6-membered Ring Research Articles

Analysis of soot formation of CH4 and C2H4 with H2 addition via ReaxFF molecular dynamics and pyrolysis–gas chromatography/mass spectrometry

A combined numerical and experimental investigation of the different chemical effects of H2 (CE-H2) on soot formation was conducted by applying the reactive molecular dynamics simulation (ReaxFF MD) and the pyrolysis–gas chromatography/mass spectrometry (Py–GC/MS) diagnostic technique. In addition, the detailed chemical reaction pathway for the different CE-H2 was explored in the combustion of methane (CH4) and ethylene (C2H4) fuels. It was found that both the experimental and numerical results reflected the evolution of polycyclic aromatic hydrocarbons (PAHs) and initial soot particles and the different CE-H2 on PAHs/soot formation. The primary reason for the different CE-H2 was that the hydrogen addition led to the production of a large number of hydrogen atoms, which promoted acetylene (C2H2) formation during the methane combustion through the chemical reactions C2H5 + H ↔ C2H4 + H2 and C2H4 + H ↔ C2H3 + H2, but inhibited acetylene formation during the ethylene combustion through the chemical reaction C2H3 ↔ C2H2 + H. The hydrogen addition only increased the number of 6-membered rings in the largest PAH/soot particle of methane combustion but decreased the numbers of all ringed compounds in the largest PAH/soot particle of ethylene combustion. Moreover, the CE-H2 promoted methane pyrolysis but inhibited ethylene pyrolysis.

Catalytic Reactions Directed by a Structurally Well-Defined Aminomethyl Cyclopalladated Complex.

The introduction of N-containing moieties into feedstock molecules to build nitrogenated functional molecules has always been widely studied by the organic chemistry community. Progress in this field paves new roads to the synthesis of N-containing molecules, which are of significant importance in biological activities and play vital roles in pharmaceuticals and functional materials. Remarkable progress has been achieved in the field of transition metal-catalyzed C-N bond-forming reactions, typified by alkene hydroamination and the aza-Wacker reaction. However, the poisoning effect of electron-donating amine substrates on late transition metal catalysts presents a key impediment to these reactions, thus limiting the scope of amine substrates to electron-deficient amide derivatives. To address this problem, our group developed a palladium-aminomethyl complex with a three-membered palladacycle structure that allowed for the incorporation of electron-rich amine building blocks via C-C bond instead of C-N bond construction. This Account details the discovery of the well-defined aminomethyl cyclopalladated complex and recapitulates its applications for the catalysis of a series of aminomethylation reactions. We highlight how the understanding of the fundamental structural properties of the defined complex guided us toward tuning the reactivity of nucleophiles to initiate aminomethylation in different modes. Moreover, principles of designing and establishing further cascade reactions are also described.Aminomethyl cyclopalladated complexes can be prepared via the oxidative addition of aminals or N,O-acetals to Pd0 species. Thorough structural investigations by single-crystal X-ray diffraction analysis of the cyclopalladated complex suggest the presence of both aminomethylene-PdII (3-membered-ring) and Pd0-iminium (π-ligated) resonance forms, which indicates that both the palladium center and the methylene site are electrophilic. This is further verified by analysis of charge distribution. Two general types of reactions can be established, differing by the selective affinity of the nucleophiles to the two electrophilic positions, which is relevant to the "hardness suitability" of the nucleophiles with each electrophilic site. Softer nucleophiles such as alkenes prefer to attack the palladium center to initiate the reaction, mainly via migratory insertion into the Pd-C bond on the 3-membered ring with high strain. Through tandem β-hydride or reductive elimination, the Heck-type aminomethylation of styrenes, the aminomethylalkoxylation of electron-rich olefins, and even the aminomethylamination of allenes, dienes, enynes, and carbenoids with full atom-economy have been realized in line with this reaction mode. In contrast, harder nucleophiles tend to attack the harder electrophilic methylene site, leading to the aminomethylation of electron-deficient dienes. For secondary amines, a "C-N bond metathesis" process would be furnished through a reductive elimination, 1,3-proton transfer, and oxidative addition sequence. More intriguingly, when using appropriate "dinucleophile" substrates such as electron-rich amine-tethered dienes, sequential C-N bond metathesis and intramolecular insertion would occur to furnish Pd-catalyzed annulation reactions, which exhibits both the hard and soft nucleophile reactivities mentioned above. These transformations provide convenient methods for the preparation of N-containing molecules, such as amines, diamines, amino acetals, and multiple types of N-heterocycles.

