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Advances in the Study of the Chichibabin Reaction
Abstract
The state of research into one of the most important reactions of heterocyclic compounds — their amination by sodium amide (the Chichibabin reaction) — is described. The mechanism of the reaction, its application to specific classes of nitrogen-containing heterocycles, and certain reactions related to the Chichibabin reaction, namely amination of heterocycles by organic derivatives of metal amides, substitutional amination with elimination of hydrocarbon groups, amination of N-heteroaromatic cations, and hydrazination and hydroxylation, are discussed.
The bibliography includes 235 references.
... [1] This reaction is now known as the Chichibabin reaction (amination), capable of installing a primary amino group (À NH 2 ) at the C2 position of pyridines and their derivatives. On the other hand, only a few successful examples have been reported for the Chichibabin amination with primary alkyl amines [2][3][4] probably due to inaccessibility of the corresponding alkyl metal amides. [5] We have recently discovered that sodium hydride (NaH) can be performed as an enhanced Brønsted base in the presence of NaI or LiI, enabling nucleophilic amination of methoxyarenes. ...
... [9] The resulting products should be of potential use for a ligand of transition metal catalysis. [10] Double amination of 4,4'-and 2,4'-bipyridines was also demonstrated using n-butylamine (2), resulting in successful formation of 27 and 28, respectively, in good yields (Scheme 5A and B). In amination of 2,4'-bipyridine, a small amount of 5,2'diaminated bipyridine 28' was formed as a minor product (Scheme 5B). ...
All about composure: A NaH‐iodide composite was found capable of mediating the Chichibabin amination under mild reaction conditions, allowing efficient access to a range of 2‐aminopyridines and their derivatives. image
... pyridine more than the 4-position. Thus, 2-aminopyridine is formed under the reaction conditions [14][15][16][17]. Due to the insolubility of the sodium amide in aprotic solvents, the reaction proceeds under the heterogeneous conditions. ...
A Molecular Electron Density Theory (MEDT) study was performed on the nucleophilic amination of pyridine and benzene to elucidate the observed regioselectivity in the Chichibabin reaction. For this purpose, three possible reaction paths were considered between NaNH2 and the 2-, 3- and 4-positions of pyridine. The reaction of NaNH2 and benzene was also investigated. The results indicated that in each reaction, the first step involves the nucleophilic attack of the NH2¯ ion toward the aromatic system to produce an anionic intermediate. The second step, proceeds via hydride elimination of the anionic intermediate to produce the corresponding aromatic amine. This step is more favourable both kinetically and thermodynamically for the reaction at the 2-position of pyridine relative to the 4-position. In contrast to the Parr functions analysis which indicates that the 4-position is activated more electrophilically in pyridine, the PES analysis reveals that the 2-position attack with the NH2¯ ion is more favorable both thermodynamically and kinetically. The results for the reaction of sodium amide and benzene indicated that this reaction is not feasible due to the high activation barriers. In consistent with the experimental results, the ELF analysis indicated that in the first step of the reaction between pyridine and sodium amide, the formation of the C2-N bond takes place via a pseudoradical coupling between the C2 carbon atom of pyridine and the N atom of NaNH2. These variations occur in the second-half of the first step of the reaction. NCI analysis on the reaction revealed that the more attractive forces between the fragments, make the transition states for the 2-position attack more stable relative to the others. Thus, the NCI analysis can satisfactorily describe the observed regioselectivity in the Chichibabin reaction.
... pyridine more than the 4-position. Thus, 2-aminopyridine is formed under the reaction conditions [14][15][16][17]. Due to the insolubility of the sodium amide in aprotic solvents, the reaction proceeds under the heterogeneous conditions. ...
