Chapter 20: Nucleophilic Acyl Substitution

Anhydride Synthesis

Anhydride Synthesis

One carboxylic acid OH and the other carboxylic acid H leave as H₂O, then the remaining oxygen bonds between the two carbonyl carbons to form the anhydride link: C(=O)–O–C(=O).

Carboxylic Acid and Carboxylate Synthesis

must add Pyridine. (It "mops up" the HCl)

Carboxylic Acid and Carboxylate Synthesis

ester → carboxylic acid

Carboxylic Acid and Carboxylate Synthesis

Carboxylic Acid and Carboxylate Synthesis

OH⁻ attacks the ester carbonyl, OCH₃ leaves, and the carboxylic acid product gets deprotonated to the carboxylate (COO⁻), while OCH₃ becomes methanol.

Carboxylic Acid and Carboxylate Synthesis

protonate N → make it a better leaving group → C=O reforms → N leaves → amine becomes ammonium
N needs a positive charge first, then it can leave neutral.

• lone pair on the hydroxide oxygen attacks the electrophilic carbonyl carbon.

  Charge

• lone pair from the negative oxygen reforms the C=O double bond, this "kicks off" the −NR2

• The nitrogen leaving group carries a negative charge (-1). The carbonyl part is now a neutral carboxylic acid

• The lone pair on the negative nitrogen attacks the acidic proton of the carboxylic acid

Carboxylic Acid and Carboxylate Synthesis

must add Pyridine. (It "mops up" the HCl)

• lone pair on the methanol oxygen attacks the electrophilic carbonyl carbon

• methanol oxygen, now bonded to the carbon, carries a positive charge (+1) , zwitterionic tetrahedral intermediate

• lone pair on the pyridine nitrogen attacks the proton on the positively charged methanol group

• lone pair from the negative oxygen reforms the C=O double bond.

• "kicks off" the chloride ion
  
  
  Reactions that produce esters

Reactions that produce esters

Reactions that produce esters

Reactions that produce amides

must use 2 equivalents of the amine. (The first equivalent attacks; the second equivalent neutralizes the HCl

Reactions that produce amides

Reactions that produce amides
Heat forces dehydration/loss of water to form the amide.

Reactions that produce amides
mild conditions

• DCC nitrogen picks up the acidic proton from the acid. Then, the resulting negative carboxylate oxygen attacks the central carbon of the protonated DCC

• lone pair on the secondary amine nitrogen attacks the carbonyl carbon of the activated intermediate

• carbonyl oxygen moves its π electrons up to become negatively charged (–1). The attacking nitrogen now carries a positive charge (+1)

• proton is transferred from the positive nitrogen to the nitrogen atom of the DCC group. A lone pair from the negative oxygen reforms the C=O bond

• kicks off dicyclohexylurea (DCU) as the leaving group

Reactions that produce amides

reagent Product Pattern

The reagent you choose is simply the version of the group you want to see in your product.

• To get a Carboxylic Acid: Use water (H2​O or H3​O+).

• To get an Ester: Use an alcohol (HOCH3​,HOEt, etc.).

• To get an Amide: Use ammonia (NH3​) or an amine (RNH2​,R2​NH)

starting with a Carboxylic Acid → Acid Chloride

To go "Uphill" to an Acid Chloride: Use SOCl2​. This is the only way to turn a less reactive acid into a more reactive chloride

When do I use pyridine in acyl chloride reactions?

Acid chloride reactions make HCl, and pyridine removes it:What pyridine does:

• removes H from the attacked nucleophile

• neutralizes HCl

• prevents acid from messing up the reaction

Common with:

• acid chloride + alcohol → ester

• acid chloride + amine → amide

• acid chloride + H2O → carboxylic acid