Isocyclicc Com- Poundscompounds

The Chemistry of Heterocycles

Structure, Reactions, Syntheses, and Applications

Mohammad Jafarzadeh Faculty of Chemistry, Razi University

The Chemistry of Heterocycles, (Second Edition). By Theophil Eicher and Siegfried Hauptmann, Wiley-VCH Veriag GmbH, 2003 1 1 The Structure of Heterocyclic Compounds 1. The Structure of Heterocyclic Compounds

• Molecules are defined by the type and number of atoms as well as by the covalent bonding within Mosthemt chemica. Therel arecompoundtwo mains consistypes tof ostructuref molecules: . The classification of such chemical compounds is base— Thed onatoms the structurform ae chainof thes-ealiphatic molecules(acyclic), whichcompounds is defined by the type and number of atoms as well as b—y thThee covalenatomst formbondina ringg withi- cyclicn themcompounds. There are two main types of structure: — The a t o m s form a chain - aliphatic (acyclic) compounds — The a t o m s form a ring - cyclic compounds CycliCyclicc compoundcompoundss iinn whicwhichh ththee rinringg isis madmadee upup ofof atomatomss ofof ononee elemenelementt onlonlyy areare callecalledd isocycliisocyclicc com- poundscompounds. If th.eIf rintheg consistring consistss of C-atomof C-atomss only,only, then thenwe speawe speakk of a carbocycliof a carbocyclicc compoundcompound,, e.g.: e.g.:

NMe? O (4 - dimethylaminophenyl) pentazole cyclopenta -1,3 - diene isocyclic isocyclic und carbocyclic

2 Cyclic compounds with at least two different atoms in the ring (as ring atoms or members of the ring) are known as heterocyclic compounds. The ring itself is called a heterocycle. If the ring contains no C-atom, then we speak of an inorganic heterocycle, e.g.:

MeO

2,4 - bis (4 - methoxyphenyl) - 1,3 - dithiadiphosphetan -2,4 - disulfide borazine (Lawesson - Reagent)

If at least one ring atom is a C-atom, then the molecule is an organic heterocyclic compound. In this case, all the ring atoms which are not carbon are called heteroatoms, e.g.:

Most chemical compounds consist of molecules. The classification of such chemical compounds is based on the structure of these molecules, which is defined by the type and number of atoms as well as by the covalent bonding within them. There are two main types of structure: — The a t o m s form a chain - aliphatic (acyclic) compounds — The a t o m s form a ring - cyclic compounds Cyclic compounds in which the ring is made up of atoms of one element only are called isocyclic compounds. If the ring consists of C-atoms only, then we speak of a carbocyclic compound, e.g.:

NMe? O (4 - dimethylaminophenyl) pentazole cyclopenta -1,3 - diene isocyclic isocyclic und carbocyclic

Cyclic compounds with at least two different atoms in the ring (as ring atoms or members of the ring) are known as heterocyclic compounds. The ring itself is called a heterocycle. If the ring contains no C-atom, then we speak of an inorganic heterocycle, e.g.:

MeO Cyclic compounds with at least two different atoms in the ring (as ring atoms or members of the ring) are known as heterocyclic compounds. The ring itself is called a heterocycle.

If the ring contains no C-atom, then we speak of an inorganic heterocycle, e.g.:

2,4 - bis (4 - methoxyphenyl) - 1,3 - dithiadiphosphetan -2,4 - disulfide borazine (Lawesson - Reagent) The Structure of Heterocyclic Compounds If at least one ring atom is a C-atom, then the molecule is an organic heterocyclic compound. In If at least one ring atom is a C-atom, then the molecule is an organic heterocyclic compound. In this this case, all the ring atoms which are not carbon are called heteroatoms, e.g.: case, all the ring atoms which are not carbon are called heteroatoms, e.g.:

oxazole 4 - H -1,4 - thiazine heteroatoms O and N heteroatoms S and N 3 In principle, all elements except the alkali metals can act as ring atoms. Along with the type of ring atoms, their total number is important since this determines the ring size. The smallesThe Chemistryt possibl ofHeterocycles,e ring Secondis three-membered Edition. By Theophi. lTh Eichee mosr andt Siegfrie importand Hauptmant ringn s are the five- and six- Copyright © 2003 Wiiey-VCH Veriag GmbH & Co. KGaA membered heterocycles. There is no upper limit; there exist seven-, eight-, nine- and larger-membered ISBN: 3-527-30720-6 heterocycles. Although inorganic heterocycles have been synthesized, this book limits itself to organic compounds. In these, the N-atom is the most common heteroatom. Next in importance are O- and S-atoms. Heterocycles with Se-, Te-, P-, As-, Sb-, Bi-, Si-, Ge-, Sn-, Pb- or B-atoms are less common. To determine the stability and reactivity of heterocyclic compounds, it is useful to compare them with their carbocyclic analogues. In principle, it is possible to derive every heterocycle from a carbo-

cyclic compound by replacing appropriate CH2 or CH groups by heteroatoms. If one limits oneself to monocyclic systems, one can distinguish four types of heterocycles as follows:

• Saturated heterocycles (heterocycloalkanes), e.g.: C cyclohexane X = O oxane X = O 1,4-dioxane X = S thiane X = S 1,4-dithiane X = NH piperidine X = NH piperazine

In this category, there are no multiple bonds between the ring atoms. The compounds react largely like their aliphatic analogues, e.g. oxane (tetrahydropyran) and dioxane behave like dialkyl ethers, thiane and 1,4-dithiane like dialkyl sulfides, and piperidine and piperazine like secondary aliphatic amines.

