Chapter 20 - Chapter 20 Carboxylic Acid Derivatives:...

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Unformatted text preview: Chapter 20 Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution 20.1 Nomenclature of Carboxylic Acid Derivatives NOMENCLATURE 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 CH3CCl O H2C CHCH2CCl O F CBr p-fluorobenzoyl bromide 3-butenoyl chloride acetyl chloride 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 O O C6H5COCC6H5 O O C H COC(CH2)5CH3 6 5 acetic anhydride benzoic anhydride 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 CH3COCH CH O 2 3 ethyl acetate CH3CH2COCH O 3 methyl propanoate COCH CH Cl 2 2 2-chloroethyl benzoate Amides having an NH2 group O RCNH 2 identify the corresponding carboxylic acid replace the -ic acid or -oic acid ending by -amide Amides having an NH2 group O CH3CNH O2 (CH3)2CHCH2CNH O CNH 2 2 acetamide 3-methylbutanamide benzamide Amides having substituents on N O RCNHR' and O 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 by the letter N(standing for nitrogen and used as a locant) Amides having substituents on N O CH3CNHCH3 O CN(CH2CH3)2 O CH3CH2CH2CNCH(CH3)2 CH N-isopropyl-N-methylbutanamide N-methylacetamide N,N-diethylbenzamide 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 by -onitrile or: name as an alkyl cyanide (functional class name) Nitriles ethanenitrile or: acetonitrile or: methyl cyanide benzonitrile CH3C N C6H5C N Most reactive O CH3C O CH3C O CH3C O CH3C 2 Cl O 3 Least stabilized OCCH 3 SCH CH 2 3 Least reactive O CH3C OCH CH 2 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 O + RC X RC X RC X + Orbital overlaps in carboxylic acid derivatives electron pair of substituent delocalized into carbonyl orbital Acyl Chlorides O R C O R C Cl Cl + acyl chlorides have the least stabilized carbonyl group delocalization of lone pair of Cl into C=O group is not effective because C--Cl bond is too long Acid Anhydrides O R C O O C O O + O R R C C R lone pair donation from oxygen stabilizes the carbonyl group of an acid anhydride the other carbonyl group is stabilized in an analogous manner by the lone pair Thioesters O R C O SR' R C + SR' Sulfur (like chlorine) is a third-row element. Electron donation to C=O from third-row elements is not very effective. Resonance stabilization of C=O in thioesters is not significant. Esters O R C O OR' R C + OR' lone pair donation from oxygen stabilizes the carbonyl group of an ester stabilization greater than comparable stabilization of an anhydride or thioester Amides O R C O NR'2 R C + NR'2 lone pair donation from nitrogen stabilizes the carbonyl group of an amide N is less electronegative than O; therefore, amides are stabilized more than esters and anhydrides Amides O R C O NR'2 R C + NR'2 amide resonance imparts significant double-bond character to C--N bond activation energy for rotation about C--N bond is 75-85 kJ/mol C--N bond distance is 135 pm in amides versus normal single-bond distance of 147 pm in amines Carboxylate ions O R C O O R C O very efficient electron delocalization and dispersal of negative charge maximum stabilization Nucleophiles not interested since it is an anion Most reactive O CH3C O CH3C O CH3C O CH3C 2 Cl O 3 Least stabilized OCCH 3 SCH CH 2 3 Least reactive O CH3C OCH CH 2 Most stabilized Reactivity is related to structure Stabilization Relative rate of hydrolysis O RCCl O O RCOCR' O RCOR' O RCNR'2 very small small moderate large 1011 107 1.0 < 10-2 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 HX Reaction is feasible when a less stabilized carbonyl is converted to a more stabilized one (more reactive to less reactive). 