alcohols properties & synthetic preps. hydroxyl groups in natural compounds. alcohols
TRANSCRIPT
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?