Articles by: Kenneth Hanson

If Necessity is the mother of Invention, is Invention’s quirky uncle named Accident?

In a previous post, The Life Cycle of a North American Research Project, I described how an unexpected publication came out of what I initially thought was a calculation anomaly. I now have another, even stranger result-to-publication story about an attempt to stabilize dye-sensitized photoelectrosynthesis cells that led to  a reaction that could be, among other things, a drug delivery method.

The goal of the University of North Carolina at Chapel Hill’s Energy Frontiers Research Center – where I am currently a postdoc – is to produce a water splitting, dye-sensitized photoelectrosynthesis cell (DSPEC). DSPECs are similar to the dye-sensitized solar cell (DSSC) I wrote about in a previous post, except that 1) DSPECs include a catalyst and 2) they directly generate chemical fuels, like hydrogen and methanol, rather than electricity. This story starts with one of the fundamental limitations to DSPEC development: their photoinstability or, in other words, their instability under light.

The instability of DSPECs is not due to the semiconducting metal oxide or light absorbing molecules (chromophores), but instead the instability of the bond between the two. While chromophores with carboxylate attachments to metal oxides, like TiO2, are relatively stable in acetonitrile and other organic solvents, they immediately desorb from the surface in water. So, water is both the hero and the villain. We want to split water with light, but water causes chromophores to fall off the DSPECs surface.

While trying to solve the instability-in-water conundrum, we found that phosphonate binding groups are much more stable than carboxylate binding groups. It didn’t take long for us to hypothesize that if phosphonates are good, more phosphonates must be great! Our thought progression is depicted below from left to right:

The structure on the far right contains bis-phosphonate groups (‑C(OH)(PO3H2)2), which are sometimes used as a treatment for breast cancer and skeletal-related degenerative diseases. They are also the easiest way to synthetically functionalize a bipyridine ligand with four phosphonate groups. A fellow lab member nicknamed this super phosphonated molecule (far right in the image above), ‘Sticky bpy’ (pronounced ‘bippy’).

You can imagine my disappointment when, ironically, ‘Sticky bpy’ desorbed from the TiO2 surface significantly faster than the diphosphonated equivalent (middle complex above). Sticky bpy clearly wasn’t going to help us reach our goal.

At this point we needed to make a decision. Should we try to figure out why Sticky bpy is unstable and hopefully use that knowledge to make something better? Or should we cut our losses and allocate our time and effort elsewhere?

One notable observation convinced me to pursue this failure further: The molecule that desorbed from the surface was a different color than Sticky bpy. Color changes, even subtle ones, are a strong indicator of a structural change. Through a series of experiments involving UV-Vis, 1H and 31P NMR (the details of which are in the paper), we discovered that the decomposition product was, quantitatively and selectively, the dicarboxylated complex and phosphoric acid depicted below. We also found out that the reaction did not require a TiO2 surface but did require light, water and, surprisingly, oxygen.

The oxygen requirement was surprising because it is, thankfully, not usually a reactive species. However, reactive oxygen species like hydrogen peroxide (H2O2), superoxide (O2) and singlet oxygen (1O2) can be formed in the presence of a ruthenium complex and light. Through the use of selective traps we discovered that the reactive oxygen species for the bis-phosphonate decomposition above was singlet oxygen (1O2).

We are surrounded by oxygen in its unreactive triplet state, the lowest energy species or ground state of O2, that has two unpaired, aligned electrons. This is why oxygen has a magnetic moment and can be suspended in a magnetic field. In the presence of an excited chromophore  (such as [Ru(bpy)3]2+) that contains a heavy atom like ruthenium, singlet oxygen is formed through a well established process known as singlet sensitization. Singlet oxygen is less stable and consequently a more reactive species. Somehow, this reactive singlet oxygen facilitates the transformation of ‑C(OH)(PO3H2)2  into -COOH.

A similar reaction occurs when light is shined on a solution containing a singlet oxygen sensitizer (S = [Ru(bpy)3]2+ or Rose Bengal), oxygen and risedronic acid. This is particularly interesting since risedronic acid is a commercially available, FDA approved drug for treating osteoporosis.

 

The balanced equation for the general bisphosphonate decomposition reaction is:

R-C(OH)(PO3H2)2 + O2 + H2O → R-COOH + 2 H3PO4

We have a fairly solid understanding of the conditions required for the reaction but many questions remain: Is the hydroxide necessary? Will it still occur with phosphonate esters? What about other bisphosphonate derivatives? Perhaps the most important question that would answer the previous is ’What is the reaction mechanism?’ My honest reply is that we have no idea. My first guess is that it involves some sort of singlet oxygen insertion. I look forward to seeing what you arrow pushing junkies come up with.

Aside from being a unique reaction there are other possible implications from this result. First is that the administration of bis-phosphonate drugs – like risedronic acid – in conjunction with photodynamic therapy (the intentional generation of singlet oxygen) could lead to both diminished drug potency and unwanted by-products in the body. In a more positive light, bis-phosphonates could possibly be used as 1) a photo-protecting group for carboxylates, 2) an on/off mineral binding agent, 3) an on/off pyrophophatase inhibitor or 4) if the reaction occurs with phosphonate esters, a method for photoinitiated phosphate-based drug delivery.

