Org Prep Daily

about Milkshake

credit: Jirí Slíva


  1. Surprisingly, all the things dealing with chemistry.

    Comment by sks — September 27, 2006 @ 1:54 pm

  2. Is milkshake the same person as secret milkshake?

    Comment by Mitch — September 28, 2006 @ 3:36 am

  3. He controls me. I am his front-man.

    Comment by milkshake — September 28, 2006 @ 3:47 am

  4. If milkshake = secret milkshake, then would it would not be a secret, would it?

    Comment by milo — September 28, 2006 @ 11:47 am

  5. are you thomas w. lee ?

    Comment by loulou — October 4, 2006 @ 3:47 pm

  6. no, I am not – although you can ask thomas w. lee if he is milkshake
    (we were good friends actually, he was in a lab across from mine. He is a great chemist and very considerate + pleasant guy)

    Comment by milkshake — October 4, 2006 @ 4:03 pm

  7. Milkshake:

    Csan you recommend a good commercial or freeware program for calculating the costof the final product of a sequence of organic reactions.


    Comment by Don Butler — March 14, 2007 @ 12:23 pm

  8. Nobody needs to use software of this kind in the normal organic synthesis lab. You are asking the wrong man. IMHO the math in quetion is very simple, you don’t need a software, arithmetics on a piece of paper will do – but the obtained cost figure will be misleading because in chemistry process things go wrong all the time and you have no idea what you are up against until you try the experiments. I suppose you are in custom synthesis, somebody just gave you a procedure you don’t know if the procedure is reproducible or if it is a poorly-documented crap that will need lots of optimisations. You cannot predict if your product will gum up or melt on the filter and decompose – or if it will crystallize in the end in shiny needles. And you would like to quote a price and win the contract. There are too many unpredictable factors and no fancy software will help you.

    Offer your customer to do the chemistry on reasonably small scale first. For the cost of the pilot run add cost of reagents, employees benefits and salaries, equipment and waste treatment, multiply it by factor of four and quote it as a price for pilot run. Expect that you can lose money on this run. After the pilot run you will get more appreciation of the problems and expenses, you can talk to your chemists and arrive at a more realistic figure that you can quote to your customer as the actual scale-up price. Leave sufficient margin for unforeseen problems. It makes no sense to try to get a contract by underbidding everybody else – only later finding out you set yourself up for failure, lost money and aggravated your customers.

    Comment by milkshake — March 14, 2007 @ 2:42 pm

  9. Hai Milkshake, this is for you!

    Comment by Taitauwai — April 24, 2007 @ 8:42 pm

  10. Thank you for the group portrait. The one detail that’s not right is the shape of the sink – the lab sinks here tend to be large, sqarish, waist-high and black-colored. Otherwise it is a correct depiction. Please can I expand your drawing and post it at the sink? – Right next to the sign “Aim away from the toothbrush”

    Comment by milkshake — April 25, 2007 @ 12:07 am

  11. Sure no problem. Have a good laugh! When I have to the time, maybe I can improvise the sink a little bit. 😉

    Comment by Taitauwai — April 25, 2007 @ 3:43 am

  12. Re: Cost calculations
    Try ChemProject from: I think there is a time-limited trial period, although you probably can’t print the results.
    I am one of those “process guys”, and have “done it myself” for years since pc’s came out (yes I am that old to remember a time before !). You can do a lot with a spreadsheet, but what you don’t get is error checking, and too often your colleagues structure their calculations diffrently so no-one knows how to edit correctly if changing a mole ratio or something like that. The commercial package provides a common structure, and this one can add up the reaction volumes from step to step as well, if you want, keep track of waste volumes etc.

    Comment by Nick — June 6, 2007 @ 4:57 pm

  13. Learn to spell, Milkshake.
    Using incorrect or bad spelling negatively affects your credibility, irrespective of your knowledge and your intelligence.

    Comment by El — January 7, 2008 @ 10:41 pm

  14. Thank you for your comment. I always had hard time spotting my own typos – I am dyslexic and english is my fourth language. WordPress spell-check does not work with this particular theme that I chose. (One can copy/paste into Word, to see the typos – a routine I have been using from time to time). Since I am not too worried about my credibility, I would suggest to all spelling bees that they go and knock themself off.

    Comment by milkshake — January 8, 2008 @ 9:41 am

  15. An inexpensive little program called Grammarian will give you much relief. It checks spelling and grammar and is very easy to use, and it will work on your blog posts very well. The developer is always willing to lend a hand. He will personally respond to questions and does not charge for new versions.

    I came to your site after reading your post on foodwishes, and I’m enjoying my visit. A brother-in-law of mine is a chemist at the company that let you go. He works in NJ. He isn’t happy there and is on the look for something else. Life it too short to spend your workday in an unhappy environment. The money may be okay, even good, but the older you get the more you understand that happiness is not dependent on money. We get value from our time when the emphasis is on the people we spend it with. Far less happiness comes from having money related experiences and “things”. Good luck to you, and keep cooking with Chef John.

    Comment by Von Day — February 26, 2008 @ 2:05 pm

  16. Milkshake,

    If you have a few moments, I have a question (after some exposition, of course).

    Some months ago, you posted an answer to the New Scientist Last Word blog – some poor creature was heating wine and olive oil and spattered himself and asked for an explanation. It was called “Kitchen Calamity.”

    I witnessed a similar (I believe) incident on a much larger scale when a co-worker was doused by a hundred or so gallons of water, which erupted out of a 4′ by 6′ deep sump pit, but was not scalded in any way. The rubber grip of the screwdriver he was holding deformed and was soft. The sump pit collects steam condensate which often reaches temperatures of 150-160 deg F before it is pumped out. We were getting ready to work on that pump when a large column of water gushed from the 2 ft. diameter access port cut into the metal cover of the sump pit, struck the ceiling 12 feet above and covered the basement floor with several inches of water. The water was hot, but not uncomfortably so and was certainly not boiling.

    The only clues were the very distinct and overwhelming odor of chlorinated solvent, such as methylene chloride or the like, and the rubber grip. The vapors were strong enough such that all four of us in the basement developed headaches or dizziness until we got fresh air.

    We sampled what water was left in the sump and found no organic solvents at all. Except for a thin film of oil, the water had no significant contamination. It is possible the heat and turbulence evaporated any volatile solvent in the pit.

    Searching literature I found little to explain this until I hit on the Last Word entry. The film of oil, mystery solvent and hot water seem to me akin to the explanation you posted.

    Finally, the question: is there a name for this phenomenon or do you know where I might find out more about it? My co-workers and I are curious types and the chemists here mostly shrug us off when we have asked.

    Thanks for any assistance you might lend. Contact me if you have any questions or wish to know any more of the incident.

    Comment by Paul — April 14, 2008 @ 1:42 pm

  17. what you described makes sense – when you have a heated vessel with a lower-boiling liquid covered by a non-miscible upper layer, it is easy to overheat it because the upper layer acts like a lid, keeping the vapors in – but as the bottom layer gets few degrees over its boiling point suddenly the whole thing erupts with or without even the mildest provocation.

    Dichloromethane is low-boiling (40C I think), it is not miscible with water and forms a bottom layer. It is a good bet that was it – and you did not get scalded because the water sitting on top was only maybe 50C warm.

    Comment by milkshake — April 14, 2008 @ 4:43 pm

    • sounds like when you heating a milk.

      Comment by james — June 24, 2010 @ 11:13 pm

  18. dear Milkshake,

    i want the procedure for the preparation of 4-Cyanopyridine. I will be highly oblidge to you if you can give me the procedure.
    Snehal Jogani

    Comment by snehal — August 29, 2008 @ 11:15 am

  19. Snehal, I have never made a 4-cyanopyridine. I suppose if you have 4-chloropyridine, heating it with CuCN in DMF or DMAc under Ar and then working up the react mix with EDTA disodium salt solution basified with ammonia, to remove Cu, should work.
    There is a nice Pd-catalysed cyanantion reaction from Merck process group that uses 0.2 equiv K4Fe(CN)6 as a cyanide source, DMAc as a solvent and Pd(OAc)2 (2 mol%) as catalyst (without ligand), heating under Ar, I suggest that you give it a try with chloropyridine also.
    Also 4-Cl pyridine should be reactive enough for you to give it a try with NaCN in DMSO.

