Org Prep Daily

March 13, 2010

A job interview

Filed under: Uncategorized — milkshake @ 3:25 pm

I just got first job interview invitation, end of this month. Its for a medicinal chemistry position – at a good place and with a group that I want to work in, and the project is also very interesting  - so please keep your fingers crossed for me.

Also, there won’t be that many updates here in the next few weeks. Maybe I can dig up some procedures from old notebooks but for now I decided put up here an ancient recording (like 40 years old) of a Czech blues song that I am quite fond of. Sorry for the incomprehensible language and less-then-awesome sound quality.

Update (4/2/10): It’s a boy!


  1. Good luck! Hopefully the new employers won’t be boring old squares.

    Comment by Wavefunction — March 13, 2010 @ 4:09 pm

    • Thank you. By the way, I updated the “Chemistry Resources” – please have a look, its at the bottom of the page

      Comment by milkshake — March 18, 2010 @ 7:46 pm

  2. Good luck! I wish you’d switch over to organic materials, though…we could really use someone with your kind of expertise. (Then all our yields would be fantastic and our reactions scaleable and our craziest, most intractable targets would actually be made. And you’d get to enjoy bright colors and shiny crystals on a pretty much daily basis!)
    The music is FANTASTIC, by the way. Any other artists you recommend?

    Comment by psi*psi — March 13, 2010 @ 5:15 pm

  3. psi*psi, thank you. The lyrics are sappy though

    Comment by milkshake — March 13, 2010 @ 5:36 pm

  4. Congrats, dude. Best of luck.

    Comment by Chemjobber — March 13, 2010 @ 6:00 pm

  5. Best of luck with your interview! We’re all pulling for you!

    Comment by Bunsen Honeydew — March 13, 2010 @ 11:35 pm

  6. Some Carbazole procedure..??!!!i’m going mad with this kind of compounds..
    Best of luck!!

    Comment by MadForIt — March 14, 2010 @ 10:38 am

    • I don’t have any experience with actually making carbazoles but its not the most pleasant class of compound – I worked with commercially-available N-ethyl carbazole compounds once and they sure liked to oxidize easily and they were quite light sensitive too – much like some indoles and pyrroles. My guess is that putting some electron-withdrawing substituents on carbazole, or replacing one benzene ring with pyridine to get aza analogs should provide more stable molecules. What do you need them for?

      Comment by milkshake — March 14, 2010 @ 2:36 pm

  7. I need them for a med.chem project, i make the diphenylamine with a buchwald reaction using 2-chloro aniline and a bromoarene (PdOAc2, P-tBu3, NaOtBu, Toluene Reflux); then using the same conditions (Palladium source, base and ligand) in refluxing dioxane i’m trying the ring closure to give the substituted’s a mess!!
    Thank you so much

    Comment by MadForIt — March 14, 2010 @ 4:44 pm

    • Nothing against tBu3P – but in my experience this ligand does not create very robust catalytic systems, they are highly active but also die easily. The phosphine is highly air sensitive, if you have to use tri-tert-Bu phosphine use the solid tetrafluoroborate salt instead, tBu3P.HBF4, that one is air stable and produces the phosphine in situ. But stil you need to be super careful when using this phosphine, maybe work with a glovebox to weigh out the material etc. You definitely need to deoxygenate the mix carefully.

      Can you use 2-bromo aniline and iodoarene instead in your scheme?

      Also, Xanphos with Pd2(dba)3 1:1 ligand/Pd is fairly general system, with peroxide-free THF as a solvent and Cs2CO3 solid from Aldrich as a base, 3 equivs. For arylations with aryl iodides, simple tetrakis Pd(PPh3)4 often works well, and it may be attenuated enough to leave the bromo untouched in the presence of iodo.

      Since you are doing a two-step reaction in one pot and it does not work too well you need to isolate the diarylamine intermediate, purify it carefully and then optimize the cyclization conditions. Having bromo instead chloro should improve the carbazole formation. You need to try different ligands, Pd sources, few different solvents and bases. So don’t do it in one pot until you optimize it – this can take time.

