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Aldehydes and Ketones
Organic Chemistry, Third Edition
•
•
Aldehydes and ketones contain a carbonyl group.
An aldehyde contains at least one H atom bonded to the
carbonyl carbon, whereas the ketone has two alkyl or aryl
groups bonded to it.
•
Two structural features determine the chemistry and
properties of aldehydes and ketones.
Janice Gorzynski Smith
University of Hawai’i
Chapter 20+21
Lecture Outline
Prepared by Layne A. Morsch
The University of Illinois - Springfield
Adapted for 2302266/272 by Tirayut Vilaivan
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
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Nomenclature of Aldehydes
•
•
•
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Common Names of Aldehydes
If the CHO is bonded to a chain of carbons, find the longest
chain containing the CHO group, and change the –e ending
of the parent alkane to the suffix –al.
If the CHO group is bonded to a ring, name the ring and add
the suffix –carbaldehyde.
Number the chain or ring to put the CHO group at C1, but
omit this number from the name.
Apply all the other usual rules of nomenclature.
•
•
Like carboxylic acids, many simple aldehydes have common
names that are widely used.
A common name for an aldehyde is formed by taking the
common parent name and adding the suffix –aldehyde.
Figure 21.1
•
3
Greek letters are used to designate the location of substituents
in common names.
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Nomenclature of Ketones
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•
•
•
•
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Common Names of Ketones
In the IUPAC system, all ketones are identified by the suffix
“one”.
Find the longest continuous chain containing the carbonyl
group, and change the –e ending of the parent alkane to the
suffix -one.
Number the carbon chain to give the carbonyl carbon the
lowest number.
Apply all of the usual rules of nomenclature.
With cyclic ketones, numbering always begins at the
carbonyl carbon, but the “1” is usually omitted from the
name.
The ring is then numbered clockwise or counterclockwise to
give the first substituent the lower number.
•
Most common names for ketones are formed by naming
both alkyl groups on the carbonyl carbon, arranging them
alphabetically, and adding the word “ketone”.
•
Three widely used common names for some simple ketones
do not follow this convention:
5
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Naming Ketones and Acyl Groups
•
•
Sometimes, acyl groups (RCO-, ArCO-) must be named as
substituents.
The three most common acyl groups are shown below:
•
•
7
Aldehydes and ketones have strong dipoles, but lack
hydrogen bonding, resulting in boiling points between
nonpolar molecules and alcohols of similar size.
Water solubility mimics that of alcohols and ethers of
similar size.
8
Spectroscopic Properties—IR Spectra
• Aldehydes and ketones exhibit a strong peak at ~1700 cm–1
due to the C=O.
• The sp2 hybridized C–H bond of an aldehyde shows two weak
bands at 2700-2775 and 2820-2900 cm−1.
Figure 21.3
The IR spectrum of
propanal, CH3CH2CHO
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IR—Conjugation Effects
IR—Carbonyl Absorption
• Most aldehydes have a carbonyl peak around 1730 cm−1,
whereas for ketones, it is typically around 1715 cm−1.
• Ring size affects the carbonyl absorption in a predictable
manner.
• Conjugation leads to a somewhat weaker C=O bond, thus
shifting the carbonyl absorption to longer wavelengths.
Figure 21.4
The effect of conjugation on
the carbonyl absorption
in an IR spectrum
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1H
and 13C NMR absorptions
1H
• The sp2 hybridized C–H proton of an aldehyde is highly
deshielded and absorbs far downfield at 9–10 ppm.
• Splitting occurs with protons on the α carbon, but the
coupling constant is often very small (J = 1–3 Hz).
• Protons on the α carbon to the carbonyl group absorb at
2–2.5 ppm.
• Methyl ketones, for example, give a characteristic singlet at
~2.1 ppm.
• In a 13C NMR spectrum, the carbonyl carbon is highly
deshielded, appearing in the 190–215 ppm region.
13
13C
NMR of Propanal
Figure 21.5
3H, t
1H, t
2H, d
• There are three signals due to the three different kinds of
Hydrogens, labeled Ha, Hb, and Hc.
