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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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June 6, 2011

Underused Lab Solvents

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Posted by Derek

Interesting post from Milkshake over at Org Prep Daily on solvents that don't get used as much as they might in synthetic chemistry. Among them: trifluoroethanol, methyl t-butyl ether, and 1-methoxy-2-propanol. Definitely worth a look for those of us who are trying to get things to work at the bench - other nominations welcomed in the comments.

And if you're looking for someone to do that, I believe that Milkshake himself is still looking for a position (unpaid advertisement!)

Comments (46) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. Anonalso on June 6, 2011 9:48 AM writes...

Trifluoroethanol is a wonderful solvent I use all the time. Spike DCM with 5% and you can extract anything out of water!

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2. Chemjobber on June 6, 2011 9:49 AM writes...

If there's someone who deserves that advertisement more than milkshake, I don't know who it might be...

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3. Toad on June 6, 2011 10:16 AM writes...

I can also vouch for trying trifluoroethanol when it makes sense. Works great as a solvolysis solvent.

Anonalso,
Excellent tip. How does your DCM/TFE conditions compare to CHCl3/MeOH?

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4. processchemist on June 6, 2011 10:28 AM writes...

2-meTHF: not cheap, but absolutely wonderful and not only because of his immiscibility with water: the use of an asymmetric ether can influence the diastereoisomeric ratio in grignard or other alkyl metal additions; far better than THF in LAH and borane reductions. It resolved some serious problems at our shop.

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5. MTK on June 6, 2011 10:32 AM writes...

When I was doing process chemistry, TBME was great. A safer alternative to diethyl ether that could be used in the pilot plant. Great recrystallization solvent too.

One time I ran a benzylic radical bromination using dimethyl carbonate as the solvent. Worked like a champ. Eventually ran the reaction on 150 kg scale without having to use benzene which was verboten, of course.

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6. Jim on June 6, 2011 10:44 AM writes...

methyl t-butyl ether solved some recrystallization problems for me.. plus, it smells great!

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7. Anonalso on June 6, 2011 10:49 AM writes...

@Toad

Unlike DCM/MeOH, DCM/TFE gives you a true phase break. I have tried the DCM/MeOH route, but often I can pull enough water it makes it a pain to dry. DCM/TFE does not look like it worked after you are done shaking, but go get a drink and come back and you have two very distinct layers.

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8. Baltic on June 6, 2011 11:21 AM writes...

Is there any reaction where you absolutely have to use diethyl ether as solvent, and can't replace it with TBME?

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9. MTK on June 6, 2011 11:49 AM writes...

Baltic,

Maybe something in a highly acidic reaction media where you could form the t-butyl cation. Of course, in that case I'm probably not using diethyl ether either.

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10. Quintus on June 6, 2011 12:20 PM writes...

I think TFE is not bio-degradable and therefore can't be allowed in the waste it has to be incinerated. TBME has a peroxide problem on scale.

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11. A Nonny Mouse on June 6, 2011 12:22 PM writes...

I still like diisopropyl ether even with the peroxide problems..... great for taking up the compound (as is toluene) and treating with a bit of silica to get rid of the colour. Never failed so far.

2-Methyl THF is also great for Grignards when they crystallise in THF; much more like diethyl ether in this case.

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12. HelicalZz on June 6, 2011 12:24 PM writes...

I too have successfully used MTBE (TBME - or whathaveyou) in process scale work. But that was when they were adding it to gas and it was reasonably cheap. Haven't looked to price lately. Wouldn't be surprised if it was even cheaper now due to excess capacity.

I'd add a shoutout for considering NMP in place of DMF.

Zz

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13. barry on June 6, 2011 12:32 PM writes...

2-MeTHF (and dimethyl ether) also shine when you have to run your reaction below the freezing point of THF. Ought to mention anhydrous ammonia in the same breath.

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14. AlienBlood on June 6, 2011 1:30 PM writes...

I like to use anhydrous HF as a solvent. It is mild and safe on my molecules and is easy to get rid of for an acid.

