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Solvatochromic study on chlortetracycline in binary and ternary solutions
Journal of Molecular Structure xxx (2015) 1e9
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Solvatochromic study on chlortetracycline in binary and ternary solutions G. Oanca a, C. Nadejde a, N. Fifere b, A. Gritco Todirascu a, D. Creanga a, *, D. Dorohoi a, Jernej Stare c a b c
University “Alexandru Ioan Cuza”, Faculty of Physics, Iasi, Romania “P. Poni” Institute of Macromolecular Chemistry, Iasi, Romania National Institute of Chemistry, Ljubljana, Slovenia
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 November 2015 Accepted 22 December 2015 Available online xxx
Molecular modeling of chlortetracycline was performed based on DFT approach implemented in Gaussian software. The differences between simulated electronic spectra and those recorded experimentally were analyzed. Experimental investigations were carried out using electronic absorption spectra as well as fluorescence ones. Spectral shift to the changing of solvent polarity was measured in various solvents (binary solutions) and graphical correlations were evidenced between the electronic band wavenumbers and some theoretical functions on solvent electro-optical macroscopic parameters (refractive index and dielectric constant); interpretation was done based on the solvatochromic theory dedicated to universal interaction forces. Fluorescence spectra, studied in mixture of solvents (ternary solutions), evidenced also specific interactions in water-alcohols not considered in the classical solvatochromic approach. © 2015 Elsevier B.V. All rights reserved.
Keywords: Chlortetracycline Molecular modeling Fluorescence Absorption Universal intermolecular forces Specific interactions
1. Introduction Previous literature sources let us know that UVeVis spectroscopy methods were reported as useful in the detection of food loading with tetracycline derivatives; HPLC/UVeVis method was applied for the identification of oxytetracycline, tetracycline and chlortetracycline in honey [1]. Simple UVeVis investigation of honey in methanol solutions allowed chortetracycline and oxitetracycline content assay based on the absorption at 319 and respectively 364 nm [2]. Fluorescence spectroscopy was found suitable for the study of the interaction of trypsin (proteolytic enzyme, excreted by the pancreas) with chlortetracycline that occurs naturally because of pharmaceutically polluted environment that seems to become a real threatening for the health of human and animals [3]. UVVisible absorption spectrometry was found adequate for the determination of dissociation constants of tetracyclines in acetonitrile-water ternary solutions which are very important for liquid chromatography and capillary electrophoresis that use such
* Corresponding author. E-mail address: [email protected] (D. Creanga).
solvent mixtures [4]. Other studies were focused on spectral assay of tetracycline compounds related to their stability and bioactivity [5,6].
2. Theoretical background Solute-solvent interactions in various solvents were investigated according to mathematical approaches proposed for describing universal intermolecular forces developed in diluted solutions. Widely used solvatochromic theories [7e10] were applied in previous studies on various molecules used as spectral probes for the investigation of intermolecular forces diluted solutions. Brief presentation of such mathematical approach [11] can be done as follows. According to [11] the total spectral shift De n of a solute molecule's electronic absorption band (EAB) when passing from isolate state (gas) to solution, can be written as the sum of the contributions of main type of universal solute-solvent interactions (Eq. (1)) e the indexes “pol”, “disp”, “ind” and “or” being assigned to the main types of universal intermolecular interactions: polarization, dispersion, induction and orientation.
http://dx.doi.org/10.1016/j.molstruc.2015.12.066 0022-2860/© 2015 Elsevier B.V. All rights reserved.
Please cite this article in press as: G. Oanca, et al., Solvatochromic study on chlortetracycline in binary and ternary solutions, Journal of Molecular Structure (2015), http://dx.doi.org/10.1016/j.molstruc.2015.12.066
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G. Oanca et al. / Journal of Molecular Structure xxx (2015) 1e9
De n ¼ De npol þ De ndisp þ De nind þ De nor
(1)
The four contributions of the universal solute-solvent interactions to the spectral shift depend on the solvent macroscopic parameters n (refractive index) and ε (dielectric constant) and thus can be grouped as follows:
hcDe n ¼ AðnÞ
n2 1 ε1 þ BðnÞ εþ2 n2 þ 2
2 2 3 II 0 he2 f 2n2 þ 1 mg me AðnÞ ¼ ag ae þ 2 0 3 3 3 2a I þ I 8pmee n þ2 n0 a a
BðnÞ ¼
2n2 þ 1 2mg mg me cos 4 a3 n2 þ 2
(2)
(3)
(4)
where the term A(n) (Eq. (2) and (3)) corresponds to the sum of the first two terms from the Eq. (1), describing dispersive-polarization forces while B(n) (Eq. (2) and (4)) describes the orientationinduction interactions. The microscopic parameters of the solute molecule in the ground and respectively the excited state are noted as mg and me (electric dipole moments), ag and ae (electric polarizabilities), while a stands for the average radius of the solute; e and me are the electron charge and mass, f is the oscillator strength, 4 is the angle between the two dipole moment vectors and, I and I0 are the ionizing potentials of the solute and the solvent molecules (Eqs. (3) and (4)). The solvent refractive index, is n, while the dielectric constant is ε. The quantities A(n) or B(n) could be estimated by statistical method (regression line), based on measured wavenumbers and known solvent macroscopic parameters. 3. Materials and methods 3.1. Quantum chemical approach Molecular optimized structure, HOMO e LUMO eigenvalues, and dipole moment by quantum chemical simulations were done using Gaussian 09 package [12] with DFT B3LYP level of theory with 6-31Gþþ(d,p) basis set. UVeVis spectra simulation was accomplished also in Gaussian 09, starting from previously found (optimized) geometry with time dependent DFT (TD-B3LYP) with 6e31þþG(d,p) basis set. For visual representation of the molecules we used VMD and Avogadro softwares. The calculations were done on the computer cluster at National Institute of Chemistry, Ljubljana, Slovenia. 3.2. Experimental Experimental recording was accomplished using Shimadzu UVeVis double beam device, and spectrofluorimeter device Model LS 55 PerkinElmer; excitation light wavelength was of 340 nm. Chlortetracycline crystallized powder (CTC) and pure solvents from Merck were used without further purification. The solvents used for recording experimental spectra and their macroscopic electro-optical parameters are given in Table 1. 4. Results and discussion The mathematically simulated optimized geometry of chlortetracycline and electrostatic potential map are presented in Fig. 1. The four atom rings were labeled from I to IV (Fig. 1 a) considering the further discussion of simulated orbitals. The map of
Table 1 The solvents used for recording experimental spectra.
