Chapter 8Chapter 8
Nucleophilic Substitution (in depth)Nucleophilic Substitution (in depth)
& Competing Elimination& Competing Elimination
8.18.1
Functional Group Functional Group
Transformation By Nucleophilic Transformation By Nucleophilic
SubstitutionSubstitution
8.18.1
Functional Group Functional Group
Transformation By Nucleophilic Transformation By 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
Nucleophilic SubstitutionNucleophilic Substitution
++
Substrate cannot be an a vinylic halide or anSubstrate cannot be an a vinylic halide or anaryl halide, except under certain conditions toaryl halide, except under certain conditions tobe discussed in Chapter 23.be discussed in Chapter 23.
XX
CCCC
XX
Nucleophilic SubstitutionNucleophilic Substitution
++ RR XX
Alkoxide ion as the nucleophileAlkoxide ion as the nucleophile
....OO::
....R'R'
––
Table 8.1 Examples of Nucleophilic SubstitutionTable 8.1 Examples of Nucleophilic Substitution
gives an ethergives an ether
++ : : XXRR....OO....
R'R' ––
(CH(CH33))22CHCHCHCH22OONa + CHNa + CH33CHCH22BrBr
Isobutyl alcoholIsobutyl alcohol
(CH(CH33))22CHCHCHCH22OOCHCH22CHCH33 + Na + NaBrBr
Ethyl isobutyl ether (66%)Ethyl isobutyl ether (66%)
ExampleExample
++ RR XX
Carboxylate ion as the nucleophileCarboxylate ion as the nucleophile
....OO::
....R'CR'C
––OO
gives an estergives an ester
++ : : XXRR....OO....
R'CR'C ––OO
Table 8.1 Examples of Nucleophilic SubstitutionTable 8.1 Examples of Nucleophilic Substitution
OOKK ++CHCH33(CH(CH22))1616CC CHCH33CHCH22II
acetone, wateracetone, water
OO
++ KKIIOO CHCH22CHCH33CHCH33(CH(CH22))1616CC
Ethyl octadecanoate (95%)Ethyl octadecanoate (95%)
OO
ExampleExample
++ RR XX
Hydrogen sulfide ion as the nucleophileHydrogen sulfide ion as the nucleophile
....SS::
....HH
––
gives a thiolgives a thiol
++ : : XXRR....SS....
HH ––
Table 8.1 Examples of Nucleophilic SubstitutionTable 8.1 Examples of Nucleophilic Substitution
KKSSH + CHH + CH33CH(CHCH(CH22))66CHCH33
BrBr
ethanol, waterethanol, water
+ K+ KBrBr
2-Nonanethiol (74%)2-Nonanethiol (74%)
CHCH33CH(CHCH(CH22))66CHCH33
SSHH
ExampleExample
++ RR XX
Cyanide ion as the nucleophileCyanide ion as the nucleophile
––CCNN:: ::
Table 8.1 Examples of Nucleophilic SubstitutionTable 8.1 Examples of Nucleophilic Substitution
gives a nitrilegives a nitrile
++ : : XXRR ––CCNN::
DMSODMSO
BrBrNaCNNaCN ++
Cyclopentyl cyanide (70%)Cyclopentyl cyanide (70%)
CNCN
++ NaNaBrBr
ExampleExample
Azide ion as the nucleophileAzide ion as the nucleophile
.... ....––
NN NN NN::::–– ++
++ RR XX
Table 8.1 Examples of Nucleophilic SubstitutionTable 8.1 Examples of Nucleophilic Substitution
....
gives an alkyl azidegives an alkyl azide
++ : : XXRR ––....NN NN NN::
–– ++
NaNaNN33 + CH + CH33CHCH22CHCH22CHCH22CHCH22II
2-Propanol-water2-Propanol-water
CHCH33CHCH22CHCH22CHCH22CHCH22NN33 + Na + NaII
Pentyl azide (52%)Pentyl azide (52%)
ExampleExample
++ RR XX
Iodide ion as the nucleophileIodide ion as the nucleophile
––
....:: II
....::
Table 8.1 Examples of Nucleophilic SubstitutionTable 8.1 Examples of Nucleophilic Substitution
gives an alkyl iodidegives an alkyl iodide
++ : : XXRR ––....:: II....
