Direct metal-free C–H functionalization of arenes with nucleophiles is a new chapter in the chemistry of aromatics. Comprehensive studies on nucleophilic substitution of hydrogen in arenes (the SNH reactions), including mechanisms, intermediates, mathematic and electrochemical modeling, kinetics, electron-transfer, etc. have shown that this is not the hydride ion, but C–H proton is departed, and this process is facilitated by the presence of an appropriate oxidant or an auxiliary group. The SNH reactions, as a part of the general C–H functionalization concept, change the logic of organic synthesis. They open new opportunities, avoiding incorporation of good leaving groups or other auxiliaries in an aromatic ring, as a prefunctionalization step, thus providing a better correspondence to the principles of green chemistry.
Structural modifications of aromatic systems have always been a subject of considerable interest to many chemists. There are several principal ways to modify the structure of aromatic compounds. The classic approach is electrophilic aromatic substitution of hydrogen (Fig. 1) . This type of C–H functionalization of aromatics is usually associated with aggressive electrophilic reagents (nitrous and sulfuric acids, halogens, etc), drastic conditions and a huge amounts of wastes, while sustainable development requires application of new chemical methodologies, based on the principles of green chemistry .
Transition-metal-catalyzed cross-coupling reactions (Buchwald–Hartwig, Heck, Kumada, Stille, Suzuku–Mijaura, Sonogashira, and others) have improved the situation considerably, providing chemists with a new tool to functionalize C–X (X-halogen) and C–H chemical bonds, however they cannot avoid a criticism, since most of these catalytic methods are based on using aryl halogenides, as starting materials. Besides that, transition metals (usually Pd) are rather expensive and toxic, and even traces of transition metals are not allowed to be impurities in drugs, organic solar cells and other high-tech materials (Fig. 2) .
In this communication we wish to discuss a relatively new synthetic methodology which is based on direct nucleophilic C–H functionalization of aromatic and heteroaromatic compounds, regarded formally as the displacement of the hydride ion (Fig. 3) , , , , , , , , , , , .
More that 40 years passed since the first examples of reactions, leading to nucleophilic substitution of hydrogen in aromatic compounds, had been analyzed systematically and published in the Russian Chemical Reviews . At that time text-books on organic chemistry claimed that “… hydrogen in an aromatic ring is not displaced with nucleophiles” . The following decades brought a great deal of data concerning these SNH reactions; a number of review articles, several monographs and hundreds of original papers have been published [see 4–15 and references therein]; this field became “…the fascinating subject…” , and one of the highlighted topics for many international journals. Many research groups all over the world (Poland, Belgium, Germany, Spain, Japan, USA, Russia and other countries) joined the field of nucleophilic C–H functionalizations, thus showing importance of the subject and its international recognition, which is reflected now in adavanced text-books on organic chemistry, for instance the Chapter 13 of the text-book  (Aromaic substitution, nucleophilic and organometallic) contains the sub-section “Hydrogen as leaving group”.
The data accumulated show that, indeed, the SNH reactions are of great fundamental and practical value, and can be used to modify a variety of nitro-, aza- and heteroaromatic compounds, including their benzo annelated analogues, as well as quinones, azinones, porphyrins, azulenes and arene-metal-complexes (Fig. 4), through the nucleophilic displacement of hydrogen and the formation of new carbon–carbon and carbon–heteroatom bonds (Fig. 5). The SNH methodology involves a lot of reactions, such as nucleophilic alkylation, alkenylation, alkynylation, amination, hydroxylation, alkoxylation, cyanation, cyanomethylation, halogenation, sulfurization, as well as cymantrenylation, carboranylation, ferrocenylation and others , , , , , , , , , , , , .
Nucleophilic C–H functionalization of aromatic compounds is one of the key topics of current organic chemistry , , , , , , , , , , , , . The scheme of the SNH reactions (Fig. 3) looks rather simple, however, a hydrogen atom has a poor tendency for elimination as the hydride ion, and nucleophilic C–H functionalization appears to be a more complicated process. It involves a number of elementary acts, and can be realized through various multi-step pathways “addition-oxidation” or “addition-elimination” in the presence of an outer oxidant or through departure of an auxiliary group from the intermediate σH-adduct (Fig. 5).
