ABSTRACT
We here explore how ball-mill-grinding frequency affects the kinetics of a disulfide exchange reaction. Our kinetic data show that the reaction progress is similar at all the frequencies studied (15-30 Hz), including a significant induction time before the nucleation and growth process starts. This indicates that to start the reaction an initial energy accumulation is necessary. Other than mixing, the energy supplied by the mechanical treatment has two effects: (i) reducing the crystal size and (ii) creating defects in the structure. The crystal-breaking process is likely to be dominant at first becoming less important later in the process when the energy supplied is stored at the molecular level as local crystal defects. This accumulation is taken here to be the rate-determining step. We suggest that the local defects accumulate preferentially at or near the crystal surface. Since the total area increases exponentially when the crystal size is reduced by the crystal-breaking process, this can further explain the exponential dependence of the onset time on the milling frequency.
ABSTRACT
We explore the effect of solvent concentration on the thermodynamic stability of two polymorphs of a 1:1 cocrystal of theophylline and benzamide subjected to ball-mill liquid assisted grinding (LAG) and we investigate how this can be related to surface solvent solvation phenomena. In this system, most stable bulk polymorph form II converts to metastable bulk polymorph form I upon neat grinding (NG), while form I can fully or partially transform into form II under LAG conditions, depending on the amount of solvent used. Careful and strict experimental procedures were designed to achieve polymorph equilibrium under ball-mill LAG conditions for 16 different solvents. This allowed us to determine 16 equilibrium polymorph concentration curves as a function of solvent concentration. Ex-situ powder X-ray diffraction (PXRD) was used to monitor the polymorph concentration and crystallite size. The surface site interactions point (SSIP) description of noncovalent interactions was used in conjunction with the SSIMPLE method for calculating solvation energies to determine which functional groups are more or less exposed on the polymorph crystal surfaces. Our results demonstrate that (i) ball-mill LAG equilibrium curves can be successfully achieved experimentally for a cocrystal system; (ii) the equilibrium curves vary from solvent to solvent in onset values and slopes, thus confirming the generality of the interconversion phenomenon that we interpret here in terms of cooperativity; (iii) the concentration required for a switch in polymorphic outcome is dependent on the nature of the solvent; (iv) the SSIP results indicate that the theophylline π-system face is more exposed on the surface of form I while the theophylline N-methyl groups are more exposed in form II; and (v) for some solvents, form II has a significantly smaller crystal size at equilibrium than form I in the investigated solvent concentration range. Therefore, the free energy of the 1:1 cocrystal of theophylline and benzamide polymorphs studied here must be affected by surface solvation under ball-mill LAG conditions.
ABSTRACT
In this article, we use (1)H NMR spectroscopy to study the spontaneous molecular motion of donor-acceptor [2]catenanes in water. Our data supports the hypothesis that conformational motion dominantly occurs through a pirouetting mechanism, which involves less exposure of hydrophobic surfaces than in a rotation mechanism. Motion is controlled by the size of the catenane rings and the arrangement of the electron-deficient and electron-rich aromatic units.
ABSTRACT
A Tutorial Review of the subtle supramolecular interactions influencing the outcomes of equilibrating systems, focusing on the dynamic covalent chemistry (DCC) of disulfide exchange reactions, is presented. We discuss the topics of cation-π interactions (2.1), hydrophobic effects (2.2), hydrogen bonding interactions (2.3) aromatic donor-acceptor interactions (2.4), and metal-ligand interactions (2.5) in the context of dynamic disulfide chemistry.
ABSTRACT
The combination of a bent diamino(nickel(II) porphyrin) with 2-formylpyridine and Fe(II) yielded an Fe(II) 4 L6 cage. Upon treatment with the fullerenes C60 or C70 , this cage was found to transform into a new host-guest complex incorporating three Fe(II) centers and four porphyrin ligands, in an arrangement that is hypothesized to maximize πâ interactions between the porphyrin units of the host and the fullerene guest bound within its central cavity. The new complex shows coordinative unsaturation at one of the Fe(II) centers as the result of the incommensurate metal-to-ligand ratio, which enabled the preparation of a heterometallic cone-shaped Cu(I) Fe(II) 2 L4 adduct of C60 or C70 .
