Substituent Pattern Research Articles

Quest for a Rational Molecular Design of Alkyl-Distyrylbenzene Liquid by Substitution Pattern Modulation.

Alkyl-π functional molecular liquids (FMLs) are of interest for fabricating soft electronic devices due to their fluidic nature and innate optoelectronic functions from the π-conjugated moiety. However, predictable development of alkyl-π FMLs with the desired liquid and optoelectronic properties is challenging. A series of alkyl-distyrylbenzene (DSB) liquids was studied in terms of the substituent position effect by attaching 2-octyldodecyl chains at (2,4-), (2,5-), (2,6-), and (3,5-). The effect of the alkyl chain length was investigated by attaching 2-hexyldecyl, 2-decyltetradecyl (C10 C14 ), and 2-dodecylhexadecyl at the (2,5-) substituent position. The 2,5-C10 C14 substituent pattern constructed a superior alkyl-DSB liquid with a lower viscosity, intrinsic optical properties, and high thermal- and photo-stabilities. The discovered 2,5-C10 C14 was applied to dicyanostyrylbenzene and comparable liquid physical and optical superiorities were confirmed. This molecular design is useful for creating alkyl-π FMLs with the aforementioned advantages, which are applicable for deformable and flowable optoelectronic devices.

Design, Synthesis, Fungicidal and Insecticidal Activities of Novel Diamide Compounds Combining Pyrazolyl and Polyfluoro-Substituted Phenyl into Alanine or 2-Aminobutyric Acid Skeletons

Thirty novel diamide compounds combining pyrazolyl and polyfluoro-substituted phenyl groups into alanine or 2-aminobutyric acid skeletons were designed and synthesized with pyflubumide as the lead compound to develop potent and environmentally friendly pesticides. The preliminary bioassay results indicated that the new compounds containing the para-hexa/heptafluoroisopropylphenyl moiety exhibit fungicidal, insecticidal, and acaricidal activities. This is the first time that the para-hexa/heptafluoroisopropylphenyl group is a key fragment of the fungicidal activity of new N-phenyl amide compounds. Most of the target compounds exhibited moderate to good insecticidal activity against Aphis craccivora at a concentration of 400 μg/mL, and some showed moderate activity at a concentration of 200 μg/mL; in particular, compounds I-4, II-a-10, and III-26 displayed higher than 78% lethal rates at 200 μg/mL. Compound II-a-14 exhibited a 61.1% inhibition at 200 μg/mL for Tetranychus cinnabarinus. In addition, some of the target compounds exhibited good insecticidal activities against Plutella xylostella at a concentration of 200 μg/mL; the mortalities of compounds I-1, and II-a-15 were 76.7% and 70.0%, respectively. Preliminary analysis of the structure-activity relationship (SAR) indicated that the insecticidal and acaricidal activities varied significantly depending on the type of substituent and substitution pattern. The fungicidal activity results showed that compounds I-1, II-a-10, II-a-17, and III-26 exhibited good antifungal effects. Enzymatic activity experiments and in vivo efficacy of compound II-a-10 were conducted and discussed.

Red-shifted and pH-responsive imidazole-based azo dyes with potent antimicrobial activity.

A novel route is described to obtain 2-aminoimidazole azo dyes with a unique substituent pattern in the heteroaryl unit that provides halochromic properties, exhibiting vibrant colours that change from magenta to deep blue. Potent antimicrobial properties against infectious yeasts were demonstrated. No cytotoxicity was detected for concentrations lower than 16 μg mL-1.

Ultrafast Dynamics and Strong Two-Photon Absorption Properties of Nonplanar β-Functionalized “Push–Pull” Copper Corroles with a Mixed Substituent Pattern

