88

Pyridines

Pyridine is the simplest heterocycle of theazine type. It is derived from benzene byreplacement of a CH group by a N-atom.

89

The structure of pyridine is completely analogous to that ofbenzene, being related by replacement of CH by N.

The key differences are:

I. The departure from perfectly regular hexagonalgeometry caused by the presence of the hetero atom, inparticular the shorter carbon-nitrogen bonds,

II. The replacement of a hydrogen in the plane of the ringwith an unshaired electron pair, likewise in the plane ofthe ring, located in an sp2 hybrid orbital, and not at allinvolved in the aromatic p-electron sextet; it is thisnitrogen lone pair which is responsible for the basicproperties of pyridines, and

90

III.A strong permanent dipole, traceable to thegreater electronegativity of the nitrogencompared with carbon.

91

I. The heteroatom make pyridines very unreactiveto normal electrophilic aromatic substitutionreactions. Conversely pyridines are susceptible tonucleophilic attack. Pyridines undergoelectrophilic substitution reactions (SEAr) morereluctantly but nucleophilic substitution (SNAr)more readily than benzene.

II. Electrophilic reagents attack preferably at the N-atom and at the b-C-atoms, while nucleophilicreagents prefer the a- and c-C-atoms.

The following reactions can be predicted forpyridines on the basis of their electronic structure:

92

In reactions which involve bond formation using thelone pair of electrons on the ring nitrogen, such asprotonation and quaternisation, pyridines behave justlike tertiary aliphatic or aromatic amines.

Electrophilic Addition at Nitrogen

Reactions of Pyridine

When a pyridine reacts as abase or a nucleophile itforms a pyridinium cation inwhich the aromatic sextet isretained and the nitrogenacquires a formal positivecharge.

93

Protonation at Nitrogen

Nitration at Nitrogen

Pyridines form crystalline,frequently hygroscopic,salts with most protic acids.

This occurs readily byreaction of pyridineswith nitronium salts,such as nitroniumtetrafluoroborate.

Protic nitrating agents such as nitric acid of courselead exclusively to N-protonation.

94

Acid chlorides and arylsulfonic acids react rapidlywith pyridines generating 1-acyl- and 1-arylsulfonylpyridinium salts in solution.

Acylation at nitrogen

95

Alkylation at nitrogenAlkyl halides and sulfates react readily with pyridinesgiving quaternary pyridinium salts.

96

Electrophilic substitution at Carbon atoms of the pyridine ring

Electrophilic substitution of pyridines at a carbon isvery difficult. Two factors seem to be responsible forthis unreactivity:I. Pyridine ring is less nucleophilic than the benzene

ring; nitrogen ring atom is more electronegativethan carbon atoms and therefore it pulls electronsaway from the carbon atoms inductively leaving apartial plus on the carbon atoms.

97

II. When pyridine compound is exposed to an acidicmedium, it forms pyridinium salt. This increasesresistance to electrophilic attack since the reactionwill lead to doubly positive charged species.

Less reactive than pyridine

98

When an electrophile attacks the pyridine ring, onlyposition 3 is attacked.

Hint: draw resonance structures that result fromelectrophilic attack at various positions. The positivecharge residing on an electronegative element withsextet configuration is unfavoured.

Why?

99

For example, 3-bromopyridine is formed whenpyridine is reacted with bromine in the presence ofoleum (sulfur trioxide in conc. sulfuric acid) at 130°C.

100

N

SO3

H

Br

Br

Mechanism of bromination of pyridine

101

Pyridine can be activated to electrophilicsubstitution by conversion to pyridine-N-oxides.

A series of preparatively interesting reactions onpyridine can be carried out by means of pyridine N-oxides such as the introduction of certain functionsinto the ring and side-chain which cannot beachieved in the parent system by direct methods.

102

The activating oxygen atom can be removed byreacting the pyridine N-oxide withphosphorous trichloride.

