Computational investigations on structural and electronic properties of CuI nanoparticles immobilized on modified poly(styrene-co-maleic anhydride), leading to an unexpected but efficient catalyzed synthesis of 1,4-dihydropyridine via Hantzsch pyridine synthesis

Article abstract of DOI:10.1139/cjc-2016-0507

A, quantitative description for the interaction of Cu(I) with poly(styrene-co-maleic anhydride) modified with 4-aminopyridine (denoted as CuI/SMI complex) is presented using density functional theory (DFT) and quantum theory of atoms in molecules (QTAIM) approaches. Topological analysis of electron density revealed the existence of effective interactions between Cu(I) ions and the nitrogen in the pyridine ring. Interestingly, the results also showed that there is considerable interaction between Cu(I) and the oxygen of the carbonyl motif in the SMI ligand. Thus, CuI/SMI was examined as a heterogeneous and recyclable catalyst in Hantzsch pyridine synthesis under solvent-free conditions, affording diverse 1,4-dihydropyridines (1,4-DHPs) in excellent yields with relatively short reaction times.

Full text of DOI:10.1139/cjc-2016-0507

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Computational investigations on structural and electronic properties of CuI nanoparticles immobilized
on modified poly(styrene-co-maleic anhydride), leading to unexpected but an efficient catalyzed synthesis
of 1,4-dihydropyridine via Hantzsch pyridine synthesis
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Majid M. Heravi*, Tayebeh Hosseinnejad*, Niousha Nazari
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Department of Chemistry, Alzahra University, Vanak, Tehran, Iran
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Corresponding authors:
Majid M. Heravi, Fax: +982188041344; Tel: +989121329147; Eꢀmail: mmh1331@yahoo.com.
Tayebeh Hosseinnejad, Fax: +982188041344; Tel: +989124775800; Eꢀmail: tayebeh.hosseinnejad@gmail.com
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Abstract:
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A quantitative description for the interaction of Cu(I) with poly(styreneꢀcoꢀmaleic anhydride) modified with 4ꢀ
aminopyridine (denoted as CuI/SMI complex) is presented using density functional theory(DFT)and quantum
theory of atoms in molecules (QTAIM)approaches. Topological analysis of electron density revealed the
existence of effective interactions between Cu(I) ions and the nitrogen in the pyridine ring. Interestingly, the
results also showed there is a considerable interaction between Cu(I) and oxygen of carbonyl motif in SMI
ligand. Thus, CuI/SMI was examined as a heterogeneous and recyclable catalyst in Hantzsch pyridine synthesis
under solventꢀfree conditions affording diverse 1,4ꢀdihydropyridines (1,4ꢀDHPs) in excellent yields and in the
relatively short reaction times.
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Keywords: CuI/SMI nanocatalyst, Density functional theory, Quantum theory of atoms in molecules, Hantzsch
pyridine synthesis, Green chemistry.
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1. Introduction
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Copperꢀcatalyzed reactions have gained increasing attentions in modern organic chemistry. In general, there
are two important kinds of functions for these catalysts in organic reactions. First, the reaction proceeds
smoothly and rapidly in the presence of catalyst, for instance, CuIꢀcatalyzed intramolecular oꢀvinylation of
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carbonyl compounds. Second, when a copper catalyst catalyzes the reaction conventionally, in the same time, it
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controls the selectivity of the reaction. In some special Cuꢀcatalyzed reactions, the regioselectivity is also
controlled. One of the most important Cuꢀcatalyzed reactions is the azideꢀalkyne 1,3ꢀdipolar cycloaddition
reaction (entitled as CuAAC reactions) leading to the highly regioselective synthesis of 1,4ꢀdisubstituted 1,2,3ꢀ
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triazoles, coined as “Click Reaction” by Sharpless et al. This reaction has been extensively studied during the
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past decade from different points of view including the computational assessments of origins and prediction
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of its regioselectivity which we have recently highlighted them in a comprehensive review. In addition, a
massive number of experimental and computational developments in this area has confirmed the coordination of
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Cu(I) to CꢀC triple and double bonds during the reaction. Cu(I) can also coordinate to several nitrogen
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heterocycles including pyridine which can efficiently catalyze several diverse organic transformations.
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In continuation of our interest on development of heterogeneous nanocatalysts and their applications,
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recently reported the synthesis, characterization and catalytic activity of CuI nanoparticles immobilized on
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poly(styreneꢀcoꢀmaleic anhydride) modified by 2ꢀamino and 4ꢀaminopyridine,
and used them successfully in
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the regioselective synthesis of 1,2,3ꢀtriazoles through Huisgen 1,3ꢀdipolar cycloaddition via click
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reaction. For being more insightful, we also computationally assessed metalꢀligand interactions for
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interpretation of some of our experimental observations.
