Post Lab #7 - I earned an A in this lab class. PDF

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Experiment #7: Friedel-Crafts Acylation of Ferrocene Name: Danielle Curtis Lab Partners: Virginia Van Grod and Yefrain Munoz TA: Katrinah Tirado

Introduction/Background Discovered in 1951, ferrocene has a chemical sandwich structure in which two anionic cyclopentadienyl rings each donate 6 ∏ electrons to the Fe2+ cation that resides between them.1 The cyclopentadienyl rings in ferrocene make the compound aromatic because each ring contains 6 delocalized ∏ electrons, similar to benzene, which follows the 4n+2 rule.1 This is apparent because when ferrocene is deprotonated by a strong base, a lone pair of electrons can combine with the 4 electrons from the two ∏ bonds to establish aromaticity within each ring.1 Ferrocene is a compound that can be easily prepared and purified in the laboratory using dicyclopentadiene, potassium hydroxide and iron chloride tetrahydrate.2 First, dicyclopentadiene is cracked via heating into a monomer – the cyclopentadiene is continuously distilled over.2 Then, the cyclopentadiene is deprotonized using a strong base, like potassium hydroxide.2 Finally, iron is added to the mixture, like in the form of iron chloride tetrahydrate, to form ferrocene.2 Due to its aromaticity, ferrocene undergoes Friedel-Crafts acylation and alkylation.3 It can also be formylated, sulfonated or metalated with n-butyllithium, phenylsodium and mercuric acetate.3 Ferrocene has the ability to be arylated with diazonium salts, as well as treated with isocyanates to produce amides.3 However, unlike typical aromatic compounds, ferrocene does not have the ability to undergo reactions like nitration or direct halogenation because it leads to the destruction of the molecule.3 This is most likely due to the oxidation of the iron atom.3

Friedel-Crafts acylation is an example of an electrophilic aromatic substitution reaction that involves the interaction of an arene with either an acyl chloride or anhydride, in the presence of a strong Lewis acid catalyst to produce a monoacylated product.4 A complex is formed between the Lewis acid and chlorine atom of the acid chloride, or the oxygen atom of the anhydride, to form an acylium cation.4 The acylium cation then acts as an electrophile and reacts with the nucleophilic arene to yield the monoacylated product, which is an aryl ketone.4 Friedel-Crafts reactions will not proceed when there are any strong activating, moderate deactivating or strong deactivating substituents on the aromatic compound involved in the reaction.4 The reaction will only proceed when there are weak activating or deactivating substiutents.4 For example, benzene can undergo a Friedel-Crafts acylation in the presence of ethanoyl chloride and AlCl3. The AlCl3 interacts wit ethanoyl chloride to form the acylium cation.4 Then, the cation is attacked by nucleophilic benzene to produce acetophenone.4 For this experiment, ferrocene can be acylated in much milder conditions because it has a high ∏ electron density.5 Therefore, acetic anhydride interacts with phosphoric acid to form the acylium cation.5 The cyclopnetadienyl ring of ferrocene attacks the acylium cation, resulting in the substitution of an acetyl group for an aromatic proton.5 Friedel-Crafts acylation is an important electrophilic aromatic substitution reaction mechanism because it is a valuable alternative to Friedel-Crafts alkylation.6 Alkylation reactions are prone to carbocation rearrangements, meaning the product is more reactive than the starting material, thus posing the problem of polyalkylated products.6 Where as, the product of Friedel-Crafts acylation is more deactivated and less

reactive than the starting material.6 Therefore, the product does not undergo a second substitution and remains monoacylated.6

Acetic anhydride

Phosphoric Acid

Acylium Intermediate

Ferrocene

Acetyl Ferrocene

Figure 1: Mechanism for Fridel-Crafts Acylation of Ferrocene Nitration Resulting in Ortho Product

Acetyl Ferrocene

Acylium Intermediate

1,1’ – diacetylferrocene

Figure 2: Mechanism for the Possible Side Reaction

Deprotonation

Experimental Section: 0.09 g of ferrocene, 0.35 mL of acetic anhydride and 0.1 mL of 85% H3PO4 was added to a small test tube that had been thoroughly cleaned and dried. A drop of pure ferrocene was spotted on a TLC plate. The test tube was capped and placed over a steam bath for 10 minutes. A drop of this mixture was spotted on the TLC plate after 10 minutes.

