Chapter 18 Carboxylic Acid Derivatives Lecture 24 Chem 30B Carboxyl Derivatives • In this chapter, we study five classes of organic compounds. – Under the structural formula of each is a drawing to help you see its relationship to the carboxyl group. O RCCl A n acid chloride -H2 O O RC-OH H-Cl O O RCOCR' An acid anhydride -H2 O O O RC-OH H-OCR' O RCOR' An ester -H2 O O RC-OH H-OR' O RCNH2 An amide -H2 O O RC-OH H-NH2 RC N A nitrile -H2 O HO H RC=N Th e enol of an amide Structure: Acid Chlorides • The functional group of an acid halide is an acyl group bonded to a halogen. – The most common are the acid chlorides. – To name, change the suffix -ic acid to -yl halide. O O RCAn acyl group O CH3 CCl O Cl Ethan oyl ch loride Benzoyl chloride (Acetyl ch loride) Cl Cl O Hexan edioyl ch loride (Adip oyl chloride) Sulfonyl Chlorides – Replacement of -OH in a sulfonic acid by -Cl gives a sulfonyl chloride. O O CH3 SOH CH3 SCl O Methanes ulfon ic acid O Methanes ulfonyl ch loride (Mesyl ch loride, MsCl) O H3 C SOH O p-Toluen esulfon ic acid O H3 C SCl O p-Toluen esulfon yl chloride (Tosyl chlorid e, TsCl) Acid Anhydrides • The functional group of an acid anhydride is two acyl groups bonded to an oxygen atom. – The anhydride may be symmetrical (two identical acyl groups) or mixed (two different acyl groups). – To name, replace acid of the parent acid by anhydride. O O CH3 COCCH3 O O COC A cetic an h ydrid e Ben zoic anh ydrid e Acid Anhydrides • Cyclic anhydrides are named from the dicarboxylic acids from which they are derived. O O O Succinic anhydride O O O O Maleic anhydride O O Phthalic anhydride Phosphoric Anhydrides • A phosphoric anhydride contains two phosphoryl groups bonded to an oxygen atom. O O O - HO- P-O- P-OH OH OH Diphosphoric acid (Pyrophosphoric acid) O O O- O- OTriphosphoric acid O- P-O-P- O O- - O- Diphosphate ion (Pyrophosphate ion) O O HO- P-O- P-O-P- OH O - O O O- P-O-P- O-P- O O- O- OTriphosphate ion - Esters • The functional group of an ester is an acyl group bonded to -OR or -OAr. – Name the alkyl or aryl group bonded to oxygen followed by the name of the acid. – Change the suffix -ic acid to -ate. O O O O O Ethyl ethan oate (Ethyl acetate) Is op ropyl ben zoate EtO OEt O D iethyl butaned ioate (D ieth yl s uccin ate) Esters • Lactone: A cyclic ester. – name the parent carboxylic acid, drop the suffix -ic acid and add -olactone. 2 3 H3 C O O 1 O 3-Bu tanolactone -Butyrolactone) 1 2 O 3 4 4-Bu tanolactone -Bu tyrolacton e) 3 4 2 O 1 O 5 6 6-Hexan olacton e -Cap rolactone) Esters of Phosphoric Acid • Phosphoric acid forms mono-, di-, and triesters. • Name by giving the name of the alkyl or aryl group(s) bonded to oxygen followed by the word phosphate. • In more complex phosphoric esters, it is common to name the organic molecule and then indicate the presence of the phosphoric ester by the word phosphate or the prefix phospho-. O CH3 OPOH OCH3 D imethyl phosp hate CHO HO C-H CHO O - HO CH2 O-P-O - CH2 -O-P-O O Glyceraldeh yd e 3-phosph ate O - O H3 C N Pyridoxal phosp hate O CO O C O P O CH2 OPhosphoenolpyruvate Amides • IUPAC: drop -oic acid from the name of the parent acid and add -amide. For the common name, drop -ic of the parent name and add -amide. • if the amide nitrogen is bonded to an alkyl or aryl group, name the group and show its location on nitrogen by N-. O CH3 CNH2 A cetamide (a 1° amide) O H CH3 C-N CH3 O CH3 H-C-N CH3 N-Methylacetamide N ,N-D imethyl(a 2° amid e) formamid e (DMF) (a 3° amide) Amides • Lactams: A cyclic amides are called lactams. – Name the parent carboxylic acid, drop the suffix -ic acid and add -lactam. 