Carbonyl Compounds

We have already seen a number of carbonyl compounds

R

O

R R

O

H R

O

OH R

O

ORR

O

NH2 R

O

Cl

Ketone two R groups

Aldehyde one R, one H

Amide one R, one N

Acid one R, one OH

Ester one R, one OR

Acid chloride one R, one Cl

In this chapter, the focus is on the reactivity of ketones and aldehydes

Nomenclature of Ketones and Aldehydes

Many of the same IUPAC rules already learned apply

With ketones: suffix is –one With aldehydes: suffix is -al

In numbering, the carbonyl takes precedence over previous functional groups learned

O O

HO

O

H

2-butanone 4-hydroxy-2-butanone (carbonyl precedence

over alcohol)

propanal (do not need to write 1)

Common Names

In addition to the IUPAC naming, many ketones and aldehydes have common names

H3C

O

CH3 H3C

OCH3 H

O

H

acetone methyl ethyl ketone (name two alkyl groups)

formaldehyde

The aceto- common name is consistent amongst many compounds

H3C

O

H3C

O

OH H3C

O

O

aceto- acetic acid ethyl acetate

The properties of ketones and aldehydes are dependent on the structure

The carbonyl double bond is a result of a π bond between the carbon and oxygen

Due to electronegativity of oxygen, this double bond is more polarized than an alkene

C ORR

R

O

R R

O

R

The increase in proportion of charged structure in resonance hybrid causes two effects: 1)  Carbonyl carbon is more electrophilic

(compared to alkene) 2)  Oxygen is more nucleophilic

(compared to alkene)

Can observe differences by looking at electron density maps

H

O

H HH

HH

Physical properties of ketones and aldehydes

Two main physical properties are a direct result of carbonyl functionality:

1)  Ketones and aldehydes have a higher boiling point than alkanes of similar mass

A result of having a greater charged component in the resonance hybrid (charged structures have a higher boiling point and melting points than uncharged)

2) Ketones and aldehydes have a higher water solubility compared to alkanes

R

O

R

HO H

Due to hydrogen bonding capability of carbonyl oxygen

Synthesis of Ketones and Aldehydes

We have already seen many ways to synthesize ketones and aldehydes

Other Routes to Ketones and Aldehydes

Many carbonyls can be converted to other types of carbonyls (chapter 21 focuses on many of these interconversions)

Carboxylic acids can be converted to ketones with organolithium reagents

H3C

O

OH

R Li

H3C

O

OR Li

H3C

OH

ROH

H3C

O

R

First equivalent of organolithium abstracts hydrogen

Second equivalent reacts at carbonyl

Upon protonation generate geminal diol

Geminal diols equilibrate with ketone

Acid Chlorides can be Converted to Either Aldehydes or Ketones

The carboxylic acid can first be converted to an acid chloride

The acid chloride can be reduced to an aldehyde with lithium tri(t-butoxy) hydride

Need to use lithium tri(t-butoxy) hydride since it is weaker than LAH (LAH would reduce aldehyde to alcohol)

Acid Chloride to Ketone

As seen earlier with most carbon based nucleophiles (e.g. Grignard reagents) two equivalents will react with an acid chloride to yield a tertiary alcohol

Dialkyl cuprates (Gilman reagent), however, only one equivalent adds to yield a ketone

Reactions with Nitriles

Cyano groups (also called nitriles) also have an electrophilic carbon

The electrophilic carbon will react with Grignard reagents

C NH3CR-MgBr

H3C

N

R

Reaction stops at imine anion stage

Upon work-up, the imine anion is protonate to an imine

Under same conditions, the imine is hydrolyzed to the ketone

H3C

N

R H3C

NH

R

H3O

H3C

O

RH3O

Nitriles to Aldehyde Conversion

Nitriles can also be converted to aldehydes using an aluminum hydride

The reagent of choice is a diisobutyl aluminum hydride [(i-Bu)2AlH] (called DIBAL)

