Energy efficient Pfitzinger reaction: A novel strategy using a surfactant catalyst

Article abstract of DOI:10.1039/c7nj01937h

A novel energy efficient method for the Pfitzinger reaction is demonstrated, which is catalysed using a surfactant, cetyltrimethylammonium hydroxide. The surfactant nature of the catalyst caused the substrate to be soluble in aqueous media, which enhanced the interaction of the catalyst with the substrate. An increase in the rate of reaction and more than 78% of energy saving were observed under ultrasonic irradiation.

Full text of DOI:10.1039/c7nj01937h

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ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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DOI: 10.1039/C7NJ01937H
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Energy Efficient Pfitzinger Reaction: A Novel strategy with
Surfactant catalyst
Priyanka A. More, Ganapati S. Shankarling*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel energy efficient method for Pfitzinger reaction catalysed by Camptothecin
surfactant, cetyltrimethylammonium hydroxide has been
demonstrated. Catalyst being surfactant in nature makes substrate
soluble in aqueous media fastening interaction of catalyst with
substrate. More increase in the rate of reaction and more than 78%
of energy saving was observed under ultrasonic irradiation.
Topotecan
Mappicine ketone
Isocryptolepine
a
Quinoline is a backbone of many natural products (Fig. 1)
such as alkaloids1 and several pharmaceuticals2, agrochemicals3
and dyestuffs4. In coordination chemistry, quinolines are used
to chelate metallic ions as N-donor ligands5. This scaffold has
been reported to possess wide range of pharmacological
activities including antiprotozoal6, antitubercular7, anticancer8,
antipsychotics9, anti-inflammatory10, antioxidant6, anti-HIV11,
antifungal12, as efflux pump inhibitors13 and for treatment of
neurodegenerative diseases14 and lupus15 etc.
Irinotecan
Fig. 1 Structures of natural products containing quinoline ring
Chloroquine
Mefloquine
Piperaquine
Quinoline is also a part of several clinically used drugs,
where their major occurrence is among antimalarial drugs (Fig
2). Other commercially available drugs containing quinoline ring
are fluoroquinolone antibiotic ciprofloxacin (and its analogues),
pitavastatin (cholesterol lowering agent), lenvatinib (kinase
inhibitor for cancer) (Fig. 2) and its other structural analogues
(such as carbozantinib, bosutinib), tipifarnib 70 (farnesyl
transferase inhibitor for leukemia), saquinavir (antiretroviral),
bedaquiline (anti-TB), etc. The 2-(2-fluorophenyl)-6,7-
methylenedioxy quinolin-4-one monosodium phosphate (CHM-
Ciprofloxacin
Pitavastatin
Lenvatinib
Fig. 2 Chemical structures of quinoline containing drugs
Several ‘Name Reactions’ have been reported for the
synthesis of quinoline: (a) Combes quinoline synthesis; (b)
Skraup synthesis; (c) Conrad-Limpach synthesis; (d) Povarov
reaction; (e) Doebner reaction; (f) Doebner-Miller reaction; (g)
1-P-Na) is a preclinical anticancer agent, showing excellent Gould-Jacobs reaction; (h) Reihm synthesis; (i) Knorr quinoline
antitumor activity in a SKOV-3 xenograft nude mice model16, 17
.
synthesis; (j) Pfitzinger reaction; (k) Friedländer synthesis; (l)
Niementowski quinoline synthesis; (m) Meth-Cohn synthesis;
and (n) Camps quinoline synthesis18. However, conventional
way of carrying out some of these methods suffer from
drawbacks such as hazardous organic solvents, high cost, longer
reaction time, low selectivity, and use of excessive amounts of
base. Therefore, this necessitates the development of facile and
environmentally benign methods for the synthesis of
quinolines.
Here we have explored environmentally benign route for
Pfitzinger reaction for the synthesis of quinoline-4-carboxylic
acids. Traditional Pfitzinger reaction involves reaction of isatin
Dyestuff Technology Department, Institute of Chemical Technology, Matunga,
Mumbai400019, India
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Journal Name
with ketone catalysed by strong bases such as NaOH, KOH19 rate and efficiency of the reaction are more thanVtiehwoAsreticloe fOntlhinee
which are difficult to recycle which further leads to the conventional thermal condition.
DOI: 10.1039/C7NJ01937H
generation of highly basic effluent. Therefore we thought of Table 1 Optimization of reaction parameters for the synthesis
using basic catalyst which is recyclable and facilitates solubility of quinoline-4-carboxylic acid
of water insoluble substrates in to water. Cetyltrimethyl
ammonium hydroxide (CTAOH) forms micelles in water20 which
solubilises organic substrates in to water. Micelles are proficient
in bringing together the reactants within their small volumes.
They can also stabilize and orient substrates in order to change
the reactivity of substrates. Therefore, they can modify the
reaction rates. It facilitates the use of water as a solvent for
NUS
yield
(%)b
Nr
Nr
59
organic reactions. In our effort for conservation of energy
required for the chemical reaction processes, we have also
made use of ultrasound as a nonconventional energy source to
US yield
(%)a
Entry
Base
-
Solvent
1
2
3
4
Water
Ethanol
Water
nrc
Nr
65
63
accelerate the rate of reaction
.
