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Stereoselective green synthesis and molecular structures of highly functionalized spirooxindole-pyrrolidine hybrids – A combined experimental and theoretical investigation
Accepted Manuscript Stereoselective green synthesis and molecular structures of highly functionalized spirooxindole-pyrrolidine hybrids – A combined experimental and theoretical investigation Raju Suresh Kumar, Abdulrahman I. Almansour, Natarajan Arumugam, Saied M. Soliman, Raju Ranjith Kumar, Mohammad Altaf, Hazem A. Ghabbour, Bellie Sundaram Krishnamoorthy PII:
S0022-2860(17)31261-9
DOI:
10.1016/j.molstruc.2017.09.073
Reference:
MOLSTR 24322
To appear in:
Journal of Molecular Structure
Received Date: 18 July 2017 Revised Date:
17 September 2017
Accepted Date: 20 September 2017
Please cite this article as: R.S. Kumar, A.I. Almansour, N. Arumugam, S.M. Soliman, R.R. Kumar, M. Altaf, H.A. Ghabbour, B.S. Krishnamoorthy, Stereoselective green synthesis and molecular structures of highly functionalized spirooxindole-pyrrolidine hybrids – A combined experimental and theoretical investigation, Journal of Molecular Structure (2017), doi: 10.1016/j.molstruc.2017.09.073. 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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Graphical Abstract
Stereoselective green synthesis of new spirooxindole-pyrrolidine hybrids 4 and 6 were synthesized and their structures were confirmed by NMR spectra, X-ray crystallography and
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DFT studies. The DFT computed polarizability values suggest the possible NLO property of the
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synthesized compounds.
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4
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STEREOSELECTIVE GREEN SYNTHESIS AND MOLECULAR STRUCTURES OF HIGHLY FUNCTIONALIZED SPIROOXINDOLE-PYRROLIDINE HYBRIDS – A COMBINED EXPERIMENTAL AND THEORETICAL INVESTIGATION
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Raju Suresh Kumar,a,* Abdulrahman I. Almansour,a Natarajan Arumugam,a Saied M. Soliman,b,c Raju Ranjith Kumar,d Mohammad Altaf,e Hazem A. Ghabbourf,g, Bellie Sundaram Krishnamoorthyh* a
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Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia b Department of Chemistry, College of Science & Arts, King Abdulaziz University, P.O. Box 344, Rabigh 21911, Saudi Arabia c Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 21321, Egypt d Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, Tamil Nadu, India e Central Laboratory, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia f Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia g Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt. h Department of Chemistry, Vivekanandha College of Arts and Sciences for Women (Autonomous), Elayampalayam, Namakkal, Tamil Nadu, India. 637 205. Abstract Highly functionalized spirooxindole-pyrrolidine hybrids have been synthesized stereoselectively through a [3+2] cycloaddition strategy in an ionic liquid, 1-butyl-3-methylimidazolium bromide
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([bmim]Br). The structure of these spiro heterocyclic hybrids was elucidated using one and two dimensional NMR spectroscopy, single crystal X-ray crystallographic studies and Density
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Functional Theory (DFT) calculations. The calculated geometric parameters are in good agreement with the experimental data obtained from the X-ray structures. The Natural Bond Orbital (NBO) calculations on these molecules confirm the electron rich carbonyl oxygen and electron deficient NH groups. The 1H- and
13
C-NMR chemical shifts calculated using GIAO
method are in good agreement with the experimental data. The DFT computed polarizability values also suggest the possible NLO activity of these molecules.
*Corresponding authors: Tel: +966-4675907; fax: +966-4675992; email: [email protected], [email protected] (Suresh Kumar R), +91-9585447505 [email protected] (Krishnamoorthy B.S.)
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Keywords: [3+2] Cycloaddition, spirooxindole-pyrrolidine hybrids, Ionic liquid, X-ray crystal
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structure - DFT studies
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Introduction The development of transformations that lead to multiple bond formation in a single step has received much attention in view of the greenness of such reactions. Often these reactions
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lead to the formation of compounds that find applications in pharmaceutical and agrochemical industries [1]. [3+2] Cycloaddition reactions play a vital role in the construction of five membered structural motifs [2] and in particular, cycloaddition of azomethine ylides with olefinic dipolarophiles represent a dominant approach for the construction of five membered ring amines also known as pyrrolidines [3]. Pyrrolidines are fundamental biological scaffolds present
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in diverse natural and synthetic compounds. Functionalized pyrrolidines are prominent synthetic targets due to their extensive applications as chiral ligands [4], organocatalysts [5] and their role
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as important building blocks in organic syntheses. On the other hand, spirooxindoles have attracted significant attention due to its unique structure and pronounced biological activities [6]. The spirooxindole-pyrrolidine heterocyclic hybrids are present as a core unit in alkaloids such as horsfiline [7], coerulescine [8] and elacomine [9]. The more complex natural spirooxindole viz., spirotryprostatins has been reported to show anticancer activity [10]. In addition to the naturally occurring spirooxindoles, the synthetic derivative, MI-888 has been in preclinical research for
Synthesis
of
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the treatment of human cancers [11] (Scheme 1). complex
molecules
through
multicomponent
reactions
using
nonconventional solvents are the main target for many research groups nowadays. Ionic liquids are well known for their high chemical and thermal stability, solvating ability, behavior as acidic
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and basic catalysts and recyclability. Owing to these credentials, ionic liquids have attracted great interest as environmentally benign reaction media [12]. Hence the synthesis of biologically
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important spirooxindole-pyrrolidine heterocyclic hybrids in ionic liquid would be of interest in the context of green chemistry. Albeit the few reports available employing ionic liquid 1-butyl-3methylimidazolium bromide, [bmim]Br as the reaction medium for this kind of chemistry [13, 14], it still gains importance in comparison to others. In continuation of our profound interest towards the synthesis of novel hybrid
heterocycles [15-24], herein we report the synthesis of spirooxindole-pyrrolidine heterocyclic hybrids via the [3+2] cycloaddition of azomethine ylide generated in situ from isatin and sarcosine or phenyl glycine to (3E,5E)-1-allyl-3,5-bis(4-methoxyphenylmethylidene)piperidin-4one in [bmim]Br. The molecular structure of these synthesized compounds were confirmed by 3
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NMR spectroscopy, X-ray diffraction studies. As the characterization of these new spirooxindole-pyrrolidine heterocyclic hybrids deserve both theoretical and experimental studies, herein we also report the DFT studies performed on these hybrids to support their novel structural features. Computational studies are being used routinely and proved to be successful in
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characterizing the molecular structures in complete manner, when there are discrepancies in experimental data like disorder, twinning in crystal structure, overlap of peaks in spectra of compounds when they present as mixture of isomers, etc., during the synthesis of novel
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compounds with diverse structural features.
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Scheme 1 Selected biologically important spirooxindole-pyrrolidine heterocyclic hybrids
2. Experimental Section 2.1. Chemistry
Melting points were recorded using open capillary tubes and are uncorrected. The 1H, 13C and 2-D NMR spectra were recorded on a Bruker 400 or 500 MHz instruments (Faellanden,
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Switzerland) in CDCl3 using TMS as internal standard. Standard Bruker software was used throughout. Chemical shifts are given in parts per million (δ-scale) and the coupling constants are given in Hertz. Elemental analyses were performed on a Perkin Elmer 2400 Series II
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Elemental CHNS analyzer (Waltham, MA, USA). 2.2. Experimental procedure for the synthesis of 4
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An equimolar mixture of (3E,5E)-1-allyl-3,5-bis(4-methoxyphenylmethylidene)piperidin-4-one 1, isatin 2 and sarcosine 3 in 200 mg of [bmim]Br was heated at 100 oC for 30 minutes. After completion of the reaction as evident from TLC, water (50 mL) was added to the reaction mixture and extracted with ethyl acetate (3x30 mL). The excess solvent was evaporated under reduced pressure. The resultant solid was dried in vacuum and purified through column chromatography using hexane: ethyl acetate (3:2 v/v) as eluent to obtain 4 as colorless solid. Spiro[2.3″]oxindole-spiro[3.3′]-1′-allyl-5′-(4-methoxyphenylmethylidene)tetrahydro-4′(1H)pyridinone-4-(4-methoxyphenyl)-pyrrolidine (4) 4
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H NMR (500 MHz, CDCl3): δH 1.83 (d, 1H, J = 13.0 Hz, 2'-CH2), 2.14, (s, 3H, N-CH3), 2.69
(dd, 1H, J = 13.5, 8.0 Hz, 7'-CH2), 2.87 (dd, 1H, J = 15.0, 2.5 Hz, 6'-CH2), 3.07 (dd, 1H, J = 13.5, 2.5 Hz, 7'-CH2), 3.29 (dd, 1H, J = 12.5, 1.5 Hz, 2'-CH2), 3.31-3.35 (m, 1H, 5-CH2), 3.42 (d, 1H, J = 14.5 Hz, 6'-CH2), 3.79 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 3.90 (dd, 1H, J = 10.5, 9.0
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Hz, H-5), 4.77 (dd, 1H, J = 11.0, 7.5 Hz, H-4), 4.95–5.00 (m, 2H, 9'-CH2), 5.55–5.58 (m, 1H, H8'), 6.66 (d, 1H, J = 7.5 Hz, ArH), 6.81 (d, 2H, J = 9.0 Hz, ArH), 6.84 (d, 2H, J = 8.5 Hz, ArH), 6.92 (t, 1H, J = 8.0 Hz, ArH), 7.04 (d, 2H, J = 9.0 Hz, ArH), 7.06–7.11 (m, 2H, Ar-H), 7.18 (s, 1H, arylmethylidene), 7.35 (d, 2H, J = 8.5 Hz, ArH), 8.32 (s, 1H, 1"-NH). 13C NMR (125 MHz,
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CDCl3): δC 34.68, 45.08, 54.20, 55.23, 55.27, 56.23, 57.16, 61.00, 65.78, 76.25, 108.66, 113.56, 113.82, 117.47, 121.89, 127.64, 127.74, 127.90, 128.67, 130.51, 130.53, 131.17, 132.11, 134.35,
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137.68, 141.99, 158.41, 160.04, 177.91, 198.87. Anal. calcd for C34H35N3O4: C, 74.29; H, 6.42; N, 7.64 %; found: C, 74.42; H, 6.23; N, 7.73 %.
2.3. Experimental procedure for the synthesis of 6
An equimolar mixture of (3E,5E)-1-allyl-3,5-bis(4-methoxyphenylmethylidene)piperidin-4-one 1, isatin 2 and phenylglycine 5 in 200 mg of [bmim]Br was heated at 100 oC for 30 minutes.
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After completion of the reaction as evident from TLC, water (50 mL) was added to the reaction mixture and extracted with ethyl acetate (3x30 mL). The excess solvent was evaporated under reduced pressure. The resultant solid was dried in vacuum and purified through column chromatography using hexane: ethyl acetate (3:2 v/v) as eluent to obtain 6 as colorless solid.