Resorcylic acid lactones from a Podospora sp. that induce apoptosis in activated T cells through MAPKs/AKT pathway

Podomycins A–L (1–12), 12 undescribed hypothemycin-type resorcylic acid lactones (RALs), were characterized from Podospora sp. G214, an endophyte harbored in the roots of Sanguisorba officinalis L. Their structures were addressed by spectroscopic data, X-ray crystallography, the modified Mosher’s method, together with Mo2(OAc)4- and Rh2(OCOCF3)4-induced electronic circular dichroism (ICD) experiments. Podomycins A–C (1–3) represent the first class of natural RALs with a 13-membered macrolactone ring, while 4–12 are rearranged methoxycarbonyl substituted RALs. Biologically, compounds 2, 6, 8, 10, and 12 displayed immunosuppressive activities against T cell proliferation with IC50 values of 14.5–21.9 μM, and B cell proliferation with IC50 values of 22.3–36.5 μM, respectively. Further mechanism of action research demonstrated that podomycin F (6) distinctly induced apoptosis in activated T cells via MAPKs/AKT pathway.

Brightly Luminescent Platinum Complexes of N∧C-∧N Ligands Forming Six-Membered Chelate Rings: Offsetting Deleterious Ring Size Effects Using Site-Selective Benzannulation.

Brightly emissive platinum(II) complexes (λemission,max = 607-612 nm) of the type RLPtCl are reported, where RL is a cyclometalated N∧C-∧N-coordinating ligand derived from 1,3-di(2-trifluoromethyl-4-phenanthridinyl)benzene (CF3LH) or 1,3-di(2-tert-butyl-4-phenanthridinyl)benzene (tBuLH). Metathesis of the chlorido ligand can be achieved under mild conditions, enabling isolation of ionic compounds with the formula [CF3LPtL']PF6 where L' = pyridine or (4-dimethylamino)pyridine (DMAP), as well as the charge-neutral species tBuLPt(C≡C─C6H4─tBu) (C≡C─C6H4─tBu = 4-tert-butylphenylacetylido). Compared with N∧N∧N-ligated Pt(II) complexes that form 5-membered chelates, these compounds all contain 6-membered rings. Expanding the chelate ring size from 5 to 6 has been previously demonstrated to enhance emission in some N∧N∧N-coordinated Pt(II) species─for example, in complexes of 2,6-di(8-quinolinyl)pyridine vs those of 2,2':6',2″-terpyridine─but in related N∧C-∧N-coordinated species, luminescence quantum yields are significantly lower for the 6-membered chelate ring complexes. Here, we demonstrate that site-selective benzannulation of the quinolinyl side-arms can offset the deleterious effect of changing the chelate ring-size and boost photophysical properties such as the quantum yield. Density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations suggest that benzannulation counterintuitively destabilizes the emissive triplet states compared to the smaller π-system, with the "imine-bridged biphenyl" form of the phenanthridinyl arm helping to buffer against larger molecular distortions, enhancing photoluminescence quantum yields up to 0.09 ± 0.02. The spontaneous formation under aerated conditions of a Pt(IV) derivative (CF3LPtCl3) is also reported, together with its molecular structure in the solid state.

Stability, optical and charge transport properties of saddle-shaped cyclooctatetrathiophene (COTh) isomers: a theoretical study

Design and structure–property relationship studies of the system containing a cyclooctatetraene (COT) ring fused with four 5-membered heterocyclic rings have been reported. The five-membered heterocycle chosen for the present study is thiophene and based on connectivity with COT, cyclooctatetrathiophene (COTh) exists in fifteen geometrical isomers. The systematic reviews of all the isomers of COTh, are carried out by utilizing density functional theory (DFT) and time dependent-density functional theory (TD-DFT) calculations. Electronic excitations, reorganization energies (transport properties of electron and hole), electron affinities (EA) and ionization potentials (IP) of all the isomers are reported. Based on the outcomes of this study, we suggest that one of the isomers, among all fifteen possible isomers, is better suited for applications that take advantage of its charge transport properties.

LiB9O15·H2dap·H2O: A Cotemplated Acentric Layer-Pillared Borate Built by Mixed Oxoboron Clusters.

