Chapter 8 nucleophilic substitution
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Chapter 8 Nucleophilic Substitution. 8.1 Functional Group Transformation By Nucleophilic Substitution. –. –. : X. Y :. Nucleophilic Substitution. +. +. R. Y. R. X. Nucleophile is a Lewis base (electron-pair donor), often negatively charged and used as Na + or K + salt.

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Chapter 8 Nucleophilic Substitution

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Chapter 8Nucleophilic Substitution


8.1Functional Group Transformation By Nucleophilic Substitution


: X

Y :

Nucleophilic Substitution

+

+

R

Y

R

X

  • Nucleophile is a Lewis base (electron-pair donor),

    • often negatively charged and used as Na+ or K+ salt.

  • Substrate is usually an alkyl halide.


X

C

C

Nucleophilic Substitution

Substrate cannot be an a vinylic halide or an

aryl halide, except under certain conditions to

be discussed in Chapter 12.

X


..

R

X

R'

O:

..

gives an ether

+

R

: X

O

..

..

R'

Table 8.1 Examples of Nucleophilic Substitution

Alkoxide ion as the nucleophile

+


(CH3)2CHCH2OCH2CH3+ NaBr

Ethyl isobutyl ether (66%)

Example

(CH3)2CHCH2ONa + CH3CH2Br

Isobutyl alcohol


O

R

X

gives an ester

..

O

+

R'C

R

:X

O

..

Table 8.1 Examples of Nucleophilic Substitution

Carboxylate ion as the nucleophile

..

+

R'C

O:

..


O

O

+

CH3(CH2)16C

KI

O

CH2CH3

Ethyl octadecanoate (95%)

Example

+

CH3(CH2)16C

OK

CH3CH2I

acetone, water


..

R

X

H

S:

..

gives a thiol

..

+

H

R

:X

S

..

Table 8.1 Examples of Nucleophilic Substitution

Hydrogen sulfide ion as the nucleophile

+


+ KBr

CH3CH(CH2)6CH3

SH

2-Nonanethiol (74%)

Example

KSH + CH3CH(CH2)6CH3

Br

ethanol, water


:

:

N

R

X

C

gives a nitrile

:

+

N

C

R

:X

Table 8.1 Examples of Nucleophilic Substitution

Cyanide ion as the nucleophile

+


Br

+

NaBr

CN

Cyclopentyl cyanide (70%)

Example

NaCN

+

DMSO


+

:

:

N

N

N

+

R

X

..

..

gives an alkyl azide

+

:

+

N

N

N

R

: X

..

..

Table 8.1 Examples of Nucleophilic Substitution

Azide ion as the nucleophile


CH3CH2CH2CH2CH2N3+NaI

Pentyl azide (52%)

Example

NaN3 + CH3CH2CH2CH2CH2I

2-Propanol-water


..

:

:

I

R

X

..

gives an alkyl iodide

..

+

:

I

R

:X

..

Table 8.1 Examples of Nucleophilic Substitution

Iodide ion as the nucleophile

+


+

NaI

CH3CHCH3

Br

+

NaBr

CH3CHCH3

I

63%

Example

acetone

NaI is soluble in acetone; NaCl and NaBr are not soluble in acetone.


8.2Relative Reactivity of Halide Leaving Groups


most reactive

RI

RBr

RCl

RF

least reactive

Generalization

  • Reactivity of halide leaving groups in nucleophilic substitution is the same as for elimination.


Problem 8.2

A single organic product was obtained when 1-bromo-3-chloropropane was allowed to react with one molar equivalent of sodium cyanide in aqueous ethanol. What was this product?

  • Br is a better leaving group than Cl

BrCH2CH2CH2Cl + NaCN


:

N

C

CH2CH2CH2Cl+NaBr

Problem 8.2

A single organic product was obtained when 1-bromo-3-chloropropane was allowed to react with one molar equivalent of sodium cyanide in aqueous ethanol. What was this product?

