What is KEKulene and is it Super-Aromatic? Organic Chemistry

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If you took any chemistry classes ever, you’ve heard that benzene is particularly stable due to its aromaticity. Well, benzene is cute but it pales in comparison to the massive Kekulene. It’s so apolar and insoluble that you can only dissolve it in spicily hot solvents and need to measure your NMR spectra in custom-made solvents at 200 °C. But is Kekulene super-aromatic?

What is Super-Aromaticity?

Before we get ahead of ourselves on super-aromaticity, we need to understand aromaticity. In the 19th century, pioneering chemists started to explore the field by doing all kinds of random reactions. They were puzzled that benzene was so unreactive towards addition reactions even though it was assumed to have a high degree of unsaturation. August Kekulé first proposed the cyclohexatriene structure for benzene in 1865. You might wonder what the big deal is – but remember that at this point in history, structures for compounds were still lacking. In one of his reports – which by the way reads as if he just watched my LSD video and ingested some – he said that a vision of ouroboros, the snake that eats it own tail, inspired him to think of the mesomeric structure.

The actual fundamentals and rationale behind aromaticity were discovered some 60 years later – with the famous Hückel rule on 4n+2 pi-electrons. His concepts were quite unrecognized for two decades – apparently also due to his lacking communication skills – but his contributions made him a cornerstone of organic and physical chemistry. Looking at molecular orbitals, it became that 4n+2 corresponded to a full set of binding molecular orbitals, resulting in higher stability of aromatic compounds.

Upping the ante, the concept of super-aromaticity envisions that macrocyclic conjugation in large, cyclic polycyclic aromatic hydrocarbons leads to an increased stabilization of the molecules. In 1951, the physical chemist McWeeny postulated the potential existence of Kekulene. In 1965, 100 years after Kekulé’s seminal work, first synthetic investigations were published and the molecule was named in Kekule’s recognition.

How Many Pi-electrons in Kekulene?

The key question for Kekulene was which electronic model best represented its structure: Is it a simple, localized structure consisting of 6 benzene rings? This is what McWeeny postulated already in 1951. Or was it rather a super-aromatic one that is based on two connected annulene rings, blue and purple, that both satisfy the 4n+2 rule?

The implications of this setup are quite significant, and one of them relates to diamagnetic anisotropy. When benzene is placed in an external magnetic field during NMR, its pi electrons circulate in the conjugated plane. This new ‘green’ magnetic field that opposes the external light blue magnetic field. If you are a benzene proton, you will feel the new magnetic field in the same direction. This leads to de-shielding and higher chemical shift in 1H-NMR. The same is true for an outer red proton in [18] annulene, where electrons are delocalized over the whole ring. What changes is however the experience for the inner, blue proton. Here, the induced magnetic field opposes the external one. This shields the proton and leads to a lower chemical shift, even negative in the case of annulene. The implications for Kekulene are clear. If global delocalization is a thing, we should see highly shielded inner protons like we see in annulenes.

Synthesis Of Kekulene (Staab, Diederich)

To answer what Kekulene looks like, we have to make it in the lab and characterize its properties. There’s only so much you can compute. We will first look at the landmark synthesis of Kekulene achieved by Staab and Diederich at the University of Heidelberg. Staab is most known for inventing the CDI reagent for hydroxyl and amine derivatization. Diederich, his PhD student at that time, majorly contributed to our current understanding of supramolecular chemistry and medicinal chemistry.

The synthesis by Staab and Diederich was based on almost 2 decades of work! It starts the nitration of meta-xylene and condensation with benzaldehyde. Next, a large-scale hydrogenation with 1.6kg of starting material in 50L of solvent, reduced the double bond. This set the stage for a nice cascade featuring a Pschorr reaction. It resembles a Sandmeyer reaction as it proceeds via oxidation of the aryl amine to the diazonium. This is reduced by copper, triggering an intramolecular cyclization reaction. The cascade happens on both sides in one pot, but yields the pentacycle in poor yield only.

To add more rings, they bromomethylated the pentacycle via an electrophilic aromatic substitution. Then, the benzylic bromide was converted into a thiol in two steps through nucleophilic substitution with thiourea and basic cleavage of the adduct.

To build the Kekulene scaffold, they coupled the two halves through double nucleophilic substitution. This reaction was performed under high-dilution conditions with only 1 mM concentration. This favored intramolecular closure to the ring instead of successive intermolecular reactions and led to a high yield of 60%.

The sulfur was a useful group to build the scaffold – but at some point, you have to remove it. To prepare this, the team methylated the dithiacyclophane, and then subjected it to base-mediated stevens rearrangement. This led to isomers of ring-contracted thio ethers.

Sulfur-Extrusion Reactions

To remove the sulfur completely, the team looked at different methods. The first approach was methylation to the sulfonium which is a leaving group, and can thus be eliminated. However, they had to explore another route as by-products were very difficult to separate from the desired product. This was accomplished by oxidation to the disulfoxide which was then pyrolysed at 450 °C.

As a side note, they also looked into the exotic Ramberg-Bäcklund contraction to give the olefin. It proceeds via alpha-halogenation of the sulfone and subsequent intramolecular substitution – leading to a three membered ring that can again eliminate SO2. It’s quite a miracle they even managed to isolate the 2 mgs or 1% yield of this reaction by preparative TLC. Obviously, they opted for the other approach instead of this one.

Finally, the product was photo-cyclized to yield octrahydro Kekulene. Here they found that using the saturated starting material was vital for success. They initially tried to install the double bond first and then perform the cyclization last, but this was unfruitful. Probably, creating the fully planar system makes it too rigid – instead, the aliphatic CH2 groups add some flexibility that is needed to enable photochemical reactivity.

Last, DDQ oxidized the octahydro derivative. Just to solubilize the reagents and achieve the reaction, they used trichlorobenzene as a solvent and let the reaction run for 3 days at 100 °C. They found Kekulene to be so insoluble that they had to recrystallize it from boiling, 400-degree hot triphenylene by “slowly” cooling to 300 °C – whatever slowly means here.

Is Kekulene super-aromatic?

Growing Kekulene crystals allowed them to investigate its molecular structure. They found very low variation in bond lengths, even for the inner protons. By looking at bond lengths, they derived that on the basis of X-ray analysis, Kekulene appeared not to have globally delocalized electrons and super-aromaticity.

What about NMR? Well, due to its low solubility, the team had to resort to creating deuterated trichlorobenzene and recording NMR spectra of saturated solutions at 200 °C to get anything usable. When they finally measured the compound, they showed the inner protons to be extremely de-shielded. Basically, the contrary of the delocalized annulene example we talked about at the start. The protons look like benzene protons, suggesting that the super-aromatic structure was incorrect.

Modern Synthesis Of Kekulene

So much for the oldschool chemistry. Remember the initial Pschorr reaction with low yield? The team of Perez envisioned a clever Diels-Alder short-cut by using this commercially available bistriflate. Addition of fluoride triggers elimination towards a triple bond, which can engage in a 4+2 cycloaddition with styrene to form a six-membered ring. After re-aromatization and release of the second triflate, another Diels-Alder reaction yields two isomers – one desired “cis”-like isomer, and a trans one. After some optimization, they managed to increase the yield to 28% with a 2:3 mixture of cis to trans. This means the net yield is also just around 11% – but you save yourself all other steps in the beginning of the synthesis.

Staab’s and Diederich’s synthesis truly stood the test of time, as the team also looked into synthetic alternatives after this step. It seems even modern methodologies could not improve or even re-create the original synthesis. The point of the Perez team by the way was to perform ultra high-resolution atomic force microscopy – basically making nice pictures of single molecules.

So, is Kekulene super-aromatic? Based on their findings and calculations, they also concluded that Kekulene does not have delocalized pi-electrons, and that the Clar model with 6×6 pi systems is the most appropriate one.

Chemists create even funkier Kekulene-like molecules like Septulene (google it’s structure!). But this is where we will stop for today. Catch you in the next one!

References on Kekulene


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