1Spring, 2011 Organic Chemistry II Carboxylic Acid Derivatives Dr. Ralph C. Gatrone Department of Chemistry and Physics Virginia State University

11Spring, 2011Spring, 2011

Organic Chemistry IIOrganic Chemistry II

Carboxylic Acid DerivativesCarboxylic Acid Derivatives

Dr. Ralph C. GatroneDr. Ralph C. GatroneDepartment of Chemistry and PhysicsDepartment of Chemistry and Physics

Virginia State UniversityVirginia State University

Spring, 2011Spring, 2011 22

Chapter ObjectivesChapter Objectives

• NomenclatureNomenclature

• PropertiesProperties

• PreparationPreparation

• ReactionsReactions

• SpectroscopySpectroscopy


Carboxylic DerivativesCarboxylic Derivatives

• Functional Groups we will consider are:Functional Groups we will consider are:


Carboxylic DerivativesCarboxylic Derivatives

• Chemistry is similarChemistry is similar

• Chemistry is dominated by one reactionChemistry is dominated by one reaction

R

O

X R

O

Nu

Nu:


NomenclatureNomenclatureAcid Halides RCOXAcid Halides RCOX

• Derived from the carboxylic acid name by Derived from the carboxylic acid name by replacing the -replacing the -ic acidic acid ending with - ending with -ylyl or the - or the -carboxylic acidcarboxylic acid ending with – ending with –carbonylcarbonyl and and specifying the halidespecifying the halide


NomenclatureNomenclature Acid Anhydrides, RCO Acid Anhydrides, RCO22COR’COR’

• If symmetrical replace “If symmetrical replace “acid”acid” with “ with “anhydride” anhydride” based on the related carboxylic acidbased on the related carboxylic acid

•

• For substituted monocarboxylic acids: use For substituted monocarboxylic acids: use bisbis- ahead of the acid name- ahead of the acid name

• Unsymmetrical anhydrides— cite the two acids alphabeticallyUnsymmetrical anhydrides— cite the two acids alphabetically


NomenclatureNomenclatureEsters, RCOEsters, RCO22RR

• Name R’ and then, after a space, the carboxylic acid Name R’ and then, after a space, the carboxylic acid (RCOOH), with the “-(RCOOH), with the “-ic acid”ic acid” ending replaced by “- ending replaced by “-ate”ate”


NomenclatureNomenclature Amides, RCONH Amides, RCONH22

• With unsubstituted With unsubstituted NHNH22 group. replace - group. replace -oic acidoic acid or - or -ic acidic acid with with --amideamide, or by replacing the -, or by replacing the -carboxylic acidcarboxylic acid ending with – ending with –carboxamidecarboxamide

• If the N is further substituted, identify the substituent groups If the N is further substituted, identify the substituent groups (preceded by “N”) and then the parent amide(preceded by “N”) and then the parent amide


ExamplesExamples

• Try theseTry these

O

O(CH2)7CH3

O

Br

O

O

O

Br

Cl

O

O

N

CH3COCH3


ExamplesExamples

• AnswersAnswers O

O(CH2)7CH3

O

Br

O

O

O

Br

Cl

O

O

N

CH3COCH3

octyl crotonate

methyl acetate

bis-bromoacetic anhydride

pentanoyl chloride

N-ethyl-N-isopropylacrylamide


PropertiesProperties

• Amides have higher boiling point Amides have higher boiling point than other derivatives due to H-than other derivatives due to H-bondingbonding

• Esters have pleasant odors Esters have pleasant odors associated with fruits and flavorsassociated with fruits and flavors

• Acid halides have pungent odors due Acid halides have pungent odors due to hydrolysis to HCl or HBrto hydrolysis to HCl or HBr


StabilityStability

• AmidesAmides more stable than more stable than• EstersEsters, more stable than, more stable than• Acid anhydridesAcid anhydrides, more stable than, more stable than• Acid halidesAcid halides

• Esters and amides are commonly found in Esters and amides are commonly found in natural materials.natural materials.