20.3 General Mechanism for Nucleophilic Acyl Substitution General Mechanism for Nucleophilic Acyl Substitution involves formation and dissociation of a tetrahedral intermediate O R C HNu X OH R C X Nu -HX R O C Nu Both stages can involve several elementary steps. The Tetrahedral Intermediate tetrahedral intermediate (TI) H O R H R O C X Nu R O C H X+ Nu C Nu Conjugate acid of tetrahedral intermediate (TI+) X Conjugate base of tetrahedral intermediate (TI) 20.4 Nucleophilic Substitution in Acyl Chlorides Preparation of Acyl Chlorides from carboxylic acids and thionyl chloride (Section 12.7) O (CH3)2CHCOH O (CH3)2CHCCl + SO2 + HCl (90%) SOCl heat 2 Reactions of Acyl Chlorides Acyl chlorides react with carboxylic acids to give acid anhydrides: O O O O RCOCR' H via: R O C Cl O OCR' + HCl RCCl + R'COH Example O CH3(CH2)5CCl + O 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 RCCl + R'OH H via: R O C Cl O RCOR' + HCl OR' Example O C6H5CCl + (CH3)3COH pyridine O C6H5COC(CH3)3 (80%) Reactions of Acyl Chlorides Acyl chlorides react with ammonia and amines to give amides: O RCCl + R'2NH + HO H via: R O C Cl NR'2 O RCNR'2 + H2O + Cl Example O C6H5CCl + HN NaOH H2O O 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 O RCO + Cl + H2O + HCl Reactions of Acyl Chlorides Acyl chlorides react with water to give carboxylic acids (carboxylate ion in base): O RCCl + H2O H via: R O C Cl OH O RCOH + HCl 20.5 Nucleophilic Acyl Substitution in Carboxylic Acid Anhydrides 20.5 Nucleophilic Acyl Substitution in Carboxylic Acid Anhydrides Some anhydrides are industrial chemicals O O O O CH3COCCH3 O O Phthalic anhydride O O Maleic anhydride Acetic anhydride 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 RCOCR + R'OH H R O C OR' O RCOR' O + RCOH via: OCR O 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 RCOCR + 2R'2NH H R O C NR'2 O O RCNR'2 + RCO + R'2NH2 via: OCR O Example O O CH3COCCH3 + H2N CH(CH3)2 O CH3CNH (98%) CH(CH3)2 Reactions of Acid Anhydrides Acid anhydrides react with water to give carboxylic acids (carboxylate ion in base): O O RCOCR + H2O O O RCOCR + 2HO O 2RCOH O 2RCO + H2O Reactions of Acid Anhydrides Acid anhydrides react with water to give carboxylic acids (carboxylate ion in base): O O RCOCR + H2O H R O 2RCOH O C OH OCR O Example O COH COH O O O + H2O O 20.6 Sources of Esters Esters are very common natural products O CH3COCH2CH2CH(CH3)2 3-methylbutyl acetate also called "isopentyl acetate" and "isoamyl acetate" contributes to characteristic odor of bananas 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 19.14) from acyl chlorides (Sections 15.8 and 20.4) from carboxylic acid anhydrides (Sections 15.8 and 20.5) Baeyer-Villiger oxidation of ketones (Section 17.16) 20.7 Physical Properties of Esters Boiling Points boiling point 28C 57C 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. CH3 CH3CHCH2CH3 O CH3COCH3 OH CH3CHCH2CH3 99C Solubility in Water Solubility (g/100 g) ~0 33 Esters can form hydrogen bonds to water, so low molecular weight esters have significant solubility in water. Solubility decreases with increasing number of carbons. CH3 CH3CHCH2CH3 O CH3COCH3 OH CH3CHCH2CH3 12.5 20.8 Reactions of Esters: A Review and a Preview Reactions of Esters with Grignard reagents (Section 14.10) reduction with LiAlH4 (Section 15.3) with ammonia and amines (Sections 20.11) hydrolysis (Sections 20.9 and 20.10) 20.9 Acid-Catalyzed Ester Hydrolysis Acid-Catalyzed Ester Hydrolysis is the reverse of Fischer esterification O RCOR' + H2O