Chapter 24. Chapter 24. Amines and HeterocyclesAmines and Heterocycles

Why this Chapter?Why this Chapter?Amines and carbonyl compounds are the most abundant and have rich chemistryIn addition to proteins and nucleic acids, a majority of pharmaceutical agents contain amine functional groups

2

Amines – Organic Nitrogen CompoundsAmines – Organic Nitrogen Compounds

Organic derivatives of ammonia, NH3, Nitrogen atom with a lone pair of electrons,

making amines both basic and nucleophilicOccur in plants and animals

24.1 Naming Amines24.1 Naming AminesAlkyl-substituted (alkylamines) or aryl-

substituted (arylamines)Classified:

◦ 1° (RNH2), methyl (CH3NH2), ◦ 2° (R2NH), ◦ 3° (R3N)

4

Quaternary Ammonium IonsQuaternary Ammonium Ions

A nitrogen atom with four attached groups is positively charged

Compounds are quaternary ammonium salts

5

IUPAC Names – Simple AminesIUPAC Names – Simple AminesFor simple amines, the suffix -amine is used as

the parent name of the alkyl substituent

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

tert-Butylamine Cyclohexylamine Aniline

1,4-Butanediamine

4,4-Dimethylcyclohexanamine

6

IUPAC Names – Amines With More Than IUPAC Names – Amines With More Than One Functional GroupOne Functional Group

Consider the NH2 as an amino substituent on the parent molecule

2-Aminobutanoic acid

2,4-Diaminobenzoic acid

4-Amino-2-butanone

7

IUPAC Names – Multiple Alkyl GroupsIUPAC Names – Multiple Alkyl GroupsSymmetrical secondary and tertiary amines are named

by adding the prefix di- or tri- to the alkyl group

DiphenylamineTriethylamine

8

IUPAC Names – Multiple, Different Alkyl IUPAC Names – Multiple, Different Alkyl GroupsGroups

Named as N-substituted primary aminesLargest alkyl group is the parent name, and

other alkyl groups are considered N-substituents

N,N-Dimethylpropylamine N-Ethyl-N-methylcyclohexylamine

9

Common Names of Heterocyclic AminesCommon Names of Heterocyclic Amines If the nitrogen atom occurs as part of a ring, the

compound is designated as being heterocyclicEach ring system has its own parent name

Learning Check:Learning Check:Name the following:

Solution:Solution:Name the following:

N-methylethanamine(or Ethyl methyl amine)

Diisopropylamine

Tricyclohexylamine

N-Ethyl-N-methylcyclohexylamine

N-methylpyrrolidine

1,3-Butanediamine

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24.2 Properties of Amines24.2 Properties of AminesBonding to N is similar to that in ammonia

◦ N is sp3-hybridized◦ C–N–C bond angles are close to 109°

tetrahedral value

13

Chirality Is Possible (But Not Observed)Chirality Is Possible (But Not Observed)An amine with three different substituents on

nitrogen is chiral (in principle but not in practice): the lone pair of electrons is the fourth substituent

Most amines that have 3 different substituents on N are not resolved because the molecules interconvert by pyramidal inversion

14

Amines Form H-BondsAmines Form H-BondsAmines with fewer than five carbons are

water-solublePrimary and secondary amines form hydrogen

bonds, increasing their boiling points

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24.3 Basicity of Amines24.3 Basicity of AminesThe lone pair of electrons on nitrogen makes

amines basic and nucleophilicThey react with acids to form acid–base salts

and they react with electrophiles

16

Relative BasicityRelative BasicityAmines are stronger bases than alcohols, ethers, or waterAmines establish an equilibrium with water in which the

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 the corresponding ammonium ion (RNH3

+)High pKa → weaker acid and stronger

conjugate base.

Most simple alkylammmonium ions have pKa's of 10 to 11

The most convenient way to measure the basicity of an amine (RNH2) is to look at the acidity of the corresponding ammonium ion (RNH3

+)

High pKa → weaker acid and stronger conjugate base.

