Tag: Organic Chemistry

A continuation from The great rotaxan debate part one. Released in honor of the ISMSC conference in Las Vegas, Nevada. See CBC for live blogging.

2.1 A rotaxane is a rotaxane unless it’s a pseudorotaxane, then it’s just a kinetically stable rotaxane:

The differences in opinions from the world’s experts are reasonably similar, to be honest. The point where people get bogged down is here (from Stu Cantrill) (section “2.6″):

What do you call something that, under one set of conditions, behaves as a pseudorotaxane (i.e., the ring can come off the axle), yet under another set if conditions behaves as a rotaxane ( i.e., the ring doesn’t come off)? Well, the solution that Excimer, Kyle and likely Sir F propose, is to simply change the description based on the conditions under which the (pseudo)rotaxane exists.

Indeed, Sir Fraser, Harry Anderson and I whole heartedly agree – (indeed, Professor Stoddart has proposed exactly that to me in our personal correspondences.) There is no surprise there, actually. I’m sure the two have conversed about the subject prior to this. But what is Stu’s retort to our point?

I find this quite unsatisfying, however. Over a certain range of temperature or solvent polarity it’s a rotaxane, but heat it up or pick a more polar solvent, hey presto, it’s a pseudorotaxane! I don’t think a molecule or complex should be defined based upon external factors such as temperature or solvent polarity, these species should be defined based only upon their own intrinsic properties (isn’t that what Excimer wanted?).

A good point, I’d say, but unconvincing. Rotaxanes, as we established in part one, are molecules. Some molecules are sensitive to solvent and temperature… but that doesn’t make them pseudomolecules! Why should we say that ‘if solvent or temperature make an inclusion complex unthread then it’s a pseudorotaxane, but, on the other hand, if solvent or heat cleaves the bonds of an ordinary (i.e. nonsupramolecular) molecule then it never was a molecule to begin with’? That argument is absurd. Should the speed of light be called something else in air as opposed to a vacuum or do we have the wherewithal to understand that the definition of c is dependent upon the conditions we are under?

Before you go nuts, let me explain the logical fallacy of this thought process: So what if you have enormous stopper groups? If your rotaxane is destroyed via solvolysis in the same solvent that my rotaxane is dethreaded yet you must still insist we have TWO different species (not just two different molecules, mind you, since pseudorotaxanes aren’t whole molecules. We wouldn’t even be comparable within a supramolecular context, since your compound, being a single molecule, can’t possibly be “beyond the molecule.” You’ve introduced a chasm of difference between our two molecules when they are, indeed, quite similar (1). So similar, they could actually differ by nothing more than a methyl group! No where in the literature can I recall ever finding a chemical that is called one thing if it reacts with DMSO one way and something else if it reacts with DMSO in a different way. The reactions may be different and the products may be different – but why would would you then call the starting material different things?

But allow me to provide you with a counter argument by David Leigh (to round this off):

[...] A structure formed by slippage is formally not a rotaxane. The IUPAC definition [The IUPAC Compendium of Chemical Terminology (A. D. McNaught, A. Wilkinson, 2nd ed., Blackwell Science, 1997)] of “rotaxanes” is “molecules in which a ring encloses another, rodlike molecule having end groups too large to pass through the ring opening, and thus holds the rodlike molecule in position without covalent bonding“. Now, IUPAC definitions are not always word perfect but this one is OK and is in keeping with the reasons for introducing the term historically. A structure formed by slippage clearly cannot be said to have “end groups too large to pass through the ring opening” because they already have passed through to form it. (If you want to argue that “too large” refers to a thermodynamic quantity rather than “steric size” in that sentence then you’re into Johnnie Cochran territory, which might be fun but it’s not a discussion about science!)

clip_image002.gifRotaxane!

Slow kinetics of exchange of the components with the bulk do not define whether something is a rotaxane. For example, compound 4-H.PF6 (above) IS a rotaxane because the stoppers are too big for the ring to dethread even though the components are extremely rapidly exchanged between others in the bulk by reversible imine bond formation.

