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2018 Natural Aroma Chemicals E-book
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Natural Aroma
Chemicals
- Natural sources and biotechnology
- High impact aroma chemistry
- Natural flavors
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with EMD Millipore as MilliporeSigma, the life science business
of Merck KGaA, Darmstadt, Germany, increases our offer to
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Our Offer
Over 1600 products, covering more than 120
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2018-10491
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Editor’s Note
From Source to Sense: Natural

Aroma Chemicals
DENIZ ATAMAN
Managing Editor
dataman@allured.com
2018 NATURAL E-BOOK
CONTENTS
6 Today’s Natural Aroma
Chemicals and their Sources
By David Rowe
10 The Future of Naturals in
O
the Fragrance Industry ur understanding of the complexity of life continues to grow as
By L. Denzil Phillips
organic chemistry adds more depth to the way we interact with
nature. The use of naturals, due to consumer perceptions of
19 Natural Aroma Chemicals: being safer, cleaner, healthier and more sustainable, is growing
More and Purer across personal care, household and cosmetics, as well as food and beverages
By David Rowe
categories. Yet, the term “natural” is still undefined by the industry, leaving
companies to rely more on transparency and safety when formulating with
22 Biological Systems and naturals. By the end of 2024, the global aroma chemicals market is expected
Flavors: Science, Technology to reach $6.57 billion with a CAGR of 6.2%a (to compare, the market was
and Applications
By Ivica Labuda valued at $3.85 billion in 2015). With this high demand comes challenges in
regulatory compliance, sourcing and developing new isolation techniques,
while balancing consumers’ affordability. Yet, creativity within constraints is
30 Learning From Nature: High-
certainly a cornerstone in F&F innovation.
Impact Aroma Chemistry
By David Brassington The future of F&F will rely heavily upon a combining nature and technol-
ogy. In this e-book, brought to you by MilliporeSigma (Sigma-Aldrich®), we
selected the most high impact articles surrounding natural aroma chemicals
33 Blending Technology and Natural
from Perfumer & Flavorist’s archives. You’ll find technical articles on new
By Jaime Gleason
sourcing techniques, sulfur aroma chemicals for savory, high impact aroma
chemistry and more. I hope you find useful tools to inspire innovative formu-
35 Evolving View of Natural Flavors lations and cost-effective, yet sustainable processes to help you in your work
By Dr. Luke Grocholl
for the flavors and fragrances of tomorrow.
38 Keeping Up With the Microbes We hope you enjoy this e-book. Happy learning to you.
By Michael Britten-Kelly
40 The Search for New

Aroma Chemicals
By Mans Boelens and Ronald Boelens
a Transparency Market Research: Aroma Chemicals Market
www.PerfumerFlavorist.com 3
Globally Inspired
Naturals
Natural ingredients that are sure to excite
your senses and bring regional tastes to your
next great formulation.
Find inspiration by downloading

our application guides by visiting us at:
SigmaAldrich.com/ff-learning-center
The life science business of

Merck KGaA, Darmstadt,
Germany operates as
MilliporeSigma in the U.S. and
Canada.
© 2018 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights
Reserved. MilliporeSigma, the vibrant M and Sigma-Aldrich are trademarks of
Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks are
the property of their respective owners. Detailed information on trademarks is
available via publicly accessible resources.
2017-10490 0318

Today’s Vol. 36 • December 2011
NA TURA L AROMA
Chemicals and their Sources
a
I
by David Rowe, Riverside Aromatics Ltd.
n the developed world, the desire for
natural flavors, and hence natural aroma
chemicals, continues unabated. Obtaining
natural aroma chemicals by direct isolation F-1. Dimethyl sulfide
from food sources is the oldest method of
obtaining such materials, and indeed, as S
H 3C CH3
has been noted before, isolation of materials
from natural sources is the de facto origin
of organic chemistry. It is the method that (1)
produces the largest volumes of natural
aroma chemicals, and it’s also the method
that is easiest for most lay persons to recognize
Whilst the basic techniques of distillation and
as natural, without needing to consult the
crystallization remain the cornerstones of isolation
definitions of EU 1334/2008 or the US Title 21
techniques, the increased demand for natural aroma
Code of Federal Regulations.
chemicals means that greater effort is expended in
aThis article is based in part on Chapter 10, “Natural Aroma Chemicals for isolating components at low concentrations, materi-
Use in Foods and Beverages,” in Natural Additives, Ingredients and Flavourings als that might be said to be “down in the noise” on
for Foods and Beverages, Edited by D. Baines and R. Seal, forthcoming from
Woodhead Publishing; ISBN# 978-1-84569-811-9. chromatographic traces. This is especially important
Reproduction in English or any other language of all or part of this article is strictly prohibited. © 2018 Allured Business Media.
6 2018 Natural Aroma Chemicals E-book | www.sigmaaldrich.com/Flavors-Fragrances

organoleptic impact and have a negative effect on
F-2. d-Limonene (2), p-menthen-8-thiol (3) and water solubility, are distilled off; the remaining pot
nootkatone (4) fraction is the folded oil. For example, grapefruit oil
can be folded to produce a terpene fraction, which
SH along with the ubiquitous d-limonene (2) contains
the grapefruit mercaptan, p-menthen-8-thiol (3) and
the less volatile material; the folded oil can be further
processed to produce the oxygenated sequiterpene
nootkatone (4, F-2).
O Orange oil, the cheapest and highest volume of
all the oils, can be processed to give d-limonene,
(2) (3) (4) aliphatic aldehydes such as octanal (5) and decanal
(6) from the terpene fraction, and the sesquiterpene
valencene (7) from the folded oil (F-3).
as the industry obtains materials as byproducts of Other examples of volatile derivatives are
either food processing or byproducts of obtaining a-pinene (8) and b-pinene (9) from pine oils;
other materials. Dimethyl sulfide (1, F-1) is a good these also yield a-terpineol (10). Mandarin oil is
example; this as the “item of commerce” has moved unusual in yielding a nitrogen derivative, methyl
from being a minor byproduct of mint oil produc- N-methylanthranilate (11; F-4).
tion to a product isolated from the effluent gasses of This approach is not unique to the citrus oils;
ethanol fermentation. for example, mint oils (Mentha arvensis and varia-
tions thereof) yield menthol (12) very easily, simply
Natural Aroma Chemicals from Essential Oils by cooling the oil and filtering off the resulting
and Extracts crystalline menthol. Distillation of the resulting dem-
This source is still the single most important entholized oil yields a terpene fraction, which can be
approach for the production of natural aroma fractionally distilled to give natural cis-3-hexenol (13;
chemicals, especially in terms of sheer volume. While F-5).
this article will try to avoid a “book of lists” approach Other important natural aroma chemicals from
featuring a table of citrus oils and their terpenes, it essential oils include linalool (14) from ho wood
is important to note
that citrus oils, pro-
duced in enormous
quantities both in F-3. Octanal (5), decanal (6) and valencene (7)
their own right and
as the byproducts of H H
the juice industry,
are of great com- O O
mercial importance
as sources of natural (5) (6) (7)
aroma chemicals
(including mono-
terpenes and their
derivatives). Some
of these chemicals
F-4. a-Pinene (8), b-pinene (9), a-terpineol (10) and methyl N-methylanthranilate (11)
are used to prepare
other natural aroma
OH
chemicals, usually
sesqui- and diter- O
penes and their
O
derivatives.1
Citrus oils are NH
often folded, i.e.
the more volatile
terpenes, frequently (8) (9) (10) (11)
hydrocarbons
which provide little
Less obvious, but also of great importance, is the
F-5. Menthol (12) and natural cis-3-hexenol (13) isolation from “off gasses.” Since aroma chemicals
are, by their nature, volatile components of food, it
should be no surprise that when food and related
natural materials are processed, useful materi-
OH als emerge as byproducts. Unless trapped or in
some way scrubbed from the effluent gasses, these
OH byproducts would fill the surrounding manufactur-
ing site’s area with an unwanted miasma. Those who
have lived or worked near to a brewery know the
strength of aromas that are given off in fermentation;
(12) (13) since this process is also used in the production of
fuel alcohol, a lot of such effluent gas is produced.
Trapping the volatiles, either cryogenically or by
oil, cinnamaldehyde (15) from cinnamon bark oil means of activated charcoal, both reduces the nui-
and (primarily) cassia oil, eugenol (16) from clove sance value of such odors and provides a feedstock
oil, and citral (17) from Litsea cubeba oil (F-6); in for natural aroma chemicals, particularly the earlier
the latter case, production is de facto solely for the mentioned dimethyl sulfide (1). Other examples
production of natural citral. include 2-methyltetrahydrofuranone (21), commonly
known as coffee furanone, from, most appropriately,
Natural Aroma Chemicals from Food the effluent gasses from coffee roasting, and trans-
Byproducts and Waste Streams 2,trans-4-decadienal, (22), which is produced in
This is potentially the most important approach the deodorization of vegetable oils (F-8). The latter
for the future. There are ethical issues arising from can also yield saturated aldehdyes such as octanal
the growth of non-food crops, most recently around (5) and decanal (6; F-3), highlighting an alternative
palm oil and its contribution to deforestation in route to the isolation from citrus oils mentioned
Indonesia. The growth of crops solely for “chemi- earlier. There is, of course, an assumption in this—
cals” is unlikely to win favor with the public. This that the nature of the processing doesn’t change
is especially a concern in the production of natural
aroma chemicals as marketing departments attempt
to associate the word natural with a green, unspoiled F-7. Benzaldehyde (18), 2-isobutylthiazole (19) and
picture—a veritable Garden of Eden. In this context, 2-isopropyl-4-methylthiazole (20)
green credentials deriving from the use of material,
which would otherwise be disposed of, can offer
H O
great advantage; sustainability is a good thing in N
N
chemistry, as well as marketing.
The stones, or pits, of peach and apricot can be S S
processed to give natural benzaldehyde (18). The
leaves and stems of tomato vine can be processed to
yield 2-isobutylthiazole (19) and 2-isopropyl-4-me- (18) (19) (20)
thylthiazole (20; F-7).
F-6. Linalool (14), cinnamaldehyde (15), eugenol (16) and citral (17)
H O
O O
OH OH
(14) (15) (16) (17)

and that the feedstock
remains essentially F-8. Dimenthyl sulfide (1), coffee furanone (21) and trans-2,trans-4-decadienal (22)
unaltered. The veg-
etable oils with longer O
shelf lives tend to be so
because they contain S
fewer unsaturated H3C CH3 O
components; might O
that also mean that it
contained less trans- (1) (21) (22)
2,trans-4-decadienal?
Future Trends
In terms of new aroma chemicals, continuing 1. Ethanol; flammable and non-halal
developments in isolations means that more materi- 2. Propylene glycol; petrochemical
als become available; however, the industry is on a 3. T
riacetin; made from glycerol, which can come
knife edge. Growing populations, especially in the from palm oil, one of the most vilified raw
developing countries, may lead to pressure to stop materials
the use of valuable agricultural land to, in effect, 4. M
CTs (medium chain triglycerides); synthe-
grow chemicals; at the moment it’s a rhetorical ques- sized from glycerol and carboxylic acids, which
tion (to which the author does not know the answer), can also be from palm oil
but is the best use of land in India to grow mint in 5. V
egetable oils; can be of GMO origin
order to make menthol, when the same material is 6. W
ater; at present, no one has identified halal,
available from non-agricultural sources? Whither kosher, organic, palm oil and GMO issues with
Litsea cubeba, grown solely to produce natural citral? water—though perhaps it’s only a matter of
Will a time come when petrochemical, currently a time?—however, despite these massive advan-
term of abuse, becomes fashionable, perhaps in the tages, there is the minor problem that most
service of the product claim “this flavor contains no aroma chemicals don’t dissolve in it
materials derived from food crops?”
In choosing to use a natural aroma chemical, or
Natural: Can We Have it Both Ways? even a solvent, issues above and beyond technical
The industry is operating in an environment in concerns such as solubility must be considered.
which marketing departments are trying to have
both “clean label” and an advantage over other
Address correspondence to David Rowe, Riverside Aromatics Ltd.,
suppliers. The difficulties associated with this,
23 Slader Business Park, Witney Road, Poole, Dorset BH17 0GP,
which are often associated with naturals, include
United Kingdom; david.rowe@riversidearomatics.com.
religious matters (kosher, halal), social concerns
such as sustainability, and fashions such as References
organic and GMO-free. This can best be illustrated, 1. DJ Rowe, Aroma Chemicals V: Natural Aroma Chemicals. In:
perhaps surprisingly, with solvents. Many natural Chemistry and Technology of Flavors and Fragrances. J Margetts,
materials are expensive per kilo; if they possess a ed., Wiley, Hoboken NJ (2009).
strong odor, then using them in solution, typically
at 1%, is a big advantage. But every solvent has
potential disadvantages:
Vol. 40 • July 2015
The Future of Naturals in

