Fragrance Chemistry ÂŠ Milestones and Perspectives

FLAVOURS AND FRAGRANCES 379 CHIMIA 2001,55, No, 5

Chimia 55 (2001) 379-387 © Schweizerische Chemische Gesellschaft ISSN 0009-4293

Fragrance Chemistry - Milestones and Perspectives

Markus Gautschi*, Jerzy A. Bajgrowicz, and Philip Kraft

Abstract: This mini-review on Fragrance Chemistry focuses on milestones in the timelines of musk, ionone/ woody and sandalwood odorants, as well as on new perspectives arising from the development of fragrance precursors. After a brief introduction of the history of perfumery, its mutual interaction with the chemistry of odorants, and the current state of the fragrance industry, the whole spectrum of musk odorants is discussed from the accidental discovery of nitro musks like Musk Ketone® via the parallel evolution of benzenoid and macrocyclic musks, to new structures like Cyclomusk® and Moxalone®. Following a description of the structure elucidation of violet odorants, ionone and irone,lso ESuper®and the structurally related Georgywood®, but also Koavone® and Timberol® are treated. Weissenborn's discovery of terpenylcyclohexanols lead to sandalwood synthetics that today are mainly derivatives of campholenic aldehyde like Sandalore®, Sandal Mysore Core®, Polysantol®, Ebanol®, and Javanol®. Finally, lipase labile precursor systems, for instance digeranyl succinate, or UV-radiation labile ones like citronellyl coumarate and citronellyl cyclohexylglyoxylate are presented, and views on 'secondary benefits', 'anti-perfumes' and exclusive 'Editions de Parfums' conclude this overview on the driving forces and the serendipities in the chemistry of fragrant substances. Keywords: Fragrance precursors· lonones . Musks· Odorants· Sandalwood

'Sailing on the scent o{your perfume 'through smoke' - per fumum - the treas- perfumes. Vanillin blended with resins, Only memories to guide ures of nature to please the Gods [2]. Al- animalic notes and a floral accord with Distant thoughts inside ... ' coholic extracts of plants and resins as hesperidic elements, was the basis of G. Duke, 'Illusions' [1] well as composites thereof were used in 'Shalimar' created by Jacques Guerlain the middle age as both perfume and med- in 1919, the prime example of an oriental icine (aqua mirabilis), aphrodisiac and fragrance. And in 'Chypre' (19]7), 1. Introduction elixir oflife (aqua vitae). After Napoleon which gave the name to the third big fra- Bonaparte had ordained by decree in grance family, Franc;:ois Coty already From the fresh, sparkling shower gel in 1810 that manufacturers and vendors had used the newly available quinolines, es- the morning to the sensual, seductive per- to make a distinction between pharma- pecially iso-butyl and iso-propyl quino- fumes that surround us during a romantic ceuticals and perfumes, eaux de Co- line, though leathery Chypre fragrances candle-light dinner, we experience fra- lognes were no longer drunk. The newly like 'Bandit' (Piguet, 1944) became fash- grances at almost any time and almost defined 'perfumes', still composed ex- ionable only much later. everywhere. Even our shopping is ac- clusively of natural ingredients, mainly With the beginning of the age of fash- companied by pleasant scents, and when essential oils, became more and more so- ion, the creativity of both designers and we reach out for personal and homecare phisticated, and consequently luxury perfumers gave another boost to a rapidly products we very often have the choice items for monarchs and their entourage, growing industry. After World War II, between different fragrance variants of aristocrats and patricians. The use of syn- the rise of the consumer purchasing the same brand. thetic ingredients marked the beginning power finally made perfumes available to The use of perfumes has a long his- of modern perfumery at the end of the everybody and led the way for their intro- tory: In biblical times people sacrificed 19th century, and enriched the perfumers duction into many functional products. palette with new odor notes. Today, perfume is an everyday item, In 1882, Paul Parquet created 'Fou- even sold in supermarkets, and people in gere Royale' around an accord composed genera] possess more than just one fra- of coumarin, oakmoss, geranium and grance. Whereas 50 years ago a perfume 'Correspondence: Dr. M. Gautschi bergamot, and with its launch by Hou- was still considered a precious item, and Givaudan Dubendorf AG Fragrance Research bigant the new era commenced. In the women would use the same fragrance Oberlandstrasse 138 following years, major achievements in over many years (while men's fragrances CH-8600 DObendorf the synthesis of fragrant compounds as were barely accepted that time), today Tel.: +41 1 8242324 Fax: +41 1 8242926 well as the discovery of new odorants men and women choose which fragrance E-Mail: [email protected] catalyzed the creation of many landmark to wear according to their daily mood. FLAVOURS AND FRAGRANCES 380 CHIMIA2001, 55, No.5

