reactivity of pyrrol
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REACTIVITY OF HETEROCYCLIC
COMPOUNDS
Jose Luis VicarioDepartment of Organic Chemistry IIFaculty of Science and TechnologyUniversity of the Basque Countryjoseluis.vicario@ehu.eshttp://www.ehu.es/GSA
Chapter 2
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SUMMARY
� Relevance of heterocycles as chemical reagents
� Acid-base behavior of nitrogen heterocycles
� Reactivity of heterocycles.
� Reactivity of five-membered heterocycles: pyrrol, furane and thiophene
� Reactivity of six-membered heterocycles: pyridine
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RELEVANCE OF HETEROCYCLES AS CHEMICAL REAGENTS
Heterocycles participate in most of the chemical processes associated with life.
Energetic processes (ATP, ….)
Nerve impulse transmission (neurotransmitters, … )
Processes associated with vision
Metabolic processes
Transmision of genetic information
Transmision of genetic information
Effect on virus and bacteria
And many more…
HETEROCYCLES AS REAGENTS IN BIOLOGICAL PROCESSES
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RELEVANCE OF HETEROCYCLES AS CHEMICAL REAGENTS
The reactivity of heterocycles is crucial in many chemical processes used in industry
Pharmaceutical industry (drugs)
Catalysts in petroleum processing
Catalysts and reagents in Fine Chemical Synthesis
Dyes (OLED-s, etc..)
Agrochemicals
Health-care consumables
Additives in polymer manufacturing
And many more…
HETEROCYCLES AS REAGENTS IN INDUSTRIAL CHEMISTRY
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ACID-BASE BEHAVIOR OF NITROGEN HETEROCYCLES
ACIDITY AND BASICITY
Measuring of the acidity of a substance: The pKa
Strong acids have low pKa values. The conjugate base is a weak base. Th e equilibriumis shifted to the right
H A A H+
Ka = [A-] [H+] / [HA]
pKa = -log Ka = log [HA ] / [A - ] + pH
Weak acids have high pKa values. The conjugate base is a strong base. The equilibriumis shifted to the left
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ACID-BASE BEHAVIOR OF NITROGEN HETEROCYCLES
PYRROLE-TYPE HETEROCYCLES
Bronsted acidity
N
H
NH+
pKa = 17,5
� Pyrrole is a weak acid
� Pyrrolyl anion is a strong base
Bronsted basicity
� Pyrrole is a weak base: Protonation breaks aromaticity ( lone pair participates in conjugationand thus it is not readily available
NH+
NHH
Non-aromatic cationAromatic compound
H
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ACID-BASE BEHAVIOR OF NITROGEN HETEROCYCLES
PYRIDINE-TYPE HETEROCYCLES
Bronsted acidity
� Pyridinium cation is a strong base
� Pyridine is a weak base
Bronsted basicity
� Pyridine does not have any acidic hydrogen (no N-H group)
� Can not behave as Bronsted acid
� The lone pair at nitrogen does not participate in conjugat ion
� Pyridine is a Bronsted base
N
H
N
+ H+ pKa = 5,23
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ACID-BASE BEHAVIOR OF NITROGEN HETEROCYCLES
HETEROCYCLES CONTAINING PYRIDINE- AND PYRROL-TYPE MOIETIES
E. g. Imidazole
� Imidazole is an amphoteric compoundN
N
H
Acidic compoundPyrrol-type heteroatom linked to hydrogen atom
Basic characterPyridine-type heteroatom with anElectron lone pair on sp 2 orbital of Nitrogen atom
N
N
H
N
N+ H+ pKa =14,2 � Imidazole can donate NH hydrogen
� Imidazole is a 10 3.3 (≈2000) times stronger acid than pyrrole (pKa = 17.5)
� Comparing acidity: imidazole vs pyrazole
� Imidazole can donate the lone pair on pyridine-like nitrogen
� Imidazole is a 10 1.72 (≈2000) times stronger base than pyridine (pyridinium cation pKa = 5.23)
� Comparing basicity: imidazole vs pyridine
HN
N
H
+ H+ pKa =6.95N
N
H
� All these effects can be rationalized in terms of resonan ce-stabilized forms
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ACID-BASE BEHAVIOR OF NITROGEN HETEROCYCLES
RELEVANCE OF ACID-BASE BEHAVIOR OF HETEROCYCLES IN BIOCHEMICAL PROCESSES
� Enzymes are proteins which participate in the chemical re actions associated with life processes by catalyzing them
� Enzymes can also be used in chemical synthesis (both in a cademic laboratories or in inductrial processes)� Enzymes are fully substrate-selective catalysts and only work on aqueous buffered media� The catalytic action takes place at the enzyme active sit e. The rest of the protein domains are only required
as an architectural feature associated with stability and shape of the complete molecule.
