Chapter 18 Ethers and Epoxides; Thiols and Sulfides

Introduction Ethers are compounds with two organic groups (alkyl, aryl, or vinyl) bonded to the same oxygen atom, R–O–R’, in a ring or in an open chain industrial solvent anesthetic perfume solvent

Thiols (R–S–H) and sulfides (R–S–R’) are sulfur analogs of alcohols and ethers, respectively Sulfur replaces oxygen

1. Naming Ethers Ethers are named according to IUPAC rules: Simple ethers with no other functional groups are named by identifying the two organic substituents and adding the word ether If other functional groups are present, the ether part is considered an alkoxy substituent

Simple ethers with no other functional groups are named by identifying the two organic substituents and adding the word ether

If other functional groups are present, the ether part is considered an alkoxy substituent

Practice Problem: Name the following ethers according to IUPAC rules Diisopropyl ether Cyclopentyl propyl ether p-Bromoanisole or 4-Bromo-1-methoxybenzene 1-Methoxycyclohexene Ethyl isobutyl ether Allyl vinyl ether

2. Structure and Properties of Ethers The geometry around the O atom of an ether (ROR) is similar to that of water (HOH) R-O-R has an ~ tetrahedral bond angle (112° in dimethyl ether) The O atom is sp3-hybridized

The oxygen atom gives ethers a slight dipole moment

Ethers have higher boiling points than alkanes with similar MW

3. Synthesis of Ethers Ethers can be synthesized by: Acid-catalyzed dehydration of alcohols Williamson ether synthesis Alkoxymercuration of alkenes

i. Acid-catalyzed dehydration of alcohols Symmetrical ethers can be prepared by acid-catalyzed dehydration of primary alcohols (SN2) Example: Diethyl ether is prepared industrially by sulfuric acid–catalyzed dehydration of ethanol Acid-catalyzed dehydration of secondary and tertiary alcohols yield alkenes (E1)

Practice Problem: Why do you suppose only symmetrical ethers Practice Problem: Why do you suppose only symmetrical ethers are prepared by the sulfuric acid-catalyzed dehydration procedure? What product(s) would you expect if ethanol and 1-propanol were allowed to react together? In what ratio would the products be formed if the two alcohols were of equal reactivity?

ii. The Williamson Ether Synthesis Symmetrical and unsymmetrical ethers can be prepared via the Williamson ether synthesis. It is a process in which metal alkoxides react with primary alkyl halides and/or tosylates via SN2 It is the best method for the preparation of ethers

Alkoxides are prepared by reaction of an alcohol with a strong base such as sodium hydride, NaH Acid Base Sodium salt of the alcohol

Silver Oxide-Catalyzed Ether Formation is a variation of the Williamson ether synthesis Direct reaction of alcohols in Ag2O with alkyl halide forms ether in one step Example: Glucose reacts with excess iodomethane in the presence of Ag2O to generate a pentaether in 85% yield

Mechanism of the Williamson Ether Synthesis The Williamson ether synthesis involves SN2 reaction of an alkoxide ion with a primary alkyl halide An alkoxide nucleophile (RO-) displaces a halide ion (X-) via SN2 Primary halides and tosylates work best for SN2 because more hindered substrates undergo competitive E2 elimination of HX

Unsymmetrical ethers should be synthesized by reaction between the more hindered alkoxide ion and less hindered alkyl halide rather than vice versa Example: Synthesis of tert-butyl methyl ether

Practice Problem: How would you prepare the following ethers Practice Problem: How would you prepare the following ethers using Williamson synthesis? Methyl propyl ether Anisole (methyl phenyl ether) Benzyl isopropyl ether Ethyl 2,2-dimethylpropyl ether

iii. Alkoxymercuration of Alkenes Ethers can be prepared via Alkoxymercuration of Alkenes followed by demercuration Alkoxymercuration occurs when an alkene reacts with an alcohol in mercuric acetate or trifluoroacetate Demercuration involves reduction of C-Hg by NaBH4

Mechanism of Alkoxymercuration/Demercuration The mechanism involves: Electrophilic addition of Hg2+ to an alkene, followed by reaction of intermediate cation with alcohol: Overall Markovnikov addition of alcohol to alkene Reduction of C-Hg by NaBH4

Practice Problem: How would you prepare the ethyl phenyl. ether Practice Problem: How would you prepare the ethyl phenyl ether? Use whichever method you think is more appropriate, the Williamson synthesis or the alkoxymercuration reaction.

