Honors Cup Synthetic Proposal - University of Michigan



Honors Cup Synthetic Proposal

Section: 210 group 4

Group Members: Yee Seng Ng,

Venus Famili,

Kristin Marie Stepanek

Title: synthesis of vanillin

Target molecule:

Vanillin (chemical name 3-methoxy-4-hydroxybenzaldehyde)

[pic]

Introduction:

Vanilla is defined by American Heritage dictionary as lacking adamants. But truly, it is the most ordinary yet highly appreciated flavor that has invaded every niche of the food industry. Vanillin, which is the chemical that we propose to synthesize, is the component that carries the very essence of vanilla. Vanillin is not only used as an ingredient in food flavors such as ice-cream and chocolates, its uses extend to the pharmaceutical industry as an important intermediate to many drugs. With such a great variety of uses, it is no wonder that there is a global demand of 3000 tonnes per year[1].

Since vanillin is found naturally in vanilla pod, one may question why vanillin is artificially synthesized. The answer lies in its cost. Vanillin costs only $15 a kg compared to $82 a kg of vanilla bean[2]. With its high worldwide demand and its high value/mass ratio, vanillin synthesis is an excellent project for investment.

The traditional synthesis of vanillin uses a Reimer-Tiemann reaction with guaiacol as a reactant. This reaction yields an 85% of vanillin which is formed along with ortho-vanillin as a sub-product. Ortho-vanillin (shown in figure 1) is a toxic substance which means that vanillin has to be separated from the mixture of the product to its purest form.

[pic]

Figure 1: ortho-vanillin, the hydroxyl group is in the ortho position.

Even with the best separation methods, a food production that leads to a toxic sub-product is not ideal. This leads us to explore a novel way of synthesizing vanillin. Our reaction starts with a para molecule and as a result, no ortho-vanillin will be produced as a sub-product.

Overall synthetic reaction scheme:

[pic]

Step 1

Synthetic transformation 1:

[pic]

4-hydroxybenzyl 4-hydroxybenzaldehyde

alcohol

Experimental 1

4-hydroxybenzaldehyde

0.871g of 4-hydroxybenzyl alcohol was mixed with 0.235 mL of HBr(48%) and 7.82 mL of DMSO and stirred in an oil bath at 100°C for 3 hours. To the reaction mixture were added 10 mL of brine followed by extraction with 40 mL of diethyl ether. The ether layer was washed with brine (20 mL). Ether in the mixture was evaporated and the subsequent solution was distilled to produce around 0.771 g of 4-hydroxybenzaldehyde. (note: boiling point of 4-hydroxybenzaldehyde is 117-119°C)

The ideal yield is 95% but the expected yield for this experiment was reduced to 90% to allow room for error[3].

Expected yield: 90% 0.771g

Safety, disposal and green issues 1:

Hydrobromic acid is a corrosive material, it must always be handled with care. Wear gloves and goggles whenever hydrobromic acid is handled.

Step 2

Synthetic transformation 2:

[pic]

4-hydroxybenzaldehyde 3-bromo-4-hydroxybenzaldehyde

Experimental 2

3-bromo-4-hydroxybenzaldehyde

Br2/MeOH solution was first prepared by dissolving 3.02 g of Br2 in 30 mL of methanol. The mixture was then cooled for 10 mins by swirling in an ice/water bath. 4-hydroxybenzaldehyde obtained from the previous synthesis step was added to the cold Br2 solution slowly with swirling. The reaction was quenched with 15ml of 5% aqueous sodium bisulfite after 30 seconds and swirled. The aqueous mixture was extracted with 100 mL diethyl ether. The solution was dried over sodium sulfate. Using rotary evaporation, around 0.699 g of 3-bromo-4-hydroxybenzaldehyde (a pink solid) was yielded.[4]

Expected yield: 65%[5] 0.699 g

Safety, disposal and green issues 2:

2.5M bromine solutions are extremely caustic and the vapors are dangerous as well. Bromine solution should be handled in the hood as much as possible.

