Download Chapter 20 reactions of carbonyls

Chapter 20
Carbonyl compounds
Introduction to carbonyls
Reductions and oxidations
Addition of organometallics (Rli, RMgX, R2CuLi)
to carbonyls
1
Compounds Containing Carbonyl Groups
R
R
OH
NH2
More reduced
O
O
H
R
R
aldehydes
O
O
R
More oxidized
Cl
R
acid chloride
More reactive
ketones
O
O
anhydride
O
O
R
Nucleophilic
addition
R
R
OH
carboxylic acid
OR
R
ester
Less Reactive
R = Alkyl, Aryl, Akenyl
O
R
Nucleophilic
substitution
NR'R"
amide
Polarity of Carbonyl Groups
Electrophiles attack here
O
O
O+
-
Nucleophiles attack here
3
General Reactions of Carbonyl Compounds
Nucleophilic addition:
Aldehydes & ketones
Nu
R
+
R
Nu
+H+
O
O -
Nucleophilic substitution:
Nu
OH
esters, acid chlorides, acids, anhyrides, amides
Nu
Nu
+
Z
O -
Nu
O
Z
O
Reactivity to Nucleophilic Addition
Nucleophilic substitution:
esters, acid chlorides, acids, anhyrides, amides
Nu
Nu
+
Z
O -
Nu
O
O
Z
5
Nucleophilic Addition to Carbonyls
O
HO
H2O
OH
Hydration (formation of hydrate)
H+
O
H
O
OH
H2
PtC
1) LiAlH4
2) NH4Cl aq.
H
H
Hydrogenation
OH
Reduction with hydride
H
6
Reactivity to Nucleophilic Substitution
Nucleophilic substitution:
esters, acid chlorides, acids, anhyrides, amides
Nu
Nu
O
O -
+
Z
Nu
O
Z
Better the leaving group, Z, the more reactive the carbonyl
O
Cl
Cl
R
acid chloride
>
O
O
O
R
>
>
NR2
O
O
R
anhydride
OR
R
O
O
OH,
R
OH
carboxylic acid
R
O
OR
R
ester
NR'R"
amide
more reactive
How does pKa change with Z?
7
Nucleophilic substitution: Not with aldehydes and ketones
Nu
Nu
+
O-
H
-H
Nu
O
O
Z
pKa of H2?
Nu
Nu
+
R
O -
-H
O
Nu
O
R
pKa of R ?
8
Nucleophilic Substitution on Carbonyls
O
H+
CH3
OH
H2O
O
Acid catalyzed hydrolysis of
ester
O
OH
O
O
Cl
Acetylation of an alcohol
O
Pyridine
O
O
O
O
NH2
HN
Pyridine
Acetylation of an amine to form an
amide
9
Preview of Oxidation and Reduction
O
O
R
OH
Reduction
oxidation
R
OH
Reduction
oxidation (difficult)
O
O
R
H
Reduction
R
oxidation
R
Reduction
oxidation
OH
R
H
Reduction
OH
H
oxidation (difficult)
R
H
Reduction
H
R
oxidation (difficult)
H
H
R
H
R
H
R
Higher energy content
Oxidation and Reduction of Carbonyl Compounds
• The three most useful oxidation and reduction reactions of
carbonyl starting materials can be summarized as follows:
Reductive Addition to Aldehydes and Ketones
Reduction of ketones to secondary alcohols
OH
O
[H]
Reduction of Aldehydes to primary alcohols
O
R
OH
[H]
R
H
H
H
R
R
R
R
H
Reductive Addition to Carboxylic acids and their derivatives
O
R
[H]
R
Z
OH
O
[H]
H
aldehyde
R
H
H
primary alcohol
Oxidation of Aldehydes
O
R
O
O]
H
R
OH
11
Reduction of carbonyls by hydrogenation
O
HO
H2
H
PtC
O
O
H
1 equiv.H2
