Cosmosen: Octa-Armed 24-Membered Cyclic Octaamine Synthesized from a Byproduct in the Preparation of 4-Benzyl-2,6-dioxocyclen

from a Byproduct in the Preparation of 4 ‑Benzyl-2,6-dioxocyclen

Note

Cosmosen: Octa-Armed 24-Membered Cyclic Octaamine Synthesized

Huiyeong Ju, Miki Iwase, Hikari Sako, Hiroki Horita, Shiori Koike, Eunji Lee, Mari Ikeda,

Shunsuke Kuwahara, and Yoichi Habata*

Cite This: J. Org. Chem. 2021, 86, 9847 −9853

Read Online

ACCESS

Metrics & More

Article Recommendations

sı Supporting Information

ABSTRACT: The synthesis of an octa-armed 24-membered cyclic octaamine (1) is

reported. When 4-benzyl-1,4,7,10-tetraazacyclododecane-2,6-dione (3a) was prepared

by the reaction of diethylenetriamine with diethyl N-benzyliminodiacetate (2), a

dimeric macrocycle (3b) was obtained as a byproduct in a 5% yield. An octa-armed 24-

membered cyclic octaamine (1), named Cosmosen, was prepared via the reductive

amination and reduction of 3b. The binding constants for the 1:1 and 2:1 (Ag /1)

complexation of 1 were estimated to be ca. 7.9 and 13.9, respectively, by titration

experiments using UV−vis spectrometry in methanol and chloroform (v/v, 9:1)

solutions at 298 K.

he macrocyclic polyamines of the series [3m]aneN (m >

6) have attracted substantial attention not only because

silver(I) complexes were formed, the aromatic side arms in the

armed cyclens covered the Ag incorporated into the cyclen

of the possibility to bind more than one metal ion within the

cavities via Ag −π and CH−π interactions, similar to an

−17

35−41

macrocyclic cavity

but also because of the development of

insectivorous plant (Venus ﬂytrap).

We called the armed

18,19

anion coordination chemistry.

In the case of 12-membered

cyclens argentivorous molecules. We also reported that a

silver(I) complex of a double-armed 24-membered macrocycle,

which consisted of two nitrogen atoms and six sulfur atoms,

macrocyclic polyamines, the formation of mononuclear

complexes is preferred. Unlike 12-membered macrocyclic

polyamines, as the size of these macrocycles increases, their

ﬂexibility increases, and the coordination features of their

formed a 2:1 (Ag :ligand) complex. In the silver(I) complex,

each aromatic side arm encapsulated the silver(I) ion from the

opposite side. Therefore, we were interested in the

conformation of the aromatic side arms in an octa-armed 24-

membered macrocyclic octaamine when they formed com-

plexes with multiple silver ions. In addition, we thought that

the analysis of these conformational changes of the aromatic

side arms would provide helpful information for the develop-

ment of a new argentivorous molecule.

−17

metal complexes depend on the metal ions.

Additionally,

the stabilities of the binuclear complexes increase in the case of

large macrocyclic polyamines. The crystal structures of

dinuclear complexes of [24]aneN₈and [30]aneN₁₀with

Cu(II), Zn(II), Pd(II), and Ni(II) have already been

1−17

reported.

The general method for synthesizing large macrocyclic

During the preparation of 4-benzyl-2,6-dioxocyclen (3a in

Scheme 1), we accidentally found a benzyl-substituted 24-

membered macrocyclic byproduct. Following our previous

works on tetra-armed cyclens, we started to prepare an octa-

armed 24-membered cyclic octaamine. A tetra-armed 24-

polyamines has been reported to include the cyclization of the

appropriate polyamine, as described by Atkins. The reported

synthetic reactions have a large number of steps and occur

under vigorous reaction conditions. Additionally, the overall

yield seriously decreases as the size of the macrocycle

increases. Another proposed synthetic method for a large

macrocycle is 2:2 cyclization. The syntheses of Schiﬀ and non-

Schiﬀ base-type large macrocycles based on 2:2 cyclization

membered macrocyclic tetraoxooctaamine and an octa-

armed 24-membered octameric cyclic peptoid have been

21−29

Received: March 30, 2021

Published: June 8, 2021

have been abundantly reported.

Usually, the synthesis of

macrocyclic compounds is carried out under high-dilution

conditions to increase the yield of the cyclic compounds and

27−34

decrease the formation of polymers.

Our group has synthesized tetra-armed cyclens with

aromatic side arms and their silver(I) complexes. When

2021 American Chemical Society

847

J. Org. Chem. 2021, 86, 9847−9853

The Journal of Organic Chemistry

armed 24-membered cyclic octaamine. Since Cosmos has eight

Note

Scheme 1. Synthesis of Cosmosen (1)

reported (Figure 1). However, there is no example of an octa-

characterized by H and C{ H} NMR spectra, fast atom

bombardment (FAB) mass spectrometry, and elemental

analysis (Figures S1 and S2). The H NMR spectra of 3a

and 3b clearly show the successful separation of the mixture’s

two components (Figures S1 and S2, respectively). When the

H NMR spectrum of 3b was compared with that of 3a (Figure

), the H proton signal of 3b was shifted downﬁeld (+0.2

Figure 1. Examples of previously reported armed 24-membered cyclic

tetraoxo and octaoxo macrocyclic octaamines.

