DOCSLIB.ORG

Synthesis and Mechanisms of Phosphoramidates

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Synthesis and Mechanisms of Phosphoramidates Review Openingmolecules Up the Toolbox: Synthesis and Mechanisms of Phosphoramidates Emeka J.Review Itumoh 1,2,3, Shailja Data 1,3 and Erin M. Leitao 1,3,* 1 SchoolOpening of Chemical Sciences, up the The Toolbox:University of Auckland, Synthesis 23 Symonds and Street, Mechanisms Auckland 1010, Newof Zealand; Phosphoramidates [email protected] (E.J.I.); [email protected] (S.D.) 2 Department of Industrial Chemistry, Ebonyi State University, Abakaliki 480001, Ebonyi State, Nigeria 3 The MacDiarmidEmeka J. Itumoh Institute1,2,3 for, Shailja Advanced Data 1,3 Materialsand Erin and M. LeitaoNanotechnology,1,3,* Wellington 6140, New Zealand * Correspondence:1 School of Chemicalerin.leitao@ Sciences,auckland.ac.nz; The University Tel.: of Auckland, +64-9923-5567 23 Symonds Street, Auckland 1010, New Zealand; [email protected] (E.J.I.); [email protected] (S.D.) Academic Editor: Frederik Wurm 2 Department of Industrial Chemistry, Ebonyi State University, Abakaliki 480001, Ebonyi State, Nigeria 3 Received: 3 TheJuly MacDiarmid 2020; Accepted: Institute 11 for Augu Advancedst 2020; Materials Published: and Nanotechnology, 12 August 2020 Wellington 6140, New Zealand * Correspondence: [email protected]; Tel.: +64-9923-5567 Abstract:Academic This review Editor: Frederik covers Wurm the main synthetic routes to and the corresponding mechanisms of phosphoramidateReceived: 3 July formation. 2020; Accepted: The 11 August synthetic 2020; Published: routes 13can August be 2020separated into six categories: salt elimination,Abstract: oxidativeThis review cross-coupling, covers the main azide, synthetic reduction, routes to andhydrophosphinylation, the corresponding and phosphoramidate-aldehyde-dienophilemechanisms of phosphoramidate formation. (PAD). The Examples synthetic routesof some can be separatedimportant into compounds six synthesizedcategories: through salt elimination,these routes oxidative are provided. cross-coupling, As azide,an important reduction, class hydrophosphinylation, of organophosphorus and phosphoramidate-aldehyde-dienophile (PAD). Examples of some important compounds compounds,synthesized the applications through these of routesphosphoramid are provided.ate compounds, As an important are classalso ofbriefly organophosphorus introduced. compounds, the applications of phosphoramidate compounds, are also briefly introduced. Keywords: phosphoramidate; synthetic routes; mechanism; applications Keywords: phosphoramidate; synthetic routes; mechanism; applications 1. Introduction1. Introduction to Phosphoramidates to Phosphoramidates and and their their Applications PhosphoramidatesPhosphoramidates (P-N) (P-N) are are a aclass class of organophosphorusorganophosphorus compounds compounds known forknown the presence for the of presence of a singlea single covalent covalent bond between between the tetracoordinatethe tetracoor P(V)dinate atom P(V) and N(III)atom atom. and ThereN(III) are atom. generally There are three types of phosphoroamidates, which are distinguished according to the substitution on the P and generallyN atomsthree (Figuretypes 1of)[ 1phosphoroamidates,]. which are distinguished according to the substitution on the P and N atoms (Figure 1) [1]. O O O P H P R' R' RO N RO N RO P N RO H RO H RO R" I II III R = H, alkyl, aryl R', R" = alkyl, aryl, heteroaryl Figure Figure1. Three 1. Three types types of P-N of P-N based based on on the the substituents directly directly attached attached to the Pto and the N. P and N. Another feature of these organophosphorous compounds, defined as (RO)2P(O)NR’2 (R, R’ = H, Anotheralkyl, aryl, feature heteroaryl), of these is a organophos stable phosphorylphorous