Book review- The Weak Hydrogen Bond: In Structural Chemistry and Biology

The Weak Hydrogen Bond: In Structural Chemistry and Biology (International Union of Crystallography Monographs on Crystallography, No 9),
By Gautam R. Desiraju, Thomas Steiner
Oxford University Press, USA; Reprint edition (July 16, 2001)

Chemistry is all about interactions, and chemists have traditionally classified interactions into various categories such as covalent and ionic, hydrogen bonding and Van der Waals. But this classification is primarily for convenience, and there are many borderline cases which any chemist should be aware of, if he wants to notice interesting phenomena.

One such borderline interaction that is very important in maintaining the structure of crystals is the weak hydrogen bond. Crystallographers are in a unique position to observe and catalog such an interaction, because they are constantly looking at structures frozen in time in the solid state. These are also structures that represent the dazzling chemical diversity inherent in nature. In this book, the authors, both of whom are leading authorities in the field, provide a comprehensive and extremely readable overview of this unique interaction, which should challenge the traditional wisdom of any chemist, and should allow him or her to greatly expand his or her horizons in the world of molecular interactions.

The book starts with a lucid and excellent introduction to what are usually described as 'normal' and 'strong' hydrogen bonds. The authors then gracefully demonstrate in the rest of the book by virtue of countless examples of organic, organometallic, and biological structures, how the strong and all important traditional picture of a hydrogen bond smoothly transitions to the domain of the weak hydrogen bond. Many of the rules that chemists usually apply to the notion of the hydrogen bond need to be modified and challenged, and excursions into weak hydrogen bonds actually exemplify the whole paradigm of weak intermolecular interactions. The authors explore all the evidence for such weak interactions including statistical, energetic, and spectroscopic. The crystal structures included reinforce the astonishing variety of molecular structures around us, both artificial as well as natural. There is also great simplicity in some of these structures, which makes them and the interactions in them truly beautiful to comprehend, in terms of their stability and symmetry. The discussion in every chapter is lucid, to the point, and shows the authors' own appreciation of their subject and its ramifications.

Their discussions drive home the point that chemists always need to think in terms of a continuum of interactions, if they truly want to understand the nature of molecules. In today's specialized compartments, with rigid definitions and rules, chemistry is often perceived as a science with rigid boundaries. This is far from being the case, and the weak hydrogen bond is a superb vehicle for demonstrating the continuous nature of the science. It also demonstrates the much more general paradigm of always thinking in terms of all kinds of interactions, 'strong' and 'weak', which any chemist, no matter what his specialty, has to appreciate. More than anything else, the study of such weak interactions proves that chemistry is still very much an art with many thin boundaries between concepts, and not just a science. It is not an exact science like physics, but it is precisely this ambiguity in it which nonetheless can be classified, that makes it a unique discipline. This book is a striking example of this fact.

Question for NMR/Internet enthusiasts

Question for the NMR/Internet enthusiasts out there:
Do you know of an online calculator that calculates the dihedral angles from the coupling constants using the modified Karplus equation (Haasnoot et al.)? There are several sites that have calculators which do the opposite, namely calculate the J from the dihedral angle using the modified Karplus. Also the calculator has to use the modified Karplus, which has six parametrized terms that depend on substituents.

Suggestions will be strongly savoured.

I wanna smell some H2Po

Derek has some thoughts on hydrides on his blog. I remembered the following endearing conversation between Linus Pauling and Matthew Meselson (co-orchestrator of the 'most beautiful experiment in biology'). This was just after Meselson joined Pauling as a grad student.

LP: Well, Matt, you know about tellurium, the group VI element below selenium in the periodic chart of the elements?

MM: Uh, yes. Sulfur, selenium, tellurium ...

LP: I know that you know how bad hydrogen sulfide smells. Have you ever smelled hydrogen selenide?

MM: No, I never have.

LP: Well, it smells much worse than hydrogen sulfide.

