Materials preparation to the practical classes
for the students of pharmaceutical faculty
LESSON № 20
Theme 27. Condensed azines. Quinoline. Isoquinoline. Acridine.
Theme 28. Diazines.
Condensed azines
Coumarin is a chemical compound (benzopyrone); a toxin found in many plants, notably in high concentration in the tonka bean, vanilla grass, woodruff, mullein, and bison grass. It has a sweet scent, readily recognised as the scent of newly-mown hay, and has been used in perfumes since 1882. It has clinical medical value as the precursor for several anticoagulants, notably warfarin, and is used as a gain medium in some dye lasers. The biosynthesis of coumarin in plants is via hydroxylation, glycolysis and cyclization of cinnamic acid. Coumarin can be prepared in a laboratory in a Perkin reaction between salicylaldehyde and acetic anhydride.
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Chemical properties
disodium salt of coumarin acid
On the benzol ring of coumarin enters into the reactions of electrophilic substitution to position 6.
6- coumarin sulphatic acid
Chromone (or 1,4-benzopyrone) is a derivative of benzopyran with a substituted keto group on the pyran ring. Derivatives of chromone are collectively known as chromones. Most, though not all, chromones are also flavonoids.
Chromone
- Cromoglicate is used as a mast cell stabilizer in allergic rhinitis, asthma and allergic conjunctivitis.
- Khellin is a naturally occurring chromone extracted from the medicinal plant Amni visnaga long used in
Egypt and theEastern Mediterranean countries for the treatment of respiratory disorders. It however has many side effects making it unsuitable. - Roger Altounyan studied chromones and eventually found disodium cromoglycate. This drug was found to inhibit antigen challenge as well as stress induced symptoms. Comparatively free of side-effects, unfortunately the short half-life limited its value.
- Nedocromil sodium was found to have a somewhat longer half-life.
Flavones are mainly found in cereals and herbs. In the West, the estimated daily intake of flavones is in the range 20-50 mg per day. In recent years, scientific and public interest in flavones has grown enormously due to their putative beneficial effects against atherosclerosis, osteoporosis, diabetes mellitus and certain cancers. Flavones intake in the form of dietary supplements and plant extracts has been steadily increasing.
Derivatives of chromone:
Isoflavone differs from flavone (2-phenyl-4H-1-benzopyr-4-one) in location of the phenyl group. Isoflavones are produced via a branch of the general phenylpropanoid pathway that produces flavonoid compounds in higher plants. Soybeans are the most common source of isoflavones in human food; the major isoflavones in soybean are genistein and daidzein. The phenylpropanoid pathway begins from the amino acid phenylalanine, and an intermediate of the pathway, naringenin, is sequentially converted in to the isoflavone genistein by two legume-specific enzymes, isoflavone synthase, and a dehydratase. Similarly, another intermediate naringenin chalcone is converted to the isoflavone daidzein by sequential action of three legume-specific enzymes: chalcone reductase, type II chalcone isomerase, and isoflavone synthase. Plants use isoflavones and their derivatives as phytoalexin compounds to ward off disease-causing pathogenic fungi and other microbes. In addition, soybean uses isoflavones to stimulate soil-microbe rhizobium to form nitrogen-fixing root nodules.
6. Receipt of quinoline and his derivatives. Synthesis of Skraupa and synthesis of Debner—Miller. Physical and chemical properties of quinoline.
The most important fused pyridine-contining heterocyclic systems are quinoline, isoquinoline and acridine:
quinoline isoquinoline acridine
Quinoline, also known as 1-azanaphthalene, 1-benzazine, or benzopyridine, is a heterocyclic aromatic organic compound. It has the formula C9H7N and is a colourless hygroscopic liquid with a strong odour. Aged samples, if exposed to light, become yellow and later brown. Quinoline is only slightly soluble in cold water but dissolves readily in hot water and most organic solvents. Quinoline is mainly used as a building block to other specialty chemicals. Approximately 4 tonnes are produced annually according to a report published in 2005. Its principal use is as a precursor to 8-hydroxyquinoline, which is a versatile chelating agent and precursor to pesticides. Its 2- and 4-methyl derivatives are precursors to cyanine dyes. Oxidation of quinonline affords quinolinic acid (pyridine-2,3-dicarboxylic acid), a precursor to the herbicide sold under the name “Assert”.
