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Chemistry 212
Clark College
Aldehydes and Ketones
Aldehydes and ketones begin our foray into carbonyl compounds, and reactions that the carbonyl group
can undergo. We will begin our discussion by considering the bonding and structure of a carbonyl
group. After reviewing the spectroscopy and nomenclature of aldehydes and ketones, we will look at
nucleophilic reactions of the carbonyl group.
Bonding and Structure
Both the carbon and oxygen are sp2-hybridized. The lone
pairs on oxygen are situated in hybrid orbitals. The pi bond
forms between the unhybridized p orbitals on the C and O.
C O
The dipole between the carbon and oxygen sets up nucleophilic attack on the partially-positively
charged carbon atom. This attack is not blocked by steric hinderance, since the carbonyl carbon has a
trigonal planar geometry – nucleophiles can easily attack the empty π* (pi anti-bonding) orbital that is
above and below the plane of the molecule.
Nomenclature
The nomenclature of an aldehyde is very straight-forward. The carbonyl carbon is always the first
carbon in the chain. From the parent hydrocarbon name, the final –e is dropped an –al is added.
O
H
4-methylpentanal
3-hexynal
H
O
For ketones, the carbonyl carbon should have the lowest number possible on the chain (see your text
for a list of functional group prioritizing). From the parent hydrocarbon, drop the –e and add –one.
Include a number to indicate the position of the ketone. If both a ketone and an aldehyde are present in
a molecule, the aldehyde takes priority and sets the numbering. The ketone is named as an “oxo”
group, and numbered like any other side group.
Br
O
O
H
O
O
5-bromo-3-methyl-2-hexanone
Z-4-methyl-4-hexen-2-one
3,6-dimethyl-5-oxoheptanal
Spectroscopy Review
NMR
O
C
Aldehyde C-H: ! = 9.5 - 10.1 ppm, always a singlet, doesn't cause splitting
H
H
Aldehydes and Ketones, " C-H: ! = 2.0 - 2.6 ppm
IR
The key peak to look for in the IR is the carbonyl peak, which is a very strong, very sharp peak around
1700 cm-1. For aldehydes only, the aldehyde C-H shows up at two different locations in the spectrum,
at 2700 cm-1 and 2900 cm-1.
Reactions of Aldehydes and Ketones
The polarity of the carbonyl group drives the chemistry of aldehydes and ketones. The partiallynegative oxygen is a nucleophile/Lewis base itself, and often seeks electrophiles, namely protons. The
partially-positive carbon is a Lewis acid, and attracts nucleophiles. The general mechanism of all
Aldehydes and Ketones Notes
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Chemistry 212
Clark College
nucleophilic addition reactions to carbonyls involves attack at the carbonyl carbon, and the “opening” of
the pi bond, forming a tetrahedral intermediate. This tetrahedral intermediate then typically goes
through a series of charge-balancing steps to form a neutral molecule.
O
O
Nuc
proton transfers and eliminations
to reach a stable product.
Nuc
Tetrahedral intermediate
As we proceed through the reactions, we need to pay attention to details in the mechanisms. Charge
conservation, reversible (equilibrium) reactions, and leaving group ability will all play a part in
determining the ultimate product of the reaction. Nucelophilic reactions themselves fall into 4 main
categories:
1. Strong, anionic carbon nucleophiles: Grignard and organolithium reagents, alkynyl reagents, CN, and Wittig reagents.
2. Strong, anionic hydride (H-) nucelophiles: lithium aluminum hydride (LiAlH4) and sodium
borohydride (NaBH4).
3. Strong, neutral nitrogen nucleophiles: ammonia, 1° amines and 2° amines.
4. Weak, neutral oxygen nucleophiles: water and alcohols.
Carbon nucleophiles
We will first review reactions with familiar carbon nucelophiles, such as Grignard reagents, terminal
alkyne salts and cyanide. All three of these reagents react in the same fashion, resulting to form the
same pattern of products  alcohols! Note that Gilman reagents have not been included in the list –
although these reagents have been known to react with aldehydes and ketones, the lowered reactivity
of Gilman reagents results in slow, low-yield reactions with aldehydes and ketones and will not be
considered.
Grignard Reagents
Reactions of aldehydes and ketones with Grignard reagents result in alcohols. The carbonyl compound
is first reacted with the Grignard, and followed with an acidic work-up.
