Mixed Macrocycles Derived from 2,6-Diformylpyridine and Opposite

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Mixed macrocycles derived from 2,6-diformylpyridine and opposite enantiomers of trans-1,2diaminocyclopentane and trans-1,2-diaminocyclohexane. Rafa# Frydrych, Katarzyna #lepokura, Andrzej Bil, and Janusz Gregoli#ski J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00614 • Publication Date (Web): 09 Apr 2019 Downloaded from http://pubs.acs.org on April 10, 2019

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The Journal of Organic Chemistry

Mixed macrocycles derived from 2,6-diformylpyridine and opposite enantiomers of trans-1,2-diaminocyclopentane and trans-1,2-diaminocyclohexane. Rafał Frydrych, Katarzyna Ślepokura, Andrzej Bil and Janusz Gregoliński* Department of Chemistry, University of Wrocław, 14 F. Joliot-Curie, 50-383 Wrocław, Poland. *[email protected] Abstract The condensation reaction of 2,6-diformylpyridine with the equimolar mixture of opposite enantiomers of trans-1,2-diaminocyclopentane and trans-1,2-diaminocyclohexane using a dynamic combinatorial chemistry approach has been examined. In nonmetal-templated reactions, depending on reaction conditions mixed 2+1+1 macrocyclic imine or bigger mixed 4+2+2 imine macrocycle are formed selectively. The 2+1+1 imine used as a precursor in the templated by CdII ions produces a library of enlarged chiral mixed imines coordinated with metal cations among which the hexanuclear CdII complex of 6+3+3 imine was isolated and characterized. All macrocyclic imine compounds have been reduced to the corresponding macrocyclic amines which have been further transformed into their hydrochlorides. Each macrocyclic compound has been obtained as two enantiomers. For imine macrocycles and for the hydrochloride derivatives of macrocyclic amines their X-ray crystal structures have been determined. Especially, the crystals of protonated 4+2+2 macrocyclic amine which contains two types of diastereomeric cations differing in terms of inverted twists of pyridine moieties and hexanuclear CdII complex of 6+3+3 imine which gives a deeper insight into expansion reaction have been investigated. A heterochiral self-sorting of 2+2 and 2+1+1 macrocyclic imines has been confirmed by competition reaction of 2,6-diformylpyridine, racemic trans-1,2-diaminocyclopentane and racemic trans-1,2-diaminocyclohexane and theoretical calculations. Introduction Macrocycles belong to a multifunctional and significant category of compounds which are applied in selective binding of metal cations, a variety of anions or organic guest molecules, catalysis, sensing, mimicking biological systems, and designing of new materials.1 The synthesis of complicated and intricate macrocycles having big sizes is enticing for chemists looking for appealing design of a new molecule but it may also pose a formidable synthetic challenge. Not only have the typical macrocycles, such as crown ethers, calixarenes, cyclodextrines and various porphyrin compounds,2,3 been intensively investigated, other types of macrocycles also rivet continual attention. Among them unsymmetrical and mixed macrocycles constructed of amino and ether moieties, as well as rarely having only different amino groups can be given as an example.4 1 ACS Paragon Plus Environment

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Although the step-by-step synthesis of large macrocycles may constitute a perplexing problem, sometimes however, the large macrocyclic compounds can be easily received by the condensation of simple bifunctional building blocks. It is worth mentioning that macrocyclic Schiff bases and amines obtained in such a way from dicarbonyl compounds and chiral diamines have been investigated paying special attention to their chiral properties, metal binding ability, interactions with DNA, organic guest hosting, catalysis, and formation of porous materials.5 The condensation reaction of diamine and dicarbonyl precursors due to reversible formation of the imine bonds leads usually to a dynamic combinatorial library of compounds.6 In such a system apart from the variety of macrocyclic imines also linear oligomeric products are formed. By alteration of reaction conditions and/or by appropriate choice of a templating agent the distribution of products of this library and can be influenced and changed. As examples of such dynamic libraries may serve reactions in 2,6-diformylpyridine (DFP) / trans-1,2-diaminocyclohexane (DACH) and 2,6-diformylpyridine (DFP) / trans-1,2-diaminocyclopentane (DACP) systems. It was shown previously that, the condensation of DFP with racemic DACH, run in boiling methanol and in the absence of any templating agent, leads to 2+2 and 4+4 meso imine products IACH and IIACH (CH – cyclohexane)* of alternating RRSS and RRSSRRSS chiralities of diamine units (figure 1).7a The same reaction of DFP with a smaller homologue of DACH, i.e. racemic DACP, delivers exclusively the 2+2 Schiff base condensation product IACP (CP – cyclopentane)* having also characteristic meso structure.7b The meso 4+4 imine IIACP derived from racemic DACP can be obtained in the non-templated reaction performed in benzene.7b,c Both 2+2 meso imine macrocycles, IACP and IACH, treated with cadmium chloride in methanol/chloroform solvent mixture undergo the unusual expansion reaction into enlarged 6+6 meso Schiff bases IIIACP and IIIACH, respectively, but also bigger ones, coordinated with several cadmiumII ions.7b-d On the contrary, when the analogues templated by CdCl2 condensation is run directly from DFP and racemic diamine precursors (rac-DACP or rac-DACH) the main products are the cadmiumII complexes of racemic heterochiral 3+3 imine macrocycles of RRRRSS/SSSSRR chirality of their diamine moieties.7e,f N N (R)

n

N

N N

NH

n

(R)

N

N

(S)

m

(S)

(R)

IACP, n=0, m=1 IACH, n=1, m=1 IIACP, n=0, m=2 IIACH, n=1, m=2 IIIACP, n=0, m=3 IIIACH, n=1, m=3

n

HN

(S)

(R)

NH N

HN

m

n (S)

IBCP, n=0, m=1 IBCH, n=1, m=1 IIBCP, n=0, m=2 IIBCH, n=1, m=2 IIIBCP, n=0, m=3 IIIBCH, n=1, m=3

Figure 1*. Even meso imine (A) compounds received in the non-templated condensation of DFP with racDACP or rac- DACH. Respective amines (B) have been obtained by reduction of imines (A).

In aforementioned condensation reactions the most striking feature is the preference in formation of macrocyclic imines mainly the products of heterogenous chiralities, i.e. RRSS, 2 ACS Paragon Plus Environment

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RRRRSS/SSSSRR, RRSSRRSS and RRSSRRSSRRSS for 2+2, 3+3, 4+4 and 6+6 macrocycles, respectively. Although, it is worth mentioning that the homochiral racemic 2+2 imine coordination compounds of RRRR/SSSS chirality are formed in the templated by lanthanideIII ions condensation of rac-DACH as well as rac-DACP with DFP run in methanol.7g,h Some traces of 3+3 macrocycles of homogenous chirality RRRRRR/SSSSSS were also detected in the reaction of rac-DACH with DFP in the presence of CdCl2. These impurities contaminated the main product which was the racemic 3+3 heterochiral macrocycle of RRRRSS/SSSSRR chirality of DACH units.7f The condensations where the heterochiral macrocycles are the main (or only) products can serve as illustrations of heterochiral self-sorting of a racemic mixture as opposed to homochiral self-sorting examples presented by some literature.8 In addition to that the smaller chiral DACP is much less often employed in the syntheses than its more common DACH homologue. The subtle changes of geometric factors of DACP9a in comparison with those of DACH9b may provide the respective products of slightly different structures. These alterations in turn, may affect the chemical properties which can result in better enantioselective catalysts. In our paper we took advantage of heterochiral macrocycle formation in the DFP / racDACP7b,c and DFP / rac-DACH7a,d systems to prepare chiral mixed macrocycles in a similar fashion. We have combined these two systems and undertaken a systematic study on the reaction conditions of a dialdehyde (DFP) simultaneously with two different diamines, which have opposite chiralities ((RR)-DACP / (SS)-DACH and vice versa ((SS)-DACP / (RR)-DACH).

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(S)

(S)

N

N

N (S)

N N (R)

N

N

N

(S)

(R)

N

N

(S)

N

(R)

N

N

(S)

(R)

(R)

N

Cd Cl

N

N

N N

N

1ARRSS

(S)

N

(S)

(S)

Cl

Cl Cl

Cl

Cl

Cd

(S)

Cd

Cl

Cl

(R)

N

Cl

Cl

N N

(R)

N

Cd

N

(R)

N

N

Cd

Cl

Cl

N

(R) (R)

N

N

N

Cd

(S)

N (S)

N

N N

2ARRSSRRSS

N (R)

(R)

[Cd6(3ARRSSRRSSRRSS)Cl12]

(R)

(R)

N

N

N (R)

N N (S)

N N

N

(R)

N

N

N (R)

(S)

N

(S)

(R)

N

(S)

(S)

N

(S)

(S)

N

(R)

N

(R)

N

Cd Cl

N

(S)

Cl

Cl Cl

Cl

Cl

Cd

N

Cd

Cl

Cl

N

2ASSRRSSRR

N

Cd

(S)

N

Cl

Cl

N (R)

(S)

N

Cd

N

(R)

N

Cd

Cl

Cl

N

N N

1ASSRR

N

N

N

N

(R)

(R)

N N (S)

N (S)

[Cd6(3ASSRRSSRRSSRR)Cl12]

Figure 2*. Chiral mixed imine macrocyclic compounds synthesized from DFP and opposite enantiomers of DACP and DACH. Respective amines (B) have been obtained by reduction of parental Schiff base compounds.

Results and discussion Theoretical calculations10a,b and synthesis The product preference - gas-phase quantum calculations for stability of heterochiral 2+2 and 2+1+1 imines. To explain the preference of DFP towards DACP or DACH in formation of the macrocycle product, we have studied the thermodynamics of 2+2 (or 2+1+1) imine formation. Consequently, three reactions have been compared, namely 4 ACS Paragon Plus Environment

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2 rac-DACP + 2 DFP → IACP +4 H2O7b,c, 2 rac-DACH + 2 DFP → IACH +4 H2O7a,d, (RR)-DACP + (SS)-DACH + 2 DFP → 1ARRSS + 4 H2O Note that 1ASSRR enantiomer must have entirely the same energy as its mirror counterpart (for structures of 1ARRSS / 1ARRSS see figure 2). For our purpose we have compared ΔE (total electronic energy difference) of the three reactions calculated at 0 K as well as Gibbs free energy difference ΔG at 338 K (65°C), which is the methanol boiling point. ΔE of formation of IACP, IACH and 1ARRSS (equiv. 1ASSRR) turns out to be -9.2 kcal×mol-1 independently of the product identity, while ΔG (338 K) values are -16.1 kcal×mol-1, -15.5 kcal×mol-1 and, -15.7 kcal×mol-1, respectively (table 1). The values indicate no essential preference of the aldehyde towards any pair of the diamine reactants in formation of any 2+2 or 2+1+1 heterochiral macrocyclic Schiff base (cf. black lines on top of each other in figure 3). Taking into account the considerations from above calculations we decided to synthesize a novel non-existing yet heterochiral 2+1+1 imine macrocycle consisting of two DFP, one DACP and one DACH units, where the diamines were used as compounds of opposite chirality. This macrocycle is the smallest representative of a new family of mixed heterochiral macrocycles (figure 2) containing these units. Table 1. Thermochemical parameters (total electronic energy difference ΔE, the energy corrected for zeropoint vibrational energy ΔEZPE, Gibbs free energy difference at 338 K ΔG) for 2+2 (or 2+1+1) imine formation reactions, for the most stable products of alternating RRSS chiralities as well as their homochiral isomers. 0K ΔE

338 K [kcal×mol-1]

ΔEZPE

[kcal×mol-1]

ΔG [kcal×mol-1]

IACP(RRSS)

-9.2

-17.1

-16.1

IACP(RRRR)-a

+0.6

-7.0

-4.7

IACP(RRRR)-u

+1.3

-6.9

-5.3

1ARRSS

-9.2

-17.2

-15.7

1ARRRR-a

+0.3

-7.4

-5.5

1ARRRR-a’

+1.3

-6.4

-4.3

1ARRRR-u

-0.1

-8.3

-6.8

IACH(RRSS)

-9.2

-17.3

-15.5

IACH(RRRR)-a

+0.8

-7.0

-5.1

IACH(RRRR)-u

-1.4

-9.7

-8.4

Thermodynamical stability of macrocycles (hetrochiral vs. homochiral products). Quantum calculations for stability of heterochiral and homochiral 2+2 and 2+1+1 imines. As mentioned before, the condensation of DFP with racemic DACH7a,d, or racemic DACP7b, delivers 2+2 product of exclusively meso structure. Similarly, the reaction of DFP with the opposite enantiomers of DACH and DACP leads to 2+1+1 imine macrocycles of alternating RRSS/SSRR chiralities. Striking lack of any imine product of homogenous chiralities, i.e. RRRR (or 5 ACS Paragon Plus Environment


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equivalently SSSS) in all these reactions calls for explanation and can be addressed with the use of quantum chemical calculations (supporting figures S1 – S8, supporting table S1). In table 1 we have collected some thermochemical data calculated for the reaction 2 diamine (DACH and/or DACP) + 2 DFP → macrocycle + 4 H2O for the most stable heterochiral and homochiral products.

Figure 3. van’t Hoff plot for 2+2 (or 2+1+1) imine formation reactions for macrocycles listed in Table 1. The lower panel expands the high temperature range of the upper one. Note, the black lines representing the temperature dependence of lnK for heterochiral products IACP, 1ARRSS, IACH are on top of each other. Similarly, the stability of the seven macrocycles of homogenous chiralities are represented by 5 red lines (cf. supporting figures S3 – S8 for further details).

While only one conformer, a meso structure (IACP) in accord to the experimental findings, seems to be the most stable form of a RRSS isomer, two conformers of almost the same energy have been found as the most stable RRRR ones, the one with the antiparallel layout of the pyridine rings (supporting figure S2a) and the one with U-shaped layout of the rings (supporting figure S2d). Thermodynamically equivalent SSSS isomers have been omitted in the following discussion. Similarly, IACH is the most stable form of a RRSS product of 2 DACH + 2 DFP condensation, while IACH(RRRR)-a and IACH(RRRR)-u, the most stable products of homogenous chiralities, have structures analogous to IACP(RRRR)-a and IACP(RRRR)-u (supporting figure S8). Condensation with the use of DACH and DACP allows two homochiral products with antiparallel layout of the pyridine rings, 1ARRRR-a and 1ARRRR-a’, and still only one U-shaped product 1ARRRR-u (supporting figure S7). Due to the fact that the relative stability of homogenous and heterogeneous 6 ACS Paragon Plus Environment

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chirality products has turned out to follow a similar pattern for the condensation products of two DACP, two DACH and DACP + DACH molecules, the detailed discussion of thermodynamical stability of macrocycles, which can be found in supporting information, will be focused on IACP (supporting figure S6) and related isomers. Synthesis A one-pot condensation of two equivalents of DFP with one equivalent of (RR)-DACP and one equivalent of (SS)-DACH (and vice versa (SS)-DACP / (RR)-DACH) run in refluxing methanol for 24 h provides a white precipitate (yield ca. 90%) which is the pure mixed heterochiral 2+1+1 imine macrocycle, 1ARRSS·0.2H2O (or 1ASSRR·0.2H2O)* (see notes) (scheme 1). These two isolated enantiomeric Schiff bases were reduced to the corresponding amines. The crude 2+1+1 macrocyclic amines 1BRRSS and 1BSSRR were further reacted with hydrochloric acid solution to form protonated tetrahydrochloride derivatives [1BRRSSH4]Cl4·1.75H2O and [1BSSRRH4]Cl4·1.75H2O, respectively. The pure free enantiomeric amines 1BRRSS·0.22CHCl3 and 1BRRSS·0.22CHCl3 were received from protonated salt water solutions by addition of sodium hydroxide and extraction of respective amine with chloroform (scheme 1). The similar non-templated condensation reaction of DFP and opposite enantiomers of DACP and DACH led in the same as previously molar ratio in benzene (24 hours at RT ) delivers also white precipitate (18%). This time however, the product is the pure mixed heterochiral 4+2+2 macrocyclic imine 2ARRSSRRSS∙0.67C6H6·H2O (or its enantiomer 2ASSRRSSRR∙0.67C6H6·H2O) (scheme 1). Each enantiomerically pure macrocyclic 4+2+2 imine was reduced to the corresponding enantiomer of macrocyclic 4+2+2 amine, 2BRRSSRRSS or 2BSSRRSSRR. The crude amine product was treated with hydrochloric acid solution to deliver respective protonated octahydrochloride [2BRRSSRRSSH8]Cl8·2.25H2O·1.75CHCl3 (or [2BSSRRSSRRH8]Cl8·2.25H2O·1.75CHCl3) atfter its recrystallization from methanol / chloroform solution. The pure 2BRRSSRRSS·1.75H2O (2BSSRRSSRR·1.75H2O) amine was released from its salt by treatment with sodium hydroxide solution and extraction of the liberated amine with chloroform. The small 2+1+1 macrocyclic imine 1ARRSS (1ASSRR) in the presence of an excess of CdCl2 template in methanol / chloroform (v/v 1/1) mixed solvent converts itself at ambient temperature into a large 6+3+3 mixed heterochiral imine 3ARRSSRRSSRRSS (3ASSRRSSRRSSRR) complexed with six CdII ions (scheme 1). This complex precipitates from this solution as highly insoluble product (40%) [Cd6(3ARRSSRRSSRRSS)Cl12]·5CdCl2 ([Cd6(3ASSRRSSRRSSRR)Cl12]·5CdCl2). The isolated complex was reduced by a large excess of sodium borohydride in methanol solution and resulting product was demetalated with ammonia solution. The crude free amine 3BRRSSRRSSRRSS (or 3BSSRRSSRRSSRR) was extracted with chloroform and next it was converted with hydrochloric acid solution into its dodecahydrochloride [3BRRSSRRSSRRSSH12]Cl12·11.5H2O (or [3BSSRRSSRRSSRRH12]Cl12·11.5H2O). The pure 6+3+3 macrocyclic amine 3BRRSSRRSSRRSS·2.7CH2Cl2 (3BSSRRSSRRSSRR·2.7CH2Cl2) was received from its salt by basification and extraction with dichloromethane.



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The filtrate left after removal of [Cd6(3ARRSSRRSSRRSS)Cl12](CdCl2)5 complex was reduced with an excess of sodium borohydride, evaporated to dryness and demetalated with ammonia solution. After extraction with chloroform the crude amine product was received. It contains the complicated mixture of huge amine macrocycles, e.g. 8+4+4 or 10+5+5 but also larger ones such as 20+10+10 (see further text for details). (S)

N

N (R)

(S)

N

N

N

N

(R)

HCl (aq.), MeOH, CHCl3

2BRRSSRRSS

(R)

(R)

N

N N

N

crude

[2BRRSSRRSSH8]Cl8 ·2.25H2O·1.75CHCl3

NaOH (aq.), CHCl3

(R)

(R)

(S)

(S)

N H

N

NH

HN

(R)

NH

HN

(R)

56%

N

N

(S)

N H

N

i) NaBH4, MeOH RT, 12 h ii) NaOH (aq.), CHCl3

H N

N

(S)

H N

(S)

N

(S)

2ARRSSRRSS·0.67C6H6·H2O

benzene RT, 24 h

2BRRSSRRSS·1.75H2O

18%

100% 2

N O NH2

(R)

NH2

(R)

N

MeOH

O +

(R)

reflux, 24 h

H 2N

N

(R)

H 2N

N

(R)

(S)

(S)

NH

HN

(S)

N

85%

1ARRSS·0.2H2O 92%

1BRRSS·0.22CHCl3 100%

(S)

(S)

N H

N H

N

N N

Cd

Cl

Cl Cl

Cl

Cl

(R)

N

Cd

Cd

Cd

Cl

Cl

i) NaBH4, MeOH RT, 12 h ii) 25% NH3 (aq.), H2O 1:1 RT, 1 h / CHCl3

N (S)

(R) (R)

HCl (aq.), MeOH

3BRRSSRRSSRRSS crude

Cd

N

(R)

N

Cl

Cl N

HN

(R)

N

Cl

(S)

crude

NH

(S)

Cl

N

[1BRRSSH4]Cl4 ·1.75H2O

N (R)

N

Cl

N

(S)

NaOH (aq.), CHCl3

(S)

Cd

N

N

HCl (aq.), MeOH, MeCN

1BRRSS

N

(S)

N N

(S)

(S)

CdCl2, MeOH, CHCl3 1:1 30 oC, 48 h

(R)

N

i) NaBH4, MeOH RT, 12 h ii) NaOH (aq.), CHCl3

[3BRRSSRRSSRRSSH12]Cl12 ·11.5H2O

(R)

HN

NH

(S)

HN

HN

NH

HN N

H N (R)

(R)

[Cd6(3ARRSSRRSSRRSS)Cl12]·5CdCl2

(R)

N

NH (S)

N

(R)

N

y = 44% (S)

N N

N

NaOH (aq.), CH2Cl2

N

NH

H N

(S)

(S)

N

(R)

3BRRSSRRSSRRSS·2.7CH2Cl2 100%

40%

Scheme 1. Synthesis of mixed heterochiral macrocyclic compounds in the DFP/(RR)-DACP/(SS)-DACH system.

X-ray crystal structures of macrocyclic compounds11 In terms of saturated rings, the macrocycles are built up from alternating DACP and DACH moieties of opposite chirality, therefore they are “pseudo-meso” compounds and could mimic their analogs consisting solely of DACP or DACH, i.e. possessing a higher symmetry (meso compounds).7a-d In consequence, some of the crystals presented herein are pseudo-isomorphous, i.e. have very similar crystal packing, cell parameters and space group of lower symmetry


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(subgroup) with the crystals of DACP or DACH analogous compounds. That results in a pseudosymmetry (pseudoinversion) observed in these non-centrosymmetric crystals. Thus, 2+1+1 crystal 1ASSRR (monoclinic, space group P21, Z′ = 1) is pseudo-isomorphous with the crystal of 2+2 meso-DACH-based IACH imine (monoclinic, space group P21/c, Z′ = 0.5; deposited at the Cambridge Structural Database, CSD11e with the refcode JAXHUM7a). The 4+2+2 [2BSSRRSSRRH8]Cl8∙5H2O crystal (triclinic, space group P1, Z′ = 2) is pseudo-isomorphous with the crystal of 4+4 meso-DACP-based amine [IIB’CPH8]Cl8∙4H2O (triclinic, space group 1 , Z′ = 1; CSD refcode EQUHAB7c), and the 6+3+3 [3BRRSSRRSSRRSSH12]Cl12∙2MeCN∙3.5MeOH∙6.5H2O crystal (triclinic, space group P1, Z′ = 1) is pseudo-isomorphous with the crystal of 6+6 meso-DACP-based amine [IIIBCPH12]Cl12∙2MeCN∙12H2O (triclinic, space group 𝑃1 , Z′ = 0.57b).

Figure 4. From left to right: X-ray crystal structures of 2+1+1 and 4+2+2 macrocyclic imines 1ASSRR and 2ASSRRSSRR·CH2Cl2 as well as hexanuclear CdII complex of 6+3+3 macrocyclic imine [Cd63ARRSSRRSSRRSSCl12]∙9H2O. Solvents and disorder are not shown for clarity. Color code: gray – carbon, blue – nitrogen, white – hydrogen, green – chlorine, golden balls – cadmium.

The X-ray crystal structure of 1ASSRR single crystal confirms the presence of a 2+1+1 macrocycle (figure 4, supporting figure S9, supporting table S2). This compound exhibits a stepped Z-type conformation. In this type of imine molecule one DACP moiety replaces (or mimics) the DACH unit (or vice versa), resembling in their structures the achiral meso 2+2 macrocycles IACP and IACH constructed of DFP and solely of DACP or DACH building blocks.7a-d This 2+1+1 imine is also similar to other 2+2 Schiff base macrocycles derived from aromatic dicarbonyl compounds and diamines.12a,b The 1ASSRR molecule is chiral and as expected, the (SS)DACP and (RR)-DACH rings are of opposite chirality and the structure is of non-crystallographic C2 symmetry, which is in accord with the symmetry observed in a solution. The molecular structure displays a compacted macrocycle with almost parallel pyridine ring arrangement (interplanar angle of 1.552(4)°). Perpendicular distance of the centroid of one pyridine ring on the other pyridine ring is about 3 Å.



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Figure 5. C−Cl···π interactions of chloride atoms of dichloromethane guest molecule (disorder is not shown) with two pyridine rings of 2ASSRRSSRR imine macrocycle (left). Crystal packing in 2ASSRRSSRR·CH2Cl2 crystal (right). Color code: gray – carbon, blue – nitrogen, white – hydrogen, green – chlorine.

Both 4+2+2 macrocyclic imine and CH2Cl2 molecule in 2ASSRRSSRR·CH2Cl2 lie in a special position, on a 2-fold axis. CH2Cl2 is slightly disordered about this axis (with the C atom lying on C2 axis). Thus, the X-ray crystal structure of 2ASSRRSSRR·CH2Cl2 (figure 4 and 5, supporting figure S10, supporting table S2) shows a molecule of 4+2+2 imine macrocycle 2ASSRRSSRR which is of C2 symmetry. The molecular structure of 2ASSRRSSRR confirms the presence of four pyridine rings, two DACP groups of SS chirality on opposite sides of the macrocycle and a similar pair of DACH moieties of opposite RR chirality. The nitrogen atoms of the two opposite pyridine rings are directed to one side of the mean macrocycle plane, whereas the nitrogen atoms of the other two rings point to opposite side of the plane. This 4+2+2 macrocycle binds in its center the disordered dichloromethane molecule (figure 5, supporting figure S10). This guest molecule is positioned in the mean plane of the macrocycle with two chlorine atoms pointing into two opposite pyridine rings. The geometry of the 4+2+2 macrocycle−dichloromethane assembly suggests the presence of C−Cl···π interactions with the respective Cl-centroid - pyridine ring distances of 3.392(5) Å. It is worth mentioning that Cl···π interactions are well established e.g. in protein-ligand complexes.12c On the other hand, the location of the dichloromethane molecule in the middle of 2ASSRRSSRR might be described to a certain extend as a mechanical blocking. Two pairs of opposite pyridine rings are positioned in a slant fashion and work as double tweezers locking the dichloromethane molecule. This doubled effect allows to maintain the guest molecule inside the macrocyclic host cavity. A similar type of organic guest (benzene) – macrocyclic host interaction displays the 4+4 meso Schiff base macrocycle IIACP derived from racemic DACP and DFP.7b The crystal packing of the macrocyclic units of 2ASSRRSSRR shows pillars which leads to formation of channels, running down


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the b-axis, occupied by dichloromethane molecules (figure 5). The analogous channel-like structure was also observed in case of IIACH imine.7a The X-ray crystal structure of [Cd63ARRSSRRSSRRSSCl12]∙9H2O single crystal (figure 4, supporting figures S11, S16, S16, supporting table S2) represents still a rare example of macrocyclic ligand bound with six metal cations.3h,i,7a,d In this coordination compound each CdII cation is coordinated with three nitrogen atoms of an almost flat section formed by one pyridine ring and two neighboring imine fragments. These imine fragments are formed by (SS)-DACP and (RR)-DACH diamine building blocks. Additionally two chloride anions complete the coordination sphere of pentacoordinate CdII cations in [Cd63ARRSSRRSSRRSSCl12]∙9H2O complex which is of a distorted square-pyramidal geometry. The globular conformation of 3ARRSSRRSSRRSS imine in the complex is multiply folded which results from interchanging up and down arrangement of six N3 compartments separated by cyclopentane and cyclohexane rings. This container-type structure embraces several disordered solvent molecules and is very similar to the structure of recently reported structure of meso-type 6+6 imine derived from DFP and racemic DACH complexed also with six CdII ions.7b The general structures of both cadmium imine complexes bear also some resemblance to lately published hexanuclear ZnII complex of a macrocyclic 6+6 amine IIIBCP synthesized from DFP and racemic DACP.3i This amine coordination compound, however, is more globular in comparison to more flattened version of hexanuclear CdII imine complexes with meso ligand IIIACH and mixed chiral ligand 3A.3i

Figure 6. From left to right: X-ray crystal structures of protonated 2+1+1, 4+2+2 and 6+3+3 macrocyclic amines [1BSSRRH4]Cl4·1.7CH3CN·1.2CH3OH·0.4H2O, [2BSSRRSSRRH8]Cl8·5H2O and [3BRRSSRRSSRRSSH12]Cl12·2CH3CN·3.5CH3OH·6.5H2O, respectively. Some solvent molecules and chloride anions are not shown for clarity. Color code: gray – carbon, blue – nitrogen, white – hydrogen, green – chlorine.

The molecular structure of the protonated 2+1+1 chiral amine (figure 6, supporting figure S12, supporting table S2) observed in the single crystal structure of [1BSSRRH4]Cl4·1.7CH3CN·1.2CH3OH·0.4H2O, similarly as its imine derivative 1ASSRR, displays a parallel arrangement of two pyridine rings, however the different diamine fragments of opposite chirality are positioned differently and form the second stair. In this crystal [1BSSRRH4]4+ cation is of C1 symmetry which is in contrast with effective C2 symmetry of this cation in a solution. The 11 ACS Paragon Plus Environment


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diameter of its macrocyclic cavity is too small to accommodate the chloride anion(s) inside the macrocycle so they are arranged and bound below and above the macrocyclic ring. The [1BSSRRH4]4+ cation present in [1BSSRRH4]Cl4·1.7CH3CN·1.2CH3OH·0.4H2O crystal is chiral in contrast to recently published structure of protonated 2+2 amine [IBCHH4]Cl4 derived from DFP and racemic DACH.7b The X-ray structure of the protonated 4+2+2 amine [2BSSRRSSRRH8]Cl8·5H2O (figure 6, supporting figure S13, supporting table S2) shows two macrocycles in the asymmetric unit of the crystal. This crystal reveals highly folded conformations of two [2BSSRRSSRRH8]8+ cations. The protonated form of the macrocycle can be considered as a kind of container, formed by the folding of a big macrocycle,1g which encompasses and hides two chloride anions in its interior. The remaining chloride anions are located outside the macrocycles and are bound at their surfaces. The degree of the folding is much bigger when compared with the parental imine macrocycle 2ASSRRSSRR, which exhibits much more flat structure. Both macrocyclic moieties are of C1 symmetry in contrast with C2 effective symmetry observed in the solution of [2BRRSSRRSSH8]Cl8·2.25H2O·1.75CHCl3. This protonated macrocycle can be regarded as a cyclic arrangement of four U-shaped fragments, which are organized in an alternating up and down orientations. Each of these compartments is constructed of one pyridine fragment and two different neighboring diamine units ((SS)-DACP vs. (RR)-DACH) of opposite chirality (supporting figure S11). Stereochemistry of [2BSSRRSSRRH8]+8 cation At the first glance the overall geometry of the protonated 4+2+2 amine [2BSSRRSSRRH8]8+ bears similarity to the structures of recently published two different forms of protonated 4+4 macrocyclic amine cations [IIBCPH8]8+ and [IIB’CPH8]8+ found in [IIBCPH8]Cl8·9H2O and [IIB’CPH8]Cl8·8H2O crystals7c, respectively (see supporting information for details). What is more, as it was mentioned earlier, the [2BSSRRSSRRH8]Cl8·5H2O crystal (P1, Z′ = 2) is even pseudoisomorphous with the [IIB’CPH8]Cl8·8H2O crystal (𝑃1 , Z′ = 1). As a consequence, in the asymmetric unit of this chiral crystal two different 4+2+2 pseudo-meso-[2BSSRRSSRRH8]8+ cations are present, replacing one 4+4 meso-DACP-based analogue (along with its inversion-related equivalent). The careful inspection and comparison of their molecular structures allowed us to reveal that these two macrocyclic cations (both 4+4 and 4+2+2) exhibit opposite twists of one of their U-shaped compartments (figure 7). This twist may be regarded as a deformation from more symmetrical conformation (of C2 symmetry) observed in the monoclinic (space group P2/n) form of protonated 4+4 amine, i.e. [IIBCPH8]Cl8·9H2O crystal (compare supporting figures 18 and 19).7c The twist in [2BSSRRSSRRH8]Cl8·5H2O crystal can be defined by torsion angle C7-C6-C50C49, which in case of the cation labelled “a” equals to -102.5(4)o and for the cation labelled “b” equals to +105.1(4)o. Both macrocyclic cations may be regarded as M (minus) and P (plus) isomers, (M)-[2BSSRRSSRRH8]8+ and (P)-[2BSSRRSSRRH8]8+, respectively (figure 7, supporting figures 20).


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Figure 7. Crystallographically independent (P)-[2BSSRRSSRRH8]8+ and (M)-[2BSSRRSSRRH8]8+ cations present in the asymmetric unit of [2BSSRRSSRRH8]Cl8·5H2O crystal (space group P1).

It is surprising how the chiral protonated amine cation [2BSSRRSSRRH8]8+ is able to imitate its achiral meso-type derivative [IIB’CPH8]8+ (supporting figure S21). In general, the (P)[2BSSRRSSRRH8]8+ and (M)-[2BSSRRSSRRH8]8+ cations are diastereomers but they look as if they were pseudo-enantiomers mimicking in their structures the pair of enantiomeric cations (P)-[IIB’CPH8]8+ and (M)-[IIB’CPH8]8+ present in centrosymmetric [IIB’CPH8]Cl8·9H2O crystal. Nonetheless, they differ not only in the twist direction but also their CP rings do not reflect into their CH rings and the whole crystal must remain chiral, in contrary to the optically inactive [IIB’CPH8]Cl8·8H2O crystal (𝑃1 centrosymmetric space group). The additional superposition of (P)-[2BSSRRSSRRH8]8+ and (P)-[IIB’CPH8]8+ cations as well as of (M)-[2BSSRRSSRRH8]8+ and (M)-[IIB’CPH8]8+ cations present in [2BSSRRSSRRH8]Cl8∙5H2O and [IIB’CPH8]Cl8·9H2O crystals (supporting figure S22) shows the differences and similarities between protonated mixed 4+2+2 amine macrocycle 2BSSRRSSRR and protonated 4+4 macrocycle IIB’CP. The X-ray crystal structure of [3BRRSSRRSSRRSSH12]Cl12·2CH3CN·3.5CH3OH·6.5H2O (figure 6, supporting figure S14, S17 and S23) single crystal of the chiral dodecahydrochloride amine derivative grown from methanol/acetonitrile mixture confirms the presence of a 6+3+3 macrocycle build up from six pyridine, three (RR)-DACP and three (SS)-DACH fragments. The 13 ACS Paragon Plus Environment


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DACP and DACH units have opposite chirality and occur in the macrocyclic ring in an interchanging fashion. This chiral macrocycle, which is approximately of D3 symmetry, consistent with its symmetry in a solution, exhibits multiply folded structure and assumes an interesting symmetrical globular conformation. The sections of the macrocycle composed of one pyridine fragment and two different adjacent diamine units of opposite chirality ((RR)-DACP vs. (SS)DACH) create U-shaped compartments (supporting figure S17) which are connected in an alternating up and down circular fashion. Such a conformation of the macrocycle resembles a container-type molecule, with the cavity occupied by four chloride anions and two acetonitrile molecules.1g As the crystal packing shows these containers are in turn packed in such a way that they lay one on top of the other and construct pillars (supporting figure S23). The molecular structure of the protonated macrocycle [3BRRSSRRSSRRSSH12]12+ as well as the occupation of its central void by guest molecules observed for [3BRRSSRRSSRRSSH12]Cl12·2CH3CN·3.5CH3OH·6.5H2O crystal take after those observed for the analogous protonated 6+6 meso-type macrocyclic amines [IIIBCPH12]Cl12 and [IIIBCHH12]Cl12, synthesized from DFP and exclusively from racemic DACP 7b or racemic DACH7d, respectively. The pseudoisomorphism observed between the crystals of protonated 4+2+2 amine [2BSSRRSSRRH8]Cl8·5H2O and protonated 4+4 meso-DACP-based amine [IIB’CPH8]Cl8·8H2O, and also between 2+1+1 crystal 1ASSRR and 2+2 meso-DACH-based imine crystal,7a as well as between crystals of protonated 6+3+3 amine, [3BRRSSRRSSRRSSH12]Cl12∙2MeCN∙3.5MeOH∙6.5H2O and protonated 6+6 meso-DACP-based amine [IIIBCPH12]Cl12∙2MeCN∙12H2O7c (supporting figure 24), indicates that for the formation of the crystal, the overall shape (conformation and the absolute configuration) is of great importance, while the size of the saturated ring (CH vs CP) is negligible, especially that these rings do not participate in any intermolecular interactions essential for the stabilization (and formation) of the crystal. This aspect is especially well displayed in the crystal of [2BSSRRSSRRH8]Cl8·5H2O (as compared with [IIB’CPH8]Cl8·8H2O), in which the overall symmetry is lowered by increasing the number of independent formula units (Z′ = 2). Spectroscopic characterization Mass spectrometry The ESI MS spectra of isolated 2+1+1, 4+2+2 and 6+3+3 macrocyclic products (see supporting figures S25 - S33) confirm their identity. The ESI mass spectrum of reduced filtrate left after removal of [Cd6(3ARRSSRRSSRRSS)Cl12](CdCl2)5 complex shows the presence of huge 8+4+4, 10+5+5, 12+6+6, 14+7+7, 16+8+8, 18+9+9 and 20+10+10 macrocycles (supporting figure S34). NMR spectroscopy The assignment of all NMR signals (see supporting information for details) of each macrocyclic imine, amine and protonated amine derivative was performed on the basis of their 1H and 13C{1H} NMR, COSY, HMQC and HMBC spectra (supporting figures S35 – S75).


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Imines 1H

NMR spectrum of 1ARRSS·0.2H2O imine recorded in CDCl3 (supporting figure S35) shows the presence of 13 signals, which is in accord with C2 symmetry of each molecule possessing C2 axis passing through the middle of DACP and DACH rings. In this case two -pyridyl protons a (see labelling scheme in supporting figure S35) become equivalent and give one resonance. In the aromatic region of 1H NMR spectrum there are two doublets of doublets with chemical shifts  equaled to 8.00 ppm and 7.90 ppm coming from -pyridyl protons b1 and b2, one triplet of pyridyl proton a ( = 7.75 ppm) and two singlets of azomethine protons d1 and d2 ( = 7.75 and 7.68 ppm), respectively (protons a and d1 are overlapped). At   3.51 ppm and   3.23 ppm two multiplets of CH protons e1 (cyclopentane) and e2 (cyclohexane) are seen. The remaining cyclopentyl and cyclohexyl protons (f1, g1, f2 and g2) give rise to several multiplets in the region of 2.30 - 1.50 ppm of the spectrum. The 13C{1H} NMR spectrum of 1A·0.2H2O imine (supporting figure S36) shows the presence of 13 signals which fact is also consistent with the C2 symmetry of the molecule in the solution. The molecule of 2ARRSSRRSS (2ASSRRSSRR) imine has D2 symmetry in a solution which is reflected by its NMR spectra. 1H NMR spectrum (in CDCl3) exhibits 12 signals (supporting figure S40) derived from non-equivalent protons of 2A molecules but two of them, resonances of protons g1/f1a (or f1e) and f2a/f2e, respectively, are randomly overlapped. The 13C{1H} NMR spectrum (supporting figure S41) displays 13 resonances equal to the number of non-equivalent carbon atoms in the asymmetric part of the molecule. In general the patterns of 1H and 13C{1H} spectra of 2A imine are very similar to those of NMR spectra of 1A Schiff base, however the crystalline 2A imine (C50H56N12·H2O∙C6H6) releases the trapped benzene guest molecule in CDCl3 solution and gives rise to one additional signal in 1H NMR spectrum ( = 7.36 ppm) and one additional signal in its 13C{1H} NMR spectrum ( =128.3 ppm). The molecule of [3ARRSSRRSSCd6Cl12] hexanuclear imine complex has D3 symmetry in a solution. In the aromatic region of its 1H NMR spectrum (CDCl3/CD3OD v/v 2/1) one triplet at  = 8.11 ppm (-pyridyl proton a), two doublets at  = 7.84 and 7.69 ppm (-pyridyl protons b1 and b2) and two singlets at  = 9.00 and 8.94 ppm (azomethine protons d1 and d2) are clearly seen (supporting figure S45). This compound is very poorly soluble in common organic solvents and is not stable in the solution. It decomposes in quite short time which prevents from recording its 13C{1H} NMR as well as 2D NMR spectra. The full assignment of its NMR signals was not performed. Protonated amines The number of 15 1H NMR signals (supporting figure S46) of protonated [1BRRSSH4]Cl4·1.75H2O derivative indicates the C2 symmetry of the molecule in a solution. In the aromatic region there is one triplet at  8.00 coming from -pyridyl proton a, two doublets of pyridyl protons b2 and b1 of chemical shifts  7.55 ppm and 7.52 ppm, respectively. Going upfield there are two quarters AB of metyhylene protons d1 and d2 and several multiplets of protons of 15 ACS Paragon Plus Environment


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both cyclopentyl and cyclohexyl rings. The 13C{1H} NMR spectrum (supporting figure S47) exhibits 13 signals which confirms C2 symmetry of the molecule. 1H

NMR

spectra of protonated [2BRRSSRRSSH8]Cl8·2.25H2O·1.75CHCl3 and [3BRRSSRRSSRRSSH12]Cl12·11.5H2O (supporting figures S51 and S56) amines exhibit 14 and 15 signals, respectively, which is in accord with D2 and D3 symmetry of corresponding 4+2+2 and 6+3+3 protonated amine molecule. In the aromatic region of each compound there is one triplet coming from -pyridyl proton a at  7.93 ppm (for [2BRRSSRRSSH8]Cl8) and 7.81 ppm (for [3BRRSSRRSSRRSSH12]Cl12) and two doublets of -pyridyl protons b1 and b2 of chemical shifts  7.45 ppm and 7.37 ppm or 7.38 ppm and 7.32 ppm for [2BRRSSRRSSH8]Cl8 and [3BRRSSRRSSRRSSH12]Cl12, respectively. The order of protons b1 and b2 is opposite as it was for [1BRRSSH4]Cl4 molecule. Going upfield there are two quarters AB of metyhylene protons d1 and d2 and several multiplets of protons e, f and g of both cyclopentyl and cyclohexyl rings. In case of smaller 4+2+2 protonated amine two signals of protons d2’ and e1 are randomly overlapped whereas in case of bigger 6+3+3 macrocycle these signals are well separated as it was in the case of the smallest 2+1+1 protonated molecule of [1BRRSSH4]Cl4. The 13C{1H} NMR spectra (supporting figures S52 and S57) exhibit 13 signals which confirms D2 and D3 symmetry of respective [2BRRSSRRSSH8]Cl8 and [3BRRSSRRSSRRSSH12]Cl12 molecule. Amines Macrocyclic amine 1BRRSS·0.22CHCl3 exhibits 16 1H NMR signals which is consistent with C2 symmetry of its molecule (figure 8, supporting figure S61). The spectrum pattern (in CDCl3) contains practically the same set of signals as its hydrochloride derivative [1BRRSSH4]Cl4·1.75H2O measured in D2O. Now additionally one peak of amine protons NH is seen. In the aromatic region there is one triplet at  7.51 ppm coming from -pyridyl proton a and one doublet at  7.02 ppm of randomly overlapped signals of -pyridyl protons b1 and b2. In the range of ca 3.7 - 4.1 ppm there are two AB quartets responsible for methylene protons d1 and d2. At about 2.7 ppm and 2.3 ppm two multiplets of CH protons of cyclopentane (e1) and cyclohexane (e2) rings are located. Also in this region the broad singlet of overlapped amine protons NH1 and NH2 is seen. The set of 7 different multipltes of CH2 groups of cyclopentane and cyclohexane rings (protons f and g) occurs in the range of 2.1 – 1.0 ppm. The 13C{1H} NMR spectrum (supporting figure S62) with 12 resonances (two signals of carbon atoms f1 and f2 are randomly overlapped) is also in accord with C2 symmetry of the 1BRRSS molecule. The 1H and 13C{1H} NMR spectra of 2BRRSSRRSS·1.75H2O and 3BRRSSRRSSRRSS·2.7CH2Cl2 amines are very similar to the spectra of 1BRRSS amine (figure 8, supporting figures S66, S67, S71 and S72) and reflect D2 and D3 symmetry, respectively, of each molecule in solution. The 1H NMR spectra of both macrocycles show this time two resolved doublets of -pyridyl protons b1 and b2, but this time in case of 1H NMR spectrum of 2BRRSSRRSS two signals of protons d1’ and d2’ are randomly overlapped, whereas in 1H NMR spectrum of 3BRRSSRRSSRRSS amine the resonance of proton e1 is covered with the NH signal. The 13C{1H} NMR spectra of 4+2+2 and 6+3+3 amines (supporting figures S617 and S72) have two separated signals of carbon atoms f1 and f2, although 16 ACS Paragon Plus Environment

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in 13C{1H} NMR spectrum of amine 3BRRSSRRSSRRSS the signals of carbon atoms b1 and b2 are now overlapped.

Figure 8. 1H NMR spectra (CDCl3, 500 MHz), signal assignment and labelling scheme (in inset) of chiral macrocyclic amines 1BRRSS·0.22CHCl3 (blue trace), 2BRRSSRRSS·1.75H2O (red trace) and 3BRRSSRRSSRRSS·2.7CH2Cl2 (green trace) * denotes the residual solvent signal.

Circular dichroism (CD) Heterochiral macrocycles ICP – IIICP and ICH – IIICH (figure 1) are meso-type compounds and are achiral. In contrast to them all investigated mixed heterochiral macrocyclic compounds 1RRSS, 2RRSSRRSS and 3RRSSRRSSRRSS and 1SSRR, 2SSRRSSRR and 3SSRRSSRRSSRR (figure 2) contain in their structures simultaneously the DACP and DACH units of opposite chirality. As the diamine units are not the same their contribution to general chirality of the respective macrocycle does not 17 ACS Paragon Plus Environment


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cancel each other out (neutralize each other) and each molecule remains chiral. This chirality is reflected by the CD spectrum of each mixed macrocycle.

Figure 9. CD (top) and UV (bottom) spectra (1 mm cuvette, CHCl3) of macrocyclic imines: 1ARRSS·0.2H2O (dark green) 0.5 mM; 1ASSRR·0.2H2O (light green), 0.5 mM; 2ARRSSRRSS·0.67C6H6·H2O (red) 0.5 mM; 2ASSRRSSRR·0.67C6H6·H2O (brown) 0.5 mM; [Cd6(3ARRSSRRSSRRSS)Cl12]·5CdCl2 (dark blue) 0.1 mM and [Cd6(3ASSRRSSRRSSRR)Cl12]·5CdCl2 (blue) 0.1 mM.

Figure 9. displays the CD spectra of the 3 enantiomeric pairs of macrocyclic imine compounds 1ARRSS·0.2H2O / 1ASSRR·0.2H2O, 2ARRSSRRSS·0.67C6H6·H2O / 2ASSRRSSRR·0.67C6H6·H2O and [Cd6(3ARRSSRRSSRRSS)Cl12]·5CdCl2 / [Cd6(3ASSRRSSRRSSRR)Cl12]·5CdCl2. The CD spectra of all enantiomerically pure macrocyclic amines 1BRRSS·0.22CHCl3 / 1BSSRR·0.22CHCl3, 2BRRSSRRSS·1.75H2O / 2BSSRRSSRR·1.75H2O and 3BRRSSRRSSRRSS·2.7CH2Cl2 / 3BSSRRSSRRSSRR·2.7CH2Cl2 as well as their protonated derivatives [1BRRSSH4]Cl4·1.75H2O / [1BSSRRH4]Cl4·1.75H2O, [2BRRSSRRSSH8]Cl8·2.25H2O·1.75CHCl3 / [2BSSRRSSRRH8]Cl8·2.25H2O·1.75CHCl3 and [3BRRSSRRSSRRSSH12]Cl12·11.5H2O / 18 ACS Paragon Plus Environment

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[3BSSRRSSRRSSRRH12]Cl12·11.5H2O are shown in the supporting figures S76 and S77, respectively. These spectra of the two corresponding enantiomers are mirror images of each other. In the spectral region of ca 200 nm (225 nm for imines) – 400 nm, all the spectra show positive and negative Cotton effects with a quite strong intensity of the absorption band for imine compounds (  up to 90 M-1cm-1) and week intensities for amine compounds (  up to 4 M-1cm-1) and for protonated amine derivatives (  up to 7 M-1cm-1). The non-templated competition reaction We found previously that the condensation reactions of DFP led in boiling methanol deliver exclusively IACP macrocyclic imine (for rac-DACP precursor) and the mixture of IACH and IIACH macrocyclic imines in the molar ratio 6:1 (for the rac-DACH precursor),7a-d however, these two reactions were not performed in identical conditions. The first one was run from DFP and dihydrochloride salt of diamine, rac-DACP·2HCl, in the presence of 2 eq. of NEt3, whereas in the second one, apart from DFP, the commercially available free diamine rac-DACH was used. When we repeated the second reaction in identical conditions as for the first condensation, i.e. we have used DFP and rac-DACH·2HCl in the presence of 2 eq. of NEt3, it turned out that this time the only product was 2+2 meso type imine IACH (yield ca. 96%, see experimental part for details). This new improved synthesis delivers directly and exclusively the 2+2 meso macrocyclic imine IACH and omits, as it was reported previously,7a,d its separation from 4+4 IIACH imine homologue. It should be added here that the condensation reactions performed in acidic conditions and led without neutralization (0 eq. of NEt3) of dihydrochloride salt of appropriate diamine, racDACP·2HCl or rac-DACH·2HCl do not produce any imine product. In this case the protection of DFP by methanol occurs which produces an acetal, 2,6-bis(dimethoxymethyl)pyridine, which is inactive in above mentioned condensation reactions. To be able to compare the three syntheses of related 2+2 and 2+1+1 macrocyclic imines IACP, IACH and 1ARRSS we have also unified the synthesis of mixed heterochiral 2+1+1 imine 1ARRSS by application of the same conditions (1 eq. of DFP, 0.5 eq. of (RR)-DACP·2HCl, 0.5. eq of (SS)-DACP·2HCl and 2 eq. of NEt3). The second enantiomer, 1ASSRR, was received from (SS)DACP·2HCl and (RR)-DACP·2HCl in the presence of NEt3 (see experimental part for details). To confirm the conclusions of the higher thermodynamical stability of heterochiral 2+2 and 2+1+1 imines over their homochiral counterparts drawn from theoretical calculations we performed the non-templated competition reaction (supporting scheme S1) of 2 eq. of DFP with 1 eq. of rac-DACP·2HCl, 1 eq. of rac-DACH·2HCl in the presence of 4 eq. of NEt3. It should be added, that in this case, the reaction environment is not neutral because the formed NEt3·HCl byproduct, being a week base – strong acid salt, is slightly acidic (pKa = 10.75 (water) or 9.0 (DMSO)). It can act as a source of protons which enables the reversibility of imine bond formation. The competition reaction was run in refluxing methanol for 120 h and after 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 24 h, 60 h and 120 hours the respective samples of a suspension were collected, the precipitate was filtrated off and 1H NMR spectra each sample of precipitate were recorded. In each 19 ACS Paragon Plus Environment


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case the 1H NMR spectra (supporting figure S78) show the presence of only 3 sets of signals belonging to a mixture of three compounds (consisting of four components), all of which are the heterochiral macrocyclic imines IACP, IACH and 1ARRSS/1ASSRR (1Arac). This observation was proved by simple comparison of the obtained 1H NMR spectra with the spectra of pure macrocyclic imines IACP, IACH and 1ARRSS. No other signals of any additional products of these competition reactions were noticed neither homochiral nor heterochiral ones (supporting figure S78). This fact proves the heterochiral self-sorting in formation of 2+2 and 2+1+1 macrocyclic imines. Alternatively, to check the yield of two extreme reaction variants the reactions of the shortest (1 h) and the longest (120 h) reflux time were also performed in separate flasks on a scale of 2 mmol of DFP in boiling methanol for appropriate time. In each case the isolated yield was ca. 90% and the distribution of heterochiral macrocyclic Schiff bases was comparable with the respective samples taken after 1 h and 120 h of reflux. Table 2. The experimental molar ratios of IACP/IACH/1Arac and mole fractions of respective components in competition reactions run for different reflux time.

The molar ratio IACP/IACH/1Arac of 2+2 and 2+1+1 imine products displays the experimental distribution of macrocycles in the sample. The ratio was estimated by rough integration of partly resolved components of appropriate doublets. The theoretical calculations (see theoretical part of this paper) suggest the very similar thermodynamic stability of all heterochiral imine macrocycles IACP, IACH, 1ARRSS (1ASSRR). In this case the molar ratio of IACP/IACH/1Arac macrocyclic imines should be statistical and equaled to 1:1:2. And indeed the close to theoretical molar ratio of products was achieved when the competition reaction was run for short time (ca 1 2 h). With extended heating time the amount mixed macrocycle 1Arac decreases, whereas the molar ratio of IACP/IACH remains more or less on the same level of ca 1/1 (table 2). The trends of competition reaction as the time depending molar distribution (mole fraction vs. time) of IACP, IACH, 1Arac imines is shown in figure 10.


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Figure 10. The time depending molar distribution of IACP, IACH, 1Arac imines in the precipitates obtained in the competition reactions.

Therefore, for reaction run for longer reflux time, the experimentally observed molar ratio IACP/IACH/1Arac, different than the expected 1:1:2 one, strongly indicates the role of the factors not present in the gas-phase model acting in favor of the IACP and IACH products. This discrepancy between theoretical and experimental distribution of macrocycles in the precipitate obtained in the competition reaction might be tentatively explained by slightly higher solubility of 1ARRSS (1ASSRR) imines (which precipitate from methanol solutions during their synthesis with the lower yield of ca 90%) over the extremely low solubility of IACP and IACH Schiff bases. IACP and IACH imines, which precipitate from methanol solutions during their syntheses almost quantitatively, with the yield of ca. 96%. Conclusions: Quantum calculations have shown that in all range of temperature the 2+2 or 2+1+1 macrocyclic products of alternating RRSS chiralities are always thermodynamically preferred to the product of homogenous chiralities, which can be attributed to the conformational changes required to facilitate the macrocycle formation. Therefore, by suitable adaptation of the reaction conditions applied for DFP/rac-DACP and DFP/rac-DACH systems the new class of mixed heterochiral imine and amine macrocycles derived from DFP and opposite enantiomers of DACP and DACH has been synthesized. Each macrocyclic compound was obtained as a pair of enantiomers and their chiral nature was confirmed by CD measurements. The 1H and 13C{1H} NMR signals of almost all macrocycles have been assigned on the basis of their COSY, HMQC 21 ACS Paragon Plus Environment


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and HMBC spectra. The NMR spectra and crystal structures prove that these chiral compounds are less symmetrical in comparison to heterochiral meso-type macrocycles derived from DFP and solely from rac-DACP or rac-DACH, although they tend to mimic strongly their achiral meso counterparts, even in solids, adopting e.g. similar (pseudo-isomorhic) crystal structures. This inclination is especially pronounced and it has been exemplified in case of the crystal of protonated 4+2+2 macrocyclic amine which contains two types of diastereomeric (pseudo-enantiomeric) (P)[2BSSRRSSRRH8]+8 and (M)-[2BSSRRSSRRH8]+8 cations differing in terms of inverted twists of pyridine rings. The crystal packing in the crystals of 4+2+2 imine, hexanuclear CdII complex of 6+3+3 imine as well as of the protonated 6+3+3 amine shows a columnar arrangement of macrocyclic units. In the competition reactions of DFP with the mixture of racemic DACP and racemic DACH only the hetreochiral 2+2 and 2+1+1 macrocyclic imines are formed which proves the heterochiral self-sorting among many possible imine products. Although the gas phase quantum chemical calculations have indicated no essential preference of DFP towards rac-DACP or rac-DACH, the experimentally observed molar ratios IACP/IACH/1Arac different from the expected 1:1:2 one strongly indicate the role of the factors not present in the gas-phase model acting in favor of the IACP and IACH products. As our preliminary study suggests that the mixed macrocycles can be promising ligands for complexations with metal cations. The small 2+1+1 imines and amines are good candidates for complexation with one metal ion whereas the larger 4+2+2 or 6+3+3 mixed amines should be able to form polinuclear complexes with transition metals. Being chiral compounds, the mixed macrocycles seem to be interesting hosts for small organic (chiral) host molecules in terms of investigation of molecular (or chiral) recognition. As some of the larger macrocycles in solid exhibit channel-like arrangement they may also find some applications as porous materials. Experimental section Methods MS and HRMS data were obtained on a Q-ToF mass spectrometer using positive polarity electrospray ionization mode, (+)ESI. The NMR spectra were taken on 500 MHz (1H NMR measurements) and 125 MHz (13C{1H} NMR measurements) spectrometer. 1H NMR data are reported as follows: chemical shift in parts per million (δ, ppm) from either residual CHCl3 (7.26 ppm) and DMSO-d6 (2.49 ppm) or DSS (0 ppm) signals. For 13C{1H} NMR data the chemical shifts are reported in ppm from either CHCl3 (77.0 ppm) or DSS (0 ppm). Coupling constants (J) are reported in Hz. Standard abbreviations s, d, t, ABq and m refer to singlet, doublet, triplet, AB quartet and multiplet. The elemental analyses were carried out on CHN elemental analyzer. CD analyses were performed on a CD spectropolarimeter. The CD data were collected over a wavelength range of 200–400 nm with bandwidth of 3 nm using a 1 mm quartz cuvette. 1 scan was recorded for imine compounds, 10 scans were measured for amine compounds and 3 scans for protonated amine derivatives. The spectra were not smoothed. Computational Details 22 ACS Paragon Plus Environment

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All electronic structure calculations were performed with the Gaussian 09,11b package of programs for molecules in their ground electronic states. Stationary points on the potential energy surface and harmonic wavenumbers were calculated using DFT/B3LYP functional coupled to 6311++g(2d,2p) basis set, while the total energies were corrected semiempirically for dispersion contributions using the method proposed by Grimme.11a Synthesis Free diamine precursors: trans-(1R,2R)-diaminocyclopentane: A solution of 4.00 g (71.4 mmol) of KOH in 6 mL of water was added to a water solution of 440 mg (2.53 mmol) of trans-(1R,2R)-diaminocyclopentane dichloride. The mixture was extracted with diethyl ether (5 × 5 mL), organic extracts were combined, dried over solid KOH. The drying agent was filtered off and the ether solution was concentrated to the theoretical mass of the free amine (255 mg). A drop of the product was dissolved in CDCl3 (660 L) to record its NMR spectrum. The integration of signals allowed to evaluate the amount of the free amine in the sample. The product was put into freezer to deliver white solid. Yield 209.3 mg (82.0 %). trans-(1S,2S)-diaminocyclopentane: The opposite enantiomer was obtained in the same way as trans-(1R,2R)-diaminocyclopentane using trans-(1S,2S)-diaminocyclopentane dichloride. Macrocycles: 2+2 imine IACH 404.8 mg (4.000 mmol) of triethylamine, NEt3, was added to the solution of 374.2 mg (2.000 mmol) of racemic trans-1,2-diaminocyclohexane dihydrochloride in 5 mL of methanol. After dissolution the solution of amine was combined with the solution of 270.2 mg (2.000 mmol) 2,6diformylopyridine in 5 mL of methanol. The resulting mixture was refluxed for 24 hours. A white solid precipitates. After cooling to room temperature the flask with the suspension was kept in a freezer for 12 hours. The white precipitate was filtered off, washed with cold methanol (2 × 0.5 mL) and dried in vacuum. Yield 409.5 g (96.0%). Its analytical and spectroscopic data are the same as previously reported.7a 2+1+1 imines 1ARRSS. a) 1531 mg (15.04 mmol) of triethylamine, NEt3, was added to the solution of 1311 mg (7.570 mmol) of trans-(1R,2R)-diaminocyclopentane dihydrochloride, 865.0 mg (7.560 mmol) of trans-(1S,2S)-diaminocyclohexane in 38 mL of methanol. After dissolution the solution of amines was combined with the solution of 2046 mg (15.04 mmol) 2,6-diformylopyridine in 38 mL of methanol. The resulting mixture was refluxed for 24 hours. A white solid precipitates. After cooling to room temperature the flask with the suspension was kept in a freezer for 12 hours. The white precipitate was filtered off, washed with cold methanol (2 × 5 mL) and dried in vacuum. Yield 2888.9 g (91.7%). b) 404.8 mg (4.000 mmol) of triethylamine, NEt3, was added to the solution of 173.1 mg (1.000 mmol) of trans-(1R,2R)-diaminocyclopentane dihydrochloride, 187.1 mg (1.000 mmol) of trans23 ACS Paragon Plus Environment


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(1S,2S)-diaminocyclohexane dihydrochloride in 5 mL of methanol. After dissolution the solution of amines was combined with the solution of 270.2 mg (2.000 mmol) 2,6-diformylopyridine in 5 mL of methanol. The resulting mixture was refluxed for 24 hours. A white solid precipitates. After cooling to room temperature the flask with the suspension was kept in a freezer for 12 hours. The white precipitate was filtered off, washed with cold methanol (2 × 0.5 mL) and dried in vacuum. Yield 366.2 g (88.0%). NMR (CDCl3, 500 MHz):  8.00 (dd, J = 7.8, 1.0 Hz, 2H, -pyr), 7.90 (dd, J = 7.7, 1.0 Hz, 2H, -pyr), 7.75 (m, 4H, -pyr, C-pyrCHN), 7.68 (s, 2H, C-pyrCHN), 3.51 (m, 2H, NCHCH2 (CP)), 3.23 (m, 2H, NCHCH2 (CH)), 2.30 (m, 2H, CHCHHCH2 (CP)), 2.24 (m, 2H, CHCHHCH2 (CP)), 2.12 (m, 2H, CHCHaxHeqCH2 (CH)), 2.03 (m, 2H, CH2CH2CH2 (CP)), 1.96 (m, 2H, CHCHaxHeqCH2 (CH)), 1.90 (m, 2H, CH2(CHaxHeq)2CH2 (CH)), 1.50 (m, 2H, CH2(CHaxHeq)2CH2 (CH)). 13C{1H} NMR (CDCl3, 126 MHz):  164.1 (C-pyrCHN), 163.4 (C-pyrCHN), 154.6 (pyr), 153.9 (-pyr), 136.7 (-pyr), 121.7 (-pyr), 121.2 (-pyr), 76.1 (NCHCH2 (CP)), 71.0 (NCHCH2 (CH)), 32.2 (CHCH2CH2 (CH)), 31.0 (CHCH2CH2 (CP)), 24.1 (CH2CH2CH2 (CH)), 21.7 (CH2CH2CH2 (CP)). HRMS (ESI/Q-FT) m/z: [M+Na]+ Calcd for C25H28N6Na 435.2268; Found 435.2274. Anal. Calcd for C25H28N6·0.2H2O: C, 72.16; H, 6.88; N, 20.20. Found: C, 72.16; H, 6.61; N, 20.18. CD [CHCl3] (0.5 mM), 298 K, nm/ λmax (Δε/dm3 mol−1 cm−1)]: 233.1 (34.89), 269.6 (-17.75).

1H

1ASSRR. The opposite enantiomer was obtained in the same way as 1ARRSS using a) trans-(1S,2S)diaminocyclopentane dihydrochloride and trans-(1R,2R)-diaminocyclohexane or b) trans-(1S,2S)diaminocyclopentane dihydrochloride and trans-(1R,2R)-diaminocyclohexane dihydrochloride. Its NMR is identical as for 1ARRSS enantiomer. HRMS (ESI/Q-FT) m/z: [M+Na]+ Calcd for C25H28N6Na 435.2268; Found 435.2273. Anal. Calcd for C25H28N6·0.2H2O: C, 72.16; H, 6.88; N, 20.20. Found: C, 72.37; H, 6.70; N, 20.20. CD [CHCl3] (0.5 mM), 298 K, nm/ λmax (Δε/dm3 mol −1 cm−1)]: 233.1 (-35.43), 269.6 (17.22). 2+1+1 amine tetrahydrochlorides [C25H36N6H4]Cl4·1.75H2O [1BRRSSH4]Cl4·1.75H2O. 707.4 mg (1.700 mmol) of 1ARRSS imine was gradually added in small portions to the solution of 774.2 mg (20.44 mmol) of sodium borohydride in 20 mL of methanol. The mixture was stirred for 12 hours at room temperature. Then the solution was evaporated to dryness on a rotary evaporator and 25 mL of 2 M solution of NaOH was added. The amine was extracted with chloroform (3 × 10 mL), the organic layers were combined, dried over anhydrous sodium sulfate and the solvent was removed in vacuum to deliver white solid of the crude amine product 1BRRSS. The crude amine was dissolved in 10 mL of methanol and 1.5 mL (ca. 17 mmol) of concentrated HCl solution was added. The mixture was evaporated to dryness, dissolved in the solution of methanol / acetonitrile (20 mL / 20 mL). The mixture was concentrated twice on the rotary evaporator, next 20 mL of acetonitrile was added and the resulting mixture was concentrated to ca. 1/3 of the volume, till precipitate appeared. The flask was kept into freezer overnight. The white crystalline precipitate was filtered off, washed with small amount of cold acetonitrile and dried in vacuum. Yield 865.2 mg (85.0%). 1H NMR (D2O, 500 MHz):  = 8.00 (t, J = 7.8 Hz, 2H, 24 ACS Paragon Plus Environment

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-pyr), 7.55 (d, J = 7.8 Hz, 2H, -pyr), 7.52 (d, J = 7.9 Hz, 2H, -pyr), 4.82, 4.55 (ABq, JAB = 15.2 Hz, 4H, C-pyrCH2NH), 4.74, 4.53 (ABq, JAB = 15.2 Hz, 4H, C-pyrCH2NH), 4.20 (m, 2H, NHCHCH2 (CP)), 3.82 (m, 2H, NHCHCH2 (CH)), 2.46 (m, 4H, CHCHaxHeqCH2 (CP), CHCHaxHeqCH2 (CH)), 2.05 (m, 2H, CHCHaxHeqCH2 (CP)), 1.99 (m, 2H, CH2CH2CH2 (CP)), 1.91 (m, 2H, CH2(CHaxHeq)2CH2 (CH)), 1.64 (m, 2H, CHCHaxHeqCH2 (CH)), 1.34 (m, 2H, CH2(CHaxHeq)2CH2 (CH)). 13C{1H} NMR (D2O 126 MHz,):   152.8 (-pyr), 152.6 (-pyr), 142.3 (-pyr), 125.7 (-pyr), 125.4 (-pyr), 63.7 (NHCHCH2 (CP)), 60.2 (NHCHCH2 (CH)), 52.2 (C-pyrCH2NH), 50.5 (C-pyrCH2NH), 29.6 (CHCH2CH2 (CP)), 29.0 (CHCH2CH2 (CH)), 25.3 (CH2CH2CH2 (CH)), 23.5 (CH2CH2CH2 (CP)). HRMS (ESI/Q-FT) m/z: [M+H]+ Calcd for C25H37N6 421.3074; Found 421.3080. Anal. Calcd for C25H36N6·4HCl·1.75H2O: C, 50.22; H, 7.33; N, 14.05. Found: C, 49.92; H, 7.43; N, 13.98. CD [MeOH] (1.0 mM), 298 K, nm/ λmax (Δε/dm3 mol−1 cm−1)]: 210.4 (-1.94), 231.8 (0.45), 246.1 (1.11), 263.7 (-1.20), 268.1 (-1.52). [1BSSRRH4]Cl4·1.75H2O. The opposite enantiomer was obtained in the same way as [1BRRSSH4]Cl4·1.75H2O starting from reduction of 1ASSRR imine. Its NMR is identical as for [1BRRSSH4]Cl4·1.75H2O enantiomer. HRMS (ESI/Q-FT) m/z: [M+H]+ Calcd for C25H37N6 421.3074; Found 421.3082. Anal. Calcd for C25H36N6·4HCl·1.75H2O: C, 50.22; H, 7.33; N, 14.05. Found: C, 50.19; H, 7.31; N, 14.00. CD [MeOH] (1.0 mM), 298 K, nm/ λmax (Δε/dm3 mol−1 cm− 1)]: 211.9 (2.18), 229.8 (-0.41), 245.1 (-1.32), 263.9 (1.38), 268.5 (1.65). Free 2+1+1 amines C25H36N6·0.22CHCl3 1BRRSS·0.22CHCl3. 865.2 mg of solid amine tetrachloride salt, [1BRRSSH4]Cl4·1.75H2O, was added to 10 mL of 2 M NaOH solution. The free amine was extracted with chloroform (3 x 5 mL), the combined organic solutions were dried over anhydrous sodium sulfate and the solvent was removed on a rotary evaporator to deliver white solid, which was dried using vacuum pump. Yield 643.1 mg (100%). 1H NMR (CDCl3, 500 MHz,):  = 7.51 (t, J = 7.6 Hz, 2H, -pyr), 7.01 (d, J = 7.6 Hz, 4H, -pyr), 4.03, 3.75 (ABq, JAB = 13.9 Hz, 4H, C-pyrCH2NH), 3.95, 3.72 (ABq, JAB = 14.1 Hz, 4H, C-pyrCH2NH), 2.71 (m, 2H, NHCHCH2 (CP)), 2.60 (s (broad), 4H, NH), 2.27 (m, 2H, NHCHCH2 (CH)), 2.15 (m, 2H, CHCHaxHeqCH2 (CH)), 1.99 (m, 2H, CHCH2CH2 (CP)), 1.71 (m, 2H, CH2(CHaxHeq)2CH2 (CH)), 1.66 (m, 2H, CH2CH2CH2 (CP)), 1.41 (m, 2H, CHCH2CH2 (CP)), 1.19 (m, 2H, CH2(CHaxHeq)2CH2 (CH)), 1.06 (m, 2H, CHCHaxHeqCH2 (CH)). 13C{1H} NMR (CDCl3, 126 MHz,):  159.6 (-pyr), 159.1 (-pyr), 136.3 (-pyr), 120.8 (-pyr), 120.6 (-pyr), 63.6 (NHCHCH2 (CP)), 60.2 (NHCHCH2 (CH)), 53.0 (C-pyrCH2NH), 51.4 (C-pyrCH2NH), 30.7 (CHCH2CH2 (CP), 30.6 (CHCH2CH2 (CH)), 25.0 (CH2CH2CH2 (CH)), 21.1 (CH2CH2CH2 (CP)). HRMS (ESI/Q-FT) m/z: [M+H]+ Calcd for C25H37N6 421.3074; Found 421.3082. Anal. Calcd for C25H36N6·0.22CHCl3: C, 67.79; H, 8.17; N, 18.81. Found: C, 67.76; H, 8.21; N, 18.79. CD [MeOH] (0.5 mM), 298 K, nm/ λmax (Δε/dm3 mol−1 cm−1)]: 205.2 (0.91), 214.4 (1.14), 235.3 (-0.02), 265.4 (1.78), 273.5 (0.96), 282.1 (-0.82). 1BSSRR·0.22CHCl3. The opposite enantiomer was obtained in the same way as 1BRRSS·0.22CHCl3 starting from [1BSSRRH4]Cl4·1.75H2O amine tetrachloride. Its NMR is identical as for 25 ACS Paragon Plus Environment


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1BRRSS·0.22CHCl3 enantiomer. HRMS (ESI/Q-FT) m/z: [M+H]+ Calcd for C25H37N6 421.3074; Found 421.3079. Anal. Calcd for C25H36N6·0.22CHCl3: C, 67.79; H, 8.17; N, 18.81. Found: C, 68.07; H, 8.22; N, 18.87. CD [MeOH] (0.5 mM), 298 K, nm/ λmax (Δε/dm3 mol −1 cm −1)]: 205.1 (1.91), 211.2 (-2.26), 239.1 (0.36), 264.7 (-1.54), 273.4 (-0.71), 282.1 (0.81). 4+2+2 imines C50H56N12∙0.67C6H6·H2O 2ARRSSRRSS∙0.67C6H6·H2O. 228.5 mg (2.281 mmol) of trans-(1R,2R)-diaminocyclopentane and 260.5 mg (2.281 mmol) of trans-(1S,2S)-diaminocyclohexane were dissolved in 20 mL of benzene. To the solution of diamines, the solution of 616.5 mg (4.563 mmol) of 2,6-diformylpyridine in 20 mL of benzene was added. A white solid precipitates. The mixture was stirred for 24 hours at room temperature. The white solid was filtered off, washed with small amount of benzene and dried in vacuum. Yield 184.1 mg (18.0 %). 1H NMR (CDCl3, 500 MHz,):   8.31 (s, 4H, C-pyrCHN), 8.26 (s, 4H, C-pyrCHN), 7.90 (dd, J = 7.8, 1.0 Hz, 4H, -pyr), 7.86 (dd, J = 7.8 Hz, 1.0 Hz, 4H, -pyr), 7.58 (t, J = 7.7 Hz, 4H, -pyr), 3.94 (m, 4H, NHCHCH2 (CP)), 3.49 (m, 4H, NHCHCH2 (CH)), 2.02 (m, 4H, CHCHHCH2 (CP)), 1.94 (m, 8H, CHCHHCH2 (CP), CH2CH2CH2 (CP)), 1.86 (m, 4H, CH2(CHH)2CH2 (CH)), 1.76 (m, 8H, CHCH2CH2 (CH)), 1.49 (m, 4H, CH2(CHH)2CH2 (CH)). 13C{1H} NMR (150 MHz, CDCl3):   161.7 (C-pyrCHN), 160.9 (C-pyrCHN), 154.2 (-pyr), 154.0 (-pyr), 136.7 (-pyr), 121.7 (-pyr), 121.7 (-pyr), 77.6 (NHCHCH2 (CP)), 73.9 (NHCHCH2 (CH)), 32.8 (CHCH2CH2 (CH)), 32.6 (CHCH2CH2 (CP)), 24.3 (CH2CH2CH2 (CH)), 21.6 (CH2CH2CH2 (CP)). HRMS (ESI/Q-FT) m/z: [M+Na]+ Calcd for C50H56N12Na 847.4643; Found 847.4645. Anal. Calcd for C50H56N12·0.67C6H6·H2O: C, 72.46; H, 6.98; N, 18.77. Found: C, 72.63; H, 6.90; N, 18.44. CD [CHCl3] (0.5 mM), 298 K, nm/ λmax (Δε/dm3 mol−1 cm−1)]: 236.6 (93.95), 269.5 (-35.88), 301.2 (-9.04). 2ASSRRSSRR∙0.67C6H6·H2O. The opposite enantiomer was obtained in the same way as 2ARRSSRRSS∙0.67C6H6·H2O starting from trans-(1S,2S)-diaminocyclopentane and trans-(1R,2R)diaminocyclohexane. Its NMR is identical as for 2ARRSSRRSS∙0.67C6H6·H2O enantiomer. HRMS (ESI/Q-FT) m/z: [M+Na]+ Calcd for C50H56N12Na 847.4643; Found 847.4651. Anal. Calcd for C50H56N12·0.67C6H6·H2O: C, 72.46; H, 6.98; N, 18.77. Found: C, 72.57; H, 7.04; N, 18.49. CD [CHCl3] (0.5 mM), 298 K, nm/ λmax (Δε/dm3 mol −1 cm −1)]: 236.8 (-94.02), 269.8 (36.34), 301.2 (9.18). 4+2+2 amine octahydrochlorides [C50H72N12H8]Cl8·2.25H2O·1.75CHCl3 [2BRRSSRRSSH8]Cl8·2.25H2O·1.75CHCl3. 220 mg (5.82 mmol) of NaBH4 was dissolved in 10 mL of methanol. Next 107.6 mg (0.1212 mmol) of 2ARRSSRRSS imine was added every 8 minutes in small portions. To finish the reduction the next part of 220 of NaBH4 (5.82 mmol) was added. The mixture was stirred 12 hours at room temperature, then evaporated to dryness. To the solid residue 8 mL of 2 M NaOH water solution of was added. Then the suspension was extracted with chloroform (3 x 4 mL), the combined organic layers were dried over anhydrous sodium sulfate and the solution was evaporated to dryness. The sticky liquid was dissolved in 8 mL of methanol and 200 L (2.20 mmol) of concentrated hydrochloric acid was added. The mixture was evaporated to dryness and recrystallized from methanol / chloroform solution (it was dissolved in 3 mL of MeOH 26 ACS Paragon Plus Environment

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and 6 mL of CHCl3 was added, the solution was concentrated to 1/3 of the volume, next 6 mL of CHCl3 was added and the solution was concentrated to 1/3 of the volume, the procedure was repeated once again till precipitation of hydrochloride salt. After overnight standing in a freezer the white crystalline precipitate was filtered off, washed with small amount of cold chloroform and dried in vacuum. Yield 93.5 mg (56.0%). 1H NMR (D2O, 500 MHz,):  = 7.93 (t, J = 7.8 Hz, 4H, -pyr), 7.45 (d, J = 7.7 Hz, 4H, -pyr), 7.37 (d, J = 7.8 Hz, 4H, -pyr), 4.64, 4.23 (ABq, JAB = 15.5 Hz, 8H, C-pyrCH2NH), 4.60, 4.35 (ABq, JAB = 15.3 Hz, 8H, C-pyrCH2NH), 4.25 (m, 4H, NHCHCH2 (CP)), 3.89 (m, 4H, NHCHCH2 (CH)), 2.36 (m, 8H, CHCHaxHCH2 (CP), CHCHaxHCH2 (CH)), 2.02 (m, 4H, CHCHHeqCH2 (CP)), 1.92 (m, 4H, CH2CH2CH2 (CP)), 1.82 (m, 4H, CH2(CHaxHeq)2CH2 (CH)), 1.64 (m, 4H, CHCHaxHCH2 (CH)), 1.40 (m, 4H, CH2(CHaxHeq)2CH2 (CH)). 13C{1H} NMR (126 MHz, D2O):   153.2 (-pyr), 152.8 (-pyr), 142.1 (-pyr), 125.1 (-pyr), 125.0 (-pyr), 64.7 (NHCHCH2 (CP)), 61.1 (NHCHCH2 (CH)), 52.8 (C-pyrCH2N), 51.4 (C-pyrCH2N), 30.4 (CHCH2CH2 (CP)), 28.7 (CHCH2CH2 (CH)), 24.7 (CH2CH2CH2 (CP)), 24.6 (CH2CH2CH2 (CH)). HRMS (ESI/Q-FT) m/z: [M+H]+ Calcd for C50H73N12 841.6076; Found 841.6093. Anal. Calcd for C50H72N12·8HCl·2.25H2O·1.75CHCl3: C, 44.96; H, 6.29; N, 12.16. Found: C, 45.24; H, 6.58; N, 12.28. CD [MeOH] (0.4 mM), 298 K, nm/ λmax (Δε/dm3 mol−1 cm−1)]: 215.3 (6.12), 229.1 (-0.53), 245.0 (-2.28), 265.7 (1.91), 269.8 (2.26). [2BSSRRSSRRH8]Cl8·2.25H2O·1.75CHCl3. The opposite enantiomer was obtained in the same way as [2BRRSSRRSSH8]Cl8·2.25H2O·1.75CHCl3 starting from reduction of 2ASSRRSSRR imine. Its NMR is identical as for [2BRRSSRRSSH8]Cl8·2.25H2O·1.75CHCl3 enantiomer. HRMS (ESI/Q-FT) m/z: [M+H]+ Calcd for C50H73N12 841.6076; Found 841.6091. Anal. Calcd for C50H72N12·8HCl·2.25H2O·1.75CHCl3: C, 44.96; H, 6.29; N, 12.16. Found: C, 44.72; H, 6.30; N, 12.12. CD [MeOH] (0.4 mM), 298 K, nm/ λmax (Δε/dm3 mol−1 cm−1)]: 214.2 (-6.62), 229.5 (0.03), 245.1 (2.03), 265.0 (-1.57), 270.1 (-1.84). Free 4+2+2 amines C50H72N12·1.75H2O 2BRRSSRRSS·1.75H2O. 93.5 mg of [2BRRSSRRSSH8]Cl8·2.25H2O·1.75CHCl3 amine octahydrochloride was dissolved in 5 mL of 2 M NaOH solution. The mixture was extracted with chloroform (3 x 5 mL), the combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed on a rotary evaporator to give sticky liquid. Yield 56.9 mg (100%). 1H NMR (CDCl3, 500 MHz,):  = 7.53 (t, J = 7.6 Hz, 4H, -pyr), 7.21 (d, J = 7.6 Hz, 4H, -pyr), 7.11 (d, J = 7.5 Hz, 4H, -pyr), 3.97, 3.77 (ABq, JAB = 14.2 Hz, 8H, C-pyrCH2NH), 3.86, 3.77 (ABq, JAB = 14.2 Hz, 8H, C-pyrCH2NH), 2.77 (m, 4H, NHCHCH2 (CP)), 2.34 (s (broad), 8H, NH), 2.27 (m, 4H, NHCHCH2 (CH)), 2.09 (m, 4H, CHCHHeqCH2 (CH)), 1.90 (m, 4H, CHCHaxHCH2 (CP)), 1.67 (m, 4H, CH2(CHaxHeq)2CH2 (CH)), 1.61 (m, 4H, CH2CH2CH2 (CP)), 1.33 (m, 4H, CHCHHeqCH2 (CP)), 1.18 (m, 4H, CH2(CHaxHeq)2CH2 (CH)), 1.03 (m, 4H, CHCHaxHCH2 (CH)). 13C{1H} NMR (CDCl 126 MHz,):  = 160.0 (-pyr), 159.3 (-pyr), 136.7 (-pyr), 120.3 (-pyr), 3 120.3 (-pyr), 64.9 (NHCHCH2 (CP)), 61.3 (NHCHCH2 (CH)), 53.7 (C-pyrCH2NH), 52.2 (CpyrCH2NH), 31.6 (CHCH2CH2 (CH)), 31.4 (CHCH2CH2 (CP)), 25.0 (CH2CH2CH2 (CH)), 21.6 (CH2CH2CH2 (CP). HRMS (ESI/Q-FT) m/z: [M+H]+ Calcd for C50H73N12 841.6076; found: 27 ACS Paragon Plus Environment


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841.6060. Anal. Calcd for C50H72N12·1.75H2O: C, 68.81; H, 8.72; N, 19.26. Found: C, 68.82; H, 8.91; N, 19.06. CD [MeOH] (0.5 mM), 298 K, nm/ λmax (Δε/dm3 mol−1 cm−1)]: 209.7 (2.52), 250.5 (-0.84), 266.8 (-0.04), 272.8 (-0.26), 275.0 (-0.11), 282.6 (-0.66). 2BSSRRSSRR·1.75H2O The opposite enantiomer was obtained in the same way as 2BRRSSRRSS·1.75H2O starting from [2BSSRRSSRRH8]Cl8·2.25H2O·1.75CHCl3 amine octahydrochloride. Its NMR is identical as for 2BRRSSRRSS·1.75H2O enantiomer. HRMS (ESI/QFT) m/z: [M+H]+ Calcd for C50H73N12 841.6076; found 841.6058. Anal. Calcd for C50H72N12·1.75H2O: C, 68.81; H, 8.72; N, 19.26. Found: C, 68.81; H, 8.92; N, 19.02. CD [MeOH] (0.5 mM), 298 K, nm/ λmax (Δε/dm3 mol−1 cm−1)]: 209.6 (-3.01), 249.9 (0.96), 267.1 (0.32), 272.9 (0.51), 275.5 (0.46), 281.0 (0.66). Hexanuclear CdII complex with 6+3+3 imine [Cd6(C75H84N18)Cl12](CdCl2)5 [Cd6(3ARRSSRRSSRRSS)Cl12](CdCl2)5. A solution of 3.2996 g (18.000 mmol) of anhydrous CdCl2 in 750 mL of methanol MeOH was combined with a solution of 1.2484 g (3.0000 mmol) of 1ARRSS in 750 mL of chloroform. The mixture was stirred for 48 hours at 30 oC. The precipitate was filtered off, washed with small amount of methanol and dried in vacuum. Yield 1.3105 g (40.3%). 1H NMR (CDCl3/CD3OD v/v 2/1, 500 MHz,):   9.00 (s, 6H, C-pyrCHN), 8.94 (s, 6H, C-pyrCHN), 8.11 (t, J = 7.8 Hz, 6H, -pyr), 7.84 (dd, J = 7.8, 0.8 Hz, 6H, -pyr), 7.69 (dd, J = 7.8 Hz, 0.8 Hz, 6H, -pyr), 4.87 (m, 6H, NHCHCH2), 4.36 (m, 6H, NHCHCH2), 2.50 (m, 6H, CH2), 2.21 (m, 6H, CH2), 2.03 (m, 12H, CH2), 1.87 (m, 6H, CH2), 1.69 (m, 6H, CH2), 1.53 (m, 6H, CH2). MS (ESITOF) m/z: 1041.5 [Cd5(C75H84N18)(Cl)8]2+, 1132.4 [Cd6(C75H84N18)(Cl)10]2+. Anal. Calcd for C75H84N18Cd11Cl22: C, 27.68; H, 2.60; N, 7.75. Found: C, 27.51; H, 2.95; N, 7.62. CD [CHCl3] (0.1 mM), 298 K, nm/ λmax (Δε/dm3 mol−1 cm−1)]: 243.1 (-41.87), 254.5 (34,61), 261.6 (78.85), 296.1 (2.27), 304.1 (-4.59), 316.0 (-41.44), 320.6 (-37.34), 327.0 (-59.26). [Cd6(3ASSRRSSRRSSRR)Cl12](CdCl2)5. The opposite enantiomer was obtained in the same way as [Cd6(3ARRSSRRSSRRSS)Cl12](CdCl2)5 starting from reaction of 1ASSRR imine. Its NMR is identical as for [Cd6(3ARRSSRRSSRRSS)Cl12](CdCl2)5 enantiomer. MS (ESI-TOF) m/z: 1041.5 [Cd5(C75H84N18)(Cl)8]2+, 1132.4 [Cd6(C75H84N18)(Cl)10]2+.Anal. Calcd for C75H84N18Cd11Cl22: C, 27.68; H, 2.60; N, 7.75. Found: C, 27.58; H, 2.86; N, 7.60. CD [CHCl3] (0.1 mM), 298 K, nm/ λmax (Δε/dm3 mol−1 cm−1)]: 243.9 (41.44), 254.7 (-31.03), 261.4 (-78.58), 297.0 (-1.49), 304.2 (4.94), 315.5 (40.82), 320.8 (37.39), 327.6 (57.57). 6+3+3 amine dodecahydrochlorides [C75H108N18H12]Cl12·11.5H2O [3BRRSSRRSSRRSSH12]Cl12·11.5H2O. 1.3105 g of the imine [3ARRSSRRSSRRSSCd6Cl12](CdCl2)5 complex was suspended in 300 mL of methanol and 3 mL of water. Next 4.20 g (111 mmol) of sodium borohydride was added quickly. After 3 hours of stirring at room temperature metallic cadmium precipitate was filtered off through a layer of celite and the clear solution was stirred for additional 9 hours. Then the solution was evaporated to dryness and 50 mL of 25 % ammonia solution and 50 mL of water were added to the dry residue. The mixture was stirred 1 hour at room temperature and then extracted with chloroform (3 x 10 mL). The organic solutions were combined, dried over anhydrous sodium sulfate and evaporated to dryness to give 439.0 mg (yield = ca 73%) 28 ACS Paragon Plus Environment

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of sticky liquid of crude free amine. The product was dissolved in 15 mL of methanol and 2.5 mL (ca. 28 mmol) of concentrated hydrochloric acid was added and the solution was left for 3 days at room temperature for crystallization. After that time the crystalline solid was filtered off, washed with small amount of methanol and dried in vacuum. Yield 336.4 mg (43.8%). 1H NMR (D2O, 500 MHz,):  = 7.81 (t, J = 7.8 Hz, 6H, -pyr), 7.38 (d, J = 7.8 Hz, 6H, -pyr), 7.32 (d, J = 7.8 Hz, 6H, -pyr), 4.61, 4.31 (ABq, JAB = 15.1 Hz, 12H, C-pyrCH2NH), 4.53, 4.42 (ABq, JAB = 15.0 Hz, 12H, C-pyrCH2NH), 4.24 (m, 6H, NHCHCH2 (CP)), 3.88 (m, 6H, NHCHCH2 (CH)), 2.30 (m, 12H, CHCHaxHCH2 (CP), CHCHaxHeqCH2 (CH)), 1.94 (m, 6H, CHCHaxHeqCH2 (CP)), 1.86 (m, 6H, CH2CH2CH2 (CP)), 1.75 (m, 6H, CH2(CHaxHeq)2CH2 (CH)), 1.64 (m, 6H, CHCHaxHCH2 (CH)), 1.34 (m, 6H, CH2(CHaxHeq)2CH2 (CH)). 13C{1H} NMR (125 MHz, D2O):  153.1 (-pyr), 153.0 (-pyr), 142.0 (-pyr), 125.3 (-pyr), 125.2 (-pyr), 64.7 (NHCHCH2 (CP)), 60.7 (NHCHCH2 (CH)), 52.8 (C-pyrCH2N), 51.5 (C-pyrCH2N), 30.9 (CHCH2CH2 (CP)), 28.5 (CHCH2CH2 (CH)), 25.0 (CH2CH2CH2 (CP)), 24.4 (CH2CH2CH2 (CH)). HRMS (ESI/Q-FT) m/z: [M+H]+ Calcd for C75H109N18 1261.9077; Found: 1261.9058. Anal. Calcd for C75H108N18·12HCl·11.5H2O: C, 47.25; H, 7.56; N, 13.22. Found: C, 47.03; H, 7.70; N, 12.95. CD [MeOH] (0.2 mM), 298 K, nm/ λmax (Δε/dm3 mol −1 cm −1)]: 220.2 (1.65), 236.8 (-1.19), 262.1 (3.07), 269.5 (-2.03). [3BSSRRSSRRSSRRH12]Cl12·11.5H2O. The opposite enantiomer was obtained in the same way as [3BRRSSRRSSRRSSH12]Cl12·11.5H2O starting from reaction of 1ASSRR imine. Its NMR is identical as for [3BRRSSRRSSRRSSH12]Cl12·11.5H2O enantiomer. HRMS (ESI/Q-FT) m/z: [M+H]+ Calcd for C75H109N18 1261.9077; Found: 1261.9071. Anal. Calcd for C75H108N18·12HCl·11.5H2O: C, 47.25; H, 7.56; N, 13.22. Found: C, 47.38; H, 7.64; N, 13.10. CD [MeOH] (0.2 mM), 298 K, nm/ λmax ( Δε/dm3 mol−1 cm−1)]: 220.3 (-2.56), 235.6 (1.18), 259.1 (3.25), 268.9 (1.79). Free 6+3+3 amines C75H108N18·2.7CH2Cl2 3BRRSSRRSSRRSS·2.7CH2Cl2. 336.4 mg of [3BRRSSRRSSRRSSH12]Cl12·11.5H2O was dissolved in 6 mL of 2 M NaOH solution and the liberated amine was extracted with dichloromethane (3 × 5 mL). The organic solutions were combined, dried over anhydrous sodium sulfate and evaporated to dryness to give sticky liquid. Yield 263.1 mg (100 %). 1H NMR (500 MHz, CDCl3):  7.54 (t, J3 = 7.6 Hz, 6H, -pyr), 7.23 (d, J3 = 7.6 Hz, 6H, -pyr), 7.14 (d, J3 = 7.6 Hz, 6H, -pyr), 3.99, 3.81 (ABq, JAB = 14.4 Hz, 12H, C-pyrCH2NH), 3.88, 3.80 (ABq, JAB = 14.2 Hz, 12H, C-pyrCH2NH), 2.80 (m, 6H, NHCHCH2 (CP)), 2.28 (s (broad), 12H, NH and m, 6H, NHCHCH2 (CH)), 2.10 (m, 6H, CHCHHeqCH2 (CH)), 1.91 (m, 6H, CHCHaxHCH2 (CP)), 1.67 (m, 6H, CH2(CHaxHeq)2CH2 (CH)), 1.61 (m, 6H, CH2CH2CH2 (CP)), 1.33 (m, 6H, CHCHHeqCH2 (CP)), 1.18 (m, 6H, CH2(CHaxHeq)2CH2 (CH)), 1.03 (m, 6H, CHCHaxHCH2 (CH)). 13C{1H} NMR (125 MHz, CDCl3):  160.0 (-pyr), 159.4 (-pyr), 136.7 (-pyr), 120.2 (-pyr), 120.2 (-pyr), 65.0 (NHCHCH2 (CP)), 61.3 (NHCHCH2 (CH)) 53.8 (C-pyrCH2NH), 52.3 (C-pyrCH2NH), 31.6 (CHCH2CH2 (CH)), 31.4 (CHCH2CH2 (CP)), 25.0 (CH2CH2CH2 (CH)), 21.6 (CH2CH2CH2 (CP). HRMS (ESI/Q-FT) m/z: [M+H]+ Calcd for C75H109N18 1261.9077; Found 1261.9054. Anal. Calcd for C75H108N18·2.7CH2Cl2: C, 62.59; H, 7.67; N, 16.91. Found: C, 62.81; H, 7.65; N, 16.71. CD 29 ACS Paragon Plus Environment


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[MeOH] (0.5 mM), 298 K, nm/ λmax ( Δε/dm3 mol − 1 cm − 1)]: 208.5 (-4.26), 232.6 (0.01), 253.1 (1.87). 3BSSRRSSRRSSRR·2.7CH2Cl2. The opposite enantiomer was obtained in the same way as 3BSSRRSSRRSSRR·2.7CH2Cl2 starting from [3BSSRRSSRRSSRRH12]Cl12·11.5H2O. Its NMR is identical as for 3BSSRRSSRRSSRR·2.7CH2Cl2 enantiomer. HRMS (ESI/Q-FT) m/z: [M+H]+ Calcd for C75H109N18 1261.9077; Found 1261.9057. Anal. Calcd for C75H108N18·2.7CH2Cl2: C, 62.59; H, 7.67; N, 16.91. Found: C, 62.27; H, 7.58; N, 16.66. CD [MeOH] (0.5 mM), 298 K, nm/ λmax (Δ ε/dm3 mol−1 cm−1)]: 209.5 (3.60), 233.5 (0.23), 254.0 (-1.48). The non-templated competition reaction. Typical procedures. a) With taking a sample after respective reflux time. The solution containing 187.1 mg (1.000 mmol) of racemic trans-1,2-diaminocyclohexane dichloride, 173.1 mg (1.000 mmol) of racemic trans-1,2-diaminocyclopentane dihydrochloride and 404.8 mg (4.000 mmol) of triethylamine in 5 mL of methanol was combined with the solution of 270.2 mg (2.000 mmol) of 2,6-diformylopyridine in 5 mL of methanol. A sample of 200 L of suspension was taken after 1 h, 2 h, 3 h, 4 h, 6 h, 12 h, 24 h, 60 h and 120 h of reflux. Each of them was filtrated and the solid was washed with several drops of methanol and dried in vacuum. b) Witch isolation of reaction product after the shortest and the longest reflux time. The same synthetic procedure was applied in two separated reaction flasks. Each reaction was heated under reflux for 1 h and 120 h, respectively. After above mentioned time each reaction content was cooled to room temperature and put into freezer. The solid was filtered off, washed with 1 mL of cold methanol and dried in vacuum. The yields are: 89.4% (1 h) and 88.8% (120 h), respectively. Supporting Information Computational and crystallographic data, Figures S1-S78 (ESI MS, NMR, CD and UV spectra, views of molecular structures), Scheme S1, Table S1 and S2, as well as X-ray crystallographic information in CIF format. This material is available free of charge via the Internet at http://pubs.acs.org. Acknowledgements This research was supported by NCN grant (Narodowe Centrum Nauki, Poland) 2017/25/B/ST5/00722. A.B. would like to thank to the Wrocław Center for Networking and Supercomputing (WCSS) for a computer time grant. Appendix A. Supplementary data CCDC 1876980–1876984, 1884478 contain the supplementary crystallographic data for 1ASSRR and 2ASSRRSSRR·CH2Cl2 macrocyclic imine compounds as well as for [1BSSRRH4]Cl4·1.7CH3CN·1.2CH3OH·0.4H2O, [2BSSRRSSRRH8]Cl8·5H2O and [3BRRSSRRSSRRSSH12]Cl12·2CH3CN·3.5CH3OH·6.5H2O protonated amine macrocycles. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the


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Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or e-mail: [email protected]. Notes: * - We decided to use in the nomenclature of mixed macrocycles Arabic numerals 1, 2, and 3 and the letter A for imines and B for amines. The chiralities of products are signed by RR and SS descriptors, where the first two letters apply to the chirality of DACP unit. As all the macrocyclic products possess the alternating diamine units of opposite chirality the two next letters apply to the DACH moiety and etc. For example, the 2BRRSSRRSS code stands for the 4+2+2 macrocyclic amine built of four DFP units, two units of (RR)-DACP and two units of (SS)-DACH. For already published not-mixed macrocycles built up from DFP and solely DACP (CP) or DACH (CH) units we decided to distinguish them with Roman numerals I, II, III and laters A and B for imines and amines, respectively. For example, the IIIACP means 6+6 imine macrocycle containing the DACP units. References: (a) Rezaeivala, M.; Keypour, H. Schiff Base and Non-Schiff Base Macrocyclic Ligands and Complexes Incorporating the Pyridine Moiety – The First 50 Years. Coord. Chem. Rev. 2014, 280, 203–253. (b) Vigato, P. A.; Tamburini, S.; Bertolo, L. The Development of Compartmental Macrocyclic Schiff Bases and Related Polyamine Derivatives. Coord. Chem. Rev. 2007, 251 (11–12), 1311–1492. (c) Mewis, R. E.; Archibald, S. J. Biomedical Applications of Macrocyclic Ligand Complexes. Coord. Chem. Rev. 2010, 254 (15–16), 1686–1712. (d) Liu, Z.; Nalluri, S. K. M.; Fraser Stoddart, J. Surveying Macrocyclic Chemistry: From Flexible Crown Ethers to Rigid Cyclophanes. Chem. Soc. Rev. 2017, 46 (9), 2459–2478. (e) Lindoy, L. F.; Park, K. M.; Lee, S. S. Metals, Macrocycles and Molecular Assemblies-Macrocyclic Complexes in Metallo-Supramolecular Chemistry. Chem. Soc. Rev. 2013, 42 (4), 1713–1727. (f) Joshi, T.; Graham, B.; Spiccia, L. Macrocyclic Metal Complexes for Metalloenzyme Mimicry and Sensor Development. Acc. Chem. Res. 2015, 48 (8), 2366–2379. (g) Gale, P. A.; Howe, E. N. W.; Wu, X.; Spooner, M. J. Anion Receptor Chemistry: Highlights from 2016. Coord. Chem. Rev. 2018, 375 (1), 333–372. 2 (a) Kaitz, J. A.; Diesendruck, C. E.; Moore, J. S. End Group Characterization of Poly(Phthalaldehyde): Surprising Discovery of a Reversible, Cationic Macrocyclization Mechanism. J. Am. Chem. Soc. 2013, 135 (34), 12755–12761. (b) Kawai, H.; Utamura, T.; Motoi, E.; Takahashi, T.; Sugino, H.; Tamura, M.; Ohkita, M.; Fujiwara, K.; Saito, T.; Tsuji, T.; et al. Hydrindacene-Based Acetylenic Macrocycles with Horizontally and Vertically Ordered Functionality Arrays. Chem. - A Eur. J. 2013, 19 (14), 4513–4524. (c) Li, M.; Klärner, F.-G.; Sakamoto, J.; Schlüter, A. D. Synthesis of Shape-Persistent Macrocycles with Three 1,8-Diazaanthracene Units and Their Packing in the Single Crystal. Chem. - A Eur. J. 2013, 19 (40), 13348–13354. (d) Lee, S.; Chen, C.-H.; Flood, A. H. A Pentagonal Cyanostar Macrocycle with Cyanostilbene CH Donors Binds Anions and Forms Dialkylphosphate [3]Rotaxanes. Nat. Chem. 2013, 5 (8), 704–710. (e) Scully, C. C. G.; Rai, V.; Poda, G.; Zaretsky, S.; Burns, D. C.; Houliston, R. S.; Lou, T.; Yudin, A. K. Bending Rigid Molecular Rods: Formation of Oligoproline Macrocycles. Chem. - A Eur. J. 2012, 18 (49), 15612– 15617. (f) Matsui, K.; Segawa, Y.; Itami, K. Synthesis and Properties of Cycloparaphenylene-2,5-Pyridylidene: A Nitrogen-Containing Carbon Nanoring. Org. Lett. 2012, 14 (7), 1888–1891. (g) Fritzsche, M.; Bohle, A.; Dudenko, D.; Baumeister, U.; Sebastiani, D.; Richardt, G.; Spiess, H. W.; Hansen, M. R.; Höger, S. Empty Helical Nanochannels with Adjustable Order from Low-Symmetry Macrocycles. Angew. Chemie - Int. Ed. 2011, 50 (13), 3030–3033. 3 (a) Stadler, A.-M.; Jiang, J.-J.; Wang, H.-P.; Bailly, C. Large Shape-Persistent Metal-Invertible 15-Nsp2-DonorAtom Macrocycles Functioning as Trinucleating Ligands. Chem. Commun. 2013, 49 (36), 3784. (b) Kim, M. J.; Choi, Y. R.; Jeon, H.-G.; Kang, P.; Choi, M.-G.; Jeong, K. A Helically Twisted Imine Macrocycle That Allows for Determining the Absolute Configuration of α-Amino Carboxylates. Chem. Commun. 2013, 49 (97), 11412. (c) Okochi, K. D.; Han, G. S.; Aldridge, I. M.; Liu, Y.; Zhang, W. Covalent Assembly of Heterosequenced Macrocycles and Molecular Cages through Orthogonal Dynamic Covalent Chemistry (ODCC). Org. Lett. 2013, 15 (17), 4296–4299. (d) Leeland, J. W.; White, F. J.; Love, J. B. Encapsulation of a Magnesium Hydroxide Cubane by a Bowl-Shaped Polypyrrolic Schiff Base Macrocycle. J. Am. Chem. Soc. 2011, 133 (19), 7320–7323. (e) Guieu, S.; Crane, A. K.; MacLachlan, M. J. Campestarenes: Novel Shape-Persistent Schiff Base Macrocycles with 5-Fold Symmetry. Chem. 1



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TOC graphics

N N 2 O

N

O

+

N

N

N

N N

N N

CdCl2

N

Cd

(S) NH

2

(S) NH2

=

(R) NH2

Cd

N

Cl Cl Cd N

=

N

Cl Cd Cl Cl Cl

Cl Cl

N N

N

N

N Cd

Cl Cl Cl

N

N

Cl

N

Cd N

N N

(R) NH2


Mixed Macrocycles Derived from 2,6-Diformylpyridine and Opposite

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