Anna-Carin C. Carlsson

Symmetric Halogen Bonding Is Preferred in Solution

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.

The cardiac ryanodine receptor N-terminal region contains an anion binding site that is targeted by disease mutations.

Ryanodine receptors (RyRs) are calcium release channels located in the membrane of the endoplasmic and sarcoplasmic reticulum and play a major role in muscle excitation-contraction coupling. The cardiac isoform (RyR2) is the target for >150 mutations that cause catecholaminergic polymorphic ventricular tachycardia (CPVT) and other conditions. Here, we present the crystal structure of the N-terminal region of RyR2 (1-547), an area encompassing 29 distinct disease mutations. The protein folds up in three individual domains, which are held together via a central chloride anion that shields repulsive positive charges. Several disease mutant versions of the construct drastically destabilize the protein. The R420Q disease mutant causes CPVT and ablates chloride binding. The mutation results in reorientations of the first two domains relative to the third domain. These conformational changes likely activate the channel by destabilizing intersubunit interactions that are disrupted upon channel opening.

Solvent effects on halogen bond symmetry

The symmetric arrangement of the iodine and bromine centred 3-center–4-electron halogen bond is revealed to remain preferred in a polar, aprotic solvent environment. Acetonitrile is unable to compete with pyridine for halogen bonding; however, its polarity weakly modulates the energy of the interaction and influences IPE-NMR experiments.

Halogen bonding in solution.

Because of its expected applicability for modulation of molecular recognition phenomena in chemistry and biology, halogen bonding has lately attracted rapidly increasing interest. As most of these processes proceed in solution, the understanding of the influence of solvents on the interaction is of utmost importance. In addition, solution studies provide fundamental insights into the nature of halogen bonding, including, for example, the relative importance of charge transfer, dispersion, and electrostatics forces. Herein, a selection of halogen bonding literature is reviewed with the discussion focusing on the solvent effect and the electronic characteristics of halogen bonded complexes. Hence, charged and neutral systems together with two- and three-center bonds are presented in separate sub-sections. Solvent polarity is shown to have a slight stabilizing effect on neutral, two-center halogen bonds while strongly destabilizes charged, two-center complexes. It does not greatly influence the geometry of three-center halogen bonds, even though polar solvents facilitate dissociation of the counter-ion of charged three-center bonds. The charged three-center bonds are strengthened by increased environment polarity. Solvents possessing hydrogen bond donor functionalities efficiently destabilize all types of halogen bonds, primarily because of halogen vs hydrogen bond competition. A purely electrostatic model is insufficient for the description of halogen bonds in polar systems whereas it may give reasonable correlation to experimental data obtained in noninteracting, apolar solvents. Whereas dispersion plays a significant role for neutral, two-center halogen bonds, charged halogen bond complexes possess a significant charge transfer characteristic.

The nature of [N–Cl–N]+ and [N–F–N]+ halogen bonds in solution

Halonium ions are synthetically useful, transient species that may be stabilized by attachment to two electron donors. Whereas studies of [C–X–C]+-type ions have greatly contributed to the fundamental understanding of chemical bonding and reaction mechanisms, investigations of the corresponding [N–X–N]+ halogen bond complexes are only at an early stage. Herein we present solution NMR spectroscopic and theoretical evidence for the nature of [N–Cl–N]+ and [N–F–N]+ complexes, and we discuss their geometries and stabilities in comparison to their iodine and bromine-centered analogues as well as the corresponding three-center [N–H–N]+ hydrogen bond. We show the chlorine-centered halogen bond to be weaker but yet to resemble the symmetric geometry of the three-center bond of heavier halogens. In contrast, the [N–F–N]+ bond is demonstrated to prefer asymmetric geometry analogous to the [N–H–N]+ hydrogen bond. However, the [N–F–N]+ system has a high energy barrier for interconversion, and due to entropy loss, its formation is slightly endothermic.

Substituent Effects on the [N−I−N]+ Halogen Bond

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.

Solvent effects on 15N NMR coordination shifts

15N NMR chemical shift became a broadly utilized tool for characterization of complex structures and comparison of their properties. Despite the lack of systematic studies, the influence of solvent on the nitrogen coordination shift, Δ15Ncoord, was hitherto claimed to be negligible. Herein, we report the dramatic impact of the local environment and in particular that of the interplay between solvent and substituents on Δ15Ncoord. The comparative study of CDCl3 and CD3CN solutions of silver(I)‐bis(pyridine) and silver(I)‐bis(pyridylethynyl)benzene complexes revealed the strong solvent dependence of their 15N NMR chemical shift, with a solvent dependent variation of up to 40 ppm for one and the same complex. The primary influence of the effect of substituent and counter ion on the 15N NMR chemical shifts is rationalized by corroborating Density‐Functional Theory (nor discrete Fourier transform) calculations on the B3LYP/6–311 + G(2d,p)//B3LYP/6–31G(d) level. Cooperative effects have to be taken into account for a comprehensive description of the coordination shift and thus the structure of silver complexes in solution. Our results demonstrate that interpretation of Δ15Ncoord in terms of coordination strength must always consider the solvent and counter ion. The comparable magnitude of Δ15Ncoord for reported transition metal complexes makes the principal findings most likely general for a broad scale of complexes of nitrogen donor ligands, which are in frequent use in modern organometallic chemistry. Copyright