Nonclassical Zwitterions as a Design Principle to Reduce Lipophilicity without Impacting Permeability.

The ionization of bioactive molecules impacts many ADME-relevant physicochemical properties, in particular, solubility, lipophilicity, and permeability. Ampholytes contain both acidic and basic groups and are distinguished as ordinary ampholytes and zwitterions. An influential review states that zwitterions only exist if the acidic pKa is significantly lower than the basic pKa. Through concordance of measured and calculated pKa and log P, we show that the zwitterionic behavior of several marketed drugs and natural products occurs despite a low or negative ΔpKa. These nonclassical zwitterions are characterized by a weak acidic and basic pKa and conjugation through an extended aromatic system, often including pseudorings via intramolecular hydrogen bonds. In contrast to most classical zwitterions, nonclassical zwitterions can exhibit excellent permeability. As permeability and lipophilicity are typically correlated, the combination of low lipophilicity and high permeability makes nonclassical zwitterions an attractive design principle in medicinal chemistry.

Photochemical C(sp)-C(sp2) Bond Activation in Phosphaalkynes: A New Route to Reactive Terminal Cyaphido Complexes LnM-C≡P.

The photochemical activation of the C(sp)-C(sp2) bond in Pt(0)-η2-aryl-phosphaalkyne complexes leads selectively to coordination compounds of the type LnPt(aryl)(C≡P). The oxidative addition reaction is a novel, clean, and atom-economic route for the synthesis of reactive terminal Pt(II)-cyaphido complexes, which can undergo [3 + 2] cycloaddition reactions with organic azides, yielding the corresponding Pt(II)-triazaphospholato complexes. The C-C bond cleavage reaction is thermodynamically uphill. Upon heating, the reverse and quantitative reductive elimination toward the Pt(0)-phosphaalkyne-π-complex is observed.

On modelling disordered crystal structures through restraints from molecule-in-cluster computations, and distinguishing static and dynamic disorder.

Distinguishing disorder into static and dynamic based on multi-temperature X-ray or neutron diffraction experiments is the current state of the art, but is only descriptive, not predictive. Here, several disordered structures are revisited from the Cambridge Crystallographic Data Center 'drug subset', the Cambridge Structural Database and own earlier work, where experimental intensities of Bragg diffraction data were available. Using the molecule-in-cluster approach, structures with distinguishable conformations were optimized separately, as extracted from available or generated disorder models of the respective disordered crystal structures. Re-combining these 'archetype structures' by restraining positional and constraining displacement parameters for conventional least-squares refinement, based on the optimized geometries, then often achieves a superior fit to the experimental diffraction data compared with relying on experimental information alone. It also simplifies and standardizes disorder refinement. Ten example structures were analysed. It is observed that energy differences between separate disorder conformations are usually within a small energy window of RT (T = crystallization temperature). Further computations classify disorder into static or dynamic, using single experiments performed at one single temperature, and this was achieved for propionamide.

Non-Innocent Methylene Linker in Bridged Lewis Pair Initiators.

Deprotonation usually occurs as an unwanted side reaction in the Lewis pair polymerization of Michael acceptors, for which the conjugated addition of the Lewis base to the acid-activated monomer is the commonly accepted initiation mechanism. This has also been reported for B-P-based bridged Lewis pairs (BLPs) that form macrocyclic addition products. We now show that the formerly unwanted deprotonation is the likely initiation pathway in the case of Al-P-based BLPs. In a detailed study of a series of Al-P-based BLPs, using a combination of single-crystal diffraction experiments (X-ray and neutron) and mechanistic investigations (experimental and computational), an active role of the methylene bridge was revealed, acting as a base towards the α-acidic monomers. Additionally, the polymerization studies proved a living behavior combined with significantly high activities, narrow molecular mass distributions, and the possibility of copolymerization.

Kinetic Trapping Effects in Amphiphilic Iron(II) Spin Crossover Compounds.

In this work, the synthesis of four new iron complexes with a Schiff base-like amphiphilic equatorial ligand (L) and dimethylaminopyridine (dmap) or 4,4'-bipyridine (bipy) as axial ligands is reported. Three of the complexes ([FeL(dmap)2] 1, [FeL(dmap)(MeOH)0.5]·MeOH 2, and [FeL(bipy)] n 3 have an iron(II) center, and two of those with an N4O2 coordination sphere (1 and 3) are spin crossover active. Both exhibit a thermal hysteresis (10 K with T1/2 = 131 K for 3 and 23 K with T1/2 = 161 K for 1) where the width depends on the velocity used for the measurement. Additionally, in both cases, the high spin state is trapped by rapid cooling, and a TTIESST was determined to be 121 K (1) and 101 K (3). Single crystals suitable for X-ray structure analysis were obtained for the three different complexes with dmap as axial ligand (1S, 2, and [µ-O-{FeL}2(dmap)] 4). The complex 1S has two dmap molecules in axial position, while the other two structures were obtained for a complex where a dmap ligand is exchanged by methanol and one where the iron(II) center is oxidized to iron(III) to form a dinuclear µ-O-complex. All three complexes were obtained under similar reaction conditions in the presence/absence of oxygen, and all three structures show the formation of lipid layer-like arrangements in the packing.