A new series of nonplanar and unsymmetrically β-functionalized "push-pull" copper corroles, CuTPC(CHO)R7 [R = H, Br, Ph, Me, or 2-thienyl (Th)], were synthesized and characterized to elucidate the effect of β-functionalization and nonplanarity on the photophysical, redox, and nonlinear optical (NLO) properties on the corrole ring. The synthetic route to unsymmetrically β-octasubstituted copper corroles includes bromination of CuTPC(CHO) to get CuTPC(CHO)Br7 in 80% yield, which was further subjected to the Pd-catalyzed Suzuki reaction. CuTPC(CHO)Br7 exhibited a large red shift in the Soret band (Δλmax = 35-40 nm) and both the Q bands (Δλmax = 10-50 nm), as compared to CuTPC and CuTPC(CHO). CuTPC(CHO)Br7 was 510 and 290 mV anodically shifted in the first oxidation and the first reduction compared to CuTPC owing to the strong -I effect of CHO and Br groups. Density functional theory studies revealed that all the β-octasubstituted copper corroles exhibited highly nonplanar saddle-shape conformation of the corrole ring. Very high torsional saddling was observed for CuTPC(CHO)Th7 (79-83°) than that for CuTPC (49-53°), even larger than that for CuTPCBr8 (67-70°). Femtosecond laser-induced third-order NLO studies from these copper corroles showed strong two-photon absorption cross-sections (0.48-6.98 × 104 GM) and self-focusing-type positive nonlinear refraction behavior. The observed structure-dependent two-photon absorption coefficients (β) are in the range of ∼2.7-20.9 × 10-12 m/W, and the n2 values are in the range of ∼0.64-6.45 × 10-18 m2/W. The present results may facilitate a new window for these copper corroles in nonlinear optical devices, femtosecond optical limiters, and many other ultrafast photonic applications.

On the protonation and deuteration of thioanisole and some of its methoxy-substituted derivatives†

The protonation of thioanisols by strong acids, such as trifluoroacetic acid or trifluoromethane sulfonic acid was investigated by 1H NMR spectroscopy, including experiments with deuterated acids. Contrary to reported literature and to general expectations, protonation of thioanisole does not occur exclusively at the methylmercapto group but also to a lower extent at the aromatic ring. In cases of methoxy-substituted thioanisols protonation can take place at both heteroatomic groups and at the aromatic ring. The sites of protonation depend on the substituent pattern as unambiguously indicated by deuteration.

Total Synthesis of (-)-Ceforalide B and (-)-Cephanolides B-D.

(-)-Ceforalide B (1) and (-)-cephanolides B-D (2-4) are benzenoid cephanolide diterpenoids possessing the same pentacyclic skeleton, which contains three C13-C15 substituent patterns and different benzylic oxidation states. An olefination/6π-electrocyclization/oxidative aromatization cascade has been verified as divergent access to three C13-C15 patterns. The benzylic aerobic oxidations enabled by the Co(OAc)2·4H2O/bromide salt/O2/PPh3/N-hydroxyphthalimide system have been developed to deliver expected site-selectivity and different oxidation states. Through the divergent strategy, total synthesis of (-)-ceforalide B and (-)-cephanolides B-D is accomplished.

A New Class of Tunable Acid-Sensitive Linkers for Native Drug Release Based on the Trityl Protecting Group.

Core-cross-linked polymeric micelles (CCPMs) are a promising nanoparticle platform due to favorable properties such as their long circulation and tumor disposition exploiting the enhanced permeability and retention (EPR) effect. Sustained release of covalently linked drugs from the hydrophobic core of the CCPM can be achieved by a biodegradable linker that connects the drug and the core. This study investigates the suitability of trityl-based linkers for the design of acid-triggered native active pharmaceutical ingredient (API) release from CCPMs. Trityl linker derivatives with different substituent patterns were synthesized and conjugated to model API compounds such as DMXAA-amine, doxorubicin, and gemcitabine, and their release kinetics were studied. Hereafter, API release from CCPMs based on mPEG-b-pHPMAmLac block copolymers was investigated. Variation of the trityl substitution pattern showed tunability of the API release rate from the trityl-based linker with t1/2 varying from <1.0 to 5.0 h at pH 5.0 and t1/2 from 6.5 to >24 h at pH 7.4, all at 37 °C. A clear difference in release kinetics was found between gemcitabine and doxorubicin, with gemcitabine showing no detectable release for 72 h at pH 5.0 and doxorubicin showing a t1/2 of less than 1 h. Based on these findings, we show that the reaction mechanism of trityl deprotection plays an important role in the API release kinetics. The first step in this mechanism, which is protonation of the trityl-bound amine, is pKa-dependent, which explains the difference in release rate. In conclusion, acid-sensitive and tunable trityl linkers are highly promising for the design of linker–API conjugates and for their use in CCPMs.

Antibiotic and Nematocidal Metabolites from Two Lichen Species Collected on the Island of Lampedusa (Sicily).

