ОПТИКА И СПЕКТРОСКОПИЯ, 2013, том 114, № 4, с. 547-555
ОТЕКТРОСКОПИЯ АТОМОВ И МОЛЕКУЛ
y%K 539.19
THEORETICAL AND FT-IR, FT-RAMAN STUDIES OF NIPECOTAMIDE
AND ITS TAUTOMERS, ISOMERS
© 2013 n Senay Yurdakul and Nefise £igdem Ya^ayan
Department of Physics, Faculty of Science, Gazi University, Teknikokullar, 06500Ankara, Turkey
Received June 15, 2012
The structure, conformers, energies and vibrational spectra of the important nipecotamide molecule have been characterized by FT-IR (mid-IR, far-IR), FT-Raman spectroscopy and by DFT calculations. The structure is optimized by B3LYP/6-311++G(d, p) calculations. All vibrational frequencies assigned in detail with the help of total energy distribution (TED). The calculated vibrational wavenumbers were compared with IR and Ra experimental data. In the most stable tautomer (NT-1), the piperidine ring adopts the chair conformation and the amide group is in the axial orientation and is stabilized by an intramolecular N-H—O hydrogen bond of 4.37 A.
DOI: 10.7868/S003040341304017X
INTRODUCTION
Nipecotamides (3-carbamoylpiperidine) derivatives inhibit platelet aggregation [1]. Platelets play a major role in thrombus formation particularly in the arterial system. Platelet deposition followed by thrombus formation has been implicated in the growth of atherosclerotic plaques [2].
Antiplatelet drugs such as aspirin and ticlopidine have been used to prevent acute thromboembolic artery occlusions in cardiovascular diseases and the benefits are evident [3]. The solubilities of poorly water-soluble drugs, such as diazepam, griseofulvin, progesterone, testesterone and nifedipine were studied in the presence of nipecotamide, nicotinamide and were found to increase the solubities of drugs in a linear fashion [4, 5].
The binding sites of piperidinecarboxamides in proteins were identified independently by NMR and by computational methods [6].
Jurkiewicz-Herbich et al. [7, 8] studied the adsorption of nipecotamide (3-piperidine carboxamide) from aqueous solutions in mercury electrodes in order to investigate the factors that govern the adsorption of molecules from aqueous solutions, upon the type of interface and the structure of the solutions, to elucidate the adsorption mechanisms and structure details of the adsorption layer.
Ribeiro da Silva and Cabral [9] presented the ther-mochemical study ofl-, 3-, and 4-piperidinecarboxa-mide, reporting their standart molar enthalpies of formation in the crystalline state derived from the standard molar enthalpy of combustion determined by static bomb calorimetry and their standard molar enthalpies of sublimation measured by Calvet microcal-orimetry. The 1H NMR investigation of the confor-mational equilibrium and intramolecular hydrogen bonding in nipecotamide are reported and analysed
[10]. The aim of this paper is to predict the structure and vibrational spectra (harmonic wavenumbers and relative intensities for Raman and IR spectra) of nipecotamide and its tautomers/isomers by means of density functional theory (DFT) levels. The FT-IR and Raman spectra are used for comparison with the theoretical spectra.
The calculated geometrical parameters for nipeco-tamide (Nip) will be compared with the X-ray results
[11]. This is the first work about experimental and theoretical calculation of vibrational spectra of nipeco-tamide molecule. The calculated energy differences between tautomeric and isomeric forms have been evaluated.
EXPERIMENTAL
Nipecotamide was obtained from Aldrich and used without any further purification. The mid-IR spectrum of nipecotamide was recorded using a Mattson 1000 Fourier transform spectrophotometer in the region 4000—400 cm-1 in KBr pellet. The spectrum was collected with a resolution of 0.2 cm-1. The Far-IR spectrum in the region 700-100 cm-1 was obtained using a Bruker IFS 66/S system. The FT-Raman spectrum in the region 3500-100 cm-1 was recorded employing a Bruker FRA 106/s Raman module.
A Nd:YAG laser at 1064 nm with an output of 300 mW was used as the excitation source and the spectrum was recorded over 500 scans at the fixed temperature. The detector is a liquid nitrogen-cooled Ge detector.
METHOD OF ANALYSIS
The calculations of geometrical parameters, vibra-tional frequencies were performed using the Gaussian 03
Table 1. Calculated total energies &ot (in Hartree) and relative AE (in kcal mol-1) energies of the species studied
Species
NT-1
NT1I-A
NT1I-B
NT1I-C
NT-2
NT2I-A
NT21-B
NT2I-C
NT-3
NT3I-A
NT31-B
NT3I-C
Etot
420.73876503 420.73437866 420.72977506 420.72932708 420.69942716 420.69869479 420.69737440 420.69672772 420.69383924 420.68295774 420.68173627 420.68045116
AE3
0.00 2.75 5.64 5.92 24.68 25.14 25.97 26.38 28.19 35.02 35.78 36.59
a AE = En — Ei are the energy differences between the nth tau-tomer/isomer (n = 2, 3, 4) and the first tautomer.
program package [12] and Gauss View molecular visualization program [13].
