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Supramolecular assembly of (Z)-ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate, crystal structure, Hirshfeld surface analysis and DFT studies
Accepted Manuscript Supramolecular assembly of (Z)-ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate, crystal structure, Hirshfeld surface analysis and DFT studies Catiúcia R.M.O. Matos, Letícia S. Vitorino, Pedro H.R. de Oliveira, Maria Cecília B.V. de Souza, Anna C. Cunha, Fernanda da C.S. Boechat, Jackson A.L.C. Resende, José Walkimar de M. Carneiro, Célia M. Ronconi PII:
S0022-2860(16)30479-3
DOI:
10.1016/j.molstruc.2016.05.033
Reference:
MOLSTR 22547
To appear in:
Journal of Molecular Structure
Received Date: 22 January 2016 Revised Date:
7 April 2016
Accepted Date: 11 May 2016
Please cite this article as: C.R.M.O. Matos, L.S. Vitorino, P.H.R. de Oliveira, M.C.B.V. de Souza, A.C. Cunha, F.d.C.S. Boechat, J.A.L.C. Resende, J.W.d.M. Carneiro, C.M. Ronconi, Supramolecular assembly of (Z)-ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate, crystal structure, Hirshfeld surface analysis and DFT studies, Journal of Molecular Structure (2016), doi: 10.1016/j.molstruc.2016.05.033. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
Supramolecular assembly of (Z)-ethyl 2-cyano-3-((4fluorophenyl)amino) acrylate, crystal structure, Hirshfeld surface analysis and DFT studies
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Catiúcia R. M. O. Matos, Letícia S. Vitorino, Pedro H. R. de Oliveira, Maria Cecília B. V. de Souza, Anna C. Cunha, Fernanda da C. S. Boechat, Jackson A. L. C. Resende, José Walkimar de M. Carneiro, Célia M. Ronconi*
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Instituto de Química, Universidade Federal Fluminense, Outeiro de São João Batista,
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s/n, Campus do Valonguinho, Centro, 24020-141, Niterói, RJ, Brazil.
Corresponding authors: Célia M. Ronconi
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E-mail: [email protected] Phone: +55 21 26292164 Fax: +55 21 26292129
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ACCEPTED MANUSCRIPT Abstract
A mixture of the E and Z isomers of ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate was synthesized and characterized by elemental analysis, attenuated total reflectance-Fourier 13
C nuclear magnetic resonance spectroscopy. The
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transform infrared spectroscopy, 1H and
structure of the Z isomer was determined by single crystal X-ray diffraction, which revealed a three-dimensional supramolecular network governed by C–H···N, C–H···O, and C–H···F hydrogen bonds and π···π stacking interactions. The combination of these interactions plays an
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important role in stabilizing the self-assembly process and the molecular conformation. Hirshfeld surface analysis indicated the roles of the noncovalent interactions in the crystal
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packing, which were quantified by fingerprint plots and DFT calculations.
Keywords: ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate E and Z isomers, noncovalent
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interactions, crystal structure, Hirshfeld surface analysis, DFT studies
1. Introduction
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Monofluorinated anilinomethylidene derivatives are building blocks for the synthesis of a variety of fluoroquinolones, which are compounds with broad-spectrum activity against
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pathogenic bacteria and commonly used for the clinical treatment of various infectious diseases [1, 2]. Particularly, ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate molecule is a versatile reagent for the synthesis of quinoline-3-carbonitrile derivatives, has been evaluated for its antitumor activity as well as for the treatment of rheumatoid arthritis [3, 4]. Ethyl 2-cyano-3-((4fluorophenyl)amino) acrylate can be easily synthesized as a mixture of E and Z isomers (Fig. 1) by alkylation of 4-fluoroaniline with ethyl 2-cyano-3-ethoxyacrylate through Michael additionelimination [3, 4]. During our investigation on the coordination properties of cyano compounds [5], we identified that ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate might be an interesting ligand 2
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several coordination groups, thus making it potentially useful in the field of
coordination chemistry. This compound is also an interesting tecton, containing hydrogen donor and acceptor atoms in which the molecules can interact with one another by noncovalent interactions. Understanding the interactions among these tectons may generate new
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supramolecular synthons, which might be used to assemble more complex aggregates with new properties [6].
Therefore, as part of our ongoing project aiming to understand the structural features of cyano compounds [5], we synthesized and characterized Z and E isomers of ethyl 2-cyano-3-
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((4-fluorophenyl)amino) acrylate. However, the structural characterization was only performed for the Z isomer because the E isomer did not provide high quality single crystals. An
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investigation of intermolecular interactions between the molecules of the Z isomer in the solid state by Hirshfeld surface analysis and 2D fingerprint plots were carried out in order to show the contribution of the short contacts for the stabilization of the extended network. DFT calculations were employed to quantify the energies of the noncovalent interactions present in the crystal
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structure.
Fig. 1. E and Z isomers of ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate.
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ACCEPTED MANUSCRIPT 2. Experimental section
2.1. Materials and Methods
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The following chemicals were used without further purification: 4-fluoraniline (Acros Organics), ethyl 2-cyano-3-ethoxyacrylate (Sigma-Aldrich), ethanol (Vetec) and methanol (Vetec). The percentage of carbon, nitrogen and hydrogen were determined using a Perkin Elmer CHN 2400 analyzer at the Analytical Center of the Institute of Chemistry, University of
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São Paulo, Brazil. The melting point was evaluated using a Fisher-Johns melting point apparatus. The 1H and 13C NMR spectra were recorded on a Varian VNMRS instrument at 500
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MHz and 75 MHz respectively, using residual solvents as internal standards. Samples were prepared using DMSO-d6 purchased from Cambridge Isotope Laboratories. The attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectrum of the ethyl 2-cyano-3-((4fluorophenyl)amino) acrylate E and Z isomers was obtained on a Varian FT-IR 660
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spectrometer. The DSC analyses were performed on a Shimadzu DSC-60 instrument in the heating/cooling range of 30-150 ºC at a rate of 5 °C/min, with an aluminum pan. Powder X-ray diffraction (XRD) measurements were carried out on a D8 ADVANCE diffractometer (Bruker)
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at 298 K with CuKα radiation (λ = 1.5406 Å). The scanning rate was fixed at 0.2 degrees/s with
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a step size of 0.02° with 2θ ranges from 5° to 50° for phase identification.
2.2. Synthesis of the ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate E and Z isomers
A mixture of 4-fluoraniline (1 mL, 10 mmol) and ethyl 2-cyano-3-ethoxyacrylate (1.69 g, 10 mmol) was dissolved in 10 mL of ethanol and stirred under reflux for 2 h. The mixture was allowed to cool and then it was poured into ice-cold water. The precipitate was collected by filtration and recrystallized with hexane. The ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate was obtained as a mixture of E and Z isomers (85 % yield); m.p.: 122 °C; (ATR-FTIR) ν(cm-1): 2210 (s), 1702 (m), 1679 (m), 1629 (m), 1604 (m), 1513 (s), 1380 (m), 1249 (w), 1213 (s), 1174 4
ACCEPTED MANUSCRIPT (m), 1147 (m), 1099 (s), 987 (m), 827 (s), 781 (s), 755 (m), (s = strong, m = medium, w = weak). 1H NMR (500 MHz, 298 K, DMSO-d6) δ E isomer: 10.71 (d, J = 15 Hz, 1H, –NH), 8.37 (d, J = 15 Hz, 1H, Hβ), 7.52 (dt, J = 9.0 and 6.0 Hz, 2H, H-3 and H-5), 7.22 (dd, J = 9.0 Hz, 2H, H-2 and H-6), 4.23 (q, J = 9.0 Hz, 2H, CH2CH3), 1.27 (t, J = 9.0 Hz, 3H, CH2CH3) ppm. Z
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isomer: 10.70 (s, 1H, –NH), 8.26 (s, 1H, Hβ), 7.42 (dd, J = 9.0 and 6.0 Hz, 2H, H-3' and H-5'), 7.21 (dd, J = 9.0 Hz, 2H, H-2' and H-6'), 4.18 (q, J = 6.0 Hz, 2H, CH2CH3), 1.24 (t, J = 6.0 Hz, 3H, CH2CH3) ppm. 13C NMR (75 MHz, 308 K, DMSO-d6) δ E isomer: 166.30 (s, CO), 161.14 (d, JC-F = 10.5 Hz, C-4), 153.90 (s, –CH=), 136.30 (s, C-1), 120.14 (s, C-2, C-6), 115.87 (s, CN),
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116.32 (d, JC-F = 3.0 Hz, C-3, C-5), 74.58 (s, C-8), 60.41 (s, CH2CH3), 14.33 (s, CH2CH3) ppm. Z isomer: 164.67 (s, CO), 157.91 (d, JC-F = 9.0 Hz, C-4’), 152.95 (s, –CH=), 135.44 (s, C-1’),
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120.04 (s, C-2’, C-6’), 118.15(s, CN), 116.02 (d, JC-F = 3.75 Hz, C-3’, C-5’), 73.53 (s, C-8’), 60.52 (s, CH2CH3), 14.24 (s, CH2CH3) ppm. Elemental analysis calculated for C12H11FN2O2: C 61.53 %, H 4.73 %, N 11.96 %; experimentally determined: C 61.74 %, H 4.90 %, N 11.45 %.
