carbonyl chemistry iv - university of texas at...
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![Page 1: Carbonyl Chemistry IV - University of Texas at Austinwillson.cm.utexas.edu/Teaching/Ch391/Files/CH391lecture10.pdf · Oxidation and Reduction. z. ... H OCO-4 -2 0 +2 +4 Wolf-Kishner](https://reader033.vdocuments.site/reader033/viewer/2022060916/60a91c2d2ffa9251ed44d064/html5/thumbnails/1.jpg)
Carbonyl Chemistry IVCarbonyl Chemistry IV
++CCOO--
CCOO
Lecture 10Lecture 10Chemistry 391 10/30/02
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Chemistry 391 10/30/02
Addition of Nitrogen Addition of Nitrogen NucleophilesNucleophiles
Primary Amines RNH2– Imines
Secondary Amines R2NH– Enamines
Hydrazine derivatives RNHNH2– Hydrazones
Hydroxyl Amine NH2OH– Oximes
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Chemistry 391 10/30/02
Imine Imine FormationFormationStep 2: protonation of the -OH followed by loss of H2O
and proton transfer to solvent
An imine
+••
•• ••
••
C N-R
N-R
H
C
O
H 2 O
••
••N-R
H
C
O
H
HH+
O HH
H
+
OH
H
••
+ H 3 O +
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Chemistry 391 10/30/02
IminesIminesOne value of imines is that the carbon-nitrogen double bond can be reduced to a carbon-nitrogen single bond
+
Dicyclohexylamine
Cyclohexanone
(An imine)
Cyclohexylamine
O H2 N
N N
H
-H 2 O
H2 /Ni
H+
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Chemistry 391 10/30/02
Enamine Enamine FormationFormationSecondary amines react with the C=O group ofaldehydes and ketones to form enamines
An enamine Piperidine (a secondary amine)
++ H-NO N H2 OH+
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Chemistry 391 10/30/02
Mechanism of Mechanism of enamine enamine formationformationO H
H
HO
OHH2O
OH
HNN
H
OH
OH2
NOH
H3O+
O HH
H
OH2
N
HN
Enamine
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Chemistry 391 10/30/02
ExampleExample
CCH3
O
+ H2NNH
phenylhydrazine
CCH3
NNH
+ H2O
a phenylhydrazone
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Chemistry 391 10/30/02
ExampleExample
CH3(CH2)9CCH3
O
H2NNHCNH2
O
+
semicarbazide
CH3(CH2)9CCH3
NNHCNH2
O
+ H2O
a semicarbazone
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Chemistry 391 10/30/02
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Chemistry 391 10/30/02
Oxidation and ReductionOxidation and ReductionAldehydes are oxidized to carboxylic acids by a variety of oxidizing agents and it is possible to do some selective reduction reactions
C OH
O
HH C
O
HCH4 O C OCH3OH
--44 --22 00 +2+2 +4+4
Oxidation
Reduction
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Chemistry 391 10/30/02
Oxidation and ReductionOxidation and Reduction• Some selective reduction reactions
CH4 CH3OH H C H
O
C OH
O
H O C O
--44 --22 00 +2+2 +4+4Wolf-KishnerClemmensen
NaBH4
LiAlH4
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Chemistry 391 10/30/02
Metal Hydride ReductionMetal Hydride ReductionThe most selective reagents for the reduction ofaldehydes and ketones are NaBH4 and LiAlH4– both are sources of hydride ion, H:-, a very powerful
nucleophile
BBBBBBBBBBHydride ionLithium aluminum
hydride (LAH) Sodium borohydride
••
H
H H
HH-B-H H-Al-HLi+Na + H
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Chemistry 391 10/30/02
NaBHNaBH4 4 ReductionReduction
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
BH
HH
HRCR
ORCR
H O-H OH
RCR
H OH + OH-
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Chemistry 391 10/30/02
NaBHNaBH44 ReductionReduction
Reductions with NaBH4 are most commonly carried out in aqueous methanol, in pure methanol, or in ethanol
RCHO
+ NaBH4 RCH2OH CH3OH
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Chemistry 391 10/30/02
LiAlHLiAlH4 4 ReductionReductionUnlike NaBH4, LiAlH4 reacts violently with water, methanol, and other protic solvents. Reductions using it are carried out in ethers such as tetrahydrofuran (THF)
+ LiAlH4 1)THFRCH2CCH3
O
RCH2CCH3
OH
H2) H2O
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Chemistry 391 10/30/02
Catalytic ReductionCatalytic ReductionCatalytic reductions are generally carried out from 25° to 100°C and from 1 to 5 atm H2
Carbon-carbon double bonds can be selectively reduced using Rhodium catalysts (sort of)
H2/RhO
NaBH4
MeOH
OH
OO
O
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Chemistry 391 10/30/02
Hydrogenolysis Hydrogenolysis of of benzylic benzylic carbonylscarbonyls
• Palladium catalysis of hydrogenation reduces only benzylic C-O bonds to methylene groups.
