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Trichloroisocyanuric acid in 98% sulfuric acid: A superelectrophilic medium for chlorination of deactivated arenes
Abstract
Trichloroisocyanuric acid (TCCA) reacts with arenes and its reactivity is highly affected by the acid strength of the reaction medium. Deactivated arenes are efficiently chlorinated by TCCA in H2SO4. Our results, along with DFT calculations and 13C NMR spectrometry suggest the formation of a monoprotonated TCCA superelectrophile as the reactive species that can efficiently transfer electrophilic Cl+ to even very weak nucleophiles, such as m-dinitrobenzene.
... Table 4 shows diverse conditions to promote de reaction of TCCA with benzene. Chlorobenzene, a slightly deactivated arene, is another unreactive substrate with TCCA under ordinary conditions or using a weak acid (HOAc) as solvent [69]. On the other hand, the reaction in 98% H 2 SO 4 led to the polychlorination of the substrate, indicating the higher reactivity of TCCA in a strong acidic medium. ...
... On the other hand, the reaction in 98% H 2 SO 4 led to the polychlorination of the substrate, indicating the higher reactivity of TCCA in a strong acidic medium. However, monochlorination of the substrate was achieved by reducing the acidity strength of the reaction medium (dilution of H 2 SO 4 with HOAc) [69]. Table 5 Other simple haloarenes, such as fluorobenzene, bromobenzene and iodobenzene, are also polybrominated by TBCA in 98% H 2 SO 4 [71]. ...
... As expected, the reaction of more reactive arenes with TCCA can also be accelerated in 98% H 2 SO 4 and an example is the impressive formation of 2,4,6-trichloroanisole from anisole in 28% (82% yield, based on unreacted anisole) after only 5 min [69], while monohalogenated products are formed within 1.5 h in ordinary conditions [61]. Similar behavior was observed in the reactions of TCCA with weakly activated arenes. ...
Haloarenes are important chemical compounds from academic, biological, and industrial point of view. They can usually be prepared by an electrophilic halogenation of aromatic compounds using the halogen in its elemental form (X2), a reaction formerly described by Couper in 1857. Recently, the interest in new reagents that can accomplish a safe, efficient, and convenient halogenation of arenes has grown enormously. The present review summarizes the utilization of trihaloisocyanuric acids in the electrophilic aromatic halogenations and focuses on their green aspects.
... We have already reported that trichloroisocyanuric acid can react with arenes bearing electron withdrawing groups under strongly acidic conditions [99], being the reactivity of TCCA highly influenced by the acidity of the reaction medium [100]. A very interesting case is depicted in (Table 4) for the preparation of 5chloroisatin from isatin and TCCA [99]. ...
... It did not react in acetanilide or HOAc, but it did react in 98% H 2 SO 4 to give a mixture of polychlorinated products [99]. Reducing the acidity of the reaction medium through dilution with HOAc [100] or by using the Brønsted-acidic ionic liquid BMIM(SO 3 H)OTf as the solvent [97a] led to monochlorination of the substrate, although the yield decreased.Once more, the reactivity of trichloroisocyanuric acid is determined by the acid strengh of the medium. The reaction of trichloroisocyanuric acid with arenes with different nucleophilic degrees (in increasing order of reactivity with an electrophile) benzene, toluene, and acetanilide (Tables 6, 7, and 8 respectively) showed similar behavior, the more acid the medium, the higher yield. ...
... The reaction of trichloroisocyanuric acid with arenes with different nucleophilic degrees (in increasing order of reactivity with an electrophile) benzene, toluene, and acetanilide (Tables 6, 7, and 8 respectively) showed similar behavior, the more acid the medium, the higher yield. It may also be noted that the reaction of TCCA with tolune in 98% H 2 SO 4 led to a mixture of polychlorinated products in only 20 min [100], and the selectivity to o-and p-toluene increases with dilution of the acidic medium. Acetanilide led to a mixture of chlorinated products in 60% yield after 120 h at room temperature, whilst in 98% H 2 SO 4 and low temperature, the pchloro isomer was regioselectively formed in 56% in only 15 min [102]. ...
The present review summarizes the synthetic application of trichloroisocyanuric acid [1,3,5-trichloro-1,3,5-triazine-2,4,6- (1H,3H,5H)-trione] as a convenient reagent for the electrophilic chlorination of unsaturated carbon-carbon bonds and focuses on its green aspects. Chlorination reactions involving alkenes, alkynes, arenes, and (di)carbonyl compounds and the chlorodecarboxylation of cinnamic acids (Hunsdiecker reaction) are presented and discussed. Trichloroisocyanuric acid is a safe, stable, easily handled, inexpensive and commercially available solid. At the end of the reactions, cyanuric acid is obtained as by-product and can be reused to produce trichloroisocyanuric acid. In accordance with green chemistry principles, the use of trichloroisocyanuric acid enables chlorination without chlorine or other harmful or dangerous reagents.
