INTRODUCTION

In organic chemistry, cyclic compounds that contain at least one ring atom that is not a carbon are called heterocycles. However, the rings of most heterocycles that pertain to organic chemistry contain more carbons than heteroatoms. However, "heterocycles" that do not contain any carbon, such as the ring,

are also known in inorganic chemistry, but that is exactly why they are classified under inorganic chemistry. Definition In organic chemistry, carbocyclic compounds that contain at least one ring atom that is not a carbon are called heterocycles. The most frequently occuring heteroatoms in heterocycles are nitrogen, oxygen, and sulfur. However, heterocycles with other heteroatoms, such as phosphorus and selenium, also appear. In nature, heterocycles are of great importance. Roughly more than one half of all natural products contains

heterocyclic components. Many of them have important functions in the human organism. In addition, many natural compounds are pharmacologically active. Nitrogen-containing heterocycles are particularly widespread in nature. The alkaloids, for instance, are a special class of nitrogen-containing, naturally occuring heterocycles. Furthermore, deoxyribonucleic acid (DNA), which is the carrier of genetic information in all living beings, contains the nitrogen-containing heterocycles adenine and guanine (purine bases), as well as cytosine and thymine (pyrimidine bases). Ribonucleic acid (RNA) additionally contains the pyrimidine base uracil. Genetic information is saved in the sequence of these purine and pyrimidine bases in the DNA and RNA chains. There are several nomenclature systems of heterocycles that are in use. Aside from systematic nomenclature, trivial names are also frequently applied.

Replacement Nomenclature
A heterocycle is considered to be a carbocycle in that one or more carbons are exchanged for heteroatoms. In replacement nomenclature, the heterocycle's name is composed of the carbocycle's name and a prefix that denotes the heteroatom. Thus, "aza", "oxa", and "thia" are prefixes for a nitrogen ring atom, an oxygen ring atom, and a sulfur ring atom, respectively. According to this nomenclature, tetrahydrofuran, for instance, is called oxacyclopentane.

Fig.1Examples of replacement nomenclature.

The replacement nomenclature is virtually only used in connection with saturated heterocycles. However, trivial names are much more frequently used for saturated heterocycles, as well. The trivial names of saturated heterocycles are often derived from the names of the corresponding unsaturated heterocycles. The names of tetrahydrofuran and tetrahydropyran, for instance, are deduced from furan and pyran. Nitrogen-containing saturated heterocycles' names are usually not attributed to the names of the corresponding unsaturated heterocycles. Piperidine, for instance, is not referred to as pentahydropyridine.

Hantzsch-Widmann nomenclature may be applied in the naming of unsaturated, as well as saturated, monocyclic heterocycles. According to this nomenclature system, the name of a heterocycle is composed of a prefix that denotes the heteroatom and a suffix (see table below) that determines the ring size and the degree of the ring's saturation. In addition, the suffixes distinguish between nitrogen-containing heterocycles and heterocycles that do not contain a nitrogen ring atom. The prefices applied in Hantzsch-Widman nomenclature are "aza" for nitrogen, "oxa" for oxygen, and "thia" for sulfur. If the prefices are combined with the suffixes, the last letter of the prefix is left out. Thus, tetrahydrofuran is called oxolane and not oxaolane, for instance. Hantzsch-Widman nomenclature may also be used in connection with various other heteroatoms. For a list of appropiate prefices, see the link at the end of this page. Tab.1Hantzsch-Widman nomenclature. Ring Maximally size 3 4 unsaturated -irene, -irine (N) -ete -etene, -etine (N) One double Saturated bond -irane, -iridine (N) -etane, -etidine (N)

5 6

-ole -ine (O, S, N, etc.), -inine (P, As, Sb. etc.)

-olene, -oline (N)

-olane, -olidine (N) -ane (O, S, etc.), -inane (N, Si, P, etc.) -epane -ocane -onane -ecane

7 8 9 10

-epine -ocine -onine -ecine

However, the use of special suffixes for partially unsaturated heterocycles is no longer recommended. Instead, partially unsaturated heterocycles may be named by either adding the prefixes "dihydro", "tetrahydro", etc. to the name of the corresponding maximally unsaturated heterocycle or by adding the prefixes "didehydro", "tetradehydro", etc. to the name of the corresponding saturated heterocycle. The former nomenclature is usually preferred.

The position number of the heteroatoms must be as low as possible. If a ring contains more than one heteroatom of the same type, an appropiate numerical prefix, such as "di", "tri", etc., is added to the prefix for the heteroatom.

In naming a ring that possesses two or more different heteroatoms, the prefixes for each heteroatom and, if necessary, the appropiate numerical prefixes for each heteroatom, are added. For more information on Hantzsch-Widman nomenclature of heterocycles, pertaining to the order of heteroatom prefixes in the naming of rings with different heteroatoms and the classification of the position of saturation in partially unsaturated rings, for example, see the detailed IUPAC page regarding this subject. Information from this page may serve as a guide in answering the questions in the second exercise.

In the case of heterocycles, systematic nomenclature is usually hardly ever applied. Instead, trivial names are frequently used. Aromatic heterocycles are typically only known by their trivial names. In the naming of heterocycles that have a more complex structure, the trivial names of simple heterocycles are often used as the parent name. In addition, the trivial names of aromatic heterocycles frequently serve as parent names for the naming of the corresponding saturated heterocycles. The cyclic ether oxacyclopentane (oxolane) is usually only

known as tetrahydrofuran, and oxacyclohexane (oxane) is usually called tetrahydropyrane.

Heterocyclic compounds
Compounds classified as heterocyclic probably constitute the largest and most varied family of organic compounds. After all, every carbocyclic compound, regardless of structure and functionality, may in principle be converted into a collection of heterocyclic analogs by replacing one or more of the ring carbon atoms with a different element. Even if we restrict our consideration to oxygen, nitrogen and sulfur (the most common heterocyclic elements), the permutations and combinations of such a replacement are numerous. Nomenclature Devising a systematic nomenclature system for heterocyclic compounds presented a formidable challenge, which has not been uniformly concluded. Many heterocycles, especially amines, were identified early on, and received trivial names which are still preferred. Some monocyclic compounds of this kind are shown in the following chart, with the common (trivial) name in bold and a systematic name based on the Hantzsch-Widman system given beneath it in blue. The rules for using this system will be given later. For most students,

learning these common names will provide an adequate nomenclature background.

