8 Terpenoids

1. Introduction
of ocur in the plant kingdom; a
The terpenoids form a group of compounds the majority which
few terpenoids have been obtained from other sources. 1The simpler mono- and sesqui-terpenoids
are the chief constituents of the essential oils; these are the volatile oils obtained from the sap and

tissues of certain plants and trees. The essential

oils
have been used in perfumery from
the earliest
times. Thedi- and tri-terpenoids whichare notsteam volatile.,are obtainedfrom plantand tree gums
and resins. The tetraterpenoids fom a group ot compounds known as the carotenoids, and it s
1sual to treat these as a separate group (se Ch. 9). Rubber is the most important polyterpenoid.
have the molecular formula (C,H,).. and the value of n
Most natural terpenoid hydrocarbons
Is used as a basis tor
class ihication.
Class
Nunber of carbon atoms
10
16 Monoterpenoids (CoH1«)
Sesquiterpenoids (C,,H2a)
tn)
DiterpenoidsC2o
(IV) esterterpenoids (C2sH4o)
V) S0
Triterpenoids (C3oHas)
(vi) 40 Tetraterpenoids (Carotenoids) (CaoHsa)
(Vin) Polyterpenoids (C,H,).
The sesterterpenoids have been discovered recently, and so far only very few are known. In
addition to the
terpenoid hydrocarbons, thereare derivatives of each class which
the oxygenated
also occur naturally, and these are mainly alcohols, aldehydes or ketones.
The group of compounds discussed in this chapter was originally classified as the "terpenes,
and although this name is still used, there is a tendency to use the more general name "terpenoids.
This is due to the fact that sinoe the suffix 'ene signifies nsaturated hydrocarbons, the name
terpene" is inappropriate to include compounds such as alcohols, aldehydes, ketones, etc. The term
"terpene" is restricted to the hydrocarbons CoH16
The thermal decomposition of almost all terpenoids gives isoprene as one of the products, and
this led to the suggestion that the skeleton structures of all naturally occurring terpenoids can be
built up o isoprene units; this is known as the isoprene rule, and was first pointed out by Wallach

Copyrightnd nm
 erpenoids 369

(1887). Thus the divisibility into isoprene units may be regarded as a necessary condition to be
satisfied by the structure of any plant-synthesised terpenoid. Furthermore, Ingold (1925) pointed
out that the isoprene units in natural terpenoids were joined "head to tail' (the hcad being the
branched end of isoprene). This divisibility into isoprene units, and their head to tail union, may
conveniently be referred to as the special isoprene rule. It should be noted, however, that this rule,
wnich nas proved very useu, can oniy be used as a gudingprincipie and not as a nxed ruie. everal
exceptions occur, eg, lavandulol (98a) and eremophilone (28d); the carotenoids are joined tail to
tail at their centre (see Ch. 9); there are also some terpenoids whose carbon content is not a multupie
of five and those whose carbon content is a multiple of five but cannot be divided into isoprene units.
The carbon skeletons of open-chain monoterpenoids and sesquiterpenoids are:

c-t-c-cic-t-c-c
head tail head tail

edeeeieee
Monocyclic terpenoids contain a six-membered ring. and in this connection Ingold (1921) pointed
out that a gem-dialkyl group tends to render the cyclohexane ring unstable. Hence, in closing the
open chain toa cyclohexane ring, use of this "gem-dialkyl rule limits the number of possibie strc
tures (but sce, eg., abietic acid, $32). Thus the monoterpenoid open chain can gve rise to oniy one
posibility for a monocyclic monoterpenoid, riz. the p-cymene structure This is shown in the
following structures, the acyclic structure being written in the conventional "ring shape (see 4)

acyclc structure P-cymene sMructure

Most natural monocyclic monoterpenoids are derivatives of p-cymene.

four,
Bicyclic monoterpenoids contain six-membered ring and three, require
a a
or five-membered ring ot
the
Ingold (1921) also pointed out that cyclopropane and cyclobutane rings introduction
them stabie to be of occurrence in nature. Thus
capable
a gem-dimethyl group to render suthiciently known.
closure of the 10C open chain gives three possible bicyclic structures; all three types are

