Chapter 19 Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

Nomenclature of Carboxylic Acid Derivatives

Acyl Halides RC O X Name the acyl group and add the word chloride, fluoride, bromide, or iodide as appropriate. Acyl chlorides are, by far, the most frequently encountered of the acyl halides.

Acyl Halides CH 3 CCl O Acetyl chloride 3-butenoyl chloride or but-3-enoyl chloride O H2CH2C CHCH 2 CCl O CBr F p-fluorobenzoyl bromide or 4-fluorobenzoyl bromide

Acid Anhydrides When both acyl groups are the same, name the acid and add the word anhydride. When the groups are different, list the names of the corresponding acids in alphabetical order and add the word anhydride. RCOCR' OO

Acid Anhydrides Acetic anhydride Benzoic anhydride Benzoic heptanoic anhydride CH 3 COCCH 3 OO C 6 H 5 COCC 6 H 5 OO C 6 H 5 COC(CH 2 ) 5 CH 3 OO

Esters Name as alkyl alkanoates. Cite the alkyl group attached to oxygen first (R'). Name the acyl group second; substitute the suffix -ate for the -ic ending of the corresponding acid. RCOR' O

Esters CH 3 COCH 2 CH 3 O Ethyl acetate Methyl propanoate 2-chloroethyl benzoate O CH 3 CH 2 COCH 3 COCH 2 CH 2 Cl O

Amides Having an NH 2 Group Identify the corresponding carboxylic acid. Replace the -ic acid or -oic acid ending with –amide. RCNH 2 O

Amides Having an NH 2 Group CH 3 CNH 2 O Acetamide 3-Methylbutanamide O (CH 3 ) 2 CHCH 2 CNH 2 CNH2CNH2 O Benzamide

Amides Having Substituents on N Name the amide as before. Precede the name of the amide with the name of the appropriate group or groups. Precede the names of the groups with the letter N- (standing for nitrogen and used as a locant). RCNHR' O and RCNR' 2 O

Amides Having Substituents on N CH 3 CNHCH 3 O N-Methylacetamide N-Isopropyl-N-methylbutanamide CN(CH 2 CH 3 ) 2 O N,N-Diethylbenzamide O CH 3 CH 2 CH 2 CNCH(CH 3 ) 2 CH 3

Nitriles Add the suffix -nitrile to the name of the parent hydrocarbon chain (including the triply bonded carbon of CN). or: Replace the -ic acid or -oic acid name of the corresponding carboxylic acid with –onitrile. or: Name as an alkyl cyanide (functional class name). RC N

Nitriles CH 3 C N Ethanenitrile or: Acetonitrile or: Methyl cyanide C6H5CC6H5C N Benzonitrile N C CH 3 CHCH 3 2-Methylpropanenitrile or: Isopropyl cyanide

Structure and Reactivity of Carboxylic Acid Derivatives

© 2013 Pearson Education, Inc.Chapter 2116 Nucleophilic Acyl Substitution  Interconversion of acid derivatives occurs by nucleophilic acyl substitution.  Nucleophile adds to the carbonyl, forming a tetrahedral intermediate.  Elimination of the leaving group regenerates the carbonyl.  This is an addition–elimination mechanism.  Nucleophilic acyl substitutions are also called acyl transfer reactions because they transfer the acyl group to the attacking nucleophile.

© 2013 Pearson Education, Inc.Chapter 2117 Mechanism of Acyl Substitution Step 1: Addition of the nucleophile forms the tetrahedral intermediate. Step 2: Elimination of the leaving group regenerates the carbonyl. File Name: AAALCMJ0 File Name: AAERSTX0

CH 3 C O Cl CH 3 C O OCCH 3 O CH 3 C O OCH 2 CH 3 CH 3 C O NH 2 Most reactive Least reactive Least stabilized Most stabilized

RC O X Electron Delocalization and the Carbonyl Group The main structural feature that distinguishes acyl chlorides, anhydrides, thioesters, esters, and amides is the interaction of the substituent with the carbonyl group. It can be represented in resonance terms as: – RC O X + RC O X + –

Electron Delocalization and the Carbonyl Group The extent to which the lone pair on X can be delocalized into C=O depends on: 1) The electronegativity of X 2) How well the lone pair orbital of X interacts with the  orbital of C=O RC O X – RC O X + RC O X + –

