Tetrahedron Letters 56 (2015) 877–883

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Tetrahedron Letters

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Digest Paper

Carbon–fluorine bond activation for the synthesis of functionalizedmolecules

http://dx.doi.org/10.1016/j.tetlet.2014.12.1450040-4039/� 2015 Published by Elsevier Ltd.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

⇑ Corresponding author. Tel.: +49 89 2180 77724; fax: +49 89 2180 77864.E-mail address: thomas.magauer@lmu.de (T. Magauer).

Teresa A. Unzner, Thomas Magauer ⇑Department of Chemistry and Pharmacy, Ludwig-Maximilians-University Munich, Butenandtstrasse 5-13, 81377 Munich, Germany

a r t i c l e i n f o

Article history:Received 15 October 2014Revised 11 December 2014Accepted 18 December 2014Available online 12 January 2015

Keywords:FluorineC–F bond activationCatalysisMedicinal chemistry

a b s t r a c t

The synthesis of fluorinated compounds as well as the use of these products as building blocks for thepreparation of complex molecules are fast growing research areas. Herein we highlight recent progressin the activation of allylic and benzylic C–F bonds for the synthesis of functionalized molecules. SN20 reac-tions of allylic difluoro and trifluoro compounds as well as transition-metal-catalyzed (nickel, palladium,platinum and copper) processes are described. The C–F bond activation of 3-fluoropropenes was achievedwith platinum- or organocatalysis. Benzylic C–F bond activation was realized with magnesium by depro-tonation leading to the formation of reactive quinone methide intermediates and with hydrogen bonddonors by forming strong F� � �H interactions.� 2015 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://

creativecommons.org/licenses/by-nc-nd/4.0/).

Contents

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 877Activation of allylic trifluoromethyl groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 878Activation of allylic difluoromethyl groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 878Activation of allylic fluorides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 880Activation of benzylic fluorides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 881Anionic activation of benzylic trifluoromethyl groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 881Hydrogen bond activation of benzylic fluorides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 882Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 883

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 883References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 883

Introduction

The incorporation of fluorine to organic molecules can dramat-ically alter the reactivity, chemical and biological properties, andphysiological activity. Fluorine can have a large influence on theacidity or basicity of functional groups by shifting the pKa valueby several orders of magnitude.1 It may also change the molecularconformation2 and generally increases the stability of hydrocar-bons.3 For instance, fluorine substituents have shown to affectthe metabolic stability, lipophilicity, and the binding affinity ofmany drugs.4 These unique properties that fluorine substitution

can achieve in pharmaceuticals, agrochemicals, and materials haveled to an increased interest in fluorine chemistry.5 It is thereforenot surprising that the synthesis of fluorine containing moleculesas well as the selective activation or cleavage of C–F bonds hasemerged as a lively research area.

Fluorine is the most electronegative element in the periodic tableand the C–F bond, which is the strongest bond in organic chemistry(CH3–F: 115 kcal mol�1; CH3–H bond: 105 kcal mol�1), is highlypolarized with the electron density being located on fluorine.6 Thus,the cleavage of C–F bonds often requires harsh reaction conditions.However, allylic and benzylic fluorides differ in that respect byhaving a lower activation barrier. For instance, geminal trifluoroallylic compounds react via a SN20 pathway with hard and softnucleophiles to form 3-substituted-1,1-difluoroalkenes under mild

Scheme 3. Proposed mechanism of the nickel(0) mediated synthesis of substitutedcyclopentadiene rings.

878 T. A. Unzner, T. Magauer / Tetrahedron Letters 56 (2015) 877–883

conditions.7 The high reactivity of trifluoromethylated alkenestoward nucleophiles results from the electron-withdrawingresonance effect (rR = 0.16) and the inductive effect (rI = 0.38) of atrifluoromethyl group attached to an alkene. The low LUMO of thedouble bond facilitates the nucleophilic attack. In 3,3-difluoroprop-enes (rI = 0.29, rR = 0.03) and 3-fluoropropenes (rI = 0.15, rR =�0.04) the inductive and resonance effects are less pronounced.8

Therefore, reactions of 3,3-difluoropropenes are restricted tometal-catalyzed reactions,9 the addition of soft nucleophiles (e.g.,organocopper and organoaluminum reagents),10 and reductionswith organocopper or aluminum reagents,11 samarium diiodide12

or N-heterocyclic carbenes.13 In this digest we will focus on recentadvances in allylic and benzylic C–F bond activation. A generalreview on C–F bond activation by Uneyama14 and reviews on aro-matic C–F bond activation by Perutz15 and Weaver16 are available.

