Benzyl Ring Research Articles

Competitive benzyl cation transfer and proton transfer: collision-induced mass spectrometric fragmentation of protonated N,N-dibenzylaniline.

Collision-induced dissociation of protonated N,N-dibenzylaniline was investigated by electrospray tandem mass spectrometry. Various fragmentation pathways were dominated by benzyl cation and proton transfer. Benzyl cation transfers from the initial site (nitrogen) to benzylic phenyl or aniline phenyl ring. The benzyl cations transfer to the two different sites, and both result in the benzene loss combined with 1,3-H shift. In addition, after the benzyl cation transfers to the benzylic phenyl ring, 1,2-H shift and 1,4-H shift proceed competitively to trigger the diphenylmethane loss and aniline loss, respectively. Deuterium labeling experiments, substituent labeling experiments and density functional theory calculations were performed to support the proposed benzyl cation and proton transfer mechanism. Overall, this study enriches the knowledge of fragmentation mechanisms of protonated N-benzyl compounds. Copyright © 2017 John Wiley & Sons, Ltd.

Crystal structure of O-benzyl-l-tyrosine N-carb-oxy anhydride.

In the title compound, C17H15NO4 (alternative name; O-benzyl-l-tyrosine N-carb-oxy anhydride), the oxazolidine ring is planer, with an r.m.s. deviation of 0.039 Å. The benz-yloxy and benzyl rings are almost coplanar, making a dihedral angle of 0.078 (10)°, and are inclined to the oxazolidine ring by 59.16 (11) and 58.42 (11)°, respectively. In the crystal, mol-ecules are linked by N-H⋯O and C-H⋯O hydrogen bonds, forming ribbons propagating along [010]. The ribbons are linked by C-H⋯π inter-actions, forming a three-dimensional supra-molecular structure. The oxazolidine rings of adjacent ribbons are arranged into a layer parallel to the ab plane. This arrangement is favourable for the polymerization of the compound in the solid state.

Experimental bond dissociation energies of benzylpyridinium thermometer ions determined by threshold-CID and RRKM modeling

Benzylpyridinium salts (BPs) have often been used as thermometer ions to obtain an energy calibration of mass spectrometric experiments (in particular to determine internal energy distributions of ions after the ionization process). Fragmentation of BP+ molecular ions is characterized by specific Bond Dissociation Energies (BDE) which depend on the substituent group and its location on the benzyl ring. Although those BDE values are regularly re-evaluated by quantum chemical calculations, their experimental determination is still missing from the literature. In this paper, a modified Quadrupole-hexapole-Quadrupole (QhQ) mass spectrometer is used to obtain such values on 4 BP+ molecular ions (characterized by a wide range of CN bond strengths) using Threshold Collision-Induced Dissociations (TCID) and Rice–Ramsperger–Kassel–Marcus (RRKM) kinetic modeling. It is found that experimental values are systematically 0.5eV lower than their most recent theoretical evaluations. Despite this shift, the absolute critical energy values are maintained in the same order (pOMe<pMe<pCl<pCN), and the relative energy differences are in very good agreement. We argue that the observed 0.5eV shift relates to the energy dependence of the Transition State’s number of states that is typical for barrier-less fragmentation processes and, relates to a kinetic rather than an energetic bottleneck. Notably, by taking into account the bond elongations characterizing the transition states and their corresponding calculated critical energies (E0), close agreement is found with experimentally obtained E0 values. We thus conclude that much care should be taken when describing the transition state during an internal energy calibration procedure where the involved energy is lower than 3–4eV.

Crystal structure of β-benzyl dl-aspartate N-carb-oxyanhydride.

In the title racemic compound, C12H11NO5 [systematic name: benzyl 2-(2,5-dioxooxazolidin-4-yl)acetate], the oxazolidine ring is planar, with an r.m.s. deviation of 0.03 Å. The benzyl ring is almost normal to the oxazolidine ring, making a dihedral angle of 80.11 (12)°. In the crystal, inversion dimers are formed between the l- and d-enanti-omers via pairs of N-H⋯O hydrogen bonds. This arrangement is favourable for the polymerization of the compound in the solid state. The dimers are linked by C-H⋯O hydrogen bonds, forming layers parallel to the ab plane.

Active-site maturation and activity of the copper-radical oxidase GlxA are governed by a tryptophan residue.

