Experimental and theoretical study on one-pot, three-component route to 2H-indazolo[2,1-b]phthalazine-triones catalyzed by nano-alumina sulforic acid

Article abstract of DOI:10.1016/j.molstruc.2012.11.014

A simple, efficient, and high yielding one-pot protocol for the synthesis of 2H-indazolo[2,1-b]phthalazine-trione derivatives has been developed by three-component coupling of phthalhydrazide, dimedone and some aromatic aldehydes in ecofriendly neat condi

Full text of DOI:10.1016/j.molstruc.2012.11.014

Journal of Molecular Structure 1036 (2013) 216–225
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Experimental and theoretical study on one-pot, three-component route to
2H-indazolo[2,1-b]phthalazine-triones catalyzed by nano-alumina sulforic acid
⇑
Ali Reza Kiasat , Siamak Noorizadeh, Mahboubeh Ghahremani, Seyed Jafar Saghanejad
Chemistry Department, Faculty of Science, Shahid Chamran University, Ahvaz, Iran
h i g h l i g h t s
"
"
"
"
2H-indazol [2,1-b]phthalazine-triones synthesized using nano-alumina sulforic acid.
The protocol extended for 1H-pyrazolo[1,2-b]phthalazine-diones synthesis.
The nature of each step of suggested mechanism investigated.
Theoretical spectra and structural analysis performed for synthesized compounds.
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 July 2012
Received in revised form 6 November 2012
Accepted 7 November 2012
Available online 24 November 2012
A simple, efficient, and high yielding one-pot protocol for the synthesis of 2H-indazolo[2,1-b]phthal-
azine-trione derivatives has been developed by three-component coupling of phthalhydrazide, dimedone
and some aromatic aldehydes in ecofriendly neat conditions promoted by nano-c-alumina sulforic acid.
This protocol avoids the use of expensive catalysts, toxic solvents and chromatographic separation. Also
the proposed protocol was extended to the linear b-diketone (acetylaceton) instead of cyclic diketone
(dimedone). The generality and functional tolerance of this convergent and environmentally benign
method is demonstrated. The nature of each step of the suggested mechanism for this condensation reac-
tion is also identified through Density Functional Theory (DFT) calculations using B3LYP/6-31Gꢀꢀ level of
theory. It is shown that the first step is charge controlled; whereas the second one is controlled by fron-
tier molecular orbitals. The 1H and 13C chemical shift values together with the structural parameters of
the title compound have been also computed and the scaled values have been compared with the corre-
sponding experimental NMR and X-ray spectra. As a result, the calculated spectroscopic data and opti-
mized geometry show a good agreement with the experimental results.
Keywords:
2H-indazolo[2,1-b]phthalazine-trione
1H-pyrazolo[1,2-b]phthalazine-diones
Multicomponent condensation reaction
Nano-c-alumina sulforic acid
DFT calculations
Fukui functions
Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction
process and handling [14]. The possibility of performing multicom-
ponent reactions under neat condition with a heterogeneous cata-
Over the years, the fast assembly of molecular diversity utilizing
multicomponent reactions (MCRs) has received a great deal of
interest because of their atom-economy and straightforward reac-
tion design due to substantial minimization of waste, labor, time,
and cost [1–4]. MCRs lead to interesting heterocyclic scaffolds
which are particularly useful for the construction of various chem-
ical libraries of privileged medicinal molecules [5–13].
In the past few decades, the main restrictions for the synthetic
chemists are the use of hazardous solvents, expensive and toxic
reagents, multistep protocols and generation of unwanted
side-products. Nowadays, neat condition, which is providing an
ecofriendly system, has attracted a lot of interest due to many
advantages such as reduced pollution, low costs and simplicity in
lyst could enhance their efficiency from an economic as well as
ecological point of view [15].
The applications of heterocyclic compounds in our life are unde-
niable. Therefore there is an increasing demand for synthesizing
new heterocyclic compounds and this has stimulated research
activities in the field of heterocyclic compound chemistry. Among
a large diversity of heterocyclic compounds, those containing
nitrogen atom are prevalent in nature, and their biological applica-
tions distinguish them [16,17]. 2H-indazolo[2,1-b]phthalazine-tri-
ones which are important N-heterocycles, comprise
a key
structural of numerous natural and synthetic bioactive molecules
[18]. They possess multiple pharmacological and biological activi-
ties such as anticonvulsant [19], cardiotonic [20], vasorelaxant
[21], antimicrobial [22], antifungal [23], anticancer [24] and anti-
inflammatory [25] together with unique electrical and optical
properties [26,27]. These compounds also could be promising
⇑
Corresponding author. Tel./fax: +98 611 3331746.
E-mail address: akiasat@scu.ac.ir (A.R. Kiasat).
