Transcript Chapter 18 Carboxylic Acid Derivatives
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 O O RCOCR' An acid anhydride O RCOR' An ester O RCNH 2 An amide RC N A nitrile O RC OH H 2 O H -Cl O RC OH H 2 O O H -OCR' O RC OH H 2 O H -OR' H 2 O O RC OH H -NH 2 H 2 HO H RC=N Th e enol of an amide O
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 RC An acyl group O O CH 3 CCl Ethan oyl ch loride (Acetyl ch loride) Cl Benzoyl chloride O 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 CH 3 SOH O Methanes ulfon ic acid O H 3 C SOH O
p-
Toluen esulfon ic acid O CH 3 SCl O Methanes ulfonyl ch loride (Mesyl ch loride, MsCl) O H 3 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 anhydride .
of the parent acid by
O O CH 3 COCCH 3 A cetic an h ydrid e O O COC Ben zoic anh ydrid e
Acid Anhydrides
• Cyclic anhydrides are named from the dicarboxylic acids from which they are derived.
O O O O O O O Succinic anhydride O Maleic anhydride Phthalic anhydride O
Phosphoric Anhydrides
• A phosphoric anhydride contains two phosphoryl groups bonded to an oxygen atom.
O O HO- P-O- P-OH OH OH Diphosphoric acid (Pyrophosphoric acid) O O O- P-O-P- O O O Diphosphate ion (Pyrophosphate ion) O O O HO- P-O- P-O-P- OH O O O Triphosphoric acid O O O O- P-O-P- O-P- O O O O Triphosphate 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 Ethyl ethan oate (Ethyl acetate) O O Is op ropyl ben zoate O OEt EtO 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 .
H 3 C
2 3 O 1 O
3-Bu tanolactone
-Butyrolactone) O
2 1
3 4
O
4-Bu tanolactone
-Bu tyrolacton e)
3 4
5 2 6
1 O O 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 .
CHO O CH 3 OPOH OCH 3 HO C-H O CH 2 -O-P-O O HO H 3 C CHO O CH 2 O-P-O O N O CO C O O P O CH 2 O D imethyl phosp hate Glyceraldeh yd e 3-phosph ate Pyridoxal phosp hate Phosphoenol pyruvate
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 CH 3 CNH 2 A cetamide (a 1° amide) O CH 3 C-N H CH 3
N-
Methylacetamide (a 2° amid e) O H-C-N CH 3 CH 3
N ,N-
D imethyl 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 .
H 3 C
2 3 1 O N H 3-Butanolactam
-Butyrolactam)
3 4
5
O 2 1 6
N H 6-Hexanolactam
-Caprolactam)
Penicillins
– The penicillins are a family of -lactam antibiotics.
HO O H H The penicillin s differ in the grou p bond ed to the acyl carb on H 2 N
-lactam NH O N S COOH Amoxicillin (a
-lactam an tib iotic)
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 H H NH 2 N H
-lactam O Cep halexin N (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 .
CH 3 C N Ethanen itrile (A cetonitrile) C N Benzon itrile CH 2 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 O O CH 3 CNH 2 Acetamide p
K
a 15-17 O SNH 2 O Ben zenesu lfonamide p
K
a 10 NH O Succinimide p
K
a 9.7
NH O Phth alimide p
K
a 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 O O N N N O O A resonance-stabilized an ion O
Acidity of N-H
– Imides such as phthalimide readily dissolve in aqueous NaOH as water-soluble salts.
O N H + N aOH O pK a 8.3
(stronger acid) (stronger base) O N Na + + H 2 O O (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 NH 3 to form water-soluble salts. The ammonium salt is used to make liquid Saccharin. Saccharin in solid form is the Ca 2+ salt.
O O NH S O
Saccharin
O + NH 3 H 2 O S N NH 4 + O O
Saccharin
A water-soluble ammonium salt
Characteristic Reactions
• Nucleophilic acyl substitution: An addition elimination sequence resulting in substitution of one nucleophile for another.
O R C Y + :Nu O C R N u Y Tetrahedral carbonyl addition intermediate O R C N u + :Y Substitution product
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.
R 2 N RO O RCO Increasin g leaving ability X Increasin g b asicity
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 H
2
O - 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 CH 3 CCl + Acetyl chlorid e H 2 O O CH 3 COH + HCl
Reaction with H
2
O - 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 CH 3 COCCH 3 + Acetic an hydrid e H 2 O O CH 3 COH + O HOCCH 3
Reaction with H
2
O - Anhydrides
– Step 1: Addition of H 2 O to give a TCAI.
H + O CH 3 -C- O-C- CH 3 O-H H H O O CH 3 -C- O-C- CH 3 H + O H O-H H H CH 3 -C- O-C- CH 3 H O O O Tetrahedral carbonyl addition intermediate + + H- O-H H
Reaction with H
2
O - Anhydrides
–Step 2: Protonation followed collapse of the TCAI.
