Transcript Nucleophilic Addition Reactions

Chapter 19
Aldehydes and Ketones: Nucleophilic
Addition Reactions
Aldehydes and Ketones
• Aldehydes (RCHO) and ketones (R2CO) are
characterized by the carbonyl functional group
(C=O)
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Structure of the Carbonyl Group
• Carbon is sp2 hybridized
• C═O bond is shorter, stronger, and more polar
than C═C bond in alkenes
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Resonance
• First resonance
– All atoms complete the octet
– No charges
• Second resonance
– Carbocation acts as an electrophile
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NOMENCLATURE
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Ketone Nomenclature
• Number chain with lowest number on carbonyl
carbon
• Replace the alkane -e with -one
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Cyclic Ketone Nomenclature
• Cyclic ketones carbonyl carbon is assigned the
number 1
• Carbonyl takes precedence over a double bond
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Aldehydes Nomenclature
• Aldehyde carbon is number 1
• Replace -e with -al.
• Use suffix carbaldehyde when aldehyde is attached
to a ring
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Naming Aldehydes and Ketones
• R–C=O as a substituent is an acyl group
• Name substituent with suffix -yl added to the
root name of the carboxylic acid
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Carbonyl as Substituent
• Molecule has a higher priority functional group
– Ketone is an oxo group
– Aldehyde is a formyl group
• Aldehydes have a higher priority than ketones
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Worked Example
• Draw structures corresponding to the following
names
– a) 3-Methylbutanal
– b) Cis-3-tert-Butylcyclohexanecarbaldehyde
Solution:
– a) 3-Methylbutanal
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Worked Example
– b) cis-3-tert-Butylcyclohexanecarbaldehyde
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PREPARING ALDEHYDES AND
KETONES
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Preparing Aldehydes
• From alcohols
– Oxidize primary alcohols with Dess-Martin
pyridinium reagent in dichloromethane solvent
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Preparing Aldehydes
• From carboxylic acids
– Partially reduce to yield aldehydes
– Use diisobutylaluminum hydride (DIBAH)
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Ozonolysis of Alkenes
Reaction found in Previous Chapter
• From alkenes
– Double bond is oxidatively cleaved by ozone
followed by reduction
– Ketones and aldehydes can be isolated as
products
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Worked Example
• How is pentanal prepared from the following
starting materials
– a) CH3CH2CH2CH2CH2OH
– b) CH3CH2CH2CH2CH=CH2
• Solution:
• a)
• b)
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Preparing Ketones
• Prepare ketones by oxidization of a secondary
alcohol
– Use Dess–Martin periodinane or a Cr(VI) reagent
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Preparing Ketones
• Disubstitued alkenes yield ketones through
ozonolysis
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Preparing Ketones
• Friedel-Crafts acylation produces ketone
– Reaction between an acyl halide and an aromatic
ring
– Use AlCl3 catalyst
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Preparing Ketones
Reaction in Previous Chapter
• Hydration of Alkynes
– Initial product is Markovnikov hydration to an enol
– Enol quickly tautomerizes to keto form
– Internal alkynes form mixtures of ketones
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Worked Example
• How are the following reactions carried out?
– a) 3-Hexyne → 3-Hexanone
– b) Benzene → m-Bromoacetophenone
• Solution:
– a)
– b)
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OXIDATION OF ALDEHYDES AND
KETONES
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Oxidation of Aldehydes and Ketones
• Aldehydes oxidize to yield carboxylic acids
– CrO3 in aqueous acid oxidizes aldehydes to
carboxylic acids
• Occur through intermediate 1,1-diols, or hydrates
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Oxidation of Aldehydes and Ketones
• Ketones undergo slow cleavage with hot,
alkaline KMnO4
– C–C bond next to C=O is broken to give carboxylic
acids
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NUCLEOPHILIC ADDITION
REACTIONS
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Nucleophilic Addition
•
•
•
•
A strong nucleophile attacks the carbonyl carbon
An alkoxide ion is formed
The alkoxide is protonated
Aldehydes are more reactive than ketones
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Nucleophilic Addition
• Nucleophiles can be
– Negatively charged (:Nu-)
– Neutral (:Nu)
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Nucleophilic Addition
• Nucleophilic additions has two general variations
– Product is a result of a tetrahedral intermediate being
protonated by water or acid
– Carbonyl oxygen is protonated then eliminated as HOor H2O where product is a C=Nu double bond
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Nucleophilic Addition
• Aldehydes are more reactive than ketones
– Aldehydes have one substituent bonded to the C=O
– Ketones have two substituent bonded to the C=O
– Transition state for addition is less crowded and
lower in energy for an aldehyde than for a ketone
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Nucleophilic Addition
• Aldehydes are more reactive than ketones
– Aldehydes are more polarized than ketones
• More alkyl groups stabilize the carbocation inductively
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Nucleophilic Addition