An acentric layer-pillared borate, LiB9O15·H2dap·H2O (1, dap = 1,3-diaminopropane), cotemplated by organic and inorganic cations and build by mixed oxoboron cluster units of B6O138- and B3O75-, has first been made under solvothermal conditions, in which the B6O138- clusters link each other to form 2D layers containing 9-membered ring (MR) windows, while the B3O75- clusters join together to produce 1D chains that further perform as the pillars to connect neighboring layers, resulting in a 3D layer-pillared framework with 13- and 7-MR channels located by H2dap2+ and Li+ cations, respectively. Its second harmonic generation shows a response of ∼2.1 times that of KDP (KH2PO4).

Implications of the Conformationally Flexible, Macrocyclic Structure of the First-Generation, Direct-Acting Anti-Viral Paritaprevir on Its Solid Form Complexity and Chameleonic Behavior.

Direct-acting antiviral regimens have transformed therapeutic management of hepatitis C across all prevalent genotypes. Most of the chemical matter in these regimens comprises molecules well outside the traditional drug development chemical space and presents significant challenges. Herein, the implications of high conformational flexibility and the presence of a 15-membered macrocyclic ring in paritaprevir are studied through a combination of advanced computational and experimental methods with focus on molecular chameleonicity and crystal form complexity. The ability of the molecule to toggle between high and low 3D polar surface area (PSA) conformations is underpinned by intramolecular hydrogen bonding (IMHB) interactions and intramolecular steric effects. Computational studies consequently show a very significant difference of over 75 Å2 in 3D PSA between polar and apolar environments and provide the structural basis for the perplexingly favorable passive permeability of the molecule. Crystal packing and protein binding resulting in strong intermolecular interactions disrupt these intramolecular interactions. Crystalline Form I benefits from strong intermolecular interactions, whereas the weaker intermolecular interactions in Form II are partially compensated by the energetic advantage of an IMHB. Like Form I, no IMHB is observed within the receptor-bound conformation; instead, an intermolecular H-bond contributes to the potency of the molecule. The choice of metastable Form II is derisked through strategies accounting for crystal surface and packing features to manage higher form specific solid-state chemical reactivity and specific processing requirements. Overall, the results show an unambiguous link between structural features and derived properties from crystallization to dissolution, permeation, and docking into the protein pocket.

Transformation synthesis of SSZ-13 zeolite from ZSM-35 zeolite

Interzeolite conversion as a promising alternative strategy for zeolite synthesis has received extensive attention. It is of great significance to understand the potential rules of conversion between zeolites with different topologies for effective regulation of zeolite synthesis. Hydrothermal conversion of ZSM-35 (FER-type) zeolite containing the mor composite building units into SSZ-13 zeolite (CHA-type) using N,N,N-trimethyl-1-adamantammonium hydroxide (TMAdaOH) as template was performed for the first time. The effects of TMAdaOH/SiO2 ratio, Na2O/SiO2 ratio, the additional starting zeolite and crystallization time on the interzeolite conversion of ZSM-35 into SSZ-13 were investigated. The interzeolite conversion mechanism concerning the synthesis of SSZ-13 from ZSM-35 zeolite was proposed and verified by DFT calculation. The results of DFT calculations suggested that ZSM-35 zeolite with mor composite building unit had the potential to decompose into 6-Membered Rings, and further transform into CHA-type zeolite containing d6r composite building unit. Therefore, zeolites containing mor structure have the potential to be converted into zeolites containing d6r structure.

Modification of graphenylene nanostructure with transition metals (Fe, Sc and Ti) to promote hydrogen storage ability: A DFT-D3 study

Hydrogen, as a clean alternative to fossil fuels, has received much attention in recent years. But its utilizing requires to overcome storage problems. Here, we investigated the hydrogen adsorption behavior of graphenylene (GPY), a 2D carbon nanostructure, and Sc, Fe and Ti transition metal (TM) decorated GPY by spin-polarized DFT calculations. For TM-decoration of GPY, seven different sites and various distances from carbon sheet were investigated, carefully. Structural and electronic properties of the structures, adsorption energies, band gap values, and the most stable configurations were considered and discussed. Results showed that 6-membered ring (H2 site) is the best site for Sc, Fe, and Ti-decoration and corresponding Eads was −3.95, −2.66, and −3.65 eV, respectively. Also, pristine GPY and Sc and Ti-decorated GPY have not magnetic character, unlike Fe-GPY. As well, entrance of Sc, Fe and Ti atoms in H2 site of the GPY structure causes its band gap increases from 0.033 eV to of 0.491, 0.080, and 0.372 eV, respectively. Eads of the H2 molecule onto pristine GPY is low (−0.160 eV), and must be improved for practical hydrogen storage applications. Sc, Fe, and Ti-decoration improves it about 2.23, 5.69 and 3.63 times. Because of this improvement, we could store up to 20H2 molecules on TM-decorated GPY systems. These results indicate that TM-decorated GPY can be a suitable option for H2 storage applications in the future.

