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Ch.21 Carboxylic Acid Derivatives and Nucleophilic Acyl Substitution

Ch.21 Carboxylic Acid Derivatives and Nucleophilic Acyl Substitution

Ch.21 Carboxylic 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' Carboxylic Carboxylic acid acid

O O O O - R C NH2 R C SR' R C O P O R C N - O Acyl Nucleophilic Acyl Substitution

O O Nu- + Y- R Y R Nu 21.1 Nomenclature Acid Halides: RCOX -oic acid → -yl - → -carbonyl O O Cl Cl

Acetyl chloride

O

Cl

Cyclohexanecarbonyl chloride Acid Anhydrides: RCO2COR' acid → anhydride O O O O O O O O O

Acetic 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 : RCONH2 -(o)ic acid → amide -carboxylic acid → -carboxamide O O O NH2 NH NH2 2 Hexanamide Cyclohexanecarboxamide

- substututed amide: N-----amide O O N CH N 3 H

N-Methylacetamide N,N-Diethylcyclohexanecarboxamide : RCO2R' - name alkyl group attached to then -ic acid → -ate

O OO

O EtO OEt Ethyl 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 ( 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 - 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 Kinds of Nucleophilic Acyl Substitutions

O

R NH2 O O further 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 Grignard reaction 21.3 Nucleophilic Acyl Substitution Reactions of Carboxylic

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 Cl-

O O O SO + Cl- + S 2 ROCl RCl Cl Conversion to acid anhydride: OO - acyclic anhydrides are difficult to prepare

- 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 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 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

- are base: direct conversion to an amide is not possible 21.4 of Acid Halides Preparation O SOCl2 O ROH CHCl3 RCl acid , acid : unstable

Reactions Friedel-Craft :

O Ar-H O

RCl AlCl3 RAr Reactions O

R NH2 O OH O Amide further R OR' R H reaction R Ester NH3 10 Alcohol R'OH [H-] O O O OH H2O R'MgX further R OH R Cl R R' reaction R R' Acid R' 30 Alcohol Hydrolysis:

O- O O Base O R Cl H RCl HO RO H2O ROH H H +HCl

- use base (, 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

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 , -78oC 92%

- diorganocopper reaction occurs only with acid - 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 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 - (solvent) - dialkyl phthalate (plasticizer: keep 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 : basic hydrolysis

+ Na O- O O R OR' + R'O-Na+ ROR'NaOH HO RO H

+ O O H3O - + + R'OH ROH RONa acid 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 building R R R' R" OH H2N N N N O H O H O H O

Amino acids A protein () 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 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()

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 : 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 , Perlon Polyesters: dialcohol + diacid

OH MeO2CCO2Me + HO

Dimethyl terephthalate 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- Antibiotics

β-lactam antibiotics: four membered lactam ring ; block bacterial cell wall synthesis

H HH N S CH3 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