Catalysis of organic reactions through halogen bonding | ACS Catalysis

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Catalysis of organic reactions through halogen bonding Revannath Sutar, and Stefan M. Huber ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b02894 • Publication Date (Web): 04 Sep 2019 Downloaded from pubs.acs.org on September 4, 2019

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ACS Catalysis

Catalysis of Organic Reactions through Halogen Bonding

Revannath L. Sutar,*† Stefan M. Huber*†

† Fakultät

für Chemie und Biochemie, Ruhr-Universität Bochum, Universitätsstraße 150,

Bochum, 44801 (Germany).

ABSTRACT: Halogen bonding, the noncovalent interaction based on electrophilic halogen substituents, features very interesting properties, as illustrated by numerous applications continuously emerging in recent years, and is by now sometimes considered as a hydrophobic and soft analogue of the well-known hydrogen bond. Conventionally studied in silico and solid state, its solution-phase applications particularly for catalyzing organic transformations are currently under active investigations. Herein we present a

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conceptual treatise on the latest developments in this regard and discuss the challenges associated with the advancement of more practical catalytic halogen bonding systems.

KEYWORDS: Organocatalysis, noncovalent interaction, halogen bonding, σ-hole, halogens.

1. INTRODUCTION

The association between the electrophilic region of a polarized halogen substituent and a Lewis basic unit, defined by IUPAC as a ‘halogen bond’ (XB),1 is recently flourishing in a variety of inorganic,2,3 organic,4 and biological domains.5 Historically, it dates back to the discovery of the NH3···I2 complex by Colin6a and its subsequent structure determination by Guthrie,6b which was followed by pioneering crystallographic works of Hassel.7 In the last 20 years, the studies by Resnati, Metrangolo, and others demonstrated the high potential of halogen bonding, albeit mostly in crystal engineering.8 Since the simplest and strong XB donors, elemental bromine and iodine, lack the possibilities for structural modifications required for tuning the properties of this


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ACS Catalysis

interaction, the evolution of new XB donors (mostly based on carbon skeletons) was stimulated.

For a rational development of strong XB donors, however, a clear understanding on the electronic origin of the interaction is crucial. One important contribution to the overall interaction energy is based on electrostatics, as the electron distribution around these halogen substituents is anisotropic: next to a ring of high electron density perpendicular to the R-X bond, there is also a region of electron depletion at the elongation of the bond, the so-called σ-hole.9 The electron-rich belt around the halogens leads to the high directionality of halogen bonding, with R-X…LB angle of ~180º, as the Pauli repulsion of the lone pair electrons of the halogen with the Lewis base prevents acute angles.10 A further contribution is based on orbital interactions: Mulliken considered this interaction as a charge-transfer process11 and indeed computational investigations support a partial n→σ* electron transfer from a nonbonding orbital of the Lewis base into the antibonding orbital of the R-X bond.12 Both theoretical and experimental studies have found a strong


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correlation between the strength of this interaction and the amount of n→σ* charge transfer.13

Somewhat obviously, the Lewis acidity of XB donors increases with the size of the interacting halogen (I > Br > Cl ≫ F), with fluorine substituents very rarely forming halogen bonds.14 Regarding the covalently linked moiety, usually but not always, more electron withdrawing groups produce stronger XB donors.15 Thus, for instance, a carbon atom bearing the halogen substituent gives more potent XB donor with increasing percentage of s-orbital contribution in its hybridization. Cationic backbones typically result stronger halogen bond donors compared to neutral (poly- or perfluorinated) ones when geometries are comparable, due to the stronger polarization of the halogen substituent.16 However, the neutral variants are usually more stable than the cationic ones. Understanding the interaction modes17 and interaction strengths16b,18,19 of various XB donors with common Lewis bases in solution, and elucidating the associated solvent effects as well as potential cooperativity effects have aided the prediction of possible solution-phase applications. One notable contribution in this regard is the development of a halogen-bond basicity


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scale of common Lewis bases with I2,18 which may potentially be extended towards other XB donors to provide a rough estimation of binding strengths. Later, the strengths of the interactions of various other XB donors with common Lewis bases in solution were also determined by methods such as UV-vis, IR, NMR, ITC, Raman and ESR.4a,4b,16b,19 In most cases, binding affinities varied linearly with the Lewis basicity of the XB acceptor and was affected by its structural features.20 In one study, the strength of this interaction was found to be solvent-independent when I2 is the XB donor,21 (except when there is some interaction with the solvent itself22) while for XB donors with a carbon backbone, it varied by the orders of 1–2 magnitudes in different solvents.19

While similar in strength to hydrogen bonding under certain conditions,23 the key distinctive features of halogen bonding are a) the bigger size of interacting electrophilic substituent, b) the polarizability (softness) and anisotropic electron density distribution of the interacting halogen atoms, c) the high level of directionality, and d) the flexibility of using different backbones and several halogen atoms (Cl, Br, I), even in different oxidation states (e.g. I(I) and I(III)), which can lead to diverse solubility profiles and binding


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strengths. All these features provide chemists various opportunities for tuning this noncovalent interaction to achieve the desired function. However a potential disadvantage of halogen bonding is the sometimes weak binding with oxyanions.24

In this perspective, we will provide an overview of the conceptual developments dealing with the utilization of halogen bonding in organic synthesis and catalysis.25 Since we have already covered this topic4d,f we will mainly focus on more recent developments and aim to be comprehensive in this regard. However, we will not include studies based on molecular iodine, as this has been covered very competently elsewhere.26 Two large sections will deal with the use of XB as primary or secondary interaction, with the former section being divided according to stoichiometric or catalytic use of the halogen bond donors. Two smaller sections on recent developments in the activation of π-systems and on enantioselective reactions will complement the overall picture. Finally, we will discuss challenges in the development of new catalytic XB systems especially concerning asymmetric reactions and will comment on some future directions of this field.