0022-2860/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2012.11.014

A.R. Kiasat et al. / Journal of Molecular Structure 1036 (2013) 216–225
217
O
O
O
O
O
O
N
H
NH
NH
+
+
Nano-ASA
N
neat/ 110 0C
O
O
R
R
Scheme 1.
materials for new luminescence or fluorescence probes [28]. De-
spite many proposing methods for the synthesis of phthalazine
derivatives [18,28,29–34] their wide utility has accentuated the
need to develop eco-compatible and clean synthetic routes. Re-
cently, Ghorbani-Vaghei et al. proposed an efficient and valuable
catalytic system for synthesis of the titled compound [32]. Also
the synthesis of 2H-indazolo[2,1-b]phthalazine-triones and their
related compound have been reported using different catalysts
such as Dodecylphosphonic acid [35], heteropoly acid in ionic li-
quid [36], Ce(SO4)2ꢁ4H2O [37], sulfuric acid-modified PEG-6000
[38], trimethylsilyl chloride (TMSCl) [39], Phosphomolybdic acid
(PMA)-SiO2 [40], silica supported polyphosphoric acid [41], silica
sulfuric acid [42] H2SO4 in water-ethanol or ionic liquid [43],
Mg(HSO4)2 [44] heteropoly acids [45], wet cyanuric chloride [46],
nanosilica sulfuric acid [47], p-toluenesulfonic acid (p-TSA) [48].
Also recently Shekouhy and Hasaninejad proposed a catalyst-free
one-pot four component methodology for the synthesis of 2H-
indazolo[2,1-b]phthalazinetriones under ultrasonic irradiation at
room temperature using 1-butyl-3-methylimidazolium bromide
([Bmim]Br) [49]. However due to the multiple pharmacological
and biological activities of these compounds, it seems that it is nec-
essary to design new, easy and clean protocol and catalytic system
for their synthesis.
associated Fukui functions. In the frozen core approximation Fukui
function represents the density of the relevant frontier molecular
orbital involved in electron receiving (nucleophilic attack) or with-
drawing (electrophilic attack) processes. The condensed Fukui
function at the kth atom using finite difference approximation is
defined as:
fkþ ¼ qkðN þ 1Þ ꢂ qkðNÞ for nucleophilic attack
fkꢂ ¼ qkðNÞ ꢂ qkðN ꢂ 1Þ for electrophilic attack
ð2-1Þ
ð3-1Þ
where qk(N), and qk(N ꢂ 1) are the charges of the kth atom of the
considered molecule in neutral, anionic and cationic forms, respec-
tively. At point r, f+(r) measures the reactivity toward a nucleophilic
attack that leads to an electron increment in the system; whereas
fꢂ(r) measures the reactivity toward electrophilic attack which re-
sult electron depletion in the system.In order to investigate the site
reactivity of a chemical system, the global descriptors of reactivity
should be included. The local softness s(r) is an appropriate local
descriptor for investigating site reactivity which is defined as [51–
53]:
sꢃðrÞ ¼ fꢃðrÞS
ð4-1Þ
Our literature survey at this stage revealed that, there is no report
yet available on the synthesis of 2H-indazolo[2,1-b]phthalazine-tri-
where S is the global softness of the considered system which could
one derivatives using c-nano-alumina sulforic acid as an efficient
be evaluated using the obtained energies of HOMO and LUMO
nanoacid catalyst under neat conditions in one-pot via three compo-
nent coupling of phthalhydrazide, dimedon and an aromatic alde-
hyde; see Scheme 1. Nano-alumina sulforic acid could be easily
prepared at room temperature using easy and clean reactions.
The utility of multicomponent reactions has been significantly
expanded if they are conducted under neat condition. The purpose
of the present study is to highlight the use of MCRs under neat con-
ditions using nano-catalyst for the development of new ecocom-
patible strategy for heterocyclic synthesis together with
investigating the nature of each step of the reaction mechanism,
theoretical structural and spectroscopic parameters.
molecular orbital from density functional calculations (eH and eL
)
as:
1
ꢂ
S ¼
ð5-1Þ
eL
eH
To investigate the nature of the each step of the reaction mech-
anism from theoretical point of views, the geometries of the reac-
tants (aldehydes, phthalhydrazide, dimedone and adduct A) were
fully optimized at B3LYP/6-31Gꢀꢀ level of theory in order to calcu-
late the charges, Fukuies and local softnesses of the corresponding
reactive sites. This level of theory was selected because it gives a
good description for electron densities and orbital energies of the
compounds studied here [54]. In all cases the vibrational frequen-
cies of the optimized structures were also calculated in order to
check if there was a true minimum on the potential energy surface.
All calculations were performed using Gaussian03 program revi-
sion A.02 [55]. Atomic coordinates of the equilibrium structures
as well as the corresponding energies are also summarized in the
Supplementary information.
