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.


Introduction
This essay aims to disclose the similarity of a great variety of reactions that proceed between nucleophiles and aliphatic and aromatic π-electrophiles. There is a common belief that these reactions are mechanistically different, which we believe to be incorrect. Therefore, we hope that understanding and acceptance of this analogy should help to expand the scope of the known reactions and inspire the search for new reactions that were so far overlooked.
Although there is a great variety of aliphatic π-electrophiles (carbonyl compounds, imines, iminium ions, nitriles, Michael acceptors, etc.) and aromatic π-electrophiles with electrophilic centers in the ring: nitroarenes, azines, etc., as well as a great, practically unlimited variety of nucleophiles; therefore, numerous reactions that proceed between them-there are just a few fundamental initial processes. All these reactions proceed via the initial reversible addition of nucleophiles to the electrophilic center of an electrophilic partner to form σ adducts that are subsequently converted into the final products in a variety of ways. The addition to aliphatic electrophiles results in the formation of a new σ bond and conversion of the π bond into a σ bond, which as a rule is energetically favorable, with the formation of adducts that are energetically stable intermediates. Due to stability, upon protonation, they can form final products, or they can react further in a great variety of ways. On the other hand, the addition of nucleophiles to electron-deficient arenes results in dearomatization, thus it is energetically unfavorable so, as a rule, the produced σ adducts are unstable, short-lived intermediates. These σ adducts tend to recover aromaticity via dissociation or fast further transformations, thus the number of different final reactions appears to be limited. However, recent literature reports indicate that adducts of nucleophiles to aromatic electrophiles can enter a variety of reactions, and thus they display reactivity identical to their aliphatic counterparts [1][2][3].
The second difference between aliphatic and aromatic π-electrophiles is that aromatic π-electrophiles usually contain more than one electrophilic center that is capable of adding The second difference between aliphatic and aromatic π-electrophiles is that aromatic π-electrophiles usually contain more than one electrophilic center that is capable of adding nucleophilic agents, and the addition can result in the formation of isomeric adducts. In turn, aliphatic π-electrophiles usually react selectively, giving single, predictable intermediates. However, the difference also seems to be apparent, as it arises from the structure of individual substrates, and varies depending on substitution or length of the conjugation pathway.
These observations should inspire the search for new processes based on the analogies between aromatic and aliphatic π-electrophiles. In this essay, the similarity of reactions of nucleophiles with aromatic and aliphatic π-electrophiles will be presented consecutively, and for the sake of clarity, electrophiles and nucleophiles with or without leaving groups will be discussed separately. We believe that the clear-cut analogy between aromatic and aliphatic π-electrophiles should inspire the search for new synthetic transformations, which were overlooked, due to the simplified picture of their reactivity, presented in chemical textbooks.

Addition of Nucleophiles without Leaving Groups
The most common and studied reaction between nucleophiles and aromatic electrophiles is substitution of halogens and other leaving groups in nitroarenes. This reaction, known for more than 150 years, proceeds via the addition of nucleophiles at positions ortho or para to the nitro group occupied by a leaving group X to form σ X adducts. As was mentioned earlier, the addition is connected with dearomatization, thus the adducts undergo fast rearomatization via the departure of X − to form products of substitution, SNAr. As a consequence, in this two-step process, the addition is the slower, rate-limiting step, therefore usually the substitution proceeds faster when X = F than X = Cl [4].
In some cases, when X = Cl, the departure of Cl − is so fast that the process has a synchronous character [5,6]. It is therefore a peculiar situation that the two-step substitution of fluorine proceeds faster than the synchronous substitution of chlorine.
Substitution of leaving groups in electron-deficient arenes (nitroarenes, azines, etc.) proceeds with various C, N, O, S, etc. nucleophiles. The most common leaving groups are halogens, but alkoxy and aryloxy groups can also behave as leaving groups (Scheme 1). The substitution of fluoride in 2-fluoropyridine is a versatile way of preparing pyridine derivatives [7]. As previously mentioned, in p-and o-halonitrobenzenes and analogues there are also positions occupied by hydrogen available for the addition of nucleophiles. It should be stressed that addition of nucleophiles at these positions is, as a rule, faster than at positions occupied by halogen, but the σ H adducts have no direct way for further conver-Scheme 1. S N Ar in nitroarenes.
As previously mentioned, in pand o-halonitrobenzenes and analogues there are also positions occupied by hydrogen available for the addition of nucleophiles. It should be stressed that addition of nucleophiles at these positions is, as a rule, faster than at positions occupied by halogen, but the σ H adducts have no direct way for further conversion; hence, they usually dissociated. Nevertheless, when such a possibility exists, further conversion of the σ H adducts results in nucleophilic substitution of hydrogen. The general picture is presented in Scheme 2 [4,8].
Molecules 2023, 28, x FOR PEER REVIEW 3 of 2 sion; hence, they usually dissociated. Nevertheless, when such a possibility exists, furthe conversion of the σ H adducts results in nucleophilic substitution of hydrogen. The gen eral picture is presented in Scheme 2 [4,8].

