Folded-to-unfolded structural switching of a macrocyclic aromatic hexaamide based on conformation changes in the amide groups induced by N-alkylation and dealkylation reactions

Article abstract of DOI:10.1016/j.molstruc.2014.10.074

A macrocyclic compound has been designed and synthesized containing six para-phenylene groups and six alternate N-butyl and N-4-methoxybenzyl substituted amides. The three N-4-methoxybenzyl groups could be removed by N-dealkylation under acidic conditions to give the corresponding secondary amides, which underwent a switch in their conformation from cis to trans. Single crystal X-ray crystallographic analysis revealed that the macrocyclic compound containing six alternate N-butyl and N-4-methoxybenzyl substituted tertiary amide groups existed as the "folded" structure, whereas the macrocyclic compound with six alternate tertiary and secondary amide groups existed as the "unfolded" structure. Furthermore, these changes in the conformation of the hexaamide displayed reversible switching between the "folded" and "unfolded" states.

Full text of DOI:10.1016/j.molstruc.2014.10.074

Journal of Molecular Structure 1082 (2015) 23–28
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Folded-to-unfolded structural switching of a macrocyclic aromatic
hexaamide based on conformation changes in the amide groups
induced by N-alkylation and dealkylation reactions
a,1
a
a
a
b
a
Kosuke Katagiri , Taichi Tohaya , Riwako Shirai , Takako Kato , Hyuma Masu , Masahide Tominaga ,
Isao Azumaya
a
c,
⇑
Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan
Center for Analytical Instrumentation, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba City, Chiba 274-8522, Japan
Graduate School of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
b
c
h i g h l i g h t s
ꢀ
ꢀ
ꢀ
ꢀ
A cyclic hexaamide containing three 4-methoxybenzyl and three butyl groups was synthesized.
The hexaamide containing six tertiary amides with cis conformation formed a ‘‘fold’’ structure.
The hexaamide containing alternate tertiary and secondary amide formed an ‘‘unfold’’ structure.
The conformational change of the hexaamide displays reversible switching.
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2014
Received in revised form 3 October 2014
Accepted 30 October 2014
Available online 8 November 2014
A macrocyclic compound has been designed and synthesized containing six para-phenylene groups and
six alternate N-butyl and N-4-methoxybenzyl substituted amides. The three N-4-methoxybenzyl groups
could be removed by N-dealkylation under acidic conditions to give the corresponding secondary amides,
which underwent a switch in their conformation from cis to trans. Single crystal X-ray crystallographic
analysis revealed that the macrocyclic compound containing six alternate N-butyl and N-4-methoxyben-
zyl substituted tertiary amide groups existed as the ‘‘folded’’ structure, whereas the macrocyclic
compound with six alternate tertiary and secondary amide groups existed as the ‘‘unfolded’’ structure.
Furthermore, these changes in the conformation of the hexaamide displayed reversible switching
between the ‘‘folded’’ and ‘‘unfolded’’ states.
Keywords:
Aromatic amide
Structural switching
Folded structure
Unfolded structure
Ó 2014 Elsevier B.V. All rights reserved.
Introduction
units for the construction of molecules and supramolecules, and
possess specific structural features that would enable them to be
Being able to exert some control over the three-dimensional
structures and conformations of molecules as well as their dynamic
behaviors is important for the development of functional molecular
switches [1,2]. Molecular switches are defined as molecules that
can be reversibly interconverted by the application of an external
stimulus, such as light [3–7], an electrical field [8,9], or a chemical
reaction [10–13]. In recent years, a variety of different molecules
have been developed with switching functions. Aromatic amide
compounds, in particular, are one of the most important structural
used in molecular switches, because they can undergo a cis/trans
conformational change [14–22]. Okamoto et al. reported the devel-
opment of several different types of aromatic amides that were con-
formationally responsive to a range of stimuli, including redox
control [23,24], different solvents [25,26], and changes in the acid-
ity of the media [27]. We previously reported the synthesis of a
macrocyclic compound containing six alternate tertiary and sec-
ondary amide moieties, which existed in their cis and trans confor-
mation, respectively [28]. This result led us to design molecules that
could undergo extensive reversible changes in their conformation
through chemical reactions, and it was envisaged that the use of
tertiary amides bearing chemically labile alkyl groups on the nitro-
gen atom of their amide group would facilitate this conformational
change through the cleavage of the alkyl groups. Herein, we
⇑
Corresponding author. Tel./fax: +81 47 472 1589.
