Interpnictogen Cations DOI: 10.1002/anie.201307658

Interpnictogen Cations: Exploring New Vistas in
Coordination Chemistry
Alasdair P. M. Robertson, Paul A. Gray, and Neil Burford*

Okay, pnictogens! Now, this is something I'll be able to understand actually. Still, I can remember a time, long long ago when I didn't really know what a pnictogen was. Yes, now to take us back to that time, when I got sent by my supervisor during my undergrad days, to the library, to look up some compound that I can't remember right now in chemical abstracts, and to figure out a way of making it. Now I may be dating myself here, but chemical abstracts still existed at the time. And after I did go to the library, I seriously thought about quitting chemistry. When you enter the rows with the abstracts there is an undescribable smell of old paper and boredom, and after half an hour of leafing through them your brain starts turning off and you begin to fall asleep, prevented from passing out by the rigid metal shelves and the stone floor of the library. Still, you find a chair and spend an hour sleeping. It was after that one hour of sleeping that I opened a random chemistry journal on another shelf, anything to get away from the sleep demon that is the chemical abstracts.

The article that I opened talked about pnictogens. It looked really crazy with phosphorous making some crazy structures when chlorophospines or alkylchlorophosphines were reacted together with something and water was present in small amounts. There was no way I could make any sense of the reactions, and now in retrospect, I'm guessing the authors couldn't either, but the products looked pretty cool. I couldn't really figure out what a pnictogen was, but I noticed that they talked about it with regards to nitrogens and phosphorous, so I guessed it was a group V element. It's not like we had Wikipedia back then. Later I asked somebody, and they said, 'yes, it is a group V element'. Then I probably forgot and learned that factoid again. Well that's it. Probably not that interesting of a story actually.

Now for something more interesting! A review about pnictogen-pnictogen bonds, where inevitably you end up with a cation when you go to the more heavy ones. The process of making them involves taking a halopnictogen RPnCl and reacting it with another pnictogen that has a free lone pair and can substitute the chloride. Because the chloride (or Br or I) is actually a pretty good Lewis Base itself, sometimes you need to activate it a bit with AlCl3, so you end up in the end with an AlCl4 counterion that leaves your resulting molecule stable. You can also do anion substitution in situ to get a PF6 in there and let the NaCl salt fall out of solution. That's it. Pretty simple, but it can get complicated as your products can dimerize to give you a cyclic product, a linear Pn-Pn-Pn-Pn compound (Figure 8) or something crazy like a sandwich in Figure 23.
The chemistry, after you look at a few mechanisms at the beginning, is easy to follow for the more simple examples, but complicated reactions that create a tetraphosphine cation that coordinates to As for example, are not so easy to predict.

I did get lost in the writing quite a bit, but I think it's because of my bad pnictogen experience back in undergrad. My eyes glaze over whenever I see that word, and all the proper name endings associated with various anions or cations of arsenic or antimony. But chemistry is a visual science and it has become much more visual with chemdraw. The authors do an excellent job with figures so that you can read almost the entire review by just looking at the pictures, which happen to be on the same page as the text about them, which is also very helpful. Of course since I was reading on a smartphone small-screen, this advantage proved to be moot. I did enjoy reading this review because I understood most of it right away and I think the figures played a very big part in that, but also when the product was predictable, the simple rules for making the products at the beginning helped me to figure out the mechanism after looking at a figure for a few seconds. If you're looking for a quick and fun review to read to make yourself smarter (but it probably won't actually, as I doubt more than 1% remains in my head a week after I slog through them), read this one.

Obviously a lot of it is basic science research. There is a big part of it where it's really unpredictable with bismuth (which has a much higher coordination number so you get 'surprised' a lot) and if you introduce water, oxygen, or even a bit too much AlCl3. It makes sense since as the authors say at the beginning the energy of a Pn-Pn bond is much less than that of many other bonds. And if one of them serves as a Lewis base for another, well water can serve as a pretty good Lewis base. Or oxygen...