Scheme 2. Addition of nucleophiles to nitroarenes.
There is a great variety of aliphatic π-electrophiles containing leaving groups at the electrophilic centers. The simplest examples of such electrophiles are acyl chloride (halides), esters of carboxylic acids, imidoyl chlorides, etc., as well as electron-deficien alkenes containing leaving groups: β-halo or β-alkoxyvinyl ketones, nitriles, esters, etc (Scheme 3). Numerous common reactions such as acylation of carbanions by acyl chlorides and esters, synthesis of esters via acylation of alcohols and transesterification, synthesis o amides, hydrazides, hydroxamic acids, etc. proceed via the addition of nucleophiles to carbonyl and amino groups substituted with a leaving group, followed by elimination o the leaving group (Scheme 4). Many names and common reactions, e.g., Claisen con densation, transesterification, etc., belong to this category. It appears difficult to see the analogy between the Claisen condensation and SNAr reaction, but indeed these reaction proceed similarly as follows: addition of nucleophile followed by elimination of a leaving group from the addition center. There is a great variety of aliphatic π-electrophiles containing leaving groups at the electrophilic centers. The simplest examples of such electrophiles are acyl chlorides (halides), esters of carboxylic acids, imidoyl chlorides, etc., as well as electron-deficient alkenes containing leaving groups: β-halo or β-alkoxyvinyl ketones, nitriles, esters, etc. (Scheme 3). sion; hence, they usually dissociated. Nevertheless, when such a possibility exists, fur conversion of the σ H adducts results in nucleophilic substitution of hydrogen. The eral picture is presented in Scheme 2 [4,8]. There is a great variety of aliphatic π-electrophiles containing leaving groups a electrophilic centers. The simplest examples of such electrophiles are acyl chlor (halides), esters of carboxylic acids, imidoyl chlorides, etc., as well as electron-defic alkenes containing leaving groups: β-halo or β-alkoxyvinyl ketones, nitriles, esters, (Scheme 3). Numerous common reactions such as acylation of carbanions by acyl chlorides esters, synthesis of esters via acylation of alcohols and transesterification, synthes amides, hydrazides, hydroxamic acids, etc. proceed via the addition of nucleophile carbonyl and amino groups substituted with a leaving group, followed by eliminatio the leaving group (Scheme 4). Many names and common reactions, e.g., Claisen densation, transesterification, etc., belong to this category. It appears difficult to see analogy between the Claisen condensation and SNAr reaction, but indeed these react proceed similarly as follows: addition of nucleophile followed by elimination of a lea group from the addition center. Numerous common reactions such as acylation of carbanions by acyl chlorides and esters, synthesis of esters via acylation of alcohols and transesterification, synthesis of amides, hydrazides, hydroxamic acids, etc. proceed via the addition of nucleophiles to carbonyl and amino groups substituted with a leaving group, followed by elimination of the leaving group (Scheme 4). Many names and common reactions, e.g., Claisen condensation, transesterification, etc., belong to this category. It appears difficult to see the analogy between the Claisen condensation and S N Ar reaction, but indeed these reactions proceed similarly as follows: addition of nucleophile followed by elimination of a leaving group from the addition center. sion; hence, they usually dissociated. Nevertheless, when such a possibility exists, further conversion of the σ H adducts results in nucleophilic substitution of hydrogen. The general picture is presented in Scheme 2 [4,8]. There is a great variety of aliphatic π-electrophiles containing leaving groups at the electrophilic centers. The simplest examples of such electrophiles are acyl chlorides (halides), esters of carboxylic acids, imidoyl chlorides, etc., as well as electron-deficient alkenes containing leaving groups: β-halo or β-alkoxyvinyl ketones, nitriles, esters, etc. (Scheme 3). Numerous common reactions such as acylation of carbanions by acyl chlorides and esters, synthesis of esters via acylation of alcohols and transesterification, synthesis of amides, hydrazides, hydroxamic acids, etc. proceed via the addition of nucleophiles to carbonyl and amino groups substituted with a leaving group, followed by elimination of the leaving group (Scheme 4). Many names and common reactions, e.g., Claisen condensation, transesterification, etc., belong to this category. It appears difficult to see the analogy between the Claisen condensation and SNAr reaction, but indeed these reactions proceed similarly as follows: addition of nucleophile followed by elimination of a leaving group from the addition center.
The reactions of nucleophiles with π-electrophiles containing leaving groups at the electrophilic centers of electron deficient alkenes are less common. Nevertheless, there are many examples of substitution of β-halogens or β-alkoxy groups in vinyl nitriles, ketones, or sulfones that proceed via an addition-elimination mechanism analogous to SNAr [9,10]. Similar to the SNAr, addition is usually the rate-determining step, hence for instance substitution of fluorine is faster than chlorine (Scheme 5). Selected synthetic examples of nucleophilic substitution in aliphatic systems are presented in Scheme 6 [11][12][13]. Similar to the case of aromatic electrophiles there are two main mechanistic variants of substituting chlorine in β-chlorovinyl ketones through two-step processes in which the adducts are intermediates or synchronous reaction when the dissociation is faster than addition and the adducts are transition states [9,10]. Occasionally, reactions other than elimination may be observed following the addition of nitrogen [14][15][16], oxygen [17,18], carbon [19][20], or fluoride [21] nucleophiles to electron-deficient fluoroalkenes, including SN2' reactions [22].

Addition of Nucleophiles Containing Leaving Groups
There are few examples of substitution of halogens in nitroarenes with nucleophiles containing leaving groups, e.g., α-chlorocarbanions, mostly because nucleophilic addition to such arenes proceeds faster from the position occupied by hydrogen. The formed σ H adducts of α-chlorocarbanions usually undergo β-elimination to form products of vicarious nucleophilic substitution (VNS) [23] faster than dissociation and addition at positions occupied by a leaving group (see below, Section 3.2). Nevertheless, there are examples of substitution of halogens, particularly fluorine, in fluoronitrobenzenes by carbanions of α-chloroalkyl sulfones [24,25], alkoxynitriles, sulfenamides, and anion of t-butylhydroperoxide (Scheme 7) [26]. These reactions have rather limited practical application. The reactions of nucleophiles with π-electrophiles containing leaving groups at the electrophilic centers of electron deficient alkenes are less common. Nevertheless, there are many examples of substitution of β-halogens or β-alkoxy groups in vinyl nitriles, ketones, or sulfones that proceed via an addition-elimination mechanism analogous to SNAr [9,10]. Similar to the SNAr, addition is usually the rate-determining step, hence for instance substitution of fluorine is faster than chlorine (Scheme 5). Selected synthetic examples of nucleophilic substitution in aliphatic systems are presented in Scheme 6 [11][12][13]. Similar to the case of aromatic electrophiles there are two main mechanistic variants of substituting chlorine in β-chlorovinyl ketones through two-step processes in which the adducts are intermediates or synchronous reaction when the dissociation is faster than addition and the adducts are transition states [9,10]. Occasionally, reactions other than elimination may be observed following the addition of nitrogen [14][15][16], oxygen [17,18], carbon [19][20], or fluoride [21] nucleophiles to electron-deficient fluoroalkenes, including SN2' reactions [22].

Addition of Nucleophiles Containing Leaving Groups
There are few examples of substitution of halogens in nitroarenes with nucleophiles containing leaving groups, e.g., α-chlorocarbanions, mostly because nucleophilic addition to such arenes proceeds faster from the position occupied by hydrogen. The formed σ H adducts of α-chlorocarbanions usually undergo β-elimination to form products of vicarious nucleophilic substitution (VNS) [23] faster than dissociation and addition at positions occupied by a leaving group (see below, Section 3.2). Nevertheless, there are examples of substitution of halogens, particularly fluorine, in fluoronitrobenzenes by carbanions of α-chloroalkyl sulfones [24,25], alkoxynitriles, sulfenamides, and anion of t-butylhydroperoxide (Scheme 7) [26]. These reactions have rather limited practical application. Similar to the case of aromatic electrophiles there are two main mechanistic variants of substituting chlorine in β-chlorovinyl ketones through two-step processes in which the adducts are intermediates or synchronous reaction when the dissociation is faster than addition and the adducts are transition states [9,10]. Occasionally, reactions other than elimination may be observed following the addition of nitrogen [14][15][16], oxygen [17,18], carbon [19,20], or fluoride [21] nucleophiles to electron-deficient fluoroalkenes, including S N 2' reactions [22].

