Download Chapter 20. Aldehydes and Ketones

C h a p t e r T w e n t y:
Aldehydes and Ketones
O
OH
O
(S)-Warfarin (named for the Wisconsin Alumni Research Foundation), a useful
clinical anticoagulant which as a racemate is also a rat poison
Note: Problems with italicized numbers are more challenging.
You may want to try them last.
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CHM 323: Summary of Important Concepts
YConcepts for Chapter 20: Aldehydes and Ketones
I.
Nomenclature and Properties
A.
IUPAC
1.
Aldehydes
a.
RCHO, alkanal
i.
Sometimes also named as alkylcarboxaldehydes, where R =
alkyl
b.
when the –CHO group is named as a substituent, it is the formyl
substituent
c.
example:
i.
CH3CH2CH2CH(CH3)CH2CH2CHO 4-methylheptanal
d.
common aldehydes:
i.
H2C=O
formaldehyde
acetaldehyde
ii.
CH3CHO
benzaldehyde
iii.
C6H5CHO
2.
Ketones
a.
RR’C=O, alkanone
i.
Sometimes also named as alkyl alkyl ketones
b.
example:
i.
CH3CH2C=OCH2CH(CH3)CH2CH(CH3)2
5,7-dimethyl-3-octanone
c.
common ketones:
i.
CH3C=OCH3 acetone
ii.
C6H5C=OCH3 acetophenone
benzophenone
iii.
C6H5C=OC6H5
B.
Properties
1.
Both C and O in C=O are sp2-hybridized
2.
Are pretty polar (RCHO have μ . 2.5 D)
3.
Thermodynamic stability: ketones > aldehydes
II.
Preparations of aldehydes and ketones
A.
Methods from previous chapters
1.
Ozonolysis of alkenes
R
R
R
1
H
2.
2
R
1. O3
2. Zn, H3O+
R
O
R
+
O
1
H
Hydrolysis of alkynes
R
R
O
H2SO4, H2O
HgSO4
155
R
R
2
3.
Oxidations of alcohols
O
RCH2OH
PCC
CH2Cl2
H
R
(Collins reagent also efffects this oxidation)
RR1CHOH
III.
Jones
reagent
O
R
1
R
Reactions of aldehydes and ketones
A.
Key element of chemical reactivity
The C of the C=O bond is electrophilic. It will react directly with a good (charged)
nucleophile to provide a new C–Nu bond.
Nu- + H2C=O 6 Nu–CH2–O-
B.
It will react with a poor (neutral) nucleophile after activation by acid catalysis
Reactions
1.
Reduction of C=O to CH2: Clemmenson or Wolff-Kishner reductions
a.
Wolff-Kishner Reduction: uses H2NNH2, KOH, Δ
b.
Clemmenson Reduction: uses Zn(Hg), HCl, Δ
2.
Reduction of C=O to alcohols
a.
Using H2 / Pt
b.
Using LiAlH4 or, less generally, NaBH4
c.
Using RM like organolithium or Grignard reagents
3.
Addition of H2O to C=O: Hydration
a.
Product is a geminal diol; also called a hydrate
b.
Mechanism is nucleophilic addition to C=O
c.
Is reversible; usually Keq < 1
d.
Is catalyzed by either H+ or -OH
e.
Aldehydes are more reactive than ketones
f.
Example: acid catalysis of the aldehyde chloral + H2O 6 chloral
hydrate:
156
.. ..
O
H
+
H
CCl3
+
H
O
H
O
H
+
H
H
CCl3
H
O
H
CCl3
H O
O
H O
+
+
H
..
.O
.
H
H
CCl3
+ H+
H
4.
Addition of two ROH to C=O: Acetal formation
a.
Product is a geminal diether, called an acetal
b.
Mechanism is nucleophilic addition to C=O followed by an SN1 ether
synthesis
c.
Is reversible; usually H2O is removed to drive the reaction is
completion
d.
Is catalyzed by H+
e.
Aldehydes are more reactive than ketones
f.
Acetals serve as "masked" C=O groups; can be hydrolyzed back to
C=O using H2O + H+, just like any ether
g.
Example: acetone + 2 CH3CH2OH 6 diethyl acetal of acetone:
157
.. ..
O
H3C
+
+
CH3
O
h3C
H+
H3C
H
H
CH3
+
H
..
.O
.
.. H
.. O
H3C
CH3
O
O
O
+
+ H+
CH3
H
H
H3C
O
+
O
H
H
H3C
CH3
O
H
H3C
O
5.
.. O
..
+
CH3
+
+
+ H3O+
O
O
H3C
CH3
O
CH3
+ H+
Addition of H–CN to C=O: Cyanohydrin formation
a.
Mechanism is essentially the same as H+-catalyzed hydration
b.
Example: methyl ethyl ketone + HCN 6 cyanohydrin of methyl ethyl
ketone:
CH3C(=O)CH2CH3 + H+ -CN 6 CH3C(OH)(CN)CH2CH3
6.
