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A Rain of Tiny Droplets

You might be surprised to know how little we chemists know about what our reactions are really doing. A case in point is the “on water” field. Water is generally not the greatest solvent for a lot of classic organic chemistry reactions, since the reactants, reagents, and products are often not very soluble (or are outright reactive with the water itself). But water would still be a great solvent for many of them if it were possible, since it’s cheap, nontoxic, and has the potential advantage that product isolation can be made easier by the insolubility.

When I was in grad school, Breslow’s group reported acceleration of the classic Diels-Alder reaction when some examples were run under aqueous conditions, and the thought at the time was “solvent pressure” – that the reactants were being literally squeezed together by the hydrogen-bonding network of the water. That sounds weird, but the Diels-Alder is one of those reactions whose transition state actually has a smaller volume than the reactants or the product, so putting pressure on it speeds it up (by lowering the energy needed to get to that transition state, thermodynamically speaking). People have put Diels-Alders in all kinds of high-pressure rigs, and some years ago I wrote about a fun example where the reaction was run in a Teflon tube that was frozen in water ice in a sealed bomb reactor, which gave it a brutally high pressure without special equipment. (I can’t seem to find a link to that one, though!)

Then just a few years ago, Barry Sharpless and co-workers introduced “on water” chemistry, which was defined as reactions that were accelerated by occurring on the water/organic solvent interface. Water at that boundary is most definitely not good old water in the bulk phase, any more than the water molecules in the pockets or around the surfaces of proteins are. There are some reactions that speed by up to hundreds of times under such conditions, and as this new paper from the Zare group at Stanford shows, there is still no consensus about just how this happens:

At first, on-water acceleration was ascribed by Breslow and co-workers primarily to the accumulation of hydrophobic species at the air-water interface. Later, Jung and Marcus put forward the idea that the acceleration was caused by “dangling” OH bonds in the hydrophobic phase surrounding water. However, calculations by Thomas, Tirado-Rives, and Jorgensen were unable to ascribe the rate acceleration to unusual participation of water molecule on the water surface. Since then, Beattie, McErlean, and Phippen have proposed that reaction with water at the interface results in both the protonated substrate and free OH-, which is stabilized by its strong adsorption at the interface. We also know from past experiments on microdroplet chemistry that additional factors causing acceleration may be the lack of three-dimensional solvation at the surface of the water droplet, the speed of two-dimensional diffusion, the large electric field at the water-air interface, and the presence of charged species that preferentially accumulate on the water surface.

Yep, it’s a different world, and the more surface you can provide for such weirdo effects to have their way, the more new chemistry you might discover. This latest paper takes things about as far as they can go, because they’re looking at the microdroplets produced by electrospray ionization, as used in mass spectrometry work. They’re using a model system, the cycloaddition of quadricyclane and diethylazodicarboxylate, that has been used by several others in the on-water field as a benchmark. If you stir those two in toluene, the reaction is pretty slow (24% yield after 24 hours), but Sharpless and co-workers found that the “on water” conditions led to a 40% yield after 4 hours, and almost 70% after 18 hours. Zare’s group finds that the reaction “on droplets” is accelerated by another 115-fold over the Sharpless conditions. Interestingly, if you run the same reaction in deuterated water, you slow down by a factor of five, which is basically the same slowdown that the Sharpless group observed – a pretty strong solvent isotope effect that shows that it’s the O-H bonds that are a big factor somehow.

I hope that it’s possible to find out more about just what’s going on here, so we can manipulate reaction conditions accordingly. Speeding things up by this amount is always welcome, and there’s also the possibility for completely new reactions. This paper, for example, also noted accelerated formation of byproducts from the breakdown of the DEAD itself, and you have to wonder what other things are waiting out there. Running reactions under electrospray conditions like this gives you an instant profile of what’s going on (by feeding the results directly into the mass spec), so this should make reaction discovery much easier.

You might object that this would be hard to scale up, but on the other hand, it’s also (it seems) a classic flow-chemistry situation, where the reaction itself is taking place in a relatively small zone. I could imagine a flow setup with some electrospray apparatus in the middle of it – if you can get things up to a first-pass-is-enough level, it could be pretty interesting. And beyond the practical applications, you do wonder what’s going on here. The details of such effects could prove useful in understanding the solvation shells around ligands and proteins for modeling purposes, and who knows what else.

28 comments on “A Rain of Tiny Droplets”

  1. Chris Phoenix says:

    A factor the Zare quote didn’t mention, and that seems like it might be important, is the physical orientation of the reactants. Assuming they have to be in a particular orientation (relative to each other) to react, then in bulk solution they’d only be in the right orientation a small fraction of the time.

    If being at the air-water interface tends to constrain their orientation, and if the range of orientations available at that interface is favorable for the reaction, then I’d expect some speedup just from that. It’d almost be an enzyme effect, except instead of a binding pocket that holds the reactants tightly, you just get a (sort of) plane that “holds” them loosely.

    1. DrOcto says:

      This is such a simple explanation that it almost hurts a little bit.

      It leads a bit into solid phase catalysis, so what’s a good simulation of water? Frozen water?if you can operate at that temperature, or how about silica gel?

  2. ef says:

    Are you maybe referring to Hayashi’s work on Mannich (and other) reactions in frozen ice?
    http://www.ykbsc.chem.tohoku.ac.jp/publication_list/pdf/55.pdf

    1. Derek Lowe says:

      That’s it exactly. And I wrote about it here on the blog at one point, but Google doesn’t seem to know about that. I’m still searching around for the link!

      1. Danny in Canada says:

        are you sure *everything* got transferred over from Corante?

  3. sendthescabsbackhome says:

    I remember being on an interview once and some idiot PhD from a Chinese university told me I was full of it because I showed a reaction of an amino acid and an acid chloride in aqueous conditions.

    Listen up pharma executive!! did you really think staffing R+D with these clowns was going to get you somewhere???

    1. Derek Lowe says:

      I’m definitely not a fan of your user name, I have to say. But if this is reported accurately, what kind of practical organic chemist are you if you don’t know the Schotten-Baumann? That’s beloved among bench chemists for the cleanliness and ease of workup. . .

      1. Love100yrOldGermanChemistry says:

        I’m a process chemist and you’d be surprised how many CDMOs I’ve had to reacquaint with the venerable Schotten-Baumann reaction. I guess if it’s not the coupling reagent du jour people don’t appreciate it.

      2. NMH says:

        I’m a dumb biochemist, and I do a demo with an amine and an acid chloride to form Nylon in an attempt not to being boring to My org class….

    2. Send sendthescabsbackhome back home says:

      I remember being on an interview once and some idiot PhD from an American university told me I was full of it because I showed a reaction of an amino acid and an acid chloride in aqueous conditions.

      Listen up pharma executive!! did you really think staffing R+D with these clowns was going to get you somewhere???

      Sound better?

  4. HGMoot says:

    “Running reactions under electrospray conditions like this gives you an instant profile of what’s going on (by feeding the results directly into the mass spec), so this should make reaction discovery much easier” … it might, but things like the McLafferty rearrangement etc. may occur, such that drawing correct conclusions about the structures generated can be a little complicated.

    1. Druid says:

      The MacLafferty rearrangement is an electron impact (1 electron hole) reaction which does not happen in electrospray. Ah – happy memories.

      1. HGMoot says:

        That’s right/my bad… thanks for the reminder. It was a busy day…
        Actually, I should remember better because I was a postdoc at a big pharma in 1992 when one of the inventors of the modern ESI concept presented to us a seminar emphasizing how gentle the ionization mode was, and how easy it was to see the molecular ions, as opposed to the EI mode. FAB was the method of choice at that time for molecular mass determination of most medchem compounds.

  5. Project Osprey says:

    Kind of makes you wonder how it would fair as an emulsion? There’s much more interfacial surface area that way – and it would scalable. Surfactants will of course lower the surface tension and if that results in it not working then it might tell you something about the conditions required.

    As an aside, one of my favorite examples of water unexpectedly improving something is with Shibasaki catalysis. The complex is somewhat water sensitive yet small amounts of water actually improve its activity.

    https://doi.org/10.1016/S0040-4039(98)01578-0

    1. Anonymous says:

      Some others: I was trying to form a ketal using Hg(OAc)2 and similar. Yields were poor. I added some water (even a lot of water, ~10% was OK) and the rate and yields improved tremendously.

      Dess-Martin Oxidation requires a trace of water to proceed.

      Although not related to this “water droplet” topic alone, many moisture sensitive reactions proceed well in the presence of water. For many decades, undergrads have been making Grignards in open test tubes using (wet) ether from a can or bottle. Li went all the way and made Grignards in water. People have done Heck couplings, Wittig couplings, etc. in water (as solvent).

      Going back to the Breslow paper, wasn’t another argument based on the formation of organic aggregates or micelles in the bulk water phase?

  6. Barry says:

    How does one measure the temperature of the droplets in electrospray? There’ll be a lot of evaporative cooling; many of the droplets will be below 0C. Some of them might even nucleate and form snow?

    1. zero says:

      Maybe if you are spraying into dry air. Cooling would be minimized by spraying into saturated air instead.

      1. Barry says:

        “electrospray” is done into an evacuated region, where the partial pressure of water (and everything else) is very low indeed.

        1. HGMoot says:

          First, the sample is heated to something like 400 degC.

  7. Uncle Al says:

    We then wonder about capillarity effects in porous Vycor glass, and smaller volumes still in initially desolvated large MOFs. Blow it through, get ‘er done?

    1. John Wayne says:

      My PhD adviser always called easy reactions, ‘pour and roar.’ I’d like to welcome in the new paradigm of ‘spray and pray.’

      1. Hap says:

        Hope it works better than that technique in other endeavors.

  8. chops says:

    From a process chemistry perspective, I have to counter your point that running reactions in, or on, water is preferable. Solvent volumes, cost to recycle and environmental impact all contribute.

    A good summary here: http://onlinelibrary.wiley.com/doi/10.1002/anie.200604952/abstract

    1. milkshaken says:

      I completely agree, in fact aqueous waste streams containing lots of inorganic salts together with residues of organic solvents, or even TFA are troublesome…

      When people talk about special properties of water, for example for Diels -Alder, they often forget about simple activation of the dienophile by protonation. Likewise, magic of concentrated LiClO4 in ether is due to the fact that Li(+) in weakly coordinating solvents like ether is a fairly competent Lewis acid.

      The reactions that work magically on water should be tried in trifluoroethanol as a solvent. If there is also acceleration, then the magic of highly ordered water structure is not responsible for the observed acceleration.

  9. anon electrochemist says:

    Someone should measure sum frequency generation spectra of these systems. It’s been specifically developed to look at strength and orientation of OH bonds at buried interfaces, and would tell you precisely what sort of organization you had at the surface.

  10. Barry says:

    Bill Doering quipped that he spent most of his career studying unimolecular reactions in the gas phase, because condensed-phase chemistry was too hard to understand. In the electrospray droplet, we don’t know the concentrations (the solvent is rapidly evaporating) we don’t know the temperate (surely there’s a lot of evaporative cooling). And we don’t know if the reactants aren’t being excluded from the lattice as the remaining solvent freezes.

    1. Curt F. says:

      Don’t forget the very large electric fields, the rapidly varying pressure, and a skyrocketing surface-to-volume ratio.

  11. Old Pump Kicker says:

    Reading “Water is generally not the greatest solvent…” made my eyebrows shoot up, because water is THE solvent for living (organic) chemical reactions. Its uniquely high dielectric constant allows charged species to move closer than otherwise possible. Of course, the rest of your sentence made it clear you were referring to the specific subset of “organic” that is your bread and butter.
    And in the world of corrosion chemistry, water is the miserably effective solvent from which there is no escape.

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