Transmission electron microscope (TEM, JEM 2100). The contents of Cu, Mg
and Al were obtained via inductively coupled plasma analysis (ICP) in a Varian Vista-AX device. The FTIR
spectra were analyzed on a Nicolet PROTÉGÉ 460 FTIR spectrometer. X-ray photoelectron spectroscopy
(XPS) was measured on a Thermo Scientific ESCALAB 250Xi instrument. ESI-MS analysis for the
intermediate was performed on a Finnigan TSQ Quantum Mass Spectrometer. Porosity and surface area
studies were conducted on a micromeritics ASAP2010C apparatus. The surface area was calculated using
the BET method and the pore size distributions were deduced from the adsorption branches of the
isotherms using the BJH method.
Temperature programmed desorption of ammonia (NH3-TPD) was conducted on an AutoChem II 2920
TPR/TPD instrument equipped with mass detector (MS). The samples (120 mg) were first pretreated for 2
h at 150 ℃with a carrier gas He flow-rate of 50 mL/min. Then ammonia was adsorbed at 50 ℃for 1 h
using 10% NH3/He with a flow-rate of 50 mL/min. He flow (50 mL /min) was purged for 1h to remove the
excess ammonia. Finally, the temperature was increased linearly at a rate of 10 ℃/min from 50 ℃until all
the ammonia was desorbed. The desorbed ammonia was detected by a mass detector,
Infrared spectra of pyridine adsorption (Py-IR) was recorded to determine the type and ratio of acid
4

sites with NICOLET 6700 spectrometer with a wedge attenuator in the reference beam. Selfsupporting
discs of samples were made by pressing 100 mg of dry powder at 108 N/m2 in a 25 mm diameter die. The
samples were outgassed for 1 h at 100 ℃. Then pyridine (1.5 mmHg) was adsorbed (0.5 h, r.t.), its excess
was eliminated by evacuation (0.5 h, r.t.) and the spectrum was recorded. Pyridine was then desorbed for 1
h at 150 ℃and spectra recorded.
2.4 CDC reaction between N-phenyl-1,2,3,4-tetrahydroisoquinoline and nitromethane
Typically, a mixture of N-phenyl-1,2,3,4-tetrahydroquinoline (1a, 0.50 mmol), nitromethane (2a, 3.0
mmol), N-CuMgAl-LDH (0.2 g), 1, 4-dioxane (2 mL) and 1,4-dinitrobenzene (0.1 mmol) in a Schlenk
reactor was stirred at 80 ℃under oxygen atmosphere. TLC was used to monitor the CDC reaction, and the
product 3aa was analyzed through a NMR spectrometer (400 MHz). After the finish, the reaction mixture
was cooled and filtrated. After being washed with ethyl acetate and dried, the obtained catalyst was
recycled in a similar reaction. The conversion of 1a and the selectivity of CDC product were calculated
according to the 1HNMR analysis (using 1,4-dinitrobenzene as the internal standard reference). The
turnover frequency (TOF) value was calculated according to the Cu content on the surface of catalyst with
a <10% conversion. The surface Cu amount was determined by the Langmuir adsorption isotherms of
phenol on the catalyst [49] (Fig. S1). The parameters are defined as follows:
moles of 1a converted
Conversion（%）
Selectivity（%）
TOF（h-1）
100%
100%
moles of 1a in feed
moles of 3aa formed
moles of 1a converted
moles of 1a converted
moles of surface active sites  reaction time
2.5 Kinetic isotope effect studies
The reactions were performed as described above except for the use of 1a-d1 instead of 1a. When
1a-d1 was completely converted, KIE values kH/kD were calculated based on the 1H-NMR analysis. For the
calculation of KIE values, it was taken into account that substrate 1a-d1 was only 89% pure, containing 11%
of the nondeuterated 1a.
3. Results and discussion
3.1 Characterization of CuMgAl LDHs
5

