Abstract:
Primary hydroxyl groups in a substrate having both primary and secondary hydroxyl groups can be selectively oxidized to carbaldehyde and/or carboxyl groups by contacting the substrate with a cyclic nitroxyl compound in the presence of a peroxosulfate as a co-oxidant and by carrying out the reaction at a temperature below 30° C. and at a pH below 9. The process is halogen-free and metal-free and is especially suitable for oxidizing polysaccharides.

Description:
This application claims priority under 35 U.S.C. §§ 119 and/or 365 to 00204483.2 filed in Europe on 13 Dec. 2000 and U.S. Provisional Application No. 60/255,899 filed on 18 Dec. 2000; the entire content of which is hereby incorporated by reference. 
    
    
     FIELD OF THE INVENTION 
     The invention relates to the selective oxidation of primary alcohols, using an oxidizing agent in the presence of a catalytic amount of a di-tertiary-alkyl nitroxyl compound, especially 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO). 
     BACKGROUND ART 
     Such a process is known from  Tetrahedron Lett . 34, 1181-1184 (1993), which describes the oxidation of monosaccharides wherein the non-primary hydroxyl groups are partly protected, using sodium hypochlorite, potassium bromide and TEMPO in a two-phase solvent system (dichloromethane and water) to produce the corresponding uronic acid. WO 95/07303 describes a process for oxidizing carbohydrates with hypochlorite and TEMPO, using a pH of 9-13 in an aqueous median. The oxidation of carboxymethyl and hydroxyethyl derivatives of starch and cellulose and other starch ethers with TEMPO is described in WO 96/38484. 
     These prior art oxidations have the advantage of being selective, in that oxidation of primary alcohol groups is strongly favored over oxidation of secondary alcohol groups. However, the known processes use hypochlorite as the actual oxidizing agent and thus produce chloride and some chlorinated byproducts: for complete oxidation of primary alcohols to carboxylic acids, two molar equivalents of hypochlorite are used and two molar equivalents of chloride are produced. WO 99/57158 describes the oxidation of carbohydrates using TEMPO and peracetic acid in the presence of bromine. 
     Recently, Kochkar et el. ( J. Catalysis  194, 343-351 (2000)) described the TEMPO-mediated oxidation of α-methyl-D-glucoside (α-MDG), 1,2-propanediol, saccharose and starch with ammonium peroxodisulfate in the presence of a supported sliver catalyst in water at pH 9.5 at 25° C. The oxidation of α-MDG and propanediol was successful (78% conversion and 99% selectivity for oxidation of primary hydroxyl group for α-MDG, 90% conversion and 75% selectivity for propanediol), but the oxidation of saccharose was mediocre (20% conversion) and oxidation of starch was unsuccessful (less than 1% conversion). In the absence of the silver catalyst, the TEMPO oxidation of α-MDG with peroxodisulfate was poor (9% conversion), while replacing peroxodisulfate by Oxone® (2KHSO 5 .KHSO 4 .K 2 SO 4 ) in the presence of silver resulted in only 6% conversion. Thus the teaching of this prior art is that the utility of persulfates for oxidizing primary alcohols is restricted to small substrate molecules and practically to the use of ammonium peroxodisulfate, and that the assistance of a silver catalyst is mandatory. The oxidation of benzyl alcohol and other alcohols with TEMPO and Oxone® in organic solvent to produce aldehydes end ketones was described by Bolm et al. ( Org. Lett  2. 1173-1175 (2000)). 
    
