Anharmonic Thermal Motion Modelling in the Experimental XRD Charge Density Determination of 1-Methyluracil at T = 23 K.

The experimental electron density distribution (EDD) of 1-methyluracil (1-MUR) was obtained by single crystal X-ray diffraction (XRD) experiments at 23 K. Four different structural models fitting an extensive set of XRD data to a resolution of (sinθ/λ)max = 1.143 Å-1 are compared. Two of the models include anharmonic temperature factors, whose inclusion is supported by the Hamilton test at a 99.95% level of confidence. Positive Fourier residuals up to 0.5 eÅ-3 in magnitude were found close to the methyl group and in the region of hydrogen bonds. Residual density analysis (RDA) and molecular dynamics simulations in the solid-state demonstrate that these residuals can be likely attributed to unresolved disorder, possibly dynamical and long-range in nature. Atomic volumes and charges, molecular moments up to hexadecapoles, as well as maps of the molecular electrostatic potential were obtained from distributed multipole analysis of the EDD. The derived electrostatic properties neither depend on the details of the multipole model, nor are significantly affected by the explicit inclusion of anharmonicity in the least-squares model. The distribution of atomic charges in 1-MUR is not affected by the crystal environment in a significant way. The quality of experimental findings is discussed in light of in-crystal and gas-phase quantum simulations.

Anharmonic motions versus dynamic disorder at the Mg ion from the charge densities in pyrope (Mg3Al2Si3O12) crystals at 30†K: six of one, half a dozen of the other.

The possible occurrence of static/dynamic disorder at the Mg site in pyrope (Mg3Al2Si3O12), with or without anharmonic contribution to the thermal vibrations even at low temperatures, has been largely debated but conclusions were contrasting. Here a report is given on the experimental charge density distribution, ρEXP, of synthetic pyrope at T = 30 K, built through a Stewart multipolar expansion up to l = 5 and based on a very precise and accurate set of in-home measured single-crystal X-ray diffraction amplitudes with a maximum resolution of 0.44 Å. Local and integral topological properties of ρEXP are in substantial agreement with those of ρTHEO, the corresponding DFT-grade quantum charge density of an ideal pyrope crystal, and those derived from synchrotron investigations of chemical bonding in olivines. Relevant thermal atomic displacements, probably anharmonic in nature, clearly affect the whole structure down to 30 K. No significant (> 2.5σ) residual Fourier peaks are detectable from the ρEXP distribution around Mg, after least-squares refinement of a multipole model with anharmonic thermal motion at the Mg site. Experimental findings were confirmed by a full analysis of normal vibration modes of the DFT-optimized structure of the perfect pyrope crystal. Mg undergoes wide displacements from its equilibrium position even at very low temperatures, as it is allocated in a ∼ 4.5 Šlarge dodecahedral cavity and involved in several soft phonon modes. Implications on the interplay among static/dynamic disorder of Mg and lattice vibrational degrees of freedom are discussed.

Progress in the understanding of the key pharmacophoric features of the antimalarial drug dihydroartemisinin: an experimental and theoretical charge density study.

The accurate, experimental charge density distribution, ρ(r), of the potent antimalarial drug dihydroartemisinin (DHA) has been derived for the first time from single-crystal X-ray diffraction data at T=100(2) K. Gas-phase and solid-state DFT simulations have also been performed to provide a firm basis of comparison with experimental results. The quantum theory of atoms in molecules (QTAIM) has been employed to analyse the ρ(r) scalar field, with the aim of classifying and quantifying the key real-space elements responsible for the known pharmacophoric features of DHA. From the conformational perspective, the bicyclo[3.2.2]nonane system fixes the three-dimensional arrangement of the 1,2,4-trioxane bearing the active O-O redox centre. This is the most nucleophilic function in DHA and acts as an important CH⋅⋅⋅O acceptor. On the contrary, the rest of the molecular backbone is almost neutral, in accordance with the lipophilic character of the compound. Another remarkable feature is the C-O bond length alternation along the O-C-O-C polyether chain, due to correlations between pairs of adjacent C-O bonds. These bonding features have been related with possible reactivity routes of the α- and ß-DHA epimers, namely 1) the base-catalysed hemiacetal breakdown and 2) the peroxide reduction. As a general conclusion, the base-driven proton transfer has significant non-local effects on the whole polyether chain, whereas DHA reduction is thermodynamically favourable and invariably leads to a significant weakening (or even breaking) of the O-O bond. The influence of the hemiacetal stereochemistry on the electronic properties of the system has also been considered. Such findings are discussed in the context of the known chemical reactivity of this class of important antimalarial drugs.

