University:
Rutgers University Newark
Course:
CHEM 335 | Organic Chemistry
Academic year:

2024
Views:

183

Pages:

43
Author:

Mahitab S.

Why Study Organic Chemistry? Organic Chemistry is an Enabling Science • K. C. Nicolaou, Essay, DOI: 10.1002/ijch. Isr. J. Chem. 2018, 58, 104-113. (Handout) ©2018 Cengage Learning. All Rights Reserved. Organic Chemistry Is an Enabling Science Chemical & Physical Sciences • Analytical • Biological • Catalysis • Inorganic • Materials • Physical • Polymers • Theoretical Chemistry • Chemoinformatics • Mechanochemistry • Spectroscopy, … Biological Sciences • Biochemistry • Biology • Medicine • Structural Biology • Pharmacy • Dentistry • Bioinformatics • Genetics • Biophysics • Bioorganic Chemistry • Bioengineering, ….. ©2018 Cengage Learning. All Rights Reserved. Organic Chemistry in Everyday Life • • • • • • • • • • • • • Polymers • Food additives Petrochemicals • Plastics Medicines • Paper Functional materials • Insect repellent Detergents • Synthetic fabrics Soap • Paint Fragrances • Enzymes Cosmetics • Hormones Shampoo • DNA, RNA • Nail polish remover, Wood, Coal, Gasoline Natural gas, Solvents, Fertilizers, Perfume Vitamins, Dyes, Candles, Asphalt,… …. Lotion ©2018 Cengage Learning. All Rights Reserved. Food Organic Chemistry in Medicine • J. T. Njardarson, https://njardarson.lab.arizona.edu/ (Handout) ©2018 Cengage Learning. All Rights Reserved. Organic Chemistry in Medicine • D. J. Brown, J. Med. Chem. 2016, 59, 4443-4458. (Handout) ©2018 Cengage Learning. All Rights Reserved. Organic Chemistry in Medicine Most Common Reactions in Drug Discovery • D. J. Brown, J. Med. Chem. 2016, 59, 4443-4458. (Handout) ©2018 Cengage Learning. All Rights Reserved. CHAPTER 15 INTRODUCTION TO ORGANOMETALLIC COMPOUNDS ©2018 Cengage Learning. All Rights Reserved. Chapter Outline • (15.1) • (15.2) • (15.3) Organomagnesium and organolithium compounds Lithium diorganocopper (Gilman) reagents Carbenes and carbenoids ©2018 Cengage Learning. All Rights Reserved. Organometallic Compounds • Compounds containing a carbon-metal bond (C-M) • This chapter focuses on transformations that are fundamental to synthetic organic chemistry • Organomagnesium, lithium, and copper reagents have been selected because of their historical importance and their continued use in modern organic synthesis • Many other reagents are now available (Zn, Si, B, Zr, Al, etc) • These reagents are particularly important in the reactions of carbonyl compounds and cross-coupling reactions (Chapter 24) ©2018 Cengage Learning. All Rights Reserved. Grignard Reagents (R-MgX) • Common name for organomagnesium compounds (RMgX, X = Br, I, Cl) (oxidation state of Mg +2) • Prepared by the slow addition of an alkyl, aryl, or alkenyl (vinylic) halide to a suspension of a slight excess of Mg metal in diethyl ether or tetrahydrofuran (THF) • Common starting materials are bromides Oxidative addition ©2018 Cengage Learning. All Rights Reserved. Grignard Reagents • An equilibrium between monoalkyl and dialkyl magnesium complexes exists for many Grignard reagents 2 RMgX É R 2 Mg + MgX 2 • Form on the surface of the metal and dissolve as coordination complexes solvated by ether • Mg acts as a Lewis acid, and ether acts as a Lewis base ©2018 Cengage Learning. All Rights Reserved. Organolithium Reagents (R-Li) • Prepared by treating an alkyl, aryl, or alkenyl halide with two equivalents of lithium metal (Li = +1) • Very reactive as nucleophiles in carbonyl addition reactions even at very low temperatures • Powerful and effective bases and are widely used in modern synthetic chemistry • Used under an inert atmosphere of N2 or Ar since they react rapidly with atmospheric oxygen and moisture ©2018 Cengage Learning. All Rights Reserved. Grignard and Organolithium Reagents • Behave as carbanions in their reactions • Carbanions: Ions in which carbon has an unshared pair of electrons and bears a negative charge (C-M) • Carbon-metal bonds are described as polar covalent ©2018 Cengage Learning. All Rights Reserved. Grignard and Organolithium Reagents • During preparation, the C atom bearing the halogen is transformed from an electrophilic center to a nucleophilic center (see scheme below) • Behave as carbon-centered nucleophiles • React with the electrophilic C of the C=O group of aldehydes, ketones, carboxylic esters, and acid chlorides • Enable the formation of new carbon-carbon bonds (C-C) ©2018 Cengage