Ionic Liquids - American Chemical Society

Chapter 11

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Green Synthesis: Aromatic Nitrations in Room-Temperature Ionic Liquids Scott T . Handy and Cristina R. Egrie Department of Chemistry, State University of New Y o r k at Binghamton, Binghamton, N Y 13902

As one of the least environmentally compatible synthetic methods, aromatic nitration has attracted a great deal of effort in terms of the design of more benign techniques. Room temperature ionic liquids (RTILs) afford a useful new method for aromatic nitration by using a simple nitrating agent (nitric acid) with a transition metal catalyst. Distillation of the nitration products affords a solvent/catalyst system that can be readily recycled for at least 4 reactions.

Introduction Electrophilic aromatic substitution chemistry is of critical importance in a wide variety of industrial, fine chemical, and academic processes (7). While this chemistry is well developed and performed on the metric ton scale, it is also a prime example of how "black" synthesis can be. The majority of these aromatic substitution processes involve large amounts of moisture sensitive and toxic reagents and produce even greater quantities of highly acidic and/or

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water-reactive wastes. For example, most Friedel-Crafts acylation reactions involve the suprastoichiometric use of aluminum trichloride. (Figure 1) Upon work-up, this results i n the formation of large amounts of highly acidic aqueous waste from the hydrolysis of the aluminum "catalyst." Although this is the most cited example of the environmentally damaging aspects of electrophilic aromatic substitution chemistry, aromatic nitrations are no better. Aromatic nitration is typically catalyzed by the use of concentrated sulfuric acid i n conjunction with concentrated nitric acid. (Figure 1) Again, upon work-up this leaves an acidic aqueous waste layer that must be disposed.

Friedel-Crafts Acylation

2

0

CN

CN

Figure 1. Electrophilic Aromatic Substitution Reactions

Alternative Methods of Aromatic Nitration Given the problems associated with aromatic nitration reactions and the tremendous demand for materials of this type, considerable effort has been directed toward making this chemistry more environmentally compatible. While a number of alternatives to the use of sulfuric acid as the catalyst for aromatic nitrations have been developed (most notably various acidic zeolites (4\ metal-exchanged clays (5), or super-acidic polymers (d)), virtually all of these reaction conditions require either the use of exotic nitrating agents (particularly N 0 or nitronium salts) or the addition of acetic anhydride (for in 2

4


136


situ formation of the acyl nitrate). (Figure 2) Further, many of these reaction conditions are "solvent-free" - that is, the aromatic substrate serves as the solvent for the reaction. This is an ideal situation for bulk industrial nitrations of simple, inexpensive aromatics such as benzene or toluene. In the case of fine chemical or academic scale synthesis, "solvent free" conditions are not as practical. Many more functionalized aromatic compounds are not liquids, which necessitates the use of a reaction solvent. Further, complete separation of the nitration product from the solid acid catalyst generally requires some type of extraction, which reintroduces the problems associated with a volatile organic solvent.

90%HNO /Ac O 3

2

+

H Beta 30 min, >99% 87:13/?:0

90%ΗΝΟ /Α(^Ο 3

K-10, CC1 reflux, 12 h 81%, 67:2:3 \p\m:o 4

N

° 2

fuming H N Q Nafion-H reflux 80%, 40:4:56p:m:o

N

0

2

Figure 2. Alternative Nitration Methods

Nitrations with Nitric A c i d From either an industrial or environmental standpoint, the ideal nitration agent is commercial grade 70% aqueous nitric acid, which is inexpensive and generates water as the only waste product. To achieve this goal, a better method to activate nitric acid than the use of excess sulfuric acid is needed. A suitable method was reported a few years ago by Barrett and co-workers (7).



137 (Figure 3) In their communication, they reported the use of ytterbium inflate as a catalyst for the nitration of aromatic substrates using stoichiometric 70% nitric acid as the nitrating agent. A number of substrates could be effectively nitrated, including modestly deactivated systems such as bromobenzene. Further, the catalyst could be recovered from the water layer following aqueous work-up. After drying, the resulting solid could be used to catalyze further nitrations. Two practical issues limit the application of this method. First, the catalyst must be separated and dried before it can be reused. In particular, the drying phase of this recycling is time and energy intensive. Second, the reaction solvent, dichloroethane, is an environmental and safety hazard. Both of these issues are precisely the types of situations where room temperature ionic liquids (RTILs) can play an important and successful role in enhancing the environmentally friendly nature of a process.

