The World of Cyclophanes

Benzene and other aromatic rings are the star players inside the field of organic chemistry. Among them, there is a subgroup of rather unique compounds called cyclophanes. This article will touch some technical discussions, but you can skip the details because I think watching the beautiful molecular structures of cyclophanes alone will be entertaining.

Small Cyclophanes
The definition of the word cyclophane would be the ggeneral term for the cyclic compounds containing aromatic ring(s) as part of their ring structure.h A wide range of compounds meet this definition, but the chemistry of cyclophane is generally divided into two parts: small and large cyclophanes.
Very roughly speaking, the former is about the chemistry of strained benzene rings and the latter studies the ability of the molecules to incorporate smaller molecules. It will be easier to explain with real examples than with words, so letfs look at the chemistry of small cyclophanes first.
A benzene ring is a hexagonal molecule which is the most stable when the six carbon atoms are all in the same plane. Then, what changes will happen to its property if itfs forced to bend? This is an old question in chemistry research.

The molecule that pioneered the field was [2.2]paracyclophane, which was discovered by the researchers at ICI in 1949 and was synthesized by Professor Donald Cram in 1951 (Figure 1). As you can see, the structure consists of a pair of benzene rings connected by the bridges of two carbon atoms. The numbers in parentheses represent the number of bridging carbon atoms, and gparah means the positions of the substitution on the benzene ring.


Fig 1 [2.2]paracyclophane

[2.2]paracyclophane is a stable molecule, but the detailed structural analysis has shown that the benzene rings are bent about eleven degrees from flat, looking more like boat-shaped as a result. Similar compounds with more bridges and bridges at different positions have been synthesized. It has been confirmed that the strain in the molecule and its stability are inversely related (Figure 2).


Fig 2 [2.2]metacyclophane(left), [2.2.2.2](1.2.4.5) cyclophane(right)

I thought shortening the bridges to one carbon atom would be too hard, but I found it in the literature (although the molecule is extremely unstable). The analysis of the analog of this compound stabilized by special functional group revealed that the bending of the benzene rings reached twenty four degrees (Figure 3)!


Fig 3 [1.1]paracyclophane

The ultimate cyclophane with bridges at all six positions, named superphane, was synthesized by Professor Virgil Boekelheide at University of Oregon in 1979 (Figure 4). The benzene rings are bent to twenty degrees in this molecule, which looks almost like an inflated balloon.


Fig 4 Superphane

Seventeen years after the landmark synthesis of superphane, Professor Teruo Shinmyozu of Kyushu University prepared a superphane analog with bridges consisting of three carbons (Figure 5).


Fig 5 [3.6](1,2,3,4,5,6)cyclophane

Interestingly, upon irradiation with light this [3]superphane is predicted to transform into a molecule having the shape of hexagonal prism with propellers attached. Synthetic triangular prism, cube, and pentagonal prism are known, but this would become the first example of hexagonal prism since it has never been made including related derivatives. So letfs wait for the good news (Figure 6).


Fig 6 hexaprismane derivative

Next up are the stacked multi-layer cyclophanes. These compounds were developed by Professor Nakazaki of Osaka University around 1972 and are called chochins (Figures 7). It might take a bit of imagination to see them as lanterns (Chochin is a Japanese lantern), but itfs funny to see a phrase like gsynthesis of [4]chochinh in serious scientific journals. The bold sense of naming must be the nature of an Osaka man, but anyway, Ifm impressed again by the fact that chemists synthesize just about any compound that can be drawn on paper.


Fig 7 [3]chochin, [4]chochin

("chochin" is japanese traditional paper lantern. (Fig 8))


Fig 8 Chochin in Ikuta shrine (Photo from Wikipedia)

Cyclophanes as Host Compound
Letfs move on to the chemistry of large cyclophanes. Large cyclophanes are the macrocyclic compounds containing many aromatic rings, majority of which are made with the purpose of capturing other small molecule or ion in the cavity. In general, what gets captured is called a gguesth, and what captures a guest is called a ghost.h But why do cyclophanes have that ability?
Molecules are naturally equipped with a weak attractive force called van der Waals force on their surface. A gas condenses into a liquid and a solid by cooling because of this force that pulls the molecules together. A linear molecule is too flexible like a rope to attract each other, but the floppy movement is limited greatly in a cyclic molecule, which provides a comfortable space for the guest molecule.
Cyclophanes play a central role in current host-guest chemistry because of the following characteristics:

(1) The pi electrons on the surface of aromatic rings tend to attract positively charged ions and molecules.
(2) Since aromatic rings are flat and not very flexible, they are suited to form a rigid macrocyclic structure.
(3) The synthesis is relatively easy, as the chemical methods to design aromatic rings are well established.

Figure 9 shows how a metal ion like silver gets trapped in the space surrounded by benzene rings. This molecule is called deltaphane, based on its triangular shape.


Fig 9 deltaphane

A host ring needs to be larger for capturing molecules larger than ions. For example, the cyclophane called CP44 shown in Figure 10 captures naphthalene. A cyclophane capable of capturing an even larger steroid molecule have been made as well.


Fig 10 naphthalene in CP44

Crown ethers are also famous for its ion-capturing property. Molecules that look like the hybrids between cyclophane and crown ether have been synthesized (Figures 11, 12). The molecule in Figure 11 changes its UV absorption wavelength after trapping a silver ion, which may be a useful property as ion sensor.


Fig 11 anthracenophane-crown ether hybrid (purple ball is Ag+)


Fig 12 cyclophane complex with sulfate anion

As Molecular Recognition Material
With the advancement of supramolecular chemistry, new functions of cyclophanes are being developed that go beyond just trapping compounds randomly.
New cyclophanes are made to selectively capture a compound from a mixture of different compounds. The molecule shown in Figure 13 recognizes and captures barbiturate. The host recognizes its guest by six hydrogen bonds, giving the highly accurate recognition which rejects compounds with even slightly different structure.


Fig 13 cyclophane complex with diethyl barbiturate

The cyclophane in Figure 14 has a rigid and nonflexible skeleton, and is designed to be just the right size for a lithium ion to fit. It rejects all other ions.


Fig 14 cyclophane complex with Li+

Further evolved version of the molecule containing a group that changes its color upon binding to lithium ion is shown if Figure 15. Since it interacts with no other ion, it should become useful as a lithium ion sensor. These ion- and molecular recognitions are one of the rapidly developing fields in recent years.


Fig 15 Lithium ion sensor

By the way, sea water contains gold dissolved at very low concentration (about a gram in the volume of five Tokyo Dome stadiums). The vast amount of entire oceanic water is said to contain a total of approximately five billion tons of gold. This is a huge amount compared to a hundred forty thousand tons, an estimated amount of gold mined to date. So, if you could invent a compound that efficiently catches gold instead of lithium, you would be able extract all gold from sea water and become wealthy enough to control the world economy. The challenge might be worth dedicating your whole life. Is anyone interested?

The cyclophane consisting of benzenes connected by acetylenes (triple bonds) at para positions has been synthesized by Professor Odafs group at Osaka University. It provides a perfectly sized hole for fullerene. The group has shown that fullerene indeed fits in the hole to make a complex that looks like the planet Saturn. Both cyclophane and fullerene are made of benzene rings, so there must be good chemistry between them. Shown in Figure X is the fullerene surrounded by the double layer of cyclophane.


Fig 16 saturn complex (left) Fig 17 solar system complex (right)


The last molecule is the ultimate macrocyclic cyclophane (Figure 18). This is an astonishing 272-membered ring composed of benzenes and thiophenes connected by triple bonding carbons.
Spectacular is the only way to describe this molecule, but there has been a man-made 700-membered ring macrocyclic compound reported in the literature. It seems that therefs just no limit to these things.


Fig 18 272-membered giant cyclophane

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