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A tetracationic pyridinium-based cyclophane with a box-like geometry, incorporating two juxtaposed alkyne functions, has been synthesized. The triple bonds are reactive through cycloadditions toward dienes and azides, promoted by the electron-withdrawing nature of the pyridinium rings, as well as by the strain inherent in the cyclophane. The cycloadditions proceeded in high yields, with the cyclophane reacting faster than its acyclic analogue. While the cyclophane contains two reactive triple bonds, there is no evidence for a stable monofunctional intermediate—only starting material and the difunctional product have been detected by 1H NMR spectroscopy. Molecular modeling of the energy landscape reveals a lower barrier for the kinetically favored second cycloaddition compared with the first one. This situation results in tandem cascading reactions within rigid cyclophanes, where reactions at a first triple bond induce increased reactivity at a distal second alkyne. [ABSTRACT FROM AUTHOR]

Acting as hosts, cationic cyclophanes, consisting of p-electron-poor bipyridinium units, are capable of entering into strong donor-acceptor interactions to form host-guest complexes with various guests when the size and electronic constitution are appropriately matched. A synthetic protocol has been developed that utilizes catalytic quantities of tetrabutylammonium iodide to make a wide variety of cationic pyridinium-based cyclophanes in a quick and easy manner. Members of this class of cationic cyclophanes with boxlike geometries, dubbed ExnBoxm4+ for short, have been prepared by altering a number of variables: (i) n, the number of "horizontal" p-phenylene spacers between adjoining pyridinium units, to modulate the "length" of the cavity; (ii) m, the number of "vertical" p-phenylene spacers, to modulate the "width" of the cavity; and (iii) the aromatic linkers, namely, 1,4-di- and 1,3,5-trisubstituted units for the construction of macrocycles (ExBoxes) and macrobicycles (ExCages), respectively. This Account serves as an exploration of the properties that emerge from these structural modifications of the pyridinium-based hosts, coupled with a call for further investigation into the wealth of properties inherent in this class of compounds. By variation of only the aforementioned components, the role of these cationic receptors covers ground that spans (i) synthetic methodology, (ii) extraction and sequestration, (iii) catalysis, (iv) molecular electronics, (v) physical organic chemistry, and (vi) supramolecular chemistry. Ex¹Box4+ (or simply ExBox4+) has been shown to be a multipurpose receptor capable of binding a wide range of polycyclic aromatic hydrocarbons (PAHs), while also being a suitable component in switchable mechanically interlocked molecules. Additionally, the electronic properties of some host-guest complexes allow the development of artificial photosystems. Ex²Box4+ boasts the ability to bind both p-electron-rich and -poor aromatic guests in different binding sites located within the same cavity. ExBox24+ forms complexes with C60 in which discrete arrays of aligned fullerenes result in single cocrystals, leading to improved material conductivities. When the substitution pattern of the ExnBox4+ series is changed to 1,3,5-trisubstituted benzenoid cores, the hexacationic cagelike compound, termed ExCage6+, exhibits different kinetics of complexation with guests of varying sizes--a veritable playground for physical organic chemists. The organization of functionality with respect to structure becomes valuable as the number of analogues continues to grow. With each of these minor structural modifications, a wealth of properties emerge, begging the question as to what discoveries await and what properties will be realized with the continued exploration of this area of supramolecular chemistry based on a unique class of receptor molecules. [ABSTRACT FROM AUTHOR]

Although pristine C60 prefers to adopt a face-centered cubic packing arrangement in the solid state, it has been demonstrated that noncovalent-bonding interactions with a variety of molecular receptors lead to the complexation of C60 molecules, albeit usually with little or no control over their long-range order. Herein, an extended viologen-based cyclophane-ExBox24+-has been employed as a molecular receptor which, not only binds C60 one-on-one, but also results in the columnar self-assembly of the 1:1 inclusion complexes under ambient conditions. These one-dimensional arrays of fullerenes stack along the long axis of needle-like single crystals as a consequence of multiple noncovalent-bonding interactions between each of the inclusion complexes. The electrical conductivity of these crystals is on the order of 10-7 S cm-1, even without any evacuation of oxygen, and matches the conductivity of high-quality, unfunctionalized C60-based materials that typically require stringent high-temperature vaporization techniques, along with the careful removal of oxygen and moisture, prior to measuring their conductance. [ABSTRACT FROM AUTHOR]