• Amides make up foundation of animalsAmides make up foundation of animals• Acid halides and anhydrides don’t exist in Acid halides and anhydrides don’t exist in

naturenature


StabilityStability


Relative Reactivity of Relative Reactivity of Carboxylic Acid DerivativesCarboxylic Acid Derivatives• Nucleophiles react Nucleophiles react

more readily with more readily with unhindered carbonyl unhindered carbonyl groups groups

• More electrophilic More electrophilic carbonyl groups are carbonyl groups are more reactive to more reactive to addition (acyl halides addition (acyl halides are most reactive, are most reactive, amides are least)amides are least)

• The intermediate The intermediate with the best leaving with the best leaving group decomposes group decomposes fastest fastest


General Reactions of General Reactions of Carboxylic Acid DerivativesCarboxylic Acid Derivatives


Reactions of Carboxylic AcidsReactions of Carboxylic Acids• OH is poor leaving groupOH is poor leaving group

• Must enhance reactivity Must enhance reactivity

• Specific reagents can produce acid chlorides, Specific reagents can produce acid chlorides, anhydrides, esters, amidesanhydrides, esters, amides


Acids to Acid ChloridesAcids to Acid Chlorides

• Reaction with thionyl chloride, SOClReaction with thionyl chloride, SOCl22


Acids to Acid AnhydridesAcids to Acid Anhydrides

• Heat cyclic dicarboxylic acids that can form five- or Heat cyclic dicarboxylic acids that can form five- or six-membered ringssix-membered rings

• Acyclic anhydrides are not generally formed this way Acyclic anhydrides are not generally formed this way - they are usually made from acid chlorides and - they are usually made from acid chlorides and carboxylic acidscarboxylic acids


Acids to EstersAcids to Esters

• Carboxylate anion with a primary alkyl halideCarboxylate anion with a primary alkyl halide


Fischer EsterificationFischer Esterification

• Heating a carboxylic acid in an alcohol solvent Heating a carboxylic acid in an alcohol solvent containing a small amount of strong acid containing a small amount of strong acid produces an ester from the alcohol and acid produces an ester from the alcohol and acid


Esterification using Esterification using DiazomethaneDiazomethane

O

CO2H

O

CO2CH3

CH2N2

ETHER

Reaction only provides the methyl ester

Glassware must be polished (no ground glass joints)


Acids to AmidesAcids to Amides

• Direct reaction cannot be doneDirect reaction cannot be done

• Due to acid base reaction that occurs Due to acid base reaction that occurs firstfirst

CO2H CO2(CH3)2NH(CH3)2NH2

-+

acid

base

salt


Acids to AmidesAcids to Amides• Must make OH a better leaving groupMust make OH a better leaving group

• Generally done in the laboratory via the acyl halideGenerally done in the laboratory via the acyl halide

• Can also use dicyclohexylcarbodiimide to activate the OHCan also use dicyclohexylcarbodiimide to activate the OH

R

O

O

N N

R

O

O

NH

N R

O

NHR

C

RNH2


Chemistry of Acid HalidesChemistry of Acid Halides

• Acid chlorides are prepared from carboxylic acids by Acid chlorides are prepared from carboxylic acids by reaction with SOClreaction with SOCl22

• Reaction of a carboxylic acid with PBrReaction of a carboxylic acid with PBr33 yields the acid yields the acid bromidebromide


Reactions of Acid HalidesReactions of Acid Halides• Nucleophilic acyl substitutionNucleophilic acyl substitution• Halogen replaced by Halogen replaced by OH, by OH, by OR, or by OR, or by NHNH22

• Reduction yields a primary alcoholReduction yields a primary alcohol• Grignard reagent yields a tertiary alcoholGrignard reagent yields a tertiary alcohol


Acid Halides into AcidsAcid Halides into Acids(Hydrolysis)(Hydrolysis)

