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Structure and vibrational spectroscopy of the fenbufen–β-cyclodextrin inclusion complex
Vibrational Spectroscopy 69 (2013) 30–39
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Vibrational Spectroscopy journal homepage: www.elsevier.com/locate/vibspec
Structure and vibrational spectroscopy of the fenbufen–-cyclodextrin inclusion complex Ferenc Billes a,b , Antonio Hernanz c,∗ , Hans Mikosch b , Ioan Bratu d a
Department of Physical Chemistry and Material Science, Budapest University of Technology and Economics, Budafoki út 8, H-1521 Budapest, Hungary Institute of Chemical Technologies and Analytics, Vienna University of Technology, A-1060 Vienna, Getreidemarkt 9/164 EC, Austria Departamento de Ciencias y Técnicas Fisicoquímicas, Universidad Nacional de Educación a Distancia (UNED), Paseo de la Senda del Rey 9, E-28040 Madrid, Spain d National R&D Institute for Isotopic and Molecular Technologies, P.O. Box 700, R-400293 Cluj-Napoca 5, Romania b c
a r t i c l e
i n f o
Article history: Received 2 October 2012 Received in revised form 20 September 2013 Accepted 20 September 2013 Available online 29 September 2013 Keywords: Fenbufen -cyclodextrin IR Raman Quantum chemistry
a b s t r a c t The structure and host–guest interactions in the inclusion complex (179 atoms) of -cyclodextrin with fenbufen are studied. Fenbufen, the biphenyl derivative ␥-oxo-(1,1 -biphenyl)-4-butanoic acid, is a widespread analgesic and non-steroidal anti-inflammatory drug. Its inclusion complex with cyclodextrin improves the oral bioavailability and entails fewer side-effects. Optimized molecular structures, atomic net charges and vibrational spectra have been computed for the host and guest molecules, as well as for the inclusion complex. The functional density theory with the B3LYP/3-21+G method/basis set has been applied. The calculated vibrational frequencies have not been scaled, and the simulated spectra have been compared with those obtained experimentally. The host–guest interactions have been investigated in detail. © 2013 Elsevier B.V. All rights reserved.
1. Introduction An extensive literature on the -cyclodextrin (CD) inclusion complexes has been published. They are applied in several fields of chemistry and pharmaceutics. An interesting review article on the applications and investigation methods of cyclodextrin inclusion complexes was published by Singh et al. [1]. One of the relevant applications of CD is the separation of enantiomers through their different aptitude to form inclusion complexes with this molecule [2,3]. The formation of inclusion complexes can also help in increasing the solubility of poorly soluble drugs [4]. Fenbufen (FBF) is an analgesic and non-steroidal antiinflammatory drug used primarily to treat inflammation in osteoarthritis, ankylosing spondylitis, and tendonitis. It can also be used to relieve backaches, sprains, and fractures. FBF acts by preventing cyclooxygenase from producing the prostaglandins that cause inflammation. Cyclodextrins are a family of compounds made up of sugar molecules bound together in a ring (cyclic oligosaccharides). They
∗ Corresponding author. Tel.: +34 91 3987377; fax: +34 91 3988376. E-mail addresses: [email protected] (F. Billes), [email protected] (A. Hernanz), [email protected] (H. Mikosch), [email protected] (I. Bratu). 0924-2031/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.vibspec.2013.09.006
are produced from starch by means of enzymatic conversion. They are used in food, pharmaceutical, and chemical industries, as well as agriculture and environmental engineering. One can find comprehensive information in del Valle’s review [5]. Cyclodextrins are composed by 5 or more ␣-d-glucopyranoside units. Typical cyclodextrins contain a number of glucose monomers ranging from six to eight units in a ring, creating a cone shape. Bea et al. [6] calculated the diastereomeric CD complexes with cizolirtine related carbinols using molecular dynamics. Alcaro et al. [7] applied the Monte Carlo method for the study of several CD inclusion complexes. In this work we deal with vibrational spectroscopy of the inclusion complex of FBF with CD (FBF*CD). In the next paragraphs we shall confine to publications in this area, especially to spectroscopy and quantum chemistry. Li et al. [8] studied the vibrational spectroscopy of the inclusion complex of permethrin with CD. They recorded its infrared (IR) and Raman spectra and calculated the inclusion complex with the Becke3LYP (B3LYP) functional and the 6-31G(d) basis set. Katritzky et al. [9] modeled the free energy of CD complexation on almost 70 inclusions. Stalin et al. [10] investigated the inclusion complexes of ortho, meta and para dihydroxy benzenes with CD. They studied their electron excitation and fluorescence spectra. Among the articles dealing with CD inclusion complexes some further guest molecules are worth mentioning: ketoprofen [11], paroxetine [12] and curcumin [13]. Gavira et al. [14] studied the dehydration of
F. Billes et al. / Vibrational Spectroscopy 69 (2013) 30–39
CD by IR spectroscopy. The FBF*CD complex was studied previously by several authors [15–17]. Bratu et al. [16] studied the 1 H NMR spectra of this inclusion complex in aqueous solutions and found a 1:1 CD/FBF complex ratio. Later the same research group [18] studied the 1 H NMR spectra of the inclusion complexes of FBF with ␣-cyclodextrin and ␥-cyclodextrin in aqueous solutions. They found that the FBF/␥-cyclodextrin complex is of 2:1 type. The FBF*CD complex improves the oral bioavailability of FBF, entails fewer side-effects and avoids the disgusting taste of the drug [19–21]. A detailed study of the structure and host–guest interactions of the FBF*CD complex is carried out in the present work. This information is basic to understand its biological activity. 2. Experimental 2.1. Materials and preparation of the complex CD (≤15% mass percentage of water) was purchased from Merck (Germany) and was used without further purification. A 5 × 10−3 mol dm−3 CD solution in distilled and deionized water was prepared considering the CD contents in molecular water. FBF, obtained from Terapia (Cluj-Napoca, Romania) is a drug with poor solubility in water, and for this reason the sodium salt of FBF was obtained by titration with NaOH. A 5 × 10−3 mol dm−3 aqueous solution of sodium FBF was prepared in the same way. Equal volumes of both solutions were mixed and stirred at room temperature for one hour; an aliquot was taken and stored in a freezer. Thereafter it was freeze-dried overnight. The 1:1 molar ratio in the FBF*CD inclusion complex was obtained by this freeze drying process [17]. FBF/CD 1:1 physical mixture was also obtained by simple blending of stoichiometric CD and FBF quantities in an agate mortar. KBr from Merck Uvasol was desiccated under vacuum at 70 ◦ C during several days before using to prepare KBr pellets of the samples to record their IR spectra. 2.2. Spectroscopic measurements The FTIR spectra of the KBr pellets were recorded by a Bomem DA3 interferometer working under vacuum (pressure ≤ 133.3 Pa). The IR spectrum, 4000–400 cm−1 , of the samples in KBr, was obtained by coadding 200 interferograms, using a Globar source, a MCT detector and an effective spectral resolution of s = 0.60 cm−1 (RES = 1.0 and Boxcar apodization). The FT-Raman spectra have been obtained with a Bomem DA3/DA8 FT-Raman accessory. A krypton discharge lamp pumped Nd3+:YAG laser (Quantronix CW114) working at 1064 nm has been the exciting source. The Raman scattering (Stokes) was collected with 180◦ geometry by an ellipsoidal mirror and passed through an adjustable iris with an aperture of 7 mm to the emission port of the interferometer. Two filters have been used to prevent that any stray light from the white light source and He–Ne laser contributes to the noise of the detector. Two plasma line filters have been used to allow only the 1064 nm laser line to excite the sample. A quartz beamsplitter and an InGaAs detector operated at 77 K have been used. Raleigh line rejection has been performed by a set of three notch filters at ∼17◦ with respect to the normal light beam. One of them has been placed prior to the aperture at the emission port and the other two in the sample assembly close to the detector, before and after an iris with an aperture of also 7 mm. The resolution was s = 4.16 cm−1 (RES = 4.0 and Blackman–Harris apodization). Correction for instrument response has also been done dividing the experimental spectra by the spectrum of a white light lamp that has been normalized for source spectral radiance. The spectra of polycrystalline samples have been obtained using a glass capillary arranged perpendicularly to the direction of the laser beam.
