Photoswitchable macrocycles incorporating acridane moieties

Article abstract of DOI:10.1055/s-2007-990829

Novel crown ethers incorporating one to three 9-phenyl-acridinium units were synthesized in moderate yields. The acridinium units within the macrocycles were converted into the photoactive N-methyl-9-methoxy-9-phenyl-9,10- dihydroacridine (N-methyl-9-methoxy-9-phenylacridane) units. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990829

PAPER
3345
Photoswitchable Macrocycles Incorporating Acridane Moieties
P
hotoswitchable Macr
a
ocycles rzena Orda-Zgadzaj, Werner Abraham*
Institute for Chemistry, Humboldt University, Brook-Taylor-Str. 2, 12489 Berlin, Germany
Fax +49(30)20937266; E-mail: abraham@chemie.hu-berlin.de
Received 18 June 2007; revised 1 August 2007
O
O
Abstract: Novel crown ethers incorporating one to three 9-phenyl-
acridinium units were synthesized in moderate yields. The acridin-
ium units within the macrocycles were converted into the
photoactive N-methyl-9-methoxy-9-phenyl-9,10-dihydroacridine
(N-methyl-9-methoxy-9-phenylacridane) units.
HO
OH
TsO
OTs
n
2
N
MeCN, Et4NOH
1
Key words: macrocycles, crown compounds, acridinium, acridane,
heterocycles
O
O
O
O
O
n
Acridine and its derivatives are well-known DNA-inter-
calating compounds. Molecular recognition of nucle-
N
N
O
O
otides by cyclic receptors containing acridine subunits has
O
N
been reported.1 Macrocyclic receptors containing posi-
n
tively charged aromatic subunits, such as acridinium ions,
linked by one or two bridges may bind to planar aromatic
substrates by intercalation. We were interested in macro-
cyclic receptors bearing photoswitchable subunits be-
cause it would be useful to switch on and off the binding
properties by means of an outside stimulus and thereby
control the interaction between host and guest. These pho-
toswitchable subunits should undergo drastic change in
their shape and electronic properties, which should alter
the binding properties of the macrocycle. We decided to
O
O
O
O
n
3
4
n = 1 12%
n = 2 15%
+
N
O
O
O
synthesize macrocycles containing acridinium subunits of
O
the type II and the corresponding acridane derivatives I,
respectively. 9-Phenyl-9-hydroxyacridane I (Scheme 1)
O
is known to convert into the corresponding acridinium hy-
droxide in the excited singlet state. The rate of the thermal
n
n
O
N
back reaction depends strongly on the solvent proper-
O
O
ties.2,3
In this paper we describe, for the first time, the preparation
of macrocycles incorporating the switchable acridane
subunit. The synthon 1 was used to prepare crown ethers
containing the 9-acridinone subunit incorporated along its
longest diameter (Scheme 2). The reactions were carried
5
6
n = 1 17%
n = 2 18%
Scheme 2
out under highly dilute conditions in order to favor mac-
rocycle formation.4
OR'
Surprisingly, macrocycles containing two and three acri-
dinone moieties were obtained. A macrocycle 8, incorpo-
rating two different recognition sites – the catechol and
the acridinone units – could be obtained by the reaction of
1 with 7 (Scheme 3). The lateral incorporation of the acri-
dinone moiety was possible using the synthon 9
(Scheme 4).
hν
+
N
∆
N
R
I
R'O–
R
R' = H, alkyl
II
Scheme 1
Unfortunately, it was not possible to incorporate two acri-
dinone units in a crown of the type 10 because only the 12-
SYNTHESIS 2007, No. 21, pp 3345–3356
Advanced online publication: 10.10.2007
DOI: 10.1055/s-2007-990829; Art ID: T09407SS
x
x.
x
x
.
2
0
0
7
© Georg Thieme Verlag Stuttgart · New York

3346
M. Orda-Zgadzaj, W. Abraham
PAPER
O
O
O
O
O
O
O
O
O
OTs
OTs
O
O
+
1
O
O
O
N
O
7
8 (28%)
Scheme 3
5, 6
8
PhMgBr
PhMgBr
O
O
O
O
O
O
O
N
HO
HO
+
7
O
O
O
O
O
O
N
O
O
OH
O
O
n
n
O
O
9
O
O
O
O
OH
OH
N
O
N
N
N
10 (34%)
NH4Cl
i) NH4Cl
ii) NH4PF6
Scheme 4
O
N
O
OTs
TsO
O
O
O
O
O
2
O
O
O
O
O
O
O
O
9
O
O
O
n
n
O
O
11 (28%)
+
N
N
Scheme 5
Cl –
16
2 PF6
crown-4 (11), was formed in the reaction of 9 with tetra-
ethylene glycol bistosylate (Scheme 5).
12 n = 1
13 n = 2
The obtained macrocycles were further functionalized by
their conversion into 9-phenyl-9,10-dihydroacridines (ac-
ridanes) through reaction with phenylmagnesium bro-
mide. The primarily formed acridanes could not be
isolated because they were transformed into the corre-
sponding acridinium salts during purification by chroma-
tography (Scheme 6). However, the macrocycles
containing the acridinium unit were subsequently trans-
formed into the corresponding macrocycles with 9-meth-
oxyacridane units by reaction with methanol in the
presence of a base (Scheme 7 and Scheme 8). The small
crown 11 could also be converted into the corresponding
acridinium derivative (Scheme 9).
Scheme 6
Generally, it can be predicted that the steric constraint im-
posed by the acridinium substituent is large due to the flat
structure of the acridinium moiety and the large twisting
angle between the acridinium ring and the phenyl ring in
the 9-position. In contrast, the phenyl group can be direct-
ed outwards of the macrocycle due to re-hybridization at
the 9-position. Therefore, it may be expected that in the
course of the photochemical reaction, the cavity of the
macrocycle will become more blocked. Similar effects
Synthesis 2007, No. 21, 3345–3356 © Thieme Stuttgart · New York

PAPER
Photoswitchable Macrocycles
3347
N
O
O
O
O
O
O
i) PhMgBr
ii) NH4Cl
O
O
O
O
OMe
OMe
11
+
N
n
n
MeOH, Et4NOH
Cl –
12, 13
20
Scheme 9
14 n = 1
15 n = 2
N
around the C9-phenyl axis, determined with the help of
the coalescence temperature of NMR spectra recorded in
DMSO-d6 solution at different temperatures, is 18 kcal
mol–1. In contrast, the phenyl groups within the larger
macrocycle 13 rotate freely at room temperature. The pro-
ton resonances of the catechol subunit of 16 are also split
into two groups and up-field shifted by 0.6 and 0.2 ppm
compared with the singlet of the same protons in the acri-
dane compound 17. We attribute this phenomenon to the
p–p interaction of the acridinium moiety with the catechol
unit. Molecular modeling (MM2) has shown that confor-
mations of the macrocycle with distances between the two
subunits of around 3 Å are possible (Figure 2). Accord-
ingly, the proton resonances of the acridinium unit of 16
are also up-field shifted, compared with the model com-
pound 21, due to the interaction with the catechol unit. If
the compound assumes the conformation depicted in
Figure 2, then both the resonances of the methyl protons
and of H3–H6 of the acridinium, may become up-field
shifted. In contrast, the resonances of H1 and H8 are
down-field shifted by 0.2 ppm due to their positions at the
edge of the catechol moiety. All of the observed interac-
tions between the subunits of the macrocycles 12 and 16
disappear in the corresponding macrocycles incorporating
the acridane subunits.
O
O
O
O
MeOH, Et4NOH
O
O
17
O
O
16
OMe
N
Scheme 7
OH
O
O
O
O
O
O
PhMgBr
10
N
O
O
O
O
O
O
O
O
O
O
NH4Cl
+
N
Cl –
18
All macrocycles with the acridane subunits underwent a
photoreaction upon excitation with 313 nm light to form
the corresponding acridinium-containing macrocycles,
both in acetonitrile and alcoholic solutions. The thermal
recovery of the acridane compound was slow in acetoni-
trile solution. The back reaction in alcoholic solution was
accomplished within two hours and gave the acridane
containing the alkoxy group of the alcohol used as sol-
vent, e.g. the methoxy leaving group was replaced by the
propoxy group in n-propanol solution. The individual
photo- and thermal reactions could be followed by UV/
Vis spectroscopy because the absorption maxima of the
acridinium compounds is around 430 nm while that of the
acridane is around 310 nm (see Figure 3 for an example).
Because of the thermal back reaction, the photoreaction
results in the formation of the acridinium compound until
the equilibrium with the back reaction has become estab-
lished.
OMe
MeOH,
Et4NOH
O
O
O
O
O
O
O
N
O
19
Scheme 8
have recently been found in calixarenes.5 Indeed, H
NMR spectra of the macrocycles 12 and 16 indicated the
interaction of the acridinium units across space. The reso-
nances of the acridinium protons at positions 4 and 5 of
the acridinium units of the smaller ring 12, are up-field
shifted by 0.2 ppm compared with the same proton reso-
nances of compound 13. Furthermore, the rotational mo-
tion of the phenyl group is frozen at room temperature,
resulting in a splitting of the proton resonances (Figure 1).
