Journal of Thermal Analysis and Calorimetry https://doi.org/10.1007/s10973-017-6843-x
Biologically active maleimido aromatic 1,3,4-oxadiazole derivatives evaluated thermogravimetrically as stabilizers for rigid PVC Nadia A. Mohamed1 Received: 11 August 2017 / Accepted: 14 November 2017 Akade´miai Kiado´, Budapest, Hungary 2017
Abstract Four novel N-aryl maleimide-bearing aromatic 1,3,4-oxadiazole systems were synthesized via a thermally induced cyclodehydration reaction of their corresponding precursors maleimido aromatic hydrazide derivatives. Their chemical structures were confirmed by elemental analyses, FTIR, 1H-NMR and mass spectroscopy. They showed a good antimicrobial activity against Bacillus subtilis, Streptococcus pneumoniae, Escherichia coli, Aspergillus fumigatus, Geotrichum candidum and Syncephalastrum racemosum using agar well diffusion method. The investigated derivatives are thermally stable and start decomposition in the temperature range above 250–300 C. They were investigated for thermal stabilization of rigid PVC using thermogravimetric analysis technique, in nitrogen. They showed a greater stabilizing efficiency as illustrated by their higher initial decomposition temperature and higher residual mass percent at particular temperatures relative to dibasic lead carbonate, cadmium–barium–zinc stearate complex and di-n-octyltin bis (isooctylmercaptoacetate) (n-octyltin mercaptide, n-OTM) reference thermal stabilizers. Their stabilizing efficiency is also demonstrated by lower rates of both discoloration and degree of chain scission of the polymer during degradation. The electron-donating substituent groups in the aromatic ring of 1,3,4-oxadiazole part of these derivatives increased their stabilizing efficiency. Keywords Maleimido aromatic 1,3,4-oxadiazole derivatives Synthesis Characterization Antimicrobial activity Thermal stability PVC Thermogravimetry
Introduction Poly(vinyl chloride) (PVC) is one of the most extraordinary useful commercial polymers, and it is a low-cost, highversatile, and non-flammable plastic. In spite of its much technical and economic importance, thermal stabilizers are most common and essentially used during its molding; because PVC undergoes extensive autocatalytic dehydrochlorination with subsequent formation of conjugated double bonds initiated at the inherent structural defects in the PVC chains [1–7]. This leads to severe discoloration of the polymer and deterioration of its physical and mechanical properties with a decrease or an increase in molecular mass as a result of chain scission or cross-linking of the polymer chains [8]. Metal-free and environmentally & Nadia A. Mohamed
[email protected] 1
acceptable fully organic stabilizers [9–12] exhibiting lower toxicity and higher stabilization efficiency relative to the industrially conventional stabilizers such as basic lead salts, metallic soaps and esters or mercaptides of dialkyl tin have attracted the attention of many researchers to overcome the toxic degradative products of the metallic stabilizers [13–15]. Because the time of fabrication of PVC is relatively short, and determination of the amount of stabilizer consumed after various processing times indicates that most of the stabilizer remains unreacted, the final product contains large amount of heat stabilizer. For this, a new trend has been established based on the use of organic thermal stabilizers of antimicrobial nature to obtain thermally stable antimicrobial PVC composites [16–18]. This allows putting PVC directly into the rank of biomedical polymers and expanding its utilization in a number of biomedical applications. This is truly a promising research field to have an edge over the conventional stabilizers.
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
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N. A. Mohamed
Significant biological activities considering bactericidal, fungicidal and anticancer properties have been reported for N-substituted maleimides [19–21]. It is known that maleimides are inhibitors of cysteine protease or other protein with an essential cysteine. Maleimides interact preferably with the hydrophobic domains of enzymes through the inactivation of sulfhydryl groups. They are usually considered as non-toxic and inexpensive family of products and could be interesting candidates for formation of new antimicrobial activity [22]. 2,5-Disubstituted-1,3,4-oxadiazole derivatives exhibited important chemical and biological properties [23] such as antibacterial [24], antifungal [25], anti-inflammatory [26], muscle relaxant [27], anticonvulsant [28], sedative and hypnotic [29] and anticancer [30] activities. N-aryl maleimides [31] and aromatic 1,3,4-oxadiazoles [32] have been proven to be effective stabilizers for PVC against thermal degradation. The stabilizing efficiency of the N-aryl maleimides is strongly affected by both the nature and position of the substituents in the aryl ring being greater for substituents of electron-donating nature and lower for those having electron-withdrawing effect, while the non-substituted derivative being in the middle [31]. On the other hand, the stabilizing efficiency of the aromatic 1,3,4-oxadiazole derivatives increased with increasing the number of the oxadiazole rings as well as with the introduction of electron-donating substituents in the aromatic ring of the stabilizer molecule [32]. In view of the above, it would be hypothesized that combination of the chemical structures of both N-aryl maleimide and aromatic 1,3,4-oxadiazole in one compound could greatly improve the thermal stability of PVC and could inhibit effectively the growth of bacteria and fungi. In the present study, we hereby report the synthesis, characterization and evaluation of antibacterial and antifungal activities of some new maleimido aromatic 1,3,4oxadiazole derivatives containing substituent groups at their aromatic rings of the 1,3,4-oxadiazole part. It is of our great interest to investigate these derivatives as new types of antimicrobial agents for the stabilization of rigid PVC against thermal degradation and to obtain thermally stable antimicrobial PVC composites. The effect of the substituent group on the inhibition of the thermal degradation of rigid PVC is also investigated.
