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Chapter 8

Introducing Nitrogen:The Importance of Amines

and Their Derivatives

Amines

n In most organic compounds, nitrogen forms three covalent bonds, and has one lone pair (which we often do not show)

n Amine is the term used to describe a nitrogen-containing functional groupn The nitrogen atom of an amine may be

bonded to one, two, or three different carbon atoms

CH3N

H

H N

CH3

CH3H H3C N

CH3

CH3

Amines

n Like alcohols, many amines are able to form hydrogen bonds

n Amines have higher boiling points than other molecules of a similar size for this reason

n In most cases, hydrogen bonds between amines are quite a bit weaker than those of alcohols (see p. 296)

Amines in Medicine

n Many of the important drugs (both legal and illegal) available today are amines, or are closely related to them

n The term alkaloid is applied to a wide range of complex amines found in nature which have various effects on the body

n These compounds serve as a template for much of the current drug research being carried out today

Amines in Medicinen Prozac and Paxil, two drugs which are used to treat

depression, are amines which alter the way nerve cells transmit signals to each other

n Signals are sent from one nerve cell to another by means of “messanger molecules” called neurotransmittersn Serotonin is among the most important of these

n A deficiency of Serotonin in the space between nerve cells (the synaptic area) is a likely cause for chronic depression

n Prozac and Paxil increase the concentration of Serotonin in this region by making it by preventing nerve cells from reabsorbing the neurotransmitter

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Heterocycles

n Many naturally-occurring amines are found in rings, as was the case for carbon and oxygenn Molecules made up of rings which contain

elements different than carbon are called heterocycles

n Pyridine and pyrrolidine are two common examples of nitrogen-containing heterocycles

NN

Hpyridinepyrrolidine

N

H

CH2CH2NH2

HO

serotonin

Nicotine

n Nicotine is one of the most well-known alkaloids

n It is found in tobacco leaves, and is drawn into the bloodstream when these are chewed or smoked

n It acts as a stimulant as well as increasing heart rate, blood pressure, and triggers the release of adrenaline (another amine) into the bloodstream

Nicotine

n While nicotine can be toxic in high doses, the chemicals produced in the burning of a cigarette are largely to blame for the negative health effects of smokingn Cigarette smoke contains well-known carcinogens,

including benzene and other polyaromatichydrocarbons (PAHs)

n Nicotine addiction can now be overcome with the help of patchs which wean the user off of the drug

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Caffeine

n Caffeine is another of the more common amines (alkaloids) we should be familiar with

n This molecule is found in many natural sources, including coffee beans, tea leaves, and cocoa

O N

CH3

N

CH 3

N

NH3C

O

Half-life

n Many of the chemicals which enter our body break down at an exponential rate, a rate that slows down with the passage of time

n We define the time it takes for one-half of the substance present to decompose as a half-life

n For example, the half-life of caffeine is four hours; that of morphine is 3 hours

Half-life

n Suppose we have 10. grams of caffeine in our system

n With a half-life of four hours, we would expect to observe the followingn After four hours, only one half (5 grams) remainsn After an additional four hours, half of this amount

(2.5 grams) remainsn After another four hours, half of this (1.25 grams)

remainsn And the process continues, until eventually none

can be detected (which is not to say that it is allentirely gone!)

Some Spicy Relatives of Amines: Amides

n Piperine is the active component of white and black pepper, and capsaicin is the molecules which gives chili peppers their kick

n Although they may initially produce pain on the tongue, these molecules are thought to stimulate the release of endorphins in the brain

n Milk and milk chocolate contain a protein called casein, which relieves the pain of this spicy molecule by knocking capsaicin out of the nerve receptors of the taste buds

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Hotness

n The “hotness” of peppers is measured in Scoville Units

n For comparison, on this scalen Bell peppers rank zeron A Habanero gets a value of 300,000n Naga Jolokia, the hottest chili, has a value of

700,000n Pure capsaicin (the pure compound, extracted

from a pepper) has a Scoville rating of 16 million!n Capsaicin can be detected by the tongue at

extremely small levels: 1 part in 17 million

Amides

n Both of these molecules are classified as amides; an amide can be thought of as an ester, where you switch the single-bonded oxygen to a nitrogen

C

O

H3C N

NCH3

H

O

CH3

OCH3

HO

O

O

N

O

piperine

capsaicin

Drugs—Legal and Illegal

n A huge number of the prescription drugs available are amines

n As was stated earlier, many of these drugs are based on alkaloids (complex amines) found in nature

n For example, morphine is derived from opium, which is extracted from a latex produced by the Opium poppy

The Opium PoppyMorphine Derivatives

n Many of our most important legal (and illegal) pain-killers are based on morphine

n By making small changes to the morphine molecule, new drugs can be created which have similar pain-killing effects

n Morphine and its derivatives suppress pain by blocking the nerve receptors responsible for this sensation

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The Lock-and-Key Model

n Morphine is like a key which is well designed to fit into specific pain receptors (which are like a lock)

n The similarity between the way a molecule interacts with another molecule based on shape and the way a key fits into a lock is the basis of the lock-and-key model

