Chemistry for Everyone

Two Faces of Alkaloids

Ji ří Dostál
Department of Biochemistry, Masaryk University, Faculty of Medicine, Komenského námestí 2, CZ-662 43 Brno,
Czech Republic; jrdostal@med.muni.cz

The term “alkaloid” was introduced around 1819 by the pKb and depends on the chemical nature of the alkaloid. The
German pharmacist Wilhelm Meissner (cited in ref 1). The free bases are formed by treating the salt with one of various
Arabic–Greek compound al-kal-oid means literally alkali like. alkalizing agents such as NaOH, Ca(OH)2, Na2CO3, NH3,
Indeed, most alkaloids are basic compounds, although there or lower amines, depending on the pKa of an ammonium
is a small group of nonbasic alkaloids (see below). The tradi- salt. Generally, the pH must be adjusted at least one pH unit
tional definitions of alkaloids (2, 3), emphasizing their bitter above the pKa of a protonated form.
taste, basicity, plant origin, and physiological actions, have The free bases of most of the alkaloids are water-insoluble
been gradually modified to become more general and rational. substances, and there are two general methods for preparing
For example, Pelletier created a simple definition of an them. In Method A, an aqueous solution of the alkaloid salt
alkaloid as “a cyclic organic compound containing nitrogen is made alkaline and the precipitate thus formed is separated,
in a negative oxidation state which is of limited distribution washed with water, and dried. The product is an amorphous
among living organisms” (4 ). material obtained almost quantitatively. Method B involves one
The presence of at least one nitrogen atom is a general additional step. The precipitate is extracted with a nonpolar
chemical feature of the alkaloids. A nitrogen atom in an or- solvent such as diethyl ether, benzene, or chloroform. The
ganic molecule can be trivalent and electroneutral or organic layer is separated, concentrated, and allowed to stand
tetravalent with a positive charge. Depending on the pH, al- until it crystallizes.
kaloids occur in two principal forms: an ionic ammonium In this article, the dualism of several well-known alka-
salt or a neutral free base. These forms differ substantially in loids is discussed in detail. Nicotine, morphine, and cocaine
their physicochemical properties, appearance, occurrence, are the examples of typical alkaloids. Sanguinarine, allo-
practical uses, and bioavailability. They are interconvertible; cryptopine, and magnoflorine are included because they are
that is, the alkalization of the salt yields the free base and the very common in plants, and although their acid–base behavior
acidification of the free base reconstitutes the salt. This re- is different, they illustrate the richness of structural motifs in
versible acid–base reaction has become a key principle in the natural products. Textbooks of (bio)organic chemistry (e.g.,
isolation of alkaloids from plant extracts (5, 6 ). Alkaloids oc- 7–9) usually do not distinguish between these forms explicitly.
cur in plants as polar salts of various organic acids and they Undergraduate students who are not majoring in chemistry,
can therefore be easily extracted with polar solvents, typically especially those in medical schools, are apt to encounter a
methanol. number of important alkaloids as medicines, drugs, or toxins,
The free bases of alkaloids are compounds having basic and often become confused about this. This article addresses
properties: their aqueous or aqueous-alcoholic solutions are such issues. Therapeutic uses for such compounds are given
alkaline to litmus. The degree of basicity is expressed by the in Table 1.

Table 1. An Illustrative List of Alkaloids Used in Human Medicine

Alkaloid Plant or Fungal Source a The Usual Form Therapeutic Category
Atropine Atropa belladona Sulfate Cholinergic antagonist, spasmolytic
Cocaine b Erythroxylon coca Hydrochloride Local anesthetic
Codeine b Papaver somniferum Phosphate Antitussive
Colchicine Colchicum autumnale Colchicine Antimitotic, gout suppressant
Emetine Cephaelis ipecacuanha Hydrochloride Antiamebic, emetic
Ephedrine Ephedra vulgaris Hydrochloride Adrenergic agonist, bronchodilator
Ergotamine Claviceps purpurea Tartrate Antimigraine
Morphine b Papaver somniferum Hydrochloride, sulfate Analgesic
Papaverine Papaver somniferum Hydrochloride Spasmolytic
Pilocarpine Pilocarpus jaborandi Hydrochloride Cholinergic agonist
Pseudoephedrine Ephedra vulgaris Hydrochloride Adrenergic agonist, vasoconstrictor
Quinidine Cinchona officinalis Sulfate Antiarrhytmic
Quinine Cinchona officinalis Sulfate Antimalarial
Sanguinarine Sanguinaria canadensis Chloride Antiplaque agent
Scopolamine Scopolia carniolica Hydrobromide Cholinergic antagonist, antiemetic
Vincristine Vinca rosea Hydrochloride Antineoplastic
Yohimbine Corynanthe yohimbe Hydrochloride Adrenergic antagonist, aphrodisiac
aOnly common examples are given.
bControlled substance.

