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Novel Noncovalent Interactions in Catalysis: A Focus on Halogen, Chalcogen, and Anion-π BondingMartin Breugst* 0000-0003-0950-8858 Daniel von der Heiden1 Julie Schmauck1

Department für Chemie, Universität zu Köln, Greinstraße 4, 50939 Köln, Germanymbreugst@uni-koeln.de

Dedicated to Professor Herbert Mayr on the occasion of his 70th birthday.

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Received: 26.04.2017Accepted after revision: 28.04.2017Published online: 23.05.2017DOI: 10.1055/s-0036-1588838; Art ID: ss-2017-z0277-sr

Abstract Noncovalent interactions play an important role in many bio-logical and chemical processes. Among these, hydrogen bonding is verywell studied and is already routinely used in organocatalysis. This ShortReview focuses on three other types of promising noncovalent interac-tions. Halogen bonding, chalcogen bonding, and anion-π bonding havebeen introduced into organocatalysis in the last few years and could be-come important alternate modes of activation to hydrogen bonding inthe future.1 Introduction2 Halogen Bonding3 Chalcogen Bonding4 Anion-π Bonding5 Conclusions

Key words noncovalent interactions, catalysis, anion-π interactions,halogen bonding, chalcogen bonding

1 Introduction

For a long time, chemists focused their research on co-valent bonding and developed an impressive collection oforganic transformations converting functional groups intoeach other. These covalent bonds are formed by an orbitaloverlap of two electron shells, which results in an increasedelectron density between them.2 As the best overlap is ob-tained for short interatomic distances, covalent bonds (in-volving carbon atoms) are usually below 2.0–2.5 Å. In con-trast, noncovalent interactions differ from the covalentbond because no electron pairs are shared between the twofragments. As a consequence, noncovalent bonds are usual-ly significantly longer and can reach up to 10–100 Å, e.g., inbiomacromolecules.3

Given that noncovalent interactions play an importantrole in different areas of chemistry (e.g., in biomoleculessuch as DNA and in molecular recognition processes), it isnot surprising that these interactions have gained signifi-cant interest also in organic catalysis over the last decades.3The best-researched type of noncovalent interactions isprobably hydrogen bonding, which plays a key role in vari-ous fields.3,4 Hydrogen bonding is routinely used today in

Martin Breugst (middle) studied chemistry at the Ludwig-Maximilians-Universität (LMU) in Munich (Germany). He received his Ph.D. in physi-cal organic chemistry from the LMU Munich under the supervision of Prof. Dr. Herbert Mayr in 2010. Afterwards, Martin moved to the Uni-versity of California, Los Angeles as a Feodor-Lynen postdoctoral fellow where he worked with Prof. Dr. Kendall N. Houk on different aspects of computational organic chemistry. Since 2013, he has worked at the De-partment of Chemistry at the University of Cologne as an independent researcher supported by a Liebig scholarship of the Fonds der Che-mischen Industrie. His research interests include noncovalent interac-tions and the elucidation of reaction mechanisms. Daniel von der Heiden (left, M.Sc. from the Westfälische Wilhelms-Uni-versität in Münster, Germany) and Julie Schmauck (right, M. Sc. from the University of Cologne, Germany) are currently pursuing their Ph.D. with Martin Breugst and are both funded through scholarships of the Fonds der Chemischen Industrie.

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many different (organo)catalytic reactions and various re-views have dealt with the application of this form of nonco-valent interaction.4b–d

In the last decade, noncovalent interactions such as hal-ogen or chalcogen bonding have gained more interest indifferent fields in chemistry including supramolecularchemistry and biochemistry.5 Various experimental andcomputational investigations showed that these interac-tions can be comparable in strength to hydrogen bonding.As a consequence, it is highly desirable to introduce thesebinding phenomena into catalysis. To date, many groupshave reported on the successful application of these nonco-valent interactions in catalysis. Based on the success storyof hydrogen-bond catalysis, it can be envisioned that othernoncovalent interactions will also play an important role infuture catalytic concepts.

In this Short Review, we will focus on three noncovalentinteractions (halogen bonding, chalcogen bonding, anion-πbonding) and describe their recent advances in noncovalentcatalysis. Thereby, we will focus on selected reactions andtheir mechanistic details that demonstrate the applicabilityof these interactions in catalysis instead of providing a com-prehensive summary. For each interaction, we will brieflydiscuss the origin of the underlying interaction and analyzeits typical strength, before catalytic applications are dis-cussed.

