Alcohols Properties & Synthetic Preps

• Hydroxyl groups in natural compounds.

Alcohols

• Naturally occurring phenols: a hydroxyl group directly attached to an aromatic ring.

Phenols

• The –OH of an alcohol has a profound effect on physical properties.

• Compare the boiling points below.

Physical Properties of Alcohols

b.p. -24 oC

• The hydrogen- (H-) in hydroxyl groups intermolecularly attracts water molecules

• Alcohols with small carbon chains are miscible in water (they mix in any ratio).

• Alcohols with large carbon chains do not readily mix with water.

Physical Properties of Alcohols

• Molecules with large hydrophobic groups are generally insoluble in water.

• Alcohols with three or less carbons are generally water miscible.

• Alcohols with more than three carbons are not miscible, and their solubility decreases as the size of the hydrophobic group increases.

• Partition Coefficient: relative solubility of a compound (ratio) in octanol vs. water (Drug absorbtion & transport)

Physical Properties of Alcoholsoctanol-water partitioning

Stress? memory? cognition? …cheating?

Propranolol: orally administered anti-hypertensive -Blocker: blocks the action of epinephrine and norepinephrine

on both β1- and β2-adrenergic receptors

“Basic sciences in the history of cardiovascular pharmacology”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC325477/

Nobel Prize 1988

Sir James W. Black

Born: 14 June 1924

Died: 21 March 2010

Affiliation at the time of the award: University of Glasgow, Scotland

Acidity of Alcohols and Phenols

• What reagents did we use to accomplish this transformation?

• Substitution can occur by SN1 or SN2.

Preparation of Alcohols

Preparation of Alcohols

Catalytic Reduction

Hydration of alkenes

Hydroboration-oxidation of alkenes

Hydrolysis of alkyl halides

New Syntheses using

Grignard reagents

Organolithium reagents

Alcohol Preps

Reactions:

Reduction of aldehydes and ketones

Reduction of carboxylic acids

Reduction of esters

Reaction of Grignard reagents with epoxides

Alcohols

New methods or reagents:

Diols by hydroxylation of alkenes

Question

• Which compound is produced when cyclohexene reacts with OsO4, (CH3)3COOH,

tert-butyl alcohol, HO-?

• A) B)

• C) D)

Reduction of Aldehydes and Ketones

C

R

H OH

H

C

R

H

O

Reduction of Aldehydes Gives Primary Alcohols

Pt, ethanol

(92%)

Example: Catalytic Hydrogenation

CH3O CH2OH

O

CH3O CH + H2

C

R

H OH

R'

C

R

R'

O

Reduction of Ketones Gives Secondary Alcohols

(93-95%)

Example: Catalytic Hydrogenation

+ H2

O

Pt

ethanol

H OH

H:–C

R

H OH

H

C

R

H

O

H:–C

R

H OH

R'

C

R

R'

O

Retrosynthetic Analysis

Question

• Which isomer of C4H10O can be

prepared by hydrogenation of a ketone?

• A) B)

• C) D)

Na+ –

B

H

H

HH

Metal Hydride Reducing Agents

Act as hydride donors (H-)

The analagous deuterated agents

NaBD4 and LiAlD4 produce (D-)

and work in the same way

Li+

Mechanism

Examples: Sodium Borohydride

O

CH

O2N

O

NaBH4

methanol

(82%)

CH2OH

O2N

H OH

(84%)

NaBH4

ethanol

Aldehyde

Ketone

Question

• Reduction of acetaldehyde (CH3CH=O)

with NaBD4 in H2O produces:

• A) B)

• C) D)

Lithium Aluminum Hydride

More reactive than sodium borohydride.

Cannot use protic solvents:

water, ethanol, methanol, etc..

Diethyl ether is most commonly used solvent.

