Ortho-methyl Substituent Research Articles

Synthesis, design, and optimization of a potent and selective series of pyridylpiperazines as promising antimalarial agents

An optimization of the pyridylpiperazine series against Plasmodium falciparum has been performed, exploring a structure-activity relationship carried out on the toluyl fragment of hit 1, a compound with low micromolar activity against Plasmodium falciparum discovered by high-throughput screening. After confirming the crucial role played by this aryl fragment in the antiplasmodial activity, the replacement of the ortho-methyl substituent of 1 by halogenated ones led to an improvement for four analogs, either in terms of potency, expected pharmacokinetics profile, or both. Further introduction of endocyclic nitrogens in this fragment identified two more optimized compounds, 20 and 23, which are expected to be much more metabolically stable than 1. Additional assessment of the cytotoxicity, Ligand Lipophilic Efficiency, potency against the chloroquine-resistant Dd2 strain and in silico ADMET predictions revealed a satisfactory profile for most compounds, ultimately identifying the four optimized compounds 7, 9, 20 and 23 as promising compounds for further lead optimization of this series against Plasmodium falciparum.

Effect of methyl substituents on the biodegradation of two-ring polycyclic aromatic hydrocarbons in crude oil identified by aerobic biodegradation simulations

Existing studies determining the effects of substituted methyl groups on polycyclic aromatic hydrocarbon biodegradation were mostly limited to an individual compound or a class of compounds. The simultaneous transformation of the multiple series of methyl-substituted two-ring polycyclic aromatic hydrocarbons (61 compounds) in crude oil through laboratory simulations has been examined, including naphthalenes, fluorenes, biphenyls, and dibenzofurans. The biodegradation sequences were in the order of dimethylnaphthalenes > trimethylnaphthalenes > biphenyls > dibenzofurans, tetramethylnaphthalenes > pentamethylnaphthalenes > fluorenes. Polycyclic aromatic hydrocarbon biodegradation was depending on both the number and the position of methyl substituents. For naphthalenes, fluorenes, biphenyls, and dibenzofurans, the more methyl groups in the parent compound, the more resistant it was to biodegradation. Among the polycyclic aromatic hydrocarbons with the same number of methyl groups, the more ortho-methyl substitutes, the more challenging it was to be decomposed. In the case of dimethylnaphthalenes or trimethylnaphthalenes with the same number of methyl and ortho-methyl substituents, their biodegradability reduced as the number of α substituents increased. The number of ortho-methyl substituents had a greater impact than that of α/β substituents. The relative significance of these two factors has not been confirmed in previous studies.

Photocontrolled Energy Storage in Azobispyrazoles with Exceptionally Large Light Penetration Depths.

Azobispyrazole, 4pzMe-5pzH, derivatives with small terminal substituents (Me, Et, i-Pr, and n-Pr) are reported to undergo facile reversible photoswitching in condensed phases at room temperature, exhibiting unprecedentedly large effective light penetration depths (1400 μm of UV at 365 nm and 1400 μm of visible light at 530 nm). These small photoswitches exhibit crystal-to-liquid phase transitions upon UV irradiation, which increases the overall energy storage density of this material beyond 300 J/g that is similar to the specific energy of commercial Na-ion batteries. The impact of heteroarene design, the presence of ortho methyl substituents, and the terminal functional groups is explored for both condensed-phase switching and energy storage. The design principles elucidated in this work will help to develop a wide variety of molecular solar thermal energy storage materials that operate in condensed phases.

Naphthalimide-phenothiazine dyads: effect of conformational flexibility and matching of the energy of the charge-transfer state and the localized triplet excited state on the thermally activated delayed fluorescence.

