22-1 Di- and Polysubstitution Orientation on nitration of monosubstituted benzenes.

22-22-11

Di- and PolysubstitutionDi- and Polysubstitution

Orientation on nitration of monosubstituted benzenes.

OCH3

Cl

Br

COOH

CN

NO2

ortho meta paraortho +para meta

44 - 55 99 trace

70 - 30 100 trace

37 1 62 99 1

18 80 2 20 80

19 80 1 20 80

6.4 93.2 0.3 6.7 93.2

Substituent

CH3 58 4 38 96 4

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Directivity of substituentsDirectivity of substituentsX

XX

E

E

E

+

ortho and para, appear together X is o,p director

major

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Directivity of substituentsDirectivity of substituents

X X

E

E

metaX is m director

major

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Two characteristics of a substituent • Orientation:

• Certain substituents direct preferentially to ortho & para positions; others to meta positions.

• Substituents are classified as either ortho-para directingortho-para directing or meta directing meta directing toward further substitution.

• Rate• Certain substituents cause the rate of a second substitution to

be greater than that for benzene itself; others cause the rate to be lower.

• Substituents are classified as activatingactivating or deactivatingdeactivating toward further substitution.

22-22-55


• -OCH3 is ortho-para directing.

• -COOH is meta directing.

OCH3

HNO3 CH3COOH

OCH3NO2

OCH3

NO2

H2O

p-Nitroanisole (55%)

o-Nitroanisole (44%)

Anisole

+++

COOH

HNO3H2SO4

NO2

COOH COOH

NO2NO2

COOH

100°C

m-Nitro-benzoic

acid(80%)

Benzoicacid

+ ++

o-Nitro-benzoic

acid(18%)

p-Nitro-benzoic

acid(2%)

22-22-66


Weakly activating

Ort

ho-p

ara

Dir

ect

ing

Weakly deactivating

Moderately activating

Strongly activating NH2 NHR NR2 OH

NHCR NHCAr

OR

OCArOCR

R

F Cl Br I

: : : : :::

: : ::

::

::

::

::

:: ::::

Strongly deactivating

Moderately deactivating

CH

O O

CR COH

SO3H

CORO

CNH2

NO2 NH3+ CF3 CCl3M

eta

Dir

ect

ing

C N

O O O O

OO

Recall the polysubstitution in FC alkylation.

22-22-77


Generalizations:• Directivity: Alkyl, phenyl, and all substituents in which

the atom bonded to the ring has an unshared pair of electrons are ortho-para directing. All other substituents are meta directing.

• Activation: All ortho-para directing groups except the halogens are activating toward further substitution. The halogens are weakly deactivating.

22-22-88

Di- and Polysubstitution. ExampleDi- and Polysubstitution. Example

• The order of steps is important.

CH3

K2Cr2O7

H2SO4

HNO3

H2SO4

CH3

NO2

COOH

H2SO4

HNO3

K2Cr2O7

H2SO4

COOH

NO2

COOH

NO2

m-Nitrobenzoicacid

p-Nitrobenzoic acid

Note the key point: transformation of o,p director into m director.

o,p

m

o,p

m

22-22-99

Theory of Directing EffectsTheory of Directing Effects

The rate of EAS is limited by the slowest step in the reaction.

For almost every EAS, the rate-determining step is attack of E+ on the aromatic ring to give a resonance-stabilized cation intermediate.

The more stable this cation intermediate, the faster the rate-determining step and the faster the overall reaction.

22-22-1010


The orientation of the subsitution is controlled by the stability of the carbocation being formed by attack of the electrophile. Different carbocations formed depending on position of substitution.

Products are formed under kinetic control. In some cases, equilibrium can be established leading to different products. (FC alkylation)

22-22-1111


• -OCH3 is directing: assume ortho-para attack. Here only para attack is shown.

OCH3

NO2+

fast

+

(d) (e) (f)

OCH3

H NO2

OCH3

H NO2

OCH3

H NO2

OCH3

H NO2

OCH3

NO2

-H+

+

slow

+

+

+

(g)

::::

: : :

Very stable resonance structure. Why?

22-22-1212


• -OCH3 is directing; assume meta attack.OCH3

NO2+

OCH3

NO2

H

OCH3

NO2

H

OCH3

NO2

H

slow

fast-H+

+

OCH3

NO2+

++

(a) (b) (c)

No corresponding very stable resonance structure. o, p preferred!

22-22-1313


• -CO2H is directing; assume meta attack.

COOH

NO2+

COOH

H

NO2

COOH

H

NO2

COOH

H

NO2

-H+

COOH

NO2

+ slow

fast

(a) (b) (c)

22-22-1414


• -CO2H is directing: assume ortho-para attack.

COOH

NO2+

COOH

H NO2

COOH

H NO2

COOH

H NO2

-H+

COOH

NO2

+ slow

fast

(d) (e) (f)The most disfavoredcontributing structure

22-22-1515

Activating-Deactivating (Resonance)Activating-Deactivating (Resonance)

Any resonance effectAny resonance effect, such as that of -NH2, -OH, and -OR, that delocalizes the positive charge on the cation has an activating effect toward further EAS.