... The initial experiment using 0.34 M equivalent of TCCA as oxidant resulted in only traces of the respective 1,3,4-oxadiazole 2a after 50 min of reaction (entry 1). This result led us to double the stoichiometric amount of TCCA and change the solvent to acetic acid, whereas it is known that acidic medium improves the electrophilicity of the trihaloisocyanuric acids [32], thus promoting a possible improvement in the oxidation reaction. These changes resulted in the formation of 2a in 51 % yield (entry 2), however, some minor byproducts arising from electrophilic aromatic substitution of the N-phenyl ring [33] were identified in the crude reaction. ...
... Unfortunately, in contrast to the halogenation of fluorobenzenes, the chlorination and bromination of chlorobenzenes and bromobenzenes resulted in low regioselectivity (29,30). Pyridine (31) and arenes with two strong electron-withdrawing groups (32,33) are not reactive in the system. Chlorination and Iodination of Arenes. ...
The electrophilic halogenation of arenes is perhaps the simplest method to prepare aryl halides, which are important structural motifs in agrochemicals, materials, and pharmaceuticals. However, the nucleophilicity of arenes is weakened by the electron-withdrawing substituents, whose electrophilic halogenation reactions usually require harsh conditions and lead to limited substrate scopes and applications. Therefore, the halogenation of arenes containing electron-withdrawing groups (EWGs) and complex bioactive compounds under mild conditions has been a long-standing challenge. Herein, we describe Brønsted acid-catalyzed halogenation of arenes with electron-withdrawing substituents under mild conditions, providing an efficient protocol for aryl halides. The hydrogen bonding of Brønsted acid with the protic solvent 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) enables this transformation and thus solves this long-standing problem.
... 10%) [68]. These results indicate that the highly protonated TBCA-species works as a powerful electrophile, whose reactivity is regulated by the acid strength of the medium [70]. The increase of the degree of protonation of TBCA can lead to higher electrophile reactivity, since the reactant is destabilized by the charge-charge repulsion in relation to the transition state for Br + release, decreasing the activation bar-rier. ...
In this chapter, we discussed about the recent advances in the synthesis and applications of chloroarenes. After an overview on the production and uses of industrially relevant chloroarene derivatives, a compilation of existing approaches to chloroaromatics is presented. Although conventional chlorination of arenes is a well‐established transformation that has been studied in great detail in many textbooks, current challenges have driven scientists to design new strategies (e.g. reagents, chlorinating systems, catalysts, reaction media, electrochemical, photochemical, and continuous flow methods) that can address the need for efficiency and sustainability. Discussion on the scope and limitations of the existing methods for the chlorination of aromatic rings is also provided. Finally, this chapter ends with a selection of recent applications of chloroarenes and future directions in this field.
Both mixed λ3-iodoarenes and λ3-iodoarenes possessing -OTf ligands are coveted for their enhanced reactivities. Here we describe the synthesis, reactivity, and comprehensive characterisation of two new ArI(OTf)(X) species, a class of compound that were previously only invoked as reactive intermediates where X = Cl, F and their divergent reactivity with aryl substrates. A new catalytic system for electrophilic chlorination of deactivated arenes using Cl2 as the chlorine source and ArI/HOTf as the catalyst is also described.
Both mixed λ3-iodoarenes and λ3-iodoarenes possessing -OTf ligands are coveted for their enhanced reactivities. Here we describe the synthesis, reactivity, and comprehensive characterisation of two new ArI(OTf)(X) species, a class of compound that were previously only invoked as reactive intermediates where X= Cl, F and their divergent reactivity with aryl substrates. A new catalytic system for electrophilic chlorination of deactivated arenes using Cl2 as the chlorine source and ArI/HOTf as the catalyst is also described.
A simple, efficient and pot-economic approach in a single vessel has been developed for conversion of aromatic and aliphatic carboxamides into primary amines with one fewer carbom atom (Hofmann reaction) in 38–89 % yield by reacting with trichloro- or tribromoisocyanuric acid and sodium hydroxide in aqueous acetonitrile. Under the same reaction conditions, cyclic imides gave amino acids (69–83 %). The role of the trihaloisocyanuric acids is the in situ generation of N-haloamides, key-intermediates for the Hofmann reaction. The scalability of the methodology was demonstrated by a multigram-scale transformation of phthalimide into anthranilic acid in 77 % yield.
An efficient chlorination of indoles and electron‐rich arenes with chlorine anion as nucleophile is described. With the use of ethyl phenyl sulfoxide as the promoter, the reaction went smoothly under metal‐free and mild conditions. Various indoles and electron‐rich arenes are converted into the corresponding chlorinated compounds in moderate to excellent yields. A plausible interrupted Pummerer reaction mechanism was proposed without the oxidation of chloride anion. In addition, the byproduct thioether could be easily converted to the starting material sulfoxide just by a simple oxidation reaction.
A variety of arenes and heteroarenes are chlorinated in moderate to excellent yields using N-chlorosuccinimide (NCS) under visible-light activated conditions. A screening of known organic dye photocatalysts resulted in the identification of methylene green as the most efficient catalyst to use with NCS. According to mechanistic studies described within, the reaction is speculated to proceed via a single electron oxidation of NCS utilizing methylene green under visible-light photoredox pathway. The photo-oxidation of NCS amplifies the electrophilicity of the chlorine atom of the NCS, thus leading to enhanced reactivity as a chlorinating reagent with aromatic substrates.