But if you spill it on you are in trouble, where 5-10% covering your skin will kill you. Plus it scares the bejeezus out of mere mortal men and women and causes the safety people to have siezures.

But we are trained professionals and have never had a problem in the 2+decades we have been using it.

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15. Hap on June 6, 2011 1:53 PM writes...

Don't all of the ethers have peroxide problems on scale? TBME seems like a better option because hydrogen abstraction generates a primary radical rather than a secondary one (THF, Et2O, DME, MeOCH2OMe) or a tertiary one (iPr2O - why I thought it had such a bad rep as a solvent - and 2-MeTHF). I don't know how much of it you can tolerate in aqueous waste streams, though, without making the neighbors unhappy. If you need an ether solvent, well, you're kind of stuck with peroxide control issues.

Trifluorotoluene's been suggested as a methylene chloride alternative. Is it used anywhere, and if not, why?

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16. CMCguy on June 6, 2011 1:55 PM writes...

I echo the comment of #12 HelicalZZ that have used extensively for large scale although likewise when was a fuel additive so very cheap and available. I wonder if price has gone up since demand disappeared so the former capacity has been redirected. As I recall the potential peroxide issue per #10 comment was not found to be significant and I don't remember any positive peroxides on many lots.

I once had TFE rejected for use at scale because possibility (low IMO) it could oxidize to the acid and that was previously ordained as "too corrosive" for the reactors in the pilot plant.

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17. okemist on June 6, 2011 3:05 PM writes...

I remember the folks at DP-Merck using chlorobutane, a concern as a class 3, and nothing is very soluble in it till you heat it to reflux, which makes it very good for recrys. Also an oft ignored ether is dibutyl used a great deal 20 years ago in the plant I worked in.

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18. bgg on June 6, 2011 4:11 PM writes...

methyl t-butyl either is also great as a cosolvent for chromatography, either in Hex/EtOAc or DCM/MeOH systems. 5% rarely changes the retention time, but improves separation.

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19. LCSquare on June 6, 2011 6:03 PM writes...

2MeTHF allows you to extract HCl salts of amines for low pH aqueous solutions into the organic layer. Very handy.

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20. milkshake on June 6, 2011 8:20 PM writes...

Derek - thank you! I figured right away it must have been you when the Orgprepdaily traffic spiked at 2 thousands visits a day

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21. Daniel Plainview on June 7, 2011 12:39 AM writes...

Milkshake- would love to talk to you, great synthetic adventures may await you- seriously. Please email me at job4milkshake at gmail dot com (not a joke...)

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22. milkshake on June 7, 2011 3:58 AM writes...

Ha. One evening, one Pipeline advertisement - and two new job contacts already - the same yield like the past 3 months combined. Again, thank you Derek!

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23. Al Chemist on June 7, 2011 7:30 AM writes...

benzotrifluoride radical rxns, brominations, and great azeotrope for workup

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24. DEchemist on June 7, 2011 8:06 AM writes...

Not as a reaction solvent, but as a chromatography and crystallization solvent I have had very good results with 1-chlorobutane. In chromatography it often pulls apart things that don't separate with hexanes as the nonpolar component.

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25. noname on June 7, 2011 8:06 AM writes...

It's not a reaction solvent, but the best flash solvent system I ever used was toluene / acetonitrile. Tight bands and great resolution. You just need to keep a heat gun nearby to blow the toluene off your TLC plates before checking the fractions for UV abs. A little more of a pain than a more volatile systems, but for tough separations, it was old "fail-me-not".

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26. S on June 7, 2011 8:24 AM writes...

I have recently been using trifluorotoluene (or benzene trifluoride BTF) as a solvent in the place of DCM. The two solvents have almost identical dielectric constants (BTF=9.18, DCM=9.04). Therefore, they tend to solvate things similarly. The advantage of BT is a higher dipole moment and more significantly a b.p. that is 102 deg C, about 60 deg higher than DCM. Therefore, I was able to heat the pants off my rxn. to get it done. Was also able to use it in the microwave, but that will only get started a whole other discussion on this forum. :)

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27. Wikipedia on June 7, 2011 9:41 AM writes...