Step 3

Synthetic transformation 3:

[pic]

3-bromo-4-hydroxybenzaldehyde 3-Methoxy-4-hydroxybenzaldehyde

Experimental 3

3-Methoxy-4-hydroxybenzaldehyde

3-bromo-4-hydroxybenzaldehyde obtained from the previous synthesis step was transferred to a 5mL reaction vial followed by the addition of sodium methoxide which was prepared by combinding 103 mL of a 4.0 M sodium methoxide in methanol solution, 4.01 mL of ethyl acetate, and 2.01 g of CuBr). The reaction vial was sealed and heated in the oil bath at 100°C for 1 hour. The mixture was cooled to room temperature and transferred to a separatory funnel. The solution was acidified with 3 M aqueous HCl until all solids were dissolved. The subsequent mixture was then extracted with 60 mL of diethyl ether. The organic extracts were combined, dried with Na2SO4 and filtered. The resulting solid was concentrated to form a dry powder on a rotary evaporator. Using 10% ethyl acetate in petroleum ether as the solvent, an elute column containing 10 g of flash silica gel was used to separate into 10 mL fractions. The fractions were checked by using TLC, comparing the results with an authentic sample of vanillin. Finally, the fractions containing vanillin was transferred onto a round bottom flask and the solvent was evaporated using a rotary evaporator, leaving vanillin (a yellowish crystalline compound).

The expected yield was reduced from 98% as written in the papers to allow room for error.

Expected yield: 80%[6] g

Safety, disposal and green issues 3:

4.0M sodium methoxide solutions are extremely caustic and very water sensitive. The lid of the container should be replaced immediately after use.

Despite being a chemical largely used in food industries, the vanillin produced in this synthesis should not be consumed in any way.

Overall budget:

|Chemical |Supplier |Cost ($) |Amt. Needed |Total ($) |

|4-hydroxylbenzyl alcohol |Pfaltz & Bauer, Inc. |1.50/gram |.871 g |1.31 |

|HBr |SpectrumChemical |.23/mL |.235 mL |.054 |

|DMSO |SpectrumChemical |.11/mL |7.82 mL |.86 |

|Diethyl ether |SpectrumChemical |.09/mL |200 mL |18.00 |

|Br2 |SpectrumChemical |.612/gram |3.02 g |1.84 |

|Aquastar H2O/methanol |Spectrum Chemical |.07/mL |30 mL |2.10 |

|standard | | | | |

|10% Sodium Bisulfate |Spectrum Chemical |.33/mL |7.5 mL |2.475 |

|Sodium Sulfate (anhydrous) |SpectrumChemical |.06/gram |.5 g |.03 |

|Sodium Methoxide |SpectrumChemical |.12/gram |22 g |2.64 |

|Ethyl Acetate |SpectrumChemical |.06/mL |4.01 mL |.24 |

|CuBr |SpectrumChemical |1.01/gram |2.01 g |2.03 |

|Petroleum ether |SpectrumChemical |.14/mL |100 mL |14.00 |

|Silica gel 40 |SpectrumChemical |.17/gram |10 g |1.70 |

|vanillin |SpectrumChemical |.16/gram |.005g |.0008 |

Total costs per synthesis: $ 47.28

References:

Introduction:





Step 1 synthesis:

Chunbao Li; Yanli Xu; Ming Lu; Zhuxuan Zhao; Lanjun Liu; Zheyuan Zhao; Yi Cui; Pengwu Zheng; Xioujie Ji; Guanjie Gao. Synlett 2002, issue 12, 2, 2041-2042.

Step 2 synthesis:



Anson, Christopher E.; Creaser, Colin S.; Malkov, Andrej V.; Mojovic, Ljubica; Stephenson, G. Richard. Journal of organometellic chemistry 2003, 668(1-2), 101-222.

Nobel, D. Cent. Rech. Carrieres, Rhone Poulenc Rech., Saint-Fons, Fr. Journal of the Chemical Society, Chemical Communications 1993, 4, 419-20.

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[1]

[2]

[3] Chunbao Li; Yanli Xu; Ming Lu; Zhuxuan Zhao; Lanjun Liu; Zheyuan Zhao; Yi Cui; Pengwu Zheng; Xioujie Ji; Guanjie Gao. Synlett 2002, issue 12, 2, 2041-2042.

[4]

[5] Anson, Christopher E.; Creaser, Colin S.; Malkov, Andrej V.; Mojovic, Ljubica; Stephenson, G. Richard. Journal of organometellic chemistry 2003, 668(1-2), 101-222.

[6] Nobel, D. Cent. Rech. Carrieres, Rhone Poulenc Rech., Saint-Fons, Fr. Journal of the Chemical Society, Chemical Communications 1993, 4, 419-20.

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