Examples: Lithium Aluminum Hydride

Aldehyde

Ketone

O

CH3(CH2)5CH

1. LiAlH4

diethyl ether

2. H2O

O

(C6H5)2CHCCH3

1. LiAlH4

diethyl ether

2. H2O

(84%)

CH3(CH2)5CH2OH

(86%)

OH

(C6H5)2CHCHCH3

Question

• Which one of the isomeric alcohols of formula C5H12O can be prepared by LiAlH4 reduction

• of a ketone?• A) 1-pentanol• B) 2-methyl-2-butanol• C) 3-methyl-2-butanol• D) 2,2-dimethyl-1-propanol

Neither NaBH4 or LiAlH4

reduces carbon-carbondouble bonds.

O

H OH

1. LiAlH4

diethyl ether

2. H2O

(90%)

Selectivity

Preparation of Alcohols By Reductionof Carboxylic Acids and Esters

lithium aluminum hydride is only effective reducing agent; not sodium

borohydride

Reduction of Carboxylic AcidsGives Primary Alcohols

C

R

H OH

H

C

R

HO

O

Example: Reduction of a Carboxylic Acid

1. LiAlH4

diethyl ether

2. H2OCOH

O

CH2OH

(78%)

• To reduce an ester, two hydride equivalents are needed.

Mechanism

Reduction of EstersGives Primary Alcohols

Lithium aluminum hydride is overwhelmingly preferred for reductions of esters.

Sodium borohydride reduction is too slow.

Catalytic hydrogenation is used in industry,but requires a special catalyst, hightemperature, and high pressure.

Example: Reduction of an Ester

1. LiAlH4

diethyl ether

2. H2O

(90%)

O

COCH2CH3

CH3CH2OHCH2OH +

Question

• Which of the esters shown, after reduction with LiAlH4 and aqueous workup, will yield two molecules of only a single alcohol?

• A) CH3CH2CO2CH2CH3

• B) C6H5CO2CH2C6H5

• C) C6H5CO2C6H5

• D) none of these

Answer: D.

 

Reduction with sodium borohydride reduces only the ketone,

not the acid. For more examples of this type of problem, SEE:

Skillbuilder 13.4.

A.

B.

C.

D.

OH

O O

NaBH4, H2O

NO REACTION

OH

OH

OH

O O

OH

OH O

Preparation of Alcohols From Epoxides

Reaction of Grignard Reagentswith Epoxides

H2C CH2

O

R MgX

CH2 CH2 OMgX

R

H3O+

RCH2CH2OH

CH3(CH2)4CH2MgBr H2C CH2

O

+

1. diethyl ether2. H3O+

CH3(CH2)4CH2CH2CH2OH

(71%)

Example

Question• Select the best combination of reagents to prepare

2-phenylethanol from bromobenzene.• A) 1. Mg, diethyl ether; 2. ethylene oxide; 3.

H3O+

• B) 1. Mg, diethyl ether; 2. acetaldehyde (CH3CH=O); 3. H3O

+

• C) 1. Mg, diethyl ether; 2. 2-chloroethanol;

3. H3O+

• D) 1. Mg, diethyl ether; 2. CH3CH2OCH2CH3;

3. H3O+

Preparation of Diols:

Reduction of dicarbonyl compounds

• If two carbonyl groups are present, and enough moles of reducing agent are added, both can be reduced.

Preparation of Diols

O O

HCCH2CHCH2CH

CH3

H2 (100 atm)

Ni, 125°C

HOCH2CH2CHCH2CH2OH

CH3

3-Methyl-1,5-pentanediol

(81-83%)

Example: Reduction of a Dialdehyde

 Question

Cl

Dilute H2SO4

1) Hg(OAc)2, H2O2) NaBH4

1) BH3.THF

2) H2O2, NaOH

H3O+

H2O

A.

B.

C.

D.

E.

A.a, bB.a, b, cC.a, b, c, dD.a, b, c, eE.a, b, c, d, e

Which of the following reactions produce alcohols?