The activation energy for the rotation of the phenyl group
1
We chose the macrocycles 18 and 19 to demonstrate that
crown ethers incorporating acridinium and acridane units
differ in their complexation behavior. We studied the abil-
ity of 18 and 19 to bind the guest 22 (Scheme 10). Pseu-
Synthesis 2007, No. 21, 3345–3356 © Thieme Stuttgart · New York

3348
M. Orda-Zgadzaj, W. Abraham
PAPER
Figure 1 1H NMR spectra (CD3CN) of macrocycles 12 and 13 showing the regions of the phenyl proton resonances and those of the ethyle-
neglycol spacers, which are split in the case of compound 12.
O
O
O
O
O
N+
O
O
O
O
O
N+
Cl–
O
O
O
O
OH
HO
21
16
Figure 2
dorotaxanes based on 1,2-bis(pyridinium)ethane (22) as
the axle and a dibenzo-24-crown-8 ether (DB24C8) as the Figure 3 UV/Vis spectra of compound 19 in MeOH (7 × 10–5 M)
wheel, have been previously reported.6 The acridane-con-
recorded after consecutive irradiations (lexc = 313 nm) for 0, 3, 6, 12
and 30 min.
taining host 19 binds the guest 22, and the complexation
1
can easily be monitored with H NMR spectroscopy be-
cause there is a slow exchange between free and com-
plexed components on the NMR timescale. The
appearance of two signal sets indicates complex forma-
tion. The binding constant could be determined by inte-
gration of suitable proton resonances of free and
complexed components of the formed pseudorotaxanes.
The association constant of 19/22 is 160 M–1 in deuterated
nitromethane solution. The question arises as to whether
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PAPER
Photoswitchable Macrocycles
3349
Dn = nA – nB, the difference of the proton resonances of the phenyl
protons, measured in Hz.
N+
N
N+
N
Compound 22 was obtained according to the literature.7
–
2 BF4
22
2,7-Dihydroxy-10-methylacridin-9(10H)one (1)
We were not able to reproduce the synthetic route proposed in the
literature,8 therefore an independent synthesis was undertaken. A
mixture of p-anisidine (1.5 g, 12.2 mmol) and 2-bromo-5-methoxy-
benzoic acid (2.0 g, 8.7 mmol) with anhydrous K2CO3 (1.7 g, 12.3
mmol) and copper (0.1 g ) in anhydrous 1-pentanol (10 mL) was
heated under reflux for 3 h. The solvent was evaporated under re-
duced pressure and the residue was dissolved in hot H2O (200 mL)
and then filtered through Celite. The Celite was washed with H2O
(500 mL) and the filtrate was acidified with concd HCl to pH 6. A
colorless solid precipitated, which was isolated by filtration and
washed with H2O (2 × 50 mL). The solid was crystallized from
CHCl3 (40 mL) to give 5-methoxy-2-(4-methoxyphenylamino)ben-
zoic acid.
– 19
+ 19
N
N+
O
OH
O
O
O
O
O
N
O
N+
O
Yield: 1.7 g (71%); mp 174–176 °C (Lit.9 162–165 °C).
–
2 BF4
1H NMR (CDCl3): d = 3.79 (s, 3 H, OCH3), 3.82 (s, 3 H, OCH3),
6.90 (d, J = 8.3 Hz, 2 H), 6.98 (s, 2 H), 7.14 (d, J = 8.3 Hz, 2 H),
7.49 (s, 1 H).
N
19/22
13C NMR (CDCl3): d = 55.5 (OCH3), 55.8 (OCH3), 109.7 (Cq),
113.8 (CH), 114.7 (CH), 115.8 (CH), 124.5 (CH), 125.5 (CH),
133.9 (Cq), 145.1 (Cq), 150.5 (Cq), 156.5 (Cq), 173.1 (Cq).
Scheme 10
the complexation of 22 by the host is influenced by replac-
ing the acridane unit by the acridinium moiety. In fact,
there is no complexation of 22 by the host 18 due to the
repulsion of the positive charges present in both the host
and the guest. The addition of 22 to 18 in acetonitrile or
nitromethane solution did not cause any change in the 1H
NMR spectrum of 18.
Anal. Calcd for C15H15NO4: C, 65.92; H, 5.53; N, 5.13. Found: C,
65.74; H, 5.44; N, 5.10.
A mixture of 5-methoxy-2-(4-methoxyphenylamino)benzoic acid
(1.7 g, 7.2 mmol) and polyphosphoric acid (10 g) was heated to
110 °C for 3 h. The solution was poured onto ice (400 mL) and the
precipitate was filtered off and washed with H2O (2 × 100 mL). The
precipitate was dissolved in hot EtOH (1.5 L) and filtered. After 24
h the solution was concentrated to 150 mL and the resulting solid
was recrystallized from EtOH to afford 2,7-dimethoxyacridin-
9(10H)one.
In summary, we have designed a series of new crown
ethers that incorporate the acridane unit, which can be
photochemically converted into the corresponding acri-
dinium subunit. This transformation gives rise to drastic
changes in the properties of the macrocycles such as elec-
tron-donor strength, shape and ability to bind. The latter
was demonstrated with the different complexation proper-
ties of crown ethers incorporating acridinium and acri-
dane units.
Yield: 1.63 g (89%); mp 350–355 °C (Lit.8 >300 °C).
1H NMR (DMSO-d6): d = 3.86 (s, 6 H, OCH3), 7.39 (dd, J = 3.0, 9.0
Hz, 2 H), 7.52 (d, J = 9.0 Hz, 2 H), 7.61 (d, J = 3.0 Hz, 2 H), 11.74
(s, 1 H, NH).
13C NMR (DMSO-d6): d = 55.4 (OCH3), 104.6 (CH), 119.3 (CH),
120.2 (Cq), 124.2 (CH), 135.5 (Cq), 153.9 (Cq), 175.5 (Cq).
Anal. Calcd for C15H13NO3: C, 70.57; H, 5.13; N, 5.48. Found: C,
70.72; H, 5.30; N, 5.36.
Column chromatography was performed on Merck silica gel 60
(0.040–0.063 mm, 230–400 mesh). 1H NMR (300 MHz) and
13C NMR (75.5 MHz) spectra were recorded on a Bruker DPX 300
spectrometer, with chemical shifts (d, ppm) referenced to TMS as
an internal standard. The 1H NMR spectra shown in Figure 1 were
recorded on a Bruker AMX 600 (600 MHz) spectrometer. Atom-
numbering for compounds is given in Figure 4 and Figure 5. ESI
mass spectrometry was carried out on a triple quadrupole instru-
ment (TSQ 700, Finnigan MAT, Bremen, Germany) equipped with
an electrospray ion source (API-ESI) operating in the positive mode
with a capillary temperature of 200 °C and a high voltage of 4.5 kV.
The samples were dissolved in MeOH (concentration 10–50 pmol
mL–1). Nitrogen was used as sheath gas at a pressure of 3.4 bar. The
spectra were composed of an average of 64 scans. UV/Vis spectra
were recorded with a Shimadzu UV 2101 PC spectrometer. Melting
points were determined using a Boetius (Rapido) apparatus and are
uncorrected.
HRMS (EI, 70 eV): m/z calcd for C15H13NO3: 255.0895; found:
255.0899.
A solution of tetraethylammonium hydroxide (25% solution in
MeOH, 11.07 g, 18.8 mmol) was added to a stirred suspension of
2,7-dimethoxyacridin-9(10H)one (1.2 g, 4.7 mmol) in MeCN (200
mL). Stirring was continued for 30 min until the mixture became
clear. MeI (2.65 g, 18.8 mmol) was added and the reaction mixture
was stirred for additional 24 h. The solvents were evaporated under
reduced pressure and the remaining residue was dissolved in CHCl3
(200 mL) then washed with H2O (200 mL). The aqueous phase was
extracted with CHCl3 (2 × 200 mL) and the combined organic phas-
es were dried (MgSO4) and evaporated. The remaining solid was re-
crystallized from cyclohexane to afford 2,7-dimethoxy-10-
methylacridin-9(10H)one.
Yield: 0.77 g (61%); Rf = 0.81 (CHCl3–MeOH, 15:1); mp 170–
172 °C (Lit.8 222.5 °C). The analytical data were in accord with lit-
erature values.
