Articles by: Phil

Elemental analysis

What analytical data are necessary to characterize a new compound in organic synthesis? In the times before NMR, melting points, elemental analysis and IR used to be the available methods (and UV, if applicable). Nowadays, EA isn’t required by the journals anymore andv IR is probably going to disappear soon. Additionally, the significance of melting points is quickly decreasing because mostly people take the product as it comes off the column without recrystallizing it. Are we losing something there?

A number of people argue that the ability to get crystalline compounds is essential to be a good chemist, so recrystallization should always be done if possible. As a reward, you get EA-pure solids that are also easy to handle and may give you the occasional X-ray crystal structure (if you want to grow crystals). On the other hand, an additional effort is required: you need substantial amounts of material, which is no problem in a short synthesis, but can be a problem if it takes twenty steps to get to the product. If I have tediously made 50 milligrams of a material, I don’t really want to give ten away to be burned.

I wonder if elemental analysis is still a necessity today. In most cases you get all the information you need from NMR (identity and purity). What EA gives you is confirmation that your compound is pure as well as dry. Still, is it worth the trouble or just a waste of time? I suppose it all depends on the kind of research you’re doing. If you are “target-oriented”, as medicinal chemists like me are, I do not think it is worth it, as long as the final compounds being tested are pure. I suppose this is being sloppy, but I want to get a series of compounds in a reasonable amount of time. It might be a bit different in a total synthesis project, where the focus is on the pathway rather than the target compound per se.

By April 19, 2009 19 comments opinion, synthetic chemistry

Not simple analogues, but ligands for biological switches

A while ago I blogged about a paper where a set of structures analogous to estrogen were made. Now a follow-up paper has appeared in Protein Engineering, Design and Selection. The aim was actually not to make simple analogues of estrogen, but to use the compounds to create specific receptor proteins.

Starting from the human estrogen receptor α, the authors employed directed evolution: they changed the residues in proximity of the ligand by mutagenesis, screened the resulting mutants, and selected the best receptor mutants for the next round. After the third round of directed evolution, they came up with an optimized mutant that bound to CV3320 with an EC50 of 55 nM, while the affinity to 17β-estradiol was reduced by a factor of 10 (4 nM).

CV3320 and estradiol

While the authors admit that the selectivity over 17β-estradiol could still be improved, it still is a nice piece of work that demonstrates the power of directed evolution. This way, a protein receptor for a substrate that does not occur in nature can be made. Such a receptor can be used to make biological switches.

By March 3, 2009 0 comments chemical biology

Hot news on an old story

Some stories never seem to end. The hexacyclinol story is one of them. Is it over now?

I assume most readers will be familiar with the controversy about the two proposed structures of hexacyclinol, the original one (1) and a revised one (2), and about a total synthesis of 1 by James LaClair that was challenged by Rychnovsky and Porco on the basis of calculations and a synthesis of 2. The debate has been extensively covered in the blogosphere, e.g. in C&EN and by Derek Lowe.

Proposed structures of hexacyclinol

Proposed structures of hexacyclinol

There is some new evidence now. An Italian group have simulated the 1H and 13C NMR spectra of both structures using DFT calculations (Org. Lett. ASAP). The calculated spectra seem to point to 2 as the correct structure. In addition, 1 cannot have the same spectra as 2 according to the calculations. The authors summarize: “The structure of hexacyclinol is confirmed to be 2. Furthermore, if 1 had been synthesized or was formed from an unforeseen reaction, its NMR spectra are sufficiently different from those of 2 as to guarantee their distinction.” This seems to exclude LaClair’s claim that structure 1, which is the target of his total synthesis, happens to have the same spectral data as 2. The authors of the paper are of course reluctant to draw the obvious conclusion.

Update: This piece of news has been covered in Derek Lowe’s blog. There has been quite a discussion, with James LaClair participating in person! It has also appeared in The Chem Blog.

By February 13, 2009 4 comments synthetic chemistry

Polyethylene bags

Politicians in Switzerland have suggested to ban the polyethylene plastic bags used in supermarkets for environmental reasons. I am no expert, but I guess a thin plastic bag cannot be so bad as long as it’s properly disposed of. What really grabbed my attention was the statement of one politician, who said that the combustion of these bags releases dioxin.

Of course he was talking about polychlorinated dibenzodioxins (PCDDs) such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which was involved in the Seveso disaster and was a contaminant of Agent Orange that caused many of its severe health effects. Any chemist can see immediately that there is no way polyethylene will release PCDDs because it contains no chlorine. Such a statement immediately indicates how little research the politician has done.

I think this is indicative of a way of thinking predominant among a large part of the population here. Let me put it in a formula: Chemistry = Evil. It really annoys me when I see how little knowledge there is to support this general damnation of all things related to a scientific branch. In addition, because chemistry is bad, some people not only refuse to learn about it, but they are even proud of their lack of knowledge! I’m sure you have heard sentences like “You know, I never understood chemistry at school”, meaning “chemistry is for nerds and you don’t really need it in daily life”. Consider the same statement about art or literature, and you can see how little chemistry is appreciated. After all, modern life as we know it would be unthinkable without the advances of the chemical industry in the last century. But still, because polyethylene is made in a chemical plant, politicians will jump to the conclusion that it must be environmentally disastrous and should be banned.

By February 6, 2009 18 comments Uncategorized