Encapsulation of Aromatic Guests in the Bisporphyrin Cavity of a Double-Stranded Spiroborate Helicate: Thermodynamic and Kinetic Studies and the Encapsulation Mechanism

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Encapsulation of Aromatic Guests in the Bisporphyrin Cavity of a

Double-Stranded Spiroborate Helicate: Thermodynamic and Kinetic

Studies and the Encapsulation Mechanism

Naoki Ousaka,* Shinya Yamamoto, Hiroki Iida, Takuya Iwata, Shingo Ito, Rafael Souza, Yuh Hijikata,*

Stephan Irle, and Eiji Yashima *

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ABSTRACT: A double-stranded spiroborate helicate bearing a

bisporphyrin unit in the middle forms an inclusion complex with

electron-deﬁcient aromatic guests that are sandwiched between the

porphyrins. In the present study, we systematically investigated the

eﬀects of size, electron density, and substituents of a series of

aromatic guests on inclusion complex formations within the

bisporphyrin. The thermodynamic and kinetic behaviors during the

guest-encapsulation process were also investigated in detail. The

guest-encapsulation abilities in the helicate increased with the

increasing core sizes of the electron-deﬁcient aromatic guests and

decreased with the increasing bulkiness and number of substituents of the guests. Among the naphthalenediimide derivatives, those

with bulky N-substituents at both ends hardly formed an inclusion complex. Instead, they formed a [2]rotaxane-like inclusion

complex through the water-mediated dynamic B−O bond cleavage/reformation of the spiroborate groups of the helicate, which

enhanced the conformational ﬂexibility of the helicate to enlarge the bisporphyrin cavity and form an inclusion complex. Based on

the X-ray crystal structure of a unique pacman-like 1:1 inclusion complex between the helicate and an ammonium cation as well as

the molecular dynamics simulation results, a plausible mechanism for the inclusion of a planar aromatic guest within the helicate is

also proposed.

We recently found that a double-stranded spiroborate

helicate bearing a bisporphyrin unit in the middle (1_X2: X =

Na⁺or tetra-n-butylammonium (TBA⁺)) formed an inclusion

complex with an electron-deﬁcient aromatic guest, such as G4

(1_X2⊃G4) (Figure 1a), in such a way that the bisporphyrin

sandwiched the guest in a parallel manner was largely stabilized

by face-to-face π-stacking.^6gInterestingly, this guest encapsu-

lation triggered the quite unique rotary motion of the

porphyrin rings in one direction, which was coupled with a

unidirectional twisting motion of the spiroborate helix.^6g,8,9

The right- (P) and left-handed (M) enantiomers of 1_X2were

readily obtained by the optical resolution of the racemic

bisporphyrin helicate through diastereomeric salt formation

with an enantiopure ammonium, followed by cation exchanges

with achiral ammoniums.^6gIn addition, the enantiopure one-

handed 1_TBA2was able to selectively include one of the

INTRODUCTION

■

Well-deﬁned three-dimensional structures with speciﬁc molec-

ular pockets or cavities are indispensable to enzymes and

proteins due to their sophisticated functions to which

substrates of a complementary size and shape can bind with

an extremely high selectivity and speciﬁcity for further

transformation reactions, energy or electron transfers, etc.

Since the ﬁrst synthesis of cryptands and cavitands,¹the

development of synthetic receptors that possess an interior

space suitable for guest binding has attracted considerable

attention because of their numerous applications²to sensory

systems,^2a,d,ecatalysts,^2f,gnanoreactors,^2band ion transpor-

ters.^2c−hAmong such artiﬁcial receptors, the bisporphyrin-

based receptors^2f,3that are composed of two porphyrins⁴or

their metalated derivatives and are linked by one,⁵two,⁶or

more^6e,7ﬂexible or rigid linkages of varying lengths are

particularly interesting because of the unique nanospace

created between the two (metallo)porphyrins with their large

π-delocalized cores. This nanospace enables the encapsulation

of not only various π-conjugated guest molecules,^{5b,e,6d,f−i,7b,c}

fullerenes,^5d,6b,e,7dand carbon nanotubes^5hthrough intermo-

lecular π−π stacking interactions but also a variety of

chiral^5a,c,f,g,7dand achiral bidentate ligands^6a,c,7athrough

metal−ligand interactions.^3b,c,f,i

Received: May 18, 2021

Published: July 20, 2021

https://doi.org/10.1021/acs.joc.1c01155

J. Org. Chem. 2021, 86, 10501−10516

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Figure 1. (a) Chemical structures of 1_X2(X = Na⁺or TBA⁺) and G1−G19 and the inclusion complexation of 1_X2with various guests. (b)

Schematic representation of a plausible mechanism for the inclusion of G18 bearing bulky stoppers at both ends in the bisporphyrin helicate 1_X2

through the reversible B−O bond cleavage/reformation of the spiroborate groups. The bulky stoppers of G18 are possible to pass through the

bisporphyrin cavity of 1_X2only when the inner cavity of 1_X2is temporarily expanded by the water-mediated B−O bond cleavages of the spiroborate

groups (see Figure 4). (c) Schematic representation of two possible mechanisms (routes A and B) for the guest encapsulation in the bisporphyrin

cavity of 1_X2.

enantiomers of a racemic naphthalenemonoimide (NMI)

derivative with a chiral aromatic substituent at one end

through eﬃcient edge-to-face CH−π interactions between the

bisporphyrin residue and an aromatic group of the

encapsulated chiral guest.⁶ⁱMoreover, the racemic 1_Na2

underwent a unique deracemization reaction upon complex-

ation with an enantiopure electron-deﬁcient NMI-based

aromatic guest through the water-mediated B−O bond

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Figure 2. Partial ¹H NMR spectra (500 MHz, CD₃CN, 25 °C) of (a) 1_Na2(0.2 mM), (b) G4 (0.5 mM), 1_Na2plus (c) 0.5 and (d) 1.0 equiv of G4,

(e) G6 (0.1 mM in CD₃CN/CDCl₃(5/2 v/v)), 1_Na2plus (f) 0.5 and (g) 1.0 equiv of G6 (CD₃CN/CDCl₃(5/2 v/v)), (h) G15 (0.5 mM), and (i)

1_Na2plus 1.0 equiv of G15. For the signal assignments of 1_Na2in the presence of 1.0 equiv of G6 and G15, see Figures S37 −S40. The signal

assignments of 1_Na2and 1_Na2plus 1.0 equiv of G4 were previously reported.^6g

cleavage/reformation of the spiroborate groups, thus produc-

ing a nonracemic helicate.⁶ⁱ

basis of molecular dynamics (MD) simulation results and the

X-ray crystal structure of a pacman-like 1:1 inclusion complex

between the helicate and a bulky quaternary ammonium

cation, which is considered to be a possible intermediate

relevant to the encapsulation mechanism of aromatic guests in

the present bisporphyrin helicate as well as the reported

bisporphyrin-based host molecules (Figure 1c).

However, the thermodynamic and kinetic stabilities of the

inclusion complexes of 1_Na2toward electron-deﬁcient aromatic

guests, the inclusion and release kinetics of 1_Na2, and the

mechanistic insight into the guest inclusion complexation

6g

process of 1_Na2are poorly understood. Herein we report our

comprehensively investigated results of the inclusion complex-

ation behaviors between 1_Na2and a series of planar aromatic

guests with various sizes, substituents, and electron densities

(Figure 1a). Among the various tested guests, a naphthalene-

diimide (NDI) derivative bearing bulky stoppers at both ends,

such as G18, was found to be included in 1_Na2to form a stable

[2]rotaxane-like complex through the unique water-mediated

dynamic B−O bond cleavage/reformation of the spiroborate

groups (Figure 1b). Moreover, a plausible mechanism for the

inclusion of a planar electron-deﬁcient aromatic guest within

the bisporphyrin cavity of the helicate is also proposed on the

RESULTS AND DISCUSSION

■

Encapsulation of Various Aromatic Guests in the

Helicate. The racemic spiroborate helicate 1_Na2and its (M)-

double-helical enantiomer complexed with achiral TBA ((M)-

1

_TBA2) were prepared according to a previously reported

method.^6gAromatic guests were either commercially available

or synthesized according to the literature or procedures in

section 2 of the Supporting Information (SI).

