Nucleophilic Aromatic Substitution Nucleophilic Aromatic Substitution

Aryl HalidesAryl Halides

SSNN2 is not reasonable because the 2 is not reasonable because the aromatic ring blocks back-side aromatic ring blocks back-side approach of the nucleophile. Inversion approach of the nucleophile. Inversion is not possible.is not possible.

Chlorobenzene is quite unreactive with nucleophiles

SN1 is also unlikely:Aryl Cations are Highly Unstable

Cl

C

+ Cl

SN1

emptysp2 orbital

Aryl Cation

SN1 not reasonable because:

1) C—Cl bond is strong; therefore, ionization to a carbocation is a high-energy process

2) aryl cations are highly unstable

nitro-substituted aryl halides nitro-substituted aryl halides dodo undergo undergonucleophilic aromatic substitution readilynucleophilic aromatic substitution readily

But...But...

ClCl

NONO22

++ NaNaOOCHCH33

CHCH33OHOH

85°C85°C

OOCHCH33

NONO22

++ NaNaClCl

(92%)(92%)

especially when nitro group is ortho and/orespecially when nitro group is ortho and/orpara to leaving grouppara to leaving group

Effect of nitro group is cumulative Effect of nitro group is cumulative

ClCl

1.01.0

ClCl

NONO22

7 x 107 x 101010

ClCl

NONO22

NONO22OO22NN

2.4 x 102.4 x 101515

ClCl

NONO22

NONO22

too fast to measuretoo fast to measure

follows second-order rate law:follows second-order rate law:rate = rate = k k [aryl halide][nucleophile][aryl halide][nucleophile]

inference:inference:both the aryl halide and the nucleophile are both the aryl halide and the nucleophile are involved in rate-determining stepinvolved in rate-determining step

KineticsKinetics

Effect of leaving groupEffect of leaving group

unusual order: F > Cl > Br > Iunusual order: F > Cl > Br > I

XX

NONO22

XX Relative Rate*Relative Rate*

FF

ClCl

BrBr

II

312312

1.01.0

0.80.8

0.40.4

*NaOCH*NaOCH33, CH, CH33OH, 50°COH, 50°C

•bimolecular rate-determining step in whichbimolecular rate-determining step in whichnucleophile attacks aryl halidenucleophile attacks aryl halide•rate-determining step precedes carbon-halogenrate-determining step precedes carbon-halogenbond cleavagebond cleavage•rate-determining transition state is stabilized byrate-determining transition state is stabilized byelectron-withdrawing groups (such as NOelectron-withdrawing groups (such as NO22))

General Conclusions About MechanismGeneral Conclusions About Mechanism

The Addition-Elimination MechanismThe Addition-Elimination Mechanismof of

Nucleophilic Aromatic SubstitutionNucleophilic Aromatic Substitution

Two step mechanism:Two step mechanism:

Step 1) nucleophile attacks aryl halide andStep 1) nucleophile attacks aryl halide and bonds to the carbon that bears the halogenbonds to the carbon that bears the halogen

(slow: aromaticity of ring lost in this step)(slow: aromaticity of ring lost in this step)

Step 2) intermediate formed in first step losesStep 2) intermediate formed in first step loseshalidehalide

(fast: aromaticity of ring restored in this step)(fast: aromaticity of ring restored in this step)

Addition-Elimination MechanismAddition-Elimination Mechanism

ReactionReaction

FF

NONO22

++ NaNaOOCHCH33

CHCH33OHOH

85°C85°C

OOCHCH33

NONO22

++ NaNaFF

(93%)(93%)

MechanismMechanism

•••• OOCHCH33••••

••••

––

NONO22

FF••••

•••• ••••

HH

HH

HH

HH

bimolecularbimolecular

consistent with second-consistent with second-order kinetics; first order order kinetics; first order in aryl halide, first order in aryl halide, first order in nucleophilein nucleophile

Step 1Step 1Step 1Step 1

MechanismMechanism

slowslow

•••• OOCHCH33••••

••••

––

NONO22

FF••••

•••• ••••

HH

HH

HH

HH

NONO22

FF••••

•••• ••••

HH

HH

HH

HH

••••––

•••• OOCHCH33••••

Step 1Step 1Step 1Step 1

MechanismMechanism

NONO22

FF••••

•••• ••••

HH

HH

HH

HH

••••––

•••• OOCHCH33••••intermediate is intermediate is

negatively chargednegatively charged

formed faster when formed faster when ring bears electron-ring bears electron-withdrawing groups withdrawing groups such as NOsuch as NO22

