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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 21, 2012

Dead Reagents, Dead Reactions

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Posted by Derek

Chemistry moves on, and it doesn't always take everything with it. There are reagents and reactions that used to be all over the literature, but have fallen out of use, superseded by easier or more reliable alternatives. The first thing I think of in this category is pyridinium chlorochromate (PCC), which I wrote about here. That was all the rage in the late 1970s and into the 1980s, but I don't know when I've last seen a bottle of the stuff.

And since that post itself is seven years old now, I wanted to throw the floor open again for a discussion of dead reagents and dusty reactions. There are plenty of obscure ones, of course, and plenty that don't get much use but still have their place in special situations. But I'm wondering about the ones that used to be big and now are disappearing. What are some that you used to use, but never expect to again?

For my part, other than PCC, I don't ever see doing a vanadium-catalyzed epoxidation, even though I did a few in grad school. And I recall doing a Jones oxidation - does anyone use that one any more? Another reagent that had a vogue in the late 1980s and early 1990s, but I don't recall seeing any time recently, was tris(trimethylsilyl)silane (a replacement for tri-n-butyltin hydride). So those are my nominees - what else?

Comments (58) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. jackgg on June 21, 2012 9:22 AM writes...

Yes, Jones Reagent. I still like to use it because my professor is Dr. Jones. :), it works neat to make an acid though.

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2. Ed on June 21, 2012 9:26 AM writes...

Reading this article 5 minutes after i just set up an oxidation with PCC made me laugh.

Originally wanted to use DMP though, couldnt find it so i desided to use PCC which i never used before. I Always like to use some new methods even if they are nearly dead now :-)

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3. 'Nothermaus on June 21, 2012 9:28 AM writes...

Is Lawesson's Reagent still in wide use?

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4. Justin Peukon on June 21, 2012 9:46 AM writes...

This post is somewhat provocative, in view of the plethora of oxidation reagents available through the literature... Yes, Jones reagent is still useful, although disposal of (highly toxic) residuals is a real problem. More difficult to spot a recent publication including a Swern oxidation. Nice reagent, very unpleasant by-products, too.

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5. zDNA on June 21, 2012 9:50 AM writes...

Here's a trick I learned for Swerns, learned from a pilot-scale chemist: Use Oxone when you work the reaction up. You'll re-oxidize the DMS back to DMSO. No more stink!

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6. UKPI on June 21, 2012 9:59 AM writes...

I used quite a bit of Lawesson's Reagent during my PhD work (ca. 6 years ago)...never since.

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7. CanChem on June 21, 2012 10:06 AM writes...

Yeah, I laughed when I saw Derek say PCC was dead, since the last 3 synthetic papers I caught in my RSS all used it early in the synthesis.

I ran my last Swern about 2 years ago, but was running them about 6 times a week back then.

A reaction I haven't run in ages (like since undergrad), but I know is supposedly still out there, is a Birch reduction... or any dissolving metal reduction for that matter.

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8. newnickname on June 21, 2012 10:11 AM writes...

Lead tetraacetate. An oldie but goodie. Gone but not forgotten.

For those who want to drive tin hydrides off the shelf and into the dustbin of history, consider "Deoxygenation of Alcohols Employing Water as the Hydrogen Atom Source", JACS, 2005, 127(36), 12513–12515. DOI: 10.1021/ja052185l which uses a trialkylborane and H2O (or D2O) as a source of H. (or D.). I haven't used it, but it looks pretty good.

Do you consider HMPA to be a reagent or a solvent for this topic? Mostly driven out of use by the safer DMPU, DMEU and NMP.

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9. David Formerly Known as a Chemist on June 21, 2012 10:16 AM writes...

DCC...what a chromatographic nightmare getting rid of the by-product. Completely replaced by the water-soluble carbodiimides and mixed anhydride reagents.

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10. Hadriel on June 21, 2012 10:18 AM writes...

I still like to use Lawesson's reagent, since it's easily handled (as long as you don't spill any!)

