CHE275 Chapter8 Slides

Organic Chemistry

CHE 275

Chapter 8Nucleophilic 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

+

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

XCC

X

Nucleophilic Substitution

+ R X

Alkoxide ion as the nucleophile

..O:

..R'

Examples of Nucleophilic Substitution

gives an ether

+ : XR..O..

R'

(CH3)2CHCH2ONa + CH3CH2Br

Isobutyl alcohol

(CH3)2CHCH2OCH2CH3 + NaBr

Ethyl isobutyl ether (66%)

Example

+ R X

Carboxylate ion as the nucleophile

..O:

..R'C

O

gives an ester

+ : XR..O..

R'C O


OK +CH3(CH2)16C CH3CH2I

acetone, water

O

+ KIO CH2CH3CH3(CH2)16C

Ethyl octadecanoate (95%)

O

Example

+ R X

Hydrogen sulfide ion as the nucleophile

..S:

..H

gives a thiol

+ : XR..S..

H


KSH + CH3CH(CH2)6CH3

Br

ethanol, water

+ KBr

2-Nonanethiol (74%)

CH3CH(CH2)6CH3

SH

Example

+ R X

Cyanide ion as the nucleophile

CN: :


gives a nitrile

+ : XR CN:

DMSO

BrNaCN +

Cyclopentyl cyanide (70%)

CN + NaBr

Example

Azide ion as the nucleophile

.. ..

N N N:: +

+ R X

..

gives an alkyl azide

+ : XR ..N N N: +


NaN3 + CH3CH2CH2CH2CH2I

2-Propanol, water

CH3CH2CH2CH2CH2N3 + NaI

Pentyl azide (52%)

Example

+ R X

Iodide ion as the nucleophile..: I..:

gives an alkyl iodide

+ : XR ..: I..


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

acetone

+ NaICH3CHCH3

Br

63%

+ NaBrCH3CHCH3

I

Example Reactivity of Leaving Groups

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

RBr

RCl

RF

most reactive

least reactive

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

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

CH2CH2CH2Cl + NaBrCN:

Many nucleophilic substitutions follow asecond-order rate law.

CH3Br + HO CH3OH + Br rate = k[CH3Br][HO ]

inference: rate-determining step is bimolecular

Kinetics and the SN2 Mechanism

HO CH3Br+ HOCH3 Br +

one stepone step

HO CH3 Br

transition state

Bimolecular Mechanism

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

Stereochemistry Inversion of Configuration

nucleophile attacks carbonfrom side opposite bondto the leaving group

three-dimensionalarrangement of bonds inproduct is opposite to that of reactant

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

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

(+)-2-Bromooctane ()-2-Octanol()-2-Bromooctane (+)-2-Octanol

Stereospecific Reaction

C

H

CH3

Br

CH3(CH2)5NaOH

(S)-(+)-2-Bromooctane

(CH2)5CH3

C

H

CH3

HO

(R)-()-2-Octanol

Stereospecific Reaction

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

H Br

CH3

CH2(CH2)4CH3

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

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

Steric Effects on SN2 reactions: Crowding at the Reaction Site

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

RBr + LiI RI + LiBrAlkyl Class Relativebromide rate

CH3Br Methyl 221,000

CH3CH2Br Primary 1,350

(CH3)2CHBr Secondary 1

(CH3)3CBr Tertiary too smallto measure

Reactivity toward substitution by the SN2 mechanism

CH3Br

CH3CH2Br

(CH3)2CHBr

(CH3)3CBr

Decreasing SN2 Reactivity

CH3Br

CH3CH2Br

(CH3)2CHBr

(CH3)3CBr


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.

Crowding Adjacent to the Reaction Site

RBr + LiI RI + LiBrAlkyl Structure Relativebromide rate

Ethyl CH3CH2Br 1.0

Propyl CH3CH2CH2Br 0.8

Isobutyl (CH3)2CHCH2Br 0.036

Neopentyl (CH3)3CCH2Br 0.00002

Effect of chain branching on rate of SN2 substitution

Interactive QuestionWhat is the major product of the reaction of the

dihalide at the right with 1 equivalent ofNaSH in dimethyl sulfoxide?