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2.3. Crystallization of (Z) ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate
Ethyl 2-cyano-3-(4 fluorophenylamino) acrylate as a mixture of the Z and E isomers (mass,
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0.0556 mmol) was dissolved in 8 mL of methanol. After slow evaporation of the solvent at room temperature, colorless needle-shaped crystals of both isomers were formed (Fig. 3a).
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However, only the Z isomer provided high quality single crystals for the X-ray diffraction analysis.
2.4. X-ray data collection and structure refinement
The crystal and refinement data for (Z) ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate are listed in Table 1. Single crystal X-ray diffraction data of the colorless crystal of (Z) ethyl 2cyano-3-((4-fluorophenyl)amino) acrylate were collected at 150.02 K on a Bruker D8 Venture diffractometer equipped with monochromatic Mo Kα radiation. The data collection and cell 5
ACCEPTED MANUSCRIPT refinement were performed using APEX 2 [7] and the structure solutions and refinements were performed using XS and XL software packages [8]. The structure was solved by direct methods and refined with full-matrix least-squares techniques on F2. The structure of all non-hydrogen atoms was refined anisotropically, and all hydrogen atoms were placed in their calculated
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positions and then refined using the riding model. The molecular graphics were computed in
Mercury 3.5 [10].
2.5. Hirshfeld surface computational method
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Olex2 [9] and the figures were prepared and analyzed using licensed Crystal Maker 9.2.2 and
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Hirshfeld surfaces and their related 2-D fingerprint plots [11], [12], [13], [14] were obtained using Crystal Explorer 3.1 software [15]. The dnorm (normalized contact distance) surface and the breakdown of the 2-D fingerprint plots were used to decode and quantify the intermolecular interactions in the crystal lattice [16], [17], [18]. The dnorm is a symmetric function of distances
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to the surface from the nuclei inside and outside the Hirshfeld surface (di and de, respectively), relative to their respective van der Waals radii (rvdW). The value of dnorm is negative or positive if the intermolecular contacts are shorter or longer
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than the rvdW, respectively. The dnorm Hirshfeld surfaces are presented using red–white–blue color scheme. A color scale of red highlights shorter separations than the rvdW, white is used for
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separations around the rvdW , and blue indicates longer separations than the rvdW.
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ACCEPTED MANUSCRIPT Table 1 Crystal data and structure refinement for (Z) ethyl 2-cyano-3-((4-fluorophenyl)amino)
Empirical formula
C12H11FN2O2
Formula weight
234.23
Temperature/K
150.02
Crystal system
Monoclinic
Space group
P21/c
Unit cell dimensions
a = 5.1531(2) Å
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b = 20.9962(7) Å
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acrylate.
c = 10.4446(4) Å
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β = 100.502(2) °
Volume/Å3
1111.13(7)
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ρ calc./g cm–3
1.400
µ/mm–1 F(000) Crystal size/mm–3
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0.108
Index ranges
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Theta range for data collection
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Reflections collected
488.0 0.331 × 0.319 × 0.287 4.42 to 52.17 ° –6 ≤ h ≤ 6, –25 ≤ k ≤ 25, –12 ≤ l ≤ 12 14 419
Independent reflections
2202 [R(int) = 0.0297, R(sigma) = 0.0171]
Data/restraints/parameters
2202/0/155
Goodness-of-fit on F2
1.063
Final R indexes [I ≥ 2σ (I)]
R1 = 0.0447, wR2 = 0.1103
Final R indexes [all data]
R1 = 0.0524, wR2 = 0.1156
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ACCEPTED MANUSCRIPT 2.6. DFT calculations
Relative energies were computed using the wB97x-D/6-31+G(d,p) combination of functional and basis sets [19]. The geometries of the monomers, dimers and trimers were obtained from the
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crystallographic structure without any further optimization. The interaction energies between the monomers in order to form the dimers or the trimer were computed using the energy of each dimer (or trimer) subtracted by the energy of each monomer, computed as an isolated species. The final interaction energies were corrected for basis set superposition error (BSSE) using the
3. Results and Discussion
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3.1. Synthesis
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programs for molecular orbital calculations.
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counterpoise approach [20, 21]. All computations were performed using the G09 suite of
4-Fluoraniline (1) was reacted with ethyl 2-cyano-3-ethoxyacrylate (2) to afford ethyl 2cyano-3-((4-fluorophenyl)amino) acrylate (3) in 85 % yield (Fig. 2). The reaction begins with a
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rapid Michael addition, followed by the elimination of the allylic ethoxy group [22, 23]. Considering that the starting reagent (2) was a mixture of E and Z isomers, the product was also
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obtained as a mixture of E and Z isomers.
Fig. 2. Synthetic route for ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate.
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ACCEPTED MANUSCRIPT 3.2. ATR-FTIR, 1H and 13C NMR spectroscopies
The ATR-FTIR spectrum of the ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate E and Z isomers shows a characteristic and strong absorption band at 2210 cm-1, corresponding to
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ν(C≡N) (Fig. S1). The medium intensity band at 1604 cm-1 is associated with the ν(C=C) bonds. The band at 1513 cm-1 is related to δ(NH), and the ν(C–F) shows an absorption band at 1249 cm-1. The two ν(C–H) stretching vibrations of the carbon atoms vicinal to the fluorine atom are
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characterized by a strong absorption band at 827 cm-1. The ν(C=O) and ν(C–O) stretching vibrations are found at 1702 cm-1 and 1099 cm-1, respectively.
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Fig. S2 shows the 1H NMR spectrum of ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate E and Z isomers in DMSO-d6 solution. The signals were attributed based on the 2D NMR spectrum (1H x 1H-COSY, Fig. S3), aided by the computation of magnetic shielding tensors and nuclear spin-spin coupling constants. Two signals at 10.70 ppm for Z and 10.71 ppm for E are due the hydrogen from the secondary amino groups (–NH) of both isomers (Fig. S2). The
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hydrogen atom from the methylene groups of both isomers shows one doublet for E at 8.37 ppm due to the coupling of the H-6 atom to the H-1 atom from the amino group and one singlet for Z at 8.25 ppm. A multiplet at 7.42 and 7.51 ppm is related to the hydrogen atoms of the aromatic
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units adjacent to the fluorine atoms. The signal over the range of 7.20-7.22 ppm arises as a multiplet due to the aromatic hydrogens. Two quartets at 4.17-4.23 ppm and two triplets at 1.24-
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1.27 ppm for the E and Z isomers indicate the CH2 and CH3 hydrogen atoms from the ethyl groups, respectively. From 1H NMR spectrum the ratio of the Z/E isomers was 1.5:1.0. Fig. S4 shows
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C NMR spectrum of ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate E
and Z isomers. Two signals at 166.30 (C-10) and 164.67 (C-10’) ppm are due to the carbonyl groups. The two signals at 161.14 and 157.91 ppm are a doublet related to the carbon atoms C-4 and C-4' coupled to adjacent fluorine atoms exhibiting JC-F = 10.5 Hz for C-4 and JC-F = 9.0 Hz for C-4’. The carbon atoms from the double bond C-7 and C-7’ are signed at 153.90 and 152.95 ppm. Two signals at 136.30 and 135.47 ppm refer to the carbon atoms adjacent to de amino
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ACCEPTED MANUSCRIPT groups (C-1 and C-1’, in this order). The equivalent C-2/C-6 and C-2’/C-6’ aromatic carbon atoms are signed at 120.14 and 120.04 ppm. The cyano group carbons (C-9 and C-9’) are signed at 118.15 and 115.87 ppm. The equivalent C-3/C-5 and C-3’/C-5’ aromatic carbon atoms are signed at 116.32 and 116.02 ppm, respectively. Two signals at 74.58 and 73.53 ppm are related
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to olefinic carbons C-8 and C-8’, respectively. The signals at 60.41 and 60.52 ppm are assigned to methylenic carbons (C-11 and C-11’, in this order) and the signals at 14.33 and 14.24 ppm
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were attributed to methylic carbons C-12 and C-12’, respectively.