• Benzyl ethers, aldehydes and alcohols are also reduced to the corresponding methylene group
O
H2 , Pd/C
O OH H2 , Pd/C
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Chemistry 391 10/30/02
ClemmensenClemmensen ReductionReductionRefluxing an aldehyde or ketone with amalgamated zinc in concentrated HCl converts the carbonyl group to a methylene groupLimitations…??
OHC(CH 2 ) 5 CH3
O
CH2 (CH 2 ) 5 CH3OH
Zn(Hg), HCl
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Chemistry 391 10/30/02
WolffWolff--KishnerKishner ReductionReduction
If aldehydes or ketones are refluxed with hydrazine and KOH in a high-boiling solvent, the reaction converts carbonyls into methylenes….
O KOH, H2NNH2, ∆Diethyleneglycol
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Chemistry 391 10/30/02
Oxidation and ReductionOxidation and Reduction
• Another way to look at selective reduction reactions
CH4 CH3OH H C H
O
C OH
O
H O C O
NaBHNaBH4
LiAlH4
4
Wolf KishnerClemmenson
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Chemistry 391 10/30/02
Oxidation and ReductionOxidation and Reduction•• “special” “special” selectiveselective reduction reactionsreduction reactions
• There is no “rhyme or reason” to this selectivity but it is very valuable
O
OH2
Pd/C OH
H H
O
H2
Rh/C O
O
NaBH4
H3O+ (Dil) OH
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Chemistry 391 10/30/02
Oxidation and ReductionOxidation and Reduction• Some selective oxidation reactions in review
CH4 CH3OH H C H
O
C OH
O
H O C O
Jones Reagent
PCC
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Chemistry 391 10/30/02
• selective oxidation reactions reviewOxidation and ReductionOxidation and Reduction
1) KMnO4, OH -
2) H3O+ O
OH
O ( dichromate too)
CH3
H
1) O3
2) (CH3)2SO
H
CH3
O
O
HAg(NH3)2OH
O
OH
OH
OH
+ Ag (s)
HIO4H
O
H
O
KMnO4 tooCH2 CH3
CH3CH3C
H3CCH3
K2Cr2O7
H2SO4
CO2H
CO2HCH3C
H3C CH3
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Chemistry 391 10/30/02
Selective Oxidation ReactionsSelective Oxidation Reactions
Jones Reagent (H2CrO4 in acetone) takes primary alcohols to acids and secondary alcohols to ketonesThe Tollen’s Test Ag(NH3)2OH…the silver mirror reaction is a qualitative test for aldehydes and an efficient but expensive way to make acids form aldehydes
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Chemistry 391 10/30/02
Examples OH O
H2CrO4, Acetone
Examples
H2SO4
OH
O
OHH2CrO4, Acetone
H2SO4C
H
O
H3C H3C
COH
O
H2CrO4, Acetone
Ag(NH3)2 OHCH
O
H3C H3C
COH
O
+ Ag0
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Chemistry 391 10/30/02
KetoKeto--enol enol Tautomerism Tautomerism
CH 3C CH 3
OCH 3C
OH
CH 2
E nolK etone
OO••••
CR'CR'
••••
RR22CC
HHOOHH
HH
••••••••
OO
HH
HH ••••••••
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Chemistry 391 10/30/02
KetoKeto--EnolEnol TautomerismTautomerism
Keto-enolequilibria for simplealdehydesand ketones lie far toward theketo form
OH
O
OCH3 CH CH2 =CH
CH3 CCH3
Keto form Enol form% Enol at
Equilibrium
6 x 10-5
OHCH3 C=CH 2 6 x 10-7
O OH4 x 10-5
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Chemistry 391 10/30/02
KetoKeto--EnolEnol TautomerismTautomerismFor certain types of molecules, the enol is the major form present at equilibrium– for β-diketones, the enol is stabilized by conjugation of