Practice Problem: Write the mechanism of the alkoxymercuration Practice Problem: Write the mechanism of the alkoxymercuration reaction of 1-methylcyclopentene with ethanol. Use curved arrows to show the electron flow in each step.

alkoxymercuration reaction. Practice Problem: How would you prepare the following ethers? Use whichever method you think is more appropriate, the Williamson synthesis or the alkoxymercuration reaction. Butyl cyclohexyl ether Benzyl ethyl ether (C6H5CH2OCH2CH3) sec-Butyl tert-butyl ether Tetrahydrofuran

3. Reactions of Ethers Ethers undergo: Acidic Cleavage Claisen Rearrangement

i. Acidic Cleavage Ethers are generally unreactive to most reagents but react with strong acids (HI and HBr) at high temperature HI, HBr produce an alkyl halide from less hindered component by SN2 (tertiary ethers undergo SN1)

Mechanism of the Acidic Cleavage The acidic cleavage reaction takes place: via SN2 mechanism at the less highly substituted site if only primary and secondary alkyl are bonded to the ether O via SN1 or E1 mechanism if one of the alkyl groups bonded to the ether O is tertiary

Ethers with primary and secondary alkyl groups react with HI or HBr via SN2 mechanism I- or Br- attacks the protonated ether at the less hindered site

Ethers with a tertiary, benzylic, or allylic group react with HI or HBr via SN1 or E1 mechanism These can produce stable intermediate carbocations Example: tert-Butyl cyclohexyl ether reacts via E1

Practice Problem: Predict the products of the following reaction: Ethers with primary and secondary alkyl groups – via SN2 Ethers with a tertiary, benzylic, or allylic group – via SN1 or E1

Practice Problem: Predict the products of each of the following Practice Problem: Predict the products of each of the following reactions:

Practice Problem: Write the mechanism of the acid-catalyzed Practice Problem: Write the mechanism of the acid-catalyzed cleavage of tert-butyl cyclohexyl ether to yield cyclohexanol and 2-methylpropene

Practice Problem: Why are HI and HBr more effective than HCl Practice Problem: Why are HI and HBr more effective than HCl in cleaving ethers? Nucleophilicity usually increases going down a column of the periodic table The halide reactivity order is I- > Br- > Cl-

ii. Claisen Rearrangement Claisen rearrangement is specific to allyl aryl ethers, ArOCH2CH=CH2 Heating the allyl aryl ether to 200–250°C leads to an o-allylphenol Result is alkylation of the phenol in an ortho position

Mechanism of the Claisen Rearrangement The reaction proceeds via a pericyclic mechanism: a concerted reorganization of bonding electrons involving a 6-electron, 6-membered ring transition state leading to 6-allyl-2,4-cyclohexadienone intermediate The mechanism is consistent with 14C labelling

Practice Problem: What product would you expect from Claisen Practice Problem: What product would you expect from Claisen rearrangement of 2-butenyl phenyl ether?

4. Cyclic Ethers: Epoxides Cyclic ether behaves like an acyclic ether, except if the ring is 3-membered Dioxane and tetrahydrofuran are used as solvents

Epoxides (Oxiranes) An epoxide is a three-membered ring ether It is also called an oxirane (root “ir” from “tri” for 3-membered; prefix “ox” for oxygen; “ane” for saturated) It has a unique chemical reactivity (behaves differently from other open-chain ethers) due to the strain of the 3-membered ring

Ethylene oxide (1,2-epoxyethane) is industrially important as an intermediate It is the simplest epoxide (oxirane) It is prepared by reaction of ethylene with oxygen at 300°C and silver oxide catalyst

