Meta-substituted Benzene Research Articles

Three-dimensional saturated C(sp3)-rich bioisosteres for benzene.

Benzenes, the most ubiquitous structural moiety in marketed small-molecule drugs, are frequently associated with poor 'drug-like' properties, including metabolic instability, and poor aqueous solubility. In an effort to overcome these limitations, recent developments in medicinal chemistry have demonstrated the improved physicochemical profiles of C(sp3)-rich bioisosteric scaffolds relative to arenes. In the past two decades, we have witnessed an exponential increase in synthetic methods for accessing saturated bioisosteres of monosubstituted and para-substituted benzenes. However, until recent discoveries, analogous three-dimensional ortho-substituted and meta-substituted biososteres have remained underexplored, owing to their ring strain and increased s-character hybridization. This Review summarizes the emerging synthetic methodologies to access such saturated motifs and their impact on the application of bioisosteres for ortho-substituted, meta-substituted and multi-substituted benzene rings. It concludes with a perspective on the development of next-generation bioisosteres, including those within novel chemical space.

Modular Access tometa-Substituted Benzenes via Mo-Catalyzed Intermolecular Deoxygenative Benzene Formation

The substituted benzene derivatives are essential to organic synthesis, medicinal chemistry, and material science. However, the 1,3-di- and 1,3,5-trisubstituted benzenes are far less prevalent in small-molecule drugs than other substitution patterns, likely due to the lack of robust, efficient, and convenient synthetic methods. Here, we report a Mo-catalyzed intermolecular deoxygenative benzene-forming reaction of readily available ynones and allylic amines. A wide range of unsymmetric and unfunctionalized 1,3-di- and 1,3,5-trisubstituted benzenes were obtained in up to 88% yield by using a commercially available molybdenum catalyst. The synthetic potential of the method was further illustrated by synthetic transformations, a scale-up synthesis, and derivatization of bioactive molecules. Preliminary mechanistic studies suggested that this benzene-forming process might proceed through a Mo-catalyzed aza-Michael addition/[1,5]-hydride shift/cyclization/aromatization cascade. This strategy not only provided a facile, robust, and modular approach to various meta-substituted benzene derivatives but also demonstrated the potential of molybdenum catalysis in the challenging intermolecular deoxygenative cross-coupling reactions.

Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane.

Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly found para-substituted benzene rings in drug design1. The utility of these cage structures derives from their superior pharmacokinetic properties compared with their parent aromatics, including improved solubility and reduced susceptibility to metabolism2,3. A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesized by ring-opening of the interbridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions4. By contrast, scaffolds mimicking meta-substituted arenes are lacking because of the challenge of synthesizing saturated isosteres that accurately reproduce substituent vectors5. Here we show that bicyclo[3.1.1]heptanes (BCHeps), which are hydrocarbons for which the bridgehead substituents map precisely onto the geometry of meta-substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on a multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally relevant carbon- and heteroatom-substituted BCHeps, including pharmaceutical analogues. Comparison of theabsorption, distribution, metabolism and excretion (ADME) properties of these analogues reveals enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this meta-arene analogue as an sp3-rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a new surrogate for meta-substituted benzene rings for implementation in drug discovery programmes.

Crescent-shaped meta-substituted benzene derivatives as a new class of non-nucleoside ribonuclease A inhibitors

Ribonuclease A is used as a model enzyme system for the design of RNase inhibitors. Previous studies have established that the geometric nature of the active site cleft is an important feature for the accommodation of crescent-shaped compounds in the active site of RNase A. In the current research, benzene-based triazolylated semicircular hybrid molecules carrying different polar functionalities were synthesized and screened for their RNase A inhibitory potency. An additional carboxylic acid group at the C1-position of the 1,3,5-trisubstituted benzene ring enhanced the inhibitory properties significantly. Furthermore, the studies revealed that the reduced arm lengths of 3,5-substituents result in a better geometric complementarity that makes the molecules fit favorably in the semicircular cavity of the active site as visualized by docking studies. In a series of ten such new compounds, the 3,5-bis[4-(sulfomethyl)-1H-1,2,3-triazol-1-yl]benzoic acid exhibited, the highest inhibition efficiency with a Ki value of 12 ± 0.9 µM. This study identifies a new class of non-nucleoside inhibitors which are competitive inhibitors of the ribonucleolytic activity of RNase A.