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11. scientistbymistake on June 21, 2012 10:22 AM writes...

I too have used PCC in recent years, and Lawesson's reagent (cue ranting at my lab mates to bleach stuff...).
Going back to the 2005 post, I used potassium permanganate on several 500g scale reactions not long ago either, it was wonderful!

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12. Jonesin' on June 21, 2012 10:31 AM writes...

Does anybody have a favorite alternative to Jones Reagent that they find better (milder). I still run them because I know they always work.

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13. myma on June 21, 2012 10:48 AM writes...

Ah, the names bring me back. Back in my school days when I had to take a couple classes of organic chemistry to be a well rounded chemist. All of these were on list of reactions to memorize.
I wonder what is on the current must-memorize list of reagents for today's students?

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14. anon the II on June 21, 2012 11:33 AM writes...

@ #13 myma

I think it is one of the great fallacies of the world that knowing organic chemistry requires memorizing reactions. A good organic chemists learns reactions and then knows them. The good news is that there are only about 5 or 6 reactions, with oxidation just being a reduction run backwards, or vice versa. I am horrible at memorizing things. I'm pretty good a mechanical things. That's why I became an organic chemist and not a biologist or a doctor.

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15. Currently unemployed on June 21, 2012 11:52 AM writes...

Olefination reactions. With the advent of catalyst that facilitated cross metathesis reactions, things like Witting reactions, while still useful in preparing alkenes, are used less so now.

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16. Nick K on June 21, 2012 12:10 PM writes...

#9 Davidformerly...: I'm not convinced DCC has been completely superseded by the newer reagents. It's very much cheaper than the newer carbodiimides, and is still used for peptide couplings on a large scale. I used it last year to make 2 mol of a dipeptide - worked beautifully.

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17. OldLabRat on June 21, 2012 12:15 PM writes...

Does any one still use sodium ribbon to dry solvents? I recall the Na ribbon maker attached to the bench at my first lab job; looked like a simple pasta machine.

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18. RB Woodweird on June 21, 2012 12:21 PM writes...

Any reaction using mercury in any form. In the Boston area, the MWRA will swoop in and shut your whole operation down if you discharge a dozen mercury atoms into the sewer.

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19. Anonymous on June 21, 2012 12:37 PM writes...

Like most practicing chemists, I refer to "Purification of Laboratory Chemicals". I often see purification via derivatives here, but never in the current literature. Does anyone still purify amines via the picrate? What about bisulfite adducts for ketones? Any advantage to this anymore?

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20. KC on June 21, 2012 1:28 PM writes...

Two fellow PhD's use the Jones Oxidation in our group....As far as I know its pretty standard for their class of natural products

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21. heretic on June 21, 2012 1:30 PM writes...

how about selenium reagents

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22. WCA on June 21, 2012 1:36 PM writes...

Magtrieve!

With the advent of so many water soluble reagents, does anyone use dicyclohexylcarbodiimide for amide couplings any longer?

Permalink to Comment

23. Anonymous on June 21, 2012 1:51 PM writes...

I use PhSeBr and (PhSe)2 all the time to form enones on complex substrates. Sure, IBX is my first choice, but when that fails, selenium works a lot more often than Saegusa conditions.

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24. milkshake on June 21, 2012 2:25 PM writes...

thalium(III) trifluoroacetate and nitrate. Lead(IV) acetate, mercury salts in general, stoechiometric copper acetylides, HMPA. 1,3-dithianes are rare these days. Crown ethers other than 18-cr-6 also fell out of fashion. Epoxidations with MTO. Deprotonations with NaNH2 and KNH2. Perbenzoic and mono-perphthalic acid. Far fewer labs work with unsubst. diazomethane these days.

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25. Nat on June 21, 2012 2:26 PM writes...

hydrazoic acid (HN3); diphenylphosphoryl azide is a good alternative

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26. Nat on June 21, 2012 2:30 PM writes...

