Tale of Two Polymorphs: Investigating the Structural Differences and Dynamic Relationship between Nirmatrelvir Solid Forms (Paxlovid).

Two anhydrous polymorphs of the novel antiviral medicine nirmatrelvir were discovered during the development of Paxlovid, Pfizer's oral Covid-19 treatment. A comprehensive experimental and computational approach was necessary to distinguish the two closely related polymorphs, herein identified as Forms 1 and 4. This approach paired experimental methods, including powder X-ray diffraction and single-crystal X-ray diffraction, solid-state experimental methods, thermal analysis, solid-state nuclear magnetic resonance and Raman spectroscopy with computational investigations comprising crystal structure prediction, Gibbs free energy calculations, and molecular dynamics simulations of the polymorphic transition. Forms 1 and 4 were ultimately determined to be enantiotropically related polymorphs with Form 1 being the stable form above the transition temperature of ∼17 °C and designated as the nominated form for drug development. The work described in this paper shows the importance of using highly specialized orthogonal approaches to elucidate the subtle differences in structure and properties of similar solid-state forms. This synergistic approach allowed for unprecedented speed in bringing Paxlovid to patients in record time amidst the pandemic.

Beyond π-π Stacking: Understanding Inversion Symmetry Breaking in Crystalline Racemates.

The design of noncentrosymmetric (NCS) solid state materials, specifically how to break inversion symmetry between enantiomers, has intrigued chemists, physicists, and materials scientists for many years. Because the chemical complexity of molecular racemic building units is so varied, targeting these materials is poorly understood. Previously, three isostructural racemic compounds with a formula of [Cu(H2O)(bpy)2]2[MF6]2·2H2O (bpy = 2,2'=bipyridine; M = Ti, Zr, Hf) were shown to crystallize in the NCS space group Pna21, of polar, achiral crystal class mm2. In this work, we synthesized five new racemic compounds with the formula [Cu(H2O)(dmbpy)2]2[MF6]2·xH2O (dmbpy = 4,4'/5,5'-dimethyl-2,2'-bipyridine; M = Ti, Zr, Hf). Single crystal X-ray diffraction reveals that the five newly synthesized compounds feature equimolar combinations of Δ- and Λ-Cu(dmbpy)2(H2O)2+ complexes that are assembled into packing motifs similar to those found in the reported NCS structure but all crystallize in centrosymmetric (CS) space groups. Seven structural descriptors were created to analyze the intermolecular interactions on the assembly of Cu racemates in the CS and NCS structures. The structural analysis reveals that in the CS structures, the inversion center results from parallel heterochiral π-π stacking interactions between adjacent Cu racemates regardless of cation geometries, hydrogen bonding networks, or interlayer architectures, whereas in the NCS structure, nonparallel heterochiral π-π interactions between the adjacent Cu racemates preclude an inversion center. The parallel heterochiral π-π interactions in the CS structures can be rationalized by the restrained geometries of the methyl-substituted ligands. This work demonstrates that the introduction of nonparallel stacking can suppress the formation of an inversion center for an NCS racemate. A conceptual framework and practical approach linking the absence of inversion symmetry in racemates is presented for all NCS crystal classes.

Two Distinct Cu(II)-V(IV) Superexchange Interactions with Similar Bond Angles in a Triangular "CuV2" Fragment.

