Jonathan W. Steed

Mechanochemistry: opportunities for new and cleaner synthesis

The aim of this critical review is to provide a broad but digestible overview of mechanochemical synthesis, i.e. reactions conducted by grinding solid reactants together with no or minimal solvent. Although mechanochemistry has historically been a sideline approach to synthesis it may soon move into the mainstream because it is increasingly apparent that it can be practical, and even advantageous, and because of the opportunities it provides for developing more sustainable methods. Concentrating on recent advances, this article covers industrial aspects, inorganic materials, organic synthesis, cocrystallisation, pharmaceutical aspects, metal complexes (including metal-organic frameworks), supramolecular aspects and characterization methods. The historical development, mechanistic aspects, limitations and opportunities are also discussed (314 references).

Metal- and Anion-Binding Supramolecular Gels

1. Importance and Scope of Supramolecular Gels 1960 2. Gel Characterization 1963 2.1. General Considerations 1963 2.2. Rheology 1964 2.3. Models for Gel Rheology 1965 3. Concepts of Gel Formation 1966 4. Metals in Gels 1967 4.1. Metals as Structural Components in Gels 1967 4.2. Discrete Metal Complex Gelators 1973 5. Metal Ion Binding by Gels and Gelators 1978 5.1. Coordination Polymers as Metallogels 1979 5.2. Tuning Gel Properties by Ion Binding 1986 5.3. Salts as Gels and Tuning Agents 1993 6. Anion Binding by Gels and Gelators 1994 7. Gels as Templates 2000 8. Conclusions 2001 9. Acknowledgments 2001 10. References 2001

Anion-tuning of supramolecular gel properties

The study of supramolecular gels has developed into a well-recognised field of materials science, pertaining to the general area of soft matter. The use of small molecules that aggregate through supramolecular interactions (such as hydrogen bonds, π–π interactions, coordination bonds and van der Waals interactions) has given materials scientists an alternative to polymeric compounds for the development of practical gels. There have been further attempts to functionalize, activate or control the physical properties of such gels by means of the reversibility of the interactions between the component molecules. Tuning of these characteristics has been accomplished by using mechanical, thermal, electrochemical, electromagnetic and chemical stimuli. The use of anions as a chemical stimulus has been a recent development and is the subject of this Perspective. Small anions can be used to modulate the physical properties of supramolecular gels by interacting with the low-molecular-weight gelators from which such materials are composed. A better understanding of this anion-tuning effect will aid in the rational design of responsive gels that may prove useful for a number of practical applications.

First- and second-sphere coordination chemistry of alkali metal crown ether complexes

Abstract Crown ethers exhibit an extremely versatile range of interactions with alkali metal cations in the solid state that goes far beyond simplistic ‘size fit’ considerations. In this review the structural chemistry of first and second-sphere alkali metal cation complexes of the crown ethers is examined with an emphasis on the role played by hydrogen bonding interactions to counter anions and other co-ligands such as water. An examination of the vast diversity of alkali metal crown ether complexes and the strong propensity of the crown ethers to act as hydrogen bond acceptors suggests that hydrogen bonding plays a crucial role in determining overall structure.

Anion-switchable supramolecular gels for controlling pharmaceutical crystal growth

We describe the use of low-molecular-weight supramolecular gels as media for the growth of molecular crystals. Growth of a range of crystals of organic compounds, including pharmaceuticals, was achieved in bis(urea) gels. Low-molecular-weight supramolecular gelators allow access to an unlimited range of solvent systems, in contrast to conventional aqueous gels such as gelatin and agarose. A detailed study of carbamazepine crystal growth in four different bis(urea) gelators, including a metallogelator, is reported. The crystallization of a range of other drug substances, namely sparfloxacin, piroxicam, theophylline, caffeine, ibuprofen, acetaminophen (paracetamol), sulindac and indomethacin, was also achieved in supramolecular gel media without co-crystal formation. In many cases, crystals can be conveniently recovered from the gels by using supramolecular anion-triggered gel dissolution; however, crystals of substances that themselves bind to anions are dissolved by them. Overall, supramolecular gel-phase crystallization offers an extremely versatile new tool in pharmaceutical polymorph screening. Supramolecular gels based on small-molecule gelators have been shown to be effective media for the growth of organic crystals, including pharmaceutical compounds. Moreover, the gel-to-sol transition can be triggered by molecular recognition with anions, thereby enabling facile recovery of the crystals.

Should solid-state molecular packing have to obey the rules of crystallographic symmetry?

About 8% of crystal structures contain more than one independent molecule or formula unit; the number being denoted by the parameter Z′. To most chemists and crystallographers such structures are nothing but a pain in the scientific rear! The crystallographer has to waste valuable data collection and computing power determining the structure of two or more often almost identical molecules, while the chemist writing a paper has to go to the trouble of making sure that “the second independent molecule does not differ significantly from the first”. With the advent of modern data collection and computational hardware these irritations have been to some extent ameliorated. Moreover, to a slowly growing body of ‘crystal chemists’ the interactions between crystallographically independent molecules represent a rich hunting ground for understanding solid state packing. Why should such structures form when nine times out of ten, crystallographic symmetry results in perfectly decent packing arrangements? Most importantly, can we learn something about the phase behaviour and materials properties of solids by understanding these special cases, perhaps with a view to using them in a predictive fashion? This survey sets out to collate existing data and interpretations on structures with high Z′ values as well as to highlight some interesting case studies and make some suggestions about future directions.

The role of co-crystals in pharmaceutical design

Pharmaceutical co-crystal formation represents a straightforward way to dramatically influence the solid-state properties of a drug substance, particularly its solubility and hence bioavailability. This short review summarises this highly topical field, covering why the topic is of interest in pharmaceutical formulation, the definitions and practical scope of co-crystals, co-crystal preparation and characterisation, and implications for regulatory control and intellectual property (IP) protection. Concepts are illustrated with highly selected examples of pharmaceutical co-crystal systems within the wider context of crystal engineering and research in molecular solids.

Exploiting Cavities in Supramolecular Gels

Endowing supramolecular gelators with cavities opens up a number of opportunities not possible with other gel systems. The well-established host-guest chemistry of cavitands can be utilized to build up and break down gel structures, introduce responsive functionalities, or enhance selectivity in applications such as catalysis and extraction. Cavity-containing gelators provide an excellent case study for how different aspects of supramolecular chemistry can be used intelligently to create responsive materials.

The chemistry of low dosage clathrate hydrate inhibitors

This review aims to introduce the chemistry of low dosage inhibitors of clathrate hydrate formation within the context of their role in the oil and gas industry. The review covers both kinetic hydrate inhibitors and anti-agglomerants from the point of view of structure-function relationships, focussing on recent refinements in mechanistic understanding and chemical design, and the consequently evolving and increasingly fine-tuned properties of these fascinating compounds.

Gelation is crucially dependent on functional group orientation and may be tuned by anion binding

The gelation ability of a series of chiral bis(urea) gels alternates between even and odd chain length and for the even numbered spacers the rheological characteristics can be tuned by the addition of anions according to the anion binding constant.