2. Computational details
Nowadays many attempts have been made to investigate mol-
ecules from theoretical point of views. Among different quantum
mechanical methods, Density Functional Theory (DFT) provides a
powerful theoretical framework for the study of both reactivity
and selectivity of molecular systems [50]. One of the key concepts
in selectivity studies is Fukui function [51] defined as:
ꢀ
ꢁ
1H and 13C NMR chemical shifts of the title compound together
with tetramethylsilane (TMS), were calculated within the GIAO ap-
proach using HF/6-311++Gꢀꢀ and B3LYP/6-311++Gꢀꢀ levels of the-
ory. The 1H and 13C NMR chemical shifts were scaled to the TMS
with the values of 32.1718 (1H) and 194.6031 (13C) ppm for HF/
6–311++Gꢀꢀ as well as 31.9260 (1H) and 183.7553 (13C) ppm for
B3LYP/6–311++Gꢀꢀ, respectively.
@
q
@N
ðrÞ
fðrÞ ¼
ð1-1Þ
mðrÞ
This function measures the differential changes in the electron
density, (r), induced by a change in the number of electrons (N)
at fixed molecular geometry ( (r)). It is shown that the highly elec-
trophilic/nucleophilic center is a site presenting a high value of the
q
m

218
A.R. Kiasat et al. / Journal of Molecular Structure 1036 (2013) 216–225
110 °C under neat conditions and afforded good to high yields of
the corresponding products with high purity.
3. Results and discussion
3.1. Chemical synthesis
With these promising results in hand and establishing the
advantages of nano-alumina sulforic acid as solid acid catalyst un-
der thermal neat conditions, we focused our attention on the linear
b-diketone instead of cyclic diketone. Hence, acetyl acetone was
chosen and its coupling with phthalhydrazide and aromatic
aldehydes under the above optimized condition and in the pres-
ence of nano-alumina sulforic acid were also examined (Scheme 3).
Table 3 summarizes the obtained data and clearly shows that the
desired products were formed in good isolated yields and no side
products were observed.
A probable mechanistic rationale portraying sequence of events
for this coupling reaction is postulated [32,42,48], which is shown in
Scheme 4. The first step is suggested to be the acid-catalyzed Knoe-
venagel condensation between the corresponding aldehyde and
dimedone to generate adduct A, which acts as Michael acceptor.
Note that the nanoacidic catalyst protonats the aldehyde and also
it cause enol–keto tautomerism of dimedone in the acidic condition
which promote the reaction. These increase the nucleophilic activ-
ity of dimedone in the first step of reaction. Also the nanocatalysts
have considerable active sites with respect to the ordinary catalysts
due to their considerable ratio of surface to volume. In the second
step the phthalhydrazide attacks to adduct A in a Michael-type
fashion to produce an open chain intermediate B. Intermediate B
undergoes intramolecular cyclization by the reaction of nucleo-
philic amino function to carbonyl group followed by dehydration
to form 2H-indazolo[2,1-b]phthalazine-triones. The characteristic
of these steps are discussed in detail in the theoretical section.
Nano-alumina sulforic acid was easily prepared by simple mix-
ing of nano-alumina and chlorosulfonic acid in CH2Cl2 at room
temperature (Scheme 2). This reaction was easy and clean, because
HCl gas was evolved from the reaction vessel immediately.
In order to determine the acidic capacity of nano-alumina sulfu-
ric acid, back titration of catalyst was applied. Hence, NaOH solu-
tion (10 ml, 0.1 M) was added to the catalyst (100 mg) in an
Erlenmeyer flask. Excess amount of the base was neutralized by
addition of HCL solution (0.1 M) to the equivalence point of titra-
tion. The required volume of HCl to this point was 4.20 mL. There-
fore 5.8 mmol H+/g of solid acid was calculated for the obtained
catalyst.
The morphology and particle size distribution of prepared alu-
mina sulforic acid nanostructure was performed by measuring
SEM using a Philips XL30 scanning electron microscope. According
to Fig. 1, nano-alumina sulforic acid with spherical shape and aver-
age distribution particle size 58 nm was obtained. FT-IR spectra of
the prepared nano-alumina sulforic acid presented in Fig. 2 shows
characteristic adsorption bands at 1010–1080 cmꢂ1 and 1120–
1230 cmꢂ1 corresponded to asymmetric and symmetric stretching
modes of O@S@O groups. The spectrum also shows a broad OH
stretching absorption around 2800–3700 cmꢂ1
.
To evaluate the catalytic activity of nano-alumina sulforic acid
in the preparation of 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-
triones derivatives, the three-component coupling reaction of
phthalhydrazide (1 mmol), dimedone (1 mmol) and bezaldehyde
(1.1 mmol) under thermal neat (110 °C) conditions in the absence
and presence of nano-alumina sulforic acid were examined. It was
found that in the absence of solid acid catalyst (entry 1 in Table 1)
and in the presence of nano-alumina (entry 2 in Table 1) just a
trace amount of the desired product was observed on TLC plate.
