Benign by Design - American Chemical Society

Chapter 11 Nucleophilic Aromatic Substitution for Hydrogen New Halide-Free Routes for Production of Aromatic Amines

Downloaded by UNIV ILLINOIS URBANA on August 29, 2013 | http://pubs.acs.org Publication Date: November 18, 1994 | doi: 10.1021/bk-1994-0577.ch011

Michael K. Stern Monsanto Company, 800 North Lindbergh Boulevard, St. Louis, MO 63167

The development of environmentally favorable routes for the production of commercially relevant chemical intermediates and products is an area of considerable interest to the chemical processing industry. These synthetic routes will ideally focus on elimination of waste at the source and will require, in most cases, the discovery of new atomically efficient chemical reactions. In light of these emerging requirements, we have focused our attention on nucleophilic aromatic substitution for hydrogen (NASH) reactions as a means to generate aromatic amines without the need for halogenated materials or intermediates. Two new routes based on NASH reactions are described for the manufacturing of 4-aminodiphenylamine (4-ADPA) and 4-nitroaniline (PNA) which illustrate the concept of alternate chemical design. In addition, mechanistic studies into the oxidation of the critical σ-complex intermediates are presented.

One of the oldest practiced industrial chemical reactions is the activation of benzene by chlorination (Figure 1). The resulting chlorobenzenes can be further activated towards nucleophilic aromatic substitution by nitration producing a mixture of ortho and para-nitrochlorobenzene (PNCB), 1. These intermediates are employed in a variety of commercial processes for production of substituted aromatic amines. For instance, in the simplest case when PNCB is reacted with ammonia, the corresponding nitroanilines are produced. Since neither chlorine atom ultimately resides in the final product, the ratio of pounds of by-products produced per pound of product generated is highly unfavorable. In addition, these processes typically generate aqueous waste streams which contain high levels of inorganic salts that are difficult and expensive to treat. By contrast, a more direct and atomically efficient route for the production of aromatic amines would be to eliminate the need for halogenation of benzene. This can be achieved by a class of reaction illustrated in Figure 2 which is known as 0097-6156/94/0577-0133$08.00/0 © 1994 American Chemical Society

In Benign by Design; Anastas, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1994.

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CI

I

+ C I

J

+ HCI

2


ÇI

NH

+

N0

NH

~

3

Il

1 N0

2

2

+

NH

4CI

2

PNCB

Figure 1. Production of aromatic amines from chlorobenzene.

Nu: + - ^ - N 0 H

2

—

u>Çy="C " 0

Nu-2H20 in DMSO revealed a single broad absorbance with a λ =494 nm which is indicative of the deprotonated form of the nitroaromatic amines (4). Thus, it was concluded that the primary products of this reaction are not 4-NODPA, 4, or 4-NDPA, 2, but rather their tetramethylammonium salts, 7, and, 8, respectively. Our investigations revealed that the amount of water present, the ratio of aniline to nitrobenzene, and whether the reaction was conducted in the presence or absence of 0 had a critical effect on selectivity and overall yield of this reaction. The effect that varying the aniline:nitrobenzene ratio (AN/NB) has on product distributions is summarized in Table I. These results clearly demonstrate that as AN/NB is increased, the yield of 7 increases at the expense of 8. That water has a profound effect on product yield and selectivity was demonstrated by a series of reactions that contained varying amounts of protic material. Thus, as the amount of water was increased in the reaction, the conversion of nitrobenzene decreased dramatically. However, increasing the amount of water also resulted in reactions which displayed a higher degree of selectivity to the desired ΜΑΧ

2


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para-substituted products (Figure 4). Accordingly, it was clear that the proper control of water would be critical if high yields and selectivity of the desired products were to be achieved. The effect that 0 has on the reaction was illustrated by a series of reactions run at various temperatures under aerobic conditions. The results of these studies are summarized in Table Π. 2


Table I: Effect of Aniline/Nitrobenzene Mole Ratio on Product Distribution

Mole Ratio Aniline/Nitrobenzene

7

% of Total 8

1.32 11.9 51.5

15 55 86

80 35 9

Table II: Effect of Temperature on Yield and Selectivity Under Aerobic Conditions

Temp. °C 23 50 80

% Conversion Nitrobenzene 4-NODPA 73 98 100

51 86 89

% Yields* 4-NDPA Azobenzene 8.5 7.6 7.0

Phenazine

12 21 55

trace 1.6 2.0

'Yields based on Moles nitrobenzene charged.