ﬂower petals, we named the octa-armed cyclic octaamine

Cosmosen. We also report the binding constants for 1:1 and 1:2

complexes (1/Ag ), which were measured by UV−vis titration

experiments.

The ﬁve-step synthesis of target compound 1, an octa-armed

cyclen with benzyl groups, starting from benzylamine is shown

in Scheme 1. The N-benzyl cyclen is an important starting

material to adopt two or more aromatic rings in the side arms.

Although Tweedle and co-workers have reported the synthesis

Figure 2. Comparison between the ¹H NMR spectra (aliphatic

region) of 3a and 3b in CD Cl

of 3a under high-dilution conditions in ethanol, the 2:2

cyclization product (3b) has not been reported. In this paper,

we attempted to synthesize compound 3b as a key precursor,

which was expected to be obtained as a byproduct. A mixture

of 3a and 3b was obtained by 1:1 and 2:2 reactions of 2 with

diethylenetriamine under high-dilution conditions at 70 °C for

ppm) because the H protons in 3a were located in the

shielding region of the neighboring CO groups; on the

other hand, the H protons in 3b were not. As we mentioned

above, 3a has already been reported without 3b. Finally, the

FAB mass spectra of 3a and 3b are m/z 291 (M + H ) and m/

z 581 (M + H ), respectively, conﬁrming that they are the 1:1

days. The majority of 3a in the reaction mixture was

obtained by recrystallization from methanol. After the crystals

were ﬁltered, the ﬁltrate was concentrated, and the remaining

reddish-yellow oil was separated by silica gel column

chromatography. The second fraction was collected and

concentrated. The oily substance was recrystallized from

methanol to obtain 3b as a white powder in a 5% yield. It is

important to note that the 2:2 cyclization product was

obtained in a 10% yield when it was converted to the 1:1

cyclization product. The resulting products 3a and 3b were

and 2:2 cyclization products. Our result is the ﬁrst instance of a

2:2 cyclization by the reaction of diethylenetriamine with a

diethyl iminodiacetate derivative.

The benzyl side arms were attached to the tetraoxo 24-

membered cyclic octaamine 3b by reductive amination. The

reaction of 3b, benzaldehyde, and sodium triacetoxyborohy-

dride (NaBH(OAc) ) in 1,2-dichloroethane for seven days

gave compound 4. The puriﬁcation of 4 was conducted via

848

J. Org. Chem. 2021, 86, 9847−9853

The Journal of Organic Chemistry

crystal X-ray analysis (Figures 3 and S4 ). The colorless single

Note

recrystallization from methanol instead of column chromatog-

content (0.0−3.0 equiv) in the presence of 5, and the

formation of complexes with diﬀerent stoichiometries was

conﬁrmed (Figure S6). The mass spectrum of 5 with 1.0 equiv

raphy. The H and C{ H} NMR spectra of 4 are shown in

Figure S3. The structure of 4 was also characterized by single-

of Ag was dominated by fragment ion peaks for the 1:1

complex at m/z 811, indicating that the species present was [5

Ag ] . When 2.0 equiv of Ag was added, a new fragment ion

− +

peak arising from the 1:2 species, [5 + 2Ag + OTf ] , was

observed at m/z 1067.

To estimate the binding constants between 5 and the Ag⁺

ions, a UV−vis titration experiment was performed by varying

the silver(I) content (0.0−2.5 equiv) in the presence of 5 (8.0

−

(

10 M) in a mixture of methanol and chloroform (v/v, 9:1)

Figure S7a ). The stability constants (logβ and logβ ) for the

:1 and 1:2 (5/Ag ) complexations were calculated by

HyperSpec software

to aﬀord 6.5(3) and 13.0(5),

respectively, suggesting the formation of the stable 1:2 complex

(

Figure S7b ).

Figure 3. Crystal structure of the precursor macrocycle 4. Hydrogen

atoms are omitted.

The octabenzyl-armed 24-membered cyclic octaamine (1)

was prepared by the reductive amination of 5 with

^b^eⁿ^z^a^l^d^e^h^y^d^eⁱⁿ^t^h^e^p^r^e^s^eⁿ^c^e^o^f^N^a^B^H⁽^O^A^c⁾3 in 1,2-

dichloroethane. The reaction mixture was separated and

puriﬁed by silica gel column, aﬀording 1 as a pale yellow oil

crystal of 4 suitable for X-ray analysis was obtained by

recrystallization from methanol. Compound 4 crystallizes in

the triclinic space group P1 (Table S1). In the crystal structure,

two crystallographically diﬀerent macrocycles with similar

conformations are arranged side by side with an adjacent

macrocycle. The cyclen unit of 4 is quite planar and elongated,

and the four benzyl arms show a 1,2-alternate conformation. It

was conﬁrmed by NMR and mass spectra as well as single-

crystal X-ray diﬀraction data that the 2:2 cyclization reaction

in a 22% yield. The structure of 1 was conﬁrmed by H and

C{ H} NMR spectra, CSI-MS, and elemental analysis

(Figures 4 and S8). To the best of our knowledge, the

compound is the ﬁrst example of an octa-armed cyclic

octaamine. Structural information on the Ag complex with 1

in a solution was obtained by Ag ion-induced CSI-MS and

UV−vis titration experiments (Figures 5 and S9 and S10,

respectively).

was again accomplished. As we expected, the H protons in 4

were not located in the shielding area of the neighboring C

O groups (Figure S3a).