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In this light and due to our interest, we decided to study a quantitative description for structural and electronic
features of metalꢀligand interactions in poly(styreneꢀcoꢀmaleic anhydride) copper complex model
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(CuI/SMI)modified with 4ꢀaminopyridine using density functional theory (DFT) and quantum theory of atoms
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in molecules (QTAIM)approaches. Encouraged byour interestingobtained computational data, weprepared our
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Cu(I) nanoparticles immobilized on poly(styreneꢀcoꢀmaleic anhydride) modified with 4ꢀaminopyridine and
identified it via FTꢀIR and inductively coupled plasma (ICP) methods which was in agreement with that of
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previously wellꢀdocumented compound. Then, we examined the catalytic activity of CuI/SMI in the Hantzsch
pyridine synthesis. Herein, we wish to reveal our computational results which led to the highly efficient, green
and high yielding Cu(I)ꢀcatalyzed synthesis of a wide range of DHPs via Hantzsch reaction (Scheme 1).
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Scheme 1. General synthesis of 1,4ꢀdihyropyridine derivatives 1
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2. Experimental
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2.1. Materials and Methods
All chemicals and solvents were purchased from Merck and Aldrich chemical companies and used without
further purification. Melting points were determined on an Electrothermal 9200ꢀBarnstead apparatus and were
uncorrected. IR spectra were obtained using a FTꢀIR Tensor 27 spectrometer instrument and samples were
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prepared as KBr plates. H NMR and C NMR spectra were recorded on a Bruker Ultrashield 400 Avance III
spectrometer at 400 MHz using DMSOꢀd as a solvent with tetramethylsilane (TMS) as an internal standard.
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Mass spectra were measured with Network mass selective detector (Agilent) 6890/5973. Most compounds were
known and their physical data were compared with those reported previously and found being identical.
2.2. Preparation of CuI/SMI Catalyst
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The catalyst was prepared in accordance with our previous procedure as follows. In a 100 ML glass reactor
SMA (1.00 g), 4ꢀaminopyridine (1.54 g, 16 mmol) and dry DMF (15 ml) were placed and then oxygen purged
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by charging N gas into the reactor and sealed. This reactor was placed into a thermostatic oil bath and the
reaction mixture was oscillated until the reagents were dissolved in DMF. Then the reaction mixture was
oscillated at 35 ºC for 3.5 h. Then, acetic anhydride (0.6 ml, 6 mmol), sodium acetate (0.33 g, 4 mmol), and
triethylamine (0.3 ml, 2 mmol) were added into the reactor using syringe. Then the temperature was raised to
75ºC and oscillating was continued for 3.5 h. The reaction mixture was then cooled to ambient temperature and
poured into 300 ml of vigorously stirring methanol, slowly. The formed fiberꢀlike precipitated polymer was
washed with methanol and dried under reduced pressure at 70ºC to constant weight.
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CuI (0.247 mg, 0.001 mmol) was dissolved in CH CN (2 ml) under ultrasonic irradiation and stirring, to give a
transparent pale yellow solution. DMF (20 ml) was then added at ambient temperature to give CuI NPs. To this
mixture, dry SMI (1.000 g) was added. Then the mixture was magnetically stirred at reflux temperature for 5 h
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under the atmosphere of nitrogen. The solid was washed with CH CN and dried under vacuum at 60ºC to obtain
the CuI/SMI. The synthesized CuI/SMI was identified by comparison of its FTꢀIR spectrum with the authentic
compound and found identical. Moreover, the copper content of the polymerꢀsupported catalyst was determined
by ICP analysis and found being 6.92% w/w and used to measure the amount of copper content after five
consecutive runs, too.
2.3. Synthesis of 1,4-DHPs: General Procedure
In a roundꢀbottomed flask, an appropriate aromatic aldehyde 2 (1 mmol), a suitableβꢀdicarbonyl compound3 (2
mmol), ammonium acetate 4 (1.5 mmol) and CuI/SMI nanocatalyst (0.04 g) were thoroughly mixed. Then, the
mixture was heated in an oilꢀbath at 80 °C with concomitant stirring. The progress of reaction was monitored by
TLC (EtOAc:nꢀhexane; 4:1). After completion of the reaction, the mixture was cooled to room temperature,
then hot ethanol was added and the catalyst was easily filtered off under reduced pressure. The filtrate was
evaporated to dryness and the crude was recrystallized from ethanol in 81ꢀ93% yields, calculated based on the
starting aldehyde. The spectroscopic and analytical data for new products and some selected known compounds
are presented as follows. The rest are provided as supplementary.