Addition of Nucleophiles Containing Leaving Groups
There are few examples of substitution of halogens in nitroarenes with nucleophiles containing leaving groups, e.g., α-chlorocarbanions, mostly because nucleophilic addition to such arenes proceeds faster from the position occupied by hydrogen. The formed σ H adducts of α-chlorocarbanions usually undergo β-elimination to form products of vicarious nucleophilic substitution (VNS) [23] faster than dissociation and addition at positions occupied by a leaving group (see below, Section 3.2). Nevertheless, there are examples of substitution of halogens, particularly fluorine, in fluoronitrobenzenes by carbanions of α-chloroalkyl sulfones [24,25], alkoxynitriles, sulfenamides, and anion of t-butylhydroperoxide (Scheme 7) [26]. These reactions have rather limited practical application.
There are also not frequent reports of reactions of such nucleophiles with acyl chlorides or esters of carboxylic acids [27]. Nevertheless, adding anions of hydroperoxides to acyl chlorides is a way of synthesis of acyl peroxides in moderate to good yields (Scheme 8) [28]. There are also not frequent reports of reactions of such nucleophiles with acyl chlorides or esters of carboxylic acids [27]. Nevertheless, adding anions of hydroperoxides to acyl chlorides is a way of synthesis of acyl peroxides in moderate to good yields (Scheme 8) [28].

Addition of Nucleophiles without Leaving Groups
For many years, the known reactions of nucleophiles with electron-deficient arenes were limited to those proceeding via addition at positions occupied by halogens or other leaving groups. Only recently was it established that adding nucleophiles to nitroaromatic rings also proceeds to rings that do not contain leaving groups. Moreover, addition to the rings containing halogens proceeds faster at positions occupied by hydrogen than halogen [1][2][3]8]. This process was overlooked because the initial fast addition is a reversible process and the initially formed σ H adducts dissociate and slower addition at positions occupied by halogens leading to SNAr taking place (see Scheme 1). It should be mentioned that σ H adducts of C, N, O, etc. nucleophiles to highly electrophilic arenes, such as trinitrobenzene, are stable and upon protonation, trinitrocyclohexadiene-type There are also not frequent reports of reactions of such nucleophiles with acyl chlorides or esters of carboxylic acids [27]. Nevertheless, adding anions of hydroperoxides to acyl chlorides is a way of synthesis of acyl peroxides in moderate to good yields (Scheme 8) [28]. Scheme 8. Nucleophilic substitution in the carbonyl group with nucleophiles containing leaving groups.

Addition of Nucleophiles without Leaving Groups
For many years, the known reactions of nucleophiles with electron-deficient arenes were limited to those proceeding via addition at positions occupied by halogens or other leaving groups. Only recently was it established that adding nucleophiles to nitroaromatic rings also proceeds to rings that do not contain leaving groups. Moreover, addition to the rings containing halogens proceeds faster at positions occupied by hydrogen than halogen [1][2][3]8]. This process was overlooked because the initial fast addition is a reversible process and the initially formed σ H adducts dissociate and slower addition at positions occupied by halogens leading to SNAr taking place (see Scheme 1). It should be mentioned that σ H adducts of C, N, O, etc. nucleophiles to highly electrophilic arenes, such as trinitrobenzene, are stable and upon protonation, trinitrocyclohexadiene-type Scheme 8. Nucleophilic substitution in the carbonyl group with nucleophiles containing leaving groups.

Addition of Nucleophiles without Leaving Groups
For many years, the known reactions of nucleophiles with electron-deficient arenes were limited to those proceeding via addition at positions occupied by halogens or other leaving groups. Only recently was it established that adding nucleophiles to nitroaromatic rings also proceeds to rings that do not contain leaving groups. Moreover, addition to the rings containing halogens proceeds faster at positions occupied by hydrogen than halogen [1][2][3]8]. This process was overlooked because the initial fast addition is a reversible process and the initially formed σ H adducts dissociate and slower addition at positions occupied by halogens leading to S N Ar taking place (see Scheme 1). It should be mentioned that σ H adducts of C, N, O, etc. nucleophiles to highly electrophilic arenes, such as trinitrobenzene, are stable and upon protonation, trinitrocyclohexadiene-type products known as "Meisenheimer complexes", that are in fact trinitrocyclohexadiene derivatives, are formed (Scheme 9) [29].
Scheme 9. Formation of stable adducts of nucleophiles to trinitrobenzene.
Carbanions generated from 1,3-dicarbonyl compounds add to such nitroarenes to form upon protonation peculiar bicyclic products in moderate yields (Scheme 10) [30]. These important and interesting observations have limited application in organic synthesis. Anionic σ H adducts of nucleophiles to mononitroarenes are short-lived species; nevertheless, protonation or silylation of such σ H adducts of some carbanions results in the elimination of water to form nitrosoarenes that can be isolated in the form of quinoneoximes [31] or further converted to anthranils (Scheme 11) [32]. Scheme 11. Addition of nucleophiles to nitroarenes followed by elimination.
Silylation of σ H adducts of methinic carbanions followed by elimination of silanol gave substituted nitrosobenzenes (Scheme 12) [33]. Carbanions generated from 1,3-dicarbonyl compounds add to such nitroarenes to form upon protonation peculiar bicyclic products in moderate yields (Scheme 10) [30]. These important and interesting observations have limited application in organic synthesis.
Scheme 9. Formation of stable adducts of nucleophiles to trinitrobenzene.
Carbanions generated from 1,3-dicarbonyl compounds add to such nitroarenes to form upon protonation peculiar bicyclic products in moderate yields (Scheme 10) [30]. These important and interesting observations have limited application in organic synthesis. Anionic σ H adducts of nucleophiles to mononitroarenes are short-lived species; nevertheless, protonation or silylation of such σ H adducts of some carbanions results in the elimination of water to form nitrosoarenes that can be isolated in the form of quinoneoximes [31] or further converted to anthranils (Scheme 11) [32]. Scheme 11. Addition of nucleophiles to nitroarenes followed by elimination.
Silylation of σ H adducts of methinic carbanions followed by elimination of silanol gave substituted nitrosobenzenes (Scheme 12) [33]. Anionic σ H adducts of nucleophiles to mononitroarenes are short-lived species; nevertheless, protonation or silylation of such σ H adducts of some carbanions results in the elimination of water to form nitrosoarenes that can be isolated in the form of quinoneoximes [31] or further converted to anthranils (Scheme 11) [32].
Scheme 9. Formation of stable adducts of nucleophiles to trinitrobenzene.
Carbanions generated from 1,3-dicarbonyl compounds add to such nitroarenes to form upon protonation peculiar bicyclic products in moderate yields (Scheme 10) [30]. These important and interesting observations have limited application in organic synthesis. Anionic σ H adducts of nucleophiles to mononitroarenes are short-lived species; nevertheless, protonation or silylation of such σ H adducts of some carbanions results in the elimination of water to form nitrosoarenes that can be isolated in the form of quinoneoximes [31] or further converted to anthranils (Scheme 11) [32]. Scheme 11. Addition of nucleophiles to nitroarenes followed by elimination.
Silylation of σ H adducts of methinic carbanions followed by elimination of silanol gave substituted nitrosobenzenes (Scheme 12) [33]. The scope of these interesting and valuable synthesis processes is rather limited. Short-lived σ H adducts of anilines to mononitroarenes upon protonation also undergo the elimination of water to form nitrosodiphenyl amines (Scheme 13) [34,35].  The scope of these interesting and valuable synthesis processes is rather limited. Short-lived σ H adducts of anilines to mononitroarenes upon protonation also undergo the elimination of water to form nitrosodiphenyl amines (Scheme 13) [34,35].

