Journal of Oleo Science Copyright ©2015 by Japan Oil Chemists’ Society doi : 10.5650/jos.ess15011 J. Oleo Sci. 64, (7) 761-774 (2015)

Synthesis and Heteroannulation of Pyridine and Related Heterocyclic Systems Having Surface and Biological Activities Refat El-Sayed1, 2＊ 1 2

Chemistry Department, College of Applied Sciences, Umm Al-Qura University, 21955Makkah, Saudi Arabia. Chemistry Department, Faculty of Science, Benha University, Benha, Egypt.

Abstract: Possible approaches to the synthesis of functionalized, pyrazole, isoxazole, pyrimidine, pyridine and fused pyridine derivatives The sequence involves the heterocyclization of ethyl 3-oxo-2-(4-stearamidobenzoyl)butanoate (3) with appropriate reagents. Propoxylated of these heterocycles using propylene oxide to produce nonionic surface active agents having a long alkyl chain with molecular weight suitable for becoming an amphiphilic molecule with correct hydrophilic-lypophilic balance which enhances solubility, biodegradability and hence lowers the toxicity to human beings and becomes environmentally friendly. The antimicrobial activity of the newly synthesized was examined and it was found that some of these compounds have similar or higher activity compared with commercial antibiotic drugs (sulphadiazine), which make them suitable for diverse applications like the manufacturing of drugs, pesticides, emulsifiers, cosmetics, etc. Key words: synthesis, heterocyclic derivatives, antimicrobial and surface activities 1 INTRODUCTION In the past few years we have been involved in a program aiming to develop new, simple procedures for the synthesis of functionally substituted heterocycles of anticipated, effective, cheap and safe new biological activity that can be used as biodegradable agrochemicals, from available laboratory starting materials1−6）. Pyrazole derivatives are an important class of compounds and attracted widespread attention due to their pharmacological properties, being reported to have a large spectrum of biological effects, especially analgesic and anti-inflammatory properties7−10）. Literature survey reveals that pyrazoles, isoxazoles and pyrimidines derivatives have wide range of biological activities ranging from antibacterial11, 12） antifungal13） to anti-inflammatory14）. A large number of heterocyclic compounds containing pyridine rings are associated with diverse pharmacological properties such as antimicrobial15, 16）, anticancer17）anticonvulsant18）, antiviral19）, anti-HlV20）, antifungal and antimycobacterial activities21）. The pyridine heterocycle continues to play a vital role in the development of human medicines. More than 100 currently-marketed drugs contain this privileged unit, which remains highly sought after synthetical-

ly22）. Pyridine derivatives and heterocyclic annulated pyridine are well known in medicinal chemistry for their pronounced therapeutic applications23−27）. It is well-known that the pyridine28, 29） and its derivatives are among the most popular N-heteroaromatic compounds integrated into the structures of many pharmaceutical compounds and the structural units occur in various molecules exhibiting diverse biological activities30−32）. Fatty acids containing hetero atoms are regarded as surface and potential antimicrobial agents33, 34）. Thus, the use of fatty acid substrates as starting materials has become significant because of their own biological activity16）. So, the fatty acids on derivatization to these heterocyclic compounds can be used as valuable oleo-chemicals35, 36）. Sustained interest in amphiphilic systems is due to their wide range of real life applications37）. For instance, oil recovery, surfactant enhanced carbon regeneration for waste water treatment, herbicide dispersions, de-inking of paper and plastic film, filtration of ultrafine particles, stabilization of particulate suspensions, and as cleaning detergents, etc. In addition to these known industrial applications, there are also numerous exploratory usages of amphiphiles in modern high technology industries38）. From a fundamental viewpoint, this field remains

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Correspondence to: Refat El-Sayed, Chemistry Department, College of Applied Sciences, Umm Al-Qura University, 21955Makkah, Saudi Arabia; Chemistry Department, Faculty of Science, Benha University, Benha, Egypt. E-mail: [email protected] Accepted April 11, 2015 (received for review January 20, 2015)

Journal of Oleo Science ISSN 1345-8957 print / ISSN 1347-3352 online

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R. El-Sayed

an important source of inspiration for researchers from many different scientific disciplines39）. These observations and our interest in the chemistry of heterocycles prompted us to synthesize different pyrazole, isoxazole, pyrimidine, pyridine and fused pyridine derivatives. These compounds fulfill the following two requirements. First, an amphiphilic molecule must contain both a hydrophobic and a hydrophilic part. Second, the presence in the molecule of active H atoms, （NH, SH, OH and COOH） which make the propyloxylation possible leading to the hydrophobic part in a desired hydrophilic-hydrophobic balance40）.

2 EXPERIMENTAL All melting points are uncorrected. IR spectra of the newly synthesized compounds were measured as KBr disc on BRUKER- FT/IR instrument. 1H NMR was recorded with Bruker AC 400 spectrometer （Fällanden, Switzerland） operating at 600 MHz and for 13C NMR was recorded at 150 MHz（ CDCl 3）as a solvent. Elemental microanalysis was carried out using CHNS elemental analyzer model EA3000 EURO VECTOR instruments. Surface active properties of the synthesized surfactants were measured at 25℃ using Du Nouy tensiometer（Kruss Type 8451）and biological activity are carried out at Microbiology Department Faculty of Applied Science, Umm Al-Qura University, Kingdom of Saudi Arabia. − 2.1 Synthesis 2.1.1 Synthesis of ethyl 3-oxo-2（4-stearamidophenyl） butanoate （3） This compound is prepared in three steps: Step 1. Formation of 4-stearamidobenzoic acid（2）: Stearic acid 1（2.48 g, 0.01 mol）was placed in a 100 mL round-bottom flask and then thionyl chloride（5 mL）was added. The mixture was refluxed for 4 h. Removed the excess thionyl chloride to afford stearoyl chloride, which added dropwise to a solution of 4-aminobenzoic acid （1.37 g, 0.01 mol）in acetone （15 mL） . The reaction mixture was stirred at room temperature for 4 h in presence of triethylamine（1 mL）and then neutralized by pouring onto ice/ water mixture containing few drops of hydrochloric acid. The obtained solid was filtered and recrystallized from ethanol. White solid, yield, 80％（1.98 g）, m.p.115-117℃; IR（ν/cm −1）: 3047（ aromatic CH）, 2915, 2949（ aliphatic （C＝O） . 1H NMR （600 MHz, CDCl3） δ: CH2）, and 1708, 1678 , 1.25-1.72 （m, 32H, 16CH2 0.87 （t, 3H, J＝9.6, terminal CH3） of alkyl chain） , 7.49-7.73 （m, 4H, ArH） , 8.50 （s, 1H, NH） and : C, 11.28（s, 1H, OH）. Anal. Calcd. for C25H41NO（403.60） 3 74.40; H, 10.24; N, 3.47. Found: C, 74.11; H, 10.05; N, 3.21. Step 2. Formation of stearamidobenzoyl chloride: 4-Stearamidobenzoic acid 2 （4.03 g, 0.01 mol） was placed in a 100

