Heterocycles

The largest Class of Compounds in Chemistry

Molecules in which the atoms form a ring structure are called cyclic. If all atoms happen to be carbon atoms, we speak of carbocyclic compounds. A heterocycle contains at least two different types of atoms. Mixed rings without any carbon atoms are inorganic heterocycles, rings with one or more carbon atom(s) are organic heterocycle. The non-carbon atoms are the heteroatoms. Over half of all known chemical compounds incorporate at least one heterocyclic system, which makes them the largest class of compounds in (organic) chemistry. Although all elements could be heteroatoms, the most abundant and important element in organic heterocycles is nitrogen (N), followed by oxygen (O) and sulfur (S). Of course, a three-member ring is the smallest. However, there is no upper limit to the number of atoms allowed in the ring (for example Cyclohexadecane).

   Cyclohexadecane-Structure
  Cyclohexadecane

As in carbocycles, saturated, unsaturated, and aromatic systems are possible. Saturated heterocycles do not chemically differ much from their aliphatic counterparts. Lactones, lactames as well as tetrahydrofuran, do have the same chemical properties as esters, amides and ethers. Fully unsaturated heterocycles following the Hückel rules are heteroaromates (for example Pyridine). They comprise the largest and most important subgroup of heterocycles. Usually non-substituted aromates are very inert due to their low state of energy. However, the incorporation of a heteroatom can have a substantial influence on the reactivity of the resulting system. Furan, the heterocyclic analogue of benzene, can undergo the Diels-Alder cycloaddition reaction. Depending on the p-electron density in the system, heterocycles can be considered either p-electron deficient or p-electron excessive, favoring nucleophilic or electrophilic substitution reactions, respectively.

     Pyridine
    Pyridine

Heterocycles in nature

Besides the vast distribution of heterocycles in natural compounds, they are also the major components of biological molecules such as DNA. DNA is without a doubt the most important macromolecule of life. Nucleotides, the building blocks of our genes are derivatives of pyrimidine and purine ring structures. Chlorophyll and heme, the oxygen carriers in plants and animals respectively are derivatives of large porphyrin rings. Three out of twenty natural amino acids are heterocyclic, as are many essential vitamins (i.e. vitamin B series and vitamin C).

      Pyrimidine                                 Vitamine-c
    Pyrimidine                                       Vitamin C

Applications of Heterocycles

The range of application of heterocycles is very wide. They are predominant among all types of pharmaceuticals, agrochemicals and veterinary products. This comes as no surprise, since the most potent natural compounds, the alkaloids, are heterocyles. Manipulations of heterocyclic compounds are easy to perform, very subtle, and nevertheless have a huge impact on their reactivity. This is why heterocycles are so widely used. Variations can be little shifts in acidity/basicity, polarity, or susceptibility to nucleophilic or electrophilic attacks. Unfortunately, most of the naturally active compounds are only available in very small quantities and are hard to isolate. Chemists have been busy finding ways to perform total synthesis in the laboratories. A successful synthesis leads to higher yields of the desired substance than extracting them from natural sources and makes research on the substance possible. Manufacturing and manipulation of active heterocyclic compounds is of great value to chemists because it enables them to customize pharmaceuticals for many applications. Only few natural heterocyclic compounds in their native form are suitable for direct use. Normally these compounds are too rare, too instable, and too toxic. Serotonin, an indole derivative, for example, once fully synthesized and investigated in the lab shows a wide range of pharmacological applications. However, in its native form, serotonin ligand-receptor interaction is short; it metabolizes too quickly than to be of practical used. Many closely related substances, have been synthesized since, like Sumatripan, for treatment of migraine and Ondansetron, for suppression of nausea and vomiting during cancer chemotherapy. Serotonin is structurally closely related to psychedelic substances like psilocybin and bufotenin [1,2,4]. Nucleoside (sugar-linked nucleotides) analogues are found in drugs, which interfere with DNA replication. Zidovudine (AZT) and Acylovit (ACV) are two examples which are used to treat viral infections like AIDS.

          Zidovudnine
        Zidovudnine (AZT)


In organic synthesis, heterocycles make helpful intermediates, since they are usually stable enough to pass through several reaction steps unaltered. In the end, they may be cleaved or further modified.

Nomenclature

The international rules of the IUPAC allow two nomenclatures, Hantzsch–Widman and replacement nomenclature. Hantzsch–Widman nomenclature is recommended for three to ten member rings. The prefix of the name of a heterocyclic compound refers to the parent ring with its hydrogen constituents and the type of the heteroatom it is. The suffix in the heterocyclic compounds' name refers to its size. The numbering of the atoms starts at the heteroatom while keeping the number of the heteroatom(s) low. When there are different heteroatoms in one molecule, numbering begins with the element of highest priority according to the periodic system. In partially saturated systems, the position is “hydrogen indicated”, a number together with the prefix H as part of the systematic name.

