Molecular Crowns – Crown Ethers

There are a few cases in the history where a mistake or an unexpected finding during an experiment led to a huge breakthrough that changed the course of scientific world. The invention of crown ethers discussed in this column could be considered one of them. With the seemingly ordinary structure, the simple but innovative concept of crown ethers had a significant influence on the field of chemistry.

Typical Crown Ethers
As you can see, typical crown ethers are macrocyclic compounds in which a pair of carbon atoms and an oxygen atom repeat in regular order (Figure 1). The name likens the large ring to a crown and the oxygens to jewels. Depending on the size of the ring and the number of oxygen atoms, they are called 12-crown-4, 15-crown-5, and 18-crown-6.

Fig 1 Crown ethers (from left) 12-crown-4, 15-crown-5,, 18-crown-6

An interesting thing about a crown ether is that the ring can capture a positively charged ion like a metal ion and an ammonium ion (the sphere shown inside the ring is the positively charged ion). The negatively charged electrons of the oxygen atoms pointing inward are used to attract and catch the ion. This property made some conventionally impossible things possible, including pulling ionic substances into organic solvent. I should emphasize here the importance of the ring structure, as it holds onto an ion ten thousand times more strongly than does the similar open chain structure.
Larger ions fit in larger crown ethers, and smaller ions fit in smaller crown ethers. The ionic radius increases in the order of lithium, sodium, and potassium, and these metal ions are known to be most compatible with twelve-, fifteen-, and eighteen-membered rings, respectively.
It’s also known that two crown ether molecules can sandwich an ion. In these cases, an ion larger than the natural fit can be captured. A crown ether with an interesting “switch” property has been synthesized.
The molecule shown in Figure 2 is composed of two crown ethers linked by the N=N bond (the central portion). The N=N bond normally has the zigzag shape as shown in the left-hand side picture, but irradiating the molecule with light changes it to the shape shown in the right-hand side picture, causing the crowns to come close to each other. The molecule can now sandwich an ion, so it’s capable of capturing a larger ion than the original state. You can only hold a softball with one hand, but can hold a basketball with both hands, so to speak. This molecule is the light-switching crown ether which has the ability to change its ion-selectivity by responding to light.

Fig 2 light-switching crown ether

Crown Ethers with Various Functions
The crown ethers having other interesting functions have been developed. For example, the compound in Figure 3 changes its color when it captures an ion like sodium. There’s a possibility that it can be used to make ion detectors.

Fig 3 colored crown ether

There have also been research efforts to boost the ion-capturing ability of crown ethers. The lariat crown developed by Professor Seiji Shinkai of Kyushu University in Japan has a long chain as its name suggests (Figure 4). It uses this chain to wrap around the ion, “fixing” the complex so that the ion won’t escape.

Fig 4 lariat crown

Pushing the idea a step further, Professor Jean Mary Lehn in France made the double-cyclic crown ether. His team named the molecule cryptand after the Greek crypto, which means “to hide” (Figure 3.5).
The two rings of cryptand provide extra strength to hold the ion. If a regular crown ether “surrounds” an ion, a cryptand “locks it up”. The ion-capturing ability of a cryptand reaches a hundred thousand times more than that of 18-crown-6.

Fig 5 cryptand

More Crown Ethers
Furthermore, many crown ethers have been designed with different shapes and different constituting elements to have various ion-selectivities. The circular crown ether containing positively charged nitrogens, for example, captures a negatively charged chloride ion selectively (Figure 6). The larger molecule containing positive nitrogens captures even a big ion like trisphosphate ion (Figure 7).

Fig 6 Cl- anion within spherical crown ether

Fig 7 triphosphate anion within aza-crown ether

Fancy-looking clown ethers with very high selectivities have been developed (Figure 8,9). Looking at these broad variations, you can tell that this field was expanded from the discovery of the original concept by a number of people sharing ideas and competing with each other.

Fig 8 "toland", rigid macrocyclic structure

Fig 9 "spherand". shere-like rigid structure

There are clown ethers that can tell the difference between right- and left-handedness. An example is this one which incorporates a binaphthyl backbone (the hexagonal parts on both ends) synthesized by the group of Professor Donald Cram (Figure 10). The structure resembles Noyori’s BINAP ligand.

Fig 10 chiral crown ether

An amino acid can be either right- or left-handed (called D- or L-isomer), the two being the mirror image of each other. The crown ether in Figure 10 binds to an L-isomer, but not to a D-isomer because of the blocking by the binaphthyls. This property is useful for the usually difficult process of separation or resolution of mirror image isomers. There’s a big demand for the efficient resolution of amino acids, so it represents one of the most important applications of crown ether.

The Discovery
The original discovery of crown ether was made in 1960 by Charles Pedersen, who was a researcher at DuPont. The first crown ether was an unexpected byproduct made from an impurity in the reaction, and it’s been said that the yield was only 0.4 percent. Pedersen was careful enough to keep and analyze the minute sample of crystals and succeeded in the landmark discovery. Aware of the potential value of the compound, he continued the research and finally got his paper published on Journal of American Chemical Society, the most recognized journal in chemistry research. This single-authored paper became one of the most cited papers of the journal, and eventually led to the Nobel Prize in Chemistry in 1987 (Pedersen was the first recipient of the Chemistry Nobel Prize who didn’t have Ph.D. degree).
What was so remarkable was the meticulous work of Pedersen, who detected the 0.4 percent of byproduct and took a time to examine it. Ordinary chemists wouldn’t even notice the byproduct, and even if they did, few would bother to study it further. The creation of crown ether was accidental but the discovery didn’t happen by chance, and there’s no doubt that his insight was worthy of the Nobel Prize. I should also mention that the generosity of DuPont that supported Pedersen’s fundamental research as scientific contribution deserves praise as well.
Afterwards, the concept of crown ethers was added more sophistication by the works of people like Cram and Lehn, and it grew into big genre such as molecular recognition and supramolecular chemistry. Maybe the seeds of major scientific progress are hidden in our backyards, but I guess ordinary people like us just don’t notice. The recent Nobel Laureates Shirakawa, Noyori, and Tanaka all agree that their discoveries were born out of experimental mistakes. Whether or not you are keen enough to gain something from it might be what separates the first-class scientists from the rest.

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