Quinoline (benzo[b]pyridine) is a fused heterocyclic system consisting of a benzene ring fused with pyridine cycle. It can be also considered as the heterocyclic analogue of naphthalene (1-azanaphthalene).
Positions in the pyridine cycle of quinoline are designated with Greek letters a- (2-), p- (3-), y-(4-). Qiunoline is a colourless liquid with an unpleasant odour. It is miscible with water, ethanol, ether; it may be distilled by steam distillation.
Methods of preparation
Quinoline and its methylated derivatives were isolated by distillation of coal tar.
The most important methods of quinoline and its derivatives preparation are the Skraup and the Doebner—Miller reactions.
In the archetypal Skraup, aniline is heated with concentrated H2S04, glycerol, and an oxidizing agent such as nitrobenzene to yield quinoline.
The Skraup synthesis is a chemical reaction used to synthesize quinolines. It is named after the Czech chemist Zdenko Hans Skraup (1850-1910). In the archetypal Skraup, aniline is heated with sulphuric acid, glycerol, and an oxidizing agent, like nitrobenzene to yield quinoline. The Skraup synthesis place is taken in three stages.
On the first stage glycerin is under the action of сoncentrated H2S04 to dehydration with formation of akrolein:
On the third stage of reaction of 1,2-dihydroquinoline oxidizes nitrobenzol in to quinoline:
Synthesis of Debner—Miller.
The Doebner—Miller synthesis. This reaction was discovered as a modifuication of the Scraup synthesis in 1881.
The Doebner— Miller synthesis is a good method for synthesis of alkyl substituted quinolines with the substituent in the pyridine ring.
As the starting materials for this method aromatic amine together with an aldehyde, which may undergo crotonic condensation are used. The reaction is catalyzed by Lewis acids such as zinc (II) chloride, tin tetrachloride, hydrochloric or other mineral acid.
For 2-methylquinoline synthesis aniline and acetaldehyde are used as the starting compounds.
At the first step a,β-unsaturated carbonyl compound is prepared in situ from two aldehyde molecules via crotonic condensation.
Next crotonic aldehyde reacts with primary aromatic amine — aniline. Azomethines C6H5—N=CH—R, formed in the course of the reaction are oxidizers.
Chemical properties:
Quinoline is an aromatic compound, it has a planar molecule with aromatic ten-electrons π-system.
Chemical properties of quinoline are similar to the properties of pyridine. The most typical reactions for quinoline are:
· heteroatom reactions;
· electrophilic and nucleophilic substitution reactions;
· oxidation and reduction.
1. Heteroatom reactions.
As in pyridine, it is the nitrogen in quinoline, which undergoes protonation, alkylation, acylation, etc. Quinoline is a weaker base than pyridine. (pKBH+ of quinoline in H20 is 4.94, pKBH+ of pyridine:
2. Electrophilic and nucleophilic substitution reactions.
Electrophilic substitution reactions occur on the ring C-atoms, mainly on those of the more activated benzene moiety. Nucleophilic substitution of quinoline occurs in the electron-deficient pyridine ring, as a rule in the position 2 or 4.
Electrophilic substitution reactions occur in positions 5 and 8 of quinoline.
Treatment of quinoline with nitrating mixture results in 5- and 8-nitroquinolines. Sulphonation of quinoline produces different products depending on the reaction temperature. At 220 °C quinoline-8-sulphonic acid is formed predominantly; at 300 °C, quinoline-6-sulphonic acid is the sole product. When heating to 300 °C quinoline-8-sulphonic acid is converted into quinoline-6-sulphonic, which is the thermodynamically favoured sulphonation product.
Nucleophilic substitution proceeds faster in quinoline than in pyridine. Nucleophilic substitution of quinoline occurs in the heterocyclic ring, as a rule in the position 2.
3. Oxidation and reduction reactions.
The pyrimidine ring is hydrogenated prior to the benzene ring of quinoline. The product of reduction depends much upon the reaction conditions.
The alkaline permanganate solution causes oxidative cleavage of the benzene ring in quinoline to give quinolinic acid (pyridine-2,3– dicarboxylic acid). The reaction of quinoline with peroxycarboxylic acids leads to its N-oxide.