Wikipedia says...

The dielectric constants for dichloromethane and trifluorotoluene are 9.04 and 9.18, respectively, indicative similar solvating properties. Dipole moments compare less favorably: 1.89 and 2.86 D for dichloromethane and trifluorotoluene, respectively. Replacing dichloromethane is advantageous when conditions require higher boiling solvents since trifluorotoluene boils 62 °C higher than dichloromethane (b.p. 40 °C).

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28. S on June 7, 2011 9:48 AM writes...

@Wikipedia: That's awesome! Thanks for pointing that out. In fact, for some of my cycloaddition chemistry, I am able to get all the contents in solution at a higher temp, thanks to BTF, something I was not able to do at lower temps with DCM.

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29. Mark on June 7, 2011 11:03 AM writes...

I used TONS of MTBE, both in my process chemistry days and in med chem.

Mark

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30. Capped Crusader on June 7, 2011 2:18 PM writes...

re. 2-MeTHF, another really useful (and Greener) solvent is CPME - cyclopentyl methyl ether: higher boiling (106C), lower aqueous miscibility, lower peroxide formation rate, and slightly cheaper....

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31. The Blue Maharajah on June 7, 2011 2:42 PM writes...

Any experience on good replacements for DCM and CHCl3?
Feels like the tide is going out on these...

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32. petros on June 8, 2011 7:25 AM writes...

A recent medchem meeting saw the GSK solvent selection guide provided as a hand out,

This highlights green solvents - water, 1- and 2-butanol and 4 esters
acceptable solvents with some issues

and those with major issues which include all all chlorinated and dipolar aprotic solvents (except DMSO)

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33. processchemist on June 8, 2011 10:05 AM writes...

About green solvents:
ok, chlorinated solvents are an issue, but I can't get rid of DCM (and 1,2-dichloropropane). By the way, talking about manufacturing, while in the western world some excellent minds talk about green solvents, their employers go for asian contractors where the "green" factor (a cost) gets no consideration at all. Amusing paradox.

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34. Hap on June 8, 2011 2:29 PM writes...

How do you get DMSO out? I was not good, but it seemed to stick around lots when I tried it and since it's not terribly volatile, it's hard to pull off. At least I could actually get DMF out of my compounds.

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35. processchemist on June 9, 2011 3:17 AM writes...

@Hap

aqueous workup (5 to ten volumes) if you're able to obtain a solid or an oily layer this way then extended washing with water. For water soluble products, eptane or cyclohexane (5 to ten volumes). No azeotropes, for DMSO. Some time ago I optimized a crystallization of an investigational API (in phase II) from DMSO/MTBE.

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36. Gerald Smith on June 9, 2011 5:04 AM writes...

I would ve careful with trifluoroethanol with respect to one issue. Beware of using it in conditions where it might link up to form the corresponding ether. This is a compound also called "Indoklon". It is a weak anethesthetic and a powerful convulsant. I think it is still used for shock therapy for mental patients who dont want to go the electrical route. Alledgedly all it takes is a whiff of the pure compound to do the trick.
Gerald Smith

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37. sepisp on June 9, 2011 8:09 AM writes...

I'll have to nominate acetic acid. Many don't seem to realize that once anhydrous, it's a fairly greasy solvent that dissolves most organic compounds. It forms dimers that in effect produce a polar solvent with a mostly hydrocarbon exterior.

Diethyl ether is often used out of sheer lazyness when you could use THF, MTBE or other ethers. For example, LiAlH4 works fine in THF. The higher boiling point and lower flammability makes it a better choice. Water solubility is a problem, but not an impossible one. You have to use water conservatively and extract the lithium salts filter cake with THF to remove the alcohol that sticks to the hydration water, then re-dissolve the product in THF and use a drying agent to remove traces of water.

Neat or high concentration/saturated are also another underused "solvents".

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38. Gerald Smith on June 10, 2011 12:45 AM writes...