BrCH2CH2CH2Cl + NaCN


8.3The SN2 Mechanism of Nucleophilic Substitution


Kinetics

  • Many nucleophilic substitutions follow asecond-order rate law.CH3Br + HO – CH3OH + Br –

  • rate = k[CH3Br][HO – ]

  • inference: rate-determining step is bimolecular






HO

CH3

Br

transition state

HO –

CH3Br

+

HOCH3

+

Br –

Bimolecular Mechanism

  • one step


Stereochemistry

  • Nucleophilic substitutions that exhibitsecond-order kinetic behavior are stereospecific and proceed withinversion of configuration.


Nucleophile attacks carbonfrom side opposite bondto the leaving group.

Three-dimensionalarrangement of bonds inproduct is opposite to that of reactant.

Inversion of Configuration


Stereospecific Reaction

  • A stereospecific reaction is one in whichstereoisomeric starting materials yieldproducts that are stereoisomers of each other.

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

  • (+)-2-Bromooctane  (–)-2-Octanol

  • (–)-2-Bromooctane  (+)-2-Octanol


H

H

CH3(CH2)5

(CH2)5CH3

C

HO

Br

C

CH3

CH3

(R)-(–)-2-Octanol

Stereospecific Reaction

NaOH

(S)-(+)-2-Bromooctane


Problem 8.4

  • The Fischer projection formula for (+)-2-bromooctaneis shown. Write the Fischer projection of the(–)-2-octanol formed from it by nucleophilic substitution with inversion of configuration.


CH3

CH3

Br

H

HO

H

CH2(CH2)4CH3

CH2(CH2)4CH3

Problem 8.4

  • The Fischer projection formula for (+)-2-bromooctaneis shown. Write the Fischer projection of the(–)-2-octanol formed from it by nucleophilic substitution with inversion of configuration.


8.4Steric Effects and SN2 Reaction Rates


Crowding at the Reaction Site

The rate of nucleophilic substitutionby the SN2 mechanism is governedby steric effects.

Crowding at the carbon that bears the leaving group slows the rate ofbimolecular nucleophilic substitution.


Table 8.2 Reactivity Toward Substitution by the SN2 Mechanism

RBr + LiI  RI + LiBr

  • AlkylClassRelativebromiderate

  • CH3BrMethyl221,000

  • CH3CH2BrPrimary1,350

  • (CH3)2CHBrSecondary1

  • (CH3)3CBrTertiarytoo smallto measure


Decreasing SN2 Reactivity

CH3Br

CH3CH2Br

(CH3)2CHBr

(CH3)3CBr


Decreasing SN2 Reactivity

CH3Br

CH3CH2Br

(CH3)2CHBr

(CH3)3CBr


Crowding Adjacent to the Reaction Site

The rate of nucleophilic substitutionby the SN2 mechanism is governedby steric effects.

Crowding at the carbon adjacentto the one that bears the leaving groupalso slows the rate of bimolecularnucleophilic substitution, but the effect is smaller.


Table 8.3 Effect of Chain Branching on Rate of SN2 Substitution

RBr + LiI  RI + LiBr

  • AlkylStructureRelativebromiderate

  • EthylCH3CH2Br1.0

  • PropylCH3CH2CH2Br0.8

  • Isobutyl(CH3)2CHCH2Br0.036

  • Neopentyl(CH3)3CCH2Br0.00002


8.5Nucleophiles and Nucleophilicity


The nucleophiles described in Sections 8.1-8.4have been anions.

..

..

..

:

etc.

:

:

:

:

N

C

HS

HO

CH3O

..

..

..

Not all nucleophiles are anions. Many are neutral.

..

..

:

for example

NH3

CH3OH

HOH

..

..

Nucleophiles

All nucleophiles, however, are Lewis bases.


..

CH3OH

HOH

..

..

Nucleophiles

Many of the solvents in which nucleophilic substitutions are carried out are themselvesnucleophiles.