Quinoline moiety is an important part of many alkaloids and drugs.
Derivatives of quinoline
8-Hydroxyquinoline is an organic compound with the formula C9H7NO. It is a derivative of the heterocycle quinoline by placement of an OH group on carboumber 8.
8-Hydroxyquinoline is a colourless crystalline substance; (melting point is 75-76 °C) with the specific odour, which is soluble in water, ester, and benzene. It is obtained from o-aminophenol, glycerol, and concentrated sulphuric acid (the Skraup synthesis). It may also be prepared by alloying of quinoline-8-sulphonic acid with sodium hydroxide.
This colorless compound is widely used commercially, although under a variety of names. It is usually prepared from quinoline-8-sulfonic acid and from a Skraup synthesis from 2-aminophenol.
8-Hydroxyquinoline is a monoprotic bidentate chelating agent. Related ligands are the Schiff bases derived from salicylaldehyde, such as salicylaldoxime and salen. The roots of the invasive plant Centaurea diffusa release 8-hydroxyquinoline, which has a negative effect on plants that have not co-evolved with it. The complexes as well as the heterocycle itself exhibit antiseptic, disinfectant, and pesticide properties. Its solution in alcohol are used as liquid bandages. It once was of interest as an anti-cancer drug.
8-Hydroxyquinoline is a monobasic bidentate chelating agent, which forms insoluble complexes with metal cations (Mg2+, Al3+, Zn2+, etc.). Therefore, it is used as an analytical reagent.
Chelating properties of 8-hydroxyquinoline find their application in medicine.
The most of its derivatives, such as chinosol, nitroxoline, enterosep– tol, as well as the heterocycle itself exhibit antiseptic, disinfectant, and antifungal properties.
7. Receipt of isoquinoline. Synthesis of Bischler-Napieralski. Physical and chemical properties of isoquinoline.
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Isoquinoline, also known as benzo[c]pyridine or 2-benzanine, is a heterocyclic aromatic organic compound. It is a structural isomer of quinoline. Isoquinoline and quinoline are benzopyridines, which are composed of a benzene ring fused to a pyridine ring. Positions of isoquinoline are numbered similarly to naphthalene.
In a broader sense, the term isoquinoline is used to make reference to isoquinoline derivatives. 1-Benzylisoquinoline is the structural backbone iaturally occurring alkaloids including papaverine and morphine. The isoquinoline ring in these natural compound derives from the aromatic amino acid tyrosine.
Isoquinoline is a crystalline substance with a quinoline-like odour; its melting point is 24.6 °C. It is soluble in water and most of organic solvents.
Impure samples can appear brownish, as is typical for nitrogen heterocycles. It crystallizes platelets that have a low solubility in water but dissolve well in ethanol, acetone, diethyl ether, carbon disulfide, and other common organic solvents. It is also soluble in dilute acids as the protonated derivative.
Preparation.
Isoqinoline is a component of the quinoline fraction of coal tar (1 %).
The laboratory method for isoquinoline and its derivatives synthesis is the Bischler-Napieralski reaction.
- In the Bischler-Napieralski reaction an β–phenylethylamine is acylated and cyclodehydrated by a Lewis acid, such as phosphoryl chloride or phosphorus pentoxide. The resulting 1-substituted-3,4-dihydroisoquinoline can then be dehydrogenated using palladium. The following Bischler-Napieralski reaction produces papaverine.
The interaction of p–phenylethylamine with carboxylic acid chlorides results in N–acyl–p–phenylethylamines, which further undergo cyclode– hydration with POCl3, P205 or polyphosphoric acid to form 3,4–dihy–droisoquinolines. The 3,4-dihydroisoquinolines can be transformed to isoquinolines by catalytic dehydrogenation.
Chemical properties
The reactions of isoquinoline are closely parallel to those of quinoline. Isoquinoline reacts with strong mineral acids to form salts. Isoquinoline is a stronger base than quinoline (pKBH+ of isoquinoline is 5.14; pKBH+ of quinoline is 4.94). Alkylation and acyla– tion occur on nitrogen.
1. Reactions of electrophilic and nucleophilic substitution.
Similarly to quinoline electrophilic substitution reactions occur mainly in the 5- or 8-position of isoquinoline.
