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ALDEHYDES AND KETONES
Aldehyde
Ketone
O
CR H
R = H, alkyl, aryl
O
CR R'
R and R' = alkyl or arylR and R' cannot be hydrogen!
STRUCTURE
NOMENCLATURENOMENCLATURE
• Choose the longest continuous carbon chain that contains the carbonyl carbon
• Number from the end of the chain closest to the carbonyl carbon
• Ketone ending is -one
IUPAC Nomenclature of KetonesIUPAC Nomenclature of Ketones
Do the ketones section of Organic Nomenclature program!
CH3
CCH2
CH2CH3
O
2-Pentanone
EXAMPLES
O
CCH2 CH
CH3 CH2
CH2
CH3
CH3
4-Ethyl-3-hexanone
O
CH
CH3
CH3
3-Isopropylcyclopentanone
or 3-(1-Methylethyl)cyclopentanone
Common, or Trivial, Common, or Trivial, NamesNames
• Name each group attached to the carbonyl group as an alkyl group
• Combine into a name, according to the pattern:
alkyl alkyl’ ketone
NOTE: This is not all one word!
KETONESKETONES
CH3
CCH2
CH2CH3
O
Methyl propyl ketone
Example of Common NamesExample of Common Names
O
CCH2 CH2
CH3 CH3
Diethyl ketone
O
CCH3 CH3
acetone
dimethyl ketone
A common laboratorysolvent and cleaningagent
SPECIAL CASESSPECIAL CASES
C
O
benzophenone
diphenyl ketone
C
O
CH3
acetophenone
methyl phenyl ketoneKNOWTHESE
• Choose the longest continuous carbon chain that contains the carbonyl carbon
• Number from the end of the chain closest to the carbonyl carbon (carbon #1!)
• Aldehyde ending is -al
IUPAC Nomenclature of AldehydesIUPAC Nomenclature of Aldehydes
Do the aldehydes section of Organic Nomenclatureprogram.
EXAMPLES
CH3
CH2CH2
CH2C
O
Hpentanal
CH3CH
CHC
O
HCH3
Cl
2-chloro-3-methylbutanal
12
34
always carbon 1aldehyde group is
O
CH H
O
CCH3 H
O
CCH2 HCH3
O
CC HCH2CH3
O
CC HCH2CH2CH3
O
CCH2 HCH2CH2CH2CH3
Formaldehyde Acetaldehyde Propionaldehyde
Butyraldehyde Valeraldehyde
Caproaldehyde
1 2 3
4 5
6
Common Names of the AldehydesCommon Names of the Aldehydes
RECOGNIZE THESE
O
CH H
O
CH CH3
C
O
H
SPECIAL CASESSPECIAL CASES
formaldehyde
acetaldehyde
benzaldehyde
KNOWTHESE
C
C C C C C C H
O
Forming Common Names of AldehydesForming Common Names of Aldehydes
CHO
Cl
-chlorocaproaldehyde
( -chlorohexanal )
CHO
Cl
-chlorocaproaldehyde
( -chlorohexanal )
USE OF GREEK LETTERS
…….
is always the end of the chain, no matter how long
REACTIVITY OF THE C=O GROUPREACTIVITY OF THE C=O GROUP
NUCLEOPHILIC ADDITION
O
C
..:+
- O
C
..::-
+
THE CARBONYL GROUPTHE CARBONYL GROUP
electrophilic at carbon
nucleophilicat oxygen
Nu:
nucleophiles attack here
H+ or E+electrophiles add here
GENERALIZED CHEMISTRY
STEREOCHEMISTRYSTEREOCHEMISTRY
C O..
..
. .
THE CARBONYL GROUP IS PLANAR THE CARBONYL GROUP IS PLANAR (SP(SP22 HYBRIDIZED) HYBRIDIZED)
nucleophiles can attack from either top or bottom
Nu:
Nu:
LUMO OF FORMALDEHYDELUMO OF FORMALDEHYDE
Nu:
*
CO
CH
CO
CH
(LUMO)
C O
H
H
:..
nO
nucleophiles addto the larger lobe(on carbon)
H H
– Relative Reactivity: Aldehydes versus Ketones• Aldehydes are generally more reactive than ketones
– The tetrahedral carbon resulting from addition to an aldehyde is less sterically hindered than the tetrahedral carbon resulting from addition to a ketone
– Aldehyde carbonyl groups are more electron deficient because they have only one electron-donating group attached to the carbonyl carbon
NUCLEOPHILIC ADDITION TO C=ONUCLEOPHILIC ADDITION TO C=O
MECHANISMS
IN ACID AND IN BASE
+ :Nuslow
::..