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3.3. Structural description
Two types of needle-shaped crystals measuring approximately 0.02 mm and 0.06 mm in thickness were isolated from the solution, Fig. 3a. The refined structure of the thickest crystals (measuring approximately 0.06 mm) revealed the Z isomer (Fig. 3b). The crystallization conditions (solvent, temperature and solution concentration) were changed in an attempt to
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obtain better single crystals of the E isomer than that obtained in methanol, however, without success.
The Z isomer crystallizes in monoclinic space group P21/c with an antiperiplanar
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conformation and four molecules in the unit cell (Z = 4) (Table 1). The ORTEP view of the Z isomer (Fig. 3b) shows that the cyano group is on the opposite side of the amino group, which is
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stabilized by intramolecular hydrogen bonding between the hydrogen from the amino group and the oxygen of the carbonyl group (N1–H···O1, interaction I) with N···O distance of 2.710(2) Å (Fig. 3b and Table 2).
The conjugated system formed by the amino, methylene and carbonyl groups is in the same plane, whereas the phenyl ring is slightly twisted, and the ethyl group is out of the plane, forming a torsion angle of -81.66(2)° (measured between C12–C11–O2–C10, Fig. S5). The most important intermolecular interactions indicated by the crystallographic data and the Hirshfeld surface analysis for the ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate Z isomer are
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ACCEPTED MANUSCRIPT C7–H7···N2 and C6–H6···N2 (interactions II and III) (Fig. 4a and Table 2), C12–H12B···O1 (interaction IV) (Fig. 5a and Table 2), C2–H2···F1 (interaction V) (Fig. 6 and Table 2) and π─π stacking interactions between the phenyl ring and the methylene double bond (interaction VI) (Fig. 5a and Table 3) may also contribute to the stabilization of the supramolecular network.
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surface analysis (section 3.4) and DFT calculations (section 3.5).
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The contribution of each interaction to the network will be further discussed using Hirshfeld
(a)
(b)
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Fig. 3. (a) Single crystals and (b) ORTEP representation of (Z)-ethyl 2-cyano-3-((4fluorophenyl)amino) acrylate showing the intramolecular hydrogen bond (I) between the
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hydrogen from the amino group and the oxygen from the carbonyl group.
Interactions II and III are responsible for the supramolecular network connectivity (Fig. 4 and
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Table 2). The N2 of the cyano group simultaneously interacts with the H7 atom of the methylene moiety (interaction II C7–H7···N2) and the H6 atom of the phenyl ring (interaction III C6–H6···N2), which are both from an adjacent molecule (Fig. 4a and Table 2). Interaction II results in a 10 supramolecular synthon (highlighted in blue), whereas interactions II and III result in a 7 supramolecular synthon (highlighted in gray) (Fig. 4).
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(a)
(b)
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10 and 7 and (b) the supramolecular network.
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Fig. 4. (a) Interactions II and III forming a dimer and the resulting supramolecular synthons
The short contact IV involves the terminal hydrogen atom of the ethyl group and the O1 atom of the carbonyl group (C12–H12B···O1) (Fig. 5a and Table 2). The C⋯C contact (interaction VI) associated to π⋯π stacking interaction between the phenyl ring and the
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methylene double bond shows C7-to-centroid distance of 3.366(2) Å and C8-to-centroid distance of 3.686(2) Å (Fig. 5a and Table 3). Both interactions are responsible for the stacking
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of the zigzag chains throughout the supramolecular network (Fig. 5b).
(a)
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Fig. 5. (a) Representation of interactions IV and VI. (b) The resultant stacking of the zigzag arrangement of the chains.
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ACCEPTED MANUSCRIPT Interaction V is formed between the F1 atom and the H2 atom from the phenyl ring (C2–
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H2···F1) (Fig. 6 and Table 2).
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Fig. 6. Representation of interaction V.
Type of d (D–H···A) interaction
I
N1–H1···O1
II
C7–H7···N2i
III
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Table 2 Hydrogen bonds and short contacts [distances are given in Å and angles in °]. d (D–H)a
Angle d (D···A)c (D–H···A)
2.043
2.710(2)
131.78
0.950
2.390
3.323(2)
167.37
C6–H6···N2i
0.950
2.693
3.631(3)
169.23
IV
C12–H12B···Oii
0.980
2.391
3.310(2)
155.89
V
C2–H2···F1iii
0.950
2.566
3.307(7)
135.03
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0.880
d (H···A)b
Symmetry codes for: (i) 2-x, 1-y, 1-z; (ii) -1+x, y, z; (iii) 1+x, 1.5-y, 1/2+z a
Distance between the donor atom and the hydrogen atom.
b
Distance between the acceptor atom and the hydrogen atom.
c
Distance between the donor atom and the acceptor atom. 13
ACCEPTED MANUSCRIPT Table 3 Parameters of the π⋯π interaction [Å, °]. Interaction VI
C7···Cg
C8···Cg
C7–C8···Cg
C8-C7···Cg1iii
3.366(2)
3.686(2)
92.16(10)
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3.4. Hirshfeld surface analysis
In order to understand the nature of the described noncovalent interactions in the supramolecular network of the (Z)-ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate, we
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performed a Hirshfeld surface analysis [12, 24, 25, 26, 27, 28]. The Hirshfeld surfaces can identify and quantify the intermolecular interactions. The dnorm surface is the distance in terms
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of de (the distance from the Hirshfeld surface to the nearest atom outside the surface) and di (distance from the Hirshfeld surface to the nearest atom inside the surface). Fig. 7 shows the dnorm surfaces of the interactions II, III, IV, V and VI (Tables 2 and 3). Interactions II and IV can be seen as deep red spots corresponding to strong C7–H7···N2 and
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C12–H12B···O1 hydrogen bonds, respectively. The interaction II is due to the nitrogen of the cyano group interacting with the hydrogen atom of the methylene moiety (Fig. 4a and Table 2). The interaction IV is due the terminal hydrogen atom of the ethyl group and oxygen atom of the
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carbonyl group (Fig. 5a and Table 2). The result of the dnorm surface is in agreement with the corresponding H···A distances for the interactions II and IV (Table 2). The dnorm surface (Fig. 7)
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shows small red spots corresponding to weak C6–H6···N2 (interaction III) and C2–H2···F1 (interaction V) hydrogen bonds. The latter interaction is associated with the fluorophenyl moiety. The C8–C7···Cg1 (interactions VI) are indicated as a white area in the dnorm surface due to C···C contacts related to π···π stacking interactions (Fig. 7). The pattern of adjacent red and blue triangles on the shape index surfaces confirms the presence of π···π stacking interactions between the phenyl ring and the methylene double bond (Fig. 8a and b). The curvedness surfaces show large and flat green areas at the same side of the molecule, which also confirm the π···π stacking interactions (Fig. 8c and d).
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(a)
(b)
Fig. 7. Views of the Hirshfeld surfaces in two orientations for (Z)-ethyl 2-cyano-3-((4-
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fluorophenyl)amino) acrylate. (b) The surface in (a) was rotated by 180° around the vertical axis
(c)
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of the plot.
