Oxidation of a-isophorone

Oxidation of a-isophorone (3) with /-butyl hydroperoxide catalyzed by PdfOAc), and N(C2Hj), results in 4 as the only oxidation product. 

Ketoisophorone (KIP) is a key intermediate in the production of nutritional products (e.g. vitamins and carotenoids) and in the flavours and fragrances industries. One option for a technical access to KIP is the catal5rtic oxidation of isophorone (Fig. 16.13). For good selectivity and yield in the oxidation step a thermal isomerisation of a-isophorone to /1-isophorone is necessary. However, in order to avoid this additional step and because the isomerisation equilibrium is strongly in favour of the a-isomer, a direct oxidation of a-isophorone to KIP would clearly be preferred. 

Even though detailed studies of the oxidation of 6-isophorone have led to highly selective homogeneous and some heterogeneous oxidation procedures for the synthesis of KIP, all of them still require the isomerisation of a-isophorone to yS-isophorone. As a-isophorone is readily available and is the thermodynamically more stable isomer, and to avoid this additional and thermodynamically unfavoured reaction, intense efforts have been made to find a direct oxidation of a-isophorone to KIP. 

The non-catalysed direct oxidation of a-isophorone with air is possible, but occurs with low yield. In the presence of transition metal salts or oxides (e.g. of V, Cr, Mn, Fe, Co, Cu, Ni, Rh), KIP can be obtained in moderate yields of 30-40%. Due to competing allyUc oxidation of the exocycUc methyl group, the direct oxidation of a-isophorone to KIP is accompanied by the formation of the structural isomer formylisophorone (Fig. 16.14). 

When the aerobic oxidation of a-isophorone is performed in the presence of heteropoly acids or salts thereof in combination with additives such as copper sulfate and/or molybdenum oxides, a selectivity of 61 % was observed at 83% conversion. Molybdovanadophosphates supported on active carbon also mediate the oxidation of a-isophorone, however in most cases oxidation occurs on the methyl group, affording formylisophorone. 

The nature of the solvent was found to play an important role for the catalytic activity and selectivity in the aerobic allylic oxidation of a-isophorone to KIP with phosphomolybdic acid (PMA). With 0.43 mol% PMA and potassium tert-butoxide as the additive in dimethyl sulfoxide (DMSO) at 115°C, KIP was obtained in 70% selectivity at 99% conversion.Using a ruthenium-porphyrin complex as the catalyst, the oxidation of a-isophorone with 2,6-dichloropyridine N-oxide in dichloromethane at 40°C afforded KIP at 99% selectivity and 75% con-... 

Mn(III) acetate catalyses the allylic oxidation of alkenes to enones with high regio- and chemo-selectivity. Using tert-butyl hydroperoxide, a-isophorone was oxidised to KIP in a 74% yield. Selective allylic oxidation of a-isophorone to KIP was carried out over ruthenium grafted onto MgAl-hydrotalcite using tert-butyl hydroperoxide. In acetonitrile, KIP was obtained in 100% selectivity at up to 74% conversion. 

Similar to the oxidation of yS-isophorone, Li et al. have recently developed a metal- and solvent-free method for the oxidation of a-isophorone to KIP. However,... 

Murphy, E., Schneider, M., Mallat, T., et al. (2001). Enhanced Catalytic Activity and Selectivity in Oxidation of a-Isophorone to Ketoisophorone with Phosphomolybdic Add, Synthesis, 4, pp. 547-549. 

Wang, C., Wang, G., Mao, J., et al. (2010). Metal and Solvent-free Oxidation of a-Isophorone to Ketoisophorone by Molecular Oxygen, Catal. Commun., 11, pp. 758-762. 

Isomerization of jS-isophorone to a-isophorone has been represented as a model reaction for the characterization of solid bases 106,107). The reaction involves the loss of a hydrogen atom from the position a to the carbonyl group, giving an allylic carbanion stabilized by conjugation, which can isomerize to a species corresponding to the carbanion of a-isophorone (Scheme 9). In this reaction, zero-order kinetics has been observed at 308 K for many bases, and consequently the initial rate of the reaction is equal to the rate constant. The rate of isomerization has been used to measure the total number of active sites on a series of solid bases. Figueras et al. (106,107) showed that the number of basic sites determined by CO2 adsorption on various calcined double-layered hydroxides was proportional to the rate constants for S-isophorone isomerization (Fig. 3), confirming that the reaction can be used as a useful tool for the determination of acid-base characteristics of oxide catalysts. 

