Process of oxidizing primary alcohols

Details Process of oxidizing primary alcohols Process of oxidizing primary alcohols

2002-09-13

2004-08-03

Wilson, James O. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S056000, C536S102000, C536S105000, C536S106000

Reexamination Certificate

active

06770755

ABSTRACT:

The present invention relates to a process of selectively oxidising primary alcohols, in particular primary alcohol functions in monosaccharides and polysaccharides.
Oxidation of primary alcohol functions in molecules to aldehydes and/or carboxylic acids is very useful for introducing functionalities into the molecule, for example for adjusting solubility, reactivity or for providing an anchor for coupling reactions with other molecules. Especially, oxidised carbohydrates having an intact carbon skeleton, i.e. carbohydrates oxidised at the primary hydroxyl function, are advantageous for certain applications, for example as metal chelating agents, viscosifiers, carrier materials, stabilisers, and superabsorbent polymers.
There is an increasing demand for selective oxidation reactions, i.e. for exclusive or almost exclusive oxidation of primary hydroxyl groups. An attractive method for selectively oxidising primary alcohol functions was developed in the late eighties, which uses a nitroxyl compound as an intermediary oxidising agent, and hypochlorite as the ultimate oxidising agent. Anelli et al.,
J. Org. Chem.
52, 2559 (1987), and 54, 2970 (1989), reported the oxidation of alcohols and diols with sodium hypochlorite, potassium bromide and 2,2,6,6-tetramethylpiperidinyloxy (TEMPO) or 4-methoxy-TEMPO in a two-phase solvent system (dichloromethane and water) at pH 9.5. Davis and Flitsch,
Tetrahedron Lett.
34, 1181-1184 (1993), reported the oxidation of mono-saccharides wherein the non-primary hydroxyl groups are partly protected, using the same oxidation system.
Advantageously, the TEMPO oxidations can also be carried out in non-toxic media, especially aqueous media. DE-4209869 discloses the oxidation of alkyl polyglucosides and other compounds having primary alcohol functions with hypochlorite and TEMPO in aqueous suspension at pH 8-9. De Nooy et al (WO 95/07303 and
Recl. Trav. Chim. Pays
-
Bas
113 (1994) 165-166) have described the oxidation of polysaccharides using TEMPO and a hypohalite in the presence of a catalytic amount of a TEMPO or a related nitroxyl radical in an aqueous reaction medium at a pH of between 9 and 13. Similarly, DE-19746805 describes the oxidation of starch with TEMPO, hypochlorite or chlorine, and bromide at pH 7-9. Thus the oxidations always require slightly alkaline conditions (pH above 7) when normal oxidants (chlorine, hypochlorite, bromine) are used.
The TEMPO oxidation has been further developed, e.g. as to the use of alternative oxidising agents. WO 99/23117 and WO 99/23240 describe the oxidation of cellulose and starch, respectively, with TEMPO and an oxidative enzyme (laccase) and oxygen at pH 4-9 resulting in products containing low numbers of carbaldehyde and carboxyl groups. For the specific application to cellulose further research has been reported by Isogai and Kato
Cellulose
1998, 5, 153-164, and Chang and Robyt,
J. Carbohydrate Chem.
15, 819-830 (1996).
Although the TEMPO oxidations usually give good results in terms of yield and selectivity, the limitation to alkaline conditions is a serious drawback.
It was surprisingly found that the TEMPO-mediated oxidation of alcohols can be effected with similar selectivity of primary over secondary alcohol functions and with even improved selectivity of alcohol to aldehyde over aldehyde to carboxylic acid oxidation, by selecting specific TEMPO analogues and by carrying out the oxidation at acidic pHs (pH below 7). The pH can be as low as about 0.2, depending on the reaction conditions and the TEMPO derivative. The oxidation of primary alcohols using TEMPO with halide and peracid (peracetic acid) at pH of 5 and higher is disclaimed.
