Publication: P(HEMA)-SO₃H katalizli Biginelli reaksiyonu
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Berthe, Mamadou Lamine
Advisor
Ölmez, Nevin Arıkan
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Bursa Uludağ Üniversitesi
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Abstract
Dihidropirimidinonlar (DHPM)'ler farmasötik ve medikal kimyada çok önemli bileşiklerdir. Dihidropirimidinonların sentezi için en yaygın kullanılan yöntem, Biginelli reaksiyonu olarak bilinen, etil asetoasetat, aril aldehit ve üre (veya tiyoüre)’ nin multikomponent reaksiyonudur. Asidik koşullar gerektiren klasik Biginelli reaksiyonunda genellikle H2SO4, HCl, HF gibi sıvı mineral asitler kullanılır. Fakat bunların birçok dezavantajından dolayı son yıllarda, polimer destekli asit katalizörler, korozif ve zehirli olmaması, katalitik miktarlarda kullanılarak yüksek verimlerle ürün elde edilmesi, basit süzme veya santrifüjleme ile reaksiyon karışımından kolaylıkla ayrılması, geniş bir sıcaklık ve basınç aralığını tolere etmesi, ucuz ve tekrar kullanılabilirliğinin yüksek olması gibi avantajları sebebiyle dikkat çekmektedir. Bu çalışmada, heterojen katı asit katalizörü olarak poli(hidroksietil metakrilat) [P(HEMA)] mikroküre destekli sülfürik asit [P(HEMA)-SO3H] hazırlanarak Biginelli reaksiyonunda katalitik aktivitesi araştırılmıştır. Sentezlenen P(HEMA)-SO3H katalizörü FTIR, SEM, BET ve EDX analizleri ile karakterize edilmiştir. Mikrokürelerin spesifik yüzey alanı ve gözenek hacminin sırasıyla 26,61 m2 /g ve 0,0392 cm3 /g, gözenek boyutunun ise 9,43-63,37 A° aralığında olduğu belirlenmiştir. P(HEMA)-SO3H katalizörünün asitliği, standartlaştırılmış NaOH çözeltisi ile titrasyonu sonucunda 8,09 ± 0,09 mmol H+ /g P(HEMA)-SO3H olarak belirlenmiştir. Katalizörün katalitik aktivitesinin belirlenmesi amacıyla, model olarak seçilen Biginelli reaksiyonunda katalizör miktarı, sıcaklık ve çözücü parametreleri araştırılarak reaksiyon koşulları optimize edilmiştir. En uygun reaksiyon koşulu, çözücüsüz ortamda % 40 mol katalizör oranı ve 60 °C olarak belirlenmiştir. Optimize edilen reaksiyon koşullarında yirmi adet 3,4- dihidropirimidinon/tiyon yüksek verimlerle sentezlenmiştir. Sentezlenen bileşikler, erime noktası, 1HNMR ve 13CNMR verileri ile karakterize edilmiştir. P(HEMA)-SO3H katalizörünün yeniden kullanılabilirliği de araştırılarak katalitik aktivitesinde belirgin bir azalma olmaksızın dört kez yeniden kullanılabileceği ortaya konmuştur.
