ALDEHYDES AND KETONES I
CHAPTER 16
Sections 16.1 and 16.2 Nomenclature of Aldehydes and Ketones
Learn onyour own.
CHEMISTRY OF THE C=O GROUP
Sections 16.3-16.5Review and Overview Read on your own
Section 16.6Cyanide addition Lecture
Section 16.7Addition of Organometallics Totally review
Section 16.8Bisulfite Addtion Read on your own
Sections 16.9-16.11 Lecture
Jump to Sections 16.15-16.19
Go Back to Sections 16.12-16-14
Lecture
Lecture
Aldehyde STRUCTURE
O
CR H
R = H, alkyl, aryl
Ketone
O
CR R'
R and R' = alkyl or arylR and R' cannot be hydrogen!
NOMENCLATURENOMENCLATURE
IUPAC Nomenclature ofIUPAC Nomenclature of KetonesKetones
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
Do the ketones section of Organic Nomenclatureprogram!
CH 3C
CH 2CH 2
CH 3
OEXAMPLES
2-Pentanone O
CCH2 CH
CH3 CH2
CH2
CH3
CH34-Ethyl-3-hexanone
O
CH
CH3
CH3
3-Isopropylcyclopentanone
or 3-(1-Methylethyl)cyclopentanone
Common, or Trivial, NamesCommon, or Trivial, NamesKETONESKETONES
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!
Example of Common NamesExample of Common Names
CH 3C
CH 2CH 2
CH 3
O
Methyl propyl ketone O
CCH2 CH2
CH3 CH3
Diethyl ketone
O
CCH3 CH3
acetone
dimethyl ketone
A common laboratorysolvent and cleaningagent
SPECIAL CASESSPECIAL CASES
CO
benzophenone
diphenyl ketone
CO
CH3
acetophenone
methyl phenyl ketoneKNOWTHESE
IUPAC Nomenclature ofIUPAC Nomenclature of AldehydesAldehydes
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
Do the aldehydes section of Organic Nomenclatureprogram.
EXAMPLES
CH3CH2
CH2CH2
CO
Hpentanal
CH3CH
CHC
O
HCH3
Cl1
23
4
always carbon 1aldehyde group is
2-chloro-3-methylbutanal
Common Names of theCommon Names of the AldehydesAldehydesO
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
RECOGNIZETHESE
O
CH H
O
CH CH3
CO
H
SPECIAL CASESSPECIAL CASES
formaldehyde
acetaldehyde
benzaldehyde
KNOWTHESE
Forming Common Names ofForming Common Names of AldehydesAldehydes
C
C C C C C C H
OUSE OF GREEK LETTERS
.
is always the end of the chain, no matter how long
CHO
Cl
CHO
Cl
-chlorocaproaldehyde( -chlorohexanal )
-chlorocaproaldehyde( -chlorohexanal )
REACTIVITY OF THE C=O GROUPREACTIVITY OF THE C=O GROUP
NUCLEOPHILIC ADDITION
GENERALIZED CHEMISTRY
THE CARBONYL GROUPTHE CARBONYL GROUP
OC
..:+
-OC
..::-
+
electrophilicat carbon
nucleophilicat oxygen
Nu:
nucleophilesattack here
H+ or E+electrophilesadd here
STEREOCHEMISTRYSTEREOCHEMISTRY
C O....
. .
THE CARBONYL GROUP IS PLANAR THE CARBONYL GROUP IS PLANAR (SP(SP22 HYBRIDIZED)HYBRIDIZED)
Nu:
Nu:nucleophiles can attack from either top or bottom
LUMO OF FORMALDEHYDELUMO OF FORMALDEHYDE
*
CO
CH
CO
CH
(LUMO)
C OH
H:
..
nO
Nu: nucleophiles addto the larger lobe(on carbon)
H H
NUCLEOPHILIC ADDITION TO C=ONUCLEOPHILIC ADDITION TO C=O
MECHANISMSIN ACID AND IN BASE
NucleophilicNucleophilic Addition to CarbonylAddition to CarbonylBasic or Neutral SolutionBasic or Neutral Solution
+ :Nuslow
: :..
:_
O
CC
O
Nu
:..
:
C
O
Nu
+ H2O
:..
C
O
Nu
Hfast
_
..analkoxideion
-
or on adding acid
Good nucleophilesand strong bases(usually charged)
BASIC SOLUTION
+ :Nuslow
:..
O
C
H
C
O
Nu
H+
O
C
H:O
C+ H+
fast
+:..
..
NucleophilicNucleophilic Addition to Carbonyl Addition to Carbonyl Acid CatalyzedAcid Catalyzed
more reactive toaddition than the un-protonated precursor
(+)
ACIDIC SOLUTIONAcid catalysis speeds the rate of addition of
weak nucleophiles andweak bases (usually uncharged). pH 5-6
stronger 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
Addition of CyanideAddition of CyanideBuffered to pH 6-8
a cyanohydrin
:C N:
A cyanohydrinIn acid solution there would be little CN-, and HCN (g) would be a problem (poison).
N
N
N
N
CH3
CH3
CH2CH2COOHCH2CH2COOH
CH3
CH3
Fe
CN..
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 --HYDROXYACIDSHYDROXYACIDS
SYNTHESIS OF AN SYNTHESIS OF AN --HYDROXYACIDHYDROXYACID
CH3
OCOH
CCH3
N
COH
CCH3
OOH
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
SYNTHESIS OF NITRILES (AND CYANOHYDRINS)SYNTHESIS OF NITRILES (AND CYANOHYDRINS)
REVIEWREVIEW
C=O + NaCN C-OHCN
cyanohydrin
R-X + NaCN R-CN + NaXacetone
SN2nitrile
.. both can be hydrolyzed
HYDROLYSIS OF THE CYANO GROUP (NITRILES)HYDROLYSIS OF THE CYANO GROUP (NITRILES)
+NaOH
H2O/C N R R C
O
O Na:NH3..
..
..:
: +-
METHOD ONE : strong base + H2O + heat
gas
H3O+
R CO
O H....
..: R-CN
R-COOH
synthesis ofcarboxylic acids
OVER ALLneutralize
Nitriles are hydrolyzed to carboxylic acids.
HYDROLYSIS OF THE CYANO GROUP (NITRILES)HYDROLYSIS OF THE CYANO GROUP (NITRILES)
METHOD TWO : strong acid + H2O + heat
C N R R CO
O H(NH4)2SO4+..
..
..:H2SO4
H2O/
no mechanismat this timeR-CN
R-COOH
OVER ALL
synthesis ofcarboxylic acids
Nitriles are hydrolyzed to carboxylic acids.
ORGANOMETALLICSORGANOMETALLICS
REVIEW FROM CHAPTER 15
Synthesis of Alcohols
Addition of Organometallic ReagentsAddition of Organometallic Reagents
+
(R-MgBr)
M_ +
H2OH +
R M
O
CR R
R C R
O
R
R C R
O
R
H
+ M(OH)x
: : : :
:
..
..
(R-Li)
ether
These reagents cannot exist in acid solution
workupstep
alcohol
:R -
Summary of Reactions ofSummary of Reactions ofOrganometallicsOrganometallics with Carbonyl with Carbonyl
CompoundsCompoundsAll reviewto you 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.
HYDRATESHYDRATES
Addition of WaterAddition of Water
+ H2O
O
CR R'
R C R'
O
O
H
H
a hydrate
H+
hydrates are unstableand cannot be isolatedin most cases
most hydrates revert to an aldehydeor ketone as soon as they form
aldehyde or ketonefavored
+ H2O
O
CR R'
R C R'
O
O
H
H
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
O H
O HH
CO
OHH
HOCO
OH
HO
HH
H
O HH O
HH
H
.. ..
....
.. ..
..
....
..
: : : :
:
+
+
+ a hydrate
catalyzed by atrace of acid
..+
for most compounds the equilibriumfavors the starting materials
and you cannot isolate the hydrateIn a reaction where all steps arereversible, the steps in the reversereaction are the same as those inthe forward reaction, reversed!
MICROREVERSIBILITY:
ACID CATALYSISACID CATALYSIS
O HO
OH
HH
..: :
+
+..
