Absolute Configurations of Topologically Chiral [2]Catenanes and the

Letter Cite This: Org. Lett. 2019, 21, 5708−5712

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Absolute Configurations of Topologically Chiral [2]Catenanes and the Acid/Base-Flippable Directions of Their Optical Rotations Tzu-Yi Tai,† Yi-Hung Liu,† Chien-Chen Lai,‡ Shie-Ming Peng,† and Sheng-Hsien Chiu*,† †

Department of Chemistry, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan, R.O.C. Institute of Molecular Biology, National Chung Hsing University, Taichung City 402, Taiwan, R.O.C.

‡

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S Supporting Information *

ABSTRACT: The absolute configurations of the two enantiomers of a topologically chiral [2]catenane were determined unambiguously based on HPLC resolution and X-ray crystal analysis. Although structurally dissimilar to simple amino acids, the optical rotations of these separated [2]catenanes share the Clough−Lutz−Jirgensons behavior of amino acids: the optical rotation flips direction in the presence of acid and base, the first example of such behavior for a mechanically interlocked topologically chiral catenane.

T

been useful techniques for probing the configurations of classical chiral compounds;9 their application to mechanically interlocked chiral molecules, however, remains unexplored, not to mention a lack of general rules for predicting the signs (or magnitudes) of their optical rotations (ORs) based solely on their molecular structures. Accordingly, for topologically chiral [2]catenanes (i.e., those lacking any classical chiral units), although some of their enantiomers have been separated using chiral HPLC,9b,10 their absolute stereochemistries remain difficult to determine without obtaining single crystals suitable for X-ray crystallographic analysis. Although not common, ORs can serve as optical outputs that report external stimuli, such as changes in solvent polarity,11 pH,12 and the presence or nature of anions.13 In most of the previously reported cases, however, the elegantly designed (macro)molecules displaying such behavior have featured at least one classical chiral unit, with the OR flipping being rationalized through the formation of new preferential rotational conformers12a,14 or helical conformations.11,12b,c,13 Interestingly, simple amino acids display inherent OR flipping upon acidification; the resulting empirical Clough−Lutz− Jirgensons (CLJ) rule states that the OR of an amino acid in the L (or D) configuration will become more positive (or negative) upon acidification.15 The CLJ rule has proven to be practically useful for the preliminary assignment of absolute configurations of chiral amino acid derivatives.16 An interesting question arises: can a similar CLJ-type effect be observed in topologically chiral catenanes?17 Herein, we report the synthesis of a topologically chiral [2]catenane and the assignment, based on chiral HPLC and X-ray crystallographic structural analysis, of the absolute configurations of its two enantiomers. We also reveal that the optical rotations of the

he construction of chiral [2]rotaxanes and [2]catenanes has drawn increasing attention for the possibility of their switchable coconformers1 leading to innovative applications in enantioselective sensing2 and asymmetric catalysis.3 The most straightforward approach toward generating chiral [2]catenanes is to attach a classical chiral unit (e.g., a 1,1′-bi-2naphthol moiety) onto one or both of the interlocked macrocyclic components.4 Perhaps less intuitively obvious, however, is that topologically chiral [2]catenanes can be generated by interlocking two achiral, but directional, macrocycles together (Figure 1) because flipping the molecular plane

Figure 1. Topological chirality generated from two directional macrocycles interlocked in the form of a [2]catenane.

of one macrocycle against that of the other is structurally prohibited when their rings are interlocked.4,5 The past three decades have witnessed many syntheses of organic [2]catenanes, but only a few of these molecules have possessed topological chirality.6 The covalent linking of classical chiral units to topologically chiral [2]catenanes can be used to aid their resolution and the elucidation of their absolute configurations. 7 Using a chiral auxiliary, it has been demonstrated recently that topologically chiral [2]catenanes, with only the mechanical bond inducing the stereogenic unit, could be obtained without the need for separation through chiral high-performance liquid chromatography (HPLC).8 Electronic and vibrational circular dichroism (CD) have © 2019 American Chemical Society