C=C reduction is faster than C=O reduction
PtC
O
H
HO
excess H2
PtC
H
H
H
Metal hydrides are an alternative
12
Alternative Reducing Agents
Aluminum hydrides and borohydrides
H
Li
H
H
Li
Al
H
H
H
LiAlH4
B
H
H
Na
H
H
B
H
H
RO
Al
OR
OR
NaBH4
LiBH4
Neutral boranes and aluminanes
O
BH
BH3-THF
O
diborane or Borane
H
Li
catecholborane
Al
H
DiBAl-H
Carbanionic-organometallics
R
Li
organolithium
R
MgX
Grignard
R
R
Cu Li
Cuprate
13
Reduction of Aldehydes and Ketones with
hydride reagents
O
R
OH
LiAlH4
2) aqueous
H
R
H
R
H
H
Li
H
+
Al
H
H -
OH
O
LiAlH4
R
H
H
Al
H
H
H
H
Al
H
H
Li
H
O
O
RO OR
Al OR
OH
H
O
H
H H
Al H
O
H
O
+
A(OH)3
R
H
O
LiAlH4
H
R
2) aqueous
Lithium Aluminum Hydride
OH
OH
OH
R
R-H
H
H
H
OH
OH
O
RCO2H
R
O
H
R-X
R
NH2
R
R
H
H
O
C N
LiAlH4
R
R
OH
R NO2
R
O
R NH2
R
O
O
NHR'
R
R
No unactivated
alkenes
R
H
Cl
OR'
OH
R
NHR'
OH
R
H
R
H
H
H
Strong reducing agent. Not very selective
15
LiAlH4 Reduction Mechanism for esters and
acid chlorides
H H
Al H
O H2O
Li
Li
O
O
O
R'
O
H
H Al H
H
R
R
H
O
R'
R
H
R
H
H Al H
H
H
H
OH
H
O H
HO OH
Al OH
O
R
H
HO
OH
OH
Al
H O
H
R
H
H
R
H
O
H
H
16
H
H H
H Al
H
O
R
O H
O
R
Al
H
O
R
H
O
Li
H H
Al H
O H2O
Li
O H H
Al H
R
O
H
H Al H
H
O
R
H
O
H H
Al H
O
R
H
Al H
O
H
H
H
H Al H
H
R
H
H
OH
H
O H
HO OH
Al OH
O
R
H
HO
OH
OH
Al
H O
H
R
H
H
R
H
O
H
H
Aldehyde intermediate is more reactive than carboxylic acid and
is immediately reduced to alcohol
17
LiAlH4 Reduction of Amides
amine
amide
O
R
N
1) LiAlH4, THF
R'(H)
R
2) H2O
R'(H)
N
R'(H)
R'(H)
O
O
NH
1) LiAlH4, THF
2) H2O
NH
NR
O
-NR2 is poor leaving group
1) LiAlH4, THF
2) H2O
NR
Mechanism for reduction of amides with LiAlH4
H
H
pKa 25
Li
O
O
R
H
Al
N
H
R
H
N
O
H
R
H2
H
H
Al
H
N
H
N
H
H
Al
R
O
H
H
H Al H
H
H
pKa 35
H
H Al H
H
H
N
H
H
Al
R
O
H
H
imine
NH
NH
R
H
H
Al
H
H
H
R
H
H
HA
NH2
R
H
H
Imine is rapidly reduced
19
Sodium Borohydride Reductions in Synthesis
O
R
OH
H
NaBH4
2) aqueous work-up
R
H
H
O
R
OH
R'
NaBH4
2) aqueous work-up
H
R'
secondary
alcohols
primary alcohols
Less reactive;
More selective
Than LiAlH4
R
Won’t reduce
esters, amides,
halides, epoxides,
carboxylic acids
20
Sodium Borohydride Reductions in Synthesis
O
H
OMe
O
O
OH
OMe
NaBH4
O
2) aqueous work-up
O
Br
Less reactive;
More selective
Than LiAlH4
Br
NR
NR
OH
R
O
RCO2H
O
R
H
H
H
R-X
NR
O
NaBH4
R
R
OH
O
R
NR
R
O
NHR'
O
R
R
Cl
R
H
Won’t reduce
esters, amides,
halides, epoxides,
carboxylic acids
OR'
OH
NR
R
H
H
21
Sodium Borohydride Reductions with CeCl3
Luche reduction
O
H
O
O
NaBH4/CeCl3
H
OH
2) aqueous work-up
Only reduces
ketones, not
aldehydes
22
Stereochemistry of Carbonyl Reduction
• Hydride converts a planar sp2 hybridized carbonyl carbon to a
tetrahedral sp3 hybridized carbon.