:_
O
CC
O
Nu
:..
:
C
O
Nu
+ H2O
:..
C
O
Nu
Hfast
_
..
Nucleophilic Addition to CarbonylNucleophilic Addition to CarbonylBasic or Neutral SolutionBasic or Neutral Solution
analkoxideion
BASIC SOLUTIONGood nucleophilesand strong bases(usually charged)
-
or on adding acid
+:Nu
slow:
..
O
C
H
C
O
Nu
H+
O
C
H:O
C+ H
+fast
+:..
..
Nucleophilic Addition to Carbonyl Nucleophilic Addition to Carbonyl Acid CatalyzedAcid Catalyzed
Acid catalysis speeds the rate of addition of weak nucleophiles and weak bases (usually uncharged).
more reactive toaddition than the un-protonated precursor
ACIDIC SOLUTION
(+)
pH 5-6stronger acidprotonates thenucleophile
CYANOHYDRINSCYANOHYDRINS
+ CN_
R C R
O
R C R
O
CN
R C R
O
CN
+ R C R
O
CN
H
: : : :
: : :
..
..
_
_..
OH2
A cyanohydrin
Addition of CyanideAddition of CyanideBuffered to pH 6-8
In acid solution there would be little CN-, and HCN (g) would be a problem (poison).
a cyanohydrin
:C N:
N
N
N
N
CH3
CH3
CH2CH2COOHCH2CH2COOH
CH3
CH3
Fe
C
N..
CYANIDE ION BONDS TO HEMOGLOBINCYANIDE ION BONDS TO HEMOGLOBIN
Cyanide bonds (irreversibly) to thesite (Fe II) whereoxygen usually bonds.
CYANIDE ISIS A POISON
You die ofsuffocation -lack of oxygen.
HCN is a gas that you can easily breathe into your lungs.
..
SYNTHESIS OF SYNTHESIS OF -HYDROXYACIDS-HYDROXYACIDS
CH3
OC
OH
C
CH3
N
C
OH
C
CH3
OOH
SYNTHESIS OF AN SYNTHESIS OF AN -HYDROXYACID-HYDROXYACID
1) NaOH/H2O/2) H3O+
NaCN
pH 8
acetophenone
a cyanohydrin
Aldehydes also work unless they are benzaldehydes,which give a different reaction (benzoin condensation).
HYDROLYSIS OF THE HYDROLYSIS OF THE NITRILE GROUPNITRILE GROUP
C=O + NaCN C-OH
R-X + NaCN R-CN + NaXacetone
SN2
CN
SYNTHESIS OF NITRILES (AND CYANOHYDRINS)SYNTHESIS OF NITRILES (AND CYANOHYDRINS)
REVIEWREVIEW
….. both can be hydrolyzed
cyanohydrin
nitrile
+NaOH
H2O/C N R R C
O
O Na:NH3..
..
..:
: +-
HYDROLYSIS OF THE CYANO GROUP (NITRILES)HYDROLYSIS OF THE CYANO GROUP (NITRILES)
METHOD ONE : strong base + H2O + heat
gas
H3O+
R CO
O H....
..: R-CN
R-COOH
synthesis ofcarboxylic acids
OVER ALL
Nitriles are hydrolyzed to carboxylic acids.
neutralize
METHOD TWO : strong acid + H2O + heat
C N R R CO
O H(NH4)2
SO4+....