• The deshielded CHO proton occurs downfield at 9.8 ppm.
• The Hc signal is split into a triplet by the adjacent CH2 group,
singlet 14
but the coupling constant is small.
Interesting Aldehydes and Ketones—Formaldehyde
NMR absorptions
• There are three signals due to the three different kinds of
carbons, labeled Ca, Cb, and Cc.
• The deshielded carbonyl carbon absorbs downfield at
203 ppm.
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• Billions of pounds of formaldehyde are produced annually by
the oxidation of methanol.
• It is sold as a 37% aqueous solution called formalin which is
used as a disinfectant, antiseptic, and preservative for
biological specimens.
• It is a product of incomplete combustion of coal, and is partly
responsible for the irritation caused by smoggy air.
• It is a known carcinogen, and its released from products such
as furniture made from pressed wood (contains urea16
formaldehyde resin) must be strictly controlled.
Interesting Aldehydes and Ketones—Acetone
Natural Aldehydes and Ketones with Strong Odors
Figure 21.6
• Acetone is an industrial solvent.
• It is also produced in vivo during breakdown of fatty acids.
• Diabetics often have unusually high levels of acetone in their
blood streams.
• Thus, its characteristic odor can be detected on the breath of
diabetic patients when the disease is poorly controlled.
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Steroids with Carbonyls
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Preparation of Aldehydes
Cr(VI) reagent เชน
• Many steroid hormones contain a carbonyl along with other
functional groups.
• Cortisone and prednisone are two anti-inflammatory steroids
with closely related structures.
• Cortisone is secreted by the body’s adrenal gland, whereas
prednisone is the synthetic analogue and is used as an antiinflammatory for asthma and arthritis.
! ก#
ก$# %&
' ( )* +
Why can’t we use LiAlH4?
This is analogous to anti-Markovnikov addition of water to alkenes.
• By formylation reaction
Q: จงแสดงตําแหนงของหมูคารบอนิลใน cortisone และ prednisone
O
O
+
19
H
NMe2
R
Li
H
R
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Common Oxidizing Agents
Selective Reduction of Acid Chlorides
• Primary alcohols are oxidized to aldehydes by
several reagents.
• The most frequently employed reagents are PCC
and PDC, although other Cr(VI) reagents like CrO3 or
K2Cr2O7+H2SO4 can be used.
O
O
N
N
O Cr Cl
H
H
O
O
N
O Cr O Cr O
O
Nucleophiles attack
at electron deficient
C in C=O.
H
O
PDC: pyridinium dichromate
O
PCC: Pyridinium chlorochromate
Oxalyl chloride
Cl
• Another commonly
Cl
H
Et N
O
used method is called R OH
O
Swern oxidation. No
-78 C
DMSO
S
CH
H C
over-oxidation is possible.
• KMnO4 is not useful because of over-oxidation to
carboxylic acids.
• Secondary alcohols give ketones and tertiary
alcohols do not undergo oxidation.
3
R
o
3
O
3
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Selective Reduction of Esters
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Preparation of Ketones
Lewis acids attack
at electron rich O
in C=O.
, -.
Nitriles can also be reduced to give imines, which upon
hydrolysis gives aldehydes.
23
!% Cu reagent $34 5
6
7)4 )8
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Ketones from Hydration of Alkynes
Ketones from Carboxylic Acid Derivatives
• Gives Markovnikov products (cf hydroboration/oxidation).
• The conditions require Hg2+ and an acid (usually H2SO4).
•
•
Carboxylic derivatives react with organometallic reagents to give
ketones, which may react further reaction to give alcohols.
In some cases, it is possible to stop after the first addition by:
•
Using a combination of highly reactive acid chlorides and very
selective cuprate reagents R2CuLi.
•
Using a substrate (RCOOH, RCN or Weinreb’s amide) that can form
stable products (usually by forming a chelate or stable anions), which
may be subsequently hydrolyzed by aqueous work-up.
