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5 Alkaloids—Amines from Plant Sources

5 Alkaloids—Amines from Plant Sources

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ALKALOIDS—AMINES FROM PLANT SOURCES



551



PROBLEM 18.12



Classify the amine in morphine as 1°, 2°, or 3°.



PROBLEM 18.13



Identify all the functional groups in heroin.



18.5B QUININE

Quinine is an alkaloid isolated from the bark of the cinchona tree native to the Andes Mountains.

Quinine is a powerful antipyretic—that is, it reduces fever—and for centuries it was the only

effective treatment for malaria. Its bitter taste gives tonic water its characteristic flavor.



CH2



CH



N

HO



CH

quinine



CH3O



N

cinchona tree



PROBLEM 18.14



(a) How many trigonal planar carbon atoms does quinine contain? (b) How many tetrahedral

carbon atoms does quinine contain?



18.5C ATROPINE

Atropine is an alkaloid isolated from Atropa belladonna, the deadly nightshade plant.



CH3



N



CH2OH

atropine



O



C



CH



O

deadly nightshade plant



During the Renaissance (fourteenth to seventeenth centuries), women used the juice of the

berries of the nightshade to enlarge the pupils of their eyes for cosmetic reasons. Sometimes ophthalmologists today use atropine to dilate pupils. Atropine also increases heart rate, so physicians

administer atropine for this purpose. Atropine relaxes smooth muscles and interferes with nerve

impulses. In higher doses atropine is toxic, leading to convulsions, coma, and death.



PROBLEM 18.15



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Identify all of the functional groups in atropine, and classify the amine as 1°, 2°, or 3°.



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552



AMINES AND NEUROTRANSMITTERS



18.6 AMINES AS BASES

Like ammonia (NH3), amines are bases; that is, they are proton acceptors. When an amine is dissolved in water, an acid–base equilibrium occurs: the amine accepts a proton from H2O, forming

its conjugate acid, an ammonium ion, and water loses a proton, forming hydroxide, –OH.

This electron pair forms

a new bond to a proton.

General

reactions



H



N



H



+



H



O



H



H



H



H

ammonia This proton is removed.



N+ H



+







O



H



+







O



H



H

ammonium ion

H



R



N



H



+



H



O



H



R



H

1° amine



N+ H

H



This acid–base reaction occurs with 1°, 2°, and 3° amines. While amines are more basic than other

families of organic compounds, they are weak bases compared to inorganic bases like NaOH.

H

Example



CH3



N



H



+



H



O



H



CH3



H

1° amine



18.6A



N+ H



+







O



H



H



REACTION OF AMINES WITH ACIDS



Amines also react with acids such as HCl to form water-soluble salts. The lone pair of electrons from the amine nitrogen atom is always used to form a new bond to a proton from the acid.

H

Example



CH3



N



CH3 +



H



Cl



CH3



N+ CH3



+



Cl−



CH3



CH3

3° amine

This proton is transferred

from the acid to the base.



• The amine [(CH3)3N] gains a proton to form its conjugate acid, an ammonium cation

[(CH3)3NH+].

• A proton is removed from the acid (HCl) to form its conjugate base, the chloride anion (Cl–).



Similar acid–base reactions occur with other inorganic acids (H2SO4), and with organic acids like

CH3COOH, as well. In each reaction, the amine gains a proton and the acid loses a proton.

This fundamental reaction of amines occurs no matter how complex the amine, as shown in

Sample Problem 18.4.

• In an acid–base reaction of an amine, the amine nitrogen always forms a new bond to a

proton forming an ammonium ion.



SAMPLE PROBLEM 18.4



What products are formed when methamphetamine (Section 18.1) reacts with HCl?

CH3

CH2CHNHCH3



+



HCl



methamphetamine



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AMINES AS BASES



553



ANALYSIS



In any acid–base reaction with an amine:

• Locate the N atom of the amine and add a proton to it. Since the amine nitrogen is neutral

to begin with, adding a proton gives it a +1 charge.

• Remove a proton from the acid (HCl) and form its conjugate base (Cl–).



SOLUTION



Transfer a proton from the acid to the base. Use the lone pair on the N atom to form the new

bond to the proton of the acid.

CH3 H



CH3

CH2CH



N



CH3



+



Cl



H



N+ CH3



CH2CH



+



Cl−



H



H

methamphetamine



This proton is transferred from

the acid to the amine base.



Thus, HCl loses a proton to form Cl–, and the N atom of amphetamine gains a proton to form

an ammonium cation.



PROBLEM 18.16



What products are formed when each of the following amines is treated with HCl:

(a) CH3CH2NH2; (b) (CH3CH2)2NH; (c) (CH3CH2)3N?



PROBLEM 18.17



Draw the products of each acid–base reaction.

a.



CH3CH2CH2CH2



NH2



+



+



c.



HCl



H2O



N

H



b.



