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Nostalgie de la Boue

Alfred Bader’s passing reminds me that there’s an earlier generation – now almost completely gone – that regarded the likes of Aldrich Chemical as fancy upstarts. There has (had?) always been a tradition in organic chemistry of making reagents fresh for your own use, either because there were no commercial suppliers (which is the market that Aldrich and others were filling) or because the needed compounds were too lively to be articles of commerce for anyone. And in some cases, although the commercial stuff will work, freshly prepared material really does work better. Manganese dioxide is one such reagent, although only once in my career have I needed the extra kick found in the home-made stuff – and a good thing, too, because filtering that mud is not a fit job for human beings. I’ve made my own Raney nickel from the alloy, too – once, and if I’m harboring any secret desires to spend another entire day washing the hydroxide out of that pyrophoric gunk then I must be repressing them pretty successfully.

By the time I was running my first synthetic organic reactions in the early 1980s, commercial Grignard and organolithium reagents had long been a feature of the landscape, but even so, you could find people to look down on them for you. I’ve never personally prepared any of the easily purchased ones (methyl Grignard, butyllthium, etc.) but I have definitely titrated some of them to make sure about the concentration listed on the label. That’s especially good practice for older or widely shared bottles, of course, because (1) not everyone handles the sealed bottles with care and (2) even if you do, the contents are going to deteriorate eventually. The first thing any bench chemist does on picking up a bottle of such a reagent is to hold it up to the light and see if it’s still a clear solution. Not all the cloudy ones are in such terrible shape, but none of the really good bottles are cloudy, either.

And you don’t have to be practicing for all that long before you can say “Now, I remember when you couldn’t buy such-and-such”, because suppliers hop onto useful reagents and reagent classes pretty quickly. There was a time, for example, when you could hardly buy any arylboronic acids, because who would want such things? And beyond reagents, there are tremendous numbers of building blocks available, which wasn’t always the case. The list of cute pyrrolidine and piperazine derivatives ready for purchase is really impressive, and a field like medicinal chemistry is always ready to hit the order button. Industrial med-chem has always been on the far extreme of the time-is-money spectrum, with cash-starved academic labs at the other end. One bunch is ordering 100-mg bottles of stuff for $500 a throw without the slightest compunction, while the other is redistilling wash acetone to do the dishes.

Those who have lived the latter lifestyle have an understandable tendency to go on about its virtues. I try to watch that stuff, myself. I’ve poured my own prep TLC plates – heck, at this point, it might be enough to say that I’ve run prep TLC in the first place – but I don’t think that it necessarily makes me a better person. I’ve worked in situations where we had to make our own dry ice (either that or drive to Little Rock to buy some), or where the nearest 300 MHz NMR was twenty miles away and we could use it two nights a week. These did not add polish to my personality. Nor did running preparations like the manganese dioxide or Raney nickel ones mentioned above. If anything, they made me slightly harder to be around, which is not a direction that most of us can afford to head casually. I got a good story out of making my own pyridinium chlorochromate with a summer undergrad, and another one out of making phenylsulfenyl chloride, but overall I think I’d rather not have the stories to tell and then get to skip the parts where I go up in a fireball of flaming solvent or have to count my fingers to see if they’re all still there.

No, the main thing that scientific deprivation does is make you happy when you’re not being deprived any more. I’ve worked in cash-strapped research environments and well-furnished ones, and rich is better. I’m willing to believe that there is such a thing as too much laboratory luxury, but I don’t think it’s a danger that most people are facing. Overall, the fewer impediments to getting your ideas reduced to practice, the better. I’m also willing to believe that necessity can indeed be the mother of invention, but there’s a flip side: lack of facilities can also kill off your ideas wholesale because you don’t even bother to think about doing experiments that you know can’t be realized.

