Industrial Fragrance Chemistry: A Brief Historical Perspective

Authors: Olivier R.P. David and Franco Doro

  1. Introduction
  2. The Rise of Synthetic Fragrance Ingredients (1870/1910)
  3. “Sell by Smell” (1920-1940)
  4. Fragrance Ingredients ‘Blockbusters’ (1950-1970)
  5. Focus on odor potency (1980-2000)
  6. Fragrance Delivery Systems & Back to Nature (2000-2020)
  7. Conclusion and Outlook


Perfumery has evolved from a handcraft activity, marking supreme aristocratic luxury in the Renaissance, to a global industry powering scent experiences for present-day consumers through the use of a myriad of consumer packaged goods. This contribution reviews major breakthroughs in the field, including landmark fragrance ingredients, technological advances in scent delivery, and key innovations in consumer products which created the demand for scientific and technological advancements in the scent domain. These innovations are presented chronologically, relying solely on information drawn from public written sources, spanning a time period of 150 years (1870-2020). We hope with this contribution to generate interest in the readership for this fascinating field, while celebrating 150 years of innovation for scented mass-market products..

1. Introduction

Scent is ubiquitous in our life as consumers. We experience scents through the multiple consumer products used in our daily routines, from personal hygiene products such as soaps and shampoo to household products ranging from all-purpose cleaners to fabric detergents.

For most of the pre-industrial area, as far back as 3000 BC,[1] fragrances were already incorporated in products such as unguents, candles and soaps. Their consumption was, however, limited to the elites of the time. It was already known in ancient times that scent could enhance mood and physical healing, making it an integral part of public rituals and healing practices. Fast forward to modern times and the psycho-physiological effects of scent are being used for more profane purposes to enhance the overall consumer experience of many products. Scent has become a powerful factor in determining consumer appeal and conveying emotional and efficacy cues for various brands on a commercial scale.

The use of scented products had not changed dramatically up to the second half of the 19th century. Since then, fragrances have been increasingly used across a wide range of products for a growing segment of the population. The mass-production of consumer goods in the household and personal hygiene space that started in the first half of the 20th century brought an explosion of scent experience to the ordinary consumers that is still in full swing today.

The primary catalyst for the increasing incorporation of scent into consumer products has been the cost optimization of synthetic fragrance ingredients. As a result, fragrances can be extensively utilized in the creation of new consumer products, as well as in the expansion into new olfactory domains for existing

scented consumer products. This resultant increase in supply and demand has been pivotal in the growth of this market segment.

The global household goods market (including laundry products) was worth USD 177.43 billion in 2021 and is projected to grow at 6.8% CAGR from 2022-2030.[2] Similarly, the global personal hygiene and grooming market was valued at USD 482.8 billion in 2021 and is expected to grow at 7.7% CAGR from 2022- 2030.[3] The combined market size of household and personal hygiene goods is approximately equivalent to the GDP generated in 2022 by a country like Austria.[4]

In this review, we will outline what we consider to be the crucial scientific and technological breakthroughs in the field of scent that have had a lasting impact on product development strategies in consumer packaged goods industry, with a focus on the household- and personal hygiene/grooming segments, as well as the reciprocal influence of the latter on the field of scent. We recognize the major influence that fine fragrances (or perfumes) have played in the expansion of scent across consumer products. With this in mind, we will report some of the key historical milestones in fine fragrance development that have had a trickle-down effect on other consumer products.[5] This review is conceived to give a flavor (or should we say a scent) of the intertwined relation between scent and consumer packaged goods in the course of the last 150 years. We aim as well to stimulate the specialized readership to contribute to the collection of scattered information and thus help the authors to continue carrying out the historical documentation of this fascinating field in future articles.

2. The Rise of Synthetic Fragrance Ingredients (1870/1910)
Figure 1. Timeline of the most important synthetic ingredients, according to the date of first academic synthesis or patent priority date for 1850-1910.
Figure 1. Timeline of the most important synthetic ingredients, according to the date of first academic synthesis or patent priority date for 1850-1910.

The burgeoning of modern perfumery can be symbolically dated to 1874 with the foundation of Haarmann & Reimer, the first company devoted to the production of synthetic ingredients for flavors and perfumes.[6] Other actors quickly joined the field to propose novel synthetic ingredients, most of them being specialists in essential oils and natural extracts that extended their offer to pure molecules. In Table 1, we report the main companies operating in synthetic ingredients at the end of the 19th century. Several of these pioneering companies merged with other ones to form some of the global fragrance companies operating today.

Essential oils were the dominant fragrance materials till the late 1800s, but their use was heavily limited by their high price and limited/unstable supply. With the entrance to the market of Haarmann & Reimer and of Fabriques de Laire, several fragrance materials were made available to perfumers through chemical synthesis by the end of the 19th century, see Figure 1.[7] Synthetic fragrance ingredients which made their entry into the palette of perfumers were: vanillin 1 (Haarmann and Tiemann, 1874) which initial profitable industrial success boosted subsequent investments in the field; coumarin 2 (1876) unlocking abstraction in fragrances by enabling the creation of Fougere perfumes with its smell of hay; nitro musks 3a-d (Baur, 1888),[8] which opened new opportunities as a ‘fixateur’ for fragrances; ionones 4a and methyl ionones 4b (Tiemann, 1893),[9] with which the much appreciated violet smell could be recreated; methyl anthranilate 5 (Erdmann brothers, 1898) isolated in neroli oil; aliphatic aldehydes 6 (C12 MNA 6a Darzens, ~1903), a series of molecules with fresh-soapy smells, critical for creating Chanel N°5; isobutyl quinoline or ‘IBQ’ 7 (Darzens, 1908), with a unique smell that evokes leather; hydroxycitronellal 8 (1905),[10] triggering the creativity of perfumers to reproduce the transparent, spring poetry of lily-ofthe-valley. Interestingly, the first molecules were rationally discovered through screening of odorous principles isolated from natural materials, while the last two were discovered by serendipity during academic investigations. Although such molecules were fairly expensive at their respective launches, even more than their natural counterparts sometimes, production optimization led to drastic cost reductions allowing for their inclusion in consumer packaged goods. Eugene Charabot, a big name in the trade, noted in his 1900 book on ‘Artificial Perfumes’[11] that vanillin was initially sold at 8750 fr/kg in 1876, to decrease to 938 fr/kg in 1885, and less than 115 fr/kg in 1900, while natural vanilla was sold at 350 fr/kg in 1823 or 40-50 fr/kg in 1909. This is even more dramatic with heliotropin 9 that dropped from 3790 fr/kg in 1876 to 37,5 fr/kg in 1899, a price divided by 100.

Click to learn the full tables.

One should not forget the persisting role of natural ingredients in the perfumer’s palette even while it is constantly extended by chemists. A novel mode of concentration of odorous principles was introduced by Etablissements Antoine Chiris in the late 1890’s with the first flower absolutes obtained by extraction with volatile solvents (diethyl ether, petroleum ether, liquified butane) immediately followed by Robertet and Lautier. This was crucial because important odorous principles were still inaccessible to chemical reproduction. Oakmoss, vetiver and patchouli, were far too complex for the analytical techniques of the time to allow identification of key odorants, or even if deciphered, the molecules were far too intricate to be duplicated by synthesis. Patchouli oil, for example, passed from being introduced in perfumery in the mid 19th century to become one of the most important fragrance ingredients only a few decades later during the Belle Epoque (late 1890’s) and it was considered indispensable for the creation of chypre notes in reports dated in the 1920’s.[12] Patchoulol 10, first named ‘patchouli camphor’,

was isolated in 1869 by M. H. Gal,[13] but the genuine tricyclic structure was deciphered only in 1963 by Jack D. Dunitz and George Büchi,[14] the latter describing the formal total synthesis one year later.[15]

The first consumer products containing fragrances of broad appeal to ordinary consumers were in fact soaps. In the 1910s there were already clear olfactory directions for soaps, though limited to the most affordable and also chemically stable ingredients. Hence, preferred scents were bitter almond (benzaldehyde 11), rose (phenyl ethyl alcohol 12), violet (ionones 4), heliotrope (piperonal/heliotropin 9), lilac (terpineol 13) or carnation (eugenol from clove 14).[17] Notably, terpineol 13 was considered one of the most important fragrance ingredients for soaps well into the 1950s.

A key event which defined how we experience fine fragrances today happened with the industrial production of atomizers in both Europe and the US from the early 1900s onwards. An atomizer is a device that allows for delivery of a fragrance in a spray of tiny droplets. This device started to be produced by artisans in the second half of the 19th century and we have a record of such a device being showcased at the Paris World Expo of 1878.[18] Marcel Frank et cie (Paris) was one of the companies most active in this area in the first decades of the 20th century.

In the US, Dr. Allen De Vilbiss and his sons designed and manufactured atomizers for the perfumery industry around the same time. These devices were based on pre-existing prototypes used by otolaryngologists, see Figure 3.[20] The advent of atomizers revolutionized consumer relationships with fragrances, making them more convenient and safer, thereby democratizing the perfuming gesture. Prior to their introduction, fragrances were enjoyed by infusing or sprinkling a cloth with a perfume or by applying a drop of perfume to the wrist and rubbing it in.[21] This paradigm shift was reported by the specialized press in these terms “There is almost as much difference between the application of perfume with cotton-wool or the corner of a towel and with the perfume spray as there is between the sensation of water thrown at the face and that of softly dropping rain. The first is a shock—the second is soothing and refreshing.”[18] The use of atomizers popularized sprays as a new delivery system for fragrances, which eventually led to the development of pressurized air fresheners and deodorant sprays in the following decades.

3. “Sell by Smell” (1920-1940)

The interwar period saw massive progress in analytical chemistry and the first spectacular successes in the total synthesis of natural products. Chemistry reached a maturity that allowed reproduction of major odorant principles. Chemistry was hence at the center of ingredient innovation from the start, while diffusion technologies defined a second axis of innovation. A major breakthrough was the comprehension by Leopold Ruzicka of the macrocyclic nature of musk and civet odorants. He would receive the Nobel prize (1939) for this discovery and his contribution to terpene chemistry (syntheses of fenchone 15, linalool 16, farnesol 17, nerolidol 18).[22] Consequently, this was the golden age for synthetic musks with the synthesis of several macrocyclic musks (exaltone 19, civettone 20, exaltolide 21, Globanone 22, muscone 23, ambrettolide 24) 1924-34 by Ruzicka and colleagues; Musk T by Wallace H. Carothers (first sold as Astrotone 25) 1933 during a side-project devoted to Polyesters, having previously invented no less than Neoprene and Nylon.

Chemical processes for established synthetic ingredients were re-designed to obtain more economically viable routes to support the expanding need of the consumer goods industry. For example, whilst some ingredients could be synthesized for the first time in the late 19th century, such as phenyl ethyl alcohol 12 (Radziszewski, 1876), these first synthetic attempts involved either tedious synthesis or yielded a poor olfactory profile with impurities that required laborious chemical separations. In the post WWI years new chemical technologies were employed for the first time to obtain fragrance ingredients more economically through higher yields. Hence, in the early 1930’s, a new phenyl ethyl alcohol quality was synthesized via a Friedel-Crafts reaction between ethylene oxide and benzene.[23]

By the late thirties, chemists were thought to have almost completely reproduced, synthetically, the key components of essential oils known at the time. Jasmone 26 (Treff, 1935) and alpha-irone 27 (Naves, 1943) were considered the latest key natural components to be reproduced synthetically on a commercial scale, see Figure 4. Synthetic chemists of the time had to go for inspiration outside of nature and this enabled the discovery of some exceptional fragrance ingredients that brought perfumery to new heights as will be witnessed in the post WWII era.[24]

In this era the potential of synthetics was clearly established, with increasing advertising activity in specialized magazines for the replacement (or complement use) of natural oils. Fragrances were reported in advertisements as the cheapest form of product promotion and industry leaders had adopted the slogan “sell by smell”.[25]

Figure 4. Timeline of the most important synthetic ingredients
Figure 4. Timeline of the most important synthetic ingredients, according to the date of first synthesis or patent priority date for 1910-1940. Pictures of prominent
chemists active in the 1910-1940 period. Photo of Leopold Ruzicka: copyright-free from ETH Bildarchiv, see ref. [26a]. Photo of Yves-René Naves: copyright-free
from “Le nouvelliste, 22 septembre 1951” retrieved at see ref. [26b]. Photo of Wallace H. Carothers: copyright-free from Commons
Wikipedia see ref. [26c].