Heteroarenes and arenes that contain electron-withdrawing groups are chlorinated in good to excellent yields (scalable to gram scale) using trichloroisocyanuric acid (TCCA) and catalytic Brilliant Green (BG). Visible-light activation of BG serves to amplify the electrophilic nature of TCCA, providing a mild alternative approach to acid-promoted chlorination of deactivated (hetero)aromatic substrates. The utility of the TCCA/BG system is demonstrated through comparison to other chlorinating reagents and by the chlorination of pharmaceuticals including caffeine, lidocaine, and phenazone.
Trichloroisocyanuric acid (TCCA) is a versatile and efficient reagent for chlorination and oxidation reactions. Depending on the reaction conditions employed, it can release either an electrophile chlorine atom (Cl+) or a radical chlorine atom (Cl.) promoting selectively different path ways of reaction. It was effectively used to synthesize many classes of compounds such as: chlorinated arenes, N‐chloramines and amides, α‐halo‐carbonyl compounds, benzyl chlorides, esters, carboxylic anhydrides and amides. The procedures, which make use of TCCA, have mild reaction conditions and optimal stoichiometric molar ratio of reactants and avoid the use of any metal‐based catalysts. In any case very high yield and selectivity were observed. The easy and safe handling, the stability and the low cost of this reagent make it particularly attractive for large‐scale use and industrial applications.
BACKGROUND
Anthranilic diamide insecticides control lepidopteran pests through selectively binding and activating insect ryanodine receptors (RyRs). In order to search for potential insecticides targeting the ryanodine receptors, a series of anthranilic diamide analogs including trifluoromethyl, nitro, or chloro group were designed and synthesized by the principle of bioisosterism and structural optimization.
RESULTS
Insecticidal data indicated that some compounds displayed good activity against oriental armyworm (Mythimna separata) and diamondback moth (Plutella xylostella). Especially, the larvicidal activity of 6p against P. xylostella was 95% at 0.01 mg L‐1, equivalent to chlorantraniliprole (85%, 0.01 mg L‐1). The CoMSIA model obtained indicated that hydrogen bond acceptor and electron‐withdrawing groups in the R′3 group are favourable for insecticidal activity against M. separata, which is consistent with the structure‐activity relationships. Moreover, the calcium imaging experiment indicated, like chlorantraniliprole, 6h and 6p are interacting with the ryanodine receptor.
CONCLUSION
Introducing trifluoromethyl, nitro, or chloro group to a specific position in the N‐phenylpyrazole could improve or maintain the activity against M. separata and P. xylostella. 6h and 6p could be used as potential lead compounds for ryanodine receptor modulators.
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A new triazine-based cationic leaving group has been developed for the acid-catalyzed alkylation of O- and C-nucleophiles. There are two synergistic driving forces, namely, stable C=O bond formation and charge-charge repulsive effects, involved in the rapid generation of the carbocation species in the presence of trifluoromethanesulfonic acid (~200 mol%). Considerable rate acceleration of benzylation, allylation, and p-nitrobenzylation was observed as compared to the reactions with less than 100 mol% of the acid catalyst. The triazine-based leaving group showed superior p-nitrobenzylation yield and stability in comparison to common leaving groups, trichloroacetimidate and bromide. A plausible reaction mechanism (the cationic leaving group pathway) was proposed on the basis of mechanistic and kinetic studies, NMR experiments, and calculations.
In order to discover potent insecticides targeting at ryanodine receptors (RyRs), a series of novel anthranilic diamides analogs (12a-u) containing N-substituted phenylpyrazole were designed and synthesized. These compounds were characterized by 1H NMR, 13C NMR and HRMS, and the structure of compound 12u was confirmed by X-ray diffraction. Their insecticidal activities indicated that these compounds displayed moderate to excellent activities. In particular, 12i showed 100% and 37% larvicidal activities against oriental armyworm (Mythimna separata) at 0.25 and 0.05 mg L-1, equivalent to that of chlorantraniliprole (100%, 0.25 mg L-1and 33 %, 0.05 mg L-1). The activity of 12i against diamondback moth (Plutella xylostella) was 95% at 0.05 mg L-1, while the control was 100% at 0.05 mg L-1. The calcium-imaging technique experiment results showed that the effects of 12i on the intracellular calcium ion concentration ([Ca2+]i) in neurons were concentration-dependent. After the central neurons of Helicoverpa Armigera were dyed by loading with fluo-5N and treated with 12i, the free calcium released in endoplasmic reticulum indicated the target of compound 12i is RyRs or IP3Rs. The activation of the RyRs by natural ryanodine completely blocked the calcium release induced by 12i, which indicated that RyRs in the central neurons of Helicoverpa Armigera third-instar larvae is the possible target of compound 12i.