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Nicotine Table 2. Some Properties of Two Forms of Nicotine

Nicotine (1a) has been known since 1809. It occurs in Nicotine (1a) Nicotine Ditartrate (1b)
Property
(Free Base) (X = Y = Tartrate)
tobacco leaves (Nicotiana tabacum, Nicotiana rustica) in a pro-
tonated form (1b) accompanied by physiological anions such Molecular formula C10H14N2 C10H14N2⭈ 2C4H6O6
as malate, citrate, or tartrate. Nicotine free base (1a) is an Molecular weight 162.23 462.41
oily liquid (Table 2), which can be isolated by either alkaline- Appearance Colorless oily liquida Colorless crystals
steam distillation or alkaline-chloroform extraction. The iso- Melting point (°C) ᎑79b 93–95
lation of nicotine from cigarettes is a common laboratory ex- pKb (15 °C) 6.16;c 10.96d —
periment in high schools and colleges (10, 11). An aqueous
Solubility in water Soluble Soluble
solution of nicotine is alkaline to litmus. Nicotine possesses
Solubility in benzene Soluble Insoluble
the methylated pyrrolidine nitrogen (pKb = 6.16) and the
1

less basic pyridine nitrogen (pKb = 10.96). To liberate free Occurrence Tobacco smokee Tobacco
2

nicotine (1a) the pH of a tobacco extract must be adjusted aSlowly darkens upon exposure to air. bBoiling point 243–248 °C.
cPyrrolidine moiety. dPyridine moiety. eThe forms of nicotine depend on
above the pKa of the protonated N-methylpyrrolidinium
the smoke’s acidity.
(8.08, 15 °C). This condition is readily fulfilled by using
NaOH, Ca(OH)2, or Ba(OH)2 solutions (10, 11).
Table 3. Some Properties of Two Forms of Morphine
Morphinea (2a) Morphinea Hydro-
N Y− Property
N H + CH3 (Free Base) chloride (2b) (X = Cl)
Molecular formula C17H19NO3 C17H19NO3⭈ HCl
X−
CH3 N+
N
1a H
1b Molecular weight 285.33 321.79
Appearance Colorless crystals Colorless crystals
During smoking, approximately one-third of the nico-
tine salts present in dry tobacco is pyrolyzed into simpler de- Melting point (°C) 253–254 285–300
rivatives. The remaining two-thirds distills into the smoke, pKb (20 °C) 6.13 —
which is inhaled. Depending on the acidity of the smoke, Solubility in water Insoluble Soluble
nicotine can be predominantly either protonated (most ciga- Solubility in benzene Slightly soluble Insoluble
rettes) or un-ionized (pipes, cigars). Nicotine passes quickly from Medically useful No Yes
the lungs to the blood and reaches nicotine acetylcholine aControlled substance.
receptors in the brain and other tissues. After binding to the
receptor, a conformational change induces the opening of a
Na+/K+ channel for microseconds. Sodium ions enter the cell
and trigger a cascade of further events, which eventually result
value it follows that morphine should be extracted at pH ~9.
in the release of neurotransmitters including dopamine, sero-
Moreover, morphine bears one phenolic hydroxyl with pKa
tonin, and β-endorphin. Nicotine’s ability to make people
9.85. Therefore, at pH > 10, formation of the phenolate will
feel good seems to be linked to dopamine liberation. The
prevent morphine from passing into nonpolar solvent.
almost instantaneous relationship between a single puff and
central nervous system effects allows smokers to modulate HO HO
the actions of nicotine to a desirable level. This is probably
behind the high addictiveness of smoking. Other effects of
nicotine can be described as cardiovascular (vasoconstriction, O O H
rise in blood pressure), endocrine (cortisol release, risk of
N CH3 N X−
osteoporosis), and metabolic (increased metabolic rate, + CH3
catecholamine release, “silent stress”). They all seriously
HO HO
contribute to smoking-related health dangers and illnesses.
2a 2b
Morphine
Morphine is used in medicine as a potent analgesic,
Morphine (2a), discovered in 1817, is the principal especially in the treatment of severe chronic pain. Morphine
alkaloid of the opium poppy (Papaver somniferum), a plant free base (2a), whose formula is frequently presented in chem-
species that has been cultivated all over the world for more istry textbooks (e.g. 7–9), is extraordinarily insoluble in
than 2,000 years (12). Morphine is obtained from opium, water and is consequently therapeutically useless. As much
the dried latex of the unripe capsules, where it is found largely as 5 L of water is required to dissolve 1 g of morphine (15).
as the salt of meconic acid. Morphine has also been isolated In contrast, morphine hydrochloride (2b, X = Cl) is highly
as a minor alkaloid from the closely related species Papaver water soluble (1 g dissolves in 17.5 mL of H2O). Morphine
setigerum (13) and Papaver decaisnei (14). hydrochloride is administered mainly by injection. Recently,
A saturated aqueous solution of morphine is alkaline to enteric-coated tablets containing morphine sulfate (2b, X =
litmus. The pKb constant of morphine (2a) is 6.13 and the 1
⁄2 SO4) have been introduced. Table 3 shows some properties
pKa of morphinium (2b) is 7.94 (20 °C). From the latter of morphine free base and its hydrochloride.

