dr. wolf's chm 201 & 202 19-1 chapter 19 carboxylic acid derivatives nucleophilic acyl...

Dr. Wolf's CHM 201 & 202 19-1

Chapter 19Chapter 19Carboxylic Acid DerivativesCarboxylic Acid Derivatives

Nucleophilic Acyl SubstitutionNucleophilic Acyl Substitution

Dr. Wolf's CHM 201 & 202 19-2

Nomenclature of Carboxylic Acid DerivativesNomenclature of Carboxylic Acid Derivatives

Dr. Wolf's CHM 201 & 202 19-3

Acyl HalidesAcyl HalidesAcyl HalidesAcyl Halides

RCRC

OO

XX

name the acyl group and add the word name the acyl group and add the word chloridechloride, , fluoridefluoride, , bromidebromide, or , or iodideiodide

as appropriateas appropriate

acyl chlorides are, by far, the most frequently encountered of the acyl halidesacyl chlorides are, by far, the most frequently encountered of the acyl halides

Dr. Wolf's CHM 201 & 202 19-4

Acyl HalidesAcyl HalidesAcyl HalidesAcyl Halides

CHCH33CClCCl

OO

acetyl chlorideacetyl chloride

3-butenoyl chloride3-butenoyl chloride

OO

HH22CC CHCHCHCH22CClCCl OO

CBrCBrFF pp-fluorobenzoyl bromide -fluorobenzoyl bromide

Dr. Wolf's CHM 201 & 202 19-5

Acid AnhydridesAcid AnhydridesAcid AnhydridesAcid Anhydrides

when both acyl groups are the same, name the when both acyl groups are the same, name the

acid and add the word acid and add the word anhydrideanhydride

when the groups are different, list the names of the when the groups are different, list the names of the

corresponding acids in alphabetical order and add corresponding acids in alphabetical order and add

the word the word anhydrideanhydride

RCOCR'RCOCR'

OO OO

Dr. Wolf's CHM 201 & 202 19-6

Acid AnhydridesAcid AnhydridesAcid AnhydridesAcid Anhydrides

acetic anhydrideacetic anhydride

benzoic anhydridebenzoic anhydride

benzoicbenzoic heptanoicheptanoic anhydride anhydride

CHCH33COCCHCOCCH33

OO OO

CC66HH55COCCCOCC66HH55

OO OO

CC66HH55CCOOC(CHC(CH22))55CHCH33

OO OO

Dr. Wolf's CHM 201 & 202 19-7

EstersEstersEstersEsters

name as name as alkyl alkanoatesalkyl alkanoates

cite the alkyl group attached to oxygen first (R')cite the alkyl group attached to oxygen first (R')

name the acyl group second; substitute the suffixname the acyl group second; substitute the suffix

-ate-ate for the for the -ic -ic ending of the corresponding acidending of the corresponding acid

RCOR'RCOR'

OO

Dr. Wolf's CHM 201 & 202 19-8

EstersEstersEstersEsters

CHCH33COCOCHCH22CHCH33

OO

ethylethyl acetate acetate

methylmethyl propanoate propanoate

2-chloroethyl 2-chloroethyl benzoate benzoate

OO

CHCH33CHCH22COCOCHCH33

COCOCHCH22CHCH22ClCl

OO

Dr. Wolf's CHM 201 & 202 19-9

Amides having an NHAmides having an NH22 group groupAmides having an NHAmides having an NH22 group group

identify the corresponding carboxylic acididentify the corresponding carboxylic acid

replace the replace the -ic acid -ic acid or or -oic acid -oic acid ending by -amide.ending by -amide.

RCRCNNHH22

OO

Dr. Wolf's CHM 201 & 202 19-10

Amides having an NHAmides having an NH22 group groupAmides having an NHAmides having an NH22 group group

CHCH33CCNNHH22

OO

acetamideacetamide

3-methylbutanamide3-methylbutanamide

OO

(CH(CH33))22CHCHCHCH22CCNNHH22

CCNNHH22

OO benzamidebenzamide

Dr. Wolf's CHM 201 & 202 19-11

Amides having substituents on NAmides having substituents on NAmides having substituents on NAmides having substituents on N

name the amide as beforename the amide as before

precede the name of the amide with the name of precede the name of the amide with the name of

the appropriate group or groupsthe appropriate group or groups

precede the names of the groups by the letter precede the names of the groups by the letter N- N-

(standing for nitrogen and used as a locant)(standing for nitrogen and used as a locant)

RCRCNNHHR'R'

OO

andand RCRCNNR'R'22

OO

Dr. Wolf's CHM 201 & 202 19-12

Amides having substituents on NAmides having substituents on NAmides having substituents on NAmides having substituents on N

CHCH33CCNNHHCHCH33

OO

NN--methylmethylacetamideacetamide

NN--isopropylisopropyl--NN--methylmethylbutanamidebutanamide

CCNN(CH(CH22CHCH33))22

OO NN,,NN--diethyldiethylbenzamidebenzamide

OO

CHCH33CHCH22CHCH22CCNNCH(CHCH(CH33))22

CHCH33

Dr. Wolf's CHM 201 & 202 19-13

NitrilesNitrilesNitrilesNitriles

add the suffix add the suffix -nitrile -nitrile to the name of the parent to the name of the parent

hydrocarbon chain (including the triply bonded hydrocarbon chain (including the triply bonded

carbon of CN)carbon of CN)

or: replace the or: replace the -ic acid -ic acid or or -oic acid -oic acid name of the name of the

corresponding carboxylic acid by corresponding carboxylic acid by -onitrile-onitrile

or: name as an or: name as an alkyl cyanide alkyl cyanide (functional class (functional class

name)name)

RCRC NN

Dr. Wolf's CHM 201 & 202 19-14

NitrilesNitrilesNitrilesNitriles

CHCH33CC NNethanenitrileethanenitrileor: acetonitrileor: acetonitrileor: methyl cyanideor: methyl cyanide

CC66HH55CC NN benzonitrilebenzonitrile

NNCC

CHCH33CHCHCHCH33 2-methylpropanenitrile2-methylpropanenitrileor: isopropyl cyanideor: isopropyl cyanide

Dr. Wolf's CHM 201 & 202 19-15

Structure of Carboxylic Acid DerivativesStructure of Carboxylic Acid Derivatives

Dr. Wolf's CHM 201 & 202 19-16

The key to this chapter is the next The key to this chapter is the next slide.slide.

It lists the various carboxylic acids in It lists the various carboxylic acids in order of decreasing reactivity toward order of decreasing reactivity toward their fundamental reaction type their fundamental reaction type (nucleophilic acyl substitution).(nucleophilic acyl substitution).

The other way to read the list is in The other way to read the list is in order of increasing stabilization of the order of increasing stabilization of the carbonyl group.carbonyl group.

The key to this chapter is the next The key to this chapter is the next slide.slide.

It lists the various carboxylic acids in It lists the various carboxylic acids in order of decreasing reactivity toward order of decreasing reactivity toward their fundamental reaction type their fundamental reaction type (nucleophilic acyl substitution).(nucleophilic acyl substitution).

The other way to read the list is in The other way to read the list is in order of increasing stabilization of the order of increasing stabilization of the carbonyl group.carbonyl group.

Dr. Wolf's CHM 201 & 202 19-17

CHCH33CC

OO

ClCl

CHCH33CC

OO

OOCCHCCH33

OO

CHCH33CC

OO

SCHSCH22CHCH33

CHCH33CC

OO

OOCHCH22CHCH33

CHCH33CC

OO

NHNH22

MostMost

reactivereactive

LeastLeast

reactivereactive

LeastLeast

stabilizedstabilized

MostMost

stabilizedstabilized

Dr. Wolf's CHM 201 & 202 19-18

Electron Delocalization and the Carbonyl GroupElectron Delocalization and the Carbonyl Group

The main structural feature that distinguishes acyl The main structural feature that distinguishes acyl

chlorides, anhydrides, thioesters, esters, and chlorides, anhydrides, thioesters, esters, and

amides is the interaction of the substituent with the amides is the interaction of the substituent with the

carbonyl group. It can be represented in carbonyl group. It can be represented in

resonance terms as:resonance terms as:

RCRC

OO

XX••••

•••••••• ––

RCRC

OO

XX••••

••••••••••••

++

RCRC

OO

XX

••••••••••••

++

––

Dr. Wolf's CHM 201 & 202 19-19

Electron Delocalization and the Carbonyl GroupElectron Delocalization and the Carbonyl Group

The extent to which the lone pair on X can be The extent to which the lone pair on X can be

delocalized into C=O depends on:delocalized into C=O depends on:

1) the electronegativity of X1) the electronegativity of X

2) how well the lone pair orbital of X interacts 2) how well the lone pair orbital of X interacts

with the with the orbital of C=O orbital of C=O

RCRC

OO

XX••••

••••••••

RCRC

OO

XX••••

••••••••••••

++RCRC

OO

XX

••••••••••••

++

––––

Dr. Wolf's CHM 201 & 202 19-20

Orbital overlaps in carboxylic acid derivativesOrbital overlaps in carboxylic acid derivatives

orbital of carbonyl grouporbital of carbonyl group

Dr. Wolf's CHM 201 & 202 19-21


lone pair orbitallone pair orbital

of substituentof substituent

Dr. Wolf's CHM 201 & 202 19-22


electron pair of substituent delocalized into electron pair of substituent delocalized into

carbonyl carbonyl orbitalorbital

Dr. Wolf's CHM 201 & 202 19-23

acyl chlorides have the least stabilized carbonylacyl chlorides have the least stabilized carbonyl

groupgroup

delocalization of lone pair of Cl into C=O group isdelocalization of lone pair of Cl into C=O group is

not effective because C—Cl bond is too longnot effective because C—Cl bond is too long

