Abstract

3,4,5-Trimethoxybenzaldehyde is a naturally occurring compound found in various plants, including Zanthoxylum ailanthoides and Cassia grandis. This compound serves as a valuable intermediate in the synthesis of several pharmaceutical drugs, including trimethoprim, cintriamide, roletamide, trimethoquinol (also known as tretoquinol), and trimazosin. Additionally, it plays a role in the synthesis of certain psychedelic phenethylamines.

Moreover, 3,4,5-Trimethoxybenzaldehyde is of interest in the field of organic chemistry due to its versatile reactivity and its ability to serve as a building block for the synthesis of various other compounds. Researchers and pharmaceutical chemists utilize its unique chemical structure as a foundation for designing and developing new drugs with enhanced efficacy and reduced side effects. The compound’s natural occurrence in different plant species underscores its ecological significance and biological relevance. Scientists continue to explore its potential applications in drug discovery and other fields, making it a subject of ongoing research and study. This article presents a comprehensive overview of 3,4,5-Trimethoxybenzaldehyde, including its general information, physico-chemical properties, Chemical Reactions, synthesis of 3,4,5-Trimethoxybenzaldehyde, conclusion and bibliography.

General Information About 3,4,5-Trimethoxybenzaldehyde [1-5]

Other synonyms names of 3,4,5-Trimethoxybenzaldehyde are: 3,4,5-Trimethoxybenzolcarbaldehyd; Eudesmic aldehyde; Trimethylgallic aldehyde

IUPAC Name of 3,4,5-Trimethoxybenzaldehyde: 3,4,5-trimethoxybenzaldehyde

CAS number is 86-81-7

Physico-Chemical Properties of 3,4,5-Trimethoxybenzaldehyde [1-5]

• Molecular Formula C₁₀H₁₂O₄
• Molar Weight 196.20 g/mol
• Melting Point 72-77 ℃
• Boiling Point 163-165 °C / 10 mm (337.6424-340.371 °C / 760 mmHg)
• Density 1.367 g/cm³
• Solubility: Slightly soluble in water; 0.1 g/mL in Methanol; in clear Indofine
• Color/Form: Light yellow flakes

Structural formula present on Figure 1.

Powder and crystalline solid possible of 3,4,5-Trimethoxybenzaldehyde the can be seen in the picture provided in Figure 2.

Chemical Reactions

The hydrogenation of aromatic aldehydes is a chemical reaction in which hydrogen gas (H₂) is added to an aromatic aldehyde molecule, resulting in the reduction of the aldehyde functional group (-CHO) to a primary alcohol functional group (-CH₂OH). This process involves the breaking of a carbon-oxygen double bond and the formation of a carbon-hydrogen single bond.

Aromatic aldehydes are organic compounds containing both an aromatic ring and an aldehyde group. The hydrogenation of these compounds typically requires a catalyst, such as a metal catalyst (e.g., palladium, platinum, or nickel), and high pressure. The reaction conditions can be controlled to selectively produce the corresponding aromatic primary alcohol.

This reaction has significant importance in the field of organic synthesis. Aromatic alcohols obtained through hydrogenation reactions are valuable intermediates for the synthesis of various pharmaceuticals, agrochemicals, and fine chemicals. Additionally, hydrogenation of aromatic aldehydes is a key step in the production of certain fragrances and flavoring compounds, enhancing their aroma and taste properties. Figure 3

The interaction of aromatic aldehydes with hydrogen cyanide (HCN) in the presence of bases represents an important chemical reaction. In this process, an aromatic aldehyde reacts with hydrogen cyanide, a compound containing a cyanide ion (CN⁻) and a hydrogen ion (H⁺), in the presence of bases, which act as catalysts or facilitators for the reaction. Bases, such as sodium hydroxide (NaOH) or potassium hydroxide (KOH), play a crucial role in this reaction by facilitating the formation of the reactive cyanide ion. The presence of these bases enhances the reactivity of the reaction and promotes the formation of desired products.

The reaction typically involves the addition of the cyanide ion to the carbonyl carbon of the aldehyde group in the aromatic aldehyde. This addition forms a cyanohydrin intermediate, which can undergo further transformations depending on the specific reactants and reaction conditions.