bond (Pcompounds,=O). Both P and defined N atoms as are (RO) key2 physiologicalP(O)NR’2 (R, R’ = H, alkyl, aryl,elements heteroaryl), present in is genetic a stable material, phosphoryl energy transfer, bond enzymes, (P=O). Both and other P and biomolecules N atoms and are are key required physiological elementsfor present various lifein processes.genetic material, As such, molecules energy containingtransfer, P-Nenzymes, linkages and are foundother in biomolecules a large array of and are requiredbiologically for various active life natural processes. products As (such,1–7) (Figure molecules2)[ 2,3]. containing For example, P-N Microcin linkages C7 (1 )are (Figure found2) is in a large an antibiotic produced by Escherichia coli [4]. Dinogunellin (2) (Figure2), which is produced in the roe array ofof biologically some fishes, isactive a natural natural toxin [ 5products]. Phosphoarginine (1–7) (Figure and phosphocreatine 2) [2,3]. For (3 example,and 6) (Figure Microcin2) are C7 (1) (Figure important2) is an biologicalantibiotic molecules produced used by as sourcesEscherichia of stored coli energies[4]. Dinogunellin in invertebrates (2) and (Figure vertebrates, 2), which is producedrespectively in the roe [6 ].of Phosphoramidonsome fishes, is (a4) natura (Figurel2 ),toxin derived [5]. from PhosphoarginineStreptomyces tanashiensis and phosphocreatine, inhibits (3 and 6) the(Figure thermolysin 2) are enzyme, important which isbiological a key factor molecules in the development used ofas varioussources diseases of stored [7,8]. Lastly, energies in invertebratesphosmidosine and vertebrates, and agrocin 84 (respectively5 and 7) (Figure 2[6].) are Phosphoramidon nucleotide antibiotics isolated(4) (Figure from Streptomyces2), derived from Streptomyces tanashiensis, inhibits the thermolysin enzyme, which is a key factor in the development Molecules 2020, 25, 3684; doi:10.3390/molecules25163684 www.mdpi.com/journal/molecules of various diseases [7,8]. Lastly, phosmidosine and agrocin 84 (5 and 7) (Figure 2) are nucleotide antibiotics isolated from Streptomyces durhameusis and Agrobacterium radiobacter and are used to control gray mold disease and crown gall disease in plants, respectively [9,10]. Molecules 2020, 25, x; doi: FOR PEER REVIEW www.mdpi.com/journal/molecules Molecules 2020, 25, 3684 2 of 37 durhameusis and Agrobacterium radiobacter and are used to control gray mold disease and crown gall diseaseMolecules in 2020 plants,, 25, x FOR respectively PEER REVIEW [9,10 ]. 2 of 37 Figure 2. Phosphoramidate motifs in natural products: Microcin C7 (1), Dinogunellin (R = residue Figure 2. Phosphoramidate motifs in natural products: Microcin C7 (1), Dinogunellin (R = residue of of fatty acid) (2), Phosphoarginine (3), Phosphoramidon (4), Phosmidosine (5), Phosphocreatine (6), fatty acid) (2), Phosphoarginine (3), Phosphoramidon (4), Phosmidosine (5), Phosphocreatine (6), Agrocin 84 (7). Agrocin 84 (7). Due to the inherent physiochemical properties of the phosphorus atom including its polarizability, Due to the inherent physiochemical properties of the phosphorus atom including its multivalency, varying oxidation states, and low coordination number, a diverse range of compounds polarizability, multivalency, varying oxidation states, and low coordination number, a diverse range containing the P-N motifs have been synthesized [11]. These P-Ns are widely used in medicine for the of compounds containing the P-N motifs have been synthesized [11]. These P-Ns are widely used in control and treatment of various diseases, in agriculture as pesticides for crop protection, in industry as medicine for the control and treatment of various diseases, in agriculture as pesticides for crop novelprotection, fire-retardant in industry compounds as novel to fire-retardant delay the flammability compounds of to polymeric delay the compounds, flammability and of in polymeric the fields ofcompounds, analytical and and coordination in the fields chemistry. of analytical Therefore, and coordination synthetic P-N chemistry. compounds Therefore, are not only synthetic researched P-N outcompounds of academic are interest, not only but researched they also have out commercialof academic applications. interest, but Uses they for also P-Ns have can becommercial separated intoapplications. 