Synthesis of 2,2,4-trimethyl-1,2-dihydroquinolines over metal-modified 12-tungstophosphoric acid-supported γ-Al2O3 catalyst

Article abstract of DOI:10.1007/s11164-020-04191-y

In spite of having significant pharmacological importance, scalable synthesis of 2,2,4-trimethyl-1,2-H-dihydroquinoline (TMQ) is always being cumbersome due to harmful solvents, drastic reaction conditions, and high recovery cost of homogeneous catalysts. Heterogeneous catalytic condensation of aniline with acetone was employed here to synthesize TMQ. As efficient materials, Zn²⁺-, Sn²⁺-, and Cu²⁺-exchanged tungstophosphoric acid (TPA) supported on γ-Al₂O₃ was synthesized by microwave-assisted hydrothermal method. The synthesized catalysts were thoroughly characterized by XRD, Raman, FE-SEM, etc. and were screened for condensation reaction. Among the metal-exchanged catalysts, Zn_0.5TPA/Al₂O₃ showed highest aniline conversion with the highest yield of TMQ up to three consecutive cycles. The acidic sites over the catalysts were probed by pyridine-adsorbed FT-IR spectra and NH₃-TPD studies. The reaction conditions were optimized, and plausible reaction mechanistic pathway was derived from FT-IR and GC–MS data.

Full text of DOI:10.1007/s11164-020-04191-y

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-020-04191-y
Synthesis of 2,2,4‑trimethyl‑1,2‑dihydroquinolines
over metal‑modifed 12‑tungstophosphoric acid‑supported
γ‑Al2O3 catalyst
Bandarupalli Krishna1 · Sounak Roy1
Received: 16 April 2020 / Accepted: 14 June 2020
© Springer Nature B.V. 2020
Abstract
In spite of having signifcant pharmacological importance, scalable synthesis of
2,2,4-trimethyl-1,2-H-dihydroquinoline (TMQ) is always being cumbersome due
to harmful solvents, drastic reaction conditions, and high recovery cost of homo-
geneous catalysts. Heterogeneous catalytic condensation of aniline with acetone
was employed here to synthesize TMQ. As efcient materials, Zn2+-, Sn2+-, and
Cu2+-exchanged tungstophosphoric acid (TPA) supported on γ-Al2O3 was synthe-
sized by microwave-assisted hydrothermal method. The synthesized catalysts were
thoroughly characterized by XRD, Raman, FE-SEM, etc. and were screened for con-
densation reaction. Among the metal-exchanged catalysts, Zn0.5TPA/Al2O3 showed
highest aniline conversion with the highest yield of TMQ up to three consecutive
cycles. The acidic sites over the catalysts were probed by pyridine-adsorbed FT-IR
spectra and NH3-TPD studies. The reaction conditions were optimized, and plausi-
ble reaction mechanistic pathway was derived from FT-IR and GC–MS data.
Keywords 2,2,4-Trimethyl-1,2-H-dihydroquinoline · Metal-exchanged
tungstophosphoric acid · Reaction intermediate
Introduction
Dihydroquinolines and its derivatives found in a wide variety of natural prod-
ucts display an extensive array of antibacterial, antidiabetic, antimalarial, and
anti-infammatory properties [1–3]. These compounds also have great practical
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s1116
4-020-04191-y) contains supplementary material, which is available to authorized users.
* Sounak Roy
sounak.roy@hyderabad.bits-pilani.ac.in
1
Department of Chemistry, Birla Institute of Technology and Science (BITS) Pilani, Hyderabad
Campus, Hyderabad 500 078, India
Vol.:(0123456789)
1 3