Two methods have been applied to prepare CuMgAl LDHs by using NH3·H2O (N-CuMgAl-LDH)
and Na2CO3 (C-CuMgAl-LDH) as the precipitant, respectively. For the two samples, the characteristic
hydrotalcite reflections can be obviously found from the XRD patterns depicted in Fig. 1. The (003) and
(006) planes can be found at 11° and 22°, respectively; and the broad peaks between 33~47° are related to
the (012), (015) and (019) planes [50,51]. The distinguishable reflections between 60～63° are related to
planes (110) and (113). The peak shape for the C-CuMgAl-LDH indicates its well ordering of both the
anions and the cations [52, 53], while N-CuMgAl-LDH exhibits lower crystallinity. The diffraction sites for
(003), (006) and (018) are varied for the two samples. The lattice parameters “c” corresponding to the sum
of the thickness of a brucite-like layer and an interlayer can be calculated from (003) reflection. The “c”
parameter increased from 7.609 to 8.874 when NH3·H2O was used as the precipitant instead of NaCO3,
indicating the main interlayer anions were NO3‒ and CO32‒ respectively for N-CuMgAl-LDH and
C-CuMgAl-LDH samples [54].
Figure 1
The DR UV-Vis results (Fig. S2) of the two samples were in accordance to the previous reports [52,
55], two main bands around 250 and 720 nm accompanied. The first band can be attributed to the O2‒
→Cu2+ ligand to metal charge transfer transition, and the other broad band is related to d–d transitions of
Cu2+ ions in the distorted octahedron. Concerning the FTIR spectra (Fig. S3), the two samples displayed
similar profiles at the band around 3456 cm-1 and 1637 cm-1, which is generally related to the OH stretching
vibration of layer hydroxyl groups and interlayer water molecules [52, 56]. The smaller half-width of the
peak at 3456 cm-1 for the C-CuMgAl-LDH than for the N-CuMgAl-LDH sample reflects a more ordered
cation distribution in the former, in consistent with the XRD analysis [57]. The band at 1384 cm-1 in
N-CuMgAl-LDH is attributed to the vibration of NO3‒ groups and a shoulder peak at 1366 cm-1 is linked to
carbonate traces [54, 57]. The strong band at 1366 cm-1 is described to the asymmetric stretching mode of
the carbonate species, indicating the intercalated CO32‒ in C-CuMgAl-LDH sample. The bands below 700
cm-1 are assigned to metal oxygen modes in the hydrotalcite lattice [52]. The SEM and TEM micrographs
(Fig. 2) show that the prepared CuMgAl LDHs with different precipitants were plate-like particle, further
indicating the formation of hydrotalcites [58,59]. And the crystallinity for C-CuMgAl-LDH was obviously
higher than N-CuMgAl-LDH.
6

Figure 2
XPS spectra were conducted to better verify the Cu species in the N-CuMgAl-LDH and
C-CuMgAl-LDH samples. As illustrated in Fig. 3, the main peaks of Cu 2p3/2 for the N-CuMgAl-LDH and
C-CuMgAl-LDH catalysts are both located at around 933.6 eV, indicating that Cu species exist in Cu(II)
state in the two prepared samples [60, 61], in consistent with DR UV-Vis analysis.
Figure 3
Then, nitrogen sorption measurement was carried out to elucidate the textural parameters of the
CuMgAl LDHs. The N2 adsorption-desorption isotherm at ‒196 ℃for the two samples are shown in Fig.
S4. According to the IUPAC classification, the isotherms for the two samples are type IV, in consistent with
the mesoporous structure of the materials. In contrast, the hysteresis loops are different, suggesting the
different types of pore shapes, further verifying the different composition in the interlayers of the two
samples. H2 type hysteresis loop was observed for the C-CuMgAl-LDH, while N-CuMgAl-LDH showed
broad H3 type hysteresis loop, which might be attributed to aggregation of plate-like particles containing
slit-shaped pores [62]. On the other hand, C-CuMgAl-LDH exhibited a BET surface area of 73.2 m2/g,
markedly higher than that of N-CuMgAl-LDH (Table 1). The pore volume and average pore diameter of
C-CuMgAl-LDH sample were all bigger than N-CuMgAl-LDH, which might be attributed to the lower
crystallinity of N-CuMgAl-LDH.
Table 1
An interesting find is that suspension of N-CuMgAl-LDH sample in water showed slight acidic
property (pH = 6.87, Table 1), while common hydrotalcites generally exhibit basicity [43, 63], just like the
prepared C-CuMgAl-LDH (pH = 8.88, Table 1). The difference might be related to the interlayer anions of
the two samples, as discussed for the XRD pattern and FTIR spectra. The NH3-TPD was further introduced
to elucidate the surface acidity of the two samples. To avoid the influence of pretreatment on the samples,
the samples were pretreated at 150 ℃to maintain the hydrotalcite structure; and MS detector was applied to
avoid the influence of H2O and CO2 formed in the desorption procedure. From the Fig. 4, it is obvious that
both of the two samples exhibited weak acidic sites around 110 ℃ and moderate acidic sites around 290 ℃,
while N-CuMgAl-LDH exhibited stronger acidic sites around 350 ℃, indicating the stronger surface acidity
7