mL two-neck round-bottom flask and then thionyl chloride was added. The mixture was refluxed for 6 hrs. Removed the excess thionyl chloride to afford 4-stearamidobenzoyl chloride which use insitu in the next step. Step 3. Formation of ethyl 3-oxo-2-（4-stearamidophenyl） butanoate（3） To an ice-cold mixture of ethyl acetoacetate（0.26 g, 2 mmol）, in ethanol 25 mL containing triethylamine 0.4 mL was added dropwise with stirring to 4-stearamidobenzoyl chloride 3（0.81 g, 2 mmol）followed by over 15 min. The stirring was continued for 30 min, then left for 2 h at room temperature and then neutralized by pouring onto ice/ water mixture containing few drops of hydrochloric acid. The solid products formed, was filtered and recrystallized from ethanol. Pale yellow solid, yield, 82％（0.66g）, m. p.165-166℃; IR（ν/cm−1）: 3055（aromatic CH）, 2916, 2950 , and 1715, 1698, 1677（C＝O） . 1H NMR（600 （aliphatic CH2） MHz, CDCl3）δ: 0.86（t, 3H, terminal CH3）, 1.19-1.64（m, 32H, 16CH2 of alkyl chain）, 1.66（t, 3H, J＝13.8, CH2CH3）, 2.34（s, 3H, CH3）, 4.59（q, 2H, CH2CH3）, 4.89（s, 1H, CH）, 7.26-7.59（m, 5H, ArH）and 11.35（s, 1H, NH）. Anal. Calcd. : C, 72.20; H, 9.58; N, 2.72. Found: C, for C31H49NO（515.72） 5 72.51; H, 9.71; N, 2.98 2.1.2 Synthesis of N-（4-（3-methyl-5-oxo-4,5-dihydro-1Hpyrazole-4-carbonyl）phenyl）stear-amide（4a） Equimolar amounts of compound 3 （1 g, 2 mmol）and hydrazine hydrate（ 0.2 g, 4 mmol）in ethanol（25 mL）was heated under reflux for 6 h. The solvent was concentrated and the reaction product was allowed to cool. The separated product was filtered off, washed with water, dried and crystallized from ethanol. White yellow solid, yield, 68％ : 3318（NH） , 3074（ar（0.68 g）, m.p.118-120℃; IR （ν/cm−1） omatic CH）, 2917, 2849（aliphatic CH）, 1698, 1681, 1669 （CO）and 1557（C＝N）; 1H NMR（CDCl3）δ: 0.86（t, 3H, J＝ 13.8, terminal CH 3）, 1.23-1.97（ m, 32H, 16CH 2 of alkyl chain）, 2.59（s, 3H, pyrazolinone CH3）, 3.91（s, 1H, CH）, 6.96-7.57（m, 5H, ArH）, 9.21（s, 1H, NH）and 9.82（s, 1H, : C, 72.01; H, 9.38; NH） . Anal. Calcd. for C29H45N3O（483.69） 3 N, 8.69. Found: C, 72.33; H, 9.57; N, 8.93. 2.1.3 Synthesis of N-（4（3-methyl-5-oxo-4,5-dihydroisoxazole-4-carbonyl）phenyl） stearamide（4b） A mixture of compound 3（1 g, 2 mmol）and hydroxyl amine hydrochloride（0.14 g, 2 mmol）in 1,4-dioxane（30 mL）containing sodium acetate（0.3 g, 4 mmol）was heated under reflux for 6 h. The reaction mixture was concentrated, cooled and then poured onto cold water. The produced solid was filtered off, dried and crystallized from ethanol. : Yellow solid, yield, 72％ （0.72 g） , m.p.127-129℃; IR （ν/cm−1） 3326（NH）, 3070（aromatic CH）, 2915, 2848（aliphatic CH） 1714, 1687（ CO）and 1558（ C＝N）; 1 H NMR spectrum δ; 0.86（t, 3H, J＝13.8, terminal CH3） , 1.24-1.63（m, （CDCl3） 32H, 16CH2 of alkyl chain）, 2.29（s, 3H, isoxazolone CH3）, 4.13（s, 1H, CH）, 6.86-7.29（m, 4H, ArH）and 8.54（s, 1H, NH）. 13C NMR（CDCl3）δ（ppm）: 14.26, 22.71, 25.53, 26.43,

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J. Oleo Sci. 64, (7) 761-774 (2015)

Synthesis and Heteroannulation of Pyridine and Related Heterocyclic Systems Having Surface and Biological Activities

29.31, 29.33, 29.37, 29.43, 29.53, 29.67, 29.8, 29.71, 31.93, 37.77, 72.09, 118.92, 128.60, 129.67, 132.42, 135.62, 141.09, 167.31, 176.11, 181.37, 187.83. Anal. Calcd. for : C, 71.87; H, 9.15; N, 5.78. Found: C, C29H44N2O（484.67） 4 71.62; H, 8.92; N, 5.51. 2.1.4 General procedure for synthesis of pyrimidine derivatives （5a,b） To a solution of compound 3（1 g, 2 mmol）in ethanolic sodium ethoxide solution（40 mL）, urea（0.12 g, 2 mmol） and/or thiourea（0.15 g, 2 mmol）was added. The reaction mixture was boiled under reflux for 7 h in each case, concentrated and the residue was triturated with cold water. The solid was collected by filtration, dried and recrystallized from a proper solvent. N-（4-（4-methyl-2,6-dioxo-1,2,5,6-tetrahydropyrimidine5-carbonyl）phenyl） stearamide （5a） . Yellow solid（ Acetone）, yield, 76％（0.76g）, m.p 124: 3333-3314（2NH）, 3045 （aromatic CH）, 126℃; IR（ν/cm−1） 2917, 2848（aliphatic CH）, 1702 broad（CO）, 1560（C＝N）; 1 H NMR spectrum（CDCl3）δ: 0.88（t, 3H, J＝13.6, terminal （s, 3H, CH3）, 1.33-1.68（m, 32H, 16CH2 of alkyl chain）, 2.39 , 7.25-7.44 （m, 5H, ArH and NH） and CH3）, 4.14（s, 1H, CH） : C, 9.55（s, 1H, NH）. Anal. Calcd. for C30H45N3O（511.70） 4 70.42; H, 8.86; N, 8.21. Found: C, 70.66; H, 9.05; N, 8.47. N-（4-（4-methyl-6-oxo-2-thioxo-1,2,5,6-tetrahydropyrimidine-5-carbonyl）phenyl）stearamide（ 5b）. Deep yellow solid（Acetone）, yield.78％（0.78 g）, m. p 131-133℃; IR （ν/cm −1）: 3345-3327（2NH）, 3054（ aromatic CH）, 2915, 2849（aliphatic CH）, 1698, 1663（CO）, 1557（C＝N）, 1203 （CDCl3） δ: 0.89 （t, 3H, J＝13.8, ter（CS） ; 1H NMR spectrum minal CH3） , 1.25-1.64 （m, 32H, 16CH2 of alkyl chain）, 2.33 （s, 1H, CH） , 7.23-7.29 （m, 4H, ArH） , 8.15 （s, 3H, CH3）, 4.15 （s, 1H, NH）. and 9.14（ s, 1H, NH）. 13C NMR spectrum （CDCl3）δ: 14.15, 22.70, 29.06, 29.25, 29.37, 29.44, 29.59, 29.70, 31.92, 65.67, 124.06, 125.29, 127.15, 129.62, 137.03, 165.67, 175.57, 181.57, 186.10, 188.04. Anal. Calcd. for C30H45N3O3S（527.76）: C, 68.27; H, 8.59; N, 7.96; S, 6.08. Found: C, 68.50; H, 8.84; N, 7.65; S, 6.31. 2.1.5 Synthesis of N-（4-（5-cyano-2-hydroxy-4-methyl6-oxo-1,6-dihydropyridine-3-carbonyl）phenyl）stearamide（6） A solution of compound 3（1 g, 2 mmol）in acetone（25 mL）, potassium hydroxide（0.2 g, 4 mmol）and cyanoacetamide（0.17 g, 2 mmol）was heated under reflux for 5 h. The resulting mixture was acidified using dilute HCl. the obtained solid was collected by filtration and washed with water, filtered off, dried and recrystallized from acetone. Pale yellow solid, yield, 61％ （0.61 g） , m.p.135-137℃; IR （ν/ （OH and NH）, 3077 （aromatic CH） , 2916, cm−1）: 3420-3184 2849（aliphatic CH）, 2191（CN）, 1739, 1698（CO）; 1H NMR spectrum（CDCl3）δ: 0.86（t, 3H, J＝13.8, terminal CH 3）, （s, 3H, CH3） , 1.21-1.73 （m, 32H, 16CH2 of alkyl chain）, 2.59 7.17-7.63 （m, 4H, ArH）, 9.28 （s, 1H, NH） , 10.12 （s, 1H, NH） and 13.32（ s, 1H, OH）; 13C NMR（CDCl3）δ（ ppm）: 14.26,

