Vinko Nemec

Halogen and Hydrogen Bonding between (N‐Halogeno)succinimides and Pyridine Derivatives in Solution, the Solid State and in Silico

A study of strong halogen bonding within three series of halogen-bonded complexes, derived from seven para-substituted pyridine derivatives and three N-halosuccinimides (iodo, bromo and chloro), has been undertaken with the aid of single-crystal diffraction, solution complexation and computational methods. The halogen bond was compared with the hydrogen bond in an equivalent series based on succinimide. The halogen-bond energies are in the range -60 to -20 kJ mol-1 and change regularly with pyridine basicity and the Lewis acidity of the halogen. The halogen-bond energies correlate linearly with the product of charges on the contact atoms, which indicates a predominantly electrostatic interaction. The binding enthalpies in solution are around 19 kJ mol-1 less negative due to solvation effects. The optimised geometries of the complexes in the gas phase are comparable to those of the solid-state structures, and the effects of the supramolecular surroundings in the latter are discussed. The bond energies for the hydrogen-bonded series are intermediate between the halogen-bond energies of iodine and bromine, although there are specific differences in the geometries of the halogen- and hydrogen-bonded complexes.

Uncommon halogen bond motifs in cocrystals of aromatic amines and 1,4-diiodotetrafluorobenzene

A number of novel halogen-bonded aromatic amine cocrystals with 1,4-diiodotetrafluorobenzene have been synthesized via both mechanochemical and solution syntheses, offering valuable insight into potential halogen bond acceptor species.

Mechanochemical and solution-based cocrystallization of 9,10-phenanthrenequinone and thiourea†

We have synthesized the first known cocrystal of 9,10-phenanthrenequinone utilizing both liquid-assisted mechanochemical synthesis and crystallization from a solution.

Halogen bonded cocrystals of active pharmaceutical ingredients: pyrazinamide, lidocaine and pentoxifylline in combination with haloperfluorinated compounds

In this work, we present the cocrystallization of three model active pharmaceutical ingredients: pyrazinamide, lidocaine and pentoxifylline. As cocrystal coformers, we selected perfluorinated halogen bond donors, 1,4-diiodotetrafluorobenzene (tfib) and 1,4-dibromotetrafluorobenzene (tfbb). From a crystal engineering standpoint, the compounds are interesting due to the presence of various potential donor and acceptor species. The choice of structurally equivalent, ditopic linear halogen bond donors, although of different donor strength, allowed us to study the competition between hydrogen and halogen bonding in the obtained solids. We have prepared six cocrystals by both mechanochemical synthesis and a conventional solution-based method. The results of our work show that the dominant supramolecular bond in pyrazinamide cocrystals is the X⋯N type halogen bond (where X = Br or I) established with the pyrazinyl nitrogen atom, in lidocaine cocrystals it is the X⋯O type halogen bond, while in pentoxifylline cocrystals it is dependent on the donor strength. In the tfib cocrystals, halogen bonds are established with both the secondary nitrogen atom and the xanthyl oxygen atom, while in the tfbb cocrystals only Br⋯O halogen bonds are formed.

A Three-Pronged Approach to Strong Halogen Bonds - Crystallographic, Solution and Computational Study of N-Halosuccinimide-Pyridine Complexes

Over the past couple of decades halogen bonds (XB) have transformed from an obscure intermolecular interactions known only to a handful of experts into an indispensable tool of crystal engineering rivalling even to hydrogen bond (HB). However, detailed studies of XB energetics are still quite scarcer than those for HB. In our study we have used commercially available N-iodo, N-bromo- and N-chlorosuccinimide (NIS, NBS, NCS) as halogen bond donors, succinimide (S) as an equivalent HB donor, and 7 p-substituted pyridines as halogen (or hydrogen) bond acceptors. The pyridins have been selected to cover as wide as possible range of Hammet coefficients (-0.88 to 0.66), while avoiding functionalities which could act as hydrogen bond donors. This has ensured a relatively large variability of XB acceptor qualities, while ensuring that the observed XB is the only strong intermolecular interaction. In order to provide a detailed description of the halogen bonding in these systems, N-halosuccinimides were crystallised with the pyridines in order to study the formed complexes in the solid state. Simultaneously, microcalorimetric measurements were made to study the formation of halogen bonded complexes in acetonitrile solution, and, extensive computations in order to study the deformation of electron density upon XB formation, as well as the effect of various geometric parameters on the energy of XB. Solid state studies have shown that NIS and NBS form strong halogen bonds with all 7 pyridine derivatives. NIS is expectedly a better XB donor (N…X distances 29-32% shorter than the sum of van der Waals radii for NIS and 23-29% shorter for NBS). In both cases the more nucleophilic pyridine nitrogen atoms were better XB acceptors forming shorter bonds. The scattering of the datapoints was larger in the case of NBS indicating wider and more shallow potential well for XB with NBS, as confirmed computationally. The differences in the measured bond lengths were mirrored in the stability of the NIS-pyridine complexes in the solution - the stability constants were found to vary by over three orders of magnitude from logK = 4.003(9) for the complex exhibiting the shortest XB to logK = 0.825(3) for the one with the longest bond. In comparisson, S was found to produce hydrogen-bonded cocrystals only with the two strongest nucleophiles used, and the corresponding stability constants were nearly four orders of magnitude lower than those for halogen bonded complexes with NIS.