4230 J. Org. Chem. 1987,52, 4230-4234 An Assessment of the Causes of the “Cesium Effect” Gerard Dijkstra, Wim H. Kruizinga, and Richard M. Kellogg* Department of Organic Chemistry, University of Groningen, Nijenborgh 16, Groningen 9747 AG, The Netherlands Received December 4, 1986 Cesium alkanoates (chiefly the propionate) have been investigated for their solubility, nucleophilic reactivity, and degree of ion pairing in dimethylformamide (DMF) and, in some cases, dimethyl sulfoxide (DMSO) solutions. 133Cs NMR has been used to establish the degree of ion pairing. From the data obtained it is concluded that the cesium ion is virtually completely solvated and that the carboxylates are essentially free and highly reactive. The consequences of this effect on macrocyclization by means of nucleophilic substitution are discussed. Introduction The cesium salts of some weak organic acids are useful for synthetic purposes. These are readily obtained on reaction with cesium carbonate, the most basic of the alkali carbonates of the group I metals.’ Carboxylic acids,2 phenol^,^ thiol^,^ sulfonamide^,^ some ureas,3 and 1,3-di- carbonyl compounds6 are deprotonated to form the cor- responding cesium salts. The choice of cesium carbonate rests on practical considerations, particularly the ease of handling and low hygroscopicity relative to the hydroxide. These cesium salts, usually dissolved in a dipolar aprotic solvent like dimethyl formamide (DMF), exhibit reactivity characteristics that have been dubbed the “cesium effe~t”.~~~,~ This term is used nowadays with reference to either or both of two different synthetic phenomena. As first employed, the term applied to the readiness with which cesium carboxylates dissolved in DMF could be alkylated with alkyl halides.2 This approach is used to anchor the carboxylate end of a peptide to be synthesized by the Merrifield method to benzyl chloride entities in a polystyrene polymer.’-9 Cesium carboxylates, (thio)- phenolates, thiolates, and amides subsequently have been shown to be well suited for sN2 displacement on primary and secondary halides, mesylates, and tosylates.’OJ1 Even for racemization prone compounds clean SN2 inversion can usually be realized. But “cesium effect” refers also to a more spectacular phenomenon. As illustrated schemati- cally in eq 1, many macrocycles, often those with very large rings and relatively apolar chain components, can be ob- tained by ring closure via an intramolecular anionic SN2 substitution of an appropriate precur~or.~,~,~~ Zntermo- (1) (a) Properties of cesium carbonate: Gmelin’s Handbuch der Anorganischen Chemie, 8th ed.; Verlag Chemie: Weinheim, FRG, 1936; Vol. 25, pp 234-236. (2) Gisin, B. F. Helu. Chim. Acta 1973, 56, 1476. (3) Van Keulen, B. J.; Kellogg, R. M.; Piepers, 0. J. Chem. Sot., Chem. Commun. 1979, 285. (4) (a) Buter, J.; Kellogg, R. M. J. Org. Chem. 1981, 46, 4481. (b) Buter, J.; Kellogg, R. M. Org. Synth., in press. (c) Lemaire, M.; Vriesema, B. K.; Kellogg, R. M. Tetrahedron Lett. 1985,6, 3499. (d) Vriesema, B. K.; Lemaire, M.; Buter, J.; Kellogg, R. M. J. Org. Chem. 1986,51, 5169. (5) Vriesema, B. K.; Buter, J.; Kellogg, R. M. J. Org. Chem. 1984, 49, 110. (6) In ethanolic solution, ethyl acetoacetate, diethyl malonate, and tosylmethyl isocyanide are slowly deprotonated by cesium carbonate: Van Keulen, B. J., unpublished results. (7) Wang, S.