O H
+
..:
:NuAcid catalysis enhances the reactivityof the carbonyl group - nucleophilicaddition proceeds more easily. weak nucleophilescan react
RECALL
ISOTOPE EXCHANGE REVEALS THE PRESENCE ISOTOPE EXCHANGE REVEALS THE PRESENCE OF THE HYDRATEOF THE HYDRATE
an excess of H2O18
shifts the equilibriumto the right
R CO
RO
H
H
O
R ROH2
O
R R18
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 cyclopropanonehydrate
120o expected60o required
109o expected60o required
sp2 sp3
+
these also indicate that hydrates are possible
SOME ADDITIONAL STABLE HYDRATESSOME ADDITIONAL STABLE HYDRATES
C CHO
HOH
OHC C
O
HH
O
C CO
HPh
O
C CPhO
HOH
OH
glyoxal
phenylglyoxal
ACETALS ANDACETALS ANDHEMIACETALSHEMIACETALS
Addition of AlcoholsAddition of AlcoholsTWO MOLES OF ALCOHOL WILL ADD
R C R'
OROH R C
OR'
O
H
R
R CO
R'O
H
RROH R C
OR'
O
R
R
+
+ H OH
+
addition of one mole
addition of second mole
hemiacetal
an acetal
H+
H+
ACETALS AND HEMIACETALSACETALS AND HEMIACETALS
C OR
HC
R
H
OH
ORC
R
H
OR
OR
CR
R
OR
ORC
R
R
OH
ORC O
R
R
ROH
ROH
ROH
ROH
aldehyde
ketone
hemiacetal acetal
(ketal)*(hemiketal)**older term *older term
hemiacetal
CO
R R
H OR
H
CO
R R
H
OH R
CO
R R
H
RHO
CO
R R
H
RO
ORH
.. ..
..
..
..
..
..
..
..
: : :
:
:
:
++
+
..R OH
H+
ACID CATALYZEDACID CATALYZEDFORMATION OF AFORMATION OF AHEMIACETALHEMIACETAL
R OH H 2SO4 R O HH
+ +..
+
Normally the startingmaterial is favored -but a second moleculeof alcohol can reactif in excess (next slide)
Like a hydroniumion
firstaddition
FORMATION OF THE ACETAL ( FORMATION OF THE ACETAL ( from the hemiacetal ))
acetal
H OR
HO
R
H
CO
R R
H
RO
ORH
CO
R R
H
RO
H
CR R
RO
CO
R R
R
RO
H
CO
R R
R
RO
O HH
ORH
H
:....
....
.. :::
:..
..
..
..
..
....
..
:
::
::
CR R
RO: :+
+
+
+ +
+
Resonancestabilizedcarbocation
SN1
second addition
hemiacetal
remove
WATER SEPARATORWATER SEPARATORAZEOTROPE
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
REMOVAL OF WATER SHIFTS THE EQUILIBRIUMREMOVAL OF WATER SHIFTS THE EQUILIBRIUM( Le Chatelier Principle )
CO
R R
H
RO
ORH
CO
R R
R
RO
O HHC
O
R R+
2
+
Removal of watershifts equilibrium
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
H2SO4H2O
+AQUEOUSACID
COR
OR
AQUEOUSBASE H2O
NaOHno reaction
CYCLIC ACETALSCYCLIC ACETALS
Formation of 2,2Formation of 2,2--DimethoxypropaneDimethoxypropaneTHIS IS A NON-CYCLIC ACETAL
+
2 CH3OH
dry acidCH3 C CH3
O
CH3 C CH3
O
O
CH3
CH3
removeH2O
Dry acid = HCl gasHCl in methanolHOTs
dry acid = HCl gas or p-toluenesulfonic acid
CH3 S OHO
OHCl (g)
(TsOH)
mp 106oC
CYCLIC ACETALSCYCLIC ACETALSCyclic acetals can be formed if a bifunctional alcohol is used.
CO
CH3
CH2 CH2OH OH CH2 CH2
O O
CCH3
1,2-ethanediol
acetophenoneH2O
H+ /benzene
OSHSH SS
H2O
H+ /benzene
1,3-propanedithiol
PROTECTING GROUP STRATEGYPROTECTING GROUP STRATEGYFunctional Group 1 Functional Group 2
TARGET NON-TARGETAdd Protecting Group
TARGET NON-TARGET
NON-TARGETNEW
GROUP
React UnprotectedGroup
RemoveProtectingGroup
NON-TARGETNEW
GROUP
UnchangedChanged
USE OF A CYCLIC ACETAL AS A PROTECTING GROUPUSE OF A CYCLIC ACETAL AS A PROTECTING GROUP
O
Br Br
OO
MgBr
OO
COOMgBr
OOO
COOH
The GrignardReaction TakesPlace in BasicSolution - TheAcetal is Stable
H3O+
Acetals Hydrolyzein Acidic Solution
CARBOHYDRATESCARBOHYDRATESAND SUGARSAND SUGARS
Review Sections 5.14-5.17Carbohydrate StructuresFischer Projections / D and L
Cyclization of MonosaccharidesCyclization of Monosaccharides
O
C
CH2 OH
OH
OHH
HOH
OHH
H
H
C
CH2 OH
H
OHH
HOH
OHH
H
O
OH
..
..
: :
1 1
2 2
3 3
4 4
5 5
6 6
a hemiacetalonly sugars seem to makestable hemiacetals
glucose glucopyranose
FURANOSE AND PYRANOSE RINGSFURANOSE AND PYRANOSE RINGS
: :
OH
H
O
H
OHO
H
H
OO
O
HOH
:..
a pyranosering
a furanosering
6
5
two anomersare possiblein each case
furan pyran
O O
for clarity nohydroxyl groups are shown on the chains or rings
123
4 5
123
4
ANOMERS ANOMERS
: :
OH
HO
H
OHO
H
H
OO
-D-(+)-Glucose
-D-(+)-Glucose
: :
O
H
HO
for clarityhydroxyl groups on the chain are not shown
anomericcarbon(hemiacetal)
anomers differ in configurationat the anomeric carbon
: :
OH
HOHO
OHOH
CH2
OH
H
OHOHO
OHOH
CH2
OH
H
H
OOHO
OHOH
CH2
OH
-D-(+)-Glucose -D-(+)-Glucose[] = + 112.2 [] = + 18.7
[] = + 52.7
Equilibrium mixture:
GlucoseGlucosehemiacetals
66%34%
open chain
O
C
CH2 OH
OH
OHH
HOH
OHH
H
H
..
..
1
2
3
4
5
6 < 0.001%
HAWORTH PROJECTIONSHAWORTH PROJECTIONS
It is convenient to view the cyclic sugars (glucopyranoses)as a Haworth Projection, where the ring is flattened.
upper-rightback
This orientation isalways used for aHaworth Projection
OCH2OH
HH
OHH
OH
OH
HOH
H O
Standard Position
-D-(+)-glucopyranose
HAWORTHPROJECTION
OHOHOH
CH2OH
CHOOH
D-(+)-glucose L-(-)-glucose
GLUCOSE ENANTIOMERSGLUCOSE ENANTIOMERS
CH2OH
CHO
OHOHOH
CH2OH
CHOOH
O
HAWORTH
FISCHER
WE WILL LEARN HOW TO CONVERT FISCHER PROJECTIONSWE WILL LEARN HOW TO CONVERT FISCHER PROJECTIONSTO HAWORTH PROJECTIONS OF EITHER ANOMERTO HAWORTH PROJECTIONS OF EITHER ANOMER
HAWORTH PROJECTIONSHAWORTH PROJECTIONSHERE ARE SOME CONVENTIONS YOU MUST LEARN
2) The -CH2OH group is placed UP for a D-sugar andDOWN for an L-sugar.
1) The ring is always oriented with the oxygen in the upper right-hand back corner.
O
OCH2OH
OCH2OH
3) -Sugars have the -CH2OH group and the anomeric hydroxyl group trans.
4) -Sugars have the -CH2OH group and the anomeric hydroxyl group cis.
