Location Of Substituents Research Articles

Effect of substituent position on assembly of compounds bearing ortho/para over meta directing groups

This research investigated the impact of substituent location on intermolecular interactions and crystal packing. A class of N-(dichlorophenyl)-2-pyrazincarboxamide derivatives were synthesized and characterized: 2,5-dichloro (2,5-diCl), 3,4-dichloro (3,4-diCl), and 2,4-dichloro (2,4-diCl). Comparison with their monochloro counterparts (2-chloro (2-Cl), 3-chloro (3-Cl), and 4-chloro (4-Cl)) revealed a distinct structural variation upon introducing a second chlorine substituent at the ortho/para positions of the phenyl ring. Conversely, incorporating a second chlorine atom at the meta position resulted in similar molecular packing. These findings suggest that ortho/para directing groups play a dominant role in dictating the crystal assemblies of the studied compounds.

Quamtum Mechanical Study on Structural and Electronic Properties of Tert-Butyl Based Bridged Dithiophene Oxide Derivatives

Computational modeling is vital to designing and creating organic semiconductors used in solar cells, organic field-effect transistors, and other areas. This work studied the structural and electronic features of a group of substituted tert-butyl bridged dithiophene oxide derivatives using Density Functional Theory (DFT) calculations. Geometry improvements were carried out using the B3LYP hybrid functional and the 6-31G(d,p) basis set in Gaussian 09. Molecular shapes, bond lengths, bond angles, and dihedral angles were studied to find out how substitution patterns change the packing and conformation of molecules. Energy levels, distribution, and makeup of frontier molecular orbitals were found. This calculation also included finding other electronic qualities, such as electronic charges, dipole moments, and polarizabilities. Findings show that tert-butyl substitution makes the molecular backbone stiffer and limits its ability to twist compared to similar molecules that have not been replaced. The chemical geometry stays mostly the same when electron-withdrawing or electron-donating substituents are added to the tert- butyl groups. Nevertheless, the strength and location of substituents have a significant impact on frontier orbital energies. The HOMO-LUMO gap grew significantly when the nitro or cyano groups firmly pulled electrons away from derivatives. For successful charge transport, electron density plots show that the HOMO and LUMO are mainly located on the thiophene and substituent moieties, respectively. Molecular dipole moments are also strongly affected by the electronic features of substituents. This research shows how to change the optoelectronic properties of tert-butyl-based dithiophene oxide derivatives and how their structure-property relationships can be improved. The results help makes new organic semiconductors that work better in various electronic and optoelectronic uses.

In-Depth Understanding of the Effect of the Distribution of Substituents on the Morphology and Physical Properties of Ethylcellulose: Molecular Dynamics Simulations Insights.

Ethylcellulose (EC) is a crucial cellulose derivative with widespread applications, particularly in the pharmaceutical industry, where precise property adjustments through chemical modification are imperative. The degree of substitution (DS) and the localization of substituents along the cellulose chains are pivotal factors in this process. However, the impact of the substituent location within the repeating unit of EC remains unexplored. To address this gap, we conducted molecular dynamics simulations on amorphous EC, comparing randomly and uniformly substituted ethyl groups in the repeating units. This comprehensive study of pairwise interactions revealed significant differences in intramolecular and intermolecular hydrogen-bonding capabilities, depending on whether the hydroxyl groups were substituted at C2, C3, or C6. While our simulations demonstrated that substituent localization in the repeating unit influenced the density, number of hydrogen bonds, and conformations, the DS emerged as the dominant determinant. This insight led us to propose and validate a hypothesis: a straightforward linear function using the properties of uniform models and molar fractions can predict the properties of randomly substituted EC with a given DS. This innovative approach is anticipated to contribute to the selection of cellulose derivatives with desirable properties for the pharmaceutical industry and new applications in other fields.

