Christopher A Hunter

University of Cambridge, Cambridge, England, United Kingdom

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Publications (213)1448.83 Total impact

  • Giulia Iadevaia · Alexander E. Stross · Anja Neumann · Christopher A. Hunter
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    ABSTRACT: The formation of well-defined supramolecular assemblies involves competition between intermolecular and intramolecular interactions, which is quantified by effective molarity. Formation of a duplex between two oligomers equipped with recognition sites displayed along a non-interacting backbone requires that once one intermolecular interaction has been formed, all subsequent interactions take place in an intramolecular sense. The efficiency of this process is governed by the geometric complementarity and conformational flexibility of the backbone linking the recognition sites. Here we report a series of phosphine oxide H-bond acceptor AA 2-mers and phenol H-bond donor DD 2-mers, where the two recognition sites are connected by isomeric backbone modules that vary in geometry and flexibility. All AA and DD combinations form stable AA·DD duplexes, where two cooperative H-bonds lead to an increase in stability of an order of magnitude compared with the corresponding A·D complexes that can only form one H-bond. For all six possible backbone combinations, the effective molarity for duplex formation is approximately constant (7–20 mM). Thus strict complementarity and high degrees of preorganisation are not required for efficient supramolecular assembly. Provided there is some flexibility, quite different backbone modules can be used interchangeably to construct stable H-bonded duplexes.
    No preview · Article · Jan 2016 · Chemical Science
  • Alexander E. Stross · Giulia Iadevaia · Christopher A. Hunter
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    ABSTRACT: A series of flexible oligomers equipped with phenol H-bond donors and phosphine oxide H-bond acceptors have been synthesised using reductive amination chemistry. H-bonding interactions between complementary oligomers leads to the formation of double-stranded complexes which were characterised using NMR titrations and thermal denaturation experiments. The stability of the duplex increases by one order of magnitude for every H-bonding group added to the chain. Similarly, the enthalpy change for duplex assembly and the melting temperature for duplex denaturation both increase with increasing chain length. These observations indicate that H-bond formation along the oligomers is cooperative despite the flexible backbone, and the effective molarity for intramolecular H-bond formation (14 mM) is sufficient to propagate the formation of longer duplexes using this approach. The product K EM, which is used to quantify chelate cooperativity is 5, which means that each H-bond is more than 80% populated in the assembled duplex. The modular design of these oligomers represents a general strategy for the design of synthetic information molecules that could potentially encode and replicate chemical information in the same way as nucleic acids.
    No preview · Article · Dec 2015 · Chemical Science
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    ABSTRACT: The association constants and enthalpies for the binding of hydrogen bond donors to group 10 transition metal complexes featuring a single fluoride ligand (trans [Ni(F)(2-C5NF4)(PR3)2] R = Et 1a, Cy 1b, trans [Pd(F)(4-C5NF4)(PCy3)2] 2, trans [Pt(F){2-C5NF2H(CF3)}(PCy3)2] 3 and of group 4 difluorides (Cp2MF2, M = Ti 4a, Zr 5a, Hf 6a; Cp*2MF2, M = Ti 4b, Zr 5b, Hf 6b) are reported. These measurements allow placement of these fluoride ligands on the scales of organic H-bond acceptor strength. The H-bond acceptor capability β (Hunter scale) for the group 10 metal fluorides is far greater (1a 12.1, 1b 9.7, 2 11.6, 3 11.0) than for group 4 metal fluorides (4a 5.8, 5a 4.7, 6a 4.7, 4b 6.9, 5b 5.6, 6b 5.4), demonstrating that the group 10 fluorides are comparable to the strongest organic H-bond acceptors, such as Me3NO, whereas group 4 fluorides fall in the same range as N-bases aniline through to pyridine. Additionally, the measurement of the binding enthalpy of 4-fluorophenol to 1a in carbon tetrachloride (-23.5 ± 0.3 kJ mol-1) interlocks our study with Laurence's scale of H-bond basicity of organic molecules. The much greater polarity of group 10 metal fluorides than that of the group 4 metal fluorides is consistent with the importance of pπ-dπ bonding in the latter. The polarity of the group 10 metal fluorides indicates their potential as building blocks for hydrogen-bonded assemblies. The synthesis of trans [Ni(F){2 C5NF3(NH2)}(PEt3)2] which exhibits an extended chain structure assembled by hydrogen bonds between the amine and metal-fluoride groups confirms this hypothesis.
