Synthesis of lariat diazacrown ethers with terminal amino groups in the side chains

Article abstract of DOI:10.1023/B:COHC.0000028631.81899.15

Treatment of diazacrown ethers with N-(haloalkyl)- and N-(haloethoxy) phthalimides gives the corresponding N,N′- substituted diazacrown ether. Hydrazinolysis of the latter then gives diazacrown ethers with terminal primary amino groups in the side chain. Their reductive methylation using formaldehyde in formic acid gives the dimethylamino derivatives. The presence of a lariat effect was demonstrated by treating the compounds obtained with picrates of alkali and alkaline-earth metals.

Full text of DOI:10.1023/B:COHC.0000028631.81899.15

Chemistry of Heterocyclic Compounds, Vol. 40, No. 3, 2004
SYNTHESIS OF LARIAT DIAZACROWN
ETHERS WITH TERMINAL AMINO
GROUPS IN THE SIDE CHAINS
N. G. Lukyanenko, T. I. Kirichenko, and S. V. Shcherbakov
Treatment of diazacrown ethers with N-(haloalkyl)- and N-(haloethoxy)phthalimides gives the
corresponding N,N'- substituted diazacrown ether. Hydrazinolysis of the latter then gives diazacrown
ethers with terminal primary amino groups in the side chain. Their reductive methylation using
formaldehyde in formic acid gives the dimethylamino derivatives. The presence of a lariat effect was
demonstrated by treating the compounds obtained with picrates of alkali and alkaline-earth metals.
Keywords: diazacrown ethers, N,N'-substituted, terminal amino groups, lariat effect.
Crown ethers with functional donor groups in the side chain (lariat crown ethers) form, in many cases,
stronger complexes with metal cations than their unsubstituted analogs and show highly selective complex
formation [1-3]. As a rule this is due to the participation of a donor group side chain in the complex formation
with the cation. For specific structural compliances this can react with the cation found in the crown ether cavity
involving axial positions (the lariat effect) and establish a three dimensional ligand environment around it [4-6].
One of the factors deciding the complex forming properties of the lariat crown ethers is the nature of the side
chain donor groups. Among the large group of synthesized lariat azacrown ethers the least studied are
compounds having a terminal amino group in the side chain [4]. Such compounds form stable complexes both
with hard alkali and alkaline-earth ions and also with weak transition and certain other metal ions [7-10]. In this
connection we have synthesized novel substituted diazacrown ethers with terminal amino groups in the side
chain and qualitatively assessed the existence of the lariat effect in their reaction with alkali and alkaline-earth
metal picrates.
Lariat azacrown ethers with amino groups in the side chain are usually prepared by the acylation of
azacrown ethers with activated derivatives of α-amino acids, by alkylation with α-halo acid N,N-dialkylamides
and subsequent reduction of the obtained compounds with lithium aluminium hydride or diborane [7, 8], by
alkylation of primary amine or secondary diamines with the corresponding dihalides or ditosylates [11, 12], and
also by the addition of azacrown ethers to acrylonitrile and reduction of the nitrile group [10]. An interesting
method for the preparation of lariat aza- and diazacrown ethers based on compounds with a benzotriazole group
in the side chain has been presented [6]. All of the listed methods are not comprehensive since they do not allow
the introduction of side chains with varying bond length and nature of functional group.
We propose a synthetic route which, in our view, is the most rational and general method for the
preparation of substituted azacrown ethers with terminal amino groups in the side chain.
__________________________________________________________________________________________
A. V. Bogatsky Physico-Chemical Institute, Odessa 65080; e-mail: physchem@paco.net. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 421-431, March, 2004. Original article submitted
February 14, 2001.
