Pendant Aromatic Rings Research Articles

Tuning the structure of pendant groups in poly(α‐arylTMC)s: A pathway to high glass transition temperature

AbstractAliphatic polycarbonates have been explored as environmentally benign alternatives to aromatic polycarbonates. Improvements to the glass transition temperature (Tg) of aliphatic polycarbonates have been pursued by several groups. We recently showed that attaching a pendant aromatic group to poly(TMC) can enhance the Tg. Also, we have shown that para substituents on the pendant group have an impact on the Tg. Here, we have explored the role of bulky pendant groups and the effect of substituent position on the pendant aromatic ring. We prepared novel naphthalene‐derived poly(TMC)s as well as 2‐Br‐substituted poly(PhTMC). The 2‐bromophenyl derivative showed a Tg of 69.5 °C which represents a nominal increase in comparison to the 4‐bromo derivative that we reported earlier. This suggests that the position of the substituent does not have a critical impact on Tg. With naphthalene derivatives, the increase in steric bulk led to an increase in Tg. Increase of chain length beyond fifty monomer units had a minimal impact on Tg. Finally, when 4‐bromonaphthyl moiety was the pendant group, we observed a Tg of 97 °C. This demonstrates that Tg can be varied significantly by modifying the pendant groups. We have also shown that the 1,3‐diols used in our polymer are non‐cytotoxic.

Construction of tetralin and chromane cores by the Lewis acid promoted ring-opening cyclization of cyclopropyl methanesulfonates

Rearrangement of cyclopropyl methanesulfonates to allylic carbocations was employed for the construction of tetralin and chromate bicyclic cores. We found that this transformation proceeds efficiently and rapidly at room temperature in the presence of dimethylaluminium triflate serving as a non-nucleophilic Lewis acid. The reaction begins with the cyclopropanol ring-opening and follows by the Friedel-Crafts cyclization of the resulting cationic intermediate with a pendant aromatic ring.

Steric and Electronic Manipulation of the Agostic and π‐Syndetic Donations in a Known Iminophosphane Ni(II) Complex Containing a Rotatable In‐Plane Aromatic Ring

AbstractDensity functional theory (DFT) calculations show that in a known nickel(II) complex containing a chelating iminophosphane ligand, where a pendant aromatic ring forms a weak agostic interaction with the metal centre, significant π‐syndetic donation is developed which establishes this kind of donation in a complex derived from experiment. Electron withdrawing and donating groups added to the carbon para to the agostic carbon do not cause the aromatic ring to rotate. Natural bond orbital (NBO) analysis shows that electron withdrawing groups cause little change to the agostic and π‐syndetic donations but electron donation switches off the π‐syndetic donation forming η1‐complexes of varying strength but which still retain a mostly unchanged agostic component. Increasing the size of the substituent ortho to the agostic carbon sequentially, cause rotation of the ring whereby the agostic donation declines slowly, the π‐syndetic donation rises followed by a rapid decline in both donations. The study shows that both donations may be manipulated where a rotatable aromatic ring is present.

Solvent-specific, DAST-mediated intramolecular Friedel-Crafts reaction: access to dibenzoxepine-fused spirooxindoles.

A facile, DAST-mediated intramolecular cyclization of 3-hydroxy-3-(2-((3-methoxybenzyl)oxy)phenyl)indolin-2-one derivatives for the synthesis of spirooxindoles fused with dibenzoxepine moieties is described. The success of this reaction is highly dependent on the choice of solvent (promoted by DCM and 1,2-DCE) and the electronic nature of the pendant aromatic ring, which is favored by the presence of electron-donating substituents. The reaction is believed to proceed through an intramolecular Friedel-Crafts-type reaction. Various dibenzoxepine-fused spirooxindoles were successfully synthesized in up to 98% yield. This methodology provides libraries of structurally diverse and medicinally important small molecules that could aid in the search for new bioactive molecules.