Received: June 15, 2019 Published: July 8, 2019 5708

DOI: 10.1021/acs.orglett.9b02062 Org. Lett. 2019, 21, 5708−5712

Letter

Organic Letters two [2]catenane enantiomers can be flipped reversibly from positive (or negative) to negative (or positive), and vice versa, over several cycles of the sequential addition of acid and base to protonate/deprotonate their amine/ammonium functionalities. After we heated a 2.2:1 mixture of the amine 2 (see the Supporting Information for its synthesis) and sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaTFPB) in CDCl3 at 323 K for 64 h, the 1H NMR spectrum displayed significantly upfield-shifted signals for the diethylene glycol units, from approximately δ 3.62 to both δ 2.50 and 2.95, suggesting the formation of corresponding Na+-templated imino-[2]catenanes.18 Subsequent NaBH4-mediated reduction of this equilibrated solution afforded the [2]catenane 1 in a yield of 45% (Figure 2). Because the macrocyclic components

reported to enhance the HPLC resolution of chiral amines;19 accordingly, we converted the racemic [2]catenane 1 to the racemic [2]catenane 3 by reacting it with CbzCl under basic conditions (Scheme 2). Scheme 2. Sequence of Protection, HPLC Separation, and Deprotection Used for Chiral Resolution of the [2]Catenane 1

Figure 3a reveals that we could now separate the two enantiomers of the topologically chiral [2]catenane 3,

Figure 2. 1H NMR spectra (CDCl3, 400 MHz, 298 K) of (a) the amine 2 (20 mM); (b−d) the solutions obtained after the addition of NaTFPB (9 mM) to the solution in (a) and heating at 323 K for (b) 0, (c) 3, and (d) 64 h, and (e) the purified [2]catenane 1.

of the [2]catenane 1 each possess directionality, this interlocked molecule was a racemic mixture of topologically chiral [2]catenanes: (S)-1 and (R)-1 (Scheme 1). Scheme 1. Synthesis of the Topologically Chiral [2]Catenane 1

Figure 3. (a) Chiral HPLC analysis [column, Chiralpak IF 5 μm; eluent, 0.1% diethylamine in EtOAc/hexane (4:6); flow rate, 5 mL/ min; detection, 254 nm] of the racemic [2]catenane 3. (b) CD spectra (0.3 mM, CH3CN) of 3a (red line) and 3b (blue line).

Presumably because the [2]catenanes (S)-1 and (R)-1 did not interact appreciably differently with the chiral stationary phases of HPLC columns, we could not separate the two enantiomeric forms sufficiently well for effective resolution under any of the conditions we tested. The protection of amino groups with carbobenzyloxy (Cbz) units has been

temporarily assigned as 3a (“ahead”) and 3b (“behind”) based on their order of HPLC elution. Relatively inverted CD absorption spectra supported the enantiomeric relationship of the two HPLC fractions (Figure 3b). Next, we removed the Cbz groups from each resolved enantiomer of the [2]catenane 3 through hydrogenation (NaBH4/Pd/C), affording two 5709


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would flip its OR signal in the opposite direction, similar to the phenomenon observed for simple amino acids. To demonstrate the switching of the OR direction, we took a cylindrical cell (3.5 mm × 100 mm) containing a THF solution (5 mg/mL) of the [2]catenane (R)-1 (giving a specific rotation of +2.0) and added 2 equiv of trifluoroacetic acid (TFA): the value of [α]D of the solution immediately switched to −14.6 (Figure 5). Addition of 2 equiv of 1,8-

enantiomerically pure [2]catenanes, labeled 1a and 1b based on the order of elution of their Cbz-protected precursors. We measured the ORs of the chiral [2]catenanes 1a and 1b in toluene and THF at 293 K; the direction of the specific rotation ([α]D) of the former was levorotatory, and the latter dextrorotatory, in both solvents (Table 1). The inverse specific Table 1. Specific Rotations ([α]D) of the Enantiomers of the [2]Catenanes 1, 3, and 1-2H·2Cl in Various Solvents at 293 K HPLC fractiona 1st (ahead)

2nd (behind)

[2]catenane

CH3CN

toluene

THF

(S)-3 (S)-1 (S)-1-2H·2Cl (R)-3 (R)-1 (R)-1-2H·2Cl

−20.2 b b +20.4 b b

−12.0 −4.0 b +12.0 +3.9 b

−15.2 −2.0 +9.5 +15.4 +2.0 −9.6

a Column: Chiralpak IF 5 μm; eluent: 0.1% diethylamine in EtOAc/ hexane (4:6); flow rate: 5 mL/min; detection: 254 nm. bNot determined because of the low solubility of the [2]catenane.

rotations of 1a and 1b in the common solvents confirmed their enantiomeric relationship. Although OR data allowed us to correlate 1a and 1b with (−)-1 and (+)-1, respectively, their absolute configurations remained unknown. X-ray structural analysis of a single crystal grown from diffusion of hexane into a CH2Cl2 solution of 1a at 276 K revealed the interlocked nature of its two directional amine-containing macrocyclic components; we determined the absolute configuration to be the (S)-form {Figure 4; Flack parameter = [0.06(4)]}.20,21

Figure 5. Cycles of acid (TFA)-/base (DBU)-operated OR switching of the chiral [2]catenanes (R)-1 (blue) and (S)-1 (red).

diazabicyclo[5.4.0]undec-7-ene (DBU) to the latter solution regenerated the original amino form of the [2]catenane (see the SI for stacked 1H NMR spectra); the value of [α]D of the solution returned to +2.0. Although the following two acid/ base addition cycles also resulted in the same switching of the OR direction, the magnitude of the specific rotation of [(R)-12H]2+ (i.e., after acid addition) after each cycle decreased continuously, while those of neutral (R)-1 (i.e., after base addition) remained nearly identical. Chirality transfer and amplification from chiral solutes to achiral solvents through the formation of hydrogen-bonded solvent shells, has been demonstrated previously;15a,22 we suspect that the significantly larger OR of [(R)-1-2H]2+, relative to that of (R)-1, in THF may have arisen in part from the ammonium ion centers (with additional +NH units and superior hydrogen bond donating ability) inducing a more stable chiral solvent shell than that present around the amino form. We observed a similar decrease in the magnitude of the specific rotation (originally +14.5) of [(S)-1-2H]2+, but with opposite direction, when using acid and base to protonate and deprotonate the [2]catenanes (S)-1 and [(S)-1-2H]2+, respectively, over three cycles (Figure 5).23 The continuous decrease in the magnitude of the OR after each switching cycle in THF was likely due to the accumulation of DBU-TFA salts in solution, disturbing or weakening the strength of the hydrogen bonds formed between the chiral ammonium [2]catenanes and the THF solvent shell. Consistent with this assumption, gradual addition of pyridinium trifluoroacetate (Py·TFA) to a 1:2 mixture of (R)-1 and TFA in THF (i.e., forming [(R)-1-2H][2TFA] in situ) led to the OR of the solution gradually approaching zero (initially −14.6, Figure S4). Thus, the accumulation of DBUTFA salts most likely played an important role in decreasing the magnitude of the OR of [(R)-1-2H]2+ upon continuous switching. We have used HPLC to resolve the two enantiomers of the topologically chiral [2]catenane 1 and then used X-ray crystallography to assign their absolute configurations. The chiral [2]catenanes (R)- and (S)-1 represent the first observed

Figure 4. X-ray crystal structure of the enantiomerically pure [2]catenane [(S)-1]. Atom coloring: C, gray; H, white; O, red; N, blue.

Thus, we could unambiguously assign the absolute configurations of 1a [i.e., (−)-1] and 1b [i.e., (+)-1] to (S) and (R), respectively. To the best of our knowledge, Figure 4 represents the first solid state structure of an enantiomerically pure topologically chiral [2]catenane with no classical chiral units present in the structure and, thus, allowed the first pair of enantiomers to be assigned unambiguously in terms of absolute configurations, without involving classical chiral units in the synthetic precursors. Unlike the enantiomerically pure [2]catenanes 3a [i.e., (S)3] and 3b [i.e., (R)-3] that rotated plane-polarized light in the same direction as (S)-1 and (R)-1, respectively, the salts (S)and (R)-1-2H·2Cl, which are poorly soluble in CH3CN and toluene, rotate plane-polarized light in directions opposite to those of their neutral forms in THF. This result suggested that addition of an acid to the chiral [2]catenane (S)-1 or (R)-1 5710


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Interlocking the catalyst: Thread versus rotaxane-mediated enantiodivergent Michael addition of ketones to β-nitrostyrene. Org. Lett. 2019, 21, 5192. (4) For recent comprehensive reviews of chiral rotaxanes and catenanes: (a) Evans, N. H. Chiral catenanes and rotaxanes: Fundamentals and emerging applications. Chem. - Eur. J. 2018, 24, 3101−3112. (b) Jamieson, E. M. G.; Modicom, F.; Goldup, S. M. Chirality in rotaxanes and catenanes. Chem. Soc. Rev. 2018, 47, 5266− 5311. (c) Pairault, N.; Niemeyer, J. Chiral mechanically interlocked molecules: Applications of rotaxanes, catenanes and molecular knots in stereoselective chemosensing and catalysis. Synlett 2018, 29, 689− 698. (5) Bruns, C. J.; Stoddart, J. F. The Nature of the Mechanical Bond: From Molecules to Machines; Wiley: Hoboken, NJ, 2016. (6) (a) Mitchell, D. K.; Sauvage, J.-P. A topologically chiral [2]catenand. Angew. Chem., Int. Ed. Engl. 1988, 27, 930−931. (b) Kaida, Y.; Okamoto, Y.; Chambron, J.-C.; Mitchell, D. K.; Sauvage, J.-P. The separation of optically active copper(I) catenates. Tetrahedron Lett. 1993, 34, 1019−1022. (c) Mohry, A.; Vögtle, F.; Nieger, M.; Hupfer, H. Regioselective template synthesis, X-ray structure, and chiroptical properties of a topologically chiral sulfonamide catenane. Chirality 2000, 12, 76−83. (d) Reuter, C.; Mohry, A.; Sobanski, A.; Vögtle, F. [1]Rotaxanes and pretzelanes: Synthesis, chirality, and absolute configuration. Chem. - Eur. J. 2000, 6, 1674−1682. (e) Loren, J. C.; Gantzel, P.; Linden, A.; Siegel, J. S. Synthesis of achiral and racemic catenanes based on terpyridine and a directionalized terpyridine mimic, pyridyl-phenanthroline. Org. Biomol. Chem. 2005, 3, 3105−3116. (7) (a) Chung, M. K.; White, P. S.; Lee, S. J.; Gagné, M. R. Synthesis of interlocked 56-membered rings by dynamic self-templating. Angew. Chem., Int. Ed. 2009, 48, 8683−8686. (b) Prakasam, T.; Lusi, M.; Nauha, E.; Olsen, J.-C.; Sy, M.; Platas-Iglesias, C.; Charbonnière, L. J.; Trabolsi, A. Dynamic stereoisomerization in inherently chiral bimetallic [2]catenanes. Chem. Commun. 2015, 51, 5840−5843. (8) Denis, M.; Lewis, J. E. M.; Modicom, F.; Goldup, S. M. An auxiliary approach for the stereoselective synthesis of topologically chiral catenanes. Chem. 2019, 5, 1512−1520. (9) (a) Berova, N.; Bari, L. D.; Pescitelli, G. Application of electronic circular dichroism in configurational and conformational analysis of organic compounds. Chem. Soc. Rev. 2007, 36, 914−931. (b) Lu, H.; Kobayashi, N. Optically active porphyrin and phthalocyanine systems. Chem. Rev. 2016, 116, 6184−6261. (10) Schalley, C. A.; Beizai, K.; Vögtle, F. On the way to rotaxanebased molecular motors: Studies in molecular mobility and topological chirality. Acc. Chem. Res. 2001, 34, 465−476. (11) (a) Langeveld-Voss, B. M. W.; Christiaans, M. P. T.; Janssen, R. A. J.; Meijer, E. W. Inversion of optical activity of chiral polythiophene aggregates by a change of solvent. Macromolecules 1998, 31, 6702− 6704. (b) Nagata, Y.; Yamada, T.; Adachi, T.; Akai, Y.; Yamamoto, T.; Suginome, M. Solvent-dependent switch of helical main-chain chirality in sergeants-and-soldiers-type poly(quinoxaline-2,3-diyl)s: Effect of the position and structures of the “sergeant” chiral units on the screw-sense induction. J. Am. Chem. Soc. 2013, 135, 10104− 10113. (12) (a) Guschlbauer, W.; Courtois, Y. pH induced changes in optical activity of guanine nucleosides. FEBS Lett. 1968, 1, 183−186. (b) Sanji, T.; Kato, N.; Tanaka, M. Induction of optical activity in an oligothiophene synchronized with pH-sensitive folding of amylose. Chem. - Asian J. 2008, 3, 46−50. (c) Lu, W.; Du, G.; Liu, K.; Jiang, L.; Ling, J.; Shen, Z. Chiroptical inversion induced by rotation of a carbon−carbon single bond: An experimental and theoretical study. J. Phys. Chem. A 2014, 118, 283−292. (13) Suk, J.-m.; Naidu, V. R.; Liu, X.; Lah, M. S.; Jeong, K.-S. A foldamer-based chiroptical molecular switch that displays complete inversion of the helical sense upon anion binding. J. Am. Chem. Soc. 2011, 133, 13938−13941. (14) Haghdani, S.; Hoff, B. H.; Koch, H.; Åstrand, P.-O. Solvent effects on optical rotation: On the balance between hydrogen bonding and shifts in dihedral angles. J. Phys. Chem. A 2017, 121, 4765−4777.

example of the enantiomers of a topologically chiral [2]catenane displaying acid-induced OR flipping (CLJ-like) behavior.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b02062. Synthetic procedures, characterization data, and NMR spectra of all new compounds (PDF) Accession Codes

CCDC 1918124 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Chien-Chen Lai: 0000-0002-7133-8266 Sheng-Hsien Chiu: 0000-0002-0040-1555 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the Ministry of Science and Technology (Taiwan) (MOST-107-2119-M-002-040) and National Taiwan University (NTU-108L880102) for financial support.

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REFERENCES

(1) For recent examples: (a) Corra, S.; de Vet, C.; Groppi, J.; La Rosa, M.; Silvi, S.; Baroncini, M.; Credi, A. Chemical on/off switching of mechanically planar chirality and chiral anion recognition in a [2]rotaxane molecular shuttle. J. Am. Chem. Soc. 2019, 141, 9129− 9133. (b) Gell, C. E.; McArdle-Ismaguilov, T. A.; Evans, N. H. Modulating the expression of chirality in a mechanically chiral rotaxane. Chem. Commun. 2019, 55, 1576−1579. (2) (a) Kameta, N.; Nagawa, Y.; Karikomi, M.; Hiratani, K. Chiral sensing for amino acid derivative based on a [2]rotaxane composed of an asymmetric rotor and an asymmetric axle. Chem. Commun. 2006, 3714−3716. (b) Ishiwari, F.; Nakazono, K.; Koyama, Y.; Takata, T. Induction of single-handed helicity of polyacetylenes using mechanically chiral rotaxanes as chiral sources. Angew. Chem., Int. Ed. 2017, 56, 14858−14862. (c) Lim, J. Y. C.; Marques, I.; Félix, V.; Beer, P. D. A chiral halogen-bonding [3]rotaxane for the recognition and sensing of biologically relevant dicarboxylate anions. Angew. Chem., Int. Ed. 2018, 57, 584−588. (3) (a) Tachibana, Y.; Kihara, N.; Takata, T. Asymmetric benzoin condensation catalyzed by chiral rotaxanes tethering a thiazolium salt moiety via the cooperation of the component: Can rotaxane be an effective reaction field? J. Am. Chem. Soc. 2004, 126, 3438−3439. (b) Cakmak, Y.; Erbas-Cakmak, S.; Leigh, D. A. Asymmetric catalysis with a mechanically point-chiral rotaxane. J. Am. Chem. Soc. 2016, 138, 1749−1751. (c) Mitra, R.; Zhu, H.; Grimme, S.; Niemeyer, J. Functional mechanically interlocked molecules: asymmetric organocatalysis with a catenated bifunctional Brønsted acid. Angew. Chem., Int. Ed. 2017, 56, 11456−11459. (d) Martinez-Cuezva, A.; MarinLuna, M.; Alonso, D. A.; Ros-Ñ iguez, D.; Alajarin, M.; Berna, J. 5711


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Organic Letters (15) (a) Autschbach, J.; Nitsch-Velasquez, L.; Rudolph, M. Timedependent density functional response theory for electronic chiroptical properties of chiral molecules. Top. Curr. Chem. 2011, 298, 1−98. (b) Simpson, S.; Izydorczak, A. M. Investigating the Clough, Lutz, and Jirgensons rule for the pH dependence of optical rotation of amino acids. J. Chem. Educ. 2018, 95, 1872−1874. (16) The CLJ behavior is rationalized by considering the opposite CD signs of the lowest-lying excitation in carboxylate and carboxylic acid functionalities after protonation: (a) Kundrat, M. D.; Autschbach, J. Computational modeling of the optical rotation of amino acids: A new look at an old rule for pH dependence of optical rotation. J. Am. Chem. Soc. 2008, 130, 4404−4414. (b) NitschVelasquez, L.; Autschbach, J. Toward a generalization of the Clough− Lutz−Jirgensons effect: Chiral organic acids with alkyl, hydroxyl, and halogen substituents. Chirality 2010, 22, E81−E95. (17) Switching of the CD signals of chiral [2]rotaxanes through the application of external stimuli (e.g., light, protons, or metal ions) had been achieved: (a) Bottari, G.; Leigh, D. A.; Pérez, E. M. Chiroptical switching in a bistable molecular shuttle. J. Am. Chem. Soc. 2003, 125, 13360−13361. (b) Nakatani, Y.; Furusho, Y.; Yashima, E. Amidinium carboxylate salt bridges as a recognition motif for mechanically interlocked molecules: Synthesis of an optically active [2]catenane and control of its structure. Angew. Chem., Int. Ed. 2010, 49, 5463− 5467. (c) Bordoli, R. J.; Goldup, S. M. An efficient approach to mechanically planar chiral rotaxanes. J. Am. Chem. Soc. 2014, 136, 4817−4820. (18) (a) Tung, S.-T.; Lai, C.-C.; Liu, Y.-H.; Peng, S.-M.; Chiu, S.-H. Synthesis of a [2]catenane from the sodium ion templated orthogonal arrangement of two diethylene glycol chains. Angew. Chem., Int. Ed. 2013, 52, 13269−13272. (b) Inthasot, A.; Tung, S.-T.; Chiu, S.-H. Using alkali metal ions to template the synthesis of interlocked molecules. Acc. Chem. Res. 2018, 51, 1324−1337. (19) Kraml, C. M.; Zhou, D.; Byrne, N.; McConnell, O. Enhanced chromatographic resolution of amine enantiomers as carbobenzyloxy derivatives in high-performance liquid chromatography and supercritical fluid chromatography. J. Chromatogr. A 2005, 1100, 108−115. (20) (a) Flack, H. D. On enantiomorph-polarity estimation. Acta Crystallogr., Sect. A: Found. Crystallogr. 1983, A39, 876−881. (b) Parsons, S. Determination of absolute configuration using X-ray diffraction. Tetrahedron: Asymmetry 2017, 28, 1304−1313. (21) A few methods have been proposed in the literature (see refs 4b,5,6c,d for assigning the stereochemistry of topologically chiral [2] catenanes. Here, we used the method described in refs 4b,8 to assign the absolute configuration of 1a: For the two interlocked macrocycles in the solid state structure of the [2]catenane 1a (Figure 4), the highest-priority atom is the central oxygen atom of the diethylene glycol motif. Among the two carbon atoms adjacent to that oxygen atom, the one that is closest to the oxygen atom linked to the m-xylyl unit (i.e., further away from the nitrogen atom) has higher priority. Thus, the direction of the two interlocked rings can be determined, and we assigned the absolute configuration of the [2]catenane 1a to be (S). (22) (a) Osipov, M. A.; Pickup, B. T.; Dunmur, D. A. A new twist to molecular chirality: Intrinsic chirality indices. Mol. Phys. 1995, 84, 1193−1206. (b) Wang, S.; Cann, N. M. A molecular dynamics study of chirality transfer: The impact of a chiral solute on an achiral solvent. J. Chem. Phys. 2008, 129, 054507. (23) For now, it is unclear to us why the chiral amino/ammonium pairs of [2]catenanes have opposite OR directions. High-accuracy computational modeling of the OR of amino acids (ref 16) required the identification of every energetically accessible conformer and their relative populations because the chiroptical response of the molecule is the weighted average of all the possible conformations. Similar analysis of the [2]catenane 1, which is more sizable and flexible in its structure when compared with a simple amino acid, appears challenging, and we believe it would be better studied by experts in that field.

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Absolute Configurations of Topologically Chiral [2]Catenanes and the

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