2 Halogen Bonding

Origin of Halogen Bonds

Halogen bonds, which are noncovalent interactions be-tween the electrophilic region of a halogen atom and aLewis base,6 were first observed in ammonia–iodine com-plexes in 1814.7 Guthrie later reported in more detail on thecomposition of these complexes and suggested a 1:1 com-plex.8 Mulliken concluded in his analysis that these com-plexes are held together by charge-transfer processes,9 andcomputational investigations support the picture of a par-

tial n→σ* electron transfer.10 However, another possible ex-planation can be based on electrostatic interactions. Theo-retical investigations revealed an anisotropic distribution ofelectron density around the halogen atoms that leads to anelectropositive region along the bonding axis, the so-calledσ-hole.11 The magnitude of the σ-hole typically increaseswithin the series F → I (see Figure 1 for an example). Lewisbases can now interact with this electropositive region,which results in a halogen bond.

In contrast to hydrogen bonds, halogen bonds are usual-ly highly directional. The R–Hal···LB angles close to 180° canbe explained by the repulsive interaction of the lone pairsof the Lewis base and those of the halogen atom.12

Thermodynamic Data

For a successful application in organic synthesis and ca-talysis, a thorough understanding of interaction strengths,solvent effects, and cooperativity is typically required. Thefirst comprehensive Lewis basicity scale for halogen bond-ing was published in 2011 and includes hundreds of com-plexation reactions of molecular iodine with various Lewisbases.13 Although this pKBI2 scale only contains one halo-gen-bond donor (I2), the interaction energies fall within a40 kJ mol–1 range and allow a rough analysis of halogen-bond acceptors. Similar investigations on the nature of thehalogen-bond acceptor have also been performed for otherhalogenated species. Among others, pentafluoroiodoben-zene,14 perfluorinated iodooctane,14 and p-nitro(io-doethynyl)benzene15 have all been studied with variousLewis bases (Table 1). Although the complexation energyfor iodine and quinuclidine is one of the largest for neutralhalogen-bond donors (ΔG = –30 kJ mol–1), most interactionsinvolving these neutral halogen-bond donors are typicallyrelatively weak (0–10 kJ mol–1). Nevertheless, these com-plexation energies indicate that the binding affinities ofhalogen-bond acceptors increase in the order C=O < S=O <P=O < quinuclidine. A remarkably strong halogen bond wasrecently reported between various pyridine N-oxides andN-iodosaccharin in CDCl3 (ΔG = –24 kJ mol–1).16

Figure 1 Calculated electrostatic potential of F3C–X with X = F, Cl, Br, and I on the 0.001 au isodensity surface (M06-2X-D3/aug-cc-pVTZ; aug-cc-pVTZ-PP for I and Br)

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In most studies on thermodynamics published so far,the analysis of halogen-bond donors concentrated mainlyon comparing structurally related compounds. For example,very good correlations between the association energiesand Hammett’s substituent constant σ have been observedfor the reactions of differently substituted iodoethynes (R–C≡C–I) and diethylacetamide,17 or for a series of para-sub-stituted (iodoethynyl)benzenes (Ar–C≡C–I) and quinucli-dine.15 In contrast, slightly worse correlations have beenobserved for the reactions of p-substituted tetrafluoroiodo-benzenes with Bu3PO.14 Therefore, the substituents (even ina remote position) had a significant effect on the interac-tion energies and the corresponding σ-holes in all cases.

Table 1 Complexation Energies (in kJ mol–1) for Selected Halogen-Bonded Complexes13–15

In contrast to neutral halogen-bond donors, the interac-tion energy significantly increases, when positively chargedhalogen-bond donors (e.g., 2-haloimidazolium salts) areemployed. Based on isothermal calorimetric titrations, theinteraction between the 2-iodo-1,3-dimethylimidazoliumion and chloride is highly attractive (ΔG = –20.5 kJ mol–1;Figure 2).18 This halogen bond is significantly stronger thanmost of those discussed in Table 1.13a Interestingly, chloridebinds better to this monodentate halogen-bond donor com-pared with Schreiner’s thiourea. Structurally related biden-tate halogen-bond donors resulted in even more exergonic

reactions (ΔG = –33.2 kJ mol–1; Figure 2), which indicatesthat halogen bonding can be comparable in strength to hy-drogen bonding.18

The number of experimentally determined associationconstants for halogen-bonded complexes in different sol-vents remains limited. Several investigations indicate thatthe association constant varies by 1–2 orders of magnitudein different solvents.14,18,19 However, different conclusionsregarding the ideal solvent for halogen bonding can bedrawn: Based on the interaction between iodine and te-tramethylthiourea, dichloromethane is among the best sol-vents,19b whereas the same solvent is less suitable com-pared with other solvents when the interactions between10 and chloride is considered.19a Goroff and co-workers in-vestigated the coordination of iodoalkynes to various Lewisbases by 13C NMR spectroscopy and compared the observedchemical shifts with different empirical parameters.20

Based on these correlations, the authors concluded that sol-vent basicity is a better model than solvent polarity to pre-dict the strengths of halogen bonds. In general, the influ-ence of the solvents is still hard to predict and interpret atthis point and further investigations are clearly needed.