HN0 Yb(OTf) (10mol%) 3

3

ce ccH ci 2

2

80°C, 12 h, 96%

N0

2

40%

50%

Figure 3. Aromatic Nitrations Using Nitric Acid

The Use of Room Temperature Ionic Liquids Prior to discussing the research efforts using RTILs in aromatic nitrations, it is necessary to briefly review what RTILs are and how they can be beneficial (8). RTILs are exactly what their name implies: salts that are liquid at or below room temperature. While there are a considerable number of materials that have been reported as members of this family, the majority can be characterized as being a combination of a large organic cation with a weakly coordinating anion. (Figure 4) By far and away the most popular RTIL to date is l-butyl-3-methylimidazolium tetrafluoroborate ( B M I M B F ) . This particular compound has been used as a solvent for a wide variety of organic reactions (8). More importantly, with this solvent there have been a number of examples of the ability to recycle both the solvent and a transition metal catalyst by simple extraction or décantation of the reaction product (9). 4


138


Cations

Anions

Figure 4. Major Classes of Room Temperature Ionic Liquids Based on this precedent, it would appear reasonable to use B M I M B F as a solvent for the aromatic nitration reaction. However, there is the possibility of nitrating the imidazolium ring as opposed to the aromatic reaction substrate. This is particularly a concern in the nitration of less electron rich (and hence less reactive) aromatic substrates. Indeed, during the course of our research, Laali and co-workers reported their study of the aromatic nitration reaction under a variety of conditions and in several RTILs (10). They did note that the imidazole ring of E M I M B F was nitrated by nitrating agents such as nitronium tetrafluoroborate. Their optimal solution to this issue was the use of a combination of ammonium nitrate and trifluoroacetic anhydride as the nitrating agent and ethyldiisopropylammonium trifluoroacetate as the solvent. By employing these conditions, they were able to effectively nitrate a variety of aromatic substrates. For example, under these conditions, toluene afforded a 58% yield of a 54:4:42 mixture of the ortho, meta, and para isomers after 1 hour at room temperature (Figure 5). 4

4

+

H N N0 7Ac 0 4

3

2

+

Et(iPr) NH F C0 " 2

3

N0

2

1 h, 58% 4% Figure 5. Laali's Nitration Conditions


9

139


Our efforts focused on the use of N-butyl, N-methylpyrrolidinium triflimide as the RTIL solvent (11). Both the cation and anion should be stable to the nitration conditions and thus could serve as a recyclable solvent system. As can be seen in Figure 6, the use of N-butyl, N-methylpyrrolidinium triflimide as the solvent with ytterbium triflate as the catalyst did afford the three nitrotoluene isomers in 95% yield. While the selectivity was not high, it was comparable to that observed under conventional conditions.

80°C, 12 h, 95% Figure 6. Aromatic Nitration of Toluene in a RTIL

Scope of Conditions Using the same reaction conditions, a number of aromatic substrates were successfully nitrated. (Table I) Using substrates that were as or more electronrich than benzene, good yields were obtained with regioselectivities typical of most nitration conditions. Importantly, anisole, a substrate that can undergo competitive oxidation in addition to nitration, afforded the desired nitration product in good yield (entry 2). However, substrates that were electron deficient, such as bromobenzene, did not undergo aromatic nitration under these conditions. In an effort to over come this limitation, the acyl nitrate was generated in situ using acetic anhydride or trifluoroacetic anhydride (12). With acetyl nitrate, very little reaction was observed (10% isolated yield of the product after 16 hours). However, by generating the trifluoroacetyl nitrate, bromonitrobenzene was isolated in 78% yield.


140

Table I. Ytterbium-Catalyzed Aromatic Nitrations Substrate

Product

3

Yield

0

Selectivity


Entry

3

a). All reactions performed on the 5 mmol scale using 1 equivalent of 70% aqueous nitric acid and 10 mol% of ytterbium inflate in 2 mL of ionic liquid at 80°C for 14-16 hours, b). Isolated yields, c). Determined by U NMR. d). 1-nitro : 2-nitro ratio, e). Reaction performed with 1 equivalent of acetic anhydride, f). Reaction performed with 1 equivalent of trifluoroacetic anhydride. l


141


Recycling A major issue is the ability of the solvent and catalyst to be recycled. Using toluene as the test case, the RTIL and ytterbium catalyst could be recycled several times following separation of the nitrotoluene products. (Figure 7) It is important to note that, while the products can be separated by extraction, they can also be readily distilled out of the reaction solvent, thereby completely eliminating organic solvent waste. In our research, we have been accomplishing this by removing all volatile components by Kugelrohr distillation. This crude distillate is then dried with magnesium sulfate and filtered to remove the water by-product. The resulting product(s) is at least 90% pure by N M R . Using fractional distillation, even the need for drying agents could be obviated.

