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Synthesis of Piperine Derivatives Mardiana Binti Muhamad Isa

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Synthesis of Piperine Derivatives Mardiana Binti Muhamad Isa SYNTHESIS OF PIPERINE DERIVATIVES MARDIANA BINTI MUHAMAD ISA UNIVERSITI TEKNOLOGI MALAYSIA SYNTHESIS OF PIPERINE DERIVATIVES MARDIANA BINTI MUHAMAD ISA A thesis submitted in fulfilment of the requirements for the award of the degree of Master of Science (Chemistry) Faculty of Science UniversitiTeknologi Malaysia AUGUST 2012 iv Special dedication to my:- cherished husband and children; Mohamed Syahrani b. Mat Nor HafezulRahman b. Mohamed Syahrani Abdullah Azam b. Mohamed Syahrani adoring family and family-in-law; and my trustworthy friends… v ACKNOWLEDGEMENT In the name of Allah, the Most Gracious and the Most Merciful. Alhamdulillah, all praises to Allah for the strengths and His blessings in finalizing this thesis. After all the efforts, it is time for me to express my deepest gratitude to my beloved and supportive husband and children for their endless love, prayers and encouragement. Notto forgetmy family and family-in-law, thank you for all the divine support. I would also love to express my special appreciation to my supervisor, Assoc. Prof. Dr. Farediah Ahmad, for all her kindness, supervision and endless assistance. With her constructive comments and helps, alhamdulillah I finally manage to complete this thesis. To Prof. Dr. Wan Azlina Ahmad as my program coordinator, thank you for all the advice, aid and moral support that had given me strength to complete this project. My sincere appreciation also goes to all the lecturers, officers and staffs of Science Faculty for their great cooperation and assistance throughout the lab process. Last but not least, I would like to express my special thanks to my supportive colleagues in MPKO (I and II) and all my ever dearest friends, thank you for everything. Again from me, thank you to all those who directly or indirectly given me this possibility to complete this thesis. May Allah bless all of you. vi ABSTRACT The berries of black pepper (P. nigrum) are well known for its pungent smell and biting taste. Piperine which is one of the major amide present in P. nigrum contributes to the medicinal properties of the species. Extraction of the berries through maceration process followed by isolation of piperine via treatment with ethanolic potassium hydroxide successfully produced piperine (5-(1,3-benzodioxol- 5-yl)-1-(1-piperidinyl)-2,4-pentadien-1-one). Several chemical modifications have been carried out to derivatize piperine. Acetal cleavage has afforded 5-(3,4- dihydroxyphenyl)-1-(1-piperidinyl)-2,4-pentadien-1-one. Basic hydrolysis of piperine then afforded piperic acid (5-(1,3-benzodioxol-5-yl)-2,4-pentadienoic acid) which had been used as the precursor to synthesize an aliphatic amide (5-(1,3- benzodioxol-5-yl)-1-(n-butylamine)-2,4-pentadien-1-one), an ester (5-(1,3- benzodioxol-5-yl)ethyl-2,4-pentadienoate) and an acid (1,3-benzodioxol-1-yl)- methanoic acid). The pure piperine and derivatives were characterized by using infrared spectroscopy (IR), nuclear magnetic resonance (NMR) and mass spectrometry (MS). The screening for antimicrobial