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Chapter 8 Chapter 8 Nucleophilic Substitution 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. - PowerPoint PPT Presentation

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Page 1: Chapter 8 Nucleophilic Substitution

Chapter 8Chapter 8

Nucleophilic SubstitutionNucleophilic Substitution

Page 2: Chapter 8 Nucleophilic Substitution

8.18.1

Functional Group Functional Group

Transformation By Nucleophilic Transformation By Nucleophilic

SubstitutionSubstitution

Page 3: Chapter 8 Nucleophilic Substitution

Y :–

R X 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 Substitution

++

Page 4: Chapter 8 Nucleophilic Substitution

Substrate cannot be an a vinylic halide or anaryl halide, except under certain conditions tobe discussed in Chapter 12.

X

CC

X

Nucleophilic Substitution

Page 5: Chapter 8 Nucleophilic Substitution

+ R X

Alkoxide ion as the nucleophile

..O:

..R'

Table 8.1 Examples of Nucleophilic Substitution

gives an ether

+ : XR..O..

R' –

Page 6: Chapter 8 Nucleophilic Substitution

(CH3)2CHCH2ONa + CH3CH2Br

Isobutyl alcohol

(CH3)2CHCH2OCH2CH3 + NaBr

Ethyl isobutyl ether (66%)

Example

Page 7: Chapter 8 Nucleophilic Substitution

+ R X

Carboxylate ion as the nucleophile

..O:

..R'C

–O

..

gives an ester

+ : XR..OR'C –O

Table 8.1 Examples of Nucleophilic Substitution

Page 8: Chapter 8 Nucleophilic Substitution

OK +CH3(CH2)16C CH3CH2I

acetone, water

O

+ KIO CH2CH3CH3(CH2)16C

Ethyl octadecanoate (95%)

O

Example

Page 9: Chapter 8 Nucleophilic Substitution

+ R X

Hydrogen sulfide ion as the nucleophile

S:–

..

..H

gives a thiol

+ : XR..S..

H –

Table 8.1 Examples of Nucleophilic Substitution

Page 10: Chapter 8 Nucleophilic Substitution

KSH + CH3CH(CH2)6CH3

Br

ethanol, water

+ KBr

2-Nonanethiol (74%)

CH3CH(CH2)6CH3

SH

Example

Page 11: Chapter 8 Nucleophilic Substitution

+ R X

Cyanide ion as the nucleophile

–CN: :

Table 8.1 Examples of Nucleophilic Substitution

gives a nitrile

+ : XR –CN:

Page 12: Chapter 8 Nucleophilic Substitution

DMSO

BrNaCN +

Cyclopentyl cyanide (70%)

CN

+ NaBr

Example

Page 13: Chapter 8 Nucleophilic Substitution

Azide ion as the nucleophile

.. ..–

N N N::– +

+ R X

Table 8.1 Examples of Nucleophilic Substitution

..

gives an alkyl azide

+ : XR –..N N N:

– +

Page 14: Chapter 8 Nucleophilic Substitution

NaN3 + CH3CH2CH2CH2CH2I

2-Propanol-water

CH3CH2CH2CH2CH2N3 + NaI

Pentyl azide (52%)

Example

Page 15: Chapter 8 Nucleophilic Substitution

+ R X

Iodide ion as the nucleophile

..: I

..:

Table 8.1 Examples of Nucleophilic Substitution

gives an alkyl iodide

+ : XR –....I:

Page 16: Chapter 8 Nucleophilic Substitution

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

acetone

+ NaICH3CHCH3

Br

63%

+ NaBrCH3CHCH3

I

Example

Page 17: Chapter 8 Nucleophilic Substitution

8.28.2Relative Reactivity of Halide Relative Reactivity of Halide

Leaving GroupsLeaving Groups

Page 18: Chapter 8 Nucleophilic Substitution

Generalization

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

RI

RBr

RCl

RF

most reactive

least reactive

Page 19: Chapter 8 Nucleophilic Substitution

BrCH2CH2CH2Cl + NaCN

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

Problem 8.2

Page 20: Chapter 8 Nucleophilic Substitution

BrCH2CH2CH2Cl + NaCN

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?

Problem 8.2

CH2CH2CH2Cl + NaBrCN:

Page 21: Chapter 8 Nucleophilic Substitution

8.38.3

The SThe SNN2 Mechanism of 2 Mechanism of

Nucleophilic SubstitutionNucleophilic Substitution

Page 22: Chapter 8 Nucleophilic Substitution

Many nucleophilic substitutions follow asecond-order rate law.