GlxA from Streptomyces lividans is a mononuclear copper-radical oxidase and a member of the auxiliary activity family 5 (AA5). Its domain organisation and low sequence homology make it a distinct member of the AA5 family in which the fungal galactose 6-oxidase (Gox) is the best characterised. GlxA is a key cuproenzyme in the copper-dependent morphological development of S. lividans with a function that is linked to the processing of an extracytoplasmic glycan. The catalytic sites in GlxA and Gox contain two distinct one-electron acceptors comprising the copper ion and a 3'-(S-cysteinyl) tyrosine. The latter is formed post-translationally through a covalent bond between a cysteine and a copper-co-ordinating tyrosine ligand and houses a radical. In GlxA and Gox, a second co-ordination sphere tryptophan residue (Trp288 in GlxA) is present, but the orientation of the indole ring differs between the two enzymes, creating a marked difference in the π-π stacking interaction of the benzyl ring with the 3'-(S-cysteinyl) tyrosine. Differences in the spectroscopic and enzymatic activity have been reported between GlxA and Gox with the indole orientation suggested as a reason. Here, we report a series of in vivo and in vitro studies using the W288F and W288A variants of GlxA to assess the role of Trp288 on the morphology, maturation, spectroscopic and enzymatic properties. Our findings point towards a salient role for Trp288 in the kinetics of copper loading and maturation of GlxA, with its presence essential for stabilising the metalloradical site required for coupling catalytic activity and morphological development.

Complex electronic interplay of σ-hole and π-hole interactions in crystals of halogen substituted 1,3,4-oxadiazol-2(3H)-thiones

In this study, we have performed a detailed analysis of the nature and strength of different intermolecular interactions present in the crystal structures of four biologically active derivatives of 1,3,4-oxadiazol-2(3H)-thiones. The study was primarily focused on obtaining detailed physical insights into the differential nature of the σ-hole and π-hole interactions that exist in the solid state in this class of compounds. It is found that the directionality of an interaction plays a very important role in categorizing these interactions as being σ-hole and π-hole in origin. The presence of a σ-hole (on the S, Cl and Br atoms) and π-holes (in the oxadiazole and benzyl rings) is clearly evident from the molecular electrostatic potential maps. The presence of these ubiquitous interactions was further confirmed via QTAIM analysis by the presence of (3, −1) bond critical points (bcps) between the interacting atoms with acceptable topological parameters (ρbcp; ∇2ρbcp). Furthermore, Hirshfeld 2D fingerprint plots helped in quantitatively determining the role of different interactions in the crystal packing of the four reported structures.

T-3-Benzyl-r-2,c-6-diphenylpiperidin-4-one oxime

In the title compound, C24H24N2O [systematic name: (E)-3-benzyl-2,6-diphenylpiperidin-4-one oxime], the piperidine ring adopts a slightly distorted chair conformation and the phenyl rings and the benzyl group substituents are attached equatorially. The oxime group makes a dihedral angle of 42.88 (12)° with the piperidine ring. The dihedral angle between the phenyl rings is 71.96 (8)°. The benzyl ring makes dihedral angles of 63.01 (8) and 59.35 (8)° with the two phenyl rings. In the crystal, molecules are linked by O—H...N hydrogen bonds, formingC(7) chains along thecaxis. The chains are linked by C—H...π interactions, forming slabs lying parallel to thebcplane.

(2Z)-2-Benzylidene-4-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-3-one

In the title molecule, C25H20N4OS, the dihedral angle between the plane of the dihydrothiazine ring and that of the fused C6ring is 1.0 (2)°, indicating a slight twist in the dihydrobenzothiophene unit; there is a roughly perpendicular relationship between the fused C6ring and the triazole ring [dihedral angle = 73.2 (1)°]. The packing comprises chains running parallel to thecaxis formed by weak C—H...O hydrogen bonds, with the benzyl rings intercalated between adjacent chains. The benzyl ring is statistically disordered. The sample was refined as a twin.

Ethyl 1-benzyl-2-(4-methoxyphenyl)-1H-benzimidazole-5-carboxylate

The title benzimidazole derivative, C24H22N2O3, is T-shaped with the methoxyphenyl and benzyl rings inclined to the imidazole ring system (r.m.s. deviation = 0.009 Å) by 46.73 (10) and 88.88 (15)°, respectively. The phenyl ring and methoxyphenyl rings are inclined at an angle of 82.14 (16)°. In the crystal, weak C—H...O hydrogen bonds link the molecules into [101]C(14) chains.

