Samuel Bina, Chem 213 Synthetic 2: FFR Thiamine Catalyzed Benzoin Condensation Introduction: The benzoin condensation shown

in Figure 1 used in many organic syntheses. This is because the benzoin condensation creates a stereogenic center, and when a thiazolium catalyst is used, an enantiomeric excess of up to 33% can be generated.1 Also, benzoin is usable as a photoinitiator in the creation and hardening of various polymers using micro-emulsion.2

Figure 1. Synthesis of Benzoin Condensation reactions are used often in chemistry to create carbon-carbon bonds. Condensation reactions bond two molecules, releasing a smaller molecule such as water. In polymer chemistry, condensations are commonly used to create polymers, as the condensation adds new monomers, while leaving the monomers side chains intact.3 Similarly, condensation reactions are used in the creation of polypeptides within cells.4 The benzoin condensation is

technically a dimerization, since there is no smaller molecule released, but it works in a similar manner to condensations. The mechanism for the condensation of benzoin is shown below in Scheme 1. First, the secondary carbon alpha to the sulfur in thiamine is deprotonated by hydroxide. Then, this carbanion donates electrons to the aldehyde carbon in benzaldehyde, leaving a negative charge on the oxygen. The negative oxygen then attracts a proton, creating an alcohol group. The carbon attached to this alcohol is then deprotonated by hydroxide, leaving electrons to double bond this carbon to the thiamine, removing the charge from the positive nitrogen atom. The double bond then donates electrons to the aldehydic carbon from another benzaldehyde molecule, again creating a negative charge on the oxygen atom. This negative oxygen is then protonated, creating an alcohol, while the other alcohol is deprotonated, giving it a negative charge. To finish the condensation, the negative charge from the oxygen creates a double bond with the carbon, causing the now formed benzoin molecule to break away from the thiamine. Thiamine is then reprotonated, and the double bond between carbon and nitrogen is reformed using the lone pair from that nitrogen, reverting thiamine back to its original form.

Scheme 1. Mechanism of thiamine catalyzed benzoin condensation The purpose of this experiment is to synthesize and purify benzoin from benzaldehyde using a condensation reaction. The products of this reaction will be purified using recrystallization and analyzed with IR spectroscopy, 1H NMR spectroscopy, and melting point analysis.

Experimental: Benzoin. Thiamine hydrochloride (0.308 g, 0.913 mmol) was added to water (1 mL) at room temperature. Ethanol (3.5 mL, 95%) was added to the mixture in an ice bath. Sodium hydroxide (1 mL, 3M) was added to the reaction mixture, maintaining a temperature below 20 enzaldehyde in a water ath at .

m , pure was added to the reaction mixture. he reaction mixture was placed and stirred for two hours, monitoring by TLC (30% ethyl acetate in

hexanes). A white precipitate formed. The reaction mixture was left at room temperature overnight. The reaction mixture was cooled in an ice bath, vacuum filtered, and dried. Crude benzoin (561 mg) was recovered. Recrystallization (95% ethanol) recovered benzoin as fine, white crystals 7. mg, mp 1

H NMR (60 MHz CDCl3 ppm 7.9 (m, 2H),

m, 8H , .9 2 s, H , .

s, H IR A R max (cm-1) 3400, 3000, 1676.

Results and Discussion: Benzoin was synthesized from benzaldehyde, using thiamine and sodium hydroxide as catalysts for a dimerization reaction known as the benzoin condensation. Thiamine was used as the catalyst rather than cyanide, since cyanide is quite toxic. Benzoin was purified using recrystallization, allowing the liquid benzaldehyde to be easily filtered out, removing the orange color from the benzoin crystals. The identity of benzoin was confirmed using melting point analysis, 1H spectroscopy, and IR spectroscopy. he reported melting point of enzoin is obtained melting point range of the product was R . he

, which falls right at the reported

temperature. This suggests that the product was pure benzoin.

IR spectroscopy further confirmed the identity of the product as benzoin. Figure 2 in Supplemental Information shows the IR spectral data for the final product. The first peak at 3400 cm-1 suggests the presence of an alcohol group. The various peaks around 3000 cm-1 offer evidence of an aromatic ring. The peak at 1676 cm-1 suggests the ketone group present in benzoin. The presence of an alcohol group shows that this product is not benzaldehyde, as that peak would not be found in the spectrum for benzaldehyde. To fully confirm the identity of the final product, 1H NMR spectroscopy was employed. The 1H NMR spectral data can be found in Figure 3 in Supplemental Information. The two multiplets between 7 and 8 ppm that integrate to 10 hydrogen atoms suggest the presence of two separate aromatic rings, each with one substituent. The next peak is a one proton singlet at 5.9 ppm, which suggests an alcohol group. The final peak is also a one proton singlet, occurring at 4.5 ppm, which is indicative of the hydrogen atom attached to the chiral center of benzoin. Melting point analysis, IR spectroscopy, and 1H NMR spectroscopy confirm the identity of the final product as benzoin without any large impurities. This synthesis gave a percent yield of 45%. A similar experiment using cyanide rather than thiamine afforded a crude yield of 86% compared to the crude yield of 54% in this experiment.5 The low yield in this experiment was possibly due to loss of material during transfer between containers, as well as during filtration. It is also likely that the reaction did not run to completion, as the final TLC plate shows that, while the spot for the product is more intense, a spot is still present for benzaldehyde. The presence of benzaldehyde in the reaction mixture before precipitation and purification is shown by the orange color.

To improve the yield of this experiment, a few different steps could have been taken. The reaction could have been run on heat for a longer period of time, allowing the reaction to progress closer to completion. Also, the filtrate from the first vacuum filtration could have been stirred and heated, allowing it to react with most of the product removed, making equilibrium more favorable. The recrystallization gave a recovery of 83%, with little to no impurities.

References: 1. Enders, Dieter and Balenseifer, Tim. Nucleophilic Carbenes in Asymmetric Organocatalysis. Acc. Chem. Res. 2004, 37, 8, 534-541 2. Araujo, Jailson; Cruz, Fernanda; Cruz, Ivana; Cardoso, Dilson. Encapsulation of Polymers in CTA-MCM-41 Via Microemulsion. Microporous and Mesoporous Materials. 2013, 180, 14-21 3. Rubinshtein, M.; James, C.R.; Young, J.L.; Ma, Y.J.; Kobayashi, Y.; Gianneschi, N.C.; Yang, J. Facile Procedure for Generating Side Chain Functionalized Poly(alpha-hydroxy acid) Copolymers from Aldehydes via a Versatile Passerini-Type Condensation. Org. Lett. 2010, 12 (15), 35603563. 4. Ochoci, Agata; Bethel, Paul; Sweeney, Joseph. Catalytic Synthesis of Riboside-Amino Acid Hybrids. Synlett. 2013, 24, 2170-2172. 5. Kuebrich, John; Schowen, Richard; Wang, Maw-song; Lupes, Mircea. The Mechanism of the Benzoin Condensation. Journal of the American Chemical Society. 1971. 93, 5, 1214-1220