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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
Chapter 8Nucleophilic Substitution


8 1 functional group transformation by nucleophilic substitution
8.1Functional Group Transformation By Nucleophilic Substitution


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.


Nucleophilic substitution1

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


Table 8 1 examples of nucleophilic substitution

..

R

X

R'

O:

..

gives an ether

+

R

: X

O

..

..

R'

Table 8.1 Examples of Nucleophilic Substitution

Alkoxide ion as the nucleophile

+


Example

(CH3)2CHCH2OCH2CH3+ NaBr

Ethyl isobutyl ether (66%)

Example

(CH3)2CHCH2ONa + CH3CH2Br

Isobutyl alcohol


Table 8 1 examples of nucleophilic substitution1

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:

..


Example1

O

O

+

CH3(CH2)16C

KI

O

CH2CH3

Ethyl octadecanoate (95%)

Example

+

CH3(CH2)16C

OK

CH3CH2I

acetone, water


Table 8 1 examples of nucleophilic substitution2

..

R

X

H

S:

..

gives a thiol

..

+

H

R

:X

S

..

Table 8.1 Examples of Nucleophilic Substitution

Hydrogen sulfide ion as the nucleophile

+


Example2

+ KBr

CH3CH(CH2)6CH3

SH

2-Nonanethiol (74%)

Example

KSH + CH3CH(CH2)6CH3

Br

ethanol, water


Table 8 1 examples of nucleophilic substitution3

:

:

N

R

X

C

gives a nitrile

:

+

N

C

R

:X

Table 8.1 Examples of Nucleophilic Substitution

Cyanide ion as the nucleophile

+


Example3

Br

+

NaBr

CN

Cyclopentyl cyanide (70%)

Example

NaCN

+

DMSO


Table 8 1 examples of nucleophilic substitution4

+

:

:

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


Example4

CH3CH2CH2CH2CH2N3+NaI

Pentyl azide (52%)

Example

NaN3 + CH3CH2CH2CH2CH2I

2-Propanol-water


Table 8 1 examples of nucleophilic substitution5

..

:

:

I

R

X

..

gives an alkyl iodide

..

+

:

I

R

:X

..

Table 8.1 Examples of Nucleophilic Substitution

Iodide ion as the nucleophile

+


Example5

+

NaI

CH3CHCH3

Br

+

NaBr

CH3CHCH3

I

63%

Example

acetone

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


8 2 relative reactivity of halide leaving groups
8.2Relative Reactivity of Halide Leaving Groups


Generalization

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
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


Problem 8 21

:

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 3 the s n 2 mechanism of nucleophilic substitution
8.3The SN2 Mechanism of Nucleophilic Substitution


Kinetics
Kinetics

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

  • rate = k[CH3Br][HO – ]

  • inference: rate-determining step is bimolecular


Bimolecular mechanism





HO

CH3

Br

transition state

HO –

CH3Br

+

HOCH3

+

Br –

Bimolecular Mechanism

  • one step


Stereochemistry
Stereochemistry

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


Inversion 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
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


Stereospecific reaction1

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
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.


Problem 8 41

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 4 steric effects and s n 2 reaction rates
8.4Steric Effects and SN2 Reaction Rates


Crowding at the reaction site
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 s n 2 mechanism
Table 8.2 Reactivity Toward Substitution by the SN2 Mechanism

RBr + LiI  RI + LiBr

  • Alkyl Class Relativebromide rate

  • CH3Br Methyl 221,000

  • CH3CH2Br Primary 1,350

  • (CH3)2CHBr Secondary 1

  • (CH3)3CBr Tertiary too small to measure


Decreasing s n 2 reactivity
Decreasing SN2 Reactivity

CH3Br

CH3CH2Br

(CH3)2CHBr

(CH3)3CBr


Decreasing s n 2 reactivity1
Decreasing SN2 Reactivity

CH3Br

CH3CH2Br

(CH3)2CHBr

(CH3)3CBr


Crowding adjacent to the reaction site
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 s n 2 substitution
Table 8.3 Effect of Chain Branching on Rate of SN2 Substitution

RBr + LiI  RI + LiBr

  • Alkyl Structure Relativebromide rate

  • Ethyl CH3CH2Br 1.0

  • Propyl CH3CH2CH2Br 0.8

  • Isobutyl (CH3)2CHCH2Br 0.036

  • Neopentyl (CH3)3CCH2Br 0.00002


8 5 nucleophiles and nucleophilicity
8.5Nucleophiles and Nucleophilicity


Nucleophiles

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.


Nucleophiles1

..

CH3OH

HOH

..

..

Nucleophiles

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

..

for example


Solvolysis
Solvolysis

The term solvolysis refers to a nucleophilic

substitution in which the nucleophile is the solvent.


