1 Aldehydes and Ketones: Nucleophilic Addition Reactions Prof. Dr. Nadhir N. A. Jafar Al-Zahraa University for Women/ Pharmacy College Dept. of Pharmaceutical Chemistry/ Organic Chemistry II
(7) Aldehydes and Ketones
Dec 23, 2022
Aldehydes and ketones are characterized by the the
carbonyl functional group (C=O)
The compounds occur widely in nature as
intermediates in metabolism and biosynthesis
They are also common as chemicals, as solvents,
monomers, adhesives, agrichemicals and
pharmaceuticals
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Chapter 19. Aldehydes and Ketones: Nucleophilic Addition ReactionsDept. of Pharmaceutical Chemistry/ Organic Chemistry II
2
carbonyl functional group (C=O)
The compounds occur widely in nature as
intermediates in metabolism and biosynthesis
They are also common as chemicals, as solvents,
monomers, adhesives, agrichemicals and
3
Naming Aldehydes and Ketones
Aldehydes are named by replacing the terminal -e of the corresponding alkane name with –al
The parent chain must contain the CHO group
The CHO carbon is numbered as C1
If the CHO group is attached to a ring, use the suffix See Table 19.1 for common names
4
Replace the terminal -e of the alkane name with –one
Parent chain is the longest one that contains the
ketone group
carbon
5
a few ketones
6
Ketones and Aldehydes as Substituents
The R–C=O as a substituent is an acyl group is used with the suffix -yl from the root of the carboxylic acid CH3CO: acetyl; CHO: formyl; C6H5CO: benzoyl
The prefix oxo- is used if other functional groups are present and the doubly bonded oxygen is labeled as a substituent on a parent chain
7
Preparing Aldehydes
Reduce an ester with diisobutylaluminum hydride (DIBAH)
8
situation (scale, cost, and acid/base sensitivity)
Prof. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
9
Ketones from Ozonolysis
Ozonolysis of alkenes yields ketones if one of the unsaturated carbon atoms is disubstituted (see Section 7.8)
Prof. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
10
Section 16.4)
11
Hydration of terminal alkynes in the presence of Hg2+
(catalyst: Section 8.5)
12
CrO3 in aqueous acid oxidizes aldehydes to
carboxylic acids efficiently
reagent) oxidizes aldehydes (no acid)
13
Reversible addition of water to the carbonyl group
Aldehyde hydrate is oxidized to a carboxylic acid by usual reagents for alcohols
Prof. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
14
Undergo slow cleavage with hot, alkaline KMnO4
C–C bond next to C=O is broken to give carboxylic
acids
Prof. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
15
Aldehydes and Ketones
Nu- approaches 45° to the plane of C=O and adds to C
A tetrahedral alkoxide ion intermediate is produced
Prof. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
16
Nucleophiles
Nucleophiles can be negatively charged ( : Nu−) or neutral ( : Nu) at the reaction site
The overall charge on the nucleophilic species is not considered
17
Ketones
Aldehydes are generally more reactive than ketones in nucleophilic addition reactions
The transition state for addition is less crowded and lower in energy for an aldehyde (a) than for a ketone (b)
Aldehydes have one large substituent bonded to the C=O: ketones have two
Prof. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
18
Aldehyde C=O is more polarized than ketone C=O
As in carbocations, more alkyl groups stabilize + character
Ketone has more alkyl groups, stabilizing the C=O carbon inductively
19
Less reactive in nucleophilic addition reactions than aliphatic aldehydes
Electron-donating resonance effect of aromatic ring makes C=O less reactive electrophilic than the carbonyl group of an aliphatic aldehyde
20
Hydration
Aldehydes and ketones react with water to yield 1,1- diols (geminal (gem) diols)
Hyrdation is reversible: a gem diol can eliminate water
Prof. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
21
over hydrate for steric reasons
Acetone in water is 99.9% ketone form
Exception: simple aldehydes
22
both acid and base
nucleophile than water
23
more electrophilic
24
Reaction of C=O with H-Y, where Y is
electronegative, gives an addition product (“adduct”)
Formation is readily reversible
to yield cyanohydrins, RCH(OH)CN
Prof. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
26
Addition of HCN is reversible and base-catalyzed, generating nucleophilic cyanide ion, CN
Addition of CN− to C=O yields a tetrahedral intermediate, which is then protonated
Equilibrium favors adduct
The nitrile group (CN) can be reduced with LiAlH4
to yield a primary amine (RCH2NH2)
Can be hydrolyzed by hot acid to yield a carboxylic
acid
28
Hydride Reagents: Alcohol Formation
reagents yields an alcohol
Nucleophilic addition of the equivalent of a carbon anion, or carbanion. A carbon–magnesium bond is
strongly polarized, so a Grignard reagent reacts for all
practical purposes as R : − MgX +.