1 2 3 4 5 6 7 8 9 12 10 11
Solvent
n, refractive index
ε, dielectric constant
acetic acid n-pentanol isopentanol n-buthanol isobuthanol isopropanol n-propanol ethanol methanol N, N0 dimethylformamide ethylene glycol water
1.3719 1.4100 1.4072 1.3993 1.3959 1.3772 1.3856 1.3614 1.3284 1.4305 1.4318 1.3330
6.20 13.90 15.19 17.51 17.93 18.92 20.45 24.55 32.66 36.71 37.70 78.36
electrostatic potential distribution corresponding to the optimized molecular structure (Fig. 1 b) highlights higher electron cloud density toward the IV ring e the molecule edge containing chloride. According to Fig. 2, during the chlortetracycline passing from ground state to excited one the electron density is redistributed from the atom rings I and II toward the rings III and IV. When dissolved in water the energy of HOMO and LUMO states remain negative eindicating stable structure [13], and do not change significantly while dipole moment increased with about 25% (Table 2). In literature we found dipole moment estimation only for basic tetracycline in buffer surrounding medium (H3Tetracycline), of about 14D as resulted from lower accuracy computational approach with PM3 [14]. The maxima of visible range electronic absorption bands of chlortetracycline provided by mathematical simulation with DFT are shifted toward lower wavenumbers (from 30,600 cm1 to 29,000 cm1 and from 37,850 cm1 to 37,500 cm1) when interactions with water surrounding molecules are considered (Fig. 3 a, b); this could be correlated also with increased dipole moment of CTC-HOH. Experimentally recorded spectrum of chlortetracycline in water (104 M) in Fig. 4 is presented being in concordance with literature data [5]. The spectrum shape is similar to the modeled one in the visible and near UV range; but the band in the visible range shifted from 29,000 cm1 at 27,170 cm1, while in the UV domain, the first band (only a shoulder at 31,800 cm1 in modeled spectrum of CTC-HOH (Fig. 3 b)) shifted to 36,360 cm1 and the next one, from 37,500 cm1 in the modeled spectrum to 44,050 cm1 in the real one. Protonation with sulfuric acid aliquot didn't change the spectrum, which usually is characteristic to pep* bands. Band assignment is based mostly on relatively low intensity, hypsochromic shift to the solvent polarity increase, and also, as mentioned, no sensitivity to solution protonation. In Fig. 5 the comparative behavior to the change of solvent characteristics can be seen for the absorption band at the highest wavelength (lowest wavenumber). Universal solute-solvent interactions were analyzed in diluted solutions according to solvatochromic theories for the electronic band at lowest wavenumbers, where solvent transparency criterion was fulfilled for alcohols, water and water-alcohol mixtures (binary solvents) e as presented further below. Since the wavenumber appears to depend linearly on the solvent parameter through the function f(ε) it seems that orientationinduction intermolecular interactions dominate (Fig. 6 a) in the chlortetracycline solutions. The contribution of dispersive-polarization forces were evidenced through the relatively slighter correlation of wavenumber
Please cite this article in press as: G. Oanca, et al., Solvatochromic study on chlortetracycline in binary and ternary solutions, Journal of Molecular Structure (2015), http://dx.doi.org/10.1016/j.molstruc.2015.12.066
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Fig. 1. (a) Optimized structure of chlortetracycline; (b) Electrostatic potential map of chlortetracycline.
Fig. 2. HOMO e highest occupied molecular orbital and LUMO e lowest unoccupied molecular orbital defining absorption transition as resulted from DFT approach.
Table 2 Calculated values for molecular orbitals and dipole moment. CTC in gaseous state (GAS) HOMO (eV)
LUMO (eV)
Dipole moment (D)
0.23565
0.08665
6.8943
CTC surrounded by water (HOH) 0.23146 0.08853
9.2767
on the solvent refractive index (Fig. 6 b). However some data points corresponding to N, N0 dimethylformamide and water (Fig. 6 a, in black) and respectively ethylene glycol, water and acetic acid (Fig. 6 b, in black) present high distances from the regression lines which suggest possible supplementary specific interactions. To get better comparison with Eq. (2), double regression approach was performed (Eq. (5)), the regression plane being represented in Fig. 6 c:
e nabs calc ¼ 25889 þ f ðnÞ1550 f ðεÞ2277
(5)
In Fig. 6 d the comparison between experimental and calculated wavenumbers for all solvents can be seen; correlation coefficient could increase when N,N0 dimethylformamide is excluded (from R2 ¼ 0.729 to R2 ¼ 0.834); acetic acid, ethylene glycol and water appeared close to the theoretical linear regression plane.
Since the computed intercept value can be taken as the wavenumber for the isolated molecule [15], the above double regression approach is able to evidence hypsochromic shift in the presence of solvents as suggested by the modeled spectra of CTC-HOH and CTCGAS (Fig. 2 a, b). Solvent effect on the electronic absorption transition is due mainly to orientation-induction but also to dispersive-polarization forces confirming the suitability of solvathochromic theory proposed for describing universal solute-solvent intermolecular interactions. For the solvents that still do not obey to the theoretical double regression calculation, specific interactions with solute molecule should be hypothesized e in this analyzed situation being the case of N, N0 dimethylformamide. According to Fig. 7 absorption and fluorescence bands of chlortetracycline in alcohols with relatively large transparency domain evidenced mirror symmetry. Fluorescence bands could be recorded in water and most alcohols, in 108 M solutions to avoid fluorescence quenching. In Fig. 8 the spectral behavior of main fluorescence band is presented. We could notice the significantly smaller intensity shoulder at smaller wavelengths. Wavenumbers in the band maximum have shown no mathematical correlation with solvent macroscopic electro-optical parameters to the change of solvent nature. Analysis of chlortetracycline fluorescence could be however studied in ternary solutions using binary mixtures of water and alcohols.