Any resonance effectAny resonance effect, such as that of -NO2, -CN, -C=O, and -SO3H, that decreases electron density on the ring deactivates the ring toward further EAS.

Next inductive

22-22-1616

Activating-Deactivating (Inductive Effects)Activating-Deactivating (Inductive Effects)

Any inductive effectAny inductive effect, such as that of -CH3 or other alkyl group, that releases electron density toward the ring activates the ring toward further EAS.

Any inductive effectAny inductive effect, such as that of halogen, -NR3

+, -CCl3, or -CF3, that decreases electron density on the ring deactivates the ring toward further EAS.

22-22-1717

Activating-Deactivating (halogens)Activating-Deactivating (halogens)

• For the halogens, the inductive and resonance effects run counter to each other, but the former is somewhat stronger.

• The net effect is that halogens are deactivating but ortho-para directing.

++

+E

HClCl Cl

H

EE

+

::

:: :: ::

22-22-1818

Nucleophilic Aromatic SubstitutionNucleophilic Aromatic Substitution

Aryl halides do not undergo nucleophilic substitution by either SN1 or SN2 pathways.

They do undergo nucleophilic substitutions, but

by two mechanisms quite different from those of nucleophilic aliphatic substitution.• Nucleophilic aromatic substitutions are far less

common than electrophilic aromatic substitutions.

22-22-1919

Benzyne Intermediates (strong base)Benzyne Intermediates (strong base)

When heated under pressure with aqueous NaOH, chlorobenzene is converted to sodium phenoxide.• Neutralization with HCl gives phenol.

Cl

2NaOHH2O

O-Na

+

NaCl H2O

Sodium phenoxide

Chloro-benzene

++pressure, 300oC

+

Halogen reactivity: I > Br > Cl > F

22-22-2020

Benzyne Intermediates (strong base) Benzyne Intermediates (strong base)

• The same reaction with 2-chlorotoluene gives ortho- and meta-cresol.

• The same type of reaction can be brought about using sodium amide in liquid ammonia. mixture (!)

3-Methylphenol(m-Cresol)

2-Methylphenol(o-Cresol)

+

CH3Cl OH

CH3 CH3

OH

1. NaOH, heat, pressure

2. HCl, H2O

CH3

Cl

NaNH2NH3(l)

CH3

NH2

CH3

NH2

NaCl

3-Methylaniline (m-Toluidine)

4-Methylaniline (p-Toluidine)

++(-33oC)

+

22-22-2121

Benzyne IntermediatesBenzyne Intermediates

• -elimination of HX gives a benzyne intermediate, that then adds the nucleophile to give products.

X

+ NaNH2-

H

X

+ NaNH3

NH2-

NH2 NH3NH2

22-22-2222


• -elimination of HX gives a benzyne intermediate, that then adds the nucleophile to give products.

H

CH3

Cl

NaNH2

CH3

A benzyneintermediate

-elimin-ation

22-22-2323


But wait, do we believe this crazy idea? We need some evidence….

Cl

* NaNH2

NH2

*

NH2

*+

47% 53%

Cl

CH3H3CO

NaNH2NR

A

B

22-22-2424


D

F

H

F

NaNH2

NH3

but

D

Br

D

NH2

NaNH2

NH3

NH2rapid

slow

+

H

NH2NH2

D

+

C

next

The deuterated fluoride below exchanges the D with solvent ammonia although the deuterated bromide does not. This indicates a relatively rapid exchange process for the fluoro compound.

22-22-2525


X

+ NH2-

H

X

k1

k-1

X

k2

+ NH3

X = F k-1 >> k2

X = Br k-1 << k2

explanation

22-22-2626


D

OCH3

Br

OCH3

NH2

and

OCH3OCH3

NH2

Br

NaNH2

NaNH2

Get same product Explation

next

22-22-2727


OCH3

Br

OCH3

Br

NaNH2

NaNH2

H

OCH3

Br

only H to remove

preferred due to inductive effect

OCH3

Br

H

OCH3

NH2-

OCH3

NH2-

OCH3

NH2

preferred due to inductive effect

explanation

22-22-2828

Addition-Elimination (Addition-Elimination (nitro nitro groups)groups)

• When an aryl halide contains electron-withdrawing NO2 groups ortho and/or para to X, nucleophilic aromatic substitution takes place readily.

• Neutralization with HCl gives the phenol.

ClNO2

NO2

Na2CO3, H2O

O- Na

+

NO2

NO2

100oC

Sodium 2,4-dinitro- phenoxide

1-Chloro-2,4-dinitrobenzene

22-22-2929

Meisenheimer ComplexMeisenheimer Complex

• Reaction involves formation of reactive intermediate called a Meisenheimer complex.

N Cl

NO2

O

O

Nu-

Cl

NuN

O

ONO2

N

O

O

NO2

Nu :Cl -fast

slow, ratedetermining

++

+ + +

A Meisenheimer complex

(1)

(2)

Similar to nucleophilic subsititution on carboxylic acid derivatives.

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22-1 Di- and Polysubstitution Orientation on nitration of monosubstituted benzenes.

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