In the 20’-30’s of the last century several technical accounts were published on how to introduce fragrances into toiletries. These technical reports share guidelines for incorporating fragrances into face powders, body lotions, soaps,[27] bath salts, shampoo or depilatory creams.[28] Regarding fragrances in shampoo, the literature of the time reports that there were no established olfactory directions yet. It seems that the first scented liquid shampoo (invented in 1927) had a violet smell, which most likely derived from scents already used in powder shampoos (the precursor of liquid shampoos).

It is likely that around the early 40’s the first olfactory directions were established for some of the upcoming branded shampoos we know today.[29] The initial benefit of shampoos was to cleanse hair from excess fats. These products would be the focus of continuous innovation in the upcoming decades (and to this date) to ensure in addition to cleaning the delivery of additional features such as optimal foaming upon use, rinse, rheology control of formulation, skin mildness or deposition of actives. The field of formulation science and ingredient performance played a crucial role in these advancements. For instance, synthetic, negatively-charged surfactants were introduced in the 1930s to replace fat-based soaps. This led, in the coming decades, to opportunities for improved fragrance delivery to the skin and hair. One notable example is the use of cationic polymers in shampoo formulation, which induce the formation of coacervates upon dilution during the rinse of shampoo with water, which aids in fragrance deposition. These developments broadened the range of available scents, allowing for the effective communication of desired beauty benefits and efficacy cues.[30]

Odorono (1912) seems to have been the first antiperspirant of wide distribution. It is unclear when scent was first introduced in antiperspirants and deodorants. The earliest source we could retrieve relates to advertisements from the 1950s.[31] Most advertisements referred to fresh and sweet scents, but we could not find more detailed sources related to the specific fragrance ingredients. The sale of antiperspirants increased 600% between the early 1940s and the late 1950s.[32] We could speculate that scent played some role in the popularization of this personal care item around this time span.

The birth of scented pressurized air freshener products could be identified in the post WWII years. At that time it was common to come across the word “space deodorants”. Aerosols were introduced as “bug bombs” to dispense insecticide from pressurized cans during WWII. Typical propellants were chlorofluorocarbons (CFCs), which due to their low cost in combination with economical packaging gave a start to scented air freshener products as new product lines in the post-WWII years. Formulation chemists had already developed clear guidelines in the 1940s on how to create fragrances in these new matrices, taking into account the solubility of fragrance ingredients in solvents and using co-solvents for optimal solubility.[33] Fluorinated propellants started to be replaced in the 1980s (and well into the 1990s) with light alkanes such as propane, butane and isobutane which have less impact on the atmosphere.[34]

4. Fragrance Ingredients ‘Blockbusters’ (1950-1970)

WWII brought a brutal stop to research programs directed towards products for ‘frivolities’ such as perfumes and luxury soaps, but the postwar period gathered the fruits of the investigations undertaken in the 1930s. Moreover, systematic studies were launched during the 1950s to explore the olfactory diversity offered by synthetic molecules randomly prepared from abundant terpenes after application of well-controlled synthetic processes. The main feedstock of terpenes is gum turpentine and crude sulfate turpentine, the latter a by-product from the pine wood pulping industry. Terpene chemistry had its origin in the late 1800s but the full modus operandi of nature in the biosynthesis of these ingredients was revealed only in the late 1940/50s. The presence of multiple isoprene units in terpenoids was observed first by Wallach (1887, Nobel Prize winner in 1910) and established as a general principle by Ruzicka in the “isoprene rule”. The mechanistic explanation for this rule was established as a result of significant advancements in the field of biochemistry. The pioneering work of Bloch and Lynen, who were awarded the Nobel Prize in Medicine in 1964, played a crucial role in generating the key evidence to define the mevalonate pathway for the synthesis of terpenes in nature.[35]

We could retrieve a dialogue from the early 1950’s by Gerrit Jan Beets, a prominent fragrance chemist of the time and biochemist Arie Haagen-Smit on the origin of terpenoid ingredients and biogenesis. Beets speculated, erroneously, that terpenoid ingredients were formed in nature by chemical reaction of small chemical molecules (such as formaldehyde and acrolein) which reacted by means of the Prins-reaction (named after Hendrik Prins, another prominent fragrance chemist)[36] and aldol condensation. This theory was considered unlikely by Haagen-Smit, as there was already evidence of the role of phosphorylated intermediates for the formation of terpenes in nature through enzyme-mediated reactions.[37] We could see in these early discoveries and dialogues the first seeds of the role biochemistry would play in the fragrance industry: first in explaining natural phenomena and in the future as a technology tool. It would still take another 60 years for the fragrance industry to commercially produce the first biotech-based perfumery ingredients.[38]

Terpenes were submitted by chemists to a large array of chemical transformations in order to produce a vast molecular diversity of synthetic molecules into which “hits” were selected for their olfactory appeal. This somewhat brutal “try-and-smell” approach however led to an impressive number of discoveries with the patenting of an unprecedented palette of artificial ingredients. Prominent examples are: dihydromyrcenol 28 displaying a diffusive lavender-like freshness (Webb, 1956); Lyral 29, derived from myrcenol, conveying a clean lily-of-thevalley impression (Steinbach, 1958); Cedramber 30, prepared from cedrene, with a dry, powerful smell of amber and wood (Blumenthal, 1966); Iso E super 31, made in two steps from myrcene, bringing a complex and rich impression of cedar, of vetiver with mineral and ambery facets (Hall, 1973); Sandalore 32, the first artificial molecule derived from pinene with a strong sandalwood smell (Naipawer, 1976).

Of course, robust aromatic chemistry based on petrochemical raw materials was more than ever productive, using the more subtle “small variation” approach by exploring a molecular domain around a known odorant. This was actually rationalized with the concept of structure-activity relationship and the birth of manifold olfactory models supposed to capture the molecular essence of lily-of-the-valley, sandalwood, amber, musk, etc.[39]

Although only vaguely predictive, this methodology brought us many splendid ingredients: Helional 33, with watery, melon-like smell (Beets, 1958); Lilial 34, among the most powerful odorants reproducing lily-of-the-valley (Carpenter, 1956); Bourgeonal 35, again conveying a lily-of-the-valley impression with greener facets (Dorsky, 1959). A series of polycyclic musks were synthesized and launched: Phantolid 36 (Fuchs, 1951), Versalide 37 (Carpenter, 1953), Celestolide 38 (Beets, 1955), culminating with Galaxolide 39 (Beets, 1962).[41] The valorization of a precursor of the latter brought us the perfumery platypus Cashmeran 40, smelling all at once woody, mineral, musky, slightly fruity and balsamic (Hall, 1969).We should not forget the serendipitous popping of marine odorants with the preparation of several oxygenated derivatives of anxiolytic benzodiazepines by the Pfizer team, resulting in Calone 1951 41 (Beereboom, 1966) all smelling watermelon with an oceanic feel.

Then, scrupulous scrutiny of expensive natural ingredients fished out trace molecules that became extremely interesting high impact odorants, Ambrox 42 with a soft and dry smell of ambergris (Stoll, 1951); Rose oxide 43, bringing the green, sharp, metallic facets of fresh roses (Stoll, 1961); damascones 44a-c important for the fruity, marmalade-like notes of roses (Demole, 1967); or slightly modified structures such as Hedione 45, a hydrogenated version of methyl jasmonate present in jasmine, with a luminous, transparent and blooming smell (Demole, 1960); ethyl maltol 46 with its characteristic scent of candy floss (Stephen, 1963); Muscenone 47, an intermediary molecule in the synthesis of muscone 23, but with a stronger soft-musky impression (Becker, 1967).

Cleansing and scenting of every aspect of domestic life, with increasing frequency, became the norm, further strengthening the professional subdivisions of the consumer goods market with specifically devoted household and personal hygiene/grooming product segments, each sub-specialized in laundry, dishwashing and house cleaning for the former, and soap, shampoo, grooming and deodorants for the latter. Cable television became a mass-media promoting consumer product brands to viewers, strongly influencing their purchasing choices and driving demand for olfactory differentiation.

Currently, a major share of fragrances manufactured globally serves the laundry market. The use of scent in laundry products first emerged in the early 1950s and has since experienced rapid growth, coinciding with the mass production of laundry products and the widespread adoption of washing machines. Synthetic surfactants like alkyl sulfates emerged in the 1930s, proving superior to fat-based soaps at cleaning in hard water. They were instrumental in the growth of the laundry product industry.

In the history of Tide, Rafael Trujillo describes the evolution journey of the scent of Tide which became the quintessential smell of clean for American consumers. A relatively simple smell based on a rose note (used merely to cover the off odors of the first synthetic detergents) developed over time into the very sophisticated scent we know today.[42]

In the late 1960s musk ingredients were already used cumulatively above 20%w/w in fragrances across both detergents and fabric conditioners. Galaxolide 39 alone is reported to be used above 20%w/w in some laundry products.[43] Musk ingredients were responsible for the post-wash scent’s tenacity on clothes, playing in this sense a technology role that would be taken over by fragrance encapsulation systems in the 2000s.

The first citrus-scented liquid dish soaps were introduced, to the best of our knowledge, in the late 1960s.[44] Citrus smell is arguably the main olfactory direction for the dishwashing category, that would grow to encompass automatic dishwasher tablets. Pine was the dominant smell for all-purpose cleaners from their introduction in the late 1920s and we had to wait until the 1970s to start seeing the first examples of diversification into other olfactory realms.[45] Pine was associated with the smell of a clean house so strongly that it seems only in the 1980s that there was a clear shift into other olfactory directions.[46] The perpetually sought after freshness was given a new expansion thanks to dihydromyrcenol 28, first prepared in 1956, but whose use was boosted by a 1966 patent,[47] unlocking the production of olfactory pure material allowing for use in large proportions in both fine and functional perfumery.

Revolutions are not always primarily directed towards the consumer. Several analytical techniques for the characterization of fragrance molecules were developed and introduced, starting from the 1950s, in both academia and fragrance houses, see Figure 6. The emergence of nuclear magnetic resonance (NMR) as an analytical technique occurred in the late 1950s. While existing analytical techniques such as IR and UV spectroscopy provide information about the nature of functional groups of organic molecules, 1H-NMR spectra from first commercial NMR spectrometers (30-60 MHz) supported the elucidation of the structure and the stereochemistry of individual hydrogen and carbon atoms. George Büchi, a former student of Ruzicka, was among the pioneers in using this technique for elucidating the structure of natural products, particularly sesquiterpenes like patchoulol[15]. The advancement of NMR in the subsequent decades would be significantly driven by the aspiration of chemists to solve the intricate structures of complex natural products. First chromatography systems were available in the early 1970s and the decade saw the exponential increase of molecule identification libraries.[48] This dramatically expanded the knowledge about odorants in natural sources, allowing for the identification of low concentration, that is high impact, molecules. In this regard the 1970 discovery of damascenone in Damas rose oil perfectly epitomizes this progress with the crucial
contribution of Ervin sz. Kováts.[50]

These tools gave a new dimension to quality control, with precise quantification performed on all goods, from raw material to finished products, aligning safety standards to the emerging regulations for humans, animals and the environment. The Research Institute for Fragrance Materials (RIFM) started its work on safety assessment of fragrances in 1966, operative regulation being then implemented by The International Fragrance Association (IFRA) from 1973 on. Thirdly, chromatographic methods opened the possibility of ‘deformulation’ with the deciphering of any perfume composition, allowing for a tight technological watch of competitors and thus largely uncovering the secrecy historically associated with fragrance compounding.

