Orientation Of Substituents Research Articles

Molecular and Crystal Structures of Some Bromocymantrenes

Crystals of mono- and dibromo as well as two isomeric tribromocymantrenes [Mn(C5H5-nBrn)(CO)2(PPh3)] (n = 1–3) were obtained and examined by X-ray diffraction. The degree of substitution has only minor influence on bond lengths and angles. However, the relative orientations of bromo substituents and PPh3 ligand as well as relative orientation of the cyclopentadienyl ring and the MnC2P tripod are sensitive to the number and position of bromines. All compounds show weak Br…O interactions, mostly combined with hydrogen bonds, while Br…Br interactions are unimportant. These interactions lead to sometimes complicated chain structures.Graphical In the crystal structures of the bromocymantrenes [Mn(C5H5-nBrn)(CO)2(PPh3)] (n = 1–3) a combination of H bonds and Br…O/Br…Br interactions leads to one-dimensional molecular chains or double-chains, which are not further connected in the other dimensions.

Electroreductive Decomplexation and Isomerism of Copper(II) Complexes with Cyclam Ligands for Medical Use

AbstractDetailed electrochemical study of copper(II) complexes of cyclam bearing two phosphonate (TE2P), phenolate (TE2PhOH) or carboxylate (TE2A) pendant arms (together with one cross‐bridged‐cyclam derivative cb‐TE2A) was performed using cyclic voltammetry (CV) and polarography. The electrochemical‐heterogeneous measurements were accompanied by UV‐vis spectra describing the situation in homogeneous phase. Reduction of complexes on mercury electrode in buffered aqueous solutions (pH 2–12) occurs generally as a two‐electron process of reductive decomposition. The formed Cu‐amalgam can be (e. g. during the anodic scan of CV) reoxidized to Cu(II) cation which undergoes re‐complexation resulting in the original complex. This process of a square diagram is manifold repeatable. The results also showed presence of several isomers differing in mutual orientation of substituents on cyclam nitrogen atoms. The primary “kinetic”, pentacoordinated isomers are irreversibly transformed to the stable, hexacoordinated “thermodynamic” ones upon heating. The development of isomerization process was followed electrochemically. The cross‐bridged cb‐TE2A derivative forms only one isomer which does not change even after heating. The higher stability of the complex manifests itself at pH>8 when the complex is reversibly reduced in one‐electron step, formally CuII/CuI, without decomposition.

Enhancing Giardicidal Activity and Aqueous Solubility through the Development of "RetroABZ", a Regioisomer of Albendazole: In Vitro, In Vivo, and In Silico Studies.

Parasitic diseases, including giardiasis caused by Giardia lamblia (G. lamblia), present a considerable global health burden. The limited effectiveness and adverse effects of current treatment options underscore the necessity for novel therapeutic compounds. In this study, we employed a rational design strategy to synthesize retroalbendazole (RetroABZ), aiming to address the limitations associated with albendazole, a commonly used drug for giardiasis treatment. RetroABZ exhibited enhanced in vitro activity against G. lamblia trophozoites, demonstrating nanomolar potency (IC50 = 83 nM), outperforming albendazole (189 nM). Moreover, our in vivo murine model of giardiasis displayed a strong correlation, supporting the efficacy of RetroABZ, which exhibited an eleven-fold increase in potency compared to albendazole, with median effective dose (ED50) values of 5 µg/kg and 55 µg/kg, respectively. A notable finding was RetroABZ's significantly improved water solubility (245.74 µg/mL), representing a 23-fold increase compared to albendazole, thereby offering potential opportunities for developing derivatives that effectively target invasive parasites. The molecular docking study revealed that RetroABZ displays an interaction profile with tubulin similar to albendazole, forming hydrogen bonds with Glu198 and Cys236 of the β-tubulin. Additionally, molecular dynamics studies demonstrated that RetroABZ has a greater number of hydrophobic interactions with the binding site in the β-tubulin, due to the orientation of the propylthio substituent. Consequently, RetroABZ exhibited a higher affinity compared to albendazole. Overall, our findings underscore RetroABZ's potential as a promising therapeutic candidate not only for giardiasis but also for other parasitic diseases.

