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Organic Lecture Series
Aldehydes
And
Ketones
Chap 16
1
Organic Lecture Series
IUPAC names
• the parent alkane is the longest chain that
contains the carbonyl group
• for ketones, change 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
O
Prop anone
(Aceton e)
O
O
A cetophen on e Benzophen on e
Commit to memory
O
1-Phenyl-1-pen tanone
2
Common Names
Organic Lecture Series
– for an aldehyde, the common name is derived from
the common name of the corresponding carboxylic
acid
O
HCH
Formaldehyde
O
HCOH
Formic acid
O
CH3 CH
A cetaldeh yd e
O
CH3 COH
Acetic acid
– for a ketone, name the two alkyl or aryl groups
bonded to the carbonyl carbon and add the word
ketone
O
O
O
Ethyl isopropyl ketone
D iethyl ketone
D icyclohexyl ketone
3
Organic Lecture Series
Drawing Mechanisms
• Use double-barbed arrows to indicate
the flow of pairs of e• Draw the arrow from higher e- density
to lower e- density i.e. from the
nucleophile to the electrophile
• Removing e- density from an atom will
create a formal + charge
• Adding e- density to an atom will
create a formal - charge
• Proton transfer is fast (kinetics) and
usually reversible
4
Organic Lecture Series
Reaction Themes
One of the most common reaction themes of
a carbonyl group is addition of a
nucleophile to form a tetrahedral carbonyl
addition compound (intermediate).
O
R
Nu
-
C
+
O
Nu
-
C
R
R
R
Tetrahedral carbonyl
add ition comp ou nd
5
Organic Lecture Series
Reaction Themes
A second common theme is reaction with a proton
or other Lewis acid to form a resonancestabilized cation-– protonation increases the electron deficiency of the
carbonyl carbon and makes it more reactive toward
nucleophiles
R
R
B
fast
B +
C O + H-B
R
R
+
C O H
R
-
R
+
H-Nu +
+
C O H
R
+
C O H
R
O-H
s low
Nu
C
+
H-B
R
R
Tetrah edral carbonyl
addition compoun d
6
Organic Lecture Series
– 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, then enantiomers will be
formed as a racemic mixture
Ap proach from
the top face
Nu
Nu
OH
O
Nu
-
R
R
R'
C O
H3 O+
R'
+
R'
R
R
R'
+
R'
R
OH
O
A pproach from
the bottom face
Nu
A n ew chiral
cen ter is created
Nu
A racemic mixture
7
Organic Lecture Series
Addition 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
– Focus on addition of these carbon nucleophiles:
RMgX
A Grignard
reagent
RLi
RC C An organolithium An alkyne
reagent
anion
-
C N
Cyanide ion
8
Organic Lecture Series
Grignard Reagents
– addition of a Grignard reagent to
formaldehyde followed by H3O+ gives a 1°
alcohol
O
CH 3 CH2 -MgBr + H-C-H
ether
Formaldehyde
-
O [ MgBr]
+
HCl
H2 O
CH3 CH2 -CH2
A magn esium
alkoxide
OH
2+
CH3 CH2 -CH2 + Mg
1-Prop anol
(a 1° alcoh ol)
9
Organic Lecture Series
Grignard Reagents
– addition to any other RCHO gives a
2°alcohol
MgBr
O
+
ether
H
Acetaldehyde
(an ald ehyde)
-
O [ MgBr]
+
OH
HCl
H2 O
A magn esiu m
alk oxid e
+ Mg2 +
1-Cycloh exyleth anol
(a 2° alcohol;
(racemic)
10
Organic Lecture Series
Grignard Reagents
– addition to a ketone gives a 3°alcohol
O
Ph-MgBr
Ph enylmagnesiu m
b romide
eth er
+
Aceton e
(a ketone)
-
O [ MgBr]
Ph
A magnes ium
alk oxid e
+
OH
HCl
H2 O
+ Mg 2+
Ph
2-Phenyl-2-propanol
(a 3° alcohol)
11
Organic Lecture Series
Problem: 2-phenyl-2-butanol can be synthesized
by three different combinations of a Grignard
reagent and a ketone. Show each combination.