B. Krishna, S. Roy
importance as lipid peroxidation inhibitors, and progesterone agonists and antag-
onists [4]. Among the large group of dihydroquinoline derivatives, 2,2,4-trime-
thyl-1,2-H-dihydroquinoline (TMQ) is one of the most important representatives
because of relatively low price and great ease of applications. Besides pharma-
cological applications, TMQ is additionally considered as a very important and
efective industrial antioxidant in rubber technologies and also employed in
preserving animal nutriments and vegetable oils [5–9]. However, in spite of its
abundant presence in the natural product angustureine, the isolation and purifca-
tion is a synthetic challenge. And therefore, the laboratory synthesis of TMQ has
attracted a signifcant attention to organic chemists [10].
The most classical method of synthesis was demonstrated by Skraup et al.
[11–13], where a mixture of nitroethane, aniline, and glycerol in presence of con-
centrated sulphuric acid. However, the process requires a large amount of sulphu-
ric acid at temperatures higher than 150 °C, and the reaction is often violent with
a very low yield. There have been numerous methods developed after Skraup syn-
thesis in recent literature, and mostly, the substrates were aryl amines with sev-
eral class of organic compounds like ketones [14–16], α,β-unsaturated ketones
[17], 2,2-dimethoxy propane [18], alkynes [19–22], α-ketoester [23, 24] in the
presence of Lewis (SnCl4, Yb(OTf)3, Sc(OTf)3, ZnCl2, InCl3) [25–28] and Brøn-
sted acid (TsOH, HClO4) [29–31] catalysts in addition to iodine [31]. In spite
of inexpensive starting materials, the primary shortcomings of these reports are
with the usage of catalysts, which make reaction times long, and reaction condi-
tions strong with formation of multiple tarry side products. Many methodologies
involve complex multistep pathways, harmful solvents, and drastic conditions,
thus limiting their utility towards scalable synthesis. Moreover, the popular metal
trifate catalysts are expensive materials with high catalyst recovery cost, which
are another serious disadvantages for industrial scale-up. Therefore, the need of
the hour is to develop heterogeneous solid acid catalysts, which may facilitate the
condensation synthesis under mild reaction condition with selectivity.
In this context, a popular category of solid Brønsted acid catalyst is Keggin
structured heteropoly acids [32, 33]. Due to their typical structural characteristics,
the acid–base property is easily engineered by changing their chemical composi-
tion, and upon partial exchange of protons with metal cations, the resulting salts
possess high thermal stability and lower solubility. However, to our knowledge,
the heteropoly acids were never being utilized in TMQ synthesis, and here, for
the frst time we report a simple and efcient procedure to synthesize 1,2-dihyd-
roquinoline that is catalysed by metal salts of 12-tungstophosphoric acid (TPA)
supported on high surface area Al2O3. The metal cations like Zn2+, Sn2+, and
Cu2+ were chosen to introduce the Lewis acid sites in the catalyst surface along
with the inherent Brønsted sites of TPA, and the support Al2O3 was chosen due
to its Lewis acid sites and high surface area. The catalysts were thoroughly char-
acterized, reaction conditions were optimized, and the reaction mechanism on the
solid catalyst support was probed. This work opens up a possibility of scaling up
the TMQ synthesis by heterogeneous catalysts.
1 3

Synthesis of 2,2,4-trimethyl-1,2-dihydroquinolines over…
Experimental
Materials and methods
TPA, aniline, acetone, and acetonitrile were obtained from Sigma Aldrich,
whereas zinc nitrate hexahydrate and aluminium oxide were obtained from SD
Fine chemicals. Stannous chlorides, cupric chlorides dehydrate were bought from
Spectrochem, India. The metal-exchanged TPA catalysts over Al2O3 support were
prepared by microwave-assisted hydrothermal method, and the detail of synthesis
is mentioned in our earlier report [32]. Briefy, a homogeneous aqueous solution
of 1 g of TPA and equivalent amount of metal nitrate was placed in a microwave-
transparent G30 vial and was subjected to heating at 120 °C for 2 h in microwave
system (Anton Parr, Monowave 300, GmbH, Europe) with 850 W power. After
the microwave treatment, the solid product was dried for overnight at 60 °C in a
hot air oven to obtain the M0.5TPA catalyst (M = Zn, Sn, and Cu). For synthesis
of M0.5TPA/Al2O3, the required quantity of M0.5TPA was dissolved in minimum
amount of water, and the solution was added drop wise to calculated amount of
Al2O3 with constant stirring. After 10 min of stirring, this solution was trans-
ferred to microwave G30 vial, and the reaming process is same as mentioned
above.
Physicochemical characterization
The structural characterization of the synthesized catalysts was done with pow-
der X-ray difraction (XRD, Rigaku Ultima IV), Fourier transform infrared
spectroscopy (FT-IR, JASCO FTIR-4200), and Raman spectroscopy (UniRAM
3300). The morphology of the catalysts was evaluated by feld emission scan-
ning electron microscopy (FE-SEM, FEI-Apreo S). To understand the elemental
oxidation state and bonding, X-ray photoelectron spectra (XPS) were collected
with Thermo Scientifc K-ALPHA surface analysis spectrometer using Al Kα
radiation (1486.6 eV). The surface acidity of the synthesized M0.5TPA/γ-Al2O3
was probed by FT-IR spectra of the pyridine-adsorbed materials and also by
NH3-temperature-programmed desorption (TPD). Pyridine was dropped on the
pellets of M0.5TPA/γ-Al2O3− with KBr before collecting the pyridine-adsorbed
FT-IR spectra. The NH3-TPD of the M0.5TPA/γ-Al2O3 was carried out in a BEL-
CAT II instrument. About 50 mg of powdered sample was taken inside a quartz
tube, and the pre-treatment was carried out in helium gas fow at 200 °C for 1 h
prior to NH3 adsorption at room temperature. The NH3 adsorption was contin-
ued for 1 h followed by degassing with helium for 1 h to remove the physically
adsorbed NH3 from the catalyst surface. The desorption profle was recorded
while heating at a rate of 10 °C min−1 till 500 °C. The desorbed NH3 was moni-
tored with a thermal conductivity detector.
1 3

