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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: Twitter: Dereklowe

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April 10, 2013

Old Friends, And Those Other Guys

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Posted by Derek

I have affection for some reagents, and have taken a dislike to others. That might be seen as odd, because if there's anything that can't return your feelings, it's a chemical reagent. But after some years in the lab, you associate some compounds (and some reactions) with good events, and others with spectacularly bad ones, so it's a natural response.

Today, for example, I'm breaking out some potassium hexamethyldisilazide, known in the trade (for obvious reasons) as K-HMDS. I'm in need of a strong base, and this one has worked for me in a couple of tight spots over the years, which makes me very friendly towards it. The first of those was back in grad school. It was, in retrospect, one of the first times I ever figured out what was going wrong with a reaction from first principles. Knowledge being power and all that, I was then able to come up with a fix, switching my base away from the lithium reagents I'd been using to KHMDS. I can still remember looking at the TLC plate in disbelief, having suddenly seen the yield go from flat zero to over 90%. I'll always be loyal after an experience like that.

There are others. As I've mentioned, I'll always love copper sulfate, just because of its color and because it was one of the first chemical reagents I ever owned as a boy. There are a couple of carbohydrate derivatives (such as good ol' "diacetone glucose") that, unlike some of their cousins, always treated me well during my PhD work, and I'm happy to see them on the rare occasions I have use for them. And as usual with the human brain, there are certain chemical smells that I immediately associate, nostalgically, with old labs. I'm not even sure what some of these are, but they're immediately recognizable, and my first thought is "Now that's chemistry".

But there's a flip side. There are reagents that have done nothing but waste my time and chew up my starting materials, and it's hard for me to warm up to them after that. I'm not sure if anyone likes trimethyl phosphite - it has a smell that seems as if would work its way through a concrete block - but I spent too much time trying to use it (unsuccessfully) for a tricky way out of a problem back in grad school, and I now associate its odor with frustration. I can tell that it's not just that it has a bad odor in general - ethyl vinyl ether is nobody's cologne, either, but that one makes me think of the summer of 1984 and bunch of Claisen rearrangements I was running, and I don't mind that at all. Mercuric oxide is colorful, so you'd think I might like it, but aside from it being toxic, I had some painful experiences with it in some old desulfurization reactions, and it'll never recover with me. And the so-called "higher-order" cuprates, made with copper cyanide - I'm not sure if anyone uses those any more, but I swore years ago to never touch one of those evil things again, and I've stuck to that.

My lists aren't always that absolute. As mentioned here, I went through a period where I absolutely could not take tosyl chloride, but not having to work with kilos of the stuff has gradually allowed it to move back into what's at least neutral territory. For me, that reagent is like running into someone from your old school that you didn't always care for at the time, but with whom you now seem to have at least some common ground in which to share memories.

So my shelves are full of friends and enemies. And now I'm off to see if my old pal, KHMDS, can come through for me again!

Comments (30) + TrackBacks (0) | Category: Life in the Drug Labs


1. John Wayne on April 10, 2013 8:05 AM writes...

I love the smell of dimethylsulfide in the morning. Smells like ... oxidation.

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2. eugene on April 10, 2013 8:38 AM writes...

Any chance you can tell us about that KHMDS reaction? It sounds intriguing. I've never used KHMDS in grad school, but relied on it heavily in the postdoc. There were a lot of times organo lithium reagents failed me, but on the other hand, there were a lot more times when they worked.

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3. Bunsen Honeydew on April 10, 2013 8:42 AM writes...

I've always taken some sort of sadistic pleasure with bad smells. I've made some things that smell like nasty male cat urine and quite enjoyed the reactions from labmates when I put it on the rotovap. I also rather like thiols. That being said, I do still enjoy things like cinnamaldehyde, anisaldehyde, carvone and limonene.

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4. TX Raven on April 10, 2013 8:55 AM writes...

Funny thing how the images from those "Kodak moments" (a tlc, an NMR trace) stay with our happy memories...
I remember someone said "a sufficiently advanced technique is not distinguishable from magic"...

I love chemistry...

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5. Calvin on April 10, 2013 9:23 AM writes...

I have a slightly different experience. A reagent that work fantastically well but I hated using.N,N-dimethylaniline and POCl3 to take and amide to a chloroimine. POCl3 was fine but that base, not so much. High boiling, a pain to get rid off and a smell of heavy rotting socks. And it stuck to you despite every effort so i could smell it even when I got home. In the end I resorted so doing 3 or 4 reactions on 500g scale in parallel so I could get the damn thing over and done with in a oner. Great yields though.....

