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Organic Chemistry II
Aldehydes
Ketones
7th
March, 2012
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Aldehydes&
Ketones
Chapter 16 Rod cells in the humaneye. Inset: a model of 11-c is-retinal, an oxidizedform of vitamin A.
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The Carbonyl Group
In this and several following chapters, we study
the physical and chemical properties of classesof compounds containing the carbonyl group,C=O
aldehydes and ketones (Chapter 16)
carboxylic acids (Chapter 17)
acid halides, acid anhydrides, esters, amides (Chapter18)
enolate anions (Chapter 19)
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Structure
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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Nomenclature
IUPAC names:
the parent chain is the longest chain that contains thefunctional group
for an aldehyde, change the suffix from -e to -al
for an unsaturated aldehyde, change the infix from -an-
to -en-; the location of the suffix determines thenumbering pattern
for a cyclic molecule in which -CHO is bonded to thering, add the suffix -carbaldehyde
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Nomenclature: Aldehydes
H
O
3-Methylbutanal 2-Propenal(Acrolein) (2E
)-3,7-Dimethyl-2,6-octadienal(Geranial)
1
2
3
4
5
6
7
8H
O
H
O
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Nomenclature: Aldehydes
CHO HO CHO
Cyclopentane-carbaldehyde
trans-4-Hydroxycyclo-
hexanecarbaldehyde
14
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Nomenclature: Aldehydes
the IUPAC retains the common names benzaldehyde
and cinnamaldehyde, as well formaldehyde andacetaldehyde
CHOC6 H5CHO
t rans -3-Phenyl-2-propenal
(Cinnamaldehyde)
Benzaldehyde
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Nomenclature: Aldehydes
Benzaldehyde is found in the kernels of bitter almonds.
Cinnamaldehyde is found in Ceylon and Chinese cinnamon oils.
Benzaldehyde
Cinnamaldehyde
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Nomenclature: Ketones
IUPAC names
the parent alkane is the longest chain that contains thecarbonyl group
indicate the ketone by changing the suffix -e to -one
number the chain to give C=O the smaller number
the IUPAC retains the common names acetone,acetophenone, and benzophenone
Propanone(Acetone)
Benzophenone 1-Phenyl-1-pentanoneAcetophenone
O O OO
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Order of Precedence
For compounds that contain more than one
functional group indicated by a suffix
HCOOH
O
COOH
O
COOHHO
OHHS
COOH
NH2
FunctionalGroup
Carb oxyl -oic acidAldehyde -al oxo-
Ketone -one oxo-
Alcohol -ol hydroxy-
Amino -amine amino-
3-Oxopropanoicacid
3-Oxobutanoic acid
4-Hydroxybutanoicacid
3-Aminobutanoicacid
Example when thefunctional group h as
a lower priority
Sulfhydryl -thiol mercapto 2-Mercaptoethanol
Suffix if
higherpriority
Pref ix iflowerpriority
Increasing precedence
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Common 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
HCH
O
HCOH
O
CH3 CH
O
CH3COH
O
Formaldehyde Formic acid Acetaldehyde Acetic acid
Ethyl isopropyl ketone Diethyl ketone Dicyclohexyl ketone
O O
O
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Physical 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 comparablemolecular weight
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Reaction Themes
One of the most common reaction themes of a
carbonyl group is addition of a nucleophile toform a tetrahedral carbonyl addition compound
Tetrahedral carbonyladdition compound
+ C
R
R
O CNu
O-
RR
Nu-
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Reaction Themes
A second common theme is reaction with a
proton or other Lewis acid to form a resonance-stabilized cation
protonation increases the electron deficiency of thecarbonyl carbon and makes it more reactive toward
nucleophiles
B-
C OR
R
H-Nu
H-B
C O
R
RH
B-
C O
R
RH
CNu
O-H
RR
C O
R
RH
H-B
+fast +
++
+slow
Tetrahedral carbonyladdition compound
++ +