@12 PDC (2+ eq) in DMF will do the same as Jones and it is lot milder

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27. milkshake on June 21, 2012 2:31 PM writes...

PS: I use DCC frequently - it is good reagent for formation and isolation of active esters such as OPfb and OSu from the carboxylic acids, the urea byproduct removal is not a problem if the reaction is run in acetonitile

Permalink to Comment

28. Useless Molecule on June 21, 2012 3:55 PM writes...

I still use PCC very often. Quench with 1M citric acid: it complexes all the brown Chromium junk. Much better than the usual "Celite filtration" work up.

God bless E J Corey

:-)

Permalink to Comment

29. CMCguy on June 21, 2012 4:17 PM writes...

Does anyone still use Benzene regularly any more? I used to use frequently in lab as great choice for crystallizations and as frozen matrix for unstable compounds. Increased concerns over toxic/cancer causing made it so even ordering Benzene was a hassle and then moved in the process world where is not even a remote option in most plants.

Permalink to Comment

30. Eric on June 21, 2012 4:48 PM writes...

#29: I use benzene almost daily, but I am a microscale organometallic chemist.

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31. stephen moratti on June 21, 2012 5:00 PM writes...

God I must be such a dinosaur as I have used most of the reagents above mentioned in the last month in the same reaction scheme!.

Jones reagent to oxidise a hindered thiophene alkylalcohol to a ketone - IBX expensive and took 2 days heating, Jones cheap and took 2 minutes - 94% yeild

Lead tetraacetate - an oxidative decarboxylation

Lawesson's reagent - cyclisation of 1,4 diketone to thiophene (how else does one do it easilly?)

Bisulphite - removal of the starting high b.p. aldehyde after a Bayliss Hilman reaction (meant I could do it on a large scale without columning)

And in a separate sequence used DCC in a Stupp polyesterification


I will still try PCC if I need an aldehyde first


Permalink to Comment

32. Ted on June 21, 2012 6:59 PM writes...

I got a process from a client about two years ago. The first step was a Jones oxidation of an aryl aldehyde to the acid, reported at 69%. I thought a chlorite oxidation sounded much more civilized, and proposed we start with it. We hit 95%, first pass. It pretty much went to kilo scale cGMP production without further modification. Every now and then, you get to feel like a rock star.

My undergrad advisor was "a big believer in making your own PCC." So I did, and in fact, I always found it enjoyable - it looked like you were making TANG! As a reagent, I found it very reliable. It was my go-to oxidant for years, particularly in carbohydrate and steroid work (both notoriously difficult carbocyclic skeletons to oxidize). I was doing commercial process work with big pharma in the mid-90s, and there was a concerted effort in our unit to convert those chromium oxidations to TEMPO oxidations. For the most part, this was successful. It's been over ten years since I last used PCC.

I always keep a bottle of benzene around in case I need to whip up a ketal - toluene, water and ethylene glycol form an azeotrope, which makes it harder to set up a DS trap and walk away overnight.

Funny thing - up until I got laid off last week, I spent most of the last two years scaling up Grignard chemistry for multiple projects... Before that? Fifteen years since the last one.

-t

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33. Sisyphus on June 21, 2012 7:43 PM writes...

Anything with Tin.

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34. milkshake on June 21, 2012 7:44 PM writes...

Ted, please drop me an e-mail - I would like to ask you about something that you mentioned in the last paragraph. My gmail account is tvojkovsky - thank you!

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35. startup on June 21, 2012 10:10 PM writes...

I think DEAD is dead.

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36. Graduate Student on June 21, 2012 10:33 PM writes...

Tin? Stille reaction is excellent, and some alternatives aren't so attractive. Negishi reagents are finnicky, and some boronic acids or boronate esters aren't all that stable.

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37. processchemist on June 22, 2012 2:54 AM writes...

Stille reaction can be excellent for mg (I find it trickier than zinc reagents, anyway), but when the usual suzuki doesn't work the choice for scaled up reactions is Neghishi (or Grignard).