0009-3122/04/4003-0343©2004 Plenum Publishing Corporation
343

[
]
n
O
O
[
]
m
Na2CO3
N
N
+
N
Y
X
O
O
O
2a–g
1a,b
1. N2H4
2. HCl
O
[
]
O
n
3. LiOH
O
[
]
m
[
]
m
N
N
Y
Y
Y
N
N
Y
Y
Y
O
O
]
O
O
3a–e
[
n
CH2O
HCOOH
O
[
]
m
[
]
m
N
N
H2N
NH2
O
O
4a–e
[
]
n
O
[
]
m
[
]
m
N
N
Me2N
NMe2
O
O
5a–e
1, 3–5 a n = 1, b n = 2; 2a,b–5a,b m = 0; 2c–5c m = 1, Y = (CH2)2;
2d–5d m = 1, Y = 0; 2e–5e m = 2, Y = 0; 2a X = Br, b–d X = Cl, e–g X = I
The synthesis of the N,N'-substituted diazacrown ethers 3a-e was carried out by treating diaza-15-crown-
5 (1a) or diaza-18-crown-6 (1b) with N-(2-bromoethyl)- (2a), N-(6-iodohexyl)- (2e), N-[2-(2-iodoethoxy)ethyl]-
(2f), and N-{2-[2-(iodoethoxy)ethoxy]ethyl}phthalimides (2g). Reaction of diazacrown ethers 1a,b with
phthalimide 2a in acetonitrile in the presence of sodium carbonate gives the N,N'-[(2-phthalimido)ethyl]diaza-
15-crown-5 (3a) and N,N'-[(2-phthalimido)ethyl]diaza-18-crown-6 (3b) in low yield. Carrying out the same
reaction without solvent at 100°C gives a markedly higher yield of compounds 3a,b. By contrast, this alkylation
of the diazacrown ethers 1a,b by the iodides 2f-g under similar conditions did not give satisfactory results. Good
yields were obtained when this reaction was carried out in refluxing acetonitrile over 18 h in the presence of
sodium carbonate. The increased heating time lowers the yield of the target products, evidently as a result of the
partial quaternization of the alkylation product.
The starting iodides 2e-g were synthesized from N-(6-chlorohexyl)- (2b), N-[2-(2-chloroethoxy)ethyl]-
(2c), and N-{2-[2-(chloroethoxy)ethoxy]ethyl}phthalimides (2d) by refluxing them with sodium iodide in
acetonitrile. The bromide 2a and chlorides 2b-d were prepared by treating potassium phthalimide with
dibromoethane, 1,6-dichlorohexane, 1-chloro-2-(2-chloroethoxy)ethane, and 1-chloro-2-[2-(chloroethoxy)-
ethoxy]ethane respectively.
Treatment of hydrazine hydrate with the diazacrown ethers 3a-e gave 70-85% yields of the lariat
diazacrown ethers 4a-e which contain terminal primary amino groups in the side chains. The diazacrown ethers
with terminal dimethylamino groups 5a-e were prepared by reductive methylation of compounds 4a-e via
reaction with formaldehyde in formic acid.
344

TABLE 1. Characteristics of the N,N'- Substituted Diazacrown Ethers 3-5
Found, %
Calculated, %
H
Mass
spectrum,
m/z
——————
Com-
pound
Empirical
formula
Yield,
%
1H NMR spectrum(CDCl3), δ, ppm, spin-spin coupling (J, Hz)
C
N
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
C30H36N4O7
63.82
63.74
6.43
6.52
9.92
9.86
564
608
720
696
784
304
348
460
436
524
2.6 (8H, m, NCH2); 2.9 (4H, t, J = 6.9, NCH2); 3.4 (8H, m, OCH2);
3.5 (4H, s, OCH2); 3.6 (4H, t, J = 6.9, CH2N); 7.7 (8H, m, C6H4)
61
87
40
65
48
84
75
85
70
79
C32H40N4O8
C40H56N4O8
C36H48N4O10
C40H56N4O12
C14H32N4O3
C16H36N4O4
C24H52N4O4
C20H44N4O6
C24H52N4O8
63.14
