Why would a molecule become more soluble at low temperature?

This is something I wanted to put out there. A colleague of mine reported a situation in which his flexible, complex organic molecule was becoming more soluble in water at low temperature and he was wondering why.

The most straightforward explanation that comes to my mind is this. When the molecule is flexible it naturally exists in several conformations in solution. The lipophilic conformations are going to be higher in energy since they are exposing non-polar groups to aqueous solvent. Conversely, the conformations that are nicely solvated and expose charged or polar groups to solvent are going to be low-energy.

At low temperatures, the higher-energy lipophilic conformations become inaccessible because of less energy in the system, leading to a preponderance of the low-energy polar conformations which are more soluble. Ergo the molecule becomes more soluble.

This can be studied by a couple of different ways, most notably by changing the solvent and altering the conformer population; previous studies have indicated that changes in solvent (say from polar to non-polar) only change populations, and not the conformations themselves.

Any other explanations?

Xtreme C-H functionalization: Natural Edition

Blogging has been swamped lately by that miracle called life but I could not help but be drawn to a paper in this week's Science which describes a most unholy and unexpected stabilizing alliance in a protein's innards.

Proteins are known to form cross-links such as disulfide bonds to stabilize interactions with ligands and substrates. Any reasonable chemist would expect these kinds of interactions to be mediated between polar residues. But nature usurps us low-lifes once again. In this week's Science, a group led by Andrew Karplus reveals a stabilizing covalent cross-link between, hold your breath, a valine and a phenylalanine. Who could have imagined these two otherwise blissfully aloof and stable partners suddenly deciding to...bond?

As chemists know however, there is only one kind of chemical entity that can create such havoc with stable functional groups- a metal. It turns out that the protein is a four-helix bundle diiron protein with two Fe atoms bound in proximity to the Val and Phe. The two irons apparently create their own cofactor by neatly supplying electrons to bond the Val and Phe to each other and molding a cosy bed for themselves. The resolution is 1.2 A so the electron density is unambiguous. The function of the unusual cross-link seems to provide a barrier to protect the iron from potential iron chelators; experiments indicate that the iron is rapidly mopped up by chelators in mutants lacking the cross-link. Intriguingly, the real function of the protein itself remains unknown.

Organometallic chemists who are keeping the midnight oil burning trying to use metals to functionalize unreactive C-H bonds would not be too surprised that a metal is mediating such strange interactions. But the observation demonstrates something that chemists are all too familiar with by now- Nature has been there, and it's done that.

Cooley, R., Rhoads, T., Arp, D., & Karplus, P. (2011). A Diiron Protein Autogenerates a Valine-Phenylalanine Cross-Link Science, 332 (6032), 929-929 DOI: 10.1126/science.1205687

Links...

1. A Nature News article on how scientists burnish their credentials online. The article describes a bizarre case where a researcher named Anil Potti who was recently accused of fabricating his credentials and research has gone to great lengths to try to salvage his reputation by creating multiple websites and posting trite banalities about his personal life.

2. "15 Amazing TED Talks for Chemistry Geeks".

3. Nature beats human beings...again. The first example of an enzyme that seems to be exclusively commited to catalyzing Diels-Alder reactions. Otto and Kurt would have been disappointed (or ecstatic, depending on how you see it).

4. The use of scaffold proteins to facilitate synthetic biology. This kind of work is hugely exciting. Whenever we discuss synthetic biology papers in our lab meetings, it's the only time when we feel like we have truly stepped into a time portal. The possibilities are endless, with the most practically exciting being the modular assembly of genes from different organisms to funnel reaction intermediates and produce virtually any natural or synthetic molecule we want on demand.

The top four publicly misused chemical terms: A layman's primer

One of the major objectives of the International Year of Chemistry is to make sure the public has a realistic and well-informed understanding of the basic features and functions of chemistry in their world. Perhaps no other aspect of the discipline is as important in this regard as a sound appreciation of the lexicon of chemical science. As they say, you need to speak their language before you can consider becoming friends with them.

Unfortunately, as often happens with scientific terminology, chemical terms seem to acquire new meanings and lives of their own when they collide with popular culture. A physicist would be aghast when he or she finds out what management consultants and new-age gurus have done with the words "quantum", "energy" and "field". Similarly we chemists find ourselves getting darker and sinking deeper into our armchairs when we are assailed with new-agers' definitions of "organic", "natural", "artificial" and "pure". For the public to appreciate the impact of chemistry on their lives, we owe them an accurate, concise and digestible overview of basic chemical terms. The following list is a personal one and makes no claim to such an overview but it simply illustrates what I believe are some of the most commonly used and misused chemical terms. The "More Transparency In Chemical Terminology" movement can only benefit from a phalanx of eager contributors so comments are welcome.