2. ORGANIC REACTIONS INVOLVING XB AS PRIMARY INTERACTION


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Inspired by the success of hydrogen bonding in noncovalent organocatalysis, chemists have consistently become interested to explore the use of other weak interactions in organic synthesis and catalysis.27 For halogen bonding, these developments started rather late compared to much earlier computational and supramolecular studies, but an increasing number of reports on catalytic reactions involving the XB-promoted activation of organic functional groups and the halogen(I) reagents have been emerging in the last few years. In 2008, Bolm and coworkers were the first to claim the involvement of halogen bonding interaction in the reduction of quinoline derivatives in the presence of perfluoroalkyl iodides.28 In 2011, our group published the first report on activation of organic halides by halogen bonding, in which hidden Brønsted acid catalysis was clearly ruled out.29 The latter issue is important, as there is a long-standing debate on the mode of action of halogen bond donors in catalyzing organic reactions,30 particularly with molecular iodine as catalyst.26b However, in many of the following reports, the catalytic role of hidden Brønsted acid has been excluded through the comparison of the rates of the reactions catalyzed by the corresponding acids, decomposed catalysts or the non-halogenated precursors. In


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addition, it has been proved recently through kinetic analyses of the iodine-catalyzed Michael additions that the Lewis acid activation is the only driving force in these type of reactions and not the hidden Brønsted acid catalysis.31

Halogen-bond donors bind comparatively weakly to organic functional groups possessing Lewis basic properties like carbonyl and imine moiety (particularly compared to anions) and therefore strong XB donors based on iodine(I and III) are preferentially used. Key structural motifs of organic XB donors developed so far are either based on cationic backbones (like halotriazoles, haloimidazoles and halobenzimidazoles) or neutral polyfluorinated and alkyne derivatives. Among these the halo-1,2,3-triazoles and their salts are the most studied XB donors due to their easy accessibility through a simple click reaction of azides with (halo)alkynes, and the additional advantage of increasing the XB donor ability via quaternization.16b,32 Furthermore, multidentate XBs (Figure 1 and 2) are superior to monodentate (Figure 3) ones due to the generation of more rigid and ordered adducts which results in strong binding to the substrate and thus show high catalytic activities.4d,f


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2.1.

STOICHIOMETRIC REACTIONS

As discussed in more detail in our earlier concept article on “halogen bonding organocatalysis”,4f the term may in principle refer to reactions involving both transient (non-stationary) and non-transient halogen bonding (Figure 4).4h

Transient LG

X(I)

Non-transient

LB

R

X(I)

LB

or R" LG

X(I)

LB

R

X(III)

LB

Figure 4: Types of halogen bonding interaction.

In the former case, bonding of a Lewis basic unit to the halogen substituent leads to the cleavage of its covalent bond and generates a (highly) reactive intermediate. Since arguably every known halogenation reaction may then be considered as “halogen bonding assisted”, we prefer to use this term primarily for non-transient halogen bonding, in which the R-X bond of the XB donor stays intact during the reaction. Overall, the XB


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donor thus acts as an inert Lewis acidic catalyst which activates the XB acceptor, as will be discussing in the section 2.1.2.

We will not further discuss cases of transient halogen bonding in classical halogenation reactions, including several reports in which the R-X bond of halogenating agents are activated by the addition of achiral or chiral Lewis bases. Such chiral Lewis base-halogen bond donor adducts induce high enantioselectivities in halocyclization reactions. These methods are now well established and there are excellent recent reviews available,4h,33 to which we direct the interested readers.

Interesting “intermediate” cases between transient and non-transient halogen bonding occur in photochemical reactions. Perfluoroalkyl iodides form stable (non-transient) halogen bonded adducts with strong Lewis bases, which leads to the activation of the halogen bond donors. Under photochemical conditions, their R-X bond is then cleaved, which is reminiscent of the non-transient halogen bonding in halogenation reactions mentioned above. Hence, on the whole, the halogen bond donors act as reagents, not as


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inert Lewis acidic catalysts. Still, the following section will feature some selected examples of this approach.

2.1.1. Stoichiometric reactions involving the activation of the XB donor

In general, the association of electrophilic halogen compounds with Lewis bases leads to an elongation and activation of the involved R-X bond. For instance, Ritter et al. noted that the 1:1 mixtures of gaseous perfluoroalkyl iodides (CF3I, CF3CF2I) with tetramethylguanidine produce the halogen bonded adducts which being liquid at room temperature are easy-to-handle perfluoroalkylating reagents (Scheme 1a).34a Using these adducts, photochemical direct fluoroalkylation of various arenes, olefins, aldehydes and thiols was achieved in the presence of a Ruthenium photocatalyst. Later, Yu et al. showed that the use of photocatalysts is not necessary to initiate these type of radical perfluoroalkylation reactions.34b Thus, the radical pair was generated upon visible light irradiation of XB-adducts of a variety of perfluoroalkyl iodides with organic bases, and it was harnessed to obtain 2-fluoroalkylated 3-iodoquinoxalines from diisocyanoarenes (Scheme 1b). Both secondary and tertiary amines were found to be good XB-acceptors,


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out of which dibenzylamine gave the best results. The formation of an XB-adduct between the amine and perfluoroalkyl iodide was supported by

19F

titrations and was also

corroborated by the fact that identical results were obtained when the preformed adduct of DABCO (1,4-diazabicyclo-[2,2,2]octane) with two molecules of C8F17I was used in the same reaction. Chen and coworkers further extended this method towards the synthesis of perfluoroalkyl substituted phenanthridines, the iodo-perfluoroalkylation of double/triple bonds and the C−H perfluoroalkylation of electron rich (hetero)arenes, using N,N,NʹNʹtetraethylethylenediamine

(TEEDA)

as

XB

acceptor.34c

Although

these

perfluoroalkyations can be carried out by irradiation from a 25W CFL, low-intensity UV lamp, or even with sunlight at room temperature, and even though they allow specific labeling of the tryptophan residues in oligopeptides, large excess of the XB acceptor (TEEDA) and the perfluoroalkyl iodides (RfIs) are generally required.


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ACS Catalysis

a. Condensed-phase perfluoroalkylating agents: NH R F

Me2N

I

R

NMe2

F F

F

H N

I

R

NMe2 [Ru(bipy) ]Cl ·6H O Me 3 2 2 h

Me2N

R = F, CF3

( ) 8

Me

( ) 8

F F

(Ritter et al.)

b. Perfluoroalkylation using amine as Lewis base: NC R2

R

R3 R N R1

R3 CH3CN N + I Rf R1

2

I

NC

Rf

h

N

I

R

Bn2NH (Yu et al.)

N

Rf

THF Ar1

Ar2

3

R R2 N R1

I

Rf &

I

O

Ar2

Ar1

CN h

Rf

N Rf

h

R

h

R I R

NEt2

(Cheng et al.)

h

Ar

I Rf

Et2N

Rf Rf

R

Ar

c. Perfluoroalkylation/alkenyl migration: N OH

O

N

R2

R1

+

I Rf

K3PO4, DME

R

R2

1

Rf

h  C

R3

(Studer et al.)

R3

d. Chloride as XB acceptor: R I

Cl (10 mol%) Rf

R

R

-

MeOH, RT, Ar h

I

Cl- (10/20 mol%)

I Rf

MeOH, RT, Ar h

R

Rf

(Vincent et al.)

e. Hydroxytrifluoromethylation: Me2N R

+

I CF3

NMe2 OH

Visible light DMSO air, RT

R

CF3

(Su et al.)