Design, synthesis, antibacterial activity and docking study of some new trimethoprim derivatives

In present study, nineteen novel trimethoprim (TMP) derivatives were designed, synthesized and evaluated for their antibacterial potential. Hydroxy trimethoprim 2 (HTMP) was synthesized by following the demethylation of 4-methoxy group at trimethoxy benzyl ring of TMP. Structure–activity relationship (SAR) studies were explored on HTMP by incorporating various substituents leading to the identification of some new compounds with improved antibacterial activities. The results revealed that the introduction of benzyloxy (4a–e) and phenyl ethanone (5a–e) group at 4-position of dimethoxy benzyl ring leads to overall increase in the antibacterial activity. The most potent antibacterial compound discovered is benzyloxy derivative 4b with MIC value of 5.0μM against Staphylococcus aureus and 4.0μM against Escherichia coli strains higher than the standard TMP (22.7μM against S. aureus and 55.1μM against E. coli). Substitution at 4-NH2 group was not tolerated and the resulting Schiff base derivatives 3a–h demonstrated very little or no antibacterial activity in the tested concentration domain. We further performed exploratory docking studies on dihydrofolate reductase (DHFR) to rationalize the in vitro biological data and to demonstrate the mechanism of antibacterial activity. For the ability to cross lipophilic outer membrane, logP was computed. It was found that the compounds possessing high hydrophobicity have high activity against E. coli.

Crystal structure of N,N'-bis[2-((benzyl){[5-(di-methyl-amino)naph-tha-len-1-yl]sulfonyl}amino)ethyl]naphthalene-1,8:4,5-tetracarboximide 1,2-di-chloro-benzene tris-olvate.

The asymmetric unit of the title compound, C56H50N6O8S2·3C6H4Cl2, contains two half-mol-ecules of the parent, A and B, which both have crystallographic inversion symmetry, together with three 2,3-di-chloro-benzene mol-ecules of solvation. Mol-ecules A and B are conformationally similar, with dihedral angles between the central naphthalenedi-imide ring and the peripheral naphthalene and benzyl rings of 2.43 (7), 81.87 (7)° (A) and 3.95 (7), 84.88 (7)° (B), respectively. The conformations are stabilized by the presence of intra-molecular π-π inter-actions between the naphthalene ring and the six-membered di-imide ring of the central naphthalenedi-imide moiety, with ring centroid-to-centroid distances of 3.5795 (8) Å (A) and 3.5640 (8) Å (B). In the crystal, C-H⋯O hydrogen bonds link the mol-ecules into infinite supra-molecular chains along the c axis. These chains are inter-connected through C-H⋯π and offset π-π inter-actions, generating supra-molecular nanotubes which are filled by 1,2-di-chloro-benzene mol-ecules.

Tribenzyltin carboxylates as anticancer drug candidates: Effect on the cytotoxicity, motility and invasiveness of breast cancer cell lines

This study seeks to investigate the relationship between the structural modification and bioactivity of a series of tribenzyltin complexes with different ligands and substitutions. Complexation with the N,N-diisopropylcarbamothioylsulfanylacetate or isonicotinate ligands enhanced the anticancer properties of tribenzyltin compounds via delayed cancer cell-cycle progression, caspase-dependent apoptosis induction, and significant reduction in cell motility, migration and invasion. Halogenation of the benzyl ring improved the anticancer effects of the tribenzyltin compounds with the N,N-diisopropylcarbamothioylsulfanylacetate ligand. These compounds also demonstrated far greater anticancer effects and selectivity than cisplatin and doxorubicin, which provides a rationale for their further development as anticancer agents.

Thermal stability and decomposition of urea, thiourea and selenourea analogous diselenide derivatives

The fusion and thermal decomposition of thirty-three diselenide compounds with a urea, thiourea or selenourea group linked with different aliphatic or aromatic substituents have been studied by thermogravimetry, differential scanning calorimetry and mass spectrometry in order to perform comparative thermal stability studies among analogs. A relationship has been found between stability and a series of effects which occur in the compound structures. Analysis of the thermal data indicated that: (a) in general, compounds with a urea or selenourea group are more stable than those with a thiourea group; (b) no difference in stability exists when an aromatic or aliphatic group is linked to the thiourea group but when linked to the urea or selenourea groups, stability does differ; (c) selenourea compounds with aliphatic chain are the most unstable; and (d) the nature of the substituent located on the benzyl ring has no effects on thermal stability. Therefore, criteria for the selection of substituents can be established in order to improve the stability of these drugs. In addition, the mass spectral fragmentation in comparison with thermal analytical data helps in confirming the thermal behavior of the compounds.

