Bazı potansiyel biyolojik aktif heterosiklik bileşiklerin sentezi, yapılarının aydınlatılması ve bazı özelliklerinin incelenmesi
The synthesis of some potential biologic active heterocyclic compounds, explaining of their structurals and investigation of some properties
Yazar: ONUR AKYILDIRIM
Danışman: PROF. DR. HAYDAR YÜKSEK
Kafkas Üniversitesi / Fen Bilimleri Enstitüsü / Kimya Ana Bilim Dalı
Derece: Doktora, 2011
Konu: Kimya = Chemistry
Dizin: 1,2,4-triazol = 1,2,4-triazole

Özet:
Bu tez çalışmasında, 10 adet 3-alkil(aril)-4-amino-4,5-dihidro-1H-1,2,4-triazol-5-on bileşiği elde edilerek bazı reaksiyonları incelenmiş ve yeni heterosiklik bileşikler elde edilmiştir.Çalışma dört bölüm olarak planlanmış olup, ilk bölüm yeni bileşiklerin sentezini kapsamaktadır. 3-Alkil(aril)-4-amino-4,5-dihidro-1H-1,2,4-triazol-5-on bileşiklerinin tez kapsamında sentezlenen 3-metoksi-4-fenilasetoksibenzaldehid, 3-metoksi-4-(4-metilbenzoksi)benzaldehid ve 1,3,5-tri-(2-metoksi-4-formilfenoksikarbonil)-benzen ile ayrı ayrı reaksiyonundan karşın olan sırasıyla 3-alkil(aril)-4-(3-metoksi-4-fenilasetoksibenzilidenamino)-4,5-dihidro-1H-1,2,4-triazol-5-on, 3-alkil(aril)-4-[3-metoksi-4-(4-metilbenzoksi)benzilidenamino]-4,5-dihidro-1H-1,2,4-triazol-5-on ve 1,3,5-tri-{2-metoksi-4-[(3-alkil/aril-4,5-dihidro-1H-1,2,4-triazol-5-on-4-il)-azometin]-fenoksikarbonil}-benzen bileşikleri elde edilmiştir. Ayrıca, bu bileşiklerin asetik anhidrid ile reaksiyonları incelenerek N-asetil türevleri elde edilmiştir. Çalışmanın sentez bölümünde ikinci olarak 3-alkil(aril)-4-(3-metoksi-4-hidroksibenzilidenamino)-4,5-dihidro-1H-1,2,4-triazol-5-on bileşiklerinin sodyum etoksitli ortamda benzil bromür ve fenasil bromür ile reaksiyonları incelenerek 1-benzil-3-alkil(aril)-4-(3-metoksi-4-fenilmetoksibenzilidenamino)-4,5-dihidro-1H-1,2,4-triazol-5-on ve 1-fenasil-3-alkil(aril)-4-(3-metoksi-4-benzoilmetoksibenzilidenamino)-4,5-dihidro-1H-1,2,4-triazol-5-on bileşikleri elde edilmiştir. Bu reaksiyonlarda 3-p-klorobenzil-4-(3-metoksi-4-hidroksibenzilidenamino)-4,5-dihidro-1H-1,2,4-triazol-5-on bileşiğinin fenasil bromürle reaksiyonundan farklı olarak 1-fenasil-3-p-klorobenzil-4-(3-metoksi-4-hidroksibenzilidenamino)-4,5-dihidro-1H-1,2,4-triazol-5-on bileşiği ele geçmiştir. Çalışmanın sentez bölümünde son olarak 3-p-klorobenzil-4-(4-hidroksibenzilidenamino)-4,5-dihidro-1H-1,2,4-triazol-5-on bileşiğinin sodyum etoksitli ortamda etil bromoasetat ile reaksiyonundan elde edilen 1-etoksikarbonilmetil-3-p-klorobenzil-4-(4-etoksikarbonilmetoksibenzilidenamino)-4,5-dihidro-1H-1,2,4-triazol-5-on [etil 3-p-klorobenzil-4-(4-etoksikarbonilmetoksibenzilidenamino)-4,5-dihidro-1H-1,2,4-triazol-5-on-1-il)-asetat] bileşiğinin hidrazin hidrat ile reaksiyonundan bir dihidrazid karakterindeki yeni 1-hidrazinokarbonilmetil-3-p-klorobenzil-4-(4-hidrazinokarbonilmetoksibenzilidenamino)-4,5-dihidro-1H-1,2,4-triazol-5-on [3-p-klorobenzil-4-(4-hidrazinokarbonilmetoksibenzilidenamino)-4,5-dihidro-1H-1,2,4-triazol-5-on-1-il]-asetohidrazid] bileşiği elde edilmiş ve bazı reaksiyonları incelenerek yeni heterosiklik bileşikler elde edilmiştir. Bu amaçla ilk olarak dihidrazidin 4-metoksibenzaldehid, 3-hidroksibenzaldehid, salisilaldehid ve metil 4-formilbenzoat ile reaksiyonlarından sırasıyla imin tipi 1-(4-metoksibenzilidenhidrazinokarbonilmetil)-3-p-klorobenzil-4-[4-(4-metoksibenzilidenhidrazinokarbonilmetoksi)benzilidenamino]-4,5-dihidro-1H-1,2,4-triazol-5-on, 