23
Hydroboration Chemistry
1) BH3 THF
R
R
2) NaOH, H2O2
1) BH3 THF
R
R
2) X2, NaOMe
1) BH3 THF
R
2) R'NH2, NaOCl
R
1) BH3 THF
OH
R
2) NaOH, H2O2
H
1) BH3 THF
X
R
R
2) X2, NaOMe
1) BH3 THF
NHR'
R
O
R
R
2) CO
X
O
C
R
3) NaOH, H2O2
Better regio control with hindered boranes:
H
B
H
thexylborane
BH
BH
9-BBN
H
B
O
BH
O
diisoamylborane
catecholborane
24
reductions with BH3
w/ NaBH4 as
catalyst
OH
R
H
H
H
H
OH
OH
fast
NR
OH
OH
O
RCO2H
slow R
O
H
R-X
R
slow
NH2
R
slow
R
H
H
O
C N
BH3
R
slow
R
OH
R NO2
R
O
NR
R
R
R
OR'
NHR'
R
2) H+
O
O
NHR'
R
R
H
Cl
R
H
OH
slow
R
H
H
slow
NR
Allows carboxylic acids to be reduced in the presence of aldehydes or ketones
Enantioselective Carbonyl Reductions
• Selective formation of one enantiomer over another can occur
if a chiral reducing agent is used.
• A reduction that forms one enantiomer predominantly or
exclusively is an enantioselective or asymmetric reduction.
• An example of chiral reducing agents are the enantiomeric
CBS reagents.
26
CBS Reducing Agents
• CBS refers to Corey, Bakshi, and Shibata, the chemists who
developed these versatile reagents.
• One B–H bond serves as the source of hydride in this reduction.
• The (S)-CBS reagent delivers (H:−) from the front side of the C=O.
This generally affords the R alcohol as the major product.
• The (R)-CBS reagent delivers (H:−) from the back side of the
C=O. This generally affords the S alcohol as the major product.
27
S CBS isomer
H
N
N
B
H
N
O
H
Lewis acid
RS
Ph
RL
B
Ph
Ph
O
B
H3B R'
nucleophile
R'
O
Ph
BH3
B
R'
Ph
S
H
Ph
Ph
O
RS
Ph
S
RS
B
N
O
H
B
H
H
Ph
RL
N
H2O
H
RL
B
R'
B
H
O
H
R alcohol
RL
opposite sides of ring;
reduction cannot occur
H
Ph
R'
O
RS
B
B
H
N
H
R'
O
O
O
H
Ph
Ph
Ph
R'
O
Ph
N
B
H
RS
B
HO
H
H
28
RL
Enantioselectivity of CBS Reagents
• These reagents are highly enantioselective.
• For example, treatment of propiophenone with the (S)-CBS
reagent forms the R alcohol in 97% enantiomeric excess (ee).
29
Enantioselective Reductions in Synthesis
• Enantioselective reductions are key steps in the synthesis of
several widely used drugs, including salmeterol, a long-acting
bronchodilator.
Figure 20.3
30
Biological Reductions
• Biological reductions that occur in cells always proceed with
complete selectivity, forming a single enantiomer.