Behind the scenes, the Flavor and ated with a commercial firm, the 'Societe Naef & Co. (today Firmenich), elucidat- Fragrance (F&F) industry is striving des produits chimiques de Thann et de ed its structure [11] - and overturned constantly to lower prices and to increase Mulhouse', and pursued his studies on Baeyer's theory of strain in multimem- quality and performance of perfumery in- nitro arenes systematically. In 1894, he bered rings [12]. Ruzicka and M. Naef & gredients, i.e. to make them more stable discovered and developed Musk Ketone Co. were originally aiming at an industri- and last longer. The fragrance industry, (1), which was prepared by nitrating al synthesis of muscone (2), which, with situated in between the petrochemical acetylated tert-butyl-m-xylene [9]. Musk an odor threshold of 4.5 ngll, was not and the pharmaceutical industry, has Ketone, possessing an excellent odor even extremely powerful. However, their been growing over the last hundred years threshold of 0.1 ngll, is considered to re- cyclization method employing thorium to an estimated market size of 7000 Mio semble the natural Tonkin musk closer salts [13] did not tolerate the ~-methyl CHF. While the production scale of fra- than any other nitro musk, and until re- substituent, and thus cyclopentadecan- grance compounds is closer to that of cently was amongst the most used per- one, under the name of Exaltone®, was pharmaceuticals, the product prices are fumery ingredients. introduced instead - at the exorbitant closer to those of the bulk-chemical in- Tonkin musk is the dried solidified se- price of 50000 CHFlkg [14], while Musk dustry. Some ingredients, namely those cretion (musk grains) from a preputial Ketone (1) cost less than 100 CHF/kg at with an extremely low odor threshold, follicle of the male musk deer (Moschus that time! are produced in kilogram quantities only. moschiferus L.), which inhabits the Considering the prices of the nitro At the other end, some perfumery Himalayas from Afghanistan to China. musks, it was more than reckless from a ingredients, mainly for use in detergents Its odoriferous principle, (- )-(3R)-mus- commercial point of view to subject Ex- and homecare products, are produced in cone (2), was isolated by Heinrich Wal- altone®, which was produced in just quantities of up to 10000 t/a, e.g. linalool baum of Schimmel & Co. in 1906 [10], about 6% yield from thapsic acid and had (8000-10000 t/a), 2-phenylethanol and makes up only 0.5-2% of the musk to be purified via its semicarbazone, to a (7000-9000 t/a), benzyl acetate (7000- grains. He was able to establish its mo- Baeyer-Villiger oxidation. The resulting 9000 t/a), Galaxolide® (7000-8000 t/a), lecular formula, and show that it was a 15-pentadecanolide (3) possessed, how- Lilial (5000-6000 t/a), Hedione® (4000- ketone, but it was only 20 years later that ever, superior olfactory characteristics, 5000 t/a) and Iso E Super® (2500-3000 t/ Leopold Ruzicka, in the laboratory of M. and was also introduced into perfumery year), cf also [3]. In the following, we want to point the reader to some selected milestones of the most important odor notes and to give an 5 idea of how Fragrance Chemistry devel- Galaxolide oped, what driving forces were active, (1965) 0.9 ng/l and which future direction the industry might take. A general overview on the developments of the F&F industry from the end of 1945-1994 was given by Paul 3 Z. Bedoukian in his annual reviews [4], 15-penta- o while processes and compounds of gen- decanolide eral technical and industrial relevance 1 (1927) 2.1 ng/l 7 were summarized in a more recent re- Musk Ketone Moxalone view [5]. Information on the newest (1894) 0.1 ng/l (1983) 1.0 ng/l trends and highlights in the chemistry of odorants can be found in [6], and details .. on the production and uses of individual I! I· I I I! 0 0 0 0 0 0' 0 0 C) 8 <0 .... lil substances are treated in [7]. c;; d'i "':C) , al §~ ~ ~ '"~ '"'~ ~ -: ~ ~ ~ ~ ",' , , , , 2. Timelines of Odor Notes 2 4 8 (-)-(3R}-muscone Phantolide Nirvanolide 2.1. Musks (1926) 4.5 ng/l (1952) 6.7 ng/l (2001) 0.1 ng/l As for many other disciplines, serendipity is also a key factor in Fragrance Chemistry, and the fortunate finding of the aromatic nitro musks by Albert Baur in 1888 marks the origin of the timeline of musk odorants (Fig. 1). Baur was actu- o ally searching for new explosives when he noticed that the product of the Friedel- Crafts reaction of trinitrotoluene (TNT) 6 with tert-butyl halides emanated a pleas- Cyclomusk ant musky smell. 2-tert-Butyl-4-methyl- (1975) 4.5 ng/l 1,3,5-trinitrobenzene was an immediate commercial success and became known as 'Musk Baur' [8]. Baur became associ- Fig. 1. The musk timeline FLAVOURS AND FRAGRANCES 381