A CSI-MS titration experiment was performed by varying

The reduction of 4 by diisobutylaluminum hydride (DIBAL-

H) gave the reduction product 5. The isolation of 5 was

performed by silica gel column chromatography (chloroform/

methanol/ammonia = 5:1:0.5) as a reddish yellow oil in a 66%

the Ag content (0−3.0 equiv) in the presence of 1 (Figures 5

and S9). When 0.5 equiv of Ag was added to 1, a fragment ion

peak for [1 + Ag ] appeared at m/z 1172. The mass spectrum

of 1 with 1.0 equiv of Ag was monopolized by peaks for the

1:2 (1/Ag ) complex at m/z 639 and 1427, indicating that the

species were [1 + 2Ag ] and [1 + 2Ag + OTf ] ,

respectively. The addition of over 1.5 equiv of Ag led to a

new set of multi-silver(I) complexes. In particular, as more

yield. Compound 5 was characterized by H and C{ H}

− +

NMR spectra, FAB-MS, and elemental analysis (Figure S5).

Ag ion-induced cold ESI mass and UV−vis spectral changes

were carried out to investigate the complexation behavior

toward Ag ions. We performed cold electrospray ionization

excess Ag was added, the peak intensity of high equivalents of

the silver complex increased (Figure 5) because these high

mass spectrometry (CSI-MS) experiments by varying the Ag⁺

Figure 4. H NMR (400 MHz, CDCl ) spectrum of 1.

849

The Journal of Organic Chemistry

J. Org. Chem. 2021, 86, 9847−9853

Note

Figure 5. CSI mass spectra of 1 (9.2 × 10⁻⁴M) in the presence of diﬀerent molar ratios of AgOTf in a mixture of CHCl and CH OH (1:19) at

298 K.

equivalents of silver complexes would form clusters under the

ESI mass conditions.

The study of rotaxane with a cationic wheel and an anionic axis

is now in progress.

A UV−vis titration experiment was performed by varying the

silver(I) content (0.0−2.5 equiv) in the presence of 1 (4.1 ×

EXPERIMENTAL SECTION

General. All reagents were of standard analytical grade and were

used without further puriﬁcation. Melting points were obtained with a

Mel-Temp capillary apparatus and were not corrected. The FAB mass

■

−

M) in a methanol and chloroform (v/v, 9:1) solution at

98 K. According to the addition of AgOTf, the absorption

increased (Figure S10a) due to the complexation of the cyclen

ring with Ag . As shown in the titration curve at 229 nm

spectra were obtained using a JEOL 600 H mass spectrometer. H

and C{ H} NMR spectra were measured on a JEOL ECP400

spectrometer (400 MHz). UV−vis spectra were recorded on a JASCO

V-650 spectrophotometer. Stability constants were calculated using

(

Figure S10a ), the absorbance of 1 gradually increased

between 0.0 and 2.0 equiv of silver(I). Above 2.0 equiv., the

absorbance shows a much smaller increase, suggesting the

formation of a stable 1:2 (ligand-to-metal) complex as a

primary product. From the titration data, the stability constants

HyperSpec ver. 1.1.33. Cold ESI mass spectra were recorded on a

JEOL JMST100CS mass spectrometer. The elemental analysis was

carried out on a Yanako MT-6 CHN microcorder.

Synthesis of 4-Benzyl-1,4,7,10-tetraazacyclododecane-2,6-

dione (3a) and 4,16-Dibenzyl-1,4,7,10,13,16,19,22-octaazacy-

clotetracosane-2,6,14,18-tetraone (3b). Compound 2 (16.7 g,

for the 1:1 and 1:2 (1/Ag ) complexation between silver(I)

and 1 were obtained using HyperSpec software, and the

logβ and logβ values were estimated to be 7.9(2) and

0.0 mmol) and diethylenetriamine (9.69 g, 93.9 mmol) were

3.9(3), respectively (Figure S10b ). The binding constants

dissolved in MeOH (1.9 L). Then, the mixture was stirred and

reﬂuxed at 70 °C (in a heating mantle) under a nitrogen atmosphere

for seven days. Then, the solvent was evaporated, and white

macrocycle 3a was aﬀorded as a white powder by recrystallization

from methanol. The residue was ﬁnally puriﬁed by column

chromatography (chloroform/methanol/aqueous ammonia =

suggest the formation of 1:2 complex that was more stable than

the 5/Ag complex due to the Ag −π interactions between the

silver(I) ions incorporated in the cyclic amine and the aromatic

side arms.

In conclusion, we have developed a synthetic method for the

preparation of an octa-armed 24-membered cyclen (Cosmosen,

:1:0.06) to obtain 3a and 3b. Flash column chromatography

aﬀorded products 3a and 3b as white solids in a 22% yield (3.91 g)

1). In the case of the key precursor 3b, we successfully

and pale yellow solids in a 5% yield (0.93 g), respectively.

obtained it as a byproduct via a 2:2 cyclization reaction. The

synthetic reaction process of the 24-membered cyclen is mild

and short compared to the reported method for [24]aneN₈.

The intermediates and ﬁnal compound were obtained at

reasonable yields. We believe that 1 can be used as a key

pseudo-rotaxane compound, which consists of a cationic

macrocyclic wheel molecule and an anionic axial molecule.