1-(3-hidroksibenzilidenhidrazinokarbonilmetil)-3-p-klorobenzil-4-[4-(3-hidroksibenzilidenhidrazinokarbonilmetoksi)benzilidenamino]-4,5-dihidro-1H-1,2,4-triazol-5-on, 1-(2-hidroksibenzilidenhidrazinokarbonilmetil)-3-p-klorobenzil-4-[4-(2-hidroksibenzilidenhidrazinokarbonilmetoksi)benzilidenamino]-4,5-dihidro-1H-1,2,4-triazol-5-on ve 1-(4-metoksikarbonilbenzilidenhidrazinokarbonil-metil)-3-p-klorobenzil-4-[4-(4-metoksi-karbonilbenzilidenhidrazinokarbonilmetoksi)-benzilidenamino]-4,5-dihidro-1H-1,2,4-triazol-5-on bileşikleri sentezlenmiştir. Ayrıca, 2,5-dimetoksitetrahidrofuran, suksinik anhidrid ve formik asit ile de reaksiyonları incelenmiş ve sırasıyla yeni iki adet pirrol halkasının oluşturulduğu 1-[(pirrol-1-il)aminokarbonilmetil]-3-p-klorobenzil-4-[4-(pirrol-1-il)-aminokarbonilmetoksi-benzilidenamino]-4,5-dihidro-1H-1,2,4-triazol-5-on, iki adet yeni suksinimid halkasının oluşturulduğu 1-(suksinimidokarbamoilmetil)-3-p-klorobenzil-4-(4-suksinimido-karbamoilmetoksibenzilidenamino)-4,5-dihidro-1H-1,2,4-triazol-5-on ve 1-(N-formilaminokarbamoilmetil)-3-p-klorobenzil-4-[4-(N-formilaminokarbamoilmetoksi-benzilidenamino)]-4,5-dihidro-1H-1,2,4-triazol-5-on bileşikleri elde edilmiştir. Çalışmada sentezlenen yeni dihidrazidin fenilizotiyosiyanat ile reaksiyonundan elde edilen 1-(feniltiyoüreidokarbamoilmetil)-3-p-klorobenzil-4-[4-(feniltiyoüreido-karbamoilmetoksibenzilidenamino)]-4,5-dihidro-1H-1,2,4-triazol-5-on bileşiğinin seyreltik sodyum hidroksit ile kaynatılmasında iki adet 4,5-dihidro-1H-1,2,4-triazol-5-tion halkası içeren 1-(4-fenil-4,5-dihidro-1H-1,2,4-triazol-5-tion-3-il)metil-3-p-klorobenzil-4-[4-(4-fenil-4,5-dihidro-1H-1,2,4-triazol-5-tion-3-il)metoksibenziliden-amino]-4,5-dihidro-1H-1,2,4-triazol-5-on bileşiği, derişik H2SO4 ile muamelesinden ise iki adet 1,3,4-tiyadiazol halkası içeren 1-(5-anilino-1,3,4-tiyadiazol-2-il)metil-3-p-klorobenzil-4-[4-(5-anilino-1,3,4-tiyadiazol-2-il)metoksibenzilidenamino]-4,5-dihidro-1H-1,2,4-triazol-5-on bileşiği elde edilmiştir. Dihidrazidin son reaksiyonunda ise potasyum hidroksitli ortamda CS2 ile reaksiyonu incelenmiş ve iki adet 4,5-dihidro-1,3,4-oksadiazol-5-tion halkası içeren 1-(4,5-dihidro-1,3,4-oksadiazol-5-tion-2-il)metil-3-p-klorobenzil-4-[4-(4,5-dihidro-1,3,4-oksadiazol-5-tion-2-il)metoksibenziliden-amino]-4,5-dihidro-1H-1,2,4-triazol-5-on bileşiği sentezlenmiştir.Çalışmanın ikinci bölümünde 3'ü benzaldehid türevi olmak üzere sentezlenen 61 yeni bileşiğin yapıları IR, 1H-NMR ve 13C-NMR spektroskopik yöntemleri ile mikroanaliz kullanılarak aydınlatılmıştır. Ayrıca, 61 bileşiğin UV spektrumları alınmış, ? max değerlerine karşın gelen ? değerleri hesaplanmıştır.Çalışmanın üçüncü bölümünde sentezlenen 58 yeni bileşiğin üç farklı yöntemle (indirgeme gücü, serbest radikal giderme aktivitesi ve metal şelat aktivitesi) antioksidan aktiviteleri incelenmiş, grafikleri çizilmiş ve sonuçlar yorumlanmıştır.Tez kapsamında son olarak 4,5-dihidro-1H-1,2,4-triazol-5-on halkasında zayıf asidik özellik gösteren N-H grubu içeren 24 yeni bileşiğin izopropil alkol, tert-butil alkol, N,N-dimetilformamid ve aseton susuz çözücülerinde tetrabutilamonyumhidroksit ile potansiyometrik olarak titrasyonları yapılarak yarı nötralizasyon metodu ile yarı nötralizasyon potansiyelleri ve karşın olan pKa değerleri tayin edilmiştir. Bu bileşiklerin asitliği üzerine çözücü etkisi ve molekül yapısının etkisi tartışılmıştır.Anahtar Kelimeler 4,5-Dihidro-1H-1,2,4-triazol-5-on, hidrazid, 1,3,4-tiyadiazol, 1,3,4-oksadiazol, Schiff bazı, asetillendirme, antioksidan, pKa