Activation of allylic trifluoromethyl groups

Fuchibe et al. described a simple method for the construction offluorinated ring systems such as fluoropyrazoles using hydrazinesas bifunctional nucleophiles.17 The SN20 reaction of 2-trifluoro-methyl-1-alkenes 1 with hydrazines and sodium hydride or n-butyl lithium as the base gave 1,1-difluoro-1-alkenes 2 which werecyclized in an addition–elimination sequence (SNV reaction) to thecorresponding 3-fluoropyrazoles 3 in good to excellent yield(Scheme 1).

The group of Ichikawa18 reported the synthesis of substitutedcyclopentadienes via a nickel-mediated [3+2] cycloaddition. The

Scheme 1. Synthesis of 3-fluoropyrazoles 3 from 2-trifluoromethyl-1-alkenes 1and hydrazines.

Scheme 2. Nickel(0) mediated synthesis of substituted cyclopentadiene rings from2-trifluoromethyl-1-alkenes 4 and alkynes 5.

cyclopentadienes were obtained from the reaction of a-trifluorom-ethylstyrenes or tert-butyl a-trifluoromethylacrylate with sym-metrical and unsymmetrical alkynes (Scheme 2). It was proposedthat the reaction proceeds via double C–F bond activation of thetrifluoromethyl group. The suggested mechanism involves an oxi-dative cyclization of 2-trifluoromethyl-1-alkenes 4 and alkynes 5with a nickel(0) species. b-Fluorine elimination affords the alkenylnickel species 8 which can undergo a 5-endo insertion. The secondb-fluorine elimination then generates the 2-fluoro-1,3-cyclopent-adienes 6 (Scheme 3).

Activation of allylic difluoromethyl groups

In 2010, Paquin and co-workers19 developed a palladium-catalyzed allylic amination reaction of 3,3-difluoropropenes. AllylicC–F bond activation first leads to an intermediate palladium p-allylcomplex 12 (Scheme 4). Nucleophilic attack at the less stronglybound allylic site,20 and also more sterically accessible carbonatom, affords b-aminofluoroalkenes 11, which are importantnon-hydrolyzable peptide isosters.21 Cyclic and acyclic 3,3-difluro-propenes and various secondary amines could be employed in thereaction scope, including morpholine, pyrrolidine, diethylamine,and N-methylbenzylamine. Furthermore, unprotected 2-(methyl-amino)ethanol and amine hydrochloride salts could be used withthe standard reaction conditions. To circumvent the problem ofdialkylation when primary amines were employed, a large excess

Scheme 4. Palladium-catalyzed allylic amination of 3,3-difluoropropenes via C–Fbond activation.

FF F

RLiR (1.2 equiv)

THF, −78 to 66 °C

13 15

FF

14

LiR

s-Bu

n-Bu

FF

FPh

15a (71%) 15b (88%) 15c (90%)

F n-Bu

15d (74%) 15e (76%)

15f (87%)

MeO

n-BuF H

Me

Ph

S

S F

t-Bu

– LiF

Scheme 5. SN20 reaction of 3,3-difluoropropenes 13 with organolithium reagentspromoted by a putative C–F� � �Li+ interaction.

Scheme 7. Platinum-catalyzed amination reaction of (hetero)cyclic 3,3-difluoro-propenes 19.

Scheme 8. Defluorinative allylic alkylation reaction of difluorohomoallyl alcohols21 with trialkylaluminums.

Scheme 9. Copper-catalyzed allylic alkylation using Grignard reagents.

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of the amine was required to obtain the desired monoalkylatedproduct in good yield. It was found that aniline derivatives donot react under the reaction conditions.

Based on their previous results, Paquin and co-workers8 alsoreported the first example of an addition of hard nucleophiles to3,3-difluoropropenes (Scheme 5). Alkyllithium reagents, vinyllithi-um, phenyllithium, the lithium reagent derived from N-methylpyr-role, and even lithiated alkynes (which are less nucleophilic)underwent the SN20 reaction with 3,3-difluoropropenes. UsingLiAlH4 or LiEt3BH as the nucleophile, the reduced products couldbe obtained in good yields. A range of cyclic and acyclic 3,3-diflu-oropropenes could be used, and various functional groups includ-ing alcohols, carboxylic acids, Boc-protected amines, and arylchlorides, are tolerated. The SN20 reaction of organolithiumreagents is promoted by a putative C–F� � �Li+ interaction22 whichincreases the leaving group ability of a fluoride anion. Additionally,the generation of LiF23 might be the driving force for the elimina-tion of fluoride.

