Ana M. Belenguer

Mechanosensitive Self-Replication Driven by Self-Organization

At Sixes and Sevens Molecular synthesis and macroscopic aggregation have often been regarded as entirely separate processes. From the researchers standpoint, once reagents have been mixed, synthesis is largely passive, whereas processes such as crystallization can be more actively manipulated. Carnall et al. (p. 1502) characterized an unusual system in which the formation of aggregated cyclic macromolecules (macrocycles) from small peptide-based building blocks was governed by intimately interdependent factors ranging from the scale of covalent bond formation all the way to micron scale fiber growth. As the macrocycles stacked against one another to form the fibers, they remained loosely bonded enough internally to incorporate or expel individual building blocks. Varying the type of mechanical force applied to the growing fibers (either through shaking or stirring the solution), alternately favored formation of either 6-membered or 7-membered covalent macrocycles. The type of mechanical agitation applied to a solution influences which of two molecular products dominate. Self-replicating molecules are likely to have played an important role in the origin of life, and a small number of fully synthetic self-replicators have already been described. Yet it remains an open question which factors most effectively bias the replication toward the far-from-equilibrium distributions characterizing even simple organisms. We report here two self-replicating peptide-derived macrocycles that emerge from a small dynamic combinatorial library and compete for a common feedstock. Replication is driven by nanostructure formation, resulting from the assembly of the peptides into fibers held together by β sheets. Which of the two replicators becomes dominant is influenced by whether the sample is shaken or stirred. These results establish that mechanical forces can act as a selection pressure in the competition between replicators and can determine the outcome of a covalent synthesis.

Real-time and in situ monitoring of mechanochemical milling reactions

Chemical and structural transformations have long been carried out by milling. Such mechanochemical steps are now ubiquitous in a number of industries (such as the pharmaceutical, chemical and metallurgical industries), and are emerging as excellent environmentally friendly alternatives to solution-based syntheses. However, mechanochemical transformations are typically difficult to monitor in real time, which leaves a large gap in the mechanistic understanding required for their development. We now report the real-time study of mechanochemical transformations in a ball mill by means of in situ diffraction of high-energy synchrotron X-rays. Focusing on the mechanosynthesis of metal-organic frameworks, we have directly monitored reaction profiles, the formation of intermediates, and interconversions of framework topologies. Our results reveal that mechanochemistry is highly dynamic, with reaction rates comparable to or greater than those in solution. The technique also enabled us to probe directly how catalytic additives recently introduced in the mechanosynthesis of metal-organic frameworks, such as organic liquids or ionic species, change the reactivity pathways and kinetics.

Enantiopure water-soluble [Fe4L6] cages: host-guest chemistry and catalytic activity.

Host-guest chemistry has its origin in biological processes involving molecular recognition through noncovalent interactions, as for example when substrates bind to enzymes. Over the last decade, organic capsules and self-assembled coordination cages have been prepared that are able to encapsulate a variety of guests, increase the rates of chemical reactions, change the course of reactions involving encapsulated molecules, or shift equilibria to stabilize otherwise unstable species. Self-assembled metal-organic capsules based on chiral ligands are of special interest because they possess a chiral internal void which can not only enable enantioselective guest recognition and separation but can also provide an asymmetric microenvironment for stereoselective reactions. Small guest molecules have been observed to be encapsulated by a water-soluble self-assembled tetrahedral M4L6 cage prepared via subcomponent self-assembly from amine, aldehyde and Fe precursors. Here we show how the use of a longer diamino terphenylene subcomponent, bearing chiral glyceryl groups, allows the enantioselective formation of larger water-soluble Fe4L6 capsules. This new cage encapsulates a wider range of guests, including larger molecules such as chiral natural products. We also demonstrate our cage’s ability to accelerate catalytically the hydrolysis of the acetylcholine esterase inhibitor insecticide dichlorvos, which shares key chemical features with the class of organophosphate chemical warfare agents (CWAs). Diaminoterphenylenes 4, SS-4, and RR-4 were prepared in three steps from diiodohydroquinone 1 as shown in Scheme 1. The studies described below were carried out using aqueous stock solutions of-5 (or-5 or 5) prepared from enantiopure SS-4 (or RR-4 or 4), 2-formylpyridine, and FeSO4 in a 6 : 12 : 4 ratio (Scheme 2). Experimental details and characterization data are provided in the Supporting Information (SI). A solution of the deep purple capsule-5 gave FTICR mass spectra consistent with an [Fe4L6] formulation (SI Fig. SS09). Its hydrodynamic radius, determined from DOSY NMR, was 15.25 (± 0.62) Å, which is consistent with the value of 16.1 Å derived from the model showin in Figure 1. This model was energy-minimized using the universal force field (UFF) of ArgusLabs (SI Fig. S005). Scheme 1. (a) i. NaOH, EtOH, ii. 3-chloro-1,2-propanediol; (b) 4nitrophenylboronic acid, K2CO3, 0.05 mol% [2,6-bis[(di-1piperidinylphosphino)amino]phenyl] palladium(II) chloride; (c) H2, 10% Pd / C.

