Acid-Base Properties

The basicity of an amiDe (with "d") group can be understood from the acidity of its protonated form. The higher the acidity of the latter, the lower the basicity of the amide.

Basicity of the amide group

The higher the participation of the third resonance form, the more stable the protonated form of a carbonyl derivative and therefore the less acidic or the more basic.

In other words, the larger the L group's capability of releasing electrons, the higher the basicity of the carbonyl group.

Protonation of an acid derivative R–CO–L at the carbonyl oxygen and resonance forms of the cation, with the positive charge on the oxygen, the carbon and the L group

Resonance form of the protonated derivative with the positive charge on the L group

Can you explain the following pK_a values just applying the previous rationale?

Acetaldehyde protonated at the carbonyl oxygen — Aldehyde

pK_a = -8.0

The third resonance form is simply not possible when L = H. Therefore the protonated form is very unstable and aldehydes are the most acidic (the least basic) in the series.

Acetone protonated at the carbonyl oxygen — Ketone

pK_a = -7.2

When L = CH₃ stabilization can only be achieved by methyl hyperconjugation. However, this weak stabilizing mechanism explains why ketones are slightly less acidic (more basic) than aldehydes.

Click here to recall hyperconjugation concerning the relative stability of carbocations.

Ethyl acetate protonated at the carbonyl oxygen — Ester

pK_a = -6.5

The alkoxy group can stabilize the positive charge by mesomeric (resonance) effect. That explains why esters are even less acidic (more basic) than ketones.

Acetic acid protonated at the carbonyl oxygen — Acid

pK_a = -6.0

The first and third resonance forms are equivalent for a protonated carboxylic acid. That makes up for an additional stabilization which leads to the apparent paradox that a protonated acid be the least acidic (the most basic) of the previously studied compounds.

Acetamide protonated at the carbonyl oxygen — Amide

pK_a = -0.4

A protonated amide possesses the least acidic group of them all (CONH⁺), proof that the blinking resonance form has in this case an overwhelming contribution.

The electron lone pair on NH₂ is very delocalized to the carbonyl group in amides.

Actually, the C=O group of an amide is more basic than the NH₂.

That makes a huge difference in basicity between amiDes ("with d") and amiNes ("with N").

Acidity of α-hydrogens

In some amides, as for example acetamide or its N-methyl derivative, one can find two kinds of α hydrogens: those bonded to nitrogen and those bonded to carbon.

Acid–base equilibria of acetamide, N-methylacetamide and N,N-dimethylacetamide: pKa of the N-protonated forms (−0.47, −0.44 and −0.41), resonance forms of the amide and pKa of the deprotonation of N–H or α C–H (16.6, 17 and 30) with the resulting anions

The hydrogens bonded to N are much more acidic than their C-bonded counterparts. This is another manifestation of the increased electronegativity of N as compared to C. This fact explains why acetamide and its N-methyl derivative display pK_a = 17 whereas pK_a = 30 for N,N-dimethyl acetamide that can only be deprotonated at C.