• Aromatic aldehyde is less reactive than
aliphatic aldehydes
– Aromatic aldehyde is less positive than non
aromatic aldehyde
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Worked Example
• Treatment of an aldehyde or ketone with
cyanide ion (–:C≡N), followed by protonation
of the tetrahedral alkoxide ion intermediate,
gives a cyanohydrin
– Show the structure of the cyanohydrin obtained
from cyclohexanone
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Worked Example
• Solution:
– Step 1 - Cyanide anion adds to the carbonyl carbon to
form a tetrahedral intermediate
– Step 2 - Intermediate is protonated to yield the
cyanohydrin
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Nucleophilic Addition: Hydration
• Aldehydes and ketones react with water to
yield 1,1-diols or geminal diols
• Hydration is reversible
• Equilibrium depends on structure of carbonyl
compound
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Nucleophilic Addition: Hydration
• A ketone or an aldehyde in aqueous
solution is in equilibrium with its hydrate
• Ketones equilibrium favors the unhydrated
keto form
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Nucleophilic Addition: Acid-Catalyzed
Hydration
• Hydration occurs through the nucleophilic addition
mechanism
• Protonation converts carbonyl compound into an electrophile
– Increases electrophilicity of carbonyl group
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Nucleophilic Addition: Base-Catalyzed
Hydration
• The hydroxide ion attacks the carbonyl group
• Protonation of the intermediate gives the hydrate
• Water is converted into hydroxide ion
– Better nucleophile
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Worked Example
• When dissolved in water,
trichloroacetaldehyde exists primarily as its
hydrate, called chloral hydrate
– Show the structure of chloral hydrate
• Solution:
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Cyanohydrin Formation
• Nucleophilic addition of HCN
– Base-catalyzed nucleophilic addition:
• Cyanide ion attacks the carbonyl group yielding a tetrahedral intermediate
• Protonation of the intermediate yields product
– Equilibrium favors cyanohydrin adduct
• HCN is highly toxic
Uses of Cyanohydrins
• The nitrile group (R–C≡N) can be
– Reduced with LiAlH4 to yield a primary amine
– Hydrolyzed by hot acid to yield a carboxylic acid
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Worked Example
• Cyclohexanone forms a cyanohydrin in good yield
but 2,2,6-trimethylcyclohexanone does not
Explain
• Solution:
– Cyanohydrin formation is an equilibrium process
• Addition of –CN to 2,2,6-trimethylcyclohexanone is sterically
hindered by 3 methyl groups, equilibrium lies toward the
side of unreacted ketone
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Nucleophilic Addition of Hydride: Alcohol
Formation
• Addition of hydride reagents produce alcohols
– Alcohols prepared by reduction of a carbonyl
• Occurs by basic nucleophilic addition mechanism
– Protonation after addition yields the alcohol
• Reduction by hydride is irreversible
• LiAlH4 and NaBH4 act as donors of hydride ion
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Nucleophilic Addition of Hydride: Alcohol
Formation
• Addition of hydride reagents produce alcohols
– Aldehyde reduction by NaBH4 yields 1o alcohols
– Ketone reduction by NaBH4 yields 2° alcohols
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Nucleophilic Addition of Grignard Reagents:
Alcohol Formation
• Grignard reagents react with carbonyl groups
to yield an alcohol
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Nucleophilic Addition of Grignard Reagents:
Alcohol Formation
• Mechanism
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Nucleophilic Addition of Amines
• RNH2 adds to aldehydes and ketones to form
imines, R2C=NR
– Called Schiff bases
– Common as intermediates in biological pathways
• R2NH adds similarly to yield enamines, R2N–
CR=CR2
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Nucleophilic Addition of Amines: Imine
Formation Mechanism
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Nucleophilic Addition of Amines: Imine
Formation Mechanism
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Nucleophilic Addition of Amines:
Enamine Formation Mechanism
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Nucleophilic Addition of Amines:
Enamine Formation Mechanism
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Worked Example
• Show the products you would obtain by acidcatalyzed reaction of cyclohexanone with
ethylamine, CH3CH2NH2 and with
diethylamine, (CH3CH2)2NH
• Solution:
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Nucleophilic Addition of Hydrazine:
The Wolff-Kishner Reaction
• Aldehyde or
ketone react
with hydrazine,
H2NNH2, and
KOH to
produce an
alkane
• More useful
than catalytic
hydrogenation
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Nucleophilic Addition of Hydrazine:
The Wolff-Kishner Reaction
• Aldehyde or
ketone react
with hydrazine,
H2NNH2, and
KOH to
produce an
alkane
• More useful
than catalytic
hydrogenation
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Worked Example
• Show how you could prepare the following
compounds from 4-methyl-3-penten-2-one,
(CH3)2C=CHCOCH3
– a)
– b)
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Worked Example
• Solution:
– a)
– b)
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Nucleophilic Addition of Alcohols:
Acetal Formation
• Aldehydes and ketones react reversibly with 2
equivalents of an alcohol in the presence of an acid
catalyst to yield acetals, R2C(OR’)2
– Called ketals if derived from a ketone
