Terpineol

Chapter 6 1904
P
i
n
e
resin colle
c
t
io
n
rom Mesopotamia through
Egypt to Greece, the
ancient cultures inhabiting
those beautiful lands have
celebrated pine trees not only for
their wood, but also for their bark
and resin, for which they found a
great many applications. In this
book we shall be examining several
compounds from evergreen trees.
Turpentine, a distillate obtained
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cussed in this chapter as a source of
fragrant compounds, although it has
many other uses. In later chapters,
the stories of longifolene and Taxol

,
the anticancer natural product iso-
lated from the bark of the yew tree,
will be recounted.
Pine resins can be distilled into two
major fractions, turpentine and rosin.
The exact composition of each of these
fractions varies according to the spe-
cies of tree and the region of the globe
from which the viscous resin is collected.
Turpentine, a pungent clear liquid with
a bitter taste, is composed of a number
of organic compounds, primarily a series
of volatile terpenes. The terpene natural
products, which arise from the mevalonic
acid biochemical pathway, have molecu-
lar skeletons consisting of isoprene units,
isoprene being a hve carbon basic build-
ing block (Box 1). Monoterpenes (C10 ter-
Terpene natural products Box 1
Terpineol
3 4
Selected fragrant natural products Box 2
penes), such as terpineol, are
unsaturated light oils, gener-
ally with heavy scents, that
have been used since time
immemorial as ingre-
dients in paints, dis-
infectants, medicines,
materials for religious
rituals, and perfumes.
For thousands of
years our ancestors have
appreciated and experi-
mented with perfumes in
what is a continuing fascination
with this luxury commodity. The art
of blending fragrances was hrst cultivated
in Mesopotamia and Egypt. Subsequently
the knowledge spread to Greece and from
there on to Rome. These traditions con-
tinued to be practiced and honed during
the Middle Ages as the Arabs became
experts at crafting exotic blends of per-
fumes. With the advent of distillation and
other techniques, perfumery hourished in
Renaissance Italy. However, as chemis-
try advanced and organic synthesis was
born in the nineteenth century, the bur-
geoning chemical industry of Germany
became a center for scent production
while France became a hub for perfume
blending. Today the coveted crown is
shared between herce rivals on opposing
sides of the Atlantic; France, Switzerland,
and Germany vie for superiority
with the relative newcomer to
the art, the United States.
The J apanese are also
fast becoming serious
players in the art of
perfumery.
The esteem in
which perfumes were
held throughout his-
tory is illustrated by
the magnihcent crafts-
manship lavished on
the vessels that con-
tained these precious
essences. Uncovering
these treasures of
artistry and skill has
allowed historians to trace
a vivid record of the apprecia-
tion of hne fragrances down through the
ages and across cultures and civilizations.
It is perhaps surprising that while these
artifacts have changed dramatically over
the centuries, the basic ingredients of
the scents themselves have remained
essentially the same. Thus, the
aroma from the Lebanese cedar
(Cedrus libani ), so highly prized
by the Mesopotamians and
enjoyed by Cleopatra and Mark
Antony, is still a key component
in some stylish scents of today.
Various fashions in perfumery can
be traced to different periods of his-
tory or geographic origins.
But what makes a perfume? In old
times, before ethanol could be purihed
by distillation, crude fatty extracts
were prepared by a tech-
nique known as enheu-
rage, wherein delicate
horal oils were drawn
out from petals. These
scented oils were
used in cosmetics and
medicine. Modern fra-
grances are mixtures
of essential oils and
synthetic aroma chem-
P
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f
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b
o
t
t
le
s
fromth
e
M
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d
d
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e
A
g
e
s
Marc Antony and Cleopatra as portrayed by
Richard Burton and Elizabeth Taylor
A
n
c
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e
n
t
G
r
e
e
k
cosmetic
b
o
x
(
p
y
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s
)
Chapter 6
3 5
icals diluted with
ethanol and water.
The description of the
hnal perfume depends
on its essential oil con-
tent. Thus, eau de parfum
contains 1530 percent of
essential oils, eau de toilette has
only 48 percent, while eau de cologne
contains less than 5 percent of the
expensive scented oils. The additional
load (and thus expense) of an eau de
parfum preparation provides a stronger
and longer lasting bouquet by virtue of
the higher concentrations of essential oil.
Creating a perfume can be likened to the
art of composing music, and the hnest
examples contain an intricate medley of
chemical compounds that vary in molec-
ular structure and, therefore, in aroma
and volatility. The perfect design yields a
layered blend that ensures the develop-
ment of the scent on the skin with time.