    Preview · Article · Aug 2015 · Journal of the American Chemical Society
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    Preview · Article · Aug 2015 · Acta Crystallographica Section A: Foundations and Advances
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    Dataset: b612307b
    Scott L Cockroft · Christopher A Hunter

    Full-text · Dataset · Jul 2015
  • Hongmei Sun · Kai Guo · Haifeng Gan · Xin Li · Christopher A Hunter
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    ABSTRACT: Atropisomers of a series of zinc tetraphenyl porphyrins were synthesized and used as supramolecular receptors. Rotation around the porphyrin-meso phenyl bonds is restricted by installing ortho-chlorine substituents on the phenyl groups. The chlorine substituents allowed chromatographic separation of atropisomers, which did not interconvert at room temperature. The porphyrin meso phenyl groups were also equipped with phenol groups, which led to the formation of intramolecular H-bonds when the zinc porphyrins were bound to pyridine ligands equipped with ester or amide side arms. Binding of the pyridine ligands with the conformationally locked chloroporphyrins was compared with the corresponding unsubstituted porphyrins, which are more flexible. The association constants of 150 zinc porphyrin-pyridine complexes were measured in two different solvents, toluene and 1,1,2,2-tetrachloroethane (TCE). These association constants were then used to construct 120 chemical double mutant cycles to quantify the influence of chlorine substitution on the free energy of intramolecular H-bonds formed between the phenol side arms of the porphyrins and the ester or amide side arms of the pyridine ligands. Conformational restriction leads to increases in the stability of some complexes and decreases in the stability of others with variations in the free energy contribution due to intramolecular H-bonding of -5 to +6 kJ mol(-1).
    No preview · Article · Jul 2015 · Organic & Biomolecular Chemistry
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    William Cullen · Katie A. Thomas · Christopher A. Hunter · Michael D Ward
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    ABSTRACT: We demonstrate the use of a simple pH swing to control the selection of one of three different guests from aqueous solution by a coordination cage host. Switching between different guests is based on the fact that neutral organic guests bind strongly in the cage due to the hydrophobic effect, but for acidic or basic guests, the charged (protonated or deprotonated) forms are hydrophilic and do not bind. The guests used are adamantane-1,3-dicarboxylic acid (H2A) which binds at low pH when it is neutral but not when it is deprotonated; 1-amino-adamantane (B) which binds at high pH when it is neutral but not when it is protonated; and cyclononanone (C) whose binding is not pH dependent and is therefore the default guest at neutral pH. Thus an increase in pH can reversibly switch the host between the three different bound states cage•H2A (at low pH) cage•C (at medium pH) and cage•B (at high pH) in succession.
    Full-text · Article · May 2015 · Chemical Science
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    Hongmei Sun · Cristina Navarro · Christopher A Hunter
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    ABSTRACT: A family of closely related zinc porphyrin-pyridine complexes were used to examine the influence of linker preorganization on supramolecular effective molarities for formation of intramolecular H-bonds. Each pyridine ligand was equipped with a side-chain containing two H-bond acceptors, one on the end of the chain (terminal) and one in the middle of the chain (linker). These H-bond acceptors make intramolecular interactions with phenol H-bond donors on the porphyrin periphery. Two different H-bonding acceptors were used as linker groups in order to construct frameworks with significantly different degrees of preorganization: ester linkers populate the H-bonded state 60-70% of the time, whereas amide linkers populate the H-bonded state 90-100% of the time. Thus the amide linkers provide a significantly more preorganised ligand framework than the ester linkers. Effective molarities (EM) for intramolecular H-bonds between the terminal H-bond acceptor groups on the ligands (esters and amides) and the porphyrin phenol groups were quantified using 32 chemical double mutant cycles. The values of EM for interactions with the terminal H-bond acceptors are independent of the nature of the linker H-bond acceptor (weakly bonded ester or strongly bonded amide), which indicates that preorganization of the linker has no effect on chelate cooperativity in these systems.