Paquin and co-workers24 further extended their methodologyto aniline derived lithium amides and sulfur-based nucleophiles.The synthesis of a variety of b-aminofluoroalkenes 17 and b-mer-captomonofluoroalkenes 18 was accomplished starting from thecorresponding lithium amides and thiolates (Scheme 6). However,this method could not be extended to O-based nucleophiles. A use-ful modification of the presented methodology is the possibility tosynthesize monofluoroalkenes bearing a primary amine. Withbenzophenone imine as a synthetic equivalent of ammonia, theprimary amine was obtained after acidic workup. In summary,they found that their palladium-catalyzed methodology was mostefficient with aliphatic amines, however, the addition of aromaticamines gave superior results when the corresponding lithiumamide derivative was employed.

Scheme 6. Allylic amination and thiolation of 3,3-difluoropropenes 16.

In 2014, the same group25 published a platinum-catalyzed ami-nation of cyclic 3,3-difluoropropenes 19 (Scheme 7) using cyclicsecondary amines, including morpholine, pyrrolidine or L-proline,and acyclic secondary amines. Primary amines or allylamine werenot compatible with the reaction conditions due to the inhibitionof the catalyst.

The group of Taguchi26 reported a defluorinative allylicalkylation reaction of difluorohomoallyl alcohols 21 with trialkyl-aluminum reagents, resulting in the formation of the correspond-ing (Z)-fluoroallyl alcohols 25. It is suggested that in the initialstep of the reaction the substrate forms an aluminum alkoxide spe-cies 22 with one equivalent of trialkylaluminum followed by C–Fbond activation via intramolecular coordination of one fluoride tothe aluminum. An additional equivalent of trialkylaluminum thenserves as the nucleophile (Scheme 8).

Taguchi and co-workers27 also published a related transforma-tion where they employed Grignard reagents together with cata-lytic amounts of copper iodide in the allylic substitutionreactions (Scheme 9). The reactions were found to be highlyZ-selective and the products could be obtained in high yields.The advantage of this method compared to the previouslydescribed one is the commercial availability and stability ofnumerous Grignard reagents compared to the aluminum reagents.

Scheme 11. Allylic alkylation of 3-alkylated 3,3-difluoropropenes having a freehydroxyl group with Grignard reagents.

Scheme 12. Benchmark reaction for the determination of the relative reactivity ofanionic leaving groups in the platinum-catalyzed allylic alkylation reaction.

Scheme 13. Platinum-catalyzed reaction of various nucleophiles with styrene 37.

Scheme 14. Kinetic resolution of allyl fluorides by catalytic asymmetric trifluo-romethylation catalyzed by (DHQD)2PHAL.

Scheme 15. Mechanism of the kinetic resolution of allyl fluorides by catalyticasymmetric trifluoromethylation.

Scheme 10. Allylic alkylation activated by an electron-withdrawing phenylsulfonylgroup at the 2-position of the 3-alkylated 3,3-difluoropropenes 28.

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To increase the electrophilicity of the terminal olefin carbon,Hong et al.28 installed an electron-withdrawing phenylsulfonylgroup at the 2-position of the 3-alkylated 3,3-difluoropropenes(Scheme 10) and thus developed a strategy for the nucleophilicaddition on 3,3-difluoropropenes. Sodium alkoxides, sodiumphenoxides, sodium thiolates, and neutral amines (instead of lith-ium amides) as well as various Grignard reagents were effectivenucleophiles under these mild reaction conditions. In contrast tothe method described by Paquin and co-workers, organolithiumreagents were not tolerated, due to their high reactivity even atlow temperatures.

Additionally, the non-protected homoallyl alcohol 32 could beconverted to the corresponding fluoroallyl alcohol 33 when 2 equivof the Grignard reagent were used (Scheme 11).

Activation of allylic fluorides

For 3-fluoropropenes inductive and resonance effects are lessdistinct and therefore, nucleophilic reactions are rare. In 2012, Gou-verneur and co-workers29 reported a platinum-catalyzed allylicalkylation with fluoride as the leaving group (Scheme 12). Theyfound that for the platinum-catalyzed reaction the relative reactiv-ity of the anionic leaving groups is F P OCO2Me� OBz P OAc. Incontrast, when a palladium catalyst was employed in the analogousreaction, a different reactivity order of the anionic leaving groupwas found: OCO2Me > OBz� F� OAc.9d Furthermore, the selectiv-ity for retention of the configuration was observed to be superior inthe platinum-catalyzed system.

