Nucleophilic substitution

• Order of carbonyl group leaving group ability:

  1. acid chloride
  2. acid anhydride
  3. ketone
  4. amine
• what are the 2 intrinsic reactivities of the carbonyl group?

  inductive effect

  resonance
• Resonance effect:

  Polarity induced by a molecule by the interaction of a lone pair of e- with a pi bond interaction of 2 pi bonds in nearby atoms
• order of strength of lone pair donation:

  1. N
  2. O
  3. Cl
• why is an acid chloride the most acidic?

  due to the inductive effect of chlorine
• why is there no resonance of an acid chloride?

  chlorine pair is too large to overlap
• why is anhydrides acidic?

  Inductive effect and conjuagtion
• why are esters acidic?


  strong resonance

  inductive effective
• why are amide acidic?

  • conjugation effect (lone pair on nitrogen is very strong as the energy and size of nitrogen lone pair in amide matches the energy size of the C=O pi* orbital better than the oxygen lone pair an ester does)
  • inductive effect (nitrogen is less electronegative than oxygen)
• Why do carboxylic acids not undergo nucleophilic attack?

  because they are acidic and will protonate nucleophile instead
• The better the pKa of the HY the better the nucleophile
• what must be consider for formation?


  reactivity of carbonyl group

  Strength of incoming nucleophile

  Leaving group ability
• what are some hard nucleophiles?

  hydride

  organometallic
• how to reduce an amide?

  LiALH4
• how to reduce a carboxylic acid?

  Lithium aluminum hydride
• Steps in selective reduction?

  1. mask functional group (protection)
  2. reduce other functional group
  3. reveal original functional group (deprotection)
• Order of reactivity of carbonyl groups?

  Acyl chlorides > acid anhydrides > aldehydes > ketones > esters > alcohols > amides
• conditions of hydrolysis of acid chloride:

  Fast at 20 degrees C
• conditions of hydrolysis of acid anhydride:

  slow at 20 degress
• conditions of hydrolysis of ester

  only on heating with acid or base catalyst
• conditions of hydrolysis of amide:

  prolonged heating with an acid or base catalyst
• what occurs to the carbonyls as they get less reactivity?

  • leaving group ability decrease
  • reactivity of carbonyl group decrease
  • Strength of the incoming nucleophiles
• carboxylic acid + base = deprotonation
• How is transesterifcation carried out?

  under acid catalysis
• esterification of amide conditions
• esterification of amide conditions:

  Alcohol and strong acid heat
• how to make an amide from a carboxylic acid?

  first convert to an acid chloride

  Then under go nucleophilic substitution
• What can be used to convert carboxylic acid to acid chloride?

  thionyl chloride (SOCl2)

  Phosphorus pentachloride