the pi system of the carbon-carbon double bond and the carbonyl group
O
O
O
O
H
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Chemistry 391 10/30/02
KetoKeto--Enol Enol Tautomerism Tautomerism in in ββ--diketonesdiketones
Open-chain β-diketones are further stabilized byintramolecular hydrogen bonding
2,4-Pentanedione (Acetylacetone)
δ+δ-
hydrogen bonding
O O
H3 CC C
O O
HCH3
H
CH3 -C-CH 2 -C-CH 3 C
80%20%
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Chemistry 391 10/30/02
Deuterium ExchangeDeuterium Exchange
Deuterium exchange at an α-carbon may be catalyzed by either acid or base
+Acetone-d 6 Acetone
+O O
CH3 CCH3 6 D2 O CD3 CCD 3 6 HODD+
or OD -
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Chemistry 391 10/30/02
αα--HalogenationHalogenationα-Halogenation: aldehydes and ketones with at least one α-hydrogen react at an α -carbon with Br2 and Cl2 action is catalyzed by both acid and base
CH3 CO2 HCCH3
O OCCH2 Br+ Br 2 + HBr
Acetophenone
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Chemistry 391 10/30/02
Mechanism of Mechanism of αα HalogenationHalogenation
Experimental FactsExperimental Facts
• specific for replacement of H at the α carbon
• equal rates for chlorination, bromination, and iodination
• first order in ketone; zero order in halogen
InterpretationInterpretation
no involvement of halogen until after theno involvement of halogen until after theraterate--determining stepdetermining step
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Chemistry 391 10/30/02
Mechanism of Mechanism of αα HalogenationHalogenation
RCHRCH22CR'CR'
OO
RCHRCH CR'CR'
OHOHslowslow XX22
fastfast RCHCR'RCHCR'
OO
XXenolenol
• Enol is the key intermediate
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Chemistry 391 10/30/02
Mechanism of Mechanism of αα HalogenationHalogenation
Two stages:Two stages:
• first stage is slow conversion of aldehyde or ketone to the corresponding enol; is rate-determining
• second stage is fast reaction of enol with halogen; is faster than the first stage
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Chemistry 391 10/30/02
General ReactionGeneral ReactionOO
RR22CCR'CCR'
OO
RR22CCR'CCR'
X2 can be Cl2, Br2, or I2.
Substitution is specific for replacement of α hydrogen.
Not a free-radical reaction.
HH
++ XX22HH++
++ HHXX
XX
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Chemistry 391 10/30/02
An ExampleAn Example
OOCl
H2O + HCl+ 1Cl2
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Chemistry 391 10/30/02
Another ExampleAnother Example
CHClCHCl33BrBr22++
HHCHCH
OO
++
BrBrCHCH
OO
HHBrBr
Notice that it is the proton on the αcarbon that is replaced, not the one on the carbonyl carbon.
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Chemistry 391 10/30/02
AcidAcid catalyzed catalyzed αα--HalogenationHalogenation
Acid-catalyzed α-halogenationStep 1: acid-catalyzed enolization
Step 2: Nucleophilic attack of the enol on halogen
•• ••
+fast+
•• ••
CR
RH-OC
R' R'C C
O Br
RRBr-Br H-Br
slowO H
R R'C C
H-O R
RR'-C-C-R
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Chemistry 391 10/30/02
Acid catalyzed aAcid catalyzed a--HalogenationHalogenation
OH
vs.