D
L
OCH2OH
OH
OCH2OH
OH
GLUCOPYRANOSES
SOME HAWORTH PROJECTIONSSOME HAWORTH PROJECTIONS
OCH2OH
HH
OHH
OH
OH
HH
OH
OCH2OH
HH
OHH
OH
OH
HOH
H
cis=
trans=
-CH2OH up = D
-CH2OH up = D
-DDD--SUGARSSUGARS
-D
ANOMERS
BOTH OF THESE ARE D-GLUCOSE
OH
CH2OHOH
HOH
H
H
OHH
OH
OH
CH2OHOH
HOH
H
H
OHOH
H
-CH2OH down=L
-CH2OH down=L
trans=
cis=
LL--SUGARSSUGARS-L
-L
SOME HAWORTH PROJECTIONSSOME HAWORTH PROJECTIONS
ANOMERS
BOTH OF THESE ARE L-GLUCOSE
CONVERTING CONVERTING FISCHER PROJECTIONSFISCHER PROJECTIONS
TO HAWORTH PROJECTIONSTO HAWORTH PROJECTIONS
CONVERTING TO HAWORTH PROJECTIONS
OHOHOH
CH2OH
CHOOH
OCH2OH
HH
OHH
OH
OH
HH
OH
D-(+)-glucose
UP
DOWN
on right= D
-CH2OH up = D cis
=
FISCHERFISCHERPROJECTIONPROJECTION
trans=
HAWORTHHAWORTHPROJECTIONSPROJECTIONS
OCH2OH
HH
OHH
OH
OH
HOH
H
BOTH ANOMERS OFA D-SUGAR(D-glucose)
1
6
2
3
4
5
1
23
4
6
5
CONVERTING TO ACTUAL CONFORMATIONS
OCH2OH
HH
OHH
OH
OH
HOH
H
OH
HH
H
HOH
H
O
OHOH
CH2OH
trans=
-D-(+)-glucopyranose
OCH2OH
HH
OHH
OH
OH
HH
OH
H
HH
H
OHOH
H
O
OHOH
CH2OH
cis= -CH2OH up = D
-D-(+)-glucopyranose
HAWORTHO
O
CONFORMATION
HAWORTH PROJECTIONS OF L-SUGARS
L-(+)-glucosetrans=
cis=
OH
CH2OHOH
HOH
H
H
OHH
OH
OH
CH2OHOH
HOH
H
H
OHOH
H
HAWORTHHAWORTHPROJECTIONSPROJECTIONS
BOTH ANOMERS OFA L-SUGAR(L-glucose)
-CH2OH down=L
DOWN
OHOHOH
CH2OH
CHOOH
UP
on left= L
FISCHERFISCHERPROJECTIONPROJECTION
CONVERTING FISCHER TO HAWORTH PROJECTIONS
CAUTION !CAUTION !Students often get the erroneousimpression that all the Haworthrules are reversed for L-sugars
- this is not the case!
These rules are the same for bothD- and L-sugars
The only difference whenconverting D- and L- sugars is :
D-sugars -CH2OH = UPL-sugars -CH2OH = DOWN
LEFT = UPRIGHT = DOWN
= cis = trans
AN OPEN CHAIN CAN CONVERT TO EITHER ANOMERAN OPEN CHAIN CAN CONVERT TO EITHER ANOMER
OPENCHAIN
-ANOMER
-ANOMER
FISCHER HAWORTH
You cant tell which anomer will result (predominate)when you look at the Fischer Projection.
That information is not contained in Fischer Projection.
FRUCTOFURANOSES
FRUCTOSE Ostandard position
cis = up = DCH2OH
OOH
OHOH
CH2OH
1
2
3
4
5
6
..
..
..:
O
HOH
H
H
OHCH2OH
OHCH2OH anomericcarbon
1
2
34
5
6
-D-(-)-FructofuranoseD-(-)-Fructose
MUTAROTATION
: :
OH
HOHO
OHOH
CH2
OH
H
OHOHO
OHOH
CH2
OH
H
H
OOHO
OHOH
CH2
OH
-D-(+)-Glucose -D-(+)-Glucose[] = + 112.2 [] = + 18.7
[] = + 52.7
Equilibrium mixture:
GlucoseGlucosehemiacetals
66%34%
open chain< 0.001%
MUTAROTATIONMUTAROTATION
TIME
+57.2o
+112o
+19o
pure -D-(+)-glucopyranose1
pure -D-(+)-glucopyranose2
[]D
66% 34%
(min)
1 Obtained by crystallization of glucose at room temperature.
2 Obtained by crystallization of glucose at 980 C.
CONVERSION TO AN ACETALCONVERSION TO AN ACETAL
H
OHOHO
OHOH
CH2
OH
-D-(+)-GlucoseH
OHO
OHOH
CH2
OH
O CH3
OHO
OHOH
CH2
OH
H+
CH3OH
dry HCl
excess
conversion isvia thecarbocation
SN1
any alcoholcould be used
1) +H+
2) - H2O
3) + ROH
4) -H+
hemiacetal acetal
THE ALCOHOL USED CAN BE ANOTHER SUGARTHE ALCOHOL USED CAN BE ANOTHER SUGAR
H
OHOHO
OHOH
CH2
OH
-D-(+)-GlucoseH
OHO
OHOH
CH2
OH
O Sugar
HO-Sugar
a monosaccharide a disaccharide
Since sugars have many -OH groups, this can continue on to make polysaccharides.
DETOXIFICATION BY THE LIVERDETOXIFICATION BY THE LIVER
In mamalian metabolism, many molecules become glycosylatedin the liver to become glycosides.
The glycosides are more soluble than the original moleculeand can be excreted because they are soluble in blood and urine.
MOLECULE-OH MOLECULE-O-Gluglucose
liver enzymes
a glycoside
Glu = glucose
POLYSACCHARIDESPOLYSACCHARIDES
O
CH2OH
H
OH
H OH
HOH
HOH
O
CH2OH
H
OH
H OH
HOH
HOH
O
CH2OH
H
OH
H OH
H
HOH
O
CH2OH
H
OH
H OH
HOH
HO
:..
bc
a
-D-(+)-Glucose
b
ca
Cellobiose
--1,41,4--Glycosidic LinkageGlycosidic LinkageCellobioseCellobiose
enzymemediated
If continued, youget cellulose.
Humans cantdigest -1,4
O
CH2OH
H
OH
H OH
HH
OHOH
O
CH2OH
H
OH
H OH
HH
OHOH
O
CH2OH
H
OH
H OH
H
OH
H O
CH2OH
H
OH
H OH
HH
OHO
:..
bc
a
-D-(+)-Glucose
bc a Maltose
--1,41,4--Glycosidic LinkageGlycosidic LinkageMaltoseMaltose
enzymemediated
Humans candigest -1,4
SucroseSucrosea disaccharide
O
CH2OH
HH
OHH
OH
OH
H OH
H OCH2OH
O
OH
H
H
OHCH2OH
H
H
O
CH2OH
HH
OHH
OH
OH
H
H OCH2OH
OH
H
H
OHCH2OH
H
O
-D-(+)-Glucose -D-(-)-Fructose
..
..
(+)-Sucrose
a b
a b
Humans candigest -1,4
Read the remaining material onRead the remaining material onpolysaccharides on your own.polysaccharides on your own.
SUMMARYSUMMARY
ADDITION OF WATER AND ALCOHOLSADDITION OF WATER AND ALCOHOLS
H2O
hydrateCO OH OHWATER
hemiacetal acetal
R-O-H
H2O
R-O-HALCOHOLS
CO OH OR RO OR
RO OR OROH+2
no reactionNaOHH2O
H2OH+ acetals are
stable to basebut not toaqueous acid
CYCLIZATIONSCYCLIZATIONS
CO O O
CH2 CH2OH OH OFTEN USEDAS A PROTECTIVE
GROUPcyclicacetal
H2O
cyclic hemiacetal
R-O-H
H2O
cyclic acetal
CO
OHO
OH
O
OR
STABLE IF FORMED FROM ACARBOHYDRATE
A STARCH ORPOLYSACCHARIDEIF FORMED FROMCARBOHYDRATES
APPENDIXAPPENDIX
These are here for practiceyou do not have to learn thenames and structures.
The D-AldohexosesCHO
CH2OH
OHH
OHH
OHH
OHH
CHO
CH2OH
HOH
OHH
OHH
OHH
CHO
CH2OH
OHH
HOH
OHH
OHH
CHO
CH2OH
HOH
HOH
OHH
OHH
CHO
CH2OH
OHH
OHH
HOH
OHH
CHO
CH2OH
HOH
OHH
HOH
OHH
CHO
CH2OH
OHH
HOH
HOH
OHH
CHO
CH2OH
HOH
HOH
HOH
OHH
(+)-Allose (+)-Altrose (+)-Glucose (+)-Mannose
(-)-Gulose (-)-Idose (+)-Galactose (+)-Talose
The L-Aldohexoses(the other half of the aldohexoses)
(-)-Allose (-)-Altrose (-)-Glucose (-)-Mannose
(+)-Gulose (+)-Idose (-)-Galactose (-)-Talose
CHO
CH2OH
OH H
OH H
OH H
OH H
CHO
CH2OH
H OH
OH H
OH H
OH H
CHO
CH2OH
OH H
H OH
OH H
OH H
CHO
CH2OH
OH H
H OH
H OH
OH H
CHO
CH2OH
H OH
OH H
H OH
OH H
CHO
CH2OH
OH H
OH H
H OH
OH H
CHO
CH2OH
H OH
H OH
H OH
OH H
CHO
CH2OH
H OH
H OH
OH H
OH H
ADDITIONS OF AMINES ADDITIONS OF AMINES TO CARBONYL GROUPSTO CARBONYL GROUPS
Aldehydes and Ketones
MANTRAMANTRAReactions with C=O :
Primary amines yield imines
Secondary amines yield enamines
Tertiary amines do not react
(Memorization Jingle)
we will come back to this again and again
N HRH
N HRR
N RRR
AMINES: .. .. ..
primary secondary tertiary
PRIMARY AMINESPRIMARY AMINES
IMINESIMINES
AdditionAddition--Elimination:Elimination:The Formation of IminesThe Formation of Imines
C
R
R
N G
O H
H
+.. HA
+ H2OC O
R
R
C
R
R
N GG NH2
an imine
.. a carbinolamineintermediate
COH
N
H
.. +
ketone oraldehyde
primaryamine
Addition of the amineis followed by a lossof water (elimination).
