Download CHAPTER 17: Carbonyl group (1)

CHAPTER 17: Carbonyl group
(1)
General Information
This chapter deals with the reactivity of the carbonyl group and preparations and
reactions of aldehydes (R=H) and ketones (R= carbon chain).
17.2-17.3 Structure of the carbonyl group and spectroscopy
Carbonyl group: carbon bonded to an oxygen via a
double bond (sp2 hybridization and planar geometry).
The electron density of the double bond is polarizes
toward the oxygen that can use its lone pair to act as a
base or nucleophile. The carbonyl carbon is electrophilic.
δ- O
δ+
R
base or
nucleophile
electrophile
R (H)
In NMR the aldehyde ptotons resonate at ca 9.5 ppm due to the dual deshielding effect of the
double bond and the electronegative oxygen. The carbonyl carbon resonates at ca 200 ppm.
In the IR, the carbonyl group absorbs strongly at ca 1700 cm-1
17.4. Preparations
1. Ozonolysis of alkenes
R2
R4
R1
O3
Me2S
-70 °C
R3
R2
R1
-70 °C
R4
+
O
O
R3
2. Hydration of alkynes
R1
H
R1
+
HOH, H
R1
R2B-H
H
OH
H
HgSO4
tautomerization
R1
H
H
R2B
H
O
H
H
H
H2O2
HO
NaOH
R1
H
H
O
R1
H
O
O
3. Friedel Crafts acylation
AlX3
+
R
X
R
H
H
R1
CHAPTER 17: Carbonyl group
(2)
4. Oxidation of alcohols [ use of Cr(VI)-based reagents]
HO
H
O
H
R
+
O
Cr
O
+6
H
- H2O
R
O
H
O
+4
O
Cr
HO
O
O
Cr +6
OH
+
H
H
O
R
H2O
H+ (cat)
O
HO
+4
O
Cr
HO
HO
+
R
HO
O
R
H
O
O
O
Cr +6
OH
+6
Cr
O
O
H
OH
R
OH
The oxidation of a primary alcohol to the carboxylic acid proceeds using CrO3 in aqueous
H2SO4 (Jones oxidation). The process involves initial oxidation to the aldehyde that in the
presence of H2O and acid exists in the form of a hydrate. The hydrate is then further
oxidized to the carboxylic acid.
Secondary alcohols produce ketones, while tertiary alcohols remain intact.
H
R
H
O
H
PCC
O +6
Cr O H N
O
Cl
H
R
O
PCC
An alternative method is the PCC oxidation (CrO3, HCl, pyridine) that oxidizes primary and
secondary alcohols only to the corresponding carbonyl groups (no overoxidation to acids).
The PCC oxidation is performed in organic solvents, such as CH2Cl2. In the absense of
H2O the primary aldehyde cannot be hydrated and therefore it does not undergo further
oxidation to acid. Aldehydes or ketones are the only products obtained.
5. Selective oxidation of allylic alcohols [ use MnO2]
OH
HO
OH
MnO2
O
Allylic alcohols are easier to oxidize than aliphatic alcohols and in the presence
of a mild oxidant they give rise to a,b unsaturated ketones.
CHAPTER 17: Carbonyl group
(3)
17.5 Reactivity of the carbonyl group
base or
nucleophile
!- O
!+
acidic
H
attack by
a base
electrophile
H
attack by
electrophile
-
H
NOT acidic
! O
!+
attack by
nucleophile
H
R
R
Nucleophilic addition at the carbonyl group (under basic conditions)
(R1)H
Nu
O
R
(R1)H
R
H+, H2O
Nu
O
(R1)H
Nu
R
OH
This mechanism implies the use of a strong charged (anionic) nucleophile and is
irreversible if the Nu is C or H. It is reversible for most heteroatom nucleophiles.
Nucleophilic addition at the carbonyl group (under acidic conditions)
O
H+
R
(R1)H
O
(R1)H
H
R
O
H
(R1)H
Nu
Nu
OH
(R1)H
R
R
This mechanism indicates the use of an acid to protonate the carbonyl oxygen. This
makes the carbonyl carbon a better electrophile and allows weak nucleophiles (such
as heteroatoms) to react with it using their lone electron pairs.
Additions of hydride (H-) at the carbonyl carbon
(R1)H
R
O
NaBH4 or
LiAlH4
then H+, H2O
(R1)H
R
H
O
H
LiAlH4: a very strong hydride donor (H-). It reduces all carbonyl group or carboxylic acid
derivatives.
NaBH4: a very mild hydride donor (H-). It reduces only carbonyl groups to alcohols. It
does not reduce esters.
CHAPTER 17: Carbonyl group
(4)
17.5 Reactivity of the carbonyl group
Additions of carbon nucleophiles (R-) at the carbonyl carbon
To prepare carbon nucleophiles, we have to either deprotonate a compound with a relatively
acidic C-H bond (ex. acetylide anions Eq.1,2), or treat an alkyl chloride with metals. In the
latter case we can insert Mg(0) between a C-X bond (ex. Grignard reagents, Eq. 3) or
exchange the C-X with a C-Li bond (ex. organolithium reagents, Eq. 4).
