Untangling the Diverse Interior and Multiple Exterior Guest Interactions of a Supramolecular Host by the Simultaneous Analysis of Complementary Observables

The entropic and enthalpic driving forces for encapsulation versus sequential exterior guest binding to the [Ga₄L₆]^12– supramolecular host in solution are very different, which significantly complicates the determination of these thermodynamic parameters. The simultaneous use of complementary techniques, such as NMR, UV–vis, and isothermal titration calorimetry, enables the disentanglement of such multiple host–guest interactions. Indeed, data collected by each technique measure different components of the host–guest equilibria and together provide a complete picture of the solution thermodynamics. Unfortunately, commercially available programs do not allow for global analysis of different physical observables. We thus resorted to a novel procedure for the simultaneous refinement of multiple parameters (Δ<i>G</i>°, Δ<i>H</i>°, and Δ<i>S</i>°) by treating different observables through a weighted nonlinear least-squares analysis of a constrained model. The refinement procedure is discussed for the multiple binding of the Et₄N⁺ guest, but it is broadly applicable to the deconvolution of other intricate host–guest equilibria

Direct Evidence of Iron Uptake by the Gram-Positive Siderophore-Shuttle Mechanism without Iron Reduction

Iron is an essential element for all organisms, and microorganisms produce small molecule iron-chelators, siderophores, to efficiently acquire Fe­(III). Gram-positive bacteria possess lipoprotein siderophore-binding proteins (SBPs) on the membrane. Some of the SBPs bind both apo-siderophores (iron-free) and Fe-siderophore (iron-chelated) and only import Fe-siderophores. When the SBP initially binds an apo-siderophore, the SBP uses the Gram-positive siderophore-shuttle mechanism (the SBPs exchange Fe­(III) from a Fe-siderophore to the apo-siderophore bound to the protein) and/or displacement mechanism (the apo-siderophore bound to the SBP is released and a Fe-siderophore is then bound to the protein) to import the Fe-siderophore. Previously, we reported that the <i>Bacillus cereus</i> SBP, YxeB, exchanges Fe­(III) from a ferrioxamine B (FO) to a desferrioxamine B (DFO) bound to YxeB using the siderophore-shuttle mechanism although the iron exchange was indirectly elucidated. Synthetic Cr-DFO (inert metal FO analog) and Ga-DFO (nonreducible FO analog) are bound to YxeB and imported via YxeB and the corresponding permeases and ATPase. YxeB exchanges Fe­(III) from FO and Ga­(III) from Ga-DFO to DFO bound to the protein, indicating that the metal-exchange occurs without metal reduction. YxeB also binds DFO derivatives including acetylated DFO (apo-siderophore) and acetylated FO (AcFO, Fe-siderophore). The iron from AcFO is transferred to DFO when bound to YxeB, giving direct evidence of iron exchange. Moreover, YxeB also uses the displacement mechanism when ferrichrome (Fch) is added to the DFO:YxeB complex. Uptake by the displacement mechanism is a minor pathway compared to the shuttle mechanism

Equilibrium Isotope Effects on Noncovalent Interactions in a Supramolecular Host–Guest System

The self-assembled supramolecular complex [Ga₄L₆]^12‑ (<b>1</b>; L = 1,5-bis­[2,3-dihydroxybenzamido]­naphthalene) can act as a molecular host in aqueous solution and bind cationic guest molecules to its highly charged exterior surface or within its hydrophobic interior cavity. The distinct internal cavity of host <b>1</b> modifies the physical properties and reactivity of bound guest molecules and can be used to catalyze a variety of chemical transformations. Noncovalent host–guest interactions in large part control guest binding, molecular recognition and the chemical reactivity of bound guests. Herein we examine equilibrium isotope effects (EIEs) on both exterior and interior guest binding to host <b>1</b> and use these effects to probe the details of noncovalent host–guest interactions. For both interior and exterior binding of a benzylphosphonium guest in aqueous solution, protiated guests are found to bind more strongly to host <b>1</b> (<i>K</i>_H/<i>K</i>_D > 1) and the preferred association of protiated guests is driven by enthalpy and opposed by entropy. Deuteration of guest methyl and benzyl C–H bonds results in a larger EIE than deuteration of guest aromatic C–H bonds. The observed EIEs can be well explained by considering changes in guest vibrational force constants and zero-point energies. DFT calculations further confirm the origins of these EIEs and suggest that changes in low-frequency guest C–H/D vibrational motions (bends, wags, etc.) are primarily responsible for the observed EIEs

A Macrocyclic Chelator with Unprecedented Th⁴⁺ Affinity

A novel macrocyclic octadentate ligand incorporating terephthalamide binding units has been synthesized and evaluated for the chelation of Th⁴⁺. The thorium complex was structurally characterized by X-ray diffraction and in solution with kinetic studies and spectrophotometric titrations. Dye displacement kinetic studies show that the ligand is a much more rapid chelator of Th⁴⁺ than prevailing ligands (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid and diethylenetriaminepentaacetic acid). Furthermore, the resulting complex was found to have a remarkably high thermodynamic stability, with a formation constant of 10⁵⁴. These data support potential radiotherapeutic applications

Nucleophilic Substitution Catalyzed by a Supramolecular Cavity Proceeds with Retention of Absolute Stereochemistry

While the reactive pocket of many enzymes has been shown to modify reactions of substrates by changing their chemical properties, examples of reactions whose stereo­chemical course is completely reversed are exceedingly rare. We report herein a class of water-soluble host assemblies that is capable of catalyzing the substitution reaction at a secondary benzylic carbon center to give products with overall <i>stereo­chemical retention</i>, while reaction of the same substrates in bulk solution gives products with <i>stereo­chemical inversion</i>. Such ability of a biomimetic synthetic host assembly to reverse the stereo­chemical outcome of a nucleophilic substitution reaction is unprecedented in the field of supra­molecular host–guest catalysis