Imines are compoundswith a C=N bond
G is a primaryalkyl group
+slow
G NH2 C 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 ofMechanism of ImineImine FormationFormationH-O
H
H-O-HH
+ H-O-HH
+proton exchangesacid-catalyzed
addition
loss of water (elimination)
..+
H-OH
NG C
R
R..
deprotonation H-O-HH
+
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 Iminesremove
overall result
These reactions do not favor the formation of theimine unless:
- the product is insoluble (crystallizes or precipitates) or
- water is removed to drive the equilibrium
Hydrolysis of Simple IminesHydrolysis of Simple IminesREVERSAL
In an excess of aqueous acid, simple imines hydrolyzeback to the aldehyde or ketone and the amine from which they were orginally formed ..
++ H2O C O
R
R
NH2 RC N
R
R
R..
an imine
H3O+
Imines that are not soluble, however, are difficult tohydrolyze.
CRYSTALLINE IMINESCRYSTALLINE IMINES
HYDRAZONE AND OXIME DERIVATIVES
There are some special amines thatyield insoluble products (imines) that are easy to crystallize ..
CRYSTALLINE IMINESCRYSTALLINE IMINES shownbelow
C NHNH2
ONH2
..:NH2OH hydroxylamine semicarbazine
NHNH2
NO2
O2N2,4-dinitrophenyl-
hydrazine
..R-NH-NH2 various
hydrazinecompounds
..
Formation ofFormation of OximesOximes
+ + H2OC O
R
R
NH2 OH C
R
R
N OH..
an oximehydroxylaminealdehydeor 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
2,42,4--DinitrophenylhydrazonesDinitrophenylhydrazones
+
+ H2O
C O
R
R
NH2 NH NO2
NO2
C
R
R
N NH
NO2
NO2
..
2,4-dinitrophenylhydrazine
2,4-dinitrophenylhydrazine
insolubleredred, orangeorange or yellowyellow
precipitate forms a 2,4-DNP
2,4-dinitrophenylhydrazone
aldehydeor ketone
(precipitates)
Formation ofFormation of SemicarbazonesSemicarbazonessemicarbazine
+
+ H2O
C O
R
R
NH2 NH C NH2
O
C
R
R
N NH C NH2
O
..
semicarbazide
a semicarbazone
aldehydeor ketone
(usually crystallizes)
DERIVATIVESDERIVATIVESCRYSTALLINE IMINES CAN BE USED AS DERIVATIVES
A derivative is a solid compound (formed from theoriginal compound) whose melting point can helpto identify the original compound.
What you will see in the tables of unknowns:
2-undecanone 231 12 122 634-chloroacetophenone 232 12 204 2364-phenyl-2-butanone 235 - 142 127
bp mpketones
semicarbazone2,4-dinitrophenyl-
hydrazone
BIOLOGICAL REACTIONSBIOLOGICAL REACTIONS
PyridoxylPyridoxyl--55--phosphate (Pphosphate (P--55--P)P)Converts amino acids to -ketoacids, and vice versa.Biologically important in transamination reactions.
NH
OH
CH3
C HO
CH2OPO
OOH NH2 C
H
R
O
OH
..
N CH
R
O
OH
NH
OH
CH3
CH
R
- H2O
first imine
pyridoxyl-5-phosphate
an amino acid+
+
( P-5-P )
formation ofthe imine
continued
N CH
R
O
OH
NH
OH
CH3
CH
R
N CR
O
OH
NH
OH
CH3
CR
H
H
NH2
NH
OH
CH3
CH2R
C COH
RO O
tautomerism
-ketoacid
pyridoxamine
H2O
:EnzEnz-H
H-Enz
Enz:
C COH
RO O
CH COH
RO
NH2
+
+
+
converts
hydrolysis ofthe new imine
first imine
new imine
Removing theamino group
TRANSFERRING THE AMINO GROUPTRANSFERRING THE AMINO GROUP
NH2
NH
OH
CH3
CH2R
C COH
RO O
a different -ketoacid
pyridoxamine
N CR
O
OH
NH
OH
CH3
CR
H
H
tautomerism
hydrolysis of the imine
NH2 CH
R
O
OHa 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
Formation of EnaminesFormation of Enamines
R C C R
H
R
O
R C C R
H
R
OH
NR2
C C
R
R R
NR2
+ R2NHH
+
H+
+ H2O
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 nitrogenhydrogenon the
nitrogen
COMPARISONCOMPARISON
hydrogen on theadjacent carbon
When there is no hydrogen onnitrogen, one is lost from carbon.
carbinolamine intermediates
NH
NH
N
O
H
piperidine
SOME SECONDARY SOME SECONDARY AMINES FREQUENTLY AMINES FREQUENTLY USED TO FORMUSED TO FORMENAMINESENAMINES
pyrrolidine
Water must be removedmorpholine
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 FormationH-O-H
H
+
H-O-HH
+
HO-H
MECHANISM
continued .
Enamine Formation (cont)Enamine Formation (cont)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
O-HH
H3O+
H2O
+
water mustbe removedto force theequilibrium
+
Nucleophilic Character of EnaminesNucleophilic Character of Enamines
2)
C C
R
R R
N
R
R
C C
R
R R
N
R
R: +..
_
nucleophilicat carbon
C
X
SN2
Reactions of Enamines as NucleophilesReactions of Enamines as Nucleophiles
SN2an iminium salt
hydrolysis
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_
R C C R
R
H
O
R C C R
R
R
O
alkylation
ALKYLATION OF A KETONEALKYLATION OF A KETONE
O
NH
N N
CH3
OH2
CH3I
O
CH3NH
..
..
+H+
+
H3O+
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
....O
H 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
H-O-HH
+
HO-H
MECHANISM
continued .
Hydrolysis of Iminium SaltsHydrolysis of Iminium SaltsMECHANISM
3)
R C C R
O
R
R H+ ..
R C C R
O
R
R
+
: :
H3O+
HO-H
SUBSTRATES FOR ENAMINE ALKYLATION SUBSTRATES FOR ENAMINE ALKYLATION (and acylation)
CH CH2CH2X
C CH3CH2XO
C OCH2XO
CH3
X CH2CH3
CCl CH3
O
CCl OO
CH2CH3
acylation
alkylation
CC
R
RR
N
R
R
CC
R
RR
N
R
R
:
+..
_
R XX = Cl, Br, I
enamine
primarysecondaryallylic
C ClRO
C ClROO
acyl compoundsmay be used
CHLORIDES, BROMIDES AND IODIDESCHLORIDES, BROMIDES AND IODIDESIn SN2 reactions you learned the rate sequence R-I > R-Br > R-Cland that iodides are better substrates than chlorides.
This is true.
many students assume that if acid chlorides are good the acid bromides and iodides must be better.
Based on this knowledge ..
C ClRO
C ClROO
However acid bromides and iodides are difficult toprepare, and the iodides are quite unstable
.. you should use the chlorides.
They are easily preparedfrom the acid by:
R-COOH + SOCl2
Enamine Reactions Enamine Reactions ---- SummarySummary
O
O
R
R2NH
H+R X
H2O+H
+N
R R
N
R R
R
secondaryamine
alkyl oracylhalide
TERTIARY AMINESTERTIARY AMINES
DO NOT REACTDO NOT REACT
C
R
R
N R
O H
H
..
R C C RH
R
OH
+
R C C RH
R
OH
loses H from N
loses H from C
:..
unstablereverses
PRIMARY AMINE
SECONDARY AMINE
TERTIARY AMINE
N RH
H
N-RR
:
N-RRR
N RR
H
N RR
R
COMPARISONCOMPARISON
H is lost to form intermediate
H is lost
no H to lose
You need to lose two Hs,one to form the intermediate,one to eliminate water.
The tertiary amine cantform the carbinolamineintermediate becauseit lacks an H on N.
FORMING RINGSFORMING RINGS
SOME GUIDELINES
NH2
NH2O C
H
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
Problem 16-18 inin your textbook.
HINT ON THE MECHANISM ..HINT ON THE MECHANISM ..