Please cite this article in press as: G. Oanca, et al., Solvatochromic study on chlortetracycline in binary and ternary solutions, Journal of Molecular Structure (2015), http://dx.doi.org/10.1016/j.molstruc.2015.12.066
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G. Oanca et al. / Journal of Molecular Structure xxx (2015) 1e9
Fig. 3a. Simulated electronic absorption spectrum of isolated chlortetracycline e(CTC -GAS).. b. Simulated electronic absorption spectrum of chlortetracycline in water (CTCHOH).
Fig. 4. Electronic absorption spectrum of chlortetracycline in water and protonated water.
Fig. 5. Solvatochromic behavior in various solvents of chlortetracycline normalized spectra.
In Figs. 9e10 CTC solvatochromic behavior in binary solvents (ternary solutions water-alcohols) is presented for CTC absorption while in next figures CTC fluorescence is presented in the same mixtures. The range of water percentage in alcohols was chosen limited by fluorescence band intensity measurement possibility up to about 33% water (v/v). In Fig. 9 the effect of water addition in propanol is presented for CTC absorption and fluorescence studied bands. The progressive hypsochromic shift of the absorption band to the increase of water percentage (Fig. 9 a) was evidenced while the fluorescence wavenumber presents a bathochromic shift up to about 15% water percentage followed by a relatively slighter hypsochromic shift for further increase of water concentration up to 33% (Fig. 9 b). Analysis of solute-solvent interactions in ternary solutions of chlortetracycline solute molecule is discussed based on the next graphs. According to [16e18] dielectric constant of a binary mixture can be calculated as: ε1,2 ¼ f1ε1 þ f2ε2 where f1 and f2 are the volume fractions of the two solvents while ε1 and ε2 are their respective dielectric constants. The estimation method can be applied for the refractive index too, by checking also through Abbe refractometer direct measurement. In Fig. 10 a, the water-propanol mixture was analyzed. One can see linear dependence of the wavenumber in the maximum of the electronic absorption band on solvent parameter function f(ε) (correlation coefficient R2 ¼ 0.9836) and in Fig. 10 b on f(n) respectively (correlation coefficient R2 ¼ 0.9514) e suggesting the co-existence of orientation-induction intermolecular interactions and dispersive-polarization forces. While water concentration increased, the absorption band wavenumber has increased with the binary solvent f(ε) (Fig. 10 a) which seems to correspond to intensification of orientationinduction forces almost linearly (R2 ¼ 0.9836). For the same array of binary solvents the absorption band wavenumber diminished to the increase of binary solvent f(n) (Fig. 10 b, linear correlation coefficient, R2 ¼ 0.9514) which seems to be the effect of diminution of dispersive-polarization forces in the same conditions. In Fig. 11 one can see intermolecular interactions situation as emphasized by chlortetracycline fluorescence changes for progressive increase of water concentration in propanol.
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Fig. 6. Solvatochromic behavior of CTC in absorption: (a) dependence on f(ε); (b) dependence on f(n); (c) Regression plan approaching wavenumber in the CTC solutions absorption in dependence on f(n) and f(ε); (d) Comparison of experimental and calculated wavenumbers of CTC absorption in pure solvents.
Fig. 7. Absorption and fluorescence bands of chlortetracycline in alcohols (1-butanol; 2-propanol).
According to Fig. 11 a, the wavenumber of studied fluorescence band shifted bathochromically up to about 16.6% water volume in propanol while for higher water percentage hypsochromic shift could be evidenced; this is, orientation induction forces weight first diminished to the increase of solvent dielectric constant but then they were enhanced. As for the wavenumber dependence on the solvent refractive index, in Fig. 11 b it is shown the bathochromic shift for relatively low water percentage (up to about 9%), indicating the diminution of dispersive-polarization forces and, further, the remarkable
Fig. 8. Chlortetracycline e main fluorescence band.
hypsochromic shift for water concentrations up to 33% - corresponding to increasing of dispersive-polarization forces weight in ternary solutions water-propanol can be seen. It is obvious that fluorescence band respond differently in comparison to the absorption one. Experimental data processing by double linear regression approach, by taking into consideration wavenumber dependence on both solvent parameters, has resulted in calculated wavenumbers that depend linearly on the experimental ones with correlation coefficient R2 ¼ 0.9841 (Fig. 12) e for the studied
Please cite this article in press as: G. Oanca, et al., Solvatochromic study on chlortetracycline in binary and ternary solutions, Journal of Molecular Structure (2015), http://dx.doi.org/10.1016/j.molstruc.2015.12.066
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Fig. 9. CTC electronic band behavior to the increase of water concentration in propanol: (a) absorption; (b) fluorescence.
Fig. 10. CTC absorption in mixtures of water-propanol: (a) dependence on f(ε); (b) dependence on f(n).
Fig. 11. CTC fluorescence in mixtures of water-propanol: (a) dependence on f(ε); (b) dependence on f(n).
absorption band. Also regression plane could be generated (not shown inhere). As can be seen in Fig. 13 double linear regression approach has led to comparable values of the experimental and statistically calculated wavenumbers in the fluorescence band; however the correlation coefficient is lower than in the case of the above analyzed absorption band since couple of data points are distanced from the theoretical line e apparently more than in the case of absorption. We assume that in the ternary solutions chlortetracycline behavior is more complex than could be anticipated; it is possible that around solute molecule a molecular complex if formed with one of the solvents e and this complex exhibits fluorescence at different wavelength. To the increase of water weight in the
solution the distinct behavior of this complex could be revealed by the processing the fluorescence recorded data. Another alcohol-water solvent array was studied using butanol (Fig. 14). As can be seen in Fig. 14 a, the absorption band wavenumber increased to the increase of water percentage as expected. Fluorescence wavenumber also presented two segment-line in the plane (wavenumber, water %) as for water-butanol binary solvents (Fig. 14 b). In Fig. 15, as in the case of previous solvent mixture, the dependence of wavenumber on solvent macroscopic parameters is presented, which was found in the form of ascendant line for f(ε) and respectively descendent line for f(n), with correlation coefficients slightly diminished compared to water-propanol.