    
     BRIEF DESCRIPTION OF THE INVENTION 
     It was found now that the TEMPO-mediated selective oxidation of primary alcohol functions can be carried out without using equivalent amounts of chlorine compounds and with high conversion rates, using a peroxosulfate as a co-oxidant. The process of the invention is characterized by being performed under mild conditions (pH below 9 and temperature below 30° C.), in the substantial absence of a metal catalyst. When carried out on polysaccharides, the reaction proceeds with little, if any, depolymerization. The pH is preferably between 6 and 9, most preferably between 6.5 and 8.5, and the temperature is preferably below 25° C., most preferably below 15° C. It is preferred that the peroxosulfate is added carefully, in order to avoid local side-reactions. 
     DETAILED DESCRIPTION OF THE INVENTION 
     In the following description, reference is made to TEMPO only for the sake of simplicity, but it should be understood that other cyclic and/or di-tert-alkyl nitroxyls, such, as 4,4-dimethyloxazolidine-N-oxyl (Doxyl), 2,2,5,5-tetramethylpyrrolidine-N-oxyl (Proxyl) and 4-hydroxy-TEMPO and derivatives thereof, especially 4-acetamido TEMPO, and those described in WO 95/07303 can be substituted for TEMPO. The catalytic amount of nitroxyl is preferably 0.1-10%, more preferably 0.2-3% by weight, based on the primary alcohol, or 0.1-10 mol % (0.2-3%) with respect to the primary alcohol. 
     The peroxosulfate present in the process of the invention serves for regenerating TEMPO. The peroxosulfate may be a straight peroxomonosulfate, MHSO 5 , M 2 SO 5  or the persulfuric acid H 2 SO 5 , wherein M is an alkali metal or other metal (taking account of its valency in the formula), ammonium or substituted ammonium. Most preferably, the peroxosulfate is Oxone® (2KHSO 5 .KHSO 4 .K 2 SO 4 ), which is commercially available. It is not necessary and not recommended to use any halogen, as a co-oxidant. The amount of peroxosulfate is equivalent to the amount of primary hydroxyl groups to be oxidized. If complete oxidation of —CH 2 OH groups to carboxyl groups —COOH is desired, 2-2.4 moles of peroxosulfate per mol of primary hydroxyl groups is advantageously used. 
     The process of the invention results in oxidation of primary alcohols initially to the corresponding aldehydes, and eventually to the corresponding carboxylic acids. In general, the second oxidation step, from aldehyde to carboxylic acid, proceeds at a faster rate than the first step, i.e. the oxidation from alcohol to aldehyde. Under usual experimental conditions, the maximum fraction of aldehyde functions present will be below about 10 (based on the number of primary hydroxyls available for oxidation). The present process is especially favorable for the selective oxidation of primary hydroxyl groups in alcohols having a secondary alcohol function in addition to the primary alcohol, such as 1,6-octanediol, 1,9-octadecanediol, sugar alcohols, glycosides, and in particular carbohydrates having primary alcohol functions, especially polysaccharides having chain lengths of at least 5 anhydroglycose units, such as glucans (starch, cellulose), furanofructans, galactans, (galacto)mannans, and the like. A particular group of compounds suitable for oxidation with the present process are hydroxyalkylated, especially hydroxyethylated carbohydrates such as hydroxyethyl starch or hydroxyethyl inulin. These derivatives result in an alternative way for producing formylmethyl and carboxymethyl carbohydrates. 
     The oxidation of carbohydrates containing primary hydroxyl groups results in the corresponding carbohydrates containing aldehydes and/or carboxylic acids with intact ring systems. Examples include α-1,4-glucan-6-aldehydes, β-2,1-fructan-6-aldehydes and β-2,6-fructan-1-aldehydes, with the corresponding carboxylic acids. Where these products still contain the aldehydes, they are useful intermediates for functional carbohydrates wherein the aldehyde groups are further reacted with e.g. amine compounds and the like. They are also useful intermediates for crosslinked carbohydrates, in which the aldehyde groups are further reacted with e.g. diamine reagents. 
     EXAMPLES 
     Example 1 
     Potato starch (3.0 g, 18.5 mmol anhydroglucose units) was gelatinized in demi-water (200 ml) at 95° C. with effective mechanical stirring. 4-Acetamido-TEMPO (61 mg, 0.29 mmol) was added and dissolved. The solution was cooled on ice and the temperature was maintained ≦10° C. throughout the reaction. The reaction was initiated by the addition of Oxone® (11.38 g, 2 mol HSO 5 /mol primary alcohol), which was added under mechanical stirring in small portions throughout the oxidation to minimize unwanted side reactions. After each addition of the acidic oxidant, pH was raised to 8.2 and then kept constant by the addition of 0.5 M NaOH using a pH stat apparatus. After completion of the reaction (8-10 hours), the remaining aldehyde intermediates were reduced to the starting alcohol using 150 mg of NaBH 4 . After one hour, pH was adjusted to Ca. 6.0 with 0.5 M HCl and the reacted polysaccharides were precipitated in 2 volumes of ethanol, filtered off, and re-dissolved in 50 ml of water. Finally the materials were freeze-dried. The conversion of the primary hydroxyls to carboxyls was estimated by  13 C NMR to be 60 mol %. 
     Example 2 
     Methyl α-D-glucopyranoside (1.0 g, 5.1 mmol) and 4-acetamido-TEMPO (20 mg, 0.09 mmol) were dissolved in water (50 ml). The solution was cooled on ice and the temperature was maintained at ≦10° C. throughout the reaction. The reaction was initiated by the addition of Oxone® (3.17 g, 2 mol HSO 5   − /mol primary alcohol), which was added in small portions under mechanical stirring throughout the oxidation to minimize unwanted side reactions. After each addition of the acidic oxidant, pH was raised to 8.2 and then kept constant by the addition of 0.5 M NaOH using a pH stat apparatus. After completion of the reaction (6-8 hours), the remaining aldehyde intermediates were reduced to the starting alcohol using sodium borohydride (100 mg). After one hour, pH was adjusted to ca. 6.0 with 0.5 M MCl. Finally the materials were concentrated by rotary evaporation and freeze-dried. The conversion of the primary hydroxyls to carboxyls was estimated by  13 C NMR to be 62 mol %. 
     Example 3 
     Amylopectin (waxy starch maize) (3.0 g, 18.5 mmol anhydroglucose units) was gelatinized in demi-water (200 ml) at 95° C. with effective mechanical stirring. 4-Acetamido-TEMPO (61 mg, 0.29 mmol) was added and dissolved. The reaction was initiated by the addition of Oxone® (11.38 g, 2 mol HSO 5   − /mol primary alcohol), which was added under mechanical stirring in small portions throughout the oxidation to minimize unwanted side reactions. The reaction procedure was identical to that in Example 1. The conversion of the primary hydroxyls to carboxyls was estimated by  13 C NMR to be 58 mol %.