O
formaldehyde
H
H
H
H
1) CH3MgBr
2) H3O+
H
CH3
OH
R
R'
1) CH3MgBr
2) H3O+
H
CH3
OH
R
R'
CH3
O
an aldehyde
R
O
a ketone
R
OH
1) CH3MgBr
2) H3O+
1° alcohol
2° alcohol
3° alcohol
The mechanism:
O
MgBr
H
O MgBr
H
OH
H+
H
Tetrahedral intermediate
Aldehydes and Ketones Notes
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Chemistry 212
Clark College
Examples:
O
OH
CH3
MgBr
1)
+
2) H3O
CH3
O
H 1) EtMgBr
2) H3O+
OH
Other carbon nucleophiles
Other carbon nucleophiles, such as terminal alkyne salts and the cyanide ion, react in the same fashion
as Grignard reagents, and follow the same mechanism. The following examples show the types of
reactions that can be formed with these carbon nucleophiles.
OH
O
1)
2) H3O+
O
Na
1) NaCN
2) H3O+
OH
CN
The (Georg) Wittig Reagent
Although other carbon nucelophiles create a new carbon-carbon single bond, Wittig reagents result in a
product that replaces the carbonyl with a C=C double bond. The reaction combines an aldehyde or a
ketone with a phosphonium ylide- a compound with a negatively-charged carbon bonded to a
positively-charged phosphorus atom. The result is the replacement of the carbonyl oxygen with the
carbon group on the ylide. We will learn how to prepare this Wittig reagent (the ylide), and how it reacts
with the aldehyde or ketone.
Ylide Preparation
A ylide can be prepared from any sp3-hybridized, 1° or 2° alkyl halide. The halogen is displaced with
triphenylphosphine (PPh3) in an SN2 reaction. Following the substitution, a hydrogen on the same
carbon is removed with butyl lithium, and the Wittig reagent is formed.
H
R C Br
R'
PPh3
H
R C PPh3
R'
Li
(BuLi)
R C PPh3
R'
The Wittig Reagent
A phosphonium ylide
Wittig Reaction
Once the ylide has been prepared, it is reacted with an aldehyde or ketone to form an alkene. Although
both alkene isomers can be formed, the major product is the E isomer, which is more stable (due to
steric hinderance).
General Reaction:
R C PPh3
R'
O
H
R
R'
H
O
Ph P Ph
Ph
The mechanism begins in the same way as any other carbon nucleophile – the negative carbon attacks
the carbonyl carbon, opening up the pi bond. From there, a series of electron-pair transfers between
the oxygen and the phosphorus creates the alkene and the triphenylphosphine oxide by-product.
Aldehydes and Ketones Notes
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Chemistry 212
Clark College
O
O PPh3
O
PPh3
H
H
PPh3
H
H
An oxyphosphatane
major product
Z isomer
Some examples:
1) PPh3
2) BuLi
Br
PPh3
O
3)
O
Hydride (H-) nucleophiles
Aldehydes and ketones can be reduced to alcohols when reacted with a hydride reagent, such as
sodium borohydride (NaBH4) or lithium aluminum hydride (LiAlH4). These reagents provide hydride
ions – H-, which react similarly to carbon nucelophiles. Hydride reagents selectively reduce carbonyl
groups, and leave alkenes untouched, as the hydride reagent seeks an electrophile, and there is no
electrophile in an alkene!
Examples:
H
O
H
1) LiAlH4
2) H2O
H
OH
O
The hydrogen attached to the carbon comes
from the hydride reagent. The H on the
alcohol comes from the aqueous work-up.
OH
1) NaBH4
2) H2O
Nitrogen Nucleophiles
Nitrogen-based nucleophiles react readily with carbonyl compounds. Although they are not as strong
as the anionic carbon and hydride nucleophiles, the basicity of amines makes them reasonable
nucleophiles. Mechanistically, the reactions with nitrogen nucleophiles begins with the nucleophile
attacking the carbonyl carbon – just like the other nucleophiles. However, in the presence of an acid
catalyst, the tetrahedral alcohol product collapses to form new, double-bond containing products. The
type of product depends on the starting amine nucleophile.
1° Amines and ammonia
When a 1° amine reacts with an aldehyde or ketone, in the presence of an acid catalyst, the product
formed is an imine – a molecule where the oxygen on the carbonyl is replaced with the nitrogen.
R
O
H
H+
N
H
H
(cat)
N
(+ H2O)
H
An imine
Aldehydes and Ketones Notes
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Chemistry 212
Clark College
As you can see, water is a byproduct of the reaction. To form water, the oxygen comes off of the
carbonyl and both hydrogens come from the nitrogen. When we consider the mechanism for this
reaction, we need to carefully consider the following factors:
1. Charge balance and conservation: Since the reaction takes place in acidic solution, we cannot
have isolated negative charges. Molecules can either have positive charges or be net neutral –
a zwitterion can be formed. A zwitterion is molecule that has both positive and negative
charges.
