Creating the ‘magic’ element in fragrances

 These compounds are the fundamental basis from which are created fragrances (= perfume oils) and flavours for non-food and food or oral care applications, respectively. With a few historical exceptions only natural or natureidentical aroma chemicals (EU definition) are utilised for flavour creations,1 while all toxicologically safe compounds2 can be used in fragrances, if they are registered according to relevant chemical legislation and in due course to REACH.3 This article will focus only on aroma chemicals used in perfumery. Provided will be insights into aroma chemicals and their importance to create the magic smell in fragrances.

Origin and classification of aroma chemicals

The majority of aroma chemicals are obtained today through chemical synthesis, but natural raw materials still play an important role in the perfumer’s palette.4 Natural raw materials are today mainly derived from plants. Animal derived products are substituted in modern perfumery through synthetic equivalents to support the protection of species and therefore are mentioned here only for historic reasons. Gland secretions from civet cats (Civettictis civetta and Viverra zibetha), musk deers (Moschus moschiferus) and beavers (Castor fiber), were once used to obtain civet, musk and castoreum, respectively. Also a metabolic product from sperm whales (Physeter catodon) called ambergris or ambra when processed could be found in the ancient perfumer’s pallet. While products from mammals are no longer in use, one inexhaustible metabolic product from an insect, beeswax from honey bees (Apris mellifera), is still processed to manufacture beeswax absolute. Approximately 250 plant species are used to produce more than 500 different natural products. They are obtained from various plant parts such as flowers, fruits, peels, leaves, barks, seeds, woods, roots, and also resinous exudates by either distillation, mechanical separation (“pressing”) or extraction with various solvents including supercritical CO2. Products produced via steam / water distillation or cold pressing are by definition called essential oils. Solvent extracts are either called concretes or resinoids. The latter are obtained from plant exudates with solvents such as ethanol, methanol etc, while concretes are extracted from various plant parts with non-polar solvents (hexane, petroleum ether, toluene etc). Concretes are rarely used in perfumery due to solubility issues. However, the corresponding wax-free absolutes are highly appreciated natural raw materials in perfumery. For this purpose the concrete is taken up in ethanol, cooled, filtered and the filtrate is concentrated under reduced pressure to obtain delicate smelling absolutes. Composition and consequential odour of natural products is influenced by external factors such as place of origin, temperature, rain and soil. Furthermore, these external factors can also affect price and availability. Aroma chemicals obtained by industrial synthesis are more predictable in terms of composition, odour, price and availability. Slight variations in odour profile can be the result of different manufacturing processes and distillation capabilities. Synthetic aroma chemicals can be grouped into three classes: commodities, specialties and captives (Table 1). Captives are considered the most important compounds of the individual fragrance houses due to the fact that they are only available to the manufacturer and protected by patents (Fig. 1). Dominant players in this field are Symrise, Firmenich, Givaudan, IFF and Takasago. Captives can give fragrances the distinctive note, which makes them impossible to copy. Captives can be also classified as captive specialties. Specialties are sometimes also linked to a unique manufacturing process or technology, which limits the amount of producers to a few or only one. Such specialties or processes often also enjoy patent protection. Commodities on the other hand are normally produced in bulk quantities and were introduced to the market usually years ago and therefore no longer have patent coverage. Today commodities are often produced in China and India due to price pressure. Despite the large amount of existing aroma chemicals, the search for, and synthesis of, new outstanding molecules are still integral parts of fragrance and flavour research.