of N-CuMgAl-LDH than C-CuMgAl-LDH. Furthermore, the amount of the acidic site for
N-CuMgAl-LDH were markedly higher than that of C-CuMgAl-LDH, confirming the above speculation.
Figure 4
Furthermore, Py-IR analysis was performed to study the contents of Brønsted and Lewis acid sites on
the two catalysts (Fig. 5). Similar to the NH3-TPD, the activation and desorption temperature were set at
100 ℃and 150 ℃, respectively, to avoid the destruction of hydrotalcite structure. The absorption peak
located at 1445 cm−1 is ascribed to pyridine molecules interacting with the Lewis acid sites, while 1540
cm−1 for Brønsted acid sites [64]. The values summarized in Table 2 show that N-CuMgAl-LDH contained
higher total amount of acid site than C-CuMgAl-LDH, in consistent with the NH3-TPD analysis. Further,
the amount of Lewis acidic site for N-CuMgAl-LDH is 37% higher than that of C-CuMgAl-LDH, while the
value reaches 436% for the Brønsted acid sites (Table 2). The observations suggest that NH3·H2O as the
precipitant has a greater impact on Brønsted acid sites on the surface of hydrotalcites.
Figure 5
Table 2
3.2 Catalytic activity of CuMgAl LDHs
3.2.1 Effect of the reaction conditions
CDC reaction between 1a and 2a was selected as the model reaction to study the effect of reaction
conditions. The effect of solvent was firstly investigated. The results summarized in Table 3 show that
toluene, DMSO and 1,4-dioxane gave higher conversions, while 1,4-dioxane provided a little higher
selectivity to the corresponding product. The observations might be ascribed to the different polarity of
these solvents, and 1,4-dioxane with moderate polarity gave relative higher activity and selectivity.
Although methanol and propylene glycol monomethyl ether have been found efficient in some catalytic
systems [8], they were not applicable in the present system. The results might be due to the fact that they
are polar protic solvents, where propylene glycol monomethyl ether is supposed to have similar polarity
with methanol. Although high conversion of 1a was observed in water, the selectivity to the CDC product
was quite low. The results should be due to its nucleophilic activity and the formation of oxygenation
product (4) as the main by-product, which has been separated and identified by NMR spectra.
Table 3
8

4
It can be observed that increasing the reaction temperature to 100 ℃could not significantly improve the
conversion of 1a (Table 4, entry 2), but the selectivity to the coupled product decreased, which should be
due to the overoxidation. Increasing the ratio of 2a/1a from 1.5 to 6, the selectivity could be markedly
improved to 97% (Table 4, entries 3-4), suggesting that increasement of the amount of nucleophile could
suppress the side reaction. Prolonging the reaction time to 18 h led to a full conversion with an excellent 96%
selectivity to the CDC product. Then, the CuMgAl LDH sample using the normally Na2CO3 precipitant
was also conducted under the same conditions for comparison. However, the C-CuMgAl-LDH only gave
78% conversion and TOF with a comparable selectivity (Table 4, entry 6). The results might be not
attributed to the morphology of the two catalysts, but probably due to the surface acidity. Higher amount of
acidic site was observed for N-CuMgAl-LDH than C-CuMgAl-LDH, and nucleophilic reaction during the
CDC transformation could be accelerated by acidic site [9]. Concerning the catalytic performance of the
two samples and the distribution of the acidic sites from Py-IR analysis, Lewis acid site might play the key
role in the reaction [65]. Boess, et al [3], have proposed that appropriate pH value for the reaction solution
is required for the efficient CDC reaction, therefore, the higher catalytic performance for the
N-CuMgAl-LDH was also probably related to its suitable surface property.
Table 4
3.2.2 Comparison with some other catalytic systems
To further elucidate the features of the catalytic system, the representative results over heterogeneous
catalytic systems with oxygen have been collected from literatures. Most of the heterogeneous catalytic
systems for the CDC reaction were based on noble metals. It can be seen from Table 5 that the present
catalyst provided comparable catalytic performance with these systems (entries 2-5). CuFe2O4 (entry 6) and
Fe3O4 nanoparticles (entry 7), developed by Li group [38, 66], could gave similar results but with higher
temperature and longer reaction time. Nevertheless, DDQ (2,3-dicyano-5,6-dichlorobenzoquinone) was
required when aromatic alkyne being used as the nucleophiles [38]. Furthermore, the synthesis procedures
for some of these catalysts were very complicated, which would limit their application. Summary,
N-CuMgAl-LDH has been developed as an efficient and simple heterogeneous catalytic system for the
9