The strength and sign of superexchange interactions are often predicted on the basis of the bond angles between magnetic ions, but complications may arise in situations with a nontrivial arrangement of the magnetic orbitals. We report on a novel molecular tetramer compound [Cu(H2O)dmbpy]2[V2O2F8] (dmbpy = 4,4'-dimethyl-2,2'-bipyridyl) that is composed of triangular "CuV2" fragments and displays a spin gap behavior. By combining first-principles calculations and electronic models, we reveal that superexchange Cu-V interactions carry drastically different coupling strengths along two Cu-F-V pathways with comparable bond angles in the triangular "CuV2" fragment. Counterintuitively, their strong disparity is found to originate from the restricted symmetry of the half-filled Cu dx2-y2 orbital stabilized by the crystal field, leading to one dominating antiferromagnetic Cu-V coupling in each fragment. We revisit the magnetic properties of the reported spin-gapped chain compound [enH2]Cu(H2O)2[V2O2F8] (enH2 = ethylene diammonium) containing similar triangular "CuV2" fragments, and the magnetic behavior of the molecular tetramer and the chain compounds is rationalized as that of weakly coupled spin dimers and spin trimers, respectively. This work demonstrates that fundamentally different magnetic couplings can be observed between magnetic ions with similar bond angles in a single spin motif, thus providing a strategy to introduce various exchange interactions combined with low dimensionality in heterometallic Cu(II)-V(IV) compounds.

Perovskite-like K3TiOF5 Exhibits (3 + 1)-Dimensional Commensurate Structure Induced by Octahedrally Coordinated Potassium Ions.

Elpasolite- and cryolite-type oxyfluorides can be regarded as superstructures of perovskite and exhibit structural diversity. While maintaining a similar structural topology with the prototype structures, changes in the size, electronegativity, and charge of cation and/or anion inevitably lead to structural evolution. Therefore, the nominal one-to-one relation suggested by a doubled formula of perovskite does not guarantee a simple 2-fold superstructure for many cases. Herein, the commensurately modulated perovskite-like K3TiOF5 was refined at 100 K from single-crystal X-ray diffraction data by using a pseudotetragonal subcell with lattice parameters of a = b = 6.066(2) Å and c = 8.628(2) Å. The length of the modulation vector was refined to 0.3a* + 0.1b* + 0.25c*. In the commensurate supercell of K3TiOF5, the B-site Ti4+ and K+ cations in [TiOF5]3- and [KOF5]6- octahedral units were found to be significantly displaced from the average atomic positions refined in the subcell. The displacements of the K+ cations are ±0.76 Å, and those for the Ti4+ cations are approximately ±0.13 Å. One- and two-dimensional solid-state 19F NMR measurements revealed two tightly clustered groups of resonances in a ratio of ca. 4:1, assigned to equatorial and axial fluorine, respectively, consistent with local [TiOF5]3- units. S/TEM results confirmed the average structure. Electronic structure calculations of the idealized I4mm subcell indicate the instability to a modulated structure arises from soft optical modes that is controlled by the octahedrally coordinated B-site potassium ions in the cryolite-type structure.

Periodic Tendril Perversion and Helices in the AMoO2F3 (A = K, Rb, NH4, Tl) Family.

Although compounds of the formula AMoO2F3 (A = K, Rb, Cs, NH4, Tl) have been known for decades, crystal structures have only been reported for CsMoO2F3 and NH4MoO2F3. The three compounds (Rb/NH4/Tl)MoO2F3 are isostructural and crystallize in the centrosymmetric space group C2/c (No. 15). The compounds contain the MoO2F3- anionic chain, composed of corner-sharing MoO2F4 octahedra, with Mo6+ coordinated by two cis bridging fluoride anions that are trans to terminal oxide anions. The MoO2F3- chain has a very unusual and complex chain structure; a single chain contains alternating zigzag and helical sections. These helical regions alternate in chirality along the chain, and thus the chains exhibit periodic tendril perversion. To the best of the authors' knowledge, no other materials with a similar chain structure have been reported. On the other hand, KMoO2F3 is noncentrosymmetric and chiral, crystallizing in the enantiomorphic space group P212121 (No. 19). KMoO2F3 also contains the MoO2F3- anionic chain. However, the chain is helical, with only one enantiomer present, resulting in a chiral, noncentrosymmetric structure.

Machine-Learning-Assisted Synthesis of Polar Racemates.

