Carboxylic Acids and Derivatives

Properties of Carboxylic Acid Derivatives

Reactivity depends on the ability of the derivative to act as a leaving group. Therefore, acid halides are the fastest-reacting derivatives, followed closely by anhydrides. Then there is a significant drop in reactivity for esters, amides, and nitriles. In 1H NMR the hydrogen atoms on the alpha carbon of a carboxylic acid derivative have a peak between 2 and 3 ppm.
Reactivity of carboxylic acid derivatives is dictated by structure. The reactivity order, from most reactive to least reactive, is:
acid halide>anhydride>ester>amide\text{acid halide}>\text{anhydride}>\text{ester}>\text{amide}
Because of their relative stability (or unreactivity), amide bonds are largely responsible for the structure of proteins.

Overall reactivity of carboxylic acid derivatives relates to the degree with which the carbonyl group is stabilized by electron donation from the atom that is attached to it. The greater the strength of the electron-donating power of the substituent group, the slower the rate of nucleophilic acyl substitution.

An acid halide is a compound characterized by a halide atom bonded to a carbonyl group. It has a general RC(=O)X{\rm{RC({=}O)X}} stoichiometry. The halide in an acid halide has unshared electron pairs but is an ineffective electron donor because the halide and carbon orbitals overlap poorly. This arrangement does not permit delocalization of an unshared electron pair from the halide, and the carbonyl group is not stabilized. Furthermore, the halide is electronegative, which makes the carbonyl group even more electrophilic and reactive toward nucleophiles. An electrophile is a molecule or ion that accepts electrons to form a covalent bond. A nucleophile is a molecule or ion rich in electrons that donates a pair of electrons to form a covalent bond.

Acid Halide Reactivity

Acid halides are very reactive because an unshared electron pair is not easily delocalized and the halogen is electronegative.
Acid anhydrides are less reactive and more stable than acid halides because the oxygen is a more effective electron donor to the sp2-hybridized carbon. However, stability of acid anhydrides is limited because both carbonyl groups are vying for the same electron pair, reducing the extent to which either individual carbonyl stabilizes.

Acid Anhydride Stability

Acid anhydrides are less reactive than acid halides, but the stability of both of the carbonyls is limited because they share the same electron pair.
Esters, like acid anhydrides, are stabilized by electron donation by oxygen. Unlike acid anhydrides, esters have only one carbonyl, and the carbonyl group maintains the stabilizing benefit of the electron pair. Esters are, therefore, more stable and less reactive than acid anhydrides.

Ester Stability

Esters are less reactive than acid anhydrides because they have only one carbonyl group receiving an electron pair from oxygen.
Amides are the least reactive of the carboxylic acid derivatives. The mechanism is the same as in an ester, but the nitrogen is less electronegative than oxygen, making the carbonyl group comparatively more stable.

Amide Stability

Amides are the least reactive carboxylic acid derivatives because of the effective resonance stabilization of the carbonyl.
Carboxylic acid derivatives are used in commercial industry and pharmaceuticals. Aspirin, for example, is the ester of salicylic acid and is made from acetic acid. Palmitic acid is used in soaps, cosmetics, candles, and protective coatings. Lucite is formed from methyl methacrylic ester in a polymerized form.

Proton NMR spectroscopy of the alpha carbon for all carboxylic acid derivatives is the same, with hydrogens attached to the alpha carbon showing up between 2 and 3 ppm. The hydrogen of an amide can show up from 0 to 5 ppm, and the alpha carbon of the OR{-}{\rm{OR}} portion of an ester usually shows up at 3 to 4 ppm. Their infrared (IR) spectroscopy stretching frequencies can vary between 1550 cm–1 to 1750 cm–1.