Rapid Synthesis of Psychoplastogenic Tropane Alkaloids.

Tropane alkaloids are an important class of biologically active small molecules characterized by their 8-azabicyclo[3.2.1]octane core. Because of their numerous medicinal applications, microbial biosynthesis and a variety of chemical syntheses have been designed for individual family members. However, current approaches are not amenable to late-stage structural diversification at N8, C3, C6, or C7, positions that are critical for modulating the biological properties of these molecules. Here, we describe a general approach to the synthesis of tropane alkaloids and their analogues that relies on the construction of the 8-azabicyclo[3.2.1]octane core through aziridination of a cycloheptadiene intermediate, followed by vinyl aziridine rearrangement. Using this strategy, we synthesized six tropane alkaloids and several analogues in only 5-7 steps. Given that the tropane alkaloid scopolamine has been reported to promote structural neuroplasticity and produce antidepressant effects, we tested five tropane-containing compounds for their ability to promote dendritic spine growth in cultured cortical neurons. We found that the orientation of the C3 substituent may play a role in the psychoplastogenic effects of tropane alkaloids. Our work provides a robust platform for producing tropane analogs for future structure-activity relationship studies.

Synthesis of gold(I) diaminocarbene complexes by the addition of amines across coordinated isocyanoferrocene

Gold(I) acyclic diaminocarbene complexes of the [AuCl{C(NHFc)(NR2)}] type (Fc = ferrocenyl) were conveniently synthesized by a one-pot procedure. In this method, 1 equiv. of isocyanoferrocene (FcNC) and an excess of primary or secondary amines R2NH (dimethylamine, morpholine, methylamine, cyclohexylamine, and p-toluidine) are sequentially added to [AuCl(SMe2)] as a gold source in dichloromethane. The stepwise synthesis, in which [AuCl(FcNC)] is the isolated intermediate, worked equally well but generated lower overall yields due to compound loss during the two purification steps. The approach was further extended to synthesize the corresponding cationic biscarbene complexes [Au{C(NHFc)(NR2)}2]Cl simply by using 2 equiv. of FcNC during the “first” reaction step. The compounds form conformational isomers in solution that differ by the orientation of substituents at the carbene units. Based on DFT calculations, these isomers exhibit similar energies (energy difference ≤ 5 kcal mol–1). The crystal structures revealed symmetrical carbene units and the dominant role of the N-H⋅⋅⋅Cl interactions in the crystal assemblies in all cases, which also control the tendency for a particular conformation in the solid state.

Supramolecular Chirogenesis in a Sterically Hindered Porphyrin: A Critical Theoretical Analysis.

The determination of molecular stereochemistry and absolute configuration is an important part of modern chemistry, pharmacology, and biology. Electronic circular dichroism (ECD) spectroscopy is a widely used tool for chirality assignment, especially with porphyrin macrocycles employed as reporter chromophores. However, the mechanisms of induced ECD in porphyrin complexes are yet to be comprehensively rationalized. In this work, the ECD spectra of a sterically hindered hexa-cationic porphyrin with two camphorsulfonic acids in dichloromethane and chloroform were experimentally measured and computationally analyzed. The influence of geometric factors such as the position of chiral guest molecules, distortion of the porphyrin macrocycle, and orientation of aromatic and non-aromatic peripheral substituents on the ECD spectra was theoretically studied. Various potential pitfalls, such as a lack of significant conformations and accidental agreement of experimental and simulated spectra, are considered and discussed.

Structure, Optical and Magnetic Properties of Two Isomeric 2-Bromomethylpyridine Cu(II) Complexes [Cu(C6H9NBr)2(NO3)2] with Very Different Binding Motives.