Scheme 12. Formation of nitrosoarenes via silylation of σ H adducts and elimination of silanol.
The scope of these interesting and valuable synthesis processes is rather limited. Short-lived σ H adducts of anilines to mononitroarenes upon protonation also undergo the elimination of water to form nitrosodiphenyl amines (Scheme 13) [34,35]. Scheme 13. Synthesis of nitrosoarylanilines.
Another important way of further transformation of σ H adducts of C, N, O, and even P nucleophiles to nitroarenes is oxidation by external oxidants to form products of oxidative nucleophilic substitution of hydrogen (ONSH). It was recently shown that this process is of the general character of wide application in organic synthesis. Examples of ONSH in nitroarenes are presented in Scheme 14 [33,36,37].

Scheme 14. Examples of ONSH in nitroarenes.
Further, adding nucleophiles to aliphatic π-electrophiles containing carbon-heteroatom double bonds that do not contain leaving groups is energetically favorable; hence, the usual protonation of the adducts provides stable products. This can be Scheme 13. Synthesis of nitrosoarylanilines.
Another important way of further transformation of σ H adducts of C, N, O, and even P nucleophiles to nitroarenes is oxidation by external oxidants to form products of oxidative nucleophilic substitution of hydrogen (ONSH). It was recently shown that this process is of the general character of wide application in organic synthesis. Examples of ONSH in nitroarenes are presented in Scheme 14 [33,36,37]. The scope of these interesting and valuable synthesis processes is rather limited. Short-lived σ H adducts of anilines to mononitroarenes upon protonation also undergo the elimination of water to form nitrosodiphenyl amines (Scheme 13) [34,35]. Scheme 13. Synthesis of nitrosoarylanilines.
Another important way of further transformation of σ H adducts of C, N, O, and even P nucleophiles to nitroarenes is oxidation by external oxidants to form products of oxidative nucleophilic substitution of hydrogen (ONSH). It was recently shown that this process is of the general character of wide application in organic synthesis. Examples of ONSH in nitroarenes are presented in Scheme 14 [33,36,37].

Scheme 14. Examples of ONSH in nitroarenes.
Further, adding nucleophiles to aliphatic π-electrophiles containing carbon-heteroatom double bonds that do not contain leaving groups is energetically favorable; hence, the usual protonation of the adducts provides stable products. This can be Further, adding nucleophiles to aliphatic π-electrophiles containing carbon-heteroatom double bonds that do not contain leaving groups is energetically favorable; hence, the usual protonation of the adducts provides stable products. This can be exemplified by the addition of cyanide anion to aldehydes and ketones that upon protonation form cyanohydrines or silylation O-silylated cyanohydrines (Scheme 15) [38,39]. Similarly, the addition of carbanions to aldehydes and ketones followed by protonation gives aldol-type products.
exemplified by the addition of cyanide anion to aldehydes and ketones that upon protonation form cyanohydrines or silylation O-silylated cyanohydrines (Scheme 15) [38,39]. Similarly, the addition of carbanions to aldehydes and ketones followed by protonation gives aldol-type products.
Addition of carbon nucleophiles to carbonyl groups.
Usually, the protonated adducts-aldols-enter fast further reactions, most often elimination of water to form alkenes (Knoevenagel reaction) [40]. Additionally, adding ammonia and a variety of amines to aldehydes and ketones results in the formation of aminals and subsequently, upon elimination of water, aldimines or enamines (Scheme 16).

Scheme 16.
Addition of nucleophiles to carbonyl groups followed by elimination.
We would like to stress the similarity of the conversion of the σ H adducts to nitroarenes and to aldehydes and ketones via protonation and the elimination of water. The addition of nucleophiles to highly electron-deficient nitroarenes upon protonation results in formation of relatively stable adducts, similarly to formation of aldols, whereas addition to mononitroarenes followed by protonation and elimination of water gives nitrosoarenes, isolated usually as methylenequinone oximes (Schemes 11-13) in a process analogous to the Knoevenagel reaction. Usually, the protonated adducts-aldols-enter fast further reactions, most often elimination of water to form alkenes (Knoevenagel reaction) [40]. Additionally, adding ammonia and a variety of amines to aldehydes and ketones results in the formation of aminals and subsequently, upon elimination of water, aldimines or enamines (Scheme 16).
exemplified by the addition of cyanide anion to aldehydes and ketones that upon protonation form cyanohydrines or silylation O-silylated cyanohydrines (Scheme 15) [38,39]. Similarly, the addition of carbanions to aldehydes and ketones followed by protonation gives aldol-type products. Usually, the protonated adducts-aldols-enter fast further reactions, most often elimination of water to form alkenes (Knoevenagel reaction) [40]. Additionally, adding ammonia and a variety of amines to aldehydes and ketones results in the formation of aminals and subsequently, upon elimination of water, aldimines or enamines (Scheme 16).

