5-ČLÁNKOVÉ

AROMATICKÉ

HETEROCYKLY

(I.)

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5-Článkové N,O,S-heteroaromáty – Názvoslovie

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Furán, pyrol a tiofén – Bioaktívne molekuly

5-Článkové aromatické heterocykly –Pyrol, furán a tiofén – Štruktúra a vlastnosti

4xygen is

5-Článkové heterocykly – Pyrol – Štruktúra a vlastnosti

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• Pyrrole has an sp2-hybridised N-atom with the lone pair perpendicular and thus conjugated with the ring p-system.

• Because the lone pair is a part of aromatic system, it is not available for protonation the pyrrole is non-basic!

• This is demonstrated by the unusually low pKa for the conjug. acid of pyrrole in comparison to its saturated analogue.

• The higher acidity of pyrrole is due to the sp2-hybridised N-atom, which is more electronegative and stabilises the anion.

DKa = 1015 (!)

Pyrrole

Colourless liquid

m.p. -23°C, b.p. 130°C

Darkens in contact with air!

Pyrrole Pyrrolidine

DKa = 1017 (!)

- 3.8

5-Článkové heterocykly – Reaktivita pyrolu – SE

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• Due to the perpendicular lone pair of N-atom to the plane of the ring, the pyrrole is an p-excessive heterocycle.

• The resonance forms show a negative charge delocalised in the pyrrole ring (with positively charged nitrogen).

• Unlike pyridine, the pyrrole easily undergoes electrophilic substitution (SE) and predominantly at C-2 (a-position).

• The bromination is so viable that it is even difficult to control and 2,3,4,5-tetrabromopyrrole is the end product.

• Analogously, the nucleophilic pyrrole has a propensity to polymerise in strongly acidic media with pKa< -4 (H2SO4).

Note: pyrrole protonates on C-2 (resulting cation is delocalised) NOT on N (would not be delocalised).

5-Článkové aromatické heterocyklyReaktivita pyrolu – Regioselektivita SE

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0.600

0.371

SEAr

• Electrophilic substitution on the pyrrole takes place preferentially at C-2 rather than C-3.

• This can be explained by the more extensive delocalisation of the positive charge via

linear conjugation (for C-2 attack) vs. cross conjugation (for C-3 attack) in the TS.

• In line with this, there are three resonance forms for the intermediate formed during SE

(e.g. bromination) of pyrrole with electrophile at C-2 but only two with electrophile at C-3.

Frontier electron populations

linear conjugation

MORE STABLE !

cross conjugation

LESS STABLE !

vs.

vs.

vs.

Alkene does not

stabilise the cation!

5-Článkové aromatické heterocyklyReaktivita pyrolu – Vilsmeyer-Haack

Mechanism: (a) Formation of electrophilic Vilsmeyer-Haack reagent „in situ“

(b) Formylation (SE) of pyrrole followed by basic hydrolysis (if R=H)

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- H+ - Cl-

- -OP(O)Cl2

Mannichova reakcia pyrolu – Príprava NSAID

NSAID – Non-Steroidal Anti-Inflammatory Drugs 9

• Tolmetine (Tolectin®) is used primarily to reduce hormones that cause pain in osteo- and rheumatoid arthritis.

• Clopirac (Clopiran®) is used for the pain management in osteoarthritis and non-articular rheumatisms.

Albert Eschenmoser (1925)

PhD.:1951, ETH Zürich (Prof. Leopold Ružička)

Profesor organickej chémie:1965-1992, ETH Zürich

Totálna syntéza vitamínu B12:1973 (spolu s R. B. Woodwardom)

Emeritný profesor: 1992Swiss Federal Institute of Technology (ETH), ZürichThe Scripps Research Institute, La Jolla, Kalifornia

Dimetylmetylidénamónium jodid(Eschenmoserova soľ)Bezfarebná hygroskopickákryštalická látka (b.t.: 116°C)(Sigma-Aldrich: 10 g / 74,- EUR)

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Cykloadície pyrolu – Syntéza epibatidínu

Pralesnička trojfarebná(Epipedobates tricolor)

Epibatidín

Ekvádorskí Indiáni už stáročia používajú sekréty zo žiab ako šípové jedyEpibatidín: - izolovaný z chránenej pralesničky trojfarebnej v roku 1992

- funguje ako selektívny depolarizátor nACh-receptorov- spôsobuje svalovú relaxáciu a kardiorespiračnú depresiu- je asi 200-krát účinnejším analgetikom ako morfín!- terapeutické dávky sú však už pre ľudí toxické...

