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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 O RC 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 O Acetyl chloride CH3CCl O H2C CHCH2CCl 3-butenoyl chloride or but-3-enoyl chloride O F CBr p-fluorobenzoyl bromide or 4-fluorobenzoyl bromide Acid Anhydrides O O RCOCR' 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. Acid Anhydrides O O CH3COCCH3 Acetic anhydride O O C6H5COCC6H5 Benzoic anhydride O O C6H5COC(CH2)5CH3 Benzoic heptanoic anhydride Esters O RCOR' 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. Esters O CH3COCH2CH3 Ethyl acetate O CH3CH2COCH3 Methyl propanoate O COCH2CH2Cl 2-chloroethyl benzoate Amides Having an NH2 Group O RCNH2 Identify the corresponding carboxylic acid. Replace the -ic acid or -oic acid ending with –amide. Amides Having an NH2 Group O CH3CNH2 Acetamide O (CH3)2CHCH2CNH2 3-Methylbutanamide O CNH2 Benzamide Amides Having Substituents on N O RCNHR' O and RCNR'2 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). Amides Having Substituents on N O N-Methylacetamide CH3CNHCH3 O CN(CH2CH3)2 N,N-Diethylbenzamide O CH3CH2CH2CNCH(CH3)2 CH3 N-Isopropyl-N-methylbutanamide Nitriles RC N 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). Nitriles CH3C C6H5C N N CH3CHCH3 C N Ethanenitrile or: Acetonitrile or: Methyl cyanide Benzonitrile 2-Methylpropanenitrile or: Isopropyl cyanide Structure and Reactivity of Carboxylic Acid Derivatives 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 21 16 Mechanism of Acyl Substitution Step 1: Addition of the nucleophile forms the tetrahedral intermediate. File Name: AAALCMJ0 Step 2: Elimination of the leaving group regenerates the carbonyl. File Name: AAERSTX0 © 2013 Pearson Education, Inc. Chapter 21 17 Most reactive O CH3C O CH3C Cl Least stabilized O OCCH3 O CH3C OCH2CH3 O Least reactive CH3C NH2 Most stabilized 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: •• – •• O •• •• O •• RC •• X RC + •• – •• O •• •• X RC + 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 •• •• – •• – •• O •• •• O •• O •• RC •• X RC + •• X RC + 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 least stabilized C=O O RCCl O O RCOCR' O RCOR' O RCNR'2 O RCO– most stabilized C=O Reactivity is Related to Structure Stabilization Relative rate of hydrolysis RCCl O O very small 1011 RCOCR' small 107 RCOR' O moderate 1.0 RCNR'2 large < 10-2 O O The more stabilized the carbonyl group, the less reactive it is. Nucleophilic Acyl Substitution In general: •• •• O •• R C O •• + X HY R C + Y Reaction is feasible when a less stabilized carbonyl is converted to a more stabilized one (more reactive to less reactive). HX least stabilized C=O O RCCl O O RCOCR' O A carboxylic acid RCOR' derivative can be O converted by RCNR'2 O nucleophilic acyl substitution to any other RCO– type that lies below it in this table. most stabilized C=O Nucleophilic Acyl Substitution in Acyl Chlorides Preparation of Acyl Chlorides From carboxylic acids and thionyl chloride (Section 12.7) O (CH3)2CHCOH O SOCl2 heat (CH3)2CHCCl + SO2 + HCl (90%) Reactions of Acyl Chlorides O RCCl O O RCOCR' O RCOR' O RCNR'2 O RCO– Reactions of Acyl Chlorides Acyl chlorides react with carboxylic acids to give acid anhydrides: O O O O RCCl + R'COH RCOCR' H via: R O O C OCR' Cl + HCl Example O O CH3(CH2)5CCl + CH3(CH2)5COH pyridine O O CH3(CH2)5COC(CH2)5CH3 (78-83%) Reactions