Recent Developments and Biological Activities of 5-Oxo-Imidazolones Derivatives: A Review

Heterocyclic compounds are essential primary units for both the synthetic and natural starting points. 5-oxo-imidazolone is a 5-member ring system that contains 3 carbons and 2 nitrogens that are arranged at 3 and 1 positions, and ─C═O at the 5th position of the ring. 5-oxo-imidazolone is known as a privileged molecule because of its all biological potency. This biological property increased the attention of many investigators to analyze this ring system and expose several activities. The present review aims to outline the various activities reported on the synthesis and the biological potencies of 5-oxo-imidazolone derivatives. 5-oxo-imidazolone is an important pharmacophore in modern drug discovery.

Energy intensity of hydrocarbons in liquid and solid states

Objectives. The increased use of unmanned aerial vehicles necessitates the search for jet fuels based on hydrocarbon materials with high energy intensity and physical density. The purpose of the work was to analyze the influence of various factors on the mass energy intensity of hydrocarbons. This analysis is required to substantiate the algorithm for locating energy-intensive CnHm structures.Methods. Combustion energy was calculated using additive procedures. The calculations were performed using Microsoft Excel.Results. During the analysis of the mass energy intensity of CnHm hydrocarbons, the m/n ratio was discovered to be the decisive factor for achieving high values of the mass energy intensity of hydrocarbons. The energy intensity decreases when moving from alicyclic to cyclic hydrocarbons, and this decrease is not compensated by the production of strain energy. An additive scheme that allows the molar volume of hydrocarbons to be predicted with sufficient accuracy is proposed for calculating the volumetric enthalpies of combustion.Conclusions. According to the thermodynamic analysis, n-alkanes have the highest mass energy intensities. The technology for extracting n-alkanes from oil fractions is well developed, and a decrease in the hydrogen content in the fuel results in a decrease in the mass energy intensity. It appears improbable that the mass and volumetric energy intensities of hydrocarbons seem will reach their maximum values simultaneously. Hydrocarbons that have a high m/n value, 2, 3, 4, 5, 6-membered rings, and phenyl fragments may have relatively high mass and volumetric energy intensities at the same time.

A new Fe3+ colorimetric sensor: Nitrophenyl bispyrazole derivative synthesis using Fe3O4@SiO2@Si-Pr-NH-(CH2)2-NH2 and its DFT study

The efficient synthesis of bispyrazole derivatives was reported in the presence of Fe3O4@SiO2@Si-Pr-NH-(CH2)2-NH2 as a nanomagnetic catalyst in solvent-free conditions. The UV–Vis spectroscopy study of 4,4'-((3-nitrophenyl)methylene)bis(3-methyl-1H-pyrazol-5-ol) derivative 6a was demonstrated that it could be used as a Fe3+ ion colorimetric chemosensor, which was shown an apparent color change from white to orange with high selectivity toward the addition of Fe3+ ion in CH3CN/H2O (1:9 v/v) as a solvent. The UV–Vis absorption was increased linearly, and its detection limit was calculated 2.19 × 10−6 M.The orientations of hydroxyl groups for 5-membered and 6-membered rings of the most stable configurations of the bispyrazoles cause generation of T-shaped conformations based on Independent Gradient Model (IGM) analysis, conformational stability of the considered complexes can be related to the formation of σ-π molecular interaction heterocyclic rings which confirms with the vibrational stretching modes of hydroxyl groups and the character of the Kohn-Sham HOMO and LUMO orbitals.

Contribution of hydrogen bonding to liquid-phase adsorptive removal of hazardous organics with metal-organic framework-based materials

Removing hazardous organics from water or fuel is important for our clean environment; adsorption over porous materials has been a competitive means to eliminate such organics. Here, the adsorption or removal of hazardous organics with metal–organic framework-based adsorbents was explained, especially adsorption that relies on hydrogen bonding (H-bonding). The bonding details (direction, quantitative contribution, importance of 6-membered rings, and characterizations to support H-bonding) and improved performance via H-bonding were investigated. Finally, prospects for further development or research in the relevant fields were suggested.

