Alcohols
Properties & Synthetic Preps
Alcohols
• Hydroxyl groups in natural compounds.
Phenols
• Naturally occurring phenols: a hydroxyl group
directly attached to an aromatic ring.
Physical Properties of Alcohols
•
•
The –OH of an alcohol has a profound effect on
physical properties.
Compare the boiling points below.
b.p. -24 oC
Physical Properties of Alcohols
•
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
octanol-water partitioning
•
•
•
•
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)
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
Preparation of Alcohols
•
What reagents did we use to accomplish this
transformation?
•
Substitution can occur by SN1 or SN2.
Preparation of Alcohols
Alcohol Preps
Reactions:
Catalytic Reduction
Hydration of alkenes
Hydroboration-oxidation of alkenes
Hydrolysis of alkyl halides
New Syntheses using
Grignard reagents
Organolithium reagents
Alcohols
Diols by hydroxylation of alkenes
New methods or reagents:
Reduction of aldehydes and ketones
Reduction of carboxylic acids
Reduction of esters
Reaction of Grignard reagents with epoxides
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
Reduction of Aldehydes Gives Primary Alcohols
R
R
C
H
O
H
C
H
OH
Example: Catalytic Hydrogenation
O
CH3O
CH
+
H2
Pt, ethanol
CH3O
CH2OH
(92%)
Reduction of Ketones Gives Secondary Alcohols
R
R
C
R'
O
H
C
R'
OH
Example: Catalytic Hydrogenation
H
O
+
H2
OH
Pt
ethanol
(93-95%)
Retrosynthetic Analysis
R
H
C
R
OH
H:–
R
C
R'
O
C
O
H
H
H
C
R
OH
H:–
R'
Question
• Which isomer of C4H10O can be
prepared by hydrogenation of a ketone?
•
A)
B)
•
C)
D)
Metal Hydride Reducing Agents
H
+
Na H
B
–
H
Li+
H
Act as hydride donors (H )
The analagous deuterated agents
NaBD4 and LiAlD4 produce (D )
and work in the same way
Mechanism
Examples: Sodium Borohydride
Aldehyde
O2N
O2N
O
NaBH4
CH2OH
CH
methanol
(82%)
Ketone
O
NaBH4
ethanol
H OH
(84%)
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
O
CH3(CH2)5CH
1. LiAlH4
diethyl ether
2. H2O
CH3(CH2)5CH2OH
(86%)
Ketone
O
(C6H5)2CHCCH3
1. LiAlH4
diethyl ether
2. H2O
OH
(C6H5)2CHCHCH3
(84%)
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
Selectivity
Neither NaBH4 or LiAlH4
reduces carbon-carbon
double bonds.
O
1. LiAlH4
diethyl ether
2. H2O
(90%)
H
OH
Preparation of Alcohols By Reduction
of Carboxylic Acids and Esters
Reduction of Carboxylic Acids
Gives Primary Alcohols
R
R
C
HO
O
H
C
OH
H
lithium aluminum hydride is only
effective reducing agent; not sodium borohydride
Example: Reduction of a Carboxylic Acid
O
COH
1. LiAlH4
diethyl ether
2. H2O
CH2OH
(78%)
Mechanism
•
To reduce an ester, two hydride equivalents are
needed.
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
O
COCH2CH3
1. LiAlH4
diethyl ether
2. H2O
CH2OH +
(90%)
CH3CH2OH
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
OH
O
A.
NaBH4, H2O
O
NO REACTION
OH
C.
O
B.
OH
OH
O
D.
OH
OH O
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
R
MgX
CH2
H2C
O
R
CH2
CH2
OMgX
H3O+
RCH2CH2OH
Example
CH2
CH3(CH2)4CH2MgBr + H2C
O
1. diethyl ether
2. H3O+
CH3(CH2)4CH2CH2CH2OH
(71%)
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
Preparation of Diols
•
If two carbonyl groups are present, and enough
moles of reducing agent are added, both can be
reduced.
Example: Reduction of a Dialdehyde
O
O
HCCH2CHCH2CH
CH3
H2 (100 atm)
Ni, 125°C
HOCH2CH2CHCH2CH2OH
CH3
3-Methyl-1,5-pentanediol
(81-83%)
Question
Which of the following reactions produce alcohols?
Dilute H2SO4
A.
1) Hg(OAc)2, H2O
2) NaBH4
B.
1) BH3.THF
2) H2O2, NaOH
C.
H3O+
D.
Cl
E.
H2O
A.a, b
B.a, b, c
C.a, b, c, d
D.a, b, c, e
E.a, b, c, d, e