We ﬁrst investigated the binding aﬃnity of 1_Na2toward a

series of planar aromatic guests (G1−G9), which were

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1

Table 1. Association Constants (K_a) of Guests (G1−G19) with 1_Na2and the Complexation-Induced H Chemical Shift

Changes (Δδ_G) of Guests G1−G19 in CD₃CN at 25 °C

a

b

c

d

guest

K_a(M⁻¹

)

Δδ_G(ppm)

Δδ(H_A−H_B) (ppm)

Δδ_NH(ppm)

Δδ_meso‑H(ppm)

G1

G2

G3

G4

G5

G6

G7

G8

(2.5 0.2) × 10⁵

(1.3 0.1) × 10⁵

(3.7 0.1) × 10⁵

(2.2 0.3) × 10⁹

8.71 (H_A)

n.a.

0.54

1.75

1.21

1.92

1.29

0.11

0.26

0.25

0.58

e

8.56 (H_A)

4.91 (H_A)

f

n.a.

g

h

(1.8 0.2) × 10⁹

(3.1 0.1) × 10²

2.66 (H_A), 4.05 (H_B)

1.39

1.14

0.68

i

n.a.

0.05 (H_A), 0.05 (H_B), 0.05 (H_C)

0.34 (H_A), 0.25 (H_B), 0.74 (H_C)

5.21 (H_A), 4.23 (H_B)

5.32 (H_A), 4.30 (H_B)

5.58 (H_A), 3.36 (H_B)

4.34 (H_A)

i

G9

n.a.

G10

G11

G12

G13

G14

G15

G16

G17

G18

G19

(6.0 0.6) × 10⁷

(9.6 0.5) × 10⁷

(2.3 0.1) × 10⁶

(2.7 0.1) × 10⁴

(5.2 0.6) × 10⁵

(2.0 0.1) × 10⁵

0.98

1.02

1.99

1.65, 1.60

2.02, 1.92

1.56, 1.48

1.15

1.50

1.48

0.22, 0.13

0.65, 0.21

1.00, 0.15

0.01

0.33

0.48

4.54 (H_A)

4.62 (H_A)

j

∼0

n.a.

f

n.a.

∼0

4.69 (H_A)

1.42

1.58

0.55

0.91

j

k

4.63 (H_A)

j

∼0

n.a.

a

b

c

Δδ_G= |δ_{free‑guest‑HX}− δ_{included‑guest‑HX}|, where X = A, B, or C for H_X; see Figure 1a. δ(H_A−H_B) = |δ_{included‑guest‑HA}− δ_{included‑guest‑HB}|. δ_NH= |δ_{free‑1‑NH}

d

e

− δ_{complex‑1‑NH}|. δ_meso‑H= |δ_{free‑1‑meso‑H}− δ_{complex‑1‑meso‑H}|. For meso-H, see Figure 1a. Could not be obtained due to the broadening of the peaks of

f

g

h

the included G2. Could not be estimated because of poor solubility of the guest in CD₃CN. In CD₃CN/CDCl₃= 5:2 (v/v). δ_meso‑H= |δ_{free‑1‑meso‑H}

i

j

(in CD₃CN) − δ_{complex‑1‑meso‑H}(in CD₃CN/CDCl₃= 5:2 (v/v))|. Too small to be estimated. G16, G18, and G19 could not form inclusion

k

complexes with 1_Na2at 25 °C due to their bulky substituents. After heating at 80 °C for 1 week.

composed of diﬀerent aromatic cores with diﬀerent electron

densities (Figure 1a). The 1:1 inclusion complexations of 1_Na2

with G1 and G4 were previously conﬁrmed by H NMR

diﬀerence in their K_avalues is presumably due to the diﬀerence

in their aromatic π-surface areas that are capable of interacting

with the electron-rich porphyrin rings, through which 1_Na2

more eﬃciently formed a sandwich complex with electron-

deﬁcient aromatic guests in a face-to-face parallel manner.

Therefore, the K_avalues of 1_Na2with the less electron-deﬁcient

G2 and G3 with small π-surface areas (K_a= 1.3 × 10⁵and 3.7

× 10⁵M⁻¹, respectively) were four orders of magnitude lower

than that with G4 (Table 1 and section 4 in the SI). A further

decrease in the K_avalue (ca. 3.1 × 10²M⁻¹, Table 1) was

observed for hexaﬂuorobenzene (G7) despite the electron-

deﬁcient nature of its fully substituted benzene ring with the

electron-withdrawing (EW) ﬂuoro atoms, which was due to

electrostatic repulsion between the electron-rich porphyrin

rings of 1_Na2and the peripheral ﬂuoro-substituents of G7.^6f

An electron-deﬁcient perylene diimide (PDI) guest (G6)

carrying two EW triethylene glycol (Tg)-bound imide groups

with an aromatic surface area larger than that of G4 was

eﬃciently included in 1_Na2by intercalation, with the high K_a

value of ca. 1.8 × 10⁹M⁻¹that is comparable to that of G4

(Table 1).¹⁰The X-ray single-crystal structure of the 1_Na2⊃G4

inclusion complex revealed that the bisporphyrin cavity is

almost ﬁlled with G4^6gso that both the imide terminal

moieties of the larger PDI unit of G6 stick out from the

bisporphyrin cavity.¹¹As anticipated, electron-rich aromatic

guests, such as pyrene (G8) and perylene (G9), could not be

1

spectroscopy in combination with absorption or ﬂuorescent

titrations and were further revealed by X-ray single crystal

analysis and electrospray ionization mass spectrometry for

G4.^6gSimilarly, the helicate 1_Na2also formed a 1:1 inclusion

complex with the other guests except for the electron-rich G8

and G9, as conﬁrmed by ¹H NMR spectroscopy and

absorption or ﬂuorescent titrations (see sections 3 and 4 in

the SI and below). Panels c and f of Figure 2 show the typical

¹H NMR spectra of 1_Na2in the presence of 0.5 equiv of the

electron-deﬁcient naphthalene- (G4) and perylene-based (G6)

guests in CD₃CN at 25 °C, respectively. The spectra exhibited

two sets of signals, which were assigned to the free 1_Na2and its

inclusion complexes due to a slow exchange between them on

the present NMR time scale at 25 °C and were accompanied

by signiﬁcant upﬁeld shifts of the aromatic protons of the

guests (H_Aand H_B) and those of 1_Na2. The further addition of

the guests (1.0 equiv) quantitatively produced the 1:1

inclusion complexes 1_Na2⊃G4 and 1_Na2⊃G6 (Figure 2d and

g, respectively) (see below for a more detailed discussion of

1

the inclusion complex formations by H NMR).

The association constants (K_a) of 1_Na2with G1 and G4

previously estimated by absorption or ﬂuorescence titrations in

CH₃CN at 25 °C were ca. 2.5 × 10⁵and ca. 2.2 × 10⁹M⁻¹,

respectively (Table 1).^6gDuring the ﬂuorescence titrations, we

conﬁrmed that the dynamic quenching process of the helicate

by an NMI derivative bearing a chiral aromatic substituent at

one end (an analogue of G11) was negligible and the static

quenching process was dominant based on the Stern−Volmer

plot of the helicate that was quenched by G11, showing the

complete linear plot.⁶ⁱTherefore, for the other aromatic guests,

the static quenching process might be dominant. The observed

eﬃciently sandwiched between the bisporphyrin unit of 1_Na2

,

as indicated by the negligible changes in their ¹H NMR spectra

upon mixing with 1_Na2(Table 1 and Figures S10 and S11).

