Converting Benzaldehyde to Benzilic Acid A Multistep Synthesis PDF

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Converting Benzaldehyde to Benzilic Acid A Multistep Synthesis...

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Converting Benzaldehyde to Benzilic Acid: A Multistep Synthesis

November 14, 2013

Abstract Through a multistep synthesis benzaldehyde was converted to benzilic acid. Using thiamine-catalyzed condensation benzaldehyde was converted to benzoin. Benzoin was converted to benzil by copper-catalyzed oxidation. The resulting benzil was treated with hydroxide ion to promote a benzilic acid rearrangement. The melting point was determined and was within literature values of benzilic acid; indicating high purity of the product. Introduction Multistep synthesis is a sequence of reactions intended to produce a specific molecule as the final outcome. Each reaction produces a product that is used in the next reaction, until the target molecule is attained as the final product. “Cells within living organisms are capable of performing highly efficient and selective multistep biosynthesis under mild conditions with all reactants simultaneously present in the solution.”¹ Multistep syntheses are also useful in the construction of organic based molecules such as pharmaceuticals. The conversion of benzaldehyde for the formation of benzilic acid is beneficial. The uses for benzilic acid are limited. “The main use of benzilic acid is in the manufacturing of glycollate pharmaceuticals including Clidinium, Dilantin, and Flutropium. These are used as antagonists of the muscarinic acetylcholine receptors.”² Benzilic acid is also used in the engineering of hallucinogenic drugs and chemical weapons.² According to W. Johnson the rearrangement of benzil to benzilic acid rearrangement, was the first demonstrated case of a rearrangement. Benzilic acid can be synthesized by a couple of common methods. It can be prepared by heating a mixture of benzil, alcohol, and potassium hydroxide. Benzilic acid can also be manufactured

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using benzaldehyde, which dimerizates to benzil and it is further transformed by benzilic acid rearrangement to benzilic acid For the condensation of benzoin thiazolium salts are effective catalyst. 3 Because of the toxicity of thiamine pyrophosphate (TPP) a green reagent, thiamine hydrochloride, is used in its place which allow the reaction to proceed into the right direction. The initial carbanion produces in the reaction between thiamine and sodium hydroxide acts a nucleophile forming a thiazole derivative by adding to the benzaldehyde carbonyl group. 3 Proceeding protonation the benzaldehyde equivalent forms a second intermediate. The resonance effects cause an increased acidity which forms a second carbanion which then forms an oxyanion. “The oxyanion is in equilibrium with a protonated oxyanion which eliminates the catalyst and forms benzoin.”3

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Benzoin can be oxidized diketone because it possesses both a ketone functional group and a secondary alcohol it can also be reduced to a diol but for the purposes of this experiment only oxidation was used. A common oxidizing reagent for this experiment could include but not limited to nitric acid however, nitric acid produces toxic nitrogen dioxide gas. Therefore, catalytic copper(II) acetate is used as the oxidizing agent, with ammonium nitrate used to regenerate the catalyst. The redox reaction of benzoin with Cu2+ forms the benzoin radical, which is then is deprotonated which stabilizes the radical, allowing a second redox reaction to occur. The radical replaces Cu2+ forming a cation which protonated, thus forming benzil.

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The rearrangement of benzilic acid occurs benzil is treated with the hydroxide ion. 3 After the addition of the hydroxide ion, the phenyl group transfers to the other carbonyl carbon forming benzilate anion. Proceeding the addition of the acid the benzilate anion product is then neutralized forming benzilic anion by the addition of an acid. The final product is separated from the byproduct by addition of the reaction mixture. For each step of the experiment the melting point was determined and the Infrared Spectroscopy was assessed to assure that the reaction was progressing correctly and the correct products were attained.

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Experimental For the condensation of benzoin in a vial 0.170g was dissolved in 350 µL of distilled water. While the mixture was stirred 0.5 mL of 2M sodium hydroxide was added dropwise and mixed until homogeneous, the mixture reacted for 7 days. To complete crystallization the reaction vial was placed in an ice bath for 5 minutes. The crystals were filtrated and rinsed with

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2mL of chilled distilled water. The crude product was recrystallized using 8.2mL of 95% ethanol, used as the boiling solvent and the melting point was determined. During the oxidation of benzoin, the benzoin product obtained from the condensation of thiamine hydrochloride, 2.60mL of glacial acetic acid was added along with 0.4g of NH 4NO3 and 0.9g of Cu(OAc)2 and the mixture was refluxed for one hour. Thin layer chromatography was used to monitor the reaction and the melting point and refractive index was determined. 10mL of ice water was added with the reaction mixture, and crystallization was induced, then vacuum filtrated. The crude product was then recrystallized with 3.0mL of 95% ethanol as the boiling solvent. The crystals were filtrated and the melting point and the Infrared Spectra were determined to further classify the product. In the rearrangement of benzilic acid, 0.5mL of ethanol, and 0.25mL of 30% of aqueous KOH were added to a test tube along with the benzil. The mixture was heated to boiling then refluxed for 15 minutes. 2mL of distilled water and 1mL HCl was added to the reaction mixture in order to precipitate it. Decolorizing carbon was added to assist in separating the filtrate from the by-product, through gravity filtration. The benzilic acid was precipitated with the use of 2mL of HCL, then filtrated. The benzilic acid crystals were used to determine the melting point. The Infrared Spectra was also used to classify to structure of the molecule.