CH3Br + HO – CH3OH + Br –

rate = k[CH3Br][HO – ]

inference: rate-determining step is bimolecular

Kinetics

Page 23: Chapter 8 Nucleophilic Substitution

HO – CH3Br+ HOCH3 Br –+one step

HO CH3 Br

transition state

Bimolecular Mechanism

Page 24: Chapter 8 Nucleophilic Substitution

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

Stereochemistry

Page 25: Chapter 8 Nucleophilic Substitution

Inversion of Configuration

Nucleophile attacks carbonfrom side opposite bondto the leaving group.

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

Page 26: Chapter 8 Nucleophilic Substitution

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 Reaction

Page 27: Chapter 8 Nucleophilic Substitution

C

H

CH3

Br

CH3(CH2)5

NaOH

(S)-(+)-2-Bromooctane

(CH2)5CH3

C

H

CH3

HO

(R)-(–)-2-Octanol

Stereospecific Reaction

Page 28: Chapter 8 Nucleophilic Substitution

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 8.4

Page 29: Chapter 8 Nucleophilic Substitution

H Br

CH3

CH2(CH2)4CH3

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.

HO H

CH3

CH2(CH2)4CH3

Problem 8.4

Page 30: Chapter 8 Nucleophilic Substitution

8.48.4Steric Effects and Steric Effects and

SSNN2 Reaction Rates2 Reaction Rates

Page 31: Chapter 8 Nucleophilic Substitution

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

Crowding at the Reaction Site

The rate of nucleophilic substitutionby the SN2 mechanism is governed

by steric effects.

Page 32: Chapter 8 Nucleophilic Substitution

RBr + LiI RI + LiBr

Alkyl Class Relativebromide rate

CH3Br Methyl 221,000

CH3CH2Br Primary 1,350

(CH3)2CHBr Secondary 1

(CH3)3CBr Tertiary too smallto measure

Table 8.2 Reactivity Toward Substitution by the

SN2 Mechanism

Page 33: Chapter 8 Nucleophilic Substitution

CH3Br

CH3CH2Br

(CH3)2CHBr

(CH3)3CBr

Decreasing SN2 Reactivity

Page 34: Chapter 8 Nucleophilic Substitution

CH3Br

CH3CH2Br

(CH3)2CHBr

(CH3)3CBr

Decreasing SN2 Reactivity

Page 35: Chapter 8 Nucleophilic Substitution

The rate of nucleophilic substitutionby the SN2 mechanism is governed

by 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.

Crowding Adjacent to the Reaction Site

Page 36: Chapter 8 Nucleophilic 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

Table 8.3 Effect of Chain Branching on Rate of

SN2 Substitution

Page 37: Chapter 8 Nucleophilic Substitution

8.58.5

Nucleophiles and NucleophilicityNucleophiles and Nucleophilicity

Page 38: Chapter 8 Nucleophilic Substitution

All nucleophiles, however, are Lewis bases.

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

..

..HO:– ..

..CH3O:–..

..HS:– –

CN: : etc.

Not all nucleophiles are anions. Many are neutral.....HOH CH3OH..

..NH3: for example

Nucleophiles

Page 39: Chapter 8 Nucleophilic Substitution

..

..HOH CH3OH....

for example

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

Nucleophiles

Page 40: Chapter 8 Nucleophilic Substitution

The term solvolysis refers to a nucleophilicsubstitution in which the nucleophile is the solvent.

Solvolysis

Page 41: Chapter 8 Nucleophilic Substitution

substitution by an anionic nucleophile

R—X + :Nu— R—Nu + :X—

+

solvolysis

R—X + :Nu—H R—Nu—H + :X—

step in which nucleophilicsubstitution occurs

Solvolysis

Page 42: Chapter 8 Nucleophilic Substitution

+

substitution by an anionic nucleophile

R—X + :Nu— R—Nu + :X—

solvolysis

R—X + :Nu—H R—Nu—H + :X—

R—Nu + HXproducts of overall reaction

Solvolysis

Page 43: Chapter 8 Nucleophilic Substitution

R—X

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

H

O

CH3

: :+

H

O

CH3

:R+ –H+

The product is a methyl ether.

O:..

CH3

R

Example: Methanolysis

Page 44: Chapter 8 Nucleophilic Substitution

solvent product from RX

water (HOH) ROHmethanol (CH3OH) ROCH3

ethanol (CH3CH2OH) ROCH2CH3

formic acid (HCOH)

acetic acid (CH3COH) ROCCH3

O

ROCH

OO

O

Typical solvents in solvolysis

Page 45: Chapter 8 Nucleophilic Substitution

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.

