Heterocycles. Nucleic acids, classification, structure and biological role.
Heterocyclic compounds are cyclic compounds in which one or more ring atoms are not carbon (that is, hetero atoms). Although heterocycles are known that incorporate many different elements into cyclic structures (for example, N, О, S, В, Al, Si, P, Sn, As, Cu), we shall consider only some of the more common systems in which the hetero atom is N, О, or S.
Heterocycles are conveniently grouped into two classes, nonaromatic and aromatic. The nonaromatic compounds have physical and chemical properties that are typical of the particular hetero atom. Thus, tetrahydrofuran and 1,4-dioxane are typical ethers, whereas 1,3,5-trioxane behaves as an acetal.
The aromatic heterocycles include such compounds as pyridine, where nitrogen replaces one of the СН groups in benzene, and pyrrole, in which the aromatic sextet is supplied by the four electrons of the two double bonds and the lone pair on nitrogen.
Other aromatic heterocycles contain more than one hetero atom, and still others contain fused aromatic rings. Examples which we will treat in more detail later include:
Saturated monocyclic rings are named according to ring size as 3-, -iran; 4-, -etan; 5-, -olan; and 6-, -ane. Even this system does not apply to nitrogencontaining rings and finds only limited use in common practice
The commonly used names for monocyclic rings with а single hetero atom will be discussed in the next section.
Nonaromatic Heterocycles. Names in common use of some fully saturated heterocycles containing only one hetero atom are shown below.
In naming substituted derivatives, the ring is numbered beginning with the hetero atom.
The common three-membered heterocycles are ethylene oxide (oxirane), ethylcneimine (aziridine), and ethylene sulfide (thirane).
Ethylene oxides have been discussed previously. Recall that the two most general syntheses are the oxidation of alkenes with peroxyacids, and the base-catalyzed cyclization of halohydrins.
Aziridines are most commonly prepared by related cyclization reactions. А classical method (the Wenker synthesis) consists of converting а b-amino alcohol into а b-amino hydrogen sulfate, which is cyclized by treatment with strong base.
They may also be prepared by cyclization of b-haloalkylamines and their derivatives. An example is the conversion of an alkene into an aziridine via the iodo isocyanate and iodo carbamate
One source of the saturated five-membered ring heterocycles is the reduction of the available aromatic compounds derived from furan and pyrrole.
Furan, Pyrrole, and Thiophene. The structures of these three heterocycles would suggest that they have highly reactive diene character.
The aromatic character of these heterocycles may also be expressed using resonance structures, which show that а pair of electrons from the hetero atom is delocalized around the ring.
This delocalization of the lone pair electrons away from the heteroatom can be inferred from the dipole moments of these aromatic heterocycles and their nonaromatic counterparts.
In the saturated compounds, the heteroatom is at the negative end of the dipole. In the aromatic heterocycles the dipole moment associated with the m system opposes the s moment. As а result, the net dipole moment of furan and thiophene is reduced. In pyrrole, the p moment is larger than the o moment so that the direction of the net dipole moment is actually reversed from its saturated counterpart.
Although руrrole is an amine, it is an extremely nonbasic one because the nitrogen lone pair is involved in the aromatic sextet and is thereby less available for bonding to а proton. The pKa of its conjugate acid is 0.4. In fact, this pKa corresponds to а conjugate acid in which protonation has occurred predominantly on carbon rather than on nitrogen.
Pyrrole compounds occur widely in living systems. One of the more important pyrrole compounds is the porphyrin hemin, the prosthetic group of hemoglobin and myoglobin. А number of simple alkylpyrroles have played an important role in the elucidation of the porphyrin structures. Thus, drastic reduction of hemin gives а complex mixture from which the four pyrroles, hemopyrrole, cryptopyrrole, phyllopyrrole, and opsopyrrole, have been isolated.
The function of hemoglobin in an organism is to transport oxygen; 1 g of hemoglobin absorbs 1.35 ml of oxygen at STP, corresponding to exactly one molecule of О2 per iron. The oxygen binds to the hemoglobin molecule in the vicinity of the iron, and the binding constant is proportional to the partial pressure of oxygen. In the lungs, where the partial pressure of oxygen is high, hemoglobin binds oxygen. In the tissues served by the blood stream, the oxyhemoglobin dissociates back into О, and hemoglobin, which returns to the lungs for another load. Carbon monoxide is а poison because it forms а tight complex with the iron of hemoglobin and prevents it from binding oxygen.
Synthesis. Furan, 2-furaldehyde (furfural), 2-furylmethanol, and 2-furoic acid are all inexpensive commercial items.