In order to investigate the joint influence of the conformation flexibility and the matching of the energies of the charge-transfer (CT) and the localized triplet excited (3LE) states on the thermally activated delayed fluorescence (TADF) in electron donor–acceptor molecules, a series of compact electron donor–acceptor dyads and a triad were prepared, with naphthalimide (NI) as electron acceptor and phenothiazine (PTZ) as electron donor. The NI and PTZ moieties are either directly connected at the 3-position of NI and the N-position of the PTZ moiety via a C–N single bond, or they are linked through a phenyl group. The tuning of the energy order of the CT and LE states is achieved by oxidation of the PTZ unit into the corresponding sulfoxide, whereas conformation restriction is imposed by introducing ortho-methyl substituents on the phenyl linker, so that the coupling magnitude between the CT and the 3LE states can be controlled. The singlet oxygen quantum yield (ΦΔ) of NI-PTZ is moderate in n-hexane (HEX, ΦΔ = 19%). TADF was observed for the dyads, the biexponential luminescence lifetime are 16.0 ns (99.9%)/14.4 μs (0.1%) for the dyad and 7.2 ns (99.6%)/2.0 μs (0.4%) for the triad. Triplet state was observed in the nanosecond transient absorption spectra with lifetimes in the 4–48 μs range. Computational investigations show that the orthogonal electron donor–acceptor molecular structure is beneficial for TADF. These calculations indicate small energetic difference between the 3LE and 3CT states, which are helpful for interpreting the ns-TA spectra and the origins of TADF in NI-PTZ, which is ultimately due to the small energetic difference between the 3LE and 3CT states. Conversely, NI-PTZ-O, which has a higher CT state and bears a much more stabilized 3LE state, does not show TADF.

Conformational control of bis-urea self-assembled supramolecular pH switchable low-molecular-weight hydrogelators

We report the synthesis and investigation into the structure-property relationships of eight different low molecular weight hydrogelators based on a bisaromatic urea core unit, all of which form gels as the pH of the solution is lowered. The low molecular weight hydrogelators are functionalized with carboxylic acid moieties on one aromatic ring, and the other aromatic ring features a nitro functional group either in the meta- or para-position relative to the urea linkage. Ortho-methyl substituents were installed on the aromatic rings to enforce a non-coplanar arrangement between the phenyl and urea moieties. Gel formation was triggered by the addition of a mineral acid or the ring-opening hydrolysis of glucono-δ-lactone. The low molecular weight hydrogelators were studied by a variety of analytical techniques, including NMR spectroscopy and rheology. In addition, their ability to uptake a dye, methylene blue, was determined by UV-vis spectroscopy.

Self-Immolative System for Disclosure of Reactive Electrophilic Alkylating Agents: Understanding the Role of the Reporter Group.

The development of stable, efficient chemoselective self-immolative systems, for use in applications such as sensors, requires the optimization of the reactivity and degradation characteristics of the self-immolative unit. In this paper, we describe the effect that the structure of the reporter group has upon the self-immolative efficacy of a prototype system designed for the disclosure of electrophilic alkylating agents. The amine of the reporter group (a nitroaniline unit) was a constituent part of a carbamate that functioned as the self-immolative unit. The number and position of substituents on the nitroaniline unit were found to play a key role in the rate of self-immolative degradation and release of the reporter group. The position of the nitro substituent (meta- vs para-) and the methyl groups in the ortho-position relative to the carbamate exhibited an influence on the rate of elimination and stability of the self-immolative system. The ortho-methyl substituents imparted a twist on the N–C (aromatic) bond leading to increased resonance of the amine nitrogen’s lone pair into the carbonyl moiety and a decrease of the leaving character of the carbamate group; concomitantly, this may also make it a less electron-withdrawing group and lead to less acidification of the eliminated β-hydrogen.

Pentamethylphenyl (Ph*) ketones: Unique building blocks for organic synthesis

Pentamethylphenyl (Ph*) ketones are rapidly emerging as versatile and useful building blocks for organic synthesis. The ortho-methyl substituents force the aromatic ring to twist out of planarity with the carbonyl, and consequently these molecules display a unique pattern of reactivity which is completely distinct to that of traditional aromatic ketones. The primary aim of this Digest is to highlight examples where new chemical reactivity is unlocked through the use of Ph* ketones, and a wide range of examples are presented including hydrogen borrowing catalysis, aldol addition and organocatalysis. Finally, methods to cleave the Ph* group to a range of other functionality are surveyed.