$2. Isolation of monoterpenoids and sesquiterpenoids

Plants containing essential oils usually have the greatest concentration at some particular time

at sunset. In general, there are four methods of extraction of the terpenoids:

eg. jasmine
370 Terpenoids (Ch.&

() expression; (i) steam distillation; (ii) extraction by means of volatile solvents; (iv) adsorption
in purified fats (enfleurage), Method (Gi) is the one most widely used, the plant
i s macerated and then
steam distilled. If the compound decomposes under these conditions, it may be extracted with light
petrol at 50 C, and the solvent then removed by distillation under reduced prLssure. Alternatively,
the method of adsorption in fats is used. The fat is warmed to about50C, and then the tlower petals
are spread on the surfaceof the fat until the latter is saturated. The fat is now digested with ethanol
any fat that dissolves being removed by cooling to 20"C. The essential oils so obtained usually
and
these are separated by fractional distillation. The terpenoid
contain a number of terpenoids, of the
nydrocarbons dista hrst, and these are 1olowed by
the
oxygenated derivatives. Dstillation
residue under reduced pressure gives the sesquiterpenoids, and these are separated by fractional
distillation. More recently, chromatography (in its various forms) has been used both for isolation
and separation of terpenoids. Gas chromatography has been paticularly useful for isolating pure
configurational forms of a given terpenoid from mixtures produced by synthesis.

3. General methods of determining structure

The following brief account gives an indication of the various methods which have been particularly
useful (especially oxidative degradation) in elucidating the structures of the terpenoids. Also included
are
the more modern methods (see the text for details)
) A pure specimen is obtained, and the molecular formula is ascertained by the usual methods
and also by means of mass spectrometry. If the terpenoid is optically active, its specinic rotation is
measured. Optical activity may be used as a means of distinguishing structures (see, eg. $12).
(i) If oxygen is present in the molecule, its functional nature is ascertained, ie. whether it is
present as hydroxyl, aldehyde, ketone, etc. (f,alkaloids, 14 4).
i ) The presence of olefinic bonds is ascertained by means of bromine. and the number of double
bonds is determined by analysis of the bromide, or by quantitative hydrogenation, or by titration
with monoperphthalic acid. These facts lead to the molecular formula of the parent hydrocarbon,
from which the number of rings present in the structure may be deduced.
(iv) The preparation of nitrosochlorides and a study of their behaviour (see also the nitroso
compounds, Vol. ).

Dehydrogenation of terpenoids with sulphur, selenium. platinum, or palladium. and an

examination of the products thereby obtained (see also 10 52vii).
(vi) Measurement of the refractive index leads to a value for the molecular refraction. From this
Also,
maydec he nature ot the carbon skeleton (se,inparticular, sesquiterpenoids),
optcal caaltation indicates the presernce of doubie bonds in conjugation (g.1 8).
(uDegradative oxidation. The usual reagents used tor this purpose are ozone, acid, neutral,
or alkaline permanganate, chromic acid and sodium hypobromite. Other reagents are osmium
tetroxide, nitric acid, lead tetra-acetate. peroxy-acids, and N-bromosuccinimide for allylic bromina-
of the
tion. Furthermore, owing to the increased knowledge behaviour of oxidising reagents, it
now possible to select a reagent for oxidising a particular group in the molecule. In general, degruda
is

tive oxidation has been the most

powerful tool for elucidating the structures of the terpenoids.
l e spectrowcopY has been much used in terpenoid chemistry. its main application
being the detection of conjugation. In simple acyclic dienes, m is 217-228 nm (e 15 000-25 000)
If the diene is heteroannular (semicyclic), ie., the conjugated double bonds are not n the samce ring
mis 230-240 nm (e I 300- 20 000), and if the diene is homoannular, Le.. both doubic bonds are in
the same ring 256265 nm (e 2,500-10000). If an zf-unsaturated carbonyl system is present.
the 220-250 nm e 10000-17 S00), and there is also a weak band at . 315-330 nm (e i5-100)
The absorption maximum of a diene system is affected by substituents and Woodward (1942)
 Terpenoids 371

found that the position uf the absorption maximum depends on their number and type. As a result,
Woodward developed a set of empirical rules (later modifed by Fieser, 1948) for calculating
from the molecular structure of the compound (see also 11 4).
Polyenes
Homoannular dienes (basic value) 33 n
dienes (basic value)
Heteroannular (and acyclic) 214 m

Increment tor each C-substituent bond

Increment for each exocyclic double
Increment for cach double bond that extends conjugation 0
nm
nm

(Of compound)= Total

It should be noted that a C-substituent may be an alkyl group or a ring residue.

a -Unsaturated ketones

R is an alkyl group or a ring residue, and the parent system isC=C-C(R)=0.

