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Carbonyl Compounds II:
Chapter 18
Reaction of Aldehydes and Ketones •
More Reactions of Carboxylic Acid
Derivatives • Reactions of , Unsaturated Carbonyl Compounds
Two Classes of Carbonyl Compounds
• Class I: Undergo nucleophilic acyl substituion. Includes carboxylic
acid derivatives – (last chapter).
• Class II: Do NOT contain a group that can be replaced by a
nucleophile – (this chapter).
O
O
H
H
formaldehyde
R
O
H
an aldehyde
R
R
a ketone
• Carbanions (R–) and hydride ions (H–) are ____________ to be
displaced by nucleophiles under normal conditions.
• Class II carbonyls undergo ________________________.
2
Relative Reactivities
•
•
See section 1 for nomenclature of the class 2 compounds.
Class II compounds are also polarized with + on carbon and – on
oxygen. Nucleophilic attack on the carbonyl carbon often results.
•
Aldehydes are usually _____ reactive than ketones in nucleophilic
addition reactions:
1. Aldehydes
2. Aldehydes
O
R
O
H
an aldehyde
R
R
a ketone
3
Relative Reactivities
• Aldehydes and ketones are moderately reactive compared to other
carbonyl compounds:
acyl halide > acid anhydride > aldehyde > ketone > ester ~ carboxylic acid > amide
• Aldehydes/ketones are not as resonance stabilized as some:
R
O
O
O
C
C
C
Y
R
R
Y
Y
• Aldehydes/ketones are more stable (less reactive) than others:
O
R
Cl
an acyl chloride
O
R
R
a ketone
4
Reactivity Considerations
•
Aldehydes and ketones do NOT undergo nucleophilic acyl
substitution. Why?
O
C
R
•
O
+
R'
R
Z:
C
Z
O
R'
R
C
Z
+
R':
Aldehydes and ketones react via nucleophilic addition:
O
R
C
R'
+
HZ
5
Reactivity Considerations
• Nucleophilic addition can occur with a less electronegative
nucleophile (Z = C– or H –):
O
R
C
R'
+
Z:
• Or with a more electronegative nucleophile (Z = O or N):
O
R
C
R'
+
HZ
6
Addition of Carbon Nucleophiles
•
•
Addition of carbon nucleophiles to aldehydes and ketones
results in the formation of new C-C bonds.
The following carbon nucleophiles will be discussed:
1. Grignard reagents (________) and organolithium compounds
(______)
2. Acetylide anions (__________)
3. Hydrogen cyanide (_______)
7
Carbon Nucleophiles: RMgX and RLi
Reagents
• Grignard reagents (RMgX) and organolithium compounds (RLi) are
both powerful nucleophiles.
CH3CH2Br
+
Mg
Et2O
CH3CH2MgBr reacts as if it were
CH3CH2Br
+
2Li
CH3CH2Li reacts as if it were
• They react with carbonyl compounds (both class 1 and 2)
resulting in new C-C bond formation.
8
Carbon Nucleophiles: RMgX and RLi
• Reaction with formaldehyde to form a 1º alcohol:
R MgX +
H
O
O
C
H C
H
H
H+
R
• Reaction with other aldehydes to form 2º alcohols:
O
O
R MgX +
R'
C
R'
H
C
H
H+
R
9
Carbon Nucleophiles: RMgX and RLi
• Reaction with other ketones to form 3º alcohols:
O
O
R MgX +
R'
C
R'
R''
C
R''
H+
R
• Reaction with carbon dioxide to form a carboxylic acid:
R MgX
+ O
C
O
10
Carbon Nucleophiles: RMgX and RLi
• Reaction with ethylene oxide to form a 1º alcohol :
MgBr
1.
O
2. H 2SO4
Note that two carbons are added to the Grignard reagent.
11
Carbon Nucleophiles: RMgX and RLi
• Reaction with carboxylic acid derivatives to form 3º alcohols :
O
O
R MgX
+
R'
C
R'
OEt
C
OEt
R
1. R MgX
2. H+
O
1. 2
Cl
MgCl
2. H3O
Note that two of the alkyl groups on the alcohol are identical.
12
Carbon Nucleophiles: Acetylide Ions
• An acetylide ion also is an effective carbon nucleophile.
