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Heterocyclic Compounds
Heterocyclic compounds, or heterocycles, are cyclic compounds that have atoms of at least two different elements as members of the ring structure. Organic heterocycles contain one or more carbon atoms and, based on their electronic structure, are classified as saturated, unsaturated, and aromatic. When the heteroatom is a part of an aromatic ring, the compound is called an aromatic heterocycle. Aromatic heterocycles can be single ring heterocycles (e.g., pyrrole, furan, thiophene, pyridine), or fused ting heterocycles (e.g., indole, quinoline, and isoquinoline).
Heterocycles are also classified on the basis of ring size with each ring size sharing similar or common features. Because of their small size, three- and four-membered heterocycles are readily opened and are therefore useful as reactive intermediates in organic synthesis. On the other hand, five- and six-membered rings are very stable and easily formed. Rings with a larger size, specifically seven-membered and larger rings, are also very stable but relatively less easily formed. Heterocyclic compounds play an important role in organic chemistry. About half of known organic compounds, including many natural products and FDA-approved drugs, are heterocycles.
Three-membered ring heterocyclics
Aziridines are three-membered organic heterocyclic compounds with one nitrogen atom. The bond angles in aziridine are approximately 60°, which is less than the normal hydrocarbon bond angle of 109.5°. Because of the increased s-character of the nitrogen free electron pair, aziridine is less basic than acyclic aliphatic amines, with a pKa of 7.9 for the conjugate acid, due to the increased s-character of the nitrogen electron pair. The weak basicity of aziridine and its derivatives is also ascribed to the strain in the 3-membered ring. It is because of this strain that aziridines are widely used as intermediates in organic synthesis, acting as precursors to complex molecules.
Azirenes are the unsaturated analogue of aziridines, i.e., they are three-membered heterocyclic compound that contains a nitrogen atom and a double bond. Azirines exist in two isomeric forms, the unstable 1H-azirine with a carbon-carbon double bond which tautomerizes to the more stable, isolable 2H-azirine with a carbon-nitrogen double bond.
Epoxides, also referred to as oxiranes, are organic compounds in which an oxygen atom is bonded to two adjacent carbon atoms, forming a 3-membered ring. The three-membered ring in epoxide is highly strained and readily opens under mild conditions, under mild conditions, a property that makes it useful in organic synthesis. For example, epoxide on treatment with reagents like water, methanol, hydrochloric acid, and base forms ethylene glycol, methyl cellosolve, 2-chloroethanol, and polyethylene glycol, respectively. A unique behavior of epoxides is trans-annular fission, which involves the cleavage of C-C and C-O bonds, and which may occur with or without the accompanying hydrogen transfer to oxygen.
An oxirene is an unsaturated three-membered ring containing two carbon atoms and one oxygen atom. Extremely strained and thus highly unstable, it has never been observed but has been studied using quantum mechanical computational techniques. There are indications that substituted oxirenes are involved as intermediates or transition states in certain rearrangement reactions.
Four-membered ring heterocyclics
Azetidines (or azacyclobutanes) are a class of four-membered heterocyclic compounds containing one nitrogen atom. They are the smallest nitrogen-containing saturated ring system possessing reasonable chemical stability, and with their inherent conformational rigidity, they are building blocks of choice. In general, the basicities of saturated heterocycles, with the exception of three-membered heterocycles, are similar to those of open chain systems. The nitrogen atom in azetidines has a tendency to form salts with acids, but is less basic than the nitrogen normal secondary amines. Azetidines can be acylated (with acyl halides, e.g., RCOCl) and nitrosated (with nitrous acid) at the nitrogen atom to yield acylazetidines and 1-nitrosoazetidines, respectively.
Azetidine derivatives have been widely used in drug design and the preparation of biologically active compounds by incorporating various functional groups at different positions of the ring. They have also been extensively used in the synthesis of new types of nitrogen-containing compounds with enhanced biological properties. For example, they have been used to synthesize azetidine-containing amino acids, such as 3-aminoazetidine-3-carboxylic acid derivatives, which are used as building blocks for short peptides.
Azetes (or azacyclobutadienes) are four-membered, unstable, highly reactive nonaromatic azaheterocycles consisting of three carbons and two double bonds. The parent azete has not yet been synthesized.
