Ethers & Epoxides

Ethers are relatively unreactive.

Ethers are often used as solvents in organic reactions.

Ethers oxidize in air to form explosive hydroperoxides and peroxides.

“Crown” ethers are useful as enhancers in nucleophilic substitution and other reactions

Reactions of Ethers

• Common names are used frequently:1. Name each –R group.2. Arrange them alphabetically.3. End with the word “ether.”

Naming Ethers

• IUPAC systematic names are often used as well:1. Make the larger of the –R groups the parent chain.2. Name the smaller of the –R groups as an alkoxy

substituent.

• SEE: SKILLBUILDER 14.1.

Naming Ethers

Crown Ethers

structurecyclic polyethers derived from repeating

—OCH2CH2— units

propertiesform stable complexes with metal ions

applicationssynthetic reactions involving anions

namingx = total # of atoms in ring: [x] Crown- # of

oxygen atoms

Crown Ethers

18-Crown-6

negative charge concentrated in cavity inside the molecule

O

O O

OO

O

O

O O

O

O

O

18-Crown-6

forms stable Lewis acid/Lewis base complex with K+

K+

not soluble in toluene

Ion-Complexing and Solubility

K+F–


O

O O

O

O

O

K+F–

add 18-crown-6

toluene


O

O O

O

O

O

O

O O

O

O

O

K+

18-crown-6 complex of K+ dissolves in benzene

toluene

F–


O

O O

O

O

O

+ F–

O

O O

O

O

O

K+

F– carried into toluene to preserve electroneutrality

toluene

Application to organic synthesis

Complexation of K+ by 18-crown-6 "solubilizes" potassium salts in tolueneAnion of salt is in a relatively unsolvated state in toluene (sometimes referred to as a "naked anion")Unsolvated anions are very reactiveOnly catalytic quantities of 18-crown-6 are needed

Example

CH3(CH2)6CH2BrKF

18-crown-6toluene

CH3(CH2)6CH2F

(92%)

Question

• Which reaction is the best candidate for catalysis by 18-crown-6? (Which reaction proceeds faster in the presence of the crown ether than in its absence?)

• A) Bromobutane + KCN (in toluene)• B) Phenol + Br2 (in water)• C) Butanol + H2CrO4 (in water)• D) CH3CH2CH2CHO + H2 (in ethanol)

Ion Size & Crown Ether Complexes

K+

Na+

Li+

18-Crown-6

12-Crown-4

15-Crown-5

Question

• What is the name of the crown ether show at the right? • A) 12-crown-4• B) 10-crown-5• C) 15-crown-5• D) 18-crown-6

Question

• Which crown ether would provide the fastest rate for the following reaction?

• A) 12-crown-4• B) 10-crown-5• C) 15-crown-5• D) 18-crown-6

Just another SN2 reaction

primary alkyl halide (substrate) + alkoxide (nucleophile)

The Williamson Ether Synthesis

(71%)

CH3CH2CH2CH2ONa + CH3CH2I

CH3CH2CH2CH2OCH2CH3 + NaI

Example

Another Example

+ CH3CHCH3

ONa

CH2Cl

(84%)CH2OCHCH3

CH3

Alkyl halide must

be primary

Alkoxide ion can be derived

from primary, secondary, or

tertiary alcohol

CH3CHCH3

OHNa (s)

CH2OH

HCl or SOCl2

CH2OCHCH3

CH3

CH2Cl + CH3CHCH3

ONa

(84%)

1o Halides & Alkoxides

What is the product of the following reaction?

1) NaH 2) ethyl iodide?????

O OA. C.

B. D.OO

OH

Question

What is the correct order of reagents needed for the following transformation?

A. 1) Hg(OAc)2, THF:H2O 2) NaBH4, OH–

B. 1) BH3:THF 2) H2O2, OH–

C. 1) Hg(OAc)2, CH3CH2OH 2) NaBH4, OH–

D. 1) MCPBA 2) H+ 3) NaH 4) Ethyl iodide

O

Question

Mechanism

Question• Which of the following best represents the rate-determining

transition state for the reaction shown below?

• A) B)

• C) D)

What if the alkyl halide is not primary?SN2 vs E2

CH2ONa + CH3CHCH3

Br

CH2OH + H2C CHCH3

Elimination producesthe major product.

Question

• The most effective pair of reagents for the preparation of tert-butyl ethyl ether is

• A) potassium tert-butoxide and ethyl bromide.• B) potassium tert-butoxide and ethanol.• C) sodium ethoxide and tert-butyl bromide.• D) tert-butyl alcohol and ethyl bromide

Limitation

Preparation of Epoxides

Two major methods:Reaction of alkenes with peroxy acids

Conversion of alkenes to vicinalhalohydrins, followed by treatmentwith base.

Preparation of Epoxides

.

Preparation of Epoxidesw/ peroxyacids (MCPBA)

Conversion of Vicinal Halohydrinsto Epoxides

HOH

BrH

NaOH

H2O

(81%)H

H

O

Example

O

Br

HH

••••

••

•• ••••–

via:

antiaddition

inversion

Epoxidation via Vicinal Halohydrins

Br2

H2O

OH

Corresponds to overall syn addition ofoxygen to the double bond.