CDC reaction between N-phenyl tetrahydroisoquinoline and nitromethane under mild conditions.
Table 5
3.2.3 The stability and recyclability of the N-CuMgAl-LDH
To elucidate the heterogeneity and stability of the N-CuMgAl-LDH, a hot filtration experiment has
been conducted under the selected conditions. To make the discussion reasonable, it should be considered
that the substrate can transform under the selected conditions even without catalyst. After 6 h (~35%
conversion), the filtrate afforded only 7% additional conversion of 1a for another 10 h under the same
conditions (Fig. 6), suggesting that N-CuMgAl-LDH was a true heterogeneous catalyst. The ICP analysis of
the reaction filtrate showed that the amount of Cu, Mg and Al ions were only 84×10-9 g/mL, 121×10-9 g/mL
and 38×10-9 g/mL, respectively, implying that leaching of metals could be ignored. The recycled
experiments showed that the N-CuMgAl-LDH could be reused at least three times with moderate loss of
activity (Table 4, entries 5-7) and almost no reduction of the selectivity. XRD patterns for the reused
catalyst suggests that the layered structure was basically preserved after several reuses (Fig. S5).
Figure 6
3.3 The scope of substrates
To test the scope of the N-CuMgAl-LDH catalyzed CDC reaction, various
N-phenyltetrahydroisoquinoline derivatives were investigated (Table 6). The substrates with methyl or
methoxyl at the para-site of N-phenyl ring could be well tolerated (3ba and 3ca). The reduction of the
yields might be due to the formation of the analogues of compound 4. Delightedly,
N-(4-tertbutylphenyl)-1,2,3,4-tetrahydroisoquinoline could give an excellent 89% isolated yield of the CDC
product (3da). The longer reaction time might be due to the influence of the bulky tertbutyl group on the
contact between the substrate and catalyst. In contrast, electron-withdrawing groups significantly slowed
the reaction, and about 4 times of the reaction time were required when F, Cl or Br sits at the 4-site of the
N-phenyl ring (3ea, 3fa and 3ga), suggesting that the electron density of N atom has a vital effect on the
substrate’s activity. Substituents located at the ortho- and meta-sites suppressed the CDC reaction, and only
30%-50% yields of the products could be obtained (3ha, 3ia, 3ja, 3ka and 3la). The reaction times were
longer than that with the same substituents at para-site, further elucidating the effect of steric hindrance.
Electronic effect was also observed in the cases of 3ma and 3na. It is noteworthy that a good yield was
10