B. Krishna, S. Roy
Catalytic synthesis of dihydroquinolines
Aniline (1.0 g, 11 mmol) and acetone (1.87 g, 32 mmol) were dissolved in a range
of solvents such as toluene, xylene, and acetonitrile along with M0.5TPA/Al2O3
catalyst loading. The reaction mixture was continuously stirred and refuxed for
2–8 h at set temperatures of 25–75 °C. The progress of the reaction was moni-
tored through gas chromatography (Shimadzu GC-2010 PLUS) and TLC (mobile
phase 30% ethyl acetate in hexane). After the completion, the reaction mixture
was cooled and the solid catalyst was recovered by centrifugation. The products
were purifed through column chromatography using silica gel column and ethyl
1
acetate–petroleum mixture (1:9). The products were analysed using H NMR-AV
NEO 400 MHz (Bruker) and GC–MS. The recovered catalyst was screened for
recyclability up to three cycles. The reaction conditions were optimized by vary-
ing the catalyst loading, reaction temperature, time, and solvents.
Results and discussion
Structural and surface morphological characterization
The XRD patterns of pristine TPA and M0.5TPA/Al2O3 are plotted in Fig. 1a. All
the materials show a very high crystallinity. The characteristic peaks at around 10°
corresponding to primitive cubic space group of Pn3m [JCPDS # 50-1857] are pre-
sent in pure TPA/Al2O3. The peaks around 30°–40° belong to the crystalline support
Al2O3. After metal exchange, there are some additional peaks, which could be due
(a)
(b)
Fig. 1 a Powder XRD of TPA/Al2O3 and M0.5TPA/Al2O3 and b Raman spectra of Zn 0.5TPA/Al2O3,
Cu0.5TPA/Al2O3, and Sn0.5 TPA/Al2O3
1 3