NH

H

Strong Acid

Strong Base

Weak Acid

Weak Base

N

H

H

H

CH3

Arylamines and heterocyclic aromatic amines are considerably less basic than alkylamines (conjugate acid pKa 5 or less)

Weak Acid (pKa ~40)

Relative BasicityRelative Basicity

Strong base

Weaker Acid (pKa ~60)

Stronger base

Purification of Amines:Purification of Amines:Amines can be separated from a mixture by

reaction with acids to form soluble amine salts

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Basicity of AmidesBasicity of Amides Amides (RCONH2) in general are not proton acceptors

except in very strong acid

•The C=O group is strongly electron-withdrawing, making the N a very 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 Arylamines24.4 Basicity of Substituted ArylaminesThe N lone-pair electrons in arylamines are

delocalized by interaction with the aromatic ring electron system and are less able to accept H+

than are alkylamines

Electrons tied up in resonance aren’t as available for bonding.

Weak BaseWeak Nucleophile

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

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

Substituted Substituted ArylaminesArylamines

Learning Check:Learning Check:Without looking at a table, Name the following compounds then Rank the structures in each set in order of decreasing basicity (#1 =

strongest)

NH2

O2N

NH2

C

O

H

NH2

Br

A.

B.NH2

CH2F

NH2

CH3

NH2

C

F

FF

Solution:Solution:Without looking at a table, Name the following compounds then Rank the structures in each set in order of decreasing basicity (#1 =

strongest)

NH2

O2N

NH2

C

O

H

NH2

Br

A.

B.NH2

CH2F

NH2

CH3

NH2

C

F

FF

p-Nitroaniline p-Aminobenzaldehyde p-Bromoaniline

p-(Trifluoromethyl)aniline p-Methylaniline p-(Fluoromethyl)aniline

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1 23

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24.5 Biological Amines24.5 Biological Amines In what form do amines exist at a physiological pH of 7.3?

CH3 N

H

H

H

pKa = 10.64

H2O CH3 N H

H

+ + H3O+

pKa = -1.7

[HA] [A-]

At pH = 10.64 we expect the amount of [HA] and [A-] to be the same.

As the solution becomes more acidic (Below a pH of 10.64) we expect methylamine to be protonated. (Higher concentration of HA)

As the solution becomes more basic (pH above 10.64) we expect the acidic proton to be removed. (Higher concentration of A-)

pH = pKa + log [A-]

[HA]

Biological AminesBiological AminesThe amino acid, alanine, at pH = 7.3

pKa = 9.69 pKa = 2.34

A pH below pKa atom is protonated.

At pH above pKa proton is removed.

Reductions of Nitriles, Amides, & Nitro’s◦ Reactions we’ve already seen:

24.6 Synthesis of Amines24.6 Synthesis of Amines

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Synthesis of AminesSynthesis of AminesArylamines are prepared from nitration of an

aromatic compound and reduction of the nitro groupReduction by catalytic hydrogenation over platinum

is suitable if no other groups can be reduced

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

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SSNN2 Reactions of Alkyl Halides2 Reactions of Alkyl Halides

Ammonia and other amines are good nucleophiles

Remember: Nucleophilicity parallels Bacisity

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Uncontrolled Multiple AlkylationUncontrolled 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

Need better method to avoid mixture of products

31

Selective Preparation of Primary Amines: Selective Preparation of Primary Amines: the Azide Synthesisthe Azide Synthesis

Azide ion, N3 displaces a halide ion from a primary

or secondary alkyl halide to give an alkyl azide, RN3Alkyl azides are not nucleophilic (but they are

explosive)Reduction gives the primary amine

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Gabriel Synthesis of Primary AminesGabriel Synthesis of Primary Amines

A phthalimide 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 & KetonesReductive Amination of Aldehydes & Ketones

Treatment of an aldehyde or ketone with ammonia or an amine in the presence of a reducing agent

Forms an imine that is then reduced

34

Reductive Amination Is VersatileReductive Amination Is VersatileAmmonia, primary amines, and secondary amines

yield primary, secondary, and tertiary amines, respectively

35

Mechanism of Reductive AminationMechanism of Reductive Amination

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Reducing StepReducing StepSodium cyanoborohydride, NaBH3CN, reduces

C=N but not C=OStable in water

Learning Check:Learning Check:Prepare using a reductive amination.

Solution:Solution:Prepare using a reductive amination.