of Acyl Chlorides Acyl chlorides react with alcohols to give esters: O O RCCl + R'OH RCOR' H O via: R C Cl OR' + HCl Example O O C6H5CCl + (CH3)3COH pyridine C6H5COC(CH3)3 (80%) Reactions of Acyl Chlorides Acyl chlorides react with ammonia and amines to give amides: O O RCCl + R'2NH + HO– RCNR'2 + H2O H + Cl– O via: R C Cl NR'2 Example O O C6H5CCl + HN NaOH H2O C6H5CN (87-91%) Reactions of Acyl Chlorides Acyl chlorides react with water to give carboxylic acids (carboxylate ion in base): O RCCl + H2O O RCCl + 2HO– O RCOH + HCl + Cl– O RCO– + H2O Reactions of Acyl Chlorides Acyl chlorides react with water to give carboxylic acids (carboxylate ion in base): O O RCCl + H2O RCOH H O via: R C Cl OH + HCl Example O C6H5CH2CCl + H2O O C6H5CH2COH + HCl Reactivity Acyl chlorides undergo nucleophilic substitution much faster than alkyl chlorides. O C6H5CCl Relative rates of hydrolysis (25°C) 1,000 C6H5CH2Cl 1 Nucleophilic Acyl Substitution in Acid Anhydrides Anhydrides can be prepared from acyl chlorides as described in previous slides Some Anhydrides are Industrial Chemicals O O O O CH3COCCH3 O Acetic anhydride Phthalic anhydride O O O Maleic anhydride From Dicarboxylic Acids Cyclic anhydrides with 5- and 6-membered rings can be prepared by dehydration of dicarboxylic acids: O H COH C H C H tetrachloroethane O 130°C COH O O H O (89%) + H2 O Reactions of Anhydrides O O RCOCR' O RCOR' O RCNR'2 O RCO– Reactions of Acid Anhydrides Carboxylic acid anhydrides react with alcohols to give esters: O O RCOCR + R'OH O RCOR' O + RCOH 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. Reactions of Acid Anhydrides Carboxylic acid anhydrides react with alcohols to give esters: O O O RCOCR + R'OH RCOR' H O via: R OR' C OCR O O + RCOH Example O O CH3COCCH3 + CH3CHCH2CH3 OH H2SO4 O CH3COCHCH2CH3 CH3 (60%) Reactions of Acid Anhydrides Acid anhydrides react with ammonia and amines to give amides: O O O RCNR'2 + RCO– RCOCR + 2R'2NH H + R'2NH2 O via: O R NR'2 C OCR O Example O O CH3COCCH3 + H2N CH(CH3)2 O CH3CNH CH(CH3)2 (98%) Reactions of Acid Anhydrides Acid anhydrides react with water to give carboxylic acids (carboxylate ion in base): O O RCOCR O + H2O O O RCOCR 2RCOH O + 2HO– 2RCO– + H2O Reactions of Acid Anhydrides Acid anhydrides react with water to give carboxylic acids (carboxylate ion in base): O O RCOCR O + H2O 2RCOH H O R OH C OCR O Example O O COH O + H2O COH O O Sources of Esters Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Esters are Very Common Natural Products O CH3COCH2CH2CH2CH3 butyl acetate Contributes to characteristic pear odor. Esters of Glycerol O O CH2OCR' RCOCH CH2OCR" O R, R', and R" can be the same or different. Called "triacylglycerols," "glyceryl triesters," or "triglycerides“. Fats and oils are mixtures of glyceryl triesters. Esters of Glycerol O O CH2OC(CH2)16CH3 CH3(CH2)16COCH CH2OC(CH2)16CH3 O Tristearin: found in many animal and vegetable fats. Cyclic Esters (Lactones) O O CH2(CH2)6CH3 H H (Z)-5-Tetradecen-4-olide (sex pheromone of female Japanese beetle) Preparation of Esters 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 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 CH3 CH3CHCH2CH3 O CH3COCH3 Boiling point 28°C 57°C OH CH3CHCH2CH3 99°C 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. Solubility in Water CH3 Solubility (g/100 g) CH3CHCH2CH3 O ~0 CH3COCH3 33 OH CH3CHCH2CH3 12.5 Esters can form hydrogen bonds to