(b)
(d)
Fig. 8. Hirshfeld surfaces mapped with shape index (a and b) and curvedness (c and d). The surfaces (a) and (b) were rotated by 180° around the vertical axis of the plot resulting in the surfaces (c) and (d).
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ACCEPTED MANUSCRIPT The 2D fingerprint plot of the main intermolecular contacts is shown in Fig. 9. Two pairs of spikes centered near (de + di) sum of approximately 2.2 and 2.3 Å correspond to C7–H7···N2 (interaction II) and C12–H12B···O1 (interaction IV) hydrogen bonds, respectively. Another pair of spikes centered near (de + di) sum of approximately 2.4 Å corresponds to weak C2–H2···F1
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near the center of the fingerprint plot at approximately (de, di) 1.8 Å.
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(interaction V) hydrogen bond. The π⋯π interactions (interactions VI) show up as a green area
Fig. 9. 2D fingerprint plots highlighting the main intermolecular interactions for (Z)-ethyl 2-
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cyano-3-((4-fluorophenyl)amino) acrylate.
The interactions II and III contribute 16.4 % to the total Hirshfeld surface (Fig. S6a). The interaction IV has also a relatively significant contribution of 12.6 % to the total Hirshfeld surface (Fig. S6b). The C2─H2···F1 (V) interaction contributes 12.2 % to the total Hirshfeld surface (Fig. S6c). The π⋯π interactions (VI) contribute 4.7 % to the total Hirshfeld surface (Fig. S6d). The full 2D fingerprint plot shows that all these interactions contribute 45.9% to the total Hirshfeld surfaces (Fig. 9).
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ACCEPTED MANUSCRIPT 3.5. DFT Studies
In an attempt to quantify the intensity of some of the intermolecular interactions revealed by the Hirshfeld surfaces, a set of calculations using the DFT approach was performed. Firstly, we
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considered the interactions II and III, identified in the Hirshfeld surface, as the most relevant for the maintenance of the supramolecular connectivity. Fig. 4a clearly shows the structure of a dimer, connected by the highlighted interactions. The interaction energy computed for this dimer revealed a value of -14.6 kcal mol-1 (after correction for BSSE). Although it was not
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possible to individually quantify interactions II and III, our results show that these interactions are sufficiently strong to maintain the connectivity of the network. The second type of
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interaction revealed by the Hirshfeld surface (interaction IV) is shown in Fig. 5a, in which a dimer can also clearly be seen. Computation of the interaction energy for this dimer also revealed a significant energy of -10.4 kcal mol-1 (after correction for BSSE). The Hirshfeld surface suggested that the main interaction point in this part of the supramolecular network is
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between the ethyl group of one monomer and the carbonyl group of the second monomer, as well as the π⋯π interactions involving the phenyl ring and the methylene double bond (interaction VI).
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For the purpose of quantify the contribution of each individual interaction (interactions IV and VI) on the maintenance of the supramolecular structure, the dimer was divided into two
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pieces, as represented in Fig. 5a; one containing the aromatic system, the amino and the double bond with the cyano group (Fig. S7a), while the second containing the ethyl ester group (Fig. S7b). Computation of the interaction energies between each subunit revealed an energy value of -6.6 kcal mol-1 for the interaction VI and -0.9 kcal mol-1 for interaction IV. An investigation of the supramolecular structure reveals that interactions II, III and IV are interconnected; therefore, the arrangement of a trimer can also be identified. Computation of the interaction energy for this trimer (Fig. S8) revealed interaction energy of -28.1 kcal mol-1, which is approximately 3.0 kcal mol-1 more negative than the sum of the individual contributions. This
17
ACCEPTED MANUSCRIPT extra energy might be originated from the cooperativity effects that also contribute to the stabilization of the entire structure.
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3.6. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC)
PXRD was performed to verify the purity of the Z isomer phase (Fig. 10). The experimental diffraction patterns of the Z isomer crystallized from the slow evaporation of the methanol solution containing the Z and E isomers of ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate
methanol can crystallize only the pure Z isomer.
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match the calculated pattern obtained from single crystal X-ray diffraction data. Therefore,
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The thermal stabilities of the bulk powder of the Z and E mixture and the crystal of the Z isomer were investigated using DSC (Fig. 11). Upon heating of the bulk powder of the E and Z mixture, two endothermic peaks at 121.5 °C and 135.8 °C are observed (Fig. 11). During the cooling process, only one exothermic peak at 99.5 °C is observed due to the solidification
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process (Fig. 11). The crystal of the Z isomer shows a unique sharp endothermic peak at 134.9 °C and an exothermic peak at 104.6 °C. From these results, we can conclude that the Z isomer is more stable than the E isomer because the former melts at a higher temperature (134.9 °C) than
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the latter. The presence of only one exothermic peak (99.5 °C) for the bulk powder of Z and E mixture indicates that no phase transformation of the Z to the E isomer occurred. There is no
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rotation on the C-N bond to allow the interconversion. In addition, a 1H NMR sepctrum of the sample obtained after the second heat of E and Z mixture (Fig. S9) was carried out. The result showed that the proportion of the isomers (Z/E 1.5:1.0) after the second heat in the DSC analysis did not change, thus confirming that no phase transformation of the Z to the E isomer occurred in this process. Most likely, both isomers interact with each other during the solidification process, resulting in only one peak.
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Fig. 10. PXRD of the Z isomer crystallized in methanol and the calculated pattern from the CIF
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file of the Z isomer.
Fig. 11. DSC of the bulk powder of the Z and E mixture and of the Z isomer crystal.
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ACCEPTED MANUSCRIPT 4. Conclusions
In
conclusion,
the
slow
evaporation
of
methanol
from
ethyl
2-cyano-3-((4-
fluorophenyl)amino) acrylate as a mixture of E and Z isomers yields only high quality single
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crystals of the Z isomer for X-ray diffraction analysis. The Z isomer crystals consist of a threedimensional supramolecular network stabilized by a combination of C–H···N, C–H···O, C–H···F and π···π interactions. DFT calculations show that the strongest interaction is C–H···N with
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energy of -14.6 kcal mol-1, which indicates that this interaction contributes more significantly than the other interactions to the stabilization of the network. Hirshfeld surfaces, 2D fingerprint
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plot and DFT calculations show that the π···π interactions also contribute to the stabilization of the supramolecular network. Thus, the Z isomer of 2-cyano-3-((4-fluorophenyl)amino) acrylate, which has a higher thermal stability than the E isomer, can be easily crystallized from methanol. The results obtained in this study might have implications in crystal engineering for the design of new of coordination networks using the Z isomer of 2-cyano-3-((4-fluorophenyl)amino)
Acknowledgments
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acrylate as a building block.
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The authors would like to thank the Brazilian agencies of the National Council for Scientific and Technological Development (CNPq grant number 550572/2012-0 and research
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fellowships), the Brazilian Federal Agency for Support and Evaluation of Graduate Education (CAPES) and the Rio de Janeiro Research Foundation (FAPERJ) for their financial support. We are also grateful to Material Characterization (http://www.uff.br/lamate/) and X-Ray Diffraction (http://www.ldrx.uff.br) Multiuser Laboratories.
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ACCEPTED MANUSCRIPT Appendix A. Supplementary data CCDC 1447701 contains the supplementary crystallographic data for (Z)-ethyl 2-cyano-3-((4fluorophenyl)amino) acrylate. These data can be obtained free of charge from the Cambridge
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Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif.
Appendix B. Supplementary data
Supplementary data related to this article can be found at http://dx.doi.org/
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References
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[6] T.-H. Chen, W. Kaveevivitchai, A. J. Jacobson, O. Š. Miljanić, Chem. Commun. 51 (2015)
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[7] APEX2, Bruker AXS Inc. Madison, Wisconsin, USA, 2014. [8] G. M. Sheldrick, Acta Crystallogr. A 64 (2008) 112–122. [9] O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K. Howard, H. Puschmann, J. Appl. Cryst. 42 (2009) 339–341.
