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  • Chapter-I

    Brief introduction of heterocycles

  • 1

    CHAPTER - I

    Brief introduction of heterocycles

    1.1 Introduction of heterocyclic chemistry

    The chemistry of heterocyclic compounds is of great interest both from the

    theoretical as well as practical standpoint. Heterocyclic compounds occur

    widely in nature and in a variety of non-naturally occurring material.

    Moreover, they are of immense importance not only both biologically and

    industrially but also to the functioning of developed society as well. It has

    become one of the largest areas of the research in Organic Chemistry. Their

    participation in a wide range of areas cannot be underestimated. A significant

    part of large number of compounds such as alkaloids, antibiotics, essential

    amino acids, vitamins, haemoglobin, the hormones, synthetic drugs and dyes

    composed of heterocyclic ring systems and have significant importance for

    human and animal health. Therefore, researchers are on continuous pursuit to

    design and produce better pharmaceuticals, pesticides, and insecticides. Other

    important practical applications of heterocycles can also be cited, for instance,

    additives and modifiers in wide variety of industries including cosmetics,

    reprography, information storage, plastics, solvents, antioxidants. Finally as the

    applied science, Heterocyclic Chemistry is an inexhaustible resource of novel

    compounds. It is therefore easy to understand why both the developments of

    new methods and the strategic deployment of known methods for the synthesis

    of complex heterocyclic compounds continue to drive the field of Synthetic

    Organic Chemistry.

    Organic compounds have a variety of structures. These structures can be

    acyclic or cyclic. The cyclic systems containing only carbon atoms are called

    carbocyclic and the cyclic systems containing carbons and at least one other

    element are called heterocyclic. Though the number of heteroatoms are known

    to be part of the heterocyclic rings, the most common are nitrogen, oxygen or

    sulphur. A heterocyclic ring may contain one or more heteroatom’s which may

    or may not be same. Also the rings may be saturated or unsaturated. Nearly half

  • 2

    of the known organic compounds contain at least one heterocyclic ring. Many

    heterocyclic compounds occur naturally and are actively involved in biology

    e.g., nucleic acids (purine and pyrimidine bases), vitamins (Thiamine B1,

    Riboflavin B2, Nicotinamide B3, Pyridoxol B6 and Ascorbic acid), heme and

    chlorophyll, penicillins, cephalosporins, macrolides etc. The study of

    heterocycles is a vast and expanding area of chemistry because of their

    applications in medicine, agriculture, photodiodes and other fields.

    Heterocyclic compounds are classified as alicyclic and aromatic

    heterocycles. The alicyclic heterocycles are the cyclic analogues of amines,

    ethers and thioethers and their properties are influenced by the ring strain. The

    three and four membered alicyclic heterocyclic rings are more strained and

    reactive compared to five and six membered rings. The common alicyclic

    heterocyclic compounds are aziridine (I), oxirane (II), thirane (III), azetidine

    (IV), oxetane (V), thietane (VI), pyrrolidine (VII), tetrahydrofuran (VIII),

    tetrahydrothiophene (IX) and piperidine (X).

    The heterocycles which show aromatic behavior as in benzene are called

    the aromatic heterocyclic compounds. These compounds follow the Hückel’s

    rule which states that cyclic conjugated and planar systems having (4n+2) π

    electrons are aromatic. Some simple aromatic heterocyclic compounds are

    pyrrole (XI), furan (XII), thiophene (XIII), imidazole (XIV), pyrazole (XV),

    oxazole (XVI), thiazole (XVII) and pyridine (XVIII).