The ultimate source of these heterocycles is furfural, which is obtained industrially by the acid hydrolysis of the polysaccharides of oat hulls, corn cobs, or straw. These polysaccharides are built up from pentose units. Dehydration of the pentose may be formulated.
Substituted furans, pyrroles, and thiophenes may be prepared by electrophilic substitution on one of the available materials discussed or by а variety of cyclization reactions. The most general is the Paal-Клоrr synthesis, in which а 1,4-dicarbonyl compound is heated with а dehydrating agent, ammonia, or an inorganic sulfide to produce the furan, pyrrole, or thiophene, respectively.
Another general method for the synthesis of substituted pyrroles is the Knorr pyrrole synthesis, the condensation of an а-aminoketone with а p-keto ester. The method is illustrated in а synthesis of diethyl 3,5-dimethylpyrrole-2,4-dicarboxylate.
m cation structures, all atoms have octets of electrons. Nevertheless, as the sets of resonance structures show, the charge on the cation resulting from attack at the a-position is more extensively delocalized than that for the cation resulting from attack at the b-position. The following examples further demonstrate the generality of a-attack.
In the last example, note that 2-iodothiophene is the sole product of iodination, eyeu though the reaction is carried out in benzene as solvent; that is, thiophene is so much more reactive than benzene that no significant amount of iodobenzene is formed.
The position of second substitution in а monosubstituted furan, pyrrole, or lhiophene is governed by а combination о1 the directing effect of the group present and the inherent a-directing effect of the heteroatom. Substitution on 3-substituted compounds occurs exclusively at an a-position. When the substituent present is electron attracting (meta directing), reaction occurs at the nonadjacent a-position (that is, meta to the group present).
When the 3-substituent is electron donating (ortho, раrа directing), substitution occurs at the adjacent а-position (that is, ortho to the group present).
Further substitution on 2-substituted furans tends to оссш at the other a-position.
With 2-substituted pyrroles and thiophenes, attack can occur at С-4 or С-5 when the group present is meta directing, or at С-3 and С-5 when the group present is ortho, раrа directing.
When both a-positions are occupied, further substitution occurs at а b-position, the direction of attack being governed by the directing effect of the two groups present.
Azoles are five-membered ring aromatic heterocycles containing two nitrogens, one nitrogen and one oxygen, or one nitrogen and one sulfur. They may be considered as aza analogs of furan, pyrrole, and thiophene, in the same way that pyridine is an aza analog of benzene.
From а molecular orbital standpoint, the azoles are similar to the simpler aromatic heterocycles. For example, in imidazole, each carbon and nitrogen may be considered to be spa hybridized. One nitrogen makes two sp2-sp2 s bonds to carbon and one sp2-s s bond to hydrogen. The other nitrogen has its lone pair in the third spa orbital. The p molecular orbital system is made up from the рz orbitals from each ring atom. Six p electrons (one from each carbon and from one nitrogen, two from the other nitrogen) complete the aromatic shell.
Derivatives of pyridine are biological active compounds, such as nicotine amide, nicotinic acid (vitamin PP).
Quinoline and Isoquinoline are benzopyridines The orbital structures of both compounds are related to those of pyridine and naphthalene Both are weak bases, with рКa,s comparable to that of pyridine. Alkaloids based on the qtunoline and isoquinoline skeleton are widespread in the plant kingdom.
In this section, we shall take а brief look at another class of heterocycles, the diazines. The three types of diazabenzenes are
In addition to these three diazines, the bicyclic tetraaza compound, purine, is an important heterocyclic system.
These ring systems, particularly that of pyrimidine, occur commonly in natural products. The pyrimidines, cytosine, thymine, and uracil are especially important because they are components of nucleic acids, as are the purine derivatives adenine and guanine.
Alkaloids constitute а class of basic, nitrogen containing plant products that have complex structures and possess significant pharmacological properties. The name alkaloid, or "alkali-like," was first proposed by the pharmacist W. Meissner in the early nineteenth century before anything was known about the chemical structures of the compounds.
The first alkaloid isolated in а pure state was morphine, by Serturner in 1805. The compound occurs in poppies and is responsible for the physiological effect of opium.
Other members of the morphine family are the 0-methyl derivative, codeine, and the diacetyl derivative, heroin.
Nicotine is the chief alkaloid of the tobacco plant.
A most remarkable property of living cells is their ability to produce exact replicas of themselves. Furthermore, cells contain all the instructions needed for making the complete organism of which they are а part. The molecules within а cell those are responsible for these amazing capabilities are nucleic acids.
