Hello
I'm trying to develop an LC-MS system for small phosphorylated organics that are polar. Polarity rules out RP (k' are about 1.00 +/- 0.25), ion exchange is ruled out due to the MS, and the phosphates rule out normal/HILIC (not soluble in ACN). Being at my whits end, I was going to go for ion pairing. I was curious if this is possible at all? If so are there pitfalls that I should watch out for in terms of compatibility of reagents with MS. Thank you for any help offered.
Regards
Jim

You can use the small volatile ion pairing reagents, but they will suppress your signal depending on your ionization mode. Some examples: trifluoroacetic acid, heptafluorobutyric acid, triethylamine.

Never use the acid reagents in negative mode, and never use the basic reagents in positive mode. If you do, you'll see nothing but their characteristic ions. Even if you don't scan that low, they'll saturate the ionization process and suppress the ionization of your analytes.

TFA is used all the time in ESI positive for example, although you'll still get some ion suppression as opposed to using formic or acetic. I've found that there is less trouble when using APCI. The rule about not using TFA in negative and not using TEA in positive still seems to apply, but I've used TFA with APCI(-), and TEA with APCI(+), with no apparent suppression.

One other pitfall: Once you use these reagents, they will tend to hang around for a long time. If you use a column with TFA, you'll see 113 ion bleed off that column forever (if you try to use it in negative mode later). You can flush your LC pumps really well and reduce the background to a tolerable level, but you'll still see some background for a long time.

Here are some references that apply to small polar bases.

Gustavsson et. al., J. Chromatogr. A., 937(2001) 41-47


McCalley, J Chromatogr. A., 987(2003) 17-28

You can still do HILIC. The sample does not need to be soluble in ACN, as long as it is still soluble in ACN-water mixtures.

Anion exchange is also definitely an option. I'm not quite sure why you completely eliminated this option since its much more compatible with MS than ion pair is. In the first place, depending on the phosphonate in question it may be totally feasible to use a volatile buffer such as ammonium acetate or ammonium hydroxide. In addition, it is common practice to use anion exchange with nonvolatile eluents by making use of a suppressor device in between the separation column and the MS interface. The suppressor removes the eluent leaving only analyte which is then sent on to the MS. Dionex has a number of applications which had been demonstrated based on this principle and its likely that it would work for your compound as well. If you're interested in more specifics you can e-mail me directly.

You had a k of 1 on an RP packing in which solvent?

At what pH did you have a k of 1?