28.97, 29.00, 29,12, 29.15, 29.27, 29.37,29.44, 29.46, 29.60, 29.66, 29.67, 29.70, 31.92, 34.41, 60.20, 112.54, 118.04, 123.90, 125.73, 138.66, 149.56, 159.66, 161.47, 162.92, 173.56, 183.38, 189.35. Anal. Calcd. for C 32 H 45 N 3 O 4 （535.72）: C, 71.74; H, 8.47; N, 7.84. Found: C, 71.53; H, 8.22; N, 7.61. 2.1.6 Synthesis of N-（4-（6-cyano-7-methyl-3,5-dioxo-3,5dihydro-2H-oxazolo［3,2-a］pyridine-8 carbonyl）phenyl）stearamide（7） A mixture of compound 6（1.1 g, 2 mmol）, chloroacetic acid（0.2 g, 2 mmol） and anhydrous sodium acetate （0.3 g, 4 mmol）in a mixture of glacial acetic acid（30 mL）and acetic anhydride（20 mL）was heated under reflux for 4 h. The reaction mixture was cooled and poured onto crushed ice（50 g）. The formed solid was collected by filtration and recrystallized from benzene. Deeply yellow solid, yield, 75％（0.82 g）; mp 122-124℃; IR（ν/cm−1）: 3332（NH）, 3050（aromatic CH）, 2915, 2848（aliphatic CH） , 2205（CN） , 1690-1675 cm− 1 1 （CO）; H NMR spectrum（CDCl3）δ: 0.85（t, 3H, J＝13.8, terminal CH3）, 1.24-1.63（m, 32H, 16CH2 of alkyl chain）, , 4.13（s, 2H, CH2 of oxazole）, 7.29-7.58（m, 2.30（s, 3H, CH3） 4H, ArH）, 8.20（s, 1H, NH, exchangeable）. Anal. Calcd for : C, 70.93; H, 7.88; N, 7.30. Found: C, C34H45N3O（575.74） 5 70.71; H, 7.64; N, 7.11. 2.1.7 Synthesis of N-（4-（2-benzylidene-6-cyano-7-methyl-3,5-dioxo-3,5-dihydro-2H-oxazolo［3,2-a］pyridine8-carbonyl）phenyl）stearamide（8）. Equimolar amounts of compound 7（1.15 g, 2 mmol） and benzaldehyde （0.21 g, 2 mmol） in glacial acetic acid （25 mL） containing anhydrous sodium acetate（0.3 g. 4 mmol）was heated under reflux for 6 h. The reaction mixture left to cool then poured onto crushed ice（30 g）and the produced solid was recrystallized from dioxane. Reddish yellow powder, yield, 68％（0.78 g）; mp 152-154℃; IR（ν/cm−1）: 3327（NH） , 3047（aromatic CH）, 2916, 2848（aliphatic CH）, 2209（CN）, 1690-1680（CO）; 1H NMR spectrum（CDCl3）δ: 0.86（ t, 3H, J＝13.8, terminal CH 3）, 1.23-1.62（ m, 32H, 16CH2 of alkyl chain）, 2.29（s, 3H, CH3）, 5.57（s, 1H, CH）, 7.25-7.47（m, 9H, ArH）, 8.00（s, 1H, NH, exchangeable）. : C, 74.18; H, 7.44; N, Anal. Calcd for C41H49N3O（663.84） 5 6.33. Found: C, 74.34; H, 7.69; N, 6.59. 2.1.8 Synthesis N-（4-（7-cyano-6-methyl-8-oxo-3-phenyl-3,8-dihydro-2H-isoxazolo［5',4':4,5］oxazolo［3,2a］pyridine-5-carbonyl）phenyl） stearamide（9）. A mixture of compound 8（1.3 g, 2 mmol）and hydroxyl amine hydrochloride（0.28 g, 4 mmol）was heated under reflux in pyridine（25 mL）for 6 h. The reaction mixture was cooled then poured onto ice-HCl（30 g, 10 mL）. the formed solid was collected by filtration and recrystallized from dioxane. Pale yellow solid, yield, 66％（0.85 g）; mp 126128℃; IR（ν/cm−1）: 3342（NH）, 3071（aromatic CH）, 2915, 2850（aliphatic CH）, 2212（CN）, 1685, 1672 cm−1（CO）; 1H NMR spectrum（CDCl 3）δ: 0.88（ t, 3H, J＝13.8, terminal CH3）, 1.30-1.7（m, 32H, 16CH2 of alkyl chain）, 2.36（s, 3H, 763