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3. Calculations 3.1. Quantum chemical calculations The objects of the quantum chemical calculations were the FBF anion, the CD molecule and the FBF*CD inclusion complex. According to previous experimental results [15,16,22] we assumed a 1:1 complex model. The Gaussian09 program package [23] was applied for the calculations with the DFT hybrid functional B3LYP. The chosen basis set was B3LYP/3-21+G. We used diffuse functions since they help to get a good description of the host–guest interactions in the inclusion complex. The mentioned basis set was also applied to the host and guest molecules in order to compare the results with those obtained for the inclusion complex. The first step of the quantum chemical calculations resulted in the optimized geometries, the atomic net charges (Mulliken [24] and NBO [25,26]) and the molecular energies. The second step of the calculations yielded the vibrational frequencies along with the definition of the normal coordinates (contributions of the individual atoms), the IR and Raman intensities of the corresponding fundamentals and the vibrational force constants. The calculations with the B3LYP/3-21+G, i.e. application of the diffuse functions for so large size molecules as FBF*CD (179 atoms) and CD (147 atoms) caused a lot of problems. In order to prevent numerical noise leading to infinite, never ending runs for mathematical standard operations, the accuracy for the calculation had to be increased beyond standard settings. Finally, we applied 99 radial shells for integral calculations, 590 angular points per shell (UltraFine keyword option in Gaussian 09) and the two-electron integral accuracy was increased to 10−12 (Acc2E = 12). As a final step of the optimization procedure, the subkeyword ReadFC for Opt (a Gaussian 09 recommended method [23]) was applied in order to use force constants determined at a lower-level (B3LYP/3-21G) in frequency calculations. They were retrieved from the checkpoint-file as the starting point for higher levels of basis set accuracy. The application of the diffuse functions is sometimes very useful, improves the results, like in our problem. However, acceptable results can be obtained without them, too [27]. 3.2. Simulation of the vibrational spectra The calculated force constants in atomic units were transformed into SI units with a home-made program. However, the large number of atoms in the FBF*CD complex makes difficult the definition of internal coordinates and the scaling of the force constants to the experimental frequencies. Therefore another way was chosen. The calculated frequencies and intensities of the normal modes have been used for the simulation of the spectra. Lorentzian band shapes with the standard full-width at half-height (FWHH) of 15 cm−1 have been assumed for the simulations. The calculated frequencies have not been scaled, i.e. their scale factor was 1.00. The calculated intensities were considered as integrated intensities. All these calculations were carried out with a home-made program [28]. Although the program includes curve fitting to the experimental overlapped band shapes through changing the FWHH of the component bands, this possibility was not applied in this work, since it decreases the intensities observed in the spectral profiles. The intensity of the Raman bands depends on the choice of the excitation wavelength. Consequently, for a better comparison to the experimental spectra, the calculated Raman intensities (Si ) were transformed taking into account the excitation wavenumber (0 ) according to [29]: Ii = f
(0 − i )4 S i [1 − exp(−hci /kT )] i
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F. Billes et al. / Vibrational Spectroscopy 69 (2013) 30–39
Fig. 1. Optimized molecular structures: (a) CD; (b) FBF; (c) FBF*CD; (d) FBF into the complex.
where i is the wavenumber of the actual normal mode and f is an arbitrary factor. 4. Results and discussion The study of the effects of host–guest interactions is very interesting. Therefore, first of all, these effects will be discussed considering the experiments and the B3LYP/3-21+G calculations in this section. According to our best knowledge, this the first time that properties of such a large inclusion complex have been calculated with a DFT quantum chemical method, completed additionally with the use of diffuse functions. 4.1. Molecular geometry The optimized geometric parameters of the host and guest molecules and the inclusion complex have been calculated, respectively. Considerable changes are found comparing the values of
these parameters for FBF and CD (column FBF + CD of the supplementary Table S1) with those of the inclusion complex, Table S1. This table contains altogether near 1100 data. Optimized structures of CD and FBF as individual molecules are shown in Fig. 1a and b respectively, the structure of the FBF*CD complex is presented in Fig. 1c and the structure of the FBF molecule into the complex is shown in Fig. 1d. The numbering of the atoms for CD and FBF are given in Figs. 2 and 3, respectively. Selected geometric parameters have been chosen according to two aspects: the effect of inclusion and host–guest interactions. Table 1 contains host and guest structural parameters that show significant differences under the effect of inclusion. Some of them increased and other decreased during the formation of the complex. This effect may be observed comparing the structures b and d of FBF in Fig. 1. Additional parameters characterizing host–guest interactions in FBF*CD are collected in Table 2. There are CD and FBF atoms that are very close in the complex. Hydrogen bonds are present in the CD molecule, as well as in the CD part of
Table 1 Selected geometric parameters characterizing the inclusion effect.a Parameterb
FBF + CDc
FBF*CD
Parameterb
FBF + CDc
FBF*CD
r (21,59) r (25,70) r (48,129) r (53,131) r (58,134) r (59,135) r (64,138) r (68,140) r (148,174) r (164,171) r (172,173) r (173,174) r (174,175) ϕ (47,6,83) ϕ (47,6,84)
1.489 1.449 1.016 1.010 0.994 0.998 1.009 0.995 1.286 1.510 1.529 1.567 1.297 110.6 104.9
1.469 1.464 1.034 1.028 1.035 1.038 1.028 1.021 1.313 1.481 1.566 1.537 1.274 105.3 110.4
ϕ (22,21,59) ϕ (59,21,100) ϕ (26,25,70) ϕ (25,26,63) ϕ (29,28,65) ϕ (28,29,66) ϕ (69,33,114) ϕ (20,58,134) ϕ (24,62,136) ϕ (27,64,138) ϕ (30,67,139) ϕ (170,171,172) ϕ (171,172,173) ϕ (176,172,177) ϕ (172,173,178)
111.3 103.6 108.4 107.5 109.6 105.6 110.0 110.6 111.7 110.4 111.1 123.7 116.6 104.4 112.2
107.1 109.5 112.9 111.5 103.1 110.9 105.9 115.4 107.2 104.2 107.0 118.8 108.6 109.5 107.8
Distances and angles not less than 0.15 A˚ and 4◦ respectively. r: bond lengths in angstroms; ϕ: valence angles in degrees. For the numbering of the atoms see Figs. 2 and 3. c FBF values in italics. a
b
F. Billes et al. / Vibrational Spectroscopy 69 (2013) 30–39
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Fig. 2. Numbering of the CD atoms.
Table 2 Geometric parameters characterizing host–guest interactions.
the location of these hydrogen bonds. All oxygen atoms of FBF participate in hydrogen bonds of the complex.
Parametera r r r ϕ ϕ ϕ ϕ ϕ ϕ ϑ ϑ
(134,148) (135,148) (140,175) (58,134,148) (59,135,148) (134,148,135) (134,148,174) (135,148,174) (140,175,174) (20,58,134,148) (21,59,135,148)
1.601 1.559 1.626 164.0 159.2 85.5 141.9 132.4 156.5 −17.7 9.0
ϑ ϑ ϑ ϑ ϑ ϑ ϑ ϑ ϑ ϑ ϑ
(33,68,175,174) (58,134,148,135) (58,134,148,174) (59,135,148,134) (59,135,148,174) (134,148,174,173) (134,148,174,175) (135,148,174,173) (135,148,174,175) (148,174,175,140) (173,174,175,140)
−105.0 0.6 −174.1 29.7 −154.8 157.0 −25.8 −15.7 161.4 64.0 −118.9
a r: bond lengths, angstroms; ϕ: valence angles, degrees; ϑ: torsional angles, degrees.
the complex and between the host and guest. They are listed in Table 3. It is interesting to notice that the internal CD hydrogen bonds in the molecule and in the complex are the same, and the corresponding parameters have also the same values. Fig. 4 shows
4.2. Atomic net charges Both the Mulliken and NBO atomic net charges have been calculated. The theoretical bases of these methods differ to a great extent. The definition of Mulliken charges is based on population analysis. The Mulliken population analysis provides a partitioning of either the total charge density or an orbital density. The number of the electrons in the molecule (N) is the integral of the charge density over the space. N is partitioned for all atoms, the overlap population is also considered. According to the theory, the overlap population of atoms A and B is divided between the two atoms in half-to-half ratio. This is one weak point of the theory. The other weak point is its strong dependence on the applied basis set. The atomic net charge is the difference between the calculated number of electrons belonging to the atom in the molecule and the number of electrons of the isolated atom.
Fig. 3. Numbering of the FBF atoms.
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F. Billes et al. / Vibrational Spectroscopy 69 (2013) 30–39
Table 3 Hydrogen bonds in CD and FBF*CD (AH· · ·B). Atomsa A
Distancesb H
B
AH
Cyclodextrin 143 44 1.006 73 74 144 68 1.020 141 63 1.006 69 138 58 1.028 64 131 59 1.027 53 129 54 1.034 48 126 49 1.018 43 47 128 52 1.010 77 145 71 1.002 Fenbufen–cyclodextrin inclusion complex 134 148 1.035 58 135 148 1.038 59 140 175 1.021 68 132 170 1.002 54 143 44 1.006 73 144 68 1.020 74 141 63 1.006 69 64 138 58 1.028 131 59 1.027 53 129 54 1.034 48 126 49 1.018 43 128 52 1.010 47 77 145 71 1.002 a b c
Anglesc HB
AB
AHB
1.929 1.710 1.810 1.642 1.626 1.608 1.696 1.756 1.944
2.911 2.718 2.757 2.604 2.650 2.637 2.709 2.722 2.931
164.5 169.0 155.4 153.7 174.4 172.9 173.1 158.6 168.1
1.601 1.559 1.626 1.777 1.929 1.710 1.810 1.642 1.626 1.608 1.696 1.756 1.944
2.611 2.556 2.629 2.659 2.911 2.718 2.757 2.604 2.650 2.637 2.709 2.722 2.931
164.0 159.2 166.3 144.9 164.5 169.0 155.4 153.7 174.4 172.9 173.1 158.6 168.1
For the atom numbering see Figs. 2 and 3. Angstroms. Degrees.