MM: I see.

LP: Now, Matt, Hydrogen telluride smells as much worse than hydrogen selenide as hydrogen selenide does compared to hydrogen sulfide.

MM: Ahh ...

LP: In fact, Matt, some chemists were not careful when working with tellurium compounds, and they acquired a condition known as "tellurium breath." As a result, they have become isolated from society. Some have even committed suicide.

MM: Oh.

LP: But Matt, I'm sure that you would be careful. Why don't you think it over and let me know if you would like to work on the structure of some tellurium compounds?

I doubt if anyone has smelt H2Te and lived to tell the tale. Me though, I would love to smell some H2Po if it exists.

Tremulous trepidation titillates.

Praise the warts please

The most important biodiversity we will destroy will be that which we will never know about. One of the telling signs of this trend is the decline in frogs round the world. Croaks and warts apart, frogs and toads are some of the most important animals not only in the ecological chain, but also as the source of potent drugs for human beings. In order to save ourselves by clearing away more forests and making space, we are actually sealing our fate forever. This is not apparent or obvious, but then, most of the important things in life never are, or become so when it's too late. The problem is that when we are dealing with such complex systems, they are very prone to what in technical fields is called 'normal error', error introduced simply by our inability to grasp the fine points of a complicated system, error introduced because of the inherent complexity of the system. We may think frogs are yet another species jumping around, but it's becoming apparent- and only after we have done irreversible damage- that they form a crucial link, a hub between different parts of the entire biosphere, whose importance tragically would manifest itself only after it has been destroyed, and by then it would have been characteristically too late.



The colourful little cute red frog above is also one of the most poisonous species on the planet- nature alluring, but red in tooth and claw. It produces a poison, a grain of which smaller than one of salt can kill a human being. South American natives coated their arow-tips with this poison from the Arrow-poison frog to deadly effect. But it was another cousin of this frog, shown to the right, that led to the discovery of Epibatidine, an alkaloid that turned out to be a potent non-addictive analgesic, whose derivatives would replace addictive drugs like morphine and lead to better painkillers. The alkaloid was extracted from the frog's skin after making painfully difficult efforts to breed it in captivity. Literally hundreds of alkaloids with diverse pharmacological actions have been isolated from just the skin of amphibians in the last thirty years. This is just one among countless examples. Sponges from the ocean, for instance, have been the source of some of the most important anti-cancer drug candidates discovered in the last twenty years. According to a recent report in Nature, around half of the drugs currently in use have originated from nature. The importance of preserving natural sources for new life-saving agents can hardly be overemphasized.
Yesterday, I was reading the reminiscences of Jerrold Meinwald, the pioneering organic chemist at Cornell University, who turned his chemical talents towards uncovering the extraordinary chemical diversity in nature, thus becoming one of the pathfinders of the science of chemical ecology. Among Meinwald's string of papers, one of the latest ones deals with the extraction of novel compounds (sulfated nucleosides) from the dreaded funnel-web spider shown below, one of the most poisonous species of spiders on the planet.



These compounds promise new leads for stroke and other neurological disorders. This is again, just one example. How much remains to be discovered? Meinwald says,

"What might one anticipate to be the future of natural products chemistry and chemical ecology in this post-genomic, post-9/11 age? Is there anything left to discover? The answer to this question is certainly a resounding "yes". To begin with a small example, there are roughly 40,000 described species of spider, all capable of paralyzing their prey, but less than 1% of their venoms have been subjected to careful analysis. Surely there are great opportunities here for the discovery of novel neuropharmacological agents. There are about a million described insect species, and a conservative estimate of three million species of insect on earth all together. We can estimate, then, that 99.9% remain as potential targets for chemical study. Among soil bacteria, something like 99% are presently unculturable. Nevertheless, these organisms are known to be genetically extremely diverse, and it appears highly likely that a knowledge of their secondary metabolites would be not only chemically fascinating but also of great value to medicine and agriculture. It is certain that the study of extremophiles will greatly broaden our understanding of what kinds of chemistry can support life. We can conclude that most of nature remains to be explored at the molecular level."