HN0 Yb(OTf) (10mol%) 3

3

Bu Θ NTf

2

80°C, 14 h Run 1 2 3 4

Isolated Yield 95% 94% 95% 80%

Figure 7. Recycling Studies

Copper-catalyzed Nitrations Despite this initial success, there is a practical issue to consider - the catalyst. Although using the RTIL conditions, both reaction solvent and catalyst can be recycled, the initial expense of using ytterbium triflate (roughly $10/g) is prohibitive on anything above an exploratory scale. One solution is to employ lower catalyst loadings to ameliorate this situation. A second alternative is to use a less expensive catalyst. A lead in this direction can be


142 found in the area of water-tolerant Lewis acids. Lanthanide triflates have found considerable utility in this area, with scandium and ytterbium being the most active (13). However, copper triflate has been shown to have sufficient activity to catalyze many of these same reactions (e.g. Mannich and aldol condensations) in aqueous media (14). When coupled with the observation that copper and iron-exchanged clays are effective catalysts for aromatic nitration reactions (75), there is significant promise for this alternative. Additionally, copper triflate is less expensive ($3/g).


Results Based on this hypothesis, copper(II) triflate was employed as the catalyst for the aromatic nitration of toluene. (Figure 8) Using the same solvent and conditions, the three isomeric nitrotoluene products were obtained in a near quantitative yield following Kugelrohr distillation from the reaction medium and drying with magnesium sulfate. Trace, colored impurities were removed by filtration through a plug of Celite to afford the nitrotoluene product in 93% yield. It is worth noting that the isomeric mixture differed only slightly from that obtained using ytterbium triflate as the catalyst.

80°C, 16 h, 93% Figure 8. Copper-Catalyzed Reactions

Scope of Conditions Employing these copper-catalyzed reaction conditions, a number of additional aromatic substrates were successfully nitrated. (Table II) As was the case with ytterbium triflate, substrates that were moderately electron-rich were nitrated in good yield, with regioselectivities typical of most nitration conditions (entries 1-3). With more electron-rich substrates, though, a major



143 difference was noted (entries 2, 4, and 5). Addition of the nitric acid at room temperature to these electron rich substrates and copper(II) triflate resulted i n an extremely exothermic reaction. After 2 hours, the nitration products could be isolated i n good yield. This spontaneous reaction at room temperature was not noted with less electron rich substrates not was it noted with ytterbium triflate as the catalyst for any of the aromatic compounds. Finally, it should be noted that the regioselectivity of the nitration of the more electron rich substrates is reduced compared to the results obtained using ytterbium triflate. Electron deficient substrates, such as bromobenzene, did not undergo aromatic nitration under these conditions, but nitration could be accomplished by generation of the acyl nitrate in situ using acetic anhydride or trifluoroacetic anhydride. As with the ytterbium triflate-catalyzed reactions, acetic anhydride afforded only modest conversion (15%). However, by generating the trifluoroacetyl nitrate in situ, bromonitrobenzene was isolated in 87% yield.

Recycling As was the case with ytterbium triflate, the copper(II) triflate catalyst could be recycled after the reaction. Results from recycled catalyst/solvent were essentially the same regardless of whether distillative or extractive work-up conditions were employed. (Figure 9) Thus, on a small scale (1 mmol), extraction of the product with diethyl ether afforded the nitrotoluene isomers in

80°C, 14 h Run 1 2 3

Method of Separation Extraction Distillation 93% 94% 90% 92% 88% Figure 9. Recycling Studies


144 3

Table Π. Copper-Catalyzed Aromatic Nitrations Entry

Substrate

Product


1

MeCX

MeO

Yield*

Selectivity"

93%

NA

53%

2.4 : 1.0 (1,2,3:1,2,4)

90%

4.0 : 1.0 (1,2,4:1,2,3)

80%

3.0 :1.0 (para.Orthro)

91%

3.5 :1.0 (1 : 2-nitro)

96%

2.0: 1.0 (4:2-nitro)

87%*

1.3 : 1.0 (para.ortho)

v

Br-

a). All reactions performed on the 2.5 mmol scale using 1 equivalent of 70% aqueous nitric acid and 10 mol% of copper(H) triflate in 2 mL of ionic liquid at 80°C for 14-16 hours, b). Isolated yields, c). Determined by Ή NMR. d). Reaction performed at room temperature for 2 hours, e). Reaction performed with 1 equivalent of trifluoroacetic anhydride.