3a. mp: 155.4−156.0 °C. H NMR (400 MHz, CD Cl ): δ 7.39−

.27 (m, 7H), 3.81 (s, 2H), 3.20−3.16 (m, 8H), 2.74 (t, J = 5.7 Hz,

H). C{ H} NMR (100 MHz, CDCl ): δ 170.7, 137.7, 129.3, 129.1,

28.3, 62.9, 60.8, 45.4, 38.1. FAB-MS (matrix DTT/TG = 1:1) m/z

91 ([M + H] , 100%). Anal. Calcd for [C H N O +0.5H O]: C,

0.18; H, 7.74; N, 18.71. Found: C, 60.22; H, 7.64; N, 18.96.

b. mp: 181.6−182.9 °C. H NMR (400 MHz, CD Cl ): δ 7.46 (t,

J = 5.1 Hz, 4H), 7.38−7.27 (m, 10H), 3.72 (s, 4H), 3.36 (q, J = 5.6

850

J. Org. Chem. 2021, 86, 9847−9853

The Journal of Organic Chemistry

https://pubs.acs.org/doi/10.1021/acs.joc.1c00737.

Note

Hz, 8H), 3.16 (s, 8H), 2.73 (t, J = 5.5 Hz, 8H). ¹³C{ H} NMR (100

obtained from a least-squares reﬁnement of the spot. Data collection,

MHz, CDCl ): δ 171.1, 137.7, 129.5, 129.1, 128.4, 60.9, 59.2, 48.9,

data reduction, and semiempirical absorption correction were carried

out using the software package APEX2. All of the calculations for

9.2. FAB-MS (matrix DTT/TG = 1:1) m/z 581 ([M + H] , 30%).

Anal. Calcd for C H N O +0.25H O: C, 61.57; H, 7.66; N, 19.15.

Found: C, 61.43; H, 7.67; N, 19.04.

Synthesis of 4,10,16,22-Tetrabenzyl-1,4,7,10,13,16,19,22-

octaazacyclotetracosane-2,6,14,18-tetraone (4). Compound

the structure determination were carried out using the SHELXTL

package. In all cases, nonhydrogen atoms were reﬁned anisotropi-

cally, and hydrogen atoms were placed in idealized positions and

reﬁned isotropically in a riding manner along with their respective

parent atoms. The relevant collected crystal data and re ﬁ nement data

for the crystal structures are summarized in Table S1 . CCDC

2071938 (4) contains the supplementary crystallographic data for this

paper. These data can be obtained free of charge from The

Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/

data_request/cif .

3b (0.17 g, 0.295 mmol) and benzaldehyde (0.430 g, 4.05 mmol)

were added to 1,2-dichloroethane (25 mL), and the mixture was

stirred for six days at room temperature under a nitrogen atmosphere.

Then, sodium triacetoxyborohydride (1.40 g, 6.62 mmol) was added

to the reaction mixture, and the mixture was stirred for one day at

room temperature under a nitrogen atmosphere. A saturated sodium

hydrogen carbonate solution (10 mL) was added, and the mixture was

extracted with chloroform (20 mL, three times). The organic layer

was separated, dried over anhydrous sodium sulfate, ﬁltered, and

evaporated. The residue was subjected to column chromatography

ASSOCIATED CONTENT

sı Supporting Information

■

(

chloroform/methanol = 10:1) to remove impurities. Silica gel

column chromatography (chloroform/methanol/aqueous ammonia =

:1:0.2) was performed to produce puriﬁed 4. Yield: 56% (0.126 g).

The Supporting Information is available free of charge at

NMR spectra, systal structure, CSI-MS data, and UV−

vis spectra (PDF)

mp: 153.8−154.2 °C. H NMR (400 MHz, CD Cl ): δ 7.32−7.22

(

m, 20H), 7.11 (t, J = 5.0 Hz, 4H), 3.70 (s, 4H), 3.58 (s, 4H), 3.28

q, J = 5.6 Hz, 8H), 3.10 (s, 8H), 2.55 (t, J = 5.7 Hz 8H). ¹³C{ H}

Accession Codes

NMR (100 MHz, CDCl ): δ 170.6, 138.7, 137.5, 129.2, 129.1, 128.5,

28.4, 127.7, 127.4, 59.7, 59.0, 57.8, 53.8, 37.4. FAB-MS (matrix

CCDC 2071938 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

data_request@ccdc.cam.ac.uk , or by contacting The Cam-

bridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Glycerin) m/z 761 ([M + H] , 20%). Anal. Calcd for

C H N O +0.5H O: C, 68.64; H, 7.46; N, 14.55. Found: C,

68.83; H, 7.41; N, 14.47.

