Ethers-12-ques

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Transcript Ethers-12-ques

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: 1. Name each –R group.

2. Arrange them alphabetically.

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.

Crown Ethers

Crown Ethers

structure cyclic polyethers derived from repeating —OCH 2 CH 2 — units properties form stable complexes with metal ions applications synthetic reactions involving anions naming x = total # of atoms in ring: [x] Crown- # of oxygen atoms

18-Crown-6

O O O O O O negative charge concentrated in cavity inside the molecule

18-Crown-6

O O O K + O O O forms stable Lewis acid/Lewis base complex with K +

Ion-Complexing and Solubility

K + F – not soluble in toluene

Ion-Complexing and Solubility

O O O O O O add 18-crown-6 K + F – toluene

Ion-Complexing and Solubility

O O O F – O O O toluene O O 18-crown-6 complex of K + dissolves in benzene O K + O O O

Ion-Complexing and Solubility

O O O O O toluene O F – carried into toluene to preserve electroneutrality O O K + O O + F – O O

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

K F CH 3 (CH 2 ) 6 CH 2 Br 18-crown-6 toluene CH 3 (CH 2 ) 6 CH 2 F (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) B) C) D) Bromobutane + KCN (in toluene) Phenol + Br 2 (in water) Butanol + H 2 CrO 4 (in water) CH 3 CH 2 CH 2 CHO + H 2 (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) B) 12-crown-4 10-crown-5 C) D) 15-crown-5 18-crown-6

Question

• Which crown ether would provide the fastest rate for the following reaction? • • • • A) B) C) D) 12-crown-4 10-crown-5 15-crown-5 18-crown-6

The Williamson Ether Synthesis Just another S N 2 reaction 

primary alkyl halide (substrate) + alkoxide (nucleophile)

Example

CH 3 CH 2 CH 2 CH 2 O Na + CH 3 CH 2 I CH 3 CH 2 CH 2 CH 2 O CH 2 CH 3 + NaI (71%)

Another Example

Alkyl halide must be primary Alkoxide ion can be derived from primary, secondary, or tertiary alcohol CH 2 Cl + CH 3 CHCH 3 O Na CH 2 O CHCH 3 CH 3 (84%)

1 o Halides & Alkoxides

CH 2 OH HCl or SOCl 2 CH 3 CHCH 3 O H Na (s) CH 2 Cl + CH 3 CHCH 3 O Na CH 2 O CHCH 3 CH 3 (84%)

Question

What is the product of the following reaction?

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

O O B. D.

Question

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

A. 1) Hg(OAc) 2 , THF:H 2 O 2) NaBH 4 , OH – B. 1) BH 3 :THF 2) H 2 O 2 , OH – C. 1) Hg(OAc) 2 , CH 3 CH 2 OH 2) NaBH 4 , OH – D. 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) • C) B) D)

What if the alkyl halide is not primary?

S N 2 vs E2

CH 2 O Na + CH 3 CHCH 3 Br CH 2 O H + H 2 C CHCH 3 Elimination produces the major product.

Question

• • • • • The most effective pair of reagents for the preparation of

tert

butyl ethyl ether is A) B) C) D) potassium potassium sodium ethoxide and

tert tert tert

-butoxide and ethyl bromide.

-butoxide and ethanol.

tert

-butyl bromide.

-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 vicinal halohydrins, followed by treatment with base.

Preparation of Epoxides w/ peroxyacids (MCPBA)

Conversion of Vicinal Halohydrins to Epoxides

Example

H O H via: Br H H NaOH H 2 O •• •• O •• – H •• Br •• •• H H (81%) O

Epoxidation via Vicinal Halohydrins

Br Br 2 NaOH H 2 O O H anti addition inversion Corresponds to overall syn addition of oxygen to the double bond.

Epoxidation via Vicinal Halohydrins

H 3 C H Br H Br 2 CH 3 H 2 O H 3 C H H CH 3 NaOH H 3 C H O H CH 3 O H anti addition inversion Corresponds to overall syn addition of oxygen to the double bond.

Question

Which of the following will produce the epoxide below? A.a, b B.a, c C. b, c D. b, d E. c, d

Stereochemistry / Optical Activity

Epoxidation Stereochemistry

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

Enantioselective Epoxidation

• 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.

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.

Reaction of Grignard Reagents with Epoxides

R Mg X H 2 C O CH 2 R CH 2 CH 2 O H 3 O + R CH 2 CH 2 O H Mg X

Example

CH 2 Mg Cl + H 2 C O 1. diethyl ether 2. H 3 O + CH 2 CH 2 CH 2 CH 2 O H (71%)

In General...

Reactions of epoxides involve attack by a nucleophile and proceed with ring-opening.

For ethylene oxide: Nu —H + H 2 C O CH 2 Nu — CH 2 CH 2 O — H

In General...

For epoxides where the two carbons of the ring are differently substituted: Nucleophiles attack here when the reaction is catalyzed by acids.

R C H O CH 2 Anionic nucleophiles attack here. (less hindered)

Nucleophilic Ring-Opening Reactions of Epoxides

Question True (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.