The conversion of nitrobenzene to 4-NODPA and 4-NDPA increased with temperature. However, the molar yield of azobezene also increased with rising temperature indicating that under aerobic conditions there must be an oxgyen dependant route for the production of azobenzene that does not consume nitrobenzene. That azobenzene was formed by two separate pathways in the presence and absence of 0 was confirmed by a series of deuterium labeling experiments. When aniline-d was used as solvent and the reaction was conducted in the absence of 0 , 4-NODPA-d , 4-NDPA-d and azobenzene-^ were observed. However, when the identical reaction was conducted in the presence of 0 a significant amount of azobenzene-d was produced indicating that under aerobic conditions the predominant route for the formation of azobezene is via the oxidative coupling of aniline (5). A mechanism consistent with these experimental observations is shown in Figure 5. Deprotonation of aniline generates the anilide ion which is required for 2

5

2

5

5

2

10


11.

STERN

c ο

Nucleophilic Aromatic Substitution for Hydrogen

'55

40

φ > c ο

30 Η

ο

Φ

c φ

Γ 12

Ί

11

h ίο r ^> 20 Η

Φ


Ν

c φ η ο

Conversion Selectivity *

Η8 en 7

10

3

4

6

% Water

Figure 4. Effect of water on nitrobenzene conversion and reaction selectivity. •Selectivity is defined as the ratio of para substituted products to ortho substituted products.

Figure 5. Proposed mechanism for the reaction of aniline and nitrobenzene.


137

138

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NH

N0

2

N

O

2

=

0 = % .

-HoO 1

+ t^l

•TMA

+ TMA(OH) 0

rvn-Q-f,: ' s

W

\-f

H Catalyst


2

TMA(OH) + H 0 + ^ ^ - N - ^ ^ - N H 2

2

3 4-ADPA

Figure 6. New route to 4-aminodiphenylamine based on NASH reaction.

-NHo

-NOo

PNA

PPD

Figure 7. Commercially important aromatic amines.

C H ° N H

+ 2

70°C Anaerobic

Ο ^

Ν

0

Ζ

S

(°

IVENT)

1) TMA(OH) 2) -H 0 2

OMX* OK) 12

13

98%

33%

+

O-TMA

Figure 8. NASH reaction between benzamide and nitrobenzene.


+


11. STERN


139

nucleophilic attack on nitrobenzene forming the σ-complex 9 (6). We interpret the inhibitory effect of water to resultfromits effect on the equilibrium between aniline and anilide. Formal oxidation of 9 can occur by two separate pathways: 1) an intramolecular redox process with the nitro group of 9 functioning as the oxidizing agent generating 2 and 7; 2) an intermolecular pathway with free nitrobenzene functioning as the oxidant producing nitrosobenzene, 8 and 10. Nitrosobenzene is not directly observed since it will condense with aniline under the reaction conditions to produce azobenzene. In either pathway, a nitro group is formally reduced to a nitroso moiety by the hydride leaving group. The small amount of phenazine observed results from ortho attack on nitrobenzene followed by a similar intramolecular oxidation andringclosure. Furthermore, the observation that equal molar amounts of 8 and azobenzene 5 are produced is consistent with this mechanism. Understanding the mechanism of the coupling reaction and, in particular, the oxidation of 9 was critical in moving this technology out of the laboratory and into a pilot plant facility. This reaction forms the basis for a new process which could be used to manufacture 4-ADPA (Figure 6). This route will generate approximately 0.07 pounds of waste per pound of 4-ADPA produced with the complete elimination of inorganic salt waste streams. The major by-product of this process is distilled water. These numbers can be put into perspective when compared to the waste generated by the current processes which typically falls in the range of 1 to 1.5 pounds per pound 4-APDA produced. Accordingly the new technology based on NASH reactions is an attractive and environmentally favorable alternative for the commercial production of 4-APDA. An Alternate Route to p-Nitroaniline and /?-PhenyIenediamine Another commercially important pair of aromatic amines are /?-nitroaniline (PNA) and its derivative p-phenylenediamine (PPD) which are shown in Figure 7. PNA is currently produced at Monsanto by the reaction of ammonia with PNCB, as described above, and can be catalytically hydrogenated to PPD. Recently a new example of NASH chemistry directly applicable to the production of PNA and PPD was discovered (7 ). We have shown that the reaction of benzamide, ll^ and excess nitrobenzene in the presence of base under anaerobic conditions generated the tetramethylammonium salt of N-(4-nitrophenyl)- benzamide, 1^ in 98% yield under mild conditions (7). The only other observable product in this reaction was azoxybenzene, ϋ which was formed in 33% yield based on benzamide charged (Figure 8). That azoxybenzene is observed as a by-product of this reaction under anaerobic conditions indicates that nitrobenzene is functioning as the primary oxidant in this system. This was confirmed by the analysis of the reaction mixture by EPR spectroscopy which revealed that nitrobenzene radical anion was also formed during the course of the reaction as evident by its distinct 54 line pattern (#). A mechanism which explains the simultaneous formation of 12 and 13 is shown in Figure 9. Intermolecular oxidation of σ-complex 14 by nitrobenzene generates 12 and initially nitrobenzene radical anion, 15, which can decompose by a variety of pathways including disproportionation to give nitrosobenzene (9). The



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Figure 9. Proposed mechanism for the reaction of benzamide and nitrobenzene under anaerobic conditions.