The natural atomic charge is based on the theory of natural population analysis. The analysis is carried out with natural bond orbitals (NBO). These are linear combinations of the natural atomic orbitals. The derivation of a valence-shell atomic orbital (NAO) involves diagonalization of the localized block of the full density matrix of a given molecule associated with basis functions of the atoms. A distinguishing feature of NAOs is that they meet the simultaneous requirement of orthonormality and maximum occupancy. In a polyatomic molecule NAOs mostly retain one-center character, and thus they are optimal for describing the molecular electron density around each atomic center. Natural bond orbitals are linear combinations of NAOs of two bonded atoms. The natural population analysis satisfies Pauli’s exclusion principle and solves the basis set dependence problem of the Mulliken population analysis.
Fig. 4. Locations of the host–guest hydrogen bonds.
The results show clearly the mentioned problems of the Mulliken population analysis. These calculated atomic net charges have impossible values: very high absolute values, over 1 atomic charge units and concentrated on the carbon atoms. These kinds of results were found in the three calculated molecules. Therefore, they are not listed in table; some of them are given next. For example, the FBF*CD calculations yielded −3.363 (C4), −5.466 (C16), 2.436 (C152), the CD calculations −2.368 (C16), −3.067 (C40), and the FBF ones 5.518 (C164) atomic charge units respectively (for atom numbering see Figs. 2 and 3). The NBO calculations led to acceptable atomic net charge values, Table 4. The formation of the complex causes an effect on the atomic net charge. Looking at the charge values in Table 4, and comparing those of the individual molecules and the inclusion complex, even the highest charge changes are less than 0.1 atomic charge units. The most remarkable charge changes are detected for O59, O69 (CD) and C160, C163, C165, O170, C171, C174, O175 (FBF) atoms. These oxygen atoms are members of OH groups involved in hydrogen bonds (see Table 3 and Fig. 4). The observed changes in carbon atom net charges of FBF indicate the large structural distortion of the FBF anion during the formation of the complex, something that may also be observed comparing Fig. 1c and d. 4.3. Energy and dipole moment The formation of the complex decreases the sum of the CD and FBF molecular energies (Table 5). The FBF*CD inclusion complex stabilizes the system reducing its energy by 503.8 kJ mol−1 . Both CD and FBF have relatively high dipole moments (Table 4). Since their dipole moments have different directions the FBF*CD dipole moment is lower than those of CD and FBF. 4.4. Vibrational spectra Measured and simulated spectra are analyzed in this section. The simulated spectrum differs from the experimental one since it is only an approximation reflecting the applied quantum chemical method and basis set with all their assumptions. Furthermore, it refers to an isolated molecule; it does not consider the chemical environment, i.e. the hydrogen bond and other interactions with the surrounding molecules. The measured and simulated spectra are shown in Figs. 5–8. The simple 1:1 mixtures of the measured and simulated CD and FBF spectra are compared in Fig. 5 with the spectra of the FBF*CD inclusion complex. The measured and simulated IR and Raman spectra of the inclusion complex are compared in Fig. 6. The measured IR spectra of the investigated molecules (FBF*CD, FBF and CD) are shown in Fig. 7 (expanded wavenumber scale in supplementary Figs. S1–S3). The corresponding simulated spectra are presented in Fig. 8. The interactions between FBF and CD are less expressed in the Raman spectra than in the IR ones. For this reason, the measured and simulated Raman spectra are given in supplementary Figs. S4–S7. A normal coordinate analysis of the inclusion complex was practically impossible considering the 531 normal modes and the work with the 537 × 537 size calculated force constant matrices in Cartesian coordinates. Taking into account the large number of combinations of the 531 independent internal coordinates, only the C H and O H stretching coordinates are going to be discussed in this work. No calculated frequency was found between 1640 and 2660 cm−1 , i.e. the frequencies of these characteristic vibrational modes are above 2660 cm−1 . Three different internal coordinate types are observed: CH and OH stretching vibrations of the CD host and CH stretching vibrations of the guest FBF anion. The IR spectra are more sensitive to the polar groups, so they are discussed first. Between 2660 and 3045 cm−1 , either the characteristic OH stretching modes or the mixed CH and OH stretching modes
F. Billes et al. / Vibrational Spectroscopy 69 (2013) 30–39
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Table 4 NBO atomic net charges. Atom
C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O
Noa
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73
Charged
Atom
A FBF + CDb
B FBF*CD
0.307 −0.018 0.018 0.022 −0.017 −0.163 0.306 −0.024 0.004 0.025 −0.009 −0.171 0.315 −0.023 0.015 0.007 −0.009 −0.167 0.320 −0.009 −0.005 0.021 −0.021 −0.155 0.317 −0.003 −0.002 0.016 −0.013 −0.157 0.314 0.002 0.005 0.008 −0.019 −0.166 0.306 −0.003 0.011 0.005 −0.012 −0.157 −0.793 −0.783 −0.583 −0.542 −0.782 −0.793 −0.789 −0.577 −0.545 −0.789 −0.790 −0.786 −0.581 −0.559 −0.770 −0.777 −0.770 −0.581 −0.549 −0.781 −0.777 −0.805 −0.573 −0.552 −0.791 −0.776 −0.809 −0.583 −0.576 −0.774 −0.770
0.313 −0.012 0.010 0.033 −0.023 −0.155 0.320 −0.024 −0.014 0.032 −0.016 −0.135 0.321 −0.004 0.004 −0.002 −0.009 −0.159 0.315 −0.002 0.009 0.018 −0.011 −0.154 0.329 −0.012 −0.043 0.018 −0.002 −0.154 0.314 0.004 −0.004 −0.004 −0.010 −0.157 0.311 0.006 0.009 0.010 −0.016 −0.153 −0.807 −0.783 −0.593 −0.552 −0.803 −0.797 −0.790 −0.574 −0.539 −0.776 −0.787 −0.778 −0.590 −0.566 −0.774 −0.807 −0.812 −0.591 −0.567 −0.765 −0.774 −0.820 −0.585 −0.564 −0.765 −0.785 −0.768 −0.577 −0.582 −0.774 −0.767
Noa
B-A Differencec 0.007 0.006 −0.008 0.011 −0.006 0.008 0.014 0.000 −0.017 0.007 −0.007 0.036 0.006 0.018 −0.011 −0.009 0.000 0.008 −0.004 0.007 0.014 −0.004 0.010 0.001 0.011 −0.009 −0.041 0.003 0.011 0.004 0.000 0.002 −0.009 −0.012 0.009 0.010 0.004 0.008 −0.002 0.005 −0.004 0.004 −0.014 0.001 −0.010 −0.011 −0.021 −0.004 −0.001 0.003 0.006 0.013 0.003 0.008 −0.009 −0.007 −0.004 −0.030 −0.041 −0.010 −0.018 0.015 0.003 −0.015 −0.012 −0.012 0.026 −0.008 0.041 0.006 −0.005 −0.001 0.003
Charged A FBF + CDb
H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H O C C C C C C H H H H H C C C C
91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163
0.238 0.266 0.256 0.264 0.260 0.261 0.235 0.256 0.243 0.288 0.232 0.261 0.249 0.223 0.264 0.255 0.255 0.255 0.266 0.241 0.253 0.257 0.253 0.257 0.262 0.258 0.237 0.254 0.239 0.264 0.241 0.258 0.253 0.202 0.260 0.534 0.535 0.512 0.527 0.534 0.523 0.541 0.508 0.535 0.511 0.528 0.540 0.534 0.522 0.538 0.528 0.511 0.524 0.524 0.499 0.243 0.515 −0.770 −0.257 −0.247 −0.226 −0.044 −0.227 −0.247 0.243 0.245 0.251 0.250 0.244 −0.238 −0.051 -0.234 −0.201
B FBF*CD 0.235 0.251 0.263 0.262 0.264 0.247 0.230 0.255 0.243 0.256 0.246 0.258 0.250 0.211 0.256 0.242 0.287 0.250 0.256 0.215 0.255 0.246 0.239 0.272 0.259 0.255 0.227 0.257 0.236 0.259 0.234 0.258 0.245 0.215 0.252 0.534 0.533 0.525 0.519 0.539 0.524 0.552 0.507 0.557 0.542 0.509 0.535 0.539 0.506 0.555 0.500 0.508 0.521 0.523 0.505 0.237 0.516 −0.792 −0.244 −0.246 −0.197 −0.081 −0.230 −0.243 0.247 0.250 0.236 0.276 0.253 −0.271 −0.037 −0.222 -0.148
B-A Differencec −0.004 −0.015 0.007 −0.002 0.004 −0.014 −0.005 −0.001 0.000 −0.032 0.013 −0.003 0.001 −0.012 −0.007 −0.014 0.032 −0.005 −0.010 −0.027 0.002 −0.011 −0.013 0.016 −0.003 −0.003 −0.010 0.004 −0.004 −0.005 −0.006 0.000 −0.008 0.013 −0.008 0.000 −0.003 0.013 −0.009 0.005 0.001 0.011 −0.001 0.023 0.031 −0.020 −0.005 0.005 −0.015 0.017 −0.028 −0.004 −0.003 −0.001 0.006 −0.006 0.001 −0.021 0.013 0.001 0.029 −0.037 −0.003 0.005 0.004 0.005 −0.015 0.027 0.009 −0.032 0.013 0.012 0.053
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F. Billes et al. / Vibrational Spectroscopy 69 (2013) 30–39
Table 4 (Continued) Atom
O O O O H H H H H H H H H H H H H a b c d
Noa
74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90
Charged
Atom
A FBF + CDb
B FBF*CD
B-A Differencec
−0.779 −0.576 −0.541 −0.777 0.243 0.259 0.254 0.245 0.251 0.237 0.239 0.259 0.260 0.256 0.242 0.264 0.268
−0.790 −0.592 −0.546 −0.780 0.234 0.247 0.244 0.237 0.266 0.246 0.224 0.249 0.252 0.271 0.233 0.260 0.240
−0.011 −0.016 −0.006 −0.002 −0.008 −0.012 −0.010 −0.008 0.015 0.008 −0.015 −0.010 −0.008 0.015 −0.009 −0.005 −0.028
C C H H H H O C C C C O H H H H
Noa
164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179
Charged A FBF + CDb
B FBF*CD
B-A Differencec
−0.138 −0.193 0.243 0.246 0.265 0.270 −0.573 0.541 −0.580 −0.566 0.719 −0.790 0.305 0.261 0.247 0.255
−0.180 −0.153 0.253 0.254 0.256 0.264 −0.650 0.586 −0.546 −0.546 0.806 −0.732 0.269 0.273 0.276 0.261
−0.043 0.040 0.010 0.008 −0.009 −0.006 −0.076 0.046 0.035 0.020 0.087 0.059 −0.036 0.013 0.028 0.006
For the atom numbering see Figs. 2 and 3. FBF in italics. Bold: difference >0.01. Atomic units.
