Lattice Energy Calculations Research Articles

Investigation on the Crystal Structures of Molecules Related to 2‐(Benzylsulfinyl)Benzoic Acid, As a Support to the Studies on the Inhibition of Human Carbonic Anhydrases

AbstractA recent interest attaches to the derivatives of the (2‐benzylsulfinyl)benzoic acid as inhibitors of human carbonic anhydrases (hCAs), an action that can be applied in innovative therapies. A set of crystal structures of six sulfides and six enantiopure sulfoxides related to this scaffold, taken from the literature, or derived from the work on the asymmetric synthesis of sulfinyl compounds, is investigated. The lattice energies of these structures are estimated by means of the Crystal Explorer 21 program. The weak interactions building up the crystal structures are identified, and their contributions are analyzed in comparison with the calculated lattice energies. The most stable conformations in the solid phase are identified. It is worth observing that the sulfides of the scaffold under investigation behave almost in the same manner; on the other hand, the presence of the sulfinyl group of the sulfoxides adds complexity, that shall be taken into account in future docking calculations of these molecules with the hCAs enzymes.

Flavone Cocrystals: A Comprehensive Approach Integrating Experimental and Virtual Methods.

The dapsone/flavone cocrystal system served as a benchmark for both experimental and virtual screening methods. Expanding beyond this, two additional active pharmaceutical ingredients (APIs), sulfanilamide and sulfaguanidine, structurally related to dapsone were chosen to investigate the impact of substituents on cocrystal formation. The experimental screening involved mechanochemical methods, slurry experiments, hot-melt extrusion, and the contact preparation method. The virtual screening focused on crystal structure prediction (CSP), molecular complementarity, hydrogen-bond propensity, and molecular electrostatic potentials. The CSP studies not only indicated that each of the three APIs should form cocrystals with flavone but also reproduced the known single- and multicomponent phases. Experimentally, dapsone/flavone cocrystals ACC, BCC, CCC, and DCC were reproduced, CCC was identified as a nonstoichiometric hydrate, and a fifth cocrystal (ECC), a t-butanol solvate, was discovered. The cocrystal polymorphs ACC and BCC are enantiotripically related, and DCC, exhibiting a different stoichiometric ratio, is enthalpically stabilized over the other cocrystals. For the sulfaguanidine/flavone system, two novel, enantiotripically related cocrystals were identified. The crystal structures of two cocrystals and a flavone polymorph were solved from powder X-ray diffraction data, and the stability of all cocrystals was assessed through differential scanning calorimetry and lattice energy calculations. Despite computational indications, a diverse array of cocrystallization techniques did not result in a sulfanilamide/flavone cocrystal. The driving force behind dapsone's tendency to cocrystallize with flavone can be attributed to the overall strength of flavone interactions in the cocrystals. For sulfaguanidine, the potential to form strong API···API and API···coformer interactions in the cocrystal is a contributing factor. Furthermore, flavone was found to be trimorphic.

Designing Organic π-Conjugated Molecules for Crystalline Solid Solutions: Adamantane-Substituted Naphthalenes.

We showcase herein organic crystalline solid solutions (CSSs) based on the simplest polycyclic aromatic hydrocarbon (PAH) scaffold, naphthalene, stabilized by dispersion forces induced by adamantane substitution. High thermal stability of the host and guest molecules synthesized by cross-coupling of dibromonaphthalene derivatives and 4-(1-adamantyl)phenyl boronic ester enabled formation of crystals by sublimation. We could generate binary monocrystalline solid solution systems proven by X-ray crystallography, the first system of designed CSSs stabilized exclusively via dispersion forces with structural evidence. These observations are additionally supported by lattice energy calculations and spectroscopic examinations. For the generation of CSSs, it is of utmost importance that the host and guest molecules have similar lattice energies and spatial compatibility. We anticipate that the thermostable organic CSS design demonstrated herein would be beneficial for functional materials and further investigation towards materials with unique properties.

Polymorphism and Multi-Component Crystal Formation of GABA and Gabapentin.

