Aldehydes and Ketones II. NUCLEOPHILIC
ADDITIONS TO THE CARBONYL GROUP
OBJECTIVES
1. Describe the reactivity of carbonyl group towards the nucleophilic
addition (PAGE : 741)
2. Predict the products of cyanohydrin from synthesis of α-hydroxy acids
and hydrolysis of nitriles (PAGE : 755)
3. Predict the products from the addition of Organometallic Reagents
Grignard and alkyl lithium reagents) to aldehydes and ketones. (PAGE
: 566-568, 776)
4. Predict the products from the addition of water (hydration) to aldehydes
and ketones (PAGE : 746)
5.. Predict the products of acetals and hemiacetal from the addition of
Alcohols and describe the formation of cyclic acetals (PAGE : 748) and
its uses as protecting group. (PAGE : 749)
6. Predict the products from the addition of amines to aldehydes and
ketones which produce Imines from 1o Amines (PAGE : 751), Enamines
from 2o Amines (PAGE : 754), Enamines for Alkylation of Ketones
(PAGE : 755)
7. Predict the products from Wittig Reaction (PAGE : 757-760)
1. Describe the reactivity of carbonyl group towards the
nucleophilic addition (PAGE : 741)
Chapter 16 3
Chapter 16 4
Nucleophilic Addition to the Carbonyl
Groups o Addition of a nucleophile to a carbonyl carbon occurs because
of the d+ charge at the carbon
o Addition of strong nucleophiles such as hydride or Grignard
reagents result in formation of a tetrahedral alkoxide
intermediate H The carbonyl p electrons shift to oxygen to give the alkoxide
H The carbonyl carbon changes from trigonal planar to tetrahedral
Chapter 16 5
6
o acid catalyst is used to facilitate reaction of weak nucleophiles
with carbonyl groups Protonating the carbonyl oxygen enhances the electrophilicity of the carbon
REACTIVITY OF ALDEHYDE AND
KETONE
Chapter 16 7
Chapter 16 8
Relative Reactivity: Aldehydes versus Ketones
o Aldehydes are generally more reactive than ketones The tetrahedral carbon resulting from addition to an aldehyde is less
sterically hindered than the tetrahedral carbon resulting from addition
to a ketone
Aldehyde carbonyl groups are more electron deficient because they
have only one electron-donating group attached to the carbonyl
carbon
2. Predict the products of cyanohydrin from synthesis of
α-hydroxy acids and hydrolysis of nitriles (PAGE :
755)
Chapter 16 9
Chapter 16 10
The Addition of Hydrogen Cyanide (PAGE : 755)
Aldehydes and ketone react with HCN to form a
cyanohydrin
• A catalytic amount of cyanide helps to speed
the reaction
The cyano group can be hydrolyzed or reduced
• Hydrolysis of a cyanohydrin produces an a-
hydroxycarboxylic acid (Sec. 18.8H)
Chapter 16 11
Reduction of a cyanohydrin produces α b-
aminoalcohol
Chapter 16 12
3. Predict the products from the addition of
Organometallic Reagents Grignard and alkyl lithium
reagents) to aldehydes and ketones. (PAGE : 566-
568, 776)
Chapter 16 13
Chapter 12 14
Reaction of Grignard Reagents with Carbonyl Compounds
Nucleophilic attack of Grignard reagents at carbonyl carbons is the
most important reaction of Grignard reagents
Reaction of Grignard reagents with aldehydes and ketones
yields a new carbon-carbon bond and an alcohol
Chapter 16 15
Chapter 12 16
Alcohols from Grignard Reagents
Chapter 12 17
Alkyl Lithium Reagents
Organolithium reagents react similarly to Grignard
reagents
4. . Predict the products from the addition of water
(hydration) to aldehydes and ketones (PAGE : 746)
Chapter 16 18
Nucleophilic Addition of H2O:
Hydration Aldehydes and ketones react with water to yield
1,1-diols (geminal (gem) diols) :the term geminal refers to the relationship between two atoms or functional groups that are attached to the same atom.
Hyrdation is reversible: a gem diol can eliminate water
Base-Catalyzed Addition of Water
Addition of water is catalyzed
by both acid and base
The base-catalyzed hydration
nucleophile is the hydroxide
ion, which is a much stronger
nucleophile than water
Acid-Catalyzed Addition of Water
Protonation of C=O makes
it more electrophilic
5. Predict the products of acetals and hemiacetal from
the addition of Alcohols and describe the formation of
cyclic acetals (PAGE : 748) and its uses as protecting
group. (PAGE : 749)
Chapter 16 22
• the addition of an alcohol nucleophile to a ketone or aldehyde.