Orbital Overlaps in Carboxylic Acid Derivatives  orbital of carbonyl group

Orbital Overlaps in Carboxylic Acid Derivatives lone pair orbital of substituent

Orbital Overlaps in Carboxylic Acid Derivatives electron pair of substituent delocalized into carbonyl  orbital

RCO – O least stabilized C=O most stabilized C=O RCCl O RCOCR' OO RCOR' O RCNR' 2 O

Reactivity is Related to Structure RCOCR' OO RCCl O RCOR' O RCNR' 2 O Stabilization very small small large moderate Relative rate of hydrolysis < The more stabilized the carbonyl group, the less reactive it is.

Nucleophilic Acyl Substitution In general: O C R X + HY O C R Y + HX Reaction is feasible when a less stabilized carbonyl is converted to a more stabilized one (more reactive to less reactive).

RCO – O least stabilized C=O most stabilized C=O RCCl O RCOCR' OO RCOR' O RCNR' 2 O A carboxylic acid derivative can be converted by nucleophilic acyl substitution to any other type that lies below it in this table.

Nucleophilic Acyl Substitution in Acyl Chlorides

Preparation of Acyl Chlorides From carboxylic acids and thionyl chloride (Section 12.7) (CH 3 ) 2 CHCOH O SOCl 2 heat (CH 3 ) 2 CHCCl O + SO 2 + HCl (90%)

RCO – O RCCl O RCOCR' OO RCOR' O RCNR' 2 O Reactions of Acyl Chlorides

+ R'COH O RCOCR' OO + HCl Acyl chlorides react with carboxylic acids to give acid anhydrides: via: C R O Cl OCR' H O RCCl O

CH 3 (CH 2 ) 5 CCl O Example + CH 3 (CH 2 ) 5 COH O pyridine CH 3 (CH 2 ) 5 COC(CH 2 ) 5 CH 3 O O (78-83%)

Reactions of Acyl Chlorides + RCOR' O + HCl Acyl chlorides react with alcohols to give esters: R'OH via: C R O Cl OR' H RCCl O

Example + (CH 3 ) 3 COH pyridine (80%) C 6 H 5 COC(CH 3 ) 3 O C 6 H 5 CCl O

Reactions of Acyl Chlorides + RCNR' 2 O + H2OH2O Acyl chlorides react with ammonia and amines to give amides: R' 2 NH + HO – + Cl – via: C R O Cl NR' 2 H RCCl O

Example C 6 H 5 CCl O + NaOH (87-91%) H2OH2O HNHN C6H5CNC6H5CN O

Reactions of Acyl Chlorides + RCOH O + HCl Acyl chlorides react with water to give carboxylic acids (carboxylate ion in base): H2OH2O + RCO – O + Cl – 2HO – + H2OH2O RCCl O O

O Reactions of Acyl Chlorides + RCOH O + HCl Acyl chlorides react with water to give carboxylic acids (carboxylate ion in base): H2OH2O via: C R O Cl OH H

Example C 6 H 5 CH 2 CCl O + H2OH2O C 6 H 5 CH 2 COH O + HCl

Reactivity C 6 H 5 CCl O C 6 H 5 CH 2 Cl Acyl chlorides undergo nucleophilic substitution much faster than alkyl chlorides. Relative rates of hydrolysis (25°C) 1,0001

Nucleophilic Acyl Substitution in Acid Anhydrides Anhydrides can be prepared from acyl chlorides as described in previous slides

Some Anhydrides are Industrial Chemicals CH 3 COCCH 3 OO Acetic anhydride O O O O O O Phthalic anhydride Maleic anhydride

From Dicarboxylic Acids Cyclic anhydrides with 5- and 6-membered rings can be prepared by dehydration of dicarboxylic acids: C C H HCOH O O O O O H H tetrachloroethane 130°C (89%) + H 2 O

RCO – O RCOCR' OO RCOR' O RCNR' 2 O Reactions of Anhydrides

Reactions of Acid Anhydrides + RCOR' O + Carboxylic acid anhydrides react with alcohols to give esters: R'OH RCOH O Normally, symmetrical anhydrides are used (both R groups the same). Reaction can be carried out in presence of pyridine (a base) or it can be catalyzed by acids. RCOCR OO