Acyl ChloridesAcyl Chlorides

••••

CC

OO

RR

ClCl•••• ••••

••••••••

••••

CC

OO

RR

ClCl••••

•••• ••••••••

++

––

Dr. Wolf's CHM 201 & 202 19-24

RCRCClCl

OO

least stabilized C=Oleast stabilized C=O

most stabilized C=Omost stabilized C=O

Dr. Wolf's CHM 201 & 202 19-25

lone pair donation from oxygen stabilizes thelone pair donation from oxygen stabilizes the

carbonyl group of an acid anhydridecarbonyl group of an acid anhydride

the other carbonyl group is stabilized in anthe other carbonyl group is stabilized in an

analogous manner by the lone pairanalogous manner by the lone pair

Acid AnhydridesAcid Anhydrides

••••CCRR

OO•••• ••••

OO••••

CC

OO•••• ••••

RR

OO•••• ••••

••••••••

++

––

CCRR

OO ••••

OO••••

CCRR

Dr. Wolf's CHM 201 & 202 19-26

RCRCOOCR'CR'

OO OORCRCClCl

OO



Dr. Wolf's CHM 201 & 202 19-27

Sulfur (like chlorine) is a third-row element.Sulfur (like chlorine) is a third-row element.

Electron donation to C=O from third-row elementsElectron donation to C=O from third-row elements

is not very effective.is not very effective.

Resonance stabilization of C=O in thioesters isResonance stabilization of C=O in thioesters is

not significant.not significant.

ThioestersThioesters

••••••••

++

––

CCRR

OO ••••

SSR'R'••••

OO•••• ••••

••••CCRR SSR'R'

••••

Dr. Wolf's CHM 201 & 202 19-28

RCRCOOCR'CR'

OO OORCRCClCl

OO



RCRCSSR'R'

OO

Dr. Wolf's CHM 201 & 202 19-29

lone pair donation from oxygen stabilizes thelone pair donation from oxygen stabilizes the

carbonyl group of an estercarbonyl group of an ester

stabilization greater than comparable stabilizationstabilization greater than comparable stabilization

of an anhydride or thioesterof an anhydride or thioester

EstersEsters

••••••••

++

––

CCRR

OO ••••

OOR'R'••••

OO•••• ••••

••••CCRR OOR'R'

••••

Dr. Wolf's CHM 201 & 202 19-30

RCRCOOCR'CR'

OO OORCRCClCl

OO

RCRCOOR'R'

OO



RCRCSSR'R'

OO

Dr. Wolf's CHM 201 & 202 19-31

lone pair donation from nitrogen stabilizes thelone pair donation from nitrogen stabilizes the

carbonyl group of an amidecarbonyl group of an amide

N is less electronegative than O; therefore, N is less electronegative than O; therefore,

amides are stabilized more than esters and amides are stabilized more than esters and

anhydridesanhydrides

AmidesAmides

••••••••

++

––

CCRR

OO ••••

NNR'R'22

OO•••• ••••

••••CCRR NNR'R'22

Dr. Wolf's CHM 201 & 202 19-32

amide resonance imparts significant double-bondamide resonance imparts significant double-bond

character to C—N bondcharacter to C—N bond

activation energy for rotation about C—N bondactivation energy for rotation about C—N bond

is 75-85 kJ/molis 75-85 kJ/mol

C—N bond distance is 135 pm in amides versusC—N bond distance is 135 pm in amides versus

normal single-bond distance of 147 pm in aminesnormal single-bond distance of 147 pm in amines

AmidesAmides

••••••••

++

––

CCRR

OO ••••

NNR'R'22

OO•••• ••••

••••CCRR NNR'R'22

Dr. Wolf's CHM 201 & 202 19-33

RCRCOOCR'CR'

OO OORCRCClCl

OO

RCRCOOR'R'

OO

RCRCNNR'R'22

OO



RCRCSSR'R'

OO

Dr. Wolf's CHM 201 & 202 19-34

very efficient electron delocalization and dispersalvery efficient electron delocalization and dispersal

of negative chargeof negative charge

maximum stabilizationmaximum stabilization

Carboxylate ionsCarboxylate ions

OO•••• ••••

••••CCRR

––

OO••••

••••

••••••••––

CCRR

OO ••••

••••••••OO

Dr. Wolf's CHM 201 & 202 19-35

RCRCOOCR'CR'

OO OORCRCClCl

OO

RCRCOOR'R'

OO

RCRCNNR'R'22

OO

RCRCOO––

OO



RCRCSSR'R'

OO

Dr. Wolf's CHM 201 & 202 19-36

Reactivity is related to structureReactivity is related to structure

RCRCOOCR'CR'

OO OORCRCClCl

OO

RCRCOOR'R'

OO

RCRCNNR'R'22

OO

StabilizationStabilization

very smallvery small

smallsmall

largelarge

moderatemoderate

Relative rateRelative rate

of hydrolysisof hydrolysis

10101111

101077

< 10< 10-2-2

1.01.0

The more The more

stabilized the stabilized the

carbonyl group, carbonyl group,

the less reactive the less reactive

it is.it is.

Dr. Wolf's CHM 201 & 202 19-37


In general:In general:

OO•••• ••••

CCRR XX

+ H+ HYY

OO•••• ••••

CCRR YY

+ H+ HXX

Reaction is feasible when a less stabilized Reaction is feasible when a less stabilized

carbonyl is converted to a more stabilized carbonyl is converted to a more stabilized

one one (more reactive to less reactive)(more reactive to less reactive)..

Dr. Wolf's CHM 201 & 202 19-38

RCRCOOCR'CR'

OO OORCRCClCl

OO

RCRCOOR'R'

OO

RCRCNNR'R'22

OO

RCRCOO––

OO

RCRCSSR'R'

OO

most reactivemost reactive

least reactiveleast reactive

a carboxylic acid a carboxylic acid derivative can be derivative can be converted by converted by nucleophilic acyl nucleophilic acyl substitution to any other substitution to any other type that lies below it in type that lies below it in this tablethis table

Dr. Wolf's CHM 201 & 202 19-39

General MechanismGeneral Mechanism

forfor


Dr. Wolf's CHM 201 & 202 19-40


OO•••• ••••

CCRR XX

+ H+ HNuNu

OO•••• ••••

CCRR NuNu

+ H+ HXX

Reaction is feasible when a less stabilized Reaction is feasible when a less stabilized

carbonyl is converted to a more stabilized carbonyl is converted to a more stabilized

one one (more reactive to less reactive)(more reactive to less reactive)..

Dr. Wolf's CHM 201 & 202 19-41

General Mechanism for Nucleophilic Acyl SubstitutionGeneral Mechanism for Nucleophilic Acyl Substitution

involves formation and dissociationinvolves formation and dissociationof a tetrahedral intermediateof a tetrahedral intermediate

OO•••• ••••

CCRR XX

HHNuNu

CC

RROHOH

XX

NuNu

OO•••• ••••

CCRR NuNu

-H-HXX

Both stages can involve several elementary steps.Both stages can involve several elementary steps.

Dr. Wolf's CHM 201 & 202 19-42


first stage of mechanism (formation of tetrahedralfirst stage of mechanism (formation of tetrahedralintermediate) is analogous to nucleophilic additionintermediate) is analogous to nucleophilic additionto C=O of aldehydes and ketonesto C=O of aldehydes and ketones

OO•••• ••••

CCRR XX

HHNuNu

CC

RROHOH

XX

NuNu

Dr. Wolf's CHM 201 & 202 19-43


second stage is restoration of C=O by eliminationsecond stage is restoration of C=O by elimination

OO•••• ••••

CCRR XX

HHNuNu

CC

RROHOH

XX

NuNu

OO•••• ••••

CCRR NuNu

-H-HXX

complicating features of each stage involvecomplicating features of each stage involveacid-base chemistryacid-base chemistry

Dr. Wolf's CHM 201 & 202 19-44


OO•••• ••••

CCRR XX

HHNuNu

CC

RROHOH

XX

NuNu

OO•••• ••••

CCRR NuNu

-H-HXX

Acid-base chemistry in first stage is familiar in thatAcid-base chemistry in first stage is familiar in thatit has to do with acid/base catalysis of nucleophilic it has to do with acid/base catalysis of nucleophilic addition to C=O.addition to C=O.

Dr. Wolf's CHM 201 & 202 19-45


OO•••• ••••

CCRR XX

HHNuNu

CC

RROHOH

XX

NuNu

OO•••• ••••

CCRR NuNu

-H-HXX

Acid-base chemistry in second stage concernsAcid-base chemistry in second stage concernsform in which the tetrahedral intermediate existsform in which the tetrahedral intermediate existsunder the reaction conditions and how it dissociatesunder the reaction conditions and how it dissociatesunder those conditions.under those conditions.

