New macrocyclic ligands. VIII di- and tri-linked macrocyclic systems incorporating N2O2-donor atoms

Article abstract of DOI:10.1071/CH99054

The synthesis and characterization of new lipophilic di- and tri-linked O₂N₂-donor macrocycles is reported. The synthesis of the dilinked species involved the initial alkylation of one secondary nitrogen of the parent 15-membered, O<

Full text of DOI:10.1071/CH99054

C S I R O P U B L I S H I N G
Australian Journal
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Volume 52, 1999
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Aust. J. Chem., 1999, 52, 351–358
.
New Macrocyclic Ligands. VIII
Di- and Tri-linked Macrocyclic Systems
Incorporating N2O2-Donor Atoms
Ian M. Atkinson,A Davar M. Boghai,B Bahram Ghanbari,B,C
Leonard F. Lindoy,C,D George V. MeehanA,D and Vinod SainiA
A
School of Biomedical and Molecular Science, James Cook University,
Townsville, Qld. 4811.
B
Department of Chemistry, Sharif University of Technology,
P.O. 11365-8693, Tehran, Islamic Republic of Iran.
C
School of Chemistry, University of Sydney, Sydney, N.S.W. 2006.
Authors to whom correspondence should be addressed.
D
The synthesis and characterization of new lipophilic di- and tri-linked O2N2-donor macrocycles is
reported. The synthesis of the dilinked species involved the initial alkylation of one secondary nitrogen of
the parent 15-membered, O2N2-donor macrocycle (1) with 2-bromoethanol or with ethylene oxide to yield
(2), followed by protection of the appended alcohol group by reaction with t-butyldiphenylsilyl chloride
to give (3). Two such moieties were then bridged via a diacylation reaction with ClCO(CH2)8COCl to
yield the corresponding diamide product (4). Deprotection of the alcohol functions followed by reduction
of the both amide linkages resulted in formation of the N ,N 0-alkyl-linked species (5) incorporating
two pendant hydroxyethyl groups. This product was then converted [via the corresponding dichloro
derivative (6)] into the diether (7) by condensation with 4-t-butylphenol.
By use of analogous chemistry, the trilinked trismacrocycle species (12), based on a phloroglucinol
core, has also been synthesized. An aim of the present study was thus the preparation of new ‘linked’
macrocyclic systems that might be expected to show higher lipophilicity than their corresponding
single-ring systems. These were designed for future use as ionophores in metal ion membrane transport
(and solvent extraction) experiments.
Introduction
have now been reported.5 One interest in such systems
has re ected their potential for exhibiting cooperative
behaviour of the type found in particular metal-
loenzymes incorporating two metal centres.6 Recent
attention has also been given to such linked species
because of the observation that a number of such com-
pounds act as anti-HIV agents, while exhibiting low
cytotoxicity.7 Many linked mixed-donor macrocycles
are also known,4,8 although these are less common
than the all-nitrogen derivatives just mentioned.
We now report the synthesis of the new di- and tri-
linked (lipophilic) macrocycles (7) and (12) (Schemes 1
and 2, respectively). A motivation for this study was
to produce linked species that would prove suitable for
use as ionophores in solvent extraction studies for the
selective extraction of heavy metal ions. In particular,
it was of interest (and of potential industrial relevance)
to compare the performance of linked ionophores in
such studies relative to the behaviour of an equivalent
We have been interested in the design of macrocyclic
ring systems for the recognition of small molecules and
ions (and especially transition and post transition metal
ions).1 Recently, we have extended these studies to
the synthesis of structurally elaborated ligand systems
based on macrocyclic rings.2 Because of their often
unique properties,3 macrocyclic rings are desirable
moieties for incorporation in larger multicomponent
molecular systems since they often give rise to kinet-
ically and thermodynamically stable complexes that,
as a consequence, tend to retain their integrity under
a range of conditions.
One category of larger macrocyclic systems is com-
posed of linked ring ligands which are capable of
binding simultaneously to two or (less commonly)
more metal ions.4 For example, many covalently linked
bis(macrocyclic) ligands incorporating polyaza rings
Part VII, Aust. J. Chem., 1995, 48, 1917.
Manuscript received 4 May 1999
᭧ CSIRO 1999
0004-9425/99/050351$ 05.00
10.1071/CH99054

352
I. M. Atkinson et al.
concentration of the corresponding monomeric ana-
logue. For this purpose, the related single-ring species
(10) (Scheme 2) was also synthesized.
1-(2-bromoethoxy)-4-t-butylbenzene under similar con-
ditions to those just described resulted in formation
of (10), but in this case the yield after workup was
only 15%.
Pendant arm derivatives of the parent N2O2-donor
macrocycle (1), incorporating hydroxyethyl9 and 2-
pyridyl arms10 appended to the nitrogen donor(s) of
(1) have been synthesized previously in the authors’
laboratory. However, such ligands are not lipophilic
enough for ideal use as ionophores in membrane
(H2O/CHCl3/H2O) transport experiments (at least,
in the absence of a lipophilic anion). Thus, prelim-
inary experiments indicated11 that bleeding into the
aqueous receiving phase occurs when either of the
above ligands was used as the extractant in solvent
extraction (water/chloroform) experiments involving
the extraction of copper(II) nitrate into the chloroform
phase.
