Para-substituted Products Research Articles

Cavity Quantum Electrodynamics Enables para- and ortho-Selective Electrophilic Bromination of Nitrobenzene.

Coupling molecules to a quantized radiation field inside an optical cavity has shown great promise to modify chemical reactivity. In this work, we show that the ground-state selectivity of the electrophilic bromination of nitrobenzene can be fundamentally changed by strongly coupling the reaction to the cavity, generating ortho- or para-substituted products instead of the meta product. Importantly, these are products that are not obtained from the same reaction outside the cavity. A recently developed ab initio approach was used to theoretically compute the relative energies of the cationic Wheland intermediates, which indicate the kinetically preferred bromination site for all products. Performing an analysis of the ground-state electron density for the Wheland intermediates inside and outside the cavity, we demonstrate how strong coupling induces reorganization of the molecular charge distribution, which in turn leads to different bromination sites directly dependent on the cavity conditions. Overall, the results presented here can be used to understand cavity induced changes to ground-state chemical reactivity from a mechanistic perspective as well as to directly connect frontier theoretical simulations to state-of-the-art, but realistic, experimental cavity conditions.

Synthesis of meta-carbonyl phenols and anilines

Phenols and anilines are of extreme importance for medicinal chemistry and material science. The development of efficient approaches to prepare both compounds has thus long been a vital research topic. The utility of phenols and anilines directly reflects the identity and pattern of substituents on the benzenoid ring. Electrophilic substitutions remain among the most powerful synthetic methods to substituted phenols and anilines, yet in principle achieving ortho- and para-substituted products. Therefore, the selective preparation of meta-substituted phenols and anilines is the most significant challenge. We herein report an efficient copper-catalyzed dehydrogenation strategy to exclusively synthesize meta-carbonyl phenols and anilines from carbonyl substituted cyclohexanes. Mechanistic studies indicate that this transformation undergoes a copper-catalyzed dehydrogenation/allylic hydroxylation or amination/oxidative dehydrogenation/aromatization cascade process.

The Essence in Selectivity of Copper-Mediated Intermolecular Nucleophilic Substitution of a meta C-H Bond in 2-Methyl-N-methoxyaniline: A Theoretical Study.

The detailed mechanism for NHC-Cu(I)-catalyzed intermolecular nucleophilic substitution of the C-H bonds at aniline (2-methyl-N-methoxyaniline) was studied via DFT methods to reveal the essence of the selectivity. Calculations revealed that the meta C-H functionalization proceeds via two nucleophilic attacks on the aromatic ring rather than a one-step meta C-H substitution to give the experimentally observed major product. The reaction is initiated by activation of the substrate via oxidative addition with an NHC-Cu(I) catalyst, through which an umpolung occurs at the ring. From the activated intermediate, methoxyl group transfer to benzyl forms a resting state, while a nucleophile can attack the ortho position of benzyl to form a more stable intermediate. The nucleophile group can then transfer to the meta position by a 1,2-Wagner-Meerwein rearrangement to form the final product through a proton shuttle. In contrast, other transfer processes affording ortho- or para-substituted products encounter higher activation barriers. This work investigates the relationship of product selectivity with the umpolung of the aromatic ring, as well as the priority of a nucleophilic attack at the ortho position of the aromatic, 1,2-Wagner-Meerwein rearrangement from the ortho-substituted intermediate, and proton shuttle from the meta-substituted intermediate.

A direct alkylation of resorcinols

Alkylation of resorcinol and methyl-substituted resorcinols and its methyl ethers with alkyl bromides in water and anhydrous organic solvents led to mono- and/or dialkylated resorcinols and alkyl cyclohexendiones, depending on the structure of the starting substrates and reaction conditions. Selective di-alkylation was achieved in both, aqueous and anhydrous conditions, up to 76% yield. Resorcinol monomethyl ethers behaved similarly to phenols, giving in dry organic solvents predominantly ortho -substituted products, and a mixture of ortho- and para-substituted products together with resorcinol ethers in aqueous solution. The alkylation of 2,4,6-trimethyl resorcinol monomethyl ether showed selective 2 C-alkylation in 53% yield. 2-Methyl resorcinol with electrophiles in excess afforded in tetra-alkylation up to 72% yield.