Two isomeric 2-bromomethylpyridine Cu(II) complexes [Cu(C6H9NBr)2(NO3)2] with 2-bromo-5-methylpyridine (L1) and 2-bromo-4-methylpyridine (L2) were synthesized as air-stable blue materials in good yields. The crystal structures were different with [Cu(L1)2(NO3)2] (CuL1) crystallizing in the monoclinic space group P21/c, while the 4-methyl derivative CuL2 was solved and refined in triclinic P1¯. The orientation of the Br substituents in the molecular structure (anti (CuL1) vs. syn (CuL2) conformations) and the geometry around Cu(II) in an overall 4 + 2 distorted coordination was very different with two secondary (axially elongated) Cu-O bonds on each side of the CuN2O2 basal plane in CuL1 or both on one side in CuL2. The two Br substituents in CuL2 come quite close to the Cu(II) centers and to each other (Br⋯Br ~3.7 Å). Regardless of these differences, the thermal behavior (TG/DTA) of both materials is very similar with decomposition starting at around 160 °C and CuO as the final product. In contrast to this, FT-IR and Raman frequencies are markedly different for the two isomers and the UV-vis absorption spectra in solution show marked differences in the π-π* absorptions at 263 (CuL2) or 270 (CuL1) nm and in the ligand-to-metal charge transfer bands at around 320 nm which are pronounced for CuL1 with the higher symmetry at the Cu(II) center, but very weak for CuL2. The T-dependent susceptibility measurements also show very similar results (µeff = 1.98 µB for CuL1 and 2.00 µB for CuL2 and very small Curie-Weiss constants of about -1. The EPR spectra of both complexes show axial symmetry, very similar averaged g values of 2.123 and 2.125, respectively, and no hyper-fine splitting.

X-ray diffraction and theoretical study of molecular and crystal structure of new crystalline aryl- and alkyl-substituted N-(adamantan-1-yl)amides: Similarities and differences

The molecular structure and crystal packing of new aryl and alkyl N-(adamantan-1-yl)amides derivatives А1–А7 were analyzed, and their intermolecular interaction parameters were found using X-ray diffraction, topological analysis within Bader's theory of “Atoms in molecules”, PIXEL method, and Hirshfeld surface analysis. N–H…O and С–Н…О hydrogen bonds and numerous Н…Н contacts are formed in the crystals of adamantylamides А1–А7. The adamantylamide molecules A1–A7 form a С(4) supramolecular chain synthon via N–H…O hydrogen bonds. An acetamide oxygen atom in the crystals of A1, A3–A5, and A7 is involved into unsymmetrical bifurcated bonds, in which one component is N–H…O and the other one is С–Н…О. The contribution of the O…Н contacts to the Hirshfeld surface is higher for alkyl adamantylamides than that for the aryl derivatives, whereas the packing index is lower for the alkyl derivatives than that for aryl one. The position of an acetamide group relative to adamantane framework in all structures is fixed by C–H…O intramolecular hydrogen bonds. The stabilization energy of the molecular pairs apparently depends on orientation of substituents and the mutual orientation of molecules in the pair that create favorable conditions for numerous intermolecular interactions.

Polymorphic Phases of Supramolecular Liquid Crystal Complexes Laterally Substituted with Chlorine.

New supramolecular complexes, based on H-bonding interactions between 4-(pyridin-4-yl) azo-(2-chlorophenyl) 4-alkoxybenzoates (Bn) and 4-[(4-(n-hexyloxy)phenylimino)methyl]benzoic acid (A6), were prepared and their thermal and mesomorphic properties investigated via differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FT-IR) in order to confirm their H-bonding interactions. The mesophase behavior of each mixture was examined by DSC and polarized optical microscopy (POM). According to the findings of the study, in all of the designed mixtures, the introduction of laterally polar chlorine atom to the supramolecular complexes produces polymorphic compounds possessing smectic A, smectic C and nematic mesophases, in addition, all products have low melting transitions. Thermal stabilities of the associated phases depend on the position and orientation of the lateral polar Cl− atom as well as the length of terminal flexible alkoxy chain. Comparisons were made between the present lateral Cl− complexes and previously investigated laterally-neat complexes in order to investigate the impact of the addition, nature and orientation of polar substituent on the mesomorphic behavior. The investigations revealed that, the polarity and mesomeric nature of inserted lateral substituent into the base component play an essential role in affecting their mesomorphic properties. Furthermore, for current complexes, induced polymorphic phases have been found by introducing the chlorine atom.

