Glycerol and Q-Tubes: Green Catalyst and Technique for Synthesis of Polyfunctionally Substituted Heteroaromatics and Anilines

Abstract

The role of glycerol as a green bio-based solvent, reactant, and/or a catalyst in the synthesis of novel heterocycles, under pressure, is studied. Synthesis of novel quinolines in good yields using a new modified Skraup synthesis, utilizing glycerol and pressure Q-tubes, is demonstrated. Novel aniline trimers are prepared using glycerol, and substituted anilines under pressure, in acidic medium and water. Glycerol was employed as a catalyst and a green solvent in the synthesis of novel pyridazines 13a–c. The mechanisms of the reactions and the catalytic effect of glycerol in protic and aprotic media are fully discussed. The structures of the synthesized compounds were determined via X-ray crystallography and spectroscopic methods.

Full text

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Article
Glycerol and Q-Tubes: Green Catalyst and Technique
for Synthesis of Polyfunctionally Substituted
Heteroaromatics and Anilines
Douaa Salman AlMarzouq 1, * and Noha M. Hilmy Elnagdi 2, *
1Department of Environmental Health, College of Health Sciences, the Public Authority of Applied
Education and Training, P.O. Box 23167, Safat 13092, Kuwait
2
Department of Organic Chemistry, Faculty of Pharmacy, Modern University for Technology and Information,
Cairo, P.O. Box 12518, Cairo 11511, Egypt
*Correspondence: nontan_83@hotmail.com (D.S.A.); elnagdinoha@yahoo.com (N.M.H.E.);
Tel.: +965-9793-2529 (D.S.A.); +20-110-557-3654 (N.M.H.E.)
Received: 2 April 2019; Accepted: 7 May 2019; Published: 10 May 2019


Abstract:
The role of glycerol as a green bio-based solvent, reactant, and/or a catalyst in the synthesis
of novel heterocycles, under pressure, is studied. Synthesis of novel quinolines in good yields
using a new modified Skraup synthesis, utilizing glycerol and pressure Q-tubes, is demonstrated.
Novel aniline trimers are prepared using glycerol, and substituted anilines under pressure, in acidic
medium and water. Glycerol was employed as a catalyst and a green solvent in the synthesis of novel
pyridazines 13a–c. The mechanisms of the reactions and the catalytic effect of glycerol in protic and
aprotic media are fully discussed. The structures of the synthesized compounds were determined via
X-ray crystallography and spectroscopic methods.
Keywords:
glycerol; green chemistry; modified Skraup’s quinoline synthesis; reactions under
pressure; Q-tubes; polyaniline
1. Introduction
Glycerol was first isolated by the Swedish chemist: Carl W. Scheele, in 1779, upon treatment of
olive oil with lead oxide [
1
,
2
]. Glycerol or propane-1,2,3-triol 1 is now produced in large quantities as a
byproduct in many industries [
3
–
5
]. The large-scale production of biodiesel from fats, where glycerol
is a waste product, has made glycerol a highly economic solvent and reactant [
6
–
12
]. This has attracted
many researchers in the last two decades to find routes for converting this surplus into value added
products [13–24]. Some of glycerol’s utilities in chemical industries are summarized in Scheme 1.
Since glycerol is highly hygroscopic and stable at high temperatures (B.P. =290
◦
C), in addition
to being environmentally friendly, nontoxic, nonvolatile, inflammable, non-corrosive, cheap,
biodegradable, and recyclable, it could be considered a green medium and solvent in organic
synthesis [
25
–
27
]. According to Arrhenius, the reaction rate doubles for every 10
◦
C rise in
temperature [
28
]. Thus, glycerol would simply decrease the time of many reactions that take
place in other low boiling-point solvents. Recently, Hamid et al. discussed the catalytic effect of glycerol
by H-bond formation, which facilitates addition and condensation processes [
29
]. Glycerol has not
yet been fully explored in the field of organic synthesis and catalysis. However, some studies have
suggested that glycerol is a medium in “catalyst-free” reactions [
30
–
32
]. We think that these studies
have neglected the possibility that glycerol itself acts as a catalyst in such reactions.
One of the oldest utilities of glycerol in organic chemistry is the synthesis of quinolines in poor
yields, known as the “Skraup synthesis of quinolines” [
33
,
34
]. Skraup’s synthesis of quinolines has
many limitations other than the low yield, including the multi-step addition of the reactants, in which
Molecules 2019,24, 1806; doi:10.3390/molecules24091806 www.mdpi.com/journal/molecules

