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.