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38. heretic on June 22, 2012 6:51 AM writes...

90% hydrogen peroxide and TFA for Bayer Villeger
carbon tetrachlorid

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39. SGP on June 22, 2012 9:36 AM writes...

I've used tin chloride to reduce a diazonium salt recently.

I used selenium dioxide in an allylic oxidation a few years back.

And, DCC is my go-to reagant for solution phase coupling reactions. It works just as well and is much cheaper than most others. Never had any trouble flashing away any remaining DCU after celite.

Also distill using Na wire.

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40. vanad on June 22, 2012 9:48 AM writes...

I always used DIAD, never DEAD.

Never used Hg2+ to take off a dithioacetal, always iodonium. Hg2+ salts are the essential Lewis acids of choice tho' in some not unrelated sulfur-acetal/orthoester rxns.

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41. Legacy Merck Guy on June 22, 2012 12:19 PM writes...

Formic acid as a hydride source. It's not a dead reagent per se but not used like that much since the borohydrides became cheap. When was the last time anyone did a Leuckart Wallach reduction?

Permalink to Comment

42. Organometallica on June 22, 2012 2:57 PM writes...

Tritylsodium- from triphenylmethane. I believe this was used as a strong, non-nucleophilic base before LDA and related amide bases became commonplace. It's supposed to be a deep red. Would like to see it.

Permalink to Comment

43. milkshake on June 22, 2012 4:58 PM writes...

formate is an excellent hydride source for transfer hydrogenations. I will take asymmetric TsDPEN-Ru catalyzed acetophenone reduction with formate over a simple borohydride reduction any day, it is that easy.
DEAD is quite good on small scale whenever you need a more reactive version of DIAD or if the spent reduced DIAD reagent is too close to your product. I think it was the transportation regulation hassle (due to the exotherm self-decomposition) that made DEAD hard to buy for awhile, and expensive too

Permalink to Comment

44. jackgg on June 22, 2012 11:34 PM writes...

Lawesson's Reagent, hhaaa, just got a bottle from Sigma last week, planning to make some thioamides. Can someone tell a better reagent instead of this one? Thanks in advance. Jackgg

Permalink to Comment

45. Hurin on June 23, 2012 11:29 AM writes...

I'm surprised noone has mentioned it, but does anyone here do oxymercuration? That reaction is still in the undergrad textbooks, but no one who I know has actually run it.

Permalink to Comment

46. Secondaire on June 23, 2012 12:18 PM writes...

Never used PCC, but PDC works really nicely in some cases - Vogel's has simple general protocols for using these things.

Jones reagent saved my synthesis in grad school, but I find you have to make it yourself for it to be any good. I had a strained secondary alcohol (fused pyrrolidinothingy that was "aza-benzylic" - Swern conditions gave me a Pummerer rearrangement, hypochlorite chlorinated the thing, DMP gave me a party by NMR - on and on and on it went, but Jones absolutely nailed it.

And on small scale for prodrugs, I used to use DCC regularly all the time. The difference in polarity between the dreaded urea by-product and my compound caused me no difficulties, and hey, it works.

@29 As a general rule, most things that will work in benzene will work just as well in toluene, as long as benzylic radicals aren't involved anywhere.

Permalink to Comment

47. mmol on June 23, 2012 1:38 PM writes...

I was taught (many yrs ago) all about the use of organocadmium reagents (rather than RMgX) as a "good way" to convert acid chlorides to ketones. NEVER have I seen that applied........

Thallium - forget it, and I'd have to be desperate to use SeO2. and, HMPA, well, if you have to use it, the reaction isn't worth doing. But tin, well the Stille almost always works.......... and usually v efficently.

Permalink to Comment

48. Nick K on June 23, 2012 5:18 PM writes...

Clemmensen and Huang-Minlon reductions....I haven't seen any in the literature in years. Anyone ever done a Willgerodt reaction, or the wonderfully-named Duff reaction?

