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Organic Organic ChemistryChemistry
William H. Brown & William H. Brown & Christopher S. FooteChristopher S. FooteWilliam H. Brown & William H. Brown & Christopher S. FooteChristopher S. Foote
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Aldehydes Aldehydes & &
KetonesKetones
Chapter 15
Chapter 16Chapter 16
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The Carbonyl GroupThe Carbonyl Group In this and several following chapters we study
the physical and chemical properties of classes of compounds containing the carbonyl group, C=O• aldehydes and ketones (Chapter 16)• carboxylic acids (Chapter 17)• acid halides, acid anhydrides, esters, amides (Chapter
18)• enolate anions (Chapter 19)
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The Carbonyl GroupThe Carbonyl Group The carbonyl group consists of • one sigma bond formed by the overlap of sp2 hybrid
orbitals, and • one pi bond formed by the overlap of parallel 2p
orbitals
C Oσ
π
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The Carbonyl GroupThe Carbonyl Group• pi bonding and pi antibonding MOs for formaldehyde.
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StructureStructure• The functional group of an aldehyde is a carbonyl
group bonded to a H atom and a carbon atom • The functional group of a ketone is a carbonyl group
bonded to two carbon atoms
Propanone(Acetone)
Ethanal(Acetaldehyde)
Methanal(Formaldehyde)
O O O
CH3CHHCH CH3CCH3
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NomenclatureNomenclature IUPAC names:• the parent chain is the longest chain that contains the
functional group• for an aldehyde, change the suffix from -e-e to -al-al• for an unsaturated aldehyde, show the carbon-carbon
double bond by changing the infix from -an--an- to -en--en-; the location of the suffix determines the numbering pattern
• for a cyclic molecule in which -CHO is bonded to the ring, name the compound by adding the suffix -carbaldehydecarbaldehyde
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Nomenclature: AldehydesNomenclature: Aldehydes
H
O
3-Methylbutanal 2-Propenal(Acrolein)
(2E)-3,7-Dimethyl-2,6-octadienal(Geranial)
1
2
3
4
5
6
78H
O
H
O
2,2-Dimethylcyclo-hexanecarbaldehyde
CHO
CH3CH3
1
2
CHOC6H5
CHO
trans-3-Phenyl-2-propenal(Cinnamaldehyde)
Benzaldehyde
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Nomenclature: KetonesNomenclature: Ketones
5-Methyl-3-hexanonePropanone (Acetone)
1 3 56
OO
1-Phenyl-1-pentanone
O1 5
IUPAC names: • select as the parent alkane the longest chain that
contains the carbonyl group• indicate its presence by changing the suffix -e-e to -one-one • number the chain to give C=O the smaller number
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Order of PrecedenceOrder of Precedence For compounds that contain more than one
functional group indicated by a suffix
-NH2
-SH
-OH
C=O
-CHO
-COOH
-amino-sulfanyl
oxo-
hydroxy-
oxo-
-amine
-thiol
-ol
-one
-al
-oic acid
Prefix If Lowerin Precedence
Suffix If Higherin Precedence
FunctionalGroup
Increasing precedence
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Common NamesCommon Names• for an aldehyde, the common name is derived from
the common name of the corresponding carboxylic acid
• for a ketone, name the two alkyl or aryl groups bonded to the carbonyl carbon and add the word ketone
FormaldehydeFormic acid Acetaldehyde Acetic acid
Ethyl isopropyl ketoneDiethyl ketoneDicyclohexyl ketone
O OO
H H
O
H OH
O
H
O
OH
O
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Physical PropertiesPhysical Properties Oxygen is more electronegative than carbon (3.5
vs 2.5) and, therefore, a C=O group is polar
• aldehydes and ketones are polar compounds and interact in the pure state by dipole-dipole interaction
• they have higher boiling points and are more soluble in water than nonpolar compounds of comparable molecular weight
C O C O –
Polarity of acarbonyl group
δ-δ+C O
+
More importantcontributing
structure
::: : :
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Reaction ThemesReaction Themes One of the most common reaction themes of a
carbonyl group is addition of a nucleophile to form a tetrahedral carbonyl addition compound
Tetrahedral carbonyl addition compound
+ CR
R
O CNu
O -
RR
Nu -: :
:::
:
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Reaction ThemesReaction Themes A second common theme is reaction with a
proton or Lewis acid to form a resonance-stabilized cation
• protonation in this manner increases the electron deficiency of the carbonyl carbon and makes it more reactive toward nucleophiles
+fast +
+C O
R
RC O
R
RH B-H-B: :: :
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Add’n of C NucleophilesAdd’n of C Nucleophiles Addition of carbon nucleophiles is one of the
most important types of nucleophilic additions to a C=O group; a new carbon-carbon bond is formed in the process
We study addition of these carbon nucleophiles
A Grignard reagent
An organolithium reagent
An anion of aterminal alkyne
Cyanide ion
RC C - NRMgX RLi - C
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Grignard ReagentsGrignard Reagents Given the difference in electronegativity between
carbon and magnesium (2.5 - 1.3), the C-Mg bond is polar covalent, with Cδ- and Mgδ+• in its reactions, a Grignard reagent behaves as a
carbanion
Carbanion:Carbanion: an anion in which carbon has an unshared pair of electrons and bears a negative charge• a carbanion is a good nucleophile and adds to the
carbonyl group of aldehydes and ketones
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Grignard ReagentsGrignard Reagents Addition of a Grignard reagent to formaldehyde
followed by H3O+ gives a 1° alcohol
ether
1-Propanol(a primary alcohol)
Formaldehyde
Mg2++
+δ+
δ- δ+δ-
OCH3 CH2 -MgBr H-C-H
CH3 CH2 -CH2 HCl
H2 O A magnesium alkoxide
CH3 CH2 -CH2
O- [ MgBr ] + OH
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Grignard ReagentsGrignard Reagents Addition to any other RCHO gives a 2° alcohol
ether
A magnesium alkoxide
Acetaldehyde(an aldehyde)
1-Cyclohexylethanol(a secondary alcohol)
+ Mg2+
+δ-
δ+
δ+δ-
MgBrO
CHCH3
O- [ MgBr ] +
OH
CHCH3
CH3 -C-H
HClH2 O
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Grignard ReagentsGrignard Reagents Addition to a ketone gives a 3° alcohol
Mg2+
ether
2-Phenyl-2-propanol (a tertiary alcohol)
Acetone
+
+δ−
δ+
δ+δ−
A magnesiumalkoxide
C6 H5 MgBr
O
C6 H5 CCH3
CH3
O- [ MgBr ] + OH
CH3
C6 H5 CCH3
CH3 -C-CH3
HCl
H2 O
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Grignard ReagentsGrignard ReagentsProblem:Problem: 2-phenyl-2-butanol can be synthesized by three different combinations of a Grignard reagent and a ketone. Show each combination.
C-CH2CH3
CH3
OH
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Organolithium CompoundsOrganolithium Compounds Organolithium compounds are generally more
reactive in C=O addition reactions than RMgX, and typically give higher yields
LiO
O-
Li+
HClH2 O
OH
3,3-Dimethyl-2- butanone
3,3-Dimethyl-2-phenyl- 2-butanol
+
Phenyl-lithium
A lithiumalkoxide
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Salts of Terminal AlkynesSalts of Terminal Alkynes Addition of an acetylide anion followed by H3O+
gives an -acetylenic alcohol
1-Ethynyl-cyclohexanol
+
O
C -
HC Na+
HClH2 O
C OHHC
Cyclohexanol
A sodium alkoxide
C O-Na+HC
:
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Salts of Terminal AlkynesSalts of Terminal Alkynes
HO C CH
O
CCH3HO
HO CH2CH
H2 SO4, HgSO4
H2 O
1. (sia)2BH
2. H2O2, NaOH
An -hydroxyketone
A β-hydroxyaldehyde
β
O
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Addition of HCNAddition of HCN HCN adds to the C=O group of an aldehyde or
ketone to give a cyanohydrin Cyanohydrin:Cyanohydrin: a molecule containing an -OH
group and a -CN group bonded to the same carbon
2-Hydroxypropanenitrile(Acetaldehyde cyanohydrin)
+ HC N CH3C-C NCH3CH
OH
H
O
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Addition of HCNAddition of HCN Mechanism of cyanohydrin formation
-••+
H3C
CH3C
CO:-
H3C
H3C
CN
NC
CO:-
H3C
H3C
CH C C
C
H3C
H3C
O-H
NN-:C++
O
NN
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CyanohydrinsCyanohydrins The value of cyanohydrins• acid-catalyzed dehydration of the 2° or 3° alcohol
• catalytic reduction of the cyano group gives a 1° amine
Propenenitrile(Acrylonitrile)
+
acidcatalyst
2-Hydroxypropanenitrile(Acetaldehyde cyanohydrin)
CH3CHC N NCH2=CHC H2 O
OH
CHC
OH
N
OH
CHCH2NH22H2
Benzaldehyde cyanohydrin 2-Amino-1-phenylethanol
Ni+
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Wittig ReactionWittig Reaction The Wittig reaction is a very versatile synthetic
method for the synthesis of alkenes from aldehydes and ketones.