Synthesis of 1,7,13,19-Tetrabenzyl-1,4,7,10,13,16,19,22-oc-

taazacyclotetracosane (5). Ten milliliters of a diisobutylaluminum

hydride solution in THF (1 M) was slowly added to compound 4

(

0.113 g, 0.148 mmol) at 0 °C. Then, the mixture was stirred for one

day at room temperature under an argon atmosphere. The reaction

AUTHOR INFORMATION

■

mixture was cooled to 0 °C. Benzene (27 mL) and sodium ﬂuoride

Corresponding Author

(1.47 g, 35.1 mmol) were added, and the mixture was stirred for 1 h at

Yoichi Habata − Department of Chemistry and Research

Center for Materials with Integrated Properties, Faculty of

Science, Toho University, Funabashi, Chiba 274-8510,

Japan; orcid.org/0000-0003-0712-6231;

Email: habata@chem.sci.toho-u.ac.jp

room temperature. The reaction mixture was cooled again to 0 °C,

and 4 mL of water was added to the reaction mixture. The reaction

mixture was stirred for one day at room temperature and then

evaporated with chloroform (30 mL, three times). The organic layer

was separated, dried over anhydrous sodium sulfate, ﬁltered, and

evaporated. The residue was subjected to column chromatography

Authors

(chloroform/methanol/aqueous ammonia = 5:1:0.5) to obtain 5 in a

reddish yellow oil state. Yield: 66% (0.068 g). mp: 153.8−154.2 °C.

Huiyeong Ju − Department of Chemistry, Toho University,

Funabashi, Chiba 274-8510, Japan; orcid.org/0000-

0003-2961-763X

Miki Iwase − Department of Chemistry, Toho University,

Funabashi, Chiba 274-8510, Japan

Hikari Sako − Department of Chemistry, Toho University,

Funabashi, Chiba 274-8510, Japan

Hiroki Horita − Department of Chemistry, Toho University,

Funabashi, Chiba 274-8510, Japan

Shiori Koike − Department of Chemistry, Toho University,

Funabashi, Chiba 274-8510, Japan

Eunji Lee − Department of Chemistry, Gangneung-Wonju

National University, Gangneung 25457, South Korea;

orcid.org/0000-0002-3031-943X

Mari Ikeda − Education Center, Faculty of Engineering, Chiba

Institute of Technology, Narashino, Chiba 275-0023, Japan

Shunsuke Kuwahara − Department of Chemistry and

Research Center for Materials with Integrated Properties,

Faculty of Science, Toho University, Funabashi, Chiba 274-

8510, Japan; orcid.org/0000-0002-9673-4580

H NMR (400 MHz, CD Cl ): δ 7.31−7.19 (m, 20H), 3.57 (s, 8H),

.61−2.53 (m, 32H). C{ H} NMR (100 MHz, CDCl ): δ 139.1,

29.0, 128.3, 127.1, 59.6, 53.3, 47.1. FAB-MS (matrix Glycerin) m/z

07 ([M + H] , 15%). Anal. Calcd for C H N +0.3 CHCl : C,

1.82; H, 8.75; N, 15.12. Found: C, 71.65; H, 8.70; N, 14.86.

Synthesis of 1,4,7,10,13,16,19,22-Octabenzyl-

,4,7,10,13,16,19,22-octaazacyclotetracosane (1). Compound

(0.61 g, 0.087 mmol), benzaldehyde (0.10 g, 0.96 mmol), and

sodium triacetoxyborohydride (0.21 g, 0.98 mmol) were added to 1,2-

dichloroethane (25 mL), and the mixture was stirred for eight days at

room temperature under a nitrogen atmosphere. Saturated sodium

hydrogen carbonate solution (40 mL) was added, and the mixture was

extracted with chloroform (20 mL, three times). The organic layer

was separated, dried over anhydrous sodium sulfate, ﬁltered, and

evaporated. The residue was subjected to column chromatography

(

chloroform/methanol/aqueous ammonia = 10:1:0.06) to remove

impurities. After silica gel column chromatography (chloroform/

methanol = 40:1) was performed, compound 1 was obtained as a pale

yellow oil. Yield: 22% (0.020 g). H NMR (400 MHz, CD Cl ): δ

.23−7.17 (m, 40H), 3.47 (s, 16H), 2.57 (m, 32H). C{ H} NMR

100 MHz, CDCl ): δ 139.7, 128.8, 128.1, 126.7, 59.4, 52.6. CSI-MS

m/z 1065.88 ([M + H] ). Anal. Calcd for C H N ·0.6CHCl : C,

6.68; H, 7.85; N, 9.85. Found: C, 76.57; H, 7.64; N, 9.72.

(

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c00737

X-ray Crystallographic Analysis. X-ray data were collected on a

Bruker SMART APEX II ULTRA diﬀractometer equipped with

Notes

graphite monochromated Mo K radiation (λ = 0.71073 Å) generated

by a rotating anode. The cell parameters for the compounds were

The authors declare no competing ﬁnancial interest.

851

J. Org. Chem. 2021, 86, 9847−9853

The Journal of Organic Chemistry

Garcia-Espana, E.; Micheloni, M.; Paoletti, P.; Paoli, P. Nickel(II)

Note

(

,4,7,10,13,16,19,22,25,28-Decaazacyclotriacontane). Inorg. Chem.

989, 28, 347−351.

ACKNOWLEDGMENTS

■

This research was supported by Grants-in-Aid for Scientiﬁc

Research from the MEXT of Japan (Grants 17K05844 and

0K05480). E.L. acknowledges support from the JSPS

International Research Fellow (Toho University, 18F18343).

H.J. was supported by fellowships from the Marubun Research

Promotion Foundation (Japan).

14) Bencini, A.; Bianchi, A.; Castelló, M.; Dapporto, P.; Faus, J.;

Complexes of [3 k ]aneN Polyazacycloalkanes (k = 7 −12) Solution

and Solid-State Studies. Inorg. Chem. 1989, 28, 3175−3181.