Thallium and mercury reactions are virtually extinct, as other posters have noted.

Photochemistry is getting rare nowadays.

32 Ted: Interesting remark on using toluene rather than benzene to make an ethylene ketal. This would explain why I had problems a few years ago. The reaction just would not go to completion. Wish I'd known that then.

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49. AnonChemist on June 23, 2012 7:37 PM writes...

@Nick K, Milkshake, & mmol:

Thallium(III) trifluoracetate is *da bomb* for on-resin disulfide cyclization in peptide chemistry. It sure outperforms Wenschuh conditions with triphenylphosphine and iodoform (I hate triphenylphosphine oxide) or slow-a$$ wet DMSO, open-air methods. Too bad red flags are raised when ordering it ever since that crazy ex-BMS lady murdered her husband with it.

In terms of extinct chemistry techniques, I would nominate spinning-band distillation, Woods metal baths, and the Birch Reduction. Who the hell wants to dry-condense ammonia and julienne-cut sodium?

DCC is okay for small-scale acylations wherein epimerization of the alpha-carbon is not a concern. Otherwise I would stick to HCTU or DIC-HOBt.

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50. Reagents that I despise... on June 23, 2012 7:54 PM writes...

...mainly consist of those that require P.I.T.A. workup.

DDQ: Even though it works better when recrystallized, it still generates that dark gunk that has funky solubility.

Anything that uses pinene auxiliaries: Sorry Brown and Midland, while the stereoselectivities are great, the purification sucks big time.

DIBAL-H: My lab ran out of Rochelle Salt, so I had to barter with another group.

Selenium reagents: I word...barf.

Although they can work well, I've never been a fan of multi-metal organometallic reactions. It was pretty daring of the Eisai chemists to use all those NHK reactions in making clinical-grade Halaven.

Permalink to Comment

51. @Ted on June 23, 2012 8:01 PM writes...

"Funny thing - up until I got laid off last week,"

Aw man, that sucks :(

How's the hiring in your area? Hope things work out for you soon!

Permalink to Comment

52. Nick K on June 24, 2012 8:45 AM writes...

#51 Anonchemist. Thanks for the info on thallium(III)trifluoroacetate - I had never heard of that use of the reagent. Doesn't it react electrophilically with tryptophan and tyrosine residues?

Permalink to Comment

53. JH on June 25, 2012 9:35 AM writes...

I used VO(acac)2 and t-BuOOH for selective epoxidation of allylic alcohol some time ago. Worked like wonder.

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54. @52 Nick K on June 25, 2012 1:44 PM writes...

AnonChemist here.

Regarding the use of Tl(TFA)3 for cyclic disulfide formation, check out these references:

Page et al. J. Pept. Sci. 2007, 13, 833–838.

Fujii et al. Chem. Pharm. Bull. 1987, 35 2339–2347.

Acm-protected cysteines are required. As far as I know, trytophan and tyrosine oxidation do not occur when the thallium-mediated cyclization is performed on-resin with fully-protected peptides. Although TFA is stoichiometrically generated, the acidic protons are neutralized in the formation of acetamide from the Acm groups. One problem can be the disposal of the thallium waste, though.

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55. Ted on June 26, 2012 12:47 PM writes...

@Milkshake & #51

Thanks for the kind wishes. Hiring in this area bites, as it does everywhere. We'll see what turns up!

-t

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56. reg cmc on June 26, 2012 8:43 PM writes...

benzene, CCl4, AIBN, any NNO group:)

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57. explosci on June 27, 2012 10:27 AM writes...

Oxymercuration: definitely dead.

But I use benzene and CCl4 regularly....

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58. CT on July 8, 2012 6:49 PM writes...

In answer to the question 'Is Lawesson's Reagent still in wide use?'

I don't know about WIDE use, but it's by far the most convenient (in spite of odour) for the synthesis of thioamides from amides.

Permalink to Comment

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