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| Figure 1 |
I would like to talk about a number of great topics I have learnt from the Como Fluorine Conference in August. 2 of the keynote lectures, by Profs. François Diederich and Makato Fujita respectively, shed light on halogen bonding and its potential applications in molecular recognition. This time I will talk about Prof. Diederich’s one, I will leave Prof. Fujita for next time, as both talks are extremely impressive.
Prof. Diederich and his group has done a lot of impressive
research in the field of molecular recognition, and some of the key
intermolecular interactions include orthogonal dipolar interaction, halogen
bonding, and pi-stacking.
An orthogonal dipolar interaction concerns an interaction of
the type C-X ----- C=O. In one of the cases, it is a C-F ----- C=O interaction.
For example, when the molecule nilotinib is interacting with the DFG loop of a
protein, the fluorine atom on the CF3 group can interact with the
C=O bond on a particular amide group in the protein, in an intermolecular and
orthogonal manner (Figure 2).
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| Figure 2 |
The other fascinating aspect of their research is the
halogen bonding interaction (Figure 3). Halogen bonding (XB) can be defined as a
non-covalent, intermolecular interaction of a Lewis basic group and the electrophilic part of a halogen
group. The term ‘σ hole’ is often termed
and it is described as the area where the lone pair of the Lewis base is
aligned with the σ* orbital of the carbon-halogen bond. Indeed, the size of the
σ hole increases with a lower hybridization (sp) of halogen-bond donor. In 2014,
Diederich et. al. has synthesized a number of (iodoethynyl)benzene derivatives,
and study their halogen bonding properties with the Lewis basic quinuclidine.
From the linear Hammett analysis, they have concluded that the para-substituent
on the aromatic ring is in electronic communication with the iodethynyl group,
and this can affect the halogen bonding interaction of the given compound (Figure 4).
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| Figure 3. The blue dotted-lines represent halogen bonding. |
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| Figure 4 |
Thereafter, they have synthesized a 2-component,
donor-acceptor type supramolecular architecture. The ‘donor’ side consists of 4
lutidine rings, where the nitrogen atom is Lewis basic (Figure 5). On the other hand, the
acceptor side consists of 4 tetrafluoro-iodophenyl groups, and the iodine atom,
closest to the donor side, is the ‘halogen donor’. Thus a N --- I halogen
bonding appears, and the group has used 19F NMR binding titration studies and
2D NMR to show this has taken place. A 1H,
19F HOESY NMR experiment has been used to map out the intermolecular H-F
coupling (Figure 5). The cross signal in the 2D spectrum showed the through space interaction,
and only the fluorine atoms ortho- to the iodine atom could couple through space
to the hydrogens on the lutidine core. Along with the other data, the
researchers have been able to verify the halogen bonding in action.
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| Figure 5. |
When looking at single halogen bonding in solution, studies
show that it is largely enthalpy driven, and also have a large unfavourable
entropy at the same time. It also seems evident from the studies that, for a
given, general structure of an inhibitor, a different substitution on the
aromatic ring can drastically alter the binding constant K. The key explanation is because in some cases, an enthalpically
frustrated water can be positioned in between the interaction sites, and in other
case it is displaced. Thus, to improve inhibitory effects, a systematic
understanding (which will involve a lot of modeling) has to be achieved, and it
is great to see that many of these insights have already emerged from the
research literature.
by Ed Law
6/9/2015
Reference for this blog article from:
Angew. Chem. Int. Ed. 2015, 54, 1.
Angew. Chem. Int. Ed. 2015, 54, 3290. A review.
Org. Lett. 2014, 16, 4722.
Phys.Chem. Chem. Phys., 2013, 15, 11178. A review.
ChemMedChem 2011, 6, 2048.
Science 2007, 317, 1881.
ChemMedChem 2006, 1, 611.
Angew. Chem. Int. Ed. 2004, 43, 5056.
ChemBioChem 2004, 5, 666.
Angew. Chem. 2003, 115, 2611.