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25CHEMICAL SCIENCES
DFT STUDY OF ROTARY BARRIERS OF CIPROFLOXACIN MOLECULE FRAGMENTS AND FORMATION OF A COMPLEX WITH ZINC(II)
Kudiyarova A.
Assistant of Karakalpak State University, Uzbekistan
Eshimbetov A.
Senior researcher of Institute of Bioorganic Chemistry AS of Uzbekistan
Ashurov J.
Doctor of Chemical Science, Leading researcher of Institute of Bioorganic Chemistry AS of Uzbekistan
Khodjaniyazov K.
Doctor of Chemical Science, Leading researcher of Institute of Bioorganic Chemistry AS of Uzbekistan
Ibragimov B.
Doctor of Chemical Science, Professor of Institute of Bioorganic Chemistry AS of Uzbekistan, Uzbekistan
Abstract
In this report, rotational barriers of cyclopropane and piperazine rings of ciprofloxacin and its NH protonated form have been considered by DFT/6-31G(d) method. Moreover, quantum chemical parameters and electrostatic potential surface have been calculated by this method. It was found that the barrier to rotation of the cyclopropane ring in a narrow range is 5.46 kcal / mol, and in a wide range - 11.16 kcal / mol. Rotation of the piperazine ring around the C-N bond revealed changes in the conformational forms of the piperazine ring relative to the plane of the quinolone fragment. The optimal structure was chosen according to DFT calculations from the two available structures of ciprofloxacin in the CCDC database. Furthermore, the metallo-complex formation using of ciprofloxacin hydrochloride with zinc sulfate was analyzed by comparison of experimental and theoretical FTIR spectra of proposed the complex structure. The low frequency shift by 104 cm-1 of the C=O absorption band (1726 cm-1) of ciprofloxacin hydrochloride in the obtained complex (1616 cm-1) is clearly assigned the complex formation.
Keywords: ciprofloxacin, piperazine, DFT, FTIR spectra, rotational barrier.
Introduction
Synthetic fluoroquinolone ciprofloxacin [CIP = 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7(1-piperazi-nyl)-3-quinolone carboxylic acid] possessing antibacterial activity have clinically been successfully used. CIP is used for the treatment of several bacterial infections (including tuberculosis). It can easily react with metal ions to form metal-ciprofloxacin complexes. Such complexes usually tested for biological activity comparing with initial drugs. Moreover, the formation of metallo-complexes leads to enhancing bioavailabil-ity and water solubility [1,2]. In other words, active pharmaceutical ingredients (API) possess enhanced pharmacological properties when administered in the form of metal complexes. Metallo-complexes of ciprof-loxacin without and together with other organic ligands have been extensively reported [3,4].
The cyclopropane and piperazine substructures are present in CIP as tertiary amines. The presence of a cyclopropylamine moiety within ciprofloxacin should be viewed with some caution since this group is a well-knownmechanism-based inactivator of cytochrome P450. Cyclopropylamines have also been implicated in inactivation of other human enzymes. The structural features necessary for bioactivation of cyclopropyla-mines still remain unclear.
Experimental
Synthesis
Ciprofloxacin hydrochloride has been purchased and used without any purification. Ciprofloxacin hydrochloride (367.5 mg, 1 ^mol) dissolved in aqueous ethanol was mixed together with ZnSO4 (287 mg, 1 ^mol) dissolved in water dropwise the latter and stirring with magnetic stirrer vigorously. HCl solution (1N, 10 mL) was added drop by drop to enhancing solubility of the reaction mixture. The obtained mixture was kept during 15 min at 60-65°C in ultrasound bath (30 kHz). Finally, the solution left for one day at room temperature. The formed precipitate was filtered off and washed with ethanol three times, air dried. Yield: 33.9 mg (70.0%). FTIR spectra of ciprofloxacin hydro-chloride, Zn(II) salts and zinc - ciprofloxacin complex were recorded using "IRTracer-100 Fourier Transform Infrared Spectrophotometer" (Shimadzu, Japan) with an ATR attachment.
DFT study
The geometry of ciprofloxacin hydrochloride and its possible complexes have been built using Avogadro program package [5].The geometry of all structures has been optimized by the B3LYP/6-31G(d) method using ORCA program package [6]. The rotational barrier of the cyclopropane and piperazine rings around N-C bond were determined by varying dihedral angles (C-N-C-C and C-C-N-C) from 0o to 360o with 5o step.
Electrostatic potential analyses have been performed by Multiwfn [7] and VMD [8] program packages.