    Preview · Article · Mar 2015 · Organic & Biomolecular Chemistry
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    Mike D Ward · William Cullen · Simon Turega · Christopher A. Hunter
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    ABSTRACT: The protein/ligand docking software GOLD, which was originally developed for drug discovery, has been used in a virtual screen to identify small molecules that bind with extremely high affinities (K ≈ 107 M-1) in the cavity of a cubic coordination cage in water. A scoring function was developed using known guests as a training set and modified by introducing an additional term to take account of loss of guest flexibility on binding. This function was then used in GOLD to successfully identify 13 new guests and accurately predict the binding constants. This approach provides a powerful predictive tool for virtual screening of large compound libraries to identify new guests for synthetic hosts, thereby greatly simplifying and accelerating the process of identifying guests by removing the reliance on experimental trial-and-error.
    Full-text · Article · Mar 2015 · Chemical Science
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    William Cullen · Christopher A Hunter · Michael D Ward
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    ABSTRACT: The self-assembly between a water-soluble bis-bidentate ligand L(18w) and Co(II) salts in water affords three high-spin Co(II) products: a dinuclear meso-helicate [Co2(L(18w))3]X4; a tetrahedral cage [Co4(L(18w))6]X8; and a dodecanuclear truncated-tetrahedral cage [Co12(L(18w))18]X24 (X = BF4 or ClO4). All three products were crystallized under different conditions and structurally characterized. In [Co2(L(18w))3]X4 all three bridging ligands span a pair of metal ions; in the two larger products, there is a metal ion at each vertex of the Co4 or Co12 polyhedral cage array with a bridging ligand spanning a pair of metal ions along every edge. All three structural types are known: what is unusual here is the presence of all three from the same reaction. The assemblies Co2, Co4, and Co12 are in slow equilibrium (hours/days) in aqueous solution, and this can be conveniently monitored by (1)H NMR spectroscopy because (i) the paramagnetism of Co(II) disperses the signals over a range of ca. 200 ppm and (ii) the different symmetries of the three species give characteristically different numbers of independent (1)H NMR signals, which makes identification easy. From temperature- and concentration-dependent (1)H NMR studies it is clear that increasing temperature and increasing dilution favors fragmentation to give a larger proportion of the smaller assemblies for entropic reasons. High concentrations and low temperature favor the larger assembly despite the unfavorable entropic and electrostatic factors associated with its formation. We suggest that this arises from the hydrophobic effect: reorganization of several smaller complexes into one larger one results in a smaller proportion of the hydrophobic ligand surface being exposed to water, with a larger proportion of the ligand surface protected in the interior of the assembly. In agreement with this, (1)H NMR spectra in a nonaqueous solvent (MeNO2) show formation of only [Co2(L(18w))3]X4 because the driving force for reorganization into larger assemblies is now absent. Thus, we can identify the contributions of temperature, concentration, and solvent on the result of the metal/ligand self-assembly process and have determined the speciation behavior of the Co2/Co4/Co12 system in aqueous solution.
