Carbon Triangles

Carbon atoms form various kinds of ring structure. In this column, I’m going to introduce the rings made of three carbon atoms, cyclopropanes.

Cyclopropanes
I think everyone knows propane as the name of a fuel gas, which is a compound in which three carbon atoms are connected linearly. A cyclopropane is a triangle made of three carbon atoms, hence the prefix “cyclo” (Figure 1). The name isn’t exactly the most creative, although accuracy and consistency are important for scientific terminology.


Fig 1 cyclopropane

By the way, cyclopropane is sometimes used as an inhalation anesthetic, but interestingly the exact mechanism of how it works isn’t well understood. Actually, the general mechanism of anesthesia isn’t either, and no one has been able to explain why a certain chemical paralyzes the central nervous system. Getting a surgery under anesthesia is a little scarier now.

Natural Products Containing Cyclopropane
A cyclopropane and its derivatives contain an equilateral triangle of carbon atoms. The bond angle (the angle between two bonding arms) of a carbon atom is the most stable at 109.5 degrees, so a cyclopropane is very strained with its bond angles narrowed down to 60 degrees. The strain makes the synthesis of three-membered rings tricky, and it is also responsible for the reactivities not seen in larger rings.
As a result, there aren’t too many natural compounds produced by plants and animals that contain cyclopropane units. Shown in Figures 2-4 are the few examples, pyrethrin, ptaquiloside, and duocarmycin. These compounds are insecticidal, carcinogenic, and antitumor agents respectively and these properties are known to be largely associated with their cyclopropane moiety.


Fig 2 pyrethrin Fig 3 ptaquiloside Fig 4 duocarmycin

For example, ptaquiloside is the toxic component isolated from warabi or bracken, and is highly carcinogenic. It’s been shown that the reactive cyclopropane opens up and forms a bond with a DNA molecule, causing the loss of its proper function and ultimately the formation of tumor. But, ptaquilosides are not stable against heat, so there’s no problem eating warabi after cooking. The old teaching to always cook warabi in boiling water is correct from the scientific point of view.
As a surprise to many organic chemists, two novel compounds have recently been discovered that contain an array of cyclopropane units, which were supposed to be rare in nature (Figure 5, 6). Even though each of these two compounds was discovered by a separate pharmaceutical company as having different biological activity, they share common features like the stereochemistry and the spacing between cyclopropanes. This is really a good case where nature sometimes makes something that’s beyond our imagination.


Fig 5 U-106305 Fig 6 FR900848

Unnatural Cyclopropanes
Now it’s the turn for synthetic organic chemists. Highly strained molecules tend to stimulate the challenge spirit of chemists, and a number of synthetic cyclopropane derivatives have been produced.
The leadoff hitter is tetrahedrane, which consists of four equilateral triangles (Figure 7). The molecule is extremely unstable because of its high bond strain, decomposing easily by reacting with other molecules. Its isolation was successful only by attaching substituents on the four vertices that serve as bulky umbrella (Figure 8).


Fig 7 tetrahedrane Fig 8 tetra-tert-butyltetrahedrane

In 2005, a molecule composed of two tetrahedranes was synthesized by the group of Professor Akira Sekiguchi at Tsukuba University in Japan (Figure 9). The bond shown in yellow is 0.1436 nanometer long, which is about seven percent shorter than normal single bond, and it is supposedly the current world record for the shortest carbon-carbon single bond. The short length has been explained as the result of the strained bond angles at each end at sixty degrees, which gives the bond a partial double bond character.


Fig 9 the shortest C-C bond

The molecule known as [1.1.1]propellane shown in Figure 10 must be the ultimate high-strain compound. First reported in 1982, this compound is unexpectedly stable and is even amenable to large scale synthesis.


Fig 10 [1.1.1]propellane

The structures composed of cyclopropanes connected at the vertices (this type of bonding is called spiro bonding) have been explored by Professor Armin de Meijere of the University of Göttingen in Germany, who calls those triangulanes. The molecule containing n cyclopropane units are written as [n]triangulane.
When four equilateral triangles are linked linearly in spiro fashion, the two ends need to dodge each other, consequently forcing the molecule to twist into a spiral structure (Figure 11). The molecule can curl either in right- or left-handed direction, so it has chirality even without a stereogenic carbon. The triangulanes with up to fifteen cyclopropane units have been reported so far.


Fig 11 [5]triangulane

A number of other beautiful triangle-containing molecules have been introduced from the de Meijere lab. I get amazed every time I see the cool structures they’ve been able to assemble (Figures 12, 13).


Fig 12 [10]triangulane Fig 13 [15]triangulane

By extending a chain of cyclopropanes in certain direction, you should get a macrocyclic structure after going full circle. The molecule consisting of six three-membered rings linked circularly (called davidane after the Star of David on the flag of Israel) is predicted to have the shape shown in Figure 14, where the triangles can’t fit in a plane but are slanting out of it alternately. Despite much effort, the actual synthesis of this compound has yet to be achieved and it remains as a “dream compound” for chemists.


Fig 14 davidane

Although the cyclic triangulane with eight cyclopropanes is considered the most stable according to theoretical calculations, the synthetic efforts for this one haven’t been successful either. It appears that these cyclic triangulanes have so much bond strain in them, and the actual syntheses are extremely challenging (Figure 15).


Fig 15 cyclo[8]triangulane

An n-membered ring compound containing cyclopropanes spiro-bonded to all of its carbon atoms is called a [n]rotane. I suppose it’s much quicker for me to explain with figures than with words (Figure 16). These are relatively easy to make, and the rotanes with n equals three to six have been reported.


Fig 16 [6]rotane

Among many other cyclopropane derivatives being produced in the chemistry laboratories around the world, I’d like to introduce a compound which could be considered the ultimate synthetic target (Figure 17). With the impressive structure composed of twenty triangles, this molecule is predicted to be stable enough to exist according to theoretical calculations. I wonder when we will hear the news about its synthesis.


Fig 17 "ultimate" traiangulane

As beautiful and full of surprises as natural products are, synthetic compounds also display fantastic creativities of chemists. If there’s one thing which can prevent the world of organic compounds from expanding, that might be only the limit of human imagination.

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