Enantiomerization of chiral uranyl-salophen complexes via unprecedented ligand hemilability: Toward configurationally stable derivatives

Article abstract of DOI:10.1021/jo800610f

(Figure Presented) In the search for configurationally stable inherently chiral uranyl-salophen complexes, the newly synthesized compound 3 featuring a dodecamethylene chain was expected to be a promising candidate. Unexpectedly, dynamic HPLC on a enantio

Full text of DOI:10.1021/jo800610f

Enantiomerization of Chiral Uranyl-Salophen Complexes via
Unprecedented Ligand Hemilability: Toward Configurationally
Stable Derivatives
Alessia Ciogli,† Antonella Dalla Cort,*,‡ Francesco Gasparrini,*,† Lodovico Lunazzi,§
Luigi Mandolini,‡ Andrea Mazzanti,§ Chiara Pasquini,‡ Marco Pierini,† Luca Schiaffino,‡
and Francesco Yafteh Mihan‡
Dipartimento di Chimica and IMC-CNR Sezione Meccanismi di Reazione, UniVersita` La Sapienza,
Box 34 Roma 62, 00185 Roma, Italy, Dipartimento di Studi di Chimica e Tecnologia delle Sostanze
Biologicamente AttiVe, UniVersita` La Sapienza, Piazzale Aldo Moro 5, 00185 Roma, Italy, and
Dipartimento di Chimica Organica “A Mangini”, UniVersita` di Bologna, Viale Risorgimento 4,
40136 Bologna
antonella.dallacort@uniroma1.it; francesco.gasparrini@uniroma1.it
ReceiVed March 28, 2008
In the search for configurationally stable inherently chiral uranyl-salophen complexes, the newly
synthesized compound 3 featuring a dodecamethylene chain was expected to be a promising candidate.
Unexpectedly, dynamic HPLC on a enantioselective column showed that it still undergoes enantiomer-
ization at high temperature. By comparison with the dynamic behavior of compounds 4 and 5, it was
found that the enantiomerization rate is independent of the size of the ligand. This finding definitely
rules out a jump rope-type mechanism for the enantiomerization process and points to reaction pathways
involving preliminary rupture of one of the O · · · U coordinative bonds. This provides unprecedented
evidence of the occurrence of ligand hemilability in metal-sal(oph)en complexes. Such findings inspired
the synthesis of compound 6 endowed with a more rigid spacer, i.e., that derived from 4,4′-(1,4-
phenylenediisopropylidene)bisphenol. DHPLC investigations showed that the new structural motif imparts
a higher configurational stability, thus raising the half-life for the enantiomerization to more than 2 months
at room temperature. This clearly establishes that this compound represents the first member of a new
class of inherently chiral receptors, whose potential in chiral recognition and catalysis now can be feasibly
explored.
Introduction
asymmetric catalysis.2 A variety of structural motifs have been
used so far in the design of such kinds of systems and among
A major motivation for the continuing interest in the design
and synthesis of novel chiral receptors arises from their potential
applications in the fields of enantioselective recognition1 and
(1) (a) Stibor, I.; Zlatuskova, P. Chiral Recognition of Anions. In Anion
Sensing; Stibor, I., Ed.; Topics in Current Chemistry 255;Springer: Berlin,
Germany, 2005; pp 31-63. (b) Heo, J.; Mirkin, C. A. Angew. Chem., Int. Ed.
2006, 45, 941–944. (c) Ikeda, T.; Hirata, O.; Takeuchi, M.; Shinkai, S. J. Am.
Chem. Soc. 2006, 128, 16008–16009. (d) Miyaji, H.; Hong, S.-J.; Jeong, S.-D.;
Yoon, D.-W.; Na, H.-K.; Hong, J.; Ham, S.; Sessler, J. L.; Lee, C.-H. Angew.
Chem., Int. Ed. 2007, 46, 2508–2511. (e) Yakovenko, A. V.; Boyko, V. I.;
Kalchenko, V. I.; Baldini, L.; Casnati, A.; Sansone, F.; Ungaro, R. J. Org. Chem.
2007, 72, 3223–3231.
* Corresponding author. Phone: +39 06 49913087 (A.D.C.), +39 06
49912776 (F.G.). Fax: +39 06 490421 (A.D.C.), +39 06 49912780 (F.G.).
† Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologica-
mente Attive, Universita` La Sapienza.
‡ Dipartimento di Chimica and IMC-CNR Sezione Meccanismi di Reazione,
Universita` La Sapienza.
§ Universita` di Bologna.
6108 J. Org. Chem. 2008, 73, 6108–6118
10.1021/jo800610f CCC: $40.75 2008 American Chemical Society
Published on Web 07/16/2008

A Configurationally Stable Chiral Uranyl-Salophen Complex
them those based on metal complexes with vacant coordination
sites appear quite appealing.3
Complexes of N,N′-phenylene-salicylidene (salophen) ligands
with the uranyl dication4 have been widely employed as
receptors for anions and neutral molecules in organic solvents,5
and as supramolecular catalysts6 of reactions that undergo
electrophilic metallocatalysis. It can be expected that once made
chiral these complexes would be of interest as enantioselective
FIGURE 1. Flipping motion in uranyl-salophen complex 1 (R ) R′
) H).
allows the build up of an easily predictable chiral spatial array
without limiting the choice of starting materials to chiral
synthons.
2+
receptors and catalysts. The UO2 cation has a well-known
preference for pentagonal bipyramidal coordination with the two
oxygen atoms in the apical positions and the N2O2 donor atoms
of the salophen ligand in four of the five equatorial coordination
sites.7 Hence the fifth position is available for labile coordination
to a monodentate ligand (G), as shown in 1. This feature makes
uranyl-salophen complexes suitable for the design of supramo-
lecular hosts because the location of the bound guest can be
clearly predicted and a structured binding site is easily shaped
by the introduction of proper substituents in one or in both ortho
positions with respect to the phenoxide oxygen atoms.
Unfortunately the finding that the two enantiomers are in fast
equilibrium through a flipping motion that inverts the ligand
curvature8 (Figure 1) has precluded so far the use of
uranyl-salophen complexes in chiral recognition and catalysis.
This motion can be slowed down by bulky substituents in the
imine bonds region as in compounds 2 whose enantiomerization
half-life is about 17 h at 25 °C (∆G# ) 24.6 kcal mol-1),10 but
this leads to an increase in the ligand curvature that reduces
the strength of the association between the metal and the ligand
and ends up in two major drawbacks. First, resolution via chiral
HPLC, as well as standard chromatographic purifications, are
precluded because upon these treatments such severely distorted
complexes dissociate to give the free ligand. Second, the half-
life reported above appears to closely approach a higher limit,
since any further increase in steric bulk destabilizes the
corresponding complexes to such an extent that they do not form
at all. Alternatively, the configurational stability can be in-
creased, without perturbing the strength of the association, by
connecting the 5,5′ positions of the side rings with a spacer of
proper length. Obviously the spacer should not be too short to
induce high strain energy in the macrocyclic derivative, neither
too long to enable curvature inversion through conformational
motions of the jump-rope type. Such requirements are fulfilled
by a 12-methylene chain, as shown by the fact that a complex
with this structural motif survived to HPLC treatment and its
enantiomers could be separated on a chiral stationary phase at
room temperature.11
Another peculiarity of these derivatives is that, upon com-
plexation, the salophen ligand is forced to assume a nonplanar
U-shaped geometry to accommodate the large uranium atom.