Synthesis of 2,2,4-trimethyl-1,2-dihydroquinolines over…
to biphasic M0.5TPA and TPA/Al2O3 [32]. To confrm the retention of Keggin ion
structure in metal-exchanged TPA/Al2O3, Raman spectra were collected. Figure 1b
shows the Raman spectra of M0.5TPA/Al2O3 catalysts. The materials show all the
characteristic four bands at 1015, 990, 933, and 530 cm−1. The bands at 1015 and
990 cm−1 are asymmetric and symmetric vibration of W=Ot (Ot is the terminal oxy-
gen), respectively. The Raman bands at 933 and 530 cm−1 are ascribed to asymmet-
ric and symmetric stretching vibration of W–Oc–W (Oc is the corner sharing bridg-
ing oxygen atom) and W–Oe–W (Oe is the edge-sharing bridging oxygen atom),
respectively [34]. Metal-exchanged heteropoly tungstate catalysts demonstrated the
retention of Keggin ion structure.
The FE-SEM micrographs of the as-synthesized fresh M0.5TPA catalyst (M=Zn,
Sn, and Cu) are shown in Fig. 2. The freshly prepared metal exchange TPA/γ-Al2O3
catalyst shows small platelet-shape morphology with cracks and kinks. A few parti-
cles are observed on top of the platelet-like morphologies. The particles are mostly
agglomerated and of sub-micrometre size. There are no distinguishable diferences
between the diferent metal-exchanged TPA/Al2O3 materials. The EDAX spectral
analysis confrmed the expected metal contents in the fresh catalysts. The EDAX
analysis of the M0.5TPA/Al2O3 catalysts (M=Zn, Sn, and Cu) show atomic metal
percentages of 1.7, 1.9, and 1.8, respectively. These results are in good agreement
with the EDXRF (data in Supporting Information). Apparently, M0.5TPA/Al2O3 cat-
alysts show W: 95.0–95.5%, P: 1.9–2.3%, and M: 1.7–2.3% with a W:P:M atomic
ratio corresponding to the molecular formula of M0.5TPA/Al2O3 catalysts (M=Zn,
Sn, and Cu).
To introspect the electronic state of the exchanged metals in TPA, core-level
X-ray photoelectron spectra were collected and the data are plotted in Fig. 3. Zn
2p3/2 is positioned at 1022.5, and 2p1/2 is positioned at 1045.8 eV corresponding to
Zn2+ [35, 36]. This confrms the Zn salt formation of TPA, where Zn is in bivalent
oxidation state. The Sn 3d5/2 was found to be positioned at 487.5 and 3d3/2 at 496 eV
confrming ionic state of Sn. In Cu core-level spectrum, Cu 2p3/2 is positioned at
932.7 and 2p1/2 at 952.0 eV with additional satellite peaks confrms cupric ion in
Cu0.5TPA/Al2O3 catalyst [37].
Catalytic screening
After the thorough characterization, the metal substituted and the pristine TPA sup-
ported on Al2O3 catalysts were explored for synthesis of dihydroquinoline from
3μm
3μm
3μm
Zn0.5TPA/Al2O3
Cu0.5TPA/Al2O3
Sn0.5TPA/Al2O3
Fig. 2 FE-SEM images of catalysts Zn0.5TPA/Al2O3, Cu0.5TPA/Al2O3, and Sn0.5 TPA/Al2O3
1 3

B. Krishna, S. Roy
Fig. 3 Core-level spectra of Zn, Sn, and Cu in the synthesized catalysts
aniline and acetone using acetonitrile as solvent. To benchmark the performances of
our synthesized catalysts, as control experiments bare Lewis acid support Al2O3 and
Brønsted acidic catalysts such as zeolite ZSM-5, and ion-exchanged resin Amber-
lyst were also screened. After 6 h of reaction at 75 °C, the observed aniline conver-
sion (%) and dihydroquinoline yield (%) calculated from the gas chromatograms are
Table 1 Conversion of aniline
Catalysts
Conversion of aniline (%) Yield of
and yield of dihydroquinoline
over heterogeneous catalysts
TMQ
(%)
TPA/Al2O3
45
51.5
52
39
0
5.5
32.1
15.5
12.5
0
Zn0.5TPA/Al2O3
Sn0.5TPA/Al2O3
Cu0.5TPA/Al2O3
Al2O3
ZSM 5
0
0
Amberlyst 15 H
0
0
1 3

