Chapter 18

• EthersEthers are compounds with two organic groups (alkyl, aryl, or vinyl) bonded to the

same oxygen atom, R–O–R’R–O–R’, in a ring or in an open chain

IntroductionIntroduction

anesthetic perfume solvent

industrial solvent

• ThiolsThiols (R–S–HR–S–H) and sulfidessulfides (R–S–R’R–S–R’) are sulfur analogs of alcohols and ethers, respectively

– Sulfur replaces oxygen

11.. Naming EthersNaming Ethers

11.. Naming EthersNaming 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 etherether

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

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

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

Practice ProblemPractice Problem: Name the following ethers according to IUPAC : Name the following ethers according to IUPAC rules rules

(a) Diisopropyl ether(b) Cyclopentyl propyl ether(c) p-Bromoanisole or

4-Bromo-1-methoxybenzene

(d) 1-Methoxycyclohexene(e) Ethyl isobutyl ether(f) Allyl vinyl ether

22.. Structure and Properties of EthersStructure and Properties of Ethers

22.. Structure and Properties of EthersStructure and Properties of Ethers

• The geometry around the O atom of an ether (ROR) is similar to that of water (HOH)

– R-O-R R-O-R has an ~ tetrahedral bond angle tetrahedral bond angle (112° in dimethyl ether)

– The OO atom is spsp33-hybridized-hybridized

• The oxygenoxygen atom gives ethers a slight dipole moment

• EthersEthers have higher boiling pointshigher boiling points than alkanes with similar MW

33.. Synthesis of EthersSynthesis of Ethers

33.. Synthesis of EthersSynthesis of Ethers

• Ethers can be synthesized by:

i.i. Acid-catalyzed dehydration of alcoholsAcid-catalyzed dehydration of alcohols

ii.ii. Williamson ether synthesisWilliamson ether synthesis

iii.iii. Alkoxymercuration of alkenesAlkoxymercuration of alkenes

• Symmetrical ethersSymmetrical ethers can be prepared by acid-catalyzed dehydration of primary alcoholsprimary alcohols (SSNN22)

– ExampleExample: Diethyl ether is prepared industrially by sulfuric acid–catalyzed dehydration of ethanol

– Acid-catalyzed dehydration of secondary and tertiary alcohols yield alkenes (E1)

i. Acid-catalyzed dehydration of alcoholsi. Acid-catalyzed dehydration of alcohols

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

• Symmetrical Symmetrical and unsymmetrical ethers unsymmetrical ethers can be prepared via the Williamson ether synthesisWilliamson ether synthesis.

– It is a process in which metal alkoxides react with primary alkyl halides and/or tosylates via SSNN22

– It is the best method for the preparation of ethers

ii. The Williamson Ether Synthesisii. The Williamson Ether Synthesis

– 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 FormationSilver 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

– ExampleExample: Glucose reacts with excess iodomethane in the presence of Ag2O to generate a pentaether in 85% yield

• The Williamson ether synthesis involves SSNN2 reaction2 reaction of an alkoxide ion with a primary alkyl halide

– An alkoxide nucleophile (ROAn alkoxide nucleophile (RO--) displaces a halide ion (X) displaces a halide ion (X--) ) via Svia SNN22

– Primary halides and tosylates work bestPrimary halides and tosylates work best for SN2 because more hindered substrates undergo competitive E2 elimination of HX

Mechanism of the Williamson Ether SynthesisMechanism of the Williamson Ether Synthesis

– Unsymmetrical ethers should be synthesized by reaction between the more hindered alkoxide ion and less hindered alkyl halide rather than vice versa

ExampleExample: Synthesis of tert-butyl methyl ether

Practice ProblemPractice Problem: How would you prepare the following ethers : How would you prepare the following ethers using Williamson synthesis? using Williamson synthesis?

a. Methyl propyl ether

b. Anisole (methyl phenyl ether)

c. Benzyl isopropyl ether

d. Ethyl 2,2-dimethylpropyl ether

• Ethers Ethers can be prepared via Alkoxymercuration of Alkoxymercuration of AlkenesAlkenes followed by demercurationdemercuration

– Alkoxymercuration occurs when an alkene reacts with an alcohol in mercuric acetate or trifluoroacetate

– Demercuration involves reduction of C-Hg by NaBH4

iii. Alkoxymercuration of Alkenesiii. Alkoxymercuration of Alkenes

Mechanism of Alkoxymercuration/DemercurationMechanism 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 ProblemPractice Problem: How would you prepare the ethyl phenyl : How would you prepare the ethyl phenyl ether? Use whichever method you think is ether? Use whichever method you think is more appropriate, the Williamson synthesis more appropriate, the Williamson synthesis or the alkoxymercuration reaction.or the alkoxymercuration reaction.