� Imidazole is a weak base which at physiological pH i s in equilibrium with its protonated form
� Very often enzymes which catalyze reactions through acid-b ase mechanisms operate with an hystidineresidue at the active site
Acid-Base catalytic enzymes
Imidazolering
� Imidazole ring participates as a “proton bank”, accepting protons on its free base form and donating them when it is protonated
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ACID-BASE BEHAVIOR OF NITROGEN HETEROCYCLES
RELEVANCE OF ACID-BASE BEHAVIOR OF HETEROCYCLES IN BIOCHEMICAL PROCESSES
� Epoxide hydrolase functions in detoxification during drug metabolism. It converts epoxides to trans-diols, which can be conjugated and excreted from the body. Epoxides result from the degradation of aromatic compounds. Deficiency in this enzyme in patients re ceiving aromatic-type anti-epileptic drugs such as phenytoin is reported to lead to DRESS syndrome (a s yndrome, caused by exposure to certain medications, that may cause fever or inflammation o f internal organs. The syndrome carries about a 10% mortality .
Example: Epoxide hydrolase
Enzyme active site
Phenytoin(antiepileptic)
Enzyme crystal structure
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ACID-BASE BEHAVIOR OF NITROGEN HETEROCYCLES
HETEROCYCLES AS METAL LIGANDS
Heterocycles can act bound to metals through their lone pai rs (Bronsted basicity) forming coordinationcompounds
Coordination compound (metal complex): A chemical entity formed by a central metal atom(typically a transition metal) surrounded by groups of n eutral or ionic molecules called ligands
Ligands Central atom
n +/ -
Complex charge
n -/ +
Counterion charge
counterion
� Heterocycles can play the role of metal ligands by donating a pair (monodentate ligand) or more thanone pair of electrons (polydentate ligand or chelatingligand) to the metal therefore forming a coordinated
� The coordinating ability (cationic capacity) is relatedto its basicity (proton affinity)
� The coordination index of the complex refers to thenumber of ligands directly attached to the central ion
� The number of ligands (heterocycles) that are coordinated with a metal depends on the type andnumber of orbitals available in the outer layer ofmetal.
� The complex may be neutral (no net charge) or ionic(with positive or negative net charge)
� The metals that form complexes are generallytransition metals. They provide the empty d orbitalsof the penultimate level to accommodate the ligandwhich donates the electron pair
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ACID-BASE BEHAVIOR OF NITROGEN HETEROCYCLES
HETEROCYCLES AS METAL LIGANDSMetal complexes with pyridine: Pyridine complexes with all metals through its nitrogen lon e pair(highly basic). Therefore pyridine is a monodentate liga nd. Geometry depends on metal atom
Ag (I): Linear
N
N
AgN
AlCl
ClCl
Al (III): tetrahedral
N
Cu
N
ClCl
Cu (II): square planar
N
Co
N Cl
Cl
Cl
Cl
2
Co (IV): Octahedral
Chlorophyl B
Heme group
Other examples: Protoporphyrin is widely found in nature
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X Reaction rate
NH 5,3 107
O 1,4 102
S 1
REACTIVITY OF FIVE-MEMBERED HETEROCYCLES
GENERAL REACTIVITY TREND
Most important five-membered heterocycles : Furane, thiophene and pyrrol
� Electrophilic aromatic substitution (SEAr): They are ππππ-excedent systems
Order of reactivity: Model system
Typical reactions:
� Diels-Alder-type reactivity : They are electron-rich dienes
� Electrophilic addition : Leads to loss of aromaticity
Resonance-stabilization energies: Benzene > thioph ene > pyrrol > furane
This means that furane has the highest tendency to undergo electrophilic addition
Pyrrol > Furane > Thiophene > Benzene
X+ (CF3CO)2O
75o CCl2C2H4
X COCF3 + CF3CO2H
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REACTIVITY OF PYRROL
ELECTROPHILIC AROMATIC SUBSTITUTION
• Electrophilic aromatic substitution normally occurs at carbon atoms instead of at the nitrogen.
• Also it occurs preferentially at C-2 (the position next to the heteroatom) rather than a t C-3 (if position 2- is occupied it occurs at position 3).