Cyanohydrins obtained from this reaction are valuable intermediates in organic synthesis. They are utilized in the preparation of pharmaceuticals, agrochemicals, and fine chemicals. Additionally, cyanohydrins serve as precursors in the synthesis of α-amino acids, which are essential building blocks in the formation of peptides and proteins. Figure 4

The interaction of aromatic aldehydes with sodium hydrosulfite. Figure 5

The formation of imines from aromatic aldehydes with ammonia or amines is a key chemical transformation in organic synthesis. An imine is a functional group that contains a carbon-nitrogen double bond (C=N). This reaction involves the condensation of an aromatic aldehyde with either ammonia (NH₃) or amines (organic compounds derived from ammonia by replacing one or more hydrogen atoms with organic groups).

In this reaction, the aldehyde group (-CHO) of the aromatic aldehyde reacts with the amino group (-NH₂) of ammonia or amines. The nucleophilic amino group attacks the electrophilic carbon atom of the aldehyde, leading to the formation of an intermediate called a Schiff base. This Schiff base can then further react with additional reagents to form various compounds, making it a versatile intermediate in organic synthesis.

The formation of imines is widely used in the synthesis of a variety of nitrogen-containing compounds, including pharmaceuticals, dyes, and complex organic molecules. Imines can also serve as intermediates in reactions leading to the formation of amines, which are essential building blocks in the synthesis of many biologically active compounds. Figure 6.

Aromatic aldehydes are organic compounds containing both an aromatic ring and an aldehyde functional group (-CHO). When these aldehydes react with oxidizing agents, they undergo oxidation, a chemical process where the aldehyde group loses electrons, leading to the formation of carboxylic acids or other oxidized derivatives. Figure 7.

Aromatic aldehydes react with acetaldehyde at elevated temperatures. Figure 8.

The synthesis of mescaline from 3,4,5-trimethoxybenzaldehyde involves several chemical reactions and transformations. Mescaline is a naturally occurring psychedelic alkaloid found in certain cacti, most notably Peyote (Lophophora williamsii) and San Pedro cactus (Echinopsis pachanoi). Due to its psychoactive properties, mescaline is classified as a controlled substance in many countries.

The synthesis of mescaline from 3,4,5-trimethoxybenzaldehyde typically proceeds through a series of steps, including reductive amination and other chemical modifications. One common route involves the reaction of 3,4,5-trimethoxybenzaldehyde with nitromethane, followed by reduction. Figure 9.

Reaction with Grignard reagent. Figure 10.

Reaction with PCl₅. Figure 11.

Reaction with HBr. Figure 12.

Synthesis of 3,4,5-Trimethoxybenzaldehyde [9]

Bromination of vanillin in methanol gave 5-bromovanillin directly from the reaction medium in 95% yield. Treatment of 5-bromovanillin in DMF with four equivalents of freshly prepared sodium methoxide in the presence of a catalytic amount of cuprous chloride gave, after acidification, syringaldehyde in 91% yield. Methylation of syringaldehyde with dimethylsulfate in the presence of Na₂CO₃ gave 3,4,5-Trimethoxybenzaldehyde in 91% yield. The synthesis is detailed in [9].

Synthesis of starting from and according to the scheme Figure 13.

Conclusion

The study of 3,4,5-Trimethoxybenzaldehyde has proven to be a rich and diverse area of research, encompassing its synthesis, physico-chemical properties, and various reactions. The compound’s significance lies not only in its natural occurrence but also in its utility as a versatile intermediate in organic synthesis.

The exploration of 3,4,5-Trimethoxybenzaldehyde has provided valuable insights into its reactivity and its potential applications, ranging from the synthesis of pharmaceutical drugs, including mescaline, to its role as a building block in the creation of complex organic molecules.

Bibliography

1. https://en.wikipedia.org/wiki/3,4,5-Trimethoxybenzaldehyde
2. https://pubchem.ncbi.nlm.nih.gov/compound/6858
3. https://www.chemspider.com/Chemical-Structure.6597.html
4. https://en.wikipedia.org/wiki/Mescaline
5. https://en.wikipedia.org/wiki/Vanillin
6. https://en.wikipedia.org/wiki/Grignard_reaction
7. https://en.wikipedia.org/wiki/Ether
8. https://bbgate.com/threads/mescaline-synthesis-with-nitromethane-1000g-scale.76/
9. Percy S. Manchand, Peter S. Belica, Harry S. Wong Synthesis of 3,4,5-
   Trimethoxybenzaldehyde. SYNTHETIC COMMUNICATIONS, 1990, 20, 17, pp. 2659 – 2666. https://doi.org/10.1080/00397919008051474 https://www.tandfonline.com/doi/abs/10.1080/00397919008051474