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Spiro[2.3″]oxindole-spiro[3.3′]-1′-allyl-5′-(4-methoxyphenylmethylidene)tetrahydro-4′(1H)pyridinone-4-(4-methoxyphenyl)-5-(phenyl)pyrrolidine (6) H NMR (500 MHz, CDCl3): δH 1.97 (d, 1H, J = 12.5 Hz, 2'-CH2), 2.49 (bs, 1H, NH), 2.75 (dd,
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1H, J = 13.0, 7.5 Hz, 7'-CH2), 2.90 (dd, 1H, J = 14.5, 2.5 Hz, 6'-CH2), 3.12 (dd, 1H, J = 13.5, 5.0 Hz, 7'-CH2), 3.41 (d, 1H, J = 12.5 Hz, 2'-CH2), 3.47-3.50 (m, 1H, 6'-CH2), 3.75 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 4.63 (d, 1H, J = 11.0 Hz, H-5), 4.98–5.03 (m, 2H, 9'-CH2), 5.38 (d, 1H, J = 10.5 Hz, H-4), 5.55–5.61 (m, 1H, H-8'), 6.65 (d, 1H, J = 7.5 Hz, ArH), 6.78 (d, 2H, J = 8.5 Hz, ArH), 6.82 (d, 2H, J = 8.5 Hz, ArH), 6.94 (t, 1H, J = 8.0 Hz, ArH), 7.04 (d, 2H, J = 9.0 Hz, ArH), 7.08 (t, 1H, J = 7.5 Hz, ArH), 7.12 (s, 1H, arylmethylidene), 7.17-7.27 (m, 4H, ArH), 7.33 (d, 2H, J = 8.0 Hz, ArH), 7.54 (d, 2H, J = 7.0 Hz, ArH), 7.86 (s, 1H, 1"-NH). 13C NMR (125 5
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MHz, CDCl3): δC 54.03, 55.12, 55.28, 56.05, 56.14, 60.93, 64.45, 66.78, 72.15, 108.88, 113.57, 113.87, 117.60, 121.92, 126.87, 127.49, 127.70, 127.80, 128.31, 128.79, 129.23, 129.49, 130.82, 131.28, 132.18, 134.30, 137.49, 141.00, 141.24, 158.34, 160.13, 180.44, 199.51. Anal. calcd for
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C39H37N3O4: C, 76.57; H, 6.10; N, 6.87 %; found: C, 76.71; H, 6.21; N, 6.70 %. 2.4. X-ray details
The compounds 4 and 6 were obtained as single crystals by slow evaporation from ethylacetate solution of the pure compound at room temperature. Data were collected on a Bruker APEX-II
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D8 Venture area diffractometer, equipped with graphite monochromatic Mo Kα radiation, λ = 0.71073 Å. Cell refinement and data reduction were carried out by Bruker SAINT. SHELXT [25, 26] was used to solve structure. The final refinement was carried out by full-matrix least-squares
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techniques with anisotropic thermal data for nonhydrogen atoms on ܨ. Crystallographic data (including structure factors) for the compound 4 and 6 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 1537473 and CCDC 1537466 respectively. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44 (0)1223 336033 or e-mail:
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[email protected]]. 2.5. Computational Details
All the quantum chemical calculations of the compounds 4 and 6 were performed by applying DFT method with the B3LYP functional and 6‒31G(d,p) basis set using Gaussian 03 software
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[27]. The input files were prepared using the Cartesian coordinates taken from the crystallographic information files (CIFs) obtained from our reported X‒ray single crystal
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measurements. The geometries were optimized by minimizing the energies with respect to all the geometrical parameters without imposing any molecular symmetry constraints. GaussView 4.1 [28] program is used to draw the molecular electrostatic potential maps (MEP). Chemcraft [29] is used to draw the optimized geometries. Frequency calculations at the optimized geometries were done and no imaginary frequency modes were detected which confirm that the optimized structures are energy minimum. The 1H and the 13C isotropic shielding tensors referenced to the TMS were carried out at the same level of theory and using the gauge including atomic orbital (GIAO) method. The effect of solvent (chloroform) on the calculated chemical shifts is computed using the Polarizable Continuum Model (PCM). The natural charges were obtained 6
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using NBO calculations as implemented in the Gaussian 03 package [30] at the DFT/B3LYP level. 3. Results and Discussion
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3.1. Synthesis The synthesis of starting substrate 3,5-bis(4-methoxyphenylmethylidene)piperidin-4-one was accomplished following a literature method [31]. The prerequisite, 1-allyl-3,5-bis(4methoxyphenylmethylidene)piperidin-4-one (1) was prepared by the reaction of 3,5-bis(4-
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methoxyphenylmethylidene)piperidin-4-one with allyl chloride in acetone [18]. With the dipolarophile (1) in hand, initially we performed the cycloaddition of 1 with azomethine ylide generated in situ from the reaction of isatin (2) and sarcosine (3). An equimolar mixture of 1, 2
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and 3 in refluxing methanol (10 mL, 60 min) furnished the spirooxindole-pyrrolidine 4 as a sole reaction product in good yield (86%). As an alternative, the same reaction was also performed in (bmim)Br at 80 oC (Scheme 2). After completion of the reaction (30 min), the reaction mixture was extracted with ethyl acetate and purified by column chromatography. The compound 4 was obtained with an improved yield (94%) over the conventional heating in methanol. The ionic liquid, [bmim]Br was recycled in pure form from the reaction mixture by removing the product
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and drying the ionic liquid in vacuum as reported by us earlier [23]. The recycled ionic liquid could be used further for subsequent reaction.
Scheme 2. Synthesis of spirooxindole-pyrrolidine hybrid 4 from 1-allyl-3,5-bis(4-
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methoxyphenylmethylidene)piperidin-4-one (1), isatin (2) & sarcosine (3) The structure of compound 4 was elucidated using elemental analysis, 1H,
13
C and 2D NMR
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spectroscopy (vide supporting data).
The above cycloaddition reaction was then carried out with a primary amino acid viz.,
phenyl glycine instead of sarcosine under similar reaction conditions, which afforded the spirooxindole-pyrrolidine 6 in excellent yield (96 %) (Scheme 3). Compound 6 has a phenyl group in position 5 and an unsubstituted N atom in position 1 of the pyrrolidine ring. The presence of NH group makes this molecule more attractive for further modifications. The structure of compound 6 was also elucidated using elemental analysis, 1H,
13
C and 2D NMR
spectroscopy (vide supporting data).
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Scheme 3 Synthesis of spirooxindole-pyrrolidine hybrid 6 from 1, 2 & phenyl glycine (5) A rational mechanism for the formation of spiroxindole-pyrrolidines 4/6 in the presence of [bmim]Br is described in Scheme 4. The hydrogen atom of [bmim]+ being electron-deficient
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could form hydrogen bond with the carbonyl group of isatin facilitating the nucleophilic attack of the amino group of phenylglycine on isatin and subsequent dehydration to furnish azomethine ylide. Simultaneously, the hydrogen bond between the imidazole ring hydrogen of [bmim]+ and the carbonyl group of 1 may facilitate the [3+2] cycloaddition of 1 with azomethine ylide to
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afford 6.
3.2. X-ray crystallographic studies
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Scheme 4. Proposed mechanism for the formation of spiroheterocyclic hybrid 4/6
X-ray crystallographic study of a single crystals of 4 (Fig. 1) and 6 (Fig. 2) confirms the structures deduced from NMR spectroscopic studies.
Figure 1. ORTEP diagram of 4. Displacement ellipsoids are plotted at the 30% probability level for non-H atoms showing the disorder parts
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Figure 2. ORTEP diagram of 6. Displacement ellipsoids are plotted at the 30% probability level for non-H atoms showing the disorder parts.
A view of the hydrogen bonding pattern of compounds 4 and 6 was shown in Fig.4.
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Figure 3. A view of the intermolecular hydrogen bonding pattern of compounds 4 and 6
The crystallographic data, conditions used for the intensity data collection and some features of
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the structure refinements are listed in Table 1. The selected geometric parameters like bond lengths from X-ray data and DFT (B3LYP/6-31G(d,p)) calculations are listed in Table 2 and Table 4 for the compounds 4 & 6 respectively. The bond angles obtained from X-ray data are listed in Tables 3 and Table 5 for the compounds 4 & 6 respectively. The unit cell of the crystal structure of compound 4 contains two independent molecules, in which molecule A is partially disordered in para-methoxy group (occupancies 0.85(3) and 0.15(3)). The molecule B has two disordered components differ from one another in the orientation of the methyl group and methoxyphenyl group over two sets of atomic sites having occupancies 0.39(2), 0.62(3) and 0.53(2), 0.47(2), respectively (Fig. 1). 8
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The molecules are packed together through two strong classical intermolecular hydrogen bonds viz., N1A-H1NA…O1A and N1B-H1NB…O1B, resulting in the formation of centrosymmetric eight-membered cyclic dimers with the D-H---A angle of 178(2)◦ and 174(2)◦ respectively (Fig. 3). The corresponding D---A bond lengths are 2.8249(19) Å for N1A-
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H1NA…O1A and 2.814(2) Å N1B-H1NB…O1B. There are three non-classical hydrogen bonding interactions also present between C-H…O (Table 6, Fig 3) atoms. On the other hand, the unit cell of compound 6 contains only one independent molecule, which has disorder over two sets of atomic sites having occupancies 0.744 (3) and 0.256 (3). The two disordered components differ
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from one another in the orientation of the propyl substituents, so that the crystal of 6 contains three distinct conformers. (Fig 4). The molecules are linked by strong classical intermolecular hydrogen bond between N3-H1N3…O4 lead to the formation of centrosymmetric eight-
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membered cyclic dimers with N3---O4 distance of 9.003(18) Å and N3-H1N3…O4 angle of 171(2)°. The non-classical hydrogen bonding interactions also observed between C-H…O (Table 7) atoms in 6.
Table 1: The crystal and experimental data of compound 4 and 6
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Table 2 Selected bond lengths (Å) from the X-ray data and from DFT (B3LYP/6-31G(d,p) level) calculations for the compound 4
Table 3 Selected bond angles (°) from the X-ray data for of compound 4
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Table 4 Selected bond lengths (Å) from the X-ray data and from DFT (B3LYP/6-31G(d,p) level)
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calculations for the compound 6
Table 5 Selected bond angles (°) from the X-ray data for of compound 6 Table 6 Hydrogen-bonding parameters (Å, °) of compound 4
Table 7 Hydrogen-bond parameters (Å, °) of compound 6
3.3. Computational study 3.3.1. Molecular structure
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The optimized bond lengths and angles of the title compounds calculated using B3LYP method with 6‒31G(d,p) basis set are given in Tables S1 & S2 (Supplementary data) while the optimized structures are given in Fig. S15 & S16 (Supplementary data). The DFT (B3LYP/631G(d,p)) computed bond lengths and bond angles are in good agreement with the corresponding
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experimental values obtained from the X-ray crystallographic method (Table 2-5). Further, the bond parameters of the disordered groups present in the crystal structure are confirmed from the corresponding DFT computed values. The compounds 4 and 6 possess C1 point group and the optimized geometries are well compared with the experimental structures. The calculated
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geometric parameters agree well with the experimental results. The correlations between the calculated and experimental data gave high correlation coefficients which are in the ranges of
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0.896-0.934 and 0.909-0.958 for bond distances and bond angles, respectively. The small deviations between the calculated and experimental geometries could be attributed to the crystal packing effects.
3.3.2. Natural atomic charge population
The charge populations at different atomic sites have great importance to define the reactive sites in the compound. This has a strong relation to its biological activity. In this regard,
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the natural atomic charges were computed and collected in Table 6. It is clear from this table that, the most electronegative regions are related to the O and N-atoms. The carbonyl oxygen and the amine (NH) nitrogen atoms are the most electronegative heteroatoms in the studied systems. On the other hand, the most positive regions are related to the H-atoms where the amine NH
respectively.