Experimental Materials The commercial PVC (suspension) used in this study was additive free, with a K value of 70, and was supplied by Hu¨ls Co. (Frankfurt, Germany). Cadmium–barium–zinc
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(Cd–Ba–Zn) stearate complex was obtained from G. Siegle and Co. (Stuttgart, Germany), di-n-octyltin bis (isooctylmercaptoacetate) (n-octyltin mercaptide, n-OTM) was supplied by Nitto Kasei Co., Ltd. (Osaka, Japan), and dibasic lead carbonate (DBLC) was obtained from the National lead Co. (Darmstadt, Germany) which were used in this study.
Synthesis of maleimido aromatic-1,3,4oxadiazole derivatives Four maleimido aromatic-1,3,4-oxadiazole derivatives 10 , 20 , 30 and 40 (Scheme 1) have been synthesized from their corresponding hydrazides 1, 2, 3 and 4 that were prepared in our previous work [33]. The syntheses were based on a thermally induced cyclodehydration reaction through thermochemical transformation technique of the maleimido aromatic hydrazides into the corresponding maleimido aromatic-1,3,4-oxadiazoles by losing water from the hydrazide linkages. Preliminary thermogravimetric analysis measurements showed that the onset temperature range of the cyclodehydration reaction of the maleimido aromatic hydrazide derivatives 1, 2, 3 and 4 was 180–220, 200–235, 220–260 and 230–275 C, respectively. Based on these data, maleimido aromatic 1,3,4-oxadiazole derivatives 10 , 20 , 30 and 40 have been synthesized by heating the corresponding hydrazides 1, 2, 3 and 4 in nitrogen atmosphere for 15 min at 220, 235, 260 and 275 C, respectively.
Measurements The Fourier transform infrared (FTIR) spectra were recorded on a Shimadzu FTIR 8201 PC spectrophotometer using KBr pellets. The proton nuclear magnetic resonance (1H-NMR) spectra were recorded with a Jeol 270 MHz (Tokyo, Japan) spectrophotometer in dimethyl sulfoxide (DMSO-d6) as a solvent, and the chemical shifts were recorded in ppm relative to tetramethyl silane (TMS) as an internal standard. Mass spectra were recorded on a GCMS-QP 1000 ex spectra Mass spectrometer (Shimadzu, Tokyo, Japan) operating at 70 eV. Elemental analyses were carried out in Perkin Elmer (Model 2410 series II) C, H, N, O, Cl Analyzer (USA) at the Micro-Analytical Center at Cairo University, Giza, Egypt. Antibacterial activities of the prepared derivatives against Bacillus subtilis (B. subtilis, RCMB 010069) and Streptococcus pneumoniae (S. pneumoniae, RCMB 010019) as Gram-positive bacteria and against Escherichia coli (E. coli, RCMB 010055) as Gram-negative bacteria were investigated by measuring the diameter of the inhibition zone (in mm) using the agar well diffusion method
Biologically active maleimido aromatic 1,3,4-oxadiazole derivatives evaluated… Scheme 1 Synthesis of novel maleimido aromatic 1,3,4oxadiazole derivatives
O
X O H H
C
C N N
N
Δ/N2/15 min
O Y
C
C
220–275 °C –H2O
O
Maleimido aromatic hydrazide derivatives (1–4) O
X N
C
N
C
N
C
Y
O
C O
Maleimido aromatic 1,3,4–oxadiazole derivatives (1'–4')
Derivative No.
1, 1ʹ
2, 2ʹ
3, 3ʹ
4, 4ʹ
X
H
OH
H
OH
Y
H
H
NH2
NH2
[34]. Ampicillin and Gentamicin were used as antibacterial standard drugs. Antifungal activities were investigated by screening the prepared derivatives separately in vitro against Aspergillus fumigatus (A. fumigatus, RCMB 02569), Syncephalastrum racemosum (S. racemosum, RCMB 05925) and Geotricum candidum (G. candidum, RCMB 05098) fungi. The antifungal activities were investigated by measuring the diameter of the inhibition zone (in mm) using the agar well diffusion method [35]. Amphotericin B was used as antifungal standard drug. The minimum inhibition concentration (MIC) was determined by counting the colonies using twofold serial dilutions of each derivative. The MIC was considered to be the lowest concentration that completely inhibits against inoculums compared with the control, disregarding a single colony or a faint haze caused by the inoculums. Thermogravimetric analysis measurements were performed under nitrogen (30 mL min-1) from room temperature to 500 C with a heating rate of 10 C min-1, where approximately 20 mg of sample was required. A Shimadzu TGA-50 H Thermal Analyzer with flowing nitrogen (50 mL min-1) as a purge gas was used. The investigated derivatives and blank PVC powder were analyzed individually followed by stabilized PVC samples prepared by thoroughly mixing in a mortar 1 g of PVC powder with 20 mg of the derivative. The extent of discoloration of the degraded PVC samples was evaluated visually by heating the PVC in absence and in the presence of various stabilizers at 180 C, in air, for various time intervals (10, 20 and 40 min). Average molecular mass of PVC was determined using GPC-HPLC, Waters 600 system controller, 717 plus Autosampler. Columns: Phenomenex phenogel 5 lm 50 A,
300 9 7.8 mm; detection: Waters model 2410 refractive index; ATTN = 16 9 Eluent: THF (100% by Vol.); flow rate: 0.7 mL min-1; temperature: 50 C; injection volume: 25 lL. Standards: polystyrene (PS) 25,000; 13,000; 4000; 2500; 500 g mol-1(1.0% m v-1). Cubic fit calibration curve by Waters Millennium 32 GPC system software. Samples: Dissolved in THF at an approximate 1.0% m v-1 concentration. Solubility tests were carried out by stirring 0.1 g of the degraded PVC samples in 10 mL of tetrahydrofuran (THF) at 35 C overnight.
