Chlorine in an Organic Molecule, a Universal Promoter-Workhorse-Of Reactions.

Due to the electronic configuration of the atom and charge of the nucleus, the chlorine in organic molecules can exert a variety of effects. It can depart as a chloride anion in the process of substitution and elimination, facilitates the abstraction of protons and stabilizes generated carbanions, exerts moderate stabilizing effect of carbenes, carbocations and radicals. There are frequent cases where chlorine substituent promotes more than one transformation. These rich effects of chlorine substituent will be illustrated by examples of our work.

Analogy of the Reactions of Aromatic and Aliphatic π-Electrophiles with Nucleophiles.

The aim of this essay is to disclose the similarity of a great variety of reactions that proceed between nucleophiles and π-electrophiles-both aromatic and aliphatic. These reactions proceed via initial reversible addition, followed by a variety of transformations that are common for the adducts of both aliphatic and aromatic electrophiles. We hope that understanding of this analogy should help to expand the scope of the known reactions and inspire the search for new reactions that were overlooked.

Synthesis of quinoxaline derivatives via aromatic nucleophilic substitution of hydrogen.

The electrophilic nature of quinoxaline has been explored in the vicarious nucleophilic substitution (VNS) of hydrogen with various carbanions as nucleophiles in an attempt to develop a general method for functionalizing the heterocyclic ring. Only poorly stabilized nitrile carbanions were found to give the VNS products. 2-Chloroquinoxaline gave products of SNAr of chlorine preferentially. A variety of quinoxaline derivatives containing cyanoalkyl, sulfonylalkyl, benzyl or ester substituents, including fluorinated ones, have been prepared in the VNS reactions with quinoxaline N-oxide.

Electrophilic and Nucleophilic Aromatic Substitutions are Mechanistically Similar with Opposite Polarity.

Confrontation of the recently formulated general mechanism of nucleophilic substitution in electron-deficient arenes with the well-known mechanism of electrophilic substitution revealed that these fundamental processes are mechanistically identical but proceed according to opposite polarity-an Umpolung relation. In this viewpoint this apparently controversial concept is supported by discussion of a variety of experimental results.

How Do Aromatic Nitro Compounds React with Nucleophiles? Theoretical Description Using Aromaticity, Nucleophilicity and Electrophilicity Indices.

In this study, we present a complete description of the addition of a model nucleophile to the nitroaromatic ring in positions occupied either by hydrogen (the first step of the SNAr-H reaction) or a leaving group (SNAr-X reaction) using theoretical parameters including aromaticity (HOMA), electrophilicity and nucleophilicity indices. It was shown both experimentally and by our calculations, including kinetic isotope effect modeling, that the addition of a nucleophile to the electron-deficient aromatic ring is the rate limiting step of both SNAr-X and SNAr-H reactions when the fast transformation of σH-adduct into the products is possible due to the specific reaction conditions, so this is the most important step of the entire reaction. The results described in this paper are helpful for better understanding of the subtle factors controlling the reaction direction and rate.

α-Chlorobenzylation of Nitroarenes via Vicarious Nucleophilic Substitution with Benzylidene Dichloride: Umpolung of the Friedel-Crafts Reaction.

Readily available α,α-dichlorotoluenes enter a vicarious nucleophilic substitution (VNS) reaction with electron-deficient arenes to give α-chlorobenzylated nitrobenzenes, as well as six- and five-membered heterocycles. Oxidation of the initially formed α-chlorobenzylic carbanions instead of protonation results in formation of diaryl ketones, providing a means for overall nucleophilic C-H benzoylation of electron-deficient aromatic rings. Alternatively, benzoylated nitroarenes can be obtained via the reaction of isolated α-chlorodiarylmethanes with sodium azide.

Interfacial Generation of a Carbanion: The Key Step of PTC Reaction Directly Observed by Second Harmonic Generation.

We present the first unambiguous evidence of the interfacial mechanism of phase-transfer catalysis (PTC) by direct observation of the formation of carbanions in the interfacial region between the aqueous and the organic phase by using a surface-sensitive spectroscopic method known as second harmonic generation (SHG). Ion exchange of carbanions adsorbed at the surface after addition of lipophilic tetraalkylammonium salts (TAA) to organic phase and transport of the lipophilic ion-pairs to the organic phase is observed. Results allow for the formulation of a more detailed mechanism of PTC.

Synthesis of α-Fluoro-α-nitroarylacetates via Vicarious Nucleophilic Substitution of Hydrogen.

Readily available ethyl chlorofluoroacetate, when treated with a strong base, forms an α-chloro-α-fluorocarbanion that adds to nitroarenes at a position ortho or para to the nitro group with formation of anionic σH adducts. Subsequent base-induced ß-elimination of HCl proceeds selectively to give nitrobenzylic α-fluorocarbanions and, upon protonation, ethyl α-fluoro-α-nitroarylacetates.