Ethanol
57
KOH
Ca(OH)2
(CH3)3CO-K+
TEAd
Water-
ethanol (1:1)
Water
Ethanol
Water-
ethanol (1:1)
Water
Ethanol
Water-
ethanol (1:1)
Water
Ethanol
Water-
ethanol (1:1)
Water
Ethanol
Water-
ethanol (1:1)
Water
Ethanol
Water-
ethanol (1:1)
5
66
62
Fig. 3 Structure of Cetyltrimethylammonium hydroxide (CTAOH)
Scheme 1 General Pfitzinger reaction for the synthesis of
quinoline-4-carboxylic acid
6
7
58
59
54
56
8
62
57
9
10
55
50
50
45
11
58
54
In order to study the catalytic effect of CTAOH for Pfitzinger
reaction, isatin was reacted with acetophenone to give 2-
phenylquinoline-4-carboxylic acid 3a. Reaction did not take
place when isatin was reacted with acetophenone in absence of
catalyst. Pfitzinger reaction takes place by basic hydrolysis of
isatin to isatoic acid therefore strong basic catalyst is needed to
trigger this reaction19. Among various bases tested for this
reaction CTAOH was found to be efficient basic catalyst which
gave 2-phenylquinoline-4-carboxylic acid 3a with 94 % yield
with water as a suitable solvent (table 1). 0.5 equivalents of
CTAOH gave highest yield of 2-phenylquinoline-4-carboxylic
acid. CTAOH being surfactant solubilises reactants in water
12
13
20
25
14
21
14
23
19
15
16
56
60
49
58
ChOH
17
55
51
18
19
95
94
94
92
CTAOH
20
21
21
93
95
93
92
94
92
through micelle formation21-23
. This homogenization of
reactants in solvent increases contact with catalyst therefore
increases rate and yield of the reaction system. Though
reactants have good solubility in ethanol water acted as a good
reaction media due to easy separation of product, higher rate
of hydrolysis of isatin than in ethanol24. Thus CTAOH fastens the
rate of reaction. After extraction of product aqueous media
containing dissolved CTAOH could be reused for the next batch
of reaction. Further to explore the generality of the optimized
reaction conditions various derivatives of quinoline-4-
carboxylic acids were synthesised (Table 2).
CTAOH (0.5
equiv.)
CTAOH (1.5
equiv.)
Water
Water
a: Ultrasound reaction condition: Isatin (0.01 mol),
acetophenone (0.01 mol), base (0.01 mol), solvent (5mL) at
ultrasound frequencies of 22 kHz, at 40% amplitude, at rt.
b: Non-ultrasound reaction condition: Isatin (0.01 mol),
acetophenone (0.01 mol), base (0.01 mol), solvent (5 mL) at
80 oC.
To enhance the rate of reaction and productivity we carried
out the same reaction under ultrasonic condition. Rate
acceleration in ultrasound assisted reaction is due to the
collapse of acoustic cavitation bubbles that generates localised
temperature and pressure25. This also avoids the need to
provide external heat. When isatin was reacted with
acetophenone under ultrasonic conditions (ultrasound
frequencies of 22 kHz, at 40% amplitude, at RT), compound 3a
was obtained in 2.5 hr where as it required 10 hr under
conventional thermal condition (80 oC) (Table 1). It is
noteworthy to mention here that under ultrasonic conditions
c: No reaction, d: Triethylamine
A number of different methyl ketones were chosen to
access the scope of the reaction method (Table 2). All the
reactions were carried out under set reaction conditions and
continued till the completion of reaction, indicated by thin layer
chromatography. Under this method simple and functionalized
methyl ketones easily reacted with isatoic acid formed after
hydrolysis of isatin giving corresponding 2-substituted
quinoline-4-carboxylic acids with good yield.
2 | J. Name., 2012, 00, 1-3
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Table 2 Synthesis of quinoline-4-carboxylic acid derivatives consequence of the specific effects of ultrasound that is
cavitation, a physical process that crDeaOtI:e1s0,.10e3Vn9iel/awCrA7gNretiJcsl0e,1O9an3ln7inHde
implodes gaseous and vaporous cavities in an irradiated liquid,
thus enhancing the mass transfer and allowing chemical
reactions to occur. The creation of hot spots in the reaction
mixture produces intense local temperatures and high
pressures generated inside the cavitation bubble and its
interfaces when it collapses. Under these conditions, very
1
2
3
reactive chemical species are produced, with a very short
lifetime, thus facilitating synthesis of quinoline-4-carboxylic
acids (3a–3l) in shorter time.