Learning. All Rights Reserved. RMgX and RLi: Reaction with Protic Acids • Both react readily with any acid (proton donor) stronger than the alkane from which they are derived since they are very strong bases • Both cannot be prepared from any organohalogen that also contains one of these functional groups or a nitro or carbonyl group ©2018 Cengage Learning. All Rights Reserved. Example 15.1 – Grignard as a Strong Base • Write an equation for the acid-base reaction between ethylmagnesium iodide and an alcohol by using curved arrows to show the flow of electrons in this reaction • In addition, show by using appropriate pKa values that this reaction is an example of a stronger acid and stronger base reacting to give a weaker acid and weaker base • Solution • Alcohol is the stronger acid, and the partially negatively charged ethyl group is the stronger base ©2018 Cengage Learning. All Rights Reserved. RMgX and RLi: Reaction with Oxiranes • Reaction with an oxirane followed by protonation of the alkoxide gives a 1°alcohol with a carbon chain two carbons longer than the original chain • Reaction with a substituted oxirane • Major product corresponds to attack of the Grignard reagent on the less hindered carbon of the three-membered ring in an SN2-like reaction ©2018 Cengage Learning. All Rights Reserved. Example 15.2 - Preparation of an Alcohol • Show how to prepare each alcohol from an organohalogen compound and an oxirane ©2018 Cengage Learning. All Rights Reserved. Example 15.2 - Solution • Shown is a retrosynthetic analysis for each compound followed by a synthesis ©2018 Cengage Learning. All Rights Reserved. Example • Which of the following molecules would not yield the desired organolithium reagent when treated with Li in pentane? 1. 2. 3. 4. 5. Iododecane 4-Bromo-1-pentanol Phenyl bromide 4-Bromobutyl methyl ether Cyclohexylbromide ©2018 Cengage Learning. All Rights Reserved. Lithium Diorganocopper (Gilman) Reagents • Prepared using organolithium reagents • Prepared by treatment of an alkyl, aryl, or alkenyllithium compound with copper(I) iodide • Have two organic groups associated with a copper(I) ion giving a negatively charged species • Lithium ion is associated with this negatively charged species as the counterion ©2018 Cengage Learning. All Rights Reserved. Coupling of Gilman Reagents with Organohalogens • Gilman reagents form a new carbon-carbon bond by coupling with alkyl chloride, bromide, or iodide • Only one of the Gilman-reagent alkyl groups is transferred in this reaction (stoichiometric in Cu, 1.0 equiv of Cu) • Because Gilman reagents are prepared from halides, this leads to effective coupling of two halides ©2018 Cengage Learning. All Rights Reserved. Coupling of Gilman Reagents with Organohalogens • Gilman reagents prepared from methyl, 1° alkyl, allylic, vinylic, and aryl halides via the corresponding organolithium compounds give the best yields of coupling products • Yields are lower with 2° and 3° haloalkanes • Coupling with a vinylic halide is stereospecific • Configuration of the carbon-carbon double bond is preserved ©2018 Cengage Learning. All Rights Reserved. Example 15.3 - Reactions with Lithium Diorganocopper Reagents • Show how to perform each conversion using a lithium diorganocopper reagent a. 1-Bromocyclohexene to 1-methylcyclohexene b. 1-Bromo-2-methylpropane to 2,5-dimethylhexane using the bromoalkane as the only source of carbon ©2018 Cengage Learning. All Rights Reserved. Example 15.3 - Solution a. Treat 1-bromocyclohexene with lithium dimethylcopper b. Treat 1-bromo-2-methylpropane with lithium diisobutylcopper, itself prepared from 1-bromo-2methylpropane ©2018 Cengage Learning. All Rights Reserved. Reaction of Gilman Reagents with Oxiranes • Produces new carbon-carbon bonds • Results in regioselective ring opening of substituted epoxides at the less substituted carbon to give alcohols • Example - Treatment of racemic styrene oxide with lithium divinylcopper followed by workup in aqueous acid gives racemic 1-phenyl-3-buten-1-ol ©2018 Cengage Learning. All Rights Reserved. Example 15.4 - Oxirane Reactions • Show two combinations of epoxide and Gilman reagent that can be used to prepare racemic 1-phenyl-3-hexanol ©2018 Cengage Learning. All Rights Reserved. Example 15.4 – 1-phenyl-3-hexanol • Carbon bearing the hydroxyl group must have been one of the C atoms of the epoxide ring • Second C of the epoxide was either the one to the right of the C now bearing the —OH or the one to the left • In these solutions, the phenyl group is written C6H5— • Either route would be satisfactory ©2018 Cengage Learning. All Rights Reserved. Example • What is the product of the following sequence of reactions? I I 1. 