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

in in each step. each step.

Practice ProblemPractice Problem: How would you prepare the following ethers? : How would you prepare the following ethers? Use whichever method you think is more Use whichever method you think is more appropriate, the Williamson synthesis or the appropriate, the Williamson synthesis or the alkoxymercuration reaction.alkoxymercuration reaction.

a. Butyl cyclohexyl ether

b. Benzyl ethyl ether (C6H5CH2OCH2CH3)

c. sec-Butyl tert-butyl ether

d. Tetrahydrofuran

33.. Reactions of EthersReactions of Ethers

33.. Reactions of EthersReactions of Ethers

• Ethers undergo:

i.i. Acidic CleavageAcidic Cleavage

ii.ii. Claisen RearrangementClaisen Rearrangement

• EthersEthers are generally unreactive to most reagents but reactreact with strong acids strong acids (HIHI and HBrHBr) at high temperature

– HI, HBr produce an alkyl halide from less hindered component by SN2 (tertiary ethers undergo SN1)

i. Acidic Cleavagei. Acidic Cleavage

• The acidic cleavage reaction takes place:

– via SSNN2 mechanism2 mechanism at the less highly substituted site if only primaryprimary and secondarysecondary alkylalkyl are bonded to the ether O

– via SSNN1 or E1 mechanism1 or E1 mechanism if one of the alkyl groups bonded to the ether O is tertiarytertiary

Mechanism of the Acidic CleavageMechanism of the Acidic Cleavage

• Ethers with primary primary and secondarysecondary alkylalkyl groups react with HI or HBr via SSNN2 mechanism2 mechanism

– II-- or Br or Br- - attacks the protonated ether at the less hindered attacks the protonated ether at the less hindered sitesite

• Ethers with a tertiarytertiary, benzylicbenzylic, or allylic allylic group react with HI or HBr via SSNN1 or E1 mechanism1 or E1 mechanism

– These can produce stable intermediate carbocations

– ExampleExample: tert-Butyl cyclohexyl ether reacts via E1

Practice ProblemPractice Problem: Predict the products of the following reaction:: Predict the products of the following reaction:

• Ethers with primary primary and secondarysecondary alkylalkyl groups – via SSNN22

• Ethers with a tertiarytertiary, benzylicbenzylic, or allylic groupallylic group – via SSNN1 or E11 or E1

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

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

Practice ProblemPractice Problem: Why are HI and HBr more effective than HCl : Why are HI and HBr more effective than HCl in cleaving ethers? in cleaving ethers?

Nucleophilicity usually increases going down a column of the periodic table

The halide reactivity order is I- > Br- > Cl-

• Claisen rearrangementClaisen rearrangement is specific to allyl aryl ethersallyl 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

ii. Claisen Rearrangementii. 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

Mechanism of the Claisen RearrangementMechanism of the Claisen Rearrangement

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

44.. Cyclic Ethers: EpoxidesCyclic Ethers: Epoxides

44.. Cyclic Ethers: EpoxidesCyclic 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)Epoxides (Oxiranes)

• An epoxideAn epoxide is a three-membered ring ether

– It is also called an oxiranean oxirane (root “ir” from “tri” for 3-membered; prefix “ox” for oxygen; “ane” for saturated)

– It has a unique chemical reactivityunique chemical reactivity (behaves differently from other open-chain ethers) due to the strain of the 3-membered ring

• Ethylene oxide Ethylene oxide (1,2-epoxyethane1,2-epoxyethane) is industrially important as an intermediate