Reactions of Acid Anhydrides + RCOR' O + Carboxylic acid anhydrides react with alcohols to give esters: R'OH RCOH O via: C R O OCR OR' H O RCOCR OO

Example (60%) H 2 SO 4 + CH 3 COCCH 3 OO CH 3 CHCH 2 CH 3 OHOH CH 3 COCHCH 2 CH 3 O CH 3

Reactions of Acid Anhydrides + RCNR' 2 O + Acid anhydrides react with ammonia and amines to give amides: 2R' 2 NH RCO – O R' 2 NH 2 + via: C R O OCR NR' 2 H O RCOCR OO

Example (98%) + CH 3 COCCH 3 OO H2NH2NCH(CH 3 ) 2 O CH 3 CNH CH(CH 3 ) 2

Reactions of Acid Anhydrides + 2RCOH O Acid anhydrides react with water to give carboxylic acids (carboxylate ion in base): H2OH2O + 2RCO – O + 2HO – H2OH2O RCOCR OO OO

Reactions of Acid Anhydrides + 2RCOH O Acid anhydrides react with water to give carboxylic acids (carboxylate ion in base): H2OH2O RCOCR OO C R O OCR OHOH H O

Example + H2OH2O O O O COHCOH O COH O

Sources of Esters Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

CH 3 COCH 2 CH 2 CH 2 CH 3 O Esters are Very Common Natural Products butyl acetate Contributes to characteristic pear odor.

Esters of Glycerol R, R', and R" can be the same or different. Called "triacylglycerols," "glyceryl triesters," or "triglycerides“. Fats and oils are mixtures of glyceryl triesters. RCOCH CH 2 OCR' O CH 2 OCR" O O

Esters of Glycerol CH 3 (CH 2 ) 16 COCH CH 2 OC(CH 2 ) 16 CH 3 O O O Tristearin: found in many animal and vegetable fats.

Cyclic Esters (Lactones) (Z)-5-Tetradecen-4-olide (sex pheromone of female Japanese beetle) O O H H CH 2 (CH 2 ) 6 CH 3

Fischer esterification (Sections 15.8 and 18.14) From acyl chlorides (Sections 15.8 and 19.4) From acid anhydrides (Sections 15.8 and 19.5) Baeyer-Villiger oxidation of ketones Preparation of Esters

Baeyer-Villiger Oxidation The Baeyer-Villiger Oxidation is the oxidative cleavage of a carbon-carbon bond adjacent to a carbonyl, which converts ketones to esters and cyclic ketones to lactones. The Baeyer-Villiger can be carried out with peracids, such as MCBPA, or with hydrogen peroxide and a Lewis acid.

Physical Properties of Esters

Boiling Points Esters have higher boiling points than alkanes because they are more polar. Esters cannot form hydrogen bonds to other ester molecules, so have lower boiling points than alcohols. CH 3 CHCH 2 CH 3 CH 3 CH 3 COCH 3 O CH 3 CHCH 2 CH 3 OH 28°C 57°C 99°C Boiling point

Solubility in Water Esters can form hydrogen bonds to water, so low molecular weight esters have significant solubility in water. Solubility decreases with increasing number of carbons. CH 3 CHCH 2 CH 3 CH 3 CH 3 COCH 3 O CH 3 CHCH 2 CH 3 OH ~ Solubility (g/100 g)

Reactions of Esters: A Preview

With Grignard reagents (Section 19.12) Reduction with LiAlH 4 (Section 19.13) With ammonia and amines (Sections 19.11) Hydrolysis (Sections 19.9 and 19.10) Reactions of Esters

Maximize conversion to ester by removing water. Maximize ester hydrolysis by having large excess of water. Equilibrium is closely balanced because carbonyl group of ester and of carboxylic acid are comparably stabilized. Acid-Catalyzed Ester Hydrolysis RCOH O + R'OH RCOR' O + H2OH2O H+H+ Is the reverse of Fischer esterification:

Example HCl, heat + H2OH2O O CHCOCH 2 CH 3 Cl + CH 3 CH 2 OH O CHCOH Cl (80-82%)