Chirogenesis in Zinc Porphyrins: Theoretical Evaluation of Electronic Transitions, Controlling Structural Factors and Axial Ligation.

In the present work, sixteen different zinc porphyrins (possessing different meso substituents) with and without a chiral guest were modelled using DFT and TD‐DFT approaches in order to understand the influence of various controlling factors on electronic circular dichroism (ECD) spectra. Two major aspects are influenced by these factors: excitation energy of the electronic transitions and their intensity. In the case of excitation energy, the influence increases in the following order: orientation of the peripheral substituents<substituent's nature<axial ligation. However, the deformation of the porphyrin plane does not affect the excitation energies. In the case of intensity, the influence increases as follows: substituent's nature<conrotatory orientation of the peripheral substituents<deformation of the porphyrin plane<disrotatory orientation of the peripheral substituents<axial ligation.

Control of Physicochemical Properties for Thiophene-Fused Naphthodiphospholes By Precise Fusion of Heterole Rings

Fused polycyclic aromatics have been vigorously pursued over the years because of their attracting structural, electronic, and photophysical features associated with the rigid and planar π-conjugated frameworks. For polycyclic aromatics with heterole-fused structures, the orientation of fused heterole rings as well as the geometry of their fused structures has a large impact on the physicochemical properties. In this regard, we expected that introducing two phosphorus atoms into polycyclic aromatics would provide an assortment of isomers originated from not only the position and orientation of the phosphole rings, but also the orientation of substituents on the phosphorus atoms (trans/cis configurations). Herein, we designed and synthesized a series of six isomers of thiophene-fused naphthodiphospholes based on our envision. Systematic investigations into the physicochemical properties revealed that the positions of heterole rings are of utmost importance to tune their electronic properties, and the orientations of heterole rings and substituents on the phosphorus atoms play critical roles in the molecular arrangements in the solid states.

Polarity Matters: Dielectric Relaxation in All-cis-Multifluorinated Cycloalkanes.

The polarity of all-cis-multifluorinated cyclohexanes can be fine-tuned by the number and relative orientation of fluoro substituents, giving rise to a series of compounds with strong dipole moments. Simulations provided the energetics, the dipole moments, and the respective molecular polarizabilities, while dielectric spectroscopy gave information on the dielectric permittivities and the molecular dynamics. In special cases, dipole moments in excess of 6 D and dielectric permittivities of over 300 were obtained by simulation and experiment. Melting temperatures within a given family of multifluorinated cyclohexanes were found to scale with the molecular volume. The less-symmetric all-cis-octafluorotetrahydronaphthalene did not readily crystallize, permitting an investigation of the molecular dynamics in an energetically unfavorable yet rigid and facially polarized isomer. The resulting dynamics above the glass temperature conform to the structural α-relaxation and to the celebrated Johari-Goldstein β-relaxation.

Understanding Ring Puckering in Small Molecules and Cyclic Peptides.