..:H2SO4
H2O/
no mechanismat this time
HYDROLYSIS OF THE CYANO GROUP (NITRILES)HYDROLYSIS OF THE CYANO GROUP (NITRILES)
R-CN
R-COOH
OVER ALL
Nitriles are hydrolyzed to carboxylic acids.
synthesis ofcarboxylic acids
HYDRATESHYDRATES
+ H2O
O
CR R'
R C R'
O
O
H
H
a hydrate
H+
hydrates are unstableand cannot be isolatedin most cases
Addition of WaterAddition of Water
most hydrates revert to an aldehyde or ketone as soon as they form
aldehyde or ketonefavored
+ H2O
O
CR R'
R C R'
O
O
H
H
• Dissolving aldehydes (or ketones) in water causes formation of an equilibrium between the carbonyl compound and its hydrate
– The hydrate is also called a gem-diol (gem i.e. geminal, indicates the presence of two identical substituents on the same carbon)
– The equilibrum favors a ketone over its hydrate because the tetrahedral ketone hydrate is sterically crowded
O H
O HH
C
O
OHH
HO
C
O
OH
H
OH
H
H
O HH O
HH
H
.. ..
....
.. ..
..
....
..
: : : :
:
+
+
+ a hydrate
WATER ADDS TO THE CARBONYL GROUP OF WATER ADDS TO THE CARBONYL GROUP OF ALDEHYDES AND KETONES TO FORM HYDRATESALDEHYDES AND KETONES TO FORM HYDRATES
for most compounds the equilibrium favors the starting materials and you cannot isolate the hydrate
catalyzed by atrace of acid
In a reaction where all steps arereversible, the steps in the reversereaction are the same as those inthe forward reaction, reversed!
MICROREVERSIBILITY:
..+
O HO
OH
H
H
..: :
+
+
..
ACID CATALYSISACID CATALYSIS
O H
+
..:
:NuAcid catalysis enhances the reactivityof the carbonyl group - nucleophilicaddition proceeds more easily.
weak nucleophilescan react
RECALL
an excess of H2O18
shifts the equilibriumto the right
R C
O
R
OH
H
O
R ROH2
O
R R
ISOTOPE EXCHANGE REVEALS THE PRESENCE ISOTOPE EXCHANGE REVEALS THE PRESENCE OF THE HYDRATEOF THE HYDRATE
18
18
18
+ H+
exchange shows the presence of a symmetricintermediate
+H2O18 -H2O
OH
OHO
CCl
Cl
Cl HOH
OHC
O
HCl
Cl
Cl
SOME STABLE HYDRATESSOME STABLE HYDRATES
chloral chloral hydrate
cyclopropanone cyclopropanone hydrate
120o expected60o required
109o expected60o required
sp2 sp3
+
these also indicate that hydrates are possible
SOME ADDITIONAL STABLE HYDRATESSOME ADDITIONAL STABLE HYDRATES
C CH
O
HOH
OHC C
O
HH
O
C C
O
HPh
O
C CPh
O
HOH
OH
glyoxal
phenylglyoxal
ACETALS ANDACETALS ANDHEMIACETALSHEMIACETALS
R C R'
O
ROH R C
O
R'
O
H
R
R C
O
R'
O
H
R
ROH R C
O
R'
O
R
R
+
+ H O
H
+
Addition of AlcoholsAddition of Alcohols
addition of one mole
addition of second mole
hemiacetal
an acetal
H+
H+
TWO MOLES OF ALCOHOL WILL ADD
C O
R
H
C
R
H
OH
ORC
R
H
OR
OR
C
R
R
OR
ORC
R
R
OH
ORC O
R
R
ROH
ROH
ROH
ROH
aldehyde
ketone
hemiacetal acetal
(ketal)*(hemiketal)*
ACETALS AND HEMIACETALSACETALS AND HEMIACETALS
*older term *older term
hemiacetal
C
O
R R
H O
R
H
C
O
R R
H
OH R
C
O
R R
H
RHO
C
O
R R
H
RO
ORH
.. ..
..
..
..
..
..
..
..
: : :
:
:
:
++
+
..R O
H
H+
ACID CATALYZEDACID CATALYZEDFORMATION OF AFORMATION OF AHEMIACETALHEMIACETAL
ROH H2SO4 R O H
H
+ +
..
+
Normally the startingmaterial is favored -but a second moleculeof alcohol can reactif in excess (next slide)
Like a hydroniumion
firstaddition
acetal
H O
R
H
OR
H
C
O
R R
H
RO
ORH
C
O
R R
H
RO
H
CR R
RO
C
O
R R
R
RO
H
C
O
R R
R
RO
O HH
ORH
H
:....