• In cells, the reducing agent is NADH.
• NADH is a coenzyme—an organic molecule that can function
only in the presence of the enzyme.
31
Mechanism of NADH Reductions
• The active site of the enzyme binds both the carbonyl
substrate and NADH, keeping them in close proximity.
• NADH then donates H:− in much the same way as a hydride
reducing agent.
32
Enantioselectivity of NADH Reduction
• The reaction is completely enantioselective.
• For example, reduction of pyruvic acid with NADH catalyzed
by lactate dehydrogenase affords a single enantiomer with
the S configuration.
• NADH reduces a variety of different carbonyl compounds in
biological systems.
• The configuration of the product (R or S) depends on the
enzyme used to catalyze the process.
33
NAD+ —Biological Oxidizing Agent
• NAD+, the oxidized form of NADH, is a biological oxidizing
agent capable of oxidizing alcohols to carbonyl compounds
(it forms NADH in the process).
• NAD+ is synthesized from the vitamin niacin.
34
Other Metal Hydride Reducing Agents:
Al
Less reactive and more selective than LiAlH4
1) isobutyl groups are bulky
2) trivalent Al is not as reactive of a H- donor
H
diisobutylaluminum hydride
DIBAL-H
1) Reaction with aldehydes and ketones
O
R
H
DIBAL-H
R(H) 2) H2O
O
R
R(H)
H
2) Reduction of acid chlorides (Z = Cl), esters (Z = OR'), amides (Z = NR'R") to aldehydes
O
R
Z
DIBAL-H
2) H2O
O
R
H
Use only 1 equiv. DiBAL-H to
avoid over reduction
LiAlH4 reduces all the way to alcohols.
35
DIBAL-H Reduction of acid chloride to aldehyde
no reaction except
with LiAlH4 or BH3
reduction to primary
alcohol
O
SOCl2
OH
-HCl and SO2
O
DIBAL-H
Cl 2) H2O
O
H
LiAlH4
or BH3
OH
36
Reductions with DiBAL-H
OH
NR
NR
NR
OH
OH
O
RCO2H
R
O
H
R-X
R
O
R
H
R
C N
H
H
O
Al H
R
R
OH
R NO2
R
O
NR
R
O
O
NHR'
R
R
Cl
OR'
O
R
R
H
NR
O
H
R
H
@ low temperature
O
OH
O
DiBAl-H
O
37
Reduction of Esters
• In the reduction of an acid chloride, Cl− comes off as the
leaving group.
• In the reduction of the ester, CH3O− comes off as the leaving
group, which is then protonated by H2O to form CH3OH.
38
DIBAL-H Reduction of an Ester
Figure 20.4
The DIBAL-H reduction of
an ester to an aldehyde in
the synthesis of the marine
neurotoxin ciguatoxin CTX3C
39
Other Metal Hydride Reducing Agents:
Li
O
Al
Less reactive and more selective than LiAlH4
1) t-BuO groups are bulky
2) Inductive electron withdrawing with three oxygens
makes (RO)3AlH less of a negative hydride
O
H
O
(t-BuO)3AlH
tri-t-butyloxyaluminum hydride
1) Reaction with aldehydes and ketones
H
O
R(H)
R
O
(t-BuO)3AlH
2) H2O
R
R(H)
H
2) Reduction of acid chlorides (Z = Cl), esters (Z = OR') to aldehydes
O
R
Z
(t-BuO)3AlH
2) H2O
O
R
H
must use only 1 equivalent to avoid
reduction of aldehyde
40
O
O
R
Cl
R
OH
O
R
H
R
OH
O
R
R
R
O
O
OH
O
R
OR'
R
OH
R
NR'R"
R
CN
R
HO
LiAlH4
R
X
R
H
OH
R
R
OH
R
R
NR'R"
NH2
R
R
R
NO2
R
R
R
N N
NR
NR
NR
NR
NR
NR
R
HO
NaBH4
NR
R
NR
OH
R
NR
NR
NR
NR
NR
NR
R
HO
NaBH4/CeCl3
BH3
NR
NR
R
HO
Slow
OH
R
NR
R
Slow
R
R
NR
Fast
OH
R
NR
R
OH
R
O
Slow
O *
R
R
H
R
H
low Temp
O
HO
(t-BuO)3AlH
R
NR
O *
HO
DIBAL-H
NR
H
R
OH
R
R
NR
R
R
NR
NR
NR
NR
Slow
Slow
NR
NR
NR
O *
O
NR
NR
NR
H
R
H
R
R
B
NR
B
R
i-Bu
*
NR
NR
NR
NR
NR
R H
NR
NR
NR
H
HO
H2/Cat
difficult
R
OH
R
R
difficult
difficult
*
HO2C
i-Bu
Al
R
CO2Me
difficult
R
NH2
R
NH2
R
R
OH with > 2 equivalents of hydride
?