CHIMIA 2001,55, No.5 in 1927. Its price at that time was 100 000 cation of benzenoid musks. Kurt Fuchs which was found by serendipity by CHF/kg (!) [14] - 1000 times more ex- discovered the first nonnitro indan musk Werner Hoffmann and Karl von Fraun- pensive than the excellent benchmark 1, 4 in 1951, and assigned his invention to berg of BASF in 1975 [29], had no which is even 20 times stronger than 3 in Polak's Frutal Works [21]. It was intro- chance against 5 at the time of their intro- terms of odor threshold (Fig. 1). For com- duced to the market only one year later, duction to the market. Now 6 constitutes parison, the price of natural muscone, even without knowledge of the correct an important lead for the development of based on the price of Tonkin musk and its chemical structure of 4 - which was re- new biodegradable musks, such as Hel- content in 2, would have been 'merely' flected in its name 'Phantolide®' (4). vetolide® of Firmenich [6]. Moxalone® around 300 000 CHF/kg at that time [15]. When the structure of 4 was elucidated (7) of Givaudan [30], also the result of a The high price that perfumers were will- four years later [22], it became apparent fortunate finding [6], demonstrates that ing to pay for 3 demonstrates the fascina- that it showed some shape similarity to polycycles do not have to be aromatic to tion for the real odoriferous principles of Musk Ketone (1). Though the odor smell musky - and that new structures nature, the macrocyclic musks. At about threshold of 4 is significantly higher than with powerful musk notes still can be the same time, Max Kerschbaum [16] of that of 1, its superior performance in de- found. Haarmann & Reimer in Germany found tergents and washing powders made Before these will be discovered, how- 15-pentadecanolide (3) in Angelica root Phantolide® (4) the new lead structure for ever, macrocyclic musks will take over a oil (Archangelica officinalis Hoffm. syn. musk odorants, and in the following substantial market share. While in 1998, Angelica archangelica L.). years numerous derivatives were synthe- 75% of the musk odorants used were With the improvements of the cy- sized in the laboratories of the F&F in- polycyclic, it is expected that in 2008 clopentadecanone synthesis by first the dustry. Some prominent introductions in- macrocycles will make up 60-65% of the Thorpe-Ziegler reaction, and then by clude Celestolide® (IFF), Tonalide® global musk market [31]. With a market acid-catalyzed cyclization of the 15-hy- (PFW), Traseolide® (Quest) and Versali- price of around 15 CHF/kg, Galaxolide® droxypentadecanoic acid according to de® (Givaudan, for structures see [7]). (5) is obviously a benchmark difficult to the Ruggli-Ziegler dilution principle, the Besides the odor intensity and character, beat in terms of cost. So on one hand selling price of 3 dropped to one fifth in the main performance and selection crite- cheaper macrocyclic intermediates (like the next eight years [14]. Another break- rion was the hydrophobicity, one of the Habanolide® [6]) are introduced and through in the synthesis of cyclopentade- factors that make musk odorants deposit even more process research is carried out canone was the Stoll-Hansley-Prelog on the fabric during the washing process to lower the prices; on the other hand process, the acyloin condensation of the - in terms of volume, laundry care had more intense macrocyclic musk odorants dimethyl pentadecadienoate, which as a already become the prime area of appli- are intensively sought. While Max Stoll of surface reaction did not require high dilu- cation for musk odorants. Firmenich stated in 1935 [32] that methyl tion. Spanagel and Carothers [17] cir- In the late 1950's, M.G.J. Beets ofIFF groups have almost no influence on the cumvented high-dilution conditions by was, therefore, looking to replace the car- odor of macrocyclic musks, and that ad- polycondensation of the 15-hydroxypen- bonyl group of the polycyclic musks by ditional oxygen atoms in macrolides de- tadecanoic acid and subsequent distilla- other (less polar) functional groups, for crease the odor intensity, today there is tion in vacuo at 270 °C/l torr. As a conse- instance nitriles. His studies of the struc- no doubt that methyl groups and addi- quence, the price of 3 decreased again by tural requirements for musk odorants tional polar groups [33] are of critical im- a factor of ten, while its production rose [23] bore fruit in the discovery of the iso- portance for the odor intensity and char- from kilogram to