5 main classes: Uses for agriculture, P-Ns can industry,be separated analytical into 5 chemistry,main classes: synthetic agriculture, chemistry, industry, and analytical medicinal chemistrychemistry, (Figure synthetic3)[12 chemistry,–18]. and medicinal chemistry (Figure 3) [12–18]. Molecules 2020, 25, x FOR PEER REVIEW 3 of 37 Molecules 2020, 25, 3684 3 of 37 Molecules 2020, 25, x FOR PEER REVIEW 3 of 37 FigureFigureFigure 3.3. 3. ApplicationsApplications Applications of ofof phosphoramidates. phosphoramidates. 1.1. Phosphoramidates in Agriculture 1.1.1.1. Phosphoramidat Phosphoramidates esin in Agriculture Agriculture This class of organophosphates (with common names such as cruformate, fenamiphos, ThisThis class class of oforganophosphates organophosphates (with (with commoncommon names suchsuch asas cruformate,cruformate, fenamiphos, fenamiphos, and and andfosthietan)fosthietan) fosthietan) has has been has been beenwidely widely widely used used in used in pest pest in management management pest management forfor crop for protectionprotection crop protection (Figure (Figure 3) 3) (Figure [19–21]. [19–21].3 )[P-Ns P-Ns19 –for21 for ]. P-Nspestpest control for control pest affect control affect the the a nervousff ectnervous the sy nervous systemstem of of system pests/insects pests/insects of pests by/insects inhibiting by inhibitingacetylcholinesteraseacetylcholinesterase acetylcholinesterase (AChE), (AChE), a a (AChE),majormajor neurotransmitter aneurotransmitter major neurotransmitter [22–25]. [22–25]. In [In22 addition, –addition,25].
Load more

Recommended publications
  • 3 + 3HC1 Effect of Water and Ammonia, Respectively, Upon
    VOL. 23, 1937 CHEMISTRY: SLOB UTSKY, A UDRIETHAND CAMPBELL 611 ACID CATALYSIS IN LIQUID AMMONIA. I. AMMONOL YSIS OF DIETHYLMALONA TE BY CHARLES SLOBUTSEY, L. F. AUDRIETH AND R. W. CAMPBELL DEPARTMENT OF CHEMISTRY, UNIVERSITY OF ILLINOIS, URBANA, ILLINOIS Communicated November 3, 1937 Numerous investigations have shown that liquid ammonia possesses unusual properties as a solvent' for many inorganic and organic compounds. Like water it is the parent substance of a system of acids, bases and salts.2 Liquid ammonia also reacts directly with many substances. Solvolysis takes place and in the case of ammonia such reactions are termed ammono- lytic reactions. Just as phosphorus trichloride is hydrolyzed by water (1), so it may be ammonolyzed3 by ammonia to give the nitrogen analogs of phosphorous and hydrochloric acids (2). PCI + 3HOH -- P(OH)3 + 3HC1 (1) PCI3 + 5HNH2 -+ P(NH)(NH2) + 3NH4C1 (2) Many hydrolytic reactions are catalyzed in aqueous solutions by acids or bases. Thus, the inversion of cane sugar is catalyzed by acids and the velocity of the reaction is a function of the concentration of the hydrogen ion. Esters also undergo hydrolysis and such reactions are markedly catalyzed by the hydrogen ion, or in terms of the modern Bronsted concept of acidity, by the onium4 ion, or solvated proton. It was, therefore, to have been expected that the rate of ammonolysis of esters in liquid ammonia would be accelerated by the presence of ammonium salts, which have been shown to possess acid character in liquid ammonia. It has already been demonstrated qualitatively that ammonium salts do exert a catalytic effect in other ammonolytic reactions.