A) B)

C) D) All nucleophiles, however, are Lewis bases.

The nucleophiles described in the bookhave mostly been anions.

..

..HO: ..

..CH3O:..

..HS:

CN: : etc.

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

..NH3: for example

Nucleophiles and Nucleophicity

..

..HOH CH3OH....

for example

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

Nucleophiles

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

Solvolysis

substitution by an anionic nucleophile

RX + :Nu RNu + :X

+solvolysis

RX + :NuH RNuH + :X

step in which nucleophilicsubstitution occurs

Solvolysis

+

substitution by an anionic nucleophile

RX + :Nu RNu + :X

solvolysis

RX + :NuH RNuH + :X

RNu + HXproducts of overall reaction

Solvolysis

RX

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: Methanolysissolvent product from RX

water (HOH) ROHmethanol (CH3OH) ROCH3ethanol (CH3CH2OH) ROCH2CH3

formic acid (HCOH)

acetic acid (CH3COH) ROCCH3

O

ROCH

OO

O

Typical solvents in solvolysis

Rank Nucleophile Relative rate strong I-, HS-, RS- >105

good Br-, HO-, 104

RO-, CN-, N3-

fair NH3, Cl-, F-, RCO2- 103

weak H2O, ROH 1very weak RCO2H 10-2

Nucleophilicity compare 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 relative rate of 1.0.

basicity

solvation

small negative ions are highly solvated in protic solvents

large negative ions are less solvated

Major factors that control nucleophilicity

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.

Nucleophilicity

basicity

solvation

small negative ions are highly solvated in protic solvents

large negative ions are less solvated

Major factors that control nucleophilicity

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

Solvation

Rank Nucleophile Relative Rate

strong 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.

Nucleophilicity

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.

The SN1 MechanismHydrolysis of tert-butyl

bromide.

+

+

H Br.... :

O: :

H

H

CCH3

CH3

CH3

Br

C OH....

..

.. :

CH3CH3

CH3

C+

+

O :

H

H

Br.... ::

CH3CH3

CH3

+ O: :

H

H

C+

+

O :

H

H

Br.... ::

CH3CH3

CH3

CCH3

CH3

CH3

Br.... :

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

Hydrolysis of tert-butyl bromide.

+ O: :

H

H

C+

+

O :

H

H

Br.... ::

CH3CH3

CH3

CCH3

CH3

CH3

Br.... :


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

rate = k[(CH3)3CBr]

+ O: :

H

H

C+

+

O :

H

H

Br.... ::

CH3CH3

CH3

CCH3

CH3

CH3

Br.... :


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

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

rate-determining step.

Proposed mechanism is called SN1(Substitution Nucleophilic unimolecular)

Kinetics and Mechanism

+....Br

: :

C....

CH3CH3

CH3

Br:

CH3C CH3

CH3

+

unimolecular slow

Mechanism

CH3C CH3

CH3

+O: :

H

H

C+O :

H

HCH3CH3

CH3

bimolecular fast

Mechanism

ROH2+

carbocation formation

R+

proton transfer

ROH

carbocation capture

RX

first order kinetics: rate = k[RX]unimolecular rate-determining step

carbocation intermediaterate follows carbocation stabilityrearrangements sometimes observed

reaction is not stereospecificSignificant racemization in reactions of optically active alkyl halides

Characteristics of the SN1 mechanism

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

RBr solvolysis in aqueous formic acid

Alkyl bromide Class Relative Rate

CH3Br Methyl 1

CH3CH2Br Primary 2

(CH3)2CHBr Secondary 43

(CH3)3CBr Tertiary 100,000,000

Reactivity toward substitution by the SN1 mechanism

CH3Br

CH3CH2Br

(CH3)2CHBr

(CH3)3CBr


Nucleophilic substitutions that exhibitfirst-order kinetic behavior are

not stereospecific.

Generalization

Which alkyl halide will react faster with CH3OH under SN1 conditions?

