Project 1 Report - Diantilis Ethers PDF

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Project 1 Report - Diantilis Ethers...

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Two-Step Synthesis of Diantilis Ethers from 3-ethoxy-4hydroxybenzaldehyde Abstract: A two-step synthesis was performed to produce both methyl and ethyl Diantilis, which are widely used in the fragrance industry. The starting compound, 3-ethoxy-4hydroxybenzaldehyde underwent a sodium borohydride reduction to produce the intermediate, 3-ethoxy-4-hydroxybenzyl alcohol. Thereafter, this intermediate was involved in an etherification reaction through the use of Amberlyst 15, an ion exchange acid resin, to produce the desired products methyl and ethyl Diantilis at yields of 61.11% and 58.62% respectively. Consistency between the intermediate and final product structures with the infrared and proton NMR spectra proved the success of this project. The incorporation of purification techniques can lead to higher quality yields and enhanced product purity.

Introduction: Smelling stimulates intense emotions due to the connection of the olfactory bulb to a primitive part of the brain, the limbic system. The early stages of the fragrance industry are firmly embedded within organic chemistry. Fragrances are a multifaceted combination of substances used widely in consumer products to reveal a pleasant smell. Humans have the ability to perceive a large range of distinct odour notes. The characterisation of compounds by perfumers range from floral, woody, fruity, spicy or musky. The combination of these odour notes results in the perfumes individuals use in their daily lives (Pageau et al. 2002). The flavouring agent, vanilla, is derived from the orchid Vanilla planifolia as an ethanolic extract. Within this vanilla extract, there are a range of compounds, however, the main compound responsible for the olfactory responsiveness is vanillin. Isolated in 1858 by French biochemist Theodore Nicolas Gobley, vanillin is used in many fragrances, along with related compounds including isoeugenol (Miles et al. 2006). Chemists involved in fragrances are continually investigating compounds with similar odour notes as vanillin, however, with added and improved chemical and physical properties (Nicolaou et al. 1998). This project is based on the research of a major fragrance and flavour company, Givaudan (Miles et al. 2006). Described in the patent, one compound, 4-hydroxy-3-ethoxybenzyl methyl ether, was released under the trade name Methyl Diantilis. Methyl Diantilis is a compound resembling isoeugenol, an essential commercial fragrance, especially through its olfactive note being described as “sweet, spicy, carnation, vanilla”. The two derivatives obtained within this project are beneficial as they do not provide discolouration as readily as isoeugenol, which is a vital characteristic in the composition of perfumes (Ochsner 1987). The main aims of this project involve the synthesis of methyl and ethyl Diantilis, starting with 3-ethoxy-4-hydroxybenzaldehyde, as well as to characterise these products through proton NMR, infrared spectroscopy and thin-layer chromatography. Within this project, the synthesis of methyl and ethyl Diantilis was completed according to Figure 1. This involved 1

the reduction of 3-ethoxy-4-hydroxybenzaldehyde to 3-ethoxy-4-hydroxybenzyl alcohol. Thereafter, the etherification of this intermediate with methanol and ethanol yielded methyl and ethyl Diantilis respectively.

R = CH3, CH2CH3 Figure 1: Synthesis of Diantilis Ethers starting with 3-ethoxy-4-hydroxybezaldehyde The first step of this project involved a sodium borohydride reduction, as seen in Figure 2. The addition of the hydrogen onto the carbonyl carbon of the 3-ethoxy-4hydroxybenzaldehyde forces electrons from the double bond to flow onto the oxygen, giving oxygen its negative charge. In order to obtain the final intermediate for this project, the oxygen collects a hydrogen, providing 3-ethoxy-4-hydroxybenzyl alcohol as the intermediate.

Figure 2: Reaction Mechanism of the Sodium Borohydride Reduction of 3-ethoxy-4hydroxybenzaldehyde As seen within Figure 3, the second step of this project involved the use of Amberlyst 15, which is an ion exchange acid resin, dissociating into two sectors needed for this step. The protonation of the OH group leads to a good leaving group as water, resulting in a benzylic carbocation. The specific alcohol is then introduced, which for methyl Diantilis is methanol and for ethyl Diantilis is ethanol. The donation of the lone pair of electrons from the Amberlyst 15 nucleophile onto the hydrogen leads to the flow of electrons onto the oxygen. This, in turn, eradicates the positive charge on the oxygen, yielding methyl and ethyl Diantilis.

