Chapter 8 Chapter 8 Nucleophilic Nucleophilic Substitution (in depth) Substitution (in depth) & Competing Elimination & Competing Elimination 8.1 8.1 Functional Group Functional Group Transformation By Transformation By Nucleophilic Nucleophilic Substitution Substitution 8.1 8.1 Functional Group Functional Group Transformation By Transformation By Nucleophilic Nucleophilic Substitution Substitution Y Y : – R X Y R + : : X – nucleophile nucleophile is a Lewis base (electron-pair donor) is a Lewis base (electron-pair donor) often negatively charged and used as often negatively charged and used as Na Na + or K or K + salt salt substrate is usually an substrate is usually an alkyl alkyl halide halide Nucleophilic Nucleophilic Substitution Substitution + Substrate cannot be an a Substrate cannot be an a vinylic vinylic halide or an halide or an aryl halide, except under certain conditions to aryl halide, except under certain conditions to be discussed in Chapter 23. be discussed in Chapter 23. X C C X Nucleophilic Nucleophilic Substitution Substitution + R X Alkoxide Alkoxide ion as the ion as the nucleophile nucleophile .. .. O: .. .. R' R' – Table 8.1 Examples of Table 8.1 Examples of Nucleophilic Nucleophilic Substitution Substitution gives an ether gives an ether + : : X R .. .. O .. .. R' R' – (CH (CH 3 ) 2 CHCH CHCH 2 ONa + CH Na + CH 3 CH CH 2 Br Br Isobutyl alcohol Isobutyl alcohol (CH (CH 3 ) 2 CHCH CHCH 2 OCH CH 2 CH CH 3 + + Na NaBr Br Ethyl isobutyl ether (66%) Ethyl isobutyl ether (66%) Example Example
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Chapter 8 8.1 Functional Group Transformation By ... 8 Nucleophilic Substitution (in depth) & Competing Elimination 8.1 Functional Group Transformation By Nucleophilic Substitution
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Chapter 8Chapter 8
Nucleophilic Nucleophilic Substitution (in depth)Substitution (in depth)
& Competing Elimination& Competing Elimination
8.18.1
Functional Group Functional Group
Transformation ByTransformation By Nucleophilic Nucleophilic
SubstitutionSubstitution
8.18.1
Functional Group Functional Group
Transformation ByTransformation By Nucleophilic Nucleophilic
SubstitutionSubstitution
Y Y ::––
RR XX YY RR++ : : XX––
nucleophilenucleophile is a Lewis base (electron-pair donor)is a Lewis base (electron-pair donor)
often negatively charged and used as often negatively charged and used as NaNa++ or K or K++ salt salt
substrate is usually an substrate is usually an alkylalkyl halidehalide
++ Substrate cannot be an aSubstrate cannot be an a vinylic vinylic halide or anhalide or anaryl halide, except under certain conditions toaryl halide, except under certain conditions tobe discussed in Chapter 23.be discussed in Chapter 23.
NaI is soluble in acetone; NaI is soluble in acetone; NaCl and NaBr are not NaCl and NaBr are not soluble in acetone.soluble in acetone.
acetoneacetone
++ NaINaICHCH33CHCHCHCH33
BrBr
63%63%
++ NaNaBrBrCHCH33CHCHCHCH33
II
ExampleExample
8.28.2Relative Reactivity of HalideRelative Reactivity of Halide
Leaving GroupsLeaving Groups
GeneralizationGeneralization
Reactivity of halide leaving groups inReactivity of halide leaving groups innucleophilic substitution is the same asnucleophilic substitution is the same asfor elimination.for elimination.
RIRI
RBrRBr
RClRCl
RFRF
most reactivemost reactive
least reactiveleast reactive
BrBrCHCH22CHCH22CHCH22ClCl + Na + NaCNCN
A single organic product was obtained when A single organic product was obtained when 1-bromo-3-chloropropane was allowed to react 1-bromo-3-chloropropane was allowed to react with one molar equivalent of sodium cyanide in with one molar equivalent of sodium cyanide in aqueous ethanol. What was this product?aqueous ethanol. What was this product?
Br is a better leavingBr is a better leavinggroup than Clgroup than Cl
Problem 8.2Problem 8.2
BrBrCHCH22CHCH22CHCH22ClCl + Na + NaCNCN
A single organic product was obtained when A single organic product was obtained when 1-bromo-3-chloropropane was allowed to react 1-bromo-3-chloropropane was allowed to react with one molar equivalent of sodium cyanide in with one molar equivalent of sodium cyanide in aqueous ethanol. What was this product?aqueous ethanol. What was this product?
