Process for selective oxidation of primary alcohols and...

Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives

Reexamination Certificate

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C536S018500, C536S105000, C536S123120, C536S124000, C435S028000, C435S101000

Reexamination Certificate

active

06831173

ABSTRACT:

The invention relates to the production of nitrosonium ions (oxoammonium ions) by oxidation of nitroxyl radicals, especially 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO). The nitrosonium ions can be used as a catalytic oxidising agent for the selective oxidation of primary alcohols to aldehydes.
Such a process in which TEMPO is reoxidised by chemical means is known from a review by De Nooy in
Synthesis
1996, 1153-1174 and from WO 95/07303.
It was found according to the invention that oxidation of alcohol functions, especially primary alcohol functions, can be carried out without using chlorine-based oxidising agents and with the use of hydrogen peroxide or oxygen as the ultimate oxidising agent. The oxidation according to the invention is performed using enzymes and/or metal complexes. This oxidation, when carried out on primary alcohols, surprisingly results in formation of aldehydes, if desired without substantial further oxidation to carboxylic groups using appropriate conditions. The aldehydes may be present in the (hemi)acetal form and related structures. An adaptation of the oxidation process of the invention can be used to oxidise secondary alcohols, especially carbohydrates, to keto derivatives. The process of the invention is further defined by the characterising features of the appending claims.
The non-prepublished International patent applications WO 99/23117 and WO 99/23240 describe the oxidation of cellulose or starch, respectively, using an oxidative enzyme such as laccase with oxygen and TEMPO mediation. The laccase/TEMPO oxidation of cellulose resulted in the presence of a low and unspecified level carboxyl and carbonyl groups, while the laccase/TEMPO oxidation of starch was reported to yield a product having 1 carboxyl group and 3 aldehyde groups per 100 glucose units; no method of determining aldehyde content was given.
In the following description, reference is made to TEMPO only for the sake of simplicity, but it should be understood that other suitable nitroxyls, i.e. organic nitroxyl compounds lacking &agr;-hydrogen atoms, such as 2,2,5,5-tetramethylpyrrolidine-N-oxyl (PROXYL), 4-hydroxy-TEMPO, 4-acetamido-TEMPO and derivatives thereof and those described in WO 95/07303 can be substituted for TEMPO. These di-tert-allyl nitroxyls are especially suitable for selectively oxidising primary alcohols to aldehyde functions, in particular in the presence of secondary alcohol functions that should not be oxidised. Less sterically hindered nitroxyls, such as 4,4-dimethyloxazolidine-N-oxyl (DOXYL), are suitable for preferentially oxidising secondary alcohols to keto functions, for example in the production of keto cellulose or keto starch. The active oxidising species is the nitrosonium ion (oxoammonium ion >N
+
═O), that is produced in situ by oxidation of the corresponding hydroxylamine and nitroxyl radical. If desired, the reaction can be performed in two steps, the production of the nitrosonium ion being the first and the oxidation of the alcohol function being the second.
A catalytic amount of nitroxyl is preferably 0.1-25% by weight, based on the primary alcohol, or 0.1-25 mol % with respect to the primary alcohol. The nitroxyl may also be immobilised, e.g. by coupling of the hydroxyl group of 4-hydroxy-TEMPO to a suitable carrier, or in the form of a polymeric nitroxyl such as:
—[(CH
3
)
2
C—NO.—C(CH
3
)
2
—A—]
n
—, wherein A may be an alkylene group and/or a heteroatom, and n is a number form e.g. 10 up to several hundreds.
The process of the invention can be used for the oxidation of primary alcohols initially to the corresponding aldehydes. If required the primary products can be further oxidised to the corresponding carboxylic acids by using known oxidising agents such as hypochlorite, chlorite, hydrogen peroxide or by using TEMPO-mediated oxidation under more vigorous conditions such as an increased temperature e.g. from 40-80° C., or for prolonged exposure to the reaction conditions. Alternatively, the aldehyde/carboxylic acid ratio can be increased by using relative low pH's (e.g. pH 3-7), by controlled addition of oxidising agent, by lowering the oxygen concentration, or by first preparing the nitrosonium ion solution (two-step process).
The present process is especially favourable 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, steroid hormones, sugar alcohols, glycosides (flavour precursors), and in particular carbohydrates having primary alcohol functions. The carbohydrates may be monosaccharides, such as glucose, fructose, disaccharides, such as sucrose, maltose, lactose, oligosaccharides and polysaccharides. The oligo- and polysaccharides may be of any type, e.g. glucans such as starch, starch components (i.e. amylose, amylopectine, dextrins), pullulan (&agr;-1,4-&agr;-1,4-&agr;-1,6-glucan), cellulose (in particular non-wood), chitin, lichenin etc., furanofructans such as inulin and levan, galactans, arabinogalactans, furanoid pentosans (xylans), (galacto)mannans (guar, locust bean gum), bacterial exopolysaccharides (EPS) and the like and derivatives of such carbohydrates, such as hydrolysates. These oligo- and polysaccharides include hetero-saccharides, i.e. those which have different structural units, even if those different units themselves may not have primary hydroxyl groups such as uronic acid units, e.g. in xanthan and carbohydrates derived form algae. The carbohydrates to be oxidised according to the invention include glycosides and other protected carbohydrates. Further examples are glyconic acids, such as lactobionic acid delta-lactone, that can be oxidised to glycaric acids and the like.
A distinct group of compounds suitable for oxidation with the present process consists of hydroxyalkylated carbohydrates such as hydroxypropyl cellulose, hydroxyethyl starch or hydroxyethylinulin, which result in an alternative way for producing formylalkyl carbohydrates. Other suitable carbohydrate substrates in which at least a part of the (6-) hydroxymethyl groups are intact, include for example (2- and 3-) carboxymethyl carbohydrates.
The oxidation of carbohydrates containing primary hydroxyl groups results in the corresponding carbohydrates containing aldehydes and, if desired, to carboxylic acids, with intact ring systems. Examples include &agr;-1,4-glucan6-aldehydes, &bgr;-1,4-glucan-6-aldehydes, &bgr;-2,1-fructan6-aldehydes and &bgr;-2,6-fructan-1-aldehydes. These products 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.
The catalysts to be used according to the invention are oxidoreductases or other enzymes that are capable of oxidation in the presence of a suitable redox system. Oxidoreductases, i.e. enzymes capable of oxidation without the presence of further redox systems, to be used in the process of the invention include peroxidases and oxidases, in particular polyphenol oxidases and laccase. Certain hydrolases, such as phytase and lipases, can be used when a further redox system is present such as a metal complex, e.g. vanadate. For example, lipases are found to be effective catalysts for selective oxidation of primary alcohol functions with TEMPO/hydrogen peroxide/copper in the presence of an organic, in particular a C
1
-C
6
carboxylic acid (e.g. acetic acid). Instead of complete enzymes, so-called “synzymes”, i.e. transition metal complexes mimicking enzymes can be used. Such complexes comprise e.g. vanadium, manganese, iron, cobalt, nickel or copper with complexing agents, in particular polyamines, such as 2,2′-bipyridyl, phenanthroline, tetramethylethylenediamine, pentamethyldiethylenetriamine and their cyclic counterparts such as 1,4,7-trimethyl-1,4,7-triazonane, and histidine and its oligomers. The metal-assisted enzymes require

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