Dr. Wolf's CHM 201 & 202 19-46

The Tetrahedral IntermediateThe Tetrahedral Intermediate

tetrahedral intermediate (TI)tetrahedral intermediate (TI) CC

RROO

XX

NuNu ••••

HH•••• ••••

••••

CC

RROO

XX

NuNu ••••

HH•••• ••••

HH ++

Conjugate acid of tetrahedral Conjugate acid of tetrahedral

intermediate (TIintermediate (TI++))

••••

OO••••

••••

CC

RR

XX

NuNu

•••• ••••––

Conjugate base of tetrahedral Conjugate base of tetrahedral

intermediate (TIintermediate (TI––))

Dr. Wolf's CHM 201 & 202 19-47

Dissociation of TI—HDissociation of TI—H++

•••• CC

RROO

XX

NuNu••••

HH ••••

HH++

++B—HB—H ++CC

OO

RR NuNu ••••

•••• ••••++ XX HH••••

BB••••

Dr. Wolf's CHM 201 & 202 19-48

Dissociation of TIDissociation of TI

BB••••

•••• CC

RROO

XX

NuNu••••

HH ••••

••••

++B—HB—H ++CC

OO


•••• ••••++ XX•••• ••••

––

Dr. Wolf's CHM 201 & 202 19-49

Dissociation of TIDissociation of TI––

CC

OO


•••• ••••++ XX•••• ••••

––

••••

CC

RROO

XX

NuNu••••

••••

••••

••••––

Dr. Wolf's CHM 201 & 202 19-50

Nucleophilic SubstitutionNucleophilic Substitution

in Acyl Chloridesin Acyl Chlorides

Dr. Wolf's CHM 201 & 202 19-51

Preparation of Acyl ChloridesPreparation of Acyl Chlorides

from carboxylic acids and thionyl chloridefrom carboxylic acids and thionyl chloride(Section 12.7)(Section 12.7)

(CH(CH33))22CHCCHCOHOH

OOSOSOClCl22

heatheat(CH(CH33))22CHCCHCClCl

OO

++ SOSO22 ++ HHClCl

(90%)(90%)

Dr. Wolf's CHM 201 & 202 19-52

RCOCR'RCOCR'

OO OORCRCClCl

OO

RCOR'RCOR'

OO

RCRCNR'NR'22

OO

RCORCO––

OO

Reactions of Acyl ChloridesReactions of Acyl Chlorides

Dr. Wolf's CHM 201 & 202 19-53

RCRCClCl

OO


++ R'CR'COOHH

OO

RCRCOOCR'CR'

OO OO

++ HHClCl

Acyl chlorides react with carboxylic acids to giveAcyl chlorides react with carboxylic acids to giveacid anhydrides:acid anhydrides:

via:via: CCRR

OO

ClCl

OOCR'CR'

HHOO

Dr. Wolf's CHM 201 & 202 19-54

CHCH33(CH(CH22))55CCClCl

OO

ExampleExample

++ CHCH33(CH(CH22))55CCOOHH

OO

pyridinepyridine

CHCH33(CH(CH22))55CCOOC(CHC(CH22))55CHCH33

OO OO

(78-83%)(78-83%)

Dr. Wolf's CHM 201 & 202 19-55

RCRCClCl

OO


++ RCRCOOR'R'

OO

++ HHClCl

Acyl chlorides react with alcohols to give esters:Acyl chlorides react with alcohols to give esters:

R'R'OOHH

via:via: CCRR

OO

ClCl

OOR'R'

HH

Dr. Wolf's CHM 201 & 202 19-56

ExampleExample

CC66HH55CCClCl

OO

++ (CH(CH33))33CCOOHHpyridinepyridine

(80%)(80%)

CC66HH55CCOOC(CHC(CH33))33

OO

Dr. Wolf's CHM 201 & 202 19-57

RCRCClCl

OO


++ RCRCNNR'R'22

OO

++ HH22OO

Acyl chlorides react with ammonia and aminesAcyl chlorides react with ammonia and aminesto give amides:to give amides:

R'R'22NNHH + HO+ HO––

++ ClCl––

via:via: CCRR

OO

ClCl

NNR'R'22

HH

Dr. Wolf's CHM 201 & 202 19-58

ExampleExample

CC66HH55CCClCl

OO

++NaOHNaOH

(87-91%)(87-91%)

HH22OO

HHNN

CC66HH55CCNN

OO

Dr. Wolf's CHM 201 & 202 19-59

RCRCClCl

OO


++ RCRCOOHH

OO

++ HHClCl

Acyl chlorides react with water to giveAcyl chlorides react with water to givecarboxylic acids (carboxylate ion in base):carboxylic acids (carboxylate ion in base):

HH22OO

RCRCClCl

OO

++ RCRCOO––

OO

++ ClCl––2H2HOO––

++ HH22OO

Dr. Wolf's CHM 201 & 202 19-60

RCRCClCl

OO


++ RCRCOOHH

OO

++ HHClCl

Acyl chlorides react with water to giveAcyl chlorides react with water to givecarboxylic acids (carboxylate ion in base):carboxylic acids (carboxylate ion in base):

HH22OO

via:via: CCRR

OO

ClCl

OOHH

HH

Dr. Wolf's CHM 201 & 202 19-61

ExampleExample

CC66HH55CHCH22CCClCl

OO

++ HH22OO CC66HH55CHCH22CCOOHH

OO

++ HHClCl

Dr. Wolf's CHM 201 & 202 19-62

ReactivityReactivity

CC66HH55CCClCl

OO

CC66HH55CHCH22ClCl

Acyl chlorides undergo nucleophilic Acyl chlorides undergo nucleophilic

substitution much faster than alkyl chlorides.substitution much faster than alkyl chlorides.

Relative rates ofRelative rates ofhydrolysis (25°C)hydrolysis (25°C) 1,0001,000 11

Dr. Wolf's CHM 201 & 202 19-63

Nucleophilic Acyl Substitution in Nucleophilic Acyl Substitution in

Carboxylic Acid AnhydridesCarboxylic Acid Anhydrides

Anhydrides can be prepared from acyl Anhydrides can be prepared from acyl

chlorides as described in Table 20.1chlorides as described in Table 20.1

Dr. Wolf's CHM 201 & 202 19-64

Some anhydrides are industrial chemicalsSome anhydrides are industrial chemicals

CHCH33CCOOCCHCCH33

OO OO

AceticAceticanhydrideanhydride

OO

OO

OO

OO

OO

OO

PhthalicPhthalicanhydrideanhydride

MaleicMaleicanhydrideanhydride

Dr. Wolf's CHM 201 & 202 19-65

From dicarboxylic acidsFrom dicarboxylic acids

Cyclic anhydrides with 5- and 6-membered Cyclic anhydrides with 5- and 6-membered

rings can be prepared by dehydration of rings can be prepared by dehydration of

dicarboxylic acidsdicarboxylic acids

CC

CC

HH

HH COHCOH

COHCOH

OO

OO

OO

OO

OO

HH

HH

tetrachloroethanetetrachloroethane

130°C130°C

(89%)(89%)

+ H+ H22OO

Dr. Wolf's CHM 201 & 202 19-66

RCOCR'RCOCR'

OO OO

RCOR'RCOR'

OO

RCRCNR'NR'22

OO

RCORCO––

OO

Reactions of AnhydridesReactions of Anhydrides

Dr. Wolf's CHM 201 & 202 19-67

Reactions of Acid AnhydridesReactions of Acid Anhydrides

++ RCRCOOR'R'

OO

++

Carboxylic acid anhydrides react with alcoholsCarboxylic acid anhydrides react with alcoholsto give esters:to give esters:

R'R'OOHHRCRCOOCRCR

OO OO

RCOHRCOH

OO

normally, symmetrical anhydrides are usednormally, symmetrical anhydrides are used

(both R groups the same)(both R groups the same)

reaction can be carried out in presence of reaction can be carried out in presence of

pyridine (a base) or it can be catalyzed by acidspyridine (a base) or it can be catalyzed by acids

Dr. Wolf's CHM 201 & 202 19-68


++ RCRCOOR'R'

OO

++

Carboxylic acid anhydrides react with alcoholsCarboxylic acid anhydrides react with alcoholsto give esters:to give esters:

R'R'OOHHRCRCOOCRCR

OO OO

RCOHRCOH

OO

via:via:

CCRR

OO

OCROCR

OOR'R'

HH

OO

Dr. Wolf's CHM 201 & 202 19-69

ExampleExample

(60%)(60%)

HH22SOSO44

++CHCH33COCCHCOCCH33

OO OO

CHCH33CHCHCHCH22CHCH33

OOHH

CHCH33CCOOCHCHCHCH22CHCH33

OO

CHCH33

Dr. Wolf's CHM 201 & 202 19-70


++ RCRCNNR'R'22

OO

++

Acid anhydrides react with ammonia and aminesAcid anhydrides react with ammonia and aminesto give amides:to give amides:

2R'2R'22NNHHRCRCOOCRCR

OO OO

RCORCO––

OO

R'R'22NNHH22

++

via:via:

CCRR

OO

OCROCR

NNR'R'22

HH

OO

Dr. Wolf's CHM 201 & 202 19-71

ExampleExample

(98%)(98%)

++CHCH33COCCHCOCCH33

OO OO HH22NN CH(CHCH(CH33))22

OO CHCH33CCNNHH CH(CHCH(CH33))22

Dr. Wolf's CHM 201 & 202 19-72


++ 2RC2RCOOHH

OO

Acid anhydrides react with water to giveAcid anhydrides react with water to givecarboxylic acids (carboxylate ion in base):carboxylic acids (carboxylate ion in base):

