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Lectures 27 and 28

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  1. Lectures 27 and 28 Carboxylic Acids and derivatives Chapter 10 Chemistry 243 - Lecture 27 and 28

  2. The Importance of Carboxylic Acids (RCO2H) • Starting materials for acyl derivatives (esters, amides, and acid chlorides) • Abundant in nature from oxidation of aldehydes and alcohols in metabolism • Acetic acid, CH3CO2H, - vinegar • Butanoic acid, CH3CH2CH2CO2H (rancid butter) • Long-chain aliphatic acids from the breakdown of fats Chemistry 243 - Lecture 27 and 28

  3. Naming Carboxylic Acids and Nitriles • Carboxylic Acids, RCO2H • If derived from open-chain alkanes, replace the terminal -e of the alkane name with -oic acid • The carboxyl carbon atom is C1 Chemistry 243 - Lecture 27 and 28

  4. Alternative Names • Compounds with CO2H bonded to a ring are named using the suffix -carboxylic acid • The CO2H carbon is not itself numbered in this system • Use common names for formic acid (HCOOH) and acetic acid (CH3COOH) – see Table 20.1 Chemistry 243 - Lecture 27 and 28

  5. Structure and Physical Properties of Carboxylic Acids • Carboxyl carbon sp2 hybridized: carboxylic acid groups are planar with C–C=O and O=C–O bond angles of approximately 120° • Carboxylic acids form hydrogen bonds, existing as cyclic dimers held together by two hydrogen bonds • Strong hydrogen bonding causes much higher boiling points than the corresponding alcohols Chemistry 243 - Lecture 27 and 28

  6. Dissociation of Carboxylic Acids • Carboxylic acids are proton donors toward weak and strong bases, producing metal carboxylate salts, RCO2+M • Carboxylic acids with more than six carbons are only slightly soluble in water, but their conjugate base salts are water-soluble Chemistry 243 - Lecture 27 and 28

  7. Acidity Constant and pKa • Carboxylic acids transfer a proton to water to give H3O+ and carboxylate anions, RCO2, but H3O+ is a much stronger acid • The acidity constant, Ka,, is about 10-5 for a typical carboxylic acid (pKa ~ 5) Chemistry 243 - Lecture 27 and 28

  8. Acidity Compared to Alcohols • Carboxylic acids are better proton donors than are alcohols (The pKa of ethanol is ~16, compared to ~5 for acetic acid) • In an alkoxide ion, the negative charge is localized on oxygen while in a carboxylate ion the negative charge is delocalized over two equivalent oxygen atoms, giving resonance stabilization Chemistry 243 - Lecture 27 and 28

  9. Substituent Effects on Acidity • Electronegative substituents promote formation of the carboxylate ion Chemistry 243 - Lecture 27 and 28

  10. Preparation of Carboxylic Acids • Oxidation of a substituted alkylbenzene with KMnO4 or Na2Cr2O7 gives a substituted benzoic acid • 1° and 2° alkyl groups can be oxidized, but tertiary groups are not Chemistry 243 - Lecture 27 and 28

  11. From Alkenes • Oxidative cleavage of an alkene with KMnO4 gives a carboxylic acid if the alkene has at least one vinylic hydrogen Chemistry 243 - Lecture 27 and 28

  12. From Alcohols • Oxidation of a primary alcohol or an aldehyde with CrO3 in aqueous acid Chemistry 243 - Lecture 27 and 28

  13. Carboxylation of Grignard Reagents • Grignard reagents react with dry CO2 to yield a metal carboxylate • Limited to alkyl halides that can form Grignard reagents Chemistry 243 - Lecture 27 and 28

  14. Mechanism of Grignard Carboxylation • The organomagnesium halide adds to C=O of carbon dioxide • Protonation by addition of aqueous HCl in a separate step gives the free carboxylic acid Chemistry 243 - Lecture 27 and 28

  15. Reactions of Carboxylic Acids: An Overview • Carboxylic acids transfer a proton to a base to give anions, which are good nucleophiles in SN2 reactions • Like ketones, carboxylic acids undergo addition of nucleophiles to the carbonyl group • In addition, carboxylic acids undergo other reactions characteristic of neither alcohols nor ketones Chemistry 243 - Lecture 27 and 28