Greetings. I have been looking up the biological properties of hexafluoroethyl ether (Indoklon) in the psychiatric literature. The effective convulsant dose of this stuff in humans inhaled is 0.5ml. Not very much is it? It otherwise has a high margin of safety, lacking somatic and neurological toxicity. The main effect of overdose in animal experiments was described as "repititious tonic, clonic seizures and sustained comatose state" but the subjects generally recovered without event. Why the intelligence agencies and military are not all over this stuff I do not know. Stable, volaatile, non-flammable, and 1 liter would be enough for a couple of thousand people, and with minimal casualties. But it brings up my point about using caution with trifluoroethanol under conditions where it might dehydrate to its ether form. You could easily end up with a lab full of chemists on the floor slowly waking up and seriously groggy with no idea what just hit them. If I were the government, I would keep an eye on anybody ordering large quantities of trifluoroethanol.....

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39. Nick K on June 10, 2011 9:45 AM writes...

38 Gerald Smith: I once found myself as you described, "in a lab full of chemists on the floor slowly waking up and seriously groggy with no idea what just hit them". We'd just learned that the site was closing.

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40. Capped Crusader on June 10, 2011 1:41 PM writes...

32 petros - turns out you can download the GSK Solvent Guides for free.

Under Supplementary Info at:
http://pubs.rsc.org/en/Content/ArticleLanding/2011/GC/c0gc00918k

Really cool and very straightforward to use.

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41. The Blue Maharajah on June 11, 2011 3:53 AM writes...

33. process chemist

Sorry but must disagree over the threat of deliberate outsourcing to "non-Green" countries.

In an age of global Corporate reputation, no sensible company will risk the PR meltdown should a disaster occur under those circumstances.

More importantly, countries like China are investing massively in Sustainable Chemistry. We should not be complacent because we may already be falling behind.

The coming threat is that they'll offer Greener, not (just) cheaper.


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42. Robur on June 12, 2011 9:52 AM writes...

At least Greener solvents offer us some new solvents to try (and the excuse to do so).

It amazes me how few solvents are actually used regularly by chemists.

Perhaps having a broader palate would give organic synthesis a much-needed kick up the backside...?


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43. Secondaire on June 12, 2011 1:58 PM writes...

I've heard good things about 2-butanone (sort of like higher-boiling acetone for those hard-to-push Finkelstein-type rxns), but it made me miserable (old solvent + a whole bunch of cyanide and ilk resulted in a sec-butyl group getting jammed somewhere into my molecule).

The first step of my PhD research (to make some hideous semisynthetic alkaloid) involved burning the carboxyl group off an amino acid with cyclohexen-2-one in cyclohexanol. Weird solvent because it's a solid at 20C and must be defrosted in a vat of hot water before being syringed out of the bottle.

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44. processchemist on June 13, 2011 4:12 AM writes...

@Blue Maharaja

It's not a matter of Bophal like meltdowns, you can do serious damage with relatively small but continuos emissions (how many VOC combustion systems are sold in Asia?). I know of some big indian pharmas where correct sovent recycling systems are at work, I know that the indian administration is more concerned about environmental issues than it was 10 years ago, and so on, but I hear that the road is still long. About China, I hope that investments will give some kind of result (I hope it for the chinese living near the manufacturing sites). But you can't say that chinese and indian environmental standards match the western ones: sad but true, this is still a driving force of the outsourcing/offshoring machine.

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45. Robur on June 13, 2011 5:05 PM writes...

43. Secondaire

While we're on the subject, where DO our common solvents originate from... eg why is acetone ubiquitous and not 2-butanone? Why ETHYL acetate... who used it first and when, what was wrong with n- or iso-propyl acetate?

I've just realised that I've been using these for 20 years and never questioned why!

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46. processchemist on June 14, 2011 1:22 AM writes...

@45

IMHO availability and price are a factor (and usually simpler solvents are cheaper, if we talk about ketones, ethers and esters). Anyway isopropyl acetate , methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK) have a pretty wide industrial use.

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