Download Aldehydes Ketones

CARBONYL COMPOUNDS:
NUCLEOPHILIC ADDITION
REACTION
Lecture 6
ORGANIC CHEMISTRY 2
CARBONYL COMPOUNDS
R
O
O
C
C
H
ALDEHYDE
R
R'
KETON
O
R
O
OR'
ESTHER
R
OH
CARBOXILIC ACID
CARBONYL COMPOUNDS
Formalin
Ibuprofen
Aspirin
Asam cuka
Asam semut
Perasa buah
CARBONYL COMPOUNDS
O
OH
H
OH
asam semut
H
H
Formaldehida
OH
O
O
H3C
O
O
O
O
H3C
CH3
Aseton (pembersih kutek)
O
aspirin
OH
asam cuka
ibuprofen
CH3
O
C
H2N
NH2
Urea
CH3
O
O
O
CH3 O
kantaridin
Preparation of Aldehydes and Ketones
1.
2.
3.
4.
Oxidation reactions
Hydrolysis of geminal dihalides
Hydration of alkynes
Reactions with acid derivatives
and nitriles
5. Reaction with carboxylic acids
6. Reaction with thioacetals
1. Aldehydes/Ketones via Oxidation Reactions
a. From Alcohols via PCC
b. From Alkenes via Ozonolysis
c. From Glycols via Periodic Acid Cleavage
RCH 2 OH
PCC
R
C
H
O
R 2 CHOH
PCC
R
C
R
O
R'CH
CR 2
ozonolysis
R' C
O
R'
R
C
OH
CH 2 OH
HIO 4
H +R
R
C
O
C
R
O
R' + H
C
O
H
Synthesis Mechanism
a.1 Oxidation of 1˚ alcohols
:Base
O
H
O
C
R
H
O
Cr
O
O
O
H
O
H
Cr
+
O
O
H
R
C
R
H
O
O
Cr
O
C
R
H
O
C
H
a.2. Oxidation of 2° alcohols w/ PCC and base
H
:Base
:Base
O
O
H
O
O
C
R
H
R
Cr
O
H
O
+
R
C
R
R
H
R
O
O
O
O
H
O
Cr
Cr
C
R
O
O
:Base
C
R
b.1 Oxidative cleavage of alkenes w/ O3, Zn, CH3COOH
O
O
O
H
R
H
C
C
O
O
R
H
R
O
O
H
H R
+
O
O
R
R
H
CH3COO-
O
R
O
+
H
+
H
O
H
O
O
R
R
H
H
CH3COO
H
R
R
H
O
O
O
H
R
b.2.Ozonolysis of alkenes, if one of the unsaturated carbon
atoms is disubstituted.
O
R
R
C
C
O
R
H
CH3COO
O
O
O
O
+
O
O
O
O
R
R
R
R
O
O
R
CH3COO-
O
O
O
+
O
H
O
+
R
R
R
R
R
R
R
R
2. Hydrolysis of Geminal Dihalides
R CH Cl2
R 2CCl2
H 2O
²
R
H 2O
²
R
C H + 2 HCl
O
C R + 2 HCl
O
3. Hydration of Alkynes
a. Markovnikov Addition
b. Anti-Markovnikov Addition
H2O / H2SO4
R
C
C
H
HgSO4
9-BBN
R
C
C
H
-
H2O2 / OH
R
R
C
C
H
R
C
OH H
O
C
C
H2
C
H
OH
H
R
CH3
C
O
H
3.a. Hydration of terminal alkynes
methyl ketones
H2O
R
C
C
R
H
C
+
H
C
+
Hg SO4
2+
Hg SO4
H
H
O
O
H
C
R
C
OH2
+
H
+
Hg SO4
H
C
C
R
+
Hg SO4
H3O+
O
H
O
C
R
tautomerization
H
C
H
+
H2O
C
R
CH3
4. Reactions with Acid Halides
a. Aldehydes via Selective Reduction
Lithium tri-tert-butoxyaluminum hydride
Rosenmund reduction
b. Ketones via Friedel-Crafts Acylation
c. Ketones via reaction with Organometallics
Gilman reagent (organocuprates)
4.a. Aldehydes from Acid Chlorides
• Lithium tri-t-butoxyaluminum hydride reduction
• Rosenmund reduction
R
C
Cl
O
R
C
O
Cl
LiAlH(O-t-bu) 3
ether
H 2 / Pd / S
BaSO 4
Rosenmund catalyst
R
C H
O
R
C H
O
4.b. Ketones via Friedel-Crafts Acylation
AlCl3
benzene
R C Cl
O
R C O C R
O
O
C R + HCl
O
AlCl3
benzene
C R + RCOOH
O
Friedel-Crafts acylation
aryl ketones
O
O
+
C
AlCl3
C
R
Cl
C
+
AlCl4-
H
O
R
C
R
+
H Cl
4.c.Ketones via Reaction with Organometallics
Use of Lithium dialkylcuprates
R'
Cu
Li
+
O
O
Ether
R'
C
C
R
Cl
R
R'
5. Aldehydes from Esters and Amides
Diisobutylaluminum hydride (DIBAH or DIBAL-H)
O
R C OR'
or
O
R C NH 2
or
O
R C NHR'
or
O
R C NR 2 '
1. Diisobutylaluminum
hydride
2.