2 3 H3 C O 1 NH 3-Butanolactam -Butyrolactam) 2 3 4 O 5 1 6 NH 6-Hexanolactam -Caprolactam) Penicillins – The penicillins are a family of -lactam antibiotics. HO The penicillin s differ in the grou p bond ed to the acyl carb on O H H S NH H2 N -lactam O N Amoxicillin (a -lactam an tib iotic) COOH Cephalosporins – The cephalosporins are also -lactam antibiotics. The cephalosporins d iffer in the group bonded to the acyl carbon an d the s ide chain of the thiazin e rin g O NH2 H H N H O N -lactam Cep halexin (Keflex) S Me COOH Imides • The functional group of an imide is two acyl groups bonded to nitrogen. – Both succinimide and phthalimide are cyclic imides. O NH O Succinimide O NH O Phthalimide Nitriles • The functional group of a nitrile is a cyano group – IUPAC names: name as an alkanenitrile. – common names: drop the -ic acid and add -onitrile. CH3 C N Ethanen itrile (A cetonitrile) C N Benzon itrile CH2 C N Phenylethan enitrile (Phenylacetonitrile) Acidity of N-H bonds • Amides are comparable in acidity to alcohols. – Water-insoluble amides do not react with NaOH or other alkali metal hydroxides to form water-soluble salts. • Sulfonamides and imides are more acidic than amides. O CH3 CNH2 Acetamide pKa 15-17 O SNH2 O O NH O NH O O Ben zenesu lfonamide Succinimide Phth alimide pK a 10 p Ka 9.7 p Ka 8.3 Acidity of N-H bonds • Imides are more acidic than amides because 1. the electron-withdrawing inductive of the two adjacent C=O groups weakens the N-H bond 2. the imide anion is stabilized by resonance delocalization of the negative charge. O N O O N O A resonance-stabilized an ion O N O Acidity of N-H – Imides such as phthalimide readily dissolve in aqueous NaOH as water-soluble salts. O NH + O pK a 8.3 (stronger acid) O N aOH - N Na + + H2 O O (stronger base) (weaker base) pK a 15.7 (weaker acid) Acidity of N-H • Saccharin, an artificial sweetener, is an imide. The imide is sufficiently acidic that it reacts with NaOH and aqueous NH3 to form water-soluble salts. The ammonium salt is used to make liquid Saccharin. Saccharin in solid form is the Ca2+ salt. O O S NH + NH3 O O Saccharin H2 O S N- NH4+ O O Saccharin A water-soluble ammonium salt Characteristic Reactions • Nucleophilic acyl substitution: An additionelimination sequence resulting in substitution of one nucleophile for another. O O R C + :Nu Y R O C Nu Y Tetrahedral carbonyl addition intermediate R C Nu Substitution product + :Y Characteristic Reactions – In the general reaction, we showed the leaving group as an anion to illustrate an important point about them: the weaker the base, the better the leaving group. O R2 N - - RO - RCO Increasin g leaving ability Increasin g b asicity - X Characteristic Reactions – Halide ion is the weakest base and the best leaving group; acid halides are the most reactive toward nucleophilic acyl substitution. – Amide ion is the strongest base and the poorest leaving group; amides are the least reactive toward nucleophilic acyl substitution. Reaction with H2O - Acid Chlorides – Low-molecular-weight acid chlorides react rapidly with water. – Higher molecular-weight acid chlorides are less soluble in water and react less readily. O CH3 CCl + H2 O Acetyl chlorid e O CH3 COH + HCl Reaction with H2O - Anhydrides – Low-molecular-weight anhydrides react readily with water to give two molecules of carboxylic acid. – Higher-molecular-weight anhydrides also react with water, but less readily. O O CH3 COCCH3 + H2 O Acetic an hydrid e O O CH3 COH + HOCCH3 Reaction with H2O - Anhydrides – Step 1: Addition of H2O to give a TCAI. H + O CH3 -C- O-C- CH 3 O-H H H O O CH3 -C- O-C- CH 3 + O H H O-H H H O O + CH3 -C- O-C- CH 3 + H- O-H O H H Tetrahedral carbonyl addition intermediate Reaction with H2O - Anhydrides –Step 2: Protonation followed collapse of the TCAI. H H H +O H H H O O CH3 -C-O-C-CH3 O H H H +O H O O + H O CH3 C O C CH3 H H CH3 O H H O O C + O C O CH3 Reaction with H2O - Esters • Esters are hydrolyzed only slowly, even