In this work, we applied the DFT method including the hybrid gradient-corrected exchange functional proposed by Becke [14, 15] with the gradient corrected correlation function of Lee, Yang and Parr [16], B3LYP, using the basis set 6-311++G(d, p). The electronic energies for all tautomer/isomer forms were also determined. The assignment of the calculated normal modes were made from the corresponding total energy distributions (TEDs). The TEDs were calculated using the Parallel Quantum Solutions software [17].
RESULTS AND DISCUSSION
Structure of Nipecotamide
Conformational analysis of substituted and saturated six-membered rings teaches that unfavorable 1,3-diaxial interactions lead to equilibria favoring equatorial conformers [18]. A striking apparent exception [19] to this long-standing generalization has recently been shown to be erroneous [20]. By contrast, sulfoxides derivatives, sulfones and piperidines represent systems in which lone-pair bearing functionalities can promote mixtures favoring the axial form [21]. The intramolecular hydrogen bonding in nipecota-mide and some methyl derivatives has been investigated by IR spectroscopy [22]. Abraham et al. [10] also gave 1H NMR study of some nipecotic acid derivatives and showed that the intramolecular hydrogen bonds between the substituent and the nitrogen atom in the axial conformer.
Here we give the all conformers (tautomeric/iso-meric forms) of nipecotamide molecule for the first time. The numbering of atoms in all conformers of
nipecotamide molecule is given in Fig. 1. Theoretically several tautomer/isomer forms could be considered in a nipecotamide molecule, which are distinguished as "NT" and "NTI" respectively in Fig. 1. Different isomers of the tautomer are distinguished as "A", "B" and "C" in Fig. 1.
By varying the N19-C16-C1-C2 and H5-N14-C2-C1 dihedral angles all "A", "B", and "C" con-formers were inspected. So three tautomers and nine isomers have been obtained for the nipecotamide molecule. The calculated total and relative energy values are gathered in Table 1. The energies were calculated at the B3LYP/6-311++G(d, p) levels at geometry optimized using the same level. As it is shown in Table 1, our calculation in the gas phase indicate that the NT-1 form of nipecotamide is the most stable than the other conformers. The NT-1 form has the lowest energy value (E = —420.73878961 Hartrees) among all conformers.
Generally the partial charge distribution on the skeletal atoms shows that the electrostatic repulsion or attraction between atoms can give a significant contribution to the intra- and intermolecular interaction [23]. So, the most stable tautomer NT-1 of nipecota-mide molecule is stabilized by two intramolecular hydrogen bonds, namely N19—H20...N14 and C16—O17...H18, the lengths ofwhich are 3.11879 and 3.72342 Á, respectively.
Molecular Geometries
The optimized bond lengths and bond angles and dihedral angles obtained in the most stable tautomer of nipecotamide (NT-1) using B3LYP level with 6-311++G(d, p) basis set is given in Table 2. We could find neither experimental data nor calculation results on molecular structure of nipecotamide in the literature, therefore the molecular structure of nipecotamide is compared with the X-ray data of piperidine-3-carboxylic acid with salicylic acid crystal [11]. It is also known that nipecotamide and its some methyl derivatives can exist in two possible chair conformations. In nipecotamide free base there are two possible modes of hydrogen bonding in the axial conformation, C=O-HN and CONH-N type. This molecule would be expected to exist entirely as conformer equatorial, if there is no intramolecular hydrogen bonding. In this case there is also a large repulsive 1,3-diaxial interaction in the axial conformation [11]. The calculated bond distances, especially, the values of piperidine cyclic, namely N14—C2, C2—C1, C1—C5, C5—C4, N14—C3, and C1—C16 are very close to those of the experimental piperidine values. As seen in Table 2 dihedral angle values of NT-1 are similar to those of the piperidine-3-carboxylic acid with salicylic acid crystal. The nitrogen atom of piperidine cyclic acid exists in the axial conformer with the amide group.
The intramolecular hydrogen bond lengths between the amide group and the atoms of piperidine
NT2I-B
NT2I-C
NT3I-B
^ NT3I-C
Fig. 1. Tautomeric/isomeric forms of nipecotamide. ОПТИКА И СПЕКТРОСКОПИЯ том 114 № 4 2013
Table 2. Calculated bond lengths (in Angstroms) and bond angles (in degrees) of tautomers of nipecotamide
Bond lengths NT-1 NT-2 NT-3 X-ray [11]
N(14)-C(2) 1.471 1.455 1.471 1.495
C(2)-C(1) 1.538 1.561 1.507 1.528
C(1)-C(5) 1.548 1.544 1.510 1.542
C(5)-C(4) 1.535 1.541 1.542 1.530
C(4)-C(3) 1.531 1.536 1.529 1.522
N(14)-C(3) 1.470 1.464 1.466 1.496
C(1)-C(16) 1.537 1.526 1.339 1.531
C(16)-O(17) 1.360 1.369 1.377 1.281
C(16)-N(19) 1.222 1.265 1.408
(AR)a 0.019 0.028 0.052
Bond angles
N(14)-C(2)-C(1) 110.72 114.90 110.23 111.95
C(2)-C(1)-C(5) 109.58 109.33 113.55 110.11
C(1)-C(5)-
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