Triphenyl-phosphine oxide
Methylene-cyclohexane
A phosphonium ylide
+
+-+
+
O
CH2 Ph3P-O-
Ph3P-CH2
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Phosphonium YlidesPhosphonium Ylides Phosphonium ylides are formed in two steps:
Triphenyl-phosphine
An alkyltriphenyl-phosphonium iodide
++Ph3P CH3-I Ph3P-CH3 I
-SN2:
A phosphonium ylide
Butane
Butyllithium
+++-
+I
-
CH2-PPh3 CH3CH2 CH2CH3 LiI
CH3CH2 CH2CH2Li + + H-CH2-PPh3
:
:
Step 1:
Step 2:
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Wittig ReactionWittig Reaction Phosphonium ylides react with the C=O group of
an aldehyde or ketone to give an alkene CR2O
CH2
-:O CR2
Ph3PCH2Ph3PCH2
O CR2
Ph3P-+
An oxaphosphetane
+
A betaine
Triphenylphosphine oxide
An alkene
+Ph3P=O R2C=CH2CH2
O CR2
Ph3P
Step 1:
Step 2:
:
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Wittig ReactionWittig Reaction• Examples:Examples:
-++
+
1-Phenyl-2-butene(87% Z isomer, 13% E isomer
OPhCH2CH Ph3P-CHCH3
PhCH2CH=CHCH3 Ph3P=O
-++
+
1-Phenyl-2-butene(87% Z isomer, 13% E isomer
OPhCH2CH Ph3P-CHCH3
PhCH2CH=CHCH3 Ph3P=O
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Addition of HAddition of H22OO Addition of water (hydration) to the carbonyl
group of an aldehyde or ketone gives a gem-diol, commonly referred to as a hydrate• when formaldehyde is dissolved in water at 20°C, the
carbonyl group is more than 99% hydrated
+
Formaldehyde Formaldehyde hydrate (>99%)
O
H
OH
HCH H2O HCOH
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Addition of HAddition of H22OO• the equilibrium concentration of a hydrated ketone is
considerably smaller
2,2-Propanediol (0.1%)
Acetone (99.9%)
+H3C
CH3C
O COH
H3C
H3C
OHH2O
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Addition of AlcoholsAddition of Alcohols Addition of one molecule of alcohol to the C=O
group of an aldehyde or ketone gives a hemiacetal
Hemiacetal:Hemiacetal: a molecule containing an -OH and an -OR or -OAr bonded to the same carbon
A hemiacetal
+
H
CH3CCH3 OCH2CH3 CH3COCH2CH3
OH
CH3
O
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Addition of AlcoholsAddition of Alcohols Hemiacetals are only minor components of an
equilibrium mixture, except where a five- or six-membered ring can form(the model is of the trans isomer)
4-Hydroxypentanal A cyclic hemiacetal(major form present at equilibrium)
O
OH O OHH3CCH3CHCH2CH2CH
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Addition of AlcoholsAddition of Alcohols Formation of a hemiacetal is base catalyzed• Step 1: proton transfer from HOR gives an alkoxide
• Step 2: Attack of RO- on the carbonyl carbon
• Step 3: proton transfer from the alcohol to O- gives the hemiacetal and generates a new base catalyst
B - + H OR B + - ORH: :
O
CH3-C-CH3– :O-R
O:–
CH3-C-CH3OR
+
OR
OH
CH3-C-CH3– :O-R++ H–OR
O:–
CH3 - C-CH3
OR
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Addition of AlcoholsAddition of Alcohols Formation of a hemiacetal is also acid catalyzed
Step 1: proton transfer to the carbonyl oxygen
Step 2: attack of ROH on the carbonyl carbon
Step 3: proton transfer from the oxonium ion to A- gives the hemiacetal and generates a new acid catalyst
O
CH3-C-CH3 H-AO
CH3-C-CH3
H
:A-
+
+ +
:
O
CH3-C-CH3
H
H-O-R
O
OH
RH
CH3-C-CH3+
+
+:
:
O
OH
RH
CH3-C-CH3
OR
OHCH3-C-CH3 H-A
++
A - ::
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Addition of AlcoholsAddition of Alcohols Hemiacetals react with alcohols to form acetals
Acetal:Acetal: a molecule containing two -OR or -OAr groups bonded to the same carbon
A diethyl acetal
+
+
A hemiacetal
OH
CH3
CH3
OCH2CH3
CH3COCH2CH3 CH3CH2OHH
+
CH3COCH2CH3 H2O
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Addition of AlcoholsAddition of AlcoholsStep 1: proton transfer from HA gives an oxonium ion
Step 2: loss of water gives a resonance-stabilized cation
HO
H
R-C-OCH3 H A:-
+
An oxonium ion
+ A
HHO
H
R-C-OCH3
+:
:H2 O+
A resonance-stabilized cation
+R-C OCH3
+
H
HHO
H
R-C-OCH3
+
R-C-OCH3H
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Addition of AlcoholsAddition of AlcoholsStep 3: reaction of the cation (a Lewis acid) with
methanol (a Lewis base) gives the conjugate acid of the acetal
Step 4: (not shown) proton transfer to A- gives the acetal and generates a new acid catalyst
H
CH3 -O
H
R-C-OCH3
OH CH3
+
A protonated acetal
+
H
R-C OCH3+
:
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Addition of AlcoholsAddition of Alcohols With ethylene glycol, the product is a five-
membered cyclic acetal
A cyclic acetalO CH2
CH2O
+O HOCH2CH2OHH
+
+ H2O
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Dean-Stark TrapDean-Stark Trap
QuickTime™ and aPhoto - JPEG decompressor
are needed to see this picture.