..

for example


Solvolysis

The term solvolysis refers to a nucleophilic

substitution in which the nucleophile is the solvent.


solvolysis

+

R—Nu—H +:X—

R—X+:Nu—H

step in which nucleophilicsubstitution occurs

Solvolysis

substitution by an anionic nucleophile

  • R—X + :Nu—

  • R—Nu + :X—


Solvolysis

substitution by an anionic nucleophile

  • R—X + :Nu—

  • R—Nu + :X—

solvolysis

+

R—Nu—H + :X—

R—X + :Nu—H

products of overall reaction

R—Nu + HX


CH3

CH3

CH3

+

–H+

:

:

R

:

R

:

O

O

O

..

H

H

The product is a methyl ether.

Example: Methanolysis

Methanolysis is a nucleophilic substitution in which methanol acts as both the solvent andthe nucleophile.

+

R—X


O

O

O

O

Typical solvents in solvolysis

solventproduct from RX

water (HOH)ROH

methanol (CH3OH)ROCH3

ethanol (CH3CH2OH)ROCH2CH3

formic acid (HCOH)

acetic acid (CH3COH)

ROCH

ROCCH3


Nucleophilicity is a measure of the reactivity of a nucleophile

  • Table 8.4 compares the relative rates of nucleophilic substitution of a variety of nucleophiles toward methyl iodide as the substrate. The standard of comparison is methanol, which is assigned a relativerate of 1.0.


Table 8.4 Nucleophilicity

  • RankNucleophileRelativerate

  • very goodI-, HS-, RS->105

  • good Br-, HO-, 104

  • RO-, CN-, N3-

  • fairNH3, Cl-, F-, RCO2-103

  • weakH2O, ROH1

  • very weakRCO2H10-2


Major factors that control nucleophilicity

  • Basicity

  • Solvation

    • Small negative ions are highly solvated in protic solvents.

    • Large negative ions are less solvated.


Table 8.4 Nucleophilicity

  • RankNucleophileRelativerate

  • good HO–, RO–104

  • fairRCO2–103

  • weakH2O, ROH1

When the attacking atom is the same (oxygenin this case), nucleophilicity increases with increasing basicity.


Major factors that control nucleophilicity

  • Basicity

  • Solvation

    • Small negative ions are highly solvated in protic solvents.

    • Large negative ions are less solvated.


Figure 8.3

Solvation of a chloride ion by ion-dipole attractiveforces with water. The negatively charged chlorideion interacts with the positively polarized hydrogensof water.


Table 8.4 Nucleophilicity

  • RankNucleophileRelativerate

  • Very goodI->105

  • good Br-104

  • fairCl-, F-103

A tight solvent shell around an ion makes itless reactive. Larger ions are less solvated thansmaller ones and are more nucleophilic.


8.6The SN1 Mechanism ofNucleophilic Substitution


A question...

Tertiary alkyl halides are very unreactive in substitutions that proceed by the SN2 mechanism.Do they undergo nucleophilic substitution at all?

  • Yes. But by a mechanism different from SN2. The most common examples are seen in solvolysis reactions.


CH3

CH3

H

H

CH3

CH3

+

..

:

:

:

+

O

O

C

:

C

Br

..

H

H

CH3

CH3

+

..

CH3

:

:

Br

CH3

..

..

..

:

+

Br

H

OH

C

..

..

CH3

Example of a solvolysis. Hydrolysis of tert-butyl bromide.


CH3

CH3

H

H

CH3

CH3

+

..

:

:

:

+

O

O

C

:

C

Br

..

H

H

CH3

CH3

+

..

:

:

Br

..

Example of a solvolysis. Hydrolysis of tert-butyl bromide.

This is the nucleophilic substitutionstage of the reaction; the one withwhich we are concerned.


CH3

CH3

H

H

CH3

CH3

+

..

:

:

:

+

O

O

C

:

C

Br

..

H

H

CH3

CH3

+

..

:

:

Br

..

Example of a solvolysis. Hydrolysis of tert-butyl bromide.

