Inherently chiral uranyl-salophen macrocycles: Computer-aided design and resolution

Article abstract of DOI:10.1021/jo0515430

A flipping motion rapidly inverts the bent structure of uranyl-salophen compounds and, consequently, causes fast enantiomerization of nonsymmetrically substituted derivatives. This process has been previously slowed by introducing bulky substituents in th

Full text of DOI:10.1021/jo0515430

Inherently Chiral Uranyl-Salophen Macrocycles: Computer-Aided
Design and Resolution
Antonella Dalla Cort,* Luigi Mandolini, Chiara Pasquini, and Luca Schiaffino
Dipartimento di Chimica and IMC-CNR Sezione Meccanismi di Reazione, Universita` La Sapienza,
Box 34 Roma 62, 00185 Roma, Italy
antonella.dallacort@uniroma1.it
Received July 25, 2005
A flipping motion rapidly inverts the bent structure of uranyl-salophen compounds and, conse-
quently, causes fast enantiomerization of nonsymmetrically substituted derivatives. This process
has been previously slowed by introducing bulky substituents in the imine bond region. Since the
resulting complexes dissociate upon chromatographic treatment, an alternative approach to the
design and synthesis of robust, nonflipping uranyl-salophen compounds is here described. Such an
approach is based on the idea that the flipping motion would be blocked by connecting the para
positions with respect to the phenoxide oxygens by means of polymethylene bridges of suitable
length. Analysis of a number of uranyl-salophen compounds by molecular mechanics, while showing
that bulky substituents in the imine bond region cause severe distortions of the ligand backbone,
suggested that the best chain lengths are those that fit the gap between the phenoxide rings without
altering the natural geometry of the parent uranyl-salophen compound. Calculations showed that
such chains are those composed of 12 and 13 methylene units. Accordingly, chiral uranyl-salophen
macrocycles bridged with 12- and 13-methylene chains were synthesized in fairly good yields and
resolved by chiral HPLC.
Introduction
recognition at the transition state level is the basis for
the development of asymmetric catalysts.3
The design of synthetic molecular receptors capable of
selective recognition of one of the two enantiomers of a
target substrate is a main topic in supramolecular
chemistry,1 with many implications in industrial pro-
cesses and biomedical research.2 Moreover, enantiomeric
The main point to be satisfied in the design of a chiral
receptor is the construction of a dissymmetric spatial
arrangement of the interaction sites. Such a request can
be in principle more easily met if the chirality of the
receptor arises from the geometry of the skeleton rather
than from a single stereogenic element. Very few ex-
amples of enantioselective receptors and asymmetric
* To whom correspondence should be addressed. Tel: +390649913087.
Fax: +3906490421.
10.1021/jo0515430 CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/21/2005
9814
J. Org. Chem. 2005, 70, 9814-9821

Inherently Chiral Uranyl-Salophen Macrocycles
catalysts based on this concept have been reported so far,4
although much attention has been devoted in the past
decades to chiral structural units devoid of the most usual
elements of chirality, such as chiral centers, planes, and
axes.
We have recently reported that the inherently chiral5
uranyl-salophen receptor 1 binds neutral chiral molecules
endowed with a donor site (e.g., amines, sulfoxides) with
good enantioselectivity.6 Chirality in nonsymmetrically
substituted uranyl-salophen compounds arises from the
marked curvature imposed to the coordinated ligand by
the large atomic radius of the uranium in UO22+. In
nonsymmetrical derivatives of the sterically unhindered
parent compound 2a, fast enantiomerization occurs
because of the existence of a flipping motion that rapidly
inverts the curvature and keeps the two enantiomers in
equilibrium (Figure 1). Nevertheless, the flipping could
be significantly slowed by introducing bulky substituents
in suitable positions (e.g., 3b).7 The highest racemization
barrier was obtained by replacing the o-phenylenedi-
amine ring with its tetramethyl derivative and by
FIGURE 1. Flipping motion of compound 2a. The calculated
structures are observed from the equatorial plane of the uranyl
unit. The blue and green hydrogen atoms differentiate the two
otherwise indistinguishable conformations.
introducing a phenyl substituent on one of the imine
carbon atoms. The racemization half-life of such com-
pounds is about 17 h at 25 °C.8
The behavior of compound 1 illustrates that in this
novel class of inherently chiral receptors the use of a
tetracoordinated uranyl dication as recognition site al-
lows a rational construction of the receptor, because the
complexed guest is bound to the fifth coordination site
of the uranium in its equatorial plane. Since synthetic
routes to salophen ligands make use of easily available
ortho-substituted phenols as starting materials, the
binding site can be shaped at will by a proper selection
of groups adjacent to the metal center. For example,
receptor 1 features a phenyl group, known to act as a
secondary binding site in the complexation of a variety
of guests,9 and a methyl group, deputed to introduce more
strict shape requirements via repulsive interactions with
the bound substrate. Figure 1 clearly shows that, once
the flipping motion is blocked, the three interaction sites,
namely, the metal center and the two adjacent groups,
are arranged in a chiral array.