Actually the metal-free cross-coupling between an aromatic substrate and nucleophile takes place as a reversible addition step, resulting in the formation σH-adducts, followed by their dehydrogenation into stable SNH products (Fig. 5) . Scale of stability of σH-adducts is varied to a great extent. Some of them are easily oxidized, and in this case the SNH reaction can be arranged as one-pot process. In other events intermediate σH-adducts are stable enough to be isolated from the reaction mixture, followed by their dehydrogenation into the final SNH products, as a result of two successive reactions (Fig. 5) .
In the frames of this short review article we wish to present the results of our recent studies in the field of nucleophilic C–H functionalization of arenes and hetarenes, and also to show the scope and value of this synthetic methodology. More attention will be paid to the series of heterocyclic compounds, since due to a lower aromaticity of heteroaromatics intermediate heterocyclic σH-adducts used to be more stable than their carbocyclic analogues, and, therefore, they can be elucidated by NMR and other physical methods, including X-ray analysis. Some of these intermediate dihydro compounds are so stable, that they can find further applications .
There are a variety of catalytic methods which are used by chemists to modify the structure of aromatic and heteroaromatic compounds . Many of them are based on using halogenated starting materials or intermediates. In particular, palladium-catalyzed cross-coupling reactions proved to be efficient synthetic tool to construct rather complicated organic molecules. This method is so popular among chemists that they use it even in those cases when other methods give better results. For instance, palladium-catalyzed amination of chloropyridine results in the target compound in a poor yield, while metal-free oxidative amination reaction, being in fact the cross-dehydrogenative coupling (CDC), provides much better yield of the same compound (Fig. 6) . Besides that, the first approach suggests that a chloro atom has first to be incorporated into the pyridine ring, just in order to be displaced later, and this procedure does not correspond to the principles of green chemistry .
Meanwhile, one of the key tasks of organic chemistry is to find direct routes for C–H functionalization of aromatics, avoiding incorporation of halogen or other functionalities in order to correspond the principles of green chemistry! American Chemical Society, Green Chemistry Institute, and pharmaceutical corporations have appealed to develop more aspirational reactions, such as direct C–H functionalization of aromatics .
The general features of the SNH reactions
It is well known that C–H carbons in electron-deficient aromatics are more vulnerable for a nucleophilic attack than those of C–X bonds bearing a substituent X (Fig. 7) , , , , , , , , , , , . Therefore, the σH-adducts, rather than the Meisenheimer complexes are expected to be formed, although appropriate conditions for elimination of hydrogen atom with pair of electrons have to be found (Fig. 7) , , , , , , , , , , , .
It has been well established that addition of a nucleophile at C–H in an aromatic ring proceeds faster than at C–X, so nucleophilic substitution of hydrogen in arenes is faster, than displacement of a halogen atom. As a consequence, the generally accepted mechanism of the SNAr reactions has recently been corrected . Indeed, there are many examples where a nucleophile attacks first an unsubstituted C–H carbon, instead of conventional nucleophilic displacement of halogen. In such cases a halogen atom appears to protect the attached carbon of the C–X bond from a nucleophiic attack. Indeed, a chloro atom in 1-chloro-4-nitrobenezene has to be regarded as the protecting group, directing a nucleophilic attack predominantly at C-3 carbon with retention of halogen at C-1 (Fig. 8) , , , , . Since this chloro atom at C-1 can be displaced with nucleophiles, it enhances opportunities for functionalization of 1-chloro-4-nitrobenzene.
Such examples indicate that it is a high time to change the logic of organic chemistry. In fact, halogen atoms and other good leaving groups, which are usually displaced by nucleophiles, have to be regarded as protecting substituents, directing a nucleophilic attack at C–H bond. American chemists Daniel Morton and Huw Davies consider this field so important for the future, that they suggested to establish the center for selective C–H functionalization .
The data accumulated in the literature , , , , , , , , , , , ,  show that, when designing synthetic ways to rather complicated aromatic molecules, and constructing C–C or C–X bonds (where X–heteroatom) with participation of nucleophilic reagents, it is not necessary at all to use preliminary derivatization of these molecules by introduction of chloro (halogen) or other auxiliary groups into an aromatic ring. It is advised to consider first an opportunity to incorporate the target nucleophilic fragments through direct nucleophilic displacement of the C–H bond in arenes and hetarenes. Even in the event, that an electron-defficient aromatic compound bears a halogen atom in an activated position, it is possible to exploit first the nucleophilic displacement of hydrogen of the C–H bond, rather than halogen or other auxiliary groups, as illustrated by the example given in Fig. 8.
