ORGANIC CHEMISTRY 2 - PowerPoint Presentation

Slide1

ORGANIC CHEMISTRY 2

Lecture 6

CARBONYL COMPOUNDS:

NUCLEOPHILIC ADDITION REACTIONSlide2

ALDEHYDE

KETON

ESTHER

CARBOXILIC ACID

CARBONYL COMPOUNDSSlide3

CARBONYL COMPOUNDS

Formalin

Ibuprofen

Aspirin

Asam cuka

Asam semut

Perasa buahSlide4

CARBONYL COMPOUNDSSlide5

Preparation of Aldehydes and Ketones

Oxidation reactions

Hydrolysis of geminal dihalides

Hydration of alkynesReactions with acid derivatives and nitriles

Reaction with carboxylic acidsReaction with thioacetalsSlide6

1. Aldehydes/Ketones via Oxidation Reactions

From Alcohols via PCC

From Alkenes via Ozonolysis

From Glycols via Periodic Acid CleavageSlide7

Synthesis Mechanism

a.1 Oxidation of 1

˚ alcohols

a.2. Oxidation of 2

° alcohols w/ PCC and baseSlide8

b.1 Oxidative cleavage of alkenes w/ O

3, Zn, CH

3COOHSlide9

b.2.Ozonolysis of alkenes, if one of the unsaturated carbon atoms is disubstituted.Slide10

2. Hydrolysis of Geminal DihalidesSlide11

a. Markovnikov Addition

b. Anti-Markovnikov Addition

3. Hydration of AlkynesSlide12

3.a. Hydration of terminal alkynes methyl ketonesSlide13

a. Aldehydes via Selective Reduction

Lithium tri-tert-butoxyaluminum hydride

Rosenmund reduction b. Ketones via Friedel-Crafts Acylation

c. Ketones via reaction with Organometallics

Gilman reagent (organocuprates)4. Reactions with Acid HalidesSlide14

Lithium tri-t-butoxyaluminum hydride reduction

Rosenmund reduction

4.a. Aldehydes from Acid ChloridesSlide15

4.b. Ketones via Friedel-Crafts Acylation

Friedel-Crafts acylation aryl ketonesSlide16

Use of Lithium dialkylcuprates

4.c.Ketones via Reaction with OrganometallicsSlide17

5. Aldehydes from Esters and Amides

Diisobutylaluminum hydride (DIBAH or DIBAL-H)Slide18

5.a. Partial reduction of certain carboxylic acid derivativesSlide19

Attack by Alkyl Lithium reagents

6. Ketones from Carboxylic AcidsSlide20

Grignard Addition to give Ketones

DIBAH Addition to give Aldehydes

8. Reactions with NitrilesSlide21

a. Thioacetal formation from an aldehyde precursor

b. Alkylation of the thioacetal intermediate using alkyl lithium reagents

c. Hydrolysis of the alkylated thioacetal to give ketone product

7. Ketones from ThioacetalsSlide22

1. Reduction reactions

a. Alcohol formation

b. Alkane formation

2. Oxidation reactions

3. Nucleophilic addition reactionsa. Grignard additions to form alcohols

b. Addition of water (hydration) to form gem-diolsc. Addition of alcohols to form acetals/ketals

d. Addition of HCN to form cyanohydrins

e. Addition of ammonia and ammonia derivatives

Characteristic Reactions of Aldehydes and KetonesSlide23

Reduction Reactions of Aldehydes & Ketones

1. Alcohol formation

a. Hydrogenation

b. Hydride reduction

2. Alkane formationa. Clemmensen reductionb. Wolff-Kishner reductionSlide24

Oxidation of Aldehydes & Ketones

Conversion of

aldehydes to carboxylic acids

Oxidation of aromatic aldehydes / ketones to benzoic acid derivatives

Haloform reaction of methyl carbonylsPeriodic acid cleavage of vicinal dials/diketonesSlide25

Aldehyde / Ketone Oxidations

1.

2.

3.

4. Slide26

Nucleophilic addition reactionsSlide27

Structure of the Carbonyl Group

Hybridization

of the carbonyl carbon is

sp

2.Geometry of the carbonyl carbon is trigonal planar

Attack by nucleophiles will occur with equal

ease from either the

top

or the

bottom

of the carbonyl group.

The carbonyl carbon is

prochiral

. That is, the carbonyl carbon is

not the center of chirality

, but it

becomes chiral

as the reaction proceeds.Slide28

These two products are

enantiomers.

In general, both enantiomers are formed in equal amount.

ProchiralSlide29

Reaction of the Carbonyl Group

1.