Nucleophilicity is a measure of the reactivity of a nucleophile

Page 46: Chapter 8 Nucleophilic Substitution

Rank Nucleophile Relativerate

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

Table 8.4 Nucleophilicity

Page 47: Chapter 8 Nucleophilic Substitution

Basicity

Solvation

Small negative ions are highly solvated in protic solvents.

Large negative ions are less solvated.

Major factors that control nucleophilicity

Page 48: Chapter 8 Nucleophilic Substitution

Rank Nucleophile Relativerate

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.

Table 8.4 Nucleophilicity

Page 49: Chapter 8 Nucleophilic Substitution

Basicity

Solvation

Small negative ions are highly solvated in protic solvents.

Large negative ions are less solvated.

Major factors that control nucleophilicity

Page 50: Chapter 8 Nucleophilic Substitution

Solvation of a chloride ion by ion-dipole attractive

forces with water. The negatively charged chloride

ion interacts with the positively polarized hydrogens

of water.

Figure 8.3

Page 51: Chapter 8 Nucleophilic Substitution

Rank Nucleophile Relativerate

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.

Table 8.4 Nucleophilicity

Page 52: Chapter 8 Nucleophilic Substitution

8.68.6

The SThe SNN1 Mechanism 1 Mechanism

ofofNucleophilic SubstitutionNucleophilic Substitution

Page 53: Chapter 8 Nucleophilic Substitution

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.

A question...

Page 54: Chapter 8 Nucleophilic Substitution

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

.. ..

..

..

+

+

H Br..

:

O: :

H

H

C

CH3

CH3

CH3

Br

C OH..

:

CH3

CH3

CH3

..

C+

+

O :

H

H

Br..

::–

CH3

CH3

CH3

Page 55: Chapter 8 Nucleophilic Substitution

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

..

..+ O: :

H

H

C

CH3

CH3

CH3

Br:

..

C+

+

O :

H

H

Br..

::–

CH3

CH3

CH3

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

Page 56: Chapter 8 Nucleophilic Substitution

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

..

..+ O: :

H

H

C

CH3

CH3

CH3

Br:

..

C+

+

O :

H

H

Br..

::–

CH3

CH3

CH3

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

rate = k[(CH3)3CBr]

Page 57: Chapter 8 Nucleophilic Substitution

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

..

..+ O: :

H

H

C

CH3

CH3

CH3

Br:

..

C+

+

O :

H

H

Br..

::–

CH3

CH3

CH3

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

Page 58: Chapter 8 Nucleophilic Substitution

rate = k[alkyl halide]First-order kinetics implies a unimolecular

rate-determining step.

Proposed mechanism is called SN1, which stands for

substitution nucleophilic unimolecular

Kinetics and Mechanism

Page 59: Chapter 8 Nucleophilic Substitution

+..

..Br–

: :

C..

..

CH3

CH3

CH3

Br:

C

H3C CH3

CH3

+

unimolecular slow

Mechanism

Page 60: Chapter 8 Nucleophilic Substitution

C

H3C CH3

CH3

+

O: :

H

H

C+O :

H

HCH3

CH3

CH3

Mechanism

bimolecular fast

Page 61: Chapter 8 Nucleophilic Substitution

ROHROH22

++

carbocation formation

RR++

proton transfer

ROHROH

carbocation capture

RXRX

Page 62: Chapter 8 Nucleophilic Substitution

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

Characteristics of the SN1 mechanism

Page 63: Chapter 8 Nucleophilic Substitution

8.78.7

Carbocation Stability and SCarbocation Stability and SNN1 1

Reaction RatesReaction Rates

Page 64: Chapter 8 Nucleophilic Substitution

The rate of nucleophilic substitutionby the SN1 mechanism is governed

by electronic effects.

Carbocation formation is rate-determining.The more stable the carbocation, the faster

its rate of formation, and the greater the rate of unimolecular nucleophilic substitution.

Electronic Effects Govern SN1 Rates

Page 65: Chapter 8 Nucleophilic Substitution

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

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

Page 66: Chapter 8 Nucleophilic Substitution

CH3Br

CH3CH2Br

(CH3)2CHBr

(CH3)3CBr

Decreasing SN1 Reactivity

Page 67: Chapter 8 Nucleophilic Substitution

8.88.8Stereochemistry of SStereochemistry of SNN1 Reactions1 Reactions

Page 68: Chapter 8 Nucleophilic Substitution

Nucleophilic substitutions that exhibitfirst-order kinetic behavior are

not stereospecific.