Two-stage directed self-assembly of a cyclic [3]catenane

Interlocked molecules possess properties and functions that depend upon their intricate connectivity. In addition to the topologically trivial rotaxanes, whose structures may be captured by a planar graph, the topologically non-trivial knots and catenanes represent some of chemistrys most challenging synthetic targets because of the three-dimensional assembly necessary for their construction. Here we report the synthesis of a cyclic [3]catenane, which consists of three mutually interpenetrating rings, via an unusual synthetic route. Five distinct building blocks self-assemble into a heteroleptic triangular framework composed of two joined Fe(II)3L3 circular helicates. Subcomponent exchange then enables specific points in the framework to be linked together to generate the cyclic [3]catenane product. Our method represents an advance both in the intricacy of the metal-templated self-assembly procedure and in the use of selective imine exchange to generate a topologically complex product.

Real-time in situ powder X-ray diffraction monitoring of mechanochemical synthesis of pharmaceutical cocrystals.

Looking in: The penetrating power of high-energy X-rays provides a means to monitor in situ and in real time the course of ball-milling reactions of organic pharmaceutical solids by detecting crystalline phases and assessing the evolution of their particle sizes. Upon switching from neat grinding to liquid-assisted grinding, cocrystal formation is enabled or tremendously accelerated, while the reaction mechanism alters its course.

Solid-state dynamic combinatorial chemistry: reversibility and thermodynamic product selection in covalent mechanosynthesis

We demonstrate the reversibility and thermodynamic control in covalent mechanosynthesis, by using the base-catalysed metathesis of aromatic disulfides as a model reaction. The mechanochemical formation of thermodynamic equilibrium mixtures is observed for both neat and liquid-assisted grinding methodologies. Different methodologies lead to mutually different equilibrium compositions, which also differ from those obtained by solution equilibration. The differences can be explained in terms of crystal packing effects superimposed onto the inherent reactivity of isolated molecules. Calculations indicate that the differences in relative energies of reactants and products in their respective crystal structures can bias the mechanochemical reaction equilibrium towards the complete conversion of reactants into the product, in that way opening the doors for the development of dynamic combinatorial synthesis in the solid state and for the rational design of solid-state synthesis using mechanochemistry.

Differentially Addressable Cavities within Metal–Organic Cage-Cross-Linked Polymeric Hydrogels

Here we report a new class of hydrogels formed by polymers that are cross-linked through subcomponent self-assembled metal-organic cages. Selective encapsulation of guest molecules within the cages creates two distinct internal phases within the hydrogel, which allows for contrasting release profiles of related molecules depending on their aptitude for encapsulation within the cages. The hydrogels were fabricated into microparticles via a droplet-based microfluidic approach and proved responsive to a variety of stimuli, including acid and competing amine or aldehyde subcomponents, allowing for the triggered release of cargo.

Dynamic combinatorial development of a neutral synthetic receptor that binds sulfate with nanomolar affinity in aqueous solution

Using dynamic combinatorial disulfide chemistry we have developed a new generation of neutral synthetic receptors for anions, based on a macrobicyclic peptide structure. These receptors show an exceptional affinity and selectivity for sulfate ions in aqueous solution [log K(a) = 8.67 in 41 mol% (67 volume%) acetonitrile in water]. The high affinity depends on a delicate balance between rigidity and flexibility in the structure of the receptor.

In situ and real-time monitoring of mechanochemical milling reactions using synchrotron X-ray diffraction

We describe the only currently available protocol for in situ, real-time monitoring of mechanochemical reactions and intermediates by X-ray powder diffraction. Although mechanochemical reactions (inducing transformations by mechanical forces such as grinding and milling) are normally performed in commercially available milling assemblies, such equipment does not permit direct reaction monitoring. We now describe the design and in-house modification of milling equipment that allows the reaction jars of the operating mill to be placed in the path of a high-energy (∼90 keV) synchrotron X-ray beam while the reaction is taking place. Resulting data are analyzed using conventional software, such as TOPAS. Reaction intermediates and products are identified using the Cambridge Structural Database or Inorganic Crystal Structure Database. Reactions are analyzed by fitting the time-resolved diffractograms using structureless Pawley refinement for crystalline phases that are not fully structurally characterized (such as porous frameworks with disordered guests), or the Rietveld method for solids with fully determined crystal structures (metal oxides, coordination polymers).

Dynamic combinatorial libraries of metalloporphyrins: templated amplification of disulfide-linked oligomers

Disulfide-linked cyclic porphyrin oligomers from dimer to tetramer can be selected and amplified virtually quantitatively from a dynamic combinatorial library using bis-thiol substituted zinc(II) porphyrin units with appropriate amine donor templates.