The activation energy of the rotation of the phenyl ring of com-
pound 12 was estimated with the help of the equation DG = RTc
(22.96 + ln Tc/Dn) with Tc, the coalescence temperature, 333 K and
A suspension of 2,7-dimethoxy-10-methylacridin-9(10H)one (1.17
g, 4.3 mmol) in aq HBr (48%, 30 mL) was heated under reflux for
Synthesis 2007, No. 21, 3345–3356 © Thieme Stuttgart · New York

3350
M. Orda-Zgadzaj, W. Abraham
PAPER
19
17
15
16
O
15
19
16
17 18
20
N
O
O
1
4
8
5
O
1
8
O
O
2
13
11
14
12
O
O
7
9
2
O
O
O
O
13
11
14
12
7
O
9
O
O
O
O
O
O
3
10
N
6
10
N
6
18
17
3
O
O
5
4
O
N
O
N
N
O
16
15
N
O
O
1
8
5
O
14
12
2
7
13
11
O
O
O
O
O
O
9
O
O
3
10
N
6
3
4
4
5
O
1
4
8
14 15
O
S
O
O
2
13
11
14
12
7
6
9
15
13
7
16
19
8
10 11
O
9
12
9
11
12
8
10
7
10
N
3
6
3
6
3
16
17
O
O
O
O
O
O
O
1
2
O
O
O
O
OH
1
O
O
17
5
18
14`
O
O
5
5
4
18
4
15`
O
S
O
2
OH
O
O
N
13`
16`
19`
19
20
10`
11`
12`
8`
9`
9`
12`
7` 8`
7`
10`
11`
O
17`
18`
O
O
7
O
5`
6
A
4`
6`
3`
O
9
20
O
23 21 19 17 15
25
20`
2`
19
18
1`
O
1
4
8
5
6
5`
4`
32
19`
18`
O
O
13
11
14
27
28
2
O
O
O
O
1
HO
6`
O
7
5
4
31
30
O
O
17
10
N
6
17`
O
N
3
3`
2`
2
12
O
O
O
1`
O
16
15
O
O
29
3
16`
15`
O
9
22 20 18 16
H
26
24
1
8
O
2
13
14
7
10
B
10
N
6
3
11
12
4
5
16 15
O
O
9
8
O
8
5
1
4
1
4
8
13
2
3
11
12
14
12
HO
HO
2
13
O
O
O
O
7
7
6
9
17
18
10
N
10
N
6
3
14
O
O
11
N
H
5
4
9
19
20
C
11
18
9
18
17
16
19
17
16
19
20
1
20
1
15
15
14
8
5
8
5
13
O
7
O
O
O
2
13
2
O
O
O
7
O
14
21
22
9
21
10
6
3
10
N+
6
3
12
11
22
N+
4
11
O
12
4
23
24
O
23
24
O
O
N+
N+
25
26
O
O
–
–
2 PF6
2 PF6
12
13
Figure 4
Synthesis 2007, No. 21, 3345–3356 © Thieme Stuttgart · New York

PAPER
Photoswitchable Macrocycles
3351
17
17
18
18
21
CH3
16
16
4`
5`
CH3
21
8
19
20
19
O
O
15
15
6`
3`
1
8
20
13
1
26
14
7
13
11
O
26`
O
O
O
2
14
O
O
O
O
O
2
7
2`
9
25
O
1`
O
9
25`
24`
22
23
22
23
24
O
18
10
N
10
N
6
6
3
3
O
O
19
12
17
11
12
23
22
5
4
O
O
5
4
23`
22`
24
25
O
O
20
16
24
25
15
14
21
1
8
5
21`
N
O
2
13
N
9
26
27
7
10
3
6
Cl–
O
N+
11
12
O
O
4
O
O
15
16
14
4`
5`
18
6`
17
3`
18
19
20
17
16
26
26`
2`
1`
O
17
16
15
25
24
25`
24`
19
O
29 27
O
21
O
O
31
25
23
29 27 25 23
31
21
O
15
14
O
18
20
1
1
8
5
38
8
23
22
38
35
O
O
2
3
13
33
O
14
O
O
O
13
2
23`
33
34
37
36
7
6
7
6
9
16
15
O
9
37
36
O
O
19
22`
21`
10
O
10
N
20
N+
8
3
21
O
O
11
12
O
1
12
O
O
O
34
O
4
O
2
O
11
14
13
5
4
35
9
26
22
24
Cl–
32 30
28
7
6
26 24 22
32 30 28
10
N
3
18
19
12
11
4
5
17
18
18
19
17
16
17
16
8
19
20
20
1
22
21
15
21
25
8
5
24
15
O
OH
13
14
O
O
2
3
23`
22`
26`
1
4
7
6
23
24
O
O
O
7
O
9
13
14
26
22
23
9
HO
O
2
3
21`
24`
25`
11 N+
6
10
O
O
12
Cl–
N+
4
12
11
5
Cl–
25 26
20
21
Figure 5
24 h. The solvent was removed in vacuo and the remaining solid
3
was recrystallized from H2O to afford 1.
Yield: 1.0 g (98%); red powder; mp >360 °C (Lit.8 >300 °C).
1H NMR (CD3OD): d = 4.50 (s, 3 H, NCH3), 7.81 (dd, J = 2.6, 9.4
Hz, 2 H), 7.99 (d, J = 2.6 Hz, 2 H), 8.26 (d, J = 9.4 Hz, 2 H).
13C NMR (CD3OD): d = 35.3 (CH3, NCH3), 105.9 (CH), 118.8
(CH), 119.4 (Cq), 127.8 (CH), 136.9 (Cq), 154.3 (Cq), 169.5 (Cq).
Yield: 0.05 g (12%); Rf = 0.40 (CHCl3–MeOH, 15:1); mp 215–
220 °C.
1H NMR (CD3OD–CDCl3, 6:1): d = 4.00 (s, 9 H, NCH3). 4.04 (m,
12 H, H-16,17), 4.28 (m, 12 H, H-15,19), 7.13 (d, J = 9.4 Hz, 4 H,
H-4,5), 7.28 (dd, J = 9.4, 3.0 Hz, 4 H, H-3,6), 7.67 (d, J = 3.0 Hz,
6 H, H-1,8).
13C NMR (CF3CO2D): d = 36.8 (CH3, NCH3), 68.7 (C-15,19), 70.8
(C-16,17), 102.7 (C-1,8), 117.9 (C-11,12), 119.8 (C-4,5), 131.5 (C-
3,6), 138.8 (C-13,14), 157.3 (C-2,7), 165.3 (C-9).
Anal. Calcd for C14H11NO3: C, 69.70; H, 4.59; N, 5.80. Found: C,
69.94; H, 4.76; N, 5.72.
Anal. Calcd for C54H51N3O12: C, 69.44; H, 5.50; N, 4.50. Found: C,
69.79; H, 5.93; N, 4.19.
HRMS-ESI: m/z [M + H]+ calcd for C54H52N3O12: 934.3546; found:
Compounds 3 and 5
To 1 (0.43 g, 1.3 mmol) in anhydrous MeCN (800 mL), tetraethyl-
ammonium hydroxide (20% solution in H2O, 3.93 g, 5.3 mmol) was
added. The mixture was heated under reflux for 30 min under an ar-
gon atmosphere. 2 (n = 1, 0.55 g, 1.3 mmol) in MeCN (40 mL) was
added dropwise to the boiling solution over 12 h. After the addition
was complete, the mixture was refluxed for 24 h. The reaction mix-
ture was evaporated under reduced pressure and the residue was
subjected to silica gel column chromatography (CHCl3–MeOH,
15:1) to give 3 (Rf = 0.40) in the first yellow-colored fraction and 5
(Rf = 0.26).
934.3552.
HRMS-ESI: m/z [M + 2H]2+ calcd for C54H53N3O12: 467.6809;
found: 467.6809.
5
Yield: 0.07 g (17%); Rf = 0.26 (CHCl3–MeOH, 15:1); mp >320 °C.
1H NMR (DMSO-d6): d = 3.76 (s, 6 H, NCH3), 3.86 (br s, 8 H, H-
16,17), 4.22 (br s, 8 H, H-15,18), 7.04 (dd, J = 9.4, 3.0 Hz, 4 H, H-
3,6), 7.48 (d, J = 9.4 Hz, 4 H, H-4,5), 7.66 (d, J = 3.0 Hz, 4 H, H-
1,8).
Synthesis 2007, No. 21, 3345–3356 © Thieme Stuttgart · New York

3352
M. Orda-Zgadzaj, W. Abraham
PAPER
13C NMR (CF3CO2D): d = 39.5 (CH3, NCH3), 69.3 (C-15,18), 71.7
(C-16,17), 98.0 (C-1,8), 115.9 (C-11,13), 120.0 (C-4,5), 144.2 (C-
3,6), 150.7 (C-12,14), 151.3 (C-2,7), 163.2 (C-9).
3.89 (t, J = 4.53 Hz, 4 H, H-8,8¢), 4.18 (t, J = 4.53 Hz, 4 H, H-7,7¢),
6.92 (s, 4 H, H-3,4,5,6).
13C NMR (CDCl3): d = 61.7 (C-9,9¢), 68.7 (C-7,7¢), 69.7 (C-8,8¢),
70.4 (C-11,11¢), 70.8 (C-10,10¢), 72.7 (C-12,12¢), 114.8 (C-4,5),
121.7 (C-3,6), 148.9 (C-1,2).
Anal. Calcd for C36H34N2O8: C, 69.44; H, 5.50; N, 4.50. Found: C,
69.48; H, 6.03; N, 2.77.
HRMS-ESI: m/z [M + H]+ calcd for C36H35N2O8: 623.2388; found:
623.2388.
Anal. Calcd for C18H30O8: C, 57.74; H, 8.07; Found: C, 57.39; H,
8.13.
A mixture of 1,2-bis-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ben-
zene (6.4 g, 0.17 mol) and pyridine (6.7 g, 0.85 mol) in CH2Cl2 (150
mL) was stirred under cooling in an ice bath. To this solution p-tol-
uenesulfonyl chloride (13.0 g, 0.68 mol) was added. The mixture
was stirred for 2 h at 0 °C and for an additional 18 h at r.t., then the
solution was washed with H2O (200 mL) and extracted with CH2Cl2
(3 × 200 mL). The organic layer was separated, dried (MgSO4) and
evaporated. The residue (17.3 g) was purified by column chroma-
tography (n-hexane–EtOAc, 3:7) to afford 7.