Fluorous Yamaguchi (FY) reagents bearing a perfluoroalkyl chain were prepared and employed in esterification reactions; the yields were similar to those obtained with the traditional Yamaguchi (TY) reagent. Fluorous benzoic acids derived from the FY reagents were separated easily after the reaction. GC analysis revealed that the initial rates of reaction with the FY reagents were higher than those with the TY reagent. The acidities of benzoic acids produced from the FY and TY reagents were predicted by DFT to be similar (1.20 and 0.96, respectively).
Listeria monocytogenes (L. monocytogenes) is a gram positive food-borne pathogen that is able to form biofilm on food factory surfaces. Formation of biofilm makes the bacteria much more resistance to environmental stresses such as disinfectant. The extracellular polymeric matrix (biofilm structure) which is mostly comprised of sticky extracellular polysaccharides (EPS) and proteins can protect bacteria in a harsh condition. The efficiency of four disinfectants on removing L. monocytogenes biofilm was investigated. Five concentration levels (100, 50, 25, 12.5, and 6.25%) of disinfectants were tested. In the microtitre assay, the optical density at 595 nm CV-OD595 value, was used to measure the amount of remained biofilm after 24 h. Results showed that disinfectants did not have significant effect on removing L. monocytogenes biofilm. Formation of L. monocytogenes biofilm significantly decreased the efficiency of disinfectants. Biofilm produced by strain number 9 showed higher resistance to disinfectant. Low concentrations (<50%) of disinfectants did not show significant effect on removing L. monocytogenes biofilm.
[87-90-1] C3Cl3N3O3 (MW 232.41) InChI = 1S/C3Cl3N3O3/c4-7-1(10)8(5)3(12)9(6)2(7)11 InChIKey = YRIZYWQGELRKNT-UHFFFAOYSA-N (powerful chlorinating agent for sulfides,3, 4 amides and imides,5 aromatic compounds,6 ketones,7 and ethers;8 oxidizing agent for secondary alcohols,9 ethers,10 alkenes,11 and oximes 12)Alternate Names: TCICA; 1,3,5-trichloro-1,3,5-triazine-2,4,6 (1H,3H,5H)-trione; trichloro-s-triazinetrione; isocyanuric chloride.Physical Data: mp 249–251 °C.Solubility: 0.2 % in H2O; very sol acetonitrile; sol acetone, acetic acid, ethyl acetate; sl sol benzene, chloroform, methylene chloride.Form Supplied in: white granular solid; widely available for swimming pool use; purity 97–99 %; available chlorine 88–91% as measured by iodometric titration.2Analysis of Reagent Purity: mp or iodometric titration.Purification: can be recrystallized from 1,2-dichloroethane or benzene.Handling, Storage, and Precautions: moisture sensitive, but may be stored under nitrogen at rt for over a year. The dust is extremely destructive to mucous membranes and upper respiratory tract, eyes, and skin. This reagent has been reported to explode after a delay period when in contact with alcohols, amines, or dialkyl sulfoxides, or when contaminated with organic compounds. As with other strong oxidizing agents, it should be added to a solvent.
An efficient and facile method has been developed for the conversion of alcohols into alkyl bromides under neutral conditions using tribromoisocyanuric acid and triphenylphosphine (molar ratio 1.0:0.7:2.0, alcohol/ tribromoisocyanuric acid/triphenylphosphine) in dichloromethane at room temperature. This method can be applied for the conversion of primary, secondary, benzylic and allylic alcohols, and their corresponding bromides are obtained in 67-82 % yield. Tertiary alcohols do not react under these conditions.
It is shown that both tribromoisocyanuric acid (TBCA) and trichloroisocyanuric acid (TCCA) are excellent reagents for direct halogenation of electron-rich aromatics under solvent-free, ball-milling conditions. The results are remarkable in light of the fact that chlorination of aromatics without any acid catalyst is heretofore unknown. The procedure is operationally simple, and the reactions occur within a few hours, affording high yields of halogenated products. Similarly, crystalline β-keto dicarbonyl compounds are shown to undergo direct α,α-dihalogenation with TBCA and TCCA with ball milling. Whereas monoketones are found to be unreactive with TBCA/TCCA, addition of 25 mol-% of p-toluenesulfonic acid as a solid catalyst catalyzes the reaction, leading to the formation of α-chloro/bromo ketones in very good isolated yields. The fact that each of the reagents, in principle, serves as a source of three halogen atoms should render solvent-free halogenation of aromatics and carbonyl compounds with TBCA/TCCA an invaluable synthetic protocol.
The environmental-friendly chlorination reaction of toluene by trichloroisocyanuric acid (TCCA, C3N3O3Cl3) was investigated applying immobilized ionic liquids (ILs) on different supports. Ionic liquids were grafted either on carbon nanofibers (CNF) or encapsulated in zeolites. Their influence on the chlorination activity as well as on the selectivity in different chlorinated products was studied. An unusually high selectivity toward meta-chlorotoluene was achieved, up to 36%. Hence, the selectivity could be tuned to produce either expected ortho-/para-chlorotoluene or meta-chlorotoluene with a proper support choice.