Scheme 16.
Addition of nucleophiles to carbonyl groups followed by elimination.
We would like to stress the similarity of the conversion of the σ H adducts to nitroarenes and to aldehydes and ketones via protonation and the elimination of water. The addition of nucleophiles to highly electron-deficient nitroarenes upon protonation results in formation of relatively stable adducts, similarly to formation of aldols, whereas addition to mononitroarenes followed by protonation and elimination of water gives nitrosoarenes, isolated usually as methylenequinone oximes (Schemes 11-13) in a process analogous to the Knoevenagel reaction. Scheme 16. Addition of nucleophiles to carbonyl groups followed by elimination.
We would like to stress the similarity of the conversion of the σ H adducts to nitroarenes and to aldehydes and ketones via protonation and the elimination of water. The addition of nucleophiles to highly electron-deficient nitroarenes upon protonation results in formation of relatively stable adducts, similarly to formation of aldols, whereas addition to mononitroarenes followed by protonation and elimination of water gives nitrosoarenes, isolated usually as methylenequinone oximes (Schemes 11-13) in a process analogous to the Knoevenagel reaction.
Oxidation analogous to that of σ H adducts of nucleophiles to nitroarenes, ONSH, also proceeds with the adducts of nucleophiles to aliphatic π-electrophiles-aldehydes. For instance, aromatic aldehydes treated with potassium permanganate in liquid ammonia form amides in moderate yields (Scheme 17) [41].
Oxidation analogous to that of σ H adducts of nucleophiles to nitroarenes, ONSH also proceeds with the adducts of nucleophiles to aliphatic π-electrophiles-aldehydes For instance, aromatic aldehydes treated with potassium permanganate in liquid am monia form amides in moderate yields (Scheme 17) [41]. Scheme 17. Synthesis of amides from aldehyde and ammonia.

Scheme 18. ONSH in aliphatic π-electrophiles.
ONSH is also a well-established process for the functionalization of two structurally similar classes of π-electrophiles-aromatic N-oxides [49][50][51]  Formally, the oxidation of protonated adducts of RLi and RMgX to aldehydes, that is alcohols, may be viewed as another example belonging to this category. ONSH reaction also proceeds with electron-deficient alkenes, for example, in quinone or maleimide derivatives [42][43][44][45][46][47]  Oxidation analogous to that of σ H adducts of nucleophiles to nitroarenes, ONSH, also proceeds with the adducts of nucleophiles to aliphatic π-electrophiles-aldehydes. For instance, aromatic aldehydes treated with potassium permanganate in liquid ammonia form amides in moderate yields (Scheme 17) [41]. Scheme 17. Synthesis of amides from aldehyde and ammonia.
Oxidation analogous to that of σ H adducts of nucleophiles to nitroarenes, ONSH, also proceeds with the adducts of nucleophiles to aliphatic π-electrophiles-aldehydes. For instance, aromatic aldehydes treated with potassium permanganate in liquid ammonia form amides in moderate yields (Scheme 17) [41]. Scheme 17. Synthesis of amides from aldehyde and ammonia.

Addition of Nucleophiles Containing Leaving Groups
Of particular interest and value are reactions of aromatic and aliphatic π-electrophiles with nucleophiles that contain leaving groups at the nucleophilic center. Such nucle-ophiles are exemplified by α-halocarbanions, sulfonium and phosphonium ylides, tbutylhydroperoxide anion, substituted amines, etc.
The addition of α-halocarbanions to nitroarenes results in the initial formation of the σ H adducts that subsequently enter base-induced β-elimination of hydrogen halide and protonation to give products of vicarious nucleophilic substitution (VNS). This reaction can proceed provided the σ H adducts exist for a sufficiently long time and the base is present in excess (Scheme 20) [23,54].

Addition of Nucleophiles Containing Leaving Groups
Of particular interest and value are reactions of aromatic and aliphatic π-electrophiles with nucleophiles that contain leaving groups at the nucleophilic center Such nucleophiles are exemplified by α-halocarbanions, sulfonium and phosphonium ylides, t-butylhydroperoxide anion, substituted amines, etc.
The addition of α-halocarbanions to nitroarenes results in the initial formation of the σ H adducts that subsequently enter base-induced β-elimination of hydrogen halide and protonation to give products of vicarious nucleophilic substitution (VNS). This reaction can proceed provided the σ H adducts exist for a sufficiently long time and the base is present in excess (Scheme 20) [23,54].

Scheme 20. Examples of the VNS reaction.
Similar reaction proceeds with carbanions containing other leaving groups able to be eliminated in the base-induced E2 process. For example, VNS cyanomethylation of ni troarenes in the reaction with aryloxyacetonitriles is widely used to synthesize indoles (Scheme 21) [55]. Similar reaction proceeds with carbanions containing other leaving groups able to be eliminated in the base-induced E2 process. For example, VNS cyanomethylation of nitroarenes in the reaction with aryloxyacetonitriles is widely used to synthesize indoles (Scheme 21) [55].

Addition of Nucleophiles Containing Leaving Groups
Of particular interest and value are reactions of aromatic and aliphatic π-electrophiles with nucleophiles that contain leaving groups at the nucleophilic center. Such nucleophiles are exemplified by α-halocarbanions, sulfonium and phosphonium ylides, t-butylhydroperoxide anion, substituted amines, etc.
The addition of α-halocarbanions to nitroarenes results in the initial formation of the σ H adducts that subsequently enter base-induced β-elimination of hydrogen halide and protonation to give products of vicarious nucleophilic substitution (VNS). This reaction can proceed provided the σ H adducts exist for a sufficiently long time and the base is present in excess (Scheme 20) [23,54].

Scheme 20. Examples of the VNS reaction.
Similar reaction proceeds with carbanions containing other leaving groups able to be eliminated in the base-induced E2 process. For example, VNS cyanomethylation of nitroarenes in the reaction with aryloxyacetonitriles is widely used to synthesize indoles (Scheme 21) [55].

Addition of Nucleophiles Containing Leaving Groups
Of particular interest and value are reactions of aromatic and aliphatic π-electrophiles with nucleophiles that contain leaving groups at the nucleophilic center. Such nucleophiles are exemplified by α-halocarbanions, sulfonium and phosphonium ylides, t-butylhydroperoxide anion, substituted amines, etc.
The addition of α-halocarbanions to nitroarenes results in the initial formation of the σ H adducts that subsequently enter base-induced β-elimination of hydrogen halide and protonation to give products of vicarious nucleophilic substitution (VNS). This reaction can proceed provided the σ H adducts exist for a sufficiently long time and the base is present in excess (Scheme 20) [23,54].

Scheme 20. Examples of the VNS reaction.
Similar reaction proceeds with carbanions containing other leaving groups able to be eliminated in the base-induced E2 process. For example, VNS cyanomethylation of nitroarenes in the reaction with aryloxyacetonitriles is widely used to synthesize indoles (Scheme 21) [55]. It should be stressed that an identical process of addition-β-elimination proceeds with an anion of t-butylhydroperoxide to produce nitrophenols and N-anions, generated from some sulfenamides, trimethylhydrazonium iodide, hydroxylamine derivatives, etc. to give nitroanilines (Scheme 23) [26,[61][62][63].
Molecules 2023, 28, x FOR PEER REVIEW 11 of 22 It should be stressed that an identical process of addition-β-elimination proceeds with an anion of t-butylhydroperoxide to produce nitrophenols and N-anions, generated from some sulfenamides, trimethylhydrazonium iodide, hydroxylamine derivatives, etc. to give nitroanilines (Scheme 23) [26,[61][62][63]. Thus, VNS is a general process for introducing carbon, nitrogen, and oxygen substituents into aromatic rings.