In the laboratory, epoxides can be prepared by: Treatment of an alkene with a peroxyacid Treatment of a halohydrin with base

i. Preparation of Epoxides Using a Peroxyacid An epoxide is prepared by treatment of an alkene with a peroxyacid (RCO3H) m-chloroperoxybenzoic acid is a common peroxyacid used

The mechanism of epoxidation by treatment of an alkene with a peroxyacid (RCO3H): is a one-step process in which peroxyacids transfer oxygen to the alkene with syn stereochemistry (no intermediates)

ii. Preparation of Epoxides from Halohydrins An epoxide is prepared by treatment of a halohydrin with base Addition of HO-X to an alkene gives a halohydrin Treatment of a halohydrin with base eliminates HX and gives an epoxide

The mechanism of epoxidation by treatment of a halohydrin with a base is an intramolecular Williamson ether synthesis: The nucleophilic alkoxide ion and the electrophilic alkyl halide are in the same molecule

Practice Problem: What product would you expect from reaction Practice Problem: What product would you expect from reaction of cis-2-butene with m-chloroperoxybenzoic acid? Show the stereochemistry

Practice Problem: Reaction of trans-2-butene with m-chloropero Practice Problem: Reaction of trans-2-butene with m-chloropero -xybenzoic acid yields an epoxide different from that obtained by reaction of the cis isomer. Explain.

5. Ring-Opening Reactions of Epoxides There are two types of ring-opening reactions of epoxides: Acid-Catalyzed Epoxide Opening Base-Catalyzed Epoxide Opening

i. Acid-Catalyzed Epoxide Opening Water adds to epoxides with dilute acid at room temperature The product is a 1,2-diol, also called vicinal glycol (on adjacent C’s: vicinal) Epoxides react under milder conditions because of ring strain

Ethylene Glycol 1,2-ethanediol is synthesized from acid catalyzed hydration of ethylene oxide Widely used as automobile antifreeze (lowers freezing point of water solutions)

The mechanism of acid-catalyzed epoxide cleavage involves: Protonation: Acid protonates oxygen Backside attack of a nucleophile: water adds to opposite side (trans addition)

The mechanism of acid-catalyzed epoxide cleavage is similar to the final step of alkene bromination

Halohydrins from Epoxides Anhydrous HF, HBr, HCl, or HI also combines with an epoxide This gives a trans product (halohydrin)

Regiochemistry of Acid-Catalyzed Opening of Epoxides When both epoxide carbon atoms are either primary or secondary, the nucleophile preferably attacks the less highly substituted site (less hindered site) When one of the epoxide carbon atoms is tertiary, the nucleophile attacks the more highly substituted site

The mechanism is neither purely SN1 nor SN2. more stable, tertiary carbocation T.S character (SN1-like) back-side displacement of leaving group (SN2-like)

Practice Problem: Predict the major product of the following reaction:

Practice Problem: Predict the major product of each of the Practice Problem: Predict the major product of each of the following reactions:

Practice Problem: How would you prepare the following diols?

ii. Base-Catalyzed Epoxide Opening Unlike other ethers, epoxides can be cleaved by base as well as by acid Strain of the three-membered ring is relieved on ring-opening Hydroxide ion cleaves epoxides at elevated temperatures to give trans 1,2-diols

Addition of Grignards to Ethylene Oxide Grignard reagents cleave the ring of epoxides Reaction of ethylene oxide with Grignard reagent adds –CH2CH2OH to the Grignard reagent’s hydrocarbon chain Acyclic and other larger ring ethers do not react Grignard reagent

Base-catalyzed epoxide opening is SN2-like Attack of the nucleophile takes place at the less hindered epoxide carbon

Practice Problem: Predict the major product of the following Practice Problem: Predict the major product of the following reactions:

6. Crown Ethers Crown ethers are large rings consisting of repeating (-OCH2CH2-) or similar units They were discovered by Charles Pedersen (Dupont; early 1960’s)

Crown ethers are named as x-crown-y x is the total number of atoms in the ring y is the number of oxygen atoms Example: 18-crown-6 ether: 18-membered ring containing 6 oxygens atoms Central cavity is electronegative and attracts cations

Uses of Crown Ethers Complexes between crown ethers and ionic salts are soluble in nonpolar organic solvents This allows reactions to be carried out under aprotic conditions It thus creates reagents that are free of water that have useful properties

Inorganic salts (eg. KF, KCN, and NaN3) dissolve in organic solvents with the help of crown ethers This leaves the anion dissociated, enhancing reactivity Purple benzene

Practice Problem: 15-Crown-5 and 12-crown-4 ethers complex Practice Problem: 15-Crown-5 and 12-crown-4 ethers complex Na+ and Li+, respectively. Make models of these crown ethers, compare the sizes of the cavities.