Molecules 2019,24, 1806 2 of 14
glycerol must first react with H
2
SO
4
to yield the hazardous acrolein (propenal), which is followed by
the addition of the aromatic amine to form hydroquinoline that is converted to the quinoline by adding
an oxidizing agent as the final step (cf. Scheme 2).
Molecules 2019, 24 FOR PEER REVIEW 2
Scheme 1. Some industrial uses of glycerol.
Since glycerol is highly hygroscopic and stable at high temperatures (B.P. = 290 °C), in addition
to being environmentally friendly, nontoxic, nonvolatile, inflammable, non-corrosive, cheap,
biodegradable, and recyclable, it could be considered a green medium and solvent in organic
synthesis [25–27]. According to Arrhenius, the reaction rate doubles for every 10 °C rise in
temperature [28]. Thus, glycerol would simply decrease the time of many reactions that take place in
other low boiling-point solvents. Recently, Hamid et al. discussed the catalytic effect of glycerol by
H-bond formation, which facilitates addition and condensation processes [29]. Glycerol has not yet
been fully explored in the field of organic synthesis and catalysis. However, some studies have
suggested that glycerol is a medium in “catalyst-free” reactions [30–32]. We think that these studies
have neglected the possibility that glycerol itself acts as a catalyst in such reactions.
One of the oldest utilities of glycerol in organic chemistry is the synthesis of quinolines in poor
yields, known as the “Skraup synthesis of quinolines” [33,34]. Skraup’s synthesis of quinolines has
many limitations other than the low yield, including the multi-step addition of the reactants, in which
glycerol must first react with H2SO4 to yield the hazardous acrolein (propenal), which is followed by
the addition of the aromatic amine to form hydroquinoline that is converted to the quinoline by
adding an oxidizing agent as the final step (cf. Scheme 2).
Scheme 1. Some industrial uses of glycerol.
Molecules 2019, 24 FOR PEER REVIEW 3
Scheme 2. Reaction mechanism of the Skraup quinoline synthesis.
Other limitations include the use of highly concentrated glycerol that contains less than one-half
percent of water known as “dynamite glycerin” to ensure good yields [35]. Precautions from
explosion and physical hazards control have to be employed since the reaction is highly vigorous due
to the use of nitrobenzene as an oxidizing agent and as a solvent. Prolonged heating in concentrated
H2SO4, and the formation of a thick tar, from which quinoline is difficult to extract are also among
the problems of the Skraup synthesis. These limitations have urged researchers to attempt to modify
the synthetic route, to increase the yield of the quinoline synthesis reactions, and to make it “greener.”
The new modified synthesis of quinolines or “green recipes” [36] involve using green solvents or
even solvent-less reactions, one-pot synthesis, new green catalysts alongside with new technologies
such as microwave energy, ultrasonication, and grinding [37–49]
There is now a boom in the use of high pressure in science [50], and reactions under high
pressure and/or temperature proved to behave in a different manner than those under normal
thermal conditions [51,52]. The newly invented borosilicate tubes known as Q-tubes have allowed
the performance of difficult or otherwise impossible chemical reactions in chemical laboratories [53–
56]. Shifts in transition state along a reaction coordinate, a switch of the rate-determining step, and
the possible transformation of a transition state into a stable minimum, are among the possible
phenomena that can occur for reactions under pressure, especially in fluids [57]. A supercritical
solvent is a solvent that is subjected to a temperature and pressure higher than those of its critical
point. However, when both the temperature and/or the pressure are lower than those of the critical
point, and the temperature is higher than that of the boiling point, with a pressure higher than 1 bar,
a subcritical solvent is obtained. A subcritical solvent can be defined as a hot compressed solvent and,
according to Galy et al., glycerol produces different products in subcritical and supercritical solvents
[58]. In this study, we combined glycerol and water as green, efficient solvents, in addition to the
pressure in Q-tubes, to modify the synthesis of quinolines and prepare new aniline trimers and
pyridazines.
2. Results and Discussion
We initially started our work with the synthesis of quinolines. Quinolines are extremely
important in the pharmaceutical industry, especially in the treatment of malaria and cancer [59–61].
Fluoroquinolines are used in many pharmaceutical compounds, especially in fluoroquinolone
antibiotics, such as ciprofloxacin (Cipro), gemifloxacin (Factive), levofloxacin (Levaquin),
moxifloxacin (Avelox), norfloxacin (Noroxin), and ofloxacin (Floxin) [62,63].
Selivanova et al. found that reacting polyfluoro-2-naphthylamines with glycerol in H2SO4 or
CF3SO3H at 150–160 °C gives, surprisingly, the respective polyfluorobenzo[f]quinolones, rather than
Scheme 2. Reaction mechanism of the Skraup quinoline synthesis.
Other limitations include the use of highly concentrated glycerol that contains less than one-half
percent of water known as “dynamite glycerin” to ensure good yields [
35
]. Precautions from explosion
and physical hazards control have to be employed since the reaction is highly vigorous due to the use of
nitrobenzene as an oxidizing agent and as a solvent. Prolonged heating in concentrated H
2
SO
4
, and the

Molecules 2019,24, 1806 3 of 14
formation of a thick tar, from which quinoline is difficult to extract are also among the problems of the
Skraup synthesis. These limitations have urged researchers to attempt to modify the synthetic route,
to increase the yield of the quinoline synthesis reactions, and to make it “greener.” The new modified
synthesis of quinolines or “green recipes” [
36
] involve using green solvents or even solvent-less
reactions, one-pot synthesis, new green catalysts alongside with new technologies such as microwave
energy, ultrasonication, and grinding [37–49].
There is now a boom in the use of high pressure in science [
50
], and reactions under high
pressure and/or temperature proved to behave in a different manner than those under normal thermal
conditions [
51
,
52
]. The newly invented borosilicate tubes known as Q-tubes have allowed the
performance of difficult or otherwise impossible chemical reactions in chemical laboratories [
53
–
56
].
Shifts in transition state along a reaction coordinate, a switch of the rate-determining step, and the
possible transformation of a transition state into a stable minimum, are among the possible phenomena
that can occur for reactions under pressure, especially in fluids [
57
]. A supercritical solvent is a
solvent that is subjected to a temperature and pressure higher than those of its critical point. However,
when both the temperature and/or the pressure are lower than those of the critical point, and the
temperature is higher than that of the boiling point, with a pressure higher than 1 bar, a subcritical
solvent is obtained. A subcritical solvent can be defined as a hot compressed solvent and, according to
Galy et al.
, glycerol produces different products in subcritical and supercritical solvents [
58
]. In this
study, we combined glycerol and water as green, efficient solvents, in addition to the pressure in
Q-tubes, to modify the synthesis of quinolines and prepare new aniline trimers and pyridazines.
2. Results and Discussion
We initially started our work with the synthesis of quinolines. Quinolines are extremely
important in the pharmaceutical industry, especially in the treatment of malaria and cancer [
59
–
61
].
Fluoroquinolines are used in many pharmaceutical compounds, especially in fluoroquinolone
antibiotics, such as ciprofloxacin (Cipro), gemifloxacin (Factive), levofloxacin (Levaquin), moxifloxacin
(Avelox), norfloxacin (Noroxin), and ofloxacin (Floxin) [62,63].
Selivanova et al. found that reacting polyfluoro-2-naphthylamines with glycerol in H
2
SO
4
or
CF3SO3H at 150–160 ◦C gives, surprisingly, the respective polyfluorobenzo[f]quinolones, rather than
the expected cyclization at the unsubstituted ortho-position [
39
]. We thought of investigating this
phenomenon as well as modifying the Skraup quinoline synthesis using pressure Q-tubes, and studying
the effect of glycerol in subcritical and supercritical solvents. Unlike the results reported by Selivanova
et al., the reaction of
1
and
3a
–
b
in the presence of conc. H
2
SO
4
, under pressure in a Q-tube at 200
◦
C
proceeded to yield quinolines
6a
and
6b
, in 58% and 60% yield, respectively. To our knowledge,
quinoline 6b has not been previously isolated (cf. Scheme 3).
Recently, Saggadi and co-workers synthesized 5-substituted, 6-substituted, 7-subsituted, and
8-substituted quinolines using microwave conditions, aniline derivatives, and glycerol in the presence
of sulfuric acid and water. The desired quinolines were obtained in 10%–66% yields [
64
]. Surprisingly,
in our hands, the reaction of aromatic amines, glycerol, sulfuric acid, and water in pressurized
conditions afforded a compound with an m/zvalue of 359.23, which was, after other spectroscopic
investigations, assigned to 4,4
0
,4”-(propane-1,2,3-triyl)tris(2-methylaniline) 7. The
1
H NMR spectrum
of compound 7 shows a singlet at
δ
=2.00 ppm for 9H that is assigned to 3-CH
3
protons, a multiplet
at
δ
=3.34 ppm for 5H of 2 methylene and 1 methine protons, and another singlet at
δ
=5.01 ppm
for 6H assigned for the 3 NH
2
protons as well as a multiplet at
δ
=7.13 for aromatic 6 protons. The
13
C-NMR spectrum of compound 7 shows a signal at
δ
=146.53 assigned for 3C-NH
2
at
δ
=76.24 for
2CH
2
and at
δ
=16.95 for 3CH
3
. Conversely, when the unsubstituted aniline 3a was reacted under the
same conditions, with glycerol and water under pressure (subcritical water), the aniline trimer 8 was
the only product obtained. The structure of compound 8 was also confirmed via spectroscopic analysis.
The mass spectrum of the reaction product 8 showed a molecular ion peak: m/z=365.173 (100%). The
1
H NMR spectrum revealed a singlet at
δ
=2.4 ppm, integrated for 6H, which was assigned to the