A) B)

C) D)

Interactive Question

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

Ionization step gives carbocation; threebonds to chirality center become coplanar

Leaving group shields one face of carbocation; nucleophile attacks

faster at opposite face.

Carbocations are intermediatesin SN1 reactions, rearrangements

are possible.

Carbocation Rearrangementsin SN1 Reactions Because...

CH3 C

H

CHCH3

Br

CH3 H2OCH3 C

OH

CH2CH3

CH3

(93%)

Example

CH3 C

H

CHCH3

CH3

+

H2O

CH3 C CHCH3

CH3

H+

SN1 Reaction Rates Increase in Polar Protic Solvents

Solvent Effects

Solvent Dielectric Relativeconstant rate

acetic acid 6 1methanol 33 4formic acid 58 5,000water 78 150,000

SN1 Reactivity versus Solvent Polarity

Most polar Fastest rate

R+

RX

R X

energy of RX not much affected by polarity of solvent

transition state stabilized by polar solvent

Ea

R+

RX

R X

energy of RX not much affected by polarity of solvent

transition state stabilized by polar solvent

activation energy decreases;

rate increases

Ea > Ea

SN2 Reaction Rates Increase inPolar Aprotic Solvents

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

In general...

Solvent Type Relative RateCH3OH polar protic 1H2O polar protic 7DMSO polar aprotic 1300DMF polar aprotic 2800Acetonitrile polar aprotic 5000

CH3CH2CH2CH2Br + N3

SN2 Reactivity vs. Type of Solvent


The reaction of butyl iodide with NaSCH3 will proceed at a faster rate in which solvent?A) acetoneB) acetic acidC) propanolD) water

Mechanism SummarySN1 and SN2

When...primary alkyl halides undergo nucleophilic substitution, they always react by the SN2 mechanismtertiary alkyl halides undergo nucleophilic substitution, they always react by the SN1 mechanismsecondary alkyl halides undergo nucleophilic substitution, they react by the

SN1 mechanism in the presence of a weak nucleophile (solvolysis) in a protic solventSN2 mechanism in the presence of a good nucleophile in an aprotic solvent


What combination is the best choice in order to prepare 3-chloro-1-iodobutane?A) 1-iodobutane + Cl2 (400C)B) 1,3-dichlorobutane + NaI (1 equiv) in

acetoneC) 1,3-iodobutane + NaCl (1 equiv) in

acetoneD) 3-bromo-1-iodobutane + NaCl (1 equiv)

in acetone


The best combination of reactants for preparing (CH3)3CSCH3 is:A) (CH3)3CCl + CH3SKB) (CH3)3CBr + CH3SNaC) (CH3)3CSK + CH3OHD) (CH3)3CSNa + CH3Br

Substitution and Eliminationas Competing Reactions

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

C C

H

X

+ Y:

C C

Y

H

X:

+

C C + H Y X:

+

-elimination

nucleophilic substitution

Two Reaction Types

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

CH3CHCH3

Br

NaOCH2CH3ethanol, 55C

CH3CHCH3

OCH2CH3CH3CH=CH2+

(87%)(13%)

Example

Example: E2

BrCH3CH2 O

Example: SN2

BrCH3CH2 O

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

When is substitution favored?

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

primary alkyl halide

CH3CH2CH2Br

NaOCH2CH3ethanol, 55C

CH3CH=CH2+CH3CH2CH2OCH2CH3(9%)(91%)

Uncrowded Alkyl Halides

primary alkyl halide + bulky base

CH3(CH2)15CH2CH2Br

KOC(CH3)3tert-butyl alcohol, 40C

+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. Interactive Question

Which one of the following alkyl halides would be expected to give the highest ratio ofsubstitution to elimination on treatment with sodium ethoxide in ethanol (50C)?A) 1-bromopentaneB) 2-bromopentaneC) 3-bromopentaneD) 2-bromo-3-methylbutane

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

When is substitution favored? 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

