Embed Size (px)
Citation preview
1
Chapter 20Carbonyl compounds
Introduction to carbonyls
Reductions and oxidations
Addition of organometallics (Rli, RMgX, R2CuLi)to carbonyls
Compounds Containing Carbonyl Groups
R H
O
R R
O
R = Alkyl, Aryl, Akenyl
aldehydes ketones
R OH
O
R OR
O
R Cl
O
R NR'R"
O
R O
O
R
O
acid chlorideanhydride carboxylic acid ester amide
More reduced
More oxidized
More reactive Less Reactive
R OH R NH2
Nucleophilic addition
Nucleophilic substitution
3
Polarity of Carbonyl Groups
O O
Nucleophiles attack here
Electrophiles attack here
Oδ+δ-
General Reactions of Carbonyl Compounds
R
ROδ+ δ-
NuNu
O+H+ Nu
OH
Nucleophilic addition: Aldehydes & ketones
ZOδ+ δ-
NuNu
ZO
NuO
Nucleophilic substitution: esters, acid chlorides, acids, anhyrides, amides
5
Reactivity to Nucleophilic Addition
ZOδ+ δ-
NuNu
ZO
NuO
Nucleophilic substitution: esters, acid chlorides, acids, anhyrides, amides
6
O
H2O
H+
HOOH
H
O
H
OHH2
PtC H
O 1) LiAlH4OH
2) NH4Cl aq. H
Nucleophilic Addition to Carbonyls
Hydration (formation of hydrate)
Hydrogenation
Reduction with hydride
7
Reactivity to Nucleophilic Substitution
How does pKa change with Z?
ZOδ+ δ-
NuNu
ZO
NuO
Nucleophilic substitution: esters, acid chlorides, acids, anhyrides, amides
Better the leaving group, Z, the more reactive the carbonyl
Cl O
O
R> > OH, OR > NR2
R OH
O
R OR
O
R Cl
O
R NR'R"
O
R O
O
R
O
acid chlorideanhydride carboxylic acid ester amide
more reactive
8
Nucleophilic substitution: Not with aldehydes and ketones
HOδ+ δ-
NuNu
ZO
NuO
-H
pKa of H2?
ROδ+ δ-
NuNu
RO
NuO
-H
pKa of R ?
9
O
OCH3
H+
H2OO
OH
O
Cl
OH
Pyridine
O
O
Acid catalyzed hydrolysis of ester
Acetylation of an alcohol
Nucleophilic Substitution on Carbonyls
O
O
O NH2
Pyridine
HN
O
Acetylation of an amine to form an amide
Preview of Oxidation and Reduction
Higher energy content
R H
O
Reduction oxidation
R H
OH
Reduction oxidation
Reduction oxidation (difficult)
R H
H
R OH
O
R R
O
Reduction oxidation
R R
OH
Reduction oxidation (difficult)
Reduction oxidation (difficult)
R R
H
R OH
O
H H
H
H
11
• The three most useful oxidation and reduction reactions of carbonyl starting materials can be summarized as follows:
Oxidation and Reduction of Carbonyl Compounds
R H
O
Reduction of Aldehydes to primary alcohols
R H
OH
HR R
O[H] [H]
R R
OH
H
Reduction of ketones to secondary alcohols
Reductive Addition to Aldehydes and Ketones
Reductive Addition to Carboxylic acids and their derivatives
R Z
O
R H
O[H] [H]
R H
OH
H
aldehyde primary alcohol
Oxidation of Aldehydes
R H
O
R OH
OO]
12
O
H2
PtC
HOH
Reduction of carbonyls by hydrogenation
O
excess H2
PtC
HOH
H
H
C=C reduction is faster than C=O reduction
O
1 equiv.H2
PtC
O
H
H
Metal hydrides are an alternative
13
HAl
HH
HLi
HB
HH
HLi
LiAlH4 LiBH4
HB
HH
HNa
ROAl
OROR
HLi
NaBH4
BH3-THF
O
O
BH AlH
DiBAl-Hcatecholboranediborane or Borane
RLi
RMgX
organolithium Grignard
RCu
RLi
Cuprate
Carbanionic-organometallics