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protons have the highest positive charge density of 0.437 e and 0.405-0.442 e for 4 and 6,
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Molecular electrostatic potential (MEP) maps are very useful three dimensional diagram used to visualize the charge distributions and charge related properties of molecules. Also, it has been used to predict the reactive sites for electrophilic and nucleophilic attack, and in studying the hydrogen bonding interactions [32, 33]. The MEP maps of the studied compounds calculated using B3LYP method with 6‒31G(d,p) basis set are shown in Fig. 4. It can be seen from this figure that, negative regions (red) are mainly localized over the carbonyl O-atoms while the positive regions (blue) are located around the H-atom of the NH groups which confirm the electron deficiency of this site. From this point of view, the most reactive sites for H-bonding
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interactions are the carbonyl O-atoms (H-acceptor) and the amine NH (H-donor) proton which agrees very well with the reported X-ray structure analysis. Table 8 The natural atomic charges calculated from DFT at the B3LYP/6-31G(d,p) level
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Figure 4 Molecular Electrostatic potentials (MEP) mapped on the electron density surface calculated by the DFT/B3LYP method. 3.3.3. NMR spectra
The isotropic magnetic shielding (IMS) values calculated using the GIAO approach at the 6-
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31G(d,p) level have been used to predict the 13C and 1H-NMR chemical shifts (δcalc) for the title compounds and the results were correlated to the experimental NMR data (δexp) in CDCl3 as 13
C-NMR chemical shift values are given in
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solvent. The experimental and theoretical 1H- and
Table S3 (Supplementary Information). According to these results, the calculated chemical shifts are in good agreement with the experimental findings. The correlation coefficients (R2) between the experimental and calculated chemical shifts are in the range of 0.943-0.972 (Fig SF6 & SF14 Supplementary Information). In the 1H NMR spectra of 4, the NH proton of the oxindole ring appears as a singlet at 8.32 ppm (Fig. 5) and the corresponding DFT computed value is 7.43
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ppm. The singlet signal at 2.14 ppm confirm the presence of -NCH3 group of pyrrolidine ring which is close to the DFT computed values for the three protons 2.38 ppm, 2.37 ppm & 2.02 ppm.
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Figure 5. 1H and 13C chemical shifts of compound 4 In the 1H NMR spectrum of compound 6, the NH proton of the oxindole ring appears as
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a singlet at 7.86 ppm (Fig. 6) and the DFT computed value is 7.52 ppm. From the DFT calculations at B3LYP/6-31G(d,p) level, the -NH proton of the pyrrolidine group resonate at 3.35 ppm which is not observed/assigned from experimental spectra due to overlap with other signals. In the 13C NMR spectra of compound 4, the two spiro carbons C2 & C3 resonate around 76.25 ppm and 65.78 ppm respectively. The corresponding DFT computed chemical shifts are 70.69 and 64.43 ppm respectively. The carbon atom of the CH3 group attached to the pyrrolidine N atom resonates at 34.7 ppm experimentally and the corresponding DFT computed value is 24.6 ppm. In the compound 6 the two spiro carbons C2 & C3 resonate around 72.15 ppm and 66.78 ppm respectively. The corresponding DFT computed values are 72.51 ppm and 60.65 11
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respectively. The carbonyl carbon of the oxindole group of 4 and 6 resonate around 177.91 ppm and 180.44 ppm respectively. Another carbonyl carbon 4’ of compounds 4 and 6 resonate around 198.87 ppm and 199.51 ppm respectively. The corresponding DFT computed values are 185.95
Figure 6. 1H and 13C chemical shifts of compound 6
3.3.4. Nonlinear optical (NLO) properties
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ppm and 192.08 ppm.
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The strength of molecular interactions, cross-section of different scattering and collision processes and non-linear optical properties are mainly governed by the polarizabilities of the molecules which lead to the applications in material chemistry. The study about these properties
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require both experimental and theoretical attention. Quantum chemical calculations are highly useful in understanding the electronic polarization of the molecules having non-linear optical properties. Nonlinear optical materials are used as key materials for photonic communications which use light instead of electron for data transmission. With the development of laser technology, nonlinear optical materials have been extensively applied to industry, national defense, medicine and research [34, 35]. Several organic materials have been used for such
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applications. The synthesized organic compounds 4 and 6 were characterized by their high polarizability (α0) and low HOMO‒LUMO gap (∆E). The α0 and ∆E values were calculated to be 407.17 Bohr3 and 3.70 eV, respectively for 4 while 466.25 Bohr3 and 3.52 eV for 6, respectively. It has been already reported that the B3LYP functional led to average
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polarizabilities with an accuracy approaching that of sophisticated wave function approach [36], the computed polarizability value of 4 and 6 are well above the polarizability values computed
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for the organic compounds possessing NLO property [37, 38], suggest these could be a good candidate for NLO applications. In particular, compound 6 could be a better candidate for NLO applications than 4.
In fact, the NLO is a phenomenon caused by the interaction of intense light with matter
and theoretically the presence of considerable charge separation resulting in polarizability lead to the NLO activity of the molecule. The energy gap between the HOMO and LUMO is also crucial in determining the electronic, redox, transport and optical properties of the materials. Thus the obtained polaizability values for compounds 4 and 6 are due to the charge separation arised from the donor-acceptor groups present in the molecule. 12
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4. Conclusions We have achieved the stereoselective synthesis of highly functionalized spiro-oxindole pyrrolidine hybrid heterocycles 4 and 6 in excellent yield through an ionic liquid, (bmim)Br mediated [3+2] cycloaddition reaction of 1-allyl-3,5-bis(4-methoxyphenylmethylidene)piperidin-
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4-one with azomethine ylide generated in situ from the reaction of isatin and sarcosine or phenylglycine. The stereochemistry of these heterocyclic hybrids were confirmed from X-ray crystallographic studies. The molecular structure of these compounds have been optimized using DFT/B3LYP method and 6-31G(d,p) basis set. The DFT calculated bond distances and bond
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angles showed good agreement with our reported X-ray crystal structure. The molecular electrostatic potential picture of these hybrid heterocycles has been calculated using the same
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level of theory. The polarizability (α0) and HOMO-LUMO energy gap (∆E) values indicated the better NLO activity of 6 compared to 4 and the α0 values are well above the already known organic compounds possessing NLO property. The GIAO 1H- and
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values correlated well with the experimental data. The correlation coefficients (R2) for carbon and proton are high (0.943-0.972).
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Acknowledgments
The authors extend their appreciation to the Deanship of Scientific Research at King Saud
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University for funding this work through research group No. RG-1438-052.
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Figure Captions
Scheme 1. Selected biologically important spirooxindole-pyrrolidine heterocyclic hybrids 2.
Synthesis
of spirooxindole-pyrrolidine hybrid
4
from
1-allyl-3,5-bis(4-
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Scheme
methoxyphenylmethylidene)piperidin-4-one (1), isatin (2) & sarcosine (3) Scheme
3.
Synthesis
of spirooxindole-pyrrolidine hybrid
6
from 1-allyl-3,5-bis(4-
methoxyphenylmethylidene)piperidin-4-one (1), isatin (2) & phenyl glycine (5)
Scheme 4. Proposed mechanism for the formation of spiroheterocyclic hybrid 4/6
for non-H atoms showing the disorder parts
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Figure 1. ORTEP diagram of 4. Displacement ellipsoids are plotted at the 30% probability level
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Figure 2. ORTEP diagram of 6. Displacement ellipsoids are plotted at the 30% probability level for non-H atoms showing the disorder parts
Figure 3. A view of the intermolecular hydrogen bonding pattern of compounds 4 and 6 Figure 4. Molecular Electrostatic potentials (MEP) mapped on the electron density surface calculated by the DFT/B3LYP method.
Figure 5. 1H and 13C chemical shifts of compound 4
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Figure 6. 1H and 13C chemical shifts of compound 6
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Table Captions Table 1. The crystal and experimental data of compound 4 and 6
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Table 2. Selected bond lengths (Å) from the X-ray data and from DFT (B3LYP/6-31G(d,p) level) calculations for the compound 4
Table 3. Selected bond angles (°) from the X-ray data for of compound 4
Table 4. Selected bond lengths (Å) from the X-ray data and from DFT (B3LYP/6-31G(d,p)
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level) calculations for the compound 6
Table 5. Selected bond angles (°) from the X-ray data for of compound 6 Table 6. Hydrogen-bonding parameters (Å, °) of compound 4
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Table 7. Hydrogen-bond parameters (Å, °) of compound 6
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Table 8. The natural atomic charges calculated from DFT at the B3LYP/6-31G(d,p) level
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Scheme 1. Selected biologically important spirooxindole-pyrrolidine heterocyclic hybrids
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Scheme
2.
Synthesis
of spirooxindole-pyrrolidine hybrid
4
from
1-allyl-3,5-bis(4-
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methoxyphenylmethylidene)piperidin-4-one (1), isatin (2) & sarcosine (3)
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Scheme 3. Synthesis of spirooxindole-pyrrolidine hybrid 6 from 1, 2 & phenyl glycine (5)
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Scheme 4. Proposed mechanism for the formation of spiroheterocyclic hybrid 4/6
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Figure 1. ORTEP diagram of 4. Displacement ellipsoids are plotted at the 30% probability level
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for non-H atoms showing the disorder parts
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Figure 2. ORTEP diagram of 6. Displacement ellipsoids are plotted at the 30% probability level
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for non-H atoms showing the disorder parts.
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Figure 3. A view of the intermolecular hydrogen bonding pattern of compounds 4 and 6
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4
6
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Figure 4. Molecular Electrostatic potentials (MEP) mapped on the electron density surface
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calculated by the DFT/B3LYP method.
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4
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Figure 5. 1H and 13C chemical shifts of compound 4
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Figure 6. 1H and 13C chemical shifts of compound 6
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Table 1. The crystal and experimental data of compound 4 and 6
4
6
Chemical formula Mr Crystal system, space group Temperature (K) a, b, c (Å)
C34H35N3O4 549.65 Triclinic, P-1 150 8.5305 (1), 12.1167 (2), 30.9259 (4) 80.454 (1), 87.904 (1), 72.421 (1) 3004.77 (7) 4 Mo Kα 0.08 0.31 × 0.30 × 0.20
C39H39N3O4 613.73 Triclinic, P-1 100 10.8634 (6), 11.3167 (6), 15.2861 (12) 98.296 (1), 104.650 (1), 113.756 (1) 1598.49 (18) 2 Mo Kα 0.08 0.52 × 0.23 × 0.17
Bruker APEX-II CCD diffractometer Multi-scan SADABS Bruker 2014 0.975, 0.984
Bruker APEX-II CCD diffractometer Multi-scan SADABS Bruker 2014 0.958, 0.986
49003, 17342, 11131
32965, 9202, 6401
0.051
0.028
0.060, 0.169, 0.98 17342 836 17 0.41, −0.24 1537473
0.052, 0.177, 1.04 9202 455 0 0.29, −0.37 1537466
α, β, γ (°)
Absorption correction
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Tmin, Tmax No. of measured, independent and observed [I > 2σ(I)] reflections Rint Refinement R[F2 > 2σ( F2)], wR( F2), S No. of reflections No. of parameters No. of restraints ∆ρmax, ∆ρmin (e Å−3) CCDC number
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V (Å3) Z Radiation type µ (mm−1) Crystal size (mm) Data collection Diffractometer
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Crystal data
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Table 2. Selected bond lengths (Å) from the X-ray data and from DFT (B3LYP/6-31G(d,p) level) calculations for the compound 4 Exp.
DFT (B3LYP/6-31G)
Atoms
Exp.