In recent years, the air pollutant species has adventured the health of humans and other organisms. One of the pollutants are polycyclic aromatic compounds which are usually produced from defective combustion of fossil fuels. The removing or inactivation of these pollutants from environment is one of the research aims of scientists. In present work, the possibility of inactivation of the one of the polycyclic aromatic hydrocarbons namely pyrene with C20 fullerene was investigated theoretically. For this purpose, several [2+2] and [4+2] cycloaddition reactions between C20 and pyrene were considered and their thermodynamic and kinetic parameters were calculated. The results indicated that a) one of the [4+2] paths is more favorable relative to others, b) the most probable [4+2] Diels-Alder reaction of C20 and pyrene occurs with the rate constant of 5.09×10⁻⁶ M⁻¹s⁻¹ at 25 °C, and c) the reaction have relative polar character so that C20 fullerene and pyrene act as electron acceptor and donor, respectively. The Frontier Effective-for-Reaction Molecular Orbital (FERMO) concept was successfully applied for the description of the reactivity of the different active sites of pyrene. Finally, the synchronicity of the reactions was calculated and its correlation with activation enthalpy was elucidated.
... 34 Eight years later, he described a method for producing 2-aminopyridine derivatives from the reaction between pyridine and sodium amide called Chichibabin reaction. 35,36 This reaction was then extended to quinoline and isoquinoline derivatives (Scheme 4). 37 This reaction is most of the time used for the modification of pyridine derivatives which are difficult to functionalize. ...
Amines are key intermediates in the chemical industry due to their nucleophilic characteristic which confers a high reactivity to them. Thus, they are key monomers for the synthesis of polyamides, polyureas, polyepoxydes, which are all of growing interest in automotive, aerospace, building, or health applications. Despite a growing interest for biobased monomers and polymers, and particularly polyamides, it should be noticed that very few natural amines are available. Actually, there is only chitosan and poly(lysine). In this review we present both fundamental and applied research on the synthesis of biobased primary and secondary amines with current available biobased resources. Their use is described as a building block for material chemistry. Hence, we first recall some background on the synthesis of amines, including the reactivity of amines. Second we focus on the synthesis of biobased amines from all sorts of biomass, from carbohydrate, terpenes, or oleochemical sources. Third, because they need optimization and technological developments, we discuss some examples of their use for the creation of biobased polymers. We conclude with the future of the synthesis of biobased amines and their use in different applications.
After the appearance of the green chemistry concept, which was introduced in the chemistry vocabulary in the early 1990s, its main statements have been continuously developed and modified. Currently, there are 10–12 cornerstones that should form the basis for an ideal chemical process. This review analyzes the accumulated experience and achievements towards the design of chemical products and processes that reduce or eliminate the use or generation of hazardous substances. The review presents the views of leading Russian scientists specializing in various fields of this subject, including homogeneous and heterogeneous catalysis, fine and basic organic synthesis, electrochemistry, polymer chemistry, chemistry based on bio-renewable feedstocks and chemistry of energetic compounds and materials. A new approach to the quantitative evaluation of the environmental friendliness of processes developed by Russian authors is described.
The bibliography includes 1761.
Oxoanions such as carboxylates, phosphates, and sulfates play important roles in both chemistry and biology and are abundant on the cell surface. We report on the synthesis and properties of a rationally designed guanidinium-containing oxoanion binder, 1-guanidino-8-amino-2,7-diazacarbazole (GADAC). GADAC binds to a carboxylate, phosphate, and sulfate in pure water with affinities of 3.6 × 104, 1.1 × 103, and 4.2 × 103 M-1, respectively. Like 2-azacarbazole, which is a natural product that enables scorpions to fluoresce, GADAC is fluorescent in water (λabs = 356 nm, λem = 403 nm, ε = 13,400 M-1 cm-1). The quantum yield of GADAC is pH-sensitive, increasing from Φ = 0.12 at pH 7.4 to Φ = 0.53 at pH 4.0 as a result of the protonation of the aminopyridine moiety. The uptake of GADAC into live human melanoma cells is detectable in the DAPI channel at low micromolar concentrations. Its properties make GADAC a promising candidate for applications in oxoanion binding and fluorescence labeling in biological (e.g., the delivery of cargo into cells) and other contexts.
