Raspberry Ketone: What Does It Do?

Raspberry ketone (also known as Rubus ketone) is naturally present in raspberry juice, with a concentration of approximately (0.1–0.2) × 10^(−6). It is an important aromatic component of raspberry essential oil and is widely used domestically and internationally as a fragrance with a delicate fruity aroma [1]. Its chemical name is 4-hydroxyphenyl-2-butanone, appearing as lustrous particles or needle-like white crystals. It has a melting point of 83°C and a boiling point of 161°C (0.67 kPa), is soluble in alcohols and oils, and is practically insoluble in water.

Raspberry ketone is extensively used in the formulation of food flavorings and cosmetic fragrances, as well as in the synthesis of pharmaceuticals [2–3], stimulants [4–5], cosmetics [6–7], cigarettes [8–9], dyes, and more. Additionally, raspberry ketone and its acetyl derivatives serve as fruit fly attractants [10–12], and can be synthesized for use as pesticides. Furthermore, due to the presence of aromatic rings, hydroxyl groups, and ketone groups in its molecular structure, raspberry ketone exhibits unique chemical activity and serves as an important intermediate in fine chemicals. Raspberry ketone possesses significant economic value and has garnered widespread attention in recent years, with demand increasing annually.

1 Synthesis of Raspberry Ketone

In recent years, various synthesis methods for raspberry ketone have been developed, primarily categorized into natural extract-based raw materials and petrochemical-based raw materials based on the starting materials.

1.1 Extraction and Synthesis of Natural-Grade Raspberry Ketone

With the growing emphasis on environmental protection, the international market has increasingly favored natural fragrance products. Zhang Baotang et al. [13] used natural raspberries as the starting material, followed by extraction, decolorization, concentration, and purification to obtain natural-grade raspberry ketone; Xu Dongqing et al. [14] used natural anethole and fermented acetone as starting materials, obtained natural-grade raspberry ketone through the Claisen-Schmidt reaction, selective hydrogenation, and demethylation, with a total yield of 75.75% (calculated as anise aldehyde) and a purity of 98.65%, featuring a pure aroma.

Gu Yun-Cui et al. [15] used natural anise aldehyde as the raw material, condensed with naturally produced acetone from fermentation to obtain aniseed acetone, which was then hydrogenated to aniseed acetone, and finally the aniseed acetone was subjected to demethylation to obtain natural raspberry ketone. The natural purity was determined to be over 98% using the ¹⁴C isotope measurement method. Additionally, this method has been reported in several patents [16–17]. Currently, the synthesis process for natural-grade raspberry ketone is relatively mature, but it is costly and has low yield, limiting its application to high-end products. Further exploration of more cost-effective synthesis methods is needed.

1.2 Synthesis of petrochemical-grade raspberry ketone

With the annual increase in global demand for raspberry ketone, and the limited supply and high cost of natural-grade raspberry ketone raw materials, which cannot meet the needs of ordinary consumers, plant extraction is not economically viable; however, raspberry ketone synthesized from petrochemical raw materials, due to its abundant raw material sources and low cost, is widely used in the formulation of cosmetic fragrances and in the agricultural sector. Currently, raspberry ketone is primarily synthesized. From the perspective of starting materials, petrochemical-grade raspberry ketone synthesis primarily includes methods using p-hydroxybenzaldehyde and acetone as raw materials, phenol and 4-butanol-2-ketone as raw materials, and phenol and methyl vinyl ketone as raw materials.

1.2.1 Using p-hydroxybenzaldehyde and acetone as raw materials

Ni Xia [18] studied the synthesis of 4-hydroxyphenyl-3-buten-2-one (yield 88.4%) via Claisen-Schmidt condensation under alkaline catalysis, followed by process optimization through orthogonal experiments. further hydrogenated under palladium-carbon catalysis to synthesize raspberry ketone (yield 84.0%); Chen Hualing [19] used NaOH solution as the Claisen-Schmidt condensation catalyst to synthesize 4-hydroxyphenyl-3-buten-2-one, and then used 5% Pd/C and nickel formate as catalysts for the second step, yielding raspberry ketone in yields of 72.55% and 65.7%, respectively.