5. Focus on odor potency (1980-2000)

Two oil crises (1973 & 1979) steeply impeded research programs; with an impressive flattening in the number of patents in the field, resulting in the absence of any new blockbuster in the 1980s, rather distinctive ingredients enriched the palette by varying known structures, see Figure 7. Installed hygiene habits were comforted and efficacy parameters of scented products like diffusion and tenacity were aligned with the societal trends of these decades valorizing performance and self-confidence. Nonetheless, important new olfactory trends were pushed in the musk direction with Helvetolide 48a (Giersch, 1990) the first member of the novel alicyclic family of musks 48a-f, or the ambery/dry woods 49 setting a trend to become massively important, with Ambrocenide 49f (Pickenhagen, 1997). Thus, beyond extensions of known olfactory territories like synthetic ambers 49, sandalwoods 50 or muguets 51, the main additions to the palette were fruity and green notes such as: Undecavertol 52, with a fatty-green smell (Kaiser, 1981); Methyl pamplemousse 53, having pink grapefruit notes (Gebauer, 1983); Cassifix 54, with a sparkling, green note of cassis (Narula, 1990).[51]

More generally, the period saw the systematization of the ‘captive’ commercial practice. A newly patented ingredient was solely proposed to perfumers within the company, without sales to competitors, in order to benefit from a distinctive olfactory advantage to answer specific needs of clients, at least for a period of time. Although punctually done in the past, with Ionone De Laire 4a used by Roger & Gallet for Vera Violetta, or pure Hedione 45 for Eau Sauvage by Christian Dior, this concept was henceforth almost universally applied to novel introductions. Scented care rituals were by then well implanted within the population, pretty equally all over the planet with the massive globalization of occidental habits and trademarks. New commercial circuits deeply influenced consumption habits, ‘selective perfumery’ distribution networks with items presented in the same manner as goods on supermarket shelves revolutionized our relationship to fine fragrance. Purchase decisions in this context are based on first impressions, emphasizing the pleasantness of the top notes, which hence must be shaped in a catchy way. The global societal atmosphere of the 1980s put a strong emphasis on the ideas of performance, self-confidence and self-promotion, so the overall appreciation of a fragrance then mostly relied on the strength of diffusion, the tenacity and the distinctive character of the sillage.

This influenced perfumers in favoring high impact odorants and led them to structure their compositions on solid foundations, as offered by modern musks like Galaxolide 39, working the woody aspects around Iso E Super 31 and the floral theme around methyl ionones 4b, while Hedione 45 and Lilial 34 were perfect to bring diffusion and bloom, finally powerful and distinctive captives gave memorable character. This modern formulation style is epitomized by the work of Sophie Grojsman with Trésor for Lancôme built around a Hedione/methyl ionone/Iso E Super/Galaxolide heart (the so called ‘hug me’ accord with 20% each) and then touches of floral and fruity notes to give the unique appeal. Hedione,[52] methyl ionones, Iso e super[53] and Musk T are nearly perfect ingredients, as they are powerful, stable, usable in many scent theme, and if we add their relative low cost when patents reached the public domain, ideal building blocks for ubiquitous utilization across household and personal hygiene/grooming products.

At the turn of the 80-90’s decades, an anxious atmosphere developed with the confluence of the Gulf war, AIDS pandemic and first awareness of environmental problems, shifting olfactory preferences to scents evoking cleanness, purification and comfort. Hence, marine, ozonic notes such as Calone 1951 41 found widespread uses. One of the most prominent example is Сalvin Klein Escape (1991) which contains 0.8%w/w of Calone 1951.[56] Sea-breeze like smells started successively a major trend in air fresheners and surface cleaners in the 1990s.

Chemists invented and established at scale new synthetic tools for preparing fragrance molecules efficiently, with special attention paid to be nature identical as for chirality.[57] The most important example is the asymmetric synthesis of L-(-)-menthol 55, at industrial scale, developed in the 1980s.[58] Noyori would receive the Nobel prize in chemistry in 2001 for his contribution to metal-catalyzed asymmetric synthesis. Menthol can be prepared in two mirror forms D and L (stereoisomers), the latter is however the most potent for inducing a cooling effect in humans as L-menthol interacts with the trigeminal system.[59]

Several other molecules would be prepared in the coming decades,[60] through the use of this technology (citronellal 56, isopulegol 57) or others, like Paradisone 58, a highly enantioenriched version of Hedione 45 developed using an asymmetric hydrogenation transformation patented in 1997.[61] Cyclopropanation is a chemical transformation that has entered the toolbox of fragrance chemists in the late 1990s. A prominent example is Javanol 50d, derived from optically active alphapinene. Interestingly, the Javanol isomer with a cis configuration between the cyclopropane at the cyclopentane ring and the side chain is reported to be tenfold weaker from an olfactory standpoint. [62]

As gas-chromatography was a well established technique for the analysis of fragrance ingredients, analytical chemists refined it, with the introduction of headspace analysis, to capture the scented air surrounding living plants.[63] Dr. Roman Kaiser was a prominent figure in developing headspace techniques, elucidating numerous compositions of floral scents, thus helping in the reproduction of fresh impressions of them.

6. Fragrance Delivery Systems & Back to Nature (2000-2020)

For more than a century, chemistry enabled ingredient manufacturers to synthesize natural and artificial molecules, producing them at scale through efficient and selective chemical processes, a seemingly permanent move away from nature. This was reversed in the 2000s with strong environmental concerns from consumers, together with geopolitical instabilities leading to limitations of supply of essential oils employed as reactants. Solutions came from biology, biochemistry and biotechnology, providing the processing tools to prepare fragrance ingredients, and Nature, once again, being the inspiration source. Fragrance ingredients produced biotechnologically[64] today are: Patchouli-scented Clearwood 59 (arguably the first ingredient launched in the industry, 2014);[65] biosynthetic santalol, Dreamwood 60 (launched in 2020); woody-ambery with Ambrox Super 61 (launched 2016) and Amberketal 62 or Z11 (a nonnatural ingredient biosynthetically made, launched in 2018); nootkatone 63, present in grapefruit or vetiver and important to shape nice citrus notes, can be made by biochemical oxidation of valencene 64, itself made by fermentation of glucose with bacteria.[66] Ongoing research programs were successful in biosynthesizing more and more diverse molecules, (R)-muscone 23 (musk note in musk grain), cis-hexenol 65 (green note of cut grass), furaneol 66 (caramelic), Frambinone 67 (raspberry), are now waiting for commercial production, see Figure 8.[67]

Akigalawood 68 (an ingredient rich in nature-identical rotundone), is not produced via biosynthesis per se, but relies on enzymatic oxidation of upcycled terpenic fractions of natural patchouli oil, thus considered a hemi-biosynthesis of rotundone (patented in 2012).

Since 2000 we have witnessed an explosion of new fragrance ingredients launched across all olfactory camps. Whilst this last generation of fragrance ingredients does not seem to offer the broad application of more established ingredients such as Iso E Super, Hedione, they do provide the desired differentiation to enable perfumers to create more sophisticated fragrances.

New product developments in the 2000s, such as scent boosters and laundry pods, gave new possibilities to perfumers to expand the olfactory territories in laundry products, as the scent could be compartmentalized and thus insulated from aggressive ingredients and oxygen through formulation and packaging solutions.

Since the 1970s, it has been recognized that fragrance ingredients alone cannot deliver a long-lasting scent for wash-off applications such as laundry products on dry clothes. Patent applications in the late 1970s and early 1980s described the first fragrance delivery systems using wax, gelatin, gum acacia, and urea-formaldehyde resins to trap the fragrance oil.[68] However, to the best of our knowledge, the commercial use of these technologies in major consumer brands took place only in the 2000s.[69] Up to 2020, synthetic polymers such as melamine-formaldehyde or poly(methyl methacrylate) have been among the most used materials for fragrance encapsulation.[70] Fragrance-containing encapsulates in consumer products typically have a diameter ranging from 10μm to 50μm and a wall thickness below 1μm, see Figure 9.[71]

Figure 9. Schematic representation of trigger-activated release of fragrances
Figure 9. Schematic representation of trigger-activated release of fragrances
through a) microencapsualtion, b) profragrances, R (organic scaffolds such as
carboxylate,glucosidecarbonate, imines, unsaturated alcohols).

The upcoming ban on microplastics in Europe has prompted the industry to develop more sustainable alternatives to current encapsulation systems. Numerous companies, several without a core focus on fragrance, have entered the market in recent years, as evidenced by several patent filings and marketing activities. Today, fragrance encapsulation systems are mainly used for laundry products. The most prominent example is in fabric conditioners which contain typically both a scent in the form of oil dispersed in the product formulation, to deliver the “out-of-the-bottle” initial smell, and an encapsulated fragrance oil to ensure the scent is delivered to the dry laundry upon use.

Pro-fragrances are delivery technologies which release selectively only one fragrance material upon activation of a chemical or physical trigger such as pH change, temperature, light exposure, physical friction or a combination thereof. The commercialization of this technology predates the more established encapsulation technology as it was introduced in the industry in the mid 1990s.[72] The first established example is digeranyl succinate incorporated in fabric conditioners, which releases geraniol upon reaction with lipases originating from detergents and still present in the wash liquor during the rinsing cycle. These technologies are typically miscible with a fragrance oil, which can simplify the manufacturing and supply chain process, and can be good replacements to microcapsules where the latter is not compatible with the product formulation.[73]

7. Conclusion and Outlook

Over the past 150 years, the fragrance industry has experienced a continuous interplay of scientific discoveries and innovation which enabled the creation of a multi-billion industry. This has encompassed advances in new molecule discovery, characterization techniques, manufacturing processes, and fragrance controlled release technologies.[55]

This progress has been fueled by the development and diversification of consumer goods, accompanied by the utilization of novel formulation and packaging materials, presenting scientists in the fragrance industry with an ever-expanding arena of challenges and opportunities.

Historically, research and innovation in the realm of scent and consumer goods have relied, to some extent, on empirical approaches. Some of the greatest inventions in the field are owed to sheer serendipity. We believe serendipity will keep playing an important role in the future, as perfumery embodies both artistry and science. We are currently witnessing a growing integration of artificial intelligence (AI) into very diverse aspects of scent innovation, such as new molecule discovery, raw material procurement, and consumer understanding.

Looking ahead, we anticipate that societal demands for a better sustainable footprint of consumer products, the integration of digital technologies into our homes, lives, and product usage, and the rise of e-commerce will provide fresh impetus for innovation in the scent industry. These factors will drive the utilization of materials with an enhanced sustainability/circularity profile and the creation of novel products and services for household and personal hygiene/grooming segments, with scent playing a central role in enhancing consumer experiences.

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Terpene Derived Auxiliaries: Miscellaneous Terpene Derived Auxiliaries – Part 1

Authors: HE Ensley, MJ Reale

3.5.1 Miscellaneous Terpene Derived Chiral Auxiliaries Carene Derivatives

The enantiomers of (þ)-2-carene, 1, and (þ)-3-carene, 2, are not available; however in many reactions, reagents prepared from the two dextrorotatory isomers have opposite (but not equal) enantioselectivities (Figure 1).

Figure 1. (þ)-2-carene and (þ)-3-carene
Figure 1. (þ)-2-carene and (þ)-3-carene. Stoichiometric carene chiral auxiliaries

Brown has reported that both (þ)-2-carene and (þ)-3-carene can be purified to 499% enantiomeric excess (ee). Pure (þ)-2-carene is prepared by hydroboration of less pure (þ)-2-carene to give di-2-isocaranylborane which can be recrystallized from tetrahydrofuran (THF). The di-2-isocaranylborane prepared from (þ)-2-carene (2-dIcr2BH) is converted to a trialkylborane on reaction with a disposable 1-alkene (1-pentene or 1-hexene) and then treated with 2.5 equivalents of benzaldehyde at 60 1C to liberate pure (þ)-2-carene. Purified (þ)-3-carene can be prepared by recrystallization from pentane at  100 1C or by treatment of less pure 3-carene with 10 mol% 9-borabicyclononane (9-BBN) which consumes the more reactive unsaturated impurities usually found in 3-carene.1 Asymmetric hydroboration

Di-2-isocaranylborane (2-dIcr2BH, 3) can be prepared easily by the reaction of borane–dimethylsulfide complex with 2-carene. Similarly, di-4-isocaranylborane (4-dIcr2BH, 4) can be prepared by the reaction of borane–dimethylsulfide complex with 3-carene.1 Brown studied the hydroboration of alkenes with 3 and 4 and found that the two dialkylboranes have opposite enantioselectivites with di-(2-isocaranyl)borane having much higher enantioselectivity (Scheme 1). Both isomers showed highest enantioselectivity in the hydroboration of cis-disubstituted alkenes. The hydroboration of other alkenes showed little to moderate enantioselectivity. The (þ)-2-carene or (þ)-3-carene could be recovered from the hydroboration product by treatment with acetaldehyde or benzaldehyde.1

Scheme 1. Hydroboration of alkenes with 3 and 4. Asymmetric allylation of aldehydes

Methanolysis of the dialkylboranes 3 and 4, followed by treatment with allyl Grignard gives the trialkylboranes 2-dIcr2Ball, 6 and 4-dIcr2Ball, 8, respectively (Scheme 2).2 These reagents are usually very enantioselective in reactions with aldehydes to afford chiral butenols (Table 1). As was the case in hydroborations with 3 and 4, 6 and 8 show opposite enantioselectivity; however, in this case, the difference in enantioselectivity is usually small (see Chapter 6.8).