HH22OO

++ 2RCO2RCO––

OO

++2H2HOO–– HH22OO

RCRCOOCRCR

OO OO

RCRCOOCRCR

OO OO

Dr. Wolf's CHM 201 & 202 19-73


++ 2RC2RCOOHH

OO

Acid anhydrides react with water to giveAcid anhydrides react with water to givecarboxylic acids (carboxylate ion in base):carboxylic acids (carboxylate ion in base):

HH22OORCRCOOCRCR

OO OO

CCRR

OO

OCROCR

OHOH

HH

OO

Dr. Wolf's CHM 201 & 202 19-74

ExampleExample

++ HH22OO

OO

OO

OO

COHCOH

OO

COHCOH

OO

Dr. Wolf's CHM 201 & 202 19-75

Sources of EstersSources of Esters

Dr. Wolf's CHM 201 & 202 19-76

CHCH33CCOOCHCH22CHCH22CH(CHCH(CH33))22

OO

Esters are very common natural productsEsters are very common natural products

3-methylbutyl acetate3-methylbutyl acetate

also called "isopentyl acetate" and "isoamyl also called "isopentyl acetate" and "isoamyl

acetate” acetate”

contributes to characteristic odor of bananascontributes to characteristic odor of bananas

Dr. Wolf's CHM 201 & 202 19-77

Esters of GlycerolEsters of Glycerol

R, R', and R" can be the same or differentR, R', and R" can be the same or different

called "triacylglycerols," "glyceryl triesters," or called "triacylglycerols," "glyceryl triesters," or

"triglycerides""triglycerides"

fats and oils are mixtures of glyceryl triestersfats and oils are mixtures of glyceryl triesters

RCRCOOCHCH

CHCH22OOCR'CR'OO

CHCH22OOCR"CR"

OO

OO

Dr. Wolf's CHM 201 & 202 19-78

Esters of GlycerolEsters of Glycerol

CHCH33(CH(CH22))1616CCOOCHCH

CHCH22OOC(CHC(CH22))1616CHCH33OO

CHCH22OOC(CHC(CH22))1616CHCH33

OO

OO

Tristearin: found in manyTristearin: found in manyanimal and vegetable fatsanimal and vegetable fats

Dr. Wolf's CHM 201 & 202 19-79

Cyclic Esters (Lactones)Cyclic Esters (Lactones)

(Z)-5-Tetradecen-4-olide(Z)-5-Tetradecen-4-olide(sex pheromone of female Japanese beetle)(sex pheromone of female Japanese beetle)

OO

OO

HH

HH

CHCH22(CH(CH22))66CHCH33

Dr. Wolf's CHM 201 & 202 19-80

Fischer esterification (Chapter 15)Fischer esterification (Chapter 15)

from acyl chlorides (Chapters 15 and 19)from acyl chlorides (Chapters 15 and 19)

from carboxylic acid anhydrides (Chapters 15from carboxylic acid anhydrides (Chapters 15and 19)and 19)

Preparation of EstersPreparation of Esters

Dr. Wolf's CHM 201 & 202 19-81

Physical Properties of EstersPhysical Properties of Esters

Dr. Wolf's CHM 201 & 202 19-82

Boiling PointsBoiling Points

Esters have higher Esters have higher

boiling points than boiling points than

alkanes because they alkanes because they

are more polar.are more polar.

Esters cannot form Esters cannot form

hydrogen bonds to hydrogen bonds to

other ester molecules, other ester molecules,

so have lower boiling so have lower boiling

points than alcohols.points than alcohols.


CHCH33

CHCH33CCOOCHCH33

OO


OHOH

28°C28°C

57°C57°C

99°C99°C

boilingboilingpointpoint

Dr. Wolf's CHM 201 & 202 19-83

Solubility in WaterSolubility in Water

Esters can form Esters can form

hydrogen bonds to hydrogen bonds to

water, so low molecular water, so low molecular

weight esters have weight esters have

significant solubility in significant solubility in

water. water.

Solubility decreases Solubility decreases

with increasing number with increasing number

of carbons.of carbons.


CHCH33

CHCH33CCOOCHCH33

OO


OHOH

~0~0

3333

12.512.5

SolubilitySolubility(g/100 g)(g/100 g)

Dr. Wolf's CHM 201 & 202 19-84

Reactions of Esters:Reactions of Esters:A Review and a PreviewA Review and a Preview

Dr. Wolf's CHM 201 & 202 19-85

with Grignard reagents (Chapters 14 & 19)with Grignard reagents (Chapters 14 & 19)

reduction with LiAlHreduction with LiAlH4 4 (Chapters 15 & 19)(Chapters 15 & 19)

with ammonia and amines (Chapter 19)with ammonia and amines (Chapter 19)

hydrolysis (Chapter 19) hydrolysis (Chapter 19)

Reactions of EstersReactions of Esters

Dr. Wolf's CHM 201 & 202 19-86

Acid-Catalyzed Ester HydrolysisAcid-Catalyzed Ester Hydrolysis

Dr. Wolf's CHM 201 & 202 19-87

maximize conversion to ester by removing watermaximize conversion to ester by removing water

maximize ester hydrolysis by having large excess of watermaximize ester hydrolysis by having large excess of water

equilibrium is closely balanced because carbonyl group ofequilibrium is closely balanced because carbonyl group of

ester and of carboxylic acid are comparably stabilizedester and of carboxylic acid are comparably stabilized

Acid-Catalyzed Ester HydrolysisAcid-Catalyzed Ester Hydrolysis

RRCOHCOH

OO

++ R'R'OOHHRCRCOOR'R'

OO

++ HH22OOHH++

is the reverse of Fischer esterificationis the reverse of Fischer esterification

Dr. Wolf's CHM 201 & 202 19-88

ExampleExample

HCl, heatHCl, heat

++ HH22OO

OO

CHCCHCOOCHCH22CHCH33

ClCl

++ CHCH33CHCH22OOHH

OO

CHCOHCHCOH

ClCl

(80-82%)(80-82%)

Dr. Wolf's CHM 201 & 202 19-89

Is the reverse of the mechanism for acid-Is the reverse of the mechanism for acid-

catalyzed esterification.catalyzed esterification.

Like the mechanism of esterification, it involves Like the mechanism of esterification, it involves

two stages: two stages:

1)1) formation of tetrahedral intermediateformation of tetrahedral intermediate

(3 steps)(3 steps)

2)2) dissociation of tetrahedral intermediate dissociation of tetrahedral intermediate

(3 steps)(3 steps)

Mechanism of Acid-CatalyzedMechanism of Acid-CatalyzedEster HydrolysisEster Hydrolysis

Dr. Wolf's CHM 201 & 202 19-90

First stage: First stage: formation of tetrahedral intermediateformation of tetrahedral intermediateFirst stage: First stage: formation of tetrahedral intermediateformation of tetrahedral intermediate

RCRC

OHOH

OHOH

OOR'R'

++ HH22OORCRCOOR'R'

OO

HH++

water adds to the water adds to the

carbonyl group of the carbonyl group of the

esterester

this stage is analogous this stage is analogous

to the acid-catalyzed to the acid-catalyzed

addition of water to a addition of water to a

ketoneketone

Dr. Wolf's CHM 201 & 202 19-91

Second stage: Second stage: cleavage of tetrahedralcleavage of tetrahedralintermediateintermediate


RCRC

OHOH

OHOH

OOR'R'

++ R'R'OOHH

HH++

RCOHRCOH

OO

Dr. Wolf's CHM 201 & 202 19-92

Mechanism of formationMechanism of formationofof

tetrahedral intermediatetetrahedral intermediate

Dr. Wolf's CHM 201 & 202 19-93

Step 1Step 1Step 1Step 1

RCRC

OO

OO R'R'

•••• ••••

••••••••

OO ••••++HH

HH

HH

••••

RCRC

OO

OO R'R'

••••

••••

++ HH •••• OO ••••

HH

HH

Dr. Wolf's CHM 201 & 202 19-94


••••

RCRC

OO

OO R'R'

••••

••••

++ HH

carbonyl oxygen is carbonyl oxygen is

protonated because protonated because

cation produced is cation produced is

stabilized by electron stabilized by electron

delocalization delocalization

(resonance)(resonance)

RCRC

OO

OO R'R'

••••••••

++

HH

••••

Dr. Wolf's CHM 201 & 202 19-95


••••

•••• OO ••••

HH

HH

RCRC

OO

OO R'R'

••••

••••

++ HH RCRC

OHOH

OOR'R'

••••••••

••••••••

OO ••••++

HH

HH

Dr. Wolf's CHM 201 & 202 19-96


•••• OO ••••

HH

HH••••

RCRC

OHOH

OOR'R'

••••••••

••••

OO ••••

HH

HH

++ OO ••••

HH

HH

HH++

••••

RCRC

OHOH

OOR'R'

••••••••

••••

OO ••••

HH

••••

Dr. Wolf's CHM 201 & 202 19-97

Cleavage of tetrahedralCleavage of tetrahedralintermediateintermediate

Dr. Wolf's CHM 201 & 202 19-98


OO ••••

HH

HH

HH++••••

RCRC

OHOH

OO

••••••••

••••

OHOH••••

••••

R'R'