The reaction rate is independentof the concentration of the nucleophileand follows a first-order rate law.

rate = k[(CH3)3CBr]


CH3

CH3

H

H

CH3

CH3

+

..

:

:

:

+

O

O

C

:

C

Br

..

H

H

CH3

CH3

+

..

:

:

Br

..

Example of a solvolysis. Hydrolysis of tert-butyl bromide.

The mechanism of this step isnot SN2. It is called SN1 and begins with ionization of (CH3)3CBr.


Kinetics and Mechanism

rate = k[alkyl halide]

First-order kinetics implies a unimolecularrate-determining step.

  • Proposed mechanism is called SN1, which stands forsubstitution nucleophilic unimolecular


CH3

CH3

..

:

Br

C

..

CH3

unimolecular slow

H3C

CH3

..

+

:

:

C

Br

..

CH3

Mechanism

+


H3C

CH3

H

+

C

:

:

O

CH3

H

bimolecular fast

CH3

H

CH3

+

:

O

C

H

CH3

Mechanism


R+

proton transfer

RX

+

ROH2

ROH

carbocation capture

carbocation formation


Characteristics of the SN1 mechanism

  • first order kinetics: rate = k[RX]

    • unimolecular rate-determining step

  • carbocation intermediate

    • ate follows carbocation stability

    • rearrangements sometimes observed

  • reaction is not stereospecific

    • much racemization in reactions of optically active alkyl halides


8.7Carbocation Stability and SN1 Reaction Rates


Electronic Effects Govern SN1 Rates

The rate of nucleophilic substitutionby the SN1 mechanism is governedby electronic effects.

Carbocation formation is rate-determining.The more stable the carbocation, the fasterits rate of formation, and the greater the rate of unimolecular nucleophilic substitution.


Table 8.5 Reactivity of Some Alkyl Bromides Toward Substitution by the SN1 Mechanism

RBr solvolysis in aqueous formic acid

  • Alkyl bromideClassRelative rate

  • CH3BrMethyl0.6

  • CH3CH2BrPrimary1.0

  • (CH3)2CHBrSecondary26

  • (CH3)3CBrTertiary~100,000,000


Decreasing SN1 Reactivity

(CH3)3CBr

(CH3)2CHBr

CH3CH2Br

CH3Br


8.8Stereochemistry of SN1 Reactions


Generalization

  • Nucleophilic substitutions that exhibitfirst-order kinetic behavior are not stereospecific.


H

CH3

Br

C

CH3(CH2)5

H

CH3

H

CH3

H2O

OH

C

C

HO

CH3(CH2)5

(CH2)5CH3

(R)-(–)-2-Octanol (17%)

(S)-(+)-2-Octanol (83%)

Stereochemistry of an SN1 Reaction

R-(–)-2-Bromooctane


Figure 8.6

Ionization stepgives carbocation; threebonds to chiralitycenter become coplanar

+

Leaving group shieldsone face of carbocation;nucleophile attacks faster at opposite face.


8.9Carbocation Rearrangementsin SN1 Reactions


Because...

  • carbocations are intermediatesin SN1 reactions, rearrangementsare possible.


CH3

CH3

H2O

C

CHCH3

C

CH2CH3

CH3

CH3

(93%)

H

Br

OH

H2O

CH3

CH3

C

CHCH3

C

CHCH3

CH3

CH3

+

+

H

H

Example


8.10Effect of Solventon the Rate of Nucleophilic Substitution


In general...

  • SN1 Reaction Rates Increase in Polar Solvents


R

X 

R+

Energy of RX not much affected by polarity of solvent.

RX


R

X 

transition state stabilized by polar solvent

activation energy decreases;

rate increases

R+

Energy of RX not much affected by polarity of solvent.

RX


In general...

  • SN2 Reaction Rates Increase inPolar Aprotic Solvents

An aprotic solvent is one that doesnot have an —OH group.