Stabilization of Rate-Determining IntermediateStabilization of Rate-Determining Intermediateby Nitro Groupby Nitro Group

NN

FF••••

•••• ••••

HH

HH

HH

HH

••••

•••• OOCHCH33••••

OO OO••••

••••

•••••••• ••••++

––

––

Stabilization of Rate-Determining IntermediateStabilization of Rate-Determining Intermediateby Nitro Groupby Nitro Group

NN

FF••••

•••• ••••

HH

HH

HH

HH

••••

•••• OOCHCH33••••

OO OO••••

••••

•••••••• ••••++

––

––

NN

FF••••

•••• ••••

HH

HH

HH

HH

••••

•••• OOCHCH33••••

OO OO••••

••••

•••••••• ••••++

––

––

MechanismMechanism

NONO22

FF••••

•••• ••••

HH

HH

HH

HH

••••––

•••• OOCHCH33••••

Step 2Step 2Step 2Step 2

MechanismMechanism

fastfast

•••• OOCHCH33••••

NONO22

HH

HH

HH

HH

NONO22

FF••••

•••• ••••

HH

HH

HH

HH

••••––

•••• OOCHCH33••••

FF••••

•••• ••••••••

––

Step 2Step 2Step 2Step 2

carbon-halogen bond breaking does not occurcarbon-halogen bond breaking does not occuruntil after the rate-determining stepuntil after the rate-determining step

electronegative F stabilizes negatively electronegative F stabilizes negatively charged intermediatecharged intermediate

Leaving Group EffectsLeaving Group Effects

F > Cl > Br > I is unusual, but consistentF > Cl > Br > I is unusual, but consistentwith mechanismwith mechanism

The Role of Leaving Groups

FNucH

NO O

ClNucH

NO O

BrNucH

NO O

INucH

NO O

Most Stabilized Least Stabilized

Related Nucleophilic AromaticRelated Nucleophilic AromaticSubstitution ReactionsSubstitution Reactions

Example: HexafluorobenzeneExample: Hexafluorobenzene

FF

FF

FF

FF

FF

FF

NaNaOOCHCH33

CHCH33OHOH

65°C65°CFF

OOCHCH33

FF

FF

FF

FF

(72%)(72%)

Six fluorine substituents stabilize negatively Six fluorine substituents stabilize negatively charged intermediate formed in rate-determining charged intermediate formed in rate-determining step and increase rate of nucleophilic aromatic step and increase rate of nucleophilic aromatic substitution.substitution.

Example: 2-ChloropyridineExample: 2-Chloropyridine

NaNaOOCHCH33

CHCH33OHOH

2-Chloropyridine reacts 230,000,000 times 2-Chloropyridine reacts 230,000,000 times faster than chlorobenzene under these faster than chlorobenzene under these conditions.conditions.

ClClNN

OOCHCH33NN50°C50°C

Example: 2-ChloropyridineExample: 2-Chloropyridine

Nitrogen is more electronegative than carbon, Nitrogen is more electronegative than carbon, stabilizes the anionic intermediate, and stabilizes the anionic intermediate, and increases the rate at which it is formed.increases the rate at which it is formed.

ClClNN

•••• OOCHCH33••••

••••

––

••••

Example: 2-ChloropyridineExample: 2-Chloropyridine

Nitrogen is more electronegative than carbon, Nitrogen is more electronegative than carbon, stabilizes the anionic intermediate, and stabilizes the anionic intermediate, and increases the rate at which it is formed.increases the rate at which it is formed.

ClClNN

•••• OOCHCH33••••

••••

––

••••

ClClNN

OOCHCH33••••

••••––

••••

••••

Nucleophilic AromaticNucleophilic AromaticSubstitution ReactionsSubstitution Reactions

ininSynthesisSynthesis

Triketones

Herbicides that inhibit HPPD

Hydroxyphenylpyruvate dioxygenase

NTBC- orphan drug for tyrosine anemia

O

O

O

N

O

2

C

F

3

O

O

O

N

O

2

S

O

2

C

H

3

O

O

O

Cl

S

O

2

C

H

3

NTBC - Pharmaceutical

Callisto (mesotrione)

MIkado (sulfotrione)