Direct synthesis of nitroaryl acetylenes from acetylenes and nitroarenes via oxidative nucleophilic substitution of hydrogen.

Acetylenic carbanions add to nitroarenes (dinitrobenzenes, nitropyridines, etc.) to form σH-adducts that are subsequently oxidized by DDQ according to the oxidative nucleophilic substitution of hydrogen (ONSH) pathway to give nitroaryl acetylenes.

How Does Nucleophilic Aromatic Substitution Really Proceed in Nitroarenes? Computational Prediction and Experimental Verification.

The aim of this paper is to present a correct and complete mechanistic picture of nucleophilic substitution in nitroarenes based on the results obtained by theoretical calculations and experimental observations coming from numerous publications, reviews, and monographs. This work gives the theoretical background to the very well documented experimentally yet still ignored observations that the addition of nucleophiles to halo nitroarenes resulting in the formation of σ(H) adducts, which under proper reaction conditions can be transformed into the product of the SNArH reaction, is faster than the competing process of addition to the carbon atom bearing a nucleofugal group (usually a halogen atom) resulting in the "classic" SNAr reaction. Only when the σ(H) adduct cannot be transformed into the SNArH reaction product, SNAr reaction is observed.

One-Pot Synthesis of Esters of Cyclopropane Carboxylic Acids via Tandem Vicarious Nucleophilic Substitution-Michael Addition Process.

α-Chlorocarbanions generated via base-induced vicarious nucleophilic substitution reaction of alkyl dichloroacetates with nitroarenes react with Michael acceptors to give esters of cyclopropane carboxylic acids substituted with p-nitroaromatic rings.

Competition between nucleophilic substitution of halogen (SN Ar) versus substitution of hydrogen (SN ArH)-a mass spectrometry and computational study.

The mechanism of intramolecular gas-phase reactions of N-(2-X-5-nitrophenyl)-N-methylacetamide carbanions (X=H, F, Cl) has been studied using negative ion electrospray mass spectrometry ((-)ESI-MS) technique and modelled computationally. It was proven that all three anions form cyclic σ(H) adducts, which undergo elimination of water. In the case of X=F, formation of the σ(F) adduct, leading to SN Ar reaction, was a competing process. This is the first proof that also in the gas phase formation of σ(H) adduct proceeds faster than σ(X) adduct and only when X=F, rates of these two processes are comparable. The experimental results are in full agreement with quantum chemical calculations.

Reactions of nucleophiles with nitroarenes: multifacial and versatile electrophiles.

In this overview, it is shown that there are many initial reactions between nitroarenes and nucleophiles: addition to the electron-deficient ring at positions occupied by halogen and hydrogen atoms, addition to the nitro group, single-electron transfer (SET), and other types of initial reactions. The resulting intermediates react further in a variety of ways to form products of nucleophilic substitution of a halogen atom (SN Ar), a hydrogen atom (SN ArH), and others. Many variants of these processes are briefly discussed, particularly in relation of rates of the initial reactions and further transformations.

Nucleophilic substitution of hydrogen in electron-deficient arenes, a general process of great practical value.

The aim of this tutorial review is to present two main messages. First, addition of nucleophilic agents to electron-deficient arenes proceeds faster in positions occupied by hydrogen than in those, equally activated, occupied by halogens or other nucleofugal groups. Thanks to numerous ways of further, fast conversion of the produced sigma(H) adducts into products of nucleophilic substitution of hydrogen, this is the main primary reaction between nucleophiles and electron-deficient arenes. Conventional nucleophilic substitution of halogen, S(N)Ar reaction, is a secondary process that takes place when ways for fast further conversion of sigma(H) adducts are not available. The second message is that nucleophilic substitution of hydrogen is an efficient tool in organic synthesis. In order to stress the preference for nucleophilic substitution of hydrogen, halonitroarenes are chosen as examples of reacting electron-deficient arenes, but it is obvious that the presence of halogen is not necessary for substitution of hydrogen.

Diastereoselective synthesis of tetrahydrofurans from aryl 3-chloropropylsulfoxides and aldehydes.

Carbanions of aryl 3-chloropropylsulfoxides react with nonenolizable aldehydes to give 2,3-disubstituted tetrahydrofurans. Deprotonation of the sulfoxides carried out in the presence of aldehydes results in the addition of the carbanions to the carbonyl group of the aldehydes, followed by 1,5-intramolecular substitution of the resulting aldol-type anion to produce the tetrahydrofuran ring. The 2-aryl and 3-arylsulfinyl substituents are always in trans relation, and the reaction proceeds with high diastereoselectivity also in respect to the chiral sulfur atom. The diastereoselectivity is attributed to the cyclic transition state of the aldol addition and increases when the aromatic ring of the sulfoxide contains electron-withdrawing substituents, whereas that of the aldehyde has electron-donating groups.