1,2-Difunctionalized bicyclo[1.1.1]pentanes: Long–sought-after mimetics for ortho/meta-substituted arenes

The development of a versatile platform for the synthesis of 1,2-difunctionalized bicyclo[1.1.1]pentanes to potentially mimic ortho/meta-substituted arenes is described. The syntheses of useful building blocks bearing alcohol, amine, and carboxylic acid functional handles have been achieved from a simple common intermediate. Several ortho- and meta-substituted benzene analogs, as well as simple molecular matched pairs, have also been prepared using this platform. The results of in-depth ADME (absorption, distribution, metabolism, and excretion) investigations of these systems are presented, as well as computational studies which validate the ortho- or meta-character of these bioisosteres.

DFT-Assisted Design and Evaluation of Bifunctional Amine/Pyridine-Oxazoline Metal Catalysts for Additions of Ketones to Unactivated Alkenes and Alkynes

Bifunctional catalyst systems for the direct addition of ­ketones to unactivated alkenes/alkynes were designed and modeled by density functional theory (DFT). The designed catalysts possess bidentate ligands suitable for binding of pi-acidic group 10 metals capable of activating alkenes/alkynes, and a tethered organocatalyst amine to ­activate the ketone via formation of a nucleophilic enamine intermediate. The structures of the designed catalysts before and after C–C bond formation were optimized using DFT, and reaction steps involving group 10 metals were predicted to be significantly exergonic. A novel oxazoline precatalyst with a tethered amine separated by a meta-substituted benzene spacer was synthesized via a 10-step sequence that ­includes a key regioselective epoxide ring-opening step. It was combined with group 10 metal salts, including cationic Pd(II) and Pt(II), and screened for the direct addition of ketones to several alkenes and an ­internal alkyne. 1H NMR studies suggest that catalyst-catalyst inter­actions with this system via amine–metal coordination may preclude the desired addition reactions. The catalyst design approach disclosed here, and the promising calculations obtained with square planar group 10 metals, light a path for the discovery of novel bifunctional catalysts for C–C bond formation.

Is the Antiresonance in Meta-Contacted Benzene Due to the Destructive Superposition of Waves Traveling Two Different Routes around the Benzene Ring?

The well-known antiresonance around the middle of the HOMO–LUMO gap observed in the transmission spectra of the meta-contacted benzene molecular junctions is often explained as being caused by the destructive interference between electronic waves following two different pathways in real space around the phenyl ring. We show one contradictory scenario where this interpretation may break down when one of the bonds in the benzene is attenuated gradually. Interestingly, the dip in the transmission spectra is not attenuated at all even after the complete breaking of the bond. This inconsistency arises from the misinterpretation of the antiresonance observed in energy space as a consequence of the superposition of waves propagating through two independent pathways in real space. We revisit the Landauer model within the Green’s function formalism and propose a different interpretation of the appearance of the antiresonance in energy space in meta-substituted benzene which is compatible with the scenario describe...

Excitation Energy Transfer in meta‐Substituted Phenylacetylene Multibranched Chromophores

A comprehensive investigation into the spectral properties and excitation energy transfer in di- or tribranched dithienyldiketopyrrolopyrrole (DPP) molecules with meta-substituted benzene as a central core (TADPP2-TT and TADPP3), by means of steady-state and transient measurements and quantum chemical calculations, is reported. Excitation in the meta-substituted chromophores is localized on one of the DPP units in the branching molecules owing to the disruption of conjugation by meta substitution for both TADPP2-TT and TADPP3. Weak electronic couplings result from the long distance between the DPP chromophores and the steric effects from the attached side chains on DPP. The attachment of the acetylene linker in each branch, which has a very low twisting barrier, could also play an important role in reducing the interaction between DPP chromophores. The dynamics of the excited states show that excitation energy transfer occurs on the picosecond scale, which is attributed to the incoherent hopping mechanism.

Design, Synthesis, and Structure−Activity Relationships of Novel Bicyclic Azole-amines as Negative Allosteric Modulators of Metabotropic Glutamate Receptor 5

A novel series of diaryl bicyclic azole-amines that are potent selective negative modulators of metabotropic glutamate receptor 5 (mGluR5) were identified through rational design. An initial hit compound 5a of modest potency (IC(50) = 1.2 μM) was synthesized. Evaluation of structure-activity relationships (SAR) on the left-hand side of the molecule revealed a preference for a 2-substituted pyridine group linked directly to the central heterocycle. Variation of the central azolo-amine portion of the molecule revealed a preference for the [4,5-c]-oxazoloazepine scaffold, while right-hand side variants showed a preference for ortho- and meta-substituted benzene rings linked directly to the tertiary amine of the saturated heterocycle. These iterations led to the synthesis of 29b, a potent (IC(50) = 16 nM) and selective negative modulator that showed good brain penetrance, high receptor occupancy, and a duration of action greater than 1 h in rat when administered intraperitoneally. Formal PK studies in rat and Rhesus monkey revealed a short half-life that was attributable to high first-pass clearance.