Scheme 2. Preparation of the trialkylboranes 2-dIcr2Ball 6 and 4-dIcr2Ball 8
Scheme 2. Preparation of the trialkylboranes 2-dIcr2Ball 6 and 4-dIcr2Ball 8.
Table 1 Comparison of asymmetric allylborations with B-allylbis(isocaranyl)boranes 6 and 8 at -78℃
AldehydeProduct alcoholReagent (% ee)
2-dIcr2Ball, 64-dIcr2Ball, 8
Acetaldehyde4-Penten-2-olS (98)R (94)
Propionaldehyde5-Hexen-3-olS (94)R (91)
n-Butyraldehyde1-Hepten-4-olS (94)R (89)
2-Methylpropionaldehyde2-Methyl-5-hexen-3-olR (94)S (95)
2,2-Dimethylpropionaldehyde2,2-Dimethyl-5-hexen-3-olR (99)S (88)
Acrolein1,5-Hexadien-3-olR (95)S (93)
Benzaldehyde1-Phenyl-3-buten-1-olR (95)S (87)
Source: Reproduced with permission from Table 1 in Brown, H. C.; Randad, R. S.; Bhat, K. S.; Zaidlewicz, M.; Racheria, U. S. J. Am. Chem. Soc. 1990, 112(6), 2389–2392. © 1990 American Chemical Society.

Sammakia used the allylboration with compound 8 as a key step in the synthesis of the oxopolyene macrolide RK-397, an antifungal, antibacterial, and antitumor agent which was isolated from a soil bacteria (Streptomyces sp. 87–397). The achiral dialdehyde 9 prepared by diisobutylaluminum hydride (DIBAL-H) reduction of dimethylglutarate, was treated with B-allylbis(4-isocaranyl)borane, 8, to give diol, 10, as a 10:1 mixture of diastereomers (98% ee for the major isomer) in 53% overall yield from dimethylglutarate (Scheme 3).3

Scheme 3. Allylboration of achiral aldehyde 9 by treatment with B-allylbis(4-isocaranyl)borane 8 in the synthesis of the oxopolyene macrolide RK-397.

Brown extended the utility of the asymmetric allylation by preparation of the E- and Z-crotylbis(isocaranyl)boranes. Cis-2-butene was metalated by treatment with n-butyllithium (BuLi) and potassium t-butoxide in THF at -45℃ and then treated with B-methoxybis(2-isocaranyl)borane, 5, at -78℃ (Scheme 4). The resulting ate complex was then treated with BF3·OEt2 to give B-(Z)-crotylbis-(2-isocaranyl)borane, 11. The same procedure using trans-2-butene affords the E-isomer. Both the E- and Z-isomers of 11 are easy to prepare and give high enantioselectivity and diastereoselectivity in reactions with aldehydes (Table 2).4

Scheme 4. Preparation of B-(Z)-crotylbis-(2-isocaranyl)borane 11.

Brown later observed that the presence of magnesium salts, from the preparation of the allylating reagents 6 and 8, were detrimental to the rate of allyl transfer and to the enantioselectivity of the reaction. When a magnesium-free solution of B-allylbis(2-isocaranyl)borane was added to an aldehyde, the reaction was ssentially instantaneous at  100 1C. Also the enantioselectivities were 99 þ % with the B-allylbis(2-isocaranyl)borane, 6, and 96–99% with B-allylbis(4-isocaranyl)borane, 8. The two isomers still displayed opposite enantioselectivities.5

Table 2. Products from the crotylation of acetaldehyde and propionaldehyde with B-[Z]-crotylbis(2-isocaranyl)borane (11), B-[E]-crotylbis(2-isocaranyl)borane (12), B-[Z]-crotylbis(4-isocaranyl)borane (13), and B-[E]-crotylbis(4-isocaranyl)borane (14).

One problem which plagued the early use of B-allylbis(2-isocaranyl)borane and B-allylbis(4-isocaranyl)borane was the fact that the chiral reagent was destroyed during the oxidative workup of the hydroboration reaction. The production of two equivalents of 2-isocaranol or 4-isocaranol could make the isolation of the desired chiral alcohol product difficult. Brown et al. developed several procedures to overcome this problem.6 One procedure involves the treatment of the initially formed Icr2BOhomoallylic borinate ester with isobutyraldehyde and 1 mol% BF3  OEt2 at 65℃ to give 2-carene or 3-carene in 80–90% yield, along with the chiral homoallylic alcohol. The homoallylic alcohols can be isolated from this mixture by distillation. Alternatively, the initially formed Icr2BO homoallylic borinate ester can be treated with 8-hydroxyquinoline which liberates the homoallylic alcohol and forms the insoluble 8-hydroxyquinoline bis(isocaranyl)borane (8-HQ-BdIcr2) adduct. The 8-HQ-BdIpc2 adduct can be converted into the corresponding B-methoxybis(isocaranyl)borane esters (5 or 7, Scheme 2) by treatment with acidic methanol at 0℃ for 30 min in quantitative yield. The 8·HQ·HCl salt can be separated by filtration to give 5 and 7 for recycle.6 Enantioselective imine-anion alkylation

Shioiri developed a procedure for the preparation of chiral benzylamines by alkylation of the dianion formed by treatment of the Schiff base 15 with three equivalents of BuLi. (-)-3-Hydroxy-2-caranone, prepared from (+)-2-carene, was converted to the Schiff base by treatment with arylmethylamines. Lithiation followed by benzylation (at -78℃) and subsequent hydrolysis gave the chiral amines in moderate yields and 60–87% ee (Scheme 5).7 The procedure gave better results (90–98% ee) when (+)-2-hydroxy-3-pinanone (prepared from (-)-α-pinene) was used rather than (-)-3-hydroxy-2-caranone (see Chapters 3.3 and 6.1).

Scheme 5. Preparation of chiral benzylamines from the Schiff base 15
Scheme 5. Preparation of chiral benzylamines from the Schiff base 15. Chiral boron enolates

Fringuelli studied the reaction of boron enolates 16 of acetic acid, mono-, and disubstituted acetic acid with benzaldehyde (Scheme 6). The dilithiated acids (R1=H, Me, Et, Ph, OPh, or SMe and R2=H, Me, Et) were treated with (-)-di-2-isocaranylchloroborane or (-)-di-4-isocaranylchloroborane to give the corresponding boron enolates, 16a and 16b (16a, L=2-isocaranyl and 16b, L=4-isocaranyl), respectively (Scheme 7).8 Interestingly, the di-2-isocaranylboron enolates of acetic acid (16a, R1 = R2 = H) add to the re-face of benzaldehyde (72% ee) and the corresponding di-4-isocaranylboron enolate (16b, R1 = R2 = H) add to the si-face (42% ee) but when disubstituted acetates are used (R1 = R2 = Me or Et) both 16a and 16b add to the si-face with high enantioselectivity (94–99% ee). When benzaldehyde reacts with monosubstituted acetic acid boron enolates, the situation is more complicated but, in general, the di-2-isocaranylboron enolates give predominantly the syn-adduct with 80–95% ee and the di-4-isocaranyl analogs give predominantly the anti-adduct with lower selectivity (20–80% ee) and the chirality of the adducts are reversed.8

Scheme 6. Preparation and reactions of boron enolates 16 of acetic acid, mono-, and disubstituted acetic acid with benzaldehyde.
Scheme 7, Facial selectivities of the reaction of boron enolates 16a and 16b with benzaldehyde. Catalytic carene chiral auxiliaries Chiral aminoalcohols

Morpholine reacts with the epoxide of (+)-3-carene to give the aminoalcohol 17 (Scheme 8). DuPont workers found 17 to be a useful ligand for directing the addition of lithium cyclopropylacetylide to the ketimine 18 to give the dihydroquinazolinone 19, a second-generation nonnucleoside, reverse transcriptase inhibitor (equation 1)9 (see Chapters 3.16 and 3.20).

Scheme 8 Synthesis of aminoalcohol 17.

Although, in theory, aminoalcohol 17 could be used catalytically in the reaction, the optimum conditions required three equivalents of 17 (as well as three equivalent cyclopropylacetylene and six equivalent lithium bis(trimethylsilyl)amide (LiHMDS)) for each equivalent of 18. Under these conditions, the crude dihydroquinazolinone 19 was obtained with 94% ee. A single recrystallization gave 19 in 85% yield and 99.6% ee.9

Malhotra used the aminoalcohol 17 for the chiral addition of diethylzinc to a variety of aldehydes (Table 3) (see Chapter 3.24).

Table 3 Enantioselective addition of diethylzinc to aldehydes catalyzed by β-aminoalcohol 17
EntryAldehydeYield (%)ee (%)Configuration
Source: Reproduced from Table 2 in Joshi, S. N.; Malhotra, S. V. Tetrahedron: Asymmetry 2003, 14(13), 1763–1766.

The aminoalcohol 17 was used at 15 mol% (in toluene at 20℃) and gave good yields with moderate to excellent selectivity (72–98% ee) for the R-alcohol. The enantioselectivity was explained by the transition state shown in Figure 2 which involves re-face attack on the aldehyde.10

Figure 2. Transition state of the chiral addition of diethylzinc to various aldehydes using aminoalcohol 17. Chiral bipyridyl ligands

Malkov et al. prepared a number of chiral bipyridine ligands from (+)-2-carene and (+)-3-carene. Ligand 20 was prepared from (+)-3-carene by Negishi coupling of the pyridyl triflate (Scheme 9).11 Since the enantiomer of (+)-3-carene is not available, ent-20 cannot be prepared the same way; however, Malkov prepared the quasienantiomer of 20, compound 21, from (+)-2-carene. A third ligand, 22, was prepared from (+)-3-carene which not only had a similar chirality to 21 but also had a wider chiral cavity.

The copper(I) complexes of the three ligands were prepared and the catalytic activity was evaluated in allylic oxidation of 5-, 6-, and 7-membered cycloalkenes. The bipyridine copper(I) complexes of 20 and 21 have a narrow chiral cavity whereas the chiral cavity of 22 is wider. This difference in cavity shape was used to explain the lower enantioselectivity of the 22 copper complex. The copper(I) complex of 21 gave the higher enantioselectivity and, as expected, 20 and 21 gave opposite enantiomers (Table 4).11

The copper(I) complex of 21 also catalyzed the asymmetric cyclopropanation of styrene (see Chapter 6.11). In the presence of 1 mol% of catalyst, treatment with tert-butyl diazoacetate gave a 96% yield of a 86:14 mixture of trans- and cis-isomers (equation 2). The trans-isomer was produced in 59% ee (1S,2S).11

Scheme 9. Preparation of chiral bipyridine ligands 20, 21, and 22 from (+)-2-carene and (+)-3-carene.
Table 4. Asymmetric allylic oxidation of cyclopentene, cyclohexene, and cycloheptene catalyzed by Cu(I) complexes of chiral ligands 20, 21,
and 22 (1 mol%) using tert-butylperbenzoate in acetone
EntryLigandAlkeneTemperature (℃)Time (h)Yield (%)ee (%), (Configuration)
120Cyclohexene2025855, (S)
221Cyclopentene2019643, (R)
321Cyclohexene2059866, (R)
421Cyclohexene0487670, (R)
521Cyclohexene-20963377, (R)
621Cyclopentene20126072, (R)
721Cyclopentene0485775, (R)
821Cyclopentene-20963582, (R)
922Cyclohexene20245235, (R)
Source: Reproduced from Table 1 in Malkov, A. V.; Pernazza, D.; Bell, M.; et al. J. Org. Chem. 2003, 68(12), 4727–4742, with permission from American Chemical Society.

Chelucci prepared a bis-N,N`-dioxide similar to 20–22 but with an isopropylidene spacer group separating the pyridine rings (equation 3). The bis-N,N`-dioxide was used as a catalyst (10 mol% in acetonitrile) for the allylation of benzaldehyde using allyltrichlorosilane; however, the yield of (S)-1-phenyl-3-buten-1-ol was low (22%) and the enantioselectivity (35% ee) was lessthan the corresponding bis-N,N`-dioxide prepared from pinocarvone (58% yield and 83% ee).12


1. Brown, H. C.; Vara Prasad, J. V.; Zaidlewicz, M. J. Org. Chem. 1988, 53(13), 2911–2916.

2. Brown, H. C.; Randad, R. S.; Bhat, K. S.; Zaidlewicz, M.; Racheria, U. S. J. Am. Chem. Soc. 1990, 112(6), 2389–2392.

3. Mitton-Fry, M. J.; Cullen, A. J.; Sammakia, T. Angew. Chem. Int. Ed. 2007, 46(7), 1066–1070.

4. Brown, H. C.; Randad, R. S. Tetrahedron 1990, 46(13-14), 4457–4462.

5. Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56(1), 401–404.