This study exploits the polymorphism and multi-component crystal formation of γ-amino butanoic acid (GABA) and its pharmaceutically active derivative, gabapentin. Two polymorphs of GABA and both polymorphs of gabapentin are structurally revisited, together with gabapentin monohydrate. Hereby, GABA form II is only accessible under special conditions using additives, whereas gabapentin converts to the monohydrate even in the presence of trace amounts of water. Different accessibilities and phase stabilities of these phases are still not fully clarified. Thus, indicators of phase stability are discussed involving intermolecular interactions, molecular conformations, and crystallization environment. Calculated lattice energy differences for polymorphs reveal their similar stability. Quantification of the hydrogen bond strengths with the atoms-in-molecules (AIM) model in conjunction with non-covalent interaction (NCI) plots also shows similar hydrogen bond binding energy values for all polymorphs. We demonstrate that differences in the interacting modes, in an interplay with the intermolecular repulsion, allow the formation of the desired phase under different crystallization environments. Salts and co-crystals of GABA and gabapentin with fumaric as well as succinic acid further serve as models to highlight how strongly HBs act as the motif-directing force in the solid-phase GABA-analogs. Six novel multi-component entities were synthesized, and structural and computational analysis was performed: GABA fumarate (2:1); two gabapentin fumarates (2:1) and (1:1); two GABA succinates (2:1) and (1:1); and a gabapentin:succinic acid co-crystal. Energetically highly attractive carboxyl/carboxylate interaction overcomes other factors and dominates the multi-component phase formation. Decisive commonalities in the crystallization behavior of zwitterionic GABA-derivatives are discussed, which show how they can and should be understood as a whole for possible related future products.

Study of strong O[sbnd]H⋯O− hydrogen bond interactions in binuclear Zn hydroxyquinoline carboxylic acid complex

Investigation of strong hydrogen bonds in crystal engineering is extensively used for the preparation of intriguing novel pharmaceutical co-crystals and ionic compounds. Strong OH⋯O− hydrogen bonds in phenolates were recently recognized as a promising supramolecular synthon for the preparation of novel ionic co-crystals, and phenolates as promising catalysts and reducing agents. Investigations of complex compounds containing uncoordinated phenolate are exceptionally rare and this particular research area is yet unexplored. As part of our continuous investigations in the supramolecular chemistry of coordination compounds, we have prepared a novel Zn(II) binuclear complex with 4-hydroxyquinoline-2-carboxylic acid as a ligand (4hqc). The compound was characterized by IR-spectroscopy, and molecular and crystal structure was determined by the single-crystal X-ray diffraction method. The compound is a binuclear Zn complex, with each Zn(II) ion coordinated by one 4hqc ligand and two water molecules in the distorted square pyramidal arrangement. The central Zn2(µ-O)2 unit is planar and Zn ions are bridged by monodentatelly coordinated carboxylate oxygen atoms. In the crystal, the discrete binuclear units are primarily connected by strong OH⋯O− hydrogen bond interactions that involve deprotonated hydroxyl oxygen atoms and coordinated water molecules. The 3D structure is additionally stabilized by offset face-to-face π⋯π interactions. Additional structural analysis has shown that geometrical parameters of OH⋯O− hydrogen bonds are very similar to those in phenolate co-crystals, thus confirming the presence of phenolate in the complex. The calculated lattice energy of the compound was found to be unusually high (-505.56 kJ/mol), and OH⋯O− bond energies were estimated to be in the range from −55.0 kJ/mol to −62.5 kJ/mol. By comparison to previously reported phenolate coordination compounds, it was proposed that such compounds could be synthesized in mildly alkaline conditions, ligand: metal stoichiometric ratio 1:1, and with ligands bearing carboxylate, imine, or pyridine groups separated from phenol group by hydrogen atom or other bulkier groups.

Two Conformational Polymorphs of a Bioactive Pyrazolo[3,4-d]pyrimidine

Two monoclinic (P21/c; Z′ = 1) polymorphs, α (from methanol) and β (from ethanol, n-propanol and iso-propanol), of a bioactive pyrazolo[3,4-d]pyrimidine derivative have been isolated and characterised by X-ray crystallography as well as by a range of computational chemistry techniques. The different conformations observed for the molecules in the crystals are due to the dictates of molecular packing as revealed by geometry-optimisation calculations. The crucial difference in the molecular packing pertains to the formation of phenylamino-N–H···N(pyrazolyl) hydrogen bonding within supramolecular chains with either helical (α-form; 21-screw symmetry) or zigzag (β-form; glide symmetry). As a consequence, the molecular packing is quite distinct in the polymorphs. Lattice energy calculations indicate the β-form is more stable by 11 kJ/mol than the α-form.