O1B—C8B O2B—C16B O2B—C19B O2X—C19X O2X—C16X O3B—C23B O4B—C34B O4B—C31B O1A—C8A O2A—C16A O2A—C19A O2Y—C16A O2Y—C19Y O3A—C21A O4A—C34A O4A—C31A N1B—C1B
1.235 (2) 1.372 (6) 1.425 (10) 1.440 (13) 1.365 (7) 1.218 (2) 1.433 (3) 1.363 (2) 1.233 (2) 1.360 (4) 1.425 (4) 1.49 (3) 1.40 (3) 1.222 (2) 1.432 (3) 1.364 (2) 1.401 (2)
1.222 1.368 1.418 1.418 1.368 1.228 1.421 1.360 1.222 1.368 1.418 1.368 1.418 1.228 1.421 1.360 1.399
N1B—C8B N2B—C12X N2B—C11B N2B—C12B N2B—C7B N3B—C21B N3B—C24B N3B—C20B N1A—C8A N1A—C1A N2A—C11A N2A—C7A N2A—C12A N3A—C23A N3A—C20A N3A—C24A
1.350 (3) 1.483 (9) 1.456 (3) 1.491 (12) 1.466 (3) 1.463 (2) 1.468 (3) 1.458 (2) 1.356 (2) 1.398 (2) 1.457 (2) 1.463 (2) 1.457 (2) 1.463 (2) 1.455 (2) 1.466 (2)
DFT (B3LYP/631G(d,p)) 1.378 1.454 1.454 1.460 1.465 1.460 1.465 1.459 1.378 1.399 1.454 1.465 1.460 1.460 1.459 1.465
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Table 3. Selected bond angles (°) from the X-ray data for of compound 4
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Bond Angle 125.3 (5) 114.7 (5) 115.5 (5) 125.1 (5) 108.96 (14) 112.12 (14) 121.47 (15) 121.46 (15) 111.82 (18) 114.94 (16) 125.19 (17) 109.84 (15) 128.17 (16) 102.91 (12) 111.16 (14) 114.36 (13) 108.61 (13) 125.60 (15) 125.73 (15) 103.04 (14) 117.3 (2) 123.3 (2) 127.2 (10) 112.0 (10) 110.14 (13) 121.08 (14) 121.77 (15) 111.94 (14) 112.44 (15) 115.28 (16) 124.95 (16)
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Atoms O2B—C16B—C17B O2B—C16B—C15B O2X—C16X—C15X O2X—C16X—C17X N3B—C20B—C9B N3B—C21B—C22B O3B—C23B—C9B O3B—C23B—C22B N3B—C24B—C25B O4B—C31B—C32B O4B—C31B—C30B N1A—C1A—C6A N1A—C1A—C2A N2A—C7A—C9A N2A—C7A—C6A N2A—C7A—C8A N1A—C8A—C7A O1A—C8A—N1A O1A—C8A—C7A N2A—C11A—C10A O2A—C16A—C17A O2A—C16A—C15A O2Y—C16A—C15A O2Y—C16A—C17A N3A—C20A—C9A O3A—C21A—C22A O3A—C21A—C9A N3A—C23A—C22A N3A—C24A—C25A O4A—C31A—C32A O4A—C31A—C30A
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Bond Angle 116.4 (5) 118.1 (6) 117.90 (16) 118.5 (3) 129 (2) 118.33 (16) 111.57 (15) 115.7 (4) 112.0 (5) 121.9 (4) 103.1 (5) 106.94 (16) 110.84 (15) 112.32 (14) 110.29 (14) 111.40 (14) 114.78 (14) 114.90 (14) 107.53 (14) 109.80 (13) 111.38 (13) 111.02 (14) 109.56 (15) 127.55 (17) 110.77 (15) 102.48 (14) 113.27 (16) 125.68 (17) 125.17 (17) 109.08 (16) 102.74 (16)
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Atoms C16B—O2B—C19B C16X—O2X—C19X C31B—O4B—C34B C16A—O2A—C19A C16A—O2Y—C19Y C31A—O4A—C34A C1B—N1B—C8B C7B—N2B—C12X C7B—N2B—C12B C11B—N2B—C12X C11B—N2B—C12B C7B—N2B—C11B C21B—N3B—C24B C20B—N3B—C24B C20B—N3B—C21B C1A—N1A—C8A C11A—N2A—C12A C7A—N2A—C12A C7A—N2A—C11A C20A—N3A—C23A C20A—N3A—C24A C23A—N3A—C24A N1B—C1B—C6B N1B—C1B—C2B N2B—C7B—C6B N2B—C7B—C9B N2B—C7B—C8B O1B—C8B—C7B O1B—C8B—N1B N1B—C8B—C7B N2B—C11B—C10B
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Table 4. Selected bond lengths (Å) from the X-ray data and from DFT (B3LYP/6-31G(d,p) level) calculations for the compound 6 Exp.
DFT (B3LYP/631G)
Atoms
Exp.
DFT (B3LYP/631G(d,p))
O1—C4 O2—C10 O2—C13 O3—C21 O3—C31 O4—C39 N1—C1
1.2104 (19) 1.365 (3) 1.393 (4) 1.371 (2) 1.417 (2) 1.2266 (19) 1.452 (2)
1.235 1.359 1.422 1.368 1.418 1.221 1.461
N1—C2 N1—C14 N1—C14A N2—C24 N2—C32 N3—C38 N3—C39
1.454 (2) 1.490 (3) 1.450 (12) 1.468 (2) 1.470 (2) 1.393 (2) 1.357 (2)
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1.468 1.470 1.461 1.472 1.466 1.397 1.371
Table 5. Selected bond angles (°) from the X-ray data for of compound 6 Bond Angle 118.7 (2) 117.52 (16) 111.75 (12) 105.60 (17) 122.7 (8) 111.0 (2) 115.5 (8) 107.33 (12) 111.65 (14) 113.50 (14) 109.83 (12) 121.27 (15) 121.78 (14) 124.27 (17) 115.57 (18)
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C10—O2—C13 C21—O3—C31 C1—N1—C2 C1—N1—C14 C1—N1—C14A C2—N1—C14 C2—N1—C14A C24—N2—C32 C38—N3—C39 N1—C1—C5 N1—C2—C3 O1—C4—C3 O1—C4—C5 O2—C10—C9 O2—C10—C11
Atoms
N1—C14—C15 N1—C14A—C15A O3—C21—C20 O3—C21—C22 N2—C24—C17 N2—C24—C25 N2—C32—C3 N2—C32—C33 N2—C32—C39 N3—C38—C37 N3—C38—C33 N3—C39—C32 O4—C39—N3 O4—C39—C32
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Bond Angle 110.0 (2) 114.4 (14) 116.77 (16) 124.22 (15) 105.35 (12) 111.12 (12) 105.87 (12) 109.43 (12) 107.86 (12) 128.39 (16) 109.78 (15) 108.54 (13) 125.65 (14) 125.74 (15)
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Table 6. Hydrogen-bonding parameters (Å, °) of compound 4
Table 7. Hydrogen-bond parameters (Å, °) of compound 6
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D—H···A D—H H···A D···A D—H···A i N1B—H1NB···O1B 0.91 (2) 1.91 (2) 2.814 (2) 174 (2) N1A—H1NA···O1Aii 0.86 (2) 1.97 (2) 2.8249 (19) 178 (2) C4A—H4AA···O3B 0.9300 2.5800 3.482 (2) 164.00 C10A—H10A···O4Aiii 0.9800 2.4900 3.307 (2) 141.00 iii C10B—H10B···O4B 0.9800 2.3900 3.177 (2) 137.00 C30B—H30B···O3Aiv 0.9300 2.5300 3.449 (3) 172.00 Symmetry codes: (i) −x, −y+1, −z+1; (ii) −x+1, −y+1, −z; (iii) x, y−1, z; (iv) x−1, y+1, z.
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D—H···A D—H H···A D···A D—H···A N3—H1N3···O4i 0.87 (2) 2.04 (2) 2.9003 (18) 171 (2) C6—H6A···O1ii 0.9300 2.5200 3.338 (2) 147.00 C15—H15B···O4 0.9700 2.3600 3.321 (3) 170.00 Symmetry codes: (i) −x+2, −y+1, −z+1; (ii) −x+1, −y, −z.
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Table 8. The natural atomic charges calculated from DFT at the B3LYP/6-31G(d,p) level
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0.247 0.317 -0.319 0.240 -0.217 0.265 -0.067 0.260 -0.040 -0.242 0.251 -0.232 0.238 -0.240 0.237 -0.233 0.238 -0.218 0.240 -0.327 0.230 0.206 0.204 0.063 -0.061 -0.211 0.258 -0.256 0.241 -0.218 0.241 -0.279 0.241 0.174 0.730 0.405 0.442 -0.235 0.229 -0.432 0.217
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Compound 6 -0.617 H43 -0.511 C44 -0.523 C45 -0.622 H46 -0.496 C47 -0.660 H48 -0.621 C49 -0.286 H50 0.207 C51 0.249 C52 -0.279 H53 0.265 C54 0.220 H55 -0.122 C56 0.571 H57 -0.126 C58 -0.129 H59 0.256 C60 -0.113 H61 -0.189 C62 0.241 H63 -0.322 H64 0.245 H65 0.339 C66 -0.276 C67 0.255 C68 -0.184 H69 0.245 C70 -0.330 H71 0.236 C72 0.209 H73 0.209 C74 -0.294 H75 0.246 C76 0.212 C77 0.228 H78 -0.257 H79 0.265 C80 -0.076 H81 -0.211 C82 0.237 H83 -0.276
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O1 O2 O3 O4 N5 N6 N7 C8 H9 H10 C11 H12 H13 C14 C15 C16 C17 H18 C19 C20 H21 C22 H23 C24 C25 H26 C27 H28 C29 H30 H31 H32 C33 H34 H35 H36 C37 H38 C39 C40 H41 C42
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-0.280 0.227 0.267 0.572 -0.129 -0.287 0.255 0.209 -0.289 0.261 0.205 -0.229 0.229 -0.435 0.215 0.223 -0.132 0.255 -0.112 -0.176 0.243 -0.325 0.245 0.337 -0.274 0.253 -0.195 0.243 -0.330 0.235 0.209 0.208 0.437 -0.522 -0.327 0.231 0.204 0.205
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Compound 4 -0.623 C39 -0.579 H40 -0.513 H41 -0.628 C42 -0.494 C43 -0.503 C44 0.175 H45 -0.281 H46 0.239 C47 -0.219 H48 0.240 H49 -0.261 C50 0.240 H51 -0.198 C52 0.264 H53 -0.079 H54 0.075 C55 0.703 H56 -0.099 C57 -0.274 C58 0.286 H59 -0.248 C60 0.214 H61 0.241 C62 -0.485 C63 0.234 H64 0.207 C65 0.236 H66 -0.068 C67 -0.214 H68 0.249 H69 -0.272 H70 0.249 H71 0.315 O72 -0.319 C73 0.240 H74 -0.217 H75 0.240 H76
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O1 O2 O3 N4 N5 N6 C7 C8 H9 C10 H11 C12 H13 C14 H15 C16 C17 C18 C19 C20 H21 C22 H23 H24 C25 H26 H27 H28 C29 C30 H31 C32 H33 C34 C35 H36 C37 H38
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Highlights Highly functionalized spirooxindole-pyrrolidine hybrid heterocycles 4 & 6 were synthesized using an ionic liquid, 1-butyl-3-methylimidazolium bromide ([bmim]Br).
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The molecular structures of these heterocyclic hybrids were confirmed from X-ray crystallographic studies, 1D & 2D NMR spectroscopy and DFT (B3LYP/6-31G[d,p]) studies.
The DFT computed bond parameters, NMR chemical shifts and reactive sites are in good agreement with experimental findings.
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The DFT computed polarizabilities suggest the possible NLO properties of the
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compounds 4 and 6.
