Carbonyl Chemistry IV - University of Texas at...

Carbonyl Chemistry IVCarbonyl Chemistry IV

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Lecture 10Lecture 10Chemistry 391 10/30/02

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


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 +


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+


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+


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


ExampleExample

CCH3

O

+ H2NNH

phenylhydrazine

CCH3

NNH

+ H2O

a phenylhydrazone


ExampleExample

CH3(CH2)9CCH3

O

H2NNHCNH2

O

+

semicarbazide

CH3(CH2)9CCH3

NNHCNH2

O

+ H2O

a semicarbazone


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


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


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


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-


NaBHNaBH44 ReductionReduction

Reductions with NaBH4 are most commonly carried out in aqueous methanol, in pure methanol, or in ethanol

RCHO

+ NaBH4 RCH2OH CH3OH


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


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


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


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


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


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


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


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


• 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


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


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


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 ••••••••


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


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


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%


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 -


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


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



RCHRCH22CR'CR'

OO

RCHRCH CR'CR'

OHOHslowslow XX22

fastfast RCHCR'RCHCR'

OO

XXenolenol

• Enol is the key intermediate



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


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


An ExampleAn Example

OOCl

H2O + HCl+ 1Cl2


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.


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


Acid catalyzed aAcid catalyzed a--HalogenationHalogenation

OH

vs.

OH

CH3

O

HI, H2O CH3

OClCl2


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


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


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


BaseBase catalyzedcatalyzed αα--HalogenationHalogenation

Base-promoted α-halogenationStep 1: formation of an enolate anion

C

OH

HH

-OH CH2

O

CH2

O

+ H2O


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-


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


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


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


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.


ExampleExample

(CH(CH33))33CCCCCCHH33

OO

BrBr22,, NaOHNaOH, H, H22OO

CCHBrHBr33++(CH(CH33))33CCONaCCONa

OO

HH++

(CH(CH33))33CCOHCCOH

OO


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––


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

Carbonyl Chemistry IV - University of Texas at...

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