Synthesis of 2,2,4-trimethyl-1,2-dihydroquinolines over…
summarized in Table 1. It is apparent from the table that pristine TPA and the metal
substituted M0.5TPA over Al2O3 support could convert around 40–50% of aniline
in average, whereas there was absolutely no conversion of aniline over the Lewis
acidic Al2O3, and the Brønsted acidic ZSM-5 and Amberlyst15H. Among the metal
substituted TPA catalysts, Zn0.5TPA/Al2O3 and Sn0.5TPA/Al2O3 showed the higher
conversion of around 52%, and Cu0.5TPA/Al2O3 showed only 39% of aniline conver-
sion. Up to 45% of aniline conversion over pristine TPA/Al2O3 indicated that doping
of Cu in TPA has degraded the catalytic activity of pristine TPA, whereas Zn and
Sn doping has played a benefcial role in catalytic conversion of aniline. When the
product yield was compared, Zn0.5TPA/Al2O3 showed the highest yield of dihyd-
roquinoline formation (32.07%), whereas Sn- and Cu-exchanged catalysts showed
poorer yield of dihydroquinoline with a production of tarry reaction mass.
As the Zn substituted catalyst turned out to be the better material in the lot, the
further optimization of reaction parameters by varying the temperature, time, cata-
lyst loading and nature of solvent were carried out with Zn0.5TPA/Al2O3. Figure 4a
shows the % conversion of aniline and % yield of dihydroquinoline over Zn0.5TPA/
Al2O3 against temperature. With raise in temperature, both the conversion and the
yield gradually increased. Among the experimental conditions, 75 °C was found
to be the optimum temperature. Next, we kept the temperature constant at 75 °C
and varied the reaction time from 2 to 10 h (Fig. 4b). The 6 h duration was found
to be optimum for aniline conversion. After the reaction temperature and duration,
the catalyst loading was varied from 5 to 20 wt%. The results that are plotted in
Fig. 4c show a volcanic pattern in aniline conversion with 10 wt% being the maxi-
mum Zn0.5TPA/Al2O3 loading. Interestingly, the % yield of TMQ was found to be
highest with 15 wt% of loading. At the fnal stage, we screened diferent solvents for
optimum reactivity of the catalyst (Fig. 4d). It is apparent from the data that acetoni-
trile is by far the best solvent for maximum conversion and yield. It should be noted
that the reaction was carried out in a solvent free conditions at elevated tempera-
tures of 120 °C, where conversion of aniline was found to be only 44% with TMQ
yield 21.6%. The major advantage of the usage the solid heterogeneous catalyst is
reusability. And therefore, at the end of frst reaction cycle under optimized reaction
condition, Zn0.5TPA/Al2O3 was separated from reaction mixture by centrifugation
and was screened for recyclability for two more cycles. The fndings are plotted in
Fig. 4e that show the robust recyclability of Zn0.5TPA/Al2O3.
Apparently, 10 wt% of Zn0.5TPA/Al2O3 loading demonstrated the highest cata-
lytic condensation efcacy of aniline at 75 °C in acetonitrile solvent medium.
Next, at this reaction condition substrate scope was expanded with diferent sub-
stituted aniline such as p-ethylaniline, p-bromoaniline, and p-methoxyaniline over
Zn0.5TPA/Al2O3. The substituents were varied with electron donating as well as
electron withdrawing group in order to observe the role of substituent group in con-
version efcacy. The derivatives of TMQ produced over each substituted aniline
were monitored by GC–MS, and the data are provided in Supporting Information.
The conversion of each substrate over Zn0.5TPA/Al2O3 is summarized in a tabulated
manner in Table 2. Apparently, substitution with both electron donating as well as
withdrawing groups showed deterioration in conversion efcacy compared to unsub-
stituted aniline.
1 3

B. Krishna, S. Roy
(a)
(b)
50
(%)
40
30
30
20
10
0
Conversion of Aniline
0
Yield of TMQ(%
80
Ti
m
Yield
Temperature(°C)
e(Hr
60
o
)
f
T
MQ
s)
40
Conversion of Aniline
20
(c)
(d)
50
(e)
ne(%)
4
0
anili
f
30
o
20
10
Conversion
0
Cycle 3
Yield of TMQ (%)
Conversion of aniline (%)
Cycle 2
Cycle 1
Fig. 4 Optimization of reaction condition with Zn0.5TPA/Al2O3; a variation of temperature, b variation
of reaction time, c variation of catalyst loading, d variation of solvent, and e recyclability of Zn0.5TPA/
Al2O3 under optimized reaction condition
1 3

Synthesis of 2,2,4-trimethyl-1,2-dihydroquinolines over…
(a)
(b)
Cu0.5TPA-Al2O3
Sn0.5TPA-Al2O3
Zn0.5TPA-Al2O3
Al O
2 3
TPA/Al O
2 3
Cu TPA/Al O
0.5
2 3
Sn TPA/Al O
0.5
2 3
TPA-Al2O3
Zn TPA/Al O
0.5
2 3
Pyridine coordinated
Pyridine ion on
Bronsted acid Sites
with Lewis acid Sites
0
100 200 300 400 500 600
1600
1550
1500
1450
Wavenumber (cm-1)
Temperature(°C)
Fig. 5 a FT-IR pyridine adsorption studies and b NH3-TPD profles of the catalyst
After the optimization of the catalyst’s reaction condition, we compared our
results with the data available in the literature. Table 3 summarizes the recent work
on TMQ production with heterogeneous catalysts. It shows that the reaction con-
ditions in the literature are quite harsh; the operative temperature is signifcantly
higher than our reaction temperature, and also many reactions were performed at
elevated pressure. The data show that that in spite of having harsh reaction con-
dition, the percentage yield of TMQ is low. On the contrary, even at fairly milder
reaction condition, Zn0.5TPA/Al2O3 showed higher yield of TMQ than the reported
values in the literature.
Probing the plausible mechanism
The surface acidity of the synthesized catalysts plays the key role in determin-
ing the efcient conversion of aniline and formation of TMQ. The FT-IR spectra
of pyridine-adsorbed catalysts can be used to investigate the presence of Brønsted
and Lewis acidic sites in metal-exchanged TPA, and NH3-TPD studies would semi-
quantitatively determine the strengths and densities of the acid sites. The pyridine-
adsorbed FT-IR spectra of pristine TPA/Al2O3 and M0.5TPA/Al2O3 catalysts are
shown in Fig. 5a. The band at 1538 cm−1 corresponds to pyridine adsorbed on Brøn-
sted acidic sites of the catalyst surface, whereas the other band located at 1488 cm−1
originates from a combination of pyridine bonded to both Brønsted and Lewis acidic
sites [34, 41]. Both the bands were very prominent over the pristine TPA/Al2O3, and
in Zn- and Sn-exchanged TPA/Al2O3, whereas the particular bands were obscured
over Sn0.5TPA/Al2O3. The other major band connected to Lewis acidic sites was
clearly observed around 1440 cm−1 over pristine TPA/Al2O3 and was slightly shifted
1 3