Unfortunately, there are major drawbacks in the
strategy of slowing down the flipping motion by introduc-
ing steric bulk in the imine bond region. First of all, this
strategy cannot be pushed further, as shown by the fact
that all our attempts at introducing either bulkier
substituents or substituents also on the second imine
carbon atom were unsuccessful.10 Second, sterically
crowded uranyl-salophen complexes, including 1, dissoci-
ate upon chromatographic treatment to give the free
ligands in a pure form,11 thus precluding enantiomeric
resolution via chiral HPLC. Given that the strategy based
on the introduction of bulky groups turned out to be a
dead end, we carried out a computational study of the
hindered complexes. A careful analysis of calculated
geometries pointed to excessive ligand distortion as a
reasonable explanation for the above-mentioned prob-
lems. So, we reasoned that the flipping motion could be
blocked by connecting the para positions of the phenoxide
rings by means of chains of appropriate length (see
Figure 1). Of course, whereas short chains would induce
severe strain energies, too-long chains would lead to
curvature inversion through conformational changes of
the jump-rope type. As a first approach to nonflipping
uranyl-salophen compounds stable under chromato-
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J. Org. Chem, Vol. 70, No. 24, 2005 9815

Dalla Cort et al.
CHART 1
graphic conditions, we report here on a computer-aided
design and synthesis of three novel macrocyclic com-
pounds, namely, the symmetric uranyl-salophen com-
pound 4a, and the chiral analogues 4b and 4c (Chart 1).
In line with expectations, the new complexes proved to
be resistant to chromatographic treatment so that the
enantiomers of 4b and 4c could be resolved by HPLC on
a chiral stationary phase.
are much more distorted than unhindered ones. It seems
likely that such an increased distortion of the ligand
backbone can be held responsible for a decrease in
thermodynamic stability of the complexes that accounts
for their chromatographic lability as well as for our
unsuccessful attempts at the synthesis of more hindered
compounds.10 To test this hypothesis and exploit it for
the rational design of stable noninterconverting struc-
tures, the deviation from planarity of the ligand should
be quantified. To this purpose we define two parameters,
δ and δ′, as in eqs 1 and 2, where R, â, γ, R′, â′, and γ′
are the torsion angles defined in Figure 2.
Computational Procedure
The structures of uranyl-salophen complexes were
calculated utilizing the force field MM3 as implemented
in Macromodel version 6.0. The parameters introduced
for uranium, uranyl oxygens, and phenoxide oxygens
have been previously published.7 Partial atomic charges
were computed using the electrostatic potential (ESP)
from the wave function obtained by an AM1 calculation
in SPARTAN version 5.0.1. Charges of +2 on the ura-
nium and 0 on the oxygens were used for the uranyl
dication. These parameters gave good agreement with the
structure of the uranyl pentahydrate cation, as well as
with several X-ray structures of salophen-uranyl com-
plexes.12
δ ) (180 - R) + (180 - â) + (180 - γ)
δ′ ) (R′ - 180) + (â′ - 180) + (γ′ - 180)
(1)
(2)
These parameters are related to the left- and right-
hand sides, respectively, of a uranyl-salophen compound
watched by an observer facing its concave face with the
o-phenylenediamine ring directed up, as in Figure 2.
The two parameters δ and δ′ will be 0° for a perfectly
planar structure, such as that observed in the Mg2+
complex of the parent salophen ligand,13 and 90° when
the planes of the phenoxyde rings are perpendicular to
the plane of the o-phenylenediamine ring. Calculated
values of δ and δ′ for the model compounds 2a, 2b, 3a,
Calculation Results
Analysis of calculated structures of uranyl-salophen
complexes led us to observe that compounds with steric
hindrance in the imine bonds region, such as 1 and 2b,
(12) For X-ray structural studies, see: (a) van Staveren, C. J.; van
Eerden, J.; van Veggel, F. C. J. M.; Harkema, S.; Reinhoudt, D. N. J.
Am. Chem. Soc. 1988, 110, 4994-5008. (b) van Doorn, A. R.; Schaaf-
stra, R.; Bos, M.; Harkema, S.; van Eerden, J.; Verboom, W.; Reinhoudt,
D. N. J. Org. Chem. 1991, 56, 6083-6094. (c) Rudkevich, D. M.;
Stauthamer, W. P. R. V.; Verboom, W.; Engbersen, J. F. J.; Harkema,
S.; Reinhoudt, D. N. J. Am. Chem. Soc. 1992, 114, 9671-9673 (d)
Cametti, M.; Nissinen, M.; Dalla Cort, A.; Mandolini, L.; Rissanen, K.
Chem. Commun. 2003, 2420-2421. (e) Cametti, M.; Nissinen, M.; Dalla
Cort, A.; Mandolini, L.; Rissanen, K. J. Am. Chem. Soc. 2005, 127,
3831-3837.
FIGURE 2. Definition of the torsion angles used in eqs 1 and
2. The uranyl-salophen complex is observed from its concave
side, and torsion angle values are within the range of 0-360°.
9816 J. Org. Chem., Vol. 70, No. 24, 2005

Inherently Chiral Uranyl-Salophen Macrocycles
TABLE 1. Calculated Values of δ and δ′ (deg)
entry
compound
δ
δ′
1
2
3
4
5
6
7
8
2a
49.0
51.2
64.6
66.5
52.2
46.6
48.5
48.7
46.0
66.9
60.2
78.7
52.4
47.6
44.2
33.0
2b
3a
3b
5, n ) 11
5, n ) 12
5, n ) 13
5, n ) 14
and 3b are listed in Table 1 (entries 1-4). The relatively
small differences between δ and δ′ values found for the
symmetric compounds 2a and 3a are presumably due to
a computational artifact. The values calculated for the
parent compound 2a (entry 1) can be compared with the
values of 45.8° and 45.6° resulting from a DFT optimized
geometry of the same compound,13 as well as with one of
45.6° obtained from its X-ray crystal structure.12 Differ-
ences between our values and the most reliable values
available in the literature amount to only a few degrees
and are much smaller than variations caused by the
introduction of bulky substituents (entries 2-4). It ap-
pears therefore that our computational approach is
accurate enough for the purposes of the present work
despite the modest level of theory employed.
