chapter 8 i. nucleophilic substitution (in depth ii....

Chapter 8Chapter 8

I.I. Nucleophilic Nucleophilic Substitution (Substitution (in depthin depth))

II.II. Competion Competion with Eliminationwith Elimination

Substrate is a sp3 hybridized carbon atom Substrate is a sp3 hybridized carbon atom (cannot be an a(cannot be an a vinylic vinylic halide or anhalide or anaryl halide except under special conditions toaryl halide except under special conditions tobe discussed in be discussed in ChemChem 227) 227)

XX

CCCC

XX

Nucleophilic Nucleophilic SubstitutionSubstitution

Many Many nucleophilic nucleophilic substitutions follow asubstitutions follow a

second-order rate law.second-order rate law.

CHCH33Br + HO Br + HO –– CHCH33OH + Br OH + Br ––

rate = rate = k k [CH[CH33Br] [HO Br] [HO –– ]]

What is the reaction order of each starting material?What is the reaction order of each starting material?

What can you infer on a molecular level?What can you infer on a molecular level?

What is the overall order of reaction?What is the overall order of reaction?

KineticsKinetics

HOHO –– CHCH33BrBr++ HOCHHOCH33 BrBr ––++

one step

concerted

one step

concerted

Bimolecular mechanismBimolecular mechanism


one step

concerted

one step

concerted



one step

concerted

one step

concerted

HOHO CHCH33 BrBrδ −δ − δ −δ −

transition statetransition state


Stereochemistry of SStereochemistry of SNN2 Reactions2 Reactions

GeneralizationGeneralization

Nucleophilic substitutions that exhibitsecond-order kinetic behavior arestereospecific and proceed withinversion of configuration.

nucleophile nucleophile attacks carbonattacks carbonfrom side opposite bondfrom side opposite bondto the leaving groupto the leaving group

Inversion of ConfigurationInversion of Configuration

nucleophile nucleophile attacks carbonattacks carbonfrom side opposite bondfrom side opposite bondto the leaving groupto the leaving group

three-dimensionalthree-dimensionalarrangement of bonds inarrangement of bonds inproduct is opposite to product is opposite to that of reactantthat of reactant

Inversion of ConfigurationInversion of Configuration

Inversion of configuration (Walden inversion) in an SN2 reaction is due to “back side attack”

P.Walden,P.Walden, BerichteBerichte, , 2929(1): 133-138 (1896)(1): 133-138 (1896)

Riga Riga Polytechnical Polytechnical CollegeCollege

Could there be another mechanism that provides the sameCould there be another mechanism that provides the same

results?results?

Roundabout SN2 Mechanism

Traditional SN2 Mechanism

Videos courtesy of William L. Hase, Texas Tech University !

http://pubs.acs.org/cen/news/86/i02/8602notw1.html

Physicist Roland Wester and his team in Matthias Weidemüller'sgroup at the University of Freiburg, in Germany, in collaborationwith William L. Hase's group at Texas Tech University, providedirect evidence for this mechanism in the gas phase. However,they also detected an additional, unexpected mechanism. In thisnew pathway, called the roundabout mechanism, chloridebumps into the methyl group and spins the entire methyl iodidemolecule 360° before chloride substitution occurs.The team imaged SN2 reactions at different collision energies,which depend on the speed at which chloride smashes intomethyl iodide. Data at lower collision energies support thetraditional SN2 mechanism. However, at higher collisionenergies, about 10% of the iodide ions fell outside of theexpected distribution. "We saw a group of iodide ions with amuch slower velocity than the rest," says Wester. "Since energyis conserved, if iodide ions are slow, the energy has to besomewhere else."On the basis of calculations performed by their colleagues atTexas Tech, the team concluded that the energy missing fromthe iodide transfers to the methyl chloride product in the formof rotational excitation, supporting the proposed roundaboutmechanism.

SN2 Reaction Mechanisms: Gas Phase (2008)

Traditional Roundabout

Published by AAAS

J. Mikosch et al., Science 319, 183 -186 (2008)

Fig. 1. Calculated MP2(fc)/ECP/aug-cc-pVDZ Born-Oppenheimer potential energy along the reactioncoordinate g = RC-I - RC-Cl for the SN2 reaction Cl- + CH3I and obtained stationary points

Published by AAAS


Fig. 2. (A to D) Center-of-mass images of the I- reaction product velocity from the reaction of Cl- withCH3I at four different relative collision energies

Published by AAAS


Fig. 3. View of a typical trajectory for the indirect roundabout reaction mechanism at 1.9 eV thatproceeds via CH3 rotation

A A stereospecific stereospecific reaction is one in whichreaction is one in whichstereoisomeric stereoisomeric starting materials givestarting materials givestereoisomeric stereoisomeric products.products.

The reaction of 2-The reaction of 2-bromooctane bromooctane with with NaOH NaOH (in ethanol-water) is (in ethanol-water) is stereospecificstereospecific..