An easy to remember, but limited, nomenclature system makes use of an elemental prefix for the heteroatom followed by the appropriate carbocyclic name. A short list of some common prefixes is given in the following table, priority order increasing from right to left. Examples of this nomenclature are: ethylene oxide = oxacyclopropane, furan = oxacyclopenta-2,4-diene, pyridine = azabenzene, and morpholine = 1-oxa-4-azacyclohexane. Element oxygen sulfur selenium nitrogen phosphorous silicon boron Valence Prefix II Oxa II Thia II Selena III Aza III Phospha IV Sila III Bora

The Hantzsch-Widman system provides a more systematic method of naming heterocyclic compounds that is not dependent on prior carbocyclic names. It makes use of the same hetero atom prefix defined above (dropping the final "a"), followed by a suffix designating ring size and

saturation. As outlined in the following table, each suffix consists of a ring size root (blue) and an ending intended to designate the degree of unsaturation in the ring. In this respect, it is important to recognize that the saturated suffix applies only to completely saturated ring systems, and the unsaturated suffix applies to rings incorporating the maximum number of non-cumulated double bonds. Systems having a lesser degree of unsaturation require an appropriate prefix, such as "dihydro"or "tetrahydro". Ring Size Suffix Unsaturated irene Saturated ete ole ine epine ocine onine ecine irane etane olane inane epane ocane onane ecane 3 4 5 6 7 8 9 10

Despite the general systematic structure of the HantzschWidman system, several exceptions and modifications have been incorporated to accomodate conflicts with prior usage. Some examples are: The terminal "e" in the suffix is optional though recommended. Saturated 3, 4 & 5-membered nitrogen heterocycles should use respectively the traditional "iridine", "etidine" & "olidine" suffix. Unsaturated nitrogen 3-membered heterocycles may

use the traditional "irine" suffix. Consistent use of "etine" and "oline" as a suffix for 4 & 5-membered unsaturated heterocycles is prevented by their former use for similar sized nitrogen heterocycles. Established use of oxine, azine and silane for other compounds or functions prohibits their use for pyran, pyridine and silacyclohexane respectively. Examples of these nomenclature rules are written in blue, both in the previous diagram and that shown below. Note that when a maximally unsaturated ring includes a saturated atom, its location may be designated by a "#H " prefix to avoid ambiguity, as in pyran and pyrrole above and several examples below. When numbering a ring with more than one heteroatom, the highest priority atom is #1 and continues in the direction that gives the next priority atom the lowest number.

All the previous examples have been monocyclic compounds. Polycyclic compounds incorporating one or more heterocyclic rings are well known. A few of these are shown in the following diagram. As before, common names are in black and systematic names in blue. The two quinolines illustrate another nuance of hetrocyclic nomenclature. Thus, the location of a fused ring may be indicated by a lowercase letter which designates the edge of the heterocyclic ring involved in the fusion, as shown by the pyridine ring in the green shaded box.

Heterocyclic rings are found in many naturally occuring compounds. Most notably, they compose the core structures of mono and polysaccharides, and the four DNA bases that establish the genetic code. By clicking on the above diagram some other examples of heterocyclic natural products will be displayed.

Five-Membered Rings

Preparation Commercial preparation of furan proceeds by way of the aldehyde, furfural, which in turn is generated from pentose containing raw materials like corncobs, as shown in the uppermost equation below. Similar preparations of pyrrole and thiophene are depicted in the second row equations. Equation 1 in the third row illustrates a general preparation of substituted furans, pyrroles and thiophenes from 1,4dicarbonyl compounds, known as the Paal-Knorr synthesis. Many other procedures leading to substituted heterocycles of this kind have been devised. Two of these are shown in reactions 2 and 3. Furan is reduced to tetrahydrofuran by palladium-catalyzed hydrogenation. This cyclic ether is not only a valuable solvent, but it is readily converted to 1,4dihalobutanes or 4-haloalkylsulfonates, which may be used to prepare pyrrolidine and thiolane. Dipolar cycloaddition reactions often lead to more complex five-membered heterocycles.

Indole is probably the most important fused ring heterocycle in this class. By clicking on the above diagram three examples of indole sysnthesis will be displayed. The first proceeds by an electrophilic substitution of a nitrogenactivated benzene ring. The second presumably takes place by formation of a dianionic species in which the ArCH2() unit bonds to the deactivated carbonyl group. Finally, the Fischer indole synthesis is a remarkable sequence of tautomerism, sigmatropic rearrangement, nucleophilic addition, and elimination reactions occuring subsequent to phenylhydrazone formation. This interesting transformation involves the oxidation of two carbon atoms and the reduction of one carbon and both nitrogen atoms. Reactions The chemical reactivity of the saturated members of this class of heterocycles: tetrahydrofuran, thiolane and

pyrrolidine, resemble that of acyclic ethers, sulfides, and 2amines, and will not be described here. 1,3-Dioxolanes and dithiolanes are cyclic acetals and thioacetals. These units are commonly used as protective groups for aldehydes and ketones, and may be hydrolyzed by the action of aqueous acid. It is the "aromatic" unsaturated compounds, furan, thiophene and pyrrole that require our attention. In each case the heteroatom has at least one pair of non-bonding electrons that may combine with the four -electrons of the double bonds to produce an annulene having an aromatic sextet of electrons. This is illustrated by the resonance description at the top of the following diagram. The heteroatom Y becomes sp2-hybridized and aquires a positive charge as its electron pair is delocalized around the ring. An easily observed consequence of this delocalization is a change in dipole moment compared with the analogous saturated heterocycles, which all have strong dipoles with the heteroatom at the negative end. As expected, the aromatic heterocycles have much smaller dipole moments, or in the case of pyrrole a large dipole in the opposite direction. An important characteristic of aromaticity is enhanced thermodynamic stability, and this is usually demonstrated by relative heats of hydrogenation or heats of combustion measurements. By this standard, the three

aromatic heterocycles under examination are stabilized, but to a lesser degree than benzene. Additional evidence for the aromatic character of pyrrole is found in its exceptionally weak basicity (pKa ca. 0) and strong acidity (pKa = 15) for a 2-amine. The corresponding values for the saturated amine pyrrolidine are: basicity 11.2 and acidity 32.