••••RCRC

OHOH

OO

••••••••

OHOH••••

••••

R'R' HH++ •••• OO ••••

HH

HH

Dr. Wolf's CHM 201 & 202 19-99


••••

RCRC

OHOH

OO

••••••••

OHOH••••

••••

R'R' HH++

••••OO••••R'R' HH

++RCRC

OHOH••••••••

OHOH••••

••••

++

Dr. Wolf's CHM 201 & 202 19-100


RCRC

OHOH••••

OHOH••••

••••

++

RCRC

OHOH••••••••

OHOH••••

••••

++

Dr. Wolf's CHM 201 & 202 19-101


RCRC

OO••••

OHOH••••

••••

++ HH

OO••••

HH HH•••• ++OOHH HH••••

HH

RCRC

OO••••

OHOH••••

••••

••••

Dr. Wolf's CHM 201 & 202 19-102

Activation of carbonyl group by protonation of Activation of carbonyl group by protonation of carbonyl oxygencarbonyl oxygen

Nucleophilic addition of water to carbonyl groupNucleophilic addition of water to carbonyl groupforms tetrahedral intermediateforms tetrahedral intermediate

Elimination of alcohol from tetrahedral intermediate Elimination of alcohol from tetrahedral intermediate restores carbonyl grouprestores carbonyl group

Key Features of MechanismKey Features of Mechanism

Dr. Wolf's CHM 201 & 202 19-103

1818O Labeling StudiesO Labeling Studies

++ HH22OO

COCHCOCH22CHCH33

OO

COCHCOCH22CHCH33

OO

++ HH22OO

Ethyl benzoate, labeled with Ethyl benzoate, labeled with 1818O at the carbonyl O at the carbonyl

oxygen, was subjected to acid-catalyzed hydrolysis.oxygen, was subjected to acid-catalyzed hydrolysis.

Ethyl benzoate, recovered before the reaction had Ethyl benzoate, recovered before the reaction had

gone to completion, had lost its gone to completion, had lost its 1818O label.O label.

This observation is consistent with a tetrahedral This observation is consistent with a tetrahedral

intermediate.intermediate.

HH++

Dr. Wolf's CHM 201 & 202 19-104

1818O Labeling StudiesO Labeling Studies CC

OOHH

OHOH

OOCHCH22CHCH33

COCHCOCH22CHCH33

OO

HH++

++ HH22OO

++ HH22OO

COCHCOCH22CHCH33

OO

HH++

Dr. Wolf's CHM 201 & 202 19-105

Ester Hydrolysis in Base:Ester Hydrolysis in Base:SaponificationSaponification

Dr. Wolf's CHM 201 & 202 19-106

is called is called saponificationsaponification

is irreversible, because of strong stabilization of carboxylateis irreversible, because of strong stabilization of carboxylate

ionion

if carboxylic acid is desired product, saponification is followedif carboxylic acid is desired product, saponification is followed

by a separate acidification step (simply a pH adjustment)by a separate acidification step (simply a pH adjustment)

Ester Hydrolysis in Aqueous BaseEster Hydrolysis in Aqueous Base

RCORCO––

OO

++ R'R'OOHHRCRCOOR'R'

OO

++ HOHO––

Dr. Wolf's CHM 201 & 202 19-107

ExampleExample

water-methanol, heatwater-methanol, heat

(95-97%)(95-97%)

CHCH22OOCCHCCH33

CHCH33

OO

++ NaOHNaOH CHCH22OOHH

CHCH33

OO

CHCH33CONaCONa++

Dr. Wolf's CHM 201 & 202 19-108

ExampleExample

(87%)(87%)

++CCOHCCOH

CHCH33

OO

HH22CC

1. NaOH, H1. NaOH, H22O, heatO, heat

2. H2. H22SOSO44

CHCH33OOHH

CCCCOOCHCH33

CHCH33

OO

HH22CC

Dr. Wolf's CHM 201 & 202 19-109

Soap-MakingSoap-Making

CHCH33(CH(CH22))yyCCOOCHCH

CHCH22OOC(CHC(CH22))xxCHCH33OO

CHCH22OOC(CHC(CH22))zzCHCH33

OO

OO

Basic hydrolysis of Basic hydrolysis of

the glyceryl the glyceryl

triesters (from fats triesters (from fats

and oils) gives and oils) gives

salts of long-chain salts of long-chain

carboxylic acids.carboxylic acids.

These salts are These salts are

soaps.soaps.

KK22COCO33, H, H22O, heatO, heat

CHCH33(CH(CH22))xxCOKCOK

OO

CHCH33(CH(CH22))yyCOKCOK

OO

CHCH33(CH(CH22))zzCOKCOK

OO

Dr. Wolf's CHM 201 & 202 19-110

Which bond is broken when esters areWhich bond is broken when esters arehydrolyzed in base?hydrolyzed in base?

RCRCOO

OO

++R'R'••••

––OOHH••••••••

••••

••••

••••••••

RCRCOO

OO

++ R'R'OOHH••••

••••

••••••••

––••••

••••

••••

One possibility is an SOne possibility is an SNN2 attack by hydroxide on the alkyl 2 attack by hydroxide on the alkyl

group of the ester. Carboxylate is the leaving group.group of the ester. Carboxylate is the leaving group.

Dr. Wolf's CHM 201 & 202 19-111

Which bond is broken when esters areWhich bond is broken when esters arehydrolyzed in base?hydrolyzed in base?

++••••

––OHOH••••••••

RCRC

OO

OORR''••••

••••

••••••••

++ OOR'R'––

••••••••

••••

A second possibility is nucleophilic acyl A second possibility is nucleophilic acyl

substitution. substitution.

RCRC

OO••••••••

••••

••••OHOH

Dr. Wolf's CHM 201 & 202 19-112

1818O Labeling gives the answerO Labeling gives the answer

1818O retained in alcohol, not carboxylate; therefore O retained in alcohol, not carboxylate; therefore

nucleophilic acyl substitution. nucleophilic acyl substitution.

CHCH33CHCH22CCOOCHCH22CHCH33

OO

NaOHNaOH++

CHCH33CHCH22CONaCONa

OO

CHCH33CHCH22OOHH++

Dr. Wolf's CHM 201 & 202 19-113

Stereochemistry gives the same answerStereochemistry gives the same answer

alcohol has same alcohol has same

configuration at configuration at

chirality center as chirality center as

ester; therefore, ester; therefore,

nucleophilic acyl nucleophilic acyl

substitutionsubstitution

not Snot SNN2 2 CHCH33COKCOK

OO

++

CHCH33CC

OO

CCOO

HHCC66HH55

CHCH33

CC

HHOO

HHCC66HH55

CHCH33

KOH, HKOH, H22OO

Dr. Wolf's CHM 201 & 202 19-114

Does it proceed via a tetrahedral intermediate?Does it proceed via a tetrahedral intermediate?

++••••

––OHOH••••••••

RCRC

OO

OORR''••••

••••

••••••••

++ OOR'R'––

••••••••

••••

Does nucleophilic acyl substitution proceed in a Does nucleophilic acyl substitution proceed in a

single step, or is a tetrahedral intermediate single step, or is a tetrahedral intermediate

involved?involved?

RCRC

OO••••••••

••••

••••OHOH

Dr. Wolf's CHM 201 & 202 19-115

1818O Labeling StudiesO Labeling Studies

++ HH22OO

COCHCOCH22CHCH33

OO

COCHCOCH22CHCH33

OO

++ HH22OO

Ethyl benzoate, labeled with Ethyl benzoate, labeled with 1818O at the carbonyl O at the carbonyl

oxygen, was subjected to hydrolysis in base.oxygen, was subjected to hydrolysis in base.

Ethyl benzoate, recovered before the reaction Ethyl benzoate, recovered before the reaction

had gone to completion, had lost its had gone to completion, had lost its 1818O label.O label.

This observation is consistent with a tetrahedral This observation is consistent with a tetrahedral

intermediate.intermediate.

HOHO––

Dr. Wolf's CHM 201 & 202 19-116

1818O Labeling StudiesO Labeling Studies CC

OOHH

OHOH

OOCHCH22CHCH33

++ HH22OO

COCHCOCH22CHCH33

OO

HOHO–– COCHCOCH22CHCH33

OO

++ HH22OO

HOHO––

Dr. Wolf's CHM 201 & 202 19-117

Involves two stages: Involves two stages:


2)2) dissociation of tetrahedral intermediatedissociation of tetrahedral intermediate

Mechanism of Ester HydrolysisMechanism of Ester Hydrolysisin Basein Base

Dr. Wolf's CHM 201 & 202 19-118


RCRC

OHOH

OHOH

OOR'R'

++ HH22OORCRCOOR'R'

OO



esterester


to the base-catalyzed to the base-catalyzed


ketoneketone

HOHO––

Dr. Wolf's CHM 201 & 202 19-119



RCRC

OHOH

OHOH

OOR'R'

++ R'R'OOHHRCOHRCOH

OO

HOHO––

Dr. Wolf's CHM 201 & 202 19-120



Dr. Wolf's CHM 201 & 202 19-121


RCRC

OO

OOR'R'

•••• ••••

••••••••

RCRC

OO

OOR'R'

••••••••

••••••••

OO ••••

HH••••

––

••••

OO ••••

HH••••

•••• ––

Dr. Wolf's CHM 201 & 202 19-122


RCRC

OO

OOR'R'

••••••••

••••••••

OO ••••

HH••••

––

••••

••••••••

HHOO

HH

RCRC

OO

OOR'R'