Neutral boranes and aluminanes
Aluminum hydrides and borohydrides
Alternative Reducing Agents
Reduction of Aldehydes and Ketones with hydride reagents
HAl
HH
HLi
LiAlH4
δ-
OH
Al
HH
H
LiH
O
HAl
H
H
HO
AlH H
H
HO
AlRO OR
OR
HO H
H
OH A(OH)3+
R H
O
R H
OH
HR R
OLiAlH4 LiAlH4
R R
OH
H2) aqueous 2) aqueous
Oδ-δ+
15
LiAlH4
R H
O
R R
O
R R
OH
R H
OH
R Cl
O
H
H
R H
OH
H
R OR'
OR NHR'
O
R-X
RCO2H O
R H
OH
H
R H
OH
H
H
OH
R-H
R NHR'
RC NR
NH2
R NO2
R NH2
OH
OH
Lithium Aluminum Hydride
Strong reducing agent. Not very selective
No unactivatedalkenes
16
LiAlH4 Reduction Mechanism for esters and acid chlorides
R
O
O
H AlH
HH
R'R
O
OR'
H AlH
HH
O
HRH
Li
HR
O
H
Li
Al
HO OHOH
HO H O
HRH
AlHO OH
OH
H
O
HRH
Al
H HH
H2O
OH
O
HRH
H
17
O
O
RH
AlHH H
O
O
R H
Al
H
H
H
O
O
R AlH
H
H
R
O
O
H AlH
HH
Li
AlH H
HR
O
OH
AlH H
H
H AlH
HH
R
O
H
Li
O
HRH
Al
H HH
H2O
O
HRH
Al
HO OHOH
HO H O
HRH
AlHO OH
OH
H
OH
O
HRH
H
Aldehyde intermediate is more reactive than carboxylic acid and is immediately reduced to alcohol
LiAlH4 Reduction of Amides
R
O
NR'(H)
R'(H)
amide
1) LiAlH4, THF
2) H2OR N
R'(H)
R'(H)
amine
NH
O
1) LiAlH4, THF
2) H2ONH NR
O
O
1) LiAlH4, THF
2) H2O
NR
-NR2 is poor leaving group
19
R
O
N
H AlH
HH
H
HR
O
NH
Al
H
HH
R
O
NH
Al
H
HH
RO
NH
AlH
HH
H AlH
HH
pKa 25
H2
pKa 35
RO
NH
AlH
HH
H
NH
HR
H AlH
HH
NH
HRH
HA NH2
HRH
imine
Li
Mechanism for reduction of amides with LiAlH4
Imine is rapidly reduced
20
Sodium Borohydride Reductions in Synthesis
Less reactive;More selectiveThan LiAlH4
Won’t reduce esters, amides, halides, epoxides, carboxylic acids
NaBH4
2) aqueous work-upR H
O
R H
OH
H
NaBH4
2) aqueous work-upR R'
O
R R'
OH
H
primary alcohols secondary alcohols
21
Sodium Borohydride Reductions in Synthesis
O
O
OMe
BrO
NaBH4
2) aqueous work-up
OH
O
OMe
BrO
H
Less reactive;More selectiveThan LiAlH4
NaBH4
R H
O
R R
O
R R
OH
R H
OH
R Cl
O
H
H
R H
OH
H
R OR'
O
NR
NR
NR
NR
NR
R NHR'
O
R-X
RCO2H O
Won’t reduce esters, amides, halides, epoxides, carboxylic acids
22
Sodium Borohydride Reductions with CeCl3
Luche reduction
Only reduces ketones, not aldehydes
O
O
H NaBH4/CeCl3
2) aqueous work-up
OH
O
H
23
• Hydride converts a planar sp2 hybridized carbonyl carbon to a tetrahedral sp3 hybridized carbon.
Stereochemistry of Carbonyl Reduction
24
R ROH
1) BH3 THF
2) NaOH, H2O2R R
O1) BH3 THF
2) NaOH, H2O2H
R RX
1) BH3 THF
2) X2, NaOMe R
1) BH3 THF
2) X2, NaOMeR
X
R RNHR'
1) BH3 THF
2) R'NH2, NaOCl R RC
1) BH3 THF
2) CO
O
R
3) NaOH, H2O2
Hydroboration Chemistry
Better regio control with hindered boranes:
BH
H
thexylborane
BH
9-BBN
BH
HB
OBH
O
diisoamylboranecatecholborane
reductions with BH3
R H
O
R R
O
R R
OH
R H
OH
R Cl
O
H
H
R OR'
OR NHR'
O
R-X
RCO2H ONR
RC N
R NO2
OH
NR
NR
OH
R NHR'
BH3
slow
R
RH
H H
OH
w/ NaBH4 as catalyst
R H
OH
H
R NH2slow
R H
OH
Hslow
2) H+
slow
slow
slow
fast
Allows carboxylic acids to be reduced in the presence of aldehydes or ketones
26
• 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.