Comparison of Novel 1,1-Diphenylethylene Alternating Copolymer and Polystyrene Based Anion Exchange Membranes

This research investigates 1,1-diphenylethylene as a monomer in polymeric ion exchange membranes through the synthesis of a novel alternating copolymer functionalized for ion transport and analysis of mechanical and conductive properties. This will further the development of cost effective and high-performance ion exchange membranes, enabling energy systems that employ ion-transporting membranes, like fuel cells and electrolyzers, to become more economically viable, which in turn would lead to cleaner and more sustainable energy production.The goal of the project is to develop an understanding of chemical structure-physical property relationships to make self-assembling ion-conducting channels in ionomers which have physical properties that prevent the excess swelling that leads to the mechanical failure of membranes. In this vein, anion exchange membranes (AEMs) based on 1,1-diphenylethylene were synthesized and their ion conducting properties and physical state were characterized. Poly(1,1-diphenylethylene-alt-butadiene) alternating copolymer was synthesized via anionic polymerization, then selectively hydrogenated to eliminate double bonds in the polymer backbone. The pendant aromatic rings of the selectively hydrogenated poly(1,1-diphenylethylene-alt-butadiene) were then subjected to quantitatively controlled functionalized by super acid catalyzed Friedel-Crafts bromoalkylation, then aminated with trimethylamine. AEMs spanning a wide range of ion exchange capacities (IECs), 0.39-1.99 milliequiv./gram (meq./g), were made. Conductivity increased with IEC and temperature. Polystyrene based AEMs of similar IECs, 0.38-2.14 meq/g, were synthesized as a standard to compare the 1,1-diphenylethylene based copolymers. The 1,1-diphenylethylene based copolymers had favorable conductivities compared to polystyrene membranes of similar IEC. The glass transition temperature, water uptake, and dimensional swelling were investigated to explain the difference in conductivities between the two species. Figure 1

Enhanced Intracellular Accumulation and Cytotoxicity of Ferrocene‐Ruthenium Arene Conjugates

AbstractCoordination of arenophilic Cp*Ru+ (Cp*=η5‐C5Me5) fragment to pendant aromatic ring(s) of either benzylferrocene (1) or dibenzylferrocene (2) gave air‐ and water‐stable dinuclear (4) or trinuclear (6) ferrocene‐ruthenium conjugates. The complexes were characterized by NMR, ESI‐MS, cyclic voltammetry (CV), elemental analysis, and the molecular structure of 4 was established by single crystal X‐ray diffraction. Contrary to the starting ferrocenes 1 and 2, conjugates 4 and 6 showed significant in vitro anticancer activity (up to IC50 0.6±0.2 μM) against various cancer cell lines (A2780, SK‐OV‐3, MDA‐MB‐231). Differential pulse voltammetry (DPV) showed that the intracellular accumulation of 4 was approximately twice that of 6 in all studied cell lines, which corresponds to a higher cytotoxicity of 4.

π-π-Stacked Poly(ε-caprolactone)-b-poly(ethylene glycol) Micelles Loaded with a Photosensitizer for Photodynamic Therapy.

To improve the in vivo stability of poly(ε-caprolactone)-b-poly(ethylene glycol) (PCL-PEG)-based micelles and cargo retention by π-π stacking interactions, pendant aromatic rings were introduced by copolymerization of ε-caprolactone with benzyl 5-methyl-2-oxo-1,3-dioxane-5-carboxylate (TMC-Bz). It was shown that the incorporation of aromatic rings yielded smaller micelles (18–30 nm) with better colloidal stability in PBS than micelles without aromatic groups. The circulation time of i.v. injected micelles containing multiple pendant aromatic groups was longer (t½-α: ~0.7 h; t½-β: 2.9 h) than that of micelles with a single terminal aromatic group (t½ < 0.3 h). In addition, the in vitro partitioning of the encapsulated photosensitizer (meta-tetra(hydroxyphenyl)chlorin, mTHPC) between micelles and human plasma was favored towards micelles for those that contained the pendant aromatic groups. However, this was not sufficient to fully retain mTHPC in the micelles in vivo, as indicated by similar biodistribution patterns of micellar mTHPC compared to free mTHPC, and unequal biodistribution patterns of mTHPC and the host micelles. Our study points out that more detailed in vitro methods are necessary to more reliably predict in vivo outcomes. Furthermore, additional measures beyond π-π stacking are needed to stably incorporate mTHPC in micelles in order to benefit from the use of micelles as targeted delivery systems.

