Preparation, spectroscopic and thermal characterization of new La(III), Ce(III), Sm(III) and Y(III) complexes of enalapril maleate drug. In vitro antimicrobial assessment studies

Journal of Molecular Structure 1059 (2014) 208–224

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Preparation, spectroscopic and thermal characterization of new La(III), Ce(III), Sm(III) and Y(III) complexes of enalapril maleate drug. In vitro antimicrobial assessment studies Moamen S. Refat a,b,⇑, Fathi M. Al-Azab c, Hussein M.A. Al-Maydama c, Ragab R. Amin d, Yasmin M.S. Jamil c a

Department of Chemistry, Faculty of Science, Taif University, Al-Hawiah, P.O. Box 888, Taif 21974, Saudi Arabia Department of Chemistry, Faculty of Science, Port Said University, Port Said, Egypt Department of Chemistry, Faculty of Science, Sana’a University, Yemen d Faculty of Dentistry, Nahda University, Egypt b c

h i g h l i g h t s  Enalapril maleate lanthanide complexes were synthesized.  Enalapril acts as a bidentate chelate.  Maleate moiety acts as a bidentate ligand.  Kinetic and thermodynamic parameters were estimated.

a r t i c l e

i n f o

Article history: Received 2 October 2013 Received in revised form 3 December 2013 Accepted 3 December 2013 Available online 11 December 2013 Keywords: Enalapril maleate Spectroscopic studies Florescence studies Antibacterial evaluation

a b s t r a c t The 1:1 M ratio metal complexes of enalapril maleate hypertensive drug with La(III), Ce(III), Sm(III) and Y(III) were synthesized. The suggested structures of the resulted complexes based on the results of elemental analyses, molar conductivity, (infrared, UV–visible and fluorescence) spectra, effective magnetic moment, thermal analysis (TG), X-ray powder diffraction (XRD) and scanning electron microscopy (SEM) were discussed. The infrared spectral data were suggested that enalapril reacts with metal ions as an ionic bidentate ligand through its carboxylate oxygen and the amide carbonyl oxygen, but in case of the Sm(III) complex, it reacted as a monodentate through its amide carbonyl oxygen. Maleate moiety acts with all these metals as bidentate ligand through its carboxylate or carbonyl oxygen. The kinetic and thermodynamic parameters such as: Ea, DH, DS and DG were estimated from the DTG curves. The antibacterial evaluation of the enalapril maleate and their complexes were also performed against some gram positive and negative bacteria as well as fungi. Ó 2013 Elsevier B.V. All rights reserved.

1. Introduction Metals and metal complexes have played a key role in the development of modern chemotherapy [1,2]. For example, complexation of non-steroidal anti-inflammatory drugs to copper overcomes some of the gastric side effects of these drugs [3–7]. A number of drugs and potential pharmaceutical agents also contain metal-binding or metal-recognition sites, which can bind or interact with metal ions and potentially influence their bioactivities and might also cause damages on their target biomolecules. Numerous examples of these metallodrugs and metallopharmaceuticals and their actions can be found in the literature, for instance: (a) several

⇑ Corresponding author at: Department of Chemistry, Faculty of Science, Taif University, Al-Hawiah, P.O. Box 888, Taif 21974, Saudi Arabia. E-mail address: [email protected] (M.S. Refat). 0022-2860/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.molstruc.2013.12.003

anti-inflammatory drugs, such as aspirin and its metabolite salicylglycine [8–11], suprofen [12], and paracetamol [13] are known to bind metal ions and affect their antioxidant and anti-inflammatory activities; (b) the potent histamine-H2-receptor antagonist cimetidine [14] can form complexes with Cu2+ and Fe3+, and the histidine blocker antiulcer drug famotidine can also form stable complex with Cu2+ [15,16]; (c) the anthelmintic and fungistatic agent thiabendazole, which is used for the treatment of several parasitic diseases, forms a Co2+ complex of 1:2 metal to drug ratio [17] and (d) the Ru2+ complex of the anti-malaria agent chloroquine exhibits an activity two to five times higher than the parent drug against drugresistant strains of Plasmodium faciparum [18]. However, it is known that some drugs act via chelation or by inhibiting metalloenzymes but most of the drugs act as potential ligands, a lot of studies are being carried out to ascertain how metal binding influences the activities of the drugs [19]. Metal complexes are gaining

M.S. Refat et al. / Journal of Molecular Structure 1059 (2014) 208–224

increasing importance in the design of drugs on coordination with a metal. Also, lanthanides ions coordinate to some vital drugs for instance; syntheses, characterization, antioxidative and antitumor activities of solid quercetin rare earth (III) complexes were studied [20–26]. Enalapril is chemically described as [(2S)-1-[(2S)-2-[[(1S)1-(ethoxycarbonyl)-3-phenylpropy] amino] propanoyl]pyrrolidin2-carboxylic acid (Z)-butenedioate] maleate (Fig. 1). Its molecular weight is 492.53 g/mol. It is a white to off-white crystalline, odorless powder which melts in the range of 143–144 °C [27]. The physical and stereochemistry behaviors of enalapril maleat were discussed in literature survey [28–32]. The drug is used for treating high blood pressure or hypertension in adults, children and congestive heart failure [33,34]. The therapeutic importance of enalapril maleate was behind the development of numerous methods for its determination. The different method techniques adapted to the analysis of enalapril maleate have been reported [35–48]. Literature survey fell to reveal any previous work or literature regarding the complexation of enalapril maleate with neither transition nor rare earth metals except for enalapril sodium compound [49,50]. An attempt of synthesizing, characterization and biological screening of enalapril maleate ligand and their metal complexes of yttrium and some lanthanides have been successfully achieved. The characteristic structure of the molecule is apparent in the existence of the carboxylic and carbonyl electron-rich ligand. However, literature survey has revealed that no attempt has been made to study the complexes of some rare earth metal ions with the above mentioned drug ligand compounds. It is a thought of interest to study the synthesis and characterization, thermal behavior and biological screening of the Y(III), La(III), Ce(III) and Sm(III) complexes of the enalapril maleate ligand. The processes of thermal degradation of the ligands and their metal complexes have been investigated by thermoanalytical method (TG, DTG). The Coats-Redfern method integral method has been used to determine the associated kinetic parameters for the successive steps in the decomposition sequence. Drug compounds are biologically active, these compounds have become of interest to be studied biologically, and compared their activities against four species of bacteria (Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa), and two fungal species (Aspergillus flavus and Candida albicans).

2. Experimental

209

2.2. Preparation of the drug metal complexes All the interested complexes under investigation were prepared similarly according to the following procedure: In general, 3 mmol of enalapril maleate ligand was dissolved in 25 mL methanol then mixed with 25 mL of methanolic solution of 1 mmol metal nitrate of La(III), Ce(III), Sm(III) or Y(III). A mixtures with molar ratio of 1:3 (Ln(NO3)3xH2O: ligand), at adjusted pH = 8–9 using 1 M methanolic ammonia solution were refluxed with continuous stirring at 60–70 °C for about 2 h. The mixtures were left overnight until precipitated. The precipitates obtained were filtered off and washed several times using methanol then left over anhydrous calcium chloride. The yield percent of the products collected were about 60–70%. 2.3. Spectral measurements IR spectra of the metal complexes were recorded on Shimadzu DR-8001 infrared spectrophotometer as potassium bromide pellets, and in the range 400–4000 cm1, at Cairo University. The electronic spectra of the complexes were measured in DMSO solvent with concentration of 1  103 M, in rang 200–1100 nm by using Unicam UV/Vis spectrometer, at Ain Shams University. Fluorescence spectra of the complexes were measured in DMSO solvent with concentration of 1  103 M by using a Perkin Elmer Luminescece spectrometer LS 50B, at Ain Shams University. The proton NMR spectra were recorded on a Varian FT- 300 MHz spectrometer in d6-DMSO solvent, using TMS as internal standard (at Cairo University, Giza, Egypt). SEM images were obtained using a Jeol Jem-1200 EX II Electron Microscope at an acceleration voltage of 25 kV. The samples were coated with a gold plate, at Ain Shams University. X-ray diffraction (XRD) patterns of the samples were recorded on a X Pert Philips X-ray diffractometer. All the diffraction patterns were obtained by using Cu Ka1 radiation, with a graphite monochromator at 0.02°/min scanning rate. The metal complexes were made in the form of tablets, which have 0.1 cm thickness, under a pressure of approximately 5  107 Pa, at Ain Shams University. 2.4. Microanalytical analysis Carbon, hydrogen and nitrogen analysis of the complexes have been carried out in Vario EL Fab. CHNS Nr.11042023, at Central Laboratory, Faculty of Science, Ain Shams University, Egypt. The amount of water and the metal content percentage were determined by thermal analysis methods.