Enabling New Modes of Reactivity via Constrictive Binding in a Supramolecular-Assembly-Catalyzed Aza-Prins Cyclization

Supramolecular assembly <b>1</b> catalyzes a bimolecular aza-Prins cyclization featuring an unexpected transannular 1,5-hydride transfer. This reaction pathway, which is promoted by constrictive binding within the supramolecular cavity of <b>1</b>, is kinetically disfavored in the absence of <b>1</b>, as evidenced by the orthogonal reactivity observed in bulk solution. Mechanistic investigation through kinetic analysis and isotopic labeling studies indicates that the rate-limiting step of the transformation is the encapsulation of a transient iminium ion and supports the proposed 1,5-hydride transfer mechanism. This represents a rare example of such an extreme divergence of product selectivity observed within a catalytic metal–ligand supramolecular enzyme mimic

Silica Microparticles as a Solid Support for Gadolinium Phosphonate Magnetic Resonance Imaging Contrast Agents

Particle-based magnetic resonance imaging (MRI) contrast agents have been the focus of recent studies, primarily due to the possibility of preparing multimodal particles capable of simultaneously targeting, imaging, and treating specific biological tissues <i>in vivo</i>. In addition, particle-based MRI contrast agents often have greater sensitivity than commercially available, soluble agents due to decreased molecular tumbling rates following surface immobilization, leading to increased relaxivities. Mesoporous silica particles are particularly attractive substrates due to their large internal surface areas. In this study, we immobilized a unique phosphonate-containing ligand onto mesoporous silica particles with a range of pore diameters, pore volumes, and surface areas, and Gd­(III) ions were then chelated to the particles. Per-Gd­(III) ionic relaxivities ranged from ∼2 to 10 mM^–1 s^–1 (37 °C, 60 MHz), compared to 3.0–3.5 mM^–1 s^–1 for commercial agents. The large surface areas allowed many Gd­(III) ions to be chelated, leading to per-particle relaxivities of 3.3 × 10⁷ mM^–1 s^–1, which is the largest value measured for a biologically suitable particle

Solvent and Pressure Effects on the Motions of Encapsulated Guests: Tuning the Flexibility of a Supramolecular Host

The supramolecular host assembly [Ga₄L₆]^12‑ [<b>1</b>; L = 1,5-bis­(2,3-dihydroxybenzamido)­naphthalene] contains a flexible, hydrophobic interior cavity that can encapsulate cationic guest molecules and catalyze a variety of chemical transformations. The Ar–CH₂ bond rotational barrier for encapsulated ortho-substituted benzyl phosphonium guest molecules is sensitive to the size and shape of the host interior space. Here we examine how changes in bulk solvent (water, methanol, or DMF) or applied pressure (up to 150 MPa) affect the rotational dynamics of encapsulated benzyl phosphonium guests, as a way to probe changes in host cavity size or flexibility. When host <b>1</b> is dissolved in organic solvents with large solvent internal pressures (∂<i>U</i>/∂<i>V</i>)_<i>T</i>, we find that the free energy barrier to Ar–CH₂ bond rotation increases by 1–2 kcal/mol, compared with that in aqueous solution. Likewise, when external pressure is applied to the host–guest complex in solution, the bond rotational rates for the encapsulated guests decrease. The magnitude of these rate changes and the volumes of activation obtained using either solvent internal pressure or applied external pressure are very similar. NOE distance measurements reveal shorter average host–guest distances (∼0.3 Å) in organic versus aqueous solution. These experiments demonstrate that increasing solvent internal pressure or applied external pressure reduces the host cavity size or flexibility, resulting in more restricted motions for encapsulated guest molecules. Changing bulk solvent or external pressure might therefore be used to tune the physical properties or reactivity of guest molecules encapsulated in a flexible supramolecular host

Improved scope and diastereoselectivity of C–H activation in an expanded supramolecular host

<p>Chiral Ga₄L₆ assembly Ga₄(L^N)₆ encapsulates cationic iridium half-sandwich complexes that activate aldehyde C–H bonds to form chiral, strongly bound piano-stool complexes. Herein, we report the expanded scope of the larger Ga₄(L^P)₆ host in mediating this transformation. The larger assembly significantly improves both the scope and the diastereoselectivity of this organometallic transformation generally, while substrate-specific interactions demonstrate that host size is an important, but not definitive, factor in determining diastereoselectivity.</p

Conformational Selection as the Mechanism of Guest Binding in a Flexible Supramolecular Host

This study offers a detailed mechanistic investigation of host–guest encapsulation behavior in a new enzyme–mimetic metal–ligand host and provides the first observation of a conformational selection mechanism (as opposed to induced fit) in a supramolecular system. The Ga₄L₄ host described features a <i>C</i>₃-symmetric ligand motif with <i>meta-</i>substituted phenyl spacers, which enables the host to initially self-assemble into an <i>S</i>₄-symmetric structure and then subsequently isomerize to a <i>T</i>-symmetric tetrahedron for better accommodation of a sufficiently large guest. Selective inversion recovery ¹H NMR studies provide structural insights into the self-exchange behaviors of the host and the guest individually in this dynamic system. Kinetic analysis of the encapsulation–isomerization event revealed that increasing the concentration of guest inhibits the rate of host–guest relaxation, a key distinguishing feature of conformational selection. A comprehensive study of this simple enzyme mimic provides insight into analogous behavior in biophysics and enzymology and aims to inform the design of efficient self-assembled microenvironment catalysts