**3. Michael-addition reactions through anion-**π **catalysis**

Michael-addition, a powerful tool in organic synthesis is a nucleophilic addition reaction which involves the addition of a nucleophile to an *α,*β-unsaturated carbonyl compounds. It is considered as one of the significant atom economic methods to generate enantioselective and diastereoselective C-C bonds under mild reaction conditions. Knowing the fact that enolates play a vital role in both biology as well as chemistry, Matile's group has revealed the role of anion-π catalysis in enolate chemistry. They have computed the catalytic strength of enolate-π interactions by reporting numerous stereoselective Michael addition reactions on NDI based anion-π catalysts (**Figure 4**) [14–17]. From the 1 H-NMR studies, a substantial upfield shift of malonate protons has been observed in cases where the malonate group is covalently linked to the π-acidic NDI surface as compared to protons of unbound diethyl malonate group. This in turn leads to enhanced acidity of the associated malonate group by means of anion-π interactions. In fact, this upfield shift display the location of malonate α-protons above the π-acidic surface [15].

**95**

**Figure 5.**

**Figure 4.**

*Anion-*π *Catalysis: A Novel Supramolecular Approach for Chemical and Biological…*

On the other hand, experimental studies have revealed that Michael-addition between malonic acid half thioester (**37**) and enolate acceptor **38** fails without anion-π catalyst and hence leads to solely the formation of a decarboxylation product **40**. Fortunately, the presence of anion-π catalyst for the same reaction leads to the formation of an addition product (**39**) selectively in comparison to decarboxylation product (**40**) **(Figure 5**) [16]. Besides these significant catalytic studies of anion-π interactions, the anion-π catalytic domain has now been explored to iminium, [18] enamine, [15] oxocarbenium, and transamination chemistry [19]. Since the Michael addition reactions through enolate chemistry has a significant relevance to several chemical and biological phenomenon, the outcomes of the studies carried out by Matile and teammates can take the domain of organocatalysis

By virtue of positive molecular electrostatic potential (MEP), the fullerene (C60) is considered as a potential candidate for anion-*π* interactions and has recently been introduced in the field of anion-π catalysis. The exceptional selectivity of fullerenes is actually due to localized positive potential areas termed as *π*-holes (**Figure 6**). By virtue of purest π-system, fullerenes offer a promising role in the exploration of polarizibility significance in a solution-phase anion-π catalysis [20]. Studies based on these facts have revealed a significant improvement in the selective addition of **37** to **38** by means of a fullerene based catalytic dyad **22** as well as catalytic triad **44** (**Figure 6**). Significantly higher selectivity was achieved after intercalating the methyl viologen **45** in between two fullerenes moieties of a catalytic triad **44** [21, 22]. Besides, the addition product selectivity over the decarboxylation product, conjugate addition protonation reaction of **46** and **47** generating 1,3-non-adjacent stereocenters have been also been carried out on the surfaces of anion-π catalyst **21** composed of

*Addition (***39)** *and decarboxylation (***40)** *products in terms of Michael-addition between* **37** *and* **38** *catalyzed by NDI-based anion-*π *catalyst* **11** *(PMP = p-methoxyphenyl). The molecular structures of transition state* 

*Schematic representation of Michael addition reaction of* **34** *with Michael acceptors (***32** *and* **33***) on the* 

*(***41***) and of reactive intermediates (***42** *and* **43***) are also given.*

*DOI: http://dx.doi.org/10.5772/intechopen.95824*

to a next level.

fullerene (**Figure 6**) [23].

π*-acidic NDI surface of* **10***.*

#### *Anion-*π *Catalysis: A Novel Supramolecular Approach for Chemical and Biological… DOI: http://dx.doi.org/10.5772/intechopen.95824*

On the other hand, experimental studies have revealed that Michael-addition between malonic acid half thioester (**37**) and enolate acceptor **38** fails without anion-π catalyst and hence leads to solely the formation of a decarboxylation product **40**. Fortunately, the presence of anion-π catalyst for the same reaction leads to the formation of an addition product (**39**) selectively in comparison to decarboxylation product (**40**) **(Figure 5**) [16]. Besides these significant catalytic studies of anion-π interactions, the anion-π catalytic domain has now been explored to iminium, [18] enamine, [15] oxocarbenium, and transamination chemistry [19]. Since the Michael addition reactions through enolate chemistry has a significant relevance to several chemical and biological phenomenon, the outcomes of the studies carried out by Matile and teammates can take the domain of organocatalysis to a next level.