OH
C-CH2 CH3
CH3
12
Organic Lecture Series
A Simple Retrosynthetic
Analysis
O
CH3
OH
CH3
O
CH3
O
CH3
13
Organic Lecture Series
14
Organic Lecture Series
Addition Reactions to Carbonyl Compounds
Note: Water can also be added to ketones & aldehydes.
15
Organic Lecture Series
Organolithium Reagents
Organolithium compounds are generally
more reactive in C=O addition reactions
than RMgX, and typically give higher
yields
O
Li
O- Li+
HCl
H2 O
+
Phenyl- 3,3-D imeth yl-2lithiu m
butan on e
OH
A lithiu m alk oxid e
(racemic)
3,3-D imethyl-2-phen yl2-bu tanol
(racemic)
16
Organic Lecture Series
Salts of Terminal Alkynes
• Addition of an alkyne anion followed
by H3O+ gives an α-acetylenic alcohol
• Note: this is a 2-C homologation
O
HC C O - Na +
HCl
H2 O
-
HC C: Na + +
S od ium
acetylid e
HC C OH
Cycloh exanone
A sodium
alkoxide
1-Eth yn ylcyclohexan ol
Homologation is a term used for extending a carbon chain
17
Organic Lecture Series
Oxidation of Terminal Alkynes
O
H2 O
HO
C CH
HO
α
CCH3
H2 SO4 , HgSO4
An α-hydroxyketone
1. (sia) 2 BH
2. H2 O2 , NaOH
O
α
HO CH2 CH
β
A β-hydroxyaldehyde
(these reactions are from O-chem I)
Pg 285: use of (sia)2BH
18
Organic Lecture Series
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
same carbon
O
C
HO
+ HCN
C
N
C
H3C
H3C
H
Acetaldehyde
H
2-Hydroxypropanenitrile
(Acetaldehyde cyanohydrin)
19
Organic Lecture Series
Addition of HCN
• Mechanism of cyanohydrin formation
– Step 1: nucleophilic addition of cyanide to the
carbonyl carbon
H3 C
•
•
H3 C
C O + C N
H3 C
O
-
C
H3 C
C N
– Step 2: proton transfer from HCN gives the
cyanohydrin and regenerates cyanide ion
H3 C
O
-
H3 C
+
H C N
H3 C
C N
pKa=9.3
O-H
+
C
-
•
•
C
H3 C
C N
C N
20
Organic Lecture Series
Cyanohydrins
– catalytic reduction of the cyano group
gives a 1°amine
OH
OH
CHC N + 2 H2
Ben zaldeh yd e
cyanohydrin
(racemic)
Ni
CHCH2 NH2
β α
2-Amino-1-ph enylethanol
(racemic)
β−Phenethylamines
21
Organic Lecture Series
Biosynthesis of Dopamine
L-Phenylalanine → L-Tyrosine → L-DOPA → Dopamine
22
Organic Lecture Series
β−Phenethylamines
(Natural)
NH2
HO
OH
OH
NH2
Dopamine
HO
OH
Norepinephrine
23
β−Phenethylamines
(synthetic)
Organic Lecture Series
H
N
CH3
CH3
N-methylamphetamine
NH2
CH3
amphetamine
24
Organic Lecture Series
Overall Synthetic Transformation of
Wittig Reagents & Its Variations
R
R'
O
C
Ketone
Can Be
Cyclic
Alkenes
or
Olefins
25
Organic Lecture Series
Wittig Reaction
The Wittig reaction is a very versatile synthetic
method for the synthesis of alkenes (olefins)
from aldehydes and ketones
O +
+ Ph3 P-CH2
Cycloh exanone A p hosp honium
ylide
CH2 +
Ph 3 P=O
MethyleneTrip hen ylcycloh exane phosp hine oxide
Ylides are reagents (or reactive intermediates) which have adjacent charges:
Ph3P
CH2
Ph3P
CH2
26
Organic Lecture Series
Phosphonium ylides
Phosphonium ylides are formed in two steps:
Step 1: nucleophilic displacement of iodine by
triphenylphosphine
Ph 3 P
SN 2
+ CH3 -I
Trip henylph os phin e
+
Ph3 P-CH3
I
Methyltriphen ylp hosph on ium iod ide
(an alk yltriph enylph os phin e salt)
Step 2: treatment of the phosphonium salt with a very