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Hofmann and Curtius RearrangementsHofmann and Curtius RearrangementsCarboxylic acid derivatives can be converted into

primary amines with loss of one carbon atom by both the Hofmann rearrangement and the Curtius rearrangement

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Amide reacts with Br2 and base

Rearranges to lose carbonyl carbon making chain 1 carbon shorter

Gives high yields of arylamines and alkylamines

Hofmann Hofmann RearrangementRearrangement

Hofmann example:Hofmann example:

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Curtius RearrangementCurtius RearrangementHeating an acyl azide prepared from an acid chlorideMigration of R from C=O to the neighboring nitrogen

with simultaneous loss of a leaving group

Curtius Example:Curtius Example:

Learning Check:Learning Check:Prepare o-methylbenzylamine from a carboxyic

acid using a Hofmann rearrangement.

Prepare o-methylbenzylamine from a carboxyic acid using a Curtius rearrangement.

Solution:Solution:Prepare o-methylbenzylamine from a carboxyic

acid using a Hofmann rearrangement.

Prepare o-methylbenzylamine from a carboxyic acid using a Curtius rearrangement.

Hofmann

Curtius

46

24.7 Reactions of Amines24.7 Reactions of AminesWe’ve already seen: Alkylation and acylation

47

Hofmann EliminationHofmann EliminationConverts amines into alkenes

NH2 is very a poor leaving group so it

converted to an alkylammonium ion, which is a good leaving group

48

Silver Oxide Is Used for the Elimination Silver Oxide Is Used for the Elimination StepStepAg2O in water forms Ag(OH)2 which exchanges hydroxide

ion for iodide ion in the quaternary ammonium salt, thus providing the base necessary to cause elimination

49

Orientation in Hofmann EliminationOrientation in Hofmann EliminationWe would expect that the more highly

substituted alkene product predominates in the E2 reaction of an alkyl halide (Zaitsev's rule)

However, the less highly substituted alkene predominates in the Hofmann elimination due to the large size of the trialkylamine leaving group

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

50

Steric Effects Control the OrientationSteric Effects Control the Orientation

51

24.8 Reactions of Arylamines24.8 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

52

Arylamines Are Not Useful for Friedel-Arylamines Are Not Useful for Friedel-Crafts ReactionsCrafts Reactions

The amino group forms a Lewis acid–base complex with the AlCl3 catalyst, preventing further reaction

Therefore we use the corresponding amide

53

Diazonium Salts: The Sandmeyer Diazonium Salts: The Sandmeyer ReactionReaction

Primary arylamines react with HNO2, yielding stable arenediazonium salts

54

Uses of Arenediazonium SaltsUses of Arenediazonium Salts

The N2 group can be replaced by a nucleophile

55

Preparation of Aryl HalidesPreparation of Aryl Halides

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

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

56

Aryl Nitriles and Carboxylic AcidsAryl Nitriles and Carboxylic Acids

An arenediazonium salt and CuCN yield the nitrile, ArCN, which can be hydrolyzed to ArCOOH

57

Formation of Phenols (ArOH)Formation of Phenols (ArOH)

From reaction of the arenediazonium salt with copper(I) oxide in an aqueous solution of copper(II) nitrate

58

Reduction to a HydrocarbonReduction to a Hydrocarbon

By treatment of a diazonium salt with hypophosphorous acid, H3PO2

59

Mechanism of Diazonium Mechanism of Diazonium ReplacementReplacement

Through radical (rather than polar or ionic) pathways

60

Diazonium Coupling ReactionsDiazonium Coupling Reactions

Arenediazonium salts undergo a coupling reaction with activated aromatic rings, such as phenols and arylamines, to yield brightly colored azo compounds, ArN=NAr

61

How Diazonium Coupling OccursHow Diazonium Coupling Occurs

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

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

62

Azo DyesAzo Dyes

Azo-coupled products have extended conjugation that lead to low energy electronic transitions that occur in visible light (dyes)

63

24.9 Heterocycles24.9 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

64

Pyrole and ImidazolePyrole and Imidazole

Pyrole is an amine and a conjugated diene, however its chemical properties are not

consistent with either of structural features

65

Chemistry of PyroleChemistry of PyroleElectrophilic substitution reactions occur at C2

b/c it is position next to the NA more stable intermediate cation having 3

resonance formsAt C3, only 2 resonance forms

66

Polycyclic HeterocyclesPolycyclic Heterocycles

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24.10 Spectroscopy of Amines -24.10 Spectroscopy of Amines -InfraredInfraredCharacteristic N–H 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

68

Examples of Infrared SpectraExamples of Infrared Spectra

69

Nuclear Magnetic Resonance Nuclear Magnetic Resonance SpectroscopySpectroscopy

N–H hydrogens appear as broad signals without clear-cut coupling to neighboring C–H hydrogens