Compounds 4 and 6
To 1 (0.45 g, 1.4 mmol) in anhydrous MeCN (800 mL), tetraethyl-
ammonium hydroxide (20% solution in H2O, 4.11 g, 5.6 mmol) was
added. The mixture was heated under reflux for 30 min under an ar-
gon atmosphere. 2 (n = 2, 0.64 g, 1.4 mmol) in MeCN (40 mL) was
added dropwise to the boiling solution over 9 h. After the addition
was complete, the mixture was refluxed for 24 h. The reaction mix-
ture was evaporated under reduced pressure and the residue was
subjected to silica gel column chromatography (CHCl3–MeOH,
15:1) to give 4 (Rf = 0.20) and 6 (Rf = 0.07).
Yield: 6.3 g (54%); colorless oil; Rf = 0.22 (n-hexane–EtOAc, 3:7).
1H NMR (CDCl3): d = 2.43 (s, 6 H, H-19,19¢), 3.68 (m, 8 H, H-
9,9¢,10,10¢), 3.85 (m, 8 H, H-8,8¢,11,11¢), 4.15 (m, 8 H, H-
7,7¢,12,12¢), 6.91 (m, 4 H, H-3,4,5,6), 7.32 (d, J = 7.9 Hz, 4 H, H-
14,14¢,18,18¢), 7.78 (d, J = 8.3 Hz, 4 H, H-15,15¢,17,17¢).
13C NMR (CDCl3): d = 21.6 (C-19,19¢), 62.2 (C-9,9¢), 68.8 (C-7,7¢),
69.3 (C-8,8¢), 69.8 (C-11,11¢), 70.7 (C-10,10¢), 70.8 (C-12,12¢),
114.8 (C-3,6), 121.7 (C-4,5), 128.0 (C-15,15¢,17,17¢), 129.8 (C-
14,14¢,18,18¢), 132.9 (C-16,16¢), 144.8 (C-13,13¢), 148.9 (C-1,2).
4
Yield: 0.09 g (15%); mp >340 °C.
1H NMR (CDCl3): d = 3.11 (s, 9 H, NCH3), 3.70 (s, 12 H, H-17,18),
3.84 (m, 12 H, H-16,19), 4.03 (m, 12 H, H-15,20), 6.76 (d, J = 9.4
Hz, 6 H, H-4,5), 6.96 (dd, J = 3.0, 9.4 Hz, 6 H, H-3,6), 7.45 (d,
J = 3.0 Hz, 6 H, H-1,8).
13C NMR (CDCl3): d = 33.2 (CH3, NCH3), 67.3 (C-15,20), 69.6 (C-
16,19), 70.8 (C-17,18), 106.0 (C-1,8), 116.2 (C-4,5), 121.4 (C-
11,12), 124.2 (C-3,6), 136.2 (C-13,14), 152.8 (C-2,7), 175.8 (C-9).
Anal. Calcd for C32H42S2O12: C, 56.29; H, 6.20; S, 9.39. Found: C,
56.47; H, 6.50; S, 9.17.
Anal. Calcd for C60H63N3O15: C, 67.59; H, 5.96; N, 3.94. Found: C,
67.34; H, 6.00; N, 3.24.
HRMS-ESI: m/z [M + H]+ calcd for C60H64N3O15: 1066.4332;
found: 1066.4353.
HRMS-ESI: m/z [M + Na]+ calcd for C60H63N3O15Na: 1088.4151;
[2,7-(10-Methylacridin-9-one)]-(1¢,2¢-phenyl)-29-crown-8 (8)
Tetraethylammonium hydroxide (25% solution in MeOH, 4 g, 6.64
mmol) was added to a suspension of 1 (0.40 g, 1.66 mmol) in anhy-
drous MeCN (800 mL). The reaction mixture was heated under re-
flux for 30 min under an argon atmosphere then a solution of 7 (1.13
g, 1.66 mmol) in MeCN (40 mL) was added dropwise over 12 h. Af-
ter the addition was complete, the mixture was refluxed for 24 h
then the mixture was evaporated under reduced pressure. H2O (200
mL) was added and the mixture was extracted with CHCl3 (4 × 200
mL) then the combined organic phases were dried (MgSO4) and
evaporated. The residue was subjected to column chromatography
(EtOAc–MeOH, 12:1) to give the pure product 8.
found: 1088.4142.
6
Yield: 0.12 g (18%); mp >350 °C.
1H NMR (CF3CO2D): d = 3.48 (s, 8 H, H-17,18), 3.59 (br s, 8 H, H-
16,19), 3.87 (br s, 8 H, H-15,20), 4.30 (s, 6 H, NCH3), 6.78 (s, 4 H,
H-1,8), 7.45 (d, J = 10.2 Hz, 4 H, H-3,6), 7.93 (d, J = 10.2 Hz, 4 H,
H-4,5).
Yield: 0.25 g (28%); Rf = 0.55 (EtOAc–MeOH, 12:1); mp 146–
149 °C.
13C NMR (CF3CO2D): d = 39.4 (CH3, NCH3), 68.9 (C-15,20), 70.4
(C-16,19), 71.1 (C-17,18), 108.7 (C-1,8), 116.3 (C-4,5), 120.0 (C-
11,12), 123.1 (C-3,6), 139.6 (C-13,14), 152.3 (C-2,7), 169.8 (C-9).
1H NMR (CD3OD): d = 3.66 (m, 16 H, H-17,17¢,18,18¢,19,19¢,20,20¢),
3.81 (s, 3 H, NCH3), 3.92 (t, J = 4.1 Hz, 4 H, H-16,16¢), 4.41 (t,
J = 4.1 Hz, 4 H, H-15,15¢), 6.60 (m, 2 H, H-4¢,5¢), 6.75 (m, 2 H, H-
3¢,6¢), 7.46 (dd, J = 3.0, 9.4 Hz, 2 H, H-3,6), 7.65 (d, J = 9.4 Hz,
2 H, H-4,5), 8.07 (d, J = 3.0 Hz, 2 H, H-1,8).
13C NMR (CD3OD): d = 34.4 (CH3, NCH3), 69.0 (C-17,17¢,18,18¢),
69.5 (C-16,16¢), 70.7 (C-19,19¢), 71.5, (C-20,20¢), 71.9 (C-15,15¢),
109.2, (C-1,8), 116.1 (C-4¢,5¢), 118.3 (C-4,5), 122.5 (C-3¢,6¢), 122.9
(C-13,14), 126.5 (C-3,6), 138.6 (C-11,12), 150.0 (C-1¢,2¢), 155.2
(C-2,7), 178.5 (C-9).
Anal. Calcd for C40H42N2O10: C, 67.59; H, 5.96; N, 3.94. Found: C,
67.28; H, 6.03; N, 3.27.
HRMS-ESI: m/z [M + H]+ calcd for C40H43N2O10: 711.2912; found:
711.2909.
1,2-Bis{2-[2-(2-tosyloxyethoxy)ethoxy]ethoxy}benzene (7)10
A mixture of catechol (3.10 g, 28 mmol), triethylene glycol mono-
tosylate (17 g, 56 mmol) and anhydrous K2CO3 (10.11 g, 56 mmol)
in acetone (300 mL) was heated under reflux for 30 h. The reaction
mixture was evaporated under reduced pressure and the residue was
dissolved in CH2Cl2 (200 mL), washed with H2O (200 mL) and the
organic layer was dried (MgSO4) and evaporated. The residue was
purified by column chromatography (EtOAc–MeOH, 8:2) to afford
Anal. Calcd for C32H37NO9·H2O: C, 64.31; H, 6.58; N, 2.34. Found:
C, 64.62; H, 6.48; N, 2.34.
HRMS-ESI: m/z [M + H]+ calcd for C32H37NO9: 580.2541; found:
580.2545.
HRMS-ESI: m/z [M + Na]+ calcd for C32H37NO9Na: 602.2361;
found: 602.2358.
1,2-bis{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}benzene
Figure 4).
(A,
Yield: 8.33 g (81%); colorless oil; Rf = 0.26 (EtOAc–MeOH, 8:2).
1H NMR (CDCl3): d = 3.04 (br s, 2 H, OH), 3.61 (t, J = 4.1 Hz, 4 H,
H-12,12¢), 3.68 (m, 4 H, H-11,11¢), 3.71 (m, 8 H, H-9,9¢,10,10¢),
[2,3-(10-Methylacridin-9-one)]-(1¢,2¢-phenyl)-24-crown-8 (10)
Prepared from 9 following the procedure described for 8 above. Af-
ter purification by column chromatography (EtOAc–MeOH, 6:1),
Synthesis 2007, No. 21, 3345–3356 © Thieme Stuttgart · New York

PAPER
Photoswitchable Macrocycles
3353
the combined fractions containing the crown ether were evaporated.
The residue was dissolved in CHCl3 (40 mL) and poured into meth-
yl tert-butyl ether (150 mL). The precipitate was filtered and the
clear filtrate was evaporated to afford 10.
123.9 (C-13), 130.6 (C-11), 135.3 (C-14), 138.5 (C-6), 143.4 (C-2),
152.7 (C-3), 173.2 (C-9).
Anal. Calcd for C15H16NO7P: C, 51.00; H, 4.56; N, 3.90; P, 8.77.