103

In such reactions there is a balance between electronwithdrawal, caused by the inductive effect of the oxygenatom, and electron release through resonance from thesame atom in the opposite direction. Here, the resonanceeffect is more important, and electrophiles react at C-2(6)and C-4.

N

O

2

34

104

Thionyl chloride, for example, gives a mixture of 2-and 4-chloropyridine N-oxides in which the 4-isomeris predominant.

PCl3

N Cl N+

Cl

105

However, pyridine N-oxide reacts with aceticanhydride first to give 1-acetoxypyridinium acetateand then, on heating, to yield 2-acetoxypyridinethrough an addition-elimination process.

N

O

2

34

O

O

O

N O

O

106

When a similar reaction is carried out upon the 2,3-dimethyl analogue, the acetoxy group rearrangesfrom N-1 to the C-2 methyl group, at 1800C, to form2-acetoxymethyl-3-methylpyridine.

N

O

O

O

O

107

H2 Pd/EtOH

N

NH2

108

NH

H

NH

H

Resonance stabilized

Anion Chemistry of Pyridine

Works for 2(6)- and 4-alkylpyridines not for 3(5)-alkylpyridines, why?

The negative chargegenerated on thecarbon goes to theelectronegativenitrogen, which canbetter accommodateit.

109

110

R Br

NR

111

Another approach to electrophilic substitutioninvolves the chemistry of 2-pyridone and 4-Pyridones which are obtained from the diazotizationof the corresponding 2-aminopyridine and 4-aminopyridines, respectively.

112

Both pyridones can react with electrophiles at positionsortho and para to the activating oxygen atom. Reaction withphosphorous oxychloride gives chloropyridines.

113

Nucleophilic substituition of pyridine

a) X=Hb) X=Good leaving group

X=H, Substitution with “hydride” transfer

Nu: NaNH2 - aminationNu: BuLi, PhLi etc - alkylation / arylationNu: NaOH - “hydroxylation”

114

At high temperature the intermediate anion canaromatize by loss of a hydride ion, eventhough, it is apoor leaving group.

115

b) X=LG, The nucleophilic substitution is much morefacile when good leaving group such as X:Halogen (F>>Cl,>Br,>I), -OSO2R, -NO2, -OR, areemployed.

116

117

-H: is a bad leaving group

N

Cl

Nu

SLOW

118

N X

N SPhN OMe

N NN NH2

Ph

Me

119

Halogenopyridines can undergo metal-halogenexchange when treated with butyllithium. Thelithium derivatives then behave in a similar mannerto arylithiums and Grignard reagents and react withelectrophiles such as aldehydes, ketones and nitriles.

120

NaOMe

MeOH N

O

NOO

OMe

- NO2

N

O

OMe

121

SCH 402

Dr. Solomon Derese

Synthesis of Heterocycles Compounds

122

:Nu

Nu

(CH2)n

Nu

(CH2)n

SCH 402

Dr. Solomon Derese 123

Synthesis of Furan,

Pyrrole

and

Thiophene

SCH 402

Dr. Solomon Derese 124

:Nu

Nu

(CH2)2

O

R1

O

R2d+ d+

Furans, pyrroles and thiophenes from 1,4-dicarbonyl compounds: Paal Knorr synthesis

:Nu = RNH2, H2S

SCH 402

Dr. Solomon Derese 125

RNH2 H

SCH 402

Dr. Solomon Derese 126

SCH 402

Dr. Solomon Derese 127

Furans, pyrroles and thiophenes from 1,3-dicarbonyl (b-ketocarbonyl) compounds

acidic hydrogens

R1

O O

R2

H

Base

enolate React with

electrophiles

SCH 402

Dr. Solomon Derese 128

Feist–Benary synthesis of furans

The Feist-Benary synthesis is an organicreaction between a-haloketones and b-dicarbonyl compounds to give substituted furans inthe presence of base.