Solvolysis1

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—


Solvolysis2
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


Example methanolysis

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


Typical solvents in solvolysis

O

O

O

O

Typical solvents in solvolysis

solvent product 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
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
Table 8.4 Nucleophilicity nucleophile

  • Rank Nucleophile Relative rate

  • very good I-, HS-, RS- >105

  • good Br-, HO-, 104

  • RO-, CN-, N3-

  • fair NH3, Cl-, F-, RCO2- 103

  • weak H2O, ROH 1

  • very weak RCO2H 10-2


Major factors that control nucleophilicity
Major factors that control nucleophilicity nucleophile

  • Basicity

  • Solvation

    • Small negative ions are highly solvated in protic solvents.

    • Large negative ions are less solvated.


Table 8 4 nucleophilicity1
Table 8.4 Nucleophilicity nucleophile

  • Rank Nucleophile Relative rate

  • good HO–, RO– 104

  • fair RCO2– 103

  • weak H2O, ROH 1

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


Major factors that control nucleophilicity1
Major factors that control nucleophilicity nucleophile

  • Basicity

  • Solvation

    • Small negative ions are highly solvated in protic solvents.

    • Large negative ions are less solvated.


Figure 8 3
Figure 8.3 nucleophile

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 nucleophilicity2
Table 8.4 Nucleophilicity nucleophile

  • Rank Nucleophile Relative rate

  • Very good I- >105

  • good Br- 104

  • fair Cl-, F- 103

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


8 6 the s n 1 mechanism of nucleophilic substitution
8.6 nucleophileThe SN1 Mechanism ofNucleophilic Substitution


A question
A question... nucleophile

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.


Example of a solvolysis hydrolysis of tert butyl bromide

CH nucleophile3

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.


Example of a solvolysis hydrolysis of tert butyl bromide1

CH nucleophile3

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.


Example of a solvolysis hydrolysis of tert butyl bromide2

CH nucleophile3

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]


Example of a solvolysis hydrolysis of tert butyl bromide3

CH nucleophile3

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
Kinetics and Mechanism nucleophile

rate = k[alkyl halide]

First-order kinetics implies a unimolecularrate-determining step.

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


Mechanism

CH nucleophile3

CH3

..

:

Br

C

..

CH3

unimolecular slow

H3C

CH3

..

+

:

:

C

Br

..

CH3

Mechanism

+


Mechanism1

H nucleophile3C

CH3

H

+

C

:

:

O

CH3

H

bimolecular fast

CH3

H

CH3

+

:

O

C

H

CH3

Mechanism


R nucleophile+

proton transfer

RX

+

ROH2

ROH

carbocation capture

carbocation formation


Characteristics of the s n 1 mechanism
Characteristics of the S nucleophileN1 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 7 carbocation stability and s n 1 reaction rates
8.7 nucleophileCarbocation Stability and SN1 Reaction Rates


Electronic effects govern s n 1 rates
Electronic Effects Govern S nucleophileN1 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 s n 1 mechanism
Table 8.5 Reactivity of Some Alkyl Bromides Toward Substitution by the SN1 Mechanism

RBr solvolysis in aqueous formic acid

  • Alkyl bromide Class Relative rate

  • CH3Br Methyl 0.6

  • CH3CH2Br Primary 1.0

  • (CH3)2CHBr Secondary 26

  • (CH3)3CBr Tertiary ~100,000,000


Decreasing s n 1 reactivity
Decreasing S Substitution by the SN1 Reactivity

(CH3)3CBr

(CH3)2CHBr

CH3CH2Br

CH3Br


8 8 stereochemistry of s n 1 reactions
8.8 Substitution by the SStereochemistry of SN1 Reactions


Generalization1
Generalization Substitution by the S

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


Stereochemistry of an s n 1 reaction

H Substitution by the S

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
Figure 8.6 Substitution by the S

Ionization stepgives carbocation; threebonds to chiralitycenter become coplanar

+

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


8 9 carbocation rearrangements in s n 1 reactions
8.9 Substitution by the SCarbocation Rearrangementsin SN1 Reactions


Because
Because... Substitution by the S

  • carbocations are intermediatesin SN1 reactions, rearrangementsare possible.


Example6

CH Substitution by the S3

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 10 effect of solvent on the rate of nucleophilic substitution
8.10 Substitution by the SEffect of Solventon the Rate of Nucleophilic Substitution


In general
In general... Substitution by the S

  • SN1 Reaction Rates Increase in Polar Solvents


 Substitution by the SR

X 

R+

Energy of RX not much affected by polarity of solvent.