(+)-2-(+)-2-Bromooctane Bromooctane ((––)-2-)-2-OctanolOctanol

((––)-2-)-2-Bromooctane Bromooctane (+)-2-(+)-2-OctanolOctanol

Stereospecific Stereospecific ReactionReaction

CC

HH

CHCH33

BrBr

CHCH33(CH(CH22))55

CC

HH

CHCH33

HOHO

(CH(CH22))55CHCH33

NaOHNaOH

(+)-2-(+)-2-BromooctaneBromooctane ((––)-2-)-2-OctanolOctanol

Stereospecific Stereospecific ReactionReaction

CC

HH

CHCH33

BrBr

CHCH33(CH(CH22))55

CC

HH

CHCH33

HOHO

(CH(CH22))55CHCH33

NaOHNaOH

(+)-2-(+)-2-BromooctaneBromooctane ((––)-2-)-2-OctanolOctanol

QuestionQuestion

The absolute configurations of (+)-2-The absolute configurations of (+)-2-bromooctanebromooctaneand (and (––)-2-)-2-octanol octanol are respectively:are respectively:

A) R- & R- B) S- and S- C) R- & S- D) S- & R-A) R- & R- B) S- and S- C) R- & S- D) S- & R-

HH BrBr

CHCH33

CHCH22(CH(CH22))44CHCH33

1)1) Draw the Fischer projection formula for (+)-S-2- Draw the Fischer projection formula for (+)-S-2-bromooctanebromooctane..

2)2) Write the Fischer projection of the Write the Fischer projection of the

( (––)-2-)-2-octanol octanol formed from it by formed from it by nucleophilic nucleophilic substitution substitution

with inversion of configuration.with inversion of configuration.

HOHO HH

CHCH33

CHCH22(CH(CH22))44CHCH33

R-R-

QuestionQuestion

True (A) / False (B)True (A) / False (B)

AA racemic racemic mixture of (R- ) and (S- )-2- mixture of (R- ) and (S- )-2-bromobutane bromobutane produces an optically activeproduces an optically activeproduct.product.

A conceptual view of SA conceptual view of SNN2 reactions2 reactions

Why does the nucleophile attack from the back side?

Steric Steric Effects in SEffects in SNN2 Reactions2 Reactions

The rate of The rate of nucleophilic nucleophilic substitutionsubstitutionby the Sby the SNN2 mechanism is governed2 mechanism is governedby by steric steric effects.effects.

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 bimolecular nucleophilic nucleophilic substitution.substitution.

Crowding at the Reaction SiteCrowding at the Reaction Site

RBr RBr + + LiI LiI RI + RI + LiBrLiBr

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

Reactivity toward substitution by the SReactivity toward substitution by the SNN22mechanismmechanism

A bulky substituent in the alkyl halide reduces thereactivity of the alkyl halide: steric hindrance

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 ReactivityReaction coordinate diagrams for (a) the SN2 reaction of

methyl bromide and (b) an SN2 reaction of a stericallyhindered alkyl bromide

QuestionQuestion

Which chloride will react faster with Which chloride will react faster with NaI NaI ininacetone?acetone?

A)A) B)B)

C)C) D)D)

The rate of The rate of nucleophilic nucleophilic substitutionsubstitutionby the Sby the SNN2 mechanism is governed2 mechanism is governedby by steric steric 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 bimolecularnucleophilic nucleophilic substitution, but the substitution, but the effect is smaller.effect is smaller.

Crowding Adjacent to the Reaction SiteCrowding Adjacent to the Reaction Site

RBr RBr + + LiI LiI RI + RI + LiBrLiBr

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

Effect of chain branching on rate of SEffect of chain branching on rate of SNN22substitutionsubstitution QuestionQuestion

Which alkyl chloride will react faster with Which alkyl chloride will react faster with NaI NaI ininacetone?acetone?

A) A) B)B)

C)C) D)D)

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 halide, (most often 1halide, (most often 1oo))

Nucleophilic Nucleophilic SubstitutionSubstitution

++

TheThe nucleophiles nucleophiles described in Sections 8.1-8.6described in Sections 8.1-8.6are anions.are anions.

....

....HOHO::–– ....

....CHCH33OO::––....

....HSHS::–– ––

CCNN:: :: NN33

....

....HOHHOH CHCH33OHOH........

NHNH33::

NucleophilesNucleophiles

––

But, allBut, all nucleophiles nucleophiles (neutral electron rich molecules) (neutral electron rich molecules) are Lewis bases. are Lewis bases.

++ 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' ––

++ RR XX

Carboxylate ion as the nucleophile

....OO::

....R'CR'C

––OO

gives an estergives an ester

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

R'CR'C ––OO


++ RR XX

Hydrogen sulfide ion as theHydrogen sulfide ion as the nucleophile nucleophile

....SS::

....HH

––

gives agives a thiol thiol

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

HH ––


QuestionQuestion

Select the major organic product when (Select the major organic product when (SS)-2-)-2-propanol is reacted with SOClpropanol is reacted with SOCl22 in pyridine in pyridine

followed by the addition of NaSH in ethanol.followed by the addition of NaSH in ethanol.