    [Show full text]
  • Synthetic Routes to Bromo-Terminated Phosphonate Films and Alkynyl Pyridine Compounds for Click Coupling
    University of Mary Washington Eagle Scholar Student Research Submissions Spring 5-7-2018 Synthetic Routes to Bromo-Terminated Phosphonate Films and Alkynyl Pyridine Compounds for Click Coupling Poornima Sunder Follow this and additional works at: https://scholar.umw.edu/student_research Part of the Biochemistry Commons Recommended Citation Sunder, Poornima, "Synthetic Routes to Bromo-Terminated Phosphonate Films and Alkynyl Pyridine Compounds for Click Coupling" (2018). Student Research Submissions. 226. https://scholar.umw.edu/student_research/226 This Honors Project is brought to you for free and open access by Eagle Scholar. It has been accepted for inclusion in Student Research Submissions by an authorized administrator of Eagle Scholar. For more information, please contact [email protected]. Synthetic Routes to Bromo-Terminated Phosphonate Films and Alkynyl Pyridine Compounds for Click Coupling Poornima Rachel Sunder Thesis submitted to the faculty of University of Mary Washington in partial fulfillment of the requirements for graduation with Honors in Chemistry (2018) ABSTRACT Click reactions are a highly versatile class of reactions that produce a diverse range of products. Copper-catalyzed azide-alkyne cycloaddition (CuAAC) click reactions require an azide and a terminal alkyne and produce a coupled product that is “clicked” through a triazole ring that can have a variety of substituents. In this work, bromo-terminated phosphonate films on copper oxide surfaces were explored as the platform for click coupling, as the terminal azide needed for the reaction can be generated through an in situ SN2 reaction with a terminal bromo group. The reactions were characterized using model reactions in solution before being conducted on modified copper oxide surfaces.
    [Show full text]
  • Sulfonyl-Containing Nucleoside Phosphotriesters And
    Sulfonyl-Containing Nucleoside Phosphotriesters and Phosphoramidates as Novel Anticancer Prodrugs of 5-Fluoro-2´-Deoxyuridine-5´- Monophosphate (FdUMP) Yuan-Wan Sun, Kun-Ming Chen, and Chul-Hoon Kwon†,* †Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John’s University, Jamaica, New York 11439 * To whom correspondence should be addressed. Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John’s University, 8000 Utopia parkway, Jamaica, NY 11439. Tel: (718)-990-5214, fax: (718)-990-6551, e-mail: [email protected]. Abstract A series of sulfonyl-containing 5-fluoro-2´-deoxyuridine (FdU) phosphotriester and phosphoramidate analogues were designed and synthesized as anticancer prodrugs of FdUMP. Stability studies have demonstrated that these compounds underwent pH dependent β-elimination to liberate the corresponding nucleotide species with half-lives in the range of 0.33 to 12.23 h under model physiological conditions in 0.1M phosphate buffer at pH 7.4 and 37 °C. Acceleration of the elimination was observed in the presence of human plasma. Compounds with FdUMP moiety (4-9) were considerably more potent than those without (1-3) as well as 5-fluorouracil (5-FU) against Chinese hamster lung fibroblasts (V-79 cells) in vitro. Addition of thymidine (10 µM) reversed the growth inhibition activities of only 5-FU and the compounds with FdUMP moiety, but had no effect on those without. These results suggested a mechanism of action of the prodrugs involving the intracellular release of FdUMP. Introduction 5-Fluoro-2´-deoxyuridine-5´-monophosphate (FdUMP) is the major metabolite responsible for the anticancer activity of 5-FU (Chart 1).
