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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 p K a is significantly lower than the basic p K a . Through concordance of measured and calculated p K a and log P , we show that the zwitterionic behavior of several marketed drugs and natural products occurs despite a low or negative Δp K a . These nonclassical zwitterions are characterized by a weak acidic and basic p K a 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.

The photochemical activation of the C( sp )-C( sp 2 ) bond in Pt(0)-η 2 -aryl-phosphaalkyne complexes leads selectively to coordination compounds of the type L n Pt(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.

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., (© Birger Dittrich 2021.)

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., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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 N 4 O 2 coordination sphere (1 and 3) are spin crossover active. Both exhibit a thermal hysteresis (10 K with T 1/2 = 131 K for 3 and 23 K with T 1/2 = 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 T TIESST 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.

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., (open access.)

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.

A series of metal-mediated cages, having multiple cavities, was synthesized from Pd II cations and tris- or tetrakis-monodentate bridging ligands and characterized by NMR spectroscopy, mass spectrometry, and X-ray methods. The peanut-shaped [Pd 3 L 1 4 ] cage deriving from the tris-monodentate ligand L 1 could be quantitatively converted into its interpenetrated [5Cl@Pd 6 L 1 8 ] 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@Pd 6 L 1 8 ] 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., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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 (PPh 3 ) 6 in 1:1 ratio, characterized fully by X-ray crystallographic analysis (SR = 2,4-SPhMe 2 ). The larger cluster has a four concentric-shell icosahedral structure of Ag@M 12 @M 42 @M 92 @Ag 120 (SR) 80 (M = Au or Ag) with the inner-core M 147 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.

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 (Cl 2 )Si{P(cAAC)} 2 (2) using 2 equiv of KC 8 . Compound 2 resulted from the reaction of 2 equiv of (cAAC)PK (1) with 1 equiv of SiCl 4 . 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.

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., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Three new alkaloids, janetinine (1a), pleiokomenine A (2), and huncaniterine B (3a), and 13 known compounds, pleiomutinine (3b), huncaniterine A (3c), 1-carbomethoxy-β-carboline (4), evoxanthine (5), deformyltalbotine acid lactone (6), pleiocarpamine (7), N 4 -methyl-10-hydroxygeissoschizol (8), spegatrine (9), neosarpagine (10), aspidofractinine (11), N 1 -methylkopsinin (12), pleiocarpine (13), and N 1 -methylkopsinin- N 4 -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 IC 50 values of 13.1, 8.4, 9.4, and 8.8 μM for 2, 3b, 6, and 12, respectively.

The self-assembly of eight Pd II cations and sixteen phenanthrene-derived bridging ligands with 60° bite angles yielded a novel M 8 L 16 metallosupramolecular architecture composed of two interlocked D 4h -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 NO 3 - anions. The importance of the anions as catenation templates became imminent when we observed the nitrate-triggered structural rearrangement of a mixture of M 3 L 6 and M 4 L 8 assemblies formed in the presence of BF 4 - anions into the same interlocked molecule. Furthermore, the densely packed structure of the M 8 L 16 catenane was exploited in the preparation of a hexyloxy-functionalized analogue, which further self-assembled into vesicle-like aggregates in a reversible manner., (© 2018 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

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.

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., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Ferrocene, Cp 2 Fe, is quantitatively protonated in a mixture of liquid HF/PF 5 to yield [Cp 2 FeH](PF 6 ), 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., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Pentaphosphaferrocenes [Cp R Fe(η 5 -P 5 )] (1) and Cu I halides are excellent building blocks for the formation of discrete supramolecules. Herein, we demonstrate the potential of Cu(CF 3 SO 3 ) for the construction of the novel 2D polymer [{Cp*Fe(μ 4 ,η 5:1:1:1 -P 5 )}{Cu(CF 3 SO 3 )}] n (2) and the unprecedented nanosphere (CH 2 Cl 2 ) 1.4 @[{Cp Bn Fe(η 5 -P 5 )} 12 {Cu(CF 3 SO 3 )} 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 D 5 and D 2 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., (© 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

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.

Two cyclic (alkyl)(amino)carbene (cAAC) stabilized mononuclear neutral radicals of aluminum have been synthesized. They contain an ethyl [(cAAC) 2 AlClEt (1)] and as well a diethyl group [(cAAC) 2 AlEt 2 (2)], and have been prepared from the reduction of EtAlCl 2 and Et 2 AlCl, respectively, with KC 8 . 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.