Efficiency of C = Se as hydrogen bond acceptor in controlling regioselective amination of 5,7-dinitroquinazoline-4-selenone: Quantum mechanical, AIM and docking analysis by density functional method

Herein, we explored the theoretical aspect of reaction between 5,7-dinitroquinazoline-4-selenone and methylamine by employing density functional theory (DFT) calculations. The energetic parameters confirmed that the reaction progressed via. concerted mechanism with the single step process instead of two step process via intermediate formation. Further, role of Se = C bond as non-conventional H-bond acceptor is reported in reaction controlling factors that monitors the regioselectivity of the present proposed reaction. Despite of substantial steric hindrance at ortho-position of 5,7-dinitroquinazoline-4-selenones, the regioselective amination resulted into ortho-substituted product (P2) rather than para-substituted product (P1) attributed to non-conventional NH---Se = C intramolecular hydrogen bonding. The topological properties of the electron density distributions have been studied by using quantum theory of atoms in molecules (QTAIM). The presence of non-conventional hydrogen bond acceptor–donor interactions (NH---Se = C) in ortho-positioned amination is achieved by electron density ρ(r) and Laplacian of electron density ∇2ρ(r) in QTAIM analysis and supported the results of DFT studies hybrid with B3LYP/6-31G(d,p) basis set. Due to the lack of intramolecular hydrogen bonding interactions (NH---Se = C), the para-positioned amination on 5,7-dinitroquinazoline-4-selenone is founded to be less feasible. Further, the DFT technique has been used to investigate frontier molecular orbital (FMO) analysis and global reactive parameters using the aforesaid level of theory and basis set. HOMO-LUMO analysis revealed that ortho-substituted product (P2) has a wider energy gap (3.0684 eV) than para-substituted product (P1) (2.6402 eV) suggesting more stability of P2. The presence of hydrogen bonding interactions is further confirmed by the change in electrostatic potential regions in ortho-substituted product (P2) as compared to reactants in molecular electrostatic potential surface (MEPS) studies. Both para-substituted product (P1) and ortho-substituted product (P2) have been docked into the protein 5FCT's active site to predict favored binding location, activity and affinity by using docking studies.

Bulky lithium amides for para-elementation of secondary m-terphenylamines

Two bulky lithium m-terphenylamides are synthesized by smooth deprotonation of secondary terphenylamines with n-BuLi, which readily react with main group electrophiles (SiCl4, SiHCl3, Me3SiCl, PCl3) to afford para-substituted products. This report demonstrates an efficient methodology for the synthesis of bis- or multi-heteroatoms involved terphenyl systems.

Regioselective and solvent-free arylation of β-nitrostyrenes with mono- and dialkyl anilines

A green and solvent-free method were developed for alkylation of N,N-dialkylanilines with substituted β-nitrostyrenes using 10 mol% of choline chloride-zinc chloride deep eutectic solvent at 70 °C. The reaction was highly regioselective and only para-substituted products have been prepared. Despite the sensitivity and weak reactivity of the aniline derivatives for the Friedel–Crafts reaction in acidic media, the presented procedure was successfully carried out this transformation. The synthetic protocol was expanded for the alkylation of pyrrole and indole to produce pharmaceutically active compounds. The reduction of the nitro group of the product to amine was performed using Pd/C and hydrazine to produce amphetamine structure.

Unexpected polymorphism during a catalyzed mechanochemical Knoevenagel condensation.

The transformation of a base-catalyzed, mechano-assisted Knoevenagel condensation of mono-fluorinated benzaldehyde derivatives (p-, m-, o-benzaldehyde) with malonodinitrile was investigated in situ and in real time. Upon milling, the para-substituted product was found to crystallize initially into two different polymorphic forms, depending on the quantity of catalyst used. For low catalyst concentrations, a mechanically metastable phase (monoclinic) was initially formed, converting to the mechanically stable phase (triclinic) upon further grinding. Instead, higher catalyst concentrations crystallize directly as the triclinic product. Inclusion of catalyst in the final product, as evidenced by mass spectrometric analysis, suggests this complex polymorphic pathway may be due to seeding effects. Multivariate analysis for the in situ Raman spectra supports this complex formation pathway, and offers a new approach to monitoring multi-phase reactions during ball milling.

A DFT study on the mechanism and origins of the ligand-controlled regioselectivity of a palladium-catalyzed dearomatic reaction of 1-(chloromethyl)naphthalene with phenylacetonitrile

DFT calculations demonstrated that the bulky ligand tBuPPh2 generates para-substituted products, while the small ligand Me2PPh provides ortho-substituted products.