Nucleophilic reactions take place on the heterocyclic ring, preferably in the 1-position.
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Reactions of reduction.
Reduction of isoquinoline is more complicated than those for quinoline.
Reactions of oxidation.
Oxidation of isoquinoline with alkaline permanganate solution yields a mixture of phthalic acid and pyridine-3,4-dicarboxylic acid.
Similarly to quinoline oxidation of isoquinoline with peroxy acids results in isoquinoline N-oxide.
Isoquinoline is the core structure of naturally occurring alkaloids, including morphine, papaverine and narcotine.
8. Structure, nomenclature, methods of getting and physical and chemical properties of acridine.
Acridine (dibenzo[b,e pyridine) is a dibenzannulated product derived from pyridine.
Acridine is an exception to systematic numbering- It is numbered in such way that the nitrogen atom has the highest number — 10.
Acridine is a pale-yellow cristallyne substance with a specific odour; its melting point is 111 °C on sublimation. Acridine is poorly soluble in water, but it is readily soluble in most of organic solvents. Acridine is characterized by its irritating action on the skin and mucous tissue. The name acridine is derived from Latin word “acer” — sharp.
Acridine was first isolated in 1871 by Carl Gräbe and Heinrich Caro. Acridine occurs naturally in coal tar. It is separated from coal tar by extracting with dilute sulfuric acid; addition of potassium dichromate to this solution precipitates acridine bichromate. The bichromate is decomposed using ammonia. Many synthetic processes are known for the production of acridine and its derivatives. A. Bernthsen condensed diphenylamine with carboxylic acids, in the presence of zinc chloride in the Bernthsen acridine synthesis. With formic acid as the carboxylic acid the reaction yields acridine it self, and with the higher homologues the derivatives substituted at the meso carbon atom are generated. Other older methods for the organic synthesis of acridines include condensing diphenylamine with chloroform in the presence of aluminium chloride, by passing the vapours of orthoaminodiphenylmethane over heated litharge, by heating salicylic aldehyde with aniline and zinc chloride to
Methods of preparation.
Acridine occurs naturally in coal tar. Acridine is prepared synthetically by cyclocondensation methods more often.
A general method for acridine synthesis is the cyclisation of N–phenylanthranilic acid or 2-(phenylamino)benzoic acid with phosphoric acid. A classic method for the synthesis of acridones is the Lehmstedt-Tanasescu reaction.
Acridine and its homologues are stable compounds of weakly basic character.It also shares properties with quinoline which is the single fused homologue. Acridine crystallizes in needles which melt at
1. Condensation of diphenylamine with carboxylic acids.
Acridine is prepared by the Bernthsen method. Diphenylamine reacts with carboxylic acids in the presence of ZnCl2 as a catalyst.
2. Cyclization of N-phenylanthranilic acid by the Magidson-Grigorowski reaction:
The chlorine atom in the molecule of 9-chloroacridine readily undergoes nucleophilic substitution, therefore, it is widely used as an intermediate for synthesis of 9-substituted acridines.
Chemical properties:
Acridine combines readily with alkyliodides to form alkyl acridinium iodides, which are readily transformed by the action of alkaline potassium ferricyanide to N-alkyl acridones. On oxidation with potassium permanganate it yields acridinic acid C9H5N(COOH)2 or quinoline-1,2-dicarboxylic acid. Acridine is easily oxidized by peroxymonosulfuric acid to the acridine amine oxide. The carbon 9-position of acridine is activated for addition reactions. The compound is reduced to the 9,10-dehydroacridine and reaction with potassium cyanide gives the 9-cyano-9,10-dehydro derivative. Numerous derivatives of acridine are known and may be prepared by methods analogous to those used for the formation of the parent base. 9-Phenylacridine is the parent base of chrysaniline or 3,6-diamino-9-phenylacridine, which is the chief constituent of the dyestuff phosphine (not to be confused with phosphine gas), a by-product in the manufacture of rosaniline. Chrysaniline forms red-coloured salts, which dye silk and wool a fine yellow; and the solutions of the salts are characterized by their fine yellowish-green fluorescence. Chrysaniline was synthesized by O. Fischer and G. Koerner by condensing ortho-nitrobenzaldehyde with aniline, the resulting ortho-nitro-para-diamino-triphenylmethane being reduced to the corresponding orthoamino compound, which on oxidation yields chrysaniline.