Weakly basic nucleophile increases substitution relative to elimination

secondary alkyl halide + weakly basic nucleophile

NaN3 pKa (HN3) = 4.6

I

(75%)N3

Weakly Basic Nucleophile

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

(CH3)2CCH2CH3

Br

+CH3CCH2CH3

OCH2CH3

CH3

CH2=CCH2CH3

CH3

CH3C=CHCH3

CH3

+

ethanol, 25C64% 36%

2M sodium ethoxide in ethanol, 25C1% 99%

ExampleInteractive Question

Which of the following is not a good nucleophile for an SN1 reaction?A) NaOCH3B) CH3OHC) CH3CH2OHD) H2O


Which one of the following compounds gives the highest subtitution-to-elimination ratio(most substitution least elimination) on reaction with 2-bromobutane?A) NaOCH3B) NaNH2C) NaCND) NaCCH

Leaving Groups

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

However, halogens are not the only possible leaving groups

Other RX compounds

ROSCH3

O

O

ROS

O

O

CH3

Alkylmethanesulfonate

(mesylate)

Alkylp-toluenesulfonate

(tosylate)

undergo same kinds of reactions as alkyl halides

Preparation

(abbreviated as ROTs)

ROH + CH3 SO2Clpyridine

ROS

O

O

CH3

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

Tosylates undergo typical nucleophilic substitution reactions

H

CH2OTs

KCN

ethanol-water

H

CH2CN

(86%)

The best leaving groups are weakly basic

Approximate Relative Reactivity of Leaving Groups

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

F 10-5 HF 3.5Cl 1 HCl -7Br 10 HBr -9I 102 HI -10

H2O 101 H3O+ -1.7TsO 105 TsOH -2.8

CF3SO2O 108 CF3SO2OH -6

Approximate Relative Reactivity of Leaving Groups

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

F 10-5 HF 3.5Cl 1 HCl -7Br 10 HBr -9I 102 HI -10

H2O 101 H3O+ -1.7TsO 105 TsOH -2.8

CF3SO2O 108 CF3SO2OH -6Sulfonate esters are extremely good leaving groups; sulfonate ions are very weak bases.

Tosylates can be converted to alkyl halides

NaBr

DMSO

(82%)

OTs

CH3CHCH2CH3

Br

CH3CHCH2CH3

Tosylate is a better leaving group than bromide.

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

C OTs

CH3

CH3(CH2)5H

C OH

CH3

CH3(CH2)5

H

C

CH3

Nu

CH3(CH2)5

C

H CH3

TosO

(CH2)5CH3

Nu

SN2

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

Tosylates allow control of stereochemistry

Secondary alcohols react with inversion

C

HH3C

OH

CH3(CH2)5

C

HH3C

Br

CH3(CH2)5

C

HCH3

(CH2)5CH3

Br

HBr

87%

13%

Secondary alcohols react with inversion

C

HH3C

OH

CH3(CH2)5

C

HH3C

Br

CH3(CH2)5

C

HCH3

(CH2)5CH3

Br

HBr

87%

13%

Most reasonable mechanism is SN1 with front side of carbocation shielded by leaving group

Rearrangements can occur

OH

Br

Br

+

93% 7%

HBr

Rearrangements can occur

OH

Br

Br

+

+

+

93%

7%

Br Br

HBr

Tosylates also undergo Elimination

NaOCH3

CH3OHheat

OTs

CH3CHCH2CH3CH2=CHCH2CH3

CH3CH=CHCH3E and Z

+

Summary: Chapter 8Summary: Chapter 8

8.1 Nucleophilic Substitution

8.2 Relative Reactivity of Halides

8.3 The SN2 Mechanism

8.4 Steric Effects in SN2

8.5 Nucleophiles and Nucleophilicity

8.6 The SN1 Mechanism

8.7 Carbocation Stability and SN1 Rate

8.8 Stereochemistry of SN1 Reactions

8.9 Carbocation Rearrangements in SN1 Reactions

Summary: Chapter 8Summary: Chapter 88.10 Solvent Effects on Nucleophilic Substitution8.11 Substitution vs. Elimination8.12 Sulfonate Esters as Substrates in SN1 and SN2

CHE275 Chapter8 Slides

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