Abstract:
In this study, ten 3-alkyl(aryl)-4-amino-4,5-dihydro-1H-1,2,4-triazol-5-one compounds were synthesized. Their some reactions had been examined and new heterocyclic compounds were obtained.The study was planned as four parts. The first part contains that synthesis of new compounds. In this thesis, the synthesized 3-alkyl(aryl)-4-(3-methoxy-4-phenylacetoxy benzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-one, 3-alkyl(aryl)-4-[3-methoxy-4-(4-methylbenzoxy)benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one and 1,3,5-tri-{2-methoxy-4-[(3-alkyl/aryl-4,5-dihydro-1H-1,2,4-triazol-5-on-4-yl)-azometin]-phenoxy-carbonyl}-benzene compounds from 3-methoxy-4-phenylacetoxy-benzaldehyde, 3-methoxy-4-(4-methylbenzoxy)-benzaldehyde and 1,3,5-tri-(2-methoxy-4-formylphenoxycarbonyl)-benzene with the reactions of 3-alkyl(aryl)-4-amino-4,5-dihydro-1H-1,2,4-triazol-5-one compounds were obtained. Moreover, N-acetylation reactions of these compounds were investigated. In the second part of the synthesis of the study, 1-benzyl-3-alkyl(aryl)-4-(3-methoxy-4-phenylmethoxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones and 1-phenacyl-3-alkyl(aryl)-4-(3-methoxy-4-benzoylmethoxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones were obtained from the reactions of 3-alkyl(aryl)-4-(3-methoxy-4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones with benzyl bromide and phenacyl bromide in medium of sodium ethoxide. In these reactions, 1-phenacyl-3-p-chlorobenzyl-4-(3-methoxy-4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-one was obtained as different from the reaction of 3-p-chlorobenzyl-4-(3-methoxy-4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-one with phenacyl bromide. The last part of study, the new dihydrazide compound namely 1-hydrazinocarbonylmethyl-3-p-chlorobenzyl-4-(4-hydrazinocarbonylmethoxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-one [3-p-chlorobenzyl-4-(4-hydrazinocarbonylmethoxybenzylidenamino)]-4,5-dihydro-1H-1,2,4-triazol-5-one-1-yl]-acetohydrazide] was obtained from the reaction of hydrazine hydrate with 1-ethoxycarbonylmethyl-3-p-chlorobenzyl-4-(4-ethoxycarbonylmethoxy-benzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-one [ethyl 3-p-chlorobenzyl-4-(4-ethoxycarbonylmethoxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-one-1-yl)-acetate] that was obtained from the reaction of 3-p-chlorobenzyl-4-(3-methoxy-4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-one with ethyl bromoacetate in medium of sodium ethoxide and some reactions of dihydrazide synthesized were investigated; new heterocyclic compounds were obtained. With this intend, first of all, imine type of compounds that 1-(4-methoxybenzylidenhydrazinocarbonylmethyl)-3-p-chlorobenzyl-4-[4-(4-methoxy-benzylidenhydrazinocarbonylmethoxy)benzyliden-amino]-4,5-dihydro-1H-1,2,4-triazol-5-one, 1-(3-hyroxybenzylidenhydrazinocarbonyl-methyl)-3-p-chlorobenzyl-4-[4-(3-hydroxybenzylidenhydrazinocarbonylmethoxy)-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one, 1-(2-hyroxybenzyliden-hydrazinocarbonylmethyl)-3-p-chlorobenzyl-4-[4-(2-hydroxybenzylidenhydrazino-carbonylmethoxy)benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one and 