Nitrogen Based Carbonyl Reactions

Some reactions of aldehydes and ketones progressSome reactions of aldehydes and ketones progressbeyond the nucleophilic addition stagebeyond the nucleophilic addition stage

Acetal formationAcetal formation

IminesImines

Compounds related to iminesCompounds related to imines

EnaminesEnamines

The Wittig reactionThe Wittig reaction

Enamine from 2Enamine from 2oo amines amines

Question

• The compound below is best classified as a(n)

(CH3)3CCH2CH=NCH3

• A) carbinolamine.• B) enamine.• C) hydrazone.• D) imine.

Question

• Identify the product isolated when cyclopentanone reacts with dimethyl amine.

• A) B)

• C) D)

The Wittig Reaction

Some reactions of aldehydes and ketones progressSome reactions of aldehydes and ketones progressbeyond the nucleophilic addition stagebeyond the nucleophilic addition stage

Acetal formationAcetal formation

Imine formationImine formation

Compounds related to iminesCompounds related to imines

EnaminesEnamines

The Wittig reactionThe Wittig reaction

The Wittig ReactionThe Wittig Reaction

Synthetic method for preparing alkenes.Synthetic method for preparing alkenes.

One of the reactants is an aldehyde or ketone.One of the reactants is an aldehyde or ketone.

The other reactant is a phosphorus ylide.The other reactant is a phosphorus ylide.

(C(C66HH55))33PP CC++

AA

BB

••••––

(C(C66HH55))33PP CC

AA

BB

A key property of ylides is that they have a A key property of ylides is that they have a negatively polarized carbon and are nucleophilic. negatively polarized carbon and are nucleophilic.

Charge distribution in a ylide

The Wittig ReactionThe Wittig Reaction

(C(C66HH55))33PP CC++

AA

BB

••••––

++

++CC CC

RR

R'R'

AA

BB

(C(C66HH55))33PP OO++

••••––••••

••••

CC OO

RR

R'R'

••••

••••

ExampleExample

++

++ (C(C66HH55))33PP OO++

••••––••••

••••

(C(C66HH55))33PP CHCH22

++ ––

••••OO••••

••••

CHCH22

DMSODMSO

(86%)(86%)

dimethyl sulfoxide (DMSO) or tetrahydrofuran dimethyl sulfoxide (DMSO) or tetrahydrofuran (THF) is the customary solvent(THF) is the customary solvent

MechanismMechanism

CC OO

RR

R'R'

••••

••••

P(CP(C66HH55))33

++CC

AA

BB––••••

OOCC

CC P(CP(C66HH55))33

RR

R'R'

BB

AA

•••• ••••

Step 1Step 1Step 1Step 1

MechanismMechanism

OOCC

CC P(CP(C66HH55))33

RR

R'R'

BB

AA

•••• ••••

Step 2Step 2Step 2Step 2

P(CP(C66HH55))33++

––OO•••• ••••••••

R'R'RR

AA BB

CC

CC++

Alkene Synthesis viathe Wittig Reaction

Retrosynthetic AnalysisRetrosynthetic Analysis

There will be two possible Wittig routes toThere will be two possible Wittig routes toan alkene.an alkene.

Analyze the structure retrosynthetically.Analyze the structure retrosynthetically.

Disconnect the doubly bonded carbons. One Disconnect the doubly bonded carbons. One will come from the aldehyde or ketone, thewill come from the aldehyde or ketone, theother from the ylide.other from the ylide.

CC CC

RR

R'R'

AA

BB

Retrosynthetic Analysis of StyreneRetrosynthetic Analysis of Styrene

CC66HH55CHCH CHCH22

HCHHCH

OO

++(C(C66HH55))33PP CHCCHC66HH55

++ ––

••••

CC66HH55CHCH

OO

++ (C(C66HH55))33PP CHCH22

++ ––

••••

Both routesBoth routesare acceptable.are acceptable.

Preparation of YlidesPreparation of Ylides

Ylides are prepared from alkyl halides by aYlides are prepared from alkyl halides by atwo-stage process.two-stage process.

The first step is a nucleophilic substitution.The first step is a nucleophilic substitution.Triphenylphosphine is the nucleophile.Triphenylphosphine is the nucleophile.

(C(C66HH55))33PP •••• ++ CHCH

AA

BB

XX

++(C(C66HH55))33PP CHCH

AA

BB

++ XX––

Preparation of YlidesPreparation of Ylides

In the second step, the phosphonium salt isIn the second step, the phosphonium salt istreated with a strong base in order to removetreated with a strong base in order to removea proton from the carbon bonded to a proton from the carbon bonded to phosphorus.phosphorus.

(C(C66HH55))33PP CC

AA

BB

++HH

basebase ••••––

(C(C66HH55))33PP CC

AA

BB

++••••

––

HHbasebase

Preparation of YlidesPreparation of Ylides

Typical strong bases include organolithium Typical strong bases include organolithium reagents (RLi), and the conjugate base of reagents (RLi), and the conjugate base of dimethyl sulfoxide as its sodium saltdimethyl sulfoxide as its sodium salt[NaCH[NaCH22S(O)CHS(O)CH33].].