Racemates have recently received attention as nonlinear optical and piezoelectric materials. Here, a machine-learning-assisted composition space approach was applied to synthesize the missing M = Ti, Zr members of the Δ,Λ-[Cu(bpy)2(H2O)]2[MF6]2·3H2O (M = Ti, Zr, Hf; bpy = 2,2'-bipyridine) family (space group: Pna21). In each (CuO, MO2)/bpy/HF(aq) (M = Ti, Zr, Hf) system, the polar noncentrosymmetric racemate (M-NCS) forms in competition with a centrosymmetric one-dimensional chain compound (M-CS) based on alternating Cu(bpy)(H2O)22+ and MF62- basic building units (space groups: Ti-CS (Pnma), Zr-CS (P1̅), Hf-CS (P2/n)). Machine learning models were trained on reaction parameters to gain unbiased insight into the underlying statistical trends in each composition space. A human-interpretable decision tree shows that phase selection is driven primarily by the bpy:CuO molar ratio for reactions containing Zr or Hf, and predicts that formation of the Ti-NCS compound requires that the amount of HF present be decreased to raise the pH, which we verified experimentally. Predictive leave-one-metal-out (LOO) models further confirm that behavior in the Ti system is distinct from that of the Zr and Hf systems. The chemical origin of this distinction was probed via fluorine K-edge X-ray absorption spectroscopy. Pre-edge features in the F1s X-ray absorption spectra reveal the strong ligand-to-metal π bonding between Ti(3d - t2g) and F(2p) states that distinguishes the TiF62- anion from the ZrF62- and HfF62- anions.

Multimodal Structure Solution with 19F NMR Crystallography of Spin Singlet Molybdenum Oxyfluorides.

Complex crystal structures with subtle atomic-scale details are now routinely solved using complementary tools such as X-ray and/or neutron scattering combined with electron diffraction and imaging. Identifying unambiguous atomic models for oxyfluorides, needed for materials design and structure-property control, is often still a considerable challenge despite their advantageous optical responses and applications in energy storage systems. In this work, NMR crystallography and single-crystal X-ray diffraction are combined for the complete structure solution of three new compounds featuring a rare triangular early transition metal oxyfluoride cluster, [Mo3O4F9]5-. After framework identification by single-crystal X-ray diffraction, 1D and 2D solid-state 19F NMR spectroscopy supported by ab initio calculations are used to solve the structures of K5[Mo3O4F9]·3H2O (1), K5[Mo3O4F9]·2H2O (2), and K16[Mo3O4F9]2[TiF6]3·2H2O (3) and to assign the nine distinct fluorine sites in the oxyfluoride clusters. Furthermore, 19F NMR identifies selective fluorine dynamics in K16[Mo3O4F9]2[TiF6]3·2H2O. These dual scattering and spectroscopy methods are used to demonstrate the generality and sensitivity of 19F shielding to small changes in bond length, on the order of 0.01 Å or less, even in the presence of hydrogen bonding, metal-metal bonding, and electrostatic interactions. Starting from the structure models, the nature of chemical bonding in the molybdates is explained by molecular orbital theory and electronic structure calculations. The average Mo-Mo distance of 2.505 Å and diamagnetism in 1, 2, and 3 are attributed to a metal-metal bond order of unity along with a 1a21e4 electronic ground state configuration for the [Mo3O4F9]5- cluster, leading to a rare trimeric spin singlet involving d2 Mo4+ ions. The approach to structure solution and bonding analysis is a powerful strategy for understanding the structures and chemical properties of complex fluorides and oxyfluorides.

NaRb3B6O9(OH)3(HCO3): A Borate-Bicarbonate Nonlinear Optical Material.