The cyclic alkyl(amino) carbene (cAAC) stabilized biradicals of composition (cAAC) 2 SiH 2 (1), (cAAC)SiMe 2 -SiMe 2 (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 SiH 2 moiety and this is the first instance, where we have isolated 1 without an acceptor molecule.

The cyclic alkyl(amino) carbene (cAAC) [:C{N-C 6 H 3 (2,6-IPr 2 )}(CMe 2 ) 2 CH 2 ] stabilized MeGeGeMe has been isolated in the molecular form with composition (cAAC)MeGe-GeMe(cAAC) (1) at room temperature. Compound 1 was synthesized from the reduction of MeGeCl 3 using three equivalents of KC 8 in the presence of one equivalent of cAAC. The corresponding silicon compound (cAAC)MeSi-SiMe(cAAC) (2) was also prepared. Compounds 1 and 2 are the first examples of REER compounds (E = Ge, Si) carrying the smallest organic group. Furthermore the structures of compounds 1 and 2 have been investigated by using theoretical methods. The theoretical analysis of the structure of 1 is in agreement with the formation as an unprecedented carbene stabilized bis-germylene whereas compound 2 can be equally described as carbene stabilized bis-silylene with coordinate bonds as with classical double bonds of a 2,3-disila-1,3-butadiene. The compounds were also characterized by X-ray crystallography.

Topological analysis using Bader and co-worker's Atoms in Molecules theory has seen many applications in theoretical chemistry and experimental charge-density research. A brief overview of successful early developments, establishing topological analysis as a research tool for characterizing intramolecular chemical bonding, is provided. A lack of vision in many `descriptive but not predictive' subsequent studies is discussed. Limitations of topology for providing accurate energetic estimates of intermolecular interaction energies are put into perspective. It is recommended that topological analyses of well understood bonding situations are phased out and are only reported for unusual bonding. Descriptive studies of intermolecular interactions should have a clear research focus.

Amino acid structures are an ideal test set for method-development studies in crystallography. High-resolution X-ray diffraction data for eight previously studied genetically encoding amino acids are provided, complemented by a non-standard amino acid. Structures were re-investigated to study a widely applicable treatment that permits accurate X-H bond lengths to hydrogen atoms to be obtained: this treatment combines refinement of positional hydrogen-atom parameters with aspherical scattering factors with constrained "TLS+INV" estimated hydrogen anisotropic displacement parameters (H-ADPs). Tabulated invariom scattering factors allow rapid modeling without further computations, and unconstrained Hirshfeld atom refinement provides a computationally demanding alternative when database entries are missing. Both should incorporate estimated H-ADPs, as free refinement frequently leads to over-parameterization and non-positive definite H-ADPs irrespective of the aspherical scattering model used. Using estimated H-ADPs, both methods yield accurate and precise X-H distances in best quantitative agreement with neutron diffraction data (available for five of the test-set molecules). This work thus solves the last remaining problem to obtain such results more frequently. Density functional theoretical QM/MM computations are able to play the role of an alternative benchmark to neutron diffraction., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Eight compounds were isolated from the stem bark of Antrocaryon klaineanum, and their structures determined by chemical and spectroscopic methods. Among these compounds, the ergostane-type antrocarine E (1a) is a new compound, although the structure had already been published by mismatching the spectroscopic data with those of 2. In this paper, we are reporting the valid spectroscopic values for antrocarine E and X-ray diffraction results., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Due to the inherent difficulties in achieving a defined and exclusive formation of multicomponent assemblies against entropic predisposition, we present the rational assembly of a heteroleptic [Pd 2 L A 2 L B 2 ] 4+ coordination cage achieved through the geometric complementarity of two carefully designed ligands, L A and L B . With Pd(II) cations as rigid nodes, the pure distinctly angular components readily form homoleptic cages, a [Pd 2 L A 4 ] 4+ strained helical assembly and a [Pd 4 L B 8 ] 8+ box-like structure, both of which were characterized by X-ray analysis. Combined, however, the two ligands could be used to cleanly assemble a cis-[Pd 2 L A 2 L B 2 ] 4+ cage with a bent architecture. The same self-sorted product was also obtained by a quantitative cage-to-cage transformation upon mixing of the two homoleptic cages revealing the [Pd 2 L A 2 L B 2 ] 4+ assembly as the thermodynamic minimum. The structure of the heteroleptic cage was examined by ESI-MS, COSY, DOSY, and NOESY methods, the latter of which pointed toward a cis-conformation of ligands in the assembly. Indeed, DFT calculations revealed that the angular ligands and strict Pd(II) geometry strongly favor the cis-[Pd 2 L A 2 L B 2 ] 4+ species. The robust nature of the cis-[Pd 2 L A 2 L B 2 ] 4+ cage allowed us to probe the accessibility of its cavity, which could be utilized for shape recognition toward stereoisomeric guests. The ability to directly combine two different backbones in a controlled manner provides a powerful strategy for increasing complexity in the family of [Pd 2 L 4 ] cages and opens up possibilities of introducing multiple functionalities into a single self-assembled architecture.

