On the Importance of Pnictogen and Chalcogen Bonding Interactions in Supramolecular Catalysis

In this review, several examples of the application of pnictogen (Pn) (group 15) and chalcogen (Ch) bonding (group 16) interactions in organocatalytic processes are gathered, backed up with Molecular Electrostatic Potential surfaces of model systems. Despite the fact that the use of catalysts based on pnictogen and chalcogen bonding interactions is taking its first steps, it should be considered and used by the scientific community as a novel, promising tool in the field of organocatalysis.

The attractive interaction (EWG-X···A) between a p-block element (Lewis acid, X) and a σ-hole acceptor (A, Lewis base, anion or π-system) is supported by the sum of different contributions (see Figure 1 for a Molecular Electrostatic Potential (MEP) surface of a prototypical CF 3 Br···NH 3 complex). These correspond to electrostatics, charge transfer, orbital mixing, polarization and dispersion forces [52,53]. Firstly, electrostatics is understood as the attraction between the electron-rich region (belonging to the electron donor (A)) and a region of diminished electrostatic potential located at the prolongation of the EWG-X bond, known as the σ-hole (which belongs to the electron acceptor). Secondly, dispersion

Pnictogen Bonding
A great deal of studies dealing with PnBs are already available in the literature [43,44,[75][76][77][78][79][80][81][82][83][84][85]. However, those presenting experimental evidence of the interaction are scarce [86][87][88][89]. Table 1 gathers the atomic polarizability values (α) and van der Waals radii of the pnictogen elements from period two to five. The atomic α value increases from 5.3 a.u. in N to 30.8 a.u. in Sb. As noted, the difference in α between N and P is substantial (~3x), and small between P and As. Lastly, the difference is again relevant between As and Sb. In Table 1, the MEP values at the σ-holes of the fluoride derivatives of the four Pn elements are also gathered, while Figure 2 includes the MEP surface for SbF3. As noted, the MEP values at the σ-hole become more positive when descending in the group, similarly to the well-characterized halogen bond interaction. Table 1. Atomic polarizabilities (α, a.u.) of pnictogen (Pn) elements, van der Waals radii (RvdW, Å) and σ-hole MEP value (MEP, kcal/mol) of their trifluoride derivatives. Data extracted from ref. [63].

Pnictogen Bonding
A great deal of studies dealing with PnBs are already available in the literature [43,44,[75][76][77][78][79][80][81][82][83][84][85]. However, those presenting experimental evidence of the interaction are scarce [86][87][88][89]. Table 1 gathers the atomic polarizability values (α) and van der Waals radii of the pnictogen elements from period two to five. The atomic α value increases from 5.3 a.u. in N to 30.8 a.u. in Sb. As noted, the difference in α between N and P is substantial (~3x), and small between P and As. Lastly, the difference is again relevant between As and Sb. In Table 1, the MEP values at the σ-holes of the fluoride derivatives of the four Pn elements are also gathered, while Figure 2 includes the MEP surface for SbF 3 . As noted, the MEP values at the σ-hole become more positive when descending in the group, similarly to the well-characterized halogen bond interaction. Table 1. Atomic polarizabilities (α, a.u.) of pnictogen (Pn) elements, van der Waals radii (R vdW , Å) and σ-hole MEP value (MEP, kcal/mol) of their trifluoride derivatives. Data extracted from ref. [63].  Figure 2 shows the MEP surface of SbF3 as an illustrative example of the pnictogen group. As noted, it presents an ample region of positive MEP values where the global maximum is located approximately in the opposite direction to the Sb-F bonds. In addition, the large and negative MEP values at the F-atoms reveal a strong polarization of the Sb-F bonds.

Arsenic and Antimony
Arsenic and antimony are known to be involved in stronger PnBs than N and P, as evidenced by the MEP analysis shown above. Their use as efficient anion binders [90] has been recently reported, with antimony being the most promising Pn atom to be used for anion recognition. In another study, Gabbaï and collaborators have reported bis-stilbonium as a supramolecular synthon to build a preorganized host [91] involved in several PnBs interactions with electron-rich species. Additionally, Cozzolino and coworkers have synthesized anion receptors based on bidentate anion-binding motifs containing two Sb(III) centers, bridged by either oxygen or sulfur atoms acting as PnB donors [92].
In the field of organocatalysis, the number of studies devoted to the development of new functional PnB-based catalysts has rapidly increased during recent years [93][94][95][96][97][98][99][100][101][102]. In this section, several selected examples involving PnB-based catalysts are discussed. For each example an MEP surface of the Pn catalyst is shown, in addition to a plausible transition state/reaction intermediate stabilization scheme.
Benz and collaborators [93] compared the catalytic activity of a series of Pn catalysts using P, As and Sb to their Ch (Se and Te) and Ha (Br and I) analogues. More precisely, the authors synthesized a series of phenyl and pentafluorophenyl (PFP)-substituted Pn, Ch and Ha moieties (see Table 2), and evaluated the dissociation constants (KD values) of their corresponding chloride complexes by 19 F NMR spectroscopic titration with TBACl in THF. Among them, Sb(PFP)3 (compound 1), gathered in Figure 3a, achieved the best results in terms of dissociation constant (KD) of the chloride complex (19 ± 7 μM). As a likely  Figure 2 shows the MEP surface of SbF 3 as an illustrative example of the pnictogen group. As noted, it presents an ample region of positive MEP values where the global maximum is located approximately in the opposite direction to the Sb-F bonds. In addition, the large and negative MEP values at the F-atoms reveal a strong polarization of the Sb-F bonds.