Scheme 23. VNS in nitroarenes with oxygen and nitrogen nucleophiles.
Thus, VNS is a general process for introducing carbon, nitrogen, and oxygen substituents into aromatic rings.
It should be stressed that an identical process of addition-β-elimination proceed with an anion of t-butylhydroperoxide to produce nitrophenols and N-anions, generated from some sulfenamides, trimethylhydrazonium iodide, hydroxylamine derivatives, etc to give nitroanilines (Scheme 23) [26,[61][62][63]. Thus, VNS is a general process for introducing carbon, nitrogen, and oxygen sub stituents into aromatic rings.
The high affinity of phosphorus to oxygen causes a different behavior of phosphonium ylides. Their anionic adducts to aldehydes and ketones react further via a combination of the O-anion with a positively charged phosphorous atom giving oxaphosphetanes, followed by the elimination of phosphine oxide to produce alkenes (Wittig reaction; Scheme 26). A similar reaction course leading to alkenes has been reported for adding phosphonium ylides to N-sulfonylimines [76,77], whereas simple N-arylimines give allenes [78]. The high affinity of phosphorus to oxygen causes a different behavior of phospho nium ylides. Their anionic adducts to aldehydes and ketones react further via a combi nation of the O-anion with a positively charged phosphorous atom giving oxaphos phetanes, followed by the elimination of phosphine oxide to produce alkenes (Wittig re action; Scheme 26). A similar reaction course leading to alkenes has been reported for adding phosphonium ylides to N-sulfonylimines [76,77], whereas simple N-arylimines give allenes [78]. The addition of the nucleophiles containing leaving groups to electron-deficient al kenes results in the formation of anionic adducts that are γ-halocarbanions and related intermediates and is followed by intramolecular 1,3-substitution to give cyclopropanes This is one of the major ways to synthesize substituted cyclopropanes (Scheme 27 [71,79,80]. A similar process-addition followed by 1,3-intramolecular substitution reac tion-proceeds between the anion of t-butylhydroperoxide and some electron-deficien alkenes to give oxiranes, although protonation of the intermediate adducts to form Mi chael-type products dominates [81]. Similarly, the addition of N-nucleophiles containing leaving groups followed by 1,3-intramolecular substitution is an efficient way of synthe sis of aziridines [75].

Scheme 25.
Formation of three-membered rings in the reactions of aliphatic π-electrophiles with nucleophiles containing leaving groups.

Scheme 25.
Formation of three-membered rings in the reactions of aliphatic π-electrophiles with nucleophiles containing leaving groups.
The high affinity of phosphorus to oxygen causes a different behavior of phosphonium ylides. Their anionic adducts to aldehydes and ketones react further via a combination of the O-anion with a positively charged phosphorous atom giving oxaphosphetanes, followed by the elimination of phosphine oxide to produce alkenes (Wittig reaction; Scheme 26). A similar reaction course leading to alkenes has been reported for adding phosphonium ylides to N-sulfonylimines [76,77], whereas simple N-arylimines give allenes [78]. The addition of the nucleophiles containing leaving groups to electron-deficient alkenes results in the formation of anionic adducts that are γ-halocarbanions and related intermediates and is followed by intramolecular 1,3-substitution to give cyclopropanes. This is one of the major ways to synthesize substituted cyclopropanes (Scheme 27) [71,79,80]. A similar process-addition followed by 1,3-intramolecular substitution reaction-proceeds between the anion of t-butylhydroperoxide and some electron-deficient alkenes to give oxiranes, although protonation of the intermediate adducts to form Michael-type products dominates [81]. Similarly, the addition of N-nucleophiles containing leaving groups followed by 1,3-intramolecular substitution is an efficient way of synthesis of aziridines [75]. The addition of the nucleophiles containing leaving groups to electron-deficient alkenes results in the formation of anionic adducts that are γ-halocarbanions and related intermediates and is followed by intramolecular 1,3-substitution to give cyclopropanes. This is one of the major ways to synthesize substituted cyclopropanes (Scheme 27) [71,79,80]. A similar process-addition followed by 1,3-intramolecular substitution reaction-proceeds between the anion of t-butylhydroperoxide and some electron-deficient alkenes to give oxiranes, although protonation of the intermediate adducts to form Michael-type products dominates [81]. Similarly, the addition of N-nucleophiles containing leaving groups followed by 1,3-intramolecular substitution is an efficient way of synthesis of aziridines [75]. Surprisingly, there are no reports of the possibility of converting adducts of α-chlorocarbanions to aliphatic π-electrophiles containing a carbon-heteroatom double bond via base-induced β-elimination, although such attempts were disclosed in the literature [82]. Motivated by the similarity of aromatic and aliphatic π-nucleophiles reac- Surprisingly, there are no reports of the possibility of converting adducts of α-chlorocarbanions to aliphatic π-electrophiles containing a carbon-heteroatom double bond via base-induced β-elimination, although such attempts were disclosed in the literature [82]. Motivated by the similarity of aromatic and aliphatic π-nucleophiles reactivity, we have attempted such reactions. β-Elimination in the adducts of α-chlorocarbanions to benzaldehyde does not proceed as it is hampered by the vicinity of the negatively charged oxygen which engages in facile intramolecular substitution to form oxiranes. On the other hand, β-elimination in the adducts of α-chlorocarbanions to electron-deficient imines proceeded satisfactorily (Scheme 28) [83]. Surprisingly, there are no reports of the possibility of converting adducts of α-chlorocarbanions to aliphatic π-electrophiles containing a carbon-heteroatom double bond via base-induced β-elimination, although such attempts were disclosed in the literature [82]. Motivated by the similarity of aromatic and aliphatic π-nucleophiles reactivity, we have attempted such reactions. β-Elimination in the adducts of α-chlorocarbanions to benzaldehyde does not proceed as it is hampered by the vicinity of the negatively charged oxygen which engages in facile intramolecular substitution to form oxiranes. On the other hand, β-elimination in the adducts of α-chlorocarbanions to electron-deficient imines proceeded satisfactorily (Scheme 28) [83].