1. Reactions of heteroatom.
Acridine is a weak base. It is weaker than pyridine and quinoline.
Similarly to pyridine acridine forms acridinium salts with acids. It is also N-oxidized by peroxycarboxylic acid.
2. Reactions of electrophilic and nucleophilic substitutions .
Acridine readily reacts with nucleophiles. The chichibabin amination with NaNH2 in liquid ammonia leads to 9-aminoacridine.
Acridine reactions with electrophiles are complicated and occur at different positions.
3. Reactions of oxidization.
Acridine is oxidation resistant. However, acridine is oxidized by dichromate in acetic acid giving 9-ac- ridone. which mav exist in two tautomeric forms.
Acridine is degraded by permanganate in an alkaline medium forming quinoline-2,3-dicarboxylic acid.
4. Reactions of reduction.
Reduction of acridine occurs in the pyridine ring yielding 9,10-dihy- droacridine. 9,10-Dihydroacridine is a product of both acridine reduction with sodium in ethanol and its catalytic hydrogenation.
Acridane is a weak base because its nitrogen atom lone-pair is conjugated with the rc-systems of both benzene rings. It forms readily hydrolysable salt only with strong acids.
Derivatives of acridine
9- Aminoacridine is an antiseptic and disinfectant.
9-Aminoacridine is a yellow crystalline substance; its melting point is 236—237 °C. It is freely soluble in ethanol and acetone.
9-Aminoacridine is a stronger base than acridine. Despite 9-aminocaridine has two basic centres the
only heterocyclic nitrogen is protonated. The lone pair of the amino- group nitrogen atom is conjugated with 7t-electrons of the pyridine ring. Therefore, the electron density of the amino-group is shifted to the pyridine ring, which makes protonation of the amino-group unfavourable. Only a heterocyclic nitrogen in 9-aminoacridine forms salts with acids.
Reactions of 9-aminoacridine with acylating agents lead to amino- group acylation.
Acidylation flows on aminogroup:
9-N-acethylaminoacridine
9-aminoacridine chloride
Diazines
In this section, we shall take а brief look at another class of heterocycles, the diazines.
Six-membered aromatic heterocycles with two nitrogen heteroatoms are called diazines. The three types of diazabenzenes are:
The commoames of these compounds: pyridazine, pyrimidine, and pyrazine are used more often.
It can be clearly understood that all these three heterocycles are isomers.
The other heterocycles, which contain the nitrogen atom together with either oxygen or sulphur, are also known. For example:
Both oxazine and thiazine are non-aromatic; their properties match the properties of acyclic compounds with the similar functional groups.
Pyridazine, pyrimidine, pyrazine are aromatic compounds similar to pyridine. Two nitrogens of the pyridine-type in the ring deactivates it much, which makes diazines to be weaker bases than pyridine. Though diazines have two nitrogen atoms, they form salts only with one equivalent of a strong mineral acid.
Aromatic electrophilic substitution reactions at the ring C-atoms are difficult to carry out. SE-reactions become possible in the presence of donor substituents, e.g. amino groups (—NH2), hydroxy-group (—OH) with the +M effect.
Diazines are more reactive than pyridine towards nucleophiles.
Methods of getting of sixmember heterocyclic connections with two heteroatoms.
These method use for obtaining pyridazine and his derivatives
Pyridazine
Pyridazine is a heteroaromatic organic compound with the molecular formulaC4H4N2, sometimes called 1,2-diazine. It contains a six-membered ring with two adjacent nitrogen atoms. It is a colorless liquid with a boiling point of 208 °C. Pyridazine has no household use. It is mainly used in research and industry as building block for more complex compounds. The pyridazine structure is found within a number of herbicides such as credazine, pyridafol and pyridate. It is also found within the structure of several pharmaceutical drugs such as cefozopran, cadralazine, minaprine, hydralazine, and cilazapril.
Pyridazine is a colourless liquid; its boiling point is 207 °C. Pyridazine and its derivatives are prepared by condensation of hydrazine with saturated or unsaturated 1,4-dicarbonyl compounds:
The only one nitrogen in pyridazine undergoes protonation and alkylation to form the corresponding salts.
