chapter 2

Euskal HerrikoUnibertsitatea

Universidaddel Pas Vasco

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REACTIVITY OF HETEROCYCLIC

COMPOUNDS

Jose Luis VicarioDepartment of Organic Chemistry IIFaculty of Science and TechnologyUniversity of the Basque [email protected]://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. The 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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PYRROLE-TYPE HETEROCYCLES

Bronsted acidity

NH

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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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 conjugation Pyridine is a Bronsted base

NH

N

+ H+ pKa = 5,23



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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 sp2 orbital of Nitrogen atom

N

NH

N

N+ H+ pKa =14,2 Imidazole can donate NH hydrogen

Imidazole is a 103.3 (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 101.72 (2000) times stronger base than pyridine (pyridinium cation pKa = 5.23)

Comparing basicity: imidazole vs pyridine

HN

NH

+ H+ pKa =6.95N

NH

All these effects can be rationalized in terms of resonance-stabilized forms



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RELEVANCE OF ACID-BASE BEHAVIOR OF HETEROCYCLES IN BIOCHEMICAL PROCESSES

Enzymes are proteins which participate in the chemical reactions associated with life processes by catalyzing them

Enzymes can also be used in chemical synthesis (both in academic 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 site. 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 is in equilibrium with its protonated form

Very often enzymes which catalyze reactions through acid-base 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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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 receiving aromatic-type anti-epileptic drugs such as phenytoin is reported to lead to DRESS syndrome (a syndrome, caused by exposure to certain medications, that may cause fever or inflammation of internal organs. The syndrome carries about a 10% mortality .

Example: Epoxide hydrolase

Enzyme active site

Phenytoin(antiepileptic)

Enzyme crystal structure



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HETEROCYCLES AS METAL LIGANDS

Heterocycles can act bound to metals through their lone pairs (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 neutral 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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HETEROCYCLES AS METAL LIGANDSMetal complexes with pyridine: Pyridine complexes with all metals through its nitrogen lone pair(highly basic). Therefore pyridine is a monodentate ligand. 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 pipipipi-excedent systemsOrder of reactivity: Model system

Typical reactions:

Diels-Alder-type reactivity: They are electron-rich dienes

Electrophilic addition: Leads to loss of aromaticityResonance-stabilization energies: Benzene > thiophene > 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 at C-3 (if

position 2- is occupied it occurs at position 3). This is because attack at C-2 gives a more stable intermediate (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

HN(CH3)2 NH H

N(CH3)2

3.- Hydrolysis of iminium salt

NH

1) POCl3, DMF2) 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.)


R C N + HCl R C NH

NH

R

NH NH

R

NH2

HCl H2O

NH

RNH2

OH2

NH4NH R

O

NHR C NH+ N

H

H

RNH N

H

R

NH



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Friedel-Crafts acylation (thermal or LA-catalyzed)

Bromination

Polyhalogenation

Diazotization

nitration

sulfonation

Other reactions:




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Addition to 3-position?: Using steric effects


E.g.



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And the second substitution?:


a) Monosubstituted pyrrole with electron withdrawing group

(incoming Electrophile directed to m-position i.e.

position 4)

One example:

Less reactive than pyrrol

a) Monosubstituted pyrrole with electron donating group

(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)


METALLATION



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Pyrrole is an electron-rich 1,3-diene: Diels-Alder reactivity


CYCLOADDITION CHEMISTRY

Diels Alder reaction involves addition of a compound containing a double or a triple bond (2 e it is Called dienophile) across the 1,4- position of a conjugated system (4 e, 1,3-diene), with the formation of a six membered ring.

The heterocyclic compounds can react as a 1,3-diene 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 dienophile 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 in 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 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 -amino ketones with a -

diketone or a -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 for binding to bioactive compounds which are released after irradiation (serve as an antenna).