The antibiotic and nematocidal activities of extracts from two coastal lichen species collected on Lampedusa Island (Sicily), Ramalina implexa Nyl. and Roccella phycopsis Ach., were tested. Methyl orsellinate, orcinol, (+)-montagnetol, and for the first time 4-chlororcinol were isolated from Roccella phycopsis. (+)-Usnic acid was obtained from Ramalina implexa. The crude organic extract of both lichen species showed strong antibiotic activity against some bacterial species and nematocidal activity. Among all the pure metabolites tested against the infective juveniles (J2) of the root-knot nematode (RKN) Meloydogine incognita, (+)-usnic acid, orcinol, and (+)-montagnetol had significant nematocidal activity, comparable with that of the commercial nematocide Velum® Prime, and thus they showed potential application in agriculture as a biopesticide. On the contrary, methyl orsellinate and 4-chlororcinol had no nematocidal effect. These results suggest that the substituent pattern at ortho-para-position in respect to both hydroxyl groups of resorcine moiety, which is present in all metabolites, seems very important for nematocidal activity. The organic extracts of both lichens were also tested against some Gram-positive and Gram-negative bacteria. Both extracts were active against Gram-positive species. The extract of Ramalina implexa showed, among Gram-negative species, activity against Escherichia coli and Acinetobacter baumannii, while that from Roccella phycopsis was effective towards all test strains, with the exception of Pseudomonas aeruginosa. The antimicrobial activity of (+)-usnic acid, methyl orsellinate, and (+)-montagnetol is already known, so tests were focused on orcinol and 4-chlororcinol. The former showed antibacterial activity against all Gram positive and Gram-negative test strains, with the exception of A. baumannii and K. pneumoniae, while the latter exhibited a potent antibacterial activity against Gram-positive test strains and among Gram-negative strains, was effective against A. baumannii and K. pneumonia. These results suggest, for orcinol and 4-chlororcinol, an interesting antibiotic potential against both Gram-positive and Gram-negative bacterial strains.

Metal Free Approach towards the Synthesis of Structurally Diverse 1, 2‐Dihydronaphthalene Scaffolds and Theoretical Investigation

AbstractBiologically potent and synthetically significant 1,2‐dihydronaphthalene derivatives have gained considerable attention due to their wide applications in industrial as well as in medicinal fields also. A mild and efficient metal‐free protocol via the rearrangement of cyclopropylcarbinols has been reported to construct these 1,2‐dihydronaphthalene skeletons utilizing cyclopropane ring as the scaffold. We obtained conjugated dienes and, in some cases, homoallylic chlorides as major products in good to excellent yields. They have no literature precedence till date. The fate of this rearrangement depends on the substituent patterns of the cyclopropane bearing aryl moiety. Besides the synthetic studies, to get deep insight into the electronic transitions, time dependent DFT studies have also been performed.

Methane Monooxygenase Mimic Asymmetric Oxidation: Self-Assembling μ-Hydroxo, Carboxylate-Bridged Diiron(III)-Catalyzed Enantioselective Dehydrogenation.

Mimicking naturally occurring metalloenzymes to enrich the diversity of catalytic asymmetric oxidation reactions is a long-standing goal for modern chemistry. Toward this end, a range of methane monooxygenase (MMO) mimic chiral carboxylate-bridged (μ-hydroxo) diiron(III) dimer complexes using salan as basal ligand and sodium aryl carboxylate as additive have been designed and synthesized. The chiral diiron complexes exhibit efficient catalytic reactivity in dehydrogenative kinetic resolution of indolines using environmentally benign hydrogen peroxide as oxidant. In particular, complex C9 bearing sterically encumbered salan ligands and a 2-naphthoate bridge is identified as the optimal catalyst in terms of chiral recognition. Further investigation reveals that this MMO mimic chiral catalyst can be readily generated by self-assembly under the dehydrogenation conditions. The self-assembling catalytic system is applicable to a series of indolines with multiple stereocenters and diverse substituent patterns in high efficiency with a high level of chiral recognition (selectivity factor up to 153). Late-stage dehydrogenative kinetic resolution of bioactive molecules is further examined.

Origin of High Diastereoselectivity in Reactions of Seven-Membered-Ring Enolates.

Unlike many reactions of their six-membered-ring counterparts, the reactions of chiral seven-membered-ring enolates are highly diastereoselective. Diastereoselectivity was observed for a range of substrates, including lactam, lactone, and cyclic ketone derivatives. The stereoselectivity arises from torsional and steric interactions that develop when electrophiles approach the diastereotopic π-faces of the enolates, which are distinguished by subtle differences in the orientation of nearby atoms of the ring.

