Chapter 8 Reactions of Alcohols

I. Oxidation and Reduction of Alcohols

A. Inorganic Oxidation and Reduction
-2 e-
1) Oxidation = loss of electrons: Cu+ Cu3+
+2 e-
2) Reduction = gain of electrons: Zn2+ Zn0

B. Organic Oxidation and Reduction

1) Oxidation = addition of electronegative atoms (O, Cl, N)
= removal of H
O
O -2H O -2H
CH4 CH3OH H2C O HC OH CO2

2) Reduction = removal of electronegative atoms (O, Cl, N)

= addition of H
O
+2H -O +2H -O
CO2 HC OH H2C O CH3OH CH4

3) Relationship between alcohols and carbonyl groups

1) C==O = carbonyl
 2) Aldehyde is an oxidized Primary Alcohol (reduced aldehyde)
oxidation O
RCH2OH reduction C
R H
3) Ketone is an oxidized Secondary Alcohol (reduced ketone)
oxidation O
RR'CHOH C
reduction R R'
C. Alcohol Synthesis by Reduction of Aldehydes and Ketones
1) Hydrogenation = adding H2 to a double bond
H H
H2
C C C C
cat
2) 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
3) Hydrogenation of Carbonyls gives Alcohols
R H R H
H2 H2
C O R C O H C O R C O H
cat cat
H R'
aldehyde H 1o ROH ketone R' 2o ROH
 D. Alcohol Synthesis by Hydride Reduction of Carbonyl’s
1) Carbonyl groups are polar
-
O O
-
O
C C C
R + R' R R' R R'
 +

-
2) Hydride = H has several efficient sources for Organic Synthesis
a) Na+H- or Li+H- M+ + H- (not very organic soluble)
b) NaBH4 Na+ + B(solvent) + 4 H-
c) LiAlH4 Li+ + Al(solvent) + 4 H-

3) Reduction of Carbonyl’s to Alcohols

R H R H
NaBH4 LiAlH4
C O R C O H C O R C O H
H R'
H R'

4) NaBH4 Mechanism
R' OH
+
H3B H C O H OR'' R' C H H3B OR'' B(OR)4
R R
 5) LiAlH4 is too reactive to use in Protic Solvents

H3Al H H OH H2(gas) + Al(OH)4

6) LiAlH4 in Aprotic Organic Solvent
R' R' R'
x4 H2O
H3Al H C O R C O Al 4 R C OH + Al(OH)3
R EtOEt 4 "aqueous
H H
workup"
E. 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' R'
Na2Cr2O7
CH OH C O
H2SO4, H2O
R R

b) Primary alcohols can be overoxidized to carboxylic acids

O
Na2Cr2O7
RCH2 OH C
H2SO4, H2O R OH
3) Do Primary alcohol oxidation without water
a) PCC = pyridinium chlorochromate = NH+ CrO3Cl -

b) Anhydrous conditions and PCC don’t overoxidize primary alcohol

O
PCC
R CH2 OH C
CH2Cl2 R H

4) Mechanism involves Chromic Ester

O O
VI VI
RCH2 OH + HO Cr OH RCH2O Cr OH + H2O
O O
Chromic Ester

O O
Like E2
RCHO Cr OH RCH + H3O+ + CrVIO3H
H O
H2O
II. Organometallic Reagents = carbon-metal bonds
A. Nucleophilic Carbon
1) H- is a nucleophilic hydrogen that gives new C—H bonds
R' OH
H3Al H C O R' C H
R R

2) Formation of new C—C bonds is the key requirement in organic synthesis

R' OH
- C O R' C CH2R''
R''CH2
R R
B. Alkylmetal Reagents
1) Haloalkanes can be transformed into organometallic compounds
a) Alkyllithium Synthesis (I > Br > Cl reactivity)
O
ether or THF
RBr + 2 Li RLi + LiBr Tetrahydrofuran
0 oC

b) Alkylmagnesium Synthesis (Grignard Reagent)

ether or THF
RI + Mg o RMgI
0 C
 2) 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

O -
R MgX
+
+ H OH RH + XMOH Hydrolysis
R Mg I
O 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
R M
- + c) Resonance forms
C M C + M

5) 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
- +
RX + Mg R MgX + H OH RH + XMOH

b) Use hydride nucleophile

LiAlH4
Br ether

c) Useful for Deuterating compounds (D = deuterium = 2H)

LiAlHD4
Br ether D

C. 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

slow
- +
R' MgX + Br R'
3) Must use Carbonyl electrophile (C+==O-)
a) Ketone gives tertiary alcohol product
O OH
O +
H , H2O
C ether or THF R'
RLi + R' C
R' R' R' C R'
R
R

b) Aldehyde gives a secondary alcohol product

O OH
+
C ether or THF H , H2O
RLi + R' C H
R' H
R

c) Formaldehyde (CH2O) gives primary alcohol product

O OH
+
C ether or THF H , H2O
RLi + H C H
H H
R
III. Synthetic Strategies
A. Use Mechanisms to predict the products of a reaction
I- I-
1)
I Br F Br F I

Br CH3 CH3 CH2Br

2)
Br2 Br2

B. Know all of the tools (reactions) you can use

Nu
Nu, DMSO H2O

Mg, ether H2CO

Br MgBr CH2OH
- O
(CH3)3CO
(CH3)3COH
OH
 C. Synthesis of Complex Alcohols Using Alkylmetal Reagents
1. Useful Reaction Sequence
+
Br2 -OH PCC RMgBr H
CH4 CH3Br CH3OH H2C O RCH2OH
CH2Cl2 THF 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 strategic CH3CH2CH2MgBr
disconnection
CH3CH2CH2 CH2CH3 + CrO3, H2SO4, H2O OH
CH3 O
H+, H2O THF H3C CH2CH3
H3C 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 40g 20g 10g

20g 10g
E F
D 10g
20g G H
10g

c) Don’t use functional groups that would interfere in the reaction

O
MgBr Protic alcohl
+ HO
kills Grignard
d) Remember mechanistic limitations
i. Br2 is very selective form tertiary H
ii. SN2 can’t happen for tertiary electrophile