I’m glad to have a walkup LC/MS machine right around the corner from me, and I’m equally glad that I don’t have to keep it running myself. My urges to set up and maintain a molten-potassium THF still are nonexistent (mind you, doing that would probably get me fired, and for good cause). I’m happy as a clam that there are so many reagents and intermediates that people are willing to sell me, so that I don’t have to make them. I have no desire whatsoever to go back to searching the literature by hand, and in retrospect, getting rid of years of hard-copy issues of JOC back in 2007 was an excellent decision. And so on. If someone wants to complain about the old days, I can join right in – but if someone tries to convince you that they were better, well, you have better things to do than listen to them.

36 comments on “Nostalgie de la Boue”

  1. Uncle Al says:

    The good old days allowed one to screw around a bit off the books. A line of vacuum polymerization ampoules diddling hydrogel compositions as neat monomers is scut work. Sneak in the occasional teensy of acrylamide – soluble in everything. Polyacrylamide dissolves in near nothing other than water. Somewhere around the Trommsdorff effect…opal!, though usually transient. Maintain lab morale.

  2. TMS says:

    But do still have files with photocopies of papers or did they go the way of the JOC hard copies? I can’t bring myself to throw them away.

  3. Anonymous says:

    I also made my own Mn02 (Attenburrow procedure) and it worked great to oxidize a very troublesome substrate. I made my own Rieke Mg and that is hot stuff. Years later, I bought some commercial Rieke Mg for a different project and it just didn’t seem to have the same zip. (I wonder if my ego influenced that perception?)

    I always had access to the commercial organolithiums, thank goodness, and used those to lithiate my own advanced intermediates, when needed. It should be noted that the solids in the bottles of nBuLi et sim are not just innocuous LiOH or other junk. They are likely to contain crystallized or ppt’d RLi’s. Be very careful when quenching or disposing of an old bottle of RLi. I usually start with dilute EtOAc in hexanes, just to get rid of the unreacted RLi. (I guess you get some 1,2-addition and some deprotonation to butane gas, but it just seemed safer to me than a straight proton quench with a low boiling alcohol or H2O.)

    Another Aldrich tie-in: They used to have those full-page reference articles — I mean advertisements — on the back covers of JOC, Synthesis, Helvetica, etc. One of them was for the whole slew of RLi titration indicators that they sold, w/references. The last ad I am thinking of must have had at least 12-15 methods / reagents on the list and there are probably others that have been published since then. (Not that anyone is interested, but my preference is to use BHT, a cheap, crystalline, air stable, non-hygroscopic solid proton source and 1,10-phenanthroline as indicator. Very sensitive, very accurate, and very reproducible. You can also do RLi titration by NMR.)

    I do not have “nostalgie de la boue” of doing Gilman double titrations. However, every once in a while you do have to be aware that your reagent might contain bases other than just the RLi. In some cases, people have added treatment steps before doing their reactions to neutralize things like LiO(-) or BuOO(-) (from Bu(-) and oxygen) that can screw up the desired reactions.

    Another item of laboratory lore is RLi storage. In every lab I’ve been in, there were those who stored their commercial BuLi in the fridge. There would always be condensation during warming to room temp for use and those Sure-Seal septa (mentioned by someone else) get pretty leaky after just a few needle punctures. Going back to the early papers of Gilman, et al. on the prep and stability of RLi’s, it turns out that they are thermally stable. You can reflux them for several days w/o decomp. However, BuLi is photolabile. I always kept my RLi’s at room temp, back inside their shipping can with a simple cover to block out light. Less precipitation, less waste, longer usable lifetime, excellent consistency of the titer, etc..

    Another item of “nostalgie de la boue” could be GRAVITY chromatography columns. In the early days of flash, some labs set up giant Soxhlets to wash and reuse the very expensive silica. As the price of flash silica came down, so did the Soxhlets. As flash became ubiquitous, gravity (63-200 um) silica gel almost disappeared. Today, flash is even the norm in undergrad lab. (And manual flash is being relegated to obscurity by pre-packed columns and automated systems.)

    I do miss the days of routine daily maintenance – trash can emptying, bathroom cleaning, etc. – that has now become weekly, if that.