Optimizing fluorine labelling for 19F solid-state NMR in oriented biological systems.

When planning a fluorine labeling strategy for 19F solid state NMR (ssNMR) studies of the structure and/or mobility of fluorine labeled compounds in situ in an oriented biological system, it is important to characterize the NMR properties of the label. This manuscript focuses on the characterization of a selection of aromatic fluorine compounds in dimyristoylphosphatidylcholine bilayers using 19F ssNMR from the standpoint of determiningthe optimum arrangement of fluorine nuclei on a pendant aromatic ring before incorporation into more complex biological systems.

Hyperstage Graphite: Electrochemical Synthesis and Spontaneous Reactive Exfoliation.

Covalent modification of the π-electron basal planes of graphene enables the formation of new materials with enhanced functionality. An electrochemical method is reported for the formation of what is referred to as a Hyperstage-1 graphite intercalation compound (GIC), which has a very large interlayer spacing d001 > 15.3 Å and contains disordered interstitial molecules/ions. This material is highly activated and undergoes spontaneous exfoliation when reacted with diazonium ions to produce soluble graphenes with high functionalization densities of one pendant aromatic ring for every 12 graphene carbons. Critical to achieving high functionalization density is the Hyperstage-1 GIC state, a weakening of the van der Waals coupling between adjacent graphene layers, and the ability of reactants to diffuse into the disordered intercalate phase between the layers. Graphene functionalization with 3,5-dinitrophenyl groups provides for exceptional dispersibility (0.24 mg mL-1 ) in N,N-dimethylformamide and for conjugation with amines.

ChemInform Abstract: Dearomatization Through Halofunctionalization Reactions

AbstractReview: [52 refs.

Dearomatization through Halofunctionalization Reactions.

Recent advances in dearomatization through halofunctionalization reactions are summarized in this Minireview. Two general categories of strategies are currently employed in this field. On one hand, the reaction can be initiated with electrophilic halogenation at an alkyne or alkene moiety. The resulting halonium ion intermediate is then captured by a pendant aromatic ring at the ipso position, affording the dearomatization product. On the other hand, electrophilic halogenation can directly take place at a substituted arene, and the final dearomatization product is furnished by deprotonation or intramolecular nucleophilic trap. Highly enantioselective variants have been realized in the latter case by organocatalysis or transition metal catalysis. By applying these methods, various valuable halogenated polycyclic molecular architectures have been obtained from readily available starting materials.

Facile synthesis of thermosensitive functional polyaspartamide derivatives by click chemistry

Biodegradable and thermosensitive polyaspartamide derivatives containing pendant azide groups P(Asp-Az)X-HPAs were synthesized from poly(l-succinimide) via the ring-opening reaction with 2-azidoethylamine (Az) and 5-hydroxypentylamine (HPA). Then hydrophobic phenethyl (PEA) and imidazole (IMZ) moieties were introduced successfully with very high reaction efficiency above 90% to the side chains of P(Asp-Az)X-HPA by click reaction to obtain thermoresponsive polyaspartamide derivatives containing pendant aromatic rings P(Asp-Az)X-HPA-PEAs and the thermo/pH-responsive polyaspartamide derivatives containing pendant imidazole rings P(Asp-Az)X-HPA-IMZs, respectively. The thermoresponsive behaviors of P(Asp-Az)X-HPA-PEAs and P(Asp-Az)X-HPA-IMZs were confirmed by dynamic light scattering (DLS) and transmittance measurements, and the cloud point can be tuned by designed amounts of azide groups and can be further adjusted by the grafting molar percentage of hydrophobic phenethyl or imidazole moieties to the side chains of P(Asp-Az)X-HPA via click chemistry. The pH-responsive behavior of P(Asp-Az)X-HPA-IMZs can also be tuned. These results indicate that the obtained polyaspartamide-based functional polymers can be further functionalized with hydrophilic long PEG chain and/or targeted moieties via click chemistry for drug delivery. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015, 53, 1296–1303