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Ethyl 4-(4-chlorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (1b):
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M.p.244ꢀ246 °C.IR (KBr): 3275, 3070, 2964, 1706, 1646 cm . H NMR (300 MHz, CDCl ): 0.67 (s, 3H), 0.83
(s, 3H), 0.95 (t, 3H), 1.85 (d, 1H), 1.96 (d, 1H), 2.05 (d, 1H), 2.10ꢀ2.13 (m, 4H), 3.79(q, 2H), 4.73 (s, 1H), 6.89ꢀ
7.01 (m, 4H), 8.17 (s, 1H) ppm.MS (m/e): 373 (M+).
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Ethyl 4-(4-methoxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (1c):
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M.p.255ꢀ256 °C.IR (KBr):3276, 2956, 1703, 1648, 1606, 1469, 1381, 1215, 1031, 765 cm . H NMR (300
MHz, CDCl ): 0.71 (s, 3H), 0.85 (s, 3H), 0.98 (t, 3H), 1.87 (d, 1H), 1.97 (d, 1H), 2.06 (d, 1H), 2.11ꢀ2.15 (m,
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4H), 3.51 (s, 3H), 3.81 (q, 2H), 4.71 (s, 1H), 6.57ꢀ6.98 (m, 4H), 8.02 (s, 1H) ppm.MS (m/e): 369 (M+).
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9-(3-Fluorophenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (1h):
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M.p.298ꢀ300°C.IR (KBr): 3279, 3069, 2956, 1636, 1218 cm . H NMR (400 MHz, DMSOꢀd ): 0.87 (s, 6H),
1.01 (s, 6H), 2.01 (d, J = 16.4 Hz, 2H), 2.18 (d, J = 16 Hz, 2H), 2.35 (d, J = 17.6 Hz, 2H), 2.45 (d, J = 16.8 Hz,
2H), 4.82 (s, 1H), 6.84ꢀ7.23 (m, 4H), 9.37 (s, 1H) ppm.MS (m/e): 367 (M+).
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9-(4-Chlorophenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (1i):
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M.p.293ꢀ295°C. H NMR (400 MHz, DMSOꢀd
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): 0.97 (s, 6H), 1.09 (s, 6H), 2.17 (d, J = 16.4 Hz, 2H), 2.23 (d, J
= 11.6 Hz, 2H), 2.27 (d, J = 11.2 Hz, 2H), 2.34 (d, J = 16.8 Hz, 2H), 5.06 (s, 1H), 7.16ꢀ7.18 (m, 2H), 7.28ꢀ7.30
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(m, 2H), 7.33 (s, 1H) ppm. C NMR (DMSOꢀd
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, 400 MHz): 27.1, 29.5, 32.7, 33.3, 40.9, 50.7, 113.1, 128.1,
129.5, 131.5, 145.1, 148.5, 195.7 ppm.
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Diethyl 4-(4-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1p):
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M.p.145ꢀ147°C. H NMR (400 MHz, DMSOꢀd
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): 1.24 (t, 6H), 2.34 (s, 6H), 4.06ꢀ4.11 (m, 2H), 4.12ꢀ4.15 (d,
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2H), 4.97 (s, 1H), 5.73 (s, 1H), 7.17ꢀ7.21 (m, 2H), 7.22ꢀ7.28 (m, 2H) ppm. C NMR (DMSOꢀd , 400 MHz):
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14.3, 19.6, 39.2, 59.8, 103.9, 127.9,129.4, 131.7, 143.9, 146.3, 167.4 ppm.
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3. Results and Discussion
3.1. Computational section
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We initially concentrated on the nature of interactions between copper metal ions and SMI ligand modified with
4ꢀaminopyridinein the aforementioned polymerꢀsupported copper complex via DFT computations. First, we
presented a comparative assessment on metalꢀligand interactions in the gas and solution phases to investigate the
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solvent effect on experimental affordance of CuI/SMI complexation reaction. In this respect, an effective
computational model for SMI ligand and CuI/SMI complex was designed (Scheme2).As illustrated in Scheme2,
two coordinating modes were modeled for the description of metalꢀligand interactions denoted as NꢀCuI/SMI
(copper coordinates to pyridine nitrogen) and OꢀCuI/SMI(copper coordinates to carbonyl oxygen), respectively.
On the other hand, our proposed computational model has a reputable embody between accuracy and time
saving efficiency of computational procedure.