obtained for the 7-bromo-2-phenyl-1,2,3,4-tetrahydroisoquinoline, where the Br group was completely
intact.
Table 6
Some other nucleophiles with Csp3‒H have been tested. To our delight, various nitroalkane could be
tolerated by the present system (Table 7) (3ab and 3ac), and slightly higher performance than the
homogeneous CuBr/TBHP system [50,51] were obtained. The reactivity discernibly decreased as the
carbon atoms increase, indicating the existence of steric effect. For the carbonyl compounds with α-C‒H,
4-methyl-2-pentanone only gave 17% yield (3ad) for the steric hindrance and the lower nucleophilicity. In
contrast, increased yields were obtained for cyclohexanone and acetophenone (3ae and 3af). The substrate
with a nitro group at the para-site of acetophenone could give significantly improved yield (3ag) for its
easier formation of nucleophile. Trimethylsilyl cyanide and diethyl malonate were also investigated in the
catalytic system, and moderate yields could be obtained (3ah and 3ai).
Table 7
Finally, some nucleophiles with Csp2‒H or Csp‒H have also been examined. Indole and its derivatives
were reacted with tetrahydroisoquinolines to produce the desired products with satisfied yields (Table 8).
The reactions occurred selectively at the C3 position of indoles, consistent with the CuBr/TBHP system
[10]. The indoles with electron-withdrawing or electron-donating groups could also be tolerated under the
selected conditions. 1-Methylpyrrole could not give satisfied yield for its low nucleophilicity parameter
(N= 5.85) (3ao) [3,67]. Similar result was found in case of benzofuran. Phenylacetylene with Csp‒H bond
reacted well with 1a under standard conditions, giving product 3ar in good yield.
Table 8
5
In summary, the present N-CuMgAl-LDH provides an efficient catalytic system for the aerobic CDC
reactions. Compared with homogeneous catalytic systems based on copper salts or complexes, most
substrates reacted under the selected conditions could give comparable or better yield of the target products.
Although the yields were not satisfactory in some cases, the present heterogeneous catalyst would be more
11

practical for its heterogeneous feature.
3.4 The possible reaction pathway
To study the possible reaction pathway over N-CuMgAl-LDH, a series of controlled experiments have
been conducted for comparison (Table 9). Only 45% selectivity could be observed with a lower conversion
in the absence of catalyst, indicating that N-CuMgAl-LDH was crucial for the CDC reaction (entry 2).
Under N2 atmosphere, a lower conversion of 1a was observed (entry 3), implying that molecular oxygen
was not essential in the reaction, and the oxygen might be only involved in the reoxidation of reduced
copper [3, 45, 68]. When air was applied instead of O2, significantly reduced reactivity and selectivity of
3aa were observed (entry 4). Mg2Al-LDH could only give a 24% conversion of 1a with a 62% selectivity
(entry 5), and 75% of 1a could be recovered after the reaction. These results implied that Cu species was
essential for the reaction, and surface basicity might suppress the transformation, because Mg2Al-LDH
generally exhibits basicity. The observations further suggested the function of acidic site on the surface of
catalyst. Only a 48% conversion with a 56% selectivity (entry 6) were obtained under CuMgAl hydroxide
with mixed phases (Fig. S6), indicating that the hydrotalcite structure was crucial to improving the catalytic
activity. The homogeneous CuCl2 gave a full conversion of the substrate under the same conditions (entry
7), indicating that Cu species was effective for the oxidative transformation of 3a. The quite lower
selectivity to 3aa than the reported result [3] might be due to the variation of reaction conditions.
Table 9
Radical scavenges (BHT (2,6-di-tert-butyl-4-methylphenol) and CCl3Br) could significantly suppress
the reaction (Table 9, entries 8 and 9), suggesting that radical might formed in the reaction. To demonstrate
the possibility of the formation of iminium intermediate, which has been proposed as the key intermediate
in the CDC reactions [3, 33, 34], the reaction was performed without a nucleophile, and the filtrate was
analysed by MS with ESI ion source. The iminum could be obviously observed at 208.13 apart from the
substrate peak (210.19) (Fig. S7). The MS2 spectra of the peak of 208.13 further verified the formation of
iminium cation (5).
A KIE experiment was conducted to gain further information for the catalytic oxidative coupling
reaction (Scheme 1). The monodeuterated 1,2,3,4-tetrahydroquinoline (1a-d1) was introduced in the CDC
reaction with 2a, and a mixture of 3aa and 1-deuterated 3aa-d1 were produced. When the substrate was
12

