FULL PAPER DOI: 10.1002/ejoc.201000828 Exceptional Superbasicity of Bis(guanidine) Proton Sponges Imposed by the Bis(secododecahedrane) Molecular Scaffold: A Computational Study Davor Margetic ´,* [a] Tsutomu Ishikawa, [b] and Takuya Kumamoto [b] Keywords: Guanidines / Basicity / Heterocycles / Dodecahedranes / Density functional calculations The exceptional superbasicity of a series of bis(guanidines) with a bis(secododecahedrane) molecular scaffold was found in the course of a computational study. The 3-syn,13-syn-di- substituted bis(secododecahedrane) skeleton ensures that ni- trogen lone pairs of electrons are in close proximity, and the rigid framework of the polycyclic cage guarantees acid/base properties similar to those of proton sponges. Amine func- tionalization with alkyl substituents, imines, and guanidines leads to high basicity. Based on DFT computations, bis(guan- idine)–bis(secododecahedrane) proton sponges with a (1,3- dimethylimidazolidin-2-ylidene)amino moiety are predicted Introduction The advantages of neutral organic superbases as catalysts have been recognized as a highly important area of organic chemistry nowadays. [1] The most important advantages are their use as a homogeneous catalysts for organic reactions and their environmentally friendly recyclability. Therefore, design and synthesis of novel organic superbases is a rapidly growing field of research. Amongst the strong organic bases, amidines, guanidines, and phosphazenes are widely used. Variation of their substitution patterns and geometri- cal arrangements are the standard methods used to enhance their basicity. A further basicity increase could be achieved by bringing two basic centers to close proximity by means of a rigid framework, as in “proton sponges”. [2] Similar ef- fects determine the high basicity of vinamidine [3] and poly- pyridine [4] proton sponges. For an illustration, the arche- typal Alder’s proton sponge, 1,8-bis(dimethylamino)naphth- alene [5] (1; DMAN) and its guanidine (2 and 3 [6,7] ) and phosphazene and guanidinophosphazene derivatives (4 and 5) [8] are depicted in Scheme 1. It was found that simple o- bis(benzoguanidines) are more basic than 1 itself; however, the geometrical constraints limit their basicity to the lower class of the superbasicity scale. [9] The strong lone-pair re- [a] Laboratory for Physical-Organic Chemistry, Division of Organic Chemistry and Biochemistry, Rueer Bos ˇkovic ´ Institute, Bijenic ˇka c. 54, 10001 Zagreb, Croatia Fax: +385-1-468-01-95 E-mail: margetid@irb.hr [b] Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201000828. Eur. J. Org. Chem. 2010, 6563–6572 © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 6563 to have very high basicities, both in the gas phase and aceto- nitrile. This skeleton provides the highest proton affinity (PA) value among all the aliphatic proton sponges reported (288.7 kcal mol –1 , whereas the gas-phase basicity is 284.3 kcal mol –1 , at the B3LYP/6-311+G**//B3LYP/6-31G* level). In acetonitrile the calculated PA is 319.4 kcal mol –1 and the estimated pK a is 38.5. Substitution of bis(secodode- cahedrane) with the intrinsically more basic nitrogen func- tionalities increases the PA to 316.3 kcal mol –1 and the pK a to 46. pulsion in these systems, in conjunction with a strong intra- molecular hydrogen bonding (IMHB) upon protonation, with the efficient relief of lone-pair repulsion are the key factors for their extraordinary basicity. Significant efforts have been put into development of basic fragments, which can be put together to enhance the basicity of such sys- tems. [10] Scheme 1. Naphthalene proton sponges (experimental values are given in parentheses in kcal mol –1 ). In this respect, new molecular polycyclic frameworks that significantly differ from the traditional proton-sponge top- ology of the aromatic skeleton have been developed. These molecular frameworks retain the close proximity of the ni- trogen lone pairs of electrons, ensure framework rigidity, and acid/base properties similar to those of proton sponges. Illustrative examples include the work by Ganguly on sim-