For the same reason, coordination complex 52+ (below) is NOT a rotaxane, even though the components are extremely slow to exchange with the bulk, because the methoxy groups are too small to prevent the rings from dethreading.

clip_image003.gif Not a Rotaxane!

If you wish the meaning of the word “rotaxane” to become based on kinetic stability then that will be a change to the current meaning of the word. And molecules such as 4-H.PF6 will then no longer be correctly described as rotaxanes and complexes such as 52+ will become rotaxanes. The meaning of the term “rotaxane” has always, since its introduction by Schill, been based on the relationship between the size of the ring and the size of the stoppers on the thread. That is why the cartoon representations of rotaxanes always feature a dumbbell with physically large stoppers and not, for example, no stoppers and a covalent or coordination bond between the components.

The mistake with “slippage” was that the consequences of describing the structures formed by that process as rotaxanes were not thought through. You cannot have rotaxanes defined in terms of EITHER the size of the stoppers OR the thermodynamic stability of the structure, it clearly is illogical and would not work. It has nothing to do with the particular wording of the IUPAC definition by the way, no definition of rotaxane that has ever been proposed by anyone is consistent both with structures form by slippage being rotaxanes and also 4-H.PF6 being a rotaxane and 52+ not being a rotaxane.

2.2 That IUPAC definition

It’s worth mentioning that IUPAC definition again:

The IUPAC definition [The IUPAC Compendium of Chemical Terminology (A. D. McNaught, A. Wilkinson, 2nd

ed., Blackwell Science, 1997)] of “rotaxanes” is “molecules in which a ring encloses another, rod-like molecule having end groups too large to pass through the ring opening, and thus holds the rod-like molecule in position without covalent bonding”

My first take on this definition is that it’s… minimal. I attempted to use it to justify my rational to David Leigh in a private email but I was subsequently smacked down. I contend that “end groups too large to pass through the ring opening” is a kinetic thing. You can read reference 1 or look at the example below from that Smith group publication (2) I profiled in the initial “sexy crystal” post that started all this. (actually, I didn’t even profile it. I just thought the crystal was pretty.)

(Those structures were a bitch to draw btw)… Anyway, from my humble estimation, going from the dimethyl compound to the propargyl compound, which makes the reaction irreversible, has had the intended consequences of “making the end groups too large to pass through the ring opening.” I was called out by the great Dave Leigh (who designed macrocycles strangely similar to the ones shown above) wrong as “a point of fact” but I’m not alone in my wrongness, apparently, since I the good Professor Anderson agrees:

I think the IUPAC definition is consistent with synthesis via slippage – it is all a matter of the activation energy of the slipping process – the end groups need to be too large to pass through the ring at a significant rate under ordinary conditions.

(and no, I defended my point of view before Anderson sent me that email, so there’s no shenanigans going on here.)

So much for that. I think the definition is too loose and poorly done. I don’t know many in the “rotaxane community” that would disagree. So, following that, here are the individual responses and opinions of the world’s leading rotaxane people:

2.2: The Leigh response:

So, like I said in part one. I sent an email out to a number of celebrity rotaxanologists to get opinions and here are the opinions I received: First, David Leigh:

There are three different sorts of answer to your question “Is a mechanically interlocked structure formed by “slippage” a rotaxane?”

[The first part of this was cut-and-pasted up above. You were a good reader and read that first, didn't you?]

(2) Despite the above being formally/technically correct, it is true that several people including major ones in the field have called structures formed by slippage “rotaxanes” in the peerreviewed literature. Therefore there is a perfectly reasonable argument for others to call such structures “rotaxanes” in line with the usage of the word by some leading figures. I think this is a perfectly reasonable position for authors to take (although I personally don’t do so) if they think it is the best way of describing their chemistry to others, even if it is not actually correct. It’s always the science that’s important, not what you call things.