• Acid chlorides react with water to yield carboxylic Acid chlorides react with water to yield carboxylic acidsacids

• HCl is generated during the hydrolysis: a base is HCl is generated during the hydrolysis: a base is added to remove the HCladded to remove the HCl


Acid Halides to AnhydridesAcid Halides to Anhydrides

• Acid halides react with carboxylate anionsAcid halides react with carboxylate anions

Cl

O

O

O

O

O O

CH2CH3CH3CH2C

-


Acid Halides to EstersAcid Halides to Esters• Esters are produced in the reaction of acid Esters are produced in the reaction of acid

chlorides react with alcohols in the presence of chlorides react with alcohols in the presence of pyridine or NaOH pyridine or NaOH

• The reaction is better with less steric bulkThe reaction is better with less steric bulk


Acid Halides into AmidesAcid Halides into Amides• Amides result from the reaction of acid chlorides Amides result from the reaction of acid chlorides

– with NHwith NH33, , – primary amines (RNHprimary amines (RNH22) ) – secondary amines (Rsecondary amines (R22NH)NH)

• The reaction with tertiary amines (RThe reaction with tertiary amines (R33N) gives an unstable N) gives an unstable species that cannot be isolatedspecies that cannot be isolated

• HCl is neutralized by the amine or an added baseHCl is neutralized by the amine or an added base


Acid Chlorides into AlcoholsAcid Chlorides into Alcohols

• LiAlHLiAlH44 reduces acid chlorides to yield primary reduces acid chlorides to yield primary alcohols through the aldehyde (not isolated)alcohols through the aldehyde (not isolated)


Acid Halides with Acid Halides with OrganometallicsOrganometallics• Grignard reagents react with acid chlorides to yield Grignard reagents react with acid chlorides to yield

tertiary alcohols in which two of the substituents tertiary alcohols in which two of the substituents are the sameare the same


Acid Chlorides to KetonesAcid Chlorides to Ketones• Reaction of an acid chloride with a lithium Reaction of an acid chloride with a lithium

diorganocopper (Gilman) reagent, Lidiorganocopper (Gilman) reagent, Li++ R R22CuCu

• Reaction of an acid chloride with organocadmium Reaction of an acid chloride with organocadmium reagentreagent

R

O

Cl R

O

R

R2Cd


Chemistry of Acid Chemistry of Acid AnhydridesAnhydrides

• Prepared by carboxylate nucleophile Prepared by carboxylate nucleophile with an acid chloridewith an acid chloride


Reactions of Acid Reactions of Acid AnhydridesAnhydrides• Similar to acid chlorides in reactivitySimilar to acid chlorides in reactivity


Anhydrides to Esters or Anhydrides to Esters or AmidesAmides• Anhydrides form esters with alcohols Anhydrides form esters with alcohols • Anhydrides form amides with aminesAnhydrides form amides with amines


Anhydrides: More Selective than Acid Anhydrides: More Selective than Acid HalidesHalides• Anhydrides react with amines in presence Anhydrides react with amines in presence

of alcohols, Not so acid chloridesof alcohols, Not so acid chlorides

NH2

OH

Cl

O

NH

OH

O

NH2

OH

NH2

O

O

O

O

NH

O

NH2

OH

O

O

ONH

OH

O


Chemistry of EstersChemistry of Esters• Many esters are pleasant-smelling liquids: Many esters are pleasant-smelling liquids:

fragrant odors of fruits and flowersfragrant odors of fruits and flowers• Also present in fats and vegetable oilsAlso present in fats and vegetable oils


Preparation of EstersPreparation of Esters

• Esters are usually prepared from Esters are usually prepared from carboxylic acidscarboxylic acids


Reactions of EstersReactions of Esters• Less reactive toward nucleophiles than are Less reactive toward nucleophiles than are

acid chlorides or anhydridesacid chlorides or anhydrides• Cyclic esters are called lactones and react Cyclic esters are called lactones and react

similarly to acyclic esterssimilarly to acyclic esters


Esters into Carboxylic AcidsEsters into Carboxylic Acids

• An ester is hydrolyzed by aqueous base or An ester is hydrolyzed by aqueous base or aqueous acid to yield a carboxylic acid plus aqueous acid to yield a carboxylic acid plus an alcoholan alcohol


