Ch.18: Ethers and Epoxides; Thiols and Sulfides Dr. Sivappa Rasapalli Chemistry and Biochemistry University of Massachusetts Dartmouth Coverage and Objectives Coverage: • The nomenclature of alcohols • Synthesis and Nucleophilic substitution reactions of ethers • Nucleophilic Opening reactions of epoxides • Chemistry of sulfur compounds Learning objectives: • Provide both IUPAC and common names for ethers, sulfides. • Recognize the physical properties of ethers, epoxides and sulfides • Know the synthesis and chemistry of the functional groups • Write the reaction and electron-pushing (arrow-pushing) mechanism for the synthesis and reactions of the functional groups • Write the acid-catalyzed ring-opening of epoxides, and explain the observed stereochemistry of the products. 18.1 Names and Properties of Ethers Nomenclature of Ethers, Epoxides, and Sulfides Ethers, Epoxides, Thiols and sulfides •Ethers (ROR) can be regarded as derivatives of alcohols (ROH). •Sulfides (RSR) can be regarded as derivatives of Thols (RSH). Nomenclature: Functional Class • simple ethers are named: “alkyl alkyl ether” • name the groups attached to oxygen in alphabetical order as separate words; "ether" is last word; • “dialkyl ether” if symmetric Nomenclature: Substituent • name as alkoxy derivatives of alkanes CH3OCH2 CH3 methoxyethane CH3CH2OCH2CH2CH2Cl 1-chloro-3-ethoxypropane CH3CH2OCH2 CH3 ethoxyethane Nomenclature: Functional Class • analogous to ethers, but replace “ether” as last word in the name by “sulfide.” CH3SCH2 CH3 ethyl methyl sulfide CH3CH2SCH2 CH3 diethyl sulfide SCH3 cyclopentyl methyl sulfide Nomenclature: Substituent • name as alkylthio derivatives of alkanes CH3SCH2 CH3 methylthioethane SCH3 (methylthio)cyclopentane CH3CH2SCH2 CH3 ethylthioethane Names of Cyclic Ethers O Oxirane (Ethylene oxide) O Oxetane O Oxolane (tetrahydrofuran) O O Oxane (tetrahydropyran) O 1,4-Dioxane Names of Cyclic Sulfides S S Thiirane Thietane S Thiane S Thiolane Examples of Nomenclature Br O OCH3 but yl ethyl et her (common) or 1-ethoxybut ane (IUP AC)trans 1-bromo-2-methoxycyclopent ane O CH3CH2O OH CH3CH2O ethyl (Z) 1-propenyl ether (common) or (Z) 1-et hoxy-1-propene (IUP AC)4,4-diethoxy-2-cyclohexenol O OCH3 O cis 3-met hoxycyclopentene oxide (E) 2-met hyl-3-hexene oxide trans 2-et hyl-3-isopropyloxirane (E) 2-met hyl-3,4-epoxyhexane cis 3-met hoxy-1,2-epoxycyclopent ane Periplenone B Epothilone B female cockroach sex pheromone ant icancer drug from soil bacteria O O O S O H OH N O O OH O Structure and Bonding in Ethers and Epoxides Bond angles at oxygen are sensitive to steric effects O O H H 105° H CH3 108.5° O O CH3 CH3 112° (CH3)3C C(CH3)3 132° An oxygen atom affects geometry in much the same way as a CH2 group most stable conformation of diethyl ether resembles pentane An oxygen atom affects geometry in much the same way as a CH2 group most stable conformation of tetrahydropyran resembles cyclohexane Physical Properties of Ethers • Boiling points (and melting points) of ethers are lower than corresponding alcohol – E.g. CH3CH2OH (bp 78°C) vs. CH3-O-CH3 (bp -25°C) • Why? No Hydrogen-bonding for ethers Ethers resemble alkanes more than alcohols with respect to boiling point boiling point 36°C 35°C O OH 117°C Intermolecular hydrogen bonding possible in alcohols; not possible in alkanes or ethers. Ethers resemble alcohols more than alkanes with respect to solubility in water solubility in water (g/100 mL) very small O 7.5 Hydrogen bonding to water possible for ethers and alcohols; not possible for alkanes. 