(3) The third answer to your question is what is the *best* way to use the term “rotaxane”. For that I can only offer my opinion (I believe answers one and two are fact). Personally I think that scientific language is best suitably defined and correctly used to accurately convey concepts in a field. When you start to use terminology in a nonrobust or casual way then you end up with terms like “selfassembly” and “nanotechnology”, which have acquired such imprecise meanings over the years that now they convey nothing as descriptors. We made this point in a recent review [Angew. Chem. Int. Ed. 2007, 46, 72191, part 1.1 and refs 182 and 194]. Terms like “rotaxane” (and “supramolecular”, another term which is often technically incorrectly used in the literature) are only going to remain useful if they are welldefined and it matters not that sometimes a structures properties make it difficult to tell what category a structure actually fits into.

The best way, in my opinion, to use these terms (and note the difference between which is a “molecule” and which is a “supramolecular complex”) is:

Rotaxane molecule with ends too big (note this “big” means steric size, it doesn’t mean a threaded structure held in place by a ringtothread covalent bond) for a ring to pass over without breaking a covalent bond.

Pseudorotaxane supramolecular complex which is threaded.

Kinetically stable pseudorotaxane threaded supramolecular complex which is slow to exchange its components with the bulk (either because of quite big stoppers or, say, extremely strong Hbonding between thread and ring which doesn’t let the components interchange with the bulk even though the terminal groups on the thread are small).

The term “kinetically stable pseudorotaxane” describes exactly, with no ambiguity, the nature of threaded structures formed by slippage.

A change in the meaning of these terms to anything else would just cause unnecessary lack of clarity in language. For example if you want to change the meaning of “rotaxane” to become

“amolecularlevelstructurethatisthreadedunderaparticularsetofconditions”, then Kyle would then be right to say that the Xray structure from the Smith group in the earlier post was a rotaxane in the solid state. In fact any threaded inclusion complex would be a rotaxane in the solid state. No bulky end groups would be necessary, any threaded structure would be a rotaxane on the femtosecond timescale. The term “rotaxane” would become virtually useless as a descriptor (why not just say “threaded” and also what would “pseudorotaxane” then mean?) and would correspond to very many structures that it was never intended to do. Such a change in meaning would be a pointless step backwards, let’s stick with the correct current definition.

One final point. The prefix “pseudo” comes from the greek meaning “false” or “erroneous” (at least I thought it did, the web seems to suggest it is latin). So “pseudorotaxane” means “false rotaxane”, not “rotaxaneunderacertainsetofconditions”.

2.3 The Harry Anderson Response:

In my opinion, a rotaxane must be kinetically stable over a reasonable period of time (weeks/years) in solution at room temperature (due to the steric bulk of the end groups, not due to strong non-covalent binding between the components).

So slippage is fine for rotaxane synthesis, provided it does not occur under ordinary conditions, but only at high temperature etc.

There are several examples in the literature of structures called “rotaxanes” which are only rotaxanes on the NMR time scale, i.e. they unthread in a few seconds. I would not call these structures rotaxanes.

2.4 The Stu Cantrill Response:

A rotaxane is a mechanically interlocked molecule in which one or more macrocycles (rings) are trapped on a molecular ‘axle’ by virtue of large stopper groups at each end. A pseudorotaxane is a complex (not a molecule) in which an axle is threaded through the centre of one or more macrocycles, but the components are free to dissociate into separate molecules because there aren’t any large stoppers on the ends of the axle.

There is a problem, however. What do you call something that, under one set of conditions, behaves as a pseudorotaxane (i.e., the ring can come off the axle), yet under another set if conditions behaves as a rotaxane ( i.e., the ring doesn’t come off)? Well, the solution that Excimer, Kyle and likely Sir F propose, is to simply change the description based on the conditions under which the (pseudo)rotaxane exists.

I find this quite unsatisfying, however. Over a certain range of temperature or solvent polarity it’s a rotaxane, but heat it up or pick a more polar solvent, hey presto, it’s a pseudorotaxane! I don’t think a molecule or complex should be defined based upon external factors such as temperature or solvent polarity, these species should be defined based only upon their own intrinsic properties (isn’t that what Excimer wanted?).

