6 Alcohols And Ethers A Notations

Any time a Carbocation is formed Rearrangements can occur. CH3 +

H3C

C

C

CH3

CH3 H3C

C CH3

H CH3CH2

CH3

CH

H

2°

+

CH2 1°

+

CH2

1°

methanide migration

methanide migration

hydride migration

Why does this happen?

CH3 +

H3C

C

3°

CH3

C 3°

C

H

CH3 CH2

H

H

H

H

+

H3 C

CH3

C

C C

+

H3C H3C

Lewis acid

Lewis base

CH3

H

H

CH2

H2C

C

H

C

+

CH3CH2 CH

2°

H

H

C

+

H H

H

H CH3

C H

H2C

Sec. 6: Alcohols, Ethers

1

Hydride and methanide shifts are very fast (faster than SN1 or E1) which is partially due to hyperconjugation in the carbocation weakening the C-H, or C-C bond:

Primary carbocations are too unstable to be formed by rearrangement. Secondary or tertiary carbocations equilibrate readily, leading to a mixture of products when trapped by a nucleophile.

Sec. 6: Alcohols, Ethers

2

What is the product of the following SN1 reaction? OCH3 CH3

H3C

CH3

Br

C

C

CH3

H

CH3

H 3C

CH3OH

weak base poor nucleophile

C

C

CH3

H

CH3

C

CH3

H

CH3

B)

C

CH2 CH2

CH3

H3C

CH3

CH3O

C

C

CH3

H

acid C CH3 + Br o H 2 +

methanide migration

acid +

H3C C 3o CH3

CH3

D)

C)

Mechanism

CH3

C

H3CO H3C

base H3C C

OCH3

A)

CH3

CH3

H3 C

CH3

CH3 C H

Sec. 6: Alcohols, Ethers

CH3OH base CH3 H3C -H+

OCH3 CH3 C

C

CH3

H

CH3

3

What is the major product formed in the following reaction? CH3 H H3C

C

C

85% H3PO4

CH3

60°C

CH3 OH

CH3 H3C

C

H3 C CH

C

CH2 H3 C

CH3

C

CH3 H

B)

A) H3 C

CH3 C

H3C

C C)

CH3

CH3 H3C

C CH3 D)

Also look in Vollhardt Chapter 11-11 (preparation of alkenes by dehydration)

Sec. 6: Alcohols, Ethers

H C

CH3

H 2C C

CH3

H3C

E)

C

CH3

H

4

What is the Mechanism of the previous reaction? CH3 H H3C

C

CH3 H

C

85% H3PO4

CH3

60°C

CH3 OH O

a O P

OH

OH

b

acid

P

H3 C

C

+

O

P

OH

OH

H

-H2O

OH

CH3 H methanide + shift β C C C CH3 H β 3° H CH3 H β b

H3 C

+ H3PO4

CH3 H H3C

C

CH3

C

H3C

C

CH3

+

CH3 C

CH3

CH3

H

OH

CH3 C

C +

a H 2C

C

CH3 O

O

H

base

O

H3C

O

CH3

2°

Zaitsev’s Rule

major

H Sec. 6: Alcohols, Ethers

5

What is the major product formed in the following reaction? H H3C

C

H C

CH3

85% H2SO4 A)

CH3 OH

B)

C)

H3C

H

H

C

C

CH3 OH

D)

Br CH3

85% H2SO4 NaBr

A)

B) H

C)

Sec. 6: Alcohols, Ethers

Br H

D) 6

The mechanism of 3-methyl-2-butanol with concentrated H2SO4 and NaBr? H3C

H

H

C

C

CH3

acid 85% H2SO4

H3C

H

H

C

C

CH3

+

HSO4

+

CH3 OH base weak base good nucleophile SN1

H3C

Br

Br

H

C

C

CH3 H

CH3

Na Br

CH3 O +

H

H H + β C C C CH3 H β 3° H CH3 H

H

hydride shift

-H2O

H3C

H

H

C

C

CH3

+

CH3

2°

If no NaBr present the only species present are H2SO4, HSO4¯ and H2O, which are weak bases and poor nucleophiles. E1 reaction H3C

C

C

H3C

CH3 H

major Sec. 6: Alcohols, Ethers

H

H2C

+

C H 3C

C

CH3

H

7

Primary alcohols may undergo rearrangement. Alkyl and hydride shifts to primary carbons bearing leaving groups can occur without the formation of primary carbocations.

Because this is not a simple primary bromoalkane, steric hindrance interferes with direct attack by the bromide ion. Instead, water leaves at the same time as the methyl group migrates, by passing the formation of a primary carbocation.

Sec. 6: Alcohols, Ethers

8

Making an ether by dehydration of an alcohol OH

base

conc. H2SO4 O

OH

H+

acid

OH

OH

base OH + H2O

+

OH2

+

H H

2° H

H

1

+ HSO4

+

H

2

acid

4 3

benzylic very stable -H+ O

O

1

H

2

3 Sec. 6: Alcohols, Ethers

+

4

9

Conversion of Alcohols into Alkyl Halides Hydroxyl groups are poor leaving groups, and as such, are often converted to alkyl halides when a good leaving group is needed

Organic and Inorganic Esters from Alcohols Organic esters are derivatives of carboxylic acids. Inorganic esters are the analogous derivatives of inorganic acids.