2Li CuI pentane ether 2. 4. ether 3. 5. ©2018 Cengage Learning. All Rights Reserved. Example • Which sequence of reagents is best to accomplish the following transformation? Br 1. 2. 3. 4. 5. D KOH followed by BD3/THF KOH followed by NaBH4 Mg/ether followed by D2O Li/pentane followed by D2/CuI NaNH2 followed by D2/Pd ©2018 Cengage Learning. All Rights Reserved. Carbenes • Neutral molecules containing a carbon atom surrounded by only six valence electrons (R2C:) • Highly reactive and act as electrophiles as they are electron deficient • Simplest carbene, methylene, is prepared by photolysis or thermolysis of diazomethane (C2H2N2) • Methylene prepared is nonselective and is of no synthetic use ©2018 Cengage Learning. All Rights Reserved. Carbenes • Carbon is sp2 hybridized with the unshared pair of electrons occupying the third sp2 orbital in the lowest electronic state of most carbenes • Carbon is sp2 hybridized with a vacant 2p orbital • Methylene in this electronic state combines features of a carbocation and a carbanion in that it has both a vacant p orbital and a lone pair ©2018 Cengage Learning. All Rights Reserved. Dichlorocarbene • More stable and chemoselective than free methylene because resonance stabilization with the lone pairs on chlorine satisfies the electron deficiency on carbon • Prepared by treating chloroform with potassium tertbutoxide (KOt-Bu), removing HCl ©2018 Cengage Learning. All Rights Reserved. Dichlorocarbene • Reacts with alkenes to give dichlorocyclopropanes • Addition of a dihalocarbene to an alkene shows syn stereoselectivity • Reaction of a cis or a trans alkene with a dihalocarbene gives only a cis or a trans dihalocyclopropane, respectively ©2018 Cengage Learning. All Rights Reserved. Formation of Dichlorocarbene (2 steps) and Its Reaction with Cyclohexene • Step 1: Take a proton away • Step 2: Break a bond to give stable molecules or ions ©2018 Cengage Learning. All Rights Reserved. Formation of Dichlorocarbene (2 steps) and Its Reaction with Cyclohexene • Step 3: Make a bond between a nucleophile (π bond) and an electrophile (carbene) • Syn addition of dichlorocarbene to cyclohexene gives a dichlorocyclopropane ©2018 Cengage Learning. All Rights Reserved. Example 15.5 - Formation of a Dibromocarbene • Predict the product from the following reaction • Solution • Bromoform gives dibromocarbene, which reacts stereospecifically (syn addition) with the alkene to give a dibromocyclopropane ©2018 Cengage Learning. All Rights Reserved. Simmons-Smith Reaction • Addition of methylene to an alkene. Recall that the methylene prepared from diazomethane is not synthetically useful • Uses diiodomethane and zinc dust activated by a small amount of copper (zinc-copper couple) to produce iodomethylzinc iodide, in a reaction reminiscent of a Grignard reaction • Iodomethylzinc iodide is the Simmons-Smith reagent ©2018 Cengage Learning. All Rights Reserved. Simmons-Smith Reaction • Simmons-Smith reagent reacts with a wide variety of alkenes to give cyclopropanes ©2018 Cengage Learning. All Rights Reserved. Simmons-Smith Reaction • Simmons-Smith reagent reacts directly with an alkene by a concerted mechanism to give the cyclopropanecontaining product as it is more selective than free methylene (stereospecific) • Is an example of a carbenoid • Carbenoid: Compound that delivers the elements of a carbene without actually producing a free carbene ©2018 Cengage Learning. All Rights Reserved. Example 15.6 - Simmons-Smith Reagent • Draw a structural formula for the product of treating each alkene with the Simmons-Smith reagent • Solution • Reaction at each carbon-carbon double bond forms a cyclopropane ring ©2018 Cengage Learning. All Rights Reserved. Problem 15.22 • Show how to convert 1-bromo-3-methylbutane into 2,7dimethyloctane • You must use 1-bromo-3-methylbutane as the source of all carbon atoms in the target molecule • Show all reagents and all molecules synthesized along the way ©2018 Cengage Learning. All Rights Reserved. Problem 15.22 - Solution • Coupling a Gilman reagent with the starting bromoalkane. • 2 intermediates, 3 reagents ©2018 Cengage Learning. All Rights Reserved.