Finally, if an aromatic substrate does not contain any electron-withdrawing group (EWG), for instance, the nitro or aza groups (examples of structures are shown in Fig. 4), and, contrary to that, it bears an electron-donating group (EDG), the SNH methodology can also be exploited. In this case the new logic of organic synthesis suggests to consider an opportunity of electrochemical activation of an aromatic system through the anodic oxidation, followed by the nucleophilic C–H functionalization through displacement of hydrogen (Fig. 9) , , , , .
This promising approach, using an anode as a “green oxidizing agent”, has recently been applied for C–H functionalization of 1,2- and 1,4-dihydroxybenzenes, as exemplified by electro-induced nucleophilic substitution of hydrogen in pyrocatechol (Fig. 10) . Also it is worth mentioning that thorough mechanistic studies of electrochemical oxidation of intermediate σH-adducts derived from nitroaromatic compounds have been performed , .
As mentioned above, the key problem of the SNH reactions is associated with elimination of hydrogen with pair of electrons (H−=2e+H+), which can be realized either oxidative or eliminative pathways (Fig. 11) , , , , , , , , , , , , , . External oxidant is usually needed to perform the SNH reaction, as illustrated by nucleophilic C–H functionalization of triazolo[a]annulated 8-azapurins, proceeding in the presence of such specific oxidant, as phenyliododiacetate (Fig. 12) .
The most plausible mechanism for oxidative SNH reactions is realized through transfer of electron from σH-adducts followed by departure of proton and one more electron (H−=e+H++e) . In some SNH reactions the starting material acts as oxidant. For instance, in the reaction of acridinium salts with aromatic amines the acridinium cation is an effective oxidant, which provides aromatization of the intermediate adduct. This mechanism has been proved by kinetic studies (Fig. 13) .
Also oxidation with air oxygen at room temperature can be arranged effectively, provided titanium dioxide TiO2 is used in this reaction as heterogeneous photocatalyst (Fig. 14) . When irradiated with UV light the system O2/TiO2 produces electron/hole pair (e−/h+), and oxygen dissolved in solution can be scavenged with exited electrons, thus affording the superoxide radicals, as very active oxidative species. Use of air oxygen is certainly attractive from ecological point of view, since it provides a better correspondence to atom economy and other principles of green chemistry .
Another principal mode of the SNH reactions is the eliminative aromatization of intermediate adducts. In this case, two electrons are taken from adducts with the help of an auxiliary group.
There are several modes of eliminative SNH reactions. The first case is that a nucleophile bears an auxiliary group. These reactions are regarded as Vicarious nucleophilic substitutions of hydrogen, as suggested by Prof. M. Makosza (Fig. 15) , , , , .
If an auxiliary group is present in aromatic substrate, we deal with tele- or cine-substituions, as exemplified by displacement of hydrogen in amination of 1,7-naphthiridines (Fig. 16)  and C–H functionalization of azine-N-oxides (Fig. 17) .
A more complicated situation is when two or several auxiliary groups are present in reagents. A new C–H functionalization protocol has been suggested to incorporate arylalkenyl fragments. It is based on using nucleophilic species, containing two auxiliary groups, which are generated in the course of the reaction. The process is initiated by the addition of morpholine at the C–C double bond of β-nitrostyrenes, and the subsequent addition of the generated carbanion to C-6 of furazano[3,4-b]pyrazines, followed by elimination of nitrous acid and morpholine (Fig. 18) .
In fact, oxidative and eliminative procedures are complementary to each other, as illustrated by the synthesis of 2-oxoindoles by using the intramolecular displacement of hydrogen. It is worth noting, that these derivatives are hardly accessible by other methods (Fig. 19) , .