Crystal Structure of Poly(7-heptalactone)

The crystal structure of poly(7-heptalactone) (PHL) is presented. PHL has been synthesized by a combination of ring-opening polymerization of η-heptalactone and reversible addition–fragmentation chain transfer polymerization using diphenyl phosphate as catalyst. The noncommercial available η-heptalactone monomer has been prepared by oxidation of cycloheptanone. The crystal structure of PHL has been determined by analysis of the X-ray powder diffraction profiles and of the electron diffraction patterns of single crystals and calculations of lattice energy. The structure has been refined with the Rietveld full-profile refinement. Chains in trans planar conformation are packed in an orthorhombic unit cell with axes a = 7.37 Å, b = 5.05 Å, and c = 10.07 Å according to the space group symmetry P21.

Tuning the physicochemical properties of axitinib by crystallization: Preparation, calculation and Structure-property relationship

Crystal engineering is a radical method to modulate the physicochemical properties of the drugs to meet the needs of the pharmaceutical industry. Examined herein are six axitinib solid-state forms, including anhydrous forms (Ⅳ and XLI), solvates (acetic acid, nitromethane and n-propanol), and cocrystal (nicotinamide). Comprehensive characterization containing morphology, hygroscopicity, solubility, fluorescence and powder tabletability were performed. Calculations of lattice energy, packing coefficient and energy framework rationalized the structure–property relationship of these six forms from the packing landscape. This system illustrates that form IV and cocrystal improve the solubility of axitinib, but the humidity stability is also decreased. Six crystal forms show polychromatic solid-state luminescence ranging from violet to indigo to green. Form IV and cocrystal with slip plane structures exhibited superior tensile strength and compactibility than isotropic form XLI. Elusive form VI can be obtained by controlling the humidity levels during desolvation of the solvate. This work not only realizes the regulation of better physicochemical properties of axtinnib for industrial manufacturing, but also provides a detailed understanding of the structure–property relationship of drugs in complex polymorphic systems.

Cascade Charge Transitions of Unusually High and Mixed Valence Fe3.5+ in the A-Site Layer-Ordered Double Perovskite SmBaFe2O6.

The A-site layer-ordered double perovskite SmBaFe2O6 was obtained by topochemical of oxidizing A-site layer-ordered SmBaFe2O5 in ozone at a low temperature. The compound contained unusually high and mixed valence Fe3.5+ and was found to show cascade charge transitions, described as SmBaFe3.5+2O6 → SmBa(Fe3+Fe4+)O6 → SmBa(Fe3+Fe(4-δ)+0.5Fe(4+δ)+0.5)O6 → SmBa(Fe3+1.5Fe5+0.5)O6, to relieve its electronic instability. The first Verwey-like charge-order transition occurred at 340 K and was accompanied by a significant structural change and a sudden increase in magnetic susceptibility. The following transition was the charge disproportionation of metastable Fe4+ to Fe3+ and Fe5+, and each of the spins resulted in the antiferromagnetic ground state. The most plausible charge-ordered patterns are proposed based on the electrostatic lattice energy calculations.

Novel Adamantane-Linked Isothiourea Derivatives as Potential Chemotherapeutic Agents: Synthesis, Structural Insights, and Antimicrobial/Anti-Proliferative Profiles.

In this study, two adamantane-linked isothiourea derivatives containing a common 4-chlorophenyl substituent coupled with 4-nitrobenzyl or 4-bromobenzyl moieties were synthesized. Both derivatives were characterized, in the solid state and in solution, through a synergistic combination of experimental and in silico techniques, and the results are of great value for the chemical and structural characterization of related compounds. The crystal structures of both derivatives were analyzed in depth, including Hirshfeld surface analysis and lattice energy calculations, revealing a predominant dispersive component of the total energy that stabilizes crystal packing. Both compounds showed potent broad-spectrum antibacterial activity and moderate activity against the pathogenic fungus Candida albicans. In addition, in vitro anti-proliferative activity assays showed that the 4-bromobenzyl analogue displays higher activity than the 4-nitrobenzyl one, with IC50 values under 30 μM against five human cancer cell lines. Our results give evidence of the potential of the adamantane/isothiourea combination to render auspicious scaffolds for new potential chemotherapeutic agents.