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CH2 CH2
O
CH2 CH2
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CuI
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CuI
N-CuI/SMI complex
O-CuI/SMI complex
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Scheme 2. A simple model for two coordinating modes in polymerꢀsupported copper catalyst
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DFT computations were performed at M06/6ꢀ31G theory level to determine the optimized structure of SMI
ligand and NꢀCuI/SMI and OꢀCuI/SMI complexes. The harmonic frequency analysis was employed to confirm
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the found structures correspond to minima. It is noteworthy to mention that M06 functional has been
introduced recently as a hybrid metaꢀGGA (generalized gradient approximation) exchangeꢀcorrelation
functional, parameterized including both transition metals and nonmetals and was recommended for application
in organometallic and inorganometallic thermochemistry, kinetic studies and nonꢀcovalent interactions. All DFT
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computations were performed using GAMESS suite of programs. Theenergy minimized structure of SMI
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ligand and NꢀCuI/SMI and OꢀCuI/SMI complexes calculated at M06/6ꢀ31G theory level have been displayed in
Figure1.
C6
C5
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O1 N2
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Cu
I
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SMI ligand
N-CuI/SMI complex
Figure1.
O-CuI/SMI complex
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In order to characterize the variation of bond orders via complexation process and interpret the interaction
strength between copper ion and SMI ligand, we have also compared the bond order of some selected key bonds
in SMI ligand with its corresponded bonds in NꢀCuI/SMI and OꢀCuI/SMI complexes. In Table 1, we have listed
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bond order and bond length of some selected chemical bonds in the coordination sphere calculated at M06/6ꢀ
311+G** theory level. The reported results in Table 1 indicate two facts as follows: i) decreasing in the bond
order of carbonyl group and also C−N of pyridine ring through complexation (C5ꢀO1 bond order from 2.440 in
SMI ligand to 2.352 in OꢀCuI/SMI complex and also N1ꢀC2 and N1ꢀC3 bond order from 1.339 and 1.391 in
SMI ligand to 1.317 and 1.288 in NꢀCuI/SMI complex, respectively)that can mainly be ascribed to the donation
of shared electrons from these chemical bonds to copper ions and is in agreement with the reported FTꢀIR
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spectroscopic observations, ii) CuꢀN interaction is stronger than CuꢀO interaction (0.512 and 0.171 for
calculated CuꢀN and CuꢀO bond order, respectively). On the basis of the obtained results, we can predict that
copper nanoparticles will bind more effectively to pyridinic nitrogen than carbonyl oxygen.It is important to
note that the variation in the calculated bond order values correlates with trend of bond distance change through
the complexation process.
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<Table 1>
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In the next step, we have focused on another significant feature in the affordance of synthesis of CuI/SMI
complex; solvent effect. In this content, we comparatively evaluated the bond orders of CuꢀN and CuꢀO in the
presence of ethanol and dimethylformamide (DMF) as solvents. It is important to mention that in an
independent work, we have experimentally observed a more effective immobilization and smaller size of CuI
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nanoparticles on SMI support modified with 4ꢀaminopyridinein DMF solution in comparison with ethanol.
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The solvent effect computations were performed via polarized continuum model (PCM) at M06/6ꢀ311+G**
theory level. In Table 2, we have presented comparatively the calculated bond orders of CuꢀN and CuꢀO
chemical bonds in DMF and ethanol solution phases. The reported result of Table 2 confirms more strength of
CuꢀN bond than CuꢀO in solution phase. Moreover, the bond orders in NꢀCuI/SMI and OꢀCuI/SMI complexes
have larger calculated values in DMF solution in comparison with those in ethanol which corroborate the
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observed practical preference of DMF as solvent rather than ethanol.
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<Table 2>
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In order to explicate the nature of metalꢀligand interactions in CuI/SMI, we concentrated on topological study of
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**
electron density via QTAIM method.
In this respect, resulting M06/6ꢀ311+G wave function files for the
optimized structures of SMI ligand, NꢀCuI/SMI and OꢀCuI/SMI complexes were used as inputs to AIM2000
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program package. Then, we focused on the calculation of some selected bond critical points (BCPs) and their
associated bond paths to perform a comparative survey on the bond strength from the electronic point of view.
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ꢃ
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The calculated values of electron density (ꢀ ), its laplacian (ꢂ ꢀ ), electronic kinetic energy density (ꢄ ),
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electronic potential energy density (ꢅ ), total electronic energy density (ꢆ ), and |ꢅ |⁄ꢄ of some selected
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critical points for SMI ligand, NꢀCuI/SMI and OꢀCuI/SMI complexes were listed in Table3. QTAIM molecular
graphs of SMI ligand, NꢀCuI/SMI and OꢀCuI/SMI complexes including all bond and ring critical points and
their associated bond paths were also displayed in Figure2.
