Synthesis of pyridine

1 – By heating the hydrochloride of pentamethylene diamine and oxidizing the product piperidine with concentrated sulphuric acid at 300 cº.

CH 2 - CH 2 - NH 2 .HCl CH2 CH 2 - CH 2 - NH 2 .HCl -NH4Cl -HCl CH 2 - CH 2 CH 2 - CH 2 H2SO4 300 co N lec 8 1

2 – from 1,5 – dicarbonyl compounds and ammonia : Ammonia react with 1,5 – dicarbonyl compounds to give 1,4 dihydropyridine which are easily dehydrogenated to pyridines .The reaction proceed via loss of two molecules of water .

H H O O H H + N - H H H -2H2O Oxidation N H 1,4 - dihydropyridine N Pyridine lec 8 2

3- From ethyl acetoacetate two mole with dichloromethane in presences of ammonia .

EtOOC CH2 | C = O CH3 EtOOC CH2 | O = C CH3 NaOEt CH2Cl2 EtOOC || C CH3 OH HC-COOEt || C OH CH3 CH 2 EtOOC - C C-COOEt -H2O CH 3 NH 2 HO CH 3 CH 3 EtOOC - C CH 3 HO CH 2 HO C-COOEt CH 3 NH3 -H2O H H N H CH 3 Oxide CH 3 N CH 3 lec 8 3

4 – From 1,3 – dicarbonyl compound and cyanoacetamide CH3 C = O | CH2 O = C | CH3 CN + CH2 C = O H2N acetylacetone cyanoacetamide CH H 3 CH H C 3 C = O C OH C H CN H 2 N C =O CH CH CH 3 -C N H C - CN -2H2O C = O H C H C OH C H CN CH 3 C OH H 2 N C =O CH CH CH 3 -C N C - CN C - OH lec 8 4

Chemical reactions

Basicity of pyridine

Pyridine behaves as abase , It react with acids to from fairly stable salt . The reason for the basic character of pyridine is that the nitrogen lone pair being in sp2 hybrid orbital is not involve in the delocalized π molecular orbital .It is readily available for the formation of a new p N – H bond with proton .

Pyridine is a stronger base than pyrrole in which the basicity is reduced by delocalization of the nitrogen lone pair

Pyrrole

<

Pyridine

<

aliphatic amine

N H N

Basicity increase

RNH 2 lec 8 5

Addition and ring – opening reaction

The acid derivatives combine with the pyridine to give a quaternary salt (e.g 2) .Which have been isolated as acidchlorides .This salt react with hydroxyl group yielding the Acyl derivative ; the liberated acid is taken up as the pyridine salt (3) .Quaternary salts as (2) are immediately decomposed by water to pyridine hydrochloride and the organic acid but with etheylcyanoacetate the ring open yielding (4) PhCoCl N EtCOOCH2CN + N CoPh ( 2 ) Cl R+/OH- H2O PhCOOR + + N H ( 3 ) Cl NH | C(CN)CO 2 Et Ph - C = C(CN)CO2Et ( 4 ) lec 8 + N Cl PhCOOH 6

The ring is comparatively easily opened by nucleophilic reagent 2,4 – Dinitrophenylpyridinum chloride (5) is a colourless crystalline solid which is formed from pyridine and 2,4 – dinitrochlorobenzene at 100 cº this reaction is reversed at 200 cº with water at 150 cº yield pyridine hydrochloride and 2,4 – dinitrophenol , but with cold aqueous alkali a deep red compound (6) is formed which on successive treatment with dilute aniline and acid yields 2,4 – dinitroaniline and glutaconic aldehyde dianil (7) . lec 8 7

NO 2 N HO PhNH2 + CH H C CH ( 6 ) Cl NO 2 aniline Acid CH H C Ph - NH - CH CH CH = NPh ( 7 ) glutaconic aldehydedianil + 100 c0 200 c0 cold aquKOH CH N CH PhNH2 NO 2 + KCl NO 2 NO 2 lec 8 Cl N NO 2 ( 5 ) NO 2 2.4 - dinitrophenylpyridinum chlorid H2O 150 c0 + N H + OH Cl Pridinium Chloride NO 2 OH NO 2 NO 2 2.4 - dinitrophenol 8

Reduction

Pyridine is easily reduce to hexahydropyridin or piperidine by a variety of method including hydrogen over Raney nickel , rubidium at 60 ºc palladium charcoal with acetic acid .1,4 – dihydropyridine has however been obtained by the reduction of pyridine with trimethylsilane .

N + Me3Si H

Pd catalyst

N SiMe 3

0.1% KOH MeOH

N H The pyridine is cleaved by ultrasonic waves giving acetylene and hydrogen cyanide .

ultra sound

2 CH CH + HCN N lec 8 9

Electrophilic subistitution reactions .