TFA as the medium avoids polybromination which is observed for the same reaction in concentrated sulfuric acid.
Dichloroiodoisocyanuric acid was prepared in 93% by heating trichloroisocyanuric acid with 1.05 mol equiv. of iodine. This new reagent is very efficient for regioselective electrophilic iodination of activated arenes. Alkenes react with dichloroiodoisocyanuric acid in the presence of oxygenated nucleophiles (water, alcohols, and acetic acid), leading to the corresponding iodohydrins, β-iodoethers and β-iodoacetates with reaction times of less than one minute and with a high degree of regioselectivity. Enol ethers resulted in the regioselective formation of the corresponding iodine-dialkylacetals. Experimental results and DFT calculations showed that dichoroiodoisocyanuric acid is more reactive with unsaturated systems than triiodoisocyanuric acid.
Os ácidos tribromo- e tricloro-isocianúricos reagem com ácidos cinâmicos na presença de NaOH/H2O/Et2O à temperatura ambiente para produzir regiosseletivamente (E)-2-halo-estirenos em 25-95% de rendimento. Estudo sobre o mecanismo da reação utilizando correlações Hammett e cálculos DFT (teoria do funcional da densidade) mostraram que esta reação tem como passo determinante a velocidade da adição eletrofílica de um átomo de cloro à ligação dupla.
Trichloroisocyanuric acid (TCCA) reacts with arenes and its reactivity is highly affected by the acid strength of the reaction medium. Deactivated arenes are efficiently chlorinated by TCCA in solid acids. Our experimental results, along with DFT calculations show that chlorination using solid acid catalysis is feasible, thus leading to possible replacement of strong liquid acids used to promote this superelectrophilic reaction. We have tested several solid acids, showing the synergic need for acid strength and pore size for promoting the reaction.
A new green chlorination process of deactivated aromatics has been developed, being environmental-friendly and allowing the continuous chlorination of 1.7 kg nitrobenzene/kg catalyst per day.The triple novelty consists of using a non-conventional chlorination agent, the trichloroisocyanuric acid (TCCA, C3N3O3Cl3), along with solid acid catalysts (mainly zeolites) in a continuous flow reactor system. Different zeolites and solid acids have been tested in the chlorination of nitrobenzene, chosen as a model deactivated aromatic substrate.HUSY zeolite was found as the more promising catalyst for performing the chlorination of nitrobenzene, with good conversions (39–64%) at high selectivity toward monochlorinated products (90–99%). Finally, it is worthy to note that HUSY zeolite could be reused for at least five successive runs.
Cohalogenation of (R)-limonene with N-halosuccinimides and N-halosaccharins followed by base treatment (Na2CO3/EtOH/H2O) of the resulting halohydrins produced stereoselectively (1S, 2R, 4R)-1,2-epoxylimonene (trans-1,2-epoxylimonene). The best results were obtained with N-bromosuccinimide (54% total yield).
N-halosaccharins proved to be useful and alternative reagents for diverse organic transformations, such as halogenation of aromatic compounds, benzylic and a-carbonylic positions, cohalogenation of alkenes, oxidation of secondary alcohols, etc. Their preparation from saccharin, a cheap and readly available starting material, is simple.
The chlorination of activated aromatic rings is efficiently achieved under mild conditions by reaction of aromatic compounds with trichloroisocyanuric acid in acetonitrile, at room temperature, leading to products in 60-95% isolated yields and good regioselectivity.
Trichloroisocyanuric acid (TICA) in H2SO4 is an efficient reagent for regioselective chlorination of isatin at the 5-position and deactivated aromatic compounds, such as nitrobenzene. DFT calculations suggest formation of a superelectrophilic polyprotonated species that can transfer Cl+ to the aromatic ring more efficiently than TICA due to charge-charge repulsion relief.
Triiodoisocyanuric acid (TICA) was prepared in 90% yield by heating trichloroisocyanuric acid with iodine in a sealed tube. The reaction of TICA with activated arenes in acetonitrile led to an efficient and highly regioselective formation of the corresponding iodoarenes, in 73-93% isolated yield. Aniline and phenol are monoiodinated regioselectively using MeOH (53%) and CH(2)Cl(2) (88%) as solvents, respectively.
The reaction of alkenes with easily handled trihaloisocyanuric acids / NaX in aqueous acetone produces the corresponding vicinal dihaloalkanes in moderate to excellent yields.
N-Cloro e N-bromo-sacarinas reagem com compostos aromáticos ricos em elétrons (anisol, acetanilida, N,N-dimetilanilina) para fornecer os produtos de halogenação do anel. As reações com a N-bromo-sacarina fornecem somente os produtos com substituição na posição para, enquanto que a utilização de N-cloro-sacarina gera mistura de produtos orto e para, com predominância do isômero para (ca. 4-5 : 1). Já as reações das halo-sacarinas com alquenos (cicloexeno, estireno, a-metilestireno e 1-hexeno) em acetona aquosa fornecem as respectivas haloidrinas.
