8Chapter 19

8Chapter 19 - Chapter 19 Chapter Carboxylic Acid...

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Unformatted text preview: Chapter 19 Chapter Carboxylic Acid Derivatives Nucleophilic Acyl Substitution 19.1 19.1 Nomenclature of Carboxylic Acid Derivatives Acyl Halides Acyl Halides Acyl O RC X name the acyl group and add the word chloride, name chloride fluoride, bromide, or iodide as appropriate fluoride bromide or iodide acyl chlorides are, by far, the most frequently acyl encountered of the acyl halides encountered Acyl Halides Acyl Halides Acyl O CH3CCl acetyl chloride O H2C CHCH2CCl 3-butenoyl chloride O F CBr p-fluorobenzoyl bromide -fluorobenzoyl Acid Anhydrides Acid Anhydrides Acid OO RCOCR' when both acyl groups are the same, name the when acid and add the word anhydride anhydride when the groups are different, list the names of the when corresponding acids in alphabetical order and add the word anhydride anhydride Acid Anhydrides Acid Anhydrides Acid OO CH3COCCH3 acetic anhydride OO C6H5COCC6H5 benzoic anhydride OO C6H5COC(CH2)5CH3 benzoic heptanoic anhydride heptanoic Esters Esters Esters O RCOR' name as alkyl alkanoates name alkyl 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 ending Esters Esters Esters O CH3COCH2CH3 ethyl acetate O CH3CH2COCH3 methyl propanoate O COCH2CH2Cl 2-chloroethyl benzoate 2-chloroethyl Amides having an NH2 group Amides having an NH2 group Amides O RCNH2 identify the corresponding carboxylic acid replace the -ic acid or -oic acid ending by -amide. replace ending Amides having an NH2 group Amides having an NH2 group Amides O CH3CNH2 acetamide O (CH3)2CHCH2CNH2 3-methylbutanamide O CNH2 benzamide benzamide Amides having substituents on N Amides having substituents on N Amides O RCNHR' O and RCNR'2 name the amide as before precede the name of the amide with the name of precede the appropriate group or groups the precede the names of the groups by the letter Nprecede (standing for nitrogen and used as a locant) (standing Amides having substituents on N Amides having substituents on N Amides O CH3CNHCH3 O N-methylacetamide CN(CH2CH3)2 N,N-diethylbenzamide O CH3CH2CH2CNCH(CH3)2 CH3 N-isopropyl-N-methylbutanamide Nitriles Nitriles Nitriles RC N add the suffix -nitrile to the name of the parent add hydrocarbon chain (including the triply bonded carbon of CN) carbon or: replace the -ic acid or -oic acid name of the or: corresponding carboxylic acid by -onitrile -onitrile or: name as an alkyl cyanide (functional class or: name) name) Nitriles Nitriles Nitriles CH3C C6H5C N N CH3CHCH3 C N ethanenitrile or: acetonitrile or: methyl cyanide benzonitrile 2-methylpropanenitrile or: isopropyl cyanide 19.2 19.2 Structure of Carboxylic Acid Derivatives The key to this chapter is the next The key to this chapter is the next The slide. slide. slide. slide. IIt lists the various carboxylic acids in t It lists the various carboxylic acids in It order of decreasing reactivity toward order of decreasing reactivity toward ttheir fundamental reaction type heir fundamental reaction type (nucleophilic acyl substitution). ((nucleophilic acyl substitution). nucleophilic (nucleophilic The other way to read the list is in The other way to read the list is in The The order of increasing stabilization of the order of increasing stabilization of the carbonyl group. carbonyl group. carbonyl carbonyl Most Most reactive O CH3C CH O Cl CH3C Least Least stabilized OCCH3 O O CH3C SCH2CH3 O CH3C Least reactive OCH2CH3 O CH3C NH2 Most stabilized Electron Delocalization and the Carbonyl Group Electron The main structural feature that distinguishes acyl The chlorides, anhydrides, thioesters, esters, and amides is the interaction of the substituent with the carbonyl group. It can be represented in resonance terms as: resonance •• •• – •• – O• •O• •O • • • •• ••+ • •• RC X RC X RC X RC + Electron Delocalization