ton scale. In the early chroman musk Galaxolide® (5) in 1965 acter [34]. If the configuration of the 60's, Wilke opened up an inexpensive in- [24]. Already in the late 60s, Galaxolide® methyl bearing carbon atom is invelted, dustrial access to cyclododecanone by (5) was used in up to 40% in fabric sof- macrocyclic musks can even become cyclooligomerization of butadiene [18], teners such as 'Comfort' and 'Softlan', odorless [34]. A 1,7-dioxa substitution and this was the chance for new process- and in detergents like 'Coral' at 27% and a (co-2)-methyl group increase the es via ring-enlargement sequences [19] [25]. More recently, overdoses could also intensity of macrocyclic musk odorants [20]. Today, 3 is sold under the trade be found in alcoholic perfumes, like in dramatically, and 12-methyl-9-oxa-14- names Cyclopentadecanolide® (Haar- 'Tresor' (Lanc6me, 1990) with 20% of 5 tetradecanolide is about one thousand mann & Reimer), Exaltolide® (Firmen- and in 'Parfum Sacre' (Caron, 1990) with times stronger than 13-methyl-l1-oxa-14- ich), Pentalide® (Soda Aromatics), and 25% [25]. Even today, it is still the most tetradecanolide in terms of odor thresh- Thibetolide® (Givaudan) for around widely used musk. old [34]. The feature of a (co-2)-methyl 60 CHF/kg, while Musk Ketone (1) is to- 'Even today', because the use of Gal- group and a polar moiety, in this case a day about 50 CHF/kg - an impressive re- axolide® (5) - and other polycyclic double bond, is also present in Nirvano- sult of process research. musks (PCM's) - is a much debated top- lide® (8) [35], the newest introduction of The 'high' price of 1 today, is of ic. Its massive production volume togeth- Givaudan. With an odor threshold of course also the result of a drastic decline er with its excellent chemical stability, its 0.1 ng/l it reaches the world record of in usage over the years. This was not due non-biodegradability and its high octa- Musk Ketone (1), and is currently the to environmental or toxicological issues, nol/water partition coefficient has led to most powerful musk in perfumery. Its but a consequence of the lack of stability bioaccumulation in fish, human fat and 17-membered analog was claimed by of the nitro musks. Their photochemical human milk [26]. Although risk assess- Quest at about the same time [36], so the reactivity and their instability in alkaline ments show that HHCB, as Galaxolide® race for the ultimate musk is again run- media led to decomposition and caused (5) is called today by the toxicologists, is ning, after Galaxolide® was dethroned! discoloration in functional products. In safe for the environment [27], perfume the late 1940's, chemists were therefore and homecare product houses frequently 2.2. lononelWoody Odorants searching for nonnitro derivatives to in- insist on PCM-free formulations [28]. Empress Josephine's wedding dress crease the stability and the range of appli- Musk odorants like Cyclomusk® (6), was embroidered with violets for her FLAVOURS AND FRAGRANCES 382

CHIMIA 2001, 55, NO.5 marriage with Napoleon, 'crystallized vi- pendently by Ruzicka and co-workers at fumery. Today almost every perfume in- olets' sprinkled with castor sugar are a Firmenich [40]. cludes them, since they blend well with delicacy, and violet petals have been used The comedy of errors in the chemistry basically all other perfumery materials. in cosmetic formulations and were spread of ionones continued. Even in his review Another material that is comparably ver- amongst the laundry of those who could on violet odorants in 1951 [41] Schinz satile and can be used in a similar way as afford it. Today, with all the affordable still believed that ionones did not occur in the ionones was found 80 years later at violet-smelling toilet soaps available, nature. A few years before, he and Ru- IFF (Fig. 2). First named Isocyclemone one easily forgets that violet flower oil zicka had isolated parmone from violet E®, 10 resulted from an exploratory work was the most expensive of all essential flower oil, which they believed to be the submitting Diels-Alder adducts of oils - at the times when it was still eco- odorous principle of violets [42]. lt was myrcene with different dienophiles to the nomic to be produced, For the production not until 1972 that Uhde and Ohloff [43] acid-catalyzed cyclization Tiemann had of one kilogram of this oil 33000 kg of were able to show that parmone was a already made use of [46]. This is an ex- violet blossoms for ca, 2.50 German gold phantome, a mixture of (R)-(+)-a-ionone, ample of how simple chemistry and inex- mark per kilogram were needed [37]. (R)-( +)-dihydro-a-ionone, p-ionone and pensive starting materials like myrcene, That makes 82500 German gold marks dihydro-p-ionone. Although