-S.; Gisin, B. F.; Winter, D. P.; Makofske, R.; Kulesha, J. D.; Tzougraki, C.; Meienhofer, J. J. Org. Chem. 1977, 42, 1286. (8) Klieser, B.; Rossa, L.; Vogtle, F. Kontakte (Darmstadt) 1984,1, 3. (9) Rajasekharan Pillai, V. N.; Mutter, M. Top. Curr. Chem. 1982, 106, 119. (10) (a) Kruizinga, W. H.; Strijtveen, B.; Kellogg, R. M. J. Org. Chem. 1981,46, 4321. (b) Lerchen, H.-G.; Kunz, H. Tetrahedron Lett. 1985,26, 5257. (c) Huffman, J.; Desai, R. Synth. Commun. 1983, 13, 553. (d) Torisawa, Y.; Okabe, H.; Ikegami, S. Chem. Lett. 1984, 1555. (e) For a somewhat different application, see: Keinan, E.; Eren, D. J. Org. Chem. 1986, SI, 3165. (f) Cainelli, G.; Manescalchi, F.; Martelli, G.; Panunzio, M.; Plessi, L. Tetrahedron Lett. 1985, 26, 3369. (11) Strijtveen, B.; Kellogg, R. M. J. Org. Chem. 1986, 51, 3664. (12) Kruizinga, W. H.; Kellogg, R. M. J. Am. Chem. SOC. 1981, 203. 5183. 0 cs X= C02.S.TsN Y= halide.OTs.OMs.etc lecular substitution is suppressed relative to the intra- molecular process. Extensive synthetic applications of this effect have been made.13 A related observation is summarized in eq 2. Very large (20-30-membered) macrocycles with extensive sections composed of polyethylene glycols are formed in remarkably good yields in the presence of cesium fluoride.14 The H -Fa ,.@ Jn - J” powerful hydrogen bond forming potential of fluoride clearly aids in activating the hydroxyl group as a nucleo- phile,15 and the cesium ion, relative to other alkali metal cations, appears to direct the reaction in an intramolecular fashion. Although these two sorts of “cesium effect” both involve sN2 nucleophilic substitutions, there are fundamental differences between the types of reactions involved. The effectiveness of intramolecular ring closure is governed by the effective molarity (E.M.), hintrahinte;l. For structurally unappended macrocyclic rings with 13 or more members E.M. values of roughly 5 X M are typical.16 However, ~ ~~ ~~~ (13) (a) Barbier, M. J. Chem. Sot., Chem. Commun. 1982, 668. (b) Potts, K. T.; Cipullo, M. J. Org. Chem. 1982, 47, 3038. (c) Hosseini, M. W.; Lehn, J. M. J. Am. Chem. SOC. 1982,104, 3524. (d) Vogtle, F.; Klieser, B. Synthesis 1982, 294. (e) Dietrich-Buchecker, C. 0.; Sauvage, J. P. Tetrahedron Lett. 1983,24,5091. (0 Dietrich-Buchecker, C. 0.; Sauvage, J. P.; Kintzinger, J. P. Tetrahedron Lett. 1983, 24, 5095. (g) Dietrich- Buchecker, C. 0.; Sauvage, J. P.; Kern, J. M. J. Am. Chem. SOC. 1984, 106,3043. (h) Sauvage, J. P.; Weiss, J. J. Am. Chem. SOC. 1985,107,6108. (i) Weber, E.; Josel, H.-P.; Puff, H.; Franken, S. J. Org. Chem. 1985, SO, 3125. 6) Vogtle, F.; Klieser, B. Synthesis 1982, 294. (k) Vogtle, F.; Bockmann, K. Chem. Ber. 1981, 114, 1048. (1) Klieser, B.; Vogtle, F. Angew. Chem. 1987,94,632. (m) Vogtle, F.; Meurer, K.; Mannschreck, A.; Stuhler, G.; Puff, H.; Roloff, A.; Sievers, R. Chem. Ber. 1983, 126, 2630. (n) Cram, D. J.; Kasbach, S.; Kim, V. H.; Baczynsky Kalleymeyn, G. W. J. Am. Chem. SOC. 1985,107, 2575. (0) Weber, E.
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