      Comment by milkshake — March 14, 2010 @ 5:09 pm

  8. Yes, i think so…i use 2-chloroaniline and bromoarene ’cause was a nice methodology on joc, with pretty nice yields. The problem is the loss of weight in the buchwald ammination, the TLC gives just one spot of the product, i really don’t know what to do..

    Comment by MadForIt — March 14, 2010 @ 5:26 pm

    • nice methodology paper in JOC does not mean that the reaction will work in your hands with a different substrate. First, some famous research groups are not forthcoming about the limitations of their methodology – they simply do not put entries which did not work into their tables – in the publication they sweep the problem with limited scope of their methodology under the rug, and only admit to it later if they find a solution to it (like an improved catalyst). I have seen this kind of salesmanship repeatedly – it is bad for the science but ambitious people sometimes do this.

      Also, please understand that these reactions are highly sensitive to the actual substitution pattern on the aryls, sensitive to a presence of functional groups like amide or pyridine N that can deactivate the Pd catalyst by coordinating to it. A nice methodology paper in JOC could be a starting point in your project but when it does not work you either need to re-optimize it for your substrate or move on and find some other scheme. When your boss tells you that it “must work” because the JOC paper makes the problem appear so simple, please tell your boss that he should try to run the reaction himself if he does not believe you.

      Comment by milkshake — March 14, 2010 @ 5:35 pm

  9. My boss told me that…
    I totally agree with you, Milkshake.
    The strange thing is that the substrate is not so different from the substrates on the paper, anyway is my first project after my thesis work…
    Thank you so much!!
    Really great blog!!

    Comment by MadForIt — March 14, 2010 @ 5:51 pm

    • The bosses who are no longer doing chemistry with their own hands get unrealistic expectations easily. They go to conference talks where the breakthrough research is presented in a way that it almost seems effortless. They read the papers where everything is polished and wonderful like in advertisement. If this is how the boss gets his chemistry information for many years – and if he does not do chemical methodology research within his own group (he just wants to use a published methodology for his synthetic project) – he can develop rather distorted views about why it takes to actually make the reaction work for a given substrate. Bosses are typically ambitious and inpatient – they write optimistic grant proposals, they make research plans for you and so on – but you need to build a relationship with your PI so that he will trust you when you tell him that something really does not work (instead of him suspecting you of being incompetent). The alternative is to find a new boss to work for.

      Comment by milkshake — March 14, 2010 @ 6:07 pm

  10. Milkshake,
    Dude, All the best for your interview.

    Comment by sks — March 14, 2010 @ 8:28 pm

  11. I wish you all the luck in the world. We need more great chemist such as yourself!

    Comment by The Curious Chemistry Graduate — March 15, 2010 @ 3:16 am

  12. All the best

    Comment by krest17 — March 15, 2010 @ 4:08 am

  13. Bonne chance!

    Comment by Sili — March 15, 2010 @ 2:34 pm

  14. Drzim palce!

    Comment by petr — March 15, 2010 @ 4:33 pm

  15. Good luck mate. Fingers are crossed for you. Hopefully there are no shenanigans at this place if you can get the job. Nice music btw, gotta love that crazy Euro music, especially the old stuff.

    Comment by OrganicOverdose — March 15, 2010 @ 8:38 pm

  16. W00t. Good luck!

    Comment by Rhenium — March 18, 2010 @ 5:23 pm

  17. Good luck!

    Comment by ristar — March 19, 2010 @ 1:57 pm

  18. good luck buddy. By your sheer quality, I am sure getting this position would be a simple walk over.

    Comment by pashu — March 20, 2010 @ 3:58 am

  19. Milkshake, I wish you the best of luck. When you were with Sugen I was with St. Louis based Pharmacica and we had a collaboration with Elan on beta-secretase right down the street from you in 2000. My how times have changed. Again I wish you the best of luck. John

    Comment by john — March 20, 2010 @ 11:45 pm

    • If history has taught us anything – it’s that no matter how bad things are they can get worse.
      Have you seen the “Life is life” video from Leibach? I think it should be adopted as the official ACS tune.