E-mail address: isao.azumaya@phar.toho-u.ac.jp (I. Azumaya).
Present address: Department of Chemistry, Faculty of Science and Engineering,
1
Konan University, 8-9-1 Okamoto, Higashinada-ku, Kobe, Hyogo 658-8501, Japan.
http://dx.doi.org/10.1016/j.molstruc.2014.10.074
0
022-2860/Ó 2014 Elsevier B.V. All rights reserved.

2
4
K. Katagiri et al. / Journal of Molecular Structure 1082 (2015) 23–28
describe our most recent work towards the synthesis and
evaluation of a cyclic aromatic hexaamide bearing alternate
N-butyl and N-4-methoxybenzyl amide groups. Furthermore, we
have confirmed the conformational changes in this aromatic hexaa-
mide system using solution NMR experiments and X-ray
crystallography.
Ethyl 4-(4-amino-N-butylbenzamido)benzoate (4)
To a solution of 3 (18.5 g, 50.0 mmol) in anhydrous ethanol
(500 mL) was added 10% palladium on carbon (1.10 g), and the
resulting mixture was stirred vigorously under an atmosphere of
hydrogen for 5 h at room temperature. Upon completion of the
reaction, as determined by TLC, the catalyst was removed by filtra-
tion and the filtrate was evaporated to dryness to give the crude
product as a residue, which was purified by recrystallization from
Experimental
a 1:5 (v/v) mixture of ethyl acetate and hexane to give 4 in 91%
General
1
yield as a white powder (15.4 g, 45.4 mmol): mp 132–133 °C;
NMR (400 MHz, CDCl
4.0 Hz, 4H), 6.38 (d, J = 8.4 Hz, 2H), 4.34 (q, J = 7.2 Hz, 2H), 3.92
brt, J = 7.6 Hz, 4H), 1.59 (q, J = 7.6 Hz, 2H), 1.38–1.31 (m, 5H) and
H
3
): d 7.90 (d, J = 8.4 Hz, 2H), 7.09 (dd, J = 5.6,
2 2
Dehydrated MeOH, pyridine and CH Cl were purchased from
1
Wako Pure Chemical Industries, Ltd. (Osaka, Japan) and used
without purification. Palladium on activated carbon (10%) was
purchased from Wako Pure Chemical Industries, Ltd. All the
other reagents used in the current study were purchased from
commercial sources and used without further purification. Col-
umn chromatography was performed over silica gel WakogelÒ
(
13
0
.89 (t, J = 7.2 Hz, 3H) ppm; C NMR (100 MHz, CDCl
C@O), 165.84 (C@O), 148.71 (C ), 148.34 (C ), 130.97 (CH),
), 126.73 (CH), 124.82 (C ), 60.94 (CH ),
), 20.11 (CH ), 14.19 (CH ) and 13.71
3
): d 170.20
(
1
5
q
q
30.30 (CH), 127.43 (C
0.22 (CH ), 29.90 (CH
q
q
2
2
2
2
3
(
1
CH
3
) ppm; IR (ATR) 3444, 3357, 3245, 2983, 2958, 2867, 1706,
C-200 (75–150
l
m). Melting points were determined on an AS
À1
646, 1621, 1593, 1559, 1510, 1432, 1370, 1308, 1270 cm
;
ONE hot-stage melting point apparatus (AS ONE, Osaka, Japan).
Elemental analyses were performed on a PE-2400 Series II system
+
FAB-MS: m/z 341.3 [M+H] ; Elemental Analysis Calc. for
: C, 70.57; H, 7.11; N, 8.23. Found: C, 70.33; H, 6.98;
20 24 2 3
C H N O
(
±
PerkinElmer Japan Co., Ltd., Yokohama, Japan) and were within
N, 8.13.