and the Carbonyl Group Electron The extent to which the lone pair on X can be The delocalized into C=O depends on: delocalized 1) the electronegativity of X 2) how well the lone pair orbital of X interacts 2) with the π orbital of C=O •• •• – •• – O• •O• •O • RC • •• X • RC + • •• X • RC •+ X Orbital overlaps in carboxylic acid derivatives Orbital π orbital of carbonyl group orbital Orbital overlaps in carboxylic acid derivatives Orbital lone pair orbital of substituent Orbital overlaps in carboxylic acid derivatives Orbital electron pair of substituent delocalized into electron carbonyl π orbital orbital Acyl Chlorides •• O• R C • • Cl • •• •• R •• – •O • •• C • Cl + •• • acyl chlorides have the least stabilized carbonyl acyl group delocalization of lone pair of Cl into C=O group is not effective because C—Cl bond is too long least stabilized C=O O RCCl RC most stabilized C=O Acid Anhydrides •• O• R – •• •O • •• O• • • C •• O •• C • R R C • •• O• + O C •• lone pair donation from oxygen stabilizes the lone carbonyl group of an acid anhydride the other carbonyl group is stabilized in an analogous manner by the lone pair • R least stabilized C=O O RCCl OO RCOCR' RC most stabilized C=O Thioesters – •• •O • •• O• R C • •• SR' •• • R C • + SR' •• Sulfur (like chlorine) is a third-row element. Sulfur Electron donation to C=O from third-row elements is not very effective. Resonance stabilization of C=O in thioesters is not significant. least stabilized C=O O RCCl OO RCOCR' RC O RCSR' most stabilized C=O Esters – •• •O • •• O• R C • •• OR' •• • R C • + OR' •• lone pair donation from oxygen stabilizes the lone carbonyl group of an ester stabilization greater than comparable stabilization of an anhydride or thioester least stabilized C=O O RCCl OO RCOCR' RC O RCSR' O RCOR' most stabilized C=O Amides – •• •O • •• O• R C • •• NR'2 • R C • + NR'2 lone pair donation from nitrogen stabilizes the lone carbonyl group of an amide N iis less electronegative than O; therefore, s amides are stabilized more than esters and anhydrides anhydrides Amides – •• •O • •• O• R C • •• NR'2 • R C • + NR'2 amide resonance imparts significant double-bond amide 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 least stabilized C=O O RCCl OO RCOCR' RC O RCSR' O RCOR' O RCNR'2 most stabilized C=O Carboxylate ions – •• •O • •• O• R C • •• – O• •• • • R C • O• •• • very efficient electron delocalization and dispersal very of negative charge maximum stabilization least stabilized C=O O RCCl OO RCOCR' RC O RCSR' O RCOR' O RCNR'2 O RCO– most stabilized C=O Reactivity is related to structure Reactivity Stabilization Relative rate of hydrolysis RCCl OO very small 1011 RCOCR' O small 107 RCOR' O moderate 1.0 RCNR'2 large < 10-2 O The more The stabilized the carbonyl group, the less reactive it is. it Nucleophilic Acyl Substitution Nucleophilic In general: •• •• O• R C O• • + X HY R C • + Y Reaction is feasible when a less stabilized Reaction carbonyl is converted to a more stabilized one (more reactive to less reactive). (more HX most reactive O RCCl OO RCOCR' RC O RCSR' a carboxylic acid carboxylic derivative can be converted by nucleophilic acyl substitution to any other type that lies below it in this table this O RCOR' O RCNR'2 O RCO– least reactive 19.3 19.3 General Mechanism for Nucleophilic Acyl Substitution Nucleophilic Acyl Substitution Nucleophilic •• •• O• R C O• • + X HNu R C • + Nu Reaction is feasible when a less stabilized Reaction carbonyl is converted to a more stabilized one (more reactive to less reactive). (more HX General Mechanism for Nucleophilic Acyl Substitution General involves formation and dissociation of a tetrahedral intermediate •• O• R C HNu • X OH O• -HX R C •• Nu R C • Nu X Both stages can involve several elementary steps. General Mechanism for Nucleophilic Acyl Substitution General first stage of mechanism (formation of tetrahedral