СИНТЕЗ ТА ДОСЛІДЖЕННЯ АНТИОКСИДАНТНОЇ АКТИВНОСТІ ДЕЯКИХ ПОХІДНИХ НА ОСНОВІ 4-ІМІНОТІАЗОЛІДИН-2-ОНУ

<p class="BodyText2" align="center"><strong>Synthesis and antioxidant activity evaluation of </strong><strong>some novel derivatives based on 4-iminothiazolydine-2-one</strong></p><p align="center">T.I. Сhaban</p><p> </p><p align="center">Lviv, Danylo Halytsky Lviv National Medical University</p><p align="center"><strong> </strong></p><p class="a"><strong>Summary</strong>: Thiazolydine derivatives belong to the group of biologically active compounds which are widely used in modern medical chemistry. They were shown to posses the wide range of biological actions.</p><p>4-Imino-2-thiazolydones are relatively unexplored with regard to their preparation synthetic protocols and biological action spectrum in the modern organic and pharmaceutical chemistry as compared to their 2-imino derivatives. Thus the objective of the present work was to synthesize a series of novel 4-imino-2-thiazolydone derivatives as the potential drug-like molecules. </p><p>3-Aryl-thiazolydine-2,4-dions were firstly prepared using the common synthetic protocol and they were then subjected to thionation reaction with phosphorus pentasulfide leading to the appropriate 3-aryl-4-thioxo-thiazolydin-2-ones obtaining.</p><p>The above-mentioned derivatives were obtained under the conditions similar to that under which well-known 4-thioxo-thiazolydine-2-one (isorhodanine) synthesis was preceded. The synthetic potential of the synthesized compounds allowed 3-aryl-4-thioxo-thiazolydones treatment with 25 % ammonia aqueous solution leading to novel 3-aryl-4-imino-thiazolydine-2-one obtaining not mentioned in the scientific literature. The reaction proceeding was possible taking into account the advantage of thione group significant activity possessing in 3-aryl-4-thioxo-thiazolydine-2-ones as cyclic thioamides owing to stronger electrophilic properties of thiocarbonyl group carbon atom as compared with carbonyl group in C<sup>4</sup> position of 3-aryl-thiazolydine-2,4-diones, consequently. One of the proofs of synthesized compounds structure was their acidic hydrolysis with 3-aryl-thiazolydine-2,4-ones generation.</p><p>The presence of active methylene group in C<sup>5</sup> position of 3-phenyl-4-imino-thiazolydine-2-one thiazolydine ring provided an entry for aldol condencation carrying out with the respective 3-phenyl-4-imino-thiazolydine-2-one 5-aryliden derivatives generation. We discovered that the high yield of the product could be achieved by introducing the equimolar amounts of 3-phenyl-4-imino-thiazolydine-2-one and appropriate aromatic aldehydes using monoaminoethanol as a catalyst.</p><p>The next stage of our strategy included the core heterocycle further structural modification in its C<sup>5</sup> position. In particular the nitrosylation reaction with nitrous acid was proceeded. It was found that 3-phenyl-4-imino-thiazolydine-2-one could interact with nitrous acid obtained in its turn under sodium nitrite treatment with hydrochloric acid. Nitrosylation reaction allowed to achiev novel 5-isonitrozo-4-imino-3-phenyl-thiazolydine-2-one which was not mentioned in chemical literature. </p><p> The structures of the obtained compounds were confirmed by <sup>1</sup>H NMR spectroscopy and elemental analysis.</p><p>The antioxidant activity of the novel compounds was determined <em>in vitro</em> on basis of free radical scavenging activity of 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical. DPPH radical has found many applications due to its high stability in a methanolic solution and intense purple color. In its oxidized form, the DPPH radical has an absorbance maximum centered at a wavelength about 540 nm. The absorbance decreases when the radical is reduced by antioxidants. Its reduction affords 2,2-diphenyl-1-picrylhydrazine (DPPH-H), or the corresponding anion (DPPH<sup>–</sup>) in basic medium. The DPPH radical acts as a scavenger for other odd-electron species which afford para-substitution products at phenyl rings.</p><p>The pharmacology screening allowed to state that the synthesized compounds had been shown to possess the moderate antioxidant activity. So it may be concluded that the functionalization of 4-iminotiazolidyn-2-one by its N<sup>3</sup> and C<sup>5</sup> positions did not lead to the free-radical-scavenging activity enhancement. </p>