(C(C66HH55))33PP CC

AA

BB

++HH

basebase ••••

(C(C66HH55))33PP CC

AA

BB

++••••

––

––HHbasebase

Question

• Select the product isolated when butanal reacts with the slide shown below.

• A) B)

• C) D)

QuestionWhat is the product of the reaction sequence below?

A. 2-methyl-1-hexene B. 2,3-dimethyl-2-pentene C. 2-methyl-2-hexene D. 3-methyl-1-hexene

Stereoselective Addition to Stereoselective Addition to

Carbonyl GroupsCarbonyl Groups

Nucleophilic addition to carbonyl Nucleophilic addition to carbonyl

groups sometimes leads to a mixture groups sometimes leads to a mixture

of stereoisomeric products.of stereoisomeric products.

20%20%

ExampleExample CHCH33HH33CC

OO

80%80%

OOHH

HH

CHCH33HH33CC

OOHH

HH

CHCH33HH33CCNaBHNaBH44

This methyl group hindersapproach of nucleophilefrom top.

This methyl group hindersapproach of nucleophilefrom top.

HH33B—HB—H––

Preferred direction ofapproach is to less hindered(bottom) face of carbonyl group.

Preferred direction ofapproach is to less hindered(bottom) face of carbonyl group.

Steric Hindrance to Approach of ReagentSteric Hindrance to Approach of Reagent

Biological Reductions are Highly StereoselectiveBiological Reductions are Highly Stereoselective

pyruvic acid pyruvic acid SS-(+)-lactic acid-(+)-lactic acid

OO

CHCH33CCOCCO22HHNADNADHH

HH++

Enzyme is Enzyme is lactate dehydrogenaselactate dehydrogenase

COCO22HH

HHOO HH

CHCH33

Figure 1Figure 1

One face of the One face of the substrate can bind to substrate can bind to the enzyme better the enzyme better than the other.than the other.

Figure 2Figure 2

Change in geometry Change in geometry from trigonal to from trigonal to tetrahedral is tetrahedral is stereoselective. stereoselective. Bond formation Bond formation occurs preferentially occurs preferentially from one side rather from one side rather than the other.than the other.

Oxidation of AldehydesOxidation of Aldehydes

KK22CrCr22OO77

HH22SOSO44

HH22OO

OO

OO

CHCH

OO

OO

COHCOH

(75%)(75%)

ExampleExample

Baeyer-Villiger OxidationBaeyer-Villiger Oxidation

of Ketonesof Ketones

Oxidation of ketones with peroxy acidsOxidation of ketones with peroxy acids

gives esters by a novel rearrangement.gives esters by a novel rearrangement.

R"COR"COOOHH

OO

RRCCR'R'

OO

++ R"COHR"COH

OO

++

KetoneKetone EsterEster

RROOCCR'R'

OO

GeneralGeneral

CC66HH55COCOOOHH

OO

(67%)(67%)

Oxygen insertion occurs between carbonyl Oxygen insertion occurs between carbonyl carbon and more substituted group.carbon and more substituted group.

Methyl ketones give acetate esters.Methyl ketones give acetate esters.

CHClCHCl33

ExampleExample

CCHCCH33

OO

OOCCHCCH33

OO

CC66HH55COCOOOHH

OO

(66%)(66%)

Reaction is stereospecific.Reaction is stereospecific.

Oxygen insertion occurs with retention ofOxygen insertion occurs with retention ofconfiguration.configuration.

CHClCHCl33

StereochemistryStereochemistry

OO

CCHCCH33HH33CC

HH HH

OOCCHCCH33

OO

HH33CC

HH HH

R"COR"COOOHH

OO

RRCCR'R'

OO

++ RROOCCR'R'

OO

R"COHR"COH

OO

++

First step is nucleophilicFirst step is nucleophilicaddition of peroxy acidaddition of peroxy acidto the carbonyl group of to the carbonyl group of the ketone. the ketone.

OO

OO

CC

OO HH

RR R'R'

OCR"OCR"

MechanismMechanism

R"COR"COOOHH

OO

RRCCR'R'

OO

++ RROOCCR'R'

OO

R"COHR"COH

OO

++

OO

OO

CC

OO HH

RR R'R'

OCR"OCR"

Second step is migrationSecond step is migrationof group of group RR from carbon from carbonto oxygen. The weakto oxygen. The weakOO—O —O bond breaks in thisbond breaks in thisstep. step.

MechanismMechanism

Certain bacteria use hydrocarbons as a source of Certain bacteria use hydrocarbons as a source of carbon. Oxidation proceeds via ketones, which then carbon. Oxidation proceeds via ketones, which then undergo oxidation of the Baeyer-Villiger type.undergo oxidation of the Baeyer-Villiger type.

Biological Baeyer-Villiger OxidationBiological Baeyer-Villiger Oxidation

OO

bacterialbacterial

oxidationoxidation

OO

OO

OO22..

cyclohexanonecyclohexanone

monooxygenase,monooxygenase,

coenzymescoenzymes

Question• What is the product of the following Baeyer-Villiger oxidation reaction?