Rationalizing the effect of halogenation on the molecular structure of simple cyclobutene derivatives by topological real-space analysis of their electron density.

The accurate gas-phase equilibrium structures on the ground-state potential energy surface of the complete series of fluorinated and chlorinated cyclobutene derivatives with C(2v) symmetry have been evaluated at DFT PBE0/6-311++G(d,p) theory level. The optimized geometries have been compared with all the available experimental data reported in the literature, as obtained by microwave spectroscopy (MW) and gas-phase electron diffraction (GED) techniques. For hexafluorocyclobutene and 1,2-dichloro-3,3',4,4'-tetrafluorocyclobut-1-ene, the results of accurate low-temperature single-crystal X-ray diffraction experiments have also been considered. Structural changes within the cyclobutene ring, as induced by fluorination and chlorination at allylic and vinylic positions, have been correlated with changes in the corresponding theoretical charge densities. To this aim, several local and nonlocal topological descriptors provided by the quantum theory of atoms in molecules, QTAIM, have been employed, with particular emphasis on the delocalization indices and integrated source function decomposition schemes. Key factors for the resulting molecular structures are the chemical nature and the steric hindrance of the substituents, as well as quantum-mechanical effects, such as delocalization and partial conjugation. When fluorine atoms replace hydrogens at allylic or vinylic positions, the corresponding Csp(3)-Csp(3) or Csp(2)═Csp(2) bonds between the substituted carbons undergo a significant strengthening, while chlorination has just the opposite effect. In the latter case the steric hindrance between bulky chlorine atoms occupying vicinal positions is crucial in determining the single Csp(3)-Csp(3) bond length. These findings are discussed in the context of the reactivity of chemically related chlorofluorocarbon compounds.

Detection and kinetics of the single-crystal to single-crystal complete transformation of a thiiranium ion into thietanium ion.

The conversion of a di-tert-butyl-methylthiiranium ion into thietanium ion, that is reported in the literature as taking place spontaneously at 25 degrees C in a CD(2)Cl(2) solution, has been discovered to occur quantitatively at room temperature (RT) also in the crystalline state. The ring enlargement reaction is accompanied, in the solid phase, by a modest deterioration of the quality of the sample under investigation, and all three specimens here studied by in situ crystallography maintained their single-crystal nature up to 100% conversion. The rearrangement reaction implies the breaking of a C-S bond and the formation of a new bond of the same type, together with the migration of a methyl group. The extent of the corresponding atomic displacements has been measured by comparing the initial and final crystal structures. Several intermediate stages of the process have been investigated and characterized by the site occupancy factor of the episulfonium ion. The RT temporal evolution of this factor and that of the unit-cell volume indicate multi-step kinetics, with processes of simple molecular reorientation or displacement before and after the main, central stage, where the conversion reaction takes place. The overall kinetics is well described by an Avrami-Erofeev equation, with exponent m = 1.75(3) and rate coefficient k = 10.4(3) x 10(-8) s(-1) at 25 degrees C. Ab initio calculations in the gas phase predict a three-step mechanism resulting in a slightly spontaneous reaction with an overall decrease of entropy.

Effect of methoxy substituents on the structural and electronic properties of fluorinated cyclobutenes: a study of hexafluorocyclobutene and its vinyl methoxy derivatives by XRD and periodic DFT calculations.