Partially unsaturatedsystems (heterocycloalkenes)', e.g.: O cyclohexene X = O 3,4-dihydro-2H-pyran X = S X = NH In principle, all elements except the alkali metals can act as ring atoms.

Along with the type of ring atoms, their total number is important since this determines the ring size.

The smallest possible ring is three-membered. The most important rings are the five- and six- membered heterocycles. There is no upper limit; there exist seven-, eight-, nine- and larger-membered heterocycles.

Although inorganic heterocycles have been synthesized, this book limits itself to organic compounds. In these, the N-atom is the most common heteroatom. Next in importance are O- and S-atoms.

Heterocycles with Se-, Te-, P-, As-, Sb-, Bi-, Si-, Ge-, Sn-, Pb- or B-atoms are less common.

To determine the stability and reactivity of heterocyclic compounds, it is useful to compare them with their carbocyclic analogues. Heterocycles derive from a carbocyclic compound by replacing appropriate CH2 or CH groups by heteroatoms.

4 The Structure of Heterocyclic Compounds

oxazole 4 - H -1,4 - thiazine heteroatoms O and N heteroatoms S and N

In principle, all elements except the alkali metals can act as ring atoms. Along with the type of ring atoms, their total number is important since this determines the ring size. The smallest possible ring is three-membered. The most important rings are the five- and six- membered heterocycles. There is no upper limit; there exist seven-, eight-, nine- and larger-membered heterocycles. Although inorganic heterocycles have been synthesized, this book limits itself to organic compounds. In these, the N-atom is the most common heteroatom. Next in importance are O- and S-atoms. Heterocycles with Se-, Te-, P-, As-, Sb-, Bi-, Si-, Ge-, Sn-, Pb- or B-atoms are less common. To determine the stability and reactivity of heterocyclic compounds, it is useful to compare them with their carbocyclic analogues. In principle, it is possible to derive every heterocycle from a carbocyclic compound by replacing appropriate CH2 or CH groups by heteroatoms. If one limits oneself to monocycliMonocyclicc systemssystems, oncane candistinguish distinguisfourh foutypesr typeofs oheterocyclesf heterocycleass asfollows follows: :

• Saturated heterocycles (heterocycloalkanes) • Saturated heterocycles (heterocycloalkanes), e.g.: C cyclohexane X = O oxane X = O 1,4-dioxane X = S thiane X = S 1,4-dithiane X = NH piperidine X = NH piperazine

IInn thithiss categorycategory,, thertheree araree nnoo multiplmultiplee bondbondss betweebetweenn ththee rinringg atomsatoms.. The compounds react largely like their aliphatic analogues, e.g. oxane (tetrahydropyran) and dioxane behave like dialkyl ethers, thiane anThed 1,4-dithiancompoundse likreacte dialkylargelyl sulfideslike, antheird piperidinaliphatice ananalogues,d piperazinee. glik. oxanee secondar(tetrahydropyran)y aliphatic aminesand. dioxane behave like dialkyl ethers, thiane and 1,4-dithiane like dialkyl sulfides, and piperidine and piperazinePartiallylike unsaturatedsystemssecondary aliphatic (heterocycloalkenes)amines. ', e.g.:

O 5 cyclohexene X = O 3,4-dihydro-2H-pyran X = S X = NH The Structure of Heterocyclic Compounds

oxazole 4 - H -1,4 - thiazine heteroatoms O and N heteroatoms S and N

cyclic compound by replacing appropriate CH2 or CH groups by heteroatoms. If one limits oneself to monocyclic systems, one can distinguish four types of heterocycles as follows:

• Saturated heterocycles (heterocycloalkanes), e.g.: C cyclohexane X = O oxane X = O 1,4-dioxane X = S thiane X = S 1,4-dithiane X = NH piperidine X = NH piperazine

Partially unsaturatedsystems (heterocycloalkenes)', e.g.: • Partially unsaturated systems (heterocycloalkenes)

The Structure of HeterocycliOc Compounds cyclohexene X = O 3,4-dihydro-2H-pyran X = S X = NH 0 X = O 3,4-dJhydro-1,4-dioxin X = O ® X=S X=S® X = NH X = NH 2,3,4,5-tetrahydropyridine

