The Grubbs catalyst and all of its brothers and sisters are tolerant of most organic functional groups, but there are some bad actors to avoid…
Strong Lewis bases can coordinate to the catalyst and de-activate it. Try to avoid (or protect) phosphines, thiols/sulfides, basic unhindered amines, pyridines, ureas, isonitriles, etc. The easiest way to protect amines and phosphines is to simply add acids. An amine hydrochloride usually works just fine. Just make sure you have a little excess HCl around, because it only takes a catalytic amount of amine to tie up your catalyst.
Mild Lewis bases can be problematic if they’re in the wrong place, even if they’re not particularly strong. If a heteroatom is proximal to one of your olefins so that it can form a chelating ligand on ruthenium, it can slow catalyst turnover way down. Especially bad are 5-membered chelates, similar to the Hoveyda-Grubbs catalysts. This effect is worse for stronger Lewis acids, so if you suspect this issue, try a protecting group or surrogate that’s a worse Lewis base.
amides are pretty Lewis-basic on carbonyl (thats why DMF is such a great solvent). I remember that people who did metathesis on molecules with amide bonds complained about the deactivation – they needed to heat alot to get turnover and then they had catalyst decomposition problem under these conditions. I wonder if some suitable Lewis acid like BF3 etherate or perhaps a lithium salt added in stoechiometric quantity could take care of this problem. Do you know if some Lewis acids are compatible with Ru metathesis catalysts?
If doing metathesis on an amine salt, what would a good solvent compatible with a Grubbs carbene be? (presumably the salt is insoluble in DCM, etc…)
I suppose a TFA salt should be fairly soluble in DCM. Also you can do a greasy non-coordinating salt like hexafluorophosphate or tetrafluoroborate. Even damned camphorsulphonates are quite soluble in organics – depending on the amine.
A thing like solubility is hard to generalize, but in my experience, HCl salts are soluble (or at least soluble enough) in DCM to allow for reaction.
thanks alot,
i may be trying bis- and tris-TFA salts. Just wondering; are there any relatively polar solvents/solvent mixtures that are compatible with Grubbs carbene that I am unaware of and used at least semi-regularly? (I have honestly never ventured outside of DCM/DCE/PhMe)
Milkshake (nice blog):
(I have personally not had any problem with amides), amines are typically nightmarish-though compatible with Schrock apparently)
as for the Lewis acids:
i have had mild success with LiCl. But my favorite is Ti(OiPr)4. Results varied widely based on my substrate, but catalyst activity was no longer the problem. I know the Ti acid has been used to disrupt stable chelates in the lit (4-pentenoate-derived dienes, etc) but it seems to work to occupy all sorts of electron-rich metathesis suppressors.
other functional groups I have had trouble with using Grubbs carbene:
N-allyl (sometimes gets ripped off-and isomerization suppressors idnt work for me)
vinyl ethers (e-rich alkene; need Schrock)
Are phenols tolerated in a cross-metathesis reaction or do they have to be protected? For example will 2-allylphenol react in a cross metathesis reaction efficiently? Any suggestions and or references would be great. Thanks.
I have had some success closing a second ring of a bicyclic oxamazins (Org. Lett. 2013, 15, 358), but haven’t had success when trying to do a cross-metathesis on an oxamazin substrate that cannot undergo RCM. I thought that perhaps the carbonyl of the b-lactam and the oxygen of the oxamazin (N-O bond) could chelate to the Ru so I tried to use Lewis acids like Ti(iOPr)4 first to try and prevent the chelation of the Ru. However, this was also unsuccessful. Are there any other suggestions on what I might try to do to get the cross-metathesis to work?
Kyle, other Lewis acids might do the trick (for examples with boron Lewis acids see Synlett 2005, 4, 670). But if RCM works and CM doesn’t it might be an issue of effective concentration. I’d try running the reaction as concentrated as possible, which would mean going to a solvent like toluene and heating it as well.
Hi, I was wondering what makes Ruthenium tolerant to functional groups compared to Molybdenum and Tungsten.. Any help is greatly appreciated.
R3,
I don’t have a good response, other than to say it’s an inherent characteristic that we are using to our advantage!
Hey, I am currently working on the ethenolysis of renewable resources with a Grubbs 1 Generation Catalyst (M101) and have a very high selectivity for my desired product ,but my main problem is the rapid decomposition of the catalyst in the presence of ethylene. Is there any easy solution to prevent/inhibit the decomposition and extend the lifetime or regenerate?