Carbonyl Compounds
We have already seen a number of carbonyl compounds
O
R
O
O
R
R
H
Ketone
two R groups
R
O
NH2
Amide
one R, one N
Aldehyde
one R, one H
R
O
R
OH
O
OR
R
Cl
Ester
one R, one OR
Acid
one R, one OH
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
2-butanone
4-hydroxy-2-butanone
(carbonyl precedence over alcohol)
O
H
propanal
(do not need to write 1)
Common Names
In addition to the IUPAC naming, many ketones and aldehydes have common names
O
H3C
O
CH3
acetone
O
CH3
H3C
methyl ethyl ketone
(name two alkyl groups)
H
H
formaldehyde
The aceto- common name is consistent amongst many compounds
O
H3C
aceto-
O
H3C
O
OH
acetic acid
H3C
O
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
R
C O
R
O
O
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
O
H
H
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
O
H
Due to hydrogen bonding capability of carbonyl oxygen
O
R
R
H
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
R
O
H3C
OH
O
Li
H3 C
R
O
OH
Li
H3 C
First equivalent of organolithium abstracts hydrogen
Second equivalent reacts at carbonyl
Upon protonation generate geminal diol
Geminal diols equilibrate with ketone
OH
R
O
H3C
R
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
H3C
NH
H3O
R
H3C
R
O
H3 O
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
H3 C C N
N
H3C
Al(i-Bu)2
O
H3 O
H
H3C
The imine anion is hydrolyzed to the carbonyl in work-up
-thus yielding an aldehyde
H
DIBAL will Also Reduce Ester Groups
An ester carbonyl is reduced to an aldehyde using DIBAL
O
H3C
O
DIBAL
OR
H3 C
H
If LAH was used, the ester is reduced to the alcohol instead
O
H3C
OH
LAH
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
H H
S
H
The carbon anion can then react with an alkyl halide in a normal SN2 reaction
S
S
H
RX
S
S
R H
1) BuLi
2) RX
S
S
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
S
S
R H
H+, HgCl2
H2 O
O
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
MgBr
H
O
O
H
H
Protonation of Carbonyl Creates more Electrophilic Carbon
Carbonyl carbon is much more electrophilic upon protonation due to resonance
O
H
H
H
O
H
H
H
O
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
O
CH3MgBr
LAH
OMgBr
OLi
H
H+
H+
OH
OH
H
Also have seen reactions at protonated carbonyls
O
O
H
H
O
CH3OH
H+
H3 C
H3C
OH
OH
H3 C
OH
H3C
OH
OH
OH
OH
OCH3
H
H3 C
H3 C
OH2
OCH3
O
H3 C
(Fischer esterification)
Methanol, or other weak nucleophiles, do not react readily with carbonyls without protonation
H
OCH3
OH
OCH3
H
Reactivity of Ketones Versus Aldehydes
O
H3 C
O
CH3
H3 C
O
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
O
H3 C
O
H+
CH3
H3C
H
H2O
CH3
HO OH
H3C
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
CH3
Wittig Reaction
Reaction converts a ketone or aldehyde into an alkene
O
H3 C
(Ph)3P=CH2
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
Ph
P
Ph
Br
(Ph)3P
Br
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
H3C
(Ph)3P
CH3
H3 C
O
CH
CH3 3
betaine
The betaine structure will form 4-membered ring
between positive phosporous and negative oxygen
(Ph)3P
H3C
O
CH
CH3 3
(Ph)3P O
H3 C
CH3
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
CH3
(Ph)3P O
H3 C
CH3
CH3
H3 C
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
O
H3 C
O
CH3
CN
H3C
OH
CH3
CN
H+
H3 C
CH3
CN
Caution – do not acidify cyanide solution, it will create hydrogen cyanide
CN
H+
HCN
toxic
Hydrolysis of Nitrile
An advantage with cyanohydrins is that the nitrile can be hydrolyzed to an acid
OH
H3C
CH3
CN
OH
H+, H2O
H3 C
CH3
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
H
CN
O
H
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
H
O
11-cis-retinal
N
(opsin)
rhodopsin
11-cis-retinal reacts with a 1˚ amine in the protein opsin in the rod cells of the eye
N
(opsin)
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
O
H3 C
NH2OH
CH3
O
H3 C
H+
CH3
H+
H3 C
H+
CH3
N
H3 C
H3 C
NH2
CH3
N
NH2NHPh
CH3
OH
oximes
NH2NH2
O
H3 C
N
hydrazones
NHPh
CH3
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)
O
H3 C
R2NH
CH3
H+
HO NR2
H3C
CH3
NR2
-H2O
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
H3 C
ROH
CH3
H+
RO OR
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
HO
O
H3 C
H
OH
H+
O
O
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
H
HS
H
SH
H+
S
H
S
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
H
HO
H
H
OH OH
OHC
OH
OH OH
glucose
CHO
OH
H
OH
OH
CH2OH
Fischer projection
While the open chain forms are often drawn for sugar molecules, in solution they often adopt a closed ring form
hemiacetal
H OH
H O
HO
HO
H
H
OH
H
H OH
H OH
H O
HO
HO
H
OH
H
OH
H
H O
O
HO
H
H
acetal
The closed ring forms have acetal or hemiacetal ring junctions OH
H
OH
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
Br
Mg
H
OH
O
BrMg
H
Cannot form this compound,
will react intramolecularly
Using acetal, however, the Grignard can be formed
HO
O
Br
H
OH
H+
O
Br
Mg
O
H
BrMg
O
O
H
With no carbonyl present, the Grignard reagent is stable
O
BrMg
O
O
H
OH
H3 C
CH3
O
O
H
OH
H+
Reaction is not possible without acetal protecting group
O
H
Baeyer-Villiger Reaction
Allows conversion of ketone to ester
O
O
RCO3H
R
R
R
O
R
Mechanism of oxygen insertion?
O
O
R
H
R
O
R
O
O
O
R
H
O
R
O
R
O
H
O
O
R
O
R
HO R
R
R
O
R
O
O
Weak oxygen-oxygen
single bond
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
R1
O
RCO3H
R2
R1
O
O
R2
or
R2
O
R1
There is a distinct preference for one group to migrate selectively
H
>
3˚ alkyl >
2˚ alkyl ~ phenyl >
1˚ alkyl >
In general, a hydrogen migrates first, but then a more substituted alkyl group migrates preferentially
methyl
Examples
O
RCO3H
O
More substituted substituent migrates preferentially
O
O
O
O
RCO3H
O
H
O
RCO3H
HO
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