C=N can undergo additions just like C=O
Both are polar multiple bondsand both can undergo acid-catalyzed nucleophilic addition.
N
NH2
CH2
H
..
+CRUCIALSTEP
protonationfirst
forms ringpH 5
mildlyacidic
.. see if you can figure out the rest of the mechanismfor Problem 16-18 on your own.
WITTIG REACTIONWITTIG REACTION
YlideYlide
X Y..- +A compound or intermediate
with both a positive and a negative charge on adjacent atoms.
BOND
Betaine or ZwitterionBetaine or Zwitterion
X-Y
+
:
MOLECULEA compound or intermediate with both a positive and a negative charge, not on adjacent atoms, but in differentparts of the molecule.
Preparation of a Phosphorous YlidePreparation of a Phosphorous Ylide( WITTIG REAGENT )
+ (C6H5)3P+
R1 C
R2
X
H
(C6H5)3P C R2
R1
HX
_
(C6H5)3P C
R2
R1
strong base
:
O-CH3-
P PhPh
Ph..
Triphenylphosphine( Ph = C6H5 )
:....
+ ..-
an ylide
benzene
heat
precipitates
ether
Resonance in YlidesResonance in Ylides
(C6H5)3P C
R
R
(C6H5)3P C
R
R+ _ ..
C..
3d 2p
d-p BACKBONDINGRemember that Phosphorousis a Period III element (d orbitals).
Backbonding to phosphorousreduces the formal chargesand stabilizes the negativecharge on carbon.
P
The Wittig ReactionThe Wittig ReactionMECHANISM
..
INSOLUBLE
very thermodynamicallystable molecule
ylide betaine
+ -
synthesis ofan alkene
+
: .. :_ +
C O
R1
R2
(C6H5)3P C
R4
R3R2 C
R1
O
C R4
R3
P(C6H5)3
+C
R1
R2
C
R4
R3O P(C6H5)3
: ..
R2 C
R1
O
C R4
R3
P(C6H5)3
oxaphosphetane(UNSTABLE)
SYNTHESIS OF AN ALKENE SYNTHESIS OF AN ALKENE -- WITTIG REACTIONWITTIG REACTION
H
CH3
CH3
CH2CH3 CH3
CH3
OH
CH2CH3Br
H
H
CH2CH3(C6H5)3P
H
:P(C6H5)3
+
H
CH2CH3(C6H5)3P:
+
CH3ONa-ylide
CH3
CH3
O
ANOTHER WITTIG ALKENE SYNTHESISANOTHER WITTIG ALKENE SYNTHESIS
CH
Br
HO
CH2Br
:P(C6H5)3
C P(C6H5)3
H
H
Br-+
PhLi
..C P(C6H5)3
H
- +ylide
: ..
+
+-triphenylphosphineoxide (insoluble)
P(C6H5)3O
O
..
CH
MuscalureMuscalure
CH2(CH2)11CH3CH3(CH2)6CH2
HH
Sex pheromone of thecommon house fly.Musca Domestica
(Z)-9-tricosene
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.
CH3(CH2)6 CO
HCl CH2(CH2)12CH3
ALDEHYDES AND KETONES II.ALDEHYDES AND KETONES II.
Oxidation and Reduction;and Synthesis
CATALYTIC REDUCTIONCATALYTIC REDUCTION
OXIDATION AND REDUCTIONOXIDATION AND REDUCTIONREDUCTION OF ALDEHYDES AND KETONES
C OHH
C O + 2H+ + 2e-
OXIDATION OF ALCOHOLS
C OHH
C O- 2H+ - 2e-
These two reactions are the inverse of each other!
MANTRAMANTRAREDUCTION OF ALDEHYDES AND KETONES
Aldehydes react with one mole of reducing agent to give a Primary Alcohol
Ketones react with one mole of reducingagent to give a Secondary Alcohol
C OR
HC O
R
R
CH OHR
HCH OH
R
R
CATALYTIC REDUCTIONCATALYTIC REDUCTION
C OH
CH2C O
H
CH2
H H
H2, 40 o C
Ni, 2 atm
.HH
H H.
. . synaddition
Often heat and pressureare required.
A specially preparedcatalyst called
Raney Nickelis often used for C=O.
Reduction of a C=O groupis more difficult than thereduction of a C=C double bond.
. and reduction of abenzene ring is moredifficult yet.
SELECTIVE HYDROGENATIONSSELECTIVE HYDROGENATIONS
O
H2
O
Pd/C
easy20O C
1 atm
+
HOH
Ni 40O C2 atm
moredifficult
O
HOH
PtO2100o C
5 atm
mostdifficult
HOH
?
HydrideHydridereagentsreagents
Conditions will varywith the specificcompound.
CATALYTIC HYDROGENATION AT 1 ATMCATALYTIC HYDROGENATION AT 1 ATM
H2
suspendedcatalyst
Hydrogen gas is just bubbled throughthe solution
magneticstir bar
solvent +compound
ROCKING BOTTLE HYDROGENATIONROCKING BOTTLE HYDROGENATION
perforated screensurrounds the bottle
NOT SHOWN
Good for pressuresup to about 2 atm. H2
HYDROGENATION BOMBHYDROGENATION BOMB
H2
heater
head bolts
pressuregauge
threaded
stirrer
Good to pressuresof 5-10 atm.
inlet
heavy steelshield
thick steelwalls
HYDRIDE REDUCING REAGENTSHYDRIDE REDUCING REAGENTS
Another Method of ReductionAnother Method of ReductionHYDRIDE REAGENTS
:_
R C RO
H
:
R C RO
HR C R
OH
H
: :.. _..
H3O+
simplified mechanism
Al HHH
HLi
lithium aluminum hydride
B HHH
HNa+ +- -
sodium borohydride
THERE IS A DIFFERENCE IN REACTIVITYTHERE IS A DIFFERENCE IN REACTIVITY
B
HAl
H
2sp3 - 1smore overlap
period 2element
NaBH4shorter, stronger bond
LESS REACTIVE
3sp3 - 1smore diffuse
less overlapperiod 3element
LiAlH4longer, weaker bond
MORE REACTIVE
COVALENT / IONIC CHARACTERCOVALENT / IONIC CHARACTER
+ - The B-H bond has more covalent character.
LESS REACTIVEB H
The Al-H bond hasmore ionic character and is a stronger base.
MORE REACTIVE
:HAl+ -
SODIUM BOROHYDRIDE SODIUM BOROHYDRIDE REDUCTIONSREDUCTIONS
SODIUM BOROHYDRIDE IS SELECTIVE
NaBH4 only reduces aldehydes and ketones
C OR
HC O
R
R
CH OHR
HCH OH
R
R
or R-CH2-OH
primary alcohol
secondaryalcohol
aldehyde
ketone
O
CO OMe
CO OMe
OHH
1
2 H3O+
NaBH4The double bondand the ester arenot touched.
SELECTIVE HYDROGENATIONSSELECTIVE HYDROGENATIONS
HOH
HOH
O
O Pd/C
Ni 40O C2 atm
PtO2100o C
5 atm
H2
20O C1 atm
HOH
1) NaBH42) H3O+
A, B, and Cprogressive
A
B
C
O
?
+
Protectivegroup!
SodiumSodium BorohydrideBorohydride Reduction ofReduction ofAldehydesAldehydes andand KetonesKetones
OC
R R R C RO
H
BH3
R C R
O
H
HNaBH4 H3O+
Na
H BH3-
workupstep
alcohol
aldehydeand ketones
+ -
ADDITION IS ADDITION IS CONCERTEDCONCERTEDAND AND SYNSYN STEREOSPECIFICSTEREOSPECIFIC
C O
H BH3
C O
H BH3-
..:
..:
reacts threemore times
SodiumSodium BorohydrideBorohydride Reduction Reduction ofof NorcamphorNorcamphor
O OH
H
H
OH+
bicyclo[2.2.1]heptan-2-one(norcamphor)
endo alcohol(86%)
exo alcohol(14%)
1
2 H3O+
NaBH4
exo attack
SodiumSodium BorohydrideBorohydrideReduction of CamphorReduction of Camphor
CH3CH3
CH3 O
CH3CH3
CH3 OH
H
CH3CH3
CH3 H
OH+
endo attack
hindered
(endo)
(exo)
camphor
borneol(15%)
isoborneol(85%)
1
2 H3O+
NaBH4
LITHIUM ALUMINUM HYDRIDELITHIUM ALUMINUM HYDRIDEREDUCTIONSREDUCTIONS
LiAlHLiAlH44 (LAH) IS NOT SELECTIVE(LAH) IS NOT SELECTIVELiAlH4 reduces anything with a polar multiple bond!
C Y:+
C=Y:+
or..