    Comment by milkshake — August 29, 2008 @ 4:51 pm

  20. Dear Milkshake

    We have a fumarate salt of a base, final API. We got assess the chloride percentage before we market the sample. When we did the AgNO3 test, we get a white ppt. My doubt is can fumarate form a silver carboxylate salt anad still give a white ppt. Is there any method to determine the chloride content for carboxylate salts. your reply in this regard is highly appreciated. take care


    Comment by pasupathy — January 12, 2009 @ 7:25 am

  21. Unfortunately I cannot help you with this – I never did this kind of analysis myself. I wonder if there is any good selective electrode for chlorides. I suppose you can send your sample to a lab for a simple elemental analysis, to determine the total halogen content after mineralization. But again, the best would be to ask a process chemist. Best luck!

    Comment by milkshake — January 12, 2009 @ 12:51 pm

  22. thx man appreciate that.

    Comment by pasupathy — January 12, 2009 @ 11:50 pm

  23. Can you tell me how is diphenylprolinol crystallized easily? I tried hexanes, heptanes, MeOH-H2O….. still having trouble…..


    Comment by Arnab Rudra — January 20, 2009 @ 3:08 am

  24. milkshake,

    We in the chemical industry are distressed over the aceto tightness.
    It’s disruptive to everyone.
    We don’t want labs to have to switch solvents.
    We’re working on new aceto sources. Write to me at as I might be able to get you some.

    Comment by V. Rincon — January 25, 2009 @ 6:11 pm

  25. Can you suggest me whether electrophilic reductions using borane complexes or alanes including DIBAL could be run in solvents other than THF OR DME or Toluene or DCM. My substrate is not soluble in any of the solvents as it contains a quaternary amonium salt. Your suggestion in this regard is highly appreciated.

    Comment by pasupathy — February 4, 2009 @ 9:23 am

  26. I am afraid this is a difficult problem with these reagents. Borane is compatible with pyridine as a solvent but pyridine greatly decreases the borane reactivity so the hydroborations need to be done at elevated temperature. DIBAL will not work with pyridine but maybe it will tolerate HMPA. The problem is that coordination of HMPA will alter DIBAL reactivity for sure. I think it is much better to modify your substrate instead.

    In your case I would make your quaternary ammonium with some very greasy anion, like Ph4B(-) or PF6- to make it soluble in dichloromethane. I would simply mix your material (as a chloride or whatever you have) with NaBPh4 or KPF6 and see if a greasy-anion salt precipitates out from aqueous solution, if not I would just extract it into DCM and evaporate. Best luck!

    PS: I should add that I have been making various tetraaryl/alkyl borate salts of quaternary ammoniums, about a decade ago, and they were greasy and quite soluble in DCM – I could even run a chromatography column on these compounds with unmodified silica and common solvents and they separated nicely.

    Comment by milkshake — February 4, 2009 @ 1:59 pm

  27. excellent man. This is the kind of input I was looking for. I really appreciate your quick response.



    Comment by pasupathy — February 4, 2009 @ 11:12 pm

  28. I have a very short list of compounds I won’t work with – Ni(CO)4 is at the top and after explosions on the part of two grad school colleagues using tBuLi and the recent death of a technician at UCLA from a tBuLi fire, concentrated tBuLi made the list. I’m planing on using TMS-N3 in the kinetic resolution of an epoxide but haven’t used it before and it looks pretty nasty. I see that you have. I’d appreciate your general thoughts on the care and feeding of this volatile toxic. Do you have to separate the waste stream or is there a standard way of treating azide containing waste to ameliorate the explosion hazard? All the cautions I read in the lit just say to treat with appropriate care, without ever elaborating.

    Many thanks.

    Comment by LibArtsProf — April 7, 2009 @ 2:48 pm

  29. TMSN3 is quite easy to work with if you keep in mind that the acute tox is high (rapid headaches etc but it does not seem to have long-term aftereffects) so you don’t want to inhale it, pour it on your fingers (it penetrates latex so the disposable gloves should be changed quite fast) and when spilled outside hood the lab needs to be evacuated promptly and the spill should be let dry by itself. Contact with moisture or protic solvents is a problem because HN3 vapors get produced but for small scale experiments the explosion risk is pretty low. But chlorinated solvents and heavy metals need to be avoided. Separate waste is probably unnecessary unless you work with very large quantities but I would make sure it goes diluted into organic waste and does not get mixed with things like copper or silver salts.

    Some people got sickened by TMSN3 but I did not hear of any fatalities; I would be far more cautious when working with TMS-CN, that can be a killer if mishandled. The unpleasant symptoms of azide poisoning can be effectively relieved by getting drunk

    Comment by milkshake — April 7, 2009 @ 4:55 pm

  30. Thanks. It’s so widely used that it seems like it can’t be quite as bad as the MSDS makes it sound, but I think I will keep it away from the undergrads and only handle it myself. I was also figuring treating waste with Ph3P should eliminate any risk.

    Comment by LibArtsProf — April 7, 2009 @ 7:50 pm

  31. I am not sure if PPh3 reacts with hydrazoic acid that easily: OH to azide direct conversion can be done under Mitsunobu conditions. Keeping TMS azide away from freshman undergrads is probably a good idea. MSDS: sometimes the useful info is missing but from the dramatic hazard description one almost couldn’t tell sand from a warfare agent.

    So you are resolving a 1,2-disubst epoxide, with a chiral salene catalyst? I have only done the kinetic hydrolytic resolution of terminal epoxides, it worked very nicely.

    Comment by milkshake — April 8, 2009 @ 1:23 am

  32. HKR is good for terminal, and I’ve used that many times as well to good effect, but it turn out the earlier TMSN3 (actually, catalytic HN3 produced in situ by hydrolysis of the TMSN3) is, by my reading of the lit, used for 2,2-disubstituted species much more. It’s what Jacobsen originally developed before he realized that the TMSN3 is a lot of atoms to throw away to get to enantiomerically pure epoxide. I tried HKR and just couldn’t get it cold enough to get good ee’s on the substrate I’m using.

    Comment by LibArtsProf — April 8, 2009 @ 8:58 am

  33. What a wonderful blog you run, milkshake!! Thank you!! BTW, are you a Prof/ Grad student?

    If you are a Grad student, man you give me an inferiority complex 🙂

    I wanted your advice about organic chemistry research, preparation for the same and couple of other queries/advice. Any email to contact you?


    Comment by ToGoOrNot — April 20, 2009 @ 6:55 pm

  34. Srini: thanks, I am a chemist working in academia – after being at few US companies in the past. I would love to give you my e-mail address but some time ago I posted here a story about working in the industry (“Such, Such Were The Joys”) and non-chemist-sounding people connecting from New York headquarters of a company mentioned in that story became eager to find out who I was and who was my employer – so I had to take down the most direct personal info including the e-mail address.

    If you have a synthetic chemistry-related question, please post it in the comment section of the latest post – I will try to answer it, within a reason, though I am not going to do a literature search for you.

    Comment by milkshake — April 20, 2009 @ 8:19 pm

  35. God, are people nosey or what?? Definitely you’d be cautious about putting your email and other personal info on the blog

    I guess, then maybe I could *chat* up with you this way??

    As of now, I don’t have any synthetic chem info to ask of you and NO!! definitely, I’d not ask you to a literature search for me.