Another characteristic of aromatic systems, of particular importance to chemists, is their pattern of reactivity with electrophilic reagents. Whereas simple cycloalkenes generally give addition reactions, aromatic compounds tend to react by substitution. As noted for benzene and its derivatives, these substitutions take place by an initial electrophile addition, followed by a proton loss from the "onium" intermediate to regenerate the aromatic ring. The aromatic five-membered heterocycles all undergo electrophilic substitution, with a general reactivity order: pyrrole >> furan > thiophene > benzene. Some examples are

given in the following diagram. The reaction conditions show clearly the greater reactivity of furan compared with thiophene. All these aromatic heterocycles react vigorously with chlorine and bromine, often forming polyhalogenated products together with polymers. The exceptional reactivity of pyrrole is evidenced by its reaction with iodine (bottom left equation), and formation of 2-acetylpyrrole by simply warming it with acetic anhydride (no catalyst).

There is a clear preference for substitution at the 2-position () of the ring, especially for furan and thiophene. Reactions of pyrrole require careful evaluation, since N-protonation destroys its aromatic character. Indeed, N-substitution of this 2-amine is often carried out prior to subsequent reactions. For example, pyrrole reacts with acetic anhydride or acetyl chloride and triethyl amine to give N-acetylpyrrole. Consequently, the regioselectivity of pyrrole substitution is

variable, as noted by the bottom right equation. An explanation for the general -selectivity of these substitution reactions is apparent from the mechanism outlined below. The intermediate formed by electrophile attack at C-2 is stabilized by charge delocalization to a greater degree than the intermediate from C-3 attack. From the Hammond postulate we may then infer that the activation energy for substitution at the former position is less than the latter substitution.

Functional substituents influence the substitution reactions of these heterocycles in much the same fashion as they do for benzene. Indeed, once one understands the ortho-para and meta-directing character of these substituents, their directing influence on heterocyclic ring substitution is not difficult to predict. The following diagram shows seven such reactions. Reactions 1 & 2 are 3-substituted thiophenes, the first by an electron donating substituent and the second by an electron withdrawing group. The third reaction has two substituents of different types in the 2 and 5-positions. Finally, examples 4 through 7 illustrate reactions of 1,2- and

1,3-oxazole, thiazole and diazole. Note that the basicity of the sp2-hybridized nitrogen in the diazoles is over a million times greater than that of the apparent sp3-hybridized nitrogen, the electron pair of which is part of the aromatic electron sextet.

Other possible reactions are suggested by the structural features of these heterocycles. For example, furan could be considered an enol ether and pyrrole an enamine. Such functions are known to undergo acid-catalyzed hydrolysis to carbonyl compounds and alcohols or amines. Since these compounds are also heteroatom substituted dienes, we might anticipate Diels-Alder cycloaddition reactions with appropriate dienophiles. These possibilities will be illustrated above by clicking on the diagram. As noted in the upper example, furans may indeed be hydrolyzed to 1,4dicarbonyl compounds, but pyrroles and thiophenes behave differently. The second two examples, shown in the middle,

demonstrate typical reactions of furan and pyrrole with the strong dienophile maleic anhydride. The former participates in a cycloaddition reaction; however, the pyrrole simply undergoes electrophilic substitution at C-2. Thiophene does not easily react with this dienophile. The bottom line of the new diagram illustrates the remarkable influence that additional nitrogen units have on the hydrolysis of a series of N-acetylazoles in water at 25 C and pH=7. The pyrrole compound on the left is essentially unreactive, as expected for an amide, but additional nitrogens markedly increase the rate of hydrolysis. This effect has been put to practical use in applications of the acylation reagent 1,1'-carbonyldiimidazole (Staab's reagent). Another facet of heterocyclic chemistry was disclosed in the course of investigations concerning the action of thiamine (following diagram). As its pyrophosphate derivative, thiamine is a coenzyme for several biochemical reactions, notably decarboxylations of pyruvic acid to acetaldehyde and acetoin. Early workers specuated that an "active aldehyde" or acyl carbanion species was an intermediate in these reactions. Many proposals were made, some involving the aminopyrimidine moiety, and others, ring-opened hydrolysis derivatives of the thiazole ring, but none were satisfactory. This puzzle was solved when R. Breslow (Columbia) found that the C-2 hydrogen of thiazolium salts

was unexpectedly acidic (pKa ca. 13), forming a relatively stable ylide conjugate base. As shown, this rationalizes the facile decarboxylation of thiazolium-2-carboxylic acids and deuterium exchange at C-2 in neutral heavy water. Appropriate thiazolium salts catalyze the conversion of aldehydes to acyloins in much the same way that cyanide ion catalyzes the formation of benzoin from benzaldehyde, the benzoin condensation. By clicking on the diagram, a new display will show mechanisms for these two reactions. Note that in both cases an acyl anion equivalent is formed and then adds to a carbonyl function in the expected manner. The benzoin condensation is limited to aromatic aldehydes, but the use of thiazolium catalysts has proven broadly effective for aliphatic and aromatic aldehydes. This approach to acyloins employs milder conditions than the reduction of esters to enediol intermediates by the action of metallic sodium .

The most important condensed ring system related to these heterocycles is indole. Some electrophilic substitution reactions of indole are shown in the following diagram. Whether the indole nitrogen is substituted or not, the favored site of attack is C-3 of the heterocyclic ring. Bonding of the electrophile at that position permits stabilization of the onium-intermediate by the nitrogen without disruption of the benzene aromaticity.

Sepecial details
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. The reaction can be conducted under neutral or weakly acidic conditions. Addition of a weak acid such as acetic acid accelerates the reaction, but the use of amine/ammonium hydrochloride salts or reactions at pH < 3 lead to furans as main products (Paal-Knorr Furan Synthesis).

Mechanism

Amarath has shown (J. Org. Chem., 1991, 56, 6924) that meso- and dl-3,4-diethyl-2,5-hexanediones cyclize at unequal rates, and that the stereochemical configuration of the unchanged dione is preserved during the reaction. Any mechanism that involves the formation of an enamine before

the rate-determining step - the cyclization - must be ruled out.