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Figure 3: Reaction Mechanism of the Etherification of 3-ethoxy-4-hydroxybenzyl Alcohol

Method: The experimental method within the project proposal titled, ‘Synthesis of Diantilis Ethers from 3-ethoxy-4hydroxybenzaldehyde’ was followed. This project proposal was approved on 28th July 2020. No alterations were made to the outlined method.

Results: Step 1: Sodium Borohydride Reduction of 3-ethoxy-4-hydroxybenzaldehyde Table 1: Physical Characteristics of Compounds Compound Molecular Boiling Melting Density Point ( ℃) point (℃) Weight (g/mL) (g/mol) 3-ethoxy-4166.17 295.1 75-77 1.186 hydroxybenzaldehyde Sodium Hydroxide 39.997 1388 318 2.13 Sodium Borohydride 37.83 500 400 1.07 Hydrochloric Acid 36.46 - 85.05 - 114.2 1.2

Quantities

1.62 g 10 mL 0.37 g 8 mL

Figure 4: Infrared Spectrum of 3-ethoxy-4-hydroxybenzyl Alcohol Table 2: Frequency Assignment of Infrared Spectrum of 3-ethoxy-4-hydroxybenzyl Alcohol Frequency (cm-1) Assignment 3406 O-H Stretch 2974 C-H Stretch 1600 C=C Stretch (Aromatic)

ne ring

3

Figure 5: NMR Spectrum of 3-ethoxy-4-hydroxybenzyl Alcohol

Table 3: PPM Assignment of NMR Spectrum of 3-ethoxy-4-hydroxybenzyl Alcohol PPM Assignment H’s Type 6.822 – 6.842 A 1 doublet of doublets 6.886 – 6.902 B 1 doublet 6.902 – 9.906 C 1 doublet 4.588 – 4.598 D 2 doublet 4.111 – 4.153 E 2 quartet 1.438 – 1.466 F 3 triplet 5.662 G 1 singlet Theoretical and Percentage Yield of 3-ethoxy-4-hydroxybenzyl Alcohol:

Figure 6: 3-ethoxy-4-hydroxybenzaldehyde to 3-ethoxy-4-hydroxybenzyl Alcohol 4

Moles of 3-ethoxy-4-hydroxybenzaldehyde: mass (g) / molar mass (g/mol) = 1.62 / 166.17 = 0.00974905217 moles Moles of Sodium Hydroxide: mass (g) / molar mass (g/mol) Density: 2.13 g/mL x 10 mL = 21.3 g = 21.3 / 39.997 = 0.5325399405 moles Moles of Sodium Borohydride: mass (g) / molar mass (g/mol) = 0.37 / 37.83 = 0.0097805974 moles Moles of Hydrochloric Acid: mass (g) / molar mass (g/mol) Density: 1.2 g/mL x 8 mL = 9.6 g = 9.6 / 36.46 = 0.263302249 moles Thus, 3-ethoxy-4-hydroxybenzaldehyde is the limiting reagent. Theoretical yield of 3-ethoxy-4-hydroxybenzyl Alcohol = Moles of 3-ethoxy-4-hydroxybenzaldehyde x Molar Mass of 3-ethoxy-4-hydroxybenzyl Alcohol = 0.00974905217 mol x 168.19 g/mol = 1.639693084 g = 1.64 g (3 significant figures) Percentage yield of 3-ethoxy-4-hydroxybenzyl alcohol = (Actual yield (g) / Theoretical yield (g)) x 100 = (1.22 g / 1.64 g) x 100 = 74.39 % Theoretical Melting Point of 3-ethoxy-4-hydroxybenzyl Alcohol: 73 – 75 ℃ (National Centre for Biotechnology Information 2020) Experimental Melting Point of 3-ethoxy-4-hydroxybenzyl Alcohol: 75 ℃

Step 2A: Etherification of 3-ethoxy-4-hydroxybenzyl alcohol to Methyl Diantilis Compound

3-ethoxy-4hydroxybenzyl 5

Table 4: Physical Characteristics of Compounds Molecular Boiling Melting Density Weight (g/mL) Point ( ℃) point (℃) (g/mol) 168.19 323.3 73-75 1.182