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Acetals as Protecting GrpsAcetals as Protecting Grps Suppose you wish to bring about a Grignard
reaction between these compounds
5-Hydroxy-5-phenylpentanal
4-BromobutanalBenzaldehyde
??+
H
O
H
O
H
OH O
Br
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Acetals as Protecting GrpsAcetals as Protecting Grps If the Grignard reagent were prepared from 4-
bromobutanal, it would self-destruct!• first protect the -CHO group as an acetal
• then do the Grignard reaction
• hydrolysis (not shown) gives the target molecule
H
OBr
A cyclic acetal
+H+
H2 OHOOH+ Br O
O
A cyclic acetal
Br O
O 1. Mg, ether
2. C6 H5CHO
O
OO-MgBr
+
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Acetals as Protecting GrpsAcetals as Protecting Grps Tetrahydropyranyl (THP) protecting group
• the THP group is an acetal and, therefore, stable to neutral and basic solutions and to most oxidizing and reducting agents
• it is removed by acid-catalyzed hydrolysis
RCH2OH +OO RCH2O
Dihydropyran A tetrahydropyranylether
H+
THP group
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Add’n of S NucleophilesAdd’n of S Nucleophiles Thiols, like alcohols, add to the C=O of
aldehydes and ketones to give tetrahedral carbonyl addition products
The sulfur atom of a thiol is a better nucleophile than the oxygen atom of an alcohol
A common sulfur nucleophile used for this purpose is 1,3-propanedithiol• the product is a 1,3-dithiane
32
1+
A 1,3-dithiane (a cyclic thioacetal)
+
An aldehyde
SC
S
R
HRCH
H+
H2 OHS SH
1,3-Propane-dithiol
O
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Add’n of S NucleophilesAdd’n of S Nucleophiles The hydrogen on carbon 2 of the 1,3-dithiane
ring is weakly acidic, pKa approximately 31
S
SC
H
RBu:- Li +
R
S
SC: Li
+ BuH+
A 1,3-dithiane(stronger acid)
pKa 31
Butane(weaker acid)
pKa 51
Butyllithium(stronger base)
A lithio-1,3-dithiane(weaker base)
+
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Add’n of S NucleophilesAdd’n of S Nucleophiles• a 1,3-dithiane anion is a good nucleophile and
undergoes SN2 reactions with methyl, 1° alkyl, allylic, and benzylic halides
• hydrolysis gives a ketone
+
Lithium salt ofa 1,3-dithiane
SN2
O
R'CH2-Br
R-C-CH2 R'H2 O, HgCl2
CH3CN
Li+
S
SC
CH2R'
R
S
SC:
R
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Add’n of S NucleophilesAdd’n of S Nucleophiles Treatment of the 1,3-dithiane anion with an
aldehyde or ketone gives an -hydroxyketone
S
SC:
RLi+
OH-C-R'
O:- Li +
S
SC
CH-R'
R
H2O, HgCl2CH3CN
O OHR C CH-R'
+
Lithium salt ofa 1,3-dithiane
An - -hydroxyketone
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Add’n of N NucleophilesAdd’n of N Nucleophiles Ammonia, 1° aliphatic amines, and 1° aromatic
amines react with the C=O group of aldehydes and ketones to give imines (Schiff bases)
CH3CH H2N H+
CH3CH=N H2 O+ +
Acetaldehyde Aniline An imine(a Schiff base)
O
An imine(a Schiff base)
AmmoniaCyclohexanone
++ NH3 H2 OO NHH
+
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Add’n of N NucleophilesAdd’n of N Nucleophiles Formation of an imine occurs in two steps
Step 1: carbonyl addition followed by proton transfer
Step 2: loss of H2O and proton transfer to solvent
:C
O
H2 N-R N-R
H
C
O:- H
N-R
H
C
O H
+
A tetrahedral carbonyl addition compound
+
:
O H
H
H
N-RH
C
OH
N-RH
C
OHH
OH
H
C N-R H2 O
An imine
+
+
++
:
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Add’n of N NucleophilesAdd’n of N Nucleophiles• a value of imines is that the carbon-nitrogen double
bond can be reduced to a carbon-nitrogen single bond
+
Dicyclohexylamine
Cyclohexanone
(An imine)
Cyclohexylamine
O
N N
H
-H2O
H2 / Ni
H+
H2N
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Add’n of N NucleophilesAdd’n of N Nucleophiles Rhodopsin (visual purple) is the imine formed
between 11-cis-retinal (vitamin A aldehyde) and the protein opsin
1
5
11
12
11-cis-Retinal
Rhodopsin(Visual purple)
H2 N-OPSIN
H N-OPSIN
H O
+
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Add’n of N NucleophilesAdd’n of N Nucleophiles Secondary amines react with the C=O group of
aldehydes and ketones to form enamines
• the mechanism of enamine formation involves formation of a tetrahedral carbonyl addition compound followed by its acid-catalyzed dehydration
• we discuss the chemistry of enamines in more detail in Chapter 19
O H-NH
+
N H2 O
An enaminePiperidine(a secondary amine)
++
Cyclohexanone
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Add’n of N NucleophilesAdd’n of N Nucleophiles The carbonyl group of aldehydes and ketones
