Lectures in Heterocyclic ChemistryChem. 4239

Collected and organized by

Prof. Dr. Adel Awadallah

Islamic University of Gaza

(2010)

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Lectures in Heterocyclic Chemistry

(Collected and organized by Prof. Dr. Adel Awadallah)

Text BookHeterocyclic Chemistry, T. L. Gilchrist

Other Books and References

* Heterocyclic Chemistry, R. Gupta, M. Kumar, V. Gupta* Heterocyclic Chemistry, J. A. Joule, G. F. Smith* An Introduction to the chemistry of Heterocyclic compounds, R.

M. Acheson* Comprehensive Heterocyclic Chemistry, edited by: A. R. Katritzky

and C. W. Rees* Journals in organic and heterocyclic chemistry such as

J. Heterocyclic Chem.HeterocyclesMoleculesSynthetic communicationsJ. Organic Chemistry

2

Nomenclature of Heterocyclic Compounds

Systematic Nomenclature system: (Hantzsch-Widman System)

Heterocycles with recognized trivial names

3

Naming Heteromonocycles

Prefix (heterotoms, number, positions) + Stem (ring size + saturation)

4

5

Examples: Name the following compounds

6

Indication of saturated positions

1 position (H)2 positions (dihydro)3 positions (dihydro + H)4 posit ions (tetrahydro)5 positions (tetrahydro + H)

Saturated positions receive the lower number

Examples:

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Compounds containing exocyclic C=O and C=S

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Nomenclature of fused ring systems

Prefix(O) + Base component

Base Component1) One ring only contains N, Choose it

2) No, Nitrogen, oxa , thia, aza

3) One consists of two or more rings, choose it

4) Two rings of different size, choose the larger

5) Choose the one with more heteroatoms

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6) Same number of heteroatoms, choose oxa > thia > aza

7) Same number of heteroatoms, same oxa, thia, aza, then choose lower numbering

Indicate the fusion by giving letters to the base components and numbers to the prefix (go in the same direction)

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Examples:

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Numbering substituents on fused rings:

1) Use rectangular coordinates2) As many rings as possible lie in a horizontal row3) A maximum number of rings are in the upper right

quadrant4) The system is numbered in a clockwise direction

commencing with that atom which is not engaged in the ring fusion and is furthest to the left:

in the uppermost ring or in the ring furthest to the right in the upper row

5) C atoms which belong to more than one ring are omitted6) Heteroatoms in such positions are, however, included7) If there are several possible orientations in the coordinate

system, a))) the one in which the heteroatoms bear the lowest

locants is valid,,,,,, b))) or the one in which the C atom that belongs to more

than one ring has the lowest locant

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13

14

15

Examples:

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17

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19

20

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Chapter 4Ring Synthesis

Cyclization Reactions Cycloaddition Reactions Ring transformation

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1) Displacement at saturated carbons

Examples

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Feist-Benary Furane Synthesis

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25

More Examples

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Intramolecular Nucleophilic Addition to Carbonyl GroupsHinzberg Synthesis of Thiophene(Carbon nucleophile)

Pall-Knorr Synthesis of Furane

Pall-Knorr Synthesis of Pyrrole

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28

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Cyclization onto the ortho position of a phenyl ringA free ortho position act as a nucleophilic center

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31

Intramolecular Nucleophilic Addition to Other double bonds (C=S, C=N, C=C)

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Cyclization onto triple bonds

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35

Cyclization onto nitriles (C≡N)

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Cyclization onto Isonitriles (R-N≡C)

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Cyclization onto triple bonds

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Cyclization onto nitriles (C≡N)

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Cyclization onto Isonitriles (R-N≡C)

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Radical Cyclization Five- and six-membered rings are most commonly formed by preferential exo-cyclization.Kinds of Radicals:

Neutral (generated by tributyltin hydride for carbon radicals, or by photolysis of N-Cl bond).

This radical is very reactive and unselective. Protonated radicals(add efficiently to many types of double

bonds, mainly C=C)

Radicals complexed to metal ions (moderate reactivity)

Neutral aminyl radical

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Neutral carbon radical

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Protonated aminyl radicalRadicals complexed to metal ions

More Examples:

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Carbene and nitrene cyclization

Carbenes are uncharged, electron deficient molecular species that contain a divalent carbon atom surrounded by a sextet of electrons. Nitrenes are uncharged, electron deficient molecular species that contain a monovalent nitrogen atom surrounded by a sextet of electrons.