The dissolved crude product was transferred to the column and allowed to elute. Hexanes were used to push the unreacted ferrocene (a yellow band) down the column. The yellow band was collected in a clean test tube. The contents of the yellow band were spotted on the TLC plate. After the yellow band fully eluted, a 50:50 (hexane:diethyl ether) mixture was used to elute the acetyl ferrocene (a red band) from the column. The red band was collected in a clean vacuum Erlenmyer flask.

The red band was spotted on the TLC plate and the plate was run in the TLC chamber. Both TLC plates were placed in an iodine chamber and the Rf values were recorded. Both products (red and yellow) were dried via vacuum filtration

The mixture was allowed to run over the steam bath for an additional 10 minutes. A drop was placed on the TLC plate after 10 minutes. The TLC plate was placed in a TLC chamber containing a solvent of 30:1 (toluene:ethanol) mixture. The Rf values were recorded. The test tube was placed on ice and allowed to cool. After cooling, 0.5 mL of ice water was added to the test tube dropwise. 3 M NaOH aq. was added to the test tube dropwise until the mixture had a neutral pH. pH was checked using litmus paper.

The crude product was dried using a Hirsch funnel and air. The crude product was weighed and a small sample was saved for melting point analysis. The crude product was dissolved in a minimal amount of hexanes and dotted on a new TLC plate. A microscale column was set up for column chromatography. Hexanes were added to the column to wet it and added occasionally so that it never dried.

Mass of both products was recorded and melting point was obtained for both products. A 1H NMR spectra was obtained for the acetyl ferrocene (red) product.

Chemicals Used: Name of Chemical IUPAC Name Formula Molar Mass Melting Point Boiling Point Density Safety

Ferrocene Bis(cyclopentadienyl)iron C10H10Fe 186.04 g/mol 172.5C 249C 1.11 g/cm3 > Eye/skin irritant > Combustible at high temperatures

Acetic Anhydride Ethanoic anhydride C4H6O3 102.09 g/mol -73C 139.8C 1.08 g/cm3 > Eye/skin irritant > Corrosive to skin > Skin permeator > Flammable

Chemical Structure

Table 1: Table of Chemicals – Starting Material and Reagent Name of Chemical IUPAC Name Formula Molar Mass Melting Point Boiling Point Density Safety

Phosphoric Acid Phosphoric acid H3PO4 97.994 g/mol 42.35C 158C 1.88 g/cm3 > Eye/skin irritant > Corrosive to eyes/skin > Skin permeator

Chemical Structure

Table 2: Table of Chemicals – Catalyst and Product Name of Chemical IUPAC Name

Acetyl Ferrocene Acetyl ferrocene

Acetic Acid Acetic acid CH3COOH 60.05 g/mol 16.6C 117.9C 1.05 g/cm3 > Skin/eye irritant > Corrosive to skin/eyes > Skin permeator > Flammable

Formula Molar Mass Melting Point Boiling Point Density Safety

C12H12FeO 228.07 g/mol 85-86C 161-163C 1.01 g/cm3 > Skin/eye irritant > Fatal if ingested

Chemical Structure

Results: Appearance of Product Crystals appeared white, fine and flakey Color of Product White Melting Point 84˚C Mass of Crystals 0.226 g Percentage Recovered 13.3% Rf of Pure Ferrocene 0.98 Rf of Crude (10 minutes) 0.58 Rf of Crude (20 minutes) 0.6 Table 3: Data Collected from the Crude Product Appearance of Product #1 Product was a flakey, yellow substance Color of Product #1 Yellow Melting Point #1 105˚C Appearance of Product #2 Product was a flakey, red substance Color of Product #2 Red Melting Point #2 88˚C Mass of Product #2 0.03 27.5% Percentage Yield of Product #2 Rf of Crude Ferrocene 1 and 0.15 Rf of Product #1 1 Rf of Product #2 0.175 Table 4: Data Collected from the Unreacted Ferrocene (#1) and Acetyl Ferrocene (#2) Product

Table 3:1 H NMR Spectra for Acetyl Ferrocene Product

CALCULATIONS: 0.09 g C10H10Fe x 1 mol C10H10Fe 186.04 g/mol C10H10Fe

x 1 mol C12H12FeO = 0.00048 mol C12H12FeO 1 mol C10H10Fe

0.38 g CH3COOH x 1 mol CH3COOH x 60.05 g/mol CH3COOH

1 mol C12H12FeO = 0.00633 mol C12H12FeO 1 mol CH3COOH

*Therefore, C10H10Fe is the limiting reagent Calculation 1: Determining the Limiting Reagent

0.00048 mol C12H12FeO x 228.07 g/mol C12H12FeO = 0.109 mol C12H12FeO 1 mol C12H12FeO