The preparation of epoxides is efficiently achieved in mild conditions by reaction of alkenes with trichloroisocyanuric acid in aqueous acetone followed by treatment of the resulting chlorohydrin with aqueous KOH in ether / pentane.
Since its original appearance in 1977, Advanced Organic Chemistry has maintained its place as the premier textbook in the field, offering broad coverage of the structure, reactivity and synthesis of organic compounds. As in the earlier editions, the text contains extensive references to both the primary and review literature and provides examples of data and reactions that illustrate and document the generalizations. While the text assumes completion of an introductory course in organic chemistry, it reviews the fundamental concepts for each topic that is discussed.
The two-part fifth edition has been substantially revised and reorganized for greater clarity. Among the changes: Updated material reflecting advances in the field since 2001’s Fourth Edition, especially in computational chemistry; A companion Web site provides digital models for study of structure, reaction and selectivity; Solutions to the exercises provided to instructors online.
The control of reactivity to achieve specific syntheses is one of the overarching goals of organic chemistry. Part B describes the most general and useful synthetic reactions, organized on the basis of reaction type. Together with Part A: Structure and Mechanisms, the two volumes are intended to provide the advanced undergraduate or beginning graduate student in chemistry with a sufficient foundation to comprehend and use the research literature in organic chemistry.
Sodium chlorate/hydrochloric acid mixtures were used to chlorinate activated arenes and the α-position of ketones. This chlorination method was used to produce selectively mono-, di-, and trichlorinated compounds by controlling the molarity of sodium chlorate. This reagent proved to be much more efficient and easier to handle than chlorine gas.
Trichloroisocyanuric acid reacts with alkynes in the presence of water in acetone or acetonitrile to form alpha,alpha-dichloro ketones and in methanol to form alpha,alpha-dichlorodimethyl ketals.
The reaction of triiodoisocyanuric acid (TICA) with deactivated arenes in acidic medium led to the efficient and regioselective formation of the corresponding iodoarenes, in 55-88% isolated yield. The acidity of the medium was found to be the most important factor influencing the electrophilic iodination of weakly nucleophilic substrates by TICA.
The chlorination of activated aromatic rings is efficiently achieved under mild conditions by reaction of aromatic compounds with trichloroisocyanuric acid in acetonitrile, at room temperature, leading to products in 60-95% isolated yields and good regioselectivity.
Efficient methodologies for the preparation of bromodichloroisocyanuric acid were developed (70-75%). This new reagent is very efficient for regioselective electrophilic bromination of activated arenes (86-93%) and cobromination of alkenes with oxygenated nucleophiles (31-98%). The reaction of bromodichloroisocyanuric acid with anisole, acetanilide, AT-methylacetanilide leads to 4-substituted monobromoarene and with 2-methoxynaphthalene leads to 1-bromo-2-methoxynaphthalene. Alkenes were cobrominated in the presence of oxygenated nucleophilic solvents (water, alcohols, and acetic acid), leading to the corresponding bromohydrins, beta-bromoethers and beta-bromoacetates.
A simple one-step method for the preparation of tribromoisocyanuric acid in good yield (87%) has been developed. The reaction of tribromoisocyanuric acid with alkenes in presence of nucleophilic solvents (MeOH, i-PrOH, AcOH and a mixture of H2O-acetone, 1:5) led to the corresponding beta-bromoethers, beta-bromoacetates and bromohydrins, in high regioselectivity and good yields (73-98%).
The reaction between amines or α-aminoacids with trichloroisocyanuric acid is studied under various conditions: N,N-dichloroamines, nitriles and ketones can be obtained from primary amines, while free aminoacids undergo oxidative decarboxylation to the corresponding nitrile of one less carbon atom.
Trichloroisocyanuric acid is an effective reagent for the chlorination of ketones in the alpha position.
Halofluorination of alkenes with a new system (trihaloisocyanuric acids and HF center dot pyridine) results in the formation of vicinal halofluoroalkanes. The reaction is regioselective leading to Markovnikov-oriented products and the halofluorinated adducts follow anti-addition in the case of cyclohexene and 1-methylcyclohexene. Reaction yields range from 67-88%.
1-Halo derivatives of the 2,2,6,6-tetramethylpiperidine series oxidize sterically hindered phenols to form dimers and p-quinones.
The reaction of deactivated arenes with tribromoisocyanuric acid (TBCA) in 98% H2SO4 produced bromoarenes in good yields. The acidity of the medium controls the strength of the brominating agent and the amount of polybrominated products. DFT calculations at B3LYP/6-311++G∗∗ level showed that the protonated TBCA (a superelectrophilic species) can easily transfer Br+ to deactivated arenes, in order to decrease internal charge–charge repulsion.
The reaction of β-dicarbonyl compounds (β-ketoesters and β-diketones) with 0.34molequiv of trichloro- and tribromoisocyanuric acids produced regioselectively the corresponding α-monohalo β-dicarbonyl compound. On the other hand, utilization of 0.68molequiv of the trihaloisocyanuric acid produced the α,α-dihalo β-dicarbonyl compound.