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<Table 3>
SMI ligand
N-CuI/SMI complex
Figure2.
O-CuI/SMI complex
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The following two facts can be deduced from the comparative assessment of the reported results of Table 3: i)
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the large positive values of electron density together with the negative values of ꢂ ꢀ and H
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and also |ꢅ |⁄ꢄ >
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2 values on C=O and C−N BCPs approbate the covalent character of these chemical bonds in SMI ligand, Nꢀ
CuI/SMI and OꢀCuI/SMI complexes. However, at CuꢀN, CuꢀO and CuꢀI BCPs, the small values of electron
ꢃ
density with the positive values of ꢂ ꢀ and small negative values of H
b
and also1 ꢇ |ꢅ |⁄ꢄ ꢇ 2 calculated
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ꢁ
values indicate the presence of semi covalentꢀelectrostatic interactions ii) decreasing in the calculated values of
ꢀꢁ at C=O and C−N BCPs via complexation affirms the donation of shared electrons to the metal center and is
in confirmation with reducing in the stretching frequency of IR spectrum iii) comparison of the calculated
electron density values of CuꢀN and CuꢀO BCPs in NꢀCuI/SMI and OꢀCuI/SMI complexes uphold that
interaction of copper cation with pyridinic nitrogen is stronger than oxygen of carbonyl group. As illustrated in
Figure 2, a more stringent assessment on QTAIM wave function analysis demonstrates that the weaker CuꢀO
interaction in OꢀCuI/SMI complex can mainly be attributed to the presence of BCPs between carbonyl oxygen
and also copper ion with facing phenyl carbon atoms. These interactions lead to the formation of new ring
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critical point (denoted as RCP in QTAIM molecular graph of OꢀCuI/SMI complex in Figure 2) and
consequently the electron density of CuꢀO BCP is distributed in the aforementioned ring and therefore
decreased.
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Although all our obtained computed results in the both gas and solution phases demonstrate that the interaction
between CuI nanoparticles with pyridinie nitrogen of SMI ligand is stronger than that of oxygen of carbonyl
group, delightfully we found that the possibility for the formation of OꢀCuI/SMI is also enough to be considered
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and not being over looked. This phenomenon has been realized previously. Moreover, it should be mentioned
that our DFT and QTAIM computational assessments on the interactions between CuI nanoparticles and
poly(styreneꢀcoꢀmaleic anhydride) modified by 2ꢀaminopyridine have demonstrated the similar behavior from
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the electronic viewpoint. Based on our obtained computational results, we were prompted to examine the
catalytic activity of CuI/SMI polymeric support in a name reaction so called “Hantzsch Pyridine Synthesis” as a
wellꢀknown approach with the wellꢀestablished mechanism for the synthesis of DHPs as an important
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biologically active compounds.
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In virtually all suggested mechanism for Hantzsch pyridine synthesis, carbonyl group of aldehyde as a starting
material is initially activated which makes it susceptible for being attacked by nucleophiles leading to the
production of corresponding1,4ꢀDHPs.
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3.2. Synthesis of 1,4-DHP derivatives
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Initially, a oneꢀpot fourꢀcomponent reaction of benzaldehyde, ethyl acetoacetate, dimedone and ammonium
acetate was selected as a model reaction. This reaction was performed in the presence of CuI/SMI in water as a
solvent to obtain the corresponding dihydropyridine1a. In order to optimize the experimental conditions for the
model reaction, we studied the effects of solvents and temperatures in the presence of CuI/SMI. As shown in
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Table 4, among the tested solvents such as water, ethanol, acetonitrile, mixture of H O/EtOH (1:1) and solventꢀ
free conditions, the solventless system gave the best output in terms of time, temperature and yield (30 min at 80
°C under solventꢀfree conditions, yield 92%) (Entry2). Conducting the reaction under lower temperature (60 °C)
led to obvious decrease in the yield of the desired product (Entry1).
<Table 4>
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In the next step, the model reaction was carried out using different quantities of CuI/SMI. Table 5 illustrates that
the best yield has been achieved when 0.04 g of CuI/SMI was used as the optimum amount (Entry 3). By
1
0

Page 11 of 24
2
2
2
43
decreasing the amount of CuI/SMI as catalyst, the reaction time should be increased for obtaining the similar
yield (Entries 1 and 2). Using the higher amounts of catalyst has generally no effect on outcome of the model
system (Entry 4).