Enantioselective Carbonyl Reductions
27
• 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.
CBS Reducing Agents
28
NB
O
H PhPh
R'
BH3 NB
O
H PhPh
R'H3B
Lewis acid
nucleophile
S CBS isomer
OB
N
Ph
Ph S
R'
BO
RL
RSH
HH
OB
N
Ph
Ph S
R'
BO
RS
RLH
HH
OB
N
Ph
PhR'
B H
HH
O
RS
RL
opposite sides of ring; reduction cannot occur
OB
N
Ph
Ph
R'
BO
RS
RL
HH
HR alcohol
H2OO
BN
Ph
Ph
R'
BHO
RS
RLH
HH
29
• These reagents are highly enantioselective.
• For example, treatment of propiophenone with the (S)-CBS reagent forms the R alcohol in 97% enantiomeric excess (ee).
Enantioselectivity of CBS Reagents
30
• Enantioselective reductions are key steps in the synthesis of several widely used drugs, including salmeterol, a long-acting bronchodilator.
Figure 20.3
Enantioselective Reductions in Synthesis
31
• 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.
Biological Reductions
32
• 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.
Mechanism of NADH Reductions
33
• 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.
Enantioselectivity of NADH Reduction
34
• 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.
NAD+ —Biological Oxidizing Agent
35
Other Metal Hydride Reducing Agents:
Al H
diisobutylaluminum hydride
DIBAL-H
R
O
R(H)
DIBAL-H2) H2O R
O
R(H)H
H
1) Reaction with aldehydes and ketones
Less reactive and more selective than LiAlH41) isobutyl groups are bulky2) trivalent Al is not as reactive of a H- donor
2) Reduction of acid chlorides (Z = Cl), esters (Z = OR'), amides (Z = NR'R") to aldehydes
R Z
ODIBAL-H
2) H2O R H
O
LiAlH4 reduces all the way to alcohols.
Use only 1 equiv. DiBAL-H to avoid over reduction
36
O
Cl
O
OH
no reaction except with LiAlH4 or BH3 reduction to primary alcohol
SOCl2
-HCl and SO2
DIBAL-H2) H2O
O
H
LiAlH4
OH
or BH3
DIBAL-H Reduction of acid chloride to aldehyde
37
Reductions with DiBAL-H
R H
O
R R
O
R R
OH
R H
OH
R Cl
O
H
H
R OR'
OR NHR'
O
R-X
RCO2H ONR
RC N
R NO2
OH
NR
NR
Al H
OH
R
O
H
@ low temperature
R
O
H
R
O
H
NR NR
O
O
O
OHDiBAl-H
38
• 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.
Reduction of Esters
39
Figure 20.4The DIBAL-H reduction ofan ester to an aldehyde in
the synthesis of the marineneurotoxin ciguatoxin CTX3C
DIBAL-H Reduction of an Ester
40
Other Metal Hydride Reducing Agents:
O
Al
OH
(t-BuO)3AlH
tri-t-butyloxyaluminum hydride
R
O
R(H) 2) H2O R
O
R(H)H
H
1) Reaction with aldehydes and ketones
Less reactive and more selective than LiAlH41) t-BuO groups are bulky2) Inductive electron withdrawing with three oxygens makes (RO)3AlH less of a negative hydride
2) Reduction of acid chlorides (Z = Cl), esters (Z = OR') to aldehydes
R Z
O(t-BuO)3AlH
2) H2O R H
O
O
Li
(t-BuO)3AlH
must use only 1 equivalent to avoid reduction of aldehyde
41
HO2CCO2Me
HO2C OH
?