In synthetic organic chemistry, sodium hydride (NaH) has been utilized almost exclusively as a routine Brønsted base, while NaH has not been considered to work as a hydride donor. Recently, our group has serendipitously found that NaH can function as a unique hydride donor by its solvothermal treatment with sodium iodide (NaI) or lithium iodide (LiI) in tetrahydrofuran (THF) as a solvent. This discovery led to the development of unprecedented reductive molecular transformations such as hydrodecyanation of α-quaternary benzyl cyanides, controlled reduction of amides into aldehydes, dearylation of arylphopsphine oxides, and hydrodehalogenation of haloarenes. Moreover, this concise protocol allows for the use of NaH as enhanced Lewis acid and Brønsted base, enabling directed aromatic C-H sodiation, nucleophilic amination of methoxy arenes, and C2-amination of pyridines (the Chichibabin amination).
It has been found that 1-dialkylamino-8-(pyrrolyl-1)naphthalenes 1 and 6, upon treatment with an equimolar amount of HBF 4 under ambient conditions, produce 1-dialkylammonium salts which are transformed into 7,7-dialkyl-7H-pyrrolo[1,2-a]perimidine-7-ium tetrafluoroborates 5 and 7, respectively. The reaction proceeds in a highly selective manner and represents the first case of nucleophilic substitution of hydrogen in the initially inactivated pyrrole ring. The scope and limitations of the transformation, apparently operating due to the joint action of the "proximity effect" and proton catalysis, are outlined.
Chemiker, Journalist, Patriot und Abtrünniger: Alexei Jewgenjewitsch Tschitschibabin lieferte bahnbrechende Beiträge zur Chemie der Pyridine. Nun, da die Tschitschibabin-Reaktion in ihr zweites Jahrhundert geht, scheint es der richtige Zeitpunkt, einen nochmaligen Blick auf das Leben dieses bemerkenswerten Chemikers und sein Vermächtnis für die heterocyclische Chemie zu werfen.
Tutor, journalist, patriot, and defector: Aleksei Yevgen'evich Chichibabin made seminal contributions to the chemistry of pyridines. As the Chichibabin reaction enters its second century, it is appropriate to re-examine the life of this remarkable chemist and his legacy to heterocyclic chemistry.
Nitrobenzenes substituted with electron-acceptor groups such as halogen, nitro, trifluoromethyl, pentafluorosulfanyl, or cyano underwent oxidative nucleophilic substitution with lithium salts of arylamines to afford N-aryl-2-nitroanilines.
Molecular rearrangements are not amenable to retrosynthesis because of their complex mechanisms. Still, in some cases retro-rearrangements are a conceivable and useful approach to selected target molecules. In this chapter, arguments for the retrosynthetic approach to some well-known rearrangements, Beckmann, Hofmann, Arndt-Eistert, Favorskii, pinacol and Bayer-Villiger, are presented. The mechanism of these rearrangements is explained. Retrosynthesis and synthesis, which include a specific rearrangement in the key step, are proposed for selected target molecules, among them paracetamol, dinestrol and spasmolytic biphenyl carboxylic acid.
The review surveys the data on amination of electron-deficient aromatic heterocycles by using the methodology of nucleophilic substitution of hydrogen (S
NH). The recent advances in this area involve many new aspects of the S
NH-amination, including a wide range of heteroaromatic substrates and new types of aminating reagents, metal-free catalysts, solvents, and the hydride ion acceptors. The review demonstrates that the S
NH approach is becoming an increasingly popular and important synthetic alternative to the classical and transition metal-catalyzed amino-dehalogenation reactions.
Graphical Abstract
This review covers the carbon-nitrogen (C-N) bond forming reactions of pyridines that include both electrophilic as well as nucleophilic substitution reactions. The electrophilic reactions, such as nitration and nitrosation, include both the classical methods and their recent modifications. Nucleophilic reactions include Chichibabin and related amination reactions, with hydrogen as the leaving group, as well as displacement reactions where the leaving group on the pyridine ring is halogen, such as the Buchwald-Hartwig amination reaction. C-N bond forming nucleophilic reactions with cyano and alkoxy leaving groups on the pyridine ring are also discussed. Reactions requiring metal catalysts and those that proceed in the absence of any catalyst are reviewed. Metallation reactions on halopyridines, often used to introduce functionality into the pyridine ring, are included. Functional group transformations including rearrangement reactions leading to C-N bond formation such as Hofmann and Curtius rearrangement on pyridine derivatives are also reviewed.