Figure 10. Proposed mechanism for the reaction of benzamide and nitrobenzene under aerobic conditions.


11. STERN


141

ultimate formation of azoxybenzene is then governed by a cascade of electron transfer and nucleophilic reactions between the radical anions of nitrobenzene, nitrosobenzene and N-hydroxyaniline, all of which can be directly accessed in the reaction mixture by the reduction of nitrobenzene to various extents (10). The overall stoichiometry required by this mechanism (equation 1) is consistent with the observed yields of 12 and 13.


N0

2

+ TMA(OH)

• 13 + 1/312 + 2 hfeO

(1)

In contrast to the case where aniline is used as the nucleophile, the benzamide reaction can be improved by utilizing dioxygen in the reaction mixture since 11 is résistent to autoxidation. Under aerobic conditions the nitrobenzene radical anion is readily trapped by 0 generating superoxide and nitrobenzene (Figure 10) (//). This reaction pathway inhibits the formation of azoxybenzene by diverting the electron transfer cascade and ultimately utilizing dioxygen as the terminal oxidant. Thus, under aerobic reaction conditions 12 is the only observed reaction product. The ability to prepare 12 in high yield and regioselectivity affords a novel route for the preparation of PNA and its derivative PPD (Figure 11). The addition of water to 12 results in protonation of the amide nitrogen producing 16 and regenerating TMA(OH). Subsequent reaction of 16 with ammonia cleaves the amide bond generating PNA which can be hydrogenated to PPD under catalytic conditions. It is important to note that this route would be catalytic in TMA(OH) and also allows for the recycling of the amide nucleophile. Accordingly, the overall stoichiometry for this series of reactions illustrates the formal amination of nitrobenzene with ammonia. The formation of substituted anilides from the reaction of amides with nitrobenzene is the first example of the direct formation of aromatic amide bonds via nucleophilic aromatic substitution for hydrogen. This reaction proceeds in high yield and regioselectivity, and does not require the use of halogenated materials or auxiliary leaving groups. Furthermore, these studies have demonstrated that the use of 0 as the terminal oxidant in NASH reactions can result in a highly selective and environmentally favorable route for the production of PNA and PPD. 2

2

Conclusion Two examples of nucleophilic aromatic substitution for hydrogen reactions were describedfromwhich we have proposed two new atomically efficient processes for the manufacturing of commercially relevant aromatic amines. Our mechanistic studies have revealed that the direct oxidation of σ-complex intermediates by either nitro groups or 0 can eliminate the need for chlorination of benzene as a starting point for the manufacturing of aromatic amines. Accordingly, these reactions demonstrate the key objective of alternate chemical design which is not to make the waste in the first place. 2



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Figure 11. New route to PNA and PPD based on NASH reaction.


11. STERN


143

Acknowledgments The author would like to thank Dr. Fred Hileman and Mr. Brian Cheng for their contributions to this work. Literature Cited 1. Wohl, A. Chem. Ber. 1903, 36, 4235.


2. Terrier, F. In Organic Nitro Chemistry Series; Feuer, H., Ed.; VCH

Publishers, Inc.: New York, NY, 1991 and references therein. 3. Stern, M. K.; Hileman, F. D.; Bashkin, J. K. J. Am. Chem. Soc. 1992, 114, 9237-9238. 4. Langford, C. H.; Burwell, R. L., Jr. J. Am. Chem. Soc. 1960, 82, 1503. 5. Jeon, S.; Sawyer, D.T. Inorg. Chem. 1990, 29, 4612-4615. 6. Buncel, E., In Supplement F : The Chemistry of Amino, Nitroso, and Nitro

Compounds and Their Derivatives; Patai, S., Ed.; Wiley: London, 1982; Part 2, Chapter 27. 7. Stern, M.K.; Cheng, Β. K. J. Org. Chem. 1993, 58, 6883-6888. 8. Geske, D. H.; Maki, A. H. J. Am. Chem. Soc. 1960, 82, 2671-2676. 9. Russel, G. Α.; Janzen, E. G.; Strom, Ε. T. J. Am. Chem. Soc. 1964, 86, 1807-1814. 10. Russel, G. Α.; Janzen, E. G. J. Am. Chem. Soc. 1962, 84, 4153-4154. 11. Guthrie, R. D.; Nutter, D. E. J. Am. Chem. Soc. 1982, 104, 7478-7482. R E C E I V E D August 4, 1994


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