In summary, the thermodynamic data indicate that hal-ogen bonds can be comparable to hydrogen bonding undercertain conditions. Strong halogen-bond donors typicallyfeature a positive charge, electron-withdrawing substitu-ents, and/or allow polydentate binding.

Application in Synthesis and Catalysis

One of the simplest halogen-bond donors, molecular io-dine, has been used as a catalyst for many different trans-formations for more than 100 years. After the initial discov-ery of the iodine-catalyzed dehydration reaction of diace-tone alcohol by Hibbert in 1914,21 the catalytic potential ofiodine has been applied to various reactions.22 For a longtime, the origin of the catalytic activity was unknown andnot associated with halogen bonding, as iodine can decom-pose under the reaction conditions and yield hydrogen io-dide.23 However, recent computational and experimentalinvestigations suggest that the mode of action in iodine ca-talysis is indeed halogen bonding and that a hidden Brønst-ed acid catalysis24 is very unlikely.25

–6.7 –11.0 –15.7 –29.8

n.a. –1.7 –6.2 –7.4

n.a. –4.5 –7.2 –8.7

–1.3 –2.7 –5.3 –6.9

O

NMe2 BuS

O

Bu BuP

O

BuBu

N

I I

(heptane)

I

(cyclohexane)

F5C6

I

(cyclohexane)

F17C8

O2N I

(C6D6)

Figure 2 Experimentally determined association energies for the coordination of chloride ions (MeCN, 30 °C)18

N

N

CH3

CH3

I Cl

ΔG = –20.5 kJ mol–1

N

H

Cl

H

N

S

CF3

F3C

CF3

CF3

N N

N NI I

H3C CH3Cl

OTf

ΔG = –18.4 kJ mol–1 ΔG = –33.2 kJ mol–1

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In 2008, Bolm and co-workers reported the first experi-mental application of halogen bonding in catalysis. 1-Io-doperfluoroalkanes (and to a lesser extent also 1-bro-moperfluoroalkanes) catalyze the reduction of 2-substitut-ed quinolines with a Hantzsch ester (Scheme 1).26 Highyields can be obtained when 10 mol% of the catalyst wasemployed, whereas no reaction took place in the absence ofthe catalyst. However, the addition of either 2,2,6,6-te-tramethylpiperidine-1-oxyl (TEMPO) or a proton sponge[1,8-bis(dimethylamino)naphthalene] inhibited the catalyt-ic reaction. As these compounds can either form halogen-bonded complexes or indicate a Brønsted acid pathway, theunderlying reaction mechanism remains unclear in thiscase.

Tan and co-workers picked up this reaction in 2014 em-ploying different bidentate iodinated dihydroimidazolinesas catalysts (Scheme 1).27 Quantitative reduction of the par-ent quinoline could be achieved with 10 mol% 1 within onehour. The much lower activity of the deiodo analogue 2 in-dicated that halogen bonding is important for the catalyticactivity. Interestingly, the monodentate halogen-bond do-nor 3 is also highly active, requiring slightly longer reactiontimes (91% after 3 h). Additional NMR experiments furthersupport the assumption of a halogen-bond activation.

In a systematic approach, Huber and co-workers syn-thesized several polydentate halogen-bond donors in thelast years (Figure 3).28 To achieve strong noncovalent inter-actions, multidentate structures were chosen that addition-

ally feature positive charges or perfluorination. Over thelast years, these compounds have successfully been appliedin many different reactions.

As halide anions strongly bind to these (and related)polydentate halogen-bond donors, the activation of car-bon–halide bonds seemed an ideal candidate for applica-tions in organic chemistry. In 2011, Huber and co-workersreported on the halogen-bond induced Ritter-type reactionof benzhydryl bromide and acetonitrile (Scheme 2, top).28a

The addition of 1 equivalent of the halogen-bond donor 4leads to an almost quantitative reaction within 96 hours.Control experiments exclude the possibility of a hiddenBrønsted acid catalysis and indicate a bidentate binding ofthe substrate to the halogen-bond donor. Given that otherstructures of Figure 3 can replace 4 as the initiator in thesereactions (Scheme 2),28b,28c a broader applicability seemedfeasible. In another recent example, glycosyl halides couldbe activated by halogen bonding, relying on the cationic do-nor 4.29

Besides cationic halogen-bond donors, neutral perfluo-rinated aryl iodides can also activate carbon–halogen bonds(Scheme 2, bottom).28d Compound 10 (10 mol%) successful-ly catalyzes the reaction between 1-chloroisochromane anda silyl ketene acetal (91%, 12 h, –78 °C).