– It is the simplestsimplest 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:

i.i. Treatment of an alkene with a peroxyacidTreatment of an alkene with a peroxyacid

ii.ii. Treatment of a halohydrin with baseTreatment of a halohydrin with base

• An epoxideAn epoxide is prepared by treatment of an alkene with a alkene with a peroxyacid (RCOperoxyacid (RCO33H)H)

– m-chloroperoxybenzoicm-chloroperoxybenzoic acid is a common peroxyacid used

i. Preparation of Epoxides Using a Peroxyacidi. Preparation of Epoxides Using a Peroxyacid

• The mechanism of epoxidation by treatment of an alkene The mechanism of epoxidation by treatment of an alkene with a peroxyacid (RCOwith a peroxyacid (RCO33H):H):

– is a one-step process in which peroxyacids transfer oxygen to the alkene with syn stereochemistry (no intermediates)

• An epoxideAn epoxide is prepared by treatment of a halohydrin a halohydrin

with basewith base

– Addition of HO-X to an alkene gives a halohydrin

– Treatment of a halohydrin with base eliminates HX and gives an epoxide

ii. Preparation of Epoxides from Halohydrins ii. Preparation of Epoxides from Halohydrins

• The mechanism of epoxidation by treatment of a The mechanism of epoxidation by treatment of a halohydrin with a base is an halohydrin with a base is an intramolecular Williamson intramolecular Williamson ether synthesisether synthesis::

– The nucleophilic alkoxide ion and the electrophilic alkyl halide are in the same molecule

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

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

isomer. Explain. isomer. Explain.

55.. Ring-Opening Reactions of EpoxidesRing-Opening Reactions of Epoxides

55.. Ring-Opening Reactions of EpoxidesRing-Opening Reactions of Epoxides

• There are two types of ring-opening reactions of epoxides:

i.i. Acid-Catalyzed Epoxide OpeningAcid-Catalyzed Epoxide Opening

ii.ii. Base-Catalyzed Epoxide OpeningBase-Catalyzed Epoxide Opening

• Water adds to epoxides with dilute acid at room temperature

– The product is a 1,2-diol1,2-diol, also called vicinal glycolvicinal glycol (on adjacent C’s: vicinal)

– Epoxides react under milder conditions because of ring strain

i. Acid-Catalyzed Epoxide Openingi. Acid-Catalyzed Epoxide Opening

Ethylene GlycolEthylene 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 The mechanism of acid-catalyzed epoxide cleavage involves:involves:

– ProtonationProtonation: Acid protonates oxygen

– Backside attack of a nucleophileBackside attack of a nucleophile: water adds to opposite side (trans addition)

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

Halohydrins from EpoxidesHalohydrins from Epoxides

• Anhydrous HF, HBr, HCl, or HI also combines with an epoxide

– This gives a transtrans product (halohydrin)

Regiochemistry of Acid-Catalyzed Opening of EpoxidesRegiochemistry of Acid-Catalyzed Opening of Epoxides

– When both epoxide carbon atoms are either primary or secondaryprimary or secondary, the nucleophile preferably attacks the less highly substitutedless highly substituted site (less hindered site)

– When one of the epoxide carbon atoms is tertiarytertiary, the nucleophile attacks the more highly substitutedmore highly substituted site

• The mechanism is neither purely SN1 nor SN2.– more stable, tertiary carbocation T.S character (SSNN1-like1-like) – back-side displacement of leaving group (SSNN2-like2-like)

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

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

Practice ProblemPractice Problem: How would you prepare the following diols?: How would you prepare the following diols?

• 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

ii. Base-Catalyzed Epoxide Openingii. Base-Catalyzed Epoxide Opening

• 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

Addition of Grignards to Ethylene OxideAddition of Grignards to Ethylene Oxide

Grignard reagentGrignard reagent

• Base-catalyzed epoxide opening is SN2-like

– Attack of the nucleophile takes place at the less hindered epoxide carbon

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

66.. Crown EthersCrown Ethers

66.. Crown EthersCrown Ethers

• Crown ethersCrown ethers are large rings consisting of repeating (-OCH2CH2-) or similar units

– They were discovered by Charles Pedersen (Dupont; early 1960’s)