Oxetanes are heterocyclic organic compounds containing a four-membered ring with three carbon atoms and one oxygen atom. In the field of pharmaceuticals, oxetane fragments are often employed as with bioisoteric replacements for such functionalities as gem-dimethyl and carbonyl groups. The introduction of an oxetane moiety into potentially bioactive molecules has been found to favorably modulate the physiochemical and pharmacokinetic profile of the molecules.
Oxetane compounds are highly reactive and will polymerize when ring-opening occurs. Compared to conventional epoxy compounds, oxetanes are unique and better-performing UV photocationic monomers; they are more effective, for example, in reducing viscosity and increasing the cure speed of glycidyl ethers.
An oxete (or oxetene) is an unsaturated, unstable, four-membered oxygen heterocycle. Substitution in the ring is reported to promote stabilization.
Five-membered ring heterocyclics
Pyrrolidine (also known as tetrahydropyrrole, azolidine, and azacyclopentane) is a five-membered saturated heterocyclic organic compound containing four carbon atoms and one nitrogen atom in the ring. The pyrrolidine ring is present as a core skeleton in some natural amino acids such as L-proline and L-hydroxyproline. Pyrrolidines are better nucleophiles than diethylamine, principally because of the less hindered lone pair. The pKa value of pyrrolidine, 11.27 is typical of amine bases. Pyrrolidines are very reactive towards aldehydes and ketones, forming enamines through a nucleophilic addition reaction.
Pyrrolidine is often present as a core structure in molecules that exhibit antitumor, analgesic, anti-inflammatory, antioxidant , and antihistamine activity. It is present, for example, in the carbapenem antibiotics meropenem and ertapenem. The pyrrolidine ring has also been found in many natural alkaloids such as nicotine, cuscohygrine, benzoylecgonine, ecgonidine, ecgonine, dihydrocuscohygrine, and hygrine.
Pyrroles are five-membered nitrogen containing heterocyclic aromatic compounds. The high resonance stabilization of the pyrrole system makes it more reactive than benzene. Hence pyrroles undergo electrophilic substitution reactions such as halogenations, nitration, and sulfonation, with mild electrophiles
Pyrrole and its derivatives are widely used as intermediates in the synthesis of pharmaceuticals, medicines, agrochemicals, dyes, photographic chemicals, perfumes and other organic compounds. Pyrroles also form part of a vast variety of many natural products including hemoglobin, chlorophyll and alkaloids. In addition, they can be used as catalysts for polymerization, corrosion inhibitors, preservatives, and as solvents.
Furans are a group of heterocyclic organic compounds, consisting of a five-membered aromatic ring with four carbon atoms and one oxygen atom. The hydrogenation of furans gives, sequentially, dihydrofurans and tetrahydrofurans (THF). THF is a cyclic ether and a versatile aprotic solvent. Due to its miscibility with water, it can form solid clathrate hydrate structures with water at low temperatures. Owing to their strong coordination property, THF, 2-methyl-THF, and other analogs can be used to make solutions of organometallic compounds such as organolithium and Grignard reagents. THF is used in the field of polymer chemistry to dissolve polymers prior to determining their molecular mass using gel permeation chromatography.
Thiophene, also known as thiacyclopentadiene, thiole, or thiofuran, is a five-membered sulfur-containing heterocyclic aromatic compound. Thiophene and its derivatives occur in natural deposits, and function as analogs of furans and pyrroles. Thiophenes undergo a large number of substitution reactions. Thiophene does not behave like thioethers, as the sulfur atom in a thiophene resists alkylation and oxidation. While the sulfur atom is relatively unreactive, carbon atoms alpha to sulfur are highly susceptible to attack by electrophiles. Halogens react with thiophenes to give 2-halothiophenes followed by 2,5-dihalo derivatives. In addition to their reactivity towards electrophiles, thiophenes can also be lithiated.
Tetrahydrothiophene is the saturated analog of thiophene. It contains a five-membered ring consisting of four carbon atoms and a sulfur atom. Also known as thiophane, thiolane, or THT, tetrahydrothiophene (with the formula (CH2)4S) is a Lewis base classified as a soft base. It is a volatile, colorless liquid with an intensely unpleasant odor. Tetrahydrothiophenes and derivatives are reported to occur in nature
Six-membered ring heterocyclics
Piperidines are six-membered saturated heterocyclic organic compounds with one nitrogen atom. Piperidine adopts two chair conformations, which rapidly interconvert through nitrogen inversion. It can be naturally obtained from black pepper, and hence the name comes from “piper,” the Latin word for pepper.