Furocumarines



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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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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 at C-3 (if

position 2- is occupied it occurs at position 3). This is because attack at C-2 gives a more stable intermediate (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 Br2 / dioxane, 0oC

Nitration NO2+ AcO-, 5oC

Sulfonation Pyridine-SO3 complex, 100oC

Formylation 1) POCl3 , Me2NCHO2) CH3COO- Na+

furfural

Acetylation



O SO3H

O NO2

O CHO

O

O O/ SnCl4

O CO-CH3

O Br

+ E+



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ELECTROPHILIC AROMATIC SUBSTITUTION through lithiation

+ RLiE+

Highly reactive nucleophile

1) t-BuLi, THF, -78C2) DMF, 0C

1) t-BuLi, THF, -78C2)

, 0C

3) H2O

1) t-BuLi, THF, -78C2) R-X, 0C Cross-coupling

(Low yield, needs Pd or Cu-catalysis)



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ELECTROPHILIC ADDITIONS (oxidation)

1,4-addition (typical 1,3-diene reactivity)+ X2

Furane as 1,4-dicarbonyl equivalent

Br2, MeOH HCl (aq.)

OMe O

HBr Br

O-HBr + MeOH

+ +

- HBr

MeO Br OMeO OMe

Mechanism: (Z)



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CYCLOADDITIONS (Diels-Alder reactivity)

Endo-diastereoselectivity+

Example: Application to the synthesis of a natural product

Cantharidin

Poison secreted by many species of blister beetle and 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 potentially fatal. (causes

severe damage to the lining of the gastrointestinal and urinary tract, and may also cause permanent renal damage



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CYCLOADDITIONS (Diels-Alder reactivity)

Initial approach:

+

but:

+heat

endo

so:

+ heat

Still endo!!!

1) H2, Pd/C2) Raney-Ni

Cantharidin



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REACTIVITY OF THIOPHENE

High aromatic character, pipipipi-excedent aromatic ring with high tendency to undergo electrophilic aromatic substitution

SEAr reactions preferably to C-2. Less reactive towards addition reactions (loss of aromaticity). Only undergoes cycloaddition reactions with good dienophiles

Example: Application to the synthesis of a natural product

()-muscone

Active ingredient of musk (natural perfume and highly 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 (-)-muscone Synthetic muscone is prepared in racemic form but is much less active

1) BuLi2) Br(CH2)10Br

1) KCN2) 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



SEAr: Pyridine as carbon nucleophile

N-SUBSTITUTED PYRIDINESREACTIONS AT CARBON ATOMS


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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SEAr: Pyridine as nitrogen nucleophile: Behaves essentially as benzene, although due to its p-defficient character reactions are slower and require 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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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 reactionActivating substituent Reactivity: Higher than the corresponding unsubstituted pyridine

Regioselectivity: orto and/or para with respect to the activating substituent

Halogenation of methylpyridines:

CH2Cl2, r.t.X2, AlCl3

EXAMPLE



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REACTIVITY OF C-SUBSTITUTED PYRIDINE


SNAr: Pyridine as electrophile:

+ Nu-

Alkylation of 2-methoxypyridine

THF, -78CMeMgBr

EXAMPLE

X should be a good leaving group (Halogen, sulfonate, etc.) High reactivity (X is a better leaving group than hydride) Regioselectivity controlled by the stability of intermediate anion

Mechanism:

+ Nu-N Nu

X

elimination addition



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REACTIVITY OF N-SUBSTITUTED PYRIDINE


SNAr: Pyridinium ions as electrophiles:

+ Nu-

Stabilization through elimination

NaCN

Highly reactive (positive nitrogen results in enhanced electrophilicity Final product arises from the evolution of the addition intermediate Evolution of addition intermediate depends on different factors

R=good leaving group

Product

aromatization

tBuOOHoxidation

Resonance-stabilized R=bad leaving group

Stabilization through ring opening

RMgBr HCl

chapter 2

Documents

conjugate base

strong base pyridine

membered heterocycles

chemical processes

chemical reagentsheterocycles

bronsted basenhn h pka

pyrroltype moietiese

conjugation pyridine