Determining the structures of nanoparticles at atomic resolution is vital to understand their structure-property correlations. Large metal nanoparticles with core diameter beyond 2 nm have, to date, eluded characterization by single-crystal X-ray analysis. Here we report the chemical syntheses and structures of two giant thiolated Ag nanoparticles containing 136 and 374 Ag atoms (that is, up to 3 nm core diameter). As the largest thiolated metal nanoparticles crystallographically determined so far, these Ag nanoparticles enter the truly metallic regime with the emergence of surface plasmon resonance. As miniatures of fivefold twinned nanostructures, these structures demonstrate a subtle distortion within fivefold twinned nanostructures of face-centred cubic metals. The Ag nanoparticles reported in this work serve as excellent models to understand the detailed structure distortion within twinned metal nanostructures and also how silver nanoparticles can span from the molecular to the metallic regime.

The synthesis of a centrally functionalized, ribbon-shaped [6]polynorbornane ligand L that self-assembles with Pd(II) cations into a {Pd2 L4 } coordination cage is reported. The shape-persistent {Pd2 L4 } cage contains two axial cationic centers and an array of four equatorial H-bond donors pointing directly towards the center of the cavity. This precisely defined supramolecular environment is complementary to the geometry of classic octahedral complexes [M(XY)6 ] with six diatomic ligands. Very strong binding of [Pt(CN)6 ](2-) to the cage was observed, with the structure of the host-guest complex {[Pt(CN)6 ]@Pd2 L4 } supported by NMR spectroscopy, MS, and X-ray data. The self-assembled shell imprints its geometry on the encapsulated guest, and desymmetrization of the octahedral platinum species by the influence of the D4h -symmetric second coordination sphere was evidenced by IR spectroscopy. [Fe(CN)6 ](3-) and square-planar [Pt(CN)4 ](2-) were strongly bound. Smaller octahedral anions such as [SiF6 ](2-) , neutral carbonyl complexes ([M(CO)6 ]; M=Cr, Mo, W) and the linear [Ag(CN)2 ](-) anion were only weakly bound, showing that both size and charge match are key factors for high-affinity binding., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A set of look-up point charges for generating molecular electrostatic potentials is provided. The set relies on atom classification of the invariom database, which has already been applied to assign aspherical scattering factors in single-crystal X-ray diffraction. The focus of the investigation is on improving the accuracy of electrostatic potentials calculated by using tabulated point charges. In this respect, the performance of invariom point charges is compared with 1) those from a restrained fit to the electrostatic potential directly following quantum-chemical DFT computations, 2) semi-empirical AM1-bcc charges, and 3) conceptually similar TPACM4 look-up charges. Invariom classification gives charges that perform better than those from TPACM4, although tabulated charges remain inferior to those from molecule-specific computations. Point-charge electrostatic potentials also agree favorably with those from charge-density studies on the basis of X-ray experiments, without requiring the considerable effort of the latter., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Substituent control in self-assembled host systems allows for a fine-tuning of structure, dynamics and guest preference. Flat banana-shaped ligands L 1 assemble with Pd(ii) cations into the interpenetrated coordination cage dimer [3BF 4 @Pd 4 L 1 8 ], capable of sequential guest uptake. In contrast, the introduction of bulky adamantyl groups in ligand L 2 prevents dimerization and results in the clean formation of monomeric cage species [Pd 2 L 2 4 ]. Owing to steric crowding, the adamantyl substituent is considerably bent sideways with respect to the ligand backbone, and is rapidly flipping between both faces of the free ligand giving rise to two energetically degenerate conformers. Surprisingly, the flipping is preserved in the cage, albeit at a lower rate due to entropic reasons. Despite the very dense packing within the self-assembled structure, the cage is able to encapsulate a series of bis-anionic guests in an induced-fit fashion. Electronic structure calculations revealed a substantial contribution from dispersion interactions between the guest and the surrounding adamantyl groups that stabilize the host-guest complex. Guest exchange kinetics were quantified and the influence that encapsulated guests imparted on the ligand flipping dynamics was examined by a series of 2D NMR experiments. Four synchrotron X-ray structures of the cage and its host-guest complexes are presented, allowing for unprecedented insight into the host-guest interactions of a sterically overcrowded host and its guest-induced distortion.

