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Review

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

by
Michał Barbasiewicz
1,
Michał Fedoryński
2,
Rafał Loska
3,* and
Mieczysław Mąkosza
3,*
1
Faculty of Chemistry, University of Warsaw, 02-093 Warsaw, Poland
2
Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
3
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(10), 4015; https://doi.org/10.3390/molecules28104015
Submission received: 6 April 2023 / Revised: 1 May 2023 / Accepted: 9 May 2023 / Published: 11 May 2023
(This article belongs to the Special Issue Feature Papers in Organic Chemistry (Volume II))
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Abstract

:
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.

Graphical Abstract

1. 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 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.

2. Addition of Nucleophiles to π-Electrophiles Containing Leaving Groups at Electrophilic Center

2.1. 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 σX 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 σH adducts have no direct way for further conversion; hence, they usually dissociated. Nevertheless, when such a possibility exists, further conversion of the σH 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].

2.2. 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 σH 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].

3. Addition of Nucleophiles to π-Electrophiles without Leaving Groups at the Electrophilic Center

3.1. 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 σH adducts dissociate and slower addition at positions occupied by halogens leading to SNAr taking place (see Scheme 1). It should be mentioned that σH 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].
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 σH adducts of nucleophiles to mononitroarenes are short-lived species; nevertheless, protonation or silylation of such σH 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].
Silylation of σH 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 σH adducts of anilines to mononitroarenes upon protonation also undergo the elimination of water to form nitrosodiphenyl amines (Scheme 13) [34,35].
Another important way of further transformation of σH 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].
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.
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).
We would like to stress the similarity of the conversion of the σH 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 (Scheme 11, Scheme 12 and Scheme 13) in a process analogous to the Knoevenagel reaction.
Oxidation analogous to that of σH 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].
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] or even nitroalkenes [48] (Scheme 18).
ONSH is also a well-established process for the functionalization of two structurally similar classes of π-electrophiles–aromatic N-oxides [49,50,51] and aliphatic nitrones (Scheme 19) [52,53].

3.2. 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 σH 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 σH adducts exist for a sufficiently long time and the base is present in excess (Scheme 20) [23,54].
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].
There are a few examples of VNS with sulfonium [56,57,58] and phosphonium ylides (Scheme 22) [59,60].
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.
Interestingly, when delocalization of the negative charge in the σH adduct of α-halocarbanions or sulfonium ylides to electron-deficient arenes is inefficient, they react further not via β-elimination but via intramolecular substitution to form aziridines or cyclopropanes (Scheme 24) [64,65,66,67].
On the other hand, adducts of α-chlorocarbanions and sulfonium ylides to aliphatic electrophiles containing carbonyl groups result in formation of anionic σ adducts that undergo intramolecular 1,3-substitution to form oxiranes (Darzens [68,69] or Corey-Chaykovsky [70,71,72,73] reactions). The reaction of such nucleophiles with imines to form aziridines proceeds similarly (Scheme 25) [74,75].
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].
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].
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 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].

4. 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 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).
Examples of the Stetter reaction with nitroarenes that gave as the final products nitrobenzophenones were reported (Scheme 34) [96,97].
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.

5. 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].
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].

6. 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 σH 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 σH 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].
In most aliphatic π-electrophiles, there is one electrophilic center to which the addition of nucleophiles occurs. Nevertheless, there are numerous electrophiles with two such centers, e.g., acrolein, vinyl ketones, acrylates, etc., reactions of which nucleophiles can proceed under kinetic or thermodynamic control (1,2- vs. 1,4-addition) [70].

7. 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 SNAr, VNS, or two variants of the ONSH reaction [106].

Author Contributions

Conceptualization, M.M.; writing—original draft preparation, M.B., M.F., R.L. and M.M.; writing—review and editing, M.B., M.F., R.L. and M.M.; visualization, M.B., M.F. and R.L.; supervision, M.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

Data sharing not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Not applicable.