C NH3C

Al H

H3C

N

H

Al(i-Bu)2

H3C

O

HH3O

The imine anion is hydrolyzed to the carbonyl in work-up -thus yielding an aldehyde

DIBAL will Also Reduce Ester Groups

An ester carbonyl is reduced to an aldehyde using DIBAL

H3C

O

OR H3C

O

HDIBAL

If LAH was used, the ester is reduced to the alcohol instead

H3C

O

OR H3C

OHLAH

HH

Dithiane Route to Ketones and Aldehydes

A dithiane has two sulfur atoms bonded to a methylene (usually see these compounds in 1,3 ring structure but can have different connectivity)

S S

H H

The methylene hydrogens have a pKa ~32

The two polarizable sulfur atoms make the methylene hydrogens far more acidic -compare to pKa of ~50 for unactivated C-H bond

Acidic Hydrogens can be Removed

S S

H H

BuLi S S

H

The carbon anion can then react with an alkyl halide in a normal SN2 reaction

S S

H

S S S S

R H R R

RX1) BuLi2) RX

The process can be repeated to yield either a mono- or dialkyl substituted dithiane

Removal of Dithiane

Once the substituted dithiane is created, the sulfur can be removed with acidic mercury

S S

R H

H+, HgCl2H2O

R

O

H

Advantages to this procedure: 1)  Either an aldehyde or ketone can be prepared depending

upon the number of alkyl substituents on dithiane 2)  Any alkyl group can be added as long as an SN2 reaction can result

3) Can make asymmetric ketones depending on type of alkyl groups added

Reactions of Ketones and Aldehydes

Reactions occur either with strong nucleophiles in basic conditions or with weaker nucleophiles on protonated carbonyls in acidic conditions

With strong nucleophiles, the nucleophile reacts with the electrophilic carbon

MgBrH

OH

OH

H

Protonation of Carbonyl Creates more Electrophilic Carbon

Carbonyl carbon is much more electrophilic upon protonation due to resonance

H H

O H

H H

O H

H H

O

Protonation thus allows a much weaker nucleophile to react at carbonyl carbon

All reactions with carbonyls are occurring through one of these mechanisms (strong nucleophile directly on carbonyl or weak nucleophile on protonated carbonyl)

Previously observed reactions with carbonyls:

O CH3MgBr OMgBrH+

OH

O LAHOLi

H

H+OH

H

Also have seen reactions at protonated carbonyls

H3C

O

OHH+

H3C OH

O H

H3C OH

O HCH3OH

H3C

OHOH

OCH3H

H3C

OHOH

OCH3H

H3C

OHOH2OCH3 H3C

O

OCH3

H

Methanol, or other weak nucleophiles, do not react readily with carbonyls without protonation

(Fischer esterification)

Reactivity of Ketones Versus Aldehydes

H3C

O

CH3 H3C

O

H H

O

H

Aldehydes in general are more reactive than ketones -aldehyde carbon is more electrophilic due to lack of inductive alkyl stabilization

Hydration Reactions

A carbonyl can become “hydrated” by reaction with water

Occurs in acidic conditions where carbonyl is first protonated

H3C CH3

O H

H3C

O

CH3H+

H3C CH3

HO OHH2O

Each step in mechanism is reversible, therefore equilibrium is dependent on concentration of each form

Ketone is more stable in carbonyl form Aldehyde has relatively more hydrated form than ketone

Formaldehyde has a higher concentration of hydrated form

Wittig Reaction

Reaction converts a ketone or aldehyde into an alkene

H3C

O

CH3(Ph)3P=CH2

H3C CH3

Merely looking at starting materials and product might cause confusion, but this reaction is another type of nucleophile reacting at electrophilic carbonyl

The nucleophile is the phosphorous ylide

An ylide is any compound that contains a cation adjacent to an anion

Formation of Phosphorous Ylides

Typically these ylides can be prepared by reacting triphenylphosphine with alkyl halide