A noncentrosymmetric mixed alkali metal borate-bicarbonate, NaRb3B6O9(OH)3(HCO3), was synthesized and characterized. The compound crystallizes in the monoclinic space group P21 (No. 4) with a = 8.988(3) Å, b = 8.889(2) Å, c = 10.068(4) Å, and ß = 114.6(4)°. The structure features a combination of chains of boron-oxygen [B6O9 (OH)3]3- groups and isolated HCO3- groups, with charge compensation provided by Rb+ and Na+ cations. It exhibits a second harmonic generation response of about 0.5 × KDP. The UV-vis-NIR absorption spectrum indicated a transparency of about 40% at 200 nm. The IR spectrum confirms the coordination environments of anionic groups, and thermogravimetric measurements indicate the material is thermally stable up to approximately 320 °C. Additionally, first-principles calculations were performed in order to gain insight into the role of boron-oxygen and HCO3- groups with respect to the band structure and NLO properties.

Assisting the Effective Design of Polar Iodates with Early Transition-Metal Oxide Fluoride Anions.

Polar materials are of great technical interest but challenging to effectively synthesize. That is especially true for iodates, an important class of visible and mid-IR transparent nonlinear optical (NLO) materials. Aiming at developing a new design strategy for polar iodates, we successfully synthesized two sets of polymorphic early transition-metal (ETM) oxide-fluoride iodates, α- and ß-Ba[VFO2(IO3)2] and α- and ß-Ba2[VO2F2(IO3)2]IO3, based on the distinct structure-directing properties of oxide-fluoride anions. α- and ß-Ba[VFO2(IO3)2] contain the trans-[VFO2(IO3)2]2- polyanion and crystallize in the nonpolar space groups Pbcn and P212121. In contrast, α- and ß-Ba2[VO2F2(IO3)2]IO3 contain the cis-[VO2F2(IO3)2]3- Λ-shaped polyanion and crystallize in the polar space groups Pna21 and P21, respectively. Detailed structural analyses show that the variable polar orientation of trans-[VFO2(IO3)2]2- polyanions is the main cause of the nonpolar structures in α- and ß-Ba[VFO2(IO3)2]. However, the Λ-shaped configuration of cis-[VO2F2(IO3)2]3- polyanions can effectively guarantee the polar structures. Further property measurements show that polar α- and ß-Ba2[VO2F2(IO3)2]IO3 possess excellent NLO properties, including the large SHG responses (∼9 × KDP), wide visible and mid-IR transparent region (∼0.5-10.5 µm), and high thermal stability (up to 470 °C). Therefore, combining cis-directing oxide-fluoride anions and iodates is a viable strategy for the effective design of polar iodates.

Why Some Noncentrosymmetric Borates Do Not Make Good Nonlinear Optical Materials: A Case Study with K3B5O8(OH)2.

Synthesis of deep-ultraviolet (DUV) transparent materials, especially those with noncentrosymmetric structures, remains a great challenge in the solid-state chemistry community. A new DUV transparent borate, K3B5O8(OH)2, was discovered with a short absorption edge below 200 nm. The title compound crystallizes in a noncentrosymmetric, polar space group, Fdd2 (point group mm2), with the following cell parameters: a = 13.736(9) Å, b = 19.317(12) Å, c = 7.606(5) Å. The structure of K3B5O8(OH)2 features a 3D framework composed of [B5O8(OH)2]3- basic building units that are linked by contacts with K+ cations and O-H···O hydrogen bonds. Second harmonic generation (SHG) measurements were performed, and an SHG efficiency of 0.5 × SiO2 was observed. Symmetry dictates that the χ14 component of the macroscopic NLO susceptibility is equal to zero in mm2, which prevents the maximal component of the microscopic NLO susceptibility for [B5O8(OH)2]3- units (χ14) from contributing to the macroscopic NLO susceptibility of the crystal and therefore limits the SHG efficiency. In contrast, large SHG effects can be observed from compounds containing [B5O10] units that crystallize in point groups with nonzero χ14, such as 222. These findings provide insight into understanding the relationship between crystal structure and SHG efficiency in [B5O10]-based compounds and discovering other borate-based DUV materials.

Syntheses, Structures, and Properties of Non-Centrosymmetric Quaternary Tellurates Bi MTeO6 ( M = Al, Ga).