strong base, most commonly BuLi, NaH, or NaNH2
-
CH3 CH2 CH2 CH2 Li
Bu tyllith ium
+
+
+ H-CH2 -PPh3 I+
CH3 CH2 CH2 CH3 + - CH2 -PPh3 + LiI
Bu tane
A phosp honium
ylide
Not exam material
27
Organic Lecture Series
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
O CR2
+
Ph3 P
-
:O
+
-
Ph3 P
CH2
CR2
O
CR2
CH2
Ph3 P
CH2
An oxaph os ph etane
A betaine
Step 2: decomposition of the oxaphosphatane
O CR2
Ph3 P
CH2
Ph3 P=O
+
Triphen ylp hosph ine
oxide
R2 C=CH2
An alkene
28
Organic Lecture Series
Wittig Reaction
O + Ph3 P
+
Acetone
2-Methyl-2-hepten e
O +
Ph3 P
Ph
Ph 3 P=O
+ Ph
+ Ph P=O
Ph
3
(Z)-1-Ph enyl-2- (E)-1-Phen yl-2b utene
b utene
(87%)
(13%)
H
Phen ylacetald ehyde
Resonance stabilized Wittig reagent:
O
H
Ph
O
Phen ylacetald ehyde
+ Ph3 P
O
OEt
Ph
+ Ph 3 P=O
OEt
Eth yl (E)-4-phen yl-2-b utenoate
(only the E is omer is formed)
29
Organic Lecture Series
Addition Reactions to Carbonyl Compounds
Note: Water can be added to ketones & aldehydes.
30
Organic Lecture Series
Addition of H2O to Carbonyls
Addition of water (hydration) to the carbonyl
group of an aldehyde or ketone gives a
geminal diol, commonly referred to a gemdiol
– gem-diols are also referred to as hydrates
C O +
acid or
b ase
OH
C
H2 O
OH
A hydrate
(a gem-diol)
Carbonyl group
of an aldeh yd e
or k eton e
31
Organic Lecture Series
Addition of H2O to Carbonyls
– when formaldehyde (g) is dissolved in water
at 20°C, the carbonyl group is more than 99%
hydrated
H
H
O + H2 O
H
Formaldehyde
OH
OH
H
Formald ehyde h yd rate
(>99%)
– the equilibrium concentration of a hydrated
ketone is considerably smaller
O + H2 O
Acetone
(99.9%)
OH
OH
2,2-Propan ediol
(0.1%)
32
Organic Lecture Series
Addition of Alcohols to Carbonyls
• Addition of one molecule of alcohol to the
C=O group of an aldehyde or ketone gives
a hemiacetal
• Hemiacetal: a molecule containing an OH and an -OR or -OAr bonded to the
same carbon
acid or
base
O + H-OR
OH
OR
A hemiacetal
33
Organic Lecture Series
Formation of a hemiacetal-- base catalyzed
– Step 1: proton transfer from HOR gives an alkoxide
B
-
+ H OR
fas t and
reversib le
B H +
-
Na+ -OCH3
OR
– Step 2: attack of RO- on the carbonyl carbon
O
CH3 -C-CH3 +
O:–
–
:O-R
CH3 -C-CH3
OR
– Step 3: proton transfer from the alcohol to O- gives the
hemiacetal and generates a new base catalyst
–
O:
CH3 -C-CH3 + H OR
OR
OH
CH3 -C-CH3 +
-
OR
OR
34
Organic Lecture Series
Formation of a hemiacetal --acid catalyzed
Step 1: proton transfer to the carbonyl oxygen
O
CH3 -C-CH3 + H-A
+
fas t and
reversib le
O
H
CH3 -C-CH3 +
A
-
Step 2: attack of ROH on the carbonyl carbon
+ H
O
O-H
CH3 -C-CH 3
O+
H
R
CH3 -C-CH3 + H-O-R
Step 3: proton transfer from the oxonium ion to A- gives
the hemiacetal and generates a new acid catalyst
OH
A
-
CH3 -C-CH3
+
O
H
R
OH
CH3 -C-CH 3 + H-A
OR
35
Organic Lecture Series
Addition of Alcohols to Carbonyls
• Hemiacetals react with alcohols to form
acetals
Acetal: a molecule containing two -OR or -OAr
groups bonded to the same carbon
OH
+
+ H-OR
OR
A hemiacetal
H
OR
OR
acetal
+ H2 O
Nota Bene: acetals are STABLE in base
36
Organic Lecture Series