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 Chemistry for Everyone

Table 4. Some Properties of Two Forms of Cocaine Cocaine, one of the most widespread stimulant drugs,
a
Cocaine (3a) Cocaine Hydro-
is a very dangerous, illegal, and highly addictive substance
Property (18). Cocaine hydrochloride (3b, X = Cl) is its water-soluble
(Free Base) chloridea (3b) (X = Cl)
Molecular formula C1 7 H2 1 NO4 C1 7 H2 1 NO4 ⭈ HCl
ammonium salt. It is abused by snorting because it is absorbed
through the nasal mucosa or, less frequently, injected intra-
Molecular weight 303.35 339.81
venously (19). The so-called “crack” cocaine became available
Appearance White powder Colorless crystals in the early 1980s. Chemically, crack is the free base of cocaine
Melting point (°C) 95–98 195–202 (3a) (20). Crack cocaine, a low-melting substance rather vola-
pKb (15 °C) 5.59 — tile above 90 ºC, is abused by smoking (Table 4). In contrast,
Solubility in water Slightly soluble Soluble cocaine hydrochloride decomposes in the burning process.
Solubility in benzene Soluble Insoluble
Abused by Smoking Snorting, injection
Sanguinarine
aIllegal substance. In 1827, the alkaloid sanguinarine (4a) was discovered
as the main red constituent of the North American herb
Sanguinaria canadensis (21). When cut, S. canadensis exudes
an intensely red latex containing salts of sanguinarine (4a)
and the related benzo[c]phenanthridine alkaloids (22). For
Table 5. Some Properties of Two Forms of Sanguinarine this reason the plant is known colloquially as “bloodroot”.
Sanguinarine Sanguinarine In Europe, the only related species producing sanguinarine
Property
(Free Base) (4b) Chloride (4a) is greater celandine (Chelidonium majus). Owing to its anti-
Molecular formula C4 0 H2 8 N2 O9 C2 0 H1 4 NO4 + Cl ᎑ microbial, antiplaque, and antiinflammatory properties,
Molecular weight 680.68 332.34 (cation) sanguinarine is used as a component in numerous toothpastes,
dental gels, and oral rinses (23).
Appearance Colorless crystals Copper-red crystals
Melting point (°C) 258–260 282–283
O
pK (25 °C) — 8.05
Solubility in water Insoluble Soluble O
Solubility in chloroform Soluble Insoluble O
N CH3 X−
O +
O
O 4a
N CH3
O
O
Cocaine O O
O
Cocaine (3a) is the main alkaloid of the South American CH3 N
coca shrub (Erythroxylon coca) (16 ). It has been known since
1860. The popular beverage Coca-Cola, invented in 1886 O
by John Pemberton (17), originally contained extracts from
coca leaves in addition to the essence of cola nuts (Cola O
acuminata). In 1904, American authorities outlawed the coca 4b
ingredient. Today, the only reminder of cocaine in Coca-Cola
is the first part of the compound name. Sanguinarine is an iminium cation with the nitrogen
An aqueous solution of cocaine is alkaline to litmus. The atom as part of an aromatic ring. The molecular weight of
pKb of cocaine (3a) is 5.59 and the pKa of the conjugate acid the sanguinarine free base is more than twice that of the cation
(3b) is 8.65 (15 °C). (Table 5). The acid–base process here is more complex than
for the previous alkaloids (24 ). The hydroxide ion adds to
COOCH3 the electron-deficient carbon of the C=N+ bond, yielding an
CH3 N
unstable hydroxy adduct, which immediately undergoes a
condensation reaction to give bis(dihydrosanguinarinyl) ether
O C
(4b). The equilibrium between the quaternary cation and a
3a
O tertiary free base is described by a pK = 8.05 which is analogous
to pKa for Brønsted acids (25, 26 ). It means that at pH ~ 10
H the conversion of sanguinarine to its free base is complete.
X−
CH3 N+ COOCH3
Because of the breakdown of its conjugation, the free base is
colorless. The process is essentially reversible; treating the base
O C 4b with an acid gives the quaternary salt 4a. This brings out
O another interesting feature: sanguinarine acts as an acid–base
3b
indicator. In acidic solution it is red; in an alkaline environ-
ment, colorless.