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 Halide Relative Reactivity of Halide
Leaving GroupsLeaving Groups
GeneralizationGeneralization
Reactivity of halide leaving groups in Reactivity of halide leaving groups in nucleophilic substitution is the same as nucleophilic substitution is the same as for 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 leaving Br is a better leaving group 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 Groups Alkyl SulfonatesImproved Leaving Groups Alkyl Sulfonates
Leaving GroupsLeaving Groups
We have seen numerous examples of We have seen numerous examples of nucleophilic substitution in which nucleophilic substitution in which XX in R in RXX is a is a halogen.halogen.
Halogen is not the only possible leaving Halogen is not the only possible leaving group, 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).
Tosylates Undergo Typical Nucleophilic Tosylates Undergo Typical Nucleophilic Substitution ReactionsSubstitution Reactions
HH
CHCH22OTsOTs
KCNKCN
ethanol-ethanol-waterwater
HH
CHCH22CNCN
(86%)(86%)
The best leaving groups are weakly basic.The best leaving groups are weakly basic.
Table 8.8Table 8.8Approximate Relative Reactivity of Leaving GroupsApproximate Relative Reactivity of Leaving Groups
Leaving Leaving Relative Relative Conjugate acidConjugate acid ppKKaa of of
Group Group RateRate of leaving group of leaving group conj. acidconj. acid
FF–– 1010-5-5 HFHF 3.53.5
ClCl–– 11 HClHCl -7-7
BrBr–– 1010 HBrHBr -9-9
II–– 101022 HIHI -10-10
HH22OO 101011 H H33OO++ -1.7-1.7
TsOTsO–– 101055 TsOH TsOH -2.8-2.8CFCF33SOSO22OO–– 10108 8 CFCF33SOSO22OHOH -6 -6
Table 8.8Table 8.8Approximate Relative Reactivity of Leaving GroupsApproximate Relative Reactivity of Leaving Groups
Leaving Leaving Relative Relative Conjugate acidConjugate acid ppKKaa of of
Group Group RateRate of leaving group of leaving group conj. acidconj. acid
FF–– 1010-5-5 HFHF 3.53.5
ClCl–– 11 HClHCl -7-7
BrBr–– 1010 HBrHBr -9-9
II–– 101022 HIHI -10-10
HH22OO 101011 H H33OO++ -1.7-1.7
TsOTsO–– 101055 TsOH TsOH -2.8-2.8CFCF33SOSO22OO–– 10108 8 CFCF33SOSO22OHOH -6 -6
Sulfonate esters are extremely good leaving groups; sulfonate ions are very weak bases.
Tosylates can be Converted to Alkyl Tosylates can be Converted to Alkyl HalidesHalides
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 the Preparation of tosylate does not affect any of the bonds to the chirality center, so configuration and bonds to the chirality center, so configuration and optical purity of tosylate is the same as the optical purity of tosylate is the same as the alcohol 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 and Having a tosylate of known optical purity and absolute configuration then allows the absolute configuration then allows the preparation of other compounds of known preparation of other compounds of known configuration 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
8.38.3
The SThe SNN2 Mechanism of 2 Mechanism of
Nucleophilic SubstitutionNucleophilic Substitution
Many nucleophilic substitutions follow aMany nucleophilic substitutions follow a
second-order rate law.second-order rate law.
CHCH33Br + HO Br + HO –– CH CH33OH + Br OH + Br ––
rate = rate = kk[CH[CH33Br][HO Br][HO – – ]]
inference: rate-determining step is bimolecularinference: rate-determining step is bimolecular
KineticsKinetics
HOHO – – CHCH33BrBr++ HOCHHOCH33 BrBr – –++one stepone stepone stepone step
HOHO CHCH33 BrBr
transition statetransition state
Bimolecular MechanismBimolecular Mechanism
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 The reaction of 2-bromooctane with NaOH NaOH (in ethanol-water) is stereospecific.(in ethanol-water) is stereospecific.
