INTRODUCTION:

A vitamin is an organic compound required as a nutrient in small amount by an organism¹.In the other word; an organic compound (or related compounds) is called a vitamin when it cannot be synthesized in sufficient quantities by an organism and must be obtained from the diet ².

Vitamins have diverse biochemical functions. Some have hormone-like functions as regulators of mineral metabolism (e.g., vitamin D), or regulators of cell and tissue growth and differentiation (e.g., some forms of vitamin A). Others function as antioxidants (e.g., vitamin E and sometimes vitamin C)³. The largest number of vitamins (e.g., B complex vitamins) functions as precursors for enzyme cofactors, that help enzymes in their work as catalysts in metabolism ⁴.

Vitamins are classified as typical fine chemical with price above US $ 10 per Kg and volume of about 1000-10,000 per anum. However, few known vitamins are classified as the class of bulk chemicals ⁵.

Among these, menadione, that is the common chemical name for vitamin K₃ (2-methyl-1, 4-naphthoquinone) is an important synthetic product and is the key intermediate for the production of all the others vitamin belonging to the K family.

The application of 2-methyl-1, 4-naphthoquinone (Vitamin K₃) has been intense in the animal food industry, due the high cost of phylloquinone (Vitamin K₁). The synthesis of phylloquinone is important for use in infant formula, medical food and pharmaceuticals. However, the addition of 2-methyl-1, 4-naphthoqinone to animal feed is important specifically to poultry rations since chemotherapeutic agents against coccidiosis and parasitic diseases inhibits intestinal synthesis and increases the dietary requirements of the chicken ⁵.

In 1910, the first vitamin complex was isolated by Japanese scientist Umetaro Suzuki, who succeeded in extracting a water soluble complex of micronutrients from rice bran and named it aberic acid (later orizanin).

Vitamin K is a group of structurally similar, fat soluble vitamins that are needed for the post-translational modification of certain proteins, mostly required for blood coagulation but also involved in metabolic pathways in bone and other tissue. They are 2-methyl-1, 4-naphthoquinone derivatives. This group of vitamins includes two natural vitamins: vitamin K₁ and vitamin K₂. Vitamin K₃ is a synthetic form of vitamin K.

All vitamins are not produced commercially. Through improvements in the methods, the prices of vitamins have dropped to a fraction of the 1945 prices. As a result, vitamins are readily available not for the humans but for animals consumption ⁶.

Vitamin K₃ is a polycyclic aromatic ketone, based on 1, 4-naphthoquinone with a 2-methyl substituent. Vitamin K₃ is also known as menadione or 2-methyl-1, 4-naphthoquinone (2MNQ) ⁷.

Vitamin K₃ shows bright yellow crystals. It has special pungent smell. It is insoluble in water, but soluble in ethanol, benzene, chloroform, carbon tetrachloride and vegetable oils etc. It is instable in the air and decomposed when meeting iron. It can be volatilized along with vapor. It has toxicity and strong irritant effect on skin ⁸.

It as an almost order less, light sensitive bright yellow crystalline powder with an empirical formula of C₁₁H₈O₂. 2MNQ is insoluble in water but soluble in vegetable oils, acetone and benzene and slightly soluble in alcohol and chloroform ⁹.

Melting Range 105-107º C ⁹

Molecular weight 172.2

IUPAC range 2-Methylnaphthalene-1, 4-Dione

Synonyms 2-Methyl-1, 4-Naphthoquinone

Vitamin K₃, Menapthone,

2-Methyl-1, 4-Naphthalenedione.

Phylloquinone (Vitamin K₁) is a gold-yellow oil with a refractive index α_D²⁰ = 1.525 – 1.528 and specific rotation [d]_D^{2 5} = +0.28º. Various menaquinone have been crystallized from the organic solvent; they melt between 35 and 65ºC, depending on the length of the isoprenoid chain. The K vitamins are sensitive to light. They are also sensitive to alkali, but are relatively stable ⁶.

Vitamin K occurring in the nature exists in two forms: phylloquinone occurring in green plants (Vitamin K₁) another is methyl napthoquinone synthesized in animals and other microorganisms (Vitamin K₂). Artificially synthesized Vitamins are Vitamin K₃ and Vitamin K₄¹⁰.

