Aurora J. Cruz-Cabeza

Facts and fictions about polymorphism

We present new facts about polymorphism based on (i) crystallographic data from the Cambridge Structural Database (CSD, a database built over 50 years of community effort), (ii) 229 solid form screens conducted at Hoffmann-La Roche and Eli Lilly and Company over the course of 8+ and 15+ years respectively and (iii) a dataset of 446 polymorphic crystals with energies and properties computed with modern DFT-d methods. We found that molecular flexibility or size has no correlation with the ability of a compound to be polymorphic. Chiral molecules, however, were found to be less prone to polymorphism than their achiral counterparts and compounds able to hydrogen bond exhibit only a slightly higher propensity to polymorphism than those which do not. Whilst the energy difference between polymorphs is usually less than 1 kcal mol(-1), conformational polymorphs are capable of differing by larger values (up to 2.5 kcal mol(-1) in our dataset). As overall statistics, we found that one in three compounds in the CSD are polymorphic whilst at least one in two compounds from the Roche and Lilly set display polymorphism with a higher estimate of up to three in four when compounds are screened intensively. Whilst the statistics provide some guidance of expectations, each compound constitutes a new challenge and prediction and realization of targeted polymorphism still remains a holy grail of materials sciences.

Metal-Exchanged β Zeolites as Catalysts for the Conversion of Acetone to Hydrocarbons

Various metal-β zeolites have been synthesized under similar ion-exchange conditions. During the exchange process, the nature and acid strength of the used cations modified the composition and textural properties as well as the Brönsted and Lewis acidity of the final materials. Zeolites exchanged with divalent cations showed a clear decrease of their surface Brönsted acidity and an increase of their Lewis acidity. All materials were active as catalysts for the transformation of acetone into hydrocarbons. Although the protonic zeolite was the most active in the acetone conversion (96.8% conversion), the metal-exchanged zeolites showed varied selectivities towards different products of the reaction. In particular, we found the Cu-β to have a considerable selectivity towards the production of isobutene from acetone (over 31% yield compared to 7.5% of the protonic zeolite). We propose different reactions mechanisms in order to explain the final product distributions.

Controlling molecular tautomerism through supramolecular selectivity

We have isolated the stable as well as the metastable tautomers of 1-deazapurine in the solid state by exploiting principles of supramolecular selectivity in the context of cocrystal design.

Crystal structure prediction: are we there yet?

This contribution comments on the advances of the latest Crystal Structure Prediction blind test and the challenges still lying ahead.

Isolation and evolution of labile sulfur allotropes via kinetic encapsulation in interactive porous networks

Reported here are the isolation and direct observation of extremely reactive S2 and its conversion into bent-S3 via a cyclo-S3 2+ intermediate on interactive sites in porous coordination networks.

Enhanced Concentration of Medium Strength Brönsted Acid Sites in Aluminium-Modified β Zeolite

A beta zeolite modified by treatment with aluminium ions has been characterized by different techniques, such as XRD, XPS, N2 adsorption, and TPD of pyridine and acetonitrile. Compared to the parent zeolite, it has shown some differences concerning the local environment of the aluminium atoms and the distribution of the acid sites. The modified zeolite has been tested as catalyst in a model reaction, i.e. the conversion of methanol to hydrocarbons, where it has exhibited higher activity than the parent zeolite.Graphical Abstract

Crystal nucleation and growth in a polymorphic system: Ostwald's rule, p-aminobenzoic acid and nucleation transition states

Ostwalds rule remains a long standing guide to crystallisation in polymorphic systems. It is often assumed that this rule has its origins in nucleation processes that favour metastable phases. Here a mathematical formalism is developed which shows that in fact the validity of this rule depends on both the relative nucleation and growth rates of the available forms. The implication of this result for previous nucleation studies is discussed. Surprisingly there is no existing comprehensive data set for both nucleation and growth kinetics of a polymorphic material. Accordingly new data for the α and β forms of p-aminobenzoic acid are reported here. These demonstrate the important contribution of growth to the polymorphic outcome and also suggest molecular scale mechanisms that dominate nucleation. In particular the uniquely rapid crystallisation behaviour observed in aqueous solutions is interpreted in both kinetic and structural terms.

Hydrogen-bond landscapes, geometry and energetics of squaric acid and its mono- and dianions: a Cambridge Structural Database, IsoStar and computational study

As part of a programme of work to extend central-group coverage in the Cambridge Crystallographic Data Centres (CCDC) IsoStar knowledge base of intermolecular interactions, we have studied the hydrogen-bonding abilities of squaric acid (H2SQ) and its mono- and dianions (HSQ(-) and SQ(2-)) using the Cambridge Structural Database (CSD) along with dispersion-corrected density functional theory (DFT-D) calculations for a range of hydrogen-bonded dimers. The -OH and -C=O groups of H2SQ, HSQ(-) and SQ(2-) are potent donors and acceptors, as indicated by their hydrogen-bond geometries in available crystal structures in the CSD, and by the attractive energies calculated for their dimers with acetone and methanol, which were used as model acceptors and donors. The two anions have sufficient examples in the CSD for their addition as new central groups in IsoStar. It is also shown that charge- and resonance-assisted hydrogen bonds involving H2SQ and HSQ(-) are similar in strength to those made by carboxylate COO(-) acceptors, while hydrogen bonds made by the dianion SQ(2-) are somewhat stronger. The study reinforces the value of squaric acid and its anions as cocrystal formers and their actual and potential importance as isosteric replacements for carboxylic acid and carboxylate functions.

On the kinetics of solvate formation through mechanochemistry

Theophylline : 2-pyrrolidone mono (1 : 1) and sesqui (2 : 3) solvates have been discovered through variable-amount liquid-assisted grinding (VALAG). The structures and stability of the solvates and the kinetics involved in their formation are investigated both experimentally and theoretically. Ex situ studies reveal a delayed appearance of the sesquisolvate and show that sesquisolvate formation occurs via the monosolvate rather than directly from pure theophylline. Theoretical calculations show that the obtained solvates are the thermodynamic products corresponding to the reactant ratio. The kinetics of the transformations was found to be related to the energy required to cleave the crystals through the softest planes. This was quantified by means of attachment energy calculations.

The Curious Case of 2-Propyl-1H-benzimidazole in the Solid State: An Experimental and Theoretical Study

2-Propyl-1H-benzimidazole (2PrBzIm) is a small molecule, commercially available, which displays a curious behavior in the solid state. 2PrBzIm, although devoid of chirality by fast rotation about a single bond of the propyl group in solution, crystallizes as a conglomerate showing chiroptical properties. An exhaustive analysis of its crystal structure and a wide range of experiments monitored by vibrational circular dichroism spectroscopy eliminated all possibilities of an artifact. What remains is a new example of the unexplained phenomenon of persistent supramolecular chirality.