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57. Electroreductive Pd-catalysed Ullmann Reactions in Ionic Liquids Laura Durán Pachón and Gadi Rothenberg* Van ’t Hoff Institute for Molecular Sciences, University of Amsterdam, Nieuwe Achtergracht 166, 1018 WV Amsterdam, The Netherlands. *[email protected] Abstract A catalytic alternative to the Ullmann reaction is presented, based on reductive homocoupling catalysed by palladium nanoparticles. The particles are generated in situ in an electrochemical cell, and electrons are used to close the catalytic cycle and provide the motivating force for the reaction. This system gives good yields using iodo- and bromoaryls, and requires only electricity and water. Using an ionic liquid solvent combines the advantages of excellent conductivity and cluster stabilising. Introduction Symmetrical biaryls are important intermediates for synthesising agrochemicals, pharmaceuticals and natural products (1). One of the simplest protocols to make them is the Ullmann reaction (2), the thermal homocoupling of aryl chlorides in the presence of copper iodide. This reaction, though over a century old, it still used today. It has two main disadvantages, however: First, it uses stoichiometric amounts of copper and generates stoichiometric amounts of CuI2 waste (Figure 1, left). Second, it only works with aryl iodides. This is a problem because chemicals react by their molarity, but are quantified by their mass. One tonne of iodobenzene, for example, contains 620 kg of ‘iodo’ and only 380 kg of ‘benzene’. In the past five years, we showed that heterogeneous Pd/C can catalyse Ullmann-type reactions of aryl iodides, bromides, and chlorides. Two reaction pathways are possible: Reductive coupling, where Pd2+ is generated and reduced back to Pd0, and oxidative coupling, which starts with Pd2+ and needs an oxidising agent. Different reagents can be used for closing the reductive coupling cycle, including HCO2– (3), H2 gas (4), Zn/H2O (5), and alcohols (6). The two pathways can even be joined, giving a tandem system that converges on one product (7). All of these examples, however, require an extra chemical reagent. In this short communication, we present a different approach, using electrochemistry to close the catalytic cycle (Figure 1, right).

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Electroreductive catalytic Ullmann reactions

X

I 2

+ Cu

Δ

+ CuI2

2

+ 2e–

+ 2X–

catalyst

Figure 1 Ullmann reaction (left) and electrochemical catalytic alternative (right). Results and Discussion In a typical experiment, the aryl halide was stirred in a specially constructed electrochemical cell (Figure 2, left) containing Pd and Pt electrodes, using the ionic liquid [octylmethylimidazolium]+[BF4]– as a solvent (8). This solvent combines two important advantages: It is an excellent conductor and it can stabilise metal nanoparticles via an ion bilayer mechanism (9). The electrolysis was done using a constant current intensity of 10 mA at 1.6 V (cf. E0 = –0.83 V for Pd0 → Pd2+ + 2e– ).

Pd anode

Pt cathode

[C8mim]+[BF4]–

solvent

Pt anode

Pd cathode

[C8mim]+[BF4]–

solvent

Figure 2 Photo of the electrochemical cell (left) and schematics showing the generation of Pd clusters using a Pd anode (middle) and the reverse case (right). Using PhI as the substrate, the reaction mixture turned from a light yellow solution to a dark brown suspension after 20 min. However, no conversion was observed by GC analysis. We assumed that Pd2+ ions, oxidised from the anode, were in turn reduced to adatoms at the Pt cathode and formed Pd0 nanoparticles. After 8 h, the PhI was totally consumed, giving 80% biphenyl and 20% benzene. Weighing the electrodes before and after the reaction showed difference of ~ 2.5 mg in the Pd anode, equivalent to 0.1 mol% of the aryl halide substrate. This corresponds to a TON of 1000 at least (assuming that all the ‘missing’ Pd participates in the catalysis). To further investigate the role of palladium nanoparticles in this system, we switched the current between the two electrodes, so that now the Pd electrode was the cathode (Figure 2, right). The rationale behind this experiment was that in theory, the coupling reaction could occur on the cathode surface. Electron transfer from a

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Pd0 atom on the cathode surface to PhI would give a [PhI]–• radical anion, that would then dissociate to Ph• and I– (10). The constant supply of electrons to the cathode would ensure the electron transfer. However, we did not observe any reaction in this case (nor were any Pd nanoparticles formed). Thus, we conclude that palladium nanoparticles are necessary for catalysing the homocoupling of aryl halides. Table 1 Ullmann homocoupling of various haloaryls.a Entry

Aryl halide

Biaryl product

Conversion (%)b

Yield (%)b

TONc

Time (h)

99

80

816

8

99

82

811

8

99

75

701

14

74

61

540

20

80

65

550

24

5

4

32

24

I

1 NO2

I

2 O2N O 2N

Br

3 NO2

Br

4 O2N O2 N

OCH3

Br

5 H3CO H3CO

NO2

Cl

6 O2N O2 N

a

Reaction conditions: 20 mmol aryl halide, 50 mL [omim]+[BF4]–, 25 ºC. Based on GC analysis, corrected for the presence of an internal standard. c Based on the difference in weight in the Pd anode before and after the reaction. b