completely converted, a primary KIE value kH/kD of 2.62 was calculated from the ratio of the signal
intensity in the 1-position relative to reference signals. The observation was consistent with a fast SET
rate-determining C‒H bond cleavage [1].
Scheme 1
Finally, XPS analysis was performed to monitor the variations of surface copper valence during the
reaction. The core fitting peaks of Cu 2p3/2 of the N-CuMgAl-LDH at different stages can be observed in
Fig. 7. For the fresh sample, the Cu 2p3/2 spectrum can be fitted at 934.7 eV, which can be indexed to Cu2+
cations [69, 70]. After being used under N2 atmosphere, the Cu 2p3/2 spectrum (Fig. 7B) shows a mixture
valence of Cu2+ (934.8 eV) and Cu+ (932.9 eV) [69, 70], indicating transfer of electron to Cu2+. Most of the
Cu+ was recovered after the normal catalytic process (Fig. 7C), indicating that the catalytic cycle has been
finished. However, there was still some Cu+ remained, which might be responsible for the slight decrease of
the catalytic activity. These XPS results implied that in the CDC reaction catalysed by N-CuMgAl-LDH
contained multi-electron transfer between the Cu cations and the substrate.
Figure 7
On the basis of reported and preliminary mechanistic studies [3, 7], we propose a reaction pathway for
the CDC reaction under N-CuMgAl-LDH (Scheme 2). The reaction is initiated by SET from N atom to
Cu2+, and the resulting amine radical species undergoes α-C–H abstraction to give an intermediate, which is
stabilized by the N-Aryl group [71]. Finally, nucleophilic attack on the iminium intermediate 5 by
nitromethane yields the coupled product 3aa, where the surface acidic sites on the N-CuMgAl-LDH
catalyst may play an important role.
Scheme 2
4. Conclusions
In summary, we have found that NH3·H2O coprecipitated CuMgAl layered hydroxide presents
redox-acidity dual functions in the CDC reactions, and provides an efficient heterogeneous catalytic system
for the functionalization of α-Csp3‒H of N-aryl-1,2,3,4-tetrahydroquinoline via aerobic CDC reaction with
various C–H bonds (Csp3–H, Csp2–H and Csp–H). The catalytic system can tolerate various
tetrahydroisoquinoline derivatives and nucleophiles, and present higher catalytic efficiency than reported
heterogeneous catalytic systems. The surface acidity of the catalyst has been found crucial for the catalytic
13

performance in the CDC reactions. Based on a series of controlled experiments, XPS analysis and kinetic
isotope effect experiment, a probable reaction pathway is suggested involving an iminium cation
intermediate and a cycle between Cu2+ and Cu+. However, the effect of precipitant on the structure and
property of the formed LDHs are needed to be further studied, which will provide new knowledge for its
catalytic application.
Author contributions
Weiyou Zhou: Ideas, analysis of experimental data, writing the initial draft, revision
Wangmingzhu Lu: Catalyst synthesis and catalytic experiments
Hui Wang: Analysis of experimental data
Zhenzhen Xia: Catalyst synthesis and characterization
Shaiyan Zhai: Analysis of experimental data
Zhong Zhang: Catalyst synthesis and characterization
Yuanjun Ma: Catalyst synthesis and catalytic experiments
Mingyang He: Oversight and leadership responsibility for the research activity planning and execution
Qun Chen: Design and direction of the project
Acknowledgements
This work was supported by Advanced Catalysis and Green Manufacturing Collaborative Innovation
Center of Changzhou University, A Project Funded by the Priority Academic Program Development of
Jiangsu Higher Education Institutions (PAPD), Jiangsu Key Laboratory of Advanced Catalytic Materials
and Technology (BM2012110), Postgraduate Research &Practice Innovation Program of Jiangsu Province
(KYCX19_1746), Qinglan Project of Jiangsu Province and Natural Science Foundation of Jiangsu Province
of China (BK20181461).
14

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17

Figures and Tables
Fig. 1. The XRD patterns of the N-CuMgAl-LDH and C-CuMgAl-LDH samples
Fig. 2. The SEM (A and B) and TEM (C and D) of N-CuMgAl-LDH and C-CuMgAl-LDH
Fig. 3. The Cu2p3/2 XPS of N-CuMgAl-LDH and C-CuMgAl-LDH
Table 1 Sample notation and chemical compositions of the prepared samples
Fig. 4. Plots of MS-NH3-TPD signal versus temperature for the prepared LDHs
Fig. 5. Py-IR spectra of the prepared C-CuMgAl-LDH and N-CuMgAl-LDH
Table 2 The amount of Lewis and Brønsted acid sites on different catalysts determined by Py-IR
Table 3 Effect of the reaction solvent on the reaction
Table 4 CDC reaction under different conditions
Table 5 Some representative results under heterogeneous catalytic systems
Fig. 6. Hot filtration test
Table 6 CDC reactions between tetrahydroisoquinoline derivatives and nitromethane
Table 7 CDC reactions between 2-phenyl-1,2,3,4-tetrahydroisoquinoline and nucleophiles with Csp3‒H
Table 8 CDC reactions between 2-phenyl-1,2,3,4-tetrahydroisoquinoline and nucleophiles with Csp2‒H or
Csp‒H
Table 9 The catalytic results under different reaction conditions
Scheme 1 KIE experiment
18