Overcoming the Hydrophobic Nature of Zinc Phenylacetate Through Co-Crystallization with Isonicotinamide

Zinc phenylacetate (Zn-PA), a substitute for sodium phenylacetate as an ammonia-scavenging drug is hydrophobic, which poses problems for drug dissolution and solubility. We were able to co-crystallize the zinc phenylacetate with isonicotinamide (INAM) and produce a novel crystalline compound (Zn-PA-INAM). The single crystal of this new crystal was obtained, and its structure is reported here for the first time. Zn-PA-INAM was characterized computationally by ab initio, Hirshfeld calculations, CLP-PIXEL lattice energy calculation, and BFDH morphology analysis, and experimentally by PXRD, Sc-XRD, FTIR, DSC, and TGA analyses. Structural and vibrational analyses showed a major modification in intermolecular interaction of Zn-PA-INAM compared to Zn-PA. The dispersion-based pi-stacking in Zn-PA is replaced by coulomb-polarization effect of hydrogen bonds. As a result, Zn-PA-INAM is hydrophilic, improving the wettability and powder dissolution of the target compound in an aqueous solution. Morphology analysis revealed, unlike Zn-PA, Zn-PA-INAM has polar groups exposed on its prominent crystalline faces, reducing the hydrophobicity of the crystal. The shift in average water droplet contact angle from 128.1° (Zn-PA) to 27.1° (Zn-PA-INAM) is strong evidence of a marked decrease in hydrophobicity of the target compound. Finally, HPLC was used to obtain the dissolution profile and solubility of Zn-PA-INAM compared to Zn-PA.

A general force field by machine learning on experimental crystal structures. Calculations of intermolecular Gibbs energy with FlexCryst.

Machine learning was employed on the experimental crystal structures of the Cambridge Structural Database (CSD) to derive an intermolecular force field for all available types of atoms (general force field). The obtained pairwise interatomic potentials of the general force field allow for the fast and accurate calculation of intermolecular Gibbs energy. The approach is based on three postulates regarding Gibbs energy: the lattice energy must be below zero, the crystal structure must be a local minimum, and, if available, the experimental and the calculated lattice energy must coincide. The parametrized general force field was then validated regarding these three conditions. First, the experimental lattice energy was compared with the calculated energies. The observed errors were found to be in the order of experimental errors. Second, Gibbs lattice energy was calculated for all structures available in the CSD. Their energy values were found to be below zero in 99.86% of the cases. Finally, 500 random structures were minimized, and the change in density and energy was examined. The mean error in the case of density was below 4.06%, and for energy it was below 5.7%. The obtained general force field calculated Gibbs lattice energies of 259 041 known crystal structures within a few hours. Since Gibbs energy defines the reaction energy, the calculated energy can be used to predict chemical-physical properties of crystals, for instance, the formation of co-crystals, polymorph stability and solubility.

The effect of polymorphism on polymer properties: crystal structure, stability and polymerization of the short-chain bio-based nylon 52 monomer 1,5-pentanediamine oxalate.

The compound 1,5-pentanediamine (PDA) is prepared by biological methods using biomass as raw material. The salt of 1,5-pentanediamine oxalate (PDA-OXA) was used directly as the monomer for the preparation of a new bio-based nylon 52 material. High-performance polymer materials require initial high-quality monomers, and crystallization is an essential approach to preparing such a monomer. In this work, three crystal forms of PDA-OXA, the anhydrate, dihydrate and trihydrate, were found and the single crystals of two hydrates were obtained. Their crystal structures were determined using single-crystal and powder X-ray diffraction. The thermal behaviors were characterized by thermodynamic analysis, and the lattice energy was calculated to further explore the relationship between the thermal stability and crystal structure. Detailed computational calculations, Hirshfeld analyses and lattice energy calculations were performed to quantify both the contribution of intra- and intermolecular interactions to the supramolecular assembly, as well as the influence on the stability of the structure. The structure-property relationship between the PDA-OXA crystal forms was established. Moreover, the phase transformation mechanism between the crystalline forms of PDA-OXA has been established, and the control strategy of specific crystal forms was developed from the water activity-temperature phase diagram and relevant thermodynamic data. Finally, the influence of the polymorphism of the monomer and the polymerization methods on the properties of the polymer was investigated. The nylon 52 product obtained showed good appearance, high hardness and thermal stability, the polymer made using the anhydrate as the monomer has better thermodynamic properties than that prepared from the dihydrate, indicating practical industrial application prospects.

Pressure-freezing of dodecane: exploring the crystal structures, formation kinetics and phase diagrams for colossal barocaloric effects in n-alkanes.