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Cykloadície pyrolu – Syntéza skeletu epibatidínu

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Synthetic plan:

[4+2] Cycloaddition

(Diels-Alder reaction)

of pyrrole as a key step

for the preparation of

epibatidine skeleton.

Actual synthesis:

Owing to its aromatic character,

pyrrole itself does not participate in

Diels-Alder reaction, instead giving

a-substitution products. However,

introduction of an electron-withdrawing

group on the N-atom turns pyrrole

into a useful diene component in

[4+2] cycloaddition. Such a group

is Boc (= tertbutoxycarbonyl).

Thus, N-Boc-pyrrole undergoes

a smooth Diels-Alder reaction

with an alkynyl sulfone to furnish

bicyclic aduct. The subsequent

reduction of non-conjugated C=C

bond followed by AdN of lithiated

pyridine yields the desired

epibatidine skeleton.

Príprava, vlastnosti a reaktivita N-aniónu pyrolu

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• Due to its increased acidity (pKa = 17.5 in THF), pyrrole reacts with strong bases giving the stabilised pyrrolyl anion.

17.5

pyrrolyl anion

___

• This ambident nucleophile allows introduction of electrophilic substituents on both N- and C-atoms of pyrrole.

• Pyrroles with N-protecting groups are usually metalated at C-2, providing an access to 2-substituted products.

• Large cations (K+, Cs+) and polar solvents (DMF, DMSO) favour N-substitution over C-substitution of pyrrole.

Syntetické využitie reaktivity N-aniónu pyrolu

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• This is how the N-Boc-pyrrole was made for use in the synthesis of epibatidine: The base used was the pyridine

derivative DMAP (pKaH = 9.7), producing small, equlibrating amounts of the pyrrolyl anion as well as acting as a

nucleophilic catalyst. Boc2O is used as the acylating agent to protect N-atom and lower the aromaticity of pyrrole.

Mechanistic role of DMAP as an efficient acylation catalyst:

5-Článkové aromatické heterocyklyFurán, tiofén – Štruktúra a vlastnosti

• Furan and thiophene possess two electrone lone pairs on heteroatoms.

• One being conjugated with two double bonds to form a sextet, and the

other one is located in the molecular plane in an sp2 hybridised orbital.

• Both compounds are planar, and thiophene is more aromatic than furan.Furan Thiophene

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(X = O, S)

Oxygen is

5-Článkové aromatické heterocyklyReaktivita furánu a tiofénu – Regioselektivita SE

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5-Článkové aromatické heterocyklyReaktivita furánu – SE

Friedel-Crafts acylation:

Vilsmeyer -Haack formylation:

Mannich aminomethylation:

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5-Článkové aromatické heterocyklyReaktivita furánu – SE (halogenácie)

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Halogenation: furan reacts vigorously with Cl2 or Br2 at room temperature to give polyhalogenated products.

When MeOH is used as a solvent for the halogenation, the end-product is furan-2,5-dimethylacetal.

5-Článkové aromatické heterocyklyReaktivita furánu – SE (nitrácia)

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Nitration: can occur by an addition - elimination (AdN-E) process producing 2-nitrofuran.

• When NO2BF4 is used as a nitrating agent, the reaction follows usual SE mechanism...

5-Článkové aromatické heterocyklyReaktivita tiofénu – SE

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Friedel-Crafts: in comparison to furan, acylation of thiophene requires forcing conditions.

Nitration: reagent AcONO2 is generated in situ from conc. HNO3 and Ac2O and is non-selective.

+

Halogenation: careful control of reaction conditions is required to ensure mono-bromination.

5-Článkové aromatické heterocyklyReaktivita furánu a tiofénu – Otváranie kruhov

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• In acidic conditions furan behaves like enol ether and undergoes a ring opening yielding 1,4-diketone.

• Thiophene ring can be opened by reductive desulfuration on Ra-Ni producing fully saturated product.

• If such a reduction of thiophene follows the preliminary Friedel-Crafts acylation, the 1,6-diketone is made.

5-Článkové aromatické heterocyklyReaktivita furánu a tiofénu – Lítiácie

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• Both furan and thiophene easily undergo deprotonation/metallation at C-2 with strong bases (e.g. BuLi).