Br

NaOH

O

antiaddition

inversion

Epoxidation via Vicinal Halohydrins

Br2

H2O

OH

NaOH

Corresponds to overall syn addition ofoxygen to the double bond.

O

HHH3C

CH3

H

H

CH3

H3CBr

HH3CCH3H

Which of the following will produce the epoxide below?

Question

A.a, b B.a, c C. b, c D. b, d E. c, d

Stereochemistry / Optical Activity

• Epoxidation forms a racemic mixture because reaction occurs with equal probability on either face of the double bond.

Epoxidation Stereochemistry

• In order to have an optically active product, one of the reactants, or reagents, or catalyst in a reaction must be chiral.

• An example is a Sharpless catalyst, which forms such a chiral complex that favors the formation of one enantiomeric epoxide versus the other.

• Catalyst:

Enantioselective Epoxidation

• The desired epoxide can be formed in excess by choosing the appropriate catalyst. Note the position of the –OH group.

• SEE: CONCEPTUAL CHECKPOINT 14.16.

Enantioselective Epoxidation


Question

Reactions of Epoxides

All reactions involve nucleophilic attack at carbon and lead to opening of the ring.

An example is the reaction of ethylene oxide with a Grignard reagent as a method for the

synthesis of alcohols.

Reactions of Epoxides

Reaction of Grignard Reagentswith Epoxides

H2C CH2

O

R MgX

CH2 CH2 OMgX

R

H3O+

RCH2CH2OH

H2C CH2

O

+

1. diethyl ether2. H3O+

(71%)

Example

CH2MgCl

CH2CH2CH2OH

Reactions of epoxides involve attack by anucleophile and proceed with ring-opening.For ethylene oxide:

Nu—H +

Nu—CH2CH2O—H

H2C CH2

O

In General...

For epoxides where the two carbons of thering are differently substituted:

In General...

CH2

O

CR

H

Nucleophiles attack herewhen the reaction iscatalyzed by acids.

Anionic nucleophilesattack here.

(less hindered)

Nucleophilic Ring-OpeningReactions of Epoxides

QuestionTrue (A) / False (B)

Refer to the reaction coordinate diagrams below.

The epoxide reaction is exergonic and the Transition State resembles the reactants whereas the ether

reaction is slower and the Transition State resembles the reactants

• Epoxides can be opened by many strong nucleophiles.

• Both regioselectivity and stereoselectivity must be considered.

Ring-opening of Epoxides

NaOCH2CH3

CH3CH2OH

(50%)

Example

O

H2C CH2

CH3CH2O CH2CH2OH

••••O

H2C CH2

CH3CH2 O••

•• ••–

••

CH3CH2 O••

••CH2CH2 O

••H O CH2CH3

••••••

–

Mechanism

–••

CH3CH2 O••

•• ••CH2CH2 O••

O CH2CH3••

••

–

H

Example

O

H2C CH2

KSCH2CH2CH2CH3

ethanol-water, 0°C

(99%)

CH2CH2OHCH3CH2CH2CH2S

Ring-opening of Epoxides

Propranolol: anti-hypertensive -Blocker

Environmental Fate?

Stereoselectivity

Inversion of configuration at carbon being attacked by nucleophile.

Suggests SN2-like transition state.

NaOCH2CH3

CH3CH2OHO

HH

HOH

HOCH2CH3

(67%)

NaOCH3

CH3OHCH3CH CCH3

CH3

OH

CH3O

(53%)

CCH

H3C CH3

CH3O

Consistent with SN2-like transition state

RegioselectivityAnionic Nucleophile Attacks Less-crowded Carbon

Question

• What is the product isolated when the epoxide below reacts with NaOCH3 in CH3OH?

• A) B)

• C) D)

NH3

H2O

(70%)

R

S

R

R

Stereochemistry

H3C CH3

H3C CH3

OH

HH

H OHH2N

Inversion of configuration at carbon being attacked by nucleophile.

Suggests SN2-like transition state.

NH3

H2O

(70%)

+ -

R

S

R

R

Stereochemistry

H3C CH3

H3C CH3

OH

HH

H OHH2N

H3N O

H3CH

H3CH

Question• What is the product of the reaction shown?

• A) B)

• C) D)

Anionic Nucleophile Attacks Less-crowded Carbon

1. diethyl ether2. H3O+

MgBr +

O

H2C CHCH3

CH2CHCH3

OH(60%)

What are the product(s) of the following reaction?

A. C.

B. D.

1) CH3MgBr2) H2OO

HO

OH

HO OH

Question

Hydride attacksless-crowded

carbon

Lithium Aluminum Hydride Reduces Epoxides

O

H2C CH(CH2)7CH3

1. LiAlH4, diethyl ether2. H2O

(90%)OH

H3C CH(CH2)7CH3

Acid-Catalyzed Ring-OpeningReactions of Epoxides

Example

O

H2C CH2 CH3CH2OCH2CH2OH

(87-92%)

CH3CH2OCH2CH2OCH2CH3 formed only on heating and/or longer reaction times.