Problem 8.2Problem 8.2
CHCH22CHCH22CHCH22ClCl + Na + NaBrBrCCNN::
8.128.12Improved Leaving GroupsImproved Leaving Groups Alkyl Sulfonates Alkyl Sulfonates
Leaving GroupsLeaving Groups
We have seen numerous examples ofWe have seen numerous examples ofnucleophilic substitution in which nucleophilic substitution in which XX in R in RXX is a is ahalogen.halogen.
Halogen is not the only possible leavingHalogen is not the only possible leavinggroup, though.group, though.
Other RX CompoundsOther RX Compounds
ROSCHROSCH33
OO
OO
ROSROS
OO
OO
CHCH33
AlkylAlkylmethanesulfonatemethanesulfonate
(mesylate)(mesylate)
AlkylAlkylpp-toluenesulfonate-toluenesulfonate
(tosylate)(tosylate)
undergo same kinds of reactions as alkyl halidesundergo same kinds of reactions as alkyl halides
PreparationPreparation
(abbreviated as ROTs)(abbreviated as ROTs)
ROHROH ++
CHCH33 SOSO22ClClpyridinepyridine
ROSROS
OO
OO
CHCH33
Tosylates are prepared by the reaction of Tosylates are prepared by the reaction of alcohols with alcohols with pp-toluenesulfonyl chloride-toluenesulfonyl chloride(usually in the presence of pyridine).(usually in the presence of pyridine).
Sulfonate esters are extremely good leaving groups;sulfonate ions are very weak bases.
Tosylates can be Converted to AlkylTosylates can be Converted to AlkylHalidesHalides
NaNaBrBr
DMSODMSO
(82%)(82%)
OTsOTs
CHCH33CHCHCHCH22CHCH33
BrBr
CHCH33CHCHCHCH22CHCH33
Tosylate is a better leaving group than bromide.Tosylate is a better leaving group than bromide.
Tosylates Allow Control of StereochemistryTosylates Allow Control of Stereochemistry
Preparation of tosylate does not affect any of thePreparation of tosylate does not affect any of thebonds to the chirality center, so configuration andbonds to the chirality center, so configuration andoptical purity of tosylate is the same as theoptical purity of tosylate is the same as thealcohol from which it was formed.alcohol from which it was formed.
CC
HH
HH33CC
OOHH
CHCH33(CH(CH22))55 TsClTsCl
pyridinepyridine
CC
HH
HH33CC
OOTsTs
CHCH33(CH(CH22))55
Having a tosylate of known optical purity andHaving a tosylate of known optical purity andabsolute configuration then allows theabsolute configuration then allows thepreparation of other compounds of knownpreparation of other compounds of knownconfiguration by Sconfiguration by SNN2 processes.2 processes.
NuNu––
SSNN22
CC
HH
HH33CC
OOTsTs
CHCH33(CH(CH22))55
CC
HH
CHCH33
(CH(CH22))55CHCH33
NuNu
Tosylates Allow Control of StereochemistryTosylates Allow Control of Stereochemistry
Nucleophilic substitutions that exhibitsecond-order kinetic behavior are stereospecific and proceed withinversion of configuration.
StereochemistryStereochemistry Inversion of ConfigurationInversion of Configuration
Nucleophile attacks carbonNucleophile attacks carbonfrom side opposite bondfrom side opposite bondto the leaving group.to the leaving group.
Three-dimensionalThree-dimensionalarrangement of bonds inarrangement of bonds inproduct is opposite to product is opposite to that of reactant.that of reactant.
A stereospecific reaction is one in whichA stereospecific reaction is one in whichstereoisomeric starting materials givestereoisomeric starting materials givestereoisomeric products.stereoisomeric products.
The reaction of 2-bromooctane with NaOH The reaction of 2-bromooctane with NaOH (in ethanol-water) is stereospecific.(in ethanol-water) is stereospecific.
The Fischer projection formula for (+)-2-bromooctaneThe Fischer projection formula for (+)-2-bromooctane
is shown. Write the Fischer projection of theis shown. Write the Fischer projection of the
((––)-2-octanol formed from it by nucleophilic substitution )-2-octanol formed from it by nucleophilic substitution
with inversion of configuration.with inversion of configuration.
Problem 8.4Problem 8.4
HH BrBr
CHCH33
CHCH22(CH(CH22))44CHCH33
The Fischer projection formula for (+)-2-bromooctaneThe Fischer projection formula for (+)-2-bromooctane
is shown. Write the Fischer projection of theis shown. Write the Fischer projection of the
((––)-2-octanol formed from it by nucleophilic substitution )-2-octanol formed from it by nucleophilic substitution
with inversion of configuration.with inversion of configuration.
