Ethylhexyl methoxycinnamate (EHMC) is among the most frequently used organic ultraviolet (UV) filters, known primarily for its role as an active ingredient in sunscreen products.1–3 EHMC also has been used in hair, skin, nail and color cosmetic products to protect substrates, e.g., hair from damage by UVB radiation, and to help stabilize formulations against photodegradation.
Chemistry and Manufacture
EHMC, shown in Figure 1, is the 2-ethylhexyl ester of para-methoxycinnamic acid. Its molecular formula is C18H26O3, corresponding to a molecular weight of 290.4 g/mol.1,4 The compound is often referred to as octyl methoxy-cinnamate (OMC) because it bears a C8 alkyl group; however, this name does not reflect the distinctly branched nature of the 2-ethylhexyl group in EHMC. The previous US Pharmacopeia (USP) name for EHMC was octyl methoxycinnamate; this name was changed to octinoxate in the year 2000 and was adopted as the US over-the-counter (OTC) drug name for EHMC in 2002.2,3
The total synthesis of EHMC starting from petrochemical feedstocks is a marvel of industrial organic chemistry that relies on a diverse array of chemical processes to deliver the compound. While a comprehensive review of EHMC synthesis is beyond the scope of this column, the brief overview presented herein will highlight some of the key materials and processes used to manufacture EHMC and demonstrate the impressive range of synthetic organic chemistry utilized to produce this important molecule.
Although the exact starting materials used to synthesize EHMC are dependent upon the specific synthetic route employed, most of these compounds can usually be traced back to propylene and phenol or para-cresol feedstocks.5, 6
For example, the 2-ethylhexanol (2-EH) used to form the 2-ethylhexyl group is derived from propylene gas according to the reaction scheme shown in Figure 2. Note that 2-EH may be used directly or in the form of acetate or acrylate esters depending on the route employed to prepare EHMC. The other key starting materials are the aromatic compounds used to form the methoxycinnamate moiety, which may include para-anisaldehyde (PA) or para-bromoanisole (PBA). These chemicals are derived from phenol or para-cresol by substitution or oxidation reactions, respectively, and methylation of the phenolic hydroxyl group. To more efficiently and economically meet the demand for EHMC, the specialty chemicals industry has focused significant attention on the development of improved processes and new synthetic routes for the production of EHMC.7–14 The traditional routes to EHMC, shown in Figure 3, are based on aldol condensation reactions of PA, an intermediate routinely used in the manufacture of fine organic chemicals.7–9 The most direct route to EHMC using this chemistry is the base-catalyzed condensation of PA with 2-ethylhexyl acetate,8 shown to the left in Figure 3. Alternatively, PA may be reacted with methyl acetate to form methyl 4-methoxycinnamate as an intermediate, which is then transesterified with 2-EH to yield EHMC, as shown to the right in Figure 3.9 The crude EHMC isolated from these reactions is then purified via vacuum distillation to remove unreacted starting materials, reaction by-products and other impurities.
Despite improvements to the PA-based processes, they are reported to suffer from several fundamental disadvantages, including the relatively high cost of the PA starting material, the risk of forming a large number of by-products, and the generation of large volumes of waste that must either be recycled or disposed of, e.g., methanol and sodium bisulfate/sodium sulfate. To overcome these disadvantages, alternative processes have been developed based on the Heck reaction,10–13 a Nobel Prize-winning chemistry discovered by Richard F. Heck, PhD.