properties of the compounds were also carried out by using disc diffusion, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) methods against Gram- positive bacteria (Bacillus subtilis and Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa). Piperine and all derivatives were found to be active towards Gram-positive bacteria with MIC value ranging from 225-900 µg/mL. vii ABSTRAK Bijiladahitam (P. nigrum) adalahdikenaliumumsebagaiherba yang mempunyaibau yang tajamdan rasa yang pahit.Piperinaadalahsalahsatuamidapenting yang wujud di dalamP. nigrum yang didapatimempunyaiciri- ciriperubatan.PengekstrakanbijiP. nigrumsecararendamandenganpelarutdiikutidenganpengasinganpiperinamelaluitinda kbalasdengankaliumhidroksidaberalkoholtelahberjayamenghasilkanpiperina (5-(1,3- benzodioksol-5-il)-1-(1-piperidinil)-2,4-pentadien-1-on). Beberapatindakbalaspengubahsuaiankimiajugatelahdijalankanuntukmenghasilkanter bitanpiperina.Tindakbalaspemutusankumpulanasetaltelahmenghasilkansebatian5- (3,4-dihidroksifenil)-1-(1-piperidinil)-2,4-pentadien-1-on. Hidrolisisberalkalikeataspiperina pula berjayamenghasilkanasidpiperik (asid 5-(1,3- benzodioksol-5-il)-2,4-pentadienoik) yang seterusnyatelahdigunakansebagaisebatianpemulauntukmensintesisamidaberantailurus (5-(1,3-benzodioksol-5-il)-1-(n-butilamina)-2,4-pentadien-1-on), ester (5-(1,3- benzodioksol-5-il)etil-2,4-pentadienoat) danasid (asid 1,3-benzodioksol-1-il)- metanoik). Sebatianpiperinatulendansebatianterbitantelahdicirikandenganmenggunakankaedahsp ektroskopiinframerah (IM), resonans magnet nukleus (RMN) danspektrometrijisim (SJ).Saringanantimikrobkeatassemuasebatiantelahdijalankanmenggunakankaedahpe mbaurancakera, kepekatanperencatan minimum (KPM) dankepekatanbakteria minimum (KBM) keatasbakteria Gram-positif(Bacillus subtilis danStaphylococcus aureus) dan Gram-negatif (Escherichia coli danPseudomonas aeruginosa).Piperinadankesemuasebatianterbitandidapatiaktifterhadapbakteria Gram-positifdengannilai KBM dalamjulat 225-900 µg/mL. viii TABLE OF CONTENTS CHAPTER TITLE PAGE SUPERVISOR’S DECLARATION ii AUTHOR’S DECLARATION iii DEDICATION iv ACKNOWLEDGEMENT v ABSTRACT vi ABSTRAK vii TABLE OF CONTENTS viii LIST OF TABLES xii LIST OF SCHEMES xiii LIST OF FIGURES xiv LIST OF ABBREVIATIONS xv LIST OF APPENDICES xviii 1 INTRODUCTION 1.1 Natural Plants and their Benefits 1 1.2 Background of Study 3 1.3 Principles of Organic Synthesis 3 1.4 Black Pepper (P. nigrum) 5 1.5 Problem Statement 6 1.6 Objectives of Study 6 1.7 Scope of Study 6 1.8 Flow Chart of Studies 8 ix 2 LITERATURE REVIEW 2.1 The Piperaceae Family 9 2.2 Botany and Distribution of Piper 10 2.3 Chemical Constituents of P. nigrum (Black Pepper) 11 2.4 Previous Study on Piperine (1) 14 2.4.1 Extraction and Isolation of Piperine (1) from P. Nigrum 14 2.4.2 Synthesis of Piperine (1) 15 2.4.3 Structural Modifications of Piperine (1) 17 3 RESULTS AND DISCUSSION 3.1 Introduction 23 3.2 Piperine (1) 23 3.3 Synthesis of Derivatives 25 3.3.15-(3,4-dihydroxyphenyl)-1-(1- piperidinyl)-2,4-pentadien-1-one (31) 27 3.3.2Reduction and Epoxidation of Piperine (1) 28 3.3.3 Piperic Acid (30) 29 3.3.4 5-(1,3-benzodioxol-5-yl)-1-(n- butylamine)-2,4-pentadien-1-one (52) 31 3.3.55-(1,3-benzodioxol-5-yl)ethyl-2,4- pentadienoate(53) 35 