Synthesis of 2º Alcohols
Grignard + aldehyde yields a secondary
alcohol.
CH3
H3C C CH2
C
H
H
CH3
H3C
H
MgBr
C O
CH3
CH CH2
CH3
CH2
H
MgBr
H
CH3
CH3
C O
CH CH2
CH3
CH2
HOH
C O H
H
=>
Synthesis of 3º Alcohols
Grignard + ketone yields a tertiary alcohol.
CH3
H3C C CH2
C
H
H
CH3
H3C
H
MgBr
C O
CH3
CH CH2
CH3
CH2
H3C
MgBr
CH3
CH3
CH3
C O
CH CH2
CH3
CH2
HOH
C O H
CH3
=>
How would you
synthesize…
OH
CH2OH
CH3CH2CHCH2CH2CH3
OH
OH
CH3
C CH3
CH2CH3
=>
Grignard Reactions
with Acid Chlorides
and Esters
• Use two moles of Grignard reagent.
• The product is a tertiary alcohol with
two identical alkyl groups.
• Reaction with one mole of Grignard
reagent produces a ketone
intermediate, which reacts with the
second mole of Grignard reagent.
=>
Grignard + Acid
Chloride (1)
• Grignard attacks the carbonyl.
• Chloride ion leaves.
CH3
H3C
R
MgBr
C O
Cl
CH3
R C O
Cl
R C O
MgBr
Cl
CH3
MgBr
R C
+
MgBrCl
O
Ketone intermediate
=>
Grignard and Ester (1)
• Grignard attacks the carbonyl.
• Alkoxide ion leaves! ? !
CH3
H3C
R
MgBr
C O
CH3O
CH3
R C O
OCH3
R C O
MgBr
OCH3
CH3
MgBr
R C
+
O
MgBrOCH3
Ketone intermediate
=>
Second step of reaction
• Second mole of Grignard reacts with the
ketone intermediate to form an alkoxide ion.
• Alkoxide ion is protonated with dilute acid.
CH3
CH3
R
MgBr
+
R C
R C O
O
MgBr
R
HOH
CH3
R C OH
R
=>
How would you synthesize...
Using an acid chloride or ester.
OH
CH3
CH3CH2CCH3
C
CH3
OH
OH
CH3CH2CHCH2CH3
=>
Grignard Reagent +
Ethylene Oxide
• Epoxides are unusually reactive ethers.
• Product is a 1º alcohol with 2 additional
carbons.
O
O
MgBr
+
CH2
CH2CH2
CH2
HOH
O H
CH2CH2
=>
MgBr
Limitations of Grignard
• No water or other acidic protons like
O-H, N-H, S-H, or -C—C-H. Grignard
reagent is destroyed, becomes an alkane.
• No other electrophilic multiple bonds, like
C=N, C—N, S=O, or N=O.
=>
Reduction of Carbonyl
• Reduction of aldehyde yields 1º alcohol.
• Reduction of ketone yields 2º alcohol.
• Reagents:
– Sodium borohydride, NaBH4
– Lithium aluminum hydride, LiAlH4
– Raney nickel
=>
Sodium Borohydride
• Hydride ion, H , attacks the carbonyl
carbon, forming an alkoxide ion.
• Then the alkoxide ion is protonated by
dilute acid.
• Only reacts with carbonyl of aldehyde or
ketone, not with carbonyls of esters or
carboxylic acids.
O
C
H
H
H
C
H
O
+
H
H3O
O H
C
H
=>
Lithium Aluminum Hydride
• Stronger reducing agent than sodium
borohydride, but dangerous to work with.
• Converts esters and acids to 1º alcohols.
O
C
OCH3
H
LAH
H3O+
C
O H
H
=>
Comparison of
Reducing Agents
• LiAlH4 is stronger.
• LiAlH4 reduces more
stable compounds
which are resistant
to reduction.
=>
Catalytic Hydrogenation
• Add H2 with Raney nickel catalyst.
• Also reduces any C=C bonds.
OH
O
NaBH4
OH
H2, Raney Ni
=>
Thiols (Mercaptans)
•
•
•
•
•
Sulfur analogues of alcohols, -SH.
Named by adding -thiol to alkane name.
The -SH group is called mercapto.
Complex with heavy metals: Hg, As, Au.
More acidic than alcohols, react with
NaOH to form thiolate ion.
Stinks!
=> •
Thiol Synthesis
Use a large excess of sodium hydrosulfide
with unhindered alkyl halide to prevent
dialkylation to R-S-R.
_
H S
_
R X
R
SH
+ X
=>
Thiol Oxidation
• Easily oxidized to disulfides, an
important feature of protein structure.
Br2
R
SH
+ HS
R
R
S
S
R +
2 HBr
Zn, HCl
Vigorous oxidation with KMnO4,
HNO3, or NaOCl, produces sulfonic acids.
•
SH
HNO3
boil
O
S
O
OH
=>