S0022-2860(17)31261-9
DOI:
10.1016/j.molstruc.2017.09.073
Reference:
MOLSTR 24322
To appear in:
Journal of Molecular Structure
Received Date: 18 July 2017 Revised Date:
17 September 2017
Accepted Date: 20 September 2017
Please cite this article as: R.S. Kumar, A.I. Almansour, N. Arumugam, S.M. Soliman, R.R. Kumar, M. Altaf, H.A. Ghabbour, B.S. Krishnamoorthy, Stereoselective green synthesis and molecular structures of highly functionalized spirooxindole-pyrrolidine hybrids – A combined experimental and theoretical investigation, Journal of Molecular Structure (2017), doi: 10.1016/j.molstruc.2017.09.073. 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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Graphical Abstract
Stereoselective green synthesis of new spirooxindole-pyrrolidine hybrids 4 and 6 were synthesized and their structures were confirmed by NMR spectra, X-ray crystallography and
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DFT studies. The DFT computed polarizability values suggest the possible NLO property of the
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synthesized compounds.
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4
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STEREOSELECTIVE GREEN SYNTHESIS AND MOLECULAR STRUCTURES OF HIGHLY FUNCTIONALIZED SPIROOXINDOLE-PYRROLIDINE HYBRIDS – A COMBINED EXPERIMENTAL AND THEORETICAL INVESTIGATION
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Raju Suresh Kumar,a,* Abdulrahman I. Almansour,a Natarajan Arumugam,a Saied M. Soliman,b,c Raju Ranjith Kumar,d Mohammad Altaf,e Hazem A. Ghabbourf,g, Bellie Sundaram Krishnamoorthyh* a
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Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia b Department of Chemistry, College of Science & Arts, King Abdulaziz University, P.O. Box 344, Rabigh 21911, Saudi Arabia c Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 21321, Egypt d Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, Tamil Nadu, India e Central Laboratory, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia f Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia g Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt. h Department of Chemistry, Vivekanandha College of Arts and Sciences for Women (Autonomous), Elayampalayam, Namakkal, Tamil Nadu, India. 637 205. Abstract Highly functionalized spirooxindole-pyrrolidine hybrids have been synthesized stereoselectively through a [3+2] cycloaddition strategy in an ionic liquid, 1-butyl-3-methylimidazolium bromide
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([bmim]Br). The structure of these spiro heterocyclic hybrids was elucidated using one and two dimensional NMR spectroscopy, single crystal X-ray crystallographic studies and Density
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Functional Theory (DFT) calculations. The calculated geometric parameters are in good agreement with the experimental data obtained from the X-ray structures. The Natural Bond Orbital (NBO) calculations on these molecules confirm the electron rich carbonyl oxygen and electron deficient NH groups. The 1H- and
13
C-NMR chemical shifts calculated using GIAO
method are in good agreement with the experimental data. The DFT computed polarizability values also suggest the possible NLO activity of these molecules.
*Corresponding authors: Tel: +966-4675907; fax: +966-4675992; email: [email protected], [email protected] (Suresh Kumar R), +91-9585447505 [email protected] (Krishnamoorthy B.S.)
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Keywords: [3+2] Cycloaddition, spirooxindole-pyrrolidine hybrids, Ionic liquid, X-ray crystal
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structure - DFT studies
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Introduction The development of transformations that lead to multiple bond formation in a single step has received much attention in view of the greenness of such reactions. Often these reactions
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lead to the formation of compounds that find applications in pharmaceutical and agrochemical industries [1]. [3+2] Cycloaddition reactions play a vital role in the construction of five membered structural motifs [2] and in particular, cycloaddition of azomethine ylides with olefinic dipolarophiles represent a dominant approach for the construction of five membered ring amines also known as pyrrolidines [3]. Pyrrolidines are fundamental biological scaffolds present
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in diverse natural and synthetic compounds. Functionalized pyrrolidines are prominent synthetic targets due to their extensive applications as chiral ligands [4], organocatalysts [5] and their role
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as important building blocks in organic syntheses. On the other hand, spirooxindoles have attracted significant attention due to its unique structure and pronounced biological activities [6]. The spirooxindole-pyrrolidine heterocyclic hybrids are present as a core unit in alkaloids such as horsfiline [7], coerulescine [8] and elacomine [9]. The more complex natural spirooxindole viz., spirotryprostatins has been reported to show anticancer activity [10]. In addition to the naturally occurring spirooxindoles, the synthetic derivative, MI-888 has been in preclinical research for
Synthesis
of
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the treatment of human cancers [11] (Scheme 1). complex
molecules
through
multicomponent
reactions
using
nonconventional solvents are the main target for many research groups nowadays. Ionic liquids are well known for their high chemical and thermal stability, solvating ability, behavior as acidic
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and basic catalysts and recyclability. Owing to these credentials, ionic liquids have attracted great interest as environmentally benign reaction media [12]. Hence the synthesis of biologically
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important spirooxindole-pyrrolidine heterocyclic hybrids in ionic liquid would be of interest in the context of green chemistry. Albeit the few reports available employing ionic liquid 1-butyl-3methylimidazolium bromide, [bmim]Br as the reaction medium for this kind of chemistry [13, 14], it still gains importance in comparison to others. In continuation of our profound interest towards the synthesis of novel hybrid
heterocycles [15-24], herein we report the synthesis of spirooxindole-pyrrolidine heterocyclic hybrids via the [3+2] cycloaddition of azomethine ylide generated in situ from isatin and sarcosine or phenyl glycine to (3E,5E)-1-allyl-3,5-bis(4-methoxyphenylmethylidene)piperidin-4one in [bmim]Br. The molecular structure of these synthesized compounds were confirmed by 3
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NMR spectroscopy, X-ray diffraction studies. As the characterization of these new spirooxindole-pyrrolidine heterocyclic hybrids deserve both theoretical and experimental studies, herein we also report the DFT studies performed on these hybrids to support their novel structural features. Computational studies are being used routinely and proved to be successful in
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characterizing the molecular structures in complete manner, when there are discrepancies in experimental data like disorder, twinning in crystal structure, overlap of peaks in spectra of compounds when they present as mixture of isomers, etc., during the synthesis of novel
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compounds with diverse structural features.
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Scheme 1 Selected biologically important spirooxindole-pyrrolidine heterocyclic hybrids
2. Experimental Section 2.1. Chemistry
Melting points were recorded using open capillary tubes and are uncorrected. The 1H, 13C and 2-D NMR spectra were recorded on a Bruker 400 or 500 MHz instruments (Faellanden,
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Switzerland) in CDCl3 using TMS as internal standard. Standard Bruker software was used throughout. Chemical shifts are given in parts per million (δ-scale) and the coupling constants are given in Hertz. Elemental analyses were performed on a Perkin Elmer 2400 Series II
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Elemental CHNS analyzer (Waltham, MA, USA). 2.2. Experimental procedure for the synthesis of 4
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An equimolar mixture of (3E,5E)-1-allyl-3,5-bis(4-methoxyphenylmethylidene)piperidin-4-one 1, isatin 2 and sarcosine 3 in 200 mg of [bmim]Br was heated at 100 oC for 30 minutes. After completion of the reaction as evident from TLC, water (50 mL) was added to the reaction mixture and extracted with ethyl acetate (3x30 mL). The excess solvent was evaporated under reduced pressure. The resultant solid was dried in vacuum and purified through column chromatography using hexane: ethyl acetate (3:2 v/v) as eluent to obtain 4 as colorless solid. Spiro[2.3″]oxindole-spiro[3.3′]-1′-allyl-5′-(4-methoxyphenylmethylidene)tetrahydro-4′(1H)pyridinone-4-(4-methoxyphenyl)-pyrrolidine (4) 4
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H NMR (500 MHz, CDCl3): δH 1.83 (d, 1H, J = 13.0 Hz, 2'-CH2), 2.14, (s, 3H, N-CH3), 2.69
(dd, 1H, J = 13.5, 8.0 Hz, 7'-CH2), 2.87 (dd, 1H, J = 15.0, 2.5 Hz, 6'-CH2), 3.07 (dd, 1H, J = 13.5, 2.5 Hz, 7'-CH2), 3.29 (dd, 1H, J = 12.5, 1.5 Hz, 2'-CH2), 3.31-3.35 (m, 1H, 5-CH2), 3.42 (d, 1H, J = 14.5 Hz, 6'-CH2), 3.79 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 3.90 (dd, 1H, J = 10.5, 9.0
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Hz, H-5), 4.77 (dd, 1H, J = 11.0, 7.5 Hz, H-4), 4.95–5.00 (m, 2H, 9'-CH2), 5.55–5.58 (m, 1H, H8'), 6.66 (d, 1H, J = 7.5 Hz, ArH), 6.81 (d, 2H, J = 9.0 Hz, ArH), 6.84 (d, 2H, J = 8.5 Hz, ArH), 6.92 (t, 1H, J = 8.0 Hz, ArH), 7.04 (d, 2H, J = 9.0 Hz, ArH), 7.06–7.11 (m, 2H, Ar-H), 7.18 (s, 1H, arylmethylidene), 7.35 (d, 2H, J = 8.5 Hz, ArH), 8.32 (s, 1H, 1"-NH). 13C NMR (125 MHz,
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CDCl3): δC 34.68, 45.08, 54.20, 55.23, 55.27, 56.23, 57.16, 61.00, 65.78, 76.25, 108.66, 113.56, 113.82, 117.47, 121.89, 127.64, 127.74, 127.90, 128.67, 130.51, 130.53, 131.17, 132.11, 134.35,
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137.68, 141.99, 158.41, 160.04, 177.91, 198.87. Anal. calcd for C34H35N3O4: C, 74.29; H, 6.42; N, 7.64 %; found: C, 74.42; H, 6.23; N, 7.73 %.
2.3. Experimental procedure for the synthesis of 6
An equimolar mixture of (3E,5E)-1-allyl-3,5-bis(4-methoxyphenylmethylidene)piperidin-4-one 1, isatin 2 and phenylglycine 5 in 200 mg of [bmim]Br was heated at 100 oC for 30 minutes.
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After completion of the reaction as evident from TLC, water (50 mL) was added to the reaction mixture and extracted with ethyl acetate (3x30 mL). The excess solvent was evaporated under reduced pressure. The resultant solid was dried in vacuum and purified through column chromatography using hexane: ethyl acetate (3:2 v/v) as eluent to obtain 6 as colorless solid.