....
.. :::
:..
..
..
..
..
....
..
:
::
:
:
CR R
RO: :+
+
+
+ +
+
FORMATION OF THE ACETAL ( FORMATION OF THE ACETAL ( from the hemiacetal ) )
Resonancestabilizedcarbocation
SN1
second addition
hemiacetal
remove
WATER SEPARATORWATER SEPARATOR
AZEOTROPE
Two miscible liquids that distillas a single substance with aboiling point that is lower thaneither of the original liquids.
benzene 80o Cwater 100o Cbenzene-water azeotrope
69.4o C
when cooled, the azeotrope separates
benzene and water do not mix,but in the azeotrope the vapors(gases) mix and distill together
benzene
water
benzene+ water
Az
C
O
R R
H
RO
ORH
C
O
R R
R
RO
O HHC
O
R R+
2
+
Removal of watershifts equilibrium
REMOVAL OF WATER SHIFTS THE EQUILIBRIUMREMOVAL OF WATER SHIFTS THE EQUILIBRIUM( Le Chatelier Principle )
starting materialsare favored
STABILITY OF ACETALS AND HEMIACETALSSTABILITY OF ACETALS AND HEMIACETALS
Most hemiacetals are not stable, except for those of sugars(see later).
Acetals are not stable in aqueous acid, but they are stable to aqueous base.
COR
ORC O
ROH
ROH
COR
OR
AQUEOUSACID
AQUEOUSBASE no reaction
H2SO4
H2O
H2O
NaOH
+
CYCLIC ACETALSCYCLIC ACETALS
+
2 CH3OH
dry acidCH3 C CH3
O
CH3 C CH3
O
O
CH3
CH3
Dry acid = HCl gas HCl in methanol HOTs
Formation of 2,2-DimethoxypropaneFormation of 2,2-Dimethoxypropane
dry acid = HCl gas or p-toluenesulfonic acid
CH3 S OH
O
O
HCl (g)
remove H2O
THIS IS A NON-CYCLIC ACETAL
(TsOH)
mp 106oC
CYCLIC ACETALSCYCLIC ACETALSCyclic acetals can be formed if a bifunctional alcohol is used.
C
O
CH3
CH2 CH2
OH OH CH2 CH2
O O
CCH3
1,2-ethanediol
acetophenoneH2O
H+/ benzene
OSHSH SS
H2O
H+/ benzene
1,3-propanedithiol
PROTECTING GROUP STRATEGYPROTECTING GROUP STRATEGY
TARGET NON-TARGET
TARGET NON-TARGET
NON-TARGET NEWGROUP
NON-TARGET NEWGROUP
Add Protecting Group
React UnprotectedGroup
RemoveProtectingGroup
Functional Group 1 Functional Group 2
UnchangedChanged
O
Br Br
OO
MgBr
OO
COOMgBr
OOO
COOH
USE OF A CYCLIC ACETAL AS A PROTECTING GROUPUSE OF A CYCLIC ACETAL AS A PROTECTING GROUP
The GrignardReaction TakesPlace in BasicSolution - TheAcetal is Stable
H3O+
Acetals Hydrolyzein Acidic Solution
SUMMARYSUMMARY
H2O
hydrate
hemiacetal acetal
R-O-H
H2O
R-O-H
ADDITION OF WATER AND ALCOHOLSADDITION OF WATER AND ALCOHOLS
WATER
ALCOHOLS
C
OOH OR RO OR
C
OOH OH
RO OR OROH+2
no reactionNaOHH2O
H2OH+ acetals are
stable to basebut not toaqueous acid
cyclic hemiacetal
R-O-H
H2O
cyclic acetal
C
OO O
CH2 CH2
OH OH cyclicacetal
H2O
C
O
OHO
OH
O
OR
OFTEN USEDAS A PROTECTIVEGROUP
STABLE IF FORMED FROM ACARBOHYDRATE
A STARCH OR“POLYSACCHARIDE”IF FORMED FROMCARBOHYDRATES
CYCLIZATIONSCYCLIZATIONS
Tuliskan mekanisme dan produk dari reaksi berikut:
H
O
HO1.H+
2.H+
O
HOCH2CH2OH
ADDITIONS OF AMINES ADDITIONS OF AMINES TO CARBONYL GROUPSTO CARBONYL GROUPS
Aldehydes and Ketones
MANTRAMANTRA
Reactions with C=O :
Primary amines yield imines
Secondary amines yield enamines
Tertiary amines do not react
we will come back to this again and again
N HR
H
N HR
R
N RR
R
primary secondary tertiary
.. .. ..