of the CD host were found in the simulated spectrum. Since the OH bonds have high polarity the corresponding IR bands are very strong, they have values of the calculated IR intensity higher than 500 km mol−1 . The bands at 2798 and 2805 cm−1 are the stronger; they have intensity values close to 1900 km mol−1 . They are overlapped and only a peak at 2800 cm−1 is observed in Fig. 8. Some OH stretching internal coordinates contribute to these bands. The CH stretching bands appear above 3045 cm−1 with low intensity in the IR spectra, less than 100 km mol−1 . The CH stretching bands of FBF appear separately from those of CD. The measured and simulated IR spectra of the inclusion complex are compared in Fig. 5. The measured IR spectra of the FBF/CD 1:1 mixture and FBF*CD complex are also compared in this figure. There are important differences between these spectra. Some changes are observed in the OH/CH stretching region. The structure
Table 5 Molecular energies and dipole moments. Molecule
Energy (Hartree)
Dipole moment (Debyes)
CD FBF FBF*CD FBF*CD stabilization with complex building (kJ mol−1 )
−4252.7717 −838.7744 −5091.738 −503.8
20.81 27.45 8.54
of the very broad 3700–3000 cm−1 band is different. The weak band at about 3600 cm−1 disappears. However, a more intense band is present in the same region including all the OH stretching vibrations of the hydrogen bonds between host and guest.
Fig. 5. Measured and simulated IR spectra of FBF*CD and FBF/CD 1:1 mixture.
F. Billes et al. / Vibrational Spectroscopy 69 (2013) 30–39
37
Fig. 6. Measured and simulated IR and Raman spectra of the inclusion complex FBF*CD.
The IR and Raman spectra of FBF*CD are compared in Fig. 6. The measured Raman spectrum of the complex reflects also the strong hydrogen bond interactions, but their effects on the Raman spectra are not so relevant. The weaker interactions between 3000 and 2200 cm−1 are observed with a better signal/noise ratio in the IR spectra. The simulated Raman spectrum reflects also
these interactions but the corresponding bands are weaker than in the measured spectrum, the environment effect has not been considered appropriately. The measured IR spectra of the three compounds, the inclusion complex, CD and FBF anion are shown in Fig. 7 and supplementary Figs. S1–S3. The comparison of the three spectra makes the study of
Fig. 7. Measured IR spectra of FBF*CD, CD and FBF.
38
F. Billes et al. / Vibrational Spectroscopy 69 (2013) 30–39
Fig. 8. Simulated IR spectra of FBF*CD, CD and FBF.
the interactions easier. The OH stretching bands of FBF*CD in the measured spectrum are more intense than in those of CD indicating the effect of the guest compound. FBF increases the polarity of some CD OH bonds. The FBF bands are also evident in the IR spectrum of the inclusion complex. They are well observable between 1800 and 1200 cm−1 comparing the FBF*CD and CD spectra (see also the FBF spectrum). The OH stretching bands of FBF*CD and CD in the measured IR spectra overlap with one another, and partly also with the CH stretching ones, giving rise to characteristic band shapes [14]. The simulated IR spectra of these compounds are presented in Fig. 8. In the simulated IR spectrum of the complex the already mentioned bands at 2798 and 2805 cm−1 dominate. The principal internal coordinates in these bands are the O48 H129· · ·O54 (from the host) and the O58 H134· · ·O145 and the O59 H135· · ·O148 (host–guest interactions). All of them are hydrogen bonded OH stretching coordinates (see Table 2 for details). The OH/CH stretching band region is in CD less broad than in FBF*CD, 3600–2950 cm−1 instead of 3600–2600 cm−1 . The CD bands in the 1200–200 cm−1 region are also dominant in the same region of the FBF*CD spectrum. Some other FBF bands appear between 1600 and 1200 cm−1 in the spectrum of the complex. The C O internal stretching coordinate of FBF contributes fundamentally to the vibrational normal mode corresponding to the band calculated at 1520 cm−1 . Nevertheless, this internal coordinate is distributed among other normal modes of the inclusion complex, mostly among those corresponding to the bands calculated at 1587, 1558 and 1532 cm−1 . The measured and simulated IR and Raman spectra of the FBF anion and the CD molecule are compared respectively in the supplementary Figs. S4–S7. The IR and Raman spectra of the FBF anion are those of the FBF sodium salt. The OH stretching vibrations of hydration water molecules appear about 3500 cm−1 in the measured IR spectrum. The measured Raman spectrum above
3100 cm−1 showed very strong spectral background and a very poor signal/noise ratio, thus it has not been included. The simulated spectra reflect only approximately the experimental ones. The simulated IR spectrum of the CD molecule is similar to the measured one, only small band shifts are observed. Considering these results it is clear that the IR spectrum of the complex is not a simple sum the CD and FBF spectra (Figs. 5, 7 and 8), the FBF–CD interaction is important (see also Table 2). The experimental Raman spectra of the three compounds show strong spectral backgrounds of fluorescence radiation that mask partly or totally the Raman signals, Figs. S4, S7 and S8. The experimental and simulated FBF*CD spectra reveal the strong hydrogen bond interactions, Figs. S4 and S6. The deviations between the measured and simulated bands of the complex in the OH/CH stretching region are similar, but significant differences in the deviations of the bands below 1700 cm−1 are observed. A strong band around 1598 cm−1 is observed in the Raman spectrum of FBF, this band is also present in the Raman spectrum of FBF*CD. According to the quantum chemical calculations the very strong bands of the complex at 1623 and 1631 cm−1 belong to the FBF guest and they have very high Raman intensities. The Raman spectra, as the IR spectra, reveal the formation of the complex, but considering the low sensitivity of the Raman spectra to these intermolecular interactions the effect is not so expressive in these spectra. 5. Conclusions The CD molecule contains several OH, CH and CH2 groups; therefore the vibrational modes involving chemically similar groups overlap. This result applies mostly to the bands associated to the OH stretching vibrations, but it is also difficult to assign the other observed bands, i.e. only global assignments are possible from quantum chemical calculations. Nevertheless, some experimental
F. Billes et al. / Vibrational Spectroscopy 69 (2013) 30–39
studies have contributed to clarify the assignment of these CD bands [14,30]. The investigation of the host–guest interactions is also an interesting problem, in our case the elucidation and interpretation of the hydrogen bonds. The experimental IR spectra reflect molecular ensembles. Comparing the spectra of the host and the inclusion compound, the existence of intermolecular hydrogen bonds is evident. The situation for the assignment based on the quantum chemical calculations is not easy. The FBF*CD inclusion complex with its 179 atoms has 531 internal coordinates, i.e. 531 vibrational modes. The definition of so many internal coordinates and the handling of 531 × 531 size matrices are difficult. Therefore the characterization of the normal modes is problematic even in this way. Nevertheless, information on intermolecular interactions has been obtained in this case. The results of the calculations make possible the characterization of bands from groups involved in hydrogen bonds using a method similar to the applied in normal coordinate treatments. We conclude that a detailed hydrogen bond analysis is possible based on the geometric, normal coordinate and frequency results of the DFT calculations. Acknowledgments Advices and recommendations from Gaussian Inc. were very useful to carry out the calculations. Two anonymous referees and the Editor offered comments and suggestions that improved this article significantly. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.vibspec.2013.09.006. References [1] R. Singh, N. Bharti, J. Madan, S.N. Hiremath, J. Pharmacol. Sci. Technol. 2 (2010) 171–183. [2] J. Debowski, J. Jurczak, D. Sybilska, J. Chromatogr. A 282 (1983) 83–88.