[10] C. F. Macrae, P. R. Edgington, P. McCabe, E. Pidcock, G. P. Shields, R. Taylor, M. Towler, J. van de Streek, J. Appl. Cryst. 39 (2006) 453–457. [11] J. J. McKinnon, D. Jayatilaka, M. A. Spackman, Chem. Commun. (2007) 3814–3816. [12] M. A. Spackman, D. Jayatilaka, CrystEngComm. 11 (2009) 19–32. 21
ACCEPTED MANUSCRIPT [13] M. A. Spackman, Phys. Scr. 87 (2013) 1–12. [14] J. J. McKinnon, M. A. Spackman, A. S. Mitchell, Acta Crystallogr., Sect. B: Struct. Sci. 60 (2004) 627–668. [15] S. K. Wolff, D. J. Grimwood, J. J. McKinnon, M. J. Turner, D. Jayatilaka, M. A.
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[18] P. Manna, S. K. Seth, A. Das, J. Hemming, R. Prendergast, M. Helliwell, S. R. Choudhury, A. Frontera, S. Mukhopadhyay, Inorg. Chem. 51 (2012) 3557–3571.
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ACCEPTED MANUSCRIPT Highlights • The (Z)-ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate isomer was crystallized. • The extended network of the isomer was investigated. • Hirshfeld surface analysis and DFT studies of the extended network were carried
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out.
S0022-2860(16)30479-3
DOI:
10.1016/j.molstruc.2016.05.033
Reference:
MOLSTR 22547
To appear in:
Journal of Molecular Structure
Received Date: 22 January 2016 Revised Date:
7 April 2016
Accepted Date: 11 May 2016
Please cite this article as: C.R.M.O. Matos, L.S. Vitorino, P.H.R. de Oliveira, M.C.B.V. de Souza, A.C. Cunha, F.d.C.S. Boechat, J.A.L.C. Resende, J.W.d.M. Carneiro, C.M. Ronconi, Supramolecular assembly of (Z)-ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate, crystal structure, Hirshfeld surface analysis and DFT studies, Journal of Molecular Structure (2016), doi: 10.1016/j.molstruc.2016.05.033. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
Supramolecular assembly of (Z)-ethyl 2-cyano-3-((4fluorophenyl)amino) acrylate, crystal structure, Hirshfeld surface analysis and DFT studies
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Catiúcia R. M. O. Matos, Letícia S. Vitorino, Pedro H. R. de Oliveira, Maria Cecília B. V. de Souza, Anna C. Cunha, Fernanda da C. S. Boechat, Jackson A. L. C. Resende, José Walkimar de M. Carneiro, Célia M. Ronconi*
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Instituto de Química, Universidade Federal Fluminense, Outeiro de São João Batista,
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s/n, Campus do Valonguinho, Centro, 24020-141, Niterói, RJ, Brazil.
Corresponding authors: Célia M. Ronconi
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E-mail: [email protected] Phone: +55 21 26292164 Fax: +55 21 26292129
1
ACCEPTED MANUSCRIPT Abstract
A mixture of the E and Z isomers of ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate was synthesized and characterized by elemental analysis, attenuated total reflectance-Fourier 13
C nuclear magnetic resonance spectroscopy. The
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transform infrared spectroscopy, 1H and
structure of the Z isomer was determined by single crystal X-ray diffraction, which revealed a three-dimensional supramolecular network governed by C–H···N, C–H···O, and C–H···F hydrogen bonds and π···π stacking interactions. The combination of these interactions plays an
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important role in stabilizing the self-assembly process and the molecular conformation. Hirshfeld surface analysis indicated the roles of the noncovalent interactions in the crystal
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packing, which were quantified by fingerprint plots and DFT calculations.
Keywords: ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate E and Z isomers, noncovalent
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interactions, crystal structure, Hirshfeld surface analysis, DFT studies
1. Introduction
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Monofluorinated anilinomethylidene derivatives are building blocks for the synthesis of a variety of fluoroquinolones, which are compounds with broad-spectrum activity against
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pathogenic bacteria and commonly used for the clinical treatment of various infectious diseases [1, 2]. Particularly, ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate molecule is a versatile reagent for the synthesis of quinoline-3-carbonitrile derivatives, has been evaluated for its antitumor activity as well as for the treatment of rheumatoid arthritis [3, 4]. Ethyl 2-cyano-3-((4fluorophenyl)amino) acrylate can be easily synthesized as a mixture of E and Z isomers (Fig. 1) by alkylation of 4-fluoroaniline with ethyl 2-cyano-3-ethoxyacrylate through Michael additionelimination [3, 4]. During our investigation on the coordination properties of cyano compounds [5], we identified that ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate might be an interesting ligand 2
ACCEPTED MANUSCRIPT due its
several coordination groups, thus making it potentially useful in the field of
coordination chemistry. This compound is also an interesting tecton, containing hydrogen donor and acceptor atoms in which the molecules can interact with one another by noncovalent interactions. Understanding the interactions among these tectons may generate new
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supramolecular synthons, which might be used to assemble more complex aggregates with new properties [6].
Therefore, as part of our ongoing project aiming to understand the structural features of cyano compounds [5], we synthesized and characterized Z and E isomers of ethyl 2-cyano-3-
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((4-fluorophenyl)amino) acrylate. However, the structural characterization was only performed for the Z isomer because the E isomer did not provide high quality single crystals. An
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investigation of intermolecular interactions between the molecules of the Z isomer in the solid state by Hirshfeld surface analysis and 2D fingerprint plots were carried out in order to show the contribution of the short contacts for the stabilization of the extended network. DFT calculations were employed to quantify the energies of the noncovalent interactions present in the crystal
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structure.
Fig. 1. E and Z isomers of ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate.
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ACCEPTED MANUSCRIPT 2. Experimental section
2.1. Materials and Methods
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The following chemicals were used without further purification: 4-fluoraniline (Acros Organics), ethyl 2-cyano-3-ethoxyacrylate (Sigma-Aldrich), ethanol (Vetec) and methanol (Vetec). The percentage of carbon, nitrogen and hydrogen were determined using a Perkin Elmer CHN 2400 analyzer at the Analytical Center of the Institute of Chemistry, University of
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São Paulo, Brazil. The melting point was evaluated using a Fisher-Johns melting point apparatus. The 1H and 13C NMR spectra were recorded on a Varian VNMRS instrument at 500
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MHz and 75 MHz respectively, using residual solvents as internal standards. Samples were prepared using DMSO-d6 purchased from Cambridge Isotope Laboratories. The attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectrum of the ethyl 2-cyano-3-((4fluorophenyl)amino) acrylate E and Z isomers was obtained on a Varian FT-IR 660
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spectrometer. The DSC analyses were performed on a Shimadzu DSC-60 instrument in the heating/cooling range of 30-150 ºC at a rate of 5 °C/min, with an aluminum pan. Powder X-ray diffraction (XRD) measurements were carried out on a D8 ADVANCE diffractometer (Bruker)
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at 298 K with CuKα radiation (λ = 1.5406 Å). The scanning rate was fixed at 0.2 degrees/s with
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a step size of 0.02° with 2θ ranges from 5° to 50° for phase identification.