Triketones Continued

Inhibition of HPPD

Hydroxyphenylpyruvate dioxygenase

Third Generation

O

O

O

Cl

S

O

2

C

H

3

O

C

H

2

C

H

3

Synthetic IntermediateSynthetic Intermediate

O

H

O

Cl

S

O

2

C

H

3

O

C

H

2

C

H

3

Triketones: Synthetic IntermediateSynthetic Intermediate

O

H

O

Cl

S

O

2

C

H

3

O

C

H

2

C

H

3

Starting from 2,3-dichlorothiophenol Starting from 2,3-dichlorothiophenol which is commercially availablewhich is commercially available

1)1) S- methylateS- methylate

2)2) EAS acylationEAS acylation

3)3) oxidationoxidation

Cl

Cl

S

O

2

C

H

3

H

O

2

C

Ofloxacin

http://www.ofloxacin.com/

Ofloxacin (trade name Floxin) is a broad-spectrum quinolone antibiotic

Ofloxacin

N

O

O O

OEt

Me

H

N

F

NMe

H

N

O

O O

OH

Me

H

N

F

NMe

H

Synthesis of Ofloxacin, Part 1

F

F

O O

OEt

F

F

OMe

H

F

F

O O

OEt

F

F

OMe

H

HN

MeOH

F

F

O O

OEt

F

F

H

NH

MeOH

NH2

MeOH -MeO

1,4-Addition

Elimination

Synthesis of Ofloxacin, Part 2

N

O O

OEt

F

F

H

FMe

OH

N

O O

OEt

F

F

H

FMe

OHF

F

F

O O

OEt

F

F

H

NH

MeOH

Elimination

Addition

NucleophilicAromatic Substition

Synthesis of Ofloxacin, Part 3

N

O

O O

OEt

Me

H

F

F

H

N

O

O O

OEt

Me

H

F

F

H

N

O O

OEt

F

F

H

FMe F

H

HO

Addition

EliminationNucleophilicAromatic Substition

-F

Synthesis of Ofloxacin, Part 4

N

O

O O

OEt

Me

H

N

F

NMe

H

N

O

O O

OEt

Me

H

F

F

H

N

N

Me

N

O

O O

OEt

Me

H

F

F

H

NH

NMe

NucleophilicAromatic Substition

Addition

Elimination

Synthesis of Ofloxacin, Part 5

Ofloxacin

N

O

O O

OH

Me

H

N

F

NMe

H

N

O

O O

OEt

Me

H

N

F

NMe

H

NaOHH2O

The Elimination-Addition MechanismThe Elimination-Addition Mechanism

of Nucleophilic Aromatic of Nucleophilic Aromatic

Substitution:Substitution:

BenzyneBenzyne

Aryl Halides Undergo Substitution WhenAryl Halides Undergo Substitution WhenTreated With Very Strong BasesTreated With Very Strong Bases

ClCl

NHNH22

KNHKNH22, NH, NH33

––33°C33°C

(52%)(52%)

CHCH33

NHNH22

new substituent becomes attached to eithernew substituent becomes attached to eitherthe carbon that bore the leaving group orthe carbon that bore the leaving group orthe carbon adjacent to itthe carbon adjacent to it

RegiochemistryRegiochemistry

++

NaNHNaNH22,,

NHNH33

––33°C33°C

CHCH33

BrBr

CHCH33

NHNH22

new substituent becomes attached to eithernew substituent becomes attached to eitherthe carbon that bore the leaving group orthe carbon that bore the leaving group orthe carbon adjacent to itthe carbon adjacent to it

RegiochemistryRegiochemistry

CHCH33

BrBr

++NaNHNaNH22, NH, NH33

––33°C33°C

CHCH33

NHNH22

CHCH33

NHNH22

RegiochemistryRegiochemistry

++

NaNHNaNH22, NH, NH33 ––33°C33°C

CHCH33

NHNH22

CHCH33

NHNH22

CHCH33

ClCl

++

CHCH33

NHNH22

Same result using Same result using 1414C labelC label

ClCl**

KNHKNH22, NH, NH33 ––33°C33°C

NHNH22**++

NHNH22

**

(48%)(48%)(52%)(52%)

MechanismMechanism

•••• NNHH22••••

––

Step 1Step 1Step 1Step 1

HH

HH

•••• ••••

HH

HH

ClCl

HH

••••

MechanismMechanism

•••• NNHH22••••

––

Step 1Step 1Step 1Step 1

HH

HH

•••• ••••

HH

HH

ClCl

HH

••••

HH

HH

HH

HHNNHH22••••

HH

••••••••ClCl••••

••••––

compound formed in this step is called compound formed in this step is called benzynebenzyne

BenzyneBenzyne

HH

HH

HH

HH

Benzyne has a strained triple bond.Benzyne has a strained triple bond.