Colorimetric investigation of the reaction between p‐phenylendiamine and meta‐substituted derivatives of benzene on a model support

The aim of this work was the employment of colorimetric techniques in the analysis of the color formed, on a proteic substrate, by the reaction between p-phenylendiamine and some meta-substituted benzene derivatives in the presence of hydrogen peroxide and in media at different pH values. In particular we investigated the chromatic variations that take place on the substrate in dependence on different reaction conditions. The obtained results show that for each couple of reagents the colorimetric data, namely the reflectance of the formed color, change considerably with the pH of the reaction medium and demonstrate how this parameter can be considered a good descriptor of the composition of the formed pigment.

Shape-Selective Sorption and Fluorescence Sensing of Aromatics in a Flexible Network of Tetrakis[(4-methylthiophenyl)ethynyl]silane and AgBF4

The large tetrapod tetrakis[(4-methylthiophenyl)ethynyl]silane was crystallized with AgBF4 to form a diamondoid network based on the Ag(I)−thioether interaction. A 4-fold interpenetration of the individual nets was observed, with the rest of the unit-cell volume occupied by the benzene guests. The benzene molecules can be removed without collapsing of the host networks, even though the benzene molecules appear to be well enclathrated in the cavities formed by the host nets. Interestingly, the apohost displays a strict size selectivity for small aromatic molecules, which effectively excludes ortho- and meta-substituted benzene derivatives from entering the pores, enabling, for example, the selective sorption of benzene over hexafluorobenzene. The fluorescence arising from the molecular building block also provides for the sensing of nitrobenzene molecules, which effectively quenches the fluorescence upon entry into the host net.

Shape-persistent macrocycles comprising perfluorinated benzene subunits: synthesis, aggregation behaviour and unexpected μ-rod formation

The synthesis of a series of shape-persistent macrocycles (SPMs) (1-4 and 6) comprising different numbers and/or spatial arrangement of meta-substituted tetrafluorobenzene and benzene subunits interlinked with diacetylenes is described. To increase their solubility, all five SPMs were functionalized by four peripheral hexyl chains. These SPMs were assembled from common diacetylene building blocks by a modular synthetic strategy based on palladium and/or copper catalyzed versions of acetylene coupling reactions (oxidative acetylene coupling and Cadiot-Chodkiewicz coupling). The aggregation properties in chloroform of SPMs 1-6 were investigated by concentration- and temperature-dependent 1H-NMR investigations and by vapour pressure osmometry studies. Aggregation constants and thermodynamic data of the process were obtained by least-squares fitting of the NMR data and by van't Hoff analysis respectively. Aggregation was only observed for SPMs 2-6 comprising electron deficient tetrafluorobenzene corner units. While dimerization was the major aggregation process for SPMs 3-6, the formation of larger aggregates in solution was only observed for SPM 2. The formation of aggregates is in all cases enthalpically driven. As the largest and the smallest enthalpic contribution and entropic loss in the series of aggregating SPMs were found for the two SPMs 3 and 4, each comprising two fluorinated corner units, the spatial arrangement of these subunits within the macrocycle seems to be at least equally important as the ratio of tetrafluorobenzene and benzene moieties. Interestingly, micro-scaled hexagonal rods were formed from SPM 3 upon heating in toluene, presumably consisting of mixtures of oligomers arising from covalently interlinked macrocycles.

Dioxygenase-catalysed oxidation of disubstituted benzene substrates: benzylic monohydroxylation versus aryl cis-dihydroxylation and the meta effect

Biotransformations of a series of ortho-, meta- and para-substituted ethylbenzene and propylbenzene substrates have been carried out, using Pseudomonas putida UV4, a source of toluene dioxygenase (TDO). The ortho- and para-substituted alkylbenzene substrates yielded, exclusively, the corresponding enantiopure cis-dihydrodiols of the same absolute configuration. However, the meta isomers, generally, gave benzylic alcohol bioproducts, in addition to the cis-dihydrodiols (the meta effect). The benzylic alcohols were of identical (R) absolute configuration but enantiomeric excess values were variable. The similar (2R) absolute configurations of the cis-dihydrodiols are consistent with both the ethyl and propyl groups having dominant stereodirecting effects over the other substituents. The model used earlier, to predict the regio- and stereo-chemistry of cis-dihydrodiol bioproducts derived from substituted benzene substrates has been refined, to take account of non-symmetric substituents like ethyl or propyl groups. The formation of benzylic hydroxylation products, from meta-substituted benzene substrates, without further cis-dihydroxylation to yield triols provides a further example of the meta effect during toluene dioxygenase-catalysed oxidations.

