Ch.21 Carboxylic Acid Derivatives and Nucleophilic Acyl Substitution Carboxylic Acid Derivatives O O O O O R C OH R C Cl R C O C R' R C O R' Ester Carboxylic Carboxylic Acid anhydride acid acid chloride O O O O - R C NH2 R C SR' R C O P O R C N - Amide Thioester O Acyl phosphate Nitrile Nucleophilic Acyl Substitution O O Nu- + Y- R Y R Nu 21.1 Nomenclature Acid Halides: RCOX -oic acid → -yl -carboxylic acid → -carbonyl O O Cl Cl Acetyl chloride Benzoyl chloride O Cl Cyclohexanecarbonyl chloride Acid Anhydrides: RCO2COR' acid → anhydride O O O O O O O O O Acetic anhydride Benzoic anhydride Succinic anhydride - anhydride from substituted monocarboxylic acid: bis- - unsymmetrical anhydride: cite two carboxylic groups alphabetically O O O O O Cl Cl O Bis(chloroacetic) anhydride Acetic benzoic anhydride Amides: RCONH2 -(o)ic acid → amide -carboxylic acid → -carboxamide O O O NH2 NH NH2 2 Acetamide Hexanamide Cyclohexanecarboxamide - substututed amide: N-alkyl----amide O O N CH N 3 H N-Methylacetamide N,N-Diethylcyclohexanecarboxamide Esters: RCO2R' - name alkyl group attached to oxygen then -ic acid → -ate O OO O EtO OEt Ethyl acetate Diethyl malonate O O tert-Butyl cyclohexanecarboxylate 21.2 Nucleophilic Acyl Substitution Reactions Nucleophilic acyl substitution: Y = OR', Cl, OCOR', NR'2 OO- Nu- O - R + Y R Y Y R Nu Nu tetrahedral intermediate (alkoxide anion) - addition-elimination mechanism: different from SN2 mechanism Relative Reactivity of Carboxylic Acid Derivatives Steric effect: O O O O R R R H C < < < C R R C H C H R H H H more reactive Electronical effect: - strongly polarized derivatives are more reactive - leaving group ability O O O O O < < < R NH2 R OR' R O R R Cl more reactive Conversion of a more reactive derivatives to less a reactive derivatives; but reverse direction is not possible O R Cl O O R O R O R OR' O R NH2 - only ester and amides are commonly found in nature - acid chloride and acid anhydride undergo nucleophilic attack by water Kinds of Nucleophilic Acyl Substitutions O R NH2 O O further Aminolysis R OR' R H reaction Alcoholysis NH3 Reduction R'OH [H-] O O O H2O R'MgX further R OH R Y R R' reaction Hydrolysis Grignard reaction 21.3 Nucleophilic Acyl Substitution Reactions of Carboxylic Acids O O R OR' R NH2 O O O O R Cl R OH R O R' Conversion to acid chloride O SOCl2 O ROH CHCl3 RCl mechanism: O S O O O Cl Cl O O S + HCl ROCl S ROH Cl ROCl H base Cl- O O O SO + Cl- + S 2 ROCl RCl Cl Conversion to acid anhydride: OO - acyclic anhydrides are difficult to prepare - acetic anhydride is commonly used H3COCH3 Acetic anhydride - 5, 6-membered cyclic anhydrides are obtained by high temperature dehydration O COOH 200oC O + H2O COOH O Conversion to esters: Alkylation of carboxylates with 1o alkyl halides O R'-X O + NaX RONa ROR' Fisher esterification: acid-catalyzed, HCl, H2SO4 O cat. H2SO4 O + H2O ROH R'OH ROR' mechanism H O O OH cat. H2SO4 R OH ROH ROH RO H HO-R' H O H O 2 O + H3O + H ROR' R O RO H - reversible process: use excess of alcohol for complete esterification - substitution of OH by OR' O cat. H2SO4 O + CH3O*H + H2O R OH R O*CH3 Conversion to amide O NH3 O - + ROH RONH4 - amines are base: direct