Download ppt

Chapter 17: Aldehydes and Ketones: Nucleophilic Addition
to the Carbonyl Group
17.1: Nomenclature (please read)
17.2: Structure and Bonding: Carbonyl groups have a
significant dipole moment
O
C
+
O
O
C
C
Aldehyde
Ketone
Carboxylic acid
Acid chloride
Ester
Amide
Nitrile
2.72 D
2.88
1.74
2.72
1.72
3.76
3.90
Water
1.85
Carbonyl carbons are electrophilic sites and can be attacked
by nucleophiles. The carbonyl oxygen is a basic site.
97
17.3: Physical Properties (please read)
17.4: Sources of Aldehydes and Ketones (Table 17.1, p. 708)
1a. Oxidation of 1° and 2° alcohols (15.10)
1b. From carboxylic acids
1c. Ketones from aldehydes
98
2. Ozonolysis of alkenes (6.20)
3. Hydration of alkynes (9.12)
4. Friedel-Craft Acylation (12.7) - aryl ketones
5. Hydroformylation of alkenes (please read)
99
17.5: Reactions of Aldehydes and Ketones: A Review and a Preview
Reactions of aldehydes and ketones: Review:
1. Reduction to hydrocarbons
a. Clemmenson reduction (Zn-Hg, HCl)
b. Wolff-Kishner (H2NNH2, KOH, )
100
2. Reduction to 1° and 2° alcohols (15.2)
3. Addition of Grignard Reagents (14.6-14.7)
101
17.6: Principles of Nucleophilic Addition:
Hydration of Aldehydes and Ketones
Water can reversibly add to the carbonyl carbon of aldehydes
and ketones to give 1,1-diols (geminal or gem-diols)
R
O
C
+ H2O
R
- H2O
OH
R C OH
R
R= H, H
R= CH3, H
R= (H3C)3C, H
R= CH3, CH3
R= CF3, CF3
99.9 % hydrate
50 %
17 %
0.14 %
> 99 %
The hydration reaction is base and acid catalyzed
Base-catalyzed mechanism (Fig. 17.1): hydroxide is a better
nucleophile than water
102
Acid-catalyzed mechanism (Fig. 17.2): protonated carbonyl is
a better electrophile
The hydration is reversible
Does adding acid or base change the amount of hydrate?
Does a catalysts affect Go, G‡, both, or neither
103
17.7: Cyanohydrin Formation
Addition of H-CN adds to the aldehydes and unhindered ketones.
(related to the hydration reaction)
The equilibrium favors cyanohydrin formation
Mechanism of cyanohydron fromation (Fig. 17.3)
104
17.8: Acetal Formation
Acetals are geminal diethers- structurally related to hydrates,
which are geminal diols.
R
O
C
+ H2O
R
- H2O
OH
R C OH
R
hydrate
(gem-diol)
R
O
C
+ R'OH
H
- R'OH
aldehyde
R
O
C
ketone
+ R'OH
- R'OH
hemi-acetal
+ R'OH
R
OH
H C OR'
R
- R'OH
OH
R C OR'
R
hemi-ketal
OR'
H C OR'
R
+ H2O
acetal
(gem-diether)
+ R'OH
- R'OH
OR'
R C OR'
R
ketal
(gem-diether)
+ H2O
105
Mechanism of acetal (ketal) formation is acid-catalyzed (Fig 17.4)
Dean-Stark
Trap
The mechanism for acetal/ketal formation is reversible
How is the direction of the reaction controlled?
106
Dioxolanes and dioxanes: cyclic acetal (ketals) from 1,2- and
1,3-diols
R
O
C
H+, - H2O
+
R
HO
OH
H3O+
O
O
R
R
1,3-dioxolane
1,2-diol
R
O
C
+
R
H+, - H2O
HO
1,3-diol
OH
H3O+
O
R
O
R
1,3-dioxane
107
17.9: Acetals (Ketals) as Protecting Groups
Protecting group: Temporarily convert a functional group that is
incompatible with a set of reaction conditions into a new
functional group (with the protecting group) that is compatible
with the reaction. The protecting group is then removed giving
the original functional group (deprotection).