the Fragrance Industry

Can we really have a green, sustainable and natural fragrance industry?a
n L. Denzil Phillips
F
or at least 25 years the or just how small a percentage of plant-based ingre-
global fragrance and dients are used in most “natural” fragrances they
cosmetic industry has would probably no longer buy these products.
turned to nature to find As Judi Beerling of Organic Monitor points out,
inspiration and build its “Natural obviously has a big emotional hook for con-
corporate image. Global sumers. It seems somehow to make a fragrance ‘real,’
retail chains like Aveda, where talking about synthetic molecules does not.”
Body Shop, Kiehl’s and “Maybe I’m cynical,” says Jennifer Hirsch of
Yves Rocher, to name just Beauty Botanist, “but I think marketers really love
a few, have built their these terms that sound good, but that don’t have one
multimillion-dollar empires fixed agreed meaning so you can make it your own.
upon this green and natural image. Baby boomers, Natural is one of those.”
like myself, who were their early customers, were And how would the public react if they read
the first green warriors—the founders of Green Charles Sell’s excellent book “The Chemistry of
Peace, Friends of the Earth and the modern Fragrances,”b which clearly shows that the produc-
environmental movement. tion of many natural essential oils consumes more
fossil fuel, produces more carbon dioxide, more
The Origins of “Natural is Better” effluent and has more negative environmental
Over the last quarter of a century, fostered by impacts than many synthetic aroma chemicals.
clever media and advertising, we were all led to Sue Curtis of Neal’s Yard Remedies thinks the
believe that “natural” beauty products were better preoccupation with natural is much more obvious:
for our health and welfare, and also for our environ- “Given that there are at least 60,000 new synthetic
ment. All things man-made were, on the contrary, chemicals that we are being exposed to in the last
considered “synthetic,” harmful and unsustainable. 50 or so years ... it is hardly surprising that many
This highly simplified outlook continues today partly consumers are seeking out ‘natural’ ingredients in
because the fragrance industry does not want to say personal care products.” But, as she points out,
too much about how fragrances are really formu- “Using only natural ingredients in fragrance can be
lated, nor inform the public about how and where seen to be very limiting, especially as regards cre-
their aromatic ingredients are sourced, processed ating ‘lasting’ fragrance profiles, so it’s a challenge
and refined.
aA version of this article was presented during a lecture to the U.K.
There is a strong and fairly well-founded belief
Society of Cosmetic Chemists.
that if the pubic really knew what natural chemical bCS Sell, The Chemistry of Fragrances: From Perfumer to Consumer.
isolates and nature-identical aroma chemicals were RSC Paperbacks, Cambridge (2006)
Only where mechanization can be cost-effectively employed, as with chamomile (pictured) and lavender, can we expect to see sustainable natural florals still on the market.
At a Glance house Creative Perfumers, adds, “And when a
perfumer thinks of the words ‘sustainable fragrance,’
they will more likely associate this term with sustain-
In this article, L. Denzil Phillips offers some ability of price, color, longevity or other technical
insight into what more might be done to ensure requirements. They are unlikely to refer to the
the future of the natural fragrance industry and sustainability of a natural source.”
asks fundamental questions, including:
• Are the targets on sustainability set by Will the Green Pioneers Remain Green?
So much of the pioneering work in the natural
multinational fragrance companies realistic
field was undertaken by committed visionaries like
given that they operate in such a celebrity-
Anita Roddick, Horst Rechelbacher, Liz Earle and
driven mass market industry?
the like. Their drive and passion changed the whole
• Is a return to nature really possible bearing in
landscape of the modern beauty care industry.
mind the poor state and under-investment in
Now that most of them have moved on and their
the present day essential oil industry? companies are in the hands of global corporations,
• Is the fragrance industry correct in promoting will this commitment to nature and grassroots sup-
natural products when so many good nature- pliers remain, or will the drive to rapidly grow these
identical aroma chemicals exist whose brands and make them mass-market global com-
carbon footprint may actually be less than modities change their image and their procurement
that of cultivated aromatic plants? policy forever? Insiders certainly report of many
• Would biodiversity and the environment radical changes taking places in companies like Body
benefit more if the fragrance industry actually Shop and Jo Malone.
reduced its purchases of naturals, particularly Examples of corporate takeovers of founding
those sourced from wild and endangered natural brands include:
aromatic plants?
• Aveda by Estee Lauder
• Burts Bees by Clorox
• Body Shop by L’Oreal
that different companies choose to take on in • Liz Earle by Avon
different ways.” • Kiehl’s by L’Oreal
Hirsch agrees: “If we’re talking about a 100% • Joe Malone by Estee Lauder
natural fragrance, I think that is incredibly limiting • Frederic Malle by Estee Lauder
for the perfumer. And, in my experience, the fra- • Aveeno by Johnson & Johnson
grances that result don’t last on the skin in the same
way as synthetic and partially synthetic fragrances Perfume Lifecycles
do. Until that issue is resolved, I don’t see how 100% The 1984 edition of Michael Edwards’
plant-derived fragrances can compete.” “Fragrances of the World” listed just 38 new fra-
The green imperative has of course more drivers grance launches. As the author himself writes in
than simply the passion and willpower of the found- the introduction of his latest edition, “In my wildest
ers of these natural beauty retail chains. There has dreams, I could never have imagined that, 30 years
been a growing necessity for global multinationals to later, I would track more than 1,400 new fragrances
play a more active corporate role in society, as well in a single year (2014).”
as pressure from the public and competitors who The question on many fragrance formulators’
realized that going green and talking about sustain- minds is this: “How can we possibly build a sustain-
ability was a way of gaining market share, customer able green supply chain for even a small percentage
loyalty and product differentiation. of such new launches, especially when the majority
The triple-bottom-line approach to business, of them will be pulled from the shelf after 18 months
which combines economic, social and environ- for failing to achieve ever-more ambitious sales and
mental objectives into the economic model, is profit targets?”
how most people in the fragrance industry see the The sheer numbers of annual launches have
sustainability agenda. radically changed the way the fragrance industry
However, as Nidhimi Kohli, founder of www. works. Speed of creation is vital, and pressure
mybeautymatches.com, points out, “For the general on profit margins means that, particularly for
public, this word sustainability has little or no fragrance (as opposed to flavor) formulations, the
meaning in terms of buying beauty care products.” driving force determining raw material selection is
Anastasia Brozler, founder of bespoke fragrance price and availability.

As Brozler points out, “Sadly, fragrance is no of the rainforest, but also the dangers of its rapid
longer a luxury. It has become a commodity. Within disappearance. Could Sting or Justin Timberlake be
this [large] market, driven by mass marketing and a persuaded to launch a green perfume, and what will
gigantic global distribution network, ‘naturals’ are no be the brief they present to the fragrance house that
longer on the priority list of compounding houses. will make it for them?
Technical requirements, ongoing changes and
demands on regulations and documentation, and The Logic of Organic Fragrances
statistics based on success rates and low risk are all For the majority of buyers, natural beauty care
aspects that put pressure on perfumers to replace … products are simply those that include some unde-
natural oils with those made in a laboratory.” fined % of natural ingredients. A growing minority of
consumers feel that only organic products are truly
Unsustainable Celebrities natural and increasingly demand certified organic or
Getting a celebrity to help brand and promote biodynamic essential oils and fragrance products.
one’s perfume has become one of the most common Even if one sidesteps the problem of the
ways that the fragrance industry has tried to woo ever-growing number of overlapping and often
the younger generation to buy more fragrances. confusing standards used to define the organic and
However, as Kathy Phillips, international beauty natural beauty care sector, can the industry really
director for Conde Naste, points out, “Are any of create fragrances made with 20–30-plus different
these celebrities really interested in promoting green ingredients, all of which are organically certified?
and sustainable products, and do their increas- Aveda originally thought so, but soon found that
ingly Asian teenage followers really understand and the quantity and variety of ingredients needed far
support these principles?” And, anyway, how many exceeded what the organic essential oil industry
of these celebrities will be around to help in the fight could cost-effectively supply.
to produce a greener and more sustainable world? As Virginie Daniau of Parfum Parfait, a for-
The industry needs to mobilize green ambas- mulation expert, points out, “To test whether all
sadors and use celebrity adventure programs like ingredients in a completed formulation are indeed
those of Bear Grylls and Les Stroud to make millions organic is almost impossible, and hence no full audit
of viewers aware of not just the thrill and adventure trail exists. I seldom encourage my clients to go the
The process of distillation using water and steam is essentially an environmentally friendly one, so long as energy-efficient boilers and condenser systems are used.
organic route in perfume, unless it plays a central Today’s essential oil industry is a pale shadow of
role in their marketing strategy.” this former glorious past. In many countries, the
industry is not much more than a tourist attrac-
The State of the Aromatic Plant and Essential tion. When one visits the great former centers of
global essential oil production like Provence, France,
Oil Industry Plovdiv, Bulgaria, Florence, Italy, or even Cairo,
While the love affair with all things natural
Egypt, one will see an industry living off its past
continues on the high street, and more and more fra-
glory, selling samples and trinkets, rather than the
grances are launched each year, just what is the state
vibrant value-added agro-industrial sector that it
of the aromatic plant and essential oil industry at the
should be.
grassroots level? The answer is, by and large, bad.
Fragrance and flavor houses may refer to this
Rapidly increasing costs of land and labor and
glorious past in their brochures and promotional
lack of investment for more than 100 years in new
material, but may not even spend 10% of their
plant and equipment means that the essential oil
R&D budget on farm technology and agro-forestry
industry is basically much smaller and less developed
research. Admittedly, when a supply problem arises
today than it was when Ernest Guenther traveled the
they may make attempts to overcome bottlenecks by
world to research his magnificent book series, “The
undertaking some ad hoc projects, but a sustained
Essential Oils,” which were published in 1948. A
long-term program of global research, development
quick review of Guenther’s works reveals the follow-
and training in essential oil production and distilla-
ing remarkable statistics:
tion simply does not exist.
• 9,500 hectares of damascene roses were planted
in Bulgaria in 1912 Agricultural Challenges
• 2,021 tonnes of Mysore sandalwood was dis- As Joseph Hunwick, an expert on African
tilled in 1927 natural oils points out, “If you look at the websites
• 132 tonnes of Reunion geranium was exported of the World Bank, UN Food and Agricultural
in 1938 Organization, the European Commission, and the
• 1,500 tonnes of jasmine flowers were picked in Asian or African Development Bank you will find it
Southern France in 1927 hard to find a single project where aromatic plant
• 95 tonnes of Guyanese rosewood was harvested breeding, cultivation, storage and processing plays
in 1929 an important part.” But, he adds, “Growing and pro-
• 1,600 tonnes of Florence orris roots were picked cessing essential oil plants is an ideal small-farmer
in 1949 activity where poor and inaccessible farmers can
• 2,400 hectares of Bergamot were grown in make a reasonable living from a small patch of land.”
Calabria in 1956 “This cannot be said for green chemistry, however
• 300 tonnes of Parma violets were picked in environmentally friendly it may be,” says Hirsch.
Grasse in 1900 While technological developments in the field
• 8,000 hectares of geraniums were planted in of extraction, analysis and fragrance formulation
Algeria in 1925 become ever-more sophisticated, the technology
used to cultivate and harvest aromatic plants is not
very different from what it was 100 years ago. With

few exceptions, the planting and harvesting of these
plants involve large amounts of labor, most of which F-1. The relationship between price and rarity for
is provided by women and children. various botanicals
This labor supply is rapidly drying up, not just in
Europe and North America, but also in India, Egypt, NATURALS PYRAMID
Morocco and China. Costs of production of essential
oils that cannot be mechanized will continue to rise
as labor becomes more and more scarce and enforce- P
ment of restrictions on the use of child labor extend R R
further across the world. I A
FLORALS R
C
I
Sustainable Processing of Naturals E
BARKS & ROOTS T
Distillation is one of the world’s oldest profes- Y
sions. The first distillation units were found in the HERBS & AROMA GRASSES
Indus valley 4,000 years ago. Without the discovery
LEAVES & FARM BY PRODUCTS
of distillation, the modern chemistry, pharmacy and
perfume industries would not exist.
Despite the importance of these skills, there
are very few training centers for distillation engi-
neers or recognized diploma courses in the art More Inventions, More Patents
and science of distillation of aromatic substances. The fragrance industry is investing in green
While perfumers are given great respect within the chemistry and new methods of sensory evaluation
fragrance industry, the distillation engineers who when it comes to essential oil technology. However,
produce fine-quality natural fragrance raw materi- figures published by Perfumer & Flavorist in 2004
als get little or no recognition. clearly show that not enough research is going on in
Tim Denny of Tasmania, perhaps the 20th this field. In the last 23 years, the authors indicated
century’s leading distiller, with whom I had the that only 990 patents were registered in the USA
privilege to work, often remarked on how little has concerning the use of essential oils and, of these,
been written about the art and science of essential 41% were connected with its use in deodorants, 21%
oil distillation (even his own brilliant book was never in dental products and only 6% in perfumes. Clearly
formally published). Distillation engineers appear to something needs to change to ensure more innova-
prefer to retain their ancient image of smoke, magic tion takes place in the field of essential oils.
and alchemy.
The process of distillation using water and steam Perfumer Education: Botanical Constraints
is essentially an environmentally friendly one, Perfumers need to be better informed as to the
so long as energy-efficient boilers and condenser agronomic and environmental characteristics of
systems are used. Too often, valuable timber or the natural ingredients they use, especially as these
charcoal is being used to fire essential oil stills, or, in characteristics largely determine the long-term price
more urban conditions, costly gas and oil burners. and availability of such raw materials. The simple
Sadly, the majority of stills, particularly in develop- pyramid in F-1 helps describe why some types of
ing countries, are extremely inefficient in terms of aromatic materials are far more likely to have a
heat and use of spent waste. They also often use long-term sustainable future than others.
excessive amounts of water for the steam boilers and Florals: The much-loved florals, such as rose,
condenser units. tuberose and jasmine, will almost without exception
While some attempts have been made to help become more expensive to grow and process as they
farmers in places like India use spent waste from as they require very large amounts of water, labor,
the stills as fuels—either directly or in compressed fertilizer and other inputs. Moreover, land, water
bale form—by and large most distillation units are and labor used for florals can also grow food crops
not efficient in the use of fuel or water. Making more in an increasingly overpopulated world. Only where
energy- and water-efficient distillation units could mechanization can be cost-effectively employed,
greatly increase the sustainability of the natural as with chamomile and lavender, can the industry
fragrance and cosmetic industry and reduce what are expect to see sustainable, affordable natural florals
often unacceptably high carbon footprints. If mobile still on the market.
stills are installed, the efficiency of the process is Bark and roots: The bark and roots of trees are
further improved, and the carbon footprint reduced equally unlikely to survive, seeing as so many of
even further. them are won from ever-endangered, slow-growing
hardwood trees. Only with cost-effective agro- bureaucratic process of getting permits to move
forestry solutions, as with sandalwood in Australia, plant material around the world. Suddenly, perfum-
will there be much chance that this category ers have gained access to limitless natural scents,
survives intact. including rare species, aromas from flowers that
Herbs and aromatic grasses: In the case of herbs cannot be cultivated in large numbers and scents
and aromatic grasses (sage, basil, mint, citronella, that had previously been impossible to reproduce
etc.), the future looks much brighter. For a start, artificially, such as lily of the valley.
herbs are usually annual crops used also as foods Apart from the pioneering work by Mookherjee,
and medicines. They receive much higher R&D several companies have now patented similar
investment and have a more stable multi-sector headspace technologies: Aromascope (Takasago),
market. Furthermore, high-technology mechanized Jungle Essence (Mane) NaturePrint (Firmenich) and
propagation, cultivation, harvesting and processing ScentTrek (Givaudan). These companies and others
methods, similar to those used in vegetable and oil can now create nature-identical perfumes with far
seed production, can be relatively easily adapted for greater accuracy and precision, as well as obtain
these types of crops. Best of all, the aromatic waste accurate aromatic fingerprints from all the world’s
materials are recovered from other agro-industries, major flowers.
meaning the cost of production and harvesting are The creation of nature identical aroma chemicals
negligible as they are by-products or residues. can certainly reduce the fragrance industry’s depen-
Aromatic leaves and twigs: All the aromatic dence on overexploited or endangered plants. One
leaves and twigs of trees, like eucalyptus, clove, example is IFF’s Helional, an aroma chemical that
orange and cinnamon, fall into this category, as do mirrors the haylike aroma of the roots of the tropical
the expressed peels of almost all citrus. Here, there sassafras tree. Natural sassafras was highly prized
are still plenty of business opportunities. Take the for products such as perfumes and soaps, so farmers
easy-peel mandarin hybrid called kinnow, which is in Asia and Latin America were cutting down more
now harvested across the Punjab region of India. and more sassafras trees to harvest their roots. IFF
There are thousands and thousands of tonnes of says that more than 110,000 trees have been saved
this peel simply going to waste! annually since the introduction of Helional.
The Impact of Headspace Technology Can Unhealthy or Dangerous Solvents