In D2O exchange of N–D for N–H occurs, and the N–H signal disappears

70

Chemical Shift EffectsChemical Shift EffectsHydrogens on C next to N and absorb at lower field

than alkane hydrogensN-CH3 gives a sharp three-H singlet at 2.2 to 2.6

71

1313C NMRC NMR

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

72

Mass SpectrometryMass SpectrometryA compound with an odd number of nitrogen

atoms has an odd-numbered molecular weight and a corresponding parent ion

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

73

Mass Spectrum of N-EthylpropylamineMass Spectrum of N-EthylpropylamineThe two modes of a cleavage give fragment ions

at m/z = 58 and m/z = 72.

Select the best classification for the Select the best classification for the following molecule:following molecule:

1. 1˚ aliphatic amine2. 2˚ aliphatic amine3. 3˚ aliphatic amine4. aromatic amine5. heterocyclic

aromatic amine

Which of the following is Which of the following is notnot represented in the molecule shown?represented in the molecule shown?

1. aliphatic amine2. aromatic amine3. heterocyclic

aromatic amine4. secondary amine5. a pyridine ring

Determine the IUPAC name for the Determine the IUPAC name for the following molecule:following molecule:

1. ethylpropylphenylamine

2. N-phenyl-N-ethylpropanamine

3. N-ethyl-N-phenylpropanamine

4. N-ethyl-N-propylaniline

5. N-phenyl-N-ethylaniline

If the pKIf the pKbb of an amine is 9.54, what is of an amine is 9.54, what is the pKthe pKaa of its conjugate acid? of its conjugate acid?

1. 6.462. 4.463. -9.544. not enough

information to determine

5. pKa is unrelated to pKb.

The major alkaloid present in tobacco leaves is The major alkaloid present in tobacco leaves is nicotine, whose structure is shown below. Which nicotine, whose structure is shown below. Which will be the major ammonium ion formed when will be the major ammonium ion formed when nicotine is treated with one equivalent of a strong nicotine is treated with one equivalent of a strong acid? acid?

1. 2.

N

N

CH3

nicotine

Arrange the above Arrange the above from strongest to from strongest to weakest base:weakest base:

1. A, B, C2. B, C, A3. C, A, B4. A, C, B5. B, A, C

Amine Amine AA is more basic than amine is more basic than amine BB..

1. True2. False

The equilibrium The equilibrium lies to the right in lies to the right in the above the above reaction:reaction:

1. True2. False

Which of the following statements is Which of the following statements is truetrue regarding the following two regarding the following two molecules?molecules?

1. Both A and B are aromatic.

2. Both A and B are aliphatic amines.

3. A is more basic than B.

4. B is more basic than A.

5. Both A and B are planar molecules.

Select the most acidic compound from Select the most acidic compound from the choices provided.the choices provided.

1. 2.

3.

4. 5.

If a protonated amine with a pKIf a protonated amine with a pKaa of 10 is of 10 is placed in a solution of pplaced in a solution of pHH 12, the 12, the predominant form of the amine in solution predominant form of the amine in solution will be the protonated form.will be the protonated form.

1. True2. False

The following transformation can be The following transformation can be accomplished as shown.accomplished as shown.

1. True2. False

Identify the major product for the Identify the major product for the following reaction.following reaction.

NH2

O1.

NH2

2.

OH

O3.

NH2

4.

NC

O5.

Cl

1) NaN32) heat

3) H2O

O

ANH2

N(CH3)2

NH21) CH3I (excess)

2) Ag2O, H2O, heat+

+

Identify the structure of A based on the Identify the structure of A based on the products that result from a Hofmann products that result from a Hofmann elimination.elimination.

N

1.

NCH3

2.

NH

3.

NH

4.

NH

5.

N(CH3)2 N(CH3)2+

Select the order of chemical shift (most Select the order of chemical shift (most downfield → most upfield) for the carbon downfield → most upfield) for the carbon atoms in the following molecule:atoms in the following molecule:

1. b, c, d, a2. a, d, b, c3. a, b, d, c4. c, b, d, a5. c, d, b, a

What is the intermediate that results from What is the intermediate that results from the treatment of aniline with HNOthe treatment of aniline with HNO22 and and HH22SOSO44??

1. a diazonium salt2. an aryl radical3. a quaternary

ammonium salt4. an isocyanate5. an aryl azide