J. Oleo Sci. 64, (7) 761-774 (2015)

R. El-Sayed

CH3）, 4.66 （s, 1H, CH of isoxazole） , 7.24-7.47 （m, 10H, ArH （CDCl3） and NH）, 8.76 （s, 1H, NH, exchangeable）; 13C NMR δ（ppm）: 14.26, 24.84, 25.57, 26.16, 29.00, 29.16, 29.19, 29.37, 29.44, 29.47, 29.59, 29.63, 29.66, 29.67, 29.70, 31.92, 116.32, 116.68, 121.55, 122.00, 125.67, 126.16, 126.23, 130.38, 133.82, 136.39, 138.47, 149.93, 153.48, 163.42, 168.63, 172.939, 177.77, 188.29. Anal. Calcd C41H50N4O5 （678.86）: C, 72.54; H, 7.42; N, 8.25. Found: C, 72.78; H, 7.64; N, 8.48. 2.1.9 Synthesis of N-（4-（8-cyano-7-methyl-9-oxo-4-phenyl-2-thioxo-3,4,4a,9-tetrahydro-2H-pyrido ［2',1':2,3］ oxazolo［4,5-d］pyrimidine-6-carbonyl）phenyl）stearamide （10） Equimolar amounts of compound 8（1.3 g, 2 mmol）and thiourea（ 0.12 g, 2 mmol）was heated under reflux in pyridine（25 mL）for 6 h. The reaction mixture was cooled then poured onto ice-HCl（30 g, 10 mL）and the obtained solid was collected by filtration and recrystallized from dioxane. Brown powder, yield, 1.5 g（66％） ; mp 133-135℃; IR（ν/cm−1）: 3342-33188（NH）, 3055（aromatic CH）, 2916, 2849（aliphatic CH）, 2212（CN）, 1685, 1678, 1658 cm −1 （CO）; 1H NMR spectrum（CDCl3）δ: 0.86（t, 3H, J＝13.8, terminal CH3）, 1.25-1.76（m, 32H, 16CH2 of alkyl chain）, （s, 1H, CH of isoxazole） , 5.23 （s, 1H, 2.80 （s, 3H, CH3）, 4.11 CH of isoxazole） , 6.95-7.59 （m, 9H, ArH） , 9.21 （s, 1H, NH,） , （721.95）: C, 12.45 （s, 1H, NH）. Anal. Calcd for C42H51N5O4S 69.87; H, 7.12; N, 9.70; S, 4.44. Found: C, 69.59; H, 6.88; N, 9.48; S, 4.19. 2.1.10 Synthesis of N-（4（7-cyano-8-methyl-6-oxo-2,3,4,6tetrahydropyrido［2,1-b］ ［1,3］oxazine-9-carbonyl） phenyl） stearamide （11） . 1,3-Dibromopropane（ 0.4 g, 2 mmol）in dimethylformamide（20 mL）was added dropwise to a stirred solution containing compound 6 （1.1 g, 2 mmol） and sodium hydroxide（ 0.08 g in H 2O, 10 mL）. The reaction mixture was heated under reflux for 3 h then stirred at room temperature for an additional 2 h. The solid product that formed was collected by filtration, washed with water and triturated with ethanol to give colorless product, which recrystallized from ethanol. Orange powder, yield 67％ （0.73 g）; mp 118-120℃. IR（ν/cm−1）: 3342-3318（NH）, 3055（aromatic CH）, 2916, 2849（aliphatic CH）, 2199（CN）, 1688, 1672, （CDCl3） δ: 0.86 （t, 3H, J 1664 cm−1（CO）; 1H NMR spectrum ＝13.8, terminal CH3）, 1.22-1.30（m, 32H, 16CH2 of alkyl , 2.80 （s, 3H, CH3） , 3.67 chain） , 1.61 （m, 2H, CH2 of oxazine） （t, 2H, J＝15, CH2）, 4.12（t, 2H, J＝14.4, CH2）, 7.26-7.55 : （m, 5H, ArH and NH）. Anal. Calcd for C35H49N3O（575.78） 4 C, 73.01; H, 8.58; N, 7.30. Found: C, 72.84; H, 8.32; N, 7.08. 2.1.11 Synthesis of N-（4-（5-cyano-2-（2-cyanoethoxy） -4-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl） phenyl） stearamide （12） . A mixture of compound 6（1.1 g, 2 mmol）and acrylonitrile （0.16 g, 3 mmol） in pyridine （30 mL） was heated under reflux for 6 h. The formed solid after concentration and

cooling was recrystallized from ethanol. Yellow solid, yield : 3311-3287（NH）, 74％ （0.81 g）; mp 119-121℃; IR （ν/cm−1） 3075（aromatic CH）, 2915, 2849（aliphatic CH）, 2210（CN）, 1685, 1674, 1666 cm−1（CO）; 1H NMR spectrum（CDCl3）δ: 0.88（ t, 3H, J＝13.8, terminal CH 3）, 1.23-1.63（ m, 32H, 16CH2 of alkyl chain）, 2.30（s, 3H, CH3）, 3.65（t, 2H, J＝ , 4.12（t, 2H, J＝14.4, CH2） , 7.18-7.82（m, 5H, 14.4, CH2 CN） ArH and NH）, 8.19（s, 1H, NH, exchangeable） . Anal. Calcd : C, 71.40; H, 8.22; N, 9.52. Found: for C35H48N4O（588.78） 4 C, 71.23; H, 8.01; N, 9.29. 2.1.12 Synthesis of N-（4-（7-cyano-8-methyl-4,6-dioxo2,3,4,6-tetrahydropyrido［ 2,1-b］ ［ 1,3］oxazine9-carbonyl）phenyl）stearamide（13）. A solution of compound 12（1.18 g, 2 mmol）in glacial acetic acid（30 mL）and hydrochloric acid（10 mL）was heated under reflux for 5 h. The reaction mixture was concentrated by evaporation under reduced pressure. The obtained solid was collected by filtration, washed with water and recrystallized from dioxane. Pale yellow solid, yield 69％（0.81 g）; mp 138-140C; IR（ν/cm−1）: 3327（NH）, 3055 （aromatic CH）, 2917, 2848（ aliphatic CH）, 2200（ CN）, 1689-1669 cm−1（CO）; 1H NMR spectrum（CDCl3）δ: 0.87（t, 3H, J＝13.8, terminal CH3）, 1.29-1.64（m, 32H, 16CH2 of alkyl chain）, 2.29（s, 3H, CH3）, 2.35（t, 2H, J＝15, CH2）, 4.14（t, 2H, J＝21.6, CH2）, 7.26-7.89（m, 4H, ArH）, 8.65（s, 1H, NH, exchangeable）. Anal. Calcd for C 35 H 47 N 3 O 5 （589.76）: C, 71.28; H, 8.03; N, 7.12. Found: C, 71.54; H, 8.25; N, 7.26 2.1.13 Synthesis of N-（4-（3-benzylidene-7-cyano-8-methyl-4,6-dioxo-2,3,4,6-tetrahydropyrido［2,1-b］ ［1,3］ oxazine-9-carbonyl）phenyl）stearamide（14）. A mixture of compound 13 （1.18 g, 2 mmol）and benzaldehyde（0.21 g, 2 mmol）in glacial acetic acid（30 mL）containing anhydrous sodium acetate（ 0.3 g, 4 mmol）was heated under reflux for 6 h. The reaction mixture was cooled, poured onto crushed ice （30 g）and the solid formed was recrystallized from ethanol. Reddish yellow, yield 66％ : 3325（NH） , 3076 （aro（0.77 g）; mp 156-158℃; IR （ν/cm−1） matic CH）, 2915, 2849（aliphatic CH）, 2212（CN）, 1681, ; 1H NMR spectrum （CDCl3） δ: 0.86（t, 1674, 1660 cm−1（CO） 3H, J＝13.8, terminal CH3）, 1.25-1.63（m, 32H, 16CH2 of , 4.13（s, 2H, CH2 of oxazine）, alkyl chain）, 2.31（s, 3H, CH3） 5.86（s, 1H, CH）, 7.13-7.90（m, 10H, ArH and NH）. Anal. : C, 74.42; H, 7.58; N, 6.20. Calcd for C42H51N3O（677.87） 5 Found: C, 74.19; H, 7.24; N, 6.02. 2.1.14 Synthesis of N-（4-（8-cyano-7-methyl-9-oxo-3-phenyl-2,3,4,9-tetrahydroisoxazolo［5,4-d］pyrido［2,1b］ ［ 1,3］oxazine-6-carbonyl）phenyl）stearamide （15） . A mixture of compound 14 （1.3 g, 2 mmol）and hydroxyl amine hydrochloride（0.28 g, 2 mmol）in pyridine（30 mL） was refluxed for 6 h. The reaction mixture was cooled, then poured onto crushed ice（40 g）and the solid product was collected by filtration and recrystallized from DMF.