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2005/0044778A1 Orr (43) Pub
    US 20050044778A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0044778A1 Orr (43) Pub. Date: Mar. 3, 2005 (54) FUEL COMPOSITIONS EMPLOYING Publication Classification CATALYST COMBUSTION STRUCTURE (51) Int. CI.' ........ C10L 1/28; C1OL 1/24; C1OL 1/18; (76) Inventor: William C. Orr, Denver, CO (US) C1OL 1/12; C1OL 1/26 Correspondence Address: (52) U.S. Cl. ................. 44/320; 44/435; 44/378; 44/388; HOGAN & HARTSON LLP 44/385; 44/444; 44/443 ONE TABOR CENTER, SUITE 1500 1200 SEVENTEENTH ST DENVER, CO 80202 (US) (57) ABSTRACT (21) Appl. No.: 10/722,127 Metallic vapor phase fuel compositions relating to a broad (22) Filed: Nov. 24, 2003 Spectrum of pollution reducing, improved combustion per Related U.S. Application Data formance, and enhanced Stability fuel compositions for use in jet, aviation, turbine, diesel, gasoline, and other combus (63) Continuation-in-part of application No. 08/986,891, tion applications include co-combustion agents preferably filed on Dec. 8, 1997, now Pat. No. 6,652,608. including trimethoxymethylsilane. Patent Application Publication Mar. 3, 2005 US 2005/0044778A1 FIGURE 1 CALCULATING BUNSEN BURNER LAMINAR FLAME VELOCITY (LFV) OR BURNING VELOCITY (BV) CONVENTIONAL FLAME LUMINOUS FLAME Method For Calculating Bunsen Burner Laminar Flame Velocity (LHV) or Burning Velocity Requires Inside Laminar Cone Angle (0) and The Gas Velocity (Vg). LFV = A, SIN 2 x VG US 2005/0044778A1 Mar. 3, 2005 FUEL COMPOSITIONS EMPLOYING CATALYST Chart of Elements (CAS version), and mixture, wherein said COMBUSTION STRUCTURE element or derivative compound, is combustible, and option 0001) The present invention is a CIP of my U.S.
    [Show full text]
  • Kinetic Study of Hydrolysis of Tri-2,5-Diethoxy Aniline Phosphate (An Organo Phosphorus Pesticide) in Acid Medium
    International Journal of Chemistry February, 2010 Kinetic Study of Hydrolysis of Tri-2,5-diethoxy Aniline Phosphate (An Organo Phosphorus Pesticide) in Acid Medium Alka Tangri Dept. of Chemistry, Brahmanand P.G. College, Kanpur Flat No.- 38 Ram Kuthr 3A/206, Azad Nagar, Kanpur (U.P.), India Tel: 91-983-950-1085 E-mail: [email protected] Pradeep Mishra Dept. of Chemistry, Brahmanand P.G. College, Kanpur 113/115-A, Swaroop Nagar, Kanpur (U.P.), India Tel: 91-983-911-6593 E-mail: [email protected] Praveen Kumar (Corresponding author) Dayanand, Near the Railway Station Road Rura, Kanpur Dehat (U.P.), India Tel: 91-933-544-9365 E-mail: [email protected] Abstract The present work pertains to synthesis, kinetic behavior and mechanism of hydrolysis of some organophosphorus pesticides. The compound investigated here was 2,5-diethoxyaniline in particular. The corresponding tri-phosphate ester was prepared in the laboratory by phosphorylation with POCI3. The process involved is that of the substitution of –OH group of orthophosphoric acid by aryl radical. The kinetics of the hydrolysis of the above ester was studied in acidic media. The acid employed was HCI. In acidic media, hydrolysis was carried out at three different temperatures 80, 90 and 980C (keeping other parameters of the experiment unchanged). The rate of hydrolysis is found to follow the Arrhenius equation. The values of the Arrhenius parameters-energy of activation and change of entropy-point to the bimolecular nature of the hydrolysis of the triester. It can be inferred from the ionic strength data in the range 0.01 to 5 M-HCI, the reactive species of the present triester is conjugate acid species.
