Heterocyclic Compounds

 

Heterocyclic compound Introduction: The IUPAC Gold Book describes heterocyclic compounds as:

Cyclic compounds having as ring members atoms of at least l east two different elements, e.g. quinoline, 1,2-thiazole

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IUPAC (2009) IUPAC Compendium of Chemical T IUPAC Terminology erminology - the Gold Book heterocyclic compounds: http://goldbook.iupac.org/H02798.html 

Any of a class of organic compounds whose molecules contain one or more

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rings atoms withmost at least one atom (the heteroatom) an element other of than carbon, frequently oxygen, nitrogen, orbeing sulfur  . Modern Heterocyclic Chemistry, Chemistry, First Edition. Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga, 2011 Wiley-VCH Verlag Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA

Heterocyclic compounds include many of the biochemical material essential to life. For example, nucleic acids, acids, the chemical substances that carry the genetic information controlling inheritance, consist of long chains of heterocyclic units held together. Many naturally occurring occurring pigments  pigments,, vitamins vitamins,, and antibiotics are heterocyclic compounds.

Ergot, a fungal disease of cereal grasses, is caused by the fungus1 Claviceps purpurea, purpurea, which produces indole alkaloids

Dr. Dina Bakhotmah

 

Heterocyclic derivatives and classification Heterocyclic derivatives as a group, can be divided into two broad areas: aromatic and non-aromatic. (note : aromatic system must have 4n+2 π-electron) 1) the 1, five-membered rings are shown below below,, the derivative furan 1 is aromatic, while tetrahydrofuran (2), dihydrofurandihydrofuran-2-one 2-one (3) (3) are not aromatic, Why?.

2) The six-memb six-membered ered rings below, below, pyridine is aromatic (5), while piperidine (6),  piperidin-2-one (7) are are not aromatic, why?  Most heterocycles have the same chemistry as their open-chain counterparts  particularly when the ring is unsaturated. unsaturated.

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In general : heterocyclic is the largest and most varied family of organic compounds, heterocyclic system can be 3, 4, 5, 6, 7 membered rings

in addition to a fused rings (two rings joined at two adjacent atoms)

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Heterocyclic analogues analogues of cyclopentadiene with one heteroatom or Five membered monoheterocyclic* *Organic chem. Solomons, Solomons, p 65 6555-

Cyclic compounds that include an element other than carbon are called heterocyclic compound

Cyclopentadiene

Cyclopentadiene anion

N H

 

O

 

S

Furan   Thiophene

Pyrrole

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Pyrrole, furan and thiophene are a five-membered heterocy Pyrrole, heterocyclic clic compound, We We might expect each of these compounds to have properties of conjugated diene of an amine , an ether or sulphide sulph ide respect respectively ively..

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On this basis pyrrole , furan and thiophene must be considered to be aromatic, this is  proved by NMR spectrum

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these heterocyclic compounds in general undergo electrophilic substitution reaction for example; nitration ,sulphonation, halogenation ,Friedel-craft Acylation and coupling with diazonium salts

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The Heat of combustion indicate resonance stabilization to the extent 22-28 kcal/mole less than the t he resonance energy of benzene (36kcal/mol)but much greater than of most conjugated diene (about 3 kcal/mol).

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Pyrrole The delocalization of the lone pair of Pyrrole pushes electrons from the nitrogen atom into the ring and we expect the ring to be electron-rich electron-ric h and  become more nucleophile. Thus, decreased basicity of the nitrogen atom and increased acidity of the  NH group as a whole whole

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Pyrrole is assumed to be an aromatic molecule. While Its protonated protonated form is not aromatic Using orbital pictures, explain why?

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Class exercise

1) In each of the following, encircle the stronger base :

2) If the proton was removed from Pyrrole to give the structure shown below, below, would it still be consider consi dered ed ar aromat omatic? ic? Why or why not? Use pictu pictures res in your explan explanation ation.

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Synthesis of heterocyclic 1. from 1,4-diketones: the Paal-Knorr synthesis

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Paal-Knorr orr synthesis: pyrroles and thiophenes Paal-Kn

-H2O

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Class exercise

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Write the Paal-Knorr synthesis of 2-ethyl-4-methyl Furan?

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Write the Paal-Knorr synthesis of 2-phenyl-5-methyl pyrrole starting from 1-phenyl-2,5dipentanon?

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2. Knorr pyrrole synthesis

α-

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Examples of pyrroles syntheses by Knorr method:

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Write the reaction mechanism for each reaction Dr. Dina Bakhotmah

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Electrophilic substitution The aromatic five-membered heterocycles pyrrole , furan and thiophene all undergo electrophilic substitution, with a general reactivity order:  pyrrole >furan > thiophene > benzene. This Due to the higher electron density at the carbons carbons as shown by the resonan resonance ce hybrids of  pyrrole as an example .

Write the resonance hybrids of furan and thiophene

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Electrophilic attack on aromatic five-membered heterocycles pyrrole , furan and thiophene

Major isomer 

Write the general electrophilic ele ctrophilic attack on furan and thiophene Dr. Dina Bakhotmah

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All these aromatic heterocycles react vigorously with chlorine and bromine, often forming polyhalogenated products rreaction eaction 3. while while reagent N  reagent N -bromosuxcinamide -bromosuxcinamide (NBS) give monosubstituted bromine

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Activity 1 in the following slid a top 200 pharmaceutical products by US prescription in 2012 http://cbc.arizona.edu/njardarson/group/top-pharmaceuticals-poster

open choose find the kinds of hetero rings system and write a short the notelink, on its used one (2-5product, lines only) see the example bellow

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