Please cite this article in press as: G. Oanca, et al., Solvatochromic study on chlortetracycline in binary and ternary solutions, Journal of Molecular Structure (2015), http://dx.doi.org/10.1016/j.molstruc.2015.12.066
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Fig. 12. Comparison of experimental and calculated wavenumbers for absorption band of chlortetracycline in binary solvents water-propanol (water percentage up to 33% v/ v).
Fig. 13. Comparison of experimental and calculated wavenumbers for the studied fluorescence band of chlortetracycline in binary solvents water-propanol (water percentage up to 33% v/v).
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interactions. Linear decrease of fluorescence wavenumber was revealed to the increase of water percentage in butanol, suggesting the diminution of orientation-induction forces, i.e. their role in the fluorescence transition energy (Fig. 16 a). The two step increase of fluorescence wavenumber when the water percentage has increased too (Fig. 16 b) shows that dispersive-polarization interactions in water-butanol act similarly like in the case of water-propanol mixtures, their influence on the fluorescence transition enhancing. In Fig. 17 the result of processing fluorescence data (collected for water-butanol binary solvents) by means of double linear regression is presented. The statistically calculated wavenumbers are rather close to the experimental ones but, compared to the case of water-propanol, the correlation coefficient is lower (R2 ¼ 0.9308) since some data points do not aligned quite well on the theoretical line. Possibly higher weight of specific interactions could be presumed for waterbutanol than for water-propanol. The regression plane could also be constructed (not shown inhere). In Fig. 18 the correlation between experimental fluorescence data in water-butanol with those calculated according to solvatochromic theory is presented. Although some points do not align very well on the trend line (Fig. 18) however the calculated linear dependence between experimental fluorescence wavenumbers and the values given by double linear regression approach is characterized by relatively good correlation coefficient e R2 ¼ 0.9797. This can be taken as indication on the evidence of universal solute-solvent interactions domination in CTC ternary solutions with butanol and water up to about 33%. Deeper insight in the peculiar spectral behavior of chlortetracycline in fluorescence for ternary solutions was provided by assembling of recorded spectra (Fig. 19). It is evident that the progressive increasing of water volume fraction in propanol resulted also in remarkable changes of fluorescence intensity, beside the wavenumber changes. To the diminution of fluorescence studied band as effect of water adding, another smaller peak was shaped toward blue domain of visible radiation range. This could be the hallmark of specific organization
Fig. 14. Chlortetracycline in butanol water binary solvents: (a) the absorption and (b) fluorescence.
Thus, the weight of orientation-induction interactions increases for increased water percentage in butanol, while dispersivepolarization interactions weight diminishes. In Fig. 16 the study of chlortetracycline fluorescence in waterbutanol is accomplished from the viewpoint of solute-solvent
of water molecules around some chlortetracycline ones which resulted in molecular complex with distinct behavior from the point of view of universal interactions with alcohol molecules. This could be related to former observations regarding the graphs for chlortetracycline fluorescence in binary solvents water-
Please cite this article in press as: G. Oanca, et al., Solvatochromic study on chlortetracycline in binary and ternary solutions, Journal of Molecular Structure (2015), http://dx.doi.org/10.1016/j.molstruc.2015.12.066
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G. Oanca et al. / Journal of Molecular Structure xxx (2015) 1e9
Fig. 15. Graphical analysis of intermolecular interactions of CTC in water-butanol (absorption): (a) dependence on f(ε); (b) dependence of f(n).
Fig. 16. Graphical analysis of intermolecular interactions of CTC in water-butanol (fluorescence): (a) dependence on f(ε); (b) dependence of f(n).
Fig. 17. Comparison of experimental and calculated wavenumbers in the CTC absorption band for water-butanol mixtures.
alcohol meaning that the complex formed to the water supplying is observable due to its fluorescence properties. Thus, chlortetracycline ternary solutions exhibit specific interactions in fluorescence data, where universal interactions contributions to the band shift presented peculiar graphs to the increase of water volume fraction. We underline that in the case of mathematical approach by double linear approach with both functions on solvent refractive index and dielectric constant the results provided only the global insight. Instead, the separate consideration of wavenumber dependence on f(n) and f(ε) enabled us to get more detailed information on the intimate processes in the studied ternary solutions. As well, absorption studies alone would not be enough to evidence local
Fig. 18. Comparison of experimental and calculated wavenumbers in the CTC fluorescence band for water-butanol mixtures.
phenomena as the fluorescence did, since for absorption data analysis mainly good linear correlations were obtained between the wavenumber and the function of n and ε recommended by solvatochtomic theory. 5. Conclusion Solvent influence on the chlortetracycline in diluted solutions was evidenced from the shift of experimentally recorded electronic absorption band compared to the band simulated by quantum chemical modeling for aqueous solutions. Universal orientationinduction interactions as well as of overlapped dispersivepolarization forces between chlortetracycline molecule and some
Please cite this article in press as: G. Oanca, et al., Solvatochromic study on chlortetracycline in binary and ternary solutions, Journal of Molecular Structure (2015), http://dx.doi.org/10.1016/j.molstruc.2015.12.066
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References
Fig. 19. Chlortetracycline fluorescence intensity in binary solvents.
pure solvents were evidenced from the linear dependence of wavenumber value in the maximum of the studied electronic absorption band on some pure solvent electro-optical macroscopic parameters ε, and n. Specific interactions were evidenced for some solvents that seemed not to obey the solvatochromic theory focused only on universal solute-solvent interactions. Fluorescence data enlarged the image on chlortetracycline behavior in polar solvents like water and alcohols from the point of view of both universal and specific interactions in binary solvents. The balance between universal orientation-induction forces and dispersive-polarization ones for water-propanol and respectively water-butanol mixtures was found to be different in the range of relatively low concentrations of water compared to the range of relatively high water volume fractions. Specific interactions could be evidenced from the measurements on fluorescence intensity that revealed the possible formation of chlortetracycline-solvent complexes with fluorescent features. Further studies are planned to explain specific interactions in pure solvents other than alcohols since practical applications in chromatographic analysis could involve such eluents. Acknowledgment This work was co-funded by the European Social Fund through Sectorial Operational Program Human Resources Development 2007e2013, project number POSDRU/187/1.5/S/155397, project title “Towards a New Generation of Elite Researchers through Doctoral Scolarships.” The authors thank to dr. V. Pohoata and dr. R. Tigoianu for technical assistance.