Alcohols react with carboxylic acids to give organic esters. Esterification is the reaction of alcohols with carboxylic acids in the presence of catalytic amounts of a strong inorganic acid (H2SO4 or HCl) which yields esters and water. This is an equilibrium process which can be shifted in either direction.

Sec. 6: Alcohols, Ethers

10

Haloalkanes can be made from alcohols through inorganic esters. As an alternative to the acid-catalyzed conversions of alcohols into haloalkanes, a number of inorganic reagents can convert the alcoholic hydroxyl group into a good leaving group under milder conditions. The reaction of PBr3 with a secondary alcohol yields a bromoalkane and phosphorous acid (all three bromine atoms can be utilized).

Can use if the alcohol is tertiary

Sec. 6: Alcohols, Ethers

11

Iodoalkanes can be prepared using PI3, which, because of its reactivity, is generated from red phosphorous and iodine in the reaction mixture itself. Chloroalkanes are commonly prepared using thionyl chloride by warming an alcohol in its presence.

An amine such as triethyl amine is usually added to consume the generated HCl. Sec. 6: Alcohols, Ethers

12

Alkyl sulfonates are versatile substrates for substitution reactions. Alkyl sulfonates are excellent leaving groups and can be generated by the reaction of an alcohol with the corresponding sulfonyl chloride. Pyridine or a tertiary amine is used to remove the HCl formed.

Alkyl sulfonates are often crystalline solids and can be isolated and purified before further reaction. What is the major product formed in the following reaction? OH

CH3SO2Cl pyridine

?

SCN

SCN

A)

B)

NaSCN acetone

Sec. 6: Alcohols, Ethers

C)

13

Ethers as solvents Ethers are very good solvents because they are fairly unreactive and slightly polar

Cyclic ethers are members of the class of cycloalkanes called heterocycles, in which one or more carbon atoms have been replaced by a heteroatom. Cyclic polyethers based on the 1,2-ethanediol unit are called crown ethers. The crown ether 18-crown-6 contains 18 total atoms and 6 oxygen atoms.

Note that the inside of the ring is electron rich.

Sec. 6: Alcohols, Ethers

The smaller alkoxyalkanes are water soluble, however solubility decreases with increasing hydrocarbon size. Methoxymethanecompletely water soluble Ethoxyethane -10% aqueous solution 14

Polyethers solvate metal ions: crown ethers and ionophores. Crown ethers can render salts soluble in organic solvents by chelating the metal cations. This allows reagents such as KMnO4 to act as an oxidizing agent in the organic solvents.

The size of the central cavity can be tailored to selectively bind cations of differing ionic radii. Three-dimensional analogs of crown ethers are polyethers called cryptands. These are highly selective in alkali and other metal cation binding.

Sec. 6: Alcohols, Ethers

15

Synthesis of Ethers Williamson Ether Synthesis OH

NaH

ONa

DMSO

Cl

O

DMSO

1-butoxybutane

What is the major product produced in the following reaction? Br

OH dilute solution

O

NaOH

-(O(CH2)5O)n

HO(CH2)5OH

O A)

B)

C)

D)

The intramolecular reaction is usually much faster than the intermolecular reaction. If necessary, the intermolecular reaction can be suppressed by using a high dilution of the haloalcohol. Sec. 6: Alcohols, Ethers

16

What is the major product produced in the following reaction? H

HO H

NaOH

Br

H H

D

H

O

O

A)

D H

H H

B)

H D

Does the following reaction proceed by an A) SN1 or B) SN2 mechanism? OH

+

15% aqu. H2SO4

OH excess

O

40oC

2-ethoxy-2-methylpropane

Sec. 6: Alcohols, Ethers

17

What is the major product produced in the following reaction? O + OH (CH3)3COH, H

H

?

1) BrMgCH2CH3

Br

Br

?

2) H2O, H+

OH OH

O

O

B)

A)

C)

OH

OH

OH

O E)

D)

OH O

OH2

OH

H O

H

OH

O H

O

OH H

H

MgBr

H O

O

Sec. 6: Alcohols, Ethers

18

What is the major product produced in the following reaction? CH3 CH2CH3

HO O H H

CH3 CH2CH3

1) CH3SNa 2) H2O, H+

H H

A)

H

SCH3 SCH3

H HO C)

CH3 CH2CH3

H

OH

H H3CS

B)

CH3 CH2CH3

H3CS H H

CH3 CH2CH3

D)

OH

Ethers are unreactive towards basic nucleophiles because alkoxides are very poor leaving groups. Why would the above reaction occur? What is the driving force for this reaction? The driving force is the release of strain that occurs in the displacement reaction Sec. 6: Alcohols, Ethers

19

Hydride and organometallic reagents convert strained ethers into alcohols LiAlH4 can open the rings of oxacyclopropanes to yield alcohols. (Ordinary ethers do not react.) In asymmetrical systems, the hydride attacks the less substituted side.