764

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Synthesis and Heteroannulation of Pyridine and Related Heterocyclic Systems Having Surface and Biological Activities

Pale yellow, yield, 69％ （0.9 g） ; mp 131-133℃; IR （ν/cm−1） : 3320-3289 （NH） , 3056 （aromatic CH） , 2916, 2850 （aliphatic CH）, 2210（CN）, 1685-1671 cm−1（CO）; 1H NMR spectrum （t, 3H, J＝13.8, terminal CH3） , 1.23-1.76（m, （CDCl3）δ: 0.86 32H, 16CH2 of alkyl chain）, 2.76（s, 3H, CH3）, 4.59（s, 2H, CH of isoxazole）, 5.02 （s, 1H, CH of oxazine）, 7.17-7.57 （m, 9H, ArH）, 7.97（s, 1H, NH）, 9.35（s, 1H, NH）. Anal. Calcd : C, 72.80; H, 7.56; N, 8.09. Found: for C42H52N4O（692.89） 5 C, 72.76; H, 7.39; N, 8.36. 2.1.15 Synthesis of N-（4（9-cyano-8-methyl-10-oxo-4-phenyl-2-thioxo-2,3,4,4a,5,10-hexahydro-pyrido ［2,1-b］ pyrimido［4,5-d］ ［1,3］oxazine-7-carbonyl）phenyl） stearamide （16） . Equimolar amounts of compound 14 （1.3 g, 2 mmol）and thiourea （0.15 g, 2 mmol） in glacial acetic acid （30 mL） was heated under reflux for 6 h. The reaction mixture was cooled, poured onto crushed ice （30 g） and the solid formed was recrystallized from ethanol. Brown solid, yield, 71％ : 1342-3321 （NH） , 3045 （0.91 g） ; mp 136-138℃; IR （ν/cm−1） （aromatic CH）, 2917, 2849（ aliphatic CH）, 2198（ CN）, 1689-1674 cm−1（CO）; 1H NMR spectrum（CDCl3）δ: 0.86（t, 3H, J＝13.8, terminal CH3）, 1.25-1.77（m, 32H, 16CH2 of , 2.70 （s, 1H, CH） , 4.11 （s, 1H, alkyl chain） , 2.27 （s, 3H, CH3） CH）, 4.89（s, 1H, CH）, 6.95-7.61（m, 9H, ArH）, 9.11（s, 1H, NH）, 12.45（ s, 1H, NH）. Anal. Calcd for C 43 H 53 N 5 O 4 S （735.98）: C, 70.17; H, 7.26; N, 9.52; S, 4.36. Found: C, 70.39; H, 7.51; N, 9.80; S, 4.58. 2.2 Preparation of nonionic surfactants from the synthesized heterocyclic compounds Propoxylation The hydrophobe of synthesized compounds containing KOH （0.01 mol）was stirred and heated to 120-160℃ while passing a slow stream of nitrogen through the system to flush out oxygen. Nitrogen addition was stopped and propylene oxide was added drop wisely with continuous stirring and heating under efficient reflux system to retain propylene oxide. The reaction was conducted for different intervals of time ranging from 1-10 hr. The apparatus was then filled with nitrogen, cooled and reaction vessel weighted. The amount of propylene oxide which was reacted and the average degree of prop-oxylation were determined through the increment in mass of the reaction mixture（increase in weight of the mixture after the addition of propylene oxide is the average amount of propoxyl41） . ation） 2.3 Antimicrobial activity. The cap-assay method containing （g/L） : peptone 6, yeast extract 3, meat extract 1.5, glucose 1 and agar 20 were used. The medium was sterilized and divided while hot （50–60℃） in 15 mL portions among sterile petri-dishes of 9 cm diameter. One mL of the spore suspension of each microorganism was spread all over the surface of the cold solid medium placed in the petri-dish. Each of the tested

compounds（0.5 g）was dissolved in 5 mL of dimethylformamide. An amount of 0.1 mL of test solution was placed on Watman paper disc of 9 mm diameter and the solvent was left to evaporate. These saturated discs were placed carefully on the surface of the inoculated solid medium; each petri-dish contains at least 3 discs. The petri-dishes were incubated at 5℃ for an hour to permit good diffusion and then transferred to an incubator of 85℃ overnight, then examined42）. 2.4 Surface active properties of the surface active agents 2.4.1 Surface and interfacial tensions Surface and interfacial tension measurements on （15-28） were carried out according to Findlay43）with a Krüss tensi（Krüss GmbH, Hambur g, Instrument Nr. K6） for ometer44） different concentrations of the synthesized surfactants （0.05–10-6 mol/L）, using a platinumiridium ring at constant temperature（25±1℃）. Paraffin oil was used for the interfacial tension measurements. The tensiometer was calibrated using the method described in ASTM Designation: D1331-0145）. 2.4.2 Cloud point The cloud point is a measure of the inverse solubility of a nonionic surface active agent. In a temperature-controlled bath, a 1.0 wt％ solution of the tested compound was gradually heated until the clear or nearly clear solution became definitely turbid46）. The temperature was then recorded and the solution was allowed to cool down until it became clear again. The process was repeated to check the reproducibility of the recorded temperature. 2.4.3 Wetting time Wetting time was measured by immersing a cotton skein （1 g）in a 0.1 wt％ solution of the prepared surfactants in distilled water at 25℃ according to the Draves technique47）. The sinking time was measured in seconds. 2.4.4 Foaming properties Foam height was measured by the Ross Miles method48）. In this procedure a given surfactant solution was allowed to fall from a set height into the same surfactant solution in a volumetric cylinder, hence creating foam. The height of the foam was visually assessed. In this procedure a 25 mL of the solution（ 1.0 wt％）was shaken vigorously for 10 seconds in a 100 ml graduated cylinder with glass stopper at 25℃. The solution was allowed to stand for 30 seconds, and then, the foam height was measured. 2.4.5 Emulsion stability The emulsifying property of the prepared surfactants was determined as follows: In a 100-mL graduated stoppered tube; an aqueous solution of the surfactant （10 mL, 20 mol）was mixed with light paraffin oil（6 mL）. The mixture was shaken vigorously by magnetic stirring ［Thermo scientific Cimarec TM stirring hot plate, model no: sp131320-30, estimated stirring speed（1,100 rpm）］for 2 min at 25℃. The tube was placed upright and the separa765