29
Reagents Complexation of C=O by Mg2+, Nucleophilic addition
of R : −, protonation by dilute acid yields the neutral alcohol
Grignard additions are irreversible because a carbanion is not a leaving group
Nadhir N. A. Jafar
LiAlH4 and NaBH4 react as donors of hydride ion
Protonation after addition yields the alcohol
31
Enamine Formation
RNH2 adds to C=O to form imines, R2C=NR (after loss of HOH)
R2NH yields enamines, R2NCR=CR2 (after loss of HOH)
(ene + amine = unsaturated amine)
Primary amine adds to C=O
Proton is lost from N and adds to O to yield a neutral amino alcohol (carbinolamine)
Protonation of OH converts into water as the leaving group
Result is iminium ion, which loses proton
Acid is required for loss of OH – too much acid blocks RNH2
Note that overall reaction is substitution of RN for O
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
33
Imine Derivatives
Addition of amines with an atom containing a lone pair of electrons on the adjacent atom occurs very readily, giving useful, stable imines
For example, hydroxylamine forms oximes and 2,4- dinitrophenylhydrazine readily forms 2,4- dinitrophenylhydrazones These are usually solids and help in characterizing
liquid ketones or aldehydes by melting points
34
carbon
C
C
O
C
C
O
35
Kishner Reaction
Treatment of an aldehyde or ketone with hydrazine, H2NNH2 and KOH converts the compound to an alkane
Originally carried out at high temperatures but with dimethyl sulfoxide as solvent takes place near room temperature
36
Two equivalents of ROH in the presence of an acid
catalyst add to C=O to yield acetals, R2C(OR)2
These can be called ketals if derived from a ketone
37
addition forming the conjugate acid of C=O
Addition yields a hydroxy ether, called a hemiacetal
(reversible); further reaction can occur
Protonation of the OH and loss of water leads to an
oxonium ion, R2C=OR+ to which a second alcohol
adds to form the acetal
38
and ketones
It is convenient to use a diol, to form a cyclic acetal
(the reaction goes even more readily)
39
The Wittig Reaction
The sequence converts C=O is to C=C
A phosphorus ylide adds to an aldehyde or ketone to yield a dipolar intermediate called a betaine
The intermediate spontaneously decomposes through a four-membered ring to yield alkene and triphenylphosphine oxide, (Ph)3P=O
Formation of the ylide is shown below
Prof. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
40
Uses of the Wittig Reaction
Can be used for monosubstituted, disubstituted, and trisubstituted alkenes but not tetrasubstituted alkenes The reaction yields a pure alkene of known structure
For comparison, addition of CH3MgBr to cyclohexanone and dehydration with, yields a mixture of two alkenes
41
42
Reductions
The adduct of an aldehyde and OH− can transfer hydride ion to another aldehyde C=O resulting in a simultaneous oxidation and reduction (disproportionation)
Prof. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
43
Unsaturated Aldehydes and Ketones
A nucleophile can add to the C=C double bond of an ,b- unsaturated aldehyde or ketone (conjugate addition, or 1,4 addition)
The initial product is a resonance- stabilized enolate ion, which is then protonated
44
Conjugate Addition of Amines
Primary and secondary amines add to , b- unsaturated aldehydes and ketones to yield b-amino aldehydes and ketones
45
Reaction of an , b-unsaturated ketone with a lithium diorganocopper reagent
Diorganocopper (Gilman) reagents from by reaction of 1 equivalent of cuprous iodide and 2 equivalents of organolithium
1, 2, 3 alkyl, aryl and alkenyl groups react but not alkynyl groups
46
Conjugate nucleophilic addition of a diorganocopper anion, R2Cu−, an enone
Transfer of an R group and elimination of a neutral organocopper species, RCu
Prof. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
Prof. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
47
Summary
Aldehydes are from oxidative cleavage of alkenes, oxidation of 1° alcohols, or partial reduction of esters
Ketones are from oxidative cleavage of alkenes, oxidation of 2° alcohols, or by addition of diorganocopper reagents to acid chlorides.