Molecules 2019,24, 1806 4 of 14
3NH
2
protons. Two doublets at
δ
=3.27 ppm and 3.29 ppm for two aliphatic CH
2
groups and multiplet
at
δ
=3.35 ppm were assigned for the methine CH proton and another multiplet at 6.94 ppm were
assigned for the aromatic protons. The
13
C-NMR spectral results were in agreement with the proposed
structure, which showed a signal at
δ
=63.09 ppm, assigned to the 2 O-CH
2
carbons, as well as another
signal at
δ
=72.49 ppm, assigned to the O-CH carbon. It is worth mentioning that trials to use 3f as
the starting aniline produced a compound with an m/zvalue of 410.5, for which we could not assign
any reasonable, suggested structure. Table 1summarizes our results and reaction conditions of the
reactions of glycerol with aromatic amines under pressure.
Molecules 2019, 24 FOR PEER REVIEW 4
the expected cyclization at the unsubstituted ortho-position [39]. We thought of investigating this
phenomenon as well as modifying the Skraup quinoline synthesis using pressure Q-tubes, and
studying the effect of glycerol in subcritical and supercritical solvents. Unlike the results reported by
Selivanova et al., the reaction of 1 and 3a–b in the presence of conc. H2SO4, under pressure in a Q-
tube at 200 °C proceeded to yield quinolines 6a and 6b, in 58% and 60% yield, respectively. To our
knowledge, quinoline 6b has not been previously isolated (cf. Scheme 3).
Scheme 3. Reaction of aromatic amines, glycerol, and sulfuric acid in the presence/absence of water,
under a high pressure, and high temperatures in the Q-tubes.
Recently, Saggadi and co-workers synthesized 5-substituted, 6-substituted, 7-subsituted, and 8-
substituted quinolines using microwave conditions, aniline derivatives, and glycerol in the presence
of sulfuric acid and water. The desired quinolines were obtained in 10%–66% yields [64].
Surprisingly, in our hands, the reaction of aromatic amines, glycerol, sulfuric acid, and water in
pressurized conditions afforded a compound with an m/z value of 359.23, which was, after other
spectroscopic investigations, assigned to 4,4′,4′′-(propane-1,2,3-triyl)tris(2-methylaniline) 7. The 1H
NMR spectrum of compound 7 shows a singlet at δ = 2.00 ppm for 9H that is assigned to 3-CH3
protons, a multiplet at δ = 3.34 ppm for 5H of 2 methylene and 1 methine protons, and another singlet
at δ = 5.01 ppm for 6H assigned for the 3 NH2 protons as well as a multiplet at δ = 7.13 for aromatic 6
protons. The 13C-NMR spectrum of compound 7 shows a signal at δ = 146.53 assigned for 3C-NH2 at
δ = 76.24 for 2CH2 and at δ = 16.95 for 3CH3. Conversely, when the unsubstituted aniline 3a was
reacted under the same conditions, with glycerol and water under pressure (subcritical water), the
aniline trimer 8 was the only product obtained. The structure of compound 8 was also confirmed via
spectroscopic analysis. The mass spectrum of the reaction product 8 showed a molecular ion peak:
m/z = 365.173 (100%). The 1H NMR spectrum revealed a singlet at δ = 2.4 ppm, integrated for 6H,
which was assigned to the 3NH2 protons. Two doublets at δ = 3.27 ppm and 3.29 ppm for two aliphatic
CH2 groups and multiplet at δ = 3.35 ppm were assigned for the methine CH proton and another
multiplet at 6.94 ppm were assigned for the aromatic protons. The 13C-NMR spectral results were in
agreement with the proposed structure, which showed a signal at δ = 63.09 ppm, assigned to the 2 O-
CH2 carbons, as well as another signal at δ = 72.49 ppm, assigned to the O-CH carbon. It is worth
mentioning that trials to use 3f as the starting aniline produced a compound with an m/z value of
Scheme 3.
Reaction of aromatic amines, glycerol, and sulfuric acid in the presence/absence of water,
under a high pressure, and high temperatures in the Q-tubes.
Table 1.
Variation of the nature of aniline products depending on the reaction conditions in the
presence and absence of H
2
O, starting from glycerol
1
under a high pressure, and high temperatures in
the Q-tubes.
Entry R1R2R3
Reaction Conditions
Product Yield% MP. (◦C) m/z
Medium Time
(min.)
Temp
(◦C)
3a H H H glycerol 60 200 6a 58 BP =238
3a H H H glycerol +H2O 15 160 8 73 240
365.17
3b F F H glycerol 60 200 6b 60 243
165.03
3c CH3I H glycerol +H2O 15 160 7 75 180
359.23
3d CH3Br H glycerol +H2O 20 160 7 70 180
359.23
3e CH3Cl H glycerol +H2O 20 160 7 70 180
359.23
3f H H Cl glycerol +H2O 30 160 not
concluded
- 410
While acrolein is a minor product of the dehydration of glycerol under neutral hydrothermal
conditions, it becomes the main product when an acid catalyst is added, but at temperatures above