Found: C, 50.91; H, 4.29; N, 3.92; P, 8.64.
Yield: 0.32 g (34%), yellow solid, Rf = 0.21 (EtOAc–MeOH, 6:1);
mp 155–157 °C.
To a suspension of 2,3-dimethoxyacridin-9(10H)one (0.8 g, 3.13
mmol) in MeCN (150 mL), tetraethylammonium hydroxide (20%
solution in H2O, 9.22 g, 12.5 mmol) was added. After stirring for 30
min at r.t., the suspension became a yellow-greenish fluorescent so-
lution. To the solution MeI (1.77 g, 12.5 mmol) was added and stir-
ring was continued for 24 h. The reaction mixture was evaporated
under reduced pressure and the residue was dissolved in CHCl3 (200
mL) and washed with H2O (200 mL). The aqueous phase was ex-
tracted with CHCl3 (3 × 200 mL) and the combined organic phases
were dried (MgSO4) and evaporated. The solid was crystallized
from cyclohexane to afford 2,3-dimethoxy-10-methylacridin-
9(10H)-one.
1H NMR (CDCl3): d = 3.84 (s, 3 H, NCH3), 3.87 (s, 8 H, H-
19,20,21,22), 3.93 (m, 4 H, H-23,24), 3.95 (t, J = 4.5 Hz, 2 H, H-
18), 4.03 (t, J = 4.5 Hz, 2 H, H-17), 4.14 (m, 4 H, H-25,26), 4.30
(m, 4 H, H-15,16), 6.86 (m, 5 H, H-4,29,30,31,32), 7.30 (t, J = 7.1
Hz, 1 H, H-7), 7.51 (d, J = 8.6 Hz, 1 H, H-5), 7.71 (dt, J = 8.6, 1.5
Hz, 1 H, H-6), 8.02 (s, 1 H, H-1), 8.55 (d, J = 7.1 Hz, 1 H, H-8).
13C NMR (CDCl3): d = 30.4 (CH3, NCH3), 63.0, 63.2, 68.8, 69.2,
69.8, 70.5, 70.6, 72.8 (C-15,26), 108.9 (C-4), 114.6, (C-1), 116.1
(C-5), 122.2 (C-7), 122.7, (C-14), 124.7 (C-13), 127.9 (C-8), 129.8
(C-6), 130.9 (C-11,12), 137.0 (C-2), 148.9 (C-3), 153.3 (C-27,28),
176.6 (C-9).
Yield: 0.62 g (74%); mp 192–195 °C (Lit.11 194–195 °C). The ana-
lytical data were in accord with literature values.9
Anal. Calcd for C32H37NO9: C, 66.31; H, 6.43; N, 2.42. Found: C,
65.91; H, 6.55; N, 2.40.
HRMS-ESI: m/z [M + H]+ calcd for C32H38NO9: 580.2541; found:
A suspension of 2,3-dimethoxy-10-methylacridin-9(10H)one (1 g,
3.70 mmol) was heated under reflux in HBr (48%, 20 mL) for 20 h.
The solvent was removed in vacuo and the resulting solid was crys-
tallized from MeOH to give pure 9.
580.2545.
HRMS-ESI: m/z [M + Na]+ calcd for C32H37NNaO9: 602.2361;
found: 602.2358.
Yield: 0.80 g (90%); red solid; Rf = 0.1 (EtOAc, 100%); mp 295–
298 °C (Lit.13 222 °C).
2,3-Dihydroxy-10-methylacridin-9(10H)-one (9)
A modified Ullmann reaction, which afforded a higher overall yield
compared to the literature,11 was used.
1H NMR (CD3OD): d = 4.07 (s, 3 H, NCH3), 7.44 (s, 1 H, H-4), 7.79
(s, 1 H, H-1), 7.81 (dt, J = 8.3, 1.5 Hz, 1 H, H-7), 8.07 (d, J = 8.7
Hz, 1 H, H-5), 8.18 (dt, J = 8.3, 1.5 Hz, 1 H, H-6), 8.54 (d, J = 9.0
Hz, 1 H, H-8).
13C NMR (CD3OD): d = 35.5 (NCH3), 84.9 (C-4), 100.3 (C-1),
104.9 (C-7), 112.6 (C-5), 118.2 (C-11,13), 124.1 (C-12), 124.39 (C-
8), 134.6 (C-14), 139.9 (C-6), 141.3 (C-2), 147.2 (C-3), 158.2 (C-9).
A mixture of 3,4-dimethoxyaniline (2.6 g, 17.0 mmol), 2-bro-
mobenzoic acid (2.6 g, 13.0 mmol), anhydrous K2CO3 (2.5 g, 18.1
mmol) and copper (0.1 g) in anhydrous 1-pentanol (10 mL) was
heated under reflux for 2 h. 1-Pentanol was removed in vacuo and
the resulting mixture was treated with H2O (200 mL) and heated to
80 °C. The hot mixture was filtered through Celite and washed with
H2O (500 mL). On acidification of the combined aqueous phases
with concd HCl (pH 2), a colorless solid precipitated, which was fil-
tered and washed with H2O (2 × 50 mL). The solid was crystallized
from CHCl3 to give 2-(3,4-dimethoxyphenylamino)benzoic acid
(B).
Yield: 2.96 g (80%); yellow crystals; mp 180–182 °C (Lit.12 180–
181 °C).
1H NMR (CDCl3): d = 3.91 (s, 3 H, CH3), 3.88 (s, 3 H, CH3), 6.71
(t, J = 8.28 Hz, 1 H, H-5), 6.80–6.90 (m, 3 H, H-2¢,5¢,6¢), 7.00 (d,
J = 8.6 Hz, 1 H, H-3), 7.30 (t, J = 8.6 Hz, 1 H, H-4), 8.02 (d, J = 8.3
Hz, 1 H, H-6), 9.16 (br s, 1 H, NH).
Anal. Calcd for C14H11NO3·H2O: C, 64.86; H, 5.05; N, 5.40. Found:
C, 64.87; H, 4.48; N, 5.62.
2,3-(10-Methylacridine-9-one)crown-4 (11)
Compound 9 (0.5 g, 2.1 mmol) was dissolved in MeCN (800 mL)
and treated with tetraethylammonium hydroxide (25% solution in
MeOH, 4.8 g, 8.4 mmol). The solution was heated under reflux for
30 min then 2 (n = 2), dissolved in MeCN (40 mL) was added drop-
wise to the boiling solution over 8 h. The reaction was heated under
reflux for an additional 24 h then the solvent was removed in vacuo.
The remaining residue was purified by chromatography (EtOAc–
MeOH, 5:1) and the yellowish fractions were collected. The solvent
was removed from the combined fractions and the remaining resi-
due was dissolved in CHCl3 (40 mL). This solution was poured into
methyl tert-butyl ether (150 mL) and the precipitate was filtered and
dried to give 11.
13C NMR (CDCl3): d = 56.1 (OCH3), 56.0 (OCH3), 109.4 (C-1¢),
109.1, 111.7, 117.0 (C-2¢,5¢,6¢), 113.7 (C-3), 116.4 (C-5), 132.5 (C-
6), 133.2 (C-2), 135.3 (C-4), 146.5 (C-4¢), 149.6 (C-3¢), 150.3 (C-
1), 173.3 (Cq, C=O).
Yield: 0.21 g (28%); mp 73–75 °C.
1H NMR (CD3CN): d = 3.61 (s, 4 H, H-17,18), 3.67 (t, J = 4.2 Hz,
2 H, H-19), 3.78 (s, 3 H, NCH3), 3.79 (t, J = 4.1 Hz, 2 H, H-16),
4.14 (t, J = 4.1 Hz, 2 H, H-20), 4.25 (t, J = 4.1 Hz, 2 H, H-15), 7.07
(s, 1 H, H-4), 7.20 (dt, J = 7.9, 1.5 Hz, 1 H, H-7), 7.59 (d, J = 8.7
Hz, 1 H, H-5), 7.69 (dt, J = 1.5, 8.7 Hz, 1 H, H-6), 7.86 (s, 1 H, H-
1), 8.30 (dd, J = 1.5, 7.9 Hz, 1 H, H-8).
13C NMR (CDCl3): d = 35.4 (NCH3), 63.7 (C-16), 64.5 (C-19), 67.8
(C-17,18), 70.4 (C-15), 72.3 (C-20), 102.6 (C-4), 115.5 (C-1), 115.9
(C-5), 122.0 (C-13,14), 122.4 (C-7), 127.0 (C-8), 131.2 (C-11,12),
137.0 (C-2), 139.9 (C-6), 146.8 (C-3), 176.0 (C-9).
Anal. Calcd for C15H15NO4: C, 65.93; H, 5.53; N, 5.13. Found: C,
66.19; H, 5.63; N, 5.37.
A mixture of 2-(3,4-dimethoxyphenylamino)benzoic acid (1.5 g,
5.49 mmol) and polyphosphoric acid (10 g) was heated at 110 °C
for 2 h. The solution was poured onto ice and the precipitate was fil-
tered off. The solid was crystallized from MeOH to give 2,3-
dimethoxyacridin-9(10H)-one (C) as the phosphate.
Yield: 1.17 g (84%); mp 284–285 °C.