••••

••••••••

OO ••••

HH••••

••••

HH

••••––••••

••••OO

HH

Dr. Wolf's CHM 201 & 202 19-123

Dissociation ofDissociation oftetrahedral intermediatetetrahedral intermediate

Dr. Wolf's CHM 201 & 202 19-124


RCRC

OO

OOR'R'

••••

••••••••

OO ••••

HH••••

••••

HH

••••––••••

••••OO

HH

••••••••

HHOO

HH

OOR'R'••••••••

–– ••••

RCRC

••••

OO•••• ••••

••••OO HH

Dr. Wolf's CHM 201 & 202 19-125


OOR'R'••••••••

–– ••••

RCRC

••••

OO•••• ••••

••••OO HH

HOHO––

RCRC

••••

OO•••• ••••

••••OO ••••

––

HH OOR'R'••••

••••

HH22OO

Dr. Wolf's CHM 201 & 202 19-126

Nucleophilic addition of hydroxide ion to carbonylNucleophilic addition of hydroxide ion to carbonylgroup in first stepgroup in first step

Tetrahedral intermediate formed in first stageTetrahedral intermediate formed in first stage

Hydroxide-induced dissociation of tetrahedralHydroxide-induced dissociation of tetrahedralintermediate in second stageintermediate in second stage

Key Features of MechanismKey Features of Mechanism

Dr. Wolf's CHM 201 & 202 19-127

Reactions of EstersReactions of Esterswith Ammonia and Amineswith Ammonia and Amines

Dr. Wolf's CHM 201 & 202 19-128

RCOR'RCOR'

OO

RCNR'RCNR'22

OO

RCORCO––

OO


Dr. Wolf's CHM 201 & 202 19-129


++ RCRCNNR'R'22

OO

++

Esters react with ammonia and aminesEsters react with ammonia and aminesto give amides:to give amides:

R'R'22NNHHRCRCOOR'R'

OO

R'R'OOHH

via:via: CCRR

OO

OOR'R'

NNR'R'22

HH

Dr. Wolf's CHM 201 & 202 19-130

ExampleExample

(75%)(75%)

++CCCCNNHH22

CHCH33

OO

HH22CC CHCH33OOHH

CCCCOOCHCH33

CHCH33

OO

HH22CC ++ NNHH33

HH22OO

Dr. Wolf's CHM 201 & 202 19-131

ExampleExample

(61%)(61%)

++FCHFCH22CCOOCHCH22CHCH33

OO NNHH22

++ CHCH33CHCH22OOHHFCHFCH22CCNNHH

OO heatheat

Dr. Wolf's CHM 201 & 202 19-132

Preparation of Tertiary AlcoholsPreparation of Tertiary Alcohols

From Esters and Grignard From Esters and Grignard

ReagentsReagents

Dr. Wolf's CHM 201 & 202Dr. Wolf's CHM 201 & 202

Grignard reagents react with estersGrignard reagents react with estersGrignard reagents react with estersGrignard reagents react with esters

RR

MgXMgX

CC

OO

••••

•••• ––MgXMgX++

–– ++RR CC

OO••••

•••• ••••

diethyldiethyletherether

OCHOCH33••••

•••• OCHOCH33••••

••••

R'R'R'R'

but species formed is but species formed is

unstable and dissociates unstable and dissociates

under the reaction under the reaction

conditions to form a ketoneconditions to form a ketone

Dr. Wolf's CHM 201 & 202 19-133


Grignard reagents react with estersGrignard reagents react with estersGrignard reagents react with estersGrignard reagents react with esters

RR

MgXMgX

CC

OO

••••

•••• ––MgXMgX++

–– ++RR CC

OO••••

•••• ••••


OCHOCH33••••

•••• OCHOCH33••••

••••

R'R'R'R'

––CHCH33OOMgXMgX

CC

OO

RR R'R'

••••••••

this ketone then goes on this ketone then goes on

to react with a second to react with a second

mole of the Grignard mole of the Grignard

reagent to give a tertiary reagent to give a tertiary

alcoholalcohol

Dr. Wolf's CHM 201 & 202 19-134


ExampleExampleExampleExample

2 CH2 CH33MgBrMgBr ++ (CH(CH33))22CHCCHCOCHOCH33

OO

1. diethyl ether1. diethyl ether

2. H2. H33OO++

(CH(CH33))22CHCCHCCHCH33

OHOH

CHCH33

(73%)(73%)

Two of the groups Two of the groups

attached to the attached to the

tertiary carbon come tertiary carbon come

from the Grignard from the Grignard

reagentreagent

Dr. Wolf's CHM 201 & 202 19-135

Dr. Wolf's CHM 201 & 202 19-136


with Lithium Aluminum with Lithium Aluminum

HydrideHydride

Dr. Wolf's CHM 201 & 202

Lithium aluminum hydride preferred forLithium aluminum hydride preferred forlaboratory reductionslaboratory reductions

Sodium borohydride reduction is too slowSodium borohydride reduction is too slowto be usefulto be useful

Catalytic hydrogenolysis used in industryCatalytic hydrogenolysis used in industrybut conditions difficult or dangerous to duplicate but conditions difficult or dangerous to duplicate in the laboratory (special catalyst, highin the laboratory (special catalyst, hightemperature, high pressuretemperature, high pressure

Reduction of EstersReduction of EstersGives Primary AlcoholsGives Primary Alcohols

Reduction of EstersReduction of EstersGives Primary AlcoholsGives Primary Alcohols

Dr. Wolf's CHM 201 & 202 19-137

Dr. Wolf's CHM 201 & 202

Example: Reduction of an EsterExample: Reduction of an EsterExample: Reduction of an EsterExample: Reduction of an Ester

1. LiAlH1. LiAlH44

diethyl etherdiethyl ether

2. H2. H22OO

(90%)(90%)

OO

COCHCOCH22CHCH33

CHCH33CHCH22OHOH

CHCH22OHOH ++

Dr. Wolf's CHM 201 & 202 19-138

Dr. Wolf's CHM 201 & 202 19-139

AmidesAmides

Dr. Wolf's CHM 201 & 202 19-140

Physical Properties of AmidesPhysical Properties of Amides

Amides are less reactive toward nucleophilic Amides are less reactive toward nucleophilic

acyl substitution than other acid derivatives.acyl substitution than other acid derivatives.

C

O

H NH

H

C

O

H NH

H

C

O

H NH

HFormamide

Dr. Wolf's CHM 201 & 202 19-141


Amides are capable of hydrogen bonding.Amides are capable of hydrogen bonding.

C

O

H NH

HC

O

H NH

H

C

O

H NH

H

Dr. Wolf's CHM 201 & 202 19-142


Amides are less acidic than carboxylic acids. Amides are less acidic than carboxylic acids.

Nitrogen is less electronegative than oxygen.Nitrogen is less electronegative than oxygen.

CH3CH2NH2 CH3CNH2

O

CH3CNCCH3

O O

H

CH3COH

O

pKa (approximate) 36 15 10 5

Dr. Wolf's CHM 201 & 202 19-143

acyl chloridesacyl chlorides

anhydridesanhydrides

estersesters

Preparation of AmidesPreparation of Amides

Amides are prepared from amines by acylationAmides are prepared from amines by acylation

with:with:

Dr. Wolf's CHM 201 & 202 19-144


Amines do Amines do notnot react with carboxylic acids to give react with carboxylic acids to give

amides. The reaction that occurs is proton-transferamides. The reaction that occurs is proton-transfer

(acid-base).(acid-base).

RCOHRCOH

OO

++ R'R'NNHH22 RCORCO

OO

++ R'R'NNHH33

++––

If no heat-sensitive groups are present, the If no heat-sensitive groups are present, the

resulting ammonium carboxylate salts can be resulting ammonium carboxylate salts can be

converted to amides by heating.converted to amides by heating.

Dr. Wolf's CHM 201 & 202 19-145


Amines do Amines do notnot react with carboxylic acids to give react with carboxylic acids to give

amides. The reaction that occurs is proton-transferamides. The reaction that occurs is proton-transfer

(acid-base).(acid-base).

RCOHRCOH

OO

++ R'R'NNHH22 RCORCO

OO

++ R'R'NNHH33

++––

heatheat

RCRCNNHR'HR'

OO

++ HH22OO

Dr. Wolf's CHM 201 & 202 19-146

ExampleExample COHCOH

OO

++

HH22NN

225°C225°C

++ HH22OO

(80-84%)(80-84%)

CCNNHH

OO

Dr. Wolf's CHM 201 & 202 19-147

Hydrolysis of AmidesHydrolysis of Amides

Dr. Wolf's CHM 201 & 202 19-148


Hydrolysis of amides is irreversible. In acid Hydrolysis of amides is irreversible. In acid

solution the amine product is protonated to solution the amine product is protonated to

give an ammonium salt.give an ammonium salt.

++ R'R'NNHH33

++RCOHRCOH

OO

RCRCNNHR'HR'

OO

++ HH22OO HH++++

Dr. Wolf's CHM 201 & 202 19-149


In basic solution the carboxylic acid productIn basic solution the carboxylic acid product

is deprotonated to give a carboxylate ion.is deprotonated to give a carboxylate ion.