Aspherical scattering factors for SHELXL - model, implementation and application.

A new aspherical scattering factor formalism has been implemented in the crystallographic least-squares refinement program SHELXL. The formalism relies on Gaussian functions and can optionally complement the independent atom model to take into account the deformation of electron-density distribution due to chemical bonding and lone pairs. Asphericity contributions were derived from the electron density obtained from quantum-chemical density functional theory computations of suitable model compounds that contain particular chemical environments, as defined by the invariom formalism. Thanks to a new algorithm, invariom assignment for refinement in SHELXL is automated. A suitable parameterization for each chemical environment within the new model was achieved by metaheuristics. Figures of merit, precision and accuracy of crystallographic least-squares refinements improve significantly upon using the new model.

Universal Method for Electrostatic Interaction Energies Estimation with Charge Penetration and Easily Attainable Point Charges.

Our new model of electron density augmented by point charges (aug-PROmol) provides an estimation of electrostatic interaction energies including penetration effects ( ChemPhysChem 2016, 17, 2455-2460). In this paper we prove that it can be applied using sources of point charges other than those from direct restrained fitting to electrostatic potential (RESP). We used a newly established databank of tabulated invariom point charges and a widely known semiempirical method. Both sources perform equivalently to the basic aug-PROmol method as well as to reference energies at the DFT-SAPT/aug-cc-pVTZ level of theory. This is possible due to the universal character of the penetration model included in the aug-PROmol. Aug-PROmol may become a basis for development of new nonbonded terms in force fields or a high success rate scoring function.

Co-crystallization of atomically precise metal nanoparticles driven by magic atomic and electronic shells.

This paper reports co-crystallization of two atomically precise, different-size ligand-stabilized nanoclusters, a spherical (AuAg)267(SR)80 and a smaller trigonal-prismatic (AuAg)45(SR)27(PPh3)6 in 1:1 ratio, characterized fully by X-ray crystallographic analysis (SR = 2,4-SPhMe2). The larger cluster has a four concentric-shell icosahedral structure of Ag@M12@M42@M92@Ag120(SR)80 (M = Au or Ag) with the inner-core M147 icosahedron observed here for metal nanoparticles. The cluster has an open electron shell of 187 delocalized electrons, fully metallic, plasmonic behavior, and a zero HOMO-LUMO energy gap. The smaller cluster has an 18-electron shell closing, a notable HOMO-LUMO energy gap and a molecule-like optical spectrum. This is the first direct demonstration of the simultaneous presence of competing effects (closing of atom vs. electron shells) in nanocluster synthesis and growth, working together to form a co-crystal of different-sized clusters. This observation suggests a strategy that may be helpful in the design of other nanocluster systems via co-crystallization.

Comparison of Two Phosphinidenes Binding to Silicon(IV)dichloride as well as to Silylene.

The cyclic alkyl(amino) carbene (cAAC) anchored silylene with two phosphinidenes was isolated as (cAAC)Si{P(cAAC)}2 (3) at room temperature, which was synthesized from the reduction of (Cl2)Si{P(cAAC)}2 (2) using 2 equiv of KC8. Compound 2 resulted from the reaction of 2 equiv of (cAAC)PK (1) with 1 equiv of SiCl4. Compounds 2 and 3 are the first examples where two terminal phosphinidenes are binding each to a silicon center characterized by single crystal X-ray structural analysis. Furthermore, the structure and bonding of compounds 2 and 3 have been investigated by theoretical methods for comparison.

Catenation and Aggregation of Multi-Cavity Coordination Cages.

A series of metal-mediated cages, having multiple cavities, was synthesized from PdII cations and tris- or tetrakis-monodentate bridging ligands and characterized by NMR spectroscopy, mass spectrometry, and X-ray methods. The peanut-shaped [Pd3 L14 ] cage deriving from the tris-monodentate ligand L1 could be quantitatively converted into its interpenetrated [5Cl@Pd6 L18 ] dimer featuring a linear {[Pd-Cl-]5 Pd} stack as an unprecedented structural motif upon addition of chloride anions. Small-angle neutron scattering (SANS) experiments showed that the cigar-shaped assembly with a length of 3.7 nm aggregates into mono-layered discs of 14 nm diameter via solvophobic interactions between the hexyl sidechains. The hepta-cationic [5Cl@Pd6 L18 ] cage was found to interact with polyanionic oligonucleotide double-strands under dissolution of the aggregates in water, rendering the compound class interesting for applications based on non-covalent DNA binding.