Enhancement of the Luminescent Efficiency in Carbene-Au(I)-Aryl Complexes by the Restriction of Renner-Teller Distortion and Bond Rotation.

A series of (carbene)Au(I)(aryl) complexes are reported. The nature of the lowest excited state in these complexes changes character from metal-to-ligand charge transfer (MLCT) to interligand charge transfer (ICT) with increasing electron-donating strength of the aryl ligand. Complexes that have the MLCT lowest excited state undergo a Renner-Teller bending distortion upon excitation. Such a distortion leads to a large rate of nonradiative decay, on the order of 108 s-1. Renner-Teller-based nonradiative decay does not occur in chromophores with an ICT emissive state. Introducing a julolidine moiety and ortho-methyl substituents to the aryl group makes the molecule rigid and hinders the rotation along the Au-Caryl-coordinate bond. Consequently, the nonradiative decay rates of these ICT emitters are decreased and become lower than the radiative decay rate constants (kr = 105 s-1). Thus, high-luminescent efficiencies (ΦPL = 0.61 and 0.77) along with short lifetimes (τ < 2 μs) are obtained for yellow and green emitters, respectively. Thermally assisted delayed fluorescence behavior is observed, owing to the small exchange energy (ΔEST < 1600 cm-1) in these emitters.

Synthesis and characterization of new polyimides from diphenylpyrene dianhydride and ortho methyl substituted diamines.

Three new polyimides were synthesized via one-step polycondensation from 3,8-diphenylpyrene-1,2,6,7-tetracarboxylic dianhydride (DPPD) with two diamines with ortho methyl substitution (MBDAM and HFI) and one diamine without ortho substituents (BAPHF). The effect of diamine structure in DPPD based polyimides' physical, thermal, mechanical and gas transport properties has been studied. The polyimide structure was confirmed by FTIR and 1H NMR. All polymers show high thermal stability with decomposition temperatures above 493 °C, and glass transition temperatures above 336 °C. Changes in packing density of polyimide membranes were assessed by wide angle X-ray diffraction and correlated to fractional free volume FFV. Polyimides based on rigid DPPD dianhydride exhibited an improved gas permeability and selectivity when ortho methyl substituents are present in the diamine used for polyimide synthesis. DPPD-MBDAM polyimide showed the best gas productivity values with 565 barrer CO2 permeability and a selectivity of 16 for CO2/CH4.

ChemInform Abstract: Palladium(II)‐Catalyzed C—H Activation and C—C Coupling/Cyclization of Benzamidine and Terminal Alkynes Using an Internal Oxidant.

Herein, an efficient palladium(II)-catalyzed C–C coupling/cyclization reaction by directed C–H activation of benzamidine and terminal alkynes has been developed. In this practical and high-yielding process, the C–N bond acts as an internal oxidant. It was found that molecules with both electron-donating and electron-withdrawing substituents were suitable substrates for this transformation, and the expected products were obtained in moderate to excellent yields, but when the benzamidine with ortho-methyl substituent is employed, the benzamidine compound may undergo the [1,5]-hydrogen migration, and then Diels–Alder reaction with terminal alkynes to produce the quinoline compound. The use of a single catalytic system to mediate chemical transformations in a synthetic operation is efficient in building complex structures from simple starting materials in an environmentally benign fashion.

High-productivity gas separation membranes derived from pyromellitic dianhydride and nonlinear diamines

Two new polyimides have been obtained from commercial and inexpensive pyromellitic dianhydride and two affordable meta-substituted diamines bearing ortho methyl substituents (i.e., 2,4,6-trimethyl-1,3-phenylene diamine (TMPD) and 5,7-diamino-1,1,4,6-tetramethylindane (TMID)). Due to a combination of dianhydride rigidity and meta substitution, in addition to the influence of the ortho substituents on the orthogonal placement of the amine and imide planes, the two polyimides exhibited a high fractional free volume and a high rigidity. Therefore, these polyimides were able to produce gas separation membranes with an excellent balance between permeability and selectivity, and these membranes performed similar to many polymers with intrinsic microporosity (PIMs) and surpassed the 1991 Robeson upper bound for all gas pairs. The behavior is more favorable than that for similar polyimides based on 6FDA, which is considered to be the best dianhydride for gas separation polyimides.

