Carboxylic Acid Derivatives

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Amides, Esters, and Anhydrides

  • These derivatives are formed by a condensation reaction with carboxylic acid in which two molecules combine into one while a small molecule is lost (water in this case).


  • General formula of RCONR2
  • Named by replacing –oic acid with –amide
    • Alkyl substituents on the nitrogen atom are listed as prefixes and their location is specified by the letter N-
  • Synthesized by reaction of other carboxylic acid derivatives with either ammonia or an amine. Loss of hydrogen is required for this reaction to take place.
    • Only primary and secondary amines will undergo this reaction
  • Lactams: Cyclic amides and are named according to the carbon atom that is bonded to the nitrogen.
  • May or may not participate in hydrogen bonding.

  • Dehydration synthesis products of other carboxylic acid derivatives and alcohols.
  • Esterification Group: substituent that is bonded to the oxygen
  • Named by placing the esterifying group as a prefix and the –oate suffix replaces -oic acid
  • Fischer Esterification: mixing carboxylic acids and alcohols under acidic conditions so that they condense into esters.
  • Lactones: Cyclic esters and named similarly to lactones, but with name of precursor acid molecule included.
  • Lack hydrogen bonding, so boiling points are lower than related carboxylic acids.
  • Triacylglycerol: storage forms of fats in the body
    • Esters of long chain carboxylic acids and glycerol
    • Can undergo Saponification to produce soap salts.

  • Also called Acid anhydrides and are the condensation dimers of carboxylic acids which have the general formula RC(O)OC(O)R
  • Symmetrical anhydrides are named by substituting anhydride for acid in a carboxylic acid.
  • If asymmetrical, name two chains alphabetically and then followed by anhydride.
  • Synthesized by the condensation reaction between two carboxylic acids and one molecule of water is lost in condensation.
    • Hydroxyl group of one acts as a nucleophile and attach the carbonyl group on the other.
  • Cyclic anhydrides can be formed by heating the carboxylic acids
    • Reaction is driven forward by the increased stability of the newly formed rings
    • Only anhydrides with five or six membered rings are made easily.
  • Have higher boiling points than corresponding carboxylic acids since they are much heavier.

Reactivity Principles

Relative Reactivity of Derivatives
  • Reactivity of the carbonyl is determined by the substituents
    • Anhydrides are most reactive since their resonance stability and three electron withdrawing oxygen atoms are the most electrophilic and thus reactive.
    • Esters are second most reactive since they contain one less oxygen atom.
    • Amides have an electron donating amine group and are thus the least reactive

Steric Effects
  • Steric hindrance is when a reaction does not proceed due to the size of its substituents.
  • Can be seen as a detrimental effect since reactivity is decreased
  • Also can be positive since it can help force a certain type of reaction or help in the generation of protecting groups.
  • In general, the size and substitution of the leaving group affects the ability of the nucleophile to access the carbonyl carbon

Electronic Effects
  • Induction: the distribution of charge across sigma bonds
    • Differing electronegativity’s between two molecules of a sigma bond cause one end to be positive and the other to be slightly negative.
    • Effect is relatively weak and gets increasingly weaker as you move farther away from the more electronegative atom.
    • Increased dipolarity increases the less electronegative (positively charged) atom to be more susceptible to nucleophilic attack
      • Anhydrides have two electron withdrawing groups while the smaller amides have nitrogen which is less electronegative than oxygen which means that the dipole is weaker.
  • Conjugation: presence of alternating single and multiple bonds
    • Implies that all bonds are either sp2 or sp-hybridized, which subsequently implies that there are unhybridized p-orbitals.
    • If p-orbitals align, resonance can help in delocalizing the pi bond electrons
    • This would form clouds of electron density above and below the plane of the molecule
    • Carbonyl-containg compounds can have conjugation established with carbonyl group itself (i.e. – enones)
    • Makes for very stable structures since the compounds have multiple resonance structures
      • Allows for the stability of a positive charge once a nucleophile has bonded, which makes them more susceptible to nucleophilic attack

Stain in Cyclic Derivatives
  • Certain lactams and lactones are more reactive to hydrolysis because they contain more strain
  • Increased strain reduces resonance which makes hydrolysis more likely.
  • Used in a lot of antibiotics. (use beta-lactams)

Nucleophilic Acyl Substitution

Anhydride Cleavage
  • Nucleophilic acyl substitution involves nucleophilic attack of the carbonyl carbon with the displacement of the leaving group.
  • All derivatives can participate in these reactions at different rates
    • Anhydrides are the most reactive, followed by esters and then amides.
  • Cleavage Reaction: splits a molecule into two
    • Amides can be formed using a cleavage reaction of any carboxylic acid or derivative and ammonia
      • Ammonia acts as nucleophile and carbonyl carbons act as electrophile. Carboxylic acid is the leaving group.
  • Alcohols can also act as nucleophiles towards anhydrides which would result in the formation of esters and carboxylic acids.
  • Anhydrides can be reverted to carboxylic acid by exposing them to water. Anhydride should be symmetric in order to avoid forming a mixture of products.
  • Alcohols act as nucleophiles and displace the esterifying group on an ester. One ester is transformed into another
Hydrolysis of Amides
  • Amides can by hydrolyzed under highly acidic conditions via nucleophilic substitution
  • Acidic conditions allow oxygen to become deprotonated which makes it more susceptible to nucleophilic attack.
  • Results in a carboxylic acid and ammonia.