2. Reversible reactions: Since most of the steps involve the breakage/formation of polar bonds,
most of the reactions are reversible, so equilibrium arrows are used.
3. Leaving group ability – we need to ensure that groups are appropriately protonated to form good
leaving groups.
With those factors in mind, let’s look at the mechanism for imine formation.
O
O
H
N
H
H+
Formation of a good leaving group.
H+
OH
OH2
OH
H
H
N
N
HH
HH
Series of proton transfers watch the overall charge!
H
Nucleophile attacks
the carbonyl, pi
bond opens up.
N
H
N
H
H
H2O
H
N
The imine!
H
H
N
N
H
H
H
A resonance-stabilized
carbocation.
Examples:
H
O
NH2
NH3
H+
H+
N
O
N
2° Amines
When a secondary amine reacts with an aldehyde or ketone, there is only one hydrogen that can come
off of the nitrogen to form water. The second hydrogen comes off of a neighboring carbon to the
carbonyl – the α-carbon – to form an enamine product. When the alkene forms, the Zaitsev alkene
when it can. Note that if there is no α–carbon, no enamine can form and the reaction does not occur.
R
O
There must be at least
one ! - hydrogen
H
H
H+
N
H
R'
(cat)
R
N
R'
(+ H2O)
H
An enamine
The mechanism for enamine formation is identical to imine formation until the last step. The final step
is still a deprotonation to form a double bond, however the proton comes from the α–carbon.
Aldehydes and Ketones Notes
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Chemistry 212
Clark College
O
O
N
H
OH
H
N
H
H
H+
OH
H
N
H
H2O
N
OH2
H
N
N
N
N
H
H
H
H
H
H2O
Examples:
O
N
H
N
The Zaitsev alkene is preferred.
H+
N
H
H
H
O
N
H+
Oxygen Nucleophiles
Oxygen nucleophiles are the weakest nucleophiles in the list (H2O is less basic than NH3). Therefore,
they do not readily react with aldehydes and ketones without assistance. This assistance comes in the
form of the acid catalyst, which is used to enhance the electrophilicity of the carbonyl carbon, making it
more attractive for a nucleophile to attack! In general, these reactions are performed in aqueous or
alcoholic solvents, setting up solvolysis conditions where the solvent is also the nucleophile.
O
General reaction:
ROH
H+
RO OH
1 equiv. ROH
A hemiacetal
ROH
H+
RO OR
2 equiv. ROH
An acetal
Equilibrium arrows are used as the reaction is completely reversible! Product isolation is difficult, and
the reaction is typically controlled by Le Chatelier’s principle and experimental conditions.
Mechanistically, acetal formation differs slightly than the other nucleophilic additions to carbonyls in that
the carbonyl group must be “primed” for reaction, to assist the weak oxygen nucleophile. After this
preliminary protonation step, the mechanism continue similarly to the nitrogen-based mechanism,
paying attention to charge conservation and balance, and to leaving group ability.
Aldehydes and Ketones Notes
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Chemistry 212
O
Clark College
H
O
H+
OH
H
HO OCH3
HOCH3
+
HO OCH3 H
Formation of a
good leaving
group!
Formation of a resonance-stabilized
cation, and a better electrophile!
H
H3CO OCH3
H3CO OCH3
CH3OH
OCH3
H2O OCH3
This cation can be stabilized
through resonance as well.
Examples:
OH
H+
O
O
A cyclic hemiacetal
OH
O
EtO OEt
EtOH
H+
Acetals as Protecting Groups
Because of the reversibility of the reaction, an acetal can be used as a protecting group for a carbonyl,
when competing reactions are planned for synthesis. When used in the fashion, 1,2-ethanediol
(ethylene glycol) is used as the alcohol and a cyclic acetal is formed. The acetal is put on in acidic
solution, and is then removed in acidic conditions.
O
OH
HO
O
O
H3O+
O
H+
A protected ketone!
This protecting group is effective against nucleophilic attack at the carbonyl carbon, which covers most
basic/nucleophilic reactions. An example:
O
OH
HO
Br
H+
O
O
Br
Mg0
Ether
O
O
O
O
1)
2) H3O+
MgBr
Without the protecting group, the formed Grignard reagent would attack the ketone of
HO
another molecule. With the protecting group, the Grignard is free to react only with the
epoxide. The acid work-up of the epoxide will also function to deprotect the ketone.
Aldehydes and Ketones Notes
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