Download - Chapter 8 8.1 Functional Group Transformation By ... 8 Nucleophilic Substitution (in depth) & Competing Elimination 8.1 Functional Group Transformation By Nucleophilic Substitution

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

Nucleophilic Nucleophilic SubstitutionSubstitution

++ 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.

XX

CCCC

XX

Nucleophilic Nucleophilic SubstitutionSubstitution

++ RR XX

Alkoxide Alkoxide ion as theion as the nucleophile nucleophile

....OO::

....R'R'

––

Table 8.1 Examples ofTable 8.1 Examples of Nucleophilic Nucleophilic SubstitutionSubstitution

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 Carboxylate ion as theion as the nucleophile nucleophile

....OO::

....R'CR'C

––OO

gives an estergives an ester

++ : : XXRR....OO....

R'CR'C ––OO

Table 8.1 Examples ofTable 8.1 Examples of Nucleophilic Nucleophilic SubstitutionSubstitution

OOKK ++CHCH33(CH(CH22))1616CC CHCH33CHCH22II

acetone, wateracetone, water

OO

++ KKIIOO CHCH22CHCH33CHCH33(CH(CH22))1616CC

EthylEthyl octadecanoate octadecanoate (95%) (95%)

OO

ExampleExample

++ RR XX

Hydrogen sulfide ion as theHydrogen sulfide ion as the nucleophile nucleophile

....SS::

....HH

––

gives agives a thiol thiol

++ : : XXRR....SS....

HH ––

Table 8.1 Examples ofTable 8.1 Examples of Nucleophilic Nucleophilic Substitution Substitution

KKSSH + CHH + CH33CH(CHCH(CH22))66CHCH33

BrBr

ethanol, waterethanol, water

+ + K KBrBr

2-2-NonanethiolNonanethiol (74%) (74%)

CHCH33CH(CHCH(CH22))66CHCH33

SSHH

ExampleExample

++ RR XX

Cyanide ion as theCyanide ion as the nucleophile nucleophile

––CCNN:: ::


gives agives a nitrile nitrile

++ : : XXRR ––CCNN::

DMSODMSO

BrBrNaCNNaCN ++

CyclopentylCyclopentyl cyanide (70%) cyanide (70%)

CNCN

++ NaNaBrBr

ExampleExample

AzideAzide ion as the ion as the nucleophile nucleophile

.... ....––

NN NN NN ::::–– ++

++ RR XX


....

gives an alkylgives an alkyl azide azide

++ : : XXRR ––....NN NN NN::

–– ++

NaNaNN33 + CH + CH33CHCH22CHCH22CHCH22CHCH22II

2-2-PropanolPropanol-water-water

CHCH33CHCH22CHCH22CHCH22CHCH22NN33 + + Na NaII

Pentyl azidePentyl azide (52%) (52%)

ExampleExample

++ RR XX

Iodide ion as theIodide ion as the nucleophile 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 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?


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).

Tosylates Undergo Typical NucleophilicTosylates Undergo Typical NucleophilicSubstitution 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 ofGroup 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 ofGroup 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 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

8.38.3The SThe SNN2 Mechanism of2 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 step

HOHO CHCH33 BrBrδ −δ − δ −δ −

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 NaOH The reaction of 2-bromooctane with 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 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.

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 smallto measureto measure

Table 8.2 Reactivity Toward Substitution by theTable 8.2 Reactivity Toward Substitution by theSSNN2 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 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

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 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


++

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


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

ethanol (CHethanol (CH33CHCH22OH)OH) ROCHROCH22CHCH33

formic acid (HCOH)formic acid (HCOH)

acetic acid (CHacetic acid (CH33COH)COH) ROCCHROCCH33

OO

ROCHROCH

OOOO

OO

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

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 8.4Table 8.4 Nucleophilicity Nucleophilicity

basicitybasicity

solvationsolvation

small negative ions are highly small negative ions are highly solvated insolvated in protic protic solvents solvents

large negative ions are less solvatedlarge negative ions are less solvated

Major factors that controlMajor factors that controlnucleophilicitynucleophilicity

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),in this case), nucleophilicity nucleophilicity increases with increases with increasingincreasing basicity basicity..


basicitybasicity

solvationsolvation

small negative ions are highly small negative ions are highly solvated insolvated in protic protic solvents solvents

large negative ions are less solvatedlarge negative ions are less solvated

Major factors that controlMajor factors that controlnucleophilicitynucleophilicity

SolvationSolvation of a chloride ion by ion-dipole attractive 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 polarizedion interacts with the positively polarized hydrogens 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 moresmaller ones and are more nucleophilic nucleophilic..


Download - 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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