Arsenic and Antimony
Arsenic and antimony are known to be involved in stronger PnBs than N and P, as evidenced by the MEP analysis shown above. Their use as efficient anion binders [90] has been recently reported, with antimony being the most promising Pn atom to be used for anion recognition. In another study, Gabbaï and collaborators have reported bisstilbonium as a supramolecular synthon to build a preorganized host [91] involved in several PnBs interactions with electron-rich species. Additionally, Cozzolino and coworkers have synthesized anion receptors based on bidentate anion-binding motifs containing two Sb(III) centers, bridged by either oxygen or sulfur atoms acting as PnB donors [92].
In the field of organocatalysis, the number of studies devoted to the development of new functional PnB-based catalysts has rapidly increased during recent years [93][94][95][96][97][98][99][100][101][102]. In this section, several selected examples involving PnB-based catalysts are discussed. For each example an MEP surface of the Pn catalyst is shown, in addition to a plausible transition state/reaction intermediate stabilization scheme.
Benz and collaborators [93] compared the catalytic activity of a series of Pn catalysts using P, As and Sb to their Ch (Se and Te) and Ha (Br and I) analogues. More precisely, the authors synthesized a series of phenyl and pentafluorophenyl (PFP)-substituted Pn, Ch and Ha moieties (see Table 2), and evaluated the dissociation constants (K D values) of their corresponding chloride complexes by 19 F NMR spectroscopic titration with TBACl in THF. explanation, the authors recalled the presence of three accessible σ-holes on the catalyst surface (only one is shown in Figure 3b) which exhibited MEP values of +38.9 kcal/mol. Bearing these promising results in mind, Benz and collaborators successfully applied PnB catalysis to two organic reactions. The first was the Reissert-type substitution of isoquinoline, which is known to be catalyzed by different anion-binding catalysts [103][104][105]. As shown in Figure 4a, compound 1 accelerates the reaction by stabilizing the rate-limiting transition state 1(TS1), that is, the elimination of chloride following the addition of Troc chloride. In a posterior stage, the resulting cationic intermediate reacts with the nucleophile to afford products (TS2). Interestingly, after an initial screen of solvents and conditions, the authors obtained a 51% of yield within 30 min at −100 ºC in THF using 5 mol% of catalyst.  [93]. All MEP surfaces corresponding to Pn and Ch catalysts have been performed using the Gaussian16 calculation package [106]. The authors also achieved success in catalyzing the more challenging transformation of 1-chloroisochromane to an ester, a reaction that proceeds through chloride abstraction in TS3 and successive attack of a silyl enol ether (see Figure 4b). The authors obtained a 91% yield after 55 h at −78 ºC in THF using a 20 mol% of compound 1. In this case, both TS3 and 4 are also stabilized by Sb···Cl PnBs, which is similar to the Reissert-type substitution of isoquinolines, resulting in the corresponding ester. Additionally, Matile's group has carried out several studies on ether cyclization reactions [94][95][96]98]. In their study [96], Hao and collaborators carried out a comparative  [93]. All MEP surfaces corresponding to Pn and Ch catalysts have been performed using the Gaussian16 calculation package [106]. explanation, the authors recalled the presence of three accessible σ-holes on the catalyst surface (only one is shown in Figure 3b) which exhibited MEP values of +38.9 kcal/mol.
Bearing these promising results in mind, Benz and collaborators successfully applied PnB catalysis to two organic reactions. The first was the Reissert-type substitution of isoquinoline, which is known to be catalyzed by different anion-binding catalysts [103][104][105]. As shown in Figure 4a, compound 1 accelerates the reaction by stabilizing the rate-limiting transition state 1(TS1), that is, the elimination of chloride following the addition of Troc chloride. In a posterior stage, the resulting cationic intermediate reacts with the nucleophile to afford products (TS2). Interestingly, after an initial screen of solvents and conditions, the authors obtained a 51% of yield within 30 min at −100 ºC in THF using 5 mol% of catalyst.  [93]. All MEP surfaces corresponding to Pn and Ch catalysts have been performed using the Gaussian16 calculation package [106]. The authors also achieved success in catalyzing the more challenging transformation of 1-chloroisochromane to an ester, a reaction that proceeds through chloride abstraction in TS3 and successive attack of a silyl enol ether (see Figure 4b). The authors obtained a 91% yield after 55 h at −78 ºC in THF using a 20 mol% of compound 1. In this case, both TS3 and 4 are also stabilized by Sb···Cl PnBs, which is similar to the Reissert-type substitution of isoquinolines, resulting in the corresponding ester. Additionally, Matile's group has carried out several studies on ether cyclization reactions [94][95][96]98]. In their study [96], Hao and collaborators carried out a comparative The authors also achieved success in catalyzing the more challenging transformation of 1-chloroisochromane to an ester, a reaction that proceeds through chloride abstraction in TS3 and successive attack of a silyl enol ether (see Figure 4b). The authors obtained a 91% yield after 55 h at −78 • C in THF using a 20 mol% of compound 1. In this case, both TS3 and 4 are also stabilized by Sb···Cl PnBs, which is similar to the Reissert-type substitution of isoquinolines, resulting in the corresponding ester.
