Hello, New Nanospace!

Hello, New Nanospace!

Synthesizing and studying molecular hosts with a cavity that can incorporate guest species is a field that we enjoy for various reasons. Notably, guest molecules incorporated into host molecules can lead to unusual phenomena (e.g. unusual reactivity and properties) in accordance with the properties of the “walls” that form the internal space. Since the first coordination-driven nanocage using “self-assembly” in 1995 (Nature 378, 469–471 (1995)), many research groups, including the Nitschke group, have reported various kind of cage- and capsule-shaped molecular hosts.

The nanocages reported so far are mostly based on walls made up of aromatic molecules (e.g. benzenes and anthracenes). Nanocages with antiaromatic walls, should have different properties to those of nanocages with aromatic walls. Especially the magnetic properties of a nanospace with antiaromatic walls are intriguing, as antiaromaticity is predicted to enhance the local magnetic field inside the nanocage. Such an antiaromatic-walled nanospace has not been reported, and therefore their properties have never been experimentally clarified. This is the essence of what is described in this manuscript.

To utilize antiaromatic compounds as building blocks for nanocage and/or nanospace constructions, some essential properties are desired: (i) high stability, (ii) high symmetry, (iii) strong antiaromaticity, (iv) small molecular size but large antiaromatic surface, and (v) facile synthesis and functionalization. In order to construct the antiaromatic-walled nanospace, we focused on “norcorrole”, which is an antiaromatic porphyrinoid reported by Prof. Hiroshi Shinokubo in 2012 (Angew. Chem. Int. Ed. 51, 8542–8545 (2012)). We realized that norcorrole can be a suitable building block for the construction of an antiaromatic-walled nanospace because it fully satisfies these requirements. However, this was only a starting point of a long, long journey to get an antiaromatic nanocage. Fortunately, we can always count on the help from fellow chemists. This whole project would not have been possible without discussions and help from different specialists, from visiting students in the Nitschke group to professors met during conferences.

Norcorrole is stable and easy to synthesize compared to other antiaromatic compounds but it still required a long time for us to get experienced skill for porphyrinoid synthesis and optimize the reaction conditions before obtaining the final norcorrole-based subcomponent. Especially, unusual chemical reactivity of norcorrole had forced us to change the target subcomponent structures many times. In our initial plan, we wanted to introduce aniline groups on the meso-position to get highly symmetric subcomponent. However, such electron donating and/or withdrawing groups induced serious instability to the norcorrole panel (see Shinokubo’s report: Chem. Commun. 53, 1112–1115 (2017)). Thus, we could not get any of our initial norcorrole-based subcomponents despite the Nitschke group’s extensive experience in constructing cages from various kinds of subcomponents (e.g. amine, aldehyde, and azide). 

When our synthetic options had almost ran out, we found a paper regarding Suzuki-Miyaura coupling following bromination of norcorrole reported by Shinokubo (J. Org. Chem. 82, 10425-10432 (2017)). This paper became “watershed” for our project. They only reported mono- and per- substitutions in the paper, but we changed our plan to get di-substituted norcorrole using their method. Norcorrole has four reactive positions to the bromination (3,7,12,16 positions). As we expected, when we put 2 equivalents of brominating reagents into norcorrole solution, random bromination occurred on all the reactive positions. We spent a lot of time trying to isolate the desired product but alas, the various brominated species were inseparable. Fortunately, 3,12-(trans) and 3,16-(cis) substituted norcorrole were obtained as the main products, thus we conducted the next step without purification. After introducing nitrobenzene group via Suzuki-Miyaura coupling, we could separate the pure cis and trans isomers of the disubstitued compounds from the rest of the products. Finally, we could obtain the desired pure trans isomer after reduction to the di-aniline subcomponent.

In the first attempt, we only got 5 mg of the subcomponent. But our struggle had come to an end at this stage. From this tiny amount of subcomponent, we could directly get our dreamed cage via subcomponent self-assembly method and the crystal structure of this huge supramolecule (m.w. = 8080.88 g/mol!!). Interestingly, we got single crystals of the cage in only three days whereas we spend over six months to obtain the subcomponent. We felt so lucky, and this was our reward for not giving up on the synthesis of this antriaromatic compound.

Thrilled by this positive result and after synthesizing more of the subcomponent, we succeeded in investigating the properties of “an antiaromatic-walled nanospace”. Notably, we demonstrated experimentally the antiaromatic deshielding effect within the nanospace as shown by 1H NMR signals of guest molecules encapsulated in this new nanocage, which are observed at chemical shift values of up to 24 parts per million (ppm) and up to 15 ppm downfield shifted compared to free guest signals. 

We have encountered a lot of barriers and problems to carry out this whole study such as large-scale synthesis, how to calculate (and display!) a 3D NICS grid, or even the nomenclature. I would like to share with you all of them but alas, I will have to stop here due to the “space” limitation. 

You can read more about our work in our paper, “An antiaromatic-walled nanospace”, in Nature. https://www.nature.com/articles/s41586-019-1661-x

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