OH
OCH3
O
NaBH4
O
OCH3
cannot be
done directly
O
OH
O
keto-ester
108
The reaction cannot be done directly, as shown. Why?
a) NaNH2
b) H3C-I
O
O
CH3
17.10: Reaction with Primary Amines: Imines (Schiff base)
R
O
C
+ R'OH
R
- R'OH
Aldehyde
or ketone
R
O
C
+ R'OH
- R'OH
hemi-acetal
or hemi-ketal
+ R'NH2
R
OH
R C OR'
R
- R'NH2
Aldehyde
or ketone
OH
R C NHR'
R
OR'
R C OR'
R
+ H2O
acetal
or ketal
+ R'NH2
- R'NH2
NHR'
R C NHR'
R
+ H2O
carbinolamine
imine
R
N
C
R'
+ H2O
R
109
Mechanism of imine formation (Fig. 17.5):
See Table 17.4 for the related carbonyl derivative, oximes,
hydrazone and semicarbazides (please read)
O
C6H2NHNH2
H2NOH
N
oxime
OH
N
N-C6H5
phenylhydrazone
H2NHNCONH2
O
N
N
H
semicarbazide
NH2
110
17.11: Reaction with Secondary Amines: Enamines
1° amine:
R
O
C
R'NH2
R
R'
O
C
2° amine:
R
ketone with
-protons
R
H H
R'
R
R'
O
C
N
H
R
N
H
R'
OH
R C NHR'
R
OH
R C N R'
R
R'
OH
R'
R C
N
H
H R R'
- H2O
R
- HO
- HO
_
_
N
C
R'
Imine
R
+
R'
N
C
R
R
R'
+
R'
N
R
C
R
H H
Iminium ion
R'
-H
iminium ion
R'
+
R
N
C
R'
R
H
enamine
Mechanism of enamine formation (Fig 17.6)
111
17.12: The Wittig Reaction
1979 Nobel Prize in Chemistry: Georg Wittig (Wittig Reaction) and H.C. Brown (Hydroboration)
R1
C O
R2
aldehyde
or ketone
+
+
The synthesis of an alkene from the reaction of an aldehyde
or ketone and a phosphorus ylide (Wittig reagent), a dipolar
intermediate with formal opposite charges on adjacent atoms
(overall charge neutral).
R4
R2
R4
+
C C
Ph3P C
R3
triphenylphosphonium
ylide (Wittig reagent)
R1
Ph3P=O
R3
alkene
triphenylphosphine
oxide
Accepted mechanism (Fig. 17.7) (please read)
112
The Wittig reaction gives C=C in a defined location, based
on the location of the carbonyl group (C=O)
CH3
CH2
1) CH3MgBr, THF
2) POCl3
+
O
CH2
Ph3P CH2
THF
1 : 9
The Wittig reaction is highly selective for ketones and aldehydes;
esters, lactones, nitriles and amides will not react but are
tolerated in the substrate. Acidic groups (alcohols, amine
and carboxylic acids) are not tolerated.
O
O
H
O
PPh3
+
O
O
O
O
CHO
O
+
O
Ph3P
O
OCH3
OCH3
O
Predicting the geometry (E/Z) of the alkene product is complex
and is dependent upon the nature of the ylide.
113
17.13: Planning an Alkene Synthesis via the Wittig Reaction
A Wittig reagent is prepared from the reaction of an alkyl halide
with triphenylphosphine (Ph3P:) to give a phosphonium salt.
The protons on the carbon adjacent to phosphorous are
acidic.
Ph3P
H3C Br
Ph3P CH3
Br
H3CLi
THF
Ph3P CH2
ylide
Ph3P
CH2
phosphorane
Phosphonium
salt
Deprotonation of the phosphonium salt with a strong base gives
the ylide. A phosphorane is a neutral resonance structure of
the ylide.
114
• There will be two possible Wittig routes to an alkene.
