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Dr. Wolf's CHM 201 & 202 20-1
Chapter 20Chapter 20Carboxylic Acid DerivativesCarboxylic Acid Derivatives
Nucleophilic Acyl SubstitutionNucleophilic Acyl Substitution
Dr. Wolf's CHM 201 & 202 20-2
20.120.1
Nomenclature of Carboxylic Acid DerivativesNomenclature of Carboxylic Acid Derivatives
Dr. Wolf's CHM 201 & 202 20-3
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 20-4
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 20-5
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 20-6
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 20-7
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 20-8
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 20-9
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 20-10
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 20-11
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 20-12
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 20-13
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 20-14
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 20-15
20.220.2
Structure of Carboxylic Acid DerivativesStructure of Carboxylic Acid Derivatives
Dr. Wolf's CHM 201 & 202 20-16
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 20-17
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 20-18
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 20-19
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 20-20
Orbital overlaps in carboxylic acid derivativesOrbital overlaps in carboxylic acid derivatives
orbital of carbonyl grouporbital of carbonyl group
Dr. Wolf's CHM 201 & 202 20-21
Orbital overlaps in carboxylic acid derivativesOrbital overlaps in carboxylic acid derivatives
lone pair orbitallone pair orbital
of substituentof substituent
Dr. Wolf's CHM 201 & 202 20-22
Orbital overlaps in carboxylic acid derivativesOrbital overlaps in carboxylic acid derivatives
electron pair of substituent delocalized into electron pair of substituent delocalized into
carbonyl carbonyl orbitalorbital
Dr. Wolf's CHM 201 & 202 20-23
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 20-24
RCRCClCl
OO
least stabilized C=Oleast stabilized C=O
most stabilized C=Omost stabilized C=O
Dr. Wolf's CHM 201 & 202 20-25
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 20-26
RCRCOOCR'CR'
OO OORCRCClCl
OO
least stabilized C=Oleast stabilized C=O
most stabilized C=Omost stabilized C=O
Dr. Wolf's CHM 201 & 202 20-27
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 20-28
RCRCOOCR'CR'
OO OORCRCClCl
OO
least stabilized C=Oleast stabilized C=O
most stabilized C=Omost stabilized C=O
RCSR'RCSR'
OO
Dr. Wolf's CHM 201 & 202 20-29
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 20-30
RCRCOOCR'CR'
OO OORCRCClCl
OO
RCRCOOR'R'
OO
least stabilized C=Oleast stabilized C=O
most stabilized C=Omost stabilized C=O
RCSR'RCSR'
OO
Dr. Wolf's CHM 201 & 202 20-31
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 20-32
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 20-33
RCRCOOCR'CR'
OO OORCRCClCl
OO
RCRCOOR'R'
OO
RCRCNNR'R'22
OO
least stabilized C=Oleast stabilized C=O
most stabilized C=Omost stabilized C=O
RCSR'RCSR'
OO
Dr. Wolf's CHM 201 & 202 20-34
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 20-35
RCRCOOCR'CR'
OO OORCRCClCl
OO
RCRCOOR'R'
OO
RCRCNNR'R'22
OO
RCRCOO––
OO
least stabilized C=Oleast stabilized C=O
most stabilized C=Omost stabilized C=O
RCSR'RCSR'
OO
Dr. Wolf's CHM 201 & 202 20-36
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 20-37
Nucleophilic Acyl SubstitutionNucleophilic Acyl Substitution
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 20-38
RCRCOOCR'CR'
OO OORCRCClCl
OO
RCRCOOR'R'
OO
RCRCNNR'R'22
OO
RCRCOO––
OO
RCSR'RCSR'
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 20-39
20.320.3
General MechanismGeneral Mechanism
forfor
Nucleophilic Acyl SubstitutionNucleophilic Acyl Substitution
Dr. Wolf's CHM 201 & 202 20-40
Nucleophilic Acyl SubstitutionNucleophilic Acyl Substitution
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 20-41
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 20-42
General Mechanism for Nucleophilic Acyl SubstitutionGeneral Mechanism for Nucleophilic Acyl Substitution
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 20-43
General Mechanism for Nucleophilic Acyl SubstitutionGeneral Mechanism for Nucleophilic Acyl Substitution
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 20-44
General Mechanism for Nucleophilic Acyl SubstitutionGeneral Mechanism for Nucleophilic Acyl Substitution
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 20-45
General Mechanism for Nucleophilic Acyl SubstitutionGeneral Mechanism for Nucleophilic Acyl Substitution
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 20-46
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 20-47
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 20-48
Dissociation of TIDissociation of TI
BB••••
•••• CC
RROO
XX
NuNu••••
HH ••••
••••
++B—HB—H ++CC
OO
RR NuNu ••••
•••• ••••++ XX•••• ••••
––
Dr. Wolf's CHM 201 & 202 20-49
Dissociation of TIDissociation of TI––
CC
OO
RR NuNu ••••
•••• ••••++ XX•••• ••••
––
••••
CC
RROO
XX
NuNu••••
••••
••••
••••––