in boiling water. – Hydrolysis becomes more rapid if they are heated with either aqueous acid or base. • Hydrolysis in aqueous acid is the reverse of Fischer esterification. – The role of the acid catalyst is to protonate the carbonyl oxygen and increase its electrophilic character toward attack by water (a weak nucleophile) to form a tetrahedral carbonyl addition intermediate. – Collapse of this intermediate gives the carboxylic acid and alcohol. Reaction with H2O - Esters • Acid-catalyzed ester hydrolysis R O C OH C + + OCH3 H2 O H R H + OH OCH3 Tetrahed ral carbonyl ad dition intermed iate R O C + OH CH3 OH Reaction with H2O - Esters • Saponification: The hydrolysis of an esters in aqueous base. – Each mole of ester hydrolyzed requires 1 mole of base – For this reason, ester hydrolysis in aqueous base is said to be base promoted. O RCOCH3 + NaOH H2 O O - RCO Na + + CH3 OH – Hydrolysis of an ester in aqueous base involves formation of a tetrahedral carbonyl addition intermediate followed by its collapse and proton transfer. Reaction with H2O - Esters – Step 1: Attack of hydroxide ion (a nucleophile) on the carbonyl carbon (an electrophile). – Step 2: Collapse of the TCAI. – Step 3: Proton transfer to the alkoxide ion; this step is irreversible and drives saponification to completion. O R- C-OCH3+ OH O (1) (2) R- C OCH3 OH O R- C + O H O OCH3 (3) R- C + HOCH3 O Reaction with H2O - Amides • Hydrolysis of an amide in aqueous acid requires one mole of acid per mole of amide. – Reaction is driven to completion by the acidbase reaction between the amine or ammonia and the acid. O O N H2 Ph 2-Phenylbutanamide + H2 O + HCl H2 O heat OH + Ph 2-Phenylbutanoic acid N H4 + Cl - Reaction with H2O - Amides • Hydrolysis of an amide in aqueous base requires one mole of base per mole of amide. – Reaction is driven to completion by the irreversible formation of the carboxylate salt. O CH3 CNH N-Phen yleth anamide (N-Phen ylacetamid e, Acetan ilide) + NaOH H2 O heat O CH3 CO- Na+ + H2 N Sodiu m acetate A niline Reaction with H2O - Amides – Step1: Protonation of the carbonyl oxygen gives a resonance-stabilized cation intermediate. O + R C NH2 + H O H H +H O R C NH2 H H O R C + O NH2 R C + NH2 Reso nance-stabil ized catio n i ntermed iate + H2 O Reaction with H2O - Amides – Step 2: Addition of water to the carbonyl carbon followed by proton transfer gives a TCAI. OH + R C N H2 + OH O H H R C NH2 O+ H H proton trans fer from O to N OH R C N H3 + H O – Step 3: Collapse of the TCAI and proton transfer. H R C NH3 + OH H + O R O C OH + NH3 R O C OH + NH4 + Reaction with H2O - Nitriles • The cyano group is hydrolyzed in aqueous acid to a carboxyl group and ammonium ion. Ph CH2 C N + 2 H2 O + H2 SO4 Phenylacetonitrile H2 O heat O + Ph CH2 COH + NH4 HSO4 Ph enylacetic Ammoniu m acid hydrogen s ulfate – Protonation of the cyano nitrogen gives a cation that reacts with water to give an imidic acid. – Keto-enol tautomerism gives the amide. + R-C N + H2 O H OH R-C NH A n imidic acid (en ol of an amide) O R-C-NH2 An amide Reaction with H2O - Nitriles – Hydrolysis of a cyano group in aqueous base gives a carboxylic anion and ammonia; acidification converts the carboxylic anion to the carboxylic acid. CH3 ( CH2 ) 9 C N Un decan enitrile NaOH, H2 O h eat O + CH3 ( CH2 ) 9 CO Na + NH3 S od ium und ecanoate HCl H2 O O CH3 ( CH2 ) 9 COH + NaCl + NH4 Cl Und ecanoic acid Reaction with H2O - Nitriles Hydrolysis of nitriles is a valuable route to carboxylic acids. KCN CH 3 ( CH2 ) 8 CH2 Cl ethanol, 1-Chlorodecane water CH3 ( CH2 ) 9 C N Undecanenitrile OH H2 SO 4 , H2 O heat O CH3 ( CH2 ) 9 COH Undecanoic acid OH CHO HCN , KCN CN H2 SO 4 , H2 O COOH ethanol, heat water Benzaldehyde Benzaldehyde cyanohydrin 2-Hydroxyphenylacetic acid (Mandelonitrile) (Mandelic