By virtue of positive molecular electrostatic potential (MEP), the fullerene (C60) is considered as a potential candidate for anion-*π* interactions and has recently been introduced in the field of anion-π catalysis. The exceptional selectivity of fullerenes is actually due to localized positive potential areas termed as *π*-holes (**Figure 6**). By virtue of purest π-system, fullerenes offer a promising role in the exploration of polarizibility significance in a solution-phase anion-π catalysis [20]. Studies based on these facts have revealed a significant improvement in the selective addition of **37** to **38** by means of a fullerene based catalytic dyad **22** as well as catalytic triad **44** (**Figure 6**). Significantly higher selectivity was achieved after intercalating the methyl viologen **45** in between two fullerenes moieties of a catalytic triad **44** [21, 22]. Besides, the addition product selectivity over the decarboxylation product, conjugate addition protonation reaction of **46** and **47** generating 1,3-non-adjacent stereocenters have been also been carried out on the surfaces of anion-π catalyst **21** composed of fullerene (**Figure 6**) [23].

**Figure 4.**

*Current Topics in Chirality - From Chemistry to Biology*

product, reactive intermediate (**31**) involves protonation of phenolate to yield the desired product **28** with the regeneration of the catalyst (**9**) (**Figure 3**) [11].

*Schematic illustration of Kemp elimination reaction along with a mechanistic cyclic pathway. Blue color* 

Michael-addition, a powerful tool in organic synthesis is a nucleophilic addition reaction which involves the addition of a nucleophile to an *α,*β-unsaturated carbonyl compounds. It is considered as one of the significant atom economic methods to generate enantioselective and diastereoselective C-C bonds under mild reaction conditions. Knowing the fact that enolates play a vital role in both biology as well as chemistry, Matile's group has revealed the role of anion-π catalysis in enolate chemistry. They have computed the catalytic strength of enolate-π interactions by reporting numerous stereoselective Michael addition reactions on NDI

upfield shift of malonate protons has been observed in cases where the malonate group is covalently linked to the π-acidic NDI surface as compared to protons of unbound diethyl malonate group. This in turn leads to enhanced acidity of the associated malonate group by means of anion-π interactions. In fact, this upfield shift display the location of malonate α-protons above the π-acidic surface [15].

H-NMR studies, a substantial

**3. Michael-addition reactions through anion-**π **catalysis**

*depicts electron deficient and red color implies electron rich.*

based anion-π catalysts (**Figure 4**) [14–17]. From the 1

**94**

**Figure 3.**

*Schematic representation of Michael addition reaction of* **34** *with Michael acceptors (***32** *and* **33***) on the*  π*-acidic NDI surface of* **10***.*

#### **Figure 5.**

*Addition (***39)** *and decarboxylation (***40)** *products in terms of Michael-addition between* **37** *and* **38** *catalyzed by NDI-based anion-*π *catalyst* **11** *(PMP = p-methoxyphenyl). The molecular structures of transition state (***41***) and of reactive intermediates (***42** *and* **43***) are also given.*

#### **Figure 6.**

*Schematic illustration of addition (***39***) and decarboxylation product (***40***) on anion-*π *catalytic surfaces of fullerenes (***22** *and* **44***) along with the depiction of conjugate addition protonation reaction and anionic transition state stabilization (***49** *and* **50***)*

Currently, catalysis by means of an electric field has gained a significant interest in molecular transformations, stereoselectivities, and multistep organic synthesis [24]. Electric fields and potentials besides accelerating the reactions have also been shown to activate the conventional catalysts, enzymes, and catalytic pores [25]. Recent studies have revealed that electric fields can just function as a remote control for anion-π catalysts. It has been observed that immobilization of anion-*π* catalysts is important before applying the electric field to polarize the *π*-acidic aromatic systems into an induced dipole (*μ*z), which in turn enhance the stabilization of anionic transition state and intermediate on the catalytic polarizable π*-*surface (**Figure 7**). In order to fulfill these expectations, a bifunctional anion-*π* catalyst (**20**) has been designed and synthesized by Matile and coworkers for addition product (**39**) selectivity over decarboxylation product (**40**). In their experimental studies, they have attached two diphosphonate groups in the NDI core of **20** through sulphide substituents in order to immobilize the bifunctional catalyst (**20**) on the surface of indium tin oxide (ITO) (**Figure 7)** [26].

