DOCSLIB.ORG

The Attempted Synthesis of Carba-Nicotinic Acid Mononucleotide

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Attempted Synthesis of Carba-Nicotinic Acid Mononucleotide A Thesis Entitled The Attempted Synthesis of Carba-Nicotinic Acid Mononucleotide Methyl Ester using the Zincke Reaction By Peng Zhao Submitted to the Graduate Faculty as partial fulfillment of the requirement for The Master of Science Degree in Medicinal Chemistry James T. Slama, Ph.D., Committee Chair L.M. Viranga Tillekeratne, D.Phil., Committee Member Isaac T. Schiefer, Ph.D., Committee Member Amanda Bryant-Friedrich, Ph.D. rer. Nat., Dean College of Graduate Studies The University of Toledo May 2017 Copyright 2017, Peng Zhao This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An abstract of The Attempted Synthesis of Carba-Nicotinic-Acid Mononucleotide Methyl Ester using the Zincke Reation Peng Zhao Submitted to the Graduate Faculty as partial fulfillment of the requirement for The Master of Science Degree in Medicinal Chemistry The University of Toledo May 2017 According to the retrosynthetic analysis, the carba-nicotinic acid mononucleotide methyl ester can be synthesized from a nucleoside made using a primary amine and a Zincke salt by the Zincke reaction. The primary amine which was the cyclopentane analog of 1-aminoribose was synthesized following the procedure described by Cermak and Vince in 1981 starting from the Vince lactam. The pyridinium part was synthesized as a Zincke salt. However carba-nicotinic acid mononucleotide methyl ester cannot be synthesized using this procedure due to the unanticipated high reactivity of the nicotinic acid esters with primary amine during the Zincke reaction. We found that pyridinium-3-carboxylic esters reacted rapidly with amines resulting in the formation of amids. A series of Zincke reaction were performed to study the Zincke reaction. Even the most sterically hindered protecting group tert-butyl ester could not prevent the formation of nicotinamide. iii Acknowledgments I am deeply grateful to my venerable advisor Dr. James T. Slama, for his valuable academic guidance, continued encouragement and considerate understanding. Without his enlightening instruction, impressive kindness and patience, I could not have completed my researches and my degree. His knowledge and guidance enlightens me not only in this period of study but also in my future study and my future life. I also would like to thank him for his help and support in many other ways during my study at Toledo. I would also like to thank all my teachers and all professors in the College of Pharmacy and Pharmaceutical Sciences who have helped me to develop the fundamental and essential academic competence. Last but not least, I'd like to thank my families and all my friends for their encouragement and support. Peng Zhao The University of Toledo May 2017 iv Table of Contents Abstract …………………….………………………………………………………...iii Acknowledgments.………………………………………………………………….iv Table of Contents……………………………………………………………………v List of Figures .....……………….……………………………………………….vi List of Abbreviations………………….…………………………………………….vii I. Introduction….……………..…………….………………………………………….1 II. Results and discussion………………….…………………………………………10 III. Experimental section……………..………………………………………………16 References…………………..………..……………………………………………29 Appendices: 1H-NMR and 13C-NMR spectra of compounds in Experimental Section………………………………………………………………………...…...…32 v List of Figures Figure 1. Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP).…...…………..1 Figure 2. Nicotinamide Adenine Dinucleotide Phosphate (NADP)…..……...…...…..2 Figure 3. Synthesis of NAADP analogs using the enzyme catalyzed pyridine base-exchange reaction…………….………….……….….…...……….…..5 Figure 4. Preparation of NAADP and NAADP derivatives using NAD kinase and cyclic ADP-ribose synthetase……………………………….