63.13
6.62
6.69
9.20
9.17
2.7 (8H, t, J = 6.1, NCH2); 2.9 (4H, t, J = 7.0, NCH2); 3.4 (8H, m, OCH2);
3.5 (8H, s, OCH2); 3.7 (4H, t, J = 7.0, CH2N); 7.7 (8H, m, C6H4)
66.64
66.70
7.83
7.85
7.77
7.72
1.4 (16H, m, CH2); 2.6 (12H, m, NCH2); 3.5 (16H, m, OCH2);
3.8 (4H, t, J = 7.2, CH2N); 7.7 (8H, m, C6H4)
2.7 (12H, m, NCH2); 3.5 (24H, m, OCH2); 3.8 (4H, t, J = 5.8, CH2N);
7.7 (8H, m, C6H4)
62.06
62.11
6.94
6.93
8.04
8.02
61.21
61.27
7.19
7.13
7.14
7.16
2.7 (12H, m, NCH2); 3.5 (32H, m, OCH2); 3.8 (4H, t, J = 5.8, CH2N);
7.7 (8H, m, C6H4)
55.24
55.16
10.59
10.62
18.40
18.50
1.5 (4H, br. s , NH); 2.5 (12H, m, NCH2); 2.8 (4H, m, CH2NH2);
3.4 (8H, m, OCH2); 3.6 (4H, s, OCH2)
1.6 (4H, br. s , NH); 2.6 (12H, m, NCH2); 2.8 (4H, m, CH2NH2);
55.15
55.20
10.41
10.37
16.08
16.13
3.4 (8H, t, J = 6.2, OCH2); 3.5 (8H, s, OCH2)
62.57
62.63
11.38
11.43
12.16
12.11
1.1 (4H, br. s , NH); 1.3 (16H, m, CH2); 2.4 (12H, m, NCH2);
2.6 (4H, m, CH2NH2); 3.5 (16H, m, OCH2)
55.02
55.05
10.16
10.12
12.83
12.75
1.5 (4H, br. s , NH); 2.5 (8H, t, J = 6.2, NCH2); 2.6 (4H, t, J = 5.8, NCH2);
2.8 (4H, t, J = 5.8, CH2NH2); 3.3 (8H, t, J = 6.2, OCH2); 3.5 (16H, m, OCH2)
54.94
54.93
9.99
9.95
10.68
10.59
1.9 (4H, br. s , NH); 2.5 (8H, t, J = 6.2, NCH2); 2.6 (4H, t, J = 5.8, NCH2);
2.8 (4H, t, J = 5.8, CH2NH2); 3.3 (8H, t, J = 6.2, OCH2); 3.5 (24H, m, OCH2)
5a
5b
C18H40N4O3
C20H44N4O4
59.97
59.91
59.37
59.44
11.18
11.25
10.96
10.89
15.54
15.48
13.85
13.87
360
404
2.2 (12H, s, CH3); 2.5 (16H, m, NCH2); 3.4 (8H, m, OCH2); 3.5 (4H, s, OCH2)
85
63
2.2 (12H, s, CH3); 2.5 (16H, m, NCH2); 3.4 (8H, t, J = 6.2, OCH2);
3.5 (8H, s, OCH2)
5c
5d
5e
C28H60N4O4
C24H52N4O6
C28H60N4O8
65.07
65.11
11.70
11.76
10.84
10.77
516
492
580
1.3 (16H, m, CH2); 2.1 (12H, s, CH3); 2.4 (16H, m, NCH2);
3.4 (8H, t, J = 6.2, OCH2); 3.5 (8H, s, OCH2)
77
75
63
58.51
58.47
10.64
10.71
11.37
11.32
2.2 (12H, s, CH3); 2.5 (12H, m, NCH2); 2.7(4H, t, J = 5.8, NCH2);
3.4 (8H, t, J = 6.2, OCH2); 3.5 (16H, m, OCH2)
57.90
57.85
10.41
10.43
9.65
9.62
2.2 (12H, s, CH3); 2.5 (8H, t, J = 6.2, NCH2); 2.6 (4H, t, J = 5.8, NCH2);
2.8 (4H, m, NCH2); 3.4 (8H, t, J = 6.2, OCH2); 3.5 (24H, m, OCH2)

TABLE 2. Maximum Positions (λmax) and Relative Shifts (∆λmax)* of the Metal Picrate Absorption Bands in the Presence
of One Hundred Fold Excess of Compounds 1b, 4, 5b-e and 6 in THF.
Com-
pound
LiPi
NaPi
KPi
MgPi
CaPi
λmax
∆λmax
λmax
∆λmax
λmax
∆λmax
λmax
∆λmax
λmax
∆λmax
1b
4b
4c
4d
4e
5b
5c
5d
5e
6
357
379
—
10
32
—
33
31
31
—
17
32
3
—
380
—
—
27
—
27
23
27
—
20
26
5
364
380
—
5
359
376
380
380
377
375
358
370
376
356
32
49
53
53
50
47
31
43
48
30
358
378
390
380
379
378
—
23
43
45
45
44
43
—
38
39
17
21
—
20
19
18
—
11
21
—
380
378
378
—
380
376
380
—
380
379
378
—
370
378
349
368
379
358
370
379
—
373
374
352
_______
* ∆λmax is the difference in position of the metal picrate absorption band in the presence and absence of the ligand.