From a mechanistic perspective, the halogen-bond do-nor coordinates to the halogen atom of the substrate andweakens the corresponding carbon–halogen bond. This

Scheme 1 Halogen-bond-catalyzed reduction of quinolines26,27

NN

N NI I

MeMe

Ph

PhPh

Ph

2 F3CSO3

N

NI

Me

Ph

Ph

F3CSO3

N Ph NH

Ph

Bolm and co-workers (2008)

NH

CH3H3C

EtO2C CO2Et

+

(2.2 equiv)

CH2Cl2, 25 °C, 24 h

98%

Tan and co-workers (2014)

N NH

NH

CH3H3C

EtO2C CO2Et

+

(2.2 equiv)

CH2Cl2, rt, 24 h

NN

N NH H

MeMe

Ph

PhPh

Ph

2 F3CSO3

199% yield (after 1 h)

268% yield (after 2 h)

391% yield (after 3 h)

CF3(CF2)7I (10 mol%)

catalyst(10 mol%)

selected catalysts:

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leads to an easier fission of that bond and the correspond-ing nucleophile (e.g., CD3CN, silyl ketene acetal) attacks theintermediate carbocations.

The halide-abstraction reactions described above in-spired Takemoto and co-workers to employ iodine(I) com-pounds as reagents in a semipinacol rearrangement(Scheme 3).30 While structures with a C–I bond (i.e., thetypical halogen-bond donors discussed above) turned outto be inactive, N-iodosuccinimide or N-iodosaccharin wereefficient reagents for this reaction. However, the underlyingmechanistic pathways remain unclear. The authors proposean initial halogen-bond interaction between the benzylbromide and the N–I bond of the halogen-bond donor thateventually generates a benzyl cation. Subsequently, the N–Ibond is also broken and I–Br is formed. The saccharin anioncould then be involved in the desilylation process. Given

that the C–I bond is much stronger than the N–I bond,31 itis, therefore, not surprising that halogen-bond donors withC–I bonds are inactive in this reaction.

Besides the activation of carbon–halogen bonds, halo-gen bonds can also be used for the activation of carbonylgroups and related imines. Huber and co-workers showedin 2014 that a bidentate 2-iodoimidazolium-based systemaccelerates the Diels–Alder reaction of cyclopentadiene andbut-3-en-2-one (Scheme 4).32 Interestingly, a strong depen-dence of the counterion was observed in these reactions.Triflate salts resulted in no rate enhancement comparedwith the uncatalyzed reactions, and only salts of the weaklycoordinating B[3,5-(CF3)2C6H3]4

– (‘BArF4

–’) were catalyticallyactive. Computational investigations (M06-2X/TZVPP) re-vealed that the activation barrier is reduced by 12 kJ mol–1

and support the proposed halogen-bond activation.

Figure 3 Selected structures of polydentate halogen-bond donors from the Huber group28

N N

N NI I

RRN

N

N

NN

N

N

NN

I I

I

CH3

Bn

H3C

Bn

H3C

Bn

8

N

N

I

I

F

F

F

I

I F

F

F

9 I

I

I I

FF

F

I

I

F

F

F

F

F

F

F

F

F10

N N

N NI I

RR

6 (R = CH3)7 (R = n-C8H17)

CF3

4 (R = CH3)5 (R = n-C8H17)

Scheme 2 Examples of the activation of carbon–halogen bonds through halogen bonding (TBS = tert-butyldimethylsilyl)28

Br HN

O

CD3

CD3CN, H2O, rt, 96 h

4 or 8 or 9(1 equiv)

pyridine (10 mol%)

OOMe

OTBSO

O

OMe

10 (10 mol%)or

7 (0.5 mol%)

THF, –78 °C, 12 h+

Cl

Scheme 3 Halogen-bond-catalyzed semipinacol rearrangement (TBS = tert-butyldimethylsilyl)30

BrOTBS Ohalogen-bond donor

(1.1 equiv)

CH2Cl2, rt

I

F

F

F

F

F

no reaction(after 24 h)

IN

N

C8H17

CH3

no reaction(after 24 h)

N I

O

O

72% (after 8.5 h)

N IS

O

OO

62% (after 15 min)

halogen-bond donors:

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Scheme 4 Halogen-bond catalyzed Diels–Alder reaction (BArF4 =

B[3,5-(CF3)2C6H3]4–)32

Similar to the Diels–Alder reaction described by Huberand co-workers, Takeda, Minakata, and co-workers success-fully applied halogen-bond activation to an aza-Diels–Alderreaction (Scheme 5).33 2-Haloimidazolium ions (5 mol%) arehighly active catalysts for the reactions of aldimines andDanishefsky’s diene. A hidden Brønsted acid catalysiscaused by hydrolysis of the imidazolium salt could be ruledout experimentally and an iodine-free catalyst was com-pletely inactive. Interestingly, kinetic analysis by 1H NMRspectroscopy revealed an unexpected result when the halo-gen atom in the 2-position was varied. 2-Bromoimidazoli-um salts were more reactive than their chloro and iodo ana-logues, which deviates from the typical pattern observedfor the strengths of the halogen bond (I > Br > Cl).12a–c How-ever, experimentally determined equilibrium constants forthe reactions of 2-haloimidazolium salts and N-phenyl-benzaldimine confirmed this unusual reactivity order (Br >Cl > I). Probably, other noncovalent interactions such as cat-ion-π or dispersion interactions are also involved in thisprocess.