….......……....6 Figure 5. Carba-Nicotinc Acid Adenine Dinucleotide Phosphate (NAADP)…......…..6 Figure 6. Retrosynthetic analysis of carba-nicotinic acid mononucleotide methyl ester...............................................................................................................7 Figure 7. Zincke reaction……...……………………….................…..….……..……..8 Figure 8. Propose synthesis of 6 from the Vince lactam (8)..........................................8 Figure 9. Propose thesis of 4 by Zincke reaction followed by a selective phosphorylation………………………………………………….…...…….9 Figure 10. Zincke salt synthesis……...…………………………………...………….11 Figure 11. Zincke reaction using reagents 6 and 7…………………….….…...…….12 Figure 12. Zincke reaction to prove the activity of nicotinate……….……..………..13 Figure 13. Total synthesis of 17…………...………………………….….…………..16 Figure 14. The study of the Zincke reaction………………………..………………..17 vi List of Abbreviations cADPR…………Cyclic adenosine diphosphate ribose DI water………..Deionized water DMAP………….Dimethylamino pyridine DMF……………N,N-dimethylformamide DMP……………2,2-Dimethoxypropane DMSO………….Dimethyl sulfoxide ER……………...Endoplasmic reticulum IP3……………...Inositol 1,4,5-trisphosphate NAADP………...Nicotinic acid adenine dinucleotide phosphate NADP…………..Nicotinamide adenine dinucleotide phosphate NMN……………Nicotinamide mononucleotide NMO……………N-Methylmorpholine N-oxide OsO4……………Osmium tetroxide PTSA…………...p-Toluene sulfonic acid monohydrate SR………………Sarcoplasmic reticulum TFA…………….Trifuoroacetic acid THF…………….Tetrahydrofuran TLC…………….Thin-layer chromatography vii Chapter One Introduction Nicotinic acid adenine dinucleotide phosphate (NAADP, 1) (Figure 1) is an intracellular second messenger for calcium ion release. NAADP was first identified as a compound that has a potent intracellular calcium ion mobilizing effect in sea urchin eggs (Lee & Aarhus, 1995), and later NAADP was shown to have the same effect in mammals (Cancela et al., 1999). 3 nicotinic acid mononucleotide half adenosine-2′,5′-diphosphate half 2′ 1 Figure 1. Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP, 1) There are three major calcium ion mobilizing messengers (Bootman, et al., 2002). They are inositol 1,4,5-trisphosphate (IP3), cyclic adenosine diphosphate ribose (cADPR) and NAADP. IP3 was discovered 1983 and it was shown to be capable of releasing calcium ion from non-mitochondrial stores in pancreatic acinar cells (Streb, et al., 1983). IP3 mediates calcium ion release by binding to IP3 receptor on a ligand-gated calcium channel on endoplasmic reticulum (ER) which releases calcium 1 ion into the cytoplasm (Barrett, et al., 2009). Studies in sea urchin eggs showed that the pyridine nucleotides, NAD and NADP (2) could mediate calcium ion release from Figure 2. Nicotinamide Adenine Dinucleotide Phosphate (NADP, 2) membranous stores which are different from IP3 (Clapper, et al., 1987). Further studies showed that the effect was caused by the NAD metabolite: cyclic adenosine diphosphate ribose (cADPR) (Lee, et al., 1989) and the NADP metabolite nicotinic acid dinucleotide phosphate (NAADP) (Lee & Aarhus, 1995). IP3 and cADPR were shown to act on the two know ER calcium ion release channels, IP3Rs (IP3 receptors) and RyRs (ryanodine receptors) (Galione, et al., 1991) respectively. NAADP was initially isolated and identified as a contaminant in NADP, and was shown to release calcium ion from intracellular vesicles from sea urchin eggs (Clapper, et al., 1987). The difference between NAADP and NADP is that the nicotinamide base of the NADP is replaced by nicotinic acid in NAADP. This slight difference in molecular structure is essential for calcium ion releasing activity and 2 produces a high degree of discrimination in biological activities. NAADP was found to release calcium ion by a pharmacologically distinct mechanism