Heck reactions involve the coupling of unsaturated organic halides with electron-deficient alkenes using palladium (Pd) metal catalysts to form substituted alkenes as the products. Using this reaction, methoxycinnamate esters are readily derived from the coupling of para-substituted haloanisoles with acrylate esters, in the presence of Pd catalyst and a base. For example, in Figure 4, a carbon-supported Pd catalyst is used to couple PBA with 2-ethylhexyl acrylate in the presence of sodium carbonate (Na2CO3) and N-methylpyrrolidone (NMP) as a solvent to yield EHMC in a simple one-step reaction.10 The reaction produces carbon dioxide (CO2) and sodium bromide (NaBr) as by-products, but the NaBr can be recycled for use PBA synthesis.13 Several variations on the Heck route to EHMC have been reported, such as a process that uses para-iodoanisole as a starting material instead of PBA,11 and a solvent-free process that first couples PBA with acrylic acid to form para-methoxycinnamic acid followed by transesterification with 2-EH to yield EHMC.12
Another innovative approach to EHMC synthesis is based on ketene chemistry, as shown in Figure 5.14, 15 Ketene is a highly reactive intermediate synthesized by high temperature (700–800°C) pyrolysis of acetic acid in the presence of an polyalkyl phosphate catalyst.5 This approach uses the dimethyl acetal of PA as a starting material, which is produced from para-cresol and methanol via a proprietary electrochemical oxidation process. The PA dimethyl acetal is reacted with ketene in the presence of boron trifluoride dimethyl etherate, a Lewis acid catalyst, resulting in the formation of 3-methoxy-3-(para-methoxyphenyl)propionate as an intermediate. The intermediate is then transesterified with 2-EH using sodium methoxide as a catalyst to yield EHMC and methanol as a by-product. This route is reported to offer significant cost advantages; it also is the basis for a 4,500 metric ton/yr EHMC plant that was commissioned in 2000.15
EHMC is supplied as a transparent, colorless to pale yellow, odorless liquid with a density slightly greater than water (specific gravity = 1.005– 1.013 g/cm3).16, 17 EHMC is nonvolatile and it boils at 350°C in atmospheric pressure. The boiling point decreases under reduced pressure, e.g., to 185–195°C at 0.75 mmHg vacuum. The compound is insoluble in water but readily dissolves in alcohols such as ethanol and isopropanol, and nonpolar solvents including a wide range of cosmetic emollient oils and esters. USP-grade EHMC, i.e., octinoxate, is minimally 98% pure by gas chromatography,4 and most commercially available grades meet or exceed this specification. Antioxidants such as butylated hydroxytoluene (BHT), may be added to EHMC at low levels (0.07–0.10% w/w) to improve stability on storage.
EHMC is a strong UVB absorber and a weakly fluorescent molecule with peak absorption and emission wavelengths of 308 ± 2 nm and 380 ± 3 nm, respectively.18 The spectroscopic properties of EHMC are slightly dependent upon the polarity of the medium in which spectra are measured, generally exhibiting absorbance peak shifts to shorter wavelengths and stronger fluorescence intensities as the dielectric constant, i.e., polarity, of the medium decreases.
Technology and Applications
The leading application of EHMC is as a UVB-absorbing active in topical sunscreen drug products. The maximum permitted use level of EHMC for this purpose varies by country, ranging from 7.5% in the United States and 8.5% in Canada, to 10% in the European Union and 20% in Japan.3 As a sunscreen active, EHMC is almost always incorporated as a part of a multi-component blend of organic (and occasionally, inorganic) UV filters in order to achieve the desired SPF value. Furthermore, to achieve adequate broad-spectrum (UVA and UVB) protection, such blends must also incorporate UVA filters, such as avobenzone (AVB).
EHMC is known to reduce the photostability of avobenzone; therefore, sunscreen blends incorporating EHMC and AVB must be carefully formulated to prevent the degradation of AVB and loss of UVA protection. To photostabilize AVB in the presence of EHMC and improve SPF and/or PFA values, UV filters such as octocrylene or ethylhexyl methoxycrylene may be added to the blend of sunscreen actives.19, 20 In terms of cosmetic applications, EHMC may be added to rinse-off and leave-in hair conditioning products at levels of 1–5% w/w to provide UV protection benefits, especially to color-treated hair.21
EHMC is typically added directly to the oil phase of emulsions, and it often is used to solubilize other organic UV filters for easier incorporation of a sunscreen blend into the oil phase. EHMC may also be dissolved in cyclomethicone, esters such as C12–15 alkyl benzoate or isopropyl palmitate, or ethanol to incorporate it into various cosmetic formulations.