HO2C
OH
41
O
O
R
Cl
R
O
H
O
R
R
R
O
O
OH
R
O
OR'
R
NR'R"
R
CN
R
HO
LiAlH4
OH
R
OH
R
R
X
R
H
OH
R
R
OH
R
OH
R
R
NR'R"
NH2
R
R
NO2
R
R
R
R
N N
NR
NR
NR
NR
NR
NR
R
HO
NaBH4
NR
R
NR
OH
R
NR
NR
NR
NR
NR
NR
R
HO
NaBH4/CeCl3
BH3
NR
NR
R
Slow
OH
R
NR
R
HO
Slow
R
R
NR
Fast
OH
R
NR
R
OH
O
Slow
O *
R
R
H
R
H
low Temp
H
R
OH
R
R
NR
R
R
NR
NR
NR
NR
Slow
Slow
NR
NR
NR
O *
O
NR
NR
NR
H
R
H
R
R
B
NR
B
R
i-Bu
Al
i-Bu
O
HO
(t-BuO)3AlH
R
R
NR
O *
HO
DIBAL-H
NR
*
NR
NR
NR
NR
NR
R H
NR
NR
NR
H
HO
H2/Cat
difficult
R
OH
R
R
difficult
difficult
*
R
difficult
R
NH2
R
NH2
R
R
OH with > 2 equivalents of hydride
O
OH
?
HO2C
HO2C
42
O
O
R
Cl
R
O
H
O
R
R
R
O
O
OH
R
O
OR'
R
NR'R"
R
CN
R
HO
LiAlH4
OH
R
OH
R
R
X
R
H
OH
R
OH
R
R
OH
R
R
NR'R"
NH2
R
R
R
NO2
R
R
R
N N
NR
NR
NR
NR
NR
NR
R
HO
NaBH4
NR
R
NR
OH
R
NR
NR
NR
NR
NR
NR
R
HO
NaBH4/CeCl3
BH3
NR
NR
R
Slow
OH
R
NR
NR
R
HO
Slow
R
R
Fast
OH
R
NR
R
OH
O
Slow
O *
R
R
R
H
low Temp
H
O
HO
(t-BuO)3AlH
R
R
NR
O *
HO
DIBAL-H
NR
H
R
OH
R
R
NR
R
R
NR
NR
NR
NR
Slow
Slow
NR
NR
NR
O *
O
NR
NR
NR
NR
NR
NR
R H
H
R
H
R
R
B
NR
B
R
i-Bu
*
NR
NR
NR
NR
NR
H
HO
H2/Cat
difficult
R
OH
R
R
difficult
difficult
*
R
difficult
NH2
R
R
NH2
R
R
OH with > 2 equivalents of hydride
O
HO2C
i-Bu
Al
O
HO
43
Oxidation of Aldehydes
• A variety of oxidizing agents can be used, including CrO3,
Na2Cr2O7, K2Cr2O7, and KMnO4.