Generalization

Page 69: Chapter 8 Nucleophilic Substitution

R-(–)-2-Bromooctane

H

C

CH3

Br

CH3(CH2)5

Stereochemistry of an SN1 Reaction

(R)-(–)-2-Octanol (17%)

H

C

CH3

OH

CH3(CH2)5

C

H CH3

HO

(CH2)5CH3

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

H2O

Page 70: Chapter 8 Nucleophilic Substitution

Leaving group shields

one face of carbocation;

nucleophile attacks

faster at opposite face.

+

Figure 8.6

Ionization step

gives carbocation; three

bonds to chirality

center become coplanar

Page 71: Chapter 8 Nucleophilic Substitution
Page 72: Chapter 8 Nucleophilic Substitution

8.98.9Carbocation RearrangementsCarbocation Rearrangements

in Sin SNN1 Reactions1 Reactions

Page 73: Chapter 8 Nucleophilic Substitution

carbocations are intermediatesin SN1 reactions, rearrangements

are possible.

Because...

Page 74: Chapter 8 Nucleophilic Substitution

CH3 C

H

CHCH3

Br

CH3H2O

CH3 C

OH

CH2CH3

CH3

(93%)

Example

CH3 C

H

CHCH3

CH3

+

H2O

CH3 C CHCH3

CH3

H

+

Page 75: Chapter 8 Nucleophilic Substitution

8.108.10Effect of SolventEffect of Solvent

on the on the Rate of Nucleophilic SubstitutionRate of Nucleophilic Substitution

Page 76: Chapter 8 Nucleophilic Substitution

SN1 Reaction Rates Increase

in Polar Solvents

In general...

Page 77: Chapter 8 Nucleophilic Substitution
Page 78: Chapter 8 Nucleophilic Substitution

R+

RX

RR X X

Energy of RX not much affected by polarity of solvent.

Page 79: Chapter 8 Nucleophilic Substitution

R+

RX

RR X X

Energy of RX not much affected by polarity of solvent.

transition state stabilized by polar solvent

activation energy decreases;

rate increases

Page 80: Chapter 8 Nucleophilic Substitution

SN2 Reaction Rates Increase in

Polar Aprotic Solvents

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

In general...

Page 81: Chapter 8 Nucleophilic Substitution

Solvent Type Relative rate

CH3OH polar protic 1

H2O polar protic 7

DMSO polar aprotic 1300

DMF polar aprotic 2800

Acetonitrile polar aprotic 5000

CH3CH2CH2CH2Br + N3–

Table 8.7 Relative Rate of SN2

Reactivity versus Type of Solvent

Page 82: Chapter 8 Nucleophilic Substitution

Mechanism SummarySN1 and SN2

Page 83: Chapter 8 Nucleophilic Substitution

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.

Page 84: Chapter 8 Nucleophilic Substitution

8.118.11

Substitution and EliminationSubstitution and Elimination

as Competing Reactionsas Competing Reactions

Page 85: Chapter 8 Nucleophilic Substitution

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

C C

H

X

+ Y:–

C C

Y

H

X:–

+

C C + H Y X:–

+

-elimination

nucleophilic substitution

Two Reaction Types

Page 86: Chapter 8 Nucleophilic Substitution

C C

H

X

+ Y:–

C C

Y

H

X:–

+

C C + H Y X:–

+

-elimination

nucleophilic substitution

Two Reaction Types

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

Page 87: Chapter 8 Nucleophilic 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.

Elimination versus Substitution

Page 88: Chapter 8 Nucleophilic Substitution

CH3CHCH3

Br

NaOCH2CH3

ethanol, 55°C

CH3CHCH3

OCH2CH3

CH3CH=CH2+

(87%)(13%)

Example

Page 89: Chapter 8 Nucleophilic Substitution

Br

E2

Figure 8.8

CH3CH2 O••

••••–

Page 90: Chapter 8 Nucleophilic Substitution
Page 91: Chapter 8 Nucleophilic Substitution

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

When is Substitution Favored?

Page 92: Chapter 8 Nucleophilic Substitution

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

primary alkyl halide

CH3CH2CH2Br

NaOCH2CH3

ethanol, 55°C

CH3CH=CH2+CH3CH2CH2OCH2CH3

(9%)(91%)

Uncrowded Alkyl Halides

Page 93: Chapter 8 Nucleophilic Substitution

primary alkyl halide + bulky base

CH3(CH2)15CH2CH2Br

KOC(CH3)3

tert-butyl alcohol, 40°C

+CH3(CH2)15CH2CH2OC(CH3)3 CH3(CH2)15CH=CH2

(87%)(13%)

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

Page 94: Chapter 8 Nucleophilic Substitution

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.

