chapter24 amine

8/7/2019 chapter24 amine

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Chapter 24. Aminesand Heterocycles

Based on McMurrys Organic Chemistry, 7th edition


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Amines Organic Nitrogen

Compounds Organic derivatives of ammonia, NH3,

Nitrogen atom with a lone pair of electrons, makingamines both basic and nucleophilic

Occur in plants and animals


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Why this Chapter?

Amines and carbonyl compounds are the

most abundant and have rich chemistry

In addition to proteins and nucleic acids, a

majority of pharmaceutical agents contain

amine functional groups


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24.1 Naming Amines

Alkyl-substituted (alkylamines) or aryl-substituted(arylamines)

Classified: 1 (RNH2), methyl (CH3NH2), 2 (R2NH),3 (R3N)


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Quaternary Ammonium Ions

A nitrogen atom with four attached groups is

positively charged

Compounds are quaternary ammonium salts


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IUPAC Names Simple Amines

For simple amines, the suffix -amine is added to the

name of the alkyl substituent


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IUPAC Names -amine Suffix

The suffix -amine can be used in place of the final -e

in the name of the parent compound


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IUPAC Names Amines With More

Than One Functional Group

Consider the NH2 as an amino substituent on the

parent molecule


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IUPAC Names Multiple Alkyl

Groups

Symmetrical secondary and tertiary amines are

named by adding the prefix di- ortri- to the alkyl

group


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IUPAC Names Multiple, Different

Alkyl Groups

Named as N-substituted primary amines

Largest alkyl group is the parent name, and otheralkyl groups are considered N-substituents


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Common Names of Heterocyclic

Amines

If the nitrogen atom occurs as part of a ring, thecompound is designated as being heterocyclic

Each ring system has its own parent name


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24.2 Properties of Amines

Bonding to N is similar to that in ammonia

N is sp3-hybridized

CNC bond angles are close to 109 tetrahedral

value


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Chirality Is Possible (But Not

Observed) An amine with three different substituents on nitrogen

is chiral (in principle but not in practice): the lone pairof electrons is the fourth substituent

Most amines that have 3 different substituents on N

are not resolved because the molecules interconvertbypyramidal inversion


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Amines Form H-Bonds

Amines with fewer than five carbons are water-

soluble

Primary and secondary amines form hydrogen

bonds, increasing their boiling points


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24.3 Basicity of Amines

The lone pair of electrons on nitrogen makes aminesbasic and nucleophilic

They react with acids to form acidbase salts andthey react with electrophiles


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Relative Basicity

Amines are stronger bases than alcohols, ethers, orwater

Amines establish an equilibrium with water in whichthe amine becomes protonated and hydroxide is

produced The most convenient way to measure the basicity of

an amine (RNH2) is to look at the acidity of thecorresponding ammonium ion (RNH3

+)

High pKa weaker acid and stronger conjugatebase.


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General Patterns of Basicity

Table 24.1: pKa values of ammonium ions

Most simple alkylammmonium ions have pKa's of 10

to 11

Arylamines and heterocyclic aromatic amines areconsiderably less basic than alkylamines (conjugate

acid pKa 5 or less)


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Amides

Amides (RCONH2) in general are not proton acceptors except invery strong acid

The C=O group is strongly electron-withdrawing, making the N avery weak base

Addition of a proton occurs on O but this destroys the double

bond character of C=O as a requirement of stabilization by N


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24.4 Basicity of Substituted

Arylamines

The N lone-pair electrons in arylamines aredelocalized by interaction with the aromatic ring Telectron system and are less able to accept H+ thanare alkylamines


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Substituted Arylamines

Can be more basic or less basic than aniline

Electron-donating substituents (such as CH3,NH2, OCH3) increase the basicity of thecorresponding arylamine

Electron-withdrawing substituents (such as Cl,NO2, CN) decrease arylamine basicity


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24.5 Biological Amines and the

Henderson-Hasselbalch Equation What form do amines exist at physiological pH insidecells


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24.6 Synthesis of Amines

Arylamines are prepared from nitration of an aromaticcompound and reduction of the nitro group

Reduction by catalytic hydrogenation over platinum issuitable if no other groups can be reduced

Iron, zinc, tin, and tin(II) chloride are effective inacidic solution


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SN2 Reactions of Alkyl Halides

Ammonia and other amines are good nucleophiles


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Uncontrolled Multiple Alkylation

Primary, secondary, and tertiary amines all have

similar reactivity, the initially formed monoalkylated

substance undergoes further reaction to yield a

mixture of products


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Selective Preparation of Primary Amines:

the Azide Synthesis

Azide ion, N3 displaces a halide ion from a primary

or secondary alkyl halide to give an alkyl azide, RN3 Alkyl azides are not nucleophilic (but they are

explosive)

Reduction gives the primary amine


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Gabriel Synthesis of Primary

Amines

Aphthalimide alkylation for preparing a primary

amine from an alkyl halide

The N-H in imides (CONHCO) can be removed

by KOH followed by alkylation and hydrolysis


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Reductive Amination of Aldehydes

and Ketones

Treatment of an aldehyde or ketone with ammonia or

an amine in the presence of a reducing agent


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Reductive Amination Is

Versatile Ammonia, primary amines, and secondary aminesyield primary, secondary, and tertiary amines,

respectively


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Mechanism of Reductive Amination