PPh

PhPh Br (Ph)3P Br

The methylene adjacent to phosphorous in phosphonium salt is acidic

Phosphonium salt

(Ph)3PBuLi

(Ph)3P (Ph)3P

With strong base therefore the ylide can be obtained

The carbanion of the ylide is nucleophilic and will react with the carbonyl

H3C

O

CH3(Ph)3P

(Ph)3P O

CH3CH3H3C

betaine

oxyphosphetane

The betaine structure will form 4-membered ring between positive phosporous and negative oxygen

(Ph)3P O

CH3CH3H3C

(Ph)3P O

H3CCH3

CH3

The oxyphosphetane is the driving force for this reaction, strong phosphorous-oxygen bonds energetically drive reaction

The oxyphosphetane will collapse to form a second phosphorous-oxygen bond

(Ph)3P O

H3CCH3

CH3 H3C CH3

CH3(Ph)3P O

Overall an alkene is formed from the initial carbonyl compound

The oxygen of the initial carbonyl forms double bond to phosphorous in phosphine oxide (driving force for reaction)

Depending upon the initial phosphonium salt, different alkyl groups can be added to alkene product

Cyanohydrin

Cyano groups (nitriles) can also add to carbonyls

Cyanide reacts in a basic mechanism

H3C

O

CH3CN

H3C

O

CNCH3 H3C

OH

CNCH3

H+

Caution – do not acidify cyanide solution, it will create hydrogen cyanide

CNH+

HCN

toxic

Hydrolysis of Nitrile

An advantage with cyanohydrins is that the nitrile can be hydrolyzed to an acid

H3C

OH

CNCH3

H+, H2O

H3C

OHCH3

CO2H

Depending upon the conditions used to protonate the alkoxide in the previous step, both reactions can occur in same step

One of the easiest methods to create an α-hydroxy acid (analogs of α-amino acids)

In nature this reaction is used as a biodefense mechanism

The formation of cyanohydrins is reversible

Insects store this cyanohydrin as a defense, if predators eat the insects they ingest the cyanohydrin

which can break down to generate HCN

The HCN will kill the predator and thus act as a deterrent

OH

CNH

O

H HCN

Imines

Carbonyls can also react with primary amines to create imines

Reaction occurs under an acid catalyzed mechanism

Each step is reversible

The imine can therefore be converted to the carbonyl with acidic water (Le Chatelier’s principle)

Imines are important for vision

OH

H2N (opsin)

NH(opsin)

11-cis-retinal rhodopsin

11-cis-retinal reacts with a 1˚ amine in the protein opsin in the rod cells of the eye

NH(opsin)

h!N (opsin)

Upon application of light, a cis/trans interconversion occurs which is converted into an electrochemical impulse by affecting the concentration of Ca2+ crossing a cell membrane

Other Substituted Amines can React in a Similar Manner

H3C

O

CH3NH2OH

H+ H3C

N

CH3

OH

H3C

O

CH3NH2NH2H+ H3C

N

CH3

NH2

H3C

O

CH3NH2NHPh

H+ H3C

N

CH3

NHPh

oximes

hydrazones

Phenyl hydrazones

These condensation products are often used for identification

These condensation derivatives with substituted amines are often crystalline solids

The melting points of these solids are known

Therefore an aldehyde or ketone can be determined by comparing the melting points of its condensation products with known values

Before many spectroscopic tools were developed this was the only way to determine structure of unknowns, run reactions and systematically determine products

Secondary Amines Condense to form Enamines

Similar process to imines (use 2˚ amine instead of 1˚ amine)

H3C

O

CH3 H+ H3C

NR2

CH2

R2NHH3C CH3

NR2HO -H2O

enamine

Forms carbon-carbon double bond after losing water, must lose hydrogen from α-carbon as there are no remaining hydrogens on nitrogen