The headspace technology pioneered in the Be Replaced?
late 1980s by IFF’s former chief scientist, Braja The use of chemical solvents to extract aromatic
Mookherjee, has done much to revolutionize our principles from many flowers and plant products
understanding of the chemistry of plants. Headspace is an increasing concern to the industry from both
analysis makes it possible for scents to be captured a marketing and environmental point of view. Not
and studied without the need to kill the plant. only are the risks of fire and explosions elevated in
This has enormous advantages as fragrance biofactories using certain solvents, but health hazards
prospectors no longer need to go through the hugely exist for both the workers and the consumer when
some types of solvent residues are not properly
eliminated. Furthermore, the disposal of solvent
waste poses growing costs as regulations increas-
ingly prevent industries from simply dumping these
in rivers and lakes.
Can these solvents be replaced? The answer is yes,
especially when the principles of green chemistry are
applied. Clearly, water, carbon dioxide and ethanol
represent safer solvents and the use of a renewable
feedstock, as well as having the widest acceptability
and range of solvent polarity.
As Beerling points out, “There is increasing pres-
sure from certifying bodies like COSMOS and Natrue
to restrict or prohibit petrochemical extraction of
[extracts] and absolutes, so I think the fragrance and
cosmetic industry could invest a lot more in research
to develop green solvents to replace materials such
as hexane.”
But the fragrance industry, unlike the food and

pharma sector, has been slow to take up CO2 or flowers, herbs and tree crops and ensure that they
water extraction methods, although they are both are used in an equitable and sustainable manner.
much greener and safer than petrochemical-based With his support, the FairWild foundation was born
solvents like hexane and toluene. in Switzerland in 2008. FairWild’s objective isn’t
Even better are florasols, which use a refrigerant- to ban the harvesting of wild plants but to foster
based material (1,1,1,2-tetrafluoroethane) as the methods of forest management and enrichment
extraction solvent. This process is so gentle that which allow the safe and sustainable harvesting of
some seeds are still alive after extraction and can these materials in a fair and equitable manner.
be germinated. It is non-toxic and non-hazardous, Curtis has successfully helped Arbor Oils in
requires very little energy, uses no water and pro- northern Kenya get FairWild certification, hence
duces no effluent. Sadly, although this technology paving the way for the introduction of the world’s
has existed for more than 25 years, it has not been first FairWild-certified frankincense beauty product
widely accepted by the fragrance industry to date. in their shops. This is an important positive step, but
is still only a rare example of how the industry can
Is Green Chemistry a Potential Savior? help the wild-harvested aromatic plant sector.
For some, like Daniau, green chemistry offers
one of the most promising avenues for the fra- Can Rare and Endangered Aromatic Plants Be
grance industry of the 21st century: “I’m excited Saved from Extinction?
about green chemistry and feel it is good way to The FairWild certification system work well for
develop sustainable and environmentally friendly the collection of aromatic starting materials such
fragrance products.” as leaves (eucalyptus) or twigs (petitgrain), but this
Green chemists, like those at the Symrise catalysis approach seldom works for bark, heartwood or roots
laboratory, which opened in Holzminden, Germany, (sandalwood, agarwood, cedarwood, etc). Such aro-
in 2013, aim to reduce the cost and increase the effi- matic timbers are almost without exception under
ciency of making aroma chemicals. Using catalysts threat from over-exploitation. Either the industry
allows certain transformations or provides access to will have to synthetically recreate these ingredients
new molecular structures which are otherwise low- using headspace technology and the like or begin to
yielding, or even impossible by classical means. seriously support agro-forestry investments such as
Australian sandalwood and Chinese star anise.
FairWild The number of endangered plants is significant.
Rainer Bachi, founder of certification agency The most acutely threatened sources are:
IMO, was one of the first people to draw special
attention to the fact that a very large number of • Indian sandalwood (Santalum album); India
medicinal and aromatic plants used in global busi- • Chinese perfume plant (Aglaia odorata);
ness were in fact wild-harvested and that special Southeast Asia
efforts were needed to foster and conserve wild • Atlas cedarwood; Morocco
technology of inoculation that allowed wounded and
unwounded trees alike to produce resin (pictured).
Together, in less than five years these few dedicated
people had found a way to make sustainable natural
agarwood. Sadly, despite the subsequent “discovery”
of oud by European perfumers and the consequent
boom in demand for agarwood oil in western
fragrances, TRP’s work has largely been ignored by
the Western fragrance industry, which has primarily
relied on the development of cheaper nature-identi-
cal substitutes. The TRP agarwood project cost about
$2.5 million. Some would say this is a great deal of
money, but compared with the long-term benefit
or the amounts spent on advertising and fragrance
launch parties, this figure is small.
As Gary Young, founder of Forever Living, boldly
stated recently, “The essential oil and aromatic raw
materials industry is failing to self-police itself with
respect to conserving threatened plant and animal
TRP agarwood nursery, Southern Vietnam. species. Green policies and any semblance of ecologi-
cal awareness with respect to these commodities
often seem to originate more from the attitudes of
• Osyris (East African sandalwood); East Africa consumers than via the raw materials producer and
• Costus root (Saussurea lappa); Nepal, Bhutan, reseller, in spite of the existent national and interna-
India tional laws restricting or forbidding trade in certain
• Agarwood (Aquilaria); Malaysia, Vietnam threatened species.”
• Guiacum officinale (Lignum vitae); Venezuela,
Brazil Both the late Mookherjee, who created one of the
• Buchu (Agathosma betulina); South Africa best private aromatic plant gardens at IFF, and
• Jatamansi (Nardostachys jatamansi); Himalayas Roman Kaiser at Givaudan, whose research work
• Sassafras (Ocotea odorifera); Brazil “Vanishing Flora—Lost Chemistry: The Scents of
• Rosewood (Aniba rosaeodora); Brazil Endangered Plants around the World” is widely
• Immortelle (Helichrysum); South Europe quoted by the fragrance industry, were well aware
of the importance of such conservation work.
Even small groups of committed people can However, until and unless the fragrance industry
have a big impact on this problem, as I found out starts to enter into serious dialogue with the
when I went to work with TRP Rainforest Project in conservation agencies like CITES, IUCN and WWF,
Vietnam some years ago. There, a private U.S. phi- it still runs the risk of being “caught on the back
lanthropist, a Dutch forester and one of the world’s foot.” Such was the case when CITES decided to
greatest plant pathologists combined their skills and apply a CITES 2 listing on rosewood and guaiac
energies to come up with a way of saving the agarwood at a time and in a manner that surprised
wood (oud) tree from total destruction, while still most and outraged some in the fragrance industry.
offering the world’s incense and perfumery industry With the Nagoya Protocol supplementary agreement
sustainable supplies of this highly interesting natural to the Convention on Biological Diversity now firmly
aromatic material. in place, fragrance producers will be put more and
Firstly, TRP needed to work out how to grow the more in the spotlight when it comes to their policy on
tree rapidly, cheaply and successfully so that they sourcing raw materials from potentially endangered
could start a massive 1-million-plant-plus replant- plants. Will it be ready?
ing program (pictured). Once they had solved that
problem with the help of the South Vietnamese
Forest Service, TRP turned its attention to the much Address correspondence to Denzil Phillips; denzil@denzil.com.
more difficult task of how the agarwood resin, an
aromatic substance that only occurs when the tree is
ill or wounded, is formed.
Enter the Minnesota University Plant Pathology
department, which came up with a now-patented

Natural
Aroma Chemicals:
More and Purer
How improvements in extraction, biotech processes and use of sidestream
sources are changing the ingredient palette
Vol. 37 • July 2012

by David Rowe
I
n chemistry you can do [almost] anything, than its source, making it hugely and prohibitively
as long as someone is willing to pay for expensive for flavor applications. When it comes
it,” says David Rowe, technical director of to naturals, he says, “It’s about identifying a more
Riverside Aromatics Ltd., highlighting the viable source.”
potential and challenges in expanding the In another example, cis-3-hexenol (FEMA# 2563,
natural aroma chemical palette. Ingredient CAS# 928-96-1, F-2), which has been found in
producers are able to isolate and extract everything from apples to carnations to fresh cut
ever smaller percentages of material from grass, the chemical could theoretically be produced
sources; the question is whether it is always by harvesting enormous amounts of grass and
economically viable to do so. distilling it. More realistically, the natural version has
To take a simplistic example, Rowe notes been derived as a component of mint oil, effectively
that in theory one could isolate 2-methyl-3-furanthiol making it a byproduct of a material that is already
(FEMA# 3188, CAS# 28588-74-1, F-1), which is a commercially viable as an essential oil or a derivative
powerful material with a roast beef odor, from meat. source for natural menthol.
Yet, he says, the derivation of the material from a “You could not grow mint simply to produce
meat source would lead to a material more costly cis-3-hexenol, but when you’re growing the mint
F-1. 2-Methyl-3-furanthiol F-2. cis-3-Hexenol
F-3. Typical sulfur compounds found in garlic F-4. 2-Isopropyl-4-methyl thiazole
for multiple products, it becomes economically (E,E)-2,4-decadien-1-al (FEMA# 3135), are valuable
viable,” Rowe says. “There has to be an added for formulators.
value to using ingredients.” Tomato leaves and vine: 2-Isobutyl thiazole
(tomato leaf thiazole, FEMA# 3134) and 2-isopropyl-
New Natural Materials, New Natural Sources 4-methyl thiazole (peach thiazole, FEMA# 3555, F-4)
Flavor companies are particularly compelled to can be derived from tomato leaves and vines. As with
find new sources of natural aroma chemicals and trimethyl pyrazine, natural 2-isopropyl-4-methyl
are thus investing more R&D resources in this area. thiazole differs from its synthetic counterpart in that
The technically driven work carried out by ingredi- it is softer, greener and less sulfurous due to impuri-
ent companies focuses on areas in which natural ties, including sub-trace levels of 2-isobutylthiazole.
options may be lacking, such as in savory. “This is an example where the source has an influ-
Fusel oil: Fusel oil, from which alcohol is ence on the quality of the end product,” says Rowe.
derived, has provided a side stream of aroma When there are differences between the natural and
chemicals for the flavor and fragrance industry synthetic materials it is crucial for formulators and
which are present in the oil at low levels, including QC staff to understand the distinctions.
b;-damascenone (FEMA# 3420) and pyrazines such
as trimethyl pyrazine (FEMA# 3244, F-3). Unlike its Biotech Future
synthetic counterpart, trimethyl pyrazine derived Biotechnology/fermentation is not a new concept,
from fusel oil residues contains isomers—impuri- says Rowe, but there may be innovations from
ties—that impart a sweet, chocolate character. (See other chemical sectors that the flavor and fragrance
The Pros and Cons of Impurities.) industry hasn’t yet exploited. “There has been a real-
Sunflower oil: “Crude sunflower oil will some- ization that microorganisms can do a lot more than
times have a quite rancid odor due to the oxidation we normally ask them to do,” he notes. Already, he
of aldehydes,” says Rowe. “Those are aroma says, fermentation has yielded a number of natural
chemicals in the wrong place. If you can get those materials, including lactones.
aldehydes out, it will extend the life of the oil “We can persuade microorganisms to do all
without damaging it.” In turn, these valuable aroma sorts of things and make all sorts of transforma-
chemicals, including decanal (FEMA# 2362) and tions that we’re not aware of [as an industry],” he

adds. “In chemistry you can do [almost] anything, have [impure] decanal from orange oil and it has a
as long as someone is willing to pay for it. I think citrus note, that’s not necessarily a positive thing.
that will be true for biotechnology. As techniques If you want to use that decanal in a savory flavor,
[emerge], prices will be lowered and more materials it’s not going to be so good. In the past 20 years
will become available. An awful lot of materials that there’s been a move toward purer and purer natural
are not currently available naturally will be—sulfur materials.”
compounds, pyrazines, thiazoles—a whole range of However, he says, there is cause for caution. If
things. There is more to come.” isopropyl methylthiazole natural and synthetic are
identically pure, it becomes harder to verify which of
The Pros and Cons of Impurities the two is natural.
“If everything was 100% pure, a natural aroma “You lose the impurity profile which actually tells
chemical pyrazine and 2-isopropyl-4-methyl thia- you about its origins,” says Rowe. “At super-pure
zole, it is crucial for formulators to determine when levels you would have to carry out isotope testing
they can do a one-for-one swap of a synthetic for a to verify origin, which is very expensive. It is a real
natural and when there are sufficient differences that problem and means that increasingly it comes down
olfactory consistency will require extra technical and to [whether] you are able to trust your supplier.”
creative finesse. No matter the challenges ahead, however, the
The benefits and challenges of impurities in opportunities in new aroma chemical sources contin-
natural ingredients has long been a feature of ues to expand.
isolates derived from essential oils. Rowe explains
that linalool ex basil, for example, is likely to differ in
some ways from linalool ex bois de rose or ex ho oil,
while geraniol ex geranium oil will likely differ from
geraniol ex citronella oil. Sometimes these differ-
ences can be due to differing isomer ratios (optical
isomers in the case of linalool, geometric isomers in
the case of geraniol), but often it’s the influence of
traces of other materials, the “impurity profile,” as it
were. “Source has an impact,” says Rowe.
Decanal ex orange oil may have been 40–50%
pure 20 or 30 years ago, says Rowe. “At that level of
purity you’re really restricted in what you can use
it for,” he adds. “As the material became purer it
extended its range [of potential applications]. If you
Biological
Systems
and Flavors:
Science, Technology and Applications
Natural, organic and clean aroma chemicals; unique complex bases; greener and
ecologically friendly processes; taste and olfactory modifiers; and regulatory issues
Vol. 33 • November 2008 Ivica Labuda, PhD, Biokeys for Flavors, LLC
T
his article aims to capture the The biological systems considered here include
bond between science, technology plants, microorganisms and enzymes. For simplicity,
and applications in the area the technologies that utilize such biological systems
of natural flavors. Demand will be referred to as applied biotechnology. These
for naturals has stimulated processes employ whole or part of living cells, which
research to find effective and can be natural or genetically engineered. One advan-
efficient solutions to scientific tage of biotechnological processes is that they yield
questions and practical problems. natural stereoselective and enantioselective products.
Imaginative implementation of It is important to recognize that, at the present
new scientific understanding time, only a fraction of these processes involve
leads to original creations and genetically manipulated organisms and enzymes.
applications. Recent developments are captured This is a consequence of the market demanding
in a number of excellent reviews on natural flavor clean, organic and all natural flavor and fragrance
and fragrance molecules.1 Here, the intention is to materials. At the same time the tools of molecular
provide selected examples of how science, when biology, metabolic and translational engineering
transformed into technology, can successfully are employed to build scientific understanding.
address the ever-changing market needs. These tools are also used as a guide for identifying

important traits in production organisms and aroma chemicals. However, the technology using
enzymes. These modern tools of DNA manipulation plant cell cultures for flavor production is not yet
deliver more controlled and precise changes than cost competitive.
the traditional hybridization techniques. Biocatalysis is a natural alternative to chemical
Sensory systems is another area where scientific synthesis during which a structurally related
progress has had critical impact, since olfaction precursor is converted into the final product using
and taste are the key instruments for evaluating enzymes, plant, animal and microbial cells as
flavors and aromas. The industry has greatly ben- catalysts. Advantages of these processes are: mild
efited from recent progress made in understanding and more environmentally friendly manufacturing
receptors, signal transduction, neurobiology and conditions, natural status, and correct stereochem-
sensory. In particular, molecular biology is an istry. Almost any chemical process can be replaced
essential tool to elucidate the biochemistry of taste by a biological system, even though some of them
and olfaction. This new knowledge is translated may not be economically practical. Numerous
into methods for the discovery of taste modifiers such processes have been patented and selected
and masking compounds to offset undesirable few were implemented.
taste and olfaction characters. In a search for novel compounds, the flavor
Additionally, biotechnology can be instrumental industry may adopt new combinatorial biosynthesis
in manufacturing; for example in selecting raw plant technology that is now used for finding novel phar-
materials, improving downstream processes and maceutical biologics. This technology can prepare
waste management. large libraries of modified natural compounds and
From these many topics, the focus will be on a combinations thereof.
few examples to illustrate how scientific progress In a typical bioconversion, a single enzyme or a
translates into new technologies that advance cocktail of enzymes is used. The source of the
the flavor and fragrance industry. Topics to be enzyme offers many trade-offs. Isolated or purified
discussed include: enzymes offer higher specificity. However, isolated
or purified enzymes may be too costly, or not even
• Natural, organic and clean aroma chemicals available. Therefore, whole plant and microbial cells
• Unique complex bases and their extracts are used as whole-cell systems
• Greener and ecologically friendly processes containing the enzymes needed for the reaction.
• Taste and olfactory modifiers Whole-cell systems are advantageous when a multi-
step biocatalysis is needed. Such processes need to
Natural, Organic and Clean Aroma Chemicals be designed carefully so that the cells accumulate the
Microbial and enzymatic biocatalysis has product and do not metabolize it. The downstream
found application in manufacturing of natural catabolism can be prevented by using bi-phasic
F-1. Enzymes in flavor production
F-2. Enzymatic biocatalysis of valencene to nootkatone
systems, by continuous product removal or by etc. have created a portfolio of enzymes from a
disruption of genes responsible for the downstream variety of sources, and with different specificities.)
metabolic pathways. Often the enzymes are immo- Here, two examples of enzymatic processes are
bilized so that they can be recycled and so lower presented: single- and multi-enzyme biocatalysis.
the cost of manufacturing. F-1 depicts the applica- The first example is the oxidation of valencene to
tion of enzymes. (Enzyme manufacturers such as nootkatone using enzymatic biocatalysis (see F-2).2
Novozyme, Biocatalysts, Valley Enzyme Research, Valencene is first oxidized to a hydroperoxide by