In another event, Matile and teammates have used foldamers (**24–26**) for the Michael addition product selectivity over decarboxylated product and noticed that the selectivity gets increased by increasing the length of stacks, thereby displaying anion-(π)n-π catalysis (**Figure 8**) [27]. This is actually due to increase in the electronic communication upon increasing the stack length of foldamers. The catalytic activity dependence on electron-sharing has been found to be superlinear on raising

**97**

stack [27].

*foldamer assisted anion-(*π*)n-*π *catalysis.*

*anion-*π *catalyst* **51** *and induced dipole (μz).*

**Figure 8.**

**Figure 7.**

enzymes [28].

*Anion-*π *Catalysis: A Novel Supramolecular Approach for Chemical and Biological…*

the stack length. It thus violates sublinear power laws of oligomeric chemistry and reveals the catalytic activity of synergistic amplification over the complete

Moreover, quite recently Matile's group has stapled short peptides to NDI-based anion-π catalysts (**16**) in order to generate selective Michael addition product (**39**) over decarboxylative product (**40**) (**Figure 9**). These results regarding anion-π catalysis will serve as an appropriate starting material subsequent to peptides in order to be in operation in larger protein structures and development of anion-π

*Schematic depiction of addition product (***39***) selectivity over decarboxylated product (***40***) by means* π*-stacked* 

*Schematic illustration of addition product (***39***) and decarboxylation product (***40***) along with immobilized* 

Anion-π catalysis play a significant role in the asymmetric synthesis and leads to the generation of chiral isomers selectively. In this regard, the same group has also incorporated NDI moiety in between a carboxylate base and a proline unit for the construction of an anion-π catalyst (**13**). On the π-acidic surface of **13**, they have carried out asymmetric addition of **54** to nitroolefin enamine acceptor **55**. The NDI π-acidic surface helps in the stabilization of transition state of anion near nitronate intermediate by anion-π interactions as can be observed from the structures of

*DOI: http://dx.doi.org/10.5772/intechopen.95824*

*Anion-*π *Catalysis: A Novel Supramolecular Approach for Chemical and Biological… DOI: http://dx.doi.org/10.5772/intechopen.95824*

**Figure 7.**

*Current Topics in Chirality - From Chemistry to Biology*

Currently, catalysis by means of an electric field has gained a significant interest in molecular transformations, stereoselectivities, and multistep organic synthesis [24]. Electric fields and potentials besides accelerating the reactions have also been shown to activate the conventional catalysts, enzymes, and catalytic pores [25]. Recent studies have revealed that electric fields can just function as a remote control for anion-π catalysts. It has been observed that immobilization of anion-*π* catalysts is important before applying the electric field to polarize the *π*-acidic aromatic systems into an induced dipole (*μ*z), which in turn enhance the stabilization of anionic transition state and intermediate on the catalytic polarizable π*-*surface (**Figure 7**). In order to fulfill these expectations, a bifunctional anion-*π* catalyst (**20**) has been designed and synthesized by Matile and coworkers for addition product (**39**) selectivity over decarboxylation product (**40**). In their experimental studies, they have attached two diphosphonate groups in the NDI core of **20** through sulphide substituents in order to immobilize the bifunctional catalyst (**20**) on the surface of indium tin oxide (ITO)

*Schematic illustration of addition (***39***) and decarboxylation product (***40***) on anion-*π *catalytic surfaces of fullerenes (***22** *and* **44***) along with the depiction of conjugate addition protonation reaction and anionic* 

In another event, Matile and teammates have used foldamers (**24–26**) for the Michael addition product selectivity over decarboxylated product and noticed that the selectivity gets increased by increasing the length of stacks, thereby displaying anion-(π)n-π catalysis (**Figure 8**) [27]. This is actually due to increase in the electronic communication upon increasing the stack length of foldamers. The catalytic activity dependence on electron-sharing has been found to be superlinear on raising

**96**

(**Figure 7)** [26].

**Figure 6.**

*transition state stabilization (***49** *and* **50***)*

*Schematic illustration of addition product (***39***) and decarboxylation product (***40***) along with immobilized anion-*π *catalyst* **51** *and induced dipole (μz).*

**Figure 8.**

*Schematic depiction of addition product (***39***) selectivity over decarboxylated product (***40***) by means* π*-stacked foldamer assisted anion-(*π*)n-*π *catalysis.*

the stack length. It thus violates sublinear power laws of oligomeric chemistry and reveals the catalytic activity of synergistic amplification over the complete stack [27].