Results and discussion Synthesis of the maleimido aromatic-1,3,4oxadiazole derivatives Four novel maleimido aromatic-1,3,4-oxadiazole derivatives 10 , 20 , 30 and 40 (Scheme 1) have been synthesized via the thermochemical transformation technique of their corresponding precursors maleimido aromatic hydrazides 1, 2, 3 and 4. The syntheses were performed smoothly through a thermally induced cyclodehydration reaction by losing water molecule from the hydrazide linkage. The structures of the synthesized derivatives 10 –40 were ascertained on the basis of their consistent elemental analyses, FTIR, 1H-NMR and mass spectral characteristics (Table 1; Figs. 1, 2). The elemental analysis and MS m/s (M?) data of these derivatives (Table 1) are in good agreement with the theoretical ones calculated for their expected structures shown in Scheme 1. The FTIR spectra of these derivatives (Table 1 and Fig. 1) showed common absorption stretching vibration bands at the following wave
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N. A. Mohamed
numbers: (1) 3043–3099 cm-1 assigned to C-H bond in aromatic and in maleimide rings; (2) 1713–1716 cm-1 is attributed to carbonyl group of the imide linkage; (3) 1625–1635 cm-1 corresponded to the C=N group of the 1,3,4-oxadiazole ring; (4) 1604–1590 and 1506–1498 cm-1 indicated the carbon–carbon double bonds and carbon–carbon single bonds in aromatic rings, respectively; (5) 1025–1030 and 945–960 cm-1 are due to –C–O–C linkage in 1,3,4-oxadiazole ring; and (6) 825–831 cm-1 corresponded to maleimide moiety. There are additional bands at 3459–3150 cm-1 corresponded to OH group in derivative 20 , at 3469 and 3279 cm-1 assigned to amino group in derivative 30 , and at 3351 and 3245 indicated OH and amino groups in derivative 40 . The 1HNMR spectra of the investigated derivatives (Table 1; Fig. 2) showed common signals at the following chemical shifts: (1) 7.168–7.229 ppm (singlet) corresponded to two protons (=CH) in imide ring; (2) 7.440–8.099 ppm (multiplet) assigned to protons in aromatic ring. There are additional signals at 12.415 ppm (singlet and broad) corresponded to a proton of the OH group in derivative 20 , at 10.466 and 10.537 ppm (two singlet) corresponded to the two protons of amino group in derivative 30 , and at 10.232 and 10.543 ppm (two singlet) and 12.102 ppm (singlet) corresponded to the two protons of amino group and a proton of OH group in derivative 40 , respectively. Thus, the results of the elemental analyses coupled with FTIR, 1HNMR and mass spectral data seemed to be in good agreement with the expected structures of the prepared derivatives (Scheme 1). The functional groups (X, Y) were chosen based on their electron donor potency, being o- and p- directing, which increased the electron density on the
conjugated structure of the maleimido aromatic 1,3,4oxadiazoles, and consequently increased their potency to interact with the degradative products of PVC chains.
Antibacterial activity of the maleimido aromatic 1,3,4-oxadiazole derivatives The agar well diffusion technique was used for measuring the in vitro antibacterial activities of maleimido aromatic 1,3,4-oxadiazole derivatives 10 –40 against Gram-positive bacteria B. subtilis and S. pneumoniae and against Gramnegative bacteria E. coli, and the results are shown in Table 2. The results of Ampicillin and Gentamicin as reference standard drugs are also given for comparison. It is noted from Table 2 that the maleimido aromatic 1,3,4-oxadiazole derivatives 10 –40 showed an effective antibacterial activity against all the tested bacteria and their inhibitory effect can be arranged in the following order: 20 [ 40 [ 30 [ 10 . Derivative 20 is the most active one in comparison with the rest of the derivatives. This indicated the role of improving antibacterial activity played by the hydroxyl group incorporated into the aromatic moiety of the 1,3,4-oxadiazole part. Derivative 30 displayed a lower antibacterial activity than the derivative 20 . Thus, the introduction of the NH2 group decreased the antibacterial activity, indicating that the NH2 group is less effective in improving the antibacterial activity than the hydroxyl group. The electron-donating power of the hydroxyl group is lower than that of the amino group. This may decrease the electron density on the hydroxyl derivative and consequently may increase its ability to interact with the negatively charged microbial cell membrane leading to
Table 1 Characterization of the prepared maleimido aromatic 1,3,4-oxadiazole stabilizers Derivative code
Characteristic FTIR peaks m/cm-1
Derivative 10
3043 (=CH), 1716 (C=O, imide), 1630 (C=N), 1590, 1500 (Ph), 1030, 945 (=C–O–C=), 825 (maleimide moiety)
Derivative 20
Derivative 30
Derivative 40
a
Characteristic 1H-NMR signals d/ppm
MS m/z /M?