Synthesis of 5-Trifluoromethyl-Substituted (Z)-N,N-Dimethyl-N′-(pyrazin-2-yl)formimidamides from 2-Aminopyrazines, LiI/Selectfluor, FSO2CF2CO2Me and DMF under Cu Catalysis

AbstractThe synthesis of 5-trifluoromethyl-substituted (Z)-N,N-dimethyl-N′-(pyrazin-2-yl)formimidamides via the iodination of 2-aminopyrazines with Selectfluor/LiI followed by a domino trifluoromethylation with FSO2CF2CO2Me and a condensation with DMF in the presence of CuI is realized under mild conditions. This three-step method offers CF3-substituted (Z)-N,N-dimethyl-N′-(pyrazin-2-yl)formimidamides in yields of 55–70% and with high regioselectivities. LiI serves as an iodine source, whilst DMF functions as both a solvent and a condensation reagent. The regioselectivity of these trifluoromethylation reactions is strongly dependent upon the substituent pattern on the 2-aminopyrazines. A possible mechanism for this method is also discussed.

The in vitro synthesis of cellulose – A mini-review

The implementation of cellulose as a green alternative to classical polymers sparks research on the synthesis of defined derivatives of this biopolymer for various high-tech applications. Apart from the scientific challenge, the in vitro synthesis of cellulose using a bottom-up approach provides specimens with absolutely accurate substituent patterns and degrees of polymerization, not accessible from native cellulose. Synthetic cellulose exhibiting a comparably high degree of polymerization (DP) was obtained starting from cellobiose by biocatalytic synthesis implementing cellulase. Cationic ring-opening polymerization has been established in the last two decades, representing an excellent means of precise modification with regards to regio- and stereoselective substitution. This method rendered isotopically enriched cellulose as well as enantiomers of native cellulose (“l-cellulose”, “d,l-cellulose”) accessible. In this review, techniques for in vitro cellulose synthesis are summarized and critically compared – with a special focus on more recent developments. This is complemented by a brief overview of alternative enzymatic approaches.

Chemoselective Synthesis of Sulfenylated Spiroindolenines from Indolyl-ynones via Organosulfenyl Chloride-Mediated Dearomatizing Spirocyclization.

A metal-free sulfenylation/spirocyclization of indolyl-ynones realized by organosulfenyl chloride, generated in situ from the reaction of disulfides and PhICl2, is presented. This cascade one-pot process enables a chemoselective synthesis of diverse sulfenylated spiroindolenines depending on the substituent pattern at the two-position of indolyl-ynones.

Substituents of life: The most common substituent patterns present in natural products

Comparison of substituents present in natural products with the substituents found in average synthetic molecules reveals considerable differences between these two groups. The natural products substituents contain mostly oxygen heteroatoms, are structurally more complex, often containing double bonds and are rich in stereocenters. Substituents found in synthetic molecules contain nitrogen and sulfur heteroatoms, halogenes and more aromatic and particularly heteroaromatic rings. The characteristics of substituents typical for natural products identified here can be useful in the medicinal chemistry context, for example to guide the synthesis of natural product-like libraries and natural product-inspired fragment collections. The results may be used also to support compound derivatization strategies and the design of pseudo-natural natural products.

Chromofluorogenic naphthoquinolinedione-based probes for sensitive detection and removal of Hg2+ in aqueous solutions

Mercury ions are an industrial and environmental toxin that need to be monitored and regulated in aqueous samples. We prepared six probes (1–6) using a naphthoquinolinedione ring as a fluorophore platform that contains different substituents on the quinolone ring. All probes showed abilities to selectively bind Hg2+, but their sensitivity to the detection of this metal ion significantly varied depending on the substituent pattern. Among these probes, probe 5 with Br and CN substituents on the quinolone ring was most effective for the sensitive detection of Hg2+ in aqueous solutions. This probe showed a naked-eye color change from yellow to purple upon binding to Hg2+. A ratio-metric method using UV–visible absorption data gave a limit of detection (LOD) of 20 nM, while the fluorescence-based result yielded an LOD of 0.047 pM. When bio-samples such as human urine and serum were used as media, the fluorescence-based LOD of this probe for Hg2+ detection increased to 50 nM. Probe 5 was also effective at detecting methylmercury, an organic mercury species, dissolved in drainage water or urine. Based on the results of DLS, FE-SEM, and DFT calculations, the probe appeared to form large aggregates and undergo photo-induced electron transfer (PET) upon Hg2+ binding, both of which are responsible for the probe fluorescence quenching. Probe 5 also showed the ability to sense Hg2+ within three different types of human cells: Brain cells (U87MG), Hela cells and skin cancer cells (SK-MEL28). Furthermore, this probe holds significant potential for on-site applications since various solid supports such as silica gel, filter papers and TLC plates were effectively used for sensitive and selective Hg2+ sensing, following probe coating/adsorption.

