FIVE METHODS OF PREPARING ALCOHOLS

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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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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).


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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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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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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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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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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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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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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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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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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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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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. 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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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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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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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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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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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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Do the practice problems in your purchased notes!

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FIVE METHODS OF PREPARING ALCOHOLS