ABSTRACT
A homochiral naphthalenediimide-based building block forms in water a disulfide library of macrocycles containing topological isomers. We attempted to identify each of these isomers, and explored the mechanisms leading to their formation. The two most abundant species of the library were assigned as a topologically chiral Solomon link (60% of the library, as measured by high-performance liquid chromatography (HPLC)) and a topologically achiral figure eight knot (18% by HPLC), competing products with formally different geometries but remarkably similar 4-fold symmetries. In contrast, a racemic mixture of building blocks gives the near-quantitative formation of another new and more stable structure, assigned as a meso figure eight knot. Taken together, these results seem to uncover a correlation between the point chirality of the building block used and the topological chirality of the major structure formed. These and the earlier discovery of a trefoil knot also suggest that the number of rigid components in the building block may translate into corresponding knot symmetry and could set the basis of a new strategy for constructing complex topologies.
Subject(s)
Disulfides/chemical synthesis , Imides/chemistry , Macrocyclic Compounds/chemical synthesis , Naphthalenes/chemistry , Chromatography, High Pressure Liquid , Disulfides/chemistry , Macrocyclic Compounds/chemistry , Models, Molecular , Molecular Structure , Stereoisomerism , Tandem Mass SpectrometryABSTRACT
We present the first polymorph interconversion study that uses solid-state dynamic covalent chemistry (DCC). This system exhibits unexpected and rich behavior, including the observation that under appropriate conditions the polymorph interconversion of a heterodimer proceeds through reversible covalent chemistry intermediates, and this route is facilitated by one of the two disulfide homodimers involved in the reaction. Furthermore, we demonstrate experimentally that in all cases a dynamic equilibrium is reached, meaning that changing the milling conditions affects the free energy difference between the two polymorphs and thus their relative stability. We suggest that this effect is due to the surface solvation energy combined with the high surface to volume ratio of the nanocrystalline powder.
ABSTRACT
Since its inception in the mid-1990s, dynamic combinatorial chemistry (DCC), the chemistry of complex systems under thermodynamic control, has proved valuable in identifying unexpected molecules with remarkable binding properties and in providing effective synthetic routes to complex species. Essentially, in this approach, one designs the experiment rather than the molecule. DCC has also provided us with insights into how some chemical systems respond to external stimuli. Using examples from the work of our laboratory and others, this Account shows how the concept of DCC, inspired by the evolution of living systems, has found an increasing range of applications in diverse areas and has evolved conceptually and experimentally. A dynamic combinatorial library (DCL) is a thermodynamically controlled mixture of interconverting species that can respond to various stimuli. The Cambridge version of dynamic combinatorial chemistry was initially inspired by the mammalian immune system and was conceived as a way to create and identify new unpredictable receptors. For example, an added template can select and stabilize a strongly binding member of the library which is then amplified at the expense of the unsuccessful library members, minimizing the free energy of the system. But researchers have exploited DCC in a variety of other ways: over the past two decades, this technique has contributed to the evolution of chemistry and to applications in the diverse fields of catalysis, fragrance release, and responsive materials. Among these applications, researchers have built intricate and well-defined architectures such as catenanes or hydrogen-bonded nanotubes, using the ability of complex chemical systems to reach a high level of organization. In addition, DCC has proved a powerful tool for the study of complex molecular networks and systems. The use of DCC is improving our understanding of chemical and biological systems. The study of folding or self-replicating macrocycles in DCLs has served as a model for appreciating how complex organisations such as life can emerge from a pool of simple chemicals. Today, DCC is no longer restricted to thermodynamic control, and new systems have recently appeared in which kinetic and thermodynamic control coexist. Expanding the realm of DCC to unexplored and promising new territories, these hybrid systems show that the concept of dynamic combinatorial chemistry continues to evolve.
