Autocatalytic Decomposition of N-Methylmorpholine N-Oxide Induced by Mannich Intermediates Thomas Rosenau, † Antje Potthast, † Paul Kosma,* ,† Chen-Loung Chen, ‡ and Josef. S. Gratzl ‡ Christian-Doppler-Laboratory, University of Agricultural SciencessVienna, Muthgasse 18, A-1190 Wien, Austria, and North Carolina State University, College of Forest Resources, Biltmore Hall, Raleigh, North Carolina 27695-8005 Received December 1, 1998 N-Methylmorpholine N-oxide (NMMO, 1) is one of the most important amine oxides in organic synthesis. 1 It is frequently used in transition metal catalyzed oxidations of various organic structures. 2 Apart from these applications in the laboratory, it is employed on a large industrial scale as a solvent for cellulose in the textile industry. 3 During our investigations on oxidation reactions, we observed in several instances that NMMO as the oxidant was consumed far beyond the stoichiometric ratio, sometimes in fast exother- mic processes. This excess consumption of 1 appeared to be rather random and did not obviously correspond to any changes in the reaction conditions. Furthermore, in these cases, the formation of large quantities of morpholine (3) was observed. This agrees with data on the formation of morpholine in randomly varying amounts during large-scale industrial applications of NMMO. 4 Despite the differences in these processes, it seemed reasonable to assume common mechanisms that cause decomposition of NMMO under specific reaction conditions. Preliminary experiments showed that this breakdown was much faster than its reaction with a reductant. This could only mean that the decomposition of NMMO was caused by NMMO-derived byproducts present in the system, but not only by the reductant. Further investigations revealed that NMMO is completely inert toward its major degradation products N-methylmorpholine and morpholine and toward minor byproducts, such as formaldehyde (HCHO, 4) or formic acid (HCOOH). However, a stoichiometric mixture of morpholine and HCHO degraded NMMO already when present in catalytic amounts (approximately 0.1% relative to 1), a very surprising result. This decomposition proceeded independent of the solvent used as long as water was present in trace amounts. 5 In all cases, only 3 and 4 were formed as the reaction products. 6 Consequently, the same compounds that induce the decomposition of NMMO are in turn gener- ated in the reaction. To test whether carbenium-iminium ions, i.e., Mannich type intermediates that can be formed from 3 and 4 in neutral and acidic media, 7 are involved in the reaction as active species, we used dimethyl(methylene)iminium iodide (Eschenmoser’s salt, 2), a stable carbenium-iminium com- pound, instead of the morpholine/formaldehyde mixture. As shown in Scheme 1, N-methylmorpholine N-oxide (1) was completely degraded by only 1% of this compound (relative to 1) into morpholine (3) and formaldehyde (4) within 70 min at room temperature, without formation of byproducts. In these reactions NMMO was either dissolved in chloroform or present as a solid. Evidently, catalytic amounts of Mannich intermediates are capable of decomposing NMMO in a “clean” process, 8 a novel reaction that has not been reported so far. Investigations into the reaction kinetics 9 demonstrated that in the case of NMMO and NMMO monohydrate the rates of the degradation of 1 by 1% Eschenmoser’s salt were fast and similar in magnitude (Figure 1, C and B). However, when NMMO‚2.5H 2 O, the second stable NMMO hydrate, 10 † University of Agricultural Sciences-Vienna. ‡ North Carolina State University. (1) Albini, A. Synthesis 1993, 263. (2) For illustrative examples, see: Godfrey, A. G.; Ganem, B. Tetrahedron Lett. 1990, 31, 4825. Suzuki, S.; Onishi, T.; Fujita, Y.; Misawa, H.; Otera, J. Bull. Chem. Soc. Jpn. 1986, 59, 3287. (3) Chanzy, H. J. Polym. Sci. Polym. Phys. Ed. 1980, 1137. (4) Buijtenhujs, F. A.; Abbas, M.; Witteveen, A. J. Papier 1986, 40, 615. Brandner, A.; Zengel, G. H. Chem. Abstr. 1982, 977727d. (5) No reaction was observed in carefully dried solvents if HCHO was supplied as a gas. The water provided by addition of HCHO as a 37% aqueous solution (formalin) was sufficient for the reaction to proceed. On the other hand, larger quantities of water stopped the reaction, e.g., addition of water in the double stoichiometric amount of NMMO. (6) Both morpholine (3) and formaldehyde (4) were identified by compar- ison with authentic samples (NMR, MS). Before analysis, HCHO was char- acterized as 2,4-dinitrophenylhydrazone and dimedone adduct, respectively. (7) Mannich reactions and intermediates have been extensively reviewed, see, for instance: Blicke, F. F. Org. React. 1942, 1, 303. Tramontini, M. Synthesis 1973, 703. (8) A typical experimental procedure is described in the following: To a 0.1 M solution of NMMO (1) in dry dichloromethane or dry chloroform were added 1% (relative to 1) of 2 and after 5 min 1% (also relative to 1) of water. The mixture was stirred at room temperature while flushing with nitrogen to remove the forming HCHO. In intervals of 10 min, a 0.5 mL aliquot was taken and analyzed by capillary ion analysis after extraction into 3 mL of ultrapure water (see ref 9). The reaction was finished when the electro- pherogram showed only morpholine (3), but no remaining starting material. The 0.1 M solution of 1 in the above procedure can be replaced with pure NMMO. Here, the initial reaction temperature has to be set at ap- proximately 100 °C to obtain a melt and then lowered gradually. Similarly, it is possible to substitute 2 and water for morpholine (3) (1% relative to 1) and formaldehyde (4) (1% relative to 1, as 37% aqueous solution). (9) Kinetic measurements were carried out by quantifying NMMO and morpholine with capillary ion analysis. A Waters QE4000 instrument with the following general parameters was used: capillary column 60 cm × 75 μm; indirect UV detection at 214 nm (zinc lamp); hydrostatic sampling, sample time 10s, run voltage 20 kV. The electrolyte was prepared by adjusting a solution of 50 mM 4-methylbenzylamine, 50 mM 2-hydroxy-2- methylpropanoic acid (hydroxy-isobutyric acid), and 20 mM 18-crown-6 in ultrapure water to a pH of 3.3 ( 0.1 with additional hydroxy-isobutyric acid. Compounds 1 and 3 can be determined in the concentration range of 0.005 M to 2.5 and 0.001 M to 1.0 M, respectively. The identity of the product was confirmed by NMR. Scheme 1 Figure 1. Degradation of NMMO into morpholine and HCHO by Eschenmoser’s salt (2). Decrease in NMMO concentration followed by capillary ion analysis: (A) NMMO, 1% 2, addition of acid; 11 (B) NMMO‚H2O, 1% 2, no additives; (C) NMMO, 1% 2, no additives; (D) NMMO, 1% 2, addition of base. 12 2166 J. Org. Chem. 1999, 64, 2166-2167 10.1021/jo982350y CCC: $18.00 © 1999 American Chemical Society Published on Web 03/11/1999