As with NaBH4 these compounds give alcohols:
C OR
HCH OH
R
Haldehyde
C OR
RCH OH
R
Rketone
LiAlHLiAlH44 IS NOT SELECTIVE (cont)IS NOT SELECTIVE (cont)These acid derivatives also give alcohols
C OR
ROCH OH
R
HROH+ester
C OR
ClCH OH
R
Hacid chloride
C OR
OHCH OH
R
H
carboxylicacid
LiAlHLiAlH44 IS NOT SELECTIVE (cont)IS NOT SELECTIVE (cont)These compounds give amines:
C OR
NH2
CH2 NH2Ramide
R C N R CH2 NH2nitrile
N ORO
R NH2+
-
nitrocompound
SIMPLE ALKENES DO NOT REACTSIMPLE ALKENES DO NOT REACT
C C C Coralkenes alkynes
they arenot polar !
.. unless they are conjugated with a polar group.
.. which polarizes them.
Lithium Aluminum HydrideLithium Aluminum HydrideReduction ofReduction of AldehydesAldehydes andand KetonesKetones
LiAlH4 + 4OC
R RH C O
R
R 4
Al Li+
H C OR
R 4
Al Li+ + 4 H2O 4 + Al(OH)3
+ LiOH
R C R
O
H
H
ether
LiAlH4 + 4 H2O
LiOH + Al(OH)3 + 4 H2 + heat
LiAlH4 Reacts Explosively With H2O, Causing Fire
REACTION OF HYDRIDES WITH WATERREACTION OF HYDRIDES WITH WATER
Ether solvents are used: diethyl ether, THF, etc.
NaBH4 Reacts With H2O (or methanol) Very Slowly
NaBH4 + 4 H2O
NaOH + B(OH)3 + H2 no fire
Water and alcohols can be used as solvents.
DISSOLVING METAL REDUCTIONSDISSOLVING METAL REDUCTIONS
THERMODYNAMIC CONTROLTHERMODYNAMIC CONTROL
H
O
H
HOHNa
EtOH
locked ineq position
H
OHH
major
minor
eq
ax
eq
CO
CO
OH Et
CO H
CO H
OH EtNa
Na
: : : ::.. ..
..
.
. ..
.. ..-
-
stereocenters can invertsodium donates electrons and the alcohol donates protons
radical anion
radicalanion
+e- +e-+H+ +H+ OH
C
H
.
More Thermodynamic ControlMore Thermodynamic ControlDissolving Metal
CH3CH3
CH3 O
CH3CH3
CH3 H
OH
Na
EtOH
exo
majorproduct
compare NaBH4 results on slides 18 and 19
O H
OHNa
EtOHexo
majorproduct
EPIMERIZATIONEPIMERIZATIONA stereoisomer that has changed configuration at only one stereocenter (a type of diastereomer) is called an EPIMER
H
OH
OH
HNaOtBu
tBuOH
epimer
OH
OH: ..-
-HO-tBu
strongbase
endo
exo
A Bof A
Epimerization generally gives the lowest energy stereocenter, the one that is most thermodynamically stable.
exoendo
ENERGY
epimerization
REDUCTION
COMPARISON OF METHODSCOMPARISON OF METHODS
REDUCTIONREDUCTIONCATALYTIC REDUCTION
THREE DISTINCT METHODSAll methods add two electrons 2e-
(gain of electrons = reduction)and two protons 2H+.
H H. .
C O
= 2e- and 2H+ are added as two H .two radicals
HYDRIDE REDUCTION
C O
H:-
H+
= 2e- and 2H+ are added as H:- and H+hydride
proton
DISSOLVING METAL REDUCTION
= 2e- and 2H+ are addedsequentially as e- , H+ , e- , H+
C O
M .C O
M+
..
.. :. -
H-S
etc.
solvent givesproton
metal giveselectron
COMPLETE REMOVAL OFCOMPLETE REMOVAL OFTHE CARBONYL GROUPTHE CARBONYL GROUP
REMOVAL OF C=OREMOVAL OF C=OO H H
THREE METHODS
1) Clemmensen Reduction Zn(Hg) + conc. HCl
strong acid conditions
2) Wolff-Kishner Reduction NH2NH2 + KOH
strong base conditions
3) Desulfurization Thioacetal + H2 + Ni
somewhat milder, but also reduces C=C
Clemmensen ReductionClemmensen ReductionRemoves the C=O Group
Zn(Hg)
HCl (conc.)R C
O
RR C
H
RH
ZnCl2Hg+
H2O
R CCl
RCl
Exact mechanism is not known.
Obviously Zn gives up electrons to Cl (reduction).
possibly via :
WolffWolff--Kishner ReductionKishner ReductionRemoves the C=O Group
R CO
R+
KOH190 - 200 C
NH2 NH2 CH2 CH2OH OH + N2
+ H2O
R C HH
R
goes via the hydrazone
high-bpsolvent
C NR
RNH2
C NR
RNH2R C
O
R+ NH2 NH2
C NR
RNH..
C NR
RNH
H
C NR
RN
H
..
....
..: CR
R HN N C
R
R H
H: :
..
....
.... ..
..:
H OHH O
H
:
O H
O H
:
:
..
..
..
..
MECHANISM OF THE WOLFFMECHANISM OF THE WOLFF--KISHNER REACTIONKISHNER REACTION
hydrazone
-
-
-
-
-
NaOH
gas
ketone
alkane
C=Oremoved
high bp solvent
(you are not required to memorize this mechanism)
+BF3
diethyl ether +H2O
OC
R RSH CH2 CH2 SH C
R RS S
H2 Raney Ni
CR RH H
++ 2 NiS
CH3 CH3
DesulfurizationDesulfurizationRemoves the C=O Group
+ H2S
Exact mechanism is not known.
HH
H H.
. . .C S C S
H H
Hydrogenation is knownto break C-S bonds ( hydrogenolysis ).
HOW WOULD YOU DO THESE ?HOW WOULD YOU DO THESE ?
Cl
O
Cl
Wolf-Kishner (base)
Clemmensen (acid)
Desulfurization
O
CH2OH CH2OH
Wolf-Kishner (base)
Clemmensen (acid)
Desulfurization
SYNTHESIS OFSYNTHESIS OFACID CHLORIDESACID CHLORIDES
ACID CHLORIDE SYNTHESISACID CHLORIDE SYNTHESISTHIONYL CHLORIDE
RECALL THIONYL CHLORIDE:
Chapter 12, Section 12.4, pp. 12-24 to 12-27.
R-OH + SOCl2 R-Cl + SO2 + HClbenzene
alcohol alkyl chloride
The -OH group of an acid reacts the same way.
R CO
OHR C
O
Cl+ SOCl2 + SO2 + HCl
benzene
RLi + CO2 Recall how tomake an acid?
acid acidchloride
REDUCTIONS OF REDUCTIONS OF ACID CHLORIDESACID CHLORIDES
LiAlHLiAlH4 4 with Acid Chlorideswith Acid Chlorides
two hydrides reactACID CHLORIDES REACT TWICE
Acid Chloride
R CX
OR C
O
HHH
LiAlH4 + LiCl + AlCl3
cleaves
CRO
HCl
AlH3..: :
-
bond is highly polar- not strong
The tetrahedral intermediatecollapses easily, because thebond to Al is not strong.
COLLAPSE OF THE INTERMEDIATECOLLAPSE OF THE INTERMEDIATE
R CO
Cl
AlH3H
R CO
H
reacts again
Cl- is lost
FIRSTADDITION
SECONDADDITION
CRO
ClCRO
ClH
CRO
HCRO
HH
CROH
HH
H3O+
LiAlH4
LiAlH4
AlH3
AlH3
Li
Li
..: :
workupreaction doesnt stop here
aldehyde
TWO HYDRIDES REACT
-
..
+
+
tetrahedralintermediatecollapses
LiAlHLiAlH4 4 Reduction of an Acid ChlorideReduction of an Acid Chloride
+ Li+ Cl- leavinggroup
-
REDUCTIONS OF ESTERS REDUCTIONS OF ESTERS
.. ESTERS ALSO REACT TWICE
LiAlHLiAlH4 4 with Esterswith Esters
two hydrides reactESTERS REACT TWICE
R CO
O
R'R C
O
HHH
R' O H
EsterLiAlH4
+
two alcoholscleaves
LiAlHLiAlH4 4 Reduction of an EsterReduction of an Ester
TWO HYDRIDES REACT
+
+-
-
..
..