The reaction of triiodoisocyanuric acid (prepared from I2 and trichloroisocyanuric acid in 90% yield) with alkenes in the presence of oxygenated nucleophilic solvents (alcohols, AcOH and H2O) led to the corresponding β-iodoethers, β-iodoacetates and iodohydrins, in 66–98% isolated yield. Enolethers reacted with triiodoisocyanuric acid in MeOH to produce dialkylacetals (70–83%).
SnCl4/Pb(OAc)4 acts as a safe source of Cl2 for the chlorination of aromatic compounds. A variety of aromatic compounds are effectively chlorinated with SnCl4/Pb(OAc)4 under mild conditions. The mixture is a selective chlorinating agent, particularly with polyalkylbenzenes, polycyclic aromatic compounds and anisoles.
An efficient and highly regioselective bromination of activated aromatic rings promoted by tribromoisocyanuric acid by in situ generation of Br⁺ has been developed. A range of aromatic compounds were reacted with tribromoisocyanuric acid and trichloroisocyanuric acid and sodium bromide.
N-Chlorination of various amides, lactams, and carbamates with very cheap trichloroisocyanuric acid proceeds efficiently under very mild conditions. Excellent results were also observed for the N-chlorination of carbamates of free amino acids.
A new and efficient procedure for the one-pot conversion of various alcohols, aldehydes and primary amines into the corresponding nitriles in excellent yields was easily achieved by trichloroisocyanuric acid (TCCA) as an oxidant and reagent in aqueous ammonia. Also, various benzylic halides were smoothly and directly converted into the corresponding aromatic nitriles in high yields under the same conditions.
A survey study on electrophilic chlorination of aromatics with trichloroisocyanuric acid (TCICA) in Bronsted-acidic imidazolium ionic liquid [BMIM(SO3H)][OTf] is reported. The reactions are performed under very mild conditions (at similar to 50 degrees C) and give good to excellent yields, depending on the substrates. Chemoselectivity for mono- v. dichlorination can be tuned by changing the arene-to-TCICA ratio and the reaction time. The survey study and competitive experiments suggest that triprotonated/protosolvated TCICA is a selective/moderately reactive transfer-chlorination electrophile. Density functional theory was used as guide to obtain further insight into the nature of the chlorination electrophile and the transfer-chlorination step.
Electrophiles that are capable of further interaction (coordination, solvation) with strong Brønsted or Lewis acids can be activated in this way. The resulting enhancement of their reactivity is great compared to that of their parent compounds under conventional conditions and indicates superelectrophile formation (i.e., electrophiles with doubly electrodeficient (dipositive) nature whose reactivity substantially exceeds that of their parent electrophiles). As representative examples the protolytic or electrophilic activation of the following electrophiles in superacidic and related strongly electrophilic media is discussed: oxonium, carboxonium, sulfonium, selenonium, and telluronium ions; acyl cations; protonated CO, CO2, COS, and carbonic and thiocarbonic acids; heteroatom-substituted carbocations (and some of their boron analogs); halonium ions; azonium (including nitronium) and carbazonium ions. Emphasis is placed on both experimental chemical investigations and theoretical treatment of the involved systems. As prototypes for protolytically activated onium ions, the protohydronium dication (diprotonated water) and its sulfur analogue, the protosulfonium dication, are of particular significance. The protoacetyl and protoformyl dication (diprotonated carbon monoxide), diprotonated carbonic acid and carbon dioxide, diprotonated hydrogen cyanide and nitriles, as well as the protonitronium dication among others—and their emerging chemistry are discussed as examples of superelectrophiles.
Aniline undergoes regioselective trichlorination by N-chlorosuccinimide (NCS) in acetonitrile in good yield. The product 2,4,6-trichoroaniline was converted into 1,3,5-trichlorobenzene by reduction of its diazonium salt. Reaction of the methyl carbamate of aniline with NCS gave only the 2,4-dichlorophenyl carbamate.
Previous attempts to combine Hartree–Fock theory with local density‐functional theory have been unsuccessful in applications to molecular bonding. We derive a new coupling of these two theories that maintains their simplicity and computational efficiency, and yet greatly improves their predictive power. Very encouraging results of tests on atomization energies, ionization potentials, and proton affinities are reported, and the potential for future development is discussed.
A new mild and efficient method for aromatic halogenation with a wide variety of halides in the presence of sodium bismuthate NaBO3 in AcOH is reported. Metal halides of groups Ia, IIa, IIIa, IVa, Va, and the first row of transition elements are suitable for this method.
The reaction of trichloroisocyanuric acid (TCICA) and triphenylphosphine in the presence of a carboxylic acid results in the in situ formation of the corresponding acid chloride under mild conditions. Subsequent addition of amines or alcohols, in the presence of a tertiary amine affords the corresponding amides, or esters, in good to excellent yields. The methodology was applied to the synthesis of a dipeptide.
A route to chemoselective oxidation and chlorination of aryltrifluoromethylsulfide using trichloroisocyanuric acid (TCCA) in ionic liquid, an efficiently O-methylation reaction and a reduction of nitro- to amido- in excellent yields have been developed.Graphical abstractA route to chemoselective oxidation and chlorination of aryltrifluoromethylsulfide using trichloroisocyanuric acid (TCCA) in ionic liquid, an efficiently O-methylation reaction and a reduction of nitro- to amido- in excellent yields have been developed.