2.1. Materials 2.5. Molar conductance All chemicals, solvents, indicators, metal(III) nitrates (i.e. lanthanum, cerium and samarium nitrate hexahydrate and yttrium nitrate pentahydrate) were commercially available from BDH and were used without further purification. The standard pure drug (enalapril maleate) was obtained as a gift sample from EIPICo Company at Egypt. The enalapril maleate used was a white or almost white crystalline powder with melting point of 143–145 °C. This powder was soluble in water, freely soluble in methanol, sparingly soluble in methylene chloride and easily dissolves in dilute solutions of alkali hydroxides [51].

The molar conductance of 103 M solutions of the enalapril maleate ligand and their metal complexes in DMF solvent were measured on a HACH conductivity meter model. All the measurements were taken at room temperature for freshly prepared solutions. 2.6. Melting point measurements Stuart Scientific electrothermal melting point apparatus was used to measure the melting points of the ligands and their metal complexes in glass capillary tubes in degrees Celsius. 2.7. Magnetic measurements

Fig. 1. Structure of enalapril maleat (Enal) ligand.

The mass susceptibility (Xg) of the solid complexes was measured at room temperature using Gouy’s method by a magnetic susceptibility balance from Johnson Metthey and Sherwood model,

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at Cairo University Central Lab. The effective magnetic moment (leff) values were obtained using the following Eqs. (1)–(3) [52].

Xg ¼

C Bal LðR  Ro Þ

ð1Þ

109 M

where Ro is the reading of empty tube, L is sample length (cm), M is sample mass (g), R is Reading for tube with sample, CBal is balance calibration constant = 2.086.

X M ¼ X g  M:Wt:

ð2Þ

The values of XM as calculated from Eq. (2) are corrected for the diamagnetism of the ligands using Pascal’s constants, and then applied in Curie’s Eq. (3).

pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi

leff ¼ 2:84 X M  T

ð3Þ

where T = t (°C) + 273 2.8. Thermal analysis Differential Thermal Analysis (DTA) and Thermogravimetric Analysis (TGA) experiments were conducted using Shimadzu DTA-50 and Shimadzu TGA-50H thermal analyzers, respectively, (at Micro Analytical Center, Cairo University, Cairo-Egypt). All experiments were performed using a single loose top loading platinum sample pan under nitrogen atmosphere at a flow rate of 30 mL/min and a 10 °C/min heating rate for the temperature range 25–800 °C.

brown, beige and orange in color and possess slightly high melting points. These complexes were partially soluble in hot methanol, dimethylsulfoxide and dimethylformamide, but insoluble in water and some other organic solvents. The suggested formula structures of the complexes were based on the results of the elemental analyses, molar conductivity, (infrared, UV–visible and fluorescence) spectra, effective magnetic moment in Bohr magnetons, as well as the thermal analysis (TG), and characterized by X-ray powder diffraction (XRD) and scanning electron microscopy (SEM).

3.1. Molar conductance The molar conductance of the complexes in DMF at room temperature Table 2 indicates that the complexes of Sm(III) and Y(III) were good electrolytes [56,57], since their nitrate ions were in the ionization sphere of the complexes. The molar conductance values recorded for all the complexes at the concentration of 103 mol cm3 were laying out in the range of 42.1–234 X1 cm2 mol1, but the free ligand shows 28.2 X1 cm2 mol1. From the results Table 2, the La(III) and Ce(III) ions were non-electrolytic in nature. However, the Sm(III) was highly electrolytic almost as twice (234 X1 cm2 mol1) as that of Y (113.1 X1cm2 mol1). This was because of the Sm(III) ion forming the [Sm(Enal-NH4)(Mal-(NH4)2) (H2O)3]H2O3NO3 complex while the Y(III) ion forms the [Y(Enal) (Mal-(NH4)2)(H2O)2]H2O2NO3 complex [56–58].

3.2. Infrared spectra 2.9. Biological screening The enalapril maleate ligand and their metal complexes were tested for their antimicrobial activity against four species of bacteria (S. aureus, B. subtilis, E. coli, P. aeruginosa), and two fungal species (A. flavus and C. albicans) using filter paper disc method [53].The screened compounds were dissolved individually in DMSO (dimethyl sulfoxide) in order to make up a solution of 1000 lg/mL concentration for each of these compounds. Filter paper discs (Whatman No. 1 filter paper, 5 mm diameter) were saturated with the solution of these compounds. The discs were placed on the surface of solidified Nutrient agar dishes seeded by the tested bacteria or Czapek’s Dox agar dishes seeded by the tested fungi. The diameters of inhibition zones (mm) were measured at the end of an incubation period, which was 24 h at 37 °C for bacteria, and 4 days at 28 °C for fungi. Discs saturated with DMSO are used as solvent control. Ampicillin 25 lg/mL was used as a reference substance for bacteria and 30 lg/mL Mycostatin for fungi [54,55]. 3. Results and discussion The metal complexes of enalapril maleate with La(III), Ce(III), Sm(III) and Y(III) were synthesized. Some physical properties and analytical data of the four complexes were summarized in Table 1. The satisfactory elemental analysis results (Table 2) show that the La(III), Ce(III) Sm(III) and Y(III) complexes with enalapril were of 1:1 (metal:Enal) molar ratio. The synthesized complexes were

The infrared absorption bands were one of the important tools of the analyses used for determining the mode of chelation. Enalapril maleate behaves as an ionic bidentate molecule and was coordinated to the metals through its carboxylate oxygen and amide carbonyl oxygen, but in case of the Sm(III) complex, it behaves as a monodentate through its amide carbonyl oxygen. Therefore, in these complexes (Figs. 2a and 2b) one metal ion were coordinated to one molecule of the Elalapril and one maleate molecule. In comparison with the published spectra [59–61] of the free enalapril spectra (Figs. 2a and 2b), the assignments of bonding sites of the ligand with metal ions were summarized in Table 3 and based on the following evidences: 1. The band at 3000–3700 cm1 in all complexes was broad. This was due to the presence of the water. The ligand band at 3215 cm1 assigned to the secondary amine mNAH [62] was either absent or very weak in all complexes, indicating the interference of the aqua and NAH bands in this region (3000– 3700 cm1). 2. The resolved bands at 3025, 2979 and 2929 cm1 in the free ligand due to the aromatic mCH, masCH3 and masCH2, respectively, were overlapped due to the complexation with metals at the range (3028–2930 cm1). 3. The new ammonium NHþ 4 formation after complexation with metals have three deformation and characteristic bands with medium to weak intensity at 2378, 2349 and 2424, 2362 cm1 [63].

Table 1 Some physical properties of the Enal ligand. Ligand

Formula

Appearance

M.p (°C)

Action and uses

Solubility 1

2

3

4

5

Dilute alkali hydroxides

Dilute acids

Enal

C24H32N2O9

White crystalline powder

143–145

Hypertensive

S

S

S

S

P.S.

S

S

S = Soluble, P.S. = Practically soluble, Ins. = insoluble solvents: (1) H2O, (2) MeOH, (3) EtOH, (4) (CH3)2CO, (5) CH2C12.