Linked Bismacrocycle (7)
A series of derivatives incorporating two linked
macrocyclic rings have been synthesized. Initially, an
attempt was made to0 link the silyl ether (protected)
species (3) in an N ,N -dialkylation procedure employ-
ing 1,6-dibromohexane. Under the conditions used
(acetonitrile/NaHCO3/60 C), this procedure failed to
produce the required product in acceptable yield.
Instead, a competing intramolecular alkylation on the
same ring nitrogen occurred to a ord the corresponding
single-ring (spiro) quaternary ammonium salt as the
major product. The latter was identi ed from its 1H
and 13C n.m.r. spectra (including an XHCORR, short-
range, n.m.r. experiment) coupled with identi cation of
bromide ion in the product. In contrast, a diacylation
procedure employing sebacoyl chloride as the linking
reagent was successful in producing the corresponding
linked-ring diamide system (4). The reaction was
performed in the presence of triethylamine and gave
(4) in high yield (c. 90%). The 1H and 13C n.m.r.
spectra of this compound were very complex, most
likely resulting from the presence of geometric isomers
(three possible) due to restricted rotation around the
amide C–N bonds. Subsequent reduction of the amide
groups with BH3.thf14 and hydrolysis of the silyl
protecting group during acid workup of the reaction
product, gave the diol (5) in c. 80% yield. The 1H
and 13C n.m.r. spectra of (5) were strictly comparable
to those of the related ‘monomeric’ precursor (2),
except for the presence of signals arising from the
10-carbon linker chain. F.a.b. mass spectrometry and
accurate peak matching of the parent ion subsequently
con rmed the ‘dimeric’ nature of (5).
Results and Discussion
Single-Ring Macrocycle (10)
The starting point for this synthesis was the N -
hydroxyethyl macrocycle (2)9 which has available both
a secondary amine and a primary alcohol site for
further functionalization (Scheme 2).
To ensure
selective reaction at the amine site, the alcohol
group was rst protected by formation of the cor-
responding t-butyldiphenylsilyl ether derivative (3);
the latter was obtained in 89% yield by reaction of
(2) with t-butyldiphenylsilyl chloride under standard
conditions.12 N -Alkylation of (3) with 1-iodoheptane
(acetonitrile/NaHCO3/60 C) was then carried out.
Cleavage of the silyl ether group of this prod-
uct was found to occur readily by acid hydrolysis
(MeOH/H2O/conc. HCl, 20 : 5 : 2). However, nucle-
ophilic cleavage (Bu4N+ F /tetrahydrofuran)13 proved
to be much less successful; only a very low yield of
the hydroxyethyl macrocycle (8) was isolated after
chromatographic workup in the latter case.
Conversion of (5) into the corresponding bis-4-t-
butylphenyl ether (7) was achieved (Scheme 1) by
the same procedure used for the preparation of the
‘monomeric’ analogue (10) (Scheme 2). Compound
(7) was obtained as a viscous oil in 33% yield after
chromatographic workup. As expected, the 1H and
13C n.m.r. spectra of this product were both quite
similar to those of (10).
Reaction of (8) with thionyl chloride in dichlorome-
thane gave the chlorinated derivative (9) in high
yield. This product was homogenous by t.l.c. and
was used without further puri cation since attempted
chromatography on silica gel led to decomposition.
The chloro derivative (9) was used to alkylate 4-
t-butylphenol (N ,N -dimethylformamide/NaI/caesium
carbonate/60 C) yielding the required ‘single-ring’
macrocycle (10) in 37% yield. Spectroscopic data
were in accord with the proposed structure; in par-
ticular, the success of the alkylation procedure was
indicated by the down eld shift of the carbinyl methy-
Trilinked Macrocycle (12)
The chloroethyl intermediate (9) (Scheme 2) was
also used to link three macrocycles of the present type
to a tritopic aromatic ‘core’. Thus, trialkylation of
phloroglucinol with (9) in N ,N -dimethylformamide in
the presence of caesium carbonate gave the ‘trimer’
lene (CH2CH2O) signal from
3 18 for the parent
hydroxyethyl macrocycle (2) to 3 99 for the phenyl
ether (10).
An alternative synthesis of (10) was also attempted
starting from the unsubstituted parent macrocycle (1).
Direct alkylation of (1) was performed by heating
it with 1-iodoheptane in the presence of NaHCO3
in acetonitrile. Reaction of this latter product with
1
(14) in moderate yield (34%). The H and 13C n.m.r.
spectra of (12) were in accord with the proposed
structure. Relative to the 1H n.m.r. spectrum of (9),
the spectrum of (12) contained a ‘new’ triplet at 3 94
for the phenyl ether methylene group (NCH2CH2OAr)

New Macrocyclic Ligands. VIII
353
Scheme 1. (i) Ethylene oxide, acetone (ref. 9); (ii) t-butyldiphenylsilyl chloride, 4-dimethylaminopyridine, triethyl-
amine, dichloromethane; (iii) sebacoyl chloride, triethylamine, dichloromethane, 0 C; (iv) borane/tetrahydrofuran,
re ux, then HCl/MeOH/H2O; (v) thionyl chloride, dichloromethane; (vi) 4-t-butylphenol, Cs2CO3, NaI, N ,N -
dimethylformamide, 60 C.