6. Brown, H. C.; Racherla, U. S.; Liao, Y.; Khanna, V. V. J. Org. Chem. 1992, 57(24), 6608–6614.

7. Irako, N.; Hamada, Y.; Shioiri, T. Tetrahedron 1995, 51(46), 12731–12744.

8. Fringuelli, F.; Piermatti, O.; Pizzo, F. J. Org. Chem. 1995, 60(21), 7006–7009.

9. Kauffman, G. S.; Harris, G. D.; Dorow, R. L.; et al. Org. Lett. 2000, 2(20), 3119–3121.

10. Joshi, S. N.; Malhotra, S. V. Tetrahedron: Asymmetry 2003, 14(13), 1763–1766.

11. Malkov, A. V.; Pernazza, D.; Bell, M.; et al. J. Org. Chem. 2003, 68(12), 4727–4742.

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α-Terpineol, a natural monoterpene: A review of its biological properties


Terpineols are monocyclic monoterpene tertiary alcohols which are naturally present in plant species. There are five common isomers of terpineols, alpha-, beta-, gamma-, delta- and terpinen-4-ol, of which α-terpineol and its isomer terpinen-4-ol are the most common terpineols found in nature. α-Terpineol plays an important role in the industrial field. It has a pleasant odor similar to lilacs and it is a common ingredient in perfumes, cosmetics, and aromatic scents.

In addition, α-terpineol attracts a great interest as it has a wide range of biological applications as an antioxidant, anticancer, anticonvulsant, antiulcer, antihypertensive, anti-nociceptive compound. It is also used to enhance skin penetration, and also has insecticidal properties. This study reviews the relevance of α-terpineol based on scientific findings on Google Scholar, Pubmed, Web of Science, Scopus and Chemical Abstracts.

Collectively, the use of α-terpineol in medicine and in the pharmaceutical industry plays an important role in therapeutic applications. This review will, therefore, support future research in the utilization of α-terpineol.


p-menth-1-en-8-ol; monoterpene utilization; monoterpenoid alcohol; monocyclic monoterpenoids; terpenic alcohols.


Terpineols are naturally occurring unsaturated monocyclicmono-terpenoid alcohols and can be found in flowers such as narcissus and freesia, in herbs, such as marjoram,oregano, rosemary and in lemon peel oil. Reports on the level of terpenoids in oils occasionally vary considerably and one wonders how much this is due to the variation inthe plants and to the variations in the isolation process as terpineols could also be an artifact [1,2]. In addition, terpineols are interesting because of their wide range of biological properties [3].

There are five common isomers of terpineols; alpha- (α-T), beta- (β-T), gamma- (γ-T), delta- (δ-T) and terpinen-4-ol (T-4-gl) (Figure 1).

Terpineol Isomers
Figure 1. Terpineol isomers

α- and β-Terpineol occur in optically active forms and as a racemate. Both α-T and T-4-ol are the most important commercial products and they occur in a large number of essential oils. On the other hand, β-, γ- and δ-terpineols do not occur very often in nature [1]. Terpineols, especially the most commonly used compounds as α-T and T-4on, exerta wide range of different biological actions on humans, animals, and also plants. They are not only popular fragrance ingredients used in perfumes, cosmetics, and household cleaning products, but also used to flavor foods and beverages. They also possess various important biological and medicinal properties [1-3].

α-T, a volatile monoterpenoid alcohol, is the major component of essential oils of several species of aromatic plants such as Origanium vulgare L. and Ocimum canum Sims which are widely used for medicinal purposes. α-T can also be isolated from a variety of sources such as cajeput oil, pine oil and petitgrain oil [1]. It is a colorless, crystalline solid, smelling of lilac, and is an optically active monoterpenoid that occurs naturally in the (+)-, (-)- and (±) forms. The presence of natural racemic mixtures of α-T was discovered in geranium oils and in Morio-Muscat-wine aroma. α-T enantiomers which are found in the Myrtaceae family, in citrus and lavender oil, were separated by means of a two-columned coupled system and a mixture of two chiral phases, respectively [1,3]. Because of its pleasant odor similar to lilac, α-T is widely used in the manufacturing of cosmetics, soaps, perfumes, antiseptic agents and is considered one of the most frequently used fragrance compounds. Its acetate and other simple esters of α-T are also used in perfumes and aromatic scents. Therefore, the most important reaction for the fragrance industry is its esterification particularly the acetylation of terpinyl acetate [1,4]. In addition, α-T possesses a wide range of biological applications as it exhibits an antihypertensive and antiproliferative effect on human erythroleukemic cells [5,6], as well as ant-iinflammatory properties [7], as it was found to be a potent inhibitor of superoxide production [8]. And many studies have reported that α-T has an obvious anticancer effect [9].

Schematic representation of review section 2.
Figure 2. Schematic representation of review section 2.

This review explores some of the important α-T biological activities from specific papers (Figure 2). We accessed electronic sources from various scientific databases such as Google Scholar, Pubmed, Web of Science, Scopus and Chemical Abstracts and interpreted existing literature on these activities.

Biological properties of α-terpineol
Cardiovascular and antihypertensive effects

Systemic arterial hypertension and cardiovascular diseases increase the risk of mortality and morbidity worldwide [10,11]. Arterial hypertension is considered to be the major risk factor for both heart attack and stroke [12]. Because “It has been shown that blood pressure levels are strongly and directly related to the relative risks of stroke and heart disease. Endothelial dysfunction in hypertension triggers an imbalance between the production and release of these factors, increasing the generation of reactive oxygen species and diminishing (nitric oxide) NO synthesis and bioavailability. L-arginine is the precursor of NO synthesis by NO synthase (NOS), an enzyme that exists in three isoforms: neuronal (nNOS), inducible (iNOS) and endothelial (eNOS)” [5]. Furthermore, inhibition of NOS activity and then NO biosynthesis by means of L-arginine analogs administration such as L-nitro arginine methyl ester (L-NAME) leads to hypertension [13,14]. Accordingly, many reports were designed to investigate the cardiovascular and antihypertensive effects of α-T in rats with hypertension induced by L-NAME [5,15]. The NOS inhibitor L-NAME has been used extensively as a mean of inducing hypertension in animal models [5].

Sabino et al. examined the effect of α-T on hemodynamic parameters which was evaluated by the treatment of non-anesthetized rats once a day with different doses of α-T (25, 50 or 100 mg/kg/day) for one week. The results indicated that the induction of a marked hypotensive effect in rats occurred by oral administration of α-T. Hypotension may be exerted due to a decrease in peripheral vascular resistance. The beneficial effects of α-T on isolated mesenteric from L-NAME–induced hypertensive rats were demonstrated, and as a result, α-T in a concentration-dependent manner, relaxed the endothelium-intact mesenteric rings pre-contracted with phenylephrine and depolarization with KCl. Furthermore, α-T-induced relaxation was not considerably reduced by the mechanical removal of the endothelium in phenylephrine pre-contracted mesenteric rings. According to these results, it was proposed that the vasorelaxant activity of α-T is endothelium-dependent and that α-T blocks Ca+2 entry through voltage-dependent Ca+2 channels, which is involved in the mechanism by which relaxation can be produced. Further results indicated that α-T was able to inhibit contractions induced by the cumulative addition of phenylephrine without endothelium preparations suggesting that α-T could exert its activity on vascular smooth muscle contractile machinery [5].

Several mechanisms for an endothelium-independent vasodilation are in its relaxant activities of vascular smooth muscles. Among these mechanisms are (a) inhibition of agonist-mediated release of Ca+2 from intracellular stores, (b) blockage of extracellular Ca+2 influx by transmembrane Ca+2 channels, (c) inhibition of the contractile apparatus and (d) opening of K+ channels. The influx of extracellular Ca+2 occurs by means of two kinds of transmembrane Ca+2 channels: receptor-operated Ca+2 channels (ROCC) and voltage-operated Ca+2 channels (VOCC) [16]. α-T attenuated significantly the concentration induced by CaCl2 which indicates that α-T can inhibit vasoconstriction induced by extracellular Ca+2 influx through VOCC [5]. It is also known that the Cav1.2 (voltage-gated calcium channel α1 subunit), which is considered as a CavL (L-type calcium channel) subtype present in various smooth muscle cells (VSMCs), is the main voltage-operated calcium channel found in VSMCs. The Cav1.2 is a subtype of the L-type calcium channel, which is found in different cell types such as myocytes, smooth muscle myocytes and they are responsible for the excitation-contraction coupling, hormone release, and regulation of transcription as well as synaptic integration [17]. In summary, the reduction of calcium influx occurring through the voltage-sensitive CavL channels may result in a decrease in vascular resistance which is attributed to α-T leading to hypotension induction. [5].

In conclusion, α-T-induced hypertension and vasorelaxation are mainly mediated by releasing NO and activating the NO-cGMP (cyclic guanosine 3’, 5’-monophosphate) pathway. In addition, oral administration of α-T was able to reduce mean arterial pressure, and in mesenteric artery rings it induced a vascular endothelium-independent vasodilatation, showing alternations in biochemical parameters which indicate an antioxidant effect as well. These data indicate that the ability of α-T to decrease the arterial pressure is mainly depending on restoring the enzymatic antioxidants in L-NAME-induced hypertensive rats and reducing the vascular resistance [5,15].

Antioxidant activity

Antioxidants, such as vitamins, enzymes or Fe+2, etc. are able to neutralize free radicals. They exert a health-enhancing effect on the human organism because they protect cells from oxidative damage” [18]. Oxidative stress has an important influence on the development and progression of many diseases, such as cardiovascular diseases, inflammation, neurodegenerative diseases and aging processes. In addition, oxidative stress is mainly characterized by the presence of high bioavailability of reactive oxygen species (ROS) [19]. α-T shows an antioxidant activity, as it was previously mentioned that it is able to suppress the superoxide production by agonist-stimulated monocytes but not neutrophils [8]. “The antioxidant action of α-T reflects its capacity to act as a preservative in food, cosmetics, and pharmaceutical products, preventing oxidative degeneration of their components” [20].

Arterial hypertension can be developed from oxidative stress and is believed to result from systemic damage in different target tissues by oxygen free radicals. Non-enzymatic antioxidants (e.g. reduced glutathione) and antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase) are the factors which are used to help the performance of intracellular defense against active oxygen species [21]. Reduction of catalase and glutathione peroxidase in L-NAME-treated rats were observed when compared with L-NAME control groups. Based on these data, α-T proved to possess a potent antioxidant activity against free radicals causing injury [5].

α-T exerts an anti-proliferative effect, therefore, it can be used in the prevention or even treatment of cancer. The anti-proliferative capacity of α-T can be measured using two methods: 2,2-Diphenyl-1-picrylhydrazyl (DPPH), which is a simple and accurate indirect method determining scavenging potential of free radical, and Oxygen Radical Absorbance Capacity (ORAC). This is used as a direct method to determine the ability of lipophilic and hydrophilic substances, via hydrogen atoms transfer, to resist the oxidation reactions with peroxyl radicals. Results revealed that α-T showed very low antioxidant activity in DPPH assays, but it could be compared to commercial antioxidants in the ORAC assay. It was shown that α-T demonstrated a potential antioxidant capacity against peroxyl radicals. Moreover, α-T also exerted cytostatic activities which were found to be very effective against six human cancer cell lines, such as prostate, breast, lung, leukemia and ovarian, especially against breast adenocarcinoma (MCF-7) and chronic myeloid leukemia (K-562). In a range of 181-588 μM the impressive results also revealed that α-T with an antioxidant potential similar to BHA (butylated hydroxyanisole), which is considered to have a potential protective activity in foodstuffs, acts as a natural preservative [20]. Thus, α-T attracts the interest for further research that can culminate in its use as a functional additive, as well as in its role in cancer-prevention in vivo. Hereafter, in vivo assays must be performed to confirm the antioxidant potential of α-T.

