Introduction

Hexyl acetate (Figure.1) is a naturally occurring ester compound that has a fruity odor and is widely used as a nature-identical flavoring agent. Its molecular formula is C₈H₁₆O₂. Hexyl acetate molecular weight is 144.21 g/mol. Other physical data are shown in Table 1.[1] It is officially registered on the list of designated additives in Japan and is listed in the Code of Federal Regulations (CFR) as one of the food additives permitted for direct addition to food for human consumption (21 CFR 172.515) in the US. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) evaluated hexyl acetate as a flavoring agent categorized as an ester of aliphatic acyclic primary alcohols with aliphatic linear saturated carboxylic acids. Hexyl acetate was assigned to Class I based on the structural class of flavoring agents. The estimated intake levels of hexyl acetate by humans in the US and Europe were 160μg/person/day and 3,200μg/person/day, respectively, and the latter was greater than the Class I threshold of 1,800μg/person/day.[2]

Synthesis of hexyl acetate

Traditionally, it has been isolated from natural sources or produced by chemical synthesis.There is a growing demand for natural flavors containing green notes represented by C-6 alcohol (hexanol) derivatives; however, this steadily growing demand has left these compounds in increasingly short supply. Therefore, the biosynthesis of such esters by lipase catalyzed chemical reactions under mild conditions has become of much current commercial interest. An optimized enzymatic synthesis of the hexyl ester improves the conversion yield and reduces the costs of production in most favorable conditions. This should benefit manufacturers and be more appealing to the consumers.The importance of the enzymatic synthesis with lipases as catalysts to produce a number of commercially important flavor esters by esterification in nonaqueous organic solvents has been emphasized in several works. Carvalho et al. reported that hexyl acetate was synthesized by the cutinase-catalyzed transesterification reaction of butyl acetate with hexanol in a reversed micelles system, and the optimization of the transesterification was described using RSM.

The ability for immobilized lipase from Mucor miehei (LipozymeIM-77) to catalyze the transesterification of hexanol with triacetin was investigated in Shieh’s study.Response surface methodology and five-level-five-factor central composite rotatable design wereadopted to evaluate the effects of synthesis variables, such as reaction time (2-10 h), temperature(25-65 °C), enzyme amount (10-50%; 0.024-0.118 BAUN), substrate molar ratio of triacetin tohexanol (1:1 to 3:1), and added water content (0-20%) on percentage molar conversion of hexylacetate. The results showed that reaction temperature and substrate molar ratio were the mostimportant parameters and that added water content had less of an effect on percent molar conversion.On the basis of canonical analysis, optimum synthesis conditions were as follows: reaction time,7.7 h; temperature, 52.6 °C; enzyme amount, 37.1% (0.089 BAUN); substrate molar ratio, 2.7:1;and added water, 12.5%. The predicted value was 88.9% molar conversion, and the actualexperimental value was 86.6% molar conversion.[3]

Chemical synthesis is the main method reported in domestic literature for preparing hexyl acetate. Method 1:Hexyl acetate was synthesized by the new type solid superacid S₂O₈^2- /TiO₂. The effects of preparation conditions of catalyst on catalytic activity and the effects of acid/alcohol molar ratio amount of catalyst S₂O₈^2-/TiO₂ and reaction time on the esterification conversion were studied. The optimum condition is :acid/alcoholmolar ratio 0.20:0.24, the amount of catalyst 0.6g, reaction time 2h, the amount of dehydrater benzne 10 ml,reaction temperature 100℃~110℃. The esterification conversion was over 96% under the optimum conditions.[4] Method 2:The hexyl acetate was synthesized from n- hexanol and acetic acid by direct esterification.The effect of reaction temperature，reaction time，materials ratio，taling water reagent，the content of catalyst on the synthesis were studied，and the proper technological conditions were given as follows：the reaction temperature is 115℃，reaction time is 70 min，n（n- hexanol）/n（acetic acid）=1.2，the content of catalyst is 1 g，the taling water reagent（benzene）is 15 mL（when acetic acid is 0.3 mol）. The yield of the product is 96.36%.[5]

References

[1] Api AM, Bartlett A, Belsito D, et al. Update to RIFM fragrance ingredient safety assessment, hexyl acetate, CAS registry number 142-92-7. Food Chem Toxicol. 2024;192 Suppl 1:114936. doi:10.1016/j.fct.2024.114936

[2] Toyoda T, Cho YM, Matsushita K, et al. A 13-week subchronic toxicity study of hexyl acetate in SD rats. J Toxicol Pathol. 2019;32(3):205-212. doi:10.1293/tox.2019-0002

[3] Shieh CJ, Chang SW. Optimized synthesis of lipase-catalyzed hexyl acetate in n-hexane by response surface methodology. J Agric Food Chem. 2001;49(3):1203-1207. doi:10.1021/jf001050q

[4] Wu ChZ,etal.Synthesis of hexyl acetate catalyzed by solid superacid S2O82-/TiO2[J].Applied Chemical Industry,2002,(04):10-12.DOI:10.16581/j.cnki.issn1671-3206.2002.04.004.

[5] Su GJ,etal.Study on Synthesis of the Hexyl Acetate by Strongly Acid Cation Exchange Resin[J].Jiangsu Chemical Industry,2006,(30):16-18.