Introduction of a phenyl group on the imine carbon
atom increases the δ value on its side by about 18-20°
(compare entries 2 and 4 with 1 and 3, respectively) but
has a very small influence, if any, on the other side of
the ligand. The methyl substituents on the o-phenylene-
diamine ring cause an increase by about 15-17° (com-
pare entries 3 and 4 with 1 and 2, respectively). When
both a phenyl and a methyl group are simultaneously
present a very significant increase by about 32° in the
side of the phenyl is seen (compare entry 4 with 1). Since
the geometrical distortion of the ligand backbone in the
parent compound 2a is expected to correspond to an
optimal situation, the straightforward conclusion was
reached that the highest stability of complexes is attained
when both δ and δ′ fall in the range of 45-50°. With this
idea in mind, we designed the bridged compounds of
general structure 5 in which the para positions of the
two phenoxyde rings are connected by polymethylene
chains of varying length. As to the choice of the chain
length, we assumed as a general criterion that the best
n values are those that keep both δ and δ′ values as close
as possible to the unperturbed values found for the parent
compound 2a. The results listed in Table 1 show that
when n ) 11 (entry 5), both δ and δ′ values are larger
than the optimum range, whereas when n ) 14 (entry
8) one of the two values is normal while the other
becomes as small as 33°, which corresponds to a consid-
erable flattening of the ligand presumably caused by
conformational constraints in the 14-methylene chain.
Entries 6 and 7 indicate that the 12- and 13-methylene
chains have the appropriate length for spanning the
uranyl-salophen unit without perturbing in a significant
way its natural shape. As shown by the calculated
geometries of the cS5 enantiomers of 4b and 4c (Figure
3), the polymethylene chains fit the gap between the
FIGURE 3. Calculated structures of uranyl-salophen com-
plexes cS-4b (left) and cS-4c (right). Hydrogen atoms are
omitted.
phenoxyde rings so well that the possibility of jump-rope
inversions of the curvature should be considered out of
question. On the basis of the above results, compounds
5, n ) 12, 13 were considered as the best candidates for
the synthesis of strainless nonflipping uranyl-salophen
compounds.
Results and Discussion
The synthethic procedure to obtain bridged complexes
4a-c was first developed for the symmetrically substi-
tuted compound 4a and subsequently extended to non-
symmetrical compounds 4b and 4c (Scheme 1). Although
compound 4a is not chiral, the isopropyl group can be
used as a NMR diastereotopic probe of the flipping
motion.7
The synthesis of R,ω-bis(p-hydroxyphenyl)alkanes re-
ported by Doroshenko14 gave us hints for the routes to
the macrocycle precursors 8a-c. Double Friedel-Craft
acylation of 2-alkylanisoles with the appropriate acid
dichloride yielded the corresponding dicarbonyl deriva-
tives 6a-c.15 When a 1:1 mixture of two different anisoles
was used, as required by the target compounds 4b and
4c, separation of the nonsymmetrical intermediates 6b
and 6c from the symmetrical byproducts was carried out
by column chromatography at this stage. Because Wolf-
Kishner reduction of diketones 6 gave poor and scarcely
reproducible results, we found more convenient the use
of ZnI2/NaCNBH3 in 1,2-dichloroethane.16 The phenolic
compounds 8a-c, obtained upon treatment of compounds
7a-c with BBr3,17 proved to be unreactive under the
Reimer-Tienmann and Hofslokken-Skattebol18 formyl-
ation conditions previously used by us in the synthesis
of salycilaldehyde derivatives.7,8,19 Good results were
obtained under the more vigorous conditions of the Gross
formylation reaction.20 Although this reaction is usually
carried out on anisoles, the phenolic compounds 8a-c
(14) (a) Doroshenko, Y. E.; Sergeev, V. A. J. Org. Chem. USSR (Engl.
Trans.) 1965, 1, 1623-1624. (b) Goldmann, H.; Vogt, W.; Paulus, E.;
Boehmer, V. J. Am. Chem. Soc. 1988, 110, 6811-6817.
(15) Lehman, J. W. Operational Organic Chemistry; Prentice Hall:
London, 1999.
(16) Lau, C. K.; Dufresne, C.; Belanger, P. C.; Pietre, S.; Scheigetz,
J. J. Org. Chem. 1986, 51, 3038-3043.
(17) McOmie, J. F. W.; West, D. E. Org. Synth. 1973, 15, 412-414.
(18) Hofslokken, N. U.; Skattebol, L. Acta Chem. Scand. 1999, 53,
258-262.
(13) Brynda, M.; Wesolowski, T. A.; Wojciechowski, K. J. Phys.
Chem. A 2004, 108, 5091-5099.
