In flagrante metallo-cyclophane self-assembly?† Peter J. Cragg, a Fenton R. Heirtzler‡,* b Mark J. Howard, c Ivan Prokes d and Thomas Weyhermüller e a School of Pharmacy and Biomolecular Sciences, University of Brighton, Cockcroft Building, UK BN2 4GJ b School of Physical Sciences, University of Kent, Canterbury, Kent, UK CT2 7NH. E-mail: heirtzler@web.de; Fax: +44-1227-827-724; Tel: +44-1227-827-041 c Research School of Biosciences, University of Kent, Canterbury, Kent, UK CT2 7NJ d Department of Chemistry, University of Exeter, Stocker Road, Exeter, UK EX4 4QD e Max-Planck-Institut für Bioanorganische Chemie, Stiftstaße 34-36, 45470 Mülheim, Germany Received (in Cambridge, UK) 31st August 2003, Accepted 28th October 2003 First published as an Advance Article on the web 7th January 2004 The dimeric self-assembly of an alkyl-substituted pyrazine– pyridine hybrid ligand with copper(I) initially affords its sterically congested, C 2 -symmetric stereoisomer, which then undergoes partial isomerisation to a dynamic mixture contain- ing the less crowded meso-configured diastereomer. Prediction and switching between self-assembled supramolecular diastereomers are current challenges 1 relevant to diverse applica- tions. 2 Its expression may be through meso/helical-type symmetry as a consequence of one stereogenic center predisposing the stereochemistry of subsequent binding sites. Self-assembled metallo-cyclophanes have internal arenes in cofacial alignment, separated by graphitic distances and intercon- nected through metallo-organic binding. These stacking inter- actions may stabilize diastereomeric arene alignment during the self-assembly process, 3 and are accentuated by steric bias and a sharply angular arrangement of ligand-binding domains. 4,5 The electron-deficient character of pyrazine derivatives is amplified by metal coordination, 6 which makes their derivatives efficient participants in p-stacked self-assembly. Such 2,3-di- substituted derivatives furthermore undergo a sterically induced, right-angle partitioning of their binding domains. This contributes to a dimeric self-assembly pattern, 4,7,8 as opposed to relatively unhindered 2,5-disubstituted pyrazine derivatives, which may form larger architectures. 9 Ligand 1a self-assembles with copper(I) to a dimeric metallo-cyclophane cation [1a 2 Cu 2 ] 2+ . 7 Stacking of pyr- azine rings promotes solution- and solid-state (rac) C 2 -symmetry in this dication, over a meso-configured metallo-cyclophane having double pyrazinyl-pyridyl hetero-overlaps. The C 2 -symmetry of the rac-stereoisomer differs from that of conventional helicate-type complexes 2 by virtue of a lesser number of C 2 -rotational axes. The postulated existence of both forms is supported by molecular model studies and semi-empirical calculations (Scheme 1). Pyrazine solid- state stacking occur in the same and related ligands. 10 We expected that selective substitution of alkyl groups into the molecular scaffolding of ligand 1a (e.g., 1b) 10 would destabilize these stacking interactions via intermolecular steric effects, thus inducing a preference for the meso-stereoisomer. Combining 1b and one equivalent of copper(I)tetrakis(acetoni- trilo) tetrafluoroborate, refluxing in methanol, precipitation with ammonium tetrafluoroborate and re-precipitatation from diethyl ether–acetonitrile gave a dark red-coloured solid. The results of FAB-MS and combustion analysis confirmed the dimeric composi- tion, [1bCu] 2 [BF 4 ] 2 .† The 1 H NMR spectrum of [1bCu] 2 [BF 4 ] 2 in CD 3 CN at 298 K displayed the expected aromatic shifts and a singlet at d 2.16 ppm. Upon cooling to 233 K, de-coalescence to two singlets of similar intensity occurred (Fig. 1); the aromatic signals only underwent minor shifts. The low temperature depend- ence of this ratio implies comparable thermodynamic stabilities and low relative entropic factors for the involved dynamic species. Assignment of the 1 H- and 13 C spectra of [1bCu] 2 [BF 4 ] 2 at 233 K agreed with a single ligand equivalent and 12 aromatic protons. The spectrum recorded in CD 3 NO 2 at 303 K displayed similar aromatic, however different aliphatic shifts relative to CD 3 CN. Two singlets appeared at d 2.20 and 2.10, and these underwent no coalescence phenomena over 243–303 K (Dd ~ 0.02 ppm). At no temperature and field strength (270–600 MHz) was a doubling of the aromatic signals observed. A NOESY experiment in CD 3 NO 2 at 303 K revealed through-space correlation of the singlet of C(7B) at d 2.20 to H(6B) in the partner ligand; this interaction is only possible for contacts < 6 Å, which allows assignment to the C 2 -symmetric diastereomer (Fig. 2). The relative magnitudes of the T 1 values (0.77 ± 0.09 vs. 0.38 ± 0.05 s for C 2 - and meso-isomers, respectively), and thus dipolar relaxation rates, are a result of increased asymmetric tumbling in the C 2 -symmetric isomer. 11 Dissimilarity in T 2 relaxation times (r.e., spin state lifetimes and Scheme 1 Stereochemistry of metallo-cyclophane self-assembly. Symmetry operators indicated in green. † Electronic Supplementary Information (ESI) available: preparation and characterization of [1bCu] 2 [BF 4 ] 2 , detailed NMR spectroscopic assign- ments, variable temperature 1 H NMR shift plots, X-ray crystallographic data (CIF file) and .pdb files of energy-minimized structures. See http: //www.rsc.org/suppdata/cc/b3/b310558j/ ‡ New address: Department of Entomology, University of California, Davis, CA 95616, USA, Tel +1-530-752-8465. This journal is © The Royal Society of Chemistry 2004 DOI: 10.1039/b310558j 280 Chem. Commun., 2004, 280–281