Org Prep Daily

About Org Prep Daily

I am going to post here synthetic procedures that pleased me. The experiments were joy to set up+run, the purifications were a piece of cake, the crystals were shiny and the yields were terrific – or maybe weren’t but I liked the preparation anyway. Many procedures came from the literature, some were modified and few are my own. I hoped (and tried) to make these write-ups reproducible and reasonably safe – but I could be wrong and lucky:
‘It is necessary that the operator takes all precautions to preserve himself from misfortune.’

Sorry if you are looking for psychoactive or energetic compounds, you won’t find help here – my work is related to cancer and neurology research. In medicinal chemistry, one often cannot present a full account. You will see some building blocks, precursors, reagents but most likely not the final stuff.

Update: End of daily posting. Please feel free to submit any good synthetic procedure you like to share here in Org Prep Daily. Cheers to Chris Douglas.

Update (8/24/08): 1,730 real comments and “Akismet has caught 33,700 spam comments” with about 30 legit ones filtered out unfairly. Please limit the number of inserted additional links in your comment-text to one link per post. Avoid foul language – the automatic spam filter is a prude. Thnx and sorry.


  1. Nice site! You should consider a quick blerb about what the reagent is used for so younger chemists can learn why they might want to make these reagents.

    Just a thought.

    Comment by d-orbital — September 8, 2006 @ 5:37 pm

  2. Delighted that you are putting up procedures for the rest. Also second the comments of d-orbital. However, i believe i look forward more to your comments on others blogs and the way you address problems in synthesis (guess it comes with doing a lot of chemistry).

    Comment by sks — September 17, 2006 @ 4:02 pm

  3. That sounds great milkshake! Great thought and all the best. I would love to see comments and appreciations for the procedures.

    Comment by Joseph — September 26, 2006 @ 4:26 am

  4. Dear Milkshake,

    I couldnt resist the temptation (while evaporating toluene) of reading one of your comments in a magazine (In these days) three years ago, and I have to say that I quite symphatize with the comments you posted there (you’ve got guts and know very well what you are talking about).

    I quite like this blog as well, (I think actually that you are really generous to the chem bloggers), and sure I will take into consideration if I will have to follow any similar procedure, but when are you going to gift us with comments in general about chemistry, chemistry news or more general topics? (and I am not speaking about gossips or any other rubbish, like it happen at one point in tenderbutton).

    Comment by HOMO-LUMO — October 4, 2006 @ 4:59 pm

  5. Thank you H-L but I put up this site for procedures that I did with my own hands (and liked for one reason or another). The motive behind doing this was that lots of work in medchem is spent on bits and pieces that are not publishable on their own and once the project is over they are forgotten and lost. But if I put these procedures on the web – with Google being so powerful and inteligent – they might be useful to someone in a medchem lab.

    So I would like to have this page much like a private version of OrgSyn. I want to keep the noise here to minimum. Also, I am not particularly eager to write and post some well-thought opinions about chemical community or pharma industry in general and I am not going to write about my colleagues, workplace or private life either. Dylan’s Tenderbutton was a wonderfull hang-in place whereas Org Prep Daily is intended to be dull.

    Comment by milkshake — October 4, 2006 @ 5:47 pm

  6. Thanks for popping by my site and linking, but more importantly, thanks for your efforts on a particular patent. We won’t let you down!


    Comment by Xcovery — January 12, 2007 @ 5:09 pm

  7. Timmy, I have been following the Xcovery kinase blog regularly for couple of months – thanks to Kinasepro – not knowing who you were. (So you can imagine my suprize when I realized that you are in charge of a company that is going to develop our compounds). It’s a small world. Best luck to you with everything.

    Comment by milkshake — January 12, 2007 @ 5:47 pm

  8. Could you please give your e-mail or drop me a note on the address here, I have a few questions…

    Comment by liquidcarbon — May 24, 2007 @ 11:03 am

  9. I want to prepare mixed anhydride using isobutyl chloroformate of N-boc-l-2-amino butyric acid. but reaction did not complted unreated isobutyl chloroformate creat problems how can i remove unreacted isobutyl chloroformate.