Searching and synthesis

Nature still remains an indispensable and inexhaustible source for new ideas and odour directions. But today equally important are new reaction types (e.g. metathesis etc), reaction technologies and reactants which help chemists to generate interesting molecules. The current approach toward new aroma chemicals is always multidisciplinary and includes, beside synthesis and analytical practices, also sensory and performance aspects. New aroma chemicals should have first and foremost outstanding odour properties. Searching for high impact chemicals is another key priority of the industry due to the fact that fragrance dosage is steadily reduced and fragrance price decrease is an ongoing topic. Moreover, ingredients must bring additional benefits such as improved substantivity or blooming and an enhanced performance in base formulations. Without any exception all compounds must be toxicologically safe (no sensitising or allergenic properties). Therefore the search for substitutes of the restricted 26 potential fragrance allergens (commonly known as the COLIPA list)7 is a topic of continuing discussion. These 26 compounds need to be labelled in the EU if dosage exceeds 0.01% in finished cosmetic rinse-off products and 0.001% in leave-on applications. In addition, state-of-the-art aroma chemicals must be eco-toxicologically benign (with excellent biodegradable performance) to enable global use. Eco-toxicological considerations were among drivers for the development of new musk odourants,8 beside the importance of musk in odour terms. While nitro-musks are nearly not biodegradable, polycyclic musks (PCM) have better properties but still present problems in this regard. Only macro-cyclic musks (MCM) and the new fourth class of musk compounds, which was recently introduced and which had Helvetolide® as one example, provided a complete answer (Fig. 2). Synthetic organic chemists in the fragrance industry have only two restrictions: their molecules need to be volatile and must give-off an odour.9 This means that the molecular mass should not exceed approximately 300 and compounds should not be too polar. Very polar compounds or molecules having a higher mass are normally non-volatile and therefore odourless. Main elements used in aroma chemicals are carbon (C), hydrogen (H) and oxygen (O) and less frequently nitrogen (N) and sulfur (S). They can be combined in any thinkable way: linear, branched, cyclic, aliphatic, aromatic etc. Nearly all functional groups can be found in aroma chemicals: double, triple bonds, alcohols, phenols, ethers /epoxides, aldehydes, ketones, acetales, esters /lactones, carbonates, nitriles, oximes, amides, amines, imines, nitro groups, thiols, thioethers, thioacetales and others. The difficulty in aroma chemical synthesis is linked to the non-existence of a key-lock principle in odour perception.10 Human olfactory receptors11 in the nose are normally not selective and operate in a combinatorial mode12 meaning that one odourant receptor recognises multiple odourants and that one odourant is recognised by multiple odourant receptors, but that different odourants are recognised by different combinations of odourant receptors. Structure-odour-relationship predications have therefore their limitations and are often nearly impossible to make.13 This means similar structures can have a similar or different odour, but also different structures can elicit a similar odour (see various musk odourants8 in Fig. 2). Small changes in a molecule can lead to big as well as small variations in odour profile and the same is true for isomers [molecules having the same molecular formula (number and types of atoms), but different constitutional formula] as shown for the structural isomers Calone 1951® and Conoline®.14 Stereoisomers/configurational isomers can show the same phenomenon, for example geometric isomers (= E/Z or cis/trans) like (E)- and (Z)-4-heptenal (Fig. 3). As in other biological processes where receptors are involved, even enantiomers (one asymmetric C-atom) and diastereoisomers (multiple asymmetric C-atoms) can be distinguished. Such chiral odourants can show no or a very pronounced odour difference as shown for carvone and iso-b-bisabolol15 (Fig. 4) as well as intensity differences.6d(i),16 Today, creative organic chemists can synthesise nearly every molecule on planet earth inspired either by nature or the chemist’s imagination if price and timelines are excluded. However, the price of aroma chemicals is often an important criterion during development. This does not mean that only “cheap” molecules are developed: price, performance, odour intensity and character are unambiguously linked meaning a high impact, excellent performing molecule with outstanding odour properties can justify an expensive multi-step synthesis. After the molecule is synthesised and fully characterised via analytical methods it has to pass various evaluations by perfumers including sensory investigations (odour threshold, blooming, diffusivity etc) and performance tests in different media (e.g. shampoo, powder detergent). Toxicological (acute oral toxicity, skin irritation and sensitisation etc) and eco-toxicological data finally decide if a molecule can be added to the global perfumer’s pallet or not. The development of new aroma chemicals is a costly (Table 2) and challenging exercise but it is worth the money and effort due to the fact that new aroma chemicals are key ingredients of fragrances. They are therefore considered the most important innovation in the fragrance industry.