The effect of the methoxy substituent on the structure, crystal packing, and electrostatic properties of hexafluorocyclobutene (C(4)F(6)) was investigated in the solid-state with DFT-B3LYP calculations. Full geometry optimizations were done for the parent compound and its two vinyl methoxy derivatives C(4)F(5)OCH(3) and C(4)F(4)(OCH(3))(2), starting from the structures obtained by single-crystal X-ray diffraction at low temperature. A full topological analysis, followed by the calculation of several electrostatic properties, was performed on the periodic electron density using the quantum theory of atoms in molecules. Eventually, the cohesive energies of the three crystals were estimated. In the cyclobutene plane, the methoxy substitution yields a significant electronic rearrangement involving the pi-electrons. The solid-state (periodic) results agree with those obtained by gas-phase calculations on C(4)F(6) and its derivatives at a comparable level of theory. It was found that the substitution of one or two vinylic fluorine atoms with the OCH(3) group considerably influences the molecular dipole moment, which undergoes an enhancement in both the solid and the gas phase as large as 200% and 235% for C(4)F(5)OCH(3) and C(4)F(4)(OCH(3))(2), respectively, with respect to that calculated for C(4)F(6). The charge rearrangement due to the substituents provides a significant electrostatic contribution to the lattice energy, and in turn it can be related to the change in the observed crystal packing on going from C(4)F(6) (space group P2(1)/c) to both of its derivatives (space group P1). It is also shown that the dispersion energy significantly contributes to the lattice stability in all three compounds. Since the DFT calculations, in the limit of large separations, entirely miss the dispersion term, this was estimated by applying a recently proposed dampening function to the semiempirical atom-atom C(6) R(-6) potentials in the mainframe of Spackman's energy decomposition scheme for Mulliken multipoles.

Estimated H-atom anisotropic displacement parameters: a comparison between different methods and with neutron diffraction results.

Anisotropic displacement parameters (ADPs) are compared for H atoms estimated using three recently described procedures, both among themselves and with neutron diffraction results. The results convincingly demonstrate that all methods are capable of giving excellent results for several benchmark systems and identify systematic discrepancies for several atom types. A revised and extended library of internal H-atom mean-square displacements is presented for use with Madsen's SHADE web server [J. Appl. Cryst. (2006), 39, 757-758; http://shade.ki.ku.dk], and the improvement over the original SHADE results is substantial, suggesting that this is now the most readily and widely applicable of the three approximate procedures. Using this new library--SHADE2--it is shown that, in line with expectations, a segmented rigid-body description of the heavy atoms yields only a small improvement in the agreement with neutron results. The SHADE2 library, now incorporated in the SHADE web server, is recommended as a routine procedure for deriving estimates of H-atom ADPs suitable for use in charge-density studies on molecular crystals, and its widespread use should reveal remaining deficiencies and perhaps overcome the inherent bias in the majority of such studies.

Physicochemical properties of zwitterionic L- and DL-alanine crystals from their experimental and theoretical charge densities.

The total experimental electron density distributions rho(r) of zwitterionic L- and DL-alanine crystals, as derived from extensive sets of X-ray diffracted intensities collected at 23 and 19 K, are compared to gain an insight into the different physical properties of the two related chiral compounds in the solid state and to explore the extent of the rho(r) transferability. Relevant parameters that characterize the two crystal forms are obtained, showing differences and similarities in terms of (i) geometric descriptors, (ii) topological indexes, (iii) molecular electrostatic potential Phi(r) distributions, (iv) atomic volumes and charges, (v) molecular electric moments, and (vi) electrostatic interaction energies. To assess the relative stability of the racemate with respect to the pure enantiomer, the crystal lattice energies, as obtained through DFT fully periodic calculations, are also discussed and compared with the experimental sublimation enthalpies after correction for the proton-transfer energies. In-crystal group charges, evaluated with the quantum theory of atoms in molecules, are found to be transferable between the racemic and the pure enantiomer, at variance with group volumes. Similarly, molecular first and third moments are not strictly transferable and indicate that for the zwitterionic alanine molecule the molecular charge distribution in the DL-crystal is more polarized in the c direction by about 10%. By contrast, quantitative agreement is observed for second and fourth moments. Significant differences arise from (1) the crystal packing of the dipole vectors, which are aligned in an antiparallel fashion in the L-crystal, to be compared with a parallel alignment in the racemate, due the polar space group Pna21 of the latter, (2) the strongly attractive electrostatic energy of a homochiral pair in the L-crystal, which is opposed to the corresponding heterochiral pair in the DL-crystal form. The difference between these Ees values amounts to 135-150 kJ mol(-1). Despite this, the two crystal forms are predicted as equally thermodynamically favored by the theoretical P-B3LYP estimates of the crystal lattice energies. Finally, the necessity of an upgrading of the dispersion and exchange-repulsion terms currently adopted within the experimental charge density approach to intermolecular interactions is recognized and discussed.