H + O H H H O O CH 3 -C-O-C-CH 3 O H H H O H O CH 3 C O H O + O H C CH 3 H + O H H CH 3 O C + O O O C H H CH 3
Reaction with H
2
O - 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 H
2
O - Esters
• Acid-catalyzed ester hydrolysis
O R C OCH 3 + H 2 O H + OH C R OCH OH 3 H + Tetrahed ral carbonyl ad dition intermed iate O R C OH + CH 3 OH
Reaction with H
2
O - 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 RCOCH 3 + NaOH H 2 O O RCO Na + + CH 3 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 H
2
O - 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-OCH 3 + OH (1) O R- C OH OCH 3 (2) O R- C O + H OCH 3 (3) O R- C + HOCH 3 O
Reaction with H
2
O - Amides
• Hydrolysis of an amide in aqueous acid requires one mole of acid per mole of amide.
– Reaction is driven to completion by the acid base reaction between the amine or ammonia and the acid.
O N H 2 Ph 2-Phenylbutanamide + H 2 O + HCl O H 2 O heat OH + Ph 2-Phenylbutanoic acid N H 4 + Cl -
Reaction with H
2
O - 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 CH 3 CNH
N-
Phen yleth anamide (
N-
Phen ylacetamid e, Acetan ilide) + NaOH H 2 O heat O CH 3 CO Na + + H 2 N Sodiu m acetate A niline
Reaction with H
2
O - Amides
– Step1: Protonation of the carbonyl oxygen gives a resonance-stabilized cation intermediate.
O R C NH 2 + H O + H H O + H R C NH 2 O H O H R C + NH 2 R C + NH 2 Reso nance -stabil iz e d catio n i ntermed iate + H 2 O
Reaction with H
2
O - Amides
R
– Step 2: Addition of water to the carbonyl carbon followed by proton transfer gives a TCAI.
proton OH C + N H 2 + O H H R H OH C O + N H 2 H trans fer from O to N R H OH C O N H 3 +
– Step 3: Collapse of the TCAI and proton transfer.
H O R C OH NH 3 + R + O C OH H + NH 3 R O C OH + NH 4 +
Reaction with H
2
O - Nitriles
• The cyano group is hydrolyzed in aqueous acid to a carboxyl group and ammonium ion.
Ph CH 2 C N Phenylacetonitrile + 2 H 2 O + H 2 SO 4 H 2 O heat O Ph CH 2 COH Ph enylacetic acid + NH 4 + HSO 4 Ammoniu m 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 + H 2 O OH H + R-C NH A n imidic acid (en ol of an amide) O R-C-NH 2 An amide
Reaction with H
2
O - Nitriles
– Hydrolysis of a cyano group in aqueous base gives a carboxylic anion and ammonia; acidification converts the carboxylic anion to the carboxylic acid.
CH 3 ( CH 2 ) 9 C N Un decan enitrile NaOH, H 2 O h eat CH 3 ( CH 2 ) 9 O CO Na + S od ium und ecanoate + NH 3 HCl H 2 O O CH 3 ( CH 2 ) 9 COH + NaCl Und ecanoic acid + NH 4 Cl
Reaction with H
2
O - Nitriles
Hydrolysis of nitriles is a valuable route to carboxylic acids.
CH 3 ( CH 2 ) 8 CH 2 Cl 1-Chlorodecane KCN e thanol, wate r CH 3 ( CH 2 ) 9 C N H 2 SO 4 , H 2 O he at Undecanenitrile O CH 3 ( CH 2 ) 9 COH Undecanoic acid OH OH CHO HCN, KCN Benzaldehyde ethanol, water CN H 2 Benzaldehyde cyanohydrin (Mandelonitrile)
(racemic)
SO 4 , H 2 O heat COOH 2-Hydroxyphenylacetic acid (Mandelic acid)
(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 O + HCl Butanoyl chloride Cyclohexan ol Cyclohexyl butan oate
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.
(
R
OH )-2-Octanol OT s + 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 CH 3 COCCH 3 Acetic anhydride + HOCH 2 CH 3 Ethanol O CH 3 COCH 2 CH 3 Ethyl acetate O + CH 3 COH Acetic acid
– Cyclic anhydrides react with alcohols to give one ester group and one carboxyl group.
O O O + HO O OH O Phth alic anh yd rid e 2-Butan ol (
sec-
Butyl alcohol) O (s ec-Bu tyl h yd rogen phth alate
Reaction with Alcohols
– Aspirin is synthesized by treating salicylic acid with acetic anhydride.
COOH OH 2-Hydroxybenzoic acid (Salicylic acid) + O O CH 3 COCCH 3 Acetic anhydride COOH O O CH 3 + O CH 3 COH Acetylsalicylic acid (Aspirin) Acetic acid
Reaction with Alcohols
• Esters react with alcohols in the presence of an acid catalyst in an equilibrium reaction called transesterification .
O OCH 3 Methyl propenoate (Methyl acrylate) (bp 81°C) + HCl HO 1-Butanol (bp 117°C) O O Butyl propenoate (Butyl acrylate) (bp 147°C) + CH 3 OH Methanol (bp 65°C)
Reaction with Ammonia, etc.
• Acid halides react with ammonia, 1 ° 2 ° amines to form amides.
amines, and – Two moles of the amine are required per mole of acid chloride.