Additionally, Matile's group has carried out several studies on ether cyclization reactions [94][95][96]98]. In their study [96], Hao and collaborators carried out a comparative analysis of the use of electron-rich and electron-poor π-surfaces and PnB-based catalysts (see Figure 5 for some of the catalysts used) on bioinspired ether cyclization reactions. More precisely, the authors explored four epoxide-opening ether cyclizations as standards for the comparative assessment of catalytic systems. analysis of the use of electron-rich and electron-poor π-surfaces and PnB-based catalysts (see Figure 5 for some of the catalysts used) on bioinspired ether cyclization reactions. More precisely, the authors explored four epoxide-opening ether cyclizations as standards for the comparative assessment of catalytic systems. Firstly, the authors studied the ring-opening reaction of two ether derivatives (8 and 10) to yield products 9 and 11. In the first transformation (Figure 6a), the Baldwin-compatible 5-exo-tet oxolane product 9 was obtained using both capsule 2 and compound 3 as catalysts. Although the initial results were not promising, since for instance the conversion using hexafluorobenzene (3) as a solvent catalyst reached around 10% in 7 h, the authors incremented the concentration of product 9 from the beginning of the reaction while using catalyst 2, thus accelerating the rate of cyclization up to kcat/kcat(0) = 30 ± 10. In a parallel way to substrate 8, the cyclization of the 4,5-epoxy alcohol 10 with an extra methyl in the cis position on the epoxide solely yielded the Baldwin product 11 (Figure 6b). In this case, the reaction within capsule 2 was faster than that for the previous reaction ( Figure 6a). Furthermore, the addition of extra product 11 at the beginning slowed down rather than accelerated the reaction, which was consistent with mildly competitive product encapsulation. On the other hand, the use of catalyst 3 achieved a faster conversion to product 11 and showed strongly autocatalytic behavior. In sharp contrast to the previous reaction, the addition of product 11 at the beginning of the cyclization of 10 using 3 did not accelerate conversion. However, the replacement of hexafluorobenzene solvent catalyst 3 by catalyst 4, which exhibited a larger π acidity (an electron-poor π system), showed noticeable autocatalysis with 10. In Figure 5a,b, a schematic representation of the plausible transition states is shown (TS-1 and TS-2), involving the "accommodation" of the Firstly, the authors studied the ring-opening reaction of two ether derivatives (8 and 10) to yield products 9 and 11. In the first transformation (Figure 6a), the Baldwin-compatible 5-exo-tet oxolane product 9 was obtained using both capsule 2 and compound 3 as catalysts. Although the initial results were not promising, since for instance the conversion using hexafluorobenzene (3) as a solvent catalyst reached around 10% in 7 h, the authors incremented the concentration of product 9 from the beginning of the reaction while using catalyst 2, thus accelerating the rate of cyclization up to k cat /k cat(0) = 30 ± 10. analysis of the use of electron-rich and electron-poor π-surfaces and PnB-based catalysts (see Figure 5 for some of the catalysts used) on bioinspired ether cyclization reactions. More precisely, the authors explored four epoxide-opening ether cyclizations as standards for the comparative assessment of catalytic systems. Firstly, the authors studied the ring-opening reaction of two ether derivatives (8 and 10) to yield products 9 and 11. In the first transformation (Figure 6a), the Baldwin-compatible 5-exo-tet oxolane product 9 was obtained using both capsule 2 and compound 3 as catalysts. Although the initial results were not promising, since for instance the conversion using hexafluorobenzene (3) as a solvent catalyst reached around 10% in 7 h, the authors incremented the concentration of product 9 from the beginning of the reaction while using catalyst 2, thus accelerating the rate of cyclization up to kcat/kcat(0) = 30 ± 10. In a parallel way to substrate 8, the cyclization of the 4,5-epoxy alcohol 10 with an extra methyl in the cis position on the epoxide solely yielded the Baldwin product 11 (Figure 6b). In this case, the reaction within capsule 2 was faster than that for the previous reaction ( Figure 6a). Furthermore, the addition of extra product 11 at the beginning slowed down rather than accelerated the reaction, which was consistent with mildly competitive product encapsulation. On the other hand, the use of catalyst 3 achieved a faster conversion to product 11 and showed strongly autocatalytic behavior. In sharp contrast to the previous reaction, the addition of product 11 at the beginning of the cyclization of 10 using 3 did not accelerate conversion. However, the replacement of hexafluorobenzene solvent catalyst 3 by catalyst 4, which exhibited a larger π acidity (an electron-poor π system), showed noticeable autocatalysis with 10. In Figure 5a,b, a schematic representation of the plausible transition states is shown (TS-1 and TS-2), involving the "accommodation" of the In a parallel way to substrate 8, the cyclization of the 4,5-epoxy alcohol 10 with an extra methyl in the cis position on the epoxide solely yielded the Baldwin product 11 ( Figure 6b). In this case, the reaction within capsule 2 was faster than that for the previous reaction ( Figure 6a). Furthermore, the addition of extra product 11 at the beginning slowed down rather than accelerated the reaction, which was consistent with mildly competitive product encapsulation. On the other hand, the use of catalyst 3 achieved a faster conversion to product 11 and showed strongly autocatalytic behavior. In sharp contrast to the previous reaction, the addition of product 11 at the beginning of the cyclization of 10 using 3 did not accelerate conversion. However, the replacement of hexafluorobenzene solvent catalyst within capsule 2 (TS-1) and the formation of two hydrogen bonds (one hydrogen-bond acceptor and one hydrogen-bond donor) in the activation of both nucleophile and leaving group in TS-2.