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Scheme 1. Photochemical additions of perfluoralkyl radicals

Furthermore, Studer and Tang combined this XB-promoted photochemical perfluoroalkylation with the intramolecular alkenyl migration.34d They employed DABCO to promote the homolysis of Rf–I bonds by visible light (400 W bulb) for the regioselective radical 1,2-difunctionalization of unactivated alkenes with a perfluoroalkyl group and an alkenyl moiety which typically originates from an internal 1,4- or 1,5-migration (Scheme 1c). Postigo et al. reported the radical perfluoroalkylation of amino(hetero)aromatics under visible light irradiation initiated by a [(TMEDA)I…I3] complex.34e On absorption of light, this complex generates iodine atoms which produce the alkyl radicals from the perfluoroalkyl iodide. Although an XB-interaction is not directly involved in the proposed catalytic cycle, NMR evidences suggests the occurrence of halogen bonding between RfIs and aminoaromatic compounds.

While all previous cases were based on nitrogen–iodine interactions, Vincent and coworkers recently described a very simple iodoperfluoroalkylation of alkenes/alkynes, in which catalytic amounts (10-20 mol%) of NaCl or NBu4Cl served as a source of Lewis


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base (Cl-) to induce the homolytic cleavage of the Rf-I bond (Scheme 1d).34f Recently, this overall approach of employing halogen bonding for the generation of perfluoroalkyl radicals was also used for the hydroxy-trifluoromethylation of alkenes with CF3I and TMEDA.34g The reaction was induced by visible light and allowed access to βtrifluoromethyl alcohols at room temperature in good yields (Scheme 1e). Addition of the trifluoromethyl radical to the olefin and subsequent capture of oxygen from the air generated a peroxide radical which lead to the final product.

2.1.2. Stoichiometric reactions leading to the activation of the XB acceptor

Motivated by the goal of utilizing this fascinating interaction to perform organic reactions, our group showed that bidentate XB donors can activate secondary halides like benzhydryl bromide29,35a,b or 2,3,4,6-tetra-O-benzyl glycosyl chloride35c by anion removal from the dissociation equilibrium during a solvolysis reaction (Scheme 2a). In a similar manner, a Koenigs−Knorr-type glycosylation was achieved using isopropanol as the nucleophile in CDCl3 (Scheme 2b). Several different types of dicationic XB donors (triflate salts of 3, 6, 7, 10; Figure 1) promoted theses reactions.35c In case of the originally


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employed bis(iodoimiazolium) derivative 3, the meta-substituted compound was more active than its para-substituted analogue, likely due to the better formation of a chelate complex with the liberated halide (bromide), the structure of which was supported by Xray crystallography. Also, a neutral polyfluorinated XB donor (11), which is structurally very similar to the pyridinium-based compound 6, clearly demonstrated the superior Lewis acidity of the former.29


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ACS Catalysis

a. Ritter reaction Br R

BnO BnO BnO

NHCOCD3

XB donor

R

CD3CN, H2O

15 (Aakeröy et al.) BnO BnO BnO

XB donor

O Cl

BnO

XB donor 3 6, 11 _ 14 (Huber et al.) _

CD3CN, H2O

O

NHCOCD3

BnO +

BnO BnO BnO

O BnO

(Huber et al.)

Cl

b. Koenigs-Knorr-type glycosylation OiPr

Cl + iPrOH

O

BnO MeO

XB donor TTBP,CDCl3 BnO 20 min MeO

O

(Huber et al.) c. Friedel-Crafts alkylation MeO Br

Ph

OMe

+

XB donor 7 _ 10

MeO

OMe Ph

CDCl3, RT

Ph

OMe Ph

OMe

(Huber et al.) d. Semipinacol rearrangement Br '

OSiR 3

R1 R

2 2R

R2

NIS or NISac MeNO2

O

R1 R2

(Takemoto et al.)

Scheme 2. Reactions involving XB promoted halide abstraction.


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Recently it has been found that for this type of bidentate charge assisted halogen bonding catalysis, the presence of an overall dicationic charge is not essential. Thus, in a halide-abstraction-induced Friedel-Crafts alkylation reaction (Scheme 2c), the catalytic activity of dicationic (7) and monocationic XB donors (8) of similar structure was almost comparable.35d In this case, the more favourable enthalpic contribution of the former is compensated with the more favorable entropic contribution of the later. In addition, the strong ion pairing in the dicationic XB donor may reduce its Lewis acidity. The combined effect of both of these factors results in similar activity. The counteranion dependency was similar for both XB donors (with BArF4- > NTf2- > OTf-) and the alkyl substituents on either of the pyridinium or triazolium moieties negligibly affected the catalytic activity. Although in the bidentate monocationic XB donor 8, the charge is on the pyridinium motif and thus the halogen-bond-donating moieties are neutral, the inactivity of the analogous non-cationic XB donor 9 clearly indicates the necessity of charge assistance for these structures.


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Aakeröy and Perera performed the Ritter-type solvolysis reaction mentioned above (Scheme 2a) with another neutral bidentate halogen-bond donor based on iodoethynyl groups (15) (Figure 4).35e While the authors ruled out non-XB modes of activation on the basis of control experiments, it is not clear yet whether the XB donor works in a chelating manner. One of the major limitations of all of the above-mentioned XB-promoted halide abstraction reactions is that they currently work only with activated secondary halides.

An operationally simple desilylative semipinacol rearrangement of various cyclic and acyclic α-silyloxyhalides promoted by N-I based XB donors like N-iodosuccinimide (NIS) or N-iodosaccharin (NISac) has been reported by the group of Takemoto (Scheme 2d).36 Substrates bearing benzylic as well as less reactive alkyl subunits underwent smooth rearrangements in nitromethane, a crucial solvent needed for this rearrangement. A carbocation mechanism of this halide-abstraction-induced rearrangement was proposed based on the loss of enantiomeric excess when an enantiopure substrate was used.


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R'

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R' I

N N R

N I

N

I

N N R

R

NX

N I

2Z

N R

N R

I

CF3

I

N

N N

N R

I

4

N

I

2Z

2Z

3

I

N

2Z

5

I

6 R

R N N N

N

N N N R

N N R

I

I

I

R N N N

I

Oct N N N

N Z R''

2Z 7

8

I

I

Oct N N N

I

N N N

N N N R

9

N I

I 10

N 3Z N R

R = Me, Bn, nOct R' = H, F R" = nOct, Bn Z = OTf, NTf2, BArF

Figure 1: Cationic multidentate XB donors.

F F

F

I

I N

F

F

N I

F

F

11

F

F F

F

I

F

I F

I

F F

N

N

12

F

I

F

F I

I F

F

I

F

F I

I F

F

F 13

I

F

F

F

I F

I F

F I

F

F

15 F

F

F 14

I

I I

I

(Aakeröy et al.)

F F

(Huber et al.)

Figure 2: Neutral multidentate XB donors.


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ACS Catalysis

R1

N

N R2 I 1

Z

R1

N R2

N

I

R1 = Me, Mes, nOct R2 = Mes, nOct Z = OTf, NTf2, BArF

Z

2

Figure 3: Cationic monodentate XB donors.