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Molecules 28 04015 sch001 550
Scheme 1. SNAr in nitroarenes.
Scheme 1. SNAr in nitroarenes.
Molecules 28 04015 sch001
Molecules 28 04015 sch002 550
Scheme 2. Addition of nucleophiles to nitroarenes.
Scheme 2. Addition of nucleophiles to nitroarenes.
Molecules 28 04015 sch002
Molecules 28 04015 sch003 550
Scheme 3. Aliphatic π-electrophiles.
Scheme 3. Aliphatic π-electrophiles.
Molecules 28 04015 sch003
Molecules 28 04015 sch004 550
Scheme 4. Nucleophilic substitution at the carbonyl group.
Scheme 4. Nucleophilic substitution at the carbonyl group.
Molecules 28 04015 sch004
Molecules 28 04015 sch005 550
Scheme 5. Nucleophilic substitution of leaving groups in electrophilic alkenes.
Scheme 5. Nucleophilic substitution of leaving groups in electrophilic alkenes.
Molecules 28 04015 sch005
Molecules 28 04015 sch006 550
Scheme 6. Examples of nucleophilic substitution of leaving groups in aliphatic systems.
Scheme 6. Examples of nucleophilic substitution of leaving groups in aliphatic systems.
Molecules 28 04015 sch006
Molecules 28 04015 sch007 550
Scheme 7. SNAr in nitroarenes with nucleophiles containing leaving groups.
Scheme 7. SNAr in nitroarenes with nucleophiles containing leaving groups.
Molecules 28 04015 sch007
Molecules 28 04015 sch008 550
Scheme 8. Nucleophilic substitution in the carbonyl group with nucleophiles containing leaving groups.
Scheme 8. Nucleophilic substitution in the carbonyl group with nucleophiles containing leaving groups.
Molecules 28 04015 sch008
Molecules 28 04015 sch009 550
Scheme 9. Formation of stable adducts of nucleophiles to trinitrobenzene.
Scheme 9. Formation of stable adducts of nucleophiles to trinitrobenzene.
Molecules 28 04015 sch009
Molecules 28 04015 sch010 550
Scheme 10. Formation of bicyclic structures from trinitrobenzene and carbanions of 1,3-dicarbonyl compounds.
Scheme 10. Formation of bicyclic structures from trinitrobenzene and carbanions of 1,3-dicarbonyl compounds.
Molecules 28 04015 sch010
Molecules 28 04015 sch011 550
Scheme 11. Addition of nucleophiles to nitroarenes followed by elimination.
Scheme 11. Addition of nucleophiles to nitroarenes followed by elimination.
Molecules 28 04015 sch011
Molecules 28 04015 sch012 550
Scheme 12. Formation of nitrosoarenes via silylation of σH adducts and elimination of silanol.
Scheme 12. Formation of nitrosoarenes via silylation of σH adducts and elimination of silanol.
Molecules 28 04015 sch012
Molecules 28 04015 sch013 550
Scheme 13. Synthesis of nitrosoarylanilines.
Scheme 13. Synthesis of nitrosoarylanilines.
Molecules 28 04015 sch013
Molecules 28 04015 sch014 550
Scheme 14. Examples of ONSH in nitroarenes.
Scheme 14. Examples of ONSH in nitroarenes.
Molecules 28 04015 sch014
Molecules 28 04015 sch015 550
Scheme 15. Addition of carbon nucleophiles to carbonyl groups.
Scheme 15. Addition of carbon nucleophiles to carbonyl groups.
Molecules 28 04015 sch015
Molecules 28 04015 sch016 550
Scheme 16. Addition of nucleophiles to carbonyl groups followed by elimination.
Scheme 16. Addition of nucleophiles to carbonyl groups followed by elimination.
Molecules 28 04015 sch016
Molecules 28 04015 sch017 550
Scheme 17. Synthesis of amides from aldehyde and ammonia.
Scheme 17. Synthesis of amides from aldehyde and ammonia.
Molecules 28 04015 sch017
Molecules 28 04015 sch018 550
Scheme 18. ONSH in aliphatic π-electrophiles.
Scheme 18. ONSH in aliphatic π-electrophiles.
Molecules 28 04015 sch018
Molecules 28 04015 sch019 550
Scheme 19. ONSH in N-oxides and nitrones.
Scheme 19. ONSH in N-oxides and nitrones.
Molecules 28 04015 sch019
Molecules 28 04015 sch020 550
Scheme 20. Examples of the VNS reaction.
Scheme 20. Examples of the VNS reaction.
Molecules 28 04015 sch020
Molecules 28 04015 sch021 550
Scheme 21. Synthesis of indoles from nitroaryl acetonitriles obtained in VNS with aryloxyacetonitriles.