The authors also analyzed the cyclization of the 4,5-epoxy alcohol 12 with four extra methyl groups around the nucleophile and electrophile to yield the Baldwin oxolane product 13 together with the anti-Baldwin oxane product 14 (Figure 7a). In capsule 2, the reaction further accelerated, likely due to stabilization by cation-π interactions (TS-1, Figure 5a). On the other hand, the use of hexafluorobenzene 3 revealed a similar result as in the case of compound 8. In this scenario, the addition of product 13 at the beginning of the reaction of 12 in 3 accelerated the reaction noticeably, although not enough to surpass the results obtained using supramolecular capsule 2, which performed better than the HB and PnB catalysts used ( Figure 8). The latter accelerated the reaction though the establishment of multiple PnBs with the three available σ-holes present in the Sb atom and a lone pair-π interaction involving the fluorinated ring moiety (TS-4). In the last stage of their study, diepoxide 15 was used, and the reaction followed 1 H NMR spectra (Figure 8b). In this case, 15 was initially used as a cis/trans mixture of isomers with a 6:4 ratio. The product mixtures contained the oxolane dimer 16 resulting from a cascade cyclization following Baldwin rules, the oxolane-oxane dimer 17 resulting from a Baldwin cyclization followed by an anti-Baldwin cyclization, and the fused bicycles 18 and 19 produced by an anti-Baldwin cyclization followed by a Baldwin and an anti-Baldwin cyclization, respectively. Interestingly, the reaction carried out within capsule 2 afforded 17 as the main product, with high apparent diastereoselectivity, with only the one 16 diastereomer as a minor side product. The formation of 18 and 19, both produced from an initial anti-Baldwin cyclization, was almost completely suppressed. This diastereoselective formation of isomers of 17 could possibly be explained by the ability to fold into the most globular structure, as outlined in TS-1.  The authors also analyzed the cyclization of the 4,5-epoxy alcohol 12 with four extra methyl groups around the nucleophile and electrophile to yield the Baldwin oxolane product 13 together with the anti-Baldwin oxane product 14 ( Figure 8a). In capsule 2, the reaction further accelerated, likely due to stabilization by cation-π interactions (TS-1, Figure 5a). On the other hand, the use of hexafluorobenzene 3 revealed a similar result as in the case of compound 8. In this scenario, the addition of product 13 at the beginning of the reaction of 12 in 3 accelerated the reaction noticeably, although not enough to surpass the results obtained using supramolecular capsule 2, which performed better than the HB and PnB catalysts used (Figure 7). The latter accelerated the reaction though the establishment of multiple PnBs with the three available σ-holes present in the Sb atom and a lone pair-π interaction involving the fluorinated ring moiety (TS-4). In the last stage of their study, diepoxide 15 was used, and the reaction followed 1 H NMR spectra (Figure 8b). In this case, 15 was initially used as a cis/trans mixture of isomers with a 6:4 ratio. The product mixtures contained the oxolane dimer 16 resulting from a cascade cyclization following Baldwin rules, the oxolane-oxane dimer 17 resulting from a Baldwin cyclization followed by an anti-Baldwin cyclization, and the fused bicycles 18 and 19 produced by an anti-Baldwin cyclization followed by a Baldwin and an anti-Baldwin cyclization, respectively. Interestingly, the reaction carried out within capsule 2 afforded 17 as the main product, with high apparent diastereoselectivity, with only the one 16 diastereomer as a minor side product. The formation of 18 and 19, both produced from an initial anti-Baldwin cyclization, was almost completely suppressed. This diastereoselective formation of isomers of 17 could possibly be explained by the ability to fold into the most globular structure, as outlined in TS-1. In the last stage of their study, diepoxide 15 was used, and the reaction followed 1 H NMR spectra (Figure 7b). In this case, 15 was initially used as a cis/trans mixture of isomers with a 6:4 ratio. The product mixtures contained the oxolane dimer 16 resulting from a cascade cyclization following Baldwin rules, the oxolane-oxane dimer 17 resulting from a Baldwin cyclization followed by an anti-Baldwin cyclization, and the fused bicycles 18 and 19 produced by an anti-Baldwin cyclization followed by a Baldwin and an anti-Baldwin cyclization, respectively. Interestingly, the reaction carried out within capsule 2 afforded 17 as the main product, with high apparent diastereoselectivity, with only the one 16 diastereomer as a minor side product. The formation of 18 and 19, both produced from an initial anti-Baldwin cyclization, was almost completely suppressed. This diastereoselective formation of isomers of 17 could possibly be explained by the ability to fold into the most globular structure, as outlined in TS-1.
Zhang and collaborators [97] developed a new family of chiral PnB-based catalysts (see Figure 9a). Concretely, 20 was obtained through the reaction of triarylstibine and mandelic acid under oxidative conditions and used as a catalyst in the reduction of benzoxazine with Hantzch ester (Figure 9b). After purification, the authors observed a decrease in the catalytic performance of 20 without noticing a clear decrease in enantioselectivity, as well as an unusual rate acceleration at the middle stage of the reaction. After further investigation, the authors assigned the catalytic active specie to the chiral antimony (V) cation/anion pair (compounds 21 and 22 in Figure 9a). As noticed in Figure 9c, the MEP surface analysis of 21 reveals an accessible and very positive Sb σ-hole (+86.6 kcal/mol), which makes it a very strong PnB donor. This ion pair promoted the reduction of benzoxazine efficiently in 2 h, obtaining the product with 99% yield with 80% ee. Zhang and collaborators [97] developed a new family of chiral PnB-based catalysts (see Figure 9a). Concretely, 20 was obtained through the reaction of triarylstibine and mandelic acid under oxidative conditions and used as a catalyst in the reduction of benzoxazine with Hantzch ester (Figure 9b). After purification, the authors observed a decrease in the catalytic performance of 20 without noticing a clear decrease in enantioselectivity, as well as an unusual rate acceleration at the middle stage of the reaction. After further investigation, the authors assigned the catalytic active specie to the chiral antimony (V) cation/anion pair (compounds 21 and 22 in Figure 9a). As noticed in Figure 9c, the MEP surface analysis of 21 reveals an accessible and very positive Sb σ-hole (+86.6 kcal/mol), which makes it a very strong PnB donor. This ion pair promoted the reduction of benzoxazine efficiently in 2 h, obtaining the product with 99% yield with 80% ee. Consequently, compound 20 analogues with different mandelic acid ligands were prepared and tested in different reaction conditions. On the other side, different substituents were used in benzoxazine to assess their influence on the reaction global performance. Lastly, to gain mechanistic insights into the chiral antimony (V) cation/anion pair catalyzed asymmetric transfer hydrogenation, nonlinear effect studies were conducted. The authors observed a weak negative nonlinear relationship between ee of the catalyst and ee of the product. This phenomenon indicated the presence of ligand exchange and/or catalyst aggregation during the course of the reaction, which was further confirmed by 1 H NMR spectra [97].