The obvious drawback of most halide abstraction reactions is the requirement to use stoichiometric amounts of XB donor due to the inhibition of the Lewis acid (as well as other potential issues like decomposition and precipitation of the halide adduct). Strategies to realize catalytic transformations with XB donors - involving halide abstractions but also other types of reactions - will be discussed in the next section.

2.2.

CATALYTIC REACTIONS

For halide abstraction reactions to happen in catalytic manner, the halide adduct either needs to be weak enough to prevent inhibition (but strong enough for action) or it needs to be quenched in situ during the reaction. The latter can be achieved by using silylnucleophiles, which liberate silyl groups once the nucleophile has reacted. The former will then abstract the halide from the noncovalent XB adduct to regenerate back the free XB-


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catalyst for further reaction (Scheme 3). The first XB-catalyzed halide abstraction was accordingly performed with a silyl enol ether and 1-chloroisochromane as substrate (Scheme 3a).37a Several monocationic (salts of 1a, 1b, 2), bidentate neutral (12, 13, 14) and dicationic (3, 6, 7 and 5) XB donors catalyzed this reaction and it was observed that preorganization of the cationic bidentate XB donor 5 significantly enhances the catalytic activity.37b Thus the syn-isomer of 5n-Oct/OTf could even be used with a loading as low as 0.5 mol%, producing good yields of the isolated product.

Later, Takemoto’s group achieved efficient direct dehydroxylative coupling of activated alcohols (e.g. benzylic alcohols and hemiaminals) with trimethylsilyl nucleophiles such as allyltrimethylsilane and trimethylsilylcyanide by the combined use of catalytic amount of XB donor and a halide source (I2) (Scheme 3b).37c In addition to mechanistic studies for the support of XB between the in-situ generated silyl halide and the XB donor, the authors also utilized one product of this reaction for the synthesis of

pimozide, an antipsychotic drug.


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Recently Yeung and coworkers have developed halogen bonding-induced additions of various carbon nucleophiles to N-acyl imminium ions which are generated by treatment of N,O-aminals with TMSCl (Scheme 3d).37d Contrary to the other reports on XB-catalysis, the imidazolium-derived monodentate XBs (1) were found more active than the bidentate (3) and the benzimidazolium-derived ones (2). Besides the experimental evidences for the proposed mechanism involving the XB-interaction between the anion and the XBdonor, a counter-anion directed diastereoselectivity and moderate enantioselectivity (44% ee) was also noted in this nucleophilic addition.


23

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a. Halide abstraction/C_C bond formation: XB donor OMe ( Br ≈ H > Cl) is roughly in line with that observed experimentally in other reactions. Afterwards, Fukuzawa’s group studied this aza-Diels-Alder reaction (Scheme 6b) using halo-triazolium salts as XB donors (21).41c They noted that the steric hindrance around the iodine center of the XB donors significantly alters the catalytic efficiency. For example, when the N-substituent is mesityl, it is orientated perpendicular to the triazolium ring, reducing steric hindrance and π-conjugation and thus leading to enhanced catalytic activity.


29

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Page 30 of 124

Furthermore, Kanger and coworkers used chiral triazolium-based monodentate XB donors (22) – which had been reported as bidentate variants before,35a to catalyze this reaction, however enantioselectivity was not achieved.41d Authors studied the mechanism of this reaction thoroughly using HMBC and HRMS. Based on the intermediates trapped, they proposed that a stepwise pathway involving Mukaiyama-Michael-type addition followed by elimination is preferred over the pericyclic one. They also claim that the XB donors decompose to the corresponding H-compounds, which seems to contradict earlier report.42

Next to these (aza)-Diels-Alder reactions, XB-catalyzed carbonyl activation has also been investigated in the context of Michael-addition reactions. Three such reports involve the 1,4-addition of indole to trans-crotonophenone in the presence of monodentate and bidentate XB donors as catalysts (Scheme 7).30,43 A study by our group43a found that BArF salts of bidentate dicationic XB donors are potent catalysts, which is consistent with earlier observations in the Diels-Alder reaction mentioned above. In particular, the preorganized syn-isomer of XB donor 5n-Oct/BArF provided the best performance.


30

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ACS Catalysis

Although no signs of catalyst decomposition were noted, the formation of catalytically active traces of iodine could not be completely ruled out. For the related brominated variants, however, it could be clearly shown that elemental bromine is not the cause of catalysis. At the same time, Breugst et al. screened salts of various monodentate iodobenzimidazolium compounds (OTf, NTf2, BF4, BPh4, BArF salts of 2) as catalysts for this reaction in different solvents.43b Unexpectedly, they reported that XB donors having coordinating triflate anions are active in this reaction. Recently, Scheidt’s group used chiral 1,2,4-triazolium-based XB donors (23−25) for promoting this reaction and based on their results they suggested that a Brønsted-acid-catalyzed pathway is preferred over XB activation.30 This finding clearly reaffirms the importance of comparison experiments to rule out hidden acid catalysis. It should be noted, though, that several other reports on the activation of neutral compounds by XB could demonstrate that acid traces were not an issue in the corresponding reaction.29,31,40 Just like in the study of Kanger described above, no asymmetric induction could be achieved by Scheidt et al. despite using either chiral XB donors or chiral anions (in combination with achiral XB donors).


31

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

+

N H

Ph

XB donor (10-20 mol%)

O Ph

Page 32 of 124

Ph O

DCM, RT

Ph

N H N

N

R

N

N

N

N

BArF X

I X

R = Me, Oct

N Oct

N

X

CF3 X

2 BArF 3/4/5 (Huber et al.) (Breugst et al.)

N Oct

N I

X

24 R

N

O N

Ph

23

2

N

N

N

O O P O O

I X

R X = BF4, PF6, SbF6, BAr

F

R = H, C6F5, 2-Naph

25 (Scheidt et al.)

Scheme 7. XB-catalyzed Michael addition reactions.

Tan et al. studied another conjugate addition in which thiophene derivatives react with

α,β-unsaturated carbonyl compounds in the presence of XB donors.44 Out of the several (neutral as well as mono and bidentate cationic) XB donors tested, bis(iodoimidazolinium) compound 19 gave best yields of the corresponding alkylated thiophenes in DCE as solvent (Scheme 8). 1H NMR spectroscopic studies and DFT calculations supported the


32

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ACS Catalysis

claim that this is an XB-induced process with limited involvement of Brønsted acid catalysis.

R3

O R

1

R2

+

S

19 (10 mol%) DCE, 23 C

R3

R2

R1 S

O

Scheme 8. XB-catalyzed conjugate addition of thiophenes to enones and enals.