CARBOXYLATION OF HYDROXYARENES WITH POTASSIUM SALTS OF ALKYLCARBONIC ACID

In this article it was demonstrated that potassium ethyl carbonate can be successfully utilized within the phenol and its derivatives carboxylation. The optimal reaction conditions for m-cresol were determined: substrate to potassium ethyl carbonate ratio 2:1, temperature 180°C, pressure 10 atmospheres and reaction time 6 hours. Importantly, the carboxylation of m-cresol is selective and resulted in the obtaining of 4-methyl-2-hydroxybenzoic acid in 90% yield.To study the impact of the nature and location of substituents in the phenyl ring on the yield of the desired products, carboxylation reactions of various phenol derivatives were carried out with the use of potassium ethyl carbonate. As a result of the investigation, the optimal carboxylation reaction parameters for each of the phenol derivatives were determined.This study may have practical applications in the development of laboratory and manufacturing approaches for the synthesizing of valuable hydroxybenzoic acids and their derivatives. It was discovered that carboxylation of phenol derivatives by potassium ethyl carbonate occurs via electrophilic substitution of the aromatic ring. The most active in this reaction are p-cresol (84%), mcresol (90%), o-cresol (80%) and resorcinol (73%). It was observed that p-chlorophenol (18%), pbromophenol (48%) and p-fluorophenol (58%) showed less pronounced activity.

Oligo-Condensation Reactions of Silanediols with Conservation of Solid-State-Structural Features.

Oligo- and polysiloxanes are usually prepared by condensation reactions in solvents without control of stereochemistry. Here we present a solventless thermal condensation of stable organosilanols. We investigated the condensation reactions of organosilanediols with different organic substituents, having in common at least one aromatic group. The condensation kinetics of the precursors observed by NMR spectroscopy revealed a strong dependence on temperature, time, and substitution pattern at the silicon atom. SEC measurements showed that chain length increases with increasing condensation temperature and time and lower steric demand of the substituents, which also influences the glass transition temperatures (Tg) of the resulting oligo- or polymers. X-ray diffraction studies of the crystalline silanediols and their condensation products revealed a structural correlation between the substituent location in the crystalline precursors and the formed macromolecules induced by the hydrogen bonding pattern. In certain cases, it is possible to carry out topotactic polymerization in the solid-state, which has its origin in the crystal structure.

Furanocoumarins as Enhancers of Antitumor Potential of Sorafenib and LY294002 toward Human Glioma Cells In Vitro.

Furanocoumarins are naturally occurring compounds in the plant world, characterized by low molecular weight, simple chemical structure, and high solubility in most organic solvents. Additionally, they have a broad spectrum of activity, and their properties depend on the location and type of attached substituents. Therefore, the aim of our study was to investigate the anticancer activity of furanocoumarins (imperatorin, isoimperatorin, bergapten, and xanthotoxin) in relation to human glioblastoma multiforme (T98G) and anaplastic astrocytoma (MOGGCCM) cell lines. The tested compounds were used for the first time in combination with LY294002 (PI3K inhibitor) and sorafenib (Raf inhibitor). Apoptosis, autophagy, and necrosis were identified microscopically after straining with Hoechst 33342, acridine orange, and propidium iodide, respectively. The levels of caspase 3 and Beclin 1 were estimated by immunoblotting and for the blocking of Raf and PI3K kinases, the transfection with specific siRNA was used. The scratch test was used to assess the migration potential of glioma cells. Our studies showed that the anticancer activity of furanocoumarins strictly depended on the presence, type, and location of substituents. The obtained results suggest that achieving higher pro-apoptotic activity is determined by the presence of an isoprenyl moiety at the C8 position of the coumarin skeleton. In both anaplastic astrocytoma and glioblastoma, imperatorin was the most effective in induction apoptosis. Furthermore, the usage of imperatorin, alone and in combination with sorafenib or LY294002, decreased the migratory potential of MOGGCCM and T98G cells.

SYNTHESIS AND PROPERTIES OF PERIPHERALLY AND NONPERIPHERALLY SUBSTITUTED ZINC AND MAGNESIUM PHTHALOCYANINES BASED ON 3/4-(4-BROMO-2-((4-METHOXYPHENYL)DIAZENYL)PHENOXY)PHTHALONITRILE