B. Krishna, S. Roy
to 1445 cm−1 over Zn0.5TPA/Al2O3. However, this specifc band was not observed
over Sn0.5TPA/Al2O3 and Cu0.5TPA/Al2O3. It is evident from the FT-IR spectra
that doping of Cu apparently destroyed the Brønsted as well as Lewis acidic sites in
TPA/Al2O3. The poorer catalytic conversion of aniline over Cu-exchanged TPA cat-
alyst can be directly correlated with its reduced surface acidity. On the other hand,
Zn0.5TPA/Al2O3 showed the intense FT-IR bands indicating the presence of strong
Lewis and Brønsted sites on its surface, whereas Sn0.5TPA/Al2O3 indicated occur-
rence of surface Brønsted sites only. It should be noted that the catalytic conversion
of aniline over Zn0.5TPA/Al2O3 and Sn0.5TPA/Al2O3 was similar; however, the yield
of TMQ was higher over Zn0.5TPA/Al2O3-. It can be inferred from the FT-IR stud-
ies that the surface Brønsted sites helped conversion of aniline, whereas the product
selectivity depended upon the presence of Lewis acid sites.
To corroborate the theory further, the acid strengths of the metal-exchanged TPA
catalysts were studied through NH3-TPD, and the obtained results are plotted in
Fig. 5b. The TPD profles of M0.5TPA/Al2O3 show a strong and broad desorption
peak at 100–250 °C, and relatively sharp peak at around 550 °C indicating two dif-
ferent acid sites for NH3 adsorption. The strong acid sites may be associated with the
Brønsted sites, as has been reported previously [41, 42]. The three metal-exchanged
Table 2 Substituted aniline and
Aniline substrate
Conversion of
aniline substrate
(%)
their conversion percentage over
Zn0.5TPA/Al2O3
Aniline
51.5
28.9
16.2
7.6
p-Ethylaniline
p-Bromoaniline
p-Methoxyaniline
Table 3 Comparison of our catalyst’s performance with the data in the literature
Serial no. Catalyst [References]
Reaction condition
Conversion TMQ yield (%)
of aniline
(%)
1.
2.
3.
[(Nb6Cl12)Cl2(H2O)4]·4H2O 300 °C, 1 h, under high
100
100
100
71.7
16.6
23.1
[38]
pressure
H-Mordenite [38]
300 °C, 1 h, under high
pressure
NH4-Y zeolite [38]
300 °C, 1 h, under high
pressure
4.
5.
6.
Ersorb-4a(E4a) [39]
SBA-Pr-SO3H [40]
Solvent: toluene, 110 °C, 8 h
160 °C, 5 h
–
65.4
51.5
96a
32.0
32.1
Zn0.5TPA/Al2O3 [this work]
Solvent: acetonitrile, 75 °C,
6 h, ambient pressure
a Yield calculated based on the 1H NMR spectra. The catalyst used was in large amount (250 wt%)
1 3