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M.S. Refat et al. / Journal of Molecular Structure 1059 (2014) 208–224 Table 2 Analytical and Physical data of the enalapril metal complexes. Complexes empirical formula M.Wt. (g/mol)

Color

Melting point (°C)

Km (X1 cm2 mol1)

[La(Enal)(Mal-NH4)(NO3)]H2O (726.46) [Ce(Enal)(Mal-NH4)(NO3)]H2O (727.67) [Sm(Enal-NH4)(Mal-(NH4)2)(H2O)3]H2O3NO3 (952.0) [Y(Enal)(Mal-(NH4)2)(H2O)2]H2O2NO3 (792.53)

Brown

135

42.1

Dark Brown Beige

148

53.1

150

234

Faint Orange

152

113.1

Elemental analysis/% found (Cal.) C

H

N

M

39.60 (39.69) 39.49 (39.61) 30.30 (30.28) 36.12 (36.37)

4.87 (4.86) 4.80 (4.85) 5.22 (5.19) 5.30 (5.47)

7.70 (7.71) 7.73 (7.70) 11.70 (11.77) 10.55 (10.60)

19.12 (19.12) 19.26 (19.26) 15.79 (15.79) 11.22 (11.22)

Enal = enalapril, Mal = maleate.

Fig. 2a. Infrared Spectra of enalapril maleate.

4. The carboxylic group band of the enalapril that appears at 1751 cm1 has disappeared in the spectra of the enalapril– metal complexes, and this indicates that this carboxylic group was taking part in the complex formation [64]. The sharp bands at 1597 cm1 and 1360 cm1 were assigned to the asymmetric and symmetric stretching of the enalapril carboxylate, respectively. The msCOO shifts toward lower wavenumbers, while the masCOO shifts towards higher wavenumber, indicating the participation of the carboxylate in the coordination [65,66]. 5. The next diagnostic band in the free ligand was that of the amide carbonyl group which appears at 1649 cm1. This band mC@O is slightly positively shifted in the spectra of the complexes due to the coordination with the trivalent metal ion, indicating the involvement of the C@O of the amide in the chelation process [67]. 6. The band at 1384–1388 cm1 in the complexes (medium–very strong band) could be assigned to m NO 3 [57]. 7. The appearance of a mMAO band at 663–626 cm1 and 559– 562 cm1 can be attributed to the carbonyl and carboxylate, respectively. These bands support the chelation through the O atoms [68]. 8. The band of the ester group(CACAO) appears at 1230 cm1 in the spectra of the enalapril free ligand and in that of its metal complexes, indicating that this group was not taking part in the complex formation [64]. 3.3. Electronic spectra and magnetic measurements The electronic spectral studies of the lanthanide(III) metal complexes were significant and were important tool for the measurement of the covalency in the complexes. The line like spectra of the lanthanide(III) metal compound that appear in the UV–visible and near IR regions arise from the electronic transitions within

Fig. 2b. IR spectra of enalapril complexes, (A) [La(Enal)(Mal-NH4)(NO3)]H2O, (B) [Ce(Enal)(Mal-NH4)(NO3)]H2O, (C) [Sm(Enal-NH4)(Mal-(NH4)2)(H2O)3]H2O3NO3, and (D) [Y(Enal)(Mal-(NH4)2)(H2O)2]H2O2NO3.

the 4f-levels. These transitions were normal forbidden [69,70], but they may become allowed after the removal of the degeneracy by the external crystal field [71,72]. Table 4 comprises the electronic (UV–visible) spectra and magnetic measurements assignments, which were important and interesting items for most chemical characterizations to draw important information about the structural aspects of the complexes. enalapril free ligand, which was a vital antihypertensive drug, has two distinguished absorption bands at 254–280 nm (p ? p) and 292–304 nm (n ? p) due to the intraligand excitation, indicating the effect of the functional groups [344].

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Table 3 Infrared absorption frequencies (cm1) of enalapril complexes. Frequency (cm1)

Assignments

Enal

La–Enal

– 3215 3025 2979 2929 –

3700–3000 3700–3000 3029 2983 2930 2378 2349 – 1666 1584 1417 1366 1311 1388 1227 626 559

1751 1649 1574 1454 1379 1360 – 1230 – –

m br m w

s s s br m m

Ce–Enal br br br m w w

s s m w m v.s w w w

3700–3000 3700–3000 3028 2983 2930 2378 2349 – 1666 1602 1446 1356 1309 1387 1226 629 560

Sm–Enal br br br m w w

s sh m w m v.s w w w

3700–3000 3700–3000 3030 2983 2930 2424 2362 – 1668 – 1420 1360 – 1384 1226 639 –

Y–Enal br br br m w w

s w w v.s v.w w

3700–3000 3700–3000 3031 2983 2930 2424 2362 – 1659 1596 1430 1363 1300 1386 1225 663 562

br br br m w w

s s w w v.w v.s v.w w w

m(H2O) m(OH, NH) m(CH) aromatic m asym(CH3) m asym(CH2) mNHþ4 m(C@O); acid m(C@O); amide masym(COO) d(CH2) d(CH) msym(COO) msym ðNO3 Þ m(CACAO); ester m(MAO)carbonyl m(MAO)carboxylate

br, broad; m, medium; sh, shoulder; s, strong; w, weak; v, very; m, stretching; d, bending.

Upon the complexation with the lanthanide ions (LaIII, CeIII, SmIII) and YIII there will be an interesting change in the electronic properties of the system due to the interaction of the ligand with the metal ions. The electronic spectra of enalapril maleate complexes were recorded in DMSO at a concentration of 103 mol/cm3. The UV–visible peaks observed at (254, 260 and 270 nm), (258, 262 and 268 nm), (276 and 284 nm), and (254, 262 and 270 nm) for the LaIII, CeIII, SmIII, and YIII complexes, respectively, can be assigned to p ? p transitions in the aromaticity of the double bond [73]. Whereas, the wavelengths at (324, 328, 346 and 362 nm), (320, 334, 338, 354 and 366 nm), (326, 340, 362 and 370 nm), and (326, 334, 350 and 366 nm) for LaIII, CeIII, SmIII, and YIII complexes, respectively were most probably due to the n ? p transitions of the carbonyl, carboxylate, and amido groups [74]. In the magnetic susceptibility measurement, using a magnetic field, the paramagnetic complexes will be attracted while the diamagnetic compounds will be repelled. The lanthanum(III) and yttrium(III) complexes were diamagnetic in nature. This is expected for their closed shell electronic configuration and the absence of unpaired electrons. The magnetic moment values observed in these coordination compounds were presented in Table 4. The cerium(III) and samarium(III) ions were paramagnetic due to their 4f-electrons that were effectively shielded by 5s25p6 electrons. Unlike the d-electrons of the transition metal ions, the f-electrons of the lanthanide ions were almost unaffected by the chemical environment and the energy levels were the same as in the free ion. This is due to a very effective shielding by the overlying of 5s2 and 5p6 shells. From the magnetic moment values, the lanthanum(III) and yttrium(III) complexes were diamagnetic, while the cerium(III) and samarium(III) were paramagnetic. Their experimental values were in good agreement with the calculated one, except for the samarium(III) which indicates an insignificant participation of the 4f-electrons in the bonding. The relatively high value obtained for the samarium (III) complex may be due to the small J–J separation that leads to thermal population of the higher energy levels and the susceptibilities due to the first-order Zeeman effect [75]. A mononuclear complex of cerium(III) of the formula [Ce(Enal) (Mal-NH4)(NO3)]H2O, with an unpaired electron (n = 1) corresponding to f1 configuration, have the calculated magnetic moment of 2.54 B.M, but its experimental value was slightly higher (2.60 B.M). The calculated and experimental values of the magnetic moment of the lanthanide(III) complexes were in agreement with each other except for the samarium(III) complexes. As in