1H NMR (DMSO-d6): d = 3.86 (s, 3 H, H-16). 3.92 (s, 3 H, H-15),
6.96 (s, 1 H, H-4), 7.22 (t, J = 7.1 Hz, 1 H, H-7), 7.49 (d, J = 8.3 Hz,
1 H, H-5), 7.57 (s, 1 H, H-1), 7.66 (t, J = 7.1 Hz, 1 H, H-6), 8.20 (d,
J = 8.3 Hz, 1 H, H-8), 11.63 (s, 1 H, NH).
13C NMR (DMSO-d6): d = 53.7 (CH3), 53.9 (CH3), 96.4 (C-4),
103.2 (C-1), 112.2 (C-5), 115.2 (C-7), 118.1 (C-12), 118.8 (C-8),
Anal. Calcd for C20H21NO5: C, 67.59; H, 5.96; N, 3.94. Found: C,
67.35; H, 6.12; N, 3.82.
HRMS-ESI: m/z [M + H]+ calcd for C20H22NO5: 356.1492; found:
356.1498.
Synthesis 2007, No. 21, 3345–3356 © Thieme Stuttgart · New York

3354
M. Orda-Zgadzaj, W. Abraham
PAPER
Di-2,7-(10-methyl-9-phenyl-9-methoxyacridane)-28-crown-6
HRMS-ESI: m/z [M + 2H]2+ calcd for C20H22NaNO5: 378.1312;
found: 378.1318.
(14)
Mp 157–160 °C.
Di-2,7-(10-methyl-9-phenylacridinium)-28-crown-6 Dihexa-
fluorophosphate (12)
1H NMR (CDCl3): d = 3.00 (s, 6 H, OCH3), 3.40 (s, 6 H, NCH3),
3.72 (m, 8 H, H-23,24), 4.08 (m, 8 H, H-22,25), 7.44–7.01 (m,
12 H, H-1,2,4,5,6,8), 7.83 (m, 10 H, H-16,17,18,19,20).
13C NMR (CDCl3): d = 33.4 (CH3, NCH3), 51.5 (CH3, OCH3), 68.7
(C-22,25), 70.5 (C-23,24), 79.8 (C-9), 113.0 (C-4,5), 115.8 (C-1,8),
116.8 (C-3,6), 125.7 (C-18), 127.6 (C-16,20), 127.8 (C-17,19),
135.7 (C-13,14), 141.8 (C-11,12), 144.2 (C-15), 152.9 (C-2,7).
A solution of 5 (0.4 g, 0.60 mmol) in THF (60 mL) was added drop-
wise over 2 h to a Grignard-compound prepared from bromoben-
zene (0.95 g, 6.1 mmol) and Mg (0.16 g, 6.1 mmol) in THF (10 mL).
After the addition was complete, the mixture was refluxed for 16 h
then the solvent was removed and the resulting oil was purified by
column chromatography [MeOH–H2O–aq NH4Cl (7 M), 20:6:0.1].
The pooled fractions containing the product were combined and the
solution was evaporated under reduced pressure. CHCl3 (200 mL)
was added, the solid was filtered off and the filtrate was evaporated.
The resulting yellow residue was dissolved in H2O and NH4PF6 was
added to precipitate the product 12, which was finally washed with
H2O (3 × 5 mL) and dried.
Anal. Calcd for C50H50N2O8: C, 74.42; H, 6.25; N, 3.47. Found: C,
74.33; H, 6.46; N, 3.21.
HRMS-ESI: m/z [M + 2H]2+ calcd for C50H50N2O8: 405.1856;
found: 405.2833.
Bis-2,7-(10-methyl-9-phenyl-9-methoxyacridane)-51-crown-12
(15)
Mp 160–165 °C.
Yield: 0.49 g (80%); Rf = 0.1 [MeOH–H2O–aq NH4Cl (7 M),
20:6:0.1]; mp 308–315 °C.
1H NMR (CD3CN): d = 3.57 (m, 8 H, H-22,24), 3.93 (m, 8 H, H-
21,24), 4.70 (s, 6 H, NCH3), 6.85 (d, J = 3.0 Hz, 4 H, H-1,8), 7.16
(d, J = 7.5 Hz, 2 H, H-16¢,20¢), 7.23 (d, J = 6.4 Hz, 2 H, H-16,20),
7.42 (dd, J = 9.8, 3.0 Hz, 4 H, H-3,6), 7.77 (m, 6 H, H-17,18,19),
8.23 (d, J = 9.8 Hz, 4 H, H-5,5).
13C NMR (CD3CN): d = 40.8 (CH3, NCH3), 69.3 (C-21,24), 71.7
(C-22,23), 107.6 (C-1,8), 120.6 (C-4,5), 128.4 (C-13,14), 130.6 (C-
16¢,20¢), 130.7 (C-16,20), 131.2 (C-18), 131.4 (C-17¢,19¢), 131.5
(C-17,19), 132.0 (C-3,6), 134.6 (C-9), 137.1 (C-11,12), 155.9 (C-
2,7), 158.8 (C-15).
1H NMR (CDCl3): d = 2.89 (s, 3 H, H-21), 2.94 (s, 3 H, H-21), 3.34
(s, 3 H, NCH3), 3.38 (s, 3 H, NCH3), 3.65 (m, 8 H, H-22,25), 3.77
(m, 8 H, H-23,26), 4.05 (m, 8 H, H-22,27), 7.24–6.96 (m, 12 H, H-
1,3,4,5,6,8), 7.65 (m, 10 H, H-16,17,18,19,20).
13C NMR (CDCl3): d = 33.5 (CH3, NCH3). 51.4 (CH3, OCH3), 67.9
(C-22,27), 69.6 (C-24,25), 70.8 (C-23,26), 90.1 (C-9), 112.9 (C-
4,5), 114.1 (C-1,8), 115.7 (C-3,6), 124.8 (C-18), 125.6 (C-16,20),
127.8 (C-19,17), 127.9 (C-13,14), 135.8 (C-11,12), 138.5 (C-15),
152.6 (C-2,7).
Anal. Calcd for C56H66N2O10: C, 72.55; H, 7.18; N, 3.02. Found: C,
74.13; H, 6.76; N, 3.36.
HRMS-ESI: m/z [M + H]+ calcd for C56H66N2O10: 927.4790; found:
Anal. Calcd for C48H44F12N2O6P2: C, 55.71; H, 4.29; N, 2.71.
Found: C, 55.41; H, 4.72; N, 2.99.
HRMS-ESI: m/z [M – 2PF6]2+ calcd for C48H44N2O6: 372.1594;
927.4786.
found: 372.1604.
[2,7-(10-Methyl-9-phenylacridinium)]-(1¢,2¢-phenyl)-29-crown-
8 Chloride (16)
Di-2,7-(10-methyl-9-phenylacridinium)-34-crown-8 Dihexa-
fluorophosphate (13)
Prepared from 6 following the procedure described for 12 above.
A solution of 8 (0.4 g, 0.69 mmol) in THF (60 mL) was added drop-
wise over 2 h to a Grignard-compound prepared from bromoben-
zene (1.1 g, 6.9 mmol) and Mg (0.16 g, 6.06 mmol) in THF (10 mL).
After the addition was complete, the mixture was refluxed for 18 h
then the solvent was removed and the resulting oil was purified by
chromatography [MeOH–H2O–aq NH4Cl (7 M), 20:6:0.1]. The
pooled fractions containing the product were evaporated under re-
duced pressure and CHCl3 (200 mL) was added. Inorganic salts
were filtered off and the filtrate was evaporated in vacuo to give 16.
Yield: 0.45 g (66%); mp 130–132 °C.
1H NMR (CD3CN): d = 3.59 (br s, 8 H, H-23,24), 3.64 (m, 8 H, H-
22,25), 3.84 (m, 8 H, H-21,26), 4.71 (s, 6 H, NCH3), 6.82 (d, J = 2.6
Hz, 4 H, H-1,8), 7.16 (d, J = 6.8 Hz, 4 H, H-16,20), 7.65 (m, 10 H,
H-3,6,17,18,19), 8.32 (d, J = 9.8 Hz, 4 H, H-5,5).
13C NMR (CD3CN): d = 40.9 (CH3, NCH3), 70.2 (C-23,24), 70.3
(C-22,25), 72.1 (C-21,26), 107.5 (C-1,8), 121.4 (C-4,5), 128.8 (C-
13,14), 130.9 (C-16,20), 131.2 (C-17,19), 131.9 (C-18), 132.1 (C-
3,6), 134.5 (C-9), 137.6 (C-11,12), 156.4 (C-2,7), 158.7 (C-15).
Yield: 0.22 g (46%); Rf = 0.5 [MeOH–H2O–aq NH4Cl (7 M),
20:6:0.1]; mp 78–80 °C.
1H NMR (CDCl3): d = 3.52 (m, 12 H, H-23,23¢,24,24¢,25,25¢), 3.81
(t, J = 4.1 Hz, 4 H, H-22,22¢), 4.25 (t, J = 4.1 Hz, 4 H, H-21,21¢),
4.98 (s, 3 H, NCH3), 6.28 (m, 2 H, H-4¢,5¢), 6.70 (m, 2 H, H-3¢,6¢),
7.23 (d, J = 2.6 Hz, 2 H, H-1,8), 7.60 (d, J = 7.5 Hz, 2 H, H-16,20),
7.70 (m, 3 H, H-17,18,19), 7.91 (dd, J = 9.8, 2.6 Hz, 2 H, H-3,6),
8.68 (d, J = 9.8 Hz, 2 H, H-4,5).