Molecules 2019,24, 1806 5 of 14
340
◦
C using conventional heating [
58
]. Under pressure, we could achieve the same results but at
much lower temperatures. Thus, using Q-tubes and heating at only 200
◦
C for 1 h, we could prepare
quinolines in high yields. Recently, the catalytic role of glycerol via H-bond was published by Hamid
and coworkers [
29
]. We think that, in our work, the reaction proceeds via a typical Skraup reaction
mechanism, but with glycerol having a dual role where one mol of glycerol acts as a starting material
reacting with H
2
SO
4
to produce acrolein
2
, and another mol of glycerol acts as a catalyst and bounds via
H-bond with acroline to generate complex
9
. This then undergoes a Michael addition with the aromatic
amines (
3a, b
). This is followed by the release of glycerol once more to produce the intermediate
4a,
b
that then cyclizes to
6a
and
6b
, respectively. Scheme 4shows a suggested reaction mechanism for
the formation of quinoline
6a, b
. In our reaction conditions, there were no need to add any oxidizing
agents since we believe that concentrated H2SO4acts as a condensation agent and an oxidant.
Molecules 2019, 24 FOR PEER REVIEW 5
410.5, for which we could not assign any reasonable, suggested structure. Table 1 summarizes our
results and reaction conditions of the reactions of glycerol with aromatic amines under pressure.
Table 1. Variation of the nature of aniline products depending on the reaction conditions in the
presence and absence of H2O, starting from glycerol 1 under a high pressure, and high temperatures
in the Q-tubes.
Entry R1 R2 R3
Reaction Conditions
Product Yield
% MP. (°C) m/z
Medium Time
(min.) Temp (°C)
3a H H H glycerol 60 200 6a 58 BP = 238
3a H H H glycerol + H2O 15 160 8 73 240 365.17
3b F F H glycerol 60 200 6b 60 243 165.03
3c CH3 I H glycerol + H2O 15 160 7 75 180 359.23
3d CH3 Br H glycerol + H2O 20 160 7 70 180 359.23
3e CH3 Cl H glycerol + H2O 20 160 7 70 180 359.23
3f H H Cl glycerol + H2O 30 160 not
concluded - 410
While acrolein is a minor product of the dehydration of glycerol under neutral hydrothermal
conditions, it becomes the main product when an acid catalyst is added, but at temperatures above
340 °C using conventional heating [58]. Under pressure, we could achieve the same results but at
much lower temperatures. Thus, using Q-tubes and heating at only 200 °C for 1 hour, we could
prepare quinolines in high yields. Recently, the catalytic role of glycerol via H-bond was published
by Hamid and coworkers [29]. We think that, in our work, the reaction proceeds via a typical Skraup
reaction mechanism, but with glycerol having a dual role where one mol of glycerol acts as a starting
material reacting with H2SO4 to produce acrolein 2, and another mol of glycerol acts as a catalyst and
bounds via H-bond with acroline to generate complex 9. This then undergoes a Michael addition with
the aromatic amines (3a, b). This is followed by the release of glycerol once more to produce the
intermediate 4a, b that then cyclizes to 6a and 6b, respectively. Scheme 4 shows a suggested reaction
mechanism for the formation of quinoline 6a, b. In our reaction conditions, there were no need to add
any oxidizing agents since we believe that concentrated H2SO4 acts as a condensation agent and an
oxidant.
Scheme 4. Mechanism of our modified-Skraup’s synthesis of quinolines under high pressure using
Q-tubes.
A member of our group investigated the x-ray structure of compound 6b, which confirmed the
suggested structure, and no loss of fluorine atoms occurred under our reaction conditions [65] (Cf.
Figure 1). The preliminary inspection of the X-ray crystallographic data of 6(b) indicated that the
molecules exist in aggregates, via intermolecular H-bonding between Fluorine at C-8 and the
hydrogen at C-8, as well as between N-1 and H at C-4 (Cf. Figure 2). A detailed discussion of the x-
Scheme 4.
Mechanism of our modified-Skraup’s synthesis of quinolines under high pressure
using Q-tubes.
A member of our group investigated the x-ray structure of compound 6b, which confirmed
the suggested structure, and no loss of fluorine atoms occurred under our reaction conditions [
65
]
(Cf. Figure 1). The preliminary inspection of the X-ray crystallographic data of 6(b) indicated that
the molecules exist in aggregates, via intermolecular H-bonding between Fluorine at C-8 and the
hydrogen at C-8, as well as between N-1 and H at C-4 (Cf. Figure 2). A detailed discussion of the
x-ray structure of these quinolines will be reported separately after exploring this phenomenon with
other compounds.