    Here are some of the questions and would like your opinions/advice on them. If you could point me to a website, that’d be fine as well. But I’d *really* like your opinion(s) about a) and b) considering your vast research experience.

    a) What according to you, would be a *good* research experience before going to a grad school? The reason I ask this is: I want to work in a lab and get to know what the research experience entails before going into grad school. More so, in my case, since I come from the Biology background. I have taken Adv Org Chem courses in my master’s and liked it a lot. Reading about the bad experiences (say with organolithiums/ organometallics) in the lab kinda overwhelms me. Is that because I have NO experience in a Chem Lab? As a prospective grad student would I have to pay so much attention to this? Or is it something which kinda wears off when one starts getting into the grind?

    b) Some of the (asst/ assoc) profs quote their interests as one or more of the following – Synth Org Chem, Natural products, Asymmetric Synth, New reactions’ methodology. Are these fields mutually exclusive? Or do all of them use the same skills set? If they use the same set of skills, why do people quote them separately? Mentioning Synth Org Chem would mean that one is doing Asymmetric Synth and New reactions’ methodology. Right??

    c) Kind of a general question – what are the future prospects of Synth Org Chem? By prospects, Iam not asking how much money I can make, but which other areas can be influenced by Synth Org Chem? Chem Bio?? I also mean where the Synth org Chem skills be used in..

    d) Do older people go to grad schools? Because of family circumstances, I think I’d have to aim at grad school only when iam 35+

    e) About univs for Organic Synth- I checked out the Farm’s, the Tech’s and the one in Cambridge websites for (young) profs who work in Organic Synthesis. The number looks pretty low. I was also checking out groups which are small (in number) but in big schools. My logic was atleast the interaction between the prof and students will be more if the group size is small. Is that a valid assumption? Any other obvious univ which I’ve not considered/ missed?

    Reason why Iam particularly checking out young (asst/assoc) profs is: by the time I go to grad school, most of the seasoned profs (who are already 65+) might be pretty old (70+) and near retirement and if they continue to remain as emeriti, they may not be interested in grad students and maybe interested in only post-docs…

    Thanks for your time and sorry about the bucketload of questions


    Comment by ToGoOrNot — April 21, 2009 @ 4:36 am

  36. You have to be slightly more careful when working with nasty and flammable chemicals, the rule is that you don’t rush or scale up synthetic experiments on the first try. Mistakes and accidents are unavoidable early in the career but they tend to be less serious when done on small scale. Nasty chemical reagents are like strangers – once you get to know them better you can be more confident about how they will behave.

    If you want to go into an organic synthesis program later on and look for a job in the meantime, the best kind of experience is in organic synthesis – that is running synthetic experiments in the lab; you can’t become a professional pilot without spending hundreds hours in the cockpit. Find a research technician job with a pharma company or custom synthesis lab. Or in a research group at academic institute/university – although industry typically pays more. Try to get your name onto some of their published stuff, journal articles and patents – it will look good on your resume. You will need at least some publications and very good personal references if you want to go to grad school in your late 30s. (It will be more difficult but a man ought to take care of his family first).

    Synthetic chemistry is quite enjoyable profession if you like spending lots of time in the lab playing with things that you design. The problem nowadays is with having a stable job: pharma industry is by far the biggest employer of synthetic chemists and as you know the pharma industry situation in US these days is quite bleak. These things can change and industry will always need synthetic chemists, except that right now there are more PhD chemists looking for job than jobs available.

    (Also if you are more physical-chemistry and instrument-oriented you could consider going into a NMR spectroscopy or a X-ray crystallography or mass-spectrometry groups – these are rather niche chemistry professions but good NMR or X-ray crystallographers are always in demand. But it is very different kind of work from organic synthesis.)

    Total synthesis is a pretty academic pursuit and mostly serves to train students and postdocs in synthetic methodology, plus to showcase the new methodology on difficult problems. It is a wonderful thesis project to have but its rare to land a total-synthesis job after you finish the school (unless you are in a position to start your new academic group dedicated to total synthesis). Most people with a chemistry degree end up working in pharma-, biomed- and material-science related industries.

    As to which academic group to apply to: You need the best possible name at best possible school, and in addition the prof needs to be a decent person who not only squeezes out maximum work out of his students but also helps them to get jobs afterwards. The relationship with your grad school advisor is the most important one for your career. I also suggest that you try someone younger, assistant prof on tenure track at a good university, maybe someone who is just starting his lab – he might be eager to get a student with a previous lab experience.

    Comment by milkshake — April 21, 2009 @ 1:24 pm

  37. Milkshake

    Any reason (other than financial/family pressures) as to why older students in grad school find it tough(er) than their younger counterparts?? Grad schools/ (asst/assoc) profs don’t look at old(er) students that kindly??

    Thanks a lot for your opinion/advice. It certainly helps in bringing clarity.

    Best Regards

    Comment by ToGoOrNot — April 21, 2009 @ 3:04 pm

  38. I think the most obvious difference is that a young guy without a family, fresh and uncritically enthusiastic, is likely to spend more time in the lab and be fanatic about doing the research. (I am not saying it is the right way to live your life, often more than five years – and people burn out if they do nothing else but their project – its just that most professors are focused on advancing their own careers rather than making the grad school experience good. If the student is an ambitious workaholic, the prof is only going to encourage it; its like a beekeeper living off the honey – so no matter how pleasant he seems to you, the foremost thing on his mind is what you can do for him to make him more famous. The main difference between good and bad advisors is in what they give you back in return, whether they help you with your career after you graduate.)

    In your case, the questions that will most likely come up are – does he have an additional experience that can make him more productive and self-sufficient in the lab, and a publication record that proves it? Where is his wife and kids, and are they likely to be a distraction in his work on the research project?

    Comment by milkshake — April 21, 2009 @ 4:17 pm

  39. Thanks Milkshake for your opinion. One last group of questions

    Do applicants to reputed Grad schools normally have (many)publications? Particularly in Experimental Sciences? Would a glowing reco from the prof/person in whose lab the research experience was gained have any value? And Subject GRE scores+ GRE+ GPA would have a lesser value towards grad school application vis-a-vis research experience+ publication (if any) + patent (if any) ?

    Comment by ToGoOrNot — April 21, 2009 @ 6:00 pm

  40. Each school and admission committee has its own preferences but all what you mentioned is important – especially the glowing recommendation letters and publications and test scores.

    You will need to pass GRE and get good scores in chemistry and general math, logic part. The language (verbal) part of GRE needs to be just around average when you are a foreign applicant but math and logic and chemistry score percentiles should be in 90s. I would recommend that you practice it – get hold of the old GRE questions, the organization that makes these tests (ETS) used to sell the old question sets – and the authors and the question types are always the same every year. The questions are not too difficult (the general math part does not go past trigonometry!!) but the question wording is sometimes awkward. Most people lose on GRE scores because there is too little time and they get stuck on one question and run out of time before they can answer all remaining questions. The final score ranking is based on percentile and the most crowded range is right about the median, it thins up as you go up – that means you can get ahead of lot just by teasing out few extra points by being slightly faster and more calm than others; getting familiar with the test format and practicing these test question with a stop-watch, for about a week, definitely helps you with the speed and anxiety.

    It will surely help you to have few publications/patents to your name (you don’t have to be the first author).

    There is usually a letter or an assay that goes with your application, where you have to explain why you want to go to chemistry grad school. It helps to be specific and write in how you are excited about total synthesis/asymmetric methodology/transition metal catalyzed reactions, and you chose it because at your previous industry research job you worked on such and such project, etc.

    It would also help you if you could get a scholarship – the chemistry grad schools in US typically provide their own funding for applicants that could not get outside scholarship (but they then make them to teach undergrad classes and score the exams for it), but even the richest schools are more excited about the applicant that brings in the outside scholarship money. So you should find out what is available to you and apply for scholarships in advance. (please don’t take a student loan, I think its a bad choice for a chemist.)

    Comment by milkshake — April 21, 2009 @ 6:53 pm

  41. Thanks Milkshake for patiently answering all my questions succintly and very clearly.

    Best Regards

    Comment by ToGoOrNot — April 22, 2009 @ 7:57 am

  42. Milkshake can u suggest me a good method to make 15% NaOCl solution. When it was attempted with 40% NaOH solution and Cl2 gas at -5 degree, Cl2 was passed over 4 to 5 h i could at the maximum get 4 to 6 % NaOCl solution. Is there any thing more to get a 15% solution. Your expert comment is appreiated.

    Comment by pasu — May 8, 2009 @ 2:05 pm

  43. …but I am not an expert. I always used the commercial Clorox bleach which is about 4-5% NaOCl. Aldrich was selling a more concentrated solution of NaOCl but that solution does not store well so I cannot recommend it.

    If you need a more concentrated source of hypochlorite you can try Ca(OCl)2, aka chlorinated lime. It is a solid and it is extremely cheap. I guess one can use it as a slurry with ice-cold diluted aqueous NaOH.