The Lock-and-Key Model

n Several drugs have a similar shape to morphine, but with only small changes to the molecule

n By “tweaking” the shape of the molecule, we can create a molecule which interacts in different ways with the pain receptors

n For example, Codeine differs from morhphineonly in that an –OH group is replaced with an –OCH3 group

The Lock-and-Key Model

n Although this change does not appear to affect the shape of the morphine molecule, it is enough to make codeine a much less addictive (as well as much weaker) drug

n Heroin is transformed to morphine by changing two of the –OH groups in morphine to CH3O2– groups

n While heroin is even more successful than morphine at masking pain, it is also much more addictive

Demerol

n Demerol, another popular pain-killer, has a similar shape to that of morphine

n Although it can be abused, it is ultimately a safer and cheaper alternative to stronger pain-killers, which are mainly reserved for terminal and severe cases

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Vicodin and Similar Preparations

n Vicodin is yet another pain killer with a structure similar to that of morphine

n It is sold under a variety of trade names, as the pure compound as well as through various mixtures

Vicodin Norco Lortab

Cocaine

n Cocaine is an alkaloid derived from the coca plant by treating its crushed leaves with hydrochloric acid

n These extracts have been used for years by South American natives as part of religious rituals and for its stimulating effects

n As you may know, the original formulation of Coca-Cola included cocaine, giving it a much bigger “kick” than the safer variety we consume today

Acids, Bases, and Amines

n Amines are classified as compounds known as bases

n Acids are essentially the opposite of basesn In chemical reactions between acids and

bases, we see what is called a proton-transfern The acid loses the H+ ion (called a proton) to

the base, who gains the proton

Acids, Bases, and Amines

n When an amine reacts with hydrochloric acid, the lone pairs of nitrogen “accept” the H+

atom, and the positive charge is then transferred to the nitrogen atom

n The chloride atom (Cl-) is left over from the reaction, and is attracted to the positive ion which was just formed

n This product is described as the hydrochloride salt of the amine

Cocaine Hydrochloride

n When an individual snorts the powder form of cocaine, they are actually taking in the hydrochloride salt of this compound

n Hydrochloride salts are generally much more soluble in water, and enter the blood stream much more rapidly as a result

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Crack Cocaine

n Crack cocaine is cocaine in its free base formn Recall that cocaine hydrochloride was formed

when acid was used to obtain itn By treating cocaine hydrochloride with a base

like sodium bicarbonate (baking soda), the freebase is formed

n The freebase powder can be smoked and is absorbed rapidly in the lungs

n Crack cocaine is highly addictive, and much of the variety sold on the streets contains impurities, making it among the most dangerous of all illegal drugs

Cocaine and Dopaminen Dopamine, like serotonin, is a neurotransmittern Cocaine blocks dopamine from re-entering the nerve

cell, allowing it to accumulate in the synaptic arean Dopamine repeatedly stimulates the receptor sites,

producing the “high” which is associated with this drug

n As dopamine accumulates, enzymes take action and begin to destroy the neurotransmitter

n Since cocaine has a half-life of only 45 minutes, the lack of cocaine in the system combined with a lack of dopamine in the synaptic area violently drop the user into a state of depression

n The drug then becomes abused in the fruitless attempt to maintain a sense of euphoria

Amphetamine and its Derivativesn Amphetamine is another commonly -abused stimulantn Its molecular structure is similar to that of

adrenaline, and the body reacts to this compound in a similar way

n Methamphetamine and Ecstasy have a similar structure to amphetamine, and have similar effects on the body

n Methamphetamine has a long half-life (12 hours) and tends to cause psychological distress to the user

n Ecstasy triggers the release of large amounts of serotonin into the synaptic area, giving it its stimulating effect

Analgesics

n An analgesic is a chemical which is used to treat pain

n Several over-the-counter medications are available for this purpose, includingn Aspirin (acetylsalicylic acid)n Acetaminophenn Ibuprofen

n It is interesting to note that, among these popular medicines, only acetaminophen is an amine-derivative (it is actually an amide)

Amides and Condensation Reactions

n Amides can be formed by the reaction of a carboxylic acid with an amine under the correct conditions

n In the process, a water molecule is eliminated, making this yet another condensation reaction

n Consider the reaction of p-aminophenol with acetic acid to produce acetaminophen

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HO

NH2

C

O

CH3HO

+

HO

NC

O

CH3

H

+ H2O

Acetaminophen Condensation Polymers

n We have previously studied addition polymers, which are formed by combining alkenes

n A condensation polymer is formed by the reaction of molecules which join together and eliminate water as a side product

n Among our most important condensation polymers is Nylon which is formed through condensation reactions between carboxylic acids and amines, forming an amide linkage

Condensation Polymers

n Polysaccharides like starch are condensation polymers, as joining glucose monomers gives off water in the process

n We will see in the next chapter how the long chains of proteins and DNA are created through condensation reactions, making these among the most important types of reactions known