Addition of 1E amines to C=O: Formation of imines
a.
Product is a C=N containing compound, called an imine
b.
Mechanism is a nucleophilic addition of RNH2 to C=O followed by
C=N formation by E1 elimination of H2O
c.
Usually is H+-catalyzed
158
d.
Different classes of RNH2 provide different classes of imines,
illustrated using acetone here:
i.
H2N–OH + (CH3)2C=O 6 (CH3)2C=NOH
an oxime
ii.
H2N–NH2 + (CH3)2C=O 6 (CH3)2C=NNH2
a hydrazone
iii.
H2N–NRR1 + (CH3)2C=O 6 (CH3)2C=NNRR1
a dialkylhydrazone
H2N–NHC(=O)NH2 +(CH3)2C=O 6
(CH3)2C=NNHC(=O)NH2
a semicarbazone
Example:
benzaldehyde + CH3CH2NH2 6 ethyl imine of
benzaldehyde using acid catalysis:
iv.
e.
. . ..
O
+
O
H
+
H
H
.. .
H O.
N
H
.. . .
O
+
+
H
N
H ..
H
H
H H
N
H O
+
+
H
N..
H
+
N
N
H
+
H
H
+
H
H
H
H
H
159
O
H
+
H
7.
Addition of 2E amines to C=O: Formation of enamines
a.
Mechanism is a nucleophilic addition of RR'NH2 to C=O followed by
C=C formation by E1 elimination of H2O
b.
Usually is H+-catalyzed
c.
Example using cyclohexanone and diethyl amine:
. . ..
O
+
H
+
H
.. .
H O.
N
O
H
+
N
H ..
+
H
H
H O
+
N
+
N
H
N
H2O + H+ +
8.
The Wittig Reaction: conversion of C=O into C=C
a.
Forms alkenes from an aldehyde or ketone and an ylide
b.
Ylide formation: Prepare according to a two step process:
i.
Make a phosphonium salt:
RR'CHBr + :P(C6H5)3 6 RR'CH–P+(C6H5)3 Brii.
Make the ylide:
RR'CH–P+(C6H5)3 Br- + C4H9Li 6 RR'C-–P+(C6H5)3 + LiBr + C4H10
c.
d.
Mechanism is somewhat unusual; an intermediate betaine is formed
Example: synthesis of a trisubstituted alkene:
160
+
P(C6H5)3
O
O
+
P(C6H5)3
+
-
P(C6H5)3
O
+
9.
O P(C6H5)3
Oxidations of aldehydes to give carboxylic acids
a.
Standard reagents can be used:
i.
Jones reagent
ii.
KMnO4, -OH, Δ
b.
A special reagent that is selective for oxidation of aldehydes to
carboxylic acids and does not oxidize alcohols is Tollens reagent
i.
AgO in aqueous base; dilute acid is added after to isolate the
carboxylic acid product
ii.
Example:
(CH3)2CHCH2CHO + AgO 6 (CH3)2CHCH2CO2H + Ag
IV.
Spectroscopic properties
A.
IR
1.
C=O stretch 1705 - 1750 cm-1, usually the strongest absorption in the
spectrum
2.
Aldehydes have a Fermi overtone bands at 2720 and 2820 cm-1; ketones do
not
1
B.
H NMR
1.
RCHO appears at δ 9.0 - 10.0
2.
H on a C α to the C=O group will appear at δ 2.1 - 2.4
13
C.
C NMR
1.
Characteristic, usually not very intense resonance at δ 190 -210.
161
162
1.
Provide the major product that is produced with the compounds below are subjected to the
stated reaction conditions, including stereochemistry when appropriate. If there is no
reaction, indicate so by writing NR.
a.
Br
HO
O
H+
+
HO
b.
O
O
+
H2NNHCNH2
c.
OH
1. H2CrO4, H2O, acetone
Br
2. 2 CH3CH2OH, H+, ∆
d.
O
O
H
5% aq. HCl
25 EC
O
e.
O
Li
1.
CH3O
, ether
2. H3O+
163
2.
Prepare the following compounds from the starting materials given and any other reagents
that you require:
a.
b.
from cyclohexane and (C6H5)3P
Br
from allyl alcohol and any other reagents you require.
OH
164
c.
O
d.
from HC/CH and any other reagents you require.
From cyclopentane and any other organic compounds of 3
carbons or less.
O
165
3.
Compounds known as nitrones are formed when N-substituted derivatives of hydroxylamine
react with aldehydes and ketones:
H
O
N
+
OH
N
+
O
a. Write a clear, reasonable mechanism for this reaction.
b. Will the (E)- or the (Z)-nitrone be formed as the major product? ________________
166
4.
Citral, C10H16O, is a natural product present in lemongrass, which gives it its distinctive
citrus odor and tea made from lemongrass their distinctive flavor. It has two possible E,Z
isomers, has the selected IR and NMR properties reported below and undergoes the
following chemical reactions:
C10H16O2
C
O
Jones
reagent
+
O
OH
HO
1. KMnO4
2.