If the ring is formed from an imine that is generated from a primary amine, a charged immonium ion must be an intermediate. Amarath tried to stabilize or destabilize the immonium ion with different aryl groups as substituents:

The use of ammonia should give an uncharged intermediate and is therefore less affected by the choice of substitutents. The substituents also influence the basicity of the imine, with the nitro group leading to a more basic nucleophile. The rates of cyclization have been compared using ammonia and methylamine. The nitro group has in every situation had a positive effect on the reaction rate. The methoxy group has a

negative effect on the cyclization rate in each case. Comparison of the relative reaction rates of all substrates (R: H, Me) showed no specific stabilization/destabilization effect for a possible mechanism involving an immonium ion. A mechanism that accounts for the influence of different substitution patterns (meso, dl) and explains the influence of a p-nitrophenyl group making a nucleophile more reactive (although not as the imine) includes the cyclization of a hemiacetal which is followed by different dehydration steps:

A more detailed description can be found in the work by Amarath, and references cited therein (J. Org. Chem., 1991, 56, 6924).

Recent Literature

Microwave-Assisted Paal-Knorr Reaction - Three-Step Regiocontrolled Synthesis of Polysubstituted Furans, Pyrroles and Thiophenes G. Minetto, L. F. Raveglia, A. Sega, M. Taddei, Eur. J. Org. Chem., 2005, 5277-5288.

Microwave mediated facile one-pot synthesis of polyarylpyrroles from but-2-ene- and but-2-yne-1,4-diones H. S. P. Rao, S. Jothilingam, H. W. Scheeren, Tetrahedron, 2004, 60, 1625-1630. Paal-Knorr Furan Synthesis

The acid-catalyzed cyclization of 1,4-dicarbonyl compounds known as the Paal-Knorr synthesis is one of the most important methods for the preparation of furans. As many methods for the synthesis of 1,4-diones have recently been developed, the synthetic utility of the Paal-Knorr reaction has improved.

Mechanism

A comparison of the cyclizations of meso- and dl-3,4-diethyl2,5-hexanediones showed that these compounds cyclize at unequal rates, and that the stereochemical configuration of unchanged dione is preserved during the reaction. These findings are at odds with the commonly accepted mechanism that involves the ring closure of a rapidly formed monoenol.

The rate of acid-catalyzed enolization is known not to be very sensitive to the structure of the ketone. Since the ratedetermining step would be the same for both substrates, the differences in the reaction rate cannot be explained by this mechanism.

A mechanism in which the substituents would interfere differently in the rate-determining step is shown below. The ease of achieving a suitable conformation for the cyclization is not the same for both molecules:

A more detailed description can be found in the work by Amarath and Amarath, and references cited therein (J. Org. Chem., 1995, 60, 301).

Recent Literature

Facile Microwave-Mediated Transformations of 2-Butene1,4-diones and 2-Butyne-1,4-diones to Furan Derivatives H. S. P. Rao, S. Jothilingam, J. Org. Chem., 2003, 68, 53925394.

Synthesis of Tri- and Tetrasubstituted Furans Catalyzed by Trifluoroacetic Acid F. Stauffer, R. Neier, Org. Lett., 2000, 2, 3535-3537.

Microwave-Assisted Paal-Knorr Reaction - Three-Step Regiocontrolled Synthesis of Polysubstituted Furans, Pyrroles and Thiophenes G. Minetto, L. F. Raveglia, A. Sega, M. Taddei, Eur. J. Org. Chem., 2005, 5277-5288. Paal-Knorr Thiophene Synthesis Paal Thiophene Synthesis

The Paal-Knorr Thiophene Synthesis allows the generation of thiophenes by condensation of a 1,4-dicarbonyl compound in the presence of an excess of a source of sulfur such as phosphorous pentasulfide or Lawesson's reagent. Attention: some toxic H2S is formed as a side product regardless of the sulfur source.

Mechanism Reagents such as phosphorus pentasulfide or Lawesson's reagent act as sulfurizing agents as well as dehydrating agents, allowing a reaction pathway that could lead first to the formation of furans. This hypothesis was tested by Foye (J. Org. Chem., 1952, 17, 1405.) by treatment of different 1,4-dicarbonyl compounds and the corresponding possible furan intermediates (such as acetonylacetone and 2,5dimethylfuran) with phosphorus pentasulfide. Using the same reaction conditions, the differences in the yields of 2,5dimethylthiophene excludes the possibility that a predominant reaction pathway could lead through furan intermediates:

Foye suggested the following reaction pathway:

Today, the occurrence of a bis-thioketone intermediate is assumed to be possible but not necessary (J. Schatz, Science

of Synthesis, George Thieme Verlag Stuttgart, 2000, Vol. 9, 298.)

The reaction mechanism still needs further elucidation before it is fully understood.

Recent Literature

Microwave-Assisted Paal-Knorr Reaction - Three-Step Regiocontrolled Synthesis of Polysubstituted Furans, Pyrroles and Thiophenes G. Minetto, L. F. Raveglia, A. Sega, M. Taddei, Eur. J. Org. Chem., 2005, 5277-5288.

Thionation Using Fluorous Lawesson's Reagent Z. Kaleta, B. T Makowski, T. Soos, R. Dembinski, Org. Lett., 2006, 8, 1625-1628.

Six-Membered Rings
Properties The chemical reactivity of the saturated members of this class of heterocycles: tetrahydropyran, thiane and piperidine, resemble that of acyclic ethers, sulfides, and 2-

amines, and will not be described here. 1,3-Dioxanes and dithianes are cyclic acetals and thioacetals. These units are commonly used as protective groups for aldehydes and ketones, as well as synthetic intermediates, and may be hydrolyzed by the action of aqueous acid. The reactivity of partially unsaturated compounds depends on the relationship of the double bond and the heteroatom (e.g. 3,4dihydro-2H-pyran is an enol ether). Fully unsaturated six-membered nitrogen heterocycles, such as pyridine, pyrazine, pyrimidine and pyridazine, have stable aromatic rings. Oxygen and sulfur analogs are necessarily positively charged, as in the case of 2,4,6triphenylpyrylium tetrafluoroborate.