Fig. 8. The Cu2p3/2 XPS of N-CuMgAl-LDH
Scheme 2 Proposed reaction pathway
Fig. 1. The XRD patterns of the N-CuMgAl-LDH and C-CuMgAl-LDH samples.
19

Fig. 2. The SEM (A and B) and TEM (C and D) of N-CuMgAl-LDH and C-CuMgAl-LDH.
(A) and (C): N-CuMgAl-LDH, (B) and (D): C-CuMgAl-LDH.
Fig. 3. The Cu2p3/2 XPS of N-CuMgAl-LDH and C-CuMgAl-LDH.
Table 1 Sample notation and chemical compositions of the prepared samples.
Weight content (%)
SBET
Pore volume
(cm3/g)
Average pore
diameter (nm)
Cu︰Mg︰Al
(mol)
Sample
pHa
(m2/g)
Cu
Mg
Al
N-CuMgAl -LDH
C-CuMgAl -LDH
18.20
21.90
7.61
7.91
8.71
7.89
1:1.11:1.13
1:0.96:0.88
13.5
73.2
0.037
0.522
7.8
6.87
8.88
26.9
aSuspension of 0.3 g hydrotalcite in 20 mL deionized water.
20

Fig. 4. Plots of MS-NH3-TPD signal versus temperature for the prepared LDHs.
Fig. 5. Py-IR spectra of the prepared C-CuMgAl-LDH and N-CuMgAl-LDH.
21

Table 2 The amount of Lewis and Brønsted acid sites on different catalysts determined by Py-IR.
Total amount of L
and B acid site
(μmol / g)
Amount of L acid
site (μmol / g)
Amount of B acid
site (μmol / g)
Catalyst
B/L
N-CuMgAl -LDH
C-CuMgAl -LDH
157.304
114.752
55.214
10.296
212.518
125.049
0.351
0.090
Table 3 Effect of the reaction solvent on the reaction.a
Entry
Solvent
Polarity
Conv. b /%
Sel. b /%
1
2
3
acetonitrile
1,4-dioxane
toluene
6.2
4.8
2.4
34
93
91
79
78
72
4
5
DMSO
7.2
6.6
93
40
74
48
methanol
proprylene glycol
monomethyl ether
6
-
46
92
7
H2O
10.2
95
56
aReaction conditions: 1a 0.5 mmol, 2a 0.75 mmol, N-CuMgAl-LDH 0.2 g, 80 ℃, reaction time 16 h,
solvent 2 mL, oxygen atmosphere. bBased on the 1H-NMR analysis (0.1 mmol 1,4-dinitrobenzene was used
as the internal standard reference), and the by-products were not quantified.
Table 4 CDC reaction under different conditions.a
22

Entry
Catalyst
2a/1a
Conv.b /%
Sel.b /%
TOF /h−1
1
2c
N-CuMgAl-LDH
N-CuMgAl-LDH
N-CuMgAl-LDH
N-CuMgAl-LDH
N-CuMgAl-LDH
C-CuMgAl-LDH
N-CuMgAl-LDH
N-CuMgAl-LDH
N-CuMgAl-LDH
1.5
1.5
3
93
94
94
97
>99
78
99
97
93
78
75
84
97
96
92
95
96
96
-
-
3
-
4
6
-
5d
6d
7d, e
8d, f
9d, g
6
6.5
4.8
6.5
6.5
6.2
6
6
6
6
aReaction conditions: 1a 0.5 mmol, N-CuMgAl-LDH 0.2 g, reaction time 16 h, 1,4-dioxane 2 mL,
oxygen atmosphere. bBased on the 1H-NMR analysis (0.1 mmol 1,4-dinitrobenzene was used as the internal
standard reference), and the by-products were not quantified. c100 ℃. d18 h. eFirst recycle. fSecond recycle.
gThird recycle.
Table 5 Some representative heterogeneous catalytic systems for the CDC reactions between
N-phenyl-1,2,3,4-tetrahydroisoquinoline and nitromethane.
Temp.
/℃
Time
/ h
Entry
1
Catalyst
Yielda /%
96 (85)
Ref.
This
work
N-CuMgAl-LDH
80
80
18
zero-valent
nanoporous gold
(AuNPore)
2
3
99 (95)
(82)
24
28
29
Fe3O4@SiO2-bipy-
AuCl2]+[AuCl4]−
complex
60
8
poly(2-methoxyaniline
-5-sulfonic acid)/gold
nanoparticles
4
5
50
60
91
18
24
64
30
graphene-supported
RuO2
(89)
Fe3O4 nanoparticles
7
6
100
100
(90)
(87)
24
24
65
38
CuFe2O4
aThe data in brackets were the isolated yield.
23