Subject(s)
Combinatorial Chemistry Techniques , Evolution, Chemical , Catalysis , Catenanes/chemistry , Hydrogen Bonding , Kinetics , Nanotubes/chemistry , ThermodynamicsABSTRACT
Molecular recognition in water involves contributions due to polar functional group interactions, partial desolvation of polar and non-polar surfaces and changes in conformational flexibility, presenting a challenge for rational design and interpretation of supramolecular behaviour. Conformationally well-defined supramolecular complexes that can be studied in both water and non-polar solvents provide a platform for disentangling these contributions. Here 1 : 1 complexes formed between four different calix[4]pyrrole receptors and thirteen different pyridine N-oxide guests have been used to dissect the factors that govern substituent effects on aromatic interactions in water. H-bonding interactions between the receptor pyrrole donors and the guest N-oxide acceptor at one end of the complex lock the geometrical arrangement of a cluster of aromatic interactions at the other end of the complex, so that a phenyl group on the guest makes two edge-to-face and two stacking interactions with the four aromatic side-walls of the receptor. The thermodynamic contribution of these aromatic interactions to the overall stability of the complex was quantified by chemical double mutant cycles using isothermal titration calorimetry and 1H NMR competition experiments. Aromatic interactions between the receptor and a phenyl group on the guest stabilise the complex by a factor of 1000, and addition of substituents to the guest phenyl group further stabilises the complex by an additional factor of up to 1000. When a nitro substituent is present on the guest phenyl group, the complex has a sub-picomolar dissociation constant (370 fM). The remarkable substituent effects observed in water for these complexes can be rationalised by comparison with the magnitude of the corresponding substituent effects measured in chloroform. In chloroform, the double mutant cycle free energy measurements of the aromatic interactions correlate well with the substituent Hammett parameters. Electron-withdrawing substituents increase the strength of the interactions by a factor of up to 20, highlighting the role of electrostatics in stabilising both the edge-to-face and stacking interactions. The enhanced substituent effects observed in water are due to entropic contributions associated with the desolvation of hydrophobic surfaces on the substituents. The flexible alkyl chains that line the open end of the binding site assist the desolvation of the non-polar π-surfaces of polar substituents, like nitro, but at the same time allow water to interact with the polar H-bond acceptor sites on the substituent. This flexibility allows polar substituents to maximise non-polar interactions with the receptor and polar interactions with the solvent, leading to remarkably high binding affinities.
ABSTRACT
Conformationally well-defined supramolecular complexes that can be studied in different solvents provide a platform for separating and quantifying free energy contributions due to functional group interactions and desolvation. Here 1:1 complexes formed between four different calix[4]pyrrole receptors and eleven different pyridine N-oxide guests have been used to dissect the factors that govern aromatic interactions with heterocycles in water and in chloroform solution. 1H NMR spectroscopy shows that the three-dimensional structures of the complexes are fixed by four H-bonding interactions between the pyrrole donors at the bottom of the receptor and the N-oxide acceptor on the guest, locking the geometrical arrangement of interacting functional groups in the binding pocket at the other end of the receptor. An aromatic heterocycle on the guest makes two stacking interactions and two edge-to-face interactions with the side walls of the receptor. Chemical double mutant cycles were used to measure the free energy contribution of these four aromatic interactions to the overall stability of the complex. In chloroform, the aromatic interactions measured with pyridine, pyrimidine, furan, thiophene and thiazole are similar to the interactions with a phenyl group, but the effect of introducing a heteroatom depends on where it sits with respect to the aromatic side-walls of the cavity. A nitrogen lone pair directed into a π-face of the side-walls of the binding site leads to repulsive interactions of up to 8 kJ mol-1. In water, the heterocycle aromatic interactions are all significantly more favourable (by up to 12 kJ mol-1). For the non-polar heterocycles, furan and thiophene, the increase in interaction energy correlates directly with hydrophobicity, as measured by the free energy of transfer of the heterocycle from n-hexadecane into water (ΔG°(water-hex)). For the heterocycles with polar nitrogen H-bond acceptors, water can access cracks in the walls of the receptor binding site to solvate the edges of the heterocycles without significantly affecting the geometry of the aromatic interactions, and these nitrogen-water H-bonds stabilise the complexes by about 15 kJ mol-1. The results highlight the complexity of the solvation processes that govern molecular recognition in water.