Experimental and theoretical charge density distribution of the colossal magnetoresistive transition metal sulfide FeCr2S4.

The total charge density distribution rho(r) of the colossal magnetoresistive transition metal sulfide FeCr(2)S(4) was evaluated through a multipole formalism from a set of structure factors obtained both experimentally, by means of single crystal high-quality x-ray diffraction data collected at T=23 K, and theoretically, with an extended-basis unrestricted Hartree-Fock periodic calculation on the experimental geometry. A full topological analysis, followed by the calculation of local energy density values and net atomic charges, was performed using the quantum theory of atoms in molecules. The experimental and theoretical results were compared. Good agreement was found for the topological properties of the system, as well as for the atomic net charges and the nature of the chemical bonds. An analysis of the electron density rho(r), its Laplacian nabla(2)[rho(r)], and the total energy density H(r) at the bond critical points was employed to classify all the interactions that resulted as predominantly closed shell (ionic) in nature. The topological indicators of the bonded interactions for Fe are distinct from those for Cr. The Fe-S bond distances were found to be 0.145 A shorter than the ideal values computed on the basis of Shannon's crystal radii, much shorter than the Cr-S distances with respect to their ideal Shannon lengths. Concomitantly, rho(r) and |H(r)| at the bond critical points are greater for Fe-S interactions, indicating that the local concentration of charge density in the internuclear region is larger for the tetrahedrally coordinated iron than for the octahedrally coordinated chromium. The isosurface in the real space for nabla(2)[rho(r)]=0 was plotted for both iron and chromium, pointing out the local zones of valence shell charge concentration and relating them to the partial d-orbital occupancy of the two transition metal atoms.

Progress in the understanding of drug-receptor interactions, part 2: experimental and theoretical electrostatic moments and interaction energies of an angiotensin II receptor antagonist (C30H30N6(O)3S).

A combined experimental and theoretical charge density study of an angiotensin II receptor antagonist (1) is presented focusing on electrostatic properties such as atomic charges, molecular electric moments up to the fourth rank and energies of the intermolecular interactions, to gain an insight into the physical nature of the drug-receptor interaction. Electrostatic properties were derived from both the experimental electron density (multipole refinement of X-ray data collected at T=17 K) and the ab initio wavefunction (single molecule and fully periodic calculations at the DFT level). The relevance of SO and SN intramolecular interactions on the activity of 1 is highlighted by using both the crystal and gas-phase geometries and their electrostatic nature is documented by means of QTAIM atomic charges. The derived electrostatic properties are consistent with a nearly spherical electron density distribution, characterised by an intermingling of electropositive and -negative zones rather than by a unique electrophilic region opposed to a nucleophilic area. This makes the first molecular moment scarcely significant and ill-determined, whereas the second moment is large, significant and highly reliable. A comparison between experimental and theoretical components of the third electric moment shows a few discrepancies, whereas the agreement for the fourth electric moment is excellent. The most favourable intermolecular bond is show to be an NHN hydrogen bond with an energy of about 50 kJ mol(-1). Key pharmacophoric features responsible for attractive electrostatic interactions include CHX hydrogen bonds. It is shown that methyl and methylene groups, known to be essential for the biological activity of the drug, provide a significant energetic contribution to the total binding energy. Dispersive interactions are important at the thiophene and at both the phenyl fragments. The experimental estimates of the electrostatic contribution to the intermolecular interaction energies of six molecular pairs, obtained by a new model proposed by Spackman, predict the correct relative electrostatic energies with no exceptions.