RX


 Substitution by the S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 general1
In general... Substitution by the S

  • SN2 Reaction Rates Increase inPolar Aprotic Solvents

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


Table 8 7 relative rate of s n 2 reactivity versus type of solvent
Table 8.7 Relative Rate of S Substitution by the SN2 Reactivity versus Type of Solvent

CH3CH2CH2CH2Br + N3–

  • Solvent Type Relative rate

  • CH3OH polar protic 1

  • H2O polar protic 7

  • DMSO polar aprotic 1300

  • DMF polar aprotic 2800

  • Acetonitrile polar aprotic 5000



When... Substitution by the S

  • 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 11 substitution and elimination as competing reactions
8.11 Substitution by the SSubstitution and Eliminationas Competing Reactions


Two reaction types

Substitution by the S-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.


Two reaction types1

Substitution by the S-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
Elimination versus Substitution Substitution by the S

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.


Example7

CH Substitution by the S3CHCH3

Br

CH3CHCH3

+

CH3CH=CH2

OCH2CH3

(87%)

(13%)

Example

NaOCH2CH3

ethanol, 55°C


Figure 8 8

Substitution by the S

••

CH3CH2

O

••

••

Figure 8.8

E2

Br


When is substitution favored
When is Substitution Favored? Substitution by the S

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 that bears the leaving group


Uncrowded alkyl halides

CH Substitution by the S3CH2CH2Br

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


But a crowded alkoxide base can favor elimination even with a primary alkyl halide

CH Substitution by the S3(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 favored1
When is Substitution Favored? Substitution by the S

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 that bears the leaving group.

  • 2) decreased basicity of the nucleophile.


Weakly basic nucleophile

CH Substitution by the S3CH(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


Weakly basic nucleophile1

I Substitution by the S

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 Substitution by the S

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.


Example8

(CH Substitution by the S3)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 12 nucleophilic substitution of alkyl sulfonates
8.12 Substitution by the SNucleophilic Substitution of Alkyl Sulfonates


Leaving groups
Leaving Groups Substitution by the S

  • 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.


Other rx compounds

O Substitution by the S

O

CH3

ROSCH3

ROS

O

O

Other RX Compounds

  • undergo same kinds of reactions as alkyl halides

Alkylmethanesulfonate(mesylate)

Alkylp-toluenesulfonate(tosylate)


Preparation

+ Substitution by the S

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


Tosylates undergo typical nucleophilic substitution reactions

H Substitution by the S

H

CH2OTs

CH2CN

(86%)

Tosylates Undergo Typical Nucleophilic Substitution Reactions

KCN

ethanol-water



Table 8 8 approximate relative leaving group abilities
Table 8.8 Approximate Relative Leaving Group Abilities Substitution by the S

  • Leaving Relative Conjugate acid pKa ofGroup Rate of leaving group conj. acid

  • F– 10-5 HF 3.5

  • Cl– 1 HCl -7

  • Br– 10 HBr -9

  • I– 102 HI -10

  • H2O101 H3O+ -1.7

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


Table 8 8 approximate relative leaving group abilities1
Table 8.8 Approximate Relative Leaving Group Abilities Substitution by the S

  • Leaving Relative Conjugate acid pKa ofGroup Rate of leaving group conj. acid

  • F– 10-5 HF 3.5

  • Cl– 1 HCl -7

  • Br– 10 HBr -9

  • I– 102 HI -10

  • H2O101 H3O+ -1.7

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

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


Tosylates can be converted to alkyl halides

CH Substitution by the S3CHCH2CH3

CH3CHCH2CH3

OTs

Br

Tosylates can be Converted to Alkyl Halides

  • Tosylate is a better leaving group than bromide.

NaBr

DMSO

(82%)


Tosylates allow control of stereochemistry

H Substitution by the S

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


Tosylates allow control of stereochemistry1

H Substitution by the S

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.


Tosylates also undergo elimination

CH Substitution by the S3CHCH2CH3

OTs

Tosylates also undergo Elimination

CH2=CHCH2CH3

NaOCH3

+

CH3OH

heat

CH3CH=CHCH3

E and Z


Secondary alcohols react with hydrogen halides predominantly with net inversion of configuration

H Substitution by the S

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


Secondary alcohols react with hydrogen halides with net inversion of configuration

H Substitution by the S

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.


Rearrangements can occur in the reaction of alcohols with hydrogen halides

O Substitution by the SH

Br

Br

Rearrangements can Occur in the Reaction of Alcohols with Hydrogen Halides

HBr

+

93%

7%


Rearrangements can occur in the reaction of alcohols with hydrogen halides1

O Substitution by the SH

+

+

Br

Br

Rearrangements can Occur in the Reaction of Alcohols with Hydrogen Halides

HBr

7%

93%

Br –

Br –

+


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