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 o C

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 Alcohols octanol-water partitioning

Stress? memory? cognition? …cheating? Propranolol: orally administered anti-hypertensive  -Blocker: blocks the action of epinephrine and norepinephrine on both β 1 - and β 2 -adrenergic receptors “Basic sciences in the history of cardiovascular pharmacology”

Nobel Prize 1988 Sir James W. Black Born: 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 S N 1 or S N 2. 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 OsO 4, (CH 3 ) 3 COOH, tert-butyl alcohol, HO - ? A)B) C)D)

Reduction of Aldehydes and Ketones

CRH OHOHOHOH H CRH O Reduction of Aldehydes Gives Primary Alcohols

Pt, ethanol (92%) Example: Catalytic Hydrogenation CH 3 O CH 2 OH O CH 3 O CH + H2H2H2H2

CRH OHOHOHOH R' C R R' O Reduction of Ketones Gives Secondary Alcohols

(93-95%) Example: Catalytic Hydrogenation + H2H2H2H2OPt ethanol HOH

H:–H:–H:–H:– CRH OHOHOHOH H CRH O H:–H:–H:–H:– CRH OHOHOHOH R' C R R' O Retrosynthetic Analysis

Question Which isomer of C 4 H 10 O can be prepared by hydrogenation of a ketone? A)B) C)D)

Na+ – B HHHH Metal Hydride Reducing Agents Act as hydride donors (H - ) The analagous deuterated agents NaBD 4 and LiAlD 4 produce (D - ) and work in the same way Li +

Mechanism

Examples: Sodium Borohydride O CH O2NO2NO2NO2N O NaBH 4 methanol (82%) CH 2 OH O2NO2NO2NO2NHOH (84%) NaBH 4 ethanol Aldehyde Ketone

Question Reduction of acetaldehyde (CH 3 CH=O) with NaBD 4 in H 2 O 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 KetoneO CH 3 (CH 2 ) 5 CH 1. LiAlH 4 diethyl ether 2. H 2 O O (C 6 H 5 ) 2 CHCCH 3 1. LiAlH 4 diethyl ether 2. H 2 O (84%) CH 3 (CH 2 ) 5 CH 2 OH (86%) OH (C 6 H 5 ) 2 CHCHCH 3

Question Which one of the isomeric alcohols of formula C 5 H 12 O can be prepared by LiAlH 4 reduction of a ketone? A)1-pentanol B)2-methyl-2-butanol C)3-methyl-2-butanol D)2,2-dimethyl-1-propanol

Neither NaBH 4 or LiAlH 4 reduces carbon-carbon double bonds. O HOH 1. LiAlH 4 diethyl ether 2. H 2 O (90%) Selectivity

Preparation of Alcohols By Reduction of Carboxylic Acids and Esters

lithium aluminum hydride is only effective reducing agent; not sodium borohydride Reduction of Carboxylic Acids Gives Primary Alcohols CRH OHOHOHOH H C R HO O

Example: Reduction of a Carboxylic Acid 1. LiAlH 4 diethyl ether 2. H 2 O COH O CH 2 OH (78%)

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

Reduction of Esters Gives 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, high temperature, and high pressure.

Example: Reduction of an Ester 1. LiAlH 4 diethyl ether 2. H 2 O (90%)O COCH 2 CH 3 CH 3 CH 2 OH CH 2 OH +

Question Which of the esters shown, after reduction with LiAlH 4 and aqueous workup, will yield two molecules of only a single alcohol? A)CH 3 CH 2 CO 2 CH 2 CH 3 B)C 6 H 5 CO 2 CH 2 C 6 H 5 C)C 6 H 5 CO 2 C 6 H 5 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.

Preparation of Alcohols From Epoxides

Reaction of Grignard Reagents with Epoxides H2CH2CH2CH2C CH 2 O R MgX CH 2 OMgX R H3O+H3O+H3O+H3O+ RCH 2 CH 2 OH

CH 3 (CH 2 ) 4 CH 2 MgBr H2CH2CH2CH2C CH 2 O + 1. diethyl ether 2. H 3 O + CH 3 (CH 2 ) 4 CH 2 CH 2 CH 2 OH (71%) Example

Question Select the best combination of reagents to prepare 2-phenylethanol from bromobenzene. A)1. Mg, diethyl ether; 2. ethylene oxide; 3. H 3 O + B)1. Mg, diethyl ether; 2. acetaldehyde (CH 3 CH=O); 3. H 3 O + C)1. Mg, diethyl ether; 2. 2-chloroethanol; 3. H 3 O + D)1. Mg, diethyl ether; 2. CH 3 CH 2 OCH 2 CH 3 ; 3. H 3 O +

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

OO HCCH 2 CHCH 2 CH CH 3 H 2 (100 atm) Ni, 125°C HOCH 2 CH 2 CHCH 2 CH 2 OH CH 3 3-Methyl-1,5-pentanediol (81-83%) Example: Reduction of a Dialdehyde

Question A.a, b B.a, b, c C.a, b, c, d D.a, b, c, e E.a, b, c, d, e Which of the following reactions produce alcohols?