Generally there are two types of carbenes; singlet or triplet carbenes. Singlet carbenes have a pair of electrons and an sp2 hybrid structure. Triplet carbenes have two unpaired electrons. They may be either sp2 hybrid or linear sp hybrid. Most carbenes have a nonlinear triplet ground state

Carbenes are called singlet or triplet depending on the electronic spins they possess. Triplet carbenes are paramagnetic and may be observed by electron spin resonance spectroscopy if they persist long enough. The total spin of singlet carbenes is zero while that of triplet carbenes is one (in units of ). Bond angles are 125-140° for triplet methylene and 102° for singlet methylene (as determined by EPR). Triplet carbenes are generally stable in the gaseous state, while singlet carbenes occur more often in aqueous media.

For simple hydrocarbons, triplet carbenes usually have energies 8 kcal/mol (33 kJ/mol) lower than singlet carbenes (see also Hund's rule of Maximum Multiplicity), thus, in general, triplet is the more stable state (the ground state) and singlet is the excited state species.

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Formation Reactions of Carbenes

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Reactions of Carbenes1) Addition to multiple bonds

Singlet carbenes generally participate in cheletropic reactions as either electrophiles or nucleophiles. Singlet carbene with its unfilled p-orbital should be electrophilic. Triplet carbenes should be considered to be diradicals, and participate in stepwise radical additions. Triplet carbenes have to go through an intermediate with two unpaired electrons whereas singlet carbene can react in a single concerted step. Addition of singlet carbenes to olefinic double bonds is more stereoselective than that of triplet carbenes. Addition reactions with alkenes can be used to determine whether the singlet or triplet carbene is involved.

Reactions of singlet methylene are stereospecific while those of triplet methylene are not. For instance the reaction of methylene generated from photolysis of diazomethane with cis-2-butene and trans-2-butene is stereospecific which proves that in this reaction methylene is a singlet.[4]

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Insertions are another common type of carbene reactions.

The carbene basically interposes itself into an existing bond. The order of preference is commonly: 1. X-H bonds where X is not carbon 2. C-H bond 3. C-C bond. Insertions may or may not occur in single step.

Carbene insertion

Intramolecular insertion reactions present new synthetic solutions. Generally, rigid structures favor such insertions to happen. When an intramolecular insertion is possible, no intermolecular insertions are seen. In flexible structures, five-membered ring formation is preferred to six-membered ring formation.

Carbene intramolecular reaction

Carbene intermolecular reaction

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Nitrenes

Formation

Nitrenes are very reactive and not isolated as such. They are formed as reactive intermediates in the reactions:

1) from thermolysis or photolysis of azides with expulsion of nitrogen gas, analogues to the formation of carbenes from diazo compounds.

a)+ _

hor

R N + N2

b) hor

c)

N NNR

R = alkyl,aryl, H

+ _N NNSO2R NSO2R + N2

hor

+ _N NNC

ORO NC

ORO + N2

d) SO2ONHROOC NO2

base

CO

RO N NO2SO2O

CO

RO N + NO2SO2O_

(nosylate)

R = alkyl, aryl

R = alkyl, aryl

_

2) from isocyanates, with expulsion of carbon monoxide, analogues to carbene formation from ketenes

R-N=C=O gives R-N

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3) From N-amino heterocycles

4) From photolysis of Sulfilimines:

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Examples:

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Carbene and nitrene cyclization

Carbenes are uncharged, electron deficient molecular species that contain a divalent carbon atom surrounded by a sextet of electrons. Nitrenes are uncharged, electron deficient molecular species that contain a monovalent nitrogen atom surrounded by a sextet of electrons.

Generally there are two types of carbenes; singlet or triplet carbenes. Singlet carbenes have a pair of electrons and an sp2 hybrid structure. Triplet carbenes have two unpaired electrons. They may be either sp2

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hybrid or linear sp hybrid. Most carbenes have a nonlinear triplet ground state

Carbenes are called singlet or triplet depending on the electronic spins they possess. Triplet carbenes are paramagnetic and may be observed by electron spin resonance spectroscopy if they persist long enough. The total spin of singlet carbenes is zero while that of triplet carbenes is one (in units of ). Bond angles are 125-140° for triplet methylene and 102° for singlet methylene (as determined by EPR). Triplet carbenes are generally stable in the gaseous state, while singlet carbenes occur more often in aqueous media.