(19) van Axel Castelli, V.; Dalla Cort, A.; Mandolini, L.; Reinhoudt,
D. N. J. Am. Chem. Soc. 1998, 120, 12688-12689.
J. Org. Chem, Vol. 70, No. 24, 2005 9817

Dalla Cort et al.
SCHEME 1. Synthesis of Bridged Uranyl-Salophen Complexes 4a-c
gave much better yields than their methylated precursors
7a-c. As a first attempt to the synthesis of bridged
compounds 4, macrocyclization was carried out batchwise
by mixing equimolar amounts of dialdehyde 9, diamine,
and uranyl salt at room temperature in methanol at a
relatively high concentration of ca. 0.1 M in each reactant
(procedure A). Macrocycle 4a spontaneously separated
from the reaction mixture as a solid material in 23% yield
uncontaminated by its higher cyclic oligomers that
remained in solution. The more soluble macrocycle 4b
was isolated instead from the reaction mixture in 22%
yield by preparative TLC on silica gel, which allowed good
separation from its higher cyclic oligomers, showing at
the same time the tolerance of such compounds to
chromatographic treatment. To increase the yield of the
desired macrocycles at the expense of their higher cyclic
oligomers, an influxion procedure was used for the slow
simultaneous addition of the reactants into the reaction
medium (Ziegler’s high dilution technique, procedure B).
No trace of the presence of higher oligomers was found
in the crude reaction products, from which compounds
4b and 4c were isolated in 70% and 73% yield, respec-
tively, by preparative TLC.
of 4b and 4c. Cleaner results were obtained from the 13
C
NMR spectra (Figure 4, on the right), where the signals
of the methyl groups are well separated from other
signals. A variable temperature 1H NMR experiment
1
The H NMR spectra of 4a-c in acetone-d6 at room
temperature show that the geminal methyl groups of the
isopropyl display in all cases a pair of doublet signals,
heavily overlapped to the resonances of the methylene
groups in the central part of the chains. The spectrum of
4a (Figure 4) is the clearest one, because of the double
intensity of the isopropyl signals compared with those
FIGURE 4. Portions of the 1H spectra of 4a (300 MHz,
DMSO-d6) displaying the resonances of the methyl groups at
298 K (left, bottom) and 386 K (left, top). Portions of the 13C
spectral regions of 4a, 4b, and 4c (50 MHz, acetone-d6)
displaying the resonances of the isopropyl group at 298 K
(right).
(20) (a) Rieche, A.; Gross, H.; Hoft, E. Chem. Ber. 1960, 93, 88-94.
(b) Gross, H.; Rieche, A.; Matthey, G. Chem. Ber. 1963, 96, 308-313.
(c) Rieche, A.; Gross, H.; Hoft, E. Org. Synth. 1967, 47, 1-6. (d) De
Haan, F. P.; Delker, G. L.; Covey, W. D.; Bellomo, A. F.; Brown, J. A.;
Ferrara, D. M.; Haubrich, R. H.; Lander, E. B.; MacArthur, C. J.;
Meinhold, R. W.; Neddenriep, D.; Schubert, D. M.; Stewart, R. G. J.
Org. Chem. 1984, 49, 3963-3969.
9818 J. Org. Chem., Vol. 70, No. 24, 2005

Inherently Chiral Uranyl-Salophen Macrocycles
FIGURE 5. HPLC resolution of the enantiomers of 4b (left) and 4c (right) at room temperature on Chiralcel-OD-H column
(eluent, n-hexane/ethanol 80:20; flow rate, 0.8 mL/min) with UV detection at 400 nm.
carried on compound 4a in DMSO-d6 (Figure 4, on the
left) showed that the splitting persists up to at least
386 K.
The tolerance of the synthesized macrocycles to chro-
matographic treatments allowed the racemic mixtures of
compounds 4b and 4c to be resolved by chiral HPLC. The
chromatograms obtained using a Chiralcel OD-H column
(Figure 5) with eluent hexanes-ethanol 80:20 at a flow
rate 0.800 mL min-1 show in both cases a nearly complete
separation of two peaks of equal intensity.
Experimental Section
General Procedure for Compounds 6. AlCl3 (0.55 g, 4.15
mmol) and dichloromethane (0.50 mL) were placed under
argon atmosphere in a dry flask cooled with an ice bath. A
solution of the proper acid dichloride (4.05 mmol) in dichlo-
romethane (0.70 mL) was added. 2-Isopropylanisole (2.00
mmol) or a mixture of 2-isopropylanisole (1.00 mmol) and
2-phenylanisole (1.00 mmol) in dichloromethane (0.50 mL) was
slowly added, and finally the mixture was diluted with
dichloromethane (0.50 mL) and stirred for 45 min at room
temperature. The resulting mixture was poured into ice cold
6 M hydrochloric acid (20 mL). The organic layer was then
washed with NaHCO3 (saturated) and dried over anhydrous
sodium sulfate.
Conclusion
1,12-Bis(3-isopropyl-4-methoxyphenyl)-dodecane-1,12-
dione (6a) was prepared starting from 2-isopropylanisole and
dodecandioic acid dichloride. The desired product was recov-
ered without any purification in 90% yield, mp ) 74-77 °C.