[Sm(Enal-NH4)(Mal-(NH4)2)(H2O)3]H2O3NO3, the experimental value was 1.11 B.M and the calculated one was 0.85 B.M. This indicates the non-involvement of 4f-orbitals in bond formation. In samarium(III) complex a little deviation from Van Vleek values indicates a little participation of 4f-electrons in the bond formation. However, the value (1.11 B.M) obtained may presumably be due to temperature dependent magnetism [76] on the account of low J-separation. The magnetic moments of the new complexes reported herein were within the range predicted and observed for the compounds of paramagnetic ions [77–79]. Thus the value of magnetic moment of a complex would give valuable insights into its constitution and structure. The magnetic susceptibility measurements thus help to predict the possible geometry of the metal complexes. 3.4. Proton nuclear magnetic resonances Different lanthanide complexes of the same ligand were almost isostructural, but each of them presents peculiar NMR properties. When Ln3+ ion interacts with an NMR active nucleus, the presence of unpaired 4f-electrons (as in Ce+3 and Sm+3 complexes) causes an increase relaxation, broadening and sometimes shifts to a different frequency of the resonance of the nucleus. Gd3+ has an isotropic distribution for its unpaired electrons and hence cannot produce a dipolar shift, while the other ions possess an anisotropic distribution. Therefore, they can generate a dipolar lanthanide induced shift (LIS) in the solution, often called the pseudo contact shift, and a property that renders them was useful as shift agents to obtain structural information. The 1H NMR spectra (Figs. 3a and 3b) of the enalapril free ligand (DMSO-d6) shows the aromatic protons shifts at d = 7.225 and 7.305 ppm, as in Table 5. A proton of the pyrrolidine ring H16 appears at d = 4.305 ppm, H13 at d = 4.183 ppm, H9 at d = 3.983 ppm, H19 at d = 3.508 ppm, H7 at d = 2.499 ppm, H14 at d = 1.323 ppm and H12 at d = 1.239 ppm, in accordance with the literature [80,81]. In the yttrium complex, H16 was shielded because of: (1) the anisotropic effect of the C@O of the chelating carboxylic and (2) the electronegativity of the nitrogen atom in the pyrrolidine ring; i.e. H13 was deshielded because of the anisotropic effect of the C@O group of the amide and the electronegativity of the nitrogen atom. The 1H NMR spectra (Figs. 3a and 3b) of the Y–Enal complex gave a new broad band centered at d = 3.367 ppm, due to H2O molecules. The NHþ 4 proton and H19 were overlapped with the huge water band. The obtained data confirm the postulated structure

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M.S. Refat et al. / Journal of Molecular Structure 1059 (2014) 208–224 Table 4 Electronic spectral bands (nm) and magnetic moments of the enalapril complexes. Complexes

k (nm) transitions 

leff g[J(J + 1)1/2] (B.M.)

n

Ground state

leff found (B.M.)



p?p

n?p

Enalapril maleate

254 272 280

292 300 304

–

–

–

–

[La(Enal)(Mal-NH4)(NO3)]H2O

254 260 270

324 328 346 362

0

0(4f0)

1

dia

[Ce(Enal)(Mal-NH4)(NO3)]H2O

258 262 268

320 334 338 354 366

2.54

1(4f1)

2

2.60

[Sm(Enal-NH4)(Mal-(NH4)2)(H2O)3]H2O3NO3

276 284

326 340 362 370

0.85

5(4f5)

6

1.11

[Y(Enal)(Mal-(NH4)2)(H2O)2]H2O2NO3

254 262 270

326 334 350 366

0

0(4d0)

4

dia

S0

F5/2

H5/2

P3/2

n = Unpaired electrons.

of the complex formation (Scheme 1), with the chelation of COO and C@O groups [58]. The chemical shift values of the ligand and the yttrium complex were summarized in Table 5. 3.5. Structure of the enalapril complexes Finally on the basis of the above discussed results, the suggested structures of the enalapril complexes can be represented [82] as in Schemes 2–4. The structure of La and Ce show three ionic and three coordination bonds. Sm and Y which non-ionic but six coordinated bonds, this was may be due to their ionic size and relatively high electronegatively than that of La and Ce. 3.6. Fluorescence spectroscopies In recent years there has been an increasing interest in luminescent lanthanide (Ln) complexes because of their attractive emission properties such as long lifetime, large stokes shift, and line-like emission [83,84]. The f–f transitions in lanthanide, Ln, ions lead to interesting light-emission properties. These ions have been widely studied for a number of applications such as luminescent materials [85,86], chemo sensors [87,88], fluorescence labels [89], and as photoluminescence devices [90,91] for their photo physical properties arising from f–f transitions. However, since the f–f transitions were forbidden by spin and parity selection rules, the emission occurs through sensitization with coordinated ligands, which function as antennas [92]. The ligands range from simple aromatic acids, such as the widely utilized dipicolinic acid, to more complicated multidentate ligand architectures capable of selectively binding different lanthanide ions [93]. It is known that, although free lanthanide metal ions were inefficient at absorbing and emitting light, many lanthanide complex compounds containing organic ligands are highly capable of emitting strong and characteristic fluorescence [94]. In the lanthanide complexes, the organic ligands that have lone pair and/or p-electrons can efficiently serve as the light absorbing chromophores. If the excited state of the antenna organic ligands is energetically high enough, and the gathered energy was transferred to the lanthanide metal ions held nearby, the

characteristic fluorescence would be emitted. For effective excitation of Ln ions, organic chromophore, so-called ‘‘antenna’’, was usually attached to Ln complex [95–97]. In these systems, the photo-excited antenna successfully transfers its energy to the adjacent Ln ion (energy transfer (ET) process), forming excited-state Ln. For practical application of luminescent Ln ions for analytical purpose, these must be encapsulated within suitable ligand groups that can stabilize the ions kinetically and thermodynamically [98]. In the present study, the fluorescence spectra of lanthanide ions [La(III), Ce(III), Sm(III) and Y(III)] complexes of enalapril were investigated. The ligand contains carbonyl and carboxylic hydroxyl which were known for their capability to bind lanthanide ions via interaction amide carbonyl oxygen atom and carboxylic hydroxyl oxygen atom [99]. When Ln(III) ions in the complexes with enalapril were irradiated with photons, a characteristic broad emission of –f transitions were observed in the visible or near infrared. The fluorescence properties of La(III), Sm(III), Ce(III) and Y(III) complexes were similar, and the emissions can give an idea about the electronic levels in the system and their modes of excitations. The characteristic fluorescence of the enalapril and its Ln(III) complexes were listed in Table 6. The free ligand, excited by the absorption band at 280 nm, exhibits a strong emission band centered at 337 nm, Fig. 4. The fluorescence spectra of the complexes (Fig. 4) exhibit one distinct emission band of different intensities as a broad band centered at 433 nm (La), 435 nm (Ce), 410 nm (Sm), and 424 nm (Y). La and Ce complexes have the same band shape and stocks’ shift of about 163 nm, but longer than that of the free ligand (57 nm). The fluorescence spectra of the samarium and yttrium complexes (Fig. 4) exhibit distinct emission bands of different intensities: a broad band, centered at 410 nm (Sm) and 424 nm (Y). The stocks’ shift of the Sm (122 nm) and the Y (154 nm) were longer than that of samarium (122 nm) and cerium (128 nm). This fluorescence behavior (higher shift) of yttrium may be due to the absence of unpaired electrons in its configuration. Therefore, to conclude, all complexes present significant fluorescence in the wavelength regions where ligand cannot be made responsible. This fluorescence emission intensity of these complexes with a suitable ligand (drug) could make possible design of new markers for the

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B

18

600

17

500 400

19

N

16

O

300

CH 3

13

20

CH 3

11

10

N H

O

12

O

15

OH

200

O

14

7

8

9

1

2 3 4

6

100

5

0

Scheme 1. Proton positions of the free enalapril ligand.

ppm (t1) 8.0

7.0

6.0

5.0

4.0

3.0

2.0

1.0

Fig. 3a. 1H NMR spectra of enalapril maleate.

8

40

HN

N

O

O

30

O

O

O

20

H2O

O

10

O

Ln

N

O O

0

ppm (t1)

7.0

6.0

5.0

4.0

3.0

2.0

O

O

Ln = La(III) or Ce(III)

H4NO

1.0

Fig. 3b. 1H NMR spectra of [Y(Enal)(Mal-(NH4)2)(H2O)2]H2O2NO3 complex.

Scheme 2. Suggested chelating of enalapril complexes with lanthanum(III) and cerium(III) metal ions.

study of the inhibitor action mechanism and can also be used in the non-invasive medical techniques [100].