The work describes the optimization of the procedure for the synthesis of 4-bromo-2-methoxyphenyldiazenylphenol, which is used as a nucleophile in the presence of 3- and 4-nitrophthalonitriles. The resulting 3-(4-bromo-2-((4-methoxyphenyl)diazenyl)phenoxy)- and 4-(4-bromo-2-((4-methoxyphenyl)diazenyl)phenoxy)phthalonitriles were used for template condensation with magnesium or zinc acetate. Methods for isolating and purifying the synthesized compounds are described. The structure and composition were confirmed using IR, 1H NMR and electron spectroscopy. Peripheral functionalization of macrocycle by a conjugate azochromophore fragment gives molecules phthalocyanine with special optical properties. This class of phthalocyanines containing an additional chromophore system in their composition is attractive for potential use not only as pigments and dyes traditional for phthalocyanine compounds, but also as chemical sensors, dye-sensitized solar cells and photosensitizers for PDT. The resulting nitriles and phthalocyanine complexes dissolve in chloroforms, toluene, THF, and DMF. The influence of the substituent location on the spectral properties of the obtained metal complexes (Zn, Mg) in organic solvents has been studied. For non-peripherally substituted metal phthalocyanines, acid-base properties are studied. To observe and study the acid-base effect, spectrophotometric titration of the trifluoroacetic acid complex in toluene is used. It is shown that the magnesium complex is more basic than the zinc complex. In this work, the luminescent properties are also studied and the quantum yields of singlet oxygen formation for synthesized complexes in THF are determined. The influence of the substituent location on the quantum yield of fluorescence, as well as on the generation of singlet oxygen, is noted in the work.

DFT based predictive model for BODIPY triplet quantum yields

Triplet photosensitizers have been developed for use in a variety of applications such as photodynamic therapy, photocatalysis, and organic LEDs. All of these require a high triplet excited-state quantum yield, which is often measured as the singlet oxygen quantum yield (ФΔ). A common method to increase ФΔ is through the heavy-atom-effect achieved by the addition of heavy-atoms to the chromophore – such as the heavy halogens bromine and iodine. Previously, our group developed an empirical model using DFT to predict the ФΔ of heavy-atom containing chromophores. The model correlates a natural atomic orbital composition calculation of the heavy-atoms to the ФΔ of a chromophore. Herein, we modify the original model to apply specifically to halogenated boron dipyrromethene (BODIPY) dyes. In addition to developing a method to predict how changes in the structure of BODIPY dyes affects the ФΔ, this model provides insight into why different structural changes have differing impacts to the ФΔ. The BODIPY core has several unique substitution positions that can be halogenated; however, the model indicates that the 2- and 6-positions on BODIPY (IUPAC numbering) have the greatest impact on the ФΔ with yields changing from 0.00 to 0.90 when replacing the two protons with iodides. Although the original model made using xanthene type dyes provided reasonably good agreement with BODIPY dyes, the new reparametrized model allows for more accurate prediction of the ФΔ of BODIPY type chromophores and provides insight in the importance of substituent location to guide future chromophore design.

TMSCF3-Mediated Conversion of Salicylates into α,α-Difluoro-3-coumaranones: Chain Kinetics, Anion-Speciation, and Mechanism.

As reported by Zhao, the TBAT ([Ph3SiF2]-[Bu4N]+)-initiated reaction of ethyl salicylate with TMSCF3 in THF generates α,α-difluoro-3-coumaranones via the corresponding O-silylated ethoxy ketals. The mechanism has been investigated by in situ 19F and 29Si NMR spectroscopy, CF2-trapping, competition, titration, and comparison of the kinetics with the 3-, 4-, 5-, and 6-fluoro ethyl salicylate analogues and their O-silylated derivatives. The process evolves in five distinct stages, each arising from a discrete array of anion speciations that modulate a sequence of silyl-transfer chain reactions. The deconvolution of coupled equilibria between salicylate, [CF3]-, and siliconate [Me3Si(CF3)2]- anions allowed the development of a kinetic model that accounts for the first three stages. The model provides valuable practical insights. For example, it explains how the initial concentrations of the TMSCF3 and salicylate and the location of electron-withdrawing salicylate ring substituents profoundly impact the overall viability of the process, how stoichiometric CF3H generation can be bypassed by using the O-silylated salicylate, and how the very slow liberation of the α,α-difluoro-3-coumaranone can be rapidly accelerated by evaporative or aqueous workup.

