1 five methods of preparing alcohols. 2 5 methods of preparing alcohols 1. hydroxide ions (oh - )...
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FIVE METHODS OF PREPARING ALCOHOLS
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5 METHODS OF PREPARING ALCOHOLS
1. Hydroxide ions (OH-) replace halogens in unhindered alkyl halides (Me° and 1°) via an SN2 reaction. The product is an alcohol.
O H....: C Br
..
.. :
H
H
H+
transition state
C Br.... :
H H
H
OH.... +
..
.. :Br:C
H
HH
OH....
CH3
CH3CHCH2I + NaOH (aq)
isobutyl iodide
CH3CHCH2OH + NaI
CH3
isobutyl alcohol
CH2CH2Cl + NaOH (aq)
1-chloro-2-phenylethane
CH2CH2OH + NaCl
2-phenylethanol
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5 METHODS OF PREPARING ALCOHOLS
But when a hindered alkyl halide (2° or 3°) is treated with a strong base such as NaOH, dehydrohalogenation occurs producing an alkene – an E2 reaction.
Aryl and vinyl halides do not react via SN1, SN2, E1or E2 reactions.
+ C C
H
X
Nu:- C C + X- + Nu H
The Nu:- removes an H+ from a -carbon & the halogen leaves forming an alkene.
BrKOH in ethanol
bromocyclohexane-HBr
+ KBr + H2O
cyclohexene
Br
KOH
bromobenzene
no reaction
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2. Alkenes are hydrated by heating with dilute aq. H2SO4 (catalyst).
5 METHODS OF PREPARING ALCOHOLS
The E+ (H+) adds to the less substituted sp2 C Nu:- in the -bond forming the more stable C+ intermediate. The C+ may rearrange.
CH3
H
H+HSO4-
OH H
....
Water, a weak Nu:-, adds to the C+.
CH3
H
H+CH3
H
H
O..+
H H
The oxonium ion is deprotonated (loses H+) by H2O or HSO4-,
regenerating the catalyst and forming the Markovnikov alcohol (1-methylcyclohexanol in this example).
HSO4-
CH3
H
H
O..H
..
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5 METHODS OF PREPARING ALCOHOLS
Recall that oxymercuration, demercuration also produces the Markovnikov alcohol, but without C+ rearrangement.
Hg(CH3COO-)2, THF, H2ONaBH4
1
2CH
CH3
CH2CH
CH3
CH3
OH
1-methyl-1-vinylcyclopentane
The Hg ion adds first and forms a bridge to the C+, stabilizing it and preventing rearrangement.
1-(1-methylcyclopentyl)ethanol
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5 METHODS OF PREPARING ALCOHOLS
Recall that hydroboration, oxidation produces the anti-Markovnikov alcohol without C+ rearrangement.
CH3
BH3, THFNaOH, H2O2, pH8
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1-methylcyclohexene
CH3
OH
2-methylcyclohexanol
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5 METHODS OF PREPARING ALCOHOLS
Carbonyl compounds are reduced to alcohols.
DIGRESSION: Order of reactivity of carbonyls.
most
reactive
acid chloride
acid anhydride
aldehyde
ketone
ester
carboxylic acid
amide
nitrile
carboxylate
least
reactive
R C
O
Cl
: :
:....
R RC
O
O C
O: : : :....
R C
O
H
: :
R RC
O: :
R RC
O
O....
: :
R C
O
OH
: :
..
..
R N
H
HC
O: :..
R
_
C
O
O:
::....
R C N:
: :
C
Ocarbonylgroup
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5 METHODS OF PREPARING ALCOHOLS
Sodium borohydride (NaBH4),lithium aluminum hydride (LiAlH4) and Grignards (RMgX) reduce many carbonyls to alcohols.
acid chloride
acid anhydride
aldehyde
ketone
ester
carboxylic acid
amide
nitrile
carboxylate
Reduced to alcohols by Grignards (RMgX)
LiAlH4 reduces all carbonyls.
NaBH4 is a good Nu:- and is safe to use in water.
LIAlH4 is a powerful Nu:- and is explosive water.
Reduced to alcohols by NaBH4
Grignards (RMgX) are very strong bases and are destroyed by water and other weak acids.