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Reaction Themes
often the tetrahedral product of addition to a carbonyl
is a new chiral center if none of the starting materials is chiral and the
reaction takes place in an achiral environment, thenenantiomers will be formed as a racemic mixture
Nu-
C OR
R'
Nu
OR'
R
Nu
OR
R'+
H3 O+
Nu
OHR
R'
Nu
OHR'
R
+
A racemic mixtureA new chiralcen ter is created
Approach fromthe bottom face
Approach fromthe top face
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Addition of C Nucleophiles
Addition of carbon nucleophiles is one of the
most important types of nucleophilic additions toa C=O group
a new carbon-carbon bond is formed in the process
we study addition of these carbon nucleophiles
RMgX RLi-
CRC C-
N
A Grignardreagent
An organolithiumreagent
An alkyneanion
Cyanide ion
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Grignard Reagents
Given the difference in electronegativity between
carbon and magnesium (2.5 - 1.3), the C-Mg bondis polar covalent, with C- and Mg+ in its reactions, a Grignard reagent behaves as a
carbanion
Carbanion:an anion in which carbon has anunshared pair of electrons and bears a negativecharge
a carbanion is a good nucleophile and adds to thecarbonyl group of aldehydes and ketones
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Grignard Reagents
addition of a Grignard reagent to formaldehyde
followed by H3O+ gives a 1 alcohol
CH3CH2 -MgBr
O
H-C-H
O-[ MgBr]
+
CH3CH2 -CH2HCl
H2O
OH
CH3CH2 -CH2 Mg2+
ether
1-Propanol
(a 1 alcohol)
Formaldehyde
+
+
A magnesium
alkoxide
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Grignard Reagents
addition to any other RCHO gives a 2 alcohol
MgBr
H
O
O-[ MgBr]
+
HCl
H2O
OH
Mg2+
+ether
Acetaldehyde(an aldehyde)
+
A magnesiumalkoxide 1-Cyclohexylethanol(a 2 alcohol;(racemic)
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Grignard Reagents
addition to a ketone gives a 3 alcohol
Ph-MgBrO
Ph
O-[ MgBr]
+HCl
H2O Ph
OHMg2+
+
Acetone(a ketone)
ether
+
A magnes iumalkoxide
2-Phenyl-2-propanol(a 3 alcohol)
Phenyl-magnesium
bromide
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Grignard Reagents
Problem:2-phenyl-2-butanol can be synthesized by three
different combinations of a Grignard reagent and aketone. Show each combination.
C-CH2 CH3
CH3
OH
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Organolithium Compounds
Organolithium compounds are generally more
reactive in C=O addition reactions than RMgX,and typically give higher yields
LiO
O-
Li+
HCl
H2O
OH
3,3-Dimethyl-2-butanone
3,3-Dimethyl-2-phenyl-2-butanol(racemic)
+
Phenyl-lithium
A li thium alkoxide(racemic)
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Salts of Terminal Alkynes
Addition of an alkyne anion followed by H3O+
gives an -acetylenic alcohol
C:-
Na+
HC
OC O
-Na
+HC
HCl
H2 O
C OHHC
1-Ethynyl-cyclohexanol
A sodiumalkoxide
+
CyclohexanoneSodiumacetylide
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Salts of Terminal Alkynes
H2 O
HO C CHH2 SO4 , HgSO4
1. (sia)2 BH
2. H2O2 , NaOH
O
HO CCH3
HO CH2CHO
An -hydroxyketone
A -hydroxyaldehyde
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Addition of HCN
HCN adds to the C=O group of an aldehyde or
ketone to give a cyanohydrin Cyanohydrin:a molecule containing an -OH
group and a -CN group bonded to the samecarbon
2-Hydroxypropanenitrile
(Acetaldehyde cyanohydrin)
+ HC N CH3C-C NCH3CH
OH
H
O
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Addition of HCN
Mechanism of cyanohydrin formation
Step 1: nucleophilic addition of cyanide to thecarbonyl carbon
Step 2: proton transfer from HCN gives thecyanohydrin and regenerates cyanide ion
- +
H3 CC
H3 C
O C
O-
H3 C
H3 C
C
N
N
C
C
O -
H3 C
H3 C
C N
NH C C
C
H3 C
H3 C
O-H
NC N++
-
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Wittig Reaction
The Wittig reaction is a very versatile synthetic
method for the synthesis of alkenes fromaldehydes and ketones
Triphenyl-phosphine oxide
Methylene-cyclohexane
A phosphoniumylide
++
-+
CH2 Ph3P=OPh3 P-CH2
Cyclohexanone
O
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Phosphonium Ylides