    Comment by milkshake — May 8, 2009 @ 3:30 pm

  44. I also want to thank you Milkshake for running this wonderful website and being very patient with answering questions. Many of ToGoOrNot’s questions were mine too.

    Comment by DC — June 4, 2009 @ 5:17 am

  45. The readers are always welcome to leave a flattering comment here – I earned it.

    Comment by milkshake — June 4, 2009 @ 10:27 am

  46. Ha ha…indeed.

    Comment by DC — June 4, 2009 @ 10:18 pm

  47. Hi…

    There seem to be lots of interdisciplinary and new areas – BioOrganic Chem, Chem Bio??

    How different is Chem Bio from Biochemistry? And Bioorganic Chem from Organic Chem/ Medicinal Chem?

    Are these new disciplines truly interdisciplinary in that exposure to techniques related to both Biology and (Organic) Chemistry? Do they focus on the same thing differently or on totally different things?

    How are these interdisciplinary areas perceived? By industry and academia? Fad?? Or Not??

    Thanks for your time

    Comment by ToGoOrNot — June 8, 2009 @ 7:03 pm

  48. I do not recommend interdisciplinary programs. They may be interesting to you but it is a really bad career choice – you will not be employable when you graduate from one. You need to specialize within a subfield. If you have some outside experience in addition to your own specialty it can be viewed as advantage but you don’t want to be in two or three fields at the same time (and perceived as not having a solid background in either one of them). In all companies and institutes where I have been so far, the chemistry, the biology, the computation modelling and the spectroscopy was all handled by different people that were specialists in their own field. And rightly so – these jobs are quite different one from another. Chemists don’t express proteins and molecular modelers don’t run butyl lithium reactions.

    Also what gets advertised as medicinal chemistry program in schools is typically being frown upon by the medchem people in the industry. The companies like to hire hardcore organic chemists who have a broad and up-to-date experience in synthetic methodology and a proven record of using it on complicated target molecules. (Graduating from a good school or a famous group is a plus.) You get a much better chance of getting impressive publications from a total synthesis project or an asymmetric methodology work rather than from a medchem project. And the medchem project often takes many years to publish because of the intellectual property problem, and when it finally gets published it often goes into low-rated journals like BMCL, and its series of simple compounds that all look very similar – a lousy project to present at a job interview.

    Comment by milkshake — June 8, 2009 @ 7:33 pm

  49. Thanks Milkshake…

    I’m not sure but think Derek Lowe had addressed this interdisciplinary thing – Chem Bio and especially getting a doctorate in these kind of programs, in his blog…

    Are these topics – Enzyme Mechanisms, Biosynthetic Pathways – considered non-interdiscplinary? I think what you are saying is that even if one gets to work with a prof. whose interests are in Bio-Organic Chem (say) then one’d either have to take either the Chemistry approach to it OR the Biology approach to it and NOT both. Right??

    Comment by ToGoOrNot — June 9, 2009 @ 4:33 pm

  50. First you need to get into a good group; when you have paper with Stuart Schreiber in Nature it does not really matter that it is interdisciplinary. But I have seen too many people from half-baked bio-org and med-chem graduate programs, being seriously disadvantaged in comparison with their total-synthesis colleagues, so in general I cannot encourage anyone to go interdisciplinary.

    Comment by milkshake — June 9, 2009 @ 5:35 pm

  51. Thanks for your advice. I read through Derek’s post about interdisciplinary research and it kind of rang a similar bell.

    Comment by ToGoOrNot — June 9, 2009 @ 6:02 pm

  52. To paraphrase the Dalai Lama, it’s a good thing to dig for water in more then one place, but if you never dig deeper then five feet, you’ll never get water. Which is to say, get a good solid grounding in something, and then work from there.

    Comment by LibArtsProf — June 9, 2009 @ 8:53 pm

  53. Hi Milkshake,

    I was always under the impression that as a grad student, you would publish more papers in methodology versus total synthesis (where you might make one or two molecules in your PhD). Whereas methodology tends to have easier targets = more papers. Is that true?

    I’ve also read that total synthesis is a dying art. I am very interested in it, but if I understand what you’re saying it seems that companies still do value that?!

    Your input is appreciated. Thanks!

    Comment by DC — June 9, 2009 @ 11:47 pm

  54. Its true that there is a growing number of people who roll their eyes (instead of being awed) when a 40+ step synthesis of a marine polyether monster is presented. It is also getting harder these days to secure a grant funding for total synthesis of ginormous natural molecules like taxol. Still there is enough groups doing total synthesis – Its a good training for the students and way of showcasing new methodology.

    If I had the option I would love to do some kind of catalytic asymmetric cyclization methodology project (that one person can complete within four years) and then use the new methodology on some small natural molecule in the end.

    Comment by milkshake — June 10, 2009 @ 12:08 am

  55. Milkshake and colleagues – I am new to this group, and am not a chemist, so please forgive me if my etiquette is a little off. I am a molecular biologist at Hopkins who has become very interested in protein kinase inhibitors such as Sutent (sunitinib, SU11248) and their derivatives. I would love to discuss issues related to these molecules with a chemist who knows about their chemistry. If you are interested, it might be best to do it offline. Please contact me at [dzack AT hmi-edu] thanks

    Comment by Don — July 4, 2009 @ 10:36 am

  56. Don, you are forgiven – and its wonderful of you stopping by.

    Comment by milkshake — July 5, 2009 @ 12:55 pm

  57. Hi Milkshake, how are you? Have you ever try inserting reference number into ChemDraw structures (during Word)? I can do it manually, but imagine a whole thesis & if I change something, I would have to change the whole number thingy and not forgetting changing the text too!!! Any idea? Thanks…

    Comment by Taitauwai — August 6, 2009 @ 5:06 am

  58. I never had such problem because when I was writing my thesis the best available text processor was XyWrite in DOS and I drew my structures into the blank spaces by hand and xeroxed the result.

    Maybe you should divide up your thesis into several Word documents by chapter – it will load up faster that way and you won’t mangle the whole thesis text by one unlucky edit. Just to be sure, separately save all Chemdraw pictures that your are pasting in. MS Word is subtle, malicious He is not.

    Also, some chemists swear on using LaTex, ask Kyle at Chemblog – I think that’s what he used for his thesis

    Comment by milkshake — August 6, 2009 @ 7:46 am

  59. DOS? Wow… It has been many many moons ago… Back then computer cost an arm & a leg; I am still a very young lad. *Grin*
    Anyway, earlier I have problem with copy and paste into MSWord, but managed to troubleshoot it with advice from Kyle’s blog. Guess I will head over and drop him a line. But, thanks for replying! XXXX (Remember tetrakis?)

    Comment by Taitauwai — August 6, 2009 @ 8:37 am

  60. I remember, it was very nice of you then; and the lab-sink-in-use drawing too. Best luck with the thesis.

    Comment by milkshake — August 6, 2009 @ 10:55 am

  61. Good nite. Work safely. XXoX

    Comment by Taitauwai — August 6, 2009 @ 11:06 am

  62. hi milkshake,
    thanks for all your posts above.
    i want to make amide coupling between 2-(methanamine)pyrazine and 3-oxocyclobutane carboxylic acid. i tried using cdi, dcc, socl2 coupling agent. it worked well but lot of impurities formed. i want to do this on large scale (>2 kg) with out any purification. so i tried making the succinimide derivative of acid using edc.hcl and then coupling it with amine. this worked well but is there any way i can reduce it to one step process?

    Comment by chemix — August 23, 2009 @ 3:05 pm

  63. In your case things can mess up both during the activation stage and the coupling, and your amine is not that reactive, and the product can over-react if there is an excess of coupling reagent. With one-pot large scale procedure it would be difficult to remove spent EDC.HCl coupling reagent.

    I would suggest that you first do HOSu(1.1 eq)+ DCC(1 eq., added last)active ester formation in acetonitrile, stir for 1 hour, filter off the urea, rinse the cake with additional acetonitrile (at this point you can check TLC and NMR of a sample from the filtrates, to see how pure the active ester is) and then add your amine with a small amount of N-methylimidazole as a catalyst to the active ester solution, and concentrate to a small volume, check the conversion and do a bicarbonate workup.