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Contents lists available at ScienceDirect
Vibrational Spectroscopy journal homepage: www.elsevier.com/locate/vibspec
Structure and vibrational spectroscopy of the fenbufen–-cyclodextrin inclusion complex Ferenc Billes a,b , Antonio Hernanz c,∗ , Hans Mikosch b , Ioan Bratu d a
Department of Physical Chemistry and Material Science, Budapest University of Technology and Economics, Budafoki út 8, H-1521 Budapest, Hungary Institute of Chemical Technologies and Analytics, Vienna University of Technology, A-1060 Vienna, Getreidemarkt 9/164 EC, Austria Departamento de Ciencias y Técnicas Fisicoquímicas, Universidad Nacional de Educación a Distancia (UNED), Paseo de la Senda del Rey 9, E-28040 Madrid, Spain d National R&D Institute for Isotopic and Molecular Technologies, P.O. Box 700, R-400293 Cluj-Napoca 5, Romania b c
a r t i c l e
i n f o
Article history: Received 2 October 2012 Received in revised form 20 September 2013 Accepted 20 September 2013 Available online 29 September 2013 Keywords: Fenbufen -cyclodextrin IR Raman Quantum chemistry
a b s t r a c t The structure and host–guest interactions in the inclusion complex (179 atoms) of -cyclodextrin with fenbufen are studied. Fenbufen, the biphenyl derivative ␥-oxo-(1,1 -biphenyl)-4-butanoic acid, is a widespread analgesic and non-steroidal anti-inflammatory drug. Its inclusion complex with cyclodextrin improves the oral bioavailability and entails fewer side-effects. Optimized molecular structures, atomic net charges and vibrational spectra have been computed for the host and guest molecules, as well as for the inclusion complex. The functional density theory with the B3LYP/3-21+G method/basis set has been applied. The calculated vibrational frequencies have not been scaled, and the simulated spectra have been compared with those obtained experimentally. The host–guest interactions have been investigated in detail. © 2013 Elsevier B.V. All rights reserved.
1. Introduction An extensive literature on the -cyclodextrin (CD) inclusion complexes has been published. They are applied in several fields of chemistry and pharmaceutics. An interesting review article on the applications and investigation methods of cyclodextrin inclusion complexes was published by Singh et al. [1]. One of the relevant applications of CD is the separation of enantiomers through their different aptitude to form inclusion complexes with this molecule [2,3]. The formation of inclusion complexes can also help in increasing the solubility of poorly soluble drugs [4]. Fenbufen (FBF) is an analgesic and non-steroidal antiinflammatory drug used primarily to treat inflammation in osteoarthritis, ankylosing spondylitis, and tendonitis. It can also be used to relieve backaches, sprains, and fractures. FBF acts by preventing cyclooxygenase from producing the prostaglandins that cause inflammation. Cyclodextrins are a family of compounds made up of sugar molecules bound together in a ring (cyclic oligosaccharides). They
∗ Corresponding author. Tel.: +34 91 3987377; fax: +34 91 3988376. E-mail addresses: [email protected] (F. Billes), [email protected] (A. Hernanz), [email protected] (H. Mikosch), [email protected] (I. Bratu). 0924-2031/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.vibspec.2013.09.006
are produced from starch by means of enzymatic conversion. They are used in food, pharmaceutical, and chemical industries, as well as agriculture and environmental engineering. One can find comprehensive information in del Valle’s review [5]. Cyclodextrins are composed by 5 or more ␣-d-glucopyranoside units. Typical cyclodextrins contain a number of glucose monomers ranging from six to eight units in a ring, creating a cone shape. Bea et al. [6] calculated the diastereomeric CD complexes with cizolirtine related carbinols using molecular dynamics. Alcaro et al. [7] applied the Monte Carlo method for the study of several CD inclusion complexes. In this work we deal with vibrational spectroscopy of the inclusion complex of FBF with CD (FBF*CD). In the next paragraphs we shall confine to publications in this area, especially to spectroscopy and quantum chemistry. Li et al. [8] studied the vibrational spectroscopy of the inclusion complex of permethrin with CD. They recorded its infrared (IR) and Raman spectra and calculated the inclusion complex with the Becke3LYP (B3LYP) functional and the 6-31G(d) basis set. Katritzky et al. [9] modeled the free energy of CD complexation on almost 70 inclusions. Stalin et al. [10] investigated the inclusion complexes of ortho, meta and para dihydroxy benzenes with CD. They studied their electron excitation and fluorescence spectra. Among the articles dealing with CD inclusion complexes some further guest molecules are worth mentioning: ketoprofen [11], paroxetine [12] and curcumin [13]. Gavira et al. [14] studied the dehydration of
F. Billes et al. / Vibrational Spectroscopy 69 (2013) 30–39
CD by IR spectroscopy. The FBF*CD complex was studied previously by several authors [15–17]. Bratu et al. [16] studied the 1 H NMR spectra of this inclusion complex in aqueous solutions and found a 1:1 CD/FBF complex ratio. Later the same research group [18] studied the 1 H NMR spectra of the inclusion complexes of FBF with ␣-cyclodextrin and ␥-cyclodextrin in aqueous solutions. They found that the FBF/␥-cyclodextrin complex is of 2:1 type. The FBF*CD complex improves the oral bioavailability of FBF, entails fewer side-effects and avoids the disgusting taste of the drug [19–21]. A detailed study of the structure and host–guest interactions of the FBF*CD complex is carried out in the present work. This information is basic to understand its biological activity. 2. Experimental 2.1. Materials and preparation of the complex CD (≤15% mass percentage of water) was purchased from Merck (Germany) and was used without further purification. A 5 × 10−3 mol dm−3 CD solution in distilled and deionized water was prepared considering the CD contents in molecular water. FBF, obtained from Terapia (Cluj-Napoca, Romania) is a drug with poor solubility in water, and for this reason the sodium salt of FBF was obtained by titration with NaOH. A 5 × 10−3 mol dm−3 aqueous solution of sodium FBF was prepared in the same way. Equal volumes of both solutions were mixed and stirred at room temperature for one hour; an aliquot was taken and stored in a freezer. Thereafter it was freeze-dried overnight. The 1:1 molar ratio in the FBF*CD inclusion complex was obtained by this freeze drying process [17]. FBF/CD 1:1 physical mixture was also obtained by simple blending of stoichiometric CD and FBF quantities in an agate mortar. KBr from Merck Uvasol was desiccated under vacuum at 70 ◦ C during several days before using to prepare KBr pellets of the samples to record their IR spectra. 2.2. Spectroscopic measurements The FTIR spectra of the KBr pellets were recorded by a Bomem DA3 interferometer working under vacuum (pressure ≤ 133.3 Pa). The IR spectrum, 4000–400 cm−1 , of the samples in KBr, was obtained by coadding 200 interferograms, using a Globar source, a MCT detector and an effective spectral resolution of s = 0.60 cm−1 (RES = 1.0 and Boxcar apodization). The FT-Raman spectra have been obtained with a Bomem DA3/DA8 FT-Raman accessory. A krypton discharge lamp pumped Nd3+:YAG laser (Quantronix CW114) working at 1064 nm has been the exciting source. The Raman scattering (Stokes) was collected with 180◦ geometry by an ellipsoidal mirror and passed through an adjustable iris with an aperture of 7 mm to the emission port of the interferometer. Two filters have been used to prevent that any stray light from the white light source and He–Ne laser contributes to the noise of the detector. Two plasma line filters have been used to allow only the 1064 nm laser line to excite the sample. A quartz beamsplitter and an InGaAs detector operated at 77 K have been used. Raleigh line rejection has been performed by a set of three notch filters at ∼17◦ with respect to the normal light beam. One of them has been placed prior to the aperture at the emission port and the other two in the sample assembly close to the detector, before and after an iris with an aperture of also 7 mm. The resolution was s = 4.16 cm−1 (RES = 4.0 and Blackman–Harris apodization). Correction for instrument response has also been done dividing the experimental spectra by the spectrum of a white light lamp that has been normalized for source spectral radiance. The spectra of polycrystalline samples have been obtained using a glass capillary arranged perpendicularly to the direction of the laser beam.