PROBLEM 18.18



(CH3)2NH



+



C6H5COOH



What products are formed when epinephrine is treated with H2SO4?

HO

OH

CHCH2NHCH3



HO



epinephrine

(adrenaline)



18.6B



AMMONIUM SALTS



When an amine reacts with an acid, the product is an ammonium salt: the amine forms a positively charged ammonium ion and the acid forms an anion.

positively charged

ammonium ion



chloride anion

H



CH3CH2CH2



N

H



H



+



H



Cl



CH3CH2CH2



N+ H



+



Cl−



H

ammonium salt



To name an ammonium salt, change the suffix -amine of the parent amine from which the salt is

formed to the suffix -ammonium. Then add the name of the anion. Two examples are shown in

Sample Problem 18.5.



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554



AMINES AND NEUROTRANSMITTERS



SAMPLE PROBLEM 18.5



Name each ammonium salt.

a.



ANALYSIS



+



Cl−



CH3CH2NH3



b.



+



CH3COO−



(CH3)3NH



To name an ammonium salt, draw out the four groups bonded to the N atom. Remove one

hydrogen from the N atom to draw the structure of the parent amine. Then put the two parts of

the name together.

• Name the ammonium ion by changing the suffix -amine of the parent amine to the suffix

-ammonium.

• Add the name of the anion.



SOLUTION



H



a.



+



CH3CH2



N



H



Cl−



• Change the name ethylamine to

ethylammonium.

• Add the name of the anion, chloride.

Answer: ethylammonium chloride



chloride



H

derived from CH3CH2



N



H



H

ethylamine

H



b.



+



CH3



N



CH3



CH3COO−



• Change the name trimethylamine to

trimethylammonium.

• Add the name of the anion, acetate.

Answer: trimethylammonium acetate



acetate



CH3

derived from CH3



N



CH3



CH3

trimethylamine



PROBLEM 18.19



Name each ammonium salt.

a.



+



CH3NH3



Cl−



b.



+



(CH3CH2CH2)2NH2



Br−



c.



+



(CH3)2NHCH2CH3



CH3COO−



Ammonium salts are ionic compounds, and as a result:

• Ammonium salts are water-soluble solids.



In this way, the solubility properties of an amine can be changed by treatment with acid. For

example, octylamine has eight carbons, making it water insoluble. Reaction with HCl forms

octylammonium chloride. This ionic solid is now soluble in water.

H

CH3CH2CH2CH2CH2CH2CH2CH2



N



H



+



H



Cl



CH3CH2CH2CH2CH2CH2CH2CH2



N+ H



Cl−



H



H

octylamine



octylammonium chloride



water-insoluble amine



water-soluble salt

The solubility properties change.



• A water-insoluble amine can be converted to a water-soluble ammonium salt by

treatment with acid.



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FOCUS ON HEALTH & MEDICINE: CAFFEINE AND NICOTINE



HEALTH NOTE



549



18.4B NICOTINE

Nicotine (Figure 18.3) is a highly toxic amine isolated from tobacco. In small doses it acts as a

stimulant, but in larger doses causes depression, nausea, and even death. Nicotine is synthesized in

tobacco plants as a defense against insect predators, and is used commercially as an insecticide.

Although inhaled tobacco smoke contains over 4,000 compounds, many of which are toxic or

cancer causing, nicotine is the compound that makes smoking addictive. Nicotine imparts a

sense of pleasure to the smoker, and once a smoker is “hooked,” an individual needs to continue

smoking to avoid the extreme discomforts of withdrawal—restlessness, anxiety, and craving.

Cigarette smoking causes lung disease, heart disease, and cancer, and it is recognized today as the

leading cause of avoidable death in the United States. Despite this well known fact, the nicotine

addiction makes it difficult for current smokers to quit. In fact, the sale of nicotine-free cigarettes

many years ago was an unsuccessful enterprise because the nicotine in cigarettes is what smokers

really crave when they light up.



Nicotine patches and nicotinecontaining chewing gum have been

effectively used by many individuals

to quit smoking.



One method employed by some to quit smoking involves the use of a nicotine patch. The patch

is applied to the skin and nicotine diffuses through the skin and into the bloodstream. In this way,

a smoker still derives pleasure from the nicotine in the system, but is no longer exposed to the ill

effects of the other components of cigarette smoke. Slowly the concentration of nicotine in the

patch is reduced, with the hope that eventually the smoker will no longer need nicotine. A similar

strategy is used with chewing gum that contains nicotine.





FIGURE 18.3 Nicotine—An Alkaloid from the Tobacco Plant



tobacco plant



nicotine

C10H14N2



dried tobacco leaves



Tobacco is grown in temperate climates. The leaves are harvested and dried, and then

converted to cigarettes and other tobacco products.



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FOCUS ON HEALTH & MEDICINE: AMMONIUM SALTS AS USEFUL DRUGS



PROBLEM 18.20



555



Label each compound as water soluble or water insoluble.

a.



b.