 Definition, stability and odour of fragrances

Fragrances are created by a perfumer having a unique talent that can be compared to musicians or artists.17 As the latter two work with a palette of single musical notes or colors to create their masterpieces, perfumers harmoniously combine single aroma chemicals to create the magic smell. Perfumers today use approximately 1,200 aroma chemicals of various odour directions to create fragrances for different applications. Fragrances can be therefore defined as complex mixtures of aroma chemicals created for non-food applications. They are normally liquids emitting at least in diluted form a pleasant smell for humans and contain in average approximately 40 to 100 single ingredients in various dosage levels (Fig. 5). Fragrances are normally created for individual applications (soap, detergent, fine fragrance etc) and dosed in the finished product between 0.1% and 20% (Table 3). Different applications often require individual fragrances and therefore fragrances should not necessarily be exchanged between them. This means a fragrance created for a blue shower gel must not be colour stable in a white soap or can smell even strange in an acid cleaner. It is always advisable for customers to seek input from the respective fragrance house before a switch-over of an existing fragrance to another application is considered. To rule out interactions between fragrance and ingredients of the base formulation, fragrances are stability tested in the respective application at elevated temperatures to simulate prolonged shelf life conditions and to guarantee a stable product. These tests include, beside colour and UV light stability, also odour evaluation – profile and strength. The main purpose to fragrance a product is first and foremost to create a pleasant scent sensation for endcustomers, but sometimes also to cover unpleasant odours from the base formulation. From the five senses (sight, hearing, taste, touch and smell) smell or better chemoreception is probably one of the oldest.19 Odour perception in humans is still not fully understood. The process starts with an interaction of odourants with receptors of the olfactory epithelium in the nose. Signals are then sent for first processing to the olfactory bulb and from there to various structures in the human brain beside others to parts of the limbic system – an area where also emotions and memory have their origin.10,20 This link explains why odour impressions can trigger such strong emotions in humans, and all readers probably can remember the experience of subconsciously perceiving a scent and suddenly being reminded of a childhood memory or some other long-forgotten events from the past. Therefore emotional connection via scent, beside advertisement power and brand loyalty, are main purchase or repurchase criteria for a product.21 Scent is directly linked to the perfume oils in the product. From the olfactory point of view fragrances normally consist of three parts: top, middle or heart and base note, interacting harmoniously with each other. The most volatile part of a fragrance is the top note giving off the first impressions such as freshness and impact. It is the “hook” of the fragrance which attracts user’s attention and is often a very important purchase criterion, especially for fine fragrances. But it lasts normally only up to 15 minutes before it evaporates. The heart or middle note is less volatile and core or heart of a fragrance. It gives volume or body and can last between 15 minutes and 6 hours. The long-lasting part, which gives substantivity, is the base note – the heavier part of a fragrance. It has an evaporation time of more than 6 hours and can be perceived up to 24 hours or much longer. These three parts of a fragrance can be equally balanced, but individual parts can be also over-represented. Fragrance structure can be visualised in the olfactory pyramid, a tool to understand design and evolution over time (Fig. 6). Everybody who has ever tried to verbalise sensory impressions knows the difficulties. We should be well aware of our language restrictions in this area. Different connotations, age, our history, cultural background and many other factors play also a role in this context. However, it is important for a successful fragrance house to speak a common fragrance language at least within the company. Symrise created a system called “Fragrance Genealogy”. This genealogy groups a fragrance into one of 11 families. A family is considered to be the dominant character of fragrance. Four of the 11 families are defined by structure (floriental, fougère, oriental and chypre) while the other 7 are characterised by main ingredients (citrus, green, mint, fruity, floral, woody and edible). In addition our 10 sub-families and 42 specifiers allow an even more detailed description of a fragrance. But words can hardly describe a magic smell. You need to use your sense of smell to be inspired and emotionally connected.

Summary

Aroma chemicals and fragrances are unambiguously linked together like Yin and Yang.22 This article can only give a brief insight into this fascinating world.23 Searching for, and synthesis of, new aroma chemicals will continue to be an integral part of the fragrance industry. This will be definitively influenced by a more detailed understanding of the human sense of smell, but despite the recent progress in this field, a rational odourant design seems to be elusive. The creativity and experience of synthetic organic chemists will remain the key drivers for successful creation of new and exiting aroma chemicals.24 New areas will be explored in more detail like fragrance precursors,25 and secondary benefits of aroma chemicals or non-volatile / nonsmelling ingredients and their influence on fragrance performance. Aroma chemicals per se are indispensable tools to enable perfumers to create masterpieces – fragrances eliciting the magic smell.

Footnote
• This article is derived from the lecture entitled “Fragrances: Creating the Magic Smell” at Formulate Asia 2008 – From Concept to Reality, 30-31 October 2008, Singapore.