    1. artjim says:

      (Not that anyone is interested, but my preference is to use BHT, a cheap, crystalline, air stable, non-hygroscopic solid proton source and 1,10-phenanthroline as indicator. Very sensitive, very accurate, and very reproducible. You can also do RLi titration by NMR

      – hi, do you happen to have a reference for BHT/1,10-phenanthroline titration handy?

      1. Anonymous says:

        artjim: BHT ref. The use of phenanthroline as an indicator goes way back and is on all of the common titration lists. BuLi in hexanes, titrated in THF forms a persistent very light brown (to dark chocolate brown, if you go past the endpoint) color. You can’t use it with dark or highly colored organometallics. E.g., some Grignards are too dark to titrate with phenanthroline. Other solvents and reagents may form other colors.

        Re: BHT. When I was just being taught how to titrate BuLi, I was shown the sec-BuOH (or t-BuOH) as-proton-source methods. First of all, you have to purify the BuOH. Then, prepare a reliable THF or other solution of known concentration … as if that will remain stable sitting on the shelf (solvent evaporation; solvent adsorption into the rubber septum; other problems). Then you have to accurately dispense it anhydrously for the titrations (which I always did in triplicate for crucial reactions). I read a lot of lit on other methods and the H-sources being used but I don’t remember a specific reference to the use of BHT. The properties I mentioned were all favorable as far as I was concerned: cheap!; easy to weigh it out on a balance, in air; soluble in most solvents of interest; easily acidic enough for BuLi; … just make sure you have a decent batch of white or translucent white crystals. If yellowish, it needs to be purified or replaced. I switched to BHT as a first-year grad student and have used it ever since.

        Note: You can buy 1,10-phenanthroline anhydrous OR the monohydrate. I usually had anhydrous on hand, but I was only using a sub-mg fraction of a needle for my titrations so a smidgen of hydrate is usually insignificant.

        “Trust me. It works.” 🙂 Seriously. I have done many high-precision titrations this way (e.g., so I could get 99% YIELD of aldehyde addition w/o touching a flanking ester).

        If I had access to the literature, my old notes or reference materials, I might be able to find a mainstream ref for you. If you need to cite a source, feel free to mention, “Anonymous, “Nostalgie de la Boue”, In the Pipeline, 27-Dec-2018″ (although I think I have posted it to Pipeline previously, as well).

        1. Li says:

          Is my recollection wrong that most BHT is so far from a pure compound that it’s properly considered to be a range of compounds? Or am I thinking of something different?

          1. Anonymous says:

            BHT is a common additive to foods, cosmetics, and other consumer items. I’m assuming that BHT for use in food and personal care items has to meet various FDA purity criteria. The prep isn’t too difficult (on paper). It is nicely crystalline thus, I assume, easy to purify on a large scale. I never had a problem batch that I can recall. (I would have tossed it and bought another bottle without thinking about it and not recall it.) I hope you’re thinking of something else!

          2. Myron says:

            I’ve always been fond of titrating menthol for my alkyl lithiums (1,10-phenanthroline as indicator). Nothing like a nice pure crystaline alcohol solid that does not seem hygroscopic. Not sure how precise the titration is.

    2. A Nonny Mouse says:

      I gave up flash chromatography in the mid 1980s; too much of a pain. Went back to doing gravity with slightly smaller silica but with sintered glass funnels (short and fat). Perfect for a gram or two of material. Within a year most of the company had switched over to doing things this way, and on a much bigger scale. I still often do a few hundred grams with a kilo or so of silica.

      1. Anonymous says:

        Absolutely NOT disputing the utility of using short columns (funnels) and various sorbents (silica, Celite, MgSO4, …) for quick cleanups, but sometimes you need a higher res method to separate “close spots”. Full length gravity columns are low res, flash and Chromatotron and MPLC are medium res, and HPLC is high res.