  16. Reduction of Carboxylic Acids • Reduced by LiAlH4 to yield primary alcohols • The reaction is difficult and often requires heating in tetrahydrofuran solvent to go to completion Chemistry 243 - Lecture 27 and 28

  17. Carboxylic Compounds • Acyl group bonded to Y, an electronegative atom or leaving group • Includes: Y = halide (acid halides), acyloxy (anhydrides), alkoxy (esters), amine (amides), thiolate (thioesters), phosphate (acyl phosphates) Chemistry 243 - Lecture 27 and 28

  18. General Reaction Pattern • Nucleophilic acyl substitution Chemistry 243 - Lecture 27 and 28

  19. Naming Carboxylic Acid Derivatives • Acid Halides, RCOX • Derived from the carboxylic acid name by replacing the -ic acid ending with -yl or the -carboxylic acid ending with –carbonyl and specifying the halide Chemistry 243 - Lecture 27 and 28

  20. Naming Acid Anhydrides, RCO2COR' • If symmetrical replace “acid” with “anhydride” based on the related carboxylic acid (for symmetrical anhydrides) • From substituted monocarboxylic acids: use bis- ahead of the acid name • Unsymmetrical anhydrides— cite the two acids alphabetically Chemistry 243 - Lecture 27 and 28

  21. Naming Amides, RCONH2 • With unsubstituted NH2 group. replace -oic acid or -ic acid with -amide, or by replacing the -carboxylic acid ending with –carboxamide • If the N is further substituted, identify the substituent groups (preceded by “N”) and then the parent amide Chemistry 243 - Lecture 27 and 28

  22. Naming Esters, RCO2R • Name R’ and then, after a space, the carboxylic acid (RCOOH), with the “-ic acid” ending replaced by “-ate” Chemistry 243 - Lecture 27 and 28

  23. Nucleophilic Acyl Substitution • Carboxylic acid derivatives have an acyl carbon bonded to a group Y that can leave • A tetrahedral intermediate is formed and the leaving group is expelled to generate a new carbonyl compound, leading to substitution Chemistry 243 - Lecture 27 and 28

  24. Relative Reactivity of Carboxylic Acid Derivatives • Nucleophiles react more readily with unhindered carbonyl groups • More electrophilic carbonyl groups are more reactive to addition (acyl halides are most reactive, amides are least) • The intermediate with the best leaving group decomposes fastest Chemistry 243 - Lecture 27 and 28

  25. Substitution in Synthesis • We can readily convert a more reactive acid derivative into a less reactive one • Reactions in the opposite sense are possible but require more complex approaches Chemistry 243 - Lecture 27 and 28

  26. General Reactions of Carboxylic Acid Derivatives • water ˝ carboxylic acid • alcohols ˝esters • ammonia or an amine ˝ an amide • hydride source ˝ an aldehyde or an alcohol • Grignard reagent ˝a ketone or an alcohol Chemistry 243 - Lecture 27 and 28

  27. Nucleophilic Acyl Substitution Reactions of Carboxylic Acids • Must enhance reactivity • Convert OH into a better leaving group • Specific reagents can produce acid chlorides, anhydrides, esters, amides Chemistry 243 - Lecture 27 and 28

  28. Conversion of Carboxylic Acids into Acid Chlorides • Reaction with thionyl chloride, SOCl2 Chemistry 243 - Lecture 27 and 28

  29. Mechanism of Thionyl Chloride Reaction • Nucleophilic acyl substitution pathway • Carboxylic acid is converted into a chlorosulfite which then reacts with chloride Chemistry 243 - Lecture 27 and 28

  30. Conversion of Carboxylic Acids into Esters • Methods include reaction of a carboxylate anion with a primary alkyl halide Chemistry 243 - Lecture 27 and 28

  31. Fischer Esterification • Heating a carboxylic acid in an alcohol solvent containing a small amount of strong acid produces an ester from the alcohol and acid Chemistry 243 - Lecture 27 and 28