(Memorization Jingle)
AMINES:
PRIMARY AMINESPRIMARY AMINES
IMINESIMINES
C
R
R
N G
O H
H
+.. HA
+ H2OC O
R
R
C
R
R
N GG NH2
an imine
Addition-Elimination:Addition-Elimination:The Formation of IminesThe Formation of Imines
Addition of the amineis followed by a lossof water (elimination).
primaryamine
Imines are compoundswith a C=N bond
G is a primaryalkyl group
.. a “carbinolamine”intermediate
C
OH
N
H
..+
ketone oraldehyde
+slow
G NH2C O
R
R
G N
H
H
C
R
R
O H G N
H
C OH
R
R
.. ..
..+ .. ..
..
.. fast +C
R
R
G N
H
O H
H
C
R
R
NG
H
Mechanism of Imine FormationMechanism of Imine FormationH-O
H
H-O-HH
+ H-O-HH
+proton exchangesacid-catalyzed
addition
loss of water (elimination)
..
+
H-O
H
NG C
R
R..
deprotonationH-O-H
H
+
an imine
+
weak base addition - acid catalyzed
1
2
+ + H2OC O
R
R
NH2 R C N
R
R
R..
an imine
Formation of Simple IminesFormation of Simple Imines
These reactions do not favor the formation of the imine unless:
- the product is insoluble (crystallizes or precipitates) or
- water is removed to drive the equilibrium
removeoverall result
Reactions occur fastest at pH 4-5 Mild acid facilitates departure of the hydroxyl group from the aminoalcohol intermediate without also protonating the nitrogen of the amine starting compound
Hydrolysis of Simple IminesHydrolysis of Simple Imines
++ H2O C O
R
R
NH2 RC N
R
R
R..
an imine
H3O+
In an excess of aqueous acid, simple imines hydrolyzeback to the aldehyde or ketone and the amine from which they were orginally formed …..
Imines that are not soluble, however, are difficult tohydrolyze.
REVERSAL
CRYSTALLINE IMINESCRYSTALLINE IMINES
HYDRAZONE AND OXIME DERIVATIVES
There are some special amines thatyield insoluble products (imines) that are easy to crystallize …..
CRYSTALLINE IMINESCRYSTALLINE IMINES
:NH2OH
R-NH-NH2
hydroxylamine
varioushydrazinecompounds
NHNH2
NO2
O2N2,4-dinitrophenyl- hydrazine
C NHNH2
O
NH2 semicarbazine..
....
shownbelow
+ + H2OC O
R
R
NH2 OH C
R
R
N OH..
an oximehydroxylamine
Formation of OximesFormation of Oximes
aldehydeor ketone
(usually crystallizes)
Formation of HydrazonesFormation of Hydrazones
+ + H2OC O
R
R
NH2 NH R C
R
R
N NH R..
a hydrazonea hydrazine
aldehydeor ketone
+
+ H2O
C O
R
R
NH2 NH NO2
NO2
C
R
R
N NH
NO2
NO2
..
2,4-dinitrophenylhydrazine
2,4-2,4-DinitrophenylhydrazonesDinitrophenylhydrazones2,4-dinitrophenylhydrazine
insolubleredred, orangeorange or yellowyellow precipitate forms a 2,4-DNP
2,4-dinitrophenylhydrazone
aldehydeor ketone
(precipitates)
+
+ H2O
C O
R
R
NH2 NH C NH2
O
C
R
R
N NH C NH2
O
..
semicarbazide
Formation of SemicarbazonesFormation of Semicarbazones
a semicarbazone
semicarbazine
aldehydeor ketone
(usually crystallizes)
DERIVATIVESDERIVATIVES
A derivative is a solid compound (formed from theoriginal compound) whose melting point can helpto identify the original compound.
