Clay Minerals (1983) 18, 437-445. SOME ORGANIC SYNTHESES WITH CLAY-SUPPORTED REAGENTS A. C O R N E L I S , P. L A S Z L O AND P. P E N N E T R E A U Universit~ de Liege, Institut de Chimie Organique B6, Sart- Tilman, B-4000 Liege, Belgium (Received 13 May 1983) A B S T R A C T : Some uses of clay-supportedreagents in fine organic synthesis are discussed, in particular the catalysis of the phase-transferpreparation of formaldehydeacetals by quaternary ammonium montmorillonites. The preparation and some applications of clay-supported ferric nitrate, a new reagent which oxidizes alcohols into carbonyl derivatives, couples thiols into disulphides, nitrates phenols, and oxidatively couples pyrrole and benzaldehyde into tetraphenylporphyrin, are also described During the last few years, organic chemists have paid considerable attention to organic reactions effected by reagents immobilized on highly-divided solids, for which the name 'supported reagents' has been coined (Posner, 1978; McKillop & Young, 1979; Frechet, 1981). These reagents may be placed in two groups depending on the nature of the support. 1. The support is an organic polymer to which, usually, the reagent is covalently bound. The archetype of such polymer-supported reagents is the famous Merrifield resin (Merrifield, 1963), which consists of a chloromethylated copolymer of styrene and divinylbenzene. 2. The support is an inorganic array, such as graphite, alumina, silica, various metal oxides or clays. In general, the reagent is adsorbed on, or intercalated within, such an inorganic matrix. A well-known, widely-used supported reagent of this second group is silver carbonate precipitated on celite (F&izon & Golfier, 1968). The reactions performed with such reagents frequently display an increase of selectivity when compared to the analogous homogeneous reactions. They also imply milder conditions, and simpler and more economical set-up and work-up as they mainly use ordinary solvents in open flasks. Separation of products requires only a simple filtration. In some cases the presence of the support activates an otherwise inert reagent or substrate. The novel applications of clay minerals towards organic syntheses developed in our laboratory belong to this second category and we describe here: (i) the use of quaternary ammonium clays as phase-transfer catalysts, and (ii) the potentialities for oxidation reactions of a new reagent--clay-supported ferric nitrate ('clayfen'). 1983 The Mineralogical Society 438 A. Corndlis et al. QUATERNARY A M M O N I U M C L A Y S AS P H A S E - T R A N S F E R CATALYSTS Phase-transfer catalysis is a preparative technique which has provoked considerable interest among organic chemists during the last decade (Caub6re, 1982; Dehmlow & Dehmlow, 1980; Starks & Liotta, 1978; Weber & Gokel, 1977). It is based on the extraction of an anionic reactive species, A-, from an inorganic phase (often a water solution) into an organic, non-miscible phase, in which it reacts with its target molecule, BX. inorganic phase (aqueous) organic phase Q+X- + A- --, Q+Ai. 1 Q+X- + AB ,- Q+A- + BX The extraction is effected by ionic coupling with a positively charged, lipophilic carrier Q+, most often a quaternary ammonium cation. The latter is introduced as a salt, Q+Y ; in order to minimize interferences between Y- and the active species A-, it is important to insure that the counterion Y- (or its degradation products) have (i) minimum nucleophilicity and (ii) maximum hydrophilicity. We reasoned that a quaternary ammonium montmorillonite would combine the potential for release of an active onium moiety Q+ with an almost ideal counterion, provided by the clay polyanionic sheets or their degradation products. Thus it should be a suitable phase-transfer catalyst. The same idea was formulated independently by Monzef-Mirzai & McWhinnie (1981). We tested this working hypothesis on the synthesis of symmetrical formaldehyde acetals, which we needed in connection with our continuing interest in the complexing of cations by polyethers (Corn61is et al., 1978; Bouquant et al., 1982) or other chelating agents (Chalais et al., 1983). Such molecules are accessible in good yields by published procedures, including phase-transfer processes (Dehmlow & Schmidt, 1976). Nevertheless, we wanted to elaborate a phase-transfer procedure, with a clay catalyst, in order to dispense with the necessity of using powdered potassium hydroxide. Tixogel VP, a quaternary ammonium montmorillonite employed in the paint industry, was the catalyst we chose. With it, we prepared the desired acetals in good yields (Table 1) by reaction of alcohols with dihalomethanes in the presence of 50% aqueous sodium hydroxide, according to the reaction (Corn61is & Laszlo, 1982): CH2X 2 + 2ROH + 2NaOHTTXOGEL a VP CHE(OR)2 + 2NaX. (aqueous) With phenols, secondary aliphatic alcohols, or in the presence of a nitrogen heterocycle, our procedure does not afford satisfactory yields. Organic syntheses with clay 439 TABLE 1. Formaldehyde acetals from dihalomethane and alcohols (Corn61is & Laszlo, 1982) Acetal ~ o ~ o C2X 2 ~ A. .oAo A. @ovo. CLAY-SUPPORTED Isolatedyield (%) CH2CI2 95 CH2CI2 83 CH2CI2 80 CH2CI2 77 