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21.2 - Part 2 Reactions of Carboxylic Acid Derivatives - Wade 7th

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Organic Chemistry, 7th Edition L. G. Wade, Jr

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21.2 - Part 2 Reactions of Carboxylic Acid Derivatives - Wade 7th

  1. 1. Chapter 21 Copyright © 2010 Pearson Education, Inc. Organic Chemistry, 7th Edition L. G. Wade, Jr. Part 2: Reactions of Carboxylic Acid Derivatives
  2. 2. Chapter 21 2 Nucleophilic Acyl Substitution  Interconversion of acid derivatives occur by nucleophilic acyl substitution.  Nucleophile adds to the carbonyl forming a tetrahedral intermediate.  Elimination of the leaving group regenerates the carbonyl.  Nucleophilic acyl substitutions are also called acyl transfer reactions because they transfer the acyl group to the attacking nucleophile.
  3. 3. Chapter 21 3 Mechanism of Acyl Substitution This is an addition–elimination mechanism.
  4. 4. Chapter 21 4 Reactivity of Acid Derivatives
  5. 5. Chapter 21 5 Interconversion of Derivatives  More reactive derivatives can be converted to less reactive derivatives.
  6. 6. Chapter 21 6 Acid Chloride to Anhydride  The carboxylic acid attacks the acyl chloride, forming the tetrahedral intermediate.  Chloride ion leaves, restoring the carbonyl.  Deprotonation produces the anhydride.
  7. 7. Chapter 21 7 Acid Chloride to Ester  The alcohol attacks the acyl chloride, forming the tetrahedral intermediate.  Chloride ion leaves, restoring the carbonyl.  Deprotonation produces the ester.
  8. 8. Chapter 21 8 Acid Chloride to Amide  Ammonia yields a 1 amide.  A 1 amine yields a 2 amide.  A 2 amine yields a 3 amide.
  9. 9. Chapter 21 9 Anhydride to Ester  Alcohol attacks one of the carbonyl groups of the anhydride, forming the tetrahedral intermediate.  The other acid unit is eliminated as the leaving group.
  10. 10. Chapter 21 10 Anhydride to Amide  Ammonia yields a 1 amide; a 1 amine yields a 2 amide; and a 2 amine yields a 3 amide.
  11. 11. Chapter 21 11 Ester to Amide: Ammonolysis  Nucleophile must be NH3 or 1 amine.  Prolonged heating is required.
  12. 12. Chapter 21 12 Leaving Groups in Nucleophilic Acyl Substitution  A strong base, such as methoxide (- OCH3), is not usually a leaving group, except in an exothermic step.
  13. 13. Chapter 21 13 Energy Diagram  In the nucleophilic acyl substitution, the elimination of the alkoxide is highly exothermic, converting the tetrahedral intermediate into a stable molecule.
  14. 14. Chapter 21 14 Transesterification  One alkoxy group can be replaced by another with acid or base catalyst.  Use large excess of preferred alcohol.
  15. 15. Chapter 21 15 Transesterification Mechanism
  16. 16. Chapter 21 16 Hydrolysis of Acid Chlorides and Anhydrides  Hydrolysis occurs quickly, even in moist air with no acid or base catalyst.  Reagents must be protected from moisture.
  17. 17. Chapter 21 17 Hydrolysis of Esters: Saponification  The base-catalyzed hydrolysis of ester is known as saponification.  Saponification means “soap-making.”
  18. 18. Chapter 21 18 Saponification  Soaps are made by heating NaOH with a fat (triester of glycerol) to produce the sodium salt of a fatty acid—a soap.
  19. 19. Chapter 21 19 Hydrolysis of Amides Amides are hydrolyzed to the carboxylic acid under acidic or basic conditions.
  20. 20. Chapter 21 20 Mechanism of Basic Hydrolysis of Amides  Similar to the hydrolysis of an ester.  Hydroxide attacks the carbonyl forming a tetrahedral intermediate.  The amino group is eliminated and a proton is transferred to the nitrogen to give the carboxylate salt.
  21. 21. Chapter 21 21 Acid Hydrolysis of an Amide
  22. 22. Chapter 21 22 Hydrolysis of Nitriles  Heating with aqueous acid or base will hydrolyze a nitrile to a carboxylic acid.
  23. 23. Chapter 21 23 Reduction of Esters to Alcohols  Lithium aluminum hydride (LiAlH4) reduces esters to primary alcohols.
  24. 24. Chapter 21 24 Mechanism of Reduction of Esters
  25. 25. Chapter 21 25 Reduction to Aldehydes  Lithium aluminum tri(t-butoxy)hydride is a milder reducing agents.  Reacts faster with acyl chlorides than with aldehydes.
  26. 26. Chapter 21 26 Reduction to Amines  Amides will be reduced to the corresponding amine by LiAlH4.
  27. 27. Chapter 21 27 Reduction of Nitriles to Primary Amines  Nitriles are reduced to primary amines by catalytic hydrogenation or by lithium aluminum hydride reduction.