Phosphonium ylidesare formed in two steps:
Step 1: nucleophilic displacement of iodine bytriphenylphosphine
Step 2: treatment of the phosphonium salt with a verystrong base, most commonly BuLi, NaH, or NaNH
2
Ph3P CH3 -I Ph3P-CH3 I
Triphenylphosphine
++
SN2
Methyltriphenylphosphonium iodide(an alkyltriphenylphosphine salt)
CH3 CH2 CH2 CH2 -Li
+H-CH2 -PPh3 I
-
-CH2 -PPh3CH3 CH2 CH2 CH3 LiI
A phosphonium
ylide
Butane
Butyllithium
+++
++
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Wittig Reaction
Phosphonium ylides react with the C=O group of
an aldehyde or ketone to give an alkene Step 1: nucleophilic addition of the ylide to the
electrophilic carbonyl carbon
Step 2: decomposition of the oxaphosphatane
CR2
O
CH2Ph3PCH2
-
:O CR2
Ph3P
O CR2
Ph3P CH2-+
An oxaphosph etane
+
A betaine
CH2
O CR2
Ph3 PPh3P=O R2 C=CH2
An alkene
+
Triphenylphosphineoxide
Wi i R i
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Wittig Reaction
Examples:
O Ph3 P+ Ph3P=O
2-Methyl-2-heptene
+
Acetone
Ph O
H
Ph3 P Ph Ph Ph3P=O
Phenyl-acetaldehyde
+ ++
(Z)-1-Phenyl-2-butene
(87%)
(E)-1-Phenyl-2-butene
(13%)
PhO
H
OEtPh3 P
O
PhOEt
O
Ph3P=O
Ethyl (E)-4-phenyl-2-butenoate
(only the E is omer is formed)
++
Phenyl-acetaldehyde
Wi i R i
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Wittig Reaction
some Wittig reactions are Zselective, others are E
selective Wittig reagents with an anion-stabilizing group, such
as a carbonyl group, adjacent to the negative chargeare generally Eselective
Wittig reagents without an anion-stabilizing group aregenerally Zselective
OEtPh3 P
O
OEtPh3 P
O
Resonance contributing structures for anylide stabilized by an adjacent carbonyl group
Wi i R i
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Wittig Reaction
Horner-Emmons-Wadsworth modification
uses a phosphonoester
Br-CH2 -C-OEt
O
( MeO)3 PBr-CH2 -C-R
O
(MeO) 2 P-CH2-C-R
OO
( MeO)2 P-CH2 -C-OEt
OO
MeBr
MeBran -bromoester
an -bromoketone
+
+
An -phosphonoester
An -phosphonoketoneTrimethyl-phosphite
Witti R ti
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Wittig Reaction
phosphonoesters are prepared by successive SN2
reactions
( MeO)3 P CH2 -C-OEt
O
Br
CH3 -O-P-CH2 -C-OEt
O
OMe
OMe
Br
( MeO)2 P-CH2 -C-OEt
OO
MeBr
+
+
SN 2
SN 2
An -phosphonoester
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Additi f H O
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Addition of H2O
Addition of water (hydration) to the carbonyl
group of an aldehyde or ketone gives a geminaldiol, commonly referred to a gem-diol
gem-diols are also referred to as hydrates
C O + H2 O C
OH
OH
Carbonyl groupof an aldehyde
or ketone
A hydrate(a gem-diol)
acid orbase
Additi f H O
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Addition of H2O
when formaldehyde is dissolved in water at 20C, the
carbonyl group is more than 99% hydrated
the equilibrium concentration of a hydrated ketone isconsiderably smaller
H
H
O H2 O+
Formaldehyde
H
HOH
OH
Formaldehyde hydrate
(>99%)
O H2 O+
2,2-Propanediol(0.1%)
Acetone(99.9%)
OH
OH
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Continue next week
Additi f Al h l
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Addition of Alcohols
Addition of one molecule of alcohol to the C=O
group of an aldehyde or ketone gives ahemiacetal
Hemiacetal:a molecule containing an -OH and an-OR or -OAr bonded to the same carbon
O H-OEtOH
OEt+
acid orbase
A hemiacetal
Ar = aryl group
Addition of Alcohols
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Addition of Alcohols
hemiacetals are only minor components of an
equilibrium mixture, except where a five- or six-membered ring can form
(S)-4-Hydroxypentanal Cyclic hemiacetals(major forms present at equilibriu m)
OH
H
O
O OH O OH+
41 14 14
OH
OH
OH
HO
H
OOH
O
OH
HO
HO
CH2OH
OH
HO
CH2OH
O
OH
HO OH1
2
3
6
6
12
anomericcarbon
Anomer ofD -glucosecyclic hemiacetal
(predominates
at equ ilibrium)
Anomer ofD -glucose cyclic
hemiacetal
+
4
5
D-Glucose(open chain form)
123
4 5
3
4 5
6
Addition of Alcohols
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Addition of Alcohols