From heat of combustion measurements, the aromatic stabilization energy of pyridine is 21 kcal/mole. The resonance description drawn at the top of the following diagram includes charge separated structures not normally considered for benzene. The greater electronegativity of nitrogen (relative to carbon) suggests that such canonical forms may contribute to a significant degree. Indeed, the larger dipole moment of pyridine compared with piperidine

supports this view. Pyridine and its derivatives are weak bases, reflecting the sp2 hybridization of the nitrogen. From the polar canonical forms shown here, it should be apparent that electron donating substituents will increase the basicity of a pyridine, and that substituents on the 2 and 4-positions will influence this basicity more than an equivalent 3substituent. The pKa values given in the table illustrate a few of these substituent effects. Methyl substituted derivatives have the common names picoline (methyl pyridines), lutidine (dimethyl pyridines) and collidine (trimethyl pyridines). The influence of 2-substituents is complex, consisting of steric hindrance and electrostatic components. 4Dimethylaminopyridine is a useful catalyst for acylation reactions carried out in pyridine as a solvent. At first glance, the sp3 hybridized nitrogen might appear to be the stronger base, but it should be remembered that N,N-dimethylaniline has a pKa slightly lower than that of pyridine itself. Consequently, the sp2 ring nitrogen is the site at which protonation occurs.

The diazines pyrazine, pyrimidine and pyridazine are all weaker bases than pyridine due to the inductive effect of the second nitrogen. However, the order of base strength is unexpected. A consideration of the polar contributors helps to explain the difference between pyrazine and pyrimidine, but the basicity of pyridazine seems anomalous. It has been suggested that electron pair repulsion involving the vicinal nitrogens destabilizes the neutral base relative to its conjugate acid. Electrophilic Substitution of Pyridine Pyridine is a modest base (pKa=5.2). Since the basic unshared electron pair is not part of the aromatic sextet, as in pyrrole, pyridinium species produced by N-substitution retain the aromaticity of pyridine. As shown below, Nalkylation and N-acylation products may be prepared as stable crystalline solids in the absence of water or other

reactive nucleophiles. The N-acyl salts may serve as acyl transfer agents for the preparation of esters and amides. Because of the stability of the pyridinium cation, it has been used as a moderating component in complexes with a number of reactive inorganic compounds. Several examples of these stable and easily handled reagents are shown at the bottom of the diagram. The poly(hydrogen fluoride) salt is a convenient source of HF for addition to alkenes and conversion of alcohols to alkyl fluorides, pyridinium chlorochromate (PCC) and its related dichromate analog are versatile oxidation agents and the tribromide salt is a convenient source of bromine. Similarly, the reactive compounds sulfur trioxide and diborane are conveniently and safely handled as pyridine complexes. Amine oxide derivatives of 3-amines and pyridine are readily prepared by oxidation with peracids or peroxides, as shown by the upper right equation. Reduction back to the amine can usually be achieved by treatment with zinc (or other reactive metals) in dilute acid.

From the previous resonance description of pyridine, we expect this aromatic amine to undergo electrophilic substitution reactions far less easily than does benzene. Furthermore, as depicted above the electrophilic reagents and catalysts employed in these reactions coordinate with the nitrogen electron pair, exacerbating the positive charge at positions 2,4 & 6 of the pyridine ring. Three examples of the extreme conditions required for electrophilic substitution are shown on the left. Substituents that block electrophile coordination with nitrogen or reduce the basicity of the nitrogen facilitate substitution, as demonstrated by the examples in the blue-shaded box at the lower right, but substitution at C-3 remains dominant. Activating substituents at other locations also influence the ease and regioselectivity of substitution. By clicking on the diagram a second time, three examples will shown on the left. The amine substituent in the upper case directs the

substitution to C-2, but the weaker electron donating methyl substituent in the middle example cannot overcome the tendency for 3-substitution. Hydroxyl substituents at C-2 and C-4 tautomerize to pyridones, as shown for the 2-isomer at the bottom left. Pyridine N-oxide undergoes some electrophilic substitutions at C-4 and others at C-3. The coordinate covalent NO bond may exert a push-pull influence, as illustrated by the two examples on the right. Although the positively charged nitrogen alone would have a strong deactivating influence, the negatively charged oxygen can introduce electron density at C-2, C-4 & C-6 by -bonding to the ring nitrogen. This is a controlling factor in the relatively facile nitration at C-4. However, if the oxygen is bonded to an electrophile such as SO3, the resulting pyridinium ion will react sluggishly and preferentially at C-3. The fused ring heterocycles quinoline and isoquinoline provide additional evidence for the stability of the pyridine ring. Vigorous permanganate oxidation of quinoline results in predominant attack on the benzene ring; isoquinoline yields products from cleavage of both rings. Note that naphthalene is oxidized to phthalic acid in a similar manner. By contrast, the heterocyclic ring in both compounds undergoes preferential catalytic hydrogenation to yield tetrahydroproducts. Electrophilic nitration, halogenation

and sulfonation generally take place at C-5 and C-8 of the benzene ring, in agreement with the preceeding description of similar pyridine reactions and the kinetically favored substitution of naphthalene at C-1 () rather than C-2 ().

Other Reactions of Pyridine Thanks to the nitrogen in the ring, pyridine compounds undergo nucleophilic substitution reactions more easily than equivalent benzene derivatives. In the following diagram, reaction 1 illustrates displacement of a 2-chloro substituent by ethoxide anion. The addition-elimination mechanism shown for this reaction is helped by nitrogen's ability to support a negative charge. A similar intermediate may be written for substitution of a 4-halopyridine, but substitution at the 3-position is prohibited by the the failure to create an intermediate of this kind. The two Chichibabin aminations in reactions 2 and 3 are remarkable in that the leaving anion

is hydride (or an equivalent). Hydrogen is often evolved in the course of these reactions. In accord with this mechanism, quinoline is aminated at both C-2 and C-4. Addition of strong nucleophiles to N-oxide derivatives of pyridine proceed more rapidly than to pyridine itself, as demonstrated by reactions 4 and 5. The dihydro-pyridine intermediate easily loses water or its equivalent by elimination of the OM substituent on nitrogen.