Table 8.7 Relative Rate of SN2 Reactivity versus Type of Solvent

CH3CH2CH2CH2Br + N3–

  • SolventTypeRelative rate

  • CH3OHpolar protic1

  • H2Opolar protic7

  • DMSOpolar aprotic1300

  • DMFpolar aprotic2800

  • Acetonitrilepolar aprotic5000


  • Mechanism SummarySN1 and SN2


When...

  • Primary alkyl halides undergo nucleophilic substitution: they always react by the SN2 mechanism.

  • Tertiary alkyl halides undergo nucleophilic substitution: they always react by the SN1 mechanism.

  • Secondary alkyl halides undergo nucleophilic substitution: they react by the

    • SN1 mechanism in the presence of a weak nucleophile (solvolysis).

    • SN2 mechanism in the presence of a good nucleophile.


8.11Substitution and Eliminationas Competing Reactions


-elimination

+

+

:

H

Y

X

C

C

H

+

:

Y

C

C

H

X

+

:

X

C

C

Y

nucleophilic substitution

Two Reaction Types

Alkyl halides can react with Lewis bases by nucleophilic substitution and/or elimination.


-elimination

+

+

:

H

Y

X

C

C

H

+

:

Y

C

C

H

X

+

:

X

C

C

Y

nucleophilic substitution

Two Reaction Types

How can we tell which reaction pathway is followed for a particular alkyl halide?


Elimination versus Substitution

A systematic approach is to choose as a referencepoint the reaction followed by a typical alkyl halide(secondary) with a typical Lewis base (an alkoxideion).

  • The major reaction of a secondary alkyl halidewith an alkoxide ion is elimination by the E2mechanism.


CH3CHCH3

Br

CH3CHCH3

+

CH3CH=CH2

OCH2CH3

(87%)

(13%)

Example

NaOCH2CH3

ethanol, 55°C


••

CH3CH2

O

••

••

Figure 8.8

E2

Br


When is Substitution Favored?

Given that the major reaction of a secondaryalkyl halide with an alkoxide ion is elimination by the E2 mechanism, we can expect the proportion of substitution to increase with:

  • 1)decreased crowding at the carbon thatbears the leaving group


CH3CH2CH2Br

NaOCH2CH3

ethanol, 55°C

+

CH3CH2CH2OCH2CH3

CH3CH=CH2

(9%)

(91%)

Uncrowded Alkyl Halides

Decreased crowding at carbon that bears the leaving group increases substitution relative to elimination.

  • primary alkyl halide


CH3(CH2)15CH2CH2Br

KOC(CH3)3

tert-butyl alcohol, 40°C

CH3(CH2)15CH2CH2OC(CH3)3

+

CH3(CH2)15CH=CH2

(13%)

(87%)

But a Crowded Alkoxide Base Can Favor Elimination Even with a Primary Alkyl Halide

  • primary alkyl halide + bulky base


When is Substitution Favored?

Given that the major reaction of a secondaryalkyl halide with an alkoxide ion is elimination by the E2 mechanism, we can expect the proportion of substitution to increase with:

  • 1)decreased crowding at the carbon thatbears the leaving group.

  • 2) decreased basicity of the nucleophile.


CH3CH(CH2)5CH3

Cl

KCN

pKa (HCN) = 9.1

DMSO

CH3CH(CH2)5CH3

(70%)

CN

Weakly Basic Nucleophile

Weakly basic nucleophile increases substitution relative to elimination

secondary alkyl halide + weakly basic nucleophile


I

NaN3

pKa (HN3) = 4.6

N3

(75%)

Weakly Basic Nucleophile

Weakly basic nucleophile increases substitution relative to elimination

secondary alkyl halide + weakly basic nucleophile


Tertiary Alkyl Halides

Tertiary alkyl halides are so sterically hinderedthat elimination is the major reaction with allanionic nucleophiles. Only in solvolysis reactionsdoes substitution predominate over eliminationwith tertiary alkyl halides.