    Acetonitrile is great for DCC couplings because DDC-urea is nearly insoluble in it. People are afraid of DCC residues but with right solvent/workup choice it actually couples cleaner than EDC.HCl, and is less expensive also.

    Comment by milkshake — August 23, 2009 @ 4:45 pm

  64. hiya! my compound is only soluble in dmf or dmso, but i can see it run up a normal phase tlc using a very polar gradient: EtOAc/MeOH/H2O/NH4OH (5:3:1:1). Any trick to be able to reproduce/scale up this gradient to a column scale (not reverse phase) without dissolving the silica. any suggestions are welcome. cheers!

    Comment by beginner — September 23, 2009 @ 8:05 pm


    Make sure the used chloroform is not acidic, and slurry-pack your column

    Comment by milkshake — September 23, 2009 @ 11:41 pm

    • Thanks for the tip, but didn’t work very well. Adsorbed the mix in silica (with DMF). Didn’t move from there anymore 😀 But didn’t clog the cartridge, weird…

      Comment by beginner — September 30, 2009 @ 2:55 pm

      • some stuff is so insoluble that silica column is not a good way of purifying it. By the way, do not use DMF for loading stuff on silica – it will never leave completely and it would mess up your separation. Also, maybe the next time please leave your comment under the relevant post (I will see it there because it shows up on my admin bar.) Thanks

        Comment by milkshake — September 30, 2009 @ 3:13 pm

  66. Hi Milkshake, how are you? Need to pick your brain: Me have a chiral compound, with 4 stereocenter, but symmetrical (hence making my life easier). Through computer modeling,calculation and mechanistic reasoning, we chose 1 (with the lowest energy). NMR gives a nice clean spectra, got the HRMS and everything else. But referee is not very convince. He thinks it will be good idea to run it down HPLC , just to check and to confirm it is not mesomeric mixture. My question, how do one choose the chiral column for HPLC?

    Me don’t have much money in me piggy bank, have to be very careful when buying. Appreciate your comments and feedbacks.

    Me thank you very very much.


    Comment by Taitauwai — November 3, 2009 @ 11:21 am

  67. Me apologize…

    If Mr Krest17 has ideas/advice for me, me like to hear it too. But don’t know him that well yet… 🙂

    Comment by Taitauwai — November 3, 2009 @ 11:23 am

  68. Milkshake…, where are you? (Sob…sob…) 😦

    Comment by Taitauwai — November 5, 2009 @ 9:01 am

    • I am hiding behind the admin dashboard

      Comment by milkshake — November 5, 2009 @ 10:08 am

      • Still waiting for your suggestions…

        Comment by taitauwai — November 8, 2009 @ 5:08 am

      • Look, I worked through the night and I am tired – I won’t be making any lewd proposals tonight

        Comment by milkshake — November 8, 2009 @ 6:08 am

  69. Hi Millkshake.

    How do you do? This is Fikrewolde from one of the universities in Ethiopia. I was impressed by the posts about Dr.Perelman in Perfect Rigour. But the thing is I haven’t read it yet and may not be able to read it within some days. I thought you would help me read it by sending me some of the interesting pages you have read in the book.

    Thanks in advance for reading it.
    Please try to contact me.

    Comment by Fikrewolde — November 7, 2009 @ 9:01 am

    • I do not have this book that you are interested in – I saw the New Yorker piece and few other articles but not his biography. My comments were only observations on whats obvious from the articles. (And he reminded me of someone I knew.)
      All best, Milkshake

      Comment by milkshake — November 7, 2009 @ 10:46 pm

  70. Ok..ok…don’t be mad… Get some rest. Will wait. 🙂

    Comment by Taitauwai — November 8, 2009 @ 9:17 am

  71. Hello milkshake,

    I saw your post on In the Pipeline last January about your frustration with the acetonitrile shortage last year. I’m currently writing a story about this for and I’d love to speak with you to get more information about how your research was affected and what your feelings are now about it all, a number of months after the fact.

    I hope to hear from you soon!

    Comment by SL writer — November 10, 2009 @ 10:48 am

    • Well thanks for the interest, we were affected a bit but our three main solvent suppliers tried to do their best and eventually they sent us at least few boxes from our two-month-backordered acetonitrile orders, enough to get through the dry spell. I think we went without MeCN for only about one week – still a huge hassle in a medchem group. Since then we stockpiled ( = hoarded up) enough to last us for at least six weeks of average usage, and we keep this inventory in reserve, and we limited our usage by switching to 50%-50% mix of methanol with MeCN instead of MeCN in prep HPLC purifications (which consume most of acetonitrile in our group, so this practically halved the MeCN consumption). The reason for MeCN consumption-cutting measure was obviously the price not only the availability, as MeCN continues to cost us about twice as much than it was a year before. I could go into more details about heated conversations with particular vendors and various wanna-be profiteers but I will leave it at this – at this point I will pass on the chance of getting interviewed. Best luck with your article!

      Comment by milkshake — November 10, 2009 @ 11:57 am

    • Hi SL writer,

      I can give you some info from the industrial supplier point of view.
      I am at


      Comment by Victor — November 16, 2009 @ 11:50 am

  72. Thanks for the comments – you were not alone in your frustration and your adaptation. No problem in declining an interview.

    Comment by SL writer — November 10, 2009 @ 1:33 pm

    • The actual reasons for turning down the interview offer are explained in my last comment under “Such, Such Were The Joys’ from February 24, 2008 (under the “Industry Life” category)

      Comment by milkshake — November 10, 2009 @ 2:38 pm

      • Understood milkshake – I understand and respect your need to be confidential on this blog. If it makes you feel any better – I innocently found you and this blog through your In the Pipeline posting re MeCN and I found that by doing a Google Blog search for “acetonitrile shortage” …sometimes this works to get interviews, sometimes not 😉

        Comment by SL writer — November 11, 2009 @ 1:07 am

  73. Milkshake,

    I am a fellow East European with quite similar early chemistry experiences to yours. I have a write-up that would be useful for grad students/postdocs who come to US and are not familiar with the system here. If you are interested in posting it please email me.

    Sorry to hear about your pending dismissal.

    Comment by drb — December 12, 2009 @ 12:29 pm

  74. Hi Milkshake,

    Maybe this isnt the right place to post this, but I am contacting as many chem-blog owners that I ritually read for useful insight and practical tips.

    I’m considering making a site of my own that deals simply with “things you don’t know that nobody will teach you that will save you a million hours in the lab” etc.

    I’ve been trying to find a reasoning for why in some cases, particular molecules tend to behave well on TLC, however utilizing the same solvent system, or even massively reducing it (or removing it alltogether!) cause everything in the mixture to ‘rush out’ in the first one or two fractions when you step up to a flash column.

    For instance, 5% MeOH in CHCl3 is a standard for me, on TLC I get seperations with a suitable RF, and good delta-RF’s (0.2-0.3, sometimes more) – yet loading onto a well packed column, everything floods out instantly.

    In 6 months of searching the only reference to this phenomena I have found is “This rule is only applicable when the weak solvent does not move the sample through the stationary phase.” (DOI 10.1007/s11030-008-9104-x)

    Naturally I am going to try other solvent systems like hexane/ethyl acetate, but I have seen this to be a common event over a number of years, with no reasoning as to why it occurs.

    If you have any ideas in your infinite wisdom, please share!


    Comment by Sebastian — May 31, 2010 @ 5:32 am

    • it is an effect of overloaded column, try to apply the stuff in less polar mix and bring the concentration of methanol up gradually. Also, methanol has huge exotherm of binding onto silica, you get local “methanol front” sharp zone with strong overheating and mixing effect, that can ruin the separation. Also, finer silica separates better, make sure you silica grade is something like 25-40 micrometer particle size. Stay away from the 65 micrometer flash silica.

      Comment by milkshake — May 31, 2010 @ 11:22 pm

  75. I feel stupid while doing postgrad chemistry. I miss the flavor of success during undergrad. What is you advice to be a really good chemist like yourself?