at equilibrium, the anomer of glucose predominatesbecause the -OH group on the anomeric carbon isequatorial
O
OH
HO
OHHO
O
OH
OH
HO
HO
CH2 OH
OHO
HO
HO
OH
O
OH
HO
HOCH2 OH
OH
1
234 5
6
anomericcarbon
Anomer
anomericcarbon
132
4 56
(equatorial)
123
4 5
6
anomericcarbon
Anomer of
anomericcarbon
13
2
4 56
(axial)
redraw asa chair
conformation
redraw asa chair
conformation
OH
OH
Addition of Alcohols
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Addition 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 thehemiacetal and generates a new base catalyst
B - H OR B H- OR+ +
fast andreversible
CH3 -C-CH3
O
:O-R
O:
CH3 -C-CH3
OR
+
O:
CH3 -C-CH3
OR
H OR
OR
OH
CH3 -C-CH3-
OR++
Addition of Alcohols
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Addition 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-
givesthe hemiacetal and generates a new acid catalyst
O
CH3 -C-CH3 H-A
O
CH3 -C-CH3
H
A-
+
+ +
fast andreversible
O
CH3 -C-CH3
H
H-O-R CH3 -C-CH3
O-H
ORH
++
+
RH
CH3 -C-CH3
O
OH
OR
OH
CH3 -C-CH3 H-A
A -
+
+
Addition of Alcohols
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Addition of Alcohols
Hemiacetals react with alcohols to form acetals
Acetal:a molecule containing two -OR or -OAr groupsbonded to the same carbon
OH
OEtH-OEt
H+
OEt
OEtH2O
A diethyl acetal
+
A h emiacetal
+
Addition of Alcohols
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Addition of Alcohols
Step 1: proton transfer from HA gives an oxonium ion
Step 2: loss of water gives a resonance-stabilized cation
HO
R-C-OCH3
H
H A
HHO
H
R-C-OCH3 A:-
+
An oxonium ion
+
+
R-C OCH3
H
OHH
H
R-C OCH3 R-C
H
OCH3 H2 O+
A resonance-stabilized cation
++
+
Addition of Alcohols
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Addition of Alcohols
Step 3: reaction of the cation (an electrophile) with
methanol (a nucleophile) gives the conjugate acid ofthe acetal
Step 4: proton transfer to A- gives the acetal andgenerates a new acid catalyst
CH3 -OH
H
R-C OCH3 R-C OCH3
H
OCH3H
A protonated acetal
++
+
A:-
R-C OCH3
H
OCH3H OCH3
H
R-C-OCH3 H-A+(4)
An acetal
+
+
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Dean Stark Trap
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Dean-Stark Trap
Acetals as Protecting Grps
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Acetals as Protecting Grps
Suppose you wish to bring about a Grignard
reaction between these compounds
5-Hydroxy-5-phenylpentanal(racemic)
4-BromobutanalBenzaldehyde
??+
H
O
H
O
H
OH O
Br
Acetals as Protecting Groups
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Acetals as Protecting Groups
a Grignard reagent prepared from 4-
bromobutanal will self-destruct! first protect the -CHO group as an acetal
then do the Grignard reaction
hydrolysis (not shown) gives the target molecule
H
O
Br
A cyclic acetal
+H
+
H2OHO
OH+Br
O
O
Br O
O1. Mg, ether
2. C6H5 CHO
O
OO-MgBr
+
A chiral magnesiu m alkoxide(produced as a racemic mixture)
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Addition of Nitrogen Nucleophiles
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Addition of Nitrogen Nucleophiles
Ammonia, 1 aliphatic amines, and 1 aromatic
amines react with the C=O group of aldehydesand ketones to give imines (Schiff bases)
CH3 CH H2 NH
+
CH3 CH=N H2 O+ +
Acetaldehyde Aniline An imine(a Schiff base)
O
An imine(a Schiff base)
AmmoniaCyclohexanone
++ NH3 H2 OO NHH
+
Addition of Nitrogen Nucleophiles
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Addition of Nitrogen 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
H2N-R
H
H
C
O:-
N-R
OH
N-R
H
C++
O H
H
H H
C
OH
N-R N-R
H
C
OHH
OH
H
C N-R OH
H
HAn imine
+
+
+ +
+
+ H2 O
Addition of Nitrogen Nucleophiles
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Addition of Nitrogen 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
Addition of Nitrogen Nucleophiles
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Addition of Nitrogen Nucleophiles
Rhodopsin (visual purple) is the imine formed
between 11-c is-retinal (vitamin A aldehyde) andthe protein opsin
11
12
11-ci s-RetinalRhodopsin