LiAlH4
NaBH4
BH3
NaBH4/CeCl3
DIBAL-H
(t-BuO)3AlH
R Cl
O
R H
O
R R
O
R OH
O
R OR'
O
R NR'R"
O
R OH R OH R OH R OH R NR'R"R
HO
R
R OHR
HO
RNR NR NR NR
R CN RO
R X R NO2
R HR
OH
R NH2
R
N N
R
NR NR NR NR
R
HO
RNR NR NR NR NR NR NR NRNR
R OH R OHR
HO
RNR Slow NR NR NRSlow Slow
R H
O
R H
O
R H
O
R H
O
low TempNR NR NR NRR OH R
HO
R
R H
O
R OH R
HO
RNR NR NR NR NR NR
H2/CatR OH R
HO
RR HR NH2
R
NR
NR
NR
NR
RB
R H
ONR
R
RB
NR
NR
NR
RAl
i-Bu
i-Bu
NR
RRNR R NH2difficult difficultdifficultdifficult
R OH with > 2 equivalents of hydride*
*
* **
SlowSlow Fast
42
O
HO2C
OH
HO2C
?
LiAlH4
NaBH4
BH3
NaBH4/CeCl3
DIBAL-H
(t-BuO)3AlH
R Cl
O
R H
O
R R
O
R OH
O
R OR'
O
R NR'R"
O
R OH R OH R OH R OH R NR'R"R
HO
R
R OHR
HO
RNR NR NR NR
R CN RO
R X R NO2
R HR
OH
R NH2
R
N N
R
NR NR NR NR
R
HO
RNR NR NR NR NR NR NR NRNR
R OH R OHR
HO
RNR Slow NR NR NRSlow Slow
R H
O
R H
O
R H
O
R H
O
low TempNR NR NR NRR OH R
HO
R
R H
O
R OH R
HO
RNR NR NR NR NR NR
H2/CatR OH R
HO
RR HR NH2
R
NR
NR
NR
NR
RB
R H
ONR
R
RB
NR
NR
NR
RAl
i-Bu
i-Bu
NR
RRNR R NH2difficult difficultdifficultdifficult
R OH with > 2 equivalents of hydride*
*
* **
SlowSlow Fast
43
LiAlH4
NaBH4
BH3
NaBH4/CeCl3
DIBAL-H
(t-BuO)3AlH
R Cl
O
R H
O
R R
O
R OH
O
R OR'
O
R NR'R"
O
R OH R OH R OH R OH R NR'R"R
HO
R
R OHR
HO
RNR NR NR NR
R CN RO
R X R NO2
R HR
OH
R NH2
R
N N
R
NR NR NR NR
R
HO
RNR NR NR NR NR NR NR NRNR
R OH R OHR
HO
RNR Slow NR NR NRSlow Slow
R H
O
R H
O
R H
O
R H
O
low TempNR NR NR NRR OH R
HO
R
R H
O
R OH R
HO
RNR NR NR NR NR NR
H2/CatR OH R
HO
RR HR NH2
R
NR
NR
NR
NR
RB
R H
ONR
R
RB
NR
NR
NR
RAl
i-Bu
i-Bu
NR
RRNR R NH2difficult difficultdifficultdifficult
R OH with > 2 equivalents of hydride*
*
* **
SlowSlow Fast
O
HO2C
O
HO
44
• 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.
Oxidation of Aldehydes
45
• 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:
Organometallic Reagents
46
• 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 δ− charge.
Reactivity of Common Organometallic Compounds
47
Preparation of Organolithium Compounds
LiLi
Li H3C Li
Li
RBr
2 Li
RLi LiBr+
Old School
Now: Commercially available organolithium as solutions in hexanes or pentane
pKa 70 pKa 65pKa of conjugate acid: pKa 62 pKa 46pKa 60
More basic, more reactive
LI
Metal-Halogen exchange
BrTHF, -78 °C
Li
Br 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
48
Br Li
-78 °C(dry ice-acetone)Hexane
Li
H
Br
Br
LiH
H
Br1) 2eq. t-BuLi, THF, -78 °C
2) RX R
organolithiums in SN2 reacctions
R Li R' X
X = Cl, Br, I, OTos
RR'
primary
49
Organolithiums and carbonyyls
O
R LiTHF, -78 °C
OH
2) aq. work-up
R
O
O
R LiTHF, -78 °C
2) aq. work-up
O
2
R
OH
R
R
O
Li
O
H+
50
R' OH
OR'
X
R R'
R'O
Lewis acidR
R'
OH
R' OR"
O
R R'R
OHR' R"
O
R R'R"
OH
R CO2H
RLi
R'
O
R'
OH
R
CO2
R' R"
O
H
X
R,
2 equiv. RLi
R
51
Grignard Reagents
R MgBrR X
X = Cl, Br, I
R = Alkyl, aryl, alkenyl
Mg(0)
ether solvent
Grignard reagent
add to electrophile
R' Y
Y = Cl, Br, I, OTs
RR'
R'
O
R'R
OH
R' Z
O
Z = H, alkyl, aryl, OR", NR2, Cl
R
HO
R'R(or Z = H, alkyl, Aryl)
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 explosion
No ether (diethyl ether, THF , glyme), no reaction
52
R MgBr
R' R'
NR"R R'
R'
NHR"
R'CNR R'
O
R'
X
R R'
R'O
Lewis acidR
R'
OH
R' OR"
O
R R'R
OHR' R"
O
R R'R"
OH
HC(OEt)3
R
O
H
R' ≠ H
or
Me2N
O
H
Acidic protons
R H
Grignard reactions
53
• Organocuprates are prepared from organolithium reagents by reaction with a Cu+ salt, often CuI.