from different subcellular fractions of egg homogenate, but the precise target for NAADP is unknown. Among these three major calcium mobilizing messengers, NAADP is the most potent, active at picomolar or low-nanomolar concentrations (Lee, 1997), and releasing calcium ion from reserve granules in the sea urchin egg and from lysosome like acidic vesicles in mammalian cells. NAADP mobilizes calcium ion from acidic stores. NAADP induces alkalinization of acidic stores in sea urchin eggs (Morgan & Galione, 2007). The concentration response relationship for NAADP mediated calcium ion release from mammalian cells is a bell shaped (Pitt & Funnell, 2010), indicating that the receptor might possess high affinity stimulatory and low affinity inhibitory binding sites. NAADP could therefore inactivate its response at a high concentrations. The carboxyl group at 3-position of the pyridine ring, the amino group of the adenine ring and the 2′-phosphate are all important for the biological activity of NAADP (Lee, 1997). The first important site is the 2′-phosphate. Lee (1997) claimed that the removal of the 2′-phosphate resulted in the loss of agonist activity of NAADP. Attaching a caging group to the 2′-phosphate similarly produces an inactive analog that can regenerate NAADP on irradiation with ultra violet light and cause a large calcium ion concentration change in many cells which provides additional evidence that the NAADP is a messenger for calcium ion mobilization. Therefore, the 2′-phosphate is essential for receptor recognition. However, the 2′-phosphate could be modified without completely losing its activity. If the 2′-phosphate was changed to 3′-phosphate or cyclically linked to both positions as a 2′,3′-cyclic phosphate the molecule will retain activity with a lower potency (Lee and Aarhus, 1997). The 3 second important site is the 3-carboxylate on pyridine ring. Billington et al. (2005) suggested that the high selectivity
Load more

Recommended publications
  • Pyrylium Salt Chemistry Emerging As a Powerful Approach for the Cite This: Chem
    Chemical Science View Article Online PERSPECTIVE View Journal | View Issue Over one century after discovery: pyrylium salt chemistry emerging as a powerful approach for the Cite this: Chem. Sci., 2020, 11, 12249 All publication charges for this article construction of complex macrocycles and metallo- have been paid for by the Royal Society of Chemistry supramolecules Yiming Li, ab Heng Wanga and Xiaopeng Li *a Over one century after its discovery, pyrylium salt chemistry has been extensively applied in preparing light emitters, photocatalysts, and sensitizers. In most of these studies, pyrylium salts acted as versatile precursors for the preparation of small molecules (such as furan, pyridines, phosphines, pyridinium salts, thiopyryliums and betaine dyes) and poly(pyridinium salt)s. In recent decades, pyrylium salt chemistry has emerged as a powerful approach for constructing complex macrocycles and metallo-supramolecules. In this perspective, we attempt to summarize the representative efforts of synthesizing and self-assembling Received 20th August 2020 large, complex architectures using pyrylium salt chemistry. We believe that this perspective not only Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Accepted 13th October 2020 highlights the recent achievements in pyrylium salt chemistry, but also inspires us to revisit this chemistry DOI: 10.1039/d0sc04585c to design and construct macrocycles and metallo-supramolecules with increasing complexity and rsc.li/chemical-science desired function. 1. Introduction pyrylium salt with perchlorate as the counterion was reported in 1911 by Baeyer;7 however, since the discovery of pyrylium salts, Pyrylium salts are a type of six-membered cationic heterocycles such salts have been underappreciated for about a half-century.