Also the effect of temperature on the conversion and reaction time
is checked and the results are given in Table 1. It is obvious that at
room temperature (25 °C) no considerable conversion is observed
and setting the reaction temperature at 60 °C and 80 °C cause a
long reaction time. Therefore 110 °C is chosen as optimum temper-
ature for the reaction. As it is shown in Table 1, this transformation
requires acidic catalyst; and also 0.04 g of nano-alumina sulforic
acid at 110 °C could be chosen for the facile preparation of 2,2-di-
methyl-13-phenyl-2,3-dihydro-1H-indazolo[2,1-b]phthalazine-
4,6,11(13H)-trione. In order to establish the true effectiveness of
the nanostructure of catalyst, the condensation reaction was also
tested using alumina sulforic acid under the same reaction condi-
tion. The results presented in Table 1 clearly show that although
the reaction proceeded in the presence of alumina sulforic acid,
the best result was obtained in the presence of nano-alumina sulf-
oric acid. This may due to considerable ratio of surface to volume in
nanoparticles.
3.2. Theoretical section
3.2.1. Investigating the nature of each step of the suggested
mechanism
The chemical reactions are charge or frontier molecular orbital
controlled and therefore the characteristic of a given reaction could
be determined by evaluating the charges, Fukui functions and local
softnesses of the reactive sites in the reactants. It is shown that the
electronic charges provide the site reactivity information of ionic
systems (for charge controlled reactions; i.e. hard–hard interac-
tions), while the Fukui functions are better suited where dealing
with neutral species (for frontier molecular orbital controlled reac-
tions; i.e. soft–soft interaction) [56]. It should be mentioned that in
charge controlled reactions those sites which have considerable
charge difference interact with each other; whereas in frontier
molecular orbital controlled reactions the sites with smallest dif-
ference in their Fukui functions are interacted.
In the first step of the considered reaction, the carbon atom of
the protonated aldehyde molecule (site I in Scheme 4) may attack
by carbon atom of the dimedone (site II in Scheme 4) or the nitro-
gen atom of phthalhydrazide molecule (site III in Scheme 4). These
reactive sites are stared and numbered in Scheme 4. According to
the suggested mechanism, it is the carbon atom of dimedone (site
II) which attacked to the carbon atom of the aldehyde molecule
(site I) to produce the adduct A in this step. In the second step
the carbon atom of this adduct (site IV) may attack by site II or
III. But the obtained product verifies the interaction between sites
III and IV in this step.
These remarkable results encouraged us to investigate the
scope and generality of the protocol for various aromatic aldehydes
under the optimized condition. A series of aromatic aldehydes (see
Table 2) containing either electron-withdrawing or electron-
donating substituents successfully react with phthalhydrazide
and dimedone in the presence of nano-alumina sulforic acid at
The calculated Hirshfeld charges for both neutral and cationic
forms together with the evaluated condensed Fukui functions as
well as the obtained local softnesses for the reactive sites of dime-
done (II) and phthalhydrazide (III) are gathered in Table 4. It is
noteworthy that the Hirshfeld [57] is a very popular population
method based on deformation density partition in which the ob-
tained Fukui functions from this population are more reliable than
those calculated from the other population analysis approaches
OH
OSO3H
ClSO3H
Al2O3
Al2O3
OH
OSO3H
OSO3H
CH2Cl2/ r. t.
OH
Scheme 2.

A.R. Kiasat et al. / Journal of Molecular Structure 1036 (2013) 216–225
219
Fig. 1. The SEM images of nano-alumina at (a) 500 nm and (b) 300 nm.
Table 2
Preparation of 2H-indazolo[2,1-b]phthalazine-triones derivatives.
Entry Aromatic aldehyde Time Isolated
mp (°C)a
(min) yield (%)
1
2
3
4
5
C6H5CHO
14
12
10
15
15
85
98
94
72
70
205–207
(204–
206)
264–266
(262–
264)
219–221
(218–
220)
221–223
(223–
225)
p-Cl C6H4CHO
p-OCH3C6H4CHO
p-NO2C6H4CHO
p-CH3C6H4CHO
228–230
(227–
229)
6
7
8
p-CNC6H4CHO
p-CF3C6H4CHO
o-NO2C6H4CHO
20
15
15
89
78
87
226–228
255–257
251–253
(227–
Fig. 2. FT-IR spectra of the prepared nano-alumina sulforic acid.
229)
9
10
11
12
o-Cl C6H4CHO
18
15
20
20
70
83
80
70
265–267
(264–
266)
271–273
(270–
272)
263–265
(265–
267)
Table 1
Optimum conditions for the three-component coupling reaction of phthalhydrazide
(1 mmol), dimedone (1 mmol) and benzaldehyde (1.1 mmol) under thermal neat
conditions.
m-NO2C6H4CHO
p-BrC6H4CHO
Entry Catalyst (g)
Temperature (°C) Time (min) Conversion (%)
1
2
3
4
5
6
7
8
9
None
Nano-alumina
Nano-ASA (0.01)
110
110
110
60
30
19
16
14
12
10
50
120
50
35
Trace
Trace
100
100
100
100
100
100
Trace
100
p-OCH3CH2C6H4CHO
228–230
a
Nano-ASA (0.015) 110
Nano-ASA (0.025) 110
The values in parantheses are from Refs. [32,41].
