Honors Cup Synthetic Proposal Section: 221 Group Members: Michelle (Yoon Young) Choi Yazhuo (Grace) Liu Beth Parker Shruti Saran Title: Synthesis of Vanillin from Catechol Introduction: Vanillin (4-hydroxy-3-methoxybenzaldehyde) is a synthetic compound used extensively as a flavoring agent in many foods like chocolate, ice cream, and baked goods. It is also used for its pleasant scent in perfumes and is a flavoring agent in beverages. A large amount of vanillin (about 40% of all synthesized) is used as a pharmaceutical intermediate as well. Vanillin is available from three different sources: the vanilla bean itself, from guaiacol, or from lignin. The following synthesis uses, as most of the chemical industry does, the guaiacol route. However, to be more cost efficient, we will synthesize guaiacol from catechol. Thus, the first step of the synthesis will be making guaiacol from catechol. Then, the guaiacol will be changed into vanillylmandelic acid (VMA). Finally, the VMA will be converted into vanillin. Target Molecule: Vanillin 4-hydroxy-3-methoxybenzaldehyde (C8H8O3) OHOCH3OOverall synthetic reaction scheme: OHOHOHOCH3NaOHCH3CH2ClOOHONaOHH2OOCH3HOOOHOHBi(0) (10%)DMSO, O2 (1atm)AcOH, 125ºCOHOCH3OStep 1 Synthetic transformation 1: OHOHOHOCH3NaOHCH3CH2Cl Experimental 1 Monomethylation of Catechol Unable to find detailed procedures. Expected yield: Safety, disposal and green issues 1: Safety Safety is a concern when dealing with many aromatic compounds, and catechol is no different. It is stable but care should be taken to limit exposure to air and light. It is a mutagen, tumorigen, and reproductive effector. It may also cause burns. It is harmful when inhaled, ingested, or absorbed by the skin. Chloroethane is a recognized carcinogen and must be used with precautions to exposure. It is very important to wear goggles, gloves, cap the bottle, and keep it under a hood when dealing with these chemicals. Sodium hydroxide is very corrosive and should be used with care also. Disposal When disposed of, catechol should be separated from strong oxidants and kept in the dark. Ventilation is also suggested. Chloroethane should not be stored with oxidants, where moisture can collect, and caution must also be taken if storing this with exposure to air. Sodium hydroxide should be stored in a container with similar bases. Green Catechol is a relatively inexpensive chemical. It is about $3.30 per gram. NaOH is a substance already found in the lab, which costs around 10 cents a gram, depending on the type used. Chloroethane is inexpensive as well, at roughly 67 cents per gram.Step 2 Synthetic transformation 2: OHOCH3OOHONaOHH2OOCH3HOOOHOH Experimental 2 Electrophilic Substitution of Glyoxylic Acid on Guaiacol Unable to find detailed procedures. Expected yield: Safety, disposal and green issues 2: Safety Guaiacol (the product of step 1) is not known to be extremely toxic, but may affect the central nervous system. It is hazardous with eye contact, ingestion, or inhalation. It is also slightly hazardous with skin contact as an irritant. It should be used only in a well-ventilated area. Glyoxylic acid is somewhat corrosive, so skin contact should be avoided, as with sodium hydroxide. Disposal Guaiacol should be kept in a cool, well-ventilated area. It should not be stored near oxidizing agents, acids, or bases. Glyoxylic acid should be kept around room temperature, but is relatively stable. Sodium hydroxide should be stored with other bases. Green In this step, guaiacol has been synthesized, so we do not need to purchase it. NaOH has already been purchased, and H2O can be taken directly from the labs’ faucets. The only compound to be purchased for this step is glyoxylic acid. This is inexpensive, at 81 cents per gram for glyoxylic acid monohydrate. In a 50:50 solution with water, it is 18 cents per milliliter.Step 3 Synthetic transformation 3: OHOCH3OHOOHOHOCH3OBi(0) (10%)DMSO, O2 (1atm)AcOH, 125ºC Experimental 3 Catalytic Oxidative Decarboxylation of VMA The commercially available products were used without further purification. The reactions were carried out under atmospheric pressure of molecular oxygen. 4-hydroxy-3-methoxy mandelic acid (vanillylmandelic acid or VMA) (2 mmol) was dissolved in DMSO (5 mL) in the presence of Bi(0) powder (0.2 mmol) and 3 mmol of ACOH (50% aqueous solution). The mixture was stirred at 125ºC for 40 minutes. The crude reaction mixture was hydrolysed with 5 mL aqueous 1 M HCl solution saturated with NaCl, and extracted with ethyl acetate (5×10 mL). Organic phases were collected and washed twice with an aqueous 0.1 M HCl solution saturated with NaCl, dried over MgSO4 and filtered off. Expected yield: 87% Safety, disposal and green issues 3: Safety DMSO is a skin, eye, and respiratory irritant. Bismuth powder is not significantly toxic. Acetic acid and and hydrochloric acid are corrosive, so care should be taken to avoid exposure to skin and eyes. HCl especially shouldn’t be inhaled and kept under a hood. Sodium chloride is relatively safe, causing only eye irritation if exposed. Ethyl acetate is an irritant, but only significantly harmful if swallowed. Magnesium sulfate may be harmful if swallowed and is an irritant. Disposal DMSO shouldn’t be stored with acid chlorides, strong acids, strong oxidizing agents, strong reducing agents, phosphorus halides, moisture, copper wool + trichloroacetic acid because it canreact violently with a number of agents. Bismuth should not be stored with strong acids, strong oxidizing agents, nitrosyl fluoride, fused ammonium nitrate, interhalogen compounds, and chlorine. It is also potentially flammable. Acetic acid should be stored with other acids, avoiding metals, oxidizing agents, alcohols, aldehydes, etc. Hydrochloric acid shouldn’t be stored with metals, strong bases, carbonates, etc. Sodium chloride shouldn’t be stored with strong oxidizing agents but is otherwise stable. Ethyl acetate should be kept in a dry place, out of contact with strong oxidizing agents. MgSO4 is stable and can be stored under many conditions. Green DMSO is relatively expensive at about $1.56 per mL; however, only 5 mL are needed. Bismuth powder is about $2.30 per gram. Again, a very slight amount is needed. Acetic acid is about 80 cents per gram. HCl is inexpensive at around 7 cents per milliliter. NaCl is found at a price