Du Zhidai et al. [20] used orthogonal experiments to study the condensation reaction conditions of p-hydroxybenzaldehyde with acetone, obtaining the optimal process conditions as follows: the molar ratio of reactants n (hydroxybenzaldehyde) : n (acetone) : n (NaOH) = 1.0 : 25 : 25 (reacted at 30°C for 5 hours), followed by conventional hydrogenation reduction, vacuum distillation, and recrystallization in a mixed solvent to obtain raspberry ketone (yield 61.8%); Tang Jian [21] used hydroxybenzaldehyde and acetone as raw materials, catalyzed by NaOH in a Claisen–Schmid condensation reaction, followed by hydrogenation reduction using nickel formate as a catalyst, isopropanol as solvent, and hydrogen reduction to obtain raspberry ketone (yield 42.0%).

1.2.2 Using phenol and 4-butanol-2-ketone as raw materials

Qi Shaohong [22] first synthesized the intermediate 4-butanol-2-ketone using acetone and formaldehyde as raw materials, then used concentrated sulfuric acid as a catalyst to react it with phenol, purified it, and synthesized raspberry ketone in two steps (yield exceeding 70%); Liu Hongxiang et al. [23] used phenol and 4-butanol-2-ketone under the catalysis of a strong acidic solid acid to synthesize raspberry ketone in a single step (yield 92.5%, purity 99%); Zhang Xiao et al. [24] first used formaldehyde and acetone as raw materials, solid-loaded alkali KF/Al₂O₃ as a catalyst to synthesize butanone alcohol, then reacted butanone alcohol with phenol, and used ion exchange resin D218 as a catalyst to synthesize crude raspberry ketone (yield 46.0%–71.0%).

Zhu Kai et al. [25] used a fixed-bed reactor with θ-ring stainless steel packing, with formaldehyde and acetone as raw materials and NaOH as a catalyst to synthesize butanone, then used butanone and phenol as raw materials, employed a fluidized-bed reactor with ion exchange resin D218 as a catalyst, to catalyze the synthesis of raspberry ketone; Qiu Guisheng et al. [26] used phenol and 4-hydroxy-2-butanone as raw materials, performed a Claisen-Schmidt condensation reaction to synthesize 4-(4-hydroxyphenyl)-3-butene-2-one, and then underwent a Friedel–Crafts alkylation reaction under acidic catalysis to obtain raspberry ketone.

1.2.3 Using phenol and methyl vinyl ketone as raw materials

Albertus et al. [27] used phenol and methyl vinyl ketone as raw materials, and under the action of an acidic catalyst, phenol and methyl vinyl ketone underwent a condensation reaction to synthesize raspberry ketone; Guo Hui et al. [28] synthesized raspberry ketone under acidic ionic liquid conditions, using phenol and methyl vinyl ketone as starting materials, through a selective addition reaction.

2 Detection of raspberry ketone

Extensive research has been conducted on methods for detecting raspberry ketone. Zhang Zhihong et al. [29] established a spectrophotometric method for determining raspberry ketone: raspberry ketone forms a stable complex with Ni(NO₃)₂, with a coordination ratio of 1:1 and a coordination constant of 8.520. The standard curve follows the Lambert-Beer law in the range of (8.152–73.370) × 10^(−6) mol/L, with a correlation coefficient of r = 0.9966, a recovery rate of 102.80%, and the relative standard deviation (RSD) is 0.190%.

Xian Yunxia et al. [30] established a method for rapidly and accurately determining the content of raspberry ketone reference standards using the nuclear magnetic resonance internal standard method: using deuterium-labeled DMSO as the solvent, benzoic acid as the internal standard, measuring temperature of 25 °C and scanning 32 times, the nuclear magnetic resonance hydrogen spectra of the raspberry ketone and benzoic acid mixture were collected. The proton signal peaks at chemical shifts δ of 6.97 in raspberry ketone and 7.95 in benzoic acid were used as quantitative peaks, The linear regression equation for the ratio of peak areas y (As : Ar) to mass ratios x (ms : mr) is y = 0.197x + 0.783, with a correlation coefficient r = 0.997. Here, As is the integrated area of the quantitative peak of the sample, Ar is the integrated area of the quantitative peak of the internal standard, ms is the sample mass, and mr is the mass of the internal standard substance. The RSD value for the repeatability of the content determination experiment is 0.47% (n = 6), the RSD value for stability is 0.58%, and the RSD value for the recovery rate of spiked samples is 1.18%.