Anticancer activity

Cancer is characterized by uncontrolled growth of cells disregarding the normal limits, by invasion and, in the worst case, by metastasis, the expansion of the disease to another non-nearby organ by lymph or blood” [13]. α-T is a bioactive component of Salvia libanotica essential oil extract and has shown antitumor activity [9]. S. libanotica (Lamiaceae) is a species endemic to the Eastern Mediterranean which induces cell cycle arrest and apoptosis in human colorectal cancer cells, depending on the synergistic action of its three bioactive components: α-T, camphor and linalyl acetate, via caspase activation, mitochondrial damage (cytochrome C release), and PARP cleavage [22].

The link between the development of cancers and chronic inflammation is found to be related to the activation of the transcription factor NF-κB. Since several types of human tumors express mainly NF-κB, blocking this factor was proposed to increase its sensitivity to the action of anti-tumor agents or stopping the proliferation caused by tumor cells [23]. Hassan et al. proved that α-T acts as a potential anticancer agent by suppressing NF-κB signaling. The cytotoxicity of α-T towards 14 different human tumor cell lines representing different hematological and non-hematological malignancies was evaluated in vitro where α-T exerted a considerable cytotoxic effect on the cell line of the small cell lung carcinoma, representing a tumor-specific activity. Interestingly, the effective cytotoxic activity of α-T shows a promising effect for treatment of patients with drug-resistant tumors due to the limited effects of resistance represented by α-T [9]. The risk of toxicity against normal lymphocytes is reduced due to tumor selectivity of α-T, helping as an important feature in many of the cytotoxic drugs which are clinically used [24]. “Treatment with α-T induces cell cycle arrest and apoptosis in the cell line tested in a dose- and time-dependent manner. The results suggest that cell cycle phase arrest by α-T may depend on drug concentration at the shorter exposure time. This finding is consistent with α-T which showed that it is active in including cell cycle changes if combined with linalyl acetate rather than if used alone in colorectal tumor cells” [9].

Hassan et al. also demonstrated that the inhibition of the NF-κB translocation and activity in tumor cells was exerted by the anticancer activity of α-T in a dose-dependent manner, as indicated by means of the two NF-κB assays. Moreover, the response of NF-κB expression to α-T treatment and other related genes as IL-1R1, IL-1β, ITK, AKT1S1, EGFR, IFNG, BAG1, and TNIK was indicated via microassay analysis showing significant down-regulation. Furthermore, the probable influence of α-T on kinases was examined by using the cell-free assay representing a modest inhibitory effect on AKT, JNK1, JNK2 and IKK beta kinases. The supposed correlation of α-T with AKT kinase and NF-κB inhibitors is attributed to this moderate inhibition of AKT and IKK beta kinases. In addition, the release of cytochrome C due to the disruption of the mitochondrial membrane potential cannot be ignored as an extra cytotoxic mechanism for α-T which helps in the induction of apoptosis in colon cancer cell lines, when linalyl acetate and camphor are combined with α-T [9,22]. On the other hand, the antifungal activity exerted by α-T is also represented by the uncommon structure of mitochondria of the fungi and its cell membrane disruption [25].

Based on the results of many experiments, α-T appears to inhibit the growth and induces cell death in tumor cells by a mechanism that involves inhibition of NF-κB activity and translocation in a dose-dependent manner by means of two NF-κB assays, and is also able to downregulate many NF-κB related genes expressions such as IL-1β and IL1R1. [9]. It was also indicated that linalyl acetate and α-T exhibit synergistic anti-proliferative effects. The potential combination of treatment showed significant suppression of a basal and tumor necrosis factor (TNF)-α-induced NF-κB activation using DNA binding assays. Moreover, IκB-α degradation and inhibition of p65 nuclear translocation are found to be in correspondence with this suppression. As a result, it is shown that the anticancer activity of α-T is partly mediated by the suppression of NF-κB activation, suggesting its use in a combination with linalyl acetate with chemotherapeutic agents to induce apoptosis [26].

Anti-nociceptive activity

Another important activity which is correlated to α-T is the anti-nociceptive activity. A nociceptor is a sensory receptor that responds to potentially damaging stimuli by sending nerve signals to the spinal cord and brain. The anti-nociceptive effect is a reduction in pain sensitivity made within neurons when endorphins or a similar opium-containing substance combines with a receptor” [18]. One of the most important symptoms of an inflammatory disease is a pain. Sanitation of primary afferent nociceptors can result in allodynia and/or hyperalgesia, known as hypernociception in animal models [27]. The main function of pain is to avoid the damage of tissue stimuli via activating the spinal reflex withdrawal mechanisms. Thus, it helps in protecting the tissues of the organism from damaging. In acute pain conditions, pain exists for a while even after healing the injury. Alternatively, chronic pain conditions can be explained by the presence of typical inflammation and neuropathy [28]. Moreover, available anti-nociceptive drugs show low efficacy to relieve painful conditions in patients and possess numerous side effects [29]. Therefore, natural products showing fewer side effects, exert promising therapeutic activities in developing new drugs which can manage certain chronic pain conditions [30].

Golshani et al. reported that the essential oil of Dracocephalum Kotschyi Boiss (Lamiaceae), containing α-T as an active component, possesses anti-nociceptive properties [31]. Therefore, many experiments based on these results took place to investigate the anti-nociceptive effect of α-T. The results of another study revealed that α-T possesses both peripheral and central analgesic properties. α-T produced significant (p<0.01 or p<0.001) analgesic effects by reduction at the early and late phases of paw licking and reduced the acetic acid-induced writhing reflex in mice. Those effects are probably in relation to the inhibition in the peritoneal fluid levels of PGE2 and PGF with the release inhibition of substance P and other inflammatory molecules, such as serotonin, histamine, bradykinin, and prostaglandins [32].

It has been investigated that glutamate plays an important role in transmitting the nociceptive signals from the peripheral nervous system to the spinal cord, mainly the dorsal horn. Moreover, glutamate injections provoked nociceptive responses, which are mediated by neuropeptides (Substance P) released from C fibers, due to the activation of glutamate receptors [i.e., N-methyl-D-aspartate acid (NMDA)] that can stimulate the production of a variety of intracellular second messengers. These are NO, then pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and IL-1β, which act synergistically in the excitation of the neurons [33]. Trink et al. indicated that the intravaginal treatment with α-T, one of the main components of Artemisia princeps Pamp (Asteraceae) essential oil (APEO), significantly decreased viable Gardnerella vaginalis and Candida albicans germs in the vaginal cavity by inhibition of the expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), COX-2, iNOS. Based on these results, α-T most potently inhibited the expression of pro-inflammatory cytokines and NF-κB activation [34]. Additionally, it was found that spinal, supraspinal, and peripheral sites of action are involved in the induced nociceptive response by glutamate which is mainly mediated by both non-NMDA and NMDA receptors [35]. Thus α-T produces an inhibition of the nociception induced by glutamate [32]. The anti-inflammatory activity of α-T was assessed in another study, where α-T showed inhibition of bovine cyclooxygenase-1 and 2 (COX-1 and COX-2). α-T exerted selective COX-2 inhibition, where its IC50 values against COX-1 and COX-2 were 5.14 mM and 0.69 mM, respectively. This indicated that α-T showed higher COX-2 activity inhibition than Aspirin®, which is the most popular NSAID [36].

Sakurada et al. suggested that the capsaicin-induced pain model examines substances which act on pain of neurogenic origin. Furthermore, capsaicin can be defined as an extracted neurotoxic substance from red pepper, resulting in the irritation of the skin when applied or injected into animals causing a painful sensation and subsequent desensitization to chemically induced pain. Many reports have revealed that capsaicin provokes the release of neuropeptides, nitric oxide (NO), excitatory amino acids (glutamate and aspartate), and pro-inflammatory mediators and also helps in the transmission of nociceptive information to the spinal cord [37]. The analgesic action of α-T was presented by Le Bars et al. involving the supraspinal as well as the spinal components by the utilization of the hot plate test [38]. The results suggested that α-T (only at a higher dose) has a central analgesic effect, due to the occurrence of time response delay during a hot plate test, when mice were exposed to a nociceptive stimulus [32].
According to Poole et al. releasing primary hypernociceptive mediators are believed to be stimulated by a cascade of cytokines and not directly by means of inflammatory stimuli [39]. Mechanical hypernociception is induced by carrageenan (CG) using this cascade of cytokines. TNF-α is the first cytokine to be set free and subsequently triggers the release of other cytokines such as IL-1β [40]. This can lead to a neurogenic inflammation which contributes to the inflammatory process resulting in central and peripheral hyperalgesia. Moreover, the α-T’s anti-nociceptive activity indicated that the development of this mechanical hypernociception is inhibited by pre-systemic treatment with α-T at doses of 25, 50 or 100 mg/kg. i.p. A similar action was also noticed upon prostaglandin E2 (PGE2) and dopamine (DA) administration, where it was observed that α-T was able to maintain the baseline nociceptive threshold and significantly inhibited the neutrophil-influx in the pleurisy model [28]. These results may conclude that the synthesis of compounds, such as eicosanoids which are correlated with the inflammatory process, is inhibited by α-T possibly by means of suppressing NF-κB signaling [5]. α-T (1, 10 and 100 μg/mL) also significantly reduced (p<0.01) nitric oxide (NO) production in macrophages stimulated by lipopolysaccharides (LPS) in vitro [28].

In summary, the data collected so far provide information about the anti-nociceptive and anti-inflammatory properties of α-T which attract great pharmaceutical interest in developing new clinical drugs which can be useful in managing and controlling painful and/or inflammatory disease [28,32].

Antiulcer activity

Peptic ulcer is one of the most common gastrointestinal diseases. Gastric ulcers are generally caused by a disruption in the balance between aggressive factors (pepsin and hydrochloric acid) and mucosal defensive factors, such as blood flow, mucus, and bicarbonate secretion. In recent years, a widespread search has been launched to identify new anti-ulcer drugs from natural sources” [41].

As α-T is an isomer of the monoterpene alcohol terpinen-4-ol (T-4-ol) which possesses anti-ulcer activity [42], it was also of interest to evaluate and present the anti-ulcer activity of α-T- in the present review. The gastroprotective activity of α-T was determined in the two ethanol-and indomethacin-induced ulcer models in rats. In the ethanol-induced ulcer model the oral administration of α-T furnished a gastroprotective activity, by reduction of the gastric lesions. Stimulation of defense mechanisms (cytoprotective effect) is the suggested mechanism of drug action showing gastroprotective activity against ethanol-induced gastric lesions, rather than the inhibition of aggressive ones (anti-secretory effect). The indomethacin-induced gastric lesions were also decreased by means of an oral treatment with α-T, but a considerable inhibition (p<0.01) was noticed only at concentrations of 30 mg/kg and 50 mg/kg. This result shows that α-T exerted its gastroprotective action in a dose-dependent manner [41]. Moreover, there is a relationship between gastric acid and the gastric lesion formation which was induced by indomethacin. Gerkens et al. proposed that the indomethacin-induced lesion formation was attributed to the decrease of gastric mucosal blood flow [43].

Pre-treatment with indomethacin (10 mg/kg) did not inhibit the gastroprotective action of α-T on ethanol-induced ulcers. Based on this result, an increase in prostaglandin synthesis is not believed to be involved in the gastroprotective action of α-T at a concentration 50 mg/kg. On the other hand, the secretion of gastric acid can be inhibited by either proton pump inhibitors and/or histamine H2 receptor antagonists, which represent the currently used drugs in order to treat ulcers. However, α-T has not changed proton concentration values, pH, and the gastric volume after pylorus ligation, indicating that its gastroprotective action is not suggested to be due to gastric secretion inhibition. On this basis of such evidence, α-T exerts its gastroprotective effect probably by means of cytoprotective mechanisms which need further investigations to be more explained [41].

Anticonvulsant and sedative activity

Around 450 million people worldwide suffer from many problems during their lives, such as neurological, mental or behavioral disturbance [44]. Epilepsy can be defined as a disorder accompanied by recurrent spontaneous seizures, caused by several complex mechanisms including different neurotransmitter systems as GABA (γ-aminobutyric acid) and cholinergic system. Despite using more efficient and modern anticonvulsant drugs to treat epilepsy patients worldwide, seizures are still considered to be unmanageable in more than 20% of the cases. Furthermore, most of the currently used antiepileptic drugs are obtained by means of chemical syntheses, such as benzodiazepines and succinimides [45]. Therefore, recent studies on monoterpene compounds such as α-T have been performed to examine their pharmacological aspects to develop new anticonvulsant drugs with lower side effects and more advantages than that of the currently used pharmaceutical drugs [45].