    [Show full text]
  • From Pyrylium to Pyridinium Salts: Understanding Physicochemical Features
    From Pyrylium to Pyridinium Salts: Understanding Physicochemical Features Antonio Franconetti, Lidia Contreras-Bernal and Francisca Cabrera-Escribano Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado de Correos No. 1203, 41071 Sevilla, Spain. Fax: +34954624960; Tel: +34954556868; E-mail: [email protected] Abstract It is known that physical properties of pyridinium salts can be modulated by their chemical characteristics. Owing to their broad range of applications in biology, biotechnology and chemical research, the design and synthesis of a series of 2,4,6-tri- arylpyridinium salts with modified structural backbone have been carried out. The main strands of work have included modifications on pyrylium cation and nature of amines used as precursors. For pyrylium moiety electronic and steric changes in ortho and para positions were performed. The steric influence of the neighbouring groups into the amine reactivity and the changes of the nucleophile strength of this function have also been investigated. Thus, we have analyzed all these aspects to understand the chemical reactivity and seeking further applications. Keywords Pyridinium salts; Pyrylium salts; Amines; Carbohydrates Introduction Pyridinium salts are widely applied as synthetic building blocks to obtain substituted pyridine, dihydropyridine or piperidine. This synthetic strategy has been described for different applications such as total synthesis of Geissoschizine,1 cannabisativine, Lepadin B, among others. Pyridinium salts have been also used to achieve asymmetric and regioselective synthesis by additions of Grignard reagents.2 Furthermore, pyridinium salts have been applied as acylating agents, phase transfer catalyst or ionic liquid and dyes as a result of its intrinsic fluorescence. More recently, bispyridinium moieties have been employed in a tandem cyclization for the synthesis of indolizine derivatives.3 Different methods are available for the synthesis of pyridinium salts depending on the symmetry around of cation.
    [Show full text]
  • Recent Applications of Isatin in the Synthesis of Organic Compounds
    The Free Internet Journal Review for Organic Chemistry Archive for Arkivoc 2017, part i, 148-201 Organic Chemistry Recent applications of isatin in the synthesis of organic compounds Razieh Moradi,a Ghodsi Mohammadi Ziarani,*a and Negar Lashgari b a Department of Chemistry, Alzahra University, Tehran, Iran b School of Chemistry, College of Science, University of Tehran, Tehran, Iran E-mail: [email protected] [email protected] Received 12-06-2016 Accepted 02-25-2017 Published on line 04-10-2017 Abstract Isatin has been used in design and synthesis of diverse types of heterocyclic and carbocyclic compounds and considered as a valuable building block in organic synthesis. There is a diversity of multicomponent reactions of this useful reagent. This article aims to review the advances in the use of isatin as starting material in the synthesis of various organic compounds and drugs up to June 2016. Keywords: Isatin, organic compounds, heterocyclic compounds, carbocyclic compounds DOI: https://doi.org/10.24820/ark.5550190.p009.980 Page 148 ©ARKAT USA, Inc Arkivoc 2017, i, 148-201 Moradi, R. et al. Table of Contents 1. Introduction 2. Reactions at the C-3 Position of Isatin 3. Synthesis of Isatin-based Spiro-fused Heterocyclic Frameworks 3.1 Synthesis involving two-component reactions of isatins 3.1.1 Three-membered heterocycles 3.1.2 Five-membered heterocycles 3.1.3 Six-membered heterocycles 3.1.4 Seven-membered heterocycles 4. Synthesis Involving Multicomponent Reactions 4.1 Three-membered heterocycles 4.2 Five-membered heterocycles 4.3 Six-membered heterocycles 4.4 Seven-membered heterocycles 5.
    [Show full text]
  • Novel Derivatives of Nicotinamide Adenine Dinucleotide (NAD) and Their Biological Evaluation Against NAD- Consuming Enzymes
    Novel derivatives of nicotinamide adenine dinucleotide (NAD) and their biological evaluation against NAD- Consuming Enzymes Giulia Pergolizzi University of East Anglia School of Pharmacy Thesis submitted for the degree of Doctor of Philosophy July, 2012 © This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with the author and that use of any information derived there from must be in accordance with current UK Copyright Law. In addition, any quotation or extract must include full attribution. ABSTRACT Nicotinamide adenine dinucleotide (β-NAD+) is a primary metabolite involved in fundamental biological processes. Its molecular structure with characteristic functional groups, such as the quaternary nitrogen of the nicotinamide ring, and the two high- energy pyrophosphate and nicotinamide N-glycosidic bonds, allows it to undergo different reactions depending on the reactive moiety. Well known as a redox substrate owing to the redox properties of the nicotinamide ring, β-NAD+ is also fundamental as a substrate of NAD+-consuming enzymes that cleave either high-energy bonds to catalyse their reactions. In this study, a panel of novel adenine-modified NAD+ derivatives was synthesized and biologically evaluated against different NAD+-consuming enzymes. The synthesis of NAD+ derivatives, modified in position 2, 6 or 8 of the adenine ring with aryl/heteroaryl groups, was accomplished by Suzuki-Miyaura cross-couplings. Their biological activity as inhibitors and/or non-natural substrates was assessed against a selected range of NAD+-consuming enzymes. The fluorescence of 8-aryl/heteroaryl NAD+ derivatives allowed their use as biochemical probes for the development of continuous biochemical assays to monitor NAD+-consuming enzyme activities.