Next, we investigated the eﬀects of the imide substituents of

NMI (G10−G12) and NDI (G13−G19) guests on their

12

binding aﬃnity toward 1_Na2

.

As expected, the K_avalues were

highly dependent on the bulkiness and number of the

substituents of the guests and were lower than that of G4

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(ca. 2.2 × 10⁹M⁻¹), thus decreasing with the increasing steric

repulsion between the imide substituents and bisporphyrin

during the inclusion complexation. The K_avalues (from ca. 2.7

× 10⁴to ca. 9.6 × 10⁷M⁻¹) decreased in the following order:

G11 > G10 > G12 > G14 > G15 > G13 (Table 1).

Thermodynamic Studies of Guest Encapsulations.

The temperature-dependent inclusion complex formations of

1_Na2toward selected guests composed of diﬀerent cores or

substituents, such as G3, G4, G10, and G13, were then studied

in CH₃CN to estimate the thermodynamic parameters using

the van’t Hoﬀ plots of the K_avalues, which were obtained by

absorption or ﬂuorescence titrations (Figure S3), and the

results are summarized in Table 2. The observed negative

form an inclusion complex with 1_Na2at room temperature

because of the bulky stoppers.^6h

On the other hand, we have recently found that optically

active (M)-1_TBA2, which is kinetically inert toward racemiza-

tion in the absence of water, readily racemizes in organic

solvents in the presence of water through the water-mediated

B−O bond cleavage/reformation of the spiroborate groups of

6i

1_Na2

.

These results provided a promising approach for

producing an inclusion complex of 1_Na2with even bulky

G16, G18, and G19 guests in aqueous solvents in which the

water-mediated B−O bond cleavages of the spiroborate groups

could be promoted, resulting in an enhancement of the

conformational ﬂexibility of 1_Na2to enlarge the bisporphyrin

cavity and forming a [2]rotaxane-like inclusion complex after

the subsequent reformation of the B−O spiroborate bonds.

With this expectation in mind, a 1:1 mixture of 1_Na2and

G18 in CD₃CN that contained a large excess of water (ca. 220

equiv) was heated at 80 °C for 92 h or 1 week, aﬀording the

desired [2]rotaxane complex 1_Na2⊃G18 in a 68% (Figure S22c

and d) or almost quantitative yield (Figure S20d), respectively.

Meanwhile, no trace amount of the inclusion complex was

formed for G16 and G19 after being heated at 80 °C for 1

week, indicating that the imide substituents of G16

(diphenylmethyl group) and G19 (1-adamantyl group) were

too bulky to form a sandwich complex with 1_Na2(Figures S18d

and S21d). We noted that a similar water-mediated inclusion

complex formation hardly proceeded in the presence of a tiny

amount of water in CH₃CN (<5 equiv), giving 1_Na2⊃G18 in

only a 4% yield upon heating at 80 °C for 92 h (Figure

S22a,b). These observations clearly indicated that the

encapsulation of the bulky guests, such as G18 bearing bulky

stoppers in the macrocyclic bisporphyrin cavity of 1_Na2, most

likely proceeds through the water-mediated B−O bond

cleavage of the spiroborate groups, followed by reformation

(Figure 1b).

Table 2. Thermodynamic Parameters for the Inclusion

Complexation of 1_Na2with Various Aromatic Guests in

a

CH₃CN

guest ΔG°₂₉₈(kJ mol⁻¹

)

ΔH° (kJ mol⁻¹

)

TΔS° (kJ mol⁻¹at 298 K)

G3

G4

G10

G13

−31.5 3.3

−54.1 7.4

−45.0 5.9

−25.3 1.5

−36.3 1.6

−71.8 3.8

−74.1 3.0

−41.2 0.7

−4.8 1.6

−17.6 3.7

−29.5 2.9

−15.9 0.7

a

The thermodynamic parameters (ΔH°, ΔS°, and ΔG°₂₉₈) were

estimated according to the following equation: lnK_a= −(ΔH°/R)(1/

T) + (ΔS°/R).

enthalpy and entropy values clearly indicate that the present

inclusion complexation is enthalpy-driven and entropically

disfavored as anticipated, since the electron-rich bisporphyrin

unit of 1_Na2sandwiches the electron-deﬁcient aromatic guests

through face-to-face double π−π stacking interactions. These

result in a signiﬁcant expansion between the porphyrin rings,

thereby substantially restricting the conformational freedom of

both the host and the guest. The ΔH° values for G4 and G10

were similar to each other, but the TΔS° value for an NMI

derivative G10 was more negative than that for G4 as a result

of the additional restricted molecular motion with respect to

that of the pendant phenyl group of the included G10.

However, both the negative TΔS° and ΔH° values for the NDI

derivative G13 carrying two phenyl substituents were

approximately half the values for G10 (Table 2), suggesting

an ineﬃcient π−π stacking interaction between the NDI core

of G13 and the bisporphyrin that resulted from the increased

steric repulsion between the pendant phenyl groups of G13

and the bisporphyrin unit of 1_Na2; therefore, its K_avalue at 25

°C was three orders of magnitude lower than that of G10.

Encapsulation of Bulky Guests via Water-Mediated

B−O Bond Cleavage/Reformation of the Spiroborate

Groups of the Helicate. In sharp contrast to the NDI guests

G13−G15 and G17, which had relatively small imide

substituents, those with bulky substituents at both ends, such

as the diphenylmethyl (G16), 3,5-di-tert-butylbenzyl (G18),

and 1-adamantylmethyl (G19) groups, hardly formed inclusion

complexes with 1_Na2in either CD₃CN or a CD₃CN/CDCl₃

mixture (5:2 v/v) at room temperature (Figures S18a −c,

S20a −c, and S21a −c, respectively), indicating that these imide

substituents were too sterically hindered to form a stable 1:1

inclusion complex or too bulky to pass through the

bisporphyrin cavity of 1_Na2. Similar behavior was also

previously observed for a PDI derivative bearing a bulky 3,5-

di-tert-butylbenzyl stopper at both ends, which was unable to

The second-order rate constants (k, M⁻¹s⁻¹) for the

formation of 1_Na2⊃G18 in the presence of a large excess of

water (220 equiv) were then estimated from the slopes of the

linear plots of 1/[1_Na2] versus time at diﬀerent temperatures

(50−80 °C), which provided the following activation

parameters from the Arrhenius and Eyring plots of the kinetic

data (Figure S23): E_a= 43.2 kJ mol⁻¹, ΔG^‡₂₉₈= 86.6 kJ mol⁻¹,

ΔH^‡= 40.4 kJ mol⁻¹, and TΔS^‡= −46.2 kJ mol⁻¹(T = 298

K). These kinetic and thermodynamic parameters, however,

would be inﬂuenced by the water content.

Interestingly, when the enantiopure (M)-1_TBA2was used

instead of the racemic 1_Na2, the resulting inclusion complex

1_TBA2⊃G18 (22%) maintained its optical activity (34%

enantiomeric excess (ee)) after being heated at 70 °C for

114 h, while the remaining free 1_TBA2(78%) almost lost its

optical activity (4% ee) (Figure 3).¹³This diﬀerence in the

optical activities of 1_TBA2in its free and included forms, which

was derived from (M)-1_TBA2, suggested that the racemization

of (M)-1_TBA2was signiﬁcantly suppressed once complexation

occurred with G18. Considering this result, two plausible

mechanisms for the inclusion complexation of the bulky G18

in the bisporphyrin cavity (A) with and (B) without the

racemization of the helicate (M)-1_TBA2through the reversible

water-mediated B−O bond cleavage/reformation of the

spiroborate groups can be proposed, as shown in Figure 4.

