A quantitative assessment of the substituent, hybridization, and crystal-packing effects on the electronic, structural, and vibrational properties of halogen bonded systems is presented. Through a combined experimental and theoretical approach employing Raman spectroscopy, X-ray crystallography, and density functional theory, a series of solid-state iodobenzene and iodoethynylbenzene derivatives substituted with electron withdrawing groups (-F 2 , -(CF 3 ) 2 , -F 5 , and -(NO 2 ) 2 ) and their complexes with two pyridine-based building blocks are characterized. Structural analysis via X-ray crystallography and density functional theory computations suggests that these 1:1 molecular assemblies are not only driven by halogen bonding, but also by other energetically competitive noncovalent interactions, such as π-stacking. The magnitude of the σ-hole localized around the C−I bond in the isolated halogen bond (XB) donors and the interaction strength in the complexes unambiguously depend on the nature of the substituents on the donors and the hybridization of the carbon atom in the C−I bond. However, the vibrational C−I stretching frequency in the halogen bond donors and/or the change in that frequency accompanying XB formation are not solely controlled by those two effects, but also by the coupling between the C−I stretch and other modes associated with the substituents on the donors and the presence of various energetically competitive non-XB contacts in the solid cocrystals. In turn, this study highlights the importance of conducting a comprehensive electronic and structural analysis of not only the halogen bond but also other interactions present in the surrounding solid-state environment.
Two
graphitic carbon nitride (g-C3N4) molecular building blocks designed for halogen bond driven
assembly are evaluated through computational quantum chemistry. Unlike
those typically reported in the literature, these g-C3N4-based acceptors each offer three unique
sites for halogen bond formation, which when introduced to their donor
counterparts, lead to 1:1, 2:1, and 3:1 donor–acceptor complexes.
Although halogen bonding interactions are present in all donor–acceptor
complexes considered in the work, intermolecular hydrogen bonding
emerges in complexes in which an iodine-based donor is directly involved.
The halogen bond complexes identified herein feature linear halogen
bonds and supportive intermolecular hydrogen bonds that lead to nearly
additive electronic binding energies of up to −9.7 (dimers),
−18.6 (trimers), and −26.5 kcal mol–1 (tetramers). Select vibrational stretching frequencies (νC–X and νCC), and the perturbative
shifts they incur upon halogen bond formation, are interrogated and
compared to those observed in pyridine- and pyrimidine-based halogen-bonded
complexes reported in the literature.
The effects of intermolecular interactions by a series of haloaromatic halogen bond donors on the normal modes and chemical shifts of the acceptor pyrimidine are investigated by Raman and NMR spectroscopies and electronic structure computations. Halogen-bond interactions with pyrimidine's nitrogen atoms shift normal modes to higher energy and upfield shift H and C NMR peaks in adjacent nuclei. This perturbation of vibrational normal modes is reminiscent of the effects of hydrogen bonded networks of water, methanol, or silver on pyrimidine. The unexpected observation of vibrational red shifts and downfield C NMR shifts in some complexes suggests that other intermolecular forces such as π interactions are competing with halogen bonding. Natural bond orbital analyses indicate a wide range of charge transfer is possible from pyrimidine to different haloaromatic donors and computed halogen bond binding energies can be larger than a typical hydrogen bond. These results emphasize the importance in strategic selection of substituents and electron withdrawing groups in developing supramolecular structures based on halogen bonding.
Tak-242 (resatorvid),
a Toll-like Receptor 4 (TLR4) inhibitor,
has been identified as a potent suppressor of innate inflammation.
As a strategy to target Tak-242 to select tissue, four TLR4-inactive
prodrugs were synthesized for activation via two different release
mechanisms. Two nitrobenzyl Tak-242 prodrugs released the parent drug
upon exposure to the exogenous enzyme nitroreductase, while the two
propargyl prodrugs were converted to Tak-242 in the presence of Pd0.
One co-crystal structure characterized to identify and quantify various non-covalent interactions with spectroscopy, X-ray crystallography and density functional theory computations.
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