Exciton migration dynamics in a dendritic molecule: quantum master equation approach using ab initio molecular orbital configuration interaction method.

We investigate the exciton migration dynamics in a dendritic molecular model composed of pi-conjugation linear-leg units (acetylenes and diacetylene) and a benzene ring (branching point) using the quantum master equation approach with the ab initio molecular orbital (MO) configuration interaction (CI) method. The efficient migration of exciton from short-length linear legs (acetylenes) to long-length linear leg (diacetylene) via a benzene ring is observed. As predicted in previous studies, the exciton (electron and hole) distributions are relatively well localized in each generation segmented by the meta-branching point (meta-substituted benzene ring) though the electron and hole distributions are delocalized and are somewhat spatially different from each other within each generation. It is found that the excitons localized in the generation composed of short linear legs occupy in higher-lying exciton states, while those in the generation composed of long linear legs do in lower-lying ones. These features suggest the decoupling of pi-conjugation at the meta-branching point. On the other hand, the relaxation effect between exciton states is found to be caused by the exciton-phonon coupling, in which the existence of common configurations (electron-hole pairs) in CI wave functions between adjacent exciton states (having primary distributions on short and long linear-leg regions, respectively) is important for the relaxation between their exciton states. This feature indicates the importance of partial penetration of pi-conjugation through the meta-substituted benzene ring in excited states for such exciton migration.

The mode of transmission of electrical effects: evidence from infrared stretching frequencies

The transmission of the universal electrical effect in infrared stretching frequencies is well fit by the modified field effect model with m ≈ −1.5 ± 0.2. The considerable variation in rm/p, the ratio of transmission of the electrical effect through meta-substituted benzene derivatives to that through para-substituted benzene derivatives and rc/t, the ratio of the transmission of the electrical effect through the s-cis conformer to that through the s-trans conformer and the failure of these ratios to show a Gaussian distribution provides further evidence against the existence of the inductive effect. The values of rm/p obtained show that, in the general case, the Hammett equation is inferior to either di- or tri-parametric equations, as it assumes the equality of ρm and ρp. This is also true of the Yukawa–Tsuno equation. It has been shown that the inductive effect does not fit the experimental data on the transmission of electrical effects in a range of chemical reactions and in infrared stretching frequencies. Recent quantum chemical calculations support the field effect as the mode of electrical effect transmission. The inductive effect model of electrical effect transmission should be abandoned. Copyright © 2001 John Wiley & Sons, Ltd.

Functionalized Azamacrocycles and Large-Ring α-Amino Esters by One-Pot Syntheses from Methyl 2-Siloxy-2-vinylcyclopropanecarboxylates

Siloxycyclopropane 1 served as starting material for intermediate alkylation products 2, 7, 11, 14, and 17, which were elongated to provide a variety of precursor compounds bearing terminal N-benzyl groups. These substrates were subjected to a cesium fluoride-promoted ring-opening/ring-closure sequence to afford azamacrocycles 19, 21, 22, 23, 25, 26, 27, and 28 in moderate to good yields. The cyclic products have different ring sizes and numbers of nitrogen atoms, and may incorporate meta-substituted benzene or pyridine units. A second approach employed glycine derivative 29 as the key building block for construction of precursors 31 and 34, which on fluoride treatment furnished macrocyclic α-amino esters 32 and 35, respectively, in moderate yields. A few reactions, such as transformations into macrocyclic pyridazinone derivatives 37 and 38, illustrate the potential of the synthesized azamacrocycles for preparation of complex compounds. Our concept for construction of macrocyclic compounds using siloxycyclopropane 1 as zwitterionic synthon A has thus successfully been extended to the synthesis of a variety of highly functionalized azamacrocycles.

Third-order nonlinear optical properties of fractal- and nonfractal-structured oligomers modeled after dendron parts in Cayley-tree-type dendrimers

As an extension of our previous study on polarizabilities [J. Chem. Phys. 115, 1052 (2001)], we investigate the molecular third-order nonlinear optical properties, i.e., the second hyperpolarizabilities (γ), of three types of model oligomers (made of phenylene vinylenes), i.e., para-oligomers and meta-oligomers with fractal and nonfractal structures, which are considered to be models of dendron parts involved in Cayley-tree-type dendrimers. Similarly to the polarizability case, the chain-length dependence of γ of para-oligomers is found to be much larger than that of nonfractal meta-oligomers, while fractal meta-oligomers exhibit an intermediate chain-length dependency of γ between them. The spatial contributions of π-electrons to γ of these systems are elucidated using hyperpolarizability density analysis. It is found that the spatial contributions of π-electrons to γ of nonfractal meta-oligomers are much smaller than those of para-oligomers and are well decoupled at the meta-substituted benzene rings, while the fractal meta-oligomers show significantly large spatial contributions of π-electrons to γ in their linear-leg (para-substituted phenylene vinylene) regions similarly to the case of para-oligomers although the distributions are also well decoupled at the meta-substituted benzene rings. This feature supports the distinct features of chain-length dependency of γ for these oligomers.