Elemental analysesa %C
%H
%N
%O
7.168 (s, 2H, =CH), 7.486–8.058 (m, 9H, ArH)
317
68.14 (68.10)
3.47 (3.49)
13.25 (13.23)
15.14 (15.18)
3459–3150 (OH), 3043 (=CH), 1716 (C=O, imide), 1630 (C=N), 1590, 1500 (Ph), 1030, 945 (=C–O–C=), 825 (maleimide moiety)
7.229 (s, 2H, =CH), 7.440–8.042 (m, 8H, ArH), 12.415 (s, broad, 1H, 1OH)
333
3469, 3279 (NH2), 3093 (= CH), 1713 (C=O, imide), 1635 (C=N), 1602, 1506 (Ph), 1025, 947 (=C–O–C=), 828 (maleimide moiety)
7.228 (s, 2H, =CH), 7.471- 8.099 (m, 8H, ArH), 10.466,10.537 (2 s, 2H, NH2 disappearing on deuteration)
332
3351, 3245 (OH, NH2), 3099 (=CH), 1715 (C=O, imide), 1625 (C=N), 1604, 1498 (Ph), 1026, 960 (=C–O–C=), 831 (maleimide moiety)
7.223 (s, 2H, =CH), 7.497–8.078 (m, 7H, ArH), 10.232, 10.543 (2 s, 2H, NH2 disappearing on deuteration), 12.102 (s, 1H, 1OH)
348
Data given between parentheses corresponded to experimental elemental analyses
123
64.87
3.30
12.61
19.22
(64.84)
(3.33)
(12.56)
(19.27)
65.06
3.61
16.87
14.46
(65.02)
(3.63)
(16.85)
(14.50)
62.07
3.45
16.09
18.39
(62.00)
(3.48)
(16.10)
(18.42)
Biologically active maleimido aromatic 1,3,4-oxadiazole derivatives evaluated… Fig. 1 FTIR spectra of maleimido aromatic 1,3,4oxadiazole derivatives
Derivative 4′
960 1026 831
3099 3351 3245 1625 1498 1604
1715
947
Derivative 3′
1025 3469
3093 828
3279 1602 16351506 1713
Derivative 2′ 945
3459 3150 3043
1030
3320 825
3270
1630 1590 1500
1716
Derivative 1′ 945 3043
1030
825 1630 1590 1500
1716
4000
3000
2000 Wavenumber/cm–1
1000
400
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N. A. Mohamed
higher antibacterial activity relative to the amino derivative. The antibacterial activity of derivative 40 is lower than that of the derivative 20 due to the presence of an additional NH2 group in it. The higher antibacterial activity of derivative 40 in comparison to derivative 30 can be attributed to its possession of an additional hydroxyl group. The non-substituted derivative 10 is the least active one among 2(CH) 7Ar-H
Derivative 4′ 2H(NH2) OH
2(CH) 8Ar-H
Derivative 3′ 2H(NH2)
Derivative 2′
2(CH) 8Ar-H
OH
2(CH)
Derivative 1′
13
12
9Ar-H
11
10
9
8
7
6
5
4
Chemical shift/ppm
Fig. 2 1H-NMR spectra of maleimido aromatic 1,3,4-oxadiazole derivatives
these derivatives against all the tested bacteria. It is worth mentioning that the derivative 20 exhibited greater activity against S. pneumoniae than that of the reference drug Ampicillin. The strongest derivative 20 showed an inhibition zone diameter of 26.2 ± 0.36 mm with MIC value of 0.24 lg mL-1 against S. pneumoniae corresponded to that of the standard drug Ampicillin (the inhibition zone diameter of 21.6 ± 0.21 mm and MIC value of 0.98 lg mL-1) (Table 2). The derivatives 10 –40 exhibited a better antibacterial activity against B. subtilis than that against S. pneumoniae. Moreover, the derivatives 10 –40 were more active against the Gram-positive bacteria than against the Gram-negative bacteria (Table 2). The most active derivative 20 exhibited inhibition zone diameter against B. subtilis and S. pneumoniae of 27.0 ± 0.27 and 26.2 ± 0.36 mm, respectively, corresponded to 18.9 ± 0.60 mm against E. coli (Table 2). This can be attributed to the structure difference in their cell walls. The wall of Gram-positive bacteria cell is fully composed of peptide polyglycogen. The peptidoglycan layer is consisted of networks with plenty of pores, which allow foreign molecules to come into the cell without difficulty