De Sousa et al. investigated the anticonvulsant activity of α-T. The results of this study indicated that the latency to pentylenetetrazole-induced convulsions is increased by treatment with α-T at concentrations of 100 and 200 mg/kg and the incidence of hind-limb extension produced by MES (maximal electroshock seizure) is reduced at concentrations 200 and 400 mg/kg in a dose-dependent manner in mice [46]. Another study analyzed the therapeutic effect of α-T as a relaxing drug and tranquilizer. The data showed that α-T increased the sleep time of the mice indicating a sedative property, due to the suggested action on central mechanisms affecting the inhibition of the metabolism of pentobarbital or the regulation of sleep in mice. In other words, α-T exhibited a depressant effect on the pentobarbital-induced sleep test, indicating a sedative property [47].

Anti-bronchitis activity

Chronic obstructive pulmonary disease (COPD) is a chronic obstructive lung disease and is frequently found in well-developed countries due to the issue of aging population. COPD can lead to the restriction of lung function” [48,49]. The current treatment options for COPD are very limited and their side effects of treatment frequently noted is Cushing Syndrome caused by long-term steroid use [50]. At the final state of severe COPD patients need lung transplants but still the survival outcome is poor [51]. Despite improvement with regard to pharmacy and drug invention the occurrence of COPD and mortality related to COPD continues to rise [52]. Clearly, efforts to stop smoking and to control pneumonia could be the appropriate prevention methods to limit deterioration in cases of COPD. However, there are no other useful ways to attempt to cure the COPD; thus it remains the leading cause of death throughout the world [53]. Therefore, prevention of the occurrence of COPD is the most important issue to address, but not only the above-mentioned methods but also by the inhibition of IκB-kinase beta (IKK2) which is linked to COPD occurrence [54,55].

Tsou et al. investigated the effect of α-T against COPD. The top three traditional Chinese medicine (TCM) compounds were found to be sinapic acid-4-O-sulphate, kaempferol and α-T belonging to the TCM herbs Magnolia officinalis (Magnoliaceae), Bupleurum chinese (Apiaceae), respectively [56]. α-T exerts an antimicrobial effect and in particular, prevents infections that originate from periodontopathic and carcinogenic bacteria [57]. As a result, it was indicated that the above mentioned TCM compounds can have an effect on IKK2 inhibition and prevent exacerbation and disease progression with regards to COPD [56].

Skin penetration enhancing activity

Over the last two to three decades, the skin has become an important route for the administration of drugs for topical, regional or systemic action. The skin has evolved as a physical and biochemical protective barrier which prevents the loss of water from the body, and guards against entry into the body of external toxic chemicals and infectious agents, thereby maintaining homeostasis. The role of the skin as a barrier to the external environment renders the absorption and transdermal delivery of most drugs problematic. The stratum corneum (SC) which is the outermost layer of the skin and comprised of keratin-rich cells embedded in multiple lipid bilayers has been considered the rate-determining structure governing percutaneous absorption of permeants. Therefore, most of the drugs are not able to penetrate the SC or to be delivered through it [58]. “Many strategies have been employed to enhance dermal and transdermal delivery. These include the use of chemical penetration enhancers, preparation of supersaturated drug delivery systems, electrically driving molecules through the tissues by iontophoresis, and physically disrupting the skin structure by electroporation or sonophoresis” [59].

Delivery of drugs via the skin has numerous advantages, like non-invasiveness, the potential for continuous or controlled delivery, and potential for delivery of certain classes of drugs that are not amenable for the administration via other routes of drug delivery. Various types of penetration enhancers with different modes of action have therefore frequently been used in the field of transdermal drug delivery research [58]. Transdermal delivery of drugs promises many advantages over oral or intravenous administration such as decreasing the side effects, improving patients compliance, first-pass effect elimination, sustained drug delivery and interruption of the drug treatment if required [60], though human skin provides an effective barrier to the permeation of most drugs in the form of SC [61,62]. Many factors have a great influence on the dermal absorption such as skin type, the origin (human, animal), environmental factors, as well as the physicochemical activities with the dermal/transdermal absorption in humans. [63]. Transdermal therapeutic systems offer a more reliable mean of administering the drug through the skin by various physical, chemical, biochemical, supersaturation and bioconvertable prodrug enhancement strategies [64].

Out of these strategies, a popular technique is the use of chemical permeation enhancers, which reversibly alters the permeability barrier of the SC. α-T is considered one of these chemical enhancers, which is currently believed to improve solubility within the SC or increase lipid fluidity of the intracellular bilayers [58,64]. Many studies have reported that α-T appears to be acceptable as a promising skin penetration enhancer as indicated by following advantages [63]:
– high percutaneous enhancement ability
– less toxic with low irritancy potential,
– reversible effect on the lipids of SC

Several studies suggest that the activity of α-T as an enhancer is a result of disrupting the intracellular lipid bilayers. Evidence from skin electrical conductivity measurements suggests that α-T may create polar pathways across the SC for ions and polar drug penetration. In addition, results from electron paramagnetic resonance have demonstrated that α-T can fluidize the SC lipids and weaken the hydrogen-bonded network of the polar interface of the SC [60,65,66]. The mechanism of action of α-T appears to be difficult, depending on the nature of permeants (e.g. hydrophilic or lipophilic). Furthermore, α-T is an alcoholic monoterpene with a high degree of unsaturation and appears to be a better candidate for enhancing the permeation of hydrophilic drugs such as e.g. 5-fluorouracil by increasing the diffusion of the drug in the SC [58,64]. “The interaction of α-T with SC lipids and keratin can be elucidated with instrumental methods such as Fourier transform infrared spectroscopy (FT-IR) and differential scanning colorimetry (DSC). The FT-IR provides the information about the molecular and conformational changes of lipids and proteins, whereas the DSC provides information about their thermotropic behavior” [60].

As skin penetration enhancer, α-T has been employed directly or in combination with co-solvents such as propylene glycol or ethanol. Synergistic activity has been reported between α-T and propylene glycol as well as between α-T and ethanol [60,65]. It was reported that the in vitro permeation of haloperidol (HP), an antipsychotic drug, is increased through human skin by using α-T at a concentration of 5% w/v in 100% propylene glycol (PG). Haloperidol is a lipophilic drug and may play an important role in developing the transdermal dosage form. Since HP is clinically needed to be found in a long-acting formulation to avoid psychosis relapse, it was required to use as a skin penetration enhancer α-T and as co-solvent PG to increase the permeation of HD [60].

Narishetty et al. investigated the effect of this monoterpene alcohol and other various oxygen-containing monoterpenes, such as 1,8-cineole, menthol, menthone, pulegone and carvone for the ex vivo permeation of zidovudine (AZT), the first approved and wide clinically used anti-HIV substance, in a solution of 66.6 % ethanol in water across rat skin. Based on the result of this study, it was indicated that a hydrogen bonding interaction is formed by α-T with the ceramide head group of SC lipids and a subsequent reduction in the skin barrier property occurred [65].

According to many skin penetration studies using the skin of hairless mice and excised animal skin, it was found that α-T was effective in enhancing the skin penetration of model permeants, such as caffeine [67] and 5-Fluorouracil [68], respectively. α-T exerted an effective penetration enhancing activity for hydrocortisone percutaneously and also increased the permeation between 3.9-fold and 5-fold, and α-T was the most active compound among several other compounds to increase the delivery of triamcinolone acetonide [63,67].

The use of local anaesthetics in combination with penetration enhancers could overcome the barrier properties of the skin to epicutaneous penetration of local anesthetic drugs. Lidocaine is a topical anaesthetic agent with low skin permeability which cannot adequately penetrate the intact skin. On the other hand, the ideal topical anaesthetic agent is one that provides 100 % anaesthesia in a short period of time, is further effective on the intact skin without systemic side effects, and invokes neither pain nor discomfort [69]. The authors of that study investigated the effects of some permeability enhancers such as polysorbate 80, polysorbate 20, dimethylsulfoxide (DMSO), tert-butyl cyclohexanol (TBCH), and α-T in different concentrations on the percutaneous permeation of lidocaine. According to that literature review, α-T showed the best permeability-enhancing effects on the lidocaine penetration through the skin. Since α-T is a relatively safe compound, it can be recommended to incorporate it into local anaesthetic cream formulations at low concentrations. α-T exerts the best effect at a concentration of 2.5%, as it is believed that it can produce eutectic mixtures with lidocaine and increase the thermodynamic activity of lidocaine in the relevant formulation [69].

Interestingly, Fang et al. found that the best method to enhance the curcumin permeation is the pre-treatment of rat skin with 5% α-T in an ethanolic solution for 1 h [70]. Curcumin exhibits various biological properties such as anticancer and anti-inflammatory. Therefore, it can be used in the treatment of several disorders, such as tumors and pro-inflammatory chronic diseases [71-73]. Because of the insufficient aqueous solubility and bioavailability of curcumin, it is not widely used in the clinical field for treatment of cancer and other diseases [74]. In another study, three terpenes, α-T, 1,8-cineole, and limonene, were used to compose an oil phase of the microemulsions. They provide another promising alternative for the dermal and transdermal delivery of both hydrophilic and lipophilic drugs [59]. Their effects on curcumin skin delivery were evaluated using neonatal pig skin mounted on a Franz diffusion cell. The results indicated that curcumin retained in the skin increased in the order limonene > α-T > 1,8-cineole [59]. Additionally, it was reported that α-T was used as a transdermal enhancer for buspirone hydrochloride, an anxiolytic, in hairless mouse skin [75]. Moreover, Jain et al. showed the effect of α-T on imipramine hydrochloride (IMH) permeation in the ethanol (EtOH): W (2:1) system. By means of unjacketed Franz diffusion cells, permeation studies of IMH were performed through rat skin. Based on the results of this literature [76], it was found that α-T is an effective permeation enhancer for IMH.

Insecticidal activity

Some facts indicate that the use of synthetic chemicals to control insects and arthropods raises several concerns as to the environment and human health. So, there is a growing demand for alternative repellents or natural products. These products possess good efficacy and are environmentally friendly. Essential oils from plants belonging to several species have been extensively tested to assess their repellent and even insecticidal properties as valuable natural resources” [18]. Searching for novel and effective natural products which are based on biopesticides, terpenoids have shown promising insecticidal activities [77-79]. Aedes aegypti L. is the principal vector of dengue, Zika and chikungunya, and the use of repellents is one of the approaches to prevent these diseases. Scientists at the Center for Medical, Agricultural and Veterinary Entomology (Gainesville, Florida, U.S.) evaluated several natural terpenes for the discovery of safe and potential repellents against the female Ae. aegypti. They found that (-)-α-T was a repellent at a minimum effective dosage (MED) of 0.039 ± 0.008 mg/cm2 compared to positive control (N,N-diethyl-3-methylbenzamide, DEET) (MED= 0.014 ± 0.002 mg/cm2) [79]. Campbell et al. also found that α-T showed prompt olfactory responses in Ae. aegypti antennae [80], however, α-T had a moderate repellent effect based on EAG responses against the stable fly Stomoxys calcitrans L. [81]. Mosquito larvae are important and attractive targets for pesticide management programs. Tabanca et al. reported that (-)-α-T did not show any mortality in the pre-screening bioassays at a concentration of 100 ppm against 1st instar Ae. aegypti [82].

The maize weevil, Sitophilus zeamais Motschulsky, causes yield losses in storage products like corn. Under laboratory conditions, α-T showed 100% mortality against S. zeamais adults after 96 h of exposure at the highest dose (30 μL/μg) [83].

Booklice, Liposcelis bostrychophila Badonnel, have a widespread distribution infesting domestic premises, manufacturing factories, raw material stores; they are also found in historical documents [84]. Due to the presence of more damaging post-harvest primary pests, they are often disregarded and are generally considered to be secondary pests. Liu et al. reported that α-T exhibited strong contact toxicity and repellent properties against booklice [85]. α-T was a major compound (37.2%) in Artemisia rupestris L. (Asteraceae) essential oil and this essential oil, can be a great potential for the development into natural insecticides or fumigants as well as repellents for the control of insects in stored grains [85]. α-T also demonstrated high fumigant toxicity against two-spotted spider mites Tetranychus urticae Koch [86].

Termites are the most damaging insect pests damaging wooden structures worldwide. There is an increasing interest in naturally occurring toxicants to Formosan subterranean (Coptotermes formosanus), invasive species of termites [87]. α-T was selected to test for its antitermitic activity against C. formosanus and showed slight toxicity at a dose of 2.5 mg g−1 after seven days. However, α-T demonstrated 100% termite mortality against C. formosanus at a dosage of 4 mg g−1 after 7 days [87].