31
3. Calculations 3.1. Quantum chemical calculations The objects of the quantum chemical calculations were the FBF anion, the CD molecule and the FBF*CD inclusion complex. According to previous experimental results [15,16,22] we assumed a 1:1 complex model. The Gaussian09 program package [23] was applied for the calculations with the DFT hybrid functional B3LYP. The chosen basis set was B3LYP/3-21+G. We used diffuse functions since they help to get a good description of the host–guest interactions in the inclusion complex. The mentioned basis set was also applied to the host and guest molecules in order to compare the results with those obtained for the inclusion complex. The first step of the quantum chemical calculations resulted in the optimized geometries, the atomic net charges (Mulliken [24] and NBO [25,26]) and the molecular energies. The second step of the calculations yielded the vibrational frequencies along with the definition of the normal coordinates (contributions of the individual atoms), the IR and Raman intensities of the corresponding fundamentals and the vibrational force constants. The calculations with the B3LYP/3-21+G, i.e. application of the diffuse functions for so large size molecules as FBF*CD (179 atoms) and CD (147 atoms) caused a lot of problems. In order to prevent numerical noise leading to infinite, never ending runs for mathematical standard operations, the accuracy for the calculation had to be increased beyond standard settings. Finally, we applied 99 radial shells for integral calculations, 590 angular points per shell (UltraFine keyword option in Gaussian 09) and the two-electron integral accuracy was increased to 10−12 (Acc2E = 12). As a final step of the optimization procedure, the subkeyword ReadFC for Opt (a Gaussian 09 recommended method [23]) was applied in order to use force constants determined at a lower-level (B3LYP/3-21G) in frequency calculations. They were retrieved from the checkpoint-file as the starting point for higher levels of basis set accuracy. The application of the diffuse functions is sometimes very useful, improves the results, like in our problem. However, acceptable results can be obtained without them, too [27]. 3.2. Simulation of the vibrational spectra The calculated force constants in atomic units were transformed into SI units with a home-made program. However, the large number of atoms in the FBF*CD complex makes difficult the definition of internal coordinates and the scaling of the force constants to the experimental frequencies. Therefore another way was chosen. The calculated frequencies and intensities of the normal modes have been used for the simulation of the spectra. Lorentzian band shapes with the standard full-width at half-height (FWHH) of 15 cm−1 have been assumed for the simulations. The calculated frequencies have not been scaled, i.e. their scale factor was 1.00. The calculated intensities were considered as integrated intensities. All these calculations were carried out with a home-made program [28]. Although the program includes curve fitting to the experimental overlapped band shapes through changing the FWHH of the component bands, this possibility was not applied in this work, since it decreases the intensities observed in the spectral profiles. The intensity of the Raman bands depends on the choice of the excitation wavelength. Consequently, for a better comparison to the experimental spectra, the calculated Raman intensities (Si ) were transformed taking into account the excitation wavenumber (0 ) according to [29]: Ii = f
(0 − i )4 S i [1 − exp(−hci /kT )] i
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F. Billes et al. / Vibrational Spectroscopy 69 (2013) 30–39
Fig. 1. Optimized molecular structures: (a) CD; (b) FBF; (c) FBF*CD; (d) FBF into the complex.
where i is the wavenumber of the actual normal mode and f is an arbitrary factor. 4. Results and discussion The study of the effects of host–guest interactions is very interesting. Therefore, first of all, these effects will be discussed considering the experiments and the B3LYP/3-21+G calculations in this section. According to our best knowledge, this the first time that properties of such a large inclusion complex have been calculated with a DFT quantum chemical method, completed additionally with the use of diffuse functions. 4.1. Molecular geometry The optimized geometric parameters of the host and guest molecules and the inclusion complex have been calculated, respectively. Considerable changes are found comparing the values of
these parameters for FBF and CD (column FBF + CD of the supplementary Table S1) with those of the inclusion complex, Table S1. This table contains altogether near 1100 data. Optimized structures of CD and FBF as individual molecules are shown in Fig. 1a and b respectively, the structure of the FBF*CD complex is presented in Fig. 1c and the structure of the FBF molecule into the complex is shown in Fig. 1d. The numbering of the atoms for CD and FBF are given in Figs. 2 and 3, respectively. Selected geometric parameters have been chosen according to two aspects: the effect of inclusion and host–guest interactions. Table 1 contains host and guest structural parameters that show significant differences under the effect of inclusion. Some of them increased and other decreased during the formation of the complex. This effect may be observed comparing the structures b and d of FBF in Fig. 1. Additional parameters characterizing host–guest interactions in FBF*CD are collected in Table 2. There are CD and FBF atoms that are very close in the complex. Hydrogen bonds are present in the CD molecule, as well as in the CD part of
Table 1 Selected geometric parameters characterizing the inclusion effect.a Parameterb
FBF + CDc
FBF*CD
Parameterb
FBF + CDc
FBF*CD
r (21,59) r (25,70) r (48,129) r (53,131) r (58,134) r (59,135) r (64,138) r (68,140) r (148,174) r (164,171) r (172,173) r (173,174) r (174,175) ϕ (47,6,83) ϕ (47,6,84)
1.489 1.449 1.016 1.010 0.994 0.998 1.009 0.995 1.286 1.510 1.529 1.567 1.297 110.6 104.9
1.469 1.464 1.034 1.028 1.035 1.038 1.028 1.021 1.313 1.481 1.566 1.537 1.274 105.3 110.4
ϕ (22,21,59) ϕ (59,21,100) ϕ (26,25,70) ϕ (25,26,63) ϕ (29,28,65) ϕ (28,29,66) ϕ (69,33,114) ϕ (20,58,134) ϕ (24,62,136) ϕ (27,64,138) ϕ (30,67,139) ϕ (170,171,172) ϕ (171,172,173) ϕ (176,172,177) ϕ (172,173,178)
111.3 103.6 108.4 107.5 109.6 105.6 110.0 110.6 111.7 110.4 111.1 123.7 116.6 104.4 112.2
107.1 109.5 112.9 111.5 103.1 110.9 105.9 115.4 107.2 104.2 107.0 118.8 108.6 109.5 107.8
Distances and angles not less than 0.15 A˚ and 4◦ respectively. r: bond lengths in angstroms; ϕ: valence angles in degrees. For the numbering of the atoms see Figs. 2 and 3. c FBF values in italics. a
b
F. Billes et al. / Vibrational Spectroscopy 69 (2013) 30–39
33
Fig. 2. Numbering of the CD atoms.
Table 2 Geometric parameters characterizing host–guest interactions.
the location of these hydrogen bonds. All oxygen atoms of FBF participate in hydrogen bonds of the complex.
Parametera r r r ϕ ϕ ϕ ϕ ϕ ϕ ϑ ϑ
(134,148) (135,148) (140,175) (58,134,148) (59,135,148) (134,148,135) (134,148,174) (135,148,174) (140,175,174) (20,58,134,148) (21,59,135,148)
1.601 1.559 1.626 164.0 159.2 85.5 141.9 132.4 156.5 −17.7 9.0
ϑ ϑ ϑ ϑ ϑ ϑ ϑ ϑ ϑ ϑ ϑ
(33,68,175,174) (58,134,148,135) (58,134,148,174) (59,135,148,134) (59,135,148,174) (134,148,174,173) (134,148,174,175) (135,148,174,173) (135,148,174,175) (148,174,175,140) (173,174,175,140)
−105.0 0.6 −174.1 29.7 −154.8 157.0 −25.8 −15.7 161.4 64.0 −118.9
a r: bond lengths, angstroms; ϕ: valence angles, degrees; ϑ: torsional angles, degrees.
the complex and between the host and guest. They are listed in Table 3. It is interesting to notice that the internal CD hydrogen bonds in the molecule and in the complex are the same, and the corresponding parameters have also the same values. Fig. 4 shows
4.2. Atomic net charges Both the Mulliken and NBO atomic net charges have been calculated. The theoretical bases of these methods differ to a great extent. The definition of Mulliken charges is based on population analysis. The Mulliken population analysis provides a partitioning of either the total charge density or an orbital density. The number of the electrons in the molecule (N) is the integral of the charge density over the space. N is partitioned for all atoms, the overlap population is also considered. According to the theory, the overlap population of atoms A and B is divided between the two atoms in half-to-half ratio. This is one weak point of the theory. The other weak point is its strong dependence on the applied basis set. The atomic net charge is the difference between the calculated number of electrons belonging to the atom in the molecule and the number of electrons of the isolated atom.
Fig. 3. Numbering of the FBF atoms.
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F. Billes et al. / Vibrational Spectroscopy 69 (2013) 30–39
Table 3 Hydrogen bonds in CD and FBF*CD (AH· · ·B). Atomsa A
Distancesb H
B
AH
Cyclodextrin 143 44 1.006 73 74 144 68 1.020 141 63 1.006 69 138 58 1.028 64 131 59 1.027 53 129 54 1.034 48 126 49 1.018 43 47 128 52 1.010 77 145 71 1.002 Fenbufen–cyclodextrin inclusion complex 134 148 1.035 58 135 148 1.038 59 140 175 1.021 68 132 170 1.002 54 143 44 1.006 73 144 68 1.020 74 141 63 1.006 69 64 138 58 1.028 131 59 1.027 53 129 54 1.034 48 126 49 1.018 43 128 52 1.010 47 77 145 71 1.002 a b c
Anglesc HB
AB
AHB
1.929 1.710 1.810 1.642 1.626 1.608 1.696 1.756 1.944
2.911 2.718 2.757 2.604 2.650 2.637 2.709 2.722 2.931
164.5 169.0 155.4 153.7 174.4 172.9 173.1 158.6 168.1
1.601 1.559 1.626 1.777 1.929 1.710 1.810 1.642 1.626 1.608 1.696 1.756 1.944
2.611 2.556 2.629 2.659 2.911 2.718 2.757 2.604 2.650 2.637 2.709 2.722 2.931
164.0 159.2 166.3 144.9 164.5 169.0 155.4 153.7 174.4 172.9 173.1 158.6 168.1
For the atom numbering see Figs. 2 and 3. Angstroms. Degrees.