      Comment by milkshake — March 21, 2010 @ 2:44 am

      • The video is hilarious. But how many people miss the irony, I wonder.

        Comment by JH — March 22, 2010 @ 4:03 pm

      • If they were born in Europe, or if they recently worked in drug discovery, they get the joke.

        Comment by milkshake — March 22, 2010 @ 6:31 pm

      • That is what I’m talking about! Hilarious! You could start a new blog with this classic musik.

        Comment by OrganicOverdose — March 30, 2010 @ 6:18 pm

  20. Yes I definitely get the joke. My song vote is all of the CEO’s of big pharma sitting around and listening to the Clash singing “I’m so bored with the USA” “What about you ?”

    Comment by john — March 24, 2010 @ 6:47 pm

  21. “it’s a boy!”


    I didn’t have any boy babies of my own, but the grand-baby is a boy. Very much fun so far, especially the hilarity when we pop a “pee-pee teepee” over the apparatus during a diaper change. :-)

    Comment by Karl — April 5, 2010 @ 10:40 pm

    • sorry for confusing you, the “It’s a boy” reference is has to do with the Mike Ivy test and Edward Teller’s reaction to it

      Comment by milkshake — April 5, 2010 @ 11:19 pm

  22. How are you doing, milkshake?

    Comment by The Curious Chemistry Graduate — April 6, 2010 @ 4:06 pm

    • I will probably get the job – but its still more than month away

      Comment by milkshake — April 6, 2010 @ 4:23 pm

  23. Congratulations, milkshake. Doubtless this will be good for you, and for all of us.

    Comment by Chemjobber — April 8, 2010 @ 3:35 pm

  24. Hi Milkshake,
    first of all I’m glad to hear that you probably got a job again soon.
    Second, I have a question. I have read the CBC blog and found a comment from you about 2 years ago in which you say something about treating orthoquinone with morpholine and getting a deep blue solution. That reminded me of a problem I had last year. When I treated a solution methyl-1,4-naphthoquinone (Vitamin K3) with DBU (under argon or on air) it turned the same inky blue color you described. Eventually it would solidify, too. I tried to get an NMR of it, but it turned solid before I could get it. It is not quite the same as what you described with the orthoquinone, but I thought maybe you had an idea what happened there? I’ve tried looking in the literature, but all I have found is that naphthoquinones are unstable towards base (NaOH), but not what actually happens. If you had any helpful literature to this it would be even better :)
    Thanks in advance

    Comment by Xing — April 14, 2010 @ 11:40 pm

  25. I think one likely scenario is a ring-opening reaction of DBU which happens with electrophiles easily: you end up with products derived from N-(3′-aminopropyl)-caprolactam after the workup.

    I suppose your mystery blue compound could have been naphtoquinone with amine substituent next to quinone carbonyl, amine-substituted quinones are typically deep-blue. One could imagine zwiterionic Michael adduct of the DBU-amidine nitrogen into the naphtoquinone C=C, followed by hydrolytic ring opening of the DBU 5-membered ring, followed oxidation of the aminohydroquinone product by another molecule of naphtoquinone (or by air), to produce the blue-colored 3-(N-caprolactamylpropyl-amino-substituted naphtoquinone.

    But it could have been easily something else, as you know quinone chemistry is quite rich and colorful

    Comment by milkshake — April 15, 2010 @ 6:16 am

  26. Thank you for your quick reply. I could imagine the colorful chemistry of naphthoquinones, but my goal in this was only to make them colorless, i.e. to epoxidize them. Blue and other colors were unwanted. The point about DBU opening as well as aminonaphthoquinones being blue is interesting though. I guess I will have to further read about this in case anyone asks me that in my defense. Thank you and good luck to you.

    Comment by Xing — April 15, 2010 @ 6:23 am

  27. Milkshake-san,

    I enjoyed your music postings and particularly the translation. That is some heavy stuff, it could be an old Johnny Cash song or something from the Drive-By Truckers today.