To highlight the practicality of the aforementioned transforma-tion, the reactivity of styrene 37 toward nucleophiles was investi-gated (Scheme 13). Various C-, N-, and O-nucleophiles underwentthe allylic alkykation under standard conditions in good yields.29

Nishimine et al.30 reported the kinetic resolution of allyl fluo-rides by catalytic asymmetric trifluoromethylation (Scheme 14).The reaction is catalyzed by (DHQD)2PHAL (41) and provides theallyl fluorides and trifluoromethylated products in high enantio-meric excess (87–96%). The presence of methyl, methoxy, chloro,

and bromo substituents on the aromatic ring were tolerated. Theopposite stereochemical outcome was observed using (DHQ)2PYRas catalyst. The C–F bond in this transformation is presumably acti-vated by coordination of the fluoride atom to the silicon atom ofthe Ruppert–Prakash reagent (Me3SiCF3) as shown in Scheme 15.

Scheme 19. Synthesis of rotameric 9-arylacridines via an anionically activatedbenzylic CF3 group.

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Activation of benzylic fluorides

Several methodologies involving magnesium metal to activateC–F bonds have been reported in the literature.31 In 2013, Uney-ama and co-workers32 established a Mg/CuCl/TMSCl system inDMI (1,3-dimethyl-2-imidazolidinone) for the reductivedefluorination of electron-deficient benzotrifluorides 44 to thecorresponding difluoro(trimethylsilyl)-methylarenes 45 or fluoro(bistrimethylsilyl)methylarenes 46 (Scheme 16). It was hypothe-sized that the activating effect of CuCl was due to generation ofcopper(0) on the magnesium surface. Two electrons are transferredto the substrate which releases a fluoride ion and the anion istrapped with TMS-Cl to produce difluoro(trimethylsilyl)-methyla-renes. These products are valuable CF2 building blocks.

The group of Gouverneur developed a method for thepalladium-catalyzed benzylic C–F substitution with a Pd(allyl)COD�BF4–DPEPhos catalyst system.33 The reaction conditions toleratebenzylic fluorides containing p-phenyl, p-nitro, p-chloro, and p-bromosubstituents and a range of C-, N-, O-, and S-nucleophiles could beapplied (Scheme 17). The reaction protocol could also be used in athe Miyaura–Suzuki coupling of 2-(fluoromethyl)naphthalene 51using 2 equiv of phenylboronic acid in the presence of K3PO4

(Scheme 18).

Anionic activation of benzylic trifluoromethyl groups

The application of an anionically activated benzylic trifluoro-methyl group for the synthesis of aromatic and heteroaromaticcompounds was intensively investigated by Kiselyov and Strekow-ski.34 The intermediate gem-difluoroalkenes formed by deprotona-tion are highly reactive toward nucleophilic attack at thefluorinated sp2-carbon. Strekowski and co-workers35 applied thisstrategy for the synthesis of rotameric 9-arylacridines. Reacting asolution of 2-(trifluoromethyl)aniline (53) in tetrahydrofuran withthe Grignard reagents derived from 1-bromo-2-ethylbenzene or

Scheme 17. Palladium-catalyzed benzylic C–F substitution.

Scheme 18. Miyaura–Suzuki coupling of 2-(fluoromethyl)naphthalene 51 withphenylboronic acid.

Scheme 16. Defluorinative silylation of substituted benzotrifluorides 44 in DMI.

1-bromo-2,6-dimethylbenzene, under refluxing conditions, gaverise to the corresponding acridines 55 and 57 in 66% and 35% yield,respectively (Scheme 19).

The proposed mechanism is depicted in Scheme 20. In the firststep a quinone methide intermediate 58 is generated which reactswith a second equivalent of the Grignard reagent to form 59. In asimilar sequence via another quinone methide intermediate 60,the diaryl-substituted compound 61 is formed. A 6p-electrocycli-zation and concomitant formal elimination of methylmagnesiumbromide leads to the final product.

Furthermore, Strekowski and co-workers described the synthe-sis of acridine derivatives from 2-(perfluoralkyl)aniline 64.36 In linewith the previously described mechanism, the formation ofperfluoroalkylated acridines is accompanied by the loss of theortho-methyl group of the arylmagnesium bromide (Scheme 21).

Scheme 20. Mechanism of the synthesis of acridines from 2-(trifluoromethyl)ani-line (53) and Grignard reagents.

Scheme 21. Synthesis of perfluoroalkylated acridines from 2-(perfluoralkyl)aniline64.

Scheme 24. Proposed reaction mechanism for the formation of 5-fluoronaphtha-len-1-ols.

Scheme 25. C–F activation by hydrogen bonding with water molecules innucleophilic substitution reactions.

Scheme 22. Transformation of 2-allyl-3-(trifluoromethyl)phenols (67) to 5-fluor-onaphthalen-1-ols (68).