Table: Prefixes indicating heteroatom in systematic nomenclature

Element Prefix
O oxa
S thia
Se selena
N aza
P phospha
Si sila
B bora


Table: Suffixes indicating size in systematic nomenclature

Suffixes    
Size unsaturated saturated
3 irene irane
4 ete etane
5 ole olane
6 (O, S, Se) ine ane
6 (N, Si) ine inane
6 (P, B) inine inane
7 epine epane
8 ocine ocane
9 onine onane
10 ecine ecane



Some examples for the nomenclature

    Silolane                  Phoshinine                     Borinane                  Thiepine
  Silolane             Phoshinine               Borinane               Thiepine

The replacement nomenclature refers to the carbocyclic analogue, with heteroatom specific prefix (and position) written in front. I.e. Silacyclopenta-1,2-dien (with cyclopentadien as analogue). However, there are many trivial names permitted and found in textbooks and older publications, like pyrrole (azole), furan (oxole) or pyrimidine (1,3-diazine). Heterocyclic chemistry reaches back to the old days of natural compound chemistry and the names given to them at that time are still commonly used today [1,2,3,4].

Alkaloids

Alkaloid is a term for naturally occurring compounds with one or more heterocyclic nitrogen atoms. Usually these compounds have very specific pharmacological activities. However, except for their natural occurrence and their basicity, alkaloids have no general characteristics and it is impossible to define this class of chemical compounds clearly. The variation of their structure is incredibly wide making them an exceptionally large and diverse group within all known organic compounds. Classification is therefore rather arbitrary. Relation to their natural source is one way to classify alkaloids. We speak of Amaryllidaceen-alkaloids, Curare-alkaloids, Coca-alkaloids or Tobacco-alkaloids, just to mention a few. Another approach to classification is grouping alkaloids according to common basic structures like chinoline-alkaloids, indole-alkaloids, and morphine-alkaloids. Common spectroscopic and/or spectrometric properties of alkaloids are an additional classification option. Often alkaloids are neurotoxins and hence are found in low quantities in animals, except for the secreted toxins on the skin of frogs and toads. Most alkaloids are found in higher plants like Apocynaceae, Papaveraceae and Solanaceae; they are less common in lower plants like ferns, mosses, and algae. Plants unusually contain more than one type of alkaloid. Isolation of alkaloids from plants depends on their solubility in organic solvents. Hydrophobic alkaloids are soluble in solvents such as chloroform and ether, while hydrophilic alkaloids are soluble in ethanol or water. Synthesis of alkaloids is by no means trivial. In fact, their synthesis can be very elaborate and difficult since most of them possess one or more chiral center. Their range of application, although mostly pharmaceutical, is quite wide. Some alkaloids are extraordinarily powerful drugs, like heroine or dangerous poisons, like strychnine and curare. However, usually we are exposed to far less harmful alkaloids on a daily basis while sipping our coffee and tea! [4,5]

Amaryllidaceen-alkaloids:

  Epipretazettine
  (+-)Epipretazettine


Curare-alkaloids:

 Gallamine-Triethiodide
      Gallamine Triethiodide


Coca-alkaloids:

 Cocain                                  Benzyl-Pseudotropine
        Cocain                                                 Benzyl-Pseudotropine


Tobacco-alkaloids:

 Nicotine                                                N-Nitrosoanabasine
       Nicotine                                                 N'-nitrosoanabasine


Chinoline-alkaloids:

 Dopamine                                      Reticuline
      Dopamine                                                    Reticuline 


Indole-alkaloids:

 Tryptamine                                    Serotonine
   Tryptamine                                                      Serotonine


Morphine-alkaloids:

  Morphine                                    Codeine
      Morphine                                                         Codeine



Selection of Biosynth's Products
Cat.No. - Product Name
B-1000 - 6-Benzyladenine horticultural grade
D-7200 - 2,2'-Dipyridyl analytical grade
D-7250 - 2,2'-Dipyridyl
F-6300 - 5-Fluoroorotic acid
K-4000 - Kinetin
T-6940 - 2,3,5-Triphenyltetrazolium chloride reagent-grade


Literature
[1] T.L. Gilchrist, Heterocyclic Chemistry, second Edition, Longman Scientific & Technical, UK, 1993
[2] J.A. Joule, K. Mills, Heterocyclic Chemistry, fourth Edition, Blackwell Publishing, 2000
[3] K. Krohn, U. Wolf, Kurze Einführung in die Chemie der Heterocyclen, Teubner Taschenbücher, 1994
[4] Römpp Chemie Lexikon, neunte Auflage, Thieme Verlag, 1991
[5] M. Hesse, Alkaloide, Wiley-VCH, 2000


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