CRYSTALLINE IMINES CAN BE USED AS DERIVATIVES
2-undecanone 231 12 122 634-chloroacetophenone 232 12 204 2364-phenyl-2-butanone 235 - 142 127
bp mpketones
semicarbazone2,4-dinitrophenyl- hydrazone
What you will see in the tables of unknowns:
BIOLOGICAL REACTIONSBIOLOGICAL REACTIONS
Pyridoxyl-5’-phosphate (P-5’-P)Pyridoxyl-5’-phosphate (P-5’-P)
N
H
OH
CH3
C HO
CH2OP
O
O
OH
Converts amino acids to -ketoacids, and vice versa.Biologically important in transamination reactions.
NH2 C
H
R
O
OH
..
N C
H
R
O
OH
N
H
OH
CH3
CH
R
- H2O
first imine
pyridoxyl-5’-phosphate
an amino acid
+
+
( P-5’-P )
formation ofthe imine
continued
N C
H
R
O
OH
N
H
OH
CH3
CH
R
N C
R
O
OH
N
H
OH
CH3
C
R
H
H
NH2
N
H
OH
CH3
CH2
R
C COH
R
O O
tautomerism
-ketoacid
pyridoxamine
H2O
:EnzEnz-H
H-Enz
Enz:
C COH
R
O O
CH COH
R
O
NH2
+
+
+
converts
hydrolysis ofthe new imine
first imine
new imine
Removing theamino group
NH2
N
H
OH
CH3
CH2
R
C COH
R
O Oa different-ketoacid
pyridoxamine
N C
R
O
OH
N
H
OH
CH3
C
R
H
H
tautomerism
hydrolysis of the imine
NH2 C
H
R
O
OH
TRANSFERRING THE AMINO GROUPTRANSFERRING THE AMINO GROUP
a differentamino acid
These steps are thereverse of those onthe previous slides.
SUMMARYSUMMARY
Amino Acid-1 + pyridoxyl-5’-phosphate -Ketoacid-1 +
pyridoxamine
-Ketoacid-2 + pyridoxamine Amino Acid-2 +
pyridoxyl- 5’-phosphate
( takes NH2 group )
( gives NH2 back )
( has NH2 )
a different one reactshere
SECONDARY AMINESSECONDARY AMINES
ENAMINESENAMINES
R C C R
H
R
O
R C C R
H
R
OH
NR2
C C
R
R R
NR2
+ R2NHH
+
H+
+ H2O
Formation of EnaminesFormation of Enamines
an enamine
..
generally removedby azeotropicdistillation
secondaryamine
-hydrogenis required
benzene
“carbinolamine”
C
R
R
N G
O H
H
..R C C R
H
R
OH
NR2
imine enamine
..
PRIMARY AMINESPRIMARY AMINES SECONDARY AMINESSECONDARY AMINES
-H2O -H2O no hydrogenon nitrogen
hydrogenon thenitrogen
COMPARISONCOMPARISON
hydrogen on theadjacent carbon
When there is no hydrogen onnitrogen, one is lost from carbon.
carbinolamine intermediates
SOME SECONDARY SOME SECONDARY AMINES FREQUENTLY AMINES FREQUENTLY USED TO FORMUSED TO FORMENAMINESENAMINES
N
H
N
H
N
O
H
piperidine
pyrrolidine
morpholineWater must be removed
1)
R C C R
H
R
O
R C C R
H
R
O H
R C C R
H
R
O H
: :
+ H+
+.. ..
:
+
2)
R C C R
H
R
O H+..
..
slow
N H
R R
+
:..
:
+..
R C C R
H
R N
R R
H
O H
R C C R
H
R
OH2
N
R R
Enamine FormationEnamine Formation
H-O-HH
+
H-O-HH
+
H
O-H
continued ….
MECHANISM
3)
:
+..
:
+
+
+
4)
: :
+ H+
R C C R
H
R
OH2
N
R R
R C C R
H
R N
R R
+ H2O
N
R R
R C C R
R
R C C R
H
R N
R R
R C C R
H
R N
R R
Enamine Formation (cont)Enamine Formation (cont)
enamine
O-HH
H3O+
H2O
+
water mustbe removedto force theequilibrium
MECHANISM
+
2)
C C
R
R R
N
R
R
C C
R
R R
N
R
R: +..