And this can be done, absolutely, with no grey areas. If, regardless of the conditions, the ring cannot be separated from the axle without breaking a covalent bond in either the ring or the axle, then what you have is a rotaxane. Basically, this means that there are no conformations that the ring or stoppers can adopt to enable passage of the ring over the stoppers. The stoppers are physically too big, even if you squish them and stretch the ring as much as you can, the ring won’t come off.

On the other hand, if the ring and axle can be separated without breaking a covalent bond under a certain set of conditions, then, no matter what those conditions are, then what you had (before it fell apart) was a pseudorotaxane, i.e., a complex – and you probably made it with a ‘slippage’ synthesis. Sure, under some conditions of temperature and solvent polarity, this pseudorotaxane looks like a rotaxane because the kinetic barrier to the ring coming off is very large, but all that means is that it’s a kinetically stable pseudorotaxane ( i.e., a kinetically stable complex, not a molecule).

I would argue that if you are going to use both the descriptors ‘rotaxane’ and ‘pseudorotaxane’, they should be distinct, otherwise, why not just use ‘rotaxane’, and then describe them as kinetically stable or kinetically unstable depending upon the conditions under which they exist? But again, I think that’s not a good idea, because then you are defining your (pseudo)rotaxane based on how hot or wet it is.

At the end of the day though, these definitions are arbitrary and the most important thing about science is what you do with it and what you learn from it, not necessarily what you call it.

In the end, someone needs to write a book called “Supramolecular Nomenclature” and everyone needs to just fucking agree on it. I’m writing a paper here where structures we have called rotaxanes appear to be pseudorotaxanes, because, after about 40 days or so, they unthread in some solvent or another. Who knew? And what a pain in the ass that would be. “You know that molecule I kept calling a rotaxane? Right, well, in HMPA it unthreads so now I have to write five corrections…” Not likely, I would guess, but people who fastidiously stick to nomenclature as gospel should feel no less compelled to fix the error in every paper!

Which sort of gets me back to another point altogether. Nomenclature is the first thing introduced in organic chemistry and the first thing to turn a lot of people off to it. Being a stickler for the whole thing is a wasted venture unless you’re too incompetent (or the terminology doesn’t exist) to describe what you’re doing. So long as we are all on the same page, does it really matter? No.

No, it doesn’t make much of a difference at all. If you correct me when I use the term in a way you don’t like, I shall shit on your pillow in Vegas. But it will be a loving shit of appreciation.

That’s a good question and I hadn’t given it much thought, but since I’m Blogger Emeritus I figured I should. The idea behind Emeritus is (to my knowledge) that they have performed their duties so well that they have earned the right to be slightly bizarre people and “work” from 1-3pm and still demand people call them “professor.” Wikipedia defines it more explicitly, of course in their Emeritus article. Since I am the first and, to my knowledge, the only Blogger Emeritus I suppose it lies upon me to come up with some guidelines to the whole thing so we can sort this out and seeing as how blogging is an international thing, we shall do it in the language of the Lord – English. Feel free to chime in, anytime.

A Blogger becomes qualified for an Emeritus position when he or she has done all of the following:

1) been profiled in a printed publication with a circulation greater than 100,000 people,
2) has contributed to the field of blogging by being very awesome and,
3) upon a vote in which the majority have agreed it to be reasonable

A blogger Emeritus is thus entitled to:

1) retain the title “blogger” for life, even if they no longer have a blog or do blogging activities
2) can ask stupid or repetitive questions in seminar or on other blogs and expect respect of their age-wise knowledge.
3) leave the blog for weeks on end if they choose without updating or apologizing for absence or really giving a fuck if the whole thing fell to pieces.

There. Let it be resolved.

Dendrimers are the new black. They’ll come with your next iPod and you’ll see Madonna flying into Chemistry labs to illegally adopt them. But they suffer from a rather attractive flaw: they’re a bitch to make.

Any reaction where you can plan a whole vacation around is GREAT. The traditional synthesis (or at least the best and highest yielding procedure I could find) for PAMAM dendrimers involves a wonderfully uncomplicated 7 day room temperature stir after you just did a 3 day reaction. Seriously, you can make all your vacations working vacations with this sort of chemistry. Karl Sharples’s came along and introduced “click” chemistry and then everyone made dendrimers filled with triazoles. Which is fine, I guess, if you want greasy heteroaromats in your dendrons (which do not, consequently aid in water solubility – sadly.)

