For those who were wondering, my copper reactions the other day worked out just fine. They started out a beautiful blue (copper iodide and an amino acid in straight DMSO – if that’s not blue it’s maybe going to be green, and if it’s not either one you’ve done something wrong). Of course, the color doesn’t stay. The copper ends up as part of a purple-brown sludge that has to be filtered out of the mix, which is the main downside of those Ullman reactions, no matter how people try to scrub them up for polite company.
And DMSO is the other downside, because you have to wash that stuff out with a lot of water. That’s one of the lab solvents that everyone has heard of, even if they slept through high school chemistry. But it’s not one that we use for reactions very much, because it’s something of a pain. It dissolves most everything, which is a good quality, but along with that one comes the ability to contaminate most everything. If your product is pretty greasy and nonpolar, you can partition the reaction between water and some more organic solvent (ether’s what I used this time), and wash it around a lot. But if your product is really polar, you could be in for a long afternoon.
That mighty solvation is something you need to look out for if you spill the stuff on yourself, of course. DMSO is famous for skin penetration (no, I have no idea if it does anything for arthritis). And while many of my compounds are not very physiologically active, I’d rather not dose myself with them to check those numbers. At the extreme end of the scale, a solution of cyanide in DMSO is potentially very dangerous stuff indeed. I’ve done cyanide reactions like that, many times, but always while paying attention to the task at hand.
Where DMSO really gets used is in the compound repository. That dissolves-everything property is handy when you have a few hundred thousand compounds to handle. The standard method for some years has been to keep compounds in the freezer in some defined concentration in DMSO – the solvent freezes easily, down around where water does (Not so! Actually, I've seen in freeze in a chilly lab a couple of times, now that I'm reminded of that in the comments to this post. Pure DMSO solidifies around 17 to 19 C, which is about 64 F C - a bit lower with those screening compounds dissolved in it, though).
But there are problems. For one thing, DMSO isn’t inert. That’s another reason it doesn’t get as much use as a lab solvent; there are many reaction conditions during which it wouldn’t be able to resist joining the party. You can oxidize things by leaving them in DMSO open to air, which isn’t what you want to do to the compound screening collection, so the folks there do as much handling under nitrogen as they can. Compounds sitting carelessly in DMSO tend to turn yellow, which is on the way to red, which is on the way to brown, and there are no pure brown wonder drugs.
Another difficulty is that love for water. Open DMSO containers will pull water in right out of the air, and a few careless freeze/thaw cycles with a screening plate will not only blow your carefully worked out concentrations, it may well also start crashing your compounds out of solution. The less polar ones will start decided that pure DMSO is one thing, but 50/50 DMSO/water is quite another. So not only do you want to work under nitrogen, if you can, but dry nitrogen, and you want to make sure that those plates are sealed up well while they’re in the freezer. (As an alternative, you can go ahead and put water in from the start, taking the consequences). All of these concerns begin to wear down the advantages of DMSO as a universal solvent, but not quite enough to keep people from using it.
And what about the compounds that don’t dissolve in the stuff? Well, it’s a pretty safe bet that a small molecule that can’t go into DMSO is going to have a mighty hard time becoming a drug, and it’s a very unattractive lead to start from, too. That’s the sort of molecule that would tend to just go right through the digestive tract without even noticing that there are things trying to get it into solution. And as for something given i.v., well, if you can’t get it to go into straight DMSO, what are the chances you’re going to get it into some kind of saline injection solution? Or the chances that it won’t crash out in the vein for an instant embolism? No, the zone of non-DMSO-soluble small organics is not a good place to hunt. We’ll leave proteins out of it, but if anyone knows of a small molecule drug that can’t go into DMSO, I’d like to hear about it. Taxol, maybe?
1. HelicalZz on May 20, 2008 8:39 AM writes...
It's not invisible biologically either. Chemists need to make sure the molecular / cell biologists are controlling for constant DMSO concentration with their dilutions. An assay in 1% or 0.1% DMSO doesn't mean 1% or 0.1% DMSO or less.
And while I may be soluble at 10 mM, stop asking me if I'm soluble at 300mM.
As for the DMSO insoluble small molecules - well amino acids, dipeptides and some other similar zwitterionic compounds can be annoying in DMSO - of course that's something of a non-issue since they do tend to be soluble in buffered aqueous solutions.
Zz
Permalink to Comment2. milkshake on May 20, 2008 9:01 AM writes...
Very greasy hydrocarbon-like stuff will have a lousy DMSO solubility. I know of alkylphosphocholine drugs that will not dissolve in DMSO, like Ilmophosine and Edelphosine. They are not widely-used though because of their severe tox problem. (They were originally developed for cancer but now are tested against parasitical tropical diseases.)
DMSO on skin gives you bad breath temporarily because dimethyl sulfide is what you exhale. Otherwise it is pretty non-toxic stuff as solvents go. The anti-inflammatory metabolite responsible for DMSO arthritis relief is dimethyl sulfone. But it is only symtomatic treatment and common stuff like ipubrufen works much better anyway, without the bad breath.
For removing DMSO (and DMAc, etc) I have a rotovap hooked up to oil pump, and I would strip the react mix down below 1 Torr, then remove the leftover DMSO by aqueous extraction. It works fine but its something I try to avoid if there is an alternative solvent.