Reduction of the neutral carbene tetrachlorosilane adduct (cAAC)SiCl4 (cAAC=cyclic alkyl(amino) carbene :C(CMe2)2 (CH2)N(2,6-iPr2C6H3) with potassium graphite produces stable (cAAC)3Si3, a carbene-stabilized triatomic silicon(0) molecule. The Si-Si bond lengths in (cAAC)3Si3 are 2.399(8), 2.369(8) and 2.398(8) Å, which are in the range of Si-Si single bonds. Each trigonal pyramidal silicon atom of the triangular molecule (cAAC)3Si3 possesses a lone pair of electrons. Its bonding, stability, and electron density distributions were studied by quantum chemical calculations., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Thiophosgene (CSCl2), a chemical reagent used in numerous organic syntheses, exists in the monomeric form while its heavier silicon analogue [siliconthiodichloride (SiSCl2)] has been isolated so far as a dimer at room temperature and as a tetramer at 180 °C. Herein, we report on the first synthesis, isolation, and characterization of cyclic alkyl(amino) carbene (cAAC) stabilized siliconthiodichloride (cAAC)SiSCl2 (3) in the neutral monomeric form. 3 is synthesized via reaction of (cAAC˙)2Si2Cl4 (1) or (cAAC)2Si2Cl2 (2) with S8 in the temperature range of -78 to 20 °C. An NHC [NHC = N-heterocyclic carbene] analogue of 3 is not isolated when (NHC)SiCl2 is reacted with S8. The bright yellow colored compound 3 is soluble in polar organic solvents. It is stable at room temperature for a month under an inert atmosphere. 3 decomposes above 160 °C. The monomeric molecular structure of 3 has been unambiguously confirmed by X-ray single crystal diffraction. 3 is also characterized by NMR, UV-vis, and IR spectroscopy. The bonding and electron density distributions of 3 have been further studied by theoretical calculations.

Invariom partitioning and notation are used to estimate anisotropic hydrogen displacements for incorporation in crystallographic refinement models. Optimized structures of the generalized invariom database and their frequency computations provide the information required: frequencies are converted to internal atomic displacements and combined with the results of a TLS (translation-libration-screw) fit of experimental non-hydrogen anisotropic displacement parameters to estimate those of H atoms. Comparison with TLS+ONIOM and neutron diffraction results for four example structures where high-resolution X-ray and neutron data are available show that electron density transferability rules established in the invariom approach are also suitable for streamlining the transfer of atomic vibrations. A new segmented-body TLS analysis program called APD-Toolkit has been coded to overcome technical limitations of the established program THMA . The influence of incorporating hydrogen anisotropic displacement parameters on conventional refinement is assessed.

In the crystal structure of the title homoleptic Cr(II) complex, [Cr(CH3CN)6](C24H20B)2·CH3CN, the [Cr(CH3CN)6](2+) cation is a high-spin d(4) complex with strong static, rather than dynamic, Jahn-Teller distortion. The electron density of the cation was determined by single-crystal X-ray refinements using aspherical structure factors from wavefunction calculations. The detailed picture of the electronic density allowed us to assess the extent and directionality of the Jahn-Teller distortion of the Cr(II) cation away from idealized octahedral symmetry. The topological analysis of the aspherical d-electron density about the Cr(II) cation showed that there are significant valence charge concentrations along the axial Cr-N axes. Likewise, there were significant valence charge depletions about the Cr(II) cation along the equatorial Cr-N bonds. These charge concentrations are in accordance with a Jahn-Teller-distorted six-coordinate complex.