7. Thiols and Sulfides Thiols (RSH), also known as mercaptans, are sulfur analogs of alcohols They are named with the suffix –thiol SH group is called “mercapto group” (“capturer of mercury”)

Sulfides Sulfides (RSR’) are sulfur analogs of ethers They are named by rules used for ethers, with sulfide in place of ether for simple compounds and alkylthio in place of alkoxy

Thiols: Formation and Reaction Thiols are prepared from alkyl halides by SN2 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 For a pure alkylthiol, thiourea (NH2(C=S)NH2) is used as the nucleophile This gives an intermediate alkylisothiourea salt, which is hydrolyzed cleanly to the alkyl thiourea This avoids the problem of thiols undergoing further reaction with the alkyl halide to give dialkyl sulfides

Oxidation of Thiols to Disulfides Reaction of an alkylthiol (RSH) with bromine (Br2) or iodine (I2) gives a disulfide (RSSR’) The thiol is oxidized in the process and the halogen is reduced It is reversed when the disulfide is reduced back to thiol by treatment with Zn and H+ Disulfide “bridges” form the cross-links between protein chains (stabilize the three dimensional conformations of proteins)

Sulfides: Formation and Reaction Thiolate ions (RS-) are formed by the reaction of a thiol with a base react with primary or secondary alkyl halide to give sulfides (RSR’) are excellent nucleophiles and react with many electrophiles via SN2 mechanism

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 via SN2 to give trialkylsulfonium salts (R3S+) This is unlike dialkyl ethers

Trialkylsulfonium salts are useful alkylating agents: A nucleophile can attack one of the groups bonded to the positively charged sulfur, displacing a neutral sulfide as leaving group

Unlike ethers, sulfides are easily oxidized. Oxidation of Sulfides Unlike ethers, sulfides are easily oxidized. 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

Practice Problem: Name the following compounds:

Practice Problem: 2-Butene-1-thiol is one component of skunk. spray Practice Problem: 2-Butene-1-thiol is one component of skunk spray. How would you synthesize this substance from methyl 2-butenoate? From 1,3-butadiene?

8. 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 are shifted downfield to 3.4  to 4.5  The 1H NMR spectrum of dipropyl ether shows the these signals at 3.4  In epoxides, these H’s absorb at  2.5 to  3.5 in their 1H NMR spectra Carbon NMR: C’s in ethers exhibit a downfield shift to  50 to  80

Infrared Spectroscopy Ethers are difficult to distinguish by IR spectroscopy C–O single-bond stretching 1050 to 1150 cm1 overlaps many other absorptions. IR spectrum: CH3CH2OCH2CH3

Nuclear Magnetic Resonance Spectroscopy Proton NMR: H on a C next to ether O are shifted downfield to 3.4  to 4.5  The 1H NMR spectrum of dipropyl ether shows the these signals at 3.4 

Proton NMR: H on a C next to ether O are shifted downfield to 3 Proton NMR: H on a C next to ether O are shifted downfield to 3.4  to 4.5  In epoxides, these H’s absorb at 2.5 to 3.5  in their 1H NMR spectra Example: 1,2-epoxypropane

Carbon NMR: C’s in ethers exhibit a downfield shift to 50  to 80  Example: These C’s in methyl propyl ether absorb at 58.5 and 74.8 d Example: These C’s in anisole absorb at 54.8 d

Practice Problem: The 1H NMR spectrum shown is that of an Practice Problem: The 1H NMR spectrum shown is that of an ether with the formula C4H8O. Propose a structure.

Chapter 18 The End