The modern era for perfumery was
ushered in by developments in chemis-
try beginning in the nineteenth
century. Improvements in
techniques allowed the frag-
ile active ingredients to be
extracted from their natural
sources using organic sol-
vents at ambient tempera-
ture for the hrst time, thus
the selection of essential
oils available was greatly
enriched (Box 2). This
advance was surpassed
only when, in the second
half of the nineteenth cen-
tury, chemists hrst began to
explore organic synthesis
as a means to reproduce
alluring natural scents.
In 1868, British chemist
William Henry Perkin,
Sr., made coumarin
(which smells of hay
and woodruff) in the
laboratory for the hrst
time. This was followed
by the syntheses of other
naturally occurring fragrances:
musk (1888), vanilla (1890), and
violet (1893). Later, camphor (see Chapter
5) and terpineol were added to the grow-
ing list of synthetic accomplishments. The
1920s and 1930s fostered yet another
creative surge, the inhuence of which still
pervades today. Thus, fragrances such as
the legendary Chanel N 5 (1921) and J oy
(1931) set a new standard, ushering in an
era of large scale production, distribution,
and consumption of hne perfumes.
Today, these items constitute an inti-
mate part of our lives and as we enjoy
them we must not forget that their exqui-
site bouquets are a result of the symbi-
otic application of scientihc and artistic
talents. Synthetic chemists can recreate
almost any known natural scent, and in
addition they have designed and syn-
thesized a whole host of new molecules
with wonderful odors to complement
those provided by nature, thereby fur-
nishing an amazing library of pleasing
smells. Chemistry, therefore, has been
pivotal to the creation of perfumes, and
has assisted in elevating them to their
current popular and accessible status as
items for everyone to enjoy (Box 3).
Simple monoterpenes extracted from
natural sources are responsible for the
characteristic smells of many plants and
Selected scent molecules from
famous perfumes
Box 3
M
a
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h
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s
distilling
p
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f
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Terpineol
3 6
"Ths rsssn1 \nvss1\_a1\on was undsr1aksn w\1h
1hs obso1 o! syn1hss\s\n_ 1sr\n, 1sr\nsol,
and d\sn1sns, no1 only on aoooun1 o! 1hs \n1sr-
ss1 wh\oh always a11aohss 1o syn1hssss o! 1h\s
k\nd, bu1 also \n 1hs hos 1ha1 a ms1hod o!
syn1hss\s m\_h1 bs dsv\ssd o! suoh a s\mls k\nd
1ha1 1hsrs would no lon_sr bs room !or
doub1 as 1o 1hs oons1\1u1\on o!
1hsss \mor1an1 subs1anoss."
fruits, including citrus fruits, pine,
spearmint, and geranium.
Recognition of this feature
spurred an intense inter-
est in these molecules
amongst chemists, who
began to study them over
one hundred years ago.
Terpin hydrate captured
the imagination of chem-
ists in the last decades
of the nineteenth century
because not only was its con-
stitution quite a puzzle, but also
it was readily crystallized from crude
turpentine in a very pure form. For many
years chemists (especially William A.
Tilden, Otto Wallach, and Georg Wagner)
toiled and argued, seeking a solution to
the conundrum of the correct formulae
to represent this and other simple related
terpenes. (Box 4).
William Henry Perkin, J r., had experi-
mental chemistry in his blood. Along with
the synthesis of coumarin, his father,
William, Sr., had discovered mauveine,
the purple dye that revolutionized the
fashion world and started an industry in
the late nineteenth century (see Chapter
8). William, Sr., passed his enthusiasm
for the unknown on to his son, leading
to William, J r.s, ambitious attempt to
synthesize and conhrm the structure of
various terpenes (Box 4).
In a style resembling that still in use
today for reporting a total synthe-
sis, William Perkin, J r., related
his progress along his syn-
thetic path to terpineol, step
by step, starting from ethyl
cyanoacetate and ethyl 3-
iodopropionate (Box 5).