The direct consequence is that compounds such as 1 belong to
the Cs or C1 symmetry group depending on whether the
substituents R and R′ are identical or not. This means that
nonsymmetrically substituted derivatives are chiral8 and might
find use in the field of enantioselective recognition and
asymmetric catalysis. Clearly the great interest toward such
inherently chiral9 derivatives is that the presence of the three
interacting sites (i.e., the metal center and the groups R and R′)
(2) (a) Jacobsen, E. N.; Pfaltz, A. Catalysis; Springer: Berlin, Germany, 1999.
(b) Matsumoto, K.; Saito, B.; Katsuki, T. Chem. Commun. 2007, 3619–3627.
(c) New Frontiers in Asymmetric Catalysis; Mikami, K., Lautens, M., Eds.; John
Wiley & Sons: Hoboken, NJ 2007, and references cited therein.
(3) (a) Rogers, C. W.; Wolf, M. O. Coord. Chem. ReV. 2002, 233-234, 341–
350. (b) Beer, P. D.; Bayly, S. R. Anion sensing by metal-based receptors. In
Anion Sensing; Stibor, I., Ed.; Topics in Current Chemistry 255;Springer: Berlin,
Germany, 2005; pp 125-162.
(4) (a) Pfeiffer, P.; Hesse, T.; Pfitzner, H.; Scholl, W.; Thielert, H. J. Prakt.
Chem. 1937, 217. (b) Bandoli, G.; Clemente, D. A.; Croatto, U.; Vidali, M.;
Vigato, P. A. J. Chem. Soc., Chem. Commun. 1971, 1330–1331.
(5) (a) Antonisse, M. M. G.; Reinhoudt, D. N. Chem. Commun. 1998, 443–
448. (b) van Axel Castelli, V.; Dalla Cort, A.; Mandolini, L.; Pinto, V.; Reinhoudt,
D. N.; Ribaudo, F.; Sanna, C.; Schiaffino, L.; Snellink-Rue¨l, B. H. M. Supramol.
Chem. 2002, 14, 211–219. (c) Dalla Cort, A.; Pasquini, C.; Miranda Murua,
J. I.; Pons, M.; Schiaffino, L. Chem. Eur. J. 2004, 10, 3301–3307. (d) Cametti,
M.; Nissinen, M.; Dalla Cort, A.; Mandolini, L.; Rissanen, K. J. Am. Chem.
Soc. 2007, 129, 3641–3648.
In the present paper we report on the synthesis of a new chiral
macrocyclic uranyl-salophen derivative 3 and on a study of
its configurational stability carried out by dynamic chiral HPLC.
Quite surprisingly, this compound still undergoes enantiomer-
ization at 80 °C on the time scale of the HPLC experiments.
This rather unexpected result, together with those obtained for
the newly synthesized complexes 4 and 5, shed light on the
mechanism of enantiomerization and provided unprecedented
evidence for the occurrence of a ligand hemilability phenomenon
in metal-sal(oph)en complexes. Such findings inspired the
(6) (a) van Axel Castelli, V.; Dalla Cort, A.; Mandolini, L.; Reinhoudt, D. N.
J. Am. Chem. Soc. 1998, 120, 12688–12689. (b) van Axel Castelli, V.; Dalla
Cort, A.; Mandolini, L.; Reinhoudt, D. N.; Schiaffino, L. Chem. Eur. J. 2000, 6,
1193–1198. (c) van Axel Castelli, V.; Dalla Cort, A.; Mandolini, L.; Reinhoudt,
D. N.; Schiaffino, L. Eur. J. Org. Chem. 2003, 62, 7–633. (d) Dalla Cort, A.;
Mandolini, L.; Schiaffino, L. Chem. Commun. 2005, 3867–3869. (e) van Axel
Castelli, V.; Dalla Cort, A.; Mandolini, L.; Pinto, V.; Schiaffino, L. J. Org. Chem.
2007, 72, 5383–5386.
(9) Dalla Cort, A.; Mandolini, L.; Pasquini, C.; Schiaffino, L. New J. Chem.
2004, 28, 1198–1199.
(7) (a) Sessler, J. L.; Melfi, P. J.; Pantos, G. D. Coord. Chem. ReV. 2006,
250, 816–843. (b) Ephritikhine, M. Dalton Trans. 2006, 2501–2516. (c) Takao,
K.; Ikeda, Y. Inorg. Chem. 2007, 46, 1550–1562.
(10) Dalla Cort, A.; Mandolini, L.; Pasquini, C.; Schiaffino, L. Org. Lett.
2004, 6, 1697–1700.
(8) Dalla Cort, A.; Mandolini, L.; Palmieri, G.; Pasquini, C.; Schiaffino, L.
Chem. Commun. 2003, 2178–2179.
(11) Dalla Cort, A.; Mandolini, L.; Pasquini, C.; Schiaffino, L. J. Org. Chem.
2005, 70, 9814–9821.
J. Org. Chem. Vol. 73, No. 16, 2008 6109

Ciogli et al.
SCHEME 1. Synthetic Procedure for Compounds 3-5a
a Reagents and conditions: (a) AlCl3, ClCO(CH2)10COCl; (b) NaCNBH3, ZnI2, ClCH2CH2Cl; (c) BBr3, dry toluene; (d) TiCl4, Cl2CHOCH3, dry CH2Cl2,
0 °C; (e) 1,2-diaminobenzene, UO2(OAc)2 ·2H2O, CH3OH; (f) 1,2-diaminonaphthalene, UO2(OAc)2 ·2H2O, CH3OH.
design and synthesis of compound 6, whose enhanced configu-
rational stability supports the proposed mechanism and offers
prospect for the use of uranyl-salophen complexes as enanti-
oselective receptors and catalysts.
using ternary mixtures of n-hexane/ethanol/CHCl3 (50/30/20,
v/v/v) as eluent (Figure 2). Chromatographic experiments at
higher temperatures (Figure 3) unexpectedly revealed that this
compound still undergoes enantiomerization at appreciable rates,
as shown by the plateau region between the peaks of the
separated enantiomers. Line shape analysis of the chromato-
grams gave numerical values of the first-order rate constants of
enantiomerization, from which the enantiomerization barriers
∆G# were calculated (Table 1).
A dissociation-reassociation process in which the ligand
releases the uranyl dication, undergoes free conformational
changes, and eventually recombines with the metal was excluded
because reassociation could hardly take place under chromato-
graphic conditions. A simple jump rope-type mechanism, in
which the polymethylene chain passes from one side to the other
without dissociation-reassociation, seemed unlikely, but was
not excluded a priori. Obviously, such a motion would be
prevented by suitable extensions of the ligand structure. For
that reason we synthesized cyclophanes 4 and 5 (Scheme 1), in
which jump rope would be strongly hindered, depending on
whether the chain swings from one side to the other over the
aromatic pendant or over the 1,2-diaminobenzene moiety,
respectively. However, when subjected to dynamic HPLC, both
compounds 4 and 5 exhibited temperature-dependent chromato-
grams (Figures 2S and 3S in the Supporting Information)
consistent with enantiomerization processes whose calculated
barriers (Table 1) were almost indistinguishable from that of 3.
These findings, consistent with the rigidity revealed by the
calculated structures of 3-5 (Figure 4), definitely ruled out the
simple jump rope hypothesis for enantiomerization and posed
an intriguing mechanistic challenge.
Results and Discussion
Macrocyclic complex 3 was prepared according to Scheme
1.11 Its chirality was confirmed by the splitting of a number of
1H NMR peaks caused by the addition of a 10-fold molar excess
of R-(-)-2,2,2-trifluoro-1-(9-anthryl)ethanol in CDCl3.12 Ana-
lytical separations of the enantiomers were carried out at 40 °C
with high enantioselectivity (k1′ ) 3.00, R ) 2.91) on a
cellulose-based Chiralcel-OD chiral stationary phase (CSP),
Ligand Hemilability: A Key to Understanding the Enan-
tiomerization Mechanism. Ligand hemilability is a well-
documented phenomenon occurring in transition metal com-
(12) Pirkle’s method was used because no diastereotopic nuclei were available
in the molecule.