• Acetylide ions add to aldehydes and ketones to form acetylenic
alcohols.
CH3C
C:
O
RC
C
+
R'
C
R''
aldehyde
or ketone
13
Carbon Nucleophiles: HCN
• HCN adds to aldehydes and ketones to form cyanohydrins.
• The reaction is usually done in basic soln (pH 9-10) so that both
CN– and HCN are present.
O
HC
+
N
R
C
R'
aldehyde
or ketone
OH
C
C
OH
N
H2SO 4, H2O
N
H2, Pt
14
Addition of Hydrogen Nucleophiles
• The hydride ion (_____) is a powerful nucleophile and reducing
agent that can add to both class I and class II carbonyl compounds.
• The two most common sources of hydride are:
– sodium borohydride –
– lithium aluminum hydride –
• ______ is the weaker and more selective reactant: Reacts only with
• ______ is more reactive and is used to reduce less reactive
compounds like
15
Addition of Hydrogen Nucleophiles
• Reaction of NaBH4 with aldehydes to form 1º alcohols:
H
+
R
O
O
C
R C
H
H
H+
R CH2 OH
H
• Reaction of NaBH4 with ketones to form 2º alcohols:
H
+
R
O
O
C
R C
R'
H
R'
H+
R CH OH
R'
16
Addition of Hydrogen Nucleophiles
• Reaction of LiAlH4 with carboxylic acids to form _____________
O
R
C
OH
1. LiAlH4
2. H 2O
mechanism for the reaction of a carboxylic acid with hydride ion
O
H3C
C
O
H
+ H
AlH3
17
Addition of Hydrogen Nucleophiles
• Reaction of LiAlH4 with esters to form ______________
O
R
C
OR'
1. LiAlH 4
2. H2O
mechanism for the reaction of an ester with hydride ion
O
O
C
C
OCH3 + H
AlH3
H
H
AlH3
18
Addition of Hydrogen Nucleophiles
• 1 equiv of diisobutylaluminum hydride (DIBAlH) reduces an ester
to an ____________. Low temps. (-78 ºC) are required.
O
R
C
OCH3
1. DIBAlH
2. H2O
DIBAlH = diisobutylaluminum hydride
[(CH3)2CHCH2]2AlH
• 1 equiv of lithium tri-t-butoxyaluminum hydride reduces an acyl
halide to an ____________. Low temps. (-78 ºC) are required.
O
R
C
Cl
1.LiAlH[(OC(CH 3)]3
2. H2O
19
Addition of Hydrogen Nucleophiles
• Reaction of LiAlH4 with amides to form amines
O
R
C
NH2
1. LiAlH4
2. H2O
• 2º and 3º amines also possible if start with N-substituted amides.
O
N
1. LiAlH 4
2. H2O
H
O
CH3CH2
C
N
CH3
CH3
1. LiAlH 4
2. H2O
20
Addition of Nitrogen Nucleophiles
• Aldehydes and ketones react with 1º amines, and other ammonia
derivatives to form ________________________:
R
C
+
O
H2N
Z
R
CH3
C
O
+
H2N CH2
C
O
+
CH3
CH3CH2
H
H2N OH
21
Addition of Nitrogen Nucleophiles
C
O
+
H2N NH2
hydrazine
CH3
O
O
+
O
H2N NH CNH2
semicarbazide
N
NH CNH2
a semicarbazone
CH3CH2
C
O
+
H2N NH
NO2
CH3CH2 CH N NH
NO2
H
O2N
2,4-dinitrophenylhydrazine
O2N
a 2,4-dinitrophenylhydrazone
22
Addition of Nitrogen Nucleophiles
mechanism for imine formation: A nucleophilic addition-elimination mechanism
O
O
+
RNH 2
NH2R
OH
proton
transfer
NHR
H
B
H
OH
NHR
23
Addition of Nitrogen Nucleophiles
• Imine formation is slow at both high pH and low pH but reaches a
maximum rate at pH 4-5.
• At low pH (high [H3O+]) the reaction is slow because
• At high pH (low [H3O+])
• A pH between _________ is an effective compromise.
24
Addition of Nitrogen Nucleophiles
• Aldehydes and ketones react with 2º amines to form ___________.