Barocaloric (BC) materials provide cheaper and more energy efficient alternatives to traditional refrigerants. Some liquid alkanes were recently shown to exhibit a colossal BC effect, matching the entropy changes in commercial vapour-liquid refrigerants. Dodecane was predicted to have the largest entropy change among the studied alkanes. Using synchrotron powder and single-crystal X-ray diffraction, Raman spectroscopy, and lattice energy calculations, we investigated the BC effects of n-dodecane at high pressures and room temperature. Remarkably, a colossal entropy change |ΔS| of 778 J kg-1 K-1 at 0.15(3) GPa and 295 K was observed. Spectroscopic studies revealed that this entropy change correlates closely with the conformational transition from mixed gauche to all-trans forms during pressure-induced crystallization. Additionally, the usage of a diamond anvil cell allowed the determination of the crystal structures of in situ crystallized n-un- and dodecane, as well as evaluation of the pressure-dependent crystal growth kinetics. Furthermore, our research suggests that the entropy change (per kilogram) upon compression should be similar for all n-alkanes within the range of 9-18 carbon atoms in the molecule, based on their lattice energies. Even-numbered alkanes are predicted to exhibit superior BC properties compared to their odd-numbered counterparts due to the more symmetric crystal structures and lower propensity to form plastic phases with lower transition entropy.

Solvent-induced polymorphism in dipodal N-donor ligands containing a biphenyl core.

Polymorph screenings for two related dipodal N-donor ligands containing a biphenyl core, namely 4,4'-bis(pyridin-4-ylmethyl)-1,1'-biphenyl (1) and 4,4'-bis(1H-imidazol-1-ylmethyl)-1,1'-biphenyl (2) were performed, and the new phases were isolated and their crystal structures analysed. Profiling included methods such as PXRD and thermal analysis. Hirshfeld surface analyses, as well as crystal lattice energy calculations provided deeper insight in the interplay of the intermolecular forces and the stability of the isolated phases. Furthermore, our studies revealed the presence of solvent-induced polymorphism, whereby the metastable phase is dominant upon crystallisation from THF (1a) and EtOH (2c). Upon heating, these phases transform into a more stable form, whereby the transformations were followed by PXRD studies (1, 2).

Exploring the CSD Drug Subset: An Analysis of Lattice Energies and Constituent Intermolecular Interactions for the Crystal Structures of Pharmaceuticals

Intermolecular (synthonic) modelling is used for a statistical analysis of crystal lattice energies, together with their contributing intermolecular interactions for the crystallographic structures selected from the CCDC's Drug Subset (https://doi.org/10.1016/j.xphs.2018.12.011). Analysis of this selected subset reveal similarities in packing compared to other organic crystals in the CSD with linear relationships between molecular weight and unit cell volume, void space, and packing coefficient. Crystal lattice energy calculations converge within a 30 Å intermolecular radius characterised by a mean lattice energy of ca. -36 kcal mol−1 with ca. 85% and 15% due to dispersive and electrostatic interactions, respectively. The distribution of the strongest synthons within the individual structures reveals an average strength of −5.79 kcal mol−1. The diversity of chemical space within the drug molecules is in agreement with the analysis of atom types across the selected subset with phenyl groups being found to contribute the highest mean energy of −11.28 kcal mol−1, highlighting the importance of aromatic interactions within pharmaceutical compounds. Despite an initial focus on Z’ = 1 structures, this automated approach enables rapid and consistent quantitative analysis of lattice energy, synthon strength and functional group contributions, providing solid-form informatics for pharmaceutical R&D and a helpful basis for further investigations.

Minimal Basis Set Hartree-Fock Corrected with Atom-Centered Potentials for Molecular Crystal Modeling and Crystal Structure Prediction.

Crystal structure prediction (CSP), determining the experimentally observable structure of a molecular crystal from the molecular diagram, is an important challenge with technologically relevant applications in materials manufacturing and drug design. For the purpose of screening the randomly generated candidate crystal structures, CSP protocols require energy ranking methods that are fast and can accurately capture the small energy differences between molecular crystals. In addition, a good ranking method should also produce accurate equilibrium geometries, both intramolecular and intermolecular. In this article, we explore the combination of minimal-basis-set Hartree-Fock (HF) with atom-centered potentials (ACPs) as a method for modeling the structure and energetics of molecular crystals. The ACPs are developed for the H, C, N, and O atoms and fitted to a set of reference data at the B86bPBE-XDM level in order to mitigate basis-set incompleteness and missing correlation. In particular, ACPs are developed in combination with two methods: HF-D3/MINIs and HF-3c. The application of ACPs greatly improves the performance of HF-D3/MINIs for lattice energies, crystal energy differences, energy-volume and energy-strain relations, and crystal geometries. In the case of HF-3c, the improvement in the crystal energy differences is much smaller than in HF-D3/MINIs, but lattice energies and particularly crystal geometries are considerably better when ACPs are used. The resulting methods may be useful for CSP but also for quick calculation of molecular crystal lattice energies and geometries.