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Solvatochromic study on chlortetracycline in binary and ternary solutions G. Oanca a, C. Nadejde a, N. Fifere b, A. Gritco Todirascu a, D. Creanga a, *, D. Dorohoi a, Jernej Stare c a b c
University “Alexandru Ioan Cuza”, Faculty of Physics, Iasi, Romania “P. Poni” Institute of Macromolecular Chemistry, Iasi, Romania National Institute of Chemistry, Ljubljana, Slovenia
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 November 2015 Accepted 22 December 2015 Available online xxx
Molecular modeling of chlortetracycline was performed based on DFT approach implemented in Gaussian software. The differences between simulated electronic spectra and those recorded experimentally were analyzed. Experimental investigations were carried out using electronic absorption spectra as well as fluorescence ones. Spectral shift to the changing of solvent polarity was measured in various solvents (binary solutions) and graphical correlations were evidenced between the electronic band wavenumbers and some theoretical functions on solvent electro-optical macroscopic parameters (refractive index and dielectric constant); interpretation was done based on the solvatochromic theory dedicated to universal interaction forces. Fluorescence spectra, studied in mixture of solvents (ternary solutions), evidenced also specific interactions in water-alcohols not considered in the classical solvatochromic approach. © 2015 Elsevier B.V. All rights reserved.
Keywords: Chlortetracycline Molecular modeling Fluorescence Absorption Universal intermolecular forces Specific interactions
1. Introduction Previous literature sources let us know that UVeVis spectroscopy methods were reported as useful in the detection of food loading with tetracycline derivatives; HPLC/UVeVis method was applied for the identification of oxytetracycline, tetracycline and chlortetracycline in honey [1]. Simple UVeVis investigation of honey in methanol solutions allowed chortetracycline and oxitetracycline content assay based on the absorption at 319 and respectively 364 nm [2]. Fluorescence spectroscopy was found suitable for the study of the interaction of trypsin (proteolytic enzyme, excreted by the pancreas) with chlortetracycline that occurs naturally because of pharmaceutically polluted environment that seems to become a real threatening for the health of human and animals [3]. UVVisible absorption spectrometry was found adequate for the determination of dissociation constants of tetracyclines in acetonitrile-water ternary solutions which are very important for liquid chromatography and capillary electrophoresis that use such
* Corresponding author. E-mail address: [email protected] (D. Creanga).
solvent mixtures [4]. Other studies were focused on spectral assay of tetracycline compounds related to their stability and bioactivity [5,6].
2. Theoretical background Solute-solvent interactions in various solvents were investigated according to mathematical approaches proposed for describing universal intermolecular forces developed in diluted solutions. Widely used solvatochromic theories [7e10] were applied in previous studies on various molecules used as spectral probes for the investigation of intermolecular forces diluted solutions. Brief presentation of such mathematical approach [11] can be done as follows. According to [11] the total spectral shift De n of a solute molecule's electronic absorption band (EAB) when passing from isolate state (gas) to solution, can be written as the sum of the contributions of main type of universal solute-solvent interactions (Eq. (1)) e the indexes “pol”, “disp”, “ind” and “or” being assigned to the main types of universal intermolecular interactions: polarization, dispersion, induction and orientation.
http://dx.doi.org/10.1016/j.molstruc.2015.12.066 0022-2860/© 2015 Elsevier B.V. All rights reserved.
Please cite this article in press as: G. Oanca, et al., Solvatochromic study on chlortetracycline in binary and ternary solutions, Journal of Molecular Structure (2015), http://dx.doi.org/10.1016/j.molstruc.2015.12.066
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G. Oanca et al. / Journal of Molecular Structure xxx (2015) 1e9
De n ¼ De npol þ De ndisp þ De nind þ De nor
(1)
The four contributions of the universal solute-solvent interactions to the spectral shift depend on the solvent macroscopic parameters n (refractive index) and ε (dielectric constant) and thus can be grouped as follows:
hcDe n ¼ AðnÞ
n2 1 ε1 þ BðnÞ εþ2 n2 þ 2
2 2 3 II 0 he2 f 2n2 þ 1 mg me AðnÞ ¼ ag ae þ 2 0 3 3 3 2a I þ I 8pmee n þ2 n0 a a
BðnÞ ¼
2n2 þ 1 2mg mg me cos 4 a3 n2 þ 2
(2)
(3)
(4)
where the term A(n) (Eq. (2) and (3)) corresponds to the sum of the first two terms from the Eq. (1), describing dispersive-polarization forces while B(n) (Eq. (2) and (4)) describes the orientationinduction interactions. The microscopic parameters of the solute molecule in the ground and respectively the excited state are noted as mg and me (electric dipole moments), ag and ae (electric polarizabilities), while a stands for the average radius of the solute; e and me are the electron charge and mass, f is the oscillator strength, 4 is the angle between the two dipole moment vectors and, I and I0 are the ionizing potentials of the solute and the solvent molecules (Eqs. (3) and (4)). The solvent refractive index, is n, while the dielectric constant is ε. The quantities A(n) or B(n) could be estimated by statistical method (regression line), based on measured wavenumbers and known solvent macroscopic parameters. 3. Materials and methods 3.1. Quantum chemical approach Molecular optimized structure, HOMO e LUMO eigenvalues, and dipole moment by quantum chemical simulations were done using Gaussian 09 package [12] with DFT B3LYP level of theory with 6-31Gþþ(d,p) basis set. UVeVis spectra simulation was accomplished also in Gaussian 09, starting from previously found (optimized) geometry with time dependent DFT (TD-B3LYP) with 6e31þþG(d,p) basis set. For visual representation of the molecules we used VMD and Avogadro softwares. The calculations were done on the computer cluster at National Institute of Chemistry, Ljubljana, Slovenia. 3.2. Experimental Experimental recording was accomplished using Shimadzu UVeVis double beam device, and spectrofluorimeter device Model LS 55 PerkinElmer; excitation light wavelength was of 340 nm. Chlortetracycline crystallized powder (CTC) and pure solvents from Merck were used without further purification. The solvents used for recording experimental spectra and their macroscopic electro-optical parameters are given in Table 1. 4. Results and discussion The mathematically simulated optimized geometry of chlortetracycline and electrostatic potential map are presented in Fig. 1. The four atom rings were labeled from I to IV (Fig. 1 a) considering the further discussion of simulated orbitals. The map of
Table 1 The solvents used for recording experimental spectra.