and allow more rapid absorption of ions into the cell, while the wall of the Gram-negative bacteria cell is made up of a thin membrane of peptide polyglycogen and an outer membrane constituted of lipopolysaccharide, lipoprotein and phospholipids. Due to the complicated bilayer cell structure, the outer membrane is a potential barrier against foreign molecules [36]. Thus, the investigated derivatives showed different effects on the two kinds of bacteria. The greater activity of these derivatives against Gram-positive bacteria than Gram-negative bacteria could also be proven from their MIC values. The MIC values of the most potent derivative 20 against B. subtilis and against S. pneumoniae were 0.12 and 0.24 lg mL-1, respectively, while its MIC value against E. coli was 3.90 lg mL-1 (Table 2). It is interesting to note that the antibacterial
Table 2 Inhibition indices and minimum inhibitory concentration (MIC) of maleimido aromatic 1,3,4-oxadiazole derivatives against B. subtilis, S. pneumoniae and E. coli Derivative code
Tested bacteria B. subtilis RCMB 010069
S. pneumoniae RCMB 010019
E. coli RCMB 010055
Inhibition zone/mm
MIC/lg mL-1
Inhibition zone/mm
MIC/lg mL-1
Derivative 10
18.4 ± 0.27
7.81
15.8 ± 0.46
Derivative 20
27.0 ± 0.27
0.12
26.2 ± 0.36
Derivative 30
20.4 ± 0.56
0.98
18.3 ± 0.45
0
Inhibition zone/mm
MIC/lgmL-1
15.65
11.4 ± 0.34
31.25
0.24
18.9 ± 0.60
3.90
7.81
14.2 ± 0.26
15.65
Derivative 4
22.7 ± 0.62
0.49
20.3 ± 0.46
0.98
17.1 ± 0.20
7.81
Ampicillin
29.8 ± 0.15
0.015
21.6 ± 0.21
0.98
–
–
Gentamicin
–
–
–
–
22.8 ± 0.22
0.98
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Biologically active maleimido aromatic 1,3,4-oxadiazole derivatives evaluated…
activity of the maleimido aromatic 1,3,4-oxadiazoles is greater than that obtained for their corresponding precursors maleimido aromatic hydrazides reported previously [33].
Antifungal activity of the maleimido aromatic 1,3,4-oxadiazole derivatives Table 3 summarizes the results of in vitro antifungal activities of maleimido aromatic 1,3,4-oxadiazole derivatives 10 –40 against G. candidum, A. fumigatus and S. racemosum measured by the agar well diffusion technique. The results of Amphotericin B as a standard reference drug are also given for comparison. The results clearly revealed that the maleimido aromatic 1,3,4-oxadiazole derivatives 10 –40 possess a good antifungal activity against all the tested fungi and their inhibitory action followed the sequence: 20 [ 40 [ 30 [ 10 . The derivatives 10 –40 were more active against G. candidum than against A. fumigates which in its turn were more active than against S. racemosum. The antifungal activity confirmed that the derivative 20 having hydroxyl group in the oxadiazole system is more potent than the standard reference drug Amphotericin B against all the tested fungi. Its inhibition zone diameters against A. fumigates, G. candidum and S. racemosum were 113.6, 108.2 and 102.5% when compared with the standard reference drug Amphotericin B. Moreover, the rest of the derivatives showed different in vitro antifungal activity with inhibition zone diameters from 14.1 ± 0.26 to 20.1 ± 0.63 mm with MIC values from 1.95 to 62.50 lg mL-1 against the tested strains of fungi. It is worth mentioning that the maleimido aromatic 1,3,4-oxadiazoles showed antifungal activity better than that obtained for their corresponding precursors maleimido aromatic hydrazides reported in our previous work [33].