Begin Mechanism from the hemiacetal stage:
Step 1: proton transfer from HA gives an
oxonium ion
H + H
O
HO
R-C-OCH3 + H A
R-C-OCH3
H
-
+ A:
H
An oxonium ion
Step 2: loss of water gives a resonancestabilized cation
+
H
O
R-C OCH3
H
+
R-C OCH3
+
R-C OCH3
+ H2 O
H
H
A resonan ce-stabilized cation
H
37
Organic Lecture Series
Step 3: reaction of the cation (an electrophile)
with methanol (a nucleophile) gives the
conjugate acid of the acetal
H
+
CH3 -OH + R-C OCH3
+ CH
3
O
R-C OCH3
H
A p rotonated acetal
H
Step 4: proton transfer to A- gives the acetal
and generates a new acid catalyst
H + CH3
O
A: + R-C OCH3
H
(4)
OCH3
R-C-OCH3 + H-A
H
An acetal
38
Organic Lecture Series
Addition of Alcohols to Carbonyls
– with ethylene glycol and other glycols, the
product is a five-membered cyclic acetal
– this a method of “protecting” ketones
O + HO
+
OH
O
H
O
Cyclic acetal
+ H2 O
39
Organic Lecture Series
Dean-Stark Trap
40
Organic Lecture Series
Acetals as Protecting Groups
• How to bring about a Grignard reaction
between these compounds:
O
OH
O
H
Br
+
Benzald ehyde
H
??
4-Bromobutanal
O
O
H
5-Hydroxy-5-phen ylpen tanal
(racemic)
This Grignard cannot be made!!
BrMg
H
41
Organic Lecture Series
Acetals as Protecting Groups
• a Grignard reagent prepared from 4bromobutanal will self-destruct (decompose).
– first protect the -CHO group as an acetal:
O
Br
H + HO
OH
H
O
+
Br
O
A cyclic acetal
+ H2 O
– then prepare the Grignard reagent:
O- MgBr+ O
O
Br
1 . Mg, ether
O
O
2 . C6 H5 CHO
A chiral magnesiu m alk oxide
(produced as a racemic mixtu re)
– hydrolysis (not shown) gives the target molecule
42
Organic Lecture Series
Addition of Nitrogen Nucleophiles
• Ammonia, 1°aliphatic amines, and 1°aromatic
amines react with the C=O group of aldehydes
and ketones to give imines (Schiff bases)
• Water is removed by Dean-Stark trap or
chemical dehydration (e.g. molecular sieves)
O
CH3 CH + H2 N
Acetaldehyde
H
+
CH3 CH =N
Aniline
O
Cyclohexanone
+
+ H2 O
An imine
(a Schiff base)
H
N H3
+
Ammonia
N H + H2 O
An imine
(a Schiff base)
43
Organic Lecture Series
Addition of Nitrogen Nucleophiles
– a value of imines is that the carbon-nitrogen
double bond can be reduced to a carbonnitrogen single bond
O +
H+
- H2 O
H2N
Cyclohexanone Cyclohexylamine
H
N
H2 / Ni
(An imine)
N
Dicyclohexylamine
Does not have to isolated
44
Organic Lecture Series
Addition of Nitrogen Nucleophiles
• Secondary amines react with the C=O
group of aldehydes and ketones to form
enamines (alkene and amine)
+
O
Cyclohexanone
H
H-N
+
+ H2 O
N
Piperidine
(a secondary amine)
An enamine
– the mechanism of enamine formation involves
formation of a tetrahedral carbonyl addition
compound followed by its acid-catalyzed
dehydration
45
Organic Lecture Series
Acidity of α-Hydrogens
Hydrogens alpha to a carbonyl group are
more acidic than hydrogens of other
hydrocarbons (e.g. alkanes, alkenes,
aromatic).
O
H
H
α
H
α
H
46
Organic Lecture Series
H 3O + + A -
H A + H 2O
K eq =
Note: l and s are
not used in K
[H 2 O ] K e q =
Ka =
[H 3 O + ] [A - ]
[H A ] [H 2 O ]
[H 3 O + ] [A - ]
[H A ]
Freshman
Flashback!!