When is Substitution Favored?

Page 95: Chapter 8 Nucleophilic Substitution

Weakly basic nucleophile increases substitution relative to elimination

(70%)CH3CH(CH2)5CH3

CN

KCN

CH3CH(CH2)5CH3

ClpKa (HCN) = 9.1

DMSO

secondary alkyl halide + weakly basic nucleophile

Weakly Basic Nucleophile

Page 96: Chapter 8 Nucleophilic Substitution

Weakly basic nucleophile increases substitution relative to elimination

secondary alkyl halide + weakly basic nucleophile

Weakly Basic Nucleophile

NaN3 pKa (HN3) = 4.6

I

(75%)

N3

Page 97: Chapter 8 Nucleophilic Substitution

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.

Tertiary Alkyl Halides

Page 98: Chapter 8 Nucleophilic Substitution

(CH3)2CCH2CH3

Br

+CH3CCH2CH3

OCH2CH3

CH3

CH2=CCH2CH3

CH3

CH3C=CHCH3

CH3

+

ethanol, 25°C64% 36%

2M sodium ethoxide in ethanol, 25°C

1% 99%

Example

Page 99: Chapter 8 Nucleophilic Substitution

8.128.12Nucleophilic Substitution of Alkyl SulfonatesNucleophilic Substitution of Alkyl Sulfonates

Page 100: Chapter 8 Nucleophilic Substitution

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.

Page 101: Chapter 8 Nucleophilic Substitution

Other RX Compounds

ROSCH3

O

O

ROS

O

O

CH3

Alkylmethanesulfonate

(mesylate)

Alkylp-toluenesulfonate

(tosylate)

undergo same kinds of reactions as alkyl halides

Page 102: Chapter 8 Nucleophilic Substitution

Preparation

(abbreviated as ROTs)

ROH +

CH3 SO2Cl

pyridine

ROS

O

O

CH3

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

Page 103: Chapter 8 Nucleophilic Substitution

Tosylates Undergo Typical Nucleophilic Substitution Reactions

H

CH2OTs

KCN

ethanol-water

H

CH2CN

(86%)

Page 104: Chapter 8 Nucleophilic Substitution

The best leaving groups are weakly basic.

Page 105: Chapter 8 Nucleophilic Substitution

Table 8.8 Approximate Relative Leaving Group Abilities

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

H2O 101 H3O+ -1.7

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

Page 106: Chapter 8 Nucleophilic Substitution

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

H2O 101 H3O+ -1.7

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

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

Table 8.8 Approximate Relative Leaving Group Abilities

Page 107: Chapter 8 Nucleophilic Substitution

Tosylates can be Converted to Alkyl Halides

NaBr

DMSO

(82%)

OTs

CH3CHCH2CH3

Br

CH3CHCH2CH3

Tosylate is a better leaving group than bromide.

Page 108: Chapter 8 Nucleophilic Substitution

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.

C

H

H3C

OH

CH3(CH2)5 TsCl

pyridine

C

H

H3C

OTs

CH3(CH2)5

Page 109: Chapter 8 Nucleophilic Substitution

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

Nu–

SN2

C

H

H3C

OTs

CH3(CH2)5

C

H

CH3

(CH2)5CH3

Nu

Tosylates Allow Control of Stereochemistry

Page 110: Chapter 8 Nucleophilic Substitution

Tosylates also undergo Elimination

NaOCH3

CH3OHheat

OTs

CH3CHCH2CH3

CH2=CHCH2CH3

CH3CH=CHCH3

E and Z

+

Page 111: Chapter 8 Nucleophilic Substitution

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

C

HH3C

OH

CH3(CH2)5

C

HH3C

Br

CH3(CH2)5

C

H

CH3

(CH2)5CH3

Br

HBr

87%

13%

Page 112: Chapter 8 Nucleophilic Substitution

Secondary Alcohols React with Hydrogen Halides with Net Inversion of Configuration

C

HH3C

OH

CH3(CH2)5

C

HH3C

Br

CH3(CH2)5

C

H

CH3

(CH2)5CH3

Br

HBr

87%

13%

Most reasonable mechanism

is SN1 with front side of carbocation

shielded by leaving group.

Page 113: Chapter 8 Nucleophilic Substitution

Rearrangements can Occur in the Reaction of Alcohols with Hydrogen Halides

OH Br

Br

+

93% 7%

HBr

Page 114: Chapter 8 Nucleophilic Substitution

Rearrangements can Occur in the Reaction of Alcohols with Hydrogen Halides

OH Br

Br

+

+

+

93%

7%

Br –Br –

HBr