intermediate) is analogous to nucleophilic addition to C=O of aldehydes and ketones •• O• R C HNu • X OH R C X Nu General Mechanism for Nucleophilic Acyl Substitution General second stage is restoration of C=O by elimination complicating features of each stage involve acid-base chemistry •• O• R C HNu • X OH X O• -HX R C •• Nu R C • Nu General Mechanism for Nucleophilic Acyl Substitution General Acid-base chemistry in first stage is familiar in that iit has to do with acid/base catalysis of nucleophilic t addition to C=O. addition •• O• R C HNu • X OH X O• -HX R C •• Nu R C • Nu General Mechanism for Nucleophilic Acyl Substitution General Acid-base chemistry in second stage concerns form in which the tetrahedral intermediate exists under the reaction conditions and how it dissociates under those conditions. •• O• R C HNu • X OH X O• -HX R C •• Nu R C • Nu The Tetrahedral Intermediate The tetrahedral intermediate (TI) •• H O• R • H R C •• O• • • C •X Nu • • • H Nu • X+ Conjugate acid of tetrahedral Conjugate intermediate (TI+) intermediate R – •• •O• •• C Nu • • •X • Conjugate base of tetrahedral Conjugate intermediate (TI–) intermediate Dissociation of TI—H+ Dissociation B• • H R •• O• • C X + H • Nu • •• + B—H B—H O• + R C + • Nu • • •X • H Dissociation of TI Dissociation B• • H R •• •• O• • C X• • • Nu • •• + B—H B—H O• + R C + • Nu • • – •X • •• Dissociation of TI– Dissociation R •• – •• •O • •• X• C • • Nu • •• O• R C + • Nu • • – •X • •• 19.4 19.4 Nucleophilic Substitution in Acyl Chlorides Preparation of Acyl Chlorides Preparation from carboxylic acids and thionyl chloride (Section 12.7) O (CH3)2CHCOH SOCl2 heat O (CH3)2CHCCl + SO2 + HCl (90%) Reactions of Acyl Chlorides O RCCl OO RCOCR' RCOCR' O RCOR' O RCNR'2 O RCO– Reactions of Acyl Chlorides Acyl chlorides react with carboxylic acids to give acid anhydrides: O OO O RCCl + R'COH RC RCOCR' H via: R O O C OCR' Cl + HCl Example O O CH3(CH2)5CCl + CH CH3(CH2)5COH pyridine OO CH3(CH2)5COC(CH2)5CH3 (78-83%) Reactions of Acyl Chlorides Acyl chlorides react with alcohols to give esters: O O RCCl + R'OH RC RCOR' H via: R O C Cl OR' + HCl Example 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– RC H via: R RCNR'2 + H2O + Cl– O C Cl NR'2 Example 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 RC O RCCl + 2HO– O RCOH + HCl O RCO– + Cl– + H2O Reactions of Acyl Chlorides Acyl chlorides react with water to give carboxylic acids (carboxylate ion in base): O O RCCl + H2O RC RCOH H via: R O C Cl OH + HCl Example Example O C6H5CH2CCl + H2O O C6H5CH2COH + HCl Reactivity Reactivity Acyl chlorides undergo nucleophilic Acyl substitution much faster than alkyl chlorides. substitution O C6H5CCl Relative rates of hydrolysis (25°C) 1,000 C6H5CH2Cl 1 19.5 19.5 Nucleophilic Acyl Substitution in Nucleophilic Carboxylic Acid Anhydrides Carboxylic Anhydrides can be prepared from acyl Anhydrides chlorides as described in Table 20.1 chlorides Some anhydrides are industrial chemicals Some OO CH3COCCH3 O O O Acetic anhydride Phthalic anhydride O O O Maleic anhydride From dicarboxylic acids From Cyclic anhydrides with 5- and 6-membered Cyclic rings can be prepared by dehydration of dicarboxylic acids dicarboxylic O H H C C COH tetrachloroethane H O 130°C COH O O H O (89%) + H2O Reactions of Anhydrides OO RCOCR' RCOCR' O RCOR' O RCNR'2 O RCO– Reactions of Acid Anhydrides Reactions Carboxylic acid anhydrides react with alcohols to give esters: OO 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 reaction pyridine (a base) or it can be catalyzed by acids pyridine Reactions of Acid Anhydrides Reactions Carboxylic acid anhydrides react with alcohols to give esters: O OO RCOCR + R'OH RCOR' H via: R O C OR' OCR O O + RCOH Example Example OO CH3COCCH3 + CH3CHCH2CH3 OH H2SO4 O CH3COCHCH2CH3 CH3 (60%) Reactions of Acid Anhydrides Reactions Acid anhydrides react with ammonia and amines to give amides: O OO