F-3. Different routes to vanillin
a number of fungal phenol oxidases. Valencene solubility of ferulic acid and thus the availability
hydroperoxide is then converted to nootkatone. As of the precursor to the biotransformation.
prepared, nootkatone can be either isolated as a pure Considerable progress has been made in charac-
aroma chemical, or the whole citrus oil can be used terizing the biochemistry and molecular-genetics of
as an enriched essential oil. Pioneering work on the the microbial catabolic pathways leading to vanil-
production of laccase by plant pathogen Botrytis lin. For example, scientific research has decoded
cinnerea by Professor James Nakas at SUNY laid the the enzymes involved in formation of vanillin
foundation for its usage. The biotechnology group at from ferulic acid in Pseudomonas fluorescence.3
Givaudan invented a process using this enzyme for Identification and characterization of the genes
nootkatone production (US 6,200,786). Building on coding for these enzymes will offer new opportuni-
Givaudan’s work, the gene for laccase was recently ties for metabolic and translational engineering
patented by an enzyme company Diversa (US patent and for the construction of recombinant strains.
application 20070105112). Further work needs to be done to prevent oxidation
Multi-enzyme process is another example of of vanillin to vanillic acid by inhibition of vanillin
biocatalysis. Formation of vanillin can serve as an dehydrogenase. Various other approaches, micro-
example. Since vanillin is a high-volume aroma organisms and conditions were reported. Some of
chemical, researchers have put great effort in the microbial processes are commercially viable
identifying various biosynthetic and biotransfor- and are used for vanillin production. Combination
mation processes (F-3). Vanillin can be formed of microbial and enzymatic processes is another
via plant, microbial or enzymatic routes. Besides approach to form vanillin. For example, recombi-
plants, microbial biotransformation of renewable nant bacteria Escherichia coli, containing part of
ferulic acid has so far been the most promising plant shikimate pathway, produces vanillic acid
for vanillin production. Biotransformation of that is subsequently reduced to vanillin by purified
ferulic acid is achieved in a series of enzymatic fungal aryl aldehyde dehydrogenase.4
steps. Typically, for ferulic acid biotransforma- At the same time, vanilla plant biosynthetic routes
tion, microbial cells are used in their stationary need to be studied and better understood. Recent
growth phase with an ample amount of alterna- work by French scientists at Reunion Island discov-
tive carbon source. The media pH determines the ered that the vanilla orchid has a very low genetic
diversity, especially the cultivated types.5 Since very pathways that are interconnected. Identification of
few of the changes on the genetic level take place in genes in vanilla orchids increases the understand-
the vanilla genome, the phenotypic variations that ing of the flavor-related biochemical pathways. This
lead to variation in vanilla extracts may be due to increases the impact of science in the art of vanilla
epigenetics (different gene expression) or polyploid- extract manufacturing and can be translated into
ity (more than two sets of chromosomes). There more predictable product.
remains a great need to uncover all the genes, their In general, biotransformation and fermentation
expression, silencing and translation, which are processes tend to have lower yields than chemical
important for vanilla flavor formation. Metabolic reactions. Typical hurdles are the initial concentra-
engineering could help eliminate dramatic variations tion of the precursor, its solubility, toxicity and the
due to a number of factors, such as an impact of accumulation of the finished product. To make good
environment on genetic expression. yields economically feasible, the engineering of the
Also of interest was an attempt to reroute the process must be coupled with a detailed understand-
tobacco plant phenylpropanoid pathway into ing of the pathways. Traditional recovery processes
vanillin. This was done by introducing a bacterial such as distillations and extraction may be sufficient
crotonase gene into a tobacco plant, which resulted to eliminate the product inhibition or toxicity of the
in phenotypical abnormalities.6 This work dem- product to the biocatalyst. More advanced technolo-
onstrated that the accumulation of intermediate gies need to be incorporated to improve product
compounds can lead to a shuffling of different path- yields, e.g. whole-cell biocatalysis in biphasic
ways leading to the variety of phenolic compounds. systems, cofactor regeneration for in vitro oxidation,
This is in line with the complexity of vanilla immobilization, thermostable enzymes, membrane
extract, which boasts more than 80 compounds, and immuno-based separation of the product, etc.
resulting from numerous interconnected metabolic These processes can also be adapted for the forma-
tion of fragrance materials when they present either
economic advantage or distinctive end products.
Unique Complex Bases

Fermentation processes are used
to prepare complex bases and matrixes
that have distinctive background notes. The flavor
compounds are formed during the microbial growth
on basic nutrients, typical of de novo synthesis. The
type of microorganism determines which particular
array of metabolic intermediates is created. This
complexity gives a product a natural unique signa-
ture that is a competitive advantage. Frequently the
entire flavor-intensive biomass is used to aromatize
the foods, as, for example, in enzyme-modified
cheese. In some instances, only a part of the flavor
bouquet is created. For instance, a microbial
fermentation can yield an intensive part of bread
aroma and taste that is then used to enhance the
taste of whole wheat products or chemically leav-
ened dough. These bread biobases are generated
by the bakers’ yeasts, lactic acid bacteria fermenta-
tions, enzymatic reactions, etc. The nutrients, such
as carbohydrates, proteins and fats, are converted
into flavor chemicals such as lactic acid, acetoin,
acetic acid, pyrazines, etc. Such a biobase carries
strong bready and fermented
notes. Their forma-
tion depends on the
genetic makeup of
the microorgan-
ism and on growth
conditions. The beauty of

T-1. Some major sources of thujone
Enzyme/organism Product Flavorant

Yeasts High and low molecular Taste modifiers such as peptides,
Lactic acid bacteria components nucleotides, oligasaccharides
Small molecular weight volatile
Carbonyls, furanones, pyrazines, alcohols
compounds
Amino Acids as intermediates for flavors,
Protease peptides, taste enhancers, sweetners, Carbonyls, furanones, pyrazines
bitter agents
Short chain fatty acids
Lipases Off-note and off-aromas
Glucose, fructose
Invertase Carbonyls, pyrazines,
Oxidation products of fatty acids,
Lipoxygenase Carbonyls
vitamins
Strengthen gluten
Oxidases
Oligosaccharides from xylan, Furanones, pyrazines, pyrroles
Carbohydrases
hemicellulose, pentosans
these processes is the creation of a distinctive array lipids. This enzymatic hydrolysis improves the yield
of metabolic intermediates. As an example, impact and shortens the processing time. Depending on
of microorganisms and enzymes on dough flavor is which enzymes are used, the addition of enzymes to
summarized the plant tissue can intensify and change the profile
in T-1. of the extracted flavors simply because of additional
Meaty and savory flavor bases can be made from flavor release. Some of the processes use a cocktail
many protein-rich materials. Yeasts and vegetable of enzymes, whereas in some instances a sequential
proteins are both good sources of savory flavors. introduction of individual enzymes is more ben-
Savory flavors from these sources are generated eficial. As a result, more efficient manufacturing is
through protein hydrolysis, peptide production coupled with higher yields and sometimes additional
and heat reaction. The nature of the protein and sensory attributes. A number of enzymes are natu-
enzymes determine the flavor outcome. rally present in the plants and are involved in the
Creation of flavor biobases requires knowledge of hydrolysis during maturation, harvesting, pressing or
biochemistry, chemistry, microbiology and fermenta- distillation. De facto, in some instances, it is only an
tions. However, the knowledge is mostly retained enhancement of the existing enzymes that is needed
within the industry and rarely published. There are to increase the yields.
an infinite number of variations and permutations Downstream processing, such as filtration,
that can lead to a range of different products. is another application of enzyme technology.
Flavorists and application chemists play an Enzymes are also helpful in eliminating the impact
integral role in finding final applications for these of annual crop variations by standardizing the
complex biobases. Success in the marketplace extraction process.
for these complex flavor ingredients relies on the
creative imagination of the flavorists and application Taste Modifiers
chemists using them. Throughout the last 15 years, scientists have
uncovered the basis of taste and olfaction little by
Improved Plant Extraction and Ecologically little. This knowledge is invaluable to progress in
Friendly Processes the food industry. Prolonging the taste experience,
Many flavor and aroma materials are derived enhancing the positive attributes and suppressing
from plants. Plant materials are complex matrixes. the negative ones are the major areas of interest. In
Aroma chemicals are chemically intertwined into all cases, science can be an engine behind progress
polysaccharides, proteins or lipids. These bonds can in the art of extending, enhancing, masking, chang-
be efficiently hydrolyzed in a short time prior to the ing and reducing tastes.
recovery processes such as extraction or distilla- Extension of the pleasant and desirable tastes can
tion. Enzymes increase the yield by hydrolyzing the be achieved through sustained release of flavorants
chemical bonds and the polysaccharides, protein and from its matrix. On the other hand, suppression of
the negative attributes can be achieved using differ- of heterologuous receptors is needed for tasting
ent approaches: (I) interaction with taste receptors, a variety of sweet compounds. This knowledge is
(II) coating of the undesirable compounds, (III) being used in rapid throughput screening.
larger particle size, (IV) modification of the active Scientific work on starch derivatives, natural
compound to bypass the receptors, etc. For example, polymers and nanotechnology succeeded in bring-
microencapsulation, used widely in the flavor ing novel materials to the market. Materials can
industry, is one of the methods used to bypass taste be selected based on their functionalities for either
receptors and improve taste and eliminate off-taste. sustained release of desired flavors or masking of
It also helps with extending of product shelf life. undesirable ones. Flavorists have additional options
Knowledge of the basic logic behind taste to target the taste perception by creating flavors that
coding and interaction between taste receptors complement the off taste. For example, bitter taste
and tastants is critical for future developments. is more acceptable in chocolate or grapefruit flavors
It will allow for more targeted modifications, where they are expected.
such as competition for receptor sites, or chang- Identification of many of the masking and
ing the receptor binding site. For example, early enhancements has been done through trial-and-error
taste receptor work by Robert Margolskee, MD, types of experiments relying on sensory panels to
PhD et al. at Mount Sinai Hospital in New York, identify compounds with certain attributes.
New York resulted in patent identifying adenosine
monophosphate analogues as bitterness suppres- Regulatory Aspects
sors.7 The unpleasant, medicinal, or harsh taste of Regulatory status is a key factor for any flavor
thymol can be masked by effective amounts of a product. Flavors can be natural, all-natural, organic
sugar alcohol, or a mixture of sugar alcohols, and or artificial. The process through which they are pre-
anethole. Elucidating different aspects of the taste pared determinesthe regulatory status. However, the
mechanism is an area of active research. Recent interpretation of the processing conditions depends
patents by Senomyx and National Institutes of on the country of origin and its regulatory system. It
Health teams demonstrated that an expression also depends on the intended product; naturalness

is preferred in flavorants and relatively unimportant on investment. A captivating product is a result of
for fragrances. Compounds derived from micro- a synchronized and progressive management that
bial, plant and enzymatic reactions are considered brings together basic and applied sciences, applica-
natural. From a regulatory perspective, products tions, manufacturing and marketing.
derived from biological processes can be classified
as natural, organic-compliant and organic. Typically, Address correspondence to Ivica Labuda, PhD, Founder, Biokeys for Flavors,
LLC ; biokeys4flavors@aol.com; adjunct professor, Georgetown University Medical
a flavor is considered natural when manufactured Center; 11226@georgetown.edu
with genetically modified microorganisms (GMO),
plants or enzymes. Such flavor does not require a
References
special labeling in the United States; however, GMO
1. S Serra, C Fuganti and E Brenna, Biocatalytic preparation of
cannot be applied to manufacture organic, organic-
natural flavours and fragrances. Trends in Biotechnology, 23,
compliant and natural flavors. It should be stressed
193–198 (2005)
that genetic engineering using molecular biology
tools is the modern version of a traditional muta- 2. R Huang, P Christenson and I Labuda, Process for the
tion protocol employed by farmers and breeders. preparation of nootkatone by laccase catalysis. US Patent
Classical breeding of plants and microbes has been 6,200,786 (2001)
with us for many centuries, and it can be expected 3. T Hitchman, DE Robertson, M Hiraiwa, Y Phillips and KA
that, in time, molecular biology tools will be fully Gray, Laccases, nucleic acids encoding them and methods for
accepted as more efficient and safe. Only new making and using them. US patent application 20070105112
technologies leading to more precise changes in DNA (2007)
are considered GMO. Transgenic organisms and
4. A Narbad and MJ Gasson, Metabolism of ferulic acid via
their usage in the food chain are an entirely differ-
vanillin using a novel CoA-dependent pathway in a newly-
ent category, since they cross DNA between species.
isolated strain of Pseudomonas fluorescens. Microbiology,
However, tools such as molecular genetics, metabolic 144, 1397–1405 (1998)
and translational engineering are indispensable
in gathering knowledge about the genes and their 5. JW Frost, Synthesis of vanillin from a carbon source.
functionalities of microorganisms, plants and their WO/2000/017319 (2000)
enzymes. Overall, this scientific backbone is essential 6. S Body, P Lubinsky, A-M Risterucci, J-L Noyer, M Grisoni, M-F
for future advances. Duval and P Besse, Patterns of introduction and diversification
of Vanilla planifolia (Orchidaceae) in Reunion Island (Indian
Conclusion Ocean). Journal of Botany, 95, 805–815 (2008)
Recent progress in biological sciences provides
7. MJ Mayer, A Narbad, AJ Parr, ML Parker, NJ Walton, FA Mellon
exceptional opportunity to create innovative prod-
and AJ Michael, Rerouting the Plant Phenylpropanoid Pathway
ucts. Translation of these innovations into successful by Expression of a Novel Bacterial Enoyl-CoA Hydratase/Lyase
processes and products heavily depends on invest- Enzyme Function. Plant Cell, 13, 1669–1682 (2001)
ment into research, on being able to predict the
shifting markets and regulatory environment, in 8. RF Margolskee and D Ming, Inhibitors of the bitter taste
response. US Patent 6,540,978 (2003)
addition to factors such as cost, rapid delivery, etc.
Successful processes are only those that offer differ-
ence from competition, cost-effectiveness and return
Learning From Nature
High-Impact Aroma Chemistry
The challenges and opportunities of sourcing high-impact aroma chemicals
from nature.
Vol. 31 • September 2006 David Brassington, Frutarom, and Robert Edwards,
University of Durham
A
s part of a long-term program Plants as Biofactories for Flavors and
to source more natural high- Fragrances
impact aroma chemistries Plants already are used extensively as sources of
(HIAC), Oxford Chemicals natural materials in the F&F industry, with essential
Ltd. (OCL) and the Center oils being an excellent example. Unlike synthetic
for Bioactive Chemistry, sources, naturals contain multiple components and
Durham University, have can be unpredictable in terms of quality and quan-
been collaborating on the tity. As the continuing increase in oil prices makes
bioproduction of sulfur- plant-based renewables increasingly attractive as
containing volatiles. Robert alternative feedstocks for biofuel and bulk chemi-
Edwards (Durham University) cal production, it is timely for the F&F industry to
and David Brassington (OCL) examine some of the review recent progress in natural product biology
technical challenges and opportunities of sourcing and chemistry, and to evaluate future opportunities
HIACs from nature. for harnessing biodiversity for its own applications.