It is mind-blowingly wonderful to imagine then, given the wealth of new and useful drug leads that we have already isolated from so small a section of the biodiversity of our planet, what potentialities lie for us in the future. But then, wonder turns to woe when we realise how much of this biodiversity we are destroying on a per day basis- the loss of species that one day would have supplied us with life saving drugs, with the cure for AIDS perhaps, is heartbreakingly incomprehensible. Most of them will silently die away, and already have, and left behind will be human beings, for whom the bell ominously tolls...Is this the true face of capitalism? The destruction of the future of our race for petty, short term gains in the present and 'near' future?

The Hallmarks of Cancer

Came across this neat review by cancer specialist Robert Weinberg from MIT. Six comprehensive and all encompassing checkpoints and regulatory regimes need to be circumvented by cancer cells to become successful cancers, and they still do this. This is much worse law-breaking than any corrupt government in history.



There's only one thing I can say; the cancer cell is one clever, slimy little weasel.

Bathroom tiles and acid trips

Paul's post on the Westinghouse science talent search contest alluded to strange and wondrous things one might do as a youngster, and reminded me of my bathroom lab.
Our house had a spare bathroom which nobody used often, and this lab became a fond retreat for me and my amateur chemical experiments. In this lab, I was sealed from the uncertainties of the human world, and surrounded by unexpected happenings from the world of Chemicia instead.

I worked in this "lab" from when I was about 11 years old till the end of high school (junior college). It began when my mother got me a chemistry set. This set contained things like copper sulfate (CuSO4) and potassium ferrocyanide (K4Fe(CN)6) which are considered "too dangerous" in chemistry sets today. But more importantly, I discovered a science store which supplied chemicals and equipment for laboratories. They would not sell caustic chemicals to me, so I used to take my dad along, who is a professor of economics. Somehow, the professorial title used to persuade them to sell me satanic elixirs. Later, I convinced them that I was a chemistry tutor for a lab; by that time, they trusted me more and did not mind slapping a kilogram of sodium on the table for me. Obviously, it was assumed that the responsibility for death or debilitating damage was mine alone.

From this store, I got the usual repository of the devil's dozen; sodium metal, magnesium metal, and the three standard "ic" acids, H2SO4, HNO3, and HCl; sufurIC, nitrIC, hydrochlorIC. Sodium, the feisty witch which burned violently and smoldered at the mere touch of water, magnesium the flaming spirit which burned bright, steady and long, and the triumvirate of the "ic" acids which, calm as they looked in their amber coloured bottles, could burn hell if hell dared to raise eyebrows at them. I experienced many acid trips (of the non-addictive kind) with these beasties.

My experiments were of the crude amateur type. I almost never documented what I did, and reveled simply in the sounds, smells, and colours of chemistry. Some of the "experiments" I did:

1. Making "soap", hydrogen sulfide, and hydrogen chloride gas (common salt + H2SO4)
2. Dying handkerchiefs various colours by mixing, say, K4Fe(CN)6 and CuSO4. Pretty sight for the eyes, but best not to wipe a nose with them.
3. Producing the quaint smell of Iodex by mixing salicylic acid with methanol

Then there were the proverbial spills and thrills. These included:

1. Spilling a whole bottle of concentrated HCl and prying loose a dozen bathroom tiles.
2. Obsessively doing the potassium permanganate (KMnO4) + glycerine reaction. Try it out if you haven't; some KMnO4 plus a few drops of glycerine, and the whole thing starts to smoke after a few seconds and then gloriously catches fire.

One time I almost blew up everything was when I did the infamous iodine + concentrated ammonia reaction. This forms a compound, nitrogen triiodide, (NI3.6NH3) which is so unbelievably shock-sensitive that a mere feather can set it off in a puff. Also, it gains potency as it become dry. Fortunately, the amount I used was small, only enough to make me jump out of my skin.

