Molecular Tweezers as Synthetic Receptors: Molecular Recognition of Electron-Deficient Aromatic and Aliphatic Substrates

Abstract

Syntheses and supramolecular properties of the molecular tweezers 1 and 2, containing naphthalene and benzene spacer units, respectively, are described. They selectively bind electron-deficient aromatic and aliphatic substrates, for example di-and tetracyanobenzenes 11 ± 14, 1,4-dinitrobenzene (15), p-benzoquinone (16), 7,7,8,8-tetracyano-p-quinodimethane (TCNQ) (17), 1,2,4,5-tetrafluorobenzene (20), acetonitrile, and malononitrile. They form stable complexes with the cationic substrate N-methylpyrazinium iodide (19) that are soluble in chloroform. A quantitative investigation using NMR titration and solid ± liquid extraction shows that the naphthalene-spaced tweezer 1 forms stronger complexes with aromatic and quinoid substrates than the benzene-spaced tweezer 2 (DDG 1.5 AE 1 kcal mol À1 ), whereas the aliphatic substrates are only complexed by receptor 2. Force-field calculations (AMBER*) and single-crystal structure analyses reveal that 1 has an almost ideal geometrical topology for the complexation of aromatic substrates, while complexation of these substrates by the smaller receptor 2 requires expansion of the tweezer tips by about 2 . This causes an extra strain energy in 2 of 1 ± 2 kcal mol À1. According to semiempirical AM1 calculations, the electrostatic potential surfaces (EPSs) of molecular tweezers 1 and 2 are surprisingly negative on the concave sides of the molecules and, hence, complementary to those of the electron-deficient substrates.

Molecular tweezers for lysine and arginine – powerful inhibitors of pathologic protein aggregation

“…Scheme 1 shows the synthesis of tweezer 1a substituted by two acetoxy groups in the central benzene bridge as a representative example. 26 The key step in this synthesis is the Diels-Alder reaction which selectively proceeds on the exo face of the bisdienophile and endo face of the diene leading to the bisadduct with all four methylene bridges syn to one another. Oxidative dehydrogenation of the cyclohexene moieties with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) produces 1a in an overall yield of 59%.…”

“…In the 1 H NMR spectra of 1k and 1l the signals assigned to the methyl group of the sidechain (R 2 = OCH 2 CH(OH)CH 2 OCH 2 CH 3 or OCH 2 CH 2 CO 2 CH 2 CH 3 ) display an upfield shift of Δ δ ≈ 0.5 or 2.0 ppm 34 indicating that the methyl groups points inside the cavity comparable to the original tweezer 1 (R 1 = R 2 = OCH 2 CH 2 CO 2 CH 2 CH 3 ). 7, 26, 27 Such self-inclusion phenomena may also hinder guest binding.…”

“…Substantial upfield shifts (towards smaller δ values) indicate that in the host-guest complex they are located inside the tweezers’ cavity. 7, 26, 27 For tweezers 1c–e Δ δ max values of lysine’s and arginine’s methylene protons were determined by 1 H NMR titrations and reach up to 6 ppm. 33 This is also true for model fragments taken directly from the sequence of the aggregation-prone polypeptides IAPP 1-14 and Aβ 15–29 : in the presence of phosphate tweezer 1c all their lysine and arginine side chains undergo substantial upfield shifts of more than 4 ppm, 41 indicating selective threading through the tweezers’ cavity.…”

“…Their structures are shown in Scheme 1. 7, 26–28 The alternating order of benzene and norbornadiene rings in 1 produces a belt-like arrangement with a horseshoe-shaped cavity, which preferentially accommodates extended alkane chains. However, if R1/R2 are anionic, only guests with a terminal ammonium or guanidinium cation are inserted because in addition to the electrostatic and dispersive attraction resulting from side-chain threading the cation efficiently forms an ion pair with the pending tweezer anion.…”

Supramolecular recognition: On the kinetic lability of thermodynamically stable host–guest association complexes

“…Thus, whereas relatively stable complexes are formed, the 9-MA guest molecules exchange rapidly between their respective sites in the association complex and with free 9-MA. The site occupancies of the 9-MA guest associated with the receptor 15 have been inferred from 1 H rotating-frame Overhauser enhancement spectroscopy (ROESY), a method of measuring rotatingframe Overhauser effects (ROE) in large molecules (18)(19)(20)(21). The ROE are informative of the relative proximity between nuclei, in this case proton nuclei.…”