Perkins synthesis made
use of the then recently
discovered Grignard reac-
tion (Box 6) on two
occasions, each time
using the Grignard
reagent methylmag-
nesium iodide. The hrst
such reaction involved the
addition of this reagent to a
ketone, forming a tertiary alcohol, which
served as a precursor for the endocyclic
alkene of terpineol. The second applica-
tion of the Grignard chemistry converted
an ester group to the tertiary alcohol of
the target, thus completing the synthe-
sis. In the same paper, Perkin reported
the conversion of terpineol into two other
monoterpenes. Dehydration of terpin-
eol gave dipentene (the racemic form
of limonene a key component in many
citrus oils), while hydration of terpineol
gave the crystalline terpin hydrate (Box
5); thus he had conclusively determined
the structures of all of these related ter-
penes. Throughout the sequence, Perkin
described the intermediates in great
detail, including such physical properties
as melting points, crystal forms, color and
smell. For example, he noted
that synthetic terpineol
had the same distinct
smell of lilac charac-
teristic of the natu-
ral material. This
synthetic achieve-
ment is all the
more impressive
when one consid-
ers the relatively
Lilac
William Henry Perkin, Jr., explains his motives in pursuing
the synthesis of terpineol
Box 4
Perkins synthesis of terpineol, terpin
hydrate and limonene
Box 5
W
i
l
l
i
a
m
H
enry Pe
rk
in
,
S
r
.
William Henry Perkin, J r.
Chapter 6
3 7
In 1901, Franois Auguste Victor Grignard published
his groundbreaking doctoral thesis describing his studies on
organomagnesium reagents. Grignard, born in Cherbourg
(France) in 1871, was part of a generation of French
chemists who made a signihcant imprint on chemical
synthesis with the invention of a number of organome-
tallic methods, many of which are still in use today. For
example, Paul Sabatier, who would share the 1912 Nobel
Prize in Chemistry with Grignard, developed the process of
hydrogenation at around this time (see Chapter 28).
Grignard reagents are formed from alkyl, alkenyl, or aryl
halides, by reaction with metallic magnesium in ethereal solvents. Although to this day the
exact nature of the species formed is poorly understood, they react as nucleophiles, and are
commonly employed in additions to carbonyl groups. In the century since the invention of the
Grignard reagent, a number of similar reagents have been developed, notably organolithium
compounds, which are also often used as strong bases. Grignard and organolithium reagents
have also been employed as precursors to other organometallic species (for example, organo-
copper reagents), each of which has subtly different reactivity.
The Grignard Reaction and the total synthesis of zeaxanthin Box 6
V
ic
tor Grigna
r
d
Today, the Grignard reaction is applied, in its various guises, to the synthesis of many
natural products, and industrial materials. The example below shows the application of a
Grignard reagent (vinylmagnesium chloride) in BASFs synthesis of the carotenoid zeaxanthin,
a compound used as a nutritional supplement.
primitive analytical tools available in
Perkins time.
The importance of the
structures established by
Perkins total synthe-
sis may not have been
fully appreciated until
much later, when it
became apparent just
how many diverse
terpenoids exist in
nature and how many
important roles they
fulhll. The chemistry of
terpenes has been greatly
advanced since the early
1900s by many scientists, includ-
ing Duilio Arigoni, whose brilliant syn-
thetic and biosynthetic contributions
have helped shape the held. Examples of
this ubiquitous class of natural products
include all the steroids, many vitamins,
and miscellaneous compounds such as
the anticancer agent Taxol

, mentioned
above. In this book you will, time and
time again, come across increasingly
complex descendants of isoprene, the
syntheses of which require sophis-
ticated and ingenious strate-
gies to master their much
more complex structures.
Perkins synthesis deliv-
ered racemic terpineol
(an equal mixture of
both enantiomers).
Chemists would later
learn tricks allowing
them to synthesize
selectively one enan-
tiomeric form of a given
substance at will. So
remember that, with Perkins
synthesis of terpineol, we are
still at the very beginning of our journey
through the synthesis archives.
D
u
ilio Arigo
n
i
Terpineol
3 8
Spindle bottle,
Late Cypriot IIA:2
(14101375 B.C.)
3HUIXPHDVN
from mid-17
th
century India
18
th
Century
pocket-sized
French perfume
bottle
Chapter 6
3 9
W. H. Perkin, J r., LXVI. Experiments on the Synthesis of the Terpenes.
Part I. Synthesis of Terpin, Inactive Terpineol, and Diterpene, J . Chem.
Soc. 1904, 85, 654671.
K. B. G. Torssell, Natural Product Chemistry, 2nd Ed.,
Apotekarsocieteten, Stockholm, 1997, pp. 251312.
E. T. Morris, Scents of Time. Perfume from Ancient Egypt to the 21
st
Century, Bulhnch Press, New York, 1999.
P. Kraft, J . A. Bajgrowicz, C. Denis, G. Frter, Odds and Trends: Recent
Developments in the Chemistry of Odorants, Angew. Chem. Int. Ed.
2000, 39, 29803010.
Further Reading
Ball and stick model of
the molecule of terpineol
Terpineol
4 0