    [Show full text]
  • Asymmetric Synthesis of Organophosphates and Their
    ASYMMETRIC SYNTHESIS OF ORGANOPHOSPHATES AND THEIR DERIVATIVES Thesis Submitted to The College of Arts and Sciences of the UNIVERSITY OF DAYTON In Partial Fulfillment of the Requirements for The Degree of Master of Science in Chemistry By Batool J. Murtadha Dayton, Ohio May 2020 ASYMMETRIC SYNTHESIS OF ORGANOPHOSPHATES AND THEIR DERIVATIVES Name: Murtadha, Batool J. APPROVED BY: __________________________________ Jeremy Erb, Ph.D. Research Advisor Assistant Professor Department of Chemistry University of Dayton ___________________________________ Vladimir Benin, Ph.D. Professor of Chemistry Department of Chemistry University of Dayton ___________________________________ Justin C. Biffinger, Ph.D. Committee Member Assistant Professor Department of Chemistry University of Dayton ii © Copyright by Batool J. Murtadha All rights reserved 2020 iii ABSTRACT ASYMMETRIC SYNTHESIS OF ORGANOPHOSPHATES AND THEIR DERIVATIVES Name: Murtadha, Batool J. University of Dayton Advisor: Dr. Jeremy Erb Organophosphorus compounds (OPs) are widely used in the agricultural industry especially in the pesticide market. Phosphates play a huge role as biological compounds in the form of energy carrier compounds like ATP, and medicine as antivirals. OPs have become increasingly important as evidenced by the publication of new methods devoted to their uses and synthesis. These well-established studies lay the basis for industrial organic derivatives of phosphorus preparations. The current work explored methods of synthesizing chiral organophosphate triesters. We experimented with different processes roughly divided into either an electrophilic or nucleophilic strategy using chiral Lewis acids, organocatalysts (HyperBTM), activating agents, and chiral auxiliaries with the goal of control stereoselectivity. These methods were explored through the use of different starting materials like POCl3, triethyl phosphate, methyl phosphordichloradate, and PSCl3.
    [Show full text]
  • Environmental Health Criteria 63 ORGANOPHOSPHORUS
    Environmental Health Criteria 63 ORGANOPHOSPHORUS INSECTICIDES: A GENERAL INTRODUCTION Please note that the layout and pagination of this web version are not identical with the printed version. Organophophorus insecticides: a general introduction (EHC 63, 1986) INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY ENVIRONMENTAL HEALTH CRITERIA 63 ORGANOPHOSPHORUS INSECTICIDES: A GENERAL INTRODUCTION This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organisation, or the World Health Organization. Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization World Health Orgnization Geneva, 1986 The International Programme on Chemical Safety (IPCS) is a joint venture of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization. The main objective of the IPCS is to carry out and disseminate evaluations of the effects of chemicals on human health and the quality of the environment. Supporting activities include the development of epidemiological, experimental laboratory, and risk-assessment methods that could produce internationally comparable results, and the development of manpower in the field of toxicology. Other activities carried out by the IPCS include the development of know-how for coping with chemical accidents, coordination
    [Show full text]
  • E-Catalog Version 18.0 Release Date: 05-10-2013
    E-Catalog Version 18.0 Release Date: 05-10-2013 ChemGenes Corporation is now ISO 9001:2008 Certified Company Bio Technology Products & Manufacturer of DNA-RNA Intermediates 33 Industrial Way Wilmington, MA 01887 USA Tel: 978-694-4500 Fax: 978-694-4502 Toll Free: 800-762-9323 Email: [email protected] www.chemgenes.com Product Highlight Extensive Product Lines: DNA amidites: Bulk Quantities for therapeutics grade oligo synthesis Natural and modified DNA amidites Natural & modified RNA amidites : Bulk Quantities 2’-O-Methyl amidites: Bulk Quantities RNA Synthesis in Reverse Direction TOM amidites for RNA synthesis : Bulk Quantities 2’-O-ALE amidites 2’-O-PivOM amidites 2’-Fluoro amidites Non-Cleavable Inert Supports ETT & BMT : Bulk Quantities DDTT Sulfurizing Reagent UnyLinker Universal Support Akta Oligonucleotide Synthesizer Reagents N-Alkylated nucleosides and amidites 5-Azacytidine and 5-Aza-2’-deoxycytidine Thio uridines & thymidines nucleosides and amidites 6 & 5-FAM NHS Esters 6 & 5-FAM-(C-6 linker) amidites Biotin (BB)-(urea nitrogen protected) Supports & amidites Polyethylene glycol (PEG) (MW. 2000 and 4500) amidites 5’-MMTr nucleoside amidites (Purines: A & G) 8-Methyl dG & rG amidites 8-Oxo dA & dG amidites 5’-O-Methyl DNA amidites Fmoc Protected Nucleoside amidites 5-Formyl dU amidites Ammonia Free Deprotection Reagents Thiol modifiers (acyclic and cyclic) DNA and RNA Purification kit Toll Free: (800) 762-9323 33 Industrial Way, Wilmington, MA 01887 • T: (978) 694-4500 • F: (978) 694-4502 www.chemgenes.com Email: [email protected] Experience Nucleic Acid Expertise Since 1981, the products and services provided by ChemGenes Corporation continue to accelerate the pace of DNA/RNA oligonucleotide synthesis, research, and develop- ment in the pharmaceutical and biotechnology industry.