3.7. Scanning electron microscopies A scanning electron microscope (SEM) is a type of electron microscope that images a sample by scanning it with a beam of electrons in a raster scan pattern. The electrons interact with the atoms that make up the sample producing signals that contain information about the sample’s surface topography, composition, and other properties such as electrical conductivity [101]. The microstructure, surface morphology and chemical composition of the free ligand enalapril and its lanthanum(III), cerium(III) and samarium(III) complexes are studied using scanning electron microscopy. Typical scanning electron micrographs were shown in Figs. 5a–5d. The surface morphology of SEM micrograph reveals the well sintered nature of the complexes with variant grain sizes and shapes. Figs. 5a–5d illustrate the SEM photographs of the free ligand and the synthesized Enal-complexes. The uniformity and similarity in the particles size, shape and forms of the synthesized enalapril complexes indicate that the morphological phases of La(III) and Ce(III) complexes have unhomogeneous matrix. It can be seen that enalapril maleate is present as rectangular crystals of irregular sizes [102], as shown in Figs. 5a–5d, and their average

N

HN O

O ONH4

O

O

H2O.3NO3

H2O OH2

Sm H2O O

O

H4NO

ONH4

Scheme 3. Suggested chelating of enalapril complex with samarium(III) metal ion.

Table 5 H NMR spectra for the enalapril and its yttrium complex.

1

Compound

Enalapril Y–Enal

Chemical shift (d)/(ppm) H12

H14

H7

H19

H9

H13

H16

H2,4,6

H3,5

H2O OH

NHþ 4

1.239 1.264

1.323 1.299

2.499 2.506

3.508 Overlap with H2O

3.983 3.966

4.183 4.189

4.305 4.278

7.225 7.248

7.305 7.279

3.343 3.367

– Overlap with H2O

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M.S. Refat et al. / Journal of Molecular Structure 1059 (2014) 208–224 Table 6 Fluorescence spectral data of the enalapril and its complexes.

N

HN a

O

O O

Compound

kex (nm)

kem (nm)

Difference (Stoke’s shift)a

Enal La–Enal Ce–Enal Sm–Enal Y–Enal

280 270 270 288 270

336s 433br 433br 410s 424s

57 163 163 122 154

The difference between excitation and emission bands.

O

O

H2 O.2NO 3 H2O

OH 2

Y

O H4NO

O ONH 4

Scheme 4. Suggested chelating of enalapril complex with yttrium(III) metal ion.

particle size is found to be 0.95 lm. The unhomogeneous phase formation of the lanthanum(III) enalapril complex was of smallto-medium particle size with different shape. The particle size distribution of this complex was evaluated and the average particle size was found to be 13 lm, as exhibited in Figs. 5a–5d. The photo (Figs. 5a–5d) shows particles of an irregular shape with big holes on their surfaces. The cerium(III) enalapril complex has an irregular shape, while the microphotograph (Figs. 5a–5d) shows the adherence of the smaller particles to the solid surface of the larger particles. The average diameter of the small-to-medium variant particles was found to be 14.7 lm. The samarium(III) enalapril complex has an irregular shape with sharp edges on their surfaces, while the microphotograph (Figs. 5a–5d) shows the adherence of the smaller particles to the borer surface of larger particles. The average diameter of the small-to-medium variant particles was found to be 12.6 lm. It can be concluded that the significance of this result is in the conversion of geometric nano-particles of free enalapril to larger unhomogenous nano-particles upon the complexation with La(III), Ce(III) and Sm(III) ions. 3.8. X-ray powder diffraction Powder diffraction is a scientific technique using X-ray, neutron, or electron diffraction on powder or microcrystalline samples for structural characterization of materials [103]. The X-ray powder diffraction patterns in the range of 10° < 2h < 80° for the free enalapril ligand and its La(III), Ce(III), Sm(III) and Y(III) complexes were carried in order to obtain an idea about the lattice dynamics of the resulted complexes. X-ray diffraction of these compounds were recorded and shown in Fig. 6. The values of 2h, d value (i.e. the volume average of the crystal dimension normal to diffracting plane), full width at half maximum (FWHM) of prominent intensity peak, relative intensity (%) and particle size of compounds were comprised in Table 7. The maximum diffraction patterns of the enalapril, Sm(III) and Y(III) complexes occurred at 2h/d-value(Å) was equal to 5.185/ 17.030, 28.945/3.082 and 28.945/3.082, respectively. The crystallite size could be estimated from XRD patterns by applying FWHM of the characteristic peaks using Deby–Scherrer equation [104].

D ¼ Kk=b cos h where D is the particle size of the crystal gain, K is a constant (0.94 for Cu grid), k is the X-ray wavelength (1.5406 Å), h is the Bragg

Fig. 4. The emission spectra of enalapril and its complexes in DMSO solution at room temperature.

diffraction angle and b is the integral peak width. The particle size was estimated relative to the highest value of intensity compared with the other peaks. X-ray powder diffraction patterns were carried out in order to obtain an idea about the lattice dynamics of the complexes. By examining of the obtained X-ray powder diffraction patterns given in Fig. 6, the X-ray powder diffraction patterns throws light only on the fact that each solid represents a definite compound of a definite structure which is not contaminated with starting materials. The identification of the complexes was performed by a known standard method [105]. Such facts suggest that the prepared La(III) and Ce(III) complexes were amorphous. On the other hand, the data give an impression that the particle size of the enalapril and of the Sm(III) and Y(III) complexes was located within the nano scale range. The XRD spectra of enalapril and its complexes show that Enal was of a crystalline character [102,106], whereas its complexes with La and Ce appear to exhibit amorphous character and these were expected to possess enhanced bioavailability and improved tabletting properties as compared with the parent drug [107,108]. It is generally understood that crystalline materials exhibit high elasticity and brittleness when subjected to mechanical stress [109]; therefore, it may be considered appropriate to introduce amorphous character by milling the enalapril complexes before granulation and compression into tablets. 3.9. Thermal analysis 3.9.1. Thermal analysis of the ligand The TG curve (Figs. 7a–7e) of the enalapril free ligand shows three main consecutive steps of mass loss at the temperature ranges (40–660 °C) with no residue left over at the end of the

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Fig. 5a. SEM morphology of enalapril maleate.

Fig. 5c. SEM morphology of Ce–Enal complex.

Fig. 5b. SEM morphology of La–Enal complex.

decomposition process. At the first step (40–282 °C), the mass loss of 23.57% with maximum rate (TDTG) at 213 °C, corresponds to an endothermic elimination of the maleate molecule (Cal. = 23.57%) at TDTA of 204 °C. The mass loss (49.60%) at the second step (282–515 °C) with TDTG at 464 °C is assigned to a strong exothermic release of 65% of the ligand’s components (Cal. = 49.60%) at about (TDTA) 463 °C. Since the second step of the peak (464 °C) overlaps with the peak at 553 and the TG curve shows continues mass loss with no plateau, a co-evolution of two different components of the ligand might take place. The activation energies calculated for the first and second steps at the reaction orders (3 and 1.2) are 160.9 and 36.8 kJ mol1, respectively (Table 8). The mass loss of 26.75% at the third step (515–660 °C) with the TDTG peak of 553 °C was due to the degradation of 35% of the ligand’s components (Cal. = 26.75%). The activation energy and order of reaction of this step was 255.8 kJ mol1 and 1.7, respectively. The DS, DH and DG

Fig. 5d. SEM morphology of Sm–Enal complex.

M.S. Refat et al. / Journal of Molecular Structure 1059 (2014) 208–224

calculated for these three-steps were (43.6, 253.8 and 12.7 J K1 mol1), (156.8, 30.7 and 249 kJ mol1) and (147.5, 148.4 and 241.9 kJ mol1), respectively. The TGA (TG and DTG) and DTA curves recorded for the enalapril La(III), Ce(III), Sm(III) and Y(III) complexes were given in Figs. 7a–7e. These curves, which characterize and compare the thermal decomposition behavior of the ligand and its complexes at the heating rate of 10 °C min1 under nitrogen, generally show consecutive steps for almost uninterrupted mass losses in the sequential decomposition of these complexes (i.e. no clear plateau between the steps on TG curves) over the experimental temperature range (20–800 °C). Therefore, the TDTG peaks were determined for all steps in the decomposition sequence as long as their DTG curve shows a maximum rate of mass loss, and the TDTA peaks are observed only for some steps in the DTA curves. 3.9.2. Thermal analysis of the enalapril complexes Tables 8 and 9 compare the characteristic thermal and kinetic parameters determined for each step in the decomposition sequence of the complexes. It can be seen clearly that the mass losses (Dm%) obtained from the TGA curves and that calculated for the corresponding molecule, molecules or fragment were in good agreement as was the case for all of these complexes. However, as the compositions of the decomposition products (fragments) of the backbone and of the final decomposition products (i.e. final residues) were not proved, thermal decomposition with

Fig. 6. XRD pattern of (A) enalapril maleate, (B) Sm–Enal complex and (C) Y–Enal complex.