The last selected example of PnB catalysis encompasses the study from Yang and coworkers [98] where they synthesized monodentate and bidentate phosphonium-stilbonium and bis-stilbonium cations as PnB catalysts. More precisely, bidentate Pn compounds 22 and 23 were synthesized and X-ray characterized. Both of them are dications, therefore bearing either one Sb(III) and one P(III) or two Sb(III) in their structure (see Figure 10). As noticed, their corresponding MEP surfaces exhibit very positive Sb and P σholes. In the case of compound 22, only the Sb σ-hole was accessible with an MEP value of +201.4 kcal/mol, whilst in compound 23 both Sb σ-holes presented spatial accessibility and an MEP value of +212.7 kcal/mol (B3LYP/def2-TZVP level of theory).
In a similar way to the study of Zhang and collaborators [97], Yang et al. used compounds 22 and 23 as catalysts for the transfer hydrogenation reaction between Hantzch ester and quinolines (see Figures 9b and 10). Furthermore, the authors also synthesized monostilbonium cations, which presented lower catalytic activity compared to bidentated Pn catalysts 22 and 23. Particularly, the use of 22 afforded a conversion of 90% after 1 h, which was assigned to the presence of two adjacent cationic Sb centers which can actuate in a cooperative way to activate the substrate. Consequently, compound 20 analogues with different mandelic acid ligands were prepared and tested in different reaction conditions. On the other side, different substituents were used in benzoxazine to assess their influence on the reaction global performance. Lastly, to gain mechanistic insights into the chiral antimony (V) cation/anion pair catalyzed asymmetric transfer hydrogenation, nonlinear effect studies were conducted. The authors observed a weak negative nonlinear relationship between ee of the catalyst and ee of the product. This phenomenon indicated the presence of ligand exchange and/or catalyst aggregation during the course of the reaction, which was further confirmed by 1 H NMR spectra [97].
The last selected example of PnB catalysis encompasses the study from Yang and coworkers [98] where they synthesized monodentate and bidentate phosphonium-stilbonium and bis-stilbonium cations as PnB catalysts. More precisely, bidentate Pn compounds 22 and 23 were synthesized and X-ray characterized. Both of them are dications, therefore bearing either one Sb(III) and one P(III) or two Sb(III) in their structure (see Figure 10). As noticed, their corresponding MEP surfaces exhibit very positive Sb and P σ-holes. In the case of compound 22, only the Sb σ-hole was accessible with an MEP value of +201.4 kcal/mol, whilst in compound 23 both Sb σ-holes presented spatial accessibility and an MEP value of +212.7 kcal/mol (B3LYP/def2-TZVP level of theory). Finally, DFT calculations were used to simulate the double activation of the substrate by the dicationic systems, a step that would precede transfer of a hydride from the Hantzsch ester. Using a simplified computational model, the authors predict the lowest energy binding mode between the substrate and the catalyst (see Figure 11). As noted, for both catalysts 22 and 23, a bifurcated N···Sb/P PnB was proposed in addition to a stacking interaction involving the π-systems of the quinoline and a phenyl ring bound to one of the Pn atoms, which further assisted in the stabilization of the supramolecular complex.
In Table 3, the atomic polarizabilities (α) and van der Waals radii of the chalcogen elements from period two to five are displayed. As noted, the atomic α value increases from 3.0 a.u. in O to 25.9 a.u. in Te. Interestingly, the difference in the atomic polarizability between O and S is quite large (~4x), which is in line with the behavior observed in Pn atoms. On the contrary, the differences between S and Se or Se and Te are negligible. The MEP values at the σ-holes of the fluoride derivatives of the four Ch elements studied in this section are also given in Table 3, and the MEP for TeF2 molecule is represented in Figure 12. They show the expected trend with σ-hole values increasing from 16.8 kcal/mol in OF2 to 52.6 kcal/mol in TeF2.  In a similar way to the study of Zhang and collaborators [97], Yang et al. used compounds 22 and 23 as catalysts for the transfer hydrogenation reaction between Hantzch ester and quinolines (see Figure 9b,10). Furthermore, the authors also synthesized monostilbonium cations, which presented lower catalytic activity compared to bidentated Pn catalysts 22 and 23. Particularly, the use of 22 afforded a conversion of 90% after 1 h, which was assigned to the presence of two adjacent cationic Sb centers which can actuate in a cooperative way to activate the substrate.
Finally, DFT calculations were used to simulate the double activation of the substrate by the dicationic systems, a step that would precede transfer of a hydride from the Hantzsch ester. Using a simplified computational model, the authors predict the lowest energy binding mode between the substrate and the catalyst (see Figure 11). As noted, for both catalysts 22 and 23, a bifurcated N···Sb/P PnB was proposed in addition to a stacking interaction involving the π-systems of the quinoline and a phenyl ring bound to one of the Pn atoms, which further assisted in the stabilization of the supramolecular complex. Finally, DFT calculations were used to simulate the double activation of the substrat by the dicationic systems, a step that would precede transfer of a hydride from th Hantzsch ester. Using a simplified computational model, the authors predict the lowes energy binding mode between the substrate and the catalyst (see Figure 11). As noted, fo both catalysts 22 and 23, a bifurcated N···Sb/P PnB was proposed in addition to a stacking interaction involving the π-systems of the quinoline and a phenyl ring bound to one o the Pn atoms, which further assisted in the stabilization of the supramolecular complex.
In Table 3, the atomic polarizabilities (α) and van der Waals radii of the chalcogen ele ments from period two to five are displayed. As noted, the atomic α value increases from 3. a.u. in O to 25.9 a.u. in Te. Interestingly, the difference in the atomic polarizability between O and S is quite large (~4x), which is in line with the behavior observed in Pn atoms. On th contrary, the differences between S and Se or Se and Te are negligible. The MEP values at th σ-holes of the fluoride derivatives of the four Ch elements studied in this section are also given in Table 3, and the MEP for TeF2 molecule is represented in Figure 12. They show the expected trend with σ-hole values increasing from 16.8 kcal/mol in OF2 to 52.6 kcal/mol in TeF2. Ch α R vdW MEP (ChF2) Figure 11. Schematic representation of the plausible transition state stabilization through bifurcated PnB and π-π stacking interactions involving compounds 22 and 23.