    [Show full text]
  • S 1 Reaction Remember That a 3˚ Alkyl Halide Will Not Undergo a S 2 Reaction the Steric Hindrance in the Transition State
    SN1 Reaction Remember that a 3˚ alkyl halide will not undergo a SN2 reaction The steric hindrance in the transition state is too high If t-Butyl iodide is reacted with methanol, however, a substitution product is obtained This product does NOT proceed through a SN2 reaction First proof is that the rate for the reaction does not depend on methanol concentration Occurs through a SN1 reaction Substitution – Nucleophilic – Unimolecular (1) SN1 - In a SN1 reaction the leaving group departs BEFORE a nucleophile attacks For t-butyl iodide this generates a planar 3˚ carbocation The carbocation can then react with solvent (or nucleophile) to generate the product If solvent reacts (like the methanol as shown) the reaction is called a “solvolysis” The Energy Diagram for a SN1 Reaction therefore has an Intermediate - And is a two step reaction CH3 Potential H3C energy CH3 I OCH CH3 3 H3C CH3 CH3 H3C CH3 Reaction Coordinate Why does a SN1 Mechanism Occur? - Whenever the potential energy of a reaction is disfavored for a SN2 reaction the SN1 mechanism becomes a possibility SN2 SN1 Potential energy I OCH3 CH3 H3C CH3 CH3 H3C CH3 Reaction Coordinate Rate Characteristics The rate for a SN1 reaction is a first order reaction Rate = k [substrate] The first step is the rate determining step The nucleophile is NOT involved in the rate determining step Therefore the rate of a SN1 reaction is independent of nucleophile concentration (or nucleophile characteristics, e.g. strength) What is Important for a SN1 Reaction? The primary factor concerning the rate of
    [Show full text]
  • Solvolysis Reaction Kinetics, Rates and Mechanism for Phenyl N-Phenyl Phosphoramidochloridate
    Studies of Phenyl N-Phenyl Phosphoramidochloridate Bull. Korean Chem. Soc. 2014, Vol. 35, No. 8 2465 http://dx.doi.org/10.5012/bkcs.2014.35.8.2465 Solvolysis Reaction Kinetics, Rates and Mechanism for Phenyl N-Phenyl Phosphoramidochloridate Hojune Choi, Kiyull Yang, Han Joong Koh,†,* and In Sun Koo* Department of Chemistry Education and Research Instituted of Natural Science, Gyeongsang National University, Jinju 660-701, Korea. *E-mail: [email protected] †Department of Science Education, Chonju National University of Education, Chonju, Korea. *E-mail: [email protected] Received March 29, 2014, Accepted April 29, 2014 The rate constants of solvolysis of phenyl N-phenyl phosphoramidochloridate (PhNHPO(Cl)OPh, Target Compound-TC1) have been determined by a conductivity method. The solvolysis rate constants of TC1 are well correlated with the extended Grunwald-Winstein equation, using the NT solvent nucleophilicity scale and YCl solvent ionizing scale, and sensitivity values of 0.85 ± 0.14 and 0.53 ± 0.04 for l and m, respectively. These l and m values were similar to those obtained previously for the complex chemical substances dimethyl thiophosphorochloridate; N,N,N',N'-tetramethyldiamidophosphorochloridate; 2-phenyl-2-ketoethyl tosylate; diphenyl thiophosphinyl chloride; and 9-fluorenyl chloroformate. As with the five previously studied solvolyses, an SN2 pathway is proposed for the solvolyses of TC1. For four representative solvents, the rate constants were measured at several temperatures, and activation parameters (∆H≠ and ∆S≠) were estimated. These activation parameters are also in line with the values expected for an SN2 reaction. Key Words : Phenyl N-phenyl phosphoramidochloridate, Extended Grunwald-Winstein equation, SN2 mech- anism, Activation parameters Introduction mediate or is the result of a single transition state (TS).2 The reaction mechanism of phosphoryl compounds, such Phosphoryl transfer is an important aspect of biological as that of ‘phenyl N-phenyl phosphoramidochloridate’ chemistry and organic synthesis.