• Aldehydes can also be oxidized selectively in the presence of
other functional groups using silver(I) oxide in aqueous
ammonium hydroxide (Tollen’s reagent).
• Since ketones have no H on the carbonyl carbon, they do not
undergo this oxidation reaction.
44
Organometallic Reagents
• Li, Mg, and Cu are the most common organometallic metals.
• Other metals found in organometallic reagents are Sn, Si, Tl,
Al, Ti, and Hg.
• General structures of common organometallic reagents are
shown:
45
Reactivity of Common Organometallic Compounds
• Since both Li and Mg are very electropositive metals,
organolithium (RLi) and organomagnesium (RMgX) reagents
contain very polar carbon-metal bonds and are therefore very
reactive reagents.
• Organomagnesium reagents are called Grignard reagents.
• Organocopper reagents (R2CuLi), also called organocuprates,
have a less polar carbon–metal bond and are therefore less
reactive.
• Although they contain two R groups bonded to Cu, only one
R group is utilized in the reaction.
• In organometallic reagents, carbon bears a − charge.
46
Preparation of Organolithium Compounds
Old School
2 Li
Br
R
R
Li
+
LiBr
Now: Commercially available organolithium as solutions in hexanes or pentane
Li
Li
Li
H3C
Li
Li
pKa of conjugate acid:
pKa 70
pKa 65
pKa 62
pKa 60
pKa 46
More basic, more reactive
Metal-Halogen exchange
Br
LI
Br
THF, -78 °C
Li
Down hill reaction by 70-65 = 5
orders of magnitude
• Crystalline solids, pyrophoric. Sold and used as solution in
pentanes. Most reactive of common carbanionic reagents.
• Low temperature prevents beta elimination (E2) to afford
alkenes instead of metal halogen exchange
• primary butyl lithiums can react readily as nucleophiles
• t-BuLi never reacts as nucleophile. Only as hindered base or
metal halogen exchange
• At room temperature BuLi will attack THF
47
organolithiums in SN2 reacctions
primary
R Li
R'
R'
R
X
X = Cl, Br, I, OTos
Br
Li
Li
-78 °C
(dry ice-acetone)
Hexane
H
Br
H
Li
H
Br
1) 2eq. t-BuLi, THF, -78 °C
Br
R
2) RX
48
Organolithiums and carbonyyls
OH R
O
R
Li
THF, -78 °C
2) aq. work-up
O
OH
O
O
2 R
R
Li
THF, -78 °C
R
2) aq. work-up
R
O
O
Li
+
H
49
R CO2H
R
2 equiv. RLi
CO2
R'
O
R'
O
R'
X
OH
R
R'
OH
X
O
R'
R
Lewis acid
R'
R"
H
R,
Li
R
O
O
R'
R'
OR"
O
R'
R"
OH
R
R
R'
OH
R
R'
OH
R"
R
R'
50
Grignard Reagents
add to electrophile
HO
O
R'
Grignard reagent
Mg(0)
R
X
R'
R(or Z = H, alkyl, Aryl)
R
Z
Z = H, alkyl, aryl, OR", NR2, Cl
R'
R MgBr
R
ether solvent
X = Cl, Br, I
R'
Y
Y = Cl, Br, I, OTs
R = Alkyl, aryl, alkenyl
O
No ether (diethyl ether,
THF , glyme), no reaction
R'
R
R'
OH
Slow, cautious addition of < 5% RX to Magnesium in refluxing ether
Once reaction starts exotherming, then slow addition of remainder of RX
DANGER: addition of all of RX to Mg can cause runaway reaction and
51
explosion
Grignard reactions
R H
R
Acidic
protons
R'
R'
NHR"
R'
R
R'
NR"
X
R'
OH
R
R'
O
R MgBr
Lewis acid
R'
R
HC(OEt)3
or
O
R'
O
R'CN
R'
OR"
R'
R' ° H
O
Me2N
O
H
R"
OH
R
R
R'
R'
O
R
H
OH
R"
R
R'
52
Preparation of Organocuprate Compounds
• Organocuprates are prepared from organolithium reagents by
reaction with a Cu+ salt, often CuI.