Ethyl 4-(N-butyl-4-(4-methoxybenzyl)amino)benzamido)benzoate (5)
-Methoxybenzyl chloride (2.71 mL, 20.0 mmol) was added to a
0.3% of the theoretical values. 1H and C NMR spectra were
13
recorded on a Bruker Avance 400 MHz spectrometers (Bruker
BioSpin K.K., Yokohama, Japan). FT-IR spectra were recorded on
a Jasco FT/IR-6300 spectrometer (Tokyo, Japan) equipped with
an ATR-system (ATR PRO410-S). Mass spectra were obtained
using a JEOL JMS-700 spectrometer (Tokyo, Japan) equipped
with a fast atom bombardment (FAB) source. X-ray data for
crystals of compound 1 and 2 were collected using a Bruker
SMART APEX II CCD diffractometer with graphite monochromated
4
solution of 4 (13.6 g, 40.0 mmol) in HMPA (50 mL), and the result-
ing mixture was heated at 100 °C with stirring under an atmo-
sphere of Ar for 4 h. The reaction mixture was then cooled to
room temperature before being poured into water and extracted
with ethyl acetate (400 mL). The organic layer was collected and
Mo K
CCD area detector (Tokyo, Japan) with synchrotron radiation
k = 0.70000 Å) at the beam line of BL38B1 at Spring-8, respec-
a (k = 0.71073 Å) radiation, and a Rigaku JUPITER 210
washed sequentially with H
and brine (100 mL) before being dried over Na
2
O (5 Â 100 mL), 1 N HCl aq. (100 mL),
2
SO . The solvent
4
(
was then removed in vacuo to give the crude product, which was
purified by silica gel column chromatography eluting with a 1:2:3
tively. Data collections for the crystals were carried out at low
temperature (100 K) using liquid nitrogen. The crystal structures
were solved by direct methods using the SHELXS-97 program
and refined by full-matrix least-squares SHELXL-97 or SHELXL-
(
v/v/v) mixture of ethyl acetate/n-hexane/dichloromethane to give
pure 5 in 75% yield as a white powder (6.91 g, 15.0 mmol): mp 159–
1
1
60 °C; H NMR (400 MHz, CDCl
J = 8.8 Hz, 2H), 7.14 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 6.84
d, J = 8.8 Hz, 2H), 6.33 (dd, J = 8.8 Hz, 2H), 4.34 (q, J = 7.2 Hz, 2H),
.17 (s, 2H), 3.93–3.89 (m, 2H), 3.77 (s, 3H), 1.63–1.55 (m, 2H),
3
): d 7.90 (d, J = 8.4 Hz, 2H), 7.19 (d,
2
013 [29]. All non-hydrogen atoms were refined anisotropically
and hydrogen atoms were included as their calculated positions.
(
4
13
Ethyl 4-(N-butyl-4-nitrobenzamido)benzoate (3)
1.38–1.31 (m, 5H) and 0.89 (t, J = 7.6 Hz, 3H) ppm; C NMR
100 MHz, CDCl ): d 170.25 (C@O), 165.90 (C@O), 158.87 (C ),
149.55 (C ), 148.96 (C ), 131.12 (CH), 130.48 (C ), 130.33 (CH),
128.68 (CH), 127.32 (C ), 126.67 (CH), 123.68 (C ), 113.96 (CH),
111.27 (CH), 60.93 (CH ), 55.18 (OCH ), 50.30 (CH ), 47.10 (CH ),
29.98 (CH ), 20.15 (CH ), 14.22 (CH ) and 13.74 (CH ) ppm; IR
(ATR) 3355, 2957, 2872, 1710, 1626, 1595, 1511, 1321, 1273,
(
3
q
4
-Nitrobenzoyl chloride (11.1 g, 60.0 mmol) was added to a
solution of ethyl 4-butylaminobenzoate (13.3 g, 60.0 mmol) in a
mixture of dry CH Cl (600 mL) and pyridine (9.70 mL, 144 mmol),
q
q
q
q
q
2
2
2
3
2
2
and the resulting mixture was stirred for 4 h at room temperature.
