The fluorous solid-phase extraction (FSPE) process is a very robust and general process. It’s utility and applicability have been demonstrated over a range of substrates and molecular classes. One of the great things is the ease of operation. One wash to remove non-fluorous components and then a wash to elute the fluorous portion. A great demonstration of this is the fluorous dye experiment. FTI has made a mixture of two dyes, a blue non-fluorous dye and an orange fluorous tagged dye, which are easily separated by FSPE as seen below. It’s a great little demonstration. However, when you’re making a library or fluorous tagging a substrate, your molecules of interest are not generally visible. In that case you’re more or less trusting that the FSPE will work as advertised. Thankfully, in the vast majority of cases that trust is well-founded and the FSPE will perform as advertised as evidenced by the number of papers that have been published by independent labs all over the world. Sometimes, though, there are cases where the fluorous components are a little harder to get elute, primarily highly basic materials which can interact with some of the free silanols on fluorous silica gel. Using an acidic or basic buffer usually solves that problem easily enough, but now you’ve gone off the reservation a little and it would be nice to be able to see what was going on.
Dr. Christopher Blackburn at Millennium Parmaceuticals has just published a Technology Note in ACS Combinatorial Chemistry to address this issue. Essentially he made a tag, pictured above, which contains three principal components; a) a fluorous domain, b) an azo dye, and c) a reactive functional group, in this instance an aldehyde. The concept for the molecule is quite similar to what Lo reported using fluorous rhenium complexes although the application is different. He was then able to tag amines through a reductive amination and purify the tagged compound by FSPE. Due to presence of the dye, he was also able to follow the FSPE process visually. He then demonstrated the utility of the tag in two applications; one a solution phase peptide synthesis and the other in sulfonamide synthesis. The tag was then easily cleaved using TFA to provide the desired products after FSPE.
At FTI, we actually have received more than one request for a visual fluorous tag such as this one, but we’ve never developed one. One of the reasons is that to develop a whole suite of visible tags which would encompass all the possible ones that people would want was always considered a daunting task. Another reason is that the FSPE is really quite a robust process so how much value would it really add? A tough question to answer. Finally, the azo tag does put some additional constraints on the fluorous tag. Dr. Blackburn notes that unlike most fluorous tag, the added dye makes the compound insoluble in MeOH, CH2Cl2, and CH3CN. It took some heating in THF to get it into solution. The dye portion also adds some functionality, and therefore reactivity, that limits some of the chemical compatibility. These issues certainly takes away from some of the appeal of fluorous chemistry.
Even with the caveats above, a visible fluorous tag could certainly have it’s place in certain applications and it’ll be interesting to see what the response to the Note is.