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We then tested several other iodo-, bromo- and chloroaryl substrates. Table 1 shows the conversions, yields and corresponding turnover number (TON). PhI and PhBr gave biphenyl in good yields, and the p-nitrophenyls were also active. The corresponding p-nitrophenylchloride was much less active. An interesting question is what closes here the catalytic cycle? Although we do not have a full mechanistic picture at this stage, we think that the complementary half-reaction of the oxidation of the aryl halide is the oxidation of water, i.e. 2H2O → O2 + 4H+ + 4e– (E0 = –1.229 V). Ionic liquids are notoriously hygroscopic, and a small water impurity is enough to close the cycle. Indeed, control experiments in the presence of 1 molar equivalent of water gave a faster reaction (complete conversion after 6 h, cf. with 8 h for the ‘dry’ system). No difference was found when excess water was added. In summary, palladium nanoparticles generated in situ catalyse Ullmann-type reaction. Using electrochemistry is a simple and efficient way to perform this catalytic reductive homocoupling, and the reaction gives good yields with aryl bromides and iodides. To the best of our knowledge, this is the first electro-reductive palladium-catalysed demonstration of a Ullmann reaction (11). Moreover, this reaction proceeds smoothly at room temperature. Further work in our laboratory will include kinetic and mechanistic studies to gain further understanding into this interesting system. Experimental Section Materials and instrumentation. Experiments were performed using a special home-made cell coupled to a dual current supply with a maximum output of 10 V/40 mA. A detailed technical description is published elsewhere (12). 1H NMR spectra were recorded on a Varian Mercury vx300 instrument at 25 °C. GC analysis was performed on an Interscience GC-8000 gas chromatograph with a 100% dimethylpolysiloxane capillary column (DB-1, 30 m × 0.325 mm). GC conditions: isotherm at 105 ºC (2 min); ramp at 30 ºC min–1 to 280 ºC; isotherm at 280 ºC (5 min). Pentadecane was used as internal standard. The ionic liquid [omim]+[BF4]– was prepared following a published procedure and dried prior to use (8).All other chemicals were purchased from commercial sources (> 98% pure). Procedure for Pd clusters-catalysed Ullmann homocoupling. Example: biphenyl from PhI. The electrochemical cell was charged with PhI (4.09 gr, 20.0 mmol) and 50 mL [omim][BF4]. After stirring 5 min, a constant current (10 mA, 1.6 V) was applied and the mixture was further stirred for 8 h at 25 ºC. Reaction progress was monitored by GC. After 8 h, the product was extracted with ether (3 × 50 mL). The ether phases were combined and evaporated under vacuum to give 1.12 g (75 mol% based on PhI) as a colourless crystalline solid. The solvent can be recycled by washing with aqueous NaBF4. δH (ppm, Me4Si): 7.36–7.42 (m, 2H), 7.45–7.51 (m, 4H), 7.62–7.68 (m, 4H). Good agreement was found with the literature values (13).

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Acknowledgements We thank B. van Groen and P. F. Collignon for excellent technical assistance and Dr. F. Hartl for discussions. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

G. Bringmann, R. Walter and R. Weirich, Angew. Chem. Int. Ed., 29, 977 (1990). F. Ullmann, Ber. dtsch. chem. Ges., 36, 2359 (1903). S. Mukhopadhyay, G. Rothenberg, D. Gitis, H. Wiener and Y. Sasson, J. Chem. Soc., Perkin Trans. 2, 2481 (1999). S. Mukhopadhyay, G. Rothenberg, H. Wiener and Y. Sasson, Tetrahedron, 55, 14763 (1999). S. Mukhopadhyay, G. Rothenberg, D. Gitis and Y. Sasson, Org. Lett., 2, 211 (2000). D. Gitis, S. Mukhopadhyay, G. Rothenberg and Y. Sasson, Org. Process Res. Dev., 7, 109 (2003). S. Mukhopadhyay, G. Rothenberg, D. Gitis and Y. Sasson, J. Org. Chem., 65, 3107 (2000). J. D. Holbrey and K. R. Seddon, J. Chem. Soc., Dalton Trans., 2133 (1999). For an overview on ionic liquids as solvents see M. J. Earle and K. R. Seddon, Pure Appl. Chem., 72, 1391 (2000). Aryl halides are effective electron acceptors in electron-transfer reactions with various donors. See T. T. Tsou and J. K. Kochi, J. Am. Chem. Soc., 101, 6319 (1979). In 2003, a process using Mg electrodes in perchlorate electrolytes was reported. See D. Kweon, Y. Jang and H. Kim, Bull. Kor. Chem. Soc., 24, 1049 (2003). L. Durán Pachón, M. B. Thathagar, F. Hartl and G. Rothenberg, Phys. Chem. Chem. Phys., DOI: 10.1039/b513587g (2005). V. Calo, A. Nacci, A. Monopoli and F. Montingelli, J. Org. Chem., 70, 6040 (2005).

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