3 Applications of Rubus fruticosus ketone

With the further development of the spice industry and organic synthesis industry, the research value of raspberry ketone has steadily increased. In addition to its use as aspice, it also has widespread applications in other fields. For example, raspberry ketone and gallic acid epicatechin are used as a new nutritional supplement combination, primarily for the treatment or prevention of obesity or obesity-related symptoms [31]; Raspberry ketone can be synthesized into ractopamine, which serves as a potent cardiac stimulant for treating congestive heart failure, obesity, and muscle atrophy [32]; Additionally, raspberry ketone has been studied for applications in environmental protection [33] and Chinese-style cigarettes [34]. With further research and continuous improvement in the future, the application areas of raspberry ketone will continue to expand.

4 Conclusions

In recent years, the demand for raspberry ketone has been increasing annually both domestically and internationally, while the natural raspberry raw material is scarce and cannot be produced on a large scale. Raspberry ketone synthesized from petrochemical raw materials, due to its abundant raw material sources and good quality, has significant economic value and has attracted widespread attention. Currently, industrial production primarily uses methods involving the synthesis of raspberry ketone from hydroxybenzaldehyde and acetone, or from phenol and 4-butanol-2-ketone. However, these methods involve the extensive use of alkalis and acids, corrosion of equipment and environmental pollution, environmental issues are concerning. In the method using phenol and methyl vinyl ketone as raw materials, methyl vinyl ketone is unstable, prone to polymerization, and has low yield. Therefore, the development of new green, environmentally friendly, energy-efficient, and high-yield synthesis methods for raspberry ketone is of great importance.

References

[1] He Jian, Sun Baoguo. Fragrance Chemistry and Technology [M]. Beijing: Chemical Industry Press, 1995: 69–72.

[2] Xie Xinmei, Pang Xiaobin, Li Xiaoting. Hypoglycemic effects of raspberry ketone on diabetic mouse models and its mechanism [J]. Chinese Journal of Pharmacy, 2012, 47(23): 1899–1904.

[3] Yang Hao, Xie Xinmei, Pang Xiaobin. Effects of Rubus coreanus extract on the expression of SHP-1 and IRS-1 in the insulin signaling pathway of HepG2 cells [J]. Chinese Traditional and Herbal Drugs, 2014, 36(8): 1579–1583.

[4] Wan Gang. Synthesis of a β-agonist—Ractopamine [D]. Shandong: Shandong University, 2006.

[5] Wang Hailong, Li Guoting, Liu Bingtao, et al. Synthesis Method of β-Adrenergic Agonist Ractopamine: China, 201110004968.8 [P]. 2011–01–12.

[6] Li Anliang, Yang Shuqin, Guo Xiuru. Research Progress on the Active Ingredient Rubus Fruticosus Glucoside in Cosmetics [J]. Fragrance and Cosmetics, 2014(4): 63–66.

[7] Lei Yonglin. A Plant-Derived Melanin-Decomposing Skin Care Liquid and Its Preparation Method: China, 201410321678. X[P]. 2014–07–07.

[8] Dong Gaofeng, Zhang Qiang, Shi Jianquan, et al. Application of Raspberry Ketone in Chinese Cigarettes: China, 201110021934. X[P]. 2011-01-19.

[9] Li Hongwu, Zhang Qiang, Sun Li, et al. A processing technology for shaping tobacco stem fibers: China, 201210091671.4[P]. 2012-03-31.

[10] Ren Zhichao, Wu Weijian, Li Meihui, et al. Screening of formulations for male attractants of melon fruit flies [J]. Journal of Tropical Crop Science, 2013, 34(4): 743–745.

[11] Chen Xia, Feng Chuanhong, Shen Youlian, et al. Synthesis of fly attractant and its lure activity against melon fruit flies [J]. Chinese Journal of Plant Protection, 2011, 31(9): 9–14.

[12] Wang Xiaohuai, Tong Zhonglin, Yuan Dingyang, et al. An insect-repelling and trapping device: China, 201410161356.3 [P]. 2014-04-21.