Discussion
Structural analysis. Analysis of the structure of ciprofloxacin (1) in the Cambridge Crystallographic Database showed the presence of several structures of ciprofloxacin and its complexes with various metals [9-15]. Some structures of ciprofloxacin (2) differentiate by the location of the piperazine ring in space relative to the quinolone plane. And also several structures of ciprofloxacin were found, where the spatial arrangement of the cyclopropane ring is differed. These findings prompted us to study the rotation barrier of the cyclopropane and piperazine ring around the C-N bond.
The results are presented in Fig. 2 and 3, which show the rotational potential curve, its maxima and
minima. We have obtained identical pictures of potential curve in the case of structures 1 and 2. The potential curve of compounds 1 (Fig. 2., 1a) has minima at 40 and 250°, where the position of the cyclopropane ring is up or down relative to the quinolone plane. The highest maxima of potential curve at 106 and 175° are caused by steric effects between hydrogen atoms of CH2 group of cyclopropane and C8 atom of quinolone fragment. The height of the barrier is equal to 11.16 kcal/mol. The maximum of potential curve at 325° is caused by spatial effects between hydrogen atoms of CH2 group of cyclopropane and C2 atom of quinolone fragment. The height of the barrier is equal to 5.46 kcal/mol. Protonation of the NH nitrogen atom leads to enhancing in the rotation barrier (at 106 and 175 degree) from 11.16 to 16 kcal/mol.
Fig.1. Optimized 3D structure of spatially different ciprofloxacin 1 and 2. Dihedral angle (Red signed atoms) were used to determination of rotational barrier of cyclopropane and piperazine rings around C-N bonds.
Dihedral angle, o
Fig.2. Potential curve of compound 1 (1a) and its protonated form (1b) obtained by rotation of the cyclopropane
ring around the N1-C bond.
Movement between conformational forms of pi-perazine ring (a-^b) was occurred during rotation of piperazine ring around C-N bond in the case of structures
1 and also 2 (Fig.3). The maxima in the potential curve of 1 (1a) and its protonated form (1b) caused by inversion of piperazine cycle from a to b:
Fig.3. Potential curve of compounds 1 (1a) and its protonated form (1b) obtained by rotation of the piperazine
ring around the C7-N bond
HN-
HN-
-N-
a
U
N
o J
"55 o
<D C LU
7 6 5 4 3 2 1 0
0
-1a
r\ ID
1 [ /
\ /
\ . / // A' w
100 200 300
Dihedral angle, °
400
b
Thus, the cyclopropane and piperazine rings are in the most optimal geometric state in optimized structures of 1 and 2. The comparison of the total energies of structures 1 and 2, as well as their protonated forms, shows the stability of structure 1 relative to 2 by approximately 2-3 kcal/mol (Table 1). Structural transformation and the transition between these two structures can be observed in solution even at room temperature or by heating.
Quantum chemical parameters.
The most commonly used quantum-chemical parameters [16-20] were calculated for an optimized structure of spatially different ciprofloxacin 1 and 2. It is known, that the highest occupied and lowest unoccupied molecular orbitals (HOMO and LUMO), which called frontier MO's are play important role in chemistry and on the basis of this MOs can be determined significantly helpful quantum chemical parameters, such as chemical hardness (n) and softness (c), energy gap (AE), electronegativity (/) and electrophilicity index
(œ). According to Koopmans' theorem, the (negative) energy of HOMO is equal to the ionization potential of a molecule while the LUMO energy describes the molecular electron affinity [16]. In addition, the HOMO and LUMO energy levels show the electron-donating and electron-withdrawing abilities of the molecules, respectively. Protonation of the terminal nitrogen atom of piperazine ring to form quaternary ammonium salt leads to the stabilization of the system by reducing energy levels of both frontier MOs HOMO and LUMO. The relative higher value of dipole moment (p) of structures 1 and 2 are showing the higher polarity of ciprofloxacin, especially in its protonated form. Chemical hardness and softness values of 1, 2 and their protonated forms are almost identical. Electronegativity and electrophilicity indexes of protonated forms are higher relative to their base form. The electronegativity and electrophilicity parameters of protonated forms are high compared to their main form and show a high propensity to nucleophiles [16].
Table 1.
