Download Relative Reactivity of Aldehydes and Ketones: Generally

Relative Reactivity of Aldehydes and Ketones:
Generally speaking, aldehydes and ketones have a similar level of reactivity although
aldehydes are slightly more reactive. Why?
a. Sterics:
O
R
O
H
aldehyde
R
R
ketone
Two alkyl groups versus only one alkyl group: Less sterics = less crowded transition
state = lower activation barrier for aldehydes = FASTER reaction!
b. Electronics:
O
R
O
H
aldehyde
R
R
ketone
Aldehydes are stronger electrophiles. They have a larger partial positive charge. Why?
Alkyl groups are electron-donating (see Ch. 7 in 8th edition about electron-donating
effects of alkyl groups with alkenes).
Ketones will be inductively stabilized by the presence of two electron-donating alkyl
groups, resulting in a smaller δ+ charge on the carbonyl carbon. Aldehydes, with only one
alkyl group, will be less stabilized and therefore have a larger δ+ charge. The larger
the partial charge = the more reactive Electrophile.
Preparation reactions for Aldehydes:
• Oxidation of 1º alcohols using PCC or Dess-Martin periodinane
• Ozonolysis of an alkene with hydrogen atoms on the double bond
Preparation reactions for Ketones:
• Oxidation of 2º alcohols using any of the five oxidizing agents we reviewed
earlier.
• Ozonolysis of an alkene with carbon groups attached.
Reactions of Aldehydes and Ketones:
1. Reductions of aldehydes and ketones- OLD
• Reagents: NaBH4 or LiAlH4
The hydride, H-, is a strong nucleophile and this reaction process is “irreversible”.
Strong nucleophiles are typically poor leaving groups (cannot stabilize an anion), thus
once the nucleophile has completed its bond formation, it cannot REVERSE and break
that bond to come back off of the molecule.
“Reversible “would mean that the following could occur:
O
O
H
+ H:-
And the products of this reverse reaction are much less stable (due to the high energy
of the hydride) so this won’t happen!
Ex:
O
NaBH4
H
2. Addition of Carbon Nucleophiles –
• Reagent: Grignard Reagents – RMgX
The Grignard is another strong nucleophile that is also not a good leaving group. Once it
attaches to the carbonyl carbon, it cannot reverse and dissociate form the molecule
(another “irreversible reaction” due to instability of Grignard reagent).
Ex:
O
MgBr
3. Formation of Cyanohydrins – Addition of “HCN”
HO
CN
Hydrogen cyanide, HCN, is a toxic gas… Would YOU want to use it?
No… So – instead use:
O
1. NaCN
HO CN
2. H2SO4, H2O
The cyanide anion, -CN, is another strong nucleophile that cannot easily stabilize an
anion and is another relatively bad leaving group (a third “irreversible” reaction).
Ex.
O
1. NaCN
H
2. H2SO4, H2O
In Chapters 20/21, we will see how nitriles can be hydrolyzed to carboxylic acids or
reduced to form amines (amino acid predecessor) as well as converted into aldehydes
and ketones.
4. Hydration: Addition of H, OH
•
•
Formations of hydrates can occur under either acidic or basic conditions
This reaction is a reversible reaction due to the nucleophile (either H2O or –OH)
having an electronegative oxygen atom that can act as a “Leaving Group”.
The equilibrium reaction favors the starting material, with the carbonyl form. Based on
this knowledge, which is more stable – the carbonyl or hydrate?
The starting material (carbonyl form) must be more stable than the product.
Why is that?
O
HO OH
hydrate
Simple sterics: Consider the hybridization of the carbon atoms involved. Sp2 versus sp3
– less steric interactions result in equilibrium moving backwards to carbonyl form AND
with no driving force to make this reaction go forward, the reaction reverses 99.9% of
the time. There are a couple of exceptions though.
Consider formaldehyde, for instance:
O
H
H2O, H+
H
HO
OH
H
H
Formaldehyde has a carbonyl carbon that is so electron-poor that it is “starving” for
electron density and forms a hydrate easily, welcoming in a second oxygen atom with
electron density. But this is an exception, as is the hydration of trichloroacetaldehyde:
O
Cl3C
H
H3O+
HO
Cl3C
OH
H
Again, this particular aldehyde has an extremely large partial positive charge and the
addition of the electron density from another oxygen atom stabilizes the molecule.
Hydrates form in both acidic and basic aqueous solutions but they won’t be isolated in
either situation since the carbonyl forms are more stable (reaction always reverses).
• Basic conditions use hydroxide, -OH, as a strong nucleophile, similar to how a
Grignard reagent attacks.
O
NaOH, H2O
HO OH
Mechanism: Base-catalyzed hydration
Forwards: Simple Nucleophilic attack…
O
O
OH
H
OH
O
H
HO
OH
Reverse:
HO
•
O
H
HO
OH
O
O
Acidic conditions use neutral water, H2O, as the nucleophile… Neutral carbonyl and
neutral water aren’t so very attracted to each other… The oxygen atom in water is
electronegative and less willing to share its electron density to form a bond to the
carbonyl. We must tweak the system to make them more appealing to each other…
add an acid catalyst to make the carbonyl a stronger electrophile (more electron
poor, therefore more attractive to the neutral water molecule).
O
H+, H2O
HO OH
While this reaction does not typically form an actual hydrate product that is isolated, it
doesn’t mean that the hydrate doesn’t form (see next reaction). It's also a good
reaction to use to demonstrate the mechanistic process of acid-catalyzed nucleophilic
additions.
Acid-catalyzed hydration - Forward Direction:
O
H2O
H
HO
OH
O
H
O
H
O
H
H
O
H
H
O
H
O H
O
H
HO
H
OH
The purpose of the acid catalyst is to create a stronger electrophile – a full positive
charge instead of a partial positive charge.
Why is it necessary? The nucleophile is a weak nucleophile and unreactive with a ketone
or aldehyde on its own.
Acid-catalyzed hydration - Reverse Direction:
HO
OH
O
H2O
H
HO
OH
H
H
H
O
O
O H
H
O
H
H
O
H
O
Mechanism? (Problem 19.8 in 8th Edition) O* = 18O isotope
O
H+, H2O*
HO O*H
H+, H2O
O*
5. Oxidations of Aldehydes to Carboxylic Acids
O
O
H
OH
Recall: Primary alcohols oxidize via aldehydes to carboxylic acids when using KMnO4 or
Na2Cr2O7 or CrO3. All of these reactions occur under aqueous acid conditions.
OH
R
H
H
O
R
O
H
R
OH
Under these aqueous conditions, aldehydes and ketones form hydrates. If an aldehyde
converts to a hydrate while the appropriate oxidizing agent is also present, the hydrate
of the aldehyde can then be further oxidized to the carboxylic acid.
O
HO OH
H
H
O
OH
Old Reagents:
• KMnO4, H2O or H3O+
• Na2Cr2O7, H3O+
• CrO3, H2SO4, H2O
New Reagent:
• Tollen’s Reagent: Ag2O or AgNO3, NH4OH, H2O
o Mild oxidant
o Selective for aldehydes ONLY
Tollen’s Reaction is a Qualitative test for aldehyde
Positive for aldehyde – formation of silver metal