In one of the most sophisticated reactions tackled by XB so far, recently a strainrelease glycosylation reaction was achieved using 5n-Oct/OTf as the XB donor to generate

O,N-glycosides with excellent anomeric selectivity, typically much better than with HB catalysis (Scheme 9).45 This methodology allows the generation of a new class of hedgehog signaling glycoside inhibitors. As the substrate can be activated by the XB donor via two different modes, the authors proposed a divergent mechanism involving multistage XB-interaction.


33

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O H RO

O

O

BnO BnO

Page 34 of 124

RO O

R H O

I

BnO

H O O

BnO

I

BnO

O

BnO BnO

BnO

XB donor (0.55mol%) I

O

O

BnO BnO

I

O BnO

O

ROH

O R

BnO BnO

O

+ + O

O H O

BnO

O

O

BnO R

OR

BnO

I

I

O BnO BnO

O H

H

O

BnO

H

O

BnO

H O

H

O

N N N

O

O

O

N N n

Oct

N I

CF3

I

N Oct

n

2 OTf

O Hedgehog Signaling Inhibitors

5

Scheme 9. Multistage XB-catalyzed strain-release glycosylation.

Furthermore, N-methyl 4-iodopyridinium triflate (26) was successfully used as XB donor in a synthetically useful and highly chemoselective bromo-carbocyclization of Ncinnamyl sulfonamides and O-cinnamyl phenyl ethers, using inexpensive 1,3-dibromo5,5-dimethylhydantoin (DBDMH) as the halogenating agent (Scheme 10).46 This is the first report of an organocatalyst-promoted selective halocyclization reaction without the electrophilic halogenation of electron rich-arenes. The XB catalyst presumably activates an N-haloamide reagent to generate a soft electrophilic halonium species for the


34

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halogenation of the olefins. The mechanistic study suggested an autocatalytic process, with the hydantoin side products (DMH or MBDMH) accelerating the reaction. The unique role of pyridinium-based cationic XB donor in promoting this carbocyclization was supported by the inefficiency of molecular iodine, neutral XB donors, TMSOTf, Lewis bases, hydrogen bonding catalysts (such as thiourea and squaramide) as well as Brønsted bases (iPr2NEt, DMAP) and acids. The usefulness of this method is highlighted by good efficiencies, excellent diastereoselectivities (d.r. > 99:1) and regioselectivities and by the fact that the resulting halogenated tetrahydroquinolines and chromanes are valuable drug cores and natural products scaffolds.

I N R2

Br O

N

+ R

1

X

O N Br

OTf Me

R2

(26) (10 mol%) DCM

Br R

1

X

X = O, NTs

Scheme 10. Bromocarbocyclization via halogen bonding.


35

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Page 36 of 124

In addition to this, the Nazarov cyclization, which typically can be catalyzed by very mild Lewis and Brønsted acids, has been shown to be susceptible to XB-catalysis (Scheme 11).47 In line with our earlier observations in the XB-promoted Diels-Alders reaction and the Michael addition reactions, higher conversions were achieved in the presence of preorganized dicationic XB donor 5n-Oct/BArF equipped with a noncoordinating counteranion (BArF).

O

O XB donor (5 mol%)

Me

Me

DCM F F syn-isomer (major) N N n

Oct

N I

CF3

I

N Oct

n

2 BArF 5

Scheme 11. XB-promoted Nazarov cyclization.

As noted in the introduction, another possible advantage of XB over HB is the fact that iodine compounds feature different oxidation states. “Hypervalent” iodine(III) derivatives


36

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ACS Catalysis

in particular have attracted the attention of organic chemists as very versatile reagents. A report by Han and Liu in 2015 had featured diaryliodonium salts (eg. 27) as catalysts in a solvent less reaction which could either proceed via a Mannich- or a Michael-type pathway (Scheme 12).48a More importantly, the mode of activation by the iodine(III) compound was unclear at that time.

O Ph

Me

+ PhCHO + PhNH2

F

I

XB donor (10 mol%) neat, RT 24 h

N H

Ph

P O 27

Ph

X O

X = OTs

Ph

O

X=

O O

7% ee

Scheme 12. Diaryliodonium salt catalyzed three component Mannich reactions.

Our group could subsequently show for variously substituted cyclic iodolium compounds (Figure 5) that the origin of their catalytic activity (in halide abstractions and a Diels-Alder reaction) is very likely based on XB:48b when both electrophilic axes were blocked by ortho-substituents (like in 29), the Lewis acidity was completely switched off.


37

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Page 38 of 124

Compared to the previously established bidentate dicationic organoiodine(I) XB donor

meta-3n-Oct/OTf, these iodine(III) derivatives (like 28) were found to be more active in the challenging solvolysis of benzhydryl chloride (Scheme 2a) and were equally effective in the Diels–Alder reaction of cyclopentadiene with methyl vinyl ketone (Scheme 6a).

I

Z

I Z

R

R R R = H, CF3 Z = OTf, BArF

R = H, CH3 Z = OTf, BArF

28

29

I Br

Br

I Cl

Interaction with halide

Figure 5. Iodine (III) derivatives used as halogen bonding organocatalysts.

Iodine(III) derivatives also played a decisive role in a further XB catalysis, albeit as substrate: Takemoto et al. showed that the umpolung alkylation of silyl enol ethers with an iodonium(III) ylide proceeds in the presence of monodentate halo(benz)imidazolium XB donors under mild conditions to afford various 1,4-dicarbonyl compounds in high yields (Scheme 13).49 Other prospective catalysts such as Schreiner’s thiourea, phosphoric acid and metal based Lewis acids didn’t catalyze this reaction efficiently. Next


38

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ACS Catalysis

to experimental hints, the crucial role of XB between the catalyst and the iodonium ylide in promoting this reaction was also supported by computational means.

O O

O

R1

O R2

I

R3

Ph

N N I

n

C12H25 OTf

Ph

N

R I Y (15 mol%) Z base (B:) n THF, 0 C 24 h

N I

n

Y

R1 I R

B:

O R2 I Ph

O H R3

O O

Z R

Z

R2 O R3

1

n

n

C12H25

OTf

Scheme 13. Umpolung C-C bond formation involving an iodolium ylide and halogen bonding.

Matsuzawa and Sugita’s group for the first time used an iodoalkyne (C(sp3)-I) bearing a pentafluorophenyl group (30) as an XB catalyst (Scheme 14).50 This compound efficiently activates thioamides, which on reaction with 2-aminophenol generate benzoxazoles in good yields. In contrast, other monodentate XB donors such as


39

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Page 40 of 124

pentafluoroiodobenzene and idodobenzimidazolium derivatives (2) typically gave low yields of the product.

HO H 2N S R1

(2 equiv.) NR2R3

F

R1

N O

I

F (30) F

F (10 mol%) F toluene, 100 C, 12 h

Scheme 14. Iodoalkyne-induced activation of thioamides.