O
R
C
H
+
CH2 R'
R''
N
R''
CH3CH2
O
+
NH
CH3CH2
O
+
N
H
25
Addition of Nitrogen Nucleophiles
mechanism for enamine formation
R
O
+
R
O
OH
proton
NH
transfer
NH R
N
R
R
R
H
B
R
H
OH
R
N
N
R
R
26
Addition of Nitrogen Nucleophiles
• Amines can be synthesized in a single step by treatment of an
aldehyde or ketone with ammonia or an amine in the presence of a
reducing agent = reductive amination.
NH3
H2/cat
O
R
R'
aldehyde
or ketone
R''NH 2
H2/cat
R'' 2NH
H2/cat
 Common catalysts include Raney Ni, Pd/C or NaBH3CN
(sodium cyanoborohydride)
27
Addition of Nitrogen Nucleophiles
• The mechanism of reductive amination is thought to proceed via
reduction of an imine intermediate for NH3 and 1 amines:
CH3
O
+
CH3
NH 3
excess
• reductive amination proceeds via reduction of an enamine
intermediate for 2 amines:
CH3
O
+
HN
CH3
28
Addition of Nitrogen Nucleophiles
• The Wolff-Kishner Reduction
– In Chap. 15 we learned that an aldehyde or ketone can be
converted into a methylene (-CH2-) group under basic
conditions in the presence of hydrazine.
O
29
Addition of Nitrogen Nucleophiles
• The mechanism of the Wolff-Kishner reduction is thought to
proceed via a hydrazone intermediate. The presence of OH– and
heat pushes the reduction of the hydrazone.
O
+
C
N
HO
NH 2NH2
N
H
CH3
N
CH3
H
C
CH3
CH
N
CH
CH3
N
H
+
HO
H
O
H
N
C
CH3
H2O
30
Addition of Oxygen Nucleophiles
•
•
The two oxygen nucleophiles we will discuss are:
1. water
2. alcohols
Water adds reversibly to aldehydes and ketones to form a _______
O
R
•
R'(H)
+
H2O
Note the reversibility of the reaction. The catalyst has no affect on
the position of the equilibrium.
31
Addition of Oxygen Nucleophiles
• Mechanism of acid-catalyzed hydrate formation:
• The position of the equilibrium depends on the relative stabilities of
the carbonyl compound and the hydrate.
H3C
O
O
O
C
C
C
CH3
H3C
H
H
OH
OH
H3C
H
C
OH
CH3
H3C
C
OH
OH
H
H C
H
OH
32
Addition of Oxygen Nucleophiles
• Therefore, formaldehyde has the greatest tendency to form
hydrates while ketones are least likely to do so:
O
H3C
C
OH
CH3
+
H2O
H3C
H
CH3
OH
H
+
H2O
H3C C
H
OH
O
C
C
OH
O
C
H3C
OH
H
+
H2O
H C
OH
H
33
Addition of Oxygen Nucleophiles
• One equivalent of an Alcohol adds reversibly to aldehydes to form a
_____________.
• Addition of a second equivalent forms an _________.
O
H3C
C
H
+
CH3OH
HCl
• One equivalent of an Alcohol adds reversibly to ketones to form a
_____________.
• Addition of a second equivalent forms an _________.
O
H3C
C
CH3
+
CH3OH
HCl
34
Addition of Oxygen Nucleophiles
• The mechanism of acetal/ketal formation is similar to that of imines.
O
H3C
C
H
CH3
B
O
H3C
C
H
+
CH3
CH3OH
35
Acetals & Ketals as Protecting Groups
• The reversibilty of these reactions allows acetals and ketals to be
used as protecting groups.
• Ketones and aldehydes react with 1,2-diols and 1,3-diols to form
five and six membered rings, respectively.
O
CH3 CH2 C CH2 CH3
O
+
+
HCl
HO
OH
HO
OH
HCl
• For example: how can the following synthesis be performed?
O
H3C
O
C
O
?
OCH3
H3C
CH2OH
36
Acetals & Ketals as Protecting Groups
• Selective reduction of the ester is not possible. Why?
O
O
C
H3C
1. NaBH4
OCH3
2. H2O
• However, the ester can be selectively reduced if the ketone is
protected first as a ketal.