Preparation of Organocuprate Compounds
Less reactive, more selective than organolithiums
54
R CuLi
RR' X
X = Cl, Br, I, OTosR' = 1°, 2° alkyl, aryl, alkenyl
R R'
Cuprates allow reactions that are not possible with organolithiums or Grignards
R' Cl
O
R' = alkyl, aryl, H
R R'
O
acidic work-upR CuLi
R
55
RCuLi
R
R'
X
R R'
R'O
RR'
OH
R'
O
R' Cl
O
R'
X
R'
R
R'X
R'R
X R
R' R
O
R'
R''
X
R'
R''
R
R'
O
R
2° halides without E2
No double addition to afford alcohols
Only 1,4 addition
Direct substitution reactions with alkenyl and aryl halides
Retention of stereochemistry
56
Br2
FeBr3
Br2 eq. t-BuLi
THF, -78 °C
Li
0.5 eq. CuBr
CuLi
2
O
O
O
2) aq. H2O, H+
2) aq. H2O, H+
OH
Convert aryl bromides into nucleophilic carbanions
57
• 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.
Preparation of Acetylide Ions
pKa 25pKa 35
58
• 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.
Preparation of Lithium Acetylides
59
• This reaction is used to prepare 1°, 2°, and 3° alcohols.
Alcohols Formed by Organometallic Addition
60
Figure 20.5
Synthesis of Ethynylestradiol
61
• To determine what carbonyl and Grignard components are needed to prepare a given compound, follow these two steps:
Retrosynthetic Analysis of Grignard Products
62
Retrosynthetic Analysis of 3-pentanol
63
• 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.
Synthesis of 3-pentanol
64
• 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.
Limitations of Organometallic Reagents
65
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.
Use of Protecting Groups
66
Figure 20.7
General Protecting Group Strategy
• 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.
67
• 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−.
Preparing Silyl Ethers
68
• 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.
Preparing Silyl Ethers
69
• Both esters and acid chlorides form 3° alcohols when treated with two equivalents of either Grignard or organolithium reagents.
Organometallic Reactions with Esters and Acid Chlorides
70
• 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.
Organocuprates—a Less Reactive Organometallic
71
• 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.
Grignard Reaction with CO2
72
• Like other strong nucleophiles, organometallic reagents—RLi, RMgX, and R2CuLi—open epoxide rings to form alcohols.
Organometallic Reactions with Epoxides
73
• 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.
Organometallic Reactions with Epoxides
74
,-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.
Organometallic Reactions with ,-Unsaturated Carbonyl Compounds
75
• This means that ,-unsaturated carbonyl compounds can react with nucleophiles at two different sites.
,-Unsaturated Carbonyl Compounds
76
• 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.
1,2-Addition Mechanism
77
78
1,2 vs. 1,4-Addition Products
1,2 vs. 1,4-Addition Products
O
LiAlH4
OH
2) aq. H2O, H+
O O
2) aq. H2O, H+
BH
Li
3
1,2- reduction of enone
1,4- reduction of enone
80
[1] Organometallic reagents (R–M) attack electrophilic atoms, especially the carbonyl carbon.
Summary of Organometallic Reactions
81
[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.
Summary of Organometallic Reactions
82
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.
83
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.
![Oxoammonium Salt Oxidations of Alcohols[PDF : 1.5MB]](https://img.dokumen.tips/doc/110x75/586702e51a28abc83f8b9241/oxoammonium-salt-oxidations-of-alcoholspdf-15mb.jpg)