The value of the induced shift of the absorption maximum of picrate anion (∆λPi) in low polarity media
[13] can serve as a test for the presence of the lariat effect. The method is based on the known dependence of the
∆λPi on the degree of separation of the ion pair of the studied metal picrate. Evidently, the greater the shielding
of the metal cation by the lipophilic envelope of the ligand the greater will be the degree of separation of the ion
pair of the picrate and, in turn, this will lead to an increase in the bathochromic shift of the picrate anion band. In
fact, the crown ether gives rise to a two dimensional ligand around the cation and this leads to a markedly
smaller value of ∆λPi than for cryptands which have a three dimensional intramolecular cavity. With the creation
of the lariat effect the value of ∆λPi markedly exceeds the shift observed for the unsubstituted compounds and
approaches that observed for cryptands and this is quite understandable since, in this case, a three dimensional
environment is created around the cation.
A spectrophotometric study of the reaction of the substituted azacrown ethers 4b-e and 5b-e with
lithium, sodium, potassium, magnesium, and calcium picrates was carried out in tetrahydrofuran. In most cases
the addition to the picrate solution of one hundred fold excesses of the ligand gave a maximal possible shift of
the picrate absorption (λPi 376-380 nm) and this points to the formation of separated ion pairs. It probably
indicates a high stability for the complex since the value of ∆λPi is only slightly sensitive to the ratio of the
picrate-ligand concentration to the extent of 1/(2-5) (Table 2).
In contrast to this, the unsubstituted diaza-18-crown-6 (1b) and N,N'-dibenzyldiaza-18-crown-6 (6),
which cannot show the lariat effect, show a much smaller shift in the absorption maximum of the picrate anion
(λPi 349-364 nm) (Table 2). This points to the presence of a lariat effect in compounds 4b-a–5b-e. Since the side
chains of these diazacrown ethers differ in length, number, and nature of the donor atoms evidently, in each
specific example, the participation of particular heteroatoms in complex formation will be determined by the
possibility of achieving a structural and electronic maximization for the cation and crown ether side chain
respectively.
The side chains in compound 4c contain six methylene groups and the lariat effect can be achieved only
with the participation of the side amino groups in complex formation. The appearance of gem-dimethyl
substituents on the nitrogen atoms in compound 5c evidently hinders their participation in interaction with a
cation and as a result, in this case, the shift observed (λPi 358 nm) is similar to that of the unsubstituted
diazacrown ether (see Table 2). A markedly smaller shift in the absorption maximum of the picrate anion is
observed for the crown ether 5d (λPi 368-373 nm) when compared with its unsubstituted analog 4d (λPi 380 nm).
In compounds with a short (4b) or longer (4e) side chain the introduction of methyl substituents at the amino
groups does not influence the shift values. Evidently, the observed differences in the spectroscopic behavior of
the studied crown ether complexes is due to the possible coordination of the ion with both the nitrogen and the
oxygen atoms of the side chain and also the possibility of realizing complexes of different structure.
Unfortunately, the data for the values of the induced shifts of picrate anion point only to the participation of the
heteroatoms of the side chains in complex formation but do not allow one to make more specific conclusions
about the structure of the complexes formed.
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker AM-250 (250 MHz) instrument using CDCl3 and HMDS
internal standard. Mass spectra were obtained on a Varian MAT 112 instrument with an electron impact
ionization of 40 and 70 eV. UV spectra were taken on a Specord M40 UV-vis spectrophotometer. The purity of
all of the compounds obtained was monitored chromatographically. Thin-layer chromatography was carried out
on glass plates with an applied layer of basic aluminium oxide (L 5/40, Chemapol) and using Silufol UV-254
bound layer silica gel plates. GLC was performed on a Chrom-5 apparatus, 3 × 1500 mm column, 5% SP 2100
on Chromaton N-Super. 1,2-Dibromoethane, 1,6-dichlorohexane, 1,5-dichloro-3-oxapentane, and 1,8-dichloro-
347

3,6-dioxaoctane were used as commercial products. The diazacrown ethers 1a,b were obtained according to the
method in [14]. N,N'-Dibenzyldiaza-18-crown-6 (6) was prepared by the method in [5].