ABSTRACT
Chemical double mutant cycles were used to measure the interaction of a N-methyl pyridinium cation with a π-box in a calix[4]pyrrole receptor. Although the cation-π interaction is attractive (-11 kJ mol-1), it is 7 kJ mol-1 less favourable than the corresponding aromatic interaction with the isosteric but uncharged tolyl group.
ABSTRACT
We report the first dynamic combinatorial synthesis in water of an all-acceptor [2]catenane and of different types of donor-acceptor [2] and [3]catenanes. Linking two electron-deficient motifs within one building block using a series of homologous alkyl chains provides efficient and selective access to a variety of catenanes and offers an unprecedented opportunity to explore the parameters that govern their synthesis in water. In this series, catenane assembly is controlled by a fine balance between kinetics and thermodynamics and subtle variations in the building block structure, such as the linker length and building block chirality. A remarkable and unexpected odd-even effect with respect to the number of atoms in the alkyl linker is reported.
ABSTRACT
Amino-acid functionalized naphthalenediimides self-assemble into hydrogen-bonded supramolecular helical nanotubes via a noncooperative, isodesmic process; the self-assembly of ordered helical systems is usually realized through a cooperative process. This unexpected behavior was rationalized as a manifestation of entropy-enthalpy compensation. Fundamental insights into the thermodynamics governing this self-assembly were obtained through the fitting of the isodesmic model to (1)H NMR spectrometry and circular dichroism spectroscopy measurements. Furthermore, we have extended the application of this mathematical model, for the first time, to quantitatively estimate the effect of guests, solvents, and side chains on the stability of the supramolecular nanotube; most significantly, we demonstrate that C(60) acts as a template to stabilize the nanotube assembly and thereby substantially increase the degree of polymerization.
Subject(s)
Imides/chemistry , Nanotubes/chemistry , Naphthalenes/chemistry , Solvents/chemistry , Models, Molecular , Molecular Conformation , Polymerization , ThermodynamicsABSTRACT
Amino acid functionalized naphthalenediimides (NDIs) when dissolved in chloroform form a dynamic combinatorial library (DCL) in which the NDI building blocks are connected through reversible hydrogen bonds forming a versatile new supramolecular assembly in solution with intriguing host-guest properties. In chlorinated solvents the NDIs form supramolecular nanotubes which complex C(60), ion-pairs, and extended aromatic molecules. In the presence of C(70) a new hexameric receptor is formed at the expense of the nanotube; the equilibrium nanotube - hexameric receptor can be influenced by acid-base reactions. Achiral NDIs are incorporated in nanotubes formed by either dichiral or monochiral NDIs experiencing the "sergeants-and-soldiers" effect.
Subject(s)
Combinatorial Chemistry Techniques/methods , Imides/chemical synthesis , Nanotubes/chemistry , Naphthalenes/chemical synthesis , Circular Dichroism , Imides/chemistry , Naphthalenes/chemistry , Polycyclic Aromatic Hydrocarbons/chemistryABSTRACT
We present the use of hydrazone dynamic combinatorial libraries (DCLs) to identify macrocyclic receptors that are selective for alkaline earth metal ions over alkali metal ions. In particular, the toxic heavy metal ions Sr(2+) and Ba(2+) induce characteristic changes in the DCLs. Four macrocycles were isolated and characterised by LCMS, HRMS, NMR and X-ray crystallography; binding studies by UV-Vis spectroscopy confirm the selectivity observed in the DCLs.