    Comment by opsomath — April 16, 2010 @ 10:20 pm

  28. That reminds me. I have been working on a textbook sophomore organic reaction lately – double addition of lithiated trimethylsilylacetylene to a molecule containing two primary alkyl bromide groups. It didn’t work at all in THF, then I learned that everyone who actually does that reaction does it in HMPA. That is fine, but I seem to always have five percent of the mono-bromo-mono-TMSacetylene intermediate in my product no matter what I recrystallize from, how many equivalents of excess lithium-TMSAc I use, or how many meticulous columns I run. Any thoughts from the synthetic ninjas on here?

    My conclusion: any reaction they taught you in undergrad, but did not have you demonstrate in lab, is total crap.

    Comment by opsomath — April 16, 2010 @ 10:40 pm

    • Allylic bromides are so reactive that it should be easy to destroy the monobromo impurity during the recrystallization, just by adding something polar that alkylates easily, like thiourea or imidazole, to the crude product.

      I wonder what you have used for deprotonating TMS-acetylene: was it straight BuLi? (I would definitely prefer to use straight BuLi in hexanes as the base). There is no reason why you shouldn’t be able to drive both bromides to total conversion with the excess of the acetylide.
      Are you absolutely sure that your impurity is monobromo – and not monochloro, or some other sideproduct? Are you sure that your starting material does not contain 5% of something else (mono bromo-chloro analog, for example)?

      Also, working with HMPA is pretty disgusting – especially the workup, on a larger scale. (And you have to CaH2-vacuum distill your own HMPA, and HMPA is genotoxic, and so on). I wonder if there is any easier alternative that uses Pd-catalyzed allylic alkylation of acetylides in something like THF or dimethoxyethane, and you just throw in some Pd-tetrakis to your substrate (and you can easily work with allyl chloride or pivaloyl allylic ester also; I am very fond of Pd-catalyzed Tsuji-Trost allylations – but I only used them with soft carbanions like Meldrum’s acid).

      I remember vaguely that Zn and Al acetylides are easy to generate and they alkylate nicely, I think with aluminum it was obtained directly by reaction TMS acetylene with Me3Al in toluene (although once I did it with BuLi in THF followed by addition of Et2AlCl, and the produced Al-acetylide worked gorgeously for a conjugated addition to 3-methyl-2-cyclohexene catalyzed by few % Co(II)salene ) – but you will need to check Scifinder. But please first have a look at what was done with Pd-catalyzed allylations of acetylides, I think there has to be something mild and clean that does not require glovebox and does not use HMPA

      Also, I remember Aldrich sells a slurry of bis-sodium salt of acetylene, I believe as a complex with ethylenediamine, and this is cheap reagent (unlike TMS acetylene which is quite dear) and the bis anion even if poorly soluble should be lot more reactive than monoanion, so unless you need the TMS groups in your product maybe you can add your allylic bromide substrate slowly into a large excess (5-10 equivs) of bis sodium acetylene…

      Comment by milkshake — April 17, 2010 @ 1:11 am

      • Oh, if only my substrate was an allylic bromide! In my experience, those react beautifully with just about any nucleophile, including the notoriously reluctant aryl Grignards. Unfortunately, my current molecule is a mere primary bromide, or rather an aromatic ring center decorated with a pair of hexyl chains ending in a primary bromide.

        In the light of a pretty Saturday, after a night’s sleep and a couple cups of coffee, I think you may be right about the impurity not being the mono-alkyne product. I have a batch of meticulously recrystallized starting material made yesterday which may give better results.

        The bis-sodium acetylide is a good tip. I do in fact need the TMS group, but perhaps I can get it by quenching with TMS-chloride?

        I’ll have to look into the Al-acetylide addition to alkenes catalyzed by the salen-Co cobalt. That sounds handy.

        Thanks for your help!

