*.. l-\

15.8Alkaloids 48t
CH"
I
/-\-cHrcH2_NH2
N\
N-H
/cH2cHz-N-CHs
*..
l-\
cH,-<
\:/
Histamine
Pvribenzamine
)
^
\-,"\
.zcH,
t<''{"-o-cH2cH'*aar,
tl
\-/
Diphenylhydramine
(benadryl)
Benadryl is also a component of Dramamine, a drug commonly used to
prevent motion sicknessor nausea.
lt, PRACTTCE
EXERCTSE
t5.tl
Identif,i the functional groups in the neosynephrine molecule. what is
the physiologic action of this drug?
15,8Alkoloids
AIM: Toname ond give examplesof usesof medicinolalkdloids.
Focus
Alkaloids are physiologically
active amines produced by
plants.
some of the most powerful drugs known are derived from plants. Some
have been used for thousands of years.Among the oldest of these drugs are
the alkaloids-agroup of ouer 2s00amines obTainedfromptnnts.The name
a.lkalgi(, meaning "alkali-like," bears testimony to ttrb weatty uasic properties of thesecompounds.
The molecular structures of the arkaloidsvaryfrom simple to complex.
Nicotine is one of the simplest.
Nicotine
Nicotine is one of severalalkaloids present in tobacco. small doses,such as
those obtained by smokers, stimulate the involuntary nervous svsrem.
Large dosesare toxic and result in nicotine poisoning. Nicotine is a iabituating drug-one on which people acquire a dependence.An addicting drug
is one that causesphysiologic changeswhen iiis not used for a time.
- severalimportant alkaloids contain the indole ring system.Lysergicacid
and reserpine are indole alkaloids.Lysergrcacid is produced uy ergot, a fungus that grows as brown bodies on infected
rye. The diethylamid" 6rryrergi"
acid is called LSD (lysergic acid diethylamide), a powerful and *ia6fy
lb"r-"_dhallucinogenic drug. As little as I g,gof LSD, scarcelyenough to see,
is sufficient to causehallucinations. The danger of overdossis highi
Reserpine,an indole alkaloid of the Indian snakeroot (Fig. rs.+a),
reduces hlpertension (high blood pressure), which, if left unchecked,
482
CHAPTER
15 Aminesand Amides
Figure| 5.4
(a) Indiansnakeroot
is the source
(b) TheCinchona
of reserpine.
tree
yieldsquinine.
could lead to a stroke or cardiac arrest. Strychnine, a bitter-tasting compound from the plant Strychnosnux t)ornica,has a long and sometimes sinister history as a poison.
CH"CH,
"ttl O
cH3cH2-N-C
N-CHr
N
I
H
Lysergicacid diethylamide (LSD)
Strychnine
HsCO
Reserpine
The antimalarial drug quinine is an alkaloid that occurs in the Cinchona (pronounced"sinkona")tree (Fig. 15.4b)of the Andes Mountains of
South America. Quinine has the aromatic quinoline ring system as part of
its molecular structure. Other drugs that act against malaria have been synthesized, but quinine is still used.
15.8 Alkaloids
485
HO-CH
CH:CHZ
Quinine
Quinoline
The tropane ring system is found in cocaine and atropine. Cocaine
stimulates the central nervous system. It is now a widely abused habituating drug. Atropine is an alkaloid obtained from belladonna, hemlane, and
deadly nightshade. It has severalmedicinal purposes, including treatment
of certain eye conditions. A tincture of atropine causes dilation of the
pupils. Roman women used belladonna to achieve this dilating effect
because they thought it attractive. Indeed, belladonna means "beautiful
lady."
I
N
N
/\
af\
1/
CH"
f"'
CH"
I
N
o
/\
af\
c-ocH3
1/
V
Tropane
\
?
o -C-CH
/cHzo:u
Atropine
Cocaine
Opium is the raw resin extracted from the seedpods of the opium
poppy (Papauersomniferum), not the poppy grown in gardens.When the
resin is refined, two important alkaloids, morphine and codeine, can be isolated in pure form. Morphine is the most effective pain-killing drug knovrn.
Codeine is a powerftrl analgesicand cough suppressant.It was an ingredient in cough medicines for many years, but it has been replaced by dextromethorphan, a synthetic alkaloid that is equally effective. Morphine and
codeine are addictive drugs.
Illegally produced "designer"
drugs chemically mimic the effects of specific drugs of abuse.
Some derivatives of fentanyl are
over 1000times more powerful
than morphine. Designer drugs
have a high risk of addiction and
can causebrain damage and
even death.
CH"
CH"
CH"
N
N
N
I
I
I
o
Morphine
Dextromethorphan
484
CHAPTER
l5 Aminesand Amides
Ironically, heroin, an acetic acid ester derivative of morphine, was
introduced because it was thought to be a better analgesicand to lack
morphine's addictive properties. It was soon found, however,that heroin
is no better than morphine as an analgesicand is even more addictive
than other opiates-drugs that produce the psychological and physiotogic
efficts of opium. Today,heroin is a destructive hard drug. Methadone, a
drug that blocks heroin action, has been introduced to wean heroin
addicts from their habit. Methadone does not produce the euphoria associated with heroin use. Its use is controversial,since it too is an addictive
drug.
HsC\
CH.
I
N
N
/.CH3
I
H3C-CH
/-\
,,
o
o-c
l-,,'
/CHS
o
CH,' / -- \
I
\r\ \ / / t \ \ /-91
//
o/c",
)
fr,
CH.
Heroin
Methadone
PRACTICE
EXERCISE
I5.I2
List some of the physiologiceffectsand usesof (a) morphine, (b) nicotine, (c) atropine, and (d) quinine.
15,9Borbiturotes
AIM: To nomeond give exomplesof usesof borbiturote drugs.