Crystal structure of the di-Mannich base 4,4'-di-chloro-3,3',5,5'-tetra-methyl-2,2'-[imidazolidine-1,3-diylbis(methyl-ene)]diphenol.

The title compound, C21H26Cl2N2O2, was prepared in a solvent-free microwave-assisted synthesis, and crystallizes in the ortho-rhom-bic space group Pna21. The imidazolidine ring adopts an envelope conformation and its mean plane is almost perpendicular to the two pendant aromatic rings [dihedral angles = 84.61 (9) and 86.54 (9)°]. The mol-ecular structure shows the presence of two intra-molecular O-H⋯N hydrogen bonds between the phenolic hy-droxy groups and imidazolidine N atoms. The two 3-chloro-6-hy-droxy-2,4-di-methyl-benzyl groups are located in a cis orientation with respect to the imidazolidine fragment. As a result, the lone pairs of electrons on the N atoms are presumed to be disposed in a syn conformation. This is therefore the first example of an exception to the 'rabbit-ears' effect in such 2,2'-[imidazolidine-1,3-diylbis(methyl-ene)]diphenol derivatives.

Can metal ion complexation compete with the self-assembly processes of calix[4]arene amine derivatives?

Self-assembly can occur spontaneously through aryl-aryl π-stacking in solution for calix[4]arenes derivatised at both the upper and lower rims with pendant aromatic rings, including pyridine rings. It was hoped that metal ion complexation would help to control the level of self-assembly occurring in solution, by disrupting these interactions. Metal ion titration studies were carried out on 3 with various zinc salts, but it was found that even with 1 : 4 ligand to metal ratio, the self-assembly process still dominated. Furthermore, in an effort to prevent the self-assembly process, the lower rim was completely substituted, but metal complexation reactions with these fully substituted calix[4]arenes still showed that the self-assembly process dominated.

Myristicyclins A and B: Antimalarial Procyanidins from Horsfieldia spicata from Papua New Guinea

An antimalarial screen for plants collected from Papua New Guinea identified an extract of Horsfieldia spicata as having activity. Isolation of the active constituents led to the identification of two new compounds: myristicyclins A (1) and B (2). Both compounds are procyanidin-like congeners of myristinins lacking a pendant aromatic ring. Myristicyclin A was found to inhibit the ring, trophozoite, and schizont stages of Plasmodium falciparum at similar concentrations in the mid-μM range.

Identification of the GPR55 Antagonist Binding Site Using a Novel Set of High-Potency GPR55 Selective Ligands

GPR55 is a class A G protein-coupled receptor (GPCR) that has been implicated in inflammatory pain, neuropathic pain, metabolic disorder, bone development, and cancer. Initially deorphanized as a cannabinoid receptor, GPR55 has been shown to be activated by non-cannabinoid ligands such as l-α-lysophosphatidylinositol (LPI). While there is a growing body of evidence of physiological and pathophysiological roles for GPR55, the paucity of specific antagonists has limited its study. In collaboration with the Molecular Libraries Probe Production Centers Network initiative, we identified a series of GPR55 antagonists using a β-arrestin, high-throughput, high-content screen of ~300000 compounds. This screen yielded novel, GPR55 antagonist chemotypes with IC50 values in the range of 0.16-2.72 μM [Heynen-Genel, S., et al. (2010) Screening for Selective Ligands for GPR55: Antagonists (ML191, ML192, ML193) (Bookshelf ID NBK66153; PMID entry 22091481)]. Importantly, many of the GPR55 antagonists were completely selective, with no agonism or antagonism against GPR35, CB1, or CB2 up to 20 μM. Using a model of the GPR55 inactive state, we studied the binding of an antagonist series that emerged from this screen. These studies suggest that GPR55 antagonists possess a head region that occupies a horizontal binding pocket extending into the extracellular loop region, a central ligand portion that fits vertically in the receptor binding pocket and terminates with a pendant aromatic or heterocyclic ring that juts out. Both the region that extends extracellularly and the pendant ring are features associated with antagonism. Taken together, our results provide a set of design rules for the development of second-generation GPR55 selective antagonists.

