Chem 336 - Spring 2004
	Organic Chemistry III
	Professor Carl C. Wamser

Carboxyl Derivatives

Carboxyl Derivatives

distinguished from aldehydes and ketones because one substituent is NOT C or H
(usually Cl, O, or N, but it could also be other F, Br, I, S, P, or many other possibilities)

Nomenclature of Carboxyl Derivatives

• acid halides
  alkanoyl halide (-oyl halide suffix)
  or use common acyl name from acid
  
• acid anhydrides
  alkanoic anhydride (-oic anhydride suffix)
  
• amides
  alkanamide (-amide suffix)
  substituents on N use prefix N- (instead of a number location)
  
• nitriles
  alkanenitrile (-nitrile suffix)
  
• carboxylate salts
  metal alkanoate (-oate suffix for anion)
  
• esters
  alkyl alkanoate (a two-part name)
  alkyl group is attached to the O

Nucleophilic Acyl Substitution

• the major reaction of carboxyl derivatives
• starts like nucleophilic addition, but becomes substitution when the leaving group departs

• the tetrahedral intermediate is like that in carbonyl additions
  
• the product is often another carboxyl derivative
  (depnding on what the nucleophile is)
  
• compared to other nucleophilic substitutions:
  SN2 - simultaneous bonding of nucleophile and loss of leaving group
  SN1 - first loss of leaving group, then bonding of nucleophile (cation intermediate)
  acyl - first bonding of nucleophile, then loss of leaving group (anion intermediate)

Reactivity in Acyl Nucleophilic Substitution

• better leaving groups increase reactivity
  acid halides > acid anhydrides > esters > amides
  
• the more reactive derivatives can be easily converted to the others
  you can make any of them with the acid chloride - a typical starting point for synthesis
  
• all the derivatives can be hydrolyzed to the carboxylic acid
  (water as the nucleophile - using acid or base catalysis)
  

Examples of Acyl Nucleophilic Substitution

Conversion of Acid Halides into Other Carboxyl Derivatives

• acid halides are the most reactive carboxyl derivative
• they can be converted to all the other derivatives

Conversion of Acid Anhydrides into Other Carboxyl Derivatives

• acid anhydrides are the second most reactive carboxyl derivative
• they can be converted to all the other derivatives except acid halides
  but acid chlorides are typically preferred

Synthesis of Esters

• from acid halides plus alcohols
• from acids plus alcohols (Fisher esterification)
• by SN2 reaction of a carboxylate as nucleophile

Hydrolysis of Esters

• water as the nucleophile with either acid or base catalysis
• acid-catalyzed hydrolysis is the exact reverse of Fisher esterification (same mechanism)
• base-catalyzed hydrolysis is often called saponification (soap-making)
  saponification is irreversible because a carboxylate salt is formed

• soaps are the salts of long-chain (fatty) acids ( C8 - C20 )
  fats are the esters of fatty acids and glycerol ( 1,2,3-propanetriol )

Other Reactions of Esters

• reduction by LiAlH4 gives primary alcohols (plus the ester alcohol)
  (H- nucleophile first gives substitution - aldehyde intermediate,
  then another H- nucleophile gives addition - alcohol product)
  
• Grignard additions give tertiary alcohols (double addition)
  (RMgX nucleophile first gives substitution - ketone intermediate,
  then another RMgX nucleophile gives addition - alcohol product)

Synthesis of Amides

• acid chloride plus ammonia (or amine)

Reactions of Amides

• hydrolysis to carboxylic acid - requires prolonged heating
  proteins are held together by amide bonds
• reduction by LiAlH4 to amines

Synthesis of Nitriles

• SN2 reaction of primary halides with CN-
• dehydration of amides

Reactions of Nitriles

• nucleophilc additions similar to carbonyl group (polar triple bond)
• hydrolysis to carboxylic acids
• reduction with LiAlH4 to amines
• addition of Grignards to make ketones

Thiol Esters

• Nature often uses sulfur groups as excellent nucleophiles (and leaving groups)
• coenzyme A contains a thiol group (coA-S-H)
• acetyl CoA acts like acetyl chloride
  e.g., acetyl CoA + amines gives acetamides
  

Summary - Hydride Reductions

Summary - Interconversion of Carboxyl Derivatives