Fig. 6. Hot filtration test.
Reaction conditions: 1a 0.5 mmol, 2a 3.0 mmol, N-CuMgAl-LDH 0.2 g, 1,4-dioxane 2 mL, 80 ℃, oxygen
atmosphere.
Table 6 CDC reactions between tetrahydroisoquinoline derivatives and nitromethane.a
3ca, 17 h, 54%
3fa, 72 h, 69%
3aa, 18 h, 85%
3ba, 18 h, 70%
3ea, 72 h, 55%
3ha, 80 h, 41%
3da, 24 h, 89%
3ga, 72 h, 77%
3ia, 35 h, 43%
3la, 17 h, 49%
3ja, 24 h, 46%
3ka, 26 h, 40%
24

3ma, 64 h, 71%
3na, 17 h, 48%
aReaction conditions:
oxygen atmosphere.
1 0.5 mmol, 2a 3.0 mmol, N-CuMgAl-LDH 0.2 g, 1,4-dioxane 2 mL, 80 ℃ ,
Table 7 CDC reactions between 2-phenyl-1,2,3,4-tetrahydroisoquinoline and nucleophiles with Csp3‒H.a
3ab, 20 h, 69%
3ad, 120 h, 17%
3ac, 24 h, 55%
3ae, 44 h, 37%
3ag, 96 h, 51%
3ah, 93 h, 48%
3af, 44 h, 40%
25

3ai, 43 h, 64%
aReaction conditions: 1a 0.5 mmol, 2 3.0 mmol, N-CuMgAl-LDH 0.2 g, 1,4-dioxane 2 mL, 80 ℃,
oxygen atmosphere.
Table 8 CDC reactions between 2-phenyl-1,2,3,4-tetrahydroisoquinoline and nucleophiles with Csp2‒H or
Csp‒H.a
3al, 40 h, 54%
3ao, 64 h, 35%
3aj, 14 h, 78%
3ak, 40 h, 49%
3an, 45 h, 53%
3am, 45 h, 56%
26

3aq, 72 h, NR
3ar, 96 h, 62%
3ap, 45 h, 66%
aReaction conditions: 1a 0.5 mmol, 2 3.0 mmol, N-CuMgAl-LDH 0.2 g, 1,4-dioxane 2 mL, 80 ℃, oxygen
atmosphere.
Table 9 The catalytic results under different reaction conditions. a
Conv.b
/%
Entry
Catalyst
Additive
Sel.b %
1
2
N-CuMgAl-LDH
-
N-CuMgAl-LDH
N-CuMgAl-LDH
Mg2Al-LDH
-
-
-
-
-
-
-
>99
76
75
70
24
48
>99
70
96
45
87
89
62
56
39
85
3c
4d
5
6
7
8
CuMgAl hydroxide
e
CuCl2
N-CuMgAl-LDH
BHT f
9
N-CuMgAl-LDH
CCl3Br f
>99
54
aReaction conditions: 1a 0.5 mmol, 2a 6.0 equiv., catalyst 0.2 g, 80 ℃, 18 h, 1,4-dioxane 2 mL, oxygen
atmosphere. bBased on the 1H-NMR analysis, and the by-products were not quantified. cNitrogen
atmosphere. dAir atmosphere. e CuCl2 0.03g. f 1.5 equiv..
Scheme 1 KIE experiment.
27

Fig. 7. The Cu2p3/2 XPS of N-CuMgAl-LDH (A) before the reaction; (B) after the reaction under nitrogen;
(C) after the reaction under oxygen.
Scheme 2 Proposed reaction pathway.
28