The subjects of this study are the structures and electron densities of the carbon/silicon analogues haloperidol/sila-haloperidol (1a/1b) and venlafaxine/sila-venlafaxine (2a/2b). The parent carbon compounds 1a (an antipsychotic agent) and 2a (an antidepressant) are both in clinical use. For haloperidol/sila-haloperidol, three published structures were studied in more detail: the structures of haloperidol hydrochloride (1a·HCl), haloperidol hydropicrate (1a·HPic) and sila-haloperidol hydrochloride (1b·HCl). For venlafaxine/sila-venlafaxine, the published structures of venlafaxine (2a), venlafaxine hydrochloride (2a·HCl; as orthorhombic (2a·HCl-ortho) and monoclinic polymorph (2a·HCl-mono)) and sila-venlafaxine hydrochloride (2b·HCl) were investigated. Based on these structures, the molecular electron densities were reconstructed by using the invariom formalism. They were further analysed in terms of Bader's quantum theory of atoms in molecules, electrostatic potentials mapped onto electron density isosurfaces and Hirshfeld surfaces. These studies were performed with a special emphasis on the comparison of the corresponding carbon/silicon analogues.

Silicondiselenide is a semiconductor and exists as an insoluble polymer (SiSe 2 ) n which is prepared by reacting elemental silicon with selenium powder in the temperature range of 400-850 °C. Herein, we report on the synthesis, isolation, and characterization of carbene stabilized molecular silicondiselenide in the form of (cAAC) 2 Si 2 Se 4 ( 3 ) [cAAC = cyclic alkyl(amino)carbene]. 3 is synthesized via reaction of diatomic silicon(0) compound (cAAC) 2 Si 2 ( 2 ) with black selenium powder at -78 °C to room temperature. The intensely orange colored compound 3 is soluble in polar organic solvents and stable at room temperature for a month under an inert atmosphere. 3 decomposes above 245 °C. The molecular structure of 3 has been confirmed by X-ray single crystal diffraction. It is also characterized by UV-vis, IR, Raman spectroscopy and mass spectrometry. The stability, bonding, and electron density distributions of 3 have been studied by theoretical calculations.

An elegant general synthesis route for the preparation of two coordinate palladium(0) and platinum(0) complexes was developed by reacting commercially available tetrakis(triphenylphosphine)palladium/platinum with π-accepting cyclic alkyl(amino) carbenes (cAACs). The complexes are characterized by NMR spectroscopy, mass spectrometry, and single-crystal X-ray diffraction. The palladium complexes exhibit sharp color changes (crystallochromism) from dark maroon to bright green if the C-Pd-C bond angle is sharpened by approximately 6°, which is chemically feasible by elimination of one lattice THF solvent molecule. The analogous dark orange-colored platinum complexes are more rigid and thus do not show this phenomenon. Additionally, [(cAAC)2 Pd/Pt] complexes can be quasi-reversibly oxidized to their corresponding [(cAAC)2 Pd/Pt](+) cations, as evidenced by cyclic voltammetry measurements. The bonding and stability are studied by theoretical calculations., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A cyclic alkyl(amino) carbene (cAAC) stabilized dimer [(cAAC)Si(P-Tip)]2 (2) (Tip = 2,4,6-triisopropylphenyl) is reported. 2 can be considered as a dimer of the heavier ketenimine (R2C═C═N-R) analogue. The dark-red rod-shaped crystals of 2 were synthesized by reduction of the precursor, cAAC-dichlorosilylene-stabilized phosphinidene (cAAC)SiCl2→P-Tip with sodium napthalenide. The crystals of 2 are storable at room temperature for several months and stable up to 215 °C under an inert atmosphere. X-ray single-crystal diffraction revealed that 2 contains a cyclic nonplanar four-membered SiPSiP ring. Magnetic susceptibility measurements confirmed the singlet spin ground state of 2. Cyclic voltammetry of 2 showed a quasi-reversible one-electron reduction indicating the formation of the corresponding radical anion 2(•-), which was further characterized by EPR measurements in solution. The electronic structure and bonding of 2 and 2(•-) were studied by theoretical calculations. The experimentally obtained data are in good agreement with the calculated values.