Molecules 2019,24, 1806 6 of 14
Molecules 2019, 24 FOR PEER REVIEW 6
ray structure of these quinolines will be reported separately after exploring this phenomenon with
other compounds.
Figure 1. X-ray crystal structure of 6,8-difluoroquinoline 6b.
Figure 2. Aggregates of 6,8-difluoroquinoline 6b that shows H-7 and F-8 H-bonding.
Subsequently, we shifted to utilizing glycerol in the synthesis of pyridazines. The pyridazine
ring is an important structural feature in a number of pharmaceutical compounds, such as
hydralazine (brand name Apresoline, vasodilator, US, FDA), cefozopran (anti-bacterial agent, Japan),
and pipofezine (brand name Azafen or Azaphen, antidepressant, STADA, Nizhny Novgorod,
Russia). Pyridazine derivatives have been reported to possess various pharmacological activities and
intermediates for drugs synthesis, including antimicrobial, analgesic, anticancer, antitubercular,
antidiabetic, antifungal, antihypertensive, anticonvulsant, anti-HIV, antiasthma, anti-inflammatory,
phosphodiesterase (PDE) inhibitors, cyclooxygenase (COX) inhibitors, antipyretic, insecticidal, and
neurological [66–73]. The reaction of arylazo 10d and ethylacetoacetate 11b in either acetic acid or
ethanolic KOH, followed by reflux to afford pyridazinones 15d, has been reported. This reaction was
limited to the formation of 12d, and was not consistently successful and Trials to form 12a failed,
Figure 1. X-ray crystal structure of 6,8-difluoroquinoline 6b.
Molecules 2019, 24 FOR PEER REVIEW 6
ray structure of these quinolines will be reported separately after exploring this phenomenon with
other compounds.
Figure 1. X-ray crystal structure of 6,8-difluoroquinoline 6b.
Figure 2. Aggregates of 6,8-difluoroquinoline 6b that shows H-7 and F-8 H-bonding.
Subsequently, we shifted to utilizing glycerol in the synthesis of pyridazines. The pyridazine
ring is an important structural feature in a number of pharmaceutical compounds, such as
hydralazine (brand name Apresoline, vasodilator, US, FDA), cefozopran (anti-bacterial agent, Japan),
and pipofezine (brand name Azafen or Azaphen, antidepressant, STADA, Nizhny Novgorod,
Russia). Pyridazine derivatives have been reported to possess various pharmacological activities and
intermediates for drugs synthesis, including antimicrobial, analgesic, anticancer, antitubercular,
antidiabetic, antifungal, antihypertensive, anticonvulsant, anti-HIV, antiasthma, anti-inflammatory,
phosphodiesterase (PDE) inhibitors, cyclooxygenase (COX) inhibitors, antipyretic, insecticidal, and
neurological [66–73]. The reaction of arylazo 10d and ethylacetoacetate 11b in either acetic acid or
ethanolic KOH, followed by reflux to afford pyridazinones 15d, has been reported. This reaction was
limited to the formation of 12d, and was not consistently successful and Trials to form 12a failed,
Figure 2. Aggregates of 6,8-difluoroquinoline 6b that shows H-7 and F-8 H-bonding.
Subsequently, we shifted to utilizing glycerol in the synthesis of pyridazines. The pyridazine ring
is an important structural feature in a number of pharmaceutical compounds, such as hydralazine
(brand name Apresoline, vasodilator, US, FDA), cefozopran (anti-bacterial agent, Japan), and pipofezine
(brand name Azafen or Azaphen, antidepressant, STADA, Nizhny Novgorod, Russia). Pyridazine
derivatives have been reported to possess various pharmacological activities and intermediates for
drugs synthesis, including antimicrobial, analgesic, anticancer, antitubercular, antidiabetic, antifungal,
antihypertensive, anticonvulsant, anti-HIV, antiasthma, anti-inflammatory, phosphodiesterase (PDE)
inhibitors, cyclooxygenase (COX) inhibitors, antipyretic, insecticidal, and neurological [
66
–
73
]. The
reaction of arylazo
10d
and ethylacetoacetate
11b
in either acetic acid or ethanolic KOH, followed by
reflux to afford pyridazinones
15d
, has been reported. This reaction was limited to the formation of
12d
, and was not consistently successful and Trials to form
12a
failed, since malononitrile dimerized
under these conditions [
74
,
75
]. In this case, we could efficiently prepare pyridazinones
13a
–
c
in
good yields, by the reaction of malononitrile
11a
, phenylhydrazono esters
10a
–
c
, and glycerol, either

Molecules 2019,24, 1806 7 of 14
under conventional heating at 250
◦
C for 5 h, or under pressure in the Q-tubes at 150
◦
C for 30 min
(cf. Scheme 5).
Molecules 2019, 24 FOR PEER REVIEW 7
since malononitrile dimerized under these conditions [74,75]. In this case, we could efficiently
prepare pyridazinones 13a–c in good yields, by the reaction of malononitrile 11a, phenylhydrazono
esters 10a–c, and glycerol, either under conventional heating at 250 °C for 5 h, or under pressure in
the Q-tubes at 150 °C for 30 min (cf. Scheme 5).
Scheme 5. Synthesis of 4-oxo-1-phenyl-1,4,5,6-tetrahydropyridazine-3-carboxylate 13a–c.
It was found that the yield of formation of 13a–c increased significantly under reactions caused
by pressure, table 2 summarizes our findings and compares these reaction yields.
Table 2. Reaction yield for 13a–c and 12d under pressure and conventional heating.
Product x y z Yield Percentage
Conventional Heating Under Pressure
13a CN COOCH2Ph H 52 76
13b CN COOEt CN 64 88
13c COOEt COOEt H 70 92
12d CN H CH3 86.16 [74] -
We assume that glycerol acts as a catalyst and a bio-based solvent. The catalytic activity of
glycerol in this reaction might be via H-bond formation with the N-atom in compound 11, to form
the intermediate 14. The H-bond formation facilitates the Michael-type addition of the active
methylene of the arylazo 10 on the even more electron-poor CN carbon forming the protonated imine
15. It is suggested that another mole of glycerol coordinates with protonated imines 15, followed by
an intramolecular cyclization and glycerol is released again to the medium, which affords the 4-oxo-
1-phenyl-1,4,5,6-tetrahydropyridazine-3-carboxylate13a–c. Scheme 6 shows our suggested mechanism for
the formation of 13a–c.
Scheme 5. Synthesis of 4-oxo-1-phenyl-1,4,5,6-tetrahydropyridazine-3-carboxylate 13a–c.
It was found that the yield of formation of
13a
–
c
increased significantly under reactions caused by
pressure, Table 2summarizes our findings and compares these reaction yields.
Table 2. Reaction yield for 13a–c and 12d under pressure and conventional heating.
Product xyz
Yield Percentage
Conventional
Heating
Under
Pressure
13a CN COOCH2Ph H 52 76
13b CN COOEt CN 64 88
13c COOEt COOEt H 70 92
12d CN H CH386.16 [74] -
We assume that glycerol acts as a catalyst and a bio-based solvent. The catalytic activity of
glycerol in this reaction might be via H-bond formation with the N-atom in compound
11
, to form
the intermediate
14
. The H-bond formation facilitates the Michael-type addition of the active
methylene of the arylazo
10
on the even more electron-poor CN carbon forming the protonated imine
15
. It is suggested that another mole of glycerol coordinates with protonated imines
15
, followed
by an intramolecular cyclization and glycerol is released again to the medium, which affords the
4-oxo-1-phenyl-1,4,5,6-tetrahydropyridazine-3-carboxylate
13a
–
c.
Scheme 6shows our suggested
mechanism for the formation of 13a–c.