Acid-Free Nitration of Benzene and Toluene in Zeolite NaZSM-5

The syntheses of nitrobenzene and p-nitrotoluene directly from benzene, toluene, and NO2 within the pore network of the initially acid-free zeolite NaZSM-5 are reported for the first time. The active species , formed by the interaction of NO2 with the Na+ cations present on the internal surface, results in the acid-free electrophilic substitution of the aromatic ring. There are two distinct reservoirs for the reagents: one associated with close proximity to the cation sites and the other associated with the siliceous areas of the pore network. Up to 34% of the hydrocarbon and 70% of the available NO2 are reacted at 50°C. Only the cation associated sites are reactive at low temperature, and there appears to be little mobility between the sites under the reaction conditions. There is no evidence of a second nitration occurring. This represents a novel route to the single nitration of benzene and toluene and for toluene, the generation of the para isomer exclusively. The pore network of the NaZSM-5 restricts the available reaction volume and transition state geometry allowing only the para-substituted product.

Methyl Salicylate: A Reactive Chemical Warfare Agent Surrogate to Detect Reaction with Hypochlorite

Methyl salicylate (MeS) has a rich history as an inert physical simulant for the chemical warfare agents sulfur mustard and soman, where it is used extensively for liquid- and vapor-permeation testing. Here we demonstrate possible utility of MeS as a reactivity simulant for chlorine-based decontaminants. In these experiments MeS was reacted with sodium hypochlorite varying stoichiometry, temperature, reaction time, and pH. No colored oxidation products were observed; however, chlorination of the aromatic ring occurred ortho (methyl 3-chlorosalicylate) and para (methyl 5-chlorosalicylate) to the position bearing the -OH group in both the mono- and disubstituted forms. The monosubstituted para product accumulated initially, and the ortho and 3,5-dichloro products formed over the next several hours. Yields from reactions conducted below pH 11 declined rapidly with decreasing pH. Reactions run at 40 °C produced predominantly para substitution, while those run at 0 °C produced lower yields of ortho- and para-substituted products. Reactions were also carried out on textile substrates of cotton, 50/50 nylon-cotton, and a meta aramid. The textile data broadly reproduced reaction times and stoichiometry observed in the liquid phase, but are complicated by physical and possibly chemical interactions with the fabric. These data indicate that, for hypochlorite-containing neutralizing agents operating at strongly alkaline pH, one can expect MeS to react stoichiometrically with the hypochlorite it encounters. This suggests utility of MeS in lieu of such highly hazardous surrogates as monochloroalkyl sulfides as a simulant for threat scenarios involving the stoichiometric decomposition of sulfur mustard. Specifically, the extent of coverage of the simulant on a fabric by the neutralizing agent can be directly measured. Similar reactivity toward other halogen oxidizing agents is likely but remains to be demonstrated.

ChemInform Abstract: Regioselective Alkylation of (η6-Triisopropylsilylbenzene)chromium( 0) Complex with Organolithium Compounds.

Reactions of tricarbonyl(η6-triisopropylsilyl(TIPS)benzene)chromium(0) complex 1b with various alkyllithiums proceed regioselectively, giving para-substituted TIPSbenzenes in high yield after oxidation with iodine. Vinyllithiums also react with the TIPSbenzenechromium complex to give para-TIPSstyrenes in good yield. In the reaction with phenyllithium, although the para-substituted product is obtained as a main product, deprotonation of the aryl group of the chromium complex also occurs competitively to afford bisTIPSbiphenyls as a by-product. Alkynyllithium, however, attacks the TIPS group to yield alkynylsilane and TIPSbiphenyl.

Multicomponent Prins-Friedel-Crafts Synthesis of 4-Aryl-5,6-Dihydropyrans

Reported is the synthesis of 4-aryl-5,6-dihydropyrans through a Lewis acid mediated multicomponent process. The reaction is proposed to proceed first by nucleophilic attack of the homopropargylic alcohol on the aldehyde to give an intermediate which undergoes Prins ­cyclization and then Friedel-Crafts reaction with the aromatic solvent. Epoxides could also be used instead of aldehydes, which further increases the scope of this reaction by providing access to substrates that would otherwise require the use of problematic aldehydes. The reaction failed for electron-donating aromatic aldehydes, such as anisaldehyde (rationalized by the increased stability of the benzylic cation intermediate which leads to an oxina-[3,3]-sigmatropic rearrangement). The attempted use of electron-rich aromatics as solvents did not provide useful yields, as they underwent Friedel-Crafts reaction with the aldehyde. Toluene gave a mixture of ortho- and para-substituted products in a 2:1 ratio.