H+ 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 Mechanism of Acid-Catalyzed Ester Hydrolysis Is the reverse of the mechanism for acidcatalyzed esterification. Like the mechanism of esterification, it involves two stages: 1) formation of tetrahedral intermediate (3 steps) 2) dissociation of tetrahedral intermediate (3 steps) 20.10 Ester Hydrolysis in Base: Saponification Ester Hydrolysis in Aqueous Base O RCOR' + HO O 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 H2C O 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 O soaps. CH3(CH2)xCOK O O CH2OC(CH2)xCH3 CH3(CH2)yCOCH CH2OC(CH2)zCH3 O K2CO3, H2O, heat O CH3(CH2)yCOK O CH3(CH2)zCOK Stereochemistry at alcohol preserved O CH3C KOH, H2O O CH3COK + HO O H C CH3 H C CH3 C6H5 alcohol has same configuration at chirality center as ester; therefore, nucleophilic acyl substitution C6H5 not SN2 Key Features of Mechanism Nucleophilic addition of hydroxide ion to carbonyl group in first step Tetrahedral intermediate formed in first stage Hydroxide-induced dissociation of tetrahedral intermediate in second stage 20.11 Reactions of Esters with Ammonia and Amines Reactions of Esters Esters react with ammonia and amines to give amides: O RCOR' + R'2NH H via: R O C OR' NR'2 O RCNR'2 + R'OH Example O H2C CCOCH3 + CH3 H2O O H2C (75%) CCNH2 CH3 + CH3OH NH3 Example O FCH2COCH2CH3 + NH2 heat O FCH2CNH (61%) + CH3CH2OH 20.12 Thioesters Thioesters Thioesters are compounds of the type: O RCSR' Thioesters are intermediate in reactivity between anhydrides and esters. Thioester carbonyl group is less stabilized than oxygen analog because C--S bond is longer than C--O bond which reduces overlap of lone pair orbital and C=O orbital Thioesters Many biological nucleophilic acyl substitutions involve thioesters. O RCSR' + Nu H H via: R O C SR' Nu O RCNu + R'S H 20.13 Amides Physical Properties of Amides Amides are less reactive toward nucleophilic acyl substitution than other acid derivatives. O H C N H H H O C N H H O C N H H H Formamide Physical Properties of Amides Amides are capable of hydrogen bonding. O H C N H + H O C - H N H H + O H C - N H H Physical Properties of Amides Amides are less acidic than carboxylic acids. Nitrogen is less electronegative than oxygen. O CH3CH2NH2 CH3CNH2 pKa (approximate) 36 15 O O O CH3CNCCH3 CH3COH H 10 5 Preparation of Amides Amides are prepared from amines by acylation with: acyl chlorides (Table 20.1) anhydrides (Table 20.2) esters (Table 20.5) 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 RCOH + R'NH2 O RCO + + R'NH3 heat O RCNHR' + H2O Example O COH + H2N 225C O CNH (80-84%) + H2O 20.14 Lactams Lactams Lactams are cyclic amides. Some are industrial chemicals, others occur naturally. N H *Caproic acid is the common name for hexanoic acid. O -Caprolactam*: used to prepare a type of nylon Lactams Lactams are cyclic amides. Some are industrial chemicals, others occur naturally. O C6H5CH2CNH O N S CH3 CH3 CO2H Penicillin G: a -lactam antibiotic 20.15 Hydrolysis of Amides Hydrolysis of Amides Hydrolysis of amides is irreversible. In acid solution the amine product is protonated to give an ammonium salt. O RCNHR' + H2O + H + + RCOH + R'NH3 O Hydrolysis of Amides In basic solution the carboxylic acid product is deprotonated to give a carboxylate ion. O RCNHR' + HO O RCO + R'NH2 Example: Acid Hydrolysis O CH3CH2CHCNH2 H2O H2SO4 heat O CH3CH2CHCOH + + NH4 HSO4 (88-90%) Example: Base Hydrolysis O CH3CNH KOH H2O heat Br NH2 O CH3COK + Br (95%) Mechanism of Acid-Catalyzed Amide Hydrolysis Acid-catalyzed amide hydrolysis proceeds via the