N-(2-Bromoethyl)phthalimide (2a). A suspension of potassium phthalimide (43 g, 0.23 mol) in
1,2-dibromoethane (284 g, 1.5 mol) was refluxed for 20 h with vigorous stirring. The excess dibromoethane was
distilled off under reduced pressure. The residue was dissolved in benzene (200 ml) and the unreacted
potassium phthalimide and 1,2-diphthalimidoethane were filtered off. The benzene was distilled off and the
residue was recrystallized from ethanol (55 ml). Yield 43.8 g (75%); mp 82-83°C which agrees with that
reported [15].
N-(6-Chlorohexyl)phthalimide (2b). A suspension of potassium phthalimide (21 g, 0.11 mol) and
1,6-dichlorohexane (177.7 g, 1.14 mol) has stirred at 130°C for 20 h. The cooled product was filtered and the
excess 1,6-dichlorohexane was distilled off under reduced pressure. The residue was crystallized from pentane
1
(200 ml). Yield 23.7 g (78%); mp 38-39°C. H NMR spectrum, δ, ppm (J, Hz): 1.5 (8H, m, CH2); 3.4 (2H, t,
J = 6.2, CH2Cl); 3.6 (2H, t, J = 7.2, CH2N); 7.8 (4H, m, C6H4). Found, %: C 63.17; H 6.11; N 5.19.
C14H16ClNO2. Calculated, %: C 63.28; H 6.07; N 5.27.
N-[2-(2-Chloroethoxy)ethyl]phthalimide (2c) was prepared similarly from potassium phthalimide (200
g, 1.08 mol) and 1,5-dichloro-3-oxapentane (1522 g, 10.6 mol). After distillation of solvent the residue was
crystallized by the addition of pentane (100 ml). The precipitate was filtered off and the product was purified by
extraction with pentane in a Soxhlet apparatus for 50 h. Yield 250 g (91.5%); mp 71-72°C. 1H NMR spectrum, δ,
ppm (J, Hz): 3.6 (4H, m, CH2O); 3.8 (2H, t, J = 6.6, CH2Cl); 3.9 (2H, t, J = 5.8, CH2N); 7.6 (4H, m, C6H4).
Found, %: C 56.87; H 4.83; N 5.44. C12H12ClNO3. Calculated, %: C 56.82; H 4.77; N 5.52.
N-{2-[2-(Chloroethoxy)ethoxy]ethyl}phthalimide (2d) was prepared similarly from potassium
phthalimide (185 g, 1.0 mol) and 1,8-dichloro-3,6-dioxaoctane (1870 g, 10 mol). Yield 89% as an oil. 1H NMR
spectrum, δ, ppm: 3.5 (8H, m, CH2O); 3.8 (4H, m, CH2Cl, CH2N); 7.5 (4H, m, C6H4). Found, %: C 56.41;
H 5.50; N 4.65. C14H16ClNO4. Calculated, %: C 56.48; H 5.42; N 4.70.
N-(6-Iodohexyl)phthalimide (2e). A mixture of N-(6-chlorohexyl)phthalimide 2b (23.7 g, 0.09 mol)
and freshly ignited sodium iodide (30 g, 0.2 mol) in dry acetonitrile (200 ml) was refluxed for 10 h with
vigorous stirring. The precipitated NaCl was filtered off and washed with acetonitrile. The filtrate was
evaporated under reduced pressure, the residue was dissolved in chloroform (100 ml), and the solution was
washed with a 5% solution of sodium thiosulfate and dried over calcium chloride. Chloroform was distilled off
and the residue was recrystallized from pentane (300 ml). The precipitated crystals were filtered off and dried in
air. Yield 28.6 g (89.7%); mp 75-76°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.5 (8H, m, CH2); 3.1 (2H, t, J = 6.5,
CH2I); 3.6 (2H, t, J = 7.2, CH2N); 7.7 (4H, m, C6H4). Found, %: C 47.12; H 4.48; N 3.88. C14H16INO2.
Calculated, %: C 47.08; H 4.51; N 3.92.
N-[2-(2-Iodoethoxy)ethyl]phthalimide (2f) was prepared similarly from the phthalimide 2c (91 g,
0.36 mol) and NaI (120 g, 0.8 mol) in acetonitrile (500 ml). After distillation of chloroform the product was
crystallized from a mixture of hexane (1250 ml) and benzene (375 ml). Yield 120 g (97%); mp 84-86°C.