• This is because attack at C-2 gives a more stable i ntermediate (it is stabilized by three resonance structures) than the one resulted from C-3 attack ( it is stabilized by two resonance structures) .
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1.- Formation of electrophile
2.- Electrophilic aromatic substitution
Formylation: Vilsmeier-Haack:
N H
OH3C
CH3
+ POCl3 N H
OHH3C
H3C ClN H
ClH3C
CH3
NH
H
N(CH3)2
OH
NH
HN(CH3)2
OH
NH(CH3)2
NH H
O
NH
Cl CH
N(CH3)2+
NH
H
H
N(CH3)2 NH
H
N(CH3)2
3.- Hydrolysis of iminium salt
NH
1) POCl3, DMF
2) Base (aq.)
REACTIVITY OF PYRROL: SEAr
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1.- Formation of electrophile
2.- Electrophilic aromatic substitution
Acylation: Houben-Hoesch:
3.- Hydrolysis of imine
NH
+ R CN
HCl (aq.)
REACTIVITY OF PYRROL: SEAr
R C N + HCl R C NH
NH
R
NH NH
R
NH2
HCl H2O
NH
RNH2
OH2
NH4NH R
O
NH
R C NH+NH
H
R
NH NH
R
NH
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Friedel-Crafts acylation (thermal or LA-catalyzed)
Bromination
Polyhalogenation
Diazotization
nitration
sulfonation
Other reactions:
REACTIVITY OF PYRROL: SEAr
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Addition to 3-position?: Using steric effects
REACTIVITY OF PYRROL: SEAr
E.g.
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And the second substitution?:
REACTIVITY OF PYRROL: SEAr
a) Monosubstituted pyrrole with electron withdrawin g group
(incoming Electrophile directed to m-position i.e.
position 4)
One example:
Less reactive than pyrrol
a) Monosubstituted pyrrole with electron donating g roup
(incoming Electrophile directed to p or o-positions
i.e. position 3 or 5)
More reactive than pyrrol
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Metallation of pyrrol:
Most acidic proton
Ortho-metallationMetallation at 3-position?
Metallation of N-substituted pyrrol:
Steric effect(be careful with basic o-directing
groups capable of chelation)
Metal-Halogen exchange(Requires introduction of the
halogen at 3-position)
REACTIVITY OF PYRROL
METALLATION
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Pyrrole is an electron-rich 1,3-diene: Diels-Alder reactivity
REACTIVITY OF PYRROL
CYCLOADDITION CHEMISTRY
�Diels – Alder reaction involves addition of a compound containing a double or a triple bond (2 π e it is Called dienophile) across the 1,4- position of a conjugated system (4 π e, 1,3-diene), with the formation of a six membered ring.
�The heterocyclic compounds can react as a 1,3-dien e in D. A. reaction with reactive dienophiles (e.g. maleic anhydride, or benzyne) or with less reactive dienophiles (e.g. acrylonitrile) in presence of catalyst.
�The diene can be activated by E.D.G while the dien ophile by EWG.
�Thus N-alkyl pyrrole and N-amino pyrrole are more reactive than pyrrole itself in D.A reaction but less reactive than furan (The order of reactivity i n D.A reaction is the reverse of aromaticity order: ) .
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1.- From 1,4-dicarbonyl compounds (Paal-Knorr synthesis): Generally Substituted pyrrole may
be synthesized through the cyclization of 1,4-diketones in combination with ammonia
(NH3) or amines, The ring-closure is proceeded by dehydration (condensation), which
then yields the two double bonds and thus the aromatic π system. The formation of the
energetically favored aromatic system is one of the driving forces of the reaction.
SYNTHESIS OF PYRROLES
2.- Pyrrole is obtained by distillation of succinimide over zinc dust.
3.- Pyrrole is obtained by heating a mixture of furan, ammonia and steam over alumina
catalyst.
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4.- By passing a mixture of acetylene and ammonia over red hot tube
SYNTHESIS OF PYRROLES
5.- Knorr-pyrrole synthesis: This involves the condensation of α-amino ketones with a β-
diketone or a β-ketoester to give a substituted pyrrole.
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REACTIVITY OF FURANE AND THIOPHENE
FURANE AND THIOPHENE COMPOUNDS. OCCURRENCE
• Furanes as flavor agents.
OSH
2-Furylmetanethiol
Constituent of coffee flavor
O
Rose furan
Constituent of rose scent
O
Mentofuran
Constituent of mint oil
Isosoraleno
preservation of cosmetics
Psolarene
Drug for psoriasis
Angelicin
O OO OOO
OO O
� Furocumarines are coumarins with a fused furan ring .