Scheme 5 Halogen-bond-catalyzed aza-Diels–Alder reaction (TMS = trimethylsilyl)33

Very recently, Sekar and co-workers reported on a halo-gen-bond catalyzed aldol-type condensation under solvent-free conditions (Scheme 6).34a CBr4 (20 mol%) efficientlycatalyzed the reaction between substituted acetophenonesand benzaldehydes yielding chalcones. The catalyst couldbe re-isolated at the end of the reactions and UV/Vis and IRspectroscopy indicated a halogen-bond interaction be-tween the aldehyde and CBr4.

The first approach towards enantioselective catalysiswas reported in 2017 by Arai and co-workers.34b A chiralbis(imidazolidine)iodobenzene induced up to 65% ee in thereaction of thiosalicyl aldehyde and nitroalkenes (Scheme7).

In conclusion, halogen bonding, which is a binding phe-nomenon that has been neglected for a long time, has foundits way into organocatalysis. Many proof-of-principle reac-tions are already known today but there are also many

open questions: We are still in need of a larger variety ofsuitable catalyst structures and, so far, only one halogen-bond-induced enantioselective reaction has been report-ed.34b However, the examples discussed above indicate thatwe are on the right track to achieve these challenges in thefuture.

3 Chalcogen Bonding

Origin of Chalcogen Bonds

Compared with the well-known and intensively investi-gated hydrogen3,4 and halogen bonding,12 chalcogen bond-ing is a more recent field of noncovalent interaction thatalso plays a role in biological systems and crystal design.35

In general, a chalcogen bond is a noncovalent interactionformed between a chalcogen atom (e.g., S, Se, Te, Po, butusually not oxygen) as the Lewis acid (chalcogen-bond do-nor) and a Lewis base (e.g., N, O) as the chalcogen-bond ac-ceptor.36 Similar to halogen bonds, these interactions havealready been observed more than 50 years ago in crystalstructures: for example, the S···O distances in 2-(2-chloro-benzoylimino)-1,3-thiazolidine and 3-benzoylimino-4-methyl-1,2,4-oxathiazane are 2.68 and 2.24 Å, respectively,which is considerably less than the sum of the van-der-Waals radii of 3.3 Å.37

As for halogen bonding, the origin of the chalcogenbond can be described by using the σ-hole concept by Clark,Murray, Politzer and others.11,38 Due to an anisotropic elec-

O O

+CD2Cl2, rt, 6 h

(10 equiv)

5–BArF4 (20 mol%)

(5 mol%)

CD2Cl2, rt, 1 h+

NPh

HPh

OMe

OTMS

NPh

OPh

I

NN C8H17

F3C

OTf

(85%)

Scheme 6 CBr4-catalyzed aldol condensation between substituted ac-etophenones and benzaldehydes34

CBr4 (20 mol%)

neat, 60 °C, 24 h

OO O

+

(84%)

Scheme 7 First approach for enantioselective halogen-bond cataly-sis34b

PhNO2

SH

CHO

S

OH

NO2

Ph

(10 mol%)+

99% yieldsyn/anti 44:56ee(syn): 69%ee(anti): 53%

I

N

NH HN

NPh

PhPh

Ph

toluene, –40 °C

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tron distribution, a region of positive electrostatic potentialis formed along the extension of the bond (σ-hole) as wellas a negative electrostatic potential on its equatorial sides(nucleophilic belt). In contrast to halogen bonding (e.g., inCF3–I; Figure 1), the sp3-hybridized selenium compound(F3C)2Se possesses two σ-holes, which are located perpen-dicular to the two lone pairs (Figure 4).36b Both σ-holesshow a positive electrostatic potential and can act as Lewisacids. In contrast, the sp2-hybridized F2C=Se displays onlyone σ-hole (Figure 4) and consequently, a higher direction-ality and stronger interactions can be expected for thesespecies.36b

Figure 4 Calculated electrostatic potential of (F3C)2Se and F2C=Se on the 0.001 au isodensity surface (M06-2X-D3/aug-cc-pVTZ)

Thermodynamic Data

The strength of the chalcogen bond depends on theelectronegativity of the substituents adjacent to the chalco-gen atom and can be comparable to hydrogen and halogenbonds.36a,39 So far, only few investigations set out to deter-mine association constants experimentally. Based on a se-ries of NMR analyses, Tomoda and co-workers estimatedthe association energy to be ca. 10–80 kJ mol–1 for Se–N in-teractions40 and 8–28 kJ mol–1 for Se–O interactions.41