1 2 3 4 5 6 7 8 9 12 10 11
Solvent
n, refractive index
ε, dielectric constant
acetic acid n-pentanol isopentanol n-buthanol isobuthanol isopropanol n-propanol ethanol methanol N, N0 dimethylformamide ethylene glycol water
1.3719 1.4100 1.4072 1.3993 1.3959 1.3772 1.3856 1.3614 1.3284 1.4305 1.4318 1.3330
6.20 13.90 15.19 17.51 17.93 18.92 20.45 24.55 32.66 36.71 37.70 78.36
electrostatic potential distribution corresponding to the optimized molecular structure (Fig. 1 b) highlights higher electron cloud density toward the IV ring e the molecule edge containing chloride. According to Fig. 2, during the chlortetracycline passing from ground state to excited one the electron density is redistributed from the atom rings I and II toward the rings III and IV. When dissolved in water the energy of HOMO and LUMO states remain negative eindicating stable structure [13], and do not change significantly while dipole moment increased with about 25% (Table 2). In literature we found dipole moment estimation only for basic tetracycline in buffer surrounding medium (H3Tetracycline), of about 14D as resulted from lower accuracy computational approach with PM3 [14]. The maxima of visible range electronic absorption bands of chlortetracycline provided by mathematical simulation with DFT are shifted toward lower wavenumbers (from 30,600 cm1 to 29,000 cm1 and from 37,850 cm1 to 37,500 cm1) when interactions with water surrounding molecules are considered (Fig. 3 a, b); this could be correlated also with increased dipole moment of CTC-HOH. Experimentally recorded spectrum of chlortetracycline in water (104 M) in Fig. 4 is presented being in concordance with literature data [5]. The spectrum shape is similar to the modeled one in the visible and near UV range; but the band in the visible range shifted from 29,000 cm1 at 27,170 cm1, while in the UV domain, the first band (only a shoulder at 31,800 cm1 in modeled spectrum of CTC-HOH (Fig. 3 b)) shifted to 36,360 cm1 and the next one, from 37,500 cm1 in the modeled spectrum to 44,050 cm1 in the real one. Protonation with sulfuric acid aliquot didn't change the spectrum, which usually is characteristic to pep* bands. Band assignment is based mostly on relatively low intensity, hypsochromic shift to the solvent polarity increase, and also, as mentioned, no sensitivity to solution protonation. In Fig. 5 the comparative behavior to the change of solvent characteristics can be seen for the absorption band at the highest wavelength (lowest wavenumber). Universal solute-solvent interactions were analyzed in diluted solutions according to solvatochromic theories for the electronic band at lowest wavenumbers, where solvent transparency criterion was fulfilled for alcohols, water and water-alcohol mixtures (binary solvents) e as presented further below. Since the wavenumber appears to depend linearly on the solvent parameter through the function f(ε) it seems that orientationinduction intermolecular interactions dominate (Fig. 6 a) in the chlortetracycline solutions. The contribution of dispersive-polarization forces were evidenced through the relatively slighter correlation of wavenumber
Please cite this article in press as: G. Oanca, et al., Solvatochromic study on chlortetracycline in binary and ternary solutions, Journal of Molecular Structure (2015), http://dx.doi.org/10.1016/j.molstruc.2015.12.066
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Fig. 1. (a) Optimized structure of chlortetracycline; (b) Electrostatic potential map of chlortetracycline.
Fig. 2. HOMO e highest occupied molecular orbital and LUMO e lowest unoccupied molecular orbital defining absorption transition as resulted from DFT approach.
Table 2 Calculated values for molecular orbitals and dipole moment. CTC in gaseous state (GAS) HOMO (eV)
LUMO (eV)
Dipole moment (D)
0.23565
0.08665
6.8943
CTC surrounded by water (HOH) 0.23146 0.08853
9.2767
on the solvent refractive index (Fig. 6 b). However some data points corresponding to N, N0 dimethylformamide and water (Fig. 6 a, in black) and respectively ethylene glycol, water and acetic acid (Fig. 6 b, in black) present high distances from the regression lines which suggest possible supplementary specific interactions. To get better comparison with Eq. (2), double regression approach was performed (Eq. (5)), the regression plane being represented in Fig. 6 c:
e nabs calc ¼ 25889 þ f ðnÞ1550 f ðεÞ2277
(5)
In Fig. 6 d the comparison between experimental and calculated wavenumbers for all solvents can be seen; correlation coefficient could increase when N,N0 dimethylformamide is excluded (from R2 ¼ 0.729 to R2 ¼ 0.834); acetic acid, ethylene glycol and water appeared close to the theoretical linear regression plane.
Since the computed intercept value can be taken as the wavenumber for the isolated molecule [15], the above double regression approach is able to evidence hypsochromic shift in the presence of solvents as suggested by the modeled spectra of CTC-HOH and CTCGAS (Fig. 2 a, b). Solvent effect on the electronic absorption transition is due mainly to orientation-induction but also to dispersive-polarization forces confirming the suitability of solvathochromic theory proposed for describing universal solute-solvent intermolecular interactions. For the solvents that still do not obey to the theoretical double regression calculation, specific interactions with solute molecule should be hypothesized e in this analyzed situation being the case of N, N0 dimethylformamide. According to Fig. 7 absorption and fluorescence bands of chlortetracycline in alcohols with relatively large transparency domain evidenced mirror symmetry. Fluorescence bands could be recorded in water and most alcohols, in 108 M solutions to avoid fluorescence quenching. In Fig. 8 the spectral behavior of main fluorescence band is presented. We could notice the significantly smaller intensity shoulder at smaller wavelengths. Wavenumbers in the band maximum have shown no mathematical correlation with solvent macroscopic electro-optical parameters to the change of solvent nature. Analysis of chlortetracycline fluorescence could be however studied in ternary solutions using binary mixtures of water and alcohols.