The natural atomic charge is based on the theory of natural population analysis. The analysis is carried out with natural bond orbitals (NBO). These are linear combinations of the natural atomic orbitals. The derivation of a valence-shell atomic orbital (NAO) involves diagonalization of the localized block of the full density matrix of a given molecule associated with basis functions of the atoms. A distinguishing feature of NAOs is that they meet the simultaneous requirement of orthonormality and maximum occupancy. In a polyatomic molecule NAOs mostly retain one-center character, and thus they are optimal for describing the molecular electron density around each atomic center. Natural bond orbitals are linear combinations of NAOs of two bonded atoms. The natural population analysis satisfies Pauli’s exclusion principle and solves the basis set dependence problem of the Mulliken population analysis.
Fig. 4. Locations of the host–guest hydrogen bonds.
The results show clearly the mentioned problems of the Mulliken population analysis. These calculated atomic net charges have impossible values: very high absolute values, over 1 atomic charge units and concentrated on the carbon atoms. These kinds of results were found in the three calculated molecules. Therefore, they are not listed in table; some of them are given next. For example, the FBF*CD calculations yielded −3.363 (C4), −5.466 (C16), 2.436 (C152), the CD calculations −2.368 (C16), −3.067 (C40), and the FBF ones 5.518 (C164) atomic charge units respectively (for atom numbering see Figs. 2 and 3). The NBO calculations led to acceptable atomic net charge values, Table 4. The formation of the complex causes an effect on the atomic net charge. Looking at the charge values in Table 4, and comparing those of the individual molecules and the inclusion complex, even the highest charge changes are less than 0.1 atomic charge units. The most remarkable charge changes are detected for O59, O69 (CD) and C160, C163, C165, O170, C171, C174, O175 (FBF) atoms. These oxygen atoms are members of OH groups involved in hydrogen bonds (see Table 3 and Fig. 4). The observed changes in carbon atom net charges of FBF indicate the large structural distortion of the FBF anion during the formation of the complex, something that may also be observed comparing Fig. 1c and d. 4.3. Energy and dipole moment The formation of the complex decreases the sum of the CD and FBF molecular energies (Table 5). The FBF*CD inclusion complex stabilizes the system reducing its energy by 503.8 kJ mol−1 . Both CD and FBF have relatively high dipole moments (Table 4). Since their dipole moments have different directions the FBF*CD dipole moment is lower than those of CD and FBF. 4.4. Vibrational spectra Measured and simulated spectra are analyzed in this section. The simulated spectrum differs from the experimental one since it is only an approximation reflecting the applied quantum chemical method and basis set with all their assumptions. Furthermore, it refers to an isolated molecule; it does not consider the chemical environment, i.e. the hydrogen bond and other interactions with the surrounding molecules. The measured and simulated spectra are shown in Figs. 5–8. The simple 1:1 mixtures of the measured and simulated CD and FBF spectra are compared in Fig. 5 with the spectra of the FBF*CD inclusion complex. The measured and simulated IR and Raman spectra of the inclusion complex are compared in Fig. 6. The measured IR spectra of the investigated molecules (FBF*CD, FBF and CD) are shown in Fig. 7 (expanded wavenumber scale in supplementary Figs. S1–S3). The corresponding simulated spectra are presented in Fig. 8. The interactions between FBF and CD are less expressed in the Raman spectra than in the IR ones. For this reason, the measured and simulated Raman spectra are given in supplementary Figs. S4–S7. A normal coordinate analysis of the inclusion complex was practically impossible considering the 531 normal modes and the work with the 537 × 537 size calculated force constant matrices in Cartesian coordinates. Taking into account the large number of combinations of the 531 independent internal coordinates, only the C H and O H stretching coordinates are going to be discussed in this work. No calculated frequency was found between 1640 and 2660 cm−1 , i.e. the frequencies of these characteristic vibrational modes are above 2660 cm−1 . Three different internal coordinate types are observed: CH and OH stretching vibrations of the CD host and CH stretching vibrations of the guest FBF anion. The IR spectra are more sensitive to the polar groups, so they are discussed first. Between 2660 and 3045 cm−1 , either the characteristic OH stretching modes or the mixed CH and OH stretching modes
F. Billes et al. / Vibrational Spectroscopy 69 (2013) 30–39
35
Table 4 NBO atomic net charges. Atom
C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O
Noa
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73
Charged
Atom
A FBF + CDb
B FBF*CD
0.307 −0.018 0.018 0.022 −0.017 −0.163 0.306 −0.024 0.004 0.025 −0.009 −0.171 0.315 −0.023 0.015 0.007 −0.009 −0.167 0.320 −0.009 −0.005 0.021 −0.021 −0.155 0.317 −0.003 −0.002 0.016 −0.013 −0.157 0.314 0.002 0.005 0.008 −0.019 −0.166 0.306 −0.003 0.011 0.005 −0.012 −0.157 −0.793 −0.783 −0.583 −0.542 −0.782 −0.793 −0.789 −0.577 −0.545 −0.789 −0.790 −0.786 −0.581 −0.559 −0.770 −0.777 −0.770 −0.581 −0.549 −0.781 −0.777 −0.805 −0.573 −0.552 −0.791 −0.776 −0.809 −0.583 −0.576 −0.774 −0.770
0.313 −0.012 0.010 0.033 −0.023 −0.155 0.320 −0.024 −0.014 0.032 −0.016 −0.135 0.321 −0.004 0.004 −0.002 −0.009 −0.159 0.315 −0.002 0.009 0.018 −0.011 −0.154 0.329 −0.012 −0.043 0.018 −0.002 −0.154 0.314 0.004 −0.004 −0.004 −0.010 −0.157 0.311 0.006 0.009 0.010 −0.016 −0.153 −0.807 −0.783 −0.593 −0.552 −0.803 −0.797 −0.790 −0.574 −0.539 −0.776 −0.787 −0.778 −0.590 −0.566 −0.774 −0.807 −0.812 −0.591 −0.567 −0.765 −0.774 −0.820 −0.585 −0.564 −0.765 −0.785 −0.768 −0.577 −0.582 −0.774 −0.767
Noa
B-A Differencec 0.007 0.006 −0.008 0.011 −0.006 0.008 0.014 0.000 −0.017 0.007 −0.007 0.036 0.006 0.018 −0.011 −0.009 0.000 0.008 −0.004 0.007 0.014 −0.004 0.010 0.001 0.011 −0.009 −0.041 0.003 0.011 0.004 0.000 0.002 −0.009 −0.012 0.009 0.010 0.004 0.008 −0.002 0.005 −0.004 0.004 −0.014 0.001 −0.010 −0.011 −0.021 −0.004 −0.001 0.003 0.006 0.013 0.003 0.008 −0.009 −0.007 −0.004 −0.030 −0.041 −0.010 −0.018 0.015 0.003 −0.015 −0.012 −0.012 0.026 −0.008 0.041 0.006 −0.005 −0.001 0.003
Charged A FBF + CDb
H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H O C C C C C C H H H H H C C C C
91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163
0.238 0.266 0.256 0.264 0.260 0.261 0.235 0.256 0.243 0.288 0.232 0.261 0.249 0.223 0.264 0.255 0.255 0.255 0.266 0.241 0.253 0.257 0.253 0.257 0.262 0.258 0.237 0.254 0.239 0.264 0.241 0.258 0.253 0.202 0.260 0.534 0.535 0.512 0.527 0.534 0.523 0.541 0.508 0.535 0.511 0.528 0.540 0.534 0.522 0.538 0.528 0.511 0.524 0.524 0.499 0.243 0.515 −0.770 −0.257 −0.247 −0.226 −0.044 −0.227 −0.247 0.243 0.245 0.251 0.250 0.244 −0.238 −0.051 -0.234 −0.201
B FBF*CD 0.235 0.251 0.263 0.262 0.264 0.247 0.230 0.255 0.243 0.256 0.246 0.258 0.250 0.211 0.256 0.242 0.287 0.250 0.256 0.215 0.255 0.246 0.239 0.272 0.259 0.255 0.227 0.257 0.236 0.259 0.234 0.258 0.245 0.215 0.252 0.534 0.533 0.525 0.519 0.539 0.524 0.552 0.507 0.557 0.542 0.509 0.535 0.539 0.506 0.555 0.500 0.508 0.521 0.523 0.505 0.237 0.516 −0.792 −0.244 −0.246 −0.197 −0.081 −0.230 −0.243 0.247 0.250 0.236 0.276 0.253 −0.271 −0.037 −0.222 -0.148
B-A Differencec −0.004 −0.015 0.007 −0.002 0.004 −0.014 −0.005 −0.001 0.000 −0.032 0.013 −0.003 0.001 −0.012 −0.007 −0.014 0.032 −0.005 −0.010 −0.027 0.002 −0.011 −0.013 0.016 −0.003 −0.003 −0.010 0.004 −0.004 −0.005 −0.006 0.000 −0.008 0.013 −0.008 0.000 −0.003 0.013 −0.009 0.005 0.001 0.011 −0.001 0.023 0.031 −0.020 −0.005 0.005 −0.015 0.017 −0.028 −0.004 −0.003 −0.001 0.006 −0.006 0.001 −0.021 0.013 0.001 0.029 −0.037 −0.003 0.005 0.004 0.005 −0.015 0.027 0.009 −0.032 0.013 0.012 0.053
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F. Billes et al. / Vibrational Spectroscopy 69 (2013) 30–39
Table 4 (Continued) Atom
O O O O H H H H H H H H H H H H H a b c d
Noa
74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90
Charged
Atom
A FBF + CDb
B FBF*CD
B-A Differencec
−0.779 −0.576 −0.541 −0.777 0.243 0.259 0.254 0.245 0.251 0.237 0.239 0.259 0.260 0.256 0.242 0.264 0.268
−0.790 −0.592 −0.546 −0.780 0.234 0.247 0.244 0.237 0.266 0.246 0.224 0.249 0.252 0.271 0.233 0.260 0.240
−0.011 −0.016 −0.006 −0.002 −0.008 −0.012 −0.010 −0.008 0.015 0.008 −0.015 −0.010 −0.008 0.015 −0.009 −0.005 −0.028
C C H H H H O C C C C O H H H H
Noa
164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179
Charged A FBF + CDb
B FBF*CD
B-A Differencec
−0.138 −0.193 0.243 0.246 0.265 0.270 −0.573 0.541 −0.580 −0.566 0.719 −0.790 0.305 0.261 0.247 0.255
−0.180 −0.153 0.253 0.254 0.256 0.264 −0.650 0.586 −0.546 −0.546 0.806 −0.732 0.269 0.273 0.276 0.261
−0.043 0.040 0.010 0.008 −0.009 −0.006 −0.076 0.046 0.035 0.020 0.087 0.059 −0.036 0.013 0.028 0.006
For the atom numbering see Figs. 2 and 3. FBF in italics. Bold: difference >0.01. Atomic units.