H3 O+
O
R C H
5.a. Partial reduction of certain carboxylic acid
derivatives
O
H
+
O
H
O
H
O
DIBAH, toluene
R
C
R
OR'
R
C
O
+
H3O+
H
R'
C
+
R'OH
H
6. Ketones from Carboxylic Acids
Attack by Alkyl Lithium reagents
RCOOH
RLi
RCOO - Li+ + RH
RCOO - Li+ RLi
R
R
R
R
R
R
C
C
O - Li+
H 2O
O - Li+
OH ( H O )
2
OH
R
R
R
C
C
O - Li+
O - Li+
OH
OH
C
O
R
8. Reactions with Nitriles
a. Grignard Addition to give Ketones
b. DIBAH Addition to give Aldehydes
R CN
R'MgX
R
C N MgX
R'
R CN
DIBAH or DIBAL-H
diisobutylaluminum hydride
R
C H
O
R
H+
H 2O
C
R'
O
C N Al(i-bu)2
H
+
R
H /H2 O
7. Ketones from Thioacetals
a. Thioacetal formation from an aldehyde precursor
b. Alkylation of the thioacetal intermediate using alkyl lithium
reagents
c. Hydrolysis of the alkylated thioacetal to give ketone product
R
C
H
R
S
C
C 4H 9Li
(
R
H
S
S
C 4H 10 )
C
R
CH 2 R'
S
S
C
Li+
(a thioacetal)
H
R'CH 2X
R
HgCl 2 / CH3OH / H2O
(
S
C
BF 3
O
S
S
HSCH 2CH 2SH
HSCH 2CH 2 SH )
S
C
R
R
S
C
O
+ LiX
CH 2 R'
CH 2 R'
Characteristic Reactions of
Aldehydes and Ketones
1. Reduction reactions
a. Alcohol formation
b. Alkane formation
2. Oxidation reactions
3. Nucleophilic addition reactions
a. Grignard additions to form alcohols
b. Addition of water (hydration) to form gem-diols
c. Addition of alcohols to form acetals/ketals
d. Addition of HCN to form cyanohydrins
e. Addition of ammonia and ammonia derivatives
Reduction Reactions of Aldehydes & Ketones
1. Alcohol formation
a. Hydrogenation
b. Hydride reduction
2. Alkane formation
a. Clemmensen reduction
b. Wolff-Kishner reduction
R
C H
O
R
C H
O
H 2 / Pt
LiAlH4
ether
R
CH 2OH
H 2O
H
+
R
C H conc. HCl R CH 3
Zn(Hg)
O
NH 2NH 2
R C H
R CH 3
OH / H2O
O
R
CH 2OH
Oxidation of Aldehydes & Ketones
1. Conversion of aldehydes to carboxylic acids
2. Oxidation of aromatic aldehydes / ketones to
benzoic acid derivatives
3. Haloform reaction of methyl carbonyls
4. Periodic acid cleavage of vicinal dials/diketones
Aldehyde / Ketone Oxidations
1.
R
H or Ar
C
C
Ag(NH3)2
H
+
(Tollens reagent)
RCOOH (ArCOOH)
O
O
C
2.