Carbazole-, Aspidofractinine-, and Aspidocarpamine-Type Alkaloids from Pleiocarpa pycnantha.

Three new alkaloids, janetinine (1a), pleiokomenine A (2), and huncaniterine B (3a), and 13 known compounds, pleiomutinine (3b), huncaniterine A (3c), 1-carbomethoxy-ß-carboline (4), evoxanthine (5), deformyltalbotine acid lactone (6), pleiocarpamine (7), N4-methyl-10-hydroxygeissoschizol (8), spegatrine (9), neosarpagine (10), aspidofractinine (11), N1-methylkopsinin (12), pleiocarpine (13), and N1-methylkopsinin- N4-oxide (14), were isolated from the stem bark of Pleiocarpa pycnantha. Janetinine (1a) is a carbazole alkaloid; in pleiokomenine A (2), two aspidofractinine-type alkaloids are bridged by a methylene unit in an unprecedented way, and huncaniterine B (3a) is a pleiocarpamine-aspidofractinine-type dimer. The structures and relative configurations of these compounds were elucidated on the basis of NMR and MS analyses. Their absolute configurations were defined by means of experimental and calculated ECD data, and additionally, the structures of 5 and 13 were determined by single crystal X-ray diffraction. Compounds 1a, 2, 3b, 4, 6, 9, and 12 displayed cancer chemopreventive properties through either quinone reductase induction ( CD = 30.7, 30.2, 29.9, 43.5, and 36.7 µM for 1a, 4, 6, 9, and 12, respectively) and/or NF-κB inhibition with IC50 values of 13.1, 8.4, 9.4, and 8.8 µM for 2, 3b, 6, and 12, respectively.

Quantum Crystallography: Current Developments and Future Perspectives.

Crystallography and quantum mechanics have always been tightly connected because reliable quantum mechanical models are needed to determine crystal structures. Due to this natural synergy, nowadays accurate distributions of electrons in space can be obtained from diffraction and scattering experiments. In the original definition of quantum crystallography (QCr) given by Massa, Karle and Huang, direct extraction of wavefunctions or density matrices from measured intensities of reflections or, conversely, ad hoc quantum mechanical calculations to enhance the accuracy of the crystallographic refinement are implicated. Nevertheless, many other active and emerging research areas involving quantum mechanics and scattering experiments are not covered by the original definition although they enable to observe and explain quantum phenomena as accurately and successfully as the original strategies. Therefore, we give an overview over current research that is related to a broader notion of QCr, and discuss options how QCr can evolve to become a complete and independent domain of natural sciences. The goal of this paper is to initiate discussions around QCr, but not to find a final definition of the field.

Hierarchical Assembly of an Interlocked M8 L16 Container.

The self-assembly of eight PdII cations and sixteen phenanthrene-derived bridging ligands with 60° bite angles yielded a novel M8 L16 metallosupramolecular architecture composed of two interlocked D4h -symmetric barrel-shaped containers. Mass spectrometry, NMR spectroscopy, and X-ray analysis revealed this self-assembled structure to be a very large "Hopf link" catenane featuring channel-like cavities, which are occupied by NO3- anions. The importance of the anions as catenation templates became imminent when we observed the nitrate-triggered structural rearrangement of a mixture of M3 L6 and M4 L8 assemblies formed in the presence of BF4- anions into the same interlocked molecule. Furthermore, the densely packed structure of the M8 L16 catenane was exploited in the preparation of a hexyloxy-functionalized analogue, which further self-assembled into vesicle-like aggregates in a reversible manner.

Reagent for Introducing Base-Stabilized Phosphorus Atoms into Organic and Inorganic Compounds.

The cyclic alkyl(amino) carbene (cAAC) stabilized monoanionic phosphorus atom in the form of lithium phosphinidene [cAACPLi(THF)2]2 (1) has been isolated as a molecular species and characterized by single crystal X-ray structure analysis. Furthermore, the structure and bonding of compound 1 has been investigated by theoretical methods. The utilization of the lithium phosphinidene as a phosphorus transfer reagent for a wide range of organic and inorganic substrates has been investigated. Herein, we report on the preparation of fascinating compounds containing P-C, P-Si, P-Ge, and P-P bonds using a single step with a base-stabilized phosphorus atom.

Validation of X-ray Wavefunction Refinement.