Molecules 2019,24, 1806 8 of 14
Molecules 2019, 24 FOR PEER REVIEW 8
Scheme 6. Mechanism of synthesis of 4-oxo-1-phenyl-1,4,5,6-tetrahydropyridazine-3-carboxylate
13a–c.
The structures of compounds 13a–c were confirmed by spectroscopic analysis. Compound 13a
had an m/z value of 362.53. The 1H NMR spectrum of 13a revealed two multiplets for the prochiral
CH2-CN at δ = 1.28 and 1.31 ppm. A two multiplets for the prochiral ring methylene protons COCH2
appears at δ = 2.39 and 2.49 ppm. A singlet at δ = 4.30 ppm is assigned for two methylene protons, a
multiplet at δ = 7.10 ppm for the aromatic 10H, and two singlets for the four NH2 protons at δ = 11.56
ppm and 14.22 ppm, respectively. The 13C-NMR spectrum of compound 13a showed a signal at δ =
196.8 ppm significant for a true carbonyl, assigned to the pyridazine ring carbonyl, and showed
another signal at δ = 163.4 ppm for the ester carbonyl. The CH2CN methylene carbon appears at δ =
25.9 ppm. Figure 3 indicates the most important 13C-NMR signals for 13a.
Scheme 6.
Mechanism of synthesis of 4-oxo-1-phenyl-1,4,5,6-tetrahydropyridazine-3-carboxylate
13a
–
c
.
The structures of compounds
13a–c
were confirmed by spectroscopic analysis. Compound
13a
had
an m/z value of 362.53. The
1
H NMR spectrum of
13a
revealed two multiplets for the prochiral CH
2
-CN
at
δ
=1.28 and 1.31 ppm. A two multiplets for the prochiral ring methylene protons COCH
2
appears
at
δ
=2.39 and 2.49 ppm. A singlet at
δ
=4.30 ppm is assigned for two methylene protons, a multiplet
at
δ
=7.10 ppm for the aromatic 10H, and two singlets for the four NH
2
protons at
δ=11.56 ppm
and
14.22 ppm, respectively. The
13
C-NMR spectrum of compound
13a
showed a signal at
δ
=196.8 ppm
significant for a true carbonyl, assigned to the pyridazine ring carbonyl, and showed another signal at
δ
=163.4 ppm for the ester carbonyl. The CH
2
CN methylene carbon appears at
δ
=25.9 ppm. Figure 3
indicates the most important 13C-NMR signals for 13a.

Molecules 2019,24, 1806 9 of 14
Molecules 2019, 24 FOR PEER REVIEW 9
72.9
60. 8
196. 8
25.9
163.4
63. 5
116.6
N
N
O
NH2
O
O
N
Figure 3. 13C-NMR spectroscopic analysis of 13a.
3. Materials and Methods
3.1. General
Q-tube assisted reactions were performed in a Q-tube safe pressure reactor from Q Labtech (East
Lyme, CT 06333, New London County, CT, USA, equipped with a cap/sleeve, pressure adapter (120
psi), needle adapter/needle, borosilicate glass tube, Teflon septum, and catch bottle. All reactions
were monitored by using TLC with 1:1 ethyl acetate-petroleum ether as eluent and were carried out
until starting materials were completely consumed. Melting points are reported uncorrected and
were determined with a Sanyo (Gallenkamp, Osaka, Japan). 1H NMR and 13C-NMR spectra were
done at the Analab Kuwait University and determined by using a Bruker DPX instrument at 600 MHz
for 1H-NMR and 150 MHz for 13C-NMR and either CDCl3 or DMSO-d6 solutions with TMS as internal
standards. Chemical shifts are reported in δ (ppm). Mass spectra and accurate mass measurements
were made using a GCMS DFS spectrometer (Thermo, Bremen, Germany) with the EI (70 EV) mode.
X-ray crystallographic structure determinations were performed by using Rapid II (Rigaku, Tokyo,
Japan) and X8 Prospector (Bruker, Karlsruhe, Germany) single crystal X-ray diffractometers.
3.2. General Procedures for Q-Tube-Assisted Synthesis of Quinolines 6a,b
Glycerol 1 (5 mL), concentrated sulfuric acid (1 mL), and 0.01 mol of the corresponding aniline
(0.93 g 3a or 1.29 g of 3b) were sequentially added in a 35 mL Q-tube pressure tube, furnished by Q
Labtech. A Teflon septum was placed on top of the tube, and an appropriate cap was used. The
mixture was heated in an oil bath at 200 °C for about 60 min. The mixture was cooled and poured
into ice-water. The solid was collected by filtration and purified by column chromatography and
crystallized from ethanol.
3.3. 6,8-Difloroquinoline 6b
Yellow crystals, yield 60%, mp >250 °C, 1H-NMR (DMSO-d6, 600 MHz): δ = 7.62–7.70 (3H, m, H-
3, H-5, H-7), 8.38 (1H, m, H-4), 8.90 (1H, t, H-2). 13C-NMR (150 MHz, DMSO-d6): δ = 105.12, 107.13,
123.37, 129.23, 135.04, 150.16, 156.90, 157.75, 158.61, 159.38. EI-HRMS: m/z for C9H5F2N, calcd.
165.0390, found: 165.0384.
3.4. General Procedure to Aniline Trimers 7 and 8
A 35 mL Q-tube pressure tube, furnished by Q Labtech was charged with aniline derivative 3c-
e (10 mmol) (2.23 g of 3c, 1.86 g of 3d, 1.41 g of 3e), 5 mL glycerol, 3 mL H2SO4, and 10 mL of water.
A Teflon septum was placed on top of the tube, and an appropriate cap was used. The mixture was
heated in an oil bath at 160 °C for 15 min. After cooling at room temperature, pH was adjusted at 8–
9 by adding NaOH and the reaction mixture was extracted with ethyl acetate (2 × 20 mL). The
combined organic layers were dried over MgSO4 and were then filtered and evaporated under
Figure 3. 13C-NMR spectroscopic analysis of 13a.
3. Materials and Methods
3.1. General
Q-tube assisted reactions were performed in a Q-tube safe pressure reactor from Q Labtech (East
Lyme, CT 06333, New London County, CT, USA, equipped with a cap/sleeve, pressure adapter (120 psi),
needle adapter/needle, borosilicate glass tube, Teflon septum, and catch bottle. All reactions were
monitored by using TLC with 1:1 ethyl acetate-petroleum ether as eluent and were carried out until
starting materials were completely consumed. Melting points are reported uncorrected and were
determined with a Sanyo (Gallenkamp, Osaka, Japan).
1
H NMR and
13
C-NMR spectra were done
at the Analab Kuwait University and determined by using a Bruker DPX instrument at 600 MHz for
1
H-NMR and 150 MHz for
13
C-NMR and either CDCl
3
or DMSO-d
6
solutions with TMS as internal
standards. Chemical shifts are reported in
δ
(ppm). Mass spectra and accurate mass measurements
were made using a GCMS DFS spectrometer (Thermo, Bremen, Germany) with the EI (70 EV) mode.
X-ray crystallographic structure determinations were performed by using Rapid II (Rigaku, Tokyo,
Japan) and X8 Prospector (Bruker, Karlsruhe, Germany) single crystal X-ray diffractometers.
3.2. General Procedures for Q-Tube-Assisted Synthesis of Quinolines 6a,b
Glycerol
1
(5 mL), concentrated sulfuric acid (1 mL), and 0.01 mol of the corresponding aniline
(0.93 g 3
a
or 1.29 g of 3
b
) were sequentially added in a 35 mL Q-tube pressure tube, furnished by
Q Labtech. A Teflon septum was placed on top of the tube, and an appropriate cap was used. The
mixture was heated in an oil bath at 200
◦
C for about 60 min. The mixture was cooled and poured
into ice-water. The solid was collected by filtration and purified by column chromatography and
crystallized from ethanol.
3.3. 6,8-Difloroquinoline 6b
Yellow crystals, yield 60%, mp >250
◦
C,
1
H-NMR (DMSO-d
6
, 600 MHz):
δ
=7.62–7.70 (3H, m,
H-3, H-5, H-7), 8.38 (1H, m, H-4), 8.90 (1H, t, H-2).
13
C-NMR (150 MHz, DMSO-d
6
):
δ
=105.12, 107.13,
123.37, 129.23, 135.04, 150.16, 156.90, 157.75, 158.61, 159.38. EI-HRMS: m/zfor C
9
H
5
F
2
N, calcd. 165.0390,
found: 165.0384.
3.4. General Procedure to Aniline Trimers 7 and 8
A 35 mL Q-tube pressure tube, furnished by Q Labtech was charged with aniline derivative
3c-e
(10 mmol) (2.23 g of
3c
, 1.86 g of
3d,
1.41 g of
3e
), 5 mL glycerol, 3 mL H
2
SO
4
, and 10 mL of water.
A Teflon septum was placed on top of the tube, and an appropriate cap was used. The mixture was
heated in an oil bath at 160
◦
C for 15 min. After cooling at room temperature, pH was adjusted at 8–9
by adding NaOH and the reaction mixture was extracted with ethyl acetate (2
×
20 mL). The combined