Nano-ASA (0.04)
Nano-ASA (0.05)
ASA (0.04)
Nano-ASA (0.04)
Nano-ASA (0.04)
Nano-ASA (0.04)
110
110
110
25
60
80
the aldehyde molecule is protonated and therefore it is a hard–
hard interaction; which is controlled by charges. On the other
hand, in the second step of those reactions
10
11
Dq(VI–II) > Dq(VI–III)
100
but f(VI–III) < f(VI–II). According to the obtained product for
D
D
ASA: alumina sulforic acid.
this reaction, sites IV and III are reacted to each other and since
these sites have less Fukui function difference, this step should
be frontier molecular orbital controlled. Note that in this step the
reactants are neutral and therefore a soft–soft interaction is
expected.
It is noteworthy that for reacting different molecules which
they have different global characteristics, the analysis based on lo-
cal softnesses are more reliable than those based on Fukui func-
tions. Therefore the local softness values are also calculated using
Eqs. (4-1) and (5-1) which are summarized in Table 6 for the con-
sidered aldehydes and adduct [A]. It is obvious from Tables 4 and 6
that the higher the Fukui function, the higher the local softness.
Hence local softness values are also successfully predict the
[58]. These quantities were also calculated for some of the consid-
ered aldehydes containing electron withdrawing or electron donat-
ing substitutes; which are shown in Table 5. Note that fkꢂ=fkþ was
calculated for dimedone and phthalhydrazide/aldehyde using
Eqs. (3-1)/(2-1). The obtained results in Table 5 shows that in the
first step, of all reactions
Dq(I–II) > Dq(I–III); while Df(I–II) > D-
f(I–III). Since according to the suggested mechanism sites I and II
(those with more charge difference) were reacted to each other
to produce adduct A, therefore it seems that this step should be
charge controlled. It may arise from this fact that in the first step

220
A.R. Kiasat et al. / Journal of Molecular Structure 1036 (2013) 216–225
O
O
O
O
O
O
N
NH
NH
H
+
Nano-ASA
neat/ 110 0
N
+
O
C
O
R
R
Scheme 3.
Table 4
Table 3
The calculated Hirshfeld charges, the evaluated condensed Fukui functions and local
softnesses for the reactive sites of dimedone (II) and phthalhydrazide (III) as well as
the calculated frontier molecular orbital energies and global softnesses (see
Scheme 4).
Preparation of 1H-pyrazolo[1,2-b]phthalazine-diones derivatives.
Entry Aromatic
aldehyde
Time
(min)
Isolated yield
(%)
mp
Site q(N)
q(N ꢂ 1)
eL
eH
S
sꢂ
fkꢂ
10
20
30
40
C6H5CHO
p-Cl C6H4CHO
p-OCH3C6H4CHO 120
p-NO2C6H4CHO
60
60
88
60
81
77
288–290
178–180
159–162
II
III
ꢂ0.0957 ꢂ0.0286 0.0672 ꢂ0.0309 ꢂ0.2269 5.1020 0.3429
ꢂ0.0350 0.1032 0.1382 ꢂ0.0574 ꢂ0.2284 5.8459 0.8079
45
215–217 (217–
218)a
50
60
p-CNC6H4CHO
o-Cl C6H4CHO
60
60
70
67
183–185
285–287
theory) is presented in Fig. 3. Both of the experimental and theoret-
ical 1H and 13C NMR spectra for the considered compound are gi-
a
The values in parantheses are from Ref. [18].
ven in Fig.
4 and the evaluated chemical shifts are also
summarized in Table 7.
All of the calculated 1H/13C chemical shifts with respect to TMS
are in the range of 0.663–9.949/25.133–199.292 ppm; whereas the
experimental values are observed at 1.211–8.402/28.43–
192.08 ppm. The correlations between the experimental and
computed 1H and 13C chemical shifts are depicted in Fig. 5. It is
clear that although significant correlations are observed between
the experimental and calculated spectra, the correlation for 13C
chemical shifts (R2 = 0.998) is to some extent better than those of
protons (R2 = 0.992). This may arise from this fact that the proton
shifts are more sensitive to the solvent effects rather than 13C
shifts, whereas all of these calculations were performed in the
interacting sites in the second step of reaction, which is frontier
molecular orbital controlled.
