pyridine is the simplest heterocycle of the azine type. it ... · 88 pyridines pyridine is the...
Post on 10-Jan-2020
7 Views
Preview:
TRANSCRIPT
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
top related