Anal. Calcd for C52H52F12N2O8P2: C, 55.62; H, 4.67; N, 2.49.
Found: C, 55.34; H, 4.91; N, 2.77.
HRMS-ESI: m/z [M – 2PF6]2+ calcd for C52H52N2O8: 416.1856;
found: 416.1586.
Preparation of Crown Ethers Containing the Acridane Unit:
General Procedure
13C NMR (CDCl3): d = 40.6 (NCH3), 68.3, 68.4, 69.2 (C-
23,23¢,24,24¢,25,25¢), 69.9 (C-22,22¢), 70.6 (C-12,21¢,26,26¢), 107.3
(C-1,8), 114.4 (C-4¢,5¢), 120.6 (C-4,5), 121.6 (C-3¢,6¢), 128.7 (C-
13,14), 128.9 (C-17,19), 129.9 (C-18), 130.1 (C-16,20), 131.3 (C-
3,6), 133.9 (C-9), 136.2 (C-11,12), 148.0 (C-2,7), 157.3 (C-15).
A mixture of the acridinium crown ether (0.3 mmol) in MeOH (40
mL) was stirred at r.t. and titrated with tetraethylammonium hy-
droxide (25% solution in MeOH) until the solution decolorized.
When the addition was complete, the mixture was stirred at r.t. for
1 h, then the solution was evaporated under reduced pressure. The
residue was dissolved in CHCl3 and the solution was filtered. The
filtrate was evaporated in vacuo to afford the acridane compounds
in quantitative yield.
Anal. Calcd for C38H42ClNO8: C, 67.50; H, 6.26; N, 2.07. Found: C,
67.28; H, 6.39; N, 2.11.
HRMS-ESI: m/z [M –Cl]+ calcd for C38H42NO8: 640.2910; found:
640.2918.
Synthesis 2007, No. 21, 3345–3356 © Thieme Stuttgart · New York

PAPER
Photoswitchable Macrocycles
3355
[2,3-(10-Methyl-9-phenylacridinium)]-(1¢,2¢-phenyl)-24-crown-
8 Chloride (18)
HRMS-ESI: m/z [M + H]+ calcd for C40H50NO9: 688.3480; found:
688.3478.
Prepared from 10 following the procedure described for 16 above.
HRMS-ESI: m/z [M + H + Na]2+ calcd for C40H50NNaO9: 355.6686;
Yield: 0.25 g (54%); Rf = 0.2 [MeOH–H2O–aq NH4Cl (7 M),
found: 355.6684.
20:6:0.1]; mp 70–72 °C.
UV/Vis (n-propanol): lmax (e) = 278 nm (29000).
1H NMR (CDCl3): d = 3.75 (m, 8 H, H-25,26,27,28), 3.82 (m, 8 H,
H-21,23,29,30), 3.88 (m, 2 H, H-24), 3.98 (m, 4 H, H-31,32), 4.92
(m, 2 H, H-22), 5.02 (br s, 3 H, NCH3), 6.66 (m, 4 H, H-
35,36,37,38), 6.69 (s, 1 H, H-1), 7.21 (m, 2 H, H-16,20), 7.59 (m,
4 H, H-7,17,18,19), 7.68 (d, J = 8.3 Hz, 1 H, H-8), 8.18 (m, 1 H, H-
6), 8.23 (s, 1 H, H-4), 8.57 (d, J = 9.0 Hz, 1 H, H-5).
13C NMR (CDCl3): d = 40.3 (CH3, NCH3), 68.9, 69.0, 69.1, 69.2,
69.5, 69.8, 69.9, 71.0, 71.1, 71.3, 71.5, 72.0 (C-
21,22,23,24,25,26,27,28,29,30,31,32), 99.5 (C-1), 105.7 (C-4),
113.6 (C-36,37), 118.2 (C-5), 121.2 (C-35,38), 122.8 (C-13), 124.5
(C-14), 126.7 (C-6), 129.1 (C-8,16,17,19,20), 130.2 (C-18), 135.8
(C-7), 139.1 (C-12), 141.5 (C-11), 148.6 (C-2), 150.1 (C-3), 154.8
(C-33,34), 160.7 (C-15).
2,3-(10-Methyl-9-phenylacridinium)crown-4 Chloride (20)
Obtained according to the general procedure used for the synthesis
of compound 12 and isolated as the chloride.
Yield: 0.22 g (46%); mp 43–45 °C.
1H NMR (CD3CN): d = 3.65 (m, 6 H, H-22,23,24), 3.94 (t, J = 4.1
Hz, 2 H, H-25), 4.15 (t, J = 4.6 Hz, 4 H, H-21), 4.63 (t, J = 4.5 Hz,
2 H, H-26), 4.71 (s, 3 H, NCH3), 7.27 (s, 1 H, H-1), 7.48 (m, 2 H,
H-16,20), 7.72 (m, 4 H, H-7,17,18,19), 7.79 (s, 1 H, H-4), 7.86 (dd,
J = 8.7, 1.5 Hz, 1 H, H-8), 8.22 (dt, J = 9.0, 1.5 Hz, 1 H, H-6), 8.50
(d, J = 9.4 Hz, 1 H, H-5).
13C NMR (CD3CN): d = 40.4 (NCH3), 69.7 (C-25), 70.5 (C-22),
71.9 (C-23,24), 73.9 (C-26), 75.8 (C-21), 102.4 (C-4), 116.7 (C-1),
119.5 (C-5), 124.8 (C-13), 126.5 (C-14), 128.5 (C-7), 130.9 (C-
17,18,19), 131.0 (C-8), 131.2 (C-16,20), 135.2 (C-12), 137.7 (C-6),
141.6 (C-11), 153.4 (C-2), 158.6 (C-3), 164.4 (C-15).
Anal. Calcd for C38H42NO8Cl: C, 67.50; H, 6.26; N, 2.07; Cl, 5.24.
Found: C, 67.64; H, 6.51; N, 2.21; Cl, 5.30.
HRMS-ESI: m/z [M – Cl]+ calcd for C38H42NO8: 640.2910; found:
640.2916.
Anal. Calcd for C26H26ClNO4: C, 69.10; H, 5.80; N, 3.10. Found: C,
68.83; H, 5.53; N, 2.99.
UV/Vis (n-propanol): lmax (e) = 277 (44000), 397 nm (8500).
HRMS-ESI: m/z [M – Cl]+ calcd for C26H26NO4: 416.1856; found:
416.1861.
[2,7-(10-Methyl-9-phenyl-9-methoxyacridane)]-(1¢,2¢-phenyl)-
29-crown-8 (17)
Obtained according to the general procedure, using toluene instead
of CHCl3.
2,7-Bis{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}-10-methyl-9-
phenylacridinium Chloride (21)
Mp 68–73 °C.
Compound 1 (1.9 g, 7.15 mmol) dissolved in anhydrous THF (120
mL) was added to a boiling solution of the Grignard-compound pre-
pared from bromobenzene (2.23 g, 14.3 mmol) and Mg (0.38 g) in
THF (30 mL). The reaction mixture was heated under reflux for 24
h then filtered and the filtrate was evaporated. The remaining resi-
due was purified by column chromatography [MeOH–H2O–aq
NH4Cl (7 M), 12:3:0.1] and the yellow fractions containing the
product were combined and evaporated. The remaining solid was
dissolved in MeCN, filtered and the solvent was removed in vacuo
to give 2,7-dimethoxy-10-methyl-9-phenylacridinium chloride.
1H NMR (CDCl3): d = 3.05 (s, 3 H, OCH3), 3.36 (s, 3 H, NCH3),
3.65 (m, 8 H, H-23,23¢,24,24¢), 3.68 (m, 4 H, H-25,25¢), 3.76 (t,
J = 6.0 Hz, 4 H, H-22,22¢), 4.10 (m, 8 H, H-21,21¢,26,26¢), 6.87 (s,
6 H, H-4,5,3¢,4¢,5¢,6¢), 7.02 (d, J = 1.5 Hz, 2 H, H-3,6), 7.10 (d,
J = 7.1 Hz, 1 H, H-18), 7.23 (t, J = 7.5 Hz, 2 H, H-17,19), 7.25 (s,
2 H, H-1,8), 7.31 (d, J = 7.5 Hz, 2 H).
13C NMR (CDCl3): d = 33.4 (CH3, NCH3), 51.3 (CH3, OCH3), 68.1,
68.9, 69.5, 69.7, 70.7 (CH2), 100.8 (Cq), 112.9 (CH), 114.3 (CH),
115.8 (CH), 116.9 (CH), 121.3 (Cq), 124.6 (CH), 126.0 (CH), 126.4
(CH), 127.8 (CH), 135.1 (Cq), 136.1 (Cq), 148.8 (Cq), 152.0 (Cq).
Yield: 1.4 g (55%); yellow solid; mp 182–185 °C.
1H NMR (CD3OD): d = 4.00 (s, 6 H, OCH3), 5.15 (s, 3 H, NCH3),
7.29 (d, J = 3.0 Hz, 2 H), 7.79 (m, 2 H), 8.03 (m, 3 H), 8.20 (dd,
J = 3.0, 9.8 Hz, 2 H), 8.88 (d, J = 9.8 Hz, 2 H).