Permalink to Comment3. Diyne on May 20, 2008 9:10 AM writes...
Itraconazole is poorly soluble in DMSO.
Permalink to Comment4. Nick K on May 20, 2008 9:40 AM writes...
One easy way of losing DMSO from an organic solvent in a workup is to wash with saturated brine. This is much more effective than washing with water, and works even with dichloromethane, which otherwise carries DMSO with it from the aqueous phase.
Permalink to Comment5. eugene on May 20, 2008 10:27 AM writes...
I'm pretty sure the freezing point of DMSO is 18 degrees, so a lot higher than water. Even a normal fridge would do. I use deuterated DMSO, which I suppose has a slightly higher freezing point, and it's regularly a solid. This backs up my assertion to the facilities people that it is too cold in my lab, despite them saying that everything is working properly and the air conditioning system is very 'modern'.
Permalink to Comment6. Jordan on May 20, 2008 12:11 PM writes...
DMSO is fairly non-toxic, as Milkshake says, but I worry about its ability to bring molecules into the bloodstream trans-dermally. In grad school I worked a lot with 0.5 M sodium azide in DMSO -- it scared the crap out of me.
Permalink to Comment7. CMC guy on May 20, 2008 2:44 PM writes...
Although toxicology favorable in process world DMSO usage is rather rare, for the removal reasons cited (dilution factor means big volume handling) although have seen applied as a rinse solvent for cleaning studies since universal dissolution power.
I believe a few places may use DMF for compound collections but it too suffers from non-inertness and handling issues (yet DMF does get used occasionally in scale up).
Unless it is an analog I thought Taxol was soluble in 100% DMSO (moderate to high?) but crashes out with water mixtures and nothing suitable for injections anyway. Most formulations people I know swear at the mention of cremophor that is part of the Taxol formulation.
Permalink to Comment8. Peter Madrid on May 20, 2008 2:45 PM writes...
We actually had a project where we put together a set of all FDA-approved drugs into screening plates and I was rather surprised by the number of compounds that would not dissolve in DMSO at 10 millimolar. Some interesting examples of compounds that do not dissolve in DMSO at that concentration are: chloroquine diphosphate, ciprofloxacin (some of the other fluoroquinolines as well) and drugs with quaternary amines. I previously had the same thought as you: "If it doesn't even dissolve in DMSO, it is not worth my time", but perhaps this is not always true!
Permalink to Comment9. MetMatt on May 20, 2008 3:17 PM writes...
Another reference for the utility of DMSO is its identified by the Breslow group at Columbia as a hit/"inspiration" for HDAC inhibitors. Probably an interesting story here where the DMSO control wasn't really a control.
Permalink to Comment10. Norepi on May 20, 2008 7:56 PM writes...
Odd. I generally never having a problem washing DMSO out of anything, as my molecules tend to partition into organic solvents really well.
I can get a fair numbers of compounds to dissolve in 1:4 water:DMSO mixtures pretty easily.
And I've also had some total brickdust. I've always wondered how some drugs are bioavailable at all (ie, tamoxifen, anything used to inhibit topoisomerases)
No. 9- I remember that story; Breslow gave a talk at some conference I went to a few years back.
Permalink to Comment11. Dennis on May 20, 2008 8:39 PM writes...
How much cyanide would you need to dissolve in lets say 10 mL of DMSO to kill you?
Permalink to Comment12. milkshake on May 20, 2008 11:30 PM writes...
You can die from about 50mg of HCN if it gets into the bloodstream rapidly, for example by inhaling it. So I suppose several hundred migs of NaCN transdermally can make you pretty sick - but that means you would have to put several mL of the DMSO solution over yourself and not notice your skin getting all warm and slick...
I think a bigger problem would be TMS-CN because it works without a co-solvent. There was a non-lethal case of a guy found unconscious hanging in sleeves of a glovebox - he knocked over a bottle of TMS-N3 and the cleanup took awhile and meanwhile the stuff soaked through the rubber gloves.
Permalink to Comment13. Ubin on May 21, 2008 6:09 AM writes...
Derek thank you so very much for this blog. I've been meaning to say this for awhile; It has become a huge part of gradschool for me; put on a three hour reaction -> read in the pipeline for three hours :) Very much educational too you are doing a great service to medchem students!
Nothing really to contribute to the on going discussion but ~5 months ago (when I was a summer student surprise surprise) I was distilling some DMSO; horrible stuff to distill with it's insane boiling point so one naturally needs a vaccum; and I was quite new to all this so I managed to connect the vacuum pump the wrong way and created a high pressure envrionment inside the distillation chamber instead of the desired vacuum. I was quite “lucky” in that one of the joints very quickly gave way and sent the thermometer flying into the fume hood. No mercury spillage but broken thermometer :( Taught me a good lesson; always check your connections before you turn on the vacuum!
Permalink to Comment14. Anonymous BMS Researcher on May 22, 2008 5:35 AM writes...
DMSO and other vehicles we regularly use for pre-clinical testing also tend to have major effects on stuff like lipid metabolism, so we always end up comparing the effects of our drug with vehicle-treated controls instead of with un-treated controls. I sometimes push for including both untreated controls and DMSO-treated controls so we can do a better job at figuring out which effects are about the DMSO. This is especially an issue when working with liver cells, which for toxicogenomics we often do.
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