1-(4-methoxybenzylidenhydrazinocarbonylmethyl)-3-p-chlorobenzyl-4-[4-(4-methoxy-benzylidenhydrazinocarbonylmethoxy)benzyliden-amino]-4,5-dihydro-1H-1,2,4-triazol-5-one were synthesized from the reactions of dihydrazide with 4-methoxybenzaldehyde, 3-hydroxybenzaldehyde, salicilaldehyde and methyl 4-formylbenzoate, respectively. Moreover, the reactions of dihydrazide with 2,5-dimethoxytetrahydrofuran, succinic anhydride and formic acid were investigated and 1-[(pirrol-1-yl)aminocarbonylmethyl]-3-p-chlorobenzyl-4-[4-(pirrol-1-yl)-aminocarbonylmethoxybenzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one, 1-(succinimidocarbamoylmethyl)-3-p-chlorobenzyl-4-(4-succinimidocarbamoylmethoxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-one and 1-(N-formylaminocarbamoylmethyl)-3-p-chlorobenzyl-4-[4-(N-formylamino-carbamoylmethoxy-benzylidenamino)]-4,5-dihydro-1H-1,2,4-triazol-5-one were obtained, respectively. In the study, 1-phenylthioureidocarbamoylmethyl-3-p-chlorobenzyl-4-[4-(phenylthioureidocarbamoylmethoxybenzylidenamino)]-4,5-dihydro-1H-1,2,4-triazol-5-one was obtained from the reaction of new dihydrazide with phenylisothiocyanate and then this compound was refluxed with diluted sodium hydroxide for synthesis 1-(4-phenyl-4,5-dihydro-1H-1,2,4-triazol-5thione-3-yl)methyl-3-p-chlorobenzyl-4-[4-(4-phenyl-4,5-dihydro-1H-1,2,4-triazol-5-thione-3-yl)methoxy-benzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one that contains two 4,5-dihydro-1H-1,2,4-triazol-5-thione ring. 1-(5-anilino-1,3,4-thiadiazole-2-yl)methyl-3-p-chlorobenzyl-4-[4-(5-anilino-1,3,4-thiadiazole-2-yl)methoxybenzyliden-amino]-4,5-dihdro-1H-1,2,4-triazol-5-one that contains 1,3,4-thiadiazole rings was synthesized from the reaction of 1-phenylthioureidocarbamoylmethyl-3-p-chlorobenzyl-4-[4-(phenylthioureidocarbamoylmethoxybenzylidenamino)]-4,5-dihydro-1H-1,2,4-triazol-5-one with concentrated H2SO4. At the last reaction of dihydrazide, it was investigated the reaction with CS2 in medium of potassium hydroxide and 1-(4,5-dihydro-1,3,4-oxadiazole-5-thione-2-yl)methyl-3-p-chlorobenzyl-4-[4-(4,5-dihydro-1,3,4-oxadiazole-5-thione-2-yl)methoxybenzylidenamino]-4,5-dihydro-1H-1,2,4-triazol-5-one that contains two 4,5-dihydro-1,3,4-oxadiazole-5-thione rings was synthesized.In the second part of the study, the structures of to be above to 3 of these compounds are benzaldehyde derivatives, new 61 compounds were characterized by using IR, 1H-NMR, 13C-NMR spectra, and microanalyses. Furthermore, UV spectrums of 61 new compounds were investigated and ?max and ? values were calculated.In third part of the study, new 58 compounds synthesized were analyzed for their in vitro antioxidant activities in three different methods (reducing power, free radical scavenging and metal chelating activity), were drawn their graphs and their results were interpreted.At end of the study, 24 compounds were titrated potentiometrically with tetrabutylammonium hydroxide in non-aqueous solvents (isopropyl alcohol, tert-butyl alcohol, N,N-dimethylformamide and acetone) because of the weak acidic properties of 4,5-dihydro-1H-1,2,4-triazol-5-one ring. The pKa values were determined by the half-neutralization method for all cases. The effects of solvents and molecular structure upon acidity were investigated and the results were discussed.Key Words 4,5-dihydro-1H-1,2,4-triazol-5-one, hydrazide, 1,3,4-thiadiazole, 1,3,4-oxadiazole, Schiff Base, acetylation, antioxidant, pKa