References
1 Ziegler H. (2007) Flavourings (2nd ed.), Wiley- VCH, Weinheim. 2 For details see home pages of (a) IFRA: http://www.ifraorg.org/; (b) RIFM: http://www.rifm.org/; (c) COLIPA: http://www.colipa.eu/ 3 For more information on REACH (= Registration, Evaluation, Authorisation and Restriction of Chemical substances) see: http://www.reach-helpdesk.de/en/ Homepage.html?__nnn=true. 4 Surburg H., Panten J. (2006) Common fragrance and flavor materials (5th ed.), Wiley-VCH, Weinheim. 5 Trade names, brands, registered trademarks etc used in this article, even when not marked as such, are not to be considered unprotected by law. Neither the presence nor the absence of such designation should be regarded as affecting the legal status of any trademark. 6 (a) Ambrocenide®: Panten J., Bertram H.-J., Surburg H. (2004) New woody and ambery notes from cedarwood and turpentine oil. Chem. Biodiversity, 1, 1936-1948; (b) Paradisamide®: Perring K.D., Bradshaw D.J., Behan J.M., Cawkill P.M. (2004) Improvements in or relating to perfume compositions. Quest International B.V. now Givaudan S.A. WO2004009750, (c) Prismantol®: Narula A.P.S. (2004) The Search for new fragrance ingredients for functional perfumery. Chem. Biodiversity, 1, 1992-2000; (d) Thesaron®: (i) Yamamoto T., Shimada A., Ohmoto T., Matsuda H., Ogura M., Kanisawa T. (2004) Olfactory study on optically active citronellyl derivatives. Flav. Fragr. J., 19, 121-133; (ii) Yamamoto T., Ujihara H., Watanabe S., Harada M., Matsuda H., Hagiwara T. (2003) Synthesis and odor of optically active trans-2,2,6-trimethylcyclohexyl methyl ketones and their related compounds. Tetrahedron, 59, 517-524; (e) Vulcanolide®: (i) Fehr C., Chaptal-Gradoz N., Galindo J. (2002) Synthesis of (-)-Vulcanolide® by enantioselective protonation. Chem. Eur. J., 8, 853-858; (ii) Fehr C., Chaptal-Gradoz N. (2002) Syntheses of the enantiomers of Vulcanolide®. Helv. Chim. Acta, 85, 533-543. 7 Potential fragrance allergens as defined by the SCCNFP (= Scientific Committee on Cosmetic and Non-Food Products) and included in the 7th Amendment to the European Cosmetics Directive for the purpose of labelling in finished cosmetic products. For details see: (a) Bassereau M., Chaintreau A., Duperrex S., Joulain D., Leijs H., Loesing G., Owen N., Sherlock A., Schippa C., Thorel P.-J., Vey M. (2007) GC-MS quantification of suspected volatile allergens in fragrances. 2. Data treatment strategies and method performances. J. Agric. Food Chem., 55, 25-31; (b) Leijs H., Broekhans J., van Pelt L., Mussinan C. (2005) Quantitative analysis of the 26 allergens for cosmetic labeling in fragrance raw materials and perfume oils. J. Agric. Food Chem., 53, 5487-5491; (c) http://www.ifraorg.org/Home/ Science+Regulatory/Analytical+Methods/ page.aspx/59?dg_p2=2&dg_p1=11 8 Kraft P., Popaj K. (2008) New musk odorants: (3E)-4-(2’-alkyl-5’,5’-dimethylcyclopent-1’- enyl)but-3-en-2-ones and (3E)-1-acetyl-3- alkylidene-4,4-dimethylcyclohexenes. Eur. J. Org. Chem., 4806-4814; (b) Eh M. (2004) New alicyclic musks: the fourth generation of musk odorants. Chem. Biodiversity, 1, 1975- 1984; (c) Kraft P. (2004) ‘Brain aided’ musk design. Chem. Biodiversity, 1, 1957-1974; (d) Kraft P., Eichenberger W. (2004) Synthesis and odor of aliphatic musks: discovery of a new class of odorants. Eur. J. Org. Chem., 354-365. 9 For reviews on recent developments see: (a) Kraft P., Bajgrowicz J.A., Denis C., Fráter G. (2000) Odds and trends: recent developments in the chemistry of odorants. Angew. Chem. Int. Ed., 39, 2980-3010; (b) Fráter G., Bajgrowicz J.A., Kraft P. (1998) Fragrance chemistry. Tetrahedron, 54, 7633-7703. 