2.Slide30

1.

Nucleophilic Addition to Carbonyl

: General MechanismSlide31

2.Slide32

Relative Reactivity of Aldehydes & Ketones

Aldehydes >>> ketones

Steric Reason

nucleophile

is able to approach aldehydes more readily because it only has 1 large substituent bonded to the C=O carbon, vs. 2 in ketones.transition state for the aldehyde rxn is therefore less crowded and has lower energy.

Aldehydes

KetonesSlide33

greater polarization of aldehyde carbonyl group

aldehyde is more electrophilic and more reactive than ketones.

1

˚ carbocation (less stable, more reactive)

ς

-

ς

+

ς

-

ς

+

2

˚

carbocation

(more stable, less reactive)

2. Electronic Reason

Aldehyde

(less stabilization of

ς

+, more reactive)

Ketone

(more stabilization of

ς

+, less reactive)Slide34

Aliphatic aldehydes >>> Aromatic aldehydes

The electon-donating resonance effect of the aromatic ring

makes the carbonyl group less electrophilic than the carbonyl

group of the aliphatic aldehyde.

Relative Reactivity of Aldehydes & KetonesSlide35

The carbocation intermediate

Nucleophile attacks the electrophilic C=O carbon from a direction ~45

˚ to the plane of the carbonyl group

At the same time: Rehybridization of the carbonyl carbon from sp2

to sp3 occurs.

The positive charge character on carbon makes this an excellent site for attack by Lewis bases (nucleophiles).Slide36

Once we have the intermediate, what happens to it?Slide37

Case 1: The Addition Product is Stable.

The reaction stops here. This happens most often when the nucleophilic atom is carbon, oxygen, or sulfur.Slide38

Case 2: Addition-Elimination

The addition product is

unstable

with respect to loss of a molecule of water. This is observed most often when the nucleophilic atom is nitrogen or phosphorus.Slide39

Case 3: Loss of Leaving Group

This process is observed when

X

is a potential leaving group. In this case we have nucleophilic acyl substitution.Slide40

Nucleophilic Addition of H

2O: Hydration

Aldehydes and ketones react with water to yield a geminal

diol. This hydration process is reversible.

1. Base-catalyzed

Nucleophilic addition of water is catalyzed by acid and base.Slide41

2. Acid-catalizedSlide42

Important only for low-molecular-weight aldehydes

Examples:Slide43

Acetals

and

Ketals are formed by reacting two equivalents of an alcohol with an aldehyde or ketone, in the presence of an

acid catalyst.Hemiacetals and

Hemiketals are formed by reacting only one equivalent of alcohol with the aldehyde or ketone in the presence of an acid catalyst. Further reaction with a second alcohol forms the acetal or ketal.

A diol, with two –OH groups on the same molecule, can be used to form cyclic acetals.

All steps in acetal/ketal formation are reversible.

Nucleophilic Addition of Alcohols: Acetal FormationSlide44

Aldehydes form hemiacetals faster than ketones

This reaction is also reversible. But, in this case, the equilibrium can be driven to the right by an application of Le Châtelier’s Principle.Slide45
Slide46

Mechanism of Acetal Formation:Slide47

Dry acid =

HCl gas

HCl in methanolHOTs

1. Formation of 2,2-Dimethoxy-propane

2. Formation of a Cyclic Acetal

Example Nucleophilic Addition of AlcoholsSlide48

Carbohydrates contain the functional groups of alcohols and aldehydes or ketones in the same molecule. They are

polyhydroxyaldehydes

or polyhydroxyketones.Thus they can form acetal-type products through the intramolecular interaction of these functional groups.

As a model, consider the reaction:

3. Cyclization of

MonosaccharidesSlide49

a pyranose

ring

a furanose

ring

6

5Slide50

Nucleophilic Addition of HCN

Aldehydes and unhindered ketones react with HCN to yield

cyanohydrins. This formation is reversible and base-catalyzed.

Mechanism :

A cyanohydrinSlide51

Example

Notice that the cyanide ion and the acid are added in

two separate steps

!Sodium carbonate is used to keep the reaction medium basic.Slide52

So, what’s it good for?

Cyanohydrins formation is unusual due to the addition of protic acid to a carbonyl group, but useful because of further chemistry.

This affords us with an important method of synthesizing a-hydroxy-carboxylic acids -- important intermediates in biochemical processes.

Reduced with LiAlH4, yielding primary amine.