3.3.6(1,3-benzodioxol-1-yl)-methanoic acid (54) 36 3.4 Antibacterial Test 38 3.4.1Disc Diffusion Method 38 3.4.2 Minimum Inhibitory Concentration (MIC) Method and Minimum Bactericidal Concentration (MBC) Method 39 x 4 EXPERIMENTAL 4.1 Material and Instrumentation 42 4.2 Solvents and Chemicals 42 4.2.1 Preparation of TLC Spraying Agent p- anisaldehyde 43 4.3 P. nigrum Seeds 43 4.4 Extraction and Isolation of Piperine (1) 44 4.5 Chemical Reactions of Piperine (1) 44 4.5.1 Acetal Cleavage of Piperine (1) 44 4.5.2Reduction of Piperine (1) 45 4.5.3Epoxidation of Piperine (1) 45 4.5.4 Base Hydrolysis of Piperine (1) 46 4.5.5 Amide (52) 46 4.5.6 Ester (53) 47 4.5.7 Acid (54) 48 4.6 Antibacterial Test 48 4.6.1 Preparation of Nutrient Agar 49 4.6.2 Preparation of Agar Plate 49 4.6.3 Preparation of McFarland Standard Solution 49 4.6.4 Preparation of Bacterial Stock 50 4.6.5 Disc Diffusion Method 50 4.6.6 Minimum Inhibitory Concentration (MIC) Method 51 4.6.7 Minimum Bactericidal Concentration (MBC) Method 52 5 CONCLUSION AND RECOMMENDATIONS 5.1 Isolation of Piperine (1) 54 5.2 Chemical Reactions of Piperine (1) 54 5.3 Antibacterial Studies 55 5.4 Recommendations 56 xi REFERENCES 57 APPENDICES 62 xii LIST OF TABLES TABLE NO. TITLE PAGE 1.1 Various medicinal properties of spices 2 1.2 Classification of reactions and their subdivision reactions 4 2.1 Summarizes on the uses of Piper from Peninsular Malaysia 11 3.1 Spectral data of compound (52) as compared with the literature [36] 34 3.2 Diameter of bacterial inhibition zone by samples 39 3.3 MIC and MBC results 40 4.1 Results for MIC 52 4.2 Results for MBC 53 5.1 Physical characteristics of piperine (1) derivatives 55 xiii LIST OF SCHEMES SCHEME TITLE PAGE NO. 2.1 Synthesis of piperine (1) from piperonal(23) 16 2.2 Synthesis of piperine (1) via modification from Wittig and Horner-Wadsworth-Emmons reactions 17 2.3 Hydrolysis of (1) to piperic acid (30) 18 2.4 Piperine (1) transformations via acetal cleavage, methylation and selective reduction 19 2.5 Synthesis of piperine conjugatesviahydrolysis of piperine(1), reaction withamino acid methyl esters and modification to carboxylgroup and reduced double bonds 21 2.6 Piperine (1)modifications viaregioselective reduction of the α- and β- double bond 22 xiv LIST OF FIGURES FIGURE TITLE PAGE NO. 1.1 P. nigrum tree 5 1.2 P. nigrum fruits before ripened 5 3.1 Derivatives of (1) and (30) 26 3.2 Mechanism of acetal cleavage of Piperine (1) 27 3.3 Mechanism of basic hydrolysis of piperine (1) 30 3.4 Fragmentation pattern of (30) 31 3.5 The formation of amides through the heating of ammonium salts of carboxylic acids 32 3.6 Mechanism of production of amide (52) from piperic acid (30) 33 3.7 The Fischer esterification reaction to form ester 35 3.8 Mechanism for the formation of ester (53) from piperic acid (30) 35 3.9 Oxidation reaction of piperic acid (30) 37 4.1 Arrangement of discs in disc diffusion method 51 xv LIST OF ABBREVIATIONS mg milligram mL millilitre µL microlitre µg/mL microgram per mililitre ppm part per million m.p melting point Rf retention factor TLC Thin Layer Chromatography UV Ultraviolet IR Infrared FTIR Fourier Transform Infrared Spectroscopy NMR Nuclear Magnetic Resonance MS Mass
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