For simple hydrocarbons, triplet carbenes usually have energies 8 kcal/mol (33 kJ/mol) lower than singlet carbenes (see also Hund's rule of Maximum Multiplicity), thus, in general, triplet is the more stable state (the ground state) and singlet is the excited state species.

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Formation Reactions of Carbenes

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Reactions of Carbenes1) Addition to multiple bonds

Singlet carbenes generally participate in cheletropic reactions as either electrophiles or nucleophiles. Singlet carbene with its unfilled p-orbital should be electrophilic. Triplet carbenes should be considered to be diradicals, and participate in stepwise radical additions. Triplet carbenes have to go through an intermediate with two unpaired electrons whereas singlet carbene can react in a single concerted step. Addition of singlet carbenes to olefinic double bonds is more stereoselective than that of triplet carbenes. Addition reactions with alkenes can be used to determine whether the singlet or triplet carbene is involved.

Reactions of singlet methylene are stereospecific while those of triplet methylene are not. For instance the reaction of methylene generated from photolysis of diazomethane with cis-2-butene and trans-2-butene is stereospecific which proves that in this reaction methylene is a singlet.[4]

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Insertions are another common type of carbene reactions.

The carbene basically interposes itself into an existing bond. The order of preference is commonly: 1. X-H bonds where X is not carbon 2. C-H bond 3. C-C bond. Insertions may or may not occur in single step.

Carbene insertion

Intramolecular insertion reactions present new synthetic solutions. Generally, rigid structures favor such insertions to happen. When an intramolecular insertion is possible, no intermolecular insertions are seen. In flexible structures, five-membered ring formation is preferred to six-membered ring formation.

Carbene intramolecular reaction

Carbene intermolecular reaction

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Nitrenes

Formation

Nitrenes are very reactive and not isolated as such. They are formed as reactive intermediates in the reactions:

1) from thermolysis or photolysis of azides with expulsion of nitrogen gas, analogues to the formation of carbenes from diazo compounds.

a)+ _

hor

R N + N2

b) hor

c)

N NNR

R = alkyl,aryl, H

+ _N NNSO2R NSO2R + N2

hor

+ _N NNC

ORO NC

ORO + N2

d) SO2ONHROOC NO2

base

CO

RO N NO2SO2O

CO

RO N + NO2SO2O_

(nosylate)

R = alkyl, aryl

R = alkyl, aryl

_

2) from isocyanates, with expulsion of carbon monoxide, analogues to carbene formation from ketenes

R-N=C=O gives R-N

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3) From N-amino heterocycles

4) From photolysis of Sulfilimines:

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Liquid phase experiment

+ _+ C

H3C

HC

CH3

H

hN NNRN

H HCH3H3C

R

(predominant aziridine product)

N

HH3C

CH3

H

R

(minor aziridine product)

+

cis trans

Point of Information: When an inert solvent is added to the reaction mixture, more trans-product is obtained at the expense of the cis-product.

Evidence of Singlet Nitrene C-H Insertion Selectivity NR + alkane alkane insertion products

Alkane Relative reactivities

(singlet)

C CCH3 CH3

CH3H3CH H

NRC CCH3 CH3

CH3H3CH NH R

C CCH3 CH3

H3CH H

CH2 NHR

+

67.0 : 1.0

CH3CH

HCH

HCH3

NRCH3CH

HCH

CH3

NH RCH3CH

HCH

HCH2 NH

R

+

9.0 : 1.0

Singlet nitrene C-H insertion selectivity: tertiary C-H > secondary C-H > primary C-H

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Examples:

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Electrocyclic Reactions

Formation of a σ-bond at the termini of a fully conjugated π-system by heat or light.

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Examples

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More Examples

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Cycloaddition Reactions

1,3-Dipolar Cycloaddition Reactions

Resonance Structures of 1,3-DipolesEach molecule has at least one resonance structure which indicates separation of opposite charges in 1,3-relationship.