A) A) B)B)

C)C) D)D)

QuestionQuestion

The best combination of reactants for preparingThe best combination of reactants for preparing(CH(CH33))33CSCHCSCH33 is: is:

A)A) (CH(CH33))33CCl + CHCCl + CH33SKSK

B)B) (CH(CH33))33CBr + CHCBr + CH33SNaSNa

C)C) (CH(CH33))33CSK + CHCSK + CH33OHOH

D)D) (CH(CH33))33CSNa + CHCSNa + CH33BrBr

++ RR XX

Cyanide ion as theCyanide ion as the nucleophile nucleophile

––CCNN:: ::


gives agives a nitrile nitrile

++ : : XXRR ––CCNN::

Azide Azide ion as theion as the nucleophile nucleophile

.... ....––

NN NN NN ::::–– ++

++ RR XX


....

gives an alkylgives an alkyl azide azide

++ : : XXRR ––....NN NN NN::

–– ++

8.28.2Relative Reactivity of HalideRelative Reactivity of Halide

Leaving GroupsLeaving Groups

GeneralizationGeneralization

Reactivity of halide leaving groups inReactivity of halide leaving groups innucleophilic nucleophilic substitution is the same assubstitution 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 1-1-bromobromo-3--3-chloropropane chloropropane was allowed to react 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 1-1-bromobromo-3--3-chloropropane chloropropane was allowed to react 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::

QuestionQuestion

What is the major product of the reaction of theWhat is the major product of the reaction of thedihalide dihalide at the right with 1 equivalent ofat the right with 1 equivalent of

NaSH in NaSH in dimethyl sulfoxidedimethyl sulfoxide??

A)A) B)B)

C)C) D)D)

8.128.12Improved Leaving Groups Improved Leaving Groups

Alkyl SulfonatesAlkyl 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)((triflate triflate = -CF= -CF3 3 ))

AlkylAlkylpp-toluenesulfonate-toluenesulfonate

(tosylate)(tosylate)

Behave in the same way as alkyl halidesBehave in the same way 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

Nucleophiles Nucleophiles and and NucleophilicityNucleophilicity

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

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..

Table 8.4Table 8.4 Nucleophilicity Nucleophilicity

Nucleophiles Nucleophiles and and NucleophilicityNucleophilicity

SSNN1 vs. S1 vs. SNN22

....

....HOHHOH CHCH33OH and OH and EtOHEtOH........

for examplefor example

Many of the Many of the proticprotic solvents in which solvents in whichnucleophilic nucleophilic substitutions can be carried outsubstitutions can be carried outare themselvesare themselves nucleophiles nucleophiles..

NucleophilesNucleophiles

The termThe term solvolysis solvolysis refers to arefers to a nucleophilic nucleophilicsubstitution in which thesubstitution in which the nucleophile nucleophile is the solvent.is the solvent.

SolvolysisSolvolysis

SSNN2 Reactions are favored in2 Reactions are favored inPolarPolar Aprotic Aprotic Non-Non-nucleophilicnucleophilic Solvents Solvents

AnAn aprotic aprotic solvent is one that doessolvent is one that doesnot have an not have an ——OH group.OH group.

SSNN1 Reactions are favored in1 Reactions are favored inPolarPolar Protic Protic SolventsSolvents

Substitution by an anionic Substitution by an anionic nucleophilenucleophile: : SSNN2 kinetics2 kinetics

RR——XX + + ::NuNu—— RR——Nu Nu + + ::XX——

++

SolvolysisSolvolysis: : SSNN1 kinetics1 kinetics

RR——XX + + ::NuNu——HH RR——NuNu——H H + + ::XX——


CarbocationCarbocationintemediateintemediate

2nd2ndintermediateintermediate

++

Substitution by an anionic Substitution by an anionic nucleophilenucleophile in an in an aproticaproticnon-non-nucleophilicnucleophilic solvent solvent SSNN2 kinetics2 kinetics

RR——XX + + ::NuNu—— RR——Nu Nu + + ::XX——

SolvolysisSolvolysis ( (proticprotic solvents) : solvents) : SSNN1 kinetics1 kinetics

RR——XX + + ::NuNu——HH RR——NuNu——H H + + ::XX——

RR——Nu Nu + + HHXXproducts of overall reactionproducts of overall reaction


RR——XX

Methanolysis Methanolysis is ais 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

Some typical solvents inSome typical solvents in solvolysis solvolysis

QuestionQuestion

Which of the following is not a good Which of the following is not a good nucleophilenucleophilein an Sin an SNN1 1 solvolysissolvolysis reaction? reaction?

A)A) NaOCHNaOCH33

B)B) CHCH33OHOH

C)C) CHCH33CHCH22OHOH

D)D) HH22OO

chapter 8 i. nucleophilic substitution (in depth ii....

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