3.3. 1H and 13C NMR study
The product of reaction between p-CNC6H4CHO, dimedone and
phthalhydrazide (entry 6 in Table 2) was selected to compare the
experimental and the obtained theoretical NMR spectra with each
other and assigning each peak to the corresponding atom. The opti-
mized geometry for this compound (using B3LYP/6-31Gꢀꢀ level of
OH+
O
Ar-C-H
*
III
I
*
HN
Ar
HN
IV
*
O
O
II
O
O
*
OH
O
Knoevenagel
condensation
O
Michael-type
fashion
-H3O+
[A]
O
O
H
Ar
N
Ar
N
HN
O
Intramolecular
cyclization
N
O
O
O
O
-H2O
[B]
Scheme 4. The suggested mechanism for the considered reaction. The reactive sites were assigned by stars.

A.R. Kiasat et al. / Journal of Molecular Structure 1036 (2013) 216–225
221
Table 5
The calculated Hirshfeld charges and the evaluated condensed Fukui functions for the reactive sites of some selected aldehydes (see Scheme 4). The bold values identify the
charge controlled and frontier molecular orbital controlled nature of first and second steps, respectively.
fkþ
Molecule
q(N)
q(N + 1)
D
f(X-II)
D
q(X-II)
D
f(X-III)
Dq(X-III)
First step-site X = I
C6H5CHO
p-Cl C6H4CHO
p-OMeC6H4CHO
p-CNC6H4CHO
0.1234
0.1249
0.1166
0.1299
ꢂ0.0252
ꢂ0.0152
ꢂ0.0326
0.0152
0.1486
0.1400
0.1492
0.1147
0.0814
0.0729
0.0820
0.0475
0.2192
0.2206
0.2123
0.2256
0.0104
0.0018
0.0110
0.0235
0.1584
0.1598
0.1515
0.1649
Second step-site X = IV
C6H5CHO
p-Cl C6H4CHO
p-OMeC6H4CHO
p-CNC6H4CHO
0.0193
0.0180
0.0161
0.0180
ꢂ0.0867
ꢂ0.0868
ꢂ0.0895
ꢂ0.0854
0.1060
0.1048
0.1056
0.1034
0.0388
0.0377
0.0384
0.0363
0.1150
0.1138
0.1118
0.1137
0.0322
0.0334
0.0326
0.0348
0.0542
0.0530
0.0511
0.0530
Table 6
The calculated local softnesses for the reactive sites of some selected aldehydes as
well as the calculated frontier molecular orbital energies and global softnesses (see
Scheme 4).
fkþ
Molecule
eL
eH
S
s+
First step-site X = I
C6H5CHO
p-Cl C6H4CHO
p-OMeC6H4CHO
p-CNC6H4CHO
ꢂ0.0634
ꢂ0.0734
ꢂ0.0520
ꢂ0.0972
ꢂ0.2552
ꢂ0.2629
ꢂ0.2337
ꢂ0.2757
5.2138
5.2770
5.5042
5.6022
0.1486
0.1400
0.1492
0.1147
0.7748
0.7388
0.8212
0.6426
Second step-site X = IV
C6H5CHO
ꢂ0.0903
ꢂ0.2393
ꢂ0.2428
ꢂ0.2213
ꢂ0.2528
6.7114
6.8700
7.1896
7.0847
0.1060
0.1048
0.1056
0.1034
0.7114
0.7200
0.7592
0.7326
p-Cl C6H4CHO
p-OMeC6H4CHO
p-CNC6H4CHO
ꢂ0.0972
ꢂ0.0822
ꢂ0.1117
gas phase. However these slight different is negligible. Note that
the evaluated slopes for both graphs are close to unity (0.952
and 1.059 for 1H and 13C spectra, respectively) which indicates
the similarity between the experimental and the corresponding
calculated spectra.
In Fig. 4 all of the observed peaks in simulated 1H and 13C spec-
tra are assigned to the corresponding atoms. In the previous re-
ports [29–34] the observed 1H peak at 3.2–3.4 ppm was assigned
to the hydrogen atoms of dimedone molecule; i.e. those hydrogen
which are close to the carbonyl group (H36 and H37 in Fig. 3). But
the presented calculations show that this peak is corresponded to
the H38 (observed at 3.677 and 3.522 ppm using B3LYP and HF
methods respectively), which because of its closeness to the nitro-
gen atom (N9) has a different chemical environment with respect
to H39 (observed at 2.715 and 2.652 ppm using B3LYP and HF
methods respectively) and therefore appears in the up field.
Fig. 3 shows that H36 and H37 are far from the carbonyl group
and therefore they appear at 2.147 and 2.238 ppm using B3LYP,
respectively. It should be mentioned that assigning the observed
peak at 3.677 to H36 or H37 reduces the correlation coefficient
of experimental vs. calculated curve to 0.971 and 0.969 from
0.991and 0.990 for HF and B3LYP methods, respectively.
Fig. 3. The optimized geometry of entry 6.
ligible intercept (0.007) imply to significant correlation between
the optimized structure and the reported experimental data.