6110 J. Org. Chem. Vol. 73, No. 16, 2008

A Configurationally Stable Chiral Uranyl-Salophen Complex
FIGURE 2. Analytical separation of the enantiomers of 3 by enantioselective HPLC at 40 °C. UV (top) and CD (bottom) chromatographic traces
at 400 nm (left) and corresponding online spectra (right).
plexes of bidentate or multidentate hybrid ligands.13 It can be
defined as the property of such complexes to undergo a metal
chelate opening process by rupture of one (usually the weakest)
coordinative bond. Although unprecedented for Schiff base
substituted macrocyclic derivatives. This explains why ligand
hemilability, to the best of our knowledge, had never been
reported before in metal-salen and -salophen complexes. It
is the chirality of complexes 3-5, coupled with their relatively
high configurational stability, that removes the degeneracy and
allows an otherwise silent process to be detected.
N2O2 tetradentate ligands,14 hemilability in complexes 3-5
2-
offers a unique key to the intriguing problem of the enanti-
omerization mechanism. In its simplest version, a mechanistic
hypothesis based on ligand hemilability involves rupture of the
O· · ·U bond on the side of the aromatic pendant. Subsequent
180° rotation around the single bond connecting the imine
carbon atom and the phenoxide ring brings the two ends of the
dodecamethylene chain closer to one another. The chain appears
now to be long enough to pass over the methyl group, as
depicted in Scheme 2, path A. A further 180° rotation, followed
by recombination of the phenoxide with the uranium, would
complete the enantiomerization process. The proposed mech-
anism is clearly consistent with the finding that identical barriers
were measured for compounds 3-5, because in the tricoordi-
nated intermediate there is no steric interaction between the
dodecamethylene chain and the aromatic pendant or the di-
amino-substituted ring. Rupture of one oxygen-metal bond,
followed by 360° rotation of the phenoxide ring and its eventual
recoordination, is clearly a silent process when occurring in
complexes such as 1 (R ) R′) or even in achiral symmetrically
To obtain further insight into the conformational behavior
of compound 3 under the hypothesis that a hemilability process
does actually take place, some calculations based on molecular
dynamics simulations were performed. The global minimum
geometry (GM) found by a conformational search was modified
by breaking the O · · ·U coordinative bond on the same side as
the aromatic pendant. The resulting structure was optimized by
a molecular mechanics method and then used as the starting
geometry for a simulation in the temperature range of 323-423
K. Under the given conditions we did not observe enantiomer-
ization, but quite an easy 360° rotation around the bond between
the imine carbon atom and the disconnected phenoxide ring.
Such a rotation leads, after O · · ·U recombination, to the
N-shaped intermediate I (Scheme 2, path B), whose energy is
some 20 kcal mol-1 higher than that of GM. Rupture of the
other O · · ·U bond, followed by 360° rotation of the correspond-
ing phenoxide ring, gives the other enantiomer, without the
methyl group skipping over the dodecamethylene chain. This
mechanism, as well as the previous one, is consistent with the
measurement of almost identical barriers for compounds 3-5.
(13) (a) Jeffrey, J. C.; Rauchfuss, T. B. Inorg. Chem. 1979, 18, 2658–2666.
(b) Braunstein, P.; Naud, F. Angew. Chem., Int. Ed. 2001, 40, 680–699. (c)
Bassetti, M. Eur. J. Inorg. Chem. 2006, 70, 4473–4482.
A Configurationally Stable Inherently Chiral Uranyl-
Salophen Complex. Although at present there are no conclusive
experimental observations to definitely support either path A
(14) If ligand hemilability does actually occur in salophen complexes, it must
involve one of the O · · ·U bonds, because rupture of a weaker N · · ·U bond would
require concomitant rupture of the adjacent O· · · U bond.
J. Org. Chem. Vol. 73, No. 16, 2008 6111

Ciogli et al.
FIGURE 4. Ball and stick stereoview (left) and CPK (right) calculated
structures of compounds 3-5.
dimerization of the benzyl chlorides. Several attempts at
resolving the statistical mixture of benzylated derivatives of
bisphenol P were unsuccessful. Therefore, the crude product
was subjected as such to macrocyclization under Ziegler’s high
dilution conditions. A pure sample of the desired nonsymmetri-
cal compound 6 was obtained by flash chromatography. The
two enantiomers of 6 were efficiently discriminated at 40 °C
by enantioselective HPLC (k1′ ) 2.65, R ) 2.12) on a Chiralcel-
OD enantioselective column, using a ternary mixture of n-
hexane/ethanol/methanol (60/30/10, v/v/v) as the mobile phase
(Figure 5). When the temperature was increased above 80 °C,
the appearance of an appreciable characteristic plateau zone
between the two peaks still denoted the occurrence of a dynamic
enantiomerization process concurrent with the chromatographic
separation. The first-order enantiomerization rate constants,
calculated by simulation of the chromatograms recorded at 80
and 90 °C, are given in Figure 6. These values correspond to
∆G# values of 26.64 and 26.99 kcal mol-1, respectively,15 which
means that the energy barrier for enantiomerization of 6 is a
couple of kilocalories per mole higher than that of 3 (Table 1).
On the basis of the assumption that ∆G# is temperature
independent, we calculate for 6 an enantiomerization half-life
of 61 d at room temperature, a value that is 32, 27, and 16
times higher than those calculated for 3, 4, and 5, respectively.
These experimental results, while offering support to the
hypothesis that enantiomerization in uranyl-salophen complexes
implies a ligand hemilability phenomenon, clearly establish that
compound 6, easily obtainable in enantiomerically pure form
by semipreparative enantioselective HPLC, represents the first
FIGURE 3. Temperature-dependent chromatograms of 3 on Chiralcel-
OD column. Experimental profiles (left) vs calculated profiles (right)
on the basis of the best first rate constants for enantiomerization (see
Figure 2S within the Supporting Information for a superimposed view
of experimental and simulated profiles).
TABLE 1. Activation Barriers ∆G# (kcal mol-1) for the
Enantiomerization of Compounds 3-5
T (°C)
3
4
5
60
24.83
25.10
65
70
75
80
24.74
24.79
24.85
24.89
24.92
25.11
25.23
25.22
25.28
24.91
24.84
24.83
mean ∆G#
24.8 ( 0.1
24.9 ( 0.1
25.2 ( 0.1
or path B in Scheme 2, the hypothesis that the enantiomerization
of inherently chiral uranyl-salophen macrocyclic complexes
originates from ligand hemilability seems quite reasonable. Thus
it was felt that an increase in the rigidity of the spacer should
destabilize any intermediate involved in the enantiomerization
process, thereby enhancing the enantiomerization half-life to
such an extent that the use of uranyl-salophen complexes in
enantioselective recognition and catalysis might become a
practical proposition. On the basis of these considerations, we
replaced the polymethylene chain of 3-5 with a more rigid
spacer, i.e., the one derived from 4,4′-(1,4-phenylenediisopro-
pylidene)bisphenol (bisphenol P), that appeared to meet the
requirement of ensuring a high rigidity to the macrocyclic
complex without compromising its formation and stability. A
molecular dynamics investigation of compound 6 showed that
a much higher temperature is required to achieve enantiomer-
ization. This complex was prepared according to Scheme 3.