The water-mediated racemization of the spiroborate (M)-1_TBA2

takes place through an inversion of the helicity, which requires

at least the simultaneous cleavage of one of the four B−O

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Figure 3. Partial ¹H NMR spectra of an equimolar mixture of (M)-1_TBA2and G18 in CD₃CN measured at 25 °C with a small amount of water (a)

before and (b) after heating at 70 °C for 114 h and (c) after the addition of 10 equiv of (−)-BnEphBr; (M)-1_TBA2]₀= [G18]₀= 0.10 mM and

[H₂O]/[1_TBA2] = ca. 0.60. The ee values of free 1_TBA2and 1_TBA2⊃G18 in panel c were estimated by the integral ratios between the diastereomeric

signals in the presence of 10 equiv of (−)-BnEphBr, which was used as a chiral shift reagent. The following symbols denote the ¹³C satellite peaks

of the solvent and the protons from TBA and (−)-BnEphBr, respectively: *, #, and ×.

bonds at each spiroborate group, probably through the

formation of an achiral meso-intermediate,^8cfollowed by the

reformation of the spiroborate groups to produce the racemic

free 1_TBA2and then its racemic inclusion complex with G18

(1_TBA2⊃G18) (Figure 4A). On the other hand, the bond

cleavage of one or more B−O bond at only one of the two

spiroborate groups of (M)-1_TBA2allows the helicate to retain

its handedness (no racemization) and further allows the bulky

stopper groups of G18 to pass through the enlarged

bisporphyrin cavity, leading to inclusion complex formation

((M)-1_TBA2⊃G18) while maintaining its one-handed helicity

(Figure 4B). These two mechanisms appear to proceed during

the inclusion complex formation of G18 with (M)-1_TBA2in

CD₃CN containing water (0.6 equiv) at 70 °C, thus producing

the almost racemic free 1_TBA2via pathway A and its complex

(1_TBA2⊃G18) with optical activity through both pathways A

and B (Figure 4).¹⁴

Mechanism of Guest Encapsulation in the Helicate.

The X-ray crystallographic analysis of the 1_BTMA2(BTMA =

benzyltrimethylammonium) single crystals grown by the slow

evaporation of an acetone solution of 1_Na2in the presence of 5

equiv of BTMA bromide revealed that 1_BTMA2adopted a

unique pacman-like structure¹⁵in which one of the two bulky

BTMA cations was encapsulated within the cleft of the

bisporphyrin, which was composed of two porphyrin rings

tilted by ca. 55° (Figures 5 and S24). This pacman-like

structure has frequently been observed in a number of cofacial

bisporphyrins that are anchored by a single rigid pillar or

spacer, but to the best of our knowledge has not been reported

15

in doubly bridged bisporphyrins like 1_Na2

.

The observed

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Figure 4. Schematic representation of two plausible pathways for the inclusion of a bulky guest G18 in the bisporphyrin helicate (M)-1_TBA2(A)

with and (B) without the racemization of (M)-1_TBA2through the reversible B−O bond cleavage/reformation of the spiroborate groups. The

inclusion complexation of (M)-1_TBA2with G18 bearing bulky substituents at both ends is possible only when the inner cavity of (M)-1_TBA2is

temporarily expanded by the water-mediated reversible B−O bond cleavage/reformation of the spiroborate groups. The racemization of (M)-1_TBA2

takes place during the simultaneous cleavage of one of the four B−O bonds at each spiroborate group (panel A).

unique pacman structure is most likely formed through an

induced-ﬁt mechanism driven by cation−π interactions, which

are probably cation−quadrupole interactions between the π

electron-rich bisporphyrin of 1²⁻and the cationic methonium

group of BTMA.¹⁶A long-range electrostatic ion−ion

interaction between the cationic methonium group of BTMA

and the negatively charged borate ions of 1²⁻as well as

solvophobic (CH−π) interactions between the bulky trime-

thylammonium group of BTMA and the bisporphyrin units of

the helicate may also contribute to enhance the stability of the

pacman formation, at least in the solid state.¹⁷The solid-state

structure is quite unique and diﬀerent from the crystal

structures of 1_Na2and its inclusion complex with G4, as

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t

Figure 5. X-ray crystal structure of 1_BTMA2(1_BTMA⊃BTMA). All hydrogen atoms, Bu groups, and another benzyltrimethylammonium (BTMA)

molecule have been omitted for clarity. The porphyrin rings (light and dark blue) and the included BTMA molecule (orange) are highlighted as a

space-ﬁlling model. The tilt angle between the two porphyrin rings is also shown.

Figure 6. Snapshot of (a) the packman form of 1²⁻⊃G4 during the DFTB/US-MD simulation and the optimized geometries of the (b) planar and

(c) packman forms of 1²⁻⊃G4, which were calculated by RI-DFT. The binding energies (E_bind) of the optimized forms, which were calculated

based on the binding energies of free helicate 1²⁻and G4 as a base value (E_bind= 0), are also shown (panels b and c).

determined by X-ray crystallography with respect to the

orientation of the two porphyrin rings (tilted or parallel).^6g

We anticipated that the observed pacman-like structure of

1_BTMA⊃BTMA is one of the possible intermediates that is most

likely relevant to the encapsulation mechanism of aromatic

guests in the bisporphyrin helicate in nonaqueous media

(Figure 1c, route A), which may be more plausible than

another mechanism (Figure 1c, route B) by which the two

porphyrin rings of the helicate are forced to expand in a parallel

fashion so as to generate a suﬃcient space to sandwich an

aromatic guest between the bisporphyrin. The latter parallel

expansion mechanism may be thermodynamically unfavorable

compared to the former pacman-type expansion of the two

porphyrin rings, judging from the crystal structure of 1_Na2in

which the two porphyrin units are stacked face-to-face at a

distance of 4.1 Å.^6g,18Therefore, the two porphyrins linked in a

face-to-face parallel arrangement favorably undergo the

dynamic motion of unfolding while maintaining a partial

overlap between the porphyrin rings to open a window for the

guest uptake in such a way as to form the pacman-like

inclusion complex, which subsequently folds into a face-to-face

sandwich structure with the guest (Figure 1c, route A).

Theoretical Studies of the Mechanism of Guest

Encapsulation in the Helicate. The complexation processes

of 1²⁻⊃G4 and 1_(BTMA)2⊃BTMA⁺were then investigated by

performing self-consistent charge density functional tight-

binding (SCC-DFTB)¹⁹MD simulations with umbrella

sampling (US) (DFTB/US-MD) using the crystal structures

as the initial geometries (Figures S25 and S27) (see section 7

in the Supporting Information for theoretical background and

computational details). During the DFTB/US-MD simulations

of 1²⁻⊃G4, we found both planar and pacman-like structures

of 1²⁻⊃G4 in the trajectories (Figures 6a and S28a and b);

such a pacman form was not observed in the corresponding

crystal structures. We then optimized the geometries of the

planar and pacman forms of the 1²⁻⊃G4 obtained by the

DFTB/US-MD simulations using resolution of identity density

functional theory (RI-DFT)²⁰(Figure 6b and c) and

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Figure 7. Snapshot of (a) the planar form of 1_(BTMA)2⊃BTMA⁺during the DFTB/US-MD simulation and the optimized geometries of the (b)

planar and (c) packman forms of 1_(BTMA)2⊃BTMA⁺, which were calculated by RI-DFT. The binding energies (E_bind) of the optimized forms, which

were calculated based on the binding energies of free helicate 1_(BTMA)2and BTMA⁺as a base value (E_bind= 0), are also shown (panels b and c).

computed binding energy (E_bind) values. The planar and

pacman forms were maintained during the optimization,

indicating that both forms are local-minimum free-energy

states; the two porphyrin rings are tilted by 21.5° in the

pacman form and by 1.2° in the planar form, respectively. The

E_bindvalue of the planar geometry was lower than that of the

pacman-like geometry by 12 kcal mol⁻¹(Figure 6b and c).