reacts with hydrazine and its derivatives in a manner similar to its reactions with 1° amines
• hydrazine derivatives include
Hydrazine
++
A hydrazone
O NNH2H2NNH2 H2O
Hydroxylamine PhenylhydrazineH2N-OH H2N-NH
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Acidity of Acidity of -Hydrogens-Hydrogens Hydrogens alpha to a
carbonyl group are more acidic than hydrogens of alkanes, alkenes, and alkynes but less acidic than the hydroxyl hydrogen of alcohols
Type of BondpKa
16
20
25
44
51
O
CH3C C-H
CH3CH2O-H
CH3CCH2-H
CH2=CH-H
CH3CH2-H
1616
16-56
Acidity of Acidity of -Hydrogens-Hydrogens -Hydrogens are more acidic because the
enolate anion is stabilized by 1. delocalization of its negative charge
2. the electron-withdrawing inductive effect of the adjacent electronegative oxygen
:
:
O
CH3-C-CH2 -H :A-
O-
CH3-C=CH2 H-A
Enolate anion
+
+
O
CH3-C CH2
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Keto-Enol TautomerismKeto-Enol Tautomerism• protonation of the enolate anion on oxygen gives the
enol form; protonation on carbon gives the keto form
Enolate anion
Enol formKeto form
-O
CH3-C-CH2 CH3-C=CH2
CH3-C=CH2
H-A
CH3-C-CH3 + A- A- +
H-AOH
O-
O
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16-58
Keto-Enol TautomerismKeto-Enol Tautomerism• acid-catalyzed equilibration of keto and enol
tautomers occurs in two steps
Step 1: proton transfer to the carbonyl oxygen
Step 2: proton transfer to the base A-
O:
CH3-C-CH3 H-A
O
CH3-C-CH3
H
A:-+
+fast
+Keto form The conjugate acid
of the ketone
O
+
+
+Keto form The conjugate acid
of the ketone
:O
CH3-C-CH2-H
H
:A-OH
CH3-C=CH2 H-A
Enol form
+
+slow
+
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16-59
Keto-Enol TautomerismKeto-Enol Tautomerism Keto-enol
equilibria for simple aldehydes and ketones lie far toward the keto form
OH
O
O
CH3CH CH2=CH
CH3CCH3
Keto form Enol form% Enol atEquilibrium
6 x 10-5
OH
CH3C=CH2 6 x 10-7
O
O OH
OH
1 x 10-6
4 x 10-5
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16-60
Keto-Enol TautomerismKeto-Enol Tautomerism For certain types of molecules, however, the
enol is the major form present at equilibrium• for β-diketones, the enol is stabilized by conjugation
of the pi system of the carbon-carbon double bond and the carbonyl group
H
H
HH
HO H
O
conjugatedsystem
1,3-Cyclohexanedione
O
O
O
OH
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16-61
Keto-Enol TautomerismKeto-Enol Tautomerism Open-chain β-diketones are further stabilized by
intramolecular hydrogen bonding
2,4-Pentanedione (Acetylacetone)
δ+δ-
hydrogenbonding
80%20%
O O O OH
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16-62
RacemizationRacemization Racemization at an -carbon may be catalyzed
by either acid or base
An achiral enol(R)-3-Phenyl-2-butanone
(S)-3-Phenyl-2-butanone
C C
O
CH3
Ph
HH3C
CH
H3C
Ph
C
CH3
OOH
CCCH3
Ph
H3C
acid or
base
acid or
base
1616
16-63
Deuterium ExchangeDeuterium Exchange Deuterium exchange at an -carbon may be
catalyzed by either acid or base
+
Acetone-d6 Acetone+
O O
CH3CCH3 6D2O CD3CCD3 6HODD+
or OD-
1616
16-64
-Halogenation-Halogenation -Halogenation: aldehydes and ketones with at
least one -hydrogen react at an -carbon with Br2 and Cl2
• reaction is catalyzed by both acid and base
Acetophenone
++CCH3
O OCCH2BrBr2 CH3COOH
HBr
1616
16-65
-Halogenation-Halogenation Acid-catalyzed -halogenation
Step 1: acid-catalyzed enolization
Step 2: nucleophilic attack of the enol on halogen
slow
R'
C C
H-O R
R
R'-C-C-R
R
HO
R'
C CH-O R
R
Br BrR'
C C
O
R H+ Br:-+fast+ +
R
Br
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16-66
-Halogenation-Halogenation Base-promoted -halogenation
Step 1: formation of an enolate anion
Step 2: nucleophilic attack of the enolate anion on halogen
:+
-
Resonance-stabilized enolate anion
+slowO H
R
O
C C
R'R'
C C
O:
R'-C-C-R -:OH H2 O
R
R
R
R
+O:-
C CR'
R
R
fast
R'
C C
O Br
R
R :Br-Br Br +
1616
16-67
-Halogenation-Halogenation Acid-catalyzed halogenation: • introduction of a second halogen is slower than the
first• introduction of the electronegative halogen on the -
carbon decreases the basicity of the carbonyl oxygen toward protonation
Base-promoted -halogenation:• each successive halogenation is more rapid than the
previous one • the introduction of the electronegative halogen on the -carbon increases the acidity of the remaining -hydrogens and, thus, each successive -hydrogen is removed more rapidly than the previous one
1616
16-68
Haloform ReactionHaloform Reaction In the presence of base, a methyl ketone reacts
with three equivalents of halogen to give a 1,1,1-trihaloketone, which then reacts with an additional mole of hydroxide ion to form a carboxylic salt and a trihalomethane