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Mechanism of Cycloaddition:1,3-Dipolar cycloaddition reactions were found to be stereoselective. Most of them are regioselective.2 π-electrons of the dipolarophile and 4 electrons of the dipolar compound participate in a concerted, pericyclic shift. The addition is stereoconservative

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1) Concerted Mechanism (suggested by R. Huisgen)

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2) Biradical mechanism (Stepwise mechanism by Firestone)

Regiochemistry

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Generation of 1,3-DipolesNitrile oxides

Nitrile Sulfides

Nitrile Imides (Nitrilimines)

Examples

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Hetero-Diels-Alder ReactionsReaction between cyclopentadiene and diethyl azodicarboxylate

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Diens and Dienophiles

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2 + 2 Cycloaddition

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Paterno-Buechi Reaction

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Cheletropic Reaction

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Heterocyclic SynthesisPyridine

********************************************************************

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Ring Synthesis

1) The Hantzsch Synthesis

1,3-dicarbonyl compound + ammonia + aldehyde

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2) Reaction of Ammonia + 1,5-diketone

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3) Diels-Alder Reaction

4) Kroehnke Synthesis

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Chemistry of Pyridinea) Reaction at nitrogen

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Electrophilic Substitution

Pyridine is million times less reactive than benzene

Nitration (less than 5%, Chlorination in moderate yield, Bromination in a good yield)

3-position is usually attacked preferably

ChiChibabin Reaction

Amination of pyridine and related heterocycles at the 2-position by sodamide

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Quinoline and Isoquinoline

Quinoline Skraup Synthesis

Doebner-von Millar

Combes Synthesis

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Friedlaender Synthesis

Isoquinoline Synthesis

Bischler-Napierlaski

Pictet-Spengler Synthesis

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Pomeranz-Fritsch Synthysis

Chemistry of Quinoline and Isoquinoline

Nucleophilic Substitution (ChiChibabin Reaction)

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Electrophilic Substitution

Occurs at the 5- or 8-positions, or both

Quinoline N-Oxides can be nitrated at the 4-position or photoisomerize as follows

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Heterocyclic Synthesis

Preparation of Pyrylium Salts

Reactions of Pyrylium Salts

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Synthesis of -Pyrones

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Diels-Alder Reactions of -Pyrones

-Pyrone

Cliasen Condensation of Ethylpropiolate with Acetone

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Pyrroleb. p. 129

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PorphobilinnogenPyrrolnitrin Pyoluteorin

Insect pheromone (s)-proline Nicotine

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Porphyrin haemin Haem (iron (II) complex)

Chlorophyll uroporphyrinogen

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Bilirubin

Vitamin B12

Synthesis of pyrrole

Knorr Synthesis

L. Knorr, Ber. 17, 1635 (1884); Ann. 236, 290 (1886); L. Knorr, H. Lange, Ber. 35, 2998 (1902).

The Knorr pyrrole synthesis is a widely used chemical reaction that synthesizes substituted pyrroles (3).[1][2][3] The method involves the reaction of an α-amino-ketone (1) and a compound containing a methylene group α- to (bonded to the next carbon to) a carbonyl group (2).[4]

The original Knorr synthesis employed two equivalents of ethyl acetoacetate, one of which was converted to ethyl 2-oximinoacetoacetate by dissolving it in glacial acetic acid, and slowly adding one equivalent of saturated aqueous sodium nitrite, under external cooling. Zinc dust was then stirred in, reducing the oxime group to the amine. This reduction consumes two equivalents of zinc and four equivalents of acetic acid.

Modern practice is to add the oxime solution resulting from the nitrosation and the zinc dust gradually to a well-stirred solution of ethyl acetoacetate in glacial acetic acid. The reaction is exothermic, and the mixture can reach the boiling point, if external cooling is not applied. The resulting product, diethyl 3,5-dimethylpyrrole-2,4-dicarboxylate, has been called Knorr's Pyrrole ever since. In the Scheme above, R2 = COOEt, and R1 = R3 = Me represent this original reaction.

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Paal-Knorr Pyrrole Synthesis

The Paal-Knorr Pyrrole Synthesis is the condensation of a 1,4-dicarbonyl compound with an excess of a primary amine or ammonia to give a pyrrole.