(CH3)2CCH2CH3

Br

CH3

CH3

CH3

CH3CCH2CH3

CH3C=CHCH3

CH2=CCH2CH3

OCH2CH3

ethanol, 25°C

36%

64%

2M sodium ethoxide in ethanol, 25°C

99%

1%

Example

+

+


8.12Nucleophilic Substitution of Alkyl Sulfonates


Leaving Groups

  • We have seen numerous examples of nucleophilic substitution in which X in RX is a halogen.

  • Halogen is not the only possible leaving group, though.


O

O

CH3

ROSCH3

ROS

O

O

Other RX Compounds

  • undergo same kinds of reactions as alkyl halides

Alkylmethanesulfonate(mesylate)

Alkylp-toluenesulfonate(tosylate)


+

SO2Cl

CH3

ROH

O

CH3

ROS

O

Preparation

Tosylates are prepared by the reaction of alcohols with p-toluenesulfonyl chloride(usually in the presence of pyridine).

  • (abbreviated as ROTs)

pyridine


H

H

CH2OTs

CH2CN

(86%)

Tosylates Undergo Typical Nucleophilic Substitution Reactions

KCN

ethanol-water


  • The best leaving groups are weakly basic.


Table 8.8 Approximate Relative Leaving Group Abilities

  • Leaving Relative Conjugate acidpKa ofGroup Rateof leaving group conj. acid

  • F–10-5HF3.5

  • Cl–1HCl-7

  • Br–10HBr-9

  • I–102HI-10

  • H2O101 H3O+-1.7

  • TsO–105 TsOH-2.8CF3SO2O– 108 CF3SO2OH -6


Table 8.8 Approximate Relative Leaving Group Abilities

  • Leaving Relative Conjugate acidpKa ofGroup Rateof leaving group conj. acid

  • F–10-5HF3.5

  • Cl–1HCl-7

  • Br–10HBr-9

  • I–102HI-10

  • H2O101 H3O+-1.7

  • TsO–105 TsOH-2.8CF3SO2O– 108 CF3SO2OH -6

  • Sulfonate esters are extremely good leaving groups; sulfonate ions are very weak bases.


CH3CHCH2CH3

CH3CHCH2CH3

OTs

Br

Tosylates can be Converted to Alkyl Halides

  • Tosylate is a better leaving group than bromide.

NaBr

DMSO

(82%)


H

H

CH3(CH2)5

CH3(CH2)5

C

C

OTs

OH

H3C

H3C

Tosylates Allow Control of Stereochemistry

  • Preparation of tosylate does not affect any of the bonds to the chirality center, so configuration and optical purity of tosylate is the same as the alcohol from which it was formed.

TsCl

pyridine


H

CH3(CH2)5

H

Nu–

C

Nu

OTs

(CH2)5CH3

SN2

C

H3C

CH3

Tosylates Allow Control of Stereochemistry

  • Having a tosylate of known optical purity and absolute configuration then allows the preparation of other compounds of known configuration by SN2 processes.


CH3CHCH2CH3

OTs

Tosylates also undergo Elimination

CH2=CHCH2CH3

NaOCH3

+

CH3OH

heat

CH3CH=CHCH3

E and Z


H

CH3

C

Br

87%

H

(CH2)5CH3

H3C

HBr

C

OH

H

CH3(CH2)5

13%

H3C

C

Br

CH3(CH2)5

Secondary Alcohols React with Hydrogen Halides Predominantly with Net Inversion of Configuration


H

CH3

C

Br

87%

H

(CH2)5CH3

H3C

HBr

C

OH

H

CH3(CH2)5

13%

H3C

C

Br

CH3(CH2)5

Secondary Alcohols React with Hydrogen Halides with Net Inversion of Configuration

  • Most reasonable mechanism

  • is SN1 with front side of carbocation

  • shielded by leaving group.


OH

Br

Br

Rearrangements can Occur in the Reaction of Alcohols with Hydrogen Halides

HBr

+

93%

7%


OH

+

+

Br

Br

Rearrangements can Occur in the Reaction of Alcohols with Hydrogen Halides

HBr

7%

93%

Br –

Br –

+


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