Experimental investigations indicate that the strengthof the chalcogen bond increases within the group (O < S <Se < Te).40 A comparison of the interaction energies of thio-phenolate complexes revealed that 3,4-dicyano-1,2,5-tellu-radiazole (ΔG < –46 kJ mol–1; Figure 5, left) formed strongerchalcogen bonds in tetrahydrofuran (THF) than the corre-sponding selenadiazole (ΔG = –28 kJ mol–1; Figure 5).42 Thistrend is also confirmed by computational investigations ofFrontera and co-workers.36b From the comparison in Table2, one can conclude that the strength of the interaction in-creases for benzene–chalcogen and trimethylamine–chal-cogen complexes when heavier chalcogen atoms are in-volved.

In a similar investigation involving substituted benzo-telluradiazoles, experimentally determined interaction en-ergies correlated well with the computed electrostatic po-tential at the tellurium center.43 The interaction energy de-termined for a perfluorinated benzotelluradiazole–chloridecomplex (Figure 5, right) falls within a comparable range forchloride binding by electron-deficient N,N-diarylureas44

and indicated once again that this noncovalent interactioncan be comparable to hydrogen bonding (see also Figure 2).Only a small change in the association constant was ob-served in this investigation when the solvent was varied,but more data is required to draw a general conclusion.

However, most studies on the strengths of these inter-actions concentrated on computational investigations em-ploying only small molecules. For example, Adhikari andScheiner analyzed the interaction energies for the complex-es of substituted thiols RSH and NH3 using MP2/aug-cc-pVDZ (Figure 6).45 Weak to medium interactions (4–33 kJmol–1) have been calculated for the different structures. Asexpected from the similar halogen bonds (see above), elec-tron-withdrawing substituents such as R = NO2 or R = F leadto stronger complexes. However, in this case, the hydrogenbond between HSH and NH3 was calculated to be somewhatstronger than the chalcogen bond (13.7 vs. 3.9 kJ mol–1).

Table 2 Calculated Interaction Energies (in kJ·mol–1; BP86-D3/def2-TZVPD) for Selected Chalcogen-Bonded Complexes36b

(F3C)2Se (F3C)2Te F2CSe F2CTe

Benzene –18.8 –22.6 –14.6 –19.2

NMe3 –15.5 –23.8 –19.2 –32.6

Figure 5 Experimentally determined interaction energies for chalco-gen-bonded complexes (25 °C, THF)42,43

Se SPhN

N

NC

NC

Te SPhN

N

NC

NC

ΔG = –28 kJ mol–1

ΔG < –46 kJ mol–1

Te ClN

NTe N

N

N

ΔG = –17 kJ mol–1

ΔG = –29 kJ mol–1

ΔG = –7 kJ mol–1

Te ClN

N

F

F

F

F

Figure 6 Interaction energies for substituted chalcogen-bonded com-plexes (data from refs.45,46)

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Application in Synthesis and Catalysis

So far, the systematic application of chalcogen bondingin organic synthesis and catalysis is still in its infancy. In2016, Matile and co-workers designed dithieno[3,2-b;2′,3′-d]thiophenes that are capable of transporting different an-ions.47 In catalysis, studies by Cheong, Smith, and co-work-ers highlight the importance of 1,5-S···O nonbonding inter-actions in isothiourea-catalyzed annulations of ben-zazoles.48 DFT calculations employing M06-2X/6-31+G(d,p)/PCM(THF)//M06-2X/6-31G(d)/PCM(THF) revealthe role of two 1,5-S···O interactions that are responsible forthe structural preorganization leading to the lactam (lefttransition state in Scheme 8). In the corresponding transi-tion state for the lactonization only one chalcogen bond ispresent (right structure in Scheme 8). Therefore, chalcogenbonds control the experimentally observed chemoselectivi-ty.

Scheme 8 Influence of chalcogen bonds in isothiourea-catalyzed an-nulations of benzazoles48

In 2017, Matile and co-workers employed for the firsttime chalcogen bonds in noncovalent catalysis.49 Variousdithieno[3,2-b;2′,3′-d]thiophenes and related compoundssignificantly accelerate the reductions of quinolines andimines by a Hantzsch ester (Scheme 9). Depending on thestructure of the catalyst, enhancements (kcat/kuncat) up to1290 have been observed. The good correlation betweencomputed chloride anion affinities and the catalytic activityas well as the inhibition by the addition of chloride ionssupport the initial hypothesis of chalcogen-bond catalysis.Non-annulated compounds such as 5,5′-bithiazoles (not

shown in Scheme 9) are almost inactive (kcat/kuncat = 2.1) in-dicating that chalcogen bonding also requires a high degreeof directionality.50

Scheme 9 Chalcogen-bond-catalyzed transfer-hydrogenation of quin-olines (TIPS = triisopropylsilyl)49

In summary, chalcogen bonding seems to be a promis-ing noncovalent interaction for catalysis, and initial proof-of-principle experiments indicate that there might be ahigh catalytic potential in the future.