customary two stages: 1) formation of tetrahedral intermediate 2) dissociation of tetrahedral intermediate Mechanism of Amide Hydrolysis in Base Involves two stages: 1) formation of tetrahedral intermediate 2) dissociation of tetrahedral intermediate 20.16 Preparation of Nitriles 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 CH3(CH2)8CH2Cl KCN ethanolwater CH3(CH2)8CH2C (95%) N SN2 Example O CH3CH2CCH2CH3 OH CH3CH2CCH2CH3 C N KCN H+ (75%) Preparation of Nitriles By dehydration of amides uses the reagent P4O10 (often written as P2O5) O P4O10 (CH3)2CHCNH2 (CH3)2CHC N 200C (69-86%) 20.17 Hydrolysis of Nitriles 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. Hydrolysis of Nitriles O RCN + H2O + HO RCO + NH3 In basic solution the carboxylic acid product is deprotonated to give a carboxylate ion. Example: Acid Hydrolysis O CH2CN H2O H2SO4 NO2 heat NO2 (92-95%) CH2COH Example: Basic Hydrolysis O CH3(CH2)9CN 1. KOH, H2O, heat 2. H+ CH3(CH2)9COH (80%) Mechanism of Hydrolysis of Nitriles O RC N H2O RCNH2 H2O O RCOH Hydrolysis of nitriles proceeds via the corresponding amide. We already know the mechanism of amide hydrolysis. Therefore, all we need to do is to see how amides are formed from nitriles under the conditions of hydrolysis. Mechanism of Hydrolysis of Nitriles OH RC N H2O RC NH O RCNH2 The mechanism of amide formation is analogous to that of conversion of alkynes to ketones. It begins with the addition of water across the carbon-nitrogen triple bond. The product of this addition is the nitrogen analog of an enol. It is transformed to an amide under the reaction conditions. 20.18 Addition of Grignard Reagents to Nitriles Addition of Grignard Reagents to Nitriles NMgX RC N R'MgX diethyl ether NH H2O RCR' RCR' Grignard reagents add to carbon-nitrogen triple bonds in the same way that they add to carbonoxygen double bonds. The product of the reaction is an imine. Addition of Grignard Reagents to Nitriles NMgX RC N R'MgX diethyl ether NH H2O RCR' H3O+ RCR' Imines are readily hydrolyzed to ketones. O Therefore, the reaction of Grignard reagents with nitriles can be used as a RCR' synthesis of ketones. Example C F3C N + CH3MgI 1. diethyl ether 2. H3O+, heat O CCH3 (79%) F3C Section 20.19 Spectroscopic Analysis of Carboxylic Acid Derivatives Infrared Spectroscopy C=O stretching frequency depends on whether the compound is an acyl chloride, anhydride, ester, or amide. C=O stretching frequency O O O CH3CCl 1822 cm-1 CH3COCCH3 1748 and 1815 cm-1 O O CH3COCH3 CH3CNH2 1736 cm-1 1694 cm-1 Infrared Spectroscopy Anhydrides have two peaks due to C=O stretching. One results from symmetrical stretching of the C=O unit, the other from an antisymmetrical stretch. C=O stretching frequency O O CH3COCCH3 1748 and 1815 cm-1 Infrared Spectroscopy Nitriles are readily identified by absorption due to carbon-nitrogen triple bond stretching in the 22102260 cm-1 region. 1 H NMR H NMR readily distinguishes between isomeric esters of the type: 1 O RCOR' and O R'COR O O C H is less shielded than C C H 1 H NMR For example: O CH3COCH2CH3 and O CH3CH2COCH3 Both have a triplet-quartet pattern for an ethyl group and a methyl singlet. They can be identified, however, on the basis of chemical shifts. O CH3COCH2CH 3 O Figure 20.4 CH CH2COCH3 3 5.0 4.0 3.0 2.0 1.0 0 5.0 4.0 3.0 2.0 1.0 0 Chemical shift ( , ppm) 13 C NMR Carbonyl carbon is at low field ( 160-180 ppm), but not as deshielded as the carbonyl carbon of an aldehyde or ketone ( 190-215 ppm). The carbon of a CN group appears near 120 ppm. ...
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