    Comment by grignard — January 17, 2008 @ 12:51 pm

  10. Milkshake: no need to publish this. Since Paul has stopped posting > 2 months, I’ve decided to take your advice and use WordPress and start my own blog. Would you be willing to answer an occasional question? If so, send me your E-mail address. Any suggestions as to naming things: Woodward’s worst grad student and Chemist in Recovery come to mind

    Comment by Retread — January 17, 2008 @ 9:34 pm

  11. The last time I used it, iBuOCOCl from Aldrich has had some stuff in it so I would recommend to re-distil it carefully. I always use EtOCOCl instead, it is very similar in terms of the racemisation problem but it tends to be cleaner. But why mess with mixed anhydride? For aminoacid coupling I would normally use HATU or EDC+HOBt.

    Retread: Please name your blog in any silly and memorable way you like – I wouldn’t overplay the Woodward thing though

    Comment by milkshake — January 17, 2008 @ 10:26 pm

  12. My goodness, where is Marcel now? We were at UCLA together.

    Comment by Paul — August 21, 2008 @ 3:38 pm

  13. right next office and hood from me – I will send you his e-mail if you want, I just gave him yours.

    Comment by milkshake — August 21, 2008 @ 3:42 pm

  14. Having trouble with a permangate oxidation of the methyl groups on a difluorobenzene – any suggestions?

    Thanks in advance.

    Comment by Andy — January 6, 2009 @ 2:05 pm

  15. Unfortunately I don’t know what kind of trouble you have – is it overoxidation, or poor conversion due to poor solubility of the starting material, or the volatility problem (your substrate is likely to azeotrop with hot water)?; without knowing your actual problem is it is difficult to propose how to fix it. For comparison there is a procedure for oxidation with aq. permanganate, posted here on Nov 14, 2006.

    I remember seeing some J Med Chem paper where they performed permanganate oxidation in pyridine as a solvent; the workup is not going to be fun though. Also I have a procedure here for organic-soluble Bu4N permanganate (March 16 2008] that I used for oxidizing material in dichloromethane as a solvent but I am not sure if it would work in your case.

    There is an alternative methyl-to-carboxyl method that uses aqueous dichromate or chromate at elevated temperatures in a pressure vial, it should be quite easy to try if you have a microwave reactor.

    If everything else fails you can try CrO3 in acetic acid, this should do the trick – but please be careful before scaling up, this mix can be treacherous if overheated, so use oil bath (not a heating mantle).

    Also, fluorinated benzenes are very easy to ortho-lithiate (and quench with CO2), if your carboxylic acid is in the ortho position to F this may a better alternative than oxidizing a methyl group.

    Comment by milkshake — January 6, 2009 @ 5:02 pm

  16. during the synthesis on a industrial scale we use sulfur for aromatization of a buta diene derivative. after this we carry out fewmore steps. But the assay of final product seems to be below expected level. Feel strongly the presence of sulfur in the final material. How do you remove unwanted sulfur completely from the reaction mixture. your expert comments is highly appreciated.

    Comment by pashu — April 15, 2009 @ 11:24 pm

  17. Its not butadiene but 1,3-cyclohexadiene as mentioned above

    Comment by pashu — April 15, 2009 @ 11:25 pm

  18. I never had this problem, with removing sulfur, but if your product is crystalline I would suggest a re-crystallization from some polar solvents, like ethanol-water mix. Sulfur is practically insoluble in polar solvents. Alternatively you may try a wash with a solution of Na2S hydrate, sulfur dissolves in sulfide to form polysulfides. (But sodium sulfide is smelly, rather alkaline and oxidizes easily so I would first try a non-chemical removal method.)

    Comment by milkshake — April 16, 2009 @ 9:02 am

  19. hello milkshake.
    plz help me !! . I have a funny problem by using K2CO3/MeOH . I wanna use that as a base system but k2co3 is not solute in neat MeOh . what must I do ? (organic media)

    Comment by saeid — June 27, 2010 @ 1:54 pm

    • K2CO3 has limited solubility in methanol but it is quite sufficient for many reactions, such as alkylations or methanolysis of esters. You need to use finely-powdered K2CO3 as a slurry in MeOH – and preferably several equivalents if you are using it as a stoechometric base (rather than a base catalyst). Make a slurry and put some of the methanolic solution onto a moistened pH paper – you will see it is basic.

      Comment by milkshake — June 27, 2010 @ 3:00 pm

  20. Hello milkshake,
    I have a great problem about my research that Its not working for the whole summer. What I usually do is just follow the procedure what the published paper has.

    Could you please give me some idea how synthetic people reproduce the result?

    I wasnot that bad but I don’t know what is going wrong on my part these days?