9 OH • Solubility of acyclic ethers in water is less than that of corresponding alcohols of equal MW. – Ethers can accept H-bonds, but not donate them Physical Properties-Uses Ethers are less dense than water and form the top layer when mixed with water. • Note: Diethyl ether (“ether”) is a good general purpose solvent for extracting non-polar and polar organic compounds from H2O. • Its low boiling pt (35 oC) is ideal for recovering organic solute by evaporation of ether. Solubility of cyclic ethers in water is greater than that of acyclic ethers of equal MW. • Compact shape more easily accommodated by H-bonding network of water ; Ex: Tetrahydrofuran 1,4-Dioxane completely miscible with water; important cosolvents Solvation Crown Ethers • structure cyclic polyethers derived from repeating —OCH2CH2— units • properties form stable complexes with metal ions • applications synthetic reactions involving anions O O O O O O 18-Crown-6 18-Crown-6 O O O K+ O O O forms stable Lewis acid/Lewis base complex with K+ Ion-Complexing and Solubility + F– O O O O O O K+ O O O benzene O O O 18-crown-6 complex of K+ dissolves in benzene F– carried into benzene to preserve electroneutrality Application to organic synthesis Complexation of K+ by 18-crown-6 "solubilizes" potassium salts in benzene Anion of salt is in a relatively unsolvated state in benzene (sometimes referred to as a "naked anion") Unsolvated anion is very reactive Only catalytic quantities of 18-crown-6 are needed KF CH3(CH2)6CH2Br 18-crown-6 benzene CH3(CH2)6CH2F (92%) 18. 2 Synthesis of Ethers Acid–catalyzed dehydration of Alcohols Diethyl ether prepared industrially by sulfuric acid– catalyzed dehydration of ethanol – also with other primary alcohols The Williamson Ether Synthesis Reaction of metal alkoxides and primary alkyl halides and tosylates Best method for the preparation of ethers Alkoxides prepared by reaction of an alcohol with a strong base such as sodium hydride, NaH Example ONa O I NaI RO-, an alkoxide ion, is both a strong nucleophile (unless bulky and hindered) and a strong base. Both SN2 (desired) and E2 (undesired side product) can occur. • Choose nucleophile and electrophile carefully. Maximize SN2 and minimize E2 reaction by choosing the R’X to have least substituted carbon undergoing substitution (electrophile). Methyl best, then primary, secondary marginal, tertiary never (get E2 instead). • Stereochemistry: the reacting carbon in R’, the electrophile which undergoes substitution, experiences inversion. The alkoxide undergoes no change of configuration. Williamson’s Ether Synthesis has Limitations 1. Alkyl halide must be primary (RCH2X) 2. Alkoxides need be derived from primary, secondary or tertiary alcohols O Na OH Secondary Alkoxide SN2 This reaction worlks particularly well with benzyl and allyl halides, which are excellent alkylating agents Br O Primary Alkyl halide Origin of Reactants OH HCl Cl O OH O Na Na What happens if the alkyl halide is not primary? Br O Na H3C CH3 SN2 is sterically disfavored and E2 predominates O H OH H3C H Silver Oxide-Catalyzed Ether Formation Reaction of alcohols with Ag2O directly with alkyl halide forms ether in one step Glucose reacts with excess iodomethane in the presence of Ag2O to generate a pentaether in 85% yield Addition of Alcohols to Alkenes (CH3)2C=CH2 + CH3OH H+ (CH3)3COCH3 tert-Butyl methyl ether tert-Butyl methyl ether (MTBE) was produced on a scale exceeding 15 billion pounds per year in the U.S. during the 1990s. It is an effective octane booster in gasoline, but contaminates ground water if allowed to leak from storage tanks. Further use of MTBE is unlikely. Alkoxymercuration Mechanism of Oxymercuration Reactions of Ethers: Summary of reactions of ethers No reactions of ethers encountered to this point. Ethers are relatively unreactive. Their low level of reactivity is one reason why ethers are often used as solvents in chemical reactions, and as protecting groups for reactive –OH group. Ethers oxidize in air to form explosive hydroperoxides and peroxides. Acid-Catalyzed Cleavage of Ethers Ethers are generally unreactive Strong acid will cleave an ether