Carbonyl Compounds

We have already seen a number of carbonyl compounds

O O O O O O

R R R H R NH2 R OH R OR R Cl

Ketone
Amide
Ester

two R groups
one R, one N
one R, one OR

Aldehyde
Acid
Acid chloride

one R, one H
one R, one OH
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 O

HO H

2-butanone
4-hydroxy-2-butanone
propanal

(carbonyl precedence
(do not need to write 1)

over alcohol)

 Common Names

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

O O O
CH3
H3C CH3 H3C H H

acetone
methyl ethyl ketone
formaldehyde

(name two alkyl groups)

The aceto- common name is consistent amongst many compounds

O O O

H3C H3C OH H3C 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

O O
R
C O
R R R R 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 H
O

H H H H
 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

H
O
H
Due to hydrogen bonding capability
O
of carbonyl oxygen

R R
 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

O R Li O OH
R Li
H3C OH H3 C O H3 C OH
R

First equivalent of organolithium abstracts hydrogen

O
Second equivalent reacts at carbonyl
H3C R
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

N
R-MgBr
H3C C N H3 C R

Reaction stops at imine anion stage

N H3O NH O
H3 O
H3C R H3C R H3C R

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

Under same conditions, the imine is hydrolyzed to the ketone

 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)

Al H Al(i-Bu)2
N O
H3 C C N H3 O
H3C H H3C H

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

O O
DIBAL
H3C OR H3 C H

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

O OH
LAH
H3C OR H3 C H
H
 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 BuLi S S
H H H

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

1) BuLi
S S RX S S 2) RX S S

H R H R R

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

H+, HgCl2
H2 O O
S S
R H
R 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

H H
MgBr O O
H H
 Protonation of Carbonyl Creates more Electrophilic Carbon

Carbonyl carbon is much more electrophilic upon protonation due to resonance

H H
O O O

H H H H H H

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 OMgBr OH
H+

O OLi OH
LAH H+
H H
 Also have seen reactions at protonated carbonyls

H H OH
O O O CH3OH
H+ H3 C OH
H3 C OH H3C OH H3 C OH OCH3
H

OH OH H
O
H3C OH H3 C OH2
OCH3 OCH3 H3 C OCH3
H

(Fischer esterification)

Methanol, or other weak nucleophiles,

do not react readily with carbonyls without protonation

 Reactivity of Ketones Versus Aldehydes

O O O

H3 C CH3 H3 C H H 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

H
O O HO OH
H+ H2O
H3 C CH3 H3C CH3 H3C CH3

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

O
(Ph)3P=CH2
H3 C CH3 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

Ph
P Br (Ph)3P Br
Ph Ph

Phosphonium salt

The methylene adjacent to phosphorous in phosphonium salt is acidic

BuLi
(Ph)3P (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

O (Ph)3P O
(Ph)3P
H3C CH3 CH
H3 C CH3 3

betaine

The betaine structure will form 4-membered ring

between positive phosporous and negative oxygen

(Ph)3P O (Ph)3P O

CH CH3
H3C CH3 3 H3 C CH3
oxyphosphetane

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 CH3

CH3 (Ph)3P O
H3 C CH3 H3 C CH3

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

O O OH
CN H+
H3 C CH3 H3C CH3 CH3
CN H3 C
CN

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

H+
CN HCN

toxic

 Hydrolysis of Nitrile

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

OH H+, H2O OH

H3C CH3 H3 C CH3

CN 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

OH O
H H
CN HCN

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

 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

H2N (opsin)

H O H N
(opsin)
11-cis-retinal

rhodopsin

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

(opsin)
N
h!

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

OH
O N
NH2OH oximes

H3 C CH3 H3 C CH3
H+

NH2
O N
NH2NH2
hydrazones

H3 C CH3 H3 C CH3
H+

NHPh
O N
NH2NHPh
Phenyl hydrazones

H3 C CH3 H3 C CH3
H+
 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)

O R2NH HO NR2 NR2

-H2O
H3 C CH3 H+ H3C CH3 H3 C CH2

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

O ROH RO OR
H3 C CH3 H+ H3C CH3

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

 Cyclic Acetals and Ketals

When both alcohols to form an acetal are intramolecular (on same molecule)

then a cyclic acetal is formed

O HO
OH O O
H3 C H H+ H3C H

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

O HS SH
S S
H H H+ H H

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

CHO
H OH
OH OH
HO H
OHC OH H OH
OH OH H OH
CH2OH
glucose
Fischer projection

While the open chain forms are often drawn for sugar molecules,

in solution they often adopt a closed ring form

H OH
H OH
hemiacetal
H OH
H O
H O HO H O
HO HO O
HO H OH HO
OH OH
H OH H H OH
H
H H H H
acetal

The closed ring forms have acetal or hemiacetal ring junctions

 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 O
Mg
Br BrMg
H H

OH Cannot form this compound,

will react intramolecularly

 Using acetal, however, the Grignard can be formed

O HO
OH O O Mg O O
Br Br BrMg
H H+ H H

With no carbonyl present, the Grignard reagent is stable

O
O O OH OH O
H3 C CH3 O O
BrMg H+
H H H

Reaction is not possible without acetal protecting group

 Baeyer-Villiger Reaction

Allows conversion of ketone to ester

O O
RCO3H
R
R R R O

Mechanism of oxygen insertion?

H
O O O O
O O
R R H O R R R O R

H
O O
HO R
R Weak oxygen-oxygen
R O O R O R
R O
single bond

O

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

 Migration with Unsymmetrical Carbonyls

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

O RCO3H O O
R2 or R1
R1 R2 R1 O R2 O

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 O More substituted substituent

RCO3H
O migrates preferentially

O
O
O Cyclic ester

RCO3H
(lactone)

O O Another way to oxidize

RCO3H
H HO 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