Probably the closest I came to being a chemical martyr was when I made large quantities of nitrogen dioxide (NO2) by dissolving copper hairpins and safety pins in concentrated nitric acid. I never felt a tinge of overexposure; no runny nose, no nausea, no feeling faint.
But that's exactly how it's supposed to be like. It was much much later when I came to graduate school that I read about the insidious, cruel villain that's NO2 from the Merck Index. The sinister gas can kill you without any warning symptoms, much later after you inhale it. From Wikipedia:

Nitrogen dioxide is toxic by inhalation. Symptoms of poisoning (lung edema) tend to appear several hours after one has inhaled a low but potentially fatal dose. Also, low concentrations (4 ppm) will anesthetize the nose, thus creating a potential for overexposure."

As John Clark says in his rollicking "Ignition! An informal history of liquid rocket propellants", a man who inhaled NO2 would cheerfully strut around, and then suddenly drop dead. Hallelujah.

The best account of amateur teenage chemistry ever by the way is Oliver Sacks's absolutely delightful "Uncle Tungsten: Memories of a Chemical Boyhood". That age is past now, as almost every interesting reactive chemical has been banished from school and teenage chemistry kits under the pretext of "safety". These chemicals have now been replaced with increasing risks in their everyday lives; drugs, air pollution, insidious foods.
One more addition to the waning of scientific temper. I hope that at least that old chemical store survives, free of "regulation", to provide inquisitive kids like me with unending excitement. So that they can also have their very own bathroom lab which will forever live in their memory.

DMSO to SAHA: Questions of toxicity

I alluded in the last post to Breslow and Friend's discovery of DMSO as a HDAC (histone deacetylase) targeting agent. The story of how such a simple molecule was made into a putative drug deserves a closer look. The Nature Biotechnology paper that was cited in the last post contains most of the details. Suffice it to say here that the following points were noted.

DMSO was postulated to bind to a metal ion. Since Zn-heteroatom interactions are well known, another known sulfur binding moiety (look here for Whistling's list of zinc binding organic motifs), hydroxamic acid, was modified after some SAR studies to give the end molecule. One of the interesting steps in the lead optimization was the simple observation that it was unlikely that there were two metal ions in the same active site which bound to two hydroxamic acid groupings. So instead, one hydroxamic acid grouping was converted into a phenyl ring to gain binding affinity from hydrophobic binding. As the picture above shows, the drug now nicely fits into the active site, with the expected metal-hydroxamic acid interaction.

A journal club meeting member realised that SAHA's structure was similar to that of TSA (trichostatin A shown above), which was known to modulate HDACs. Thus came the hypothesis, later validated, that SAHA binds to HDACs. The details however are not yet clear, as HDAC interaction leads to a cascade of different events, and there are a dozen HDACs which are crucial for transcription.

There is one paragraph in the paper however, which I don't completely agree with. The authors were testing a few analogs, and came up with a branched structure with two hydrophobic rings that was much more potent than SAHA. However, it was later found to be quite toxic. While the authors make a good point that increased potency (increased binding affinity) can translate into greater toxicity because of continuous target activation, they also say:

"SAHA has hit the happy medium. It is potent enough to be useful and tolerated in patients. If the dosing is intermittent, such as not to maintain a continuous ‘therapeutic’ level of SAHA, it can be released from the binding site periodically so as to allow the deacetylation activities in cells. This is a general consideration, which could well be true of many other medicinal compounds. Thus, it is probably a mistake for medicinal chemists to set out first to find the most potent compound they can achieve in a series and then to look at any question of toxicity, as is often done."

The first thought that came to my mind after reading this was; this can't be quite right. Aren't some of the best-selling drugs of all time both highly potent and not particularly toxic? Toxicity and potency cannot always coincide.