1H NMR (200 MHz, CDCl3) δ ) 7.84 (dd, 2H, J ) (Hz, 2.3
Hz); 7.77 (d, J ) 2.3 Hz); 6.84 (d, 2H, J ) 8.5 Hz); 3.87 (s,
6H); 6.84 (d, 2H, J ) 6.9 Hz); 3.87 (s, 6H); 3.3 (m, 2H, J ) 6.9
Hz); 2.9 (t, 4H, J ) 7.6 Hz); 1.22 (d, 12H, J ) 6.9 Hz); 1.15-
1.80 (m, 26H) ppm. 13C NMR (75 MHz, CDCl3) δ ) 200.4,
161.4, 137.7, 130.6, 128.6, 127.0, 110.2, 56.2, 38.9, 30.2, 27.5,
25.4, 23.1 ppm. MS-ESI-TOF for C32H46O4 ) 494.3, found m/z
(+) 517.3 ([M + Na]+).
1-(3-Isopropyl-4-methoxy-phenyl)-12-(6-methoxy-bi-
phenyl-3-yl)-dodecane-1,12-dione (6b) was prepared start-
ing from 2-isopropylanisole, 2-phenylanisole, and dodecandioic
acid dichloride. Chromatographic purification of the statistical
mixture (silica gel, 10% ethyl acetate in light petroleum)
afforded the desired product in 38% yield, mp ) 77-79 °C. 1H
NMR (200 MHz, CDCl3) δ ) 7.99-7.93 (m, 2H); 7.85-7.78 (m,
2H); 7.52-7.50 (d, 2H, J ) 7.0 Hz); 7.44-7.32 (m, 3H); 7.02-
6.99 (d, 1H, J ) 8.6 Hz); 6.86-6.83 (d, 1H, J ) 8.4 Hz); 3.88
(s, 3H); 3.87 (s, 3H); 3.35-3.25 (m, 1H, J ) 6.96 Hz); 2.95-
2.87 (m, 4H); 1.74-1.60 (m, 4H); 1.32-1.29 (m, 12H); 1.23-
1.21 (d, 6H, J ) 6.96 Hz) ppm. 13C NMR (50 MHz, CDCl3) δ )
200.0, 161.4, 160.9, 138.3, 137.8, 131.9, 131.3, 130.9, 130.6,
130.22, 130.25, 128.8, 128.6, 128.1, 127.0, 111.3, 110.2, 56.5,
56.2, 39.1, 39.0, 30.2, 30.1, 27.5, 25.5, 25.3, 23.2 ppm. MS-
ESI-TOF for C35H44O4 ) 528.3, found m/z (+) 551.4 ([M +
Na]+).
Three complexes belonging to a new class of macro-
cyclic uranyl salophen derivatives have been prepared.
The goal of obtaining configurationally stable complexes
that do not dissociate under chromatographic treatments
was achieved on the basis of a computational study that
relates the stability of uranyl-salophen compounds to the
extent of the deviation from planarity of the ligand upon
complexation. Stable noninterconverting complexes were
obtained by linking the para positions with respect to the
oxygen atoms of the phenoxide rings in cyclic structures,
by means of a polymethylene chain. The optimized
synthetic procedure is fast and reliable and leads to the
dialdehydic precursor with good overall yields. The
variety of ortho-substituted phenols easily available as
starting materials makes the procedure very flexible.
The complexes 4 a-c have proven to be stable under
chromatographic conditions in that they have been easily
purified by preparative silica gel TLC and furthermore
the enantiomers of nonsymmetrical complexes 4b and 4c
have been resolved by chiral HPLC.
In view of the well recognized ability of uranyl-
salophen compounds to behave as receptors for anions
and neutral molecules, and as catalysts in a number of
important reactions, the present work opens the way
toward a new family of chiral receptors with prospects
of applications to enantioselective recognition and ca-
talysis.
1-(3-Isopropyl-4-methoxy-phenyl)-13-(6-methoxy-bi-
phenyl-3-yl)-tridecane-1,13-dione (6c) was prepared from
2-isopropylanisole, 2-phenylanisole, and tridecandioic acid
J. Org. Chem, Vol. 70, No. 24, 2005 9819

Dalla Cort et al.
dichloride. Chromatographic purification of the statistical
mixture (silica gel, 10% ethyl acetate in light petroleum)
afforded the desired product in 37% yield, mp ) 81-83 °C. 1H
NMR (300 MHz, CDCl3) δ ) 7.99-7.95 (dd, 1H, Jo ) 8.34 Hz,
Jm ) 2.19 Hz); 7.94-7.93 (d, 1H, J ) 2.19 Hz); 7.86-7.85 (d,
1H, J ) 1.97 Hz); 7.82-7.79 (dd, 1H, Jo ) 10.76 Hz, Jm ) 2.2
Hz); 7.52-7.50 (d, 2H, J ) 7.03 Hz); 7.44-7.35 (m, 3H); 7.02-
6.99 (d, 1H, J ) 8.57 Hz); 6.86-6.83 (d, 1H, J ) 8.57 Hz);
3.37-3.23 (m, 1H, J ) 6.81 Hz); 2.95-2.87 (m, 4H); 1.77-
1.66 (m, 4H); 1.33 (m, 8H); 1.27 (m, 8H); 1.23-1.21 (d, 6H,
J ) 6.81 Hz) ppm. 13C NMR (75 MHz, CDCl3) δ ) 200.4, 200.0,
161.3, 160.8, 138.3, 137.7, 131.9, 131.3, 130.6, 130.2, 128.8,
128.6, 128.0, 127.0, 111.2, 110.2, 56.4, 56.2, 39.0, 38.9, 30.24,
30.16, 30.09, 27.5, 25.5, 25.3, 23.1 ppm. MS-ESI-TOF for
C36H46O4 ) 542.3, found m/z (+) 565.5 ([M + Na]+).
