synthetic chemistry

Molecular Strain: Make me, I dare you

Roald Hoffmann and Henning Hopf have a great new paper out in Angewandte titled Learning from Molecules in Distress. The paper is a romp through the field of “unhappy” hydrocarbon chemistry. It starts with a rationalization of the field of highly strained molecules, but quickly goes to the psychology of sadomasochism and vexing contemporary philosophical dilemmas as the Trolley problem and the Swampman.

On an aside, the Swampman thought experiment is thus,

Suppose lightning strikes a dead tree in a swamp; I am standing nearby.My body is reduced to its elements, while entirely by coincidence (and out of different molecules) the tree is turned into my physical replica. My replica, The Swampman, moves exactly as I did; according to its nature it departs the swamp, encounters and seems to recognize my friends. It moves into my house and seems to write articles on radical interpretation. No one can tell the difference.

As many of the elements in your brain get replaced within a month or so from the food you eat, this really shouldn’t be such a dire philosophical dilemma, than a common curiosity of everyday life. But I understand lightning is more theatrically appealing than a sandwich.

This is all within the context of explaining the glamorous life of the investigative synthetic experimentalist. Mission accomplished, if that was an intended goal. The paper also does discuss chemistry, and special attention was given to cyclic ozone 1, dicarbon dioxide 2, hexaazabenzene 3, and hexaprismane 4.

stressed molecules

The masochistic chemist has 2 problems with the synthesis of these types of molecules. The first is near and dear to my heart, stability. Although, these molecules lie in a potential minimum and thus are thermodynamically “stable”, they can be quite reactive with itself or other molecules within the atmosphere or the medium it finds itself in. Plus, even thermodynamic stability have qualifiers, the size of the potential well may be so shallow to never see these peculiars at room temperature, which is likely the case for hexaazabenzene.

The second problem for molecules in distress is the inability of a clear synthetic strategy to the target; these molecules are unknown for a reason. Thus, the ever enterprising physical organic chemist needs to utilize chemistry outside a pure organic chemistry approach and may have to chase these molecules down within the complexation with metals, or in low temperature inert matrixes, or even perhaps atom by atom in an STM. In any case this paper is a fun read and should definitely be shared.


Note 1: The Hoffmann & Hopf paper: Learning from Molecules in Distress
Note 2: Paper originally covered by CBC: kinky!
Note 3: RajaLab Weblog has covered some interesting sulfur helicene chemistry: Carbon-Sulfur [11]Helicenes: Syntheses, Structures and Properties
Note 4: Also covered by selenized: the value of making things

By April 26, 2008 3 comments synthetic chemistry

“Danishefsky 2-component reaction”

This JACS communication by Danishefsky’s group is inspired by the well-known Passerini 3-component (isonitrile + aldehyde + acid) and Ugi 4-component (isonitrile + aldehyde + amine + acid) reactions. They ask the question if isonitriles 1 react with carboxylic acids 2. At room temperature, they do not, but under microwave irradiation they furnish N-formyl amides 3 in good yields. The authors go on to propose the mechanism shown, which could probably be further supported by isotope labeling.


They wanted to apply this new kind of reaction to the synthesis of asparagine-linked glycopeptides. Therefore glycosylisonitrile 4 was reacted with aspartate 5. Instead of the expected product, ester 6 was formed. In the paper, the formation of a “β-GlcNAc donor” by participation of the NAc group is assumed. Its structure is not specified, but I suppose it could be something like 7.


To get around this problem, non-participating neighboring groups like OBn and N3 were used (8). Now, reaction under the same conditions furnished the expected glycosyl amino acids 9. Even better, the reaction was anomerically specific; that is, β-isonitrile 8 gave exclusively the β-linked product 9, while α-isonitrile 10 yielded only 11.


The formyl group could also be converted into methyl or completely removed, which sets the stage for building up a peptide chain. What is really striking about this new type of reaction is its simplicity. To quote the paper: “[The results described herein]… might well have been discovered a century ago.” Why has nobody ever tried this before? Is it because of the bad smell of isonitriles?

By April 21, 2008 2 comments synthetic chemistry

Estrogen analogues

The authors of this paper (Chem. Eur. J. 2008, early view) have synthesized a series of new estrogen analogues where the B and C ring of estrone (1) and 17β-estradiol (2) are replaced with a simple alkyne spacer. The steric bulk of the omitted rings is replaced by suitable substitution of the two remaining “A” and “D” rings (phenols 3 and 4).

