Ch.18: Ethers and Epoxides; Thiols and Sulfides Dr. Sivappa Rasapalli Chemistry and Biochemistry University of Massachusetts Dartmouth

Coverage and Objectives 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.

Nomenclature of Ethers, Epoxides, and Sulfides 18.1 Names and Properties of Ethers Nomenclature of Ethers, Epoxides, and Sulfides 2

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 3

Nomenclature: Substituent name as alkoxy derivatives of alkanes CH3OCH2 CH3 CH3CH2OCH2CH2CH2Cl methoxyethane 1-chloro-3-ethoxypropane CH3CH2OCH2 CH3 ethoxyethane 3

Nomenclature: Functional Class analogous to ethers, but replace “ether” as last word in the name by “sulfide.” CH3SCH2 CH3 SCH3 ethyl methyl sulfide cyclopentyl methyl sulfide CH3CH2SCH2 CH3 diethyl sulfide 3

Nomenclature: Substituent name as alkylthio derivatives of alkanes CH3SCH2 CH3 SCH3 methylthioethane (methylthio)cyclopentane CH3CH2SCH2 CH3 ethylthioethane 3

Names of Cyclic Ethers O O O Oxirane (Ethylene oxide) Oxetane Oxolane (tetrahydrofuran) Oxane (tetrahydropyran) 1,4-Dioxane O O O 3

Names of Cyclic Sulfides Thiirane Thietane Thiolane Thiane S 3

Examples of Nomenclature

Structure and Bonding in Ethers and Epoxides 8

Bond angles at oxygen are sensitive to steric effects H O (CH3)3C C(CH3)3 112° 105° 108.5° 132° CH3 9

An oxygen atom affects geometry in much the same way as a CH2 group most stable conformation of diethyl ether resembles pentane 10

An oxygen atom affects geometry in much the same way as a CH2 group most stable conformation of tetrahydropyran resembles cyclohexane 10

Physical Properties of Ethers 11

• 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 Intermolecular hydrogen bonding possible in alcohols; not possible in alkanes or ethers. 36°C 35°C O 117°C OH 12

Ethers resemble alcohols more than alkanes with respect to solubility in water solubility in water (g/100 mL) very small 7.5 Hydrogen bonding to water possible for ethers and alcohols; not possible for alkanes. O 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 12

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 18-Crown-6 14

18-Crown-6 O K+ forms stable Lewis acid/Lewis base complex with K+ 15

Ion-Complexing and Solubility + F– O O K+ benzene 18-crown-6 complex of K+ dissolves in benzene F– carried into benzene to preserve electroneutrality 16

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 CH3(CH2)6CH2Br KF 18-crown-6 benzene CH3(CH2)6CH2F (92%) 20

18. 2 Synthesis of Ethers 21

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 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. 25

Williamson’s Ether Synthesis has Limitations 1. Alkyl halide must be primary (RCH2X) 2. Alkoxides need be derived from primary, secondary or tertiary alcohols 26

Origin of Reactants 26

What happens if the alkyl halide is not primary? 27

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 (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. 23

Alkoxymercuration

Mechanism of Oxymercuration

Reactions of Ethers: 28

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. 27

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) 31

Example CH3CHCH2CH3 HBr CH3CHCH2CH3 + CH3Br heat OCH3 Br (81%) 31

Mechanism CH3CHCH2CH3 Br HBr CH3 CH3CHCH2CH3 O CH3CHCH2CH3 O CH3 H + H • • •• CH3CHCH2CH3 O CH3 H + •• H Br • • •• •• • • CH3 Br CH3CHCH2CH3 O H Br – •• • • 31

Cleavage of Cyclic Ethers HI ICH2CH2CH2CH2I 150°C (65%) 32

Mechanism O ICH2CH2CH2CH2I HI HI H O + I – H O I •• •• •• • • •• • • 32

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

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 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.

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

Addition of Grignards to Ethylene Oxide Adds –CH2CH2OH to the Grignard reagent’s hydrocarbon chain Acyclic and other larger ring ethers do not react

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 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 This bond was created by the nucleophile The pattern to be recognized in the product is –C(-OH) – C-Nu

Synthetic Applications nucleophile Realize that the H2NCH2- was 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.

Example – Retrosynthesis Analysis A b blocker

Why does Acid Catalyzed Opening Give Inversion?

Propose a Mechanism

2 Successive SN2 Reactions

Provide a Mechanism

Sulfur-containing amino acids • Methionine and Cysteine Important in protein secondary and tertiary structure

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 in particular are smelly - e.g. crotyl thiol and prenyl thiol are present in excretions from skunks! But can be pleasant - as in coffee =furfuryl mercaptan ( furan with CH2SH in the 2-position). Ethyl mercaptan is added to natural gas. The nose can detect it in concentrations as low as 1 part in 50 billion parts of air. The name mercaptan comes form the Latin, mercurium captans, which means capturing mercury. Diminished difference in pKa due to less effective resonance stabilization of S- (3p-2p) compared to O- (2p-2p) Note that sulfur is not very electronegative - it has the same Pauling value of electronegativity as carbon (2.5)! So a carbon-sulfur bond is not polarized. However it is polarizable and large, with 3p orbitals (to give sp3 lone pair), so it is nucleophilic.

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 J. Am. Chem. Soc., 2005, 127, 15668 Excess H2S passed through the solution Thioacetate and an alkyl halide (or can use thioacetic acid, an alcohol, PPh3, DEAD in Mitsunobu, eg 07BMCL2250) Diazotization then potassium xanthate 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 oxygen-compound 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 Tetrahedron Lett., 2005, 46, 8931 TBAI probably as phase transfer cat 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 cm1 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