General Procedure for Compounds 7. ZnI2 (0.97 g, 3.04
mmol) and 1,2-dichloroethane (10 mL) were placed in a flask
together with the appropriate precursor 6 (1.07 mmol). NaC-
NBH3 (0.936 g, 14.90 mmol) was added, and the reaction
mixture was stirred for 24 h at room temperature and then
filtered on a Celite plug that was washed throughly with
dichloromethane. By evaporation of the solvent, the desired
products were isolated as colorless oils in quantitative yields.
1,12-Bis(3-isopropyl-4-methoxyphenyl)-dodecane (7a).
1H NMR (300 MHz, CDCl3) δ ) 6.9-7.0 (m, 6H); 6.77 (d, 2H,
J ) 5.2 Hz); 3.8 (s, 6H); 3.3 (m, 2H, J ) Hz); 2.5 (t, 4H, 7.8
Hz); 1.57 (m, 4H); 1.19-1.29 (m, 28H) ppm. 13C NMR (75 MHz,
CDCl3) δ ) 155.5, 137.3, 135.6, 126.8, 126.7, 110.9, 56.2, 36.1,
32.6, 30.4, 30.3, 30.2, 30.1, 27.4, 23.4 ppm. MS-ESI-TOF for
C32H50O2 ) 466.4, found m/z (+) 489.5 ([M + Na]+).
1-(3-Isopropyl-4-methoxy-phenyl)-12-(6-methoxy-bi-
phenyl-3-yl)-dodecane (7b). 1H NMR (300 MHz, CDCl3)
δ ) 7.53-7.51 (d, 2H, J ) 7.05 Hz); 7.42-7.37 (t, 2H, J )
7.62 Hz); 7.33-7.31 (d, 1H, J ) 7.04 Hz); 7.13(s, 1H); 7.13-
7.10 (d, 1H, J ) 7.63 Hz); 6.99-6.88 (m, 3H); 6.77-6.74 (d,
1H, J ) 8.22 Hz); 3.80 (s, 3H); 3.78 (s, 3H); 3.33-3.24 (m, 1H,
J ) 7.04 Hz); 2.61-2.50 (m, 4H); 1.58 (m, 4H); 1.30 (m, 6H);
1.26 (m, 6H); 1.1.21-1.19 (d, 6H, J ) 7.04 Hz) ppm. 13C NMR
(75 MHz, CDCl3) δ ) 155.5, 155.2, 139.4, 137.3, 135.9, 135.6,
131.6, 131.1, 130.2, 128.9, 128.6, 127.5,126.8, 126.7, 111.9,
110.9, 56.4, 56.2, 36.1, 35.8, 32.5, 32.4, 30.34, 30.30, 30.2, 30.1
ppm. MS-ESI-TOF for C35H48O4 ) 500.4, found m/z (+) 523.5
([M + Na]+).
1-(3-Isopropyl-4-methoxy-phenyl)-13-(6-methoxy-bi-
phenyl-3-yl)-tridecane (7c). 1H NMR (300 MHz, CDCl3)
δ ) 7.54-7.52 (d, 2H, J ) 7.43 Hz); 7.42-7.31 (m, 3H); 7.13-
7.10 (m, 2H); 7.00-6.88 (m, 3H,); 6.77-6.74 (d, 1H, J ) 8.23
Hz); 3.80 (s, 3H), 3.78 (s, 3H), 3.34-3.25 (m, 1H, J ) 7.03 Hz);
2.61-2.50 (m, 4H); 1.59 (m, 4H); 1.30 (m, 9H); 1.26 (m, 9H);
1.22-1.19(d, 6H, J ) 7.03 Hz) ppm. 13C NMR (75 MHz, CDCl3)
δ ) 155.5, 155.2, 139.4, 137.3, 135.9, 135.6, 131.7, 131.1, 130.2,
128.9, 128.6, 127.5, 126.8, 126.7, 111.9, 110.9, 56.4, 56.2, 36.1,
35.8, 32.6, 32.4, 30.4, 30.3, 30.2, 30.1, 30.0, 27.4, 23.4 ppm.
MS-ESI-TOF for C36H50O2 ) 514.4, found m/z (+) 537.5
([M + Na]+).
General Procedure for Compounds 8. The proper com-
pound 7 (0.29 mmol) and dry toluene (2.0 mL) were placed
under an argon atmosphere in a dry flask. A solution of boron
tribromide (0.069 mL, 0.73 mmol) in dry toluene (2.0 mL) was
added dropwise to the stirred solution cooled at 0 °C. The
reaction mixture was stirred for 24 h at room temperature and
then cooled again in an ice bath, and water (20 mL) was added.
The solution was extracted with three portions of diethyl ether
(10 mL each), and the combined organic layers were washed
twice with water and dried over anhydrous sodium sulfate.
Evaporation of the solvent afforded the products as dark brown
oils, pure enough to be used as such in the following steps.
added dropwise over 1 h to the stirred solution cooled at 0 °C.
After 2 h, the reaction mixture was diluted with water (30 mL).