    [Show full text]
  • Heterocyclic Chemistrychemistry
    HeterocyclicHeterocyclic ChemistryChemistry Professor J. Stephen Clark Room C4-04 Email: [email protected] 2011 –2012 1 http://www.chem.gla.ac.uk/staff/stephenc/UndergraduateTeaching.html Recommended Reading • Heterocyclic Chemistry – J. A. Joule, K. Mills and G. F. Smith • Heterocyclic Chemistry (Oxford Primer Series) – T. Gilchrist • Aromatic Heterocyclic Chemistry – D. T. Davies 2 Course Summary Introduction • Definition of terms and classification of heterocycles • Functional group chemistry: imines, enamines, acetals, enols, and sulfur-containing groups Intermediates used for the construction of aromatic heterocycles • Synthesis of aromatic heterocycles • Carbon–heteroatom bond formation and choice of oxidation state • Examples of commonly used strategies for heterocycle synthesis Pyridines • General properties, electronic structure • Synthesis of pyridines • Electrophilic substitution of pyridines • Nucleophilic substitution of pyridines • Metallation of pyridines Pyridine derivatives • Structure and reactivity of oxy-pyridines, alkyl pyridines, pyridinium salts, and pyridine N-oxides Quinolines and isoquinolines • General properties and reactivity compared to pyridine • Electrophilic and nucleophilic substitution quinolines and isoquinolines 3 • General methods used for the synthesis of quinolines and isoquinolines Course Summary (cont) Five-membered aromatic heterocycles • General properties, structure and reactivity of pyrroles, furans and thiophenes • Methods and strategies for the synthesis of five-membered heteroaromatics
    [Show full text]
  • Versatile Synthetic Methods for Photoluminescent Pyrylium Tosylates Jung Jae Koh University of Nevada, Las Vegas, [email protected]
    UNLV Theses, Dissertations, Professional Papers, and Capstones 8-1-2015 Versatile Synthetic Methods for Photoluminescent Pyrylium Tosylates Jung Jae Koh University of Nevada, Las Vegas, [email protected] Follow this and additional works at: https://digitalscholarship.unlv.edu/thesesdissertations Part of the Chemistry Commons Repository Citation Koh, Jung Jae, "Versatile Synthetic Methods for Photoluminescent Pyrylium Tosylates" (2015). UNLV Theses, Dissertations, Professional Papers, and Capstones. 2487. https://digitalscholarship.unlv.edu/thesesdissertations/2487 This Thesis is brought to you for free and open access by Digital Scholarship@UNLV. It has been accepted for inclusion in UNLV Theses, Dissertations, Professional Papers, and Capstones by an authorized administrator of Digital Scholarship@UNLV. For more information, please contact [email protected]. VERSATILE SYNTHETIC METHODS FOR PHOTOLUMINESCENT PYRYLIUM TOSYLATES by Jung Jae Koh Bachelor of Biochemistry University of Nevada, Las Vegas 2011 A thesis submitted in partial fulfillment of the requirements for the Master of Science - Chemistry Department of Chemistry and Biochemistry College of Science The Graduate College University of Nevada, Las Vegas August 2015 Copyright by Jung Jae Koh, 2015 All Rights Reserved Thesis Approval The Graduate College The University of Nevada, Las Vegas July 21, 2015 This thesis prepared by Jung Jae Koh entitled Versatile Synthetic Methods for Photoluminescent Pyrylium Tosylates is approved in partial fulfillment of the requirements for the degree of Master of Science – Chemistry Department of Chemistry and Biochemistry Pradip K. Bhowmik, Ph.D. Kathryn Hausbeck Korgan, Ph.D. Examination Committee Co-Chair Graduate College Interim Dean Vernon F. Hodge, Ph.D. Examination Committee Co-Chair Dong-Chan Lee, Ph.D.