J. Oleo Sci. 64, (7) 761-774 (2015)

R. El-Sayed

tion of the formed emulsion was observed. The time taken for the separation of（9 mL）of the aqueous layer indicates the emulsion stability of the surfactant49）. 2.5 Biodegradability The biodegradation tests of the synthesized nonionic surfactants were performed according to the River Water Die-Away method 50）. The river water for testing was sampled from the River Nile. In this test, a stirred solution containing the tested surfactant （1,000 ppm）was incubated at 25℃. Samples were withdrawn daily, filtered using Whatman filter paper and the surface tension was measured using a Du-Nouy tensiometer （Kruss type K6）. The process was repeated for 7 days. The biodegradation percentage D％ was calculated in terms of the measured surface tension according to the following relation. D＝［ （γt −γo） （γbt−γo） ］ ×100, where γt＝surface tension at time t, γo＝surface tension at zero time, γbt＝surface tension of blank experiment at time （without t samples） .

3 RESULTS AND DISCUSSION 3.1 Synthesis The required ethyl 3-oxo-2-（4-stearamidobenzoyl）butanoate （3） was prepared via reaction of stearic acid （1） with thionyl chloride afforded stearoyl chloride（ 2）which reacted with 4-amino-benzoic acid, followed by treated with thionyl chloride furnished 4-stearamidobenzoyl chlo-

ride, which was coupled smoothly with active methylene compounds via ethyl acetoacetate by stirring in ethanol containing catalytic amounts of triethylamine via electrophilic substitution reaction. The structure of compound 3 was assigned by elemental analysis and spectroscopic data （IR, and 1H NMR spectra）which agree with the assigned structure. The IR spectrum revealed absorption bands at 3247 cm−1 due to NH group, 3055 cm−1 for CH aromatic, 1715-1690 cm−1 are due to the stretching vibration of the C＝O groups. While, the 1H NMR spectrum showed a characteristic CH signal at 4.19 ppm. The reactivity of the conveniently accessible amide derivative 3 toward a variety of chemical reagents was investigated. It was found that the reaction of compound 3 with either hydrazine hydrate or hydroxyl amine hydrochloride in boiling in 1,4-dioxane for 6 hr, the respective pyrazole and/or isoxazole systems 4a,b were obtained in good yield. The structures of 4a,b were established by analytical and spectroscopic data. Thus, the IR spectrum of 5a showed absorption bands at 3266-3245 cm−1 are due to NH groups, 1688, 1672 cm−1 are due to（C＝O）groups and 1599 cm−1 for（ C＝N）. Moreover, 1H NMR（CDCl 3）spectrum of 5a showed a signal at 3.95 for CH of pyrazole ring and 8.15, 9.61 for 2NH protons. While, the IR spectrum of 4b showed absorption bands at 1710-1685 cm −1 are due to（C＝O） groups, 1595 cm −1 for（ C＝N）group. Also, the 1H NMR spectrum（CDCl3）of 4b showed a signal characteristic for CH of isoxazole ring at 4.08 ppm（Scheme 1） . The work was further extended to shed more light on

Scheme 1　‌i ) SOCl 2, ii) NH 2C 6H 4COOH(p), iii) CH 3COCH 2COOEt, iv) N 2H 4, v) NH 2OH, vi) NH 2CONH 2, vii) NH2CSNH2, viii) NCCH2CONH2/KOH. 766

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Synthesis and Heteroannulation of Pyridine and Related Heterocyclic Systems Having Surface and Biological Activities

the reactivity of compound 3 as functional reagent toward other nucleophilic reagents. Thus, the reaction of 3 with equimolar amounts of urea and/or thiourea in boiling ethanolic sodium ethoxide solution furnished the corresponding pyrimidine derivatives 5a,b. All collected data for compounds 5a,b were consistent with the proposed structures. Thus, the observation of CH proton of pyrimidine ring at 4.12 ppm in the 1H NMR spectrum of 5a while appearance at 4.18 ppm in the 1H NMR spectrum of 5b. As an extension of this synthetic route, the reaction of compound 3 and cyanoacetamide in boiling acetone containing potassium hydroxide as a catalyst yielded the pyridine derivative （6）. The structure of compound 6 was assigned on the basis of elemental analysis and compatible spectro-scopic data. Thus, its IR spectrum showed characteristic absorption bands at 3420-3184 cm−1 are due to（OH and NH）, 2214 cm−1 due to the stretching vibration of the CN group and 1688 cm−1 due to the stretching vibration of the C＝O group. Also, the 1H NMR（CDCl3）spectrum showed signals at δ 2.65 ppm for methyl protons, multiplet signals（5H）for aromatic protons and NH of pyridine ring at（7.21-7.95） ppm, singlet at 9.78 ppm for NH of amide proton and singlet at 10.61 ppm for OH. Pyridine derivative 6 used as a versatile intermediate allowing access for preparation of a variety of multifunctionalized polyheterocycles, due to the presence of two adjacent reactive functional groups. Thus, the alkylation of 7 with chloroacetic acid in a mixture of glacial acetic acid/ acetic anhydride containing anhydrous sodium acetate afforded N-（4-（6-cyano-7-methyl-3,5-dioxo-3,5-dihydro-2Hoxazolo［3,2-a］pyridine-8-carbonyl）phenyl）stearamide（7）. The structural assignments of 7 were based on analytical and spectral data. Thus, the IR spectrum exhibited absorption bands 3282 cm−1 due to NH, 2195 cm−1 due to CN