The aqueous layers were extracted with two portions of
dichloromethane (30 mL each). The combined organic layers
were washed with water (50 mL), dried over anhydrous sodium
sulfate, and concentrated to afford oils that were purified by
flash chromatography (silica gel, 3% ethyl acetate in light
petroleum) to give the desired products as yellow oils.
1,12-Bis(3-formyl-4-hydroxy-5-isopropylphenyl)-do-
decane (9a) was prepared from 8a in 41% yield. 1H NMR
(200 MHz, CDCl3) δ ) 11.12 (s, 2H); 9.77 (s, 2H); 7.09 (s, 2H);
3.2 (m, 2H, J ) 6.7 Hz); 2.5 (t, 4H, J ) 7,3 Hz); 2.08 (s, 2H);
1.50 (m, 4H); 1.00-1.35 (m, 24H); ppm. 13C NMR (50 MHz,
CDCl3) δ ) 196.8, 157.3, 136.9, 134.2, 133.9, 130.2, 119.9, 35.0,
31.5, 29.62, 29.57, 29.5, 29.2, 26.3, 22.3 ppm. MS-ESI-TOF for
C32H46O4 ) 494.3, found m/z (+) 517.5 ([M + Na]+).
1-(3-Formyl-4-hydroxy-5-isopropyl-phenyl)-12-(5-formyl-
6-hydroxy-biphenyl-3-yl)-dodecane (9b) was prepared from
8b in 35% yield. 1H NMR (200 MHz, CDCl3) δ ) 11.18 (s, 1H);
11.02 (s, 1H); 9.73 (s, 1H); 9.65 (s, 1H); 7.42-7.39 (d, 2H, J )
6.7 Hz); 7.29-7.20 (m, 4H); 7.16 (s, 1H); 7.08 (s, 1H); 6.98 (s,
1H); 3.23-3.10 (m, 1H, J ) 6.85 Hz); 2.48-2.34 (m, 4H); 1.41
(m, 4H); 1.12 (m,12H); 1.07-1.04 (d, 6H, J ) Hz, 6.85 Hz) ppm.
13C NMR (50 MHz, CDCl3) δ ) 197.7, 197.6, 158.1, 157.7,
139.0, 137. 7, 137.5, 137.2, 135.1, 135.0, 134.6, 131.0, 133.1,
130.9, 130.0, 129.0, 128.3, 127.2, 123.6, 122.7, 121.4, 120.6,
118.5, 109.6, 36.3, 35.7, 35.6, 32.5, 32.3, 32.2, 30.4, 30.3, 30.2,
30.0, 27.0, 23.1 ppm. MS-ESI-TOF for C35H44O4 ) 528.3, found
m/z (+) 551.4 ([M + Na]+).
1-(3-Formyl-4-hydroxy-5-isopropyl-phenyl)-13-(5-formyl-
6-hydroxy-biphenyl-3-yl)-tridecane (9c) was prepared from
8c in 36% yield. 1H NMR (200 MHz, CDCl3) δ ) 11.28 (s, 1H);
11.12 (s, 1H); 9.82 (s, 1H); 9.75 (s, 1H); 7.56-7.49 (m, 2H);
7.39-7.25 (m, 4H); 7.19-7.16 (m, 2H); 7.08 (bs, 16H); 3.33-
3.19 (m, 1H, J ) 6.92 Hz); 2.58-2.45 (m, 4H); 1.54-1.51 (m,
4H); 1.22 (m, 9H); 1.18 (m, 9H); 1.17-1.14 (d, 6H, J ) 6.92
Hz) ppm. 13C NMR (50 MHz, CDCl3) δ ) 197.6, 197.5, 158.0,
157.6, 138.9, 137.4, 137.2, 135.0, 134.9, 134.5, 133.0, 130.9,
130.8, 129.9, 128.9, 128.2, 121.3, 120.6, 35.6, 35.5, 32.2, 32.1,
30.31, 30.26, 30.1, 30.0, 29.9, 29.8, 26.9, 23.0 ppm. MS-ESI-
TOF for C36H46O4 ) 542.3, found m/z (+) 565.4 ([M + Na]+).
Complex 4a. Procedure A. A solution of 1,12-bis(3-formyl-
4-hydroxy-5-isopropylphenyl)-dodecane (9a) (0.227 g, 0.46
mmol) and 1,2-diaminobenzene (0.050 g, 0.46 mmol) in MeOH
(5 mL) was stirred at room temperature. After 30 min UO2-
(OAc)2‚2H2O (0.191 g, 0.46 mmol) was added, and the solution
was stirred for 30 min. The reaction mixture was filtered, and
the desired product was obtained as a pale orange solid in 23%
yield. Elemental analysis calcd (%) for C38H48N2O4U‚3H2O: C,
1
51.35; H, 6.12; N, 3.15. Found: C, 51.48; H, 6.28; N, 3.35. H
NMR (200 MHz, acetone-d6) δ ) 9.30 (s, 2H); 7.69 (m, 2H);
7.50 (m, 2H); 7.24 (m, 4H) 3.84 (m, 2H); 2.56 (t, 4H); 1.0-1.6
(m, 18H); 0.30-1.0 (m, 14H) ppm. 13C NMR (50 MHz, acetone-
d6) δ ) 205.8, 167.7, 166.7, 147.6, 138.6, 132.8, 131.4, 130.4,
129.2, 123.1, 119.3, 34.8, 31.9, 30.6, 29.8, 29.3, 28.2, 26.7, 23.4,
22.8 ppm. HRMS-ESI-TOF for C38H48N2O4UNa+ calcd 857.4020;
found 857.4031.
