Due to the reactive nature of both the carbonyl and hydroxyl group on the carboxylic acid, they are most useful with nucleophilic attacks, particularly with amines and esters, but anhydride formation and reduction of the functional groups within the carboxylic acids are possible.
Carboxylic acids belong to a class of organic compounds in which a carbon (C) atom is bonded to an oxygen (O) atom by a double bond and to a hydroxyl group (−OH) by a single bond. A fourth bond links the carbon atom to a hydrocarbon group (R). The carboxyl (COOH) group is named after the carbonyl group (C=O) and hydroxyl group.
Carboxyl Group Reactions
Due to the electron-poor carbon in the carboxylic acid, carboxylic acids can be functionalized via nucleophilic addition. In this case, the hydroxyl (-OH) in the carboxylic acid leaves and is replaced by the nucleophile (R) attacking the carbon, which can be represented by (R-C=O).
In certain circumstances, the oxygen in the hydroxyl can act as the nucleophile and attack the carbon on a different carboxylic acid,
Amides, Esters, and Anhydride Formation
The direct conversion of a carboxylic acid to an amide is difficult because amines are very basic and tend to convert carboxylic acids to their highly unreactive carboxylate ions. Therefore, DCC (Dicyclohexylcarbodiimide) is used to drive this reaction.
Esters are derived when a carboxylic acid reacts with an alcohol. Esters containing long alkyl chains (R) are main constituents of animal and vegetable fats and oils. Many esters containing small alkyl chains are fruity in smell, and are commonly used in fragrances.
The acid-catalyzed esterification of carboxylic acids with alcohols to give esters is termed Fischer esterification.
An acid anhydride is a compound that has two acyl groups (R-C=O) bonded to the same oxygen atom. Anhydrides are commonly formed when a carboxylic acid reacts with an acid chloride in the presence of a base.
Similar to the Fischer esterification, this reaction follows an addition-elimination mechanism in which the chloride anion (Cl–) is the leaving group. In the first step, the base abstracts a proton (H+) from the carboxylic acid to form the corresponding carboxylate anion (1). The carboxylate anion’s negatively charged oxygen attacks the considerably electrophilic acyl chloride’s carbonyl carbon. As a result, a tetrahedral intermediate (2) is formed. In the final step, chloride – a good leaving group – is eliminated from the tetrahedral intermediate to yield the acid anhydride.
- Acid chloride formation: carboxylic acid + HX
- Ester formation: carboxylic acid + ROH
- Amide formation: carboxylic acid + RNH2
- Anhydride formation: carboxylic acid + RCOOH
Carboxylic acids are easily reduced by strong reducing agents, such as lithium aluminum hydride (LiAlH4) and sodium borohydride (NaBH4). Most reductions of carboxylic acids lead to the formation of primary alcohols.
Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain.
The term “decarboxylation” usually means replacement of a carboxyl group (-COOH) with a hydrogen atom:
RCO2H → RH + CO2
Decarboxylation is usually exothermic, but the activation energy is unusually high, making the reaction difficult to carry out. The activation energy is lower when the β-carbon is a carbonyl because either the anion intermediate is resonance stabilized or the acid forms a more stable cyclic intermediate.
This reaction is a key reaction of the citric acid cycle.
Reactions at 2-position, substitution
When a carboxylic acid reacts with a diatomic halogen molecule, halogenation at the alpha carbon occurs. The alpha carbon is usually located in the 2-position for carboxylic acids. When a carboxylic is reacted with an electrophile, substitution occurs at the alpha carbon. The carboxylic acid is converted to an acyl halide which can tautomerize into its enol form through a manipulation of the alpha carbon. Next, a halogen or other electrophile gets attacked by this alpha carbon and the molecule reverts back to a carboxylic acid. Overall, the alpha hydrogen on the alpha carbon gets substituted for the halogen or other electrophile:
In general, carboxylic acids undergo a nucleophilic substitution reaction where the nucleophile (-OH) is substituted by another nucleophile (Nu). The carbonyl group (C=O) gets polarized (i.e. there is a charge separation), since oxygen is more electronegative than carbon and pulls the electron density towards itself. As a result, the carbon atom develops a partial positive charge (δ+) and the oxygen atom develops a partial negative charge (δ-). In some cases, in the vicinity of a strong electrophile, the partially negatively charged carbonyl oxygen (δ-) can act as a nucleophile and attack the electrophile:
Compounds in which the −OH group of the carboxylic acid is replaced by other functional groups are called carboxylic acid derivatives, the most important of which are acyl halides, acid anhydrides, esters, and amides:
- Carboxylic acid converted to Acyl Halide, which can enolize
- Acyl Halide tautomerizes to its enol form by abstraction of acidic alpha hydrogen
- Halogen (or some other E+) gets attacked by alpha position
- Revert back to carboxylic acid. The net effect is that the alpha H get substituted by an electrophile
MCAT Official Prep (AAMC)
Practice Exam 4 C/P Section Passage 8 Question 41
Practice Exam 4 C/P Section Passage 9 Question 50
Biology Question Pack, Vol. 1 Question 17
• Carboxylic acids can be highly reactive and can undergo nucleophilic addition.