OH
CH3
O
HI, H2O CH3
OClCl2
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Chemistry 391 10/30/02
What about Base Catalysis??What about Base Catalysis??Hydrogens α to carbonyls are “acidic”
CH3C C
OH
H H-OH
C
O
H3C CH2- H2O+
CH3C CH2
O-Resonance stabilizedenolate anion
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Chemistry 391 10/30/02
Acidity of protons Acidity of protons αα to to carbonylscarbonyls
The anion is stabilized by resonsancethe better the stabilization, the more acidic the α proton Acidity of a protons on“normal” aldehydes and ketones is about that of alcohols and less than water…pKa ~ 18-20Some are far more acidic, i.e. β-dicarbonyl compounds that have quite low pKa’s
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Chemistry 391 10/30/02
CH3CO2H
HF
HCl
OH
H C C C H
O O
H
H
CH3OH
CH3CCH2CCH3
O O
CH3CCH3
O
CH3CH3
4.753.45
-9.0!!
10
5.0
16
9
20
50
A span of 59 powers of 10!!!
pKa pKa of some acids andof some acids andsome some αα protonsprotons
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Chemistry 391 10/30/02
BaseBase catalyzedcatalyzed αα--HalogenationHalogenation
Base-promoted α-halogenationStep 1: formation of an enolate anion
C
OH
HH
-OH CH2
O
CH2
O
+ H2O
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Chemistry 391 10/30/02
Base catalyzedBase catalyzed αα--HalogenationHalogenation
Base-promoted α-halogenationStep 2: nucleophilic attack of the enolate anion on halogen
CH2
O
Br Br CH2 Br
O
Br-
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Chemistry 391 10/30/02
αα--HalogenationHalogenationSo…there are So…there are majormajor differences between differences between acidacid--catalyzed and basecatalyzed and base--promoted promoted αα--halogenationhalogenation
• Acid catalysis gives the most substituted product• The rate of acid-catalyzed introduction of a second
halogen is slower than the firstintroduction of the electronegative halogen on the α-carbon decreases the basicity of the carbonyl oxygen toward protonation
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Chemistry 391 10/30/02
αα--HalogenationHalogenation
In base catalyzed α-halogenation, each each successivesuccessive halogenationhalogenation is more rapid than is more rapid than the previous one the previous one – the introduction of the electronegative halogen
on the α-carbon increases the acidity of the remaining α-hydrogens and, thus, each successive α-hydrogen is removed more rapidly than the previous one
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Chemistry 391 10/30/02
HaloformHaloform ReactionReactionIodoform ReactionA qualitative test for methyl ketonesA decent way to synthesize carboxylic acids
R C
O
CH3
3I2
NaOHR C
O
CII
I
HO-
R C
O
O- + HCI3
Iodoform
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Chemistry 391 10/30/02
TheThe HaloformHaloform ReactionReaction
• Under basic conditions, halogenation of a methyl ketone often leads to carbon-carbon bond cleavage.
• Such cleavage is called the haloformreaction because chloroform, bromoform, oriodoform is one of the products.
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Chemistry 391 10/30/02
ExampleExample
(CH(CH33))33CCCCCCHH33
OO
BrBr22,, NaOHNaOH, H, H22OO
CCHBrHBr33++(CH(CH33))33CCONaCCONa
OO
HH++
(CH(CH33))33CCOHCCOH
OO
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Chemistry 391 10/30/02
First stage is substitution of all available First stage is substitution of all available ααhydrogens hydrogens by halogenby halogen
RCCHRCCH33
OO
RCCRCCXX33
OO
XX22, HO, HO– XX22, HO, HO–– –
RCCHRCCH22XX
OO
RCCHRCCHXX22
OOXX22, HO, HO––
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Chemistry 391 10/30/02
Formation of theFormation of the trihalomethyltrihalomethyl ketone is ketone is followed by its hydroxidefollowed by its hydroxide--induced cleavageinduced cleavage
HOHO ••••––
••••••••
RCRC
OO ••••••••
CCXX33++
•••• ––
RCRC
OO ••••
HOHO ••••••••
••••
CCXX33
––•••• CCXX33
••••
RCRC
OO ••••
OHOH••••
••••++– +–
••••
••••
RCRC
OO ••••
OO••••
••••+ HCHCXX33