  32. Mechanism of the Fischer Esterification • The reaction is an acid-catalyzed, nucleophilic acyl substitution of a carboxylic acid • When 18O-labeled methanol reacts with benzoic acid, the methyl benzoate produced is 18O-labeled but the water produced is unlabeled Chemistry 243 - Lecture 27 and 28

  33. Fischer Esterification: Detailed Mechanism 1 3 2 4 Chemistry 243 - Lecture 27 and 28

  34. Chemistry of Acid Halides • Acid chlorides are prepared from carboxylic acids by reaction with SOCl2 • Reaction of a carboxylic acid with PBr3 yields the acid bromide Chemistry 243 - Lecture 27 and 28

  35. Reactions of Acid Halides • Nucleophilic acyl substitution • Halogen replaced by OH, by OR, or by NH2 • Reduction yields a primary alcohol • Grignard reagent yields a tertiary alcohol Chemistry 243 - Lecture 27 and 28

  36. Hydrolysis: Conversion of Acid Halides into Acids • Acid chlorides react with water to yield carboxylic acids • HCl is generated during the hydrolysis: a base is added to remove the HCl Chemistry 243 - Lecture 27 and 28

  37. Conversion of Acid Halides to Esters • Esters are produced in the reaction of acid chlorides react with alcohols in the presence of pyridine or NaOH • The reaction is better with less steric bulk Chemistry 243 - Lecture 27 and 28

  38. Aminolysis: Conversion of Acid Halides into Amides • Amides result from the reaction of acid chlorides with NH3, primary (RNH2) and secondary amines (R2NH) • The reaction with tertiary amines (R3N) gives an unstable species that cannot be isolated • HCl is neutralized by the amine or an added base Chemistry 243 - Lecture 27 and 28

  39. Reduction: Conversion of Acid Chlorides into Alcohols • LiAlH4 reduces acid chlorides to yield aldehydes and then primary alcohols Chemistry 243 - Lecture 27 and 28

  40. Reaction of Acid Chlorides with Organometallic Reagents • Grignard reagents react with acid chlorides to yield tertiary alcohols in which two of the substituents are the same Chemistry 243 - Lecture 27 and 28

  41. Formation of Ketones from Acid Chlorides • Reaction of an acid chloride with a lithium diorganocopper (Gilman) reagent, Li+ R2Cu • Addition produces an acyl diorganocopper intermediate, followed by loss of RCu and formation of the ketone Chemistry 243 - Lecture 27 and 28

  42. Chemistry of Acid Anhydrides • Prepared by nucleophilic of a carboxylate with an acid chloride Chemistry 243 - Lecture 27 and 28

  43. Reactions of Acid Anhydrides • Similar to acid chlorides in reactivity Chemistry 243 - Lecture 27 and 28

  44. Acetylation • Acetic anhydride forms acetate esters from alcohols and N-substituted acetamides from amines Chemistry 243 - Lecture 27 and 28

  45. Chemistry of Esters • Many esters are pleasant-smelling liquids: fragrant odors of fruits and flowers • Also present in fats and vegetable oils Chemistry 243 - Lecture 27 and 28

  46. Preparation of Esters • Esters are usually prepared from carboxylic acids Chemistry 243 - Lecture 27 and 28

  47. Reactions of Esters • Less reactive toward nucleophiles than are acid chlorides or anhydrides • Cyclic esters are called lactones and react similarly to acyclic esters Chemistry 243 - Lecture 27 and 28

  48. Hydrolysis: Conversion of Esters into Carboxylic Acids • An ester is hydrolyzed by aqueous base or aqueous acid to yield a carboxylic acid plus an alcohol Chemistry 243 - Lecture 27 and 28

  49. Mechanism of Ester Hydrolysis • Hydroxide catalysis via an addition intermediate 1 3 2 4 Chemistry 243 - Lecture 27 and 28

  50. Acid Catalyzed Ester Hydrolysis • The usual pathway is the reverse of the Fischer esterification Chemistry 243 - Lecture 27 and 28