    [Show full text]
  • Pyrylium Salts with Long Alkyl Substituents, II
    Pyrylium Salts with Long Alkyl Substituents, II [1] 2,4-Dimethyl-6-undecylpyrylium Perchlorate and Derived Pyridinium Salts Mariana Bogatian, Calin Deleanu, Gheorghe Mihai, and Teodor Silviu Balaban* Center of Organic Chemistry of the Roumanian Academy Splaiul Independentei 202 B, 71141 Bucharest, PO 15/258, Roumania Z. Naturforsch. 47b, 1011-1015 (1992); received September 25, 1991/January 10, 1992 Pyrylium Salts, Pyridinium Salts, Synthetic Amphiphiles, NMR Spectra The crystalline title pyrylium salt was obtained by SnCl4 catalysed acylation of mesityl oxide with lauroyl chloride followed by treatment with perchloric acid and column chromatography. This new pyrylium salt was converted in high yields into the corresponding pyridine and N-substituted pyridinium salts (N-methyl, N-phenyl, N-(4-«-butylphenyl), and N-dodecyl) whose proton (300 MHz) and carbon-13 (75 MHz) NMR spectra are presented. Introduction eleven carbon a-alkyl side-chain and pyridinium One long aliphatic (lipophilic) chain attached to salts derived therefrom. strongly polar (hydrophilic) groups leads to com­ pounds with tensioactive properties. These are due either to micelar aggregates or to membranes. Two Results and Discussion long lipophilic chains attached to one polar group The acylation of mesityl oxide (1) was effected lead to amphiphiles, which can form bilayer mem­ with lauroyl chloride of comercial source, by branes [2]. Some such synthetic analogs of bio­ known methods [ 8], When A1C1 3 was used as acy- membranes have been prepared and their catalytic lating catalyst, the yields were low (<5% ) due to activity has been investigated and compared with the poor isolation of the desired title salt 2, while that of phospholipids and lecithins [3].
    [Show full text]
  • Nucleophilic Dearomatization of Activated Pyridines
    Review Nucleophilic Dearomatization of Activated Pyridines Giulio Bertuzzi *, Luca Bernardi * and Mariafrancesca Fochi * Department of Industrial Chemistry “Toso Montanari” and INSTM RU Bologna, Alma Mater Studiorum-University of Bologna, Via Risorgimento 4, 40136 Bologna, Italy * Correspondence: [email protected] (G.B.); [email protected] (L.B.); [email protected] (M.F.); Tel.: +39-051-209-3626 (M.F.) Received: 16 November 2018; Accepted: 1 December 2018; Published: 6 December 2018 Abstract: Amongst nitrogen heterocycles of different ring sizes and oxidation statuses, dihydropyridines (DHP) occupy a prominent role due to their synthetic versatility and occurrence in medicinally relevant compounds. One of the most straightforward synthetic approaches to polysubstituted DHP derivatives is provided by nucleophilic dearomatization of readily assembled pyridines. In this article, we collect and summarize nucleophilic dearomatization reactions of - pyridines reported in the literature between 2010 and mid-2018, complementing and updating previous reviews published in the early 2010s dedicated to various aspects of pyridine chemistry. Since functionalization of the pyridine nitrogen, rendering a (transient) pyridinium ion, is usually required to render the pyridine nucleus sufficiently electrophilic to suffer the attack of a nucleophile, the material is organized according to the type of N-functionalization. A variety of nucleophilic species (organometallic reagents, enolates, heteroaromatics, umpoled aldehydes) can be productively engaged in pyridine dearomatization reactions, including catalytic asymmetric implementations, providing useful and efficient synthetic platforms to (enantioenriched) DHPs. Conversely, pyridine nitrogen functionalization can also lead to pyridinium ylides. These dipolar species can undergo a variety of dipolar cycloaddition reactions with electron-poor dipolarophiles, affording polycyclic frameworks and embedding a DHP moiety in their structures.