Tiemann which is industrially easily available for material costs alone per kilogram of and Kruger had inaccurately analyzed or- from p-pinene by pyrolysis, can inspire the oil, much more than even the most ris root oil in the search of the odorous inventions in Fragrance Chemistry. Oth- precious musk grains. principle of violets, they had actually dis- er products of this approach with This high price was the reason why a covered what they were initially looking myrcene include the aldehyde Cyclemo- synthetic violet odorant was highest on for. In the violet flower oil, Uhde and ne A®, the non-cyclized Precyclemone the agenda of the young fragrance indus- Ohloff found 8.22% of (R)-( +)-a-ionone B®, the tricyclic Lactoscatone®, Myrac try. Ferdinand Tiemann of the University and 0.22% of ~-ionone [43]. A recent Aldehyde® and its myrcenol analog Lyr- of Berlin therefore started, in collabora- headspace analysis of violets in bloom al® [7]. The latter in particular became tion with Haarmann & Reimer in Holz- [44] even gave 35.7% of a-ionones, fairly popular, but no other myrcene de- minden and Laire & Co. in Paris, an ex- 21.1 % of p-ionone, and 18.2% of dihy- rivative had more influence on perfumery tensive search for the odorous principle dro-p-ionone, which makes together 75% than Iso E Super® (10), as a better quality of violets (Viola odorata L., fam. Viol- of the headspace. of IsocycIemone E® was named later. aceae). However, violet flower oil was This chemical confusion did however Curiously enough, the patented main too expensive to be used for isolation and not injure the commercial success of the constituent 10 [46] of Iso E Super® was structure elucidation with traditional ionones (9). Together with the stronger found to be almost odorless by GC-olfac- techniques. Therefore, assuming the methylionones, which were also discov- tometry (47]. 10 possesses an odor same odorous principle, the similarly ered by Tiemann in 1893 [45], employing threshold of around 500 ng/I, while the smelling but more readily available and ethyl methyl ketone instead of acetone, impurity 13 (ca. 5%) with a threshold of much cheaper orris root oil (Iris paUida the a-/p-ionones (9) revolutionized per- only 5 pg/l is responsible for the pleasant Lam., fam. Iridaceae) was used instead for these investigations. Another advan- tage of orris root oil was the high content of its odorous principle, which can reach up to 70-80% in the oil. Via its phenylhy- o drazone, Tiemann and Kruger [38] isolat- ..~ ed the odorous principle irone and (incor- (fJ " 0 13 rectly) determined its molecular formula "Iso E Super Plus" by elemental analysis as C'3H200. This ~ (1990) 0.005 ng/I incorrect elemental analysis together a.-/~-ionone with some oxidative degradation prod- (1893) 0.8 ng/I W2Koavone ucts let them believe that irone could be a -----·-----·------1 (1982) 75 ng/I , base-catalyzed condensation product of . acetone with citra!. But the product of I I • I I I I I I!· I· ; • I • this reaction possessed 'a strange but not o o o o 0 0 0 0 O' 0 0 0> o N ~ ~ ~ ~ ~: m 00 0> a; al very characteristic odor'; however, ~ ~ m m ,....,....m m m m. m 0> 8 ~ .- ~ ,....:.- ~ C\I when they cleaned the glassware with di- 10 i luted sulfuric acid, Tiemanns nose de- Iso E Super ------~ tected the typical scent of violets in (1972) 500 ng/I bloom. What they had actually discov- 11 14 ered was ionone (9), and because of the Timberol Georgywood similar smell and their incorrect elemen- ~ ..~ (1979) 26 ng/I tal analysis of the earlier isolated irone, (1996) 0.015 ng/I they concluded that the latter compound ~o must be a double-bond isomer of the syn- thesized ionone (9). The correct constitu- tion of the irones, homologs of the ion ones (9), was not established until more than 50 years later, in 1947, by Naves et al. of Givaudan [39], and inde- Fig. 2. The ionone/woody timeline FLAVOURS AND FRAGRANCES 383 CHIMIA 2001,55, No.5 woody-ambery odor characteristics of like Iso E Super® (10). The Timberol® product was sold under different names Iso E Super® [47]. At Givaudan, this im- chapter, however, illustrates the strategy such as Sandela®, (16) (Givaudan [62]), purity 13 became known as 'Iso E Super of switching to more and more powerful Sandel H&RTM (Haarmann & Reimer), Plus' and was patented in 1990 [48]. It isomers of successful odorants. Sandiff®, (IFF), Santalex®, (Takasago), served as a lead for more powerful Koavone® (10), acetyl diisoamylene, and Santalydol™ (in Russia). It took woody-ambery odorants, of which Geor- was the first (prominent) example for the more than half a century to identify the gywood® (14), with an odor threshold of application of molecular-modeling tech- odorous principle that constituted initial- 15 pg/l, turned