Please cite this article in press as: G. Oanca, et al., Solvatochromic study on chlortetracycline in binary and ternary solutions, Journal of Molecular Structure (2015), http://dx.doi.org/10.1016/j.molstruc.2015.12.066
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Fig. 3a. Simulated electronic absorption spectrum of isolated chlortetracycline e(CTC -GAS).. b. Simulated electronic absorption spectrum of chlortetracycline in water (CTCHOH).
Fig. 4. Electronic absorption spectrum of chlortetracycline in water and protonated water.
Fig. 5. Solvatochromic behavior in various solvents of chlortetracycline normalized spectra.
In Figs. 9e10 CTC solvatochromic behavior in binary solvents (ternary solutions water-alcohols) is presented for CTC absorption while in next figures CTC fluorescence is presented in the same mixtures. The range of water percentage in alcohols was chosen limited by fluorescence band intensity measurement possibility up to about 33% water (v/v). In Fig. 9 the effect of water addition in propanol is presented for CTC absorption and fluorescence studied bands. The progressive hypsochromic shift of the absorption band to the increase of water percentage (Fig. 9 a) was evidenced while the fluorescence wavenumber presents a bathochromic shift up to about 15% water percentage followed by a relatively slighter hypsochromic shift for further increase of water concentration up to 33% (Fig. 9 b). Analysis of solute-solvent interactions in ternary solutions of chlortetracycline solute molecule is discussed based on the next graphs. According to [16e18] dielectric constant of a binary mixture can be calculated as: ε1,2 ¼ f1ε1 þ f2ε2 where f1 and f2 are the volume fractions of the two solvents while ε1 and ε2 are their respective dielectric constants. The estimation method can be applied for the refractive index too, by checking also through Abbe refractometer direct measurement. In Fig. 10 a, the water-propanol mixture was analyzed. One can see linear dependence of the wavenumber in the maximum of the electronic absorption band on solvent parameter function f(ε) (correlation coefficient R2 ¼ 0.9836) and in Fig. 10 b on f(n) respectively (correlation coefficient R2 ¼ 0.9514) e suggesting the co-existence of orientation-induction intermolecular interactions and dispersive-polarization forces. While water concentration increased, the absorption band wavenumber has increased with the binary solvent f(ε) (Fig. 10 a) which seems to correspond to intensification of orientationinduction forces almost linearly (R2 ¼ 0.9836). For the same array of binary solvents the absorption band wavenumber diminished to the increase of binary solvent f(n) (Fig. 10 b, linear correlation coefficient, R2 ¼ 0.9514) which seems to be the effect of diminution of dispersive-polarization forces in the same conditions. In Fig. 11 one can see intermolecular interactions situation as emphasized by chlortetracycline fluorescence changes for progressive increase of water concentration in propanol.
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Fig. 6. Solvatochromic behavior of CTC in absorption: (a) dependence on f(ε); (b) dependence on f(n); (c) Regression plan approaching wavenumber in the CTC solutions absorption in dependence on f(n) and f(ε); (d) Comparison of experimental and calculated wavenumbers of CTC absorption in pure solvents.
Fig. 7. Absorption and fluorescence bands of chlortetracycline in alcohols (1-butanol; 2-propanol).
According to Fig. 11 a, the wavenumber of studied fluorescence band shifted bathochromically up to about 16.6% water volume in propanol while for higher water percentage hypsochromic shift could be evidenced; this is, orientation induction forces weight first diminished to the increase of solvent dielectric constant but then they were enhanced. As for the wavenumber dependence on the solvent refractive index, in Fig. 11 b it is shown the bathochromic shift for relatively low water percentage (up to about 9%), indicating the diminution of dispersive-polarization forces and, further, the remarkable
Fig. 8. Chlortetracycline e main fluorescence band.
hypsochromic shift for water concentrations up to 33% - corresponding to increasing of dispersive-polarization forces weight in ternary solutions water-propanol can be seen. It is obvious that fluorescence band respond differently in comparison to the absorption one. Experimental data processing by double linear regression approach, by taking into consideration wavenumber dependence on both solvent parameters, has resulted in calculated wavenumbers that depend linearly on the experimental ones with correlation coefficient R2 ¼ 0.9841 (Fig. 12) e for the studied
Please cite this article in press as: G. Oanca, et al., Solvatochromic study on chlortetracycline in binary and ternary solutions, Journal of Molecular Structure (2015), http://dx.doi.org/10.1016/j.molstruc.2015.12.066
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Fig. 9. CTC electronic band behavior to the increase of water concentration in propanol: (a) absorption; (b) fluorescence.
Fig. 10. CTC absorption in mixtures of water-propanol: (a) dependence on f(ε); (b) dependence on f(n).
Fig. 11. CTC fluorescence in mixtures of water-propanol: (a) dependence on f(ε); (b) dependence on f(n).
absorption band. Also regression plane could be generated (not shown inhere). As can be seen in Fig. 13 double linear regression approach has led to comparable values of the experimental and statistically calculated wavenumbers in the fluorescence band; however the correlation coefficient is lower than in the case of the above analyzed absorption band since couple of data points are distanced from the theoretical line e apparently more than in the case of absorption. We assume that in the ternary solutions chlortetracycline behavior is more complex than could be anticipated; it is possible that around solute molecule a molecular complex if formed with one of the solvents e and this complex exhibits fluorescence at different wavelength. To the increase of water weight in the
solution the distinct behavior of this complex could be revealed by the processing the fluorescence recorded data. Another alcohol-water solvent array was studied using butanol (Fig. 14). As can be seen in Fig. 14 a, the absorption band wavenumber increased to the increase of water percentage as expected. Fluorescence wavenumber also presented two segment-line in the plane (wavenumber, water %) as for water-butanol binary solvents (Fig. 14 b). In Fig. 15, as in the case of previous solvent mixture, the dependence of wavenumber on solvent macroscopic parameters is presented, which was found in the form of ascendant line for f(ε) and respectively descendent line for f(n), with correlation coefficients slightly diminished compared to water-propanol.
Please cite this article in press as: G. Oanca, et al., Solvatochromic study on chlortetracycline in binary and ternary solutions, Journal of Molecular Structure (2015), http://dx.doi.org/10.1016/j.molstruc.2015.12.066
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Fig. 12. Comparison of experimental and calculated wavenumbers for absorption band of chlortetracycline in binary solvents water-propanol (water percentage up to 33% v/ v).