Less reactive, more selective than organolithiums
53
Cuprates allow reactions that are not possible
with organolithiums or Grignards
R
R CuLi
R'
X
R R'
X = Cl, Br, I, OTos
R' = 1°, 2° alkyl, aryl, alkenyl
R
R CuLi
O
O
R'
Cl
R
R'
acidic work-up
R' = alkyl, aryl, H
54
R'
R
R
R'
X
X
R
R
CuLi
R
R'
O
R'
R'
Cl
R'
X
R''
O
R'
O
R
R
R'
O
R'
R'
Only 1,4 addition
X
R'
X
OH
Direct substitution
reactions with
alkenyl and aryl
halides
R'
R'
R
Retention of
stereochemistry
R''
O
R'
R
2° halides without E2
R
No double addition to
afford alcohols
55
Convert aryl bromides into nucleophilic carbanions
O
Br2
FeBr3
Br
2 eq. t-BuLi
OH
Li
THF, -78 °C
2) aq. H2O, H+
0.5 eq. CuBr
O
CuLi
2
O
2) aq. H2O, H+
56
Preparation of Acetylide Ions
• Acetylide ions are another example of organometallic
reagents.
• Acetylide ions can be thought of as “organosodium
reagents”.
• Since sodium is even more electropositive than lithium, the
C–Na bond of these organosodium compounds is best
described as ionic, rather than polar covalent.
pKa 35
pKa 25
57
Preparation of Lithium Acetylides
• An acid–base reaction can also be used to prepare sp
hybridized organolithium compounds.
• Treatment of a terminal alkyne with CH3Li affords a lithium
acetylide.
• The equilibrium favors the products because the sp
hybridized C–H bond of the terminal alkyne is more acidic
than the sp3 hybridized conjugate acid, CH4, that is formed.
58
Alcohols Formed by Organometallic Addition
• This reaction is used to prepare 1°, 2°, and 3° alcohols.
59
Synthesis of Ethynylestradiol
Figure 20.5
60
Retrosynthetic Analysis of Grignard Products
• To determine what carbonyl and Grignard components are
needed to prepare a given compound, follow these two steps:
61
Retrosynthetic Analysis of 3-pentanol
62
Synthesis of 3-pentanol
• Writing the reaction in the synthetic direction—that is, from
starting material to product—shows whether the synthesis is
feasible and the analysis is correct.
• Note that there is often more than one way to synthesize a 2°
alcohol by Grignard addition.
63
Limitations of Organometallic Reagents
• Addition of organometallic reagents cannot be used with
molecules that contain both a carbonyl group and N–H or O–H
bonds.
• Carbonyl compounds that also contain N–H or O–H bonds
undergo an acid–base reaction with organometallic reagents,
not nucleophilic addition.
64
Use of Protecting Groups
Solving this problem requires a three-step strategy:
[1] Convert the OH group into another functional group that does
not interfere with the desired reaction.
• This new blocking group is called a protecting group, and
the reaction that creates it is called “protection”.
[2] Carry out the desired reaction.
[3] Remove the protecting group.
• This reaction is called “deprotection”.
• A common OH protecting group is a silyl ether.
65
General Protecting Group Strategy
Figure 20.7
• In Step [1], the OH proton in 5-hydroxypentanone is replaced with a protecting
group, written as PG.
• Because the product no longer has an OH proton, it can now undergo
nucleophilic addition.
• In Step [2], CH3MgCl adds to the carbonyl group to yield a 3o alcohol after
protonation with water.
• Removal of the protecting group in Step [3] forms the desired product.