1H NMR spectrum, δ, ppm (J, Hz): 3.2 (2H, t, J = 7.0, CH2I); 3.6 (2H, t, J = 6.0, CH2CH2N); 3.7 (2H, t, J = 7.0,
CH2CH2I); 3.9 (2H, t, J = 6.0, CH2N); 7.6 (4H, m, C6H4). Found, %: C 41.82; H 3.56; N 4.02. C12H12INO3.
Calculated, %: C 41.76; H 3.50; N 4.06.
N-{2-[2-(Iodoethoxy)ethoxy]ethyl}phthalimide (2g) was prepared similarly from the phthalimide 2d
(89.1 g, 0.3 mol) and NaI (105 g, 0.7 mol). After distillation of chloroform the product was extracted from the
residue with refluxing heptane (1.0 l). The heptane was evaporated to give compound 2g as a light-yellow oil.
Yield 113 g (96%). 1H NMR spectrum, δ, ppm (J, Hz); 2.9 (2H, t, J = 6.9, CH2I); 3.5 (4H, m, CH2O); 3.6 (2H, t,
J = 5.8, CH2CH2N); 3.7 (2H, t, J = 7.0, CH2CH2I); 3.9 (2H, t, J = 5.8, CH2N); 7.6 (4H, m, C6H4). Found, %:
C 43.15; H 4.21; N 3.67. C14H16INO4. Calculated, %: 43.21; H 4.14; N 3.60.
348

2-(2-{13-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1,4,10-trioxa-7,13-diazacyclopentadecan-
7-yl}ethyl)-1H-isoindole-1,3(2H)-dione (3a). A mixture of the diaza-15-crown-5 1a (2.18 g, 10 mmol),
phthalimide 2a (12.7 g, 50 mmol), and freshly ignited sodium carbonate (5.3 g, 50 mmol) was stirred for 10 h at
100°C. Chloroform (30 ml) was added dropwise to the hot solution which was then cooled and the precipitate
formed was filtered off and the chloroform evaporated under reduced pressure. The residue was dissolved in a
1:1 mixture of benzene and HCl (1 N). The benzene layer was separated and the aqueous extracted with benzene
(50 ml). The aqueous solution was treated with sodium carbonate to pH 9-10 and extracted with benzene
(2 × 50 ml). After distillation of benzene 3a was obtained as a light-yellow oil. Yield 4.0 g.
2-(2-{16-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1,4,10,13-tetraoxa-7,16-diazacycloocta-
decan-7-yl}ethyl)-1H-isoindole-1,3(2H)-dione (3b) was prepared similarly from diaza-18-crown-6 1b (2.62 g,
10 mmol) and phthalimide 2a (12.7 g, 50 mmol). After distillation of benzene the residue was recrystallized
from a 1:1 mixture of heptane and benzene (70 ml). Yield 5.0 g; mp 116-117°C.
2-(6-{16-[6-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)hexyl]-1,4,10,13-tetraoxa-7,16-diazacycloocta-
decan-7-yl}hexyl)-1H-isoindole-1,3(2H)-dione (3c). A mixture of diaza-18-crown-6 1b (7.86 g, 30 mmol),
phthalimide (28.6 g, 0.08 mol), and freshly ignited sodium carbonate (32 g, 0.3 mol) in dry acetonitrile (150 ml)
was refluxed with stirring for 18 h. After cooling, the precipitate was filtered and the acetonitrile was distilled
from the filtrate under reduced pressure. Benzene (100 ml) and 1N HCl (100 ml) were added to the residue. The
oily lower layer separated in this way crystallized over 10-12 h. The crystals were filtered off, washed with
benzene, and treated with a saturated solution of sodium carbonate (100 ml) at 60°C. The product was removed
using benzene and the extract was dried over anhydrous sodium sulfate and the solvent distilled off. The residue
was crystallized from heptane (400 ml). Yield 9.2 g; mp 41-42°C.
2-{2-[2-(16-{2-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethyl}-1,4,10,13-tetraoxa-7,16-
diazacyclooctadecan-7-yl}ethyl)-1H-isoindole-1,3(2H)-dione (3d) was prepared similarly by refluxing diaza-
18-crown-6 1b (1.05 g, 4 mmol) and the phthalimide 2f (3.45 g, 10 mmol) in the presence of lithium carbonate
(3.0 g, 40 mmol) in acetonitrile (20 ml) for 30 h. After distillation of benzene the residue was crystallized from
an 18:11 mixture of heptane and benzene. Yield 1.8 g; mp 96-97°C.