• Lithiation is promoted by O,S-heteroatom activation and the metalated product is stabilised by solvation.

5-Článkové aromatické heterocykly(Anti)aromaticita furánu, pyrolu a tiofénu

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• Aromaticity and bonding in furan, pyrrole, and thiophene were investigated through the behavior

of the isotropic shielding σiso(r) within the regions of space surrounding these molecules.

K. E. Horner, P. B. Karadakov: Chemical Bonding and Aromaticity in Furan, Pyrrole, and Thiophene: A Magnetic Shielding Study

(J. Org. Chem. 2013, 78, 8037−8043).

Resonance energies: furan (68 kJ/mol) pyrrole (90 kJ/mol) thiophene (122 kJ/mol) c.f. benzene (152 kJ/mol)

5-Článkové aromatické heterocyklyReaktivita furánu a tiofénu – Diels-Alder

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• Furan is particularly reactive in cycloaddition and due to its reversibility provides an exo-adduct as major product.

• The aromatic thiophene does not undergo cycloaddition, but its oxidation to the sulfone allows the Diels-Alder reaction.

• If the dienophile is an alkyne, the elimination of gaseous SO2 from the cycloadduct furnishes the substituted benzene.

5-Článkové aromatické heterocyklySyntéza pyrolu, furánu a tiofénu – Paal-Knorr

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Príprava tioketónov – Lawessonovo činidlo

Používa sa na prípravu tioketónov, tioesterov a tioamidov z príslušných karbonylových zlúčenín za miernych reakčných podmienok.

2,4-bis(4-metoxyfenyl)-1,3,2,4-ditiadifosfetán-2,4-disulfideBledožltá kryštalická látka (b.t.: 228-231°C)

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Benzofúzovaný pyrol – Indol – Bioaktivita

=

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• Serotonine (5-hydroxytryptamine) is an important monoamine neurotransmiter in human CNS.

• Tryptophan (Trp) is an essential amino acid and serves as biochemical precursor for serotonine.

• LSD is a potent semisynthetic psychedelic drug derived from the ergot fungus natural alkaloid.

• Indomethacin is a NSAID drug commonly used to reduce fever, pain, stiffness, and swelling.

Benzofúzovaný pyrol – Indol – Reaktivita

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0.219

0.595

SEAr

0.345

0.233

0.217

0.058

Frontier electron populations

and the sites of nitration

Electrophilic substitution: takes places (almost) exclusively on the pyrrole ring of indole.

Regioselectivity of SE on indole: linear vs. cross-conjugation

• Moreover, during SE at C-2 of indole the aromaticity of benzene ring must be (temporarily) destroyed...

Benzofúzovaný pyrol – Indol – Reaktivita

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Vilsmeyer -Haack formylation:

Mannich aminomethylation:

Príprava indolu – Fischerova syntéza

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• The reaction of (substituted) hydrazine and aldehyde (or ketone) in acidic media furnishes the indole.

• The first step of the Fischer synthesis involves the formation of hydrazone (an imine) via condensation (AdN-E).

• Next, imine tautomerises to an enamine, which is protonated and undergoes [3,3]-sigmatropic rearrangement.

Príprava indolu – Fischerova syntéza

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• The H+-transfer rearomatises the benzene ring and the formed amine attacks the imine (AdN-E) to form (hemi)aminal.

• The subsequent protonation, followed by the elimination of NH3 and final H+-transfer furnishes the indole.

At the time of discovery, Emil Fischer had no idea about any [3,3]-sigmatropic rearrangement.However, he knew that he has made indole !

Hermann Emil Fischer (1852-1919)

PhD. :1874, University of Strasbourg (výskum fenolftaleínu)

Profesor organickej chémie:1881-1888, University of Erlangen1888-1892, University of Würzburg1892-1919, University of Berlin

Výsledky: objav hydrazínu, určenie konfigurácie cukrov,identifikácia aminokyselín, syntéza peptidov...

Nobelova cena za chémiu: 1902Syntéza purínov a sacharidov

Fischerova syntéza indolu Fischerova syntéza oxazoluFischerova syntéza peptidov Fischerova projekciaFischerova esterifikácia Fischerova redukciaFischerova glykozidácia Fischerova fenylhydrazínová reakcia

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