        Comment by opsomath — April 17, 2010 @ 9:52 am

  29. I did similar alkylations of greasy chain primary alkyl bromides during my Ph. D. work. I always used 1.5 equiv of TMS-acetylene, 1.4 equiv of n-BuLi in hexanes, let deprotonate for 15 min at 0C under Ar in THF, then cooled to -78C and added a THF/HMPA solution of alkyl bromide to it. Let marinate overnight as T gradually goes back to r.t. Your product being greasy, can be extracted with 5-20% EtOAc/hexanes, in which HMPA is essentially immiscible. So, yes, HMPA is crazy toxic, but stays in the brown aqueous layer – so as long as you double-glove your hands and don’t drink your aqueous phase (!) you’re essentially in business. :-) Always washed the combined organics 3x with brine, after which there never ever remained any HMPA in the crude compound, by 1H NMR.

    A search of Trepanier and Palladium off the library web site should take you to my Ph. D. thesis in less than 5 mins, for further details… Look up the retarded 100+ pages of experimental procedures of Chapter 3… it is in the General Procedures! :P

    Comment by HPCC — April 19, 2010 @ 11:58 am

    • Hey, that’s excellent! Thanks for your contribution, and if it makes you feel better I read a lot more of that thesis than was directly related to my alkynylation. Cool stuff! I may be meddling with a bit of Pd/Pt coupling chemistry for an upcoming project, so it was helpful to take a look at some of your mechanisms.

      My procedure to this point has been extremely similar – prepare the TMS-acetylide by dropping nBuLi into a slight xs of TMSacetylene, starting at -70->-20, then dropping alkyl bromide in 50:50 THF/HMPA at -50. The major difference is that the one time I let it warm to RT over a weekend, it turned brown and gave me total garbage (millions of spots on TLC, and pretty blue fluorescence) so I keep the whole thing below -20 until TLC of an aliquot is not changing any longer. The reaction essentially works, it’s just that since I have two alkyl bromide groups in my starting material, I get a bit of mono-bromide mono-TMSAc intermediate with is INCREDIBLY hard to separate from the product.

      Perhaps I will let warm to RT and carefully monitor the whole time til finished.

      Comment by opsomath — April 19, 2010 @ 1:33 pm

      • maybe you can parafilm the septa all over and leave the flask in a freezer overnight, then do the workup next morning.

        How sure are you that the impurity is monobromo? Is there by chance a possibility that the impurity is a bromide elimination product with C=C?

        Comment by milkshake — April 19, 2010 @ 2:18 pm

      • Funny you should mention that, Milkshake, a related procedure where I install propargyl groups in place of the bromines using NaH + propargyl alcohol does lead to a small fraction of mono-dehydrobrominated product. Fortunately this is relatively easy to separate from the bis-propargyl ether product. Anyway, the resulting vinyl protons show up like a beacon in 1H NMR – I do not have those in the product from my TMS-acetylene procedure.

        You could be right about the impurity being something else besides monobromo. However, when you see the spots on TLC it makes you “want to believe” (a la x-files) that it is monobromo – since aliquots of the unfinished reaction give a classic pattern of three spots on TLC, corresponding to dibromo, monobromo, product. Perhaps the monobromo spot co-elutes with (like you were saying) the chloro, or some other inert impurity such as R-C6H13 instead of R-C6H12Br.

        The freezer is a good idea for keeping it frosty overnight. I might just try that one, as well as Dr. HPCC Trepanier’s slightly-modded-and-probably-superior procedure above.

        Comment by opsomath — April 19, 2010 @ 2:46 pm

  30. In any ways, opsomath, i’ve separated grease from greasier grease for those 5 (still pleasurable) years… from the structures of the products therein, you can see I was jumping with joy whenever I had a single methoxy on my compounds! :) And now, I’m in Big Pharma, making actual relevant molecules with heteroatoms… different challenges altogether!

    All the best!

    Comment by HPCC — April 19, 2010 @ 3:40 pm

    • The point I wanted (and forgot) to make was that, I feel all your pain during those purifications!