    Comment by james — June 24, 2010 @ 5:18 am

    • first I am not that successful chemist – I did not finish grad school. Also, frustration and boredom happen in most projects, its a quite normal state of affair. It matters how long it lasts and whether you could do anything about it. My suggestion would be to find something that excites you and a boss that motivates you. At this point you probably want to finish your thesis project as soon as possible and move on to some better things. Try to get enjoyable chemistry project as a postdoc. I wrote on similar subject:

      Comment by milkshake — June 24, 2010 @ 9:06 am

  76. Dear Milkshake,

    Do you have some ideas how to cleave C(O)-N bond of an amide to give a primary amine? Amide hydrolysis…I can try acid or base. Any preferences?

    Comment by TCCG — July 1, 2010 @ 4:51 am

  77. Is there any solvent in which 1,3-dicyclohexyl urea is soluble.

    Comment by pash — August 12, 2010 @ 4:33 am

    • methanol+chloroform mixture. Also in straight TFA.

      Comment by milkshake — August 12, 2010 @ 12:01 pm

      • thanks dude

        Comment by pash — August 16, 2010 @ 2:36 am

  78. Hey! I´d like to know what´s the maximum percentage of MeOH, Ethanol or Acetone you would put through a silica or neutral alumina colummn (before starting dissolving the stationary phase)?

    Comment by polar stuff — September 2, 2010 @ 8:38 am

    • I do not think you can actually dissolve silica in methanol – please do an experiment with straight MeOH – filter, evaporate, weight out the residue (if there is any). The problem with polar solvents pushing silica through is with a local overheating/overpressure zone that happens because the polar component is absorbed out of the eluent completely and it forms a sharp second front – and since absorbtion of polar solvents to silica is strongly exothermic… you end up with hot zone moving down the column. If you use MeOH in mobile phase you need to slurry-pack the silica into the column in your mobile phase (not dry-pack your silica). Also, ramping up the concentration of the polar component (ie MeOH) in the mobile phase during elution needs to be done gradually and the flow rate needs to be reduced so that the heat from MeOH binding to silica generated on the column has a chance to dissipate.

      Comment by milkshake — September 2, 2010 @ 2:27 pm

  79. Hi Milkshake,

    I need some help. How to test if a DIBALH reagent is still good to use?


    Comment by TCCG — September 21, 2010 @ 5:54 am

    • I don’t know – when in doubt I would buy a new can of DIBAL, it is not that expensive and one botched experiment is worth more. People did NMR of organolithiums in non-deuterated solvents without locking so i suppose one can use the same technique.

      Comment by milkshake — September 21, 2010 @ 10:12 am

  80. Unfortunately, not something I can do easily with Blogspot. Sorry — wish it weren’t so.

    Comment by Chemjobber — October 3, 2010 @ 2:31 pm

  81. Hi Milkshake,

    I wonder if you could give some tips of how to prepare isopropyl substituted alkynes from alkylated terminal alkynes.

    Seems like using BuLi and isopropyl iodide is not doing the job. Thanks so much!


    Comment by Charles — October 23, 2010 @ 6:37 am

    • unfortunately I have not done it myself. I wonder if adding a catalytic amount of CuI might help with the cross-coupling. Have you looked up precedents in Scifinder/Beilstein – what kind of isopropyl electrophile can be used for this purpose?

      Comment by milkshake — October 25, 2010 @ 11:55 am

  82. Hey, Milkshake:

    Any speculation as to why iPrMgCl seems to be the reagent of choice for Knochel-type chemistry, instead of EtMgBr? I imagine it has something mechanistic to do with the halogen-metal exchange and 2′ vs. 1′, but I don’t know what…

    Comment by Chemjobber — June 1, 2011 @ 2:51 pm

    • I don’t know the mechanistic explanation. Few years ago there was a paper in J. of Process R&D where they had a table of various grignards they tried for halogen-Mg exchange on their pharma intermediate and from the yield/conversion standpoint there was a clear advantage with secondary grignards, with sec-butylMgCl and cyclopentylMgCl somewhat better/faster than iPrMgCl. So they were recommending to use sec-Bu-MgCl for scale-ups. But I also remember that few years back I was using a procedure for Br-Mg exchange on N-(3-bromo-5-fluorophenyl)-pyrrolidine, a procedure that called for mixed metal Knochel-like reagent that was made by mixing nBuLi with nBuMgCl in 1:2 ratio, and it worked very well.

      Comment by milkshake — June 2, 2011 @ 5:20 pm

  83. MILKSHAKE! Congrats on the new gig! When are you going to post about all the cool new molecules you’ll be making?

    Comment by See Arr Oh — June 19, 2011 @ 4:06 pm

    • No kidding, SAO. Congratulations on the new position, milkshake. Could not have happened to a better guy.

      Comment by Chemjobber — June 19, 2011 @ 4:44 pm

  84. Is there any diagnostic test to distingusih two different qualities of dibromodimethylhydantoin and also to distinguish two different qualities of AIBN. Based on the current method of analysis, two different qualities meet the requirements, but it doesn’t behave in the same way during the bromination reaction.

    Comment by pasupathy — October 12, 2011 @ 3:14 am

    • for dibromohydantoin you can try melting point and UV-vis spectra of a freshly-made solution in acetonitrile. I have never done a rigorous process batch quality control myself but I know that with NBS brominations a trace of elemental bromine or residual acidity sometimes improves the bromination outcome – paradoxically an old brownish NBS bottle sometimes works better than a freshly re-crystallized colorless one. If I remember correctly the reproducibility fix was to add 1 drop of concentrated HBr solution to the reaction mix, to emulate the effect of an aged batch.

      AIBN solid decomposes easily with evolution of gaseous products – sometimes explosively – I wonder if you can do thermogravimetry or microcalorimetry, to see the temperature of the onset of decomposition. But maybe the easiest thing would be to take NMR.

      Comment by milkshake — October 12, 2011 @ 2:13 pm

  85. Do you tweet?

    Comment by Ian Mat Som — October 26, 2011 @ 11:43 pm

  86. Can you suggest some protocol to isolate piperazine from water to get anhydrous piperazine

    Comment by pasupathy — March 7, 2012 @ 11:58 pm

    • I dont know but it is going to be difficult – piperazine is very water soluble, it forms a solid hydrate with water and bicarbonate with CO2 and it is quite volatile as a solid. I wonder if you can neutralize and evaporate it to make an anhydrous sulfate salt and then melt the salt it with solid CaO to sublimate anhydrous piperazine from the mix. By the way, anhydrous piperazine is quite cheap – why dont you just buy it?

      Comment by milkshake — March 8, 2012 @ 6:03 am

  87. We’re in the process of re-designing our organic teaching labs for “honors” students.

    I’d like to have a lab – after they’ve had 1 semester of Orgo and training in basic techniques – as a “frustration problem solving lab”.

    This is not the kind of frustration that is from an intractable problem, but rather, to begin to train them to realize they don’t just have one hammer (i.e. if all you have is a hammer everything looks like a nail).

    In this context, I’d like an experiment that shows that with purification: the goal is not to * do chromatography * , but rather to separate compounds in order to purify them.

    i) With this in mind, do you know of any pairs – or trios – of *commercially available* compounds that are a bitch to separate (delta RF of <0.05) on Normal phase tlc,
    but would be amenable to acid/basic/other kind of extraction

    e.g. alcohol vs carboxylic acid with similar Rfs
    alcohol vs amine with Similar Rfs
    or even fluorous vs nonfluorus or hyrophobic vs hydropilic pairs with similar Rfs


    ii) is there a resource of TLC rfs available with diff solvent systems

    Also: if you had any other suggestions for LIMITED yet real technical problem solving experiences that are similar to the and applicable to 4h sophomore organic labs, I'm all ears……i

    From A Big Academic Fan of Milkshake's Synthetic Mojo.


    …….the origin of this is from a research advisor bemoaning that "trained" students don't know how to attack simple optimizations of reactions and their workup based on obvious chemical properties.

    Comment by psl — March 20, 2012 @ 1:45 pm

    • If you want things that are very close on TLC (in all solvent systems) the natural choice would be a mixture of isomeric compounds. (Of course you cannot separate them by acid/base extraction). One thing that comes to mind are o- and p-hydroxybenzaldehyde. The ortho isomer co-distils with water steam, the para isomer remains in the distillation flask. Look up Reimer-Tiemann preparation of salicylaldehyde from phenol, I am sure it will be in J. Chem. Ed. or Orgsyn. I think there was some similarly simple technique for separating o- and p-nitrophenol after nitration of phenol with 20% aqueous nitric acid – look it up too.