I think there are two issues here. First is the fact that 'toxicity is in the eye of the beholder'. Cancer drugs are some of the most toxic drugs ever produced, but they are tolerated because of their essential requirement. So toxicity is a relative phenomenon whose impact has to be judged based on the disease. Secondly, even for very potent compounds, toxicity will depend on the exact nature of the target modulated, and its role in life processes. There may be a target like HDAC which plays a central role in the crucial process of transcription. You wouldn't want to keep this target activated/deactivated for too long. On the other hand, there might be another target which could be activated or deactivated for relatively longer periods because of its less sensitive nature and role in metabolism. So while the opinion of Breslow et al. is not wrong, it misses the other big part of the picture- the protein- on whose nature toxicity will depend too.

Least favourite NMR solvent, but a swell liquid nonetheless

Coronene has a poll on what everyone's least favourite NMR solvent is. I have not used all the solvents on the list, but among the ones I have used, DMSO was probably my least favourite, as it also seems to be for others taking the poll.

In my case, the reason was specific. I needed to do NOESY spectroscopy on a degassed, sealed sample. And even ice kept freezing up the DMSO when we were connecting it to the vacuum. For CDCl3, we could happily use lig. N2 and be happy, but not so for DMSO; we had to patiently do the degassing for almost half an hour. In addition, DMSO is viscous and radically changes the tumbling of molecules, causes aggregation and hydrogen bonding etc. Needless to say, one has to re-experiment with his/her NOESY parameters.

On the other hand, it is instructive to see what a great molecule DMSO is for biological applications. It can be used as a drug-delivery vehicle, although this use is debated. DMSO is widely used as a cryo-protectant, and the serine protease inhibitor PMSF is dissolved in DMSO as it will naturally get inactivated in water.

Ronald Breslow and the late Charlotte Friend also discovered that this simple molecule can induce cell differentiation and later, it was found to be a HDAC (histone deacetylase) inhibitor, a class of molecules that's heavily researched these days. Interaction with HDACs intimately interferes with transcription. For example, the recent celebrity 'wine molecule' resveratrol is purported to increase expression of the HDAC protein SIRT1, possibly affecting longevity.
Incidentally, Breslow's latest paper is an article in Nature Biotechnology, in which DMSO is used as the starting lead to develop SAHA, a HDAC inhibitor which is now in Phase 2 clinical trials as an anticancer agent.

DMSO also "enters the cell and kills the herpes virus". Apparently, this is an 'indisputable fact', and seems to be the basis of scented DMSO creams as the picture above shows. More interesting talk for the cocktail party; guys, beware of the DMSO girl.

A remarkably simple molecule with some remarkable (and occasionally annoying) properties, this DMSO.

The passing of Gossypium extraordinarium

Whenever I hear the name "cotton", the first thing that comes to my mind is "...and wilkinson". The second thing, apart from the cotton we all love to wear, is the dreaded group theory, for which Cotton's again was the pioneering text.

I could never really make sense of group theory. But today, the author of my (and millions of others') favourite advanced inorganic textbook has passed into history, and I regret his loss along with everyone else.

"Cotton and Wilkinson" has the same relation to its discipline as "Samuelson" and "The Feynman Lectures on Physics" have to theirs. Cotton was a truly prolific chemist. I am not qualified to judge whether his discovery of metal-metal quadruple bonds merits a Nobel or not, but I suspect that he would more than deserve a Coreyesque lifetime achievement prize. His output, honours, and contributions to research and teaching are immense. F. Albert Cotton, RA (Rest Assured) rather than RIP. Your legacy will live. My dog-eared copy of "C & W" and thousands of others bear witness to that.

P.S. Since we are on the topic, I have to say that my all-time favourite descriptive introductory inorganic text is J D Lee's "Concise Inorganic Chemistry", an affair that dates back to early college days. The book is so engaging and informative that it makes for great bedtime reading. For a more advanced treatment, I also love Huheey.