• Analyze the structure retrosynthetically, i.e., work the synthesis
out backworks
• Disconnect (break the bond of the target that can be formed by
a known reaction) the doubly bonded carbons. One
becomes the aldehyde or ketone, the other the ylide
Disconnect
this bond
R2
R4
C C
R3
R1
R2
R2
R4
+ Ph3P C
R3
C O
R1
- OR -
R4
C PPh3 + O C
R3
R1
CH3CH2CH2
CH2CH3
C C
CH3
H
115
17.14: Stereoselective Addition to Carbonyl Groups
(please read)
17.15: Oxidation of Aldehydes
Increasing oxidation state
C C
C C
C C
Cl
C Cl
Cl
C Cl
Cl
C Cl
Cl
O
C OH
C NH2
C O
C NH
C
Cl
C Cl
Cl
CO2
OR
C N
116
H2Cr2O7
PCC
CHO
CH2Cl2
OH
Aldehyde
RCH2-OH
1Ў alcohol
Carboxylic Acid
1Ў alcohol
O
H2Cr2O7
H3O+,
acetone
R
H2O
H hydration
CO2H
H3O+,
acetone
HO OH
R
H
O
H2Cr2O7
H3O+,
acetone
R
OH
Aldehydes are oxidized by Cr(VI) reagents to carboxylic acids
in aqueous acid. The reactions proceeds through the
hydrate
117
17.16: Baeyer-Villiger Oxidation of Ketones. Oxidation of
ketones with a peroxy acid (mCPBA) to give as esters
O
O
O
R
R'
O
+
OH
O
R
Cl
O
OH
+
R'
ester
Cl
Oxygen insertion occurs between carbonyl carbon and more
the substituted -carbon
O
O
mCPBA
CH3
O
O
O
H3C
mCPBA
O
H3C
118
19.17: Spectroscopic Analysis of Aldehydes and Ketones
Infrared Spectroscopy: highly diagnostic for carbonyl groups
Carbonyls have a strong C=O absorption peak between
1660 - 1770 cm1
Aldehydes also have two characteristic C–H absorptions
around 2720 - 2820 cm1
Butanal
C-H
H
O
C
2720,
2815 cm-1
C=O (1730 cm-1)
2-Butanone
C-H
C=O (1720 cm-1)
119
C=O stretches of aliphatic, conjugated, aryl and cyclic
carbonyls:
O
O
O
H
H
aliphatic aldehyde
1730 cm-1
H
conjugated aldehyde
1705 cm-1
aromatic aldehyde
1705 cm-1
O
O
H3C
O
CH3
aliphatic ketone
1715 cm-1
CH3
CH3
conjugated ketone
1690 cm-1
aromatic ketone
1690 cm-1
O
O
O
1715 cm-1
1750 cm-1
1780 cm-1
O
1815 cm-1
Conjugation moves the C=O stretch to lower energy (right,
lower cm-1)
Ring (angle) strain moves the C=O stretch to higher energy
120
(left, higher cm-1)
1H NMR
Spectra of Aldehydes and Ketones: The 1H chemical
shift range for the aldehyde proton is  9-10 ppm
The aldehyde proton will couple to the protons on the -carbon
with a typical coupling constant of J  2 Hz
A carbonyl will slightly deshield the protons on the -carbon;
typical chemical shift range is  2.0 - 2.5 ppm
 = 2.4, dt,
J= 1.8, 7.0, 2H
 = 1.65, sextet,
J= 7.0, 2H
 = 1.65, t,
J= 7.0, 3H
 = 9.8, t,
J= 1.8, 1H
121
O
H3C H2C C CH3
= 2.5 (2H, q, J = 7.3)
2.1 (3H, s)
1.1 (3H, t, J = 7.3)
O
H
H3C
C
C
C
CH2CH3
H
= 6.8 (1H, dq, J =15, 7.0)
6.1 (1H, d, J = 15)
2.6 (2H, q, J = 7.4)
1.9 (3H, d, J = 7.0 )
1.1 (3H, t, J = 7.4)
 7.0 -6.0
 2.7 1.0
122
13C
NMR:
The intensity of the carbonyl resonance in the 13C spectrum
usually weak and sometimes not observed.
The chemical shift range is diagnostic for the type of carbonyl
ketones & aldehydes:
carboxylic acids, esters,
and amides
O
= 220, 38, 23
 = ~ 190 - 220 ppm
 = ~ 165 - 185 ppm
O
H3CH2CH2C C OCH2CH3
= 174, 60, 27,
14, 9
carbonyl
carbonyl
CDCl3
123
C9H10O2
IR: 1695 cm-1
13C NMR: 191
163
130
128
115
65
15
1H
s
2H
d, J= 8.5
2H
d, J= 8.5
3H
(t, J= 7.5)
2H
q, J= 7.5
C10H12O
IR: 1710 cm-1
13C NMR: 207
134
130
128
126
52
37
10
2H
(q, J= 7.3)
3H
(t, J= 7.3)
2H
5H
124
C9H10O
9.8
(1H, t, J =1.5)
7.3
(2H, m)
 9.7 - 9.9
7.2
(3H, m)
2.9
(2H, t, J = 7.7)
 7.0 - 7.8
2.7
(2H, dt, J = 7.7, 1.5)
 3.1 - 2.5
129,128, 125
28
45
201
140
CDCl3
125