SoapSoap

• Ester (Fat) hydrolysis into carboxylate Ester (Fat) hydrolysis into carboxylate anionanion

O

O

O

O

RR

O

O R

R O

O

OH OH

OH

R = C11 to C17 hydrocarbon

triglyceride (animal fat)

NaOH- Na+

soap


Esters to AmidesEsters to Amides• Ammonia reacts with esters to form amidesAmmonia reacts with esters to form amides

• Reaction is easier from the acid chlorideReaction is easier from the acid chloride


Esters into Alcohols: ReductionEsters into Alcohols: Reduction

• Reaction with LiAlHReaction with LiAlH44 yields primary alcohols yields primary alcohols


Reduction of EstersReduction of Esters• LAH is reducing agent of choiceLAH is reducing agent of choice

• NaBHNaBH44 does not reduce esters does not reduce esters

• HH22 does not reduce esters does not reduce esters

• BHBH33 – THF does not reduce esters – THF does not reduce esters

• DIBAH reduces esters to the aldehydeDIBAH reduces esters to the aldehydeO

OMe

O

H

Al H

DIBAH

toluene

DIBAH =


Esters with Grignard ReagentsEsters with Grignard Reagents• Reacts with 2 equivalents of a Grignard Reacts with 2 equivalents of a Grignard

reagent to yield a tertiary alcoholreagent to yield a tertiary alcohol


Chemistry of AmidesChemistry of Amides• Prepared by reaction of an acid chloride with Prepared by reaction of an acid chloride with

ammonia, primary amines, or secondary aminesammonia, primary amines, or secondary amines• Amides are the least reactive of derivativesAmides are the least reactive of derivatives


Reactions of AmidesReactions of Amides• Heating in either aqueous acid or aqueous Heating in either aqueous acid or aqueous

base produces a carboxylic acid and the base produces a carboxylic acid and the amineamine


Amides into AminesAmides into Amines

• Reduced by LiAlHReduced by LiAlH4 4 to an amine rather than an alcohol to an amine rather than an alcohol

• Converts C=O Converts C=O CH CH22


Reduction of AmidesReduction of Amides

• Works with cyclic and acyclicWorks with cyclic and acyclic• Good route to cyclic aminesGood route to cyclic amines


Amides to NitrilesAmides to Nitriles

O

NH2

CN

SOCl2 or POCl3 can be used


Amide to AmineAmide to AmineThe Hoffmann RearrangementThe Hoffmann Rearrangement

• Preparation of amine with loss of a carbonPreparation of amine with loss of a carbon

O

NH2

NH2Br2/NaOH/H2O + CO2


Infrared SpectroscopyInfrared Spectroscopy

• Acid chlorides: 1800cmAcid chlorides: 1800cm-1-1

• Acid anhydrides: 1820 and 1760cmAcid anhydrides: 1820 and 1760cm-1-1

• Esters: 1735cmEsters: 1735cm-1-1

• Amides: 1650 - 1690cmAmides: 1650 - 1690cm-1 -1 depending depending on N substitutionon N substitution


NMR SpectroscopyNMR Spectroscopy

• Carbon-13 NMRCarbon-13 NMR

• Difficult to assign with certaintyDifficult to assign with certainty


NMR SpectroscopyNMR Spectroscopy

• Proton NMRProton NMR

• Protons adjacent to C=O resonate Protons adjacent to C=O resonate near 2near 2

• Identity of the C=O cannot be Identity of the C=O cannot be determineddetermined

Documents

1Spring, 2011 Organic Chemistry II Carboxylic Acid Derivatives Dr. Ralph C. Gatrone Department of Chemistry and Physics Virginia State University