It cannot be isolated in this reaction, but is It cannot be isolated in this reaction, but is formed as a reactive intermediate.formed as a reactive intermediate.

Benzyne - A Reactive MoleculeWith an Abnormal -Bond

Benzyne has a reactive triple bond.

It cannot be isolated in this reaction, but is formed as a reactive intermediate.

H

H

H

H

Benzyne

H

H

H

H

2pZ-2pZ Bond

H

H

H

H

sp2-sp2

Bond

Benzyne - A Reactive Aromatic MoleculeWith An Abnormal, In-Plane -Bond

C

C

R

R

'Normal' C-C Triple Bond

CC

C

CCCH

H H

H

Benzyne C-C Triple Bond

overlapping sp2 orbitalspoor overap resultsin a weak, reactive bond

MechanismMechanism

•••• NNHH22••••

––

Step 2Step 2Step 2Step 2

HH

HH

HH

HH

MechanismMechanism

•••• NNHH22••••

––

Step 2Step 2Step 2Step 2

HH

HH

HH

HH

HH

HH

HH

HH

NNHH22

––••••

••••

Angle strain is relieved. The two Angle strain is relieved. The two spsp-hybridized -hybridized ring carbons in benzyne become ring carbons in benzyne become spsp22 hybridized hybridized in the resulting anion.in the resulting anion.

MechanismMechanism

Step 3Step 3Step 3Step 3

HH

HH

HH

HH

NNHH22

––••••

••••

NNHH22••••

HH

MechanismMechanism

•••• NNHH22••••

––

Step 3Step 3Step 3Step 3

HH

HH

HH

HH

NNHH22

––••••

••••

NNHH22••••

HH

HH

HH

HH

HH

HH NNHH22••••

Hydrolysis of ChlorobenzeneHydrolysis of Chlorobenzene

ClCl**

NaOH, HNaOH, H22OO 395°C395°C

OOHH**++

OOHH

**

(54%)(54%)(43%)(43%)

1414C labeling C labeling indicates that indicates that the high-the high-temperature temperature reaction of reaction of chlorobenzene chlorobenzene with NaOH with NaOH goes via goes via benzyne.benzyne.

Diels-Alder Reactions of BenzyneDiels-Alder Reactions of Benzyne

Other Routes to BenzyneOther Routes to Benzyne

Benzyne can be prepared as a reactive Benzyne can be prepared as a reactive intermediate by methods other than treatment of intermediate by methods other than treatment of chlorobenzene with strong bases.chlorobenzene with strong bases.

Another method involves loss of fluoride ion Another method involves loss of fluoride ion from the Grignard reagent of 1-bromo-2-from the Grignard reagent of 1-bromo-2-fluorobenzene.fluorobenzene.

Other Routes to BenzyneOther Routes to Benzyne

••••

BrBr

FF••••

••••

Mg, THFMg, THF

heatheat ••••

MgMgBrBr

FF••••

••••

FFMgMgBrBr++

Benzyne as a DienophileBenzyne as a Dienophile

Benzyne is a fairly reactive dienophile, and Benzyne is a fairly reactive dienophile, and gives Diels-Alder adducts when generated in gives Diels-Alder adducts when generated in the presence of conjugated dienes.the presence of conjugated dienes.

The Diels-Alder Reaction Revisited

BA

X Y

A

X

B

Y

cycloaddition

diene dienophile cycloadduct

H

H

H

H

isoprene maleic anhydride cycloadduct

O

O

O

H3C H3C

O

O

O

100°C

Electron-Deficient AlkynesBehave as Dienophiles

butadiene but-3-yn-2-one cycloadduct

120°C

CH3O

HH

CH3

O

Benzyne Behaves as a Dienophile

Benzyne is a fairly reactive dienophile, and gives Diels-Alder adducts when generated in the presence of conjugated dienes.

CH3O

H

H

H

O

O

O

H

H

H

H

Benzyne

Benzyne as a DienophileBenzyne as a Dienophile

BrBr

FF

Mg, THFMg, THF

heatheat++

(46%)(46%)