Aldehydes and ketones are reduced to yield 1° and 2° alcohols , respectively
Grignard reagents also gives alcohols
Addition of HCN yields cyanohydrins
1° amines add to form imines, and 2° amines yield enamines
Reaction of an aldehyde or ketone with hydrazine and base yields an alkane
Alcohols add to yield acetals
Phosphoranes add to aldehydes and ketones to give alkenes (the Wittig reaction)
b-Unsaturated aldehydes and ketones are subject to conjugate addition (1,4 addition)
Slide 1: Aldehydes and Ketones: Nucleophilic Addition Reactions
Slide 2: Aldehydes and Ketones
Slide 3: Naming Aldehydes and Ketones
Slide 4: Naming Ketones
Slide 6: Ketones and Aldehydes as Substituents
Slide 7: Preparation of Aldehydes and Ketones
Slide 8: Preparing Ketones
Slide 10: Aryl Ketones by Acylation
Slide 11: Methyl Ketones by Hydrating Alkynes
Slide 12: Oxidation of Aldehydes and Ketones
Slide 13: Hydration of Aldehydes
Slide 14: Ketones Oxidize with Difficulty
Slide 15: Nucleophilic Addition Reactions of Aldehydes and Ketones
Slide 16: Nucleophiles
Slide 18: Electrophilicity of Aldehydes and Ketones
Slide 19: Reactivity of Aromatic Aldehydes
Slide 20: Nucleophilic Addition of H2O: Hydration
Slide 21: Relative Energies
Slide 24: Addition of H-Y to C=O
Slide 25: Nucleophilic Addition of HCN: Cyanohydrin Formation
Slide 26: Mechanism of Formation of Cyanohydrins
Slide 27: Uses of Cyanohydrins
Slide 28: Nucleophilic Addition of Grignard Reagents and Hydride Reagents: Alcohol Formation
Slide 29: Mechanism of Addition of Grignard Reagents
Slide 30: Hydride Addition
Slide 31: Nucleophilic Addition of Amines: Imine and Enamine Formation
Slide 32: Mechanism of Formation of Imines
Slide 33: Imine Derivatives
Slide 34: Enamine Formation
Slide 35: Nucleophilic Addition of Hydrazine: The Wolff–Kishner Reaction
Slide 36: Nucleophilic Addition of Alcohols: Acetal Formation
Slide 37: Formation of Acetals
Slide 38: Uses of Acetals
Slide 39: Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction
Slide 40: Uses of the Wittig Reaction
Slide 41: Mechanism of the Wittig Reaction
Slide 42: The Cannizzaro Reaction: Biological Reductions
Slide 43: Conjugate Nucleophilic Addition to ,b-Unsaturated Aldehydes and Ketones
Slide 44: Conjugate Addition of Amines
Slide 45: Conjugate Addition of Alkyl Groups: Organocopper Reactions
Slide 46: Mechanism of Alkyl Conjugate Addition
Slide 47: Summary
2
carbonyl functional group (C=O)
The compounds occur widely in nature as
intermediates in metabolism and biosynthesis
They are also common as chemicals, as solvents,
monomers, adhesives, agrichemicals and
3
Naming Aldehydes and Ketones
Aldehydes are named by replacing the terminal -e of the corresponding alkane name with –al
The parent chain must contain the CHO group
The CHO carbon is numbered as C1
If the CHO group is attached to a ring, use the suffix See Table 19.1 for common names
4
Replace the terminal -e of the alkane name with –one
Parent chain is the longest one that contains the
ketone group
carbon
5
a few ketones
6
Ketones and Aldehydes as Substituents
The R–C=O as a substituent is an acyl group is used with the suffix -yl from the root of the carboxylic acid CH3CO: acetyl; CHO: formyl; C6H5CO: benzoyl
The prefix oxo- is used if other functional groups are present and the doubly bonded oxygen is labeled as a substituent on a parent chain
7
Preparing Aldehydes
Reduce an ester with diisobutylaluminum hydride (DIBAH)
8
situation (scale, cost, and acid/base sensitivity)
Prof. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
9
Ketones from Ozonolysis
Ozonolysis of alkenes yields ketones if one of the unsaturated carbon atoms is disubstituted (see Section 7.8)
Prof. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
10
Section 16.4)
11
Hydration of terminal alkynes in the presence of Hg2+
(catalyst: Section 8.5)
12
CrO3 in aqueous acid oxidizes aldehydes to
carboxylic acids efficiently
reagent) oxidizes aldehydes (no acid)
13
Reversible addition of water to the carbonyl group
Aldehyde hydrate is oxidized to a carboxylic acid by usual reagents for alcohols
Prof. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
14
Undergo slow cleavage with hot, alkaline KMnO4
C–C bond next to C=O is broken to give carboxylic
acids
Prof. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
15
Aldehydes and Ketones
Nu- approaches 45° to the plane of C=O and adds to C