O Hexanoyl chloride Cl + 2 NH 3 Ammon ia O NH 2 Hexan amid e + NH 4 + Cl Ammon ium chloride
Reaction with Ammonia, etc.
• Acid anhydrides react with ammonia, and 1 ° 2 ° amines to form amides.
and – Two moles of ammonia or amine are required.
O O CH 3 COCCH 3 Acetic anh yd rid e + 2 NH 3 Ammon ia O CH 3 CNH 2 + O CH 3 CO NH 4 Acetamid e Ammon ium acetate +
Reaction with Ammonia, etc.
• Esters react with ammonia and with 1 ° 2 ° amines to form amides.
and – Esters are less reactive than either acid halides or acid anhydrides.
O Ph OEt + NH 3 Ethyl p henylacetate O Ph NH 2 Phenylacetamide + Et OH Ethanol
• Amides do not react with ammonia or with 1 ° or 2 ° amines.
Acid Chlorides with Salts
• Acid chlorides react with salts of carboxylic acids to give anhydrides. – Most commonly used are sodium or potassium salts.
O CH 3 CCl Acetyl chloride + N a + O OC Sodium benzoate O O CH 3 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 CH 3 -C-OCH 3 + R MgX 1 2 O CH 3 -C [MgX] + OCH 3 R 2 A magnesiu m s alt (a tetrahed ral carbonyl addition intermediate) O CH 3 -C + R A ketone CH 3 O [ MgX] +
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 HCOCH 3 + 2 RMgX An ester of formic acid magn esium alkoxide salt H 2 O, HCl OH HC-R + R A 2° alcohol CH 3 OH
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 CH 3 COCH 3 + 2 RMgX An ester of an y acid other than formic acid magnesiu m alk oxid e salt OH H 2 O, HCl CH 3 C-R R + A 3° alcohol CH 3 OH
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 3 CH 3 -C R A k eton e + 3 R MgX CH 3 O - [MgX] + -C-R H 2 O, HCl R (4) Magnesiu m salt CH 3 OH -C-R R A 3° alcohol
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 RCOCH 3 1 . 2 R' Li 2 . H 2 O, HCl OH R- C-R' R' + CH 3 OH
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 Pentanoyl chloride Cl 1 . ( CH 3 ) 2 CuLi, eth er, -78°C 2 . H 2 O 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.
H 3 CO O O 1 . ( CH 3 ) 2 CuLi, eth er, -78°C Cl 2 . H 2 O O H 3 CO O
Reduction - Esters by LiAlH
4 • Most reductions of carbonyl compounds now use hydride reducing agents.
– Esters are reduced by LiAlH 4 to two alcohols.
– The alcohol derived from the carbonyl group is primary.
Ph O OCH 3 1 . LiA lH 4 , e t he r 2 . H 2 O, HCl Methyl 2-phenyl propanoate (racemic) Ph OH + CH 3 OH 2-Phenyl-1 propanol (racemic) Methanol
Reduction - Esters by LiAlH
4 • Reduction occurs in three steps plus workup: – Steps 1 and 2 reduce the ester to an aldehyde.
O R C OR' + H O (1) (2) R C OR' H A tetrahedral carbonyl addition intermediate O R C H + OR'
– 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 (4) OH R C H H A 1° alcohol
Reduction - Esters by NaBH
4 • NaBH 4 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 OEt NaBH 4 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 OCH 3 1 . DIBALH , toluen e, -78°C Methyl hexanoate 2 . H 2 O, HCl O H + CH 3 OH Hexanal
Reduction - Amides by LiAlH
4 • LiAlH 4 reduction of an amide gives a 1 2 ° , or 3 ° ° , amine, depending on the degree of substitution of the amide.
O NH 2 Octanamide 1 . LiAlH 4 2 . H 2 O 1-Octanamine NH 2 O
N,N
NMe 2 1 . LiAlH 4 2 . H 2 O -D imethylben zamide NMe 2
N ,N
-D imeth ylb enzylamine
Reduction - Amides by LiAlH
4 • 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 NH 2 + H AlH 3 (1) O R C NH 2 H + AlH 3 (2) O AlH 3 R C NH 2 H
Reduction - Amides by LiAlH
4 – Step 3: Redistribution of electrons and ejection of H 3 AlO gives an iminium ion.
– Step 4: Transfer of a second hydride ion to the iminium ion completes the reduction to the amine.
O AlH 3 R C H N H H H (3) R C N H H H An iminium ion (4) R-CH 2 -NH A 1° amine 2
Reduction - Nitriles by LiAlH
4 The cyano group of a nitrile is reduced by LiAlH 4 a 1 ° amine.
to
CH 3 CH= CH( CH 2 ) 4 C 6-Octenenitrile N 1 . LiA lH 4 2 . H 2 O CH 3 CH= CH ( CH 2 ) 4 CH 2 N H 2 6-Octen-1-amine
Interconversions
Problem: Show reagents and experimental conditions to bring about each reaction.
O Ph Cl (a) (b ) (c) O Ph OH Ph enylacetic acid (d ) Ph O OMe (e) Ph (g) (f) Ph Ph OH O (h ) NH 2 NH 2