Heterocyclic Chemistry

Introduction

• Organic compounds can be defined as a large group of compounds where the molecules contain carbon (with valency of 4).
• The number of organic compounds is massive. And they can be classified in many ways.
• One of the ways to classify the organic compounds is by their structural feature. In this method organic compounds can be classified as:

Acyclic/Open chain compounds

• The compounds in which there is no cyclic structure or rings present are called acyclic compounds.

Cyclic compounds

• The compounds in which some atoms of the molecule are connected with each other to form one or more rings or cycles are called cyclic compounds.
• Cyclic compounds are of two types: Carbocyclic and heterocyclic.

Carbocyclic compounds

• Carbocyclic compounds are those cyclic compounds where the ring(s) is made of carbon atoms only.

Definition

• Heterocyclic compounds are defined as cyclic compounds where the ring (or one of the rings) is composed of atoms of at least two elements.
• 
• Heteroatom
• Any atom which is not carbon, but a part of the ring of a heterocyclic compound is called a heteroatom.
• The most common heteroatoms are Nitrogen (N), Oxygen (O) and Sulfur (S).
• Other elements which may exist as heteroatoms include:
• Phosphorus (P)
• Boron (B)
• Arsenic (As)
• Tellurium (Te)
• Selenium (Se)
• Silicone (Si)
• Germanium (Ge)

Aromaticity of Heterocyclic Compounds

• Many heterocyclic compounds are aromatic in nature.
• The conditions for a compound to be aromatic are:
• The ring must be planar (or near planar).
• Each atom of the ring must be sp2 hybridized.
• Each atom of the ring must be a p orbital and these p orbitals must be arranged parallel to each other.
• The compound follows Huckel’s rule (contain 4n+2 number pi electrons in the ring, where n is zero or integer).
• Many of the heterocyclic compounds fulfill these conditions.
• The Huckel’s rule can be fulfilled by heteroatoms of the compound in mainly two ways:
• It can form π bond (i.e. double bond)
• It can donate lone pair of electrons to the π system
• 
• In Pyridine, Nitrogen is the heteroatom. It completes the π system by forming a double bond.
• 
• In Pyrrole, Nitrogen is the heteroatom. It completes the π system by placing the lone pair in the p orbital and donating it to the π system.
•  
• Compounds which do not follow the previously mentioned conditions, are non-aromatic.
• If the ring contains 4n number of π electrons, then it is highly unstable, and called anti-aromatic.
• Rules for Numbering Atoms in Heterocyclic Compounds
• Numbering of atoms in heterocyclic compounds is a little more complex than carbocyclic (homocyclic) compounds. But it is necessary to name substituted and complex heterocyclic compounds.
• Rules
• For monocyclic compounds with one heteroatom, the heteroatom is numbered 1.
• 
• If there is any substituent or a functional group attached to the ring, numbering is done as such that the substituent/group receives a number as low as possible.
• If there are more than one functional group in a monocyclic compound, the numbering of the functional groups also considering their order of preference (see 3-chloro-5-methyl pyridine).
• 
• If there are more than one heteroatom of the same element in a monocyclic compound, they are numbered as such that they both receive lowest number.
• 
• If in a monocyclic compound there are more than one heteroatom but of different elements, number 1 is given to the heteroatom which has higher priority in the following series:
• O>S>Se>Te>N>P>As>Sb>Bi>Si>Ge>Sn>Pb>B>Hg
• 
  
• 
• If there are more than one atom of a higher priority heteroatom as well as other heteroatoms, one of the higher priority is given number 1 as such that the heteroatom of other element gets next lowest number.
• For polycyclic and fused ring compounds, numbering starts from the ring which is at the top and farthest to the right.
• In that ring, the atom farthest to the left but not a junction atom is numbered 1.
• Then numbering is continued in the clockwise direction.
• Junction atoms are not numbered if they carbon. If they are heteroatoms, they are numbered.
• 
• It should be noted that there are many exceptions to the rules above. For example:
• Purines
• Penicillins
• Cephalosporins
• Phenothiazines
• Morphine and analogues
• Xanthene (not xanthine)
• 
  

Rules for Naming Heterocyclic Compounds

• Many heterocyclic compounds have trivial names. These trivial names do not provide any information about the structure, but are widely used.
• But for complex heterocyclic compounds, a more systematic approach is required.
• The IUPAC has used the Hantzsch-Widman system for the naming of heterocyclic compounds.
• In this method, there are different names for rings of different size and heteroatoms.

