Crystal clear. Engineering complexity.

A Holistic View of Water Environments in Molecular Crystals

Hydrates are common solid forms that can significantly affect a compound’s stability, physicochemical properties, and commercial viability. Despite their importance in pharmaceutical development, hydrate structures, their relationship to material properties, and their propensity for formation remain poorly understood. In 2003, Gillon et al. introduced a simple yet powerful framework for the structural classification of hydrates based on the hydrogen-bonding environment of crystalline water molecules. This framework categorizes water molecules according to the number of hydrogen-bond donor (D) and acceptor (A) interactions in which they participate, giving rise to eight distinct environments. In the original study, the DDA environment, where water donates two hydrogen bonds and accepts one, was reported as the most common. The statistical distribution of these environments in the Cambridge Structural Database (CSD) has since provided a useful benchmark for the qualitative assessment of hydrate structures. Here, we revisit Gillon’s water environment classification using a substantially expanded data set comprising 13,881 hydrate entries from the CSD and provide updated statistics on hydrate structures. Our analysis confirms that the DDA environment remains the most prevalent, followed by DDAA and DD, while the remaining environments occur less frequently. Extending beyond the original work, we quantify the energetics associated with each environment and demonstrate that the four-hydrogen-bond DDAA environment is energetically the most favorable, followed by environments involving three, two, and one hydrogen bonds, respectively. We further show that water-mediated intermolecular interactions contribute up to 40% of the total lattice interaction energy in the hydrate structures, highlighting the surprisingly large influence of this small solvent molecule on crystal stability. Despite its superior energetic stability, the DDAA environment is not the most frequently observed experimentally. This apparent discrepancy arises because the hydrogen-bonding capability and topology of the main component in the hydrate constrains the maximum hydrogen-bonding environment that water can achieve. Overall, this work provides a comprehensive analysis of hydrate structures and energetics across the CSD. The resulting insights offer a valuable framework for the qualitative assessment of newly discovered hydrate forms and for evaluating whether their structures conform to established crystallographic trends.

Engineering Small-Molecule Proton-Transfer Ferroelectrics by Crystal Structure Prediction: Design Limits at the Salt–Cocrystal Boundary

Organic molecular ferroelectrics hold significant potential in organic electronics due to their chemical tunability and straightforward fabrication methods. Among these, acid–base proton-transfer (PT) salts are notable for their low coercive fields and fast switching capabilities but are limited by relatively low spontaneous polarization. Using smaller molecular species can in principle increase the polarization, but requires both stabilization of the monovalent salt state and crystal packing that supports ferroelectric PT pathways. Using a crystal-structure prediction (CSP)-based design combined with density functional theory (DFT), we investigate 30 combinations of molecular acids and bases aimed at enhancing the dipole density. We identified several crystal structures with PT-capable hydrogen-bonding networks, and in our initial DFT ranking, three candidate ferroelectric packings and one antiferroelectric. Subsequent experimental work on two representative systems, while confirming the ability of CSP to predict PT-capable packing motifs, found neutral cocrystals rather than the desired monovalent salts supporting ferroelectricity. More detailed computational analysis traced the disparity to the relative stability of protonation states, which is strongly sensitive to the exchange–correlation functional and to vibrational zero-point energy contributions. Thus, while our CSP study correctly identified proton-transfer crystal packing motifs, it failed at the level of protonation-state stability, which we found to be strongly influenced by exchange–correlation choice and vibrational free energy.

Crystallographic Visualization of the Missing Structural Evolution of Copper Nanoclusters.

Copper nanoclusters have recently garnered immense interest across chemistry and materials science, yet precise control over their growth processes is hindered by a limited fundamental understanding of structural evolution. Here, we unlock atomic-level insights into their structural evolution by determining the structures of six distinct clusters─Cu12, Cu23-a, Cu23-b, Cu25-a, Cu25-b, and Cu61─isolated from a single synthetic system employing a disulfide-mediated protection strategy. By precisely tuning the reaction temperature and time, we strictly control the growth kinetics within this system. Single-crystal X-ray diffraction uncovers that hexameric Cu3S3 and octameric Cu4S4 rings act as versatile modular motifs, which encapsulate well-defined metal kernels to direct the structural evolution of all-thiolate-protected copper nanoclusters. Notably, structural isomerization is observed within this cluster series. By presenting the first experimental evidence from a homologous series of size-incremental copper-thiolate nanoclusters, this work provides atomic-level insights into how fundamental building motifs and surface coordination chemistry cooperatively direct the targeted synthesis of functional copper nanoclusters.

Beyond Familiar Phases: Discovering New Crystal Chemistry at the Nanoscale

Colloidal nanocrystal chemistry is highly developed within a narrow range of binary and simple ternary compositions, with reliable control over size, shape, surface chemistry, and the optical, electronic, and magnetic properties they govern. That control covers a small set of structure types, and the mechanisms by which precursors convert to colloidal products remain incompletely understood even within it. Compositionally complex multinary phases have proven a more difficult target. The cooperative phenomena that motivate sustained interest in multinary compounds in bulk, including geometric magnetic frustration, superconductivity, and charge density wave behavior, remain largely inaccessible to size-effect studies because the relevant compositions do not exist as well-defined nanocrystals. Bulk multinary chemistry achieves structural complexity through site differentiation, in which chemically distinct cations or anions occupy crystallographically distinct positions. Colloidal multinary nanocrystals, by contrast, are typically composed of chemically similar elements with comparable coordination and bonding preferences. The structures they form are accordingly limited to solid solutions in simple parent structures, such as wurtzite, zincblende, and rocksalt. This Perspective examines the synthetic, methodological, and analytical infrastructure that will be needed to translate site-differentiated structures from bulk to the nanoscale. Three synthetic strategies that route the reaction through a structurally informative intermediate are surveyed, alongside complementary mechanistic, statistical, and combinatorial approaches to synthetic discovery and the characterization techniques that will be required to identify new phases at sub-100-nm length scales.

CryoTEM as an advanced analytical tool for materials chemists

Chemical identity beyond structure in reactive metal systems.

Chemistry has long relied on the premise that molecular structure dictates biological function. This paradigm becomes incomplete for systems whose speciation changes on the timescale of the biological response. For many bioactive metal systems, however, the structure-based description is necessary but not always sufficient. The initial structure remains essential because it defines the accessible coordination, redox and transformation landscape, but the function observed in biological media may also depend on environmental selection and kinetic evolution. In these settings, the surrounding medium is not a passive milieu but an active driver that reshapes coordination spheres and redox states in real-time. To reconcile these emerging experimental realities, environment-driven chemical evolution (EDCE) is proposed as a unifying framework that shifts the unit of chemical identity from a single molecular entity to a dynamic trajectory through a network of interconverting states. Chemical evolution ratio (RCE) is introduced as a heuristic tool to identify the tipping point where environmental selection acts within the transformation landscape defined by the initial structure. By unifying coordination complexes and nanoparticle-based systems under this dynamic framework, a new basis for interpreting mechanistic divergence is provided. Recognizing EDCE enables the rational design of metal-based functions that are selectively dictated by the pathological microenvironment, rather than merely delivered to it.