Slow addition of a mixture of 11 and 12 to a solution of sodium
hydride and bisphenol P in DMF was necessary to prevent
(15) As suggested by a reviewer, one strongly enriched enantiomer of 6,
obtained from semipreparative chromatographic enantioseparation of a small
sample of racemic 6 (CHIRALPAK IA, 250 × 100 mm i.d., chiral stationary
phase; mobile phase n-hexane/CH2Cl2/MeOH 60:10:30 v/v/v), was subjected to
classical determination of the enantiomerization kinetics under homogeneous
conditions in the solvent mixture (n-hexane/EtOH/MeOH 60:30:10 v/v/v) used
in the dynamic HPLC measurements. Racemization was monitored as a function
of time by analytical enantioselective chromatography at 20 °C. A value of 7.5
× 10-5 s-1 was determined for the enantiomerization rate constant at 65 °C,
which corresponds to an activation barrier of ∆G* ) 26.26 kcal mol-1. This
value compares fairly well with the values determined by dynamic HPLC,
showing that major contributions to enantiomerization from the stationary phase
are very unlikely.
6112 J. Org. Chem. Vol. 73, No. 16, 2008

A Configurationally Stable Chiral Uranyl-Salophen Complex
SCHEME 2. Enantiomerization of Uranyl-Salophen Complex 3 Based on Ligand Hemilability via the One-Step Mechanism
(path A) and via a Two-Step Mechanism (path B)a
a For the cR-cS chirality descriptors see ref 9.
twice with 30 mL portions of CH2Cl2. The organic layers were
combined, washed with 25 mL of H2O, and dried over Na2SO4.
Chromatographic purification of the crude product (silica gel, 2%
ethyl acetate in hexanes) afforded 4′-tert-butyl-2-methoxybiphenyl
as a colorless oil (1.48 g, 88% yield). 1H NMR (200 MHz, CDCl3)
δ 7.54-7.42 (m, 4H), 7.35-7.28 (m, 2H), 7.05-6.97 (m, 2H), 3.82
(s, 3H), 1.36 (s, 9H) ppm.
1-(6-Methoxy-1,1′-biphenyl-3-yl)-12-(3-methyl-4-methoxyphe-
nyl)dodecane-1,12-dione (7a). AlCl3 (2.29 g, 17.2 mmol) and
CH2Cl2 (2.0 mL) were placed under argon atmosphere in a dry
flask cooled with an ice bath. A solution of dodecanedioic acid
dichloride (2.19 g, 8.19 mmol) in CH2Cl2 (2.0 mL) was added.
2-Methylanisole (1.00 g, 8.19 mmol) and 2-methoxy-1,1′-biphenyl
(1.51 g, 8.19 mmol) in CH2Cl2 (2.0 mL) were slowly added and
finally the mixture was diluted with CH2Cl2 (2.0 mL) and stirred
for 40 min at room temperature. The resulting mixture was slowly
poured into ice cold 6 M hydrochloric acid (20 mL) and CH2Cl2
member of a new family of inherently chiral receptors whose
potential in chiral recognition and catalysis actually can be
explored.
Experimental Section
Solvents and chemicals were used as received unless otherwise
stated. 2-Hydroxy-3-phenylbenzaldehyde was available from a
previous work.6e
4′-tert-Butyl-2-methoxy-1,1′-biphenyl. A solution of p-tert-
butylbromobenzene (1.50 g, 7.0 mmol) and Pd(PPh3)4 (0.152 g,
0.131 mmol) in 23 mL of anhydrous toluene was added to a solution
of 2-methoxyphenylboronic acid (1.34 g, 8.82 mmol) in 20 mL of
absolute ethanol under argon atmosphere, followed by addition of
K2CO3 (2.15 g, 15.5 mmol). The mixture was stirred and heated to
reflux for 20 h and allowed to cool to room temperature. NaOH
(55 mL, 0.5 M solution) was added and the mixture was extracted
J. Org. Chem. Vol. 73, No. 16, 2008 6113

Ciogli et al.
SCHEME 3. Synthetic Procedure for Compound 6a
a Reagents and conditions: (a) NaH, DMF; (b) 1,2-diaminobenzene, UO2(OAc)2 ·2H2O, CH3OH.
FIGURE 5. Analytical separation of the enantiomers of 6 by enantioselective HPLC at 25 °C. UV (top) and CD (bottom) chromatographic traces
at 400 nm (left) and corresponding online spectra (right).
(15 mL) was added. The organic layer was washed twice with 20
mL of NaHCO3 (sat.) and then with 20 mL of brine, then it was
dried over anhydrous sodium sulfate. Chromatographic purification
of the crude product (silica gel, 5% acetone and 10% CHCl3 in
6114 J. Org. Chem. Vol. 73, No. 16, 2008

A Configurationally Stable Chiral Uranyl-Salophen Complex
136.1, 135.9, 131.7, 130.8, 130.0, 129.9, 129.7, 129.0, 128.5, 127.5,
124.1, 116.3, 115.4, 35.9, 35.8, 32.6, 32.5, 30.5, 30.4, 30.3, 30.1,
16.0 ppm. MS-ESI-TOF for C31H40O2 444.30, found 467.4 ([M +
Na]+).
1-(5-Formyl-6-hydroxy-1,1′-biphenyl-3-yl)-12-(3-formyl-4-hy-
droxy-5-methylphenyl)dodecane (10a). Compound 9a (0.880 g,
1.98 mmol) was dissolved in dry dichloromethane (70 mL) and
placed under an argon atmosphere in a dry two-necked flask
together with R,R′-dichloromethyl methyl ether (4.6 mL, 51.5
mmol). Titanium tetrachloride (2.6 mL, 23 mmol) was added
dropwise over 20 min to the stirred solution cooled at 0 °C. After
2 h, the reaction mixture was diluted with water (300 mL). The
aqueous layer was extracted with 2 portions of dichloromethane
(200 mL each). The combined organic layers were washed twice
with 150 mL of water, dried over anhydrous sodium sulfate, and
concentrated to afford an oil that was purified by flash chroma-
tography (silica gel, 5% ethyl acetate in hexanes) to give the desired
product as a pale yellow oil (0.180 g, 18% yield). Elemental Anal.
Calcd (%) for C33H40O4: C, 79.16; H, 8.05. Found: C, 79.20; H,
7.96. 1H NMR (200 MHz, CDCl3) δ 11.34 (s, 1H), 11.08 (s, 1H),
9.91 (s, 1H), 9.83 (s, 1H), 7.59-7.57 (m, 2H), 7.44-7.33 (m, 5H),
7.20-7.15 (m, 2H), 2.62 (t, 2H, J ) 7.63 Hz), 2.53 (t, 2H, J )
7.90 Hz), 2.24 (s, 3H), 1.67-1.51 (m, 4H), 1.29-1.25 (m, 16H)
ppm. 13C NMR (50 MHz, CDCl3) δ 197.5, 197.4, 158.8, 157.7,
139.1, 139.0, 137.2, 135.0, 134.4, 133.0, 131.0, 130.9, 130.0, 128.9,
128.3, 127.2, 121.3, 120.4, 35.5, 35.4, 32.2, 32.1, 30.3, 30.2, 30.1,
29.9, 15.7 ppm. MS-ESI-TOF for C33H40O4 500.29, found 523.9
([M + Na]+).
1-(4′-tert-Butyl-5-formyl-6-hydroxy-1,1′-biphenyl-3-yl)-12-(3-
formyl-4-hydroxy-5-methylphenyl)dodecane (10b). AlCl3 (0.707
g, 5.31 mmol) and CH2Cl2 (0.7 mL) were placed under argon
atmosphere in a dry flask cooled with an ice bath. A solution of
dodecanedioic acid dichloride (0.549 g, 2.05 mmol) in CH2Cl2 (0.7
mL) was added. 2-Methylanisole (0.255 g, 2.08 mmol) and 4′-tert-
butyl-2-methoxy-1,1′-biphenyl (0.505 g, 2.10 mmol) in CH2Cl2 (1.0
mL) were slowly added and finally the mixture was diluted with
CH2Cl2 (1.0 mL) and stirred for 150 min at room temperature. The
resulting mixture was slowly poured into ice cold 6 M hydrochloric
acid (10 mL) and CH2Cl2 (5 mL) was added. The organic layer
was washed twice with 10 mL of NaHCO3 (sat.) and then with 10
mL of brine, then it was dried over anhydrous sodium sulfate.