Quantities

1g

Alcohol Amberlyst 15 Methanol Sodium Bicarbonate Hexane Ethyl Acetate

314.399 32.04 84.007

516.7 64.7

86.18 88.11

68 -70 76.5 – 77.5

- 97.6 50

0.75 0.791 2.2

1g 7.5 mL 0.5 g

- 95 - 84

0.672 0.902

10 mL 10 mL

Figure 7: Infrared Spectrum of Methyl Diantilis Table 5: Frequency Assignment of Infrared Spectrum of Methyl Diantilis Frequency (cm-1) 3388 2931 1513 1435 1079 818

Assignment O-H Stretch C-H Stretch C=C Stretch (Aromatic) CH2 Bending C-O Stretch C-H Stretching of 1,2,4-trisubstituted benzene ring

Figure 8: NMR Spectrum of Methyl Diantilis

Table 6: PPM Assignment of NMR Spectrum of Methyl Diantilis PPM 6

Assignment

H’s

Type

6.793 – 6.813 6.863 – 6.873 6.873 – 6.889 4.361 4.107 – 4.149 1.431 – 1.459 5.651 3.355

A B C D E F G H

1 1 1 2 2 3 1 3

doublet of doublets doublet doublet singlet quartet triplet singlet singlet

Thin-Layer Chromatography:

A: 3-ethoxy-4-hydroxybenzyl Alcohol (Intermediate) B: Methyl Diantilis (Product) Retention Factor (Rf) = Distance travelled by solute / Distance travelled by solvent Rf (A) = 1.4 cm / 5 cm = 0.28 Rf (B) = 2.6 cm / 5 cm = 0.52

Figure 9: TLC Plate of Methyl Diantilis

Theoretical and Percentage Yield of Methyl Diantilis:

R = CH3 7

Figure 10: 3-ethoxy-4-hydroxybenzyl Alcohol to Methyl Diantilis

Moles of 3-ethoxy-4-hydroxybenzyl Alcohol: mass (g) / molar mass (g/mol) = 0.5 / 168.19 = 0.00297282834 moles Moles of Methanol: mass (g) / molar mass (g/mol) Density: 0.791 g/mL x 7.5 mL = 5.9325 g = 5.9325 / 32.04 = 0.185159176 moles Moles of Sodium Bicarbonate: mass (g) / molar mass (g/mol) = 0.25 / 84.007 = 0.00297594248 moles Thus, 3-ethoxy-4-hydroxybenzyl Alcohol is the limiting reagent. Theoretical yield of Methyl Diantilis = Moles of 3-ethoxy-4-hydroxybenzyl Alcohol x Molar Mass of Methyl Diantilis = 0.00297282834 mol x 182.22 g/mol = 0.5417087801 g = 0.54 g (2 significant figures) Percentage yield of Methyl Diantilis = (Actual yield (g) / Theoretical yield (g)) x 100 = (0.33 g / 0.54 g) x 100 = 61.11 %

Step 2B: Etherification of 3-ethoxy-4-hydroxybenzyl alcohol to Ethyl Diantilis Table 7: Physical Characteristics of Compounds

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Compound

3-ethoxy-4hydroxybenzyl Alcohol Amberlyst 15 Ethanol Sodium Bicarbonate Hexane Ethyl Acetate

Molecular Weight (g/mol) 168.19

Boiling Point ( ℃) 323.3

314.399 46.07 84.007

516.7 78.37

86.18 88.11

68 -70 76.5 – 77.5

Melting point (℃)

Density (g/mL)

Quantities

73-75

1.182

1g

- 114.1 50

0.75 0.789 2.2

1g 7.5 mL 0.5 g

- 95 - 84

0.672 0.902

10 mL 10 mL

Figure 11: Infrared Spectrum of Ethyl Diantilis Table 8: Frequency Assignment of Infrared Spectrum of Ethyl Diantilis

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Frequency (cm-1) 3416 2976 1511 1436 1086 814

Assignment O-H Stretch C-H Stretch C=C Stretch (Aromatic) CH2 Bending C-O Stretch C-H Stretching of 1,2,4-trisubstituted benzene ring