[H 3 O + ] [A - ]
[H A ]
47
Organic Lecture Series
Acidity of α-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
pKa = -log Ka
Type of Bond
pKa
CH3 CH2 O-H
O
CH3 CCH2 -H
CH3 C C-H
CH2 =CH-H
CH3 CH2 -H
16
20
25
44
51
48
Organic Lecture Series
α-Hydrogens are more acidic because the
enolate anion is stabilized by:
1. delocalization of its negative charge
(resonance effect)
2. the electron-withdrawing inductive effect of
the adjacent electronegative oxygen
O-
O
O
CH3 -C-CH2 - H + :A
-
CH3 -C=CH2 + H-A
CH3 -C CH2
Resonance-stabilized en olate anion
49
Organic Lecture Series
Keto-Enol Tautomerism
– protonation of the enolate anion on oxygen
gives the enol form*; protonation on carbon
gives the keto form
O
-
O-
CH3 - C-CH2
CH3 - C= CH2
Enolate anion
O
H- A
A - + CH3 - C-CH3
Keto form
H- A
OH
CH3 - C= CH2 + A
-
Enol form
*Enol: made from 2 functional groups-alkene and alcohol
50
Organic Lecture Series
Keto-Enol Tautomerism
– acid-catalyzed equilibration of keto and enol
tautomers occurs in two steps
Step 1: proton transfer to the carbonyl oxygen
•
•
O
CH3 -C-CH3 + H-A
Keto form
fas t and
reversib le
+
O
H
CH3 -C-CH3
+ A
-
The conju gate acid
of the ketone
Step 2: proton transfer to the base A+
O
H
slow
-
CH3 -C-CH2 -H + :A
OH
CH3 -C=CH2 + H-A
En ol form
51
Organic Lecture Series
Keto-Enol Tautomerism
Keto-enol
equilibria
for simple
aldehydes
and
ketones lie
far toward
the keto
form
Keto form
Enol form
O
OH
CH2 = CH
CH3 CH
O
OH
CH3 CCH3
CH3 C= CH2
O
% Enol at
Equilibrium
6 x 10-5
6 x 10-7
OH
1 x 10-6
O
OH
4 x 10-5
52
O
O
C
C
R
Oxidation
R
OH
R
C a rb o x y lic A c id s & E s te rs
OR'
O
O
C
C
H
Organic Lecture Series
R
K e to n e s & A ld e h y d e s
R'
OH
A lc o h o ls
C
R
R'
H
H
H y d r o c a rb o n (lo w e s t o x id a tio n )
C
R
R'
53
H
Organic Lecture Series
Oxidation from O-Chem I
54
Organic Lecture Series
Oxidation of Aldehydes
Aldehydes are oxidized to carboxylic acids
by a variety of oxidizing agents, including
*H2CrO4
CHO
H 2 Cr O4
COOH
Hexanal
Hexanoic acid
55
* See 10.8 for Jones reagent & PCC: pyridine+•ClCrO3-
Organic Lecture Series
Oxidation of Aldehydes
• 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
O
CH
CH3 O
HO
Vanillin
T HF, H 2 O
+ A g2 O
N aOH
HCl
H2 O
CH3 O
O
COH
+ Ag
HO
Vanillic acid
56
Organic Lecture Series
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
O
2
O
CH
+ O2
2
COH
Benzaldehyde
Benzoic acid
57
Organic Lecture Series
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
OH
O
RCH 2 OH
O
RCHR'
RCR'
RCH
RCH 3
RCH 2 R'
58
Organic Lecture Series
Metal 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
H
H
Al
H
H
L i+
H
H
B
H
Na+
H
Hydride
H
Lithium Aluminum Hydride
LAH
Sodium Borohydride
NaBH4
59
Organic Lecture Series
Sodium Borohydride 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
O
methanol
4 RCH + NaBH4
-
+
( RCH2 O) 4 B Na
A tetraalkyl borate
H2 O
4 RCH2 OH + borate
salts
60
Organic Lecture Series
Sodium Borohydride Reduction
• 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
This H comes from w ater
du rin g hydrolys is
H
O
+
Na H-B-H + R-C-R'
H
O BH3 Na
+
O-H
R-C-R'
H2 O
R-C-R'
H
H
This H comes from the
hydride reducing agen t
Not exam material
61