(15) Bencini, A.; Bianchi, A.; Dapporto, P.; Garcia-Espana, E.;

Paoletti, P.; Paoli, P.; Ramirez, J. A.; Rodriguez, A. Thermodynamic

and Structural Properties of Palladium(II) Polynuclear Complexes of

Azamacrocycles. Crystal Structure of the [Pd ([24]aneN )](ClO )

4 4

REFERENCES

■

Complex. Inorg. Chem. 1993, 32, 1204−1208.

(16) Andres, A.; Bencini, A.; Carachalios, A.; Bianchi, A.; Dapporto,

P.; García-Espana, E.; Paoletti, P.; Paoli, P. Interaction of Lead(II)

with Highly-Dentate Linear and Cyclic Polyamines. J. Chem. Soc.,

Dalton Trans. 1993, 3507−3513.

(17) Schumann, H.; Bottgef, U. A.; Zietzke, K.; Hemling, H.;

Kociok-Kohn, G.; Pickardt, J.; Ekkehardt Hahnb, F.; Zschunke, A.;

Schiefnef, B.; Gries, H.; Radiichel, B.; Platzeke, J. 1,4,7,10,13,16,19,22-

Octaazacyclotetracosane-1,4,7,10,13,16,19,22-octaacetic Acid

1) Bianchi, A.; Micheloni, M.; Paoletti, P. Large polyazacycloal-

kanes: ligational properties and anion coordination chemistry. Pure

Appl. Chem. 1988, 60, 525−532.

2) Bencini, A.; Bianchi, A.; Micheloni, M.; Paoletti, P.; Garcia-

(

Espan

a, E.; Nin

o, M. A. Coordination Tendency of [3 k ]aneN _k

Polyazacycloalkanes. Thermodynamic Study of Solution Equilibria.

J. Chem. Soc., Dalton Trans. 1991 , 1171 −1174.

3) Micheloni, M. Large Polyazacycloalkanes and Small Macrocyclic

Cages. Comments Inorg. Chem. 1988, 8, 79−100.

4) Micheloni, M.; Paoletti, P.; Bianchi, A. 1,4,7,10,13,16,19-

OTEC) and 1,4,7,10,14,17,20,23-Octaazacyclohexacosane-

OHEC): Synthesis and

1,4,7,10,14,17,20,23-octaacetic Acid (H

Heptaazacycloheneicosane. A Large, Potentially Dinucleating Poly-

azacycloalkane. Synthesis and Equilibria between Hydrogen and

Copper(II) Ions. Inorg. Chem. 1985, 24, 3702−3706.

Characterization of Two Large Macrocyclic Polyamine Polycarboxylic

Ligands and Some of Their Copper(II) and Lanthanide(III)

Complexes. Chem. Ber. 1997, 130, 267−277.

(18) Dietrich, B.; Hosseini, M.; Lehn, J. M.; Sessions, R. B. Anion

Receptor Molecules. Synthesis and Anion-Binding Properties of

Polyammonium Macrocycles. J. Am. Chem. Soc. 1981, 103, 1282−

1283.

(

5) Bencini, A.; Bianchi, A.; Garcia-Espan

a, E.; Giusti, M.;

Micheloni, M.; Paoletti, P. Solution Chemistry of Macrocycles. 5.

Synthesis and Ligational Behavior toward Hydrogen and Copper(II)

Ions of the Large Polyazacycloalkane 1,4,7,10,13,16,19,22,25-Non-

aazacycloheptacosane ([27]aneN ). Inorg. Chem. 1987, 26, 681−684.

(19) Kimura, E.; Sakonaka, A.; Kodama, M. A Carbonate Receptor

Model by Macromonocyclic Polyamines and Its Physiological

Implications. J. Am. Chem. Soc. 1982, 104, 4984−4985.

(20) Atkins, T. J.; Richman, J. E.; Oettle, J. E. MACROCYCLIC

POLYAMINES: 1,4,7,10,13,16-HEXAAZACYCLOOCTADECANE.

Org. Synth. 1978, 58 , 86.

(21) Brooker, S. Complexes of thiophenolate-containing Schiff-base

macrocycles and their amine Analogues. Coord. Chem. Rev. 2001, 222,

33−56.

(

6) Bencini, A.; Bianchi, A.; Garcia-Espana, E.; Micheloni, M.;

Paoletti, P. Synthesis and Ligational Properties of the Two Very Large

Polyazacycloalkanes [33]aneN ₁ ₁ and [36]aneN ₁ ₂ Forming Trinuclear

Copper(II) Complexes. Inorg. Chem. 1988, 27, 176−180.

(

7) Bencini, A.; Bianchi, A.; Garcia-Espana, E.; Micheloni, M.;

Paoletti, P. Anaerobic Complexation of Cobalt(II) by [3 k ]aneN (k =

(

−12) Polyazacycloalkanes. Inorg. Chem. 1989, 28, 2480−2482.

8) Bencini, A.; Bianchi, A.; Garcia-Espana, E.; Giusti, M.; Mangani,

S.; Micheloni, M.; Orioli, P.; Paoletti, P. Synthesis and Complexing

Properties of the Large Polyazacycloalkane 1,4,7,10,13,16,19,22,25,28-

Decaazacyclotriacontane (L). Crystal Structure of the Monoproto-

nated Dicopper(II) Complex [Cu (L)HCl ](ClO ) ·4H O. Inorg.