Results/Discussion Though out this experiment, the results, melting point and appearance, lined up fairly well with the literature values of the desired products in each of the different parts. A decrease in the percent recovery from benzaldehyde can be seen through the progression of this multistep

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synthesis, especially through the second part of this synthesis. The summarization of the results for each part along with the comparison to the documented literature values. In the first part of this multistep synthesis, benzaldehyde was converted to benzoin. The reaction mixture, after the NaOH was added to the thiamine and ethanol, was yellow in color. This could have been an indication of the oxidation of the thiamine molecules. After the reaction mixture sat for 7 days in a cool room, the color noted was more of an orange color with white crystals. Benzoin is documented as having white to off white colored crystals. 4 A fair amount of crystals were already visible before placing the reaction mixture in an ice bath. The melting point that was obtained for the produced benzoin was with close proximity of literature melting point values for benzoin is 135-137°C. This indicates that there was a slight impurity to the resulting product. Some possible causes for impurity might be due to unclean glassware leading to contamination or improper measurement of reactants added during the experiment. The second part of this multistep synthesis of benzilic acid involved the conversion of benzoin to benzil. Upon the addition of copper (II) acetate, the solution took on a blue-greenish color that dissipated through the reflux. By monitoring the retention factor (Rf) value of the reaction mixture, the progress of the reaction was determined. The final TLC plate indicated that there was still a presence of benzil in the reaction mixture. The product for this part of the synthesis showed spots of the same Rf value for both benzil and benzoin; indicating that there was an incompletion of this reaction. This could have been due to the reaction mixture not refluxing at a high enough temperature. The product percent yield from benzaldehyde was 83%. The melting point of this product was 92°C-94.3°C. The literature value melting point of benzoin is 94°C-95°C. The benzoin crystals obtained during this part of the experiment were at first light

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yellow in color. After 7 days of drying, the crystals appeared to be a darker yellow color. Benzil has been documented as having a yellow color. 4 In the final part of this experiment, Benzil was rearranged and treated with acid to form benzilic acid. While refluxing the reaction mixture during this part of the experiment, the mixture turned from a yellow liquid to a blue liquid to a brown liquid. This indicated that the benzil was dissolving and that the rearrangement was occurring. After adding the reaction mixture to the 1M HCL, the mixture turned white and had the appearance of milk with orangebrown precipitate that formed on the bottom of the flask. The orange-brown sticky precipitate the settled on the bottom on the flask was the byproduct of this reaction, diphenylmethanol. Upon the addition of the decolorizing carbon and after letting the reaction mixture gravity filter, the liquid produced from this step was perfectly clear and looked like water. After adding the liquid to the 1M HCL in the final step, the final product appeared thick and white in color. The appearance and color indicate the desired product of benzilic acid. Benzilic acid has been documented as having a white to off white color or tan.3

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Table 1: Benzoin Condensation mL Amount of benzaldehyde used

g

1mL

Product obtained, before recrystallization Product obtained, after recrystallization Product theoretically yield Recovery from recrystallization % Product percent yield % Melting point

1.044g

mol 9.84 x 10-3

1.139g

0.00537mol

0.867g

0.00408mol

1.04g

0.00489mol 76.12% 83.37%

132.3°C-134.9°C

Table 2: Benzoin Oxidation g

mol

Amount of benzoin used

0.867g

0.00408mol

Product obtained, before recrystallization

0.371g

0.01764mol

Product obtained, after recrystallization

0.286g

0.0136mol

Product theoretical yield from amount benzoin used Product theoretical yield from beginning benzaldehyde

0.859g

0.00408mol

1.04g

0.00489mol

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Recovery from recrystallization %

77.1%

Product percent yield from bezoin, %

33.3%

Product percent yield from benzaldehyde, %

27.5%

Melting point of Benzil

92.6°C-94.2°C

Table 3: TLC Refractive Index Rf 0.2547 0.4713

Benzoin Benzil Product

0.3822

0.5605

Table 4: Benzilic Acid Rearrangement

Amount benzil used Amount benzilic acid produced Theoretical yield benzilic 10 | P a g e

g 0.202g 0.136g

mol 0.000962mol 0.000597mol

0.2191g

0.00961mol

acid from amount benzil used Theoretical yield benzilic acid from amount benzaldehyde Product percent yield from benzil, % Product percent yield from benzaldehyde, %

1.122g

0.00492mol

62.1% 12.1%

Conclusions

In this experiment, benzaldehyde was converted to benzilic acid in a multistep synthesis. The final percent yield from benzaldehyde was 12.1%. The biggest drop in percent yield can be seen in the recrystallization of benzil. This could be due to overheating the ethanol, using too much ethanol, or by allowing the mixture to boil too long in the ethanol. Through more careful measurements of reactants and monitoring the temperatures of the reaction mixtures during reflux more carefully, the percent yield could have probably been increased. Over all, this method of producing benzilic acid from benzaldehyde is inexpensive and easy to accomplish, but was rather time consuming and produced a lower than desired amount of product.

Bibliography 1. He, Y; Liu D.R. Autononmous multisteporganic synthesis in a single isothermal solution

mediated by a DNA walker [Online] 2010 http://evolve.harvard.edu/66-DNA%20Walker %20Multistep%20DTS-%20Nat%20Nano.pdf (accessed November 13, 2013).

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2. Johnson W. S. Nerve Agent Precursors:Benzilic acid and Methyl Benzilate [Online] 2004 http://cbwinfo.com/Chemical/Precursors/p25.html (accessed November 13, 2013).

3. Staudt, M., Stranz, M. Chemistry 2011 Cengage Learning: Ohio, 2011; p 65-87. 4. Klien, D Organic Chemistry; John Wiley &Sons, Inc.: New Jersey, 2012; p 940, 946.

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