H
O
KMnO 4 or K2Cr 2O 7
or
C
²
COOH
R
O
3.
CH 3
C
R
-
X2
OH / H2O
HCX 3 + RCOO
O
4.
R
C
C
O
O
H
HIO 4
RCOOH + HCOOH + HIO 3
Nucleophilic
addition
reactions
Structure of the Carbonyl Group
C
O
 Hybridization of the carbonyl carbon is sp2.
 Geometry of the carbonyl carbon is trigonal planar
 Attack by nucleophiles will occur with equal ease from
either the top or the bottom of the carbonyl group.
 The carbonyl carbon is prochiral. That is, the carbonyl
carbon is not the center of chirality, but it becomes chiral
as the reaction proceeds.
Prochiral
Nu
C
:Nu
OH
R'
R
These two products
are enantiomers.
R'
C
O
R
:Nu
R
R'
C
Nu
OH
In general, both
enantiomers are
formed in equal
amount.
Reaction of the Carbonyl Group
1.
H
O
C
2.
O
+
H+
C
O
O
C
C
+
B
B:
Nucleophilic Addition to Carbonyl:
General Mechanism
1.
+
:OH
:O :
C
+
+
H
C
..
: OH
+
: OH
C
fast
slow
+
:Nu
C
Nu
2.
.. _
:O:
:O :
C
slow
+
:Nu
C
Nu
.. _
:O:
..
: OH
fast
C
Nu
+
H2O
C
Nu
Relative Reactivity of Aldehydes & Ketones
Aldehydes >>> ketones
1. Steric Reason
• nucleophile is able to approach aldehydes more
readily because it only has 1 large substituent
bonded to the C=O carbon, vs. 2 in ketones.
• transition state for the aldehyde rxn is therefore less
crowded and has lower energy.
Aldehydes
Ketones
2. Electronic Reason
• greater polarization of aldehyde carbonyl group
• aldehyde is more electrophilic and more reactive than
ketones.
H
R
C
H
+
H
1˚ carbocation
(less stable, more reactive)
O
R
R
C
+
R'
2˚carbocation
(more stable, less reactive)
ς-
ς+
+
C
O
ς-
ς+
+
H
Aldehyde
(less stabilization of ς+,
more reactive)
R
C
R'
Ketone
(more stabilization of
ς+, less reactive)
Relative Reactivity of Aldehydes & Ketones
Aliphatic aldehydes >>> Aromatic aldehydes
The electon-donating resonance effect of the aromatic ring
makes the carbonyl group less electrophilic than the carbonyl
group of the aliphatic aldehyde.
The carbocation intermediate
H
H
O
O
C
C
 The positive charge character on
carbon makes this an excellent site
for attack by Lewis bases
(nucleophiles).
 Nucleophile attacks the electrophilic C=O carbon from a
direction ~45˚ to the plane of the carbonyl group
 At the same time: Rehybridization of the carbonyl carbon from
sp2 to sp3 occurs.
Once we have the
intermediate, what
happens to it?
Case 1: The Addition Product is Stable.
OH
R
C
R
Nu
The reaction stops here. This happens most often when
the nucleophilic atom is carbon, oxygen, or sulfur.
Case 2: Addition-Elimination
OH
R
R
C
R
R
C
O
+
H
H
Nu
Nu
H
The addition product is unstable with respect to loss
of a molecule of water. This is observed most often
when the nucleophilic atom is nitrogen or
phosphorus.
Case 3: Loss of Leaving Group
O
O
R
C
Nu
X
R
C
+
X
Nu
This process is observed when X is a potential
leaving group. In this case we have nucleophilic
acyl substitution.
Nucleophilic Addition of H2O: Hydration
 Nucleophilic addition of water is catalyzed by acid and base.
1. Base-catalyzed
1.
O
O-
slow
OH
:OHO
H
2,
H
OH
O-
fast
+ OHOH
OH
2. Acid-catalized
1)
H
O
O
+
C
H+
O
H
C
C
Resonance places greater positive charge
character on the carbonyl carbon.