(+)-2-Bromooctane (+)-2-Bromooctane (–)-2-Octanol (–)-2-Octanol
(–)-2-Bromooctane (–)-2-Bromooctane (+)-2-Octanol (+)-2-Octanol
Stereospecific ReactionStereospecific Reaction
CC
HH
CHCH33
BrBr
CHCH33(CH(CH22))55
NaNaOOHH
((SS)-(+)-2-Bromooctane)-(+)-2-Bromooctane
(CH(CH22))55CHCH33
CC
HH
CHCH33
HHOO
((RR)-(–)-2-Octanol)-(–)-2-Octanol
Stereospecific ReactionStereospecific Reaction
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 and Steric Effects and
SSNN2 Reaction Rates2 Reaction Rates
Crowding at the carbon that bears Crowding at the carbon that bears the leaving group slows the rate ofthe leaving group slows the rate ofbimolecular nucleophilic substitution.bimolecular nucleophilic substitution.
Crowding at the Reaction SiteCrowding at the Reaction Site
The rate of nucleophilic substitutionThe rate of nucleophilic substitutionby the Sby the SNN2 mechanism is governed2 mechanism is governed
by steric effects.by steric effects.
RBr + LiI RBr + LiI RI + LiBr RI + LiBr
AlkylAlkyl ClassClass RelativeRelativebromidebromide raterate
CHCH33BrBr MethylMethyl 221,000221,000
CHCH33CHCH22BrBr PrimaryPrimary 1,3501,350
(CH(CH33))22CHBrCHBr SecondarySecondary 11
(CH(CH33))33CBrCBr TertiaryTertiary too smalltoo small
to measureto measure
Table 8.2 Reactivity Toward Substitution by the Table 8.2 Reactivity Toward Substitution by the
SSNN2 Mechanism2 Mechanism
CHCH33BrBr
CHCH33CHCH22BrBr
(CH(CH33))22CHBrCHBr
(CH(CH33))33CBrCBr
Decreasing SDecreasing SNN2 Reactivity2 Reactivity
CHCH33BrBr
CHCH33CHCH22BrBr
(CH(CH33))22CHBrCHBr
(CH(CH33))33CBrCBr
Decreasing SDecreasing SNN2 Reactivity2 Reactivity
The rate of nucleophilic substitutionThe rate of nucleophilic substitutionby the Sby the SNN2 mechanism is governed2 mechanism is governed
by steric effects.by steric 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 bimolecularnucleophilic substitution, but the nucleophilic substitution, but the effect is smaller.effect is smaller.
Crowding Adjacent to the Reaction SiteCrowding Adjacent to the Reaction Site
RBr + LiI RBr + LiI RI + LiBr RI + LiBr
AlkylAlkyl StructureStructure RelativeRelativebromidebromide raterate
EthylEthyl CHCH33CHCH22BrBr 1.01.0
PropylPropyl CHCH33CHCH22CHCH22BrBr 0.80.8
IsobutylIsobutyl (CH(CH33))22CHCHCHCH22BrBr 0.0360.036
NeopentylNeopentyl (CH(CH33))33CCHCCH22BrBr 0.000020.00002
Table 8.3 Effect of Chain Branching on Rate of Table 8.3 Effect of Chain Branching on Rate of
SSNN2 Substitution2 Substitution
8.58.5
Nucleophiles and NucleophilicityNucleophiles and Nucleophilicity
All nucleophiles, however, are Lewis bases.All nucleophiles, however, are Lewis bases.
The nucleophiles described in Sections 8.1-8.6The nucleophiles described in Sections 8.1-8.6have been anions.have been anions.
....
....HOHO::–– ....
....CHCH33OO::––....
....HSHS::–– ––
CCNN:: :: etc.etc.
Not all nucleophiles are anions. Many are neutral.Not all nucleophiles are anions. Many are neutral.....
....HOHHOH CHCH33OHOH........
NHNH33:: for examplefor example
NucleophilesNucleophiles
....
....HOHHOH CHCH33OHOH........
for examplefor example
Many of the solvents in which nucleophilic Many of the solvents in which nucleophilic substitutions are carried out are themselvessubstitutions are carried out are themselvesnucleophiles.nucleophiles.
NucleophilesNucleophiles
The term The term solvolysis solvolysis refers to a nucleophilicrefers to a nucleophilicsubstitution in which the nucleophile is the solvent.substitution in which the nucleophile is the solvent.