Moreover, quite recently Matile's group has stapled short peptides to NDI-based anion-π catalysts (**16**) in order to generate selective Michael addition product (**39**) over decarboxylative product (**40**) (**Figure 9**). These results regarding anion-π catalysis will serve as an appropriate starting material subsequent to peptides in order to be in operation in larger protein structures and development of anion-π enzymes [28].

Anion-π catalysis play a significant role in the asymmetric synthesis and leads to the generation of chiral isomers selectively. In this regard, the same group has also incorporated NDI moiety in between a carboxylate base and a proline unit for the construction of an anion-π catalyst (**13**). On the π-acidic surface of **13**, they have carried out asymmetric addition of **54** to nitroolefin enamine acceptor **55**. The NDI π-acidic surface helps in the stabilization of transition state of anion near nitronate intermediate by anion-π interactions as can be observed from the structures of

transition states (**59** and **60**) (**Figure 10**). By means of the presence of carboxylate base and proline unit at opposite sides of NDI, it has been found that both the rate of enamine addition and enantioselectivity gets enhanced on increasing the π-acidity of NDI [29, 30]. Thus, it gives an essential indication of the participation of anion-π contacts in stereoselectivity. Moreover, anion-π catalyst (**12**) based on NDI was used for the imine isomerization of undesired achiral substrate **57** to the desired chiral product **58** (**Figure 10**) [18].

On the other occasion, the same group has also carried out asymmetric synthesis on anion-π catalytic surfaces of perylenediimides (PDIs). It has been observed that twist in the π-acidic surface determines the catalytic activity of these PDI-based anion-π catalysts in case of Michael addition reactions of enolates and enamines. This is in contrary to the catalytic activity of NDIs, where reducibility of π-surfaces plays a prominent role. Experimental studies have revealed asymmetric addition of **62** to **38** through PDI-based anion-π catalyst (**17**), which leads to the formation of product **63** containing two chiral centers (**Figure 11**) [31]. Furthermore, the PDIbased anion-π catalyst (**18**) also offers Michael addition product (**39**) selectivity over decarboxylated product (**40**) (**Figure 11**).

In another event, Matile's group has also observed anion-π interactions in anion-π enzymes after preparing anion-π enzyme artificially. They have equipped a range of anion-π catalysts with a water-soluble vitamin known as biotin in order to determine the selectivity of Michael addition product (**39**) over decarboxylation one (**40**) in the chemistry of enolates. [32] Additionally, they screened artificially prepared

$$\begin{array}{ccccc} \stackrel{\text{O}}{\underset{\text{H}^{2}}{\overset{\text{O}}{\rightleftharpoons}}} & \stackrel{\text{O}}{\underset{\text{SO}^{2}\text{M}^{2}}{\overset{\text{O}}{\rightleftharpoons}}} & \stackrel{\text{O}^{2}}{\underset{\text{SO}^{2}}{\overset{\text{O}^{2}}{\rightleftharpoons}}} & \stackrel{\text{O}^{2}}{\underset{\text{SO}^{2}}{\overset{\text{O}}{\rightleftharpoons}}} & \stackrel{\text{O}^{2}}{\underset{\text{SO}^{2}}{\overset{\text{O}}{\rightleftharpoons}}} & \stackrel{\text{O}^{2}}{\underset{\text{SO}^{2}}{\overset{\text{O}}{\rightleftharpoons}}} \quad \stackrel{\text{O}^{2}}{\underset{\text{SO}^{2}}{\overset{\text{O}}{\rightleftharpoons}}} \quad \stackrel{\text{O}}{\text{A}} \end{array}$$

**Figure 9.**

*Schematic depiction of addition product (***39***) selectivity over decarboxylated product (***40***) by means of peptide stapled NDI-based anion-*π *catalyst (***16***).*

#### **Figure 10.**

*Representation of asymmetric addition (***56***) and imine isomerization product (***58***) along with the molecular structures of transition states (***59***–***61***).*

**99**

**Figure 12.**

*anion-*π *enzymes are also given.*

**Figure 11.**

*Anion-*π *Catalysis: A Novel Supramolecular Approach for Chemical and Biological…*

anion-π enzyme against a cluster of the mutants of streptavidin (**Figure 12**). The presence of S112Y mutant leads to desired Michael addition product (**39**) with 95% enantiomeric excess (ee) along with a complete suppression of the decarboxylation

*Schematic representation of addition (***39***) and decarboxylation product (***40***) by means of anion-*π *catalyst (***11***). The structures of transition states and reactive intermediates along with the diagrammatic illustration of* 

