Hydroxylation Reactions of Substituted Cyclohexanes Using FeII Complex-Triethylamine Oxide-Trifluoroacetic Acid (Received January 17, 1986) Substituted cyclohexanes, such as methyl-, ethyl-, and tert-butyl-cyclohexanes, were hydroxylated using a FeII complex -Et3NO-CF3COOH system. The system was well characterized by a regioselective hydroxylation at 3-position except that 4-hydroxy-tert-butylcyclohexane was also formed in the case of tert-butylcyclohexane. On the other hand, stereoselectivity of the hydroxylation was found to depend on the nature of alkyl substituents. The role of FeII complex is discussed. 1. Introduction Biochemical hydroxylation reaction of saturated hydrocarbons is an important process producing a variety of final products and intermediates in biosynthesis. The reaction is well known to be regiospecific and stereospecific.1) In organic syntheses, however, a regioselective and stereoselective hydroxylation reaction has been considered difficult to master.2) Recently, it has been reported1)-3) that a system of FeII complex -Et3NO-CF3COOH catalyzes hydroxylations of alkanes, though it takes part in the reaction in very different manner from a monoxygenase. This reaction involves the formation of carbonium ion of an alkane as an intermediate, followed by trifluoroacetate anion attack on the carbonium ion (see, Eqs. (3)-(7)). The stability of the carbonium ion determines regioselectivity of The reaction system mentioned above, however, has never been studied in terms of its stereochemistry. In this study, hydroxylation reaction of substituted cyclohexanes is reported, especially for the purpose of establishing stereochemistry of the reaction. 2. Experimental 2.1 Procedure A typical hydroxylation was carried out by heating a substituted cyclohexane (10mmol), triethylamine oxide (Et3NO) (18mmol), and FeII complex (1.0mmol) in trifluoroacetic acid (CF3COOH) (40 * To whom correspondence should be addressed. 2.2 Materials Methylcyclohexane, ethylcyclohexane, and tertbutylcyclohexane were purified under nitrogen atmosphere by conventional methods. Trifluoroacetic acid was also distilled under nitrogen before use.
464 FeII acetylacetonate (FeII(acac)2), FeIIIacetylacetonate (FeIII(acac)3), FeIIpolyphthalocyanine (FeII polypc), and FeII, MoIVpolyphthalocyanine (FeII, MoIVpolyPC) were obtained commercially or synthesized by general methods. Authentic samples of trifluoroacetate esters of substituted cyclohexanols were synthesized by esterification of the corresponding cyclohexanols with trifluoroacetic acid in the presence of sulfuric acid. Substituted cyclohexanols were obtained by hydrogenation of the corresponding phenols in the presence of a platinum catalyst. For example, 3-tbutyl-cyclohexanol was prepared as follows: 3-t- Butylphenol (1.0g), platinum oxide (30mg), and hexane (ca. 40ml) as solvent were allowed to be continuously stirred under hydrogen atmosphere at room temperature for a few days. After sufficient amount of hydrogen was uptaken to form 3-t-butylcyclohexanol, the catalyst was removed and unreacted phenol was washed out with 1N aqueous sodium hydroxide. The solution was dried over anhydrous magnesium sulfate and was evaporated. The product, 3-t-butylcyclohexanol, was sufficiently pure. 1-Cyclohexylethanol, on the other hand, was synthesized as follows: To a suspension of lithium aluminum hydride (2g) in ethyl ether (5ml), cooled (1ml) in ethyl ether (5ml) was added in drops, at the constant temperature. After completion of the addition, the ice bath was replaced by a water bath, which then was gradually heated to reflux. The product, 1-cyclohexylethanol, was isolated by addition of water and subsequent extraction with ethyl ether. All of alkyl-substituted cyclohexyl trifluoroacetates were newly synthesized compounds. These were identified by ir, nmr, and elementary analyses. Analyses and nmr data of authentic samples are summarized in Table 1. 3. Results 3.1 Hydroxylation of Methylcyclohexane Hydroxylations of methylcyclohexane were carried out in the presence of several kinds of iron complexes. The results from reactions catalyzed main product of this reaction was 3-methylcyclohexanyl trifluoroacetate, and the other products, if any, were neglected because of insignificance in Table 1 Analyses and NMR Data of Authentic Samples a) Values in parentheses are calculated. b) 13C-NMR data of the carbon having trifluoromethyl carbonyloxy group. c) 1H-NMR data of the methine proton of the same carbon for ethyl-substituted esters. NMR signals were assigned referring the literature.6)