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Spiro[2.3″]oxindole-spiro[3.3′]-1′-allyl-5′-(4-methoxyphenylmethylidene)tetrahydro-4′(1H)pyridinone-4-(4-methoxyphenyl)-5-(phenyl)pyrrolidine (6) H NMR (500 MHz, CDCl3): δH 1.97 (d, 1H, J = 12.5 Hz, 2'-CH2), 2.49 (bs, 1H, NH), 2.75 (dd,
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1H, J = 13.0, 7.5 Hz, 7'-CH2), 2.90 (dd, 1H, J = 14.5, 2.5 Hz, 6'-CH2), 3.12 (dd, 1H, J = 13.5, 5.0 Hz, 7'-CH2), 3.41 (d, 1H, J = 12.5 Hz, 2'-CH2), 3.47-3.50 (m, 1H, 6'-CH2), 3.75 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 4.63 (d, 1H, J = 11.0 Hz, H-5), 4.98–5.03 (m, 2H, 9'-CH2), 5.38 (d, 1H, J = 10.5 Hz, H-4), 5.55–5.61 (m, 1H, H-8'), 6.65 (d, 1H, J = 7.5 Hz, ArH), 6.78 (d, 2H, J = 8.5 Hz, ArH), 6.82 (d, 2H, J = 8.5 Hz, ArH), 6.94 (t, 1H, J = 8.0 Hz, ArH), 7.04 (d, 2H, J = 9.0 Hz, ArH), 7.08 (t, 1H, J = 7.5 Hz, ArH), 7.12 (s, 1H, arylmethylidene), 7.17-7.27 (m, 4H, ArH), 7.33 (d, 2H, J = 8.0 Hz, ArH), 7.54 (d, 2H, J = 7.0 Hz, ArH), 7.86 (s, 1H, 1"-NH). 13C NMR (125 5
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MHz, CDCl3): δC 54.03, 55.12, 55.28, 56.05, 56.14, 60.93, 64.45, 66.78, 72.15, 108.88, 113.57, 113.87, 117.60, 121.92, 126.87, 127.49, 127.70, 127.80, 128.31, 128.79, 129.23, 129.49, 130.82, 131.28, 132.18, 134.30, 137.49, 141.00, 141.24, 158.34, 160.13, 180.44, 199.51. Anal. calcd for
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C39H37N3O4: C, 76.57; H, 6.10; N, 6.87 %; found: C, 76.71; H, 6.21; N, 6.70 %. 2.4. X-ray details
The compounds 4 and 6 were obtained as single crystals by slow evaporation from ethylacetate solution of the pure compound at room temperature. Data were collected on a Bruker APEX-II
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D8 Venture area diffractometer, equipped with graphite monochromatic Mo Kα radiation, λ = 0.71073 Å. Cell refinement and data reduction were carried out by Bruker SAINT. SHELXT [25, 26] was used to solve structure. The final refinement was carried out by full-matrix least-squares
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techniques with anisotropic thermal data for nonhydrogen atoms on ܨ. Crystallographic data (including structure factors) for the compound 4 and 6 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 1537473 and CCDC 1537466 respectively. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44 (0)1223 336033 or e-mail:
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[email protected]]. 2.5. Computational Details
All the quantum chemical calculations of the compounds 4 and 6 were performed by applying DFT method with the B3LYP functional and 6‒31G(d,p) basis set using Gaussian 03 software
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[27]. The input files were prepared using the Cartesian coordinates taken from the crystallographic information files (CIFs) obtained from our reported X‒ray single crystal
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measurements. The geometries were optimized by minimizing the energies with respect to all the geometrical parameters without imposing any molecular symmetry constraints. GaussView 4.1 [28] program is used to draw the molecular electrostatic potential maps (MEP). Chemcraft [29] is used to draw the optimized geometries. Frequency calculations at the optimized geometries were done and no imaginary frequency modes were detected which confirm that the optimized structures are energy minimum. The 1H and the 13C isotropic shielding tensors referenced to the TMS were carried out at the same level of theory and using the gauge including atomic orbital (GIAO) method. The effect of solvent (chloroform) on the calculated chemical shifts is computed using the Polarizable Continuum Model (PCM). The natural charges were obtained 6
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using NBO calculations as implemented in the Gaussian 03 package [30] at the DFT/B3LYP level. 3. Results and Discussion
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3.1. Synthesis The synthesis of starting substrate 3,5-bis(4-methoxyphenylmethylidene)piperidin-4-one was accomplished following a literature method [31]. The prerequisite, 1-allyl-3,5-bis(4methoxyphenylmethylidene)piperidin-4-one (1) was prepared by the reaction of 3,5-bis(4-
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methoxyphenylmethylidene)piperidin-4-one with allyl chloride in acetone [18]. With the dipolarophile (1) in hand, initially we performed the cycloaddition of 1 with azomethine ylide generated in situ from the reaction of isatin (2) and sarcosine (3). An equimolar mixture of 1, 2
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and 3 in refluxing methanol (10 mL, 60 min) furnished the spirooxindole-pyrrolidine 4 as a sole reaction product in good yield (86%). As an alternative, the same reaction was also performed in (bmim)Br at 80 oC (Scheme 2). After completion of the reaction (30 min), the reaction mixture was extracted with ethyl acetate and purified by column chromatography. The compound 4 was obtained with an improved yield (94%) over the conventional heating in methanol. The ionic liquid, [bmim]Br was recycled in pure form from the reaction mixture by removing the product
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and drying the ionic liquid in vacuum as reported by us earlier [23]. The recycled ionic liquid could be used further for subsequent reaction.
Scheme 2. Synthesis of spirooxindole-pyrrolidine hybrid 4 from 1-allyl-3,5-bis(4-
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methoxyphenylmethylidene)piperidin-4-one (1), isatin (2) & sarcosine (3) The structure of compound 4 was elucidated using elemental analysis, 1H,
13
C and 2D NMR
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spectroscopy (vide supporting data).
The above cycloaddition reaction was then carried out with a primary amino acid viz.,
phenyl glycine instead of sarcosine under similar reaction conditions, which afforded the spirooxindole-pyrrolidine 6 in excellent yield (96 %) (Scheme 3). Compound 6 has a phenyl group in position 5 and an unsubstituted N atom in position 1 of the pyrrolidine ring. The presence of NH group makes this molecule more attractive for further modifications. The structure of compound 6 was also elucidated using elemental analysis, 1H,
13
C and 2D NMR
spectroscopy (vide supporting data).
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Scheme 3 Synthesis of spirooxindole-pyrrolidine hybrid 6 from 1, 2 & phenyl glycine (5) A rational mechanism for the formation of spiroxindole-pyrrolidines 4/6 in the presence of [bmim]Br is described in Scheme 4. The hydrogen atom of [bmim]+ being electron-deficient
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could form hydrogen bond with the carbonyl group of isatin facilitating the nucleophilic attack of the amino group of phenylglycine on isatin and subsequent dehydration to furnish azomethine ylide. Simultaneously, the hydrogen bond between the imidazole ring hydrogen of [bmim]+ and the carbonyl group of 1 may facilitate the [3+2] cycloaddition of 1 with azomethine ylide to
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afford 6.
3.2. X-ray crystallographic studies
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Scheme 4. Proposed mechanism for the formation of spiroheterocyclic hybrid 4/6
X-ray crystallographic study of a single crystals of 4 (Fig. 1) and 6 (Fig. 2) confirms the structures deduced from NMR spectroscopic studies.
Figure 1. ORTEP diagram of 4. Displacement ellipsoids are plotted at the 30% probability level for non-H atoms showing the disorder parts
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Figure 2. ORTEP diagram of 6. Displacement ellipsoids are plotted at the 30% probability level for non-H atoms showing the disorder parts.
A view of the hydrogen bonding pattern of compounds 4 and 6 was shown in Fig.4.
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Figure 3. A view of the intermolecular hydrogen bonding pattern of compounds 4 and 6
The crystallographic data, conditions used for the intensity data collection and some features of
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the structure refinements are listed in Table 1. The selected geometric parameters like bond lengths from X-ray data and DFT (B3LYP/6-31G(d,p)) calculations are listed in Table 2 and Table 4 for the compounds 4 & 6 respectively. The bond angles obtained from X-ray data are listed in Tables 3 and Table 5 for the compounds 4 & 6 respectively. The unit cell of the crystal structure of compound 4 contains two independent molecules, in which molecule A is partially disordered in para-methoxy group (occupancies 0.85(3) and 0.15(3)). The molecule B has two disordered components differ from one another in the orientation of the methyl group and methoxyphenyl group over two sets of atomic sites having occupancies 0.39(2), 0.62(3) and 0.53(2), 0.47(2), respectively (Fig. 1). 8
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The molecules are packed together through two strong classical intermolecular hydrogen bonds viz., N1A-H1NA…O1A and N1B-H1NB…O1B, resulting in the formation of centrosymmetric eight-membered cyclic dimers with the D-H---A angle of 178(2)◦ and 174(2)◦ respectively (Fig. 3). The corresponding D---A bond lengths are 2.8249(19) Å for N1A-
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H1NA…O1A and 2.814(2) Å N1B-H1NB…O1B. There are three non-classical hydrogen bonding interactions also present between C-H…O (Table 6, Fig 3) atoms. On the other hand, the unit cell of compound 6 contains only one independent molecule, which has disorder over two sets of atomic sites having occupancies 0.744 (3) and 0.256 (3). The two disordered components differ
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from one another in the orientation of the propyl substituents, so that the crystal of 6 contains three distinct conformers. (Fig 4). The molecules are linked by strong classical intermolecular hydrogen bond between N3-H1N3…O4 lead to the formation of centrosymmetric eight-
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membered cyclic dimers with N3---O4 distance of 9.003(18) Å and N3-H1N3…O4 angle of 171(2)°. The non-classical hydrogen bonding interactions also observed between C-H…O (Table 7) atoms in 6.
Table 1: The crystal and experimental data of compound 4 and 6
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Table 2 Selected bond lengths (Å) from the X-ray data and from DFT (B3LYP/6-31G(d,p) level) calculations for the compound 4
Table 3 Selected bond angles (°) from the X-ray data for of compound 4
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Table 4 Selected bond lengths (Å) from the X-ray data and from DFT (B3LYP/6-31G(d,p) level)
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calculations for the compound 6
Table 5 Selected bond angles (°) from the X-ray data for of compound 6 Table 6 Hydrogen-bonding parameters (Å, °) of compound 4
Table 7 Hydrogen-bond parameters (Å, °) of compound 6
3.3. Computational study 3.3.1. Molecular structure
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The optimized bond lengths and angles of the title compounds calculated using B3LYP method with 6‒31G(d,p) basis set are given in Tables S1 & S2 (Supplementary data) while the optimized structures are given in Fig. S15 & S16 (Supplementary data). The DFT (B3LYP/631G(d,p)) computed bond lengths and bond angles are in good agreement with the corresponding
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experimental values obtained from the X-ray crystallographic method (Table 2-5). Further, the bond parameters of the disordered groups present in the crystal structure are confirmed from the corresponding DFT computed values. The compounds 4 and 6 possess C1 point group and the optimized geometries are well compared with the experimental structures. The calculated
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geometric parameters agree well with the experimental results. The correlations between the calculated and experimental data gave high correlation coefficients which are in the ranges of
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0.896-0.934 and 0.909-0.958 for bond distances and bond angles, respectively. The small deviations between the calculated and experimental geometries could be attributed to the crystal packing effects.
3.3.2. Natural atomic charge population
The charge populations at different atomic sites have great importance to define the reactive sites in the compound. This has a strong relation to its biological activity. In this regard,
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the natural atomic charges were computed and collected in Table 6. It is clear from this table that, the most electronegative regions are related to the O and N-atoms. The carbonyl oxygen and the amine (NH) nitrogen atoms are the most electronegative heteroatoms in the studied systems. On the other hand, the most positive regions are related to the H-atoms where the amine NH
respectively.
