Halogen bonding is a recently rediscovered secondary interaction that shows potential to become a complementary molecular tool to hydrogen bonding in rational drug design and in material sciences. Whereas hydrogen bond symmetry has been the subject of systematic studies for decades, the understanding of the analogous three-center halogen bonds is yet in its infancy. The isotopic perturbation of equilibrium (IPE) technique with (13)C NMR detection was applied to regioselectively deuterated pyridine complexes to investigate the symmetry of [N-I-N](+) and [N-Br-N](+) halogen bonding in solution. Preference for a symmetric arrangement was observed for both a freely adjustable and for a conformationally restricted [N-X-N](+) model system, as also confirmed by computation on the DFT level. A closely attached counterion is shown to be compatible with the preferred symmetric arrangement. The experimental observations and computational predictions reveal a high energetic gain upon formation of symmetric, three-center four-electron halogen bonding. Whereas hydrogen bonds are generally asymmetric in solution and symmetric in the crystalline state, the analogous bromine and iodine centered halogen bonds prefer symmetric arrangement in solution.
We have investigated the influence
of electron density on the three-center
[N–I–N]+ halogen bond. A series of [bis(pyridine)iodine]+ and [1,2-bis((pyridine-2-ylethynyl)benzene)iodine]+ BF4– complexes substituted with electron
withdrawing and donating functionalities in the para-position of their pyridine nitrogen were synthesized and studied
by spectroscopic and computational methods. The systematic change
of electron density of the pyridine nitrogens upon alteration of the para-substituent (NO2, CF3, H, F,
Me, OMe, NMe2) was confirmed by 15N NMR and
by computation of the natural atomic population and the π electron
population of the nitrogen atoms. Formation of the [N–I–N]+ halogen bond resulted in >100 ppm 15N NMR coordination
shifts. Substituent effects on the 15N NMR chemical shift
are governed by the π population rather than the total electron
population at the nitrogens. Isotopic perturbation of equilibrium
NMR studies along with computation on the DFT level indicate that
all studied systems possess static, symmetric [N–I–N]+ halogen bonds, independent of their electron density. This
was further confirmed by single crystal X-ray diffraction data of
4-substituted [bis(pyridine)iodine]+ complexes. An increased
electron density of the halogen bond acceptor stabilizes the [N···I···N]+ bond, whereas electron deficiency reduces the stability of
the complexes, as demonstrated by UV-kinetics and computation. In
contrast, the N–I bond length is virtually unaffected by changes
of the electron density. The understanding of electronic effects on
the [N–X–N]+ halogen bond is expected to
provide a useful handle for the modulation of the reactivity of [bis(pyridine)halogen]+-type synthetic reagents.
The solution symmetry of [N–Cl–N]+and [N–F–N]+halogen bonds is discussed, in comparison to the iodine and bromine-centered bonds as well as to the corresponding three-center [N–H–N]+hydrogen bond.
The first investigation of halogen bond symmetry is presented. In contrast to related hydrogen bonds, the iodous halogen bond is symmetric in solution and in the crystal. The bromous analogue is symmetric in solution, but shows asymmetry in the solid state. NMR results are in agreement with DFT predictions.
The halogen bond (XB) has become an important tool for molecular design in all areas of chemistry, including crystal and materials engineering, and medicinal chemistry. Its similarity to the hydrogen bond (HB) makes the relationship between these interactions complex-at times competing against, other times orthogonal to each other. sRecently, our two laboratories have independently reported and characterized a new synergistic relationship, in which the XB is enhanced through direct intramolecular HBing to the electron-rich belt of the halogen. In one study, intramolecular HBing from an amine, polarized iodopyridinium XB donors in a bidentate anion receptor, resulting HB enhanced XB (or HBeXB) preorganized and further augmented the donors. Consequently, the affinity of the receptor for halogen anions was significantly increased. In a parallel study, a metachlorotyrosine was engineered into T4 lysozyme, resulting in an HBeXB that increased the thermal stability and activity of the enzyme at elevated temperatures. Computational studies on the two systems show that the HBeXB extends the range of interaction energies to being significantly greater than that of the XB alone. Additionally, surveys of structural databases indicate that the components for this interaction are already present in many existing molecular systems; however, the HBeXB has not been previously recognized. The confluence of the independent studies from our two laboratories demonstrates the reach of the HBeXB across both chemistry and biochemistry, and that intentional engineering of this enhanced interaction will extend the applications of XBs beyond these two initial examples.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.