2)
O
H
H
O
slow
C
C
O
O
H
H
H
H
3)
H
H
H
O
O
C
C
O
O
H
+
H
H+
 Important only for low-molecular-weight aldehydes
Examples:
O
C
H
in water
20 °C
>99.99% hydrate
H
O
58%
C
CH3
H
O
ca. 0%
C
CH3
CH3
Nucleophilic Addition of Alcohols:
Acetal Formation
 Acetals and Ketals are formed by reacting two equivalents
of an alcohol with an aldehyde or ketone, in the presence of
an acid catalyst.
 Hemiacetals and Hemiketals are formed by reacting only
one equivalent of alcohol with the aldehyde or ketone in the
presence of an acid catalyst. Further reaction with a second
alcohol forms the acetal or ketal.
 A diol, with two –OH groups on the same molecule, can be
used to form cyclic acetals.
 All steps in acetal/ketal formation are reversible.
O
+
C
O H
+
H
ROH
R
R'
C
R'
R
O
R
a hemiacetal
Aldehydes form hemiacetals faster than ketones
O
O H
H
R
C
O
R'
R
+
ROH
R
+
R
C
R'
+
H2O
O R
an acetal
(or ketal)
This reaction is also reversible. But, in this case, the equilibrium can
be driven to the right by an application of Le Châtelier’s Principle.
OR
R
OR
H
R
OR
OR
OH
OH
R
H
OR
R
R
R
OR
Mechanism of Acetal Formation:
H
: O:
:O
+
H
H
+
Cl
:O
+
.. ..
aldehyde/ketone
R
O:
H
O
.. ..
H
R
H
+ R
:O
+
H
+ OH2
Cl
H
H
H
O
..
R
R
O
Hemiacetal/
Hemiketal
.. ..
O
H
:O
R
+ R
O:
H
:O
.. ..
H
O
H
H
:O
O
R
O
R
O
Acetal/
Ketal
R
+
H3O
+
+
+
H3O
Example Nucleophilic Addition of Alcohols
1. Formation of 2,2-Dimethoxy-propane
O
CH3 C
CH3
O
CH3
C
CH3
O
CH3
dry acid
+
CH3
2 CH3OH
2. Formation of a Cyclic Acetal
O
Dry acid =
HCl gas
HCl in methanol
HOTs
+ H2 O
O
CH 2
CH 2
dry HCl
O
+
HO
CH 2 CH 2 OH
Ethylene glycol
1,2-Ethanediol
a 1,3-dioxolane
+ H 2O
3. Cyclization of Monosaccharides
Carbohydrates contain the functional groups of alcohols and aldehydes or
ketones in the same molecule. They are polyhydroxyaldehydes or
polyhydroxyketones.
Thus they can form acetal-type products through the intramolecular
interaction of these functional groups.
As a model, consider the reaction:
H
O
CH2
HO
CH2
CH2
C
H+
C
CH2
OH
H
CH2
O
CH2
CH2
CH2
O
H
H
HO
H
H
1
1C
C
2
H
OH
3
HO
H
4
OH
H
H
OH
..
O
..
5
6
H
H
2
OH
3
:O:
H
4
OH
5
6
CH2 OH
CH2 OH
H
: O:
O
O
H
..
OH
H
6
H
a pyranose
ring
O
O:
H
O
H
5
OH
a furanose
ring
Nucleophilic Addition of HCN
1)
O
O
slow
C
R
R
R
C
R
C
C
N
N
2)
O
R
C
R
+
H+
R
O
H
C
R
C
C
N
N
A cyanohydrin
Example
O
O
+
C
N
Na2CO3
C
N
(NaCN)
•Notice that the cyanide ion and
the acid are added in two
separate steps!
•Sodium carbonate is used to
keep the reaction medium basic.
H2O, H+
OH
C
N
So, what’s it good for?
OH
1. LiAlH4,THF
CHCH2NH2
2. H2O
OH
O
2-Amino-1-phenylethanol
CHCN
HCN
OH
H3O, heat
CHCO2H
Mandelic Acid
Addition of Organometallic Reagents
R
R
-
"R: "
slow
+
C
O
R
R'
C
O
R'
(from R-MgX)
H+
R, R' = H, alkyl, or aryl
R
R
C
R'
The products of the addition are always alcohols.
OH
Whatever is attached to the carbonyl group will be attached
to the resulting alcohol carbon.