2.2. Synthesis of the ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate E and Z isomers
A mixture of 4-fluoraniline (1 mL, 10 mmol) and ethyl 2-cyano-3-ethoxyacrylate (1.69 g, 10 mmol) was dissolved in 10 mL of ethanol and stirred under reflux for 2 h. The mixture was allowed to cool and then it was poured into ice-cold water. The precipitate was collected by filtration and recrystallized with hexane. The ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate was obtained as a mixture of E and Z isomers (85 % yield); m.p.: 122 °C; (ATR-FTIR) ν(cm-1): 2210 (s), 1702 (m), 1679 (m), 1629 (m), 1604 (m), 1513 (s), 1380 (m), 1249 (w), 1213 (s), 1174 4
ACCEPTED MANUSCRIPT (m), 1147 (m), 1099 (s), 987 (m), 827 (s), 781 (s), 755 (m), (s = strong, m = medium, w = weak). 1H NMR (500 MHz, 298 K, DMSO-d6) δ E isomer: 10.71 (d, J = 15 Hz, 1H, –NH), 8.37 (d, J = 15 Hz, 1H, Hβ), 7.52 (dt, J = 9.0 and 6.0 Hz, 2H, H-3 and H-5), 7.22 (dd, J = 9.0 Hz, 2H, H-2 and H-6), 4.23 (q, J = 9.0 Hz, 2H, CH2CH3), 1.27 (t, J = 9.0 Hz, 3H, CH2CH3) ppm. Z
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isomer: 10.70 (s, 1H, –NH), 8.26 (s, 1H, Hβ), 7.42 (dd, J = 9.0 and 6.0 Hz, 2H, H-3' and H-5'), 7.21 (dd, J = 9.0 Hz, 2H, H-2' and H-6'), 4.18 (q, J = 6.0 Hz, 2H, CH2CH3), 1.24 (t, J = 6.0 Hz, 3H, CH2CH3) ppm. 13C NMR (75 MHz, 308 K, DMSO-d6) δ E isomer: 166.30 (s, CO), 161.14 (d, JC-F = 10.5 Hz, C-4), 153.90 (s, –CH=), 136.30 (s, C-1), 120.14 (s, C-2, C-6), 115.87 (s, CN),
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116.32 (d, JC-F = 3.0 Hz, C-3, C-5), 74.58 (s, C-8), 60.41 (s, CH2CH3), 14.33 (s, CH2CH3) ppm. Z isomer: 164.67 (s, CO), 157.91 (d, JC-F = 9.0 Hz, C-4’), 152.95 (s, –CH=), 135.44 (s, C-1’),
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120.04 (s, C-2’, C-6’), 118.15(s, CN), 116.02 (d, JC-F = 3.75 Hz, C-3’, C-5’), 73.53 (s, C-8’), 60.52 (s, CH2CH3), 14.24 (s, CH2CH3) ppm. Elemental analysis calculated for C12H11FN2O2: C 61.53 %, H 4.73 %, N 11.96 %; experimentally determined: C 61.74 %, H 4.90 %, N 11.45 %.
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2.3. Crystallization of (Z) ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate
Ethyl 2-cyano-3-(4 fluorophenylamino) acrylate as a mixture of the Z and E isomers (mass,
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0.0556 mmol) was dissolved in 8 mL of methanol. After slow evaporation of the solvent at room temperature, colorless needle-shaped crystals of both isomers were formed (Fig. 3a).
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However, only the Z isomer provided high quality single crystals for the X-ray diffraction analysis.
2.4. X-ray data collection and structure refinement
The crystal and refinement data for (Z) ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate are listed in Table 1. Single crystal X-ray diffraction data of the colorless crystal of (Z) ethyl 2cyano-3-((4-fluorophenyl)amino) acrylate were collected at 150.02 K on a Bruker D8 Venture diffractometer equipped with monochromatic Mo Kα radiation. The data collection and cell 5
ACCEPTED MANUSCRIPT refinement were performed using APEX 2 [7] and the structure solutions and refinements were performed using XS and XL software packages [8]. The structure was solved by direct methods and refined with full-matrix least-squares techniques on F2. The structure of all non-hydrogen atoms was refined anisotropically, and all hydrogen atoms were placed in their calculated
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positions and then refined using the riding model. The molecular graphics were computed in
Mercury 3.5 [10].
2.5. Hirshfeld surface computational method
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Olex2 [9] and the figures were prepared and analyzed using licensed Crystal Maker 9.2.2 and
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Hirshfeld surfaces and their related 2-D fingerprint plots [11], [12], [13], [14] were obtained using Crystal Explorer 3.1 software [15]. The dnorm (normalized contact distance) surface and the breakdown of the 2-D fingerprint plots were used to decode and quantify the intermolecular interactions in the crystal lattice [16], [17], [18]. The dnorm is a symmetric function of distances
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to the surface from the nuclei inside and outside the Hirshfeld surface (di and de, respectively), relative to their respective van der Waals radii (rvdW). The value of dnorm is negative or positive if the intermolecular contacts are shorter or longer
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than the rvdW, respectively. The dnorm Hirshfeld surfaces are presented using red–white–blue color scheme. A color scale of red highlights shorter separations than the rvdW, white is used for
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separations around the rvdW , and blue indicates longer separations than the rvdW.
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ACCEPTED MANUSCRIPT Table 1 Crystal data and structure refinement for (Z) ethyl 2-cyano-3-((4-fluorophenyl)amino)
Empirical formula
C12H11FN2O2
Formula weight
234.23
Temperature/K
150.02
Crystal system
Monoclinic
Space group
P21/c
Unit cell dimensions
a = 5.1531(2) Å
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b = 20.9962(7) Å
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acrylate.
c = 10.4446(4) Å
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β = 100.502(2) °
Volume/Å3
1111.13(7)
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ρ calc./g cm–3
1.400
µ/mm–1 F(000) Crystal size/mm–3
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0.108
Index ranges
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Theta range for data collection
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Reflections collected
488.0 0.331 × 0.319 × 0.287 4.42 to 52.17 ° –6 ≤ h ≤ 6, –25 ≤ k ≤ 25, –12 ≤ l ≤ 12 14 419
Independent reflections
2202 [R(int) = 0.0297, R(sigma) = 0.0171]
Data/restraints/parameters
2202/0/155
Goodness-of-fit on F2
1.063
Final R indexes [I ≥ 2σ (I)]
R1 = 0.0447, wR2 = 0.1103
Final R indexes [all data]
R1 = 0.0524, wR2 = 0.1156
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ACCEPTED MANUSCRIPT 2.6. DFT calculations
Relative energies were computed using the wB97x-D/6-31+G(d,p) combination of functional and basis sets [19]. The geometries of the monomers, dimers and trimers were obtained from the
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crystallographic structure without any further optimization. The interaction energies between the monomers in order to form the dimers or the trimer were computed using the energy of each dimer (or trimer) subtracted by the energy of each monomer, computed as an isolated species. The final interaction energies were corrected for basis set superposition error (BSSE) using the
3. Results and Discussion
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3.1. Synthesis
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programs for molecular orbital calculations.
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counterpoise approach [20, 21]. All computations were performed using the G09 suite of
4-Fluoraniline (1) was reacted with ethyl 2-cyano-3-ethoxyacrylate (2) to afford ethyl 2cyano-3-((4-fluorophenyl)amino) acrylate (3) in 85 % yield (Fig. 2). The reaction begins with a
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rapid Michael addition, followed by the elimination of the allylic ethoxy group [22, 23]. Considering that the starting reagent (2) was a mixture of E and Z isomers, the product was also
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obtained as a mixture of E and Z isomers.
Fig. 2. Synthetic route for ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate.
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ACCEPTED MANUSCRIPT 3.2. ATR-FTIR, 1H and 13C NMR spectroscopies
The ATR-FTIR spectrum of the ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate E and Z isomers shows a characteristic and strong absorption band at 2210 cm-1, corresponding to
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ν(C≡N) (Fig. S1). The medium intensity band at 1604 cm-1 is associated with the ν(C=C) bonds. The band at 1513 cm-1 is related to δ(NH), and the ν(C–F) shows an absorption band at 1249 cm-1. The two ν(C–H) stretching vibrations of the carbon atoms vicinal to the fluorine atom are
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characterized by a strong absorption band at 827 cm-1. The ν(C=O) and ν(C–O) stretching vibrations are found at 1702 cm-1 and 1099 cm-1, respectively.