Estrogen structures

An overlay of the 3D structures of estrone (1, yellow) and 3 (white, R = 2-Cl, R’ = Me) shows a considerable offset between the corresponding carbonyl groups (O – O distance of 1.67 Å). I also wonder about the rotational flexibility of the linker – the “text-book”-property of steroids is their rigidity, but the new analogues can rotate about the triple bond.

Estrogen overlay with analogue

The biological properties of these new compounds have not yet been measured. I wonder if they will be comparable to estrogens. If this radical structural simplification still yields bioactive compounds, this will be a remarkable achievement. On the other hand, flexibility always has an entropic cost when the molecules bind to their target, so I don’t expect the activities to be too high. Also, the new class of compounds is probably less selective than the original estrogens. But this is all speculation as long as the biology hasn’t been done.

By March 28, 2008 2 comments synthetic chemistry

Diaza[12]annulene: Would You have Known Better?

The recent retraction of two papers regarding diaza[12]annulenes by Yamaguchi et al. and Shi et al. from separate groups have strengthened the argument for stronger peer review and more thorough literature review by authors.

But anyone can be an armchair synthetic chemist and point fingers at what should have been done after the fact. The easiest finger to point, is presumably between 7 coauthors, 4 reviewers, 2 editors no one ran the appropriate literature searches to find that these reactions are known and yield products with exactly 1/2 the mass as those reported in the papers. But, now we come to the bitter truth in modern chemical research, we simply do not perform the thorough literature searches of yester’year. Some will say this is a problem, but assuming those 13 scientists are typical of scientists of today then it simply isn’t a fair commentary to make. So, I thought it would be more beneficial to reread the papers and see if I would have come to the same conclusions given the same series of data, as I’m oblivious to heterocyclic chemistry in general and the Zincke reaction in particular, and have a typically topical background like most chemistry graduate students (I’m a Nuclear Chemist after all).

First up the Yamaguchi paper:
The title is the One-Pot Synthesis of N-Substituted Diaza[12]annulenes. Just looking at the title, we should be expecting 1H,13C-NMR, definitely MS data, and likely a crystal structure since the molecule would have two cationic-like centers. Picture shown below.

As can be seen in the structure this monstrosity should have some serious pi-pi stacking possibilities, and isolating crystals shouldn’t have been too problematic, but none are isolated. An image of their NMR data for the structure above is below.

It would be at this point that the little voice in my head would be like, “hmm…. why do I have aromatic proton peaks? I should probably count those pesky buggers again. Yup, 12 delocalized electrons.” If one is postulating that this is antiaromatic, then one hallmark of antiaromatic hydrogens, located on the outside ring, are that they shift upfield (lower ppm) and lie to the right of 8 ppm and likely 7ppm. So, it would have been at that point where the paper would of confused me.

Second up the Shi paper:
The title is the [12]Annulene Gemini Surfactants: Structure and Self-Assembly. So, we should be expecting yucky yellow oils, and with the word structure, perhaps even a crystal structure. The molecules examined are shown below.

Independently, they confirm the odd aromatic protons of Yamaguchi and they obtained a yellow powder, not necessarily an oil, but well within reasonable expectations. They did some calculations with Gaussian and discovered the results below.

The expected distorted structure is seen in II but lied 1.7 kcal/mol higher in energy than I. This is just odd, for a cyclic antiaromatic system we should expect to see 2nd order Jahn-Teller distortions shift the molecule away from planarity and this was not seen by calculations. This is where the authors and reviewers can be faulted, at that point some one should have suggested an experiment to see whether the NMR peaks would move upfield as a function of temperature. As scientists, we love making graphs, and that would have been a neat confirmation of both the structural predictions from calculations, and an easily verifiable hypothesis.

In summary, I don’t feel it is fair to fault the authors, reviewers, editors for not knowing every obscure heterocyclic named reaction. However, it is prudent upon all of us to ask the right questions about our research, to put-off deadlines if necessary, and to apply our full intellect and diligence to our experiments.

Some Armchair commentary here:


By December 14, 2007 2 comments synthetic chemistry