145 93, 90, and 88% yield over three runs, while on a larger scale (5 mmol), Kugelrohr distillation of the products afforded the same isomeric mixture in 94 and 92% yield over two runs. As such, it appears that either separatory method is compatible with recycling of the catalyst/solvent mixture.


Conclusion In conclusion, we have developed a method for the nitration of aromatic compounds that utilizes 70% aqueous nitric acid as the nitrogen source and employs the less expensive copper(II) triflate in place of ytterbium triflate. In combination with RTILs, the catalyst can be recycled several times. Further, the reaction products can be removed by distillation, thus completely eliminating the need for conventional organic solvents. Efforts are underway to extend these reaction conditions to other types of aromatic substitution reactions, in particular Friedel-Crafts acylation and alkylation reactions.

References 1. 2. 3. 4.

5.

6.

Taylor, R. "Electrophilic Aromatic Substitution." John Wiley and Sons: New York, 1990. Horning, E . C . , ed. "p- Chloroacetylacetanilide." Org. Synth. Coll. Vol. III, John Wiley and Sons, Inc.: New York, 1955, 183-184. Blatt, A . H . , ed. "o-Nitroaniline." Org. Synth. Coll. Vol. I, John Wiley and Sons, Inc.: New York, 1941, 388-289. For an example of nitrations using acidic zeolites, see: Smith, K . E . ; Musson, Α.; DeBoos, G . A . "Superior methodology for the nitration of simple aromatic compounds." Chem. Commun. 1996, 469-470. For an example of nitrations using exchanged clays, see: Cornells, Α.; Gerstmans, Α.; Laszlo, P. "Regioselective Liquid-phase Toluene Nitration with Modified Clays as Catalysts." Chem. Lett. 1988, 1839-1842. For an example of nitrations using acidic ion-exchange resins, see: Olah, G.A.; Malhotra, R.; Narang, S.C. "Aromatic Substitution. 43. Perfluorinated Resinsulfonic Acid Catalyzed Nitration of Aromatics." J. Org. Chem. 1978, 48, 4628-4630.


146 7.

8.


9.

10. 11.

12.

13.

14.

15.

Waller, F.J.; Barrett. A . G . M . ; Braddock, D . C . ; Ramprasad, D . "Lanthanide (III) Triflates as Recyclable Catalysts for Atom Economic Aromatic Nitration." Chem. Commun. 1997, 613-614. For a review of room temperature ionic liquids, see: Welton, T.; "RoomTemperature Ionic Liquids. Solvents for Synthesis and Catalysis." Chem. Rev. 2000, 100, 2071-2083 For a review of the use of transition-metal catalysts in room temperature ionic liquids, see: Wasserscheid, P.; Keim, W. "Ionic Liquids - New "Solutions for Transition Metal Catalysis." Angew. Chem. Int. Ed. 2000, 39, 3772-3789 Laali, K . K . ; Gettwert, V.J. "Electrophilic Nitration of Aromatics i n Ionic Liquids Solvents." J. Org. Chem. 2001, 66, 35-40. MacFarlane, D.R.; Meakin, P.; Sun, J.; Amini, N . ; Forsyth, M . "Pyrrolidinium Imides: A New Family of Molten Salts and Conductive Plastic Crystal Phases." J. Phys. Chem. Β 1999, 103, 4164-4170 For a recent study of the differences between various acyl nitrates generated in situ, see: Smith, K.; Gibbins, T.; Millar, R.W.; Claridge, R.P. " A Novel Method for the Nitration of Deactivated Aromatic Compounds." J. Chem. Soc., Perkins Trans. I 2000, 2753-2758. For a review, see: Kobayashi, S. "Rare-Earth-Metal Trifluoromethanesulfonates as Water-Tolerant Lewis-Acid Catalysts i n Organic-Synthesis." Synlett 1994, 689-701. Manabe, K . ; Kobayashi, S. "Effects of Metal Cations in Lewis AcidSurfactant Combined Catalyst-Mediated Aldol Reactions i n Water." Synlett 1999, 547-548. And references cited therein. For examples of this, see: Laszlo, P.; Vandormael, J. "Regioselective Nitration of Aromatic Hydrocarbons by Metallic Nitrates on the K10 Montmorillonite under Menke Conditions." Chem. Lett. 1988, 18431846. Cornelis, Α.; Laszlo, P.; Pennetreau, P. "Nitration of Estrone into 2-Nitroestrone by Clay-supported Ferric Nitrate." J. Org. Chem. 1983, 48, 4771-4472. A n d references cited therein.


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