(CH3CH2)3N



+



(CH3CH2)3NH



Br−



c.



+



d.



CH3CH2NH2



H



Cl−



N

H



Ammonium salts can be re-converted to amines by treatment with base. Base removes a proton

from the nitrogen atom of the amine, regenerating the neutral amine.

This proton is removed by the base.



H

CH3CH2CH2CH2CH2CH2CH2CH2



N+ H



Cl−



Na+−OH



+



CH3CH2CH2CH2CH2CH2CH2CH2



H



+



H



+



OH



NaCl



H

octylamine

water-insoluble amine



H

octylammonium chloride

water-soluble salt



PROBLEM 18.21



N



What product is formed when each ammonium salt is treated with NaOH?

a.



+



(CH3CH2)3NH



Br−



b.



+



CH3CH2NH3



HSO4−



+



c.



H



N



Cl−



H



CONSUMER NOTE



18.7 FOCUS ON HEALTH & MEDICINE

AMMONIUM SALTS AS USEFUL DRUGS

Many amines with useful medicinal properties are sold as their ammonium salts. Since the ammonium salts are more water soluble than the parent amine, they are easily transported through the

body in the aqueous medium of the blood.

For example, diphenhydramine is a 3° amine that is sold as its ammonium salt under the name

of Benadryl. Benadryl, formed by treating diphenhydramine with HCl, is an over-the-counter

antihistamine that is used to relieve the itch and irritation of skin rashes and hives.

H

C



H

OCH2CH2



N



CH3



CH3



+



HCl



C



H

OCH2CH2



N



+



CH3



Cl−



CH3

ammonium salt



diphenhydramine



Benadryl



Medicines sold as ammonium salts are often derived from the names of the amine and the

acid used to form them. Since Benadryl is formed from diphenhydramine and HCl, it is called

diphenhydramine hydrochloride.

Many antihistamines and decongestants are sold as their hydrochloride salts.



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Two other examples of amines sold as their ammonium salts are phenylephrine hydrochloride,

the decongestant in Sudafed PE, Theraflu, and DayQuil, and methadone hydrochloride, a longacting narcotic taken orally to treat chronic painful conditions. Methadone hydrochloride is also

used as a substitute narcotic for heroin addicts.



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556



AMINES AND NEUROTRANSMITTERS



O



HO



CCH2CH3



H



OH

CHCH2



N



+



CH3



Cl−



C



H

CH



CH2



N+ CH3



Cl−



CH3 CH3



H

phenylephrine hydrochloride

(decongestant in Sudafed PE,

Theraflu, and DayQuil)



methadone hydrochloride

(narcotic analgesic)



Some quaternary ammonium salts (R4N+ X–, Section 18.1)—that is, ammonium salts with

nitrogen atoms bonded to four alkyl groups—are also useful agents. Bitrex is a foul-tasting nontoxic salt used on children’s fingers to keep them from biting their nails or sucking their thumbs.

Benzalkonium chloride is a disinfectant and antiseptic in mouthwash.

CH3

O

NHCCH2



CH2CH3

N



+



CH3



CH2



CH2



CH2CH3

CH3

Bitrex



N



+



(CH2)17CH3



Cl−



CH3

COO−



benzalkonium chloride



PROBLEM 18.22



Draw the structures of the amines from which phenylephrine hydrochloride and methadone

hydrochloride are derived.



PROBLEM 18.23



When Benadryl is treated with a base like NaOH, the free amine, diphenhydramine, is reformed, as we learned in Section 18.6. Explain why a similar reaction does not occur with a

quaternary ammonium salt like Bitrex.



18.8 NEUROTRANSMITTERS

A neurotransmitter is a chemical messenger that transmits nerve impulses from one nerve

cell—neuron—to another cell. As shown in Figure 18.4, a neuron consists of many short filaments called dendrites connected to a cell body. A long stem called an axon also protrudes from

the cell body. The axon ends in numerous small filaments at its opposite end. These filaments are

separated from the dendrites of a nearby neuron by a small gap called the synapse.

Neurotransmitters are stored in small packets called vesicles in the filaments of the axon near the

synapse. When an electrical signal flows from the cell body of the neuron along the axon to the

filaments, the neurotransmitter is released, diffuses across the synapse, and binds to a receptor on

the dendrites of an adjacent neuron.

• The presynaptic neuron releases the neurotransmitter.

• The postsynaptic neuron contains the receptors that bind the neurotransmitter.



Once the neurotransmitter is bound to the receptor, the chemical message is delivered. The neurotransmitter is then degraded or it is returned to the presynaptic neuron to begin the process again.

Drugs may be used to affect neurotransmitters in many different ways. Some drugs prevent the

release of a neurotransmitter or prevent its binding to a receptor. Other drugs increase the amount

of neurotransmitter released. Some drugs affect the degradation of a neurotransmitter or prevent

its reuptake by the presynaptic neuron.



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