Figure 12: NMR Spectrum of Ethyl Diantilis

Table 9: PPM Assignment of NMR Spectrum of Ethyl Diantilis PPM Assignment 6.809 – 6.829 A 6.876 – 6.887 B 6.887 – 6.892 C 4.423 D 4.103 – 4.145 E 1.430 – 1.458 F 5.793 G 3.504 – 3.546 H 1.245 – 1.259 I Thin-Layer Chromatography: 10

H’s 1 1 1 2 2 3 1 2 3

Type doublet of doublets doublet doublet singlet quartet triplet singlet quartet triplet

A: 3-ethoxy-4-hydroxybenzyl Alcohol (Intermediate) B: Ethyl Diantilis (Product) Retention Factor (Rf) = Distance travelled by solute / Distance travelled by solvent Rf (A) = 2 cm / 4.3 cm = 0.47 Rf (B) = 3.1 cm / 4.3 cm = 0.72 Figure 13: TLC Plate of Ethyl Diantilis

Theoretical and Percentage Yield of Ethyl Diantilis:

R = CH2CH3 Figure 14: 3-ethoxy-4-hydroxybenzyl Alcohol to Ethyl Diantilis Moles of 3-ethoxy-4-hydroxybenzyl Alcohol: mass (g) / molar mass (g/mol) = 0.5 / 168.19 = 0.00297282834 moles Moles of Ethanol: mass (g) / molar mass (g/mol) Density: 0.789 g/mL x 7.5 mL = 5.9175 g = 5.9175 / 46.07 = 0.185159176 moles Moles of Sodium Bicarbonate: mass (g) / molar mass (g/mol) = 0.25 / 84.007 = 0.00297594248 moles Thus, 3-ethoxy-4-hydroxybenzyl Alcohol is the limiting reagent.

Theoretical yield of Ethyl Diantilis = 11

Moles of 3-ethoxy-4-hydroxybenzyl Alcohol x Molar Mass of Ethyl Diantilis = 0.00297282834 mol x 196.2466 g/mol = 0.5834074541 g = 0.58 g (2 significant figures) Percentage yield of Ethyl Diantilis = (Actual yield (g) / Theoretical yield (g)) x 100 = (0.34 g / 0.58 g) x 100 = 58.62 %

Discussion: The first step within this project involved the sodium borohydride reduction of 3-ethoxy-4hydroxybenzaldehyde to produce the benzylic alcohol intermediate at an acceptable yield of 74.39%. The performance of both proton NMR and infrared spectroscopy was undertaken to determine if the desired intermediate was synthesised. According to the infrared spectrum, there is evidence of the successful reduction of the starting material. This is proven through the absence of the aldehyde C-H stretches, as well as the C=O stretch of the aldehyde. The appearance of the bands in the OH region was also more complex. This was further complemented through the analysis of the proton NMR spectrum, especially by the appearance of the two-proton doublet at 4.588 ppm, as well as the absence of the aldehyde proton signal. Moreover, the melting point of this benzylic alcohol intermediate was measured to be 75℃, which corroborates with the literature value of 73-75℃ (National Centre for Biotechnology Information 2020). After obtaining and comparing all characterisation techniques of 3-ethoxy-4-hydroxybenzyl alcohol, it is clear that the successful derivation of this compound occurred. The second step of this project allowed for the etherification of 3-ethoxy-4-hydroxybenzyl alcohol to take place, producing methyl Diantilis at a yield of 61.11%. Comparing methyl Diantilis to the intermediate, the same structure is derived, however, there is a replacement of the alcohol group into an ether, which is the main characteristic to determine the successful conversion to this product. Upon analysing the infrared spectrum of methyl Diantilis, there was a simplification in the OH region, where a broad single band was observed when compared to the benzylic alcohol. Due to structural similarities between the intermediate and methyl Diantilis, infrared spectroscopy was a weak technique in determining the conversion into the desired product. For this reason, proton NMR was undertaken, displaying the upfield shift of the protons on the methylene group, as well as its conversion from a doublet to a singlet. Furthermore, there was an appearance of a new signal due to the added methyl group into the structure following the etherification of the alcohol group. This was observed at 3.355 ppm as a singlet due to the absence of neighbouring protons. Moreover, thin-layer chromatography was also performed to determine the successful conversion following the refluxing stage. Due to the decreased polarity of methyl Diantilis compared to the intermediate, it is clear that the product spot had moved further along the plate than the intermediate spot. This TLC analysis, along with 12