• The initially formed vinyl alcohols (enols) rearrange readily to
the (more stable) ketones.
Nitriles:
• Terminal alkynes give methyl ketones as the sole products.
Weinreb’s
amides:
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O
R
R'
Li
Li
N
OMe
R
Me
One exception: Hydration of acetylene gives acetaldehyde.
Solved Problem : Synthesize 5-nonanone using
1-butanol as your only starting material
O
OMe
R'
N
H3O
O
+
H2O
R
R'
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Me
Carbonyl Compounds from Oxidative
Cleavage of Alkenes
• Aldehydes and ketones are also both obtained as products of the
oxidative cleavage of alkenes.
• This can be done by ozonolysis followed by reductive work-up
(using Zn or DMS as the reducing agent).
• Alkenes can be cleaved indirectly by dihydroxylation (to give 1,2diol) and then oxidatively cleaved with sodium metaperiodate,
which selectively cleave 1,2-diol to yield two molecules of
aldehydes.
R'
R
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aq KMnO4
or OsO4
HO
R
R'
OH
NaIO4
O
R'
H + H
R
O
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Reactions of Aldehydes and Ketones
Reactivities of Carbonyl Compounds
Two broad classes of compounds contain the carbonyl group:
•
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Aldehydes and ketones react with nucleophiles.
As the number of R groups around the carbonyl carbon
increases, the reactivity of the carbonyl compound
decreases, resulting in the following order of reactivity:
[1] Compounds that have only carbon and hydrogen atoms
bonded to the carbonyl. (“carbonyl compounds”)
[2] Compounds that contain an electronegative atom bonded to
the carbonyl. (“carboxylic acid derivatives”)
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General Reactions of Carbonyl Compounds
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General Reactions of Aldehydes and Ketones
[1] Reaction at the carbonyl carbon—the elements of
H and Nu are added to the carbonyl group.
• Carbonyl carbons are electrophilic and react with nucleophiles.
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[2] Reaction at the α carbon.
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Reactivity to Nucleophilic Addition
Addition of Nucleophiles to C=O
• The net result is that the π bond is broken, two new σ bonds
are formed, and the elements of H and Nu are added across
the π bond.
• Aldehydes are more reactive than ketones towards
nucleophilic attack for both steric and electronic reasons.
• Aldehydes and ketones react with nucleophiles to form
addition products by a two-step process: nucleophilic attack
and protonation.
• Under basic conditions, nucleophilic attack precedes
protonation.
• This mechanism occurs with negatively charged or strong
neutral nucleophiles. ยกตัวอยาง?
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Reduction of Aldehydes and Ketones
• The net result of adding H:− (from NaBH4 or LiAlH4) and H+
(from H2O) is the addition of the elements of H2 to the carbonyl
π bond.
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• Under acidic conditions, protonation precedes nucleophilic
attack as shown above.
• With some neutral nucleophiles, nucleophilic addition only
occurs if an acid is present to activate the carbonyl by
protonation.
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Seleceted Nucleophilic Addition to C=O
Metal Hydride Reduction of Carbonyls
• The most useful reagents for reducing aldehydes and ketones
are the metal hydride reagents.
Figure 21.7
Reduction
Addition of
organometallics
Cyanohydrin
formation
Strong
nucleopiles:
No catalysts
are required
Wittig reaction
• Treating an aldehyde or ketone with NaBH4 or LiAlH4, followed
by H2O or some other proton sources affords an alcohol.
Weak
nucleophiles:
Require an
acid catalyst
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Metal Hydride Reduction of Carbonyls
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Organometallic Reagents as Sources of R¯
• Li, Mg, and Cu are the most common organometallic metals.
• Other synthetically useful organometallic reagents are Sn, Si,
Zn, Al, Ti (Cd, Tl and Hg are less popular due to their toxicity).
• General structures of common organometallic reagents are as
Reactivity
shown:
• The net result of adding H:− (from NaBH4 or LiAlH4) and H+
(from H2O) is the addition of the elements of H2 to the carbonyl
π bond.