1. "Chemical": We hear people constantly talking about "chemicals" in the "environment", as if the two were independent entities. From a chemist's standpoint this distinction completely breaks down; a chemical is anything that's a molecule, which means any material entity that you can imagine. Thus the air, sun, trees, soil, your clothes, food, perfumes, houses, cars, office buildings, sharks, clarinets, refrigerators and stuffed teddy bears are all composed of chemicals. Hate, jealousy, political ideology and the soul are not, although most of these emerge from a particularly convoluted and exotic brew of chemicals- your brain. The take home message here is that, when seen simply as molecules, it becomes rather meaningless to attach any definite negative connotation to chemicals. Chemicals may be good or bad, it all depends on the context. Detergents are good in your washers, mostly bad when they are flowing in the nearby creek. Rat poison is good for you, bad for the rats. The chemicals that make up a chocolate smoothie are good when you are the one that's consuming them on a hot day, bad when the neighbor's kid is the recipient. Again, it all depends on the context; things are relative. Next time you hear a paper or TV channel get all grim about "chemicals", count to ten and think about the context.

2. "Pure" and "impure": This one is easy and you should rid yourself of any illusion right away. At the molecular level, pretty much everything that you encounter in your life is impure. The confusion about pure and impure arises mainly because of one of those endlessly startling simple science facts- molecules are just too damn small. If you metaphorically shrink yourself down to their size, you will probably spend an entire lifetime without encountering a uniform collection of them. Dive into water and it has all kinds of dissolved impurities, no matter how well-distilled it is. You think that olive oil you are using is "pure"? Time to run it through a gas chromatograph, an ultra-sensitive machine that separates out the chemical components of a mixture. You will be surprised at what comes out.

Now that does not of course mean that there are no grades of purity. There are. Standards for purity usually talk about "parts per billion" (ppb) or even parts per trillion (ppt) of foreign contaminants as acceptable level of contamination. Again, from the above discussion, remember that these standards are relative; a ppt level of sodium phosphate is quite different from a ppt level of botulinum toxin. These standards are also not just theoretical curiosities; they can and have led to trade disputes when the ppb standards of one country's exports don't meet the ppt standards of another country's imports. But from a molecule's standpoint all this bickering is piffle. Even if a substance had a parts per trillion level of a contaminant, that would still mean a massive number of foreign molecules in it. Remember, a few grams of a substance can contain Avogadro's number or about 1o^23 molecules, an unimaginably large number. Divide this number by a trillion and it's still 10^11, still uncomfortably large. You stand scant chance at surmounting purity beyond a certain extent. Remember: molecules are too damn small, you just cannot get rid of them.

However, all this discussion about pure and impure ignores the most common misunderstanding about the terms- the belief that impure is "bad" and pure is "good". This belief takes you nowhere. For a professional chemist, pure can be decidedly boring; chemistry is about change, and it's only when pure things combine into impure mixtures that things start to change and get interesting. But even otherwise the prejudice toward pure does not stand much scrutiny. That's because most of the useful things you consume in your lives, including the air you breathe and the balanced diets which your parents force you to eat, are actually quite impure. They are mixtures of myriad substances. One of the startling and wonderful facts of chemistry is that any of these substances would in fact kill you if it were really pure. Air made up of pure oxygen would be eminently toxic to living beings. Air composed of pure nitrogen or argon would likewise be quite unbreathable. It's best for air to remain an impure mixture. On the other hand, a single other substance such as carbon monoxide added to an otherwise viable mixture (at ppb levels, mind you) leads to a cocktail that is rapidly fatal. The reality of pure and impure mirrors the reality of human relationships. You want the right combination at the right time for the mix to work. Ever heard of someone getting smothered by too much pure love? Pure is not always healthy, and impure is not always toxic. Which leads us to the next key point.

3. "Toxic": When one speaks of toxicity, the last word has always belonged to Paracelsus, the wily sixteenth century chemist, botanist, occultist and metaphysical physician of Basel who said that:

"All things are poison, and nothing is without poison; only the dose permits something not to be poisonous."

Or more succinctly, "The dose is the poison".

Paracelsus's words should be carved in the foundation stone of every kitchen, hospital, laundry and grocery store. There is virtually no substance in the world that is universally toxic or universally safe. Even toxic "thoughts" and "assets" can be useful if marshaled under the right circumstances. You think cyanide is toxic (vida supra)? Think again; the body produces minute quantities of it during its normal metabolism. You think water is safe? Tell that to the citizens of London who suffered in the great cholera epidemic of the nineteenth century (there's pure and impure again). Or tell that to the writer of this post who once experimented with "Chinese water therapy" that entailed drinking sixteen glasses of water twice a day and ended up in a hospital. You think radiation is unsafe at any levels? An unproven assertion at best, and one that ignores possible salutary effects in the form of low doses- a phenomenon called "hormesis".