The geometry of a molecule plays a significant role in determining its physical and chemical properties. Despite its importance, there are relatively few studies on ring puckering and conformations, often focused on small cycloalkanes, 5- and 6-membered carbohydrate rings, and specific macrocycle families. We lack a general understanding of the puckering preferences of medium-sized rings and macrocycles. To address this, we provide an extensive conformational analysis of a diverse set of rings. We used Cremer–Pople puckering coordinates to study the trends of the ring conformation across a set of 140 000 diverse small molecules, including small rings, macrocycles, and cyclic peptides. By standardizing using key atoms, we show that the ring conformations can be classified into relatively few conformational clusters, based on their canonical forms. The number of such canonical clusters increases slowly with ring size. Ring puckering motions, especially pseudo-rotations, are generally restricted and differ between clusters. More importantly, we propose models to map puckering preferences to torsion space, which allows us to understand the inter-related changes in torsion angles during pseudo-rotation and other puckering motions. Beyond ring puckers, our models also explain the change in substituent orientation upon puckering. We also present a novel knowledge-based sampling method using the puckering preferences and coupled substituent motion to generate ring conformations efficiently. In summary, this work provides an improved understanding of general ring puckering preferences, which will in turn accelerate the identification of low-energy ring conformations for applications from polymeric materials to drug binding.

Halogenation of N′-(Arenesulfonyl)-N-[2,6(3,5)-dialkyl-4-oxocyclohexa-2,5-dien-1-ylidene]benzenecarboximidamides and Their Reduction Products

Halogenation of N′-(arenesulfonyl)-N-[2,6(3,5)-dialkyl-4-oxocyclohexa-2,5-dien-1-ylidene]benzenecarboximidamides and their reduction products gave derivatives containing up to four halogen atoms. The degree of halogenation can be controlled by variation of the reaction conditions only in the reactions with 2,6(3,5)dimethyl derivatives. The maximum number of halogen atoms were introduced into 2,6(3,5)-dimethyl- and 3,5-diisopropyl-substituted substrates. The presence of bulky tert-butyl groups in the quinoid ring significantly reduced the degree of halogenation, and halogen molecule added to only one C=C double bond of the quinoid ring. The axial orientation of alkyl substituents in the cyclohexene products suggests syn addition of halogens to the C=C double bond of the quinoid ring.

Computational investigations, Hirshfeld surface analysis, interaction energy calculations, and energy framework crystal structure of methyl 2-amino-5-hydroxybenzoate

The title compound with the molecular formula C8H9NO3 is synthesized by refluxing 2-amino-5-hydroxybenzoic acid in methanol. The molecular structure of the compound is determined by single crystal X-ray diffraction. Methyl 2-amino-5-hydroxybenzoate crystallizes in the orthorhombic space group P212121 with a = 4.973(2) Å, b = 10.923(5) Å, c = 14.074(6) Å, Z = 4 and V = 764.4(6) Å3. DFT is used to compute HOMO—LUMO energy levels, to predict the reactivity of substituents (NH2 and OH), and to determine the nucleophilic character of these two groups. The orientation and nature of substituents on benzene favors the formation of a stable six-membered ring via hydrogen bonding which plays a key role in the properties of the investigated compound. The natural bond orbital (NBO) population analysis demonstrates that the hyperconjugative effect between the donor lone pairs located on the carbonyl oxygen atom and the N—H group, via the lp O → σ*(N—H) 1,6-remote interaction, is responsible for the preferred conformation. The molecular electrostatic potential (MEP) surface shows the electrical neutrality in the molecule. To get an insight to the intermolecular interactions in the crystal a Hirshfeld surface analysis is also carried out.

Structure-activity relationship of novel acridone derivatives as antiproliferative agents

Unlike other DNA topoisomerase II (topo II) inhibitors, our recently identified acridone derivative E17 exerted strong cytotoxic activity by inhibiting topo II without causing topo II degradation and DNA damage, which promoted us to explore more analogues of E17 by expanding its chemical diversification and enrich the structure–activity relationship (SAR) outcomes of acridone-oriented chemotypes. To achieve this goal, 42 novel acridone derivatives were synthesized and evaluated for their antiproliferative efficacies. SAR investigations revealed that orientation and spatial topology of R3 substituents make greater contributions to the bioactivity, exemplified by compounds E24, E25 and E27, which has provided valuable information for guiding further development of acridone derivatives as promising drug candidates.