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 Chemistry for Everyone

This property can be easily demonstrated using an over- Table 6. Some Properties of Two Forms of Allocr yptopine
head projector and an oral rinse containing sanguinarine. I Allocryptopine Allocryptopine Hydro-
used Santoin (CZ), but the demonstration should work simi- Property
(5a) (Free Base) chloride (5b) (X = Cl)
larly with other sanguinarine dental rinses such as Viadent,
Molecular formula C2 1 H2 3 NO5 C2 1 H2 3 NO5 ⭈ HCl
Dentosan S, or Perioguard. A Petri dish (60 mm o.d.) is
placed on the projector stage. A small amount (5–10 mL) of Molecular weight 369.40 405.86
a rinse is poured in and its typical coloring is projected on a Appearance Colorless crystals Colorless crystals
screen. Then 6 M NaOH is added dropwise (stir gently) until 160–161a
Melting point (°C) 210–212
the color disappears. The addition of 6 M HCl reconstitutes 171–172b
the quaternary salt of sanguinarine and the original color re- pKb (25 °C) 4.89 —
emerges. Other components in oral rinse formulas (ethanol, Solubility in water Insoluble Soluble
glycerol, menthol, thymol, zinc chloride, sodium saccharine, Solubility in chloroform Soluble Insoluble
etc.) do not disturb the reaction. The color change is striking,
Feature IR band (cm᎑1 )c 1646 (C=O) 3377 (OH)
and at the same time, the experiment may stimulate students’
interest in oral hygiene.
aFor α-allocryptopine.
bFor β-allocryptopine (crystal modification).
cKBr pellets.

Allocryptopine
Allocryptopine (5a) is a protopine alkaloid, ubiquitous Table 7. Some Properties of Two Forms of Magnoflorine
in plants of the Papaveraceae and Fumariaceae families (27, Property
Magnoflorine Magnoflorine
28). It has been known since 1890. The structural formula Iodide (6a) (X = I) "Free Base" (6b)
5a with a nonphysiological 10-membered heterocycle depicts Molecular formula C2 0 H2 4 NO4 + I ᎑ C2 0 H2 2 NO4 ᎑
its free base. X-ray analysis of the base shows that the distance Molecular weight 342.40 (cation) 340.40
between the nitrogen atom and the carbonyl carbon opposite is Appearance Colorless crystals Not known
2.44 Å. This is substantially less than the sum of the van der
Melting point (°C) 264–266 Not known
Waals radii of these atoms (3.15 Å) (29). This indicates a
strong electrostatic interaction, which probably stabilizes the Solubility in water Soluble Soluble
conformation of this unusual heterocycle. The action of acid Solubility in chloroform Poorly soluble Insoluble
triggers a transannular nucleophilic addition of the tertiary
nitrogen to the carbonyl carbon. The resulting allocryptopine
salt (5b) is a tetracyclic system with a hydroxyl group and an charged phenolate-ammonium species is water soluble and
ammonium nitrogen (30, 31) (Table 6). It is, in fact, the cannot pass into nonpolar solvents as do most other alkaloids
natural skeleton of the protoberberines, another interesting (Table 7). Standard isolation procedures fail in the case of
group of isoquinoline alkaloids (32, 33). Allocryptopine free magnoflorine. Difficulty with the “free base” of magnoflorine
base is readily extractable into ether after alkalization with was apparently the reason why this alkaloid was discovered only
sodium carbonate at pH 10–11 (34 ). in 1954, considerably later than the other alkaloids discussed
here (38, 39). Magnoflorine used to be obtained by precipi-
O tation with styphnate, Mayer, or Reineckate reagent (6, 35),
CH3 X − but the method is rather tedious and provides a low yield.
N
O + The more efficient method of extracting magnoflorine iodide
HO
OCH3 (6a, X = I) into chloroform at pH 6–7 has been introduced
(36, 37 ). With this more effective extraction and purification
O 5b scheme now at hand new and useful properties and uses may
CH3 OCH3 emerge for this widely distributed alkaloid.
N
O
O
OCH3 CH3O CH3O
CH3 CH3
5a N X− N
HO + CH3 −O + CH3
OCH3
HO −O