H
H
R
M
+
(M = Li or MgX)
C
O
H
formaldehyde
R
M
+
R
C
O
H
other aldehydes
R
M
+
C
OH
H
secondary alcohol
R
R
R
OH
H
primary alcohol
R
R
C
C
R'
ketones
O
R
C
OH
R'
tertiary alcohol
Nucleophilic Addition of Grignard (R-MgX)
O
+ MgX R
MgX
MgX
O
O
R
R
Tetrahedral intermediate
OH2
OH
+
R
An Alcohol
HOMgX
Addition of Hydride Reagents
O
O
R
":H-"
R'
fr:NaBH4
OH
H3O
C
R
R'
C
H
R
R'
H
Compounds that bear an amino group
G
NH 2
Form Imines
The G group can be one of many different possibilities
Addition-Elimination:
The Formation of Imines
G
..
NH2
R
R
C
+
R
O
HA
C
N
G
+
H2O
R
an imine
All of the imine reactions, regardless of G, go by the
same mechanism.
Mechanism of Imine Formation:
Step 1
H
R
..
NH2
G
C
+
slow
..
O
..
G
R
R
+
N C
H
R
.. _
O
.. :
G
R
..
N
C
H
R
Step 2
R
G
..
N
C
H
R
..
OH
..
R
fast
G
HA
+
+
N
C
+
H2 O
+
_
A
+
H
R
H
Step 3
R
G
+
N
H
_
C
+
R
A
fast
G
..
N
R
C
R
A
..
OH
..
Formation of Simple Imines
A. Simple primary amines
R
R
C
R
O
..
+ H2N
R
acid
C
N
R
+
H2O
R
an imine
Aldehydes and ketones react with simple primary amines
to yield imines.
The equilibrium is unfavorable; the products are much
less stable than the reactants.
B. Simple secondary amines
 When secondary amines are allowed to react with
aldehydes or ketones, dehydration of the type shown in the
elimination step cannot take place (there is no labile
hydrogen on the nitrogen atom of the addition product).
OH
R
C
R
N
R'
R'
 If the starting aldehyde or ketone has an α -hydrogen,
however, dehydration toward the α -carbon can occur,
yielding an enamine.
R
H
O
C
C
+
H
R
R
R2NH
+
R
H
+
R
OH
C
C
R
NR2
R
NR2
C
R
H
+
C
H2O
R
an enamine
The acid catalyst is generally a dry acid, such as p-toluene
sulfonic acid (HOTs)
Amines that are used typically to form enamines:
CH3 CH2
N
CH3 CH2
Diethylamine
H
N
H
Piperidine
O
N
H
N
Pyrrolidine
H
Morpholine
Enamine Formation
1)
R
H
:O :
C
C
R
+
H
+
R
R
..
+ OH
C
C
R
R
R
R
2)
H
H
..
+ OH
C
C
R
..
N
R
R
H
R
slow
R
H
..
:OH
C
C
R
R
+N
H
R
R
H
..
:OH
C
C
+
R
R
H
..
+OH2
C
C
R
N:
R
R
R
R
3)
+ ..
R
H
OH2
H
C
C
R
N:
R
R
R
H
+
C
C
R
N:
R
R
R
R
R
+ H2O
H
+
C
C
R
N:
R
R
R
R
C
C
R
N:
R
R
R
C
R
N+
R
4)
R
C
+
H
+
R
R
Formation of Oximes
R
R
C
O
+
..
H 2N
OH
acid
C
N
OH
+
H2O
R
R
hydroxylamine
an oxime
Aldehydes and ketones react with hydroxylamine to yield
oximes.
Oximes are important derivatives in qualitative organic
analysis.
Formation of Hydrazones
R
R
C
O
+
..
H2 N
acid
C
NH R
N
NH R
+
H2O
R
R
a hydrazine
a hydrazone
Aldehydes and ketones react with substituted hydrazines to
yield substituted hydrazones.
The equilibrium is generally unfavorable.
Exception: when R is an aromatic ring.
Wolff-Kishner Reaction: Nu- Addition of Hydrazine
N
O
+
R
N
H2NNH2
R'
-OH
+
OH2
R'
R
N
R
OH2
H
OH
+
R
H
R'
alkane
OH2
+
OH2
C
N N+ R
R'
H
R'
R
NH2
N
H
N
N
H
OH
R
R'
H
C
N
R'
H
Formation of Semicarbazones
O
R
C
R
O
..