Single crystals of two new metal tellurates Bi MTeO6 ( M = Al, Ga) with a honeycomb layered structure were obtained by the molten flux method and characterized. The Bi MTeO6 compounds both crystallize into a non-centrosymmetric trigonal space group of P312 (no. 149) with cell parameters of a = 5.0667(8) Å, c = 4.9920(16) Å and a = 5.107(3) Å, c = 4.932(6) Å, respectively. The non-centrosymmetry of BiAlTeO6 and BiGaTeO6 originates from the packing order of the octahedra. In these two structures, TeO6 octahedra and MO6 octahedra share edges and form a honeycomb open-framework with [Te MO6]∞ layers. The layers of [ MTeO6]∞ and [BiO6]∞ alternate and are connected along the c-axis by corner-sharing oxygen atoms to form the three-dimensional framework. The chiral compound BiGaTeO6 exhibits a powder second harmonic generation (SHG) response of ∼0.2 times that of potassium dihydrogen phosphate (KDP) and an absorption edge of 355 nm.

Crystal structures of anhydrous and hydrated ceftibuten.

Ceftibuten, C15H14N4O6S2, with the systematic name (6R,7R)-7-{[(Z)-2-(2-amino-1,3-thia-zol-4-yl)-4-carb-oxy-but-2-eno-yl]amino}-8-oxo-5-thia-1-aza-bicyclo-[4.2.0]oct-2-ene-2-carb-oxy-lic acid, is a third generation, orally administered cephalosporin anti-biotic with broad anti-microbial activity and stability against extended spectrum ß-lactamases. Ceftibuten can exist in various hydration states and to better understand the location of the water mol-ecules of crystallization and their effect on the structure, the crystal structures of anhydrous (I) and hydrated (II) ceftibuten were determined and both occur as zwitterions with proton transfer from the carboxyl-ate group adjacent to the ß-lactam ring to the N atom of the thia-zole ring. The ß-lactam ring in (I) is almost planar but the equivalent grouping in (II) is slightly buckled. In the extended structure of (I), O-H⋯O and N-H⋯O hydrogen bonds link the mol-ecules into a three-dimensional network. In (II), O-H⋯Oc, N-H⋯Oc, O-H⋯Ow, N-H⋯Ow and Ow-H⋯Ow (c = ceftibuten, w = water) hydrogen bonds link the components into a three-dimensional network. A large void space is present within the anhydrous crystal structure that can accommodate between two and three mol-ecules of water.

Crystal structures of two copper(I)-6,6'-dimethyl-2,2'-bipyridyl (dmbpy) compounds, [Cu(dmbpy)2]2[MF6]·xH2O (M = Zr, Hf; x = 1.134, 0.671).

The syntheses and crystal structures of two bimetallic mol-ecular compounds, namely, bis[bis-(6,6'-dimethyl-2,2'-bi-pyridine)-copper(I)] hexa-fluorido-zir-con-ate(IV) 1.134-hydrate, [Cu(dmbpy)2]2[ZrF6]·1.134H2O (dmbpy = 6,6'-di-methyl-2,2'-bipyri-dyl, C12H12N2), (I), and bis[bis-(6,6'-dimethyl-2,2'-bi-pyr-idine)-copper(I)] hexa-fluorido-hafnate(IV) 0.671-hydrate, [Cu(dmbpy)2]2[HfF6]·0.671H2O, (II), are reported. Apart from a slight site occupany difference for the water mol-ecule of crystallization, compounds (I) and (II) are isostructural, featuring isolated tetra-hedral cations of copper(I) ions coordinated by two dmbpy ligands and centrosymmetric, octa-hedral anions of fluorinated early transition metals. The tetra-hedral environments of the copper complexes are distorted owing to the steric effects of the dmbpy ligands. The extended structures are built up through Coulombic inter-actions between cations and anions and π-π stacking inter-actions between heterochiral Δ- and Λ-[Cu(dmbpy)2]+ complexes. A comparison between the title compounds and other [Cu(dmbpy)2]+ compounds with monovalent and bivalent anions reveals a significant influence of the cation-to-anion ratio on the resulting crystal packing architectures, providing insights for future crystal design of distorted tetra-hedral copper compounds.