    [Show full text]
  • Heterocyclic Compounds
    Lecture note- 3 Organic Chemistry CHE 502 HETEROCYCLIC COMPOUNDS Co-Coordinator – Dr. Shalini Singh DEPARTMENT OF CHEMISTRY UTTARAKHAND OPEN UNIVERSITY UNIT 4: HETEROCYCLIC COMPOUNDS- I CONTENTS 4.1 Objectives 4.2 Introduction 4.3 Classification of heterocyclic compounds 4.4 Nomenclature of heterocyclic compounds 4.5 Molecular orbital picture 4.6 Structure and aromaticity of pyrrole, furan, thiophene and pyridine 4.7 Methods of synthesis properties and chemical reactions of Pyrrole, Furan, Thiophene and Pyridine 4.8 Comparison of basicity of Pyridine, Piperidine and Pyrrole 4.9 Summary 4.10 Terminal Question 4.1 OBJECTIVES In this unit learner will be able to • Know about the most important simple heterocyclic ring systems containing heteroatom and their systems of nomenclature and numbering. • Understand and discuss the reactivity and stability of hetero aromatic compounds. • Study the important synthetic routes and reactivity for five and six member hetero aromatic compounds. • Understand the important physical and chemical properties of five and six member hetero aromatic compounds. • Know about the applications of these hetero aromatic compounds in the synthesis of important industrial and pharmaceutical compounds 4.2 INTRODUCTION Heterocyclic compound is the class of cyclic organic compounds those having at least one hetero atom (i.e. atom other than carbon) in the cyclic ring system. The most common heteroatoms are nitrogen (N), oxygen (O) and sulphur (S). Heterocyclic compounds are frequently abundant in plants and animal products; and they are one of the important constituent of almost one half of the natural organic compounds known. Alkaloids, natural dyes, drugs, proteins, enzymes etc. are the some important class of natural heterocyclic compounds.
    [Show full text]
  • Photochemical Transformations of Pyridinium Salts: Mechanistic Studies and Applications in Synthesis
    PERSPECTIVE www.rsc.org/obc | Organic & Biomolecular Chemistry Photochemical transformations of pyridinium salts: mechanistic studies and applications in synthesis Teresa Damiano,* Daniel Morton* and Adam Nelson Received 24th April 2007 First published as an Advance Article on the web 29th June 2007 DOI: 10.1039/b706244n The discovery, understanding and synthetic exploitation of the photochemical transformation of pyridinium salts are described. The investigations surrounding the remarkable transformation of pyridinium salts into a host of structurally complex motifs have helped extend the comprehension of aromatic and heteroaromatic photochemistry. The synthetic community has, in recent years, recognised the potential inherent in these compounds and has since exploited the irradiation of variously substituted pyridinium salts as key steps in the preparation of advanced intermediates in numerous synthetic programmes. 1. Introduction of a range of photochemical transformations,2 methods have been developed that enable photochemical reactions to be routinely Photochemical reactions can transform structurally simple performed on a large scale, making these processes more accessible molecules into compounds with complex skeletons, often with to the synthetic organic chemistry community. The irradiation of 1 high stereo- and regiocontrol. Recently, during a detailed study pyridinium salts provides the facile, stereocontrolled synthesis of a range of molecular architectures such as bicyclic aziridines, fused School of Chemistry, University of Leeds, Leeds, UK LS2 9JT heterocycles and various functionalised aminocyclopentenes.1 Teresa obtained her PhD from the University of Geneva (Switzerland), where she worked on the application of the phototransformation of pyridinium salts to synthesis of aminocyclopentitols. She then moved as a Marie Curie Fellow to the HTMC department of Sanofi-Aventis (France).