In almost all earlier studies on XB catalysis involving neutral carbon-based XB donors, the latter are typically polyfluorinated and the fluorine substituents polarize the iodine atoms through the inductive effect. Recently, however, other motifs for neutral XB donor catalysts have started to appear. For instance, the rather simple CBr4 was used as XB donor to promote the aldol condensation between substituted benzaldehydes and ketones under solvent-free conditions (Scheme 15a).51 The involvement of XB has been postulated based on UV/Vis and IR spectroscopic measurements. In addition, several


40

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ACS Catalysis

acid-sensitive groups (like esters and ketals) were sustainable under the reaction conditions, which thus enable the synthesis of medicinally important oxygenated chalcones.

In another approach a C(sp3)-halogen moiety involving the strongly electronwithdrawing capabilities of the fluorobis(sulfonyl)-methane scaffold was utilized to create powerful neutral XB donors (31 and 32) which catalyzed Mukaiyama aldol reactions and hydrogen-transfer reductions under neutral and mild conditions (Scheme 15b).52 The Lewis acidity of these XB donors was confirmed by NMR titrations, single-crystal XRDs, and DFT calculations.


41

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a. Selective activation of substituted benzaldehydes Br Br

O

O R

O

Br (20-30 mol%)

H

+

Br

neat, 60-70 C

R

R''

R'

R'

O

OMe

O

O

OMe

O

anti-leishmanial

R'' OMe

OMe anti-malarial

b. Fluorobissulfonylmethyl iodides as XB donors O

OTBS H +

OMe

F

PhO2S

XB donor (10 mol%) DCM RT, 6 h

SO2Ph

F I (FBSM-I) 31

OH CO2Me F O O S F S

I

O O (FBDT-I) 32

Scheme 15. Organocatalysis by neutral C(sp3)−halogen-based XB donors.

XB-promoted reactions in aqueous media would combine this emerging activation concept with green chemistry approaches. A first such examples was realized by Metrangolo et al. using the amino-acid-based XB donor 4-iodotetrafluorophenylalanine (33), which combines XB donor properties with good water solubility (Scheme 16).53a It


42

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ACS Catalysis

catalyzes the synthesis of bis-(heterocyclic)methanes in water at higher temperature (> 60 °C). The role of XB has been investigated by NMR studies and XRD of co-crystals. Two modes of XB activation were proposed, either the direct coordination to the carbonyl group or the acidification of a water molecule which then interacts with the substrate. In this context, we note that recently an acyclic tetrapodal XB receptor comprised of four 2iodoimidazolium motifs has been reported, which showed moderate to strong binding of halides in organic and aqueous media.53b This further stipulates the possibilities of performing XB-catalysis in water.

F CO2H

F I F

OH

O

60 C, 1 h H 2O

O

O

F

F

F

O

HOOC

Or

F

I HOOC H 2N F

F

O H

OH

OO

O

F I

H 2N F

OH

(0.2 mol%)

+ R

R

NH2 F (33)

H

O

O R

R

Scheme 16. XB-catalyzed organocatalysis in water by an amino-acid-based XB donor.


43

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Page 44 of 124

Finally, Sekar et al. reported the selective oxidation of aryl(heteroaryl)methanes with the aid of XB donors:54 in the presence of catalytic amounts of NBS, ketones were selectively obtained in DMSO while selective acyloxylation (ester formation) occurs in the presence of catalytic amounts of iodine (and tert-butyl hydroperoxide as oxidant) (Scheme 17). The mechanistic proposal for the former process involves, inter alia, halogen bonding of NBS to the pyridine moiety as well as bromination of the methylene position (with cleavage of the N-Br bond). Thus, this transformation seems to involve both transient and non-transient halogen bonding.

R N O

R'

I I (30 mol%) TBHP (2 equiv.) R'CO2H 100 C

O

Br N

O

R

R (30 mol%) N

DMSO, 100 C

N O

O

Scheme 17. XB-promoted selective oxidation of aryl(heteroaryl)methanes.

3. REACTIONS INVOLVING XB AS SECONDARY INTERACTION IN CATALYSIS


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ACS Catalysis

Since supramolecular chemistry deals with rather weak interactions, it is often the combination of several such forces which allows powerful applications. While the focus of this perspective is on the use of XB as the primary interaction in catalysis, there are several very interesting examples in which XB acts as a secondary interaction and thereby allows the realization of a particular goal. It is well known, for instance, that noncovalent interactions help to form or rigidify (enantiopure) ligand backbones in metal complexes,55 provided that the ligands (or components) contain both self-complementary binding motifs as well as metal-coordinating groups.

In the context of organic reactions, Metrangolo and Resnati have demonstrated that halogen bonding - along with π stacking – can play an important role in controlling the reactivity of substrates in the solid state.56 The XB-induced rigidification of a chiral catalyst structure in solution has been reported by Charette et al. in 2009.57a,b Also, the interplay of XB and HB has been shown to be crucial in a zinc-acetate-catalyzed asymmetric halolactonization.57c A fascinating approach towards XB-based ligand assembly was reported by the group of Vidal-Ferran in the construction of chelate ligands for Rh(I)


45

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Page 46 of 124

complexes.58 Monodentate pyridyl- and iodo(tetrafluoro)aryl-substituted phosphines were assembled around a Rh(I) precursor to form the corresponding halogen-bonded complexes 33 in-situ (Scheme 18). Interestingly, in this case, due to a template effect by the metal center, the presence of electron-withdrawing fluorine substituents on the iodocontaining phosphine unit was not necessary for XB formation. The fluorine-containing XBphos-Rh complex 34 showed impressive performance in the hydroboration of terminal alkynes and provided a high selectivity for the branched products.58a Later the same group demonstrated that the formation of such halogen bonded chelates around a metal center favors the oxidative addition of CAr–I bonds, resulting in cyclometallated species.58b

R X 1

R P R2

Y +

3

P R R4

X

[MLn]

Y

1

R P R2

N

I

R

3

M

P R R4

Ph2P Rh PPh2 R BArF

O

R = H, F

'

R

+ (R O)2BH

Cat. (5 mol%)

'

R

R

B(OR )2 + R

B(OR')2

34

B(OR')2

+ R


46

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ACS Catalysis

Scheme 18. XB-based assembly of a bidentate phosphine ligand on a Rh(I) complex and its use in a hydroboration reaction.

In addition, there are a few more reports in which the formation of a halogen bond has been shown to improve the solubility and stability of reaction precursors (Figure 6).59,60

N I O

S O t

Bu

Ts

N I

Ts

OMe

N I

Ts

O R

(Protasiewicz et al.) (Woodward et al.) (Zhdankin et al.)

N I

PG

n OMe PG = COCF3, SO2R' (Takemoto et al.)

Figure 6. Stabilization of reaction precursors through XB.