      Comment by HPCC — April 19, 2010 @ 3:42 pm

    • If Opsomath does re-crystallization of his product from a hydrocarbon solvent, I would recommend to include some benzene in the mix. Benzene health risk is vastly overhyped and benzene is a great solvent for crystallizations: It likes to co-crystal with many compounds, co-crystals of a product with benzene saved me repeatedly in difficult purifications when nothing else worked.

      My favorite hydrocarbon system for recrystallization is benzene + cyclohexane. (The mix does not freeze in the fridge, and the boiling point of PhH and Cyhex is similar).

      Another good solvent for re-crystallizing very greasy compounds is straight acetonitrile.

      Comment by milkshake — April 21, 2010 @ 5:58 am

  31. Milkshake, I would be tremendously honored if you were to share your favorite chemistry things, like such:


    Comment by Chemjobber — May 15, 2010 @ 7:31 pm

  32. Question about Pd tetrakis:

    Purification: What’s the easiest way to recover the bright yellow stuff back from the brown darkness that is bad tetrakis ? I’ve heard washing with MeOH / EtOH, but that’s about it, and you seem to loose a lot (or maby my brown stuff was really bad).

    Also, there seems to be a lot of lore about tetrakis… can someone set the record straight for me : Is it :
    a) light sensitive
    b) air sensitive
    c) temperature sensitive (must be kept in the fridge)

    or a&b but not c, or a&c but not b… etc . Everyone seems to have their own rules… is any of this backed up by experience / data ?

    Comment by Adam L — May 16, 2010 @ 2:21 pm

    • it makes no sense to try to clean up or recycle bad tetrakis. You just throw it away and get a new lemony-yellow stuff. You can make your own, from PdCl2 and PPh3 and hydrazine in DMSO (with heating under Ar, tetrakis crystallizes out), the procedure is for example in Carbon Based Curiosities blog.

      Pd tettrakis is quite air sensitive in solution and moderately air sensitive as a solid. It is best stored under argon in a freezer. Strem packages tetrakis in a narow mouth clear bottle – that way you can tell the color of what is inside, and the bottle is easy to flush with Ar and re-seal with parafilm. Strem also makes a high-quality product, packages it under Ar and ships it sealed with parafine wax. When you receive tetrakis you place it in freezer. When you are about to use it, let the botttle warm up for few minutes. You weight out your tetrakis, then flush the tetrakis bottle with a gentle stream of Ar flowing from a wide tube (for example, straight from the tubing connector on the Ar tank regulator), you cap it quickly, parafilm and place back in a freezer. The stuff is not bench and air-stable. You can work with it for few minutes without protective atmosphere but do not let your already-opened tetrakis bottle sit around for hours, or it will go bad. With the few simple precautions I had often my own bottle of Strem tetrakis in a freezer that was good a year after being opened. Next to it were bottles from people that were more careless and they stuff was chocolate brown. Its the flushing with Ar that makes all the difference.

      Comment by milkshake — May 16, 2010 @ 3:11 pm

      • Huh.. interesting… I always though the argon/nitrogen flushing of reagents really didnt do much unless it was done in a real argon/N2 atmosphere (i.e. glovebox). I’m a lot more willing to believe argon b/c it’s heavy.. but I always smile to myself when people “flush” with N2 without any sort of septum, or add things under “a cone” of N2 (inverted powder addn funnel with septum) as if the N2 will just stay in there all by itself.

        Thoughts on this ?

        Comment by Adam L — May 16, 2010 @ 3:28 pm

  33. Well, N2 must have similar density as air (around 80% is N2) so I think if you fill something with N2 after vacuum and tap it, I think it is possible that N2 remains there. A cone of N2 of enough pressure can prevent sucessfully moisture to contact with a solid filtered for instance, and avoid oiling or making chewing-gum of it.

    Comment by vasili — May 17, 2010 @ 3:36 pm

  34. It’s been a long time milkshake. I miss the new chemistry update.

    Comment by james — May 28, 2010 @ 7:39 am

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