Quantum chemical parameters for 1, 2 and their protonated form
QCP 1 1 cation 2 2 cation
Etot, kcal/mol -720202.79 -720431.90 -720200.79 -720428.18
Ehomo, eV -5.94 -8.48 -5.75 -8.58
Elumo, eV -1.48 -4.15 -1.45 -4.22
|AE|= Ehomo - Elumo, (eV) 4.46 4.33 4.30 4.36
Ionisation potentials, I = - Ehomo, (eV) 5.94 8.48 5.75 8.58
Electron affinity, A = - Elumo, (eV) 1.48 4.15 1.45 4.22
Electronegativity, x = (I + A)/2 (eV) 3.71 6.31 3.6 6.4
Chemical hardness, n = (I - A)/2 (eV) 2.23 2.16 2.15 2.18
Chemical potential, ^p = - (I + A)/2 (eV) -3.71 -6.31 -3.6 -6.4
Chemical softness, c = 1/(2n) (eV-1) 0.22 0.23 0.23 0.23
Electrophilicity index, œ = ^p2/2n (eV) 3.08 9.21 3.01 9.39
Dipole moment, ^ (Debye) 11.27 30.84 11.32 29.11
Another important parameter in chemistry is the electrostatic potential [21, 22], which indicates the electron donor (rich in electrons) and electron acceptor (poor in electrons) centers of the molecules. ESP analyses show the presence of maximum on vicinity of H of NH group in the case of structures 1 and 2 (Fig. 4 and 5). At the same time, ESP minima are located in the
vicinity of oxygen atoms of C=O groups. The electron-donor ability of the oxygen atom of COOH groups is higher than oxygen atom of C=O groups due to the intramolecular H bond. However, protonization of the NH nitrogen atom greatly reduces the electron-donor ability of oxygen atoms.
Fig.4. ESP surface minima and maxima of ciprofloxacin (1) and its cation. Blue and purple circles are positive
and negative points, respectively.
Fig.5. ESP surface minima and maxima of ciprofloxacin (2) and its cation. Blue and purple circles are positive
and negative points, respectively.
FTIR study of complex formation
It was noted above that the interaction of ciprofloxacin hydrochloride with zinc sulfate was carried out in a 1:1 ratio with adding of hydrochloric acid (1N HCl) by dropwise. The FTIR spectra of all compounds are given in Fig. 6. The FTIR spectrum of ciprofloxacin hy-drochloride is characterize by presence of absorption bands caused by OH (3441 cm-1), C=O (1720, 1625 cm-1), C-N (1271 cm-1) group vibrations. The wavenumber of C4=O group is located in higher frequency region relative to C=O of COOH group [19]. The ZnSO4 spectrum is characterized by the presence of absorption bands due to the sulfate anion at 1089, 758 and 611 cm-1 (Fig.6) [24]. The absence of absorption bands characteristic to the sulfate anion in the spectrum of the complex indicates their non-participation in the final product. Maybe the chloride anion added during the reaction takes its place in the complex. To compare our FTIR
results with literature data a literary analysis have been carried out. The obtained literature data are collected in table 2. According to the literature data, the shift of the absorption band of the C=O group (1720 cm-1) of ciprofloxacin hydrochloride is a clear sign of the formation of a complex. In the case of our complex, the shift of the C=O absorption band of ciprofloxacin hydrochloride is 104 cm-1 (1616 cm-1) in the complex.
Several possible structures were prepared to determine the proposed structure of the complex. Then the structures were optimized by the B3LYP / 6-31G (d) method and the theoretical IR spectra were calculated for comparison with the experimental spectrum. As a result of comparison of theoretical and experimental spectra, the proposed structures of the complex were proposed:
Zinc can replenish the remaining coordination number with water molecules. The presence of an intense absorption band in the region of 3100-3400 cm-1 confirms the presence of a water molecule in the complex.
Fig.6. FTIR spectrum of ZnSO4-7H2O (red), ciprofloxacin hydrochloride (black) and complex (green).
* Av - the shift relative to the absorption band of ciprofloxacin hydrochloride (1720 cm-1)
Table 2.