Chromatographic treatment of the crude product (silica gel, 3%
acetone, and 15% CHCl3 in hexanes) allowed the recovery of 0.424
g of a mixture of product 7b and its symmetrical byproduct. Since
all attempts were unsuccessful, no further purification was carried
on. This mixture was then dissolved in 8.0 mL of 1,2-dichloroet-
hane. ZnI2 (0.729 g, 2.28 mmol) and NaCNBH3 (0.718 g, 11.4
mmol) were added in the given order and the reaction mixture was
stirred at room temperature for 22 h, after which it was filtered on
a celite plug that was washed thoroughly with dichloromethane.
Evaporation of the solvent afforded 0.4 g of a mixture of 8b and
the corresponding symmetrical products. Since even at this stage
all attempts at further purification were unsuccessful, this mixture
was used as is, dissolved in dry toluene (5.0 mL), and placed under
an argon atmosphere in a dry flask. A solution of boron tribromide
(0.18 mL, 1.9 mmol) in dry toluene (5.0 mL) was added dropwise
to the stirred solution cooled at 0 °C The reaction mixture was
stirred for 23 h at room temperature, then cooled again in an ice
bath and water (50 mL) was added. The solution was extracted
with 3 portions of diethyl ether (40 mL each), the combined organic
layers were washed twice with 30 mL of water and dried over
anhydrous sodium sulfate. Evaporation of the solvent afforded a
mixture of 9b and its symmetrical counterparts that was again used
as such in the following step. The above mixture (0.880 g, 1.98
mmol) was dissolved in dry dichloromethane (70 mL) and placed
under an argon atmosphere in a dry two-necked flask together with
R,R′-dichloromethyl methyl ether (4.6 mL, 51.5 mmol). Titanium
tetrachloride (2.6 mL, 23 mmol) was added dropwise over 20 min
to the stirred solution that was cooled at 0 °C. After 2 h, the reaction
FIGURE 6. Temperature-dependent chromatograms of 6 on Chiralcel-
OD column. Experimental profiles (left) vs calculated profiles (right)
on the basis of the best first rate constants for the enantiomerization.
(see Figure 3S in the Supporting Information for a superimposed view
of experimental and simulated profiles).
hexanes) afforded 7a as a colorless oil (1.08 g, 24% yield).
Elemental Anal. Calcd (%) for C33H40O4: C, 79.16; H, 8.05. Found:
1
C, 79.25; H, 7.94. H NMR (200 MHz, CDCl3) δ 7.98-7.77 (m,
4H), 7.53-7.34 (m, 5H), 7.00 (d, 1H, J ) 8.48 Hz), 6.83 (d, 1H,
J ) 8.48 Hz), 3.88 (s, 6H), 2.96-2.85 (m, 4H), 2.23 (s, 3H),
1.75-1.66 (m, 4H), 1.38-1.24 (m, 12H) ppm. 13C NMR (50 MHz,
CDCl3) δ 200.3, 200.0, 162.2, 160.9, 138.3, 131.9, 131.4, 131.3,
130.9, 130.4, 130.2, 130.1, 128.8, 128.1, 127.4, 111.3, 109.9, 56.5,
56.2, 39.0, 38.9, 30.1, 25.4, 25.3, 17.0 ppm. MS-ESI-TOF for
C33H40O4 500.29, found 523.6 ([M + Na]+).
1-(6-Methoxy-1,1′-biphenyl-3-yl)-12-(3-methyl-4-methoxyphe-
nyl)dodecane (8a). Compound 7a (0.125 g, 0.250 mmol) was
dissolved in 2.5 mL of 1,2-dichloroethane. ZnI2 (0.239 g, 0.749
mmol) and NaCNBH3 (0.235 g, 3.94 mmol) were added in the given
order and the reaction mixture was stirred at room temperature for
20 h. The mixture was then filtered on a celite plug that was washed
thoroughly with dichloromethane. Evaporation of the solvent
afforded the desired product as a colorless oil in quantitative yield.
1H NMR (200 MHz, CDCl3) δ 7.59 (br d, 2H, J ) 7.25 Hz), 7.46
(br t, 2H), 7.38 (m, 1H), 7.20-7.16 (m, 2H), 7.01 (m, 2H), 6.95
(d, 1H, J ) 8.12 Hz), 6.78 (d, 1H, J ) 8.78 Hz), 3.85 (s, 3H), 3.83
(s, 3H), 2.65 (t, 2H, J ) 7.68 Hz), 2.57 (t, 2H, J ) 7.90 Hz), 2.27
(s, 3H), 1.65-1.63 (m, 4H), 1.37-1.33 (m, 16H) ppm. 13C NMR
(50 MHz, CDCl3) δ 156.4, 155.2, 139.4, 135.9, 135.3, 131.6, 131.4,
131.1, 130.2, 128.9, 128.6, 127.5, 127.0, 126,9, 111.8, 110.5, 56.3,
56.0, 35.8, 35.7, 30.2, 30.0, 16.9 ppm. MS-ESI-TOF for C33H44O2
472.33, found 495.5 ([M + Na]+).
1-(6-Hydroxy-1,1′-biphenyl-3-yl)-12-(3-methyl-4-hydroxyphe-
nyl)dodecane (9a). Compound 8a (0.119 g, 0.250 mmol) and dry
toluene (3.0 mL) were placed under an argon atmosphere in a dry
flask. A solution of boron tribromide (0.062 mL, 0.66 mmol) in
dry toluene (3.0 mL) was added dropwise to the stirred solution
cooled at 0 °C. The reaction mixture was stirred for 24 h at room
temperature, then cooled again in an ice bath, and then water (40
mL) was added. The solution was extracted with 3 portions of
diethyl ether (30 mL each), then the combined organic layers were
washed twice with 20 mL of water and dried over anhydrous sodium
sulfate. Evaporation of the solvent afforded 9a as a dark brown oil
pure enough to be used as such in the following step (0.113 g,
1
96% yield). H NMR (200 MHz, CDCl3) δ 7.46-7.27 (m, 4H),
7.22-7.04 (m, 3H), 6.91-6.85 (m, 3H, J ) 8.12 Hz), 6.66 (d, 1H,
J ) 8.03 Hz), 5.29 (s, 2H), 2.55 (t, 2H, J ) 7.68 Hz), 2.48 (t, 2H,
J ) 7.90 Hz), 2.21 (s, 3H), 1.59-1.52 (m, 4H), 1.28-1.18 (m,
16H) ppm. 13C NMR (50 MHz, CDCl3) δ 152.4, 151.0, 138.2,
J. Org. Chem. Vol. 73, No. 16, 2008 6115

Ciogli et al.
mixture was diluted with water (300 mL). The aqueous layer was
extracted with 2 portions of dichloromethane (200 mL each). The
combined organic layers were washed twice with 150 mL of water,
dried over anhydrous sodium sulfate, and concentrated to afford
an oil that was purified by flash chromatography (silica gel, 5%
ethyl acetate in hexane) to give the desired product as a pale yellow
oil (0.180 g, 18% yield). Elemental Anal. Calcd (%) for C37H48O4:
5-Chloromethyl-2-hydroxy-3-phenylbenzaldehyde (11). 2-Hy-
droxy-3-phenylbenzaldehyde (0.402 g, 2.03 mmol) was dissolved
in a mixture of dioxane (3.6 mL), glacial acetic acid (0.760 mL),
85% phosphoric acid (0.760 mL), and 35% hydrochloric acid (36.4
mL). p-Formaldehyde (1.21 g, 40.3 mmol) was added and the
reaction mixture was stirred at 80 °C for 24 h, after which time
H2O (25 mL) and dichloromethane (25 mL) were added. The
organic phase was washed with H2O until neutrality and dried over
sodium sulfate. Evaporation of the solvent afforded the desired
product as a colorless oil (0.500 g, 100% yield). Elemental Anal.