354
I. M. Atkinson et al.
Scheme 2. (i) See Scheme 1; (ii) see Scheme 1; (iii) 1-iodoheptane, NaHCO3, acetonitrile, 60 C; (iv) same as (iii); (v)
1-(2-bromoethoxy)-4-t-butylbenzene, NaHCO3, acetonitrile, 60 C; (vi) 2-bromoethanol, NaHCO3, acetonitrile, re ux; (vii)
HCl/MeOH/H2O, re ux; (viii) thionyl chloride, dichloromethane; (ix) 4-t-butylphenol, Cs2CO3/NaI, 60 C; (x) phloroglucinol,
Cs2CO3, N ,N -dimethylformamide, 60 C.

New Macrocyclic Ligands. VIII
355
ArCH2; 61 0, NCH2CH2O; 65 4, 66 5, OCH2CH2O, 110 8,
119 3, 120 4, 121 5, 125 4, 127 7, 129 4, 129 6, 131 3, 132 6,
133 0, 133 3, 135 6, 156 6, 156 9, aromatic C.
and a ‘new’ singlet at
6 01 for the phloroglucinol
aromatic proton. The ‘trimeric’ composition of (12)
was further con rmed by the presence of a molecular
ion peak (MH+) at m/z 1436 in its mass spectrum
(l.s.i.m.s.).
Acylation of (3) with Sebacoyl Chloride to Yield Linked
Derivative (4)
Macrocycle (3) (0 598 g, 1 0 mmol) and triethylamine
(0 167 ml, 1 2 mmol) were dissolved in dry dichloromethane
(5 ml) and cooled to 0 C in an ice bath. To this mixture was
added a solution of freshly distilled sebacoyl chloride (0 107 ml,
0 5 mmol) in dry dichloromethane (5 ml) via a syringe over
30 min. The mixture was stirred at room temperature for
3 h, while the reaction progress was followed by t.l.c. The
solvent was then removed on a rotary evaporator and the
resulting oil was distributed between dichloromethane (40 ml)
and H2O (20 ml). The aqueous layer was reextracted with
dichloromethane (2 20 ml). The combined dichloromethane
layers were dried (anhydrous Na2SO4) and the solvent was
removed by rotary evaporation. The resulting crude oil was
chromatographed on silica gel. Elution with CHCl3 and then
5% MeOH/CHCl3 a orded the linked macrocycle (4) as a
viscous oil (0 607 g, 89 5%), RF 0 44 (Found: C, 74 4; H,
Experimental
The 1H and 13C n.m.r. spectra were determined on Bruker
AM200 or AM300 spectrometers; all chemical shifts are rel-
ative to tetramethylsilane. All n.m.r. spectra were recorded
in (D)chloroform solution. Spectral assignments are based
on those given previously for the parent ring systems.15
High-resolution electron impact (e.i.) and liquid secondary ion
(l.s.i.) mass spectra were determined at the Central Science
Laboratory, University of Tasmania; high-resolution Fourier-
transform electrospray (e.s.) spectra were determined at the
Australian Institute of Marine Science, Townsville. The fast
atom bombardment (f.a.b.) spectrum was determined at the
Division of Energy and Fuel Technology, CSIRO, Lucas Heights
Laboratories.
All syntheses were carried out under nitrogen.
7 9; N, 4 0.
4 1%. Found (e.s.m.s.): m/z 1355 7659.
(MH+) requires 1355 7621). The 1H and 13C n.m.r. spectra of
(4) were in accordance with the proposed structure but were
too complex for unambiguous interpretation (see Results and
Discussion section).
C
84H106N4O8Si2 requires C, 74 4; H, 7 9; N,
84H107N4O8Si2
1-(2-Bromoethoxy)-4-t-butylbenzene
C
To a mixture of 4-t-butylphenol (18 03 g, 0 12 mol) and
1,2-dibromoethane (35 0 g, 0 19 mol) at the re ux was added
a solution of sodium hydroxide (5 4 g, 0 13 mol) in water
(38 ml) over 30 min. Re uxing was continued for 20 h, then the
reaction mixture was cooled to room temperature. The organic
phase was separated, and the aqueous phase was extracted with
dichloromethane (3 20 ml). The combined organic fractions
were then washed with 10% sodium hydroxide (10 ml), dried
(anhydrous Na2SO4), and distilled under vacuum. The pure
product was obtained as a colourless oil, b.p. 117 /0 02 mmHg;
yield 12 9 g, 42% (Found (e.s.m.s.): m/z 279 0349. C12H17BrO
(MNa+) requires 279 0355.) 1H n.m.r. 1 28, s, 9H, C(CH3)3;
3 55, t, 2H, OCH2CH2Br; 4 20, t, 2H, OCH2CH2Br; 6 8–7 3,
Reduction and Hydrolysis of (4) to Yield (5)
Linked macrocycle (4) (0 321 g, 0 24 mmol) was dissolved
in dry tetrahydrofuran (5 ml). To this solution was added
borane/tetrahydrofuran complex (1 5 ml, 0 48 mmol) dropwise
via a syringe over 20 min. The reaction mixture was re uxed for
6 h. The excess borane/tetrahydrofuran complex was destroyed
by the addition of MeOH (1 ml) and the solvent was removed by
rotary evaporation. To the residue, 10 ml of MeOH/H2O/conc.
HCl (20 : 5 : 2) were added and the mixture was re uxed for 1
h. The solvent was removed by rotary evaporation and the
residue partitioned between H2O (5 ml) and dichloromethane
(20 ml). The aqueous layer was basi ed with 2 M sodium
hydroxide to pH 11–12. The basi ed layer was extracted with
dichloromethane (3 20 ml) and the combined dichloromethane
extracts were dried (anhydrous Na2SO4). The solvent was then
removed by rotary evaporation. The resulting crude product
(5) (0 162 g, 79%) was homogenous by t.l.c. Final puri cation
was achieved by chromatography on silica gel. Elution with
CHCl3 and then 5% MeOH/CHCl3/0 5%NH4OH a orded (5)
as a viscous oil, RF 0 25 (10% MeOH/CHCl3/1%NH4OH)
(Found (e.s.m.s.): m/z 851 5674. C52H75N4O6 (MH+) requires
851 5681). Mass spectrum (f.a.b.) m/z 851 5, MH+ (82%),
281 1 (31), 133 0 (70), 107 1 (100). 1H n.m.r. 1 2–1 35,
m, 12H, NCH2CH2(CH2)6CH2CH2N; 1 65, br quin, 2 2H,
NCH2CH2(CH2)6; 1 77, quin, 2 2H, NCH2CH2CH2N; 2 47–
2 6, m, 2 6H, NCH2CH2CH2N, NCH2CH2(CH2)6; 2 70, t,
m, 4H, aromatic H. 13C n.m.r.
C(CH3)3; 33 9, C(CH3)3; 67 8, OCH2CH2Br; 114 1, 114 6,
126 2, 143 9, 155 7, aromatic C.
29 2, OCH2CH2Br; 31 4,
Protection of (2) to Yield (3)
Macrocycle (2)9 (0 713 g, 2 0 mmol), 4-dimethylamino-
pyridine (0 0269 g, 0 22 mmol) and triethylamine (0 340 ml,
2 40 mmol) were dissolved in dry dichloromethane (10 ml). To
this solution was added t-butyldiphenylsilyl chloride (0 58 ml,
2 30 mmol) dropwise via a syringe. The reaction mixture
was stirred at room temperature for 3 h and refrigerated
overnight. Extra dichloromethane (20 ml) and saturated aque-
ous NH4Cl solution (10 ml) were added, and the aqueous layer
was reextracted with dichloromethane (20 ml). The combined
dichloromethane extracts were dried (anhydrous Na2SO4) and
the solvent was removed by rotary evaporation. The result-
ing oil was chromatographed on silica gel. Elution with 5%
MeOH/CHCl3 a orded a colourless oil (1 06 g, 89%) which
crystallized upon addition of dry ether. The resulting solid
was recrystallized from acetonitrile and light petroleum to give
the silyl ether (3) as a colourless crystalline solid (as its 2 5
hydrate), m.p. 163–164 C, RF 0 73 (Found (e.i.m.s.): m/z
594 3281. C37H46N2O3Si (M+) requires 594 3278. Found: C,
69 4; H, 7 9; N, 4 0. C37H51N2O5 5Si requires C, 69 45; H,
2
2H, NCH2CH2OH; 3 49, s, 2 2H, ArCH2; 3 92, s, 2 2H,
ArCH2; 4 37, s, 2 4H, OCH2CH2OH; 6 9–7 3, m, 2 8H,
aromatic H. 13C n.m.r.
23 2, 26 2, 27 3, 29 4, 29 5,
CH2, NCH2CH2CH2CH2CH2, NCH2CH2CH2N; 50 8, 50 9,
5
51 2, 51 4, 54 0, 54 2, 6 CH2N; 58 6, NCH2CH2OH; 66 1,
OCH2CH2O; 110 7, 111 3, 120 5, 128 9, 129 8, 132 6, 132 8,
157 1, aromatic C.
8 0; N, 4 4%). I.r. (Nujol) 767, 939, 1245, 1600, 1692, 2918,
3015, 3312 cm
.
1H n.m.r. 1 00, s, 9H, SiC(CH3)3; 1 97,
1
Chlorination of (5) to Yield (6)
quin, 2H, NCH2CH2CH2N; 2 63, 2 71, 2 79, 3 br t, 3 2H,
NCH2CH2CH2N, NCH2CH2OSi; 3 58, t, 2H, NCH2CH2OSi;
3 67, 4 00, 2 s, 2 2H, ArCH2; 4 20, 4 36, 2 t, 2 2H,
OCH2CH2O; 6 70–7 61, m, 18H, aromatic H. 13C n.m.r.
19 0, SiC(CH3)3; 22 0, NCH2CH2CH2N; 26 8, SiC(CH3)3;
48 7, 49 3, NCH2CH2CH2NH; 52 7, NCH2CH2O; 53 5, 57 0,
Linked macrocycle (5) (1 06 g, 1 24 mmol) was dissolved in
dry dichloromethane (6 ml) and the solution was cooled (dry
ice/acetone bath). To this solution was added freshly distilled
thionyl chloride (0 5 ml, 6 78 mmol) dropwise via a syringe.
The reaction mixture was allowed to warm to room temperature

356
I. M. Atkinson et al.
over 3 h. Excess thionyl chloride was destroyed by the addition
of ethanol (0 235 ml, 4 24 mmol) and the solvent was removed
by rotary evaporation. The residue was partitioned between
2 M sodium hydroxide solution (15 ml) and dichloromethane
(25 ml) and the organic layer was separated and dried (anhy-
drous Na2SO4). The solvent was removed by rotary evaporation
to give the bismacrocycle (6) as a brown oil (0 744 g, 67%).
This product was shown to be homogeneous by t.l.c. and was
used without further puri cation. 1H n.m.r. 1 2–1 35, br,
m, 12H, NCH2CH2(CH2)6CH2CH2N; 1 49, br quin, 2 2H,
NCH2CH2CH2; 1 64, quin, 2 2H, NCH2CH2CH2N; 2 3–2 5,
m, 2 6H, NCH2CH2CH2N, NCH2CH2(CH2)6; 2 79, t, 2 2H,
NCH2CH2Cl; 3 65, s, 2 2H, ArCH2; 3 68, s, 2 2H, ArCH2;
4 34, br s, 2 4H, OCH2CH2O; 6 9–7 3, m, 2 8H, aromatic H.
13C n.m.r. 23 6, 27 1, 27 5, 29 6, NCH2CH2CH2CH2CH2,
NCH2CH2CH2; 42 0, NCH2CH2Cl; 51 2, 51 4, 52 1, 53 1,
53 4, 55 7, 6 CH2N; 66 5, OCH2CH2O; 110 8, 110 9, 120 5,
127 3, 128 2, 128 5, 131 8, 132 4, 157 0, 157 1, aromatic C.
2
br t, 2 2H, NCH2CH2CH2N; 3 61, t, 2H, NCH2CH2OSi;
3 67, 4 25, 2 s, 2 2H, ArCH2; 4 27, 4 37, 2 br t, 2 2H,
OCH2CH2O; 6 77–7 77, m, 18H, aromatic H. 13C n.m.r.
13 7, CH2CH3; 18 8, SiC(CH3)3; 21 7, 22 3, 23 3, 26 5, 28 5,
31 3, 6 CH2, CH3(CH2)4CH2CH2N, NCH2CH2CH2N; 51 3,
51 6, 52 6, 52 7, 54 3, 55 6, 6 CH2N; 60 5, NCH2CH2O;
66 2, 66 6, OCH2CH2O; 110 9, 111 2, 118 1, 120 7, 121 4,
125 7, 127 6, 129 3, 129 7, 131 5, 132 2, 133 7, 135 4, 156 6,
157 0, aromatic C.
The above product (1 94 g) was dissolved in 20 ml of
MeOH/H2O/conc. HCl (20 : 5 : 2) and the solution was heated
at re ux for 1 h. The solvent was removed by rotary evaporation
and the residue taken up in water (10 ml). The aqueous layer
was extracted with dichloromethane (3 20 ml) and then basi-
ed with 2 M NaOH solution to pH 11–12. The basi ed layer
was extracted with dichloromethane (3 20 ml), and combined
dichloromethane phases were dried (anhydrous Na2SO4) and the
solvent was removed by rotary evaporation. The crude hydrox-
yethyl macrocycle (8) (1 34 g) which resulted was homogeneous
by t.l.c. Final puri cation was achieved by chromatography
on silica gel (10% MeOH/CHCl3) to a ord (8) as a yellow
oil, RF 0 45 (Found (e.i.m.s.): m/z 454 3190. C28H42N2O3
(M+) requires 454 3195). 1H n.m.r. 0 88, t, 3H, CH2CH3;
1 2–1 35, m, 8H, NCH2CH2(CH2)4CH3; 1 53, br quin, 2H,
NCH2CH2(CH2)4CH3; 1 64, quin, 2H, NCH2CH2CH2N; 2 3–
2 6, m, 8H, NCH2CH2CH2, NCH2CH2(CH2)4CH3, NCH2-
CH2OH; 3 48, t, 2H, NCH2CH2OH; 3 64, 3 75; 2 s, 2 2H,
ArCH2; 4 36, s, 2 2H, OCH2CH2O; 6 88–7 27, m, 8H, aro-
matic H. 13C n.m.r. 14 0, CH2CH3; 22 6, 23 6, 26 8, 27 4,
29 1, 31 8, 6 CH2, CH3(CH2)4CH2CH2N, NCH2CH2CH2N;
Linked Macrocycle (7)
Linked macrocycle (6) (2 31 g, 2 60 mmol) was dissolved
in dry N ,N -dimethylformamide (15 ml). To this solution were
added 4-t-butylphenol (1 20 g, 7 80 mmol), caesium carbonate
(2 54 g, 7 80 mmol) and sodium iodide (0 050 g). The reaction
mixture was stirred at 60 C for 48 h and the solvent was then
removed by rotary evaporation. The residue was dissolved
in dichloromethane (50 ml). This solution was washed with
10% sodium hydroxide (50 ml) and the aqueous layer was
reextracted with dichloromethane (3 20 ml). The combined
dichloromethane extracts were dried (anhydrous Na2SO4) and
the solvent was removed by rotary evaporation to give a brown oil,
which was puri ed by chromatography on silica gel. Elution with
CHCl3 and then 3% MeOH/CHCl3 a orded linked macrocycle
(7) as a light brown oil (1 06 g, 33%), RF 0 35 (Found (e.s.m.s.):
m/z 1115 7565. C72H99N4O6 (MH+) requires 1115 7486). 1H
n.m.r. 1 2–1 25, m, 12H, NCH2CH2(CH2)6CH2CH2N; 1 28,
s, 18H, C(CH3)3; 1 53, quin, 2 2H, NCH2CH2CH2; 1 73, quin,
50 7, 50 8, 51 3, 51 7, 53 8, 54 15,
6 CH2N; 58 8,
NCH2CH2O; 66 0, 66 2, OCH2CH2O; 110 7, 111 1, 120 4,
120 5, 124 8, 126 3, 128 8, 129 9, 132 5, 132 6, aromatic C.
(B) Directly from (11). Derivative (11) as its HI salt (0 90
g, 2 0 mmol) was dissolved in acetonitrile (50 ml) to which
were added sodium bicarbonate (0 48 g, 5 7 mmol) and 2-
bromoethanol (1 8 g, 14 4 mmol). The mixture was re uxed
for 72 h, and the solvent was then removed under vacuum.
The residue oil was dissolved in dichloromethane (50 ml) and
this solution was washed with 10% sodium hydroxide (20 ml).
The combined dichloromethane layers were dried (anhydrous
Na2SO4) and the solvent was removed by rotary evaporation.
The resultant oil was chromatographed on silica gel (10%
MeOH/CHCl3) to a ord (8) as a yellow oil (0 15 g, 20%).
The 1H and 13C n.m.r. spectra of this product were identical
to those of the product obtained from preparation (A).
2
2H, NCH2CH2CH2N; 2 4–2 6, m, 2 6H, NCH2CH2CH2N,
NCH2CH2CH2; 2 88, t, 2 2H, NCH2CH2O; 3 6–3 8, m,
8H, ArCH2; 3 97, t, 2H, NCH2CH2O; 4 3–4 4, br s,
2
8H, OCH2CH2O; 6 75–7 29, m, 24H, aromatics. 13C n.m.r.
23 0, 26 7, 27 4, 29 5, 5 CH2, NCH2CH2CH2CH2CH2,
NCH2CH2CH2N; 31 5, C(CH3)3; 34 0, C(CH3)3; 51 2, 51 4,
51 5, 53 4, 6 CH2N; 66 5, 66 6, NCH2CH2O, OCH2CH2O;
110 9, 111 0, 113 9, 120 5, 120 6, 126 1, 128 4, 132 1, 157 0,
aromatics.
Macrocycle (8)
Chlorination of (8) to Yield (9)
(A) From the silyl-protected species (3). Macrocycle (3)
(2 38 g, 4 0 mmol) was dissolved in dry acetonitrile (40 ml).
To this warm solution were added 1-iodoheptane (1 31 ml, 5 2
mmol) and NaHCO3 (0 672 g, 8 8 mmol) and the solution was
stirred at 60 C for 3 h, then stored in a refrigerator overnight.
The solvent was removed by rotary evaporation and the
resulting oil was distributed between dichloromethane (160 ml)
and H2O (80 ml). The aqueous layer was reextracted with
dichloromethane (2 80 ml), and the combined dichloromethane
phases were washed with saturated NaCl solution (120 ml) and
then with 0 1 M sodium thiosulfate solution (160 ml). The
organic phase was dried (anhydrous Na2SO4) and the solvent
removed by rotary evaporation. The resulting crude oil was chro-
matographed on silica gel. Elution with 2 5% MeOH/CHCl3
a orded the N -heptyl derivative of the silyl-protected species
(3) as a viscous oil (2 04 g), RF 0 52 (Found (l.s.i.m.s.):
m/z 693 4444. C44H61N2O3Si (MH+) requires 693 4451). 1H
Macrocycle (8) (0 909 g, 2 0 mmol) was dissolved in dry
dichloromethane (10 ml) and the solution was chilled (dry
ice/acetone bath). To this chilled solution was added freshly dis-
tilled thionyl chloride (0 25 ml, 3 47 mmol) dropwise by means
of a syringe. The reaction mixture was allowed to warm to room
temperature over 3 h. The excess thionyl chloride was destroyed
by addition of ethanol (0 26 ml, 4 42 mmol) and the solvent was
removed by rotary evaporation. The residue was distributed
between 2 M NaOH (10 ml) and dichloromethane (20 ml) and the
aqueous layer was reextracted with dichloromethane (3 20 ml).
The combined dichloromethane phases were dried (anhydrous
Na2SO4) and the solvent was removed by rotary evaporation
to give the chloroethyl macrocycle (9) as a brown oil (0 921 g,
94%). This material was homogeneous by t.l.c. and was used
without further puri cation. 1H n.m.r. 0 88, t, 3H, CH2CH3;
1 2–1 35, m, 8H, NCH2CH2(CH2)2CH3; 1 49, br quin, 2H,
NCH2CH2(CH2)4CH3; 1 63, quin, 2H, NCH2CH2CH2N; 2 35–
2 55, m, 8H, NCH2CH2CH2, NCH2CH2(CH2)4CH3; 2 83, t,
2H, NCH2CH2Cl; 3 41, t, 2H, NCH2CH2Cl; 3 63, 3 69, 2 s,
n.m.r.
0 85, t, 3H, CH2CH3; 1 04, s, 9H, SiC(CH3)3;
1 2–1 35, m, 8H, NCH2CH2(CH2)4CH3; 1 60, br quin,
NCH2CH2(CH2)4CH3; 1 65, quin, 2H, NCH2CH2CH2N; 2 5–
2 65, m, 4H, NCH2CH2(CH2)4CH3, NCH2CH2OSi; 2 82, 3 10,
2
2H, ArCH2; 4 35, s, 4H, OCH2CH2O; 6 86–7 27, m, 8H,
aromatic H. 13C n.m.r. 14 1, CH2CH3; 22 6, 23 8, 27 4, 27 5,

New Macrocyclic Ligands. VIII
357
29 2, 31 9, 6 CH2, CH3(CH2)4CH2CH2N, NCH2CH2CH2N;
42 0, 51 3, 51 4, 52 1, 53 6, 55 8, 6 CH2N; 66 5, 2 CH2,
OCH2CH2O; 110 8, 111 9, 120 3, 127 3, 128 1, 128 4, 131 8,
132 3, 157 0, aromatic C.
58 0; H, 7 3; N, 5 5%). Mass spectrum (e.s.) m/z 411 3,
MH+. 1H n.m.r. 0 85, t, 3H, CH2CH3; c. 1 0–1 3, m, 10H,
NCH2(CH2)5CH3; 1 50, br quin, 2H, NCH2CH2(CH2)4CH3;
2 1, quin, 2H, NCH2CH2CH2N; 2 47, 2 57, 2 96, 3 t, 3 2H,
NCH2CH2CH2N, NCH2CH2(CH2)4CH3; 3 50, 4 07,
2 s,
2
2H, ArCH2; 4 45, m, 4H, OCH2CH2O; 6 89–7 71, m, 8H,
Macrocycle (10)
aromatic H. 13C n.m.r. 13 7, CH2CH3; 21 6, 22 2, 26 5, 28 4,
28 6, 31 1, 6 CH2, CH3(CH2)4CH2CH2N, NCH2CH2CH2N;
48 4, 50 2, 53 2, 53 6, 55 7, 5 CH2N; 66 4, 66 5, 2 CH2,
OCH2CH2O; 110 7, 110 8, 119 8, 120 2, 121 0, 123 0, 129 6,
131 0, 132 7, 132 8, 156 5, 156 6, aromatic C.
(A) Reaction of 4-t-butylphenol with chloroethyl macrocycle
(9) to yield (10). The chloroethyl macrocycle (9) (0 473 g,
1 0 mmol) was dissolved in dry N ,N -dimethylformamide (5 ml).
To this solution were added 4-t-butylphenol (0 167 g, 1 1 mmol),
caesium carbonate (0 360 g, 1 1 mmol) and sodium iodide
(0 015 g). The reaction mixture was stirred at 60 C for 48 h.
The solvent was then removed by rotary evaporation. The resid-
ual oil was dissolved in dichloromethane (20 ml). This solution
was washed with 10% sodium hydroxide solution (40 ml) and the
aqueous layer was re-extracted with dichloromethane (3 15 ml).
The combined dichloromethane phases were dried (anhydrous
Na2SO4) and the solvent was removed by rotary evaporation
to yield a brown oil (0 5 g). This material was puri ed by
chromatography on silica gel (elution with CHCl3 and then 3%
MeOH/CHCl3) to a ord the 4-t-butylphenol ether (10) as a brown
oil (0 221 g, 37%), RF 0 46 (Found (e.s.m.s.): m/z 587 4216.
Trilinked Macrocycle (12)
Macrocycle (9) (0 71 g, 1 5 mmol) was dissolved in dry
N ,N -dimethylformamide (10 ml). To this solution were added
phloroglucinol (0 058 g, 0 46 mmol) and caesium carbonate
(0 49 g, 1 5 mmol). The reaction mixture was stirred at 60 C
for 48 h. The solvent was removed by rotary evaporation
and the residual oil was dissolved in dichloromethane (50 ml).
This solution was washed with 10% sodium hydroxide (75 ml)
and the aqueous layer was extracted with dichloromethane
(3 20 ml). The combined dichloromethane phases were washed
with H2O (100 ml), dried (anhydrous Na2SO4) and the sol-
vent was removed by rotary evaporation. The resulting oil
was puri ed by chromatography on silica gel (elution with
CHCl3 and then 5% MeOH/CHCl3) to give trilinked macro-
cycle (12) as a brown oil (0 22 g, 34%), RF 0 16 (Found
C
38H55N2O3 (MH+) requires 587 4207). 1H n.m.r. 0 87, t,
3H, CH2CH3; 1 2–1 35, m, 8H, NCH2CH2(CH2)4CH3; 1 29,
s, C(CH3)3; 1 50, br quin, 2H, NCH2CH2(CH2)4CH3; 1 71,
quin, 2H, NCH2CH2CH2N; 2 40–2 60, m, 6H, NCH2CH2CH2N,
NCH2CH2(CH2)4CH3; 2 89, t, 2H, NCH2CH2O; 3 68, 3 71,
(l.s.i.m.s.): m/z 1435 9453.
1435 9665). 1H n.m.r.
C
90H127N6O9 (MH+) requires
0 86, t, 3 3H, CH2CH3, 1 15–
2
s, 2 2H, ArCH2; 3 99, t, 2H, NCH2CH2O; 4 33–4 35, m,
4H, OCH2CH2O, 6 77–7 30, m, 12H, aromatic H. 13C n.m.r.
14 1, CH2CH3; 22 6, 23 2, 27 3, 27 5, 29 3, 31 9, 6 CH2,
CH3(CH2)4CH2CH2N, NCH2CH2CH2N; 31 5, C(CH3)3; 34 0,
C(CH3)3; 51 2, 51 5, 52 4, 52 6, 52 8, 53 7, 6 CH2N; 66 6,
66 7, 3 CH2, OCH2CH2O, NCH2CH2O; 110 9, 111 0, 114 0,
120 5, 126 1, 127 6, 128 0, 128 2, 132 1, 143 1, 156 6, 157 0,
157 1, aromatic C.
1 35, m, 3 8H, CH3(CH2)4CH2CH2N; 1 49, br quin, 3 2H,
CH3(CH2)4CH2CH2N; 1 70, quin, 3 2H, NCH2CH2CH2N;
2 35–2 55, m, 3 6H, NCH2CH2CH2N, CH3(CH2)4CH2CH2N;
2 88, t, 3 2H, NCH2CH2O; 3 66, br s, 3 2H, ArCH2; 3 75, br
s, 3 2H, ArCH2, 3 94, t, 3 2H, NCH2CH2O; 4 33, br s, 3 4H,
OCH2CH2O; 6 01, s, 3H, C6H3; 6 80–7 30, m, 24H, aromatic H.
13C n.m.r. 14 0, C(CH3)3; 22 5, 23 1, 26 9, 27 3, 29 1, 31 7,
NCH2(CH2)4CH2CH3, NCH2CH2CH2N; 51 2, 51 4, 52 2,
52 8, 53 5, 6 CH2N; 66 5, 66 6, NCH2CH2O, OCH2CH2O;
93 9, phloroglucinol CH; 110 8, 110 9, 120 4, 127 4, 128 2,
131 9, 132 1, 156 9, 157 0, 160 54, remaining aromatic C.
(B) Alternative synthesis of (10). In a second procedure
(10) was prepared as follows: (11) as its HI salt (0 245
g, 0 54 mmol) was dissolved in acetonitrile (15 ml) to which
were added sodium bicarbonate (0 084 g, 1 0 mmol) and 1-
(2-bromoethoxy)-4-t-butylbenzene (0 33 g, 1 3 mmol). The
mixture was stirred at 60 C for 24 h and the solvent was
then removed under vacuum. The residual oil was dissolved in
dichloromethane (50 ml). The solution was washed with 10%
sodium hydroxide (10 ml). The combined dichloromethane
phases were dried (anhydrous Na2SO4) and the solvent was
removed by rotary evaporation. The resultant oil was chro-
matographed on silica gel: rst eluted by CHCl3 and then 3%
MeOH/CHCl3 to a ord (10) as a yellow oil (0 15 g, 15%).
The 1H and 13C n.m.r. spectra of this product were identical
to those obtained for the product obtained from preparation
(A).
Acknowledgments
B.G. wishes to thank the Ministry of Culture and
Higher Education of Iran for a scholarship to visit
the University of Sydney. We thank the Australian
Research Council for support.
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