Parent sy'stem (basic value) 215 m
for each C substituent:
Increment
at a-C m

at p-C 12 nn

at -or &-C 18 nm

Increment for each exocyclic double bond 5 nm

Increment for each double bond that extends conjugution 30 nm

Total
(of compound)
The following examples illustrate the application of these rules (see also various individual
terpenoids)

Observed, 224 nm.

Calculated (for an acyclic diene with one C-substituent):

214+5 219 nm.
myreene

Observed, 232 nm.

Calculated (for a heteroannular diene with two C-substituents and one exocyclic
double bond):
214 + 2x 5+ 5 229 nm.
=

Fphellandrene

Observed,235 nm.
Calculated: Parent system 215 nm
C-substituent at z-C 10 nm
C-substituent at p-c

carvone =237 nmn

Copyrigied material
372 Terpenoids [Ch. 8
There is generally good agreement between the calculated and observed values, but notable
exceptions are five-membered ring a,p-unsaturated ketones. These have a calculated about
10
nm longer than the observed value.
Allinger et al. (1965) have calculated ma for a number of unsaturated hydrocarbons, and have
established a quantitative theoretical basis for Woodward's rules in these compounds.
In addition to their use for detecting conug, u
the presence of an isolated double bond (17520 nm), and this is particularly valuable for et
a Gor tetra-
substituted ethylenes, Since this grouping cannot be ascertaincd with certainty in the intrared region.
Also, a-unsaturated acids, esters, and lactones may otten be recognised by their absorption
maxima which occur in the region of 220 nm. Conjugated enes and ketones have absorption bands
in about the same region, but they may, however, often be distinguished by treating them with a
reducing agent, eg., lithium aluminium hydride. Since conjugated enes are usually unafifected, their
spectra will remain unchanged, but the spectrum of the original conjugated ketone will now be
very different (see also infrared spoctroscopy below).
(ix) Infrared spectroscopy is also useful in terpenoid chemistry, and is very valuable for detecting
the presence of a hydroxyl group(3 400 Cm )or an oxo group (saturated: 1 750-1 700 cm
ap-unsaturated: 1 700H 660 cmsee also Table 1.2). Examination of Wcodward values shows
that heteroannular dienes and unsubstituted a,p-unsaturated ketones cannot be distinguished by
means of their ultraviolet spectra, but usually can from their infrared spectra (see also above). Also,

infrared spectroscopy is particularly useful for detecting the presence of the isopropenyl group, and
may often distinguish between cis- and trans-isomers.
)NMRspectroscopy has been used to deteet and identify double bonds, to determine the nature
of end groups
groups and also
also the
the number of rings present, and to ascertain the orientation of methyl
numr o e stractures have been assigned on the basis ot M K
Spectra.
Cxi) Mass spectrometry is now being increasingy used as a means of elucidating the structurecof
terpenoids. Thus, it is possible to determine molecular weights, molecular fomulae, the nature of
various functional groups, and the relative positions of double bonds. Since even simple terpenoids
give complicated fragmentation patterns, structural identification of an unknown terpenoid by
means of mass spectrometry must be carried out with some caution. It is possible, however, to
dentity a terpenoid by comparison of ts mass spectrum with the relerence spectrum ol an authentic
specimen.
(xii) Optical rotation methods have been successtuly applied to the elucidation of the structure of
terpenoids, and ORD studies have been used to assign absolute configurations (see Text).
xii) X-ray analysis is very useful, where applicable, for elucidating structure and stereochemistry
of terpenoids.
(xiv) After the analytical evidence has led to a tentative structure (or structures), the final proof
of
structure depends on synthesis. In terpenoid chemistry, many of the syntheses are ambiguous,
and in such cases analytical evidence is used in conjunction with the synthesis. Also, because of the
introduction of stereoselective syntheses, it is now possible to prepare particular configurational
forms of many terpenoids (see Text; see also 11 9).