A tetrahedral alkoxide ion intermediate is produced
Prof. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
16
Nucleophiles
Nucleophiles can be negatively charged ( : Nu−) or neutral ( : Nu) at the reaction site
The overall charge on the nucleophilic species is not considered
17
Ketones
Aldehydes are generally more reactive than ketones in nucleophilic addition reactions
The transition state for addition is less crowded and lower in energy for an aldehyde (a) than for a ketone (b)
Aldehydes have one large substituent bonded to the C=O: ketones have two
Prof. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
18
Aldehyde C=O is more polarized than ketone C=O
As in carbocations, more alkyl groups stabilize + character
Ketone has more alkyl groups, stabilizing the C=O carbon inductively
19
Less reactive in nucleophilic addition reactions than aliphatic aldehydes
Electron-donating resonance effect of aromatic ring makes C=O less reactive electrophilic than the carbonyl group of an aliphatic aldehyde
20
Hydration
Aldehydes and ketones react with water to yield 1,1- diols (geminal (gem) diols)
Hyrdation is reversible: a gem diol can eliminate water
Prof. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
21
over hydrate for steric reasons
Acetone in water is 99.9% ketone form
Exception: simple aldehydes
22
both acid and base
nucleophile than water
23
more electrophilic
24
Reaction of C=O with H-Y, where Y is
electronegative, gives an addition product (“adduct”)
Formation is readily reversible
to yield cyanohydrins, RCH(OH)CN
Prof. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
26
Addition of HCN is reversible and base-catalyzed, generating nucleophilic cyanide ion, CN
Addition of CN− to C=O yields a tetrahedral intermediate, which is then protonated
Equilibrium favors adduct
The nitrile group (CN) can be reduced with LiAlH4
to yield a primary amine (RCH2NH2)
Can be hydrolyzed by hot acid to yield a carboxylic
acid
28
Hydride Reagents: Alcohol Formation
reagents yields an alcohol
Nucleophilic addition of the equivalent of a carbon anion, or carbanion. A carbon–magnesium bond is
strongly polarized, so a Grignard reagent reacts for all
practical purposes as R : − MgX +.
29
Reagents Complexation of C=O by Mg2+, Nucleophilic addition
of R : −, protonation by dilute acid yields the neutral alcohol
Grignard additions are irreversible because a carbanion is not a leaving group
Nadhir N. A. Jafar
LiAlH4 and NaBH4 react as donors of hydride ion
Protonation after addition yields the alcohol
31
Enamine Formation
RNH2 adds to C=O to form imines, R2C=NR (after loss of HOH)
R2NH yields enamines, R2NCR=CR2 (after loss of HOH)
(ene + amine = unsaturated amine)
Primary amine adds to C=O
Proton is lost from N and adds to O to yield a neutral amino alcohol (carbinolamine)
Protonation of OH converts into water as the leaving group
Result is iminium ion, which loses proton
Acid is required for loss of OH – too much acid blocks RNH2
Note that overall reaction is substitution of RN for O
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
33
Imine Derivatives
Addition of amines with an atom containing a lone pair of electrons on the adjacent atom occurs very readily, giving useful, stable imines
For example, hydroxylamine forms oximes and 2,4- dinitrophenylhydrazine readily forms 2,4- dinitrophenylhydrazones These are usually solids and help in characterizing
liquid ketones or aldehydes by melting points
34
carbon
C
C
O
C
C
O
35
Kishner Reaction
Treatment of an aldehyde or ketone with hydrazine, H2NNH2 and KOH converts the compound to an alkane
Originally carried out at high temperatures but with dimethyl sulfoxide as solvent takes place near room temperature
36
Two equivalents of ROH in the presence of an acid
catalyst add to C=O to yield acetals, R2C(OR)2
These can be called ketals if derived from a ketone
37
addition forming the conjugate acid of C=O
Addition yields a hydroxy ether, called a hemiacetal
(reversible); further reaction can occur
Protonation of the OH and loss of water leads to an
oxonium ion, R2C=OR+ to which a second alcohol
adds to form the acetal
38
and ketones
It is convenient to use a diol, to form a cyclic acetal
(the reaction goes even more readily)
39
The Wittig Reaction
The sequence converts C=O is to C=C
A phosphorus ylide adds to an aldehyde or ketone to yield a dipolar intermediate called a betaine