44
45
2
46
<Table 5>
2
2
2
2
2
2
2
47
48
49
50
51
52
53
When the optimal reaction conditions were secured, we examined the generality and substrate scope of this
reaction. Divers βꢀdicarbonyl compounds3 were reacted with a wide variety of aldehydes 2 and ammonium
acetate 4 in the presence of CuI/SMI as catalyst in solventꢀfree conditions to obtain the corresponding desired
products1 in good to excellent yields. The results are summarized in Table 6. Under the optimal reaction
conditions, the reactions were completed within 25ꢀ45 minutes. By using this effective nanocatalyst, the
aldehydes carrying both electronꢀdonating groups such as methyl and methoxy and electronꢀwithdrawing groups
such as nitro and halide gave products in good to excellent yields.
2
54
<Table 6>
2
2
2
2
2
55
56
57
58
59
To study the recyclability and reusability of the catalyst, we repeated the model reaction under optimized
reaction conditions. After the completion of the model reaction, the mixture was filtered and thoroughly washed
with acetone. The catalyst was dried under reduced pressure at 70 °C for 3 h and being reused for subsequent
run. We found that the catalyst can effectively be reused for at least 5 cycles without any significant loss in its
catalytic activity or the yield of products (Figure3).
1
00
90
80
70
60
50
40
30
20
10
0
1
2
3
4
5
Run number
2
2
60
61
Figure3.
2
2
2
62
63
64
The possible mechanism for the synthesis of substituted 1,4ꢀDHP derivatives 1 catalyzed by copper catalyst is
proposed as illustrated in Scheme3. The synthesis of 1,4ꢀDHPs 1beginswith the Knoevenagel condensation of
the activated aldehyde 2and βꢀdicarbonyl compound3using Cu(I), and proceeds through a Michael addition of
1
1

Page 12 of 24
2
2
2
2
65
66
67
68
the second equivalent of activated methylene compound 3 into the Knoevenagel intermediate 5. After the
formation of enamine intermediate 6, intramolecular cyclization gives the desired product 1. The important role
of copper catalyst is vividly observed in the first and second step where it catalyzes the Knoevenagel
condensation and Michael addition, respectively.
2
2
69
70
Scheme 3. Plausible mechanism for the synthesis of substituted 1,4ꢀDHP derivatives
2
71
4. Conclusion
2
2
2
2
2
72
73
74
75
76
In summary, we have made a comparative assessment on structural and electronic features of metalꢀligand
interactions in poly(styreneꢀcoꢀmaleic anhydride) copper complex models (CuI/SMI) modified with 4ꢀ
aminopyridine using DFT and QTAIM approaches. Strictly speaking, we focused on theoretical interpretation of
metalꢀligand interaction strength in the gas and solution phases to analyze experimental observations in terms
and conditions of immobilization of copper nanoparticles on SMI. In overall, our obtained computed results
1
2

Page 13 of 24
2
2
2
2
2
2
77
demonstrated that the interaction between CuI nanoparticles and pyridine nitrogen of SMI ligand is stronger
than oxygen of carbonyl group, but the possibility for the formation of OꢀCuI/SMI complex is also considerable
and should not be over looked. The interaction between CuI nanoparticles and carbonyl group was good enough
to accelerate a classical name reaction so called Hantzsch pyridine synthesis. In this computational context, we
examined the catalytic activity of CuI/SMI in Hantzsch reaction to interact and activate aldehyde species for
producing 1,4ꢀDHPcompounds.
78
79
80
81
82
2
2
2
2
2
2
2
2
2
83
84
85
86
87
88
89
90
91
Thus, we have developed an efficient, facile and green method utilizing CuI/SMI as catalyst for a oneꢀpot
synthesis of various types of 1,4ꢀDHPs via a multiꢀcomponent reaction under solventꢀfree conditions which is
also important from the green chemistry viewpoint. Furthermore, wide scope, simple operation, high yields,
short reaction times, simple workꢀup and reusing the catalyst at least for five consecutive runs without any preꢀ
activation and any appreciable loss of activity are other advantages and merits of the present method. In
conclusion, CuI/SMI can be introduced as an effective and recyclable catalyst in Hantzsch pyridine synthesis for
the synthesis of a wide range of substituted 1,4ꢀDHP derivatives. Examination of activity for this catalyst in
other catalytic reactions involving at least one compound bearing a carbonyl group is underway in our
laboratory.
2
92
Acknowledgment
2
2
93
94
We are thankful to Alzahra university research council for partial financial supports. Tayebeh Hosseinnejad is
also thankful to Iran National Science Foundation (INSF) for its financial support.