RCOCR + 2R'2NH RCNR'2 + RCO– H via: O R + R'2NH2 O NR'2 C OCR O Example Example OO CH3COCCH3 + H2N CH(CH3)2 O CH3CNH CH CH(CH3)2 (98%) Reactions of Acid Anhydrides Reactions Acid anhydrides react with water to give carboxylic acids (carboxylate ion in base): OO RCOCR + H2O OO RCOCR + 2HO– O 2RCOH O 2RCO– + H2O Reactions of Acid Anhydrides Reactions Acid anhydrides react with water to give carboxylic acids (carboxylate ion in base): OO RCOCR + H2O O H R 2RCOH O C OH OCR O Example Example O O + H2O O O COH COH COH O 19.6 19.6 Sources of Esters Esters are very common natural products O CH3COCH2CH2CH(CH3)2 CH 3-methylbutyl acetate also called "isopentyl acetate" and "isoamyl also acetate” contributes to characteristic odor of bananas contributes Esters of Glycerol Esters O O CH2OCR' RCOCH CH2OCR" O R, R', and R" can be the same or different called "triacylglycerols," "glyceryl triesters," or called "triglycerides" "triglycerides" fats and oils are mixtures of glyceryl triesters Esters of Glycerol Esters O O CH2OC(CH2)16CH3 CH3(CH2)16COCH CH2OC(CH2)16CH3 O Tristearin: found in many animal and vegetable fats Cyclic Esters (Lactones) Cyclic O O CH2(CH2)6CH3 H H (Z)-5-Tetradecen-4-olide (sex pheromone of female Japanese beetle) Preparation of Esters Fischer esterification (Chapter 15) Fischer from acyl chlorides (Chapters 15 and 19) from carboxylic acid anhydrides (Chapters 15 and 19) 19.7 19.7 Physical Properties of Esters Boiling Points Boiling CH3 boiling point CH3CHCH2CH3 O 28°C CH3COCH3 57°C OH CH3CHCH2CH3 99°C Esters have higher Esters boiling points than alkanes because they are more polar. are Esters cannot form Esters hydrogen bonds to other ester molecules, so have lower boiling points than alcohols. points Solubility in Water Solubility CH3 Solubility (g/100 g) CH3CHCH2CH3 O ~0 CH3COCH3 33 OH CH3CHCH2CH3 12.5 Esters can form Esters hydrogen bonds to water, so low molecular weight esters have significant solubility in water. Solubility decreases with increasing number of carbons. of 19.8 19.8 Reactions of Esters: A Review and a Preview Reactions of Esters Reactions with Grignard reagents (Chapters 14 & 19) with reduction with LiAlH4 (Chapters 15 & 19) (Chapters with ammonia and amines (Chapter 19) hydrolysis (Chapter 19) hydrolysis 19.9 19.9 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 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 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 acidIs catalyzed esterification. Like the mechanism of esterification, it involves Like two stages: 1) formation of tetrahedral intermediate 1) (3 steps) 2) dissociation of tetrahedral intermediate dissociation (3 steps) (3 First stage: formation of tetrahedral intermediate First stage: formation of tetrahedral intermediate First O RCOR' + H2O water adds to the water carbonyl group of the ester ester H+ OH RC OH OR' this stage is this analogous to the acidanalogous catalyzed addition of catalyzed water to a ketone water Second stage: cleavage of tetrahedral Second stage: cleavage of tetrahedral Second intermediate intermediate O + R'OH RCOH H+ OH RC OH OR' Mechanism of formation Mechanism of tetrahedral intermediate Step 1 Step 1 H •• O• H • RC •O •• • •• +O •H R' H H RC •O •• • O• + R' •O • • •H Step 1 Step 1 •• •O • H RC + O R' •• •• +O H RC •O •• • R' carbonyl oxygen is carbonyl protonated because cation produced is stabilized by electron delocalization (resonance) (resonance) Step 2 Step 2 •• • OH • + RC RC H O• • OR' •• • •• +O •H H RC •O •• • R' H •O • • •H Step 3 Step 3 •• • OH • + RC H H O• •H • OR' •• • •O • • •H •• • OH • RC • OR' •• • H O• •• • + H O• H •H Cleavage of tetrahedral Cleavage intermediate Step 4 Step 4 •• • OH • •• H RC OH •• + O R' •• H •• •O• • •H •• • OH • •• RC R' O• •• • OH H •• H O• + •H Step 5 Step 5 •• • OH • •• RC OH •• + O R' •• H •• • OH • RC + •• OH •• + •• •• R' O •• H Step 5 Step 5 •• • OH • RC + •• OH •• •• + OH RC •• OH •• Step 6 Step 6 H •• O• RC •• O+ H H H • •• O •• •• OH •• •• +O RC •• H OH •• H Key Features of Mechanism Activation of carbonyl group by protonation of carbonyl oxygen carbonyl Nucleophilic addition of water to carbonyl group forms tetrahedral intermediate Elimination of alcohol from tetrahedral intermediate Elimination restores carbonyl group restores O Labeling Studies 18 18 O COCH2CH3 + H2O COCH 18 Ethyl benzoate, labeled with 18O at the Ethyl at carbonyl oxygen, was subjected to acidcarbonyl catalyzed hydrolysis. H+ Ethyl benzoate, recovered before the reaction Ethyl 18 had gone to completion, had lost its 18O label. O This observation is consistent with a This tetrahedral intermediate. tetrahedral COCH2CH3 COCH + H2O O Labeling Studies 18 18 O COCH2CH3 + H2O COCH H+ OH C H+ O COCH2CH3 + H2O COCH OH OCH2CH3 19.10 19.10 Ester Hydrolysis in Base: Saponification Ester Hydrolysis in Aqueous Base O RCOR' O + HO– RCO– + R'OH is called saponification 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 Example O CH2OCCH3 CH CH3 + NaOH water-methanol, heat O CH2OH CH (95-97%) CH3 + CH3CONa Example Example O H2C CCOCH3 CH3 1. NaOH, H2O, heat 2. H2SO4 O H2C (87%) CCOH CH3 + CH3OH O Soap-Making Soap-Making Basic hydrolysis Basic of the glyceryl triesters (from fats and oils) gives salts of long-chain carboxylic acids. carboxylic These salts are These O soaps. soaps. CH3(CH2)xCOK 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 Which hydrolyzed in base? •• •• •O • •• RCO •• – •• R' + • OH • •• •O • •• – •• RCO • + R'OH •• •• • One possibility is an SN2 attack by hydroxide on attack the alkyl group of the ester. Carboxylate is the leaving group. leaving Which bond is broken when esters are Which hydrolyzed in base? •• •• •O • RC – •• OR' + • OH •• •• • •• •O • RC RC – •• OH + • OR' •• •• A second possibility is nucleophilic acyl second substitution. • •• O Labeling gives the answer 18 18 O CH3CH2COCH2CH3 + CH NaOH O CH3CH2CONa + CH3CH2OH O retained in alcohol, not carboxylate; retained therefore nucleophilic acyl substitution. 18 Stereochemistry gives the same answer Stereochemistry H O CH3C alcohol has same alcohol configuration at chirality center as ester; therefore, nucleophilic acyl substitution substitution C6H5 O C KOH, H2O O CH3COK + HO CH CH3 H C6H5 C CH3 not SN2 Does it proceed via a tetrahedral intermediate? Does •• •• •O • RC – •• OR' + • OH •• •• • •• •O • RC RC – •• OH + • OR' •• •• • Does nucleophilic acyl substitution proceed in Does a single step, or is a tetrahedral intermediate involved? involved? •• O Labeling Studies 18 18 O COCH2CH3 + H2O COCH HO– 18 Ethyl benzoate, labeled with 18O at the Ethyl at carbonyl oxygen, was subjected to hydrolysis in base. in Ethyl benzoate, recovered before the reaction Ethyl 18 had gone to completion, had lost its 18O label. This observation is consistent with a This O tetrahedral intermediate. tetrahedral COCH2CH3 COCH + H2O O Labeling Studies 18 18 O COCH2CH3 + H2O COCH HO– OH C HO– O COCH2CH3 + H2O COCH OH OCH2CH3 Mechanism of Ester Hydrolysis in Base Involves two stages: 1) formation of tetrahedral intermediate 1) 2) dissociation of tetrahedral intermediate First stage: formation of tetrahedral intermediate First stage: formation of tetrahedral intermediate First O RCOR' + H2O HO– OH RC OH OR' water adds to the water carbonyl group of the ester ester this stage is this analogous to the base-catalyzed addition of water to a ketone ketone Second stage: cleavage of tetrahedral Second stage: cleavage of tetrahedral Second intermediate intermediate O + R'OH RCOH HO– OH RC OH OR' Mechanism of formation Mechanism of tetrahedral intermediate Step 1 Step 1 •• O• RC H • •O • •• – •• • OR' •• • – •• •O• • RC RC • • OR' •• • H O• •• • Step 2 Step 2 •• – • O• •• •O • H O• H RC RC H •• •• H • O• •• • OR' •• • H – •• •O• • RC • • OR' •• • • H O• •• • Dissociation