The Replacement nomenclature

• A common nomenclature method is the Replacement nomenclature.
• In this method, the name of the heterocyclic compound depends on two factors:
• The heteroatoms present in the compound
• The name of the corresponding carbocyclic compound.
• The compound is named by placing the prefix(es) of the heteroatoms in front of the carbocyclic compounds.
• The heteroatoms are serialized in the order O(oxa)>S(thia)>N (aza).

• The Replacement nomenclature
• A common nomenclature method is the Replacement nomenclature.
• In this method, the name of the heterocyclic compound depends on two factors:
• The heteroatoms present in the compound
• The name of the corresponding carbocyclic compound.
• The compound is named by placing the prefix(es) of the heteroatoms in front of the carbocyclic compounds.
• The heteroatoms are serialized in the order O(oxa)>S(thia)>N (aza).
• Examples of the Replacement Nomenclature
• 

Hantzsch-Widman System (IUPAC System)

Naming of heteroatom

• The heteroatom(s) are named using the following prefixes:
• When naming, the prefix is placed in following priority:

O > S > N

• The prefix(es) of the heteroatom(s) is followed by the name of the ring.

Element	Valency	Prefix
Oxygen (O)	2	Oxa
Nitrogen (N)	3	Aza
Sulfur (S)	2	Thia
Phosphorus (P)	3	Phospha
Selenium (Se)	2	Selena
Tellurium (Te)	2	Tellura
Arsenic (As)	3	Arsa
Silicon (Si)	4	Sila
Germanium (Ge)	4	Germa

Naming of ring

• Naming of ring depends on:
• Whether there are any nitrogen in it.
• Whether the ring is fully saturated or fully unsaturated.

Ring size	Suffixes for fully unsaturated compounds		Suffixes for fully saturated compounds
	With N	Without N	With N	Without N
3	-irine	-irene	-iridine	-irane
4	-ete	-ete	-etidine	-etane
5	-ole	-ole	-olidine	-olane
6	-ine	-in	-inane	-ane
7	-epine	-epin	-epane	-epane
8	-ocine	-ocine	-ocin	-ocane

Naming compounds which are NOT fully unsaturated

• The table shown before (slide 19) can be used to name compounds which are saturated or fully unsaturated.
• But the rings are not named specifically for partially unsaturated compounds.
• To name these partially unsaturated compounds, the prefixes ‘dihydro’, ‘tetrahydro’ are placed before the name where full unsaturation is present.

Indicating which atom contains the (extra) hydrogen

• Let us consider the following three compounds:
• 
• All three compounds are named ‘pyrrole’. However the location of the double bond is different. In another words, the location of the Hydrogen is different.
• Thus they are isomers.
• So this needs to be denoted. To denote this, the name is prefixed as ‘1H’, ‘2H’ etcetera. Here, the number is the number of the atom which contains hydrogen.
• Indicating how two rings are fused…
• Let us consider the following two compounds:
• 
• In both cases, benzene has fused with furan. But they are not the same because they fused at different positions.
• For these cases, the heterocyclic compound is taken as the parent (in this case, furan). Then the other ring is prefixed (benzene is prefixed benzo).
• The bonds in furan are labeled a, b, c (from the heteroatom towards the fusion) etcetera and the bond where fusion occurred is placed in the name as shown above.
• Five-membered Heterocyclic Compounds
• Common Five-membered Heterocyclic Compounds
• 
  

Pyrrole

Introduction

• Pyrrole is a five-membered aromatic heterocyclic compound and contains one nitrogen atom.
• 
  

Pyrrole is aromatic

• The ring is planar.
• Each atom of the ring is sp2 hybridized.
• Each atom contains p orbital (which are parallel).
• Follows Hückel’s rule (contains 6 pi electrons (electrons in the p orbitals).

Normal electronic configuration of N = 1s22s22px12py12pz1

Electronic configuration of N in pyrrole = 1s22(sp2)1 2(sp2)1 2(sp2)1 2pz2

• The lone pair of electrons in nitrogen of pyrrole is placed in the p orbital instead of a hybrid (sp2) orbital.
• Thus this lone pair of electrons can π electron cloud and maintain the Hückel’s rule.

