Choosing the Best Metathesis Catalyst for a Reaction

I decide to run an organometallic coupling reaction. I go to the literature to see what conditions people have used for similar transformations, and I’m overwhelmed. Every paper I see uses a different combination of precatalyst, ligand, additive(s), and solvent.  Which is best? Are they different for a reason, or is it a matter of taste?

Fortunately this isn’t a big problem in ruthenium catalyzed olefin metathesis reactions – there just aren’t that many variables to play around with. But one of the biggest questions remains, “which is the best catalyst to use for my reaction?” Chemistry is still an experimental science, and that’s not changing any time soon. The only real way to know what’s best is to try everything, but with proper planning, you can hopefully get there sooner rather than later.

Where to start?
There are exceptions to these rules, but in general,

1. If a 1^st generation catalyst can do it, a 2^nd generation catalyst can do it.
2. If a phosphine catalyst can do it, a Hoveyda catalyst can do it

Therefore a good starting point for most metathesis reactions is the 2^nd Generation Hoveyda-Grubbs catalyst. It usually works when others work, and sometimes works when others fail. Unfortunately, it’s also one of the more expensive catalysts out there, so you’ll want to optimize from there.

1^st Gen vs. 2^nd Gen?
2^nd Generation catalysts will almost always give you more turnovers in your reactions. The 1^st generation catalysts have a few things going for them, though.

1. They’re easier to make/cheaper. Even though the overall cost for a reaction with a 1^st generation catalyst is often more expensive than with a 2^nd Gen. (because of need for higher catalyst loadings), it’s always worth a shot to use the cheap catalyst and see if it works!
2. They’re less reactive. Sometimes this is a good thing. 1^st Generation catalysts can be selective in reactions if you want to avoid side reactions with hindered or electron-poor olefins (Grubbs JACS, 2003, 11360-11370).

Do you have temperature limitations?
In general, the ruthenium metathesis catalysts are designed to be used at or around room temperature. If, for one reason or another, you need to run a metathesis reaction cold (<0 °C), you’ll have to go with one of the fast-initiating catalysts, like the bisbromopyridine or Piers catalyst shown below.

Is your substrate extra hindered?
If you’re trying to make a tetrasubstituted olefin by ring closing metathesis or a hindered di-substituted olefin by cross- or ring closing metathesis, you’ll need a 2^nd generation catalyst, and you want the most space around the ruthenium atom as possible. The N-phenyl catalysts shown below (an alkyl-substituted NHC backbone is required for stability) is a good example of this.  The commercially available o-tolyl catalysts serve the same purpose but are easier to prepare.

There are lots of substrates out there, and each one has its subtleties so it’s hard to generalize too much. But here are a few more special cases where one catalyst (or class of catalysts) outperforms: 

• Acrylonitrile Cross Metathesis. The Grubbs catalyst-acrylonitrile adduct (think of Grubbs catalyst with a cyano on the alkylidene instead of a phenyl) is slow to initiate. Likely due to a combination of sterics and electronics, it means that once phosphine traps the active intermediate, it deactivates it. The way to solve this problem is either to a) use a phosphine-free catalyst, such as a Hoveyda or bisbromopyridine catalyst, or b) use a Lewis acid additive to sequester phosphine, keeping it from causing trouble. Both methods have been used successfully for this challenging transformation.
• Low Polydispersity Polymers. In order to effect a controlled living polymerization, you need a catalyst which has a rate of initiation faster than the rate of propagation. Typically, people will use the bisbromopyridine catalyst shown above (more recently, reports are surfacing of the bromine-free bispyridine ruthenium complex being used for this).
• Cross Metathesis to make Trisubstituted Olefins. A singular report from the Grubbs group in 2008 showed that cross metathesis to make trisubstituted olefins is more efficient with catalysts containing bulkier carbene ligands (structure shown below, first reported by Ken Wagener). They rationalize the counterintuitive data by arguing that the less hindered catalysts are more apt to undergo non-productive turnover events. I encourage you to read the arguments from the source (Grubbs Org. Lett. 2008, 441-444).

I’m sure there are other classes of substrates where one catalyst shines. What am I missing?

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