217

ill-defined fragments (i.e. equivalent fragments) and ill-defined final states’ products were considered for describing the thermal decomposition of these four complexes. The activation energies (Ea) were calculated from the slopes of the best fit straight lines, which regress satisfactory (0.9911 6 r2 6 0.9987) for using the best values of the reaction order (n) in the plots of the Coats–Redfern equation [110]. The TG/DTG curves of the metal-complexes reveal that with overlapping steps being various, four or five steps in the sequential decomposition of enalapril metal-complexes were observed. The thermal decomposition process of these four complexes can be described as follows: 3.9.2.1. La–Enal. The TG thermogram of [La(Enal)(Mal-NH4)(NO3)]H2O (Figs. 7a–7e) involves four successive degradation steps at 58–122, 122–311, 311–376 and 376–703 °C. The first step (58– 122 °C) at TDTG of 77 °C, the mass loss of 2.49% was consistent with the evolution of the uncoordinated water molecule (Cal. 2.48%) with weak exothermic (TDTA) at 73 °C. The activation energy calculated from the order of reaction (n = 2) is 94 kJ mol1 (Table 9). Consequently, ammonium maleate molecule, one nitrate molecule and 16% of the enalapril molecule (found 34.97%; Cal. 34.98%) may be eliminated in the second step (122–311 °C) at TDTG of 263 °C. The activation energy calculated from the order of reaction (n = 0.9) for this step was found to be 63.5 kJ mol1. At the second step the peaks may be due to the co-evolution of Mal-NH4, NO3 and 16% Enal consequently. The mass loss of 10.49% at the third step (311–376 °C) of the TDTG peak (343 °C) and exothermally (TDTA) at 343 °C was due to the evolution of 20.3% of the enalapril molecule (Cal. 10.49%). The activation energy and order of reaction of this step were 220.5 kJ mol1 and 2, respectively. The fourth step (376–703 °C) at TDTG of 477 °C and strong exothermic peak (TDTA) at 479 °C, the mass loss of 29.62% is consistent with the elimination of 57.3% of the enalapril molecule (Cal. 29.62%). The activation energy and order of reaction obtained were 184.2 kJ mol1 and 1.9, respectively (Table 9). At the end of the decomposition proses the final residue of an ill-defined state was 22.43%, corresponding to one lanthanum and one and half oxygen (22.43%). The DS, DH and DG calculated for these four-steps were (21.8, 176.5, 71 and 28.6 JK1 mol1), (91.1, 59, 215.3 and 178 kJ mol1) and (92.8, 105.5, 191 and 191.6 kJ mol1), respectively. 3.9.2.2. Ce–Enal. The thermolysis of [Ce(Enal)(Mal-NH4)(NO3]H2O (Figs. 7a–7e) was characterized by four decomposition steps in the range 48–460 °C. The first step (48–136 °C) of 2.47% mass loss and a TDTG peak at 68 °C represents the dehydration of adsorbed-water (Cal. 2.47%). The activation energy and the reaction order were found to be 69.7 kJ mol1 and 2, respectively. The mass loss of 39.72% at the second step (136–332 °C) with TDTG at 273 °C corresponds to the elimination of the ammonium maleate molecule along with nitrate molecule and 25.3% of the enalapril molecule (Cal. 39.72%). The associated activation energy and order of reaction were 58.2 kJ mol1 and 1.1, respectively. The third step (332–390 °C) with TDTG at 374 °C and exothermic TDTA peaks at 376 °C was due to the release of 32.6% of the enalapril molecule (found 16.83%, Cal. 16.82%). The activation energy and reaction order of this step were 212.8 kJ mol1 and 1.1, respectively. At the fourth step (390–460 °C), the mass loss of 18.42% with sharp TDTG (374 °C) and strong exothermic TDTA (376 °C) was due to releasing the remaining 35.7% of the enalapril molecule (found 18.42 and Cal. 18.43%). The activation energy and order of reaction calculated were 255.6 kJ mol1 and 0.8, respectively (Table 9). At the end of the decomposition presses, the total residual mass of 22.56% is in agreement with the final product of one Ce atom and one and half oxygen atoms (½Ce2O3) of an ill-defined state. The values (93, 189.7, 40.6 and 75.2 JK1 mol1), (66.8, 53.7,

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Table 7 XRD spectral data of the highest value of intensity of the enalapril ligand and its complex. Compounds

2h

d value (Å)

FWHM

Relative intensity (%)

Particle size (nm)

Enal Sm–Enal Y–Enal

5.185 28.945 28.945

17.030 3.082 3.082

0.001 0.001 0.001

100 100 100

145 150 150

Fig. 7a. TGA, DTG and DTA curves of enalapril maleate. Fig. 7b. TGA, DTG and DTA curves of [La(Enal)(Mal-NH4)(NO3)]H2O. 1

207.4 and 249.8 kJ mol ) and (73.2, 105.5, 192.2 and 218.1 kJ mol1) were the entropy, enthalpy and free energy changes of activation calculated for the four decomposition steps, respectively. 3.9.2.3. Sm–Enal. The TG and DTG curves of [Sm(Enal-NH4)(Mal(NH4)2)(H2O)3]H2O3NO3 (Figs. 7a–7e) show five degradation steps of a sequential mass loss with various DTG peaks, and mass loss processes. The first-step (27–135 °C) at a Tdtg of 39 °C was assigned to the dehydrate of one adsorbed-water and two coordinated-water molecules (found 5.67%, Cal. 5.67%). The second (135–226 °C), third (226–274 °C), fourth (274–388 °C) and fifth (338–539 °C) steps were accompanied by 23.97%, 13.03%, 18.75% and 20.26% mass loss due to the release of (H2Ocoord. + Mal(NH4)2 + 15.3% Enal-NH4; Cal. 23.98%), (2NO3; Cal. 13.03%), (NO3 + 29.6% Enal-NH4; Cal. 18.75%) and (49% Enal-NH4; Cal. 20.25%), respectively. Their Tdtg peaks occur at 194, 247, 318 and 478 °C, whereas their TDTA peaks were weak exothermic at 195 °C, very weak endothermic at 250 °C, weak endothermic at 319 °C and a very sharp strong exothermic one at 478 °C, respec-

tively. The final residue (18.32%) is assigned to one Sm atom and one and half oxygen atoms (Cal. 18.32%) of an ill-defined state (½Sm2O3). The activation energies calculated of these five steps are 44.6, 134.6, 174.2, 138 and 174.9 kJ mol1, respectively, and the values (154.6, 0.9, 43.6, 62.2 and 53.4 JK1mol1), (42, 130.7, 169.9, 133.1 and 168.6 kJ mol1) and (48.1, 130.5, 159.1, 152.9 and 194.2 kJ mol1) were their entropy, enthalpy and free energy changes of activation, respectively. 3.9.2.4. Y–Enal. The TG degradation curve of [Y(Enal)(Mal(NH4)2)(H2O)2]H2O2NO3 (Figs. 7a–7e) reveals four decomposition steps at 26–104, 104–286, 286–400 and 400–530 °C. The elimination of one water adsorbed and one coordinated water molecules (found 4.54%, Cal. 4.54%) at the first step (26–104 °C) exhibits two overlapped peaks at TDTG of 49 °C. The activation energy of 55.8 kJ mol1 and order of reaction (n = 2) were obtained for this step. The removal of one coordinated water, di-ammonium maleate molecule and 30% of the enalapril molecule (found 35.41%, Cal. 35.42%) takes place at the second step (104–286 °C) with TDTG

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Fig. 7c. TGA, DTG and DTA curves of [Ce(Enal)(Mal-NH4)(NO3)]H2O.

at 206 °C and a weak exothermic peak (TDTA) at 200 °C. At third step (286–400 °C) with TDTG of 333 °C, the mass loss of 18.50% was consistent with the release of two nitrate molecules along with the decomposition of 6% of the enalapril molecule (Cal. 18.49%). The activation energy calculated and order of reaction were 135.4 kJ mol1 and 0.8, respectively (Table 9). At the fourth step (400–530 °C), the mass loss of 27.30% with a strong TDTG (486 °C) and a very sharp exothermic TDTA (487 °C) was due to the release of 57.6% of the remaining enalapril molecule (Cal. 27.30%). The activation energy and order of reaction of this step is 137.6 kJ mol1 and 0.9, respectively. The ill-defined residue at the end of the decomposition reaction may be ½Y2O3 molecule (Cal. 14.25%, found 14.25%). The DS, DH and DG calculated for these four steps were (119.5, 118.1, 71.8 and 92.4 JK1 mol1), (53.1, 80.2, 130.4 and 131.3 kJ mol1) and (58.9, 104.5, 154.3 and 176.2 kJ mol1), respectively.