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Selectivity
40
Preparation of Organolithium Compounds
• Organolithium and Grignard reagents are typically prepared by
reaction of an alkyl halide with the corresponding metal.
Ethereal
solvents like
Et2O, THF or
dyglyme are
essential!
Addition of Organometallics to Aldehydes
and Ketones
• Treatment of an aldehyde or ketone with either an
organolithium or Grignard reagent followed by water forms an
alcohol with a new carbon–carbon bond.
• This reaction is an addition because the elements of R’’ and H
are added across the π bond.
• Metal acetylides can be prepared by direct deprotonation of the
relatively acidic sp-hybridized C-H.
• Organometallic reagents are highly reactive. They react with air and
water as well as protic solvents and other acidic H. All reactions
must be performed in dry solvents under inert atmosphere.
Li + H2O
H
+ LiOH
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Alcohols Formed by Organometallic Addition
• This reaction is used to prepare 1°, 2°, and 3°alco hols.
The reaction always proceeds in two steps. Addition followed by protonation.
But the second protonation step is often missing from the equation as it occur
readily on contact with any acids, including protic solvents like water.
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Retrosynthetic Analysis of Grignard Products
• To determine what carbonyl and Grignard components are
needed to prepare a given compound, follow these two steps:
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Retrosynthetic Analysis of 3-Pentanol
Synthesis of 3-Pentanol
• 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.
• There is often more than one way to synthesize a 2° alcohol
by Grignard addition. Can you think of other ways to
synthesize 3-pentanol starting from a carbonyl compound?
45
Limitations of Organometallic Reagents
• Organometallic reagents cannot carry N–H or O–H groups and the
carbonyl compounds cannot bear such groups because the N–H or
O–H group readily protonates the organometallic reagents.
• In some cases it is possible to employ the reagents in excess, the
OH or NH regenetrates upon protonation in the second step.
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Organometallic Reactions with α,β
βUnsaturated Carbonyl Compounds
• α,β
β-Unsaturated carbonyl compounds are conjugated molecules
containing a carbonyl group and a C=C separated by a single σ
bond.
• Resonance shows that the carbonyl carbon and the β carbon
bear a partial positive charge.
• For similar reasons, other reactive groups like ester, nitriles,
carbonyl (other than the one intended to react), cannot be
present in the organometallic or carbonyl components.
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α,β
β-Unsaturated Carbonyl Compounds
1,2 vs. 1,4-Addition Products
• This means that α,β
β-unsaturated carbonyl compounds can
react with nucleophiles at two different sites.
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Nucleophilic Addition of ¯ CN
Hydrolysis of Cyanohydrins
• Treatment of an aldehyde or ketone with NaCN and a strong
acid such as HCl adds the elements of HCN across the C–O π
bond, forming a cyanohydrin.
• The mechanism involves the usual two steps of nucleophilic
addition—nucleophilic attack followed by protonation.
• Cyanohydrins can be reconverted to carbonyl compounds by
treatment with base.
• This process is just the reverse of the addition of HCN:
deprotonation followed by elimination of ¯ CN.
• The cyano group of a cyanohydrin is readily hydrolyzed to a
carboxy group by heating with aqueous acid.
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H+
52
Cyanohydrins in Nature
Addition of Ylids: Wittig Reaction
• Linamarin and Amygdalin are two naturally occurring
cyanohydrin derivatives.
cassava
• The Wittig reaction uses a carbon nucleophile (ylids, or the
Wittig reagent) to form alkenes—the carbonyl group is
converted to a C=C.
bitter almonds
http://www.channelstv.com/home/2012/10/03/
scientists-develops-new-nigerian-cassava/
• Both compounds are toxic because they are metabolized to
cyanohydrins, which are hydrolyzed to carbonyl compounds and
HCN gas (cf normal nitriles). “cyanogenic glycosides”
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Synthesis of Wittig Reagents
Ylids (Wittig Reagents)
• The Wittig reagent is an organophosphorus reagent.