of the CD host were found in the simulated spectrum. Since the OH bonds have high polarity the corresponding IR bands are very strong, they have values of the calculated IR intensity higher than 500 km mol−1 . The bands at 2798 and 2805 cm−1 are the stronger; they have intensity values close to 1900 km mol−1 . They are overlapped and only a peak at 2800 cm−1 is observed in Fig. 8. Some OH stretching internal coordinates contribute to these bands. The CH stretching bands appear above 3045 cm−1 with low intensity in the IR spectra, less than 100 km mol−1 . The CH stretching bands of FBF appear separately from those of CD. The measured and simulated IR spectra of the inclusion complex are compared in Fig. 5. The measured IR spectra of the FBF/CD 1:1 mixture and FBF*CD complex are also compared in this figure. There are important differences between these spectra. Some changes are observed in the OH/CH stretching region. The structure
Table 5 Molecular energies and dipole moments. Molecule
Energy (Hartree)
Dipole moment (Debyes)
CD FBF FBF*CD FBF*CD stabilization with complex building (kJ mol−1 )
−4252.7717 −838.7744 −5091.738 −503.8
20.81 27.45 8.54
of the very broad 3700–3000 cm−1 band is different. The weak band at about 3600 cm−1 disappears. However, a more intense band is present in the same region including all the OH stretching vibrations of the hydrogen bonds between host and guest.
Fig. 5. Measured and simulated IR spectra of FBF*CD and FBF/CD 1:1 mixture.
F. Billes et al. / Vibrational Spectroscopy 69 (2013) 30–39
37
Fig. 6. Measured and simulated IR and Raman spectra of the inclusion complex FBF*CD.
The IR and Raman spectra of FBF*CD are compared in Fig. 6. The measured Raman spectrum of the complex reflects also the strong hydrogen bond interactions, but their effects on the Raman spectra are not so relevant. The weaker interactions between 3000 and 2200 cm−1 are observed with a better signal/noise ratio in the IR spectra. The simulated Raman spectrum reflects also
these interactions but the corresponding bands are weaker than in the measured spectrum, the environment effect has not been considered appropriately. The measured IR spectra of the three compounds, the inclusion complex, CD and FBF anion are shown in Fig. 7 and supplementary Figs. S1–S3. The comparison of the three spectra makes the study of
Fig. 7. Measured IR spectra of FBF*CD, CD and FBF.
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F. Billes et al. / Vibrational Spectroscopy 69 (2013) 30–39
Fig. 8. Simulated IR spectra of FBF*CD, CD and FBF.
the interactions easier. The OH stretching bands of FBF*CD in the measured spectrum are more intense than in those of CD indicating the effect of the guest compound. FBF increases the polarity of some CD OH bonds. The FBF bands are also evident in the IR spectrum of the inclusion complex. They are well observable between 1800 and 1200 cm−1 comparing the FBF*CD and CD spectra (see also the FBF spectrum). The OH stretching bands of FBF*CD and CD in the measured IR spectra overlap with one another, and partly also with the CH stretching ones, giving rise to characteristic band shapes [14]. The simulated IR spectra of these compounds are presented in Fig. 8. In the simulated IR spectrum of the complex the already mentioned bands at 2798 and 2805 cm−1 dominate. The principal internal coordinates in these bands are the O48 H129· · ·O54 (from the host) and the O58 H134· · ·O145 and the O59 H135· · ·O148 (host–guest interactions). All of them are hydrogen bonded OH stretching coordinates (see Table 2 for details). The OH/CH stretching band region is in CD less broad than in FBF*CD, 3600–2950 cm−1 instead of 3600–2600 cm−1 . The CD bands in the 1200–200 cm−1 region are also dominant in the same region of the FBF*CD spectrum. Some other FBF bands appear between 1600 and 1200 cm−1 in the spectrum of the complex. The C O internal stretching coordinate of FBF contributes fundamentally to the vibrational normal mode corresponding to the band calculated at 1520 cm−1 . Nevertheless, this internal coordinate is distributed among other normal modes of the inclusion complex, mostly among those corresponding to the bands calculated at 1587, 1558 and 1532 cm−1 . The measured and simulated IR and Raman spectra of the FBF anion and the CD molecule are compared respectively in the supplementary Figs. S4–S7. The IR and Raman spectra of the FBF anion are those of the FBF sodium salt. The OH stretching vibrations of hydration water molecules appear about 3500 cm−1 in the measured IR spectrum. The measured Raman spectrum above
3100 cm−1 showed very strong spectral background and a very poor signal/noise ratio, thus it has not been included. The simulated spectra reflect only approximately the experimental ones. The simulated IR spectrum of the CD molecule is similar to the measured one, only small band shifts are observed. Considering these results it is clear that the IR spectrum of the complex is not a simple sum the CD and FBF spectra (Figs. 5, 7 and 8), the FBF–CD interaction is important (see also Table 2). The experimental Raman spectra of the three compounds show strong spectral backgrounds of fluorescence radiation that mask partly or totally the Raman signals, Figs. S4, S7 and S8. The experimental and simulated FBF*CD spectra reveal the strong hydrogen bond interactions, Figs. S4 and S6. The deviations between the measured and simulated bands of the complex in the OH/CH stretching region are similar, but significant differences in the deviations of the bands below 1700 cm−1 are observed. A strong band around 1598 cm−1 is observed in the Raman spectrum of FBF, this band is also present in the Raman spectrum of FBF*CD. According to the quantum chemical calculations the very strong bands of the complex at 1623 and 1631 cm−1 belong to the FBF guest and they have very high Raman intensities. The Raman spectra, as the IR spectra, reveal the formation of the complex, but considering the low sensitivity of the Raman spectra to these intermolecular interactions the effect is not so expressive in these spectra. 5. Conclusions The CD molecule contains several OH, CH and CH2 groups; therefore the vibrational modes involving chemically similar groups overlap. This result applies mostly to the bands associated to the OH stretching vibrations, but it is also difficult to assign the other observed bands, i.e. only global assignments are possible from quantum chemical calculations. Nevertheless, some experimental
F. Billes et al. / Vibrational Spectroscopy 69 (2013) 30–39
studies have contributed to clarify the assignment of these CD bands [14,30]. The investigation of the host–guest interactions is also an interesting problem, in our case the elucidation and interpretation of the hydrogen bonds. The experimental IR spectra reflect molecular ensembles. Comparing the spectra of the host and the inclusion compound, the existence of intermolecular hydrogen bonds is evident. The situation for the assignment based on the quantum chemical calculations is not easy. The FBF*CD inclusion complex with its 179 atoms has 531 internal coordinates, i.e. 531 vibrational modes. The definition of so many internal coordinates and the handling of 531 × 531 size matrices are difficult. Therefore the characterization of the normal modes is problematic even in this way. Nevertheless, information on intermolecular interactions has been obtained in this case. The results of the calculations make possible the characterization of bands from groups involved in hydrogen bonds using a method similar to the applied in normal coordinate treatments. We conclude that a detailed hydrogen bond analysis is possible based on the geometric, normal coordinate and frequency results of the DFT calculations. Acknowledgments Advices and recommendations from Gaussian Inc. were very useful to carry out the calculations. Two anonymous referees and the Editor offered comments and suggestions that improved this article significantly. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.vibspec.2013.09.006. References [1] R. Singh, N. Bharti, J. Madan, S.N. Hiremath, J. Pharmacol. Sci. Technol. 2 (2010) 171–183. [2] J. Debowski, J. Jurczak, D. Sybilska, J. Chromatogr. A 282 (1983) 83–88.
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