SolvolysisSolvolysis
substitution by an anionic nucleophilesubstitution by an anionic nucleophile
R—R—XX + + ::NuNu—— R—Nu + R—Nu + ::XX——
++
solvolysissolvolysis
R—R—XX + + ::Nu—HNu—H RR—Nu—H —Nu—H + + ::XX——
step in which nucleophilicstep in which nucleophilicsubstitution occurssubstitution occurs
SolvolysisSolvolysis
++
substitution by an anionic nucleophilesubstitution by an anionic nucleophile
R—R—XX + + ::NuNu—— R—Nu + R—Nu + ::XX——
solvolysissolvolysis
R—R—XX + + ::Nu—HNu—H RR—Nu—H —Nu—H + + ::XX——
RR—Nu —Nu + + HHXXproducts of overall reactionproducts of overall reaction
SolvolysisSolvolysis
R—R—XX
Methanolysis is a nucleophilic substitution in Methanolysis is a nucleophilic substitution in which methanol acts as both the solvent andwhich methanol acts as both the solvent andthe nucleophile.the nucleophile.
HH
OO
CHCH33
:: ::++
HH
OO
CHCH33
::RR++ ––HH++
The product is a The product is a methyl ether.methyl ether.
OO::
CHCH33
RR ....
Example: MethanolysisExample: Methanolysis
solventsolvent product from RXproduct from RX
water (HOH)water (HOH) ROHROHmethanol (CHmethanol (CH33OH)OH) ROCHROCH33
ethanol (CHethanol (CH33CHCH22OH)OH) ROCHROCH22CHCH33
formic acid (HCOH)formic acid (HCOH)
acetic acid (CHacetic acid (CH33COH)COH) ROCCHROCCH33
OO
ROCHROCH
OOOO
OO
Typical solvents in solvolysisTypical solvents in solvolysis
Table 8.4 compares the relative rates of Table 8.4 compares the relative rates of nucleophilic substitution of a variety of nucleophilic substitution of a variety of nucleophiles toward methyl iodide as the nucleophiles toward methyl iodide as the substrate. The standard of comparison is substrate. The standard of comparison is methanol, which is assigned a relativemethanol, which is assigned a relativerate of 1.0.rate of 1.0.
Nucleophilicity is a measure of the Nucleophilicity is a measure of the reactivity of a nucleophilereactivity of a nucleophile
RankRank NucleophileNucleophile RelativeRelativerate rate
strongstrong II--, HS, HS--, RS, RS-- >10>1055
good good BrBr--, HO, HO--, , 101044
RORO--, CN, CN--, N, N33--
fairfair NHNH33, Cl, Cl--, F, F--, RCO, RCO22-- 101033
weakweak HH22O, ROHO, ROH 11
very weakvery weak RCORCO22HH 1010-2-2
Table 8.4 NucleophilicityTable 8.4 Nucleophilicity
basicitybasicity
solvationsolvation
small negative ions are highly small negative ions are highly solvated in protic solventssolvated in protic solvents
large negative ions are less solvatedlarge negative ions are less solvated
Major factors that control Major factors that control nucleophilicitynucleophilicity
RankRank NucleophileNucleophile RelativeRelativerate rate
good good HOHO––, RO, RO–– 101044
fairfair RCORCO22–– 101033
weakweak HH22O, ROHO, ROH 11
When the attacking atom is the same (oxygenWhen the attacking atom is the same (oxygenin this case), nucleophilicity increases with in this case), nucleophilicity increases with increasing basicity.increasing basicity.
Table 8.4 NucleophilicityTable 8.4 Nucleophilicity
basicitybasicity
solvationsolvation
small negative ions are highly small negative ions are highly solvated in protic solventssolvated in protic solvents
large negative ions are less solvatedlarge negative ions are less solvated
Major factors that control Major factors that control nucleophilicitynucleophilicity
Solvation of a chloride ion by ion-dipole attractiveSolvation of a chloride ion by ion-dipole attractive
forces with water. The negatively charged chlorideforces with water. The negatively charged chloride
ion interacts with the positively polarized hydrogension interacts with the positively polarized hydrogens
of water.of water.
Figure 8.3Figure 8.3
RankRank NucleophileNucleophile RelativeRelativeraterate
strongstrong II-- >10>1055
good good BrBr-- 101044
fairfair ClCl--, F, F-- 101033
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 more nucleophilic.smaller ones and are more nucleophilic.
Table 8.4 NucleophilicityTable 8.4 Nucleophilicity