By clicking on the above diagram, five additional examples of base or nucleophile reactions with substituted pyridine will be displayed. Because the pyridine ring (and to a greater degree the N-oxide ring) can support a negative charge, alkyl substituents in the 2- and 4-locations are activated in the same fashion as by a carbonyl group. Reactions 6 and 7 show alkylation and condensation reactions resulting from this activation. Reaction 8 is an example of N-alkylpyridone

formation by hydroxide addition to an N-alkyl pyridinium cation, followed by mild oxidation. Birch reduction converts pyridines to dihydropyridines that are bis-enamines and may be hydrolyzed to 1,5-dicarbonyl compounds. Pyridinium salts undergo a one electron transfer to generate remarkably stable free radicals. The example shown in reaction 9 is a stable (in the absence of oxygen), distillable green liquid. Although 3-halopyridines do not undergo addition-elimination substitution reactions as do their 2- and 4-isomers, the strong base sodium amide effects amination by way of a pyridyne intermediate. This is illustrated by reaction 10. It is interesting that 3-pyridyne is formed in preference to 2-pyridyne. The latter is formed if C-4 is occupied by an alkyl substituent. The pyridyne intermediate is similar to benzyne.

Specific details about pyridine

Pyridine is a chemical compound with the formula C5H5N. It is a liquid with a distinctively putrid, fishy odour. Pyridine is a simple and fundamentally important heterocyclic aromatic organic compound that is structurally related to benzene, wherein one CH group in the six-membered ring is replaced by a nitrogen atom. The pyridine ring occurs in many important compounds, including the nicotinamides. Pyridine

is sometimes used as a ligand in coordination chemistry. As a ligand, it is usually abbreviated py.

Basicity

Pyridinium cation Pyridine has a lone pair of electrons at the nitrogen atom. Because this lone pair is not delocalized into the aromatic pisystem, pyridine is basic with chemical properties similar to tertiary amines. The pKa of the conjugate acid is 5.30. Pyridine is protonated by reaction with acids and forms a positively charged aromatic polyatomic ion called pyridinium cation. The bond lengths and bond angles in pyridine and the pyridinium ion are almost identical] because protonation does not affect the aromatic pi system.

Pyridine as solvent Pyridine is widely used as a versatile solvent, since it is polar but aprotic. It is fully miscible with a very broad range of solvents including hexane and water. Deuterated pyridine, called pyridine-d5, is a common solvent for1H NMR spectroscopy. Preparation & Ocarrance Many methods exist in industry and in the laboratory (some of them named reactions) for the synthesis of pyridine and its derivatives:

Pyridine is obtained industrially from crude coal tar or is synthesized from acetaldehyde, formaldehyde and ammonia. The Hantzsch pyridine synthesis is a multicomponent reaction involving formaldehyde, a keto-ester and a nitrogen donor. Other examples of the pyridine class can be formed by the reaction of 1,5-diketones with ammonium acetate in acetic acid followed by oxidation. This reaction is called the Krhnke pyridine synthesis. Pyridium salts can be obtained in the Zincke reaction.

The Ciamician-Dennstedt Rearrangement (1881) is the ring-expansion of pyrrole with dichlorocarbene to 3chloropyridine and HCl In the Chichibabin pyridine synthesis (Aleksei Chichibabin, 1906) the reactants are three equivalents of a linear aldehyde and ammonia

Organic reaction In organic reactions pyridine behaves both as a tertiary amine with protonation, alkylation, acylation and Noxidation at nitrogen and as an aromatic compound with Nucleophilic substitutions.

Pyridine is a good nucleophile with a donor number of 33.1. It is easily attacked by alkylating agents to give Nalkylpyridinium salts. Nucleophilic aromatic substitution takes place at C2 and C4 for example in the Chichibabin reaction of pyridine with sodium amide to 2-aminopyridine. In the Emmert reaction (B. Emmert, 1939) pyridine is reacted with a ketone in presence of aluminium or magnesium and mercuric chloride to the carbinol also at C2

Hantzsch pyridine synthesis The Hantzsch pyridine synthesis or Hantzsch dihydropyridine synthesis is a multi-component organic

reaction between an aldehyde such as formaldehyde, 2 equivalents of a -keto ester such as ethyl acetoacetate and a nitrogen donor such as ammonium acetate or ammonia [1]. The initial reaction product is a dihydropyridine which can be oxidized in a subsequent step to a pyridine. The driving force for this second reaction step is aromatization. A 1,4-dihydropyridine dicarboxylate is also called a 1,4-DHP compound or a Hantzsch compound. These compounds are an important class of calcium channel blockers and as such commercialized in for instance nifedipine, amlodipine or nimodipine. The reaction has been demonstrated to proceed in water as reaction solvent and with direct aromatization by ferric chloride or potassium permanganate in a one-pot synthesis.

The Hantzsch dihydropyridine synthesis is found to benefit from microwave chemistry.

Specific details about indole

Indole is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. The participation of the nitrogen lone electron pair in the aromatic ring means that indole is not a base, and it does not behave like a simple amine. Indole is solid at room temperature. It occurs naturally in human feces and has an intense fecal odor. At very low concentrations, however, it has a flowery smell, and is a constituent of many flower scents (such as orange blossoms) and perfumes. It also occurs in coal tar. The indole structure can be found in many organic compounds like the amino acid tryptophan and in tryptophan-containing protein, in alkaloids, and in pigments. Indole undergoes electrophilic substitution, mainly at position 3. Substituted indoles are structural elements of (and for some compounds the synthetic precursors for) the tryptophan-derived tryptamine alkaloids like the neurotransmitter serotonin, melatonin, the hallucinogens psilocybin, DMT, 5-MeO-DMT, or the ergolines like LSD. Other indolic compounds include the plant hormone Auxin (indolyl-3-acetic acid, IAA), the anti-inflammatory drug indomethacin, and the betablocker pindolol.

