Practical Heterocyclic Chemistry
The values of stability constants were found to decrease with increasing ionic strengths and temperature. The stoichiometries were studied using spectrophotometric and conductimetric methods, the results indicate the existence of and M:L metal:ligand species. The relationships between the stability constants of the complexes, ionization constants of the ligands have been discussed and correlated.
The thermodynamic parameters? H and? S and the thermodynamic stability constants for all of the investigated complexes were determined potentiometrically. Related Articles:. Agamenon R.
Date: September 1, Furan is reduced to tetrahydrofuran by palladium-catalyzed hydrogenation. This cyclic ether is not only a valuable solvent, but it is readily converted to 1,4-dihalobutanes or 4-haloalkylsulfonates, which may be used to prepare pyrrolidine and thiolane. Dipolar cycloaddition reactions often lead to more complex five-membered heterocycles. Indole is probably the most important fused ring heterocycle in this class. By clicking on the above diagram three examples of indole synthesis will be displayed.
The first proceeds by an electrophilic substitution of a nitrogen-activated benzene ring. The second presumably takes place by formation of a dianionic species in which the ArCH 2 — unit bonds to the deactivated carbonyl group. Finally, the Fischer indole synthesis is a remarkable sequence of tautomerism, sigmatropic rearrangement , nucleophilic addition, and elimination reactions occurring subsequent to phenylhydrazone formation.
This interesting transformation involves the oxidation of two carbon atoms and the reduction of one carbon and both nitrogen atoms. These units are commonly used as protective groups for aldehydes and ketones, and may be hydrolyzed by the action of aqueous acid. It is the "aromatic" unsaturated compounds, furan, thiophene and pyrrole that require our attention. This is illustrated by the resonance description at the top of the following diagram. The heteroatom Y becomes sp 2 -hybridized and acquires a positive charge as its electron pair is delocalized around the ring.
An easily observed consequence of this delocalization is a change in dipole moment compared with the analogous saturated heterocycles, which all have strong dipoles with the heteroatom at the negative end. As expected, the aromatic heterocycles have much smaller dipole moments, or in the case of pyrrole a large dipole in the opposite direction. An important characteristic of aromaticity is enhanced thermodynamic stability , and this is usually demonstrated by relative heats of hydrogenation or heats of combustion measurements.
By this standard, the three aromatic heterocycles under examination are stabilized, but to a lesser degree than benzene.
Practical Heterocyclic Chemistry
Additional evidence for the aromatic character of pyrrole is found in its exceptionally weak basicity pK a ca. The corresponding values for the saturated amine pyrrolidine are: basicity Another characteristic of aromatic systems, of particular importance to chemists, is their pattern of reactivity with electrophilic reagents.
Whereas simple cycloalkenes generally give addition reactions, aromatic compounds tend to react by substitution. As noted for benzene and its derivatives, these substitutions take place by an initial electrophile addition, followed by a proton loss from the "onium" intermediate to regenerate the aromatic ring.
The reaction conditions show clearly the greater reactivity of furan compared with thiophene. All these aromatic heterocycles react vigorously with chlorine and bromine, often forming polyhalogenated products together with polymers. The exceptional reactivity of pyrrole is evidenced by its reaction with iodine bottom left equation , and formation of 2-acetylpyrrole by simply warming it with acetic anhydride no catalyst.
Reactions of pyrrole require careful evaluation, since N-protonation destroys its aromatic character. For example, pyrrole reacts with acetic anhydride or acetyl chloride and triethyl amine to give N-acetylpyrrole. Consequently, the regioselectivity of pyrrole substitution is variable, as noted by the bottom right equation. The intermediate formed by electrophile attack at C-2 is stabilized by charge delocalization to a greater degree than the intermediate from C-3 attack. From the Hammond postulate we may then infer that the activation energy for substitution at the former position is less than the latter substitution.
Functional substituents influence the substitution reactions of these heterocycles in much the same fashion as they do for benzene. Indeed, once one understands the ortho-para and meta-directing character of these substituents, their directing influence on heterocyclic ring substitution is not difficult to predict. The following diagram shows seven such reactions.
Handbook of Heterocyclic Chemistry (3rd Edition) - Knovel
The third reaction has two substituents of different types in the 2 and 5-positions. Finally, examples 4 through 7 illustrate reactions of 1,2- and 1,3-oxazole, thiazole and diazole. Note that the basicity of the sp 2 -hybridized nitrogen in the diazoles is over a million times greater than that of the apparent sp 3 -hybridized nitrogen, the electron pair of which is part of the aromatic electron sextet.
Other possible reactions are suggested by the structural features of these heterocycles. For example, furan could be considered an enol ether and pyrrole an enamine. Such functions are known to undergo acid-catalyzed hydrolysis to carbonyl compounds and alcohols or amines.