• A typical Wittig reagent has a phosphorus atom bonded to
three phenyl groups, plus another alkyl group that bears a
negative charge.
• A Wittig reagent is an ylide, a species that contains two
oppositely charged atoms bonded to each other, with both
atoms having octets.
• Phosphorus ylides are also called phosphoranes.
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• Wittig reagents are synthesized by a two-step procedure.
Example
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Mechanism of Wittig Reaction
Use of the Wittig Reaction
• One limitation of the Wittig reaction is that a mixture of
stereoisomers sometimes forms.
• Nevertheless, it is often possible to control the geometry of
the double bond by the choice of the Wittig reagents and
reaction conditions.
• An advantage of the Wittig reaction over elimination methods
used to synthesize alkenes is that the Wittig reaction always
gives a single constitutional isomer (cf the possiblilties of
Saytzeff and Hofmann products formation in 1,2-elimination
reactions such as dehydration of alcohols).
• The Wittig reaction has been used to synthesize many natural
products.
Figure 21.8
A Wittig reaction used to
synthesize β-carotene
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Addition of Amines: Formation of Imines
• Treatment of an aldehyde or a ketone with a 1° amine affords
an imine (also called a Schiff base).
Removal of water drives
the equilibrium forward.
• Imine formation is fastest when the reaction
medium is weakly acidic (pH 4–5).
59
Q: What would be the potential problems at too low or
too high pH?
60
The Key Reaction in the Chemistry of Vision
Formation of Hydrazones
• Aldehydes or ketones react with the reagent 2,4dinitrophenylhydrazine to give a yellow or red hydrazone,
which generally precipitate from the solution.
• This is the basis of 2,4-DNP test for carbonyl compounds.
Figure 21.9
R
NHNH2
H
N
cat H3O+
O
N
R'
+
O2 N
NO2
R
R'
O2 N
2,4-dinitrophenylhydrazine
NO2
2,4-dinitrophenylhydrazone
• Carbohydrates similarly react with phenylhydrazine, but the
reaction is accompanied by oxidation of the C2-OH to form
crystalline compounds called osazones.
CHO
H
H
N
H
OH
PhNHNH2
OH
phenylhydrazine
(as nucleophile)
H
NHPh
PhNHNH2
(as oxidant)
N
O
NHPh
PhNHNH2
(as nucleophile)
H
N
NHPh
N
NHPh
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62
Addition of Amines: Formation of Enamines
• A 2° amine reacts with an aldehyde or ketone to give an
enamine.
• Enamines have a nitrogen atom bonded to a C–C double
bond.
Removal of water drives
the equilibrium forward.
Reactions of Enamines
N
N
iminium ion
+
E
R
R
H2O, H+
N
O
E
E
R2NH
63
• Enamines react with electrophiles, usually at α-C analogously to
64
enols and enolates. Subsequent hydrolysis gives carbonyl derivatives.
Formation of Imines vs. Enamines
Hydrolysis of Imines and Enamines
Figure 21.10
• Because imines and enamines are formed by a reversible set
of reactions, both can be converted back to carbonyl
compounds by hydrolysis, which is catalyzed by mild acids.
• The mechanism of hydrolysis is the exact reverse of the
mechanism written for formation of imines and enamines.
• With a 1o amine, the intermediate iminium ion still has a
proton on the N atom that may be removed to form a C=N.
• With a 2o amine, the intermediate iminium ion has no proton
on the N atom.
• A proton must be removed from an adjacent C–H bond, and
65
this forms a C=C.
Q: Try to write the mechanisms for both reactions.
66
Addition of Water: Hydration Reaction
Factors Affecting Hydrate Stability
• Treatment of a carbonyl compound with H2O in the presence
of an acid or base catalyst adds the elements of H and OH
across the C–O π bond, forming a gem-diol or hydrate.
• Increasing the number of alkyl groups on the carbonyl carbon
decreases the amount of hydrate at equilibrium.