Monoterpenoids

The monoterpenoids may be groups: acyclic,

subdivided into three monocyclic and bicyelic. This
classification affords a convenient means of study of the monoterpenoids.
4. Myrcene, CoHe. b.p. 166-168'C
This is an acyclic monoterpenoid hydrocarbon (i.e, is a terpene) which occurs in verbena and bay
oils.
Catalytic hydrogenation (platinum) converts myrcene into a decane, CoH2: thus myrcene
contains three doubie bonds, and is an open-chain compound. Furthermore,Since myrene torms

an adduct with maleic anhydride, two of the double bonds are conjugated (Diels et al., 1929 see
the Diels-Alder reaction, Vol. ). This conjugation is supported by the fact that myrcene shows
optical exaltation (see also below). These facts, ie, that myrcene contains three double bonds, two
of which are in conjugation, had been established by earlier investigators (eg, Semmler, 190).
Ozonolysis of myrcene produces acetone, formaldehyde and a ketodialdehyde, CsH,O3, and the
latter, on oxidation with chromic acid, gives succinic acid and carbon dioxide (Ruzicka et al., 1924).
These results can be explained byassigning structure (1) to myrcene. In terpenoid chemistry it has
become customary to use conventional tormulae rather than those of the type ( . In these conven

tional formulae only lines are used; carbon atoms are at the junctions of pairs of lines or at the end of
a line, and unsaturation is indicated by double bonds (see Vol. I, Ch. 19). Inspection of () shows
that the structure of myroene is based on the 2,6-dimethyloctane skeleton. This would normally be
drawn in a zig-zag fashion, but it is common practice in terpenoid chemistry to draw the carbon
skeleton in a ring fashion (the 'open" cyclohexane ring), since this representation usually clearly
shows the reiationships between vanous clasSses of terpenoids. Even so, theseTingstructures have
been, and still are, written differently, eg. ( ) , (1), and (UV), but (OV) is now the one that is
recommended.

CH
çH CH,fH=CH,

The systematic name of the compound is obtained by use of the rule for acyclic polyenes. Thus,
myrcene is 7-methyl-3-methyleneocta- l,6-diene.
We can now represent the process of ozonolysis and oxidation of the ketoaldehyde as shown.

CH,O
Co
CHO CO CO
CHO coH
This structure for myrcene is supported by the fact that on hydration (under the inffuence of sul-
phuric acd). myrcene torms an alcohol which, on oxIdation, gives citral. The structure of this
compound is known (see $5), and its formation is in accord with the structure given to myrcene.
Myrcene has 224 (e 14 600) nm (calc. value is 214 +5 - 219 nm) and, according to Suther
land et al. (1950), the absence of the band at 890 cm" shows the complete absence of the isopro
penyl form (see also $5).

Cooyighted matorial
molecular-ion peak (M 136), whereas the latter shows a strong one (M" 136). This difference i
attributed to the stability of the extended conjugated system in allo-ocimene. In myrcene, there are
two allylic systems, and allylic fission a: the bond common to both can therefore be expecied to
occur readily(1 S1 3a). This accounts for the extremely strong peak m/e 69 (CsHJ) and the weak peak
at mje 67 (CH;). The base peak for myrcene is m/e 41 (C3H3): its formation can only be explained
by rearrangement. The base peak for allo-ocimene is mje 121, corresponding to a loss ofa methyl
free radical (M-15 121). There are aso peaks m/e 27 (C,H;) and m/e 91 (C,H;; tropylium ion)
Peent m both spectra.

5. Citral, C1oH,,0.
This is the most important member of the acyclic monoterpenoids, since the structures of most of
the other compouads in this group are based on that of citral. Citral is widely distributed and occurs
60-80 per in lemon grass is a
to
an extent of cent oil. Citral liquid which has the smell of lemons
Citral was shown to contain an oxo group, eg., it forms an oxime, etc. On heating with potassium
hydrogen sulphate, citral forms p-cymene (I) (Semmler, 1891). This reaction was used by Semmer
to determine the positions of the methyl and isopropyl groups in citral; Semmler realised that the
citral molecule was acyclic, and gave it the skeleton structure () (two isoprene units joined head to

tail), Citral can be reduced by sodium amalgam to an alcohol, geraniol, C1oH,,O, and is oxidised
by silver oxide to geranic acid, CoH,02; since there is no loss of carbon on oxidation to the acid,
the oxo group in citral is therefore an aldehyde group (Semmler, 1890). Oxidation of citral with
alkaline permanganate, followed by chromic acid, gives acetone, oxalic and laevulic acids (Tiemann
and Semmler, 1895). Thus, if citral has structure (1), the fomation of these oxidation products