R
!- !+
H
R
!- !+
H
!- !+
+
Et-Mg-I
!+
+
!-
Na-NH2
!+ !R I + Mg
ether
!- !+
R Mg-I
!+ !R I + Li
ether
!- !+
R Li
ether
ether
R
!- !+
MgI
R
!- !+
Na
(Eq. 1: acetylenic
nucleophiles)
(Eq. 2: acetylenic
nucleophiles)
(Eq. 3: Grignard nucleophiles)
(Eq. 4: Lithium nucleophiles)
-LiI
The general mechanism for the addition of C nucleophiles at the carbonyl carbon is as follows:
O
-
! !
R2 [M]
+
R
(R1)H
O
+
R2
[M]
R
O
(R1)H
MeMgI
H
H+,
H2O
then H+, H2O
Isolated double bonds do not react with nucleophiles
Me
-[M]-OH
OH
H
HO
R
R2
(R1)H
CHAPTER 17: Carbonyl group
(5)
17.6 Addition of water to the carbonyl group
O
HO
H+, or HO-
R
(R1)H
+ H2O
OH
R
(R1)H
hydrate
Aldehyde carbonyl groups react with water (or alcohols) in a reversible manner to form
hydrates. This reaction can be catalyzed with H+ or OH-.
The more reactive (!+) the carbonyl group is, the more tendency it has to be hydrated. Thus,
an aldehyde should be easier to hydrate than a ketone. The reactivity order is as follows:
O
O
O
O
Cl3C
H
H
H
R
R
H
R
17.7 Addition of alcohols to the carbonyl group
H
HO
O
OH
O
hemiacetal
(5,6 membered ring)
The proposed general mechanism of this type of reaction is as shown:
O
R
OH
H+
R2 OH
R
R1
R
R1
H
R2-O
R
- H+
O-R2
H
OH
R2 OH
O-R2
R
R1
R2-O
R
O-R2
R1
R1
HO
R1
-H2O
H2O
R
O-R2
R
R1
O-R2
H+
R1
- H+
HO
R
O-R2
R1
CHAPTER 17: Carbonyl group
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17.8 Acetals as protecting groups
Due to interference of functional groups during a reaction we often need to transform them to
"unreactive species". This is accomplished using "protecting groups" which should be inert to
the subsequent reactions. At the end of the synthetic strategy, these protecting groups
should be removable easily to reveal the original functionalities.
Ex. Compound 3 should be made using compounds 1 and 2 and any other reagent.
3
2
H
1
O
6
I
4
5
1
5
3
2
1
H
4 H
6
O
3
2
General approach:
Number all key carbons in the starting materials and identify where they are in the product.
Find what bond connections need to be built or cleaved.
Try to construct (or cleave) the bonds you need to form on the basis of the functionalities
present in the starting materials. Consider E/Nu, B/A or ox./red. chemistry.
Look at the starting materials and think about potential interference with other functional
groups. Then protect the functional groups that interfere with your strategy.
O
a. protect the
carbonyl group I
6
4
5
+
H
HO
H+
OH
O
6
I
5
2
H
4
4
Bu-Li
3
2
b. form C3-C6
bond
O
H
1
3
2
Li
1
1
c. deprotect
the carbonyl
5
3
2
1
4
H
H+, H2O
1
6
O
3
3
2
-
6 O
HO
HO
5
5
4
H
O
CHAPTER 17: Carbonyl group
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17.9 Nucleophilic addition of ammonia and derivatives
R2
RNH2
amine
HO-NH2
hydroxylamine
hydrazine
O
+ R2
(R1)H
R2
(R1)H
(R1)H
R2NH
sec. amine
oxime
N OH
(R1)H
R2
-H2O
H2N-NH2
imine
N R
hydrazone
N NH2
R2
NR2
enamine
(R1)H
17.10 Deoxygenation of the carbonyl group
O
R
+ H2N-NH2
R1
R
H
R
N-NH2
-H2O
R
H
H
N H
N
N
N
OH
R
R1
H
R1
R
R1
H
R
H-OH
R1
-N2
H
R
R1
H
N
N
R1
H
H-OH
R
heat -N2
R1
H
H
NaOH
H
N
N
R
R1
N N
OH
R1
Deoxygenation via the thioketal functionality
O
+
R
R1
HS
SH
H+
S
S
-H2O
R
R1
thioketal
Raney Ni
H
R
H
R1
CHAPTER 17: Carbonyl group
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17.11 Addition of HCN to carbonyl group (formation of cyanohydrins)
O
Na CN
R
O
C N
Na
(R1)H
H+,
H2O
R
HO
C N
R
(R1)H
(R1)H
17.12 The Wittig reaction (conversion of carbonyls to alkenes)
Wittig reaction: The reaction between phosphorus ylids and aldehydes or ketones to form
an alkene.
+
O
+ Ph3P=O
Ph3P
Proposed mechanism:
!+
!-
O
!+ !-
+
Ph3P
O
PPh3
O
PPh3
Preparation of Wittig ylids (phosphorus ylids)
I
Ph3P +
I
Bu-Li
Ph3P
Ph3P
H
17.13 The Baeyer-Villiger reaction (from carbonyls to carboxyls)
O
1
R1
O
2
R
HO
R
O
O
O H O
-
R
HO
R2
O O
R
Oxidation of carbonyl groups to carboxylic acid groups
Migration order of R2: Me < primary < secondary < tertiary
R
R1
O
O
R2