RCCH3
O3Br2
3NaOHRCCBr3
ONaOH
RCO-Na
+O
CHBr3+
Tribromomethane (Bromoform)
+
5-Methyl-3-hexen-2-one 4-Methyl-2-pentenoicacid
Trichloromethane(Chloroform)
1. Cl2 / NaOH
2. HCl/ H2 OCHCl3
O
OH
O
1616
16-69
Haloform ReactionHaloform Reaction The final stage is divided into two steps
Step 1: addition of OH- to the carbonyl group gives a tetrahedral carbonyl addition intermediate and is followed by its collapse
Step 2: proton transfer from the carbonyl group to the haloform anion
:O
RC-CBr3-:OH
O-
RC-CBr3
OH
ORC
OH
-:CBr3+ +
Conjugate baseof bromoform
-:CBr3
O
RC-O:-
O
RC-O-H + + H-CBr3Bromoform
1616
16-70
Oxidation of AldehydesOxidation of Aldehydes Aldehydes are oxidized to carboxylic acids by a
variety of oxidizing agents, including H2CrO4
They are also oxidized by Ag(I) • in one method, a solution of the aldehyde in aqueous
ethanol or THF is shaken with a slurry of silver oxide
CHO H2CrO4 COOH
Hexanal Hexanoic acid
Vanillic acidVanillin
++CH
HO
CH3OO O
CH3O
HO
COH
Ag2OTHF, H2O
NaOHAgHCl
H2O
1616
16-71
Oxidation of AldehydesOxidation of Aldehydes Aldehydes are oxidized by O2 in a radical chain
reaction• liquid aldehydes are so sensitive to air that they must
be stored under N2
Benzoic acidBenzaldehyde
+CH
O O
COH2O22
1616
16-72
Oxidation of KetonesOxidation of Ketones• ketones are not normally oxidized by chromic acid• they are oxidized by powerful oxidants at high
temperature and high concentrations of acid or base
Hexanedioic acid (Adipic acid)
Cyclohexanone(keto form)
Cyclohexanone(enol form)
HNO3
O
HOOH
OO OH
1616
16-73
ReductionReduction• aldehydes can be reduced to 1° alcohols• ketones can be reduced to 2° alcohols • the C=O group of an aldehyde or ketone can be
reduced to a -CH2- group
AldehydesCan BeReduced to Ketones
Can BeReduced to
O OOH
RCHRCH2 OH
RCH3
RCR'RCHR'
RCH2 R'
1616
16-74
Catalytic ReductionCatalytic Reduction Catalytic reductions are generally carried out at
from 25° to 100°C and 1 to 5 atm H2
+25oC, 2 atm
Pt
Cyclohexanone Cyclohexanol
O OH
H2
1-Butanol trans-2-Butenal(Crotonaldehyde)
2H2
NiH
O
OH
1616
16-75
Catalytic ReductionCatalytic Reduction A carbon-carbon double bond may also be
reduced under these conditions
• by careful choice of experimental conditions, it is often possible to selectively reduce a carbon-carbon double in the presence of an aldehyde or ketone
1-Butanol trans-2-Butenal(Crotonaldehyde)
2H2
NiH
O
OH
1616
16-76
Metal Hydride ReductionMetal Hydride Reduction The most common laboratory reagents for the
reduction of aldehydes and ketones are NaBH4 and LiAlH4
• both reagents are sources of hydride ion, H:-, a very powerful nucleophile
Hydride ionLithium aluminum hydride (LAH)
Sodium borohydride
H
H H
H
H-B-H H-Al-HLi +Na+
H:
1616
16-77
NaBHNaBH44 Reduction Reduction• reductions with NaBH4 are most commonly carried out
in aqueous methanol, in pure methanol, or in ethanol
• one mole of NaBH4 reduces four moles of aldehyde or ketone
4RCHO
NaBH4
(RCH2O)4B- Na
+ H2O4RCH2OH
A tetraalkyl borateborate salts
+
+ methanol
1616
16-78
NaBHNaBH4 4 ReductionReduction The key step in metal hydride reduction is
transfer of a hydride ion to the C=O group to form a tetrahedral carbonyl addition compound
from water
from the hydride reducing agent
+
H
H O O BH3
OH
H
H
H-B-HNa+
R-C-R' R-C-R'
Na+
H2 O
R-C-R'
1616
16-79
LiAlHLiAlH4 4 ReductionReduction• unlike NaBH4, LiAlH4 reacts violently with water,
methanol, and other protic solvents• reductions using it are carried out in diethyl ether or
tetrahydrofuran (THF)
4RCR LiAlH4
(R2CHO)4Al- Li+H2O
4RCHR
OH
+
+ aluminum salts
ether
A tetraalkyl aluminate
O
1616
16-80
Metal Hydride ReductionMetal Hydride Reduction• metal hydride reducing agents do not normally reduce
carbon-carbon double bonds, and selective reduction of C=O or C=C is often possible
O OH
RCH=CHCR' RCH=CHCHR'1. NaBH4
2. H2O
+Rh
O
RCH=CHCR' RCH2 CH2CR'H2
O
1616
16-81
Clemmensen ReductionClemmensen Reduction• refluxing an aldehyde or ketone with amalgamated
zinc in concentrated HCl converts the carbonyl group to a methylene group
Zn(Hg), HClOH O OH
1616
16-82
Wolff-Kishner ReductionWolff-Kishner Reduction• in the original procedure, the aldehyde or ketone and
hydrazine are refluxed with KOH in a high-boiling solvent
• the same reaction can be brought about using hydrazine and potassium tert-butoxide in DMSO
+
diethylene glycol (reflux)
KOH
N2
Hydrazine
+ H2 NNH2
+ H2O
O
1616
16-83
Prob 16.19Prob 16.19 Draw a structural formula for the product formed by
treating each compound with propylmagnesium bromide followed by aqueous HCl.