Molecules 2019,24, 1806 10 of 14
organic layers were dried over MgSO
4
and were then filtered and evaporated under reduced pressure.
The crude residue was purified by column chromatograph (cyclohexane–EtOAc) on silica gel yielding
the corresponding quinoline.
3.4.1. 4,40,4”-(propane-1,2,3-triyl)tris(2-methylaniline) 7
Yellow crystals yield 75%. mp 178–180
◦
C,
1
H-NMR (DMSO-d
6
, 600 MHz) :
δ
=2.00 (9H,s, 3-CH
3
),
3.34 (5H, m, 2CH
2
and CH aliphatic), 5.01 (6H, s, 3NH
2
), 6.42 (3H, d, Ar-H), 7.13–7.20 (6H, m, Ar-H),
13
C-NMR (150 MHz, DMSO-d
6
):
δ
=16.95 (3CH
3
), 74.0 (CH-aliphatic), 76.24 (2CH
2
-aliphatic), 116.27
(3 ortho-C), 124.21 (3C-CH
3
), 134.63 (6 meta-C), 137.55 (3para-C), 146.53 (3C-NH
2
). EI-HRMS: m/zfor
C24H29 N3, calcd. 359.2361, found: 359.2362.
3.4.2. 4-(2-(4-amionphenoxy)-3-(4-amoinophenoxy))aniline 8
Brown crystals, yield 72%. mp 240
◦
C.
1
H-NMR (DMSO-d
6
, 600 MHz):
δ
=2.49 (6H, s, 3NH
2
),
3.27 (2H, d, J=6 Hz, CH
2
), 3.29 (2H, d, J=6 Hz, CH
2
), 3.35 (1H, m, CH), 6.94-7.26 (14H, m, Ar-H).
13
C-NMR (150 MHz, DMSO-d
6
):
δ
=63.09 (2C, CH
2
), 72.49 (CH), 118.57 (3C, C-NH
2
), 122.01 (2C-O),
129.32 (12C, Ar-C), 140.07 (C-O), EI-HRMS: m/zfor C21H23N3O3; calcd. 365.1739; found: 365.1736.
3.5. General Procedure for Syntheses of 13a–c
3.5.1. Method A: Conventional Heating
A mixture of 0.01 mol of the appropriate azo compound
10a
–
c
(
10a
, 2.96 g,
10b
, 2.59 g,
10c
, 2.34 g)
is added to
11a
(0.66 g, 0.01 mol) in glycerol (5 mL). The reaction mixture was refluxed for 3–5 h
(followed until completion by TLC using 1:1 ethyl acetate- petroleum ether as an eluent). The mixture
was cooled and then was poured onto ice-water. The solid, so formed, was collected by filtration and
recrystallized from EtOH.
3.5.2. Method B: Q-Tube Assisted Reactions
A 35 mL Q-tube pressure tube, furnished by Q Labtech was charged with 0.01 mol of the
appropriate azo compound
10a
–
c
(2.96 g of
10a
, 2.59 g of
10b
, 2.34 g of
10c
), (0.66 g, 0.01 mol) of
malononitrile
11a
and 5mL glycerol. A Teflon septum was placed on top of the tube, and an appropriate
cap was used. The mixture was heated at 150
◦
C for 30 min followed until completion by TLC using
1:1 ethyl acetate-petroleum ether as an eluent. The mixture was cooled and then was poured onto
ice-water. The solid, so formed, was collected by filtration and recrystallized from EtOH.
3.6. Benzyl 6-amino-6-(cyanomethyl)-4-oxo-1-phenyl-1,4,5,6-tetrahydropyridazine-3-carboxylate 13a
Yellow crystals, yield 52% (method A), 76% (method B); mp >340
◦
C.
1
H-NMR (DMSO-d
6
,
600 MHz):
δ
=1.28,1.31 (2H, m, CH
2
), 2.39,2.49 (2H, CH
2
, m), 4.30 (2H, s, CH
2
), 7.10–7.53 (10H, m,
2-Ph), 11.56, 14.22 (2H, 2s, NH
2
).
13
C-NMR (150 MHz, DMSO-d
6
):
δ
=196.8 (C=O), 164.5 (C=O), 163.0
(N-C-Ar), 142.8 (N=C), 132.0 (2C-Ar), 131.2 (3C-Ar), 129.8 (2C-Ar), 125.8 (2C-Ar), 116.6 (CN), 115.6
(2C-Ar), 72.9 (C-NH
2
), 60.8 (CH
2
-O), 30.8 (CH
2
), 25.9 (CH
2
). HRMS: m/z(EI) for C
20
H
18
N
4
O
3
, calcd.
362.1379, found: MS: m/z(%) =362.53 (M+).
3.7. Ethyl-6-amino-5-cyano-6-(cyanomethyl)-4-oxo-1-phenyl-1,4,5,6-tetrahydropyridazine-3-carboxylate 13b
Red crystals, yield 64% (method A), 88% (method B); m.p. 256-258
◦
C, IR (KBr): 3425 (NH), 2202
(CN), 1620 (CO) cm
−1
,
1
H-NMR (DMSO-d
6
, 600 MHz):
δ
=1.04 (3H,t, CH
3
), 1.05 (2H,m, CH
2
), 2.03 (1H,s,
CH), 3.33 (2H,s, CH
2
), 4.32 (2H,m, CH
2
), 7.27-7.64 (5H, m, H-Ph).
13
C-NMR (150 MHz, DMSO-d
6
)):
δ=13.90 (CH3)
, 24.0 (C-CN), 26.69 (CH
2
), 61.23 (C-O), 66.0 (C-NH
2
), 115.90 (2C; 2CN), 119.21 (2C-Ar),
123.87 (C-Ar), 128.88 (2C-Ar), 129.51 (C=N), 138.34 (C-Ar), 160.97 (2C=O).
MS (EI): m/z=326.0 (M+)
.
HRMS: m/z(EI) for C16H15 N5O3, calcd. 325.1175, found: MS: m/z(%) =326.0 (M+).