CH3CH2OH

H2SO4, 25°C

Example

O

H2C CH2 HBr

10°CBrCH2CH2OH

(87-92%)

BrCH2CH2Br formed only on heating and/or longer reaction times.

Mechanism

Br••

••••–••

••

••O••

Br

CH2CH2 H

••••

••O

H2C CH2+

••HBr

••••

••••O

H2C CH2+

H

Acid-Catalyzed Hydrolysis of Ethylene Oxide

••O

H2C CH2+

••O••

H

H

H+

••O

H2C CH2+

HO••

H

H••

Step 1

••O

H2C CH2+

H

O••

••

H

H

Step 2

••+

••O

O

CH2CH2

H

H

H

••


Step 3

••+

••O

O

CH2CH2

H

H

H

O••

••

H

H

••

O••

H

H+

H

••

••O

O

CH2CH2

H

H

••

••


Acid-Catalyzed Ring Opening of Epoxides

Regioselectivity and Stereoselectivity

Nucleophile attacks more substituted carbon of protonated epoxide.

Inversion of configuration at site of nucleophilic attack.

CH3OH

CCH

H3C CH3

CH3O

Consistent with carbocation character at transition state

Nucleophile Attacks More-substituted Carbon

H2SO4

CH3CH CCH3

CH3OH

OCH3

(76%)

Stereochemistry

Inversion of configuration at carbon being attacked by nucleophile

(73%)

H

H

O HBr

HOH

BrH

(57%)

R

S

R

R

Stereochemistry

H3C CH3

H3C CH3

OH

HH

H OHCH3O

Inversion of configuration at carbon being attacked by nucleophile

CH3OH

H2SO4

R

S

R

R

Stereochemistry

H3C CH3

H3C CH3

OH

HH

H OHCH3OCH3OH

H2SO4

+ +CH3O O

H3CH

H3CH

H+

H

Question• What is the product isolated when the epoxide at the right

reacts with CH3OH and H2SO4?

• A) B)

• C) D)

anti-Hydroxylation of Alkenes

H

H

CH3COOH

O

H

H

O

H2O

HClO4

(80%)

HOH

OHH


A. C.

B. D.

HBr

OH

Br

Br

Br

OH OH

Br OH

O

Question

Thiols & Thio Ethers

• Sulfur appears just under oxygen on the periodic table.

• Sulfur appears in THIOLS as an –SH group analogous to the –OH group in alcohols.

Thiols

• Thiols are also known as mercaptans.• The –SH group can also be named as part of a side

group rather than as part of the parent chain.

• The mercaptan name comes from their ability to complex mercury.

• 2,3-dimercapto-1-propanol is used to treat mercury poisoning.

Thiols / Mercaptans

• Thiols are known for their unpleasant odor.• Skunks use thiols as a defense mechanism: (E)-2-

butene-1-thiol, 3-methyl-1-butanethiol, and 2-quinolinemethanethiol, and acetate thioesters of these.

• Methanethiol is added to natural gas (methane) so that gas leaks can be detected.

• The hydrosulfide ion (HS–) is a strong nucleophile and a weak base.

• HS– promotes SN2 rather than E2.

Thiols / Mercaptans

http://en.wikipedia.org/wiki/Acetate

http://en.wikipedia.org/wiki/Thioesters

• Sulfur analogs of ethers are called SULFIDES or THIOETHERS.

• Sulfides can also be named as a side group.

Thioethers / Sulfides

• Sulfides are generally prepared by nucleophilic attack of a thiolate on an alkyl halide.



A.a, b, fB.a, b, gC.a, b, hD.a, b, iE.a, c, g

Question

Sulfide reactions:Nucleophilic substitution of an alkyl halide:

The process produces a strong alkylating reagent that can add an methyl group to a variety of nucleophiles such as genetic bases and histones, as noted in the Epigenetics bonus Webinar


Methylation of cytosine, a genetic base: Nucleophilic substitution of SAM-CH3

(SAM = S-adenosylmethionine)

Where cytosine is the nucleophile.


Sulfide reactions:Oxidation: sodium meta-periodate produces a sulfoxide.


Consider the IR of dimethylsulfoxide (DMSO) and the resonance structures below it. An S=O bond has a strong peak @ ~1050 cm-1 and an S-O bond @ 700-900 cm-1. Which resonance form should predominate?


Sulfide reactions:Oxidation: hydrogen peroxide produces a sulfone.



A. a, f, e, dB. a, g, e, dC. a, h, e, dD. b, f, e, dE. b, g, e, d

A. F.

B.

G.C.

D. H.

E. H2O

Br

Mg, diethyl ether

1) LAH 2) H2O

Na2Cr2O7, H2SO4, H2O

O

1) NaBH4 2) H2O

O

O

O

Question

Ethers & Epoxides

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