      Sory, I am the wrong person to ask, I have no experience with designing teaching experiments.

      PS: A non-Mickey Mouse experiment to try would be preparation of racemic 2,2′-binaphtol from beta naphtol – the starting material is quite close to the product on TLC and can co-crystallize with the product but beta naphtol is somewhat soluble in hot water (and volatile with water steam) and therefore it can be removed by boiling the crude product from the reaction mixture with lots of water. The preparation of binaphtol goes like this: ethanolic solution of beta napthol is added in parallel at the same rate as separately-made aqueous solution of FeCl3 hexahydrate (1.05 eq.) into a big beaker full of hot water at 90-100C with stirring C dropwise, over half an hour. Collect the precipitated crude product by filtration, wash it with lots of boiling water, dry. Re-crystallize from large volume benzene (toluene or ethanol+water works as well but benzene gives a superb product purity and yield after one re-crystallization). The starting beta naphtol has often dark-colored tarry impurities which can carry over into the binaphtol product so it is worth to re-crystallize the commercial beta naphtol from water-ethanol before the use if you care for the binaphtol purity.

      Maybe you can give this as assignment: Develop a procedure for producing beautiful colorless crystals of racemic binaphtol from beta naphtol in better than 50% yield, preferably as simple as possible, and figure out what factors are important for achieving the best purity (rather than yield), try different solvents for re-crystallization of the crude product, try to re-crystallize the starting material to see if it improves the product purity. Measure the melting point, develop a TLC system for detecting the starting material impurity in the product.”

      Comment by milkshake — March 20, 2012 @ 2:23 pm

  88. Hello Milkshake:
    You should consider publishing your interesting blog entries instead at
    Thereby, they are permanently archived, are citable via a DOI, are post-publication peer-reviewed via comments and shares to social networks, and you can report these additional metrics on your resume.

    Comment by Dirk — April 12, 2013 @ 8:55 am

  89. Milkshake would you allow me to put some of your tips and tricks on Not Voodoo? I’m updating…. finally…. lmk please

    Comment by Alison Frontier — January 21, 2014 @ 4:02 pm

  90. Hello Milkshake:
    I would like your opinion about the Snap-Reactor, an apparatus for hydrogenations, carbonylations and conducting organic reactions under a medium pressure.
    Please, visit

    Comment by Helena — June 5, 2014 @ 7:52 pm

    • Helena, hi

      The reactor looks very useful and the prices are fairly reasonable. It is exactly the type of apparatus I was seeking.

      We will first test the idea of using a stainless steel keg (from a solvent purification station) that we already have in house, for our hydrogenation, but if there are any difficulties we will likely go with your system.

      Comment by milkshake — June 6, 2014 @ 11:18 am

  91. Hello Milkshake,
    I need your help with a difficult reaction. I am trying to esterify the OH group on tyrosine with fumaryl chloride. I have tried potassium carbonate and cesium carbonate and its not working. I do not want to use organic amines because the reaction turns black! Kindly advice on the best reaction conditions


    Comment by Simeon — September 21, 2014 @ 7:13 pm

    • Simeon,

      this is going to be tricky. First, I need to know if and how the tyrosine is protected (is tere BocNH protection group, is there ester or amide on the carbonyl?). I have had unpleasant results with acyl chlorides that were alpha,beta unsaturated: Michael-addition related polymerization seems to be the source of dark impurities. You probably want to use a very weak and very poorly nucleophilic base (less nucleophilic and basic than triethylamine), such as N-ethylmorpholine (CAS # 100-74-3) or 2,6-lutidine. Another possibility is to use heating with maleic anhydride without a base, and then treat the resulting maleic acid monoester with catalytic thiourea at room temp on a sonicator bath, to bring about C=C isomerisation from cis to trans

      Comment by milkshake — September 21, 2014 @ 10:59 pm

  92. Thank you milkshake for your prompt response. To answer your questions, the amine on tyrosine is fmoc protected and the carboxylic acid on the tyrosine is esterified. I have tried the reaction with succinyl chloride with the same deep black color obtained. If N-ethylmorpholine will not make the reaction black, what about increasing the nucleophilicity of the tyrosine -OH which requires a strong base to convert to the phenoxide for reaction with the acyl chloride? To make things worse, the tyrosine is esterified at the -COOH with a compound that contains a disulfide bond!

    Comment by Simeon — September 24, 2014 @ 8:21 am

    • that looks quite terrifying. You definitely cannot go too basic. The advantage of N-methyl and N-ethylmorpholine is that their basicity is low. For esterification with acyl chloride (or anhydride) you don’t need to form phenolate anion. One thing you could also try is to use acrylonitrile (5 equivs) as HCl scavenger, in DCM or dichloroethane at room temperature. I remember 20 years ago I was esterifying Tentagel OH groups with acryloyl chloride, and acrylonitrile (instead of base) was the only thing that worked for me. Acrylonitrile is very nasty and must be redistilled before use.

      Comment by milkshake — September 24, 2014 @ 12:19 pm

  93. Thanks will try N-ethylmorpholine and/or acrylonitrile. I appreciate your help

    Comment by Simeon — September 24, 2014 @ 1:08 pm

  94. Hi Milkshake,

    I tried N-ethylmorpholine as suggested and I still had the black impurities. On further purification and proton NMR analysis, the product was not obtained. I see that similar reactions have utilized anhydrous pottasium carbonate as base with some luck. I am thinking of using Cesium carbonate. Could you please suggest some anhydrous solvents that is compatible with acid chlorides, ester and disulfide bonds and at the same time will dissolve cesium carbonate to some degree? Any product isolation tips will also help.

    Thank you for your kind assistance!

    Comment by Simeon — November 22, 2014 @ 10:29 am

    • acetonitrile would be my first choice, high-purity DMF second choice with cesium carbonate. Please keep in mind that commercial grades of Cs carbonate from different vendors have different moisture levels. Another good base with low basicity and high nucleophility for acylchlorides is N-methylimidazole (if you use 1-Me-imidazole, I think DCM at 0C to -20C would be best). Yet another exceptionally mild base is KF (best to use spray dried grade and dry it at 100C under vacuum overnight before use) in acetonitrile or acetone. With KF, you would need to use more than two equivalents of KF because the product of KF scavanging is KCl and KF.HF

      Comment by milkshake — November 22, 2014 @ 2:18 pm

  95. Hello Milkshake,
    I thank you for your great help with my reactions! I am trying to conjugate folic acid to a primary amine using HATU. The reaction requires about 15 grams of folic acid which is very insoluble in most solvents! I have tried to dissolve it in DMSO, DMSO + DIPEA with the aid of heat with no luck. Could you please suggest a solvent or combination of solvents that I can use for this reaction? Thank you!

    Comment by Simeon — March 29, 2015 @ 9:36 am

    • I was asked by our biologists once to couple folic acid onto a polymer, and just one look at the structure of folic acid (and the procedure they waned me to use – DCC in DMSO) convinced me it was hopeless. There is going to be a large amount of literature on the subject, which you should look up before you do anything – and I would recommend that in your search you should focus on folic acid protection/deprotection schemes. I am pretty sure you can’t get any good result from trying to couple folic acid directly without amine-protecting it first. And you will still have problem differentiating between the two carboxy groups.

      Comment by milkshake — March 30, 2015 @ 1:30 am

  96. Dear Milkshake, I reduced l-leucine with NaBH4, H2SO4, THF, etc, the method you said you used on a blog a few years ago ( .I’m writing a paper and I would be extremely grateful if you could clarify the mechanism, does the NaBH4 become BH3 and then reduce the amino acid?