    Full-text · Article · Feb 2015 · Inorganic Chemistry
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    Christopher A Hunter · Rafel Prohens
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    ABSTRACT: A new model for cocrystal formation could be a powerful tool for formulation scientists – no crystal structures required, it's all about the surface contacts. Cocrystals – two or more molecular entities combined in a homogenous crystalline structure – have recently become attractive targets for the pharmaceutical industry, as cocrystallization can have a positive effect on the properties of solid dosage forms. However, predicting which potential coformers will successfully cocrystallize with a given active pharmaceutical ingredient (API) has proved difficult. Here, we describe a new computational method that does not require any knowledge or prediction of three-dimensional crystal structures, making it fast enough to virtually screen very large libraries of compounds to successfully identify new API cocrystals. Hunting cocrystals Formulation of a drug as a cocrystal can change the bioavailability, dissolution rate, physical and chemical stability, compressibility and hygroscopicity, and new multicomponent solid forms offer the possibility of releasing an API without infringing the originator's patent (1). Cocrystals may also occur as multiple polymorphs, suggesting additional options to modify properties, increased patent protection and improved formulations. In 2012, the FDA issued a set of guidelines to regulate the use of pharmaceutical cocrystals and concluded that a cocrystal should be considered as a drug product intermediate and not as a new API (2). In July 2014, the European Medicines Agency (EMA) published a reflection on the use of cocrystals of active substances in medicinal products and determined that cocrystals were eligible for generic applications in the same way as salts (3). Cocrystals have a number of advantages over salts. For example, there are a large number of potential coformers contained in the GRAS (Generally Regarded as Safe) and EAFUS (Everything Added to Food in the United States) lists published by the FDA. In contrast to salts, the formation of a cocrystal does not rely on ionization, so it is not limited to APIs containing acidic or basic functional groups. This means that the structure space of potential formulations with improved properties is vast. However, this spectacular potential presents the experimental scientist with a difficult challenge: how can we navigate such a vast molecular landscape?
    Full-text · Article · Feb 2015
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    Hongmei Sun · Christopher A. Hunter · Eva Marina Llamas
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    ABSTRACT: Synthetic supramolecular complexes provide an opportunity for quantitative systematic exploration of the relationship between chemical structure and molecular recognition phenomena. A family of closely related zinc porphyrin–pyridine complexes was used to examine the interplay of conformational flexibility and geometric complementarity in determining the selectivity of molecular recognition events. The association constants of 48 zinc porphyrin–pyridine complexes were measured in two different solvents, toluene and 1,1,2,2-tetrachloroethane (TCE). These association constants were used to construct 32 chemical double mutant cycles to dissect the free energy contributions of intramolecular H-bonds between the phenol side arms of the porphyrins and the ester or amide side arms of the pyridine ligands. Effective molarities (EM) for the intramolecular interactions were determined by comparison with the corresponding intermolecular H-bonding interactions. The values of EM do not depend on the solvent and are practically identical for amide and ester H-bond acceptors located at the same site on the ligand framework. However, there are variations of an order of magnitude in EM depending on the flexibility of the linker used to connect the H-bond acceptors to the pyridine ligands. Rigid aromatic linkers give values of EM that are an order of magnitude higher than the values of EM for the corresponding ester linkers, which have one additional torsional degree of freedom. However, the most flexible ether linkers give values of EM that are also higher than the values of EM for the corresponding ester linkers, which have one less torsional degree of freedom. Although the penalty for conformational restriction on binding is higher for the more flexible ether linkers, this flexibility allows optimization of the geometric complementarity of the ligand for the receptor, so there is a trade off between preorganization and fit.
    Preview · Article · Dec 2014 · Chemical Science
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    ABSTRACT: Although protein folding is often described by motion on a funnel-shaped overall topology of the energy landscape, the many local interactions that can occur result in considerable landscape roughness which slows folding by increasing internal friction. Recent experimental results have brought to light that this roughness also causes unusual diffusional behaviour of the backbone of an unfolded protein, i.e. the relative motion of protein sections cannot be described by the normal diffusion equation, but shows strongly subdiffusional behaviour with a nonlinear time dependence of the mean square displacement, <r2(t)> ∝ tα (α << 1). This results in significantly slower configurational equilibration than had been assumed hitherto. Analysis of the results also allows quantification of the energy landscape roughness, i.e. the root-mean-squared depth of local minima, yielding a value of 4-5 kBT for a typical small protein.