Palladium(II)-Catalyzed C–H Activation and C–C Coupling/Cyclization of Benzamidine and Terminal Alkynes Using an Internal Oxidant

Herein, an efficient palladium(II)-catalyzed C–C coupling/cyclization reaction by directed C–H activation of benzamidine and terminal alkynes has been developed. In this practical and high-yielding process, the C–N bond acts as an internal oxidant. It was found that molecules with both electron-donating and electron-withdrawing substituents were suitable substrates for this transformation, and the expected products were obtained in moderate to excellent yields, but when the benzamidine with ortho-methyl substituent is employed, the benzamidine compound may undergo the [1,5]-hydrogen migration, and then Diels–Alder reaction with terminal alkynes to produce the quinoline compound. The use of a single catalytic system to mediate chemical transformations in a synthetic operation is efficient in building complex structures from simple starting materials in an environmentally benign fashion.

Synthesis and structure–activity relationships of small molecule inhibitors of the simian virus 40 T antigen oncoprotein, an anti-polyomaviral target

Polyomavirus infections are common and relatively benign in the general human population but can become pathogenic in immunosuppressed patients. Because most treatments for polyomavirus-associated diseases nonspecifically target DNA replication, existing treatments for polyomavirus infection possess undesirable side effects. However, all polyomaviruses express Large Tumor Antigen (T Ag), which is unique to this virus family and may serve as a therapeutic target. Previous screening of pyrimidinone–peptoid hybrid compounds identified MAL2-11B and a MAL2-11B tetrazole derivative as inhibitors of viral replication and T Ag ATPase activity (IC50 of ∼20–50μM). To improve upon this scaffold and to develop a structure–activity relationship for this new class of antiviral agents, several iterative series of MAL2-11B derivatives were synthesized. The replacement of a flexible methylene chain linker with a benzyl group or, alternatively, the addition of an ortho-methyl substituent on the biphenyl side chain in MAL2-11B yielded an IC50 of ∼50μM, which retained antiviral activity. After combining both structural motifs, a new lead compound was identified that inhibited T Ag ATPase activity with an IC50 of ∼5μM. We suggest that the knowledge gained from the structure–activity relationship and a further refinement cycle of the MAL2-11B scaffold will provide a specific, novel therapeutic treatment option for polyomavirus infections and their associated diseases.

Quantum chemical study of the arylacyl azide complexes with Lewis acids and their Curtius rearrangement to isocyanates

The structures of donor-acceptor complexes of syn-benzoyl azide, its 2-methyl- and 2,6-dimethyl-substituted derivatives with BF3, AlCl3, and SbCl5, and the corresponding transition states of the rearrangement into isocyanates were studied by the PBE/TZ2P method in the framework of the density functional theory (DFT). The complexes are formed at the oxygen and nitrogen atoms of the acyl azide group and have the composition 1: 1 or 1: 2 depending on the Lewis acid (L) structure. The complexes at the oxygen atom are more stable; the most stable complexes are formed by the reactions of acyl azides with AlCl3. Complex formation with Lewis acids decreases the activation energy of the transformation of acyl azides into isocyanates owing to the +M effect and stabilization of the Ar-C(O-L(1−))=N(1)-N(2)(1+)≡N(3) mesomeric form. The activation energy decreases with an increase in the number of ortho-methyl substituents in benzoyl azide due to the +I effect of the phenyl group. The turn of the phenyl ring at almost 90° with respect to the CON3 group is needed for the rearrangement to occur, and the energy necessary for this process is ∼8 kcal mol−1.

Kinetics and Mechanism of the Pyridinolysis of Bis(2,6-dimethylphenyl) Chlorophosphate in Acetonitrile

correlations for substituent X variations in the nucleophiles exhibit biphasic concave upwards with a breakpoint at a X = 3-Cl. Unusual positive ρX (= +5.40) and negative βX (= –0.83) values are obtained with the weakly basic pyridines. The pyridinolysis rate of 5 is hundreds times slower compared to that of bis(phenyl) chlorophosphate because of the steric hindrance of the four ortho-methyl substituents in the two phenyl rings. Ion-pair mechanism is proposed and positive ρX and negative βX values are substantiated by an imbalance of the transition state.