Scheme 21. Synthesis of indoles from nitroaryl acetonitriles obtained in VNS with aryloxyacetonitriles.
Molecules 28 04015 sch021
Molecules 28 04015 sch022 550
Scheme 22. Substitution of hydrogen in electron-deficient aromatic systems with ylides.
Scheme 22. Substitution of hydrogen in electron-deficient aromatic systems with ylides.
Molecules 28 04015 sch022
Molecules 28 04015 sch023 550
Scheme 23. VNS in nitroarenes with oxygen and nitrogen nucleophiles.
Scheme 23. VNS in nitroarenes with oxygen and nitrogen nucleophiles.
Molecules 28 04015 sch023
Molecules 28 04015 sch024 550
Scheme 24. Aziridination and cyclopropanation of aromatic systems.
Scheme 24. Aziridination and cyclopropanation of aromatic systems.
Molecules 28 04015 sch024
Molecules 28 04015 sch025 550
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.
Molecules 28 04015 sch025
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Scheme 26. The Wittig reaction.
Scheme 26. The Wittig reaction.
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Scheme 27. Formation of cyclopropanes and oxiranes from Michael acceptors.
Scheme 27. Formation of cyclopropanes and oxiranes from Michael acceptors.
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Scheme 28. VNS in imines.
Scheme 28. VNS in imines.
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Scheme 29. VNS in malononitrile derivatives and in nitroalkenes.
Scheme 29. VNS in malononitrile derivatives and in nitroalkenes.
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Scheme 30. VNS in aliphatic systems.
Scheme 30. VNS in aliphatic systems.
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Scheme 31. VNS with a nitrogen nucleophile in aliphatic systems.
Scheme 31. VNS with a nitrogen nucleophile in aliphatic systems.
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Scheme 32. 1,3-Dipolar cycloaddition of azomethine ylides to aliphatic and aromatic systems.
Scheme 32. 1,3-Dipolar cycloaddition of azomethine ylides to aliphatic and aromatic systems.
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Scheme 33. Benzoin condensation and Michael addition of masked acyl carbanions.
Scheme 33. Benzoin condensation and Michael addition of masked acyl carbanions.
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Scheme 34. Stetter reaction with SNAr in nitroarenes with a NHC as catalyst.
Scheme 34. Stetter reaction with SNAr in nitroarenes with a NHC as catalyst.
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Scheme 35. Reactions with deprotonated cyanohydrine ethers as masked acyl carbanions.
Scheme 35. Reactions with deprotonated cyanohydrine ethers as masked acyl carbanions.
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Scheme 36. VNS and SNAr in chloronaphthoquinones.
Scheme 36. VNS and SNAr in chloronaphthoquinones.
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Scheme 37. Kinetic and thermodynamic control in the VNS reaction. Distributions of 2- and 4-substitution products are given.
Scheme 37. Kinetic and thermodynamic control in the VNS reaction. Distributions of 2- and 4-substitution products are given.
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MDPI and ACS Style

Barbasiewicz, M.; Fedoryński, M.; Loska, R.; Mąkosza, M. Analogy of the Reactions of Aromatic and Aliphatic π-Electrophiles with Nucleophiles. Molecules 2023, 28, 4015. https://doi.org/10.3390/molecules28104015

AMA Style

Barbasiewicz M, Fedoryński M, Loska R, Mąkosza M. Analogy of the Reactions of Aromatic and Aliphatic π-Electrophiles with Nucleophiles. Molecules. 2023; 28(10):4015. https://doi.org/10.3390/molecules28104015

Chicago/Turabian Style

Barbasiewicz, Michał, Michał Fedoryński, Rafał Loska, and Mieczysław Mąkosza. 2023. "Analogy of the Reactions of Aromatic and Aliphatic π-Electrophiles with Nucleophiles" Molecules 28, no. 10: 4015. https://doi.org/10.3390/molecules28104015

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