Although various TEMPO analogues can be used in the process according to the invention, preference is given to 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (4-hydroxy-TEMPO) and acylated derivatives thereof such as 4-acetoxy, 4-phosphonooxy and 4-benzoyloxy-TEMPO, as well as to 4-amino-TEMPO and acylated derivatives thereof such as 4-acetamido- and 4-maleimido-TEMPO. 4-Hydroxy-TEMPO is most preferred. Combinations of nitroxyls can also be used, for example to adjust the aldehyde to acid ratio. A suitable combination is e.g. unsubstituted TEMPO and 4-acetamido-TEMPO. Precursors can also be used. A precursor is understood to comprise a compound that under the reaction conditions can form nitroxyl radicals, such as the corresponding hydroxylamines and nitrones; the di-tert-alkyl nitroxyl may also be prepared for example by oxidation of the corresponding di-tert-alkylamine with hydrogen peroxide and tungstate. A catalytic amount of nitroxyl is preferably 0.05-15% by weight, based on the dry weight of the primary alcohol, or 0.05-15 mol % with respect to the hydroxymethyl (—CH
2
OH) groups of the molecule, especially the carbohydrate molecule. Preferably the nitroxyl is present in an amount of 0.2-5%.
The oxidising agent can be any oxidising agent capable of reoxidising reduced nitroxyls, such as ozone and especially hypohalites. Also hydrogen peroxide or organic hydroperoxides may be used, suitably with a metal catalyst. Furthermore, peracids such as peracetic acid, and perbenzoic acid may be used without the necessity of concomitantly using halide. The amount of oxidising agent is e.g. 0.1-20 wt. %, especially 0.1-20 wt. %, preferably 0.5-7.5 wt. % with respect to the dry weight of the alcohol. The oxidation can be performed at ambient temperature or increased temperature. The oxidation should be performed at a pH between 2 and 7, especially between 3 and 6 to give best results. The reaction temperature is advantageously kept between 5° C. and 50° C.
It was furthermore found that the oxidation can be successfully performed without further oxidising agent, especially when 4-acetamido TEMPO or another 4-amido TEMPO or hydroxy-TEMPO is used under acidic conditions. Acidic conditions can be adjusted e.g. by addition of an inert organic or inorganic acid, e.g. sulphuric acid or a sulphonic acid such as toluenesulphonic acid. A lower pH, generally between 0.5 and 3, is used in this embodiment. This embodiment has the advantage that the product is free of any halogen reagent. The actual oxidising species may be the nitroxyl radical, but it may also be a disproportionation product of TEMPO, such as the nitrone. The spent TEMPO derivative can be regenerated off-line, using e.g. ozone or another oxidising agent.
Although the process can be used for introducing low levels of oxidation, it is preferred that at least 10%, more preferably at least 25% of the primary hydroxyl groups are converted to carbaldehyde groups and/or carboxylic groups. Especially the product contains both carbaldehyde groups and carboxylic groups, in a ratio of at least 1:5, preferably at least 1:2, up to e.g. 2:1.
The process according to the invention can be used for oxidising compounds having primary and/or secondary alcohol functions. The process can be used for oxidising compounds having both primary and secondary alcohol functions, such as 1,6-octanediol and, in particular, carbohydrates and their reduced derivatives (glycitols), as the process exhibits a preference of primary over secondary alcohol functions. Both monomeric carbohydrates (monosaccharides), and dimeric, oligomeric and polymeric carbohydrates, as well as sugar alcohols can be oxidised, if they have a primary alcohol function.
Examples of polymeric carbohydrates are &bgr;-glucans, such as cellulose and chitin (1,4-&bgr;), curdlan and scleroglucan and other 1,3-&bgr;-glucans and fractions, derivatives and hydrolysis products thereof, &agr;-glucans, in particular starch (1,4-&agr;) and pullulan (1,6/1,4/1,4-&agr;) and fractions, derivatives and hydrolysis products thereof —such as amylose and maltodextrins-, and cyclic equivalents thereof such as cyclodextrin, also other polysaccharides such as fructans including inulin, and natural or artificial gums such as xanthan (1,4-&bgr;, with side chains), guar, carob flower, algin, gum arabic, dragacanth, agar, ghatti, carrageenin, and the like. In particular, the method is suitable for the

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