Intermediate species dichlorosilylene was generated in situ from trichlorosilane and inserted into the P-Cl bond of diphenylchlorophosphine (Ph2P-Cl) to obtain Ph2P-SiCl3 (1). Monodechlorination of 1 by cyclic alkyl(amino) carbenes (cAACs)/KC8 in THF at low temperature led to the formation of stable radicals Ph2P-Si(cAAC·)Cl2 (2a,b). Compounds 2a,b were characterized by X-ray single crystal diffraction, mass spectrometry and studied by cyclic voltammetry and theoretical calculations. Radical properties of 2 are confirmed by EPR measurements that suggest the radical electron in 2 couples with (14)N (I = 1), (35/37)Cl (I = 3/2), and (31)P (I = 1/2) nuclei leading to multiple hyperfine lines. Hyperfine coupling parameters computed from DFT calculations are in good agreement with those of experimental values. Electronic distributions obtained from the theoretical calculations suggest that the radical electron mostly resides on the carbene C of 2.

A simple self-assembled [Pd2 L4 ] coordination cage consisting of four carbazole-based ligands was found to dimerize into the interpenetrated double cage [3 X@Pd4 L8 ] upon the addition of 1.5 equivalents of halide anions (X=Cl(-) , Br(-) ). The halide anions serve as templates, as they are sandwiched by four Pd(II) cations and occupy the three pockets of the entangled cage structure. The subsequent addition of larger amounts of the same halide triggers another structural conversion, now yielding a triply catenated link structure in which each Pd(II) node is trans-coordinated by two pyridine donors and two halide ligands. This simple system demonstrates how molecular complexity can increase upon a gradual change of the relative concentrations of reaction partners that are able to serve different structural roles., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Single-crystal X-ray diffraction (XRD) is often considered the gold standard in analytical chemistry, as it allows element identification as well as determination of atom connectivity and the solid-state structure of completely unknown samples. Element assignment is based on the number of electrons of an atom, so that a distinction of neighboring heavier elements in the periodic table by XRD is often difficult. A computationally efficient procedure for aspherical-atom least-squares refinement of conventional diffraction data of organometallic compounds is proposed. The iterative procedure is conceptually similar to Hirshfeld-atom refinement (Acta Crystallogr. Sect. A- 2008, 64, 383-393; IUCrJ. 2014, 1,61-79), but it relies on tabulated invariom scattering factors (Acta Crystallogr. Sect. B- 2013, 69, 91-104) and the Hansen/Coppens multipole model; disordered structures can be handled as well. Five linear-coordinate 3d metal complexes, for which the wrong element is found if standard independent-atom model scattering factors are relied upon, are studied, and it is shown that only aspherical-atom scattering factors allow a reliable assignment. The influence of anomalous dispersion in identifying the correct element is investigated and discussed., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Molecular encapsulation processes under the control of an external trigger play a major role in biological signal transduction processes and enzyme catalysis. Here, we present an artificial mimic of a controllable host system that forms via self-assembly from a simple bis-monodentate ligand and Pd(II) cations. The resulting interpenetrated double cage features three consecutive pockets which initially contain one tetrafluoroborate anion, each. Activation of this host system with two halide anions triggers a conformational change that renders the central pocket susceptible to the uptake of small neutral guest molecules. Thereby, the pentacationic cage expels the central anion and replaces it with a neutral molecule to give a hexacationic species. The cage structures prior and after the halide triggered binding of benzene were examined by X-ray crystallography, ESI MS, and NMR techniques. The kinetics and thermodynamics of the encapsulation of benzene, cyclohexane, and norbornadiene are compared.

This article reviews efforts in accurate experimental charge-density studies with relevance to medicinal chemistry. Initially, classical charge-density studies that measure electron density distribution via least-squares refinement of aspherical-atom population parameters are summarized. Next, interaction density is discussed as an idealized situation resembling drug-receptor interactions. Scattering-factor databases play an increasing role in charge-density research, and they can be applied both to small-molecule and macromolecular structures in refinement and analysis; software development facilitates their use. Therefore combining both of these complementary branches of X-ray crystallography is recommended, and examples are given where such a combination already proved useful. On the side of the experiment, new pixel detectors are allowing rapid measurements, thereby enabling both high-throughput small-molecule studies and macromolecular structure determination to higher resolutions. Currently, the most ambitious studies compute intermolecular interaction energies of drug-receptor complexes, and it is recommended that future studies benefit from recent method developments. Selected new developments in theoretical charge-density studies are discussed with emphasis on its symbiotic relation to crystallography.