With its high surface area and the accessibility to the amino groups, chitosan aerogel appeared as a good candidate to play the double role of support for metal complexes and organic base. Silica supported metallophthalocyanine are efficient catalysts for the oxidation of aromatic compounds [139]. The immobilization of hydrosoluble metallophthalocyanines (MPcS with M = Fe or Co) on chitosan aerogels afforded new heterogeneous catalysts for the aerobic oxidation of p-isophorone [140]. 

The oxidation reactions were performed in a closed, mechanically stirred 100 ml glass batch reactor under Ar. For the epoxidation of a-isophorone, 0.2 g catalyst, 9 ml solvent, 7.2 mmol cumene (internal standard) and 77 mmol olefin were introduced into the reactor. The slurry was heated to the reaction temperature and the reaction stauted by adding 13.4 mmol t-butyl hydroperoxide (TBHP, ca. 3 M in isooctane) from a dropping funnel to the vigorously stirred slurry (n = 1000 min ). For the epoxidation of P-isophorone, 20 ml ethylbenzene solvent, 61 mmol P-isophorone, 7.2 mmol cumene and 5.6 mmol TBHP or ciunene hydroperoxide (CHP) were introduced into the reactor in this order. The solution was heated to 80 °C and... 

Influence of solvents and reaction temperature on initial rates and selectivities in the epoxidation of a- isophorone catalyst 20 wt% titania - 80 wt% silica, oxidant TBHP... 

It is also interesting to compare various types of solid catalysts in the epoxidation of a-isophorone. Unfortunately, a real comparison is rather difficult, as the reaction conditions (temperature, oxidant, concentrations) are different for each catalyst. Due to the lack of information, the comparison shown in Table 2 is based only on the productivity, i.e. the amount of isophorone oxide produced in unit time using unit amount of catalyst. Two set of data were chosen for the 20 wt% titania - 80 wt% silica aerogel, and the best published data were chosen for the hydrotalcite [16, 17] and the alumina-supported KF [17, 18]. We assumed that the... 

The epoxide selectivity is considerably lower in the other model reaction, the oxidation of P-isophorone. The acid-catalyzed side reactions could be suppressed by a treatment of the mixed oxide catalyst with a weakly basic salt prior to the reaction. The epoxide selectivity related to the olefin converted could be increased up to 94 % at 90 % peroxide conversion. 

In early vitamin and carotenoid syntheses, the oxidation of j6-isophorone was accomplished by epoxidation of /1-isophorone followed by tbe ring-opening of the epoxide and oxidation (Fig. 16.13). A significant improvement of the three-step synthesis of KIP was made by the one-step liquid phase oxidation of j6-isophorone using oxygen or an oxygen-containing gas in the presence of a transition metal catalyst. In 1975, the aerobic oxidation of j6-isophorone in tbe presence of Cu(II)-or V(III)-acetylacetonate was published, in which KIP was obtained in a yield of up to 55%. ... 

The addition of a tertiary amine (triethylamine) to the reaction mixture of the oxidation of yS-isophorone, catalysed by supported precious metal catalysts (e.g. Ag/C), allowed a yield increase to 11% When pyridine was used as the base and solvent in the V(acac)3-catalysed oxidation with molecular oxygen, up to 91% yield was achieved at 70°C. A combination of the Cu(acac)2-catalysed oxidation in pyridine as the solvent was filed by Hiils AG in 1988 which allowed a decrease in the required amount of base/solvent by a factor of 10, which thus reduces the volume and facilitates the removal of the base. ° ... 

Researchers from BASF developed the Mn(II)-salen- or [Mn(ni)-salen]X-catalysed oxidation of y6-isophorone using salen derivatives with electron-withdrawing substituents without or in the presence of acetates as additives. The increase of ignition temperature of the hase/solvent mixture (ignition point of triethylamine/cUglyme 0°C) and thus a reduction of the explosion risk, was successfully achieved using tripropylamine in dimethylformamide (DMF) or dimethyl acetamide (DMA). With a chloro-substituted [Mn(in)-salen]Cl catalyst in the presence of Uthium acetate and tripropylamine in DMA, KIP was obtained in an 89.4% yield with minor amounts of by-products (1.5% a-isophorone, 1.3% hydroxy-isophorone) (Fig. 16.14). 