Synthesis of pyrrole

• Industrial synthesis
• When a mixture of furan, ammonia and steam is passed though aluminum oxide catalyst at high temperature, pyrrole is produced.
• 
  
• Paal-Knorr Synthesis

Chemical activity

• Pyrrole is a very weak base
• Normally organic nitrogen compounds are basic due to the lone pair of electron of nitrogen which can easily accept a proton.
• But in pyrrole, the lone pair is delocalized and present in the π cloud. So it is not easy to use that lone pair to accept a proton.
• Hence it is only weakly basic, reacts with only strong acids.

• Pyrrole is also a very weak acid
• Since the lone pair on the nitrogen is delocalized, the nitrogen becomes partially positive. Hence it can take electron from the hydrogen and release it.
• 
  
• Pyrrole undergoes electrophilic substitution at C-2 position
• Pyrrole is attacked by electrophile at C-2 position and substitution reaction occurs.
• Attack at C-3 will occur only when both C-2 (i.e. C-2 and C-4) are occupied.
• Why electrophilic substitution preferentially occur at C-2 position?
• If electrophilic substitution occurs at C-2 positions, then more resonance structures are obtained compared to when attack occurs at C-3 positions.
• Hence attack at C-2 yields more stable compound.
• This is why electrophilic substitution occurs at C-2.

• Some electrophilic substitution reactions
• 

Pharmaceutical importance of Pyrrole

• Many drugs and biological molecules contain the pyrrole structure.
• For example, Atorvastatin, Vitamin B12, Heme, Chlorophyll etcetera.

Furan

Introduction

• Furan is a five-membered heterocyclic compound which contains one oxygen atom as the only heteroatom.

Furan is aromatic

• Just like pyrrole, furan is aromatic (but less; Why???).
• Normal electronic configuration of O = 1s22s22px22py12pz1
• Electronic configuration of O in Furan = 1s22(sp2)2 2(sp2)1 2(sp2)1 2pz2

Synthesis of Furan

• Industrial synthesis
• Commercially, furan is produced by the decarbonylation of Furfural.
• Furfural is commonly available from bran, sawdust, wood tar etcetera, so it is used.
• 
• Paal-Knorr Furan synthesis
• 
• Chemical activity
• Weak base
• Like pyrrole, furan is also a weak base.
• 
• Electrophilic substitution
• Similar to pyrrole.
• 
• Diels-Alder reaction
• Furan reacts with maleic anhydride to form Diels-Alder adduct.
• This reaction is not shown by pyrrole or thiophene.
• 
  
• Pharmaceutical importance of furan
• Many drugs contain the Furan ring. e.g. Ranitidine, Nitrofurantoin, Furosemide.
• Many biological substances are also derivatives of furan. e.g. Furaneol is obtained from pineapple and strawbeery and it is a flavoring agent used in food and pharma industry.
• Thiophene
• Introduction
• Thiophene is a five-membered aromatic heterocyclic compound which contains one sulfur atom as the lone heteroatom.
• It is commonly found in coal-tar.
• Thiophene is aromatic
• Like pyrrole and furan, thiophene also fulfills the conditions of aromaticity.
• Normal electronic configuration of S = 1s22s22p63s23px23py13pz1
• Electronic configuration of S in Thiophene = 1s22s22p63(sp2)2 3(sp2)1 3(sp2)1 3pz2
• 
• Synthesis of Thiophene
• Industrial synthesis
• Thiophene is prepared by heating sulfur and n-butane at very high temperature.
• 
• Paal-Knorr synthesis
• 
• Chemical activity
• Thiophene is neither basic nor acidic.
• Thiophene is even more aromatic than pyrrole and furan.
• It undergoes electrophilic substitution reactions. Such reactions preferentially occur at C-2 position rather than C-3 position.
• 
  
• Pharmaceutical importance of thiophene
• Usually, thiophene derivatives are more toxic than benzene derivatives. Hence the number of drugs containing the thiophene ring is less.
• Examples of drugs containing the thiophene ring include Tiaprofenic acid (an NSAID), Duloxetine (anti-depressant), Pyrantel pamoate (anthelmintic) etcetera.
• Imidazole
• Introduction
• Imidazole is a five-membered aromatic heterocyclic compound containing two nitrogen atoms.
• It is a diazole. It is also known as 1,3-diazole.
• Imidazole is aromatic
• In imidazole, one of the nitrogen forms a double bond, and the other nitrogen gives its lone pair to the π cloud. Thus 6 π electrons are present, fulfilling the Hückel’s rule.
• It also fulfills other conditions of aromaticity.
• 
• Synthesis of imidazole
• Various methods have been developed to synthesize Imidazole, or at least the Imidazole nucleus.
• Among them Debus-Radziszewski Imidazole synthesis is a very popular method. 
• 
  