Thermal stability of the maleimido aromatic 1,3,4-oxadiazole derivatives Figure 3 shows the results of the thermal stability and degradation behavior of the prepared maleimido aromatic 1,3,4-oxadiazole derivatives containing –OH and/or –NH2 groups in the aromatic ring of their 1,3,4-oxadiazole part. These results demonstrate the mass losses of these derivatives obtained from thermogravimetric analysis (TG) measurements done at a heating rate of 10 C min -1 and under nitrogen flow rate of 30 mL min-1. TG measurements were performed on these derivatives in order to evaluate the influence of the differences of their structure on their degradation behavior. The results clearly revealed that all the investigated derivatives showed a distinctive similar degradation behavior which happened in only one stage in which appreciable mass losses were detected. This mass loss step was severe and specified for the decomposition of the investigated derivatives. It can be noted that the improvement in the resistance to high temperatures was associated with the presence of –OH and/or –NH2 groups in the investigated derivatives (Fig. 3). Thus, at all used temperatures, the hydroxy amino derivative 40 emerged as the most potential thermally stable derivative relative to the other derivatives. This is illustrated not only by its highest initial decomposition temperature but also by its lowest mass losses at particular temperatures. On the other hand, the non-substituted derivative 10 exhibited the lowest thermal stability. The thermal stability of the derivatives 20 and 30 is in between these two extreme cases, so that regarding their initial decomposition temperature and their mass losses at any particular temperature, their order of stability was 40 [ 30 [ 20 [ 10 . Thus, the introduction of – OH and/or –NH2 into the aromatic ring of the 1,3,4-oxadiazole part of these derivatives resulted in improvement in their stability at high temperatures. This should allow for formation of stronger intermolecular hydrogen bonds
Table 3 Inhibition indices and minimum inhibitory concentration (MIC) values of maleimido aromatic 1,3,4-oxadiazole derivatives against G. candidum, A. fumigatus and S. racemosum Derivative code
Tested fungi G. candidum RCMB 05098
A. fumigatus RCMB 02569
S. racemosum RCMB 05925
Inhibition zone/mm
MIC/lg mL-1
Inhibition zone/mm
MIC/lg mL-1
Inhibition zone/mm
MIC/lg mL-1
Derivative 10
16.7 ± 0.41
15.65
15.1 ± 0.37
Derivative 20
28.9 ± 0.38
0.12
25.9 ± 0.67
31.25
14.1 ± 0.26
62.50
0.24
20.8 ± 0.28
0
1.95
Derivative 3
18.0 ± 0.41
3.90
Derivative 40
20.1 ± 0.63
1.95
17.0 ± 0.26
7.81
16.1 ± 0.26
15.65
18.2 ± 0.61
3.90
17.2 ± 0.26
Amphotericin B
26.7 ± 0.15
0.12
7.81
22.8 ± 0.11
0.98
20.3 ± 0.19
1.95
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N. A. Mohamed Temperature/°C 0
100
200
300
400
500
0
Mass loss/%
20
40
60 Derivative 4′ Derivative 3′ 80
Derivative 2′ Derivative 1′
100
Fig. 3 Typical TG curves patterns of novel maleimido aromatic 1,3,4-oxadiazole derivatives. All the curves were recorded at a heating rate of 10 C min-1 and under nitrogen flow rate of 30 mL min-1
Table 4 Thermogravimetric analyses of novel maleimido aromatic 1,3,4-oxadiazole derivatives at a heating rate of 10 C min-1 and under a nitrogen flow rate of 30 mL min-1 Derivative code
Onset degradation temperature/C
Mass loss/% at 350 C
400 C
450 C
500 C
Derivative 10
250
36.32
57.71
82.26
92.10
Derivative 20
260
30.10
50.00
73.66
83.33
Derivative 30 Derivative 40
280 300
24.00 18.75
44.00 37.50
64.00 56.50
72.00 67.50
which would be more difficult to break and therefore more resistance to elevated temperatures. The investigated maleimido aromatic 1,3,4-oxadiazole derivatives (10 , 20 , 30 and 40 ) started to decompose in the temperature range above 250–300 C without mass loss at lower temperature (Table 4). They lost 67.5–92.1% of their original masses at 500 C. Their high thermal stability may be attributed to their chemical structure which possesses an aromatic, an imide, a 1,3,4-oxadiazole rings, a phenolic –OH and/or aromatic –NH2 groups. These groups have been known to be highly resistance to elevated temperatures. This is in addition to the strong intermolecular hydrogen bonding formed between the imide carbonyl, the phenolic –OH and –NH2 groups of the neighboring molecules. Thus, the results indicate that the investigated derivatives are stable at processing temperature of the PVC and could be applied as thermal stabilizers for it.
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Thermal stabilization of PVC using maleimido aromatic 1,3,4-oxadiazole derivatives Figure 4 represents the results of TG measurements of rigid PVC stabilized by various maleimido aromatic 1,3,4-oxadiazole derivatives (10 , 20 , 30 and 40 ). All the TG measurements were performed from room temperature to 500 C at a heating rate of 10 C min-1 and under a nitrogen flow rate of 30 mL min-1. The results of the nonstabilized blank PVC and those of the PVC samples stabilized by dibasic lead carbonate (DBLC), barium–cadmium–zinc (Ba–Cd–Zn) stearate and n-octyltin mercaptide (n-OTM) as reference stabilizers are also given for comparison. These reference stabilizers were selected on the basis that they represent the three major classes of the industrially conventional used stabilizers, which are basic salt stabilizers, soap stabilizers and organotin stabilizers, respectively. For all the measurements, the stabilizers were used in a concentration of 2 mass % of PVC and the results
Biologically active maleimido aromatic 1,3,4-oxadiazole derivatives evaluated… 120
Residual mass/%
100
80 Blank PVC PVC + DBLC
60 PVC + Cd–Ba–Zn stearate PVC + n-OTM
40
PVC + Derivative 1′ PVC + Derivative 2′
20
PVC + Derivative 3′ PVC + Derivative 4′
0 0
100
200
300
400
500
Temperature/°C
Fig. 4 Thermogravimetric curves of rigid PVC in the presence of 2 mass% of various maleimido aromatic 1,3,4-oxadiazole derivatives and reference stabilizers at a heating rate of 10 C min-1 and a nitrogen flow rate of 30 mL min-1