Similarly to pyridine pyridazine undergoes N-oxidation.
When reduced pyridazine undergoes ring-opening to form tetra- methylenediamine.
Pyridazine derivatives are widely used as medicines and herbicides.
Pyrimidine
Pyrimidine is a colourless crystalline compound (m.p. 225 °C); it is freely soluble in water and ethanol.
The first step of pyrimidine synthesis according to the following scheme is preparation of barbituric acid by the reaction of malonic ester with urea.
Barbituric acid (2,4,6-trihydroxypyrimidine) can be converted to pyrimidine by treatment with phosphorous oxychloride with the further reduction of the product formed.
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 2-aminopyrimidine 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.
Pyrimidine forms salts with one equivalent of strong mineral acids.
Electrophilic substitution reactions of pyrimidine are complicated, electron-donating substituents increase the SE reactivity in the pyrimidine system; SE reactions in pyrimidine occur at the position 5.
Electron-withdrawing properties of both nitrogen atoms in the molecule of pyrimidine decrease electron density and activate the ring for nucleophilic substitution reactions (SN); the nucleophilic attack occurs at the positions 2, 4 and 6.
Derivatives of pyrimidine
Barbituric acid (2,4,6-trihydroxypyrimidine)
Barbituric acid is one of the most important substituted pyrimidine derivatives; it is also called malonylurea. It is a crystalline substance, freely soluble in hot water, poorly soluble in cold water.
Alkaline hydrolysis of barbituric acid results in malonic acid, CO2 and NH3. This fact confirms that barbituric acid is not an aromatic compound.
The methylene group (—CH2—) in position 5 of barbituric acid is bonded to two carbonyl groups is somewhat more acidic than similar groups connected to only one carbonyl group and can lose a hydrogen ion.
Barbituric acid can exist in a few tautomeric forms. Both lactam– lactim and keto-enol types of tautomerism are possible for barbituric acid.
Keto-enole and lactam-lactim tautomery
Barbituric acid can exist in two tautomeric forms, one is the trioxo- form and another is the trihydroxy-form.
Barbituric acid is six-times stronger than acetic acid. Acidic properties of barbituric acid are caused by the acidity of the methylene-active CH2-group in position 5. Therefore, the substitution of one hydrogen in position 5 induces a small decrease of acidic properties; in the case when both hydrogen atoms are substituted, acidity abruptly decreases.
Condensation of substituted malonic ester derivatives with urea is the method for barbiturates preparation. Barbiturates are used as drugs.
Barbituric acid or malonylurea or 4-hydroxyuracil is an organic compound based on a pyrimidine heterocyclic skeleton. It is an odorless powder soluble in hot water. Barbituric acid is the parent compound of a large class of barbiturates that have central nervous system depressant properties, although barbituric acid itself is not pharmacologically active.
The compound was discovered by the German chemist Adolf von Baeyer on 4. December 1864—the feast of St Barbara and therefore the name given to the compound—by combining urea and malonic acid in a condensation reaction. Malonic acid has since been replaced by diethyl malonate.
Pyrazine
Pyrazine is a colourless crystalline compound; its melting point is 57 °C.
Pyrazine and its derivatives are prepared by condensation of 1,2-diamines with 1,2-dicarbonyl compounds.
Pyrazine is a heterocyclic aromatic organic compound. It is found in folic acid in the form of pterin. Derivatives like Phenazine are well known for their antitumor, antibiotic and diuretic activity. Pyrazine is less basic iature than pyridine, pyridazine and pyrimidine. Tetramethylpyrazine (also known as ligustrazine) is reported to scavenge superoxide anion and decrease nitric oxide production in human polymorphonuclear leukocytes. Tetramethylpyrazine is also a component of some herbs in Traditional Chinese Medicine.
Synthesis of pyrazine
Many methods exist for the organic synthesis of pyrazine and derivatives and some of them very old. Staedel-Rugheimer pyrazine synthesis (1876) is the condensation of 1,2-diamine with 1,2-dicarbonil compounds and then oxidation to a pyrazine. A variation is the Gutknecht Pyrazine Synthesis (1879) also based on this selfcondensation but differing in the way that alpha-ketoamine is synthesised (the chlorine compound in the above method is a lachrymatory agent).