    No preview · Article · Nov 2014 · Physical Chemistry Chemical Physics
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    ABSTRACT: A new strategy for determining thermodynamic effective molarities (EM) for macrocylisation reactions using dynamic combinatorial chemistry under dilute conditions is presented. At low concentrations, below the critical value, Dynamic Libraries (DLs) of bifunctional building blocks contain only cyclic species, so it is not possible to quantify the equilibria between linear and cyclic species. However, addition of a monofunctional chain stopper can be used to promote the formation of linear oligomers allowing measurement of EM for all cyclic species present in the DL. The effectiveness of this approach was demonstrated for DLs generated from mixtures of 1,3-diimine calix[4]arenes, linear diaminoalkanes and monoaminoalkanes. For macrocycles deriving from one bifunctional calixarene and one diamine, there is an alternating pattern of EM values with the number of methylene units in the diamine: odd numbers give significantly higher EMs than even numbers. For odd numbers of methylene units, the alkyl chain can adopt an extended all anti conformation, whereas for even numbers of methylene units, gauche conformations are required for cyclisation, and the associated strain reduces EM. The value of EM for the five-carbon linker indicates that this macrocycle is a strainless ring.
    Preview · Article · Sep 2014 · Chemical Science
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    William Cullen · Simon Turega · Christopher A. Hunter · Michael D. Ward
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    ABSTRACT: A range of organic molecules with acidic or basic groups exhibit strong pH-dependent binding inside the cavity of a polyhedral coordination cage. Guest binding in aqueous solution is dominated by a hydrophobic contribution which is compensated by stronger solvation when the guests become cationic (by protonation) or anionic (by deprotonation). The Parkinson's drug 1-amino-adamantane (‘amantadine’) binds with an association constant of 104 M−1 in the neutral form (pH greater than 11), but the stability of the complex is reduced by three orders of magnitude when the guest is protonated at lower pH. Monitoring the uptake of the guests into the cage cavity was facilitated by the large upfield shift for the 1H NMR signals of bound guests due to the paramagnetism of the host. Although the association constants are generally lower, guests of biological significance such as aspirin and nicotine show similar behaviour, with a substantial difference between neutral (strongly binding) and charged (weakly binding) forms, irrespective of the sign of the charged species. pH-dependent binding was observed for a range of guests with different functional groups (primary and tertiary amines, pyridine, imidazole and carboxylic acids), so that the pH-swing can be tuned anywhere in the range of 3.5–11. The structure of the adamantane-1-carboxylic acid complex was determined by X-ray crystallography: the oxygen atoms of the guest form CHO hydrogen bonds with one of two equivalent pockets on the internal surface of the host. Reversible uptake and release of guests as a function of pH offers interesting possibilities in any application where controlled release of a molecule following an external stimulus is required.
    Full-text · Article · Aug 2014 · Chemical Science
  • N. Nikogeorgos · C.A. Hunter · G.J. Leggett

    No preview · Article · Aug 2014 · Langmuir
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    Craig C Robertson · Robin N Perutz · Lee Brammer · Christopher A Hunter
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    ABSTRACT: The effect of solvent on the stabilities of complexes involving a single H-bond or halogen-bond (X-bond) has been quantified. Association constants for binary complexes of 4-(phenylazo)phenol, molecular iodine, tetramethylurea and tetramethylthiourea have been measured in fifteen different solvents by UV/vis absorption and 1H NMR titration experiments. The stabilities of the H-bonded complexes decrease by more than three orders of magnitude with increasing solvent polarity. In contrast, the X-bonded complex of molecular iodine with tetramethylthiourea is remarkably insensitive to the nature of the solvent (association constants measured in alkanes and alcohols are similar). The results suggest that, in contrast to H-bonds, where electrostatics determine thermodynamic stability, charge-transfer interactions make a major contribution to the stability of these X-bonded complexes rendering them resistant to increases in solvent polarity.