Crystal structures of three 3,4,5-tri-meth-oxy-benzamide-based derivatives.

The crystal structures of three benzamide derivatives, viz. N-(6-hy-droxy-hex-yl)-3,4,5-tri-meth-oxy-benzamide, C16H25NO5, (1), N-(6-anilinohex-yl)-3,4,5-tri-meth-oxy-benzamide, C22H30N2O4, (2), and N-(6,6-di-eth-oxy-hex-yl)-3,4,5-tri-meth-oxy-benzamide, C20H33NO6, (3), are described. These compounds differ only in the substituent at the end of the hexyl chain and the nature of these substituents determines the differences in hydrogen bonding between the mol-ecules. In each mol-ecule, the m-meth-oxy substituents are virtually coplanar with the benzyl ring, while the p-meth-oxy substituent is almost perpendicular. The carbonyl O atom of the amide rotamer is trans related with the amidic H atom. In each structure, the benzamide N-H donor group and O acceptor atoms link the mol-ecules into C(4) chains. In 1, a terminal -OH group links the mol-ecules into a C(3) chain and the combined effect of the C(4) and C(3) chains is a ribbon made up of screw related R 2 (2)(17) rings in which the ⋯O-H⋯ chain lies in the centre of the ribbon and the tri-meth-oxy-benzyl groups forms the edges. In 2, the combination of the benzamide C(4) chain and the hydrogen bond formed by the terminal N-H group to an O atom of the 4-meth-oxy group link the mol-ecules into a chain of R 2 (2)(17) rings. In 3, the mol-ecules are linked only by C(4) chains.

1-Benzyl-5-bromoindoline-2,3-dione

In the title compound, C15H10BrNO2, the indoline ring system, the two ketone O atoms and the Br atom lie in a common plane, with the largest deviation from the mean plane being 0.073 (1) Å for the Br atom. The fused-ring system is nearly perpendicular to the benzyl ring, as indicated by the dihedral angle between them of 74.58 (10)°. In the crystal, molecules are linked by weak C—H...O hydrogen bonds and by π–π interactions [inter-centroid distance = 3.625 (2) Å], forming a two-dimensional structure.

Synthesis of Germanosilicate Molecular Sieves from Mono- and Di-Quaternary Ammonium OSDAs Constructed from Benzyl Imidazolium Derivatives: Stabilization of Large Micropore Volumes Including New Molecular Sieve CIT-13

A series of monoquaternary and diquarternary benzyl-imidazolium derivatives are prepared and used as organic structure direction agents (OSDAs) in germanosilicate syntheses. The goal of this work is to create new multidimensional large pore zeolites. For the OSDA made and tested, we looked for relationships based upon stereochemistry from the benzyl ring as part of each structure. Several known molecular sieves with the *BEA, BEC, IWS, or LTA topologies are obtained. Molecular modeling is carried out with the goal of understanding: (a) the product selectivity correlation with the OSDA and the zeolite obtained, and (b) why differential rates of crystallization are observed for isomers that lead to different zeolite products. Additionally, a new molecular sieve denoted CIT-13 is prepared and shown to possess intersecting 14- and 10-membered ring pores, which gives confidence to the soundness of this approach for OSDA construction to yield new multidimensional large pore zeolites. CIT-13 is the first molecul...