Here, we report the copper-catalyzed C2 selective cross-dehydrogenative C-N bond formation of azines with azoles. This straightforward method enables us to address the key limitation of prior N-O activation strategy in C2 amination of azines. The wide substrate scope, high functional group tolerance, and ease of operation of the present method are expected to promote its potential application in synthetic chemistry.
The retrosynthetic approach for the preparation of heterocycles is a highly useful synthetic strategy based on a disconnection analysis consisting in the construction of the target molecule by going steps backwards through the precursors and conditions needed. This study intends to give classical and more updated examples of methods for preparing five and six members rings which are more diverse and widespread in pesticides used to control, unwanted or harmful insects, rodents, or weeds. The schemes used in this study tend to avoid multi schematic pathways focussing on the key steps and synthons required, obviating the dehydrations, molecular hydrogen loss or beta eliminations which are the main events during the aromatization processes. The arrows represent the interactions between the reactive sites existing within the functionalities of each intermediate in a way to show from a perspective view in which way the annulation process is taking place, and the new bonds formed during the heterocyclic ring formation are highlighted in colour for better understanding. The approaches outlined are classified in five and six member rings fused and not fused, and with one or two heteroatoms, giving examples of pesticides either synthetic or natural with an heterocyclic moiety and their impact and applicability in agriculture.
Abstract During the past two decades the classical concept of nucleophilic aromatic substitution (SNipso Ar) has been complemented with a new synthetic methodology (SNHAr or briefly SNH), enabling one to perform direct functionalization of aromatic C–H bonds and to build new carbon–carbon C(sp 2)–C(sp 3), C(sp 2)–C(sp 2), and C(sp 2)–C(sp) or carbon–heteroatom C(sp 2)–X bonds (X is O–, N–, P–, S–, Si–, halogen) through nucleophilic displacement of hydrogen in aromatic and heteroaromatic compounds. Graphical Abstract
6-Aryl(hetaryl)amino-1,3,7-triazapyrenes were prepared by direct oxidative nucleophilic substitution of hydrogen. Nucleophilic ipso substitution of methoxy groups gave 6,8-bis(aryl(hetaryl)amino)-1,3,7-tri-azapyrenes.
This chapter includes monographs and reviews published during the period 1979-1986, and is not restricted to reviews in English. Sources in Russian, German, Japanese, French, Czech, Polish, and other languages are surveyed and classified. The survey is based mainly on short bibliographic articles published by the author and co-workers in the Soviet journal Khimiya Geterotsiklicheskikh Soedinenii (Chemistry of Heterocyclic Compounds) since 1979. Several important reviews and monographs published before 1979 in languages other than English are also included. Although all the references are given to original publications, other journals also have informative abstracts and their schemes, also lists of the references are quite understandable and very useful.
A synthetic strategy has been developed for the synthesis of 2‐dialkylaminoquinolines from easily available quinoline N ‐oxides, tertiary amines, diisopropyl H‐phosphonate and carbon tetrachloride (CCl 4 ) in one pot under metal‐free conditions at room temperature.
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SNH methodology finds significant use in organic synthesis. A major advantage of this methodology is that it eliminates the necessity of first introducing a good leaving group into an aromatic substrate. Moreover, in classical SN ipso reactions an acid, such as HHal, H2SO4 or HNO2 is normally liberated that has to be scavenged. However, in SNH processes, a water molecule is typically formed that can contribute to “green chemistry.” This chapter deals with SNH cyclizations. SNH based heterocyclizations allow the synthesis of a great variety of heterocyclic structures differing in ring size, number of heteroatoms and their type, and degree of unsaturation. Various arenes and hetarenes with appropriate electron deficiency can be used as substrates. In context to future prospects, it is observed that a large number of known SNH cyclizations deals with the pyrrole ring closure, therefore search for new substrates, reagents, and cyclization schemes for the annulation of other heterocyclic rings is desirable. It is also important to optimize reaction conditions as many existing transformations do not provide high enough yields.
