U-M CHEM 216 - Two-Step Semi-Microscale Preparation of a Cinnamate Ester Sunscreen Analog

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In the Laboratory1488 Journal of Chemical Education • Vol. 81 No. 10 October 2004 • www.JCE.DivCHED.orgSeveral laboratory experiments concerning the physicalproperties of sunscreens have appeared in this Journal dur-ing the last decade (1–5). These include quantification ofcommercial formulations by liquid chromatography (1) andultraviolet (UV) spectrophotometry (2–4). The photochem-istry of sunscreens has also been reviewed (6). Significantly,a student procedure focusing on multistep sunscreen synthesisand spectroscopic analysis has not, to our knowledge, beenreported. Given the current high profile nature of skin can-cer (7) and media attention towards sunscreens, we designeda two-step synthetic pathway towards an analog of a com-mercially available UV light blocker. This methodology is in-corporated into a third-year undergraduate organic synthesiscourse at the University of Toronto.Esters derived from trans-4-methoxycinnamic acid (R =H, Figure 1) are effective absorbers of UV radiation (8). The2-ethylhexyl ester 2 (commonly called octyl methoxy-cinnamate) is a high boiling point liquid found in many sun-screen preparations such as Bain de Soleil All Day Sunblock,Coppertone Sport, and Solbar Shield. For ease of isolationwe chose to generate an analog of 2 (ethyl ester 1, absent insunscreens), which is obtained as a low melting point solidin two four-hour laboratory periods. Esters of trans-4-methoxycinnamic acid are showcased in several introductoryorganic chemistry textbooks (9). These highly conjugatedcompounds absorb UVB radiation between 290–320 nm andare oil soluble. UVB radiation promotes dermal cell DNAdamage, causing skin cancer (10).A two-step procedure using 4-methoxybenzaldehyde asthe starting material (Scheme I) synthesizes ethyl trans-4-methoxycinnamate 1. In the first laboratory session studentsare exposed to an important carbon–carbon bond formingcondensation reaction. The Verley–Doebner modification ofthe Knoevenagel condensation (11) affords facile synthesisof trans-4-methoxycinnamic acid, which is isolated and char-acterized. During the second period, esterification is effectedby a cesium base mediated O-alkylation approach. This ex-emplifies the so-called “cesium effect” (12) and the useful-ness of cesium carboxylates as nucleophiles in SN2 reactions.In addition to stimulating class enthusiasm towards syn-thetic chemistry, this experiment impresses many organicpedagogical concepts, both practical and theoretical. Studentsbecome reacquainted with laboratory techniques such as heat-ing under reflux, extraction, vacuum filtration, and thin-layerchromatography. Melting point measurements and spectro-Two-Step Semi-Microscale Preparationof a Cinnamate Ester Sunscreen Analog WRyan G. Stabile and Andrew P. Dicks*Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada, M5S 3H6;*[email protected] Microscale Laboratoryedited byR. David CrouchDickinson CollegeCarlisle, PA 17013-2896Figure 1. UV light absorbers derived from trans-4-methoxycinnamicacid.OOORCHRCompoundnumber2CH31CH2CHCH2CH2CH2CH3CH2CH32Scheme I. Synthesis of ethyl trans-4-methoxycinnamate.OHCO+ COOHCOOHOCOOHtrans-4-methoxycinnamic acidethyl trans-4-methoxycinnamate1OOO1) β-alanine, pyridine, ∆2) H3OⴙCs2CO3, DMFC2H5IIn the Laboratorywww.JCE.DivCHED.org • Vol. 81 No. 10 October 2004 • Journal of Chemical Education 1489scopic methods (1H and 13C NMR, MS, UV, IR) readilycharacterize both carboxylic acid and ester products. Of es-pecial interest is the 1H NMR spectrum of ethyl trans-4-methoxycinnamate 1, which illustrates exceptional examplesof proton shielding–deshielding and spin–spin splitting. Stu-dents may be challenged to deduce the alkene geometry intrans-4-methoxycinnamic acid by calculation of proton cou-pling constants. As this compound is commercially available,1the esterification reaction can be undertaken if only a singlelaboratory session is accessible in the curriculum.Synthetic OverviewVerley–Doebner Synthesis of trans-4-MethoxycinnamicAcidtrans-4-Methoxycinnamic acid, (E )-3-(4-methoxy-phenyl)-2-propenoic acid, is synthesized by adapting and scal-ing up the microscale procedure described by Kolb et al. (13).In a 25-mL round-bottomed flask, 4-methoxybenzaldehyde(0.804 mL, 6.61 mmol), malonic acid (1.75 g, 16.8 mmol)and β-alanine (0.1 g, 1.12 mmol) are dissolved in pyridine(3 mL, 37.1 mmol). The mixture is heated under reflux for90 min. After cooling to room temperature and then in anice bath, 8 mL of concentrated HCl is added slowly causinga white precipitate to form. This solid is collected by vacuumfiltration, washed with cold water (2 × 10 mL), and driedthoroughly to typically yield 0.8–1.1 g pure product (68–93%).mp 169–171 ⬚C [lit. (14) 170–172 ⬚C].1H NMR (200 MHz, CDCl3, δ): 3.85 (s, 3H), 6.33 (d,1H, J = 15.8 Hz), 6.92 (d, 2H, J = 8.8 Hz), 7.51 (d,2H, J = 8.8 Hz), 7.75 (d, 1H, J = 16.0 Hz).13C NMR [300 MHz, DMSO-d6 (product insufficientlysoluble in CDCl3), δ]: 55.98, 115.03, 117.18, 127.51,130.65, 144.47, 161.63, 168.58.Synthesis of Ethyl trans-4-MethoxycinnamateEthyl trans-4-methoxycinnamate 1, (E )-ethyl 3-(4-methoxyphenyl)-2-propenate, is generated by the method ofParrish et al. (15) with some modification. trans-4-Methoxycinnamic acid (0.6 g, 3.36 mmol, product of Verley–Doebner synthesis)1 is dissolved in 10 mL of dryN,N-dimethylformamide (DMF) in a 25-mL round-bot-tomed flask. Cesium carbonate (1.65 g, 5.06 mmol) is addedfollowed by iodoethane (1 mL, 12.5 mmol). The flask iscapped (rubber septum) and the heterogeneous mixture isstirred vigorously at 50 ⬚C for one hour. After this time 4mL of HCl (1 M) is added to quench the reaction. The liq-uid is decanted from any solid Cs2CO3 remaining and ex-tracted with 3:1 hexanes兾ethyl acetate (2 × 10 mL). Theorganic layer is washed with brine (20 mL) and dried usingMgSO4. Removal of the drying agent by filtration is followedby solvent removal (under vacuum). An oil remains that so-lidifies on standing to form colorless prisms (0.3–0.55 g,43–80%).mp 47–48.5 ⬚C [lit. (16) 49–50 ⬚C].TLC: stationary phase, silica gel; eluent, 5:1hexanes兾ethyl acetate; Rfproduct = 0.48 (UV lamp, 254nm).1H NMR (200 MHz, CDCl3, δ): 1.35 (t, 3H, J = 7.2 Hz),3.84 (s, 3H), 4.26 (q, 2H, J = 7.2 Hz), 6.31 (d, 1H,J = 16.0 Hz), 6.91 (d, 2H, J = 8.6 Hz), 7.49 (d, 2H,J = 8.8 Hz), 7.66 (d, 1H, J = 16.0 Hz).13C NMR (300 MHz, CDCl3, δ): 14.51,


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U-M CHEM 216 - Two-Step Semi-Microscale Preparation of a Cinnamate Ester Sunscreen Analog

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