Design and Synthesis of Indenoisoquinolines Targeting Topoisomerase I and Other Biological Macromolecules for Cancer Chemotherapy

The discovery that certain indenoisoquinolines inhibit the religation reaction of DNA in the topoisomerase I-DNA-indenoisoquinoline ternary complex led to a structure-based drug design research program which resulted in three representatives that entered Phase I clinical trials in cancer patients at the National Cancer Institute. This has stimulated a great deal of interest in the design and execution of new synthetic pathways for indenoisoquinoline production. More recently, modulation of the substitution pattern and chemical nature of substituents on the indenoisoquinoline scaffold has resulted in a widening scope of additional biological targets, including RXR, PARP-1, MYC promoter G-quadruplex, topoisomerase II, estrogen receptor, VEGFR-2, HIF-1α, and tyrosyl DNA phosphodiesterases 1 and 2. Furthermore, convincing evidence has been advanced supporting the potential use of indenoisoquinolines for the treatment of diseases other than cancer. The rapidly expanding indenoisoquinoline knowledge base has provided a firm foundation for further advancements in indenoisoquinoline chemistry, pharmacology, and therapeutics.

Synthesis and biological evaluation of BU-4664L derivatives as potential anticancer agents

BU-4664L is a naturally occurring N-farnesylated dibenzodiazepinone with important biological activities. Herein, we report the synthesis and antitumor evaluation of two series of BU-4664L derivatives bearing different substituent patterns on the dibenzodiazepinone core and with diverse side chains. All of the derivatives displayed micromolar activity against the human prostate cancer PC-3 cells, while lower or no activity against the human lung H460 cells. The most active derivatives were 10a and 16c which exerted antiproliferative activity against PC-3 cells with GI50 values of 5.66 and 5.94 μM, respectively, and thus represent promising lead compounds for further development.

Fluorescent mesoionic 1-(2-aryl-4H-thieno[3,4-d][1,2,3]triazol-2-ium-4-ylidene)ethan-1-olates: One-pot synthesis, photophysics, and biological behavior

This paper reports the one-pot synthesis of a rare type of mesoionic compounds, which are condensed mesoionics. A series of new bicyclic arylthienotriazoliumolates was synthesized by an improved synthetic method. This approach has a large scope of starting materials and was used to obtain diverse structures with outstanding photophysical properties. The pattern of substituents decorating the mesoionic ring was the important factor determining the electronic distributions of the synthesized compounds. Pull–pull (А–π–A), push–push (D–π–D), pull–push (A–π–D), and push–pull (D–π–A) systems were designed, synthesized and their absorption, emission, stability, and biological behavior were studied. Quantum chemical calculations were performed to deepen the knowledge about the absorption and emission properties of these systems and explain their unusual geometries and electronic structures. Confocal microscopy experiments showed that thienotriazoliumolates easily penetrated into living cells and selectively accumulated near the cell membrane, Golgi apparatus, and endoplasmic reticulum.

Iron/2,6‐Di(pyrazol‐1‐yl)pyridine Complexes with a Discotic Pattern of Alkyl or Alkynyl Substituents

Abstract2,6‐Di(4‐iodopyrazol‐1‐yl)pyridine is converted to 2,6‐di(4‐{alkyn‐1‐yl}pyrazol‐1‐yl)pyridine (L1R; R’=CnH2n−3, n=12, 14, 16) derivatives by Sonogashira reactions. Hydrogenation of these intermediates yields the corresponding 2,6‐di(4‐alkylpyrazol‐1‐yl)pyridine (L2R; R=CnH2n+1) derivatives. Homoleptic Fe[BF4]2 complexes of all these ligands were prepared, bearing four long chain substituents in a discotic‐type array. Crystallographic data from two L1R ligands imply the alkynyl substituents do not undergo intermolecular interdigitation in the solid state, which could explain the lower crystallinity and ill‐defined spin‐crossover in their iron complexes. Solid [Fe(L2R)2][BF4]2 (n=12 and 14) exhibit an irreversible, abrupt low→high‐spin event near 350 K, which is not associated with solvent loss and may involve disordering of their alkyl chain conformations. No mesophase behavior was observed from any of these compounds.