(Visual purple)
H2
N-opsin
H N-opsinH O
+
Addition of Nitrogen Nucleophiles
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Addition of Nitrogen Nucleophiles
Secondary amines react with the C=O group of
aldehydes and ketones to form enamines
the mechanism of enamine formation involvesformation of a tetrahedral carbonyl addition compoundfollowed by its acid-catalyzed dehydration
we discuss the chemistry of enamines in more detail inChapter 19
O H-NH
+
N H2 O
An enaminePiperidine(a secondary amine)
++
Cyclohexanone
Addition of Nitrogen Nucleophiles
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Addition of Nitrogen Nucleophiles the carbonyl group of aldehydes and ketones reacts
with hydrazine and its derivatives in a manner similar
to its reactions with 1 amines
O H2 NNH2 NNH2 H2 O+
Hydrazine
+
A hydrazone
H2
N-NHCNH2
H2N-OH
H2 N-NH
H2 N-NH NO2
O2 N
Reagent, H2N-R
Hydroxylamine Oxime
Phenylhydrazine
2,4-Dinitrophenyl-hydrazine
Semicarbazide
2,4-Dinitrophenylhydrazone
Semicarbazone
Name of Derivative FormedName of Reagent
Phenylhydrazone
O
Acidity of -Hydrogens
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Acidity of Hydrogens Hydrogens alpha to a
carbonyl group are moreacidic than hydrogens ofalkanes, alkenes, andalkynes but less acidic than
the hydroxyl hydrogen ofalcohols
CH3 CH2O-HO
CH3 CCH2 -H
CH2 =CH-H
CH3 CH2 -H
CH3C C-H
T yp e of Bond p K a
16
20
25
44
51
Acidity of -Hydrogens
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Acidity of Hydrogens -Hydrogens are more acidic because the
enolate anion is stabilized by1. delocalization of its negative charge
2. the electron-withdrawing inductive effect of theadjacent electronegative oxygen
CH3 -C-CH2-H
O
:A-
O
CH3 -C CH2
O-
CH3 -C=CH2 H-A
Resonance-stabilized enolate anion
+ +
Keto-Enol Tautomerism
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Keto 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-
-
+
H- AOH
O-
O
To be continued
Keto-Enol Tautomerism
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Keto Enol Tautomerism
acid-catalyzed equilibration of keto and enol tautomers
occurs in two stepsStep 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-
+
+
+
Keto form
The conjugate acidof the ketone
fast andreversible
OCH3 -C-CH2 -H
H
:A-
OHCH3 -C=CH2 H-A
Enol form
+
+
slow+
Keto-Enol Tautomerism
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Keto Enol Tautomerism
Keto-enol
equilibria forsimplealdehydesand ketones
lie far towardthe keto form
OH
O
O
CH3 CH CH2 = CH
CH3 CCH3
Keto form Enol form
% Enol at
Equilibrium
6 x 10-5
OH
CH3 C=CH2 6 x 10-7
O
O OH
OH
1 x 10-6
4 x 10-5
Keto-Enol Tautomerism
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Keto Enol Tautomerism
For certain types of molecules, however, the enol
is the major form present at equilibrium for -diketones, the enol is stabilized by conjugation of
the pi system of the carbon-carbon double bond andthe carbonyl group
for acyclic -diketones, the enol is further stabilized byhydrogen bonding
Oxidation of Aldehydes
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Oxidation 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 H2 CrO4 COOH
Hexanal Hexanoic acid
Vanillic acidVanillin
++CH
HO
CH3 O
O O
CH3 O
HO
COHAg2 O
THF, H2 O
NaOHAgHCl
H2 O
Oxidation of Aldehydes
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Oxidation 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
Oxidation of Ketones
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Oxidation of Ketones
ketones are not normally oxidized by chromic acid
they are oxidized by powerful oxidants at hightemperature and high concentrations of acid or base
Hexanedioic acid(Adipic acid)
Cyclohexanone(keto form)
Cyclohexanone(enol form)
HNO3
O
HOOH
OO OH
Reduction
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Reduction
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
Aldehydes
Can Be
Reduced to Ketones
Can Be
Reduced to
O OOH
RCH
RCH2OH
RCH3
RCR'RCHR'
RCH2R'
Metal Hydride Reduction
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Metal Hydride Reduction
