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
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
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
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