• Esters, amides, and acid anhydrides can be derived from carboxylic acids.
• Amides are formed via the addition of a carboxylic acid and a primary amine using DCC as an activating agent.
• Esters are formed by the addition of carboxylic acid and an alcohol under the presence of a strong acid. The most common reaction for this is Fischer Esterification.
• In the presence of a base, acid anhydrides are formed by the addition of a carboxylic acid and an acid chloride.
• Carboxylic acids are easily reduced to alcohols by strong reducing agents like LiAlH4 and NaBH4.
• Decarboxylation is the removal of carbon dioxide (CO2) from a carboxylic acid group. In the case of a carboxylic acid compound, such as (R-COOH), decarboxylation would produce (-R-H) and (O=C=O).
• When a carboxylic acid reacts with a diatomic halogen molecule, halogenation at the alpha carbon occurs. The alpha carbon is usually located in the 2-position for carboxylic acids
• In general, carboxylic acids undergo a nucleophilic substitution reaction where the nucleophile (-OH) is substituted by another nucleophile (Nu).
Carboxylic acids: An organic acid containing a carboxyl group.
Nucleophilic addition: An addition reaction where a chemical compound with an electron-deficient or electrophilic double or triple bond, a π bond, reacts with electron-rich reactant, termed a nucleophile, with disappearance of the double bond and creation of two new single, or σ, bonds.
Amide: An organic compound containing the group —C(O)NH2, related to ammonia by replacing a hydrogen atom by an acyl group.
Ester: An organic compound made by replacing the hydrogen of an acid by an alkyl or other organic group.
Fischer esterification: The esterification of a Carboxylic acid by heating it with an alcohol in the presence of a strong acid as the catalyst.
Acid anhydride: A nonmetal oxide which reacts with water to form an acidic solution.
Addition-elimination mechanism: An addition-elimination reaction is a two-stage reaction process of an addition reaction followed by an elimination reaction.
Primary alcohols: An alcohol in which the hydroxy group is bonded to a primary carbon atom.
Decarboxylation: A chemical reaction that removes a carboxyl group and releases carbon dioxide.
Exothermic: Noting or pertaining to a chemical change that is accompanied by a liberation of heat
β-carbon: The carbon atom one removed from an atom, group, functional group, or other moiety of interest.
Resonance stabilized: Because resonance allows for delocalization, in which the overall energy of a molecule is lowered since its electrons occupy a greater volume, molecules that experience resonance are more stable than those that do not. These molecules are termed resonance stabilized.
Citric acid cycle: A series of chemical reactions used by all aerobic organisms to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins, into adenosine triphosphate (ATP) and carbon dioxide.
Halogenation: The replacement of a hydrogen atom by a halogen atom in a molecule.
Alpha carbon: Refers to the first carbon atom that attaches to a functional group, such as a carbonyl
Nucleophilic substitution reaction: A fundamental class of reactions in which a leaving group (nucleophile) is replaced by an electron rich compound (nucleophile).
Nucleophile: A molecule or substance that has a tendency to donate electrons or react at electron-poor sites such as protons.
Electrophile: An atom or molecule that accepts an electron pair to make a covalent bond.
Carboxylic acid derivatives: Compounds with the acyl group, RCO-, bonded to an electronegative atom or substituent, -Y, that can act as a leaving group in substitution reactions (nucleophilic acyl substitution).