Carboxylic Acid Derivatives: Nomenclature, Reactivity, and Synthesis - Prof. Pradipsinh Ra, Study notes of Organic Chemistry

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Carboxylic Acid Derivatives Chem 239: Chapter 20 Goals: Nomenclature Reactivity Nucleophilic acyl substitution ACYL CHLORIDES ANHYDRIDES ESTERS AMIDES and LACTAMS NITRILES Reading: (7th Ed.) pages 828-870 Problems: All end-of-chapter problems, particularly (6th Ed.): 20.24, 20.26, 20.32, 20.34, 20.35 R OH O Carboxylic acid Carboxylic acid derivative R O X R O Cl R O O R O R O O R' R O N R' R'' Acyl chloride Acid anhydride Ester Amide Carboxylic acid derivatives Acyl group bound to electronegative element Reactivity is related to structure Stabilization of carbonyl by e-–donation Reactivity order: acyl chloride > anhydride > ester > amide R O X R O X R O X :: :: : :: : : : R O Cl R O O R O R O O R' R O N R' R'' > > > Derivatives differ in degree stabilization R O Cl : :: : : R O Cl :: : : : : R O Cl :: : : : not a significant contributor R O NR'2 R O NR'2 R O NR'2 :: :: : :: : : : poor orbital overlap very effective significantcontributor R O O : :: : O R :: R O O : :: : O R :: R O O :: : O R :: : R O O : :: : R'R O O : :: : R' Acyl chlorides: Anhydrides: Esters: Amides: Reactivity Compound Structural Molecular Stabilization of formula model carbonyl! group Most reactive Acetyl chloride Acetic anhydride Ethyl thioacetate Ethyl acetate Least reactive — Acetamide Figure 20.1 0 e @ ll CH,C—Cl e& @ Least stabilized c So © ; ll ll @ CH,C—OCCH, & e & 0 e 3 CHC—SCHLCH, a ., © “e © & @ 6 G ee & 9 e ® ll CH,C—NH; o&® Most stabilized © ll CH,C—OCH,CH, Synthesis of acyl chlorides O OH O Cl SOCl2 Overall Reaction: Mechanism: O OH Cl S O Cl + Acyl chloride hydrolysis Acyl chlorides react with water to give: carboxylic acids or carboxylate ion *pay attention to pH!!! R O Cl + H2O + 2 NaOH R O OH + HCl carboxylic acid (in water) R O O- + Cl- + 2 Na+ carboxylate ion (in base) Acyl chloride hydrolysis mechanism First Stage: H O H : : + O R Cl slow +O C O- R Cl H H fast O C O R Cl H H Tetrahedral intermediate O C O R Cl H H Tetrahedral intermediate Second Stage: + H O H :: fast O R OH + H3O+ + Cl- Reactivity Compound Structural Molecular Stabilization of formula model carbonyl! group Most reactive Acetyl chloride Acetic anhydride Ethyl thioacetate Ethyl acetate Least reactive — Acetamide Figure 20.1 0 e @ ll CH,C—Cl e& @ Least stabilized c So © ; ll ll @ CH,C—OCCH, & e & 0 e 3 CHC—SCHLCH, a ., © “e © & @ 6 G ee & 9 e ® ll CH,C—NH; o&® Most stabilized © ll CH,C—OCH,CH, Acid anhydride nomenclature O O O Acid anhydrides: when both acyl groups are same, replace acid with anhydride when both acyl groups are different, cite acids alphabetically and add anhydride Acetic anhydride O O O O O O (CH2)5 Benzoic anhydride Benzoic heptanoicanhydride Acid anhydride reactivity R O O R O + HY: R O Y: + HO R O bond cleavage Anhydrides readily converted to more stable carboxylic acids, esters, amides, not acid chlorides Nucleophilic acyl substitutions can be catalyzed by acids Ester nomenclature O O Esters: name alkyl attached to oxygen, then acyl (replace -ic acid with -ate) Ethyl acetate O O OH Methyl salicylate (wintergreen oil) O O Cl 2-chloroethyl benzoate Ester synthesis O OH MeOH O O via OH OH OCH3 Tetrahedral intermediate H2SO4 Fischer esterification Esters also from acyl chlorides and acid anhydrides Br OH O NH2 MeOH Br O O NH2 H2SO4 CDCl3 (solvent) EtOAc EtOAc EtOAc H2O -OCH3 -CH3 Methyl ester NMR Amide nomenclature O N H Amides: replace -ic acid with -amide N-ethyl acetamide O NH2 acetamide O NH2 3-methyl butanamide O NH2 benzamide O N N,N-dimethyl benzamide Amide properties H O NH2 H O NH2 H O NH2 :: :: : :: : : : significant contributorFormamide Delocalization of electrons decreases positive character of carbonyl carbon Amides less reactive than other carboxylic acid derivatives toward nucleophilic acyl substitution N less electronegative than O increasing acidity NH2 O NH2 O N H O O OH pKa: 36 15 10 5 imideamine amide carbox. acid Amide properties DMSO (solvent) H2O H3C O N CH3 CH3: H3C O- N CH3 CH3 N,N-dimethyl acetamide Amide hydrolysis R NH2 O + H O H H Step 1: Step 2: Step 3: Step 4: Step 5: R NH2 OH + H O H R NH2 OHH O H + R OH O NH2 H H R OH O NH2 H H + H O H R OH OH NH2 + H O H H Step 6: R OH OH NH2 + H O H H R OH OH NH3 + H O H R OH OH NH3 R OH OH + :NH3H O H H + + H O H R OH OH + H O H R O OH + H3O+ Tetrahedral intermediate NH3 NH4+ IRREVERSIBLE!!! Amide hydrolysis Acid-catalyzed IRREVERSIBLE Base-catalyzed IRREVERSIBLE + H3O+ + H2ONH3 NH4+ R O OH + HO- R O O- + H2O Lactams Lactams are cyclic amides (like lactones are cyclic esters) Ring can be many sizes NH O Addition to nitriles Nitrile C less reactive to nucleophilic addition than a carbonyl Strongly basic nucleophiles, ie. Grignards, do react The resulting imine can be hydrolyzed to a ketone R C N R'MgX+ R NH R' H3O+ heatR O R' Et2O R NMgX R' H3O+ Nitrile Grignard ImineKetone Nitrile hydrolysis Hydrolysis yields a carboxylic acid IRREVERSIBLE in the presence of acids or bases R C N + Nitrile H2O + H3O+ R O OH + R C N + Nitrile H2O + HO- R O O- + NH3 NH4+ Reactivity order: acyl chloride > anhydride > ester > amide Reactivity toward more stable derivative All undergo hydrolysis to carboxylic acid Pay attention to pH!!! It will tell you if the reaction is IRREVERSIBLE Summary R O Cl R O O R O R O O R' R O N R' R'' > > >