On-surface Ullmann coupling of halo-derivatives of arenes: Monte Carlo simulations for tetracene

On-surface synthesis of C–C covalent low-dimensional nanomaterials is a promising method of obtaining structures with tailored and novel physicochemical and electric properties. In this contribution, the Monte Carlo simulation approach was proposed to predict the topology of metal–organic (MO) intermediates formed in the Ullmann homocoupling of halogenated isomers of tetracene. The coarse-grained model of polyaromatic hydrocarbons (PAH) haloderivatives and divalent copper adatoms on a metallic crystal surface (111) was used, where locations of substituents in the molecules were encoded as active centres with directional C–Cu interactions. The computations were performed for various structural isomers of tetracene, from disubstituted to tetrasubstituted units. As a result, diverse superstructures were obtained, such as dimers, trimers, and other oligomers, chains and ladders, and metal–organic (MO) networks, both chiral and achiral. Additionally, for the prochiral linkers, simulations of the racemic mixtures were performed. Our study provided useful insight into the influence of substituents’ position and the carbon backbone’s size on the topology of the modelled precursor architectures.

Substituent Effects on Torsional Strain in Cyclopentene Derivatives: A Computational Study.

Density functional theory calculations were used to create a library of ring strain energies (RSEs) for 73 cyclopentene derivatives with potential use as monomers for ring-opening metathesis polymerization (ROMP). An overarching goal was to probe how substituent choice may influence torsional strain, which is the driving force for ROMP and one of the most understudied types of RSEs. Potential trends investigated include substituent location, size, electronegativity, hybridization, and steric bulk. Using traditional and recently developed homodesmotic equations, our results show that the size and substitution (bulk) of the atom directly bonded to the ring have the greatest influence on torsional RSE. A complex interplay between bond length, bond angle, and dihedral angle dictates the relative eclipsed conformations between the substituent and its neighboring hydrogens and was found to be responsible for the notable differences in RSEs. Furthermore, substituents placed on the homoallylic position resulted in higher RSEs than the same substituent placed on the allylic position due to increased eclipsing interactions. Different levels of theory were also assessed, and it was determined that consideration of electron correlation in calculations increased RSEs by ∼2-5 kcal mol-1. Further increasing the level of theory did not significantly change RSEs, indicating that the increased computational cost and time may not be necessary for improved accuracy.

Phosphonomethylated acetoxymethyl derivatives of acetylfurans and alkyl furoates with the remote location of substituents: synthesis and further transformations

Methods of synthesis of phosphonomethylated acetoxymethyl derivatives of acetylfurans and alkyl furoates with the remote location of functional groups were developed. Investigation of methanolysis of these compounds in presence of sodium methylate showed that complete transesterification of acetates is achived when the equimolar amount of base is used. It takes place due to high acidity of furan alcohols. If acetoxymethyl group is located in the position 3 of the furan ring, and diethoxyphosphorylmethyl one - in the position 2, cleavage of P-C bond takes place. If phosphonomethyl group is located in the position 3, and acetoxymethyl one occupies position 2 or 4, transesterification of ester groups of phosphonate takes place, but P-C bond is not touched. The ester group of carbonic acid is transesterified in any case. The alcohols formed are oxidized according to Kollins to give the corresponding aldehydes. 2-Furylbenzo[ d ]thiazole having ester and diethoxyphosphorylmethyl groups in the furan ring was synthesized by reacting methyl 2-(diethoxyphosphorylmethyl)-5-formylfuran-3-carboxylate with 2-aminothiophenol.

Phosphonomethylated Acetoxymethyl Derivatives of Acetylfurans and Alkyl Furoates with the Remote Location of Substituents: Synthesis and Further Transformations

Phosphonomethylated Acetoxymethyl Derivatives of Acetylfurans and Alkyl Furoates with the Remote Location of Substituents: Synthesis and Further Transformations

Effect of Substituent Location on the Relationship between the Transition Dipole Moments, Difference Static Dipole, and Hydrophobicity in Squaraine Dyes for Quantum Information Devices.

