Mohammed G. Sarwar

Thermodynamics of halogen bonding in solution: substituent, structural, and solvent effects.

A detailed study of the thermodynamics of the halogen-bonding interaction in organic solution is presented. (19)F NMR titrations are used to determine association constants for the interactions of a variety of Lewis bases with fluorinated iodoalkanes and iodoarenes. Linear free energy relationships for the halogen bond donor ability of substituted iodoperfluoroarenes XC(6)F(4)I are described, demonstrating that both substituent constants (sigma) and calculated molecular electrostatic potential surfaces are useful for constructing such relationships. An electrostatic model is, however, limited in its ability to provide correlation with a more comprehensive data set in which both halogen bond donor and acceptor abilities are varied: the ability of computationally derived binding energies to accurately model such data is elucidated. Solvent effects also reveal limitations of a purely electrostatic depiction of halogen bonding and point to important differences between halogen bonding and hydrogen bonding.

A Tridentate Halogen-Bonding Receptor for Tight Binding of Halide Anions†

The selective recognition of anions by synthetic receptors is a problem that continues to fascinate chemists. Hydrogen bonding has been the most frequently employed noncovalent interaction for the design of such receptors: molecular scaffolds that place H-bond donor groups in geometries suitable for an anion of interest demonstrate remarkable levels of selectivity and affinity. Nonetheless, anion receptors that rely upon other noncovalent forces, including Lewis acid–base and anion–p interactions, have been investigated, with considerable success. Such studies have provided insight into the interactions employed, and have offered new opportunities to achieve selectivity in anion recognition. Here, we describe simple receptors capable of tight binding of halide anions through multidentate halogen bonding interactions (Figure 1). These represent the first systems in which the cooperative action of multiple halogen-bond donors is employed to achieve high-affinity binding in dilute solution. The selectivities of these receptors differ substantially from those of related receptors based on hydrogen bonding. Although halogen bonds between electron-deficient organohalides and electron donors were observed decades ago, it is only recently that the generality and utility of this noncovalent interaction have gained widespread appreciation. Halogen bonding has now been established as a powerful strategy for self-assembly in condensed phases, and its implications in biological systems are emerging. Anions, particularly halides, participate readily as halogen-bond acceptors in the solid state, including examples of crystalline networks in which a single anion accepts multiple halogen bonds. This last observation suggests that a multidentate halogen-bond donor capable of donating several halogen bonds in a convergent fashion might be capable of anion binding in dilute solution. Designing such a receptor presented a challenge. Applications of halogen bonding in self-assembly have relied extensively on para-substituted iodotetrafluorobenzene derivatives prepared by nucleophilic aromatic substitution (for example, 2a). This strategy results in divergent arrays of halogen-bond donors useful for constructing noncovalent polymers as well as twoand three-dimensional networks. In contrast, it is poorly suited for orienting multiple donors in a convergent fashion for binding to a single acceptor as is generally required of a high-affinity host. 2] The most successful example of anion binding by a halogen-bond donor achieved to date makes use of ion-pair recognition: receptor 2 a shows a 20-fold higher affinity for sodium iodide than does control receptor 2 b, indicating a modest but measurable increase in affinity resulting from halogen bonding of iodide to the iodoarene groups (Figure 1). We chose to explore ortho-substituted iodoperfluoroarenes as the basis for receptors capable of multidentate halogen bonding. Esters of 2,3,4,5-tetrafluoro-6-iodobenzoic acid (which is easily prepared on multigram scale in one step) emerged as attractive targets (1a–1d, Figure 1): we anticipated that the electron-withdrawing carboxy group would promote halogen-bond donor ability, while enabling a straightforward receptor synthesis through coupling reactions of readily available diols and triols. Receptors 1b and 1c were prepared to test the feasibility of bidentate halogen Figure 1. Structures of the multivalent halogen-bond donors 1a–1d, and the ion-pair receptor 2a of Resnati and co-workers (Ref. [11a]).

Amplified Halogen Bonding in a Small Space

Weak, intermolecular forces are difficult to observe in solution because the molecular encounters are random, short-lived, and overwhelmed by the solvent. In confined spaces such as capsules and the active sites of enzymes or receptors, the encounters are prolonged, prearranged, and isolated from the medium. We report here the application of encapsulation techniques to directly observe halogen bonding. The small volume of the capsule amplifies the concentrations of both donor and acceptor, while the shape of the space permits their proper alignment. The extended lifetime of the encapsulation complex allows the weak interaction to be observed and characterized by conventional NMR methods under conditions in which the interaction would be negligible in bulk solvent.

Halogen bonding and π–π interactions in the solid-state structure of a butadiynylene-linked bis(iodoperfluoroarene)

The solid-state structures of a butadiynylene-linked bidentate halogen bond donor, both as a single component and as a co-crystal with tetra-n-butylammonium iodide, are discussed. Solution-phase binding data indicate that this donor, which possesses only a single degree of conformational freedom, interacts with halides in a 1 : 1 stoichiometry through a convergent binding mode. In contrast, it forms a zigzag-type chain with iodide in the solid state. The X-ray crystallographic data enable detailed studies of the changes in molecular structure and supramolecular organization that accompany the formation of a halogen-bonded network.

Inhibition of DNA Topoisomerase Type IIα (TOP2A) by Mitoxantrone and Its Halogenated Derivatives: A Combined Density Functional and Molecular Docking Study

In this study, mitoxantrone and its halogenated derivatives have been designed by density functional theory (DFT) to explore their structural and thermodynamical properties. The performance of these drugs was also evaluated to inhibit DNA topoisomerase type IIα (TOP2A) by molecular docking calculation. Noncovalent interactions play significant role in improving the performance of halogenated drugs. The combined quantum and molecular mechanics calculations revealed that CF3 containing drug shows better preference in inhibiting the TOP2A compared to other modified drugs.