    Thanks in advance

    Comment by Bhoj — August 11, 2010 @ 10:43 pm

    • I don’t know the details of your problem so it is hard to suggest a fix. There is always a possibility that the procedure itself is crappy, or that some important detail is missing, or that they made error in some essential aspect like order of reagent addition or cooling when they wrote the procedure for the paper. You may want to be especially circumspect if the procedure came from a patent or from an Indian journal, and if details (like spectra or solvent volumes etc) are missing.

      Another possibility is that you are doing something wrong, or that there are peroxides in your THF, ethanol stabilizer in your DCM or water in somewhere, that your tetrakis in the bottle is oxidized, whatever. I suggest that you ask a some more experienced colleague to give it a try as well, with new reagents and purified (or anhydrous) solvents, and if you both cannot reproduce it then, in all likelihood, the problem is with the procedure. You would not believe what kind of stuff sometimes gets published…

      Comment by milkshake — August 12, 2010 @ 12:14 pm

  21. Hi Milkshake,

    Your reputation spreads around. So I wanted to pick your brain on this one….I call it “Stille reaction on a desert island”:

    Here’s the situation: I work as a volunteer on my own research at a small, impoverished state university campus. I’m literally the only one here who does organic synthesis . The lab where I am located has three Pd-catalysts available. No money. The three catalyst systems off the shelf are:
    a. Pd(Ph3P)2Cl2
    b. tris(dibenzylideneacetone)-dipalladium(0) (unknown age)
    c. PdCl2(dppf) complex w/ CH2Cl2 (unknown age)
    d. Some Pd(Ph3P)4, presumably long since dead (ok, ok under more modern conditions I could just make some fresh stuff up)

    I want to couple 2-(tri-n-butylstannyl)pyridine with a 2-chloropyridine derivative (relatively sterically hindered, substituted on the 6-position with more nitrogen heterocyclage). So far, both Pd(Ph3P)2Cl2, slight excess of the tin derivative in DMF/N2, reflux and ditto but w/ 2 equiv. Ph3P in xylenes/N2 give incomplete conversion (S.M. elutes close to product).

    And so I was seeking advice under those circumstances. How stable is the dibenzylidineacetone complex or is it probably all crapped up? Should the ferrocenyl precursor complex be more reactive than simple Pd(Ph3P)2Cl2 because of electron-donating ability & wider Tolman angle? Or maybe I just need to add in 1 equiv. of an inorganic base?

    The caveat is that one of these three bottles has to work!


    Comment by fentonh — October 1, 2010 @ 12:15 am

    • I have never done Stille coupling. In Sonogashira I noticed that for substrates that are strongly coordinating (2,4-diamino-5-bromopyrimidines), the PdCl2(dppf) complex was slightly faster/cleaner than PdCl2.2PPh3
      That system used NEt3 as a base in THF and has CuI and acetylene in it – I think the reduction of the Pd(II) happened only after the CuI addition (from red-orange color of of PdCl2(dppf) the mix promptly became greyish, finally pale yellow).

      I would not trust old Pd(PPh3)4 unless it was stored in the freezer under Ar – and its color should be lemon-yellow. Brown or greenish-gray tetrakis is crap.

      Pd2(dba)3 is quite stable at RT under air (it is supposed to be dark). I would add 2 equivs of PPh3 to Pd2(dba)3, the mix should be similar to fresh Ph(PPh3)4

      Comment by milkshake — October 1, 2010 @ 7:48 am

  22. Thanks for your advice. Am trying out 1.5 mol% Pd2(dba)3, 3 mol% Ph3P, 3 mol% CuI…heating briefly under reflux in degassed xylenes before adding the Py-2-SnBu3. So far, it’s a strongly red color.

    Comment by fentonh — October 1, 2010 @ 4:32 pm

  23. Hi back again with another question on palladium catalysis. People talk about the presence of finely reduced Pd(0) being deposited from solution as coupling reaction progresses. I, too, notice this and ask myself (and you): what is the significance of this observation:
    (a) is the deposited Pd(0) thereby removed from the catalytic cycle?
    (b) shouldn’t the stuff be in solution with accompanying ligands?
    (c)does its formation somehow indicate that the reaction is working, or even complete?

    Thanks again for your time and insight.


    Comment by fentonh — October 1, 2010 @ 5:38 pm

    • I think formation of Pd black is a sign of catalyst decomposition. It is true that Pd can go back and enter catalytic cycle again under more harsh conditions (people have done Pd-catalyzed reactions like Heck with 10% Pd-C) but Pd black formation is undesired. I would try to add one extra PPh3 to keep the Pd(0) catalyst more stable.