Chloral (2,2,2-trichloroacetaldehyde)
exists almost exclusively in the form
of hydrate - Cl3CCH(OH)2.
67
• Electron-donating groups near the carbonyl carbon stabilize the
carbonyl group, decreasing the amount of the hydrate at
equilibrium.
• Electron-withdrawing groups near the carbonyl carbon destabilize
the carbonyl group, increasing the amount of hydrate at
equilibrium.
68
1H
NMR Spectrum of Aqueous Formaldehyde
Addition of Alcohols: Hemiacetal and Acetal Formations
• Aldehydes and ketones react with one equivalent of alcohol
to form hemiacetals or two equivalents to form acetals.
• The reactions are catalyzed by acids, such as TsOH.
O
R
R"OH, H+
st
R' (1 equivalent)
HO
R
OR"
R'
hemiacetal
R"OH, H+
nd
(2
equivalent)
"RO
OR"
R
R'
acetal
• For intermolecular reactions, the reaction usually proceeds to
acetal rather than stopping at the hemiacetal stage.
TsOH =
Maiwald et al. Anal. Bioanal. Chem. 2003, 375, 1111-1115.
H3C
SO3H
(p-toluenesulfonic acid)
69
Addition of Alcohols—Acetal Formation
• When a diol such as ethylene glycol is used in place of two
equivalents of ROH, a cyclic acetal is formed.
70
Dean-Stark Trap for Removing Water
Figure 21.11
• Like gem-diol formation, the synthesis of acetals is reversible,
and often, the equilibrium favors the reactants.
• In acetal synthesis, since water is formed as a by-product, the
equilibrium can be driven to the right by removing H2O as it is
formed using distillation or other techniques.
• Driving an equilibrium to the right by removing one of the
products is an application of Le Châtelier’s principle.
71
72
Carbohydrates Exist as Cyclic Hemiacetals
Formation of Cyclic Hemiacetals
• Cyclic hemiacetals are formed by intramolecular cyclization
of hydroxy aldehydes.
• Such intramolecular reactions to form five- and six-membered
rings are faster than the corresponding intermolecular
reactions.
• The two reacting functional groups (OH and C=O), are held in
close proximity, increasing the probability of reaction.
• Simple carbohydrates are polyhydroxyaldehydes or polyhydroxyketones. These can form more complex oligomers.
• They generally cyclize to 5- or 6-membered cyclic hemiacetals.
• The hemiacetal in glucose (A) is formed by cyclization between the
aldehyde C=O and the C5-OH to give a 6-membered ring (most
stable).
• Cyclization forms a new stereogenic center—the new OH group
of the hemiacetal can occupy the equatorial or axial position.
73
74
Mechanism: Hemiacetal Formation
Mechanism: Acetal from Hemiacetal
• The mechanism for acetal formation can be divided into two
parts, the first of which is addition of one equivalent of
alcohol to form the hemiacetal.
• The second part of the mechanism involves conversion of the
hemiacetal into the acetal.
75
76
Hydrolysis of Acetals
Acetals as Protecting Groups
• Because conversion of an aldehyde or ketone to an acetal is a
reversible reaction, an acetal can be hydrolyzed to an
aldehyde or ketone by treatment with aqueous acid.
• Since the reaction is also an equilibrium process, it is driven
to the right by using a large excess of water for hydrolysis.
• Acetals are valuable protecting groups for aldehydes and
ketones.
• Suppose we wish to selectively reduce the ester to an alcohol
in compound A, leaving the ketone untouched.
• Because ketones are more readily reduced, methyl-5hydroxyhexanoate is formed instead.
• To solve this problem, we can use a protecting group to block
the more reactive ketone carbonyl.
77
Protection–Deprotection Process
78
Oxidation of Aldehydes
• 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).
• Ketones do not normally undergo this oxidation reaction
(except α-hydroxyketones, which can be readily oxidized).
• The overall process requires three steps.
[1] Protect the interfering functional group—the ketone
carbonyl.
[2] Carry out the desired reaction.
[3] Remove the protecting group.
79
80