Synthesis of 2,2,4-trimethyl-1,2-dihydroquinolines over…
(a)
(b)
TMQ
300
280
260
240
220
200
180
160
140
120
100
80
TPA/Al2O3
Zn0.5TPA/Al2O3
60
40
20
Aniline
0
1000
1500
2000
2500
3000
3500
-1
Wavenumber (cm )
Fig. 6 a GC–MS and b FT-IR spectra of post-synthesis reaction mixture
catalysts show a very minor diference in their TPD profles. Our previous estima-
tions showed that Zn0.5TPA/Al2O3 possessed the total acidity of 0.948 mmol g−1,
whereas the unsubstituted TPA/Al2O3 demonstrated total acidity of 0.596 mmol g−1
only [32]. The highest acidity for Zn0.5TPA/γ-Al2O3 may be due to the formation of
monolayer coverage of Zn0.5TPA/γ-Al2O3. Haider et al. [42] also observed a similar
pattern of higher acidity with partially replaced protons, which they attributed to the
mobility of residual protons in the secondary structure of the heteropolyacid.
1 3

B. Krishna, S. Roy
Scheme 1 a Synthesis pathway of TMQ from aniline and acetone via Skraup mechanism. b Synthesis
pathway of TMQ from aniline and acetone via Doebner–Miller mechanism
The above discussion correlates the strengths and densities of surface acid sites
with yield of TMQ. There are two well-established mechanisms of synthesis of
TMQ; (1) Skraup and (2) Doebner–Miller mechanism (Scheme 1). According to
Skraup method, in the frst step aniline reacts with protonated enol of acetone with
the formation of aniline Schif base known as acetanil. This is also one of the side
product of this condensation reaction [40]. Acetanil, further on condensation with
enol forms TMQ. In addition to formation of monomeric TMQ, its oligomers are
also formed. TMQ up on oligomerization forms DiTMQ (Scheme 1a). In the Doeb-
ner–Miller mechanism, the key step is aldol condensation of acetone with the for-
mation of mesityl oxide [43]. In the next step, mesityl oxide reacts with protonated
aniline in the sequence reaction TMQ and its oligomer is produced (Scheme 1b).
1 3

Synthesis of 2,2,4-trimethyl-1,2-dihydroquinolines over…
To probe the exact mechanistic pathway over our Zn0.5TPA/Al2O3 catalyst, we
have thoroughly characterized the post-synthesis reaction mixture. It must be noted
there was a formation of tarry mass after 6 h reaction, and therefore, to check the
oligomerized product, GC–MS of post-synthesis reaction mixture was performed.
According to the GC–MS spectrum in Fig. 6a there was no peak corresponding to
DiTMQ indicating formation of no such by-product. A next, FT-IR spectrum was
collected to check the formation of the side product acetanil. The FT-IR spectrum
(Fig. 6b) did not show any presence of C=N band signifying no acetanil formation.
These two experiments suggest that Skraup mechanism may not be taking place with
Zn0.5TPA/Al2O3 catalyst, and also there is no formation of oligomerized product.
In order to confrm the Doebner–Miller mechanism for synthesis of TMQ over
the synthesized catalysts, only acetone was refuxed with M0.5TPA/γ-Al2O3 with-
out aniline under the identical optimized reaction condition. The reaction mixture
was probed by GC, and the data (Fig. 7) did show the formation of mesityl oxide at
1.6 min of retention time. This was further corroborated by standard GC profle of
mesityl oxide. The metal-exchanged catalysts showed signifcant formation of the
intermediate mesityl oxide, whereas the pristine TPA/Al2O3 showed the least forma-
tion of the intermediate. The higher amount of intermediate formation facilitated
the higher yield of TMQ over the metal-exchanged catalysts, and consequently, the
pristine TPA/Al2O3 showed least amount of TMQ yield.
However, it should be noted that in spite of formation of signifcant amount of
intermediate mesityl oxide, the yield of TMQ was diferent over diferent metal-
exchanged TPA/Al2O3 and Zn0.5TPA/Al2O3 showed the highest amount of product
Fig. 7 GC plot for intermediate
Mesityl oxide
mesitylene oxide formation
Standred
TPA/Al2O3
Cu TPA/Al O
0.5
2 3
Zn TPA/Al O
0.5
2
3
Sn0.5TPA/Al2O3
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Retention time (min)
1 3