In 1975, Ohloff etal. studied the gas-phase oxidation of ot-isophorone to KIP over a vanadia/pumice catalyst modified with 1 wt% of hthium phosphate at 230°C. Under these conditions, simultaneous formation of KIP and formylisophorone occurred. More than 20 years later, Baiker et al. revisited the catalytic gas-phase oxidation of isophorone. At 200-250°C, 75% combined yields of KIP and formyhsophorone were obtained at 17% ot-isophorone conversion over vanadia/pumice impregnated with hthium phosphate j6-isophorone was found as a major by-product (18%). Bismuth molybdate or vanadium phosphate showed poor selectivity and rapid deactivation. The Ag/y-alumina-catalysed oxidation was unselec-tive and resulted mainly in isomerisation to j6-isophorone. Chromia-based catalysts led to an increased formation of 3,5-xylenol. To efficiently remove coke deposits and to re-oxidise vanadium oxides to vanacha, temperatures higher than 300°C would be needed however, under these conditions isophorone and KIP are not stable. Thus, highly selective catalysts would be required which are active at lower temperatures. 

The catalytic oxidation of isophorone (259—261) or P-isophorone (262,263) to ketoisophorone [1125-21 -9] (2,6,6-trimethyl-2-cyclohexen-l,4-dione) has been reported. Ketoisophorone is a building block for synthesis in terpene chemistry and for producing compounds of the vitamin A and E series. 

If desired, the course of the reaction may be followed by means of the optical density of the reaction mixture at 235 m/. The ultraviolet spectrum of isophorone has a maximum at 235 mp (e 13,300) the ultraviolet spectrum of isophorone oxide has a maximum at 292 mju (e 43). A total reaction time of 4 hours under the conditions specified was found to be ample for the complete conversion of isophorone to its oxide. If the conversion is not complete, the product cannot be separated from the unchanged isophorone without recourse to precise fractional distillation. The absence of isophorone from the final product may be verified by examination of the spectrum at 235 mp. 

Reduction of a, ji-epoxy ketones with NaHTe (typical procedure) ji-Epoxy ketonesP To a solution of NaHTe (prepared from Te (1.30 g, 10 mmol) and NaBH (0.90 g, 0.24 mmol)) in EtOH is added isophorone oxide (0.616 g, 4 mmol) in EtOH (4 mL). An instantaneous... 

Noteworthy features of these reactions are the high predominance of E stereochemistry in the case of aldehydes and the good results obtained even with highly enolizable ketones (such as cyclopentanone), a, -epoxy ketones (isophorone oxide) and a,j8-unsaturated compounds (benzalacetophenone and cinnamaldehyde). 

Environmental Fate. Sensitized photolysis studies in water and oxidation/reduction studies in both air and water are lacking, as are biodegradation studies in surface and groundwaters. These kinds of studies are important, since they represent the fundamental removal mechanisms available to isophorone in the environment. In addition, the kinetic studies for the atmospheric reactions are important for understanding the significance of a removal mechanism and predicting the reactions that may control the fate of a chemical in the environment. 

Hydroxy-3,5,5-trimethyl-2-cyclohexen-l-one has been prepared in 22% yield by lead(IV) acetate oxidation of isophorone followed by hydrolysis of the resulting acetate. The HCPBA method gives high yields of both a-hydroxy... 

An analogous process, involving the interaction of a cross-conjugated dienamine with a linear dienamine, has been suggested in the self-condensation of acetone in the presence of pyrrolidine and hydroiodic acid, via the intermediacy of the dienamines of isophorone and mesityl oxide, to give a spiro-diketone43 (Scheme 28). 

A material such as Na°/NaY catalyzes the aldol condensation of acetone, to form mesityl oxide and eventually isophorone. Another strong base catalyzed reaction is the side chain alkylation of toluene with ethylene. In contrast with acid catalysis, side chain reaction is strongly preferred over ring alkylation. With a Na°/NaX in the gas phase at 473 K, toluene reacts to give n-propylbenzene (66%) and the dialkylated product, 3-phenylpentane (32%) (41). 

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