acid) (racemic) (racemic) Chapter 18 Carboxylic Acid Derivatives Lecture 25 Chem 30B Reaction with Alcohols • Acid halides react with alcohols to give esters. – Acid halides are so reactive toward even weak nucleophiles such as alcohols that no catalyst is necessary. – If the alcohol or resulting ester is sensitive to HCl, the reaction is carried out in the presence of a 3° amine to neutralize the acid. O O Cl + HO Butanoyl chloride Cyclohexan ol O Cyclohexyl butan oate + HCl Reaction with Alcohols – Sulfonic acid esters are prepared by the reaction of an alkane- or arenesulfonyl chloride with an alcohol or phenol. – The key point here is that OH- is transformed into a sulfonic ester (a good leaving group) with retention of configuration at the chiral center. OT s OH + (R)-2-Octanol T sCl pyridine p-Toluenesulfonyl chloride (Tosyl chloride) (R)-2-Octyl p-t oluenesulfonate [(R)-2-Octyl tosylate] Reaction with Alcohols • Acid anhydrides react with alcohols to give one mole of ester and one mole of a carboxylic acid. O O CH3 COCCH3 + HOCH2 CH 3 Acetic anhydride Ethanol O O CH3 COCH2 CH3 + CH3 COH Acetic acid Ethyl acetate – Cyclic anhydrides react with alcohols to give one ester group and one carboxyl group. O O O O Phth alic anh yd rid e + O OH HO O 2-Butan ol (sec-Butyl alcohol) (s ec-Bu tyl h yd rogen phth alate Reaction with Alcohols – Aspirin is synthesized by treating salicylic acid with acetic anhydride. COOH OH O O + CH COCCH 3 3 2-Hydroxybenzoic acid (Salicylic acid) Acetic anhydride COOH O CH 3 O Acetylsalicylic acid (Aspirin) + O CH 3 COH Acetic acid Reaction with Alcohols • Esters react with alcohols in the presence of an acid catalyst in an equilibrium reaction called transesterification. O OCH3 Methyl propenoate (Methyl acrylate) (bp 81°C) + HCl HO 1-Butanol (bp 117°C) O O Butyl propenoate (Butyl acrylate) (bp 147°C) + CH3 OH Methanol (bp 65°C) Reaction with Ammonia, etc. • Acid halides react with ammonia, 1° amines, and 2° amines to form amides. – Two moles of the amine are required per mole of acid chloride. O O Cl + 2 NH3 Hexanoyl chloride Ammon ia + - NH2 + NH4 Cl Hexan amid e Ammon ium chloride Reaction with Ammonia, etc. • Acid anhydrides react with ammonia, and 1° and 2° amines to form amides. – Two moles of ammonia or amine are required. O O CH3 COCCH3 + 2 NH3 Acetic Ammon ia anh yd rid e O O + + CH CO NH CH3 CNH2 3 4 Acetamid e Ammon ium acetate Reaction with Ammonia, etc. • Esters react with ammonia and with 1° and 2° amines to form amides. – Esters are less reactive than either acid halides or acid anhydrides. O Ph O OEt + NH3 Ethyl p henylacetate Ph NH2 + Phenylacetamide • Amides do not react with ammonia or with 1° or 2° amines. Et OH Ethanol Acid Chlorides with Salts • Acid chlorides react with salts of carboxylic acids to give anhydrides. – Most commonly used are sodium or potassium salts. O O + CH3 CCl + N a - OC Acetyl chloride Sodium benzoate O O CH3 COC Acetic benzoic anhydride + N a+ Cl - Chapter 18 Carboxylic Acid Derivatives Lecture 26 Chem 30B Interconversions of Acid Derivatives Reaction with Grignard Reagents 1. Addition of 1 mole of RMgX to the carbonyl carbon of an ester gives a TCAI. 2. Collapse of the TCAI gives a ketone (an aldehyde from a formic ester). 