Ch.21 Carboxylic Acid Derivatives and Nucleophilic Acyl Substitution
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