_
Nucleophilic Character of EnaminesNucleophilic Character of Enamines
nucleophilicat carbon
C
X
SN2
SN2
Reactions of Enamines as NucleophilesReactions of Enamines as Nucleophiles
an iminium salt
hydrolysis
R C C R
R
R
O
R C C R
R
H
O
C C
R
R R
N
R
R:
R X
R C C R
R
R
N
R R
R C C R
R
R
N
R R
+
+
:
+ X_
alkylation
O
NH
N N
CH3
OH2
CH3I
O
CH3
NH
..
..
+H+
+
H3O+
ALKYLATION OF A KETONEALKYLATION OF A KETONE
pyrrolidine
iminiumsalt
enamine
removewater
workup
Az
1)
R C C R
O
R
R
H H
N
R R
R C C R
O
R
R H
N
R R
H
R C C R
O
R
R H
..
..OH H
+
slow
:+
+
..:
+
..:
2)
N
R R
H+..
+..
R C C R
R
R
N
R R
:
N
R R
H
R C C R
O
R
R H
Hydrolysis of Iminium SaltsHydrolysis of Iminium Salts
continued ….
H-O-HH
+
H
O-H
MECHANISM
3)
R C C R
O
R
R H+..
R C C R
O
R
R
+
: :
H3O+
H
O-H
Hydrolysis of Iminium SaltsHydrolysis of Iminium SaltsMECHANISM
CC
R
RR
N
R
R
CC
R
RR
N
R
R
:
+..
_
R X
enamine
CH CH2CH2X
C CH3CH2X
O
C OCH2X
O
CH3
X CH2CH3
CCl CH3
O
CCl O
O
CH2CH3
SUBSTRATES FOR ENAMINE ALKYLATION SUBSTRATES FOR ENAMINE ALKYLATION (and acylation)
acylation
alkylation
primarysecondaryallylic
C ClR
O
C ClRO
Oacyl compoundsmay be used
X = Cl, Br, I
C ClR
O
C ClRO
O
many students assume that if acid chlorides are good the acid bromides and iodides must be better.
However …… acid bromides and iodides are difficult toprepare, and the iodides are quite unstable
….. you should use the chlorides.
In SN2 reactions you learned the rate sequence R-I > R-Br > R-Cland that iodides are better substrates than chlorides.
This is true.
Based on this knowledge …..
CHLORIDES, BROMIDES AND IODIDESCHLORIDES, BROMIDES AND IODIDES
They are easily prepared from the acid by: R-COOH + SOCl2
O
O
R
R2NH
H+
R X
H2O+H
+N
R R
N
R R
R
Enamine Reactions -- SummaryEnamine Reactions -- Summary
secondaryamine
alkyl oracylhalide
TERTIARY AMINESTERTIARY AMINES
DO NOT REACTDO NOT REACT
C
R
R
N R
O H
H
..
R C C R
H
R
OH
+
R C C R
H
R
OH
loses H from N
loses H from C
:..
unstablereverses
PRIMARY AMINE
SECONDARY AMINE
TERTIARY AMINE
N R
H
H
N-R
R
:
N-R
RR
N R
R
H
N R
R
R
COMPARISONCOMPARISON
H is lost to form intermediate
H is lost
no H to lose
You need to lose two H’s,one to form the intermediate,one to eliminate water.
The tertiary amine can’tform the carbinolamineintermediate becauseit lacks an H on N.
FORMING RINGSFORMING RINGS
SOME GUIDELINES
NH2
NH2
O CH
H+
N
N
CH2
CH2
NH
NHCH2
DILUTE SOLUTION AND EXACT STOICHIOMETRYDILUTE SOLUTION AND EXACT STOICHIOMETRYFAVOR RING FORMATIONFAVOR RING FORMATION
Excess formaldehyde (>2:1)and a more concentratedsolution favor the diimime.
1:1 molar ratio anddilute solution favorthe ring formation
In dilute solution the molecule is morelikely to react internally with itselfbecause encounters with other moleculeswill be less frequent.