Ethyl 4-(5-bromo-2-hydroxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate

In the title compound, C21H24BrNO4, the dihedral angle between the heterocyclic ring and the pendant aromatic ring is 80.20 (13)°. The hexahydroquinone [i.e. the one with the C=O group] ring adopts a sofa conformation. An intra­molecular O—H⋯O hydrogen bond generates an S(6) ring motif. The ethyl group is disordered over two sets of sites with a refined site occupancy ratio of 0.633 (10):0.366 (10). In the crystal, mol­ecules are linked by N—H⋯O inter­actions, forming chains parallel to [101]. There are no significant C—H⋯π or π–π inter­actions in the crystal structure.

Exploring the scope of Bergman Cyclization mediated cascade reaction of alkenyl enediynes: synthesis of [5]helicene and amino acid appended [4]helicenes

Bergman Cyclization mediated cascade radical process is employed for the synthesis of [5]helicenes as well as diastereoselective mixtures of chiral amino acid appended [4]helicenes. Maximum selectivity (2.5:1) was found in case of l-leucine attached cyclic enediyne. Mechanistic considerations for this tandem radical reaction revealed that the major pathway probably involved quenching of the biradical, formed after aryl radical addition to pendant aromatic ring, by the solvent followed by aromatization. Intramolecular H-abstraction by the sp2-hybridized radical in the central ring or a 1,5-H shift followed by self-quenching could be the other possible ways to lead to the helicenes.

4,4′-Dimethyl-2,2′-[imidazolidine-1,3-diylbis(methylene)]diphenol

The imidazolidine ring in the title compound, C19H24N2O2, adopts a twist conformation and its mean plane (r.m.s. deviation = 0.19 Å) makes dihedral angles of 72.38 (9) and 71.64 (9)° with the two pendant aromatic rings. The dihedral angle between the phenyl rings is 55.94 (8)°. The mol­ecular structure shows the presence of two intra­molecular O—H⋯N hydrogen bonds between the phenolic hydroxyl groups and N atoms with graph-set motif S(6). In the crystal, C—H⋯O hydrogen bonds lead to the formation of chains along the b-axis direction.

Systematic Evaluation of Structure-Activity Relationships of the Riminophenazine Class and Discovery of a C2 Pyridylamino Series for the Treatment of Multidrug-Resistant Tuberculosis

Clofazimine, a member of the riminophenazine class of drugs, is the cornerstone agent for the treatment of leprosy. This agent is currently being studied in clinical trials for the treatment of multidrug-resistant tuberculosis to address the urgent need for new drugs that can overcome existing and emerging drug resistance. However, the use of clofazimine in tuberculosis treatment is hampered by its high lipophilicity and skin pigmentation side effects. To identify a new generation of riminophenazines that is less lipophilic and skin staining, while maintaining efficacy, we have performed a systematic structure-activity relationship (SAR) investigation by synthesizing a variety of analogs of clofazimine and evaluating their anti-tuberculosis activity. The study reveals that the central tricyclic phenazine system and the pendant aromatic rings are important for anti-tuberculosis activity. However, the phenyl groups attached to the C2 and N5 position of clofazimine can be replaced by a pyridyl group to provide analogs with improved physicochemical properties and pharmacokinetic characteristics. Replacement of the phenyl group attached to the C2 position by a pyridyl group has led to a promising new series of compounds with improved physicochemical properties, improved anti-tuberculosis potency, and reduced pigmentation potential.