Calcd (%) for C14H11ClO2: C, 68.16; H, 4.49. Found: C, 68.07; H,
1
C, 79.82; H, 8.69. Found: C, 79.93; H, 8.55. H NMR (200 MHz,
CDCl3) δ 11.40 (s, 1H), 11.14 (s, 1H), 9.96 (s, 1H), 9.87 (s, 1H),
7.62-7.20 (m, 8H), 2.71-2.55 (m, 4H), 2.29 (s, 3H), 1.68-1.50
(m, 4H), 1.40-1.24 (m, 25H) ppm. 13C NMR (50 MHz, CDCl3) δ
197.6, 197.5, 158.8, 157.7, 139.2, 139.0, 135.1, 134.5, 133.1, 132.3,
131.1, 130.0, 129.9, 129.6, 128.3, 127.2, 120.5, 35.5, 32.3, 30.5,
30.3, 30.2, 29.9, 15.8 ppm. MS-ESI-TOF for C37H48O4 556.77,
found 579.8 ([M + Na]+).
1
4.71. H NMR (200 MHz, CDCl3) δ 11.58 (s, 1H), 9.94 (s, 1H),
7.64-7.38 (m, 7H), 4.63 (s, 2H) ppm. 13C NMR (50 MHz, CDCl3)
δ 196.4, 158.9, 138.0, 135.6, 132.8, 131.2, 129.6, 129.2, 128.3,
124.6, 120.6, 45.2 ppm. GC-MS m/z (+) 211 (M+ - Cl, 100%).
5-Chloromethyl-2-hydroxy-3-methylbenzaldehyde (12). 2-Hy-
droxy-3-methylbenzaldehyde (1.10 mL, 9.07 mmol), formaldehyde
37 wt % in H2O (0.7 mL), and concentrated hydrochloric acid (9.5
mL) were mixed and stirred overnight. The solid that separated
from the reaction mixture was filtered, dissolved in diethyl ether,
and dried over sodium sulfate. Recrystallization from light petro-
leum afforded 12 in 65% yield (mp 76-77 °C, lit.16 mp 81.5-82.5).
1H NMR (200 MHz, CDCl3) δ 11.31 (s, 1H), 9.86 (s, 1H), 7.42
(br s, 2H), 4.55 (s, 2H), 2.27 (s, 3H) ppm.
Complex 3. A solution of 10a (0.064 g, 0.128 mmol) in
dichloromethane (2.5 mL) and a solution of 1,2-diaminobenzene
(0.0138 g, 0.127 mmol) in a 1:1 mixture of methanol and
dichloromethane (2.5 mL) were added separately and simulta-
neously by a syringe pump over 5.5 h to a solution of uranyl acetate
(0.055 g, 0.129 mmol) in methanol (100 mL). Formation of a red
precipitate was observed. The mixture was left to stand overnight
at room temperature and then concentrated to a volume of 10 mL
and dissolved again in dichloromethane (100 mL). The organic
phase was extracted with 2 portions of a saturated solution of
NaHCO3 (50 mL each), washed to neutrality with 2 portions of
water (40 mL each), dried over anhydrous sodium sulfate, and
concentrated to afford a dark red product that was purified by flash
chromatography (silica gel, 30% acetone in cyclohexane) to give
the desired products as a dark red solid (0.060 g, 56% yield).
Elemental Anal. Calcd (%) for C39H42N2O4U·3H2O: C, 52.35; H,
Complex 6. Sodium hydride 60% dispersion in mineral oil (1.78
g, 44.5 mmol) was placed under argon atmosphere in a dry flask,
washed three times with n-hexane, and suspended in anhydrous
DMF (9 mL). 4-(1-{4-[1-(4-Hydroxyphenyl)-1-methylethyl]phe-
nyl}-1-methylethyl)phenol (0.843 g, 2.43 mmol) was slowly added.
After the evolution of hydrogen had ceased, a solution of 11 (0.599
g, 2.44 mmol) and 12 (0.450 g, 2.44 mmol) in DMF (7 mL) was
slowly added by a syringe pump over 24 h. The resulting yellow
solution was gently poured over ice, acidified with concentrated
hydrochloric acid to pH 3-4, and extracted with two 25 mL
portions of dichloromethane. The organic layers were collected,
washed with brine, and dried over anhydrous sodium sulfate.
Chromatographic treatment of the crude product (silica gel, toluene)
afforded 0.940 g of a mixture of product 13 and its symmetrical
counterparts. Since all attempts were unsuccessful, no further
purification was carried on. A solution of this mixture in dichlo-
romethane (60 mL) and a solution of 1,2-diaminobenzene (0.159
g, 1.47 mmol) in a 1:1 mixture of methanol and dichloromethane
(60 mL) were added separately and simultaneously by syringe pump
over 24 h to a solution of uranyl acetate (0.725 g, 1.71 mmol) in
methanol (380 mL). The reaction mixture was filtered to remove
an orange precipitate containing the higher oligomers of the desired
product, concentrated to a volume of 100 mL, and diluted with
dichloromethane (250 mL). The organic phase was washed to
1
5.41; N, 3.13. Found: C, 52.63; H, 5.28; N, 3.33. H NMR (200
MHz, acetone-d6) δ 9.43 (s, 1H), 9.38 (s, 1H), 7.86-7.73 (m, 4H),
7.60-7.40 (m, 7H), 7.29 (br m, 1H), 7.21 (br m, 1H), 2.69-2.64
(m, 2H), 2.58-2.54 (m, 2H), 2.39 (s, 3H), 1.62-1.08 (m, 20H)
ppm. 13C NMR (75 MHz, acetone-d6) δ 167.6, 167.4, 147.6, 140.5,
137.4, 133.8, 131.6, 131.5, 130.8, 130.4, 129.4, 129.3, 128.3, 126.8,
124.6, 122.8, 119.6, 34.5, 33.0, 32.2, 31.9, 31.8, 31.8, 28.3, 27.0,
16.4 ppm. MS-ESI-TOF for C39H42N2O4UNa+ calcd 863.36, found
863.32.
Complex 4. Preparation was accomplished following the same
procedure as described for 3 and replacing 10a with 10b. The
desired product was purified by flash chromatography (silica gel,
20% ethyl acetate in cyclohexane) to give the desired products as
a dark red solid in a 38% yield. Elemental Anal. Calcd (%) for
C43H50N2O4U·3H2O: C, 54.31; H, 5.94; N, 2.95. Found: C, 54.55;
H, 6.06; N, 2.79. 1H NMR (200 MHz, acetone-d6) δ 9.44 (s, 1H),
9.39 (s, 1H), 7.88-7.23 (m, 12H), 2.65-2.51 (m, 4H), 2.39 (s,
3H), 1.71-1.10 (m, 29H) ppm. 13C NMR (75 MHz, acetone-d6) δ
167.8, 167.7, 147.7, 147.3, 137.4, 134.0, 133.0, 131.4, 130.5, 130.0,
129.5, 129.4, 128.4, 128.1, 127.0, 124.8, 123.3, 123.2, 122.4, 119.8,
119.7, 35.8, 35.4, 35.2, 34.9, 34.7, 32.4, 32.0, 30.7, 26.7, 23.5, 23.0,
22.9, 22.5, 22.3, 16.3 ppm. MS-ESI-TOF for C43H50N2O4UNa+
calcd 919.42, found 919.15.