B. Krishna, S. Roy
8
7
6
5
4
3
2
1
0
Fig. 8 UV–visible spectrum of
reaction mass in comparison
with polyaniline and TMQ
Poly aniline
Cu TPA-Al
0.5
O
3
2
Sn TPA-Al O
0.5
2
3
Zn TPA-Al O
0.5
2
3
TPA-Al O
2
3
Standerd TMQ
200
300
400
500
Wavelength(nm)
formation. Moreover, the formation of tarry mass after reaction could be an indica-
tion of formation of any side product other than DiTMQ. Therefore, we have col-
lected the UV–Vis spectra of the reaction mixture and plotted the data in compari-
son with polyaniline in acetonitrile and TMQ in acetonitrile (Fig. 8). Polyaniline
showed two broad absorption maxima at 275 and 365 nm. The band in the region
250–300 nm is associated with a π–π* transitions of the benzenoid rings of poly-
aniline [44], and the band at 350–400 nm is assigned to the polaron/bipolaron reso-
nance absorption of the electrons [45]. The standard TMQ in acetonitrile showed the
characteristic peak maxima at 225 nm. The pristine TPA/Al2O3 and the M0.5TPA/
Al2O3 showed both the set of bands suggesting formation of TMQ as well as emeral-
dine salt form of polyaniline. The high intensity of the polyaniline peak in the reac-
tion mixture of TPA/Al2O3, Sn0.5TPA/Al2O3, and Cu0.5TPA/Al2O3 indicates more
polymerization of aniline in presence of these catalysts. On the contrary, the least
intensity of the polyaniline peak in the reaction mixture of Zn0.5TPA/Al2O3 makes it
a more selective catalyst towards TMQ formation.
From the above experiments, we can conclusively comment on the mechanistic
aspect of TMQ formation over the metal-exchanged heterogeneous TPA/Al2O3
catalysts. The reaction follows the Doebner–Miller mechanism with formation of
intermediate mesityl oxide, which was identifed in gas chromatography. Lesser
formation of mesityl oxide resulted in poorer yield over pristine TPA/Al2O3.
Among the metal-exchanged catalysts, Sn0.5TPA/Al2O3 and Cu0.5TPA/Al2O3
showed poorer yield due to polymerization of aniline to polyaniline that resulted
in a tarry reaction mass. On the contrary, Zn0.5TPA/Al2O3 showed insignifcant
1 3

Synthesis of 2,2,4-trimethyl-1,2-dihydroquinolines over…
(a)
(b)
Scheme 2 Schematic representation of reaction mechanism to form TMQ over M0.5TPA/Al2O3 catalysts
side reaction of aniline polymerization and yielded highest amount of TMQ.
However, a prolonged reaction of more than 6 h over Zn0.5TPA/Al2O3 yielded
PANI with more selectivity that might have reduced aniline conversion. The Zn2+
incorporated TPA over Al2O3 possessed optimum Brønsted and Lewis acidic
sites, which were accessed easily by aniline and acetone for synthesis of TMQ.
Schematics of the reaction mechanism over the Zn0.5TPA/Al2O3 are provided in
Scheme 2. In Scheme 2a, acetone undergoes self-aldol condensation with the help
of Brønsted and Lewis acidic sites over Zn0.5TPA/Al2O3 to form the intermedi-
ate mesityl oxide. In the next step, mesityl oxide upon reaction with quaternary
salt of aniline forms arylamino ketone ketone, which undergoes intramolecular
1 3

B. Krishna, S. Roy
cyclization to fnally yield TMQ [46]. Scheme 2b is almost similar to the previ-
ous one, except the Michael addition type of condensation between aniline and
mesityl oxide over Zn0.5TPA/Al2O3 [47]. In both the proposed mechanism, ani-
line upon protonation from Brønsted acidic sites yields the side product PANI.
Conclusion
This article deals with heterogeneous catalytic condensation of aniline and acetone
to form TMQ over M0.5TPA/Al2O3 (M=Sn, Cu, and Zn). The catalysts were syn-
thesized by microwave-assisted hydrothermal method. The metallic salt of TPA
was crystalline in nature. The condensation reaction was optimized by varying
the parameters such as temperature, time, catalyst loading, and nature of solvent.
The optimum reaction condition was found to be at 75 °C for 6 h of duration with
10 wt% of catalyst loading in acetonitrile solvent. Among the metal-exchanged and
pristine catalysts, Zn0.5TPA/Al2O3 showed highest yield of TMQ with a steady recy-
clability. The details study on reaction mechanism established that both the Lewis
and Brønsted type sites are required for the condensation, and the reaction proceeds
with Doebner–Miller mechanism. A facile side reaction of polyaniline formation
over Sn0.5TPA/Al2O3 and Cu0.5TPA/Al2O3 resulted in poorer yield of TMQ over
these materials compared to Zn0.5TPA/Al2O3.
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