out to be one of the best. niques in the design of odorants. A super- ly only 0.5% of these complex isomeric Its synthesis by Diels-Alder reaction of position analysis with IO-methyl ionone mixtures. The relative configurations of homomyrcene with methyl isopropenyl was applied to rationalize their similar the active stereoisomers, 3-trans-isocam- ketone and subsequent acid-catalyzed cy- odor profiles [57]. On paper, Koavone® phylcyclohexanols with axial OH groups clization is straightforward [49]. Georgy- (10) can be regarded as a seco-7,8- (16), were established by Demole and wood® (14), named after its inventor dimethylionone. Already in 1962, Ses- coworkers in 1969 [63] and their absolute Georg Frater, was not introduced into tanj [58] had shown that cutting out the configurations published only two years perfumery until 1996 and still is reserved carbon atom C(3) does not alter the odor ago in a Japanese patent [64]. The con- for internal (captive) use only. Recently, characteristics of ~-ionone (9). So either tent of the sandalwood-smelling isomers Mark Erman of Millenium Specialty with the help of computers or by making 16 in these complex mixtures of terpenyl- Chemicals [50] found conditions to en- use of Dreiding models the rational de- cyclohexanols is still quite low, in spite rich the content of 13 in the cyclization sign of odorants definitely made impor- of process improvements consisting step of the Iso E Super® synthesis by em- tant contributions to the palette of the mainly in oxidation of the hydrogenation ploying phosphoric acid in methanol - so perfumer, and certainly will continue to product to the corresponding cyc1ohex- more than hundred years after Tiemann, do so in the future. Koavone conveys lift anones and subsequent catalytic reduc- there is still work on this cationic cycliza- and elegance to accords with methyl tion. Using hydrogenation with a catalyst tion. ionones and Iso E Super® (10) [56], system comprising ruthenium, triphenyl- Before we leave the family of ionone/ though its threshold is certainly not out- phosphine, ethylenediamine and potassi- woody odorants we have to mention two standing. um hydroxide in isopropanol, Takasago more milestones: Timberol® (11) of was able to increase the ratio of axial cy- Dragoco and Koavone® (12) of IFF. It 2.3. Sandalwood Synthetics clohexanols [65][66] and the content of had long been known that the diastereo- In the late 1930's, at the LG. Farben- 16 rose from 8% in Santalex®, to 24% in meric mixture of the tetrahydroionols industrie, Abt. Riechstoffe, a number of Super Santalex [65]. The successful in- [51] possesses only very weak and un- diverse olefins were reacted with phenols troduction of these first synthetic sandal- characteristic odor notes, but if the side in a random approach, targeting at floral wood oil substitutes triggered not only a chain is elongated by just two carbon at- odorants, and smelling for instance like more general use of sandalwood notes in oms, a surprisingly powerful woody- violet, iris and lily of the valley [59]. The perfumery, but also the synthesis of many powdery odorant of animalic, steroid- standard sequence consisted of acid-cata- other molecules structurally more or less type tonality is obtained. L -(2,2,6-Tri- lyzed alkylation, hydrogenation ofthe ar- similar to 16 and the santalols [5][6]. methylcyclohex-l-yl)hexan-3-01 (11) was omatic ring and oxidation to ketones. However, only Osyrol® (17, Bush Boake discovered by Klein and Rojahn of Drag- When Albert Weissenborn, a former stu- Allen [67]) turned out to be commercial- oco [52], and introduced into perfumery dent of OUo Wallach, hydrogenated a ly successful and until today remains the as Timberol®. Its success inspired the re- mixture of terpenylphenols obtained by only acyclic material of sandalwood searchers of Firmenich to investigate the boron trifluoride catalyzed alkylation of smell. structure-odor correlation of related guaiacol with camphene, he discovered a The real breakthrough in sandalwood ionols [53], and they found the attractive product mixture with a strong sandal- synthetics is however due to another for- steroid-type note of 11 to be mainly due wood odor. Sandalwood oil (Santalum tuitous finding, claimed in 1968 in an to the trans-isomer with both cyclohex- album L.), documented already 2000 BC East Gennan patent [68], one year before ane ring substituents in equatorial posi- in one of the oldest pieces of Indian liter- Demole published the configuration tions. Firmenich introduced this com- ature, the Ramayana, has long been a pre- of the odoriferous isocamphylcyclo- pound as Norlimbanol® for captive use. cious ingredient not only of the Indian hexanols 16. Using inexpensive a-camp- Later also all four