    Full-text · Article · Jul 2014 · Chemical Science
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    Simon Turega · William Cullen · Martina Whitehead · Christopher A Hunter · Michael D Ward
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    ABSTRACT: Size and shape criteria for guest binding inside the cavity of an octanuclear cubic coordination cage in water have been established using a new fluorescence displacement assay to quantify guest binding. For aliphatic cyclic ketones of increasing size (from C5 to C11), there is a linear relationship between ∆G for guest binding and the guest's surface area: the change in ∆G for binding is 0.3 kJ mol-1 Å-2, corresponding to 5 kJ mol-1 for each additional CH2 group in the guest, in good agreement with expectations based on hydrophobic desolvation. The highest association constant was K = 1.2 x 106 M-1 for cycloundecanone, whose volume is approximately 50% of that cavity volume; for larger C12 and C13 cyclic ketones, the association constant progressively decreases as the guests become too large. For a series of C10 aliphatic ketones, differing in shape but not size, ∆G for guest binding showed no correlation with surface area. These guests are close to the volume limit of the cavity (cf. Rebek's 55% rule), so the association constant is sensitive to shape complementarity, with small changes in guest structure resulting in large changes in binding affinity. The most flexible members of this series (linear aliphatic ketones) did not bind, whereas the more preorganised cyclic ketones all have association constants of 104 -105 M-1. A crystal structure of the cage•cycloundecanone complex shows that the guest carbonyl oxygen is directed into a binding pocket defined by a convergent set of CH groups, which act as weak H-bond donors, and also shows close contacts between the exterior surface of the disc-shaped guest and the interior surface of the pseudo-spherical cage cavity despite the slight mismatch in shape.
    Full-text · Article · May 2014 · Journal of the American Chemical Society
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    Rafel Prohens · Tudor Grecu · Christopher A. Hunter · Jim McCabe · Anna Portell · Harry Adams
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    ABSTRACT: Formulation of solids as cocrystals offers an opportunity to modulate physical properties, so identification of cocrystal formers (CCFs) for an active pharmaceutical ingredient is an area of significant interest. Exhaustive experimental screening would be time-consuming, but we have developed a computational method for identifying CCFs that have a high chance of success based on calculated functional group interaction energies. This virtual screening tool has been applied to nalidixic acid cocrystals. Calculations on a library of 310 compounds identified the 44 most promising CCFs for formation of nalidixic acid cocrystals. Six of these compounds were already known to form cocrystals, and experimental work was undertaken on the remaining 38 compounds. X-ray powder diffraction (XRPD) of mixtures obtained from grinding experiments identified seven CCFs that form new solid phases with nalidixic acid. Infrared spectroscopy and differential scanning calorimetry confirm that these new solid phases are different from the pure components. Further structural characterization was not possible for the skatole, 2,4-dihydroxybenzoic acid, and 3,4-dihydroxybenzoic acid cocrystals, but X-ray crystal structures were obtained from single crystals of the 1:1 tert-butylhydroquinone cocrystal and of the 1:1 propyl gallate cocrystal and from the XRPD pattern for the 1:1 2-phenylphenol cocrystal and for the 1:2 indole cocrystal. The results suggest that success rates in cocrystal screening can be significantly improved by application of computational filters to select the most appropriate CCFs for experimental study
    Full-text · Article · Mar 2014 · Crystal Growth & Design
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    Dataset: To list 1
    Dan Andrew Smith · Lee Brammer · Christopher A Hunter · Robin Noel Perutz

    Full-text · Dataset · Feb 2014

Publication Stats

9k Citations
1,448.83 Total Impact Points


  • 2014-2016
    • University of Cambridge
      • Department of Chemistry
      Cambridge, England, United Kingdom
  • 1993-2014
    • The University of Sheffield
      • Department of Chemistry
      Sheffield, England, United Kingdom
  • 2007
    • University of Nottingham
      Nottigham, England, United Kingdom
  • 2006
    • Catalan Institution for Research and Advanced Studies
      Barcino, Catalonia, Spain
  • 2003
    • Università degli studi di Parma
      • Department of Chemistry
      Parma, Emilia-Romagna, Italy
  • 1996
    • University of Birmingham
      • School of Chemistry
      Birmingham, England, United Kingdom
  • 1991-1996
    • University of Otago
      • Department of Chemistry
      Taieri, Otago Region, New Zealand