4. Conclusion
Efficient one-pot condensation of aldehyde, dimedone, and
phthalhydrazide has been achieved in the presence of a catalytic
amount of nano-alumina sulfuric acid under neat conditions. A
variety of 2H-indazolo-[1,2-b] phthalazinetrione derivatives were
prepared in high to excellent yields in short time. Also the pro-
posed protocol was extended to the linear b -diketone (acetylace-
ton) instead of cyclic diketone (dimedone). Moreover, DFT
calculations are applied to identify the nature of each step of the
suggested mechanism for this condensation reaction. The obtained
results show that the first step is charge controlled; whereas the
second one is controlled by frontier molecular orbitals. The calcu-
lated 1H and 13C chemical shifts and some structural parameters
(bond lengths) for the titled compound show a good agreement
with the experimental data.
3.4. Structural study
The optimized geometry for the product of reaction between p-
BrC6H4CHO, dimedone and phthalhydrazide (entry 11 in Table 2)
using B3LYP/6-311++Gꢀꢀ level of theory is presented in Fig. 6. To
check the reliability of the optimized structure, it is attempted to
find the correlation between the obtained bond lengths from this
calculation and those which are reported in the X-ray data [48].
The calculated values for some selected bond lengths and the cor-
responding experimental data are given in Table 8 for comparison;
and the correlation between these bond lengths are also shown in
Fig. 7. The closeness of the obtained slope to unity (0.996) and neg-
5. Experimental
5.1. General
All commercially available chemicals were purchased from Flu-
ka and Merck companies and used without further purification. IR

222
A.R. Kiasat et al. / Journal of Molecular Structure 1036 (2013) 216–225
Fig. 4. The obtained experimental (a) 1H NMR and (b) 13C NMR spectra together with theoretical (c) 1H NMR and (d) 13C NMR spectra simulated at HF/6-311++Gꢀꢀ together
with (e) 1H NMR and (f) 13C NMR spectra simulated at B3LYP/6-311++Gꢀꢀ for the entry 6 (see Fig. 3).
spectra were recorded on a BOMEM MB-Series 1998 FT-IR spectro-
photometer. 1H and 13C NMR spectra were recorded in CDCl3 on a
Bruker Advanced DPX 400 MHz spectrometer using TMS as inter-
nal standard. Reaction monitoring were accomplished by TLC on
silica gel polygram SILG/UV 254 plates.
dry CH2Cl2 to remove the unreacted chlorosulfonic acid. Finally, a
white solid powder was obtained.
5.3. Typical procedure for the preparation of 2H-indazolo[2,1-
b]phthalazine-triones
5.2. Preparation of nano-
c-alumina-sulforic acid (nano-ASA)
A mixture of dimedone (0.14 g, 1 mmol), phthalhydrazide
(0.16 g, 1 mmol), aromatic aldehyde (1 mmol) or acetyl acetone
(0.20 g, 2 mmol), phthalhydrazide (0.16 g, 1 mmol), aromatic alde-
hyde (1 mmol) together with Nano-ASA (0.04 g) was heated at
110 °C for the corresponding time (see Table 2 and 3). Completion
of the reaction was indicated by TLC [TLC acetone/n-hexane
(3:10)]. After completion of the reaction, the solid residue was dis-
solved in ethanol and nano-alumina sulfuric acid was filtered. The
crude product was purified by recrystallization in aqueous ethanol
to afford the pure product.
A 50 mL suction flask which is equipped with a constant pres-
sure dropping funnel was applied. It contained nano- -alumina
c
(3 g) and charged with chlorosulfonic acid (0.8 mL, 12 mmol) in
dry CH2Cl2 (3.5 mL) which was added dropwise over a period of
30 min at room temperature. Note that during this process HCl
gas was evolved immediately, hence the gas outlet was connected
to a vacuum system through an alkali trap. The obtained mixture
was shaken for 1 h. Then the mixture was washed with excess

A.R. Kiasat et al. / Journal of Molecular Structure 1036 (2013) 216–225
223
Table 7
The calculated (dCalc.) and experimental (dExp.) chemical shift values of 1H NMR and 13C NMR for the entry 6.
Atom
dCalc.
dExp.
Atom
dCalc.
dExp.