the proton NMR and infrared spectroscopy results provided clarity in the successful conversion of the benzylic alcohol into methyl Diantilis. Within the second step of this project, ethyl Diantilis was also synthesised along with methyl Diantilis at a yield of 58.62%. Due to the etherification of the alcohol group of the intermediate into an ethyl group, infrared spectroscopy was not of great assistance, as all other functional groups remained constant. Within the infrared spectra, the main characteristic to identify the conversion into ethyl Diantilis was the simplified OH region when compared to the more complex bands in the intermediate spectra. Furthermore, within the proton NMR spectra, there was a retainment of the aromatic region signals, including the doublet of doublets due to a hydrogen on the ring demonstrating ortho and meta coupling to two separate hydrogen neighbours. The well-resolved signals within the aromatic region were extremely instructive because of the illustration of long-range coupling within the aromatic compound. There was also the appearance of two new signals due to the introduction of an ethyl group into the structure. The first signal was a quartet due to the new CH2 group having three neighbouring protons from the methyl group, as well as a triplet at 1.245 ppm as a result of the added methyl group to the structure. The methyl group signal appeared more upfield when compared to the CH2 group due to the lack of influence from the electronegative oxygen within the structure and is therefore more shielded. There was also an upfield shift of the protons on the methylene group which was also observable on the methyl Diantilis proton NMR spectra. Moreover, thin-layer chromatography was also performed. Due to the etherification process, there was a removal of one hydroxyl group from the intermediate, meaning that ethyl Diantilis is less polar. These differences in polarity affect the distances in which substances travel along the plate. Through observing the TLC plate of ethyl Diantilis, the intermediate spot was closer to the baseline on the TLC plate compared to the product. Therefore, upon the analysis of all characterisation techniques, there was a clear indication of the successful conversion of 3ethoxy-4-hydroxybenzyl alcohol into ethyl Diantilis. The major issue encountered within this project was the inadequate filtering of the Amberlyst 15, resulting in the loss of products and, in turn, a reduced percentage yield. After removing the excess alcohol, any remaining Amberlyst 15 within the crude reaction mixture will lead to the catalysis of the decomposition of the ether products (Miles et al. 2006). Moreover, another issue was the loss of products during the transfer between different vessels, especially when using the Hirsch funnel to filter the reaction mixture. Lastly, the overheating of the product may have led to a reduction in the yields due to the decomposition of the ether products, regardless of whether any Amberlyst 15 was present in the product itself. For this reason, the temperature setting during the reflux stage should be relatively low and the incorporation of a sand bath can result in the moderation of the temperature and allow for more gradual heating.

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Conclusion: In summation, the purpose of this project was to convert 3-ethoxy-4-hydroxybenzaldehyde to the benzylic alcohol intermediate through a chemo selective etherification reaction, followed by the conversion of this intermediate to methyl and ethyl Diantilis via a polymersupported reaction. Overall, the results of this project were accurate, especially through the consistency between the structures of the intermediate and final products with the data obtained from the IR and proton NMR spectra. This proved the success of the two-step synthesis in the formation of products that are widely used in the fragrance industry. To obtain enhanced outcomes, synthesis should be carried out over a longer period of time, allowing for sufficiency in the reaction of the starting materials. Purification techniques should also be incorporated to obtain higher quality yields and pure products.

References: Kumar, R., Sharma, P. & Mishra, P. 2012, ‘Vanillin Derivatives Showing Various Biological Activities’, International Journal of PharmTech Research, vol. 4, no. 1. Miles, W.H. & Connell, K.B. 2006, ‘Synthesis of Methyl Diantilis, a Commercially Important Fragrance’, In the Laboratory, vol. 83, no. 2, pp. 285-86. Miles, W.H. & Connell, K.B. 2008, ‘Modification to Synthesis of Methyl Diantilis’, Chemical Education Today, vol. 85, no. 7, pp. 917. National Centre for Biotechnology Information 2020, PubChem Compound Summary for 3ethoxy-4-hydroxybenzyl alcohol, Bethesda, viewed 9 October 2020, . Nicolaou, K. C., Sorensen, E. J. & Winssinger, N. J. 1998, ‘The Art and Science of...