SYNTHESIS, CRYSTAL STRUCTURE, AND STABILITY OF N-LUPINYLPHTHALIMIDE CONFORMERS

As a result of studying the interaction of chlorolupinine with potassium phthalimide, the optimal synthesis conditions for N-lupinylphthalimide by the Gabriel method are identified. The crystal structure of N-lupinylphthalimide is determined for the first time by single crystal XRD. The energy characteristics are calculated using the quantum chemical method. It is found that the conformer with the chair conformation of the cycles with the axial orientation of the phthalimide substituent is more stable than that with the equatorial orientation.

Conformational preferences of fluorine-containing agrochemicals and their implications for lipophilicity prediction

Molecular polarity governs lipophilicity, which in turn determines important agrochemical and environmental properties, such as soil sorption and bioconcentration of organic compounds. Since the C–F bond is the most polar in organic chemistry, the orientation of fluorine substituents originating from the rotation around C–C(F) bonds should affect the polarity and, consequently, the physicochemical and biological properties of fluorine-containing agrochemicals. Accordingly, this study aims to determine the most likely conformers of some fluorine-containing agrochemicals and to correlate their molecular dipole moments with the respective n-octanol/water partition coefficients (log P), in order to investigate the dependence of the lipophilicity with the molecular conformation.

Synthesis, spectral characterization, solution and solid-state conformations of N-nitroso-2,7-diaryl-1,4-diazepan-5-ones by NMR and XRD studies

Nitroso derivative of 2,7-diaryl-1,4-diazepan-5-ones 9–12 are synthesized and characterized using spectroscopic techniques such as IR, EI-MS and NMR spectra. The stereochemical investigation of nitroso compounds has been carried out with 1D (1H, 13C & DEPT-135) and 2D (COSY & HSQC) NMR spectral data. Rotational isomers (syn and anti rotamers) of 9–12 are identified and categorized by room temperature NMR spectral studies. Furthermore, the conformation of the ring and the orientation of NN=O function have been arrived on the basis of chemical shifts, coupling constants and dihedral angles. In solution state, syn and anti rotamers of the compounds 9–11 exist in equilibrium between flattened boat conformation with quasi-axial orientations of the aryl groups at C-2 and C-7. Nevertheless, compound 12 and its syn and anti rotamers prefer to adopt equilibrium between chair conformations with axial orientation of aryl substituents. In order to validate the solution state conformation, the compound 12 is crystallized and the crystal structure is solved by single crystal XRD study. The compound 12 exists in an alternate chair conformation and aryl groups at C-2 & C-7 occupy axial orientations in solid state also.

Temperature-Dependent Blue Shifting of O-H Stretching Frequencies in Crystalline Cellulose Explained.

Increasing the temperature of a chemical system generally causes covalent bonds to lengthen and weaken, often the first step in initiating chemical reactions. However, for some hydrogen-bonded systems, infrared (IR) spectroscopy measurements reveal that covalent O-H bonds actually strengthen and therefore shorten when heated. In 1957, Finch and Lippincott proposed a simple one-dimensional (1D) model to explain this effect, in which thermal excitation of intermolecular stretching modes leads to lengthening and weakening of intermolecular O-H···O hydrogen bonds, thereby indirectly strengthening the associated covalent O-H bonds. Taking cellulose (an infinitely repeating polymer of d-glucose) as an example, we use molecular dynamics modeling to show that the same mechanism is responsible for temperature-dependent blue shifting of O-H stretching bands in IR spectra of carbohydrate biopolymers, except that interchain hydrogen bonds are weakened by thermal excitation of chain-separation modes, while intrachain hydrogen bonds are weakened by thermally induced changes in ring puckering and orientation of ring substituents but not reorientation of glucose units relative to one another or overall twisting of the cellulose chains.