HF
B3LYP
HF
B3LYP
C-16
C-10
C-7
C-15
C-22
C-2
C-27
C-6
C-25
C-23
C-3
199.292
163.000
160.087
158.761
150.278
140.430
139.948
139.322
139.628
137.883
135.744
135.122
135.632
134.929
129.412
125.750
123.982
118.918
70.113
202.941
170.355
168.365
166.988
155.969
143.908
143.539
141.470
141.470
139.140
138.432
138.008
138.008
136.140
130.403
126.363
120.331
119.932
59.902
192.080
155.970
154.550
151.610
141.590
134.820
133.950
132.620
132.620
128.950
128.670
128.230
128.230
127.900
127.790
118.450
117.400
112.530
64.420
33-H
31-H
34-H
32-H
49-H
48-H
46-H
47-H
35-H
38-H
39-H
37-H
36-H
40-H
43-H
44-H
45-H
41-H
42-H
9.149
9.006
8.185
8.213
8.177
7.900
8.483
7.383
6.300
3.522
2.652
2.064
2.145
1.097
1.124
1.265
1.065
0.765
0.663
8.745
8.631
7.932
7.921
7.786
7.621
8.283
7.030
6.589
3.677
2.715
2.238
2.147
1.237
1.223
1.206
1.025
0.671
0.638
8.262–8.402 (8.332)
7.891–7.914 (7.903)
7.646–7.666 (7.565)
7.553–7.574 (7.564)
6.476
3.244–3.440 (3.342)
C-5
C-4
C-1
2.356
1.211–1.256 (1.234)
C-24
C-14
C-26
C-29
C-13
C-17
C-19
C-18
C-21
C-20
54.623
41.615
41.319
34.908
47.690
35.559
31.245
30.055
50.840
38.040
34.750
28.690
26.101
25.133
28.430
Fig. 5. The correlations between the experimental and calculated (a) and (b) 13C NMR together with (c) and (d) 1H NMR chemical shifts of the entry 6 using HF and B3LYP
methods.
– 13-(4-Cyanophenyl)-3,3-dimethyl-3,4-dihydro-2H-indazol-
o[1,2-b]phthalazine-1,6,11(13H)-trione (Table 2, entry 6). Yel-
low powder (89%); mp 226–228 °C; Rf (23% acetone/n-hexane)
CDCl3); 28.43, 28.69, 34.75, 38.04, 50.84, 64.42, 112.53, 117.4,
118.45, 127.79, 127.9, 128.23, 128.67, 128.67, 128.95, 132.62,
133.95, 133.95, 134.82, 141.59, 151.61, 154.55, 155.97, 192.08.
– 3,3-Dimethyl-13-(4-trifluoromethylphenyl)-3,4-dihydro-2H-
indazolo [1,2-b]phthalazine-1,6,11(13H)-trione (Table 2, entry
7). Yellow powder (78%); mp 255–257 °C; Rf (23% acetone/n-
0.25; IR (KBr) (m
max, cmꢂ1) 2961, 2227, 1667, 1623, 1473; dH
(400 MHz, CDCl3) 1.23 (6H, s, 2Me), 2.35 (2H, s,CH2CO), 3.24–
3.414 (2H, AB system, CHaHbCH2), 6.47 (1H, s, CHN), 7.29–
7.66 (4H, dd, ArCN), 7.89–8.40 (4H, m, Ph); dc (400 MHz,
hexane) 0.25; IR (KBr) (m
max, cmꢂ1) 2961, 1654, 1667, 1357,

224
A.R. Kiasat et al. / Journal of Molecular Structure 1036 (2013) 216–225
Fig. 7. The correlation between the calculated and experimental values of some
selected bond lengths in the backbone of the entry 11.
(400 MHz, CDCl3) 2.22 (s, 3H, CH3), 3.09 (s, 3H, COCH3), 6.52
(s, 1H, CH), 7.60–769 (dd, 2H, ArH), 7.85–7.88 (m, 2H, ArH),
8.22–8.24 (dd, 3H, ArH), 8.36–8.39 (m, 1H, ArH).
Fig. 6. The optimized geometry of entry 11.
Acknowledgment
Table 8
Some of the optimized (B3LYP/6-311++Gꢀꢀ) and experimental bond lengths of the
entry 11(see Fig. 6).
We are grateful to the Research Council of Shahid Chamran Uni-
versity for financial support.
Bond
RCalc.
RExp.
Bond
RCalc.
RExp.
C26ABr48
C18AC19
C17AC18
C18AC20
C18AC21
C16AC17
C13AC22
C13AC14
C19AC15
C3AC7
N8AC13
C14AC16
N8AN9
C3AC4
C2AC6
1.904
1.555
1.548
1.544
1.539
1.526
1.526
1.512
1.497
1.483
1.480
1.457
1.418
1.407
1.403
1.403
1.891
1.541
1.527
1.534
1.528
1.510
1.514
1.449
1.488
1.476
1.480
1.449
1.419
1.386
1.380
1.404
C1AC3
1.400
1.399
1.398
1.397
1.396
1.395
1.394
1.393
1.392
1.392
1.391
1.372
1.356
1.230
1.229
1.228
1.400
1.387
1.390
1.379
1.377
1.384
1.367
1.380
1.362
1.381
1.387
1.356
1.344
1.221
1.223
1.216
Appendix A. Supplementary material
C24AC22
C15AN9
C22AC23
C23AC27
C25AC24
C26AC25
C27AC26
C1AC2
N9AC10
C6AC5
C7AN8
C14AC15
C7AO11
C16AO28
C10AO12
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.molstruc.2012.
11.014.
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