- Ethylhexyl methoxycinnamate, monograph ID 1792, in International Cosmetic Ingredient Dictionary and Handbook, 13th edn, Personal Care Products Council, Washington DC, USA (2010)
- Final monograph: Sunscreen drug products for over-the-counter human use, 21 CFR 352.10, available at www.access.gpo.gov/nara/cfr/waisidx_06/21cfr352_06.html (Accessed Dec 12, 2011)
- Ethylhexyl methoxycinnamate, Safety/regulatory information, in Personal Care Products Council On-Line INFOBASE, available at http://online.personalcarecouncil.org/jsp/Home.jsp (Accessed Dec 12, 2011)
- Octinoxate, official monograph, in United States Pharmacopeia 34, United Book Press Inc., Baltimore, USA (2011) pp 3703
- HA Wittcoff, BG Reuben and JS Plotkin, Industrial Organic Chemicals, John Wiley & Sons Inc., Hoboken, NJ, USA (2004)
- C Maliverney and M Mulhauser, Hydroxybenzaldehydes, in Kirk-Othmer Encyclopedia of Chemical Technology, John Wiley & Sons Inc., published online (Dec 4, 2000) pp 1–12
- US 4713473, Process for treating 2-ethyhexyl p-methoxycinnamate in the presence of a phenol, P Schudel, R Schwarzenbach and HU Gonzenbach, assigned to Givaudan Corp. (Dec 15, 1987)
- US 6680404, Method of producing alkoxycinnamic acid ester, W Kuhn, W Marks and K Zahlmann, assigned to Symrise GmbH & Co. KG (Jan 20, 2004)
- US 5527947, Process for preparation of cinnamate sunscreen agents, A Alexander and RK Chaudhuri, assigned to ISP Van Dyk Inc. (Jun 18 1996)
- US 5187303, Process for the preparation of octyl methoxy cinnamate, A Eisenstadt and Y Keren, assigned to IMI (TAMI) Institute for Research and Development Ltd. (Feb 16, 1993)
- US 4970332, Process for producing 2-ethylhexyl-p-methoxycinnamate, DC Caskey, assigned to Mallinckrodt Inc. (Nov 13, 1990)
- US 5728865, Process for the preparation of octyl p-methoxy cinnamate, A Ewenson, B Croitoru and A Shushan, assigned to Bromine Compounds Ltd. (Mar 17 1998)
- JG de Vries, The Heck reaction in the production of fine chemicals, Can J Chem 79(5/6) 1086–1092 (2001)
- US 5359122, Preparation of 3-arylacrylic acid and their derivatives, M Huellmann, J Gnad and R Becker, assigned to BASF AG (Oct 25, 1994)
- Part Three, Aroma chemicals derived from petrochemical feedstocks, in Study into the establishment of an aroma and fragrance fine chemicals value chain in South Africa, Final Report, National Economic Development & Labour Council, South Africa, available at www.nedlac.org.za/research/fridge-studies/fine-chemicals/petrochemical.aspx (2004) (Accessed Dec 21, 2011)
- Uvinul MC 80, in Univul, T-Lite and Z-COTE Grades, BASF Technical Bulletin MEMC 050103e-02, BASF: Ludwigshafen, Germany (Jun 2006)
- Parsol MCX, DSM product brochure, DSM Nutritional Products Ltd.: Basel, Switzerland (2009)
- R Krishnan, A Carr, E Blair and TM Nordlund, Optical spectroscopy of hydrophobic sunscreen molecules adsorbed to dielectric nanospheres, Photochem Photobio 79(6) 531–539 (2004)
- LR Gaspar and PMBG Maia Campos, Evaluation of the photostability of different UV filter combinations in a sunscreen, Int J Pharmaceutics 307(2) 123–128 (2004)
- C Bonda, A Pavlovic, K Hanson and C Bardeen, Singlet quenching proves faster is better for photostability, Cosmet & Toil 125(2) 40–48 (2010)
- P Maillan, UV protection of artificially colored hair using a leave-on formulation, Int J Cosmet Sci 24(2) 117–122 (2002)