• Under acidic conditions reactivity of the carbonyl
group is increased by protonation
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Nucleophilic Addition of Alcohols:
Acetal Formation
• Acetals can serve as protecting groups for
aldehydes and ketones
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Nucleophilic Addition of Alcohols:
Acetal Formation
Mechanism
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Nucleophilic Addition of Alcohols:
Acetal Formation
Mechanism
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Worked Example
• Show the structure of the acetal obtained by
acid-catalyzed reaction of 2-pentanone with
1,3-propanediol
• Solution:
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Nucleophilic Addition of Phosphorus Ylides: The
Wittig Reaction
• Wittig reaction converts aldehydes and ketones
into alkenes by nucleophilic addition
– Triphenylphosphorus ylide adds to a carbonyl group
to yield a four-membered cyclic intermediate called
an oxaphosphetane
– Oxaphosphetane spontaneously decomposes to give
an alkene plus triphenylphosphine oxide
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Mechanism of the Wittig Reaction
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Worked Example
• What carbonyl compound and what
phosphorus ylide might be used to prepare
the following compounds
– a)
– b)
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Worked Example
• Solution:
– a)
– b)
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Conjugate Nucleophilic Addition to
-Unsaturated Aldehydes and Ketones
• 1,2-addition: Addition of a nucleophile directly
to the carbonyl group
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Conjugate Nucleophilic Addition to
-Unsaturated Aldehydes and Ketones
• Conjugate addition (1,4-addition):
– Adds a nucleophile to the C=C double bond of an
-unsaturated aldehyde or ketone
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Conjugate Nucleophilic Addition to
-Unsaturated Aldehydes and Ketones
• Conjugate addition of amines
– Primary and secondary amines add to   unsaturated aldehydes and ketones to yield amino aldehydes and ketones
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Conjugate Nucleophilic Addition to
-Unsaturated Aldehydes and Ketones
• Conjugate addition of water
– Yields -hydroxy aldehydes and ketones,
• Adds reversibly to -unsaturated aldehydes and
ketones
• Position of the equilibrium generally favors unsaturated
reactant
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Conjugate Nucleophilic Addition to
-Unsaturated Aldehydes and Ketones
• Organocopper reactions with -unsaturated ketone
adds conjugate addition products
– 1, 2, 3 alkyl, aryl, and alkenyl groups react
• Alkynyl groups react poorly
• Mechanism
– Conjugate nucleophilic addition of a diorganocopper
anion, R2Cu–, to a ketone
– Transfer of an R group and elimination of a neutral
organocopper species, RCu, gives the final product
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Worked Example
• How might conjugate addition reactions of
lithium diorganocopper reagents be used to
synthesize
• Solution:
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Spectroscopy of Aldehydes and
Ketones
• Infrared Spectroscopy
– Aldehydes and ketones show a strong C=O peak
from 1660 to 1770 cm-1
– Aldehydes show two characteristic C–H
absorptions in the 2720 to 2820 cm-1 range
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Spectroscopy of Aldehydes and
Ketones
• Nuclear magnetic resonance spectroscopy
– Aldehyde proton signals absorb near 10  in 1H
NMR
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Spectroscopy of Aldehydes and
Ketones
– Carbonyl-group carbon atoms of aldehydes and
ketones signal is at 190  to 215 
• No other kinds of carbons absorb in this range
– Saturated aldehyde or ketone carbons absorb in
the region from 200  to 215 
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Spectroscopy of Aldehydes and
Ketones
• Mass spectrometry - McLafferty
rearrangement
– Aliphatic aldehydes and ketones that have
hydrogens on their gamma () carbon atoms
rearrange as shown
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Mass Spectroscopy:
-Cleavage
• Cleavage of the bond between the carbonyl
group and the  carbon
– Yields a neutral radical and an oxygen-containing
cation
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Worked Example
• Describe the prominent IR absorptions and
mass spectral peaks expected for the following
compound:
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Worked Example
• Solution:
– The important IR absorption for the compound is
seen at 1750 cm-1
– Products of alpha cleavage, which occurs in the
ring, have the same mass as the molecular ion
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Worked Example
• The McLafferty rearrangement appears at
m/z = 84
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Summary
• Most common general reaction type for
aldehydes and ketones is nucleophilic addition
reaction
• Addition of HCN to aldehydes and ketones yields
cyanohydrins
• Primary amines add to carbonyl compounds
yielding imines, or Schiff bases, and secondary
amines yield enamines
• Wolff-Kishner reaction is the reaction of an
aldehyde or a ketone with hydrazine and base to
give an alkane
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Summary
• Acetals, valuable protecting groups, are
produced by adding alcohols to carbonyl
groups
• Phosphorus ylides add to aldehydes and
ketones in the Wittig reaction to give alkenes
• -unsaturated aldehydes and ketones react
with nucleophiles to give product of conjugate
addition, or 1,4-addition
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