In this work, the quality of the electron density in crystals reconstructed by the multipolar model (MM) and by X-ray wavefunction refinement (XWR) is tested on a set of high-resolution X-ray diffraction data sets of four amino acids and six tripeptides. It results in the first thorough validation of XWR. Agreement statistics, figures of merit, residual- and deformation-density maps, as well as atomic displacement parameters are used to measure the quality of the reconstruction relative to the measured structure factors. Topological analysis of the reconstructed density is carried out to obtain atomic and bond-topological properties, which are subsequently compared to the values derived from benchmarking periodic DFT geometry optimizations. XWR is simultaneously in better agreement than the MM with both benchmarking theory and the measured diffraction pattern. In particular, the obvious problems with the description of polar bonds in the MM are significantly reduced by using XWR. Similarly, modeling of electron density in the vicinity of hydrogen atoms with XWR is visibly improved.

Using invariom modelling to distinguish correct and incorrect central atoms in `duplicate structures' with neighbouring 3d elements.

Modelling coordination compounds has been shown to be feasible using the invariom method; for the best fit to a given set of diffraction data, additional steps other than using lookup tables of scattering factors need to be carried out. Here such procedures are applied to a number of `duplicate structures', where structures of two or more supposedly different coordination complexes with identical ligand environments, but with different 3d metal ions, were published. However, only one metal atom can be plausibly correct in these structures, and other spectroscopic data are unavailable. Using aspherical scattering factors, a structure can be identified as correct from the deposited Bragg intensities alone and modelling only the ligand environment often suffices to make this distinction. This is not possible in classical refinements using the independent atom model. Quantum-chemical computations of the better model obtained after aspherical-atom refinement further confirm the assignment of the element in the respective figures of merit.

Synthesis and characterization of Lewis base stabilized mono- and di-organo aluminum radicals.

Two cyclic (alkyl)(amino)carbene (cAAC) stabilized mononuclear neutral radicals of aluminum have been synthesized. They contain an ethyl [(cAAC)2AlClEt (1)] and as well a diethyl group [(cAAC)2AlEt2 (2)], and have been prepared from the reduction of EtAlCl2 and Et2AlCl, respectively, with KC8. Compounds 1 and 2 are monoradicals, which were confirmed by EPR measurements to have the spin located on the carbene carbon of one of the cAAC ligands.

Protonation of Ferrocene: A Low-Temperature X-ray Diffraction Study of [Cp2 FeH](PF6 ) Reveals an Iron-Bound Hydrido Ligand.

Ferrocene, Cp2 Fe, is quantitatively protonated in a mixture of liquid HF/PF5 to yield [Cp2 FeH](PF6 ), which was characterized by 1 H/13 C NMR and 57 Fe Mössbauer spectroscopy as well as single-crystal X-ray diffraction analysis. X-ray diffraction analysis at 100 K revealed a disordered, iron-coordinated hydrido ligand, which was unambiguously located by aspherical atom refinement at 100 K, and by analyzing the non-disordered crystal structure at 30 K, revealing a non-agostic structure.

An Icosidodecahedral Supramolecule Based on Pentaphosphaferrocene: From a Disordered Average Structure to Individual Isomers.

Pentaphosphaferrocenes [CpR Fe(η5 -P5 )] (1) and CuI halides are excellent building blocks for the formation of discrete supramolecules. Herein, we demonstrate the potential of Cu(CF3 SO3 ) for the construction of the novel 2D polymer [{Cp*Fe(µ4 ,η5:1:1:1 -P5 )}{Cu(CF3 SO3 )}]n (2) and the unprecedented nanosphere (CH2 Cl2 )1.4 @[{CpBn Fe(η5 -P5 )}12 {Cu(CF3 SO3 )}19.6 ] (3). The supramolecule 3 has a unique scaffold beyond the fullerene topology, with 20 copper atoms statistically distributed over the 30 vertices of an icosidodecahedron. Combinatorics was used to interpret the average disordered structure of the supramolecules. In this case, only two pairs of enantiomers with D5 and D2 symmetry are possible for bidentate bridging coordination of the triflate ligands. DFT calculations showed that differences in the energies of the isomers are negligible. The benzyl ligands enhance the solubility of 3, enabling NMR-spectroscopic and mass-spectrometric investigations.

Organosilicon Radicals with Si-H and Si-Me Bonds from Commodity Precursors.

The cyclic alkyl(amino) carbene (cAAC) stabilized biradicals of composition (cAAC)2SiH2 (1), (cAAC)SiMe2-SiMe2(cAAC) (2), and (cAAC)SiMeCl-SiMeCl(cAAC) (3) have been isolated as molecular species. All the compounds are stable at room temperature for more than 6 months under inert conditions in the solid state. All radical species were fully characterized by single-crystal X-ray structure analysis and EPR spectroscopy. Furthermore, the structure and bonding of compounds 1-3 have been investigated by theoretical methods. Compound 1 contains the SiH2 moiety and this is the first instance, where we have isolated 1 without an acceptor molecule.