X-ray crystallographic characterization of products derived from natural and fully synthetic trioxacarcins, molecules with potent antiproliferative effects, illuminates aspects of their reactivity and mechanism of action. Incubation of the fully synthetic trioxacarcin analog 3, which lacks one of the carbohydrate residues present in the natural product trioxacarcin A (1) as well as oxygenation at C2 and C4 yet retains potent antiproliferative effects, with the self-complimentary duplex oligonucleotide d(AACCGGTT) led to production of a crystalline covalent guanine adduct (6). Adduct 6 is closely analogous to gutingimycin (2), the previously reported guanine adduct derived from incubation of natural trioxacarcin A (1) with duplex DNA, suggesting that 3 and 1 likely share a common basis of cytotoxicity. In addition, we isolated a novel, dark-red crystalline guanine adduct (7) from incubation of trioxacarcin A itself with the self-complimentary duplex oligonucleotide d(CGTATACG). Crystallographic analysis suggests that 7 is an anthraquinone derivative, which we propose arises by a sequence of guanosine alkylation within duplex DNA, depurination, base-catalyzed elimination of the trioxacarcinose A carbohydrate residue, and oxidative rearrangement to form an anthraquinone. We believe that this heretofore unrecognized chemical instability of natural trioxacarcins may explain why trioxacarcin analogs lacking C4 oxygenation exhibit superior chemical stabilities yet, as evidenced by structure 3, retain a capacity to form lesions with duplex DNA., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Compound (Me2 -cAAC:)2 Co(0) (2; Me2 -cAAC:=cyclic (alkyl) amino carbene; :C(CH2 )(CMe2 )2 N-2,6-iPr2 C6 H3 ) was synthesized by the reduction of the precursor (Me2 -cAAC:)2 Co(I) Cl (1) with KC8 in THF. The cyclic voltammogram of 1 exhibited one-electron reduction, which suggests that synthesis of a bent 2-metallaallene (2) from 1 should be possible. Compound 2 contains one cobalt atom in the formal oxidation state zero, which is stabilized by two Me2 -cAAC: ligands. Bond lengths from X-ray diffraction are 1.871(2) and 1.877(2) Å with a C-Co-C bond angle of 170.12(8)°. The EPR spectrum of 2 exhibited a broad resonance attributed to the unique quasi-linear structure, which favors near degeneracy and gives rise to very rapid relaxation conditions. The cAACCo bond in 2 can be considered as a typical Dewar-Chatt-Duncanson type of bonding, which in turn retains 2.5 electron pairs on the Co atom as nonbonding electrons., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Hirshfeld atom refinement (HAR) is a method which determines structural parameters from single-crystal X-ray diffraction data by using an aspherical atom partitioning of tailor-made ab initio quantum mechanical molecular electron densities without any further approximation. Here the original HAR method is extended by implementing an iterative procedure of successive cycles of electron density calculations, Hirshfeld atom scattering factor calculations and structural least-squares refinements, repeated until convergence. The importance of this iterative procedure is illustrated via the example of crystalline ammonia. The new HAR method is then applied to X-ray diffraction data of the dipeptide Gly-l-Ala measured at 12, 50, 100, 150, 220 and 295 K, using Hartree-Fock and BLYP density functional theory electron densities and three different basis sets. All positions and anisotropic displacement parameters (ADPs) are freely refined without constraints or restraints - even those for hydrogen atoms. The results are systematically compared with those from neutron diffraction experiments at the temperatures 12, 50, 150 and 295 K. Although non-hydrogen-atom ADPs differ by up to three combined standard uncertainties (csu's), all other structural parameters agree within less than 2 csu's. Using our best calculations (BLYP/cc-pVTZ, recommended for organic molecules), the accuracy of determining bond lengths involving hydrogen atoms from HAR is better than 0.009 Å for temperatures of 150 K or below; for hydrogen-atom ADPs it is better than 0.006 Å(2) as judged from the mean absolute X-ray minus neutron differences. These results are among the best ever obtained. Remarkably, the precision of determining bond lengths and ADPs for the hydrogen atoms from the HAR procedure is comparable with that from the neutron measurements - an outcome which is obtained with a routinely achievable resolution of the X-ray data of 0.65 Å.