Craig J. Hawker (DOI: 10.1021/ja8006325 And how about that title? Now there’s a man that knows the value of his work.) has come to change that. He successfully used the word “click” correctly to produce a new method to make dendrimers in one of those brilliant advancements. He took chemistry that was well known and applied it to a big problem to produce an elegant solution. Bravo, I’d say.

The Thiol-ene reaction, which doesn’t even have its own Wiki entry, is a remarkably clean and simple reaction for a radical mediated process. Using a photoinitiator, with a bit of UV radiation, you can promote the radical coupling of thiols with alkenes.

thiol-ene.png

The article then goes on to detail the experiments done to prove that the reaction is nigh quantitative, requires only 1.5 equivalents of starting material and requires no chromatography. The dendrimer is continued by addition of 4-pentenoic anhydride (quantitativly) to produce another round of alkenes for reaction with thioglycerol.

The final product, take out to 4 generations (read the wiki article if you’re unfamiliar with the concept of “generations in dendrimer synthesis) was then “coated” or functionalized with different compounds, including compounds with benzylic protons and acidic protons and any other number of easily extracted protons…

funcationlizedcrap.png

Solid work, IMHO. I think this can be put to serious use in a very short period of time.

Which is more awesome/impressive

  • Writing a review article (57%, 112 Votes)
  • Writing a book chapter (43%, 85 Votes)

Total Voters: 197

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Shit

That’s right. I said it. SHIT. It’s what we all do and, for some of us, it’s the best part of our day. Nothing quite like relaxing on the porcelain throne, flipping through the latest SciAm (or CEN) and droppin’ some ripe deuces. My own personal theory on why pooping is so fun is because of all the various organs the turd caresses on its way out. But that’s waaaaay off point. This post is about a drug that makes you shit. BAD. Like horribly bad. Like Ratemypoo.com bad. That drug’s name is Alli and, if there’s any truth in advertising, you’d rather bunker with the enemy.

Orlistat is an interesting drug and here in the good old YOU ESS OF EH, we can get it over the counter. Alli does what it says it does: it helps people loose weight. It does it without all the hyper jittery super tense bullshit you get from taking most apatite suppressants because it doesn’t work on the CNS. Indeed, it’s never even taken up by the body.

To understand how Orlistat works, we must first understand how fatness happens, biochemically at least. You see, when you cook fatty foods you do various chemical reactions that make food tastier (including hydrolysis of the fat) but nevertheless, a substantial amount remains as unmolested triglyceride. The intestines poorly (or don’t) absorb triglycerides and they must be broken into their constituent fatty acids via triglyiceride lipases. From there, the miracle of fatness occurs where the fatty acids are shunted around the body until they finally find their way into a hilarious and gross picture of you sitting at your computer:
fatamericans.png

The bacteria, Streptomyces toxytricini, which secretes the compound lipstatin was discovered one day and the structure of the little guy was elucidated. Lipstatin actually irreversibly bound to lipases and prevented them from breaking down triglycerides. The intestines weren’t able to break them down and the triglycerides would pass through the bowl into the poor victim’s underwear as a gross orange oil:
ohnoespoop.png

Lipstatin turns out to be too unstable and/or expensive to make and the hydrogenated product is the commercially marketed one. Thus, the synthesis and structure of Orlistat is straight forward:
synthesisoforlistat.png

From an article by Fernand Schneider (DOI: 10.1002/hlca.19870700124):

The synthesis of (Orlistat) starts from the known keto ester which, on condensation with dodecanal, gave (the next) compound. Protection of the alcohol function as its tetrahydropyranyl ether and reduction of the keto group gave (a) hydroxy ester. Saponification and ring closure of the resulting β-hydroxy acid with benzenesulfonyl chloride in pyridine yielded β-lactones. After deprotection of the OH group, the resulting mixture of racemic hydroxy-β-lactones was separated by chromatography into racemic cis-β-lactones which were discarded and into racemic trans-β-lactones. Esterification with (S)-N-formylleucine using Mitsunobu’s conditions (inversion of configuration of alcohol) yielded two diastereoisomeric esters.) One of the four diastereoisomers, was identical with tetrahydrolipstatin (hydrogenated lipstatin – aka Orlistat) obtained from natural sources.