Calculation 2: Determining Theoretical Yield

% Yield = Actual Yield x 100% = 0.03 g C12H12FeO x 100% = 27.5% Theoretical Yield 0.109 g C12H12FeO Calculation 3: Determining % Yield

% Recovered = Mass of Pure Product x 100% = 0.03 g x 100% = 13.3% Mass of Crude Product 0.226 g Calculation 4: Determining % Recovered

Rf of Pure Ferrocene = Distance Spot Travels = 4.9 cm = 0.98 Distance Solvent Travels 5 cm Rf of Crude Product (10 mins) = Distance Spot Travels = 2.9 cm = 0.58 Distance Solvent Travels 5 cm Rf of Crude Product (20 mins) = Distance Spot Travels = 3.0 cm = 0.6 Distance Solvent Travels 5 cm Calculation 5: Determining Rf of Crude Product Compared to Pure Ferrocene

Rf of Crude Product = Distance Spot Travels = 4 cm = 1.0 Distance Solvent Travels 4 cm = Distance Spot Travels = 0.6 cm = 0.15 Distance Solvent Travels 4 cm Rf of Yellow Product = Distance Spot Travels = 4 cm = 1.0 Distance Solvent Travels 4 cm

Rf of Red Product = Distance Spot Travels = 0.7 cm = 0.175 Distance Solvent Travels 4 cm Calculation 5: Determining Rf of Crude Product Compared Yellow and Red Band

Discussion: At the end of the experiment, when the red band was eluted from the column and dried, a melting point was obtained. The red band in the column is the fraction containing acteyl ferrocene. According to the literature, acetylferrocene has a melting point range of 85-86˚C. Whereas, the melting point obtained from the synthesized acetylferrocene was 88˚C. Although this melting point is slightly above the range suggested by the literature, such a close resemblance suggests that the product produced was relatively pure acetylferrocene. This assumption can be confirmed when analyzing the 1H NMR spectra. At the end of the experiment, and 1H NMR spectra was obtained for the red band product – acetylferrocene. According to the literature, if pure acetylferrocene was synthesized, the spectra would contain 4 unique peaks. One peak at around 2.5 ppm is indicative of the methyl protons. Another peak at around 4 ppm is indicative of the protons on the unsubstituted cylcopentyl group. The last two peak, at around 4.4-4.5 ppm, are indicative of the protons on the substituted cylcopentyl group. The protons closest to the acetyl group represent the peak at around 4.4 ppm because they are more deshielded. Where as, the protons furthest from the acetyl group represent the peak at 4.5 because they are slightly more shielded than the former. Based on the spectra in the literature, it is apparent that the product produced was pure acetylferrocene because all of the appropriate peaks are represented on the spectra obtained from the synthesized product.

Moreover, the integrations on both spectras match as well. Both spectras have an integration of 3 on the peak at 2.5 ppm for the 3 hydrogens on the methyl, an integration of 5 on the peak at 4 ppm for the 5 hydrogens on the unsubstituted cyclopentyl and an integration total of 4 for the two peaks between 4.4-4.5 ppm for the 4 hydrogens on the substituted cyclopentyl group. To further reiterate the idea that the final product produced was pure acetylferrocene, the Rf values of ferrocene (yellow), acteylferrocene (red), and the crude product (a mixture of both) can be compared. According to the data obtained, the crude product contained two different Rf values; 1 and 0.15. This represents the two different products in the crude mixture. According to the literature, ferrocene is less polar than acetylferrocene and will have a higher affinity to the less polar mobile phase7. Where as, acteylferrocene will have a higher affinity for the more polar stationary phase.7 This means that acetylferrocene will proceed up the TLC plate much slower than ferrocene, resulting in a smaller Rf value for acetylferrocene.7 Based on this information, the Rf value of 1 obtained from the crude product is representative of the ferrocene product in the mixture, whereas the Rf value of 0.15 is representative of the acetylferrocene product in the mixture. The Rf value obtained from the yellow band was higher than the Rf value of the red band, which was 1 and 0.175 respectively. This is the expected result because the yellow band contained the ferrocene product and the red band contained the acteylferrocene product. Percent yield of the product was also determined at the end of the experiment. To find the percent yield, ferrocene was identified as the limiting reagent and this information was used to determine the theoretical yield. Based on the theoretical yield

and actual yield, the percent yield was 27.5%. This is an extremely poor yield and is often a result of possible side reactions or human errors. However, because the melting point, spectra and Rf values suggest the product obtained was pure acteylferrocene, it is logical to assume that most of the product loss was due to human error. For example, during the procedure the acetic anhydride and phosphoric acid were added to the test tube before the ferrocene was. As a result, much of the ferrocene powder was stuck to the sides of the test tube and was unable to participate in the reaction. Moreover, the test tube was placed over the steam bath for 3 minutes without the cap on, which could have resulted in some evaporation of the crude product.

