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Chemistry 2131:
Organic Chemistry for the Life Sciences (3)

Nucleophilic Acyl Substitution Reactions

• the nucleophilic acyl substitution reactions have a lot in common with nucleophilic addition reactions to carbonyls. Both reaction types rely on the electron deficiency of the carbonyl carbon, making it an electrophile, and susceptible to attack by a nucleophile.
• the major difference between the two reaction types is that the carbonyl group is regenerated in nucleophilic acyl substitution with the loss of a leaving group.
• the best way to see this isto compare the two reaction types. In the first step of each (regardless of the catalysis, this is the first major step), a nucleophile attacks the carbonyl carbon pushing electrons up onto the carbonyl oxygen generating a tetrahedral carbonyladdition intermediate.
• in nucleophilic addition, the alkoxide generated acquires a proton to become an alcohol
• in the acyl substitution reaction, the electrons come back down to form a pi bond, regenerating the carbonyl group and pushing off a leaving group
• obviously, the big difference between aldehydes and ketones and the carboxylic acid derivatives is the presence of a good leaving group.
• the best leaving groups are the weaker bases. Thus, the stronger the base, the worse the leaving group.
• aldehydes and ketones have only carbanions or hydrides as leaving groups. These are very poor leaving groups.
• if we look at the common derivatives of carboxylic acids, we see that the halide ions are the weakest bases and thus the best leaving groups, then the carboxylates, then the alkoxides then the amide ion.
• the acid halides and the acid anhydrides are so reactive that they are not stable in water (the reason will be seen in a minute
• this can lead us to an order of reactivity. The acid halides are most reactive, then the anhydrides, then the esters, then the amides.

2. Hydrolysis:

• let's start by loooking at the simplest reaction: hydrolysis. This is the splitting of the molecule by water
• the reaction of water with acid chlorides and acid anhydrides doesn't requires catalysis.
• let's look at the example of ethanoyl chloride reacting with water. A lone pair on water attacks the carbonyl carbon, pushing the pair of electrons from the pi bond up onto the oxygen atom to give a tetrahedral carbonyl addition intermediate
• the oxonium can be deprotonated by water
• in the final step, a pair of electrons on the carbonyl oxygen come down to reform the pi bond pushing the halide group off.
• a very similar reaction occurs with acid anhydrides, except that in the last step a carboxylate leaves
• esters are more stable than acid halides and anhydrides, and generally need acid or base catalysis for hydrolysis to proceed
• let's first look at the acid catalysed hydrolysis of an ester. This is the reverse of Fischer esterification
• the first step is the protonation of the carbonyl oxygen to make the carbonyl carbon more electron deficient. It cn then be attacked by water to give and oxonium ion. This oxonium can be deprotonated by water generating a tetrahedral carbonyl addition intermediate
• the oxygen of the ester oxygen (the one that will become the alcohol) becomes protonated from the hydronium, setting it up as a good leaving group
• water can remove a proton from oneof the hydroxyl groups, the electrons come down to form a pi bond pushing off the alcohol group.
• in the base catalyzed reaction, a hydroxide ion attacks the carbonyl carbon, leading to the formation of a TCAI. The electrons come back down to form a pi bond pushing off the alkoxide (deprotonated alcohol). There is a swap of the proton from the carboxylic acid to the alkoxide to give the carboxylate and the alcohol.
• there are two important differences between the acid and base catalysed reactions.
  1. In the acid-catalysed reaction the acid is required catalytically, whereas in the base catalysed reaction the hydroxide is required in equimolar amounts since it is a reactant
  2. Acid catalysed hydrolysis of the ester is reversible, base catalysed is not.

• the base catalysed hydrolysis of an ester was used to generate soap from lard
• amides can undergo acid catalysed hydrolysis as well.
• protonation of the carbonyl oxygen can be resonance stabilized by electrons on the nitrogen atom
• attack by water leads to an oxonium, there is proton swap to the nitrogen to give a TCAI
• a pair of electrons come back down to form a carbonyl and NH₃ leaves. There is a final swap of a proton to give the acid and the ammonium ion.
• base catalysed hydrolysis of amides also occurs. The hydroxide ion attacks the carbonyl carbon pushing the pi electrons up onto oxygen to generate a TCAI.
• the electrons come back down to reform the carbonyl pushing off the NH₂, which picks up a proton from water as it leaves.
• finally there is a proton swap between the hydroxide and the carboxylic acid.

3. Reactions with Alcohols:

• acid halides and acid anhydrides react spontaneously with alcohols to generate esters.
• If the ester is acid sensitive, a base such as a pyridine or a tertiary amine is including to remove the HCl produced
• acid anhydrides react similarly. This is the reaction that you did in the lab when making aspirin from salicyclic acid
• alcohols can also react with esters in a transesterification reaction.
• for this reaction you get a mix of products
• amides don't react with alcohols

4. Reactions with Ammonia and Amines:

• acid halides, acid anhydrides and esters react with ammonia and amines to give amides
• for the reactions with acid halides and acid anhydrides, 2 moles of amine or ammonia are required. One to react with the carbonyl, one to neutralize the chloride or carboxylate formed.
• esters react as well but more slowly