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6. David Formerly Known as a Chemist on April 10, 2013 9:48 AM writes...

My old friends (that, alas, I never see anymore) are not reagents but instead alkaloids being extracted from plant components, which is what I spent the first two years of graduate school doing. I will always love that unmistakable nutty smell of thick oils, semi-solids, and alkaloids crystallizing out of tarry looking goo. We had an entire walk-in closet stacked with round-bottom flasks and vials containing extracts spanning two decades. Ah, the inability to throw anything away!

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7. spacer on April 10, 2013 9:56 AM writes...

Iron/ammonium chloride redction of nitro to amine has got me out a tight spot a few times. As did Lithium borohydride for ester to alcohol reduction....avoiding the pains associated with lithal.

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8. DeusEtV on April 10, 2013 10:03 AM writes...

Seeing Greg Fu talk about his catalyst, unlike most academics that you could actually buy, really changed Pd chemistry for me.

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9. NU chemist on April 10, 2013 10:03 AM writes...

Diphenylcarbamyl chloride has gotten me out of several tight spots. It's a good base-labile protecting group, which selectively reacts with phenols in the presence of alcohols. (just stir in neat pyridine) Regular acyl chlorides and chloroformates gave me problems no matter what conditions I tried.

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10. A Nonny Mouse on April 10, 2013 10:49 AM writes...

And don't forget to try sodium carbonate if potassium doesn't work; we did this recently and the yield, as above, went from 0 to 90+%.

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11. Yancey Ward on April 10, 2013 11:52 AM writes...

Egads! Higher-order cuprates! I had similarly bad experiences!

My first real experience with organic chemistry was my my first day in the undergrad organic laboratory- the shelves where filled with various chemicals. Being the lab alone, I went from bottle to bottle sniffing. To this day, whenever I smell wintergreen oil, or even nail polish, it brings back that memories of that day.

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12. Anonymous on April 10, 2013 3:19 PM writes...


Good thing I didn't share your hobby of sniffing the reagents.

My first Summer job (after HS) was being my late Father's lab tech at Dupont. I was formulating Dupont 1179 for him -- now known as Methomyl. A nasty pesticide. At the time, one of the intermediates was methyl isocyanate (Bhopal was in the future...).

My first day I got trained in how to use the Scott air pack on the wall, and where Medical was.

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13. PMP on April 10, 2013 4:57 PM writes...

Higher order cuprates with copper cyanide and methyllithium - whenever I have used this reagent it has worked like a charm. Five minutes and the reaction is over, near-perfect diastereoselectivity, very clean, and the workup with ammonia/NH4Cl gives the color of Cu(II)tetrammine complex which is one of the most beautiful blues ever, reminding me of the sky of my childhood in the north. I am nearly moved to tears when I think of this reaction. Definitely one of my favorites.

Hint: one needs to titrate the MeLi before use - stoichiometry is important here.

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14. Anonymous on April 10, 2013 5:13 PM writes...

@3 'Wow this smells bad. Here, smell it.'

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15. Derek Lowe on April 10, 2013 5:58 PM writes...

#13, PMP: it worked like a charm for me. Three times, on the same substrate in my total synthesis. Then, despite every effort, it never, ever worked again, at all. On the same substrate. Titrated the MeLi, used new bottles of everything, old/same bottles that had worked, freshly synthesized CuCn, what have you. No dice. Never did figure out what was going wrong.

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16. milkshake on April 10, 2013 9:12 PM writes...

@ 15 Derek: sometimes the reproducibility problem appears when you finish an old bottle/old batch of material that had something secret but essential in it, and the new bottle does not have. Then of course no matter how much care you invest into purifying everything, things do not behave the same way. A classical examples are Nozaki–Hiyama–Kishi (trace of Ni) and Bolm FeCl3-catalyzed arylations (trace of Cu).

In your case I would guess either the original CuCN had some other metal in it, or, it is more likely that the nBuLi that you initially used in lithiations was old and partly oxidized and had contained nBuOLi - it is a common occurence and it does not show up on phenanthridine titration. Knochel and Schlosser have shown over and over again that adding extra equivalent of LiCl and Li alkoxides etc to various organometallic reagents and Li-amide bases sometimes completely ramps up the reactivity and changes their selectivity.

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17. milkshake on April 10, 2013 9:18 PM writes...

to previous comment - I just realized that you were actually using MeLi. "Halide-free" Methyl lithium in ether has in fact a notorious problem with the presence of variable amounts of LiBr or LiI from manufacture. My bet is thats what it was, the secret ingredient

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18. utbiotech on April 10, 2013 11:05 PM writes...