3.9.3. Comparison between the decomposition rates of the enalapril complexes The decomposition rates of the complexes were deduced from the plot of log [(1  (1  a)1n/(1  n)T2 ] against 1/T (where, T in Kelvin) for the main decomposition reaction steps in the sequential decomposition of the complexes [110]. Examining the steepness of the curves (Figs. 8a and 8b) indicates that the decomposition rates of these complexes vary from one another. As the steepness of the curves increases activation energy increases and consequently, the decomposition rate decreases. Accordingly, the decomposition rates of the enalapril complexes can be described as follows:

Fig. 7d. TGA, DTG (NH4)2)(H2O)3]H2O3NO3.

and

DTA

curves

of

[Sm(Enal-NH4)(Mal-

3.9.3.1. The first step. This step corresponds to the dehydration of uncoordinated-water in La and Ce, but in the case of Sm and Y, this step corresponds to the dehydration of both uncoordinated and coordinated water. As shown in Figs. 8a and 8b, the decomposition rates of the first step increase in the following order: Sm–Enal > Y–Enal Ce–Enal > La–Enal consequently, the activation energies (kJ mol1) are: Sm–Enal (44.6) < Y–Enal (55.8) and Ce–Enal (69.7) < La–Enal (94) In this dehydration process, the ease of adsorbed water desolvation (26 °C 6 T 6 136 °C) in these complexes suggests the weak interaction of water, i.e. water plays little or no role in the lattice forces and occupies the crystal voids [111,112]. The relatively small differences in the TDTG values of the La (77 °C) and Ce (68 °C) complexes and in that of the Sm (39 °C) and Y (49 °C) complexes, the reaction order of 2 in all cases and the activation energies of almost comparable values, suggest that the adsorbed water in these complexes may be identical. The shape and the strength of the dehydration DTG peaks indicate that the rate of dehydration in each group of these complexes is almost the same. 3.9.3.2. The second step. These complexes start losing their maleate molecules simultaneously with the nitrate molecule in this second

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lanthanum complex (58 °C) show a higher thermal stability than those of, cerium (48 °C), samarium (27 °C) and yttrium (26 °C), i.e. on the basis of Ti values, the thermal stability of these complexes follows the order: La > Ce > Sm > Y. This behavior can be discussed in terms of the repulsion among electron pairs in the valence shell of the central ion. lanthanum, cerium, samarium and yttrium ions under investigation have multiple bonding (six bonds) in their valence shells. But due to the biggest size of lanthanum than that of cerium, samarium and yttrium, the space occupied by a bonding pair in the valence shell of lanthanum is smaller than that of the other ions. This leads to a lower repulsion between the bonding pairs in the valence shell of lanthanum (biggest ionic size, i.e. Y < Sm < Ce < La) comparing with the higher repulsion (smallest size) in the valence shell of yttrium, which in turn alters the bond angles, giving lower stability [114,115], but after losing the first coordinated water molecule, the electronegativity becomes effective and dominant. For this reason, the complex of Y loses its coordinated water more rapidly than the others, as indicated by the apparent Ti (26 °C) of the lowest value among the others ions and this leads to an early initial collapse of the structure around the ion. 3.9.5. General remarks

Fig. 7e. TGA, DTG and DTA curves of [Y(Enal)(Mal-(NH4)2)(H2O)2]H2O2NO3.

step as in the case of the La and Ce complexes, but in the Sm and Y complexes, the maleate molecule coevalutes along with the coordinated water and some fragment of the enalapril molecule. Therefore, comparison couldn’t be made between the reactions at this stage. The comparable activation energy of La and Ce complexes for (Figs. 8a and 8b) almost the same reactions (kJ mol1) are: Ce–Enal (58.2) > La–Enal (63.5) Y–Enal (84.2) > Sm–Enal (134.6) This result may be due to more crowded outer sphere (smallest size) of the Ce with respect to La, and of the Y with respect to Sm. The shape and strength of these steps in the DTG curves and their endothermic DTA peaks indicate that the rate of these complexes was almost the same [113]. In these first and second steps, the rate of releasing the molecules, temperature range, order of reaction and activation energy are relatively close in value (Table 9). This reflects a similarity in the kinetics of the decomposition reactions and nature of the activated molecule of the water, maleate or nitrate molecule at the transition-state reaction, i.e. their activated molecules were of similar reaction natures [113]. 3.9.4. Comparison of the thermal stability of the enalapril Complexes On the other hand, if the initial temperatures (Ti) concerning the release of the uncoordinated water molecule (Table 8) were taken as a measure of the thermal stabilities of these complexes, the

1. The thermal decompositions of the ligand and its La(III),Ce(III) Sm(III) and Y(III) complexes seem to be complex and were associated with several thermal events. The processes in many-thermograms involve overlapping steps, together with a great diversity of possible intermediate products. 2. It is found that the release of the uncoordinated coordinated water and nitrate molecules fairly accord with the literatures [111,116–118]. 3. In these complexes, the second, third and fourth stages were overlapped or semi- overlapped and that may be due to the continuity of the reactions. 4. The values of activation energy of the second stages of decomposition, in case of Sm and Y complexes were found to be higher than that of the first stages, while that of the third stage were found to be higher than that of the second stage. This may indicate that the rate of decomposition of the second stage was lower than that of the first stage, whereas that of the third stage is lower than that of the second stage. This may be attributed to the structural rigidity of the ligand as compared with H2O and maleate molecules, which requires more energy for its rearrangement before undergoing any compositional change [117,119]. 5. The elimination of the last remaining of the ligand was associated with a sharp and very strong exothermic peak (TDTA). 6. A plateau is obtained at the end of reaction, which indicates the formation of stable metal oxides (Ln2O3). 7. The standard equations from the transition-state theory were summarized in Table 9. The negative DS values indicate that the activated complexes have more ordered structure than the reactants and the reactions were slower than normal [120]. The positive values of DG indicate the non-spontaneous character for the reactions at the transition-state. The positive DH values show endothermic transition-state reactions [121]. From the abnormal values of Z, the reactions of the complexes at the transition-state can be classified as a slow reaction [122]. It can be concluded that the thermal decomposition of these four complexes was of a several of degrees of similarity (Tables 8 and 9). The variation in the thermal stability of these complexes may be attributed to the differences of the electronegativities of the central metal ions and the ionic size. This can be discussed in terms of the associated repulsion between the non-bonded

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M.S. Refat et al. / Journal of Molecular Structure 1059 (2014) 208–224 Table 8 Characteristic parameters of thermal decomposition (10 °C min1) of enalapril and its metal complexes. Compounds

Step

TGA

DTA

Enal.Mal

1 23.57 (23.57) 2 49.60 (49.60) 3 26.75 (26.75) Final residue = 0%

Dm% found (Cal.)

n

Ea (kJ mol1)

Reaction

Ti (°C)

Tf (°C)