Chemical properties of pyrazine
2,3-Dihydropyrazine formed at the first stage is conveniently oxidized to pyrazine.
Similarly to pyridazine the only one nitrogen in pyrazine undergoes protonation and N-oxidation.
Under the action of sodium amide in liquid ammonia pyrazine forms 2-aminopyrazine.
Reduction of pyrazine with sodium in ethanol leads to piperazine, which is the cyclic diamine.
Piperazine as a secondary amine has a strong basic properties, it can form salts with two equivalents of an acid. Piperazine adipate is used as a wormer.
2,5-Dioxopiperazines (diketopiperazines), which are formed by the dimerizing cyclocondensation of a-aminoacids or their esters, are important derivatives of piperazine.
Diketopiperazines can de reduced to piperazine.
References:
1. Clayden Jonathan. Organic Chemistry. Jonathan Clayden, Nick Geeves, Stuart Warren // Paperback, 2nd Edition. – 2012. – 1234 p.
2. Bruice Paula Y. Organic Chemistry / Paula Y. Bruice // Hardcover, 6th Edition. – 2010. – 1440 p.
3. Brückner Reinhard. Organic Mechanisms – Reactions, Stereochemistry and Synthesis / Reinhard Brückner // Hardcover, First Edition. – 2010. – 856 p.
4. Moloney Mark G. Structure and Reactivity in Organic Chemistry / Mark G. Moloney // Softcover, First Edition. – 2008. – 306 p.
5. Carrea Giacomo. Organic Synthesis with Enzymes in Non-Aqueous Media / Giacomo Carrea, Sergio Riva // Hardcover, First Edition. – 2008. – 328 p.
6. Smith Michael B. March’s Advanced Organic Chemistry. Reactions, mechanisms, and structure / Michael B. Smith, Jerry March // Hardcover, 6th Edition. – 2007. – 2384 p.
7. Carey Francis A. Advanced Organic Chemistry / Francis A. Carey, Richard A. Sundberg // Paperback, 5th Edition. – 2007. – 1199 p.
Additional:
1. Francotte Eric. Chirality in Drug Research / Eric Francotte, Wolfgang Lindner //
Hardcover, First Edition. – 2006. – 351 p.
2. Quin Louis D. Fundamentals of Heterocyclic Chemistry: Importance in Nature and in the Synthesis of Pharmaceuticals / Louis D. Quin, John Tyrell // Hardcover, 1st Edition. – 2010. – 327 p.
3. Zweifel George S. Modern Organic Synthesis – An Introduction / George S. Zweifel, Michael H. Nantz // Softcover, 1st Edition. – 2007. – 504 p.
4. K. C. Nicolaou. Molecules that changed the World / Nicolaou K. C., Tamsyn Montagnon // Hardcover, First Edition. – 2008. – 385 p.
5. Mundy Bradford P. Name Reactions and Reagents in Organic Synthesis / Bradford P. Mundy, Michael G. Ellerd, Frank G. Favaloro // Hardcover, 2nd Edition. – 2005. – 886 p.
6. Li Jie Jack. Name Reactions. A Collection of Detailed Reaction Mechanisms / Jie Jack Li // Hardcover, 4th Edition. – 2009. – 621 p.
7. Gallego M. Gomez. Organic Reaction Mechanisms / M. Gomez Gallego, M. A. Sierra // Hardcover, First Edition. – 2004. – 290 p.
8. Sankararaman Sethuraman. Pericyclic Reactions – A Textbook / Sethuraman Sankararaman // Softcover, First Edition. – 2005. – 418 p.
9. Tietze Lutz F. Reactions and Syntheses / Lutz F. Tietze, Theophil Eicher, Ulf Diederichsen // Paperback, First Edition. – 2007. – 598 p.
10. Olah George A. Superelectrophiles and Their Chemistry / George A. Olah, Douglas A. Klumpp // Hardcover, First Edition. – 2007. – 301 p.
11. Grossmann Robert B. The Art of Writing Reasonable Organic Reaction Mechanisms / Robert B. Grossmann // Hardcover, 2nd Edition. – 2003. – 355 p.
12. Cole Theodor C.H. Wörterbuch Labor – Laboratory Dictionary / Theodor C.H. Cole // Hardcover, 2nd Edition. – 2009. – 453 p.