We also calculated the potential of mean force (PMF)

NMR spectra of mixtures of 1_Na2with 0.5 equiv of the NMI

(G10−G12) and NDI (G13−G15) derivatives derived from

G4 also displayed two sets of signals due to the presence of

free 1_Na2and the corresponding 1:1 inclusion complexes as

already described for G4 and the PDI derivative G6 (Figures

S7 and S9, respectively), which were almost independent of

their K_avalues (Figures S12 −S17, respectively, and Table 1).²²

Similar but rather broad signals appeared when 1_Na2was mixed

with 0.5 equiv of G1 and G3 (Figures S4c and S6c,

respectively), indicating that the exchanges between the free

1_Na2and its complexes with G1 and G3 were faster than that

with G4. Although the K_avalue of 1_Na2with G2 was similar to

those with G1, G3, G14, and G15 and approximately ﬁve-

times greater than that with G13 (Table 1), the exchange

between the free 1_Na2and its complex with G2 was much faster

than those with G1, G3, G4, G6, and G10−G15. Therefore,

F_T(ξ), which is the Helmholtz free energy as a function of the

0

reaction coordinate ξ in the original unbiased system, using the

DFTB/US-MD simulation as shown in Figure S29. The PMF

shows that the planar form at around ξ(r) = 0.0 Å is more

stable than the pacman form at around ξ(r) = 4.0 Å,

corresponding to the E_bindvalue. The PMF also shows that the

free-energy barrier from the planar form to the pacman form is

less than 1.0 kcal mol⁻¹(Figure S29). According to the

computational results, we found one case where the pacman

form is one of the intermediate states, which immediately

transformed into the planar form by overcoming a low free-

energy barrier. This might be the reason why only the planar

1²⁻⊃G4 has been found by X-ray analysis. This mechanism

suggests that it should be diﬃcult to capture the pacman form

in experiments.

1

the mixing of 1_Na2with 0.5 equiv of G2 showed broad H

NMR signals that were averaged between the free 1_Na2and its

inclusion complex with G2, and the ¹H signals of G2

complexed with 1_Na2could not be observed (Figure S5).

The kinetics of the guest inclusion and release into and from

1_Na2were further investigated by the 2D EXSY measurements

of 1:1 mixtures of 1_Na2and its inclusion complexes with

selected guests, 1_Na2⊃GX (X = 4, 14, and 15). Each 1:1

mixture was generated upon the addition of 0.5 equiv of the

guest to a solution of 1_Na2in CD₃CN at 30 °C, which

displayed a number of chemical exchange cross-peaks between

the free 1_Na2and 1_Na2⊃GX (X = 4, 14, and 15) (Figures S31 −

S33, respectively). By measuring the peak volumes of the cross

and diagonal peaks at diﬀerent mixing times, the apparent

exchange rate constants (k_ex) between the free 1_Na2and its

inclusion complexes with GX (X = 4, 14, and 15) were

estimated to be 0.023, 4.3, and 0.40 s⁻¹, respectively. The

results revealed that the inclusion and release process of the

nonsubstituted G4 toward 1_Na2was extremely slow, as was

anticipated from its very high binding aﬃnity (K_a= ca. 2.2 ×

10⁹M⁻¹) compared to those of the NDI-based guests 14 (ca.

5.2 × 10⁵M⁻¹) and 15 (ca. 2.0 × 10⁵M⁻¹) derived from G4

(Table 1). On the other hand, the exchange rate for G15

bearing the benzyl substituents is approximately 10× slower

than that for G14 bearing less bulky n-butyl substituents but

approximately 17× faster than that for G4. These 2D EXSY

and 1D NMR results suggested that the guest inclusion and

release process into and from 1_Na2is highly dependent on the

presence or absence of the substituents of the guests as well as

In the same way, we performed the DFTB/US-MD

si m u l a t i o n s a n d g e o m e tr y o p t i mi z a t i o n s o f

21

1_(BTMA)2⊃BTMA⁺by RI-DFT and computed both the E_bind

values (Figure 7) and the PMF (Figure S30). The optimized

planar and pacman forms obtained from the DFTB/US-MD

simulations are shown in Figure 7b and c, respectively.

Although the planar form has not been obtained by the X-ray

analysis (Figure 5), the optimized geometries still maintained

both the planar and pacman forms. The E_bindvalue of the

pacman form was lower than that of the planar one by 1.3 kcal

mol⁻¹(Figure 7b and c), indicating that the pacman form of

1_(BTMA)2⊃BTMA⁺is more stable than the planar one. In the

PMF of 1_(BTMA)2⊃BTMA⁺(Figure S30), the pacman form

located at around ξ(r) = 2.2 Å is more stable than the planar

form located at around ξ(r) = 0.0 Å. This is consistent with the

tendency of E_bind, and it seems that the planar form tends to

transform into the pacman form because of the lower free-

energy of the pacman form. Therefore, this energetic

relationship points to the likely reason why only the pacman

form of 1_BTMA⊃BTMA was observed by X-ray analysis.

Kinetic Studies of the Inclusion and Release of

1

Aromatic Guests into and from the Helicate. The H

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Figure 8. Summary of the complexation-induced ¹H chemical shift changes of (a) the aromatic protons of guests (Δδ_G), (b) those of the pyrrole

NH (Δδ_NH), and (c) the meso-H protons (Δδ_meso‑H) of 1_Na2

.

the type of substituents (aliphatic or aromatic), which likely

contributes to the strength of the π-stacking interaction

between the aromatic core of the guests and the bisporphyrin

unit of the helicate.

Encapsulated Guest Structures within the Helicate.

The encapsulation of electron-deﬁcient aromatic guests

between the bisporphyrin causes signiﬁcant changes in the

chemical shifts of the aromatic protons of the guests (Δδ_G)²³

along with the speciﬁc porphyrin proton signals of 1_Na2, such as

the pyrrole NH (Δδ_NH) and meso-H protons (Δδ_meso‑H) (see

Figure 1a), due to the porphyrin ring current eﬀect and the

shielding eﬀect of the included aromatic rings of the guests,

respectively. These changes provide useful information

The H_Aor H_Bproton NMR signals for all of the tested

electron-deﬁcient aromatic guests were signiﬁcantly shifted

upﬁeld upon the formation of a 1:1 sandwich complex with

1

_Na2. A more pronounced upﬁeld shift of the H_Asignals was

observed for G1 and G3, which were composed of a smaller

phenylene core (Δδ_G= 8.71 and 8.56 ppm, respectively),

indicating that the protons of smaller aromatic guests (G1 and

G3) are located at the center of the bisporphyrin. Therefore,

the Δδ_Gvalues of the guests tended to decrease in the

following order: G1 and G3 > G4, G10−G15, G17, and G18

> G6, which is in good agreement with the order of the

aromatic core size (Figure 8a).

As anticipated, the guest-induced chemical shift changes of

the inner pyrrole NH protons of the porphyrin rings of 1_Na2

(Δδ_NH) were always greater than those of the meso-H protons

on the periphery of the porphyrin rings (Δδ_meso‑H) independent

of the guest structures as a result of the π-stacked geometry

and showed roughly similar values except for the guests with

small (G1 and G3) and large cores (G5 and G6) (Figure 8b).