All transition metals exist only in +1 state (or a close approximation thereof)

Yes, I know; reading this statement might make people think that megagallons of ethanol are coursing through my arteries. It sounds quite counterintuitive. But I have become convinced that this is the case. I have not explored the matter in exhaustive detail, and some questions still linger. The explanation can get long-winded and I will reserve it for sometime when my own thoughts are clearer. But here's the summary.

There is a very simple reason why all transition metals will prefer only the +1 state in their complexes; Pauling's electroneutrality principle.
More simply put, consider this; won't it be improbable for a charge of +2 or +3 to accumulate on a metal ion? There will be repulsive destabilization. We know that charge tries to disperse itself and stabilize any system. So this positive charge will try to redistribute itself and get delocalized, thereby making the system close to electrostatically neutral. Where can it do this? Well, we don't want to forget 'the other half'- the ligands. What this means is that it's actually the ligands that are getting oxidised by helping to delocalize the positive charge. So even in a compound like AuCl3, the Au has a +1 charge, and it's really the chlorides that are getting oxidised.

The whole root of the problem is that chemists' definition of oxidation state actually is quite arbitrary, based on qualitative notions of electronegativity. We think that since chlorine is more electronegative than gold, it will carry all the negative charge. But Pauling's electroneutrality principle tells us otherwise.

However, this is not something we usually think about. Consider the simple ammonium cation. Organic chemists depict it with the positive charge on nitrogen. But it's a well-known fact that the positive charge in fact is distributed over the hydrogens. Any system will try to stabilize itself by dispersing charge as much as it can. That's what the ammonium cation does, nicely dispersing the positive charge over the hydrogens.

We might say; but how can halogens get oxidised? They are supposed to be among the most strongly oxidising elements. But note, that this statement applies to diatomic halogen molecules, not to halogen ions in solution.

You can take my word that even the fiercely electronegative CF3- anion in the complex [Cu(CF3)4]- is oxidised, and that the copper exists as Cu(I) in this state. Even a look at the formula suggests otherwise; the Cu must be existing as Cu(III). But you don't have to take my word for it. Consider this publication in Angewandte Chemie. There was also a small debate, published in another issue of the same journal, which further combs some fine points and definitions and clarifies things. High level calculations strongly suggest that the Cu exists as Cu(I).

High level calculations, but more logically, the electroneutrality principle and basic concepts of electrostatics.

The point is, many things in chemistry are defined either arbitrarily, or with respect to some standard. Based on the existence of another chemical species, many things can change for a given species. Given the right conditions, almost anything can get oxidised or reduced. Given the right conditions, anything can be made stable. After all, nobody had thought that stable carbocations could exist. But George Olah opened up an entire new field of carbocation chemistry with his pioneering work. In chemistry, there are no absolutes. Which again proves why it is so interesting.

Actually, it's simple to think about. Usually we assume that the metal is changing its oxidation state. Instead of that, let's adopt the other perspective; the metal makes the ligand change its oxidation state. The result is the same. We still see AuCl3 in solution. But it's really the Cl- that has changed, and not the Au.

Some questions still linger; then why do all these metals seem to exist in different oxidation states. More importantly, how can one prove this contention by experiment? After all, ours is an experimental science.

But even in the absence of definite experiments, if one ad hoc concept is taken for granted, then another ad hoc concept surely cannot be worse. Especially if it sounds more logical and convincing. Like all metals existing only in +1 oxidation state (or something close to that).

Important addendum: I should mention that when I say +1, the actual number is better defined as "close to +1". Calculations show that it can change from +0.7 to about +1.2 (this bears on the question d_orbital asked in the comments) depending on the ligand environment. Thus, in hemoglobin for example, in the oxidised and reduced form, Fe won't exist as exactly +1 both of the times. Its oxidation state will fluctuate between decimal places close to one.
And, as Mitch quite rightly says, in most of our daily life, metals have an unequivocal oxidation state of 0!!