Co-Crystalline ZSM-5/ZSM-11 Nanostructures for Alkylation of Benzene with Ethanol

The interzeolite transformation approach has been used extensively for the quick synthesis of zeolites at a lower cost. Herein, an interzeolite transformation method for the quick synthesis of co-crystalline ZSM-5/ZSM-11 (CDM-5) nanoaggregates has been developed by precisely controlling the synthesis parameters and using 1,6-hexamethylenediamine as an organic structure-directing agent. In contrast, the irregular CDM-5 zeolite block obtained from an amorphous aluminosilicate gel takes a longer crystallization time using the conventional method. Combined with the related results of characterization, UV-Raman spectra show that double 6-membered rings in the parent USY zeolite framework are broken, and an ordered aluminosilicate aggregate species (OAAS) containing 4-membered rings (4Rs) are formed during the interzeolite transformation. HRTEM and SEM images demonstrate that the block OAAS is dissolved into amorphous nanoparticles, followed by converting into CDM-5 nanoaggregates. These results reveal that an OAAS is essential for the synthesis of CDM-5 nanoaggregates via the interzeolite transformation method. In addition, the CDM-5 nanoaggregate catalyst exhibits superior stability and resistance to carbon deposition in the alkylation reaction of benzene with ethanol compared with the irregular block CDM-5 catalyst.

On the radical behavior of large polycyclic aromatic hydrocarbons in soot formation and oxidation

The mechanism of evolution of polycyclic aromatic hydrocarbons (PAHs) into carbonaceous particles in combustion, atmosphere, and interstellar space has been the subject of intense debate. Recently, there has been emerging evidence supporting resonantly-stabilized radicals as key players in PAH growth. In this work, we build on this hypothesis and propose that, beyond a critical size, PAH reactivity can be assimilated to that of radicals. We found that odd-C-numbered PAHs embedding 5-membered rings rapidly lose a hydrogen atom to form resonantly-stabilized radicals in combustion conditions, while even-C-numbered PAHs react as open-shell rather than closed-shell molecules independently of temperature, as usually assumed. Acenes were used as molecular models of large even-C-numbered PAHs. The construction of a kinetic model including these findings allows to interpret experimental soot oxidation data otherwise irreconcilable with existing chemical kinetic mechanisms.

Electrophotochemical Ring-Opening Bromination of tert-Cycloalkanols.

An electrophotochemical ring-opening bromination of unstrained tert-cycloalkanols has been developed. This electrophotochemical method enables the oxidative transformation of cycloalkanols with 5- to 7-membered rings into synthetically useful ω-bromoketones without the use of chemical oxidants or transition-metal catalysts. Alkoxy radical species would be key intermediates in the present transformation, which generate through homolysis of the O-Br bond in hypobromite intermediates under visible light irradiation.

Molecular dynamics simulation of evolution of nanostructures and functional groups in glassy carbon under pyrolysis

With the continued and sustained growth of the field of carbon MEMS (C-MEMS) in several application areas, there is a corresponding increased and renewed interest in understanding the exact molecular structure of the ensuing glassy carbon (GC) material and, therefore, potential to engineer some of its key characteristics. Associated with that interest, the effects of key process parameters like temperature ramping, holding and cooling times on carbonization, the final nanostructures and – importantly – on the nature and distribution of functional groups remain to be of significant research importance to the GC community. While recent in-situ imaging approaches during the synthesis process have opened up opportunities for better understanding of these nanostructures, the 2D nature of the approaches, however, had introduced significant barriers. In this paper, therefore, we present a simulation-based approach using reactive molecular dynamics (MD) where we model the synthesis process and investigate in detail (i) the intermediate and final stages of carbonization with particular focus on GC nanostructures and (ii) formation of functional groups and the processes and parameters that drive their evolution. Our simulation captured the pyrolysis-driven synthesis process where the polymer structure degraded followed by increased carbonization and formation of flakes of 3-, 4-, membered carbon rings that further grew into graphene-type 6-member carbon rings as well as 5- and 7-member rings. These eventually evolved into a complex multi-layer 3D nanostructure consisting of connected but distinct zones of (a) dominant cage-like tubular components and (b) long chains of flat graphene-like parts rich with functional groups. Taken together, the MD simulations demonstrate that (i) holding time at the maximum temperature has the most significant effect in the formation of complex cage-like 3D nanostructures with stacked layers, (ii) the closed cage-like zones have crystallite diameter (La) in the range of 3.2 Å - 9.5 Å with clear and well-defined curved and stacked graphene-like sheets of stacking thickness (Lc) = 3.0 Å - 3.3 Å, (iii) carbonyl, ether, epoxide, hydroxyl, and alkyne groups form predominately on the edges of flat components of GC where abundant non-6 membered rings, dangling bonds, long sp carbon chains, and intermediate structures exist, and to a lesser extent on edges of vacancy defects inside cage-like zones.

