6 Alcohols and Ethers A Notations

Sec. 6: Alcohols, Ethers 1

Any time a Carbocation is formed Rearrangements can occur.

C

CH3

H3C

CH3

C

H

CH3methanide

migrationCH3C

CH3

C

H

CH3

CH3++

C

C

C

H3CH3C H

H

HHC

H

H

H

Lewisbase

Lewisacid

Why does this happen?

C

CH3

H3C

CH3

CH2

methanide

migration

+

CH3C

CH3

CH2

CH3+

CH3CH2 CH

H

CH2hydride

migration

+

CH3CH2 CH CH2

H+

3°

3°

2°

2°

1°

1°

C

CH3

CH2C

H2C H

C

HH HH

H

+

+


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.


C C

CH3

H3C

CH3

Br

CH3

H

CH3OH

C C

CH3

H3C

CH3

CH3

H

+

+ Br

methanidemigration

C CH3C

CH3

CH3

H

CH3+

CH3OH

-H+

C CH3C

CH3

CH3

H

CH3OCH3

What is the product of the following SN1 reaction?

acidacid

base

weak basepoor nucleophile

base

C C

CH3

H3C

CH3

OCH3

CH3

H

C C

OCH3

H3C

CH3

CH3

CH3

H

C CH2

CH3

H3C

CH3

CH2

C C

CH3

H3C

CH3

CH3O

CH3

H

A) B)

C) D)

H3CO

Mechanism

2o 3o


What is the major product formed in the following reaction?

85% H3PO4

60°CC

CH3

H3C

CH3

C

H

CH3

OH

C

H3C

H3C

C

CH3

CH3

C

H2C

H3C

C

CH3

CH3

H

C

CH3

H3C

CH3

CH CH2 C

H3C

H3C

CCH3

H

C

CH3

H3C

CH3

C

H

CH3

A)

C)

B)

E)D)

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


What is the Mechanism of the previous reaction?

85% H3PO4

+

+

60°C

C

CH3

H3C

CH3

C

H

CH3

OH

P

O

OH

OH

OH

acid

base

C

CH3

H3C

CH3

C

H

CH3

O

H H

P

O

OH

OH

O+

-H2O

C

CH3

H3C

CH3

C

H

CH3

2°

methanideshift

CC

CH3

C

CH3

CH3

H

H

HH

+

3°

P

O

OH

OH

O

C

H2C

H3C

C

CH3

CH3

H

a

a

b

b

C

H3C

H3C

C

CH3

CH3

major

Zaitsev’sRule

+ H3PO4


What is the major product formed in the following reaction?

85% H2SO4C

H

H3C

CH3

C

H

CH3

OH

NaBrC

H

H3C

CH3

C

H

CH3

OH

85% H2SO4

A)

C)

B)

D)

Br

H

Br

H

A)

C)

B)

D)


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

85% H2SO4

+

+

C

H

H3C

CH3

C

H

CH3

OH

acid

base

C

H

H3C

CH3

C

H

CH3

O

H H

+

-H2O

C

H

H3C

CH3

C

H

CH3

2°

hydrideshift

CC

CH3

C

H

CH3

H

H

HH

+

3°

HSO4

Na Br+

Br

CH3C

CH3

C

H

CH3

H

Br

weak base good nucleophile

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

SN1

CH3C

H3C

CCH3

H C

H2C

H3C

C

H

CH3

H

+

major


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.


Making an ether by dehydration of an alcohol

OH

OH

conc. H2SO4O

acid

base

OH

OH2

2°

+

OH

H2O+

+

OH

H2O+

H H

OH

H

H H

+

benzylicvery stable

acid

base

OH

O

-H+

+

H+

1 23

4

1

23

4

+ HSO4


Organic and Inorganic Esters from AlcoholsOrganic 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.

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


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


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.


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?

NaSCN

acetone

SCN SCN

A) B) C)


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.

The smaller alkoxyalkanes are water soluble, however solubility decreases with increasing hydrocarbon size.Methoxymethane- completely water solubleEthoxyethane -10% aqueous solution


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.


Williamson Ether Synthesis

Synthesis of Ethers

OHNaH

ONaCl

DMSODMSOO

1-butoxybutane

What is the major product produced in the following reaction?

Br OH NaOH

O

HO(CH2)5OH

O

dilute solution

-(O(CH2)5O)-n

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.



NaOH

A) B)

HO

D

BrH

HH

O

HD

H

H

O

DH

H

H

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

OH OH+

excess

15% aqu. H2SO4

40oCO

2-ethoxy-2-methylpropane



HOH

O

(CH3)3COH, H+

?1) BrMgCH2CH3

2) H2O, H+?

OH

OH

Br

O

Br OH

OOH

OH

O

A) B) C)

D)E)

OH2

HOH

O

HO

O

H O

O MgBr

H OH

OH

H O

OH H



O

CH2CH3

CH3HH

CH3SNa

SCH3H

H

CH3CH2CH3

HO

HOCH2CH3

CH3

HH SCH3

OHH

H

CH3CH2CH3

H3CS

H3CSCH2CH3

CH3

HH OH

A) B)

C) D)

1)

2) H2O, H+

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


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 openingRing opening of oxacyclopropane by acid catalysis proceeds through an initial cyclic alkyloxonium ion.

This acid catalyzed ring opening is both regioselective and stereospecific.



O

CH2CH3

CH3HH

H2SO4

CH3OH OCH3H

H

CH3CH2CH3

HO

HOCH2CH3

CH3

HH OCH3

OHH

H

CH3CH2CH3

H3CO

H3COCH2CH3

CH3

HH OH

A) B)

C) D)

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.


Order the intermediates and final product in the reaction of oxacylclopentane (tetrahydrofuran) with excess HBr

Oexcess conc HBr.

HOBr

BrBr

O

H

H2OBr

1)2)

3) 4)

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.

A) 1, 2, 3, final product 4B) 2, 1, 4, final product 3C) 2, 4, 1, final product 3D) 1, 4, 3, final product 2



H

O

LiAlH4 PBr3

A)B)

C)

D) E)

2) H3O+

1)?

/Et2O /Et2O?

/Et2OMg1)

2) H2CO

3) H3O+

?1) NaH

2) CH3Br?

O OBr

O

OH

O

O

O


Sulfur Analogs of Alcohols and EthersThe 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:


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.


Sulfides can attack haloalkanes to form sulfonium ions.

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

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 sulfonic acids:

Sulfides can also be oxidized to sulfoxides and then sulfones:


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:


The polymer chain crosslinking of rubber is called vulcanization.

C H2

CH3

CH3

C H2

CH3

CH3

CH3

H2

C

C H2

CH3

CH3

n

C H2

CH3

CH3

C H2

CH3

CH3

CH3

H2

C

C H2

CH3

CH3

m

S

heat

C H2

CH3

CH3

C H2

CH 3

CH3

CH 3

CH2

H2

C

C H2

CH3

CH3

n

C H2

CH 3

CH3

C H2

CH3

CH3

CH3

CH2

H2 C

C H2

CH 3

CH3

m

S x

x = 1 (sulfide or thioether crosslink)

x > 1 (polysulfide crosslink)

S

NS H

mercaptobenzothiazole(MBT)

S

NS S

xH

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

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6 Alcohols and Ethers A Notations