Complex 4b. Procedure A. A solution of 1-(3-formyl-4-
hydroxy-5-isopropyl-phenyl)-12-(3-formyl-4-hydroxy-5-phenyl-
phenyl)-dodecane (9b) (0.243 g, 0.46 mmol) and 1,2-diami-
nobenzene (0.050 g, 0.46 mmol) in MeOH (5 mL) was stirred
at room temperature. After 30 min UO2(OAc)2‚2H2O (0.191 g,
0.46 mmol) was added, and the solution was stirred for 30 min.
The reaction mixture was concentrated and purified by
preparative TLC (0.25 mm, silica gel, 30% acetone in cyclo-
hexane) to separate 4b from its higher oligomers. The desired
product was obtained as a pale orange solid in 22% yield.
Procedure B. A solution of 9b (0.056 g, 0.106 mmol) in
dichloromethane (2.5 mL) and a solution of 1,2-diaminoben-
zene (0.0115 g, 0.109 mmol) in the same solvent (2.5 mL) were
added separately and simultaneously by syringe pump over 7
h to a solution of uranyl acetate (0.045 g, 0.106 mmol) in
General Procedure for Compounds 9. The proper com-
pound 8 (1.8 mmol) was dissolved in dry dichloromethane (9
mL) and placed under an argon atmosphere in a dry two-neck
flask together with R,R′-dichloromethyl methyl ether (1.06 mL,
11.7 mmol). Titanium tetrachloride (0.594 mL, 5.4 mmol) was
9820 J. Org. Chem., Vol. 70, No. 24, 2005

Inherently Chiral Uranyl-Salophen Macrocycles
methanol (100 mL). The mixture was left to stand overnight
at room temperature and then concentrated to a volume of 5
mL and dissolved again in dichloromethane (100 mL). The
organic phase was extracted with two portions of NaHCO3
(saturated) (50 mL each), washed to neutrality with two
portions of water (30 mL each), dried over anhydrous sodium
sulfate, and concentrated to afford a dark red oil. Preparative
TLC (0.25 mm, silica gel, 30% acetone in cyclohexane) gave
the desired product as an orange solid in 70% yield. Elemental
analysis calcd (%) for C41H46N2O4U‚3H2O: C, 53.36; H, 5.68;
N, 3.04. Found: C, 53.62; H, 5.80; N, 3.30. 1H NMR (200 MHz,
acetone-d6) δ ) 9.41 (s, 1H); 9.36 (s, 1H); 7.90-7.28 (m, 13H);
3.85-3.71 (m, 1H); 2.69-2.53 (m; 4H); 1.74-1.00 (m, 20H);
0.84-0.68 (m, 6H) ppm. 13C NMR (75 MHz, acetone-d6) δ )
167.8, 166.7, 147.7, 140.6, 138.6, 137.5, 134.0, 133.1, 131.7,
131.5, 130.9, 130.7, 130.6, 130.0, 129.5, 129.4, 128.4, 128.1,
127.3, 127.0, 124.8, 123.4, 123.2, 122.4, 119.85, 119.78, 118.4,
35.7, 35.4, 34.9, 34.7, 32.4, 32.1, 31.9, 28.4, 26.8, 23.6, 23.0
ppm. HRMS-ESI-TOF for C41H46N2O4UNa+ calcd 891.3863;
found 891.3875.
analysis calcd (%) for C42H48N2O4U‚3H2O: C, 53.84; H, 5.81;
N, 2.99. Found: C, 54.12; H, 6.10; N, 3.24. 1H NMR (200 MHz,
acetone-d6) δ ) 9.47 (s, 1H); 9.42 (s, 1H); 7.89-7.31 (m, 13H);
3.84-3.71 (m, 1H); 2.63-2.42 (m, 4H); 1.78-0.27 (m, 28H)
ppm. 13C NMR (50 MHz, acetone-d6) δ ) 174.0, 167.4, 147.6,
140.5, 139.0, 137.0, 134.6, 132.5, 132.4, 132.1, 132.0, 130.8,
130.6, 130.4, 129.3, 129.2, 128.3, 126.9, 124.4, 122.8, 119.9,
119.8, 35.1, 34.9, 31.5, 30.9, 30.5, 30.4, 28.0, 26.7, 23.2, 23.0
ppm. HRMS-ESI-TOF for C42H48N2O4UNa+ calcd 905.4020;
found 905.4032.
Acknowledgment. We thank Francesco Yafteh
Mihan for his assistance in the synthesis. We thank Dr.
Paola Galli for elemental analyses. We acknowledge
MIUR, COFIN 2003, Progetto Dispositivi Supramole-
colari for financial contribution.
Supporting Information Available: General experimen-
tal methods and computational details for calculated struc-
tures of compounds 2a, 2b, 3a, 3b, 5 (n )11, 12, 13, 14). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Complex 4c. Preparation was accomplished following
procedure B as described for 4b. The desired product was
recovered by preparative TLC (0.25 mm, silica gel, 30% acetone
in cyclohexane) as an orange solid in 73% yield. Elemental
JO0515430
J. Org. Chem, Vol. 70, No. 24, 2005 9821