    3. Lloyd Evans says:

      I can definitely confirm what you say about the random junk in partially decomposed alkyl-lithiums. When I was doing my own organometallic Ph.D, we had a visiting post-doc from a company in Germany that made alkyl-lithiums, and he brought with him a 1 litre bottle of each one they made to donate to our lab, for which we were very grateful.
      Unfortunately, he forgot to put the methyl-lithium in the fridge, so it sat in a cupboard for a couple of months until we ran out of what we already had and needed more. By that time, there was a lot of precipitated material in the bottle, but I thought it might be worth decanting the liquid and seeing if there was still any in solution. It was originally (according to the label) a 1.6 M solution, but after filtering and titrating it, it was down to only 0.3 M – which we subsequently kept in the fridge and seemed to work just fine.

      The real fun came when I disposed of the pile of white crud in the original bottle. I had suspected it might be a bit fizzy, so I didn’t really want to throw any flammable proton sources into it, no matter how dilute. So I took it outside and to the end of a gravel yard, with nothing flammable nearby and nothing to get damaged. I wedged a big plastic funnel into the bottle, put on a face shield, and squirted water at it from about 20 yards away. My aim was fairly good and managed to get maybe 200 ml into the bottle, and to begin with, it just made a bit of smoke. So I started walking away, intending to come back to it later, when behind me I hear what sounded like a dozen firework rockets launching at once. I turn round to see the bottle spitting a volcano of intense pinkish-purple flames about a metre high, which continued at a fairly consistent rate for almost a minute. Incredibly, the bottle itself survived this process without so much as a crack, though it was fairly thick glass.

      So yes, though methyl-lithium does decompose at room temperature, the precipitated products from that are definitely still rather active, despite being insoluble and looking innocuous. Some have speculated that most of this material is lithium hydride, though by what mechanism this is formed from methyl lithium, I am not sure.

      1. Anonymous says:

        Re: “the precipitated products.” BuLi, MeLi, etc. are purified by crystallization from hexanes or pentanes (and that’s how the xtal structures are known, too). As solvent evaporates and the nominal 1.6 M commercial solutions become more concentrated, I am pretty sure that they deposit insoluble aggregates and even ordered xtals of RLi. That, to me, is the number one danger. Those solids could also be shock sensitive – DON’T poke the residue with a spatula, needle, or pointy stick! I don’t recall any literature about LiH from MeLi, but I guess you can draw a simple disproportionation that forms LiH but still leaves a hot EtLi:
        H-CH2-Li
        v ^
        Li-CH3
        ————–
        H-Li + CH3-CH2-Li
        (I hope the ascii “arrows” are properly aligned. Derek: Ask Science to add a free structure drawing widget so we can embed simple drawings!)

        1. Scott says:

          *Is* there a free structure-drawing widget? If so, where can one acquire such a toy, erm, TOOL?

  4. Old Timer says:

    We have an in-house machine shop that will rebuild broken pumps for a nominal fee. I find our pumps break down at a fantastic rate and nobody cools traps unless taking off residual DMSO. It’s a pity… Too much luxury.

  5. Polynices says:

    Next you’ll be telling us that walking uphill to school in the snow as kids didn’t build character.

    Sheesh.

  6. RTW says:

    One word about making your own MnO2. Ascorbic Acid. Keep a big bottle around in case your addition of methanol to KMnO4 gets to going too fast. Early on in my pharma career I made a large batch in a 10 L RB Flask and the stirring rod connecting the bearing to the motor broke because it got too thick. Addition kept going from the addition funnel but cooling wasn’t as efficient – I wasn’t thankfully standing at the hood when it blew the contents out through the necks of the RB flask. Ended up with quite a mess in the hood and on the floor to clean up. Thankfully someone suggested using ascorbic acid solution to clean up the mess.

    The next time I ran the reaction I did so in a very large open beaker in a huge ice bath, with instead of a glass rod an aluminum one and I used a metering pump to add the methanol slowly with the pump connected to a thermowatch to turn it off should the solution get too warm. This MnO2 worked well, but I got tired of making it and despite my supervisor telling me only fresh made would work for the oxidation I was doing I ended up using a bottle of MnO2 from I think DuPont (like a 2 Kg bottle I found in the stock room). Worked just as well. It was just always a mess to deal with filtering and drying the stuff before use when I had to make it.