So, like I said in the introduction, our attempt at creating a stable dye-sensitized photoelectrosynthesis cell led to the unexpected discovery of a reaction that could be a drug delivery method. My main take-away and advice is: although we have specific goals, scientists should not ignore interesting observations. A number of Nobel prizes were the result of anomalous/inadvertent observations: water channels, buckyballs, cosmic microwave background radiation and others. The next Nobel Prize-worthy discovery may, at first glance, just be an annoying distraction from your goals.

 

By October 24, 2012 0 comments Uncategorized

I’ll Have an Order of Water with Extra Neutrons Please

This week’s lab highlight: I received 1 gram of water in the mail. This delivery was exciting because it contained a tiny brown bottle of 97% 18O water that would allow me to perform an experiment to appease a reviewer. The excitement teetered into childlike glee once I saw the size of the box, made it through the Russian Nesting Doll packaging, and finally reached the gram of water inside.  Here’s a picture-book version of the experience:

By September 16, 2012 1 comment fun

Emergent Complexity: The Fourth Law of Thermodynamics?

The transfer of energy dictates everything on earth from the movement of atoms to the global economy. In high school/first-year chemistry we learn that the rules governing the movement of energy are simply defined by three laws of thermodynamics (four if you count the zeroth law). Yet, this simplicity can be misleading –  as demonstrated by how often the second law is misunderstood, misused and abused. The second law states:

The entropy of closed systems undergoing real processes must increase.

For some people the second law translates to “everything progresses from order to disorder” or “it is impossible for complexity to arise from randomness.” The biggest promoters for this misguided interpretation are advocates for intelligent design and/or irreducible complexity, which are just thinly veiled pseudonyms for creationism. They argue that complex systems like the flagellum or the human eye could not evolve spontaneously because they are complex – A logically precarious stance to take since these claims have been thoroughly debunked by evolutionary biologists.1

A quick bit of reflection on our day-to-day lives produces examples of complexity arising from less complex components. Ants, neurons, and transistors are just some examples of small building blocks that become infinitely more complex systems when combined in the right circumstances.

It is easy to argue that the above examples are the result of agency but there are also many examples of objects naturally arranging themselves into complex structures. In fact, the natural world is very good at arranging atoms.  Diamonds, ice crystals, and polycyclic aromatic hydrocarbons are just a few examples. Ambipolar molecules are an especially useful illustration of this tendency. When these molecules come into contact with water they form beautiful monolayers, bilayers, micelles and other structures.

So, returning to the 2nd law of thermodynamics, the correct interpretation is that complex structures – like those listed above – are possible, but at the cost of increased entropy in the surrounding environment.2

The tendency for a system to self-organize, when given the right circumstance and some energy from the surrounding environment, is one of the most important phenomena we observe. Yet, this transition from energy to order is not obvious when looking at our current laws of thermodynamics. This has led some researchers to suggest it may be possible to formalize a fourth law of thermodynamics that describes how complex systems arise.

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By July 18, 2012 15 comments Uncategorized

Great Research is Dull

This post is contributed by Brandon Findlay, and the author of the blog “Chemtips

The best talks, the ones that I go to conferences hoping to see, are the least exciting.  They aren’t sleep inducing, far from it.  But the best talks don’t usually have a lot of flair.  There’s no brilliance at play, and nothing indicates that what I’m hearing will one day change the world.  Instead, I think, “Why doesn’t everyone do things like that?”

Strange as it may sound, such moments are (for me) what make great research stand out.  Great research is the end product of an idea so simple and straightforward that doing things any other way is nonsensical.  If you’re curious about understanding the interplay between drugs and antibiotic resistance, of course you should go isolate millennia old permafrost bacteria.  If you want to discover new reactions, semi-randomly mixing reagents is the way to go.  And if you want to make macrocycles, just dream up a reaction that holds the two ends together with electrostatic charge.  After the fact each idea makes perfect sense, and I wind up feeling an amnesiac; remembering things I didn’t even know I’d forgotten.

Good research (and a lot of flawed work), draws more press, and generally leads to a faint sense of awe.  Almost all of the upper tier total synthesis work is good research, as every sufficiently complicated structure stands out like an Everest on the horizon [1].  “Conquering” each structure grabs the headlines and extends the limits of what’s possible, usually leading to a new technique or two along the way.  But at the end of the day, what have we learned?   Dozens of small discoveries are made while climbing, but they are rarely broadly applicable.  From the top the climbers can see far, but their only concern is even greater mountains on the horizon.  The only follow-up to their work is to reach the same summit again, better [2].

It’s easy for a field to fall into a groove, using the same approach again and again, until every mountain—no matter how small—has at least one flag waving at the top.  Great research shifts your perspective, revealing new worlds and new peaks.  Once the blinders have been removed it’s hard not to look back and think, “Why didn’t I think of that?”

[1] Why climb Everest?  “Because it’s there.

[2] Higher yield, fewer steps, green, single pot, atom economy, protecting group free.  All different ways of seeking out some synthetic Platonic ideal [3].

[3] Disclaimer: Total synthesis requires dedication, intelligence, and perhaps a touch of madness.  I have nothing but respect for those who do it so well.