conversion to an amide is not possible 21.4 Chemistry of Acid Halides Preparation O SOCl2 O ROH CHCl3 RCl acid bromide, acid iodide: unstable Reactions Friedel-Craft acylation: O Ar-H O RCl AlCl3 RAr Reactions O R NH2 O OH O Amide further R OR' R H reaction R Ester NH3 Aldehyde 10 Alcohol R'OH [H-] O O O OH H2O R'MgX further R OH R Cl R R' reaction R R' Acid R' Ketone 30 Alcohol Hydrolysis: O- O O Base O R Cl H RCl HO RO H2O ROH H H +HCl - use base (pyridine, NaOH) to neutralize HCl Alcoholysis: Ester formation O R'OH O + pyridine ROR' RCl N Cl- (or Et3N) H - use base (pyridine, Et3N) to neutralize HCl formed - reactivity: 1o > 2o > 3o alcohol - selective esterification of unhindered alcohol O O OH H CCl 3 O CH3 HO pyridine HO Aminolysis O 2 R'NH O 2 + - +R'NH3 Cl RCl R NHR' - use 2 equiv. of amine O 2 eq. O HN(CH ) Cl 3 2 N(CH3)2 + - +Me2NH2 Cl - for valuable amines; use external bases MeO MeO O HN O O MeO C Cl MeO C N O + NaCl aq. NaOH MeO MeO Reduction: O 1. LiAlH4 R CH OH + 2 RCl2. H3O - little practical value: acid is more readily available and reduced to alcohol - O O O R Cl R H RCl H- H H- + HH H3O HH ROH RO- Reaction of acid chloride with organometallic reagents O 1. 2 R'MgX R' R' C + RCl2. H3O R OH - O O O R' R' R Cl RClR'MgX R' R R' ROH R'MgX Diorganocopper reagent: Gilman reagent O O O R'2CuLi RCl R R' R CuR'2 O O Et2CuLi Cl ether, -78oC 92% - diorganocopper reaction occurs only with acid chlorides - carboxylic acid, ester, anhydride, amide do not react with diorganocopper reagents 21.5 Chemistry of Acid Anhydride Preparation O O OO + + NaCl RONa R' Cl ether ROR' Reactions O O R NH R OR' 2 Ester Amide R'OH NH3 O O O - O further OH H2O [H ] R OH ROR' R H reaction R Acid 0 Aldehyde 1 Alcohol - Acetic anhydride is commonly used - selective reaction is possible if two functional groups have different reactivity O O OH Pyridine OH +AcOH OO OH O H COCH 3 3 O CH3 Ac2O Aspirin H N NH2 Pyridine +AcOH OO O HO HO H3COCH3 Acetaminophen - AcCl: highly reactive, HCl (NaCl) as by-product -Ac2O/pyr: moderate reactivity, AcOH (AcONa) as by-product 21.6 Chemistry of Esters - fragrant odors of fruits and flowers O O OCOR OCOR O O OCOR from pineapples from bananna A fat (R = C11-17 chains) industrial use - Ethyl acetate (solvent) - dialkyl phthalate (plasticizer: keep polymers from becoming brittle) O O Dibutyl phthalate (a plasticizer) O O Preparation of esters o O 1 alkyl halides R OH R'OH O R'-X O H+ R OR' R ONa S 2 O pyr N R'OH R Cl Reactions of esters O R'' R'' ROH R NH2 0 Amide 3 Alcohol NH3 R''MgX O O - O further OH H2O [H ] R OH ROR' R H reaction R Acid 0 Aldehyde 1 Alcohol Hydrolysis: O H2O O + R'OH ROR'NaOH ROH + or H3O Saponification: basic hydrolysis + Na O- O O R OR' + R'O-Na+ ROR'NaOH HO RO H + O O H3O - + + R'OH ROH RONa acid salt Acid-catalyzed hydrolysis: reversible H OH O H+ O R OR' ROR' ROR' HO H H2O H O H O 2 O + R'OH + H3O + R' ROH R O HO H Aminolysis: not often used, acid chloride method is commonly used O O NH3 + CH3OH ROCH3 RNH2 not so reactive to amine Reduction: LiAlH4 -NaBH4 cannot reduce ester under normal condition O LiAlH 4 +CH3OH ROCH3 ether ROH - O O O R OR' R H ROR'H- H H- + HH H3O HH ROH RO- - intermediate