In Table 3, the atomic polarizabilities (α) and van der Waals radii of the chalcogen elements from period two to five are displayed. As noted, the atomic α value increases from 3.0 a.u. in O to 25.9 a.u. in Te. Interestingly, the difference in the atomic polarizability between O and S is quite large (~4x), which is in line with the behavior observed in Pn atoms. On the contrary, the differences between S and Se or Se and Te are negligible. The MEP values at the σ-holes of the fluoride derivatives of the four Ch elements studied in this section are also given in Table 3, and the MEP for TeF 2 molecule is represented in Figure 12. They show the expected trend with σ-hole values increasing from 16.8 kcal/mol in OF 2 to 52.6 kcal/mol in TeF 2 .  Figure 12 shows the MEP surfaces of TeF2 as an illustrative example of the wh series. As noted, TeF2 exhibits an extended region of positive MEP values in the molecu plane, with two σ-holes located approximately on the extension of the F-Te bonds. A s ilar behavior is observed in SbF3 (see Figure 2).
In 2017, Benz and collaborators [112] proposed neutral benzodiselenazole (BDS) prototypical molecular synthon for the catalysis of the transfer hydrogenation of qui lines (see Figure 13). Concretely, the authors proposed several functionalized BDS structural motifs involving Se ChB donors using zero, one or two sulfoxide moieties the substituents R 1 and R 2 , which accounted for CN, CH3 and iBu groups (R 1 ) and p tercbutylphenyl (PTBP), adamantane and octyl groups (R 2 ) (see Figure 13a). In this rega the MEP analysis of one of the most promising candidates (24, see Figure 13b), as the C donor is shown. As noticed, two strong Se σ-holes are present, located along the C bonds and overlapping between the Se atoms (+31.7 kcal/mol).   Figure 12 shows the MEP surfaces of TeF 2 as an illustrative example of the whole series. As noted, TeF 2 exhibits an extended region of positive MEP values in the molecular plane, with two σ-holes located approximately on the extension of the F-Te bonds. A similar behavior is observed in SbF 3 (see Figure 2).
In 2017, Benz and collaborators [112] proposed neutral benzodiselenazole (BDS) as a prototypical molecular synthon for the catalysis of the transfer hydrogenation of quinolines (see Figure 13). Concretely, the authors proposed several functionalized BDS as structural motifs involving Se ChB donors using zero, one or two sulfoxide moieties and the substituents R 1 and R 2 , which accounted for CN, CH 3 and iBu groups (R 1 ) and paratercbutylphenyl (PTBP), adamantane and octyl groups (R 2 ) (see Figure 13a). In this regard, the MEP analysis of one of the most promising candidates (24, see Figure 13b), as the ChB donor is shown. As noticed, two strong Se σ-holes are present, located along the C-Se bonds and overlapping between the Se atoms (+31.7 kcal/mol).
Using the ChB-donor ability of 24, the authors demonstrated its catalytic activity in the hydrogenation reaction of quinolines (see Figure 14) through a transition-state stabilization in the focal point of the Se σ-holes of the BDS. Concretely, in the transition state, the negative charge carried out by the hydride is located on the endocyclic nitrogen, which can be stabilized through the formation of a bifurcated Se ChB, therefore resulting in rate enhancement of the transfer hydrogenation. The authors reported a catalytic rate enhancement of five orders of magnitude by compound 24, with presented maximized σ-holes by two strong sulfone-and two strong cyano-acceptors.
lines (see Figure 13). Concretely, the authors proposed several functionalized BDS as structural motifs involving Se ChB donors using zero, one or two sulfoxide moieties and the substituents R 1 and R 2 , which accounted for CN, CH3 and iBu groups (R 1 ) and paratercbutylphenyl (PTBP), adamantane and octyl groups (R 2 ) (see Figure 13a). In this regard, the MEP analysis of one of the most promising candidates (24, see Figure 13b), as the ChB donor is shown. As noticed, two strong Se σ-holes are present, located along the C-Se bonds and overlapping between the Se atoms (+31.7 kcal/mol). Using the ChB-donor ability of 24, the authors demonstrated its catalytic activity in the hydrogenation reaction of quinolines (see Figure 14) through a transition-state stabilization in the focal point of the Se σ-holes of the BDS. Concretely, in the transition state, the negative charge carried out by the hydride is located on the endocyclic nitrogen, which can be stabilized through the formation of a bifurcated Se ChB, therefore resulting in rate enhancement of the transfer hydrogenation. The authors reported a catalytic rate  Other interesting examples are the studies by Wang [113,114] and Bao [115] and col laborators, which effectively designed a series of catalysts based on Ch···Ch interactions In one of their works [114], the authors carried out the synthesis, X-ray and NMR charac terization and the evaluation of the catalytic activity of a series of ChB catalysts for the Rauhut-Currier reaction based on dual Se···O ChBs (see Figure 15 for one of the mos promising candidates). As noticed, there are two available Se σ-holes on the catalyst which exhibit an electrostatic potential value of +142.5 kcal/mol, owing to the positively charged nature of the molecule. The dual binding ability of this family of catalysts was used to interact with the two nucleophile species needed for the Rauhut-Currier reaction, which are an enone and an alcohol. Particularly, the simultaneous interaction of a ChB catalyst with these two reac Other interesting examples are the studies by Wang [113,114] and Bao [115] and collaborators, which effectively designed a series of catalysts based on Ch···Ch interactions. In one of their works [114], the authors carried out the synthesis, X-ray and NMR characterization and the evaluation of the catalytic activity of a series of ChB catalysts for the Rauhut-Currier reaction based on dual Se···O ChBs (see Figure 15 for one of the most promising candidates). As noticed, there are two available Se σ-holes on the catalyst which exhibit an electrostatic potential value of +142.5 kcal/mol, owing to the positively charged nature of the molecule.  