4 Anion-π Bonding

Origin of Anion-π Interactions

The anion-π interaction is defined as a favorable nonco-valent interaction between an anion and π-acidic aromaticsurfaces with positive quadrupole moments.5e,51 In contrastto the well-studied cation-π interactions with numerousexamples in catalytic reactions,5b,52 anion-π interactions be-came the focus of more recent research.53

Compared with cation–π interactions, anion–π interac-tions typically feature shallower potential energy surfacesand allow for three distinct structures (Figure 7).54 The an-ion can interact with one of the π* orbitals of the aromaticsystems similar to a Meisenheimer complex (left in Figure7). If the aromatic system includes a hydrogen atom, a hy-drogen-bonded complex is also feasible (middle). Finally,the anion can be placed directly above the ring centroid, re-sulting in a structure similar to a cation-π interaction(right).

N Ph NH

PhNH

CH3H3C

EtO2C CO2Et

+CD2Cl2, 20 °C

96% yieldkcat/kuncat = 490

catalyst(30 mol%)

selected catalysts:

S

SSNC CN

O O

N

SS

N

TIPS TIPS

O

62% yieldkcat/kuncat = 100

S

SS

N N

O

O

O

O

78% yieldkcat/kuncat = 500

S

SS

N N

O

O

O

OO O

94% yieldkcat/kuncat = 1290

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Figure 7 Calculated structures for different anion-π interactions in 1,3,5-triazine–chloride complexes (geometries taken from ref.55)

One of the reasons that anion-π interactions were ne-glected for a long time is the fact that aromatic rings usuallyhave a negative quadrupole moment (Qzz < 0) and are morelikely to interact with cations than anions (Figure 8, left).This quadrupole moment inverts by adding strongly elec-tron-withdrawing substituents to the aromatic ring (Figure8, right). In these structures, an electron-poor surface isformed that can interact with anions.

Figure 8 Schematic representation of the quadrupole moment of ben-zene (left) and hexafluorobenzene (right). Quadrupole moments are given in Buckingham (B) and are taken from ref.54

Three pioneering studies were performed in 2002 thatconfirmed the existence of favorable anion-π interactionsbetween anions and electron-poor aromatic rings based ongas-phase computations and crystallography.55,56 Based ontheir investigations, Deyà, Frontera, and co-workers sug-gested the term ‘anion-π interactions’ for this type of non-covalent interaction.56b

Computational investigations indicate that the nature ofthis noncovalent interaction mainly results from electro-static forces and ion-induced polarizations.54–56 London dis-persion forces,5g which usually play an important role innoncovalent interactions involving aromatic rings, onlyplay a minor role in anion-π bonding.54–56

Thermodynamic Data

Anion-π interactions have gained significant interest inthe field of supramolecular chemistry, and various excellentreviews summarize those achievements.5e,53 Here, we willonly focus on some selected examples that will serve as ageneral orientation. Small anions (e.g., F–) are more polariz-ing, which results in short equilibrium distances and morenegative interaction energies (Table 3). Planar anions suchas nitrate or carbonate, however, can benefit from addition-al π-π interactions, which has been confirmed experimen-tally for nitrate–pyrimidinium complexes.57

Johnson and co-workers analyzed the association be-tween different halide anions and a series of neutral, tripo-dal receptors. NMR titrations indicated 1:1 complexes withbinding energies between –6 and –10 kJ mol–1 in C6D6. Ad-ditional DFT calculations suggested that different arrange-ments of Figure 7 can be found within the receptors.59

The first direct experimental observation of anion-π in-teractions was reported in 2010. Relying on electrospraytandem mass spectrometry, the researchers concluded thatmonomeric π-surfaces are ideal for chloride recognition.Based on their findings, Matile and co-workers concludedthat ‘a big impact on organocatalysis can be expected fromthe stabilization of anionic transition states on chiral π-acidic surfaces.’60

Application in Synthesis and Catalysis

One of the first systematic applications of anion-πbonding in catalysis was published in 2013. Matile and co-workers reported that naphthalenediimides are excellentcatalysts for the Kemp elimination (Scheme 10).61 In this re-action, the key step is the deprotonation of a benzisoxazoleby a general base and the nitrophenolate is obtainedthrough a negatively charged transition state. The anionicnature of the transition state makes the Kemp eliminationthe ideal reaction to study the role of anion-π interactions.Differently substituted naphthalenediimides resulted in asignificant acceleration of the Kemp elimination. Rate en-hancements (kcat/kuncat) of up to 7606 were observed exper-imentally and a transition-state stabilization of up to 30 kJmol–1 was estimated based on these results. However, a the-oretical investigation of this reaction by Lu and Wheelerquestioned the importance of anion-π interactions for therate acceleration of this reaction.62 Based on their computa-tional studies on smaller model systems, they concludedthat naphthalenediimides actually stabilize the substratecomplex by anion-π bonding at least equally well as thetransition state. As a consequence, the activation energy inthis reaction is actually slightly increased (ΔΔG‡ = 1.3 kJmol–1). Therefore, the question of how anion-π interactionsare involved in this remarkable catalytic effect remains un-clear.