Enamines have different subsequent reactivity than imines (study more in chapter 22)

Acetals and Ketals

Acetals and ketals are related to hydrates, Instead of geminal dialcohols have geminal ethers

If geminal ether came from a ketone it is called a ketal, if geminal ether came from an aldehyde it is called an acetal

This process is once again an equilibrium process

Aldehydes (which are more reactive than ketones) typically favor acetals

H3C

O

CH3 H+ H3C CH3

ORROROH

Cyclic Acetals and Ketals

When both alcohols to form an acetal are intramolecular (on same molecule) then a cyclic acetal is formed

H3C

O

H H+ H3C H

HO OH OO

Cyclic acetals and ketals are often used because they have a higher equilibrium for the acetal form

Entropy favors two molecules condensing to one more than when three molecules condense to one

Cyclic Thioacetals

Already seen cyclic acetals being used with thiol groups

H

O

H H+ H H

HS SH SS

The dithiane unit is a cyclic thioacetal that was used for synthesis of longer chain aldehydes and ketones

Acetals and Hemiacetals are Common with Sugar Compounds

OHC OH

OH

OH

OH

OH

CHOOHHHHOOHHOHH

CH2OH

O

H

HO

H

HO

H

HOHH OH

OHO

H

HO

H

HO

H

HOHH O

OH

O

H

H

HO

H

HOHH OH

OH

While the open chain forms are often drawn for sugar molecules, in solution they often adopt a closed ring form

The closed ring forms have acetal or hemiacetal ring junctions

glucose Fischer projection

hemiacetal

acetal

Protecting Groups

Protecting groups are extremely important in organic synthesis

Acetals are stable under basic conditions, but will revert to aldehyde under acidic

Thus acetals can be used as a protecting group for the carbonyl and allow reactions that would not be possible otherwise

O

HBr MgO

HBrMg

Cannot form this compound, will react intramolecularly

OH

Using acetal, however, the Grignard can be formed

O

HBrHO OH

H+ HBrOO Mg

HBrMgOO

With no carbonyl present, the Grignard reagent is stable

HBrMgOO H3C

O

CH3HOOOH

H+H

OH O

Reaction is not possible without acetal protecting group

Baeyer-Villiger Reaction

Allows conversion of ketone to ester

R

O

RRCO3H

R

O

O R

Mechanism of oxygen insertion?

R

O

R H O O

O

R R

O

RO O

O

R

H

R

HO

O

RO

O

RR

O

O R O

O

R

H

Mechanism is not an insertion, but rather a reaction at carbonyl followed by a migration

Weak oxygen-oxygen single bond

Migration with Unsymmetrical Carbonyls

If the two alkyl components of the ketone are different, which one migrates?

RCO3HR1

O

R2 R1

O

O R2 R2

O

O R1or

There is a distinct preference for one group to migrate selectively

H > 3˚ alkyl > 2˚ alkyl ~ phenyl > 1˚ alkyl > methyl

In general, a hydrogen migrates first, but then a more substituted alkyl group migrates preferentially

Examples

O RCO3HO

O

RCO3H

OO

O

RCO3HH

O

HO

O

More substituted substituent migrates preferentially

Cyclic ester (lactone)

Another way to oxidize aldehyde to carboxylic acid

Stereospecific Migration

Migration occurs with RETENTION of configuration for the migrating group

Tollen’s Test

Convenient test for the presence of aldehydes Again this test was prevalent before spectroscopic tools became so powerful

Whenever an aldehyde is present when silver-ammonia is added, metallic silver results

The formation of metallic silver is therefore indicative of an aldehyde present, ketones will not react under these conditions

Reduction of Ketones and Aldehydes

Have learned many ways to reduce a carbonyl to alcohol

Also have seen how to reduce a carbonyl to a methylene

The main difference between these two mechanisms is acidic versus basic conditions, both require strong conditions (high temperature) for reaction to occur