2-methyl-1, 4-napthquinone has been used as an anti-hemorrhagic substance and also in the preparation of other anti-hemorrhagic compounds such as (Vitamin K₁), 2-methyl-3-phytyl-1, 4-naphthoquinone and 2-methyl-1, 4-napthoquinone-3-acetic acid ¹².

Anticarcinogenic activities of vitamin K have been observed in various cancer cell lines, including prostate cancer cells ¹³.

Vitamin K₃is significantly used in the fine chemical industry because it has about twice in anti-bleeding activity of the natural vitamin K₂ and thrice the activity of the natural vitamin K₁¹¹.

The synthetic menadione (vitamin K₃) inhibits carcinogenic cell growth, especially in combination with vitamin C, by oxidative processes leading to oxidative stress and depletion of cellular thiols, the anticancer actions of the natural K vitamins are mediated by oncogene-associated cell cycle arrest and apoptosis, which are likely to play a major role in the promotion phase, a reversible process lasting several years and therefore most susceptible to the influence of cancer preventive agents ¹³.

2-methyl-1, 4-napthoquinone has been intensely used in the animal food industry, due to the high cost of phylloquinone (Vitamin K₁). Water soluble forms of menadione are commonly used to the swine diet ¹⁴.

Menadione is sometimes administered to new born, and also to the pregnant women shortly before child birth, to prevent hemorrhage in the new born. Menadione reduces the glutathione level in the blood, it interact with the redox system of the erythrocytes and causes hemolysis ⁶. Vitamin K relies on protein and peptide participation in calcium metabolism ¹⁵.

The term vitamin K refers to a group of compounds that have a 2-methyl-1, 4-naphtoquinone ring in common but that differ in the length and structure of their isoprenoid side chain at the 3-position. The 2 forms of vitamin K that occur naturally in foods are phylloquinone (Vitamin K₂) and the group of menaquinones (Vitamin K₂,MK-n), which vary in the number of prenyl units ¹³. The number of isoprene units (not of the C atoms) is the basis for the characterization of the side chain. The hexahydrotetraprenyl side chain is called “phytyl”. The compound 2-methyl-3-phytyl-1, 4-naphthoquinone is called “phylloquinone”; however the term vitamin K₁ is also used ⁶.

The parent structure of the vitamin K group of compounds is 2-methyl-l, 4-naphthoquinone. This compound, as far as is known, does not occur in nature but does possess biological activity in vertebrates because of their ability to add on a geranylgeranyl side chain at the 3 position (thus converting it into Menaquinones) ¹⁶.

Various synthetic schemes are employed for the synthesis of 2-methy-1, 4-naphthoquinone. The oldest method used for the synthesis of menadione is oxidation in the acetic acid and chromic acid.

Oxidation Synthesis by Chromic acid

Price et al. (1943)¹⁷ oxidized 2-methylnaphthalene in the presence of acetic acid and chromic acid. 2-methylnaphthalene was dissolved in the acetic acid and added in the mixture of chromic acid and acetic acid (80%) in 1hr. The reaction temperature during addition was 30-65ºC, whereas after addition the reaction mixture was heated to about 60-65ºC.

Figure 1.2 Catalytic oxidation of menadione by chromium (VI)

Regioselective Oxidation by chromium

Yamazaki et al. (2001)¹⁸ oxidized 2-methyl naphthalene to 2-methyl-1, 4-naphthoquinone in the presence of acetonitrile. This oxidation was catalyzed by chromium (VI) with high yield and regioselectivity.

Gas Phase Oxidation

Guidetti et al. (2010)¹⁹ synthesized menadione by two step process: the first one was the selective methylation in the gas phase of 1-naphthol to 2-methyl-1-naphthol with methanol as the alkylating agent and the second step was the oxidation of 2-methyl-1-naphthol in the liquid phase, using hydrogen peroxide as the oxidant. The first step was catalyzed by the Mg-Fe mixed oxides, whereas the oxidation step was catalyzed by H₂O₂. The highest selectivity of menadione was achieved in high concentration of hydrogen peroxide i.e. 93%.