On the interplay between CH...O and OH...O interactions in determining crystal packing and molecular conformation: an experimental and theoretical charge density study of the fungal secondary metabolite austdiol (C12H12O5).

The total experimental electron density rho(r), its Laplacian inverted delta(2)rho(r), the molecular dipole moment, the electrostatic potential phi(r), and the intermolecular interaction energies have been obtained from an extensive set of single-crystal X-ray diffracted intensities, collected at T = 70(1) K, for the fungal metabolite austdiol (1). The experimental results have been compared with theoretical densities from DFT calculations on the isolated molecule and with fully periodic calculations. The crystal structure of (1) consists of zigzag ribbons extended along one cell axis and formed by molecules connected by both OH...O and CH...O interactions, while in a perpendicular direction, adjacent molecules are linked by short CH...O intermolecular contacts. An extensive, quantitative study of all the intra- and intermolecular H...O interactions, based not only on geometrical criteria, but also on the topological analysis of rho(r), as well as on the evaluation of the pertinent energetics, allowed us (i) to assess the mutual role of OH...O and CH...O interactions in determining molecular conformation and crystal packing; (ii) to identify those CH...O contacts which are true hydrogen bonds (HBs); (iii) to determine the relative hydrogen bond strengths. An experimental, quantitative evidence is given that CH...O HBs are very similar to the conventional OH...O HBs, albeit generally weaker. The comparison between experimental and theoretical electric dipole moments indicates that a noticeable charge rearrangement occurs upon crystallization and shows the effects of the mutual cooperation of HBs in the crystal. The total intermolecular interaction energies and the electrostatic energy contribution obtained through different theoretical methods are reported and compared with the experimental results. It is found that the new approach proposed by Spackman, based on the use of the promolecular charge density to approximate the penetration contribution to intermolecular electrostatic energies, predicts the correct relative electrostatic interaction energies in most of the cases.

Progress in the understanding of drug-receptor interactions, Part 1: experimental charge-density study of an angiotensin II receptor antagonist (C30H30N6O3S) at T = 17 K.

An experimental study of the electron-density distribution rho(r) in an angiotensin II receptor antagonist 1 has been made on the basis of single-crystal X-ray diffraction data collected at a low temperature. The crystal structure of 1 consists of infinite ribbons in which molecules are connected by an N-H...N hydrogen bond and several interactions of the C-H...O, C-H...N, and C-H...S type. The molecular conformation, characterized by the syn orientation of a tetrazole and a pyrimidinone ring with respect to a phenyl spacer group, is stabilized by two short SO and SN intramolecular contacts between a substituted thiophene fragment and the other two heterocycles of 1. The electrostatic nature of these interactions is documented. Furthermore, the Laplacian of rho(r) in the plane defined by the sulfur, oxygen, and nitrogen atoms involved in these interactions shows their strongly directional character as the regions of charge concentration on the valence shell of the nitrogen and oxygen atoms directly face the regions of charge depletion on the valence shell of the sulfur atom. All the chemical bonds and the relevant intra- and intermolecular interactions of 1 have been quantitatively described by the topological analysis of rho(r). Simple relationships between the bond path lengths (R(b)) and the values of rho at the bond critical points (rho(bcp)) have been obtained for the 28 C-C bonds, the seven N-C bonds, and the four O-C bonds. For the first two classes of bonds the relationship is in the form of a straight line, whose parameters, for the C-C bonds, agree, within experimental uncertainty, with those previously derived in our laboratory from a 19 K X-ray diffraction study of crystals of a different compound. Maps of the molecular electrostatic potential phi(r) derived from the experimental charge density display features that are important for the drug-receptor recognition of 1.