group and 1705, 1691, 1678 cm −1 due to C＝O groups. While, the 1H NMR（CDCl3）spectrum showed signals at δ 4.35 ppm for CH2 protons of oxazole rin g, and 9.38 ppm for NH of amide proton. Also, condensation of 7 with benzaldehyde by refluxing in glacial acetic acid containing anhydrous sodium acetate gave the corresponding benzylidene derivative 8. The structure of 8 was confirmed by analytical and spectroscopic data. The 1H NMR spectrum revealed the presence of a singlet at 6.32 ppm characteristic for δ-1H benzylidine C＝CH group. Additionally, compound 8 underwent cyclization into N-（4-（7-cyano6-methyl-8-oxo-3-phenyl-3,8-dihydro-2H-isoxazolo ［5',4':4,5］oxazolo［3,2-a］pyridine-5-carbonyl）phenyl）stearamide（9）and/or N-（4-（8-cyano-7-methyl-9-oxo-4-phenyl2-thioxo-3,4,4a,9-tetrahydro-2H-pyrido［2',1':2, 3］oxazolo ［4,5-d］pyrimidine-6-carbonyl）phenyl）stearamide（ 10） upon treatment with hydroxylamine hydrochloride and/or thiourea in refluxing pyridine, respectively. Microanalysis and spectral data of 9, 10 were fully consistent with the proposed structures（Scheme 2）. The preparative use of pyridine derivative 6 was extended to prepare new annulated pyridine derivatives. Thus, the condensation of 6 with 1,3-dibromopropane yielded the corresponding pyridoxazine derivative 11. The structural assignments of 11 were based on analytical and spectral data. Thus, the 1H NMR spectrum of compound 11 revealed three signals at δ 2.11, 3.85 and 4.24 ppm due to the three CH2 groups. At the other extreme, cyanoethylation of compound 6 with an equimolar amount of acrylonitrile in pyridine underwent a Michael type addition to the activated double bond of the nitrile to afford the propionitrile derivative 12, which underwent cyclization to pyridoxazine 13 by refluxing in a mixture of glacial acetic acid and hydrochloric acid （3:1）. Finally, condensation of compound 13 with benzal-

Scheme 2　‌ i) ClCH2COOH, ii) Ac2O/AcOH, iii) PhCHO, iv) NH2OH, v) NH2CSNH2, vi) 1,3-Dibromopropane/DMF. 767

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weight should be suitable to become an amphiphilic molecule with the suitable hydrophilic-lipophilic balance. Therefore, the reaction of compounds（4,5）a,b and（6-16） with 5 moles of propylene oxide in presence of KOH as a catalyst gave the corresponding propoxylated products （17-29）. This addition reaction is one of the principal processes used to introduce hydrophilic functional groups into a hydrophobic moiety and the reaction conditions are shown in Table 1. The structures of which were confirmed via IR and 1H NMR spectra. Thus, in addition to the original bands reported for these compounds, IR spectrum showed and two a broad band in the region（3413–2610）cm−1（OH）

dehyde afforded the corresponding benzylidene derivative 14, which reacted with hydroxylamine hydrochloride and/ or thiourea to give the cyclized tricyclic derivative 15 and/ or 16, respectively （Scheme 3） . The structures of the synthesized compounds were assigned on the basis of elemen. tal analysis and spectral data （cf. experimental） 3.2 Preparation of surface active agents For the compounds acting as nonionic surface active agents two requirements are needed first one, the hydrogen containing group present should be active enough to react with alkylene oxide and second is the molecular

Scheme 3　i) CH2 = CHCN, ii) AcOH/HCl, iii) PhCHO, iv) NH2OH, v) NH2CSNH2. Table 1　Reaction conditions of propoxylated compounds. Compounds

Temperature ℃

Propoxylated products

Yield %

4a

130

17a

66

4b

140

17b

69

5a

135

18a

67

5b

145

18b

62

6

150

19

68

7

130

20

67

8

160

21

65

9

140

22

63

10

145

23

69

11

125

24

65

12

130

25

66

13

150

26

70

14

165

27

61

15

145

28

68

16

150

29

64

* Degree of propoxylation was calculated by weight. 768

J. Oleo Sci. 64, (7) 761-774 (2015)

Degree of Propoxylation*

5 moles

Synthesis and Heteroannulation of Pyridine and Related Heterocyclic Systems Having Surface and Biological Activities

other bands in the region（1125-1030）and（961-850）cm−1 for（C–O–C）ether linkage of polypropoxy chain. The 1H NMR spectrum showed the protons of the propoxy groups which appear as broad multiple signals in the region（3.004.01）ppm.The propoxylation of compounds 4a and 9 as representative examples are shown in （Scheme 4） . 3.3 Antimicrobial activity All the newly surface active agents were tested for activity against Gram-positive and Gram-negative bacteria using Streptomycin as a reference standard drug. Based on the previous preliminary test, the tested compounds were dissolved in 10％ acetone （v/v） . A qualitative screen was performed on all compounds, while quantitative assays were done on active compounds only. The results were tabulated in Table 2 which displayed that compounds 23 and 29 are highly active toward Escherichia coli, Staphylococcus aureus. Pyrazoles derivatives 17a showed moderate activity against both bacteria strains（gram＋ve & gram−ve）, but it exhibited no activity against fungi. Construction of a pyrimidine ring 18b showed highly activity against bacteria with moderate activity against fungi. On the other hand, the pyridine 19 has revealed an increase in the antibacterial activity and antifungal activity. It has been reported that compounds 23, 29 possess greater antimicrobial activities than the other pyridine derivatives. The results obtained from microbiological screening of the synthesized compounds showed highly antibacterial and antifungal activities comparable to that of Streptomycin. 3.4 Evaluation of nonionic surface active agents properties Nonionic surfactants are used extensively, because of their good detergency, easy rinsing and low foaming in

cleaning of milk and beer bottles. The surface active properties were independent of heterocyclic moieties but it depended on the hydrophobic part（long chain）and hydrophilic part（propylene oxide units）.The surface properties as surface and interfacial tension, cloud point, wettin emulsification properties, and foaming height were investigated systematically under neutral conditions in aqueous solution in order to evaluate the possible application of these products in the different industrial fields and were illustrated in Table 3 high cloud points which gave a performance in hot water, this may be due to the strong hydrogen bonds formed. Also, the synthesized surfactants were efficient wetting agents（ can be used in dying process of fiber） . 3.4.1 Surface tension and interfacial tension Surface tension measurements were performed to investigate the adsorption of the prepared compounds. The measured data of surface and interfacial of the compounds （17-29） are listed in Table 3. These data revealed dropping in surface and interfacial tension, which mean a good pronounced surface activity. The results showed the surfactants 18a,b have maximum ability while amphiphile 23 have minimum ability to reduce surface tension of aqueous system in the series of amphiphile being reported. 3.4.2 Cloud point The cloud point of non-ionic arises because the solubility of the propylene oxide entity is due to hydrogen bonding. When heating a non-ionic aqueous solution a separation into two phases occurs at a certain temperature, this temperature is called the cloud point. The surface activity of the surfactant solution is affected just below and high the cloud point. The results Table 3 showed the surfactants 21 and 23 have maximum cloud point while amphiphile 18b have minimum cloud point in the series of amphiphile

Scheme 4　Propoxylation of compounds 4a and 9. 769

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Table 2　Antimicrobial activity of some synthesized compounds. Inhibition zone diameter (mm / mg sample) Sample