PCC, bad reagent, but I always want to try again and figure out some reasons for the failure, although the reasons maybe ridiculous.

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19. Jan on April 11, 2013 12:28 AM writes...

Tributyltin hydride - it has a nasty smell, it's ridiculously toxic, and what is more, I never achieved the hydrostannylation I was trying to do. Since those days, I have a burning hatred for tin-based reagents.

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20. Nick K on April 11, 2013 3:24 AM writes...

Derek: My experience with higher-order cuprates may be of interest. I traced the non-reproducibility of a methyllithium/CuCN reaction to two things: one was the batch of CuCN (the Aldrich material failed completely). The other was the THF. It HAD to be distilled from Na/benzophenone. The commercial anhydrous THF (Aldrich again) killed the reaction.

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21. Søren Furbo Skov on April 11, 2013 4:31 AM writes...

I spent nearly a year on my masters thesis trying to synthesize isoflavones through a two-step one-pot synthesis. The first step var a Friedel Craft acylation with boron trifluoride diethyl etherate as the solvent, and then a cyclization with DMF and some inorganic acid chloride. Every time, it gave me a reddish-purple sticky mess that smelled like play-doh. I eventually managed to do the first part of the reaction in another way*, and then went on to the second step. Years later, I think i figured out what went wrong: The article didn't mention the temperature of the first step, i just said "heat in water bath", so I assumed it to be with boiling water. However, the second step ran at 70 degrees centigrade, so I assume that the first step should also have been running at that temperature. I probably synthesized my product, but it was destroyed before the second step because of the higher temperature.

*Hoesch reaction, really easy cleanup, as the primary product is a salt, so everything dissolvable in ether is easily removed. The salt can then be hydrolyzed, so everything inorganic can be removed. It uses freshly fused ZnCl2 and HCl(g), so it is a bit cumbersome, but the purity of the product is remarkable.

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22. GladToMoveToProcess on April 11, 2013 9:10 AM writes...

Polyphosphoric acid has gotten me out of several tight spots. Messy, tough to stir, a pain to work up, but the results are often worth the trouble. One of my all-time favorites!

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23. "nothermaus on April 11, 2013 9:47 AM writes...

Always had good success using trimethyloxonium tetrafluoroborate/4-DMAP in some methylation reactions. Quite often methyliodide/inorganic base didn't do the trick.

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24. VRK on April 11, 2013 9:56 AM writes...

I always had to use Selenium based compounds during my PhD days that is awful to work with. But I ended getting some nice papers and patents afterwards.

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25. freddy on April 11, 2013 10:07 AM writes...

Per-trifluoroacetic acid for epoxidizing inductively e-poor olefins with high stereoselectivity. Made it beforehand from TFAA and 80% peroxide (which you just can't find anymore).

Toluene as a flash solvent for tight separations. Keep the heat gun handy!

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26. sciencemonkey on April 11, 2013 11:12 AM writes...

On the topic of important contaminants, I remember people in my PhD group mentioning how some nanoparticle syntheses are really dependent on the other 10-30% making up the technical grade oleic acid.

In terms of favourite reagents, I will definitely go with DMTMM, aka 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride. It's a great amide coupling agent for sterically crowded systems and solved a big problem in my PhD work.

Oxalyl chloride in DCM with a drop of DMF, for making acyl chlorides, is also a sweetheart.

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27. PMP on April 12, 2013 1:41 AM writes...

@15, 16: In my experience Et2O always worked better than THF for these cuprates. I agree with milkshake that LiBr/LiCl might be an important "secret ingredient".

The cuprate addition I used was used till the very end of the total synthesis project (also by other people, and with a variety of a,b-unsaturated d-lactones).

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28. AnonChemist on April 12, 2013 9:45 AM writes...

LiN3 works better than NaN3 for X-N3 exchange and in grad school we prepared LiN3 from NaN3 and Li2SO4. We also made our own reagents in grad school such as; HN3 for mitsunobu and michael, TMS-CN for strecker, IBX for oxidation, sugar diacetonides, wittig salts and ylides, BuLi, cuprates, Et2Zn, and the list went on...

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29. John T on April 17, 2013 9:11 PM writes...

I will speak for trimethyl phosphite!!! I have been a big fan of it for a series of different reactions and have never had issues. Then again, DISTILL, DISTILL, DISTILL. Words to live by.


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30. HK on April 22, 2013 2:38 PM writes...

KHMDS is awesome. DR jumped tenfold switching from LHMDS.

And I don't know about trimethylphosphite, but dimethylphosphite has been pretty good to me so far in my post-doc.

Homemade IBX is another "old friend" - always did what I wanted it to cleanly and without complaint.

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