• Crown ethersCrown ethers are named as xx-crown--crown-yy– xx is the total number of atomstotal number of atoms in the ring

– yy is the number of oxygen atomsnumber of oxygen atoms

– ExampleExample: 18-crown-6 ether: 18-membered ring containing 6 oxygens atoms

• Central cavity is electronegative and attracts cations

Uses of Crown EthersUses 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 conditionsaprotic conditions

– It thus creates reagents that are free of waterfree 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 benzenePurple benzene

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

77.. Thiols and SulfidesThiols and Sulfides

77.. Thiols and SulfidesThiols and Sulfides

• ThiolsThiols (RSHRSH), also known as mercaptans, are sulfur analogs of alcohols

– They are named with the suffix ––thiolthiol– SHSH group is called “mercapto groupmercapto group” (“capturer of

mercury”)

SulfidesSulfides

• SulfidesSulfides (RSR’RSR’) are sulfur analogs of ethers

– They are named by rules used for ethers, with sulfidesulfide in place of etherether for simple compounds and alkylthioalkylthio in place of alkoxyalkoxy

• ThiolsThiols are prepared from alkyl halidesalkyl halides by SSNN22 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

Thiols: Thiols: Formation and ReactionFormation and Reaction

• For a pure alkylthiolalkylthiol, thioureathiourea (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

Using Thiourea to Form AlkylthiolsUsing Thiourea to Form Alkylthiols

Oxidation of Thiols to DisulfidesOxidation of Thiols to Disulfides

• Reaction of an alkylthiolalkylthiol (RSH) with brominebromine (Br2) or iodineiodine (I2) gives a disulfidedisulfide (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: Sulfides: Formation and ReactionFormation and Reaction

Thiolate ionsThiolate ions (RSRS-) – are formedformed by the reaction of a thiol thiol with a basebase– reactreact with primary primary or secondary alkyl halide secondary alkyl halide to give

sulfidessulfides (RSR’RSR’)– are excellent nucleophilesexcellent nucleophiles and react with many

electrophiles via SSNN2 2 mechanism

Sulfides as NucleophilesSulfides as Nucleophiles

• SulfurSulfur compounds are more nucleophilicmore nucleophilic than their oxygen-compound analogs

– 3p electrons valence electrons (on S) are less tightly held than 2p electrons (on O)

• SulfidesSulfides react with primary alkyl halidesprimary alkyl halides via SSNN22 to give trialkylsulfonium trialkylsulfonium saltssalts (R3S+)

– This is unlike dialkyl ethers

• Trialkylsulfonium saltsTrialkylsulfonium 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

Oxidation of SulfidesOxidation of Sulfides

• Unlike ethers, sulfides are easily oxidized.

– SulfidesSulfides are easily oxidizedoxidized with HH22OO22 to the sulfoxidesulfoxide (R2SO)

– OxidationOxidation of a sulfoxidesulfoxide with a peroxyacidperoxyacid yields a sulfonesulfone (R2SO2)

• Dimethyl sulfoxide (DMSO) is often used as a polar aprotic solvent

Practice ProblemPractice Problem: Name the following compounds: : Name the following compounds:

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

88.. Spectroscopy of EthersSpectroscopy of Ethers

88.. Spectroscopy of EthersSpectroscopy of Ethers

• InfraredInfrared: C–O single-bond stretching 1050 to 1150 cm1 overlaps many other absorptions.

• Proton NMRProton 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 NMRCarbon NMR: C’s in ethers exhibit a downfield shift to 50 to 80

Infrared SpectroscopyInfrared Spectroscopy

• Ethers are difficult to distinguish by IR spectroscopy

– C–O single-bond stretching 1050 to 1150 cm1 overlaps many other absorptions.

IR spectrum: CH3CH2OCH2CH3

Nuclear Magnetic Resonance SpectroscopyNuclear Magnetic Resonance Spectroscopy

• Proton NMRProton 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 NMRProton 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 NMRCarbon 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

– Example: These C’s in anisole absorb at 54.8

Practice Problem:Practice Problem: The The 11H NMR spectrum shown is that of an H NMR spectrum shown is that of an ether with the formula C ether with the formula C44HH88O. Propose a O. Propose a

structure. structure.

Chapter 18