Is called saponification Is irreversible, because of strong stabilization of carboxylate ion If carboxylic acid is desired product, saponification is followed by a separate acidification step (simply a pH adjustment). Ester Hydrolysis in Aqueous Base Saponification RCO – O + R'OH RCOR' O + HO –

Example water, methanol, heat (95-97%) CH 2 OCCH 3 CH 3 O + NaOH CH 2 OH CH 3 O CH 3 CONa +

Example (87%) + CCOH CH 3 O H2CH2C 1. NaOH, H 2 O, heat 2. H 2 SO 4 CH 3 OH CCOCH 3 CH 3 O H2CH2C

Soap-Making CH 3 (CH 2 ) y COCH CH 2 OC(CH 2 ) x CH 3 O CH 2 OC(CH 2 ) z CH 3 O O Basic hydrolysis of the glyceryl triesters (from fats and oils) gives salts of long-chain carboxylic acids. These salts are soaps. K 2 CO 3, H 2 O, heat CH 3 (CH 2 ) x COK O CH 3 (CH 2 ) y COK O CH 3 (CH 2 ) z COK O

Which Bond is Broken when Esters are Hydrolyzed in Base? RCO O + R' – OH RCO O + R'OH – One possibility is an S N 2 attack by hydroxide on the alkyl group of the ester. Carboxylate would be the leaving group.

Which Bond is Broken when Esters are Hydrolyzed in Base? + – OH RC O OR' + OR' – A second possibility is nucleophilic acyl substitution. RC O OH

18 O Labeling Gives the Answer 18 O retained in alcohol, not carboxylate; therefore nucleophilic acyl substitution is mechanism. CH 3 CH 2 COCH 2 CH 3 O NaOH + CH 3 CH 2 CONa O CH 3 CH 2 OH +

Stereochemistry Gives the Same Answer Alcohol has same configuration at chirality center as ester; therefore, nucleophilic acyl substitution is mechanism. not S N 2 CH 3 COK O + CH 3 C O C O H C6H5C6H5 CH 3 C HOHO H C6H5C6H5 KOH, H 2 O

Reactions of Esters with Ammonia and Amines

RCOR' O RCNR' 2 O RCO – O Reactions of Esters

+ RCNR' 2 O + Esters react with ammonia and amines to give amides: R' 2 NH RCOR' O R'OH via: C R O OR' NR' 2 H

Example (75%) + CCNH 2 CH 3 O H2CH2C CH 3 OH CCOCH 3 CH 3 O H2CH2C + NH3NH3 H2OH2O

Example (61%) + FCH 2 COCH 2 CH 3 O NH2NH2 + CH 3 CH 2 OH FCH 2 CNH O heat

R MgX Grignard reagents react with esters to yield tertiary alcohols C O – MgX + –– ++ R C O diethyl ether OCH 3 OCH 3 R' but species formed is unstable and dissociates under the reaction conditions to form a ketone

R MgX Grignard reagents react with esters C O – MgX + –– ++ R C O diethyl ether OCH 3 OCH 3 R' –CH 3 OMgX C O R R' This ketone then goes on to react with a second mole of the Grignard reagent to give a tertiary alcohol.

Example 2 CH 3 MgBr + (CH 3 ) 2 CHCOCH 3 O 1. diethyl ether 2. H 3 O + (CH 3 ) 2 CHCCH 3 OH CH 3 (73%) Two of the groups attached to the tertiary carbon come from the Grignard reagent.

Lithium aluminum hydride preferred for laboratory reductions. Sodium borohydride reduction is too slow to be useful. Catalytic hydrogenolysis used in industry but conditions difficult or dangerous to duplicate in the laboratory (special catalyst, high temperature, high pressure). Reduction of Esters with LiAlH 4 Gives Primary Alcohols

Example: Reduction of an Ester 1. LiAlH 4 diethyl ether 2. H 2 O (90%) O COCH 2 CH 3 CH 3 CH 2 OH CH 2 OH +

Amides Physical Properties of Amides Amides are less reactive toward nucleophilic acyl substitution than other acid derivatives.

Physical Properties of Amides Amides are capable of hydrogen bonding.

Acyl chlorides (Table 19.1) Anhydrides (Table 19.2) Esters (Table 19.4) Preparation of Amides Amides are prepared from amines by acylation with:

Preparation of Amides Amines do not react with carboxylic acids to give amides. The reaction that occurs is proton-transfer (acid-base). RCOH O + R'NH 2 RCO O + R'NH 3 + – If no heat-sensitive groups are present, the resulting ammonium carboxylate salts can be converted to amides by heating.