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5 METHODS OF PREPARING ALCOHOLS
Prep. of NaBH4 & LiAlH4 are shown. These reactions are reversible.
B H
H
H
Na H
borane
sodiumhydride
+
empty 2pz
orbitalvery goodnucleophile
good electrophile
B
H
HH
HNa+
sodium borohydride NaBH4
very goodnucleophile
good electrophile
Al
H
HH
HLi+
lithium aluminum hydride LiAlH4
Al
H
H
HLi H
aluminumhydride
lithiumhydride
+
empty 2pz
orbital
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5 METHODS OF PREPARING ALCOHOLS NaBH4 and LiAlH4 dissociate in the presence of carbonyl
compounds producing hydride (H:-) ion, an excellent Nu:-. Grignards (RMgX) dissociate in the presence of carbonyl
compounds producing an alkide (R:-) ion, an excellent Nu:-
3. Reduction of aldehydes with NaBH4 or LiAlH4 producing 1° alcohols.
Mechanism:
R C
O
H
: :
H:-1.
aldehydealkoxide
..
H
R
: :
HC
OO
H H
..
H
+2.
+ OH H
....
alcohol
R C
O
H
:..
H
H
E+
Nu:-
Nu:-
E+
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5 METHODS OF PREPARING ALCOHOLS
3. Reduction of ketones with NaBH4 or LiAlH4 producing 2° alcohols.
Mechanism:
R RC
O: :
H:-1.
ketone alkoxide
..
H
R
: :
RC
OO
H H
..
H
+2.
+ OH H
....R C
O
R
:..
H
H
2° alcohol
Although both NaBH4 and LiAlH4 are effective, NaBH4 is normally used as it is safer. LiAlH4 is reserved for less reactive carbonyl compounds such as esters and carboxylic acids.
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5 METHODS OF PREPARING ALCOHOLS
Draw and name the products of the following hydride reduction reactions.
CH2
OH
cyclohexylmethanol
C
O
H
cyclohexylmethanal
NaBH4
H3O+
1
2
NaBH4
H3O+
1
2O
2-cyclopenten-1-one
OH
H
2-cyclopenten-1-olHydrides do not react with alkenes. Both are nucleophiles.
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5 METHODS OF PREPARING ALCOHOLS
4. Reduction of esters (and carboxylic acids) with LiAlH4 producing 1° alcohols. NaBH4 is not strong enough. LiAlH4 must be used for these carbonyls.
Mechanism:
R RC
O
O....
: :
1. H:-
ester
OR-....:
alkoxide
R C
O
H
: :
aldehyde
R C
O
H
: :
H:-1.
aldehydealkoxide
..
H
R
: :
HC
OO
H H
..
H
+2.
+ OH H
....
alcohol
R C
O
H
:..
H
H
E+Nu:-
R RC
O
O....
: :..
H
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5 METHODS OF PREPARING ALCOHOLS Note that aldehydes and ketones have no leaving groups. The
alkoxide intermediate will not lose a H:- or R:- so NaBH4 only adds once. Esters, however, lose an alkoxide (OR-).
OR- (pKb = -2) , like OH- (pKb = -1.74), is a poor leaving group but LiAlH4 is powerful enough to displace it from the carbonyl. Two moles of LiAlH4 are required for reduction of esters.
Draw and name the product of hydride reduction of the ester,methyl benzoate.
C
O
O CH3
methyl benzoate
1 LiAlH4
2 H3O+
2 equiv.
CH2
OH
benzyl alcohol
CH3OH+
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5 METHODS OF PREPARING ALCOHOLS
Carboxylic acids react with 3 moles LiAlH4 producing 1° alcohols.
MECHANISM:
R C
O
O
: :
..
..
carboxylic acid
H1. H:-
AlH3
R C
O
O
: :
..
..AlH3
H:-
R C
O
O
: :
..
..AlH3
..
H
pKa = 5
pKb = -21
R C
O
H
: :
H:-1.
aldehydealkoxide
..
H
R
: :
HC
OO
H H
..
H
+2.
+ OH H
....
alcohol
R C
O
H
:..
H
H
R C
O
O
: :
..
..:
carboxylate
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5 METHODS OF PREPARING ALCOHOLS
LiAlH4 is reactive enough to reduce even carboxylates, the weakest electrophile of the carbonyl compounds.