of Dissociation tetrahedral intermediate Step 3 Step 3 •• – • O• •• H •• •O • H •• O• H RC • H O• •• • OR' •• • H • •• O• RC • •O •• • H – •• • OR' • •• Step 4 Step 4 •• O• RC • •O• •• •• – HO – H •• O• RC • •O •• • •• OR' •• H2O H – •• • OR' • •• Key Features of Mechanism Nucleophilic addition of hydroxide ion to carbonyl Nucleophilic group in first step Tetrahedral intermediate formed in first stage Hydroxide-induced dissociation of tetrahedral intermediate in second stage 19.11 19.11 Reactions of Esters with Ammonia and Amines Reactions of Esters O RCOR' RCOR' O RCNR'2 O RCO– Reactions of Esters Reactions Esters react with ammonia and amines to give amides: O O RCOR' + R'2NH RCNR'2 + H via: R O C OR' NR'2 R'OH Example Example O H2C CCOCH3 + NH3 CH3 H2O O H2C (75%) CCNH2 CH3 + CH3OH Example Example O FCH2COCH2CH3 + NH2 heat heat O FCH2CNH (61%) + CH3CH2OH 19.12 19.12 Preparation of Tertiary Alcohols From Esters and Grignard From Reagents Reagents Grignard reagents react with esters Grignard reagents react with esters Grignard δ– R R' •• δ+ OCH3 •• C MgX O • •• •• • diethyl ether R' •• OCH3 RC •• + • O •– MgX •• •• but species formed is but unstable and dissociates under the reaction conditions to form a ketone conditions Grignard reagents react with esters Grignard reagents react with esters Grignard δ– R R' •• δ+ OCH3 •• C R' diethyl ether •• OCH3 RC •• + • O •– MgX •• •• –CH3OMgX MgX O • •• •• • this ketone then goes on to react with a second mole of the Grignard reagent to give a tertiary alcohol alcohol R C O• •• • R' Example Example Example O 2 CH3MgBr + (CH3)2CHCOCH3 1. diethyl ether 2. H3O+ OH (CH3)2CHCCH3 CH3 (73%) Two of the groups Two attached to the tertiary carbon come from the Grignard reagent Grignard 19.13 19.13 Reactions of Esters with Lithium Aluminum with Hydride Hydride Reduction of Esters Reduction of Esters Gives Primary Alcohols Gives Primary Alcohols Lithium aluminum hydride preferred for Lithium laboratory reductions Sodium borohydride reduction is too slow to be useful Catalytic hydrogenolysis used in industry but conditions difficult or dangerous to duplicate but in the laboratory (special catalyst, high in temperature, high pressure Example: Reduction of an Ester Example: Reduction of an Ester Example: O COCH2CH3 1. LiAlH4 diethyl ether 2. H2O CH2OH + CH (90%) CH3CH2OH 19.14 19.14 Amides Physical Properties of Amides Physical Amides are less reactive toward nucleophilic Amides acyl substitution than other acid derivatives. acyl O H C O O N H H H C N H H Formamide H C N H H Physical Properties of Amides Physical Amides are capable of hydrogen bonding. O H C H N δ+ H H δ− O C δ+ N H δ− H O H C N H H Physical Properties of Amides Physical Amides are less acidic than carboxylic acids. Amides Nitrogen is less electronegative than oxygen. Nitrogen O CH3CH2NH2 CH3CNH2 pKa (approximate) 36 15 OO O CH3CNCCH3 CH3COH H 10 5 Preparation of Amides Amides are prepared from amines by acylation with: acyl chlorides acyl anhydrides esters Preparation of Amides Preparation Amines do not react with carboxylic acids to give Amines not amides. The reaction that occurs is proton-transfer (acid-base). O O + –+ R'NH3 RCO RCOH + R'NH2 If no heat-sensitive groups are present, the If resulting ammonium carboxylate salts can be converted to amides by heating. converted Preparation of Amides Preparation Amines do not react with carboxylic acids to give Amines not amides. The reaction that occurs is proton-transfer (acid-base). O O + –+ R'NH3 RCO RCOH + R'NH2 heat O RCNHR' + H2O Example Example O COH + COH H2N 225°C O + H2O CNH (80-84%) 19.15 19.15 Hydrolysis of Amides Hydrolysis of Amides Hydrolysis Hydrolysis of amides is irreversible. In acid Hydrolysis solution the amine product is protonated to give an ammonium salt. give O O + + RCNHR' + H2O + H RCOH + R'NH3 Hydrolysis of Amides Hydrolysis In basic solution the carboxylic acid