Nitrogen-containing bases. Five nitrogen-containing bases are nucleotide components. Three of them are derivatives of pyrimidine, а monocyclic base with а six-membered ring, and two are derivatives of purine, а bicyclic base with fused five- and six-membered rings.
These two parent bases and their derivatives are bases because their nitrogen atoms, which possess а nonbonding pair of electrons, can accept protons.
The three pyrimidine derivatives found in nucleotides are thymine (Т), cytosine (С), and uracil (U).
Thymine is the 5-methyl-2,4-dioxo derivative, cytosine the 4-amino-2-охо derivative, and uracil the 2,4-dioxo derivative of pyrimidine.
The two purine derivatives found in nucleotides are adenine (А) and guanine (G).
Adenine is the 6-amino derivative of purine, and guanine is the 2-amino-6-охо purine derivative.
Adenine, guanine, and cytosine are found in both DNA and RNA. Uracil is found only in RNA, and thymine usually occurs only in DNA.
. Two purine bases and three pyrimidine bases are found in the nucleotides present in nucleic acids.
Phosphate, the third component of а nucleotide, is derived from phosphoric acid (Н2РO4). Under cellular рН conditions, the phosphoric acid loses two of its hydrogen atoms to give а –2-charged hydrogen phosphate ion.
Nucleotide formation. The formation of а nucleotide from sugar, base, and phosphate can be visualized as occurring in the following manner:
Important characteristics of this combining of three molecules into one molecule (the nucleotide) are that
1. Condensation, with formation of а water molecule, occurs at two locations: between sugar and base, and between sugar and phosphate.
2. The base is always attached at the С-1’ position of the sugar. For purine bases, attachment is through N-9; for pyrimidine bases, N-1 is involved. The С-1’ carbon atom of the ribose unit is always in а β configuration, and the bond connecting the sugar and base is а β-N-glycosidic linkage.
3. The phosphate group is attached to the sugar at the С-5’ position through а phosphate – ester linkage.
There are four possible RNA nucleotides, differing in the base present (А, С, G, or U) and four possible DNA nucleotides, differing in the base present (А, С, G, or Т).
Primary nucleic acid structure is the sequence of nucleotides in the molecule. Because the sugar – phosphate backbone of а given nucleic acid does not vary, the primary structure of the nucleic acid depends only on the sequence of bases present. Further information about nucleic acid structure can be obtained by considering the detailed four-nucleotide segment of а DNA molecule.
1. Each nonterminal phosphate group of the sugar - phosphate backbone is bonded to two sugar molecules through а 3’,5’-phosphodiester linkage. There is а phosphoester bond to the 5’ carbon of one sugar unit and а phosphoester bond to the 3’ carbon of the other sugar.
2. А nucleotide chain has directionality. One end of the nucleotide chain, the 5’end, normally carries а free phosphate group attached to the 5’ carbon atom. The other end of the nucleotide chain, the 3’ end, normally has а free hydroxyl group attached to the 3’ carbon atom. By convention, the sequence of bases of а nucleic acid strand is read from the 5’ end to the 3’ end.
3. Each nonterminal phosphate group in the backbone of а nucleic acid carries а -1 charge. The parent phosphoric acid molecule from which the phosphate was derived originally had three -ОН groups. Two of these become involved in the 3’,5’-phosphodiester linkage. The remaining –ОН group is free to exhibit acidic behavior - that is, to produce an Н+ ion.
This behavior by the many phosphate groups in а nucleic acid backbone gives nucleic acids their acidic properties.
Mutations are changes in the base sequence in DNA molecules. These changes alter the genetic information that is passed on during transcription. The altered information can cause changes in amino acid sequence during protein synthesis. Sometimes, such changes have а profound effect on an organism.
Mutagens are the substances or agents that cause а change in the structure of а DNA molecule. Radiation and chemical agents are two important types of mutagens. Radiation in the form of ultraviolet light, Х rays, radioactivity, and cosmic rays, has the potential to be mutagenic. Ultraviolet light from the sun is the radiation that causes sunburn and can cause changes in the DNA of the skin cells. Sustained exposure to ultraviolet light can lead to serious problems such as skin cancer.
Chemical agents can also have mutagenic effects. Nitrous acid (НNО2) is а mutagen that causes deamination of heterocyclic nitrogen bases. For example, HNO2 can convert cytosine to uracil.
Deamination of а cytosine that was part of an mRNA codon would change the codon; for example, CGG would become UGG.