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protons have the highest positive charge density of 0.437 e and 0.405-0.442 e for 4 and 6,
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Molecular electrostatic potential (MEP) maps are very useful three dimensional diagram used to visualize the charge distributions and charge related properties of molecules. Also, it has been used to predict the reactive sites for electrophilic and nucleophilic attack, and in studying the hydrogen bonding interactions [32, 33]. The MEP maps of the studied compounds calculated using B3LYP method with 6‒31G(d,p) basis set are shown in Fig. 4. It can be seen from this figure that, negative regions (red) are mainly localized over the carbonyl O-atoms while the positive regions (blue) are located around the H-atom of the NH groups which confirm the electron deficiency of this site. From this point of view, the most reactive sites for H-bonding
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interactions are the carbonyl O-atoms (H-acceptor) and the amine NH (H-donor) proton which agrees very well with the reported X-ray structure analysis. Table 8 The natural atomic charges calculated from DFT at the B3LYP/6-31G(d,p) level
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Figure 4 Molecular Electrostatic potentials (MEP) mapped on the electron density surface calculated by the DFT/B3LYP method. 3.3.3. NMR spectra
The isotropic magnetic shielding (IMS) values calculated using the GIAO approach at the 6-
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31G(d,p) level have been used to predict the 13C and 1H-NMR chemical shifts (δcalc) for the title compounds and the results were correlated to the experimental NMR data (δexp) in CDCl3 as 13
C-NMR chemical shift values are given in
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solvent. The experimental and theoretical 1H- and
Table S3 (Supplementary Information). According to these results, the calculated chemical shifts are in good agreement with the experimental findings. The correlation coefficients (R2) between the experimental and calculated chemical shifts are in the range of 0.943-0.972 (Fig SF6 & SF14 Supplementary Information). In the 1H NMR spectra of 4, the NH proton of the oxindole ring appears as a singlet at 8.32 ppm (Fig. 5) and the corresponding DFT computed value is 7.43
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ppm. The singlet signal at 2.14 ppm confirm the presence of -NCH3 group of pyrrolidine ring which is close to the DFT computed values for the three protons 2.38 ppm, 2.37 ppm & 2.02 ppm.
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Figure 5. 1H and 13C chemical shifts of compound 4 In the 1H NMR spectrum of compound 6, the NH proton of the oxindole ring appears as
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a singlet at 7.86 ppm (Fig. 6) and the DFT computed value is 7.52 ppm. From the DFT calculations at B3LYP/6-31G(d,p) level, the -NH proton of the pyrrolidine group resonate at 3.35 ppm which is not observed/assigned from experimental spectra due to overlap with other signals. In the 13C NMR spectra of compound 4, the two spiro carbons C2 & C3 resonate around 76.25 ppm and 65.78 ppm respectively. The corresponding DFT computed chemical shifts are 70.69 and 64.43 ppm respectively. The carbon atom of the CH3 group attached to the pyrrolidine N atom resonates at 34.7 ppm experimentally and the corresponding DFT computed value is 24.6 ppm. In the compound 6 the two spiro carbons C2 & C3 resonate around 72.15 ppm and 66.78 ppm respectively. The corresponding DFT computed values are 72.51 ppm and 60.65 11
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respectively. The carbonyl carbon of the oxindole group of 4 and 6 resonate around 177.91 ppm and 180.44 ppm respectively. Another carbonyl carbon 4’ of compounds 4 and 6 resonate around 198.87 ppm and 199.51 ppm respectively. The corresponding DFT computed values are 185.95
Figure 6. 1H and 13C chemical shifts of compound 6
3.3.4. Nonlinear optical (NLO) properties
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ppm and 192.08 ppm.
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The strength of molecular interactions, cross-section of different scattering and collision processes and non-linear optical properties are mainly governed by the polarizabilities of the molecules which lead to the applications in material chemistry. The study about these properties
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require both experimental and theoretical attention. Quantum chemical calculations are highly useful in understanding the electronic polarization of the molecules having non-linear optical properties. Nonlinear optical materials are used as key materials for photonic communications which use light instead of electron for data transmission. With the development of laser technology, nonlinear optical materials have been extensively applied to industry, national defense, medicine and research [34, 35]. Several organic materials have been used for such
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applications. The synthesized organic compounds 4 and 6 were characterized by their high polarizability (α0) and low HOMO‒LUMO gap (∆E). The α0 and ∆E values were calculated to be 407.17 Bohr3 and 3.70 eV, respectively for 4 while 466.25 Bohr3 and 3.52 eV for 6, respectively. It has been already reported that the B3LYP functional led to average
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polarizabilities with an accuracy approaching that of sophisticated wave function approach [36], the computed polarizability value of 4 and 6 are well above the polarizability values computed
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for the organic compounds possessing NLO property [37, 38], suggest these could be a good candidate for NLO applications. In particular, compound 6 could be a better candidate for NLO applications than 4.
In fact, the NLO is a phenomenon caused by the interaction of intense light with matter
and theoretically the presence of considerable charge separation resulting in polarizability lead to the NLO activity of the molecule. The energy gap between the HOMO and LUMO is also crucial in determining the electronic, redox, transport and optical properties of the materials. Thus the obtained polaizability values for compounds 4 and 6 are due to the charge separation arised from the donor-acceptor groups present in the molecule. 12
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4. Conclusions We have achieved the stereoselective synthesis of highly functionalized spiro-oxindole pyrrolidine hybrid heterocycles 4 and 6 in excellent yield through an ionic liquid, (bmim)Br mediated [3+2] cycloaddition reaction of 1-allyl-3,5-bis(4-methoxyphenylmethylidene)piperidin-
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4-one with azomethine ylide generated in situ from the reaction of isatin and sarcosine or phenylglycine. The stereochemistry of these heterocyclic hybrids were confirmed from X-ray crystallographic studies. The molecular structure of these compounds have been optimized using DFT/B3LYP method and 6-31G(d,p) basis set. The DFT calculated bond distances and bond
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angles showed good agreement with our reported X-ray crystal structure. The molecular electrostatic potential picture of these hybrid heterocycles has been calculated using the same
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level of theory. The polarizability (α0) and HOMO-LUMO energy gap (∆E) values indicated the better NLO activity of 6 compared to 4 and the α0 values are well above the already known organic compounds possessing NLO property. The GIAO 1H- and
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values correlated well with the experimental data. The correlation coefficients (R2) for carbon and proton are high (0.943-0.972).
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Acknowledgments
The authors extend their appreciation to the Deanship of Scientific Research at King Saud
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University for funding this work through research group No. RG-1438-052.
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35. V.M. Geskin, C. Lambert, J.L. Bredas, J. Am. Chem. Soc. 125 (2003) 15651-15658. 36. W. Koch, M.C. Holthausen, A Chemist’s guide to Density Functional Theory, 2nd Ed. Wiley-VCH Verlog, Germany, 2001, p. 185. 37. H. Wynberg, M.B. Groen, H. Schadenberg, J. Org. Chem. 36 (1971) 2797-2809.
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Figure Captions
Scheme 1. Selected biologically important spirooxindole-pyrrolidine heterocyclic hybrids 2.
Synthesis
of spirooxindole-pyrrolidine hybrid
4
from
1-allyl-3,5-bis(4-
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Scheme
methoxyphenylmethylidene)piperidin-4-one (1), isatin (2) & sarcosine (3) Scheme
3.
Synthesis
of spirooxindole-pyrrolidine hybrid
6
from 1-allyl-3,5-bis(4-
methoxyphenylmethylidene)piperidin-4-one (1), isatin (2) & phenyl glycine (5)
Scheme 4. Proposed mechanism for the formation of spiroheterocyclic hybrid 4/6
for non-H atoms showing the disorder parts
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Figure 1. ORTEP diagram of 4. Displacement ellipsoids are plotted at the 30% probability level
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Figure 2. ORTEP diagram of 6. Displacement ellipsoids are plotted at the 30% probability level for non-H atoms showing the disorder parts
Figure 3. A view of the intermolecular hydrogen bonding pattern of compounds 4 and 6 Figure 4. Molecular Electrostatic potentials (MEP) mapped on the electron density surface calculated by the DFT/B3LYP method.
Figure 5. 1H and 13C chemical shifts of compound 4
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Figure 6. 1H and 13C chemical shifts of compound 6
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Table Captions Table 1. The crystal and experimental data of compound 4 and 6
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Table 2. Selected bond lengths (Å) from the X-ray data and from DFT (B3LYP/6-31G(d,p) level) calculations for the compound 4
Table 3. Selected bond angles (°) from the X-ray data for of compound 4
Table 4. Selected bond lengths (Å) from the X-ray data and from DFT (B3LYP/6-31G(d,p)
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level) calculations for the compound 6
Table 5. Selected bond angles (°) from the X-ray data for of compound 6 Table 6. Hydrogen-bonding parameters (Å, °) of compound 4
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Table 7. Hydrogen-bond parameters (Å, °) of compound 6
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Table 8. The natural atomic charges calculated from DFT at the B3LYP/6-31G(d,p) level
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Scheme 1. Selected biologically important spirooxindole-pyrrolidine heterocyclic hybrids
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Scheme
2.
Synthesis
of spirooxindole-pyrrolidine hybrid
4
from
1-allyl-3,5-bis(4-
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methoxyphenylmethylidene)piperidin-4-one (1), isatin (2) & sarcosine (3)
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Scheme 3. Synthesis of spirooxindole-pyrrolidine hybrid 6 from 1, 2 & phenyl glycine (5)
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Scheme 4. Proposed mechanism for the formation of spiroheterocyclic hybrid 4/6
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Figure 1. ORTEP diagram of 4. Displacement ellipsoids are plotted at the 30% probability level
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for non-H atoms showing the disorder parts
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Figure 2. ORTEP diagram of 6. Displacement ellipsoids are plotted at the 30% probability level
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for non-H atoms showing the disorder parts.
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Figure 3. A view of the intermolecular hydrogen bonding pattern of compounds 4 and 6
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4
6
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Figure 4. Molecular Electrostatic potentials (MEP) mapped on the electron density surface
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calculated by the DFT/B3LYP method.
6
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4
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Figure 5. 1H and 13C chemical shifts of compound 4
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Figure 6. 1H and 13C chemical shifts of compound 6
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Table 1. The crystal and experimental data of compound 4 and 6
4
6
Chemical formula Mr Crystal system, space group Temperature (K) a, b, c (Å)
C34H35N3O4 549.65 Triclinic, P-1 150 8.5305 (1), 12.1167 (2), 30.9259 (4) 80.454 (1), 87.904 (1), 72.421 (1) 3004.77 (7) 4 Mo Kα 0.08 0.31 × 0.30 × 0.20
C39H39N3O4 613.73 Triclinic, P-1 100 10.8634 (6), 11.3167 (6), 15.2861 (12) 98.296 (1), 104.650 (1), 113.756 (1) 1598.49 (18) 2 Mo Kα 0.08 0.52 × 0.23 × 0.17
Bruker APEX-II CCD diffractometer Multi-scan SADABS Bruker 2014 0.975, 0.984
Bruker APEX-II CCD diffractometer Multi-scan SADABS Bruker 2014 0.958, 0.986
49003, 17342, 11131
32965, 9202, 6401
0.051
0.028
0.060, 0.169, 0.98 17342 836 17 0.41, −0.24 1537473
0.052, 0.177, 1.04 9202 455 0 0.29, −0.37 1537466
α, β, γ (°)
Absorption correction
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Tmin, Tmax No. of measured, independent and observed [I > 2σ(I)] reflections Rint Refinement R[F2 > 2σ( F2)], wR( F2), S No. of reflections No. of parameters No. of restraints ∆ρmax, ∆ρmin (e Å−3) CCDC number
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V (Å3) Z Radiation type µ (mm−1) Crystal size (mm) Data collection Diffractometer
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Crystal data
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Table 2. Selected bond lengths (Å) from the X-ray data and from DFT (B3LYP/6-31G(d,p) level) calculations for the compound 4 Exp.
DFT (B3LYP/6-31G)
Atoms
Exp.