    [Show full text]
  • Rotation Barriers in Pyridinium Salts Depend on the Number of Available Ground State Conformations*
    CROATICA CHEMICA ACTA CCACAA 77 (1–2) 391¿396 (2004) ISSN-0011-1643 CCA-2940 Original Scientific Paper Rotation Barriers in Pyridinium Salts Depend on the Number of Available Ground State Conformations* Ion Ghiviriga,a,** Edmund W. Czerwinski,b and Alexandru T. Balabanc aUniversity of Florida, Chemistry Department, Gainesville, FL 32611-7200, USA bUniversity of Texas Medical Branch, Department of Human Biological Chemistry & Genetics, Galveston, TX 77555, USA cTexas A&M University at Galveston, Galveston, TX 77553-1675, USA RECEIVED JULY 18, 2003; REVISED NOVEMBER 3, 2003; ACCEPTED NOVEMBER 4, 2003 The enthalpy and entropy of activation for the rotation about the C–N bond were measured in a Key words series of five N-(1-hydroxybutan-2-yl)pyridinium salts, the 2,6-substituents being methyl, ethyl pyridinium and isopropyl. Replacement of a methyl by an ethyl does not change the activation parameters, conformation while replacement by an isopropyl increases both the activation enthalpy and the activation en- isopropyl tropy. The latter is due to the decreased number of conformations available in the ground state. activation parameters The activation entropies fit a simple model based on entropy of mixing. INTRODUCTION was found that the rotation barrier for a C-bonded isopropyl flanked by two methyl groups in pyridines or The low-energy conformation of the isopropyl group in pyridinium salts was 46–50 kJ mol–1. For a similar iso- isopropylbenzene is with the a-hydrogen eclipsed with propyl bonded to the nitrogen heteroatom in pyridinium the benzene ring.1 In this conformation, the ortho and salts the barrier was 58–63 kJ mol–1.2 This difference was meta positions on an aromatic ring are not equivalent ascribed to the bond distance, which was shorter for C–N anymore.
    [Show full text]
  • ABSTRACT the Synthesis of New Pyrylium and Pyridinium Salts
    ABSTRACT The Synthesis of New Pyrylium and Pyridinium Salts Holland T. Korbitz Director: Charles Garner, Ph.D. The synthesis, properties, and applications of symmetrical and unsymmetrical pyrylium and pyridinium salts is investigated. Our group has found particular interest in chiral pyrylium salts due to the fact that they are almost unknown in the literature. We have applied the reaction of acyl chlorides with tert-butanol to the preparation of new pyrylium tetrafluoroborate salts. Some of these pyrylium salt derivatives form diastereomers when prepared. Moreover, they are favorable to study epimerization at the alpha centers. The ease of epimerization at pyrylium chiral centers has not been studied previously. We also applied the reaction of acyl chlorides with dypnone to form asymmetrical pyrylium salts. Our group has also found interest in positively charged pyridinium salts, which provide a route for the possible improvement on the bioavailability of hydrophobic compounds and also an interesting interaction with different substrates. We optimized reaction conditions for reacting substituted pyrylium salts with primary amines to obtain pyridinium salts. Future work will be directed towards obtaining pyridinium salts from primary amines with known biological activity. The objective of this study is to synthesize new pyrylium and pyridinium salts. APPROVED BY DIRECTOR OF HONORS THESIS: ______________________________________________ Dr. Charles Garner, Department of Chemistry APPROVED BY THE HONORS PROGRAM: ____________________________________________
    [Show full text]