#1:

A B

D

C

C D

A B

The 1H NMR spectra contains 4 signals, which indicates 4 unique protons. The peak at about 2.5 ppm is indicative of protons on the methyl (D). These protons present a a peak at 2.5 ppm because they are the most deshielded. Moreover, there are 3 protons residing in this environment, therefore giving an integration of 3. The second peak at around 4 ppm is indicative of the protons on the unsubstituted cyclopentyl group (C). Moreover, there are 5 protons in this unique environment, thus resulting in an integration of 5. The last two peaks, around 4.4-4.5 pm, are indicative of the protons on the substituted cyclopental group. The peak at around 4.4 ppm represents the protons closest to the acetyl substitutent (A) because they are more deshielded. This is due to the electron withdrawing effect of the substitutent. The peak at around 4.5 ppm represents the protons furthest from the acetyl substituent because these protons are slightly more shielded, thus forcing the peak upfield (B).

#2. The melting point obtained by the student is similar to the literature value for acetyl ferrocene, 85-86˚C. At 75-78˚C, the obtained products melting point is slightly lower than the literature value, thus indicating that a relatively impure product was obtained. There are two explanations for this impurity; the mixture contained contaminants or the mixture contained unreacted ferrocene. However, when the spectra is analyzed it strongly indicates that the explanation is that there is unreacted ferrocene in the obtained product. This is because there is only one significant difference in the spectra; the peak at around 4 ppm, indicative of the unsubstituted cyclopentyl group, contains 15 hydrogens instead of 5. These 10 extra hydrogens belong to the cyclopentyl group of unreacted ferrocene, which contains two unsubstituted cyclopentyl groups containing 5 hydrogens each.

Conclusion: The goal of this experiment was to prepare acetylferrocene by performing a Friedel-Crafts acylation of ferrocene. The data collected throughout this experiment indicates that the product produced was acetylferrocene. It can be seen that the appropriate peaks are visible in the 1H NMR spectra. The melting point can also be used to confirm the theory that acetylferrocene was produced. The determined melting point, 88˚C, fell just above the melting point range established by the literature, 85-86˚C, thus allowing the conclusion to be made that the final product formed was relatively pure acetylferrocene. However, the percent yield of the product, 27.5%, was extremely low. This is most likely due to the fact that errors were made throughout the experiment that had a detrimental effect on the product yield. The skills learned throughout this experiment are important because FriedelCrafts acylation reactions and ferrocene have many real world applications. For example, there is active research into the use of ferrocene and its derivative compounds for medicinal applications. Much research has demonstrated that these derivatives can fight against many diseases, including cancer and HIV.8 For example, some drugs containing ferrocene derivatives performed as promising anti-HIV agents by inhibiting the synthesis of viral DNA.8 Overall, this experiment was successful because the correct product, acetylferrocene, was produced at pure composition despite being a poor yield. Moreover, the skills learned throughout this experiment are important because they have many real world applications that are important outside of the laboratory setting. References:

[1] Ferrocene. Faculty Sites. University of California, Irvine. Accessed March 8, 2018. [2] Ferrocene Preparation - Organometallic Compounds. Piece of Science. Accessed March 8, 201. [3] Marr, G., and Webster, D. (1959) The electrophilic reactivity of (trimethylsilyl)ferrocene, -ruthenocene, and -osmocene. Journal of Organometallic Chemistry 2, 99. [4] Wildegirma, S. Experimental Organic Chemistry Lab Manual; University of South Florida: Tampa, FL, 2016; P. 92-95 [5] Friedel–Crafts Acylation. Sigma-Aldrich. Accessed March 8, 2018. [6] Hunt, D. I. R. Review of Limitations of Friedel-Crafts reactions . Ch12: FriedelCrafts limitations. University of Calgary. Accessed March 8, 2018. [7] Thin Layer and Column Chromatography. Organic Lab 1. Xavier University of Louisiana. Accessed March 8, 2018. [8] Ferrocene: A powerful organometallic compound that has various medicinal applications. Communicating Chemistry 2017W1 Section 110. Accessed March 8, 2018....