Hydrolyzed with hot aqueous acid, yielding carboxylic acid.Slide53

Addition of Organometallic Reagents

The products of the addition are always alcohols.Slide54

Whatever is attached to the carbonyl group will be attached to the resulting alcohol carbon.Slide55

Nucleophilic Addition of Grignard (R-MgX)

Grignard reagents R-MgX, strongly polarized reacts with an acid-base behavior. Nucleophilic addition of a carbanion to an aldehyde or ketone, followed by protonation of alkoxide intermediate, yields an alcohol.Slide56

Addition of hydride ion, from

LiAlH4

or NaBH4, and water or aqueous acid yields an alcohol

.

Addition of

Hydride ReagentsSlide57

Compounds that bear an amino group

Form

Imines

The

G group can be one of many different possibilitiesSlide58

Addition-Elimination:

The Formation of Imines

All of the imine reactions, regardless of G, go by the same mechanism.Slide59

Mechanism of Imine Formation: Slide60

Formation of Simple Imines

Aldehydes and ketones react with simple

primary amines

to yield imines

.The equilibrium is unfavorable; the products are much less stable than the reactants

.A. Simple

primary aminesSlide61

When

secondary amines

are allowed to react with aldehydes or ketones, dehydration of the type shown in the elimination step cannot take place (there is no labile hydrogen on the nitrogen atom of the addition product).

B. Simple

secondary aminesSlide62

The acid catalyst is generally a dry acid, such as

p

-toluene sulfonic acid (HOTs)

If the starting aldehyde or ketone has an α

-hydrogen, however, dehydration toward the α -carbon can occur, yielding an enamine.Slide63

Amines that are used typically to form enamines:Slide64

Enamine FormationSlide65
Slide66

Formation of Oximes

hydroxylamine

Aldehydes and ketones react with hydroxylamine to yield

oximes

.

Oximes are important derivatives in qualitative organic analysis.Slide67

Formation of Hydrazones

a hydrazine

Aldehydes and ketones react with substituted

hydrazines

to yield substituted hydrazones

.The equilibrium is generally unfavorable.Exception: when R is an aromatic ring.Slide68

Addition of hydrazine converts aldehyde/ketone to an alkane. An intermediate hydrazone forms,

followed by base catalyzed

double bond migration, loss of N2 gas, finally protonation yields an alkane.

Wolff-Kishner

Reaction: Nu

-

Addition of HydrazineSlide69

Formation of Semicarbazones

semicarbazide

Aldehydes and ketones react with semicarbazide to yield

semicarbazones

.

Semicarbazones are the second-most important of the derivatives of aldehydes and ketones.Slide70

The enamine is

quite nucleophilic, owing to resonance of the type:

As a consequence of this resonance, the

α

-carbon of an enamine has a great deal of carbanion-like (nucleophilic

) character.Slide71

Reactions of Enamines as Nucleophiles

S

N

2Slide72

Hydrolysis of Iminium SaltsSlide73

Enamines can react with alkyl halides -- Here’s an example.Slide74

Nucleophilic Addition of Phosphorus Ylides:

The

Wittig Reaction

Converts an aldehyde/ketone into an alkene.

A phosphorus ylide(aka phosphorane), acts as the Nu-

Ylide

: A compound or intermediate with both a positive and a negative formal charge on adjacent atoms.

The ylide is nucleophilic, owing to the negative charge character on carbon (structure on the right).Slide75

A phosphorus

ylide(aka phosphorane), acts as the Nu-

to attack the carbonyl carbon and yields a four-membered ring, dipolar intermediate called the betaine.The betaine decomposes spontaneously to yield an alkene and a triphenylphosphine oxide.

Can produce monosubstituted, disubstituted, and trisubstituted alkenes.

This is a type of

condensation reaction -- we use it to “dock” to large structures together.This is another example of addition-elimination

.Slide76

Mechanism of the Witting Reaction:Slide77

Conjugate Nucleophilic Addition to

α-β-

Unsaturated Aldehydes and Ketones

Direct addition (aka 1,2 addition) occurs when a nucleophile attacks the carbon in the carbonyl directly.Conjugate addition (aka 1,4 addition) occurs when the nucleophile attacks the carbonyl indirectly by attacking the second carbon away from the carbonyl group, called the beta carbon, in an unsaturated aldehyde or ketone.

Conjugate addition reactions form an initial product called an enolate, which is protonated on the carbon next to the carbonyl, the alpha carbon, to give the final saturated aldehyde/ketone product.

Conjugate addition can be carried out with nucleophiles such as primary amines, secondary amines, and even alkyl groups like in organocopper reactions. It is the carbonyl that activates the conjugated C=C double bond for addition which would otherwise not react.Slide78

Conjugate (1,4) addition mechanism: