Synthesis of new receptors highly selective for ammonium cations

Full text of DOI:10.1021/jo952283x

3870
J . Org. Chem. 1996, 61, 3870-3873
Syn th esis of New Recep tor s High ly
Selective for Am m on iu m Ca tion s
Silvio Quici,* Amedea Manfredi, and Marco Buttafava
Centro CNR and Dipartimento di Chimica Organica e
Industriale dell’Universita`, Via C. Golgi 19,
20133 Milano, Italy
Received December 28, 1995
In tr od u ction
The design of macrocyclic and macropolycyclic ligands
featuring high selectivity for complexation of ammonium
cations has received an enormous interest since the
beginning of studies of molecular recognition using
artificial receptors.1 Complexation of ammonium cations
occurs through specific hydrogen-bonding interactions;
hence a receptor capable of forming highly stable and
selective complexes should have complementarity with
these substrates in terms of nature, number, and topology
of binding sites.2 It is well-known that macrocyclic
polyethers are capable of complexing both alkali and
ammonium salts though the stability and selectivity of
complexes is in favor of alkali cations.3 The replacement
of one or more oxygen binding sites with nitrogen atoms
strongly increases the selectivity for ammonium to the
detriment of alkali cations,4 in fact +N-H‚‚‚N hydrogen
bonding is stronger than +N-H‚‚‚O.5
nitrogen atoms are protected by two benzyl and two
p-toluenesulfonyl groups, alternate to each other, whose
selective deprotection allows a suitable building block for
the synthesis of more sophisticated polycyclic receptors
with new topological arrangements of binding sites. To
our knowledge there are no reports, in the very large
literature on polyoxapolyazacoronands, dealing with the
preparation and study of complexation of tetraaza-
macrocyclic receptors like 1 and of its derivatives.11
In the present paper we report: (i) a new and high-
yielding synthetic procedure allowing 1 as the only
macrocyclic product, thus making easier its isolation and
purification; (ii) the synthesis of a new macrobicyclic
lipophilic receptor 14 using 1 as building block; and (iii)
the study of the complexation capabilities of these new
receptors, with ammonium cations and amino acid ester
hydrochlorides, under solid/liquid two-phase conditions.
The importance of topological arrangement of nitrogen
donor sites is well documented; indeed the strongest
+NH4 complex is obtained with a spherical macrotricyclic
cryptand featuring four nitrogens situated at the corners
of a tetrahedron.6 Cylindrical macrotricyclic cryptands,
in which two 1,7,10,16-tetraoxa-4,13-diazacycloocta-
decane, [18]-N2O4, are connected through two lateral
bridges, form complexes with R-ω bisammonium salts
[H3N(CH2)nNH3]2+ whose stability and selectivity strongly
depend on the complementarity between the length of
Resu lts a n d Discu ssion
New synthetic routes allowing 1 and its tetratosyl-
amido derivative 11 are reported in Schemes 1 and 2.
Starting from the already reported dimethanesulfonyl
derivative 4, it is possible to obtain, through Gabriel’s
procedure and subsequent treatment of the resulting
amine 5 with p-toluenesulfonyl chloride, the 6-p-toluene-
sulfonyl-3,9-dioxa-1,6,11-triazaundecane 6 in quantita-
tive yield. Condensation of 6 with 2 molar equiv of
benzaldehyde gave the diimino derivative 7 which was
hydrogenated at room temperature and atmospheric
pressure in the presence of PtO2 affording 8 in 95%
overall yield. Condensation of 8 with 1 molar equiv of
4, under usual conditions (CH3CN and Na2CO3 solid as
base, at reflux for 48 h), afforded the desired macrocycle
1 in 45% yield after purification by column chromatog-
raphy.12 Reductive detosylation of 1 with LiAlH4 in
refluxing THF allowed quantitatively the 4,16-dibenzyl-
1,7,13,19-tetraoxa-4,10,16,22-tetraazacoronand, 2.
+
the bridging chains and the spacer between the two NH3
groups.7-9
In previous studies, concerning the synthesis of new
macropolycyclic lipophilic receptors capable of forming
very stable and selective complexes with sodium cation,
we have isolated, in only 5% yield, a new compound:
4,16-di-p-toluenesulfonyl-10,22-dibenzyl-1,7,13,19-tetraoxa-
4,10,16,22-tetraazacyclotetracosane (1) deriving from a
two plus two condensation pathway (eq 1).10
The main features of 1 are (i) the presence of eight
binding sites, four nitrogens and four oxygens, alternat-
ing in a 24-membered macrocyclic structure; (ii) the four
(1) Lehn, J .-M. Supramolecular Chemistry; VCH: Weinheim, Ger-
many, 1995.
(2) Lehn, J .-M. Structure Bonding 1973, 16, 1-70.
(3) Izatt, R. M.; Bradshaw, J . S.; Nielsen, S. A.; Lamb, J . D.;
Christiansen, J . J .; Sen, D. Chem. Rev. 1985, 85, 271-339.
(4) Lehn, J .-M.; Vierling, P. Tetrahedron Lett. 1980, 21, 1323.
(5) Vinogradov, S. N.; Linnel, R. H. Hydrogen Bonding; Van Nos-
trand Reinhold Co.: New York, 1971; Chapter 5.
(6) Graf, E.; Lehn, J .-M. Helv. Chim. Acta 1981, 64, 1040.
(7) Pascard, C.; Riche, C.; Cesario, M.; Kotzyba-Hibert, F.; Lehn,
J .-M. J . Chem. Soc., Chem. Commun. 1982, 557.
(8) Fages, F.; Desvergne, J . P.; Kampke, K.; Bouas-Laurent, H.;
Lehn, J .-M.; Meyer, M.; Albrecht-Gary, A. M. J . Am. Chem. Soc. 1993,
115, 3658.
(9) Ballardini, R.; Balzani, V.; Credi, A.; Gandolfi, M. T.; Kotzyba-
Hibert, F.; Lehn, J .-M.; Prodi, L. J . Am. Chem. Soc. 1994, 116, 5941.
(10) Anelli, P. L.; Montanari, F.; Quici, S.; Ciani, G.; Sironi, A. J .
Org. Chem. 1988, 53, 5292.
The synthesis of the fully deprotected tetraazacoronand
3 is reported in Scheme 2.
(11) Bradshaw, J . S.; Krakowiak, K. E.; Izatt, R. M. Azacrown
Macrocycles. Heterocyclic Compounds; Interscience Publ., J . Wiley:
New York, 1993; Vol. 51.
(12) Unexpectedly when the condensation was carried out with the
di-p-toluenesulfonyl derivative 10 (Scheme 2), the isolated yield of 1
was very low.
(13) Quici, S.; Manfredi, A.; Raimondi, L.; Sironi, A. J . Org. Chem.
1995, 60, 6379.
S0022-3263(95)02283-3 CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 11, 1996 3871
Sch em e 1
Sch em e 2
The tetratosyl derivative 11, prepared by condensation
(see the Experimental Section). Values of the extent of
complexation of 2, 3, and 14 are reported in Table 1, in
comparison with those obtained by using [18]-N2O4 15
as ligand.
of 9 and 10 in DMF at 100 °C and isolated in 50% yield
after column chromatography, was reacted with LiAlH4
in THF at reflux for 48 h, giving pure 3 in quantitative
yield.
The preparation of a macrobicyclic receptor using
tetraoxatetraaza coronand 1 as building block (Scheme
3) was achieved in three steps, namely (i) catalytic
debenzylation of 1 which afford 12; (ii) condensation of
12 with 2-benzyl-1,3-propanediol bis(p-toluenesulfonate),
which provided the ditosylamido macrobicycle 13 in 60%
yield, after column chromatography; (iii) reductive de-
tosylation of 13 to give, quantitatively, 14.
Complexation experiments were carried out in solid/
liquid two-phase conditions by equilibrating, with mag-
netic stirring, equimolecular amounts of the ligand
dissolved in CH2Cl2 and solid ammonium, amino acid
ester hydrochlorides, or alkali metal salts for 2 h at rt
As expected, the tetraazamacrocyclic ligands are better
complexing agents for ammonium cations than the diaza
derivative. This efficiency is demonstrated by comparing,
in the series of ammonium halides, the extents of
complexation of ligand 3 (94% for NH4Cl and 100% for
NH4Br and NH4I) and those of 15 which are 6%, 8%, and
15% for NH4Cl, NH4Br, and NH4I, respectively. A small
increase in the extent of complexation is observed with
the latter ligand when amino acid ester hydrochlorides
are used, and this is likely due to the higher overall
lipophilic character of the cation. An alternative ex-
planation of the increased affinity of the amino acid ester
hydrochlorides is a possible role of an additional hydrogen
bond to the ester unit from the macrocycles.

3872 J . Org. Chem., Vol. 61, No. 11, 1996
Notes
Sch em e 3
KCl, and KBr the obtained values are quite low, ranging
from 10% to 23% solubilization for tetraaza macrocycles
and from 2% to 6% for [18]-N2O4. The extents of
complexation observed for NaBr (15%, 35%, 44%, and
54% for 15, 3, 2, and 14, respectively), likely seem to
reflect the flexibility/rigidity balance 3 > 2 > 14; indeed
higher rigidity tends to reduce the molecular cavity and
allows preference for small cations. In fact, in any case,
Na+ is favored over K+, the highest values being observed
for the more rigid macrobicyclic system 14.
Exp er im en ta l Section 14
1,11-Dip h th a lim id o-6-p-tolu en esu lfon yl-3,9-d ioxa -6-a za -
u n d eca n e (5). A solution of 6-p-toluenesulfonyl-3,9-dioxa-1,11-
undecanediol bis(methanesulfonate) 4 (10.38 g, 20.6 mmol) and
potassium phthalimide (8.4 g, 45.3 mmol) in 250 mL of dry DMF
was stirred at 110 °C for 2 days. The reaction mixture was
allowed to cool to rt, and the solvent was evaporated under
reduced pressure. The residue was dissolved in 150 mL of
CH2Cl2, and the white potassium methanesulfonate precipitate
was filtered off. Evaporation of the solvent afforded a thick
orange oily residue which was crystallized with 96% EtOH to
give 5 (10 g, 80%) as a white solid: mp ) 108-110 °C; 1H NMR
(CDCl3) δ 2.37 (s, 3H), 3.28 (t, 4H, J ) 5.8 Hz), 3.45-3.60 (m,
8H), 3.81 (t, 4H, J ) 5.8 Hz), 7.20 (d, 2H, J ) 8.2 Hz), 7.61 (d,
2H, J ) 8.2 Hz), 7.65-7.75 (m, 4H), 7.80-7.90 (m, 4H). Anal.
Calcd for C31H31N3O8S: C, 61.48; H, 5.16; N, 6.94. Found: C,
61.12; H, 5.00; N, 6.78.
Ta ble 1. Exten ts of Com p lexa tion of 2, 3, 14, a n d 15
u n d er Solid /Liqu id Tw o-P h a se Con d ition s
ligand (E (%)]b
saltsa
2
3
14
40
67
90
98
95
100
11
54
11
10
15
NH4Cl
NH4Br
NH4I
A
B
C
NaCl
NaBr
KCl
KBr
53
75
92
100
100
100
17
44
23
17
94
100
100
100
100
100
17
35
17
16
6
8
15
17
33
20
3
15
2
6
6-p-Tolu en esu lfon yl-3,9-d ioxa -1,6,11-tr ia za u n d eca n e (6).
A solution of diphthalimido derivative 5 (3.18 g, 5.25 mmol) in
100 mL of EtOH and hydrazine hydrate (2.7 mL, 52.5 mmol)
was heated to reflux with stirring for 5 h, with formation of
phthalhydrazide as a heavy white precipitate. The reaction
mixture was allowed to cool to rt and filtered, and the precipitate
was carefully washed with 20 mL of cold EtOH. Evaporation
of the combined filtrates under reduced pressure afforded 1.78
g (98%) of 6 as a light yellow viscous oil: 1H NMR (CDCl3) δ
2.35 (s, 3H), 2.75 (t, 4H, J ) 5.2 Hz), 3.34 (t, 4H, J ) 6.0 Hz),
3.37 (t, 4H, J ) 5.2 Hz), 3.56 (t, 4H, J ) 6.0 Hz), 7.25 (d, 2H, J
) 8.2 Hz), 7.66 (d, 2H, J ) 8.2 Hz). Anal. Calcd for
a
A ) L-serine methyl ester hydrochloride; B ) L-cysteine methyl
b
ester hydrochloride; C ) glycine methyl ester hydrochloride.
E
(%) ) [M⊂L)+X-]/[L]0.
Values of extents of complexation of receptors 2, 3, and
14 with ammonium halides likely depend on a combina-
tion of several factors, namely (i) the nature of binding
sites responsible of hydrogen bonding (i.e., two tertiary
and two secondary amines for 2 and 14 and four second-
ary amines in the case of 3), (ii) the flexibility/rigidity
balance which is in the order 3 > 2 > 14, and (iii) the
lipophilicity of the counterion I > Br > Cl. The data here
reported are not sufficient to discriminate which one of
these factors is responsible for the decreased extent of
complexation of receptors 2 and 14 with respect to 3.
Nevertheless the results obtained clearly evidence that
the novel [24]-N4O4 macrocycles exhibit a good selectivity
for complexation of ammonium and amine salts in
comparison with the [18]-N2O4 ligand. Although all
measurements were carried out at a fixed time, and the
dependence of extraction with time has not been consid-
ered, we do not believe that the lower extraction capabil-
ity of 15 is due to a slower complexation process. This
seems more likely in the case of rigid macropolycyclic
receptors which require major conformational changes
in order to have maximum interactions between binding
sites and substrate. Indeed it must be stressed that in
all the experiments a solid salt/ligand ratio ) 1 was used;
thus no mass effect could be expected and the reported
values evidence the real strength of the receptor for
complexation.
C
15H27N3O4S: C, 52.15; H, 7.88; N, 12.16. Found: C, 52.40; H,
7.79; N, 11.80.
1,11-Bis(b e n zylim in o)-6-p -t olu e n e su lfon yl-3,9-d ioxa -
1,6,11-tr ia za u n d eca n e (7). A solution of diamine 6 (5.44 g,
15.7 mmol) and benzaldehyde (3.33 g, 31.4 mmol) in 100 mL of
benzene was heated to reflux in a Dean-Stark apparatus, with
stirring, for 4 h. During this time the theoretical amounts of
H2O (0.56 mL) separated. The solvent was evaporated under
reduced pressure to afford 8.1 g (quantitative yield) of 7 as a
viscous oil: 1H NMR (CDCl3) δ 2.36 (s, 3H), 3.31 (t, 4H, J ) 6.0
Hz), 3.53 (t, 4H, J ) 6.0 Hz), 3.58-3.64 (m, 4H), 3.64-3.70 (m,
4H), 7.20 (d, 2H, J ) 8.2 Hz), 7.32-7.39 (m, 6H), 7.62 (d, 2H, J
) 8.2 Hz), 7.66-7.71 (m, 4H), 8.20 (s, 2H). Anal. Calcd for
C
29H35N3O4S: C, 66.77; H, 6.76; N, 8.05. Found: C, 66.52; H,
6.48; N, 7.92.
1,11-Dib en zyl-6-p -t olu en esu lfon yl-3,9-d ioxa -1,6,11-t r i-
a za u n d eca n e (8). A solution of the diimino derivative 7 (8.2
g, 15.7 mmol) in 120 mL of CH3COOH was hydrogenated at rt
and atmospheric pressure in the presence of PtO2 (100 mg, 0.44
mmol). The reaction was complete in 6 h, during which time a
theoretical amount of H2 (700 mL) was absorbed. The reaction
mixture was filtered through Celite and the solvent evaporated
under reduced pressure. The residue was dissolved in 100 mL
of H2O, the pH was made alkaline with 30% aqueous NaOH and
extracted with CH2Cl2 (3 × 50 mL), and the combined organic
phases were dried over MgSO4 and evaporated to afford 8.0 g
(quantitative yield) of 8 as a colorless oil: 1H NMR (CDCl3) δ
1.70 (br s, 2H, D2O exchange), 2.35 (s, 3H), 2.73 (t, 4H, J ) 5.2
Hz), 3.35 (t, 4H, J ) 6.0 Hz), 3.49 (t, 4H, J ) 5.2 Hz), 3.56 (t,
4H, J ) 6.0 Hz), 3.77 (s, 4H), 7.20-7.35 (m, 12H), 7.68 (d, 2H,
J ) 8.2 Hz). Anal. Calcd for C29H39N3O4S: C, 66.26; H, 7.48;
N, 7.99. Found: C, 65.94; H, 7.18; N, 7.85.
In order to gain insights about complexation of alkali
cations we have investigated Na+ and K+ by using, for
both, chloride and bromide salts. In the case of NaCl,
(14) See refs 10 and 13 for a listing of general experimental details.

Notes
4,16-Di-p -t olu en esu lfon yl-10,22-d ib en zyl-1,7,13,19-t et -
J . Org. Chem., Vol. 61, No. 11, 1996 3873
(quantitative yield) of 3 as a pale yellow viscous oil: 1H NMR
(CDCl3) δ 2.20-2.40 (br s, 4H, D2O exchange), 2.73 (t, 16H, J )
5.0 Hz), 3.51 (t, 16 H, J ) 5.0 Hz); MS-FAB(+) m/z 348 (M+),
calcd for C16H36N4O4 348. Anal. Calcd for C16H36N4O4: C, 55.15;
H, 10.41; N, 16.07. Found: C, 55.05; H, 10.50; N, 16.11.
4,16-Di-p -t olu en esu lfon yl-1,7,13,19-t et r a oxa -4,10,16,22-
tetr a a za cyclotetr a cosa n e (12). A solution of 1 (2.6 g, 3.1
mmol) in 50 mL of CH3COOH was hydrogenated at rt and
atmospheric pressure in the presence of Pd/C, 5% (300 mg). The
reaction mixture was filtered through Celite and the solvent
evaporated under reduced pressure. The residue was dissolved
in 100 mL of CH2Cl2 and washed with 10% aqueous Na2CO3
and the solvent evaporated to give 1.77 g (87%) of 12 as a white
r aoxa-4,10,16,22-tetr aazacyclotetr acosan e (1). Solid Na2CO3
(10.1 g, 95.1 mmol) was added to a solution of the bis-
(benzylamino) derivative 8 (10 g, 19 mmol) and the diol bis-
(methanesulfonate) 4 (9.6 g, 19 mmol) in 220 mL of CH3CN, and
the resulting suspension was stirred at reflux for 4 days. The
reaction mixture was allowed to cool to rt and filtered through
Celite and the solvent evaporated to afford 16.5 g of the crude
product, as an orange viscous oil. Purification by column
chromatography (SiO2, CH2Cl2/CH3OH ) 95:5 v/v) afforded 7.1
1
g (45%) of pure 1: mp ) 128-130 °C; H NMR (CDCl3) δ 2.39
(s, 6H), 2.70 (t, 8H, J ) 5.8 Hz), 3.34 (t, 8H, J ) 5.8 Hz), 3.56 (t,
8H, J ) 5.8 Hz), 3.63 (s, 4H), 7.20-7.30 (m, 14H), 7.66 (d, 2H,
J ) 8.2 Hz); MS-FAB(+) m/z 836 (M+), calcd for C44H60N4O8S2
836. Anal. Calcd for C44H60N4O8S2: C, 63.13; H, 7.22; N, 6.69.
Found: C, 62.85; H, 6.91; N, 6.52.
1
solid: mp ) 95-96 °C; H NMR (CDCl3) δ 1.74 (br s, 2H, D2O
exchange), 2.40 (s, 6H), 2.73 (t, 8H, J ) 5.0 Hz), 3.36 (t, 8H, J
) 6.0 Hz), 3.49 (t, 8H, J ) 5.0 Hz), 3.58 (t, 8H, J ) 6.0 Hz), 7.27
(d, 4H, J ) 8.2 Hz), 7.67 (d, 2H, J ) 8.2 Hz); MS-FAB(+) m/z
656 (M+), calcd for C30H48N4O8S2 656. Anal. Calcd for
4,16-Dib en zyl-1,7,13,19-t et r a oxa -4,10,16,22-t et r a a za cy-
clotetr a cosa n e (2). A solution of 1 (0.5 g, 0.6 mmol) in 30 mL
of dry THF was slowly added to a magnetically stirred suspen-
sion of LiAlH4 (0.23 g, 5.97 mmol) in 30 mL of dry THF in an
inert atmosphere. After the addition was complete, the reaction
mixture was refluxed and stirred for 4 days and then allowed
to cool to rt, and the excess LiAlH4 was decomposed with the
stoicheometric amounts of H2O. The aluminum oxide was
filtered off and carefully washed with 50 mL of THF and the
solvent evaporated to afford 320 mg (quantitative yield) of 2 as
a colorless viscous oil: 1H NMR (CDCl3) δ 2.00 (br s, 2H, D2O
exchange), 2.50-2.90 (m, 16H), 3.30-3.60 (m, 16 H), 3.70 (s,
4H), 7.00-7.30 (m, 10H); MS-FAB(+) m/z 528 (M+), calcd for
C
30H48N4O8S2: C, 54.86; H, 7.37; N, 8.53. Found: C, 55.05; H,
7.50; N, 8.42.
26-Ben zyl-7,19-d i-p-tolu en esu lfon yl-4,10,16,22-tetr a oxa -
1,7,13,19-tetr a a za bicyclo[12.12.3]h ep ta cosa n e (13). Solid
Na2CO3 (1.57 g, 14.8 mmol) was added to a solution of 12 (0.97
g, 1.48 mmol) and 2-benzyl-1,3-propanediol bis(p-toluene-
sulfonate)13 (0.70 g, 1.48 mmol) in 80 mL of CH3CN, and the
resulting suspension was stirred at reflux for 6 days. The
reaction mixture was allowed to cool to rt and filtered through
Celite. The Celite was carefully washed with 50 mL of CH2Cl2,
and the combined filtrates were evaporated. Purification of the
residue by column chromatography (SiO2, CHCl3/CH3OH ) 90:
10 v/v) gave 0.48 g of pure 13: mp ) 167-170 °C; 1H NMR
(CDCl3) δ 1.95-2.05 (m, 1H), 2.40 (s, 3H), 2.42 (s, 3H), 2.50-
2.90 (m, 14H), 3.15-3.95 (m, 24H), 7.10-7.40 (m, 9H), 7.60-
C
30H48N4O4 528. Anal. Calcd for C30H48N4O4: C, 68.15; H, 9.15;
N, 10.60. Found: C, 67.95; H, 8.98; N, 10.37.
1,6,11-Tr i-p -t olu e n e su lfon yl-3,9-d ioxa -1,6,11-t r ia za -
u n d eca n e (9). A solution of p-toluenesulfonyl chloride (2.06 g,
10 8 mmol) in 10 mL of dry pyridine was slowly added to a
magnetically stirred solution of the diamine 6 in 30 mL of dry
pyridine, keeping the temperature below 5 °C. After the addition
was complete, the reaction mixture was stirred at 0 °C for
further 2 h and then was left overnight in the refrigerator. The
mixture was poured in 100 g of crushed ice containing 40 mL of
37% aqueous HCl and extracted with CH2Cl2 (3 × 30 mL). The
combined organic phases were washed with 50 mL of H2O and
50 mL of 5% aqueous NaHCO3, dried over MgSO4, and evapo-
rated to afford 3.55 g of a viscous brown oil. Purification by
column chromatography (SiO2, CH2Cl2/CH3OH, 99:1 v/v) gave
2.17 g (64%) of 9 as a viscous oil: 1H NMR (CDCl3) δ 2.36 (s,
6H), 2.38 (s, 3H), 3.04 (t, 2H, J ) 5.2 Hz), 3.06 (t, 2H, J ) 5.2
Hz), 3.21 (t, 4H, J ) 5.2 Hz), 3.42 (t, 4H, J ) 4.9 Hz), 3.50 (t,
4H, J ) 5.2 Hz), 5.67 (t, 2H, D2O exchange, J ) 6.0 Hz), 7.25 (d,
4H, J ) 8.2 Hz), 7.27 (d, 2H, J ) 8.2 Hz), 7.64 (d, 2H, J ) 8.2
Hz), 7.71 (d, 4H, J ) 8.2 Hz). Anal. Calcd for C29H39N3O8S3:
C, 53.27; H, 6.01; N, 6.43. Found: C, 53.02; H, 5.80; N, 6.22.
4,10,16,22-Tet r a -p -t olu en esu lfon yl-1,7,13,19-t et r a oxa -
4,10,16,22-tetr a a za cyclotetr a cosa n e (11). Solid K2CO3 (2.16
g, 15.65 mmol) was added to a solution of tri-p-toluenesulfon-
amido derivative 9 (2.05 g, 3.13 mmol) and the bis(p-toluene-
sulfonate) 10 (2.06 g, 3.13 mmol) in 60 mL of DMF, and the
resulting suspension was stirred at 100 °C for 4 days. After this
time the reaction mixture was allowed to cool to rt and filtered
through Celite, the precipitate was carefully washed with 20 mL
of DMF, and the filtrates were evaporated to dryness under
reduced pressure to afford 3.1 g of a deep orange viscous oil.
Purification by column chromatography (SiO2, CH2Cl2/CH3OH,
97:3 v/v) afforded an oily product which solidified with acetone
giving 11 as a white solid: mp )149.5-151 °C; 1H NMR (CDCl3)
δ 2.41 (s, 12H), 3.29 (t, 16H, J ) 5.8 Hz), 3.53 (t, 16H, J ) 5.8
Hz), 7.29 (d, 8H, J ) 8.2 Hz), 7.66 (d, 8H, J ) 8.2 Hz); MS-
FAB(+) m/z 964 (M+), calcd for C44H60N4O12S4 964. Anal. Calcd
for C44H60N4O12S4: C, 54.75; H, 6.27; N, 5.80. Found: C, 53.60;
H, 6.15; N, 5.71.
7.72 (m, 4H); MS-FAB(+) m/z ) 810 (M + 1 + Na+), 787 (M+
1), calcd for 40H58N4O8S2Na 809. Anal. Calcd for
40H58N4O8S2: C, 61.04; H, 7.43; N, 7.12. Found: C, 60.92; H,
+
C
C
7.30; N, 6.87.
26-Ben zyl-4,10,16,22-tetr a oxa -1,7,13,19-tetr a a za bicyclo-
[12.12.3]h ep ta cosa n e (14). A solution of 13 (0.45 g, 0.57 mmol)
in 30 mL of dry THF was slowly added to a stirred suspension
of LiAlH4 (0.22 g, 5.70 mmol) in 20 mL of dry THF in an inert
atmosphere. The reaction mixture was refluxed and stirred for
3 days and then cooled to rt, and the excess LiAlH4 was
decomposed with the stoicheometric amounts of H2O. The
aluminum oxide was filtered off and carefully washed with 50
mL of THF and the solvent evaporated to afford 270 mg
(quantitative yield) of pure 14 as viscous oil: 1H NMR (CDCl3)
δ 1.90-2.10 (m, 1H), 2.20-3.00 (m, 24H), 3.45-3.65 (m, 16 H),
7.00-7.30 (m, 5H); MS-FAB(+) m/z 501 (M + Na+), 478 (M+),
calcd for C26H46N4O4Na 501. Anal. Calcd for C26H46N4O4: C,
65.24; H, 9.69; N, 11.70. Found: C, 65.03; H, 9.55; N, 11.58.
Deter m in a tion of th e Exten t of Com p lexa tion . Into a
20 mL centrifuge test tube were introduced 5 mL of a 1.53 ×
10-2 M solution of the ligand (L) as free base in CH2Cl2, 7.65 ×
10-2 mmol of the solid salt, and a small magnetic stir bar. The
tube was stoppered to prevent evaporation, stirred for 2 h at 20
°C, and then centrifuged at 3000 rpm for 10 min. A 3 mL aliquot
of the organic solution was diluted with 30 mL of CH3OH,
acidified with 1 mL of 6 N HNO3, and potentially titrated with
1 × 10-2 N aqueous AgNO3. Extents of complexation percent,
E (%), are the ratio between the concentration of complexed
ligand [(M⊂L)+X-], which correspond to the amount of halide
measured in the organic phase, and the initial concentration of
the ligand used [L]0 (eq 2).
E (%) ) [(M⊂L)+X-]/[L]0
(2)
Experiments in the absence of ligands showed that all the salts
used are totally insoluble in CH2Cl2. Results are reported in
Table 1, values are within (5% error.
1,7,13,19-Tetr a oxa -4,10,16,22-tetr a a za cyclotetr a cosa n e
(3). A solution of 11 (3.68 g, 3.81 mmol) in 100 mL of dry THF
was slowly added to a stirred suspension of LiAlH4 (1.37 g, 76.24
mmol) in 40 mL of dry THF in an inert atmosphere. After the
addition was complete, the reaction mixture was refluxed and
stirred for 4 days and then allowed to cool to rt, and the excess
LiAlH4 was decomposed with the stoicheometric amounts of H2O.
The aluminum oxide was filtered off and carefully washed with
80 mL of THF and the solvent evaporated to afford 1.30 g
Ack n ow led gm en t. The authors wish to thank Mr.
Angelo Girola for recording 300 MHz NMR spectra and
the Progetto Strategico Tecnologie Chimiche Innovative
(CNR Roma) for financial support.
J O952283X