dr. wolf's chm 201 & 202 19-1 chapter 19 carboxylic acid derivatives nucleophilic acyl...
TRANSCRIPT
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
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 19-22
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 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
least stabilized C=Oleast stabilized C=O
most stabilized C=Omost stabilized C=O
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
least stabilized C=Oleast stabilized C=O
most stabilized C=Omost stabilized C=O
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
least stabilized C=Oleast stabilized C=O
most stabilized C=Omost stabilized C=O
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
least stabilized C=Oleast stabilized C=O
most stabilized C=Omost stabilized C=O
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
least stabilized C=Oleast stabilized C=O
most stabilized C=Omost stabilized C=O
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
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 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
Nucleophilic Acyl SubstitutionNucleophilic Acyl Substitution
Dr. Wolf's CHM 201 & 202 19-40
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 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
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 19-43
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 19-44
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 19-45
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 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
RR NuNu ••••
•••• ••••++ XX•••• ••••
––
Dr. Wolf's CHM 201 & 202 19-49
Dissociation of TIDissociation of TI––
CC
OO
RR NuNu ••••
•••• ••••++ 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
Reactions of Acyl ChloridesReactions of Acyl Chlorides
++ 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
Reactions of Acyl ChloridesReactions of Acyl Chlorides
++ 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
Reactions of Acyl ChloridesReactions of Acyl Chlorides
++ 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
Reactions of Acyl ChloridesReactions of Acyl Chlorides
++ 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
Reactions of Acyl ChloridesReactions of Acyl Chlorides
++ 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
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
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
Reactions of Acid AnhydridesReactions of Acid Anhydrides
++ 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
Reactions of Acid AnhydridesReactions of Acid Anhydrides
++ 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
Reactions of Acid AnhydridesReactions of Acid Anhydrides
++ 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.
CHCH33CHCHCHCH22CHCH33
CHCH33
CHCH33CCOOCHCH33
OO
CHCH33CHCHCHCH22CHCH33
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.
CHCH33CHCHCHCH22CHCH33
CHCH33
CHCH33CCOOCHCH33
OO
CHCH33CHCHCHCH22CHCH33
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
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
Step 1Step 1Step 1Step 1
••••
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
Step 2Step 2Step 2Step 2
••••
•••• OO ••••
HH
HH
RCRC
OO
OO R'R'
••••
••••
++ HH RCRC
OHOH
OOR'R'
••••••••
••••••••
OO ••••++
HH
HH
Dr. Wolf's CHM 201 & 202 19-96
Step 3Step 3Step 3Step 3
•••• 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
Step 4Step 4Step 4Step 4
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
Step 5Step 5Step 5Step 5
••••
RCRC
OHOH
OO
••••••••
OHOH••••
••••
R'R' HH++
••••OO••••R'R' HH
++RCRC
OHOH••••••••
OHOH••••
••••
++
Dr. Wolf's CHM 201 & 202 19-100
Step 5Step 5Step 5Step 5
RCRC
OHOH••••
OHOH••••
••••
++
RCRC
OHOH••••••••
OHOH••••
••••
++
Dr. Wolf's CHM 201 & 202 19-101
Step 6Step 6Step 6Step 6
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:
1)1) formation of tetrahedral intermediateformation of tetrahedral intermediate
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
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
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 base-catalyzed to the base-catalyzed
addition of water to a addition of water to a
ketoneketone
HOHO––
Dr. Wolf's CHM 201 & 202 19-119
Second stage: Second stage: cleavage of tetrahedralcleavage of tetrahedralintermediateintermediate
Second stage: Second stage: cleavage of tetrahedralcleavage of tetrahedralintermediateintermediate
RCRC
OHOH
OHOH
OOR'R'
++ R'R'OOHHRCOHRCOH
OO
HOHO––
Dr. Wolf's CHM 201 & 202 19-120
Mechanism of formationMechanism of formationofof
tetrahedral intermediatetetrahedral intermediate
Dr. Wolf's CHM 201 & 202 19-121
Step 1Step 1Step 1Step 1
RCRC
OO
OOR'R'
•••• ••••
••••••••
RCRC
OO
OOR'R'
••••••••
••••••••
OO ••••
HH••••
––
••••
OO ••••
HH••••
•••• ––
Dr. Wolf's CHM 201 & 202 19-122
Step 2Step 2Step 2Step 2
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
Step 3Step 3Step 3Step 3
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
Step 4Step 4Step 4Step 4
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
Reactions of EstersReactions of Esters
Dr. Wolf's CHM 201 & 202 19-129
Reactions of EstersReactions of Esters
++ 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
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'
––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
Dr. Wolf's CHM 201 & 202Dr. Wolf's CHM 201 & 202
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
Reactions of EstersReactions of Esters
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