1 O 2 CH3 -C-OCH3 + R MgX 1 O [MgX] + CH3 -C OCH3 R 2 A magnesiu m s alt (a tetrahed ral carbonyl addition intermediate) O + CH3 -C + CH3 O [ MgX] R A ketone Reaction with Grignard Reagents – Treating a formic ester with two moles of Grignard reagent followed by hydrolysis in aqueous acid gives a 2° alcohol. O HCOCH3 + 2 RMgX An ester of formic acid OH magn esium H O, HCl 2 alkoxide HC-R + CH3 OH salt R A 2° alcohol Reaction with Grignard Reagents – Treating an ester other than formic with a Grignard reagent followed by hydrolysis in aqueous acid gives a 3° alcohol. O CH3 COCH3 + 2 RMgX An ester of an y acid other than formic acid magnesiu m H O, HCl 2 alk oxid e salt OH CH3 C-R + CH3 OH R A 3° alcohol Reaction with Grignard Reagents 3. Reaction of the ketone with a second mole of RMgX gives a second TCAI. 4. Treatment with aqueous acid gives the alcohol. O CH3 -C - 3 3 R A k eton e + R MgX O [MgX] + OH H2 O, HCl CH3 -C-R (4) R R Magnesiu m salt A 3° alcohol CH3 -C-R Reactions with RLi • Organolithium compounds are even more powerful nucleophiles than Grignard reagents. – They react with esters to give the same types of 2° and 3° alcohols as do Grignard reagents – and often in higher yields. O RCOCH3 1 . 2 R' Li 2 . H2 O, HCl OH R- C-R' + CH3 OH R' Gilman Reagents • Acid chlorides at -78°C react with Gilman reagents to give ketones. – Under these conditions, the TCAI is stable, and it is not until acid hydrolysis that the ketone is liberated. O O 1 . ( CH3 ) 2 CuLi, eth er, -78°C Cl 2 . H O 2 Pentanoyl chloride 2-Hexanone Gilman Reagents – Gilman reagents react only with acid chlorides. – They do not react with acid anhydrides, esters, amides or nitriles under the conditions described. O H 3 CO O 1 . ( CH3 ) 2 CuLi, eth er, -78°C Cl 2 . H O 2 O H 3 CO O Reduction - Esters by LiAlH4 • Most reductions of carbonyl compounds now use hydride reducing agents. – Esters are reduced by LiAlH4 to two alcohols. – The alcohol derived from the carbonyl group is primary. O Ph OCH3 Methyl 2-phenylpropanoate (racemic) 1 . LiA lH4 , e t he r 2 . H2 O, HCl Ph OH + CH3 OH 2-Phenyl-1propanol (racemic) Methanol Reduction - Esters by LiAlH4 • Reduction occurs in three steps plus workup: – Steps 1 and 2 reduce the ester to an aldehyde. O R C OR' + H (1) O R C OR' (2) H O R C + OR' H A tetrahedral carbonyl addition intermediate – Step 3: Reduction of the aldehyde followed by work-up gives a 1° alcohol derived from the carbonyl group. O R C H + H (3) O R C H H OH (4) R C H H A 1° alcohol Reduction - Esters by NaBH4 • NaBH4 does not normally reduce esters, but it does reduce aldehydes and ketones. • Selective reduction is often possible by the proper choice of reducing agents and experimental conditions. O O NaBH4 OEt EtOH OH O OEt (racemic) Reduction - Esters by DIBALH • Diisobutylaluminum hydride at -78°C selectively reduces an ester to an aldehyde. – At -78°C, the TCAI does not collapse and it is not until hydrolysis in aqueous acid that the carbonyl group of the aldehyde is liberated. O 1 . DIBALH , toluen e, -78°C OCH3 2 . H2 O, HCl Methyl hexanoate O H + CH 3 OH Hexanal Reduction - Amides by LiAlH4 • LiAlH4 reduction of an amide gives a 1°, 2°, or 3° amine, depending on the degree of substitution of the amide. O NH2 Octanamide 1 . LiAlH4 2 . H2 O NH2 1-Octanamine O NMe2 1 . LiAlH4 2 . H2 O N,N -D imethylben zamide NMe2 N ,N-D imeth ylb enzylamine Reduction - Amides by LiAlH4 • The mechanism is divided into 4 steps: – Step 1: Transfer of a hydride ion to the carbonyl carbon. – Step 2: A Lewis acid-base reaction and formation of an oxygen-aluminum bond. O R C NH2 + H AlH3 (1) O R C NH2 + AlH3 H (2) AlH3 O R C NH2 H Reduction - Amides by LiAlH4 – Step 3: Redistribution of electrons and ejection of H3AlO- gives an iminium ion. – Step 4: Transfer of a second hydride ion to the iminium ion completes the reduction to the amine. O H AlH3 R C N H H H (3) R C N H H H An iminium ion (4) R-CH2 -NH2 A 1° amine Reduction - Nitriles by LiAlH4 The cyano group of a nitrile is reduced by LiAlH4 to a 1° amine. 1 . LiA lH4 CH3 CH= CH( CH 2 ) 4 C N 2 . H2 O 6-Octenenitrile CH3 CH= CH ( CH2 ) 4 CH2 N H2 6-Octen-1-amine Interconversions Problem: Show reagents and experimental conditions to bring about each reaction. O Ph Cl (a) (b ) O Ph OH Ph enylacetic acid O O (d ) Ph (c) (e) Ph OMe (g) (f) Ph OH NH2 (h ) Ph NH2