10 (a) Buck L.B. (2005) Unraveling the sense of smell (Nobel lecture). Angew. Chem. Int. Ed., 44, 6128-6140; (b) Axel R. (2005) Scents and sensibility: a molecular logic of olfactory perception (Nobel lecture). Angew. Chem. Int. Ed., 44, 6110-6127. 11 (a) Krautwurst D. (2008) Human olfactory receptor families and their odorants. Chem. Biodiversity, 5, 842-852; (b) Mombaerts P. (1999) Seven-transmembrane proteins as odorant and chemosensory receptors. Science, 286, 707-711. 12 Malnik B., Hirono J., Sato T., Buck L.B. (1999) Combinatorial receptor codes for odors. Cell, 96, 713-723. 13 Sell C. S. (2006) On the unpredictability of odor. Angew. Chem. Int. Ed., 45, 6254-6261. 14 (a) Hügel H.M., Drevermann B., Lingham A.R., Marriott P.J. (2008) Marine fragrance chemistry. Chem. Biodiversity, 5, 1034-1044; (a) Gaudin J.-M., Nikolaenko O., de Saint Laumer J.-Y., Winter B., Blanc P.-A. (2007) Structure-activity relationship in the domain of odorants having marine notes. Helv. Chim. Acta, 90, 1245- 1265, (c) Kraft P., Eichenberger W. (2003) Conception, characterization and correlation of new marine odorants. Eur. J. Org. Chem., 3735-3743. 15 Braun N.A., Meier M., Schmaus G., Hölscher B., Pickenhagen W. (2003) Enantioselectivity in odor perception: synthesis and olfactory properties of iso-‚-bisabolol, a new natural product. Helv. Chim. Acta, 86, 2698-2708. 16 For reviews see: (a) http://www.leffingwell.com/ chirality/chirality.htm; (b) Bentley R. (2006) The nose as a stereochemist: enantiomers and odor. Chem. Rev., 106, 4099-4112; (c) Leffingwell J.C. (2006) Chirality and odor perception: scents of precious woods. Chim. Oggi Chem. Today - Suppl. Chiral Technol., 24(4), 26-38; (d) Brenna E., Fuganti C., Serra S. (2003), Enantioselective perception of chiral odorants. Tetrahedron Asymmetry, 14, 1-42; (e) Kraft P., Fráter, G. (2001) Enantioselectivity of the musk odor sensation. Chirality, 13, 388- 394, (f) Boelens M.H., Boelens H., van Gemert L.J. (1993) Sensory properties of optical isomers. Perfum. Flavor., 18 (6), 1-16. 17 Ellena C. (2008) Perfume formulation: words and chats. Chem. Biodiversity, 5, 1147-1153. 18 Kraft P., Ledard C., Goutell P. (2007) From Rallet NO1 to Chanel NO5 versus Mademoiselle Chanel NO1. Perfum. Flavor., 32 (10), 36-48. 19 Krieger J., Breer H. (1999) Olfactory reception in invertebrates. Science, 286, 720-723. 20 (a) Hatt H. (2004) Molecular and cellular basis of human olfaction. Chem. Biodiversity, 1, 1857-1869; (b) Mori K., Nagao H., Yoshihara Y. (1999) The olfactory bulb: coding and processing of odor molecule information. Science, 286, 711-715. 21 Lindstrom M. (2005) Brand sense (1st ed.), Free Press, New York. 22 Schön G. (2008) ‘Escentric’ molecules. Chem. Biodiversity, 5, 1154-1158. 23 For more details see for example: (a) Sell C. (2008) Understanding Fragrance Chemistry (1st ed.), Allured Publishing, Carol Stream; (b) Sell C. (2006) The chemistry of fragrances (2nd ed.), Royal Society of Chemistry, Cambridge; (c) Rowe D.J. (2004) Chemistry and technology of flavors and fragrances (1st ed.), Blackwell Publishing, Oxford. 24 Gautschi M., Bajgrowicz J.A., Kraft P. (2001) Fragrance chemistry – milestones and perspectives. Chimia, 55, 379-387. 25 Herrmann A. (2007) Controlled release of volatiles under mild reaction conditions: from nature to everyday products. Angew. Chem. Int. Ed., 46, 5836-5863.