Physical Properties of AmidesPhysical Properties of Amides
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
Physical Properties of AmidesPhysical Properties of Amides
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
Preparation of AmidesPreparation of Amides
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
Preparation of AmidesPreparation of Amides
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 AmidesHydrolysis of Amides
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
Hydrolysis of AmidesHydrolysis of Amides
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:
1)1) formation of tetrahedral intermediateformation of tetrahedral intermediate
2)2) dissociation of tetrahedral intermediatedissociation of tetrahedral intermediate
Mechanism of Acid-CatalyzedMechanism of Acid-CatalyzedAmide HydrolysisAmide Hydrolysis
Dr. Wolf's CHM 201 & 202 19-153
First stage: First stage: formation of tetrahedral intermediateformation of tetrahedral intermediateFirst stage: First stage: formation of tetrahedral intermediateformation of tetrahedral intermediate
RCRC
OHOH
OHOH
NNHH22
++ HH22OORCRCNNHH22
OO
HH++
water adds to the water adds to the
carbonyl group of the carbonyl group of the
amideamide
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 19-154
Second stage: Second stage: cleavage of tetrahedralcleavage of tetrahedralintermediateintermediate
Second stage: Second stage: cleavage of tetrahedralcleavage of tetrahedralintermediateintermediate
++
HH++
RCOHRCOH
OO
RCRC
OHOH
OHOH
NNHH22
NNHH44
++
Dr. Wolf's CHM 201 & 202 19-155
Mechanism of formationMechanism of formationofof
tetrahedral intermediatetetrahedral intermediate
Dr. Wolf's CHM 201 & 202 19-156
Step 1Step 1Step 1Step 1
OO ••••++HH
HH
HH
RCRC
OO
NNHH22
••••
••••
++ HH •••• OO ••••
HH
HH
RCRC
OO
NNHH22
•••• ••••
••••
Dr. Wolf's CHM 201 & 202 19-157
Step 1Step 1Step 1Step 1
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
Step 2Step 2Step 2Step 2
RCRC
OHOH
NNHH22
••••••••
••••
OO ••••++
HH
HH
•••• OO ••••
HH
HH
RCRC
OO
NNHH22
••••
••••
++ HH
Dr. Wolf's CHM 201 & 202 19-159
Step 3Step 3Step 3Step 3
•••• 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
Step 4Step 4Step 4Step 4
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
Step 5Step 5Step 5Step 5
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
Step 6Step 6Step 6Step 6
RCRC
OHOH••••
OHOH••••
••••
++
RCRC
OHOH••••••••
OHOH••••
••••
++
Dr. Wolf's CHM 201 & 202 19-165
Step 6Step 6Step 6Step 6
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:
1)1) formation of tetrahedral intermediateformation of tetrahedral intermediate
2)2) dissociation of tetrahedral intermediatedissociation of tetrahedral intermediate
Mechanism of Amide HydrolysisMechanism of Amide Hydrolysisin Basein Base
Dr. Wolf's CHM 201 & 202 19-167
First stage: First stage: formation of tetrahedral intermediateformation of tetrahedral intermediateFirst stage: First stage: formation of tetrahedral intermediateformation of tetrahedral intermediate
RCRC
OHOH
OHOH
NNHH22
++ HH22OORCRCNNHH22
OO
water adds to the water adds to the
carbonyl group of the carbonyl group of the
amideamide
this stage is analogous this stage is analogous
to the base-catalyzed to the base-catalyzed
addition of water to a addition of water to a
ketoneketone
HOHO––
Dr. Wolf's CHM 201 & 202 19-168
Second stage: Second stage: cleavage of tetrahedralcleavage of tetrahedralintermediateintermediate
Second stage: Second stage: cleavage of tetrahedralcleavage of tetrahedralintermediateintermediate
++RCORCO
OO
RCRC
OHOH
OHOH
NNHH22
NNHH33––
HOHO––
Dr. Wolf's CHM 201 & 202 19-169
Mechanism of formationMechanism of formationofof
tetrahedral intermediatetetrahedral intermediate
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
Step 2Step 2Step 2Step 2
••••••••
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
Step 3Step 3Step 3Step 3
HH22NN
RCRC
OHOH••••••••
••••
OO ••••
HH
••••
OO ••••
HH
HH••••
RCRC
OHOH
HH22NN
••••••••
OHOH••••
••••
HH++ •••• OO ••••
HH
•••• ––
Dr. Wolf's CHM 201 & 202 19-174
Step 4Step 4Step 4Step 4
RCRC
OO
HH33NN
•••• ••••
OHOH••••
••••
++
HH
••••––••••
••••OO
HH
••••••••
HHOO
HH
NNHH33••••
RCRC
••••
OO•••• ••••
••••OO HH
Dr. Wolf's CHM 201 & 202 19-175
Step 5Step 5Step 5Step 5
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
Preparation of NitrilesPreparation of Nitriles
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))
Preparation of NitrilesPreparation of Nitriles
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 NitrilesHydrolysis of Nitriles
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
Hydrolysis of NitrilesHydrolysis of Nitriles
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
Step 1Step 1Step 1Step 1
OO ••••
HH
••••••••
––
RCRC NN •••• RCRC
OO
NN
••••
•••• ••••––
••••
HH
Dr. Wolf's CHM 201 & 202 19-192
Step 2Step 2Step 2Step 2
RCRC
OO
NN
••••
•••• ••••––
••••
HH
OO ••••••••
HH
HH ••••––OO ••••••••
HHRCRC
OO
NN
••••
••••
HH
HH
••••
Dr. Wolf's CHM 201 & 202 19-193
Step 3Step 3Step 3Step 3
••••––OO ••••••••
HH
RCRC
OO
NN
••••
••••
HH
HH
••••
••••
––
••••
RCRC
OO
NN
••••
•••• HH
•••• OO ••••
HH
HH
Dr. Wolf's CHM 201 & 202 19-194
Step 4Step 4Step 4Step 4
••••
––
••••
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
diethyldiethyletherether
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
diethyldiethyletherether
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.
Infrared SpectroscopyInfrared Spectroscopy
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.
Infrared SpectroscopyInfrared Spectroscopy
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