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The Hantzsch pyrrole synthesis

The Hantzsch pyrrole synthesis, named for Arthur Rudolf Hantzsch, is the chemical reaction of β-ketoesters (1) with ammonia (or primary amines) and α-haloketones (2) to give substituted pyrroles (3).[1][2]

Note: direct reaction of β-ketoesters (1) with α-haloketones (2) gives furan [Fiest-Benary furan synthesis], and this can be a troublesome side reaction.

References1. ̂ Hantzsch, A. Ber. 1890, 23, 1474. 2. ̂ Feist, F. Ber. 1902, 35, 1538.

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Reactions of PyrroleSubstitution at nitrogenA) Metallation of Pyrrole

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B) Formation of N-substituted pyrroleN-substituted products are normally isolated only from reaction of pyrrole anions with electrophiles

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Electrophilic Substitution

Intermediates in the electrophilic substitution of pyrrole

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The Vilsmeier Haack reaction

Cycloaddition Reactions with dichlorocarbeneReimer-Tieman Reaction

Ring Expansion

Diels-Alder Reactions of pyrrolePyrroles normally do not undergo DA reactionsException

[2 +2] Cycloaddition

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Furan

b.p. = 31 oC

Natural products containing furane

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Rosefuran Ascorbic

Synthesis of Furan

Paal-Knorr Synthesis

Feist-Benary Furane Synthesis

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Reactions of Furan

a) Protonation

b) Electrophilic aromatic substitution

Bromination of furane:

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Nitration of Furane

Vilsmeier-Haack reaction produces 2-formylfuran

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Cycloaddition Reactions

Diels-Alder reaction with maleic anhydride

Reaction with Acrylonitrile

Reaction with dimethylacetylendicarboxylate

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Thiopheneb. p. 84 oC from coal tarelectron rich aromatic compound which is more aromatic than benzene.

Pyrantal 49, is a broad spectrum anthelmintic agent ( المعوية للديدان طارد ) effective against pinworm and hookwormBioten (Vitamin H), 50, occurs in yeast and egg

Thiophene also occurs in organic conducting polymers

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Ring Synthesisa) The Pall Synthesis

b) The Hinzberg Synthesis

c) The Gewald Synthesis

Lawesson's reagent can be used also in the first synthesis.

Simple carbonyl compounds can be used in the third synthesis in the presence of elemental sulfur

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Lawesson's reagent

From Wikipedia, the free encyclopedia

Jump to: navigation, searchLawesson's reagent

IUPAC name  [show]

Other names Lawesson's reagent, LR

Identifiers

CAS number [19172-47-5]

SMILES  [show]

Properties

Molecular formula C14H14O2P2S4

Molar mass 404.47 g/mol

Appearance Slightly yellow powder

Density , solid

Melting point 228 - 231 °C

Solubility in Insoluble

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water

Hazards

EU classification IrritantHarmful (XN)

R-phrases 15/29 20/21/22

S-phrases 22 45 7/8

Related compounds

Related thiation agents

Hydrogen sulfide,Phosphorus pentasulfide

Except where noted otherwise, data are given for

materials in their standard state(at 25   °C, 100   kPa) Infobox references

Lawesson's reagent, or LR, is a chemical compound used in organic synthesis as a thiation agent. Lawesson's reagent was first made popular by Sven-Olov Lawesson, who did not, however, invent it. Lawesson's reagent was first made in 1956 during a systematic study of the reactions of arenes with P4S10.[1]

Contents[hide]

1 Preparation 2 Mechanism of action 3 Applications 4 References

5 External links

[edit] Preparation

Lawesson's reagent is commercially available. It can also be conveniently prepared in the laboratory by heating a mixture of anisole with phosphorus pentasulfide until the mixture is clear and no more hydrogen sulfide is formed,[2] then recrystallized from toluene or xylene.

As Lawesson's reagent has a strong and unpleasant smell, it is best to prepare the compound within a fume-hood and to treat all glassware used with a decontamination solution before taking the glassware outside the fume-hood. One common and effective method of destroying the foul smelling residues is to use an excess of sodium hypochlorite (chlorine bleach).

[edit] Mechanism of action

Lawesson's reagent has a four membered ring of alternating sulfur and phosphorus atoms. With heating, the central phosphorus/sulfur four-membered ring can open to

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form two reactive dithiophosphine ylides (R-PS2). Much of the chemistry of Lawessons's reagent is in fact the chemistry of these reactive intermediates.