The efficacy of the drug appears sound, but it is opposed (as all OTC drugs are) by some faction of people who have nothing better to do then bitch about a drug that, at its worst, makes you shit yourself. Aspirin still makes children retarded, btw. Just thought I’d toss that out there. Does it make you poop yourself? Yes. Yes, it does. And guess what you’re pooping – fat. It’s just like shitting Crisco or butter. Imagine, right now, trying to wipe a schmear of butter off your butthole. Sounds like a challenge doesn’t it? It quickly spreads to the cheeks if it wasn’t broadcast there by an ill timed fart. That’s a rather unfortunate side effect. But so is death, which happens to be an apparent side effect of being fat… or living, for that matter.

There’s a good review in Angew ASAP (or whatever they call them) (DOI: 10.1002/anie.200705568) about Möbius aromaticity that everyone should read, if only because it’s the sort of shit that makes you look smart at parties where chemistry geeks are all over making their gay little chemistry jokes and someone drops Möbius and you can quickly strike back with a repartee of your own. You know, the kind that start out Well, there was just this thing in Angew about a number of different compounds, but I really question… blahblahblalabhalbhalbh metal masturbation splurge splurge splurge 8====D…”

Briefly, aromaticity follows the Hückel's rule, where 4n+2 pi electrons in a flat ring provides magical stability we call “aromaticity”. However, the same magical stability can be created if said ring were twisted like a Möbius strip and there were actually 4n pi electrons, a condition that is clearly disfavored on two accounts: 1. Möbius strips in molecular form would require (upon first consideration) tremendous amounts of ring strain unless they were very large rings which means 2. the reliable synthesis of very large rings with lots of double bonds all over the place isn’t easy, even if said magic stability comes into play since, as we should know, pi clouds are reactive in their own right (usually more so than they are stabilizing.) Not only that but as rings get large they become quite flexible and a nice fixed topology is necessary for these things.

mobiushuckle.PNG

The relatively recent advent of a stable Möbius compound (Nature 2003) did settle the question if such a compound could be created, but the structure lacked a clear crystal structure. I.E. they were able to view the topology of the system, but could acquire no meaningful information about bond lengths and angles. Nevertheless, the synthetic concept was groundbreaking and the method was clever, but complicated. You can see their idea in the figure below. Follow the surface with your mind and see how it’s a Möbius structure. You can read that Nature paper if you’re so inclined. It’s a good read.

mobiussynthesis.PNG

But further elaboration on this concept was done using porphyrin systems, which seems like a very natural place to begin looking, actually, as opposed to complicated photochemical mishmashing. One can, with a bit of effort, produce truly massive porphyrin systems which are far more stable than if they were just massive annulenes. The first use of such a porphyrin system resulted in a structure which has Möbius aromaticity in the solid state but is configurationally unstable and its “Möbiusness” was highly solvent dependent. In a textbook example of not allowing the terms “unstable” be a bad thing, the PI (in this case Lechosław Latos-Grazynski DOI: 10.1002/anie.200700555) decided to call this object a “switch” which is just a nanothingiee term for “it moves but we’re not sure what to do with it.” But, victory of the “switch” would prove to be short lived as soon, another sufficiently clever PI (in the form of porphyrin God Atsuhiro Osuka DOI 10.1002/anie.200704407), one that recognized that, not only can one create large rings with these porphyrins, but one could limit their flexibility by binding metals to them, an “unswitchale” but real stable Möbius aromatic porphyrin system was born.

Click on the image below to play with the crystal structure and follow it around and see the Möbiusness. It’s pretty cool.

mobius.png

Jux, N. (2008). The Porphyrin Twist: Hückel and Möbius Aromaticity. Angewandte Chemie International Edition DOI: 10.1002/anie.200705568