Use of the SNH methodology in material science
The next few examples are entitled to demonstrate that metal-free SNH reactions and metal-catalyzed cross-coupling reactions might be complementary to each other (Fig. 20) , . Actually, the Suzuki cross-coupling reaction can be used for modification of C-5 position of the pyrimidine ring, which is less activated for nucleopilic attack than C-4, while the SNH methodology is effective for nucleophilic C–H functionalization of position 4. It is worth mentioning that various combinations of these two types of C–C coupling reactions, Addition-oxidation or addition-elimination, and also various sequences of steps can be realized to obtain 4,5-disubstituted pyrimidines (Fig. 20) , , , , , , , , .
These SNH reactions have found application in material science to obtain new fluorescent compounds, which can be used as organic sensors for detection of nitroaromatic explosives , , and also as compounds of the D-A type for dye-sensitized solar cells (Fig. 21) , . Indeed, compounds of this family have rather promising photophysical properties , , , , , .
Use of the SNH methodology in medicinal chemistry
The characteristic feature of the SNH reactions is that they take place without catalysis by transition metals. This is why the metal-free C–H functionalization reactions are of special interest for medicinal chemists.
It has already been mentioned above that the advantage of the SNH methodology is that it requires neither a preliminary functionalization, nor use of transition metals (usually Pd), as catalysts. It is very important for the synthesis of drugs, where even traces of transition metals are not permitted. This is why this methodology is so aspirational for both academic and industrial chemists, thus enabling them to avoid impurities of metals in the target products.
Use of the SNH methodology in the chemistry of antibacterial fluoroquinolones is illustrated by intramolecular sybstitution of hydrogen, leading to the tricyclic pyrazolo[2,3-a]quinoline system (Fig. 22) .
The construction of antivirals of the indole family is a good example of vicarious cyanomethylation of nitroaromatics, as illustrated by the synthesis of Eudistomin C, the antiviral agent of marine origin (Fig. 23) .
The next example exploits the oxidative version of the SNH methodology in the synthesis of potential drugs of the coumarine family. Being activated with the Lewis acid coumarins become electrophilic enough to react with nucleophilic thiophens to give σH adducts, which can be oxidized with DDQ into C–H/C–H coupling products (Fig. 24) .
On the other hand, 5,7-dihydroxycoumarins can be regarded as nucleophilic species, capable of C–H/C–H cross-coupling with highly electron-deficient azines. A simple, selective and environmental friendly method has recently been developed in our laboratory to modify 7-nitroquinoxalin-2-ones (Fig. 25) .
A similar approach has been used for C–H/C–H cross coupling of 6-ntroazolopyrimidines with quercetin . Also a number of antimycobacterials of the pyrimidine family have recently been obtained by using the SNH methodology , , .
Other applications of the SNH methodology
In the 21st century chemists should pursue the principle of practical elegance, which means that a synthesis should be not only logical and perfect from technical point of view, but also ecologically benign. In this respect SNH methodology has advantages over traditional chemistry, including industrial applications. For instance, a new method for the synthesis of 4-aminodiphenylamine, the well-known anti-aging agent for rubber materials (Fig. 26) has been developed , . In contrast to the traditional approach, which suggests incorporation of chlorine atom followed by its displacement, this approach exploits the SNH methodology (Fig. 26) , , , .
Amination of nitrobenzene with benzamide is also a good example of green chemistry based on use of the SNH methodology , .
In the frames of this communication we have tried to provide agruments that metal free C–H functionalization through nucleophilic displacement of hydrogen is a powerful synthetic methodology of great practical value. We believe that it is a high time to draw attention of both academic and industrial chemists to this methodology, based on using “chlorine-free” ecologically benign process and “green oxidizing agents”, such as air oxygen and anodic oxidation. Research studies in the field of the SNH reactions are currently in progress, as evidenced by numerous examples, presented in this paper, including electrochemical version of the SNH reactions , , , , , , and anodic dehydro-aromatization of intermediate σH-adducts , , . Further development of experimental methods and mechanistic studies of the SNH reactions are expected to enhance synthetic potential of metal-free C–H functionalizations, thus providing a progress in this promising field of organic synthesis.
A collection of invited papers based on presentations at the XX Mendeleev Congress on General and Applied Chemistry (Mendeleev XX), held in Ekaterinburg, Russia, September 25–30, 2016.
This work was supported by the grant no. 3656-2014.310 for Leading Scientific Schools of the Russian Federation.
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