CHO
CO,H
COH

may be accounted for. This strueture is supported by the work of Verley (897), who found that
aqueous potasium carbonateconvertedcitralinto6-methylher-5-en-2-one
The tormation ot these products s readily expla ined by assuming (
(V) and acetaldehyde
undc gos c e v a
zj-doubie bond: this cleavage by alkaline reagents is a general reaction ot a5-unsaturated OxO

CHO
on CHO
CH,

V)

malerial
compounds (see Vol. ). Furthermore, methylheptenone itself is also oxidised to acetone and
laevulic acid; this is again in accord with structure (11). The structure of citral was confirmed by the
synthesis of methylheptenone (IV), the conversion of this into geranic ester (Barbier et al., 1896),
which was then converted into citral by heating a mixture of the calcium salts of geranic and formic
acids (Tiemann, 1898).

NaTHCOMe

aV)

co,Et

o,Et HCO,CG

A more recent synthesis of citral is that of Arens et al. (1948).

+CH,
X
- ma50,

It should be noted that an allylic rearrangement occurs in both parts of this synthesis (see also $8).
Ethoxyacetylenemagnesium bromide may conveniently be prepared from chloroacetaldehyde
diethyl acetal as follows (Jones et al., 1954):
CICH,CHOC,H,) CH=COC,H, BMsCCOC,H,
Examination of the formula of citral shows that two geometrical isomers are possible. The func
tional group (aldehyde) is trans or cis with respect to the methylene group of the main chain. Both
isomers occur in natural citral, eg, two semicarbazones are formed by citral; both forms of citral
been has and
itselfhave also obtained: citraka (also known as geraunial) ab.p. 18-119 C20 mm.
citral-b (also known as neral) has a b.p. 117-118 C/20 mm. The configurations of these two foms
have been determined from a consideration of the ring closures of the corresponding alcohols (see

CHO

frans-ior E-} torm; c-for 2-) Torm:

Citral-a: gcranial catra-b,neral

Copyrgod fatotral
 Terpenoids 377

geraniol. $7). These assignments have been confirmed by the examination of the NMR spectra of
citral-a and citral-b (in CDCl,: Ohtsuru et al, 1967). Thus, for example. the t-values of CH, (a)
and CH, 6) are different due to the different magnetic shielding effects of the carbonyl double bond
(in CHO).

()CH, CH, (a) CH,6)

citral-a t776 7-84

citral-b t 742 t 802
citral-a
citral-b

Ozonolysis was very much used by the classical workers in the determination of structures of
terpenoids. In most cases, this method produced two types ot products, one arnsing trom the

terminal isopropylidene group, Me,C (to give acetone), and the ofother arising from the terminal
isopropeny! group, CH,CMe-(to give formaldehyde). Becausc this, it was originaly believed
that many acyclic monoterpenoids were mixtures of both structures. However, infrared spectro
scopic studies showed the presence of exclusively (or almost exclusively) the isopropylidene group
(Barnard et al., 1950). In particular, a detailed study of the infrared spectrum of citronellol 9a)
showed a maximum at 890 cm. This corresponds to some isopropenyl structure (the absorption
region of R,CCH, is 895-885 em, whereas that of the isopropylidenestructure, R,C=CHR, iS
850-790 cm"). Also, on the basis of the intensities of the bands, the authors calculated that there
was about 2-3 per cent of isopropenyl form present. According to the authors, during oxidative
degradation,. from the
partial rearrangement to the isopropenyl structure occurs, and
isopropylidene
so this method of determining fine structure is unreliable.

H
=CH- H,C
CH
All recent work appears to support this and so the compounds are considered to have isopropylidene

Itraviolet also be noted that the presence of the B-unsaturated carbonyl systemis shown from the
uitravioiet absorption spectrum o citral, mas 15 258 (E 13 S00) nm, but this does not distinguish
between the isopropyidene and iSopropenyl forms.

Tonones
When citral is condensed with acetone in the presence of barium hydroxide, v-ionone is formed
and this, on heating with dilute sulphuric acid in the presence of glycerol, formsa mixture of a- and

-1onone

-1onone -ionone

opyrgntet materia