: :
+ RO-: :
workupreaction doesnt stop here
R-OH
twoalcohols
aldehyde
leavinggroup
workup
+
CRO
OR'CRO
OR'H
CRO
HCRO
HH
CROH
HH
H3O+
LiAlH4
LiAlH4
AlH3
AlH3
Li
Li
tetrahedralintermediatecollapses
ROSENMUND REDUCTIONROSENMUND REDUCTION
Converts Acid Chlorides to Aldehydes
This reaction allows you to stop the reduction atthe aldehyde stage and not continue to the alcohol(which would be the result with LiAlH4).
Acid Chloride Aldehyde
Alcohol
X
one stage ofreduction
stops here
second stepdoes not occur
This is an older method. Yields are not alwaysadequate, but it is sometimes a useful method.
RosenmundRosenmund ReductionReduction
R C ClO
R C HO
+ H2Pd/BaSO4
sulfurquinoline
Rosenmund catalyst
Ordinary catalystswould continue andreduce the aldehyde.
R C OHO
SOCl2
.HH
H H.
. .R C Cl
OR C
O
HClH
DIBALDIBAL--HH
A Newer Method ...
DIISOBUTYL ALUMINUM HYDRIDEDIISOBUTYL ALUMINUM HYDRIDE( DIBAL( DIBAL--H )H )
SYNTHESIS
LiAlH4 + 2 CH CH2
CH3
CH3
OH Al OiBuH
OiBuH + 2 H2
( iBuOH )isobutyl alcohol DIBAL-H
less active than LiAlH4
two moles
Remember:
H:- + H-O-R H-H + :O-R....
-
strongbase
takes the placeof hydride
gas
Reduction of Esters to AldehydesReduction of Esters to AldehydesDIBALH is soluble in hydrocarbon solvents because of the isobutyl groups;ethers must be used for LAH.
R CO
O
R'R C
H
O
+
H2O
HCl
R' OH
DIBAL-HAt 20o C,LiAlH4 willreduce thealdehyde, DIBAL-Hstops at thealdehyde atthe lowertemperature.
esters- 70o Ctoluene
RCOOHsome carboxylicacids may be reduced
NOTESometimes LiAlH4 will also stop at the aldehyde if the temperature is below -60o C. DIBAL-H is more consistent.
R C ClO
R C HO
+ H2Pd/BaSO4
sulfurquinoline
DIBALDIBAL--H ALSO REDUCES H ALSO REDUCES ACID CHLORIDES TO ALDEHYDESACID CHLORIDES TO ALDEHYDES
DIBAL-H
This method gives better yields than theRosenmund reduction.
Apparently the tetrahedralintermediate does not collapse at -70o C (expel the leaving group). This doesnt happenuntil you warm the solution and add aqueous acid whichdestroys the DIBAL-H.
CRO
ClH
AlH
Li+ -
does notreact again
-70o ether
stable at -70o
HYDROLYSIS OF THE INTERMEDIATEHYDROLYSIS OF THE INTERMEDIATE
CRO
ClH
AlH
Li+
- H3O+
CRO
ClH
H
CRO
H
:..
Aqueous acid breaks thecomplex apart.
+ LiCl
DIBALH ALSO REDUCES ALDEHYDES AND KETONES
The main feature of DIBALH is that it reacts only ONCE to form a stable tetrahedral complex. Since the complex doesnt fall apart until workup, a second reduction is avoided.
Aldehydes and ketones only need one hydride to be fully reduced ...
therefore, DIBAL-H reduces aldehydes and ketones.
With esters, acid chlorides and acids, more than onehydride is required. Since DIBAL-H reacts only once,they are not fully reduced, stopping at the aldehyde.
ORGANOMETALLIC COMPOUNDSORGANOMETALLIC COMPOUNDSWITH ESTERS AND ACID CHLORIDESWITH ESTERS AND ACID CHLORIDES
RLi RLi with Esters and Acid Chlorideswith Esters and Acid Chlorides( also RMgX )
REACT TWICEtwo RLi react
Acid Chloride
R CCl
OR C
O
R'R'H
R CO
O
R"R C
O
R'R'H
R" O H
RLiether
RLiether
+
Ester
two alcoholscleaves
RMgX with Esters and Acid Chlorides RMgX with Esters and Acid Chlorides
CRO
OR'CRO
OR'R"
R"MgX
CRO
R"CRO
R"R"
R"MgX
MgX
MgX
CROH
R"R"
H3O+
Reacts Twice !
ketone
: :
: :
..
..
doesnt stop here
+ RO-RO-
R-OH
( also R-Li )
Tetrahedralcomplex notstable -weak O-Mgbond.
DECOMPOSES
COLLAPSE OF THE INTERMEDIATECOLLAPSE OF THE INTERMEDIATE
CRO
ORR'
Li+
..: :
-
bond is highly polar- not strong
The tetrahedral intermediatecollapses easily, because thebond to Li+ is not strong.
The leaving group RO- isexpelled.
DECOMPOSES & REACTS AGAIN
The complexes formed fromGrignard reagents react inthe same way. The bond toMg is not strong.
breaks down andyields a ketone whichreacts again
ORGANOCADMIUMREAGENTS
Ketone Synthesis Ketone Synthesis Organocadmium ReagentsOrganocadmium Reagents
2 + CdCl2 + 2 MgXCl
2
R MgX R Cd R
R C ClO
R C RO
+ R Cd R 2 + CdCl2
organocadmiumcompound R2Cd
Less active thanRLi or RMgX reacts once
ORGANOCADMIUM REAGENTSORGANOCADMIUM REAGENTSDO NOT REACT TWICE WITH ESTERSDO NOT REACT TWICE WITH ESTERS
C O
O
CH3 C OO
CH3
CH3
CH3 Cd CH3
C CH3
O
:..reacts
once
:O-CH3..-
STOPS HERE
ketone
H3O+
Cd-R
workup
HO-CH3+
Acid chlorides also react this way.
STABLE TETRAHEDRAL COMPLEXSTABLE TETRAHEDRAL COMPLEX
Apparently the tetrahedralintermediate does not collapse (expel the leaving group) during the reaction. It onlybreaks down on hydrolysis, and then the leaving group is expelled.
Cd OR
CRO
ORR'
-
The bond has more covalentcharacter than a bond to Lior Mg - it is stronger.
The complex is stable and does not break downand react again.
HYDROLYSIS OF THE INTERMEDIATEHYDROLYSIS OF THE INTERMEDIATE
Aqueous acid breaks thecomplex apart.
CRO
ORR
H:..
CRO
ORR
Cd R H3O+
CRO
R + LiCl
Ketone is isolated.
LITHIUM DIALKYL CUPRATES
Ketone Synthesis Ketone Synthesis Lithium DialkylcupratesLithium Dialkylcuprates
R C ClO
R C RO
+ R2CuLi +
+ LiCl
0ether
R Cu
Less active thanRLi or RMgX
ketone
SUMMARYSUMMARY
MANTRAMANTRA Aldehydes react with one mole of reducing
agent to give a Primary Alcohol
Ketones react with one mole of reducingagent to give a Secondary Alcohol
Acid Chlorides react with two moles of reducingagent to give a Primary Alcohol
Esters react with two moles of reducingagent to give a Primary Alcohol
+ a second alcohol
BIOLOGICALBIOLOGICALREDUCING REAGENTSREDUCING REAGENTS
Nicotinamide Adenine DinucleotideNicotinamide Adenine DinucleotideNADHNADH
N N
N N
NH2
O
HOH
H
OH
HH
CH2 O P O
O
O
P O
O
O
CH2 O
HOH
H
OH
HH
N
HHC NH2
O
_ _
adenine
ribose ribose
nicotinamide
diphosphate
..
..
....
..
:
:
COENZYMEbiological
works withan enzyme
Reduction of Acetaldehyde Reduction of Acetaldehyde in Fermentationin Fermentation
RED OX
N
C NH2
OH H
R
N
C NH2
O
R
H
H+CH3 C HO
CH3 C HOH
H
+
NADH NAD+
..This coenzymecan also oxidizedepending on theassociated enzyme.
REVERSIBLE
hydridetransfer
ethanolacetaldehyde
N
C NH2
OH H
R
N
C NH2
O
R
H
H+CH3 CO
C OHO
+
NADH NAD+
C OHO
CH3 COH
H
Reduction of Pyruvic Acid Reduction of Pyruvic Acid in Muscle Tissuein Muscle Tissue
..
lactic acid
formed whenmuscles contract
pyruvic acid
OXIDATIONS OF ALCOHOLSOXIDATIONS OF ALCOHOLS
OXIDATION OF AN ALCOHOLOXIDATION OF AN ALCOHOL( LOSS OF 2H+ and 2e- )
carbon
C OH H
C OOXIDATION
REDUCTION
- 2H
+ 2H
hydrogen LOSS OF TWOHYDROGENS
one an -H
OxidationsOxidations
no reaction
have -hydrogens.The alcohol must
OC
R H
OC
R H
OC
R R'
OC
R OHR C OH
H
H
R C OHR'
H
R C OHR'
R''
Remember: A dehydrogenation (loss of hydrogen)is also a form of oxidation!