465 comparison with the ester of 3-methylcyclohexanol. The product ester was identified as outlined below. Mass spectrometry showed that products were esters of methyl-substituted cyclohexanols with trifluoroacetic acid (m/e: 210 (P), 141 (CH3-0-OC=O-), 92 (CH3-0), 82 (0), and 69 (CF3)). When the retention times of reaction products by gas-liquid phase chromatography were compared with those of the authentic samples which were synthesized from cyclohexanyl carbinol, 3-methylcyclohexanol, and 4-methylcyclohexanol, the reaction products were identified as trifluoroacetic acid esters of 3-methylcyclohexanol and/or 4-methylcyclohexanol. In addition, 13C-nmr spectrum of the product was compared with those of 3-methyland 4-methylcyclohexanol esters. Main peaks were 39.18, 33.30, 30.45, 28.75, 23.23, and 21.35ppm; 3-methylcyclohexanol ester, 77.79, 75.65, 39.08, 33.04, 30.30, 28.65, 23.23, and 21.39ppm; 4-methylcyclohexanol ester, 77.97, 74.92, 32.07, 30.72, 30.48, 28.65, 20.97, and 13.71ppm. These results strongly suggest that the product is a mixture of trans/cis ester of 3-methylcyclohexanol (see, Table 1). The yield of the product was rather low, but it linearly increased with reaction time (Table 2). Table 3 Effect of the Kind of Fe Complexes on the Stereoselectivity in Hydroxylation of Methylcyclohexane Methylcyclohexane: 11.8mmol, Et3NO: 18mmol, CF3COOH: 40ml, Reaction time: 48hr The configuration, trans (e, a)/cis (e, e), of the product seemed to be independent of reaction factors such as concentration of triethylamine oxide and FeIISO4. These phenomena, also, could be observed replacing FeIISO4 with other iron complexes such as acetylacetonates and polyphthalocyanines. The trans/cis ratios obtained with several iron complexes are summarized in Table 3. The ratios were almost constant, 0.72-0.76, regardless of the kinds of complexes. 3.2 Hydroxylation of Ethylcyclohexane In hydroxylations of ethylcyclohexane, four kinds of products might be expected on the basis of regioselectivity. Only two esters, 3-ethylcyclohexanol and 1-cyclohexanylethanol esters, however, were detected in the reaction mixture. Thus, one of the reaction sites was only 3-position in the cyclohexane ring, while the other was the methylene group of the side chain. Results are shown in Table 4. The stereochemistry of trifluoroacetate group at 3-position was richer in cis (e, e) form in comparison with that of trans (e, a). 3.3 Hydroxylation of tert-butylcyclohexane In a hydroxylation of tert-butylcyclohexane, trans and cis isomers having a trifluoroacetate group at 3- or 4-position were produced. These four products could not be completely separated by means of a gas liquid phase chromatography method, but could be quantitatively determined by 13C-NMR method (see Table 1). Results are shown in Table 5. The reaction gave 3- and 4-tert-butylcyclohexanol esters in selectivity>96%, regardless of the kind of catalyst used, but yields of products ranged from 1.7 to 13.4%, significantly dependent on the nature of the catalyst used. The ratio of regioselectivity of hydroxylation at 3- or 4-position was about 1.0 to 0.5, except for the results obtained in the pre- 4-trans and e, a for 3-traps and 4-cis were preferred. A hydroxylation reaction as mentioned above was Table 4 Hydroxylation of Ethylcyclohexane FeII complex: 1.0mmol, Ethylcyclohexane: 10mmol, Et3NO: 18mmol, CF3COOH: 40ml, Reaction time: 96hr
466 Table 5 Hydroxylation of tert-butylcyclohexanea) a) FeII complex: 1.0mmol, tert-butylcyclohexane: 10mmol, Et3NO: 18mmol, CF3COOH: 40ml, Reaction time: 96hr in the amount of thrice moles per mole of tertbutylcyclohexane. In this case, the ratio of products hydroxylated at 3- to 4-position was 1.0 to 1.7, as compared with 1.0 to 0.52 when no cyclodextrin was added. This suggests that a hydroxylation reaction of tert-butylcyclohexane occurs with inclusion of the cyclohexane in cyclodextrin. 