Chapter 8 Reactions of Alcohols
I.
Oxidation and Reduction of Alcohols
A.
B.
Inorganic Oxidation and Reduction
1) Oxidation = loss of electrons: Cu+
2) Reduction = gain of electrons: Zn2+
-2 e-
+2 e-
Cu3+
Zn0
Organic Oxidation and Reduction
1) Oxidation = addition of electronegative atoms (O, Cl, N)
= removal of H
O
CH4
O
2)
CO2
+2H
CH3OH
H2C O
O
HC OH
-2H
CO2
Reduction = removal of electronegative atoms (O, Cl, N)
= addition of H
O
HC OH
3)
-2H
-O
H2C O
+2H
CH3OH
Relationship between alcohols and carbonyl groups
1) C==O = carbonyl
-O
CH4
2)
Aldehyde is an oxidized Primary Alcohol (reduced aldehyde)
O
oxidation
RCH2OH
3)
reduction
C
R
Ketone is an oxidized Secondary Alcohol (reduced ketone)
O
oxidation
RR'CHOH
C.
H
reduction
C
R
R'
Alcohol Synthesis by Reduction of Aldehydes and Ketones
1) Hydrogenation = adding H2 to a double bond
H H
H2
cat
C C
2)
3)
Catalyst = reactant that doesn’t get destroyed; it speeds up the reaction by
lowering the Ea for the reaction
a) Heterogeneous Catalyst = insoluble, reaction occurs at its surface
i. Fine powder increases surface area (put cat. on fine charcoal)
ii. Pd/C or Pt metal or Ni metal work as hydrogenation cat.’s
b) Homogeneous Catalyst = soluble, reaction occurs in solution
Hydrogenation of Carbonyls gives Alcohols
C O
H2
cat
aldehyde
R C O H
H
H
R
H
R
H
C C
1o ROH
C O
R'
ketone
H2
cat
R C O H
R'
2o ROH
D.
Alcohol Synthesis by Hydride Reduction of Carbonyl’s
1) Carbonyl groups are polar
-
O
-
O
C
R + R'

C
+ R'

R
C
R'
-
2)
Hydride = H has several efficient sources for Organic Synthesis
a) Na+H- or Li+HM+ + H- (not very organic soluble)
b) NaBH4
Na+ + B(solvent) + 4 Hc) LiAlH4
Li+ + Al(solvent) + 4 H-
3)
Reduction of Carbonyl’s to Alcohols
R
R
O
H
R
H
NaBH4
C
R
O
C
O
H
4)
H
C
LiAlH4
O
H
R
R'
C
O
H
R'
NaBH4 Mechanism
OH
R'
H3B H
C O
R
H OR''
R'
C H
R
+
H3B OR''
B(OR)4
5)
LiAlH4 is too reactive to use in Protic Solvents
H3Al H
H3Al
H
E.
H2(gas) + Al(OH)4
H OH
6) LiAlH4 in Aprotic Organic Solvent
R'
R'
x4
H2O
C O
R C O Al
EtOEt
"aqueous
4
R
H
workup"
R'
4
R C OH + Al(OH)3
H
Oxidation of Alcohols to Carbonyls
1) Reduction reactions can be reversed to give the aldehydes or ketones
2) Oxidizing Reagent is Cr(VI)
a) (Na2Cr2O7 or K2Cr2O7 or CrO3) and H2SO4 and H2O
R'
CH OH
R
b)
Na2Cr2O7
H2SO4, H2O
R'
C
O
R
Primary alcohols can be overoxidized to carboxylic acids
RCH2 OH
Na2Cr2O7
H2SO4, H2O
O
R
C
OH
3)
Do Primary alcohol oxidation without water
NH+ CrO3Cl a) PCC = pyridinium chlorochromate =
b) Anhydrous conditions and PCC don’t overoxidize primary alcohol
R CH2 OH
4)
O
PCC
CH2Cl2
R
C
Mechanism involves Chromic Ester
O
O
RCH2
OH +
VI
VI
HO Cr
OH
RCH2O Cr
O
RCHO Cr OH
H
O
OH + H2O
O
Chromic Ester
O
H2O
H
Like E2
O
RCH
+
H3O+
+
CrVIO3H
II. Organometallic Reagents = carbon-metal bonds
A.
Nucleophilic Carbon
1) H- is a nucleophilic hydrogen that gives new C—H bonds
OH
R'
H3Al
H
C O
R'
R
2)
R
Formation of new C—C bonds is the key requirement in organic synthesis
OH
R'
R''CH2-
C O
R
B.
C H
R'
C CH2R''
R
Alkylmetal Reagents
1) Haloalkanes can be transformed into organometallic compounds
a) Alkyllithium Synthesis (I > Br > Cl reactivity)
ether or THF
RBr + 2 Li
0 oC
b)
O
RLi + LiBr
Tetrahydrofuran
Alkylmagnesium Synthesis (Grignard Reagent)
ether or THF
RI + Mg
RMgI
0 oC
2)
O
R
R- MgX+ + H OH
Mg
O
R

