Ureyleno Macrobicyclic Amines. 1. Cooperative Protonation of 4,6,12,14,19,21-Hexaaza-5,13,20- trioxobicyclo[7.7.7]tricosane

Since their discovery few decades ago, cryptands have become a major subject of study in organic and bioorganic chemistry.1 Of particular interest are the basic principles that govern the binding behavior of cryptands. Previous investigations clearly demonstrated that the size, the shape, the rigidity, and the noncovalent interactions of the cavity are extremely crucial for binding. At an early stage of cryptand studies, chemists recognized that highly flexible large cryptands often make the binding entropically unfavorable.1 Accordingly, structurally rigid cryptands have become an important area of investigation.2 Our recent efforts have been focused on receptors bearing polar rigid linkages. We are intrigued with the N,N ′-substituted ureyleno group because of its rigidity, polarity, and hydrogen-bonding characteristics. First, N,N ′-substituted ureas are polar compounds that can act as hydrogen-bond donors as well as acceptors.3 Moreover, the mesomeric π-character of the C(O)-N group restricts the C-N bond rotation. This makes the ureyleno unit a rigid-coplanar structure with the substituents in the sterically favored Z,Z-conformations. We report herein the synthesis and the unexpected protonation behavior of the rigid ureyleno cryptand (CT) 1. CT 1 was synthesized in a two-step sequence.4 Treatment of 2 with 3 equiv of n-BuLi and 3 equiv of LiN(SiMe3)2 at -78 °C followed by addition of (MeS)2CO and subsequent warming to room temperature gave 3 in moderate yield. Coupling of 2 with 3 in methanol at 80 °C in high dilution conditions afforded CT 1 as colorless crystals (Scheme 1). CT 1 is soluble in H2O and MeOH, partially soluble in MeCN, and insoluble in most of the nonpolar solvents. The 1H NMR spectrum of 1 in D2O shows two multiplets centered at δ 2.36 and 2.92 ppm, respectively, in a ratio of 1:1. The multiplet at δ 2.36 ppm is assigned to the methylene protons adjacent to the bridgehead tertiary nitrogen. The other multiplet at δ 2.92 ppm is attributed to the methylene protons next to the ureyleno bridge. The 13C NMR spectrum of 1 also agrees with the assigned structure. It shows three sets of resonance signals, including two signals at δ 37.4 and 51.1 ppm for the ethano carbons and one signal at δ 161.1 ppm for the carbonyl carbons. Protonation of 1 with 2 equiv of HCl leads to the diprotonated cryptand (DPCT) 4 as colorless crystals. The 1H NMR spectrum of 4 in D2O shows two sets of multiplets at δ 3.17 and 3.30 ppm. The downfield shift of the resonance signals is attributed to the electric-field effects arising from the positively charged quaternary ammonium groups. No in-out stereoisomerism of the tetrahedral bridgehead nitrogen atoms is evidenced on the basis of the NMR analysis. This observation is further confirmed by 13C NMR analysis, which shows only three resonance signals at δ 34.6, 58.9, and 161.9 ppm. The protonation behavior of 1 was first followed by titrimetric methods, using HCl (0.1N) as a titration standard. Surprisingly, the pH titration curve shows only a single sharp change at the second equivalence point; the change associated with the first equivalence point is indistinct. To further understand this unusual neutralization behavior, we monitored the reaction by using NMR experiments. CT 1 was treated with 1 equiv of aqueous HCl, followed by removal of H2O under reduced pressure to afford colorless crystalline solid. The solid was then redissolved in D2O and analyzed by NMR methods. The 1H NMR spectrum shows four sets of distinctive methylene hydrogen signals, centered at δ 2.36, 2.91, 3.19, and 3.33 ppm in a ratio of 1:1:1:1, respectively. These findings indicate the coexistence of CT 1 and DPCT 4 in a ratio of 1:1; no monoprotonated cryptand (MPCT) 5 was identified according to the 1H NMR analysis. In addition, proton exchange between 1 and 4 is relatively slow on the NMR time scale, and therefore, the average spectrum of 1, and 4 would not be observed. This conclusion was further supported by the 13C NMR analysis. The spectrum shows four distinctive methylene carbon signals and two carbonyl carbon signals. The signals appearing at δ 37.4, 51.1, and 161.1 ppm are wellmatched with the spectrum of 1, while other remaining signals at δ 34.6, 58.9, and 161.9 ppm are consistent with the spectrum of 4. Except for the two minor signals at δ 53.4 and 55.0 ppm that were observed after careful examination of the spectrum, no further compelling evidence for the existence of MPCT 5 was found. Similar results were obtained when direct titration of 1 was performed in D2O, using TsOH-H2O as the standard. (1) (a) Dietrich, B.; Viout, P.; Lehn, J.-M. Macrocyclic Chemistry, Aspects of Organic and Inorganic Supramolecular Chemistry; VCH: New York, 1993. (b) Vögtle, F.; Weber, E. Host Guest Complex Chemistry, Macrocycles: Synthesis, Structures, Applications; SpringerVerlag: Berlin, 1985. (c) Dietrich, B. In Inclusion Compounds; Atwood, J. C., Davies, T. E. D., MacNicol, D. D., Eds.; Academic Press: London, 1984; Vol. 2, p 337. (d) Izatt, R. M.; Pawlak, K.; Bradshaw, J. S. Chem. Rev. 1995, 95, 2529. (2) An, H.; Bradshaw, J. S.; Krakowiak, K. E.; Tarbet, B. J.; Dalley, N. K.; Kou, X.; Zhu, C.; Izatt, R. M. J. Org. Chem. 1993, 58, 7694 and references cited therein. (3) For representative examples, see: (a) Ge, Y; Lilienthal, R. R.; Smith, D. K. J. Am. Chem. Soc. 1996, 118, 3976. (b) Schwiebert, K. E.; Chin, D. N.; MacDonald, J. C.; Whitesides, G. M. J. Am. Chem. Soc. 1996, 118, 4018. (c) Scheerder, J.; Vreekamp, R. H.; Engbersen, J. F. J.; Verboom, W.; van Duynhovers, J. P. M.; Reinhoudt, D. N. J. Org, Chem. 1996, 61, 3476. (d) Hughes, M. P.; Shang, M.; Smith, B. D. J. Org. Chem. 1996, 61, 4510. Scheme 1a