The Δδ_meso‑Hvalues are highly aﬀected by the guests, namely,

their core sizes and substituents (Figure 8c). G1 exerted little

regarding the structures of the encapsulated guests, such as

24

the orientations relative to the two porphyrin rings of 1_Na2

.

The complexation-induced chemical shift changes (Δδ_G,

Δδ_NH, and Δδ_meso‑H) of 1_Na2with 0−5 equiv of GX (X = 1−

6, 10−15, 17, and 18) were then investigated in CD₃CN at 25

°C (Figures S4 − S21), and the results are summarized in

Table 1 and Figure 8.

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Figure 9. Summary of the complexation-induced CD intensity (|Δε_first| + |Δε_second|) and absorption maximum (Δλ) changes of (M)-1_TBA2

.

inﬂuence compared to G2−G4, while G5 and G6, which were

composed of large perylene cores, induced a greater upﬁeld

shift of the meso-H protons.

The CD spectral patterns and intensities and the λ_maxvalues

of (M)-1_TBA2complexed with G4 and the NMI- (G10−G12)

and NDI-based guests (G13−G15) were almost similar to

each other, showing enhanced Cotton eﬀects independent of

the structures and the number of substituents of the guests

composed of a naphthalene core (Figure 9). In contrast, the

inclusion complexes of (M)-1_TBA2with smaller and less

electron-deﬁcient aromatic guests (G2 and G3) showed

almost no enhancement of the CD, while that with G1

induced a slightly intense split-type CD; all were accompanied

by a gradual red-shift of the λ_maxin the following order: G1 <

G2 < G3 < (G4, G10−G15) (Figure 9). On the other hand, a

PDI-based guest G6 with a large perylene core also displayed

almost no enhancement of the CD intensity, but its bisignated

CD at higher wavelengths and spectral pattern were diﬀerent

from those of the other inclusion complexes, mostly due to the

exciton coupling between the bisporphyrin and PDI

chromophores (Figures 9 and S34).

These results suggested that the guest-encapsulation-

induced CD spectral changes of (M)-1_TBA2and with their

¹H NMR spectral changes (Δδ values) (Figures 8 and 9) may

provide useful information about the spatial arrangement or

alignment of the guests sandwiched between the bisporphyrin

unit, which may be responsible for the dual rotary and twisting

motions of the helicate.

When complexed with nonsymmetric NMI-based guests

(G11 and G12) (Figures S13 and S14), one of the meso-H

protons was shifted more upﬁeld than the other meso-H proton

of the porphyrin rings on the opposite side due to the aromatic

shielding eﬀects of the N-benzyl and N-diphenylmethyl groups

of the pendants. Hence, relatively high Δδ_meso‑Hvalues (0.48−

0.91) were observed for the NDI-based guests G15, G17, and

G18 bearing N-benzyl and bulky N-3,5-dimethy- and 3,5-di-

tert-butylbenzyl substituents on both sides, respectively

(Figures 8c, S17, S19, and S20, respectively, and Table 1).

Interestingly, the N-benzyl methylene proton signals of the

NDI-based achiral guests (G15, G17, and G18) complexed

with 1_Na2were shifted upﬁeld and split into a pair of doublets

with relatively large chemical shift diﬀerences (Δδ_CH2) of 0.23,

0.32, and 0.16 ppm, respectively (Figures 2h,i, S17, S19, and

S20), indicating that the N-benzyl methylene groups were

magnetically nonequivalent once encapsulated in the double-

stranded helical 1_Na2. The helical chirality of 1_Na2appears to

force the guests to bind in a diastereotopic environment,

thereby allowing the recognition of the enantiotopic methylene

groups.²⁵Therefore, the enantiopure left-handed double-

helical (M)-1_TBA2can discriminate between the enantiomers

of NMI-based racemic guests bearing a chiral aromatic

substituent at one end and can form an inclusion complex

with one of the enantiomers in a highly diastereoselective

CONCLUSIONS

■

In this study, we systematically investigated the formation of an

inclusion complex between the porphyrin-linked double-

stranded spiroborate helicate and a series of electron-deﬁcient

aromatic guests. We have found that the thermodynamic and

kinetic stabilities of the inclusion complexes are highly

dependent on the core sizes of the aromatic guests as well as

the bulkiness and number of substituents of the guests.

Although naphthalenediimide-based guests with bulky sub-

stituents at both ends could not pass through the bisporphyrin

cavity, a small amount of water promoted the dynamic B−O

bond cleavage/reformation of the spiroborate groups of the

helicate, resulting in the formation of a [2]rotaxane-like

inclusion complex. The unique pacman-like 1:1 inclusion

complex revealed by an X-ray crystal structure analysis and

further supported by MD simulations suggests that a pacman-

like structure may be more plausible as an intermediate for the

inclusion of a planar aromatic guest within the bisporphyrin

cavity of the helicate. Taking advantage of both the right- and

left-handed porphyrin-linked spiroborate helicates that are

readily available,^6gthe present results will provide a promising

way to control the rotary and twisting motions of the helicate

6i

1

fashion, as detected by H NMR.

The enantiopure (M)-1_TBA2helicate showed a bisignated

exciton-coupled Cotton eﬀect in the porphyrin Soret band

region due to the two porphyrin rings being twisted into a

right-handed orientation.^6gUpon the encapsulation of an

electron-deﬁcient aromatic guest, such as G4, the exciton-

coupled circular dichroism (CD) spectral pattern and the

intensity of (M)-1_TBA2were drastically changed and enhanced,

respectively. This was accompanied by a large red-shift of its

absorption maximum (λ_max), which resulted from the

expansion of the bisporphyrin cavity and the subsequent

rotary motion of the porphyrin rings in one direction coupled

with a unidirectional twisting motion of the spiroborate helix.^6g

We anticipated that these unidirectional dual rotary and

twisting motions of the helicate could be changed by guests

composed of diﬀerent-sized aromatic cores. We then measured

the CD spectra of (M)-1_TBA2complexed with a series of guests

(Figures S34 −S36), and the results are summarized in Figure 9

and Table S6.

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G15. mp: 271.8 °C (decomp.). IR (KBr, cm⁻¹): 1703 (ν_CO),

in one direction in a more precise manner that can be triggered

by the inclusion of speciﬁc chiral aromatic guests within the

bisporphyrin chiral cavity, which may be further applicable to

the development of unique supramolecular asymmetric

catalysts. Its catalytic activity and enantioselectivity will be

regulated by the guest-induced unidirectional rotary and

twisting motions of the helicate.

1

1665 (ν_CO). H NMR (500 MHz, CDCl₃, 25 °C): δ 8.77 (s, 4H),

7.56 (br dd, 4H), 7.32 (br dd, 4H), 7.35 (br tt, 2H), 7.26 (m, 2H),

5.39 (s, 4H). ¹³C{¹H} NMR (125 MHz, CDCl₃, 25 °C): δ 163.0,

136.7, 131.3, 129.3, 128.7, 128.0, 126.9, 126.8, 44.2. HRMS (ESI-

TOF) m/z: [M − H]⁻Calcd for C₂₈H₁₈N₂O₄446.1267, found

446.1275.

G12 and G16. To a solution of G4 (300 mg, 1.11 mmol) in DMF

(3.0 mL) was added 1,1-diphenylmethylamine (0.19 mL, 1.1 mmol)

at 160 °C under argon in an oil bath, and the reaction mixture was

stirred at 160 °C for 30 min in an oil bath. After cooling to ambient

temperature, the solvent was removed under reduced pressure. The

resulting brown residue was then suspended in acetone, and to the

mixture was slowly added 1 M aqueous HCl with vigorous stirring.