One of the primary objectives in using plant-based species (e.g., garlic, onion) illustrate several useful
feedstocks in any industrial application is to standard- challenges and opportunities in applying biotech-
ize the composition of the starting material as much nological approaches for HIAC production and the
as possible, ensuring its suitability for downstream development of new “value-added” markets for these
processing. For example, in order to derive oil-based naturals.
products for large-scale extraction, it is desirable to
control the chain length and degrees of saturation of Biological Control of Allium HIAC Production
plant lipids. This can be achieved by genetic engineer- The two best-known groups of Allium-derived
ing technology. Alternatively, genes encoding specific F&F principles are the allyl or prop-2-enyl sulfides
quality traits can be identified by searching within from garlic, and the saturated methyl and propyl
the naturally diverse genetic pool from which modern sulfides from onions. These form a series of mer-
crops are derived. Once identified, these useful trait captans, sulfides and trisulfides with distinctive
genes can be crossed back into high-yielding modern odor charac-teristics (F-1). Some 50 volatile Allium
crops using classical breeding techniques for large- sulfides have been described, arising from six
scale production of the new feedstocks. Although such precursor S-alk(en)yl-L-cysteine sulfoxides (ACS), of
an approach has been applied for polysaccharide and which only four are found in appreciable quantities
oil-based products, the technology remains underuti- (F-2). These can accumulate up to 1 percent of total
lized by the F&F industry. bulb fresh weight in harvested plants, such as garlic.
In addition to the benefits of moving to technolo- Upon tissue damage, the ACSs mix with the plant
gies based on renewables, the use of naturals rather enzyme alliinase, which releases a reactive sulfenic
than synthetics has obvious advantages in terms of acid intermediate, along with pyruvate and ammonia
consumer acceptance and also may help to develop (F-2). The sulfenic acids then undergo condensation
new marketing opportunities through scientifically reactions with one another to form either symmetri-
defined health benefits. cal or asymmetrical thiosulfinites, which then will
readily undergo further reactions and decomposition
Allium Aroma Chemistry to form the HIACs shown in F-1. Whereas a skilled
Among the high-impact aroma chemicals chemist can partially control the products derived
(HIACs), the sulfur-containing materials from Allium after thiosulfinite formation through selective
F-1. (1) Allyl disulfide (OCL code A0600), (2) Allyl propyl disulfide (OCL code A0960), (3) Ethyl propyl disulfide
(OCL code E01282) and (4) Ethyl trisulphide (OCL code E01289); all of these molecules have differing nuances in
dilution, offering more than just a basic onion/garlic note to the flavorist
S S
S S
(1) (2)
S S
S S S
(3) (4)
F-2. HIAC formation from ACS precursors
R, R1 = —CH3 , —CH2—CH==CH2 , —CH2—CH2—CH3 , —CH==CH—CH3
essential pathways in even distantly related species.
F-3. Alliumlike HIAC precursors from As potential sources of natural novel HIACs, these
unrelated species alternative biological sources may be of future
commercial value when the principles of selective
breeding and molecular genetics are applied to
“fishing” for the metabolic traits of interest so as to
enhance production in plants.
Health Benefits of Allium HIACs

S-benzyl cysteine sulfoxide from Petiveria The health benefit of the garlic sulfides long has
alliacea (garlic weed) been recognized, but it is only recently that a mecha-
nistic appreciation of the importance of individual
compounds as phytoceuticals in the human diet
has been understood. When pure Allium sulfides
were tested, a wide range of biological activities
were recorded at the molecular level — including
functions as antioxidants, inducers of protective
S-(methylthiomethyl)cysteine-4-oxide from enzymes, inhibition of deleterious enzymes and
Tulbaghia violacea (society garlic); radical scavenging activity. In turn, these biological
in Marasmius fungi the same compound is activities have health-promoting effects, including
made, but with the opposite configuration about reducing the incidence of cancers and cardiovascular
the sulfoxide disease, as well as counteracting inflammation and
infection. Importantly, these effects are compound-
specific, and as pharmacologists identify their
heating and distillation, all the steps providing the mechanism of action, there will be an increased
basic substrates for the reactions are determined by demand for specific natural Allium HIACs as func-
the relative rates of ACS turnover by the alliinases in tional nutraceuticals.
the plant extracts. Because a diverse set of natural
HIACs can be generated from a small number of Plant Biotechnology and F&F Production
biological precursors, controlling the availability of Controlling the quality of biological feedstocks
the ACSs would standardize the biological material using genetics is essential if we are to increase the
prior to distillation. Although attempts to regulate usage of plant products in the chemical industry. To
ACS content by controlling plant nutrition and date, the focus of such approaches has been at either
growth have been partially successful, a far more end of the scale of bioproduction — from biomass
desirable strategy would be to achieve selective and and biofuel production at one end to improving the
stable production through focused breeding for the yields of small-scale medicinal natural products at
respective metabolic traits. When combined with the other. As an important sector of the fine chemi-
selective downstream processing during extraction, cals market, the F&F industry also would benefit
this could be extremely useful in producing specific from adopting this technology.
natural HIACs to order. In conclusion, the global demand for natural
products with additional benefits, such as wellness
Potential for Extending Allium- Related Natural and health, is growing. The main issue facing food
HIAC Diversity and beverage manufacturers is the availability of
Although the large-scale commercial production cost-effective and natural ingredients. This, in turn,
of these sulfides is restricted to Allium species, the challenges F&F companies to deliver natural flavors
ability to produce related compounds is widespread that support the longer-term needs. This is why
in nature and has been described in Brassica species, the focus on the development of natural HIACs
several tropical plants and basidiomycete fungi is so important.
(F-3). These represent cases in which characteristic
garliclike notes have been easily detected, but this
probably characterizes only a small fraction of the Address correspondence to David Brassington, Oxford Chemicals Ltd., North
Gare, Seaton Carew, Hartlepool, TS25 2DT, UK; e-mail:
natural biodiversity of this type of chemistry. An david.brassington@oxfordchemicals.com.
interesting feature of the ACSs is that they are closely
related to common plant primary metabolites, so
that they have the potential to arise as byproducts of

Blending Technology
and Natural
Jamie Gleason, Head of Flavors & Fragrances
T
MilliporeSigma (Sigma-Aldrich®)
he future of F&F is less volatile or heat-sensitive chemicals. In this

a unique blend of technique the material is flash heated under high
technology and natural. vacuum using a short path still. The requirement
Expanding natural to rapidly heat, however, requires small batch sizes
aroma chemicals to the driving up costs and limiting yields.
flavorist or perfumer’s Another isolation method is wiped film or
palette requires falling film vacuum distillation. In this technique
improved extraction as liquid travels down the column it is spread
and isolation methods, by a blade under heat and vacuum resulting in
sustainable sourcing of evaporation of the volatile components which are
raw materials (including then condensed and collected. The advantage of
biotech processes) and transparency within the supply this continual flow process is cost reduction, but
chain. In this exclusive P&F interview, Jamie Gleason, the challenge of this relatively new approach is
head of flavors and fragrances, MilliporeSigma optimizing its method.
(Sigma-Aldrich®), shares her insight on the current
and future state of natural aroma chemicals.
Perfumer & Flavorist (P&F): What new devel- P&F: In terms of sustainability and supply,
opments are you seeing in isolation techniques? what are new sources for natural aroma
What are the challenges? chemicals?
Sigma-Aldrich® (SA): There are three techniques SA: Ingredient suppliers are looking for new
that I want to highlight starting with CO2 extraction. sources that focus on innovation, including biotech-
While this is not new to the industry, super-critical, nology methods of production. Biotechnology can be
liquid carbon dioxide extraction is being applied to used to reprocess or recycle food waste into useful
new different raw materials to extract a wide variety products and we are all concerned about envi-
of aroma chemicals. This method is useful in isolat- ronmental responsibility. Despite some consumer
ing low molecular weight molecules but it can be concerns about GMO, this technology provides the
costly compared to traditional approaches. industry with the opportunity to reduce its footprint
while offering new aroma chemicals. New GMO
Molecular distillation is a recent innovation methods including CRISPR and synthetic biology set
and becoming more popular. It is used to isolate the tone for an exciting future.
P&F: How is Sigma Aldrich using biotechnol- reaction flavor components, fragrance ingredients
ogy in obtaining natural aroma chemicals? aligned to IFRA requirements and Halal certified
aroma ingredients. These new ingredients can be
SA: Our strategy in this area is to partner with
used across the industry, expanding from just flavors
biotech companies to develop and produce prod-
into personal care and cosmetic products. From a
ucts. We are continually reviewing opportunities for
market perspective, the rapid economic growth in
partnership. Our overall corporation has many facets
developing regions is furthering usage of natural
including a focus on new microbial gene editing
ingredients in areas like South East Asia, Africa and
products and services which could tie nicely with
India. The regulatory requirements of these regions
biotech companies focused on innovating aroma
along with the cultural requirements adds a layer
chemicals.
of complexity for all suppliers to navigate. Close
relationships and transparency between supplier and
P&F: What new opportunities and innovations customer is a key focus for us.
are you seeing in high impact aroma chemicals?
SA: Consumer trends including the demand for
P&F: What is the future of natural aroma
natural ingredients along with vegetarian and vegan
chemicals?
lifestyles are driving the need for innovation in flavor
and fragrance profiles which utilize high impact SA: With the need for responsible sourcing and
aroma chemicals. If we couple this with the desire concern for our natural resources, the future of
and need for more sustainable sourcing options natural aroma chemicals will most likely heavily rely
we may see additional transition to biotechnology on biotechnology engineered naturals. Additionally,
methods of production. greater scrutiny of naturalness demanded by our
consumers will drive the need for laboratory built
naturals. This will however require our consumers to
P&F: Where are aroma chemicals most used? adapt to the idea of lab built naturals. There is con-
Are you seeing any other emerging categories? flict between having natural products that are pure
SA: From our vantage point, we still see the and responsibly sourced. Furthermore, the growing
most consumption on the flavor side of the industry trend for transparency in our consumer products
particularly for naturals. We are working to continu- may create an interesting dynamic for the flavors
ally add new natural products for both flavor and and fragrance industry. Will we see a “local source”
fragrance applications. Specifically unique lactones, or “farm to fork” type requirement in the future?

Evolving View of
Natural Flavors
By: Dr. Luke Grocholl, Regulatory Affairs Expert,
MilliporeSigma (Sigma-Aldrich®), Flavors & Fragrances
M
ondelez, Campbell’s sweeteners (i.e., high fructose corn syrup) to cheese
Soup, Kellogg’s, and made with genetically modified clotting agents (a
Nestlé have all recently very common practice in the modern dairy industry).
announced they plan Not surprisingly public opinion varied considerably,
to phase out artificial sometimes with little understanding of the modern
ingredients (flavors, food supply chain, with particular confusion
colors, etc.) in favor of distinguishing between natural and certified organic.
natural alternatives. This Some public groups even proposed preventing the
industry trend is driven use of the term ”natural” for any food labeling since
by consumer perception food sources have been modified by man since they
that natural is healthier were first domesticated. With so much consumer
and more sustainable. “All natural” is a common passion over the term “natural” it is interesting to
claim on food in the US and other regions, but what review how the public perception has changed over
does this really mean? Neither the US nor Europe time and how the flavor industry continues to evolve
have regulatory definitions of what constitutes to meet consumers’ demands.
natural foods, however, both the US and Europe The earliest natural flavors were spices, and the
have regulatory definitions for natural flavors. To spice trade dates to antiquity. The handling and
address this labeling ambiguity, the US FDA sought trade in spices led to the extraction of essential oils
comments from the public on what they feel “natural to reduce costs in transporting spices and increase
food” should mean.1,2 This was partially in response their life and potency. The ability to extract, isolate
to petitions from consumer groups regarding natural and store essential oils allowed natural flavors to be
claims on such diverse products as processed added to beverages and candies and similar flavored
products. Some of the earliest flavored products were disreputable or poor quality flavor ingredient
liquors, where alcohols were aged with botanicals to suppliers. Unfortunately the term “imitation” had
extract and absorb their unique flavors and aromas. a negative connotation and gave the impression
The birth of organic chemistry in the nineteenth that synthetic flavors were less pure or inferior to
century led to some of the first synthetic flavors. natural counterparts. Some of these fears proved
Many of these flavors were not known in nature at unfounded, as consumers showed they’d readily
the time but were selected solely for their pleasant purchase products made with synthetic flavors. Part
odor or taste. Methyl anthranilate, for example, was of the public’s acceptance of synthetic flavors was a
used in grape flavored products for over a decade general embrace of technology. Old, dirty, industrial
before it was detected in grapes. As the food industry revolution era factories were being modernized to be
became more industrialized, however, the impact of cleaner and safer. Regulatory agencies were cracking
poor food safety controls became greater. Growing down on manufacturers who misrepresented their
public concern led the United States to pass the Pure products. Chemists were introducing new, clean
Food and Drug Act (a precursor to the FDA) in 1906. vibrant colors, as well as, more consistent and potent
An important impact on the budding flavor indus- pharmaceuticals. Taking a lead from other industries
try was the requirement to label all ingredients in that promoted their newly engineered products
processed foods, a departure from earlier regulations as an improvement, the food industry began to
which focused strictly on food safety. In addition, promote synthetic flavors as more pure than natural
this law required synthetic flavors to be identified counterparts.
as “imitation,” for example synthetic vanillin was As industrialization grew and the tools science
identified as imitation vanilla. For the first time a had available to it expanded, the number of synthetic
regulatory agency made the labelling of synthetic flavors exploded. New methods for identifying and
flavors a food label requirement. isolating natural flavors could not keep pace with
Some flavor manufactures initially supported early twentieth century organic chemists. However,
the regulation, hoping it would help counter increased technologies being discovered by organic
F-1. The Flavor Industry: A Brief History Overview (not to scale)
36 2018 Naturals Aroma Chemicals E-book | www.sigmaaldrich.com/Flavors-Fragrances

T-1. Comparison of Regional Regulatory Definitions of Natural Flavors
US Regulations EU Regulations Japan China