Complexes of ciprofloxacin with different metals and C=O wavenumbers
Complex Vc=o (Av)*, cm-1 Me:CipRatio Literature
[Ba2(cf)2(1,4-bdc)(H2O)2]H2O 1618 (102) 1:1 [9]
[Sr6(cf)6(1,4-bdc)3(H2O)6]2H2O 1623 (97) 3:3 [9]
[Mn2(cfH)2(bptc)(H2O)2]8H2O 1629 (91) 1:1 [9]
[Cd2(cfH)2(bptc)(H2O)2]8H2O 1626 (94) 1:1 [9]
[Zn(cfH)(1,3 -bdc)] 1615 (105) 1:1 [9]
[Zn2(cfH)4( 1,4-bdc)](1,4-bdc)- I3H2O 1628 (92) 1:1 [9]
[Ca(cfH)2(1,2-Hbdc)2] 2H2O 1631 (89);1615 1:2 [9]
[Mn(cf)2]2.5H2O 1622 (98) 1:2 [9]
[Co(cf)2]2.5H2O 1622 (98) 1:2 [9]
[Zn(cf)2]2.5H2O 1622 (98) 1:2 [9]
[Cd(cf)2]2.5H2O 1620 (100) 1:2 [9]
[Mg(cf)2]2.5H2O 1629 (91) 1:2 [9]
[Cu(HCip)2](NO3)2 6H2O 1640 (80);1620 1:2 [10]
[Cd(cfH)(bpdc)]dH2O 1627 (93) 2:1:1 [11]
[Cd(norfH)(bpdc)]dH2O 1624 (96) 1:1:1 [11]
[Mn(norfH)(bpdc)]dH2O 1634 (86) 2:1:1 [11]
[Mn2(cfH)(odpa)(H2O)3]d0.5H2O 1627 (93) 2:1:1 [11]
[Co2(norfH)(bpta)(m2-H2O)(H2O)2]dH2O 1628 (92) 2:1:1 [11]
[Co3(salaH)2(Hbpta)2(H2O)4]d9H2O 1616 (104) 2:1:1 [11]
[Cu(H-Cip)2].(ClO4)2.6H2O 1628 (92) 1:1 [12]
[Cu(Ofl)2.H2O].2H2O 1622 (98) 1:1 [12]
[CuII(cfH)2(CuICl2)2]. 1628 (92) 1:1:1 [13]
[Mg(H2O)2(cfH)2] (NO3)2 • 2H2O 1621 (99) 1:2 [13]
[Mg(cfH)3](SO4)5H2O 1614 (106) 1:3 [14]
[Co(Cip)2].4H2O 1628 (92) 1:1 [16]
Conclusion
From the available two structures of ciprofloxacin in the CCDC database it was found the optimal one by DFT calculations. The optimal structure (1) is energetically stable for 2.00 kcal/mol then the structure (2). It was found that the rotation barrier of the cyclopropane ring in a narrow range is 5.46 kcal/mol, while in a wide range - 11.16 kcal/mol. Rotation of the piperazine ring around the C-N bond is revealed to geometric changes as axial and equatorial displacements of the ring. Axial-equatorial displacement (relative to the quinolone plane) is observed during rotation of piperazine ring in both structures. However, chair form of piperazine ring remains unchanged at the rotation process. It was the reason to appearance of two structures in the database. According to our calculations, the presence of two structures (1 and 2) in the database exists due to the rotation of the piperazine ring around the single C-N bond. Structural movement and the transition between these two structures can be observed in solution even at room temperature or by heating. It was found that the considered conformational transformations could affect the UV and IR spectral characteristics.
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DEPENDENCE OF THE ACTIVITY OF Ti-W-O CATALYSTS IN THE ETHANOL OXIDATION REACTION ON THE ACIDIC PROPERTIES OF THE SURFACE
Mammadova A.
Master Student, Chemical technology faculty, Azerbaijan State Oil and Industry University, Baku, Azerbaijan
Abstract
In this work it was studied the activity of the binary tin-vanadium oxide catalysts in reaction of ethanol oxidation to acetic acid. It was found that the main products of ethanol oxidation over tin-vanadium oxide catalysts are acetaldehyde and acetic acid. It is shown that high activity of tin-vanadium oxide catalysts rich in one of the elements due to the formation of solid solutions.
Keywords: ethanol oxidation, binary catalysts, tin oxide, vanadium oxide, acetic acid, acetaldehyde.
Introduction.
Acetic acid is one of the important chemicals and solvents used in industry [1]. One of the promising methods for producing acetic acid is the direct gasphase oxidation of ethanol on heterogeneous catalysts, proceeding according to the equation.
C2H5OH + O2 ^ CH3COOH + H2O Catalysts based on vanadium oxides, molybdenum oxide and others are highly active in the oxidation of
ethanol to acetic acid [2, 3]. Therefore, this work is devoted to the study of the oxidation reaction of ethanol to acetic acid on mixed tin-vanadium oxide catalysts.
Experimental part.
We prepared binary tin-vanadium oxide catalysts of various compositions by coprecipitation from aqueous solutions of tin tetrachloride and ammonium vana-date. The obtained mixture was successively evaporated and dried at 100-120°C, decomposed at 250°C