Chemical activity

• Imidazole is more basic than pyridine
• Imidazole has two nitrogens. One of the nitrogens has its lone pair of electrons outside the ring. It can accept proton using this lone pair electrons.
• Imidazole is more basic than pyridine. This is because the positive charge can be distributed between the two nitrogen atoms, which is not possible in pyridine. 
• 
• Imidazole is more acidic than pyrrole
• The NH nitrogen of Imidazole can easily release its proton compared to pyrrole. Hence it is a stronger acid than pyrrole.
• The reason for this is – the other nitrogen is electronegative and therefore attracts electrons. As a result, NH nitrogen will take electrons from Hydrogen and release it.
• 
  

• Imidazole can form hydrogen bond
• Hydrogen bond is a type of bond where two electronegative atoms are attached to one hydrogen.
• In Imidazole, the double-bonded nitrogen has a lone pair of electrons. It can use this to form bond with a hydrogen, i.e. act as a donor.
• On the other hand, the N-hydrogen is electron-deficient so it can accept electrons and form bonds.
• This property is very important in the biological system.

• Imidazole can undergo electrophilic substitution reactions
• The C-4 and C-5 are electron rich, so electrophilic substitutions occur at these two positions.
• 
• Imidazole can undergo nucleophilic substitution reactions
• The C-2 is electron deficient, so nucleophilic substitution reaction occurs at this position. But there must be a leaving group.

Biological importance of Imidazole

• Histidine, an important amino acid contains an imidazole ring. This ring is very useful for many proteins, specially the enzymes.
• Histamine is an autacoid, neurotransmitter, and hormone and it contains the Imidazole ring.
• So many drugs contain the imidazole rings – specially some antihistamines. Other drugs include Cimetidine, clotrimazole, caffeine, theophylline, vardenafil etcetera.

Six-membered Heterocyclic Compounds

Pyridine

Definition

• Pyridine is a six-membered aromatic heterocyclic compound containing one nitrogen atom as the lone heteroatom.
• Pyridine is aromatic
• Pyridine is aromatic because:
• The ring is planar
• The atoms of the ring are sp2 hybridized
• Each atom of the ring contains p orbitals which are parallel to each other
• Follows the Hückel’s rule. Here nitrogen provide one π electron to the π cloud (contrary to the two π electrons provided in pyrrole).

Synthesis of pyridine

• Chichibabin synthesis
• It is a very common method of industrial synthesis of pyridine and substituted pyridines.
• Here, 3 molecules of aldehyde, ketone, or α, β-unsaturated carbonyl compounds or a combination of these three is reacted with ammonia.
• 
• Other methods of preparation
• Pyridine can be obtained from the light oil fraction of coal-tar by acidic extraction followed by distillation.

Chemical activities

• Pyridine is basic
• Pyridine is basic and reacts with acid to form salts. It is more basic than pyrrole.
• 
• The reason for greater basicity is that the lone pair of electron in nitrogen is not a part of π cloud. So it can be easily donated to accept a proton.
• 
  
• Pyridine shows aromatic electrophilic substitution reactions
• Pyridine does show electrophilic substitution reactions, but it is less reactive to electrophilic substitution than benzene.
• This is because, nitrogen is electronegative, so it draws π electrons towards itself. So, the carbons are not very electron-rich.
• Another reason is, nitrogen is electron-rich so electrophiles attack nitrogen instead.
• It does undergo some electrophilic substitution reactions.
• When electrophilic substitution reactions do occur, they preferentially occur at C-3.

• Examples of aromatic electrophilic substitution
• 
• Pyridine shows aromatic nucleophilic substitution reactions
• Pyridine shows nucleophilic substitution reactions for the same reason it doesn’t like electrophilic substitution reactions.
• The carbons of the pyridine are slightly electron-deficient (since nitrogen draws π electrons), hence they are partially positive and seek electrons from nucleophile.
• When nucleophilic substitution reactions occur, they preferentially occur at C-2 or C-4.