(21 CFR 101.22) (EU 1334/2008) Regulations (GB 29938-2013)
(FSA Article 4, 3)
Botanical, animal or Botanical, animal or Botanical,
Raw Material Origin Botanical, animal
microbiological microbiological animal
Physical,
Physical, enzymatic,
Production Method Not defined Not defined enzymatic,
microbiological*
microbiological*
Must be known in
Extraction Extraction solvents
Other restrictions Not defined nature Extraction
solvents defined defined
solvents defined**
*Chemical processes, non-natural catalysts not allowed
** 2009/32/EC
chemists also had a dark side. Some of those same and low cost of the synthetic flavors developed over
scientific advancements contributed to the devasta- the decades made it impossible to wholly replace
tion of the World Wars. No modern event had as synthetic flavors.
much impact on today’s society as the Second World In today’s internet age the public has more
War. In the aftermath of Great Depressions and access to information than ever before. This lends
World War II, a devastated world looked to processed to mixed feelings on natural flavors. Safety studies
and preserved food as a way to feed and provide have shown there is no known health impact to the
for the survivors; driving the need for cost sensitive consumer regardless of whether a product is derived
flavors. The post war years also saw rapid economic from synthetic or natural sources. Public perception
growth, industrialization, and further technological still embraces natural as healthier, though consum-
advances. People embraced science with the begin- ers are still unable to agree on what natural means.
ning of the space age and high technology foods with Modern biology and biochemistry facilities are
their exciting new flavors drove a rapid growth in the highly technical with many natural flavors now being
flavor industry. isolated and purified in production facilities similar
New isolation techniques and analytical detec- to those used by synthetic flavor manufacturers. The
tion methods allowed for the identification of many US and Canada, as well as Spain and other southern
natural flavors components. Chemically identical European countries, are much more comfortable
synthetic analogs (nature identical) were developed with genetically modified organism (GMO) derived
to control costs and improve flavor purity while materials and large industrial food processes.
avoiding the challenges associated with limited Northern European and France are especially wary
natural raw material supplies. It was also believed of GMOs and feel natural should preclude industrial
these nature identical flavors were inherently safe processes as much as possible. As a result, in order
since they duplicated substances found in nature that to meet their peoples’ needs, the US, EU, China,
had been consumed for centuries. New flavors also and Japan have defined natural flavors somewhat
entered the marketplace as advances in biological differently. See Table 1 for some highlights on the
techniques, particularly bioengineered fermentation, different regional regulatory definitions of natural
allowed for new flavors to be developed. flavors.
By the 1960s and 1970s consumers began to Will the public perception that natural is better
push back against synthetic flavors. A return to ever change? Probably not. But, regulatory defini-
nature and distrust of large industrialized processes tions likely will, as the flavor market continues to
began to creep into the public perception. Industry evolve to meet changing public perceptions.
and political scandals, as well as pollution and
References
enhanced environmental awareness, started to
make consumers question the chemicals in their 1. FDA call for Natural; https://www.
fda.gov/Food/GuidanceRegulation/
food. Public perceptions that natural was good and GuidanceDocumentsRegulatoryInformation/LabelingNutrition/
artificial was bad began to push the food industry ucm456090.htm
to explore natural flavors once again. Not surpris- 2. FDA results; docket folder FDA-2014-N-1207 on Regulations.
ing, the incredible variety, versatility, high purity, gov.
Keeping Up With the
Microbes
The desire for clean labeled products has brought non-GMO technology
to produce new and novel compounds in creative ways by focusing on
microbial ecosystems, or polyculture.
Vol. 42 • September 2017 by James Stephens, Co-founder, CEO and Chief scientific officer,
Blue Marble Biomaterials
C
onsumer sentiment and open access manipulation of microorganisms seemed to be a
to information through digital silver bullet for elevating volume, price and utiliza-
communication are shifting the debate tion pressures on natural compounds in the market.
on the development of bio-based and It demonstrated the ability to control nature in a way
“natural” products. Around the globe, that fit the paradigm of classical industrial thinking.
consumer and governmental backlash However, unfettered access to information, concepts
against genetically modified organisms and opinions has created a dynamic where upward
(GMO) has generated new and novel of 89% of Americans favor the labeling of GMO.a
opportunities—and challenges—for the This holds true across the pond, as well, with more
delivery of authentic aroma chemical than 63% of the E.U. governments instituting full
ingredients from microbial sources bans on GMO crops in response to strong consumer
without the utilization of genetic modification. dislike for known GMO ingredients.
As the industry knows, many natural compounds Is this the beginning of the end of industrial
come from scarce and relatively rare natural biotechnological solutions for food ingredients
resources. Industrial biotechnology was a potential and aroma chemicals? The answer is no. A certain
solution to this limitation. Genetic modification and a The Mellman Group, 2015

market segment will always accept genetically The primary challenges of pursuing non-GMO
modified solutions. However, there are many bio- biotechnology solutions include target products,
technology solutions that do not require the direct predictability, yield and feedstock sources.
genetic modification of organisms, which creates an An existing example of a successful non-GMO bio-
opportunity for those who want to search for and technology solution is nitrite from high nitrate celery
create solutions that partner with nature instead of juice. This is a simple microbial bio-conversion—
control nature. generally called biocatalysis—for meat preservation
systems to make a “no nitrate added” meat product.
The Polyculture Approach Another example is the production of propionic acid
In this innovative space, we can explore advanced for preservative-free breads fermentation pathways.
uses of biomimicry, cradle-to-cradle thinking, eco- These pathways naturally lend themselves well into
based manufacturing and permaculture to create the world of aroma chemicals because the organisms
sustainable pathways to meet consumer desires for producing organic acids can be used to generate
natural and non-GMO ingredients. Unfortunately, natural solvents and esters.
there is no silver bullet leading to any one approach When searching for more complex and diverse
over another. To meet the demands of a growing pathways for aroma chemicals, one need not look
world population, we need to take the “golden buck- further than sourdough bread for the inspiration
shot” approach. for polyculture flavor fermentation or biocataylsis.
Non-GMO biotechnology-based solutions can The mixture of microorganisms and mother culture
focus on utilizing microbial ecosystems, or polycul- highly influences the flavors and flavor notes of a
ture, to overcome traditional problems of yield and target bread production and at least one company
feedstock utilization by following the tenets outlined has commercialized the sourdough bread process to
by David Holmgren in his book, Permaculture: capture natural flavoring aroma chemicals for the
Principles and Pathways Beyond Sustainability. By bakery and grain-based industries.
using a microbial ecosystem approach, many of Polyculture ecosystems create a complex mixture
the estimated 98% of uncultivable bacteria become of target products in a generally predictable volume.
potentially available for biotechnology-based Organisms within an ecosystem can break down
solutions.
Sourdough bread’s mixture of microorganisms and mother culture is inspiration for a polyculture flavor fermentation to capture natural flavoring aroma chemicals for the
bakery and grain-based industries
a variety of feedstocks because of a mixture of Largely due to the desire for clean labeled
microorganisms, which possess metabolic pathways products, interest is high in the development and
to break down cellulose and other biopolymers—in production of target existing aroma compounds
addition to traditional sugars, fats and proteins. By from feedstocks that can lend themselves to having
identifying target metabolic pathways in nature for a “cultured” identity for a partner. Because we have
products and bringing them into the ecosystem as access to ecosystems that can break down an array
either pure culture or polyculture additions, thou- of feedstocks, we can use almost any side stream or
sands of products can be identified and targeted. biomass waste from a partner, allowing for greater
flexibility in starting material choices.
Challenges in Polyculture Fermentation Perhaps the most important aspect of pursing
The most complicated aspects of polyculture non-GMO biotechnology strategies is the ability to
fermentation fall into handling predictability and harness and produce new and novel compounds in
yield. Product predictability can be achieved by creative ways. The myriad approaches to non-GMO
studying the metabolites in the ecosystem environ- biotechnology strategies include natural pure
ment, meta-genomic studies and metabolic pathway cultures, novel aging techniques, passive chemistry
analysis. However, there is significant white space in and new enzymes and metabolic pathways. Because
this realm and it does require fundamental research of the extreme diversity in nature and, therefore, in
to map out fermentation behaviors and shifts. microbial environments, there are many degradative
Yield is a more complex issue, with some path- and additive pathways that have yet to be exploited
ways offering robust yields, while others require by traditional microbiologists and chemists. The
novel strategies to cost effectively recover target information in these new pathways can be identi-
products from the soup of materials produced. fied and brought forward to create a new tool chest
One strategy is the subsidization of high-volume, of natural, non-GMO compounds for the modern
lower-value compounds with the production of perfumer and flavorist.
higher-value, low-volume compounds, such as Those looking for inspiration for non-GMO
supplementing the production of natural esters with biotechnology solutions should study the prin-
the co-manufacturing of various mercaptans. ciples of biomimicry, permaculture and green
This complex endeavor does not come without chemistry, which can lead to solutions and improve-
reward and opportunity. New intellectual property ments outside of the traditional biotechnology
development for existing and new compounds lens. Studying the ways in which ecosystems and
coupled with non-GMO production pathways is one ecologies adapt, perform and produce can generate
of the greatest assets of a new paradigm in innova- marvelous insights for new product development.
tive thinking. When one can develop new pathways
to products, new applications and opportunities
present themselves.

The
Search
Aroma Chemicals
for
New
by Mans Boelens and Ronald Boelens, Boelens Aroma Chemical
A
Vol. 28 • March/April 2003 Information Service (BACIS), and Harrie Boelens, Leiden University
lthough up to 10,000 natural • Studying biogeneration (biochemical forma-
and synthetic aroma chemicals tion) of new volatile compounds.
exist, the search for new or • Investigation of reaction occurring during
improved products is ongoing food processing (e.g. cooking, baking, frying).
in the flavor and fragrance • Predicting new groups of substances from
industry (F-1). The search for structure-odor relationships.
new substances starts with the
analysis of the possible benefits, Some recently published programs for the
the existing knowledge and the isolation of new products from nature will be
routes that can be followed. discussed herein. In addition, a series of ideas for
The hunt for new flavor and the development of new or improved flavor and
fragrance substances can, for example, be initiated fragrance substances will be presented. These
by the following guidelines: ideas concern new mono- and sesquiterpenoids,
substitution of sterical or electronical parts
• Isolation of new natural products (mixtures or (functional groups) of molecules by more stable
character-impact compounds). ones. New materials with greater organoleptic or
• Searching for open spots in groups of existing olfactive value-for-money will be suggested.
natural compounds.

F-1. Molecular structures of well-known and little known aromatic compounds
www.PerfumerFlavorist.com 41 41
General Introduction from living natural products, and quantification
One may question whether the search for new in depth of natural isolates.
aroma chemicals is economic. In other words, are • Chemical or Biogenesis Formation:
the costs for research in the flavor and fragrance often used for the identification and prepara-
industry a value for the money? Recent studies tion of new flavor materials: examples are the
of the American Council for Chemical Research Strecker degradation of amino acids, the
revealed that during the period of 1975 to 1998 Maillard reaction of amino acids and sugars,
every $1 invested by 83 chemical industries pro- followed by Amadori or Heinz rearrangements,
duced a profit of $2.6. The conclusion: research in the biochemical oxidation of unsaturated fatty
the chemical industry does pay off. Recently some acids and the biochemical formation of terpe-
interesting publications appeared regarding the noids and fatty acids.
search for and the design of new flavor and fragrance • Analogues of Existing Odorants: the synthesis
materials.1c,2a,4a-b,6 of analogues of irones (ionones and methyli-
The initiation of a research program for new onones), analogues of methyl jasmonates and
flavor and fragrance materials and improved damasc(en)ones, nitro-free benzenoid musk
preparation methods may have the following guiding compounds.
thoughts: • Petrochemicals and Other Raw Materials:
• What is already known and what has fragrance materials derived from dicyclopenta-
been done in the past? diene and from substituted phenols.
• How are the materials formed, what are the • Common Sense and Serendipity: functional-
precursors and (bio)chemical routes to the end ization of monoterpenes and sesquiterpenes,
products? C-10 derivatives.
• Are there reasonable reliable relationships Sometimes new aroma chemicals have been
between a designed molecular structure and discovered by pure accident.1c,2a It seems rather
expected olfactive and organoleptic qualities, unscientific and uneconomic to carry out random
and what is the target? organic synthetic research, to sit and wait until a
If one analyzes the search for new materials in valuable material comes out. However, even the
the flavor and fragrance industry during the last half unexpected discovery of a new aroma chemical as a
century one may divide this work in different areas, certain reason for its preparation.
as they are based on:
• Natural Products: new character-impact
compounds, quantification of compounds
emitting from new naturals, identification and
quantification of existing compounds emitting

F-2. Proposal of molecular structures for new flavor and fragrance compounds
For the production of computerized databases we Much know-how regarding the search of and the
studied:5d design for new materials was gathered from this study.
To develop a new aroma chemical, the investiga-
• Forty-two hundred perfumery materials, e.g. tion of structure-activity relationships is not just
aroma chemicals and natural isolates with their useful/helpful, but necessary. The reasons for studying
performance. odor-structure relationships can be, for instance, to
• Fifty-seven hundred fragrances with their quali- produce an aroma chemical (flavor or fragrance mate-
tative composition. rial) with:
• Fifty-five hundred flavor raw materials, e.g.
• Modified, new or unknown sensory properties,
natural, nature identical and artificial products.
e.g. concerning odor quality and appreciation.
• The quantitative analysis of 4,000 essential oils
• More odor value-for-money, e.g. tenacity,
with 4,500 constituents.
persistence.
• Over 7,000 volatile compounds in food prod-
• Other improved physiological properties, e.g.
ucts with their qualitative and quantitative
better biodegradability, less toxicity.
occurrence.
• Better application properties, e.g. fiber, hair and
skin substantivity.
• Improved physicochemical properties, e.g. • Improved and new monoterpene alcohols,
chemical stability, desired volatility and esters and aldehydes.
solubility. • New sesquiterpene derivatives.
• Substitution of isobutenyl by phenyl in
The purpose of the search for new flavor and monoterpenoids.
fragrance materials or improved methods for their • Substitution of isopentyl by cyclohexyl in some
preparation has various facets: aroma chemicals.
• Isobutyrates in place of acetates.
• Economics: less raw material, lower variable,
• Substitution of functional groups: aldehyde
fixed and investment costs, for instance the
by nitrile, ester by ketone, cis-double bond
synthesis of a macrocyclic musk compound.
by sulfur, chloro by methyl, allyl and geminal
• Sensory Properties: organoleptic and olfac-
dimethyl by cyclopropyl.
tive qualities, for instance character-impact
• New natural sulfur compounds by addition
compounds from natural isolates or (prepared)
of hydrogensulfide and methylmercaptan to
food products—preferred odor quality, higher
unsaturated natural flavor compounds.
intensity, longer tenacity.
• Volatile Schiff bases (F-2).
• Other Physiological Properties: lower toxicity,
less negative dermato logical peroperties.
• Application Properties: better fiber, hair or Recent Research
skin substantivity. In 1999, Givaudan carried out an innovative
• Chemical: good stability in functional perfume experimental program to discover new tastes, new
compounds, less vulnerable for (air) oxidation, molecules and new ingredients. A mission took
hydrolysis, hydration. their co-workers deep into the Gabonese rainfor-
• Physical: optimal volatility, evaporation, diffu- est to a place called Foret d’Abeille — one of the
sion properties. last unspoiled forests in Central Africa. In close
cooperation with ProNatura, a non-profit rainforest
In the following sections we will discuss: preservation group, Givaudan accomplished a highly
• Recently published programs for the isolation challenging expedition. Together with botanists
of new products from nature. and entomologists, the company’s research teams

from the United States and Switzerland explored
the rainforest’s incredible biodiversity, foraging on
foot and hovering above the treetops on the world’s
largest hot air balloon.6a Altogether, more than 250
samples were collected and evaluated. The following
new fruit flavors were developed: Ginger Strawberry
from Aframomum giganteum, Mangolino from
Dacryodes klaineana, Gabonese Pineapple from
Diospyros mannii, Rainforest Melon from a Drypetes
species, Wild Garcinia from Garcinia epunctata,
Bush Pearl from Irvingia gabonensis, jungle fruit
from Landolphia owariensis and Paradise Fruit from
Pentadesma butyracca.
In 1998 IFF sent, for the first time, a miniature
rose into space to produce three alternatives to the
hybrid rose plant under the influence of micrograv-
ity. A new rose fragrance was developed from the
results of this experiment. IFF is now engaged in and underwater headspace sampling in Madagascar.
a second NASA project exploring new perfumery The goal was to find new scent molecules, which
molecules.7b This project will be continued in the could be created in vitro later on. Samples were
coming years. taken from waterfalls, aquatic plants, forest mosses,
Recently, IFF (in the United States) has pre- tropical flowers, uncatalogued species of resinous
pared ground for a new hydroponic greenhouse to plants and native woods and barks. New mono- and
complement an existing greenhouse facility. The sesquiterpenoids were discovered in the process.
hydroponics technique concerns the growing of Quest believes that new fragrance profiles will
plants in water with essential chemicals in solution, spur new fragrance trends.6b
instead of in soil. The new facility will be used for the From these and earlier investigations, one may
extraction of fruit and flower aromas from hydro- draw the preliminary conclusion that new character-
ponically grown plants. The addition will feature impact compounds are seldom found. These studies
climate controls for each section, including under- often lead to new combinations and concentra-
ground heat. IFF states that there is a high interest in tions of already existing odoriferous materials as
this method of growing plants to discover innovative a consequence of new flavor and fragrance bases.
natural products that will enhance the quality of life Because much of this work is extremely expensive,
of consumers all over the world.6c one may question whether it is not more economic
Quest International, in conjunction with Oxford to investigate plant materials that are easily available
University and the Ecole Superieur du Science and which possess unknown sensory properties (e.g.
Agronomique, has announced the results of open-air witch hazel, sweet pea, petunia, phlox).
Isolation Techniques and Chemistry