All (okay, let's say 'most' since I don't know for sure) these compounds are very sensitive to moisture and air. Also halogen substituted amine starting materials are very hard to work with, plus a lot of the heavy pnictogens are toxic and especially their compounds, with a notable exception being bismuth for some reason. I did a few experiments with making air sensitive phosphines and inevitably, my lab would always have some few specialized pieces of equipment missing. You're supposed to have a Schlenk line, but also some specialty glassware to filter under nitrogen, distill under nitrogen, etc...  it's always a few more extra steps than common organic chemistry. But this is still some basic science that makes interesting stuff and needs to be done. Some of it can't be predicted so well. The review focuses on saying whether a bond is ionic or covalent by looking at bond lengths and comparing them to the sum of the covalent radii and making comments to the effect that the bond is short because such and such substitution makes one of the pnictogens a better Lewis base. I always found that as filler since you just get an interesting product, but you now need to describe it in detail. I don't really care much for the bond lengths and I won't remember them tomorrow, but I will remember the crazy bismuth compound with an antimony donor.

The authors end the review with: "We anticipate that the fundamental development of coordination chemistry between the pnictogens, and the p-block elements in general, will lead to the discovery of new materials and catalysts to rival those developed from the chemistry of carbon and transition metals."

This is not true. There is not even a single planet in the universe that doesn't have lots of oxygen in some sort of pnictogen devouring form probably. It's fun basic chemistry that maybe someone will use in a practical process in a reactor some years from now. But rival the chemistry of carbon and transition metals? No...

One last not to someone who wants a quick JACS Angewandte article, is to take a look at Figure 1 in the beginning and more importantly (since many of those in Figure 1 will remain imaginary forever) at Table 2 at the end. If you can make any of those that have not been made yet, make sure to submit them to the aforementioned journal first. Don't worry... I won't be your competition, but the Burford lab at UVic might be. Good luck.

Insung S. Choi Date of birth: January 9, 1969 Professor of Chemistry and of Bio and Brain Engineering KAIST

DOI: 10.1002/anie.201310974

I thought about doing a post about that microfluidics minireview, but that would require me reading it in detail. And I'm already getting ready for next week's review. Eventually as I'll get better at this, maybe I'll have time to comment on the second review that comes out with each issue as well. And maybe even on some of the more inane two page 'comments' written by some famous professor. But until then, more of these fun posts that make me relax after reading an intense review.

Right, let's see here. Piece of equipment the person would like to be is 'stopwatch'. Okay, moving on we have a safe-bet pick of a famous French expressionist as favorite painter... Well, to tell the truth I actually like this one. You don't get any useful information really out of these profiles, and I thought the answer about following your curiosity in science as great. Not enough people do this these days. Especially with tight funding and universities wanting you to bring in money. Writing a sci-fi novel is also what I wanted to do if I ever became unemployed... but after looking into it seriously for a bit, I decided the competition was a bit too stiff and I'm better off reading Angewandte reviews.

The best answer of course, is as to what he sees himself doing in the future. Raising rabbits. That might seem like a whimsical answer, but it actually reveals that Insung Choi has thought deeply about the future and the coming apocalypse, where the few human survivors are forced to survive in a cruel, radioactive world. That, coupled with a story I saw on TV about a giant rabbit breed from Russia being grown for meat to be shipped to Asia, makes me think that being a giant rabbit farmer is a useful post-apocalyptic occupation. Another one is being an giant rabbit farm guard to stop the raiders, but you need some serious firearms training for that. I mean, have you seen some of these things!? They are freakin' huge. Lots of meat.

http://en.wikipedia.org/wiki/Flemish_Giant

Saxitoxin: Arun P. Thottumkara, William H. Parsons, and J. Du Bois

DOI: 10.1002/anie.201308235

I have to admit, I really wanted to read the minireview instead on microfluidic chemistry... Okay, maybe I will read it anyways since it's ten pages, and I'm still alive after getting through that Saxitoxin review. Which is more than can be said for anyone ingesting 1 mg of the stuff.

Admittedly, the review starts off kind of easy with a good historical background on this toxin and some color pictures of poisonous living things and structures of some other related toxins. But, since I read the abstract and I'm somewhat familiar with what the group from which this review came from does (and it's not my field, once again), I was ready for slogging through total synthesis schemes which, while I might see how you got from point A to point B with this reagent, I have no idea of the mechanism really, since it's been a while since my Advanced Orgo grad course and the hardest things I had to make didn't have as many nitrogens in it as saxitoxin. Which reminds me, that thing has a lot of nitrogens. Together with the four oxygens, it has 11 heteroatoms, more than the 9 carbons. Still, it'll kill you dead with only 1 mg, and that is because of the two guanidinium residues, that makes it a dication actually. That quality makes it really good for blocking the ion transport channels, and mainly the sodium transport channels in mammalian, and especially primate, cells. That means the review will have lots of other things such as talking about the structure of the Na transport proteins and how exactly its function is blocked, plus the synthesis of saxitoxin analogues that will attack a specific Na transport protein, something that will only block the ones responsible for pain but not the ones that keep your heart muscles moving for example. Humans have a lot of these different type of membrane proteins and some of these analogues can be pretty selective for just one of them (a several hundred fold difference in activity, which ideally means 1 mg could stop pain, but you would need 200 mg to end it all).