Aggregates of organic dyes that exhibit excitonic coupling have a wide array of applications, including medical imaging, organic photovoltaics, and quantum information devices. The optical properties of a dye monomer, as a basis of dye aggregate, can be modified to strengthen excitonic coupling. Squaraine (SQ) dyes are attractive for those applications due to their strong absorbance peak in the visible range. While the effects of substituent types on the optical properties of SQ dyes have been previously examined, the effects of various substituent locations have not yet been investigated. In this study, density functional theory (DFT) and time-dependent density functional theory (TD-DFT) were used to investigate the relationships between SQ substituent location and several key properties of the performance of dye aggregate systems, namely, difference static dipole (Δd), transition dipole moment (μ), hydrophobicity, and the angle (θ) between Δd and μ. We found that attaching substituents along the long axis of the dye could increase μ while placement off the long axis was shown to increase Δd and reduce θ. The reduction in θ is largely due to a change in the direction of Δd as the direction of μ is not significantly affected by substituent position. Hydrophobicity decreases when electron-donating substituents are located close to the nitrogen of the indolenine ring. These results provide insight into the structure-property relationships of SQ dyes and guide the design of dye monomers for aggregate systems with desired properties and performance.

Phosphonomethylated Acetoxymethyl Derivatives of Acetylfurans and Alkyl Furoates with Neighboring Location of Substituents: Synthesis and Following Transformations

Phosphonomethylated Acetoxymethyl Derivatives of Acetylfurans and Alkyl Furoates with Neighboring Location of Substituents: Synthesis and Following Transformations

Effect of Electron-Withdrawing Chlorine Substituent on Morphological and Photovoltaic Properties of All Chlorinated D-A-Type Quinoxaline-Based Polymers.

The choice of the chlorine (Cl) atom as an electron-withdrawing substituent in conjugated polymers leads to a higher potential in the commercialization of polymer solar cells than its fluorine counterpart because of the versatility and cost-effectiveness of the chlorination process. In addition, the population and location of Cl substituents can significantly influence the photovoltaic characteristics of polymers. In this study, three chlorinated quinoxaline-based polymers were invented to examine the numerical and positioning effects of the Cl atom on their photovoltaic characteristics. The number of Cl substituents in the reference polymer, PBCl-Qx, was adjusted to three: two Cl atoms in the benzodithiophene-type D unit and one Cl atom in the quinoxaline-type A unit. Subsequently, two more Cl atoms were selectively introduced at the 4- and 5-positions of the alkylated thiophene moieties at the 2,3-positions of the quinoxaline moiety in PBCl-Qx to obtain the additional polymers PBCl-Qx4Cl and PBCl-Qx5Cl, respectively. The conventional PBCl-Qx4Cl device exhibited a better power conversion efficiency (PCE) of 12.95% as compared to those of PBCl-Qx (12.44%) and PBCl-Qx5Cl (11.82%) devices. The highest PCE of the device with PBCl-Qx4Cl was ascribed to an enhancement in the open-circuit voltage and fill factor induced by the deeper energy level of the highest occupied molecular orbital and the favorable morphological features in its blended film with Y6.

Cytotoxic analogues of marine diterpenoid plumisclerin A by shifting the lipophilic branch on the characteristic tricyclic core.

Plumisclerin A is one of the most complex cytotoxic xenicane diterpenes from marine sources, featuring a unique congested and rigid tricyclo[4.3.1.01,5]decane core and a lipophilic acyl chain. This work explored a number of new analogues of plumisclerin A through modifying the characteristic tricyclo[4.3.1.01,5]decane core with lipophilic chains starting from a common lactone intermediate. Bioactivity examination of all the synthetic analogues shows that new analogues 2a, 18 and 21 exhibited comparable inhibitory potencies to that of the natural product against the proliferation of cancer cells. Structural comparison of these bioactive natural and unnatural compounds reveals that the location of lipophilic substituent(s) on the tricyclo[4.3.1.01,5]decane core is spatially flexible, and this work thus offers a new channel to diverse bioactive analogues of plumisclerin A.

Discovery Sulfoglycomics and Identification of the Characteristic Fragment Ions for High-Sensitivity Precise Mapping of Adult Zebrafish Brain-Specific Glycotopes.