trans-enantiomers and Islamic culture but also of ancient holenic aldehyde, Manfred Miihlstadt et have been prepared in enantiomerically European perfumery, and its affordable at. of the VEB Miltitz, formerly the re- pure form, and the configuration of the price allowed its use even in higher con- nowned and initially biggest flavor and hydroxy-bearing carbon atom was found centrations, mainly in oriental fine fra- fragrance company Schimmel & Co., to be of utmost importance [54][55]. grances. were the first to prepare substituted 4- Both (3R)-trans-diastereoisomers are The patent describing Weissenborn's (2,2,3 -trimeth yIcycl open t-3-enyI)butan- odorless, while the (+)-(3S, l' R,6' S)-Nor- discovery was filed in 1942, but due to l-ols [68], just a few years before the limbanol® was found to be the most pow- the events of World War II was published price of natural sandalwood oil suddenly erful and most steroid-like smelling ste- only ten years later [60]. Together with a increased - from 40 $/kg in 1973 to ap- reoisomer of Timberol® (11). It has been vast amount of other chemical data of the proximately 210 $/kg at the end of 1974. introduced recently as 'Dextro-Norlimb- I.G. Farben and other companies, the in- The allylic aIcohol19 and its 2-ethyl ana- anol' [56], but is also reserved for captive formation was collected by US Army In- log were the first two representatives of use only. In the future, we will probably telligence, and was presented to the per- this new class of sandalwood odorants, also see 'overdoses' of Timberol®-type fumery community by Byers in 1947 though the original description in the pat- notes in perfumery, though these materi- [61]. The Weissenborn process was soon ent as 'fine, resembling musk and sandal- als cannot be used like an ionone (9) or applied by different companies, and the wood' [68] was somehow misleading, FLAVOURS AND FRAGRANCES 384

CHIMIA 2001, 55, No, 5 since the musk facet is certainly not one of their main olfactory characteristics. 16 OH Nevertheless, their real olfactory value for Sandela '-X 1 perfumery was discovered immediately. (1960) 8.3 ng/l ~ "

ary benefits, like for instance insect re- pealing to other persons, but should 'cre- use new and unusual odorants or to over- pellent activity. It is therefore obvious to ate around you the smell that you like' - dose existing materials long before these use fragrance materials also for their 'your own air' [99]. Consequently these are accepted in market tests. antimicrobial properties, and to improve should be used not only on skin, but also these activities deliberately by structure on furniture and clothes, as air fresheners Note on trademarks modifications. Although this concept has and pillow sprays, to clean overhead Words which we know or have reason to been discussed for a long time, it only transparencies or CD boxes - all in one. believe constitute registered trademarks are recently received more attention, since The first two were named 'Odeur 53' designated as such. However, neither the pres- ence nor the absence of such designation should cases of resistance to the widely used an- [100] and 'Odeur 71' [101], playing with be regarded as affecting the legal status of any tibacterial agents like Triclosan were re- images like 'cellulosic smell', the 'min- trademark. ported. Fragrance ingredients such as eral intensity of carbon', a 'salty taste of a Received: March 28, 2001 eugenol, carvacrol and thymol are known battery' or 'the smell of dust on a hot to have bactericidal activity. However, light bulb'. What sounds like olfactory their use is limited because at a certain action paintings, are actually quite mono- concentration their odor becomes un- lithic compositions, in the case of 'Odeur pleasant. In order to overcome this prob- 53' with over 63% of one single odorant lem, fragrance chemists have been look- - a portrait of Hedione® [6]. The concept [1] G. Duke, on 'Illusions', Warner Bros. ing for compounds that not only exhibit of sheer 'single-note' perfumes featuring, Records Inc., Burbank, 1995, 9362- pleasant odor characteristics, even in for instance, flowers (soliflores like 45755-2, track 5. higher concentrations, but also possess 'Rosa Magnifica', Aqua Allegoria, Guer- [2] The Metropolitan Museum of Art, 'Scents good antibacterial activity [98]. Today, lain, 1998 [102]), leaves (e.g. 'Shiso', of Time-Perfume from Ancient Egypt to new odorants are therefore routinely Comme des gar\ons, parfumsP AR- the 2ISt Century', 1st edition, Ed. E.T. screened for these secondary benefits. FUMS, 2001 [103]) or classic raw mate- Morris, Bulfinch Press, Boston, 1999. [3] L.P. Somogyi, Chern. & Ind. 1996 (March The search for performant molecules rials (e.g. 