N-(4-Bromo-2-methylphenyl)pivalamide

The conformation of the N—H bond in the title compound, C12H16BrNO, is syn to the ortho-methyl substituent. There are two unique molecules in the asymmetric unit. In the crystal structure, inter­molecular N—H⋯O hydrogen bonds link the mol­ecules, forming infinite chains down [010].

Living/controlled olefin polymerization initiated by nickel diimine complexes: The effect of ligand ortho substituent bulkiness

Abstract Polymerization of hex-1-ene and propene initiated by several methylalumoxane-activated diimine complexes was critically investigated. Effect of bulkiness of ortho aryl diimine substituents on extent of transfer reactions was examined. All of the complexes allowed us to prepare poly(hex-1-ene) with a very narrow molar mass distribution, molar mass being controlled by stoichiometry in a broad range of reaction conditions. Poly(hex-1-ene)s with molar mass between 15 and 220 kg mol −1 and dispersity ( M w / M n ) between 1.01 and 1.20 were prepared by varying the catalyst, temperature and monomer concentration. Livingness of hex-1-ene polymerization was demonstrated for the first time for nickel complex bearing ethyl ortho aryl substituents by reinitiation of chain growth upon addition of a new portion of monomer. Complexes with ortho methyl substituents did not allow complete reinitiation of chain growth and despite its good control over molar mass cannot be classified as a living polymerization catalyst. Chain branching can effectively be controlled by the choice of the ligand structure due to the chain-walking mechanism. Transfer reactions were more pronounced in propene polymerization. Polypropylene with narrow molar mass distribution could not be prepared using complexes with methyl substituents.

N-(2-Chloro-phen-yl)-2-methyl-benzamide.

In the structure of the title compound (N2CP2MBA), C14H12ClNO, the conformations of the N—H and C=O bonds are trans to each other. Furthermore, the conformation of the N—H bond is syn to the ortho-chloro group in the aniline ring and the C=O bond is syn to the ortho-methyl substituent in the benzoyl ring, similar to what is observed in 2-chloro-N-(2-chloro­phen­yl)benzamide and 2-methyl-N-phenyl­benzamide. The amide group makes almost the same dihedral angles of 41.2 (14) and 42.2 (13)° with the aniline and benzoyl rings, respectively, while the dihedral angle between the benzoyl and aniline rings is only 7.4 (3)°. The mol­ecules in N2CP2MBA are packed into chains through N—H⋯O hydrogen bonds.

N-(3-Chlorophenyl)-2-methylbenzamide

The conformation of the N—H bond in the structure of the title compound, C14H12ClNO, is anti to the meta-chloro substituent in the aniline ring, while the C=O bond is syn to the ortho-methyl substituent in the benzoyl ring. The conformations of the N—H and C=O bonds are anti to each other, similar to those observed in 2-methyl-N-(3-methyl­phen­yl)benzamide (N3MP2MBA). The –NHC(=O)– group makes a dihedral angle of 55.8 (7)° with the benzoyl ring, while the angle between the benzoyl and aniline rings is 37.5 (1)°; the respective values for N3MP2MBA are 55.2 (7) and 36.2 (1)°. N—H⋯O hydrogen bonds link the mol­ecules into infinite chains running along the c axis.

Ethylene Polymerizations with Unsymmetrical (α-Diimine)nickel(II) Catalysts

Four unsymmetrical (α-diimine)nickel(II) catalysts were synthesized by sequential stepwise condensation of acenaphthenequinone with the corresponding aniline compounds and subjected to ethylene polymerizations with MAO. Interestingly, when the catalysts have the same composition of the ortho substituents, the catalyst with two ortho isopropyl substitients on one side and two ortho methyl substituents on the other side produced polyethylenes with higher branching densities and lower molecular weights than the catalyst with one ortho isopropyl and one ortho methyl substituent on each side. However, branch distribution was not changed by the position of the ortho substituents.