Thiamin production and chemical reactions

Vitamin B1 (Thiamin)

vitamin B1 (Thiamin)

Thiamin chloride hydrochloride, also known as Vitamin B1, is a crystalline white substance that forms colorless monoclinic needles and exhibits a slightly bitter taste and characteristic odor.

The systematic name for thiamin is 3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-5-(2-hydroxyethyl)-4-methylthiazolium chloride. It contains a thiazole ring and a pyrimidine ring as its basic skeleton. While its IUPAC–IUB name is thiamin, the term thiamine is often used in official and commercial documents.

Thiamin is primarily used in the form of its chloride hydrochloride and nitrate. In animal tissue, it exists mainly in phosphorylated forms, particularly as the pyrophosphate, and is bound to an enzyme as a protein complex.

Organs such as the liver, heart, kidney, and brain have a high concentration of thiamin, approximately 100 mg/100 g. On the other hand, normal human blood contains about 90 ng of thiamin per liter, with significant variations among individuals.

Free thiamin is the most prevalent form of thiamin found in plant products, especially in the pericarp and seeds of cereal grains, yeast, rice, dried vegetables, and potatoes. Oils, fats, and highly processed foods, such as refined sugars, are virtually devoid of thiamin.

Table of Contents

1. Production of Vitamin B1

Several syntheses of thiamin have been published, and basically two general methods have evolved over the years.

1.1. Condensation of the Pyrimidine and Thiazole Rings

The initial process, known as the convergent approach, involves distinct syntheses of 4-amino-5-bromomethyl-2-methylpyrimidine hydrobromide and the thiazole moiety or its acetate.

The combination of the two intermediate heterocycles results in thiamin bromide hydrobromide, which can be transformed into thiamin chloride hydrochloride by utilizing silver chloride in methanol or an ion-exchange resin.

The first commercial production of vitamin B1 was established by Merck-Rahway in the United States.

1.2. Construction of the Thiazole Ring on a Preformed Pyrimidine Portion

The second method for synthesizing thiamin, referred to as the linear approach, involves the sequential formation of the thiazole ring on a preformed pyrimidine intermediate, the Grewe diamine.

Hoffmann-La Roche industrialized this approach shortly after the Merck-Rahway process.

Currently, all commercial production of vitamin B1 follows the linear approach via Grewe diamine through to thiothiamin.

1.2.1. Pyrimidine Moiety

The key building block, Grewe diamine, is constructed from either acrylonitrile or malononitrile.

Acrylonitrile is produced through ammonoxidation of propene, while malononitrile is manufactured using a continuous high-temperature process where acetonitrile and cyanogen chloride are reacted in a tube reactor above 700°C.

Other processes use β-aminopropionitrile obtained by adding ammonia to acrylonitrile, which is then subjected to oxidative dehydrogenation in the gas phase at high temperature and in the presence of molecular oxygen and a metallic catalyst.

Malononitrile is transformed into the corresponding C4 unit by adding a carbonyl group and further with ammonia or alcohols to 2-(aminomethylene)propanedinitrile. The required C2-building block acetimino ether is made from acetonitrile by derivatization with HCl and methanol for condensation with enamine leading to 5-cyanopyrimidine.

Grewe diamine is obtained by further hydrogenation over metal catalysts.

1.2.2. Thiamin Synthesis

After obtaining Grewe diamine, three chemical steps are required to obtain thiamin (vitamin B1): extension of the aminomethyl side chain at the 5-position, cyclization to the thiazole ring, and conversion to thiamin.

Similar approaches with 3-chloro-5-hydroxypentan-2-one or 3-chloro-4-oxopentylacetate as the main building block for chain elongation are used by all competitors.

2. Chemical Reactions of Vitamin B1

2.1. Thiamin Hydrolysis

Thiamin can be converted to the thiol form under mildly alkaline aqueous conditions, specifically at pH 7.0 or above. The rate-limiting step appears to be the ring opening.

Under normal conditions, an aqueous solution of thiamin is stable below pH 5.5, even to oxidation. However, when heated in a sealed tube at 140°C, it decomposes into (4-amino-2-methyl-5-pyrimidinyl)methanol and 4-methyl-5-(2-hydroxyethyl)thiazole.

By treating thiamin chloride with sulfite in weakly acidic solutions, it splits into the methanesulfonate derivative and the thiazole compound.

Thiamin chloride can be converted to oxythiamin, which has no vitamin activity, under strongly acidic conditions.

2.2. Intramolecular Aminolysis

Under strongly basic but anhydrous conditions (using 2 mol of sodium ethoxide in ethanol), the 4′-amino group of thiamin can add to the thiazole ring, leading to tricyclic dihydrothiochrome, which then eliminates a thiolate ion to give the sodium salt of the yellow form of thiamin.

The addition of acid can convert it to the thermodynamically more stable thiol form.

2.3. Oxidation

In the presence of an oxidant, thiolate is irreversibly converted to thiochrome, which is a yellow crystalline compound isolated from yeast but has no physiological importance.

In solution, it exhibits a strong blue fluorescence that can be used to quantitatively determine thiamin. Reduction of thiochrome can convert it back to thiamin.

2.4. Ylide Formation

Upon abstraction of the hydrogen atom from the 2-position of the thiazole ring, the ylide of thiamin is formed, which plays a central role in both the coenzymatic reaction of vitamin B1 and in non-enzymatic reactions such as the acyloin condensation.

The ability of thiamin to form a ylide can be rationalized in terms of molecular orbital theory and resonance structures.

However, there is still widespread disagreement about whether the 4′-amino group acts as an intramolecular acid or base in either the chemistry or the enzymology of ylide formation from thiamin.

2.5. Reduction

Thiamin can undergo reduction of the thiazole ring by various reducing agents, such as lithium aluminum hydride, sodium borohydride, to produce tetrahydrothiamin via the intermediate dihydrothiamin.

3. Biochemical Functions of Vitamin B1

Thiamin is an indispensable nutrient with several vital metabolic functions, and its inadequacy is linked to disturbances in carbohydrate metabolism, leading to harmful effects on nerve functions.

In biological systems, thiamin pyrophosphate, also known as TPP or cocarboxylase, is the only known biologically active form of thiamin. This compound is generated by the reaction between thiamin and ATP within hepatic cells.

As a coenzyme for enzymes involved in intermediate metabolism, TPP partakes in the decarboxylation of α-keto acids (pyruvate and α-ketoglutarate dehydrogenase complex) and in the reversible α-ketol transfer reactions catalyzed by transketolase in the pentose phosphate cycle.

Thiamin might serve as an active constituent in the nervous system. It has been hypothesized that thiamin, presumably as thiamin triphosphate, could play a critical function in stimulating peripheral nerves.

References