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Ethers & Epoxides. Reactions of Ethers. 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.

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Ethers & Epoxides

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Ethers & Epoxides


Reactions of Ethers

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


Naming Ethers

  • Common names are used frequently:

    • Name each –R group.

    • Arrange them alphabetically.

    • End with the word “ether.”


Naming Ethers

  • IUPAC systematic names are often used as well:

    • Make the larger of the –R groups the parent chain.

    • Name the smaller of the –R groups as an alkoxy substituent.

  • SEE: SKILLBUILDER 14.1.


Crown 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


O

O

O

O

O

O

18-Crown-6

negative charge concentrated in cavity inside the molecule


O

O

O

O

O

O

18-Crown-6

forms stable Lewis acid/Lewis base complex with K+

K+


Ion-Complexing and Solubility

K+F–

not soluble in toluene


O

O

O

O

O

O

Ion-Complexing and Solubility

K+F–

toluene

add 18-crown-6


O

O

O

O

O

O

O

O

O

O

O

O

Ion-Complexing and Solubility

F–

K+

toluene

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


O

O

O

O

O

O

O

O

O

O

O

O

+

F–

Ion-Complexing and Solubility

K+

toluene

F– carried into toluene to preserve electroneutrality


Application to organic synthesis

Complexation of K+ by 18-crown-6 "solubilizes" potassium salts in toluene

Anion of salt is in a relatively unsolvated state in toluene (sometimes referred to as a "naked anion")

Unsolvated anions are very reactive

Only catalytic quantities of 18-crown-6 are needed


Example

KF

CH3(CH2)6CH2Br

CH3(CH2)6CH2F

18-crown-6

(92%)

toluene


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+

18-Crown-6

Na+

15-Crown-5

Li+

12-Crown-4


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


The Williamson Ether Synthesis

Just another SN2 reaction 

primary alkyl halide (substrate) + alkoxide (nucleophile)


Example

CH3CH2CH2CH2ONa +CH3CH2I

CH3CH2CH2CH2OCH2CH3+ NaI

(71%)


Alkoxide ion can be derived from primary, secondary, or tertiary alcohol

Alkyl halide must be primary

CH3CHCH3

CH2Cl

+

ONa

CH2OCHCH3

(84%)

CH3

Another Example


CH3CHCH3

CH2OH

OH

HCl or SOCl2

Na (s)

CH3CHCH3

CH2Cl

+

ONa

CH2OCHCH3

(84%)

CH3

1o Halides & Alkoxides


Question

What is the product of the following reaction?


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

Question

  • 1) Hg(OAc)2, THF:H2O 2) NaBH4, OH–

  • 1) BH3:THF 2) H2O2, OH–

  • 1) Hg(OAc)2, CH3CH2OH 2) NaBH4, OH–

  • 1) MCPBA 2) H+ 3) NaH 4) Ethyl iodide


Mechanism


Question

  • Which of the following best represents the rate-determining transition state for the reaction shown below?

  • A) B)

  • C) D)


+

CH3CHCH3

CH2ONa

Br

CHCH3

H2C

+

CH2OH

Elimination producesthe major product.

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


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


Preparation of Epoxides

Two major methods:

Reaction of alkenes with peroxy acids

Conversion of alkenes to vicinalhalohydrins, followed by treatmentwith base.


Preparation of Epoxidesw/ peroxyacids (MCPBA)

.


Conversion of Vicinal Halohydrinsto Epoxides


H

OH

H

Br

••

O

via:

••

••

H

H

Br

••

••

••

Example

H

NaOH

O

H2O

H

(81%)


NaOH

O

Epoxidation via Vicinal Halohydrins

Corresponds to overall syn addition ofoxygen to the double bond.

Br

Br2

H2O

OH

antiaddition

inversion


H3C

H

H3C

H

H

CH3

CH3

H

Epoxidation via Vicinal Halohydrins

Corresponds to overall syn addition ofoxygen to the double bond.

Br

H3C

Br2

H

NaOH

H2O

H

O

CH3

OH

antiaddition

inversion


Question

Which of the following will produce the epoxide below?

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


Stereochemistry / Optical Activity


Epoxidation Stereochemistry

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


EnantioselectiveEpoxidation

  • 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 aSharplesscatalyst, which forms such a chiral complex that favors the formation of one enantiomericepoxide versus the other.

  • Catalyst:


EnantioselectiveEpoxidation

  • 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.


Question

What is the product of the following reaction?


Reactions of Epoxides


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.


R

MgX

R

CH2

CH2

CH2

OMgX

H2C

O

H3O+

RCH2CH2OH

Reaction of Grignard Reagentswith Epoxides


CH2MgCl

CH2CH2CH2OH

Example

CH2

H2C

+

O

1. diethyl ether

2. H3O+

(71%)


CH2

H2C

O

Nu—CH2CH2O—H

In General...

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

+

Nu—H


Nucleophiles attack herewhen the reaction iscatalyzed by acids.

Anionic nucleophilesattack here.

(less hindered)

R

CH2

C

H

O

In General...

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


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


Ring-opening of Epoxides

  • Epoxides can be opened by many strong nucleophiles.

  • Both regioselectivity and stereoselectivity must be considered.


