Carbohydrate acids, and in particular carbohydrate diacids (aldaric acids) offer significant economic potential as carbon based chemical building blocks for the chemical industry, as safe additives or components of products use in pharmaceutical preparations and food products, and as structural components of biodegradable polymers, if they can be effectively produced on an industrial scale. Glucaric acid, for example, is produced through the oxidation of glucose and in salt form is currently in use as a nutraceutical for preventing cancer. The price of this material however is high, approximately $100/lb. Industrial scale production of aldaric acids would also provide sufficient materials for the production of other useful compounds, that include environmentally degradable polyamides with varying properties and applications, which are otherwise not commercially available.
Carbohydrate diacids are produced a number of ways from reducing sugars using a variety of oxidizing agents, nitric acid being among the earliest reported.1 An example of a nitric acid oxidation of a carbohydrate is that of D-glucose to give D-glucaric acid, typically isolated as its mono potassium salt.2,3,4 Alternatively, D-glucaric acid can be isolated from nitric acid oxidation of D-glucose as a disodium salt5 or as the 1,4:6,3-dilactone.6 Routes have been described showing synthesis of diacids through catalytic oxidation with oxygen over a noble metal catalyst.7 An additional route of synthesis exists by use of oxoammonium salts in combination with hypophalites as the terminal oxidants. For example, Merbough and coworkers describe oxidation of D-glucose, D-mannose and D-galactose to their corresponding diacids using 4-acetylamino-2,2,4,6-tetamethyl-1-piperidinyloxy (4-AcNH-TEMPO) with hypohalites as the oxidizing medium.8,9 A microbial oxidation of myo-inositol to glucuronic acid which is then oxidized enzymatically or by catalytic oxidation to glucaric acid has also been recently described.10 
When used to oxidize carbohydrates to carbohydrate acids, nitric acid offers the advantages of conveniently serving as the solvent medium for the oxidation and as an oxidizing agent. However, there are also specific disadvantages. Such oxidation reactions can be very exothermic and may run away if care is not taken to control the exotherm in the early stages of the reaction. These reactions also generate significant amounts of NOX gases which are environmental hazards if they are vented into the atmosphere rather than being captured and rendered harmless and/or recycled in a process that regenerates nitric acid. Thus, it would be desirable to utilize a more controlled nitric acid oxidation process that does not run the burdensome, time consuming, and inefficient risk of over-reaction, thereby rendering the products essentially useless, while at the same time employing a process that does not vent NOX gases into the atmosphere, and recycles these gases into nitric acid.
In the nitric acid oxidation of many compounds, product isolation can be encumbered by the residual nitric acid that remains in the usually syrupy product. Thus, in order to properly isolate the desired oxidation product, it is generally necessary to remove the residual nitric acid. This is particularly the case in the nitric acid oxidation of alcohol compounds, such as carbohydrates. In order to isolate the desired oxidation product of a carbohydrate, nitric acid must be at least partially removed. A number of methods have been described for removing residual nitric acid.
The first technique involves neutralizing aqueous nitric acid and organic/carbohydrate acids solution at the end of the oxidation step with hydroxide solution. In the case of D-glucose oxidation to obtain D-glucaric acid, potassium hydroxide is the base of choice and back titration with nitric acid yields the monopotassium salt of D-glucaric acid.3,4 This technique is not advantageous due to the cost and difficulty involved in the neutralization step.
A second technique for removing residual nitric acid from the oxidation product involves repeated concentrations, by a distillation process, using additions of fresh quantities of water between each step,2,6 after the bulk of the nitric acid has been removed by a distillation process of some type. Removal of residual nitric acid in this manner is very energy intensive requiring multiple additional distillations and does not efficiently remove all of the nitric acid.
Yet a third technique for removing residual nitric acid involves adding large volumes of 2-propanol in order to destroy any excess nitric acid.11 The 2-propanol addition is followed by water dilution and concentration of the remaining product. This process further requires the consumption of 2-propanol, resulting in acetone and other residuals that must also be isolated and separated from the oxidation product. Further, this technique also describes treatment with water and hydrogen chloride, both of which must be removed from the oxidation product. This third technique involves too many steps to be economically viable.
As mentioned earlier, another disadvantage to nitric acid carbohydrate oxidation processes previously reported is the big exotherm normally associated with these oxidations. In those previous processes, the entire amount of solid carbohydrate, along with the entire amount of inorganic nitrite, which serves as a reaction activating agent, is mixed with the nitric acid at the outset of the reaction, thereby creating the conditions for a large and difficult to control exotherm that develops as the reaction warms. Alternatively, the solid carbohydrate is added portion-wise to the nitric acid. This process still promotes an extensive exothermic reaction and is also encumbered by the difficulty in adding solid carbohydrate portion-wise to the liquid/gaseous reaction mixture. Furthermore, isolation of the carbohydrate acid as a salt can also be made difficult due to the presence of inorganic nitrate which can contaminate carbohydrate acid salts during their isolation process.
Thus, significant industrial scale production of aldaric acids requires an economically efficient and a less complicated method for synthesizing aldaric acids from their corresponding carbohydrates. At this time, for example, D-glucaric is not manufactured on a significant industrial scale because there is no economically viable means for such production. The potential importance of D-glucaric acid as a chemical staple from renewable resources was recently underscored in a report by T. Werpy and G. Petersen.12 From among hundreds of compounds considered as potential key chemical building blocks from renewable resources, glucaric acid was targeted as one of the top twelve molecules with significant potential as a chemical building block for a range of potential applications. Also included with glucaric acid were the structurally related pentaric acids, xylaric acid11 from biomass xylose and arabinaric acid from biomass arabinose. The need for suitable oxidation methods of the precursor monosaccharides was emphasized by Werpy and Peterson. If a suitable economic means for the oxidation of carbohydrates could be found, the production of D-glucaric acid and other aldaric acids could see increased production, lower prices, and greater public availability.
All patents, patent applications, provisional patent applications and publications referred to or cited herein, are incorporated by reference in their entirety to the extent they are not inconsistent with the teachings of the specification.