Draw and name the product of the following hydride reductions.
C
O
OH
1 LiAlH4
2 H3O+
3 equiv.
CH2OH
1-dodecanoldodecanoic acid
Cl C
O
O- Na+
sodium 4-chlorobenzoate
1 LiAlH4
2 H3O+ Cl CH2OH
(4-chlorophenyl)methanol
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5 METHODS OF PREPARING ALCOHOLS
5. Reduction of carbonyls with Grignards (RMgX) producing alcohols.
Grignards (RMgX) dissociate in the presence of carbonyl compounds producing an alkide (R:-) ion, an excellent Nu:-
C
O
+ HOMgXC R
OHO- +MgX
C R1. RMgX in ether
2. H3O+
Grignards are prepared by mixing finely divided Mg and an alkyl halide in ether solvent. Mg is inserted between the alkyl group and the halogen.
R-X + Mg R-MgX
where R = 1º, 2, or 3 alkyl, aryl, or vinylic
where X = Cl, Br, or I
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5 METHODS OF PREPARING ALCOHOLS
Grignards react with formaldehyde, CH2=O, to give
1 alcohols. They react with higher aldehydes to give 2 alcohols and esters to give 3 alcohols.
MgBr
+ C
O
H H
1. Mix
2. H3O+
cyclohexyl
bromidemagnesium
formaldehyde cyclohexylmethanol
(a 1º alcohol with a longer C chain)
C
H
HOH
+
phenyl
bromidemagnesium
MgBr
3-methylbutanal
1. Mix in ether
2. H3O+CH3CHCH2
CH3
C H
O
CH3CHCH2
CH3
C
OH
H
3-methyl-1-phenyl-1-butanol (a 2º alcohol)
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5 METHODS OF PREPARING ALCOHOLS Grignards react with ketones and esters to give 3 alcohols.
1. Mix in ether
2. H3O+
CH3CH2MgBr +
O
ethylmagnesiumbromide
cyclohexanone
OH
CH2CH3
1-ethylcyclohexanol ( a 3º alcohol)
ethyl pentanoate
CH3CH2CH2CH2 C OCH2CH3
O 1. CH3MgBr2
2. H3O+2
+CH3CH2CH2CH2 C
OH
CH3
CH3
CH3CH2OH
+ 2 MgBrOH
2-methyl-2-hexanol ( a 3º alcohol)
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5 METHODS OF PREPARING ALCOHOLS
Unlike LiAlH4, Grignards do not reduce carboxylic acids to alcohols.
Grignards (strong bases) neutralize carboxylic acids to carboxylates, but, unlike LiAlH4, Grignards are not strong enough nucleophiles to react with carboxylates (weak electrophiles) .
CH3 MgBrCH3CH2 C
O
OHpropanoic acid
CH3CH2 C
O
O- +MgBr + CH4
methane
magnesium bromide acetate
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5 METHODS OF PREPARING ALCOHOLS
Grignards are destroyed (protonated) by even very weakly acidic functional groups.
All the groups listed below have a H acidic enough to protonate the highly basic Grignard reagents.
ArCOOH RCOOH ArSH RSH ArOH R-OH amide -CC-H ArNH2 RNH2
pKa 4 5 7 10 10 16 17 25 ~30 35
Assuming alkyl amines (pKa =35) to be the weakest acid that would protonate a Grignard, calculate the approximate pKb of a Grignard.
pKeq = pKa + pKb – 14 0 = 35 + pKb -14
pKb = 14 – 35 = -21
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5 METHODS OF PREPARING ALCOHOLS
Draw products formed when methyl magnesium bromide (CH3MgBr) reacts with the following.
O
1 CH3MgBr
2 H3O+
excess OHCH3
1-methylcyclopentanol
1 CH3MgBr
2 H3O+
excess
C
O
benzophenone
C
OH
CH3
1,1-diphenylethanol
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5 METHODS OF PREPARING ALCOHOLS
The following product was formed using Grignards.
Draw all possible sets of reagents.
2-phenyl-2-butanol
C
O
H3C CH2 CH3 MgBr+
C
O
CH2 CH3 MgBrCH3+
C
O
CH3 MgBrCH3CH2+
C
OH
H3C CH2 CH3
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