2-[2-(2-{2-[16-(2-{2-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy}ethyl)-1,4,10,13-tetra-
oxa-7,16-diazacyclooctadecan-7-yl]ethoxy}ethoxy)ethyl]-1H-isoindole-1,3(2H)-dione (3e) was prepared
similarly from diaza-18-crown-6 1b (1.05 g, 4 mmol) and phthalimide 2g (3.9 g, 10 mmol) in the presence of
lithium carbonate (3.0 g, 40 mmol). Distillation of benzene gave 3e as a light-yellow oil. Yield 1.5 g.
2-[13-(2-Aminoethyl)-1,4,10-trioxa-7,13-diazacyclopentadecan-7-yl]ethylamine (4a), 2-[16-(2-Amino-
ethyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl]ethylamine (4b), 6-[16-(6-Aminohexyl)-1,4,10,13-
tetraoxa-7,16-diazacyclopentadecan-7-yl]hexylamine
tetraoxa-7,16-diazacyclooctadecan-7-yl]ethoxy)ethylamine
ethoxy)ethoxy]ethyl}-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)ethoxy]ethoxy}ethylamine
(4c),
2-(2-{16-[2-Aminoethoxy)ethyl]-1,4,10,13-
(4d), and 2-{2-[2-(16-{2-[2-(2-Amino-
(4e).
(General Method). Hydrazine hydrate (67 mmol) was added dropwise with vigorous stirring to a refluxing
solution of the diazacrown ether 3 (33 mmol) in ethanol (100 ml). The mixture was refluxed for 7 h and diluted
with HCl (6 N, 22 ml). The precipitate was filtered off and ethanol was removed at reduced pressure. Water (120
ml) was added to the residue and the precipitate was filtered off. A saturated aqueous solution of LiOH was
added to the filtrate to pH 10-11. The product was extracted with chloroform over 10 h. Distillation of the
chloroform gave the diazacrown ether 4 as a light-yellow oil.
N-(2-{13-[2-(Dimethylamino)ethyl]-1,4,10-trioxa-7,13-diazacyclopentadecan-7-yl}ethyl)-N,N-di-
methylamine (5a), N-(2-{16-[2-(Dimethylamino)ethyl]-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-
yl}ethyl)-N,N-dimethylamine (5b), N-6-{16-[6-(Dimethylamino)hexyl]-1,4,10,13-tetraoxa-7,16-diazacyclo-
pentadecan-7-yl}hexyl)-N,N-dimethylamine (5c), N-{2-[2-(16-{2-[2-dimethylamino)ethoxy]ethyl}-1,4,10,13-
tetraoxa-7,16-diazacyclooctadecan-7-yl)ethoxy]ethyl}-N,N-dimethylamine (5d), and N-[2-(2-{2-[16-(2-{2-
[2-(dimethylamino)ethoxy]ethoxy}ethyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl]ethoxy}ethoxy)-
ethyl]-N,N-dimethylamine (5e). (General Method). An aqueous solution of formaldehyde (40%, 5 ml) was
349

added to a solution of the diazacrown ether 4 (1.5 mmol) in formic acid (5 ml). The mixture was refluxed for
10 h, diluted with conc. HCl (10 ml), and evaporated to dryness under reduced pressure. This operation was
repeated once more. The residue was dissolved in water (10 ml), diluted with a saturated solution of LiOH to
pH 10-11, and extracted with chloroform (5 × 5 ml). After distillation of chloroform, the product was removed
from the residue using refluxing hexane (3 × 10 ml). The hexane was evaporated to give the diazacrown ether 5
as a light-yellow oil.
Method for Determining the Value of the Induced Shift (∆λ) of the Absorption Band of Metal
Picrates in the Presence of Diazacrown Ethers. A sample of the diazacrown ether (5 mmol) was dissolved in a
solution of the appropriate metal picrate (5 ml, 0.05 M) in THF. Subsequent dilution with the metal picrate
solution then gave solutions with the diazacrown ether:picrate ratios of 50, 10, 2, 1, 0.75, 0.5, and 0.2.
Measurements were carried out over 12 h in order to reach system equilibrium. The value of ∆λ was calculated
as the difference between the λmax of the picrate with a one hundred fold excess of the diazacrown ether and the
picrate λmax in its absence. The results are given in Table 2.
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