INTRODUCTION:

Hopp et al. in the year 1985 in their patent claimed the synthesis of 2, 4-dimethyl-4’-methoxydibenzoyl methane by reacting with 1.0 mol of 2, 4-dimethylacetophenone with 2.0 mol of methyl anisate in 180g of toluene in the presence of 1.5mol of NaH under nitrogen. The yield reported was 70.2% of theory. Mp of the product was 48^oC.¹

In the year 2009 Tischenbach et al. established the use of Parsol as phtostabilizing agent in the sunscreen lotions as investigated by them.²

De Polo et al. in the year 1983 claimed the synthesis of 4-(1, 1-dimethylethyl)-4’-methoxydibenzoylmethane in their US Patent. Firstly they synthesized p-tert-butyl benzoic acid methyl ester with acetyl anisole to prepare Parsol with 64.5% yield.³

Avobenzone^1-4 is an oil soluble ingredient used in sunscreen products to absorb the full spectrum of UVA rays. It is a dibenzoyl methane derivative. Avobenzone exists in the ground state as a mixture of the enol and keto forms, favoring the chelated enol. Its ability to absorb ultraviolet light over a wider range of wavelengths than many organic sunscreen agents has led to its use in many commercial preparations marketed as "broad spectrum" sunscreens. Avobenzone has an absorption maximum of 357 nm.

Avobenzone was patented in 1973 and was approved in the EU in 1978. It was approved by the FDA in 1988. Its use is approved worldwide.

Avobenzone is sensitive to the properties of the solvent, being relatively stable in polar protic solvents and unstable in non polar environments. Also, when it is irradiated with UVA light, it generates a triplet excited state in the keto form which can either cause the avobenzone to degrade or it can transfer energy to biological targets and cause deleterious effects.

Avobenzone has been shown to degrade significantly in light, resulting in less protection over time. The UV-A light in a day of sunlight in a temperate climate is sufficient to break down most of the compound. Data presented to the Food and Drug Administration by the Cosmetic, Toiletry and Fragrance Association indicates a 36% change in Avobenzone's UV absorbance following one hour of exposure to sunlight. Avobenzone can degrade faster in light in combination with mineral UV absorbers like zinc oxide and titanium dioxide, though with the right coating of the mineral particles this reaction can be reduced. A manganese doped titanium dioxide may be better than undoped titanium dioxide to improve avobenzone's stability.^4-6

Avobenzone reacts with minerals to form colored complexes. Manufacturers of Avobenzone like DSM recommend including a chelator to prevent this from happening. They also recommend avoiding the inclusion of iron and ferric salts, heavy metals, formaldehyde donors and PABA and PABA esters.

The makers of Coppertone advise that avobenzone binds iron and can cause staining of clothes washed in iron-rich water. Sun block is an important part of summer fun. Sun block can work in two ways, physically and chemically. A sun block is simply a barrier between the skin and the sun; it can be physical, chemical or both. Sunscreens are made up of chemicals that can absorb specific wavelengths of the sun's spectrum. Physical protectors, such as zinc oxide, reflect UVA rays, whereas most chemical protectors absorb UVB rays. There are a few chemical agents that absorb UVA rays, such as Parsol; however, it is impossible to block out all of the UVA rays using sun block. Octyl methoxycinnamate, Parsol, Octisalate Titanium dioxide, Octicrylene, are some of the important sun blocking agents.

Compounds with high molar absorptive in the UVA/UVB range can be used as sun blocks. There are many compounds that have this characteristic, however many of them are harmful for human skin, such as PABA, a sunscreen agent that isn't used anymore because of widespread allergic reactions to the skin. Therefore, compounds that are stable, hypoallergenic, and sometimes water proof are needed to be successful sun screening agents.