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Reducing Step

Sodium cyanoborohydride, NaBH3CN, reduces C=Nbut not C=O

Stable in water


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Hofmann and Curtius

Rearrangements

Carboxylic acid derivatives can be converted intoprimary amines with loss of one carbon atom by boththe Hofmann rearrangement and the Curtiusrearrangement


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Hofmann Rearrangement

RCONH2 reacts with Br2 and base

Gives high yields of arylamines and alkylamines

Figure 24.5 See Mechanism


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Curtius Rearrangement

Heating an acyl azide prepared from an acid chloride

Migration ofR from C=O to the neighboring

nitrogen with simultaneous loss of a leaving group


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24.7 Reactions of Amines

Alkylation and acylation have already been presented


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Hofmann Elimination

Converts amines into alkenes

NH2 is very a poor leaving group so it converted to

an alkylammonium ion, which is a good leaving group


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Silver Oxide Is Used for the

Elimination Step

Exchanges hydroxide ion for iodide ion in the

quaternary ammonium salt, thus providing the base

necessary to cause elimination


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Orientation in Hofmann Elimination

We would expect that the more highly substitutedalkene product predominates in the E2 reaction of analkyl halide (Zaitsev's rule)

However, the less highly substituted alkene

predominates in the Hofmann elimination due to thelarge size of the trialkylamine leaving group

The base must abstract a hydrogen from the moststerically accessible, least hindered position


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Steric Effects Control the

Orientation


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24.8 Reactions of Arylamines

Amino substituents are strongly activating, ortho- and

para-directing groups in electrophilic aromatic

substitution reactions

Reactions are controlled by conversion to amide


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Arylamines Are Not Useful for

Friedel-Crafts Reactions

The amino group forms a Lewis acidbase complex

with the AlCl3 catalyst, preventing further reaction

Therefore we use the corresponding amide


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Diazonium Salts: The Sandmeyer

Reaction

Primary arylamines react with HNO2, yielding stable

arenediazonium salts


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Uses of Arenediazonium Salts

The N2 group can be replaced by a nucleophile


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Preparation of Aryl Halides

Reaction of an arenediazonium salt with CuCl orCuBr gives aryl halides (Sandmeyer Reaction)

Aryl iodides form from reaction with NaI without acopper(I) salt


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Aryl Nitriles and Carboxylic

Acids An arenediazonium salt and CuCN yield the nitrile,

ArCN, which can be hydrolyzed to ArCOOH


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Formation of Phenols (ArOH)

From reaction of the arenediazonium salt with

copper(I) oxide in an aqueous solution of copper(II)

nitrate


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Reduction to a Hydrocarbon

By treatment of a diazonium salt with

hypophosphorous acid, H3PO2


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Mechanism of Diazonium

Replacement

Through radical (rather than polar or ionic) pathways


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Diazonium Coupling Reactions

Arenediazonium salts undergo a coupling reactionwith activated aromatic rings, such as phenols andarylamines, to yield brightly colored azo compounds,

ArN=NArd


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How Diazonium Coupling Occurs

The electrophilic diazonium ion reacts with theelectron-rich ring of a phenol or arylamine

Usually occurs at the para position but goes ortho ifpara is blocked


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Azo Dyes

Azo-coupled products have extended T conjugationthat lead to low energy electronic transitions thatoccur in visible light (dyes)


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24.9 Heterocycles

A heterocycle is a cyclic compound that

contains atoms of two or more elements in its

ring, usually C along with N, O, or S


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Pyrole and Imidazole

Pyrole is an amine and a conjugated diene,

however its chemical properties are not

consistent with either of structural features


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Chemistry of Pyrole

Electrophilicsubstitutionreactions occur atC2 b/c it is position

next to the N

A more stableintermediate cationhaving 3 resonance

forms At C3, only 2

resonance forms


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Polycyclic Heterocycles


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24.10 Spectroscopy of Amines -

Infrared

Characteristic NH stretching absorptions 3300 to

3500 cm1

Amine absorption bands are sharper and less intense

than hydroxyl bands

Protonated amines show an ammonium band in

the range 2200 to 3000 cm1


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Examples of Infrared Spectra


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Nuclear Magnetic Resonance

Spectroscopy

NH hydrogens appear as broad signals without

clear-cut coupling to neighboring CH hydrogens

In D2O exchange of ND for NH occurs, and the N

H signal disappears


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Chemical Shift Effects

Hydrogens on C next to N and absorb at lower fieldthan alkane hydrogens

N-CH3 gives a sharp three-H singlet at H 2.2 to H 2.6


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13C NMR

Carbons next to amine N are slightly deshielded -about 20 ppm downfield from where they wouldabsorb in an alkane


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Mass Spectrometry

A compound with an odd number of nitrogen atomshas an odd-numbered molecular weight and acorresponding parent ion

Alkylamines cleave at the CC bond nearest thenitrogen to yield an alkyl radical and a nitrogen-containing cation


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Mass Spectrum of N-

Ethylpropylamine

The two modes of a cleavage give fragment ions atm/z= 58 and m/z= 72.

chapter24 amine

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