      By the way, Pd2(dba)3 has usually a molecular weight of the whole complex written on the bottle – a molecular weight that covers 2 equivalents of Pd(0). People often make that mistake, adding twice as much Pd2(dba)3 – then they are surprised when Pd black falls out

      Comment by milkshake — October 2, 2010 @ 3:00 pm

  24. hello milk-shake i have a problem in coupling heterocyclic halo aryl compound with replacible hydrogen of benzimidazolone ..plz suggest procedure to obtain result ..or catalyst and conditions

    Comment by hezy — February 28, 2011 @ 3:02 pm

    • one would obviously use Pd(II) and Cu(I) catalysts for this type of arylation but the literature is huge and the choice of metal/ligand/base very strongly depends on what is in your substrate. I would recommend that you do a thorough Scifinder search and look for the closest possible precedents. Look up papers from Buchwald group too. You can try Pd2(dba)3+Xanphos or CuI with 1,2-bis(methylamino)-cyclohexane, maybe in dioxane, with powdered Cs2CO3 as a base.

      Comment by milkshake — February 28, 2011 @ 3:32 pm

  25. hi milkshake,

    very nice blog indeed. i am wondering. do you know standard recipes for “simple” organic reactions. i myself perfrom an esterification via acid chloride route but wondering which steps i have to take extra care to get a good yield. the yield actually sucked when i tried to scale up the reaction.
    wondering if i should go for dcc, but since the urea is kinda loving to hang around the product this route seems to be not so valuable either.
    do you have any other recommendations for esterifications or do you have a favorite one?
    my email is hpchemist ät gmail dot com if you would like to answer me in person.

    keep up the work

    p.s.: my world are actually polymers, so i’m not the best organic chemist around 😉

    Comment by mathias — March 18, 2012 @ 7:50 pm

    • orgsyn (organic syntheses) is a good starting point, you can browse the reactions by the reaction type (“acylations” etc). There is lots of ground to cover but in short acyl chlorides are very reactive and moisture sensitive (so you want to have your solvents anhydrous) and first you have to make sure that your acyl chloride has a good purity (re-distilled etc, take 1H-NMR ind CDCl3) and you want to use a mild base such as pyridine or N-methylmorpholine or N-methyl imidazole since more basic amines (NEt3, iPr2NEt) are prone to cause ketene-related sidereactions which result in lots of dark stuff. You may want to cool the reaction on ice bath or salt+ice and add your acyl chloride into stirred mix of alcohol and amine in some inert solvent like dichloromethane or acetonitrile or THF

      Comment by milkshake — March 18, 2012 @ 10:28 pm

  26. thanks q lot for your info. i am actually using dry dcm due to the reactive nature of the acid chloride. after formation via oxalylchloride (and a few drops of DMF) i just “purify” by removing the excess oxalylchloride. then i add dry dcm to dissolve the acyl chloride, add the alcohol (in large excess) and in the end dry DIPEA (gas formation starts (all done at rt) under a septum. actually i thought that acylations were straight forward reactions and did not know that there are so many side reactions possible (4 spots tlc). i don’t understand how you are going to run an NMR with such a substance which decomposes in contact with water towards the acid. is there dry CDCl3 available at your place?
    also i don’t get it why i should use pyridine (i could use it; it’s available) as a base instead of DIPEA, i was told DIPEA is excellent due to it’s large size (less chance of attacking the acid chloride function). i have to admit though, that the stuff in my flask turned dark.
    is it important to add the acid chloride to the alcohol? other way round is a bad idea?
    does it matter when to stop the reaction? once the ester is formed, it stays like this “forever”, right?

    Comment by mathias — March 19, 2012 @ 4:45 am

    • Mathias. sorry but these are quite elementary questions that you are asking and you can find the answer in a freshman textbook. Look up the ketene formation mechanism, then look up pKa of tertiary amine bases (iPr2NEt, NEt3, N-methylmorpholine, pyridine, N-methylimidazole)

      Comment by milkshake — March 19, 2012 @ 7:57 pm

  27. hi milkshake,

    thanks for the advice, will check this out. have a nice day 🙂

    Comment by mathias — March 20, 2012 @ 6:05 am

  28. Hi Milkshake!
    I have a question.
    How did you put chemical strucutres in this blog? Did you use any special program or did you upload it as jpg file or something? I tried to draw something in ChemDraw and saved it in bmp file, but when I uploaded my structure it looked horrible. Any tips for great looking structures?

