Synthesis of Î´-Aminolevulinic Acid - ACS Symposium Series (ACS

Chapter 4

Synthesis of δ-Aminolevulinic Acid Luc Moens

Downloaded by MICHIGAN STATE UNIV on February 18, 2015 | http://pubs.acs.org Publication Date: February 26, 2001 | doi: 10.1021/bk-2001-0784.ch004

National Renewable Energy Laboratory (NREL), 1617 Cole Boulevard, Golden, CO 80401

Improvements in the industrial production of levulinic acid from lignocellulosic materials have revived the interest in the use of this renewable chemical as a 'platform chemical' for the chemical industry. Here, an improved synthetic method is presented for the production of δ-aminolevulinic acid (DALA) from levulinic acid. DALA is attracting much attention as an environmentally benign pesticide, and antitumor agent.

The oil refinery as we know it today has made it possible for the chemical industry to get immediate access to a wide variety of hydrocarbons that serve as starting material or 'platform chemicals' for a plethora of chemicals and materials which have become the basis for the production of most consumable goods in our society. However, petroleum is a non-renewable resource and, as we witnessed during the 1970's, its supply can easily become jeopardized by global socio-political events. In addition, the use of fossil resources to produce energy and chemicals is one of the primary causes of carbon dioxide buildup in the atmosphere that is believed to cause global climate changes. This has caused a renewed global interest in the use of lignocellulosic biomass as a renewable feedstock for energy and chemicals. However, the chemical structures that make up biomass are much more complex, and this creates a challenge for the chemical industry. Thus, entirely new chemical processes must be developed

© 2001 American Chemical Society In Chemicals and Materials from Renewable Resources; Bozell, J.; ACS Symposium Series; American Chemical Society: Washington, DC, 2001.

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that convert the complex lignocellulosics into chemicals. In analogy with the oil refineries that specialize in the 'cracking' of petroleum into smaller molecules, one can speak of a 'biorefinerv' wherein biomass is broken down into well defined molecules that can be used for further processing to other chemicals. This concept has already been realized to some extent in the case of sugar and alcohol production, as well as specialty chemicals such as furans. However, by no means is the concept as advanced as the 'state of the art' in a current petroleum refinery. Key to the success of a biorefinery will be the progress in three different areas: a) a better understanding of the physico-chemical behavior of the many available biomass feedstocks in process reactors, b) the development of new chemical technologies that can deal with the complex and heterogeneous nature of biomass, and c) a better understanding of the reactivities and secondary condensation reactions of the reaction intermediates and products that are formed during the chemical conversion process. Especially the latter is an important requirement for biomass processing, since the intermediates and products often are very reactive due to their higher degree of oxygenation compared to petrochemicals. One of the unique chemicals that can be produced from the cellulosic fraction of biomass is levulinic acid. For a long time, this compound has been known as a by-product of the acid hydrolysis of cellulose or monomeric hexoses such as glucose, but until recently, no good method existed for producing levulinic acid in high yields through this type of reaction (1,2). The acidcatalyzed degradation of e. g., cellulosefirstgenerates glucose, which undergoes further dehydration to form 5-hydroxymethylfurfural (5-HMF). The latter is known to be very unstable under the acidic conditions, and tends to hydrolyze further with formation of levulinic acid (Cs-unit) and formic acid (Ci-unit) (Scheme 1). H 0

+

3

CELLULOSE

Glucose

HC

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Levulinic acid

H

C

0

0

H

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Scheme 1. Formation of levulinic acidfrom cellulose through acid hydrolysis Along this pathway, a number of condensation reactions can take place, and it has been found that when the levulinic acid is not removed quickly from the reaction medium, tarry materials are formed that drastically lower the yield of the levulinic acid. Historically, this has kept the cost of levulinic acid too high

In Chemicals and Materials from Renewable Resources; Bozell, J.; ACS Symposium Series; American Chemical Society: Washington, DC, 2001.