Parsol also known as Avobenzone, this compound absorbs wavelengths from 320nm to 400nm, in the UVA region. Ultra violet light has been categorized into three main sections. The wavelength of ultra violet light is shorter than that of the visible spectrum, and UVC is the shortest, and also the most dangerous of the three. UVC's wavelength is from 100nm to 290nm, and lucky for us, the ozone keeps all UVC light off of the surface of the Earth. UVB light, responsible for sunburn, has a wavelength from 290nm to 320nm. Scientists have not yet determined the full effects of UVA light on our health, but it is under suspicion as a potential cancer-causing agent. It takes hundreds of thousands of times more UVA light than UVB light to achieve the equivalent skin damage. UVA light has a wavelength from 320nm to 400nm.^6-11

Avobenzone having phenyl ketone group and sterically hindered group in one molecule is an oil soluble sunscreen agent that absorbs a wider range of UV wavelengths. It absorbs both UV-A (380–315 nm that is associated with long term skin damage) and UV-B (315–280 nm that causes sunburn) rays. Avobenzone is known as one of the most effective sunscreen ingredient.^12-15

Our aim was to develop the Parsol with the foolproof process and with chemicals that may be economical if it was needed further to be carried out commercially. We have employed Para-toluene sulfonic acid as catalyst. The prepared ester was distilled without using Widmer column as mentioned in the US Patent. It was after synthesis isolated and purified employing column chromatography and was eluted using chloroform and methanol. Thus the Parsol was prepared in good yield and quality.

MATERIAL AND METHODS:

Reagents and chemicals:

All chemicals, reagents and solvents were purchased from SD fine, LOBA and Spectrochem. They were used without further purification. Products were characterized by IR and thin layer chromatography. (TLC) was employed for the purity determination of reactants, products and monitoring reaction. All the preparation was carried out in triplicate to ascertain the reproducibility of the result obtained.

Synthesis of p-tert-butyl benzoic acid from p-tert-butyl benzoic acid:

Part 1

5g (0.02mol) of p-tert-butyl benzoic acid, 10g (0.312mol) of methyl alcohol and 0.50g (0.0003 mol) of p-toluene sulphonic acid were added to 3 necks round bottom flask which was provided with a stirrer and a condenser. The mixture was held for 10 hours at reflux temperature with slight stirring. The condenser was then replaced with distillation and the excess methyl alcohol was distilled off, towards the end a slight vacuum but without the temperature exceeding 95^oC. The mixture was cooled and poured on to ice. The phases were left to separate, the organic phase was washed with ice-water with a saturated sodium bicarbonate solution in presence of ice and finally with ice until neutral. The organic phase was then dried over sodium sulphate in the desiccators. The organic phase was then passed through the column containing silica gel. It was then eluted using chloroform and methanol. Colorless organic phase was recovered. The precipitate weighed 4.5g (0.0252mol), the boiling point of the ester was 76⁰ C/ 0.02 mmHg.^1-3

Synthesis of 4-(1, 1-dimethylethyl)-4’-methoxydibenzoylmethane)-PARSOL:

Part 2

To a round bottom flask which has been well dried and nitrogen flushed were added 1.98g of soda amide (0.021mol) (powder) and 5g of isopropyl ether and there now added drop wise thereto at a temperature of 60-65^oC, 3.5g (0.023mol) of acetyl anisole in 5g of isopropyl ether. The reaction starts immediately and mass of white color was formed. When addition was completed, the mixture was further stirred for an hour at room temperature then for four hours at 60-70^oC. It was then added with 10g ice and added with HCl. It was stirred until dissolution of salt complete. The phases were separated and the organic phase was washed with ice water until neutral. The organic phase was concentrated on rotary evaporator and the solvent was thus recovered. 11.5g of crude product was obtained and was further dried under vacuum. It was then added with methanol and completely dissolved. The solution was then kept in the freezer for crystallization and filtered to obtain the product. The product was dried in the vacuum drier for about 5 hour at 60-65^oC and the dried 4-(1, 1-dimethylethyl)-4’-methoxydibenzoylmethane recovered weighed 8.50g and yields (73.9%). The melting point was 85^oC (Mp 81-85^oC).^1-3

RESULTS AND DISCUSSION:

Effect of agitation on the yield of the ester:

Agitation plays (Figure 1) an important role in kinetics, collision and orientation of the reaction (Table 1). It has well supported the output of the product, as seen in the figure increasing yield of the ester. Since, it was esterification reaction involving a PTSA, so the dissociation of an acid due to high mass transfer may have been initiated faster. Methyl carbocation may have undergone the faster generation as to facilitate the nucleophihlic attack on carbocated carboxylate to form respective ester. As PTSA was a phase transfer catalyst and hence the phase transfer of the reactant may also be faster as the agitation was increased from mild-moderate-fast.^1-3

Since this reaction is of SN¹ nature, so carbocation generation expected to be slower as this was rate determining step but dissociation of p-tert-butyl benzoic acid was presumed to be slow for generating carbocation and hence higher agitation may have been found to influence the fast generation of carbocation and found to give an increased yield as seen from the figure 1.

Figure 1 Effect of agitation on the yield of ester

Effect of temperature on the yield, of ester:

As seen in figure 2 with increase in temperature a rise in the yield of ester was obtained. This indicated that at higher temperature vapor phase generation of the reacting molecules was faster and resulted in decrease in the activation energy of the reacting molecules during the course of reaction. At higher temperature acid dissociation enhanced and thus made available the nucleophile for the carbocation attack. The yield of the ester was 94% and 98% at 65 and 85^oC respectively. Scheme 1 and 2 may be referred for the reaction. Scheme 3 explains overall mechanism of the molecule synthesized.

From 65-85^oC the yield was shown to increase up to 4% whereas from 85-95^oC only 1% increase in the yield was obtained. At 95oC no appreciable increase in the yield was noticed by the time the reaction may have achieved equilibrium and hence vapor pressure-liquid equilibrium didn’t help in the further increase in the yield of an ester (Table 1).

Figure 2 Effect of temperature on yield of ester

Effect of increase in molar concentration of PTAS on the yield of ester:

Various moles of PTSA were used (Figure 3) to study the yield of the ester with 2.5g (0.013mol), 3.5g (0.0184mol) and 4.5g (0.023mol). The role of catalyst is to lower the activation energy of the reacting molecules. At 2.5g (0.013mol) and 3.5g (0.0184mol) of catalyst there was noticeable increase in the yield from 9.5g (0.074mol) to 13.7g (0.0691mol). With 4.5g (0.023mol), though the yield was 15.1g (0.0762mol) but after 4 hour the ester was found to be decomposed (Table 1).

Figure 3 Effect of mole concentration of methanol on yield of ester

This may have happen due to the presence of un-dissociated PTSA and moisture within the catalyst. This further rendered the acidic hydrolysis that destroyed the ester.

Effect of molar concentration of methanol on the yield of ester:

With increase in molar concentration of methanol a marginal increase in the yield of ester was observed. With 25 ml (21.5g; 0.233mol) methanol have yielded 90% of ester. 35 ml (30.1g; 0.3266mol) gave 92% and 45 ml (38.7g; 0.4246mol) yielded 95%. Increase in the yield was 2% from 21.5-30.1g of methanol and 3% with 38.7g (Table 1).

Table 1 Conditions for synthesis of P-tert. Butyl benzoic acid methyl ester.

PTBBA: MeOH	MeOH	PTBBA	PTSA	Temp. ^oC	Agitation	PTBME g	% yield	b.p. ^oC mmHg
^a1:5	25ml (21.5g, 0.233mol)	5	2.5g (0.013mol)	65	Low	^b4.5	94	76
^a1:7	35ml (30.1g, 0.3266mol)	5	3.5g (0.0184mol)	85	Medium	^c5.5	98	76
1:9	45ml (38.7g, 0.4246mol)	5	4.5g (0.023mol)	95	Fast	-	99	76

a ester was found to degraded after standing for 4 h. b and c ester was purified with the column chromatography.