One and a half decades ago the formation of Si2Cl4 from the intermediate species SiCl2 was theoretically predicted to be exothermic. The hypothetical Si2Cl4 has never been experimentally synthesized and isolated. Herein, we report that the Si2Cl4 species was stabilized as singlet biradical (Cy-cAAC·)2Si2Cl4 utilizing two cAAC (cyclic alkyl(amino) carbene). This compound is stable, isolable, and storable at rt under an inert atmosphere. The electronic structure and bonding were studied by theoretical calculations which revealed that the molecule possesses a singlet biradical ground state with an unpaired electron on each carbene C atom having opposite spin.

Chemical re-examination of the roots of T. calophylla led to the isolation of four isoflavones, namely 2',4',5-trihydroxy-6,7-(2",2"-dimethylchromene)-8-gamma,gamma-dimethylallylisoflavone (1a, auriculatin), 2',5-dihydroxy-6,7-(2",2"-dimethylchromene)-4'-gamma,gamma-dimethylallyloxyisoflavone (2a, isoauriculatin), 3',4',5-trihydroxy-6,7-(2",2"-dimethylchromene)-8-gamma,gamma-dimethylallylisoflavone (1b, auriculasin), and 3',5-dihydroxy-6,7-(2",2"-dimethylchromene)-4'-gamma,gamma-dimethylallyl-oxyisoflavone (2b, isoauriculasin). Auriculasin and isoauriculasin are reported for the first time with full NMR assignments. All metabolites were fully characterized by 1D and 2D NMR techniques including COSY, HSQC, HMBC experiments, mass spectra and in part on the basis of X-ray diffraction. Accurate 'invariom' refinements with aspherical scattering factors were carried out for 1a, 1b and 2a.

The temperature dependence of H-U(iso) in N-acetyl-L-4-hydroxyproline monohydrate is investigated. Imposing a constant temperature-independent multiplier of 1.2 or 1.5 for the riding hydrogen model is found to be inaccurate, and severely underestimates H-U(iso) below 100 K. Neutron diffraction data at temperatures of 9, 150, 200 and 250 K provide benchmark results for this study. X-ray diffraction data to high resolution, collected at temperatures of 9, 30, 50, 75, 100, 150, 200 and 250 K (synchrotron and home source), reproduce neutron results only when evaluated by aspherical-atom refinement models, since these take into account bonding and lone-pair electron density; both invariom and Hirshfeld-atom refinement models enable a more precise determination of the magnitude of H-atom displacements than independent-atom model refinements. Experimental efforts are complemented by computing displacement parameters following the TLS+ONIOM approach. A satisfactory agreement between all approaches is found.

A disiladicarbene, (Cy-cAAC)2Si2 (2), was synthesized by reduction of Cy-cAAC:SiCl4 adduct with KC8. The dark-colored compound 2 is stable at room temperature for a year under an inert atmosphere. Moreover, it is stable up to 190 °C and also can be characterized by electron ionization mass spectrometry. Theoretical and Raman studies reveal the existence of a Si═Si double bond with a partial double bond between each carbene carbon atom and silicon atom. Cyclic voltammetry suggests that 2 can quasi-reversibly accept an electron to produce a very reactive radical anion, 2(•-), as an intermediate species. Thus, reduction of 2 with potassium metal at room temperature led to the isolation of an isomeric neutral rearranged product and an anionic dimer of a potassium salt via the formation of 2(•-).

Protein-DNA interactions play a major role in all aspects of genetic activity within an organism, such as transcription, packaging, rearrangement, replication and repair. The molecular detail of protein-DNA interactions can be best visualized through crystallography, and structures emphasizing insight into the principles of binding and base-sequence recognition are essential to understanding the subtleties of the underlying mechanisms. An increasing number of high-quality DNA-binding protein structure determinations have been witnessed despite the fact that the crystallographic particularities of nucleic acids tend to pose specific challenges to methods primarily developed for proteins. Crystallographic structure solution of protein-DNA complexes therefore remains a challenging area that is in need of optimized experimental and computational methods. The potential of the structure-solution program ARCIMBOLDO for the solution of protein-DNA complexes has therefore been assessed. The method is based on the combination of locating small, very accurate fragments using the program Phaser and density modification with the program SHELXE. Whereas for typical proteins main-chain α-helices provide the ideal, almost ubiquitous, small fragments to start searches, in the case of DNA complexes the binding motifs and DNA double helix constitute suitable search fragments. The aim of this work is to provide an effective library of search fragments as well as to determine the optimal ARCIMBOLDO strategy for the solution of this class of structures.