45433-AC1
Development of Coupling Reactions Catalysed by Ultra-Low Concentrations of Metal Catalysts Using Microwave Heating
The academic year 2007 / 2008 is the second year of our Type AC project. We have spent the year building on our previous work on the grant directed at low catalyst loading coupling reactions using microwave heating. In the area of C-C bond forming reactions we have focused mainly on use of gaseous reagents in conjunction with microwave heating. In the previous year we developed a methodology for the hydroxy and alkoxycarbonylation of aryl iodides using small quantities of palladium catalysts. This year we have continued to develop the chemistry with an eye to scale. and have managed to scale the reaction up to the mole level using near-stoichiometric loadings of carbon monoxide gas, making it safer and easier than conventional processes. In the area of Heck coupling chemistry we have focused attention on the use of ethene as a coupling partner. Our interest in this comes from the observation that there are very few reports on the use of ethene as a substrate in Heck couplings. This is despite the fact that it is the simplest alkene coupling partner that could be imagined in a Heck reaction. Also, the styrene and stilbene products formed have a rich variety of chemical and biological properties. The reason behind the scarcity of reports using ethene as a reagent in the Heck reaction is that it is fraught with difficulties. The main problem is over-reaction with the aryl halide coupling partner to give the symmetric stilbene product rather than the monosubstituted alkene. It is therefore necessary to control precisely the amount of gas used; this usually implying a complex experimental set-up. Another problem is that under the high temperature / long reaction time conditions often used, polymerization of the desired monosubstituted alkene product can occur. During this year working on the grant we have overcome these problems and developed a selective one-pot two step protocol for the preparation of non-symmetric substituted stilbenes. One criticism leveled at microwave heating is that it is not an energy efficient technology for working on large scales given that the magnetron which generates the microwaves is not particularly efficient in turning electrical energy into microwave energy. To probe this in detail we have looked at the scale-up of a range of reactions from the mmol to the mole level and recorded the power consumed in each run. We have then correlated the power consumed with the product yield obtained to give us a metric for the energy efficiency of the process (moles of product formed per kilowatt hour consumed). We find that as we scale up the reactions, they become significantly more energy efficient, contrary to what has been speculated previously. This shows that microwave heating is indeed a versatile tool for fast, easy and efficient scale up of reactions. We have also turned attention to improving our screening methods for developing new reaction methodologies for low-level metal-catalyzed couplings. We have taken two approaches. A SUMR student has focused attention on the use of in-situ reaction monitoring as a tool for optimizing reactions. His work involved using an apparatus recently built by us for following reactions in a microwave unit while they run by using Raman spectroscopy. In an alternative approach, the graduate student working on the grant has focused attention on performing reactions in a parallel format, this enabling us to screen a range of catalysts, bases, solvents and substrates in one run. We have used specially made silicon carbide plates to perform up to 48 reactions at a time in one of our larger scientific microwave units. Silicon carbide heats very rapidly in a microwave field so using plates capable of holding 24 reaction vessels, each in separate wells, we are able to heat all of our reaction mixtures to the same temperature rapidly and efficiently. Using this approach we have probed the effect of different catalysts on the low-loading Suzuki coupling of aryl chloride substrates. This work is still in progress Over the last two months we have returned to the area of carbonylation chemistry and reaction scale-up. In the case of the former we have some promising results in the area of multicomponent chemistry. We have performed some initial trials on reactions to yield cyclopentenones, a very valuable class of organic compounds. We believe it will be possible to develop a fast, easy methodology to these compounds using low loadings of cheap cobalt catalysts rather than, as is often used, stoichiometric quantities of expensive cobalt carbonyl compounds. In the scale-up area we have the opportunity to trial our chemistry on a prototype of a batch microwave reactor in the Spring of 2009. Both these pieces of chemistry, together with the reaction monitoring and the parallel synthesis are areas we are keen to pursue with the no-cost extension of our PRF grant if allowed.