2
2
2
95
96
97
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3
3
3
3
3
3
3
3
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4
4
4
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93
94
95
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97
98
99
00
01
02
03
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Page 18 of 24
4
04
Tables:
4
4
4
05
06
07
Table 1.M06/6ꢀ311+G** calculated values of bond order and bond length for some selected key bonds in SMI
ligand, NꢀCuI/SMI and OꢀCuI/SMI complexes. Note that the calculated bond length values have been presented
in the parenthesis. Numbering of atoms is in accordance with Figure 1.
NꢀCuI/SMI
complex
OꢀCuI/SMI
complex
SMI ligand
N1ꢀC2
N1ꢀC3
N2ꢀC4
N2ꢀC5
N2ꢀC6
C5ꢀO1
C6ꢀO2
CuꢀN1
CuꢀO1
CuꢀI
1.339(1.332)
1.391(1.333)
0.847(1.420)
0.808(1.407)
0.710(1.405)
2.440(1.205)
2.433(1.205)
ꢀꢀꢀꢀꢀꢀ
1.317(1.345)
1.288(1.344)
0.912(1.412)
0.870(1.395)
0.706(1.412)
2.509(1.185)
2.518(1.186)
0.512(1.907)
ꢀꢀꢀꢀꢀꢀ
1.388(1.320)
1.430(1.318)
1.067(1.411)
0.951(1.389)
0.622(1.413)
2.352(1.212)
2.409(1.220)
ꢀꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀꢀ
0.171(2.099)
1.396(2.458)
ꢀꢀꢀꢀꢀꢀ
1.337(2.490)
4
08
4
4
09
10
Table 2.The bond orders of CuꢀN and CuꢀO chemical bonds in DMF and ethanol solution phases, calculated at
M06/6ꢀ311+G** level of theory via PCM approach
CuꢀN
NꢀCuI/SMI complex
0.562
CuꢀO
OꢀCuI/SMI complex
0.229
Ethanol
DMF
0.594
0.243
4
4
4
11
12
13
1
8

Page 19 of 24
4
4
4
14
Table 3.Mathematical properties of BCPs associated to some selected bonds in SMI ligand, NꢀCuI/SMI and Oꢀ
CuI/SMI complexes. The properties have been obtained via QTAIM analysis on M06/6ꢀ311+G**calculated
wave functions of electron density. Note that numbering of atoms is in accordance with Figure 2.
15
16
ꢀꢁ
ꢂꢃꢀꢁ
Gꢈ
Vꢈ
Hꢈ
|V |⁄Gꢈ
ꢈ
SMI ligand
N
1
ꢀC
ꢀC
ꢀO
ꢀO
2
3
1
2
0.3469
0.3473
0.4225
0.4218
ꢀ0.8428
ꢀ0.8462
ꢀ0.0427
ꢀ0.0360
0.3394
0.3393
0.7238
0.7234
ꢀ0.8895
ꢀ0.8902
ꢀ1.4583
ꢀ1.4560
ꢀ0.5501
ꢀ0.5509
ꢀ0.7345
ꢀ0.7326
2.6208
2.6236
2.0147
2.0127
N
1
C
5
6
C
NꢀCuI/SMI
complex
N ꢀC2
0.3449
0.3454
0.0954
ꢀ0.6968
ꢀ0.6978
0.4106
0.3741
0.3749
0.1451
ꢀ0.9226
ꢀ0.9243
ꢀ0.1877
ꢀ0.5485
ꢀ0.5494
ꢀ0.0426
2.4661
2.4654
1.2935
1
1 3
N ꢀC
CuꢀN1
CuꢀI
0
.0586
0.1232
0.0740
ꢀ0.0900
ꢀ0.0159
1.2154
OꢀCuI/SMI
complex
C
5
6
ꢀO
ꢀO
1
2
0.4236
0.4421
0.0532
0.0636
ꢀ0.0700
ꢀ0.1520
0.2899
0.1125
0.7499
0.8185
0.0864
0.0534
ꢀ1.4823
ꢀ1.5990
ꢀ0.1004
ꢀ0.0787
ꢀ0.7324
ꢀ0.7805
ꢀ0.0139
ꢀ0.0253
1.9766
1.9535
1.1614
1.4738
C
CuꢀO
CuꢀI
1
4
4
4
4
4
4
17
18
19
20
21
22
1
9

Page 20 of 24
4
23
Table 4.Optimization of reaction conditions for the synthesis of 1a
a
Entry Solvent
Temperature (°C)
Time (min)
Yield (%)
1
2
3
4
5
6
ꢀ
60
55
30
45
35
80
50
78
92
83
80
68
85
-
80
Water
Ethanol
Acetonitrile
Reflux
Reflux
Reflux
Reflux
2
H O/EtOH (1:1)
a
4
4
24
25
Yields of isolated pure products
4
4
26
27
Table 5. The effect of different amount of CuI/SMI nanocatalyst on the synthesis of substituted 1,4ꢀ
dihydropyridine 1a
a
Entry
Catalyst amount (g)
Time (min)
Yield (%)
1
2
3
4
0.020
0.030
0.040
0.050
55
45
30
35
76
87
92
90
a
4
4
28
29
Yields of isolated pure products
4
4
4
4
4
30
31
32
33
34
2
0

Page 21 of 24
4
35
Table 6.Synthesis of substituted 1,4ꢀDHP derivatives 1a-r in the presence of CuI/SMI nanocatalyst
Time
Yield
Product
R
H
Compound 3
Mp (°C)
206ꢀ208
244ꢀ246
255ꢀ256
261ꢀ262
220ꢀ221
Mp (Lit.)