*Asymmetric synthesis of* **63** *through PDI-based anion-*π *catalyst (***17***) and transition state (***64***) depicting formation of C-C bond. Moreover, Michael addition of* **37** *to* **38** *through PDI-based anion-*π *catalyst (***18***) and* 

*DOI: http://dx.doi.org/10.5772/intechopen.95824*

*a structure of involved transition state (***65***) is also given.*

*Anion-*π *Catalysis: A Novel Supramolecular Approach for Chemical and Biological… DOI: http://dx.doi.org/10.5772/intechopen.95824*

#### **Figure 11.**

*Current Topics in Chirality - From Chemistry to Biology*

desired chiral product **58** (**Figure 10**) [18].

over decarboxylated product (**40**) (**Figure 11**).

*peptide stapled NDI-based anion-*π *catalyst (***16***).*

transition states (**59** and **60**) (**Figure 10**). By means of the presence of carboxylate base and proline unit at opposite sides of NDI, it has been found that both the rate of enamine addition and enantioselectivity gets enhanced on increasing the π-acidity of NDI [29, 30]. Thus, it gives an essential indication of the participation of anion-π contacts in stereoselectivity. Moreover, anion-π catalyst (**12**) based on NDI was used for the imine isomerization of undesired achiral substrate **57** to the

On the other occasion, the same group has also carried out asymmetric synthesis on anion-π catalytic surfaces of perylenediimides (PDIs). It has been observed that twist in the π-acidic surface determines the catalytic activity of these PDI-based anion-π catalysts in case of Michael addition reactions of enolates and enamines. This is in contrary to the catalytic activity of NDIs, where reducibility of π-surfaces plays a prominent role. Experimental studies have revealed asymmetric addition of **62** to **38** through PDI-based anion-π catalyst (**17**), which leads to the formation of product **63** containing two chiral centers (**Figure 11**) [31]. Furthermore, the PDIbased anion-π catalyst (**18**) also offers Michael addition product (**39**) selectivity

In another event, Matile's group has also observed anion-π interactions in anion-π enzymes after preparing anion-π enzyme artificially. They have equipped a range of anion-π catalysts with a water-soluble vitamin known as biotin in order to determine the selectivity of Michael addition product (**39**) over decarboxylation one (**40**) in the chemistry of enolates. [32] Additionally, they screened artificially prepared

*Schematic depiction of addition product (***39***) selectivity over decarboxylated product (***40***) by means of* 

*Representation of asymmetric addition (***56***) and imine isomerization product (***58***) along with the molecular* 

**98**

**Figure 10.**

*structures of transition states (***59***–***61***).*

**Figure 9.**

*Asymmetric synthesis of* **63** *through PDI-based anion-*π *catalyst (***17***) and transition state (***64***) depicting formation of C-C bond. Moreover, Michael addition of* **37** *to* **38** *through PDI-based anion-*π *catalyst (***18***) and a structure of involved transition state (***65***) is also given.*

#### **Figure 12.**

*Schematic representation of addition (***39***) and decarboxylation product (***40***) by means of anion-*π *catalyst (***11***). The structures of transition states and reactive intermediates along with the diagrammatic illustration of anion-*π *enzymes are also given.*

anion-π enzyme against a cluster of the mutants of streptavidin (**Figure 12**). The presence of S112Y mutant leads to desired Michael addition product (**39**) with 95% enantiomeric excess (ee) along with a complete suppression of the decarboxylation

**Figure 13.**

*Schematic illustration of selective addition product (***39***) on the polarizability induced* π*-acidic carbon nanotubes (SWCNT and MWCNT).*

product (**40**). The existence of anion-π contacts in proteins has been established through the nitrate inhibition of mutant S112Y. The optimum performance has been found at acidic pH = 3, which clearly indicates that enolate gets formed by virtue of the stabilization on π-acidic surfaces. Moreover, K121 mutant has been found in concurrence with the docking results as far as the function of catalyst composed of tertiary amine is concerned at an ideal pH 3. By means of diverse mutants, it is established that enhancing enantioselectivity continuously agrees with the stabilization of particular transition state [32].

More interestingly, the same group has reported innovative anion-π catalysis on the surfaces of carbon nanotubes and synthesized selective addition products on their π-acidic surfaces (**Figure 13**). Studies have revealed that tertiary amine based multi-walled carbon-nanotubes (MWCNT) display much higher efficiency as compared to single-walled carbon nanotubes (SWCNT). This is by virtue of the fact that between and along the nanotubes of MWCNT, there exists a polarizibility induced π-acidic surfaces [33].