'PureVetiver', Azzaro Collec- 4), 170. with new and innovative odor character- tion, 2000 [104]), is today a major trend. [4J P.Z. Bedoukian, '50 Years of Perfumery istics is, however, still the main focus of But why not do the same around new & Flavoring Materials', Allured Publish- the industry and in almost every odor 'salty', 'milky' or 'vegetal' odorants in ing, Carol Stream, 1995. note there are still plenty of new odorants the future, as suggested by the Comme [5] G. Frater, lA. Bajgrowicz, P. Kraft, Tet- to be discovered; stronger in odor, more des gar~ons advertisement? rahedron 1998,54,7633. transparent or more easy to overdose, At the beginning of this paragraph, [6] P. Kraft, lA. Bajgrowicz, C. Denis, G. exhibiting better performance in special we mentioned market research and ad- Frater, Angew. Chern. 2000, 1/2, 3106; Angew. Chern. Int. Ed. 2000, 39, 2980. functional products, or possessing unique vertisement campaigns, certainly needed [7] K. Bauer, D. Garbe, H. Surburg, 'Com- combinations of different odor tonalities. and justified for big international product mon Fragrance and Flavor Materials', 3rd There are endless possibilities and varia- launches. But recently the Internet has completely revised edition, Wiley- YCH, tions, and in this article we have shown opened up a forum for smaller launches Weinheim,1997. just some motivations and driving forces and more experimental perfumes that [8] A. Baur, Ber. Dtsch. Chern. Ges. 1891,24, for the development of a few prominent never existed before. For his 'Editions de 2832. odoants. Current trends in the chemistry Parfums' Frederic Malle gave (promi- [9] A. Baur- Thurgau, Ber. Dtsch. Chern. Ges. 1898,31, 1344. of odorants were presented in a recent re- nent) perfumers total freedom to create [10] H. Walbaum, J. Prakt. Chern. 1906, 73, view [6]. rare scents without norms or limits. 488. We close this review with a glance at These authentic artistic creations are all [11] L. Ruzicka, M. Stoll, H. Schinz, He/v. the latest trends in perfumery. Trends in presented in the same bottle, with the Chirn. Acta 1926, 9, 1008. perfumery have always influenced the name of the perfumer and the name of the [12] A. Baeyer, Ber. Dtsch. Chern. Ges. 1885, development of new odorants. Tradition- fragrance as given by the perfumer [105]. 18,2269. ally there was a 'tickle-down' phenome- Two examples are 'Angeliques sous la [13] L. Ruzicka, M. Stoll, H. Schinz, He/v. non of odor notes from luxury fine fra- pluie' from Jean-Claude Ellena, a bou- Chirn. Acta 1926, 9, 249. [14] G. Ohloff, Chirnia 1987, 41, ]81. grances via mass-market perfumes into quet of angelicas after the rain, and 'Lip- [15] L. Ruzicka, He/v. Chirn. Acta 1926, 9, personal & laundry care, and even house- stick rose' from Ralf Schwieger, the sym- 230. hold products. Today, fine fragrances bolization of pure powdered floral har- []6] M. Kerschbaum, Ber. Dtsch. Chern. Ges. perfumers are inspired to a great extent mony. These fragrances can be ordered 1927,60,902. by odor notes used in the cosmetic and via Internet [106] or bought in a little [17] E.W. Spanagel, W.H. Carothers, J. Arn. toiletries segment. One example was the shop at the Rue de Grenelle in Paris; and Chern. Soc. 1936, 58, 654. [18] G. Wilke, B. Bogdanovic, P. Bomer, H. pear trend, which started in personal care needless to say there is no market re- Breil, P. Hardt, P. Heimbach, G. Herr- products and then spread to fine fra- search or advertisement campaign behind mann, H.-J. Kaminsky, W. Keirn, M. grances [6]. The attribute 'fresh and the range. Another paradise for unusual Kroner, H. Mi.iller, E.W. Mi.iller, W. clean' is not only a catchy phrase when it scents is the Salons du Palais Royal Oberkirch, J. Schneider, l Stefeder, K. comes to fabric care, but does frequently Shiseido at the Rue de Valois in Paris, Tanaka, K. Weyer, Angew. Chern. 1963, occur in fine-fragrance briefs. So 'fresh managed by Serge Lutens [107]. Besides 75, 10; Angew. Chern. Int. Ed. Engl. 1963, and clean' green top notes are currently a series of exclusive eaux de parfums, 2,105. en vogue in fine fragrances, smell for in- 'Feminite du Bois' (Shiseido, 1992) with []9] J. Becker, G. Ohloff, Helv. Chirn. Acta 1971,54,2889. stance 'Truthfem.' (C. Klein, 2000). its overdose of 43% of Iso E Super®(10) [20] R. Hopp, K. Bauer (Haarmann & Reimer), The Japanese designer Rei Kawakubo also had its origins there. Shops of this Ger. Offen. DE 2 136496,1973. recently promoted the rebellious concept kind could bear and catalyze new trends, [2]] K. Fuchs (Polak's Frutal Works), US 2 of 'anti-peifumes' that should not be ap- and the people behind them could dare to 759 022, 1956. FLAVOURS AND FRAGRANCES 387

CHIMIA 2001.55. NO.5

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