On the role of data quality in experimental charge-density studies.

High-resolution X-ray diffraction data were collected at T = 19 K from two similar spherical crystals of the fungal metabolite citrinin, C(13)H(14)O(5). The two data sets were of markedly different quality, one data set (MQ, medium quality) comprising a single octant of the reciprocal lattice and including reflections with obviously peculiar intensity profiles while the second (HQ, high quality) comprised a hemisphere of reflections and showed no flawed profiles. Parallel multipolar refinements were carried out for both. While most of the resulting geometric parameters, including bond lengths and angles, were in close agreement (the standard uncertainties were approximately twice as large for the MQ data, reflecting the smaller number of observations), the agreement is noticeably worse for electronic properties such as electron densities and their Laplacians at the bond and ring critical points. These latter features are especially sensitive to the quality of the low-angle (and strong) intensities, which was not high for the MQ data. By contrast, the magnitudes of the molecular dipole moment from the two experiments are the same within 1 standard uncertainty, with an angle of about 13 degrees between the two vectors. It is concluded that only true high-quality data allow a fully significant and quantitative analysis of the details of the experimental electron density rho(exp), while high-resolution medium-quality data, measured at very low temperature and adequately processed, can still be used for a qualitative analysis, or for the derivation of overall electronic properties.

Electron density investigation of a push-pull ethylene (C14H24N2O2.H2O) by X-ray diffraction at T = 21 K.

The electron charge distribution in a strongly twisted push-pull ethylene [PPE, 3-(1,3-diisopropyl-2-imidazolidinylidene)-2,4-pentanedione] has been determined by low temperature (T = 21 K) single-crystal X-ray diffraction analysis. The derived electronic properties are consistent with a zwitterionic molecule, as indicated by a charge transfer of 0.82(16) e from the push to the pull moieties and a charge polarization of 0.29(7) e on the olefinic bond. A dipole moment of 12(3) D has been determined, which compares well with ab initio theoretical results in terms of both modulus and orientation. The second moments, which have also been obtained with good precision, characterize PPE as a highly quadrupolar molecule. The special electronic features of the molecule confer particular topological properties to the electron density distribution, as evidenced by comparison with "standard" organic molecules. The crystallographic asymmetric unit of the present system includes one water molecule, which is hydrogen bonded to PPE. Its topological properties have also been investigated, together with an analysis of the hydrogen bonds involved.

The fungal metabolite austdiol.

The title compound, (7R,8S)-7,8-dihydroxy-3,7-dimethyl-6-oxo-7,8-dihydro-6H-isochromene-5-carbaldehyde, C(12)H(12)O(5), is a trans-vicinal diol. Of the two fused rings, which lie approximately in the same plane, the pyran ring is almost perfectly planar, while the cyclohexenone ring adopts a slightly distorted half-chair conformation. The crystal packing is dictated by two strong intermolecular O-H.O interactions, one involving hydroxy and keto groups, the other involving two hydroxy groups. Molecules are linked together through twofold axes, forming zigzag ribbons extended along the a axis.

tert-Butyl (3S,6R,9R)-(5-oxo-3-[[1(R)-phenylethyl]carbamoyl]-1,2,3,5,6,7,8,8a-octahydroindolizin-6-yl)carbamate monohydrate at 95 K.

The asymmetric unit of the title compound, C(22)H(31)N(3)O(4).H(2)O, incorporates one water molecule, which is hydrogen bonded to the 3-oxo O atom of the indolizidinone system. The two rings of the peptidomimetic molecule are trans-fused, with the six-membered ring having a slightly distorted half-chair conformation and the five-membered ring having a perfect envelope conformation. The structure is stabilized by intermolecular O-H...O interactions between the water and adjacent peptide molecules, and by N-H...O interactions between the peptide molecules, which link the molecules into infinite chains.