represent the average of three comparable measurements of each stabilizer. The investigated derivatives displayed a better stabilizing efficiency than all the industrially used reference stabilizers. The better stabilizing efficiency is illustrated not only by the higher initial decomposing temperature, but also by the higher rate of residual masses of PVC stabilized with the investigated derivatives during the subsequent stages of degradation as compared with the reference stabilizers (Fig. 4). It has been previously suggested that N-aryl maleimides [31] and aromatic 1,3,4-oxadiazoles [32] owe their stabilizing efficiency to the replacement of the labile chlorine atoms on the PVC chains by more relative thermally stable maleimide and 1,3,4-oxadiazole moieties. Thus, the maleimides and 1,3,4-oxadiazoles are able to be incorporated into the body of the polymeric chains deactivating the reactive sites (primarily allylic chlorines bearing carbon atoms) on the PVC. Furthermore, both the N-aryl maleimides and aromatic 1,3,4-oxadiazole derivatives can exhibit their stabilizing efficiency through effective absorption of the degradation product (hydrogen chloride gas) by their basic groups preventing or at least minimizing its catalytic degradation effect. This mode of action has previously been published together with experiments to prove it [31, 32]. In view of structural similarity of the investigated stabilizers to maleimides combined with 1,3,4oxadiazoles, their mechanism is outlined by assuming that both of their parts (maleimide and 1,3,4-oxadiazole) can displace the labile chlorine atoms on PVC chains
deactivating their reactivity and also can act as hydrogen chloride neutralizers. Moreover, the results revealed that the nature of the substituent groups in the aryl nucleus of the 1,3,4-oxadiazole part (–OH and/or –NH2 groups) of the investigated derivatives affects the initial decomposition temperature value to different extent, as well as the rate of the residual mass of the PVC stabilized with the maleimido 1,3,4oxadiazole derivatives. This indicates the important role played by the substituent groups at the aromatic ring in the stabilization process. The introduction of the –OH group and/or –NH2 group into the phenyl rings resulted in an appreciable increase in the initial decomposition temperature (at the early stages of degradation) and slight increasing in the residual mass (at subsequent stages of degradation). This may be attributed to the nature of these substituents (electron rich substituent), which could donate electrons toward the conjugated structure of the maleimido aromatic 1,3,4-oxadiazoles, increasing their ability to intervene in the degradation process of PVC relative to that of the non-substituted derivative 10 . An experimental proof supporting this conclusion could be seen in the greater efficiency of the derivatives containing amino group (30 and 40 ) relative to that of the hydroxy derivative 20 . This is in accordance with the greater electron-donating power of -NH2 group relative to that of the –OH group. The enhanced efficiency of the amino derivatives could also be related to another two reasons: (1) At the early stages of degradation, the presence of the amino group in the para-position in the phenyl ring may make its electron donation proceed to a greater extent and be much easier; and (2) the ability of the amino group to act as a hydrogen chloride gas absorber at the subsequent stages of degradation based on its basic character, thus protecting the polymer from the deleterious effect of this acidic degradation promoter.
Effect of the maleimido aromatic 1,3,4oxadiazole derivatives on the discoloration of thermally degraded rigid PVC The extent of discoloration of PVC samples stabilized with maleimido aromatic 1,3,4-oxadiazole derivatives and degraded at 180 C, in air, for various time intervals (10, 20 and 40 min), is lower than that of the blank PVC and PVC stabilized with any of the reference stabilizers as shown in Table 5. This indicates the higher stabilizing efficiency of the maleimido aromatic 1,3,4-oxadiazole stabilizers through replacement the labile chlorine on PVC chains by a more thermally stable stabilizer moiety, disrupting the formation of conjugated double bonds that are responsible for discoloration. The results also show that derivative 40 leads to a lowest degree of discoloration
123
N. A. Mohamed Table 5 Extent of discoloration of thermally degraded rigid PVC at 180 C, in air, for various time intervals in the presence of maleimido 1,3,4-oxadiazole derivatives
Stabilizer code
a
Color at 0 min
Color at 10 min
Color at 20 min
Color at 40 min
Blank PVC
DBLC
Cd-Ba-Zn stearate
n-OTM
Derivative 1'
Derivative 2'
relative to the other derivatives. This can be attributed to the presence of the amino and hydroxyl groups with their highest electron donation power that can increase electron density on both the aromatic 1,3,4-oxadiazole and maleimide moieties most easily and thus accelerate the replacement of the labile chlorines and increase the disruption of the formation of conjugated double bonds resulting in increasing the stability of the PVC sample and consequently the degree of the discoloration decreased. Moreover, the lowering of the extent of discoloration in the presence of the investigated stabilizers may be attributed to their dienophilic property which allows them to intervene with the conjugated double bonds systems formed on the PVC chains at subsequent stages of degradation process by Diels–Alder type of addition. The good color stability of the dibutyltin maleate stabilizer has been attributed to the same type of addition reaction [37]. The results obtained for the degree of discoloration give an additional proof for the stabilization mechanism reported previously [31, 32]. Moreover, the maleimido aromatic 1,3,4-oxadiazoles showed a lower extent of discoloration than that obtained for their corresponding precursors maleimido aromatic hydrazides reported previously [33].