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Fig. S2 shows the 1H NMR spectrum of ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate E and Z isomers in DMSO-d6 solution. The signals were attributed based on the 2D NMR spectrum (1H x 1H-COSY, Fig. S3), aided by the computation of magnetic shielding tensors and nuclear spin-spin coupling constants. Two signals at 10.70 ppm for Z and 10.71 ppm for E are due the hydrogen from the secondary amino groups (–NH) of both isomers (Fig. S2). The
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hydrogen atom from the methylene groups of both isomers shows one doublet for E at 8.37 ppm due to the coupling of the H-6 atom to the H-1 atom from the amino group and one singlet for Z at 8.25 ppm. A multiplet at 7.42 and 7.51 ppm is related to the hydrogen atoms of the aromatic
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units adjacent to the fluorine atoms. The signal over the range of 7.20-7.22 ppm arises as a multiplet due to the aromatic hydrogens. Two quartets at 4.17-4.23 ppm and two triplets at 1.24-
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1.27 ppm for the E and Z isomers indicate the CH2 and CH3 hydrogen atoms from the ethyl groups, respectively. From 1H NMR spectrum the ratio of the Z/E isomers was 1.5:1.0. Fig. S4 shows
13
C NMR spectrum of ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate E
and Z isomers. Two signals at 166.30 (C-10) and 164.67 (C-10’) ppm are due to the carbonyl groups. The two signals at 161.14 and 157.91 ppm are a doublet related to the carbon atoms C-4 and C-4' coupled to adjacent fluorine atoms exhibiting JC-F = 10.5 Hz for C-4 and JC-F = 9.0 Hz for C-4’. The carbon atoms from the double bond C-7 and C-7’ are signed at 153.90 and 152.95 ppm. Two signals at 136.30 and 135.47 ppm refer to the carbon atoms adjacent to de amino
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ACCEPTED MANUSCRIPT groups (C-1 and C-1’, in this order). The equivalent C-2/C-6 and C-2’/C-6’ aromatic carbon atoms are signed at 120.14 and 120.04 ppm. The cyano group carbons (C-9 and C-9’) are signed at 118.15 and 115.87 ppm. The equivalent C-3/C-5 and C-3’/C-5’ aromatic carbon atoms are signed at 116.32 and 116.02 ppm, respectively. Two signals at 74.58 and 73.53 ppm are related
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to olefinic carbons C-8 and C-8’, respectively. The signals at 60.41 and 60.52 ppm are assigned to methylenic carbons (C-11 and C-11’, in this order) and the signals at 14.33 and 14.24 ppm
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were attributed to methylic carbons C-12 and C-12’, respectively.
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3.3. Structural description
Two types of needle-shaped crystals measuring approximately 0.02 mm and 0.06 mm in thickness were isolated from the solution, Fig. 3a. The refined structure of the thickest crystals (measuring approximately 0.06 mm) revealed the Z isomer (Fig. 3b). The crystallization conditions (solvent, temperature and solution concentration) were changed in an attempt to
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obtain better single crystals of the E isomer than that obtained in methanol, however, without success.
The Z isomer crystallizes in monoclinic space group P21/c with an antiperiplanar
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conformation and four molecules in the unit cell (Z = 4) (Table 1). The ORTEP view of the Z isomer (Fig. 3b) shows that the cyano group is on the opposite side of the amino group, which is
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stabilized by intramolecular hydrogen bonding between the hydrogen from the amino group and the oxygen of the carbonyl group (N1–H···O1, interaction I) with N···O distance of 2.710(2) Å (Fig. 3b and Table 2).
The conjugated system formed by the amino, methylene and carbonyl groups is in the same plane, whereas the phenyl ring is slightly twisted, and the ethyl group is out of the plane, forming a torsion angle of -81.66(2)° (measured between C12–C11–O2–C10, Fig. S5). The most important intermolecular interactions indicated by the crystallographic data and the Hirshfeld surface analysis for the ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate Z isomer are
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ACCEPTED MANUSCRIPT C7–H7···N2 and C6–H6···N2 (interactions II and III) (Fig. 4a and Table 2), C12–H12B···O1 (interaction IV) (Fig. 5a and Table 2), C2–H2···F1 (interaction V) (Fig. 6 and Table 2) and π─π stacking interactions between the phenyl ring and the methylene double bond (interaction VI) (Fig. 5a and Table 3) may also contribute to the stabilization of the supramolecular network.
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surface analysis (section 3.4) and DFT calculations (section 3.5).
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The contribution of each interaction to the network will be further discussed using Hirshfeld
(a)
(b)
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Fig. 3. (a) Single crystals and (b) ORTEP representation of (Z)-ethyl 2-cyano-3-((4fluorophenyl)amino) acrylate showing the intramolecular hydrogen bond (I) between the
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hydrogen from the amino group and the oxygen from the carbonyl group.
Interactions II and III are responsible for the supramolecular network connectivity (Fig. 4 and
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Table 2). The N2 of the cyano group simultaneously interacts with the H7 atom of the methylene moiety (interaction II C7–H7···N2) and the H6 atom of the phenyl ring (interaction III C6–H6···N2), which are both from an adjacent molecule (Fig. 4a and Table 2). Interaction II results in a 10 supramolecular synthon (highlighted in blue), whereas interactions II and III result in a 7 supramolecular synthon (highlighted in gray) (Fig. 4).
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(a)
(b)
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10 and 7 and (b) the supramolecular network.
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Fig. 4. (a) Interactions II and III forming a dimer and the resulting supramolecular synthons
The short contact IV involves the terminal hydrogen atom of the ethyl group and the O1 atom of the carbonyl group (C12–H12B···O1) (Fig. 5a and Table 2). The C⋯C contact (interaction VI) associated to π⋯π stacking interaction between the phenyl ring and the
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methylene double bond shows C7-to-centroid distance of 3.366(2) Å and C8-to-centroid distance of 3.686(2) Å (Fig. 5a and Table 3). Both interactions are responsible for the stacking
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of the zigzag chains throughout the supramolecular network (Fig. 5b).
(a)
(b)
Fig. 5. (a) Representation of interactions IV and VI. (b) The resultant stacking of the zigzag arrangement of the chains.
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H2···F1) (Fig. 6 and Table 2).
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Fig. 6. Representation of interaction V.
Type of d (D–H···A) interaction
I
N1–H1···O1
II
C7–H7···N2i
III
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Table 2 Hydrogen bonds and short contacts [distances are given in Å and angles in °]. d (D–H)a
Angle d (D···A)c (D–H···A)
2.043
2.710(2)
131.78
0.950
2.390
3.323(2)
167.37
C6–H6···N2i
0.950
2.693
3.631(3)
169.23
IV
C12–H12B···Oii
0.980
2.391
3.310(2)
155.89
V
C2–H2···F1iii
0.950
2.566
3.307(7)
135.03
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0.880
d (H···A)b
Symmetry codes for: (i) 2-x, 1-y, 1-z; (ii) -1+x, y, z; (iii) 1+x, 1.5-y, 1/2+z a
Distance between the donor atom and the hydrogen atom.
b
Distance between the acceptor atom and the hydrogen atom.
c
Distance between the donor atom and the acceptor atom. 13
ACCEPTED MANUSCRIPT Table 3 Parameters of the π⋯π interaction [Å, °]. Interaction VI
C7···Cg
C8···Cg
C7–C8···Cg
C8-C7···Cg1iii
3.366(2)
3.686(2)
92.16(10)
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3.4. Hirshfeld surface analysis
In order to understand the nature of the described noncovalent interactions in the supramolecular network of the (Z)-ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate, we
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performed a Hirshfeld surface analysis [12, 24, 25, 26, 27, 28]. The Hirshfeld surfaces can identify and quantify the intermolecular interactions. The dnorm surface is the distance in terms
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of de (the distance from the Hirshfeld surface to the nearest atom outside the surface) and di (distance from the Hirshfeld surface to the nearest atom inside the surface). Fig. 7 shows the dnorm surfaces of the interactions II, III, IV, V and VI (Tables 2 and 3). Interactions II and IV can be seen as deep red spots corresponding to strong C7–H7···N2 and
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C12–H12B···O1 hydrogen bonds, respectively. The interaction II is due to the nitrogen of the cyano group interacting with the hydrogen atom of the methylene moiety (Fig. 4a and Table 2). The interaction IV is due the terminal hydrogen atom of the ethyl group and oxygen atom of the
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carbonyl group (Fig. 5a and Table 2). The result of the dnorm surface is in agreement with the corresponding H···A distances for the interactions II and IV (Table 2). The dnorm surface (Fig. 7)
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shows small red spots corresponding to weak C6–H6···N2 (interaction III) and C2–H2···F1 (interaction V) hydrogen bonds. The latter interaction is associated with the fluorophenyl moiety. The C8–C7···Cg1 (interactions VI) are indicated as a white area in the dnorm surface due to C···C contacts related to π···π stacking interactions (Fig. 7). The pattern of adjacent red and blue triangles on the shape index surfaces confirms the presence of π···π stacking interactions between the phenyl ring and the methylene double bond (Fig. 8a and b). The curvedness surfaces show large and flat green areas at the same side of the molecule, which also confirm the π···π stacking interactions (Fig. 8c and d).