  • 3

    1.2 Medicinal Chemistry

    Medicinal chemistry is of great academic and intellectual interest. The

    elucidation of the arachidonic acid cascade is one of the most fascinating bits

    of chemistry of our generation. The study of the chemistry of the brain is one of

    the great frontiers of science. Unlike astrophysics and evolutionary theory,

    however, medicinal chemistry is an applied science. It is lavishly funded not

    because of its philosophical centrality, but because it provides the hope that

    human disease can be cured or alleviated. Its paymasters intend that mankind,

    or at least those sections of it with access to advanced medical care, live longer

    and more comfortably. Its practitioners are judged by this criterion. There are

    few Nobel prizes for those who discover, say, the biochemical origins of

    rodent-specific dermatitis. As the test of success is pragmatic, serendipity plays

    an important role in medicinal chemistry. The discoverers of sulfonamides

    thought that dye stuffs might prove efficacious because they bonded

    specifically to certain tissues, as in Ehrlich’s classic experiment. In the end,

    Prontosil worked not because it was a dye but because it cleaved in the gut to

    p-aminobenzenesulfonic acid. Fleming, whose chance discovery of penicillin

    would have been meaningless, had not Florey and Chain solved the problem of

    its purification and Coghill and his co-workers (who did not get Nobel prizes)

    solved the problem of its large-scale production. Medicines are thus judged by

    their results. A successful drug can be manufactured reasonably easily, has

    negligible side effects, is widely prescribed, makes a lot of money and is

    perceived as making a major contribution to health care.

  • 4

    1.3 Overview of Nitrogen and Sulfur heterocycles

    For more than a century, heterocycles have constituted one the largest

    areas of research in organic chemistry. They have contributed to the

    development of society from a biological and industrial point of view as well as

    to the understanding of life processes and to the efforts to improve the quality

    of life. Heterocycles play an important role in biochemical processes because

    the side groups of the most typical and essential constituents of living cells,

    DNA and RNA, are based on aromatic heterocycles. [1]

    Among the

    approximately 20 million chemical compounds identified by the end of the

    second millennium, more than two-thirds are fully or partially aromatic, and

    approximately half are heterocyclic. The presence of heterocycles in all kinds

    of organic compounds of interest in biology, pharmacology, optics, electronics,

    material sciences, and so on is very well known.

    Among them, sulfur and nitrogen-containing heterocyclic compounds

    have maintained their interest of researchers through decades of historical

    development of organic synthesis. Nitrogen-containing compounds are

    ubiquitous in nature and many of them are biologically active. The grounds of

    this interest were their biological activities and unique structures that led to

    several applications in different areas of pharmaceutical and agrochemical

    research or, more recently, in material sciences. [2]

    The family of sulfur–nitrogen

    heterocycles includes highly stable aromatic compounds that display

    physicochemical properties with relevance in the design of new materials,

    especially those relating to molecular conductors and magnets. During the past

    few decades, interest has been rapidly growing in gaining insight into the

    properties and transformations of these heterocycles. The interesting

    characteristics found in many of them have led to the development of modern

    synthetic methods that are the subject of this special issue. Nitrogen and sulfur

    organic aromatic heterocycles are formally derived from aromatic carbon

    cycles with a heteroatom taking the place of a ring carbon atom or a complete -

    CH=CH- group. The presence of heteroatoms results in significant changes in

    the cyclic molecular structure due to the availability of unshared pairs of

  • 5

    electrons and the difference in electronegativity between hetero-atoms and

    carbon. Therefore, nitrogen and sulfur heterocyclic compounds display

    physicochemical characteristics and reactivity quite different from the parent

    aromatic hydrocarbons. On the other hand, the presence of many nitrogen and

    sulfur atoms in a ring is normally associated with instability and difficulties in

    the synthesis but, in fact, surprisingly stable heterocycles with unusual

    properties can be frequently obtained from simple organic substrates and the

    appropriate inorganic reagent. Carbon atoms confer high stability to such rings,

    according to the aromaticity and anti-aromaticity rules. The nitrogen-sulfur

    core gives unusual properties to the compounds, in accordance with their

    electron rich p-excessive nature. The physicochemical properties of this family

    of compounds have relevance in the design of new materials, especially

    concerning organic conductors.

    In contrast with the number and variety of such heterocycles, the

    numbers of synthetic methods to a

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