Mass spectrometry–based high-sensitivity mapping of terminal glycotopes relies on diagnostic MS2 and/or MS3 ions that can differentiate linkage and define the location of substituents including sulfates. Unambiguous identification of adult zebrafish glycotopes is particularly challenging due to the presence of extra β4-galactosylation on the basic building block of Galβ1-4GlcNAc that can be fucosylated and variably sialylated by N-acetyl, N-glycolyl, or deaminated neuraminic acids. Building on previous groundwork that have identified various organ-specific N- and O-glycans of adult zebrafish, we show here that all the major glycotopes of interest can be readily mapped by direct nano-LC-MS/MS analysis of permethylated glycans. Homing in on the brain-, intestine-, and ovary-derived samples, organ-specific glycomic reference maps based on overlaid extracted ion chromatograms of resolved glycan species, and composite charts of summed intensities of diagnostic MS2 ions representing the distribution and relative abundance of each of the glycotopes and sialic acid variants were established. Moreover, switching to negative mode analysis of sample fractions enriched in negatively charged glycans, we show, for the first time, that a full range of sulfated glycotopes is expressed in adult zebrafish. In particular, 3-O-sulfation of terminal Gal was commonly found, whereas terminal sulfated HexNAc as in GalNAcβ1-4GlcNAc (LacdiNAc), and 3-O-sulfated hexuronic acid as in HNK-1 epitope (SO3-3GlcAβ1-3Galβ1-4GlcNAc) were identified only in the brain and not in the intestine or ovaries analyzed in parallel. Other characteristic structural features of sulfated O- and N-glycans along with their diagnostic ions detected in this discovery mode sulfoglycomic work collectively expand our adult zebrafish glycome atlas, which can now allow for a more complete navigation and probing of the underlying sulfotransferases and glycosyltransferases, in search of the functional relevance of zebrafish-specific glycotopes. Of particular importance is the knowledge of glycomic features distinct from those of humans when using adult zebrafish as an alternative vertebrate model, rather than mouse, for brain-related glyco-neurobiology studies.

Substituent effect on the thermophysical properties and thermal dissociation behaviour of 9-substituted anthracene derivatives.

The chemical structure and location of substituents on anthracene derivatives influence the electron balance of the aromatic system, thus determining the wavelengths at which light is absorbed, which results in the photochemically induced dimerization or monomerization. Here, the thermal dissociation kinetics of 7 photodimers of 9-substituted anthracene derivatives are studied using a combination of spectroscopic and calorimetric techniques in the condensed state and compared to scarce literature data on thermal dissociation of other anthracene derivatives. The length and chemical structure of the substituent chains have a clear impact on the melting temperatures of the anthracene derivatives and corresponding photodimers. The crystallinity of the photodimers and monomers in turn influences the thermal dissociation kinetics. The thermal dissociation behaviour and previously published photochemistry data are related to the electronic effects of the substituents by means of the Hammett parameters. Stronger electron-withdrawing effects result in larger red shifts of the maximum wavelength λmax for the photodimerization of the anthracene derivatives. It is also shown that for the studied substitutions on the 9-position of anthracene, the higher the magnitude of the electronic effect - both electron-donating and electron-withdrawing - the faster the thermal dissociation kinetics and thus the lower the thermal stability. The strong electronic effects of the substituents on the thermal and photochemical reactivity of the anthracene derivatives and their photodimers allow tuning of the thermal or photochemical responsiveness, e.g. for polymer networks.

Two-Color Resonant Two-Photon Mass-Analyzed Threshold Ionization of 2,4-Difluoroanisole and the Additivity Relation of Ionization Energy.

We used the two-color resonant two-photon ionization and mass-analyzed threshold ionization spectroscopic techniques to record the vibronic, photoionization efficiency, and cation spectra of 2,4-difluoroanisole. The cation spectra were obtained through ionization via seven intermediate vibronic states, which involved out-of-plane ring-F, in-plane ring-F, and ring-OCH3 bending vibrations as well as in-plane ring deformation vibrations. The band origin of the S1 ← S0 electronic transition of 2,4-difluoroanisole appeared at 35 556 ± 2 cm-1, and the adiabatic ionization energy was determined to be 67 568 ± 5 cm-1. The experimental data provided information on the active vibrations of aforementioned compound in the electronically excited state S1 and ground cationic state D0. A comparison of the experimental data obtained for 2,4-difluoroanisole in this study with the data obtained for other fluorine-substituted benzenes in previous studies indicated that the nature, location, and number of substituents influence electronic transition energy, ionization energy, and molecular vibration. In addition, a simple additivity relation might exist for predicting the ionization energy of multiply substituted benzene derivatives.