Reaction of electrophilic bromination of aniline containing various ortho, meta, and para substituents in the aromatic ring
was studied. The optimal conditions for synthesis of mono-, di-, tri-, and tetrabromo derivatives of aniline and brominated
analog of Aniline Black were found.
para-Regioselective bromination of phenol and analogues, promoted by p-toluenesulfonic acid, is achieved in high to excellent yields at room temperature with N-bromosuccinimide. Chlorination with N-chlorosuccinimide and catalysed by p-toluenesulfonic acid also gives para-chlorinated phenol analogues in good yields at room temperature. para-Bromination of phenol, promoted by p-toluenesulfonic acid, is achieved in excellent yields at room temperature with N-bromosuccinimide. p-Toluenesulfonic acid is also effective as a promoter of para-chlorination with N-chlorosuccinimide.
Despite the remarkable thermochemical accuracy of Kohn–Sham density-functional theories with gradient corrections for exchange-correlation [see, for example, A. D. Becke, J. Chem. Phys. 96, 2155 (1992)], we believe that further improvements are unlikely unless exact-exchange information is considered. Arguments to support this view are presented, and a semiempirical exchange-correlation functional containing local-spin-density, gradient, and exact-exchange terms is tested on 56 atomization energies, 42 ionization potentials, 8 proton affinities, and 10 total atomic energies of first- and second-row systems. This functional performs significantly better than previous functionals with gradient corrections only, and fits experimental atomization energies with an impressively small average absolute deviation of 2.4 kcal/mol.
The hydroxyalkylation reactions of aceanthrenequinone (6) and acenapthenequinone (7) with a series of arenes have been studied. In reactions with the Brønsted superacid CF(3)SO(3)H (triflic acid), the condensation products are formed in good yields (58-99%, 10 examples) with high regioselectivity. Computational studies were also done to examine the structures and energies of mono- and diprotonated species from 6 and 7. The results from the condensation reactions are consistent with the formation of superelectrophilic species involving protosolvation of carboxonium ion intermediates.
A trichloroisocyanuric acid (TCCA) mediated Hofmann rearrangement was utilized to synthesize methyl-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylate. A variety of functional groups are tolerated in this reaction including vinyl, cyclopropyl, pyridyl, aryl, benzyl, and nitro groups.
A correlation-energy formula due to Colle and Salvetti [Theor. Chim. Acta 37, 329 (1975)], in which the correlation energy density is expressed in terms of the electron density and a Laplacian of the second-order Hartree-Fock density matrix, is restated as a formula involving the density and local kinetic-energy density. On insertion of gradient expansions for the local kinetic-energy density, density-functional formulas for the correlation energy and correlation potential are then obtained. Through numerical calculations on a number of atoms, positive ions, and molecules, of both open- and closed-shell type, it is demonstrated that these formulas, like the original Colle-Salvetti formulas, give correlation energies within a few percent.
The reaction of phenol, 2-nitrophenol, thymol, 1-naphthol and 1-hydroxy-2-naphthoic acid with HCl-H2O2 was carried out in the presence and in the absence of ultrasound. In the presence of ultrasound phenol, 2-nitrophenol and thymol gave only the chlorinated products, while 1-naphthol and 1-hydroxy-2-naphthoic acid gave chlorinated quinones as the major products. The reactions with ultrasound were compared with those without ultrasound.
Nucleophilic solvation is the interaction of electron-donor solvents with electron-deficient reagents. Electrophilic solvation is the related reverse interaction. Superelectrophilic solvation involves the interaction of electron-donating groups (ligands) of overall electron-deficient species (electrophiles) with strongly electron-acceptor superacids. It occurs with liquid superacids, on solid acids, and even in some enzymatic biological systems. Diminishing neighboring group participation of the electrophilic centers by the affected groups greatly enhances their electrophilic reactivities (superelectrophilic activation), resulting in unusual reactions of substantial interest. Representative examples of superelectrophilic solvation are discussed.
N-Halosuccinimides (NXS, 1) are efficiently activated in trifluoromethanesulfonic acid and BF(3)-H(2)O, allowing the halogenations of deactivated aromatics. Because BF(3)-H(2)O is more economic, easy to prepare, nonoxidizing, and offers sufficiently high acidity (-H(0) approximately 12, only slightly lower than that of trifluoromethanesulfonic acid), an efficient new electrophilic reagent combination of NXS/BF(3)-H(2)O has been developed. DFT calculations at the B3LYP/6-311++G//B3LYP/6-31G level suggest that protonated N-halosuccinimides undergo further protosolvation at higher acidities to reactive superelectrophilic species capable either in the transfer of X(+) from the protonated forms of NXS to the aromatic substrate or in forming a highly reactive and solvated X(+) which would readily react with the aromatic substrates. Structural aspects of the BF(3)-H(2)O complex have also been investigated.
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