Magnoflorine
CH3O CH3O
Magnoflorine (6a) is a strongly polar quaternary 6a 6b
aporphine alkaloid widely distributed in plants of the
Papaveraceae, Magnoliaceae, Berberidaceae, Ranunculaceae, Conclusions
and several other families (35–37 ). It possesses a
dimethylammonium group and two phenolic hydroxyl 1. Depending on the pH value, alkaloids can occur in
groups. In acidic or neutral solutions, it exists in the form of two forms denoted as ammonium/iminium salts and free
the salt 6a, which is also present in plant tissues. When a bases. The properties of these two forms differ substantially.
solution of the salt is made strongly alkaline (pH > 11) The transformation of one form into another is a reversible
magnoflorine takes the form of a phenolate anion, 6b. This acid–base reaction.

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 Chemistry for Everyone

2. The structural differences between these two forms

vary from simple proton transfer (nicotine, morphine, co- CH3O
caine) to fundamental skeleton alterations (sanguinarine, NHCOCH3
allocryptopine). In most alkaloids, the two forms represent a CH3O
conjugate pair; that is, they differ in one covalently bonded CH3O
proton on the nitrogen.
3. Almost all medically important alkaloids are applied O

exclusively in the forms of their salts of various organic or 7 OCH3

inorganic acids (Table 1). The alkaloid colchicine (7), used
in the treatment of gout, is an exception (see below). The O
salt–base pair provides a good and interesting example of a
O
conjugate acid–base pair in general chemistry courses. Students N
can be given the formula of an alkaloid base and asked to
O 8
write the formula and the name of a salt.
4. Both forms of alkaloids should be carefully distin-
O
guished for students and their opposing properties empha-
sized. Different intermolecular forces in two alkaloid forms CH3O
N
are one aspect of general chemistry that can be demonstrated.
H
Weak London dispersion forces and dipole–dipole forces are HO 9
usually the only interactions in alkaloid free bases. Much
stronger electrostatic attractions in alkaloid salts result in their O
having higher melting points than their corresponding free
base. Typical examples are nicotine (Table 2, ∆mp = 174 °C) O
and cocaine (Table 4, ∆mp = 107 °C). Other nice examples
are (᎑)-ephedrine free base (mp 36 °C) vs (᎑)-ephedrine hydro- N
CH3
O
chloride (mp 220 °C, ∆mp = 184 °C) and papaverine free
base (mp 147 °C) vs papaverine hydrochloride (mp 225 °C, O O
10
∆mp = 78 °C). In morphine, sanguinarine, and allo-
cryptopine, this feature is less pronounced. O
5. Another useful concept is the application of the “like
dissolves like” (similia similibus solvuntur) rule, which states O
that a solvent will dissolve a solute if the two have similar
N
properties. As nonpolar species, alkaloid free bases are readily CH3
O
soluble in nonpolar solvents (morphine is an exception). The
O 11
salts of alkaloids are ionic compounds, which dissolve well
in polar solvents. It is understood that only polar alkaloid
salts are distributed in a polar aqueous environment of blood CH3
plasma and other body fluids and therefore only these forms +N CH3
are used in medicine.
H
6. In some cases, the free base of an alkaloid is hard O
to obtain (magnoflorine). Under specific conditions, some
alkaloids may decompose upon alkalization; for example, O COO −
the hydrolysis of an ester bond in some pyrrolizidine or
aconitum alkaloids or the more complex conversions in some CH3O OCH3
O
other alkaloids (berberine).
7. The free bases of alkaloids may be considered as a kind 12 OCH3
of artifact because they do not occur in more or less acidic
plant tissues.
8. The group of nonbasic alkaloids is limited. In view of Acknowledgment
the title of this article they could be portrayed as “one-face”
I thank Professor Ji ří Slavík of Masaryk University Brno
alkaloids. Chemically, these belong to the amides—for example,
for valuable comments and suggestions.
colchicine (7) from meadow-saffron (Colchicum autumnale),
piperine (8) and related alkaloids of black pepper (Piper
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