Computational and NMR Conformational Analysis of Galactofuranoside Cycles Presented in Bacterial and Fungal Polysaccharide Antigens.

Unlike pyranoside cycles which are generally characterized by strictly defined conformational preferences, furanosides are flexible and may adopt a wide range of available conformations. During our previous studies, conformational changes of galactofuranoside cycles upon total sulfation were described computationally, using a simple Hartree–Fock (HF) method, and principal conformers of the 5-membered galactose ring were revealed. However, in the case of more complex disaccharide structures, it was found that this method and the widely applied DFT-B3LYP produced results that deviated from experimental evidence. In this study, other DFT functionals (PBE0 and double hybrid B2PLYP) along with RI-MP2 are employed to study the conformational behavior of the galactofuranoside ring. Reinvestigation of galactofuranosides with a lactic acid substituent at O-3 revealed that changes in the orientation of lactic acid residue at O-3 might induce conformational changes of the furanoside cycle. Such findings are important for further modeling of carbohydrate–protein interaction.

Synthesis of 1-(2,4-Dinitrophenyl)-3,5-diphenyl-1H-pyrazol-4-ol via trans-1,3-Diphenyl-2,3-epoxy-1-propanone

The trans-1,3-diphenyl-2,3-epoxy-1-propanone was synthesized from benzaldehyde and 2-bromoacetophenone in 20 min which is more economical. The presence of ethanol and Br in 2-bromoacetophenone facilitated the reaction. The vicinal diaxial coupling constant of trans-1,3-diphenyl-2,3-epoxy-1-propanone was zero, an indication of trans configuration for a rigid 3-membered ring at ~90o dihedral angle. 1-(2,4-Dinitrophenyl)-3,5-diphenyl-1H-pyrazol-4-ol was synthesized from trans-1,3-diphenyl-2,3-epoxy-1-propanone and 2,4-dinitro phenylhydrazine in glacial CH3COOH to give 85.5% yield and characterized using FTIR, 1H, 13C NMR, DEPT 135 and MS spectra. The 1-(2,4-dinitrophenyl)-3,5-diphenyl-1H-pyrazol-4-ol can be exploited for unique biological activities and in the synthesis of synthetic fibers.
 Keywords: 1-(2,4-dinitrophenyl)-3,5-diphenyl-1H-pyrazol-4-ol, trans-1,3-diphenyl-2,3-epoxy-1-propanone; synthesis; 2,4-dinitro phenylhydrazine

Ribosome-binding and anti-microbial studies of the mycinamicins, 16-membered macrolide antibiotics from Micromonospora griseorubida.

Macrolides have been effective clinical antibiotics for over 70 years. They inhibit protein biosynthesis in bacterial pathogens by narrowing the nascent protein exit tunnel in the ribosome. The macrolide class of natural products consist of a macrolactone ring linked to one or more sugar molecules. Most of the macrolides used currently are semi-synthetic erythromycin derivatives, composed of a 14- or 15-membered macrolactone ring. Rapidly emerging resistance in bacterial pathogens is among the most urgent global health challenges, which render many antibiotics ineffective, including next-generation macrolides. To address this threat and advance a longer-term plan for developing new antibiotics, we demonstrate how 16-membered macrolides overcome erythromycin resistance in clinically isolated Staphylococcus aureus strains. By determining the structures of complexes of the large ribosomal subunit of Deinococcus radiodurans (D50S) with these 16-membered selected macrolides, and performing anti-microbial studies, we identified resistance mechanisms they may overcome. This new information provides important insights toward the rational design of therapeutics that are effective against drug resistant human pathogens.