Piperidine, a widely used secondary amine, can be used as a solvent and a base. It is commonly used to convert ketones to enamines, which can be used in the Stork enamine alkylation reaction. It is also used both as a reagent and building block in several synthetic research applications. A salt of piperidine with acetic acid is used as a catalyst for many condensation reactions.
The piperidine skeleton is present in several natural alkaloids, for example, coniine, piperine, anabasine, solenopsin, and lobeline. In addition, it can be used in chemical degradation reactions, such as the sequencing of DNA in the cleavage of particular modified nucleotides. Piperidine is widely used as an excellent base for quantitative deprotection of the Fmoc group from peptides in solid-phase peptide synthesis.
Pyridines (azabenzenes) are six-membered aromatic heterocycles with one nitrogen atom in the ring. Electrophilic substitution with pyridine takes place under severe conditions, predominantly at the 3-position. Pyridine behaves both as a tertiary amine (alkylation, acylation, and N-oxidation), and as an aromatic compound (nucleophilic substitutions at the 2-position). Generally pyridine is much less basic than alkylamines and more basic than pyrrole and aniline. However, it is a sufficiently strong enough base to form salts with mineral acids. The pyridine ring is present in many important compounds, including agrochemicals, pharmaceuticals, and vitamins
Pyrans, also known as oxines, are six-membered heterocyclic, non-aromatic compounds, consisting of five carbon atoms and one oxygen atom in the ring with two double bonds. The two isomers of pyran, 2H-pyran and 4H-pyran, differ only in the location of the double bonds.
Tetrahydropyrans, also called oxanes, are organic compounds consisting of a saturated six-membered ring containing five carbon atoms and one oxygen atom. The tetrahydropyran ring system forms the core of pyranose sugars, such as glucose. As a protecting group, the 2-tetrahydropyranyl group is extensively used in organic synthesis for the protection of alcohols as tetrahydropyranyl ether. This confers protection to the alcohol from a variety of reaction conditions. The deprotection is relatively simple, involving acidic hydrolysis with formation of 5-hydroxypentanal as by product.
Cyclic compounds with two heteroatoms
Morpholines are six-membered saturated organic heterocycles, containing nitrogen and oxygen at the 1- and 4- positions in the ring. Morpholine is a mild base; its conjugate acid is called morpholinium. The presence of ether oxygen renders morpholines less basic than the analogous piperidines. Morpholine acts as a solvent for a number of organic compounds, such as resins, dyes, and waxes. Morpholine-based enamines are widely used in organic synthesis for C-C and C-X bond formations. Morpholine fatty acid salts are used as surface-active agents and emulsifiers.
Thiomorpholines are six-membered saturated organic heterocyclic compounds containing nitrogen and sulfur at the 1- and 4- positions of the ring. Thiomorpholines can be considered a thio analog of morpholine.
Dioxanes (dioxacyclohexanes), are six-membered cyclic organic compounds containing two oxygen atoms. Depending on the relative positions of oxygen atoms, three isomers are possible: 1,2-dioxane, 1,3-dioxane, and 1,4-dioxane. Most dioxanes are 1,4-isomers. Simple 1,4-dioxane is a versatile aprotic solvent used for a variety of practical laboratory applications. It has a higher boiling range and is less toxic compared to tetrahydrofuran and hence used as a substitute for THF in some chemical processes. Owing to the presence of the oxygen atoms, dioxanes act as a Lewis base and are used to solvate many inorganic compounds. A dioxane solution of sulfur trioxide is useful for Beckmann rearrangements, sulfonation of alkenes and arenes. Dioxane-based compounds find use as chiral solvating agents for the determination of enantiomeric excess and as chiral derivatizing agents in the determination of absolute configuration. 1,3-dioxanes are employed as a means of protection of carbonyl groups during organic transformations.
Dioxin is a heterocyclic organic, non-aromatic compound with the chemical formula C4H4O2. It exists in two isomerc forms: 1,4-dioxin (or p-dioxin) and 1,2-dioxin (or o-dioxin); the latter is quite unstable due to irs peroxide-like characteristics. The term “dioxins” is most commonly used for a family of derivatives of dioxin, known as polychlorinated dibenzodioxins which are toxic and persistent organic pollutants.
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