Based on these above research results, we can conclude that α-T had responded to selective insects and dose-dependent activity. To discover, develop and understand the naturally based bio-pesticides, we need more scientific research on the insect diversity, and α-T is one of the natural compounds to be widely investigated.


α-T is a monocyclic monoterpene tertiary alcohol with a pleasant scent similar to lilac. Therefore, it is widely used in the manufacturing of perfumes, cosmetics, soaps, antiseptic agents and is considered one of the most frequently used fragrant compounds [1]. In addition, α-T possesses a wide range of biological actions which attract a great interest in the medicinal field [4].

The cardiovascular and the antihypertensive effects of α-terpineol were investigated in several studies. These results indicated that the oral administration of α-T was able to reduce the mean arterial pressure and endothelium-independent vasodilatation. Moreover, α-T was able to restore enzymatic antioxidant in L-NAME-induced hypertensive [5,15].

Additionally, α-T showed an anti-proliferative (antioxidant) activity, which could be used in the prevention or even treatment of cancer, as it was found that α-T demonstrated a potential antioxidant capacity effect against different human cancer cell lines (breast, lung, prostate, ovarian and leukemia). α-T inhibits the growth and induction of cell death in tumor cells by means of an inhibition of NF-κB activity [9,20].

The anti-nociceptive activity is one of the most important biological actions correlated to α-T. It was indicated that α-T produced significant analgesic effects by reduction at the early and late phases of paw licking and reduced the acetic acid-induced writhing reflexes in mice (formalin and writhing tests, respectively). Those effects are probably in relation to the inhibition in the peritoneal fluid levels of PGE2 and PGF2α and to the release inhibition of substance P and other inflammatory molecules [32]. However, α-T exerted also a selective COX-2 inhibition (0.69mM), therefore, it is believed that α-T showed higher COX-2 activity inhibition than Aspirin® [36]. α-T might be potentially interesting in the development of new drugs for the management of painful and/or inflammatory diseases, as well as the development of novel therapies for COPD [56].

Several studies have reported that α-T also possesses antiulcer activity. The results suggested that it presented a gastro-protective activity by reducing the gastric lesions at the doses 10, 30 and 50 mg/kg without the involvement of gastric acid secretion inhibition or increase in prostaglandin synthesis [41,42]. Furthermore, α-T showed anticonvulsant and sedative activities via a depressant effect on the pentobarbital-induced sleep test [47]. In addition, it increased the latency to convulsions induced by pentylenetetrazole and decreased the incidence of hind limb extension produced by MES in a dose-related manner [46].

Another important biological activit of α-T was its promising effect as a chemical skin penetration enhancer, currently believed to improve the solubility within the stratum corneum (SC) or to increase the lipid fluidity of the intracellular bilayers [58,64]. In addition, the insecticidal activity of α-T attracted the interest of many scientists. Therefore, it is suggested that α-T may be a potential agent for the development into natural insecticides or fumigants, as well as repellents for control of insects [77-87].

Consequently, α-T has exhibited a potential satisfaction in certain activities due to its usage in pharmaceutical and agricultural industries. Encouraging results from these wide range of biological activities show that α-T is very promising candidate in pharmaceutical and agricultural applications.

Disclaimer: No potential conflict of interest was reported by the authors.

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Fragrance material review on 1,3,3-trimethyl-2-norbornanyl acetate (Fenchyl acetate)


A toxicologic and dermatologic review of 1,3,3-trimethyl-2-norbornanyl acetate when used as a fragrance ingredient is presented.


In 2007, a complete literature search was conducted on 1,3,3-trimethyl-2-norbornanyl acetate. On-line databases that were surveyed included Chemical Abstract Services and the National Library of Medicine. In addition, fragrance companies were asked to submit pertinent test data. All relevant references are included in this document. Any papers in which the vehicles and/or the doses are not given have not been included in this review. The number of animals, sex and strain are always provided unless they are not given in the original report or paper.

This individual Fragrance Material Review is not intended as a stand-alone document. Please refer to the Toxicologic and Dermatologic Assessment of Cyclic Acetates (Belsito et al., 2008) for an overall assessment of this material.

1. Identification (Fig. 1)
  • Synonyms: Bicyclo[2.2.1]heptan-2-ol, 1,3,3-trimethyl-, acetate; 3,3-Dimethyl-8,9-dinorbornan-2-yl acetate; Fenchyl acetate; 1,3,3-Trimethylbicyclo[2.2.1]hept-2-yl acetate. 1.2 CAS Registry Number: 13851-11-1.
  • CAS Registry Number: 13851-11-1.
  • EINECS Number: 237-588-5.
  • Formula: C12H20O2.
  • Molecular weight: 196.29.
  • FEMA: Flavor and Extract Manufacturers’ Association: Generally Recognized as Safe as a flavor ingredient – GRAS 6. (3390) (FEMA, 1973).
  • Joint Expert Committee on Food Additives: The Joint FAO/WHO Expert Committee on Food Additives (JECFA No.1399) concluded that the substance does not present a safety concern at current levels of intake when used as a flavouring agent (JECFA, 2004).
Fenchyl acetate
Fig. 1. 1,3,3-Trimethyl-2-norbornanyl acetate (Fenchyl acetate).
2. Physical properties
  • Physical description: Colorless, mobile liquid with a mild, sweet, fir needle oil-type odor.
  • Log Kow (calculated): 3.86.
  • Vapor pressure (calculated): 0.07 mm Hg at 20℃.
  • Water solubility (calculated): 23.23 mg/l at 25℃.
  • Specific gravity: 0.967.
Table 1. Calculation of the total human skin exposure from the use of multiple cosmetic products containing 1,3,3-trimethyl-2-norbornanyl acetate
Type of cosmetic productGrams appliedApplications per dayRetention factorMixture/productIngredient/mixturea (%)Ingredient mg/kg/dayb
Bath products17.000.290.0010.020.010.0000
Body lotion8.000.711.000.0040.010.0000
Eau de toliette0.751.
Face cream0.802.001.000.0030.010.0000
Fragrance cream5.
Hair spray5.
Shower gel5.
Toilet soap0.
a Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.
b Based on a 60 kg adult.
Table 2. Summary of acute toxicity data.
RouteSpeciesAnimals/dose groupLD50References
OralRat10> 5 g/kgIRIFM (1975a)
DermalRabbit10> 5 g/kgIRIFM (1975a)
3. Usage

1,3,3-Trimethyl-2-norbornanyl acetate is a fragrance ingredient used in many fragrance compounds. It may be found in fragrances used in decorative cosmetics, fine fragrances, shampoos, toilet soaps and other toiletries as well as in non-cosmetic products such as household cleaners and detergents. Its use worldwide is in the region of 10–100 metric tonnes per annum.

The maximum skin level that results from the use of 1,3,3-trimethyl-2-norbornanyl acetate in formulae that go into fine fragrances has been reported to be 0.011% assuming use of the fragrance oil at levels up to 20% in the final product. The 97.5 percentile use level in formulae for use in cosmetics in general has been reported to be 0.01% (IFRA, 2007), which would result in a conservative calculated maximum daily exposure on the skin of 0.0003 mg/kg for high end users of these products (see Table 1).

4. Toxicology data

4.1 Acute toxicity

See Table 2.

Oral studies

  • The acute oral LD50 was reported to exceed 5.0 g/kg. Ten rats received single oral doses of 5.0 g/kg test material each. Animals were observed for 14 days. Two animals died (2/10). No adverse clinical signs were observed (RIFM, 1975a).

Dermal studies

  • The acute dermal LD50 in rabbits exceeded 5 g/kg based on no (0/10) deaths at that dose. Ten rabbits each received a single dermal application of neat test material. Animals were observed for 14 days. No clinical signs were observed (RIFM, 1975a).
  • Acute dermal toxicity was evaluated during a skin absorption study. Two mice were each administered a single 4-hour dermal application of neat 1,3,3-trimethyl-2-norbornanyl acetate on the shaved abdominal skin. Observations were made after 4 hours. No deaths (0/2) or adverse clinical signs (Meyer and Meyer, 1959).

4.2 Skin Irritation

Human studies

  • In a pre-test for a maximization study, a 48 h occluded patch test was conducted on 5 healthy volunteers. No irritation was produced by 1,3,3-trimethyl-2-norbornanyl acetate at 5% in petrolatum (RIFM, 1975b).

Animal studies

  • Irritation was evaluated as a part of an acute dermal LD50 study conducted on 10 rabbits. A single 24 h occluded dermal application of neat (5 g/kg) test material produced moderate erythema (10/10) and slight (1/10) to moderate (7/10) edema, observed after patch removal (RIFM, 1975a).

4.3 Mucous membrane (eye) irritation

No data available on this material.

4.4 Skin sensitization

Human studies

  • A human maximization (Kligman, 1966) study was carried out with 5% (3450 lg/cm2) 1,3,3-trimethyl-2-norbornanyl acetate in petrolatum on 25 (10 male:15 female) healthy volunteers. Application was under occlusion to the same site on the forearms of all subjects for five alternate-day 48-hour periods. Patch sites were pretreated for 24 h with 5% aqueous sodium lauryl sulfate (SLS) under occlusion. Following a 10 day rest period, challenge patches were applied under occlusion to fresh sites for 48 h. Challenge applications were preceded by 1-hour applications of 10% aqueous SLS under occlusion. Challenge sites were read on removal of the patch and 24 h thereafter. No sensitization reactions (0/25) were observed (RIFM, 1975b).

Animal studies

No data available on this material.

4.5 Phototoxicity and photoallergy

UV spectra revealed that 1,3,3-trimethyl-2-norbornanyl acetate peaked in the 200–220 nm range, with slight absorption in the 240 to 300 nm range.

4.6 Absorption, distribution and metabolism

In vivo animal studies

  • Meyer and Meyer (1959) studied the skin absorption of 1,3,3-trimethyl-2-norbornanyl acetate in 5 male mice. An area of 2.2 cm2 on the shaved abdominal skin was used. Eserine (0.23%) was used as an indicator and the test material was used as a carrier for eserine. The latency period between application to the skin and the appearance of the eserine effect in the periodically stimulated masticatory muscles was used as a measure of the absorption rate. Absorption for 1,3,3-trimethyl-2-norbornanyl was 54 min.

4.7 Repeated dose toxicity

No data available on this material.

4.8 Reproductive and developmental toxicity

No data available on this material.

4.9 Mutagenicity and genotoxicity

No data available on this material.

4.10 Carcinogenicity

No data available on this material.

This individual Fragrance Material Review is not intended as a stand-alone document. Please refer to the Toxicologic and Dermatologic Assessment of Cyclic Acetates (Belsito et al., 2008) for an overall assessment of this material.

Conflict of interest statement
This research was supported by the Research Institute for Fragrance Materials, an independent research institute that is funded by the manufacturers of fragrances and consumer products containing fragrances. The authors are all employees of the Research Institute for Fragrance Materials.

  1. Belsito, D., Bickers, D., Bruze, M., Calow, P., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H., Sipes, I.G., Tagami, H., 2008. A Toxicologic and Dermatologic Assessment of Cyclic Acetates When Used as Fragrance Ingredients. Food and Chemical Toxicology 46(12S), S1–S27.
  2. FEMA Flavor and Extract Manufacturers Association, 1973. Recent progress in the consideration of flavoring ingredients under the food additives amendment 4.GRAS substances. Food Technology 27 (1), 64–67.
  3. IFRA (International Fragrance Association), 2007. Use Level Survey, September 2007. Joint Expert Committee on Food Additives, 2004. Safety Evaluation Of Certain Food Additives. Who Food Additives Series: 54 Prepared by the Sixty-third Meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA). World Health Organization, Geneva 2004.
  4. Kligman, A.M., 1966. The identification of contact allergens by human. III. The maximization test. A procedure for screening and rating contact sensitizers. Journal of Investigative Dermatology 47, 393–409.
  5. Meyer, F., Meyer, E., 1959. Absorption of ethereal oils and substances contained in them through the skin. Arzneimittel-Forsch 9, 516–519.
  6. RIFM (Research Institute for Fragrance Materials, Inc.), 1975a. Acute Toxicity Studies on Rats, Rabbits and Guinea Pigs. RIFM Report Number 2020, May 22, RIFM, Woodcliff Lake, NJ, USA.
  7. RIFM (Research Institute for Fragrance Materials, Inc.), 1975b. Report on Human Maximization Studies. RIFM Report Number 1799, May 19, RIFM, Woodcliff Lake, NJ, USA.

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