In general, the more electron rich a carbonyl is, the faster the carbonyl group will be converted into the corresponding thiocarbonyl by Lawesson's reagent.

[edit] Applications

The chemistry of Lawesson's reagent and related substances has been reviewed by several groups.[3][4][5][6] The main use of Lawesson's reagent is the thionation of carbonyl compounds. For instance, Lawesson's reagent will convert a carbonyl into a thiocarbonyl.[7] Additionally, Lawesson's reagent has been used to thionate enones, esters [8] , lactones [9] , amides, lactams [10] , and quinones.

In one study, reaction of maltol with LR results in a selective oxygen replacement in two positions.[11]

A combination of silver perchlorate and Lawesson's reagent is able to act as an oxophilic Lewis acid with the ability to catalyze the Diels-Alder reaction of dienes with α,β-unsaturated aldehydes.

[edit] References

1. ̂ Lecher, H. Z.; Greenwood, R. A.; Whitehouse, K. C.; Chao, T. H. (1956). "The Phosphonation of Aromatic Compounds with Phosphorus Pentasulfide". J. Am. Chem. Soc. 78: 5018. doi:10.1021/ja01600a058.

2. ̂ Thomsen, I.; Clausen, K.; Scheibye, S.; Lawesson, S.-O. (1990). "Thiation with 2,4-Bis(4-methoxyphenyl)-1,3,2,4-Dithiadiphosphetane 2,4-disulfide: N-Methylthiopyrrolidone". Org. Synth.; Coll. Vol. 7: 372. 

3. ̂ Cherkasov, R. A.; Kutyrev, G. A.; Pudovik, A. N. (1985). "Tetrahedron report number 186 Organothiophosphorus reagents in organic synthesis" (Review). Tetrahedron 41 (41): 2567. doi:10.1016/S0040-4020(01)96363-X.

4. ̂ Foreman, M.S.; Woollins, J.D. (2000). "Organo-P-S and P-Se heterocycles". J. Chem. Soc., Dalton Trans.: 1533–1543. doi:10.1039/b000620n.

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5. ̂ Martin Jesberger, Thomas P. Davis, Leonie Barner (2003). "Applications of Lawesson’s Reagent in Organic and Organometallic Syntheses" (Review). Synthesis 2003: 1929–1958. doi:10.1055/s-2003-41447.

6. ̂ Cava, M. P.; Levinson, M. I. (1985). "Thionation reactions of Lawesson's reagents". Tetrahedron 41 (22): 5061–5087. doi:10.1016/S0040-4020(01)96753-5.

7. ̂ Pedersen, B. S.; Scheibye, S.; Nilsson, N. H.; Lawesson, S.-O. (1978). Bull. Soc. Chim. Belg. (87): 223.

8. ̂ Jones, B. A.; Bradshaw, J. S. (1984). "Synthesis and reduction of thiocarboxylic O-esters" (Review). Chem. Rev. 84 (84): 17. doi:10.1021/cr00059a002.

9. ̂ Scheibye, S.; Kristensen, J.; Lawesson, S.-O. (1979). "Studies on organophosphorus compounds—XXVII Synthesis of thiono-, thiolo- and dithiolactones". Tetrahedron 35 (35): 1339. doi:10.1016/0040-4020(79)85027-9.

10. ̂ Shabana, R.; Scheibye, S.; Clausen, K.; Olesen, S. O.; Lawesson, S.-O. (1980). Nouv. J. Chim. (4): 47.

11. ̂ Daniel Brayton, Faith E. Jacobsen, Seth M. Cohen and Patrick J. Farmer (2006). "A novel heterocyclic atom exchange reaction with Lawesson's reagent: a one-pot synthesis of dithiomaltol". Chemical Communications 2006: 206–208. doi:10.1039/b511966a.

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Reactions of Thiophene

Electrophilic Substitution Substitution takes place at the 2- position

Reactivity pyrrole >> furan > thiophene > benzeneThiophene tends to undergo substitution rather than addition reactions and it is not so readily cleaved by acids as is furan.

Substitution of 2-substituted thiophene

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Nucleophilic Substitution

Cycloaddition ReactionThiophene is a poor diene

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