Toward electrophilic subistitution pyridine resembles a deactivated benzene derivative it is often compared to nitrobenzene in reactivity N N ( + ) ( + ) N ( + ) N O N = O O N ( - ) O ( + ) O N ( - ) O ( + ) ( + ) O N ( - ) O lec 8 10

when the reaction take place the attack at β position can be understood in term of the resonance forms shown above in which ( α ) and ( γ ) position have a positive charge , this orientation can be understood also by comparison of the intermediate resulting from attack at various position H H H E H E H E H

Attack at β position

H E H H E H E H

Attack at γ position

lec 8 11

three resonance can be written for each intermediate but one of these in the case of attack at the γ ( or α ) leaves positive charge on nitrogen this must be regarded as an unfavorable structure as compared to one in which carbon has a positive charge for nitrogen more electronegative than carbon .

KNO3 H2SO4 370 c0 N HgSO4 H2SO4 Br2 300 c0 NO 2 N 3 - nitropyridine SO 3 H N Br 3 - pyridinesulphonicacid N 3 - bromo pyridine Rx or RCox AlCl3 No reaction lec 8 12

Nucleophilic subistitution in pyridine

The reactivity of pyridine toward nucleophilic subistitution is so great even the powerfully basic hydride ion , H- , can be displaced .Two important example of this reaction are amination by sodium amide and Alkylation by organolithium compounds . N + + NaNH2 heat N Na H NH 2 NH3 N NH 2 + + NaNH2 + NH3 N NHNa Sod salt of 2 - amino pyriine N + + C6H5Li heat N Li H Ph N Ph + LiH 2 - phenylpyridine N KOH 320 N OH N H O The attack take place at α – position because the positive charge arises in α – position lec 8 13

Pyrylium salt and pyrans

Very few simple derivatives of the aromatic pyrylium cation (1) are known , although benzopyrylium are widely distributed as flower petal colouring matters .The potentially very reactive 4-pyran (3) has been obtained recently and the pyranes ( 4 and 5 ) are well known .2,3 – Dihydro – 4 – pyran (6) has received some attention now it is easily available , and tetrahydropyran ( 7 ) is used as a synthetic intermediate .The sulphur analogues of these compounds have received little attention until very recently 5 6 O 4 4 3 O 1 3 + 2 O O O O O 2 O 1 5 6 O 1 2 3 4 5 6 7 Pyriliumcation 2pyrone 4 pyrone 6 7 5 8 4 + O 1 3 2 lec 8 14

Pyrylium salts

The sodium salt of glutaconic aldehyde with perchloric acid at – 20 cº gives ared oxonium salt , which on standing at o cº cyclizes to the colourless pyrylium perchlorate (8) .This perchlorate has received little attention ,but with ammonia it yields 2,4,6 – triphenylpyrylium ferrichloride ( 9 ) can be prepared easily . It is stable in acid solution and nitrates . with ammonia it yields 2,4,6 – triphenylpyridine while with alkali the ring is opened , yielding (II) through the intermediate (10 ) + Na O CH CH CH Oxonium salt CH CH = O H ClO 4 O 2 CH CH CH CH CH HO ClO 4 sod . salt of glutaconic aldehyde = + OH c 0 0 -H 2 O 5 4 2 3 ClO 4 6 O 1 ) 8 ( Pyrylium perchlorate lec 8 15

CH + Ph CH H CH 2 O = C-Ph FeCl 3 Ph C = O 1 - phenyl 2 - benzoyl ethylene phenyl methyl ketone Ph CH 2 Ph CH CH 2 C = O C= O Ph Ph Ph + O Ph FeCl4 2,4,6 - triphenyl Pyrylium ferricchloride

NaHCO3 NaOAC orr aq ( B )

NH 3 (A) Ph Ph N Ph Ph Ph O Ph OH Ph lec 8 CH Ph CH CH 2 C = O OC Ph 16

Mechanism

CH Ph C + Ph CH + = O O H CH 2 = C Ph FeCl 3 Ph CH C 2 = Ph CH O CH 2 C = O Ph keto form HC Ph C Ph H C O CH C Ph -H 2 O CH Ph CH CH HO Ph C enol form C OH Ph Ph HC Ph CH CH C + O C Ph FeCl 4 ) A ( NH 3 Ph C H HC Ph CH CH + C Ph O NH 2 lec 8 17

Ph HC C N : H 2 Ph CH CH HO + C - Ph Ph HC Ph CH CH Ph C H + N H C - Ph OH -H2O Ph Ph + N H Ph Ph N Ph Ph Ph + O FeCl4 Ph

