I dare you to find an issue of Organic Letters in the past five years that doesn’t have an example of ruthenium-catalyzed olefin ring closing metathesis. Chances are that most of the examples are run in CH2Cl2 at a concentration of <0.1 M. And they probably work pretty well. If you ask any of the authors, they’d tell you that CH2Cl2 is a good solvent because it’s polar (to promote phosphine dissociation) but non-coordinating (to allow for olefin binding), and that the reactions need to be run dilute to cut down on intermolecular reactions. While there’s a good deal of truth to these statements, “dilute in DCM” isn’t always the best way to go, and is rarely a requirement.
In general, the phosphine-bound ruthenium precatalysts initiate faster in polar solvents than in non-polar solvents (Grubbs, J. Am. Chem. Soc. 2001, 123, 6543). Fast initiation is good, but it isn’t everything. For a given application, just about any solvent on the following list could be the best. And this is by no means comprehensive. Keep your eyes (and mind) open to the literature.
|Avoid if Possible
|pentane, hexane, etc.||MeOH, iPrOH, etc.||acetonitrile|
|benzene, toluene, etc.||acetone||DMSO|
|TBME||Et2O, THF, etc.||DMF|
|CH2Cl2, ClCH2CH2Cl, PhCl, etc.||neutral/acidic water||pyridine|
|EtOAc, HOAc, iPrOAc, etc.||free amines|
Ring Closing Metathesis – Consider ring strain, substituted pattern (acyclic conformation), and entropy. The easier the ring is to form, the more concentrated you can run your reaction. All things being equal, higher dilution will favor intramolecular reactions. But in metathesis as in life, things are never equal. Diluting a reaction will slow the rate, meaning you’ll need to increase your catalyst loading and/or temperature, each of which can lead to more side reactions. Each reaction has a different set of optimal conditions, but as a rule of thumb:
Small rings (5 & 6): >0.5 M
Medium rings (7-9): ~0.5 M
Large rings (10+): higher dilution as ring size increases
Cross Metathesis – In cross metathesis reactions, you want to favor intermolecular reactions. And unless you have a strained olefin in your system, the reactions are thermoneutral, so you don’t have to worry about an exotherm. This makes for the perfect scenario to run reactions neat. If you’re lucky enough to have liquid substrates that will dissolve your catalyst (it helps to pre-dissolve the catalyst in a small amount of solvent prior to addition), go for it! If not, try to run the reaction as concentrated as possible.