Anal. Calcd for C40H49NO9: C, 69.85; H, 7.18; N, 2.04. Found: C,
69.55; H, 7.21; N, 2.37.
[2,3-(10-Methyl-9-phenyl-9-methoxyacridane)]-(1¢,2¢-phenyl)-
13C NMR (CDCl3): d = 38.8 (NCH3), 55.9 (OCH3), 105.3 (CH),
119.9 (CH), 127.8 (Cq), 129.5 (CH), 129.9 (CH), 130.6 (CH), 130.8
(CH), 134.0 (Cq), 136.7 (Cq), 129.0 (Cq), 157.6 (Cq).
24-crown-8 (19)
Obtained according to the general procedure using toluene instead
of CHCl3.
Anal. Calcd for C22H20ClNO2: C, 72.16; H, 5.46; N, 3.82. Found: C,
71.95; H, 5.87; N, 3.94.
Mp 47–50 °C.
1H NMR (CDCl3): d = 2.90 (s, 3 H, OCH3), 3.45 (s, 3 H, NCH3),
3.67 (s, 8 H, H-25,26,27,28), 3.81 (m, 2 H, H-24), 3.75 (m, 6 H, H-
23,29,30), 4.04 (m, 6 H, H-21,31,32), 4.18 (m, 2 H, H-22), 6.66 (s,
1 H, H-4), 6.74 (s, 1 H, H-1), 6.84 (s, 6 H, H-5,7,35,36,37,38), 7.08
(t, J = 7.2 Hz, 2 H, H-17,19), 7.23 (m, 5 H, H-6,8,16,18,20).
13C NMR (CDCl3): d = 33.7 (CH3, NCH3), 56.1 (CH3, OCH3), 68.8,
69.7, 69.9, 70.7, 70.8, 71.3 (C-21,22,23,24,25,26,27,28,29,30,
31,32), 97.2 (C-9), 112.1 (C-4), 114.9 (C-36,37), 115.5 (C-8), 119.9
(C-5), 121.4 (C-7), 121.6 (C-35,38), 124.0 (C-13), 125.8 (C-14),
126.1 (C-18), 126.6 (C-16,20), 127.6 (C-17,19), 128.2 (C-6), 134.9
(C-11), 140.8 (C-12), 142.4 (C-2), 143.1 (C-15), 145.4 (C-3), 150.7
(C-33,34).
HRMS-ESI: m/z [M – Cl]+ calcd for C22H20NO2: 330.1489; found:
330.1492.
2,7-Dimethoxy-10-methyl-9-phenylacridinium chloride (1 g, 3.0
mmol), dissolved in aq HBr (47%, 20 mL), was heated under reflux
for 2 h. The solvent was removed in vacuo and the crude product
was recrystallized from MeOH to give 2,7-dihydroxy-10-methyl-9-
phenylacridinium bromide.
Yield: 1.06 g (92%); yellow-orange solid; mp 210–214 °C.
1H NMR (CD3OD): d = 4.87 (s, 3 H, NCH3), 7.06 (d, J = 2.6 Hz,
2 H), 7.50 (m, 2 H), 7.73 (m, 3 H), 7.88 (dd, J = 2.6, 9.8 Hz, 2 H),
8.60 (d, J = 9.8 Hz, 2 H).
13C NMR (CD3OD): d = 38.1 (NCH3), 107.6 (CH), 120.1 (CH),
128.4 (Cq), 129.0 (CH), 129.9 (CH), 129.0 (CH), 129.5 (CH), 129.6
(CH), 130.6 (CH), 134.7 (Cq), 135.9 (Cq), 153.9 (Cq), 156.6 (Cq).
Anal. Calcd for C40H49NO9: C, 69.85; H, 7.18; N, 2.04. Found: C,
69.90 H, 6.83; N, 2.09.
Synthesis 2007, No. 21, 3345–3356 © Thieme Stuttgart · New York

3356
M. Orda-Zgadzaj, W. Abraham
PAPER
Anal. Calcd for C20H16BrNO2: C, 62.84; H, 4.22; N, 3.66; Br, 20.90.
Found: C, 62.49; H, 4.11; N, 3.23; Br, 21.05.
Acknowledgment
We gratefully acknowledge the Deutsche Forschungsgemeinschaft
for financial support.
2,7-Dihydroxy-10-methyl-9-phenyl-acridinium bromide (0.55 g,
1.4 mmol), dissolved in MeCN (200 mL), was treated with tetra-
methylammonium hydroxide (25% in MeOH, 4.3 g, 7.28 mmol).
The violet solution was heated under reflux for 1 h. After cooling,
tris-ethyleneglycol-bis-tosylate (1.66 g, 5.46 mmol) was added and
the reaction mixture was heated under reflux for 24 h. The solvent
was removed in vacuo and the crude product was purified by col-
umn chromatography [MeOH–H2O–aq NH4Cl (7 M), 11:3:0.1]. Af-
ter evaporation of the solvents, NH4Cl was removed with water. The
residue was taken up in CH2Cl2 (50 mL), then the solution was treat-
ed with H2O (2 × 10 mL). The solution was dried and evaporated to
give 21.
References
(1) (a) Teulode-Fichou, M.-P.; Vigneron, J. P.; Lehn, J.-M.
Supramol. Chem. 1995, 5, 139. (b) Cudic, P.; Vigneron, J.-
P.; Lehn, J.-M.; Cesario, M.; Prange, T. Eur. J. Org. Chem.
1999, 2479. (c) Rebek, J. Acc. Chem. Res. 1990, 23, 399.
(2) Grigoreva, T. M.; Ivanov, V. L.; Kuzmin, M. G. Zh. Obshch.
Khim. 1981, 17, 423.
(3) Abraham, W.; Buck, K.; Orda-Zgadzaj, M.; Schmidt-
Schäffer, S.; Grummt, U.-W. Chem. Commun. 2007, 3094.
(4) (a) Parker, D. A. Macrocyclic Synthesis: A Practical
Approach; Oxford University Press: Oxford, 1996.
(b) Knops, P.; Sendhoff, N.; Mekelburger, H. B.; Voegtle, F.
Top. Curr. Chem. 1992, 161, 1.
Yield: 0.8 g (73%); Rf = 0.42 [MeOH–H2O–aq NH4Cl (7 M),
11:3:0.1]; mp 55–57 °C.
1H NMR (CDCl3): d = 3.41 (s, 2 H, OH), 3.53 (t, J = 4.9 Hz, 4 H,
H-26,26¢), 3.62 (m, 12 H, H-23,23¢,24,24¢,25,25¢), 3.78 (t, J = 4.9
Hz, 4 H, H-22,22¢), 4.02 (t, J = 3.7 Hz, 4 H, H-21,21¢), 5.16 (s, 3 H,
N-CH3), 6.91 (d, J = 2.6 Hz, 2 H, H-1,8), 7.35 (m, 2 H, H-16,20),
7.64 (m, 3 H, H-17,18,19), 7.98 (dd, J = 2.6, 9.8 Hz, 2 H, H-3,6),
8.82 (d, J = 9.8 Hz, 2 H, H-4,5).
(5) Grubert, L.; Abraham, W. Tetrahedron 2007, 63, 10778.
(6) Loeb, S. J.; Wisner, J. A. Chem. Commun. 1998, 2757.
(7) Loeb, S. J.; Tiburcio, J.; Vella, S. J.; Wisner, J. A. Org.
Biomol. Chem. 2006, 4, 667.
(8) Vichet, A.; Patellis, A.-M.; Galy, J.-P.; Galy, A.-M.; Barbe,
13C NMR (CD3OD): d = 40.1 (NCH3), 61.2 (C-26,26¢), 68.5 (C-
21,21¢), 69.6 (C-22,22¢), 70.5 (C-23,23¢), 70.8 (C-25,25¢), 72.7 (C-
24,24¢), 105.9 (C-1,8), 121.1 (C-4,5), 128.4 (C-13,14), 129.0 (C-
16,20), 130.4 (C-17,18,19), 134.4 (C-9), 137.2 (C-11,12), 155.4 (C-
15), 157.6 (C-2,7).
J.; Elguero, J. J. Org. Chem. 1994, 59, 5156.
(9) Hannig, E.; Becke, E. Pharmazie 1975, 30, 289.
(10) Ashton, P. R.; Bartsch, R. A.; Cantrill, S. J.; Hanes, R. E. Jr.;
Hickingbotton, S. K.; Lowe, J. N.; Preece, J. A.; Stoddart, J.
F.; Talanov, V. S.; Wang, Z.-H. Tetrahedron Lett. 1999, 40,
3661.
(11) Ionescu, M.; Mester, I. Rev. Roum. Chim. 1969, 14, 789.
(12) Borsche, W.; Runge, F.; Trautner, W. Ber. Dtsch. Chem.
Ges. B 1933, 66, 1315.
Anal. Calcd for C32H40ClNO8: C, 63.77; H, 6.64; N, 2.32; Cl, 5.90.
Found: C, 63.49; H, 6.44; N, 2.61; Cl, 6.00.
(13) Dhif, D.; Galy, J.-P.; Barbe, J. Synth. Commun. 1991, 21,
969.
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