Electrochemical, Photophysical, Morphological and DFT Study of Polymorphic Sn(IV)-Porphyrins Containing Fluorinated Axial Ligand.

In this study, we report the polymorphism of six coordinated Sn(IV)- tetrabromophenyl porphyrins axially armed with fluorine-substituted phenolate ligands (structural formula [Sn(TBrPP)2+ (A- )2 ], where A is the axial ligand=3,5-difluoro phenol, compound 1). One form stabilizes in triclinic system (namely, 1α), and the other stabilizes in monoclinic system (namely, 1β). The two 1α and 1β polymorphs display distinct photophysical and morphological properties in the solid state. X-ray diffraction study reveals that these polymorphs 1α and 1β significantly differ in their supramolecular architecture, different axial phenolate conformations, and noncovalent interactions, which are responsible for their distinct solid-state properties. The crystal packing of these polymorphs dominates by intermolecular C-H⋅⋅⋅F, C-H⋅⋅⋅π and C-Br⋅⋅⋅F interhalogen interactions. Furthermore, the solid-state emission spectra of 1α showed red-shifted emission bands with respect to 1β, in addition the redox behavior of 1α is slightly different in comparison to 1β. Complementary theoretical studies with Hirshfeld surface analysis show the definite role of Br⋅⋅⋅F interhalogen interactions in the overall stability. Mapping the electrostatic potential isosurfaces with the aid of density functional theory in compound 1 clearly shows the presence of σ-hole, a requisite feature to show halogen interactions in the crystalline state. In addition, lattice energy and single point energy calculation shows that 1α was found to be energetically more favorable and thermodynamically more stable compare to 1β.

Study of Cycloxaprid Co-crystals: Characterization, Theory Calculation, Solubility, and Stability

Cycloxaprid (CYC) is a potentially commercially available pesticide with high activity, but its further development is limited due to the poor solubility and stability. In this paper, the co-crystallization strategy is applied to improve the physical and chemical properties of CYC for the first time. The cycloxaprid-succinimide (CYC–SM) co-crystal and the cycloxaprid-trifluoromethanesulfonamide (CYC–TS) co-crystal with a stoichiometric ratio of 1:1 between API and co-crystal former were successfully prepared through experimental screening and systemically characterized by powder X-ray diffraction, nuclear magnetic resonance, differential scanning calorimetry, thermogravimetry, Fourier transform infrared spectroscopy, and single-crystal X-ray diffraction techniques. The weak interaction of CYC–SM and CYC–TS co-crystals was quantified and analyzed by quantum chemistry calculations. Compared with CYC–TS, the molecular orbital and lattice energy calculation results of CYC–SM show lower chemical reactivity and better stability, which is consistent with the results of solid-state and solution stability tests. The partially weak interaction remained in the solution, and the weakly basic nature of SM and the relatively slow release of CYC from CYC–SM contributed to the promoted solution stability of CYC–SM. In addition, due to the introduction of SM molecules, the solubility of CYC–SM was significantly improved. The CYC–SM co-crystal could be a candidate solid-state form that provides an opportunity for the further development of CYC.

Synthesis and crystal structure of Ge(SO4)2

AbstractColourless single crystals of Ge(SO4)2 were obtained as single phase products from the binary oxides GeO2 and SO3. The reaction was carried out in a silica glass ampule enclosed in an autoclave at 350 °C. Ge(SO4)2 forms a layer structure with corner‐linked GeO6 octahedra and SO4 tetrahedra. The crystal structure (R c, Z=6, a=4.622 Å, c=42.576 Å) belongs to the Ni(ClO4)2‐type. The SO4 tetrahedra are rotated by 24°. The sense of rotation alternates between adjacent layers. This rotation is connected to a super structure with a doubled c‐axis and a disorder between the layers according to the sense of rotation. Ge(SO4)2 is one of the very rare examples of a sulphate of a tetravalent cation and is the representative with the smallest ionic radius. Lattice energy calculations confirm the electrostatic consistency. Vibrational spectra were recorded and show the typical features of GeO6 and SO4 units.