Synthetic utility of 4-bromo-2,3,5,6-tetrafluoropyridine

The regiochemistry of nucleophilic substitution of 4-bromo-2,3,5,6-tetrafluoropyridine has been investigated. Efficient, regioselective reactions occur with alkylamine, benzylamine and alkoxide nucleophiles, yielding products where substitution occurs ortho to the ring nitrogen. The resulting 2-substituted-4-bromo-3,5,6-trifluoropyridines can be functionalised further, either by a second regioselective nucleophilic displacement or palladium catalysed elaboration at the 4-position. Reactions with aromatic N-nucleophiles yield mixtures of ortho- and para-substituted products.

Mechanism of the Kolbe-Schmitt reaction with lithium and sodium phenoxides

The mechanisms of the carboxylation reactions of lithium and sodium phenoxides are investigated by means of the DFT method with a CEP-31 + G(d) basis set. The introduction of diffusion functions does not affect the outcome of the calculations. As a consequence, the results of this investigation are in good agreement with the findings obtained by means of the LANL2DZ basis set. Lithium phenoxide yields only salicylic acid in the Kolbe-Schmitt reaction. The reaction of sodium phenoxide can proceed in the ortho and para positions, but the para-substituted product can be expected at a very low concentration in the reaction mixture. The deviation of lithium and sodium phenoxides from the mechanisms of carboxylations of other alkali metals is a consequence of the small ionic radii of lithium and sodium.

Chemistry of Unprotected Amino Acids in Aqueous Solution: Direct Bromination of Aromatic Amino Acids with Bromoisocyanuric Acid Sodium Salt under Strong Acidic Condition

Brominations of unprotected aromatic amino acids such as phenylalanine, tyrosine, and glycine, with bromoisocyanuric acid mono sodium salt (BICA-Na) were conducted in 60% aq. H(2)SO(4) at 0 degrees C to give a mixture of mono-brominated products in good yield. Unexpectedly, meta-bromophenylglycine was obtained as main product accompanied by ortho- and para-substituted products, while phenylalanine gave only ortho- and para-substituted products. Bromination of 2-phenylethylamine or benzylamine showed a tendency similar to the corresponding amino acids.

Synthesis and Properties of N‐(2,2,2‐Trichloroethyl)‐2‐thiophenesulfonamides.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis and Properties of N-(2,2,2-Trichloroethyl)-2-thiophenesulfonamides

Chlorination of 2-thiophenesulfonamide gave unstable N,N-dichloro-2-thiophenesulfonamide which was brought into reactions with 1,2-polyhaloethenes. The condensation of 2-thiophenesulfonamide with trichloroacetaldehyde afforded N-(2,2,2-trichloro-1-hydroxyethyl)-2-thiophenesulfonamide which reacted with benzene, toluene, 2-chlorothiophene, and phenol to form the corresponding N-(1-aryl-2,2,2-trichloroethyl)-2-thiophenesulfonamides. Under more severe conditions, the latter were converted into 1,1-diaryl-2,2,2-trichloroethanes. The reaction of N-(2,2,2-trichloro-1-hydroxyethyl)-2-thiophenesulfonamide with substituted arenes, including phenol, was regioselective: only the corresponding para-substituted products were obtained. Hydrolysis of N-[2,2,2-trichloro-1-(4-tolyl)ethyl]-2-thiophenesulfonamide yielded N-(2-thienylsulfonyl)-2-(4-tolyl)glycine.

The Anomalous Reactivity of Fluorobenzene in Electrophilic Aromatic Substitution and Related Phenomena

Fluorobenzene (PhF) displays a reactivity in electrophilic aromatic substitution (EAS) that is, at first glance, anomalous in comparison to the reactivity of the other halobenzenes. This is borne out by the fact that the rates of typical EAS reactions on PhF, such as nitration and chlorination, are 15–80% as fast as that of benzene while the same reactions on the other halobenzenes are five to ten times slower than that of PhF. Most striking, however, is the fact that reactions at the para position of PhF are typically faster than the corresponding reactions at a single position of benzene. Furthermore, EAS on PhF results in ∼ 90% of the para-substituted product, while the other halobenzenes give ratios of ortho- and para-substituted products that are closer to the simple statistical distribution. These striking observations are not discussed or, for that matter, even reported in introductory or advanced textbooks of organic chemistry and are clearly not compatible with the typically superficial textbook ...