The reaction mixture was then poured into water (200 mL) and
2
3
2
3
À1
+
extracted with CH
sequentially with 2 N HCl aq. (100 mL), aqueous NaHCO
100 mL), and brine (100 mL), before being dried over Na SO . The
2
Cl
2
(200 mL). The organic layer was washed
1248 cm ; FAB-MS: m/z 461.3 [M] ; Elemental Analysis Calc. for
: C, 73.02; H, 7.00; N, 6.08. Found: C, 72.80; H, 6.89;
3
28 32 2 4
C H N O
(
2
4
N, 6.01.
solvent was then removed in vacuo to give the crude product as a
residue, which was washed with hexane to give 3 in 92% yield as
a white powder (20.6 g, 55.6 mmol): mp 104–105 °C; H NMR
4-(N-Butyl-4-(4-methoxybenzyl)amino)benzamido)benzoic acid (6)
1
(
7
2
400 MHz, CDCl
3
): d 8.03 (d, J = 8.8 Hz, 2H), 7.93 (d, J = 8.8 Hz, 2H),
.46 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 4.34 (q, J = 7.2 Hz,
H), 3.98 (t, J = 7.6 Hz, 2H), 1.63–1.58 (m, 2H), 1.40–1.35 (m, 5H)
To a solution of 5 (4.60 g, 10.0 mmol) in ethanol (100 mL) was
added 4 N NaOH (50 mL), and the resulting mixture was stirred at
50 °C for 4 h. The reaction mixture was then cooled in an ice-water
bath to 0 °C and neutralized by the addition of 2 N HCl aq. (100 mL).
13
and 0.92 (t, J = 7.2 Hz, 3H) ppm; C NMR (100 MHz, CDCl
3
): d
), 141.94 (C ),
30.66 (CH), 129.37 (CH), 129.04 (CH), 127.28 (CH), 123.05 (CH),
1.13 (CH ), 50.01 (CH ), 29.57 (CH ), 19.94 (CH ), 14.09 (CH
1
1
6
67.86 (C@O), 165.24 (C@O), 147.93 (C
q
), 146.32 (C
q
q
The resulting mixture was extracted with CHCl
organic layer was collected and washed with brine before being
dried over Na SO . The solvent was then removed in vacuo to give
3
(200 mL), and the
2
2
2
2
3
)
2
4
and 13.59 (CH
3
) ppm; IR (ATR) 3105, 3083, 3060, 2978, 2957,
the crude product as a residue, which was purified by recrystalliza-
À1
2
931, 2867, 1711, 1641, 1596, 1514, 1394, 1346, 1275 cm ; FAB-
tion from ethyl acetate to give pure 6 in 96% yield as a white powder
+
1
MS: m/z 371.2 [M+H] ; Elemental Analysis Calc. for C20
H
22
N
2
O
5
:
(4.15 g, 9.60 mmol): mp 134–135 °C; H NMR (400 MHz, DMSO-
C, 64.85; H, 5.99; N, 7.56. Found: C, 64.70; H, 5.70; N, 7.54.
6
d ): d 12.89 (brs, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.8 Hz,

K. Katagiri et al. / Journal of Molecular Structure 1082 (2015) 23–28
25
Scheme 1. Reagents and conditions: (a) conc. H
2
SO
4
, EtOH, reflux, 4 h; (b) 4-nitrobenzoyl chloride, pyridine, CH
2
Cl
2
, rt, 23 h; (c) 10% Pd/C, H
2
, EtOH, rt, 5 h; (d) 4-
3 2 2 2
methoxybenzyl chloride, HMPA, 120 °C, 4 h; (e) 4 M NaOH aq., EtOH, 50 °C, 4 h; (f) Ph PCl , (CHCl ) , reflux, 6 h.
Table 1
Intramolecular aromatic–aromatic interactions in the crystal 1.