Effect of the maleimido aromatic 1,3,4oxadiazole derivatives on the molecular mass of the thermally degraded rigid PVC
Derivative 3'
Derivative 4'
All the stabilizers were used in concentration of 2 mass% based on PVC mass a
All the synthesized derivatives are white in color
Molecular mass of both PVC, before and after 30 min of thermal degradation at 180 C, in air, in the presence or absence of maleimido 1,3,4-oxadiazole stabilizers was determined using gel permeation chromatography (GPC) technique. Table 6 summarizes the values of Mw, Mn and polydispersity (PD). The results of the GPC measurements clearly revealed that the investigated stabilizers exhibited a small decrease in the values of molecular masses of PVC samples. The GPC measurement results showed that the Mw value of blank PVC sample decreased from 24.4730 9 104 to 18.7020 9 104 g mol-1 upon 30 min of
Table 6 GPC measurements of thermally degraded rigid PVC at 180 C, in air, in the presence of maleimido aromatic 1,3,4-oxadiazole stabilizers Stabilizer code Blank PVC
Degradation time/min 0
Mw/g mol-1 9 104
Mn/g mol-1 9 104
PD
24.4730
9.1520
2.6741
Blank PVC
30
18.7020
4.2958
4.3536
Derivative 10
30
20.8168
6.1689
3.3745
Derivative 20
30
21.5470
6.9432
3.1033
Derivative 30
30
22.2900
7. 3741
3.0227
Derivative 40
30
23.5283
8.3886
2.8048
123
Biologically active maleimido aromatic 1,3,4-oxadiazole derivatives evaluated…
thermal degradation with a % decrease in Mw value of 23.58. After the same time of degradation, the PVC samples stabilized with 10 , 20 , 30 and 40 displayed a relatively smaller decrease in Mw of only 14.94, 11.96, 8.92 and 3.86%, respectively. This is an additional proof for the higher stabilizing efficiency of the investigated derivatives that decreases the degree of chain scission of PVC. Moreover, the thermally degraded PVC samples were found to be soluble in THF indicating the absence of gel formation which reflects the absence of cross-linking during degradation. Thus, the investigated stabilizers can decrease the chain scission and prevent cross-linking, so they can preserve both the physical and mechanical properties of the polymer. Further, the maleimido aromatic 1,3,4-oxadiazoles showed a lower degree of the chain scission and efficiently prevent cross-linking of rigid PVC more than that obtained for their corresponding precursors maleimido aromatic hydrazides reported in our previous work [33].
Conclusions Four novel N-aryl maleimides containing aryl 1,3,4-oxadiazole moiety have been designed and synthesized via thermally induced cyclodehydration reaction of the corresponding precursors maleimido aromatic hydrazide derivatives. Structural modification of N-aryl maleimides through combination with 1,3,4-oxadiazole moieties in one system has been taken as a way to achieve promising templates for antibacterial and antifungal agents. They showed a good antimicrobial activity illustrated by their high inhibition zone diameter and low minimum inhibition concentration (MIC) against B. subtilis and S. pneumoniae as Gram-positive bacteria and against E. coli as Gramnegative bacteria and against A. fumigatus, G. candidum and S. racemosum fungi using agar well diffusion method. They are more potent against Gram-positive bacteria than against Gram-negative bacteria. The derivative 20 having OH group in the oxadiazole system is the most active one especially against S. pneumoniae with inhibition zone diameter of 26.2 ± 0.36 mm and MIC value of 0.24 lg mL-1 which are better than those of the standard drug Ampicillin (21.6 ± 0.21 mm and 0.98 lg mL-1). Derivative 20 also emerged as the most potential candidates against G. candidum, A. fumigatus and S. racemosum with inhibition zone diameters of 28.9 ± 0.38, 25.9 ± 0.67 and 20.8 ± 0.28 mm with MIC values of 0.12, 0.24 and 1.95 lg mL-1, respectively, which are better than those of the standard drug Amphotericin B (inhibition zone diameters of 26.7 ± 0.15, 22.8 ± 0.11 and 20.3 ± 0.19 mm with MIC values of 0.12, 0.98 and 1.95 lg mL-1, respectively). The investigated derivatives are thermally
stable and start decomposition in the temperature range above 250–300 C without mass loss at lower temperatures. The development of maleimide-bearing oxadiazole system also resulted in new potentially efficient stabilizers for rigid PVC against thermal degradation using thermogravimetric analysis technique, in nitrogen. They showed a greater stabilizing efficiency as illustrated by their higher initial decomposition temperature and higher residual mass percent at particular temperatures relative to dibasic lead carbonate (DBLC), cadmium–barium–zinc (Cd–Ba–Zn) stearate complex and di-n-octyltin bis (isooctylmercaptoacetate) (n-octyltin mercaptide, n-OTM) reference thermal stabilizers. Their stabilizing efficiency is also demonstrated by lower rates both of discoloration and degree of chain scission of the polymer during degradation. The introduction of electron-donating substituent groups in the aromatic ring of 1,3,4-oxadiazole part of these derivatives increased their stabilizing efficiency. Thus, it is possible to recommend the use of maleimido aromatic 1,3,4oxadiazole derivatives as antimicrobial thermal stabilizers for rigid PVC, to obtain thermally stable antimicrobial PVC/maleimido aromatic 1,3,4-oxadiazole composites.
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