(22) Pilkington, N. H.; Robson, R. COMPLEXES OF BINU-

CLEATING LIGANDS III. NOVEL CONPLEXES OF A MACRO-

CYCLIC BINUCLEATING LIGAND. Aust. J. Chem. 1970, 23,

2225−2236.

(23) Menif, R.; Martell, A. E.; Squattrito, P. J.; Clearfield, A. New

Hexaaza Macrocyclic Binucleating Ligands. Oxygen Insertion with a

Dicopper(I) Schiff Base Macrocyclic Complex. Inorg. Chem. 1990, 29,

4723−4729.

(24) MacLachlan, M. J.; Park, M. K.; Thompson, L. K. Coordination

Compounds of Schiff-Base Ligands Derived from Diaminomaleoni-

trile (DMN): Mononuclear, Dinuclear, and Macrocyclic Derivatives.

Inorg. Chem. 1996, 35, 5492−5499.

(25) Kim, H.-S.; Kwon, I.-C.; Choi, J.-H. Synthesis of Crown Ethers

Containing a Thiazole Subcyclic Unit. J. Heterocycl. Chem. 1999, 36,

1285−1289.

Chem. 1987, 26, 1243−1247.

9) Bencini, A.; Bianchi, A.; Garcia-Espan

Micheloni, M.; Orioli, P.; Paoletti, P. Polynuclear Zinc(II) Complexes

with Large Polyazacycloalkanes. Equilibrium Studies and Crystal

(

a, E.; Mangani, S.;

Structure of the Binuclear [Zn ([30]aneN )(NCS)](ClO ) Com-

4 3

plex. Inorg. Chem. 1988, 27, 1104−1107.

(

10) Bencini, A.; Bianchi, A.; Dapporto, P.; Garcia-Espana, E.;

Marcelino, V.; Micheloni, M.; Paoletti, P.; Paoli, P. Heptacoordina-

tion of Manganese(II) by the Polyazacycloalkane [21]aneN . Crystal

Structure of the [Mn([21]aneN )](ClO ) Solid Compound and

4 2

Thermodynamics of Complexation in Water Solution. Inorg. Chem.

990, 29, 1716−1718.

11) Bianchi, A.; Mangani, S.; Micheloni, M.; Nanini, V.; Orioli, P.;

(

(26) Cameron, S. A.; Brooker, S. Metal-Free and Dicopper(II)

Complexes of Schiff Base [2 + 2] Macrocycles Derived from 2,2 ’-

Iminobisbenzaldehyde: Syntheses, Structures, and Electrochemistry.

Inorg. Chem. 2011, 50, 3697−3706.

Paoletti, P.; Seghi, B. Dicopper(II) Complex of the Large

Polyazacycloalkane 1,4,7,10,13,16,19,22-Octaazacyclotetracosane

bistrien). Synthesis, Crystal Structure, Electrochemistry, and

Thermodynamics of Formation. Inorg. Chem. 1985, 24, 1182−1187.

12) Bencini, A.; Bianchi, A.; Dapporto, P.; Garcia-Espana, E.;

(27) Habata, Y.; Seo, J.; Otawa, S.; Osaka, F.; Noto, K.; Lee, S. S.

Synthesis of diazahexathia-24-crown-8 derivatives and structures of

(

Ag Complexes. Dalton Trans. 2006, 2202−2206.

Micheloni, M.; Paoletti, P. Polynuclear Zinc(II) Complexes with

(28) Xu, Z.; Huang, X.; Liang, J.; Zhang, S.; Zhou, S.; Chen, M.;

Tang, M.; Jiang, L. Efficient Syntheses of Novel Cryptands Based on

Bis(m -phenylene)-26-crown-8 and Their Complexation with Para-

quat. Eur. J. Org. Chem. 2010, 2010, 1904−1911.

Large Polyazacycloalkanes. 2. Equilibrium Studies and Crystal

Structure of the Binuclear Complex [Zn LCl ](Cl)ClO ·4H O (L =

(

,4,7,10,13,16,19,22-Octaazacyclotetracosane). Inorg. Chem. 1989, 28,

188−1191.

(29) Jung, D.; Chamura, R.; Habata, Y.; Lee, S. S. Extra Large

Macrocycle: 40-Membered Macrocycle via 2:2 Cyclization and Its

Dimercury(II) Complex. Inorg. Chem. 2011, 50, 8392−8396.

(30) Borisova, N. E.; Reshetova, M. D.; Ustynyuk, Y. A. Metal-Free

Methods in the Synthesis of Macrocyclic Schiff Bases. Chem. Rev.

2007, 107, 46−79.

13) Bencini, A.; Bianchi, A.; Castelló, M.; Di Vaira, M.; Faus, J.;

Garcia-Espana, E.; Micheloni, M.; Paoletti, P. Thermodynamic Study

of the Formation in Aqueous Solution of Cadmium(II) Complexes

with Polyazacycloalkanes. Synthesis and Crystal Structure of the

Dicadmium(II) Complex Na[Cd (L)Cl ](ClO ) (L

4 3

852

J. Org. Chem. 2021, 86, 9847−9853

The Journal of Organic Chemistry

(31) Pattenden, G.; Thompson, T. Design and synthesis of novel

Note

tubular and cage structures based on thiazole-containing macro-

lactams related to marine cyclopeptides. Chem. Commun. 2001, 717−

32) Hesford, M. J.; Levason, W.; Matthews, M. L.; Reid, G.