B NaOaC NaHCO3 aq

Ph Ph Ph Ph O + Ph

H+/ OH-

Ph Ph Ph Ph O + OH Ph Ph O OH Ph

enol form

Ph O OH Ph O O Ph

keto form 1,3,5 - triphenyl glutaconicdialdehyde

lec 8 18

Reaction of pyrylium cation

A –Reaction with electrophilic reagent 2,4,6 –Triphenyl pyrylium undergoes exchange at 3 – and 5 – position in hot deuteroacetic acid Ph Ph + O Ph

ACDO

Ph Ph O OAC Ph

D

+ Ph Ph + O 5 D H OAC Ph B – No nitration of pyrylium are known lec 8 19

Synthesis of α – pyrones

6 – hydroxyl – α – pyron can be prepared by heating a glutaconic acid with acetic anhydride .

H 2 C CH CH O = C OH C = O OH

- H2O ( CH3CO)2O

HO O O lec 8 20

Synthesis of γ – Pyrones

1 γ – pyrone may be prepared by heating chelidonic acid just above its melting point .chelidonic acid may be prepared from acetone and ethyl oxalate O = C CH 3 CH 3 + 2 (COOEt )2 C 2 H 5 ONa -2(EtOH) O = C CH 2 CO . COOEt CH 2 CO . COOEt OH CH = C- COOEt O = C CH = C - OH COOEt O heat γ O Pyrone heat O = C CH = C- COOEt O CH = C COOEt chelidonic acid lec 8 21

2 – The dimethyl γ – pyrone may be prepared from the copper salt of ethylacetoacetate as follows CH CH 3 3 -CO - CH - COOEt Cu -CO - CH - COOEt

hyd heat

CH 3 -CO - CH2 C = O CH 3 -CO - CH2

heat -H2O

CH 3 C O CH 3 C CH C = O CH CoCl 2 CH 3 -CO - CH - COOEt C = O CH 3 -CO - CH - COOEt CH 3 -C = CH OH C = O OH CH 3 -C = CH lec 8 22

Reaction of α and γ – Pyrone .

1 O O α - pyrone O 2 O NaOH NaOH H+ 3 O O + NH2NH2 COONa ONa HCl O OH OH O COOH OH O O O OH OH NH NH O | | NH 2 -H2O N | NH 2 O 1 - amino pyridone lec 8 23

5 CH 3 O O CH 3 NH3 O -H2O O CH 3 OH CH 3 NH2 CH 3 N H CH 3 2,6 - di methyl - 4 - pyrone R R 6 R O + CH3MgBr O R O CH 3 OH 7 CH 3 8 CH 3 O O O + CH3MgBr CH 3 CH 3 CH3I CH 3 CH HO 3 OCH 3 + O CH 3 I-

..

O CH 3 CH 3 HClO4 CH 3 HClO4 -H2O CH 3 + O ClO4 CH 3 pyrylium salt OCH 3 -H I CH 3 + O ClO4 CH 3 lec 8 24

R R P2S5 9 R O O R O S O 10 R O R P2S5 S R O R 11 R 12 CH 3 O R R O O Br2 / ACOH Br R O O 3 -bromo - 2 - pyrone O CH 3 O Br Br2 / ACOH CH 3 O CH 3 3 -bromo - 4 - pyrone lec 8 25

R R 13 R 14 NO 2 CH 3 HNO3 / ACOH O O O O R O O O NO 2 CH 3 HNO3 / ACOH CH 3 O CH 3 3 -bromo - 4 - pyrone lec 8 26

Sulphur – containing analogues

4 H – Thiopyran ( 1 ) has been obtained in asimilar way to its oxygen analogue and has b.p 30 cº at 12 mm it is readily oxidized by chlorine to thiapyrylium (2) chloride , and an alternative way of making this class of compound is outlined 2,4,6 triphenylthia pyrylium perchlorate (3) with phenyllithum gives the deep purple 1,2,4,6 – tetraphenylthia (IV) benzene (4) . On standing it isomerizes to colurless 4H - thiapyran (5) Cl Ph S Ph + S (3) Cl PhNMe2 Ph ClO4 PhLi S Cl2 40 + S (1) (2) Ph Ph Ph

isomerize

S Ph Ph Ph S (4) (5) Ph lec 8 27

1- methyl – 3,5 – diphenylthia(IV)benzene 1- oxide (6) has been obtained as indicated below .It has m.p 148 º and can be sublimed at near this temperature at 0 – 0.5 mm pressure .The compound is therefore very much more stable than (IV) benzene such as (4) Ph O + S ( 6 ) Me Ph lec 8 28