    [Show full text]
  • H-Phosphonates: Versatile Synthetic Precursors to Biologically Active Phosphorus Compounds*
    Pure Appl. Chem., Vol. 79, No. 12, pp. 2217–2227, 2007. doi:10.1351/pac200779122217 © 2007 IUPAC H-Phosphonates: Versatile synthetic precursors to biologically active phosphorus compounds* Adam Kraszewski1,‡ and Jacek Stawinski1,2,‡ 1Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland; 2Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-10691 Stockholm, Sweden Abstract: In this review, a short account of H-phosphonate chemistry and its application to the synthesis of biologically important phosphates and their analogs is given. Keywords: H-phosphonates; phosphate analogs; biological activity; nucleic acids; drugs. INTRODUCTION Located at the crossroad of various bioinformation exchange pathways, phosphorus-containing com- pounds play a key role in living organisms as carriers of genetic information and important signalling, regulatory, energy transfer, and structural compounds [1]. Due to this pivotal role, biologically impor- tant phosphorus compounds have become therapeutic targets in various modern medicinal techniques, such as antisense [2] and antigene [3] approaches to modulation gene expression, or a gene silencing technique using short interfering RNA (siRNA) [4]. To maximize the desired biological effect and to minimize cytotoxicity, a biologically active com- pound has to have very precisely adjusted chemical and pharmacokinetic properties. This can be achieved by, e.g., changing pKa values of the ionizeable functions, changing electronegativity of the substituents, their size, hydrophobicity, etc. These features can also influence transport of a drug across cell membranes, its preferential degradation in normal or activation in the neoplastic or virus-infected cells, and can contribute to the overall efficiency of the drug. A prominent example here are antiviral pronucleotides in which the phosphate moiety is masked with alkyl or aryl groups that are removed chemically and enzymatically in cells to produce an active antiviral nucleotide [5].
    [Show full text]
  • The Hydrolysis of Phosphinates and Phosphonates: a Review
    molecules Review The Hydrolysis of Phosphinates and Phosphonates: A Review Nikoletta Harsági and György Keglevich * Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary; [email protected] * Correspondence: [email protected]; Tel.: +36-1-463-1111 (ext. 5883) Abstract: Phosphinic and phosphonic acids are useful intermediates and biologically active com- pounds which may be prepared from their esters, phosphinates and phosphonates, respectively, by hydrolysis or dealkylation. The hydrolysis may take place both under acidic and basic conditions, but the C-O bond may also be cleaved by trimethylsilyl halides. The hydrolysis of P-esters is a challenging task because, in most cases, the optimized reaction conditions have not yet been explored. Despite the importance of the hydrolysis of P-esters, this field has not yet been fully surveyed. In order to fill this gap, examples of acidic and alkaline hydrolysis, as well as the dealkylation of phosphinates and phosphonates, are summarized in this review. Keywords: hydrolysis; dealkylation; phosphinates; phosphonates; P-acids 1. Introduction Phosphinic and phosphonic acids are of great importance due to their biological activity (Figure1)[ 1]. Most of them are known as antibacterial agents [2,3]. Multidrug- resistant (MDR) and extensively drug-resistant (XDR) pathogens may cause major problems Citation: Harsági, N.; Keglevich, G. in the treatment of bacterial infections. However, Fosfomycin has remained active against The Hydrolysis of Phosphinates and both Gram-positive and Gram-negative MDR and XDR bacteria [2]. Acyclic nucleoside Phosphonates: A Review. Molecules phosphonic derivatives like Cidofovir, Adefovir and Tenofovir play an important role 2021, 26, 2840.
    [Show full text]