Also rememberthat unstrained5- and 6-rings form easily,other sizes aredifficult.
pH = 5
HINT ON THE MECHANISM …..HINT ON THE MECHANISM …..
C=N can undergo additions just like C=O
N
NH2
CH2
H
..
+
forms ring
CRUCIALSTEP
Both are polar multiple bondsand both can undergo acid-catalyzed nucleophilic addition.
….. see if you can figure out the rest of the mechanism for Problem 16-18 on your own.
protonationfirst
pH 5
mildlyacidic
WITTIG REACTIONWITTIG REACTION
YlideYlideA compound or intermediate with both a positive and a negative charge on adjacent atoms.
X Y..- +
Betaine or ZwitterionBetaine or Zwitterion
A compound or intermediate with both a positive and a negative charge, not on adjacent atoms, but in differentparts of the molecule. X
-Y
+
:
BOND
MOLECULE
+ (C6H5)3P+
R1 C
R2
X
H
(C6H5)3P C R2
R1
H
X_
(C6H5)3P C
R2
R1
Preparation of a Phosphorous YlidePreparation of a Phosphorous Ylide
strong base
:
O-CH3
-
P Ph
Ph
Ph..
Triphenylphosphine( Ph = C6H5 )
:....
( WITTIG REAGENT )
+ ..-
an ylide
benzene
heat
precipitates
ether
C
(C6H5)3P C
R
R
(C6H5)3P C
R
R+
_ ..
Resonance in YlidesResonance in Ylides
..
3d 2p
d-p BACKBONDING
Remember that Phosphorousis a Period III element (d orbitals).
Backbonding to phosphorousreduces the formal chargesand stabilizes the negativecharge on carbon.
P
..
INSOLUBLE
very thermodynamicallystable molecule
ylide betaine
+ -
The Wittig ReactionThe Wittig ReactionMECHANISM
synthesis ofan alkene
+
:..
:_ +
C O
R1
R2
(C6H5)3P C
R4
R3
R2 C
R1
O
C R4
R3
P(C6H5)3
+C
R1
R2
C
R4
R3
O P(C6H5)3
:..
R2 C
R1
O
C R4
R3
P(C6H5)3
oxaphosphetane(UNSTABLE)
H
CH3
CH3
CH2CH3 CH3
CH3
O
H
CH2CH3Br
H
H
CH2CH3(C6H5)3P
H
:P(C6H5)3
+
H
CH2CH3(C6H5)3P
:
+
CH3ONa-ylide
CH3
CH3
O
SYNTHESIS OF AN ALKENE - WITTIG REACTIONSYNTHESIS OF AN ALKENE - WITTIG REACTION
ANOTHER WITTIG ALKENE SYNTHESISANOTHER WITTIG ALKENE SYNTHESIS
C
H
Br
HO
CH2Br
:P(C6H5)3
C P(C6H5)3
H
HBr-
+
PhLi
..C P(C6H5)3
H
- +
ylide
: ..
+
+-
triphenylphosphineoxide (insoluble)
P(C6H5)3O
O
..
C
H
MuscalureMuscalure
CH2(CH2)11CH3CH3(CH2)6CH2
HH
(Z)-9-tricosene
Sex pheromone of thecommon house fly.Musca Domestica
CH3(CH2)6 C
O
HCl CH2(CH2)12CH3
Wittig The reaction can be made to give the cis alkene (Z) by correct choice of solvent and temperature, or by theseparation of a mixture of cis and trans.
ORGANOMETALLICSORGANOMETALLICS
+
(R-MgBr)
M
_+
H2O
H +
R M
O
CR R
R C R
O
R
R C R
O
R
H
+ M (OH)x
: : : :
:
..
..
(R-Li)
Addition of Organometallic ReagentsAddition of Organometallic Reagents
ether
These reagents cannot exist in acid solution
workupstep
alcohol
:R -
Synthesis of Alcohols
Summary of Reactions of Summary of Reactions of Organometallics with Organometallics with Carbonyl CompoundsCarbonyl Compounds
• Organometallics with ketones yield tertiary alcohols• Organometallics with aldehydes yield secondary alcohols• Organometallics with formaldehyde yield primary alcohols.• Organometallics with carbon dioxide yield carboxylic acids.
etc.
All reviewto you