Example

H 2 C O CH 2 NaOCH 2 CH 3 CH 3 CH 2 OH CH 3 CH 2 O CH (50%) 2 CH 2 O H

CH 3 CH 2 CH 3 CH 2 •• O – •• •• O H 2 C O •• •• CH 2 CH 2 CH 2 •• O •• –

Mechanism

– •• •• O H CH 2 CH 3 CH 3 CH 2 •• O CH 2 CH 2 •• O H – •• •• O •• CH 2 CH 3

Example

H 2 C O CH 2 KSCH 2 CH 2 CH 2 CH 3 ethanol-water, 0 °C CH 3 CH 2 CH 2 CH 2 S CH 2 CH 2 O H (99%)

Ring-opening of Epoxides

Environmental Fate? Propranolol: anti-hypertensive  -Blocker

Stereoselectivity

H H NaOCH 2 CH 3 OCH H O CH 3 CH 2 OH H O H (67%) Inversion of configuration at carbon being attacked by nucleophile.

Suggests S N 2-like transition state.

2 CH 3

Regioselectivity

Anionic Nucleophile Attacks Less-crowded Carbon

H 3 C H C O C CH 3 CH 3 Na OCH 3 CH 3 OH CH 3 O CH 3 C H CH 3 CCH 3 O H (53%) Consistent with S N 2-like transition state

Question

• What is the product isolated when the epoxide below reacts with NaOCH 3 in CH 3 OH? • A) • C) B) D)

Stereochemistry

H H H 3 C

3 C H

O NH 3 H 2 O H 2 N

H CH 3

O H H CH 3

(70%)

Inversion of configuration at carbon being attacked by nucleophile.

Suggests S N 2-like transition state.

Stereochemistry

H H H 3 C

3 C H

O  + H 3 N NH 3 H 2 O H 3 C H H 2 N

H CH 3

O H H CH 3

(70%)

O 

-

H 3 C H

Question

• What is the product of the reaction shown? • A) • C) B) D)

Anionic Nucleophile Attacks Less-crowded Carbon

Mg Br + H 2 C CHCH 3 O 1. diethyl ether 2. H 3 O + CH 2 CHCH 3 O H (60%)

Question

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

O 1) CH 3 MgBr 2) H 2 O HO OH OH

B. D.

Lithium Aluminum Hydride Reduces Epoxides

H 2 C O CH(CH 2 ) 7 CH 3 Hydride attacks less-crowded carbon H 3 C 1. LiAlH 4 , diethyl ether 2. H 2 O CH(CH 2 ) 7 CH 3 O H (90%)

Acid-Catalyzed Ring-Opening Reactions of Epoxides

Example

H 2 C O CH 2 CH 3 CH 2 OH H 2 SO 4 , 25 °C CH 3 CH 2 O CH 2 CH 2 O H (87-92%) CH 3 CH 2 OCH 2 CH 2 OCH 2 CH 3 and/or longer reaction times. formed only on heating

Example

H 2 C O CH 2 H Br 10 °C Br CH 2 CH 2 O H (87-92%) BrCH 2 CH 2 Br formed only on heating and/or longer reaction times.

Mechanism

•• •• Br •• H 2 C + •• CH 2 H •• •• Br •• •• – H 2 C + O •• CH 2 H •• •• Br •• CH 2 CH 2 •• O H

Acid-Catalyzed Hydrolysis of Ethylene Oxide

Step 1 H •• O + H H 2 C + O •• •• CH 2 H H •• O •• H H 2 C + O •• CH 2 H

Acid-Catalyzed Hydrolysis of Ethylene Oxide

Step 2 H H + O •• H CH 2 CH 2 •• O H •• H H 2 C + O •• CH 2 H

Acid-Catalyzed Hydrolysis of Ethylene Oxide

Step 3 H H + O •• H H •• H + O •• H CH 2 CH 2 •• O H •• O •• H H CH 2 CH 2 •• O •• 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.

Nucleophile Attacks More-substituted Carbon

H 3 C H C O C CH 3 CH 3 CH H 2 3 OH SO 4 CH 3 CH OCH 3 C CH O H CH 3 (76%) 3 Consistent with carbocation character at transition state

Stereochemistry

H H O H H Br O H Br (73%) H Inversion of configuration at carbon being attacked by nucleophile

Stereochemistry

H H H 3 C

3 C H

O CH 3 OH H 2 SO 4 CH 3 O

H CH 3

O H H CH 3

(57%)

Inversion of configuration at carbon being attacked by nucleophile

Stereochemistry

H H H 3 C

3 C H

O  + CH 3 O CH H 2 3 OH SO 4  + H 3 C H CH 3 O

H CH 3 CH 3

OH H  + O H H H 3 C H

•

Question

What is the product isolated when the epoxide at the right reacts with CH 3 OH and H 2 SO 4 ? • A) B) • C) D)

anti-Hydroxylation of Alkenes

O H CH 3 CO O H O H H O H H 2 O HClO 4 H (80%) OH H

Question

What is the product of the following reaction?

O HBr OH

A. C.

Br Br OH Br

B. D.

OH Br OH

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 merc aptan name comes from their ability to complex merc ury.

• 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 S N 2 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.a, b, f B.a, b, g C.a, b, h D.a, b, i E.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

Methylation of cytosine, a genetic base:

Nucleophilic substitution of SAM-CH 3 (SAM = S-adenosylmethionine) Where cytosine is the nucleophile.

Thioethers / Sulfides

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

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?

O O A. F.

C. D. H.

O O E. H 2 O

A. a, f, e, d B. a, g, e, d C. a, h, e, d D. b, f, e, d E. b, g, e, d