at elevated temperature HI, HBr produce an alkyl halide from less hindered component by SN2 (tertiary ethers undergo SN1) Example CH3CHCH2CH3 HBr OCH3 heat CH3CHCH2CH3 Br (81%) + CH3Br Mechanism CH3CHCH2CH3 CH3CHCH2CH3 O •• Br CH3 •• H •• Br •• HBr •• CH3CHCH2CH3 CH3CHCH2CH3 •• – •• Br •• •• O CH3 •• + H •• O •• •• •• Br •• H CH3 Cleavage of Cyclic Ethers O HI 150°C ICH2CH2CH2CH2I (65%) Mechanism •• ICH2CH2CH2CH2I O •• HI •• – •• I • • •• HI •• O+ H •• •• I •• •• •• O H Claisen Rearrangement • Specific to allyl aryl ethers, ArOCH2CH=CH2 • Heating to 200–250°C leads to an o-allylphenol • Result is alkylation of the phenol in an ortho position Epoxides (Oxiranes) • Three membered ring ether is called an oxirane (root “ir” from “tri” for 3-membered; prefix “ox” for oxygen; “ane” for saturated) • Also called epoxides • Ethylene oxide (oxirane; 1,2-epoxyethane) is industrially important as an intermediate • Prepared by reaction of ethylene with oxygen at 300 °C and silver oxide catalyst Epoxides are Extremely Reactive Preparation of Epoxides Using a Peroxyacid • Treat an alkene with a peroxyacid O O RCOOH H O H in CH2Cl2 R C O O Cl H O CO3H MCPBA meta chloroperoxybenzoic acid + RCOH Epoxide Ring Opening reactions: 1. Epoxide Ring Opening in Acid In acid: protonate the oxygen, establishing the very good leaving group. More substituted carbon (more positive charge although more sterically hindered) is attacked by a weak nucleophile. Very similar to opening of cyclic bromonium ion. Review that subject. Due to resonance, some positive charge is located on this carbon. Inversion occurs at this carbon. Do you see it? Classify the carbons. S becomes R. 2. Epoxide Ring Opening in Base In base: no protonation to produce good leaving group, no resonance but the ring can open due to the strain if attacked by good nucleophile. Now less sterically hindered carbon is attacked. A wide variety of synthetic uses can be made of these reactions as shown in the following slides Base-Catalyzed Epoxide Opening • Strain of the three-membered ring is relieved on ring-opening • Hydroxide cleaves epoxides at elevated temperatures to give trans 1,2-diols In base: no protonation to OH O NaOCH3 in CH3OH OCH3 produce good leaving group, no resonance but the ring can open H OCH3 due to the strain if attacked by O Na OCH3 regenerates base catalyst good nucleophile. Now less sterically hindered carbon is attacked. 18.6 Reactions of Epoxides: Ring-Opening • Water adds to epoxides with dilute acid at room temperature • Product is a 1,2-diol (on adjacent C’s: vicinal) • Mechanism: acid protonates oxygen and water adds to opposite side (trans addition) Halohydrins from Epoxides • Anhydrous HF, HBr, HCl, or HI combines with an epoxide • Gives trans product Epoxides from Halohydrins • Addition of HO-X to an alkene gives a halohydrin • Treatment of a halohydrin with base gives an epoxide • Intramolecular Williamson ether synthesis O OH Br2 + HBr Br Addition of Grignards to Ethylene Oxide • Adds –CH2CH2OH to the Grignard reagent’s hydrocarbon chain • Acyclic and other larger ring ethers do not react O RCO3H CH3MgBr OH MgBrO CH3 + enant . H 3O + CH3 Different isomers Variety of products can be obtained by varying the nucleophiles H2O/ NaOH Do not memorize this chart. But be sure you can figure it out from the general reaction: attack of nucleophile in basic media on less hindered carbon 1. 