This confusion about dosage pervades misunderstandings about all kinds of potentially hazardous entities that are either harmless or even beneficial. Curiously, this is in spite of the fact that we have absolutely no qualms about consuming many pharmaceutical drugs which we know would kill us at higher doses (just think of the number of deaths from acetaminophen overdoses). In fact drugs provide the best example of substances that routinely defy the toxic/safe dichotomy. Consider bradykinin, a peptide from snake venom that was the basis for a blood pressure-lowering medicine. Or conversely, consider digoxin, a potent toxin isolated from the foxglove plant which has the opposite effect on the heart and is used to counter heart failure. It is a fitting testament to man's supposed mastery over nature that chemists can violate the toxic/safe distinction with impunity and turn some of nature's most noxious creations into life-saving drugs.

Perhaps the ultimate and extreme manifestation of the Paracelsian doctrine is the use of Botox. Very few adventures in human history have involved funneling one of the deadliest toxins (even by relative standards) known in nature into a quest for eternal beauty, which also happens to sustain a multimillion dollar industry. It would be hard to find a more wonderfully grotesque inversion of chemical property through human ingenuity.

4. "Natural" and "Artificial": Of all the widespread beliefs about chemical substances, this is the one richest in chemical insight. Ever since antiquity, chemists have tried to improve over nature through the creation of synthetic molecules. The culmination of this effort was the art of organic synthesis as perfected in the twentieth century, a development that has provided inestimable benefits to humanity. If we really think "artificial" is bad, then we must cast a baleful glance over the foundation of our entire standard of living. Similarly if we think natural is "good", we are committing multiple sins against the definitions of "chemicals", "toxic" and "dose". These are the kinds of sins that have been committed by muddle-headed politicians when they have talked about carbon dioxide being "good" because it's "natural".

A related distinction is between "organic" and "inorganic". Fortunately we have not been much assailed by critics of "inorganic" food, but the proponents of "organic" food have already done harm by defining it as food grown locally without using pesticides and sold without chemical additives. This is not the place to dispute the virtues or the lack thereof of organic food, but the definition itself has absolutely nothing to do with that used by chemists. If the meaning of organic had anything to do with chemistry, then food with pesticides and additives would be equally organic since these contain organic compounds. If proponents of organic food have favorable opinions about everything organic, they might benefit from a visit to their nearest college chemistry laboratory where they will meet mild-mannered organic compounds like benzyl bromide, triphosgene and picric acid. Organic is also sometimes used synonymously with "natural" which creates even more problems. But this takes us back to the distinction between natural and artificial.

The word artificial itself is far from sharply defined. Every single drug that you can think of for example is natural in so far as it is derived from cheap, simple chemicals derived from coal tar. The same goes for plastics and polymers, paints, fertilizers, perfumes and food additives. At the same time, chemists have been masters at creating combinations of these simple compounds that are decidedly artificial. Here too there are very interesting subtleties. The number of patterns one can create from simple linkages of various bonds and rings in chemistry is virtually limitless and it's easy to discover a pattern that to our knowledge does not exist in nature. Clearly this pattern is a hybrid of natural and artificial; it uses naturally occurring arrangements of chemical parts to create an artificial whole.

But things can get trickier. For instance one might make a pattern that is indeed found in nature, but with an inverted stereochemistry that is artificial. A simple example constitutes natural sugars whose mirror images may be artificial. It is a testament both to the power of modern chemistry and the wondrous chemistry developed by nature that a chemist, in one broad stroke, can change the chirality of a single atom in a natural molecule and turn it into something that does not exist in nature. An analogy would be in painting, where a single dash of color or the wrong brush can change a Renaissance painting into something quite different.

When it comes to artificial and natural then, what's artificial may in fact be natural and vice versa. The great achievement of chemistry is in being able to interconvert these definitions using the simplest of laboratory transformations. The chemist in this sense is like a mathematician, a creator and manipulator of patterns who can change the identity of an entire theorem by changing a rational number into an irrational one. The fuzzy boundaries between artificial and natural convey yet again how language can often be inadequate in describing nature's wondrous creations.

What then, to make of the use and misuse of these chemical terms as outlined above? To some extent they reflect the human fallibility that bedevils all of us, an incessant urge to oversimplify reality and use it to our own ends, ends that are sadly too often directed toward narrowly defined self-interests. We, all of us, are the victims of our prejudices. The shining virtue of science has been in gradually but inexorably eroding these prejudices. Trying to get its language right and most importantly, appraising its definitions in the right context, is an essential start.

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