Since these compounds are also heteroatom substituted dienes, we might anticipate Diels-Alder cycloaddition reactions with appropriate dienophiles. These possibilities will be illustrated above by clicking on the diagram. As noted in the upper example, furans may indeed be hydrolyzed to 1,4-dicarbonyl compounds, but pyrroles and thiophenes behave differently.
The second two examples, shown in the middle, demonstrate typical reactions of furan and pyrrole with the strong dienophile maleic anhydride. The former participates in a cycloaddition reaction; however, the pyrrole simply undergoes electrophilic substitution at C Thiophene does not easily react with this dienophile. The pyrrole compound on the left is essentially unreactive, as expected for an amide, but additional nitrogens markedly increase the rate of hydrolysis.
This effect has been put to practical use in applications of the acylation reagent 1,1'-carbonyldiimidazole Staab's reagent.
Practical heterocyclic chemistry
Another facet of heterocyclic chemistry was disclosed in the course of investigations concerning the action of thiamine following diagram. As its pyrophosphate derivative, thiamine is a coenzyme for several biochemical reactions, notably decarboxylations of pyruvic acid to acetaldehyde and acetoin. Early workers speculated that an "active aldehyde" or acyl carbanion species was an intermediate in these reactions.
Many proposals were made, some involving the aminopyrimidine moiety, and others, ring-opened hydrolysis derivatives of the thiazole ring, but none were satisfactory. This puzzle was solved when R. Breslow Columbia found that the C-2 hydrogen of thiazolium salts was unexpectedly acidic pK a ca. As shown, this rationalizes the facile decarboxylation of thiazoliumcarboxylic acids and deuterium exchange at C-2 in neutral heavy water.
Appropriate thiazolium salts catalyze the conversion of aldehydes to acyloins in much the same way that cyanide ion catalyzes the formation of benzoin from benzaldehyde, the benzoin condensation. By clicking on the diagram , a new display will show mechanisms for these two reactions. Note that in both cases an acyl anion equivalent is formed and then adds to a carbonyl function in the expected manner. The benzoin condensation is limited to aromatic aldehydes, but the use of thiazolium catalysts has proven broadly effective for aliphatic and aromatic aldehydes.
This approach to acyloins employs milder conditions than the reduction of esters to enediol intermediates by the action of metallic sodium. The most important condensed ring system related to these heterocycles is indole. Some electrophilic substitution reactions of indole are shown in the following diagram.
Whether the indole nitrogen is substituted or not, the favored site of attack is C-3 of the heterocyclic ring. Bonding of the electrophile at that position permits stabilization of the onium-intermediate by the nitrogen without disruption of the benzene aromaticity.
These units are commonly used as protective groups for aldehydes and ketones, as well as synthetic intermediates, and may be hydrolyzed by the action of aqueous acid. The reactivity of partially unsaturated compounds depends on the relationship of the double bond and the heteroatom e.
Fully unsaturated six-membered nitrogen heterocycles, such as pyridine, pyrazine, pyrimidine and pyridazine, have stable aromatic rings. Oxygen and sulfur analogs are necessarily positively charged, as in the case of 2,4,6-triphenylpyrylium tetrafluoroborate. The resonance description drawn at the top of the following diagram includes charge separated structures not normally considered for benzene.
The greater electronegativity of nitrogen relative to carbon suggests that such canonical forms may contribute to a significant degree. Put another way, the heterocyclic compounds probe the mechanism of action of biological systems. What I find most attractive about chemical biology from the point of view of an academic scientist interested both in basic science and practical applications is that chemical biology bridges these two endeavours.
In our own work, for example, we have designed some anti-infective compounds to be fluorescent so that we can follow their passage in the target infectious agent, typically a fungus or a parasite. This gives us important information about how our compounds work. In another project we have some very effective potential therapeutic compounds that treat inflammatory diseases but until recently, we did not understand how they worked.
Thanks to a collaboration with the US Army Laboratory, AMRID, we have found out a good deal about their mechanism of action using a variety of techniques within the chemical biology domain. Save my name, email, and website in this browser for the next time I comment. Monday, September 23, Open Access Government. Heterocyclic chemistry is linked to a number of scientific discoveries and breakthroughs, both directly and indirectly. Professor Colin Suckling of the University of Strathclyde discusses the links and the thinking behind it There are fashions in science just as much as in any well-populated walk of life.
Theory and practice What I find most attractive about chemical biology from the point of view of an academic scientist interested both in basic science and practical applications is that chemical biology bridges these two endeavours. To discover more from the University of Strathclyde, click here Facebook.
Characterisation of Photonic Nanostructures in an Electron Microscope. Swindon and Wiltshire — The home of life sciences.