Scheme 28. VNS in imines.
No examples of β-elimination of HCl from the adducts of α-chlorocarbanions to electron-deficient alkenes were known for a long time. We have shown that such processes, identical to VNS in nitroarenes, proceed under appropriate conditions with electron-deficient alkenes and carbanions containing an aryloxy leaving group or even with α-chlorocarbanions (Scheme 29) [42,84,85]. Scheme 29. VNS in malononitrile derivatives and in nitroalkenes.

Scheme 28. VNS in imines.
No examples of β-elimination of HCl from the adducts of α-chlorocarbanions to electron-deficient alkenes were known for a long time. We have shown that such processes, identical to VNS in nitroarenes, proceed under appropriate conditions with electrondeficient alkenes and carbanions containing an aryloxy leaving group or even with αchlorocarbanions (Scheme 29) [42,84,85]. Surprisingly, there are no reports of the possibility of converting adducts of α-chlorocarbanions to aliphatic π-electrophiles containing a carbon-heteroatom double bond via base-induced β-elimination, although such attempts were disclosed in the literature [82]. Motivated by the similarity of aromatic and aliphatic π-nucleophiles reactivity, we have attempted such reactions. β-Elimination in the adducts of α-chlorocarbanions to benzaldehyde does not proceed as it is hampered by the vicinity of the negatively charged oxygen which engages in facile intramolecular substitution to form oxiranes. On the other hand, β-elimination in the adducts of α-chlorocarbanions to electron-deficient imines proceeded satisfactorily (Scheme 28) [83].

Scheme 28. VNS in imines.
No examples of β-elimination of HCl from the adducts of α-chlorocarbanions to electron-deficient alkenes were known for a long time. We have shown that such processes, identical to VNS in nitroarenes, proceed under appropriate conditions with electron-deficient alkenes and carbanions containing an aryloxy leaving group or even with α-chlorocarbanions (Scheme 29) [42,84,85]. More examples of this kind appeared in recent years, including a reaction of nitroalkanes with NO 2 acting as a carbanion-stabilizing and leaving group (Scheme 30) [86,87]. A reaction of a nitrogen nucleophile bearing a Ph 2 S leaving the group with maleimides and naphthoquinone in good yields has also been reported (Scheme 31) [88][89][90]. More examples of this kind appeared in recent years, including a reaction of nitroalkanes with NO2 acting as a carbanion-stabilizing and leaving group (Scheme 30) [86,87]. A reaction of a nitrogen nucleophile bearing a Ph2S leaving the group with maleimides and naphthoquinone in good yields has also been reported (Scheme 31) [88][89][90].

Reactions of Specific Nucleophiles
Several kinds of specific nucleophiles also enter analogous reactions with aromatic and aliphatic π-electrophiles. To this category belong 1,3-dipoles that enter 1,3-dipolar cycloaddition both to electron-deficient arenes [91,92] and alkenes [93,94] (Scheme 32). Of substantial interest are masked acyl carbanions, key intermediates in the Stetter reaction [95]. This reaction proceeds via addition of cyanide anion or nucleophilic car-Scheme 31. VNS with a nitrogen nucleophile in aliphatic systems.

Scheme 30. VNS in aliphatic systems.
Scheme 31. VNS with a nitrogen nucleophile in aliphatic systems.
Of substantial interest are masked acyl carbanions, key intermediates in the Stetter reaction [95]. This reaction proceeds via addition of cyanide anion or nucleophilic carbenes to aldehydes and subsequent intramolecular migration of proton to generate masked acyl carbanions that add to active electrophiles, mainly Michael acceptors. Subsequent dissociation gives Michael adducts of acyl carbanions (Scheme 33). It should be mentioned that the Stetter reaction follows the concept of Umpolung introduced by Seebach to invert the polarity of the carbonyl group in aldehydes [98]. Conversion of aldehydes into dithioacetals followed by deprotonation produced masked acyl carbanions. Subsequent reactions with a variety of electrophiles, followed by deacetalization, give products of reactions of acyl carbanions. Reactions of such carbanions with nitroarenes were also reported. A more convenient approach is generating masked acyl carbanions via the conversion of aldehydes into cyanohydrines, followed by protection in the form of acetals via reactions with vinyl ethers (Scheme 35). Deprotonation of such protected cyanohydrins gave stable equivalents of acyl carbanions [99][100][101]. It should be mentioned that the Stetter reaction follows the concept of Umpolung introduced by Seebach to invert the polarity of the carbonyl group in aldehydes [98]. Conversion of aldehydes into dithioacetals followed by deprotonation produced masked acyl carbanions. Subsequent reactions with a variety of electrophiles, followed by deacetalization, give products of reactions of acyl carbanions. Reactions of such carbanions with nitroarenes were also reported. A more convenient approach is generating masked acyl carbanions via the conversion of aldehydes into cyanohydrines, followed by protection in the form of acetals via reactions with vinyl ethers (Scheme 35). Deprotonation of such protected cyanohydrins gave stable equivalents of acyl carbanions [99][100][101]. Thanks to the stability of all intermediates involved, this way of generating masked acyl carbanions appears to be more versatile than the original Stetter reaction.
Molecules 2023, 28, x FOR PEER REVIEW 16 of 22 Thanks to the stability of all intermediates involved, this way of generating masked acyl carbanions appears to be more versatile than the original Stetter reaction.

General Comments
Finally, an interesting general question should be addressed. As it was mentioned earlier, nucleophilic addition to ortho and para halonitrobenzenes proceeds faster at positions occupied by hydrogen than halogens, therefore nucleophilic substitution of hydrogen: VNS, ONSH, etc. proceeds as a rule faster than conventional SNAr of halogens. Based on these observations, it was often considered that halogens in electron-deficient arenes partially protect their positions against nucleophilic addition. It was interesting to see that the same observation was made in rather few experiments with aliphatic π-electrophiles. Thus in 2-chloronaphthoquinone VNS reaction with α-chlorocarbanions proceeds exclusively (Scheme 36) [42]. Mayr has shown that nucleophilic addition to

General Comments
Finally, an interesting general question should be addressed. As it was mentioned earlier, nucleophilic addition to ortho and para halonitrobenzenes proceeds faster at positions occupied by hydrogen than halogens, therefore nucleophilic substitution of hydrogen: VNS, ONSH, etc. proceeds as a rule faster than conventional S N Ar of halogens. Based on these observations, it was often considered that halogens in electron-deficient arenes partially protect their positions against nucleophilic addition. It was interesting to see that the same observation was made in rather few experiments with aliphatic π-electrophiles. Thus in 2-chloronaphthoquinone VNS reaction with α-chlorocarbanions proceeds exclusively (Scheme 36) [42]. Mayr has shown that nucleophilic addition to chlorobenzoquinones also proceeds faster at positions occupied by hydrogen [102].

