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Ingredient Profile—Ethylhexyl Methoxycinnamate
May 7, 2013 Contact Author	Michael J. Fevola, PhD, Johnson & Johnson
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Figure 1. Chemical structure of EHMC
Figure 2. Synthesis of 2-EH starting from propylene gas
Figure 3. Synthesis of EHMC starting from PA
Figure 4. Synthesis of EHMC via the Heck reaction
Figure 5. Synthesis of EHMC via the ketene route
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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.
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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)
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Figure 3. Synthesis of EHMC starting from PA, a) via direct aldol condensation with 2-ethylhexylacetate, and b) via aldol condensation with methyl acetate to yield methyl para-methoxycinnamate as an intermediate, followed by transesterification with 2-EH
Michael J. Fevola, PhD, is a manager in the New Technologies group at Johnson & Johnson Consumer and Personal Products Worldwide in Skillman, NJ, where he leads R&D in polymer and surface chemistry. Fevola has authored 12 peer-reviewed articles and book chapters, is an inventor on six US patents, and is a member of the Personal Care Product Council's International Nomenclature Committee and the Society of Cosmetic Chemists.