• an alcohol adds to an aldehyde, the result is called a hemiacetal;
when an alcohol adds to a ketone the resulting product is
a hemiketal.
Chapter 16 23
Chapter 16 24
The Addition of Alcohols: Hemiacetals and
Acetals
Hemiacetals
An aldehyde or ketone dissolved in an alcohol will form an
equilibrium mixture containing the corresponding hemiacetal A hemiacetal has a hydroxyl and alkoxyl group on the same carbon
Acylic hemiacetals are generally not stable, however, cyclic five- and six-
membered ring hemiacetals are
Chapter 16 25
Hemiacetal formation is catalyzed by either acid or base
Chapter 16 26
Dissolving aldehydes (or ketones) in water causes formation of an
equilibrium between the carbonyl compound and its hydrate The hydrate is also called a gem-diol (gem i.e. geminal, indicates the presence of
two identical substituents on the same carbon)
The equilibrum favors a ketone over its hydrate because the tetrahedral ketone
hydrate is sterically crowded
Chapter 16 27
Acetals
è An aldehyde (or ketone) in the presence of excess alcohol and an
acid catalyst will form an acetal H Formation of the acetal proceeds via the corresponding hemiacetal
H An acetal has two alkoxyl groups bonded to the same carbon
Chapter 16 28
è Acetals are stable when isolated and purified
è Acetal formation is reversible H An excess of water in the presence of an acid catalyst will hydrolyze an acetal to
the corresponding aldehyde (or ketone)
Chapter 16 29
è Acetal formation from ketones and simple alcohols is less
favorable than formation from aldehydes H Formation of cyclic 5- and 6- membered ring acetals from ketones is, however,
favorable
H Such cyclic acetals are often used as protecting groups for aldehydes and
ketones
H These protecting groups can be removed using dilute aqueous acid
Chapter 16 30
Acetals as Protecting Groups
è Acetal protecting groups are stable to most reagents except
aqueous acid
è Example: An ester can be reduced in the presence of a ketone
protected as an acetal
6. Predict the products from the addition of amines to
aldehydes and ketones which produce Imines from 1o
Amines (PAGE : 751), Enamines from 2o Amines
(PAGE : 754), Enamines for Alkylation of Ketones
(PAGE : 755)
Chapter 16 31
Chapter 16 32
The Addition of Primary and Secondary Amines
Aldehydes and ketones react with primary amines
(and ammonia) to yield imines
• They react with secondary amines to yield
enamines
Chapter 16 33
Imines
These reactions occur fastest at pH 4-5
• Mild acid facilitates departure of the hydroxyl
group from the aminoalcohol intermediate
without also protonating the nitrogen of the
amine starting compound
Chapter 16 34
Chapter 16 35
Enamines
Secondary amines cannot form a neutral imine
by loss of a second proton on nitrogen
• An enamine is formed instead
Chapter 16 36
7. Predict the products from Wittig Reaction (PAGE :
757-760)
Chapter 16 37
Chapter 16 38
The Addition of Ylides: The Wittig Reaction
Aldehydes and ketones react with phosphorous
triphenyl phosphonium ylide to produce alkenes
• An ylide is a neutral molecule with adjacent
positive and negative charges
Chapter 16 39
Reaction of triphenylphosphine with a primary or
secondary alkyl halide produces a phosphonium salt
The phosphonium salt is deprotonated by a strong base to form
the ylide
Chapter 16 40
Addition of the ylide to the carbonyl leads to formation of a four-
membered ring oxaphosphetane
The oxaphophetane rearranges to the alkene and triphenylphosphine oxide
The driving force for the last reaction is formation of the very strong
phosphorus-oxygen double bond in triphenylphosphine oxide
Chapter 16 41
è Solved Problem: Make 2-Methyl-1-phenylprop-1-ene by a Wittig
reaction
Unlike elimination reactions (such as
dehydrohalogenation of alkyl halides), which
produce mixtures of alkene regioisomers
determined by Saytzeff's rule, the Wittig reaction
forms the double bond in one position with no
ambiguity.
Chapter 16 42