+ H2N
acid
NH C
NH2
semicarbazide
O
R
C
N
NH C
NH2
+
H2O
R
a semicarbazone
Aldehydes and ketones react with semicarbazide to yield
semicarbazones.
Semicarbazones are the second-most important of the derivatives
of aldehydes and ketones.
The enamine is quite nucleophilic,
owing to resonance of the type:
R'
R
N
C
R
R'
R'
R
C
N
C
R
R
R'
C
R
As a consequence of this resonance, the α-carbon
of an enamine has a great deal of carbanion-like
(nucleophilic) character.
Reactions of Enamines as Nucleophiles
R
:N
R
C
R
R
C
R
R
R
R
R
R
+N
C
C
R
R
an iminium salt
R
X
_
+
SN2
R
:N
C
C
+
R
R
X
R
R
Hydrolysis of Iminium Salts
1)
R
R
R
+N
R
R
R
R
N:
C
C
R
+O :
R
R
+N
H
C
C
R
R
:O
..
H
slow
R
C
C
R
..
O
..
H
R
R
H
R
R
H
H
2)
R
R
R
R
+N
H
C
C
R
R
:O
..
H
R
R
R
C
C
R
R
+O
..
H
+
R
N
..
H
3)
R
R
R
C
C
R
R
+O
..
H
R
C
C
R
:O :
R
+
+
H
Enamines can react with alkyl halides -- Here’s an example.
O
O
N
N
O
CH3
CH3
+
CH3 I
H2O
H+
from cyclohexanone
Nucleophilic Addition of Phosphorus Ylides:
The Wittig Reaction
 Converts an aldehyde/ketone into an alkene.
 A phosphorus ylide(aka phosphorane), acts as the NuYlide : A compound or intermediate with both a positive and
a negative formal charge on adjacent atoms.
R
(C6H5)3P
C
R
+
(C6H5)3P
_ R
..
C
R
The ylide is nucleophilic, owing to the negative charge
character on carbon (structure on the right).
A phosphorus ylide(aka phosphorane), acts as the Nu- to attack the
carbonyl carbon and yields a four-membered ring, dipolar intermediate called
the betaine.
The betaine decomposes spontaneously to yield an alkene and a
triphenylphosphine oxide.
Can produce monosubstituted, disubstituted, and trisubstituted alkenes.
R3
R1
C
O
+
(C6H5)3P C
R2
R4
R2
R1
R3
C
C
R4
P(C6H5)3
+
a betaine
: O:
.. _
an ylide
R1
C
R2
R3
+
C
R4
O
P(C6H5)3
This is a type of condensation reaction -- we use it to “dock” to large
structures together.
This is another example of addition-elimination.
Mechanism of the Witting Reaction:
: O:
+
P
ketone/aldehyde
:
+
R
-: ..:
+
R'
R'
ylide
P O
P
O
R
betaine
R'
+
..
:O
alkene
P
R
R'
R
Conjugate Nucleophilic Addition to
α-β-Unsaturated Aldehydes and Ketones
 Direct addition (aka 1,2 addition) occurs when a nucleophile attacks
the carbon in the carbonyl directly.
 Conjugate addition (aka 1,4 addition) occurs when the nucleophile
attacks the carbonyl indirectly by attacking the second carbon away
from the carbonyl group, called the beta carbon, in an unsaturated
aldehyde or ketone.
 Conjugate addition reactions form an initial product called an enolate,
which is protonated on the carbon next to the carbonyl, the alpha
carbon, to give the final saturated aldehyde/ketone product.
 Conjugate addition can be carried out with nucleophiles such as
primary amines, secondary amines, and even alkyl groups like in
organocopper reactions.
 It is the carbonyl that activates the conjugated C=C double bond for
addition which would otherwise not react.
Conjugate (1,4) addition mechanism:
-: ..:
O
: O:
Nu
-
O
: Nu
Nu
H
H
alpha,beta-unsaturated
aldehyde or ketone
O+
H
:O:
- ..
Nu
Enolate ion
H
Saturated
aldehyde or ketone