Escherichia Coli

Bacillus cereus

Staphylococcus Aureus

Aspergillus Flavus A

Candida Albicans MIC

A

Penicillium italicum

MIC

A

MIC

A

MIC

A

MIC

17a

125

+

125

+

250

+

125

17b

250

+

250

+

125

250

+

125

250

+

18a

125

+

125

+

250

++

250

++

250

++

250

++

18b

250

++

250

+++

125

+

125

+

125

+

125

+

19

250

++

250

++

250

++

250

+++

250

++

500

+

20

125

+

125

125

+

125

+

125

+

125

+

21

250

++

250

+

500

+

500

+

500

+

500

+

22

125

++

125

+

250

+++

250

++

250

++

250

+

23

250

+++

250

++

24

250

++

125

25

250

++

250

26

250

++

27

250

28

250

29 Strepto mycin

250

MIC

A

125

500

+++

500

+++

500

++

500

++

250

++

125

+

125

+

125

+

+++

500

++

250

++

250

+

250

+

250

+

500

+

500

++

500

++

500

++

++

250

++

200

++

125

+

125

+

125

+

++

125

+

500

+

500

++

500

++

500

+

250

+++

125

++

500

+++

500

++

500

+++

500

++

250

++

125

++

125

++

125

++

125

+

500

+

A = Antimicrobial activity of tested compounds; MIC = Minimum inhibitory concentration; ( ), inactive; + > 5mm, slightly active; ++ > 7 mm, moderately active; +++ > 9 mm, highly active being reported. These results reflect the fact that these compounds can be used over a wide range of temperatures. 3.4.3 Wetting time The ability of a surfactant solution to displace air from a weighted skein of cotton by spreading wetting. The wetting behavior of a surfactant or auxiliary on a surfactant substrate greatly affects its potential applicability in, for example, biomaterials, textiles, and thin film adhesion. The results in Table 3, revealed that the surfactants 18b and 23 exhibited the shortest sinking time, consequently, are the most efficient wetting agents among the studied group. 3.4.4 Foaming properties The foaming process can be defined as the dispersion of gas in a liquid; it can be improved dramatically by the presence of surfactants that accumulate at the liquid–gas interface. Recent developments in the design of dyeing machines, such as their more rapid circulation of liquor, can result in greater foam formation in the dye bath. This inconvenience has increased the importance of developing low-foaming dyeing auxiliaries51）. The results shown in Table 3, the low-foaming properties of our surfactants. Each compound exhibited not only low foam production （measured by the height of foam initially produced）but

also high-foaming stability（measured by the height of foam produced after 5 min）. It appears that positioning the multiple hydrophilic groups at an internal position increases the area per molecule, decreases the cohesive force at the surface, and results in lower foaming efficiency. 3.4.5 Emulsion stability An emulsifier is usually added to make the preparation of an emulsion easier and to increase its stability. The emulsifying efficiency of a surfactant was related to the polarity of the molecule or the relation between the contribution of the polar hydrophilic head and the nonpolar lipophilic tail. The good dispersion, emulsification and leveling capacities of propoxylated surfactants made them very useful in the pulp, viscose and textile industries, and also in those concerned with metals, paints, plastics and mineral oils52）. The results presented in Table 3, indicated moderate emulsifying properties for the synthesized surfactants. 3.5 Biodegradability of the synthesized surfactants In addition to microbial protection, consumers now are more aware of the environmental impact of products. The class of nonionic surfactants exhibit advantages such as excellent biocompatibility and wide biological activity, low

770

J. Oleo Sci. 64, (7) 761-774 (2015)

Synthesis and Heteroannulation of Pyridine and Related Heterocyclic Systems Having Surface and Biological Activities

Table 3　Surface properties of the synthesized compounds. Foam height (mm)

Compds

Surface tension (dyne/cm) 0.1 m/l

Interfacial tension (dyne/cm) 0.1 m/l

Cloud Point ℃

Wetting time (sec.)

Emulsion stability (min.)

0°mm

5°mm

17a

34

9.5

78

42

32

69

72

17b

33

9.0

76

41

32

71

74

18a

30

8.4

72

38

31

82

85

18b

29

8.2

68

35

30

80

83

19

32

8.7

75

39

33

77

80

20

31

8.5

73

37

30

78

81

21

35

9.7

80

45

33

75

79

22

33

8.8

77

41

32

74

77

23

37

10.3

82

47

35

78

82

24

35

9.8

79

46

33

83

87

25

31

8.6

72

38

32

76

80

26

30

8.3

73

39

30

76

79

27

33

9.1

75

41

33

81

84

28

34

9.6

77

40

31

85

88

29

30

8.4

73

37

30

80

84

Error of measurements was: Surface and interfacial tensions = ±0.1 dynes/cm. Cloud point = ±1℃. Foam height = ±2 mm., Wetting time = ±1 sec., Emulsion = ±1 min

Table 4　Biodegradability of the nonionic surfactants. Compounds

1st day

2nd day

3rd day

4th day

5th day

6th day

7th day

17a

39

48

59

73

86

92

－

17b

37

47

66

78

91

－

－

18a

36

43

52

65

79

93

－

18b

34

45

55

68

83

92

－

19

38

48

60

73

86

97

－

20

36

45

56

69

83

94

－

21

41

50

62

76

89

－

－

22

38

39

53

68

81

95

－

23

43

52

62

77

91

－

－

24

42

50

61

75

88

98

－

25

37

49

61

77

90

－

－

26

36

46

57

70

86

97

－

27

38

47

59

74

88

98

－

28

40

51

63

77

92

－

－

29

36

48

61

75

89

99

－

Error of calculations was: Biodegradation rate =±0.5% environmental impact and low potential toxicity53）, which have been found to have excellent properties such as good water solubility and rapid biodegradability. The synthesized compounds are ecofriendly, the biodegradation die-away

test in river water has been estimated and gave good to excellent results Table 4. In the river-die away test, the amount of surfactant presented in river water was determined at certain time intervals. Generally, the results re771

J. Oleo Sci. 64, (7) 761-774 (2015)

R. El-Sayed

vealed that the synthesized surfactants were biodegradable until the 7th day, which mean that these compounds are safe for human beings as well as environments.

4 CONCLUSION The new family of ecologically safe surface active agents containing heterocyclic moieties as pyridine and fused pyridine derivatives in different molecular weights were designed and synthesized in our laboratory from easily renewable and cheap resources. Since they are easily prepared, show excellent biodegradability, are non toxic, and exhibit improved properties. These surfactants have antimicrobial and surface activities. Moreover, they exhibited good degradation susceptibility within 7 days. These compounds may be applied more broadly, as conditioning agents, antimicrobial agents, solubilizing agents, and in various cosmetics based formulations.

5 ACKNOWLEDGEMENTS The authors are thankful to Microbiology Department, Faculty of Science, Umm Al-Qura University, Saudi Arabia for providing the necessary facilities.

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