CH2

H2C

O

CH3CH2O

CH2CH2OH

Example

NaOCH2CH3

CH3CH2OH

(50%)


••

CH3CH2

O

••

••

CH2

H2C

O

••

••

••

O

CH2CH3

••

••

••

CH3CH2

O

O

CH2CH2

H

••

••

••

••

••

••

CH3CH2

O

O

CH2CH2

O

CH2CH3

H

••

••

••

••

Mechanism


CH2

H2C

O

CH3CH2CH2CH2S

CH2CH2OH

(99%)

Example

KSCH2CH2CH2CH3

ethanol-water, 0°C


Ring-opening of Epoxides

Environmental Fate?

Propranolol: anti-hypertensive-Blocker


H

NaOCH2CH3

H

CH3CH2OH

O

Stereoselectivity

Inversion of configuration at carbon being attacked by nucleophile.

Suggests SN2-like transition state.

OCH2CH3

H

H

OH

(67%)


CH3O

CH3

H3C

CH3

CH3CH

CCH3

C

C

OH

H

CH3

O

RegioselectivityAnionic Nucleophile Attacks Less-crowded Carbon

Consistent with SN2-like transition state

NaOCH3

CH3OH

(53%)


Question

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

  • A)B)

  • C)D)


Stereochemistry

CH3

H3C

Inversion of configuration at carbon being attacked by nucleophile.

Suggests SN2-like transition state.

R

R

H

NH3

H

OH

O

H2N

H

R

H2O

S

H

H3C

CH3

(70%)


Stereochemistry

CH3

H3C

R

R

H

NH3

H

OH

O

H2N

H

R

H2O

S

H

H3C

CH3

(70%)

H3C

H

+

-

O

H3N

H

H3C


Question

  • What is the product of the reaction shown?

  • A)B)

  • C)D)


MgBr

CHCH3

H2C

O

CH2CHCH3

OH

(60%)

Anionic Nucleophile Attacks Less-crowded Carbon

+

1. diethyl ether

2. H3O+


Question

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


CH(CH2)7CH3

H2C

O

CH(CH2)7CH3

H3C

OH

(90%)

Lithium Aluminum Hydride Reduces Epoxides

Hydride attacksless-crowdedcarbon

1. LiAlH4, diethyl ether

2. H2O


Acid-Catalyzed Ring-OpeningReactions of Epoxides


CH2

H2C

O

Example

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

CH3CH2OH

CH3CH2OCH2CH2OH

H2SO4, 25°C

(87-92%)


CH2

H2C

O

Example

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

HBr

BrCH2CH2OH

10°C

(87-92%)


••

Br

••

••

••

CH2

H2C

CH2

H2C

+

+

O

O

••

••

••

Br

H

H

••

••

••

Br

••

••

••

H

O

CH2CH2

••

Mechanism

••


CH2

H2C

+

O

H

••

H

H

O

H

O

••

+

••

••

H

H

Acid-Catalyzed Hydrolysis of Ethylene Oxide

Step 1

CH2

H2C

+

O

••

••


H

O

H

••

••

CH2

H2C

+

O

••

H

H

+

O

H

••

••

H

O

CH2CH2

••

Acid-Catalyzed Hydrolysis of Ethylene Oxide

Step 2


H

+

O

H

••

H

H

H

O

••

••

O

H

••

••

••

H

H

O

CH2CH2

••

+

O

H

••

••

H

O

CH2CH2

Acid-Catalyzed Hydrolysis of Ethylene Oxide

Step 3

••


Acid-Catalyzed Ring Opening of EpoxidesRegioselectivity and Stereoselectivity

Nucleophile attacks more substituted carbon of protonatedepoxide.

Inversion of configuration at site of nucleophilicattack.


OCH3

H3C

CH3

CH3CH

CCH3

C

C

CH3

OH

H

CH3

O

(76%)

Nucleophile Attacks More-substituted Carbon

Consistent with carbocation character at transition state

CH3OH

H2SO4


H

O

H

Stereochemistry

H

Inversion of configuration at carbon being attacked by nucleophile

OH

HBr

H

Br

(73%)


CH3OH

H2SO4

Stereochemistry

CH3

H3C

Inversion of configuration at carbon being attacked by nucleophile

R

R

H

H

OH

O

CH3O

H

R

S

H

H3C

CH3

(57%)


CH3OH

H2SO4

Stereochemistry

CH3

H3C

R

R

H

H

OH

O

CH3O

H

R

S

H

H3C

CH3

H3C

H

+

+

+

H

O

CH3O

H

H

H3C


Question

  • What is the product isolated when the epoxide at the right reacts with CH3OH and H2SO4?

  • A)B)

  • C) D)


H

O

H

CH3COOH

O

H

H

H2O

H

OH

HClO4

H

OH

(80%)

anti-Hydroxylation of Alkenes


What is the product of the following reaction?

Question


Thiols & Thio Ethers


Thiols

  • 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 / Mercaptans

  • 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.


Thioethers / Sulfides

  • 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.


Question

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

a, b, f

a, b, g

a, b, h

a, b, i

a, c, g


Thioethers / Sulfides

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


Thioethers / Sulfides

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


Thioethers / Sulfides

Methylation of cytosine, a genetic base:

Nucleophilic substitution of SAM-CH3(SAM = S-adenosylmethionine)

Where cytosine is the nucleophile.


Thioethers / Sulfides

Sulfide reactions:

Oxidation: sodium meta-periodate produces asulfoxide.


Thioethers / Sulfides

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?


Thioethers / Sulfides

Sulfide reactions:

Oxidation: hydrogen peroxide produces a sulfone.


Question

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

  • a, f, e, d

  • a, g, e, d

  • a, h, e, d

  • b, f, e, d

  • b, g, e, d


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