HHOO HH
CHCH33
CHCH22(CH(CH22))44CHCH33
Problem 8.4Problem 8.4
8.48.4Steric Effects andSteric Effects and
SSNN2 Reaction Rates2 Reaction RatesCrowding at the carbon that bears Crowding at the carbon that bears the leaving group slows the rate ofthe leaving group slows the rate ofbimolecular bimolecular nucleophilic nucleophilic substitution.substitution.
Crowding at the Reaction SiteCrowding at the Reaction Site
The rate of The rate of nucleophilicnucleophilic substitution substitutionby the Sby the SNN2 mechanism is governed2 mechanism is governedby by stericsteric effects. effects.
The rate of The rate of nucleophilicnucleophilic substitution substitutionby the Sby the SNN2 mechanism is governed2 mechanism is governedby by stericsteric effects. effects.
Crowding at the carbon adjacentCrowding at the carbon adjacentto the one that bears the leaving groupto the one that bears the leaving groupalso slows the rate of bimolecularalso slows the rate of bimolecularnucleophilicnucleophilic substitution, but the substitution, but the effect is smaller.effect is smaller.
Crowding Adjacent to the Reaction SiteCrowding Adjacent to the Reaction Site
Table 8.3 Effect of Chain Branching on Rate ofTable 8.3 Effect of Chain Branching on Rate ofSSNN2 Substitution2 Substitution
8.58.5
NucleophilesNucleophiles and and Nucleophilicity Nucleophilicity
AllAll nucleophiles nucleophiles, however, are Lewis bases., however, are Lewis bases.
TheThe nucleophiles nucleophiles described in Sections 8.1-8.6 described in Sections 8.1-8.6have been anions.have been anions.
....
....HOHO::–– ....
....CHCH33OO::––....
....HSHS::–– ––
CCNN:: :: etc.etc.
Not allNot all nucleophiles nucleophiles are anions. Many are neutral. are anions. Many are neutral.....
....HOHHOH CHCH33OHOH........
NHNH33:: for examplefor example
NucleophilesNucleophiles
....
....HOHHOH CHCH33OHOH........
for examplefor example
Many of the solvents in whichMany of the solvents in which nucleophilic nucleophilicsubstitutions are carried out are themselvessubstitutions are carried out are themselvesnucleophilesnucleophiles..
NucleophilesNucleophiles
The termThe term solvolysissolvolysis refers to arefers to a nucleophilic nucleophilicsubstitution in which thesubstitution in which the nucleophile nucleophile is the solvent. is the solvent.
SolvolysisSolvolysis
substitution by an anionicsubstitution by an anionic nucleophile nucleophile
RR——XX + + ::NuNu—— RR——NuNu + + ::XX——
++
solvolysissolvolysis
RR——XX + + ::NuNu——HH RR——NuNu——H H + + ::XX——
step in whichstep in which nucleophilic nucleophilicsubstitution occurssubstitution occurs
SolvolysisSolvolysis
++
substitution by an anionicsubstitution by an anionic nucleophile nucleophile
RR——XX + + ::NuNu—— RR——NuNu + + ::XX——
solvolysissolvolysis
RR——XX + + ::NuNu——HH RR——NuNu——H H + + ::XX——
RR——NuNu + + HHXXproducts of overall reactionproducts of overall reaction
SolvolysisSolvolysis
RR——XX
MethanolysisMethanolysis is a is a nucleophilic nucleophilic substitution in substitution in which methanol acts as both the solvent andwhich methanol acts as both the solvent andthethe nucleophile nucleophile..
HH
OO
CHCH33
:: ::++
HH
OO
CHCH33
::RR++ ––HH++
The product is aThe product is amethyl ether.methyl ether.
OO::
CHCH33
RR ....
Example:Example: Methanolysis Methanolysis
solventsolvent product from RXproduct from RX
water (HOH)water (HOH) ROHROHmethanol (CHmethanol (CH33OH)OH) ROCHROCH33
Typical solvents inTypical solvents in solvolysis solvolysis
Table 8.4 compares the relative rates ofTable 8.4 compares the relative rates ofnucleophilicnucleophilic substitution of a variety of substitution of a variety ofnucleophilesnucleophiles toward methyl iodide as the toward methyl iodide as thesubstrate. The standard of comparison issubstrate. The standard of comparison ismethanol, which is assigned a relativemethanol, which is assigned a relativerate of 1.0.rate of 1.0.
NucleophilicityNucleophilicity is a measure of the is a measure of thereactivity of areactivity of a nucleophile nucleophile
When the attacking atom is the same (oxygenWhen the attacking atom is the same (oxygenin this case),in this case), nucleophilicity nucleophilicity increases with increases with increasingincreasing basicity basicity..
A tight solvent shell around an ion makes itA tight solvent shell around an ion makes itless reactive. Larger ions are less solvated thanless reactive. Larger ions are less solvated thansmaller ones and are moresmaller ones and are more nucleophilic nucleophilic..