Acids catalyze oxacyclopropane ring opening Ring opening of oxacyclopropane by acid catalysis proceeds through an initial cyclic alkyloxonium ion. This acid catalyzed ring opening is both regioselective and stereospecific.

Sec. 6: Alcohols, Ethers

20

What is the major product produced in the following reaction? CH3 CH2CH3

HO O H H

CH3 CH2CH3

H2SO4 CH3OH

H H

A)

H

OCH3 OCH3

H HO C)

CH3 CH2CH3

H

OH

H H3CO

B)

CH3 CH2CH3

H3CO H H

CH3 CH2CH3

D)

OH

In the alkyloxonium ion, more positive charge is located on the tertiary carbon than on the primary carbon. This effect counteracts the effect of steric hindrance and the alcohol attacks the tertiary carbon. Because inversion of configuration occurs during ring opening, free carbocations cannot be involved in the reaction mechanism. Sec. 6: Alcohols, Ethers

21

Ethers are unreactive towards basic nucleophiles and are very weak bases and thus are generally good solvents. However ethers will react (ether cleavage) with strong acids in the presence of a good nucleophile, ie HBr, HI or NaBr, NaI in H2SO4. Order the intermediates and final product in the reaction of oxacylclopentane (tetrahydrofuran) with excess HBr H O

HO

O

excess conc HBr.

1)

Br 3)

A) B) C) D)

Br

Br

2)

H2O 4)

Br

1, 2, 3, final product 4 2, 1, 4, final product 3 2, 4, 1, final product 3 1, 4, 3, final product 2

Sec. 6: Alcohols, Ethers

22

What is the major product produced in the following reaction? O H

1) LiAlH4 /Et2O +

?

PBr3 /Et2O

2) H3O

?

? 2) H2CO

1) NaH 2) CH3Br

?

3) H3O+

O

O

A)

Br C)

B)

O

OH O D)

1) Mg /Et2O

O

O

E)

Sec. 6: Alcohols, Ethers

23

Sulfur Analogs of Alcohols and Ethers The IUPAC system calls the sulfur analogs of alcohols, R-SH, “thiols.” The –SH group in more complicated compounds is referred to as “mercapto.”

The sulfur analogs of ethers are called “sulfides” (common name, thioethers). The RS group is called “alkylthio,” and the RS- group is called “alkanethiolate.”

Thiols are less hydrogen-bonded and more acidic than alcohols. Thiols are more acidic than water and can therefore be easily deprotonated by hydroxide and alkoxide ions:

Sec. 6: Alcohols, Ethers

24

Thiols and sulfides react much like alcohols and ethers The sulfur in thiols and sulfides is more nucleophilic than the oxygen in the analogous compounds. Thiols and sulfides are readily made through nucleophilic attack by RS¯ or HS¯ on haloalkanes:

A large excess of HS¯ is used to prevent the reaction of the product with the starting halide. The nucleophilicity of the generated thiolates is much greater than that of hydroxide which eliminates the competing SN2 substitution by hydroxide ion.

Sec. 6: Alcohols, Ethers

25

Sulfides can attack haloalkanes to form sulfonium ions.

Sulfonium ions are subject to nucleophilic attack, the leaving group being a sulfide.

Sulfides can also be oxidized to sulfoxides and then sulfones:

Valence-shell expansion of sulfur accounts for the special reactivity of thiols and sulfides. Sulfur can expand its valence shell from 8 to 10 or 12 electrons using its available 3d orbitals, allowing oxidation states not available to its oxygen analogs. Oxidation of thiols with strong oxidizing agents (H2O2, KMnO4) gives the corresponding Sec. 6: Alcohols, Ethers sulfonic acids:

26

Milder oxidizing agents (I2) yield disulfides. These can be reduced back to thiols by alkali metals

Reversible disulfide formation is important in stabilizing the folding of biological enzymes:

Sec. 6: Alcohols, Ethers

27

The polymer chain crosslinking of rubber is called vulcanization. CH 3 CH 3 C H2

CH 3

CH 3

CH 3

C H2

C H2

C H2 CH 3

CH 3

H2 C

C H2

CH 3

H2 C

n

CH 3

H2 C

CH 3 C H2

CH 3

CH 3

CH 2 C H2

C H2 CH 3

CH 3

CH 3

CH 3

m

C H2

C H2 CH 3

CH 3

Sx

heat CH 3

C H2 CH 2

n S

CH 3

CH 3

CH 3

C H2 CH 3

CH 3

H2 C

CH 3

CH 3

CH 3

x = 1 (sulfide or thioether crosslink) CH 3

m x > 1 (polysulfide crosslink)

N

N S

SH S

S

mercaptobenzothiazole (MBT)

Sx

H

a hypothetical intermediate acelerated vulcanization

In older vulcanization processes, the co-polymer was simply heated with elemental sulfur to form sulfide or poly sulfide crosslinks, however this reaction is usually very slow. Current vulcanization processes use so-called vulcanization accelerators such as MBT Sec. 6: Alcohols, Ethers

28