39 to make this compound attractive as a 'platform chemical' for the production of a series of derived chemicals and materials. However, recent work at Biofine, Inc. (Massachusetts), led to the development of an optimized process that generates levulinic acid in yields of 70-90% starting from waste paper (3). Economic evaluations of the new process indicated a much lower cost for levulinic acid, and this bodes very well for the expanded use of this chemical in the very near future. Today, levulinic acid is primarily produced starting from maleic acid, and serves as a catalyst in the manufacture of specialty adhesives, rubber, pharmaceutical, plastic, and synthetic fiber products. It is predicted that the cheaper biomass-derived levulinic acid will make it more suitable as a platform chemical for the production of many new chemicals and materials. This chapter deals with the synthesis of δ-aminolevulinic acid (DALA), and an improved synthetic method starting from levulinic acid will be presented that was recently developed in our laboratory.

Use of δ-Aniinolevulinic Acid (DALA) as a Herbicide DALA is a naturally occurring substance present in all plant and animal cells. It serves as the precursor molecule in the cellular production of tetrapyrroles such as chlorophyll and the heme of hemoglobin, and thus it plays a key role in such vital processes as photosynthesis and oxygen transport (4,5). Interestingly, DALA can turn into a powerful herbicide when it is applied externally, in which case the metabolic balance is disturbed and an excess of tetrapyrrole intermediates builds up within the plant cells. Under light exposure, i. e., as soon as the plants are exposed to daylight, the accumulated tetrapyrroles use the sunlight to convert oxygen into singlet oxygen that kills plant cells by excessively oxidizing the cell material (6). DALA has also been found to have insecticidal (7,8) and antitumor properties (9). Because DALA is completely metabolized, no unnatural residues remain. DALA that is not taken up by the plants decomposes within a day or two, so toxicity and impact on the environment are minimal. Under greenhouse conditions, D A L A is only effective on dicotyledons or broadleaf plants. Monocotyledons such as grasses and grains are able to tolerate it. As such, DALA may be ideal for killing broadleaf weeds in grass such as in turf farms, golf courses, and residential lawns. Similarly, it can be used for monocotyledon crops such as corn, wheat, oats, and barley. For both of these uses, DALA requires the addition of small amounts of chemical "modulators" to trigger its herbicidal action. By varying the modulator, DALA can be formulated such that a variety of weeds are killed while leaving grass or crops unharmed. Unfortunately, the production cost for DALA has been very high, and this has prevented its widespread application. With the advent of cheaper levulinic acid through the Biofine process, the development of better synthetic routes towards D A L A may lead to its commercialization.


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Overview of Known Synthetic Pathways for DALA Production Since the 1950's, the synthesis of D A L A has undergone continuous improvements and a variety of starting materials have been tested, including levulinic acid. The following is an overview of successful synthetic approaches that have been described in both the scientific and patent literature. Note that throughout the text the acronym DALA will be used for both the hydrochloride salt and the free DALA. The free D A L A is a very unstable compound (1,2aminoketone) that undergoes spontaneous dimerization to form a stable pyrazine 2 after oxidation of the intermediate dihydropyrazine 1 (Figure 1) (10). The initial reports described routes that involved a sequential build-up of the carbon chain, combined with the introduction of the amino group through the use of potassium phthalimide (Gabriel synthesis) (11-15). The use of furans as starting material offered a route that was relatively simple, as was shown in the conversion of N-benzoylfurfury lamine (3) to DALA (Figure 2) (16).

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DALA

Figure 1. Dimerization ofDALA to form a stable pyrazine. (Adapted with permission from reference 10. Copyright 1981 Japan Inst. Heterocyclic Chem.)

The application of the electrochemical variant of the Clauson-Kaas oxidation allowed the formation of the dihydrodimethoxyfuran 4. Catalytic hydrogénation of this hemiacetal led to a tetrahydrofuran that after oxidation and hydrolysis resulted in the formation of DALA. A similar pathway, shown in Figure 3, is the oxidation of 5-acetamido-methylfurfural (5) with singlet oxygen (17J8). This generates a butenolide (6) that after selective reduction with borohydride, is converted into a furan-2(5H)-one 7. Zinc powder, activated under sonication in acetic acid, can cause ring opening of the butenolide ring. An analogous sequence was patented that applied this photochemical protocol to the phthalimide form of furfural. In a more recent report, ruthenium trichloride was used as an oxidizing agent in the ring opening of the phthalimide of tetrahydrofiirfurylamine(/P,20). Closely related to this work is the oxidative ring opening of amine 8 to DALA with chromium oxide in sulfuric acid (Figure 4) (21).


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Synthesis of Î´-Aminolevulinic Acid - ACS Symposium Series (ACS

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