Nature and natural isolates have always
stood as the models for the flavor and fragrance
chemist. In former times these scientists used
classical organic chemistry to synthesize new
materials. This chemistry was in principle
simple; the organic reactions were divided into
ionogenic and radical. The ionogenic reactions
could be either electrophile or nucleophile. As
reaction types, one could, for instance, recog-
nize additions, eliminations, substitutions and
rearrangements. Ionogenic reactions often were
carried out in polar solvents with a great deal
of inorganic materials and wastewaters. Radical
reactions were characterized by rather higher
temperatures that allowed the formation of free
radicals. Some catalytic processes were known
as, for example, hydrogenations and oxidations.
What has changed during the past decennium? For acetic acid to myrcene, acetylation cedarwood terpenes
one thing, more and more knowledge about bio- (thujopsene), or for the preparation of amber com-
chemical processes has been gained. Approximately pounds. In another instance, a mixture of macrocylic
1,500 flavor raw materials are now prepared by biomusk compounds could economically be prepared
these processes.5d New techniques and spectro- in a few reaction steps from 10-undecenoic acid and
scopic methods have been developed to isolate and 1,4-butanediol or tetrahydrofuran.
analyze constituents from nature down to parts per
billion. Is this all old wine in new barrels or new Substitution of Functional Groups
wine in old barrels? No. New isolation techniques,
More than 95 percent of the commercially available
such as the production of important organic
fragrance and flavor chemicals contain one or more
compounds from natural products by specific
functional groups. One may question, then, whether
membrane separation at room temperature, will
a functional group is necessary for the odor of a
allow progress. In addition, new membranes will
compound. No, it is not, because alkanes and benze-
be developed for these techniques. The biochemical
noid hydrocarbons sometimes have very pronounced
(enzymatic) manufacture of flavor and fragrance
odors. We wondered whether a trained observer would
materials will be improved and extended. These
be able to recognize an odorant by its functional
reactions will be carried out with greater specific-
group. Therefore we tested 100 aliphatic (normal
ity and in higher concentrations. Scientists will
C-3 to C-15) compounds with and without functional
increasingly realize what is happening in nature,
groups. Seven odor-trained chemists were used.
as in the example of the plant exudate labda-
Each observer received known standards with eight
num gum on Cistus ladaniferus in a subtropical
carbon atoms and 13 different functional groups, e.g.
climate at temperatures of up to 100°C in an acidic
octane, octanol, octanal, octanoic acid, hexyl acetate,
medium. Complete new reactions will be found as
octanethiol, octylamine, and so forth. The chemists
rearrangements (ring contractions) followed by
received all samples under codes, and upon smelling
photochemical oxidation (formation of amberox-
and comparing with the standards, had to write the
ide). In addition, many new homogenic catalytic
general chemical name, e.g. “This is an alkane, alcohol
enzymatic biological reactions will be discovered.
or thiol.”
In flavor and fragrance chemistry it is normally
The results were:
accepted that natural isolates are mixtures of some-
times hundreds of chemical compounds, whereas in • Seven hundwred six tests were performed, from
the search for new aroma chemicals, one often strives which 58 percent were correct and 42 percent
for chemically and olfactively pure compounds. It is far wrong.
easier and more economic to make olfactively accept- • For the C-3 to C-6 compounds, more than 80
able mixtures, as for instance with the addition of percent were identified based on their
functional groups.

T-1. Odor tests with aliphatic compounds: how seven experienced test persons identified aliphatic methyl ketones
and acetates based on their functional groups*
Compound Number Number Identified Most Frequent

of Compounds of Tests Type of
Correct Incorrect Mistakes
methyl ketone C-3 to C-63 3 21 76 24 spread
idem C-7 to C-10 3 26 46 54 ester (50 percent)
idem C-11 to C-15 3 21 0 100 alcohols (62 percent)
esters C-3 to C-6 7 52 58 42 methyl ketones (25 percent)
idem C-7 to C-10 8 51 80 20 spread
idem C-11 to C-15 9 56 29 71 alcohols (29 percent)
*The methyl ketones C-7 to C-10 and the esters C-3 to C-10 were identified on their fruity odor character; the C-11 to C-15 compounds (methyl ketones, esters and
alcohols) were often incorrectly identified because of their fatty odor characteristics.
T-2. Examples of substitution of functional groups with the same odor character
Original Example Aroma Subsituted Substituted Odor

Functional Chemical Functional Aroma Description
Group Group Chemical
aldehyde citral nitrile geranlynitrile citrusy, lemon-like
aldehyde benzaldehyde nitro nitrobenzene aromatic, spicy, bitter-almond-like
acetate isopentyl acetate methyl ketone 5-methyl-heptan-2-one fruity, banana-like
(Z)-hex-3-en-1-ol
(Z)-ethylene sulfur 3-thiapentan-1-ol (acetate) green, freshly mown grass
(acetate)
(trichloromethyl)- trimethylmethyl-benzyl
chloro methyl floral, rose-like
benzyl acetate acetate
nitro musk ambrette acetyl acetyl musk ambrette musky, erogenic
gem.dimethyl damasc(en)jone cyclopropyl damasc(en)one derivative floral-fruity, rose and rum-like
floral-fruity, orris and strawberry-
allyl/propenyl (methyl)ionones cyclopropyl (methyl)ionone derivatives
like
• For the C-7 to C-10 compounds, over 80 • Aldehyde for nitro in benzenoid compounds.
percent of the aldehydes, alcohols and thiols • cis-Olefine for sulfur in straightchain
were correctly recognized; from the other func- aliphatic compounds.
tional group compounds, more than 50 percent • Chloro by methyl in aliphatic and benzoid
were wrong. esters.
• For the C-11 to C-15 compounds, only the • Allyl and geminal dimethyl for cyclopropyl in
thiols could be identified correctly from the damasc(en)nones and ionones (F-2).
other functional groups; 50 to 100 percent were
Some examples of replacement functional groups
incorrectly identified.
in odorants with the maintenance of the more or
less same odor character are shown in T-2. From
The results with the methyl ketones and acetates
this table it is clear that, at times, functional groups
are shown in T-1.
can be replaced by others without a big change in
From this experiment it seems likely that experi-
the odor character. Substitution of functional groups
enced odor-perception observers can mistake certain
in molecules with more or less the same electronic
functional groups (ketones) by others (esters), even
charge distribution and similar odor characteris-
with the use of odor standards. The same holds true
tics are examples of “isoelectronic” molecules with
for other functional groups, such as the case of the
similar olfactive properties.
following substitutions:
The straight chain aliphatic aldehydes octanal
• Aldehyde for nitrile in monoterpenoid and decanal are organoleptically character-impact
and benzoid compounds. compounds of orange peel oil and could have been
T-3. Commercially available acetates and isobutyrates of C-4 to C-10 alcohols*
No. Alcohol Part Acetate Isobutyrate No. Alcohol Part Acetate Isobutyrate
1 butyl + + 18 citronellyl + +
2 sec.butyl + – 19 dihydromyrcenyl + –
3 isobutyl + + 20 tetrahydromyrcenyl + –
4 tert.butyl + – 21 tetrahydrolavandulyl + –
5 n-pentyl + – 22 neryl + +
6 2-methylbutyl + + 23 geranyl + +
7 3-methylbutyl + + 24 dimethyloctyl + –
8 hexyl + + 25 linalyl + +
9 2,4-hexadienyl + – 26 tetrahydrolinalyl + –
10 heptyl + – 27 myrcenyl + –
11 2-heptenyl + – 28 α-terpinyl + +
12 (Z)-3-heptenyl + – 29 dihydroterpinyl + –
13 octyl + – 30 benzyl + +
14 nonyl + – 31 phenethyl + +
15 decyl + – 32 α-methylbenzyl + –
16 2-decenyl + – 33 3-phenylpropyl + +
17 9-decenyl + – 34 cinnamyl + +
Total Number: 34 16
*Source: 2002 Allured’s Flavor and Fragrance Materials
used a lot more in perfume compounds. In fact, they food flavors and essential oils. Applications of these
are used in alcoholic perfumery in several luxury esters in functional perfume compounds for alkaline
perfumes such as Chanel No. 5. The application of media possess the disadvantage that they can sapon-
these aldehydes in functional perfumery (soap, deter- ify. In some cases, one may substitute the acetate
gents and other household products), however, has function with an isobutyrate or even a pivalate one
severe limitations because of the chemical stability without great change in the olfactive character of the
of the aldehyde function (oxidation, condensation). compounds. New aroma chemicals of this type are a-
Even in alcoholic perfumery, the aldehydes will terpinyl isobutyrate, phenethyl pivalate and vanillyl
form hemiacetals. The chemist working on odor- isobutyrate. As can be seen from T-3, of the commer-
structure relationships will modify the functional cially available acetates and isobutyrates there is still
aldehyde group. room for a series of isobutyrates.
There are several tools available to accomplish this:
• Substituting of the aldehyde function by a Substitution of Isobutenyl With Phenyl in
chemically more stable group such as nitrile, Monoterpenoids
acetyl or oxim. Various examples of the replacement of an iso-
• Preparing a vinyl ether of the aldehyde to give butenyl group with a phenyl group are presented
the slow release of the aldehyde in acidic media. in the literature. Substitution of the butenyl group
• Making an acetal of a lower alcohol with the by a phenyl group causes little effect on the odor
same target. character of linalool, rose oxide and geranonitrile.
• Forming an equilibrium in a Schiff base with Turin could predict with his method for spectrum
methyl anthranilate. calculation (inelastic electron tunneling spectros-
copy) the similarieites in odor character of these
Isobutyrates in Place of Acetates different structural classes.4b
Esters of lower fatty acids, e.g. formic and acetic, The isobutenyl part in the original molecules
have fruity-floral odor characters and occur in many is more vulnerable to oxidation than the phenyl

T-4. Commercially available aroma chemicals with isobutenyl by phenyl substitution
Original Aroma Chemical Substituted Aroma Commercial Name Odor Description

(Chemical Identity) Chemical (Supplier)
methyl phenethyl carbinol slightly floral, roselike,
6-methyl-5-hepten-2-ol 4-phenylbutan-2-ol
(F-3) sweet aromatic
Mefrosol (Quest),
citronellol 3-methyl- diffusive, fresh floral, rose
Phenoxanol (IFF),
(3,7-dimethyloct-6-enol) phenylpentan-1-ol absolute type
Phenylhexanol (Firmenich)
3-methyl-5-
citronellal Mefranal (Quest) green aldehydic
phenylpentanal
citronellylnitrile Hydrocitronitril (Haarmann
3-methyl-5-phenyl-
(3,7-dimethyloct-6- & Reimer), Citralis nitrile citrusy, lime, fresh
pentanenitrile
enenitrile) (IFF)
3-methyl-5-methyl- Citronitrile (Haarmann & fresh citrusy, lemon-like, somewhat
geranylnitrile
pent-2-enenitrile Reimer) aromatic-balsamic notes
part in substituted molecules. And while the odor cyclohexyl salicylate, cyclohexyl phenethyl ether
qualities of both molecules show a clear resem- and allyl cyclohexyloxyacetate (see T-5).
blance, the intensities of the phenyl substitutes In T-6 the commercially available isoamyl and
will sometimes decrease. On the other hand, the cyclohexyl esters are shown; there is still room for
odor tenacity of the phenyl derivatives is greater, more of the latter.
and their substantivities better. Several of these
phenyl substitutes are commercially available. New Terpenoid Alcohols, Esters and
There is room for many more monoterpenoid Aldehydes in Natural Products
substitutes, as for instance with: nerol/geraniol It is general knowledge that citrus oils contain
(esters), neryl/geranyl hemi-acetals, neric/geranic farnesenes and the corresponding aldehydes α- and
acid (esters), neryl/geranyl acetone, linalyl esters β-sinensal. Citrus oils also contain myrcene and
and hemi-acetals, and citronellyl derivatives (see ocimenes, but the corresponding aldehydes, myrce-
neryl/geranyl). Examples of commercially available nal and ocimenals (see F-2), have not been detected
aroma chemicals in which the isobutenyl part is up to now. During our studies of the composition
substituted by a phenyl part are shown in T-4. of 3,225 quantitative analyses of essential oils it
Examples of commercially available aroma was noted that more than 50 percent of these oils
chemicals in which the isopentyl part is substituted contained either myrcene or ocimenes. However,
by a cyclohexyl part are shown in T-5. Substitution less than 1 percent of these oils showed the pres-
of certain groups in molecules with more or less ence of myrcenol or ocimenols (see F-2), and none
the same profile (shape, volume) and similar odor of them contained the aldehydes. Synthesis of
characteristics are examples of “isosteric” molecules
with reminiscent olfactive properties.
Substitution of Isoamyl by Cyclohexyl in

Some Aroma Chemicals
The isoamyl group is a natural degradation
product from leucine and often occurs in natural
isolates, mostly as an ester. The lower aliphatic
isoamyl esters may have strong fruity odors. A
disadvantage of the application of these esters
is that they are highly volatile and can easily
saponify. One may substitute the isoamyl group
with a cyclohexyl group without disturbing the
odor character to any great extent. Some examples
of this substitution can be found in the odors of
T-5. Commercially available aroma chemicals with isopentyl by cyclohexyl substitution
Original Aroma Chemical/ Substituted Aroma Commercial Name Odor Description