А variety of chemicals – including nitrites, nitrates, and nitrosamines – can form nitrous acid in the body. The use of nitrates and nitrites as preservatives in foods such as bologna and hot dogs is а cause of concern because of their conversion to nitrous acid in the body and possible damage to DNA.
Fortunately, the body has repair enzymes that recognize and replace altered bases. Normally, the vast majority of altered DNA bases are repaired, and mutations are avoided. Occasionally, however, the damage is not repaired, and the mutation persists.
Use of synthetic nucleic acid bases in medicine. Many hundreds of modified nucleic acid bases have been prepared in laboratories, and their effects on nucleic acid synthesis investigated. Several of them are new in clinical use as drugs for controlling, at the cellular level, cancers and other related disorders.
The theory behind the use of these modified bases involves their masquerading as legitimate nucleic acid building blocks. The enzymes associated with the DNA replication process incorporate the modified bases into growing nucleic acid chains. The presence of these "pseudonucleotides" in the chain stops further growth of the chain, thus interfering with nucleic acid synthesis.
Examples of drugs now in use include 5-fluorouracil, which is employed against а variety of cancers, especially those of the breast and digestive tract, and б-mercaptopurine, which is used in the treatment of leukemia.
The rapidly dividing cells that are characteristic of cancer require large quantities of DNA. Anticancer drugs based on modified nucleic acid bases block DNA synthesis and therefore block the increase in the number of cancer cells. Cancer cells are generally affected to а greater extent than normal cells because of the rapid growth factor. Eventually, the normal cells are affected to such а degree that use of the drugs must be discontinued. 5-fluorouracil inhibits the formation of thymine-containing nucleotides required for DNA synthesis. 6-mercaptopurine, which substitutes for adenine, inhibits the synthesis of nucleotides that incorporate adenine and guanine.
Biologically Important free nuclkeotides: Many important nucleotides which are components of the nucleic acid are also found in the tissues. Тheу have important special functions which have been discussed at appropriate places. Here the structure of some of these compounds is discussed.
Adenine derivatives: When а second phosphoric acid residue is attached to the phosphoric acid residue of adenosine 5-mono-phosphate (AMP), adenosine diphosphate (ADP) is obtained, which in the same wav may add on а third phosphate group to yield adenosine triphospbate (ATP). In ATP, the phosphate group nearest the ribose is termed as the a-phosphate group while the other phosphates are labelled as b and g.
Adenosine diphosphate and adenosine triphosphate [(ATP) are involved in oxidative phosphorylation.
In the cell, the conversion of ADP to ATP is used to store energy. This energy can become readily available by the conversion of ATP to ADP. This energy producing system is a cyclic process in the cell.
Moreover, ATP is one of the most important compounds in the cell since its two terminal phosphate groups are linked by the high energy phosphate bonds, i.е. it has two energy-rich bonds. It has а high potential for group transfers. Depending on the nature of the bond of the ATP molecule which reacts, it can transfer following four different types of groups.
(а) Transfer of orthophosphate group with the release of ADP.
(b) Transfer of the pyrophosphate group with the release of AMP.
(c) Transfer of adenosyl monophosphate group with the release of pyrophosphate (an activated compound).
(d) Transfer of adenosyl group with the release of orthophosphate as well as pyrophosphate.
Of the above four reactions, reaction “а” is the most common. In case the orthophosphate residue is transferred to water, hydrolysis results. Enzymes catalyzing the reaction are known as adenosine triphosphatases (ATPases). Reaction “b” (transference of а pyrophosphate group) occurs rarely, one example is the conversion of ribose 5-phosphate to 5-phosphoribose -1-pyro-phosphate (PRPP). The reaction “'с”(transference of adenosine monophosphate) is again quite common. The reaction “d” (transfer of the adenosyl residue) plays а part in the formation of the active methyl groups.
It is important to note that ATP is not the only reactive triphosphate; other purine or pyrimidine bases may take the place of adenine in the molecule. The corresponding triphosphates replace ATP in several metabolic reactions. In general, by analogy with AMP, ADP and ATP the nucleosides guanosine, uridine, cytidine and inosine form GMP, GDP, GTP; UMP, UDP, UTP; CMP, CDP, СТР; IMP, IDP and ITP.
In addition to ATP, there are several other free nucleotides, some with vitamins in their structure, which act as coenzymes in metabolic reactions.
1. Andrew Streltwieser, Jr. Clayton H. Hcathcocr. Introduction to
Organic Chemistry. -
2. David Gutsche C., Baniel J. Pasto.
Fundamentals of Organic Chemistry. -
3. Lewis D.E. Organic chemistry. A modern perspective. – Copyright, 1996. 1138 p.