The precipitate was dissolved in CHCl₃, and the solution was dried

over anhydrous Na₂SO₄, ﬁltered, and concentrated under reduced

pressure. The crude product contained a mixture of G12 and G16,

which was separated by SEC (CHCl₃as the eluent) into G12 (136

mg, 28% yield) and G16 (57.3 mg, 8.6% yield) as white and pale

yellow solids, respectively.

EXPERIMENTAL SECTION

General Information. The NMR spectra were recorded using a

Bruker Ascend 500 (Bruker Biospin, Billerica, MA) or a Varian 500AS

(Varian, Palo Alto, CA) spectrometer operating at 500 MHz for H

■

1

and 125 MHz for ¹³C, using tetramethylsilane (TMS) or a residual

undeuterated solvent peak as the internal standard. The absorption

and CD spectra were measured in a 0.1 or 1 cm quartz cell using a

JASCO V-570 spectrophotometer and a JASCO J-820 or a J-1500

spectropolarimeter, respectively. The ﬂuorescence spectra were

recorded in a 1 cm quartz cell on a JASCO FP-6500 spectro-

ﬂuorometer. The SEC fractionations were performed using an LC-

908W−C60 liquid chromatograph (Japan Analytical Industry)

equipped with two SEC columns (JAIGEL-1H-40 (4 (i.d.) × 60

cm) and JAIGEL-2H-40 (4 (i.d.) × 60 cm)) in series and UV−visible

(JAI UV-3702) and RI (JAI RI-5) detectors; chloroform (CHCl₃) was

used as the eluent at a ﬂow rate of 12 mL min⁻¹. All starting materials,

including aromatic guests (G1−G5 and G7−G9), were purchased

from commercial suppliers and used without further puriﬁcation

unless otherwise noted. The spiroborate helicate 1_Na2and its

enantiomer complexed with an achiral tetra-n-butylammonium

G12. mp: 315 °C (decomp.). IR (KBr, cm⁻¹): 1782 (ν_CO), 1745

(ν_CO), 1712 (ν_CO), 1674 (ν_CO). ¹H NMR (500 MHz, CDCl₃, 25

°C): δ 8.80 (m, 4H), 7.63 (s, 1H), 7.45 (br dd, 4H), 7.36 (br dd,

4H), 7.32 (br tt, 2H). ¹³C{¹H} NMR (125 MHz, CDCl₃, 25 °C): δ

162.4, 158.9, 137.9, 133.3, 131.8, 129.0, 128.9, 128.6, 128.2, 127.9,

127.1, 123.0, 60.1. Anal. Calcd for C₂₇H₁₅NO₅: C, 74.82; H, 3.49; N,

3.23. Found: C, 74.82; H, 3.53; N, 3.25.

G16. mp: 321 °C (decomp.). IR (KBr, cm⁻¹): 1709 (ν_CO), 1671

(ν_CO). ¹H NMR (500 MHz, CDCl₃, 25 °C): δ 8.72 (s, 4H), 7.63 (s,

2H), 7.45 (br dd, 8H), 7.35 (br dd, 8H), 7.30 (br tt, 4H). ¹³C{¹H}

NMR (125 MHz, CDCl₃, 25 °C): δ 162.9, 138.0, 131.5, 128.8, 128.4,

127.60, 126.9, 126.8, 59.6. HRMS (ESI-TOF) m/z: [M − H]⁻Calcd

for C₄₀H₂₆N₂O₄598.1893, found 598.1877.

(TBA) cation, (M)-1_TBA2,

^6gG6,²⁶G13,²⁷G14,²⁸3,5-dimethylbenzyl-

amine,²⁹and 3,5-di-tert-butylbenzylamine,²⁹were prepared according

to the literature.

Synthesis of Naphthalene-Based Guests. G10. To a solution

of G4 (300 mg, 1.11 mmol) in DMF (20 mL) was added aniline (0.10

mL, 1.1 mmol) at 90 °C under argon in an oil bath, and the reaction

mixture was stirred at 150 °C for 30 min in an oil bath. After cooling

to ambient temperature, the solvent was removed under reduced

pressure. The resulting brown residue was then suspended in acetone,

and to the mixture was slowly added H₂O with vigorous stirring. The

precipitate was dissolved in CHCl₃, and the solution was dried over

anhydrous Na₂SO₄, ﬁltered, and concentrated under reduced

pressure. The crude product was puriﬁed by SEC (CHCl₃as the

eluent), aﬀording G10 as a white solid (109 mg, 28% yield). mp: 321

°C (decomp.). IR (KBr, cm⁻¹): 1781 (ν_CO), 1750 (ν_CO), 1719

G17. To a solution of G4 (200 mg, 0.746 mmol) in DMF (3.0 mL)

was added 3,5-dimethylbenzylamine (0.33 mL, 2.3 mmol) at ambient

temperature under argon, and the reaction mixture was stirred at 140

°C for 30 min in an oil bath. After cooling to ambient temperature,

the solvent was removed under reduced pressure. The resulting brown

residue was washed with Et₂O and dried under vacuum to aﬀord G17

(319 mg, 85% yield) as a yellow solid. mp: 384 °C (decomp.). IR

(KBr, cm⁻¹): 1706 (ν_CO), 1666 (ν_CO). ¹H NMR (500 MHz,

CDCl₃, 25 °C): δ 8.77 (s, 4H), 7.14 (s, 4H), 6.90 (s, 2H), 5.32 (s,

4H), 2.28 (s, 12H). ¹³C{¹H} NMR (125 MHz, CDCl₃, 25 °C): δ

163.0, 138.3, 136.5, 131.3, 129.7, 126.91, 126.87, 126.8, 44.1, 21.4.

HRMS (ESI-TOF) m/z: [M − H]⁻Calcd for C₃₂H₂₆N₂O₄502.1893,

found 502.1899.

G18. To a solution of G4 (200 mg, 0.746 mmol) in DMF (3.0 mL)

was added 3,5-di-tert-butylbenzylamine (0.33 mL, 2.3 mmol) at

ambient temperature under argon. The reaction mixture was stirred at

150 °C for 30 min in an oil bath and further at 100 °C for 11 h in an

oil bath. After cooling to ambient temperature, the solution was

poured into a large amount of Et₂O. The resulting precipitate was

ﬁltered, washed with Et₂O, and dried under vacuum to aﬀord G18

(449 mg, 85% yield) as a white solid. mp: 318.9−320.8 °C. IR (KBr,

cm⁻¹): 1708 (ν_CO), 1666 (ν_CO). ¹H NMR (500 MHz, CDCl₃, 25

°C): δ 8.75 (s, 4H), 7.47 (d, J = 1.9 Hz, 4H), 7.35 (dd, J = 1.9 Hz,

2H), 5.37 (s, 4H), 1.30 (s, 36H). ¹³C{¹H} NMR (125 MHz, CDCl₃,

25 °C): δ 163.0, 151.1, 135.9, 131.2, 126.9, 126.8, 124.2, 122.1, 44.6,

35.0, 31.6. HRMS (ESI-TOF) m/z: [M − H]⁻Calcd for C₄₄H₅₀N₂O₄

670.3771, found 670.3775.