    Thanks in advance.

    Comment by chemfish — June 14, 2012 @ 7:30 am

    • I have a Chemdraw version thats about 2 years old. I use JACS drawing settings, when done I edit the entire scheme in ChemDraw “edit object – scale – change the object so that the median bond is = ” (and change the atoms font to match the size – it will ask you automatically) to 0.3inch for large structure or 0.2 inch for regular structure. I save files from ChemDraw “save as gif” file. WordPress imports gif files without too many problems and the generated files have a reasonable size. Png files from Chemdraw work too but are somewhat bigger. Try to have the imported file within reasonable limits (50-80kB) – otherwise people with slow internet connection may see broken links instead of structures.

      Comment by milkshake — June 14, 2012 @ 12:17 pm

      • Thanks. I tried what you suggested and it still looks weird. The, I noticed I imported the picture and put it shrinked to medium size. After I changed to full size, it all looks better. Thanks again!

        Comment by chemfish — June 15, 2012 @ 6:02 am

  29. Dear Milk shake
    Johnson Matthey’s markets wide variety of metal scavengers (polymer supported resins). In the Smopex product range, Smopex – 103 (quaternary ammonium), Smopex-105 (pyridinium hydrochloride) does the job of scavenging Pd(0) and Pd(II). It is not clear to me how can positively charged nitrogen in these products scavenge Pd(0) and Pd(II). Appreciate comments and clarification with respect to this chemistry.

    Comment by pash — November 7, 2012 @ 5:24 am

    • this is quite interesting but I don´t know much about scavenging Pd. Pyridinium hydrochloride dissociates to an appreciable degree, perhaps you get Pd – dichloro bispyridino complex, or a pyridinium salt of tetrachloropalladate anion. I think the first possibility is more likely

      Comment by milkshake — November 7, 2012 @ 7:07 am

  30. Hey milkshake, what are you waiting for?

    Comment by NMR — July 22, 2015 @ 9:19 am

  31. Hey Milkshake, you can email me at atchemblog (at) gmail (dot) com. Or suggest an alternative way to communicate re: Open Flask / In The Pipeline comments.

    Comment by atchemblog — January 18, 2016 @ 7:13 pm

    • I am not very interested in this stuff – it seems pointless arguing with you, if you think students publishing their work on new methodology in Nature are getting a raw deal from big pharma, or their advisor. You should find out what goes on elsewhere in academia, before you try to point out the supposed exploitation in Baran group

      Comment by milkshake — January 18, 2016 @ 7:44 pm

  32. I have a query.
    We are doing the depolymerization of polysaccharide using Cat H2SO4 and H2O2 (used in volumes).
    Depolymerization of polysaccharide is known either using H2SO4 alone or H2O2 alone.
    Many literature suggests to use the combination of Cat H2SO4 and H2O2.
    Is it going to produce OH radicals which will react at the reducing end of the sugar to do the depolymerization. Under these conditions, will the reducing end remain intact.
    Looking forward to your expert comments

    Comment by Pash — August 31, 2017 @ 8:11 am

    • I don’t know but I doubt it. If you combine excess of conc. sulfuric acid with 30-35% H2O2 you get so called piranha mixture – it is pretty unstable hot mix that mineralizes organic residues to CO2 and water, and it ignites and detonates in contact with sugars.

      I have no experience with cleaving polysaccharides but I would not use the combo you are proposing

      Comment by milkshake — August 31, 2017 @ 9:13 am

  33. Is this still active?

    Comment by Will — March 11, 2021 @ 5:49 pm

  34. Milkshake,
    Thank you for your assistance over the years. I need your help yet again. How can I selectively form an ether at a primary benzylic hydroxy of a molecule that has a free phenolic hydroxy?

    Thank you

    Comment by Simeon — January 5, 2022 @ 9:18 am

    • You will need to protect phenol first. It should not be too difficult because phenols are more acidic and phenolate is a better nucleophile than benzylic alcohol. The thing you don’t want is an excess of strong base like NaH or tBuOK or LDA because with two equivalents you would generate alkoxide also, and alkoxide is still more nucleophilic and basic than phenolate. I would recommend to use 1 equiv of DBU in acetonitrile and protect the phenol with 1.05 equiv of MOM-Cl, MEM-Cl, or with TBS-Cl. Anything that you can cleave easily after the ether formation (I don’t know what is in your molecule, the choice of protecting group and conditions very much depends on it)

      Comment by milkshake — January 5, 2022 @ 3:52 pm

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