Fig. 13. Comparison of experimental and calculated wavenumbers for the studied fluorescence band of chlortetracycline in binary solvents water-propanol (water percentage up to 33% v/v).
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interactions. Linear decrease of fluorescence wavenumber was revealed to the increase of water percentage in butanol, suggesting the diminution of orientation-induction forces, i.e. their role in the fluorescence transition energy (Fig. 16 a). The two step increase of fluorescence wavenumber when the water percentage has increased too (Fig. 16 b) shows that dispersive-polarization interactions in water-butanol act similarly like in the case of water-propanol mixtures, their influence on the fluorescence transition enhancing. In Fig. 17 the result of processing fluorescence data (collected for water-butanol binary solvents) by means of double linear regression is presented. The statistically calculated wavenumbers are rather close to the experimental ones but, compared to the case of water-propanol, the correlation coefficient is lower (R2 ¼ 0.9308) since some data points do not aligned quite well on the theoretical line. Possibly higher weight of specific interactions could be presumed for waterbutanol than for water-propanol. The regression plane could also be constructed (not shown inhere). In Fig. 18 the correlation between experimental fluorescence data in water-butanol with those calculated according to solvatochromic theory is presented. Although some points do not align very well on the trend line (Fig. 18) however the calculated linear dependence between experimental fluorescence wavenumbers and the values given by double linear regression approach is characterized by relatively good correlation coefficient e R2 ¼ 0.9797. This can be taken as indication on the evidence of universal solute-solvent interactions domination in CTC ternary solutions with butanol and water up to about 33%. Deeper insight in the peculiar spectral behavior of chlortetracycline in fluorescence for ternary solutions was provided by assembling of recorded spectra (Fig. 19). It is evident that the progressive increasing of water volume fraction in propanol resulted also in remarkable changes of fluorescence intensity, beside the wavenumber changes. To the diminution of fluorescence studied band as effect of water adding, another smaller peak was shaped toward blue domain of visible radiation range. This could be the hallmark of specific organization
Fig. 14. Chlortetracycline in butanol water binary solvents: (a) the absorption and (b) fluorescence.
Thus, the weight of orientation-induction interactions increases for increased water percentage in butanol, while dispersivepolarization interactions weight diminishes. In Fig. 16 the study of chlortetracycline fluorescence in waterbutanol is accomplished from the viewpoint of solute-solvent
of water molecules around some chlortetracycline ones which resulted in molecular complex with distinct behavior from the point of view of universal interactions with alcohol molecules. This could be related to former observations regarding the graphs for chlortetracycline fluorescence in binary solvents water-
Please cite this article in press as: G. Oanca, et al., Solvatochromic study on chlortetracycline in binary and ternary solutions, Journal of Molecular Structure (2015), http://dx.doi.org/10.1016/j.molstruc.2015.12.066
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G. Oanca et al. / Journal of Molecular Structure xxx (2015) 1e9
Fig. 15. Graphical analysis of intermolecular interactions of CTC in water-butanol (absorption): (a) dependence on f(ε); (b) dependence of f(n).
Fig. 16. Graphical analysis of intermolecular interactions of CTC in water-butanol (fluorescence): (a) dependence on f(ε); (b) dependence of f(n).
Fig. 17. Comparison of experimental and calculated wavenumbers in the CTC absorption band for water-butanol mixtures.
alcohol meaning that the complex formed to the water supplying is observable due to its fluorescence properties. Thus, chlortetracycline ternary solutions exhibit specific interactions in fluorescence data, where universal interactions contributions to the band shift presented peculiar graphs to the increase of water volume fraction. We underline that in the case of mathematical approach by double linear approach with both functions on solvent refractive index and dielectric constant the results provided only the global insight. Instead, the separate consideration of wavenumber dependence on f(n) and f(ε) enabled us to get more detailed information on the intimate processes in the studied ternary solutions. As well, absorption studies alone would not be enough to evidence local
Fig. 18. Comparison of experimental and calculated wavenumbers in the CTC fluorescence band for water-butanol mixtures.
phenomena as the fluorescence did, since for absorption data analysis mainly good linear correlations were obtained between the wavenumber and the function of n and ε recommended by solvatochtomic theory. 5. Conclusion Solvent influence on the chlortetracycline in diluted solutions was evidenced from the shift of experimentally recorded electronic absorption band compared to the band simulated by quantum chemical modeling for aqueous solutions. Universal orientationinduction interactions as well as of overlapped dispersivepolarization forces between chlortetracycline molecule and some
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References
Fig. 19. Chlortetracycline fluorescence intensity in binary solvents.
pure solvents were evidenced from the linear dependence of wavenumber value in the maximum of the studied electronic absorption band on some pure solvent electro-optical macroscopic parameters ε, and n. Specific interactions were evidenced for some solvents that seemed not to obey the solvatochromic theory focused only on universal solute-solvent interactions. Fluorescence data enlarged the image on chlortetracycline behavior in polar solvents like water and alcohols from the point of view of both universal and specific interactions in binary solvents. The balance between universal orientation-induction forces and dispersive-polarization ones for water-propanol and respectively water-butanol mixtures was found to be different in the range of relatively low concentrations of water compared to the range of relatively high water volume fractions. Specific interactions could be evidenced from the measurements on fluorescence intensity that revealed the possible formation of chlortetracycline-solvent complexes with fluorescent features. Further studies are planned to explain specific interactions in pure solvents other than alcohols since practical applications in chromatographic analysis could involve such eluents. Acknowledgment This work was co-funded by the European Social Fund through Sectorial Operational Program Human Resources Development 2007e2013, project number POSDRU/187/1.5/S/155397, project title “Towards a New Generation of Elite Researchers through Doctoral Scolarships.” The authors thank to dr. V. Pohoata and dr. R. Tigoianu for technical assistance.
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Please cite this article in press as: G. Oanca, et al., Solvatochromic study on chlortetracycline in binary and ternary solutions, Journal of Molecular Structure (2015), http://dx.doi.org/10.1016/j.molstruc.2015.12.066