Finally, halogen bonding to Lewis basic centers of hydrogen-bond donors may enhance the Lewis acidity of the latter.61 This was realized in a proof-of-principle case by Takemoto et al. with a cooperative catalyst system consisting of a 2-iodobenzimidazolium salt as XB donor and Schreiner’s thiourea as HB catalyst.61a Coordination of the former to the sulfur atom of the latter enhanced its activity towards glycosyl trichloroacetimidates. Thereby this co-catalyst duo induced the direct coupling of various amides (including the asparagine residues of several peptides) with glycosyl trichloroacetimidates to give


47

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Page 48 of 124

several N-acylorthoamides along with the corresponding β-N-glycosides in good yields (Scheme 19).

In a subsequent report, the authors observed the reversal of anomeric selectivity of the N-glycoside product from β to α when the protecting group at the 2-position was changed from Ac to Bn and the solvent was changed from DCM to ether.61b XB-activation was effective in several solvents and among them n-butyl methyl ether significantly promoted α-selectivity.

(OR)n

R2 Ar OTf N H N I S N N H Ar R1

O

O m AcO O + R'' NH2 HN

(10 mol%)

(OR)n m



4 A MS, DCM, RT

O (OR)n O O

CCl3 mildly acidic catalysis

N H

R'' O

+

O

m AcO

H N

R'' O

Scheme 19. Thiourea/XB donor co-catalysis for direct N-glycofunctionalization of amides.

4. XB-ORGANOCATALYSIS THROUGH π-ACTIVATION

All examples of XB activation or catalysis described in section 2 fall into one of two categories: the XB donor either binds to a halide leaving group or – presumably - to the


48

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ACS Catalysis

lone pairs of an organic functional group like a carbonyl derivative. In crystal engineering and in biomolecular systems, however, halogen bonding to π-system has also been observed.62 A first example of its significance in catalysis was observed in a selective substrate recognition during the nitrilase-catalyzed synthesis of chlorophenylacetic acids.63a Very recently, Arai and coworkers have utilized this phenomenon for the first time in organocatalysis to achieve the homo- and cross-[4+2] cycloadditions of 2alkenylindoles (Scheme 20).63b Out of the several monodentate XB donors tested, the cationic imidazolidinium compound ((±)-18) was found to be the most active. The authors supported the postulated electrophilic activation of 2-alkenylindoles by C−I···π halogen bonds by experimental indications as well as by quantum-chemical calculations.

R2

R2

(±)-18 (2.55 mol%) N R1

+

N

CHCl3, RT

R1

N R1

N

R1

Ph

Ph

OTf N Me

Bn N R2

R2

R2

I N1 R


49

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Page 50 of 124

Scheme 20. [4+2] Cycloaddition reactions via 2-alkenylindole activation by a cationic XB donor.

5. ASYMMETRIC CATALYSIS THROUGH HALOGEN BONDING

Chiral hydrogen-bond donors have by now been successfully employed in many enantioselective reactions.27c,64 Also, there are a few reports on chiral resolution or enantioselective recognition through halogen bonding.32a-b,65 However, there are only very few studies dealing with asymmetric catalysis using this interaction, and – in our opinion – a clear-cut proof-of-principle case for the realization of this concept seems still missing.

In 2012, our group prepared the first (bidentate) chiral XB catalyst, which was based on a bis(5-iodo-1,2,3-triazolium)benzene motif (35), but it did not yield any enantioselectivity.35a Subsequently, Kanger’s group reported several more complex chiral variants of this core structure (36-39) as well as a multifunctional iodotriazolium-based XB donor containing a HB-donating urea unit (40) (Figure 7).32a,32c Both types of compounds can be easily obtained through the click reaction of chiral azides. While the


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compounds were reasonably potent catalysts in benchmark reactions, they did not induce any noticeable asymmetric induction. In addition, as noted in the chapters above, in a few studies several monodentate chiral cationic XB donors based on imidazolinium (18),39 1,2,3-triazolium (22),41d 1,2,4-triazolium (24, 25)30 and bidentate imidazolinium (19)39 units were unsuccessfully employed as possible enantioselective catalysts. Next to the relatively weak strength of XB, there is a further aspect which renders enantioselective catalysis based purely on XB very difficult: the size of the halogen substituent X (typically iodine), the length of the corresponding covalent R-X bond in XB donors as well as the high directionality in R-X…LB interactions means that any chiral information in the backbone R will be placed quite far away from a potential substrate LB (= Lewis base). Thus, it is a formidable challenge to construct a suitable chiral pocket or to induce facial selectivity in prochiral substrates.


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N N N

N HN N

N I

N N

I

N I

O

35

N N

I

N

N N N

N I

N N

I

N

HN

NH 2 OTf

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CF3 F3C

O

MeO

N

N

OMe

37

2 OTf 36

CF3

CF3 O N

N

N N

I

I

OH

N N

N

N N N

I

I

HO 2 OTf

MeO

N H

N

N N Bn

4 OTf

N

N H

I N N

CF3 CF3

N OTf

39

38

O

CF3

40

Figure 7. Triazolium-based chiral XB donors.

An alternative approach is the combined use of XB with another interacting group, e.g. a Brønsted basic moiety, in a bifunctional catalyst system. In these cases, however, the assessment of the relevance of XB is much more difficult, particularly in cases in which the isolated XB moiety would not be catalytically active in a given reaction.

In 2014, Kee, Tan, and co-workers used halogenated pentanidium salts (41a) as phase transfer catalysts for the highly enantioselective alkylation of sulfenate anions to obtain


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various chiral sulfoxides (Figure 8).66 The involvement of multiple noncovalent interactions, including halogen bonding, has been postulated by computational studies.

t

R1 R1 N N

Ph Ph

N R

2

N Cl

Ph

2

Bu

2

41a: R = R =

Ph

N R

1

I t t

41b: R1 =

t

Bu

Bu

CF3

R2 =

Bu

CF3

Figure 8. Chiral pentanidium salts as phase-transfer catalysts.

In 2017, Arai and coworkers achieved moderate enantiomeric excesses in a Michael/Henry reaction of thiosalicyl aldehydes with nitroalkenes using bis(imidazolidine)based compound 42 (I-Bidine) as organocatalyst (Scheme 21).67 The role of XB in this reaction (and in the phase-transfer reaction mentioned above) is not entirely clear, as non-fluorinated iodobenzene derivatives typically do not form any reasonable XBs in solution.


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CHO + Ar SH

NO2

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OH

I-Bidine (10 mol%)

NO2

toluene, -40 °C

S

N

N

Ph

NH

Ar Ph

I

Ph

HN

42 (I-Bidine)

Ph

Scheme 21. Thiochromane synthesis using an XB-catalyzed asymmetric Michael/Henry reaction.