• Example of aromatic nucleophilic substitution
• 

Importance of pyridine

• Pyridine is a very commonly used organic solvent for the purpose of organic synthesis.
• A large number of drugs contain the pyridine ring in their structures. For example, omeprazole, loratadine, pioglitazone and some other thiazolidinediones contain the pyridine ring in their structure.
• Benzo-fused Five-membered Heterocyclic Compounds
• 
• Indole
• Definition
• Indole is a bicyclic aromatic heterocyclic compound where six-membered benzene is fused with five-membered pyrrole at b bond.
• 
• Indole is aromatic
• The molecule is planar.
• All 9 atoms that make up Indole molecule are sp2 hybridized
• Each atom contains a p orbital which are parallel to each other.
• Contains a total of 10 π electrons (4 double bonds and the lone pair from nitrogen), fulfilling Hückel’s rule.

Synthesis of indole

• Indole is widely available in nature. It is present in coal-tar and can be extracted from it. Various synthetic procedures have been developed also.
• Fischer Indole synthesis
• Very common method of indole synthesis. In this method, phenylhydrazine is reacted with an aldehyde, or ketone, or certain keto acids in presence of an acid (including Lewis acid) to produce indole.
• 
• Leimgruber-Bacho indole synthesis
• Recently this method is being employed for the synthesis of indoles.
• Chemical activities
• The chemical properties of indole are similar to that of pyrrole with few exceptions.
• Indole is a weak base and weak acid
• Similar to pyrrole, indole shows very weak basic property and weak acidic property.
• Indole undergoes electrophilic substitution
• Similar to pyrrole, indole undergoes electrophilic substitution reaction.
• However, where electrophilic substitution occurs preferentially at C-2 in pyrrole, it occurs at C-3 in indole.
• The reason for this is, if electrophile is attached to C-2, then the aromaticity of benzene ring is lost i.e. the molecule becomes less stable.
• But if electrophile is attached to C-3, then aromaticity remains. So, molecule remains stable. Hence, attack occurs at C-3.
• 
• Some examples of electrophilic substittutions
• 
  

• Importance of indole
• Tryptophan, one of the 20 amino acids of the body contains indole ring.
• Two important hormones, serotonin and melatonin are also indole derivatives.
• Many drugs such as vincristine, vinblastine, ergotamine, LSD, psilocybin, ondansetron, sumatriptan, indomethacin, delavirdine contain the indole ring.

Benzo-fused Six-membered Heterocyclic Compounds

Quinoline & Isoquinoline

Quinoline

• Quinoline is a bicyclic aromatic heterocyclic compound when benzene is fused to pyridine at b bond.
• 
  

Isoquinoline

• Isoquinoline is an aromatic heterocyclic compound where benzene is fused to pyridine at c bond.

Aromaticity of quinoline & isoquinoline

• Both benzene and pyridine are aromatic. Quinoline and isoquinoline are also aromatic.
• They both fulfill all for conditions for aromaticity. Here Hückel’s rule is fulfilled by 5 double bonds totalling 10 π electrons. However, here the lone pair of electrons in nitrogen is located in sp2 orbital.

Synthesis of quinoline

• It is found in coal-tar and other natural sources (plants).
• Skraup synthesis
• In this method, aniline and glycerol is heated in presence of conc. sulfuric acid and an oxidizing agent (e.g. nitrobenzene) to produce quinoline.
• 

Synthesis of isoquinoline

• It is also found in coal-tar and in different plants.
• Bischler-Napieralski synthesis

Chemical activity of quinoline & isoquinoline

• Quinoline & Isoquinoline are basic
• Quinoline is a weak base and slightly weaker than pyridine. Isoquinoline is a stronger base than quinoline.
• 
• Quinoline & Isoquinoline undergo electrophilic substitution
• Similar to pyridine, electrophilic substitution occurs only at elevated conditions. Substitution occurs at C-5 or C-8 for both quinoline and isoquinoline.

• Quinoline and isoquinoline undergo nucleophilic substitution
• Similar to pyridine, quinoline and isoquinoline undergo nucleophilic substitution.
• In quinoline substitution occur at C-2 or C-4. In isoquinoline substitution occur at C-1. This is because in isoquinoline, C-1 is most positive.

Importance of quinoline & isoquinoline

• Quinoline and isoquinoline are abundant in nature.
• A large number of alkaloids are derivatives of quinoline and isoquinoline. For example, quinine, quinidine, papaverine etcetera. These have significant medicinal activity.
• Nowadays, fluoroquinolone antibiotics are quite popular. They are derivatives of quinoline.

Finished

Thank You

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