Cyclophanes, especially those where pyridinium units in conjugation with each other are linked up face-to-face within platforms that are held approximately 7 Å apart by rigid linkers, are capable of forming inclusion complexes with polycyclic aromatic hydrocarbons (PAHs) with high binding affinities as a result of a combination of noncovalent bonding interactions, including face-to-face [π•••π] stacking and orthogonal [C–H•••π] interactions. Here, we report the template-directed, catalyst-assisted synthesis of a three-fold symmetric, extended pyridinium-based, cage-like host (ExCage6+) containing a total of six π-electron-deficient pyridinium units connected in a pairwise fashion by three bridging p-xylylene linkers, displayed in a trigonal (1,3,5) fashion around two opposing and parallel 1,3,5-tris(4-pyridinium)benzene platforms. The association constants (Ka) of eight complexes have been measured by isothermal titration calorimetry (ITC) in acetonitrile and were found to span the range from 2.82 × 103 for naphthalene up to 5.5 × 106 M–1 for perylene. The barriers to decomplexation, which were measured in DMF-d7 for phenanthrene, pyrene, triphenylene, and coronene by dynamic 1H NMR spectroscopy undergo significant stepwise increases from 11.8 → 13.6 → 15.5 → >18.7 kcal mol–1, respectively, while complexation experiments using rapid injection 1H NMR spectroscopy in DMF-d7 at −55 °C revealed the barriers to complexation for pyrene and coronene to be 6.7 and >8 kcal mol–1, respectively. The kinetic and thermodynamic data reveal that, in the case of ExCage6+, while the smaller PAHs form complexes faster than the larger ones, the larger PAHs form stronger complexes than the smaller ones. It is also worthy of note that, as the complexes become stronger in the case of the larger and larger PAHs, the Rebek 55% solution formula for molecular recognition in the liquid state becomes less and less relevant. [ABSTRACT FROM AUTHOR]

Although pristine C60 prefers to adopt a face-centered cubic packing arrangement in the solid state, it has been demonstrated that noncovalent-bonding interactions with a variety of molecular receptors lead to the complexation of C60 molecules, albeit usually with little or no control over their long-range order. Herein, an extended viologen-based cyclophane—ExBox2(4+)—has been employed as a molecular receptor which, not only binds C60 one-on-one, but also results in the columnar self-assembly of the 1:1 inclusion complexes under ambient conditions. These one-dimensional arrays of fullerenes stack along the long axis of needle-like single crystals as a consequence of multiple noncovalent-bonding interactions between each of the inclusion complexes. The electrical conductivity of these crystals is on the order of 10(-7) S cm(-1), even without any evacuation of oxygen, and matches the conductivity of high-quality, unfunctionalized C60-based materials that typically require stringent high-temperature vaporization techniques, along with the careful removal of oxygen and moisture, prior to measuring their conductance.

A rapid and efficient synthesis of the extended bipyridinium-based class of cyclophanes--that is, Ex(n)Box(4+) (n = 0-3), where n is the number of p-phenylene rings inserted between the pyridinium rings--is demonstrated, resulting in much higher yields of products along with a reduced output of oligomeric byproducts. Although each cyclophane can be synthesized readily without the use of a precise stoichiometric amount of template, ExBox(4+) can be prepared in 66% yield (following crystallization) using six equivalents of pyrene in a template-directed protocol. This new methodology has been employed to synthesize, in modest yield, a nearly 2.5 nm long cyclophane consisting of 12 aromatic rings.

Diseases caused by the apicomplexan protozoans Toxoplasma gondii and Cryptosporidium parvum are a major health concern. The life cycle of these parasites is regulated by a family of calcium-dependent protein kinases (CDPKs) that have no direct homologues in the human host. Fortuitously, CDPK1 from both parasites contains a rare glycine gatekeeper residue adjacent to the ATP-binding pocket. This has allowed creation of a series of C3-substituted pyrazolopyrimidine compounds that are potent inhibitors selective for CDPK1 over a panel of human kinases. Here we demonstrate that selectivity is further enhanced by modification of the scaffold at the C1 position. The explanation for this unexpected result is provided by crystal structures of the inhibitors bound to CDPK1 and the human kinase c-SRC. Furthermore, the insight gained from these studies was applied to transform an alternative ATP-competitive scaffold lacking potency and selectivity for CDPK1 into a low nanomolar inhibitor of this enzyme with no activity against SRC.

Toxoplasmosis is a disease of prominent health concern that is caused by the protozoan parasite Toxoplasma gondii. Proliferation of T. gondii is dependent on its ability to invade host cells, which is mediated in part by calcium-dependent protein kinase 1 (CDPK1). We have developed ATP competitive inhibitors of TgCDPK1 that block invasion of parasites into host cells, preventing their proliferation. The presence of a unique glycine gatekeeper residue in TgCDPK1 permits selective inhibition of the parasite enzyme over human kinases. These potent TgCDPK1 inhibitors do not inhibit the growth of human cell lines and represent promising candidates as toxoplasmosis therapeutics.