Radiolabeled hydroxamate-based matrix metalloproteinase inhibitors: How chemical modifications affect pharmacokinetics and metabolic stability

IntroductionDysregulated MMP expression or activation is associated with several diseases. To study MMP activity in vivo by means of PET a radiolabeled MMP inhibitor (MMPI) functioning as radiotracer has been developed by our group based on the lead structure CGS 25966. Materials and methodsAiming at the modification of the pharmacokinetics of this lipophilic model tracer a new class of MMPIs has been discovered, consisting of additional fluorinated hydrophilic substructures, such as mini-PEG and/or 1,2,3-triazole units. To identify the best candidate for further clinical applications, radiofluorinated compounds of each subgroup have been (radio) synthesized and evaluated regarding their biodistribution behavior and their metabolic stability. ResultsRadiosyntheses of different triazole based MMPIs could be realized using two step “click chemistry” procedures. Compared to lead structure [18F]FEtO-CGS 25966 ([18F]1e, log D(exp) =2.02, IC50=2–50nM) all selected candidates showed increased hydrophilicities and inhibition potencies (log D(exp) =0.23–1.25, IC50=0.006–6nM). Interestingly, despite different hydrophilicities most triazole based MMPIs showed no significant differences in their in vivo biodistribution behavior and were cleared predominantly via the hepatobiliary excretion route. Biostability and metabolism studies in vitro and in vivo revealed significant higher metabolic stability for the triazole moiety compared to the benzyl ring in the lead structure. Cleavage of ethylene glycol subunits of the mini-PEG chain led to a faster metabolism of mini-PEG containing MMPIs. ConclusionThe introduction of hydrophilic groups such as mini-PEG and 1,2,3-triazole units did not lead to a significant shift of the hepatobiliary elimination towards renal clearance. Particularly the introduction of mini-PEG chains led to an intense metabolic decomposition. Substitution of the benzyl moiety in lead structure 1e by a 1,2,3-trizole ring resulted in an increased metabolic stability. Therefore, the 1,2,3-triazole-1-yl-methyl substituted MMPI [18F]3a was found to be the most stable candidate in this series and should be chosen for further preclinical evaluation.

1-Benzyl-5-methylindoline-2,3-dione

The title compound, C16H13NO2, is an isatin (indole-2,3-dione) derivative. The isatin moiety is almost planar with an r.m.s. deviation of 0.022 Å, and its mean plane makes a dihedral angle of 74.19 (12)° with the benzyl ring. In the crystal, molecules are linked by C—H...O hydrogen bonds, formingC(6) chains propagating along thea-axis direction. The chains are linkedviaC—H...π interactions, forming slabs parallel to theabplane. Within the slabs there are weak π–π interactions present involving inversion-related isatin moieties.

Targeting methionyl tRNA synthetase: design, synthesis and antibacterial activity against Clostridium difficile of novel 3-biaryl-N-benzylpropan-1-amine derivatives

The synthesis of a series of benzimidazole-N-benzylpropan-1-amines and adenine-N-benzylpropan-1-amines is described. Subsequent evaluation against two strains of the anaerobic bacterium Clostridium difficile was performed with three amine derivatives displaying MIC values of 16 μg/mL. Molecular docking studies of the described amines determined that the amines interact within two active site pockets of C. difficile methionyl tRNA synthetase with methoxy substituents in the benzyl ring and an adenine biaryl moiety resulting in optimal binding interactions.

Highly Permeable Artificial Water Channels that Self-Assemble into Two-Dimensional Arrays

Artificial nanoscale water channels are the future of cheap, low-power water filtration and desalinization. Biological water channels such as the aquaporin membrane protein selectively pass water across the cell membranes of living creatures, but are prohibitively difficult to incorporate into large-scale technological applications. In response to these challenges, many artificial channels have been designed to imitate the function of aquaporins, including a new single-molecule water channel we introduce here, peptide-appended pillar[5]arene (PAP). PAP is comprised of a single benzyl ring decorated by hydrophobic phenylalanine amino acid arms. Stopped-flow light scattering measurements combined with fluorescence correlation spectroscopy accurately characterized single channel PAP permeability as near to that of aquaporin itself, orders of magnitude better than first-generation artificial water channels. Molecular dynamics simulation supported this assessment and further predicted wetting-dewetting transitions to occur in individual PAP channels on the nanosecond timescale. Molecular dynamics simulation also predicted PAP self-assembly into two-dimentional arrays of lattice size 21 Å, driven by hydrogen bonds among the channel's peptide arms. Aggregation and lattice size were verified to within 1 Å by cryo-electron microscopy. The self-assembly of individual, highly permeable water channels into densely packed two-dimensional arrays can be potentially utilized to design a new generation of high-flux water filtration membranes. Furthermore, as the phenylalanine arms of PAP can be switched out for other amino acids, the individual channels and their self-assembly can be programmed to enable selective transmembrane transport.