Interactiona
Distance (Å)b
Angle (°)
Ph1–Ph2
Ph1–Ph6
Ph2–Ph3
Ph2–Ph5
Ph3–Ph4
Ph4–Ph5
Ph5–Ph6
4.626(1)
4.577(1)
4.555(1)
5.309(1)
4.612(1)
4.348(1)
4.451(1)
73.2(1)
65.5(1)
68.3(1)
69.4(1)
59.1(1)
50.3(1)
71.0(1)
a
Refer to under figure for phenyl group number.
b
The distances between the centers of the rings.
2
H), 7.15 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 6.85 (d,
J = 8.8 Hz, 2H), 6.55 (brt, J = 6.4 Hz, 1H), 6.35 (d, J = 8.8 Hz, 2H),
4
.12 (brd, J = 4.8 Hz, 2H), 3.82 (t, J = 7.2 Hz, 2H), 3.70 (s, 3H), 1.47–
.44 (m, 2H), 1.28–1.23 (m, 2H) and 0.83 (t, J = 7.2 Hz, 3H) ppm;
1
1
3
C NMR (100 MHz, DMSO-d
58.65 (C ), 150.63 (C ), 148.99 (C
30.59 (CH), 129.01 (CH), 127.97 (C
6
): d 169.88 (C@O), 167.20 (C@O),
), 131.73 (C ), 131.07 (CH),
), 127.30 (CH), 122.50 (C ),
1
1
q
q
q
q
Fig. 1. Crystal structure of 1 in the thermal ellipsoid model. The ellipsoids of all
non-hydrogen atoms have been drawn at the 30% probability level.
q
q

2
6
K. Katagiri et al. / Journal of Molecular Structure 1082 (2015) 23–28
Scheme 2. Dealkylation of the tertiary amides of macrocycle 2.
product as a residue, which was purified by silica gel column chro-
matography eluting with a 1:1 (v/v) mixture of ethyl acetate and n-
hexane, followed by gel permeation chromatography (JAIGEL
1
H + 2H, chloroform) to give pure cyclic trimer 1 in 40% yield as
1
a white powder (2.48 g, 2.00 mmol): mp 168–169 °C; H NMR
400 MHz, CDCl , 323 K): d 7.09 (brd, J = 8.8 Hz, 6H), 6.97 (brd,
J = 7.2 Hz, 6H), 6.79 (brd, J = 7.2 Hz, 6H), 6.74 (brd, J = 8.8 Hz, 6H),
(
3
6
3
.67 (brd, J = 7.2 Hz, 6H), 6.51 (brd, J = 7.2 Hz, 6H), 5.00 (brs, 6H),
.87 (brs, 6H), 3.68 (s, 9H), 1.47–1.42 (m, 6H), 1.33–1.27 (m, 6H)
1
3
and 0.86 (t, J = 7.2 Hz, 9H) ppm; C NMR (100 MHz, CDCl
68.28 (C@O), 159.35 (C@O), 144.51 (C ), 144.20 (C ), 134.39
), 134.32 (C ), 129.95 (CH), 129.78 (C ), 128.98 (C ), 127.25
CH), 127.08 (CH), 55.17 (OCH ), 53.13 (CH ), 50.00 (CH ), 29.63
CH ), 22.56 (CH ) and 13.64 (CH
3
): d
1
q
q
(
(
(
C
q
q
q
q
3
2
2
2
2
3
) ppm; IR (ATR) 2959, 2870,
640, 1601, 1510, 1379, 1299, 1245, 1217, 1175 cm ; FAB-MS:
À1
1
+
m/z 1243.5 [M+H] ; Elemental Analysis Calc. for C78
78 6 9
H N O : C,
7
5.34; H, 6.32; N, 6.76. Found: C, 75.09; H, 6.24; N, 6.62.
Unfolded macrocycle (2)
Cyclic trimer 1 (117 mg, 0.094 mmol) was suspended in a mix-
ture of TFA (3.27 mL) and CH Cl (1 mL), and the resulting mixture
2
2
was stirred under an Ar atmosphere for 3 days. The solvent was
then removed by evaporated to give a residue, which was treated
with ethyl acetate to give pure Cyclic trimer 2 in 83% yield as a
Fig. 2. Crystal structure of 2 in the thermal ellipsoid model. The ellipsoids of all
non-hydrogen atoms have been drawn at the 50% probability level. The disordered
atoms and included solvent molecules have been omitted for clarity.
1
white powder (68.9 mg, 0.078 mmol): mp 266–268 °C; H NMR
(
400 MHz, DMSO-d
6
): d 10.09 (brs, 3H), 7.75 (d, J = 8.4 Hz, 6H),
.56 (d, J = 8.8 Hz, 6H), 7.18 (d, J = 8.4 Hz, 6H), 7.14 (d, J = 8.4 Hz,
H), 3.90 (t, J = 7.2 Hz, 6H), 1.520–1.464 (m, 6H), 1.33–1.28 (m,
7
6
6
1
3
2
1
14.15 (CH), 111.17 (CH), 55.46 (OCH
0.05 (CH ), 20.07 (CH ), and 14.16 (CH
870, 1683, 1626, 1593, 1569, 1513, 1417, 1362, 1316, 1285,
3
), 49.71 (CH
2 2
), 45.91 (CH ),
2
2
3
) ppm; IR (ATR) 3354,
1
3
H) and 0.86 (t, J = 7.2 Hz, 9H) ppm; C NMR (100 MHz, CDCl
), 140.12 (C ), 131.86
), 129.24 (CH), 128.59 (CH), 127.62 (CH), 118.88
), 29.60 (CH ), 19.74 (CH ) and 13.88 (CH ) ppm;
3
):
À1
+
d 169.17 (C@O), 164.63 (C@O), 146.55 (C
q
q
243, 1176 cm ; FAB-MS: m/z 433.3 [M+H] ; Elemental Analysis
: C, 72.20; H, 6.53; N, 6.48. Found: C, 72.04;
(C
q
), 131.23 (C
q
Calc. for C26
28 2 4
H N O
(CH), 48.64 (CH
2
2
2
3
H, 6.43; N, 6.20.
IR (ATR) 2955, 2922, 2870, 1634, 1600, 1501, 1403, 1316, 1247,
À1
+
1
181, 1124 cm ; FAB-MS: m/z 883.4 [M+H] ; Elemental Analysis
Calc. for C54 : C, 73.45; H, 6.16; N, 9.52. Found: C, 73.22;
H, 6.10; N, 9.55.
54 6 6
H N O
Folded macrocycle (1)
Dichlorotriphenylphosphorane (3.67 g, 11.0 mmol) was added
to a solution of 6 (2.16 g, 5.00 mmol) in 1,1,2,2-tetrachloroethane
Results and discussion
(
50 mL), and the resulting mixture was heated at 130 °C with stir-
ring under an Ar atmosphere for 4 h. The mixture was then
reduced in volume by evaporation to give a precipitate, which
was separated from the solution by decantation. The remaining
decanted solution was evaporated to dryness to give the crude
Macrocyclic compound 1 was synthesized in the current study
and contained six alternate amide bonds, including three N-butyl
amides and three N-4-methoxybenzyl amides (Scheme 1). Follow-
ing esterification of N-4-butylaminobenzoic acid, the product was

K. Katagiri et al. / Journal of Molecular Structure 1082 (2015) 23–28
27
Fig. 3. (a) Dimeric structure via H-bonding between NAH and C@O. (b) Dimeric structure that occurred through the formation of a CH/
p-interaction between the terminal CH
moieties of the butyl group in one molecule of 2 and the phenyl groups of a second molecule of 2. The red-dotted lines indicate the hydrogen-bonding interactions. (For
interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Scheme 3. The synthesis of 1 from the 2.
treated with 4-nitrobenzoyl chloride to give the corresponding
amide 3. Subsequent hydrogenation of the nitro group over Pd/C
gave the corresponding aniline derivative 4 (63% in three steps),
which was monoalkylated directly using 0.5 equivalents of 4-
methoxybenzyl chloride to give 5 with the 4-methoxybenzyl group
used as a protecting group for the amino function. Subsequent
hydrolysis of the ester moiety in 5 gave the corresponding carbox-
ylic acid 6, which underwent the final cyclization reaction in the
peaks of the aromatic region were in the range of 6.43–7.03 ppm,
which suggested that all the phenylene groups were located in
close proximity to each other, even in the solution. Due to the
restricted motion of the twisted structure of 1, the methylene pro-
tons of N-ethyl groups and 4-methoxy benzyl groups were broad-
ened and split into multiple peaks at low temperature (Figs. S13
and S14).