OCH2O
O(c)
(b)(a)
(d)O
1616
16-84
Prob 16.20Prob 16.20 Suggest a synthesis of each alcohol from an aldehyde or
ketone and a Grignard reagent. Under each is the number of combinations of Grignard reagents and aldehyde or ketone that might be used.
(a) (b) (c)
3 Combinations 2 Combinations 2 Combinations
OH OHOH
OCH3
1616
16-85
Prob 16.21Prob 16.21 Show how to prepare this alcohol from the three given
starting materials.
+ +
several stepsBr O
OHCHO
1616
16-86
Prob 16.22Prob 16.22 Show how to synthesize 1-phenyl-2-butanol from these
starting materials.
1-ButeneBromobenzene
+
several steps
1-Phenyl-2-butanol
Br OH
1616
16-87
Prob 16.24Prob 16.24 Draw the Wittig reagent formed from each haloalkane,
and for the alkene formed by treating the Wittig reagent with acetone.
(a) (b)
(c)
Br Br
Cl(d)
(e) (f)
ClO
O
Br Ph Cl
1616
16-88
Prob 16.25Prob 16.25 Show how to bring about each conversion using a Wittig
reaction.O
(a)
(b)
O
(c) O CH OCH3
OCH3
1616
16-89
Prob 16.26Prob 16.26 Show two sets of reagents that might be combined in a
Wittig reaction to give this conjugated diene.
1-Phenyl-1,3-pentadiene
CH=CHCH=CHCH3
1616
16-90
Prob 16.27Prob 16.27 Wittig reactions with an -haloether can be used for the
synthesis of aldehydes and ketones. To see this, convert each -haloether to a Wittig reagent, and react the Wittig reagent with cyclopentanone followed by hydrolysis in aqueous acid.
ClCH2OCH3 ClCHOCH3
CH3
(A) (B)
1616
16-91
Prob 16.28Prob 16.28Suggest a mechanism for the reaction of a sulfur ylide with a ketone to give an epoxide.
Ph
S CH
CH3
Ph CH3
Br-
Ph
S C
CH3
Ph CH3
OO
CH3
C
CH3
S
Ph
CH3Ph
(Ph)2S
-++strong base
A sulfonium bromide salt A sulfur ylide
-++ +
:
:
1616
16-92
Prob 16.29Prob 16.29Propose a structural formula for compound D and for the product C9H14O.
S
C6H5
C6H5
Br - BuLiD
O
C9H14O+
1616
16-93
Prob 16.30Prob 16.30Draw a structural formula for the cyclic hemiacetal. How many stereoisomers are possible for it? Draw alternative chair conformations for each possible stereoisomer.
a cyclic hemiacetal
5-Hydroxyhexanal
H+
H
OOH
1616
16-94
Prob 16.31Prob 16.31Draw structural formulas for the hemiacetal and acetal formed from each pair of reagents in the presence of an acid catalyst.
(a)
(b)
(c)
+
+
+
OH
OH
O
CH3CH2 OH
CH3CH2 CH2CH CH3OH
CH3CCH3
O
O
1616
16-95
Prob 16.32Prob 16.32Draw structural formulas for the products of hydrolysis of each acetal in aqueous acid.
(a)
(c)
(b)O
OCH3
H
CH3O OCH3
O
O CHO
1616
16-96
Prob 16.33Prob 16.33Propose a mechanism for this reaction. If the carbonyl oxygen is enriched with oxygen-18, will the oxygen label appear in the cyclic acetal or in the water?
A cyclic acetal
+4-Hydroxypentanal
OCH3O
H+
CH3OH
H2 O
OHH
O
+
1616
16-97
Prob 16.34Prob 16.34Propose a mechanism for this acid-catalyzed reaction.
+ H+
H2 OOCH3 O
+ CH3OH
1616
16-98
Prob 16.35Prob 16.35Propose a mechanism for this acid-catalyzed rearrangement.
AcetonePhenolCumenehydroperoxide
+CCH3
CH3
OOH
OH
OH2 SO4CH3CCH3
1616
16-99
Prob 16.37Prob 16.37Show how to bring about this conversion.
H
O
H
O
HOOH
1616
16-100
Prob 16.39Prob 16.39Which compound will cyclize to give the insect pheromone frontalin?
Frontalin
CBA
O
O
O OOH
OH
OO
HOO
O
1616
16-101
Prob 16.41Prob 16.41Draw a structural formula for the product formed by treating each compound with (1) the lithium salt of the 1,3-dithiane derived from acetaldehyde and then (2) H2O,
HgCl2.