product is deprotonated to give a carboxylate ion. O RCNHR' O – + HO – RCO + R'NH2 Example: Acid Hydrolysis Example: O O CH3CH2CHCNH2 CH3CH2CHCOH CH H2O H2SO4 heat + + NH4 HSO4– (88-90%) Example: Basic Hydrolysis Example: O CH3CNH O KOH H2O NH2 CH3COK + heat Br Br Br Br (95%) Mechanism of Acid-Catalyzed Amide Hydrolysis Acid-catalyzed amide hydrolysis proceeds via Acid-catalyzed the customary two stages: 1) formation of tetrahedral intermediate 2) dissociation of tetrahedral intermediate First stage: formation of tetrahedral intermediate First stage: formation of tetrahedral intermediate First O RCNH2 + H2O water adds to the water carbonyl group of the amide amide H+ OH RC OH NH2 this stage is this analogous to the acidanalogous catalyzed addition of catalyzed water to a ketone water Second stage: cleavage of tetrahedral Second stage: cleavage of tetrahedral Second intermediate intermediate O RCOH + + NH4 H+ OH RC OH NH2 Mechanism of formation Mechanism of tetrahedral intermediate Step 1 Step 1 H •• O• H • RC RC O• + •H • NH2 • •• +O RC • NH2 • H H •O • • •H Step 1 Step 1 •• •O • H RC + NH2 •• +O RC RC • NH2 • H carbonyl oxygen is carbonyl protonated because cation produced is stabilized by electron delocalization (resonance) (resonance) Step 2 Step 2 •• • OH • + RC H O• • NH2 • •H •• +O RC RC • NH2 • H H •O • • •H Step 3 Step 3 •• • OH • + RC H H O• •H • NH2 • •O • • •H •• • OH • RC • NH2 • H O• •• • + H O• H •H Cleavage of tetrahedral Cleavage intermediate Step 4 Step 4 •• • OH • •• H RC OH •• + H2N H •O• • •H •• • OH • RC H O• •• H2N • • H • H O• + •H Step 5 Step 5 •• • OH • •• RC OH •• + H2N H •• • OH • RC + •• OH •• + • NH3 • Step 6 Step 6 •• • OH • •• RC OH •• + H2N H + NH4 •• • OH • RC + •• OH •• + H3O + • NH3 • Step 6 Step 6 •• • OH • RC + •• OH •• •• + OH RC •• OH •• Step 6 Step 6 H •• O• RC •• O+ H H H • •• O •• •• OH •• •• +O RC •• H OH •• H Mechanism of Amide Hydrolysis in Base Involves two stages: 1) formation of tetrahedral intermediate 1) 2) dissociation of tetrahedral intermediate First stage: formation of tetrahedral intermediate First stage: formation of tetrahedral intermediate First O RCNH2 + H2O HO– OH RC OH NH2 water adds to the water carbonyl group of the amide amide this stage is this analogous to the base-catalyzed addition of water to a ketone ketone Second stage: cleavage of tetrahedral Second stage: cleavage of tetrahedral Second intermediate intermediate O – RCO + NH3 HO– OH RC OH NH2 Mechanism of formation Mechanism of tetrahedral intermediate Step 1 Step 1 •• O• RC H • •O • •• – •• • NH2 • – •• •O• • RC RC • • NH2 • H O• •• • Step 2 Step 2 •• – • O• •• •O • H H O• H RC H •• •• H • O• •• • NH2 • – •• •O• • RC RC • • NH2 • • H O• •• • Dissociation of Dissociation tetrahedral intermediate Step 3 Step 3 •• • OH • •• H RC OH •• + H2N H •O• – •• •• •• • OH • RC H O• •• H2N • • H • H O• •• • Step 4 Step 4 •• – • O• •• H •• •O • H H •• H O• RC • •• OH H3N + •• •• O• RC • •O •• • H • NH3 • Step 5 Step 5 •• O• RC • •O• •• •• – HO – •• O• RC • •O •• • H • NH3 • 19.16 19.16 Lactams Lactams Lactams Lactams are cyclic amides. Some are industrial chemicals, others occur naturally. γ β α δ ε N O ε-Caprolactam*: used to prepare a type of nylon H *Caproic acid is the common name for hexanoic acid. Lactams Lactams Lactams are cyclic amides. Some are industrial chemicals, others occur naturally. O C6H5CH2CNH α O βS CH3 CH N CH3 CO2H Penicillin G: a β-lactam antibiotic Penicillin 19.17 19.17 Preparation of Nitriles Preparation of Nitriles Nitriles are prepared by: nucleophilic substitution by cyanide on nucleophilic alkyl halides cyanohydrin formation dehydration of amides Example Example CH3(CH2)8CH2Cl KCN ethanolwater SN2 CH3(CH2)8CH2C (95%) N Example Example O CH3CH2CCH2CH3 KCN H+ OH CH3CH2CCH2CH3 C N (75%) Preparation of Nitriles By dehydration of amides uses the reagent P4O10 (often written as uses P2O5) O P4O10 (CH3)2CHCNH2 (CH3)2CHC N 200°C (69-86%) 19.18 19.18 Hydrolysis of Nitriles Hydrolysis of Nitriles Hydrolysis O RCN + 2H2O + H + + RCOH + NH4 Hydrolysis of nitriles resembles the hydrolysis of amides. The reaction is irreversible. of irreversible Ammonia is produced and is protonated to ammonium ion in acid solution. ammonium Hydrolysis of Nitriles Hydrolysis O – RCN + H2O + HO – RCO + NH3 In basic solution the carboxylic acid product is deprotonated to give a carboxylate ion. Example: Acid Hydrolysis Example: O CH2CN CH CH2COH CH H2O H2SO4 NO2 heat NO2 (92-95%) Example: Basic Hydrolysis Example: O CH3(CH2)9CN 1. KOH, H2O, heat 2. H + CH3(CH2)9COH (80%) Mechanism of Hydrolysis of Nitriles O RC N H2O RCNH2 O H2O Hydrolysis of nitriles proceeds via the Hydrolysis corresponding amide. We already know the mechanism of amide hydrolysis. Therefore, all we need to do is to see how Therefore, amides are formed from nitriles under the conditions of hydrolysis. RCOH Mechanism of Hydrolysis of Nitriles OH RC N H2O RC O NH RCNH2 The mechanism of amide formation is analogous The 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 The analog of an enol. It is transformed to an amide analog under the reaction conditions. Step 1 Step 1 H H – •O • •• •• RC N• • • O• •• RC •N• – •• Step 2 Step 2 H • O• •• RC •N• – •• H O• •• RC •N • • H H •O • – •• •• H H O• •• • Step 3 Step 3 H •O • •• H H •O • – •• •• •• •• O• H • RC – •N H O• •• RC •N • • • H •• Step 4 Step 4 •• •• O• O• • • RC •N • H RC H – •• •O• • • H – •N H • •• H •• O• • H 19.19 19.19 Addition of Grignard Reagents to Nitriles Addition of Grignard Reagents to Nitriles NMgX RC N R'MgX diethyl ether RCR' NH H2O RCR' Grignard reagents add to carbon-nitrogen triple Grignard 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 Addition NMgX RC N R'MgX diethyl ether RCR' NH H2O RCR' H3O+ Imines are readily hydrolyzed to ketones. O Therefore, the reaction of Grignard Therefore, reagents with nitriles can be used as a RCR' synthesis of ketones. synthesis Example Example C CH N + CH3MgI F3C 1. diethyl ether 2. H3O+, heat O CCH3 F3C (79%) Section 19.20 Section Spectroscopic Analysis of Carboxylic Acid Derivatives Infrared Spectroscopy C=O stretching frequency depends on whether the C=O compound is an acyl chloride, anhydride, ester, or amide. C=O stretching frequency ν C=O O OO CH3CCl CH3COCCH3 1822 cm-1 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 One unit, the other from an antisymmetrical stretch. C=O stretching frequency ν C=O OO CH3COCCH3 1748 and 1815 cm-1 Infrared Spectroscopy Nitriles are readily identified by absorption due to carbon-nitrogen triple bond stretching in the 2210carbon-nitrogen 2260 cm-1 region. H NMR 1 H NMR readily distinguishes between isomeric esters of the type: 1 O RCOR' O and R'COR O O C H iis less shielded than C s C H H NMR 1 For example: O CH3COCH2CH3 O and 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 O Figure 20.9 CH3CH2COCH3 CH3COCH2CH3 5.0 4.0 3.0 2.0 1.0 0 5.0 Chemical shift (δ, ppm) Chemical 4.0 3.0 2.0 1.0 0 C NMR 13 13 Carbonyl carbon is at low field (δ 160-180 ppm), but not as deshielded as the carbonyl carbon of an aldehyde or ketone (δ 190-215 carbon ppm). The carbon of a CN group appears near δ 120 ppm. 120 UV-VIS UV-VIS n→π* absorption: λmax absorption: O OO CH3CCl CH3COCCH3 235 nm 225 nm O O CH3COCH3 CH3CNH2 207 nm 214 nm Mass Spectrometry Most carboxylic acid derivatives give a prominent Most peak for an acylium ion derived by the fragmentation shown. •• O• • •+ O• • RCX • RCX • • • RC + O• + • • X• • Mass Spectrometry Amides, however, cleave in the direction that gives Amides, a nitrogen-stabilized cation. •• O• • RCNR'2 •• •+ O• • RCNR'2 •• •• R• + •O • C + NR'2 End of Chapter 19 End ...
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This document was uploaded on 01/03/2012.

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