Chemical Identity (Commercial Chemical (Supplier)
Name and Supplier)
isopentyl salicylate/ sweet aromatic- floral,
Cyclohexylsalicylat
3-methylbutyl 2-hydroxybenzoate cyclohexyl salicylate somewhat medicinal-
(Cognis)
(isoamyl salicylate) phenolic
allyl isopentoxyacetate/
prop-2-enyl-1
6-methyl-3-oxaheptanoate
Allyvert (Quest)
(A.I.A.A.-Inoue)
Cyclogalbanat (Dragoco)
(Allonate-Quest) green, fruity, herbal,
Cyclogabaniff (IFF)
(Allyfate-Quest) allyl cyclohexoxyacetate reminiscent of galbanum,
Hexylix (Charabot)
(Allyl amyl glycolate-IFF) pineapple connotation
Isoananat (Haarmann &
(Galballynate-Bell Aromatics)
Reimer)
(Isoamylix-Charabot)
(Isogalbanate-Dragoco)
(Pentyrate-Sensient)
isopentyl phenylethyl ether/
2-isopentoxy-1-phenylethance
(Anther-Quest) cyclohexyl phenylethyl floral note with hyacinth
Phenafleur (IFF)
(Iphaneine-IFF) ether associations
(phenylethyl isoamyl ether-Toyotama)
(Treflon-Takasago)
T-6. Commercially available isoamyl and cyclohexyl esters*
No. Ester/Acid Part Ester/Alcohol Part No. Ester/Acid Part Ester/Alcohol Part
Isoamyl Cyclohexyl Isoamyl Cyclohexyl
1 acetate + + 19 isobutyrate + +
2 acetoacetate + – 20 isovalerate + +
3 angelate + – 21 lactate + –
4 anthranilate – + 22 laurate + –
5 benzoate + – 23 2-methylbutanoate + –
6 butyrate + + 24 nonanoate + –
7 cinnamate + + 25 octanoate + –
8 crotonate + + 26 phenylacetate + +
9 cyclopentenylacetate – + 27 3-phenylpropionate + –
10 decanoate + – 28 propionate + +
11 eugenyl + – 29 pyruvate + –
12 formate + + 30 salicylate + +
13 4-(2-furan)-butyrate + – 31 senecioate + –
3-(methylthio)-
14 3-(2-furan)-propionate + – 32 + –
propionate
15 geranate + – 33 + – tiglate
16 heptanoate + – 34 + – undecylenate
17 heptinecarbonate + – 35 + – valerate
18 hexanoate + +
Total Number: 33 13
*Source: 2002 Allured’s Flavor and Fragrance Materials

pure myrcenyl and ocimenyl acetate revealed that comparisons to be made between valencene and
they possess excellent olfactive properties, and an nootkatone, and α-cedrene and cedrenone.
extremely fresh floral character that improves those Regarding the epoxidation of sesquiterpenes and
of linalool and its acetate. T-7 shows the frequency the conversion of the epoxide to ketones (isolongifola-
of the occurrence and the concentration ranges of none, cedranone, caryophylla-none, etc.), epoxidation
some monoterpenoids in essential oils. T-8 shows can easily be carried out with hydroperoxide and
the commercially available citronellyl, geranyl and formic acid (or ester) to a mixture of epoxides, diols
linalyl esters. It is clear that more linalyl esters can and formats, which in turn can be converted into
be prepared; moreover, it is likely that new myrcenyl simple sesquiterpene ketones. It should also be noted
and ocimenyl esters will be found in nature and that methanol may be added to sesquiterpene hydro-
manufactured. carbons (such as IFF’s cedryl methyl ether).
New Sesquiterpenoid Derivatives Studying the Biochemical Formation

The allylic oxidation of sesquiterpenes in analogy of New Volatile Compounds
with that of limonene for the formation of C-15 will The biogenesis of fatty acids and isoprenoids from
lead to analogues of carvone (F-2), perilla alde- acetyl-coenzym-A has been known for decennia.
hyde and isopiperitenone. Sesquiterpene carbonyl Fatty acids are linearly built up via aceto-acetyl-ScoA
analogues should be developed from other olfac- to higher β-oxo-acyl-ScoA derivatives, followed by
tively interesting monoterpenoid ketones: thujones, reduction, dehydration and again by reduction into
verbenone and chrysanthenone (F-2). These sesqui- fatty acids with the general formula: CH3 (CH2)
terpene ketones could have useful odor qualities. nCOOH, where n is zero or an even number.
F-2 to F-3 reveal the molecular structures of some of Isoprenoids are biochemically formed via aceto-
these sesquiterpenylcarbonyls. There are interesting acetyl-ScoA via β-hydroxy-β- methyl-glutaryl-ScoA
T-7. Frequency of the occurrence and concentration of some mono- and sesquiterpenoids in 3,225 essential oils
Monoterpenoid In Total Number Concentration In Concentration Range In Concentration Range

of Oils Range (Percent) (Percent)/Number of Oils (Percent)/Number of Oils
myrcene 2,180 0.01-95 1-95/1,063 10-95/81
myrcenol 20 0.01-8.2 – –
myrcenyl acetate 2 0.01-6.0 – –
myrcenal 0 – – –
(Z)-ocimene 880 0.01-43 1-43/228 10-43/41
(E)-ocimene 975 0.01-95 1-95/252 10-95/95
(Z)-ocimenol 3 0.01-1.5 – –
(E)-ocimenol 4 0.01-1.5 – –
ocimenals 0 – – –
menthol 195 0.01-85 1-85/123 10-85/101
menthyl acetate 126 0.01-52 1-52/102 10-52/101
menthone 262 0.01-60 1-60/171 10-54/18
thymol 405 0.01-90 1-90/180 10-90/91
carvone 364 0.01-80 1-80/87 10-80/46
carvomenthone 5 0.01-1 – –
carvomenthol 0 – – –
carvomenthyl acetate 1 0.01-1 – –
carvacrol 364 0.01-90 1-90/154 10-90/94
α-farnesenes 286 0.01-40 1-40/82 10-40/15
β-farnesenes 530 0.01-90 1-90/150 10-90/16
α-sinensal 71 0.01-3 – –
β-sinensal 59 0.01-3 – –
and mevalonate to branchedchain (CH3)2C=CH- up to now less than 10 percent, or 420 esters in total,
[CH2-CH(CH3)-CH=CH]- derivatives, where x is zero have been found in these fruits.
or a whole number. One could imagine that a combi-
nation of the two biogenetic pathways should lead to Investigation of Reactions During
geminal-methylor 3-methyl-alk-2-enyl derivatives. If Food Processing
this combination of the two routes is indeed pos- The most important chemical event during food
sible, one could expect a series of these compounds processing is the Maillard reaction of amino acids
in natural products, which contain the proper pre- and sugars, followed by Amadori or Heinz rearrange-
cursors and enzyme. We supposed that citrus fruits, ments. A European scientific committee was formed
containing fatty acid derivatives and isoprenoids, from universities and the flavor industry to study this
should present a fair chance of finding 3-methylalk- reaction in detail. It was discovered that hydrogen
2-enyl derivatives. Therefore, we prepared a series of sulfide (from cysteine) and methyl-mercaptan (from
3-methylalkenals and searched for their occurrence methylcysteine) can be added to (Z)-3-hexenol and
in different citrus oils. Indeed, it was possible to limonene during flavor formation.
detect 3-methyloct-2-enal in lemon oil by a combined New flavor constituents can be formed by the
gaschromato-graphic/mass spectrometric technique. addition of hydrogen sulfide or methylmercaptan
3-Methyloct-2-enal has a distinct lemon flavor and to unsaturated compounds [e.g. (Z)-4-heptenal,
improves the organoleptic quality of the natural (E,Z)-2,6-nonadienal, monoterpenes, sesquiterpenes,
oil. β-Methyl-γ-octanoic lactone has been found in damasc(en)ones]. About 10 percent of all published
alcoholic beverages. The compound has a coconut- volatile compounds are sulfur compounds. 7,10 An
like odor, but is indispensable for a good flavor of important group of these compounds are disulfides,
brandy, whiskey or rum. Geminaldimethyl- alkanoic of which (until now) about 60 have been found in
acids have been found in various meat and in dairy food products. On the basis of all the ca. 50 (= n)
products, e.g. 9-methyl-dodecanoic acid in mutton, thiols one could expect n(n + 1)/2 = 1,275 disulfides.
and 11-methyldodecanoic acid in powdered milk. Although not all the 50 thiols occur in the same
Hundreds of new substances can be designed and foods or beverages, many more disulfides surely exist
possibly found in nature following these biochemical and will be found.
guidelines.
So far, up to 70 volatile alcohols and about 60 Volatile Schiff’s Bases
fatty acids have been detected in food flavors, such A Schiff’s base of methyl anthranilate with
as apple, banana, guava, grape, papaya, raspberry olfactively interesting aldehydes is well known in
and strawberry.5d A simple calculation makes it clear perfumery. However, this Schiff’s base is a mixture
that 70 x 60 = 4,200 esters should occur. However, of the starting materials in equilibrium with the
T-8. Commercially available citronellyl, geranyl and linalyl esters
No. Ester/Acid Part Ester/Alcohol Part No. Ester/Acid Part Ester/Alcohol Part
Citronellyl Geranyl Linalyl Citronellyl Geranyl Linalyl
1 acetate + + + 12 hexanoate + + +
2 acetoacetate – + – 13 isobutyrate + + +
3 anthranilate + + + 14 isovalerate + + +
4 benzoate + + – 15 2-methylbutanoate + + –
5 butyrate + + + 16 phenylacetate + + +
6 cinnamate – – + 17 octanoate – + +
7 crotonate + + – 18 propanoate + + +
8 decanoate + + – 19 tiglate + + –
9 dodecanoate + + – 20 undecylenate – + –
10 ethyl oxalate + – – 21 valerate + + –
11 formate + + +
Total Number: 7 19 11

end product. If one purifies the end product, e.g. 2. C.S. Sell, a.Ingredients for the Modern Perfumery Industry;
in: The Chemistry of Fragrances compiled by D.H. Pybus and
by high vacuum distillation, the resulting mate-
C.S. Sell; The Royal Soc. Of Chem. Letchworth, UK (1999);
rial is often odorless. One may produce volatile b. Cracking the Code: How Does Our Sense of Smell Work?;
N-alkylidene methyl anthranilates (F-2) (from Perfum. Flav., Vol. 26, 2-7 (Jan/Feb 2001).
ethanal, propanal, butanal, isobutanal, pentanal,
3. G. Frater, J.A. Bajgrowicz and P. Kraft, Fragrance Chemistry,
2- and 3- methylbutanal, hexanal and hexenal) in
Tetrahedron, Vol. 54, 7633-7703 (1998).
pure form, which likely occur in natural products.
Only one pure N-alkylidene methyl anthranilates 4. L. Turin, a. and F. Yoshii; Structure-odor relations: a modern
perspective in the Handbook of Olfaction and Gustation, R.
(from 2- methylpentanal, mevanthral from Quest)
Doty, Editor; Marcel Dekker, New York (2001); b. A method for
is commercially available today. the calculation of odor character from molecular structure, to be
published.
Conclusion 5. H. Boelens, a. Chemische Konstitution und Geruch; Chemischer
New groups of aroma chemicals can be Zeitung, Vol. 97, 1-8 (1973); b. Relationships between the
designed by the substitution of isosteric groups chemical structure of compounds and their olfactive properties;
(e.g. isobutenyl by phenyl and isopentyl by Cosm. Perf., Vol. 89, 1-7 (1974); c. Molecular structure and
cyclohexyl, gem-dimethyl by cyclopropyl) and olfactive properties; Structure-Activity Relationships in
Chemoreception, G. Benz (ed.), Information Retrieval Ltd.,
of isoelectronic groups (e.g. aldehyde by nitrile,
London, UK, 197-209 (1976); d. Computerized Databases:
acetate by methyl ketone, allyl by cyclopropyl, Perfumery Materials and Performance (PMP); Analyses of
chloro by methyl). Essential Oils (ESO); Volatile Compounds in Food (VCF), Flavor
In closing, new flavor and fragrance materials Raw Materials (FRM) (2002).
can be developed by:
6. a. Perf. Flav., Vol. 27, 18-19, July/August 2002; b. Perf. Flav. Vol.
• Exploring new natural materials. 26, 8, July/August 2001; c. Perf. Flav., Vol. 26, 11, Sept/Oct 2001.
• Extending characteristic monoterpenoids 7. B.D. Mookherjee et al., a. Fruits and Flowers: Live versus Dead
to sesquiterpenoids. — which do we want? In: Flavors and Fragrances: a World
• Developing new monoterpenoids from Perspective. Proceedings of the 10th International Congress of
similar sesquiterpenoids. Essential Oil, Fragrances and Flavors, Washington, DC, USA,
16-20 November 1986, 415- 424; b. The effect of microgravity on
• Functionalization of mono- and sesquiterpenes.
the fragrance of a miniature rose ‘overnight sensation’ on STS95;
• New biochemical pathways. Lecture Flavours and Fragrances 2001: From the Sensation to
• Volatile Schiff’s bases. the Synthesis, 16-18 May 2001, University of Warwick, Coventry,
• New biochemical pathways. UK.
• New products formed during food processing. 8. R, Kaiser, The Scent of Orchids, Olfactory and chemical
• Extension of esters of naturally occurring investigations; Elsevier, Amsterdam, Editiones Roche, Basel
alcohols and esters. 1993.
• Addition of hydrogensulfide and
9. R. Pelzer et al.; in: Recent Developments of Flavour and
methylmercaptan to natural and unsaturated Fragrance Chemistry: Proceedings of the 3rd International
compounds. Haarmann & Reimer Symposium, R. Hopp and K. Mori (eds.),
• Extension of sulfides and disulfides from VCH Publishers, Weinheim, 1993, 29.
existing thiols.
10. S. Arctander, Perfume and Flavor Chemicals (Aroma Chemicals)
(1969); Allured Publishing Corp., Carol Stream, IL, USA (1994).
11. K. Bauer, D. Garbe and H. Surburg, Common Fragrance and

Address correspondence to Mans Boelens, Boelens Aroma Chemical Information
Service, Groen van Prinstererlaan 21, 1272 GB Huizen, The Netherlands. Flavor Materials; VCH Verlagsgesellschaft GmbH, Weinheim,
Germany (1990).
References
12. G. Ohloff, Scent and Fragrances, Springer Verlag, Berlin (1994).
1. K.J. Rossiter, a. Structure-Odor Relationships, Chem. Rev., Vol.
96, no. 8, 2101-3240 (1996); b. The Design and Synthesis of 13. P.M. Mueller and D. Lamparsky, Perfumes: Art, Science and
Novel Odorous Materials, Diss. Univ. of Kent, Canterbury (1998); Technology, Elsevier, Amsterdam (1994).
c.The Search for New Fragrance Ingredients; in: The Chemistry
of Fragrances compiled by D.H. Pybus and C.S. Sell; The Royal
Soc. Of Chem. Letchworth, UK (1999).
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From Source to Sense: Natural

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The Future of Naturals in

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The Impact of Headspace Technology Can Unhealthy or Dangerous Solvents

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Vol. 37 • July 2012

F-3. Typical sulfur compounds found in garlic F-4. 2-Isopropyl-4-methyl thiazole

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F-2. Enzymatic biocatalysis of valencene to nootkatone

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Unique Complex Bases

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Enzyme/organism Product Flavorant

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functionalities of microorganisms, plants and their WO/2000/017319 (2000)

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F-2. HIAC formation from ACS precursors

R, R1 = —CH3 , —CH2—CH==CH2 , —CH2—CH2—CH3 , —CH==CH—CH3

Health Benefits of Allium HIACs

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he future of F&F is less volatile or heat-sensitive chemicals. In this

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F-1. The Flavor Industry: A Brief History Overview (not to scale)

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US Regulations EU Regulations Japan China

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Isolation Techniques and Chemistry

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Compound Number Number Identified Most Frequent

Original Example Aroma Subsituted Substituted Odor

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Original Aroma Chemical Substituted Aroma Commercial Name Odor Description

Substitution of Isoamyl by Cyclohexyl in

Original Aroma Chemical/ Substituted Aroma Commercial Name Odor Description

T-6. Commercially available isoamyl and cyclohexyl esters*

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New Sesquiterpenoid Derivatives Studying the Biochemical Formation

Monoterpenoid In Total Number Concentration In Concentration Range In Concentration Range

T-8. Commercially available citronellyl, geranyl and linalyl esters

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11. K. Bauer, D. Garbe and H. Surburg, Common Fragrance and

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