4. Discussion 4.1 Hydroxylation Rates Effect of substituents on rates of hydroxylation may be understood from Tables 2 to 5. When yield of products was in the order of methylcyclohexane>ethylcyclohexane>tert-butylcyclohexane. In the case of FeII, MoIV polyphthalocyanine catalyst, the selectivity of methylcyclohexane seemed to be lower than that of ethyl- and tert-butyl-cyclohexane. To this may be ascribed the fact that reaction time for methylcyclohexane is just half of those for the other cyclohexanes. The above-mentioned order, which is in the reverse order of bulkiness of substituents, suggests that the reaction includes a steric hindrance in its rate determining step. 4.2 Regioselectivity Regioselectivity of hydroxylations for alkyl-substituted cyclohexanes is summarized below (figures in parentheses representing results obtained in the It was found that the hydroxylation reactions was apt to occur at 3-position, as far as the reaction on cyclohexane ring is concerned. But the bulkiest substituent, t-butyl group, also resulted in the hydroxylation of the 4-position, probably due to its steric hindrance. In the case of ethylcyclohexane, the methylene of the ethyl side group was also hydroxylated. This is very interesting, considering that methylene group at 2- or 5-position of a cyclohexane ring is not hydroxylated. This may be based on the difference in the degree of freedom of the methylene groups: the ethyl group is considerably flexible, while the cyclohexane ring is rather rigid. Hydroxylated products can be also formed in the autoxidation of cyclohexanes. The following ratio of positions hydroxylated are reported7) for ethylcyclohexane. Although this ratio suggests flexibility of the ethyl group, it is completely different from that of the product distribution in this work mentioned above. This fact shows that the hydroxylation by Fe(II)- Et3NO does not proceed through a chain reaction
467 mechanism. 4.3 Stereoselectivity Configuration ratio of ((e, a) (e, e)) of hydroxyl groups introduced on cyclohexane rings are shown below. The ratio of (e, a)/(e, e) was almost constant, regardless of the kind of catalysts, but was clearly dependent on the nature of substituents of cyclohexanes. Considering hydroxylation at 3-position, the ratio was 0.72 to 0.76 for the methyl substituent, but about 0.25 for the bulkier substituent such as ethyl and tert-butyl. This suggests that the methyl group does not influence, due to its smaller bulkiness, the key step which determines configuration. When stereochemistry on the ring of ethylcyclohexane is considered, on the other hand, the ratio markedly decreased to 0.21-0.32. The bulkiest substituent, tert-butyl, did not cause the ratio to drop further at 3-position as compared with the ethyl group, but it still was preferred for the formation of the (e, e) product. In addition, it was found that the substituent increased the ratio at 4- position, which is rather far from that of the tertbutyl group. Provide that a generally accepted mechanism8) is applicable to the hydroxylation reaction of this study, the following scheme may be proposed: (3) (4) (5) (6) (7) The reaction includes a substituted cyclohexanyl carbonium ion, which reacts with a trifluoroacetate anion to produce a final product. This esterification mechanism is just the same as that observed in the general acid catalyzed esterification reactions, including the above-mentioned esterification of cyclohexanols in preparation of authentic samples. The decrease in the above-mentioned FeII catalyzed hydroxylation ratio suggests a steric control of the reactivity of a cyclohexanyl carbonium ion with a trifluoroacetate. When this assumption is combined with respect to stereochemistry mentioned above, the existence of an intermediate, such as the complex A shown below, can be reasonably considered. The trifluoroacetate anion attack on complex A in SN2 manner will produce 3-alkylcyclohexanol trifluoroacetate having (e, e) configuration. In concluding, we would like to express our gratitude to Professor Teiji Tsuruta of Science University of Tokyo for the valuable advice provided this work. References 1) Hayaishi, O., Nozaki, M., Science, 164, 309 (1969). 2) Ohkatsu, Y., Kagakukogyo, 34, 754 (1983). 3) Yamamoto, A., Yasumoto, K., Mitsuda, H., Agree. Biol. Chem., 34, 1169 (1970). 4) Christopher, J., Piostorius, E., Axelrod, B., Biochim. Biophys. Acta, 198, 12 (1970). 5) Deno, N. C., Pohl, D. G., J. Am. Chem., Soc., 96, 6680 (1974). 6) Gaudemer, A., "Determination of Configurations by NMR Spectroscopy", in "Determination of Configurations by Spectrometric Methods" Ed. by H. B. Kagan, Vol. 1, p. 44 (1977), Georg Thieme Publishers, Stuttgart. 7) Hoffmann, J., Board, C., J. Am. Chem, Soc., 78, 4973 (1956). 8) Deno, N. C., Jedziniak, E. J., Messer, L. A., Tomezsko, E. S., "The Hydroxylation of Alkanes", in "Bioorganic Chemistry" Ed. by E. E. van Tamelen, Vol. 1, p. 79 (1977), Academic Press, New York.
Keywords Cyclohexane, Hydroxylase model reaction, Hydroxylation, Regioselectivity, Stereoselectivity