The name indole is a portmanteau of the words indigo and oleum, since indole was first isolated by treatment of the indigo dye with oleum. Indole chemistry began to develop with the study of the dye indigo. This was converted to isatin and then to oxindole. Then, in 1866, Adolf von Baeyer reduced oxindole to indole using zinc dust. In 1869, he proposed the formula for indole (left) that is accepted today. Certain indole derivatives were important dyestuffs until the end of the 19th century. In the 1930s, interest in indole intensified when it became known that the indole nucleus is present in many important alkaloids, as well is in tryptophan and auxins, and it remains an active area of research today. Synthesis of indoles Indole is a major constituent of coal-tar, and the 220-260 C distillation fraction is the main industrial source of the material. Indole and its derivatives can also be synthesized by a variety of methods. [edit] Leimgruber-Batcho indole synthesis Main article: Leimgruber-Batcho indole synthesis

The Leimgruber-Batcho indole synthesis is an efficient method of sythesizing indole and substituted indoles. Originally disclosed in a patent in 1976, this method is highyielding and can generate substituted indoles. This method is especially popular in the pharmaceutical industry, where many pharmaceutical drugs are comprised of specifically substituted indoles. [edit] Fischer indole synthesis Main article: Fischer indole synthesis

One of the oldest and most reliable methods for synthesizing substituted indoles is the Fischer indole synthesis developed in 1883 by Emil Fischer. Although the synthesis of indole itself is problematic using the Fischer indole synthesis, it is often used to generate indoles substituted in the 2- and/or 3positions.

Imidazol

Imidazole is a heterocyclic aromatic organic compound. It is further classified as an alkaloid. Imidazole refers to the parent compound C3H4N2, whereas imidazoles are a class of heterocycles with similar ring structure but varying substituents. This ring system is present in important biological building blocks such as histidine, and the related hormone histamine. Imidazole can act as a base and as a weak acid. Imidazole exists in two tautomeric forms with the hydrogen atom moving between the two nitrogens. Many drugs contain an imidazole ring, such as antifungal drugs and nitroimidazole Imidazole was first synthesized by H. Debus in 1858, but various imidazole derivatives had been discovered as early as the 1840s. His synthesis, as shown below, used glyoxal and formaldehyde in ammonia to form imidazole. This synthesis, while producing relatively low yields, is still used for creating C-substituted imidazoles.

In one microwave modification the reactants are benzil, formaldehyde and ammonia in glacial acetic acid forming 2,4,5-triphenylimidazole (Lophine). Preparation

Imidazole can be synthesized by numerous methods besides the Debus method. Many of these syntheses can also be applied to different substituted imidazoles and imidazole derivatives simply by varying the functional groups on the reactants. In literature, these methods are commonly categorized by which and how many bonds form to make the imidazole rings. For example, the Debus method forms the (1,2), (3,4), and (1,5) bonds in imidazole, using each reactant as a fragment of the ring, and thus this method would be a three-bond-forming synthesis. A small sampling of these methods is presented below. Formation of One Bond The (1,5) or (3,4) bond can be formed by the reaction of an immediate and an -aminoaldehyde or -aminoacetal, resulting in the cyclization of an amidine to imidazole. The example below applies to imidazole when R=R1=Hydrogen.

Formation of Two Bonds The (1,2) and (2,3) bonds can be formed by treating a 1,2diaminoalkane, at high temperatures, with an alcohol, aldehyde, or carboxylic acid. A dehydrogenating agent, such

as platinum with alumina, must be present in the reaction for the imidazole to form. The example below applies to imidazole when R=Hydrogen.

The (1,2) and (3,4) bonds can also be formed from Nsubstituted -aminoketones and formamide and heat. The product will be a 1,4-disubstituted imidazole, but here since R=R1=Hydrogen, imidazole itself is the product. The yield of this reaction is moderate, but it seems to be the most effective method of making the 1,4 substitution.

Formation of Four Bonds This is a general method which is able to give good yields for substituted imidazoles. The starting materials are substituted glyoxal, aldehyde, amine, and ammonia or an ammonium salt.

Formation from other Heterocycles

Imidazole can be synthesized by the photolysis of 1vinyltetrazole. This reaction will only give substantial yields if the 1-vinyltetrazole is made efficiently from an organotin compound such as 2-tributylstannyltetrazole. The reaction, shown below, produces imidazole when R=R1=R2=Hydrogen.

Imidazole can also be formed in a vapor phase reaction. The reaction occurs with formamide, ethylenediamine, and hydrogen over platinum on alumina, and it must take place between 340 and 480 C. This forms a very pure imidazole product. Structure and properties Imidazole is a 5-membered planar ring, which is soluble in water and polar solvents. The compound has an aromatic sextet, which consists of one electron from the =N- atom and one from each carbon atom, and two from the NH nitrogen. Some resonance structures of imidazole are shown

below.

Imidazole is a base and an excellent nucleophile. It reacts at the NH nitrogen, attacking alkylating and acylating compounds. It is not particularly susceptible to electrophilic attacks at the carbon atoms, and most of these reactions are substitutions that keep the aromaticity intact. One can see from the resonance structure that the carbon-2 is the carbon most likely to have a nucleophile attack it, but in general nucleophilic substitutions are difficult with imidazole. Biological significance and applications Imidazole is incorporated into many important biological molecules. The most obvious is the amino acid histidine, which has an imidazole side chain. Histidine is present in many proteins and enzymes and plays a vital part in the structure and binding functions of hemoglobin. Histidine can be decarboxylated to histamine, which is also a common biological compound. It is a component of the toxin that causes urticaria, which is basically an allergic reaction. The

structures of both histidine and histamine are:

One of the applications of imidazole is in the purification of His-tagged proteins in immobilised metal affinity chromatography(IMAC). Imidazole is used to elute tagged proteins bound to Ni ions attached to the surface of beads in the chromatography column. An excess of imidazole is passed through the column, which displaces the His-tag from nickel co-ordination, freeing the His-tagged proteins. Imidazole has become an important part of many pharmaceuticals. Synthetic imidazoles are present in many fungicides and antifungal, antiprotozoal, and antihypertensive medications. Imidazole is part of the theophylline molecule, found in tea leaves and coffee beans, which stimulates the central nervous system. It is present in the anticancer medication mercaptopurine, which combats leukemia by interfering with DNA activities. Industrial applications

Imidazole has been used extensively as a corrosion inhibitor on certain transition metals, such as copper. Preventing copper corrosion is important, especially in aqueous systems, where the conductivity of the copper decreases due to corrosion. Many compounds of industrial and technological importance contain imidazole. The thermostable polybenzimidazole PBI contains imidazole fused to a benzene ring and linked to a benzene, and acts as a fire retardant. Imidazole can also be found in various compounds which are used for photography and electronics. Salts of imidazole

Salts of imidazole where the imidazole ring is in the cation are known as imidazolium salts (for example, imidazolium chloride). These salts are formed from the protonation or substitution at nitrogen of imidazole. These salts have been used as ionic liquids and precursors to stable carbenes. Salts where a deprotanated imidazole is an anion are also possible; these salts are known as imidazolide salts (for example, sodium imidazolide).