Berkessel and co-workers employed electron-deficientpyridinium ions for the activation of carbon–halogen bonds(Scheme 11).63 Similar to the halogen-bond-based catalystsdescribed above (Scheme 2), these pyridinium ions success-fully catalyze the reactions of 1-chloroisochromane and dif-

Table 3 BSSE-Corrected Calculated Interaction Energies (in kJ mol–1; MP2/6-31++G(d,p)) for Selected Anion-π Complexes to Hexafluoroben-zene58

Anion H– F– Cl– Br– NO3– CO3

2–

ΔE –51 –76 –53 –49 –51 –145

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ferent silyl ketene acetals in 2–10 mol% catalyst loadings.Crystal structures support the picture of an anion-π inter-action and NMR titrations indicate a 1:1 complex with abinding energy of 13 kJ mol–1.

Inspired by studies of Wennemers and co-workers onstereoselective amino-catalyzed 1,4-additions of aldehydesto nitroolefines using a tripeptide as catalyst,64 Matile andco-workers introduced π-acidic surfaces to increase the en-antioselectivity in these transformations.65 To allow for ad-

ditional anion-π interactions, the authors added differentlysubstituted naphthalenediiminides between the prolineresidue and the carboxylic acid (Scheme 12, top). Increasingthe π-acidity of the catalyst leads to faster reaction ratesand higher enantioselectivities, indicating that anion-π in-teractions are at work. Very recently, naphthalenediimidescould also be replaced by structurally related perylenediim-ides in catalysis.66

Similar catalysts have also been used by the same groupin enolate chemistry.67 In the absence of any catalyst,malonate half thioesters undergo a decarboxylation reac-tion instead of enolate addition in the presence of ni-troalkenes. By using naphthalenediimide-based π-acidiccompounds, the disfavored addition product can be ob-tained in very good yields (Scheme 12, middle).67a Similarly,these catalysts can also be employed in demanding cascadereactions of enals and dinitropropanes (Scheme 12, bot-tom). In these reactions, six-membered rings with five ad-jacent stereocenters are formed and the π-acidic catalystsare comparable to typical organocatalysts (e.g., a mixturefrom Jørgensen–Hayashi catalyst and 1,4-diazabicyc-lo[2.2.2]octane (DABCO)).67b

Although anion-π interactions have been overlooked forquite some time next to the corresponding cation-π inter-actions, the recent experimental investigations discussedabove clearly demonstrate the catalytic potential of thisnoncovalent interaction for reactions involving negativelycharged transition states or intermediates.

5 Conclusions

Catalysis with noncovalent interactions no longer refersprimarily to hydrogen-bond activation. Other types of non-covalent interactions are not only comparable in strength,they are also widely used in many areas of chemistry andbiology. Most of these interactions started off as toys fortheoretical chemists or as curiosities and, today, the appli-cation of these interactions in catalysis is still at an earlystage. Based on the different geometries required for opti-mal interactions, these noncovalent forces should comple-ment the existing hydrogen-bond approach. The manyproof-of-principle examples described above will eventual-ly pave the way for a systematic application in the near fu-ture. The success of hydrogen-bond catalysis can certainlyprovide the motivation to achieve these goals.

Funding Information

Financial support from the Fonds der Chemischen Industrie (Liebigscholarship to M.B. and Ph.D. scholarships to J.S. and D.v.d.H.) as wellas from the University of Cologne within the Excellence Initiative isgratefully acknowledged.Fonds der chemischen Industrie ()

Scheme 10 Anion-π catalysis in the Kemp elimination and the initially proposed, calculated transition state61a

Scheme 11 Electron-deficient pyridinium ions as catalysts in halide-abstraction reactions (crystal structure CONQAZ from ref.63a)

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Acknowledgment

We thank Eric Detmar for support during the preparation of thismanuscript.

References

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Scheme 12 Selected examples of anion-π interactions in catalysis (PMP = p-methoxyphenyl)

O

H

PhNO2

H

O Ph

NO2* *+

NN

O

O

O

O

O

NH

C6 S

S

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HN

O

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dr: 10.9:1ee: 82%

H11

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