1) Step 1

Scheme 1 Synthesis of p-tert-butyl benzoic acid methyl ester

Mechanism

2) Step two

Scheme 2 synthesis of 4-(1, 1-dimethylethyl)-4’-methyldibenzoylmethane

Mechanism

Scheme 3 Mechanism of overall reaction

Table 2 Conditions for synthesis of PARSOL

PTBME g	^aSoda amide g	Isopropyl ether g	Acetyl anisole g	Temp. ^oC	Agitation	%yield	mp. ^oC	Parsol g
4.50	1.98 (0.021mol)	5.00	3.5g (0.023mol)	RT, 60-70	Medium	73.9	85	8.50
4.50	1.98 (0.021mol)	5.00	3.5g (0.023mol)	RT, 60-70	Medium	73.66	85	8.25
4.50	1.98 (0.021mol)	5.00	3.5g (0.023mol)	RT, 60-70	Medium	73.47	85	8.45

a Soda amide powder was used instead of soda amide suspension (50% in Toluene). Nucleophile generated much faster.

It may be due to water of reaction formation, as amount of methanol increases the water of reaction may also have been increased and due to lower concentration this trend may be explained. Figure 3 may be referred.

Synthesis of Para-tert-butyl benzoic acid methyl ester from tert-butyl benzoic acid is mentioned in US Patent. This goal was achieved by employing different parameters such a temperature, agitation, molar concentration of MeOH. It was decided to study the increase in the yield of the ester by using aforesaid parameters. As p-tert-butyl benzoic acid methyl ester acts as UVA absorber so it was decided to increase the yield of the ester. Scheme 1 and 2 may be referred for the synthesis of ester and subsequent Parsol. Scheme 2 explains the complete mechanism of the reaction.^1-3

In order to optimize the reaction conditions, p-tert-butyl benzoic acid and methanol used as reactant for the synthesis of ester. As these are the prerequisite compounds which is used for the synthesis of the ester, so the different parameters for the synthesis of the ester like temperature, agitation, and different molar ratios of solvent was studied.

Foremost the effect of agitation was studied on the yield of ester. Then the reaction was performed at different molar concentrations of PTSA and methanol at different agitation and temperature. We have optimized the conditions viz. effect of agitation, effect of varying molar concentrations of PTSA, effect of varying molar concentrations of methanol and the effect of temperature on the yield and quality of ester and Parsol (Table 2).

IR characterization of p-tert-butyl benzoic acid methyl ester:

IR spectra was determined by FTIR 8400 F Siamdzu Japan, of p-tert-butyl benzoic acid methyl ester shown the characteristic frequencies; C-H stretch (alkanes) 2964.69, -C=O stretch (aldehyde ketone) 1722.2, -C=C stretch (aldehyde, ketone) 1610.61, -C-H bending (trans RCH=CHR) 968.30, -C-H (out of plane) (p-sub-benzene) 854.49/819.77,-C-H bending (trans RCH=CHR) 775.41,-C-H out of plane (m-sub-benzene) 707.90, and -C=C- (bending) alkanes 1375.65 cm-¹ respectively. Figure 4 may be referred.

Figure 4 IR characterization of p-tert-butyl benzoic acid methyl ester

IR characterization of 4-(1, 1-dimethylethyl)-4’-methoxydibenzoylmethane (Parsol):

IR spectra of 4-(1, 1-dimethylethyl)-4’-methoxydibenzoylmethane shown the characteristic frequencies; -O-H stretch (alcohol) 3431.48, -O-H stretch (carboxylic acid) 2962.76, -C=O (aldehyde, ketone) 1703.20, C-H out of plane (p-sub-benzene) 858.35, C-H out of plane (m-sub-benzene) 786.98 and –C-H (mono-sub-benzene) 709.83 cm-¹respectively. Figure 5 may be referred.