Molecules 2019,24, 1806 11 of 14
3.8. Ethyl-6-amino-6-(2-ethoxy-2-oxoethyl)-4-oxo-1-phenyl-1,4,5,6-tetrahydropyridazine-3-carboxylate 13c
Brown crystals, yield 70% (method A), 92% (method B), m.p. 266–268
◦
C, IR (KBr): 3439 (NH),
2222 (CN), 1670 (CO) cm
−1
,
1
H-NMR (DMSO-d
6
, 600 MHz) :
δ
=1.20 (3H,t, CH
3
), 1.40 (3H,t, CH
3
),
2.50 (2H,s, CH
2
), 3.36 (2H,s, CH
2
), 4.10 (2H,m, CH
2
), 4.35 (2H,m, CH
2
), 7.07-7.55 (5H, m, H-Ph), 10.29
(1H, s, NH).
13
C-NMR (150 MHz, DMSO-d
6
):
δ
=8.37 (2C- CH
3
), 62.59 (CH
2
), 63.06 (CH
2
), 66.24
(CH
2
-O), 68.81 (CH
2
-O), 72.48 (C-NH
2
), 114.96 (C-Ar), 116.15 (CN), 116.30 (C-Ar), 123.62 (C-Ar), 129.05
(C-Ar), 129.62 (C-Ar), 130.16 (C=N), 142.42 (C=O), 161.72 (C=O), 196.22 (C=O). HRMS: m/z(EI) for
C17H21 N3O5: 347.1481, found: MS: m/z(%) =347.1 (M+).
4. Conclusions
In this study, we combined glycerol and water as green, efficient solvents, in addition to pressure
in Q-tubes, to modify the synthesis of quinolines and prepare new aniline trimers and pyridazines.
Glycerol was efficiently employed either as a catalyst or a reactant and green bio-based solvent in
the synthesis of novel quinolines, aniline trimers, and pyridazines. The dual use of glycerol along
with reactions under pressure proved its efficiency as a green method for synthesis of quinolines as
reactions products were obtained in higher yields, shorter time, and without any oxidizing agents.
Reactions of anilines, sulphuric acid, water, and glycerol under pressure allowed for the synthesis of
unexpected novel aniline trimers. Lastly, glycerol also proved to be an efficient medium/catalyst for
synthesis of novel pyridazines in very good yields under pressure. Future perspectives for this work
are various since our techniques should open the appetite of researchers to extend this work for the
synthesis of azoles, azines, and other polyanilines.
Author Contributions:
Conceptualization, N.M.H.E. Data curation, D.S.A. Investigation, N.M.H.E. and
D.S.A. Methodology, N.M.H.E. Resources, D.S.A. Supervision, N.M.H.E. Writing—original draft, N.M.H.E.
Writing—review & editing, N.M.H.E and D.S.A.
Funding: This research received no external funding.
Acknowledgments:
The authors would like to express their deepest gratitude and acknowledgment for M. H.
Elnagdi Emeritus Professor at Cairo University, Cairo, Egypt, for his valuable scientific consultations, guidance,
and valuable criticism throughout this work.
Conflicts of Interest: The authors declare no conflict of interest.
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