Later, the same group achieved excellent enantioselectivities in an asymmetric Mannich reaction between malononitrile and N-Boc imines using a quinidine-based chiral catalyst equipped with a neutral XB donor functionality (43) (Scheme 22).68 The authors postulated a mechanism involving XB and the action of the quinidine core based on NMR studies and due to the fact that the analogous non-iodinated analogue provided lower yield and enantioselectivity. While these finding is very noteworthy as indication for the active role of the iodine substituent, it will require further studies to elucidate whether this action is indeed based on halogen bonding or other (e.g. steric) effects.


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R

R

NC BocHN

NBoc

N

Boc

O CN O

N Me

N Me

R NC

43 (2 mol%)

CN

HN

1

Boc CN

43 (0.5 mol%)

R

1

CN





CHCl3, -50 C

CHCl3, -50 C

ee up to 98%

ee up to 85% N

N

O

I F

N H F OMe

F F

43

Scheme 22. Enantioselective Mannich reactions with a quinidine-based catalyst.

Recently an enantioconvergent substitution reaction of activated tertiary bromides by thiocarboxylates (or azides) was reported by the group of Tan.69 It was catalyzed by one of the above-mentioned chiral pentanidium salts (41b) via a less common variant of SN2 reactions, the halogenophilic SN2(X) (Scheme 23). Activation of the tertiary bromides occurs through halogen bonding with thiocarboxylate salts, resulting in the generation of a carbanionic intermediate which forms an ion pair with the chiral cation of the catalyst. Thus, this mechanism involves only transient XB and the chirality transfer originates


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primarily from ion pairing which is reminiscent of ACDC (asymmetric counterion directed catalysis).

R1 R2

R1 X + Nu

R

3

R2

R1 X

R

Nu

3

R2

X R

Nu

3

XB-adduct

R1

R1 Nu

R2 R

3

R2

R3

chiral cation Nu X

ee up to 97%

Scheme 23. SN2(X) reaction with subsequent chirality transfer via ion pairing.

To conclude, so far there seems to be no report on the asymmetric catalysis of an organic reaction solely and unambiguously based on XB activation.

5. CHALLENGES AND OUTLOOK

In the last decades, halogen bonding has (re)emerged as an important noncovalent interaction, and this year marks the 10-year anniversary of the first postulation of XBbased catalysis.28 Particularly in the first reports on this concept, the focus of most studies was to rule out other modes of activations, particularly hidden acid catalysis. While this is


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sometimes difficult to realize, we feel that by now a significant enough number of cases have been reported in which the mode of action is very likely due to XB.29,31 In order to strongly support the involvement of halogen bonding in a particular organic reaction, the experimental evidences should ideally a) exclude a strong background reaction and autocatalytic effects, b) provide indications for the relevance of the halogen center (e.g. by comparison with a non-halogenated precursor or another suitable reference compound) and thus rule out other modes of activation by the XB donors (like anion- or counterion effects), as well as c) dismiss catalytic activity by potential impurities or decomposition products (like elemental halogens or acid traces).

In several cases, theoretical70 and experimental29 results indicated that XB-catalysis is at least competitive (and sometimes superior) with the corresponding HB catalysis reported in the literature. For instance, bidentate neutral XB donors were more active than a thiourea derivative in halide abstraction benchmark reactions.29 Thus, XB donors could in the mid- and long-term become viable alternatives to HB catalysts, at least for selected organic transformations. This is particularly true for multidentate XB donors, which


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provide many advantages over their monodentate analogues like superior binding strength and a more ordered and rigid adduct environment. The latter should in principle be beneficial for example in enantioselective transformations.

While studies on the mode of activation will continue to be important, the focus has recently also shifted towards other aspects. It is clearly necessary to apply XB catalysis in more challenging reactions (and reaction environments) than the ones used in early proof-of-principle cases. The successful application of XB donors in a complex glycosylation reaction45 (Scheme 9) and in water as solvent53b,65g (Scheme 16) provide first promising hints in this direction.

Furthermore, there is a need to develop novel XB donor motifs and innovative modes of activation. Examples of such studies comprise XB donors with sulfonyl-based backbones (Scheme 14a) and the activation of π-systems (section 3). Until now, most neutral XB donors are based on polyfluorinated iodobenzene derivatives and most cationic ones feature imidazolium or triazolium backbones. Generally, most donors contain sp2-hybridized carbons bound to the halogen substituents. Only few examples of


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XB catalysts based on sp-hybridized carbon moieties have been reported and also core structures featuring sp3-hybridized carbons are quite rare, despite the many possible structural variations which could arise from a tetrasubstituted (potentially asymmetric) carbon center.

The development of new XB donor motifs faces several challenges, though: currently, very few backbones are available to construct multidentate Lewis acids, and their synthesis is sometimes challenging. This seems particularly true for neutral polyfluorinated XB donors, which have some clear differences (advantages and disadvantages) compared to their cationic counterparts most notably with respect to solubility issues and XB donor strength. The strict geometric requirements of XB (especially its high directionality compared to HB) necessitates a very careful design of potential binding motifs. Also, the quest for ever-stronger XB donors often hits a natural limit: there is a fine line between a strong XB donor and a very reactive halogenation reagent, or in other words very strong XB donors are prone to decompose due to


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dehalogenation. This is comparable to hydrogen bonding, as an ever-stronger polarization of an O-H or N-H bond will at some point simply yield a strong Brønsted acid.

Finally, asymmetric catalysis purely or primarily based on XB still remains a challenge, for the reasons indicated in section 4.

Overall, the isolated effect of halogen bonding in solution has its limits and even multidentate pure XB donors will only be able to catalyze reactions which will benefit from a lowering of the activation barrier (or the shift of an equilibrium) by several kcal/mol. The last years have shown, however, that carefully designed XB donors may in the future become an established further tool in organocatalysis. For this vision to become reality, the applications of XB in synthesis need to be put on a broader basis, the distinct advantages of XB need to be exploited more systematically, and the interaction likely will need to be combined with other interactions in a cooperative fashion. There is no reason to assume that we have seen the best of XB catalysis already.

AUTHOR INFORMATION


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Corresponding Author * [email protected]

Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

ACKNOWLEDGMENT The authors thankfully acknowledge financial support from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant Agreement No. 638337) and from the Fonds der Chemischen Industrie (Dozentenstipendium to S.M.H.).

ABBREVIATIONS XB: halogen bonding; HB: hydrogen bonding; LB: Lewis base; LG: leaving group. REFERENCES


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=

X Y

R I X=I

-activation

R X

R

XB donor

X = I, Br

R

Y R'

X

Y R' (Y = O, NR) Y

R'

X

Y

R'

=

I

R ,O

'2 NR  h

Page 92 of 124

-+ R + X Y R' Radical generation

X = I, Br R X Y + R' Y = Cl, Br Halide abstraction X= YR I(III ' = ) or R" ba se R X Y R'

Hypervalent/transient/Ion pairing

Electrophile activation


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Catalysis of organic reactions through halogen bonding | ACS Catalysis

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