Figure 5 IR characterization of 4-(1, 1-dimethylethane)-4'-methyldibenzoyloxymethane

Chromatography Methods:

Thin layer Chromatography (TLC):

The products obtained were identified and compared using silica-gel-G coated TLC plates. Plates were prepared by spreading as the uniform thin layer of silica gel –G in the form of slurry; it was dried at room temperature following by activation at 120°C for 40 min. The spotting of compound was done by fine capillary and the plates were developed in the chloroform and methanol solvents. Visualization of spots was done in UV chamber.

IR Spectroscopy:

IR spectra were obtained from instrumentation laboratory, department of Chemistry, Lovely professional University Employing FT – IR 8400 spectrophotometer with maxima in cm^-¹.

CONCLUSIONS:

Most of the US Patents claim the synthesis and may not be exactly performed to get the Parsol as per the process disclosed therein. We have simplified the process avoiding Widmer’s column and using column chromatography.

Amongst three agitation conditions studied on the yield of the ester, medium agitation was found to be the best conditions for the yield of the ester. Temperature of 85±5^oC was the best for the reaction and yield. 3.5g (0.0131mol) of PTSA was the best catalyst dose for the reaction. 45ml (38.7g; 0.4246mol) of methanol as solvent and esterifying agent was the best optimized condition. Out of the two catalysts viz. NaNH₂ and NaH, NaNH₂ was the best catalysts for the Parsol synthesis.

The yield of the Parsol obtained was 73.9% against reported of 65% in the US Patent.

ACKNOWLEDGEMENT:

This project was funded by Lovely Professional University’s Chemistry department. All the laboratory assistant and technicians deserves special thanks for their continuous support.

REFERENCES:

1. Hopp, R., Finkelmeier, H. Preparation of novel dibenzoylmethane derivative sunscreen agents. US Patent 4,562,067, 1985.

2. D Polo, K. F. 4-(1, 1-Dimethylethyl)-4'-methoxy dibenzoylmethane US Patent 4,387,089, 1983.

3. Tischenbach, I., Saclier, S. Use of Alpha Olefin Copolymers as Photostabilizing Agents in Sunscreen Compositions. US Patent 0074684 A1, 2009

4. Tarras-Wahlberg, N.; Stenhagen, G.; Larko, O.; Rosen, A.; Weinberg, A. M.; Wennerstrom, O. J Invest Dermatology 1999, 113(4):547–53.

5. Wetz, F.; Routaboul.; C, Denis, A,.; Rico-Lattes, I . Avobenzone, J Cosmet. Sci, 2005 , 56(2): 135–48.

6. CTFA letter re: Tentative Final Monograph for OTC Sunscreen

7. Bonda, C.; Steinberg, D. C. A new photostabilizer for full spectrum sunscreens. J Cosmet. Toiletries, 2000, 115(6):37–45.

8. http://www.dsm.com/en_US/downloads/dnp/Parsol_SLX_Skin.pdf

9. Chaudhuri, R K,; Lascu, Z.; Puccetti, G.; Deshpande, A. A.; Paknikar, S. K. J. Design of a photostabilizer having built in antioxidant. Photochem Photobiol, 2006, 82(3):823–8.

10. http://www.hallstar.com/techdocs/PolycryleneandCorapanTQAvobenzoneStabilization.pdf

11. "Product Information Sheet: SolaStay® S1". The Hall Star Company. http://www.hallstar.com/pis.php?product=1H044. Retrieved 16 February 2010.

12. Warwick, L..; Morison, M .D. Photosensitivity The New England Journal of Medicine, 2004, 350:1111–1117.

13. "Sunscreen Drug Products for Over-the-Counter use; Marketing Status of Products Containing Avobenzone; Enforcement Policy" (PDF). US Food and Drug Administration. 1997 04-30::233-54.

14. Stability Study of Avobenzone with Inorganic Sunscreens, Kobo Products Poster, 2001, Online version

15. Wakefield, G.; Lipscomb, S.; Holland, E.; Know land, J. J. Organic sunscreen components Photochem Photobiology Sci. 2004, 3(7):648–52.

Received on 12.06.2011 Modified on 21.07.2011

Asian J. Research Chem. 4(11): Nov., 2011; Page 1671-1677