(16) Stoermer, R.; Behn, K. Chem. Ber. 1901, 34, 2455–2460.
(17) (a) QCPE program No. 633 by Martin Jung, Indiana University,
Bloomington, IN, 1991. (b) Trapp, O.; Schurig, V. Comp. Chem. 2001, 25, 187-
195.
(18) (a) Gasparrini, F.; Lunazzi, L.; Mazzanti, A.; Pierini, M.; Pietrusiewicz,
K. M.; Villani, C. J. Am. Chem. Soc. 2000, 122, 4776–4780. (b) Dell’Erba, C.;
Gasparrini, F.; Grilli, S.; Lunazzi, L.; Mazzanti, A.; Novi, M.; Pierini, M.; Tafani,
C.; Villani, C. J. Org. Chem. 2002, 67, 1663–1668. (c) Gasparrini, F.; Grilli, S.;
Leardini, R.; Lunazzi, L.; Mazzanti, A.; Nanni, D.; Pierini, M.; Pinamonti, M.
J. Org. Chem. 2002, 67, 3089–3095. (d) Dalla Cort, A.; Gasparrini, F.; Lunazzi,
L.; Mandolini, L.; Mazzanti, A.; Pasquini, C.; Pierini, M.; Rompietti, R.;
Schiaffino, L. J. Org. Chem. 2005, 70, 8877–8883. (e) Cirilli, R.; Ferretti, R.;
La Torre, F.; Secci, D.; Bolasco, A.; Carradori, S.; Pierini, M. J. Chromatogr.
A 2007, 117, 160–169.
Complex 5. Preparation was accomplished following the same
procedure as described for 3 and replacing 1,2-diaminobenzene with
2,3-diaminonaphthalene. The desired product was purified by flash
chromatography (silica gel, 20% ethyl acetate in cyclohexane) to
give the desired products as a dark red solid in a 62% yield.
Elemental Anal. Calcd (%) for C43H44N2O4U·3H2O: C, 54.66; H,
1
5.33; N, 2.96. Found: C, 54.48; H, 5.59; N, 3.14. H NMR (200
(19) (a) Giddings, J. C. J. Chromatogr. 1960, 3, 443–453. (b) Kramer, R.
J. Chromatogr. 1975, 107, 241–252. (c) Schurig, V.; Burkle, W. J. Am. Chem.
Soc. 1982, 104, 7573–7580. (d) Burkle, W.; Karfunkel, H.; Schurig, V.
J. Chromatogr. 1984, 288, 1–14. (e) Veciana, J.; Crespo, M. I. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 74–77. (f) Trapp, O.; Schoetz, G.; Schurig, V. Chirality
2001, 13, 403–414. (g) Trapp, O. Anal. Chem. 2006, 78, 189–198. (h) Oxelbark,
J.; Allenmark, S. J. Chem. Soc., Perkin Trans. 2 1999, 8, 1587–1590. (i) Wolf,
C. Chem. Soc. ReV. 2005, 34, 595–608. (j) Cabrera, K.; Jung, M.; Fluck, M.;
Schurig, V. J. Chromatogr. A 1996, 731, 315–321. (k) Trapp, O.; Schurig, V.
Chirality 2002, 14, 465–470. (l) Trapp, O.; Trapp, G.; Schurig, V. J. Biochem.
Biophys. Methods 2002, 54, 301–313.
MHz, acetone-d6) δ 9.62 (s, 1H), 9.56 (s, 1H), 8.22-7.86 (m, 4H),
7.87 (br d, 2H), 7.56-7.26 (m, 9H), 2.69-2.56 (m, 4H), 2.42 (s,
3H), 1.80-1.10 (m, 20H) ppm. 13C NMR (75 MHz, acetone-d6) δ
167.4, 167.3, 147.6, 147.3, 139.4, 139.0, 137.5, 137.0, 134.6, 132.4,
132.0, 130.8, 130.5, 130.4, 129.3, 129.2, 128.3, 128.0, 127.7, 126.9,
125.4, 125.0, 124.4, 122.8, 117.7, 117.6, 35.1, 34.9, 31.4, 30.9,
30.5, 30.4, 28.0, 16.2 ppm. MS-ESI-TOF for C43H44N2O4UNa+
calcd 913.37, found 913.49.
6116 J. Org. Chem. Vol. 73, No. 16, 2008

A Configurationally Stable Chiral Uranyl-Salophen Complex
neutrality with 3 portions of water (200 mL each) and dried over
anhydrous sodium sulfate. The crude product was purified twice
by flash chromatography (silica gel, 15% acetone in cyclohexane)
to give the desired product as a red solid (0.041 g, 1.6% yield).
Elemental Anal. Calcd (%) for C53H46N2O4U·3H2O: C, 57.92; H,
performed by inserting the apparent enantiomerization rate constants
k determined by DHPLC simulations at the suitable temperatures
into the Eyring equation:
γkBT
∆G# ) RT ln
1
4.77; N, 2.55. Found: C, 57.79; H, 4.95; N, 2.70. H NMR (300
hk
MHz, CDCl3) δ 9.30 (s, 1H), 9.27 (s, 1H), 7.86-7.49 (m, 12H),
6.95-6.56 (m, 13H), 5.35 (d, 1H, J ) 13.8 Hz), 5.27 (d, 1H, J )
13.6 Hz), 5.07-4.96 (m, 2H), 2.54 (s, 3H), 1.49-1.41 (m, 12H)
ppm. 13C NMR (50 MHz, CDCl3) δ 166.8, 166.6, 156.1, 148.1,
148.0, 147.1, 146.9, 142.1, 141.9, 139.6, 136.4, 135.9, 133.8, 132.5,
131.9, 130.5, 129.8, 129.6, 129.4, 128.7, 128.3, 127.6, 127.4, 126.6,
126.3, 124.3, 122.7, 119.7, 119.6, 114.4, 114.3, 68.7, 68.5, 42.2,
31.9, 31.8, 31.2, 17.2 ppm. MS-ESI-TOF for C53H446N2O6U calcd
1044.39, found 1045.20 ([M + H+]), 1067.12 ([M + Na+]), 1083.18
([M + K+]).
where kB is the Boltzmann constant, T is temperature, R is the gas
constant, h is the Planck constant, γ is the transmission factor, and
k is the rate constant. In all calculations the transmission factor γ
was set to 1. A quite comprehensive view of both fundamental
works concerning principles on which dynamic chromatography
is based on and applications of the dynamic chromatography
technique to the study enantiomerization processes is given in ref
19.
Computational Methods. Molecular modeling calculations were
performed by the program HyperChem Professional for Windows
OS, release 7.5, running on a PC equipped with Intel Pentium 4,
CPU 3.40 GHz, 2 GB of RAM, and OS Windows 2000 Profes-
sional. The conformational search of compounds 3 and 6 was carried
out by using the following options: MM+ Force Field with
electrostatic contributions evaluated by atomic charges; all rotatable
bonds on dodecamethylene (compound 3) or the aromatic (com-
pound 6) chain were varied by the “torsional flexing” procedure of
Kolossva´ry and Guida,20 as implemented in the program; maximum
number of retained conformers ) 1000; acceptance energy criterion
3 kcal mol-1 above global minimum; maximum number of iterations
and optimizations 100 000, 1000; maximum number of cycles 1000;
rms gradient 0.01 kcal/(Å mol); conformations selected to vary
chosen by usage directed; random number generation based on the
computer’s clock. Molecular dynamic simulations were performed
in vacuum by molecular mechanics calculations (MM+ force field),
with the electrostatic contributions evaluated by atomic charges.