Focus
Barbiturate drugs are derivatives ofurea.
Urea has a simple molecular structure. In structural terms, we can consider
it the diamide of carbonic acid (HzCOg):
o
HO-C-OH
Carbonic
acid
o
H2N-C-NH2
Urea
Urea is important in its own right, since it is the form in which our bodies
disposeof excessnitrogen in the urine. Its high water solubility (125g/ 100
mL of water) and low toxicity make it ideal for this purpose.
Condensationof malonic acid with urea produces barbituric acid, the
parent compound of a number of drugs.
15.9 Barbiturates
H
H
o\
,/o-H
f
H-N.
/o-H +
I
oy-t-',o
tc:o
I
H-N
I
cH2-c\o
I
\/*-"
tl
""utt
|
+2rl2o
o
H
Barbituric acid
Urea
Malonic acid
485
Note that barbituric acid contains the pyrimidine ring system. It is an acid
because the hydrogens on the ring nitrogens readily dissociate in basic
solution to form barbiturate salts.
H
Na*
o\-t--tro
o\-*:fo
+NaoH-
|
I
\--*-"
tl
o
o
Sodium barbiturate
Barbituric acid
Hypnotic
hupnos(Greek): sleep
Sedative
sedare (Latin): to calm
+H2o
|
|
\.,.t-"
tl
Salts of barbituric acid and its deriuatiuesare calledbarbiturates. The
sodium salts are often administered becausetheyionize in solution and are
more water soluble than the acid forms. Barbituric acid is not physiologically active, but some of its substituted derivatives are among the most
potent hypnotics (sleep-inducers) and sedatives (tranquilizers) knovrn.
Barbitalwas introduced in Gqrmanyin 1903under the nameVeronal, and it
is still used as a hypnotic. Since the introduction of barbital, medicinal
chemists have synthesized thousands of variations on the barbituric acid
structure, but only about a dozen are clinically useful.
H
H
oY*Yo
oY*Yo
I
cH3cH,+\-/.N-H
Phenobarbital
(Luminal)
Barbital
(Veronal)
cH."Yt"lt
H
H
I
N\ -o
N
Y
CH3CH2CH2CH-\_,,.N-H
cH2:cHCH2 ll
o
Secobarbital
(Seconal)
?fi:*;rr-*-"
o
o
I
CH.,Y,.-Y"
tll
cH3cH2cH2cH--y'\ -NCH3CH'Y
o
Thiopental
H
485
CHAPTER
I5 Aminesand Amides
As hypnotics, barbiturates are often classifledas long-acting or shortacting. Barbital is long-acting.A 0.3-g dose produces six or more hours of
sleepin an adult. Thiopental sodium salt (sodium pentothal), on the other
hand, acts only briefly; it is used in surgery to put patients to sleep before a
generalanestheticis administered.
PRACTICE
EXERCISE
I5.I5
Write the structure of sodium pentothal.
PRACTICE
EXERCISE
I5.I4
Explain why the hydrogens on the ring nitrogens of barbituric acid and
its derivatives are readily lost as protons.
s#&#ffiseRY
Amines and amides are major nitrogen-containing
classesof organic compounds.Amines are organic
derivatives of ammonia. They are classified as primary (1";RNHj, secondary(2";RNHR),and tertiary
(3'; RNRR).A quaternary ammonium salt has four
carbon groups attached to the amine nitrogen; the
nitrogen is positively charged.Carbon rings that contain amine nitrogen are called heterocyclic amines.
The acid-base properties of amines are similar to
those of ammonia. That is, the ability of the unshared
electronpair of amine nitrogen to accepta proton in
acidic solutions makes amines weak bases.Because
of their weak basicity, certain amines act as pH
buffers in biological fluids.
Amides are derivatives of acids and amines.
\Mhen formed from carboxylic acids, they have the
general formulas RCONH2 (simple amides),
RCONHR(monosubstitutedamides),and RCONRR
(disubstituted amides). Amides are neutral compounds; the unshared electron pair of the amide
nitrogen is pulled toward carbonyl o)rygen,rendering
it less available for protonation than it is in amines.
Many amines are physiologically important. The
catecholamines are neurotransmitters of the central
nervous system. Amphetamine and several hallucinogenic drugs are similar in structure to catecholamines.Alkaloids are a classof over 2500amines
isolated from plants. Many have useful medicinal
properties. Lysergic acid diethylamide (LSD), reserpine, quinine, atropine, and cocaine are a few alkaloids. Morphine, another alkaloid, is the most effective pain killer kno',,rrn.
Barbiturates are derivativesof
urea (NH2CONH2).A dozen or so barbiturates are
used in medicine, mainly ashlpnotics and sedatives.
SEJffi
IS&*Y {3FREA€TE*tr5
Here are examples of the reactions covered in this
chapter.
1 Preparationof amines.(The amine is 1" or 2'.)
HH
ll*
R-N:
tl
+ R-CI
-+
R-N-R
3. Preparationof amides.
(a) By dehydration of ammonium salts of acids.
(The nitrogen compound is ammonia or a l'or
2'amine.)
o?
CI_
R-c-o
NHr* #
HH
Tieatment with base liberates the free amine.
2. Preparation of quaternary ammonium salts. (The
amine is 3'.)
R-N:
II
RR
+ R-Ct -----' *-'{a*
Cl
+ uro
(b) By reactionsof ammoniaor amineswith esters
(Theamineis 1'or 2'.)
or anhydrides.
oo
r
R-C-OR
RR
n-t-NH,
..
+ H-NHR
oooo
llli..,,..l
R-C-O-C-R
-+
+ H-NHR
l
R-C-NHR
+ ROH
--- R-C-NHR
+ R-C-OH