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(a)
(b)
Fig. 7. Views of the Hirshfeld surfaces in two orientations for (Z)-ethyl 2-cyano-3-((4-
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fluorophenyl)amino) acrylate. (b) The surface in (a) was rotated by 180° around the vertical axis
(c)
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of the plot.
(b)
(d)
Fig. 8. Hirshfeld surfaces mapped with shape index (a and b) and curvedness (c and d). The surfaces (a) and (b) were rotated by 180° around the vertical axis of the plot resulting in the surfaces (c) and (d).
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ACCEPTED MANUSCRIPT The 2D fingerprint plot of the main intermolecular contacts is shown in Fig. 9. Two pairs of spikes centered near (de + di) sum of approximately 2.2 and 2.3 Å correspond to C7–H7···N2 (interaction II) and C12–H12B···O1 (interaction IV) hydrogen bonds, respectively. Another pair of spikes centered near (de + di) sum of approximately 2.4 Å corresponds to weak C2–H2···F1
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near the center of the fingerprint plot at approximately (de, di) 1.8 Å.
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(interaction V) hydrogen bond. The π⋯π interactions (interactions VI) show up as a green area
Fig. 9. 2D fingerprint plots highlighting the main intermolecular interactions for (Z)-ethyl 2-
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cyano-3-((4-fluorophenyl)amino) acrylate.
The interactions II and III contribute 16.4 % to the total Hirshfeld surface (Fig. S6a). The interaction IV has also a relatively significant contribution of 12.6 % to the total Hirshfeld surface (Fig. S6b). The C2─H2···F1 (V) interaction contributes 12.2 % to the total Hirshfeld surface (Fig. S6c). The π⋯π interactions (VI) contribute 4.7 % to the total Hirshfeld surface (Fig. S6d). The full 2D fingerprint plot shows that all these interactions contribute 45.9% to the total Hirshfeld surfaces (Fig. 9).
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ACCEPTED MANUSCRIPT 3.5. DFT Studies
In an attempt to quantify the intensity of some of the intermolecular interactions revealed by the Hirshfeld surfaces, a set of calculations using the DFT approach was performed. Firstly, we
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considered the interactions II and III, identified in the Hirshfeld surface, as the most relevant for the maintenance of the supramolecular connectivity. Fig. 4a clearly shows the structure of a dimer, connected by the highlighted interactions. The interaction energy computed for this dimer revealed a value of -14.6 kcal mol-1 (after correction for BSSE). Although it was not
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possible to individually quantify interactions II and III, our results show that these interactions are sufficiently strong to maintain the connectivity of the network. The second type of
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interaction revealed by the Hirshfeld surface (interaction IV) is shown in Fig. 5a, in which a dimer can also clearly be seen. Computation of the interaction energy for this dimer also revealed a significant energy of -10.4 kcal mol-1 (after correction for BSSE). The Hirshfeld surface suggested that the main interaction point in this part of the supramolecular network is
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between the ethyl group of one monomer and the carbonyl group of the second monomer, as well as the π⋯π interactions involving the phenyl ring and the methylene double bond (interaction VI).
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For the purpose of quantify the contribution of each individual interaction (interactions IV and VI) on the maintenance of the supramolecular structure, the dimer was divided into two
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pieces, as represented in Fig. 5a; one containing the aromatic system, the amino and the double bond with the cyano group (Fig. S7a), while the second containing the ethyl ester group (Fig. S7b). Computation of the interaction energies between each subunit revealed an energy value of -6.6 kcal mol-1 for the interaction VI and -0.9 kcal mol-1 for interaction IV. An investigation of the supramolecular structure reveals that interactions II, III and IV are interconnected; therefore, the arrangement of a trimer can also be identified. Computation of the interaction energy for this trimer (Fig. S8) revealed interaction energy of -28.1 kcal mol-1, which is approximately 3.0 kcal mol-1 more negative than the sum of the individual contributions. This
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ACCEPTED MANUSCRIPT extra energy might be originated from the cooperativity effects that also contribute to the stabilization of the entire structure.
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3.6. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC)
PXRD was performed to verify the purity of the Z isomer phase (Fig. 10). The experimental diffraction patterns of the Z isomer crystallized from the slow evaporation of the methanol solution containing the Z and E isomers of ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate
methanol can crystallize only the pure Z isomer.
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match the calculated pattern obtained from single crystal X-ray diffraction data. Therefore,
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The thermal stabilities of the bulk powder of the Z and E mixture and the crystal of the Z isomer were investigated using DSC (Fig. 11). Upon heating of the bulk powder of the E and Z mixture, two endothermic peaks at 121.5 °C and 135.8 °C are observed (Fig. 11). During the cooling process, only one exothermic peak at 99.5 °C is observed due to the solidification
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process (Fig. 11). The crystal of the Z isomer shows a unique sharp endothermic peak at 134.9 °C and an exothermic peak at 104.6 °C. From these results, we can conclude that the Z isomer is more stable than the E isomer because the former melts at a higher temperature (134.9 °C) than
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the latter. The presence of only one exothermic peak (99.5 °C) for the bulk powder of Z and E mixture indicates that no phase transformation of the Z to the E isomer occurred. There is no
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rotation on the C-N bond to allow the interconversion. In addition, a 1H NMR sepctrum of the sample obtained after the second heat of E and Z mixture (Fig. S9) was carried out. The result showed that the proportion of the isomers (Z/E 1.5:1.0) after the second heat in the DSC analysis did not change, thus confirming that no phase transformation of the Z to the E isomer occurred in this process. Most likely, both isomers interact with each other during the solidification process, resulting in only one peak.
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Fig. 10. PXRD of the Z isomer crystallized in methanol and the calculated pattern from the CIF
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file of the Z isomer.
Fig. 11. DSC of the bulk powder of the Z and E mixture and of the Z isomer crystal.
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ACCEPTED MANUSCRIPT 4. Conclusions
In
conclusion,
the
slow
evaporation
of
methanol
from
ethyl
2-cyano-3-((4-
fluorophenyl)amino) acrylate as a mixture of E and Z isomers yields only high quality single
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crystals of the Z isomer for X-ray diffraction analysis. The Z isomer crystals consist of a threedimensional supramolecular network stabilized by a combination of C–H···N, C–H···O, C–H···F and π···π interactions. DFT calculations show that the strongest interaction is C–H···N with
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energy of -14.6 kcal mol-1, which indicates that this interaction contributes more significantly than the other interactions to the stabilization of the network. Hirshfeld surfaces, 2D fingerprint
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plot and DFT calculations show that the π···π interactions also contribute to the stabilization of the supramolecular network. Thus, the Z isomer of 2-cyano-3-((4-fluorophenyl)amino) acrylate, which has a higher thermal stability than the E isomer, can be easily crystallized from methanol. The results obtained in this study might have implications in crystal engineering for the design of new of coordination networks using the Z isomer of 2-cyano-3-((4-fluorophenyl)amino)
Acknowledgments
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acrylate as a building block.
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The authors would like to thank the Brazilian agencies of the National Council for Scientific and Technological Development (CNPq grant number 550572/2012-0 and research
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fellowships), the Brazilian Federal Agency for Support and Evaluation of Graduate Education (CAPES) and the Rio de Janeiro Research Foundation (FAPERJ) for their financial support. We are also grateful to Material Characterization (http://www.uff.br/lamate/) and X-Ray Diffraction (http://www.ldrx.uff.br) Multiuser Laboratories.
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ACCEPTED MANUSCRIPT Appendix A. Supplementary data CCDC 1447701 contains the supplementary crystallographic data for (Z)-ethyl 2-cyano-3-((4fluorophenyl)amino) acrylate. These data can be obtained free of charge from the Cambridge
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Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif.
Appendix B. Supplementary data
Supplementary data related to this article can be found at http://dx.doi.org/
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ACCEPTED MANUSCRIPT Highlights • The (Z)-ethyl 2-cyano-3-((4-fluorophenyl)amino) acrylate isomer was crystallized. • The extended network of the isomer was investigated. • Hirshfeld surface analysis and DFT studies of the extended network were carried
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out.