Crystal structures of three copper(II)-2,2'-bi-pyridine (bpy) compounds, [Cu(bpy)2(H2O)][SiF6]·4H2O, [Cu(bpy)2(TaF6)2] and [Cu(bpy)3][TaF6]2 and a related coordination polymer, [Cu(bpy)(H2O)2SnF6] n.

We report the hydro-thermal syntheses and crystal structures of aqua-bis-(2,2'-bi-pyridine-κ2 N,N')copper(II) hexa-fluorido-silicate tetra-hydrate, [Cu(bpy)2(H2O)][SiF6]·4H2O (bpy is 2,2'-bi-pyridine, C10H8N2), (I), bis-(2,2'-bi-pyridine-3κ2 N,N')-di-µ-fluorido-1:3κ2 F:F;2:3κ2 F:F-deca-fluorido-1κ5 F,2κ5 F-ditantalum(V)copper(II), [Cu(bpy)2(TaF6)2], (II), tris-(2,2'-bi-pyridine-κ2 N,N')copper(II) bis[hexa-fluorido-tantalate(V)], [Cu(bpy)3][TaF6]2, (III), and catena-poly[[di-aqua-(2,2'-bi-pyridine-κ2 N,N')copper(II)]-µ-fluorido-tetra-fluorido-tin-µ-fluorido], [Cu(bpy)(H2O)2SnF6] n , (IV). Compounds (I), (II) and (III) contain locally chiral copper coordination complexes with C 2, D 2, and D 3 symmetry, respectively. The extended structures of (I) and (IV) are consolidated by O-H⋯F and O-H⋯O hydrogen bonds. The structure of (III) was found to be a merohedral (racemic) twin.

Crystal structures of [Cu(phen)(H2O)3(MF6)]·H2O (M = Ti, Zr, Hf) and [Cu(phen)(H2O)2F]2[HfF6]·H2O.

The crystal structures of three bridged bimetallic mol-ecular compounds, namely, tri-aqua-2κ3 O-µ-fluorido-penta-fluorido-1κ5 F-(1,10-phenanthroline-2κ2 N,N')copper(II)titanium(IV) monohydrate, [Cu(TiF6)(phen)(H2O)3]·H2O (phen is 1,10-phenanthroline, C12H8N2), (I), tri-aqua-2κ3 O-µ-fluorido-penta-fluorido-1κ5 F-(1,10-phenanthroline-2κ2 N,N')copper(II)zirconium(IV) monohydrate, [Cu(ZrF6)(phen)(H2O)3]·H2O, (II), and tri-aqua-2κ3 O-µ-fluorido-penta-fluorido-1κ5 F-(1,10-phenanthroline-2κ2 N,N')copper(II)hafnium(IV) monohydrate, [Cu(HfF6)(phen)(H2O)3]·H2O, (III), and one mol-ecular salt, bis-[diaqua-fluorido-(1,10-phenanthroline-κ2 N,N')copper(II)] hexa-fluorido-hafnate(IV) dihydrate, [CuF(phen)(H2O)2]2[HfF6]·2H2O, (IV), are reported. The bridged bimetallic compounds adopt Λ-shaped configurations, with the octa-hedrally coordinated copper(II) center linked to the fluorinated early transition metal via a fluoride linkage. The extended structures of these Λ-shaped compounds are organized through both intra- and inter-molecular hydrogen bonds and inter-molecular π-π stacking. The salt compound [Cu(phen)(H2O)2F]2[HfF6]·H2O displays an isolated square-pyramidal Cu(phen)(H2O)2F+ complex linked to other cationic complexes and isolated HfF6 2- anions through inter-molecular hydrogen-bonding inter-actions.