The most common laboratory reagents for the
reduction of aldehydes and ketones are NaBH4and 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:
NaBH4 Reduction
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a 4 educt o
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
4RCH
O
NaBH4
( RCH2O) 4B-
Na+ H2O
4RCH2OH
A tetraalkyl borate
boratesalts
+
+ methanol
NaBH4 Reduction
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a 4 educt o
The key step in metal hydride reduction is
transfer of a hydride ion to the C=O group toform a tetrahedral carbonyl addition compound
Na+
H
H
H-B-H
O
R-C-R'
O BH3
H
R-C-R'
Na+H2O
O-H
H
R-C-R'
This H comes from waterduring hydrolysis
This H comes from the
hydride reducing agent
+
LiAlH4 Reduction
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4
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 ( R2 CHO)4Al-
Li+ H2O
H
+
or OH
-
OH
4RCHR+ + aluminum
saltsA tetraalkylaluminate
etherO
Catalytic Reduction
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y
Catalytic reductions are generally carried out at
from 25 to 100C and 1 to 5 atm H2
+25oC, 2 atm
Pt
Cyclohexanone Cyclohexanol
O OH
H2
1-Butanolt rans-2-Butenal(Crotonaldehyde)
2H2
NiH
O
OH
Catalytic Reduction
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y
A carbon-carbon double bond may also be
reduced under these conditions
by careful choice of experimental conditions, it is oftenpossible to selectively reduce a carbon-carbon doublein the presence of an aldehyde or ketone
1-Butanolt rans-2-Butenal
(Crotonaldehyde)
2H2
NiH
O
OH
O OHRCH=CHCR' RCH=CHCHR'
1. NaBH4
2. H2O
O
RCH=CHCR' H2Rh
RCH2 CH2CR'
O
+
Clemmensen Reduction
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refluxing an aldehyde or ketone with amalgamated zinc
in concentrated HCl converts the carbonyl group to amethylene group
Zn(Hg), HCl
OH O OH
Wolff-Kishner Reduction
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in the original procedure, the aldehyde or ketone and
hydrazine are refluxed with KOH in a high-boilingsolvent
the same reaction can be brought about usinghydrazine and potassium tert-butoxide in DMSO
+
diethylene glycol(reflux)
KOH
N2
Hydrazine
+ H2 NNH2
+ H2 O
O
Racemization
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Racemization at an -carbon may be catalyzedby either acid or base
O
Ph
OH
Ph
O
Ph
An achiralenol
(R)-3-Phenyl-2-butanone
(S)-3-Phenyl-2-butanone
omit
Deuterium Exchange
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g
Deuterium exchange at an -carbon may becatalyzed by either acid or base
+
Acetone-d 6Acetone
+
O O
CH3 CCH 3 6 D2 O CD3 CCD 3 6 HODD
+
or OD-
omit
-Halogenation
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g
-Halogenation: aldehydes and ketones with atleast one -hydrogen react at an -carbon withBr2 and Cl2
reaction is catalyzed by both acid and base
O
Br2CH3COOH
O
BrHBr
Acetophenone
++
-Bromo-acetophenone
omit
-Halogenation
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g
Acid-catalyzed -halogenationStep 1: acid-catalyzed enolization
Step 2: nucleophilic attack of the enol on halogen
Step 3: (not shown) proton transfer to solvent completesthe reaction
H
R
R'-C-C-R
O
R'
C C
H-O R
R
slow
C
R
RH-O
C
R'
Br BrR'
C C
O Br
R
R
H
Br:-
+fast
+
omit
-Halogenation
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g
Base-promoted -halogenationStep 1: formation of an enolate anion
Step 2: nucleophilic attack of the enolate anion onhalogen
+-
-
Res onance-stabilized enolate anion
+slow
O H
R
O
C C
R'R'
C C
O:
R'-C-C-R-:OH H2O
R
R
R
R
+fast
R'
C CO Br
R
R BrBr Br +
-
R'
C CO: R
Romit
-Halogenation
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Acid-catalyzed halogenation:
introduction of a second halogen is slower than thefirst
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 theprevious one
the introduction of the electronegative halogen on the-carbon increases the acidity of the remaining -hydrogens and, thus, each successive -hydrogen isremoved more rapidly than the previous one
omit
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End