Preparation of Amides Amines do not react with carboxylic acids to give amides. The reaction that occurs is proton-transfer (acid-base). RCOH O + R'NH 2 RCO O + R'NH 3 + – heat RCNHR' O + H2OH2O

Example COH O + H2NH2N 225°C + H2OH2O (80-84%) CNHCNH O

© 2013 Pearson Education, Inc.Chapter 2192 Hydrolysis of Amides Amides are hydrolyzed to the carboxylic acid under acidic or basic conditions. File Name: AAALCNU0

© 2013 Pearson Education, Inc.Chapter 2193 Acid Hydrolysis of Amides File Name: AAALCNW0

Example: Acid Hydrolysis (88-90%) CH 3 CH 2 CHCNH 2 O CH 3 CH 2 CHCOH O H2OH2O H 2 SO 4 heat + NH4NH4 + HSO 4 –

© 2013 Pearson Education, Inc.Chapter 2195 Basic Hydrolysis of Amides  Similar to the hydrolysis of an ester.  The hydroxide ion 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. File Name: AAALCNV0

Example: Basic Hydrolysis (95%) CH 3 COK O KOH H 2 O heat + CH 3 CNH O Br NH2NH2

© 2013 Pearson Education, Inc.Chapter 2197 Reduction of an Amide to an Amine  Amides will be reduced to the corresponding amine by LiAlH 4. File Name: AAALCOE0

© 2013 Pearson Education, Inc.Chapter 2198 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. File Name: AAALCPQ0

© 2013 Pearson Education, Inc.Chapter 2199  -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. File Name: AAALCPS0

© 2013 Pearson Education, Inc.Chapter 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. File Name: AAALCPR0

© 2013 Pearson Education, Inc.Chapter Action of  -Lactam 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. File Name: AAALCPT0

Nucleophilic substitution by cyanide on alkyl halides (Sections 8.1 and 8.11) Cyanohydrin formation (Section 17.7) Dehydration of amides Preparation of Nitriles Nitriles are prepared by:

Example (95%) CH 3 (CH 2 ) 8 CH 2 Cl KCN ethanol- water CH 3 (CH 2 ) 8 CH 2 C N SN2SN2

Example (75%) KCN H+H+ CH 3 CH 2 CCH 2 CH 3 O OHOH C N

© 2013 Pearson Education, Inc.Chapter Dehydration of Amides to Nitriles  Strong dehydrating agents can eliminate the elements of water from a primary amide to give a nitrile.  Phosphorus oxychloride (POCl 3 ) or phosphorus pentoxide (P 2 O 5 ) can be used as dehydrating agents. File Name: AAALCPO0

Hydrolysis of Nitriles Hydrolysis of nitriles resembles the hydrolysis of amides. The reaction is irreversible. Ammonia is produced and is protonated to ammonium ion in acid solution. + NH4NH4 + RCOH O RCN + 2H 2 O H + +

Example: Acid Hydrolysis (92-95%) O H2OH2O H 2 SO 4 heat CH 2 CN NO 2 CH 2 COH NO 2

© 2013 Pearson Education, Inc.Chapter Hydrolysis of Nitriles  Heating with aqueous acid or base will hydrolyze a nitrile to a carboxylic acid. File Name: AAALCNX0

Example: Basic Hydrolysis (80%) CH 3 (CH 2 ) 9 COH O CH 3 (CH 2 ) 9 CN 1. KOH, H 2 O, heat 2. H +

© 2013 Pearson Education, Inc.Chapter Reduction of Nitriles to Primary Amines  Nitriles are reduced to primary amines by catalytic hydrogenation or by lithium aluminum hydride reduction. File Name: AAALCOG0

© 2013 Pearson Education, Inc.Chapter Reaction of Nitriles with Grignards  A Grignard reagent or organolithium reagent attacks the cyano group to form an imine, which is hydrolyzed to a ketone. File Name: AAALCON0

Example (79%) F3CF3C C N + CH 3 MgI 1. diethyl ether 2. H 3 O +, heat F3CF3C CCH 3 O