Other options were the following: heat time 0.5 ps, run time 3 ps,
cool time 1 ps, step size 0.001 ps, starting temperature 0 K,
simulation temperature variable from 323 to 423 K for 3 and from
323 to 675 K for 6, final temperature 0 K, temperature step 30 K,
constant temperature, and bath relaxation time 0.1 ps. Geometries
of global minima (GM) coming from the conformational search
on 3 and 6 were used as such within molecular dynamic simulations
of the mechanism reported in Scheme 2, path A. Under the
aforementioned conditions we did not observe enantiomerization
for both 3 and 6 derivatives. GM of 3 and 6 were also modified by
breaking the O · · ·U coordinative bond on the side as the aromatic
pendant and, after optimization in vacuum by the molecular
mechanics method, the resulting geometries (GMU+O-) were used
as starting species to simulate the mechanism reported in path B.
In both optimizations and dynamic simulations charges on oxygen
and uranium atoms derived by the heterolytic O · · ·U bond cleavage
were set scaling their formally unitary values by a suitable factor
to simulate the shielding effect of the solvents employed within
the DHPLC determinations. The used factors, expressed as the
reciprocal of the solvent permittivity, were 0.16 for 3 and 0.14 for
6 (permittivity values for the mixtures n-hexane/ethanol/CHCl3 50/
30/20 and n-hexane/ethanol/methanol 60/30/10 were assessed
according to the Kirkwood theory).21 All molecular dynamic
simulations on GMU+O- of 3 led to an easy 360° rotation around
the bond between the imine carbon atom and the disconnected
phenoxide ring, independently from the set temperature. Instead,
the same transformation was observed on GMU+O- of 6 only at a
temperature of 675 K. Analogous transformation was also recorded
on GMU+O- 6 at 363 K when charges on oxygen and uranium atoms
were scaled by a factor 0.04, corresponding to a formal solvent
permittivity of 25. In all cases of favorable rotation of the
disconnected phenoxide ring, simulations of molecular dynamic
Chromatography. Analytical liquid chromatography was per-
formed on a chromatograph equipped with a Rheodyne model 7725i
20 µL loop injector, PU-1580-CO2 and PU-980 Jasco HPLC pumps,
and a Jasco 995-CD chiro-optical UV/CD detector. Chromato-
graphic data were collected and processed with Jasco Borwin
software.
Enantioseparations were performed on a Chiralcel-OD column,
using n-hexane/ethanol/CHCl3 (50/30/20, v/v/v, for 3 and 4; 55/30/
15, v/v/v, for 5) and n-hexane/ethanol/methanol (60/30/10, v/v/v, for
6) as the mobile phases at different flow rates with UV detection at
400 nm. Chiralcel-OD (cellulose tris(3,5-dimethyl phenylcarbamate)
coated on a 5 µm mesoporous silica gel column (250 × 4.6 mm, L ×
i.d.)) was obtained from Chiral Technologies. Variable-temperature
chromatography with UV and CD detection was performed by placing
the column inside a homemade thermally insulated container cooled
by the expansion of liquid carbon dioxide. The flow of liquid CO2
and the column temperature were regulated by a solenoid valve, a
thermocouple, and an electric controller. Temperature variations after
thermal equilibration were within (0.1 °C.
Dynamic High Performance Liquid Chromatography (DH-
PLC). Reproducibility of all variable-temperature experimental
chromatograms (VTECs) employed in on-column rate constants
determinations was checked by comparing the retention times
registered within three independent injections at identical conditions.
Simulation of VTECs was performed by use of the dedicated home
made computer program Auto DHPLC y2k (Auto Dynamic HPLC),
which implements both stochastic and theoretical plates models
according to mathematical equations and procedures described in
refs 17a and 17b, respectively. The implemented algorithm may
take into account all types of first-order interconversions, i.e.,
enantiomerizations as well as diastereomerizations or constitutional
isomerizations (e.g., pseudo-first-order tautomerizations). Program
functionality was validated on several first-order isomerizations
(both enantiomerizations and nonenantiomerizations) by comparing
DHPLC results with the equivalent ones obtained by DNMR
technique18a–d or classical method.18e The used algorithm also
allows for taking tailing effects into account. Both chromatographic
(retention times, number of theoretical plates, peaks’ tailing) and
kinetic parameters (apparent rate constants) can be automatically
optimized by simplex procedure to obtain the best agreement
between experimental and simulated dynamic chromatograms. In
the present paper all simulations were performed employing the
stochastic model and taking into account tailing effects. The
agreement between experimental and simulated dynamic chromato-
grams was quantitatively evaluated as root-mean-square differences
(rmsd) between the two normalized chromatograms. Rmsd mini-
mizations were obtained refining both chromatographic and kinetic
parameters by simplex procedure working in automatic fashion. In
all cases, simulations were run until achievement of rmsd conver-
gence in the simplex procedure (rmsd gradient <1 × 10-4). Errors
associated with the so evaluated rate constants were estimated to
be lower than 2%. Calculations of ∆G# barriers related to
enantiomerization equilibria of compounds 3, 4, 5, and 6 were
(20) Kolossva´ry, I.; Guida, W. C. J. Comput. Chem. 1993, 14, 691–698.
(21) Wang, P.; Anderko, A. Fluid Phase Equilib. 2001, 186, 103–122.
J. Org. Chem. Vol. 73, No. 16, 2008 6117

Ciogli et al.
were completed by performing three other steps: (1) restoration of
the O · · ·U coordination bond within the GMU+O- and subsequent
optimization of the obtained structures to give the intermediates I;
(2) rupture within the intermediates of the O · · ·U bond placed on
the same side as the methyl substituent on the second phenoxy
moiety and subsequent optimization of the resulting structures
to those of 4 and 5 shows that it is independent of the extension
of the salophen ligand. This is strongly suggestive of an
enantiomerization mechanism based on ligand hemilability,
heretofore unknown for metal complexes of sal(oph)en ligands.
The dynamic behavior of complex 6, featuring a more rigid
bridge, fulfilled the expectations of a greater configurational
stability. Compound 6, whose half-life at room temperature was
estimated to be a couple of months, turns out to be configura-
tionally stable enough for use as a chiral receptor in enantiose-
lective recognition and catalysis.
CH3
CH3
GMU+O-; and (3) use of the
GMU+O- structures as starting
geometries to perform new molecular dynamic simulations at the
same conditions aforementioned. Always these simulations led to
final geometries corresponding, after restoration of the O· · ·U
coordination bond and simple optimization, to the enantiomeric
forms of the starting GM structures.
Acknowledgment. The work was supported by the Ministero
dell’Universita` e della Ricerca (MUR) COFIN 2006 and PRIN,
contract no. 2005037725.
Summary and Conclusions
The chiral uranyl-salophen complex 3 featuring a dodeca-
methylene chain was expected by design to be configurationally
stable. It was found, however, that 3 undergoes enantiomeriza-
tion at high temperature, as revealed by DHPLC on an
enantioselective column. A dissociation-reassociation mecha-
nism of enantiomerization was immediately ruled out, because
it would imply loss of material and release of the pure ligand
in the HPLC runs. A simple jump rope mechanism was also
excluded on the basis of a comparison with the dynamic
behaviors of the structurally modified analogous derivatives 4
and 5. The close similarity of the enantiomerization rate of 3
Supporting Information Available: HPLC resolution and
temperature-dependent chromatograms of 4 and 5, calculated
structure of the intermediate I for the enantiomerization of 3,
1H NMR spectra of 3 and 5 in the absence and presence of
Pirkle alcohol, 1H NMR spectra of all compounds, and 13C NMR
spectra of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO800610F
6118 J. Org. Chem. Vol. 73, No. 16, 2008