2. OH LiAlH4 H2O An Example of Synthetic Planning Reactions of a nucleophile (basic) with an epoxide/oxirane ring reliably follow a useful pattern. The epoxide ring has to have been located here The pattern to be recognized in the product is –C(-OH) – C-Nu This bond was created by the nucleophile Synthetic Applications nucleophile Realize that the H2NCH2was derived from nucleophile: CN N used as nucleophile twice. Formation of ether from alcohols. Epichlorohyrin and Synthetic Planning, same as before but now use two nucleophiles Observe the pattern in the product Nu - C – C(OH) – C - Nu. When you observe this pattern it suggests the use of epichlorohydrin. Both of these bonds will be formed by the incoming nucleophiles. Why does Acid Catalyzed Opening Give Inversion? O CH3CH2 CH3 NaOH, H2O (S) + H 3O HO CH3CH2 CH3 CH2OH (S) HO CH3 CH3CH2 CH2OH (R) Propose a Mechanism Br O 1) NaOCH3 2) heat CH3OCH2 O + NaBr 2 Successive SN2 Reactions OCH3 Br 1) NaOCH3 2) heat O Br CH3O O CH3OCH2 O + NaBr Provide a Mechanism OH + H , H2O O OH • Sulfur-containing amino acids • • Methionine and Cysteine • Important in protein secondary and tertiary structure H N O S N O penicillin H N H S MeO O O S O N N H2N CO2H N H OMe omeprazole dapsone SO3 Na Physical Properties • Thiols and sulfides are more volatile (lower bp) than corresponding alcohols or ethers. Stench! Skunky! • Hydrogen bonding less important for thiols compared to alcohols • Dipoles are less pronounced Thiols are more acidic than alcohols (pKa) – Size mismatch between small hard proton and large, polarizable sulfur atom favours formation of thiolate anion. Thiols: Formation and Reaction • From alkyl halides by displacement with a sulfur nucleophile such as –SH – The alkylthiol product can undergo further reaction with the alkyl halide to give a symmetrical sulfide, giving a poorer yield of the thiol Using Thiourea to Form Alkylthiols • Thiols can undergo further reaction with the alkyl halide to give dialkyl sulfides • For a pure alkylthiol use thiourea (NH2(C=S)NH2) as the nucleophile • This gives an intermediate alkylisothiourea salt, which is hydrolyzed cleanly to the alkyl thiourea Preparation of Thiols Use an alkyl halide and H2S or AcSH H2S, KOH, EtOH Br N Ph SH N i, (COCl)2, DMF, CH2Cl2, r.t. OH ii, KSAc, DMF, r.t. iii, KOH, EtOH, r.t. then HCl pH 5 Ph SH J. Am. Chem. Soc., 2005, 127, 15668 OH OH NH2 Br SH i, NaNO2, HCl ii, KS OEt , H2O Br S iii, LiAlH4 J. Org. Chem., 1990, 55, 2736 For palladium coupling of AcS– and ArX, see Tetrahedron Lett., 2007, 48, 3033 Oxidation of Thiols to Disulfides • Reaction of an alkyl thiol (RSH) with bromine or iodine gives a disulfide (RSSR) • The thiol is oxidized in the process and the halogen is reduced Sulfides • Thiolates (RS) are formed by the reaction of a thiol with a base • Thiolates react with primary or secondary alkyl halide to give sulfides (RSR’) • Thiolates are excellent nucleophiles and react with many electrophiles Sulfides as Nucleophiles • Sulfur compounds are more nucleophilic than their oxygencompound analogs – 3p electrons valence electrons (on S) are less tightly held than 2p electrons (on O) • Sulfides react with primary alkyl halides (SN2) to give trialkylsulfonium salts (R3S+) Sulfides as Nucleophiles Oxidation of Sulfides • Sulfides are easily oxidized with H2O2 to the sulfoxide (R2SO) • Oxidation of a sulfoxide with a peroxyacid yields a sulfone (R2SO2) • Dimethyl sulfoxide (DMSO) is often used as a polar aprotic solvent Oxidation of Sulfides Reaction of Thiols Good nucleophiles BuBr, Cs2CO3 SH S DMF, Bu4NI, r.t. 93% HO PhCH2Cl, Cs2CO3 SH HO DMF, Bu4NI, r.t. S Ph 73% MeO BrCH2CO2tBu, Cs2CO3 SH DMF, Bu4NI, r.t. MeO S CO2tBu 97% Tetrahedron Lett., 2005, 46, 8931 Suitable for alkyl-alkyl and aryl-alkyl thioethers Successful for secondary alkyl iodides (iPrI) but not tertiary halides No racemization using L-cysteine methyl ester 18.9 Spectroscopy of Ethers • Infrared: C–O single-bond stretching 1050 to 1150 cm1 overlaps many other absorptions. • Proton NMR: H on a C next to ether O is shifted downfield to 3.4 to 4.5 – The 1H NMR spectrum of dipropyl ether shows this signal at 3.4 – In epoxides, these H’s absorb at 2.5 to 3.5 d in their 1H NMR spectra • Carbon NMR: C’s in ethers exhibit a downfield shift to 50 to 80