Still, to get to all of that, you do have to get through the total synthesis part, which if you're not a total synthesis person, or a pharma researcher working on saxitoxin analogues, will be probably painful. Still, this blog is part of my self-challenge to make it through one review a week, reading the whole thing faithfully (up to a point), so, here's hoping there will only a bit of total synthesis since I actually enjoy reading through one or two of them once in a while.

First comes the biosynthesis, but beyond looking at one change and another, and seeing arginine turn into ornithine, I didn't really get much from it. The authors weren't probably too inspired by that 1 page section either. Maybe drawing out the structure of ornithine would have been better. I'm not going to look it up when I have a ton of total synthesis to still go through. Speaking of that total synthesis, I have to say that I did enjoy reading through the first two. I was wondering how easy it was to separate all the intermediate products on the column, since they are highly polar and have a ton of nitrogens probably. The first one by Kishi in 1977 answered that question by introducing the guanidium units as late as possible. I guess after you have preparative HPLC, it gets a bit easier, but back in 1977 there was a shortage of that instrument in academic labs. The second synthesis by Jacobi in 1984 has a very inspired transformation which you can see in Figure 10, where a ring expansion occurs through an NN cleavage of a hydrozide. Technically the word 'inspired' came from the review authors, but I thought that was a very neat transformation as well. Plus this transformation of compound 12 to 11 occurs with Na in NH3... always a reaction I wanted to try someday.

After this, the total synthesis got more modern and more involved, with all them fancy reagents. I couldn't really follow it so well beyond where the authors guided me through some mechanism that resulted in particular distereoselectivity. Especially the DuBois total synthesis started cheating on me, by talking about analogues, and I was getting stuck for so long on each scheme, my eyes started to glaze over at some point and I just power-read through it. Which means I probably didn't retain much.

Anyways, no reason to make my review of a review longer than necessary. On page 13 we once again come to the biochemistry part. Saxitoxin and friends are apparently used to figure out binding sites to these proteins. Since these are membrane proteins, they are very difficult to crystallize and there is not structure of them as of yet. Probably the structure highly depends on the membrane environment anyways. Everyone is really certain that these toxins target the channel through which the cations pass, and not some other part of the protein (that is responsible for sensing Na+ levels or receiving some other substrate that opens the channel), but they are probably right since I don't know anything. Plus the guanidiniums are cations like Na+ and people made models of them sticking in the channels (where they presume that that is the structure of the channel), so let's just go with it. Maybe the positive charge of saxitoxin sticking in there repels Na+ electrostatically, since from the picture it doesn't seem that they are blocking the entire thing so well.

What's really interesting, is that just one amino acid mutation, but often a couple, can have a dramatic effect on mortality, and it explains that while all living things and especially multicellular organisms (nerve communication) need to transport sodium in order to live, the from and the mollusk seem to be fine while humans die from a very small amount. It effects them too of course, as at a big enough concentrations even other forms of the Na transport proteins get blocked up, but they can deal up to a point.

The review then talks about computational attempts to guess the structure of the sodium channel part of the protein by sticking residues that they think make up that channel around the toxin structure that binds the best, but who knows if that is going to be even close to the real thing, once a crystal structure is available. While I was reading this of course, I thought of using saxitoxin for probing how many channels a cell has by attaching some sort of fluorescent probe. Well, the people working in the field thought of that long before I did at the end of reading the review. All these total synthesis introduced a route where you can modify a part right at the end and attach a fluorescent probe, then send it to the cell and gunk up all its channels and watch them move for a bit until the cell dies I guess. This is how they found that these channels move around a bit and are swallowed up by endocytosis once in a while. Still, maybe they were swallowed up because a cell decided it was gummed up by a toxin and needed replacing...

Interesting. I have to admit that I actually enjoyed reading through the last part, even if I don't understand much about the particulars of biochemistry and don't really know my amino acids by heart.

Okay, that's long enough. If you read this far, you should probably read the review of Saxitoxin by the DuBois group. Maybe I will read that microfluidics micro-review.