O1B—C8B O2B—C16B O2B—C19B O2X—C19X O2X—C16X O3B—C23B O4B—C34B O4B—C31B O1A—C8A O2A—C16A O2A—C19A O2Y—C16A O2Y—C19Y O3A—C21A O4A—C34A O4A—C31A N1B—C1B
1.235 (2) 1.372 (6) 1.425 (10) 1.440 (13) 1.365 (7) 1.218 (2) 1.433 (3) 1.363 (2) 1.233 (2) 1.360 (4) 1.425 (4) 1.49 (3) 1.40 (3) 1.222 (2) 1.432 (3) 1.364 (2) 1.401 (2)
1.222 1.368 1.418 1.418 1.368 1.228 1.421 1.360 1.222 1.368 1.418 1.368 1.418 1.228 1.421 1.360 1.399
N1B—C8B N2B—C12X N2B—C11B N2B—C12B N2B—C7B N3B—C21B N3B—C24B N3B—C20B N1A—C8A N1A—C1A N2A—C11A N2A—C7A N2A—C12A N3A—C23A N3A—C20A N3A—C24A
1.350 (3) 1.483 (9) 1.456 (3) 1.491 (12) 1.466 (3) 1.463 (2) 1.468 (3) 1.458 (2) 1.356 (2) 1.398 (2) 1.457 (2) 1.463 (2) 1.457 (2) 1.463 (2) 1.455 (2) 1.466 (2)
DFT (B3LYP/631G(d,p)) 1.378 1.454 1.454 1.460 1.465 1.460 1.465 1.459 1.378 1.399 1.454 1.465 1.460 1.460 1.459 1.465
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Table 3. Selected bond angles (°) from the X-ray data for of compound 4
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Bond Angle 125.3 (5) 114.7 (5) 115.5 (5) 125.1 (5) 108.96 (14) 112.12 (14) 121.47 (15) 121.46 (15) 111.82 (18) 114.94 (16) 125.19 (17) 109.84 (15) 128.17 (16) 102.91 (12) 111.16 (14) 114.36 (13) 108.61 (13) 125.60 (15) 125.73 (15) 103.04 (14) 117.3 (2) 123.3 (2) 127.2 (10) 112.0 (10) 110.14 (13) 121.08 (14) 121.77 (15) 111.94 (14) 112.44 (15) 115.28 (16) 124.95 (16)
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Atoms O2B—C16B—C17B O2B—C16B—C15B O2X—C16X—C15X O2X—C16X—C17X N3B—C20B—C9B N3B—C21B—C22B O3B—C23B—C9B O3B—C23B—C22B N3B—C24B—C25B O4B—C31B—C32B O4B—C31B—C30B N1A—C1A—C6A N1A—C1A—C2A N2A—C7A—C9A N2A—C7A—C6A N2A—C7A—C8A N1A—C8A—C7A O1A—C8A—N1A O1A—C8A—C7A N2A—C11A—C10A O2A—C16A—C17A O2A—C16A—C15A O2Y—C16A—C15A O2Y—C16A—C17A N3A—C20A—C9A O3A—C21A—C22A O3A—C21A—C9A N3A—C23A—C22A N3A—C24A—C25A O4A—C31A—C32A O4A—C31A—C30A
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Bond Angle 116.4 (5) 118.1 (6) 117.90 (16) 118.5 (3) 129 (2) 118.33 (16) 111.57 (15) 115.7 (4) 112.0 (5) 121.9 (4) 103.1 (5) 106.94 (16) 110.84 (15) 112.32 (14) 110.29 (14) 111.40 (14) 114.78 (14) 114.90 (14) 107.53 (14) 109.80 (13) 111.38 (13) 111.02 (14) 109.56 (15) 127.55 (17) 110.77 (15) 102.48 (14) 113.27 (16) 125.68 (17) 125.17 (17) 109.08 (16) 102.74 (16)
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Atoms C16B—O2B—C19B C16X—O2X—C19X C31B—O4B—C34B C16A—O2A—C19A C16A—O2Y—C19Y C31A—O4A—C34A C1B—N1B—C8B C7B—N2B—C12X C7B—N2B—C12B C11B—N2B—C12X C11B—N2B—C12B C7B—N2B—C11B C21B—N3B—C24B C20B—N3B—C24B C20B—N3B—C21B C1A—N1A—C8A C11A—N2A—C12A C7A—N2A—C12A C7A—N2A—C11A C20A—N3A—C23A C20A—N3A—C24A C23A—N3A—C24A N1B—C1B—C6B N1B—C1B—C2B N2B—C7B—C6B N2B—C7B—C9B N2B—C7B—C8B O1B—C8B—C7B O1B—C8B—N1B N1B—C8B—C7B N2B—C11B—C10B
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Table 4. Selected bond lengths (Å) from the X-ray data and from DFT (B3LYP/6-31G(d,p) level) calculations for the compound 6 Exp.
DFT (B3LYP/631G)
Atoms
Exp.
DFT (B3LYP/631G(d,p))
O1—C4 O2—C10 O2—C13 O3—C21 O3—C31 O4—C39 N1—C1
1.2104 (19) 1.365 (3) 1.393 (4) 1.371 (2) 1.417 (2) 1.2266 (19) 1.452 (2)
1.235 1.359 1.422 1.368 1.418 1.221 1.461
N1—C2 N1—C14 N1—C14A N2—C24 N2—C32 N3—C38 N3—C39
1.454 (2) 1.490 (3) 1.450 (12) 1.468 (2) 1.470 (2) 1.393 (2) 1.357 (2)
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1.468 1.470 1.461 1.472 1.466 1.397 1.371
Table 5. Selected bond angles (°) from the X-ray data for of compound 6 Bond Angle 118.7 (2) 117.52 (16) 111.75 (12) 105.60 (17) 122.7 (8) 111.0 (2) 115.5 (8) 107.33 (12) 111.65 (14) 113.50 (14) 109.83 (12) 121.27 (15) 121.78 (14) 124.27 (17) 115.57 (18)
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C10—O2—C13 C21—O3—C31 C1—N1—C2 C1—N1—C14 C1—N1—C14A C2—N1—C14 C2—N1—C14A C24—N2—C32 C38—N3—C39 N1—C1—C5 N1—C2—C3 O1—C4—C3 O1—C4—C5 O2—C10—C9 O2—C10—C11
Atoms
N1—C14—C15 N1—C14A—C15A O3—C21—C20 O3—C21—C22 N2—C24—C17 N2—C24—C25 N2—C32—C3 N2—C32—C33 N2—C32—C39 N3—C38—C37 N3—C38—C33 N3—C39—C32 O4—C39—N3 O4—C39—C32
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Bond Angle 110.0 (2) 114.4 (14) 116.77 (16) 124.22 (15) 105.35 (12) 111.12 (12) 105.87 (12) 109.43 (12) 107.86 (12) 128.39 (16) 109.78 (15) 108.54 (13) 125.65 (14) 125.74 (15)
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Table 6. Hydrogen-bonding parameters (Å, °) of compound 4
Table 7. Hydrogen-bond parameters (Å, °) of compound 6
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D—H···A D—H H···A D···A D—H···A i N1B—H1NB···O1B 0.91 (2) 1.91 (2) 2.814 (2) 174 (2) N1A—H1NA···O1Aii 0.86 (2) 1.97 (2) 2.8249 (19) 178 (2) C4A—H4AA···O3B 0.9300 2.5800 3.482 (2) 164.00 C10A—H10A···O4Aiii 0.9800 2.4900 3.307 (2) 141.00 iii C10B—H10B···O4B 0.9800 2.3900 3.177 (2) 137.00 C30B—H30B···O3Aiv 0.9300 2.5300 3.449 (3) 172.00 Symmetry codes: (i) −x, −y+1, −z+1; (ii) −x+1, −y+1, −z; (iii) x, y−1, z; (iv) x−1, y+1, z.
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D—H···A D—H H···A D···A D—H···A N3—H1N3···O4i 0.87 (2) 2.04 (2) 2.9003 (18) 171 (2) C6—H6A···O1ii 0.9300 2.5200 3.338 (2) 147.00 C15—H15B···O4 0.9700 2.3600 3.321 (3) 170.00 Symmetry codes: (i) −x+2, −y+1, −z+1; (ii) −x+1, −y, −z.
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Table 8. The natural atomic charges calculated from DFT at the B3LYP/6-31G(d,p) level
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0.247 0.317 -0.319 0.240 -0.217 0.265 -0.067 0.260 -0.040 -0.242 0.251 -0.232 0.238 -0.240 0.237 -0.233 0.238 -0.218 0.240 -0.327 0.230 0.206 0.204 0.063 -0.061 -0.211 0.258 -0.256 0.241 -0.218 0.241 -0.279 0.241 0.174 0.730 0.405 0.442 -0.235 0.229 -0.432 0.217
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Compound 6 -0.617 H43 -0.511 C44 -0.523 C45 -0.622 H46 -0.496 C47 -0.660 H48 -0.621 C49 -0.286 H50 0.207 C51 0.249 C52 -0.279 H53 0.265 C54 0.220 H55 -0.122 C56 0.571 H57 -0.126 C58 -0.129 H59 0.256 C60 -0.113 H61 -0.189 C62 0.241 H63 -0.322 H64 0.245 H65 0.339 C66 -0.276 C67 0.255 C68 -0.184 H69 0.245 C70 -0.330 H71 0.236 C72 0.209 H73 0.209 C74 -0.294 H75 0.246 C76 0.212 C77 0.228 H78 -0.257 H79 0.265 C80 -0.076 H81 -0.211 C82 0.237 H83 -0.276
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O1 O2 O3 O4 N5 N6 N7 C8 H9 H10 C11 H12 H13 C14 C15 C16 C17 H18 C19 C20 H21 C22 H23 C24 C25 H26 C27 H28 C29 H30 H31 H32 C33 H34 H35 H36 C37 H38 C39 C40 H41 C42
M AN U
-0.280 0.227 0.267 0.572 -0.129 -0.287 0.255 0.209 -0.289 0.261 0.205 -0.229 0.229 -0.435 0.215 0.223 -0.132 0.255 -0.112 -0.176 0.243 -0.325 0.245 0.337 -0.274 0.253 -0.195 0.243 -0.330 0.235 0.209 0.208 0.437 -0.522 -0.327 0.231 0.204 0.205
TE D
Compound 4 -0.623 C39 -0.579 H40 -0.513 H41 -0.628 C42 -0.494 C43 -0.503 C44 0.175 H45 -0.281 H46 0.239 C47 -0.219 H48 0.240 H49 -0.261 C50 0.240 H51 -0.198 C52 0.264 H53 -0.079 H54 0.075 C55 0.703 H56 -0.099 C57 -0.274 C58 0.286 H59 -0.248 C60 0.214 H61 0.241 C62 -0.485 C63 0.234 H64 0.207 C65 0.236 H66 -0.068 C67 -0.214 H68 0.249 H69 -0.272 H70 0.249 H71 0.315 O72 -0.319 C73 0.240 H74 -0.217 H75 0.240 H76
EP
O1 O2 O3 N4 N5 N6 C7 C8 H9 C10 H11 C12 H13 C14 H15 C16 C17 C18 C19 C20 H21 C22 H23 H24 C25 H26 H27 H28 C29 C30 H31 C32 H33 C34 C35 H36 C37 H38
34
ACCEPTED MANUSCRIPT
Highlights Highly functionalized spirooxindole-pyrrolidine hybrid heterocycles 4 & 6 were synthesized using an ionic liquid, 1-butyl-3-methylimidazolium bromide ([bmim]Br).
RI PT
The molecular structures of these heterocyclic hybrids were confirmed from X-ray crystallographic studies, 1D & 2D NMR spectroscopy and DFT (B3LYP/6-31G[d,p]) studies.
The DFT computed bond parameters, NMR chemical shifts and reactive sites are in good agreement with experimental findings.
SC
The DFT computed polarizabilities suggest the possible NLO properties of the
AC C
EP
TE D
M AN U
compounds 4 and 6.