Effect of Temperature on Olefin Metathesis Reactions

As is the case with many chemical reactions, temperature can be both friend and foe.  Heating a reaction will invariably make it go faster, but can also increase the rate of side reactions and decomposition. For ruthenium catalyzed olefin metathesis reactions, choosing the right temperature for a reaction invariably comes down to trial and error. But there are a few rules of thumb that can limit your trials (and more importantly, your errors!) before you find the sweet spot.

Best Temperature for a Reaction

• Don’t heat reactions unless you need to. The lower the temperature, the longer your catalyst will survive. Particularly nasty metathesis catalyst decomposition products are ruthenium hydrides, which can be excellent olefin isomerization catalysts.
• Situations when you need some heat
  • To overcome an entropic barrier. This is often the case when forming large rings.
  • To compensate for dilution. People run RCM reactions dilute to avoid intermolecular reactions. Dilution will slow your rate way down, so you may need to compensate.
  • If the reaction just won’t go. If nothing’s happening at low temperature, heat it up. Sometimes you just need heat for strained rings or hindered olefins.

The choice of reaction temperature depends a lot on the catalyst used for the reaction. The 2^nd generation Piers catalyst will start turning over even at -50 °C. Most other Grubbs-type 2^nd generation catalysts will initiate at room temperature or at 0 °C. Some catalysts require higher temperature to initiate.

Running reactions at lower temperature can be beneficial for the yields of the reaction due to the generation of fewer impurities. (E)-5-decenyl acetate, the major component of the peach twig borer pheromone, was prepared by cross metathesis at 5 °C yielding the desired product with less than 0.1% double bond migrated impurities (this reaction is an equilibrium and the maximum yield is 50%). When the reaction was run at a higher temperature, a considerably larger amount of impurities was formed (Adv. Synth. Catal. 2002, 344, 728).

It was found by the Danishefsky group that increasing the temperature can improve yields of RCM macrocyclization reactions (Tetrahedron Lett. 2003, 44, 3297, see also J. Am. Chem. Soc. 2007, 129, 1024). Running the reactions in refluxing toluene increased the yields of the desired macrocyclic products from ~30% to 55%. Similarly, researchers at Boehringer Ingelheim showed that macrocyclization at elevated temperatures was preferred (Org. Lett. 2008, 10, 1303). Using Grela’s nitro-Hoveyda-Grubbs catalyst, higher reaction temperatures allowed for both a lower catalyst loading and a higher yield!

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