Citral
C10H16O
H3O+
H2NOH
O
C10H17ON
B
IR: 1710, 820, 810 cm-1
+
NMR: d 10, s, 1H
5.1, s, 1H
O
OH
O
a. Provide chemical structures for citral, compound A, and compound B.
167
5.
A naïve graduate student (who for our purposes will remain nameless) set out to prepare the
compound (C6H5)2CHOH by adding C6H5MgBr to benzaldehyde. To insure that the
chemical yield would be high, our dedicated student prepared one mole of the Grignard
reagent, added two moles of benzaldehyde, and, after working up the reaction, was delighted
to obtain a good yield of a crystalline product. Unfortunately, the product that had been
formed was benzophenone! On closer examination of the reaction, an equimolar amount of
C6H5CH2OH also was found to have formed. Provide our bewildered friend with reasonable
mechanistic interpretation of why these products form.
168
6.
An alternative to Clemmenson and Wolff-Kishner reductions of ketones is a process called
dithioacetalization–desulfurization. It is illustrated below using the ketone cyclohexanone:
O
S
+ HSCH2CH2SH
S
H+
+ H2O
H2
Raney Ni
A
The first step of the reaction sequence is analogous to acetal formation. The ketone is
reacted with dithioethanol (HSCH2CH2SH) using a catalytic amount of acid to provide a
dithioacetal, A. Provide a clear, reasonable, detailed mechanism that accounts for the
synthesis of A from cyclohexanone.
169
7.
Formaldehyde, H2C=O, actually is a highly unstable gas that cannot be stored. It readily
undergoes a spontaneous, exothermic reaction upon standing to provide a compound called
1,3,5-trioxane. 1,3,5-Trioxane is a stable, crystalline solid, mp 61-62EC, of molecular
formula C3H6O3. It has an NMR spectrum that consists of a single resonance at δ 5.4 ppm;
its IR spectrum shows no significant absorptions outside of the fingerprint region other than
C–H stretching immediately below 3000 cm-1.
a. Draw the structure of 1,3,5-trioxane.
b. Provide a reasonable, clear, detailed mechanism indicating how formaldehyde is
transformed into 1,3,5-trioxane.
170
8.
Provide a clear, detailed, reasonable mechanism for the following reaction:
O
OCH3
H
Cl
CH3ONa
CH3OH
171
OCH3
OH
9.
Allylic alcohols are found to be oxidized to ketones when treated with Br2, light, and a base
such as sodium carbonate:
OH
O
+ Br2
NaCO 3
light
Provide
a clear, detailed, reasonable mechanism for the reaction.
172
10.
Will the following reaction proceed if a stoichiometric amount instead of a catalytic amount
of acid is used? Provide a mechanistic reason for your answer.
NCH3
O
+ CH3NH2
H2SO4
toluene
173
+ H2O
11.
Bombykol is the sex pheromone of the silkworm moth. Provide structures for compounds
A through G and for Bombykol when it is prepared by the following route:
1-pentyne + n-C4H9MgBr ))))Q™ A C5H7MgBr
))))Q™ B C6H10O
A + formaldehyde
B + PBr3
))))Q™ C
C + (C6H5)3P
))))Q™
D C24H24BrP
D + n-C4H9Li
))))Q™
E
C6H9Br
C24H23P
E + HC(=O)(CH2)8CO2C2H5 ))))Q™
F + H2
G + LiAlH4
Lindlar
))))Q™
catalyst
1. ether
))))Q™
2. H2O
G
F
C18H30O2
C18H32O2
Bombykol
C16H30O
174
(Note: Wittig reagents don’t
react with esters)
12.
When dimethoxyacetophenone is reacted with lithium aluminum hydride, compound A is
produced. Compound A in turn is found to undergo unusual reactions with acids and bases.
When reacted with dilute, aqueous HCl, A provides product C, which exhibits no C=O
stretch in its IR spectrum. When A is reacted with the strong base lithium diisopropyl amide,
product B is isolated; it has neither C=O or O–H stretches in its IR spectrum. Provide
structures for A, B, and C:
N
O
OCH3
OCH3
1. LiAlH4
2. H2O
B
C9H10O2
NMR: δ 7.1 (s, 5H);
5.6 (d, 1H); 4.4 (d, 1H);
3.9 (s, 3H)
Li
A
C10H14O3
IR: 3550 cm-1
aq.
HCl
175
C
C16H16O4
IR: 3550 cm-1
NMR: δ 7.1 (s, 10H); 5.6 (d, 2H);
4.4 (d, 2H); 3.3 (s, 2H)
13.
Identify two different ways to prepare alcohol Z using a Grignard reagent
and an aldehyde or a ketone by drawing a clear chemical reaction for each
way below.
HO
Z
176
177