    Even then I improved the process a lot by reducing the amount needed in the reaction and utilizing a improvised fluidized bed reactor set up. Pumping my substrate into the bottom of a column of MnO2 in a tall chromatography column and taking my product out the top as a clear solution. I would actually cycle it back into the substrate flask to get the reaction to go to completion. Everyone thought I was nuts… (I got my degree where the chemistry department was dominated by chemical engineers) but they soon learned I was an out of the box thinker.

    1. Anonymous says:

      RTW: MnO2 column reactor. Here’s a version from Org Synth:
      Org. Synth. 2017, 94, 34-45.
      DOI: 10.15227/orgsyn.094.0034
      “Continuous Flow Hydration of Pyrazine-2-carbonitrile in a Manganese Dioxide Column Reactor.”
      Submitted by Claudio Battilocchio, Shing-Hing Lau, Joel M. Hawkins, and Steven V. Ley
      Checked by Frederic Buono, Andrew Brusoe and Chris Senanayake
      (Link to PDF in my handle.)

      1. RTW says:

        Re MnO2 reaction – I ran this in the late 80s. At the time Steven Ley was one of our consultants. Might have mentioned this in one of our consultations back then, as it solved a lot of problems using this reagent at the time. Perhaps he remembered it or just reinvented it. Thanks for the reference though. Back in those days our organization was experimenting a lot as well with solid supported reagents. Fluidized Bed reactors would have been useful in a lot of this type of chemistry on scale, but probably not economic in most instances compared to non supported reagents in standard batch conditions.

      2. RTW says:

        Oops on reading the Org Syn reference you made it appears this is not actually a fluidized bed reactor as the column is packed solid and heated. Similar concept though I suspect there is considerable back pressure not experienced in the fluidized bed situation. Still overall an alternative that beats doing this sort of stuff in an RB flask or standard reaction vessels.

    2. Barrry says:

      is KMnO4 compatible with an aluminum stir-shaft??

      1. RTW says:

        Off hand I couldn’t say. I think it might have been Teflon coated. It was over 30 years ago

  7. Tocrat says:

    I made sodium amalgam as a masters student ( one year after BSc). Dropping mercury into a flask of molten sodium (which I melted using a Bunsen). I was absolutely terrified during the process but the stuff I ended up with worked brilliantly for subsequent dissolving metal reductions

  8. Rhodium says:

    Puts me in mind of a postdoc who came to EJ’s lab from HC Brown. The reactions that got him his Ph.D. did not work in Cambridge. Turned out in Brown’s lab they made their own diborane. The commercial stuff was decidedly inferior.

    1. Anonymous says:

      And another tie-in to Alfred Bader: HC Brown pioneered many borane reagents and “In the spring of 1972, Dr. Brown was able to persuade Dr. Alfred R. Bader, Pres of the Aldrich Chemical Company, to set up a subsidiary, Aldrich-Boranes, Inc., to make readily available the various boron based reagents necessary to facilitate application of this new field of synthetic chemistry.”

      Clinton F. Lane (RIP, 2007), got his PhD with Brown at Purdue and joined Aldrich in 1971. He joined the Aldrich board in 1986. As I recall, Lane played a role in the establishment of Aldrich-Boranes and promoted the utility of boron reagents via numerous publications and seminars.

      Another tie-in to EJ and commercial reagents. PCC and/or PDC came up in Pipeline recently (I think). Many of us associate PCC and PDC with EJ. The commercial products were not always as brightly colored as freshly prepared material and not as reactive as freshly made reagent. (I’ve found a few clearly bad bottles on the shelves over the years.) Some (many?) of us would just make their own small batches, as needed.

  9. An Old Chemist says:

    Back in 70’s, when I got my Ph. D. in an Asian country, I activated my own Magnesium metal for Grignard reactions, made activated Zinc dust, and we all used to make anhydrous ether by storing it over sodium wire. We also used to use water-circulatory pumps, held in a bucket, due to the unreliable water supply in labs. Our US chemistry journals used to arrive a few months after their publication date because they were shipped via sea mail due to shortage of funds. Of course, we had not heard of safety glasses and lab coats.

    1. Anonymous says:

      Water pumps: I used to use Little Giant Submersible Pumps from Fisher, VWR, etc. but I switched to using submersible fountain pumps from Harbor Freight at a fraction of the cost. And I got a free tape measure for the tool drawer, as a bonus.

      1. hn says:

        Cool! Anything other Harbor Freight items that are good for the lab?

        1. Anonymous says:

          HF has lots of cheap stuff! Cheap Teflon tape. A $60 drill press makes a good, strong stirring motor … except that it isn’t explosion proof. How about a hydraulic jack for use as a lab jack … although I think “1.5 ton” is overkill for most of my reactions. An off-brand “Sawzall” comes in handy.

          If it doesn’t move and it should, use WD-40. If it moves and it shouldn’t, use duct tape. If neither works, get the Sawzall.

          Disclaimer: I do not work for Harbor Freight and have no financial interest in Harbor Freight. Don’t forget to bring the discount and free stuff coupons!

          1. RTW says:

            I was reading through a catalog I got from HF and I see they also have some pretty inexpensive Vacuum pumps at 2.5 CFM and a better one at 3.5 CFM.

          2. Squib says:

            Do NOT use paint stirrers/drill presses for a mechanical stirrer unless you want some surprises. I had a reaction that was generating hydrogen almost catch on fire this way. I heard that telltale ignition sound and turned around to see a quick fireball in my >2L round bottom. Luckily I think it ran out of oxygen before it could catch the THF on fire. Needless to say the scale up went to crap and I had a long day of chromatography ahead.

  10. Fluorine Chemist says:

    Ah, the good old days! I was a grad student in a Big10 school in the Midwest (1993 onwards). I still remember activating zinc powder for insertion reactions; activating Cu(I)Br for generating fluorinated organocopper reagents – the activated powder was off-white in color and used to store real good under nitrogen…
    Preparing anhydrous fresh zinc iodide… first time I added the iodine a tad too fast, the reaction got a bit exothermic on me and painted my fume hood a vivid violet; the second and subsequent times were much better! Filtering the solution and flash distilling the ether to generate ultra pure ZnI was fun…
    Cutting TLC plates, drawing spotters…
    Flash columns, gravity columns…
    Good times, good times…

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  12. HFM says:

    I did my undergrad work in a couple of unfunded labs. They survived on castoffs, surplus from the teaching labs, and occasional theft. Buying stuff was not an option.

    Then I did an internship in an industry lab. First day, I walk in, and the boss asks me to do a simple reaction. No problem, I say. Then I take inventory of what’s at my station, and I start sweating. But I figure it out, and several days later, I’m back at the boss’ door with the desired product. I describe the rather hairy multi-step process that was involved. Boss gives me a strange look. Okay, that’s actually kind of impressive, but…there’s a one-step reaction, I know you know it, so why do it this way? Yeah, but I didn’t have that reagent.

    Boss facepalms. He’s forgotten to show me the supply area. Which is basically Willy Wonka’s candy factory, except for biochemists. Mind = blown.

    There was some training value in learning how to make what I needed from semi-arbitrary inputs. But not enough to outweigh the bad habits that I had to unlearn. And for serious work, forget about it. Resource constraint makes easy stuff hard, and hard stuff impossible. Science is hard enough without handicapping yourself. Zero nostalgia here. I’ll take the well stocked lab every single time.

  13. Dr. Nemo says:

    I needed to synthesize the pinacol derivative of diboronic acid, as a (now widely available) precursor to the abovementioned aryl boronic acids. I had to use metallic potassium to make the B-B bond. Never having handled solid potassium before, I was pretty sure I could run into trouble. I rigged a device to squash glass ampules containing potassium under a layer of solvent in an inerted flask and ran the reaction in the same flask. It worked well, but I distinctly remember the feeling “I never want to do this again”.

  14. Humble Scrivener says:

    This is the first live use of the idiom “nostalgie de la boue” I have seen outside a language reference work. And it’s unlike any other use that has ever existed. Kudos.

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