RCRCNNHR'HR'

OO

++ R'R'NNHH22

––RCORCO

OO

HOHO++––

Dr. Wolf's CHM 201 & 202 19-150

Example: Acid HydrolysisExample: Acid Hydrolysis

(88-90%)(88-90%)

CHCH33CHCH22CHCCHCNNHH22

OO CHCH33CHCH22CHCOHCHCOH

OO HH22OO

HH22SOSO44

heatheat

++ NNHH44

++HSOHSO44

––

Dr. Wolf's CHM 201 & 202 19-151

Example: Basic HydrolysisExample: Basic Hydrolysis

(95%)(95%)

CHCH33COKCOK

OOKOHKOH

HH22OO

heatheat

++

CHCH33CCNNHH

OO BrBr

NNHH22

BrBr

Dr. Wolf's CHM 201 & 202 19-152

Acid-catalyzed amide hydrolysis proceeds viaAcid-catalyzed amide hydrolysis proceeds via

the customary two stages:the customary two stages:



Mechanism of Acid-CatalyzedMechanism of Acid-CatalyzedAmide HydrolysisAmide Hydrolysis

Dr. Wolf's CHM 201 & 202 19-153


RCRC

OHOH

OHOH

NNHH22

++ HH22OORCRCNNHH22

OO

HH++



amideamide


to the acid-catalyzed to the acid-catalyzed


ketoneketone

Dr. Wolf's CHM 201 & 202 19-154



++

HH++

RCOHRCOH

OO

RCRC

OHOH

OHOH

NNHH22

NNHH44

++

Dr. Wolf's CHM 201 & 202 19-155



Dr. Wolf's CHM 201 & 202 19-156


OO ••••++HH

HH

HH

RCRC

OO

NNHH22

••••

••••

++ HH •••• OO ••••

HH

HH

RCRC

OO

NNHH22

•••• ••••

••••

Dr. Wolf's CHM 201 & 202 19-157


carbonyl oxygen is carbonyl oxygen is

protonated because protonated because

cation produced is cation produced is

stabilized by electron stabilized by electron

delocalization delocalization

(resonance)(resonance)

RCRC

OO

NNHH22

••••••••

++

HH

RCRC

OO

NNHH22

••••

••••

++ HH

Dr. Wolf's CHM 201 & 202 19-158


RCRC

OHOH

NNHH22

••••••••

••••

OO ••••++

HH

HH

•••• OO ••••

HH

HH

RCRC

OO

NNHH22

••••

••••

++ HH

Dr. Wolf's CHM 201 & 202 19-159


•••• OO ••••

HH

HH

OO ••••

HH

HH

HH++

NNHH22

RCRC

OHOH••••••••

••••

OO ••••

HH

••••

RCRC

OHOH

NNHH22

••••••••

••••

OO ••••++

HH

HH

Dr. Wolf's CHM 201 & 202 19-160

Cleavage of tetrahedralCleavage of tetrahedralintermediateintermediate

Dr. Wolf's CHM 201 & 202 19-161


OO ••••

HH

HH

HH++

HH22NN

RCRC

OHOH••••••••

••••

OO ••••

HH

••••

•••• OO ••••

HH

HH

RCRC

OHOH

HH22NN

••••••••

OHOH••••

••••

HH++

Dr. Wolf's CHM 201 & 202 19-162


RCRC

OHOH

HH22NN

••••••••

OHOH••••

••••

HH++

++RCRC

OHOH••••••••

OHOH••••

••••

++NNHH33

••••

Dr. Wolf's CHM 201 & 202 19-163

Step 6Step 6Step 6Step 6 ++RCRC

OHOH••••••••

OHOH••••

••••

++

RCRC

OHOH

HH22NN

••••••••

OHOH••••

••••

HH++

NNHH33••••

HH33OO++

NNHH44++

Dr. Wolf's CHM 201 & 202 19-164


RCRC

OHOH••••

OHOH••••

••••

++

RCRC

OHOH••••••••

OHOH••••

••••

++

Dr. Wolf's CHM 201 & 202 19-165


OO••••

HH HH••••

••••

RCRC

OO

OHOH••••

••••

++ HH ++OOHH HH••••

HH

RCRC

OO••••

OHOH••••

••••

••••

Dr. Wolf's CHM 201 & 202 19-166

Involves two stages: Involves two stages:



Mechanism of Amide HydrolysisMechanism of Amide Hydrolysisin Basein Base

Dr. Wolf's CHM 201 & 202 19-167


RCRC

OHOH

OHOH

NNHH22

++ HH22OORCRCNNHH22

OO



amideamide


to the base-catalyzed to the base-catalyzed


ketoneketone

HOHO––

Dr. Wolf's CHM 201 & 202 19-168



++RCORCO

OO

RCRC

OHOH

OHOH

NNHH22

NNHH33––

HOHO––

Dr. Wolf's CHM 201 & 202 19-169



Dr. Wolf's CHM 201 & 202 19-170

Step 1Step 1Step 1Step 1 RCRC

OO

NNHH22

••••••••

••••

OO ••••

HH••••

––

••••

OO ••••

HH••••

•••• ––RCRC

OO

NNHH22

•••• ••••

••••

Dr. Wolf's CHM 201 & 202 19-171


••••••••

HHOO

HH

RCRC

OO

NNHH22

••••••••

••••

OO ••••

HH••••

––

••••

RCRC

OO

NNHH22

••••

••••

OO ••••

HH••••

••••

HH

••••––••••

••••OO

HH

Dr. Wolf's CHM 201 & 202 19-172

Dissociation ofDissociation oftetrahedral intermediatetetrahedral intermediate

Dr. Wolf's CHM 201 & 202 19-173


HH22NN

RCRC

OHOH••••••••

••••

OO ••••

HH

••••

OO ••••

HH

HH••••

RCRC

OHOH

HH22NN

••••••••

OHOH••••

••••

HH++ •••• OO ••••

HH

•••• ––

Dr. Wolf's CHM 201 & 202 19-174


RCRC

OO

HH33NN

•••• ••••

OHOH••••

••••

++

HH

••••––••••

••••OO

HH

••••••••

HHOO

HH

NNHH33••••

RCRC

••••

OO•••• ••••

••••OO HH

Dr. Wolf's CHM 201 & 202 19-175


RCRC

••••

OO•••• ••••

••••OO HH

HOHO––

RCRC

••••

OO•••• ••••

••••OO ••••

––

NNHH33••••

Dr. Wolf's CHM 201 & 202 19-176

LactamsLactams

Dr. Wolf's CHM 201 & 202 19-177

LactamsLactams

Lactams are cyclic amides. Some are industrialLactams are cyclic amides. Some are industrial

chemicals, others occur naturally.chemicals, others occur naturally. NN

HH

OO

-Caprolactam*: used to-Caprolactam*: used to

prepare a type of nylonprepare a type of nylon

*Caproic acid is the common name for hexanoic acid.*Caproic acid is the common name for hexanoic acid.

Dr. Wolf's CHM 201 & 202 19-178

LactamsLactams

Lactams are cyclic amides. Some are industrialLactams are cyclic amides. Some are industrial

chemicals, others occur naturally.chemicals, others occur naturally.

Penicillin G: a Penicillin G: a -lactam antibiotic-lactam antibiotic

CHCH33

CHCH33

SS

COCO22HHOO

NN

CC66HH55CHCH22CCNNHH

OO

Dr. Wolf's CHM 201 & 202 19-179

Preparation of NitrilesPreparation of Nitriles

Dr. Wolf's CHM 201 & 202 19-180

nucleophilic substitution by cyanide onnucleophilic substitution by cyanide onalkyl halidesalkyl halides

cyanohydrin formationcyanohydrin formation

dehydration of amidesdehydration of amides


Nitriles are prepared by:Nitriles are prepared by:

Dr. Wolf's CHM 201 & 202 19-181

ExampleExample

(95%)(95%)

CHCH33(CH(CH22))88CHCH22ClClKKCNCN

ethanol-ethanol-waterwater

CHCH33(CH(CH22))88CHCH22CC NN

SSNN22

Dr. Wolf's CHM 201 & 202 19-182

ExampleExample

(75%)(75%)

KKCNCN

HH++CHCH33CHCH22CCHCCH22CHCH33

OO

CHCH33CHCH22CCHCCH22CHCH33

OOHH

CC NN

Dr. Wolf's CHM 201 & 202 19-183

uses the reagent Puses the reagent P44OO1010 (often written as P (often written as P22OO55))


By dehydration of amidesBy dehydration of amides

(CH(CH33))22CHCHCNCNHH22

OOPP44OO1010

200°C200°C(CH(CH33))22CHCHCC NN

(69-86%)(69-86%)

Dr. Wolf's CHM 201 & 202 19-184

Hydrolysis of NitrilesHydrolysis of Nitriles

Dr. Wolf's CHM 201 & 202 19-185


Hydrolysis of nitriles resembles the hydrolysisHydrolysis of nitriles resembles the hydrolysis

of amides. The reaction is of amides. The reaction is irreversibleirreversible. .

Ammonia is produced and is protonated to Ammonia is produced and is protonated to

ammonium ion in acid solution.ammonium ion in acid solution.

++ NNHH44

++RCOHRCOH

OO

RCRCNN ++ 2H2H22OO HH++ ++

Dr. Wolf's CHM 201 & 202 19-186


In basic solution the carboxylic acid productIn basic solution the carboxylic acid product

is deprotonated to give a carboxylate ion.is deprotonated to give a carboxylate ion.