If the multiple bonds are between two C-atoms of the ring, for instance, in 3,4-dihydro-2H-pyran, the compoundsIf the multiplreacte bondessentiallys are betweelike alkenesn two C-atomor alkyness of. the ring, as, for instance, in 3,4-dihydro-2//-pyran,

the compounds react essentially like alkenes or alkynes. The heteroatom can +also be involved in a dou- The heteroatom can also be involved+ in a double bond. In the case of X = O , the compounds behave+ likebleoxenium bond. Insalts, the casine theof Xcase = Oof, thXe =compoundS+, like sulfeniums behave liksalts,e oxeniuand min saltsthe ,case in theof casX e= oN,f Xlike = Simines, like (azomethines)sulfenium salts. , and in the case of X = N, like imines (azomethines). 6

• Systems with the greatest possible number of noncumulated double bonds (heteroannulenes), e.g.:

[6]annulene X = O® pyryliumsalts X = N pyrimidine benzene X = S® thiiniumsalts X = N py r i d i n e , pyridine-like N - atom o

X = 0 furan X = S thiophene X = NH pyrrole, pyrrole-like N - atom

[8]annulene X = cP X = N 1,3 - diazocine cyclooctatetraene X = S X = N azocine .

X = 0 oxepine X = S thiepine X = NH azepine The Structure of Heterocyclic Compounds

0 X = O 3,4-dJhydro-1,4-dioxin X = O ® X=S X=S® X = NH X = NH 2,3,4,5-tetrahydropyridine

If the multiple bonds are between two C-atoms of the ring, as, for instance, in 3,4-dihydro-2//-pyran, the compounds react essentially like alkenes or alkynes. The heteroatom can also be involved in a dou- The Structure of Heterocyclic Compounds ble bond. In the case of X = O+, the compounds behave like oxenium salts, in the case of X = S+, like sulfenium salts, and in the case of X = N, like imines (azomethines). 0 • Systems with the greatest possible number of noncumulated double bonds (heteroannulenes), e.g.: X = O 3,4-dJhydro-1,4-dioxin X = O ® X=S X=S® X = NH X = NH 2,3,4,5-tetrahydropyridine

[6]annulene X = O® pyryliumsalts X = N pyrimidine benzene X = S® thiiniumsalts If the multiple bonds are between two C-atoms of the ring, as, for instance, in 3,4-dihydro-2//-pyranX, = N py r i d i n e , the compounds react essentially like alkenes or alkynes. The heteroatom can also be involved in a dou- pyridine-like N - atom ble bond. In the case of X = •OSystems+, the compoundwith thes behavgreateste likpossiblee oxeniumnumber salts, iofn thnoncumulatede case of X = Sdouble+, like bonds (heteroannulenes) sulfenium salts, and in the case of X = N, like imines (azomethines). o Annulenes derive two types of heterocycles: X = 0 furan — systems of the same ring size, if CH is replaced by X • Systems with the greatest possible number of noncumulated double bonds (heteroannulenes), e.g.: X = S thiophene — systems of the next lower ring size, if HC=CH is replaced by X. X = NH pyrrole, pyrrole-like N - atom

[6]annulene X = O® pyryliumsalts X = N pyrimidine benzene X = S® thiiniumsalts [8]annulene X = cP X = N 1,3 - diazocine X = N py r i d i n e , cyclooctatetraene X = S pyridine-like N - atom X = N azocine . o

X = 0 furan X = S thiophene X = 0 oxepine X = NH pyrrole, X = S thiepine pyrrole-like N - atom X = NH azepine

[8]annulene X = cP X = N 1,3 - diazocine cyclooctatetraene X = S X = N azocine .

X = 0 oxepine X = S thiepine X = NH azepine In both cases, the resulting heterocycles are iso-�-electronic with the corresponding annulenes, i.e. the number of �-electrons in the ring is the same.

This is because in the pyrylium and thiinium salts, as well as in pyridine, pyrimidine, azocine and 1,3- diazocine, each heteroatom donates one electron pair to the conjugated system and its nonbonding electron pair does not contribute.

However, with furan, thiophene, pyrrole, oxepin, thiepin and azepine, one electron pair of the heteroatom is incorporated into the conjugated system (delocalization of the electrons).

Where nitrogen is the heteroatom, this difference can be expressed by the designation pyridine-like N-atom or pyrrole-like N-atom.

8 • Heteroaromatic systems

This includes heteroannulenes, which comply with the HÜCKEL rule, i.e. which possess (4n+2) �- electrons delocalized over the ring. The most important group of these compounds derives from [6]annulene (benzene). They are known as heteroarenes, e.g. furan, thiophene, pyrrole, pyridine, and the pyrylium and thiinium ions.

As regards stability and reactivity, they can be compared to the corresponding benzenoid compounds.

The antiaromatic systems, i.e. systems possessing 4n delocalized electrons, e.g. oxepin, azepine, thiepin, azocine, and 1,3-diazocine, as well as the corresponding annulenes, are, by contrast, much less stable and very reactive.

The classification of heterocycles as heterocycloalkanes, heterocycloalkenes, heteroannulenes and heteroaromatics allows an estimation of their stability and reactivity.

In some cases, this can also be applied to inorganic heterocycles. For instance, borazine, a colourless liquid, bp 55 °C, is classified as a heteroaromatic system.