18.

Synthesis and complexation of the mixed tellurium-oxygen macro-

cycles 1-tellura-4,7-dioxacyclononane, [9]aneO Te, and 1,10-ditel-

lura-4,7,13,16-tetraoxacyclooctadecane, [18]aneO Te ₂ and their

selenium analogues. Dalton Trans. 2003, 2852−2858.

(33) Levason, W.; Manning, J. M.; Nirwan, M.; Ratnani, R.; Reid,

G.; Smith, H. L.; Webster, M. Selenoether macrocyclic chemistry-

syntheses and properties of new potentially tridentate and

hexadentate Se/O-donor macrocycles. Dalton Trans. 2008, 3486−

(

492.

34) Shimizu, H.; Cojal González, J. D.; Hasegawa, M.; Nishinaga,

T.; Haque, T.; Takase, M.; Otani, H.; Rabe, J. P.; Iyoda, M. Synthesis,

Structures, and Photophysical Properties of π -Expanded Oligothio-

phene 8-mers and Their Saturn-Like C ₆ ₀ Complexes J . J. Am. Chem.

Soc. 2015, 137, 3877−3885.

(35) Habata, Y.; Ikeda, M.; Yamada, S.; Takahashi, H.; Ueno, S.;

Suzuki, T.; Kuwahara, S. Argentivorous Molecules: Structural

Evidence for Ag -π Interactions in Solution. Org. Lett. 2012, 14,

36) Habata, Y.; Oyama, Y.; Ikeda, M.; Kuwahara, S. Argentivorous

576−4579.

molecules with two kinds of aromatic side-arms: intramolecular

competition between side-arms. Dalton Trans. 2013, 42, 8212−8217.

(37) Habata, Y.; Taniguchi, A.; Ikeda, M.; Hiraoka, T.; Matsuyama,

N.; Otsuka, S.; Kuwahara, S. Argentivorous Molecules Bearing Two

Aromatic Side-Arms: Ag −π and CH −π Interactions in the Solid

State and in Solution. Inorg. Chem. 2013, 52, 2542−2549.

38) Habata, Y.; Okeda, Y.; Ikeda, M.; Kuwahara, S. The water-

soluble argentivorous molecule: Ag -π interactions in water. Org.

Biomol. Chem. 2013, 11, 4265−4270.

(39) Habata, Y.; Kizaki, J.; Hosoi, Y.; Ikeda, M.; Kuwahara, S.

Argentivorous molecules bearing three aromatic side arms: synthesis

of triple-armed cyclens and their complexing property towards Ag .

Dalton Trans. 2015, 44, 1170−1177.

(40) Ikeda, M.; Sah, A. K.; Iwase, M.; Murashige, R.; Kuwahara, S.;

Habata, Y. Double-armed and tetra-armed cyclen-based cryptands.

Supramol. Chem. 2017, 29, 370−377.

(41) Ju, H.; Tenma, H.; Iwase, M.; Lee, E.; Ikeda, M.; Kuwahara, S.;

Habata, Y. Inclusion of alkyl nitriles by tetra-armed cyclens with

styrylmethyl groups. Dalton Trans. 2020, 49, 3112−3119.

(

42) “Argentivorous” is diﬀerent from “argentophilic”. “Argento-

philic” is used in the sense of Ag −Ag interactions. For example, see:

Schmidbaur, H.; Schier, A. Argentophilic Interactions. Angew. Chem.,

Int. Ed. 2015, 54, 746−784.

(43) Lohse, J.; Wernberg, O.; Yi-Min, H.; Bao-Yu, X.; Dou-Man, J.;

Liao-Rong, C.; Bao-Sheng, L. A Convenient Route to 24-Membered

Macrocycles Incorporating Two EDTA Units. Acta Chem. Scand.

(

995, 49, 768−770.

44) D’Amato, A.; Pierri, G.; Tedesco, C.; Della Sala, G.; Izzo, I.;

Costabile, C.; De Riccardis, F. Reverse Turn and Loop Secondary

Structures in Stereodefined Cyclic Peptoid Scaffolds. J. Org. Chem.

(

019, 84, 10911−10928.

45) Dischino, D. D.; Delaney, E. J.; Emswiler, J. E.; Gaughan, G. T.;

Prasad, J. S.; Srivastava, S. K.; Tweedle, M. F. Synthesis of Nonionic

Gadolinium Chelates Useful as Contrast Agents for Magnetic

Resonance Imaging. l,4,7-Tris(carboxymethyl)-10-substituted-

l,4,7,10-tetraazacycIododecanes and Their Corresponding Gadoli-

nium Chelates. Inorg. Chem. 1991, 30, 1265−1269. The synthesis of

a was mentioned in this paper, but no description on the

characterization was reported.

46) Gans, P.; Sabatini, A.; Vacca, A. Investigation of equilibria in

solution. Determination of equilibrium constants with the HYPER-

QUAD suite of programs. Talanta 1996, 43, 1739−1753.

(

47) APEX2; Bruker AXS Inc.: Madison, WI, 2008.

48) Sheldrick, G. Crystal structure refinement with SHELXL. Acta

Crystallogr., Sect. C: Struct. Chem. 2015, 71, 3−8.

853