water, so low molecular weight esters have significant solubility in water. Solubility decreases with increasing number of carbons. Reactions of Esters: A Preview Reactions of Esters With Grignard reagents (Section 19.12) Reduction with LiAlH4 (Section 19.13) With ammonia and amines (Sections 19.11) Hydrolysis (Sections 19.9 and 19.10) Acid-Catalyzed Ester Hydrolysis Is the reverse of Fischer esterification: O RCOR' + H+ H2O O RCOH + R'OH 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. Example O CHCOCH2CH3 + H2O Cl HCl, heat O CHCOH Cl (80-82%) + CH3CH2OH Ester Hydrolysis in Aqueous Base Saponification O RCOR' O + HO– RCO– + R'OH 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). Example O CH2OCCH3 CH3 + NaOH water, methanol, heat O CH2OH (95-97%) CH3 + CH3CONa Example O H2C CCOCH3 CH3 1. NaOH, H2O, heat 2. H2SO4 O H2C (87%) CCOH CH3 + CH3OH Soap-Making Basic hydrolysis of the glyceryl triesters (from fats and oils) gives salts of long-chain carboxylic acids. These salts are soaps. O CH3(CH2)xCOK O CH2OC(CH2)xCH3 O CH3(CH2)yCOCH CH2OC(CH2)zCH3 O K2CO3, H2O, heat O CH3(CH2)yCOK O CH3(CH2)zCOK Which Bond is Broken when Esters are Hydrolyzed in Base? •• •• •• O •• RCO •• – •• R' + •• OH •• •• O •• •• •– RCO • + R'OH •• •• One possibility is an SN2 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? •• •• •• O RC – •• OR' + •• OH •• •• •• •• O RC – •• OH + •• OR' •• •• •• A second possibility is nucleophilic acyl substitution. 18O Labeling Gives the Answer O CH3CH2COCH2CH3 + NaOH O CH3CH2CONa 18O + CH3CH2OH retained in alcohol, not carboxylate; therefore nucleophilic acyl substitution is mechanism. Stereochemistry Gives the Same Answer H O CH3C Alcohol has same configuration at chirality center as ester; therefore, nucleophilic acyl substitution is mechanism. C6H5 O C KOH, H2O O CH3COK + HO CH3 H C6H5 C CH3 not SN2 Reactions of Esters with Ammonia and Amines Reactions of Esters O RCOR' O RCNR'2 O RCO– Reactions of Esters Esters react with ammonia and amines to give amides: O O RCOR' + R'2NH RCNR'2 + H O via: R C OR' NR'2 R'OH Example O H2C CCOCH3 + NH3 CH3 H2O O H2C (75%) CCNH2 CH3 + CH3OH Example O FCH2COCH2CH3 + NH2 heat O FCH2CNH (61%) + CH3CH2OH Grignard reagents react with esters to yield tertiary alcohols R' •• R' + OCH diethyl 3 – R •• R C ether C MgX O •• •• •• OCH3 •• • O • + MgX • •• •– but species formed is unstable and dissociates under the reaction conditions to form a ketone Grignard reagents react with esters – R R' •• + OCH 3 •• C R' diethyl ether R OCH3 •• • O • + MgX • •• •– MgX O •• •• This ketone then goes on to react with a R second mole of the Grignard reagent to give a tertiary alcohol. C •• –CH3OMgX R' C O •• •• Example O 2 CH3MgBr + (CH3)2CHCOCH3 1. diethyl ether 2. H3O+ OH (CH3)2CHCCH3 CH3 (73%) Two of the groups attached to the tertiary carbon come from the Grignard reagent. Reduction of Esters with LiAlH4 Gives Primary Alcohols 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). Example: Reduction of an Ester O COCH2CH3 1. LiAlH4 diethyl ether 2. H2O CH2OH + (90%) CH3CH2OH 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. Preparation of Amides Amides are prepared from amines by acylation with: Acyl chlorides (Table 19.1) Anhydrides (Table 19.2) Esters (Table 19.4) Preparation of Amides Amines do not react with carboxylic acids to give amides. The reaction that occurs is proton-transfer (acid-base). O RCOH + R'NH2 O – RCO + + R'NH3 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). O O RCOH + R'NH2 – RCO + + R'NH3 heat O RCNHR' + H2O Example O COH + H2N 225°C O + H2O CNH (80-84%) Hydrolysis of Amides File Name: AAALCNU0 Amides are hydrolyzed to the carboxylic acid under acidic or basic conditions. © 2013 Pearson Education, Inc. Chapter 21 92 Acid Hydrolysis of Amides File Name: AAALCNW0 © 2013 Pearson Education, Inc. Chapter 21 93 Example: Acid Hydrolysis O O CH3CH2CHCNH2 CH3CH2CHCOH H2O H2SO4 heat + + NH4 HSO4– (88-90%) Basic Hydrolysis of Amides File Name: AAALCNV0 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. © 2013 Pearson Education, Inc. Chapter 21 95 Example: Basic Hydrolysis O NH2 CH3CNH O KOH H2O heat Br CH3COK + Br (95%) Reduction of an Amide to an Amine File Name: AAALCOE0 Amides will be reduced to the corresponding amine by LiAlH4. © 2013 Pearson Education, Inc. Chapter 21 97 Formation of Lactams File Name: AAALCPQ0 Five-membered lactams (g-lactams) and sixmembered lactams (-lactams) often form on heating or adding a dehydrating agent to the appropriate g-amino acid or -amino acid. © 2013 Pearson Education, Inc. Chapter 21 98 b-Lactams File Name: AAALCPS0 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. © 2013 Pearson Education, Inc. Chapter 21 99 Mechanism of b-Lactam Acylation File Name: AAALCPR0 The nucleophile attacks the carbonyl of the fourmembered 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. © 2013 Pearson Education, Inc. Chapter 21 100 Action of b-Lactam Antibiotics File Name: AAALCPT0 The b-lactams work by interfering with the synthesis of bacterial cell walls. The acylated enzyme is inactive for synthesis of the cell wall protein. © 2013 Pearson Education, Inc. Chapter 21 101 Preparation of Nitriles Nitriles are prepared by: Nucleophilic substitution by cyanide on alkyl halides (Sections 8.1 and 8.11) Cyanohydrin formation (Section 17.7) Dehydration of amides Example KCN CH3(CH2)8CH2Cl ethanolwater SN2 CH3(CH2)8CH2C (95%) N Example O OH KCN CH3CH2CCH2CH3 H+ CH3CH2CCH2CH3 C N (75%) Dehydration of Amides to Nitriles File Name: AAALCPO0 Strong dehydrating agents can eliminate the elements of water from a primary amide to give a nitrile. Phosphorus oxychloride (POCl3) or phosphorus pentoxide (P2O5) can be used as dehydrating agents. © 2013 Pearson Education, Inc. Chapter 21 105 Hydrolysis of Nitriles O RCN + 2H2O + H + + RCOH + NH4 Hydrolysis of nitriles resembles the hydrolysis of amides. The reaction is irreversible. Ammonia is produced and is protonated to ammonium ion in acid solution. Example: Acid Hydrolysis O CH2CN CH2COH H2O H2SO4 heat NO2 NO2 (92-95%) Hydrolysis of Nitriles File Name: AAALCNX0 Heating with aqueous acid or base will hydrolyze a nitrile to a carboxylic acid. © 2013 Pearson Education, Inc. Chapter 21 108 Example: Basic Hydrolysis O CH3(CH2)9CN 1. KOH, H2O, heat 2. H+ CH3(CH2)9COH (80%) Reduction of Nitriles to Primary Amines File Name: AAALCOG0 Nitriles are reduced to primary amines by catalytic hydrogenation or by lithium aluminum hydride reduction. © 2013 Pearson Education, Inc. Chapter 21 110 Reaction of Nitriles with Grignards File Name: AAALCON0 A Grignard reagent or organolithium reagent attacks the cyano group to form an imine, which is hydrolyzed to a ketone. © 2013 Pearson Education, Inc. Chapter 21 111 Example C N + CH3MgI F3C 1. diethyl ether 2. H3O+, heat O CCH3 F3C (79%)