� These show high UV-absorption which can be used for the generation of singlet oxygen.
� Therefore these compounds are used as antioxidants (for the preservation of food and cosmetics) and also as UV filters.
� The capacity to absorb UV light makes them useful f or binding to bioactive compounds which are released after irradiation (serve as an “antenna”).
• Furocumarines
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REACTIVITY OF FURANE AND THIOPHENE
REACTIONS
� Electrophilic aromatic substitution
� Electrophilic addition (loss of aromaticity)
� Cycloaddition
Order of reactivity : Remember, The order of reactivity is the reverse of aromaticity order
Pyrrol > Furane > Thiophene > Benzene
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REACTIVITY OF FURANE AND THIOPHENE
ELECTROPHILIC AROMATIC SUBSTITUTION
• Similar reactivity pattern as pyrrole
• Electrophilic aromatic substitution only occurs at carbon atoms instead of at the oxygen.
• Also it occurs preferentially at C-2 (the position next to the heteroatom) rather than a t C-3 (if position 2- is occupied it occurs at position 3).
• This is because attack at C-2 gives a more stable i ntermediate (it is stabilized by three resonance structures) than the one resulted from C-3 attack ( it is stabilized by two resonance structures) .
Order of reactivity: Remember Pyrrol > Furane > Thiophene > Benzene
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Reaction type Reagents and conditions Product
Halogenation Br 2 / dioxane, 0 oC
Nitration NO2+ AcO -, 5oC
Sulfonation Pyridine-SO 3 complex, 100 oC
Formylation 1) POCl3 , Me2NCHO2) CH3COO- Na+
furfural
Acetylation
REACTIVITY OF FURANE AND THIOPHENE
ELECTROPHILIC AROMATIC SUBSTITUTION
O SO3H
O NO2
O CHO
O
O O/ SnCl4
O CO-CH3
O Br
+ E+
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REACTIVITY OF FURANE AND THIOPHENE
ELECTROPHILIC AROMATIC SUBSTITUTION through lithiation
+ RLiE+
Highly reactive nucleophile
1) t-BuLi, THF, -78ºC2) DMF, 0ºC
1) t-BuLi, THF, -78ºC2)
, 0ºC
3) H2O
1) t-BuLi, THF, -78ºC2) R-X, 0ºC Cross-coupling
(Low yield, needs Pd or Cu-catalysis)
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REACTIVITY OF FURANE AND THIOPHENE
ELECTROPHILIC ADDITIONS (oxidation)
1,4-addition (typical 1,3-diene reactivity)
+ X2
Furane as 1,4-dicarbonyl equivalent
Br 2, MeOH HCl (aq.)
OMe O
HBr Br
O-HBr + MeOH+ +
- HBr
MeO Br OMeO OMe
Mechanism: (Z)
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REACTIVITY OF FURANE AND THIOPHENE
CYCLOADDITIONS (Diels-Alder reactivity)
Endo-diastereoselectivity+
Example: Application to the synthesis of a natural product
Cantharidin
� Poison secreted by many species of blister beetle a nd by the Spanish fly� It is secreted by the male and given to the female during mating. Afterwards
the female will cover its eggs as a defense against predators. � Diluted solutions of cantharidin can be used to remove warts (papiloma)
and tattoos and to treat the small papules of Molluscum contagiosum� When ingested by humans, a dose of 10mg is potentia lly fatal. (causes
severe damage to the lining of the gastrointestinal and urinary tract, and may also cause permanent renal damage
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REACTIVITY OF FURANE AND THIOPHENE
CYCLOADDITIONS (Diels-Alder reactivity)
Initial approach:
+
but:
+heat
endo
so:
+ heat
Still endo!!!
1) H2, Pd/C
2) Raney-Ni
Cantharidin
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REACTIVITY OF FURANE AND THIOPHENE
REACTIVITY OF THIOPHENE
� High aromatic character, ππππ-excedent aromatic ring with high tendency to under go electrophilic aromatic substitution
� SEAr reactions preferably to C-2. � Less reactive towards addition reactions (loss of a romaticity).� Only undergoes cycloaddition reactions with good di enophiles
Example: Application to the synthesis of a natural product
(±)-muscone
� Active ingredient of musk (natural perfume and high ly appreciated)� Musk is extracted from a glandular secretion of the musk deer which is
native from central Asia de Asia Central� Physiological function: pheromone� For obtaining 1 kg of muscone 3000 animals have to be killed (chemical
synthesis required)� Natural muscone is enantiomerically pure (-)-muscon e� Synthetic muscone is prepared in racemic form but i s much less active
1) BuLi
2) Br(CH2)10Br
1) KCN
2) HCl (aq.)