    Comment by tanc44 — August 13, 2015 @ 12:25 pm

    • I believe it works by borane formation in situ: functional group the selectivity is the same (free carboxyls and amides are reduced to alcohols and amines, but urethane protecting groups like Cbz, Boc are stable and carboxyesters are reduced fairly slowly, and olefins are not compatible). There is a version of this reduction that uses methanesulfonic acid instead of sulfuric acid, the solvent is typically THF

      Comment by milkshake — August 13, 2015 @ 2:22 pm

      • Thanks, that would make sense. Sorry to bother you further but I’m doing a comparison on ways to reduce amino acids and was wondering whether you’ve ever come across the method of reducing amino acids with NaBH4 in the presence of NiCl2 or MoO3. From the research I’ve found and my own experiments the yield seems to be higher. Also I have a vague idea about the mechanism for this however I’m not sure, was wondering if you had any ideas. Thanks

        Comment by tanc44 — August 14, 2015 @ 3:43 pm

        • This is really interesting, that you could reduce free carboxy group to alcohol with these systems, I never used them myself but the presumption was that you form nickel-boride-hydride species, so you would have a system more akin to Raney nickel fed with hydrogen from borohydride decomposition. This is unusual, to get aminoalchohols in this way. What solvent are you using?

          Comment by milkshake — August 14, 2015 @ 6:45 pm

          • thanks. I dissolve the NiCl2 in water with the amino acid (cooled it to around -10 C) and then added the NaBH4. From papers I have read they added the NaBH4 as a solid, however I found that it worked better if you added the NaBH4 to some water and then added it to NiCL2 and amino acid. I’m confused by what you mean: “system more akin to the Raney nickel fed with hydrogen from borohydride decomposition”, could you please elaborate? Thanks

            Comment by tanc44 — August 15, 2015 @ 7:12 am

          • Raney nickel catalyzes decomposition of borohydride and amine-borane complexes, so borohydride can be used as a hydrogen source with RaneyNi reductions. But this system does not reduce free carboxyls to alcohols, so I am very surprised NiCl2-borohydride does reduce carboxyl, and even in water. (I may be wrong but I think this is not a commonly known fact.)

            Comment by milkshake — August 15, 2015 @ 7:26 am

          • Thanks for your help, one of the clear articles about this happening is, i thought you might be interest in looking at it. Before I left for the summer I came across an anomaly in my results which suggested that the solvent was affecting the direction of rotation, as far as I know this is not possible, I didn’t have time to check the value rigorously but was wondering if you knew what could have caused it.

            Comment by tanc44 — August 15, 2015 @ 10:22 am

          • this is odd, both the optical rotation discrepancy and the paper. The change in rotation could be due to contamination with something, make sure your aminoalkohol does not have salts or inorganics in it – boric acid complexes, etc.

            Be very cautious about anything published in Turkish journals – they are well bellow indian chemistry journals, research integity-wise. Find out if someone else published a similar thing before, and if you cannot find a similar work anywhere else…

            Comment by milkshake — August 15, 2015 @ 4:37 pm

          • Dear Milkshake,
            I will keep that in mind next time i’m looking at a journal (I have found other journals that state such a reduction amino acids with transition metals is possible however I have not found any other paper specifically on it) . The discrepancy might be an impurity but Leucinol is air sensitive. What does Leucinol form when it reacts with air though?

            Comment by tanc44 — August 16, 2015 @ 5:00 am

          • I don’t know – maybe absorbs CO2 to form amine salt of bicarbonate and carbamic acid, like some primary amines do? I don’ know. Ethanolamine is used as a CO2 scrubber in industry.

            Comment by milkshake — August 16, 2015 @ 9:19 am

  97. Hey, I’ve got a question: do you know if anyone’s successfully made ClF5O yet (where the Cl would have a +7 formal charge)? if not, could you use a computer program to simulate some of its properties?
    Also, is there some way to rank high energy oxidizers in terms of their strength? (E.G. comparing ozone to OF2)

    Comment by Ksr15 — December 8, 2015 @ 10:19 pm

    • Sorry, this is not my field, I think ClO3F and ClO3-OF are known, but I never heard of a compound with hexacoordinate chlorine atom.

      Comment by milkshake — December 8, 2015 @ 10:49 pm

      • Thank you very much for the fast answer! do you know anyone who does research on this kind of stuff? I doubt it’d be classified, due to the numerous oxidizers that won’t eat your glassware and burn up your concrete floors lol.

        Comment by Ksr15 — December 17, 2015 @ 10:49 pm

  98. Hi, I am wondering if you know of a tlc stain that works well for ethers? Ideally, it would be specific for the ether. I can’t seem to find any that will stain them and not stain everything else in the process (i.e. general stains). Even staining a couple other functional groups would be ok. Thanks

    Comment by CMS — January 25, 2016 @ 7:36 pm

    • I don’t believe there is anything specific. You know, ethers are quite chemically stable…

      Comment by milkshake — January 25, 2016 @ 7:40 pm

  99. Dear Milkshake – just discovered this lovely website. Thanks for the efforts you put in. I am in need of tetrahydropyran-4-boronic acid and they are very expensive. Do you know a procedure to make them? Thanks.

    Comment by Elle_JD — July 17, 2017 @ 6:41 am

    • Dear Elle, have you looked up Scifinder a Reaxys? I don’t have access to them right now but if you are close to a university library this would be my place to start.
      Aliphatic boronic acids like yours are typically made by metalation of a bromo or iodo compound, to the corresponding organolithium or Grignard, followed by in situ reaction with B(OMe)3 or B(OiPr)3

      So I would look up price and availability of 4-bromo-tetrahydropyran, and try the Grignard route. But do a literature search first

      Comment by milkshake — July 17, 2017 @ 10:20 am

  100. Dear Milkshake,
    I work for a chemistry magazine (Chemistry World) with a whole bunch of ex-lab-chemists and every once in a while our discussion turns to recounting our ‘that time in the lab’ stories. I remembered that time I sent your post to my supervisor, which saved me from having to synthesise P-chiral phosphines. I still love that story and was wondering if you would be interested in retelling it for the magazine? It would be great to hear from you.


    Comment by Katrina — August 1, 2017 @ 5:28 am

    • Katrina, hi – thank you for remembering this stuff, the story really happened and it is not even much exaggerated. The difficulty is that because of publishing it here, together with some other ridiculous lab stories, several people that I knew from Prague and Arizona stopped talking to me and that unfortunately included also my first research advisor (the young assistant prof in the story) whom I admired.

      Comment by milkshake — August 1, 2017 @ 11:05 am

      • That is a shame – things like that happen in every lab and I think it’s important to share those stories. It never felt like you were showing anyone in a bad light, just simply recounting what happened.
        In any case, thanks for replying (and if you do change your mind, feel free to get in touch at 🙂

        Comment by Katrina — August 2, 2017 @ 4:22 am

  101. Dear Milkshake,

    I am trying to deprotect the cbz protecting group used to protect the amino group in alanine using pd/c in ethanol. I use ESI-MS for analysis. I am getting my mass and a very huge mass of my compound plus 40 (i.e. m + 40). I also see m x 2 +40. What could be responsible for the increase in the mass of 40?

    Thank you for your help over the years

    Comment by Simeon — February 2, 2020 @ 5:27 pm

    • I don’t know. Please have you tried to isolate the product, to take NMR, run a TLC and HPLC? You should not rely just on MS for finding out if your reaction worked.

      Comment by milkshake — February 4, 2020 @ 11:32 pm

  102. Hi Milkshake. Hope you are well and safe. I wanted your advise on choosing between two job options: one is in med chem ( academia), other is process chem ( industry).
    I currently work in another med chem academic setup.
    My question is which experience would be helpful ( in terms of rigor, transferable skills etc) to pursue a PhD in methodology/ synthesis?
    Thanks and have a good weekend.

    Comment by Guha — May 7, 2022 @ 8:16 pm

    • It depends on the job, and I cannot give you advice without knowing the details. As a general rule, contract research organizations (CROs) are the least desirable kind of industry job (you can’t publish anything and you work under a great pressure in a rather short time frame for each project, based on poorly reproducible procedures from customers unwilling to pay for process development), whereas established large pharma company is the most desirable kind of job. Startups are somewhere in the middle.

      Academia medchem programs are usually not a great choice, industry tends to look down on academic medchem programs, many of them are not that good. But it depends also on the academic group itself, its record of achievement, and the name of the of the academic institution.

      Comment by milkshake — May 17, 2022 @ 12:43 pm

RSS feed for comments on this post. TrackBack URI

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

Blog at

%d bloggers like this: