Nucleus: The Chemical Blogspace Blog

Flowing, Not So Gently

March 4th, 2010, No Comments

I’ve written both here and elsewhere about flow chemistry, the technique where you pump your reactions through a reaction tube of some sort rather than mixing them up in a flask. And I freely admit that I have a fondness for the idea, but it’s definitely not the answer to every problem.

For one thing, I tend to like the idea of sending reactants over a bed of catalyst or solid-supported reagent (what I call Type II or Type III flow reactions in that 2008 link above). Type I reactions, in my scheme, are the ones where you just use a plain tube or channel, and all the reactants are present in solution. A big advantage of those, as far as I can tell, is to handle tricky intermediates that you wouldn’t want to have large amounts of or to control potential runaway exothermic reactions. There’s also the possibility of running the reaction stream through some solid-phase purifications and scavengers, the way Steve Ley and his group like to work, which is convenient since you’re already pumping the stuff along anyway.

But the sorts of reactions that you often see in the flow-chemistry equipment brochures. . .well, that’s something else again. More than one outfit has earnestly tried to sell me a machine based on how well it did a Fischer esterification. My problem wasn’t that the reaction was discovered almost in Neanderthal times – it was that Thag run reaction in round bottom flask, work fine, not need flow reactor. I mean, really, this is a nonexistent problem and needs no solution.

So I read this new paper in Angewandte Chemie with interest. The authors are looking at some standard catalytic organic transformations and comparing them carefully between batch mode and a flow setup. They stipulate at the beginning that flow chemistry has the advantages mentioned above, but they’re wondering about what it can do for more ordinary chemistry:

“In addition to these developments, general and rather sweeping claims have been made that microreactor systems accelerate organic reactions and that lower catalyst loadings and higher yields can routinely be achieved in these systems compared to those of reactions carried out in flasks. Despite these potential advantages, examples of successful implementation of microflow reaction technologies in either academic organic synthesis or industrial process research and manufacturing remain more isolated than these reports would suggest. However, the implication is that it is only a matter of time before microflow reactors will dominate laboratory studies aimed at both fundamental research and practical applications of complex organic reactions, with our current mode of operation in reaction flasks ultimately becoming a relic of the past. It seems therefore worthwhile to examine the assumptions behind this viewpoint to provide a critical analysis of “flask versus flow” as a means for effecting reactions.”

What they find is that there’s very little difference. A catalyzed aldol reaction that was studied under flow conditions by the Seeburger lab is shown to perform identically to a batch reaction, if you make sure to run them at the same temperature and with the same catalyst loading. The paper then looks at asymmetric addition of diethyl zinc to benzaldehyde, a model reaction that I often wish would disappear from human consciousness so it would afflict us no more. But here, too, under more challenging heat-transfer conditions, flow showed no differences from batch. The authors point out that this reaction is, in fact, run under industrial conditions, but not in a flow apparatus. Rather, it’s done in batch mode, but though good old slow addition of reagent, which also gives you control over exotherms.

The authors specifically exempt all supported-reagent chemistry from their analysis, so that preserves what I like about flow systems. But for homogeneous reactions, the only time they can see an advantage for the flow reactors is when there’s a potential for a dangerous rise in temperature. So now we’ll see what some of the more flow-oriented people have to say in reply. . .

Together At Last

February 8th, 2010, No Comments

Well, I have no particular need to make azo-linked compounds (see this morning’s post for one reason!). And I have to say, although it’s mechanistically interesting, I definitely feel no desire to make them by combining a hydroperoxide and a diazonium salt in one pot. This is not a moment destined to take its place alongside the legendary invention of the chocolate/peanut butter cup.

Sure About That?

January 11th, 2010, No Comments

There was a natural products paper (abstract) that I missed last fall which has finally come out in Bioorganic and Medicinal Chemistry Letters. Let’s have a show of hands: how many chemists out there think that this structure is the correct one?

Right. Going back through SciFinder, I don’t find any anti-Bredt cyclobutene structures of this sort in the modern era – only speculations about whether or not they could even exist. I hope, for their sake, that the authors have assigned this one correctly, and it certainly would be neat and interesting if they have. But doubts afflict me.

Note – the most recent entry on the (inactive?) med-chem blog “One in Ten Thousand” was a raised eyebrow about this exact paper. Fear not, there’s no curse – I’ll continue posting. . .

More Binding Site Weirdness

November 30th, 2009, No Comments

Now here’s an oddity: medicinal chemists are used to seeing the two enantiomers (mirror image compounds, for those outside the field) showing different activity. After all, proteins are chiral, and can recognize such things – in fact, it’s a bit worrisome when the enantiomers don’t show different profiles against a protein target.

There are a few cases known where the two enantiomers both show some kind of activity, but via different binding modes. But I’ve never seen a case like this, where this happens at the same time in the same binding pocket. The authors were studying inhibitors of a biosynthetic enzyme from Burkholderia, and seeing the usual sorts of things in their crystal structures – that is, only one enantiomer of a racemic mixture showing up in the enzyme. But suddenly of their analogs showed both enantiomers simultaneously, each binding to different parts of the active site.

Interestingly, when they obtained crystal structures of the two pure enantiomers, the R compound looks pretty much exactly as it does in the two-at-once structure, but the S compound flips around to another orientation, one that it couldn’t have adopted in the presence of the R enantiomer. The S compound is tighter-binding in general, and calorimetry experiments showed a complicated profile as the concentration of the two compounds was changed. So this does appear to be a real effect, and not just some weirdo artifact of the crystallization conditions.

The authors point out that many other proteins have binding sites that are large enough to permit this sort of craziness (P450 enzymes are a likely candidate, and I’d add PPAR binding sites to the list, too). We still do an awful lot of in vitro testing using racemic mixtures, and this makes a person wonder how many times this behavior has been seen before and not understood. . .

K. C. Nicolau, Call Your Office

November 23rd, 2009, No Comments

While I’m putting up odd chemical structures today, I thought I’d add this one, Alasmontamine A, from the latest Organic Letter preprint stream. Natural products scare me:

Anyone who wants to take a crack at this one synthetically, you just go right ahead without me. It is pretty much a dimer, though, so it’s only about half as awful as it looks. Which is still enough. It doesn’t seem to have much biological activity, but if you can sell it as something to do with green chemistry, nanotech, or alternative energy, you should be able to round up some money, right?

K. C. Nicolaou, Call Your Office

November 23rd, 2009, No Comments

While I’m putting up odd chemical structures today, I thought I’d add this one, Alasmontamine A, from the latest Organic Letters preprint stream. Natural products scare me:

Anyone who wants to take a crack at this one synthetically, you just go right ahead without me. It is pretty much a dimer, though, so it’s only about half as awful as it looks. Which is still enough. It doesn’t seem to have much biological activity, but if you can sell it as something to do with green chemistry, nanotech, or alternative energy, you should be able to round up some money, right?

Hoist, Petard, Etc.

October 8th, 2009, No Comments

Hmmm. As a colleague just pointed out to me, I’ve spent some time here defending “me-too” drugs. And just this morning (see the previous post) I take off after what can only be described as “me-too reactions”, saying that I don’t see the use for so many of them.

Well! The only defense I can offer (until I think of a better one) is that there is no drug category so populated as the aldoxime-to-nitrile conversion is in synthetic chemistry (or acetal formation/deprotection, desilylation, or the other categories I spoke of in that other post). I suppose I might have a tougher time standing up for me-too drugs if there were (say) twenty-nine statins on the market. But still. . .”I’d better put up a post on that”, I said. “Better you than someone with a funny pseudonym in your comments section”, came the reply.

Retire These Reactions!

October 8th, 2009, No Comments

Here’s a question you don’t hear discussed very often: are there some synthetic organic chemistry reactions that don’t need any more work? I’m moved to ask this because I just came across yet another way that someone has reported to dehydrate an oxime to a nitrile. (No, I won’t link to it. You don’t need it. No one needs it).

If asked to count the number of times I have seen new reagents that dehydrate oximes to nitriles, I would be at a total loss to even try to guess. But I’ve seen it over and over and over. Is it possible that we now have enough ways to do this? And that anyone who is contemplating adding another one to the list should instead go do something else?

I’ll vote for that. And there are several other transformations that could go on the same list. That doesn’t mean that I think that our existing methods for these are all perfect, or that they couldn’t be improved. I mean, even for forming amides, I would like an inexpensive reagent that never fails, even with crappy unreactive hindered coupling partners, works at room temperature in about five minutes, and has a ridiculously simple workup. We don’t quite have that, do we? But no one’s publishing on coupling reagents like that, because they’re rather hard to realize. What we get are a bunch of things that are about as useful as what we have already.

And I agree that it’s worth having multiple methods to accomplish the same reaction. I’ve been saved several times by being able to move down the list and find something that works. But how long should the list be? Eight reagents? Ten? Twenty? At what point should something like this cease to become an acceptable field for human effort?

My first nomination, then, for the Retirement Home for Organic Transformations is aldoxime to nitrile. I am willing to face the rest of my chemistry career with only the monstrously long list of reagent systems we have today for that reaction. Further nominations can be made in the comments – I’ll assemble a list for another post.

Microwaves Aren’t Magic

September 30th, 2009, No Comments

Many synthetic chemists these days use microwave reactors to speed up their reactions, especially metal-catalyzed couplings. But there’s been a debate ever since the technique became popular about why it works so well. Some people think that microwave irradiation is just a very efficient and fast way to heat up a reaction, while others have hypothesized some sort of microwave-specific effect, outside of the heating behavior. Metal catalysts have been particular favorites for this possibility.

The former view has been gaining ground, though, and I think we can now say that it’s won. A new paper from the lab of microwave chemistry pioneer Oliver Kappe has an ingenious way to settle the argument. They’ve fabricated a microwave reactor vial out of silicon carbide. It’s chemically inert and has very high thermal conductivity, but SiC is completely opaque to microwave frequencies. Reactions run in this vessel heat up just as quickly as those run in the same-sized glass tube, and reach the same internal pressures and working temperatures. But the contents experience no microwave irradiation at all.

Kappe and his co-workers ran a wide variety of reactions head-to-head in the two kinds of vial, including a range of metal catalysts. No differences were observed in the yields, purities, or side products for any of eighteen different types of reaction. That’s good enough for me: unless someone can come up with a weirdo outlier catalyst, there is no nonthermal microwave effect on organic chemistry.

Nobel Season 2009

September 29th, 2009, No Comments

Fall is in the air, which (for a very small group of people) brings thoughts of a call from Stockholm. The Nobel Prizes will be announced next week, starting the Physiology and Medicine on Monday. And as in years past, people are lining up with predictions.

Predicting the Chemistry prize is tricky, since it’s so often used as a surrogate for the nonexistent Biology prize (and, once in a while, as an overflow Physics one as well). But let’s take a look at the field and see if the Scandinavians surprise us or not.

The two best roundups I’ve seen so far are from the Wall Street Journal and Thomson/Reuters. For Chemistry, the Journal has a pair of biology prize possibilities going to (1) Hartl and Horwich for chaperone proteins, or (2) Winter and Lerner for antibodies (humanized, monoclonal, catalytic). They also have a material-science one for Matyjaszewski (atom-transfer radical polymerization). Note that that last Wikipedia entry seems to show (at least as of this morning) the hand of an interested editor.

Meanwhile, the Thomson people, using a citation-based algorithm, have no overlaps with this list at all. They suggest (1) Michael Grätzel (dye-based solar cells), (2) Jackie Barton, Bernd Giese, and Gary Schuster (electron transfer in DNA), or (3) Benjamin List (asymmetric catalysis).

And over at the Chem Blog, the current favorites are Grätzel and also Richard Zare, Allan Bard, and William Moerner for single-molecule spectroscopy. Those last two have already picked up the Wolf Prize in Chemistry for that work in 2008, and Zare won one in 2005. It’s worth noting that Richard Lerner, from the Thomson list, won back in 1994-1995, along with Peter Schultz, who also is often mentioned when Nobel time comes around.

I think that Grätzel is a good bet, considering that the work seems solid and that solar power is such a hot topic these days. I would like to see Bernd Giese get in on a prize, since I did my post-doc with him, but I consider the electron-transfer work to be more of a long shot, at least for now. List is probably the best shot at a “pure organic chemistry” prize; although I also doubt that this is the way it’ll go this year. As always, it wouldn’t surprise me a bit if things bleed over from biology – the committee might go as far as to consider telomeres to be chemicals and give it to Blackburn, Greider, and Szostak. And that’s certainly worth an award, just not in Chemistry.

We’ll know soon. Feel free to put your favorites into the comments, and I’ll update this post with the list of suggestions. One of has to get it right, you’d think.