Sonogashira coupling of iodoanilines: Evidence for the absence of non-thermal effects during microwave heating

Máté Erdélyi^1,2, Adolf Gogoll¹

1, Dept. of Organic Chemistry, Uppsala University, Sweden

2, Dept. of Organic Pharmaceutical Chemistry, Uppsala University, Sweden

E-mail: mate@kemi.uu.se, adolf@kemi.uu.se Fax.: +46-18-512524

Introduction

Today, microwave heating is closely associated with high-speed reactions in organic chemistry. The cause of the advantages¹ of microwave promoted reactions have been discussed since the first reports on the use of microwaves appeared in the literature.² In the beginnings, the existence of “non-thermal microwave effects” was proposed,³ later on theoretical⁴ and kinetic studies⁵ have forced these statements to be reinterpreted. However, there is still rather few experimental evidence for the absence of non-thermal effects in the literature. When microwave heating is applied the reaction conditions are in many aspects different (high pressure, super heating, hot-spots in case of multimode reactors) from conventional conditions and the reactions applying conventional respective microwave heating are therefore rarely comparable.

Here, we present an experimental comparison of Sonogashira couplings using microwave and conventional heating, as well as demonstrate the importance of superheating in synthetic organic chemistry.

Experimental

2-, 3- and 4-Iodoaniline were allowed to react with trimethylsilyl acetylene in the presence of Pd(PPh₃)₂Cl₂ and CuI catalysts using a large excess of diethylamine and dimethylformamide as solvent. All reactions were conducted under nitrogen gas atmosphere in heavy-walled glass Smith Process Vials sealed with aluminum crimp caps fitted with a silicon septum. The reaction mixtures were stirred with a magnetic stir bar during the irradiation respective the wall heat-transfer. Microwave heating was performed at 120°C in a Smith Synthesizer^TM single mode microwave cavity producing continuous irradiation at 2450 MHz. The temperature, pressure and irradiation power were monitored during the course of the reaction (Figure 1). The average pressure during the reactions was 3-4 bar. Conventional heating was performed in an oil bath kept at 120°C.

Figure 1: Temperature, pressure and irradiation power monitored during microwave-assisted preparation.


		Conventional heating⁷		Microwave heating⁷	Literature⁶
	Iodoaniline	5 h, 20°C	5 min, 120°C	5 min, 120°C	18-20 h, 25°C

1		98%	98%	98%	96%
2		99%	99%	99%	72%
3		97%	97%	98%	90%

Table 1: The Sonogashira coupling of iodoanilines with trimethylsilylacetylene.

Discussion

The Sonogashira coupling of iodoanilines was achieved in excellent yields within considerably shorter time than earlier published in the literature.⁶ The coupling reaction was optimized⁷ regarding the type of catalyst (Pd₂(dba)₃, Pd₃(AcO)₆, Pd(PPh₃)₂Cl₂ or Pd(PPh₃)₄, CuI) and their amount (0 -7%), the solvent (THF or DMF), as well as temperature (60-240°C) and reaction time (2 min –16 h). Excellent yields were obtained at room temperature within 5 hours and at elevated temperature (120°C) within 5 minutes using either a conventional oil-bath or microwaves as heat source. The shorter reaction time at 120°C is a combined result of higher reaction rate at high temperature and of superheating when reactions are run in sealed vials. According to the theory (Arrhenius equation), the reaction rate increases ~1000 times for a 100°C rise of temperature. This effect is reinforced by superheating the mixture in a sealed vial under pressure, i.e., allowing the heating of mixtures above their boiling point (at atmospheric pressure), and simultaneously retaining volatile reagents (trimethylsilyl acetylene, diethylamine) in the system.

Conclusion

The way of energy transfer is different when conventional wall heat transfer (primarily conduction and convection) as compared to internal heating, i.e., microwave heating (dipolar polarization and ionic conduction) is used. However, obtaining the same yields by these two heating methods indicates that identical thermal and pressure effects cause the increase in reaction rate of the Sonogashira couplings, compared to the experiments performed at room temperature.

Acknowledgement

We would like to thank Personal Chemistry AB for access to the Smith Synthesizer^TM and the referees of our publication on Sonogashira coupling reactions using microwave heating for suggesting the experiments with conventional heating.

References

1. Larhed, M.; Hallberg, A. Drug Discovery Today, 2001, 6, 406.

2. (a) Gedye, R. N.; Smith, F.; Westaway, K.; Ali, H., Baldisera, L.; Laberge, L.; Rousell, J. Tetrahedron Lett. 1986, 27, 279. (b) Giguere, R. J.; Bray, T. L.; Duncan, S. M.; Majetich, G. Tetrahedron Lett. 1986, 27, 4945.

3. (a) Sun, W.C.; Guy, P. M.; Jahngen, J. H.; Rossomando, E. F.; Jahngen, E. G. E. J. Org. Chem. 1988, 53, 4414. (b) Berlan, J.; Giboreau, P.; Lefeuvre, S.; Marchand, C. Tetrahedron Lett. 1991, 32, 2363.

4. Stuerga, D. A. C.; Gaillard, P. J. Microwave Power E. E. 1996, 31, 101.

5. (a) Caddick, S. Tetrahedron 1995, 51, 10403. (b) Strauss, C. R.; Trainor, R. W. Aust. J. Chem. 1995, 48, 1665.

6. Lavastre, O.; Cabioch, S.; Dixneuf, P. H. Tetrahedron 1997, 53, 7595.

7. Erdélyi, M.; Gogoll, A. J. Org. Chem. 2001, 66, 4165.