66
Preparing Silyl Ethers
• tert-Butyldimethylsilyl ethers are prepared from alcohols by
reaction with tert-butyldimethylsilyl chloride and an amine
base, usually imidazole.
• The silyl ether is typically removed with a fluoride salt such
as tetrabutylammonium fluoride (CH3CH2CH2CH2)4N+F−.
67
Preparing Silyl Ethers
• The use of tert-butyldimethylsilyl ether as a protecting group
makes possible the synthesis of 4-methyl-1,4-pentanediol by
a three-step sequence.
68
Organometallic Reactions with Esters and
Acid Chlorides
• Both esters and acid chlorides form 3° alcohols when treated
with two equivalents of either Grignard or organolithium
reagents.
69
Organocuprates—a Less Reactive Organometallic
• To form a ketone from a carboxylic acid derivative, a less
reactive organometallic reagent—namely an organocuprate—
is needed.
• Acid chlorides, which have the best leaving group (Cl−) of the
carboxylic acid derivatives, react with R’2CuLi to give a
ketone as the product.
• Esters, which contain a poorer leaving group (−OR), do not
react with R’2CuLi.
70
Grignard Reaction with CO2
• Grignards react with CO2 to give carboxylic acids after
protonation with aqueous acid.
• This reaction is called carboxylation.
• The carboxylic acid formed has one more carbon atom than the
Grignard reagent from which it was prepared.
71
Organometallic Reactions with Epoxides
• Like other strong nucleophiles, organometallic reagents—
RLi, RMgX, and R2CuLi—open epoxide rings to form alcohols.
72
Organometallic Reactions with Epoxides
• The reaction follows the same two-step process as opening
of epoxide rings with other negatively charged nucleophiles—
that is, nucleophilic attack from the back side of the epoxide,
followed by protonation of the resulting alkoxide.
• In unsymmetrical epoxides, nucleophilic attack occurs at the
less-substituted carbon atom.
73
Organometallic Reactions with ,Unsaturated Carbonyl Compounds
• ,-Unsaturated carbonyl compounds are conjugated molecules
containing a carbonyl group and a C=C separated by a single 
bond.
• Resonance shows that the carbonyl carbon and the  carbon
bear a partial positive charge.
74
,-Unsaturated Carbonyl Compounds
• This means that ,-unsaturated carbonyl compounds can
react with nucleophiles at two different sites.
75
1,2-Addition Mechanism
• The steps for the mechanism of 1,2-addition are exactly the
same as those for the nucleophilic addition of an aldehyde or
a ketone—that is, nucleophilic attack, followed by
protonation.
76
77
1,2 vs. 1,4-Addition Products
78
1,2 vs. 1,4-Addition Products
O
OH
LiAlH4
1,2- reduction of enone
2) aq. H2O, H+
Li
O
BH
3
2) aq. H2O, H+
O
1,4- reduction of enone
Summary of Organometallic Reactions
[1] Organometallic reagents (R–M) attack electrophilic atoms,
especially the carbonyl carbon.
80
Summary of Organometallic Reactions
[2] After an organometallic reagent adds to the carbonyl group, the
fate of the intermediate depends on the presence or absence of
a leaving group.
[3] The polarity of the R–M bond determines the reactivity of the
reagents:
• RLi and RMgX are very reactive reagents.
• R2CuLi is much less reactive.
81
Synthesis Practice
• Synthesize 1-methylcyclohexene from cyclohexanol and any
organic alcohol.
• Begin with Retrosynthetic Analysis:
• Form double bond from alcohol dehydration.
• Make the 3o alcohol by Grignard addition.
• Prepare the Grignard from methanol.
82
Synthesis Practice
• Four steps are required to accomplish the synthesis.
• Convert methanol to the Grignard reagent by forming the alkyl
halide, followed by reaction with Mg.
• Add the Grignard reagent to cyclohexanone, followed by
protonation, to form the alcohol.
• Acid-catalyzed elimination of water forms the desired product
as the major product.
83