TDTG

Tdta

Peak

40 282 515

282 515 660

213 464 553

204 463 550

endo exo exo

3 1.2 1.7

160.9 36. 8 255.8

– [Mal] – [65% Enal] – [35% Enal]

La–Enal

1 2.49 (2.48) 58 122 77 2 34.97 (34.98) 122 311 263 3 10.49 (10.49) 311 376 343 4 29.62 (29.62) 376 703 477 Final residue = ½La2O3 (found = 22.43%, Cal. = 22.43%)

73 – 343 479

exo – exo exo

2 0.9 2 1.9

94.0 63.5 220.5 184.2

– – – –

[H2O uncoord] [(Mal-NH4) + NO3 + 16%Enal] [20.3% Enal] [57.3% Enal]

Ce–Enal

1 2.47 (2.47) 48 136 68 2 39.72 (39.72) 136 332 273 3 16.83 (16.82) 332 390 374 4 18.42 (18.43) 390 460 422 Final residue = ½Ce2O3 (found = 22.56%, Cal. = 22.56%)

89 – 376 422

exo – exo exo

2 1.1 1.1 0.8

69.7 58.2 212.8 255.6

– – – –

[H2O uncoord] [(Mal-NH4) + NO3 + 25.3% Enal] [32.6% Enal] [35.7% Enal]

Sm–Enal

1 5.67 (5.67) 27 135 39 2 23.97 (23.98) 135 226 194 3 13.03 (13.03) 226 274 247 4 18.75 (18.75) 274 388 318 5 20.26 (20.25) 388 539 478 Final residue = ½Sm2O3 (found = 18.32%, Cal. = 18.32%)

43 195 250 319 478

exo exo endo endo exo

2 1.1 1.2 0.8 0.8

44.6 134.6 174.2 138.0 174.9

– – – – –

[H2O uncoord + 2H2O coord] [H2O coord + (Mal-(NH4)2) + 15.3%Enal-NH4] [2NO3] [NO3 + 29.6% Enal-NH4] [49% Enal-NH4]

Y–Enal

1 4.54 (4.54) 26 104 2 35.41 (35.42) 104 286 3 18.50 (18.49) 286 400 4 27.30 (27.30) 400 530 Final residue = ½Y2O3 (found = 14.25%, Cal. = 14.25%)

44 200 334 487

exo exo exo exo

2 0.8 0.8 0.9

55.8 84.2 135.4 137.6

– – – –

[H2O uncoord + H2O coord] [H2O coord + (Mal-(NH4)2) + 30% Enal] [2NO3 + 6% Enal] [57.6% Enal]

49 206 333 486

n = Order of reaction, exo = exothermic peak, endo = endothermic peak.

Table 9 Kinetic and thermodynamic parameters of the thermal decomposition of enalapril and its metal complexes. Compounds

Step

r

n

Z (s1)

Tmax (k)

E (kJ mol1)

DS (J k1 mol1)

DH (kJ mol1)

DG (kJ mol1)

Enal.Mal

1 2 3

0.9985 0.9933 0.9974

3 1.2 1.7

1.92  1015 8.53  101 7.96  1013

486 737 826

160.88 36.78 255.84

43.6 253.8 12.7

156.8 30.7 249.0

147.5 148.4 241.9

La–Enal

1 2 3 4

0.9962 0.9962 0.9985 0.9946

2 0.9 2 1.9

5.33  1011 6.76  103 6.59  1016 4.99  1011

350 536 616 750

94.03 63.49 220.46 184.20

21.8 176.5 71.0 28.6

91.1 59.0 215.3 178.0

92.8 105.5 191.0 191.6

Ce–Enal

1 2 3 4

0.9915 0.9980 0.9980 0.9987

2 1.1 1.1 0.8

9.90  107 1.40  103 1.78  1015 1.22  1017

341 546 647 695

69.67 58.23 212.77 255.56

93.0 189.7 40.6 75.2

66.8 53.7 207.4 249.8

73.2 105.5 192.2 218.1

Sm–Enal

1 2 3 4 5

0.9958 0.9981 0.9971 0.9954 0.9911

2 1.1 1.2 0.8 0.8

5.50  104 1.09  1013 2.04  1015 6.92  109 2.55  1010

312 467 520 591 751

44.64 134.59 174.22 138.03 174.89

154.6 0.9 43.6 62.2 53.4

42.0 130.7 169.9 133.1 168.6

48.1 130.5 159.1 152.9 194.2

Y–Enal

1 2 3 4

0.9973 0.9963 0.9929 0.9987

2 0.8 0.8 0.9

3.85  106 6.76  106 2.26  109 2.36  108

322 479 606 759

55.75 84.15 135.44 137.61

119.5 118.1 71.8 92.4

53.1 80.2 130.4 131.3

58.9 104.5 154.3 176.2

r = Correlation coefficient of the linear plot, n = order of reaction, Z = pre-exponential factor.

electrons (on the donating oxygen) and the bonding electron pairs in the valance shell of the metal ions. The extent of the covalent character in the metal–ligand bond influences the stabilities of the complexes [115,123]. It was noticeable that as the electronegativities of the central metal increases the thermal stability increases because the covalent bond character increases, giving a strong interaction between the metal and the ligand [123]. The higher stabilities of the metal complexes than that of the ligand may be due to the formation of two stable 7-membered rings structures in the La, Ce and Y complexes, and one stable 7-membered ring structure in the Sm complex [124,125]. On the other

hand, the higher was the molecular symmetry the more stable was the molecule [126]. 3.10. Antimicrobial studies In vitro biocidal activities results of both enalapril free ligand and their metal complexes clearly show that the compounds have both antibacterial and antifungal potency against the tested organisms (Table 10 and illustrated in Figs. 8a and 8b). By comparing between the biological evaluation of enalapril complexes with the standards Tetracycline as antibacterial agent and Amphotericin B

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Fig. 8a. Coats–Redfern plots for the first step of the enalapril complexes, where h i aÞ1n Y ¼ log 1ð1 for n – 1. T 2 ð1nÞ

Fig. 9. Inhibition zone diameter of enalapril complexes towards some kind of bacteria and fungi.

Y > Sm > La > Ce (v) A. flavus Y = Sm = La = Ce (vi) C. albicans Y = Sm = Ce = La From these results, we can summarize that:

Fig. 8b. Coats–Redfern plots for the second step of the enalapril complexes, where h i aÞ1n Y ¼ log 1ð1 for n – 1. T 2 ð1nÞ

as antifungal agent, the items’ results of highest-to-lowest effective can be summarized as follows: (i) B. subtilis: Sm > La = Ce > Y (ii) S. aureus Y > Sm > Ce = La (iii) P. aeruginosa Y > Sm = La = Ce (iv) E. coli

1. Generally, the active property of the free drug against the used strains was reduced by complexation. 2. The antibacterial activity of these complexes was slightly stronger than the antifungal activity. 3. Enalapril and its four complexes don’t affect the fungi used in this study. 4. The antimicrobial activity of Y(III) complex was slightly enhanced against the used bacteria, but does not affect the fungi. 5. Ce(III) has the lowest antimicrobial activity than the other complexes and the free ligand drug. 6. The growth of B. subtilis is slightly inhibited by Sm(III) compared to the free ligand and other complexes. In general, the behavior of the lipophilicity of these complexes seems to be responsible for their potent against the antibacterial

Table 10 The inhibition zone diameter (mm) of enalapril and its metal complexes against some kind of bacteria and fungi. Inhibition zone diameter (mm)

Sample

Candida albicans/ Fungus

Aspergillus flavus/ Fungus

Escherichia coli (G)

Pseudomonas aeruginosa (G)

Staphylococcus aureus (G+)

Bacillus subtilis (G+)

0.0 –

0.0 –

0.0 24

0.0 28

0.0 21

0.0 22

14

12

–

–

–

–

0 0 0 0 0

0 0 0 0 0

13 10 8 11 12

12 8 8 8 12

10 0 0 9 10

11 11 11 12 10

G: Gram reaction.

Control: DMSO Tetracycline Antibacterial agent Amphotericin B Antifungal agent Enalapil La(III) Ce(III) Sm(III) Y(III)

Standard

M.S. Refat et al. / Journal of Molecular Structure 1059 (2014) 208–224

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