Other interesting examples are the studies by Wang [113,114] and Bao [115] and collaborators, which effectively designed a series of catalysts based on Ch···Ch interactions. In one of their works [114], the authors carried out the synthesis, X-ray and NMR characterization and the evaluation of the catalytic activity of a series of ChB catalysts for the Rauhut-Currier reaction based on dual Se···O ChBs (see Figure 15 for one of the most promising candidates). As noticed, there are two available Se σ-holes on the catalyst which exhibit an electrostatic potential value of +142.5 kcal/mol, owing to the positively charged nature of the molecule. The dual binding ability of this family of catalysts was used to interact with the two nucleophile species needed for the Rauhut-Currier reaction, which are an enone and an alcohol. Particularly, the simultaneous interaction of a ChB catalyst with these two reactants provoked a shift from the intermolecular alcohol addition of enone to an "intramolecular" manner, thus facilitating the addition process (see Figure 16 for the proposed reaction mechanism and transition state stabilization). To verify this hypothesis, the authors The dual binding ability of this family of catalysts was used to interact with the two nucleophile species needed for the Rauhut-Currier reaction, which are an enone and an alcohol. Particularly, the simultaneous interaction of a ChB catalyst with these two reactants provoked a shift from the intermolecular alcohol addition of enone to an "intramolecular" manner, thus facilitating the addition process (see Figure 16 for the proposed reaction mechanism and transition state stabilization). To verify this hypothesis, the authors performed several experiments, altering the concentrations of either of the nucleophiles or modifying the substituents of the Se atom to evaluate the effect of the steric hindrance of the catalytic activity. They concluded that a proper balance between the concentrations of the two electron donors is essential, as the catalyst needs to simultaneously interact with both the alcohol and the enone to drive this reaction. In 2019, Wonner and collaborators [116] proposed the synthesis and catalytic activity of a series of Ch-based organocatalyts. Figure 17 shows the chemical structure and MEP surface of compound 26, a tellurium-based catalyst which exhibited a promising activity for the nitro Michael reaction. As noted in Figure 17b, the MEP surface of this compound shows two very positive electrostatic potential regions corresponding to the location of two Se σ-holes (+141.8 kcal/mol). Similarly, in the previous study from Wang and collaborators [113], the cationic nature of the catalyst provokes and enhancement of the σ-hole donor ability of the Te atoms. The authors achieved better reaction yields when using low coordinating counterions (such as BF4 or BARF), suggesting a higher accessibility of the Te σ-holes. The proposed mechanism of action is shown in Figure 18, and as noted, compound 26 undergoes two simultaneous ChBs with the two negatively charged O atoms from the nitro derivative, thus likely stabilizing the reaction intermediate. This aspect was further demonstrated by DFT calculations (M062X-D3/def2-TZVP level of theory) which pro- In 2019, Wonner and collaborators [116] proposed the synthesis and catalytic activity of a series of Ch-based organocatalyts. Figure 17 shows the chemical structure and MEP surface of compound 26, a tellurium-based catalyst which exhibited a promising activity for the nitro Michael reaction. As noted in Figure 17b, the MEP surface of this compound shows two very positive electrostatic potential regions corresponding to the location of two Se σholes (+141.8 kcal/mol). Similarly, in the previous study from Wang and collaborators [113], the cationic nature of the catalyst provokes and enhancement of the σ-hole donor ability of the Te atoms. The authors achieved better reaction yields when using low coordinating counterions (such as BF 4 or BARF), suggesting a higher accessibility of the Te σ-holes. In 2019, Wonner and collaborators [116] proposed the synthesis and catalytic activity of a series of Ch-based organocatalyts. Figure 17 shows the chemical structure and MEP surface of compound 26, a tellurium-based catalyst which exhibited a promising activity for the nitro Michael reaction. As noted in Figure 17b, the MEP surface of this compound shows two very positive electrostatic potential regions corresponding to the location of two Se σ-holes (+141.8 kcal/mol). Similarly, in the previous study from Wang and collaborators [113], the cationic nature of the catalyst provokes and enhancement of the σ-hole donor ability of the Te atoms. The authors achieved better reaction yields when using low coordinating counterions (such as BF4 or BARF), suggesting a higher accessibility of the Te σ-holes. The proposed mechanism of action is shown in Figure 18  The proposed mechanism of action is shown in Figure 18,   As the final example, Weiss and collaborators [117] designed and synthesized a Tellurium organocatalyst (compound 27, Figure 19a), able to efficiently catalyze three different reactions: the Friedel-Crafts bromination of anisole, the bromolactonization of ω-unsaturated carboxylic acids and the aza-Diels-Alder reaction between Danisehfsky's diene and imines. In Figure 19b the MEP surface of compound 27 is shown, which involves CF3 substitution in both benzene rings. As noted, the MEP value around the three available Te σ-holes is very positive (+125.5 kcal/mol), which makes it suitable for the establishment of strong Te ChBs. The authors used the three reactions shown in Figure 20 as benchmark tests to evaluate the effectiveness of Te catalyst 27. Concretely, in the Friedel-Crafts bromination of anisole (Figure 20a), the authors used two aromatic substituents (-OMe and -CF3), obtaining very high yields in all the cases (80-90%). However, those catalysts using [BArF4] -as a counterion achieve the best results, in agreement with previous studies [114], likely due to a greater Te σ-hole availability. They concluded that increasing or decreasing the catalyst amount did not affect the catalyst efficiency, and interestingly, even 0.5 mol% of catalyst still promoted this reaction very efficiently within 5 min. Finally, the authors also confirmed the catalyst stability by performing NMR monitoring of the reaction.