ABSTRACT
A new type of neutral donor-acceptor [2]-catenane, containing both complementary units in the same ring was synthesized from a dynamic combinatorial library in water. The yield of the water soluble [2]-catenane is enhanced by increasing either building-block concentrations or ionic strength, or by the addition of an electron-rich template. NMR spectroscopy demonstrates that the template is intercalated between the 2 electron-deficient naphthalenediimide units of the catenane.
Subject(s)
Anthracenes/chemical synthesis , Combinatorial Chemistry Techniques/methods , Water/chemistry , Anthracenes/chemistry , Catalysis , Chromatography, High Pressure Liquid , Magnetic Resonance Spectroscopy , Models, Chemical , Models, Molecular , Molecular Structure , Spectrometry, Mass, Electrospray Ionization , Spectrophotometry, UltravioletABSTRACT
It was shown for the first time that solid amines can act as catalysts for disulfide-based dynamic combinatorial chemistry (DCC) by ball mill grinding. The mechanochemical equilibrium for the two disulfide reactions studied was reached within 1-3â h using ten different amine catalysts. This contrasts with the weeks to months to achieve solution equilibrium for most solid amine catalysts at 2 %mol mol-1 concentration in a 2â mMolar disulfide dynamic combinatorial library in a suitable solvent. The final mechanochemical equilibrium was independent of the catalyst used but varied with other ball mill grinding factors such as the presence of traces of solvent. The different efficiencies of the amines tested were discussed.
Subject(s)
Disulfides , Catalysis , SolventsABSTRACT
We describe the use of dynamic combinatorial chemistry to discover a new series of linear hydrazone-based receptors that bind multiple dihydrogen phosphate ions. Through the use of a template-driven, selection-based approach to receptor synthesis, dynamic combinatorial chemistry allows for the identification of unexpected host structures and binding motifs. Notably, we observed the unprecedented selection of these linear receptors in preference to competing macrocyclic hosts. Furthermore, linear receptors containing up to nine building blocks and three different building blocks were amplified in the dynamic combinatorial library. The receptors were formed using a dihydrazide building block based on an amino acid-disubstituted ferrocene scaffold. A detailed study of the linear pentamer revealed that it forms a helical ditopic receptor that employs four acylhydrazone hydrogen-bond donor motifs to cooperatively bind two dihydrogen phosphate ions.
Subject(s)
Combinatorial Chemistry Techniques , Phosphoric Acids/chemistry , Chromatography, High Pressure Liquid , Circular Dichroism , Hydrogen Bonding , Magnetic Resonance SpectroscopyABSTRACT
The discovery through dynamic combinatorial chemistry (DCC) of a new generation of donor-acceptor [2]catenanes highlights the power of DCC to access unprecedented structures. While conventional thinking has limited the scope of donor-acceptor catenanes to strictly alternating stacks of donor (D) and acceptor (A) aromatic units, DCC is demonstrated in this paper to give access to unusual DAAD, DADD, and ADAA stacks. Each of these catenanes has specific structural requirements, allowing control of their formation. On the basis of these results, and on the observation that the catenanes represent kinetic bottlenecks in the reaction pathway, we propose a mechanism that explains and predicts the structures formed. Furthermore, the spontaneous assembly of catenanes in aqueous dynamic systems gives a fundamental insight into the role played by hydrophobic effect and donor-acceptor interactions when building such complex architectures.
ABSTRACT
We describe here the assembly of new types of donor-acceptor [2]catenanes from dynamic combinatorial libraries (DCL) in water. These new catenanes contain both the donor and acceptor components in at least one of the interlocked rings, thereby possessing unusual and unexpected DAAD or DADD stacking sequences of the π units in their structures. The efficiency of the catenane assembly process can be enhanced by manipulating the DCL equilibrium in a variety of ways: adding a guest, changing the building block stoichiometries, or increasing the library concentration or the ionic strength of the solvent. The formation of catenanes and their constitutions are found to be dependent on subtle differences in the geometry, dimension, and flexibility of the donor building blocks.