  28. 28. Chapter 21 28 Organometallic Reagents  Grignard and organolithium reagents add twice to acid chlorides and esters to give alcohols after protonation.
  29. 29. Chapter 21 29 Mechanism of Grignard Addition  Esters react with two moles of Grignards or organolithium reagents.  The ketone intermediate is formed after the first addition and will react with a second mole of organometallic to produce the alcohol. Step 1: Reacts with a 2nd mole of Grignard.
  30. 30. Chapter 21 30 Reaction of Nitriles with Grignards  A Grignard reagent or organolithium reagent attacks the cyano group to yield an imine, which is hydrolyzed to a ketone.
  31. 31. Chapter 21 31 Acid Chloride Synthesis  Thionyl chloride (SOCl2) and oxalyl chloride (COCl2) are the most convenient reagents because they produce only gaseous side products.
  32. 32. Chapter 21 32 Acid Chloride Reactions (1)
  33. 33. Chapter 21 33 Acid Chloride Reactions (2)
  34. 34. Chapter 21 34 Friedel–Crafts Acylation
  35. 35. Chapter 21 35 General Anhydride Synthesis  The most generalized method for making anhydrides is the reaction of an acid chloride with a carboxylic acid or a carboxylate salt.  Pyridine is sometimes used to deprotonate the acid and form the carboxylate.
  36. 36. Chapter 21 36 Reaction of Anhydrides
  37. 37. Chapter 21 37 Friedel–Crafts Acylation Using Anhydrides  Using a cyclic anhydride allows for only one of the acid groups to react, leaving the second acid group free to undergo further reactions.
  38. 38. Chapter 21 38 Acetic Formic Anhydride  Acetic formyl anhydride, made from sodium formate and acetyl chloride, reacts primarily at the formyl group.  The formyl group is more electrophilic because of the lack of alkyl groups.
  39. 39. Chapter 21 39 Reactions of Esters
  40. 40. Chapter 21 40 Formation of Lactones  Formation favored for five- and six-membered rings.  For larger rings, remove water to shift equilibrium toward products. O OCOOH OH H+ H2O+ H+ H2O+ O O OH COOH
  41. 41. Chapter 21 41 Reactions of Amides
  42. 42. Chapter 21 42 Dehydration of Amides to Nitriles  Strong dehydrating agents can eliminate the elements of water from a primary amide to give a nitrile.  Phosphorus oxychloride (POCl3) or phosphorus pentoxide (P2O5) can be used as dehydrating agents.
  43. 43. Chapter 21 43 Formation of Lactams  Five-membered lactams ( -lactams) and six- membered lactams ( -lactams) often form on heating or adding a dehydrating agent to the appropriate -amino acid or -amino acid.
  44. 44. Chapter 21 44 -Lactams  Unusually reactive four-membered ring amides are capable of acylating a variety of nucleophiles.  They are found in three important classes of antibiotics: penicillins, cephalosporins, and carbapenems.
  45. 45. Chapter 21 45 Mechanism of -Lactam Acylation  The nucleophile attacks the carbonyl of the four- membered ring amide, forming a tetrahedral intermediate.  The nitrogen is eliminated and the carbonyl reformed.  Protonation of the nitrogen is the last step of the reaction.
  46. 46. Chapter 21 46 Action of Antibiotics  The -lactams work by interfering with the synthesis of bacterial cell walls.  The acylated enzyme is inactive for synthesis of the cell wall protein.
  47. 47. Chapter 21 47 Reactions of Nitriles
  48. 48. Chapter 21 48 Resonance Overlap in Ester and Thioesters  The resonance overlap in a thioester is not as effective as that in an ester.
  49. 49. Chapter 21 49 Structure of Coenzyme A (CoA)  Coenzyme A (CoA) is a thiol whose thioesters serve as a biochemical acyl transfer reagents.
  50. 50. Chapter 21 50 Mechanism of Action of Acetyl CoA  Acetyl CoA transfers an acetyl group to a nucleophile, with coenzyme A serving as the leaving group.  Thioesters are not so prone to hydrolysis, yet they are excellent selective acylating reagents; therefore, thioesters are common acylating agents in living systems.
  51. 51. Chapter 21 51 Synthesis of Carbamate Esters from Isocyanates
  52. 52. Chapter 21 52 Polycarbonate Synthesis  Polycarbonates are polymers bonded to the carbonate ester linkage.  The diol used to make Lexan® is a phenol called bisphenol A, a common intermediate in polyester and polyurethane synthesis.
  53. 53. Chapter 21 53 Synthesis of Polyurethanes  Reaction of toluene diisocyanate with ethylene glycol produces one of the most common forms of polyurethanes.

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