Figure 1.3 Synthesis of 2-Methyl-Naphthalen-1-ol

Figure 1.4 Catalytic synthesis of Menadione by hydrogen peroxide

Another gas phase oxidation employed to yield menadione was:

Shu-juan et al. (2004)²⁰ synthesized ß-methyl-1, 4-naphthoquinone by gas phase oxidation using V₂O₅ and ß-methylnaphthalene as a starting material. The carrier used for the catalyst in the oxidation reaction was 20-40 mesh macroporous silica. The effect of calcinations temperature (i.e. 350-470ºC) was inversely propositional to conversion of ß-methyl-naphthoquionone. But for the selectivity temperature, the optimum temperature was 400-450º C.

Metal-Free synthesis of Vitamin K₃

Bohle et al. (2006)²¹ 2-methylnaphthalene is oxidized in about 80% yield with 7-9/1 regioselectivity to 2-methyl-1, 4-naphthoquinone by hydrogen peroxide with a mineral acid as the catalyst. The most active catalyst for the oxidationof 2-methylnaphthalene to 2-methyl-1, 4-naphthoquinone is MeReO₃ (MTO), the oxidation of 2-methylnaphthalene require a strong acidic reaction system. The reaction is carried out with glacial acetic acid as the solvent and 85% H₂O₂ as the oxidizing agent. Metal catalyst was required for this transformation. The reported yield oxidation reaction was 80%.

Diene Synthetic reaction in solution of MO-V phosphoric heteropoly acid obtained Menadione

Simonova et al. (2005)²² synthesized menadione by the diene synthesis reaction from substrates 2-methylphenol (o-cresol) and 2-methyl aniline (o-toluidine). Solution of Mo-V phosphoric heteropoly acids were used as catalyst in the present study. The selective catalysis of the oxidizing and diene synthesis carried out by the solution of Mo-V phosphoric heteropoly acids of composition H_3+XPMo_12+XV_XO₄₀ (HPA-x, where x was the number of vanadium atoms in a molecules. The reported yield by this process is 30%.

Figure 1.5 Diene Synthesis of Menadione

Oxidation by hydrogen peroxide in acetic acid

Narayanan et al. (2002)²³ carried out oxidation of 2-methylnaphthalene in acetic acid with aqueous hydrogen peroxide. Selectivity of the desired oxidizing product (2-Methyl-1, 4-naphthoquinone) was nearly 90% at 100^◦C for 3 hrs. Different parameters were studied on the present oxidizing reaction like concentration of hydrogen peroxide, strength of acetic acid, molar ratio of 2-methylnaphthalene to hydrogen peroxide, reaction temperature and time.

Figure 1.6 Synthesis of Menadione in acetic acid with aqueous hydrogen peroxide

Oxidation by Monopersulfate

Song et al. (1997)²⁴ carried out the oxidation of 2-methylnaphthalene by potassium monopersulfate in the presence of metalloporphyrin catalyst produced mainly two napthoquinone: 2-methyl-1, 4-naphthoquinone (menadione or vitamin K₃) and 6-methyl-1, 4-naphthoquinone. 2-methylnaphthalene was oxidized to quinines in the presence of 5mol% aqueous solution of water-soluble metalloporphyrins MnTPPS or FeTMPS at room temperature.

Figure 1.7 Catalytic synthesis of Menadione by potassium monopersulfate

Electrosynthesis of menadione, directly from 2-methyl-5, 8-dihydro-1, 4-naphthalenediol by a four-electron oxidation procedure

Torh et al. (1982)²⁵ synthesized menadione by electrolysis of 2-methyl-5, 8-dihydro-1, 4-naphthalenediol in MeCN-t-BuOH (9/1) – LiClO₄– (Pt or C electrodes) system. The synthetic result of vitamin K₃ was improved by the use of per chlorates salts or tetrafluroborate salts as supporting electrolytes in various electrolysis systems, and gave good results. 2-methyl-1, 4-naphthoquinone (Vitamin K₃) and its homologs constitute a class of biologically active quinine as well as precursors in the synthesis of vitamin K series.

Figure 1.8 2-methyl-5, 8-dihydro-1, 4-naphthalenediol in MeCN-t-BuOH (9/1) – LiClO₄– (Pt or C electrodes) system

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Received on 14.07.2012 Modified on 10.08.2012

Asian J. Research Chem. 5(9): September, 2012; Page 1200-1204