[13] Zhang Baotang, Tan Jiazhong, Li Fang. A method for extracting raspberry ketone from raspberries: China, 201310540732.5[P]. 2013-11-04.

[14] Xu Dongqing, Li Zirong, Zhang Xuemei, et al. Study on the synthesis process of natural isomer raspberry ketone [J]. Chemical Research and Application, 2014, 26(2): 301–305.

[15] Gu Yuncui, Qian Liqun, Huan Yueqin, et al. Preparation of natural raspberry ketone [J]. Fragrances, Flavors, and Cosmetics, 2013 (Supplement 1): 39–41.

[16] Xia Jin, Jin Jinsong, Zhao Bin, et al. A Method for the Synthesis of Raspberry Ketone: China, 201310669809.9 [P]. 2013–12–11.

[17] Chen Tiandu, Xiang Zhengrong. A Method for the Synthesis of Raspberry Ketone: China, 201410456993.3 [P]. 2014–09–10.

[18] Ni Xia. Study on the Synthesis of Raspberry Ketone and Its Analogues [D]. Jiangsu: Nanjing Forestry University, 2006.

[19] Chen Hualing. Kinetic and Process Study on the Synthesis of Raspberry Ketone [D]. Guangxi: Guangxi University, 2012.

[20] Du Zhida, Zeng Zhaoguo. Study on the Synthesis of Raspberry Ketone [J]. Fine Chemical Industry, 2000, 17 (6): 331–333.

[21] Tang Jian. Synthesis and application of raspberry ketone [J]. Chemical Technology and Development, 2006, 35 (9): 21–23.

[22] Qi Shaohong. Synthesis of 4-hydroxyphenyl-2-butanone [J]. Hebei Chemical Industry, 2004(2): 35–36.

[23] Liu Xianghong, Zhang Mingfeng, Chen Gang, et al. Solid Acid Catalyzed Synthesis of Raspberry Ketone [J]. Zhejiang Chemical Industry, 2015, 46(4): 14–18.

[24] Zhang Xiao, Zhu Kai, Zhang Qian. A Method for the Synthesis of Raspberry Ketone Using Solid Acid-Base Catalysis: China, 201410759348.9[P]. 2014-12-11.

[25] Zhang Xiao, Zhu Kai, Zhang Qian, et al. A synthesis process for raspberry ketone: China, 201410618724.2 [P]. 2014-11-06.

[26] Qiu Guisheng, Wang Yunfeng, Ma Long, et al. A method for preparing the flavoring agent raspberry ketone: China, 201110350786.6[P]. 2011-11-09.

[27]Albertus J M, Robert Van Helden, Johu Ernest Hawes. Process for preparation of beta-aryl-substituted ketones: British, 1458562[P]. 1976-12-15.

[28]Guo Hui, Zhang Guobao, Zhuang Yuwei, et al. A method for preparing raspberry ketone in acidic ionic liquids: China, 201110442699.3[P]. 2011-12-27.

[29] Zhang Zhihong, Xu Limin, and Yao Baoqiang. Spectrophotometric determination of raspberry ketone [J]. Journal of Beijing University of Petrochemical Technology, 2005, 13 (4): 15–17.

[30] Xian Yunxia, Geng Yanling, Zhou Honglei, et al. Determination of the content of raspberry ketone reference standards by nuclear magnetic resonance internal standard method [J]. Shandong Science, 2015, 28 (1): 7–11.

[31] Daniel Redlerschdorf, Peter Weber, Sven Wolfram. Nutritional supplement composition containing gallic acid-bound catechin and raspberry ketone: China, 200380104594.0[P]. 2003-11-20.

[32] Hu Houcai. A new method for preparing ractopamine from hydroxybenzyl acetate and raspberry ketone: China, 200410039274.8[P]. 2004–02–11.

[33] Meng Lu. A Natural Green Formaldehyde High-Efficiency Remover: China, 200910011178.5[P]. 2009-04-15.

[34] Dong Gaofeng, Zhang Qiang, Shi Jianquan, et al. Application of Rubus fruticosus ketone in Chinese-style cigarettes: China, 201110021934. X[P]. 2011-01-19.