The 4-methoxybenzyl groups on three of amides in 1 are acid
labile alkyl groups and the treatment of 1 with TFA under reflux
therefore resulted in the formation of macrocycle 2 with six
para-phenylene groups and alternating array of secondary and
tertiary amide moieties in 83% yield (Scheme 2).
3 2
presence of Ph PCl to give the target macrocyclic aromatic amide
1. Single crystals of 1 were obtained via the vapor diffusion of
cyclohexane into a chloroform solution of 1.
Single crystals of macrocyclic aromatic amide 1 were obtained
from a chloroform solution and subjected to X-ray crystallographic
analysis. The results revealed that the crystals existed as a triclinic
system with space group P-1 (Fig. 1). All six of the tertiary amide
moieties existed in their cis conformation, and the phenylene
groups were located in close proximity to each other through aro-
matic–aromatic interactions (Table 1). 1H NMR analysis of 1 in
Macrocycle 2 was crystallized from methanol and the resulting
single crystals were subjected to X-ray crystallographic analysis.
The results revealed that the crystals existed as a monoclinic sys-
1
tem with space group P2 /c, and that each unit cell included four
molecules of 2 and eight molecules of methanol. Furthermore, the
X-ray crystal structure revealed that the amides in the ring existed
as alternate secondary and tertiary amide moieties, which formed
3
CDCl (see Supplementary data, Fig. S9) revealed that the high field

2
8
K. Katagiri et al. / Journal of Molecular Structure 1082 (2015) 23–28
an ‘‘unfolded’’ macrocyclic structure with a triangular-shaped cav-
ity (Fig. 2). As shown in Fig. 3, macrocycle 2 formed dimeric units
through hydrogen-bonding interactions (Fig. 3a), with one mole-
cule of macrocycle 2 being sequestered within the cavity of another
Centre (CCDC) in the CIF format as supplementary publication
Nos. CCDC-989525, and 989526. Copies of these data can be
obtained free of charge on application to the CCDC, 12 Union Road,
Cambridge CB21EZ, UK, (Fax: +44 1233 336 033; E-mail:
deposit@ccdc.cam.ac.uk). Supplementary data associated with this
article can be found, in the online version, at doi: XX.XXXX/j.mol.
struc.2012.XX.XXX. Supplementary data associated with this arti-
cle can be found, in the online version, at http://dx.doi.org/
10.1016/j.molstruc.2014.10.074.
molecule of macrocycle 2 through the formation of CH/
p interac-
tions between the terminal CH bonds of the butyl group of one mol-
ecule of 2 and the phenyl group of another molecule of 2 (Fig. 3b).
Furthermore, molecules of macrocycle 2 interacted with each other
through the formation of hydrogen-bonding interactions between
their oxygen and nitrogen atoms and the oxygen atoms of methanol
1
(
See Supplementary data, Fig. S27). H NMR analysis of 2 revealed
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Acknowledgments
We would like to thank Drs. S. Baba and K. Miura (the Japan
Synchrotron Radiation Research Institute (JASRI) for their valuable
help with the collection of data for the X-ray analysis of 2. The syn-
chrotron radiation experiment was performed on the BL38B1 at
SPring-8 with the approval of JASRI (Proposal No. 2009A1981). This
work was supported in part by a Grant-in-Aid for Scientific
Research (C, 21590035) from the Ministry of Education, Culture,
Sports, Science and Technology of Japan (MEXT) (I.A.). We are also
thankful to MEXT. Senryaku, 2008–2012 (I.A.).
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Appendix A. Supplementary material
Additional materials including full details of the X-ray data col-
lection and final refinement parameters (i.e. anisotropic thermal
parameters and a full list of the bond lengths and bond angles)
have been deposited with the Cambridge Crystallographic Data