1

(ν_CO), 1681 (ν_CO). H NMR (500 MHz, CDCl₃, 25 °C): δ 8.88

(d, 2H, J = 7.5 Hz), 8.86 (d, J = 7.5 Hz, 2H), 7.60 (br dd, 2H), 7.55

(br tt, 1H), 7.33 (br dd, 2H). ¹³C{¹H} NMR (125 MHz, CDCl₃, 25

°C): δ 162.5, 158.9, 134.4, 133.4, 131. 8, 129.8, 129.6, 129.2, 128.5,

128.2, 127.4, 123.3. Anal. Calcd for C₂₀H₉NO₅: C, 69.98; H, 2.64; N,

4.08. Found: C, 69.99; H, 2.58; N, 4.06.

G11 and G15. To a solution of G4 (300 mg, 1.11 mmol) in DMF

(3.0 mL) was added benzylamine (0.12 mL, 1.1 mmol) at 140 °C

under argon in an oil bath, and the reaction mixture was stirred at 170

°C for 30 min in an oil bath. After cooling to ambient temperature,

the solvent was removed under reduced pressure. The resulting brown

residue was then suspended in acetone, and to the mixture was slowly

added 1 M aqueous HCl with vigorous stirring. The precipitate was

dissolved in CHCl₃, and the solution was dried over anhydrous

Na₂SO₄, ﬁltered, and concentrated under reduced pressure. The crude

product contained a mixture of G11 and G15, which was separated by

SEC (CHCl₃as the eluent) into G11 (93.9 mg, 24% yield) and G15

(111 mg, 22% yield) as white solids.

G19. To a solution of G4 (200 mg, 0.746 mmol) in DMF (10 mL)

was added 1-adamantanemethylamine (0.31 mL, 1.9 mmol) at

ambient temperature under argon, and the reaction mixture was

stirred at 140 °C for 30 min in an oil bath. After cooling to ambient

temperature, the solution was poured into a large amount of Et₂O.

The resulting precipitate was ﬁltered, washed with Et₂O, and dried

under vacuum to aﬀord G19 (328 mg, 78% yield) as a pale pink solid.

mp: 365 °C (decomp.). IR (KBr, cm⁻¹): 1708 (ν_CO), 1671 (ν_CO).

¹H NMR (500 MHz, CDCl₃, 25 °C): δ 8.76 (s, 4H), 4.05 (s, 4H),

1.96 (s, 6H), 1.59−1.69 (m, 24H). ¹³C{¹H} NMR (125 MHz,

G11. mp: 279.1−280.9 °C. IR (KBr, cm⁻¹): 1785 (ν_CO), 1742

(ν_CO), 1710 (ν_CO), 1671 (ν_CO). ¹H NMR (500 MHz, CDCl₃, 25

°C): δ 8.84 (d, 2H, J = 8.0 Hz), 8.81 (d, J = 7.5 Hz, 2H), 7.55 (br dd,

2H), 7.33 (br dd, 2H), 7.28 (br tt, 1H), 5.40 (s, 2H). ¹³C{¹H} NMR

(125 MHz, CDCl₃, 25 °C): δ 162.4, 158.9, 136.4, 133.3, 131.6, 129.4,

129.0, 128.8, 128.2, 128.0, 127.0, 123.1, 44.4. Anal. Calcd for

C₂₁H₁₁NO₅: C, 70.59; H, 3.10; N, 3.92. Found: C, 70.60; H, 3.12; N,

3.96.

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CDCl₃, 25 °C): δ 163.9, 131.3, 126.82, 126.81, 51.1, 41.5, 36.9, 36.2,

28. 6. Anal. Calcd for C₃₆H₃₈N₂O₄: C, 76.84; H, 6.81; N, 4.98. Found:

C, 76.85; H, 6.80; N, 5.00.

Rafael Souza − Department of Chemistry, Graduate School of

Science, Nagoya University, Nagoya 464-8602, Japan

Stephan Irle − Department of Chemistry, Graduate School of

Science, Nagoya University, Nagoya 464-8602, Japan;

Institute of Transformative Bio-Molecules (WPI-ITbM),

Nagoya University, Nagoya 464-8601, Japan; Present

Address: S.I.: Computational Sciences & Engineering

Division, Oak Ridge National Laboratory, Oak Ridge,

Tennessee 37831-6129, USA.; orcid.org/0000-0003-

4995-4991

ASSOCIATED CONTENT

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c01155.

■

sı

Full experimental details, characterizations of inclusion

complexes, modeling procedures, and additional sup-

porting data (PDF)

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c01155

Accession Codes

CCDC 1559425 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.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

This work was supported in part by JSPS KAKENHI (Grant-

in-Aid for Specially Promoted Research, no. 18H05209

(E.Y.)). We thank Dr. Daisuke Taura (Nagoya University)

for his help in the modeling of the helicates.

AUTHOR INFORMATION

■

Corresponding Authors

Naoki Ousaka − Department of Molecular Design and

Engineering, Graduate School of Engineering and Department

of Molecular and Macromolecular Chemistry, Graduate

School of Engineering, Nagoya University, Nagoya 464-8603,

Japan; Present Address: N.O.: Molecular Engineering

Institute, Kyushu Institute of Technology, Tobata-ku,

Kitakyushu 804-8550, Japan; orcid.org/0000-0002-

3398-3328; Email: ousaka.naoki@gmail.com

Yuh Hijikata − Department of Chemistry, Graduate School of

Science, Nagoya University, Nagoya 464-8602, Japan;

Institute of Transformative Bio-Molecules (WPI-ITbM),

Nagoya University, Nagoya 464-8601, Japan; Present

Address: Y.H.: Institute for Chemical Reaction Design

and Discovery (WPI-ICReDD), Hokkaido University,

Sapporo, 001-0021, Japan.; orcid.org/0000-0003-4883-

5085; Email: hijikata@icredd.hokudai.ac.jp

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1

as evidenced by its H NMR spectral changes with time (Figure S8).

(11) The K_avalue of a G6 analogue bearing the same Tg-bound

imide substituent at one end and a bulky 3,5-di-tert-butylbenzyl

stopper at the other end was almost identical to that of G6 (ca. 1.1 ×

10⁹M⁻¹).^6h

(12) G17 is hardly soluble in CH₃CN but became soluble in

CD₃CN in the presence of 1_Na2, producing a 1:1 inclusion complex

(Figure S19).

(13) To avoid the complete racemization of (M)-1_TBA2upon heating

with G18, a 1:1 mixture of (M)-1_TBA2and G18 in CD₃CN that

contained a small amount of water (ca. 0.6 equiv) was heated at 70 °C

for 114 h and then cooled to ambient temperature before reaching an

equilibrium state (Figure 3).

(14) Previously, we reported that the water-mediated racemization

of the free (M)-1_TBA2at 70 °C was slower than that of its inclusion

complex with the less bulky G4 ((M)-1_TBA2⊃G4),⁶ⁱwhich is diﬀerent

from the present results. The reason for this is unclear at present but

is considered to be due to the hydrophobic and bulky 3,5-di-tert-

butylbenzyl substituents of G18, which may prevent the access of

water molecules to the spiroborate groups once they are encapsulated

into the helicate.

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the helicate 1²⁻to stably simulate the binding process. Locating

BTMA⁺on only one side of the helicate induced an unbalanced

charge distribution in the system, which caused problems in the

convergence of the iteration of SCC by DFTB. Therefore, we

neutralized the helicate 1²⁻using two BTMA⁺molecules. The binding

energy (E_bind) of BTMA⁺toward the 1_(BTMA)2helicate was then

calculated by RI-DFT (see Section 5.2 in the Supporting

Information).)

(22) Upon mixing 1_Na2with 0.5 equiv of nonsymmetric G10−G12,

1

the H NMR signals due to the inclusion complexes of 1_Na2further

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pseudo-D₂-symmetric structure of 1_Na2via complexation with the

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1

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Encapsulation of Aromatic Guests in the Bisporphyrin Cavity of a Double-Stranded Spiroborate Helicate: Thermodynamic and Kinetic Studies and the Encapsulation Mechanism

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