Scheme 23. One-pot synthesis of 68a from 69.

Scheme 26. C–F activation using commercially available 1,1,1-tris(hydroxy-methyl)propane (80) as hydrogen bond donor.

882 T. A. Unzner, T. Magauer / Tetrahedron Letters 56 (2015) 877–883

The Magauer group developed a synthesis of 5-fluoronaphtha-len-1-ols from readily available 2-allyl-3-(trifluoromethyl)phenols67.37 Using the optimized reaction conditions (5 equiv KOt-Bu, 1 MDMSO, 120 �C), numerous di-, tri-, and tetra-substituted fluoro-naphthols could be synthesized (Scheme 22). Both electron-richand electron-poor substrates underwent the described

transformation. Halogen substituents (Cl, F), ethers (OCH3, SCH3),amides (CONEt2), and acids (COOH) were tolerated, while estersand nitro functional groups were found to be unstable under thereaction conditions.

The procedure was further optimized and, finally, a one-potprotocol where sulfolane emerged as the solvent of choice wasdeveloped. Notably, it was found that combining the standard con-ditions of the individual steps (allylation, Claisen-rearrangement,cyclization reaction) in a one-pot procedure did not afford theexpected product. Instead, a 5-exo cyclization of the free phenolonto the adjacent allyl group occurred, giving rise to the corre-sponding dihydrobenzofuran. However, careful analysis of theone-pot protocol revealed that exchanging potassium carbonatefor diisopropylethylamine in the allylation step, allowed the prep-aration of 68a in 24% yield (Scheme 23).

The free phenol plays a crucial role for the cyclization reaction.It is hypothesized that coordination of the potassium phenoxide tothe double bond and activation of the trifluoromethyl group facil-itates the reaction. The assumed reaction pathway is depicted inScheme 24. In the initial step, the isomerization of 72 by KOt-Buto its more stable vinyl isomer 73 was observed, leading to anequilibrium between 72 and 73. Elimination of a fluoride anion,which is promoted by an attractive C–F� � �K+ interaction, then gen-erates the quinone methide intermediate 74 that contains a highlyreactive gem-difluorohexatriene motif. Subsequent 6p-electrocyc-lization and rearomatization by loss of a second fluoride leads tothe observed product 68. The C–F bond activation is believed toresult from a beneficial C–F� � �K+ interaction which might increaseability of fluoride to act as the leaving-group.

Hydrogen bond activation of benzylic fluorides

In 2013, Paquin and co-workers38 reported a C–F activationmediated by hydrogen bonding with water molecules. Employingwater as co-solvent and hydrogen bond donor, the reaction of ben-zylic fluorides with a number of N-, O-, S-, and C-nucleophilescould be accomplished (Scheme 25). Results of DFT calculationssuggested that the activation of the C–F bond is facilitatedthrough the stabilization of the transition state by strong F� � �H2O

T. A. Unzner, T. Magauer / Tetrahedron Letters 56 (2015) 877–883 883

interaction. It was shown that the best activating effect is achievedby a triad of water molecules aligned in a distinct geometry aroundthe fluoride. The C–F activation could be optimized using commer-cially available 1,1,1-tris(hydroxymethyl)propane (80) as thehydrogen bond donor (Scheme 26), where the three donatingmoieties are covalently linked together.39 This strategy allows ametal-free C–F bond activation method mediated by hydrogenbond donating small molecules.

Conclusion

In conclusion, recent progress in the C–F bond activation ofallylic and benzylic fluorides was highlighted. Due to the impor-tance of fluorine substituents in medicinal chemistry, much effortwas put into the development of novel methods for the synthesisof fluorinated molecules. For the activation of the C–F bond transi-tion-metal-mediated processes as well as SN20 reactions with awide range of nucleophiles are predominant. Benzylic trifluoro-methyl groups could be anionically activated by deprotonation toform reactive quinone methide intermediates. Mediated by hydro-gen bond donors, benzylic fluorides were successfully activatedtoo. Despite the recent progress, the development of general strat-egies for the selective activation of less activated C–F bonds or theapplication of fluorinated building blocks for the synthesis ofcomplex molecules remain challenging research areas. Furtherprogress will allow us to regard formerly inert C–F units as valu-able functional groups in the future.

Acknowledgments

We gratefully acknowledge financial support from the Fondsder Chemischen Industrie, the Deutsche Forschungsgemeinschaft(Emmy-Noether Fellowship to T. M.) and Prof. Dirk Trauner. Wethank M.Sc. Adriana Grossmann, M.Sc. Cedric Hugelshofer andM.Sc. Tatjana Huber for helpful discussions during the preparationof this manuscript.

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