MANTRAMANTRA Primary alcohols oxidize to give
Carboxylic acids (via aldehyde)*
Seconday alcohols oxidize to giveKetones
Tertiary alcohols do not oxidizeno oxidation
Aldehydes oxidize easily to giveCarboxylic acids
* With special reagents, the oxidation of a primary alcoholcan be stopped at the aldehyde.
PRIMARY ALCOHOLS
Oxidation of Primary Alcohols Oxidation of Primary Alcohols with KMnOwith KMnO44
two -hydrogens
+ MnO2precipitate
KMnO4R CH2 OH C HO
R
KMnO4
R C OHO
heat
heat
REQUIRESHEAT
C=C Double bonds are also oxidized by this reagent.
Oxidation of Primary Alcohols Oxidation of Primary Alcohols with Kwith K22CrCr22OO77
K2Cr2O7H2SO4
R CH2 OH R C HO
R C OHO
K2Cr2O7H2SO4
+ Cr3+
CHROMIC ACIDTEST
SECONDARY ALCOHOLS
Oxidation of Secondary AlcoholsOxidation of Secondary AlcoholsCHROMIC ACID
TEST
R C ROH
HR C R
OK2Cr2O7H2SO4
+ Cr3+
Jones OxidationJones Oxidation
JONES REAGENTJONES REAGENT
CHROMIC ACIDCHROMIC ACIDEQUILIBRIA
H O OO
OCr H
CrO3 + H2O H2CrO4H2SO4 H2SO4
H2Cr2O7 H2O+x2
H O OO
OCr HCr
O
OO
Chromic acid Dichromic acid
CrO3H2SO4
H2CrO4 NaCr2O7H2SO4H2SO4
ALL OF THESE ARE CHROMIC ACID SPECIES
oxidizingagents
C OH
HR O
O
OCr H
CrO
OOHO
H
H
C OH
HR
H
Alcohols react with chromic acid to formchromate esters.
Primary alcoholhas two -H
MECHANISMMECHANISM
Chromate ester
H2SO4H2O
CrO
OOHHO
..+ :
:....
..
..
MECHANISMMECHANISM ( continued )
OHH
H
OO
OCr H
C OH
R
OHH
C OH
HR O
O
OCr H
Oxidationcontinues
: :..
..
......
+
..
....
:
aldehyde:
Loss of twoelectrons
Loss of -hydrogen
FIRST OXIDATION
The two lostelectrons end up here.
(next slide)
MECHANISMMECHANISM ( continued )
C OH
OR
HH
C OH
RH+
H2O
hydrate
Requireswater and acid
(an alcohol !)
Oxidation continues becausethe aldehyde forms a hydrate.
The hydrate is an alcohol (diol)that has an -hydrogen.
Oxidationcontinues
MECHANISMMECHANISM ( continued )
hydrate
Carboxylicacid
Chromateester
..:
::..
..
..
......
..
....:
:
+
+
:.. Loss of -hydrogen,loss of 2 electrons.
SECOND OXIDATION
O HH
OHH
H
OO
OCr H
C OOH
R
C OH
OHR O
O
OCr H
CrO
OOHO
H
H
C OH
OR
HH
HOW CAN WE
STOP OXIDATION OF THE ALDEHYDE ?STOP OXIDATION OF THE ALDEHYDE ?
Oxidation of the aldehyde requires the hydrate to form.
Formation of the hydrate requires acid and water.
H2O
H+
C OH
R C OH
OR
HH
What if we do the reaction in basic medium with no water ?
SARRETT AND PCC REAGENTSSARRETT AND PCC REAGENTS
Oxidation with Oxidation with Chromic Oxide and PyridineChromic Oxide and Pyridine
R C ROH
HR C R
OCrO3
N
.
CH2Cl2aldehydes do notoxidize further
SarettSarett OxidationOxidation
Oxidation withOxidation withPyridinium ChlorochromatePyridinium Chlorochromate
R C ROH
H
R C RO
CrO3ClN
CH2Cl2
.
aldehydes do notoxidize further
except in DMFwhich enhancesreactivity
PCC OxidationPCC Oxidation
MEERWEINMEERWEIN--PONNDORFPONNDORF--VERLEYVERLEYREDUCTIONREDUCTION
MEERWEINMEERWEIN--PONNDORFPONNDORF--VERLEY REDUCTIONVERLEY REDUCTION
aluminumisopropoxide
CO
R RR C R
OH
HCH3 C CH3
OH
HCO
CH3 CH3
Al(OiPr)3+ +
isopropyl alcohol acetone
Use an excess of isopropyl alcohol to reduce a ketone.
Use an excess of acetone to oxidize an alcohol.
EQUILIBRIUM
O
H CH3
CH3
AlO O
OC
R R
HYDRIDEHYDRIDEDONORDONOR
The alcohol complexes with thealuminum isopropoxide and acts as a hydride donor to the ketone.
TOLLENS TESTTOLLENS TEST
TheThe TollensTollens TestTest
2 Ag(NH3)2OH
RC
O
OCO
R H NH4+ 2 Ag
+ H2O + NH3
+
aldehyde
metallicsilver
Ketones do not react. silver mirrorsilver mirror
Remember that aldehydesare easily oxidized.
CARBOHYDRATESCARBOHYDRATESAND THE TOLLENS TEST
aldehyde
COHHHOHOHHOHH
CH2 OH
OH The open chain formis an aldehyde andgives a Tollens test.
H
OHOHO
OHOH
CH2
OH
-D-(+)-glucopyranose
REDUCING SUGAR
Pyranose and open-chainforms are in equilibrium in solution.
D-(+)-glucose
ketone
CARBOHYDRATESCARBOHYDRATESAND THE TOLLENS TEST
aldehydeTAUTOMERIZATION
CCH OH
HOHOHHOHH
CH2 OH
OH
C OCH2
CH2
OH
HOHOHHOHHOH
D-(-)-fructose
C OHCH
CH2
OH
HOHOHHOHHOH
*
* both diastereomersREDUCING SUGAR
enediol
-D-(-)-fructofuranose
Ketoses also give the test because they tautomerize! in solution.
CARBOHYDRATESCARBOHYDRATESAND THE TOLLENS TEST
H
OHOHO
OHOH
CH2
OH
H
OHO
OHOH
CH2
OH
OMe
COHHHOHOHHOHH
CH2 OH
OH
X
hemiacetals open in solution= REDUCING SUGAR
acetals do not open in solution unless hydrolyzed in acid= NONREDUCING SUGAR
aldehyde
ketosestautomerizeto reducingsugars
CARBOHYDRATESCARBOHYDRATESAND THE TOLLENS TEST
Any polysaccharide which has a hemiacetal ring willgive a positive Tollens test = reducing sugar.
O
CH2OH
HH
OHH
OH
OH
H
HO
CH2OH
OH
H
H
OH
CH2OH
H
O
a b(+)-Sucrosenon-reducing
Neither sugar is in ahemiacetal link.
O
CH2OH
H
OH
H OH
H
OH
H O
CH2OH
H
OH
H OH
HH
OHO
bc a
Maltosereducing sugar
Hemiacetal link at a.
SYNTHESIS PROBLEMSSYNTHESIS PROBLEMS
A Simple Synthesis ProblemA Simple Synthesis Problem
C CH2
O
Make from benzyl alcohol
complete synthesis on board
A Synthesis ProblemA Synthesis Problem
CH3 C OHO
CH3 C CH3
O?
complete synthesis on board
Another Synthesis ProblemAnother Synthesis Problem
C CH2C HO ?
complete synthesis on board
Yet Another ConversionYet Another Conversion
+
CH OHCH3
CH3
CH3 CH2 CH2 OH
C CHCH3
CH3
CH2 CH3?
complete synthesis on board
O
OH
O
OH C CH
Norethisterone
O
CH3O
progesterone
PHARMACEUTICALSPHARMACEUTICALS
the pill
better absorbed throughthe stomach and intestinesthan progesterone
must beinjected
Mexican YamsMexican Yams
STEROIDSTEROID
A BC D
O
OH
O
OH C CH
OH
O
O
O
O
O
O
O
O
C CH
CrO3pyridine
NaNH3(liq)
H3O+
H+
C CH
HOCH2CH2OH
(-H2O)
norethisterone
Mexican YamsMexican Yams
Na
acetalprotecting group
Common, or Trivial, NamesSummary of Reactions of Organometallics with Carbonyl CompoundsSodium Borohydride Reduction of NorcamphorSodium Borohydride Reduction of Camphor
Recommended