A Green Chemistry Module

Nucleophilic Aromatic Substitution

Presidential Green Chemistry Challenge Award Elimination of Chlorine in the Synthesis of 4-Aminodiphenylamine. A New Process Which Utilizes Nucleophilic Aromatic Substitution

for Hydrogen

LG

Nu

LG

NuNu

LGslow fast

RDS

Meisenheimer Complex Resonance Stabilized

ADDITION ELIMINATION

SNAr Mechanism - addition / elimination

CF3, CN, CHO, COR, COOH, Br, Cl, I Common Activating Groups for NAS

LG

Nu

LG

Nu Nu

LG

Resonance Stabilization of the Intermediate Anion [The Meisenheimer Complex]

LG

H B/Nu

H B/Nu H

Nu

ELIMINATION ADDITION

BENZYNE [Aryne]

LG

Benzyne Mechanism - elimination / addition

LG

HB/Nu

LG

BENZYNE

k1 k2

Step-wise formation of Benzyne

C

O

O

N H 3

C

O

O

N N

D i e l s / A l d e rO

O

B E N Z Y N E

Dienophile Diene A d d u c t

Evidence for the Benzyne Mechanism

Trapping in Diels/Alder Reaction

LGSubstituentSubstituent

BaseNo Reaction

Substrate Modification – absence of hydrogens

LG

H

Nu

Nu

Isotopic Labeling

SN1 Mechanism

N N

slow

NuNu

Aryl Cation

N2

RDS

SNR1 Mechanism

I

electron donor

I

I -

NH2-

NH2

I

NH2 I NH2I

Initiation

1

2

3

Chain

Propagation

Steps

Brown Chemistry Route to 4-ADPA

Cl 2

c a t a l y s t

Cl

HNO3

Cl

NO2

Cl

P N C B

E l e c t r o p h i l i c A r o ma t i c S u b s t i t u t i o n

NO2

Cl

NO2

N H

CO

H

K2CO3

N

H

NO2 KCl CO CO2

4-NDPA

H2 Catalyst

N

H

NH2

4-ADPA

Nucleophilic Aromatic Substitution

PNCB

various organics

Atom Economy of the Traditional Chemistry

Cl2

Cl

HNO3

Cl

NO2

Cl

NO230% 70%

N

H

CO

H

K2CO3N

H

NO2

H2

N

H

NH2

1

2 3

45

6

Reagent formula Reagent FW Utilized Atoms Wt Unutilized Atoms Wt

1 C6H6 78 6C ,4H 53 2 H 2

2 Cl2 70 ------------ 0 2 Cl 703 HNO3 63 1 N 14 1 H, 3 O 49

4 C7H7NO 121 6 C, 6 H, 1 N 92 1 C, 1 O, 1 H 29

5 K2CO3 98 ------------ 0 2 K, 1 C, 3 O 986 H2 2 2 H 2 -------------- 0

TOTAL 432 12C ,12H, 2N  161  2C ,4H, 2C ,2K, 7O 248

Brown Chemistry Nucleophilic Aromatic Substitution for Chlorine

Large amount of chlorinestoragehandling

Waste stream componentsinorganic saltsorganics

Large amounts of water consumed

Heavy metal catalyst

H

NO2

Nu:H Nu

NO O

H Nu

NO O

Nu

NO O

Nucleophilic Aromatic Substitution for Hydrogen

General Mechanism

NO2

H NH2

Base N

H

N

O

OH

Base-Promoted Coupling Reaction

Flexsys Route to 4-ADPA

Base-Promoted Coupling Reaction

N

H

N

O

O

N

H

NO N

H

NO2

N

H

NH2

simultaneous reactions

and

intramolecular intermolecular

H2 Catalyst

4-ADPA

4-NODPA 4-NDPA

Flexsys - Anaerobic Oxidation to 4-NDPA

Flexsys - Intermolecular Oxidation Pathway

Atom Economy of the Flexsys Chemistry

HNO3

NO2 NHH

N NO2

H

H2

N NH2

H

1

2

3

4

Reagent Formula Reagent FW Utilized Atoms Wt Unutilized Atoms Wt

1 C6H6 78 6 C, 4 H 76 2 H 2

2 HNO3 63 1 N 14 1 H, 3 O 49

3 C6H7N 93 6 C, 6 H, N 92 1 H 1

4 H2 2 2 H 2 ----------- 0

TOTAL 236  12C, 12 h, 2 n 184  4H, 3O  52

Green Chemistry Advantages for Nucleophilic Aromatic Substitution for Hydrogen

Reduction in chemical waste generation

elimination of

74% of organic waste

99% of inorganic waste

Eliminates use of chlorine

Reduction in waste water

more than 97% savings

Eliminates use of xylene

a SARA chemical

Improves process safety

lower reaction temperatures