CH2Br2 58 CH2Br2 79 FERRIC NITRATE The reagent Clay-supported ferric nitrate, 'clayfen', is a promising new reagent made in our laboratory (Corn61is & Laszlo, 1980). Whereas the use ofiron(III) nitrate as a catalyst for organic reaction is not unusual (for a recent example see Perumal & Baker, 1980), we are not aware of any previous application of this salt as a reagent for the preparation of fine organic chemicals. In addition to some elementary physico-chemical considerations, the rationale for its initial selection as a potential guest for a clay was its low cost and ready availability. The K-10 host was chosen after a few empirical tests, on the basis both of its strong acidity and of its ease of manipulation during the various stages of the process. Moreover, its availability from industrial suppliers gave us the assurance of invariable specifications. The 'clayfen' reagent is prepared by dissolution of iron(III) nitrate nonahydrate in acetone, which results in a clear, rust-coloured solution which rapidly decays to a muddy, light-brown suspension to which the K-10 catalyst is added. (The proportions are 45 g of Fe(NO3) 3. 9H20 in 750 ml of acetone for 60 g of K-10 clay.) The solvent is removed with a rotatory evaporator under water-pump vacuum at 50~ affording a free-flowing yellow powder. The freshly prepared reagent shows maximum chemical reactivity. For some applications, however, aged reagent (up to two weeks old) may be used, at the expense of the rapidity of the process. For most applications, the typical experimental procedure achieves both simplicity and low cost. 'Clayfen' is added, while stirring, to the substrate dissolved in an appropriate solvent (a hydrocarbon, if possible). Stirring is continued, with heating if necessary, until the reaction is complete. A simple filtration then affords a solution from which the products are recovered by solvent evaporation. Some reactions result in the evolution of NO and must be carried out under a fume hood. A. Corndlis et al. 440 Oxidation of alcohols 'Clayfen' converts alcohols into carbonyl compounds under mild reaction conditions (Cornblis & Laszlo, 1980). The overall reaction is best represented as: 3RIR2CHOH + 2H § + 2NO~- ~ 3R1R2CO + 2NO + 4HzO With the exception of primary alcohols, which result in complex mixtures, excellent yields of carbonyl compounds are obtained (Table 2), with a remarkable absence of other oxidation products in the case of benzyl alcohol. From a mechanistic point of view, we have demonstrated (Corn61is et al., 1982) that nitrous acid esters are intermediates of the reaction, which involves at least the following two steps: R~R2CHOH - , R 1 R 2 C H N O RIR2CHNO -, R1RECO (step 1) (step 2) The 'clayfen' reagent is essential in the first step; control experiments wRh ferric nitrate alone, or with the association of K-10 and another nitrate (NaNO~ or NH4NO ~) show little or no reaction. TABLE 2. Carbonyl compounds from alcohols (Corn61is & Laszlo, 1980). Carbonyl compound ~ ~ Isolated yield O H 86 83 0 65* 80* ~ O O * From the mixture of epimeric alcohols 82* Organic syntheses with clay 441 In the second step, control experiments demonstrate that the K-10 clay alone is sufficient to promote the reaction. These experimental observations are accounted for fairly well by a mechanism analogous to that proposed by Barton et al. (1967) for the acid-catalysed decomposition of alkyl nitrites: R1R~CHONO ~ H§ H ~ RIRzCHONO ~RIRzCHOH + NO + O II R1RECHONO + NO + ~ R1R2C'~ ('N I~' "NI 0 H --, RxR2C = O + H + + 2NO Study of the nitrites formed from cis and trans 4-t-butyl-cyclohexanols or from optically-active 2-octanol shows that the first step is stereospecific, with retention of configuration of the starting alcohol. Such behaviour suggests that 'clayfen' acts as a source of nitrosonium NO + ions. Organic nitrites are also key intermediates in the Barton reaction, an important process in steroid chemistry (Barton & Beaton, 1961). Since our preparation of nitrites using 'clayfen' is so convenient, this remote functionalization reaction becomes a prime candidate for extension of our work. Oxidative coupling of thiols In order to test the nitrosating abilities of 'clayfen' we have investigated its efficiency in the coupling of thiols into disulphides. A priori, two pathways, at least, are possibilities in a 'clayfen' environment: (i) oxidation by Fe 3+, a well-documented reaction (Capozzi & Modena, 1974), (ii) conversion to thionitrites, with subsequent homolytic decomposition, according to RSH + NO + -, RSNO + H + RSNO -, RS" + NO 2RS" -, RSSR or some variant of this scheme (Van Zwett & Kooyman, 1968; Barrett et al., 1965; Oae et al., 1977; Aldred et al., 1982). When 'clayfen' is added to a hydrocarbon solution of a thiol, an intense colouration develops which is indicative of thionitrite formation. A sudden evolution of nitric oxide follows, accompanied by discolouration. Work-up affords the expected coupling product, with fair to excellent isolated yields (Table 3). The intermediacy of the thionitrite was unambiguously established for the reaction of triphenylmethanethiol: the corresponding thionitrite was identified and its quantity determined in