OR1

X O R2

OEt

O

+Na2CO3

O

R1

R2

OEt

O

a-haloketonesX = Cl, Br, I

SCH 402

Dr. Solomon Derese 129

O

R1

R2

OEt

OHO

130

SCH 402

Dr. Solomon Derese 131

Knorr-pyrrole synthesis

This involves the condensation of a-amino ketoneswith a b-diketone or a b-ketoester to give asubstituted pyrrole in the presence of a base likepyridine.

a-amino ketones

SCH 402

Dr. Solomon Derese 132

NH

R3

O

OEt

R2

HOR1

H

SCH 402

Dr. Solomon Derese 133

Fiesselmann synthesis1,3-Dicarbonyl compounds or b-chlorovinylaldehydes react with thioglycolates or other thiolspossessing a reactive methylene group to givethiophenes in the presence of pyridine.

SCH 402

Dr. Solomon Derese 134

SCH 402

Dr. Solomon Derese 135

Synthesis of Pyridine

1,5-Dicarbonyl compound

O OR1 R2

:Nu = RNH2

136

I. Reaction between a 1,5-diketone and ammonia

Ammonia reacts with 1,5-diketones to give unstable1,4-dihydropyridine, which can be easilydehydrogenated (using nitrobenzene or nitric acid)to give pyridine.

1,4-dihydropyridine

137

II. The Guareschi synthesis

Unsymmetrical pyridines can be synthesised from areaction between a b-dicarbonyl compound and a b-enaminocarbonyl compound or nitrile.

138

NOH

H

OO

H

139

140

III. The Hantzsch synthesis

Symmetrical 1,4-dihydropyridines, which can beeasily dehydrogenated (to form pyridines), areproduced from the condensation of an aldehyde,ammonia, and two equivalents of a 1,3-dicarbonylcompounds (commonly a β-ketoester) which musthave a central methylene.

The product from the classical Hantzsch synthesis isnecessarily a symmetrically substituted 1,4-dihydropyridine. Subsequent oxidation (ordehydrogenation) gives a symmetrical pyridinecompound.

141

STEP IThe reaction is believed to proceed via KnoevenagelCondensation.

STEP II

A second key intermediate is an ester enamine,which is produced by condensation of the secondequivalent of the β-ketoester with ammonia:

142

STEP III

Further condensation between these two fragmentsgives the dihydropyridine derivative:

143

144

OH

Ph

NH3

O

O

OH

HO

O

O

H

O

O

OPh

OHH

- H2O

O

O

OPh

I

MECHANISM

NH3 O

O

O

H

- H2O

II

NH2 OH

O

OH

NH2

O

O

145

146

Nifedipineis in a group of drugscalled calcium channelblockers. It works byrelaxing the muscles ofyour heart and bloodvessels. Nifedipine is usedto treat hypertension (highblood pressure) andangina (chest pain).

NH

NO2

MeMe

MeO2C CO2Me

Nifedipine

147

O Me

CO2Me

NO2

MeMe

MeO2C CO2Me

O O

NH3

148

OXAZOLE

149

IMIDAZOLES

THIAZOLES

150

Cl N

NO

Diazepam

Diazepam (Valium) used for the treatment ofanxiety disorders. Diazepamalso is used for thetreatment ofagitation, tremors, delirium,seizures, and hallucinationsresulting from alcoholwithdrawal. It is used for thetreatment of seizures andrelief of muscle spasms insome neurological diseases

151

NaOH (Aq)

Cl

NH

OCl N

NO

Diazepam

NH3

152

Antifungal drug

153

NaNO2, HCl

0oC N

N

N

154

N

N

HN

HN

F

155

ClopiracNonsteroidal Antiinflammatory Drug)

N CH3H3C

C

Cl

O

HO

156

H3C I

N CH3H3C

C

Cl

N

KOHN CH3H3C

C

Cl

O

HO