Chapter 18

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 (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

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 sp 3 -hybridized

• The

oxygen

atom gives ethers a slight dipole moment

• Ethers have higher boiling points similar MW than alkanes with

3 .

Synthesis of Ethers

• Ethers can be synthesized by: i.

Acid-catalyzed dehydration of alcohols ii. Williamson ether synthesis iii. Alkoxymercuration of alkenes

i. Acid-catalyzed dehydration of alcohols

• Symmetrical ethers can be prepared by acid-catalyzed dehydration of primary alcohols (S N 2) –

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 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 S N 2 – 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 Ag 2 O with alkyl halide forms ether in one step –

Example:

Glucose reacts with excess iodomethane in the presence of Ag 2 O to generate a

pentaether

in 85% yield

Mechanism of the Williamson Ether Synthesis

• The Williamson ether synthesis involves S N 2 reaction of an alkoxide ion with a primary alkyl halide – An alkoxide nucleophile (RO ) displaces a halide ion (X ) via S N 2 – Primary halides and tosylates work best for S N 2 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 using Williamson synthesis?

a. Methyl propyl ether b. Anisole (methyl phenyl ether) c. Benzyl isopropyl ether d. 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 NaBH 4

Mechanism of Alkoxymercuration/Demercuration

• The mechanism involves: – Electrophilic addition of Hg 2+ to an alkene, followed by reaction of intermediate cation with alcohol: Overall Markovnikov addition of alcohol to alkene – Reduction of C-Hg by NaBH 4

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 reaction of 1-methylcyclopentene with ethanol. Use curved arrows to show the electron flow in each step.

Practice Problem

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

a. Butyl cyclohexyl ether b. Benzyl ethyl ether (C 6 H 5 CH 2 OCH 2 CH 3 ) c. sec-Butyl tert-butyl ether d. Tetrahydrofuran

3 .

Reactions of Ethers

• Ethers undergo: i.

Acidic Cleavage ii. Claisen Rearrangement

i. Acidic Cleavage

• Ethers react are generally unreactive to most reagents but with strong acids ( HI and HBr ) at high temperature – HI, HBr produce an alkyl halide from less hindered component by S N 2 (tertiary ethers undergo S N 1)

Mechanism of the Acidic Cleavage

• The acidic cleavage reaction takes place: – via S N 2 mechanism site if only primary at the less highly substituted and secondary alkyl are bonded to the ether O – via S N 1 or E1 mechanism if one of the alkyl groups bonded to the ether O is tertiary

• Ethers with primary and secondary alkyl with HI or HBr via S N 2 mechanism groups react – I or Br site attacks the protonated ether at the less hindered

• Ethers with a tertiary , benzylic , or allylic group react with HI or HBr via S N 1 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 Ethers with a tertiary and , secondary alkyl benzylic , or groups – via S N 2 allylic group – via S N 1 or E1

Practice Problem

: Predict the products of each of the following reactions:

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 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 , ArOCH 2 CH=CH 2 – 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 14 C labelling

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: i.

Treatment of an alkene with a peroxyacid ii. 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 (RCO 3 H) – m-chloroperoxybenzoic acid is a common peroxyacid used

• The mechanism of epoxidation by treatment of an alkene with a peroxyacid (RCO 3 H): – 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 of cis-2-butene with m-chloroperoxybenzoic acid? Show the stereochemistry

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: i.

Acid-Catalyzed Epoxide Opening ii. 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 S N 1 nor S N 2.

– more stable, tertiary carbocation T.S character ( S N 1-like ) – back-side displacement of leaving group ( S N 2-like )

Practice Problem

: Predict the major product of the following reaction:

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 –CH 2 CH 2 OH to the Grignard reagent’s hydrocarbon chain • Acyclic and other larger ring ethers do not react

Grignard reagent

• Base-catalyzed epoxide opening is S N 2-like – Attack of the nucleophile takes place at the less hindered epoxide carbon

Practice Problem

: Predict the major product of the following reactions:

6 .

Crown Ethers

• Crown ethers are large rings consisting of repeating (-OCH 2 CH 2 -) 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 NaN 3 ) 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 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

place of

ether

for simple compounds and

alkylthio

in place of

alkoxy

in

Thiols:

Formation and Reaction

• Thiols

are prepared from

alkyl halides

by

S

N

2

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

as the nucleophile (NH 2 (C=S)NH 2 ) is used – 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 or

iodine

(I 2

alkylthiol

) gives a (RSH) with

bromine disulfide

(RSSR’) (Br 2 ) – 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 sulfides ( RSR’ ) – are secondary alkyl halide excellent nucleophiles electrophiles via S N 2 mechanism to give and react with many

Sulfides as Nucleophiles

• Sulfur compounds are more nucleophilic their oxygen-compound analogs than – 3

p

electrons valence electrons (on S) are less tightly held than 2

p

electrons (on O) • Sulfides to give react with primary alkyl halides trialkylsulfonium salts (R 3 S + ) via S N 2 – 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

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

– Sulfides sulfoxide are easily oxidized (R 2 SO) with H 2 O 2 to the – Oxidation sulfone (R of a 2 SO 2 sulfoxide ) with a peroxyacid yields a

• 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. 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 1 H NMR spectrum of dipropyl ether shows the these signals at 3.4  – In epoxides, these H’s absorb at 1 H NMR spectra  2.5 to  3.5 in their •

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: CH 3 CH 2 OCH 2 CH 3

Nuclear Magnetic Resonance Spectroscopy

•

Proton NMR:

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

•

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

Practice Problem:

The 1 H NMR spectrum shown is that of an ether with the formula C 4 H 8 O. Propose a structure.

Chapter 18