aldehyde is more reactive than ester O OH LiAlH O 4 OH ether - intermediate aldehyde can be isolated by DIBAH (i-Bu2AlH) O O 1. DIBAL toluene ROCH + RH 3 2. H3O O OH DIBAL O O -78oC Grignard addition: add 2 equivalent of RMgX, yield 3o alcohol product O OH 2 eq. MeMgBr OMe Me Me ether - intermediate ketone is more reactive than ester O 2 eq.MeMgBr OH O H3C ether H3C OH 21.7 Chemistry of Amides Preparation O R Cl NH 3 R'2NH R'NH2 O O O R NH2 R NR'2 R NHR' Reactions - amide bonds are stable, used for protein building R R R' R" OH H2N N N N O H O H O H O Amino acids A protein (polyamide) Hydrolysis: require severe conditions, synthetically not useful heat O O H2O + RNH2 R NHR' NaOH ROH + or H3O slow (inefficient) Reduction: LiAlH4 -NaBH4 cannot reduce amides O 1. LiAlH 4 RNH2 + RNH2 2. H3O mechanism Al O H O HH H- R RNH NH2 2 RNH RNH2 H- H 2 - oxygen atom leaves as an aluminate anion O 1. LiAlH4 R NHR' + R NHR' 2. H3O O NH 1. LiAlH 4 NH + 2. H3O 21.8 Thiol Esters and Acyl Phosphate: Biological Carboxylic Acid Derivatives O O O R C SR' R C O P O- - Thioester O Acyl phosphate NH2 N N O O O O N N H C S O P O P O 3 N N O H H O- O- O OH O OH Acetyl CoA O P O- (a thiol ester) O- O O Nu- + -SCoA H3C SCoA H3C Nu OH OH O O HO + O + HSCoA HO HO H3C SCoA HO NH 2OH NH O OH Glucosamine CH3 O O O 2- - NADH 2- 3- O POCH CH C O P O O POCH CH C H + PO4 3 2 - 3 2 O- "H " HO Mg2+ HO 3-Phosphoglyceroyl phosphate Glyceraldehyde 3-phosphate 21.9 Polymers and Polyesters: Step-Growth Polymers Chain-growth polymers: chain-reaction process of one type of monomer R In + R n Step-growth polymers: polymerization between two difunctional molecules AB AB n Step-growth polymers: O O O O H2N(CH2)nNH2 + Cl C (CH2)n C Cl HN(CH2)nNH C (CH2)n C A diamine A diacid chloride A polyamide(Nylon) O O O O HO(CH2)nOH + HO C (CH2)n C OH O(CH2)nO C (CH2)n C A diol A diacid A polyester Nylons: polyamide = diamine + diacid O OH H2N HO + NH2 Adipic acid O Hexamethylenediamine Fibers, heat clothing, O tire cord, H N N +2n H2O bearings H O n Nylon 66 O H O N H Fibers, N large cast articles n Caprolactam Nylon 6, Perlon Polyesters: dialcohol + diacid OH MeO2CCO2Me + HO Dimethyl terephthalate Ethylene glycol 200oC O O O Fibers, O CC+ 2n CH3OH clothing, n tire cord, Polyester, Dacron, Mylar film Polycarbonate: dialcohol + carbonate CH3 O + HOC OH OO CH3 Diphenylcarbonate Bisphenol A 300oC CH3 O OOC C + 2n PhOH CH3 n Lexan - high impact strength; machinery housing, telephone, safety helmet Polyurethane: dialcohol + diisocyanate CH3 O C NCON + HO(CH2CH=CHCH2)nOH Toluene-2,6-diisocyanate Poly(2-buteno-1,4-diol) CH H 3 H O N N O(CH2CH=CHCH2)nO O O n Spandex - foams, fibers, coatings 21.10 Spectroscopy of Carboxylic Acid Derivatives IR Spectroscopy CO 1650-1850 cm-1 RCOCl 1800 cm-1 RCOOR' 1735 cm-1 NMR Spectroscopy 1H NMR CHCOY ~ 2 ppm, 13C NMR acid derivatives 160-180 ppm aldehyde, ketone 200 ppm 1H NMR Spectrum Chemistry @ Work β-Lactam Antibiotics β-lactam antibiotics: four membered lactam ring ; block bacterial cell wall synthesis H HH N S CH3 Penicillin G O N O CH3 CO2Na NH H 2 HH N S Cephalexin O N (a cephalosporin) O CH3 COOH Problem Sets Chapter 21 32, 36, 37, 42, 53, 62.