Size-dependency of polarizabilities of fractal- and nonfractal-structured oligomers modeled after dendron parts in Cayley-tree-type dendrimers

We investigate the size-dependency of static polarizabilities (α) (in the chain-length direction) of three types of model oligomers (made of phenylene vinylenes), i.e., para-oligomers and meta-oligomers with fractal and nonfractal structures by the finite-field method using molecular orbital calculations. The fractal-structured meta-oligomers are considered to be models of dendron parts involved in Cayley-tree-type dendrimers. The chain-length dependence of α of para-oligomers is found to be much larger than that of nonfractal-structured meta-oligomers, while the fractal-structured meta-oligomers exhibit an attractive chain-length dependence of α; the α values of meta-structured oligomers are near to those of nonfractal-structured meta-oligomers in small chain-length region, while they are close to those of para-oligomers in sufficiently large chain-length region. Using the polarizability density analysis, the spatial contributions of π-electrons to α of nonfractal-structured meta-oligomers are found to be smaller than those of para-oligomers and to be well decoupled at the meta-substituted benzene rings. In contrast, it is found that the spatial contributions of π-electrons to α in linear-leg regions for fractal-structured meta-oligomers are similar to those for the para-oligomers though the α density distributions for fractal-structured meta-oligomers are also well decoupled at the meta-substituted benzene rings. Such features, which reflect the fractal structure, is predicted to cause the attractive size-dependency of α for fractal-structured meta-oligomers.

Crystal structures of the cis and trans isomers of a tetrathia[3.3.3.3]cyclophane

Both the cis and trans isomers of 3,11,18,26-tetrathiatricyclo[26.2.2.15,9.213,16.120,24] hexatriaconta-5,7,9,20,22,24-hexene have been prepared and structurally characterized. Each of these centrosymmetric tetrathia dimers includes two cyclohexane rings in chair conformations with either 1,4-cis or 1,4-trans bonding and two meta-substituted benzene rings. The cis isomer packs into the monoclinic space group P21/a with a = 10.485(3)A, b = 10.3956(18)A, c = 14.1343(10)A, β = 105.200(13)°, Z = 2 and refined to an R factor of 0.046. The trans isomer crystallizes in the monoclinic space group P21/c with a = 10.7217(12)A, b = 5.6797(7)A, c = 25.415(5)A, β = 96.001(12)°, Z = 2 and refined to an R factor of 0.043. In the cis structure each benzene ring faces a cyclohexane ring while in the trans structure the cyclohexane rings face one another.

Living Coupling Reaction in Living Cationic Polymerization. 1. Coupling Reaction of Living Polyisobutylene

The living coupling reaction of living polyisobutylene (PIB), prepared by the 2,4,4-trimethyl-2-chloropentane/TiCl4/hexane:methyl chloride (60:40, v:v)/−80 °C system, has been studied using 1,3-bis(1-phenylethenyl)benzene (MDDPE), 2,2-bis[4-(1-phenylethenyl)phenyl]propane (BDPEP), and 2,2-bis[4-(1-tolylethenyl)phenyl]propane (BDTEP) as coupling agents. The reaction of living PIB with MDDPE yielded the monoadduct, possibly due to delocalization of positive charge over the meta-substituted benzene ring upon monoaddition and thereby decreased reactivity of the second double bond. Using BDPEP and BDTEP which have two diphenylethylene (DPE) moieties separated by an electron-donating spacer group, rapid and quantitative coupling was achieved independently of the chain length of the original PIB. The coupled product exhibited doubled molecular weight and narrowed molecular weight distribution. Direct evidence of the quantitative coupling reaction was also obtained by comparison of the 1H NMR spectra of the samples before and after the coupling reaction. Kinetic studies by 1H NMR spectroscopy indicated the coupling reaction of living PIB by BDPEP is a consecutive reaction where the second addition is faster than the first one. By kinetic treatment of the experimental results, it was found that the second addition is about 5 times faster than the first one. As a result, high coupling efficiency was also observed when excess BDPEP was used.