chapter 8 nucleophilic substitution (in depth) & competing elimination 8.1 functional group...

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


++ 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


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 ––


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:: ::


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


....

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

....::


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?


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


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.


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


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

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


++

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


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.


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.


chapter 8 nucleophilic substitution (in depth) & competing elimination 8.1 functional group...

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better leaving group

possible leaving group

nucleophilic substitution8

relative reactivity

alkyl halidestosylate

anaryl halide

vinylic halide

acid f105hf3