a
(
min)
(%)
Ethyl
5
5
5
5
5
7
1a
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
30
92
90
89
85
90
206ꢀ208
244ꢀ246
255ꢀ257
260ꢀ262
220ꢀ221
acetoacetate
Ethyl
7
7
7
8
1b
4ꢀCl
4ꢀMeO
H
30
35
45
35
acetoacetate
Ethyl
1c
acetoacetate
Methyl
1d
acetoacetate
Methyl
1e
4ꢀCl
acetoacetate
Methyl
5
5
8
9
1
f
4ꢀMe
H
Dimedone
Dimedone
40
30
88
89
274ꢀ276
278ꢀ280
275ꢀ276
279ꢀ280
acetoacetate
1
1
g
h
Dimedone
3ꢀF
Dimedone
Dimedone
Dimedone
Dimedone
25
25
93
91
298ꢀ300
298ꢀ299
New
5
5
9
9
1
i
j
4ꢀCl
297ꢀ299
1
2ꢀMeO
H
Dimedone
Dimedone
30
40
90
84
293ꢀ295
115ꢀ117
293ꢀ295
115ꢀ117
Methyl
acetoacetate
Methyl
Methyl
acetoacetate
Methyl
5
5
5
5
6
8
8
8
8
0
1
k
1l
4ꢀCl
35
40
30
30
80
81
87
90
197ꢀ198
166ꢀ168
186ꢀ188
157ꢀ158
196ꢀ198
167ꢀ169
186ꢀ188
156ꢀ158
acetoacetate
Methyl
acetoacetate
Methyl
1
m
4ꢀNO
2
acetoacetate
Methyl
acetoacetate
Methyl
1
n
o
4ꢀMeO
H
acetoacetate
Ethyl
acetoacetate
Ethyl
1
acetoacetate
acetoacetate
2
1

Page 22 of 24
Ethyl
acetoacetate
Ethyl
Ethyl
acetoacetate
Ethyl
6
6
6
0
0
0
1
p
q
4ꢀCl
4ꢀMeO
3ꢀMe
35
30
30
88
90
91
145ꢀ147
157ꢀ158
123ꢀ124
144ꢀ146
157ꢀ159
122ꢀ124
1
acetoacetate
Ethyl
acetoacetate
Ethyl
1
r
acetoacetate
acetoacetate
a
4
36
Yields of isolated pure products
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
2
2

Page 23 of 24
4
55
Figure captions:
*
4
4
56
57
Figure1.Atomic numbering and optimized structures obtained at M06/6ꢀ31G level of theory for SMI ligand, Nꢀ
CuI/SMI and OꢀCuI/SMI complexes
4
4
4
58
59
60
Figure2. Complete molecular graphs (MGs) of SMI ligand, NꢀCuI/SMI and OꢀCuI/SMI complexes obtained by
QTAIM analysis of M06/6ꢀ311+G** electron density functions. Bond Critical Points: red circles; Ring Critical
Points: yellow circles; Bond Paths: pink lines.
4
4
4
4
4
4
4
4
4
4
4
61
62
63
64
65
66
67
68
69
70
71
Figure3. The recyclability of the CuI/SMI nanocatalyst in the synthesis of 1a
2
3

Page 24 of 24
4
4
4
4
4
4
4
4
72
73
74
75
76
77
78
79
4
4
80 Graphical Abstract
81
Computational investigations on structural and electronic properties of CuI nanoparticles
immobilized on modified poly(styrene-co-maleic anhydride), leading to unexpected but an efficient
catalyzed synthesis 1,4-dihydropyridine via Hantzsch reaction
Majid M. Heravi*, Tayebeh Hosseinnejad*, Niousha Nazari
Department of Chemistry, Alzahra University, Vanak, Tehran, Iran
4
82
2
4