Alkylmetals are very strong Nucleophiles
a) Use them as soon as you make them (…made in situ…)
b) Air and water sensitive, must do reaction under N2 or Ar
Hydrolysis
RH + XMOH
I
3)
True structure involves coordinated solvent—require ether or THF
4)
Very polar bond, metal is very electropositive
a) Opposite of usual situation for carbon, as in Haloalkanes
b) Treat the molecule like R- = Carbanion
c) Resonance forms
M
+

C
5)
M
C
+ M
Alkylmetals are very basic
a) Basicity: RCH2- > RNH- > RO- (electronegativity)
b) Acidity: RCH3 < H2NR < ROH
c) Leads to fast hydrolysis (see above) in protic solvents
6)
Making Alkanes from Haloalkanes
a) Use alkyl metal hydrolysis
R- MgX+ + H OH
RX + Mg
b)
Use hydride nucleophile
Br
c)
LiAlH4
ether
Useful for Deuterating compounds (D = deuterium = 2H)
Br
C.
RH + XMOH
LiAlHD4
ether
D
Alkylmetal reagents in Alkanol Synthesis
1) Formation of new C—C bond by using C Nucleophile
2) Nucleophilic attack of Haloalkane by alkylmetal reagent is too slow
-
+
R' MgX
slow
+
Br
R'
3)
Must use Carbonyl electrophile (C+==O-)
a) Ketone gives tertiary alcohol product
O
RLi +
ether or THF
C
R'
O
R'
R'
C
OH
+
H , H2O
C
R'
R'
R
R
b)
Aldehyde gives a secondary alcohol product
O
RLi +
ether or THF
C
R'
OH
+
H , H2O
H
H
C
R'
R
c)
R'
Formaldehyde (CH2O) gives primary alcohol product
O
RLi +
ether or THF
C
H
H
+
H , H2O
OH
H C
R
H
III. Synthetic Strategies
A.
Use Mechanisms to predict the products of a reaction
II1)
I
2)
B.
Br
F
Br
F
CH3
Br CH3
Br2
I
CH2Br
Br2
Know all of the tools (reactions) you can use
Nu, DMSO
Br
Mg, ether
(CH3)3CO(CH3)3COH
Nu
H2O
H2CO
MgBr
CH2OH
O
OH
C.
Synthesis of Complex Alcohols Using Alkylmetal Reagents
1. Useful Reaction Sequence
CH4
Br2
CH3Br
-OH
CH3OH
PCC
CH2Cl2
H2C O
+
RMgBr
H
THF
RCH2OH
OH2
2. Retrosynthetic Analysis = Work Backwards from Target
a) Complex molecules are made from simple parts
b) Look for C—C bonds to break (form)
OH
CH3CH2CH2
CH2CH3
strategic
disconnection
CH3CH2CH2MgBr
+
CH3
CrO3, H2SO4, H2O
O
H+, H2O
THF
H3C
H3C
CH2CH3
OH
CH2CH3
H
H+, H2O
THF
O
CH3Li
+
H
CH2CH3
3)
Avoid Synthetic Pitfalls
a) Use fewest possible steps
i. 2 steps at 90% yield = (0.9)(0.9) = 81% total yield
ii. 4 steps at 95% yield = (0.95)(0.95)(0.95)(0.95)= 81% total yield
b)
Convergent Synthesis is better than Linear Synthesis
A
B
C
D (50% yield at each step)
80g
20g
E
40g
F
20g
10g
10g
D 10g
20g
c)
G
H
10g
Don’t use functional groups that would interfere in the reaction
O
MgBr
d)
+
HO
Remember mechanistic limitations
i. Br2 is very selective form tertiary H
ii. SN2 can’t happen for tertiary electrophile
Protic alcohl
kills Grignard