the quenched reaction medium by UV spectral analysis. It represented a significant fraction (10%) of the starting thiol. Moreover, an authentic sample of this thionitrite (Van Zwet & Kooyman, 1968), exposed to 'clayfen', was coupled into the corresponding disulphide. These arguments, even if they do not preclude the possibility of a competition from Fe 3+ oxidation, establish undoubtedly that the thionitrite route contributes significantly, if not 442 A. Corndlis et al. TABLE 3. Disulphide from thiols and thiophenols (Corn61iset al. 1983). Disulphide (C6H5S)2 (4 NO2C6H4S)2 (2,4,5 Cl3C6HzS)2 (C6H~CH2S)2 ((C6H5)3C8)2 (n C4H98)2 (/ C3H78)2 (t C4H95)2 Isolated yield (%) 97 58 80 85 65 88 39 0 solely, to the observed coupling. This conclusion is also consistent with the original hypothesis: in this reaction, forming disulphide from thiols, 'clayfen' appears again to serve as a source of nitrosonium NO + ions. Nitration of phenols The coexistence in 'clayfen' of the ability to produce nitrosonium ions, and a significant concentration of nitrate ions suggests that it may, to some extent, mimic the properties of NzO 4, via the coupling (Oae et al., !977): NO + + NO]- = N 2 0 4 N204 is known to effect nitrations (Ross et al., 1980; Riebsomer, 1945). Moreover, there is a constant interest in the chemistry of nitrogen oxides as substitutes for highly corrosive reagents such as hot mixtures of nitric and sulphuric acids, as used in industry. Such reagents are costly both in terms of energy and of capital investments (Audley et al., 1982; Seifert, 1963). We therefore decided to explore the potentialities of 'clayfen' for nitration of aromatics such as phenols, a most important process, for which there are yield and selectivity problems (Ouertani et al., 1982). Our preliminary results (Table 4) indicate that 'clayfen' carries out efficient mono-nitration of various phenolic derivatives, with, in some examples, remarkable regioselectivity. It should be noted that in toluene, in which it is insoluble, ferric nitrate is not a nitration agent unless it is associated with the clay. So, whenever it is possible to use that peculiar solvent, we can obtain excellent yields coupled with a remarkable ease of work-up. Synthesis of porphyrins This application of 'clayfen' belongs in a different category to those just described. It illustrates the remarkable versatility of this new reagent. The idea of using 'clayfen' for such a purpose arose from linking several facts. 1. The reaction of equimolar amounts of pyrrole and benzaldehyde on the surface of montmorillonite, in various cationic forms, leads to a strongly adsorbed porphomethene, from which tetraphenylporphyrin may be obtained by desorption and aging (Cady & Pinnavaia, 1977). According to our own experience, the desorption is extremely difficult to achieve, and this precludes, in the present state of the art, the use of this method for preparative purposes. Organic syntheses with clay 443 TABLE4. Nitrophenolsfrom phenols. Solventused in parentheses. Phenol Nitrophenol OH Isolated yield (%) OH I ~ NO2 39 (ether) 36 (toluene) OH 41 (ether) 27 (toluene) NO: OH OH NO2 CH 3 CH3 OH OH 0 2 N ~ ~CH3 58 (ether) 20 (ether) CH3 OH ~ CH3 34 (ether) NO2 88 (ether) NO2 - - (THF) 65 (toluene) NO2 OH CI OH OH C1 OH 2. In the presence of montmorillonite, starting from various forms of tetraphenylporphyrin, the free base may be released in chloroformic solution (Bergaya & Van Damme, 1982). 3. Adler et al. (1968) have clearly established that the coupling reaction of benzaldehyde and pyrrole into tetraphenylporphyrin requires an oxidant which, in the classical acid-catalysed synthesis, is atmospheric oxygen. Since 'clayfen' combines a clay structure and a high surface acidity with the oxidizing character of ferric nitrate, we reasoned that it might promote formation of tetraphenyl- 444 A . C o r n ~ l i s et al. porphyrin from pyrrole and benzaldehyde, and would release the adduct into the chloroform solvent. We did observe that when a chloroform solution of benzaldehyde and pyrrole was treated with 'clayfen' a complex mixture of pigments containing ~0.5% (based on pyrrole starting material) of the expected porphyrin formed within minutes. Fortunately, the mixture is easy to separate, and the porphyrin is easily recovered, almost quantitatively, by a non-chromatographic work-up. While promising, this new method is not yet competitive compared with the classical synthesis, but we are actively improving it, and are optimistic that we may achieve this goal. CONCLUSIONS We have presented some examples of the use of clay-supported reagents for organic synthesis, which reflect current interests of our laboratory. In our opinion, phase-transfer catalysis by quaternary a m m o n i u m exchanged clays is a viable and promising process. Nevertheless, the examples to which it has been applied to date do not allow us to conclude that there is yet a clear-cut superiority over conventional catalysts. On the other hand, clay-supported ferric nitrate ('clayfen') shows a surprisingly widespread reactivity which still remains largely unexplored and almost totally unexplained. 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