(c)
(b)
(a) CH
CH2 CHO
ClCH2CH=CH2
O
1616
16-102
Prob 16.42Prob 16.42Show how to bring about each conversion using a 1,3-dithiane.
(a)
(b)
OO
H
H
O
PhPh
OOH
(c) OH
OO
H
1616
16-103
Prob 16.44Prob 16.44Show how each compound can be synthesized by reductive amination of an aldehyde or ketone and an amine.
(a) (b)
Amphetamine Methamphetamine
NH2 NH
1616
16-104
Prob 16.45Prob 16.45Show how to bring about this final step in the synthesis of the antiviral drug rimantadine.
O NH2
1616
16-105
Prob 16.46Prob 16.46Draw a structural formula for the -hydroxyaldehyde and -hydroxyketone with which this enediol is in equilibrium.
-Hydroxyketoneα-Hydroxyaldehyde
An enediol
CH-OH
C-OH
CH3
1616
16-106
Prob 16.47Prob 16.47Propose a mechanism for the isomerism of (R)-glyceraldehyde to (R,S)-glyceraldehyde and dihydroxyacetone.
CHO
CHOH
CH2OH
NaOHCHOH
CH2OH
CHO CH2OH
C=O
CH2OH
+
Dihydroxyacetone(R)-Glyceraldehyde (R,S)-Glyceraldehyde
1616
16-107
Prob 16.48Prob 16.48When cis--decalone is dissolved in ether containing a trace of HCl, the following equilibrium is established. Propose a mechanism for the isomerization and account for the fact that the trans isomer predominates.
H
Hcis-2-Decalone trans-2-Decalone
O
H
HO
HCl
1616
16-108
Prob 16.49Prob 16.49When this bicyclic ketone is treated with D2O in the presence of an acid catalyst, only two of the three -hydrogens exchange. Propose a mechanism for the exchange and account for the fact that the bridgehead hydrogen does not exchange.
These two - hydrogens exchange
This -hydrogen does not exchange
H
HO
H
1616
16-109
Prob 16.51Prob 16.51Propose a mechanism for the formation of the bracketed intermediate and for the formation of the sodium salt of cyclopentanecarboxylic acid.
NaOH
OCl
CO-Na+
OHCl COH
O
THF
O
H2O
A proposedintermediate
NaOH
THF
1616
16-110
Prob 16.52Prob 16.52If the Favorskii rearrangement is carried out using sodium ethoxide in ethanol, the product is an ethyl ester. Propose a mechanism for this reaction.
CH3CH2O-Na+O
ClCOCH2CH3
O
CH3CH2OH
1616
16-111
Prob 16.53Prob 16.53Propose a mechanism for each step in this transformation, and account for the regioselectivity of the HCl addition.
1. NaOHO
2. HCl
(R)-(+)-Pulegone
HCl
OCl
(R)-3,7-Dimethyl-6-octenoic acid (R)-Citronellic acid
C
O
OH
1616
16-112
Prob 16.57Prob 16.57Show how to convert cyclopentanone to each compound.
(a) OH (b) Cl
(c)OH
(d)CH-CH=CH2
1616
16-113
Prob 16.59Prob 16.59Propose structural formulas for A, B, and C. Show how C can also be prepared by a Wittig reaction.
Lindlarcatalyst
heat
A
B C
1. HC CH, NaNH2 C7H1 0OH2
C7H1 2OKHSO4 C7H1 0
2. H2O
O
1616
16-114
Prob 16.60Prob 16.60Given this retrosynthetic analysis, show how to synthesize cis-3-penten-2-ol from the three given starting materials.
OH OH +HCCH3
CH3I +HC CH
O
1616
16-115
Prob 16.61Prob 16.61Propose a synthesis for Oblivon from acetylene and a ketone.
OblivonHO
1616
16-116
Prob 16.62Prob 16.62Propose a synthesis for Surfynol from acetylene and a ketone.
Surfynol
OHOH
1616
16-117
Prob 16.63Prob 16.63Propose a mechanism for this acid-catalyzed rearrangement.
C CH
CH
OH CHOH
+
1616
16-118
Prob 16.64Prob 16.64Propose a mechanism for this acid-catalyzed rearrangement.
O ArSO3H
O
1616
16-119
Prob 16.66Prob 16.66Propose mechanisms for Steps (1) and (4) and reagents for Steps (2), (3), and (5).
+
(4)
(5)Vitamin A acetate
(1) (2 )
(3)
β-IononePseudoionone
PPh3 OCCH3
O
O O
OH OHPh3 P, HBr
H2 SO4
Br-
1616
16-120
Prob 16.68Prob 16.68Propose a mechanism for this Lewis acid catalyzed isomerization. Account for the fact that only a single stereoisomer of isopulegol is formed.
H
O
(S)-Citronellal(C10H18O)
1. SnCl4, CH2Cl2
2. NH4Cl OH
Isopulegol(C10H18O)
1616
16-121
Aldehydes Aldehydes & &
KetonesKetonesEnd Chapter 16End Chapter 16
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