++––

RCORCO

OO

HOHO++––

NNHH33RCRCNN ++ HH22OO

Dr. Wolf's CHM 201 & 202 19-187

Example: Acid HydrolysisExample: Acid Hydrolysis

(92-95%)(92-95%)

OO

HH22OO

HH22SOSO44

heatheat

CHCH22CNCN

NONO22

CHCH22COHCOH

NONO22

Dr. Wolf's CHM 201 & 202 19-188

Example: Basic HydrolysisExample: Basic Hydrolysis

(80%)(80%)

CHCH33(CH(CH22))99COHCOH

OO

CHCH33(CH(CH22))99CNCN1. KOH, H1. KOH, H22O, heatO, heat

2. H2. H++

Dr. Wolf's CHM 201 & 202 19-189

Hydrolysis of nitriles proceeds via theHydrolysis of nitriles proceeds via the

corresponding amide.corresponding amide.

We already know the mechanism of amideWe already know the mechanism of amide

hydrolysis.hydrolysis.

Therefore, all we need to do is to see how Therefore, all we need to do is to see how

amides are formed from nitriles under the amides are formed from nitriles under the

conditions of hydrolysis. conditions of hydrolysis.

Mechanism of Hydrolysis of NitrilesMechanism of Hydrolysis of Nitriles

RCRC NNHH22OO

RCRCNNHH2 2

OOHH22OO

RCOHRCOH

OO

Dr. Wolf's CHM 201 & 202 19-190

The mechanism of amide formation is analogousThe mechanism of amide formation is analogous

to that of conversion of alkynes to ketones.to that of conversion of alkynes to ketones.

It begins with the addition of water across theIt begins with the addition of water across the

carbon-nitrogen triple bond.carbon-nitrogen triple bond.

The product of this addition is the nitrogen The product of this addition is the nitrogen

analog of an enol. It is transformed to an amideanalog of an enol. It is transformed to an amide

under the reaction conditions.under the reaction conditions.

Mechanism of Hydrolysis of NitrilesMechanism of Hydrolysis of Nitriles

RCRC NNHH22OO

RCRCNNHH2 2

OO

RCRC NNHH

OHOH

Dr. Wolf's CHM 201 & 202 19-191


OO ••••

HH

••••••••

––

RCRC NN •••• RCRC

OO

NN

••••

•••• ••••––

••••

HH

Dr. Wolf's CHM 201 & 202 19-192


RCRC

OO

NN

••••

•••• ••••––

••••

HH

OO ••••••••

HH

HH ••••––OO ••••••••

HHRCRC

OO

NN

••••

••••

HH

HH

••••

Dr. Wolf's CHM 201 & 202 19-193


••••––OO ••••••••

HH

RCRC

OO

NN

••••

••••

HH

HH

••••

••••

––

••••

RCRC

OO

NN

••••

•••• HH

•••• OO ••••

HH

HH

Dr. Wolf's CHM 201 & 202 19-194


••••

––

••••

RCRC

OO

NN

••••

•••• HH

OO ••••HH

HH

•••• NN

••••

RCRC

OO ••••

•••• HH

HH

––OO ••••

HH

••••••••

Dr. Wolf's CHM 201 & 202 19-195

Addition of Grignard ReagentsAddition of Grignard Reagents

to Nitrilesto Nitriles

Dr. Wolf's CHM 201 & 202 19-196

Grignard reagents add to carbon-nitrogen tripleGrignard reagents add to carbon-nitrogen triple

bonds in the same way that they add to carbon-bonds in the same way that they add to carbon-

oxygen double bonds.oxygen double bonds.

The product of the reaction is an imine.The product of the reaction is an imine.

Addition of Grignard Reagents to NitrilesAddition of Grignard Reagents to Nitriles

RCRC NNR'MgXR'MgX

RCR'RCR'

NNMgXMgXHH22OO

RCR'RCR'

NNHH


Dr. Wolf's CHM 201 & 202 19-197

Addition of Grignard Reagents to NitrilesAddition of Grignard Reagents to Nitriles

RCRC NNR'MgXR'MgX

RCR'RCR'

NNMgXMgXHH22OO

RCR'RCR'

NNHH


RCR'RCR'

OO

HH33OO++

Imines are readily hydrolyzed to ketones.Imines are readily hydrolyzed to ketones.Therefore, the reaction of Grignard Therefore, the reaction of Grignard reagents with nitriles can be used as a reagents with nitriles can be used as a synthesis of ketones.synthesis of ketones.

Dr. Wolf's CHM 201 & 202 19-198

ExampleExample

(79%)(79%)

FF33CC

CC NN + + CHCH33MgIMgI

1. diethyl ether1. diethyl ether

2. H2. H33OO++, heat, heat FF33CC

CCCHCH33

OO

Dr. Wolf's CHM 201 & 202 19-199

Spectroscopic Analysis ofSpectroscopic Analysis of

Carboxylic Acid DerivativesCarboxylic Acid Derivatives

Dr. Wolf's CHM 201 & 202 19-200

C=O stretching frequency depends on whether theC=O stretching frequency depends on whether thecompound is an acyl chloride, anhydride, ester, orcompound is an acyl chloride, anhydride, ester, oramide.amide.

Infrared SpectroscopyInfrared Spectroscopy

CHCH33CClCCl

OO

CHCH33COCHCOCH33

OO

CHCH33COCCHCOCCH33

OO OO

CHCH33CNHCNH22

OO

1822 cm1822 cm-1-1 17481748andand

1815 cm1815 cm-1-1

1736 cm1736 cm-1-1 1694 cm1694 cm-1-1

C=O stretching frequency C=O stretching frequency

Dr. Wolf's CHM 201 & 202 19-201

Anhydrides have two peaks due to C=O stretching. Anhydrides have two peaks due to C=O stretching. One results from symmetrical stretching of the C=OOne results from symmetrical stretching of the C=Ounit, the other from an antisymmetrical stretch.unit, the other from an antisymmetrical stretch.


17481748andand

1815 cm1815 cm-1-1

CHCH33COCCHCOCCH33

OO OO

C=O stretching frequency C=O stretching frequency

Dr. Wolf's CHM 201 & 202 19-202

Nitriles are readily identified by absorption due to Nitriles are readily identified by absorption due to carbon-nitrogen triple bond stretching in the 2210-carbon-nitrogen triple bond stretching in the 2210-2260 cm2260 cm-1-1 region. region.


Dr. Wolf's CHM 201 & 202 19-203

11H NMR readily distinguishes between isomericH NMR readily distinguishes between isomericesters of the type:esters of the type:

11H NMRH NMR

RRCOCOR'R'

OO

andand R'R'COCORR

OO

OO CC HH is less shielded than is less shielded than

OO

CC CC HH

Dr. Wolf's CHM 201 & 202 19-204

11H NMRH NMR

CHCH33CCOOCHCH22CHCH33

OO

andand

For example:For example:

CHCH33CHCH22CCOOCHCH33

OO

Both have a triplet-quartet pattern for an ethylBoth have a triplet-quartet pattern for an ethyl

group and a methyl singlet. They can begroup and a methyl singlet. They can be

identified, however, on the basis of chemicalidentified, however, on the basis of chemical

shifts.shifts.

Dr. Wolf's CHM 201 & 202 19-205Chemical shift (Chemical shift (, ppm), ppm)

Figure 20.9Figure 20.9

01.02.03.04.05.0

CHCH33COCOCHCH22CHCH33

OO

01.02.03.04.05.0

CHCH33CHCH22COCOCHCH33

OO

Dr. Wolf's CHM 201 & 202 19-206

1313C NMRC NMR

Carbonyl carbon is at low field (Carbonyl carbon is at low field ( 160-180 160-180

ppm), but not as deshielded as the carbonyl ppm), but not as deshielded as the carbonyl

carbon of an aldehyde or ketone (carbon of an aldehyde or ketone ( 190-215 190-215

ppm). ppm).

The carbon of a CN group appears near The carbon of a CN group appears near

120 ppm.120 ppm.

Dr. Wolf's CHM 201 & 202 19-207

UV-VISUV-VIS

CHCH33CClCCl

OO

235 nm235 nm

CHCH33COCHCOCH33

OO

225 nm225 nm

CHCH33COCCHCOCCH33

OO OO

207 nm207 nm

CHCH33CNHCNH22

OO

214 nm214 nm

nn* absorption: * absorption: maxmax

Dr. Wolf's CHM 201 & 202 19-208

Most carboxylic acid derivatives give a prominentMost carboxylic acid derivatives give a prominentpeak for an acylium ion derived by thepeak for an acylium ion derived by thefragmentation shown.fragmentation shown.

Mass SpectrometryMass Spectrometry

++RCRCXX

••••OO ••••

•••• RCRCXX

••++OO ••••

•••• RCRC OO++

•••• •• ••••XX

Dr. Wolf's CHM 201 & 202 19-209

Amides, however, cleave in the direction that givesAmides, however, cleave in the direction that givesa nitrogen-stabilized cation.a nitrogen-stabilized cation.

Mass SpectrometryMass Spectrometry

++••RRRCRCNNR'R'22

••••OO ••••

••••

••++

RCRCNNR'R'22

OO ••••

••••

++OO CC•••• NNR'R'22••••

Dr. Wolf's CHM 201 & 202 19-210

End of Chapter 19End of Chapter 19

dr. wolf's chm 201 & 202 19-1 chapter 19 carboxylic acid derivatives nucleophilic acyl...

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