The second benchmark reaction used was the bromolactonization of ω-unsaturated carboxylic acids (Figure 20b). Concretely, a series of ω-unsaturated carboxylic acids was As the final example, Weiss and collaborators [117] designed and synthesized a Tellurium organocatalyst (compound 27, Figure 19a), able to efficiently catalyze three different reactions: the Friedel-Crafts bromination of anisole, the bromolactonization of ω-unsaturated carboxylic acids and the aza-Diels-Alder reaction between Danisehfsky's diene and imines. In Figure 19b the MEP surface of compound 27 is shown, which involves CF 3 substitution in both benzene rings. As noted, the MEP value around the three available Te σ-holes is very positive (+125.5 kcal/mol), which makes it suitable for the establishment of strong Te ChBs. As the final example, Weiss and collaborators [117] designed and synthesized a Tellurium organocatalyst (compound 27, Figure 19a), able to efficiently catalyze three different reactions: the Friedel-Crafts bromination of anisole, the bromolactonization of ω-unsaturated carboxylic acids and the aza-Diels-Alder reaction between Danisehfsky's diene and imines. In Figure 19b the MEP surface of compound 27 is shown, which involves CF3 substitution in both benzene rings. As noted, the MEP value around the three available Te σ-holes is very positive (+125.5 kcal/mol), which makes it suitable for the establishment of strong Te ChBs. The authors used the three reactions shown in Figure 20 as benchmark tests to evaluate the effectiveness of Te catalyst 27. Concretely, in the Friedel-Crafts bromination of anisole (Figure 20a), the authors used two aromatic substituents (-OMe and -CF3), obtaining very high yields in all the cases (80-90%). However, those catalysts using [BArF4] -as a counterion achieve the best results, in agreement with previous studies [114], likely due to a greater Te σ-hole availability. They concluded that increasing or decreasing the catalyst amount did not affect the catalyst efficiency, and interestingly, even 0.5 mol% of catalyst still promoted this reaction very efficiently within 5 min. Finally, the authors also confirmed the catalyst stability by performing NMR monitoring of the reaction.
The second benchmark reaction used was the bromolactonization of ω-unsaturated The authors used the three reactions shown in Figure 20 as benchmark tests to evaluate the effectiveness of Te catalyst 27. Concretely, in the Friedel-Crafts bromination of anisole (Figure 20a), the authors used two aromatic substituents (-OMe and -CF 3 ), obtaining very high yields in all the cases (80-90%). However, those catalysts using [BArF 4 ] − as a counterion achieve the best results, in agreement with previous studies [114], likely due to a greater Te σ-hole availability. They concluded that increasing or decreasing the catalyst amount did not affect the catalyst efficiency, and interestingly, even 0.5 mol% of catalyst still promoted this reaction very efficiently within 5 min. Finally, the authors also confirmed the catalyst stability by performing NMR monitoring of the reaction.
Interestingly, the expected bromolactones were obtained within 30 min in good quantitative yields for 4-to-6-membered rings, although in lower yields for larger rings, while no reaction occurred without the catalyst. The authors also confirmed the stability of the catalyst during the reaction. Finally, the authors further tested compound 27 on the aza-Diels-Alder-type reaction, using the Danishefsky's diene condensation with various imines as a prototypical reaction. In this case, all the examined imines readily afforded the expected N-phenyl 2,3-dihydro-4-pyridinones in good-to-high yields with only 1 mol% of catalyst within 2 h at room temperature.

Conclusions
The data of MEP and polarizability data summarized in this review show that the polarizability of the p-block elements increases when moving from period two to five, with large differences between periods two and three. Moreover, the MEP values increase when descending in the group, similarly to the behavior observed for the polarizability.
The selected examples shown in Sections 2.1 and 2.2 of this review, which is not intended to be comprehensive, give significant experimental support to the fact that the elements from groups 15 and 16 have a strong tendency to establish directional PnB and ChB interactions with Lewis bases or anions. This in turn can be used for the stabilization of reaction intermediates as well as transition states, thus accelerating and improving reaction rates. Although the applications of these novel NCIs in this field of research are in its mere naissance, the use of catalysts based on PnB and ChB interactions should be considered and used by the scientific community as a novel and efficient tool in the field of organocatalysis.   The second benchmark reaction used was the bromolactonization of ω-unsaturated carboxylic acids (Figure 20b). Concretely, a series of ω-unsaturated carboxylic acids was submitted to NBS in the presence of telluronium catalyst shown in Figure 20a. Interestingly, the expected bromolactones were obtained within 30 min in good quantitative yields for 4-to-6-membered rings, although in lower yields for larger rings, while no reaction occurred without the catalyst. The authors also confirmed the stability of the catalyst during the reaction. Finally, the authors further tested compound 27 on the aza-Diels-Alder-type reaction, using the Danishefsky's diene condensation with various imines as a prototypical reaction. In this case, all the examined imines readily afforded the expected N-phenyl 2,3-dihydro-4-pyridinones in good-to-high yields with only 1 mol% of catalyst within 2 h at room temperature.

Conclusions
The data of MEP and polarizability data summarized in this review show that the polarizability of the p-block elements increases when moving from period two to five, with large differences between periods two and three. Moreover, the MEP values increase when descending in the group, similarly to the behavior observed for the polarizability. The selected examples shown in Sections 2.1 and 2.2 of this review, which is not intended to be comprehensive, give significant experimental support to the fact that the elements from groups 15 and 16 have a strong tendency to establish directional PnB and ChB interactions with Lewis bases or anions. This in turn can be used for the stabilization of reaction intermediates as well as transition states, thus accelerating and improving reaction rates. Although the applications of these novel NCIs in this field of research are in its mere naissance, the use of catalysts based on PnB and ChB interactions should be considered and used by the scientific community as a novel and efficient tool in the field of organocatalysis. Funding: This research was funded by the MICIU/AEI of Spain (project PID2020-115637GB-I00 FEDER funds).