Synthesis of alpha-(nitroaryl)benzylphosphonates via oxidative nucleophilic substitution of hydrogen in nitroarenes.

Carbanions of diethyl benzylphosphonate and diethyl 1-phenylethylphosphonate add to nitroarenes to form relatively long-lived sigma(H) adducts that can be oxidized to products of oxidative nucleophilic substitution of hydrogen. By variation of the conditions, o- and p-nitroarylated derivatives of the starting phosphonates can be synthesized regioselectively. It has been proven that addition of carbanions of diethyl benzylphosphonate and diethyl 1-phenylethylphosphonate to nitroarenes is a fast process and the respective sigma(H) adducts are formed almost quantitatively.

Substituent effects on the electrophilic activity of nitroarenes in reactions with carbanions.

The effect on electrophilic activity of substituents located para, ortho, and meta to the nitro group of nitrobenzenes was determined by using vicarious nucleophilic substitution of hydrogen (VNS) with the carbanion of chloromethyl phenyl sulfone (1) as the model process. Values for the relative activities of substituted nitroarenes are given relative to nitrobenzene, which was taken as the standard. This process was chosen as a model reaction because it meets key criteria, such as the wide range of substituents that can be present on the nitrobenzene ring, a low sensitivity to steric hindrance, and in particular the possibility of ensuring conditions in which the overall relative rates of reaction in competitive experiments are equal to the relative rates of nucleophilic addition. The values of relative rates of addition, which were taken to be a measure of electrophilic activity, were determined by competitive experiments in which pairs of nitroarenes competed for the VNS reaction with carbanion of 1. A comprehensive set of data for effects of substituents on the electrophilic activity of nitroarenes is presented for the first time.

Synthesis of alpha-trifluoromethyl-beta-lactams and esters of beta-amino acids via 1,3-dipolar cycloaddition of nitrones to fluoroalkenes.

Nitrones derived from aromatic or aliphatic aldehydes or ketones react with hexafluoropropene (HFP) or 2H-pentafluoropropene (PFP) to give the respective fluorinated isoxazolidine derivatives in good yields with complete regioselectivity and moderate diastereoselectivity. Catalytic hydrogenolysis of the N-O bond under ambient pressure and temperature leads to fluorides of beta-amino acids that undergo cyclization to alpha-trifluoromethylated beta-lactams or, under acidic conditions, form esters of alpha-trifluoromethylated beta-amino acids.

Reactions of nitroheteroarenes with carbanions: bridging aromatic, heteroaromatic, and vinylic electrophilicity.

The relative rate constants for the vicarious nucleophilic substitution (VNS) of the anion of chloromethyl phenyl sulfone (1-) with a variety of nitroheteroarenes, for example, nitropyridines, nitropyrroles, nitroimidazoles, 2-nitrothiophene, and 4-nitropyrazole, have been determined by competition experiments. It was shown that nitropyridines are approximately four orders of magnitude more reactive than nitrobenzene. Among the five-membered heterocycles 2-nitrothiophene is the most active followed by nitroimidazoles and 4-nitropyrazole. Nitropyrroles are the least electrophilic nitroheteroarenes with reactivities comparable to nitrobenzene. Quantum chemically calculated methyl anion affinities (B3LYP/6-311G(d,p)//B3LYP/6-31G(d)) of the nitroarenes correlated only moderately with the partial relative rate constants. The correlation of these activities with the LUMO energies of nitroarenes is even worse. By measuring the second-order rate constants of the addition of 1- to nitroarenes and to diethyl arylidenemalonates 10, it was possible to link the electrophilic reactivities of nitroheteroarenes with the comprehensive electrophilicity scale based on the linear-free-energy-relationship log k(20 degrees C)=s(N+E).

New synthesis of 2-heteroarylperfluoropropionic acids derivatives by reaction of azine N-oxides with hexafluoropropene.

Hexafluoropropene reacts with aromatic azine N-oxides under mild conditions to produce fluorides of 2-heteroarylperfluoropropionic acids. The reaction proceeds as 1,3-dipolar cycloaddition followed by spontaneous scission of the N--O bond in the isoxazolidine ring and elimination of HF. When the reaction is carried out in the presence of alcohols or N-alkyl anilines, the in situ formed acyl fluorides give the corresponding esters and amides. They can be also treated separately with nucleophiles to produce the respective acylation products, whereas their hydrolysis leads to unstable carboxylic acids that undergo spontaneous decarboxylation to 1-aryl-1,2,2,2-tetrafluoroethanes. This new reaction provides a simple and general method of synthesizing 2-heteroarylperfluoropropionic acid derivatives that were previously unknown and unavailable.