Energy (KJ) Yiel
d
Time (hr)
Energy efficiency has been calculated and compared
using CTAOH in the conventional (NUS) and ultrasound (US)
methods. Method for energy calculation have been reported by
Singh et al.26 (see Supporting Information) shows the calculation
of the energy of the two methods: conventional (NUS) and
ultrasound (US) method used for the synthesis of quinoline-4-
carboxylic acid derivatives. The energy utilized for the synthesis
is the total energy supplied (kJ) per unit weight of the material
processed/obtained (g). The time required for the synthesis of
compound 3a is 10 hr for the NUS method and 2.5 hr for the US
method. Total energy required per unit weight of the material
processed to synthesize compound 3a is 17.76 kJ/g for the NUS
method and 3.79 kJ/g for the US method. It was observed that
the US method saved more than 78 % energy as compared to
the NUS method.
The mechanism of CTAOH catalysed formation of 2-
substituted quinoline-4-carboxylic acids can be explained on the
basis of mechanism reported in the literature19 (Scheme 2). The
isatin 1 is converted by the action of CTAOH into the salt of
isatoic acid 2, which condense with ketone 3 with the release of
water. The latter undergo cyclization through the CO and CH2
groups and are converted into the salt of quinolone-4-
carboxylic acid, which further gives corresponding product 5.
Most micellar catalyzed reactions are supposed to occur in the
Stern layer27 (Fig. 4). Micelles can attract an organic substrate
by means of both electrostatic and hydrophobic interactions.
Entry
1
R
3
NUS US
NUS
10
US
(%)
C6H5
p-CH3-
C6H5
3a
2.5 17.7 3.8
95
80
18.4 4.5
2
3b
10.5
3.0
2.7 15.5 4.0
5
3
4
5
p-Cl-C6H5 3c
9
82
78
77
p-Br-C6H5 3d
10
11
3.0 16.7 4.2
p-OCH3-
3e
19.0 5.9
4.0
C6H5
p-NH2-
3f
22.8 6.7
4.5
6
7
8
9
13
7
75
85
79
89
C6H5
p-NO2-
3g
12.0 2.9
2.0
C6H5
o-OH-
3h
22.9 6.7
4.5
13
18
C6H5
3i
3j
6.5 31.9 9.8
10
11
15
13
6.0 24.4 8.2
4.0 24.2 6.4
78
88
CH3
3k
3l
12
14
4.5 23.8 6.5
85
Scheme 2 Plausible mechanism for CTAOH catalysed Pfitzinger
reaction
Reaction condition: Isatin (0.01 mol), acetophenone (0.01
mol), CTAOH (0.005 mol), water (5.0 mL).
NUS: non ultrasound US: ultrasound
The recyclability of CTAOH was investigated in the synthesis
of compound 3a from the reaction of isatin and acetophenone.
After separation of the product, the aqueous layer containing
the CTAOH was reused in the next run without further
purification. Same reaction of isatin and acetophenone was
carried out in spent aqueous layer under the same reaction
conditions. The yield was found to be decreased by 10 % by the
The method to obtain quinoline-4-carboxylic acid
derivatives (3a–3m) under ultrasonic irradiation offers several
significant advantages including faster reaction rates, higher
purity, higher yields, and lower temperature. In comparison
with conventional methods, the main advantage of ultrasound
application is the significant decrease in the reaction times.
Thus, while conventional heating method requires 7-18 h for
the completion of this reaction, ultrasonic irradiation affords
the respective products in only 2-7 h. These results support the
assumption that the energy provided by ultrasound accelerates
these reactions. The difference in reaction times may be a
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fourth recycle (Fig. 5(A)). This decrease in the yield may be due 1. J. P. Michael, Nat. Prod. Rep., 2008, 25, 166.
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to loss of catalytic aqueous system during work up procedure. 2. V. R. Solomon and H. Lee, Curr. Med. Chem., 2011, 18, 1488.
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Fig. 4 Micellar catalyzed reaction at stern layer
5A
6
5B
a
b
c
d
e
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Fig. 5 (A) Bar graph showing recyclability of CTAOH aqueous
solution. (B) Aqueous CTAOH solution (a) before addition of
reactants, (b) after addition of isatin, (c) after addition of
acetophenone, (d) after reaction, (e) spent aqueous CTAOH
solution after separation of product.
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,
Conclusions
In conclusion, we have explored catalytic activity of CTAOH
for the Pfitzinger reaction of 2-substituted quinoline-4-
carboxylic acid synthesis. CTAOH being surfactant in nature
increases solubility of reactants in water by entrapping
substrate molecules in to the micelles. Ultrasonic irradiation
was found to reduce reaction time, temperature and make this
method energy efficient when compared with conventional
thermal method. Synergistic effects of both CTAOH and
ultrasound make this method green with silent features
including operational simplicity, use of water as a solvent,
improved reaction rates, high yields of products and avoidance
of the use of hazardous acids or bases.
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Acknowledgement
Authors are thankful to UGC-CAS for providing financial assis-
tance and the Institute of Chemical Technology, for recording
ESI–MS and TIFR Mumbai for 1H and 13C NMR.
Notes and references
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7NJ01937H
Energy efficient Pfitzinger Reaction: A Novel strategy with Surfactant Catalyst
Priyanka A. More, Ganapati S. Shankarling*
Graphical Abstract
A novel ultrasound assisted synthesis rout for quinolone-4carboxylic acid catalysed by surfactant.