The aqueous alkaline reaction of 1,3-bis(4-cyanopyridinium) propane dibromide, a reactant constituted of two pyridinium rings linked by a three-methylene bridge, generates a novel compound, 1-(4-cyano-2-oxo-1,2-dihydro-1-pyridyl)-3-(4-cyano-1,2-dihydro-1-pyridyl ) propane. The reaction pathway is attributed to the proximity of the OH-ion inserted between two pyridinium moieties, which occurs only in bis(pyridinium) derivatives connected by short methylene spacers, where charge-conformational effects are important.
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1-Nitro-4-(pentafluorosulfanyl)benzene underwent direct amination with 1,1,1-trimethylhydrazinium iodide in the presence of tBuOK in DMSO to give 2-nitro-5-(pentafluorosulfanyl)aniline in good yield. 1-Nitro-3-(pentafluorosulfanyl)benzene, under similar conditions, gave 2-nitro-4-(pentafluorosulfanyl)aniline, also in good yield. Reduction of either product with hydrogen in the presence of Raney nickel provided 4-(pentafluorosulfanyl)benzene-1,2-diamine, which served as a precursor for the efficient synthesis of SF5-containing benzimidazoles, quinoxalines, and benzotriazoles.
The review deals with studies devoted to the methods of synthesis, physical and chemical properties, and the practical applications of perimidines — the first class of heteroaromatic compounds with distinct amphoteric chemical properties, i.e. the ability to react readily with both electrophiles and nucleophiles.
The bibliography includes 266 references.
Pyridopyridazines have been oxidized under acid and alkaline conditions and the sites of oxidation have been rationalized on the basis of charge densities. Pyrido-[2,3-d]pyridazine has been brominated, aminated, and made to react with hypo-chlorous acid and with peracids. The positions of substitution and addition are discussed in relation to calculated π-electron densities and bond lengths. Attention is drawn to some unusual features of the N.M.R. spectra of 1,2-diazine N-oxides.
The acid properties of primary C-amino-groups in amines, amides, and amidines have been examined. The methods of
preparation and the physical and chemical properties of the metal salts of amines are discussed.
The bibliography includes 227 references.
Es werden die Reaktionen des Acridins in der meso-Stellung mit Wasserstoff, Natriumamid, Benzoylchlorid und Blausäure beschrieben. Für die Ullmannsche Diphenylamin-Kondensation wird Raney-Kupfer als Katalysator vorgeschlagen.
Electron transmission spectroscopy is used to study shape resonances (temporary negative ions) in benzene and some isolectronic N−heterocyclic molecules (pyridine, diazines, and s−triazine), in the energy range 0−6 eV. The lowest shape resonance in each of these molecules exhibits vibrational structure which is interpreted in all cases as the totally symmetric C−C stretch mode. The ground vibrational level of this lowest shape resonance is accessible by electron impact only in benzene and pyridine. Thus, their electron affinities can be determined from the present experiment (−1.15 eV for C6D6 and −0.62 eV for C5H5N). Only excited vibrational levels are accessible in the diazines and s−triazine, indicating that the electron affinities for these molecules have positive values. For benzene, pyridine, and some other aromatic hydrocarbons, we compare the electron affinities established in the gas phase with the polarographic potentials established in the liquid phase and we find a linear relationship. Using this correlation in conjunction with the measured values of the polarographic potentials, we estimate the electron affinities for pyridazine (0.25 eV), pyrimidine (0 eV), pyrazine (0.40 eV) and s−triazine (0.45 eV).
The intramolecular nucleophilic cyclization of 4-(3-pyridyl)butylamine (4a) to yield 6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine (5) was investigated. Of eleven different alkali metal reagents sodium, sodium hydride, sodium amide, and potassium hydride gave good yields of 5. The sodium conditions when applied to 3-(3-pyridyl)propylamine (4b) afforded 1,2,3,4-tetrahydro-1,8-naphthyridine (6) in good yield.