Organic Lecture Series
LAH Reduction
– unlike NaBH4, LiAlH4 reacts violently with
water, methanol, and other protic solvents
– reductions using it are carried out in dry
(anhydrous) diethyl ether or tetrahydrofuran
(THF)
O
ether
4 RCR + LiAlH4
-
( R2 CHO) 4 Al Li
A tetraalk yl
alu min ate
OH
H2 O
+
+
-
H or OH
4 RCHR + aluminum
salts
62
Organic Lecture Series
Catalytic Reduction
• Catalytic reductions are generally carried
out at from 25°to 100°C and 1 to 5 atm H2
OH
O
+
H2
Pt
25 o C, 2 atm
Cyclohexanone
Cyclohexanol
O
H
trans- 2-Butenal
(Crotonaldehyde)
2 H2
Ni
OH
1-Butanol
Note: Both the olefin and the carbonyl are reduced
63
Organic Lecture Series
64
Organic Lecture Series
Catalytic Reduction
• A carbon-carbon double bond may also be
reduced under these conditions:
O
2 H2
H
Ni
trans-2-Butenal
(Crotonaldehyde)
OH
1-Butanol
– 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
O
1 . NaBH4
RCH=CHCR'
2 . H2 O
OH
RCH=CHCHR'
O
O
RCH=CHCR' + H2
Rh
RCH2 CH2 CR'
65
Organic Lecture Series
Clemmensen Reduction
– refluxing an aldehyde or ketone with amalgamated
zinc in concentrated HCl converts the carbonyl group
to a methylene group
– Classic reaction but harsh conditions limit its use
OH O
OH
Zn( H g) , HCl
66
Organic Lecture Series
Wolff-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 (Dimethyl sulfoxide)
O
+ H2 NN H2
Hydrazine
KOH
diethylene glycol
(reflux)
+ N 2 + H2 O
67
Organic Lecture Series
Racemization
• Racemization at an α-carbon may be
catalyzed by either acid or base
• Once stereochemistry is set, this is usually
an undesirable side reaction.
O
Ph
(R)-3-Phenyl-2b utanone
OH
Ph
An achiral
enol
O
Ph
(S)-3-Phenyl-2butan one
68
Organic Lecture Series
α-Halogenation
α-Halogenation: aldehydes and ketones
with at least one α-hydrogen react at an αcarbon with Br2 and Cl2
O
O
Br
+ Br2
+ HBr
CH3 COOH
Acetop henone
α -Bromoacetoph enone
– reaction is catalyzed by both acid and base
– Caution!! These are lachrymators
69
Organic Lecture Series
α-Halogenation
• Acid-catalyzed α-halogenation
Step 1: acid-catalyzed enolization- forms the enol
OH
R'-C-C-R
H-O
slow
R
C
R'
R
C
R
Step 2: nucleophilic attack of the enol on halogen
R
H-O
C
R'
C
H O
+ Br
R
Br
fast
Br
C C R
R'
+
-
Br:
R
Step 3: (not shown) proton transfer to solvent completes
the reaction
70
Organic Lecture Series
α-Halogenation
• Base-promoted α-halogenation
Step 1: formation of an enolate anion
OH
slow
-
R'-C-C-R + :OH
O
C
O:
- R
••
C
-
R
C
+ H2 O
C
R'
R'
R
R
Res on ance-stab ilized enolate anion
R
Step 2: nucleophilic attack of the enolate anion
on halogen
O:
C
R'
R
O
+ Br
C
R
Br
fast
Br
C
C R +
R'
α-Halogenation
Br
R
71
Organic Lecture Series
• Acid-catalyzed α-halogenation:
– introduction of a second halogen is slower than the
first
– introduction of the electronegative halogen on the αcarbon decreases the basicity of the carbonyl oxygen
toward protonation
• Base-promoted α-halogenation:
– each successive halogenation is more rapid than the
previous one
– the introduction of the electronegative halogen on the
α-carbon increases the acidity of the remaining αhydrogens and, thus, each successive α-hydrogen is
removed more rapidly than the previous one
72