Dihydropyrimidinones (DHPMs) are very important compounds in pharmaceutical and medicinal chemistry. The known most widely used method for the synthesis of dihydropyrimidinones is the Biginelli reaction, which is a multicomponent reaction of ethyl acetoacetate, aryl aldehyde and urea (or thiourea). Since the classical Biginelli reaction requires acidic conditions, liquid mineral acids such as H2SO4, HCl, HF are usually used. However, due to many disadvantages of mineral acids, in recent years, polymer-supported acid catalysts have drawn a particular attention. They provide advantages such as being non-corrosive and non-toxic, obtaining high yields of product using catalytic quantities, easy separation from the reaction mixture by simple filtration or centrifugation, tolerating a wide range of temperatures and pressures, being inexpensive and highly reusable. In this study, poly(hydroxyethyl methacrylate) [P(HEMA)] microsphere supported sulfuric acid [P(HEMA)-SO3H] was prepared as a heterogeneous solid acid catalyst and its catalytic activity was investigated in Biginelli reaction. The synthesized P(HEMA)- SO3H catalyst was characterized by FTIR, SEM, BET and EDX analysis. It was determined that the specific surface area and pore volume of the microspheres were 26,61 m2 /g and 0,0392 cm3 /g, respectively, and the pore size was in the range of 9,43-63,37 A°. The acidity of P(HEMA)-SO3H catalyst was determined as 8,09 ± 0,09 mmol H+ /g P(HEMA)-SO3H by titration with standardized NaOH solution. In order to determine the catalytic activity of the catalyst, the reaction conditions were optimized by investigating the amount of catalyst, temperature and solvent parameters in the Biginelli reaction selected as a model. The optimum reaction condition was determined as 40 mol% catalyst ratio and 60 °C in solvent-free medium. Twenty 3,4-dihydropyrimidinones/thiones were synthesized in high yields under the optimized reaction conditions. The synthesized compounds were characterized by melting point, 1HNMR and 13CNMR data. The reusability of the P(HEMA)-SO3H catalyst was also investigated and it was demonstrated that it can be reused four times without any significant decrease in its catalytic activity.
Dihydropyrimidinones (DHPMs) are very important compounds in pharmaceutical and medicinal chemistry. The known most widely used method for the synthesis of dihydropyrimidinones is the Biginelli reaction, which is a multicomponent reaction of ethyl acetoacetate, aryl aldehyde and urea (or thiourea). Since the classical Biginelli reaction requires acidic conditions, liquid mineral acids such as H2SO4, HCl, HF are usually used. However, due to many disadvantages of mineral acids, in recent years, polymer-supported acid catalysts have drawn a particular attention. They provide advantages such as being non-corrosive and non-toxic, obtaining high yields of product using catalytic quantities, easy separation from the reaction mixture by simple filtration or centrifugation, tolerating a wide range of temperatures and pressures, being inexpensive and highly reusable. In this study, poly(hydroxyethyl methacrylate) [P(HEMA)] microsphere supported sulfuric acid [P(HEMA)-SO3H] was prepared as a heterogeneous solid acid catalyst and its catalytic activity was investigated in Biginelli reaction. The synthesized P(HEMA)- SO3H catalyst was characterized by FTIR, SEM, BET and EDX analysis. It was determined that the specific surface area and pore volume of the microspheres were 26,61 m2 /g and 0,0392 cm3 /g, respectively, and the pore size was in the range of 9,43-63,37 A°. The acidity of P(HEMA)-SO3H catalyst was determined as 8,09 ± 0,09 mmol H+ /g P(HEMA)-SO3H by titration with standardized NaOH solution. In order to determine the catalytic activity of the catalyst, the reaction conditions were optimized by investigating the amount of catalyst, temperature and solvent parameters in the Biginelli reaction selected as a model. The optimum reaction condition was determined as 40 mol% catalyst ratio and 60 °C in solvent-free medium. Twenty 3,4-dihydropyrimidinones/thiones were synthesized in high yields under the optimized reaction conditions. The synthesized compounds were characterized by melting point, 1HNMR and 13CNMR data. The reusability of the P(HEMA)-SO3H catalyst was also investigated and it was demonstrated that it can be reused four times without any significant decrease in its catalytic activity.
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Keywords
Multikomponent reaksiyonlar, Biginelli reaksiyonu, Dihidropirimidinonlar (DHPMs), Polimer destekli asit katalizörler, P(HEMA) mikroküreler, Multicomponent reactions, Biginelli reaction, Dihydropyrimidinones (DHPMs), Polymer supported acid catalysts, P(HEMA) microspheres