General Comments
Finally, an interesting general question should be addressed. As it was mentioned earlier, nucleophilic addition to ortho and para halonitrobenzenes proceeds faster at positions occupied by hydrogen than halogens, therefore nucleophilic substitution of hydrogen: VNS, ONSH, etc. proceeds as a rule faster than conventional SNAr of halogens. Based on these observations, it was often considered that halogens in electron-deficient arenes partially protect their positions against nucleophilic addition. It was interesting to see that the same observation was made in rather few experiments with aliphatic π-electrophiles. Thus in 2-chloronaphthoquinone VNS reaction with α-chlorocarbanions proceeds exclusively (Scheme 36) [42]. Mayr has shown that nucleophilic addition to chlorobenzoquinones also proceeds faster at positions occupied by hydrogen [102].

Scheme 36. VNS and SNAr in chloronaphthoquinones.
We have also found that carbanions add faster at carbon occupied by hydrogen (in position 2) of 1-chlorofumarate and maleate [103]. However, the statement that chlorine decelerates nucleophilic addition at positions it occupies, although supported by many observations, is unjustified simply because competition between addition of nucleophiles at a position occupied by hydrogen and chlorine in para or ortho chloronitrobenzenes is unfair. Positions occupied by hydrogen are additionally activated by electron withdrawing chlorine substituent in the ring or at the π bond, whereas those occupied by chlorine are not additionally activated. This interesting and important problem should be Scheme 36. VNS and S N Ar in chloronaphthoquinones.
We have also found that carbanions add faster at carbon occupied by hydrogen (in position 2) of 1-chlorofumarate and maleate [103]. However, the statement that chlorine decelerates nucleophilic addition at positions it occupies, although supported by many observations, is unjustified simply because competition between addition of nucleophiles at a position occupied by hydrogen and chlorine in para or ortho chloronitrobenzenes is unfair. Positions occupied by hydrogen are additionally activated by electron withdrawing chlorine substituent in the ring or at the π bond, whereas those occupied by chlorine are not additionally activated. This interesting and important problem should be solved using unbiased models. For instance, we have observed that in competition between nitrobenzene and p-chloronitrobenzene for the reaction with a bulky methinic carbanion which does not react in the ortho position, the addition of this carbanion in position para of nitrobenzene proceeds faster. Similarly, the VNS reaction of chloromalonates with 2-chloronaphthoquinones proceeds faster than with 2,3-dichloronaphthoquinones, also 1,2-dichloromaleate reacts slower than monochloro with carbanion of chloromethyl phenyl sulfone (Scheme 36).
These observations support the hypothesis that chlorine substituents indeed decelerate nucleophilic addition at positions they occupy in aromatic and aliphatic π-electrophiles. These interesting observations and hypotheses need further studies.
For instance, there remains an important matter of the relative activity of aldehydes and the corresponding acyl chlorides. We hypothesize that the electrophilic activity of aldehydes is higher, but we are not aware of any experimental evidence. The formation of benzoate of benzaldehyde cyanohydrine when KCN or LiCN is added to a mixture of benzaldehyde and benzoyl chloride is not sufficient [38,104].

Kinetic vs. Thermodynamic Control
In the electron-deficient aromatic rings, e.g., nitroarenes, there are usually two or even three electrophilic sites able to add nucleophiles, thus the question of kinetic and thermodynamic control is of crucial importance. According to the recently formulated general mechanism of nucleophilic aromatic substitution in nitroarenes, the addition of nucleophiles to nitroarenes proceeds rapidly at positions ortho or para to the nitro group to form σ H adducts [1,8,105]. The adducts are short-lived species and usually dissociate and slower addition at positions occupied by halogens X followed by the fast departure of halide anion results in the substitution of halogens, thus this process can be considered thermodynamically controlled. Furthermore, when, with proper structure of nucleophiles and conditions, the initially formed σ H adducts are converted into products of substitution of hydrogen, the process can be considered kinetically controlled. Additionally, the orientation of nucleophilic substitution of hydrogen can be kinetically and thermodynamically controlled. For instance, VNS in nitrobenzene with methylenic carbanions under kinetic control-excess of base, low temperature-proceeds mostly in the ortho position, whereas under thermodynamic control (r.t., slow addition of the carbanion solution to a solution of nitroarene) para substitution dominates. Exemplification of the kinetic vs. thermodynamic control in the reaction of an α-chlorocarbanion with nitroarenes is shown in Scheme 37. general mechanism of nucleophilic aromatic substitution in nitroarenes, the addition of nucleophiles to nitroarenes proceeds rapidly at positions ortho or para to the nitro group to form σ H adducts [1,8,105]. The adducts are short-lived species and usually dissociate and slower addition at positions occupied by halogens X followed by the fast departure of halide anion results in the substitution of halogens, thus this process can be considered thermodynamically controlled. Furthermore, when, with proper structure of nucleophiles and conditions, the initially formed σ H adducts are converted into products of substitution of hydrogen, the process can be considered kinetically controlled. Additionally, the orientation of nucleophilic substitution of hydrogen can be kinetically and thermodynamically controlled. For instance, VNS in nitrobenzene with methylenic carbanions under kinetic control-excess of base, low temperature-proceeds mostly in the ortho position, whereas under thermodynamic control (r.t., slow addition of the carbanion solution to a solution of nitroarene) para substitution dominates. Exemplification of the kinetic vs. thermodynamic control in the reaction of an α-chlorocarbanion with nitroarenes is shown in Scheme 37. These experimental observations are confirmed by calculations of free energies of transition states of the addition and σ adducts [105].

Conclusions
We hope that the general concept of this paper-the analogy between reactions of nucleophiles with aliphatic and aromatic π-electrophiles-is convincingly supported by the presented examples and their interpretation. The mechanism of reactions of nucleophiles with both kinds of π-electrophiles are in fact identical; they are all initiated by a nucleophilic addition to the π system, at the position occupied by a leaving group or by hydrogen, with the latter process usually faster. There are several ways of further conversion of the adducts which are common for both aromatic and aliphatic systems. If the π system of the electrophilic partner contains a heteroatom, Knoevenagel-type elimination may also be possible. Importantly, examples of each type of reaction course can be given for both aliphatic and aromatic electrophiles.
Two important conclusions can be drawn from our analysis. First, some types of reactions are underrepresented within either the aliphatic or aromatic electrophiles group, which should inspire the search for new reactions that remain to be discovered. Second, this essay should change the general opinion that reactions of aliphatic electrophiles are more diversified than those of aromatic ones. It is just the opposite, as exemplified by benzoyl chloride, which is capable only of chloride substitution, and chloronitrobenzene which, upon nucleophilic addition, undergoes S N Ar, VNS, or two variants of the ONSH reaction [106].