O
H3C
O
C
OCH3
O
H3C
CH2OH
37
Alcohol Protecting Groups
• The trimethylsilyl (TMS) group is an excellent alcohol protecting
group:
CH3
R
OH
+
H3C
Si Cl
Et3N
CH3
chlorotrimethylsilane (TMSCl)
H3O+
38
Alcohol Protecting Groups
HO
H
Br
O
Ph
O
C
Ph
OH
39
Carboxylic Acid Protecting Groups
• The –OH group of a carboxylic acid can be protected by converting
it to an ________:
OH
HO
O
OH
O
O
OH
40
The Wittig Reaction
• The Wittig reaction is the standard method of preparing alkenes.
• The reaction involves the reaction of aldehydes or ketones with
phosphonium ylides.
• A ylide is a compound with opposite charges on adjacent
covalently bonded atoms, each of which has an octet of electrons.
(C6H5)3P
CH2
(C6H5)3P
CH2
a phosphonium ylide
R"
O
+
R
R'
(C 6H5)3P
C
R'''
41
The Wittig Reaction
By Wittig Reaction:
O
CH3 CH2 C CH2 CH3
+
(C6H5)3P
CH2
By elimination:
CH3
CH3 CH2 C CH2 CH3
Base
Br
CH3
C
CH3
+
(C6H5)3P
O
42
The Wittig Reaction
• The Wittig reaction involves an addition-elimination mechanism.
Mechanism of the Wittig Reaction
(C 6H5)3P
CH2
R
O
C
R
43
The Wittig Reaction
• The phosphorus ylides are easily prepared from triphenylphoshine
(an excellent nucleophile and weak base) with 1º and 2 º alkyl
halides via an SN2 mechanism.
• A strong base (usually an alkyllithium or phenyllithium) is required
to remove a proton from the intermediate
alkyltriphenylphosphonium salt.
(C 6H5)3P
+ CH3CH2
Br
44
The Wittig Reaction
• The Wittig reaction has several advantages over E1 or E2 reactions
– The reaction is completely regioselective – there is no question
as to where the double bond will be.
– It is also stereoselective – the E form dominates.
• Synthesize the molecule below using both dehydrohalogenation
and the Wittig reaction.
CHCH 2CH3
45
Nucleophilic Addition to
Unsaturated Carbonyl Compounds
•
, -unsaturated aldehydes and ketones contain two sites that are
susceptible to nucleophilic attack.
O
RCH
•
CH CR
Two modes of nucleophilic addition are possible:
1. direct (1,2) addition – nucleophile adds to the ______________.
2. conjugate (1,4) addition – nucleophile adds to the ___________
forming an enolate ion intermediate.
46
Nucleophilic Addition to
Unsaturated Carbonyl Compounds
• Direct (1,2) addition
O
Y: +
RCH
CH CR
• Conjugate (1,4) addition
O
Y: +
RCH
CH CR
47
1,2 (Direct) vs 1,4 (Conjugate) Addition
Reversible with
weak bases
RCH
O
RCH
CH CR
OH
CH CR
1,2 addtion Nu
+
NuH
irreversible
O
RCH
CH2 CR
Nu
• 1,2-addition is usually the kinetic product
1,4 addtion
• 1,4-addition is the thermodynamic product:
48
1,2 (Direct) vs 1,4 (Conjugate) Addition
• Direct addition (v. strong bases)
LiAlH4
NaBH4 (esp. with aldehydes)
RLi or ArLi
RMgX (subject to sterics)
Conjugate addition (weak bases)
NH3, RNH2, & R2NH
CN– and R–SH
R2CuLi (Gilman)
-carbanions (Michael addition)
O
1. (CH3)2CuLi
2. H, H 2O
O
1. CH3MgBr
2. H, H 2O
49
Nucleophilic Addition to
Unsaturated Carbonyl Compounds
• Outline two ways in which 4-methyl-2-octanone can be prepared by
conjugate additon of an organocuprate to an
-unsaturated
ketone.
CH3
O
CH3 CH2 CH2 CH2 CH CH2 C CH3
50
Nucleophilic Addition to
Unsaturated Carbonyl Compounds
•
, -Unsaturated carboxylic acid derivates can also undergo the
same two modes of nucleophilic attack.
– Nucleophilic acyl substitution is favored with acyl chlorides and
anhydrides.
O
Cl
+
CH 3OH
– Conjugate addition is favored with esters and amides:
O
OCH3
+
CH 3OH
51