The intermediate spontaneously decomposes through a four-membered ring to yield alkene and triphenylphosphine oxide, (Ph)3P=O
Formation of the ylide is shown below
Prof. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
40
Uses of the Wittig Reaction
Can be used for monosubstituted, disubstituted, and trisubstituted alkenes but not tetrasubstituted alkenes The reaction yields a pure alkene of known structure
For comparison, addition of CH3MgBr to cyclohexanone and dehydration with, yields a mixture of two alkenes
41
42
Reductions
The adduct of an aldehyde and OH− can transfer hydride ion to another aldehyde C=O resulting in a simultaneous oxidation and reduction (disproportionation)
Prof. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
43
Unsaturated Aldehydes and Ketones
A nucleophile can add to the C=C double bond of an ,b- unsaturated aldehyde or ketone (conjugate addition, or 1,4 addition)
The initial product is a resonance- stabilized enolate ion, which is then protonated
44
Conjugate Addition of Amines
Primary and secondary amines add to , b- unsaturated aldehydes and ketones to yield b-amino aldehydes and ketones
45
Reaction of an , b-unsaturated ketone with a lithium diorganocopper reagent
Diorganocopper (Gilman) reagents from by reaction of 1 equivalent of cuprous iodide and 2 equivalents of organolithium
1, 2, 3 alkyl, aryl and alkenyl groups react but not alkynyl groups
46
Conjugate nucleophilic addition of a diorganocopper anion, R2Cu−, an enone
Transfer of an R group and elimination of a neutral organocopper species, RCu
Prof. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
Prof. Dr. Nadhir N. A. Jafar
Al-Zahraa University for Women/ Pharmacy College
47
Summary
Aldehydes are from oxidative cleavage of alkenes, oxidation of 1° alcohols, or partial reduction of esters
Ketones are from oxidative cleavage of alkenes, oxidation of 2° alcohols, or by addition of diorganocopper reagents to acid chlorides.
Aldehydes and ketones are reduced to yield 1° and 2° alcohols , respectively
Grignard reagents also gives alcohols
Addition of HCN yields cyanohydrins
1° amines add to form imines, and 2° amines yield enamines
Reaction of an aldehyde or ketone with hydrazine and base yields an alkane
Alcohols add to yield acetals
Phosphoranes add to aldehydes and ketones to give alkenes (the Wittig reaction)
b-Unsaturated aldehydes and ketones are subject to conjugate addition (1,4 addition)
Slide 1: Aldehydes and Ketones: Nucleophilic Addition Reactions
Slide 2: Aldehydes and Ketones
Slide 3: Naming Aldehydes and Ketones
Slide 4: Naming Ketones
Slide 6: Ketones and Aldehydes as Substituents
Slide 7: Preparation of Aldehydes and Ketones
Slide 8: Preparing Ketones
Slide 10: Aryl Ketones by Acylation
Slide 11: Methyl Ketones by Hydrating Alkynes
Slide 12: Oxidation of Aldehydes and Ketones
Slide 13: Hydration of Aldehydes
Slide 14: Ketones Oxidize with Difficulty
Slide 15: Nucleophilic Addition Reactions of Aldehydes and Ketones
Slide 16: Nucleophiles
Slide 18: Electrophilicity of Aldehydes and Ketones
Slide 19: Reactivity of Aromatic Aldehydes
Slide 20: Nucleophilic Addition of H2O: Hydration
Slide 21: Relative Energies
Slide 24: Addition of H-Y to C=O
Slide 25: Nucleophilic Addition of HCN: Cyanohydrin Formation
Slide 26: Mechanism of Formation of Cyanohydrins
Slide 27: Uses of Cyanohydrins
Slide 28: Nucleophilic Addition of Grignard Reagents and Hydride Reagents: Alcohol Formation
Slide 29: Mechanism of Addition of Grignard Reagents
Slide 30: Hydride Addition
Slide 31: Nucleophilic Addition of Amines: Imine and Enamine Formation
Slide 32: Mechanism of Formation of Imines
Slide 33: Imine Derivatives
Slide 34: Enamine Formation
Slide 35: Nucleophilic Addition of Hydrazine: The Wolff–Kishner Reaction
Slide 36: Nucleophilic Addition of Alcohols: Acetal Formation
Slide 37: Formation of Acetals
Slide 38: Uses of Acetals
Slide 39: Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction
Slide 40: Uses of the Wittig Reaction
Slide 41: Mechanism of the Wittig Reaction
Slide 42: The Cannizzaro Reaction: Biological Reductions
Slide 43: Conjugate Nucleophilic Addition to ,b-Unsaturated Aldehydes and Ketones
Slide 44: Conjugate Addition of Amines
Slide 45: Conjugate Addition of Alkyl Groups: Organocopper Reactions
Slide 46: Mechanism of Alkyl Conjugate Addition
Slide 47: Summary
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