Quinolines
Quinoline, also known as 1-azanaphthalene, 1-benzazine, or benzo[b]pyridine, is a heterocyclic aromatic organic compound. It has the formula C9H7N and is a colourless hygroscopic liquid with a strong odour. As it ages, if exposed to light, the liquid tends to become yellow and later brown. It is only slightly soluble in water but dissolves readily in many organic solvents. Quinoline is an intermediate in metallurgical processes and in dye, polymer, and agrochemical production. It is also a preservative, disinfectant, and solvent. It is toxic: short-term exposure to the vapour causes irritation of the nose, eyes, and throat as well as dizziness and nausea. Longer-term effects are uncertain, but quinoline has been linked to liver damage.

Isolation and synthesis Quinoline is naturally found in coal tar and was first extracted from this source in 1834 by F. Runge. It can be prepared using various methods

Purines
Purine (1) is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines make up one of the two groups of nitrogenous bases. Pyrimidines make up the other group. These bases make up a crucial part of both deoxyribonucleotides and ribonucleotides, and the basis for the universal genetic code. The general term purines also refers to substituted purines and their tautomers. The purine is the most widely distributed nitrogencontaining heterocycle in nature Notable purines The quantity of naturally occurring purines produced on earth is enormous, as 50 % of the bases in nucleic acids, adenine (2) and guanine (3), are purines. In DNA, these bases form hydrogen bonds with their complementary pyrimidines thymine and cytosine. This is called complementary base pairing. In RNA, the complement of adenine is uracil (U) instead of thymine.

Other notable purines are hypoxanthine (4), xanthine (5), theobromine (6), caffeine (7), uric acid (8) and isoguanine (9).

Functions Aside from DNA and RNA, purines are biochemically significant components in a number of other important biomolecules, such as ATP, GTP, cyclic AMP, NADH, and coenzyme A. Purine (1) itself, has not been found in nature, but it can be produced by organic synthesis. History The name 'purine' (purum uricum) was coined by the German chemist Emil Fischer in 1884. He synthesized it for the first time in 1899. The starting material for the reaction

sequence was uric acid (8), which had been isolated from gallstones by Scheele in 1776. Uric acid (8) was reacted with PCl5 to give 2,6,8-trichloropurine (10), which was converted with HI and PH4I to give 2,6-diiodopurine (11). This latter product was reduced to purine (1) using zinc-dust.

Metabolism Main article: Purine metabolism Many organisms have metabolic pathways to synthesize and break down purines. Purines are biologically synthesized as nucleosides (bases attached to ribose).

Food Sources Purines are found in high concentration in meat and meat products, especially internal organs such as liver and kidney. Plant based diet is generally low in purines.

Examples of high purine sources include: sweetbreads, anchovies, sardines, liver, beef kidneys, brains, meat extracts (e.g Oxo, Bovril), herring, mackerel, scallops, game meats, and gravy. A moderate amount of purine is also contained in beef, pork, poultry, fish and seafood, asparagus, cauliflower, spinach, mushrooms, green peas, lentils, dried peas, beans, oatmeal, wheat bran and wheat germ. Moderate intake of purine-containing food is not associated with an increased risk of gout.

Synthesis Purine (1) is obtained in good yield when formamide is heated in an open vessel at 170 oC for 28 hours.

Procedure: Formamide (45 gram) was heated in an open vessel with a condenser for 28 hours in an oil bath at 170-190
o

C. After removing excess formamide (32.1 gram) by

vacuum distillation, the residue was refluxed with methanol. The methanol solvent was filtered, the solvent removed from the filtrate by vacuum distillation, and almost pure purine obtained; yield 4.93 gram (71 % yield from formamide consumed). Crystallization from acetone afforded purine as colorless crystals; melting point 218 oC. Oro, Orgel and co-workers have shown that four molecules of HCN tetramerize to form diaminomaleodinitrile (12), which can be converted into almost all important natural occurring purines.

Pyrimidines
Pyrimidine is a heterocyclic aromatic organic compound similar to benzene and pyridine, containing two nitrogen atoms at positions 1 and 3 of the six-member ring.[1] It is isomeric with two other forms of diazine

Nucleotides Three nucleobases found in nucleic acids, namely cytosine, thymine, and uracil, are pyrimidine derivatives:

In DNA and RNA, these bases form hydrogen bonds with their complementary purines. Thus the purines - adenine (A) and guanine (G) - pair up with the pyrimidines thymine (T) and cytosine (C) respectively. In RNA, the complement of A is U instead of T and the pairs that form are adenine:uracil and guanine:cytosine. These hydrogen bonding modes are for classical WatsonCrick base pairing. Other hydrogen bonding modes ("wobble pairings") are available in both DNA and RNA, although the additional 2'-hydroxyl group of RNA expands the configurations through which RNA can form hydrogen bonds.

Chemical properties A pyrimidine has many properties in common with pyridine, as the number of nitrogen atoms in the ring increases the ring pi electrons become less energetic and electrophilic aromatic substitution gets more difficult while nucleophilic aromatic substitution gets easier. An example of the last reaction type is the displacement of the amino group in 2aminopyrimidine by chlorine and its reverse. Reduction in resonance stabilization of pyrimidines may lead to addition and ring cleavage reactions rather than substitutions. One such manifestation is observed in the Dimroth rearrangement Compared to pyridine N-alkylation and N-oxidation is more difficult and pyrimidines are also less basic: the pKa value for protonated pyrimidine is 1.23 compared to 5.30 for pyridine Organic synthesis Pyrimidines can also be prepared in the laboratory by organic synthesis. One method is the classic Biginelli reaction. Many other methods rely on condensation of carbonyls with amines for instance the synthesis of 2-Thio-6methyluracil from thiourea and ethyl acetoacetate or the synthesis of 4-methylpyrimidine with 4,4-dimethoxy-2butanone and formamide.

A novel method is by reaction of certain amides with carbonitriles under electrophilic activation of the amide with 2-chloro-pyridine and trifluoromethanesulfonic anhydride: