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| Figure 1. Taken from Ref. [2]. |
On the second day of the Como Fluorine Conference, Prof. Makato Fujita has given an impressive talk on supramolecular chemistry and molecular recognition involving fluorous compounds. How to make ‘chemical nemesis’ to become pals? You have to see this, mate!
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| Figure 2. Blue dotted lines represent halogen bonding. |
Let’s take a closer look at halogen bonding involving heavily fluorinated compounds, as the fluorine atoms are certainly not in the most low-key presence here (Figure 2). In a sense, the electron withdrawing nature of fluorine atoms induces halogen bonding. The nature of the iodine atom is also important. First, the electron deficiency on the iodine atoms on the perfluoroalkyl compounds is caused by large electron deformation of the soft lone-pair electron on the iodine atom, which is in turn induced by electron-withdrawal through sigma bonds. That will lead to a strong interaction with the Lewis basic component. On the other hand, the fact that halogen bonding is strongest in iodides may point to the fact the softness of the lone-pair electron on the iodine atom is likely to play an essential role in this intermolecular interaction.
How can we observe a halogen bonding experimentally? Well,
we can do NMR (vide infra), and after complexation of the Lewis base and the
halogen donor, a upfield shift of the CF2 signal in the 19F NMR can
be observed. What is even better, is that the complexation through halogen
bonding can induce liquid crystallinity from non-mesomorphic components.In many
cases, a crystalline 1:1 adduct can be afforded, and its structure can be confirmed
by X-ray crystallographic analysis. So, we have an elegant approach to verify
halogen bonding – don’t you find crystals beautiful?
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| Figure 3. Taken from Ref. [1]. |
Prof. Fujita and his group wants to achieve a ‘fluorous recognition’ in synthetic cavities, such as molecular cages. The idea is to form a host-guest complex, where the ‘guest’ this time is of course the fluorous compound. Traditionally, there are 2 methodologies to do so – solvent size exclusion (driving force is CxFy group) or through hydrophobic effects (like CxFyCOO–Na+. Indeed, they have published in Science Magazine in 2006 (Figure 3), where they have found a host-guest complex by putting 24 ligands to 12 metals (Pd2+). What is spectacular is that the complex, which contains non-polar fluorous groups, can be dissolved in the polar NMR solvent d6-DMSO and D2O! That means the fluorous tails are protected by the host cage, which can be solvated in a polar solvent. Once again, by looking at the structure of the ligand, we can see the importance of having a (CH2)n spacer in the fluorous compound. The ‘spacer’ idea is a common theme in so many of the talks in the conference, from ligand design to fluorous membranes to biological inhibitors. Except if you want all the electron-withdrawing fluorine atoms to cast a huge impact on your ligand core, you have to put these spacers in between the fluorous groups and the ligand core, and hopefully, by careful design, it will still achieve a reasonable fluorine-phase solubility.
Then, Prof. Fujita
proposed 2 new and interesting strategies to achieve his aim – fluorous
aggregation and halogen bond (XB)-assisted fluorous recognition. For the first
concept, consider the following 2 equilibriums (Figure 4).
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| Figure 4. Taken from Ref. [2]. |
We can easily see that, when the host:RF = 1 : 1, the
equilibrium is in favour of the direction where the fluorous compound is NOT in
the cage. However, if a number of fluorous compounds are in the system, then
due to the like-dissolve-like principle, the fluorous compounds will aggregate
and they will stay inside the host cage (Figure 5). Indeed, a number of fluorous compounds
are capable of doing this, and what is even more fascinating is that the system
is showing a phenomenon molecular biologist should be familiar –
co-operativity. Just like the case of hemoglobin, when multiple fluorous
compounds enter the case, the binding shows the classic, sigmoidal Hill
co-operativity. Different cage : fluorous-compound complex shows different
stiochiometries. For example, a perfluorocycloalkane C5F7H3
, gives a 1:4 adduct; while a linear HO-CH2-(CF2)n-CH2-OH
gives a 1:2 adduct. All these have been verified by 19F NMR studies, and the
complexes can be crystallized and subject to X-ray analysis, affirming the
complex formation.
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| Figure 5. Taken from Ref. [2]. |
For the other strategy, Fujita et. al. has also employed
halogen bonding to meet the challenge (Figure 6). From Figure 2, we can see the halogen
bonding network in between the nitrogen and iodine atoms, and the establishment
of the sigma hole (also in Prof. Diederich lecture).
 |
| Figure 6. Taken from Ref. [3]. |
While the space in the molecular cage is confined, the water molecules or counteranion NO3– can form halogen bonding with the iodine atoms on the fluorous compounds, and this has been verified by 19F NMR titration experiments and also X-ray crystallography. When aromatic compounds C6F3I3 and C6H5NMe2 are mixed, a donor-acceptor pair can be formed in the confined cavity, through the N---I halogen bonding (Figure 7).
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| Figure 7. Taken from Ref. [3]. |
Thus, even the worst of enemies can become the best of friends – at least in a chemical sense.
Reference:
1. Science 2006, 313, 1273.
2. J. Am. Chem. Soc. 2014, 136, 1786.
3. Angew. Chem. Int. Ed. 2015, 54, 8411.