Tf2OH3PO4
Raney-Ni
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REACTIVITY OF PYRIDINE
GENERAL REACTIVITY
UNSUBSTITUTED PYRIDINES
REACTIONS AT NITROGEN
� AN: Pyridine as nitrogen nucleophile
REACTIONS AT CARBON ATOMS
� SNAr: Pyridine as carbon electrophile
� SEAr: Pyridine as carbon nucleophile
C-SUBSTITUTED PYRIDINES
REACTIONS AT CARBON ATOMS
� SNAr: Pyridine as carbon electrophile
� SEAr: Pyridine as carbon nucleophile
N-SUBSTITUTED PYRIDINESREACTIONS AT CARBON ATOMS
� SNAr: Pyridine as carbon electrophile
Pyridine
� Acid-Base: Pyridine as a Bronsted base
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REACTIVITY OF UNSUBSTITUTED PYRIDINE
REACTIONS AT NITROGEN
� AN: Pyridine as nitrogen nucleophile: The nitrogen lone pair (it does not participate in conjugation) reacts with electrophiles
� Acid-Base: Pyridine as a Bronsted base
+ HCl Pka = 5.2
N-Acylation: +
N-Alkylation: + R-X
N-Nitrosation: + RONO
N-Sulfonation: + SO3
N-Oxidation: + H2O2
Ylide formation: +Base
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REACTIVITY OF UNSUBSTITUTED PYRIDINE
REACTIONS AT CARBON ATOMS
� SEAr: Pyridine as nitrogen nucleophile: Behaves essentially as benzene, although due to its p-defficient character reactions are slower and requi re harsher conditions
+ E+
C-3 attack
Regioselectivity:
N+ E+
N E N E N E
N
E
N
E
N
E
N
E
N
E
N
E
C-2 attack
C-3 attack
C-4 attack
Poor contribution
Poor contribution
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REACTIVITY OF UNSUBSTITUTED PYRIDINE
REACTIONS AT CARBON ATOMS
� SNAr: Pyridine as nitrogen electrophile: DOES NOT behave as benzene. Reaction does not proceed via benzyne intermediates. Pyridine should be regarded essentially as a cyclic imine
+ Nu-
C-2 attack
Mechanism:
� Hydride anion is a bad leaving group� Second step is very slow� Sometimes the elimination does not take place:
N
+ Nu-
N Nu
H
Addition elimination
Hydroxylation:High temp.
KOH
Amination: NaNH2
Chichibabin reaction
Cyanation:KCN
Alkylation:RLi or RMgX
High temp.
Loss of aromaticity slow reaction
Highly reactive organometallic reagentsPrevious N-acylation can be carried out for
accelerating the reaction
Loss of aromaticity slow reaction
EXAMPLES
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REACTIVITY OF C-SUBSTITUTED PYRIDINE
REACTIONS AT CARBON ATOM
� SEAr: Pyridine as carbon nucleophile:
+ E+
C-2 attack
Deactivating substituent: No reaction
Activating substituent Reactivity : Higher than the corresponding unsubstituted pyrid ineRegioselectivity : orto and/or para with respect to the activating substituent
Halogenation of methylpyridines:
CH2Cl2, r.t.
X2, AlCl 3
EXAMPLE
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REACTIVITY OF C-SUBSTITUTED PYRIDINE
REACTIONS AT CARBON ATOM
� SNAr: Pyridine as electrophile:
+ Nu-
Alkylation of 2-methoxypyridine
THF, -78ºC
MeMgBr
EXAMPLE
� X should be a good leaving group (Halogen, sulfonat e, etc.)� High reactivity (X is a better leaving group than h ydride)� Regioselectivity controlled by the stability of int ermediate anion
Mechanism:
+ Nu-
N Nu
X
elimination addition
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REACTIVITY OF N-SUBSTITUTED PYRIDINE
REACTIONS AT CARBON ATOM
� SNAr: Pyridinium ions as electrophiles:
+ Nu-
Stabilization through elimination
NaCN
� Highly reactive (positive nitrogen results in enhan ced electrophilicity � Final product arises from the evolution of the addi tion intermediate� Evolution of addition intermediate depends on diffe rent factors
R=good leaving group
Product
aromatization
tBuOOH
oxidation
Resonance-stabilized R=bad leaving group
Stabilization through ring opening
RMgBr HCl
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